DESIGN, SYNTHESIS AND TESTING OF NEW CHIRAL SULFIDE CATALYSTS FOR COREY-CHAYKOVSKY REACTION

VESAMYLLYMÄKI

Department of Chemistry,University of Oulu

OULU 2001

VESA MYLLYMÄKI

DESIGN, SYNTHESIS AND TESTING OF NEW CHIRAL SULFIDE CATALYSTS FOR COREY-CHAYKOVSKY REACTION

Academic Dissertation to be presented with the assent ofthe Faculty of Science, University of Oulu, for publicdiscussion in Raahensali (Auditorium L10), Linnanmaa, onDecember 5th, 2001, at 12 noon.

OULUN YLIOPISTO, OULU 2001

Copyright © 2001University of Oulu, 2001

Manuscript received 16 November 2001Manuscript accepted 19 November 2001

Communicated byProfessor Liisa KanervaProfessor Tapio Hase

ISBN 951-42-6571-8 (URL: http://herkules.oulu.fi/isbn9514265718/)

ALSO AVAILABLE IN PRINTED FORMATISBN 951-42-6570-XISSN 0355-3191 (URL: http://herkules.oulu.fi/issn03553191/)

OULU UNIVERSITY PRESSOULU 2001

Myllymäki, Vesa, Design, synthesis and testing of new chiral sulfide catalysts forCorey-Chaykovsky reaction Department of Chemistry, University of Oulu, P.O.Box 3000, FIN-90014 University of Oulu,Finland 2001Oulu, Finland(Manuscript received 16 November 2001)

Abstract

The first part of this monograph discusses the asymmetric, ylide based, reagent controlledepoxidations. Both different chiral ylides and epoxidation processes, stoichiometric and catalytic, arereviewed.

In the following part, new chiral sulfide catalysts were discovered as enantioselective catalystsfor the Corey-Chaykovsky reaction (epoxidation of aldehydes via sulfonium ylides). Using a crystalstructure of an oxazolidine derivative as a starting point, a thiazolidine ligand family was designed,synthesized and finally employed as catalysts in the asymmetric epoxidation of benzaldehyde. Theligands were prepared starting from L-valine, L-tert-leucine, D-penicillamine and L-cysteine. Thedifferently tuned thiazolidine ligands were demonstrated to catalyze the formation of trans-stilbeneoxide with varying enantioselectivities. On the basis of these results, a mechanistic rationale for theasymmetric induction was presented. The results heavily demonstrated the importance of ringrigidity as an affecting factor in the enantioselectivity of the tested thiazolidines.

Keywords: Corey-Chaykovsky reaction, catalysis, epoxidation, thiazolidines, ylides, enan-tioselectivity, sulfides

To my Mother

Acknowledgements

The present study was carried out in the Department of Chemistry at the University of Oulu in 1997-2001. Part of the work was also carried out in the Laboratory for Organic Chemistry, Helsinki University of Technology, during the years 2000-2001. I thank Head of Department, Professor Jouni Pursiainen, University of Oulu, as well as Head of Department, Professor Jukka Seppälä, for allowing me to use the facilities of the department.

I am grateful to my supervisor Professor Ari Koskinen for his guidance and advice throughout the research. It was you, who finally catalyzed me to finish off this work.

I am indepted to referees, Professor Tapio Hase and Professor Liisa Kanerva, for their careful reading of my manuscript and Petri Moilanen for revising the language of my thesis.

My sincere thanks go to all members of the Koskinen Group and Lajunen Group. In particular, I want to thank Professor Marja Lajunen for her help, friendship and motherly care. Special thanks go to Mika Lindvall for his friendship and fruitful co-operation in our common research project, to my undergraduate student Tomi Heikkinen, as well as to Teemu Törmänen and Johanna Kemppainen for their contribution to my work. I want to thank Markku Lämsä for his friendship and support during this study. Tatja, Mirka, Timo, Olli, Sulo, Janne and Miia are acknowledged as reliable mates at coffee times. Petri does not drink coffee, but was always ready for long, strategic discussions.

I thank all the staff in the Department of Chemistry for the support they gave me. Especially, I wish to thank Seppo and Martti for building up a Kugelrohr-apparatus for me. Special thanks to Professor Varindel K. Aggarwal for the chemical samples that allowed us to reproduce his experiments and thus to test our experimental setup.

My warmest thanks go to my mother for all her support and care during all these years. Mika & Sirpa, Paula & Jouni, and Katja, thank you for your love and support.

Funding and financial support provided by Neste Oy, TEKES, Neste Research Foundation, Tauno Tönning Foundation, the University of Oulu and Emil Aaltonen Foundation is gratefully acknowledged.

Oulu, November 2001 Vesa Myllymäki

Symbols and abbreviations

acac acetylacetonate 9-BBN 9-borabicyclo[3.3.0]nonane Bn benzyl BOC t-butoxycarbonyl Bz benzoyl CBz benxyloxycarbonyl m-CPBA m-chlorobenzoic acid DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIAD diisopropyl diazodicarboxylate DIBAL-H diisobutylaluminium hydride DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine ee enantiomeric excess MTBE methyl-t-butylether TFA trifluoroacetic acid TMEDA N,N,N�,N�-tetramethylethylenediamine

Contents

Abstract Acknowledgements Symbols and abbreviations Contents Preface 1 Asymmetric ylide based reagent controlled epoxidations .............................................. 15 1.1 General .................................................................................................................. 15

1.2 General description of the reaction ....................................................................... 16 1.3 Chiral sulfonium ylides ........................................................................................ 18 1.3.1 Trost............................................................................................................. 18 1.3.2 Furukawa ..................................................................................................... 19 1.3.3 Durst ............................................................................................................ 21 1.3.3.1 C2 symmetric sulfide ligands ......................................................... 21 1.3.3.2 Camphor acid based non-C2 symmetric sulfide ligands................... 23 1.3.3.3 Asymmetric induction ..................................................................... 25 1.3.4 Solladié-Cavallo .......................................................................................... 27 1.3.4.1 Ligand and asymmetric induction ................................................... 27 1.3.4.2 Exploitation of the results ............................................................... 30 1.3.5 Dai ................................................................................... 33 1.3.5.1 Stoichiometric enantioselective epoxidations.................................. 34 1.3.5.2 Catalytic enantioselective epoxidation ............................................ 37 1.3.6 Metzner ................................................................................... 39 1.3.6.1 C2 symmetric sulfide ligand............................................................. 39 1.3.6.2 Asymmetric induction ..................................................................... 41 1.3.7 Aggarwal ................................................................................... 42 1.3.7.1 Development of a catalytic cycle..................................................... 44 1.3.7.2 Choice of aldehyde ...................................................................... 48 1.3.7.3 Choice and generation of diazo compound...................................... 48 1.3.7.3.1 Preparation of phenyl diazomethane ............................... 49 1.3.7.3.2 Generation of diazo compound in situ .............................. 49

1.3.7.4 Choice of sulfide.............................................................................. 53 1.3.7.4.1 Employment of Durst's sulfides in catalytic cycle ............ 53

1.3.7.4.2 Design, preparation and testing of oxathiane ligand family .................................................................. 54

1.3.7.4.2.1 Origin of diastereoselectivity ......................... 61 1.3.7.4.2.2 Origin of enantioselectivity............................ 63 1.3.7.4.3. [2.2.1] bicyclic sulfide .................................................. 69 1.3.7.5. Choice of metal catalyst................................................................ 71 1.3.7.6. Choice of solvent .......................................................................... 74 1.3.7.7. Application to ketones .................................................................. 75 1.3.7.8. Application of Simmons-Smith epoxidation................................. 75 1.4. Chiral aminosulfonium ylides.............................................................................. 78 1.5. Chiral arsonium ylides ....................................................................................... 81 1.6. Related reagents................................................................................................... 83 1.7. Concluding remarks............................................................................................. 86 2. Design, synthesis and testing of new chiral sulfide ligands for the Corey-Chaykovsky reaction ...................................................................................... 87

2.1. Project background .............................................................................................. 87 2.2. Ligand design....................................................................................................... 88 2.2.1. Structural requirements.............................................................................. 88 2.2.2. The inventive step...................................................................................... 89 2.2.3. Idea refinement .......................................................................................... 90 2.2.4. Target ligands ............................................................................................ 92 2.3. Ligand syntheses.................................................................................................. 94 2.3.1. L-Valine derived ligands............................................................................ 94 2.3.3.1. BOC-protected amino thiol ........................................................... 94 2.3.1.2. Attempts at direct ring closure ...................................................... 95 2.3.1.3. Alternative synthetic route ............................................................ 96 2.3.1.3.1. BOC-deprotection ......................................................... 96 2.3.1.3.2. Thiazolidine ring formation .......................................... 97 2.3.1.3.3. Aminal protection ......................................................... 99 2.3.1.3.3.1. Attempts at benzoylation and acetylation... 99 2.3.1.3.3.2. Attempts at BOC-protection..................... 100 2.3.1.3.3.3. cis-Diastereoselectivity ............................ 102 2.3.2. L-tert-Leucine derived ligands................................................................. 103 2.3.2.1. Synthesis of amino thiol.............................................................. 103 2.3.2.2. Thiazolidine ring formation ........................................................ 104 2.3.2.3. BOC-protection........................................................................... 105 2.3.3. D-Penicillamine derived ligands.............................................................. 106 2.4. Ligand testing .................................................................................................... 108 2.4.1. Model reaction ......................................................................................... 108 2.4.2. Preparation of phenyl diazomethane........................................................ 109 2.4.3. Employment of dimethyl sulfide as a mediator ....................................... 110 2.4.4. Employment of Aggarwal�s chiral sulfide 84a as a ligand ...................... 110

2.4.5. Employment of own ligands .................................................................... 111 2.5. Ligand evaluation .............................................................................................. 114 2.5.1. Evaluation of conformational properties.................................................. 114 2.5.2. Asymmetric induction.............................................................................. 115 2.6. Concluding remarks........................................................................................... 118 3. Experimental......................................................................................................... 119 3.1. Preparation of amino thiols............................................................................ 120 3.1.1. L-valinol (176) ..................................................................................... 120 3.1.2. N-(tert-butoxycarbonyl)-L-valinol (177) ............................................. 120 3.1.3. (S)-1-thio-acetyl-2-amino-N-(tert-butoxycarbonyl)-3-methyl-butane (178)..................................................................................................... 121 3.1.4. (S)-1-thio-2-amino-N-(tert-butoxycarbonyl)-3-methyl-butane (179) .. 121 3.1.5. (S)-1-thio-2-amino-3-methyl-butane hydrochloride salt (180) ............ 122 3.1.6. L-tert-leucinol (192)............................................................................. 122 3.1.7. N-(tert-butoxycarbonyl)-L-leucinol (193) ........................................... 123 3.1.8. (S)-1-thio-acetyl-2-amino-N-(tert-butoxycarbonyl)-3,3-dimethyl- butane (194) ......................................................................................... 123 3.1.9. (S)-1-thio-2-amino-N-(tert-butoxycarbonyl)-3,3-dimethyl-butane (195)..................................................................................................... 124 3.1.10. (S)-1-thio-2-amino-3,3-dimethyl-butane hydrochloride salt (196) .... 124 3.2. Preparation of thiazolidine hydrochloride salts.............................................. 125 3.2.1. (S)-2,2-dimethyl-4-isopropyl-thiazolidine hydrochloride salt (182).... 125 3.2.2. (S)-2-dimethyl-4-isopropyl-thiazolidine hydrochloride salt (183)....... 125 3.2.3. (S)-2-isopropyl-4-isopropyl-thiazolidine hydrochloride salt (184) ...... 126 3.2.4. (S)-2-cyclohexyl-4-isopropyl-thiazolidine hydrochloride salt (185).... 127 3.2.5. (S)-2-cyclopentyl-4-isopropyl-thiazolidine hydrochloride salt (186) .. 127 3.2.6. (S)-4-isopropyl-thaizolidine hydrochloride salt (187).......................... 128 3.2.7. (S)-4-tert-butyl-thiazolidine hydrochloride salt (197).......................... 128 3.2.8 (S)-2-methyl-4-tert-butyl-thiazolidine hydrochloride salt (198) ........... 129 3.2.9 (S)-2,2-dimethyl-4-tert-butyl-thiazolidine hydrochloride salt (199)..... 129 3.3. tert-Butoxycarbonylations ............................................................................. 130 3.3.1 (S)-2,2-dimethyl-3-tert-butoxycarbonyl-4-isopropyl- thiazolidine (163)................................................................................. 130 3.3.2 (S)-3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (160) .................... 130 3.3.3 (2S,4S)-2-methyl-3-tert-butoxycarbonyl-4-isopropyl- thiazolidine (161)................................................................................. 131 3.3.4 (2S,4S)-2-isopropyl-3-tert-butoxycarbonyl-4-isopropyl- thiazolidine (166)................................................................................. 132 3.3.5 (S)-2-cyclohexyl-3-tert-butoxycarbonyl-4-isopropyl- thiazolidine (165)................................................................................. 132 3.3.6 (S)-2-cyclopentyl-3-tert-butoxycarbonyl-4-isopropyl- thiazolidine (164)................................................................................. 133 3.3.7 (S)-3-tert-butoxycarbonyl-4-tert-butyl-thiazolidine (167) .................... 133

3.3.8. (2S,4S)-2-methyl-3-tert-butoxycarbonyl-4-tert-butyl-............................... thiazolidine (168)................................................................................. 134 3.3.9. Attempts at (S)-2,2-methyl-3-tert-butoxycarbonyl-4-tert-butyl- thiazolidine (151)................................................................................ 135 3.3.9.1. Standard method ..................................................................... 135 3.3.9.2. via Naked anion ...................................................................... 135 3.4. D-penicillamine derivatives ........................................................................... 136 3.4.1. (S)-1-aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyl-octan-4-one (201)... 136 3.4.2. (S) -5,5-dimethyl-thiazolidin-4-yl-dimethyl-methanol (202)............... 136 3.5. Attempts at benzoylation ............................................................................... 137 3.5.1. (S)-2,2-dimethyl-3-benzoyl-4-isopropyl-thiazolidine (188) ................ 137 3.6. Attempts at acetylation .................................................................................. 138 3.6.1. (S)-2,2-dimethyl-3-acetyl-4-isopropyl-thiazolidine (190).................... 138 3.7. Preparation of phenyl diazomethane.............................................................. 139 3.7.1. N-benzyl-p-toluenesulfonamide (75) ................................................... 139 3.7.2. N-nitroso-N-benzyl-p-toluenesulfonamide (76)................................... 139 3.7.3. Phenyl diazomethane (68).................................................................... 140 3.8. General procedure for epoxidation ............................................................... 140 References ................................................................................................................ 141

1 Asymmetric ylide based reagent controlled epoxidations

1.1 General Nonracemic epoxides are significant intermediates in the synthesis of, for instance, pharmaceuticals and agrochemicals. The different preparation methods can be divided into oxidative and nonoxidative approaches. In the former approach a prochiral C=C bond is oxidized (route a), in the latter enantioselective cycloaddition of a prochiral C=O bond, such as via an ylide, carbene or Darzens reaction (route b), is taking place (Scheme 1).

Asymmetric epoxidation of olefins was first reported by Sharpless et al. in 1980 (1). In this method allylic alcohols were epoxidized stoichiometrically and an improved, catalytical (molecular sieves) version was reported later (2). Catalytic asymmetric epoxidation of unfunctionalized olefins using salen-manganese complexes have been reported independently by Jacobsen et al. (3), Katsuki et al. (4) and Mukaiyama et al. (5). Also optically active dioxiranes (6) and hydroperoxide (7) have been used in this manner. Catalytic asymmetric epoxidation of α,β-unsaturated ketones has been studied intensively after the initial report from Juliá et al. (8). For instance, methodologies such as asymmetric ligand-metal catalysis (9), asymmetric phase transfer catalysis (10), polyamino acid catalysis (11), as well as the use of lanthanoid-BINOL complexes (12) have been introduced.

The oxidative method is not omnipotent, though. Due to structural requirements of substrates the Sharpless asymmetric epoxidation can only be employed with allylic alcohols, the Jacobsen method, in turn, works well only with cis double bonds, and the dioxane method is helpful with some trans olefins. Carbenes have predominately found their synthetic applications in the preparation of cyclopropanes. The Darzens reaction (13), in turn, is a helpful tool when preparing asymmetric α,β-epoxyesters (also called glycidic esters).

16

O

R1 R4

R3R2a)

b)

Chiral epoxides

R1 R3

R4R2[O]

R1

R2O

R4

R3

LG

R3

R4:

LnMR3

R4

Darzens reagents

carbenes

ylides

(a)

(b)

Scheme 1. Preparation of nonracemic epoxides.

The third nonoxidative alternative, the ylide route has received a lot of attention and

offers a complementary method to the processes mentioned above (14). Since the resulting epoxides must be chiral, the asymmetric induction has its origin either in an ylide precursor or in a nonracemic carbonyl compound. In the former case we speak about reagent controlled, in the latter substrate controlled asymmetric epoxidations. The following will concentrate on reagent controlled ylide based applications.

1.2 General description of the reaction

Fourty years have passed since sulfur ylides were first reported to react with aldehydes and ketones to furnish oxiranes (15). The reaction was published first by Johnson et al. (15a) but is for some reason better known as Corey-Chaykovsky reaction (15b,d). An ylide can be viewed as a special carbanion in which the negative charge on carbon is stabilized by an adjacent positively charged hetreroatom, Scheme 2. The ylides are electrically neutral, yet they possess a significant degree of charge separation. The

17

reaction between this and an electrophilic carbon atom of a C=X (X = O, C, N) bond (carbonyl compounds, Michael acceptors, imines) gives a betaine or an oxetane intermediate.

LnM-CHR

LnM=CHR

R1

R2X

X = O, C, N

R1

R2

RCH MLn

X

R1

R2

RCH MLn

X

or

Ylides

X

R2R1

R H

R2R1

HR

-LnM(X = O, C, N)

Cyclization

-LnM=X(X = O)

Olefination

M = S, As, Te etc

M = P, As etc

Scheme 2. Reaction between carbonyl compounds and an ylide.

Elimination of the heteroatom-containing group from this intermediate can, in turn,

occur in either one of two different possibilities resulting in either the desired cyclization or olefination. In epoxidations the most important ylides are sulfonium ylides and, to some extent aminosulfoxonium, arsonium and other related ylides. In reagent controlled epoxidation the asymmetric induction has its origin in a chiral ligand. The reaction of an achiral aldehyde or ketone with a chiral ylide gives optically active epoxides and the ylide precursor (ligand) can usually be recovered (Scheme 3).

R1

R2O L*nM-CHR

O RR2

R1 * *L*nM

chiral ylide recovery

1) RCH2X; 2) base

possibility of catalytic epoxidation

Scheme 3.

18

In the traditional version of the reaction a stoichiometric amount of the ylide precursor is usually required. The process of epoxidation involves two steps: alkylation of the ligand and isolation of the resulting salt, followed by treatment with a base in the presence of a carbonyl compound. Also catalytic cycles, where only a catalytic amount of ligands are required, have been developed.

1.3 Chiral sulfonium ylides

1.3.1 Trost

Chiral sulfonium ylides are by far the most common and useful ylides in the preparation of nonracemic epoxides. Since sulfonium salts and their corresponding ylides are tetrahedral, they are capable of inducting asymmetry (16,17). The racemization of sulfonium salts by inversion is possible but the barrier is relatively high and elevated temperatures are required (17). Sulfonium ylides, in turn, racemize more easily but decompose at the same temperatures that are required for the racemization (17). Trost showed that ylide 2 was configurationally stable under the reaction conditions required for epoxidation as deprotonation of 1 followed by treatment with HBF4 gave back 1 with identical optical rotation (Scheme 4) (18).

S C2H5

CH3

BF4-

S C2H5

CH2n-BuLi PhCHOO

Ph

H

ee: 0%

1 2 3

HBF4

Scheme 4. Quenching the ylide with benzaldehyde under the same reaction conditions gave

styrene oxide 3 as a racemate (18). According to our knowledge, this was the first attempt to use chiral sulfonium ylides for asymmetric epoxidation and its failure probably significantly delayed the progress in this area for the subsequent 16 years. It has since been shown that the transfer of methylene from sulfur ylides is a very poor reaction, furnishing epoxides with very low enantioselectivity, whereas the benzylidene transfer is much more selective (19).

19

1.3.2 Furukawa

The first successful example of using chiral sulfonium ylides for asymmetric epoxidation was reported by Furukawa et al. (20). They reported a catalytic process where 0.5 equivalent of a sulfide is converted initially to a sulfonium salt and then subsequently to the corresponding ylide in situ under phase-transfer conditions. Thus, the sulfide works as a mediator that transfers an alkyl group to the aldehyde (Scheme 5).

RS

R

O R2

R1

R2CH2X

RS

R

R2

HO

RS

R

R2

R1CHO

liquid

solid

Scheme 5. They tried several optically active sulfides and found that for the formation of

optically active oxiranes sulfides derived from (+)-10-camphorsulfonic acid 4 worked best as both mediators and chiral auxiliaries. Optically active sulfides 6 and 7 were prepared in three steps as shown in Scheme 6 (20).

20

4 5a, exo b, endo

6a, R = Me, R' = H b, R = Et, R' = H c, R = Me, R' = Me

7

1. SOCl22. LiAlH4

RX

OSO3H SH SR SMe

OR'

OMe

OH

Scheme 6. Preparation of sulfides 6 and 7 starting from (+)-10-camphorsulfonic acid 4.

Generally, the synthesis of optically active epoxides was carried out using an

equimolar amount of aryl aldehyde and benzyl bromide in the presence of 0.5 equivalent of the sulfides 6 and 7 in THF or in CH3CN under liquid-solid two-phase conditions. Powdered KOH was used as a base. The reaction is portrayed in Scheme 7.

RCHO CH2BrO

R H

HsulfideKOH, CH3CN

rt, 36 h

9 a,b8a, R = C6H5 b, R = 4-ClC6H4

Scheme 7.

Sulfide-bearing camphor moiety as a ligand seems to give optically active epoxides in

one step without isolating the corresponding sulfonium salts. The highest enantiomeric excess was obtained when the reaction was carried out in acetonitrile at room temperature by using a combination of the sulfide 6a, having an exo-OH group, and benzaldehyde and benzyl bromide. The optical yield achieved for trans-stilbene oxide 9a was 47%, Table 1 (20). A large solvent effect was observed in the chemical yield of the oxirane. In comparison with THF, CH3CN gives better results because it increases the solubility of the solid KOH in solution and, furthermore, the ylides once generated exhibit high nucleophilic activity toward the aldehyde by the formation of the naked carbanion in the solvent.

The sign of optical rotation was found to be depending on the sulfides 6 employed in the reaction, particularly on the configuration of the carbon atom bearing the hydroxyl or methoxy group in the ligand. The level of asymmetric induction varied between 7-47% in the terms of enantiomeric excess (ee). No mechanistic rationale for the low asymmetric induction was given but this might be explained by the formation of a diastereomeric mixture of chiral sulfonium salts, which react with different and possibly opposite selectivity.

21

Table 1. Preparation of optically active oxiranes(20).

Sulfide RCHO solvent time, h yield,d % ee configuration

6a 8a CH3CN 36 100a 47 (+)-R,R

6c 8a THF 48 16a 14 (_)-S,S

6a 8b THF 36 15b 34 (+)-R,R

6a 8b CH3CN 36 100b 43 (+)-R,R

6ac 8b CH3CN 36 230b 31 (+)-R,R

6bc 8b CH3CN 36 90b 31 (+)-R,R

6c 8b THF 48 30 28 (_)-S,S

7 8b THF 48 17 7 (+)-R,R

a Product is 9a. b Product is 9b. c Mole ratio of RCHO/PHCH2Br/sulfide = 10:10:1. d The yields were calculated on the basis of the sulfide used in the reactions.

1.3.3 Durst

1.3.3.1 C2 symmetric sulfide ligands The presence of a C2 symmetry axis within the chiral auxiliary can serve a very important function of dramatically reducing the number of possible competing, diastereomeric transition states (21). Possibly this in mind, Durst et al. decided to overcome the problems with low selectivities Furukawa and co-workers had encountered by introducing a new family of C2-symmetric sulfide ligands to be used in asymmetric epoxidations (19,22). The employed sulfonium salts 10, 11 and 12 are presented in Figure 1.

SBnOH2C CH2OBn

CH2PhSBnOH2C CH2OBn

CH2PhS

CH2PhClO4

- ClO4- ClO4

-

OBn TBDMSO OTBDMSBnO

10 11 12 Figure 1.

22

The sulfonium salt formation was carried out by treating the precursor thiol 13 with benzylbromide, followed by addition of AgClO4, and the epoxidations themselves were conducted under phase transfer conditions, Scheme 8 (22).

SBnOH2C CH2OBn SBnOH2C CH2OBn

CH2PhClO4

- 1013

O

H

H

9aRecovered

SBnOH2C CH2OBn

13

i

ii

Scheme 8. Reagents: i) PhCH2Br, AgClO4, Et2O; ii) 50% NaOH (aq), BnEt3NCl, CH2Cl2, 0 °C.

In order to have the potential for the synthesis of optically active epoxides, the chiral sulfides employed in the reaction must be recyclable without loss of optical activity. Durst with co-workers proved this when they were able to recover thiolane 13 in 80% yield with essentially no loss of optical purity.

Despite the fact that the substituents at C-3 and C-4 in the ylide form of 13 have opposite senses of chirality compared to C-2 and C-5 in the ylide form of sulfonium salt 11, they afforded the same absolute configuration for the product trans-stilbene oxide 9a. The results of the experiments are collected in Table 2 where it can be seen that the highest enantiomeric excesses were obtained with ylides derived from thiolanes having substituents close to the ylide reaction center, i.e., at C-2 and C-5. No mechanistic rationale was given, however. The highest enantiomeric excess, 83%, was obtained when using an ylide formed from 11. The chemical yields obtained were fairly good varying from 27 to 94%.

23

Table 2. Preparation of stilbene oxides via optically active sulfur ylides derived from sulfonium salts 10, 11 and 12 (22).

Sulfonium salt RCHO Reaction condition

yield, % ee

10 PhCHO A 53 60

11 PhCHO A 27 64

11 4-NO2C6H4CHO A 41 83

12 PhCHO B 30 15

12 4-MeC6H4CHO B 49 11

12 4-ClC6H4CHO B 94 7

12 4-NO2C6H4CHO B 72 13

Method A: NaOH 50% / cat. BnEt3NHCl / CH2Cl2, 0 oC. Method B: NaCH2S(O)CH3 / THF , -10 oC.

1.3.3.2 Camphoric acid based non-C2 symmetric sulfide ligands

Higher asymmetric induction was reported by the same group (19,23) using non-C2 symmetric (1R,3S)-(+)-camphoric acid-derived sulfonium ylides 14-19 (Figure 2).

S S SCH2

S S S

Cl14 15 16

17 18 19 Figure 2.

24

The reactions were conducted under the phase transfer conditions (PTC), initially at 0 oC, then at room temperature for three hours. Both trans- and cis-stilbene oxides 9a and 20 were formed and in some cases also β-elimination took place. The asymmetric epoxidation employing ylide 14 is presented in Scheme 9. As in previous work with C-2 symmetric ligands, stoichiometric amounts of sulfides were employed in the reactions (23).

S

14

PhCHONaOH, 50%, CH2Cl2

BTEAC

O

H

H OH H

S

21

9a 20

Scheme 9.

The alkylation of the sulfides had resulted in the formation of single diastereomeric sulfonium salts. From a single diastereomeric sulfonium salt only one ylide isomer having a defined conformation at sulfur would be formed and, therefore, high enantioselectivities could be expected. Indeed, benzylidene transfer gave enantioselectivities up to 96% but only low enantioselectivity for methylene transfer (16 gave up to 4% ee) with less than 50% chemical yield obtained.

Also asymmetric epoxidations of one ketone (cyclohexanone) as well as two aliphatic aldehydes were conducted. When employing cyclohexanone as the carbonyl component the corresponding epoxide was obtained with ≥ 96% enantioselectivity. The transfer of the p-chlorobenzylidene group from 15 to formaldehyde gave the (S)-enantiomer of the corresponding epoxide, and the benzylidene transfer from 14 to cyclohexanecarboxaldehyde, in turn, afforded a mixture of trans- and cis-epoxides in only fair yields. The optical purities of stilbene oxides were determined using the chiral shift reagent [Eu(hfc)] and configurations were simply based on [α]D measurements. All results are presented in Table 3.

25

Table 3. Preparation of stilbene oxides via optically active sulfur ylides 14-19 (23).

Sulfonium salt

Aldehyde or ketone trans-Epoxide, yield / %ee

cis-Epoxide, yield / %ee

β-elimination

14 PhCHO 38 / ≥ 96 (S,S) 8 / meso 22

14 4-MeC6H4CHO 32 / ≥ 96 (S,S) - 15

14 C6H11CHO 9 / 84 (-) 14 / 86 (+) 32

14 cyclohexanone ~5 / ≥ 96 (S) 35

15 CH2O 49 / 24 (S) 10

16 4-ClC6H4CHO 46 / ~4 (S) 5

17 PhCHO 45 / 34 (R,R) 12 / meso -

18 PhCHO 42 / 73 (R,R) 20 / meso -

18 4-ClC6H4CHO 52 / 63 (R,R) 25 / 66 (-) -

19 PhCHO 39 / 15 (R,R) 16 / meso -

1.3.3.3 Asymmetric induction

Durst et al. rationalized the asymmetric induction in the following manner (23). The ylide 14 should adopt preferentially the conformation A rather than B since the aryl ring on ylide 14 has severe steric interactions with the endo hydrogens on the two-carbon bridge (Figure 3). Electrophilic attack by the carbonyl group on the ylide A will occur preferentially from the back (i.e. the si-face) of the ylide. This inducts the chirality of that center as (R) in the intermediate betaine and as (S) in the final product (24). The chirality of the second center is dependent on the approach of the carbonyl compound to the ylide. The concept that facial selectivity, with respect to the ylide rather than the carbonyl carbon, controls the stereochemical outcome predicted that all transfers from A will result in products having preferentially the (S) chirality at benzylic carbon derived from ylide, was verified by these studies.

26

S

H

OR

H

S H

H

H H

H

S

H

R

S H

H S

H

A

E

C

D

B

Figure 3.

In turn, the excess of the (R,R)-isomer of the trans-stilbene oxide obtained from ylides

17 and 18 (Figure 2) is due to the blocking of the si-face of the ylide carbon by either the benzyl or isopropyl group (structure C, Scheme 12). The lower chiral induction observed for the benzylidene transfer was proposed to be caused by the greater conformational mobility of the α-benzyl group in C vs A because the former lacks the additional β-methyl group (23).

The approach of the cyclohexanecarboxaldehyde to A was found to be almost random with respect to the facial selectivity of the aldehyde as was evidenced by an almost 1:1 trans/cis product mixture. Since the carbon of the methylene ylide 16 (D) is not prochiral, resulted approach of benzaldehyde to D in a racemic product. In contrast, the S-p-chlorobenzyl analog of A (ylide 15) reacted with formaldehyde to produce p-chlorostyrene oxide with 24% ee. Again, the sense of chirality of the product was due to the facial selectivity in the attack on the ylide and not the carbonyl carbon.

The formation of (R,R)-stilbene oxide from 19 suggested that, in this case, the ylide would preferentially adopt structure E. A small preference for attack from the rear, in this case the re-face, should generate preferentially the (R,R)-product (23).

27

1.3.4 Solladié-Cavallo

1.3.4.1 Ligand and asymmetric induction

Durst also claimed that in order to ensure high sulfur nucleophility, the sulfide should be devoid of other electronegative heteroatoms. Solladié-Cavallo et al. have diligently reported very successful asymmetric epoxidations with chiral oxathiane derived sulfonium ylides (25, 26, 27, 28, 29, 30), however.

During the work on the asymmetric synthesis of adregenic drugs, Solladié-Cavallo et al. were confronted with the difficulty of obtaining optically pure epoxides and decided to investigate the use of chiral, optically pure sulfur ylides to convert aldehydes into chiral epoxides (25). The chiral oxathiane 23 (Eliel�s reagent) was obtained from (+)-R pulegone 22 by a literature method (31), Scheme 10.

O

O S

2322

Scheme 10. The S-alkylation of sulfide 23 with benzylbromide in the presence of AgClO4 afforded

sulfonium salt 24 (25). NMR-analysis of 24 showed only one diastereomer and it could thus be expected that, in basic medium, 24 would yield only one ylide, a prerequisite for high asymmetric selectivity.

The reaction of sulfonium salt 24 with benzaldehyde and substituted benzaldehydes under phase transfer condititions (PTC) afforded only trans-epoxides in satisfying (60-82%) yields and enantiomeric purities up to 70-100%. Oxathiane 23 was employed in stoichiometric amounts and could be recovered and reused. The results of the epoxidations are presented in Table 4 (25).

28

Table 4. Preparation of arylphenylepoxides from 24 and under PTC (25).

RCHO Yield, % ee% Config. Recovered sulfide, %

PhCHO 80 72 RR 82

4-NO2C6H4CHO 60 0 80

4-MeC6H4CHO 75 26-32 RR 78

4-ClC6H4CHO 82 62-100 RR 80

No cis-epoxides were observed and (+) rotations obtained for trans-epoxides clearly

indicated that the configuration of the major epoxides was 2R,3R. The asymmetric induction was interpreted in terms of conformation A in the ylide form of 24 together with a sterically directed approach of the aldehyde as shown in Scheme 11.

O SH

OAr

H

24O

Ph

Ar(+) RR, majorConformation A

O S

H

OAr

H

24(+) SS, minorConformation B

124

Scheme 11.

29

The proposed induction was based on the fact that, from a single sulfonium salt�s isomer, only one ylide isomer having the same configuration at sulfur is formed at low temperature and because in the sulfonium salts derived from six membered cyclic sulfides the third S-substituent was found equatorial (32,33), the CHPh group was, at that time, envisaged to be equatorial (conformation A). On the other hand, according to literature results (16a,16c,23,34), a 120° value was chosen for the torsional angle C4-S-C12H; therefore, as a consequence of the R absolute configuration obtained at C12, the rather hindered position of the phenyl ring had to be considered (A), instead of the less hindered position of the phenyl ring existing in conformation B. Confronted with this unecpectedly required conformation, Solladié-Cavallo decided to determine the structure of the starting sulfonium salt.

They were able to crystallize the salt, and X-ray analysis finally revealed that the benzyl group is axial in solid state. Therefore, conformation A� (Scheme 12) should be used in their model of approach instead of conformation A, Scheme 14 (26).

OAr

H

O

Ph

Ar(+) RR

Conformation A'

O S O S

ClO4-

O S

H23

Scheme 12.

This was the first example of a six-membered sulfonium salt having the third axial group at sulfur. The explanation was proposed to be the 1,3-anomeric effect: the equatorial lone pair may overlap with σ* of the axial C-O bond and so be less nucleophilic than the axial lone pair. There is also an alternative steric argument, with the consideration of gauche interaction with a neigbouring methyl group, that may also operate (14).

30

1.3.4.2 Exploitation of the results

The developed asymmetric ylide epoxidation method was successfully applied for the preparation of the two (R)-β-adrenergic compounds 29 and 30, Scheme 13 (27).

Ar

O S

X- H

OAr

H

ArN

OH Hi ii

Cl

Cl

25 Ar =

26 Ar =

R-(+)-27, 73%, 96% ee

R-(+)-28, 55%, 84% ee

29: (R)-(-)-DCI; 77%

30: (R)-(-)-pronethalol; 50%

Scheme 13. Reagents: i) NaH, -40 °C; (CH2O)n; ii) LiAl(NHPr-i)4, i-PrNH2

In the first step, (R)-monoaryl epoxides were prepared in high enantiomeric purity under monophasic aprotic conditions employing NaH as a base. The corresponding amino alcohols 29 and 30 were then obtained in one step, opening the epoxides regiospecifically by using a secondary amine developed by themselves (35). Encouraged by the results they decided to extend this method to trans-(R,R)diaryl-epoxides to be used as intermediates for the synthesis of diaryl chiral ligands (28).

O

Ph

Ar

O S

O S TfO-

23

PhCH2OHTf2O/Py

NaH/CH2Cl2R

CHO

32a-e

31a-e

Scheme 14.

31

The reaction of the sulfonium salt derived from Eliel�s oxathiane 23 with various para- and ortho substituted benzaldehydes 31a-e under aprotic conditions (Scheme 14) afforded the desired epoxides 32a-e in 76% to 84% isolated yields, Table 5. Table 5. Preparation of pure trans-(R,R)-diaryl-epoxides using NaH as a base.

Comp. RCHO Yield, %

ee%a Config. Recovered sulfide, %

32a PhCHO 80 99.0 RR 87

32b 4-MeC6H4CHO 56 99.6 RR 82

32c 4-ClC6H4CHO 76 99.0 RR 78

32d 4- NO2C6H4CHO 77 97.9 RR 90

32e 2-FC6H4CHO 84 99.9 RR 92

a Enantiomeric excess determined by chiral HPLC using a Chiralcel OD column. In their latest studies (29,30) phosphazene base EtP2 (EtN=P(NMe2)2-N=P(NMe2)3),

instead of NaH, has been employed to generate the ylide. The conversions into desired epoxides are very high and the reaction times were significantly shortened (30 minutes instead of 1 to 2 days). The 2- and 3-pyridyl epoxides 33 and 34, as well as the only known 2-furyl epoxide 35, were synthesized for the first time in enantiomerically pure form, Scheme 15 (30).

O

Ph

R

O S

O S TfO-

23

PhCH2OHTf2O/Py

EtP2

RCHO N33, R =

N34, R =

O

O

35, R =

36, R =

9a, R =

Scheme 15.

32

The results are gathered in Table 6.

Table 6. Asymmetric synthesis of epoxides 33-9a using EtP2 as a base (30).

Epoxide Temp (°C) Yield, % trans/cis ee%a-trans (config)

ee%-cis (config)

33 -78 94 88/12 99.2 (1R,2R) 99.9 (1S,2R)

34 -78 81 100/0 96.8 (1R,2R)

35 -78 11 100/0 99.2 (1R,2R)

36 -78 82 100/0 99.8 (1R,2R)

9a -40 69 100/0 97.0 (1R,2R)

a Enantiomeric excess determined by chiral HPLC using a Chiralcel OD column. In agreement with previous studies with NaH as a base (28) only trans-epoxides were

formed. Only in the case of 2-pyridyl epoxide 33, 12% of the cis-isomer was obtained. The R,R absolute configurations are reasonably explained by the model already proposed in the previous cases. The very high ee values observed (97-99.8%) were proposed to be caused by the participation of the salt present (Et-P2H+TfO-) in a coordinative and/or electrostatic interaction in the transition state leading to the cyclization (Figure 4).

O S

H

TfO- EtP2H+

O R

H

Figure 4. The participation of the salt present in this manner was proposed for the first time in

the mechanistic rationale for the preparation of trans-2-acrylcyclopropane carboxylates by the use of a phosphazene base (36).

33

Also trans-disubstituted aryl-vinyl epoxides were prepared in the same manner, with high enantioselectivities and yields (30). The reactions yielded both epoxides as well as cyclopropanes. Both CH2Cl2 and THF were used as a solvent but when a p-methoxy group was present in the arylsulfonium salt, the epoxide was the sole product, whatever the solvent. It was proposed that the methoxy group would lead to a less stabilized and more reactive ylide, favoring the formation of epoxides. It was also found that higher percentages of cis-epoxides were formed in CH2Cl2 (3-23%) than in THF (3%).

1.3.5 Dai

Dai with co-workers have developed an efficient stoichiometric and even a catalytic ylide based epoxidation using D-(+)-camphor 37 derived sulfide ligands (37). The syntheses of the sulfides containing exo- (Scheme 16) and endo- (Scheme 17) alkylthio groups outside the camphor ring system were performed by a method published earlier by Haynes et al. (38).

O O

SCH2Ph

O

SCH3

SCH2Ph SCH3

SCH2Ph SCH3

OH OH

OMe OMe

37 38 39

40 41

42 43

i-iii

iv-v

vi-vii

Scheme 16. Reagents: i) LDA (1,0 eq), THF, -78 °C; ii) PhSO2SCH2R, THF, -78 °C; iii) NaHSO4; iv) DIBALH, CH2Cl2, rt, 30 min; v) NH4Cl (aq); vi) NaH, THF, rt, 15 min; vii) MeI, 30 min.

34

O O O

37 44 45

46 47

48 49

i-iii

iv-v

SCH2Ph SCH3

SCH2Ph SCH2PhOH OH

SCH2PhOH

SCH3OH

Scheme 17. Reagents: i) LDA (2,0 eq), THF, -78 °C; ii) PhSO2SCH2R, THF, -78 °C; iii) NaHSO4; iv) DIBALH, CH2Cl2, rt, 30 min; v) NH4Cl (aq).

1.3.5.1 Stoichiometric enantioselective epoxidations

Stoichiometric enantioselective epoxidations were performed employing sulfides 40, 42, 46 and 48, i.e. those with benzylthio-moiety. The sulfides were found to react smoothly with methyl iodide furnishing the corresponding sulfonium salts without the aid of silver salts. Various aldehydes were tested and reactions were conducted in CH3CN at room temperature, Scheme 18.

For aromatic aldehydes, the reaction proceeded perfectly giving selectively the trans products, mostly with excellent yields and moderate to good ee values (19-77%). Any efforts to extend this reaction to aliphatic and heteroaromatic aldehydes and ketones were unsuccessful due to the side reactions of the aliphatic and heteroaromatic aldehydes, and the low reactivity of the ketones. The results are gathered in Table 7 (37).

35

SCH2PhOR''

40, 42, 46, 48

RCHO MeI

1,0 eq. 1,2 eq. 2,0 eq.

KOH(s) 2,0 eq.

CH3CN, rt, 30 h.

O PhH

R' H

Scheme 18.

Table 7. Stoichiometric preparation of trans-2,3-diaryloxiranes using sulfides 40, 42, 46 and 48 as ylide precursors (37).

Sulfide R� Yield, % ee%a configuration

40 Ph 87 74 (2R,3R)

40 4-ClC6H4 96 77 (2R,3R)

40 4-MeC6H4 89 72 (2R,3R)

42 4-ClC6H4 48 19 (2R,3R)

46 4-ClC6H4 94 35 (2S,3S)

46 Ph 92 35 (2S,3S)

46 4-MeC6H4 90 32 (2S,3S)

48 4-ClC6H4 98 32 (2S,3S)

48 Ph 89 37 (2S,3S)

48 4-MeC6H4 90 33 (2S,3S)

a Enantiomeric excess calculated on the specific rotations reported for optically pure compounds (39). The opposite asymmetric induction was achieved when employing 40 and 42

(benzylthio group at exo position) versus 46 and 48 (benzylthio group at endo position) as chiral auxiliaries.

It was also noted that the free hydroxyl group at C2 plays an important role; when OH was converted to a methoxyl group, both the yield and the ee value of the resulting epoxide were greatly lowered. This led to postulate that there might be a nonbonded

36

interaction between the OH and the carbonyl group of aldehydes before attack by an ylide, Scheme 19.

SCH2PhOH

40, 46, 48

MeI

O PhH

Ph H

SCH2PhOH

Me I-

KOHPhCHO

SO

HCH3

HO

H SOH

HCH3

HO-

41

O HPh

H Ph47

SO H

H

O

H

Me SMeOH

R R

HH

O-

S S

O HPh

H Ph49

SMe SMe

HS S

OH

H

O

H

O-

H

50

51

52

53

Scheme 19. This interaction forced the aldehydes to approach the reactive site of the ylide,

preferentially from the si-face, and the aldehyde carbonyl to be attacked on the re-face.

37

1.3.5.2 Catalytic enantioselective epoxidation

Generally, chiral substances, other than natural products, are difficult to obtain. Therefore, an attempt to make a stoichiometric reaction catalytic is believed to be of practical significance (40).

Sulfonium salt 50 (Scheme 23) could be prepared either by methylation of 40 or by benzylation of 41. In addition, the stoichiometric ylide epoxidation was realized through the transfer of the benzylidene group of ylide 51 instead of the methylene group. Dai reasoned that it should be possible to make this reaction catalytic when sulfides 41,43,47 and 49 were used to mediate the reaction between benzyl bromide and aldehydes. In these reactions, the sulfides were converted initially to sulfonium salts by the corresponding ylides in situ under phase-transfer conditions. The ylide was subsequently reacted with aldehydes to furnish epoxides and release the sulfide and permit it to enter a new cycle. The process employing sulfide 41 as a catalyst is illustrated in Scheme 20 (37).

O Ph

R

HO

liquid

solid

KOH (s)

RCHO

H

H

PhCH2Br

SCHPhOH

Me

SMeOH

SCH2PhBrOH

Me

41

5451

Scheme 20. The catalytic epoxidations proceeded smoothly in the presence of 0.2 equivalents of

the above mentioned chiral sulfides. The results are gathered in Table 8.

38

Table 8. Catalytic preparation of trans-2,3-diaryloxiranes using sulfides 41, 43, 47 and 49 as ylide precursors (37).

Sulfide R Yield, % ee%a configuration

41 Ph 97 42 (2R,3R)

41 4-ClC6H4 93 60 (2R,3R)

41 4-MeC6H4 89 36 (2R,3R)

43 4-ClC6H4 97 4,7 (2S,3S)

43 Ph 90 4,1 (2S,3S)

43 4-MeC6H4 94 1,4 (2S,3S)

47 4-MeC6H4 94 34 (2S,3S)

47 4-ClC6H4 96 40 (2S,3S)

47 Ph 96 29 (2S,3S)

49 4-ClC6H4 94 15 (2S,3S)

49 Ph 92 20 (2S,3S)

49 4-MeC6H4 90 19 (2S,3S)

a Enantiomeric excess calculated on the specific rotations reported for optically pure compounds (39). As expected, the opposite asymmetric induction was again observed in the catalytic

reaction when 41, which contains an exo-methylthio group, and 47 or 49, which contain an endo-methyl thio group, were used.

The opposite asymmetric induction in the catalytic epoxidation was also observed in the cases using 41, which possesses a free OH group, and 43, which contains a methoxy group instead, although the asymmetric induction of the latter was rather low. The same phenomenon was reported earlier by Furukawa et al. (20).

Also the effects of solvents and bases were investigated. In strong polar solvents, such as DMSO and DMF, the ee values of the products were decreased. Under other conditions, the ee values remained nearly the same. In the commonly used THF, the yields were low due to the low solubility of the base (KOH), leading to difficulties in producing ylides. Acetonitrile was reported to be the best solvent for this reaction, and strong bases like KOH (s), NaOH (s), and aqueous NaOH are useful. Solid KOH was mentioned to be the most suitable base when convenience was taken into account.

Increase in the amount of the sulfides did not influence the ee values, but did shorten the reaction time (15 h with 20 mol% of sulfides) and improved the yields. From the

39

practical standpoint they came to the conclusion that 20 mol% of the sulfides are suitable for the catalytic reaction (37).

1.3.6 Metzner

1.3.6.1 C2 symmetric sulfide ligand

Metzner et al. (41,42,43) have reported the preparation and exploitation of a cyclic, C2 symmetric sulfide, (2R,5R)-dimethylthiolane 56, Scheme 21.

OH

OH

i, ii

SMe Me

55 56

Scheme 21. Reagents: i) MsCl, NEt3, CH2Cl2, -20 °C; ii) Na2S, EtOH, rt. Thiolane 56 was prepared easily in two steps starting from the commercially available

(2S,5S)-hexanediol 55 (41,42). This diol can also be obtained by the enzymatic reduction of the cheap 2,5-hexanedione with baker�s yeast (44). Another yeast, Pichia farinose leads to an opposite enantiomer (45) and, thereby, to opposite asymmetric induction in the epoxidation process. The activation of the hydroxyl groups into mesylates and subsequent cyclization with sodium sulfide, by two nucleophilic substitutions with inversion, furnished the desired C2 symmetric sulfide 56 in 95% yield.

The epoxidation procedure was the same as reported earlier by Furukawa (20) and Dai (37), i.e. a mineral base is involved and all reagents are mixed together in one pot at room temperature, Scheme 22. The reaction of benzaldehyde (1 eq) with benzyl bromide (2eq) and thiolane 56 was carried out with KOH or NaOH (2 eq) in various solvents. Experiments in nonpolar or moderately polar solvents, under heterogenous (toluene/aqueous NaOH) or homogenous (THF/ aqueous NaOH) conditions, furnished poor yields or selectivities. In more polar solvents (DMF, DMSO, CH3CN, alcohols) with powdered KOH they observed various predominant side reactions. These problems were largely avoided by simply adding 10% of water into the solvent and, thus, stilbene oxide was obtained in excellent yields and enantioselectivities, in one or two days at ambient temperature (41), Table 9.

40

SMe Me

56

PhCH2Br PhCHOKOH

rt.

O

Ph

Ph

9a (S,S)

Scheme 22. Table 9. Asymmetric synthesis of stilbene oxide 9a in various solvents with KOH (41).

Entry solvent Time (days) yield de (trans) % ee (S,S) %a

1 9:1 CH3CN:H2O 1 92 88 84

2 9:1 t-BuOH:H2O 2 92 86 88

3 9:1 i-PrOH:H2O 8 59 86 90

4 9:1 EtOH:H2O 3 15 84 94

5 H2O 4 90 74 86

a Enantiomeric excess determined by chiral HPLC using a Chiralcel OD or Chiralsep Chirose-Bond column. It is noticeable that the reaction could even be carried out in pure H2O (Table 9, entry

5). In all cases, the trans isomer of stilbene oxide (9a) was formed preferentially, i.e. not diastereoselectivically, and the major isomer was identified as the trans-(2S,3S)-diphenyloxirane. The best enantiomeric excess, 94%, was achieved with the 9:1 EtOH:H2O solvent system.

The reaction times are rather long varying between one and eight days. The feasibility of the catalytic process was tested by employing only 0.1 equivalents of thiolane 56 in the presence of benzyl bromide (2 eq) and benzaldehyde (1 eq) in 9:1 t-BuOH:H2O with NaOH. Both yield and selectivity remained high but it took a whole month to complete the reaction.

41

1.3.6.2 Asymmetric induction

The high asymmetric induction was rationalized as shown in Scheme 23 (41).

SMe Me

Br

B S

HMe

Me

S

HMe

Me

S

HMe

Me

H

O

O

9a, (S,S)

SMe Me

56

57 58a 58b

Scheme 23.

The C2 symmetry of 56 dictated the formation of the single sulfonium salt 57 by reaction with benzyl bromide. Deprotonation afforded the ylide 58 with a planar carbon and a tetrahedral sulfur, the sulfur doublet lying in the plane of the ylide carbon substituents to avoid repulsive interaction with the carbanion doublet. Out of two possible conformations, 58a and 58b, the former is favored as the phenyl group is away from the thiolane ring. Attack from the si face of the ylide is suggested to be preferred because the re face is hindered by the methyl group cis to the benzylidene group. A 109° approach of the aldehyde, leading to the trans epoxide 9a, avoids gauche interaction between the ylide and aldehyde phenyl groups. This model results in the formation of the trans- (S,S) enantiomer, exactly as observed experimentally (41).

42

1.3.7 Aggarwal

Aggarwal et al., by far the most successful group in the field of asymmetric sulfonium ylide reactions started with quite modest results employing pinene derived chiral sulfides in the asymmetric epoxidation of aldehydes (46).

Due to the ready availability of homochiral alcohols they reasoned that chiral sulfides should be readily accessible by displacement of the hydroxyl group with a suitable thiol. They chosed (+)-isopinocampheol 59 as a precursor and tried direct displacement of the alcohol with benzyl mercaptan and thiophenol under Mitsunobu conditions (47,48) and modifications thereof, but without success. The required displacement was finally conducted by using zinc N,N-dimethyl dithiocarbamate under modified Mitsunobu conditions (49). Reduction of the resulting thiocarbamate with LiAlH4 gave the corresponding thiol 60, Scheme 24.

OH

SH

SRS PhR

ClO4

i, ii

iii

iv

59 60

61, R = Me, 72%62, R = i-Pr, 66%63, R = Bn, 63%

64, 82% (70:30)65, 66% (55:45)66, 40%

Scheme 24. Reagents: i) PPh3, Zn(CS2NMe2), EtO2CN=NCO2Et; ii) LiAlH4, Et2O; iii) RX, DBU; iv) BnBr, AgClO4, CH2Cl2

Sulfides 61, 62 and 63 and their corresponding sulfonium salts 64, 65 and 66 were

prepared from this thiol by alkylation as shown in Scheme 24. Sulfonium salt formation using benzyl bromide proceeded in good yields but diastereomeric mixtures were obtained in the cases of 64 and 65. As no new stereocentre was formed in the alkylation of 63 with benzyl bromide the sulfonium salt 66 was obtained as a single diastereoisomer. The sulfonium salts were treated with a base and an aldehyde under two different conditions (A: phase transfer catalyst employed; B: no phase transfer catalyst employed) (46). The results are gathered in Table 10.

43

Table 10. Preparation of trans-2,3-diaryloxiranes using sulfides 61, 62 and 63 as ylide precursors (46).

Salt Aldehyde Reaction condition

trans epoxide cis epoxide Recov sulfide

yield eea yield eea

64 PhCHO A 66 0 6 meso 54

64 PhCHO B 67 13 (R,R) 20 meso 10

64 4-ClC6H4CHO B 62 12 (R,R) 8 b 22

64 C6H11CHO A 28 22 6 28c d

64 C6H11CHO B 27 14 10 32c d

65 PhCHO A 5 43 (R,R) 0 meso d

65 PhCHO B 12 19 (R,R) 0 meso d

65 4-ClC6H4CHO A 55 42 (R,R) 0 b 75

65 C6H11CHO A - - - - d

a Enantiomeric excesses were determined by chiral HPLC using a chiralcel OD column. bEnantiomeric excess could not be determined by HPLC or NMR shift reagents. cThe cis and trans isomers could not be separated and the yields indicated represent ratios of the two products with the sum being the total yield. dThe starting sulfide could not be isolated in pure form.

It was found that the presence of the phase transfer catalyst (PTC) had no substantial effect on the yields of the epoxides. This was somewhat surprising as literature examples before have often described reactions only with PTC. The yields in reactions employing sulfonium 64 (methyl substituted) were generally much higher compared to the isopropyl substituted 65. This indicates that the increased steric hindrance around the sulfur atom reduces yields. Logically, enantiomeric excesses were significantly lower with the smaller methyl substituted sulfonium salt 64, indicating that increased steric hindrance around the sulfur atom increases enantioselectivity (46).

Since sulfonium salts 64 and 65 are diastereomeric mixtures, the same diastereomeric ratio should automatically be found in the corresponding ylides. Therefore, the low enantioselectivities obtained could more or less be expected.

44

To avoid the formation of diastereomeric salts, 66 was prepared and treated with a base in the presence of an aldehyde. However, no epoxide could be obtained in this case. Instead, the major product isolated was sulfide 67, which presumably arose from the Stevens rearrangement (50), Scheme 25.

S PhBn

ClO4

S

Ph

Ph

66 67

i

Scheme 25. Reagents: i) RCHO, 50% NaOH, CH3CN.

1.3.7.1 Development of a catalytic cycle To render the ylide epoxidation more synthetically useful, the catalytic mode was set as the main target for the group (53). It is plausible that the formation of the sulfonium salt in the catalytic cycle is rate-determining, and it is essential that this step is fast. Compared to previous work made in the field of asymmetric epoxidation of aldehydes, an alternative method for ylide formation, i.e., by the reaction of carbenes or carbenoids with heteroatom lone pairs, was taken into account (51,52). The reaction between sulfonium salts and carbonyl compounds giving epoxides, had usually been mediated by a base. However, carbonyl compounds containing sensitive functional groups may not be compatible with those basic conditions required. The catalytic cycle (Scheme 26) presented by Aggarwal et al. (53,54) reduced the conventional two-step sequence for ylide formation to one step.

O R'

R S

R' S

RCHO N2CHR'

Rh=CHR'

N2

[Rh2(OAc)4]

Scheme 26.

45

Moreover, the reaction was now carried out under neutral conditions and is, therefore,

applicable to readily enolizable and base-sensitive aldehydes (53). The metal-catalyzed decomposition of diazo compounds in the presence of sulfides

has often been used to prepare unsaturated sulfur ylides, which can then undergo [2,3]- sigmatropic rearrangements (55). In the catalytic cycle itself, ylides are generated in situ in the presence of carbonyl compounds in a reaction between a sulfide and a carbenoid, which in turn is generated from a diazo compound and a metal catalyst. At the same time ylides react with carbonyl compounds to give epoxides and are simultaneously regenerated to continue the process, as shown in Scheme 26. This method had never been used to generate sulfur ylides in the presence of carbonyl compounds and was therefore patented by Aggarwal et al. at 1995 (56).

Mixing together an aldehyde, a sulfide, a metal catalyst and a diazo compound certainly leads to competitive side reactions. For example, diazo compounds are well-known to react with carbonyl compounds directly to give homologated products (57), eq 1, Scheme 27. They are also known to dimerize in the presence of metal salts (58) (eq 2).

PhCHO N2CHPhPh

Ph

O

H

O

Ph

Ph

k Hom

N2CHPhRh=CHPh k Dim PhPh

1)

2)

68

68

69 70

71

Scheme 27.

To minimize the extent of these potential side reactions one needs to maintain a low cocncentration of the diazo compound, and this can be achieved by slow addition (53).

Due to the convenience of the laboratory, Aggarwal et al. chose to start with diphenyl sulfide (a nonvolatile sulfide). Phenyldiazomethane 68 was chosen, in the first place due to its greater stability (59) compared to alkyldiazo compounds. The diazo compound was added, over three hours, to a solution of the above reagents, but the only product isolated was stilbene 71. This showed that the reaction of the intermediate metallocarbene with phenyl diazomethane 68 (kDim) was faster than the reaction of the metallocarbene with the sulfide (53). To improve the rate of the latter reaction, diphenyl sulfide was replaced with the more nucleophilic dimethyl sulfide 72, Scheme 28. This time stilbene oxide 9a was obtained in good yield. Besides benzaldehyde also other aromatic and aliphatic aldehydes worked well, giving good yields of epoxides, Table 11.

46

RCHO Me2S Rh2(OAc)4N2CHPh

> 3h

O Ph

R

72

1 eq. 1 eq. 0,01 eq.

Scheme 28. Table 11. Synthesis of stilbene oxides using dimethyl sulfide 72 as a mediator (53).

Entry Aldehyde Yield, % trans:cis

1 PhCHO 70 88:12

2 4-NO2PhCHO 62 100:0

3 C6H11CHO 66 56:44

4 C5H11CHO 55 79:21

Epoxides were now formed with minimal interference from alternative side reactions.

Without Rh2(OAc)4 only homologated products were obtained, showing that ylide formation required metal catalysis.

To give the reactions the greatest chance of success they were carried out using stoichiometric amount of sulfide in the presence of a catalytic amount of metal salt. The first attempts to use dimethyl sulfide 72 in catalytic quantities (20 mol%) gave reduced yields of epoxides together with stilbene 71 and homologated products. Aggarwal et al. reasoned that the sulfide was being �held up� in the catalytic cycle at either the sulfur ylide stage (slow k3, eq 3) or at the betaine stage (slow k4, eq 4) and decided to add the diazo compound over 24 hours, Scheme 29. Under these conditions good yields of epoxides were obtained for both aromatic and aliphatic aldehydes (53), Table 12.

47

N2CHPh k 1 Rh=CHPh

RCHO Me2S Rh2(OAc)4N2CHPh, over 24h

O Ph

R

72

1 eq. 0,2 eq. 0,01 eq.MTBE/CH2Cl2

Rh2(OAc)41)

k 2Rh=CHPh2) Me2S Me2S CHPh

k 33) Me2S CHPh PhCHOO

SR2Ph

Ph

k 44)O

SR2Ph

Ph O Ph

RMe2S

Scheme 29.

The success of their catalytic cycle was reasoned to rely on the reactions represented in equations 1-4 in Scheme 29. They proceed at a significantly faster rate than the potential side reactions presented in Scheme 27.

48

Table 12. Synthesis of stilbene oxides using a catalytic amount of dimethyl sulfide 72 as a mediator (53).

Entry Aldehyde Yield, % trans:cis

1 PhCHO 74 88:12

2 4-ClPhCHO 76 80:20

3 4-NO2PhCHO 89 100:0

4 C6H11CHO 51 56:44

5 C5H11CHO 45 79:21

1.3.7.2 Choice of aldehyde

As seen in Table 12, aromatic aldehydes gave much greater ratios of trans epoxides than aliphatic aldehydes. For comparison, benzaldehyde was chosen as the representative aldehyde (60).

1.3.7.3 Choice and generation of diazo compound

From the beginning of the project evolution Aggarwal felt that the most critical choice would be the choice of the diazo compound (60). He considered the possibility of using ethyl diazoacetate, phenyl diazomethane and diazomethane itself. Ethyl diazoacetate was, however, ruled out because the corresponding sulfur ylide that would have been generated is known not to react with aldehydes to give epoxides because it is too stabilized (61,62,63,64). Because of the greater reactivity and hazards associated with diazo methane, he primarily decided to focus on phenyl diazomethane 68, Scheme 30.

Preparation of phenyl diazomethane. The diazo compound was prepared by a literature method (59) in which sulfonamide 75 is first prepared from p-toluenesulfonyl chloride 73 and benzylamine 74 followed by nitrosation yielding the corresponding nitroso compound 76. The treatment of 76 with sodium methoxide in an ethereal solution gives phenyl diazomethane 68 as a blood red solution, Scheme 30.

49

S

O

O

N

H

S

O

O

N

NO

N N

i

ii

73 74

68

iii

O

O

ClNH2

75

76

Scheme 30. Reagents: i) pyridine; ii) Ac2O/AcOH, NaNO2; iii) NaOMe, MTBE/MeOH, reflux 30 min.

Generation of diazo compound in situ. Diazo compounds are commonly known to be

potentially explosive and this was regarded as a certain limitation of the original protocol (65). It was, therefore, of great interst to generate the diazo compound in situ and incorporate this reaction into an established epoxidation process. They managed to develop a pocess for the direct coupling of two different aldehydes to form epoxides with control over the relative and absolute stereochemistry (66). The process was patented (67) and extended to cyclopropanations and aziridinations, as well (68).

They focused their efforts on the use of the Bamford-Stevens reaction to generate the diazo compound (69), and found, after some experiments, that warming the suspension of the tosylhydrazone salt 77 (Scheme 31) in the presence of a phase-transfer catalyst (to aid the passage from the solid to the liquid phase), allowed the generation of the diazo compound at slightly elevated temperatures.

This protocol proved to be compatible with their established epoxidation process and was remarkably efficient. Furthermore, these new conditions proved to be general (66), Table 13. All the aromatic, heteroaromatic and unsaturated aldehydes investigated furnished the corresponding epoxide in high yields and with high trans selectivites. Aliphatic aldehydes gave lower yields as well as selectivities, though. Tetrahydrothiophene (20 mol%) was employed as a mediator (66), Scheme 31.

50

O R'

Ph

PhCHO

Rh=CHR'

N2

[Rh2(OAc)4]

N2CHR

S

S

R PTC40 oC R N

NTs

Na+

NaH

R NN

Ts

77

H

H2O

1,4-dioxane

RCHOH2N

NTs

H

Na+Ts-

Scheme 31.

Table 13. Yields and ratios of epoxides formed from aldhydes and phenyl tosylhydrazone (R = Ph) salt 77 using 20 mol% of tetrahydrothiophene as a mediator (66).

Entry Aldehyde Yield (%) trans:cis

1 benzaldehyde 95 >98:2

2 p-nitrobenzaldhyde 94 >98:2

3 p-chlorobenzaldehyde 86 >98:2

4 p-methoxybenzaldehyde 98 >98:2

5 3-pyridinecarboxaldehyde 71 >98:2

6 trans-cinnamaldehyde 97 >98:2

7 trans-crotonaldehyde 78 91:9

8 cyclohexanecarboxaldehyde 69 65:35

9 valeraldehyde 59 70:30

51

A more diverse range of tosylhydrazone salts was investigated in the epoxidation process (66), Scheme 32 and Table 14.

Ar NN

Ts

Na+

77

PhCHOO PhR'

Ar

1 mol% Rh2(OAc)420 mol% tetrahydrothiophene

20 mol% BnEt3N+Cl-MeCN, 40 oC, 3h

Scheme 32. The yields of epoxides obtained were excellent, except where a sterically hindered aryl

reagent was employed (entry 6). In general trans epoxides were obtained exclusively, but tosylhydrazone salts bearing electron-donating substituents led to lower diastereoselectivities (66).

Table 14. Yields and ratios of epoxides formed from benzaldehyde (100 mol%) and tosylhydrazone salts 77 using 20 mol% of tetrahydrothiophene as a mediator (66).

Entry Ar R�

Yield (%) trans:cis

1 4-ClC6H4 H 95 >98:2

2 4-MeOC6H4 H 96 67:33

3 4-MeC6H4 H 73 80:20

4 2-MeC6H4 H 86 >98:2

5 4-CNC6H4 H 89 >98:2

6 2,4,6-Me3C6H2 H 17 >98:2

7 C6H5 Me 86 >98:2

The next step was to consider the possibility of generating the hydrazone itself in situ.

This worked as well, providing a one-pot, atom-economical method for coupling two different aldehydes to give epoxides (66), Scheme 33 and Table 15.

52

O Ph

RTsNHNH2

110 mol%

i-iii

Scheme 33. Reagents: i) PhCHO (105 mol%), 1.4-dioxane, rt, 0.5h; ii) NaH (110 mol%), rt, 1h; iii) Rh2(Oac)4 (1 mol%), tetrahydrothiophene (20 mol%), BnEt3N-Cl- (20 mol%), RCHO (100 mol%), 40 °C, 6h.

Table 15. Yields and ratios of epoxides formed from aldhydes and tosylhydrazone salt (generated in situ) using 20 mol% of tetrahydrothiophene as a mediator(66).

Entry Aldehyde (RCHO) Yield (%) trans:cis

1 benzaldehyde 70 >98:2

2 p-nitrobenzaldhyde 81 >98:2

3 p-methoxybenzaldehyde 70 >98:2

4 3-pyridinecarboxaldehyde 40 >98:2

5 cyclohexanecarboxaldehyde 30 70:30

6 valeraldehyde 43 80:20

Thereby, Aggarwal et al. had developed a general, user-friendly catalytic process for

preparing epoxides by coupling together a carbonyl compound with either a tosylhydrazone or a second carbonyl compound.

1.3.7.4 Choice of sulfide

Employment of Durst�s sulfides in catalytic cycle. The first sulfides Aggarwal et al. tested (Scheme 24, Table 10) in asymmetric epoxidation had sulfur atom situated outside the ring system, resulting in low enantioselectivities (46) (up to 43%). Encouraged by the results achieved by Durst et al. (19,23) they decided to prepare Durst�s chiral sulfides 78 and 79 and to test those in their original catalytic cycle for epoxidation (53,70), Scheme 34.

53

O Ph

Ph

9b

58%, 11% ee,86:14, cis:trans

S

S

78

PhCHO Rh2(OAc)4N2CHPh, over 24h

MTBE, CH2Cl2

1 mol%20 mol%100 mol%

PhCHO

100 mol%

79

100 mol%

Cu(acac)2

5 mol%

N2CHPh 150 mol%,over 3h

MTBE, CH2Cl2

O Ph

Ph

9b

40%, 72% ee

Scheme 34.

The unhindered sulfide 78 participated well in the catalytic process, furnishing trans-stilbene oxide 9a in good yield but as expected, with low enantioselectivity (53). Under these neutral conditions the yield was significantly higher, though. Aggarwal et al. achieved 58% yield compared to 39% presented by Durst and co-workers (19,23).

To test, whether hindered sulfides could be applied in the catalytic cycle, Aggarwal et al. decided to run a test with sulfide 79 (70). Durts et al. had received remarkable results employing the very same mediator in their own studies (38%, ≥ 96% ee). No epoxides were obtained at all when employing Rh2(OAc)4 as a metal catalysts, only stilbenes. However, using Cu(acac)2 in place of Rh2(OAc)4 and employing a stoichiometric amount of Durst�s sulfide 79, they were delighted to find that epoxidation was the dominant process again. The enantioselectivity was surprisingly moderate, only 72% (71).

To obtain higher enantiomeric excess, Aggarwal et al. assumed that the two groups attached at sulfur needed to be more dissimilar as compared, for example, to the unhindered sulfide 78, (72).

Design, preparation and testing of oxathiane ligand family. Thus, chiral sulfides 80 and 81 were chosen for study and were easily prepared in two steps (72), Scheme 35. Reduction of (+)-camphorsulfonyl chloride 80 with lithium aluminium hydride gave a mixture of the exo and endo products 5a and 5b, respectively. The thiols were separated by chromatography before cyclization.

54

SOCl2

SH

SH

OH

OH

O

SO

SO

80

5b

5a

82

81i

ii

ii

Scheme 35. Reagents: i) LiAlH4, THF; ii) (MeO)2CH2, BF3.OEt2, CHCl3, AcOH

The chiral sulfides 81 and 82 were then employed in the epoxidation cycle to prepare

stilbene oxide 9a. The reactions were conducted using both stoichiometric and catalytic amounts of sulfides (72), Table 16.

Table 16. Preparation of stilbene oxide 9a from benzaldehyde employing sulfides 81 and 82 (72).

Entry Sulfide Mol% of sulfide Yield (%), trans:cis ee (%)a

1 81 100 70 (10:1) 41 (R,R)

2 81 20 12 (11:1) 41 (R,R)

3 82 100 55 (4:1) 26 (S,S)

4 82 20 11 (4:1) 23 (S,S)

aEnantiomeric excesses were determined by chiral HPLC using a chiralcel OD column.

55

The employment of sulfide 82 resulted in only moderate selectivity, but sulfide 81 gave improved ee�s of 41% and a diastereoselectivity of 10:1. The use of stoichiometric amounts of sulfides gave good yields of epoxide, but as the amounts of sulfides were reduced, a notable drop in epoxide yield was observed. The reduced amounts of sulfides result in lowering the rates of sulfur ylide formation as well as the subsequent reactions which, in turn, can be noticed as reduced yields of epoxides.

In order to maintain similar reaction rates the concentration of the sulfide was maintained the same by simply reducing the volume of the solvent used. Employing the sulfide 81 under these conditions stilbene oxide 9a could be prepared in 83% yield. The corresponding yield with sulfide 82 was 75% (72).

There is very little steric difference between the two faces of ylide 83. Therefore, Aggarwal et al. were a little surprised at the level of enantioselection shown by this sulfide. No mechanistic rationale was presented but it was believed that a single sulfonium ylide is formed as the alkylation of 81 furnishes the sulfonium salt 83, Scheme 36.

SO

81

SO

83

i ClO4-

SO

CH2

ClO4-

HH

83

Scheme 36. Reagents: i) PhCH2Br, NaClO4, acetone, 41%.

The stereochemistry of 83 was confirmed by the studies. Irradiation of the benzylic protons gave an enhancement of the axial protons flanking the sulfide moiety, thus, indicating its equatorial position and also the orientation of the phenyl group (72).

56

Aggarwal et al. deemed important that in the design of other chiral sulfides single sulfonium salts or single sulfonium ylides should be formed. If mixtures of diasteromeric sulfonium salts were formed then these would certainly react with different, but possibly opposite enantioselectivity and would therefore reduce the levels of enantiomeric excess observed in the product epoxides (70).

Thus, any chiral sulfide that is designed should include one lone pair that is accessible and reactive and another lone pair which is hindered and unreactive. The previously prepared oxathiane 81 seemed like an ideal templade for next generation studies. Of the two lone pairs only the equatorial one should react with the metallocarbene as the axial one is hindered by the bridging gem-dimethyl group. Moreover, it should be easy to alter the steric and electronic environment around the sulfide to maximize enantioselectivity by simply changing the aldehyde or ketone used to form the thioacetal. On this bases they designed and prepared a (+)-camphorsulfonyl chloride 80 based ligand family of general structure 84 (73), Scheme 37.

SH

OH

6

acid/lewis acidaldehydeketoneacetal hydrate

SO

R

R'

84

81 R = H, R' = H84a R = Me, R' = H84b R = i-Pr, R' = H84c R = t-Bu, R' = Me84d R = Ph, R' = H84e R = Bn, R' = H84f R = CH2OPh, R' = H84g R = CH2OMe, R' = H84h R = CH2OBn, R' = H84i R = R' = Me

84j R = R' = C3H684k R = CH2OH, R' = H84l R = CCl3, R' = H84m R = CH2OAc, R' = Ha

84n R = CH2OPNB, R' = Ha

84o R = TMS, R' = Hb

84p R = CF3, R' = H84q R = H, R' = OMe

Scheme 37. aPrepared from 84k; bprepared from 81.

Most of these thiocetals were easily prepared via the known hydroxy thiol 6 (74,75,76), preparation of ligands 84p as well as 84q proved to be unsuccessful, though (Table 17).

57

Table 17. Preparation of sulfides 83a-q from mercaptoisoborneol 6 (73).

Entry Precursor Thioacetal Yield %

1 acetaldehyde 84a 99

2 isobutyraldehyde 84b 100

3 pivalaldehyde 84c 95

4 benzaldehyde 84d 84

5 phenylacetaldehyde 84e 98

6 phenoxyacetaldehyde dimethyl acetal 84f 85

7 methoxyacetaldehyde dimethyl acetal 84g 81

8 benzyloxyacetaldehyde dimethyl acetal 84h 83

9 2,2-dimethoxypropane 84i 97

10 cyclobutanone 84j 94

11 glycolaldehyde diethyl acetal 84k 81

12 chloral hydrate 84l 93

13 trifluoroacetaldehyde dimethyl acetal 84p 0

14 trimethyl orthoformate 84q 0

The thioacetals were tested in a catalytic epoxidation process (Scheme 38), and the

results are summarized in Table 18 (73). Sulfide 84a (R = Me, R� = H) proved to be the most effective catalyst both in terms of enantioselectivity and yield. Increasing the size of the R group did not give any increase in enantioselectivity but instead lovered the yield (entries 2-4). For R = t-Bu (84c), no epoxide was obtained, stilbenes were formed instead. Evidently, the rate at which the sulfides react with the metal carbenoid is dependent upon the size of R and R�, and if either one is too hindered, epoxide formation slows down and stilbene formation dominates (73).

58

SO

R

R'84

PhCHO PhCHN2Cu(acac)2CH2Cl2

O Ph

Ph

9b

20 mol% 100 mol% 150 mol% Scheme 38. Table 18. Reactions of sulfides 83 in the catalytic cycle with benzaldehyde (73).

Entry Sulfide R R� Yield %a Ee %b

1 81 H H 83 41

2 84a Me H 71 93

3 84b i-Pr H 57 93

4 84c t-Bu H 0

5 84d Ph H 0

6 84e CH2Ph H 56 88

7 84f CH2OPh H 43 83

8 84g CH2OMe H 70 92

9 84h CH2OBn H 71 90

10 84i Me Me 11 70

11 84j spiro-cyclobutyl 18 89

12 84k CH2OH H not reported

13 84l CCl3 H 0

14 84m CH2OAc H 68 93

14 84m TMS H 9 62

aOnly trans-stilbene oxide was obtained (>98:2 trans:cis).bThe ee values were measured by HPLC using a chiralcel OD column. (R,R) enantiomer was the major product in each case.

For R = Ph (84d), no epoxide was obtained but only limited amounts of stilbenes were

formed. In this case, ring expanded thioacetals 85 were believed to have been formed via

59

the Stevens rearrangement (73). The Stevens rearrangement of the ylide competes with carbonyl epoxidation and, in this case, is facilitated by the stability of the intermediate phenyl-substituted radical, Scheme 39.

SO

SO O

H

S

84d 85

Scheme 39.

A single heteroatom in the side chain can be tolerated (entries 7-9 and 14), and the

similar enantioselectivities obtained for R = Me showed there was no substantial electronic effect. The trichloro-derivative 84l gave no epoxide, only stilbenes. It was suggested that this sulfide is either sterically too hindered or electronically too deactivated by the chlorines to react with the metal carbenoid, and therefore stilbene is obtained instead.

Aggarwal et al. expected the TMS derivative 84m to be less sterically hindered than the corresponding sulfide 84c and to be electronically activated to react with the metal carbenoid. Indeed, epoxide was obtained but in low yield and with reduced enantioselectivity. The presence of two alkyl groups adjacent to sulfur gave much reduced yields of epoxide, and it was supposed this was due to increased steric hindrance. The enantioselectivity was also low (73).

The next step was to test the optime catalyst 84a for a range of aldehydes (73), Table 19. It was found that good yields and high diastereo-and enantioselectivities were obtained for other aromatic as well as unsaturated aldehydes. However, reduced yields and diastereoselectivities were observed with aliphatic aldehydes, but the level of enantioselectivity was essentially maintained. The reaction of valeraldehyde (entry 6) gave considerably reduced enantioselectivity, Table 19.

60

Table 19. Yields, enantioselectivities and ratios of epoxides formed from aldehydes and using 20 mol% of sulfide 84a as a catalyst (73).

Entry Aldehyde (RCHO) Yield % ee %a trans:cis

1 benzaldehyde 73 94 (R,R) >98:2

2 p-chlorobenzaldhyde 72 92 (R,R) >98:2

3 p-tolualdehyde 64 92 (R,R) >98:2

4 cinnamanaldhyde 55 89 (R,R) >98:2

5 cyclohexanecarboxaldehyde 32 90 (R,R) 70:30

6 valeraldehyde 35 68 (R,R) 92:8

aEnantiomeric excesses were determined by chíral HPLC using a chiralcel OD column.

Origin of diasteroselectivity. To account for the origin of the enantio- and

diastereoselectivity it was necessary to find out whether the sulfur ylide reactions were under kinetic or thermodynamic control. From crossover experiments Aggarwal et al. found that the addition of benzylsulfonium ylide to aldehydes was remarkably fine balanced (77).

Epoxide formation is essentially under kinetic control. The trans epoxide was derived directly from the irreversible formation of the anti betaine or indirectly from the resversible formation of the syn betaine. The cis epoxide was derived from the partially reversible formation of the syn betaine. The higher trans selectivity observed in reactions with aromatic aldehydes, compared to those with aliphatic aldehydes, was proposed to be due to greater reversibility in the formation of the syn betaine (77), Scheme 40.

61

SR2R1

Ph

PhCHO

k-3

k3

k1

k-1

O

Ph H

H Ph

SR2R1

O

H Ph

H Ph

SR2R1

anti betaine

syn betaine

k2

k4

O

Ph

Ph

O

Ph Ph

Scheme 40.

The reactions of simple sulfides (dimethylsulfide, tetrahydrothiophene) in the catalytic cycle with benzaldehyde gave stilbene oxide as an 86:14 ratio of trans/cis epoxides (53). However, when the camphor derived oxathiane 84a was employed, only trans epoxides were formed with a wide variety of aldehydes (70). This higher selectivity was proposed to be due to an increase in k-3 relative to k4. An increase in k-3 relative to k4 would be expected for sulfides of increasing steric hindrance or where the ylide had increased stability. In the case of the 1,3-oxathiane, Aggarwal et al. proposed that the corresponding ylide shows increased stability relative to simple benzyl sulfonium ylides as a result of the anomeric effect (73). The positive charge on sulfur can be delocalised over the oxygen, and this will lead to increased stability and therefore greated reversibility and thus greater trans selectivity. A moderate increase in the stability of the ylide is evidently not sufficient to promote reversibility in the syn betaine formation with aliphatic aldehydes, however (77).

Origin of enantioselectivity. Having established that trans epoxides are derived from the irreversible formation of anti betaines, Aggarwal et al. focused on the transition state leading to the formation of epoxides in order to understand the origin of enantioselectivity. As this was not possible, they concentrated on gaining information on the structure of the ylide (73). It was shown earlier that the alkylation of the related

62

oxathiane 81 only gave equatorial sulfonium salt (72). Thus, a single sulfonium ylide was believed to be formed again. Ylide conformation has been studied by X-ray diffraction (16f,g), NMR (16a,c,63,78,79,80) and computation (81,82,83). All of these studies indicate that the preferred conformation of the sulfur ylides is the one in which the filled orbital of the ylide carbon is orthogonal to the lone pair of the sulfur. The barrier of rotation around the C-S bond of the semistabilized ylide, dimethyl sulfonium fluorenide, has been found to be 42 ±1.0 kJ mol-1 (80). This information implied that the sulfonium ylide derived from 84a will adopt conformations 86 and 87 (Scheme 41) and these will be in rapid equilibrium at room temperature (73).

Of these two, conformation 87 will be favored because 86 suffers from 1,3-diaxial interactions between the phenyl ring and the axial groups. The aldehyde can then approach either face of the ylide, but the re face is more accessible as the si face is hindered by the equatorial methyl group (70,73), Scheme 41.

86 87

SO

SO

SO

H HHH

H

O H

Re face favoured O Ph

Ph

9a (R,R)

SO

84a

Scheme 41. The aldehyde can react in an end-on or [2 + 2] mode, but there is no evidence,

experimental or theoretical, to indicate which one is preferred. While most examples invoke the end-on mode, circumstantial evidence that the [2 + 2] mode may be favored has been reported (19). The end-on and [2 + 2] transition states in the reaction of ylide 87 with benzaldehyde are shown in Scheme 42 (73).

63

SO

H

O H

O Ph

Ph

9a (R,R)

SO

84a

SO

H

O

H

O Ph

Ph

9a (R,R)

SO

84a

SO

H

O H

O Ph

Ph

9a (R,R)

SO

84a Scheme 42.

From the analysis of the molecular models of these transition states it was clear that they all could be accommodated. Thus, the results did not provide any further evidence as to which mode is favored. All the transition states presented in Scheme 42 account for the high enantioselectivities observed.

The enantioselectivity obtained for sulfide 84a in the epoxidation of benzaldehyde was 93% (70). Therefore, Aggarwal et al. studied whether the minor enantiomer arose from the si attack (73). If so, enantioselectivity should be highly dependent upon the size of the equatorial substituent. Increasing the size of this substituent from Me to i-Pr did not result in any contominant increase in selectivity, however. The enantioselectivity was essentially the same for a range of substituents suggesting that the facial selectivity was rather complete. Lower selectivities with ligands having an aromatic ring in the side chain were proposed to be caused by possible π-stacking opportunities to an incoming aromatic aldehyde.

Even in the absence of a substituent (sulfide 81), good re-face selectivity was still observed (41% ee) (70). Aggarwal et al. reasoned that the oxygen of the oxathiane would

64

affect the facial selectivity of the ylide exerting through a combination of anomeric (84) and Cieplak effects (85,86,87).

SO

SO

4

62

Scheme 43.

A resonance form of the ylide derived from 84a is presented in Scheme 43. Aggarwal et al. reasoned that if there were be a contribution from this resonance form to the ground-state structure of the ylide, then the C4-S bond should be more electronrich than the corresponding C2-S bond which, in turn, should affect the face selectivity of the ylide. The resonance form in Scheme 43 is a result of the anomeric effect and should appear in the shortening of the C4-O bond relative to the C6-O bond and the lengthening of the C4-S bond relative to the C2-S bond (73). A significant anomeric effect was indeed proved true by preparing oxathiane 88, sulfoxides 89 and 90 and studying the structures by X-ray diffraction, Figure 5.

SO

4

62 S

O

4

62 S

O

4

62

O

O

OHO O

NO2

88 89 90

Figure 5. The assumptions came true already with oxathiane 88. The ylide mimicking sulfoxide

89 showed even greater differences in bond lengths (73), Table 20. The control compound, sulfoxide 90, showed essentially no differences in bond lengths.

65

Table 20. Bond lengths from X-ray structures of 88, 89 and 90 (73).

Compound C2-S/Å S-C4/Å C4-O/Å O-C6/Å C4-C5/Å C6-C5/Å

88 1.798 1.814 1.406 1.439

89 1.815 1.854 1.402 1.447

90 1.809 1.801 1.537 1.524

In order to gain further evidence of this combined anomeric and Cieplak effect, Aggarwal et al. decided to prepare and test the sulfur and carbon analogues of 81 (73). The preparation of sulfides 93 and 99 are presented in Schemes 44 and 45.

SH

91

O SH

SHS

S

92 93

i-iii iv

Scheme 44. Reagents: i) PhCOCl, DMAP, CH2Cl2, 0 °C; ii) Lawesson�s reagent, PhMe, 110 °C; iii) LiAlH4, Et2O, iv) (CH2O)n, p-TSA, PhMe, 110 °C.

Dithiane 93 was furnished from dithiol 92 by treating it with paraformaldehyde and tosic acid under Dean-Stark conditions. The preparation of carbon analogue was started by adding vinylcerium to 91 giving the exo alcohol 94, which upon treatment with 9-BBN gave the corresponding 4-hydroxythiane 103. The treatment of 95 with oxalylchloride resulted in elimination, giving sulfide 96. The unsaturated thiane was reduced to thiane 97, which was obtained as a mixture of diastereomers (3:1). Oxidation to sulfoxide 98 led to a substrate that they were able to crystallize, and subsequent reduction gave 99, Scheme 45.

66

SH

91

O SH

OH

S

94 95

i ii

SS

S

OH

S

O

969798

99

iii

ivv

vi

Scheme 45. Reagents: i) CH2CHMgBr, CeCl3, THF, 75%; ii) 9-BBN, THF, 79%; iii) oxalylchloride, benzene, rt, 74%; iv) H2, Pd/C, 15-20 atm., MeOH, 89%; v) mCPBA, CH2Cl2, 98%; vi) NaI, (CF3CO)2O, acetone, 89%.

Dithiane 93 and sulfide 99 were now tested in the epoxidation process. Sulfur analogue was expected to show enhanced selectivity (greater anomeric effect), and the carbon analogue should show reduced selectivity (no anomeric effect). Dithiane gave only slightly higher selectivity, while the carbon analogue, sulfide 99, gave much reduced selectivity (73), Table 21.

67

Table 21. Epoxidation of benzaldehyde using 20 mol% of sulfides 81, 93 and 99 (73).

Entry Sulfide Yield (%) ee (%)c

1 81 O 96a 41

2 93 S 83a 44

3 99 C 83b 20

aOnly trans-stilbene oxide observed. b96:4 trans:cis ratio observed. cEe values were measured by HPLC

using a Chiralcel OD column. The (R,R) enantiomer was the major product in each case. The stereochemical outcome of the ylide reaction is supposed to be determined by two

factors, the face selectivity of the ylide and the conformation of the ylide (73), Scheme 46.

SX

SX

HHH H

Si face(S,S) epoxide

Re face(R,R) epoxide

Re face(R,R) epoxide

87 X=O100 X=S101 X=CH2

86 X=O102 X=S103 X=CH2

Scheme 46.

Dithiane 93 was expected to give enhanced selectivity due to an increase in the

anomeric effect, which in turn should increase the face selectivity. It seemed, however, that the replacement of oxygen by sulfur results in a more distorted chair and, therefore, reduced 1,3-diaxial interactions, which in turn result in an increase in the population of conformer 102, Scheme 46. The ylide conformations may very well react with increased face selectivity, but a greater proportion of conformer 102 will, in turn, reduce the enantioselectivity. As expected, the carbon analogue 99 gave reduced selectivity. Since both dithiane 93 and oxathiane 81 adopt a verysimilar conformation (C-O and C-C have similar bond lengths), the ratio of conformers 87/86 and 101/103 will be similar. The difference in selectivity must result from a difference in the face selectivity of the ylide. Thus, the oxygen of the oxathiane exerts a significant stereoelectronic effect in promoting the reaction on the face opposite to this group (73).

68

The facial selectivity in the reaction of 84 was confirmed to be dependent on the size of the aldehyde; α-branched, aromatic and unsaturated aldehydes reacted with complete facial selectivity, while unbranched aldehydes reacted with moderate facial selectivity. Therefore, the source of the minor enantiomer was proposed to be the reaction of the minor ylide conformation 86, Scheme 45.

In order to reduce the amount of this minor conformation, Aggarwal et al. prepared thioacetals bearing axial substituents 84i (R, R� = Me) and 84j (R = spiro-cyclobutyl) to increase 1,3-diaxial interactions. However, instead of increased selectivity, a decrease in enantioselectivity was observed. A reliable explanation was found with nOe experiments. They found that while 84a adopted the chair form only, sulfide 84i existed in both chair and boat forms. The reaction of the corresponding ylide from the boat conformer of 84i should give the opposite enantiomer to that from the chair form. The boat form could be favored because of the severe 1,3-diaxial interactions in the chair form (73).

The role of the minor conformer was further confirmed by replacing phenyl diazomethane with the bulkier mesityl diazomethane (2,4,6-MePhCHN2). Thus, employing sulfide 84a as a catalyst increased greatly enantioselectivity. The epoxidation of benzaldehyde produced the corresponding trans-di-aryl epoxide with 98% ee (73).

[2.2.1] bicyclic sulfide. The employment of sulfide 84a in previously developed conditions, where the diazo compound is generated in situ (Scheme 31, page 51), resulted in failure, only low yields of the epoxide were obtained (66). Therefore, Aggarwal et al. embarked on the synthesis of a range of stable, mono and bicyclic chiral sulfides based on thiolanes, thianes and 1,4-oxathianes. From this study they found that the bridged bicyclic sulfides 108 and 109 performed exceptionally well (66). The bicyclic sulfides 108 and 109 were prepared in four steps from camphorsulfonyl chloride 80, Scheme 47.

The key step in the synthesis was the cycloaddition of thiolaldehyde 105 (generated photochemically from phenacyl sulfide 104) with cyclopentadiene (88,89). This reaction was reported to be both highly endo- (20:1) and diastereoselective (20:1).

69

SOCl2O S O O

S

PhO

S

O

S

O

nn

80 104 105

106, n=1107 n=2

108, n=1109 n=2

i,ii iii

n

iv

Scheme 47. Reagents: i) PPh3, 1,4-dioxane:H2O (4:1), 1h, reflux, 92%; ii) PhCOCH2Cl, K2CO3, THF, rt, 20h, 82%; iii) sun lamp (hv), CH2Cl2, 20 °C, 6h, cyclopentadiene → 106, 76% or cyclohexadiene → 107, 40%; iv) H2, Pd-S/C, EtOH, rt, 3h, 108, 84%; 109, 82%.

The conditions for epoxidation were optimised with sulfide 108 and it was found that the sulfide loading could be reduced from 20 mol% to 5 mol% without significantly affecting the yield or ee value. The asymmetric epoxidation of benzaldehyde, employing sulfide 108 as a catalyst, produced trans-stilbene oxide with 94% ee and 82% yield. The results were essentially the same (92% ee, 82% yield) when sulfide 109 was employed. The process was even scaled up to a 50-mmol scale without any significant loss of yield (92% ee, 78% yield) (66).

The following model was proposed to account for the high enantioselectivities observed, Scheme 48. Of the two lone pairs only the exo lone pair reacts to form a single sulfonium ylide. The ylide can adopt conformations 110 or 111, but 111 should be strongly favored because of the 1,4-steric interactions present in 110 (66).

70

S

O

S

O

HH H H

H

H

(S,S)

(R,R)

110 111

Scheme 48.

The face selectivity of the ylide is then controlled by the bulky camphor group which blocks attack from the si face, thus leading to the R,R epoxide. High enantioselectivities require both control of the conformation and high face selectivity of the ylide. The control in the ylide rigidity is proposed to arise from the conformational rigidity of sulfides 108 and 109, which would mean that the ylide conformer 110 can not be easily accommodated through small changes in the bond angles around the sulfur atom. Thus, there is a significant difference in the energy between the two ylide conformers 110 and 111, which in conjunction with the high face selectivity imposed by the bulky camphor moiety resulted in the high enantioselectivity observed (66).

1.3.7.5 Choice of metal catalyst

The first catalytic epoxidations were conducted employing Rh2(OAc)4 as a metal catalyst (53). As noted earlier, Rh2(OAc)4 did not work with the sterically hindered Durst sulfide 79 (70). Evidently, when the sulfide is slightly more hindered, the reaction of the metallocarbene with the sulfide becomes significantly lower and the reaction of the metallocarbene with phenyl diazomethane begins to dominate (70). Therefore, the relative rates of these competing reactions should be changed and this was supposed to be possible by simply changing the ligands of the rhodium. In the case of the intramolecular reactions of metal carbenes it has been shown that reaction pathways can be dramatically influenced by altering the ligands around rhodium (90,91,92,93). Therefore, a range of rhodium salts were prepared and tested in the catalytic cycle with the hindered Durst sulfide 79 (94). Ligands on rhodium, from strongly electron withdrawing to strongly electron donating groups, were tested without any success, only stilbenes were formed.

Aggarwal et al. reasoned that the wall of ligands around the rhodium carbene would present significant steric hindrance towards an incoming hindered sulfide. To make the carbene transfer to hindered sulfides more efficient, less crowded metal carbenoids were

71

required (70). Copper salts seemed ideal as prior to the formation of the carbenoid, copper (II) is reduced to copper (I) and one of the charged ligands dissociates (95), Scheme 49.

O OR

Rh Rh

O O

R

OR O O

R

O OR

Rh Rh

O O

R

OR O O

R

N2

OCu

O

O

ON2

OCu

O

Scheme 49.

Using Cu(acac)2 in catalytic cycle with the hindered Durst sulfide 79 they indeed

obtained trans-stilbene oxide (70). The first attempts at employing their best sulfide 84a with Cu(acac)2 resulted in failure, only 3% yield of epoxide was obtained. This was due to the rapid decomposition of the thiocetal (within a few seconds) catalyzed by Cu(acac)2. Under strictly anhydrous conditions the rate of hydrolysis could be reduced, but the desired improvement in yield was not obtained. There was a strong indication that the commercial material contained small quantities of impurities that showed high levels of catalytic activity in thioacetal hydrolysis. The solution to the problem was the sublimation of the metal catalyst. Thus, when the purified Cu(acac)2 was employed in the catalytic cycle with 20 mol% of 84a, stilbene oxide was obtained in good yield and high enantioselectivity (70), Table 18.

Aggarwal et al. also tested whether the choice of metal salt would have any effect on the yield or diastereo- or enantioselectivity of the epoxidation process. The reactions were carried out in CH2Cl2 using 20 mol% of their optimum sulfide 84a with benzaldehyde and a range of metal catalysts (73), Scheme 50, Table 22.

72

SO

84a

PhCHO PhCHN2catalystCH2Cl2

O Ph

Ph

9b

20 mol% 100 mol% 150 mol%

Scheme 50. Table 22. Epoxidation of benzaldehyde using 20 mol% of sulfide 84a with different metal salts (73).

Entry Catalysta Yield (%)b ee (%)c

1 Copper acetyl acetonate 73 93

2 Copper tetramethylheptanedionate 64 92

3 Copper hexafluoropentanedionate 0

4 Copper bronze 35 91

5 Rhodium acetate 61 92

a5 mol% of copper salts or 1 mol% of Rh2(OAc)4. bOnly trans-stilbene oxide observed. cEe values were measured by HPLC using a Chiralcel OD column. The (R,R) enantiomer was the major product in each case.

All the metal salts employed gave essentially the same enantioselectivity. The results

showed that the choice of metal salt used for the diazo decomposition had little effect on the enantioselectivity of the process. It also showed that metal did not participate in any way in the reaction of the sulfur ylide with the aldehyde. The optimum metal salt for sulfide 84a was copper acetylacetonate, Cu(acac)2 (73). It is also important to note that Rh2(OAc)4 now worked well with the hindered sulfide 84a whilst tests with the hindered Durst sulfide 79 had resulted in complete failure.

73

1.3.7.6 Choice of solvent

Aggarwal et al. also investigated the effect of the solvent on the epoxidation process (73). Reactions were carried out employing copper tetramethylheptanedionate as a metal catalyst because this catalyst was soluble in all of the solvents they wished to investigate. The results are collected in Table 23.

Table 23. Reactions on sulfide 84a with benzaldehyde in the catalytic cycle in different solvents (73).

Entry Solvent Yield (%)a ee (%)b

1 CH2Cl2 64 92

2 MTBE 35 94

3 EtOAc 39 94

4 Toluene 42 93

5 CH3CN 31 92

6 THF 43 89

aOnly trans-stilbene oxide observed. bEe values were measured by HPLC using a Chiralcel OD column. The (R,R) enantiomer was the major product in each case.

The most successful sulfide catalyst 83a was employed. As it can be seen all the

solvents gave essentially the same enantioselectivity and the highest yields were obtained using CH2Cl2 as a solvent (73).

1.3.7.7 Application to ketones

It is known that the dimethylbenzylsulfonium ylide reacts with ketones to give epoxides, but the reactions require elevated temperatures (60 °C) (96). Thus, Aggarwal et al. investigated reactions with cyclohexanone at various temperatures, Table 24 (94). In order to make various temperatures possible they chose the higher boiling tetrahydrothiophene instead of dimethyl sulfide as a mediator. It was found that optimum yields were obtained at 35 °C.

74

Table 23. Reactions on 100 mol% of tetrahydrothiophene with ketones in the catalytic cycle in different solvents (94).

Entry Ketone T/ °C Yield (%)

1 cyclohexanone rt 10

2 cyclohexanone 35 45

3 cyclohexanone 60 0

4 p-nitroacetophenone 35 62

5 acetophenone 35 38

At lower temperatures the ylide most probably does not react rapidly enough while at

elevated temperature the ylide may suffer decomposition.

1.3.7.8 Application of Simmons-Smith epoxidation

The Simmons-Smith reaction (97) and recent modifications (98) thereof are known as a powerful method for the diastereo- (99) and enantioselective cyclopropanation of alkenes (100). Some attempts to explore the reaction of Simmons-Smith reagents with sulfides had already been published (101) and Aggarwal et al. were interested to test whether the Simmons-Smith reagents could react with sulfides to generate ylides (102,103). If so, these zinc-derived sulfur ylides could then be used to generate epoxides from aldehydes. Aggarwal et al. investigated the reaction of the zinc carbenoid derived from Et2Zn and ClCH2I with tetrahydrothiophene, Scheme 51.

75

O H

R

RCHO

S

S

H

EtZnCl

EtZnCH2Cl

Et2Zn + ClCH2I

Scheme 51.

In these organozinc-mediated epoxidation reactions of aldehydes three equivalents of sulfide were employed, Scheme 52. Terminal epoxides were obtained in high yield (103). Some of the results are collected in Table 24.

Et2Zn + ClCH2IS

RCHOO

R

200 mol% 200 mol% 300 mol% 100 mol%

Scheme 52.

Aromatic and aliphatic aldehydes worked well and the reaction even tolerated unsaturated aldehydes (entry 5) without undergoing cyclopropanation. This indicated that the reaction of the zinc carbenoid with the sulfide was much more rapid than the reaction with the alkene (103).

76

Table 24. Organozinc mediated epoxidation reactions of aldehydes employing 300 mol% of tetrahydrothiophene as a mediator(103).

Entry Aldehyde Product(s) Yield (%)

1 O

H

O

74

2

O2N

O

H

O

O2N

95

3

Cl

O

H

O

Cl

65

4 O

H

O

60

5

H

O

O

70

6 O

O

O

H

O

O

O

O

OO

1:1

71

7 Bn

H

O

NBn2

Bn

NBn2

Bn

NBn2

OO

5:1

84

77

When diastereomers were formed, the diastereoselectivity was similar to that observed in the reactions of the trimethylsulfonium ylide with the aldehydes (104). In no case any racemization could be detected while it has been reported that in the case of the aldehyde derived from phenylalanine, substantial racemization occurs in the ylide epoxidation process (105). The epoxides derived from phenylalanine (entry 79) are reported to be key intermediates in the syntheses of many HIV protease inhibitors (105,106).

1.4 Chiral aminosulfonium ylides

While it is questionable whether tetrahedral sulfonium ylides can racemize (16,17), there is no dispute about the configural stability of the aminosulfonium ylides. Johnson et al. were first to prepare enantiomerically pure ylide (R)-(-)-114 starting from sulfoxide (R)-(+)-112, which reacted with benzaldehyde, gave (R)-styrene oxide 115 in 20% ee, Scheme 53 (24a,107,108,109,110).

H3C S p-Tolyl

O

H3C S p-Tolyl

O

NMe2

BF4-

H2C S p-Tolyl

O

NMe2

NaHDMSO

112 113 114

H2C S p-Tolyl

O

NMe2

114

PhCHOO

Ph

H

115

60%, 20% ee

CH2SPh

O

NMe2

n-C6H13CHOO

H

n-C6H13

117

39%, [ ]D: -0.77

116

R

S

Scheme 53.

78

The reaction of ylide 116 with heptaldehyde gave the corresponding epoxide 117 with opposite enantioselectivity as expected (107,109). Also a mechanistic rationale was presented, Schemes 58-60. Assuming a two-step mechanism for epoxidation, ylides can react reversibely or irreversibely with carbonyl compounds (step 1) prior to irreversible ring closure (step 2), Scheme 54.

Z CH2

Ok1

k-1Z CH2

Ok2

O

Step 1 Step 2

Ar S

O

NMe2

Z = (aminosulfoxonium ylide) k-1> k2, "reversible"

R1 S

R2Z = (sulfonium ylide) k-1<< k2, "irreversible"

Scheme 54.

In order to probe whether ylide additions to carbonyl compounds were reversible or not, Johnson et al. prepared sulfonium salt 119 (Scheme 55) and sulfide 124 (Scheme 56) in diastereo- and enantiomerically pure form (24a,108).

The treatment of 119 with a base gave styrene oxide 115 with 22% ee. As this is the same value as that expected from direct addition of ylide 114 to benzaldehyde, this indicated that the intermediate betaine from aminosulfoxonium ylides was formed reversibly. This was confirmed by deprotonating 119 with a base in the presence of chalcone. Only cyclopropane was formed.

79

CH2LiSPh

O

NMe2

O

H

Ph

115118

i-iiiPhSO

NMe2

CH2H

OHPh

BF4-

119

ivS

71%, 22% ee

PhPh

O

v

120

PhCHO

80%

vi

CH3SPh

O

NMe2

121

BF4-

PhCHO

Scheme 55. Reagents: I) PhCHO; ii) H3O+; iii) Me3O+BF4; iv) t-BuOK, t-BuOH; v) NaH, DMSO, chalcone; vi) OH-, H2O

In contrast, the treatment of sulfide 124 with MeI followed by base gave styrene oxide with exceptionally high 90% ee, Scheme 56.

CH2LiSn-Bu

O

NMe2

122

i-iiiCH2

OHH

PhS

O

n-Bu

123

ivCH2

OHH

PhS

124

n-Bu

CH2

OH

PhS

125

n-Bu

Me

v

O

Ph

H

115

R

90% ee

Scheme 56. Reagents: i)n-Buli; ii) PhCHO; iii) H3O+; iv) NaHSO3, H2O, 100 °C; v) MeI, NaH, DMSO.

80

As the alkylation of sulfide 124 gave a mixture of diastereomers, reverse betaine formation would have produced a mixture of enantiomeric ylides, which could naturally not have produced such high levels of enantiomeric excess. It was therefore concluded that the intermediate betaine from sulfonium ylides was formed irreversibely (24a, 108).

Asymmetric epoxidations using aminosulfoxium ylides have not been explored to the same extent as the employment of chiral sulfonium ylides. In conjunction with the total synthesis of the furaquinocins Suzuki et al. employed aminosulfoxonium ylide (S)-116 in stereoselective epoxidation of aldehyde 125 (111). The desired epoxide 126 was obtained in high selectivity, Scheme 57.

OOMe

MeO

OMe

OMOM

CHO OOMe

MeO

OMe

OMOM

OOMe

MeO

OMe

OMOM

O O

30:1

125 126

CH2SPh

O

NMe2

(S)-116

Scheme 57.

1.5 Chiral arsonium ylides

Also the use of chiral arsonium ylides in the asymmetric ylide epoxidation has received considerably less attention compared to sulfonium ylides. In fact, Wild�s two papers (112,113) represent the only examples to date. The optically pure arsonium salts 127-129 and 131-134 were obtained from the resolution of the corresponding racemates and (-)-menthol-derived 130, Scheme 58. These arsonium ylides were then employed for the asymmetric benzylidene transfer.

81

As

As

Me

MeCH2Ph

Ph

PhBr-

As

As

Me

PhMe

CH2Ph

Ph

Br-

As

As

Me

MeCH2C6H4OMe

Ph

PhBr-

AsPh2

CH2Ph

Br-

AsMeCH2Ph

AsMeCH2Ph

N

AsMeCH2Ph

AsMeCH2Ph

Br- PF6- Br- PF6

-

(R,S)-127 (S,R)-128 (R,S)-129 (+)-130

(R)-131 (R)-132 (R)-133 (R)-134

As

As

Me

MeCH2C6H4OMe

Ph

PhBr-

(R,S)-129

1) EtONa, EtOH

2) o-MeOC6H4CHO

O

H

H

OMe

OMe

(2R,3R)-135

86%, 38% ee

Scheme 58.

These ylide reactions proceeded via a similar mechanism to the sulfonium ylides. The highest ee observed for these epoxidations was 38% (112). This was obtained with arsonium ylide 129 for compound 135.

1.6 Related reagents

The asymmetric methylene transfer from chiral sulfonium ylides to C=O bonds has been known as an unrewarding task (18,19,23). High ee for optically active styrene oxide (up to

82

97%) was, as a matter of fact, reported by Hiyama et al. (114) but this work was questioned and considered incorrect five years later by Rosenberger et al. (115). Aggarwal et al. obtained promising results employing achiral tetrahydrothiophene in their application of the Simmons-Smith epoxidation (102,103) and intended to publish their ongoing studies employing chiral sulfides in asymmetric methylene transfer in due course.

Fortunately, several other methods have been documented as well. Asymmetric methylene transfer from chiral sulfoximine anions to C=O was reported by Johnson et al. (116). Optically active (S)-(-)-2-methyl-2-phenyloxirane 138 was successfully prepared by the reaction of (S)-137 and acetophenone, Scheme 59.

Ph S CH3

O

NTs

(S)-136

Ph S CH2

O

NTs

(S)-137

Ph

O

O

Me

Ph

(S)-138

40%, [ ]D = -6,9o

Scheme 59.

This reaction was applied again by Soman et al. twenty years later (117,118). They employed the (-)-menthol and D-(+)-camphor derived sulfoximines 139-142 (Figure 6) in the asymmetric methylene transfer and obtained 2,2-disubstituted oxiranes in up to 86% ee, Table 25.

OMe

NTs

(Ss)-(-)-139

NTsMe

O

NTsO

Me

SO

O

NO

MeO

(Ss)-(-)-140 (Rs)-(+)-141 (Rs)-(+)-142

Figure 6.

83

Table 25. Reactions of sulfoximines 139 (117) and 140-142 (118) with different carbonyl compounds. Optical yields detected.

Carbonyl compound 139a 140 141 142

O

H

66,2%, (R)-(+)-

28,6%, (S)-(-)-

28,5%, (S)-(-)-

61,0%, (S)-(-)-

O

H

Cl

55,8%, (R)-(+)-

21,7%, (S)-(-)-

18,6%, (S)-(-)-

49,9%, (S)-(-)-

O

82,3%, (-)- - 56,9%, (+)-

86,1%, (+)-

O

Cl

86,0%, (-)- 58,1%, (-)- 68,2%, (+)-

81,2%, (+)-

aThe oxiranes obtained from (Rs)-(+)-139 showed [α]D practically equal in magnitude, but opposite in sign to those of oxiranes from (Ss)-(-)-139.

The influence of chirality at sulfur as well as the nature of the group at nitrongen on

the asymmetric induction of the epoxidation process was investigated. By changing the chirality at sulfur (140 vs 141) they obtained similar levels of asymmetric induction in the reactions with aldehydes but opposite selectivity with ketones (118). Changing the substituent on nitrogen made little difference to the asymmetric induction observed (142 vs 139). The results revealed that the chirality on the carbon substituent was the most important factor in determining the outcome of the epoxidation process. Changing the chirality at sulfur had a mixed effect. Lately, Reggelin et al. published an excellent rewiev article surveying the chemistry of sulfoximines (119). According to them no further studies employing sulfoximines in asymmetric epoxidation processes have been published lately.

The first asymmetric methylene transfer from chiral sulfimides to C=O bonds was communicated and discussed in full detail later by Taylor et al. (120,121,122), Scheme 60.

84

NTs

SCH3p-Tolyl

NTs

SCH2p-Tolyl

R1

O

R2 O

R1

R2

R

(S)-143 (S)-144

NaH, THF

-5 oC - reflux

Scheme 60.

Anion 144 was formed by deprotonation of sulfimide (S)-143. Treatment with aldehydes and ketones gave (R)-epoxides in 21-70% ee (122), Table 26.

Table 26. Reactions of sulfimide (S)-144 with different carbonyl compounds. Optical yields detected (122).

Carbonyl compound Optical yield % (ee)

O

H

70%

O

45%

O

H

-

O

21%

H

O

42%

85

The predictable sense of the asymmetric induction for the epoxides can be rationalized by means of an open chain model, Figure 7. The model assumes that the largest groups in both the sulfimide and the carbonyl component will prefer an antiperiplanar relationship with respect to the newly forming chain, i.e. Ar antiperiplanar to the forming carbon-carbon bond and RL antiperipalanar to the CH2-S bond (120).

SO RS

RLAr

TsNS

RS O

RLAr

TsN

A B

Figure 7.

This assumption generates two transition states A and B. Taylor et al. propose that the unfavourable electrostatic interaction between the highly negatively charged oxygen and nitrogen centres in A will lead to a preference for B in all cases. Increasing the size of the small groups RS will raise the energy of B more than the energy of A, as in B there are unfavourable steric interactions between RS and TsN. Thus, the mode predicts that (S)-sulfinimide 144 will lead to (R)-epoxide (via B) and that the enantiomeric excess will increase as the size of group RS decreases, as observed (120).

1.7 Concluding remarks

In the synthesis of non-racemic epoxides by asymmetric alkylidene transfer reactions (to aldehydes/ketones), both the relative and absolute configurations of the product are established in one single step. A completely stereoselective method for this transformation, therefore, would be superior to the asymmetric synthesis by epoxidations where alkenes of defined configuration are generally required but not always available.

Asymmetric ylide epoxidations have been extensively developed for almost fourty years. During this time some stereoselective processes have been developed, several new ideas and new reagents have been presented as well as new catalytic processes have been developed. In the field of reagent controlled asymmetric epoxidations chiral sulfonium ylides are the ones that have gained most of the attention both in terms of making the processes catalytic and designing and preparing chiral sulfides capable of high asymmetric induction. As professor Aggarwal comments, the application of chiral catalysts is still in its infancy, however. Although promisingly high enantioselectivites have been obtained, the optical yields are still far away from enantiospecificity. Therefore, more efforts on these asymmetric processes are definitely needed.

86

2 Design, synthesis and testing of new chiral sulfide ligands for the Corey-Chaykovsky reaction

2.1 Project background

In early 1997 TEKES (the national technology agency), several Finnish chemical companies and academic partners started a Marketing Molecules Technology Programme aimed for the years 1997-2000. The Koskinen Group participated in some of the subprojects, among others in the Aldehyde Activation & New Oxidation Technologies �Programme, in which the original aim was to develop new routes including oxidation processes for converting aldehydes, alkanes and alkenes to higher value products. The industrial partner in this subproject was Neste corporation.

The objective of my subproject was to design, synthesize and test new chiral sulfide catalysts primarily for the Corey-Chaykovsky reaction, i.e. for the catalytic epoxidation of aldehydes. The catalytic version of the Corey-Chaykovsky reaction, published previously by Aggarwal et al. (72), turned out to be expandable to the Simmons-Smith epoxidations (103), cyclopropanations (123) and aziridinations (124) as well. The successful work they had performed and were still performing, made us convinced that their catalytic cycle would definitely be the right frame for us to work with. At the same time another graduate student, Mika Lindvall, was looking for a suitable synthetic objective where computer-aided molecular methods could be reasonably applied. Of several choices he luckily decided to work with me. We now had a rare possibility for collaboration where the full design cycle could be exploited.

2.2 Ligand design To obtain high levels of asymmetric induction chiral sulfides are required. Thus, the goal for this project was to design, synthesize and develop new ligand families in which the

87

steric and/or electronic environment of the sulfur atom should be easily tunable to maximize stereoselectivity. The table was open to ideas, no reservations concerning starting materials etc. were claimed neither by Neste corporation or anybody else.

2.2.1 Structural requirements

The ligand design was started with a literature update in order to find out the general structural properties required for the sulfide catalysts. The survey revealed that the structure should fulfil the following claims:

1. Only one of the sulfur electron pairs should be reactive 2. Only one of four possible ylide conformations should be formed 3. A wall directing the aldehyde approach should be incorporated in the sulfide

structure Substituent effects in the transition state determining the stereochemistry of the

products are roughly presented in Scheme 61.

os

Single sulfur electron pair reacts

Aldehyde approachesfrom this side

Single ylide conformation

Steric hindrance

Scheme 61. It was reasoned that, in order to fulfil the first two claims, the sulfur atom should be

incorporated in a rigid, cyclic structure possessing only one single ring conformation. The facial selectivity (aldehyde approach) should then be achieved by a sterical wall

88

incorporated in this cyclic structure. To some extent, facial selectivity could even be affected through a combination of anomeric and Cieplak effects (73).

Other valuable design features were that the designed sulfides were easily accessible from common starting materials, could be synthesized in both enantiomeric forms, would be easily tunable and could, if necessary, be linked to solid support.

2.2.2 The inventive step

The literature update and database searching in Cambridge Structural Database did not give rise to any individual ideas. Instead, it was the X-ray structure (125) of one specific diastereomeric amino alcohol 145 prepared in authors Master�s thesis (126) that literally woke him up, Scheme 62.

ON

OH

BOC

Steric hindrance affectingfacial selectivty

Sterical shielding over theother oxygen electron pair

Oxygen (sulfur) atom incorporated in a cyclic scaffold

145

Scheme 62.

The initial thought was simply to replace the oxazolidine oxygen with sulfur (thiazolidine) in this structure, which amazingly, well seemed to fulfil the earlier presented demands. In the crystal, the alkyl side chain is pseudoaxial, the phenyl ring

89

effectively shielding the other oxygen electron pair. The gem-dimethyl group, in turn, forms a wall effectively forcing the molecules to approach the oxygen from one direction.

An important feature of the thiazolidine ring system that makes it synthetically useful is its inability to undergo a cyclopentanelike pseudorotation (127). The introduction of the heteroatoms, various substituents, and the sp2-hybridized nitrogen creates a potential barrier restricting any pseudorotation (128), an absolute prerequisite for forming a single ylide conformation yielding high enantioselectivities in the epoxidation processes.

Thiazolidine crystal structures having sp2-hybridized nitrogen were searched the found ones having an alkyl side chain in pseudoaxial orientation (129).

2.2.3 Idea refinement

The idea was refined as presented in Scheme 63.

O N

OH

Ph

BOC

S N

OH

Ph

BOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

Ph

Ph

Ph

Ph

Ph

Ph

145 146 147 148

149150151

Scheme 63.

A stepwise process applying computer-assisted manipulation of models and energy minimizations to aid the process was started (130). The oxazolidine oxygen of 145 was replaced with sulfur yielding the corresponding thiazolidine 146. The hydroxyl group had to be removed due to its reactivity towards carbenes. In the resulting sulfide 147 the benzyl side chain can rotate risking the steric protection of the sulfur. While two phenyl rings increase the protection, the side chain rotation is made irrelevant by a symmetric system having three phenyl groups (149). Subsequently it was recognized that a tert-butyl

90

group could offer sufficient protection and, even more importantly, be easily accessible from L-tert-leucine, yielding finally 151.

Preliminarily, two different synthetic strategies towards the sulfide family 155 were envisaged, Scheme 64. In the first route, the carboxyl group of the amino acid 152 would be reduced to the corresponding amino alcohol 153. The conversion of the hydroxyl group to a sulfide would be followed by ring closure and aminal protection, resulting in 155.

S N

R

Y'Y Z

155

NH2

RHOOC

NH2

RHO

NH

RHS

Z152 153 154

NH2

COOHHS

156

S NH

COOMe

Y'Y

S N

COOMe

Y'Y Z

S N

Y'Y Z

R1 R1

OH

157 158 159

Scheme 64. In the cysteine-based strategy the sulfide moiety is already incorporated in the amino

acid structure. Esterification and ring formation are followed by aminal protection to yield the fully protected thiazolidine derivative 158. The side chain is then constructed by alkylation of the carboxyl function. The subsequent reduction or acylation of the tertiary hydroxyl group would lead to 155, allowing a wide variety of alkyl side chains.

Compounds resulting from both strategies share two other variable moieties as well. The ketal function (Y,Y�) provides a steric hindrance that can easily be tuned by employing different aldehydes or ketones. The aminal protective group (Z) does not necessarily have to be BOC; it can be replaced by different amides and carbamates allowing attachment of molecular auxiliaries, such as chromophores, or attachment to

91

solid support. Amino acids are also accessible in both enantiomeric forms allowing the preparation of opposite enantiomeric products in the reactions exploitable.

2.2.4 Target ligands

The ligand design is at its best an ongoing process. Therefore, the next schemes contain target catalysts which were designed at different stages of the project. The idea refinement resulted in L-tert-leucine derived sulfide 151, Scheme 69. Due to contemporary lack of starting material, the synthetic work yielding the first ligand 163, Figure 8, was started with another choice of chiral precursor, L-valine, instead.

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

160 161 162 163

164 165 166

Figure 8. L-valine derived target ligands. The first four ligands 160-163 were chosen as preliminary tasks. Of these, sulfide 163

was expected to give the highest asymmetric induction and sulfide 160 would act as a control compound lacking, the �wall� and, therefore, providing information about the direction and magnitude of the residual chiral induction. The diastereomeric pair of sulfides 161 and 162 was expected to give important knowledge about the significance of methyl groups� spatial orientation.

The L-tert-leucine derived ligands (Figure 9) have, compared to the L-valine derived ones, one additional methyl group in alkyl side chain giving improved shielding over another sulfur electron pair as well as freezing further the pseudorotation of the ring system.

92

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

S NBOC

167 168 169 151

Figure 9. L-tert-leucine derived target ligands.

Also two additional amino acids, D-penicillamine (the corresponding L-antipode causes optic athropy, which can lead to blindness) and L-cysteine (target molecules 173 and 174) were employed in the ligand design, Figure 10.

S NBOC

S NBOC

Ph Ph

XS NO

O

S NBOC

S NBOC

S NBOC

Ph Ph

XS NO

O

170 171 172

173 174

Figure 10. D-penicillamine and L-cysteine derived target ligands.

Here, the idea was to prepare sulfide pairs where the sterical wall (gem-dimethyl moiety) is situated on opposite faces of the ligand, thus offering a possibility to study the impact of this on asymmetric iduction. Such pairs would be sulfides 163 and 171 as well as 172 and 174. The preparation of sulfide 172 was a task for my undergraduate student Tomi Heikkinen (131).

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2.3 Ligand syntheses

2.3.1 L-Valine derived ligands

The ligand syntheses were started employing L-valine as a chiral precursor. The first two catalysts prepared, and employed later in the epoxidation process, were ligands 163 and 160 (132).

2.3.1.1 BOC-protected amino thiol

In the first reaction, L-valine 175 was reduced with LiAlH4 to the corresponding amino alcohol L-valinol 176 by a literature method (133), Scheme 65.

NH2

HOOC

NH2 NH

HO HO

BOC

NH

AcS

BOCNH

HS

BOC

NH

S

BOC

NH

S

BOC

i ii

iii

iv

175 176 177

178179180

Scheme 65. Reagents: i) LiAlH4, THF, ii) (BOC)2O, CH2Cl2, iii) DIAD, (PH)3P, CH3COSH, THF, iv) KOH, MeOH

Careful quenching with 1.3 equivalents of water during at least two hours was a prerequisite for high yields. Made with less attention the reaction easily resulted in a rubbery, glue-like mixture and dramatically reduced yields. The crude L-valinol 176 was purified by Kugelrohr-distillation and the yields varied normally between 64 and 70%. The standard BOC-aminal protection employing BOC-anhydride proceeded smoothly (45 min) at room temperature without any catalysts giving BOC-protected amino alcohol 177 in quantitative yield (132). The same compound has even been prepared in reversed order (134).

94

The conversion of alcohols to thiolesters generally needs two transformations; initial activation of the hydroxyl group by conversion to a halide or tosylate and displacement with a suitable sulfur containing nucleophile (135). Therefore, we decided to prepare thiolacetate 178 in one step using a modification of the triphenylphosphine � dialkyl azodicarboxylate inversion procedure of Mitsunobu (136).

It is important that the starting material and thioacetic acid are not added into the reaction mixture before DIAD and triphenyl phosphine have formed an adduct. This takes approximately 30 minutes at 0 °C. Good yields up to 81% were obtained even when scaling up the reaction to 56 mmol. The purification process turned out to be problematic and time consuming. Even if some of the side products formed could be precipitated from cold diethyl ether, neither traditional flash chromatography nor Kugelrohr distillation gave satisfying results. The thiolacetate 178 could finally be separated with MPLC under carefully chosen conditions.

Saponification of thiol ester 178 to the corresponding thiol 179 was carried out with potassium hydroxide in dry methanol (132). Since thiols are easily air-oxidized into corresponding dimers in alkaline and even in neutral solutions, great care must be taken when conducting these reactions. Using only 1.1 equivalents of base resulted in prolonged reaction times and subsequently in dimer formation. Using two equivalents of base without monitoring the reaction with TLC, the reaction proceeded in 20 minutes giving amino thiol 179 after fast work up in quantitative yield. Being solid, thiol 179 can be storaged without risk of dimerization.

2.3.1.2 Attempts at direct ring closure

We first attempted direct ring closure to afford 163, Scheme 66, as such ring closure has been reported in the synthesis of oxazolidines (137,138). Boron trifluoride diethyl etherate and scandium triflate were chosen as Lewis acids for ketal protection. To our knowledge, the latter had not been employed earlier in ketalizations but had proven to be an effective catalyst in acetalizations (139) instead.

S NBOCNH

HS

BOC

OMeMeO

OMeMeO

BF3 OEt2.CH2Cl2, rt

CH2Cl2, rt4Å crushed mol.s.

4Å crushed mol.s.

x

xSc(OTf)3

179 163

Scheme 66.

95

To capture the methanol formed in the reaction, 4 Å crushed molecular sieves were employed. The reaction started in both cases but it seemed that 2,2-dimethoxy propane reacted readily with thiol moiety but no further. Prolonged reaction time (> 10 hours) resulted only in different elimination products. Different acidities of the protons in the carbamate/thiol and carbamate/hydroxyl pairs were suspected to be the source of the failure. Calorimetrically, ethanethiol has been estimated to be 12 pKa units more acidic than ethanol in DMSO (140).

2.3.1.3 Alternative synthetic route

Since the direct ring closure to furnish the first sulfide catalyst 163 proved to be unsuccessful, an alternative synthetic route had to be considered. Thus, the amino thiol should be deprotected followed by ring closure and subsequent aminal protection.

BOC-deprotection. The standard procedure to cleave the BOC-protective group employing TFA in CH2Cl2 (1:1) was unsuccessful, Scheme 67.

NH3+Cl-

HS

HN

HS

BOC

NH2.TFA

HS

1) TFA:DCM, 1:1, rt

2) TFA (neat), rt->40 oC

NH3+Cl-

HS

4M HCl:THF, 1:1,reflux, 20h

NH3+Cl-

HS

1:10 conc.HCl:EtOAc, rt, 3 days

1:1, conc. HCl:MeOHreflux, 16h, quantitative

180

181

181

181179

Scheme 76. There was no improvement by using neat TFA and after a few hours even some

decomposing could be detected. Employing 4 M hydrochloric acid in THF (1:1) resulted,

96

after twenty hours of refluxing, in amino thiol hydrochloride salt 181. Under these conditions cyclic ether THF had opened and further polymerized, however. This made the product isolation very difficult and, thus, other choices were brought up to consideration. In deed, by changing THF to ethylacetate the reaction proceeded cleaner. Due to the probable reaction between the amino group and ester at elevated temperatures the reaction had to be conducted at ambient temperature. Thus, after three days there was still plenty of starting material left.

Finally, refluxing in concentrated hydrochloric acid in methanol (1:1) overnight provided us with deprotected amino thiol in quantitative yield (132). In principle, there was a risk that the liberated t-butyl cations could have alkylated the thiol. Fortunately, that did not occur. In theopposite case however, this could have been avoided by using scavengers such as thiophenol, anisole and thiocresol (141).

Thiazolidine ring formation. Being naturally a solid, amino thiol hydrochloride salt 181 can be easily storaged without any risk of dimerization. The catalyst for thiazolidine ring formation was now inbuilt in the structure. The product separation should then even in the following phase be convenient due to the ease of handling hydrochoride salts.

This assumption proved true and even more. The starting material, amino thiol 181 was soluble in acetone:2,2-dimethyl propane (5:2) and the product, (S)-2,2-dimethyl-4-isopropyl-thiazolidine hydrochloride salt 182 precipitated from the reaction medium (132), Scheme 68. The ring formation would proceed in plain acetone as well, but in order to enhance yields, 2,2-dimethyl propane was used as a dehydrating agent (142). Sulfide 182 was obtained between 67% and 70% yields.

Thiazolidine 183 was obtained as a mixture of (2S,4S) and (2R,4S) diastereomers in a ratio of 71/29 as measured by 1H NMR (143). Also here the product precipitated from the from the reaction medium from the very start. The addition of acetaldehyde to an ethanolic soution of amino thiol at 0 oC, followed by stirring for four hours at ambient temperature, gave the product as white powder in up to 75% yield. Thiazolidine 184 was prepared in the same manner, yielding a mixture of diastereomers (2S,4S) and (2R,4S) in a ratio of 76/24.

Both bicyclic thiazolidines 185 and 186 were obtained in reduced yields (up to 51% and 41%, respectively) compared to the previously synthesized ones. This time, the products did not precipitate from the refluxing reaction medium.

Maybe the most interesting ring formation was the synthesis of thiazolidine 187 employing one equivalent of paraformaldehyde in ethanol. Stirring thirty minutes at ambient temperature was followed by 30 minutes at 70 oC (144) furnishing 187 in up to 70% yield. The product once again precipitated from the reaction medium, making the isolation of the compound easy.

97

SNH2

+Cl-

5:2 acetone:2,2-DMP,reflux, 16h, 70%

NH3+Cl-

HS

SNH2

+Cl-

paraformaldehyde, 1eqEtOH, rt, 30 min +70oC, 30 min, 70%

SNH2

+Cl-

SNH2

+Cl- SNH2

+Cl-

SNH2

+Cl-

acetaldehyde,EtOH, 0 oC->rt, 4h,75%

cyclohexanone,reflux, 16h,51%

cyclopentanone,reflux, 16h,41%

isobutyradehyde,EtOH, 0 oC->rt, 16h,69%

Diast.mixture

Diast.mixture

182

181

183

187

186

184 185

Scheme 68.

Due to the ease of product isolation and storage thereafter in thiazolidine as well as most likely in oxazolidine syntheses one should always carefully consider whether hydrochlorides could be applied. In most of the synthetic applications, oxazolidine and thiazolidine rings are formed in order to protect the aminal and hydroxyl or thiol groups, the structural properties of the protecting group having seldom any implication for this main purpose. Thus, by replacing the most often used 2,2-gem-dimethyl moiety with a formaldehyde derivative one would certainly spare his or her time without missing the bare goal of protection itself.

98

Aminal protection. At this stage there was no particular reason to reintroduce the BOC-protective group. Thus, other aminal protective groups were considered. If a phenyl ring could be incorporated into the sulfide structure, the reaction monitoring as well as product separations would become easier due to the UV-chromophore which would then be incorporated.

Attempts at benzoylation and acetylation. Szarek et al. had successfully benzoylated 2,2-dimethyl-4(R)-carboxythiazolidine hydrochloride employing benzoyl chloride in 200 equivalents of pyridine (145). When conducted in chloroform using only two equivalents of pyridine the reaction had resulted in a racemic product.

The first attempt at benzoylation was made using an excess of benzoyl chloride (2.5 equivalents) in 200 eq. of pyridine, Scheme 69. The reaction resulted in six different products of which, after troublesome separation efforts with MPLC, none proved to be sulfide 183.

SNH2

+Cl- SN

Bz

1) BzCl, 1.2+1.3 eq pyridine, 200 eq., 10 oC->rt, 24h

NH

S

Bz

Bz

2) BzCl, 1.0 eqpyridine, 200 eq.,10 oC->rt, 6h

3) BzCl,1.1 eqDIPEA 2.1 eq.,CH2Cl2, rt

4) BzCl, 1.0 eqDIPEA 1.0 eq,CH2Cl2, rt

5) BzCl, 1.1 eqDIPEA 2.0 eq.,DMAP 0.2 eq, CH2Cl2, rt

SN

Ac

1) AcCl, 1.1 eq,DIPEA 2.1 eq,CH2Cl2, rt, decomp.after 1h

2) Ac2O, 1.0 eq,DIPEA1.1 eq,CH2Cl2, rt, no reaction in 24h,DMAP, no reaction,reflux->decomposition

182 188

189

190

Scheme 69.

Attempts with only one equivalent of benzoyl chloride, with a different base (DIPEA) and even a different catalyst (DMAP), all resulted in the same kind of failure. It seemed that, simultaneously with aminal benzoylation, a ring opening, followed by benzoylation of thiol was taking place (146). From this intractable mixture, the only definitely identified compound was the twice benzoylated amino thiolester 189.

Attempts at acetylation were conducted in CH2Cl2 employing DIPEA as a base. Using acetyl chloride, decomposition of thiazolidine 182 started after one hour. Latest at this stage it had to be accepted that no acid chlorides could be employed and milder acetic anhydride was decided to be used instead. The reaction was carried out in CH2Cl2 at ambient temperature employing DIPEA as a base. After 24 hours there were no signs of any reaction, not even after adding DMAP. Elevated temperatures (refluxing), in turn,

99

resulted in decomposition. Failures in both benzoylations and acetylations could well be explained by the facile ring opening � ring closure reactions followed by the esterification of the thiol moiety during the aminal protection reaction described later in page 101.

Attempts at BOC-protection. Since attempts at both benzoylation and acetylation proved unsuccessful tert-butoxycarbonylation (BOC) had to be considered once again. The standard procedure employing a slight excess of BOC-anhydride in CH2Cl2, triethyl amine as a base, resulted in an intractable product mixture, of which no 163 could be found, Scheme 70.

SNH2+Cl-

(BOC)2O, 1.05 eq.

TEA, 1.15 eq.CH2Cl2, 0 oC->rt

SN

BOC

(BOC)2O, 1.33 eq,DIPEA, 1.02 eq,

CH3CN, rt---> 50oC, 10 days, 70%,with DMAP->decomp.

182 163

Scheme 70.

This reaction is particularly difficult because the nitrogen of the starting thiazolidine 182 is very hindered, being bound to a tertiary and a secondary carbon. Secondly, thiazolidines substituted at 2-position are very susceptible to alkaline hydrolysis (147). The same problem was faced by Kemp and Carey (148) and they solved it by conducting the reaction in CH3CN without any catalysts and with practically no excess of base. Employing the same procedure, sulfide 163 was finally furnished. After ten days at 50 oC the first target sulfide could be separated (MPLC) as a clear liquid in 70% yield (132). In order to enhance the reaction rate, the reaction was even carried out employing DMAP as a catalyst. As anticipated, this resulted in decomposition. The ligands from 191 to 195 could now be furnished employing the same conditions, Scheme 71.

100

SNH2

+Cl-

SNH2

+Cl-

SNH2

+Cl-

SN

SN

SN

BOC

BOC

BOC

(BOC)2O, 1.33 eq

DIPEA, 1.02 eq,CH3CN, 28h, rt, 82%

(BOC)2O, 1.33 eq

DIPEA, 1.02 eq,CH3CN, 36h, rt, 94%

(BOC)2O, 2 eq

DIPEA, 1.02 eq,CH3CN, 24h, 50 oC, 98%

(BOC)2O, 2+2 eq

DIPEA, 1.02 eq,CH3CN, 10 days, 50 oC, 34%

(BOC)2O, 1.33+1 eq

DIPEA, 1.02 eq,CH3CN, 7 days, 50 oC, 79%

SNH2

+Cl-

SNH2

+Cl-

SN

SN

BOC

BOC

187 160

183 161

184 166

185 165

186 164 Scheme 71.

The second ligand prepared was sulfide 160. The dramatical influence of sterical

shielding or lack of it (on nitrogen) on the reaction rate and yield was now efficiently

101

demonstrated. The reaction proceeded practically to the end at 50 °C in 24 hours with almost quantitative yield (132). The product was purified with MPLC and isolated as a clear liquid.

The tert-butoxycarbonylation of both diastereomeric thiazolidine salts 183 and 184 resulted in single BOC-protected sulfide diastereomers 161 and 166, respectively. This was remarkable, because the separation of eventual diastereomers would surely have been difficult, maybe impossible. Diastereomeric mixtures could naturally not be employed as ligands in asymmetric target reactions. Even these sulfides were isolated as clear liquids after purification with MPLC. The yields and reaction times remained reasonable demonstrating again the influence of sterical shielding on nitrogen to the reaction rate.

For the same reason, the formation of sulfides 165 and 164 proceeded slowly (7 vs. 10 days). These spiro-sulfides were obtained in up to 79% and 34% yields, respectively. Unlike the other sulfides, ligand 165 is a solid.

cis-Diastereoselectivity. The phenomen behind the cis-selectivity is the facile ring opening-ring closure reactions (143,149). In Scheme 72, a conceivable mechanism presented originally by Györgydeák et al. (149d) for the acetylation of 2-phenylthiazolidine-4-carboxylic acid is depicted for the tert-butoxycarbonylation of sulfide 161.

SN

BOC

SNHS

NBOC

SNH

HSN

I cis II cis IIItrans IItrans III

Scheme 72.

The base-catalyzed isomerization of thiazolidines through Schiff-base intermediates (I) is a well-known process (149b). The preferential formation of cis-III is simply rationalized by assuming that step cis-II -> cis-III is much more faster than step trans-II -> trans-III.

2.3.2 L-tert-Leucine derived ligands

2.3.2.1 Synthesis of amino thiol

Having established the route towards L-valine derived amino thiol 181 it was easy to perform the same route (132) employing L-tert-leucine 191 as a chiral precursor instead.

102

The reactions proceeded very much in the same way than with the earlier route. The reduction of 191 gave, after Kugelrohr distillation, L-tert-leucinol 192 with slightly reduced yields (up to 60.5%) compared to L-valinol 176, Scheme 73.

HO2C

NH2 NH2

HO

NH

HS

BOC

NH

HO

BOC

NH

AcS

BOC

NH3+Cl-

HS

i ii

iii

ivv

191 192 193

194195196

Scheme 73. Reagents: i) LiAlH4, THF; ii) (BOC)2O, CH2Cl2, 45 min, rt; iii) DIAD, Ph3P, AcSH, THF; iv) KOH, MeOH, 30 min, rt; v) conc. HCl:MeOH, 1:1, reflux, 16h

Quantitative tert-butoxycarbonylation to 193 was followed by the conversion of the hydroxyl group to the thioacetal, furnishing 194 in up to 81% yield. This was in line with the equivalent L-valine derived compound, the purification process being equally hard and time consuming.

Ester hydrolysis proceeded smoothly giving quantitative yields. BOC-deprotection

carried out in a refluxing mixture of concentrated hydrochloric acid and methanol (1:1) finally gave the crude amino thiol hydrochloride salt 196 as a pale yellow solid in quantitative yields.

103

2.3.2.2 Thiazolidine ring formation

The condensation of amino thiol 196 with formaldehyde gave thiazolidine hydrochloride salt 197 with excellent yields (from 74% up to 94.4%), Scheme 74. Thiazolidine 198 was obtained as a mixture of (2S,4S) and (2R,4S) diastereomers in a ratio of 86/14 in agreement with literature results (150).

NH3+Cl-

HSSNH2

+Cl-

SNH2

+Cl-

SNH2

+Cl-5:2 acetone:2,2-DMP,

196197 199

198

paraformaldehyde, 1eq

EtOH, rt, 30 min;70 oC, 30 min, 94.4%

acetaldehyde,EtOH, 0 oC->rt, 4h, 74%

reflux, 16h, 67%

Scheme 74.

The yields of 198 varied between 70% and 74%. As the earlier thiazolidine hydrochloride salts also 2,2-dimethyl-4-tert-butyl-thiazolidine hydrochloride salt 199 was conveniently isolated as a white solid. Refluxing in acetone:2,2-DMP gave yields between 50% and 67%.

2.3.2.3 BOC-protection

The tert-butoxycarbonylation of 197 proceeded smoothly affording sulfide ligand 167 in 88% yield, Scheme 75.

104

SNH2

+Cl-

SNH2

+Cl-

SNH2

+Cl-

(BOC)2O, 1.33 eq

DIPEA, 1.02 eq,CH3CN, 48h, 50 oC, 88%

SN

(BOC)2O, 1.33 eq

DIPEA, 1.02 eq,CH3CN, 48h, rt, 90%

1) (BOC)2O, 1.33 eq +1 eq

DIPEA, 1.02 eq,CH3CN; 50 oC, 48h +

70 oC, 8 days

BOC

SN

BOC

SN

BOC

2) (BOC)2O, 1.33 eq +8 eq

DIPEA, 1.02 eq,CH3CN, 14 days,

70->90 oC

3)TMEDA 10 eq, t-BuLi, THF, -84 oC

(BOC)2O, 10 eq, THF, -84 oC

-> rt, 48h

197 167

198 168

199 151

Scheme 75. Single cis diastereomer 168 was achieved after the BOC-protection of the

diastereomeric thiazolidine 198. Purification with MPLC gave this chiral sulfide catalyst as a clear liquid in yields between 64% and 90%.

Attempts to synthesize sulfide 151 were started, with similar conditions employed as with the L-valine derived ligand of comparison (163). Two days at 50 oC, followed by eight days at 70 oC resulted in the partial decomposition of the starting material and, after tedious separations, sulfide 151 could not be found among the fractions. BOC-anhydride (2 x 1.33 eq) was added during the process due to its lability in higher temperatures. This

105

anhydride can be monitored with TLC, visualizing the plates with vanillin followed by cautious heating of the plate. The spot is visible in dark blue colour.

In the next experiment the temperature was elevated up to 90 cC employing a big excess of BOC-anhydride, other conditions being left unchanged. Two weeks of relentless refluxing afforded the same intractable mixture of remaining starting material and decomposition products.

To enhance the reaction, the amine moiety was deprotonated with tert-butyllithium followed by the addition of resulting naked anion to a large excess of BOC-anhydride (10 eq) in THF at �84 oC. The mixture was gradually warmed up to ambient temperature and stirred for 48 hours. The slight decomposition of the starting thiazolidine 199 was the only detectable change, ligand 151 remaining an insuperable task.

2.3.3 D-Penicillamine derived ligands

D-penicillamine 200 has the gem-dimethyl moiety needed to affect the aldehyde approach incorporated in the aminoacid sceleton. Probably due to its relatively high cost it has been rarely applied in organic syntheses. Gonzáles et al. (149f) have developed a simple and efficient way to condensate (R)-cysteine with paraformaldehyde in one pot to bicyclic thiazolidine derivatives.

The method was employed by Martens et al. (151) when preparing the bicyclic thiazolidine derivative 201, Scheme 76. Here, the carboxyl group of the parent α-amino acid is activated and the amino group is protected at the same time.

The bicyclic lactone was reproducibly prepared with quantitative yield in seven days at ambient temperature. The separation proceeded smoothly through a short silica column eluting with CH2Cl2. This bicyclic thiazolidine 201 was later employed as a ligand in the asymmetric Corey-Chaykovsky reaction.

The treatment of bicycle 201 with methyllithium in anhydrous THF afforded thiazolidine alcohol 202, a compound, which during the work up proved to cause sudden nausea and dizziness leading to evacuation of the laboratory.

106

HSNH2

OH

O

S NO

O

S NHOH

S NBOC

i ii

200 201 202

171

Scheme 76. Reagents: i) paraformaldehyde, MgSO4, CH2Cl2, rt, 7 days; ii) MeLi, THF, -30 °C -> rt, 16 h.

Simultaneously, insuperable problems (131) were faced in converting the tertiary

hydroxyl group by hydrogenation, esterification as well as etherification in the synthetic efforts aiming at ligand 172, Figure 10, page 94. Thus, it was an easy decision to drop out ligand 171 from the target compounds.

For the same reason, the synthetic work towards L-cysteine derived target sulfide 174 (Figure 10, page 94) was interrupted. Bicyclic L-cysteine derived ligand 173 was prepared and employed later as a chiral catalyst in the asymmetric epoxidation process (131).

2.4. Ligand testing

2.4.1. Model reaction

As already mentioned in chapter 2.1. the convincing work performed by Aggarwal et al. (73) made us choose their catalytic version of the Corey-Chaykovsky reaction as our model reaction, Scheme 77.

107

O R'

RS

R' S

RCHO N2CHR'

Rh=CHR'N2

Rh2(OAc)4

Cu=CHR'or

orCu(acac)2

Scheme 77. The literature conditions (70) were mimicked as closely as possible in order to make

the results directly comparable to those of reported catalysts. The reactions were conducted employing benzaldehyde (usually 1 mmol) as an aldehyde and Rh2(OAc)4 as a metal catalyst with a few exceptions where Cu(acac)2 was employed. All the reactions were conducted using phenyl diazomethane as the choice of diazo compound even if some information of the genaration of the diazo compound in situ was available already in the summer of 1999 (152).

2.4.2 Preparation of phenyl diazomethane

The phenyl diazomethane 68 was repeatedly prepared by the method published by Overberger and Anselme (59), Scheme 78.

108

S

O

O

N

H

S

O

O

N

NO

N2

i

ii

73 74

68

iii

O

O

ClNH2

75

76

Scheme 78. Reagents: i) pyridine; ii) Ac2O/AcOH, NaNO2; iii) NaOMe, MTBE/MeOH, reflux 30 min.

After recrystallization from ethanol, sulfonamide 75 was obtained as a pale yellow

solid in up to 88% yield. The nitrosation of 75 afforded in our hands the rather unstable N-nitroso-N-benzyl-p-toluenesulfonamide 76 as pastel yellow needles in up to 84% yield. Even when stored in dark and under argon atmosphere this nitroso compound proved rather unstable, repeatedly decomposing rapidly after approximately three months. Thus, it had to be prepared regularly.

Phenyl diazomethane 68 was always prepared right before their employment in Corey-Chaykovsky epoxidations. Reportedly potentially explosive, great care was taken when preparing and handling this compound. Still, one explosion occured when generating the diazo compound by refluxing the ethereal solution of 76 and sodium methoxide.

2.4.3 Employment of dimethyl sulfide as a mediator

As it was necessary to learn to conduct the epoxidations, we decided to repeat some of reactions presented by Aggarwal et al. (53,70) The first sulfide to be employed was dimethyl sulfide 72, Scheme 79 (53).

109

O

HS Rh2(OAc)4

PhCHN2, 2 mmol

CH2Cl2, 17h, rt

0.5 mmol 0.01 mmol1 mmol

O

H

HOH H

9a 20

Scheme 79. The reaction was conducted at ambient temperature and ethereal phenyl diazomethane

solution was added slowly with a syringe pump during 17 hours. Both the flask and the syringe were wrapped with tin paper in order to prevent too early decomposition of the light sensitive diazo compound. For the same reason it was reasonable to use teflon tubing instead of metal needles. The products were purified with MPLC one hour after finishing the addition of the diazo compound, a protocol employed hereafter.

The literature results were reproduced, the yield being evenslightly improved (78% vs 70%, trans isomer). Our trans:cis ratio of 89:11 was well in line with 88:12 published by Aggarwal et al. The small changes are quite understandable because the diastereomers are separated quantitatively and the scale of the reaction is rather small. As expected, HPLC studies revealed the trans isomer being formed as a racemate.

2.4.4 Employment of Aggarwal�s chiral sulfide 84a as a ligand

In order to find out whether we had the competence to reproduce high enantioselectivities and measure them reliably, it was of utmost importance to get a sample of ligand already employed in catalytic cycle. Thus, the samples of sulfide 84a and sublimated Cu(acac)2 contributed by professor Aggarwal were truly appreciated. The reaction was conducted mimicking the published conditions (70), Scheme 80.

O

HCu(acac)2

PhCHN2, 1.5 mmol

CH2Cl2, 3h, rt

0.2 mmol 0.05 mmol1 mmol

O

H

H

9a

SO

84a

Scheme 80.

110

The optical yield was reproducible, 94% vs 93% (no cis detected), but the chemical yield remained lower (30% vs 71%). There was a significant formation of trans-stilbene, which might be explained by the metal needles employed that time as well as by the unsteady addition of phenyl diazomethane.

2.4.5 Employment of own ligands

After testings with dimethyl sulfide 72 and 84a it was time to test our first own ligand, sulfide 163. In the first attempt Rh2(OAc)4 was employed as a metal catalyst. The reaction proceeded yielding (S,S)-trans-stilbene oxide in 16% chemical and in 90% optical yield (132), Table 27. No cis-epoxide was detected. The yield was well in line with Aggarwal�s structurally corresponding catalyst 84i. In the next two attempts freshly sublimed Cu(acac)2 was employed as a metal catalyst. The reactions resulted in a racemic product indicating the partial decomposition of chiral sulfide 163. Therefore, all the following epoxidations were conducted employing Rh2(OAc)4 as a metal catalyst.

As expected, the control compound 160 yielded the product with the same absolute configuration but with low enantioselectivity, underlining the crucial role of the gem-dimethyl function. (S,S)-trans-stilbene oxide was obtained in 62% chemical and in 19% optical yield and trans:cis ratio of 92:8 (132).

The introduction of one methyl group into the ketal function resulted in enhanced enantioselectivity. Employing cis-diastereomer 161 as a chiral catalyst gave (S,S)-trans-stilbene oxide with 52% enantioselectivity. No cis-epoxide was formed and trans-form was obtained in 61% yield.

Increasing the sterical bulkiness from methyl to iso-propyl (161 to 166) gave further enhanced selectivity. The enantioselectivity rised up to 77%, the chemical yield being acceptable 52%.

The structural rigidity was further increased by incorporating spiro-moieties in the sulfide structures. The increased sterical shielding presumably slowed down the ylide formation enhancing thus the competing reactions.

111

Table 27. Catalytic asymmetric epoxidations of benzaldehyde employing L-valine derived ligands 160, 161, 166, 163,164 and 165.

Ligand Metal catalyst Yield % ee %a trans:cis

SN

BOC 160 S

N

Rh2(OAc)4

62

19

92:8

SN

BOC161

SN

Rh2(OAc)4

61

54

SN

BOC

166

SN

Rh2(OAc)4

52

77

SN

BOC163

SN

Rh2(OAc)4

Cu(acac)2

16

-

90

SN

BOC

164

SN

Rh2(OAc)4

-

SN

BOC

165

SN

Rh2(OAc)4

5

>90

aEnantiomeric excesses were determined by chiral HPLC using a chiralcel OD column. On one exceptional occasion, when employing sulfide 165, (S,S)-trans-stilbene oxide

was obtained in high optical yield. Due to the low chemical yield there were difficulties to

112

get absolutely reliable HPLC-data about the exact selectivity. In any case, it was well over 90%. The reaction was repeated four times resulting in a racemic (partial ring opening) product each time. Even a new batch of Rh2(OAc)4 was purchased and tested to rule out the possibility of the �moulding� of the metal catalyst.

Two attempts were made employing the structurally very similar spiro-sulfide 164 resulting, as feared, in racemic trans-stilbene oxide indicating once again partial ring opening.

At last, only two L-tert-leucine derived sulfides were fully prepared and tested. Ligand 167 lacking sterical shielding directing the aldehyde approach, gave, as expected, trans-stilbene oxide with the same absolute configuration as the earlier ones. The enantioselectivity was slightly enhanced compared to corresponding L-valine derived sulfide 160, Table 28.

Table 28. Catalytic asymmetric epoxidations of benzaldehyde employing L-tert-leucine derived ligands 167and 168 and D-penicillamine derived ligand 170.

Ligand Metal catalyst Yield % ee %a trans:cis

SN

BOC 167 S

N

Rh2(OAc)4

60

26

93:7

SN

BOC 168

SN

Rh2(OAc)4

49

52

S NO

O

170 S

NOO

Rh2(OAc)4

41

34

aEnantiomeric excesses were determined by chiral HPLC using a chiralcel OD column. The optical yield for (S,S)-trans-stilbene oxide was 26% and trans:cis ratio 93:7. The

next sulfide catalyst, thiazolidine derivative 168 gave lower selectivity than expected (repeated with exactly the same results) yielding trans epoxide in only 52% enantioselectivity. Compared to the corresponding L-valine derived ligand 161 even the chemical yield was somewhat reduced.

113

The only D-penicillamine derived ligand 170 gave repeatedly (S,S)-trans-stilbene oxide with low 34% ee chemical yield being at its best 41%. The catalyst itself sustained well all three attempts without any ring opening occurring.

2.5 Ligand evaluation

2.5.1 Evaluation of conformational properties

The design of the target sulfides was based on the ring conformation in which the alkyl side chain (R = iso-propyl, tert-butyl) has a pseudoaxial orientation. It was important to confirm the conformational preference experimentally. Thus, Ph.D Mika Lindvall calculated the vicinal coupling constants between H4 and H5/H5� in ligand 163 (R = iso-propyl) and compared those to the experimental ones (1.1 and 6.0 Hz at rt in (CDCl2)2) (130,132), Figure 11.

N

S

N

S

84° (1.1 Hz)

-39° (6.6 Hz) 33°(6.8 Hz)

155°(10.4 Hz)

H4

H5

H5'

H4

H5

H5'

Figure 11. Pseudoaxial (left) and pseudoequatorial (right) conformations of 163 with the calculated coupling constants. The BOC group has been omitted for clarity.

Comparison of the calculated (130) and experimental coupling constants for the two

conformers suggested that only the ring conformation with iso-propyl pseudoaxial is consistent with the experimental values (132). The pseudoaxial ring conformation was thus also implicated by experiment.

2.5.2 Asymmetric induction

The asymmetric induction employing chiral sulfide 163 leading to (S,S)-trans-stilbene oxide is depicted in Schemes 91 and 92. The two ring conformers of 163 are expected to lead to enantiomeric products. In the pseudoaxial conformation of 163 (Scheme 90, left)

114

the iso-propyl group extends over the pseudoaxial electron pair of the sulfur preventing its reaction with electrophiles. The ylide derived from the remaining reactive sulfur electron pair can adopt two conformations (Figure 12, 1 and 2). Since the anti ylide 2 suffers from 1,3 interactions between the phenyl and methyl groups and even between the phenyl and pseudoaxial H5�, the only possible ylide conformation resulting from the pseudoaxial conformation of 163 is 1 (syn), Figure 12 (132).

N SBOC

SN

BOC

N SBOC

SN

BOC

H

1 2

3 4

Figure 12. In the corresponding pseudoequatorial conformation of 163 the iso-propyl moiety is

pseudoequatorial leaving both sulfur electron pairs reactive. The resulting two different ylide conformations 3 and 4 lead to opposite enantiomeric products.

In syn ylide 1 the aldehyde can approach either face of the ylide, but the si face is more accessible as the re face is hindered by the gem-dimethyl moiety leading to the formation of (S,S)-isomer, Scheme 81. The BOC group has been obmitted for clarity.

115

NS

O

H

Si face favouredO Ph

Ph

9a (S,S)

NS

163

Scheme 81. As expected, increase in the sterical bulkiness in L-valine derived ligands led to

enhanced enantioselectivities, Figure 13. The ring pseudorotation decreases from left to right, sulfide 163 giving even better face selectivity than sulfide 166.

SN

SN

SN

SN

SN

SN

SN

< < < <

<

!!

160 161 166 163 165

167 168

Figure 13. The replacement of the sulfur electron pair shielding the iso-propyl group with the

bulkier tert-butyl moiety (160 -> 167) freezes somewhat the ring pseudorotation resulting in slightly enhanced enantioselectivity (19% -> 26%). Therefore, the practically same selectivities (54 % vs 52%) obtained with sulfides 161 and 168 were a little surprising. The explanation might be the possible interaction between the ketal methyl and tert-butyl moiety resulting in somewhat increased pseudorotation and, thus, reduced selectivity.

The importance of ring rigidity was strongly demonstrated when comparing the two bicyclic chiral ligands 170 and 173, Figure 14 (131). One could easily assume that the gem-dimethyl moiety incorporated in the D-penicillamine derived 170 would enhance the enantioselectivity when compared to sulfide 173 which is lacking this wall affecting the aldehyde approach.

116

S NO

O

S NO

O

S

NOO

S

NO O

III III

170 173

34% (S,S) 54% (R,R) Figure 14.

Here, however, the gem-dimethyl moiety seemed to decrease the ring rigidity leading

to reduced selectivity.

2.6 Concluding remarks New ligand families to be employed in catalytic asymmetric epoxidations were designed, synthesized, tested and evaluated. The computer-assisted design was made in close cooperation with Ph.D Mika Lindvall, allowing the full design cycle to be operated. The designed sulfides are accessible from amino acids allowing the preparation of opposite enantiomeric products in the reactions exploitable, and are easily tunable and can, if necessary, be linked to solid support from their aminal moiety.

The synthetic routes for ligand preparation were developed and nine ligands of our own were completely synthesized and applied in the model reaction. Besides, laborious attempts were made in order to prepare, from the inductive point of view, the most promising ligand 151. The enantioselectivities obtained in catalytic Corey-Chaykovsky reactions gave valuable and logical information about the asymmetric induction when employing differently tuned thiazolidine derivatives. Thus, it was a quite an easy task to determine the mechanistic rationale of these asymmetric ylide reactions.

The ligands and their preparation method were patented (153) and a part of the results have already been published (132).

When comparing tested thiazolidine ligands to Aggarwal�s sulfides it seems that camphor derived ligands have sulfur moiety incorporated in a more rigid ring system restricting thus pseudorotation, and giving a single ylide conformation as a result. Aggarwal et al. did not achieve enantiospecifity with their ligands due to the somewhat

117

deficient ylide face selectivity. Thiazolidine derivatives 163 (90% ee) and 165 (>90% ee) have, in turn, compared to Aggarwal�s sulfide 84a, better face selectivity but have, especially ligand 163, sulfur incorporated in a less rigid ring system, resulting in reduced selectivities. With this information in hand it is again easier to go on in the design cycle towards more efficient sulfides.

118

3 Experimental

THF was distilled prior to use from sodium/benzophenone, MeCN from phosphorus pentoxide, MeOH from magnesium methoxide and CH2Cl2 from CaH2. All other solvents and reagents, unless otherwise noted, were used as obtained from the supplier without further purification. All air and moisture sensitive reactions were carried out under positive argon atmosphere with magnetic stirring. Melting points were measured with Gallenkamp melting point apparatus MFB-595 and are uncorrected. NMR spectra were determined on Bruker AM200 (1H 200.13 MHz, 13C 50.32 MHz). Chemical shifts are reported in ppm (δ) with respect to scale calibrated to solvent�s residual signal.

Unless aqueous, all reactions were carried out under protective atmosphere (Ar). Temperatures refer to bath temperatures unless otherwise noted. Organic extracts were first treated with brine, dried over Na2SO4, filtered and evaporated with a Büchi rotary evaporator (water aspirator) followed by static evaporation with an oil pump. The Kieselgel 60 F254 impregnated aluminum plates were used for analytical TLC. The TLC plates were visualized with UV (λ=254) and either phosphomolybdic acid in 90% EtOH (10 mg/100 ml), ninhydrin/glacial acetic acid/EtOH (1 g/0.1 ml/100 ml) or with vanillin/H2SO4/EtOH (12 g/5 ml/100 ml). The chromatographic separations were done with MPLC using Silica gel 60 (E. Merck) as the stationary phase. Chiral HPLC chromatograms were measured using the following columns: Daicel chiralcel OD 25 cm x 0.46 cm with Daicel chiralcel OD 5 cm x 0.46 cm precolumn. In all cases a racemic sample was run to check the retention times of the enantiomers.

The mass spectra were measured by the University of Oulu mass spectrometry laboratory on a Kratos 80 mass instrument. Elemental analyses were performed by the University of Oulu Trace Element Laboratory. Optical rotations were determined with Perkin-Elmer 243 B polarimeter (c = g/100 mL).

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3.1 Preparation of amino thiols

3.1.1 L-valinol (176)

NH2

HOOC

NH2

HO

L-valine 176

L-valine 175 (9.92 g, 84.5 mmol, 100 mol %) was carefully added to a stirred suspension of lithium aluminium hydride (4.81 g, 126.8 mmol, 150 mol %) in 110 ml of THF at 0 °C. The reaction mixture was allowed to warm up to room temperature. After the most vigorous reaction had settled the reaction mixture was refluxed for 16 hours. After cooling to ambient temperature 80 ml of Et2O was added, the reaction was very cautiously quenched with water (2.0 ml, 110 mmol, 130 mol %) and the resulting mixture was stirred for 2 hours. Slightly greyish alumina was removed by filtration and washed with Et2O. The filtrate was evaporated to dryness and the yellowish crude product was purified by Kugelrohr distillation (58 °C, 0.11 torr) to yield 176 (6.10 g, 59.2 mmol, 70%) as a white solid. mp. 29-31 °C, literature (154) mp. 29-31 °C. [α]D

20 = +12.4 (c 0.93, MeOH). The 1H NMR spectrum was identical to literature data (154).

3.1.2 N-(tert-butoxycarbonyl)-L-valinol (177)

NH2 HNHO HO

176 177BOC

L-valinol 176 (5.00 g, 48.5 mmol, 100 mol %) was dissolved in 18 ml of CH2Cl2 and the mixture was cooled to 0 °C. To this solution was carefully added di-tert-butyldicarbonate (10.07 g, 46.2 mmol, 95 mol %) in 7 ml of CH2Cl2. The reaction mixture was allowed to warm up to room temperature and stirred for 45 minutes. The reaction mixture was washed with 3 x 30 ml of 20% citric acid and once with 40ml of brine. The organic layer was evaporated to dryness to yield pure 177 (9.85 g, 48.5 mmol, quant.) as a yellow, viscous oil. Rf (1:1 MeOH:EtOAc) = 0.40. [α]D

20 = -15.2 (c 1.0, MeOH). The 1H NMR spectrum was identical to literature data (155).

120

3.1.3 (S)-1-thio-acetyl-2-amino-N-(tert-butoxycarbonyl)-3-methyl-butane (178)

HNHO

HNAcS

177 178

BOC BOC

Triphenylphosphine (17.69 g, 67.4 mmol, 200 mol %) was dissolved in 100 ml of THF and the solution was cooled to 0 °C. Di-isopropyl azodicarboxylate (14.0 ml, 67.4 mmol, 200 mol %) was added and the reaction mixture was stirred for 30 minutes. A white precipitate formed. BOC-L-valinol 177 (6.85 g, 33.7 mmol, 100 mol %) and thiolacetic acid (5.0 ml, 67.4 mmol, 200 mol %) in 50 ml of THF was added dropwise over 15 minutes and the mixture was stirred for 1 hour at 0 °C and 4 hours at ambient temperature. The resulting yellow solution was evaporated to dryness and dissolved in Et2O. The precipitated triphenylphosphine oxide was filtered off, and the filtrate was evaporated to dryness. The precipitation procedure was repeated several times. The crude product was purified by MPLC (12.5% MTBE in hexanes) to yield 178 (7.13 g, 27.3 mmol, 81%) as a white solid. mp. 59-60 °C. Rf (1:1 MeOH:EtOAc) = 0.40. [α]D

20 = +71.2 (c 1.0, MeOH). The 1H NMR spectrum was identical to literature data (155).

3.1.4 (S)-1-thio-2-amino-N-(tert-butoxycarbonyl)-3-methyl-butane (179)

HNAcS

HNHS

178 179BOC BOC

Thiol acetate 178 (1.50 g, 5.74 mmol, 100 mol %) and KOH (644 mg, 11.5 mmol, 200 mol %) were dissolved in 10 ml of methanol. The solution was stirred for 30 minutes at ambient temperature after which the reaction was quickly quenched with 50% citric acid (25 ml). Dichloromethane (30ml) was added and the resulting organic layer was washed with 2 x 20 ml of 20% citric acid and once with 30 ml of brine, dried and evaporated to dryness to yield 179 (1.26 g, 5.74 mmol, quant.) as a white solid. mp. 48-49 °C. Rf (33% MTBE in hexanes) = 0.38. [α]D

20 = +2.2 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.89 (d, 3H, J = 6.8 Hz), 0.90 (d, 3H, J = 6.8 Hz), 1.28 (t, 1H, J = 8.4 Hz), 1.43 (s, 9H), 1.85 (app. septet, 1H, J = 6.8 Hz), 2.66 (dd, 2H, J = 8.3 Hz, 5.4 Hz), 3.49 (m, 1H), 4.61 (d, 1H, J = 7.9 Hz). 13C NMR (CDCl3) δ 18.0, 19.4, 27.6, 28.3, 30.2, 57.1, 79.3, 155.7. HRMS m/z calcd. for C9H18NO2S (M-CH3)+ 204.1058, found 204.1091.

121

3.1.5 (S)-1-thio-2-amino-3-methyl-butane hydrochloride salt (180)

NH3+Cl-

HSHN

HS

180179BOC

Thiol 179 (1.32 g, 6.02 mmol, 100 mol %) was dissolved in 10 ml of methanol and 10 ml of concentrated HCl (37% aqueous solution) was added. The reaction mixture was refluxed for 8 hours. Evaporation to dryness followed by evaporation from a suspension with toluene yielded 180 (915 mg, 5.87 mmol, 98%) as a semi-solid mass. [α]D

20 = +34.2 (c 1.0, MeOH). The substance was used for subsequent reactions without further purification. HRMS m/z calcd. for C11H23NO3 (M)+ 120.0847, found 120.0867.

3.1.6 L-tert-leucinol (192)

NH2

HOOC

NH2

HO

L-tert-leucine 192

L-tert-leucine 191 (22.17 g, 169.0 mmol, 100 mol %) was carefully added to a stirred suspension of lithium aluminium hydride (9,8 g, 258.2 mmol, 153 mol %) in 250 ml of THF at 0 °C. The reaction mixture was allowed to warm up to room temperature. After the most vigorous reaction had settled the reaction mixture was refluxed for 16 hours. After cooling to ambient temperature 160 ml of Et2O was added, the reaction was very cautiously quenched with water (4.0 ml, 220 mmol, 260 mol %) and the resulting mixture was stirred for 2 hours. Slightly greyish alumina was removed by filtration and washed with Et2O. The filtrate was evaporated to dryness and the yellowish crude product was purified by Kugelrohr distillation (75 °C, 0.45 torr) to yield 192 (11.98 g, 102.22 mmol, 70%) as a crystal solid. mp. 33-35 °C, literature (156) mp. 33-35 °C. [α]D

20 = +33.8 (c 0.93, MeOH). The 1H NMR spectrum was identical to literature data (157). HRMS m/z calcd. for C6H16NO (M)+ 118.1232, found 118.1194.

122

3.1.7 N-(tert-butoxycarbonyl)-L-tert-leucinol (193)

NH2 HNHO HO

192 193BOC

L-tert-leucinol 192 (5.72 g, 48.81 mmol, 100 mol %) was dissolved in 20 ml of CH2Cl2 and the mixture was cooled to 0 °C. To this solution was carefully added di-tert-butyldicarbonate (10.15 g, 46.49 mmol, 100 mol %) in 15 ml of CH2Cl2. The reaction mixture was allowed to warm up to room temperature and stirred for 45 minutes. The reaction mixture was washed with 3 x 30 ml of 20% citric acid and once with 40ml of brine. The organic layer was evaporated to dryness to yield pure 193 (10.59 g, 48.73 mmol, quant.) as white solid. Rf (1:1 MeOH:EtOAc) = 0.71. mp. 113-144 °C, literature (158) mp. 113-114 °C.[α]D

20 = +9.0 (c 1.0, MeOH). The 1H NMR spectrum was identical to literature data (159). HRMS m/z calcd. for C11H23NO3 (M)+ 218.1756, found 218.1724.

3.1.8 (S)-1-thio-acetyl-2-amino-N-(tert-butoxycarbonyl)-3,3-dimethyl-butane (194)

HNHO

HNAcS

193 194

BOC BOC

Triphenylphosphine (17.68 g, 67.4 mmol, 200 mol %) was dissolved in 100 ml of THF and the solution was cooled to 0 °C. Di-isopropyl azodicarboxylate (14.04 ml, 67.4 mmol, 200 mol %) was added and the reaction mixture was stirred for 30 minutes. A white precipitate formed. BOC-L-tert-leucinol 193 (7.32 g, 33.7 mmol, 100 mol %) and thiolacetic acid (5.02 ml, 67.4 mmol, 200 mol %) in 50 ml of THF was added dropwise over 15 minutes and the mixture was stirred for 1 hour at 0 °C and 4 hours at ambient temperature. The resulting yellow solution was evaporated to dryness and dissolved in Et2O. The precipitated triphenylphosphine oxide was filtered off, and the filtrate was evaporated to dryness. The precipitation procedure was repeated several times. The crude product was purified by MPLC (11% MTBE in hexanes) to yield 194 (7.52 g, 27.3 mmol, 81%) as a white solid. mp. 72-73 °C. Rf (1:1 MTBE:hexanes) = 0.41. [α]D

20 = +103.6 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.92 (s, 9H), 1.43 (s, 9H), 2.33 (s, 3H), 2.76-2.94 (dd, 1H, J = 13.8 Hz, 2.2 Hz), 3.01-3.15 (dd, 1H, J = 13.8 Hz, 3.3 Hz), 3.40-3.57 (td, 1H, J =

123

13.6 Hz, 3.2 Hz), 4.4 (br d, 1H). 13C NMR (CDCl3) δ 27.2, 27.3, 29.4, 35.8, 79.3, 79.5, 156.5. HRMS m/z calcd. for C13H25NO3S (M)+ 276.1633, found 276.1654.

3.1.9 (S)-1-thio-2-amino-N-(tert-butoxycarbonyl)-3-methyl-butane (195)

HNAcS

HNHS

194 195

BOC BOC

Thiol acetate 194 (2.50 g, 9.08 mmol, 100 mol %) and KOH (1.02 g, 18.16 mmol, 200 mol %) were dissolved in 20 ml of methanol. The solution was stirred for 30 minutes at ambient temperature after which the reaction was quickly quenched with 50% citric acid (30 ml). Dichloromethane (30ml) was added and the resulting organic layer was washed with 2 x 20 ml of 20% citric acid and once with 30 ml of brine, dried and evaporated to dryness to yield 195 (2.12 g, 9.08 mmol, quant.) as a white solid. mp. 104-105 °C. Rf (25% MTBE in hexanes) = 0.36. [α]D

20 = +103.6 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.89 (s, 9H), 1.43 (s, 9H), 2.32 (qd, 1H, J = 10.7 Hz, 7.3 Hz), 2.83 (dd, 1H, J = 8.3 Hz, 3.1 Hz), 3.48 (td, 1H, J = 10.7 Hz, 3.1 Hz). 13C NMR (CDCl3) δ 26.7, 26.8, 28.8, 35.8, 59.5, 62.0, 79.5, 156.6. HRMS m/z calcd. for C11H23NO2S (M)+ 234.1528, found 234.1543.

3.1.10 (S)-1-thio-2-amino-3,3-dimethyl-butane hydrochloride salt (196)

NH3+Cl-

HSHN

HS

196195BOC

Thiol 195 (2.02 g, 8.66 mmol, 100 mol %) was dissolved in 15 ml of methanol and 15 ml of concentrated HCl (37% aqueous solution) was added. The reaction mixture was refluxed for 12 hours. Evaporation to dryness followed by evaporation from a suspension with toluene yielded 196 (1,59 g, 9.37 mmol, 108%) as a semi-solid mass. The substance was used for subsequent reactions without further purification. [α]D

20 = +98.5 (c 1.0, MeOH). HRMS m/z calcd. for C6H16NO2S (M)+ 134.1004, found 134.0976.

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3.2 Preparation of thiazolidine hydrochloride salts

3.2.1 (S)-2,2-dimethyl-4-isopropyl-thiazolidine hydrochloride salt (182)

NH3+Cl-

HS

181 182

S NH2+Cl-

Thiol hydrochloride salt 181 (915 mg, 5.88 mmol, 100 mol %) was dissolved in 25 ml of acetone and 10 ml of 2,2-dimethoxypropane was added. The mixture was refluxed for 12 hours, with thiazolidine hydrochloride salt 182 gradually precipitating from the reaction medium. The crude product was filtered and washed several times with acetone to yield 15 (802 mg, 4.10 mmol, 70%) as a white solid. mp. 220-223 °C. Rf (25% MTBE in hexanes) = 0.35. [α]D

20 = +30.8 (c 1.0, MeOH). 1H NMR (CD3OD) δ 1.09 (d, 3H, J = 6.6 Hz), 1.16 (d, 3H, J = 6.6 Hz), 1.81 (s, 3H), 1.84 (s, 3H), 2.05 (m, 1H), 3.15 (dd, 1H, J = 11.5 Hz, 9.2 Hz), 3.57 (dd, 1H, J = 11.5 Hz, 7.3 Hz), 3.83 (m, 1H). 13C NMR (CD3OD) δ 20.0, 21.0, 27.6, 29.2, 32.6, 34.3, 69.4, 73.2. HRMS m/z calcd. for C8H17NS (M)+ 159.1082, found 159.1121. Anal. calcd. for C8H18ClNS C 49.08, H 9.27, Cl 18.11, N 7.16, S 16.38; found C 49.16, H 9.26, N 7.34, S 16.68.

3.2.2 (S)-2-methyl-4-isopropyl-thiazolidine hydrochloride salt (183)

NH3+Cl-

HS

181 183

S NH2+Cl-

Thiol hydrochloride salt 181 (804 mg, 5.16 mmol, 100 mol %) was dissolved in 5 ml of ethanol and 6 ml of acetaldehyde was added at 0 °C. The mixture was gradually warmed up to ambient temperature and stirred for 4 hours, with thiazolidine hydrochloride salt 183 gradually precipitating from the reaction medium. The crude product was filtered and washed several times with acetone to yield 183 (565 mg, 3.89 mmol, 75%) as a white solid. mp. 199-202 °C. Rf (25% MTBE in hexanes) = 0.36. [α]D

20 = +1.62 (c 1.0, MeOH). 1H NMR (CDCl3) δ. 0.96 (d, 3H, J = 6.7 Hz), 1.05 (d, 3H, J = 6,7 Hz), 1.42 (d, 3H, J = 6.1 Hz, minor diastereomer), 1.52 (d, 3H, J = 6.1 Hz, major diastereomer),1.75 (septet, 1H, J = 6.9 Hz) 2.55 (q, 1H, J = 9.6 Hz), 2.85 (qd, 1H, J = 9.9 Hz, 7.5 Hz), 3.05 (dd, 1H, J = 9.9 Hz, 5.8 Hz), 4.50 (q, 1H, J = 6.0Hz, major diastereomer), 4.65 (q, 1H, J = 6.0Hz, minor

125

diastereomer . 13C NMR (CDCl3) δ 20.2, 20.4, 21.2, 21.5, 21.7, 25.1, 30.1 (minor), 32.7 (major), 39.2 (minor), 39.8 (major), 64.9 (minor), 66.2 (major), 69.9 (minor), 72.8 (major). HRMS m/z calcd. for C7H16NS (M)+ 146.1003, found 146.0092.

3.2.3 (S)-2-isopropyl-4-isopropyl-thiazolidine hydrochloride salt (184)

NH3+Cl-

HS

181 184

S NH2+Cl-

Thiol hydrochloride salt 181 (600 mg, 3.84 mmol, 100 mol %) was dissolved in 5 ml of ethanol and 6 ml of iso-butyraldehyde was added at 0 °C. The mixture warmed gradually up to ambient temperature and stirred for 16 hours, with thiazolidine hydrochloride salt 184 gradually precipitating from the reaction medium. The crude product was filtered and washed several times with acetone to yield 184 (554 mg, 2.65 mmol, 69%) as a white solid. mp. 149-155 °C. Rf (25% MTBE in hexanes) = 0.35. [α]D

20 = +44.4 (c 1.0, MeOH). 1H NMR (CDCl3) δ. 1.05 (m, 12H), 1.75 (sept. 1H, J = 6,7 Hz), 1.85 (sept. 1H, J = 6,7 Hz), 2.55 (qd, 1H, J = 9.8 Hz), 2.90 (m, 1H, J = 6.4 Hz), 3.05 (dd, 1H, J = 9.9 Hz, 5.8 Hz), 4.22 (d, 1H, J = 6.7Hz, minor diastereomer), 4.37 (d, 1H, J = 6.7Hz, major diastereomer). 13C NMR (CDCl3) δ 18.8, 19.8 ,20.1, 20.5, 20.6, 21.1, 21.2, 30.0, 31.8, 32.7, 34.1, 37.6, 58.8, 70.5, 72.4. HRMS m/z calcd. for C9H20NS (M)+ 174.1316, found 174.1304.

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3.2.4 (S)-2-cyclohexyl-4-isopropyl-thiazolidine hydrochloride salt (185)

NH3+Cl-

HS

181 185

S NH2+Cl-

Thiol hydrochloride salt 181 (332 mg, 2.13 mmol, 100 mol %) was dissolved in 15 ml of cyclohexane. The mixture was refluxed for 16 hours and thiazolidine hydrochloride salt 186 precipitated from the reaction medium after cooling to ambient temperature. The crude product was filtered and washed several times with acetone to yield 185 (240 mg, 1.01 mmol, 51%) as a white solid. mp. 233-235 °C. Rf (25% MTBE in hexanes) = 0.34. [α]D

20 = +25.5 (c 1.0, MeOH). 1H NMR (CD3OD) δ 1.08 (d, 3H, J = 6.7 Hz), 1.19 (d, 3H, J = 6.7 Hz), 1.79 (m, 6H), 3.06 (dd, 1H, J = 11.5 Hz, 9.7 Hz), 3.40 (dd, 1H, J = 11.5 Hz, 6.9 Hz), 3.80 (trd, 1H, J = 16.6 Hz, 9.7 Hz) 13C NMR (CD3OD) δ 19.1, 20.1, 23.2, 24.6, 24.9, 31.2, 32.3, 36.7, 36.9, 67.5, 77.6. HRMS m/z calcd. for C11H22NS (M)+ 200.1498, found 200.1511.

3.2.5 (S)-2-cyclopentyl-4-isopropyl-thiazolidine hydrochloride salt (186)

NH3+Cl-

HS

181 186

S NH2+Cl-

Thiol hydrochloride salt 181 (282 mg, 1.81 mmol, 100 mol %) was dissolved in 14 ml of cyclopentanone.. The mixture was refluxed for 16 hours and thiazolidine hydrochloride salt 182 precipitated from the reaction medium after cooling to ambient temperature. The crude product was filtered and washed several times with acetone to yield 186 (165 mg, 0.74 mmol, 41%) as a pale brown solid. mp. 204-205 °C. Rf (25% MTBE in hexanes) = 0.35. [α]D

20 = +28.9 (c 1.0, MeOH). 1H NMR (CD3OD) δ 0.94 (d, 3H, J = 6.7 Hz), 1.04 (d, 3H, J = 6.7 Hz), 1.93 (m, 9H), 3.00 (dd, 1H, J = 11.5 Hz, 8.9 Hz), 3.60 (dd, 1H, J = 16.6 Hz, 8.9 Hz). 13C NMR (CD3OD) δ 18.9, 20.1, 23.6, 23.8, 31.4, 32.6, 37.0, 39.9, 68.6, 80.5. HRMS m/z calcd. for C10H20NS (M)+ 186.1341, found 186.1340.

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3.2.6 (S)-4-isopropyl-thiazolidine hydrochloride salt (187)

NH3+Cl-

HS

181 187

S NH2+Cl-

Thiol hydrochloride salt 181 (258 mg, 1.66 mmol, 100 mol %) was dissolved in 2,5 ml of ethanol and 131 µl of 35% aqueous formaldehyde solution (1.66 mmol, 100 mol %) was added. The mixture was stirred at ambient temperature for 30 minutes and then at 70 °C for 30 minutes. The reaction mixture was cooled down and evaporated to dryness. The crude product was washed several times with acetone to yield 187 (194 mg, 1.16 mmol, 70%) as a white solid. mp. 157-158 °C. Rf (50% MTBE in hexanes) = 0.38. [α]D

20 = +22.1 (c 1.0, MeOH). 1H NMR (CD3OD) δ 1.09 (d, 3H, J = 6.6 Hz), 1.15 (d, 3H, J = 6.6 Hz), 2.07 (m, 1H), 2.99 (dd, 1H, J = 11.5 Hz, 9.7 Hz), 3.47 (m, 2H), 4.35 (d, 1H, J = 10.0 Hz), 4.42 (d, 1H, J = 10.0 Hz). 13C NMR (CD3OD) δ 19.6, 20.3, 31.3, 33.3, 70.7. HRMS m/z calcd. for C6H13NS (M)+ 131.0769, found 131.0755. Anal. calcd. for C6H14ClNS C 42.97, H 8.41, Cl 21.14, N 8.35, S 19.12; found C 42.89, H 8.29, N 8.76, S 18.58.

3.2.7 (S)-4-tert-butyl-thiazolidine hydrochloride salt (197)

NH3+Cl-

HS

196 197

S NH2+Cl-

Thiol hydrochloride salt 196 (200 mg, 1.18 mmol, 100 mol %) was dissolved in 2,5 ml of ethanol and 101 µl of 35% aqueous formaldehyde solution (1.18 mmol, 100 mol %) was added. The mixture was stirred at ambient temperature for 30 minutes and then at 70 °C for 30 minutes. The reaction mixture was cooled down and evaporated to dryness. The crude product was washed several times with acetone to yield 197 (202 mg, 1.11 mmol, 94%) as a white solid. mp. 160-162 °C. Rf (50% MTBE in hexanes) = 0.38. [α]D

20 = +21.2 (c 1.0, MeOH). The 1H NMR spectrum was identical to literature data (150). HRMS m/z calcd. for C7H15NS (M) 145.0925, found 145.0929.

128

3.2.8 (S)-2-methyl-4-tert-butyl-thiazolidine hydrochloride salt (198)

NH3+Cl-

HS

196 198

S NH2+Cl-

Thiol hydrochloride salt 196 (832 mg, 4.90 mmol, 100 mol %) was dissolved in 6 ml of ethanol and 5 ml of acetaldehyde was added at 0 °C. The mixture was gradually warmed up to ambient temperature and stirred for 4 hours, with thiazolidine hydrochloride salt 198 gradually precipitating from the reaction medium. The crude product was filtered and washed several times with acetone to yield 198 (451 mg, 3.64 mmol, 74%) as a white solid. mp. 212-214 °C. Rf (25% MTBE in hexanes) = 0.35. [α]D

20 = -14.6 (c 1.0, MeOH). 1H NMR (CD3OD) δ). The 1H NMR spectrum was identical to literature data (150). HRMS m/z calcd. for C8H17NS (M)+ 159.1082, found 159.1100.

3.2.9 (S)-2,2-dimethyl-4-tert-butyl-thiazolidine hydrochloride salt (199)

NH3+Cl-

HS

196 199

S NH2+Cl-

Thiol hydrochloride salt 196 (1.22 g, 7.19 mmol, 100 mol %) was dissolved in 25 ml of acetone and 10 ml of 2,2-dimethoxypropane was added. The mixture was refluxed for 16 hours, with thiazolidine hydrochloride salt 199 gradually precipitating from the reaction medium. The crude product was filtered and washed several times with acetone to yield 199 (1.02 g, 4.86 mmol, 67%) as a white solid. mp. 226-228 °C. Rf (25% MTBE in hexanes) = 0.34. [α]D

20 = +22.2 (c 1.0, MeOH). 1H NMR (CD3OD) δ 1.12 (s, 9H), 1.87 (s, 9H), 2.05 (m, 1H), 2.40 (m, 2H), 3.0 (dd, 1H, J = 9.1 Hz, 7.9 Hz). 13C NMR (CD3OD) δ 25.7, 26.6, 27.2, 30.8, 33.2, 72.6, 73.4. HRMS m/z calcd. for C9H19NS (M) 173.1238, found 173.1203.

129

3.3 tert-Butoxycarbonylations

3.3.1 (S)-2,2-dimethyl-3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (163)

182

S NH2+Cl-

163

S NBOC

Thiazolidine hydrochloride salt 182 (673 mg, 3.44 mmol, 100 mol %) and di-tert-butyldicarbonate (998 mg, 4.57 mmol, 133 mol %) were dissolved in 10 ml of acetonitrile. DIPEA (611 µl, 3.51 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 50 °C for 14 days. The reaction mixture was cooled down and evaporated to dryness. The crude product was purified by MPLC (14% MTBE in hexanes) to yield 163 (625 mg, 2.41 mmol, 70%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.61. [α]D

20 = +115.0 (c 0.5, MeOH). 1H NMR ((CDCl2)2, 50 °C) δ 0.96 (d, 3H, J = 6.9 Hz), 0.97 (d, 3H, J = 6.9 Hz), 1.48 (s, 9H), 1.77 (s, 3H), 1.80 (s, 3H), 2.20 (app. septet, 1H, J = 6.9 Hz), 2.69 (dd, 1H, J = 11.7 Hz, 1.5 Hz), 3.10 (dd, 1H, J = 11.7 Hz, 6.1 Hz), 4.20 (app. td, 1H, J = 6.4 Hz, 1.5 Hz). 13C NMR (CDCl3) δ 19.4, 19.9, 28.4, 29.4, 30.6, 31.6, 69.3, 70.0, 79.8, 153.3. HRMS m/z calcd. for C13H26NO2S (M+H)+ 260.1684, found 260.1696.

3.3.2 (S)-3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (160)

187

S NH2+Cl-

160

S NBOC

Thiazolidine hydrochloride salt 187 (99 mg, 0.59 mmol, 100 mol %) and di-tert-butyldicarbonate (255 mg, 1.18 mmol, 200 mol %) were dissolved in 5 ml of acetonitrile. DIPEA (105 µl, 0.60 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 50 °C for 24 hours. The reaction mixture was cooled down and evaporated to dryness. The crude product was purified by MPLC (14.29% MTBE in hexanes) to yield 160 (134 mg, 0.58 mmol, 98%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.56. [α]D

20 = +102.5 (c 3.46, MeOH). 1H NMR (CDCl3) δ 0.91 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 6.7 Hz), 1.45 (s, 9H), 1.94 (app. septet, 1H, J = 6.8 Hz), 2.86 (dd, 1H, J = 11.0 Hz, 3.4 Hz), 2.99 (dd, 1H, J = 11.0 Hz, 6.5 Hz), 4.06 (d,

130

1H, J = 9.0 Hz), 4.13 (b s, 1H), 4.83 (b d, J = 9.0 Hz). 13C NMR (CDCl3) δ 18.9, 19.1, 28.3, 30.3, 47.5, 65.0, 80.3, 153.9. HRMS m/z calcd. for C11H22NO2S (M+H)+ 232.1371, found 232.1339.

3.3.3 (2S,4S)-2-methyl 3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (161)

183

S NH2+Cl-

161

S NBOC

Thiazolidine hydrochloride salt 183 (400 mg, 2.20 mmol, 100 mol %) and di-tert-butyldicarbonate (640 mg, 2,93 mmol, 133 mol %) were dissolved in 8 ml of acetonitrile. DIPEA (391 µl, 2.24 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at ambient temperature for 36 hours. The reaction mixture evaporated to dryness. The crude product was purified by MPLC (14.29% MTBE in hexanes) to yield 161 (507 mg, 2.07 mmol, 94%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.58. [α]D

20 = -14.6 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.89 (d, 3H, J = 5.1 Hz), 0.92 (d, 3H, J = 5.1 Hz), 1.42 (s, 9H), 1.45 (d, 3H, J = 6.3 Hz),2.06 (m, 1H), 2.86 (dd, 1H, J = 11.4 Hz, 3.2 Hz), 2.96 (dd, 1H, J = 11.4 Hz, 6. 0 Hz), 4.04 (m, 1H), (q, 1H, J = 6.0 Hz). 13C NMR (CDCl3) δ 19.8, 20.0, 25.1, 28.8, 31.2, 33.6, 58.9, 67.4, 154.2. HRMS m/z calcd. for C12H24NO2S (M)+ 246.1528, found 246.1539.

3.3.4 (2S,4S)-2-isopropyl-3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (166)

184

S NH2+Cl-

166

S NBOC

Thiazolidine hydrochloride salt 184 (133 mg, 0.64 mmol, 100 mol %) and di-tert-butyldicarbonate (185 mg, 0.85 mmol, 133 mol %) were dissolved in 5 ml of acetonitrile. DIPEA (113 µl, 0.65 mmol, 102 mol %) was added dropwise to this solution at room

131

temperature. The mixture was stirred at ambient temperature for 28 hours. The reaction mixture was evaporated to dryness. The crude product was purified by MPLC (14.29% MTBE in hexanes) to yield 166 (143 mg, 0.52 mmol, 82%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.57. [α]D

20 = +15.3 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.97 (m, 12H), 1.46 (s, 9H), 1.92 (m, 2H), 2.91 (m, 2H, J = 18.1 Hz, 11.5 Hz), 4.14 (m, 1H), 4.87 (d, 1H, J = 9.6 Hz). 13C NMR (CDCl3) δ 19.7, 20.5, 21.0, 28.7, 31.8, 36.5, 68.1, 71.1, 80.7, 155.6. HRMS m/z calcd. for C14H27NO2S (M+Na) 296.1626, found 296.1637.

3.3.5 (S)-2-cyclohexyl-3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (165)

185

S NH2+Cl-

165

S NBOC

Thiazolidine hydrochloride salt 185 (130 mg, 0.55 mmol, 100 mol %) and di-tert-butyldicarbonate (159 mg, 0.73 mmol, 133 mol %) were dissolved in 5 ml of acetonitrile. DIPEA (98 µl, 0.56 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 50 °C for 7 days. More di-tert-bytul-dicarbonate (120 mg, 0.55 mmol, 100 mol%) was added after 5 days. The reaction mixture was cooled down and evaporated to dryness. The crude product was purified by MPLC (14.29% MTBE in hexanes) to yield 165 (130 mg, 0.44 mmol, 79%) as a pale yellow solid. mp. 40-43 oC Rf (25% MTBE in hexanes) = 0.60. [α]D

20 = +31.0 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.93 (d, 3H, J = 3.1 Hz), 0.96 (d, 3H, J = 3.1 Hz), 1.47 (s, 9H), 1.52 (m, 5H), 2.12 (m, 1H), 2.61 (d, 1H, J = 11.7 Hz), 2.8 (m, 1H), 2.96 (dd, 1H, J = 5.9 Hz), 4.23 (m, 1H). 13C NMR (CDCl3) δ 19.9, 20.7, 25.1, 26.2, 28.8, 30, 9, 32.4, 38.3, 69.1, 80.2, 152.0.

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3.3.6 (S)-2-cyclopentyl-3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (164)

186

S NH2+Cl-

164

S NBOC

Thiazolidine hydrochloride salt 186 (120 mg, 0.54 mmol, 100 mol %) and di-tert-butyldicarbonate (234 mg, 1.18 mmol, 200 mol %) were dissolved in 6 ml of acetonitrile. DIPEA (96 µl, 0.55 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 50 °C for 10 hours. More di-tert-bytul-dicarbonate (234 mg, 1.18 mmol, 200 mol %) was added after 5 days. The reaction mixture was cooled down and evaporated to dryness. The crude product was purified by MPLC (11% MTBE in hexanes) to yield 164 (53 mg, 0.18 mmol, 34%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.57. [α]D

20 = +24.2 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.97 (d, 3H, J = 4.6 Hz), 0.99 (d, 3H, J = 4.6 Hz), 1.45 (s, 9H), 1.96 (m, 9H), 2.70 (dd, 1H, J = 11.3 Hz, 6.3 Hz), ( sextet, 1H, J = 5.9 Hz),4.14 (m, 1H).13C NMR (CDCl3) δ 20.1, 20.3, 24.7, 25.0, 28.5, 30.1, 31.7, 68.7, 80.3, 143.3. MS (CI + Na)+: m/z 308 (M + Na).

3.3.7 (S)-3-tert-butoxycarbonyl-4-tert-butyl-thiazolidine (167)

202

S NH2+Cl-

167

S NBOC

Thiazolidine hydrochloride salt 202 (202 mg, 1.11 mmol, 100 mol %) and di-tert-butyldicarbonate (322 mg, 1.49 mmol, 134 mol %) were dissolved in 5 ml of acetonitrile. DIPEA (198 µl, 1.11 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 50 °C for 48 hours. The reaction mixture was cooled down and evaporated to dryness. The crude product was purified by MPLC (14.29% MTBE in hexanes) to yield 167 (240 mg, 0.98 mmol, 88%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.58. [α]D

20 = +10.9 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.92 (s, 9H), 1.45 (s, 9H), 3.02 (m, 2H), 4.02 (d, 1H, J = 4.02 Hz), 4.29 (m, 1H), 5.02 (m, 1H) 13C NMR (CDCl3) δ 27.5, 28.9, 33.3, 36.9, 50.9, 67.8, 81.3, 155.7 HRMS m/z calcd. for C12H23NO2S (M+H)+ 246.1528, found 246.1535.

133

3.3.8 (2S,4S)-2-methyl-3-tert-butoxycarbonyl-4-tert-butyl-thiazolidine (168)

203

S NH2+Cl-

168

S NBOC

Thiazolidine hydrochloride salt 203 (552 mg, 2.82 mmol, 100 mol %) and di-tert-butyldicarbonate (817 mg, 3.75 mmol, 133 mol %) were dissolved in 5 ml of acetonitrile. DIPEA (501 µl, 2.88 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at ambient temperature for 48 hours. The reaction mixture was evaporated to dryness. The crude product was purified by MPLC (14.29% MTBE in hexanes) to yield 168 (658 mg, 2.54 mmol, 90%) as a colorless liquid. Rf (25% MTBE in hexanes) = 0.56. [α]D

20 = +12.5 (c 1.0, MeOH). 1H NMR (CDCl3) δ 0.98 (s, 9H), 1.45 (s, 9H), 1.53 (d, 3H), 2.89 (dd, 1H, J = 11.7 Hz, 2.7 Hz), 3.09 (dd, 1H, J = 11.7 Hz, 7.6 Hz), 4.26 (d, 1H), 5.20 (q, 1H, J = 6.1 Hz). 13C NMR (CDCl3) δ. 24.0, 25.1, 28.4, 28.7, 31.8, 36.0, 60.7, 69.8, 80.7, 155.9. MS (CI + Na)+: m/z 282 (M + Na).

3.3.9 Attempts at (S)-2,2-dimethyl- 3-tert-butoxycarbonyl-4-tert-butyl-thiazolidine (151)

3.3.9.1 Standard method

204

S NH2+Cl-

151

S NBOC

a) Thiazolidine hydrochloride salt 204 (686 mg, 3.27 mmol, 100 mol %) and di-tert-butyldicarbonate (949 mg, 4.39 mmol, 134 mol %) were dissolved in 12 ml of acetonitrile. DIPEA (580 µl, 3.34 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 50 °C for 48 hours folled by 8 days at 70 oC. More di-tert-bytul-dicarbonate (708 mg, 3.27 mmol, 100 mol %) was added after 5 days. The reaction mixture was cooled down and evaporated to dryness. The crude product mixture was purified by MPLC (6% + 10% MTBE in hexanes, gradiently). Part of the starting material was recovered as liberated amine, otherwise only decomposition products were found among the fractions.

134

b) Thiazolidine hydrochloride salt 204 (438 mg, 2.09 mmol, 100 mol %) and di-tert-butyldicarbonate (601 mg, 2.78 mmol, 133 mol %) were dissolved in 8 ml of acetonitrile. DIPEA (371 µl, 2.13 mmol, 102 mol %) was added dropwise to this solution at room temperature. The mixture was stirred at 70 °C for 48 hours folled by 12 days at 90 oC. More di-tert-bytul-dicarbonate (3.62 g, 16.72 mmol, 800 mol %) was added after 7 days. The reaction mixture was cooled down and evaporated to dryness. The crude product mixture was purified by MPLC (6% MTBE in hexanes). Part of the starting material was recovered as liberated amine, otherwise only decomposition products were found among the fractions.

3.3.9.2 via Naked anion

Thiazolidine hydrochloride salt 204 (80 mg, 0.29 mmol, 100 mol %) was dissolved in 10 ml of THF. To increase solubity, 3 ml of acetonitrile was added. The resulting mixture was cooled to � 84 °C and TMEDA (442 µl, 2.93 mmol, 1000 mol %) was added. t-Buli (517µl, 0.88 mmol, 300 mol %) was added and the resulting solution was cannulated to cooled (-84 °C) solution of di-tert-butyldicarbonate (634 mg. 2.93 mmol, 1000 mol%) in 10 ml of THF. The reaction mixture was gradually warmed up to ambient temperature and stirred for 48 hours. The crude product mixture was purified by MPLC (6% MTBE in hexanes). Part of the starting material was recovered as liberated amine, otherwise only decomposition products were found among the fractions.

3.4 D-penicillamine derivatives

3.4.1 (S)-1-aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyl-octan-4-one (201)

HSNH2

OH

O

S NO

O

200 201

D-penicillamine 200 (5 g, 33.51 mmol, 100 mol %) was dissolved in 200 ml of dichloromethane. Dry MgSO4 (4.36 g, 36.26 mmol, 108 mmol) and paraformaldehyde (2.18 g, 72,5 mmol, 200 mol%) was added and the resulting heterogenous mixture was stirred at ambient temperature for 4 days. Additional batch of paraformaldehyde (2.18 g, 72,5 mmol, 200 mol%) was added and the solution was stirred 3 days. The reaction

135

mixture was eluted through a short silica column with dichloromethane. Evaporation of solvents afforded 201 as a pale yellow glue in quantitative yield (5.80 g, 33.48 mmol). The 1H NMR spectrum was identical to literature data (151).

3.4.2 (S)-5,5-dimethyl-thiazolidin-4-yl-dimethyl-methanol (202)

S NO

O

S NHOH

201 202

The D-penicillamine derived bicycle 201 (4.71 g, 27.20 mmol, 100 mol %) was dissolved in 100 ml of THF. The resulting solution was cooled to � 30 °C and MeLi (54.4 ml, 81.6 mmol, 300 mol%) was added cautiously with syringe. The reaction mixture was stirred one hour at � 30 °C and gradually wapmed up to ambient temperature. After stirring 16 hours at ambient temperature the reaction was quenched with 100 ml of aqueous ammonium chloride solution. At this phase the work up had to be stopped due to sudden nausea and dizziness caused to persons present at laboratory.

3.5 Attempts at benzoylation

3.5.1 (S)-2,2-dimethyl-3-benzoyl-4-isopropyl-thiazolidine (188)

182

S NH2+Cl-

188

S NBz

a) Typical procedure in pyridine: Thiazolidine hydrochloride salt 182 (137 mg, 0.70 mmol, 100 mol %) was dissolved in pyridine (11.3 ml, 140.2 mmol, 200 mol%) at 10 oC and benzoyl chloride (106 µl, 0.84 mmol, 120 mol%) was added slowly with syringe. Additonal benzoyl chloride (115 µl, 0.91 mmol, 130 mol%) was added after 8 hours and the reaction mixture was stirred at ambient temperature for extra 16 hours. The pyridine was evaporated and the crude product mixture was diluted onto dichloromethane (30 ml).

136

The resulting solution was washed with water (3 x 30 ml) and 20% citric acid (1 x 30 ml). Combined organic layers were dried over Na2SO4. Filtration and evaporation of solvents was followed by separation of products with MPLC (18% MTBE in hexanes). None of the separated products proved to be 188. b) Typical procedure in dichloromethane DIPEA as a base: Thiazolidine hydrochloride salt 182 (100 mg, 0.51 mmol, 100 mol %) was dissolved in 5 ml of dichloromethane and DIPEA (90 µl, 0.51 mmol, 100 mol%) was added slowly with syringe. Benzoyl chloride (65 µl, 0.56 mmol, 110 mol%) and DIPEA (98 µl, 0.56 mmol, 110 mol%) were added onto 7 ml of dichloromethane. Liberated amine 182 in dichloromethane was slowly added to the mixture of benzoyl chloride and DIPEA. The reaction mixture was stirred at ambient temperature for five hours and quenched by pouring it to water (40 ml). The organic layer was washed with water (3 x 40 ml). Combined organic layers were dried over Na2SO4. Filtration and evaporation of solvents was followed by separation of products with MPLC (18% MTBE in hexanes). None of the separated products proved to be 188.

3.6 Attempts at acetylation

3.6.1 (S)-2,2-dimethyl-3-acetyl-4-isopropyl-thiazolidine (190)

182

S NH2+Cl-

190

S NAc

a) Attempt with AcCl: Thiazolidine hydrochloride salt 182 (200 mg, 1.02 mmol, 100 mol %) was dissolved in 10 ml of dichloromethane and DIPEA (374 µl, 2.15 mmol, 210 mol%) was added slowly with syringe. Acetyl chloride (80 µl, 1.12 mmol, 110 mol%) was added cautiously with syringe and the reaction mixture was stirred at ambient temperature for one hour. After quenched by pouring the mixture to water (40 ml) the organic layer was washed with water (3 x 40 ml). Combined organic layers were dried over Na2SO4. Filtration and evaporation of solvents was followed by separation of products with MPLC (18% MTBE in hexanes). None of the separated products proved to be 190.

b) Attempt with Ac2O: Thiazolidine hydrochloride salt 182 (85 mg, 0.43 mmol, 100 mol %) was dissolved in 10 ml of dichloromethane and DIPEA (83 µl, 0.47mmol, 110 mol%) was added slowly with syringe. Acetic anhydride (41 µl, 0.43 mmol, 100 mol%) was added cautiously with syringe and the reaction mixture was stirred at ambient temperature for 24 hours. Since no signs of reaction could be detected DMAP (6 mg, catalyst) was

137

added. Additional stirring at ambient temperature resulted inno reaction and the reaction mixture was thus refluxed for 16 hours. After quenched by pouring the mixture to water (40 ml) the organic layer was washed with water (3 x 40 ml). Combined organic layers were dried over Na2SO4. Filtration and evaporation of solvents was followed by separation of products with MPLC (18% MTBE in hexanes). None of the separated products proved to be 190.

3.7 Preparation of phenyl diazomethane

3.7.1 N-benzyl-p-toluenesulfonamide (75)

S

O

O

N

H

73 74

O

O

ClNH2

75

Benzylamine 74 (10 g, 93.30 mmol, 100 mol%) was dissoleved in 50 ml of pyridine. Tosyl chloride 73 (20 g, 104.90 mmol, 112 mol%) was added cautiously and the resulting reaction mixture was stirred one hour at ambient temperature. The reaction was quenched by pouring it to 180 ml of water. The solid product was recryrstallized from ethanol to give 75 (21.57 g, 82.54 mmol, 88%).

3.7.2 N-nitroso-N-bezyl-p-toluenesulfonamide (76)

S

O

O

N

H

S

O

O

N

NO

75 76

N-benzyl-p-toluenesulfonamide 75 (21.0 g, 80.35 mmol, 100 mol%) was dissolved in 500 ml of acetic anhydride:acetic acid (4:1). The resulting solution was cooled to + 2 °C and sodium nitrite (120 g, 1.74 mol, 2166 mo%) was added during 12 hours keeping reaction temperature constantly between 2 to 10 °C. The reaction mixture was allowed to come to ambient temperature and stirred for additional 18 hours. The reaction was quenched by pouring it onto excess of icy water and stirring it for one hour. The precipitated crude 76 was recrystallised from ethanol (19.5 g, 67.16 mmo, 84%) as yellow

138

needles. mp. 90-92 °C, literature mp. 90-92 °C (59). Nitroso compound 76 was stored under argon atmosphere and in dark decomposing rapidly after approximately three months.

3.7.3 Phenyl diazomethane (68)

N2

68

S

O

O

N

NO

76

Nitroso compound 76 (966 mg, 3.33 mmol, 100 mol%) added during 20 minutes to a mixture of 12 ml of MTBE and methanolic solution of NaOMe (4 ml, 4.00 mmol, 120 mol%, 1 M solution) a characteristic red colour gradually forming. After finishing the addition the reaction mixture was refluxed for 30 minutes and cooled to ambient temperature. The solution was washed with water (3 x 30 ml) and the organic layer was dried over Na2SO4 (30 min, at dark). After filtration and evaporation of solvents the resulting blood red 68 solution was adjusted to desired volyme (typically 1 ml) with dry dichloromethane and used directlty thereafter.

3.8 General procedure for epoxidation

PhCHOO Ph

Ph

Sulfide catalystRh2(OAc)4

N2CHPh

CH2Cl2/MTBE

9a

O

Ph

20

Ph

Phenyldiazomethane (150 mol % in 1ml of CH2Cl2) was added to a solution of Rh2(OAc)4 (4 mg, 0.01 mmol, 1 mol %) [(13mg, 0.05 mmol, 5 mol%), when Cu(acac)2 was employed], sulfide (0.2 mmol, 20 mol %) and benzaldehyde (102 µl, 1 mmol, 100 mol %) in 0.5 ml of CH2Cl2 over 3 hours by means of a syringe pump. After the addition was complete the reaction was stirred at ambient temperature for 1 hour. The reactions were conducted in dark. Evaporation of the solvents followed by instant purification with MPLC (25% CH2Cl2 in hexanes) yielded 9a and in some cases in 20. The NMR spectrum compared favorably with literature data (160). The enantiomeric excesses of 9a were determined with HPLC (chiralcel OD column) using iso-propanol:hexane (5:95 ->3:97) as an eluent and flow rates varying between 0.8 � 1.0 ml/min.

139

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