(Penmacric acid - shodhganga.inflibnet.ac.inshodhganga.inflibnet.ac.in/bitstream/10603/15769/8/08_part b chapt… · bulgecinine,3 (-)-domic acid,4 enantiomerically pure proline derivatives5

PARTB

Chapter 3

Jlpproach towards the synthesis of (Penmacric acid

Approach towards the synthesis of Penmacric acid Chapter 3

3.1. Introduction

Unnatural and non-proteinogenic amino acids have become very important and

attractive synthetic targets due to their intrinsic biological activities and applications as

conformational modifiers for physiologically active peptides. Pyroglutamic acid (1), due

to its unique structural features, is utilized as a versatile chiral building block for the

synthesis of several natural products such as pyrrolidine alkaloids/ kainoids,2 (-)-

bulgecinine,3 (-)-domic acid,4 enantiomerically pure proline derivatives5 and a wide

variety of non-proteinogenic amino acids.6 Derived from glutamic acid, derivatives of

pyroglutamic acids are an inexpensive source of chirality and have been used as chiral

auxiliaries in Diels-Aider reactions7, alkylation and aldol reactions8 of chiral enolates,

kinetic resolution of amino acids and Michael addition processes (Fig. 1).

Rl, __ ,R2

~R3 H

Amino acid derivatives Pyrrolidines & Kainoids

Peptidomimetics ¢::== ===:> Chiral Auxiliaries

'"Q"' ~ln

Pyrrolizidines & lndolizidines N-bridged bicyclic compounds

Figure 1. Applications of pyrogluatamic acid {1}

In the area of amino acids, differently substituted prolines9 as well as y-amino

acid derivatives10 have been synthesized from pyroglutamic acid (1). Chiral saturated

heterocyclic compounds such as pyrrolidines11, (+)-adalinine12, indolizidines13 and fused

lactams14 have also been prepared. Alkaloids such as (-)-stemoamide15 and (+)-

ipalbidine16, (+)-lentiginosine17, PKC modulators18, ACE and esterase inhibitors19 and

119


gastro protective substances such as Al-77-820 are representative compounds

synthesized using pyroglutamic acid derivatives. Other significant natural products such

as dihydro-kikumycin 82\ anthelvencin22, heliotridane23, several alexines24, swainsonine

derivative25

, manzamine alkaloids26, calyculins27, bulgainine28 and carzinophin A29 are

representative examples which have been synthesized employing pyroglutamic acid as

the source of chirality.

In the recent years, C-C bond forming reactions at various positions of

pyroglutamates have attracted attention from a number of research groups and

considerable thought has been paid on the stereochemical outcome of such reactions,

and consequently in recent years, a number of total syntheses of several complex

natural products and bioactives have been reported (Fig. 2).

HO H

HO"d) 90 CIH. H2N ', C02H

( + )-Lentiginosine TL, 2001, 2509

0

0

e~02H

Ar'',· l_;NH

HO

Chlorpheg TL, 2003, 5271

(-) Stemoamide JACS, 2000, 4295

N

( + )-lpalbidine TL, 2003, 3035

~ 0 N C02Me H

D eoxydysibetaine TL, 2003, 5961

Mona tin TL, 2001, 6793

(+) & (-) Aza-muricatacin TA, 2001, 1503

0~C11H23 H OH

Figure 2. Natural products synthesized using pyroglutamate template

120


The advantage of pyroglutamic acid in asymmetric synthesis lies in a rigid five-

membered skeleton with strong stereo-electronic influence of two different carbonyl

entities in the molecule which can be differentially functionalized. Thus, due to their

importance of substituted pyroglutamates have been the favored targets of many

groups and need of more simpler and safe route is still to exist {Fig. 3).

C-4 Functionalisation C-3 Functionalisation

'- I

I I

Functionalisation ____ .. O~CO H of lactam carbonyl 1 N '

2

I H ', I '

I

~----· Functionalisation of Carboxylic acid

N-Functionalisation C-2 Functionalisation

Figure 3. Possible sites of functionalisation on pyroglutamate skeleton

3.2. Basis of work

H, NH2

H02C~ ~~ 0 N C02H

H

2

Figure 4. Penmacric acid (2)

Penmacric acid {2) {Fig. 4) is an unusual amino acid isolated in 1975 independently by

Welter et al. 31 and Mbadiwe32 from the seeds of the leguminous tree Pentaclethra

macrophyl/a, commonly known as "pauco nuts" or "owala seeds" in less than 0.5% w/w

of the dry bean endosperm; these legumes are indigenous to the humid lowlands of

West Africa, the seeds of which are used both as staple food in the local diet, and also

find application for their medicinal value as anti-inflammatories.33'34 The absolute

configuration of penmacric acid was initially assigned from 1H NMR studies in

association with CD measurements and this was later supported by a single crystal X-ray

121


structure.35 A number of chemical studies were carried out on penmacric acid by the

Belgian workers who originally reported its isolation;36 thus, the lactam of penmacric

acid is hydrolysed under a variety of acidic conditions to the substituted adipic acid 3

which recloses in dilute acid solution to give either of two possible substituted pipecolic

acids 4 and 5 (Scheme 1). Despite detailed chemical studies nothing is known about the

biological origin or role of penmacric acid.

3

aC02H+ NH3 H02C',· N 0

/ ; +

HOzC::aNH3 H02C' N 0

H

5

Scheme 1. Chemical studies on penmacric acid

The impressive biological properties, low natural abundance, and the distinctive

architecture have made penmacric acid and its analogs attractive target for the

synthetic efforts. From a structural perspective, assembling the glycine motif at beta

position of C-4 of pyroglutamate poses a significant synthetic challenge, and to date,

only three research groups have documented strategies to address the synthetically

demanding C-4 stereocenter in the context of its synthesis.

Moloney's approach (2003)37

The first synthetic approach for 2 was attempted by Moloney and co-workers in 2003

(Scheme 2). They have utilized the bicyclic lactams 6a and 6b which is derived from

pyroglutaminol following a simultaneous protection of the hydroxyl and amide

functionalities by a single benzylidene protecting group.38'39 Lithium enolate of bicyclic

lactam 6a react with various aldehydes gave a diastereomeric mixture of exo and endo

products (7a:7a'=2:1, PhCHO; 1:2.7, chloral). With this outcome, they anticipated that

122


H NHTs

Rl~-~ ArCH=NTs

o~NAO

LDA, -78 °C

OH OH

LDA, -78 °C, THF Ph-


material and 22% of the elimination product 9b'. Compound 9b was then converted to

ester 10 in low yield. Deprotection (TFA, 45%) was followed by the usual oxidation-

protection sequence, gave lactam 12 in 8% yield over the three steps, a compound with

the correct relative configuration for penmacric acid (2).

Naito's approach (2007t0

H2N~02H

i) CbzCI, NaHC03 ii) H2S04, MeOH

iii) Mel, DEAD, PPh3

H NHBoc

3M HCI, Me02C~. AcOEt

1

£)._ 0 N C02Me

I

3M HCI, AcOEt

Boc

18a

H, C02Me

i) DBU, PhMe ii) mCPBA

iii) Mgl2, PhMe

H NHOBn

Me02c~ ___ .PH 4steps C)...

N C02Me I Cbz

17a

H, C02 Me

BnOHN~ L pH

"'In 0 N C02H BocHN~

---- 0 N C02Me I

4steps C)... N C02Me

H Boc I Cbz

(1'-epi)-2 18b 17b

Scheme 3. Naito's approach to 2

In 2007, Naito and co-workers described the first total synthesis of 2 in 12 steps (5.4%

overall yield) as well as the synthesis of the {1'-epi)-2 (3.0% overall yield). The key step

of Naitos approach involves the Et3B-induced radical reaction of oxime ether 16 and

iodoproline 15 via an iodine atom-transfer process (Scheme 3}. 3-hydroxy-4-iodoproline

(15) required for the Et3B-induced radical reaction was prepared by a Mitsunobu

reaction on protected trans-4-hydroxy-L-proline (13) to convert hydroxyl group to iodide

124


to give 1441 following the elimination of HI using DBU to obtain 3A-dehydroproline

which was epoxidated with mCPBA in the presence of 4A'-thiobis(6-t-butyl-o-cresol) as

a radical scavenger, the epoxide ring of which was regioselectively opened with

magnesium iodide to afford the expected 3-hydroxy-4-iodoproline (15) via nucleophilic

attack of the iodide ion on less hindered carbon of the epoxy ring.42.43 Radical addition

of hydroxyproline 15 to oxime ether 16 using Et3B as the radical indicator gave

inseparable 1:1 diastereomers, 17a and 17b which was converted into separable fully

protected penmacric acid 18 a and epi-penmacric acid 18b via number of steps involving

removal of Cbz group, introduction of Boc group, removal of hydroxyl group using

Barton-McCombie radical deoxygenation and oxidation of the corresponding pyrrolidine

into separable pyrrolidinone. Finally, deprotection of two Boc groups and hydrolysis of

two methyl esters 18a and 18b gave penmacric (2) and (1'-ep1}2 acid respectively.

Pelloux-Leon & Minassian approach (2009}44

Penmacric acid (2) has also been synthesized by Minassian and co-workers starting from

N-triisopropylsilylpyrrole (19) (Scheme 4). The key-steps of the Minassians route are the

addition of the pyrrole nucleus onto a chiral nitrone and the formation of the

pyroglutamic acid moiety by reductive hydrogenation of the pyrrole followed by

oxidation of the corresponding pyrrolidine into pyrrolidinone. The chiral glycinyl

substituent was introduced by the addition of 1945 onto the cyclic chiral nitrone (S}-2046

followed by methanolysis to give intermediate 21, which on treatment with palladium

black as catalyst in formic acid gave amino ester, the free amino group of which was

then protected with Boc followed by the removal of bulky silyl group using TBAF/acetic

acid to give 22. The carbmethoxy group at the a-position was introduced by subsequent

trichloroacetylation and treatment of the crude mixture with sodium methoxide to give

corresponding methyl ester and protection of nitrogen of the pyrrole nucleus with Boc

following typical procedures gave 23.47 The later was hydrogenated using Rh/Ab03 as

catalyst at 60 bars pressure in methanol to give {1:1) mixture of inseparable pyrrolidines

125


24a & 24b which on subsequent oxidation with ruthenium tetraoxide was converted

into fully protected separable diastereomers 18a and 25, which were finally deprotected

in two step sequence to give free 2 and (S-ep1}2.

0 e o,w~o

N + I ,.~0 TIPS Ph'

19 20

24a,b

l RuCI3.3H20/Nal04 (dr = 1:1)

18a

i) TFA, CH2CI2

HCI, CH2CI2

then MeOH

23

2

TIPS-N::x~~ 0 OMe OH

21

i) Pd/MeOH/HC02H j ii) Boc20, NEt3 iii) TBAF, AcOH

NHBoc

Meo2c-\ i) CI3CCOCI 0

ii) MeONa/MeOH N iii) Boc protection ~

22

+ NHBoc Meo,c-::6 ii) liOH, THF/H20 (3/1) NH2 Ho2c-


products, with 4a- adduct predominating due to facial preference induced by the

carboalkoxy group.49 Titanium enolates, however, give almost exclusively the 4a- aldol

adducts.50 Similar facial preferences have been reported by Moloney and co-workers37

for the aldol reaction of bicyclic lactam (Fig. 5). Extension of this strategy to penmacric

acid synthesis using N-Tosyl benzaldimine51 however proved unsuccessful as only 4a-

products were obtained.37 These results were in consonance with an earlier report that

the reaction of pyroglutamate derived enolates with N-Tosyl benzaldimine provides only

two diastereomeric 4a- products in 4:1 ratio.52 We hypothesized that exclusive

formation of 4a- adducts in the reaction might be due to steric bulk of N-Tosyl group

and its replacement with N-Boc might reduce this facial selectivity to provide direct

access to penmacric acid (Fig 5).

Moloney's approach

H NHTs

Ph~.

0~ La

{

several steps

Penmacric acid (2) ====:> A 0 N C02Me + I Boc

Figure 5. Retrosynthetic analysis

3.4. Results and discussion

R

Penmacric acid

_..Boc N

)I

We initiated our efforts with the preparation of N-Boc benzaldimine (27)53 by reacting

benzaldehyde, benzenesulfinic acid sodium salt and t-butyl carbamate in presence of

formic acid resulted in a-amido benzenesufone 26 as white solid which was filtered,

127


dried and then treated with K2C03 in THF under refluxing condition to give benzaldimine

27 in 90% yield for two steps (Scheme 5). Imine 27 was fully characterized by

comparison of its spectral data with that of the reported data. The MS spectrum of 27

~CHO v BocNH2, PhS02Na HCOOH, CH 30H, Hp

rt, 3 days

HN_..Boc

~so2Ph 26

THF, reflux

Scheme 5. Synthesis of N-Boc benzaldimine {27)

showed M+1 peak at m/z 198. TheIR spectrum of 27 showed characteristic absorptions

at 1717 (s, C=O), 1633 (m, C=N) cm-1 whereas the 1H-NMR showed characteristic peaks

at l5 7.48-7.94 (SH, m, ArH), 8.88 (1H, s, CH=N), 1.61 (9H, s, C(CH3h) (Fig. 6).

~ I

1H-NMR, 300 MHz, CDCI3

9.0 8_'\ 8.0 !.5 7,0 (i.S f>.O 55 5.0 4.;'\ 4.0 3.5 3J) 2.5 2.0 15 1.0 05 0.0 ppm

r§1 ~~~ (:1~ hi

Figure 6. 1H-NMR of compound 27

128


The common methodology used for the functionalisation of pyroglutamate at C-

4 position is the regioselective deprotonation at C-4 of N-carbamate protected

pyroglutamate using LiHMDS followed by quenching with electrophiles. The

deprotonation at C-4 is facilitated by the urethane protecting group at nitrogen as the

ring carboxyl becomes imidic in nature thus facilitating the deprotonation at C-4. In

addition, the carbamate group may also stabilize the resulting enolate by coordinating

with the lithium (Fig. 7).

Figure 7. C-4 lithium eno/ate

Thus, Methyl N-Boc pyroglutamate (28},54 prepared from glutamic acid following

literature procedures, on treatment with LiHMDS at -78 oc afforded the ester enolate which reacted with N-Boc benzaldimine (27) at same temperature to give a

diastereomeric mixture of three products (29, 30 and 31) in 5:2:3 ratio as judged by the

integration of signals in the 1H-NMR spectrum (Scheme 6}.

YNHBoc Yh H~-Ph J\ ,< -------Ph 6~R'-._45

25

Boc+HN 65JY..'-._45

25

BocH+N GR 4R 25

~ ~ i) LiHM DS, THF, -78 oc 0 N C02Me

I ii) 27, 2 h, -78 oc 0 N C02Me 0 N C02 Me 0 N C02Me Boc 1 I I

28 Boc Boc Boc 29 30 31

(87%, 29-30-31 ratio 5:2:3)

Scheme 6. Reaction of imine 27 with Li enolate of 28

129


A mixture of two compounds 29 and 30 (83:17) could be separated from the

third 31 by flash column chromatography. Repeated recrystallisations of the mixture of

29 and 30 from diethyl ether gave a pure sample of 29 as distinct crystalline white solid

(29%) and 31 as clear viscous oil (7.0%). All the three diastereomers were fully

characterized by their spectral data ie MS, IR and NMR (Table 1).

Table 1. Spectral data of compounds 29, 30 and 31

1 H NMR {CDCI3)

Compound IR

No. -1 H-35,

em ArH NH H-6 H-2 C02 Me H-4 Boc1 Boc2 H-3R

0 7.30 5.65 9.78 4.47 3.75 3.17 2.2, 2.06 1.48 1.39

Multi- 1791 m d dd d s m m,m s s

29 plicity 1753

1717 1NH,6 16,NH 7.2 1 {Hz) - h3S 8.6 - - -- - -

7.2 16,4 4.9

0 7.30 6.64 4.84 4.10 3.74 3.21 2.09, 1.95 1.45 1.39

Multi- 1787 m br dd d s m m,m s s

plicity 1751 30

1710 16,NH 4.8 1 {Hz) - - 12,35 8.6 - - -- - -

16,4 9.1

0 7.29 6.50 4.94 4.2 3.57 3.16 2.41,1.65. 1.46 1.38

Multi- 1788 m br dd ddb s m m, brm s s

31 plicity 1751

1709 18.8 1 {Hz) - - - - - -- - -

14.9

•H-35 and H-3R were not assigned; bunresolved dd

With all the isomers in hand after chromatography and crystallisation, a series of

two dimensional NMR experiments were performed in order to assign the relative

stereochemistry at C-4 and C-6 The stereochemistry at C-4 of the major isomer 29 was

judged to be trans with respect to C-2 ie (45) using NOE experiments in CDCI3 (Fig. 8).

130


First we irradiated the hydrogen at C-2 in order to determine the spatial orientation of

the hydrogens at C-3. The proton at 2.2 ppm was assigned as H-35 by its enhancement

of 6.7% on irradiating the signal for H-2 at 4.47 ppm, and irradiation of H-4 at 2.83 ppm

gave an enhancement of 5.1% to H-3R at 2.06 ppm.

29, NOE, 300 MHz, CDCI3

H-2

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm

Figure B. Key NOESY correlations for compound 29

131


The isomer 30 was deemed to have the same (45) stereochemistry as the

transfer of magnetization was observed between H-2 proton and H-35 and H-4 and H-3R

in its NOESY spectrum (Fig. 9). Thus both isomers exhibited trans stereochemistry at C-4

with respect to C-2.

H·3R~

H·3S~

H-4~

H-2~

30

30, NOESY, 400 MHz, CDCI3

+ &; a a

Q ) ·~@ • 0 " ~


Careful crystallization of 29 enabled the isolation of crystals suitable for single-

crystal X-ray analysis and confirmed its (6R) stereochemistry at C-6 (Fig. 10). Hence 30, the

other 4a.- product, was assigned 25,45,65 configuration.

Figure 10. X-ray structure of compound 29.

The stereochemistry at C-4 of 31 was thus deductively assigned as (4R). In order

to establish its relative stereochemistry at C-4 and C-6, phenyl group in 31 was

oxidatively transformed using in situ generated Ru04 from RuCI3fNai04 to carboxylic

H NHBoc H Ph H Ph

Ph~. BocHN~. BocHN~

O~C02Me O.J:')....C02Me 0 N C02Me I I I Boc Boc Boc

29 30 31

H NHBoc

Me02C~, 45 O~C02Me

I Boc

(4,6-epi-) 33 (36.2%)

BocHN~~~:Me BocHN,; O~C02Me 0 N C02Me

I I Boc Boc

(4-epi-) 34 (23%) (6-epi-) 32 (35.6%)

Scheme 7. Synthesis of epimers of penmacric acid

133

a


function and esterified to 32 using diazomethane in overall 35.6% yield (Scheme 7). 32

was found to be C6-epimer of penmacric acid ester having spectral data identical with

that of methyl ester of epi-penmacric acid reported by Takeaki Naito et a/.40 Similarly,

4,6-epi-, and 4-epi-penmacric acids (33 and 34) were prepared from 29 and 30

respectively following the same protocol. All the three epimers of penmacric acid were

fully characterized by their spectral data ie MS, IR and NMR. The C-4 trans relationship

of compound 33 and 34 was reconfirmed by NOE experiments in deuterobenzene (Fig.

11 and 13) and the absolute configuration [(25,45,6R}-33 and {25,45,65)-34] was later

supported by single crystal X-ray structure of compound 33 (Fig. 12).

Table 2. Spectral data of compounds 32, 33 and 34

2H NMR"

Compound IR ester ester H-35, Boc Boc

No. cm·1 NH H-6 H-2 H-4 1 2 H-3R 1 2

8 1789 5.67 4.5 3.80 3.77 3.08 2.56,2.08° 1.50 1.45

32 Multi- 1750 br m s s m m,brm s s

plicity 1717

8 5.38 4.61 4.28 3.29 3.22 3.44 2.02,1.65 1.36 1.34

Multi- 1790 d dd dd s s m m,m s s

plicity 1750 33

J (Hz) 1717 JNH,6 J6,NH 8.9 J2,35 10.8 - - - - - -

8.9 J6,4 2.6 J2,3R 2.6

8 5.76 4.67 4.43 3.26 3.20 2.97 2.07,1.69 1.38 1.35

Multi-1789 br dd dd s s m m,ddd s s

plicity 34 1749

1718 )6,4 9.4 J2,35 9.8 J3R,35 10.5

J (Hz) - - - - J3R,4 9.2 - -J6,NH 4.2 J2,3R 1.4

J3R,2 1.4

- b, Internal standard for 32 (CDCI3), 33 (C6D6) and 34 (C6D6), H-35 and H-3R were not ass1gned

6-epi, 4-epi, 4,6-epi corresponds to l'-epi, 3-epi, 3,1'-epimers of penmacric acid (2) respectively according to usual

pyroglutamate numbering.

134

Approach towards the synthesis of Penmacric acid

H-2

l. ______ ____

l~~ .5 4.0 3.5 . 3.0

H-4

1.5 4.0 3.5 3.0

2.5

2.5

N I Boc

33

2.0

2.0

2.2%

H-35

i

Chapter 3

33, NOE, 400 MHz, C.D6 H-3R

1.5 1.0 0.5 ppm

H-3R

i

r 1.5 1.0 0.5 ppm

S-40

Figure 11. Key NOESY correlations for compound 33

Figure 12. X-ray structure of compound 33

135


H-35 34, NOE, 400 MHz, C60 6

H-2 t J,

1 I~( 1=1 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

H-4 H-3R

t i--r r~l I~( I~(

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

H-2

t H-3R H-35 t t

1~r I~( I~( 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

Figure 13. Key NOESY correlations for compound 34

As titanium enolates are known to enhance the diastereoselectivity in aldol

reactions,50'55 addition of chlorotitanium enolate of 28 with imine 27 was also studied.

Thus, pyroglutamate derived titaniumtrichloro enolate, prepared by dropwise addition

of TiCI4 (1M in CH2CI 2) to a solution of 28 in CH2CI2 at -78 oc followed by slow addition of DIPEA after 5 min resulted in deep violet enolate solution, reacted with N-Boc

136


benzaldimine (27) at same temperature for 2 h. In contrast to the results obtained with

lithium enolate, only a single diastereomer 29 was obtained in excellent yield (Scheme

8).

O~C02Me I Boc

28

i) TiCI4, CH2CI2, Dl PEA, -78 ·c iil 21, 2 h, -78 ·c

H NHBoc

Ph~-.4s

O~C02Me I Boc

29 (72%)

Scheme 8. Reaction of imine 27 with Ti enolate of 28

Since the structure of penmacric acid consists of pyroglutamic acid residue with

glycine motif at C-4 and also carboxylate group is expected to be sterically less hindered

than phenyl group, in order to achieve one step synthesis of penmacric acid we next

studied the reaction of lithium enolate of 28 with Methyl N-Boc-a-iminoacetate {37)56

(Scheme 9) prepared in situ from Methyl N-Boc-2-bromoglycinate (36).

35

NBS, CCI4

hv (500 W) 10-30 °C

NHBoc

~ Me02C Br

36

TEA, THF

-78 ·c Me02C

Scheme 9. Synthesis of Methyl N-Boc-a-iminoacetate {37)

NBoc

)

37

2-bromoglycine ester 36 required for the synthesis was prepared by irradiating a

solution of Methyl N-Boc-glycinate (35)57 and N-bromosuccinimide {NBS) in CCI4,

keeping the reaction mixture between 10-30 oc using a water bath. Subsequent elimination with TEA was achieved at -78 oc and the cold crude imine 37 was rapidly filtered and transferred into a pre-prepared lithium enolate solution of 28, prepared

with 1.2 equiv of LiHMDS in THF at -78 oc for 30 minutes. No aldol product was obtained and the starting pyroglutamate 28 was recovered unchanged. This may be due to

inefficiency of the transfer and filtration procedure which allowed the sensitive imine 37

137


to warm considerably above -78 oc. To overcome this problem, the cold lithium enolate solution of pyroglutamate 28 was rapidly transferred via cannula to the crude imine 37

solution at -78 oc without isolating the later. This method gave a mixture of two

diastereomeric products, 33 and 34 (Scheme 10) in 71% yield in a ratio of 7:3 as judged

by integration of signals in the 1H NMR spectrum.

O~C02Me I Boc

28

i) LiHMDS, THF, -78 oc ii) 37, 2 h, -78 oc

i) TiCI4, CH2CI 21 DIPEA, -78 oC

ii) 37, 2 h, -78 oc

(4-epi-) 34 (62.3%)

H NHBoc

Me02C~ .. 45 J:X. 0 N C02Me

I Boc

(4,6-epi-) 33 (41.3%)

+

H C02Me

BocHN~ .. 45 J:X. 0 N C02Me

I Boc

(4-epi-) 34 (18%)

(11%, 10-11 ratio 7:3)

Scheme 10. Reaction of imine 37 with Li & Ti enol ate of 28

High stereoselectivity (exclusive 65) was also observed in reaction of titanium

enolate of 28 with imine 37, where 34 was obtained as the sole product (Scheme 10).

The attack of Ti-enolate to the si-face of imine in reaction could be rationalized through

a more chelated intermediate (Fig. 14).

Figure. 14. Proposed transition state model

In an effort to establish our proposed chelated transition state assembly, we

next investigated the reaction of Ti-enolate of 28 with activated N-tosyl benzaldimine

(38) derived from benzaldehyde (absence of chelation due to carbmethoxy group). 138


PhCHO + TsNH2 + TEA

,....Ts N

ci 38(72%)

Scheme 12. Synthesis of N-tosyl benzaldimine (38)

Chapter 3

N-tosyl benzaldimine (38)51 was prepared following the method reported in

literature by treating TiCI4 to a ice-cooled solution of benzaldehyde, tosylamide and TEA

in CH2CI2 for 30 min to give 38 in 72% yield. Imine 38 was fully characterized by

comparison of its melting point and spectral data with that of the reported data. The MS

spectrum of 38 showed M+l peak at m/z 260 whereas its 1H-NMR showed characteristic

peaks at o 7.33-7.94 (9H, m, ArH), 9.03 (lH, s, CH=N), 2.44 (3H, s, PhCH3) (Fig. 15).

1H-NMR, 300 MHz, CDCI3

~ 1'

9.0 8.5 8.0 'l.S 1.0 65 b.O 5'..5 .S.O 4 . .S 4.0 3 .. '\ J.O ::!.5 Z.O I . .S 1.0 0.5 ppm

~ ~~~ ~


139


It is pertinent to note that in absence of such chelation in N-Tosyl imine 38, its

reaction with titanium enolate of 28 afforded a diastereomeric mixture of 4a-products

{39 and 40) in a ratio of 65:35 (by 1H-NMR) similar to the results observed in case of Li-

enolate as reported by Young eta/52 (Scheme 12).

O~C02Me I Boc

28

ii) 38, 2 h, -78 oc

H NHTs

Ph~, 45 ~ 0 N C02Me

I Boc

39 (23%)

H Ph

TsHN~

+ O~C02Me I Boc 40

(85%, 39-40 ratio 65:35)

Scheme 12. Reaction of imine 38 with Ti enolate of 28

The structure and stereochemisty of both the diastereomers 39 and 40 were

assigned by comparison of their delta and coupling values with the reported analogues

(41a and 41b).52 Chromatography and recrystallisation gave the pure major isomer 39 in

23% yield and impure 40 but the spectrum of minor isomer was obtained by subtraction

(Table 3 and 4).

Type of proton

NH

H-2

H NHTs

Ph~-.45 ~ 0 N C02CH2Ph

I Boc

41a

H Ph

TsHN~_- 45 O~C02CH2Ph

I Boc 41b

Table 3. Comparison of 1H-NMR data b/w 41a and 39

reported (40a) observed (39)

() multiplicity 1 (Hz) () multiplicity

6.37 d 1NH,6= 4.0 6.46 d

4.46 dd 12,35 = 9.6

4.42 d 12,3R = 1.2

140

1 (Hz)

1NH,6= 4.0

12,35 = 9.5


J6.4=7.1 dd

)6,4 = 6.9 H-6 4.26 dd 4.34

J6,NH = 4.0 J6,NH = 4.0

H-4 3.02 m - 3.05 m -

H-35 2.05 ddd - 2.06 m -

H-3R 1.78 ddd - 1.81 m -

Table 4. Comparison of 1H-NMR data b/w 41b and 40

reported {41b) observed {40) Type of proton

0 multiplicity J (Hz) 0 multiplicity J (Hz)

NH 6.78 d JNH,6= 9 6.76 d JNH,6= 9.1

H-2 4.17 dd J2,35 = 9.6

4.15 dd J2,35 = 9.1

h_3R = 2.2 J2,3R = 2.3

dd )6,4 = 4.7

dd )6.4 = 4.8

H-6 4.61 4.65 J6,NH = 9.0 J6,NH: 9.1

H-4 3.21 m - 3.2 m -

H-35 1.90 m - 1.79- -m

H-3R 2.05 m - 2.12

The high exo-stereoselectivity observed in the reaction of imine 37 with lithium

enolate of 28 is indeed surprising and hence it appeared interesting to study the

condensation of unsubstituted N-Boc imine 43 (Scheme 13) with lithium enolate of 28.

K2C03 THF, reflux

X ..

HN_...Boc NaH _...Boc

H BocNH2, PhS02Na N

)=o H~S02Ph /'\ )l

H HCOOH, CH30H, Hp H H

rt, 3 days 42 (86%) LiHMDS 43 X ..

Scheme 13. Unsuccessful efforts to tert-butyl methylenecarbamate {43)

141


We attempted to prepare the N-Boc imine 43 employing the same strategy as

described for N-Boc benzaldimine (27) ie synthesis of sulfone corresponds to

formaldehyde followed by its elimination with base (Scheme 13). Treatment of 30% aq.

formaldehyde solution with benzene sulfinic acid sodium salt , tert-butyl carbamate in

the presence of formic acid for 3 d gave sulfone 42 as white solid in 86.4% yield which

was fully characterized by MS, NMR and IR. The MS spectrum of 42 showed [M+NH4t peak at m/z 298 whereas 1H-NMR showed characteristic peaks at 5 7.53-7.94 (5H, m,

ArH), 5.42 (lH, br, NH), 1.26 (9H, s, C(CH3h) (Fig. 16).

~~~~~~!§ ~ a~ .,., \\\\IP \1

1H NMR, 300 MHz, CDCI3

t;~:Ph 42


~

" 1i I

-~~-~~ :-~=


attempts to isolate the imine 43 were unsuccessful. Intrigued by the instability of 43 it

was decided to generate the imine 43 in situ from the sulfone 42 with UHMDS. The

addition of Lithium enolate of pyroglutame 28, generated by treatment with 2.3 equiv

of UHMDS at -78 oc with the sufone 42 (1.1 equiv) at same temperature, expectedly

found to be non-stereoselective, giving an almost 1:1 ratio of 4a- and 4~-products 44

and 45, respectively (Scheme 14) as judged by integration of signals in the 1H-NMR

spectrum.

O~C02Me I Boc

28

i) LiHMDS, THF, -78 "C

ii) 42, 2 h, -78 ·c

BocHN-,,

~ 0 N C02Me I Boc

44 (35%)

BocHNn 4R

2

0 N C02Me I Boc

45 (33.2%)

{74%, 44-45 ratio 52:48)

Scheme 14. Reaction of sulfone 42 with Li enol ate of 28

Both the diastereomers were fully characterized by their spectral data ie MS, IR and

NMR (Table 5).

Table 5. Spectral data of compound 44 and 45

lH NMR (CDCI 3)

compound IR mp

No. . ·1 H-35/

em ·c NH H-2 C02 Me H-6 X 2 H-4 Bocl Boc2 H-3R

3.49/ 0 5.15 4.58 3.78 2.81 2.14 1.50 1.42

3.33 1772

multi 44 1707 96 br dd s m/m m m s s

plicity

J (Hz) 12,35 8.9

- - - - - - -J2,3R 1. 7

3.49/ 0 1786 5.17 4.5 3.77 2.75 2.51/1.79 1.49 1.42

3.34 1784 106

45 multi 1710 br dd3 s m/m m m,m s s

plicity

"unresolved dd

143


With both the isomers in hand after chromatographic separation, 4-~

stereochemistry of the isomer 45 was assigned using NOE experiments in CDCI3, by the

irradiation of H-2, H-3 and H-4 (Fig. 17). This experiment was similar to the one on

intermediate 29. First we determined the spatial orientation of hydrogens at C-3. The

3.5%

~~'Hs BocHN nd:_ -~H 5.s%

0 N C02Me I

Boc 45

H-35 H-2 t 45, NOE, 300 MHz, CDCI3 l

1 1~1 l~l 1~r 45 4.0 35 3.0 2.5 2.0 1.5 1.0 05 ppm

H-2 H-35

i H-4 t l

!~( l l~l 45 4.0 35 3.0 2.5 2.0 15 1.0 0.5 ppm

S-43

Figure 17. Key NOE5Y correlations for compound 45

proton at 2.51 ppm was assigned as H-35 by its enhancement of 5.8% on irradiating the

signal for H-2 at 4.5 ppm, and irradiation of H-4 at 2. 75 ppm gave an enhancement of

3.5% to H-35 at ppm. Also, an 2.3% enhancement of H-4 was also observed on

144


irradiation of H-2. All these results indicated that N-Boc aminomethyl moiety and ~

oriented H-3R have a cis-relationship.

In contrast to the results obtained with Li enolate, reaction of chlorotitanium

enolate of 28 with imine 42 gave predominantly 4a-isomer 44 in 67% yield {Scheme 15).

Incidentally, this also constitutes a one step synthesis of 44 and 45 as intermediates for

{45) and {4R) 4-aminomethyl glutamic acid respectively serving as glutamate transport

inhibitors which were otherwise have been synthesized in multisteps.58

o¥co2Me I Boc

28

i) TiCI4, CH2CI2, DIPEA, -7s•c

ii) 42, 2 h, -78 ·c

BocHN-,, '.45

O~C02Me I Boc

44(67%)

Scheme 15. Reaction of sulfone 42 with Ti enolate of 28

3.5. Conclusion

In conclusion, we have accomplished a short formal synthesis of three epimers of

penmacric acid, and have shown dependency of the stereochemical outcome in the

reaction of imines with Li enolates of pyrogluatmate, to the steric bulk of substituents.

On the other hand, chelation seems to be predominant factor in reaction with titanium

enolates.

145


3.6. Experimental

3.6.1. General methods

All enolate reactions were done using flame-dried glassware under nitrogen

atmosphere. THF was distilled from sodium/benzophenone ketyl immidiately before

use. Triethylamine, N,N-diisopropylethylamine and dichloromethane were distilled

over calcium hydride. N-bromosuccinimide was recrystallised from water prior to

use. Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm E.

Merck pre-coated (Merch 60 F254) silica gel plates using ninhydrine as visualizing

agent. Purification was performed by flash chromatography using silica gel {230-400

mesh}. NMR spectra were recorded either on a Bruker Advance-300 or Advance-400

spectrometers. Chemical shifts are reported as ppm {delta) relative to TMS as

internal standard. Mass spectra were recorded on LCQ Advantage MAX (ESI}, JOEL

JMS-600H (EI/HRMS) and Accu. TOF JMS T100 LC (DART/HRMS) mass spectrometer.

IR spectra were recorded on a Perkin-Elmer FT-IR RXI spectrometer. Optical rotations

were determined on an Autopol Ill polarimeter. Unit cell determination and intensity

data collection (29 = 50°} was performed on a Bruker Smart Apex diffractometer with CCD area detector at 293 K. Structure solutions by direct methods and refinements

by full-matrix least-squares methods on F2. XSCANS [Siemens Analytical X-ray

Instrument Inc.: Madison, Wisconsin, USA 1996] was used for data collection and

reduction. SHELXTL-NT [Bruker AXS Inc.: Madison, Wisconsin, USA 1997] was used

for structure refinement.

3.6.2. Experimental details

Two-step preparation of N-tert-butoxycarbonyl benzaldimine {27)

Step 1: tert-Butyl carbamate (2.93 g, 25 mmol) and benzenesulfinic acid sodium salt (8.2

g, 50 mmol) were taken into a 250 ml round bottom flask and dissolved in a mixture of

methanol (25 ml) and water (50 ml). Benzaldehyde (50 mmol) was then added, followed

146


by formic acid {1.9 ml) and the reaction mixture was stirred for 3 days at room

temperature. The resulting white solid was filtered off and washed with water and

ether, redissolved in dichloromethane, dried over Na2S04, and concentrated under

reduced pressure to afford the respective a-ami do benzenesulphone {26} as white solid.

Step 2: An oven dried round bottom flask was charged with anhydrous potassium

carbonate (16 g) and dry THF {10 ml/mmol) under nitrogen atmosphere. Then, the a.-

amido benzenesulphone 26 {19.4 mmol) was added and the mixture was heated to

reflux with stirring under a nitrogen atmosphere for 17 h. The mixture was then cooled

to room temperature, filtered through a short pad of celite and concentrated under

reduced pressure. The residue was redissolved in dichloromethane, dried over Na2504,

filtered and concentrated under reduced pressure to afford the corresponding N-Boc

aldimine 27 in 90% yield (for two steps) which was kept under high vacuum at rt for

several hours before use.

Colorless oil; IR (thin film, cm-1) 2983, 1713, 1627, 1263, 1217, 1157;

1H NMR {300 MHz, CDCI3) o 8.88 {1H, s, CH=N), 7.91-7.94 (2H, m, ArH), 7.54-7_57 {1H, m, ArH), T48-7.50 {2H, m, ArH), 1.61{9H, s,

{CH3hCO); 13C NMR (75 MHz, CDCI3) o 169.8, 162.7, 134.1, 133.6,

130.3, 128.9, 82.4, 28.0; MS (ESI): m/z 205, found 205[M+Ht, 106[M-C2H80 2t,

Methyi{2S,4RS)-N-tert-butoxycarbonyi-4-[{6RS)-N-tert-

butoxycarbonylamidobenzyl)pyroglutamate {29, 30, 31}

Lithium enolate

Under nitrogen atmosphere and at -78 °(, LiHMDS {1.0 M in THF, 7.63 ml, 7.64 mmol)

was added slowly to the magnetically stirred solution of Methyl (25)-N-tert-

butoxycarbonypyroglutamate 28 {1.54 g, 6.36 mmol) in freshly distilled THF {30 ml), and

the reaction mixture was stirred for 1 hat -78 oc. A solution of N-Boc aldimine 27 (1.69 g, 8.27 mmol) in tetrahydrofuran {20 ml) was added dropwise to the reaction mixture

and stirring was continued for additional 2 h at -78 oc . The reaction mixture was 147


quenched with saturated aqueous ammonium chloride {15 ml), allowed to warm to

room temperature, diluted with water (25 ml), and extracted with ethyl acetate {3 x 25

ml). The combined organic layer was washed with brine (25 ml), dried (Na2S04), and

concentrated in vacuo to give a mixture of three diastereoisomers 29, 30 and 31 (2.48 g,

87%) as white foam which was flash chromatograped on a silica gel column using ethyl

acetate-hexane {30:70) as eluant to give a mixture of 29, 30 (83:17) and pure 31 as clear

viscous oil {0.68g, 23.8%}. Repeated recrystallisations of the mixture of 29 & 30 from

diethyl ether gave a pure sample of 29 as distinct crystalline white solid (0.82 g, 29%)

and 30 as clear viscous oil {0.19 g, 7.0%}.

Titanium enolate

A solution of TiCI4 {1.0 M in CH2Cb, 1.16 ml, 1.16 mmol,) was added dropwise to a

stirred solution of 28 (0.26 g, 1.07 mmol) in anhydrous CH2CI2 {10 ml) at -78 oc under nitrogen, giving a yellow slurry. After 5 minutes, N,N-diisopropylethylamine (0.37 ml,

2.14 mmol) was added slowly over a period of 15 min. The resulting violet colored

solution was stirred at -78 oc under nitrogen for 1.5 h, a solution of N-Boc aldimine 27

{0.26 g, 1.28 mmol) in CH2CI2 (5 ml) was added to it over a period of 10 mins, and the

stirring was continued at -78 oc for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (5 ml), allowed to warm to room temperature,

diluted with water (15 ml), and extracted with CH2CI2 (3 x 10 ml). The combined organic

extracts were washed with brine {2x10 ml), dried (Na2S04) and concentrated in vacuo to

give a white foam which was purified using flash chromatography over a silica gel

column using ethyl acetate-hexane as eluant (30:70) to give pure 29 as white crystalline

solid {0.34 g, 72%).

H NHBoc

Ph~

h 0 N C02 Me I Boc

29

Methyi(2S,4S)-N-tert-butoxycarbonyi-4-[(6R)-N-tert-

butoxycarbonylamidobenzyl)pyroglutamate (29)

Colorless crystalline solid; mp 172-175 oc; [found: C, 61.51; H, 7.12; N, 6.32. C23H32N201 requires C, 61.59; H, 7.19; N, 6.25%];

148


Rt (30% EtOAc/hexane) 0.35;1H NMR {300 MHz, CDC13) b 7.26-7.35 (5H, m, ArH), 5.64-

5.67 {1H, d, JNH,6 7.2 Hz, NH), 4.87-4.91 {1H, dd, J 6,NH 7.2 Hz, J6,4 4.9, H-6), 4.46-4.49 {1H,

d, h,35 8.6 Hz, H-2), 3.75 {3H, s, C02CH3), 3.13-3.21 (1H, m, H-4), 2.14-2.26 (1H, m, H-35),

2.03-2.10 {1H, m, H-3R), 1.48 {9H, s, {CH3}3CO), 1.39 {9H, s, {CH3}3CO); 13C NMR (75 MHz,

CDCI3) b 172.6, 171.6, 155.7, 149.1, 140.3, 128.7, 127.6, 127.0, 84.0, 80.0, 56.9, 54.9,

52.7, 46.9, 28.3, 27.9, 26.1; IR(thin film, cm-1) 2980, 1791, 1753, 1717, 1500, 1456, 1370,

1314, 1156, 1047; M5 (E51): m/z 448, found 471 [M+Nat; HRM5 (DART): m/z calcd. for

C23H33N201 [M+Ht: 449.2287; found: 449.2271; [a]28o= -10.3 (c 0.81, CHCI3).

H Ph BocHN~

h 0 N C02Me I Boc

30

Methyi{2S,45)-N-tert-butoxycarbonyi-4-[{65)-N-tert-

butoxycarbonylamidobenzyl]pyroglutamate {30)

Clear viscous oil; R1(30% EtOAc/hexane) 0.35/H NMR {400

MHz, CDCI3) b 7.27-7.34 (5H, m, ArH), 6.64 (1H, br, NH),

4.85-4.88 {1H, dd, J6,4 9.1 Hz, J6,NH 4.8 Hz, H-6), 4.09-4.12

{1H, d, h,3s 8.4 Hz, H-2), 3.74 {3H, s, C02CH3), 3.18-3.24 (1H, m, H-4), 2.06-2.12 {1H, m,

H-3R), 1.91-2.00 (1H, m, H-35), 1.45 (9H, s, (CH3)3CO), 1.39 {9H, s, (CH3)3CO); 13C NMR

(75 MHz, CDCI3) & 173.8, 171.4, 155.0, 148.8, 138.3, 128.7, 128.0, 127.9, 83.9, 79.7, 57.0,

54.6, 52.7, 46.1, 28.3, 27.8, 25.1; IR (thin film, cm-1) 3021, 2366, 1787, 1751, 1710, 1492,

1370, 1313, 1217, 1157; M5 (E51): m/z 448, found 471[M+Nat; HRM5 (DART): m/z calcd.

for C23H33N201 [M+Ht: 449.2287; found: 449.2288; [a]28o= -47.7 (c 0.84 CHCI3).

H Ph

BocHN~--6 4 2

Methyi{2S,4R)-N-tert-butoxycarbonyl-4-[ ( 6R)-N-tert-

butoxycarbonylamidobenzyl] pyroglutamate {31)

Clear viscous oil; [found: C, 61.45; H, 7.26; N, 6.22.

C23H32N201 requires C, 61.59; H, 7.19; N, 6.25%]; R1 {30%

EtOAc/hexane) 0.31;1H NMR {300 MHz, CDCI3) b 7.26-7.32

(5H, m, ArH), 6.50 (1H, br, NH), 4.92-4.97 (1H, dd, J 8.8, 4.9 Hz, H-6), 4.39-4.45 (1H, dd

0 N C02 Me I Boc

31

(unresolved), H-2), 3.57 {3H, s, C02CH3), 3.12-3.20 (1H, m, H-4), 2.36-2.47 (1H, m, H-3), 149


1.64-1.67 (1H, b m, H-3), 1.46 (9H, s, (CH3}3CO), 1.38 (9H, s, (CH3)3CO); 13C NMR (75 MHz,

CDCI3) 8 173.4, 171.1, 155.1, 148.8, 138.4, 128.7, 127.9, 127.0, 84.1, 79.7, 57.0, 54.6,

52.5, 46.9, 28.3, 27.9, 24.0; IR (thin film, cm-1) 2923, 1788, 1751, 1709, 1497, 1455,

1370, 1313, 1217, 1157, 1028; MS (ESI}: m/z 448, found 471 [M+Nat; HRMS (ESI): m/z

calcd. for C23H33N20 7 [M+Ht: 449.2287; found: 449.2315; [a]29o= +22.5 (c 0.88, CHCI3).

General procedure for Methyl (25,4RS)-N-tert-butoxycarbonyi-4-[(6RS)-

methoxycarbonyi-N-tert-butoxycarbonylaminomethyl]pyroglutamate (32, 33, 34)

To a stirred solution of 31 (0.22 g, 0.51 mmol) in a mixture of CH3CN (4 ml) and CCI4 (4

ml) was added a solution of Nal04 (1.14 g, 5.34 mmol) in water (7 ml) and the stirring

was continued for additional 15 min. RuCI3.3H20 (10 mg, cat.) was added to it and the

reaction mixture was vigorously stirred for 12 h. CH2CI2 (15 ml) was added and the

aqueous layer was extracted with CH2CI2 (3 x 10 ml) and dried (Na2S04). The residue

obtained after concentration was redissolved in THF (5 ml) to which a solution of

diazomethane in ether was added with swirling. Water (15 ml) was added to it and

extracted with ethyl acetate (3 x 15 ml). The combined organic phases were dried

(Na2S04) and concentrated in vacuo to give a colorless oil (0.094 g, 43%); purified by

flash column chromatography on silica gel using ethyl acetate-hexane as eluant (45:65)

to give 32 as viscous oil (0.078 g, 35.6%) which was crystallised from diethyl ether to

white solid after standing overnight.

Methyi(25,4R)-N-tert-butoxycarbonyi-4-[(6R)methoxycarbonyi-N-tert-

butoxycarbonylaminomethyl] pyroglutamate (32}

H, C02Me BocHNh 0 N C02 Me

I Boc

32

White solid; mp 122-125 oc; [found: C, 53.11; H, 7.09; N,

6.57. C19H3oN209 requires C, 53.02; H, 7.02; N, 6.51%]; Rt

(50% EtOAc/hexane) 0.4/H NMR {300 MHz, CDCI3) 8 5.67

(1H, br, NH), 4.50-4.61 (2H, m, H-6+H-2}, 3.80 (3H, s,

C02CH3), 3.77 {3H, s, C02CH3), 3.04-3.12 (1H, m, H-4), 2.51-

150


2.61 {1H, m, H-3), 2.04-2.13 (1H, b m, H-3), 1.50 {9H, s, (CH3hCO), 1.45 (9H, s, (CH3hCO);

Be NMR {100 MHz, CDCI3) o 171.1, 170.3, 169.5, 154.2, 147.9, 83.0, 79.3, 56.0, 51.9, 51.6, 51.5, 44.4, 27.1, 26.7, 23.0; IR (thin film, cm-1) 2960, 2923, 1789, 1750, 1717, 1501,

1457, 1396, 1259, 11S6, 1027; M5 (E51}: m/z 430, found 4S3 [M+Nat; HRM5 (DART):

m/z calcd. for C9H15N20 5 [M-C10H1504t: 231.0981; found : 231.1008; [a]30

0= -7.7 (c 0.31 CHCI3).

Methyi(2S,4S}-N-tert-butoxycarbonyi-4-[(6R} methoxycarbonyl

-N-tert-butoxycarbonylaminomethyl] pyroglutamate {33}

H NHBoc

Meo2c_:;( .. 4 J:'X. 0 N C02 Me

I Boc

Colorless crystalline solid; 36.2%; mp 137-139 °C; [found:

C, S3.09; H, 7.12; N, 6.48. C19H3oNz09 requires C, S3.02; H,

7.02; N, 6.S1%]; Rt {SO% EtOAc/hexane) 0.62;1H NMR (400

MHz, C6D6} o S.37-S.39 (1H, d, JNH,6 8.9 Hz, NH), 4.6S-4.S7 33

(1H, dd, J6,NH 8.9 Hz, )6,4 2.6 Hz, H-6), 4.27-4.30 (1H, dd, Jz,3s

10.8 Hz, h,3R 2.6, H-2), 3.41-3.47 (lH, m, H-4), 3.29 (3H, s, C02CH3), 3.22 {3H, s, C02CH3),

1.98-2.07 {1H, m, H-35}, 1.63-1.68 (1H, m, H-3R); 1.36 {9H, s, (CH3hCO}, 1.34 {9H, s,

(CH3hCO); Be NMR {100 MHz, C6D6) o 171.5, 171.3, 170.7, 1S6.7, 1S0.2, 83.3, 80.0, S6.9, S2.6, S2.3, S1.9, 4S.6, 28.2, 27.8, 2S.O; IR (thin film, cm-1) 3021, 2981, 1790, 17SO, 1717,

1S01, 1370, 1316, 1216, 11S4; M5 (E51}: m/z 430, found 4S3[M+Nat; HRM5 (EI): m/z

calcd. for C19H3oNz09[Mt: 430.19S1; found: 430.1977; [a]29

0= -6S.O (c 0.32 CHCh).

Methyi(2S,4S}-N-tert-butoxycarbonyl-4-[(65}-methoxycarbonyi-N-tert-

butoxycarbonylaminomethyl] pyroglutamate {34}

H C02Me

BocHN~

h 0 N C02 Me I Boc

34

White foam; 23%; Rt (SO% EtOAc/hexane) O.S3;1H NMR

(400 MHz, C6D6) o S. 78 (1H, br, NH), 4.6S-4.69 (1H, dd, J6,4 9.4 Hz, J6,NH 4.2 Hz, H-6), 4.42-4.4S (1H, dd, Jz,3s 9.8 Hz,

h,3R 1.4 Hz, H-2), 3.26 (3H, s, COzCH3), 3.20 (3H, s, C02CH3),

2.9S-2.99 (1H, m, H-4), 2.03-2.11 (1H, m, H-35}, 1.66-1.72

151


(1H, ddd, hR,3s 10.5 Hz, hRA 9.2 Hz, J 3R,2 1.4 Hz, H-3R); 13C NMR {100 MHz, C6D6) 0 172.1,

171.6, 171.1, 155.4, 150.3, 83.2, 79.8, 57.1, 53.3, 52.08, 52.05, 45.3, 28.3, 27.9, 25.0; IR

(thin film, cm-1) 3020, 2979, 1789, 1749, 1718, 1501, 1370, 1316, 1216, 1154; MS (ESI):

m/z 430, found 453 [M+Nat; HRMS (EI): m/z calcd. for C19H3oN209 [Mt: 430.1951;

found: 430.1984; [a)27 0= +3.3 (c 0.56, CHCI3).

Methyi(25,45)-N-tert-butoxycarbonyi-4-[(6RS)-methoxycarbonyi-N-tert-

butoxycarbonylaminomethyl] pyroglutamate (33 and 34) [Scheme 10]

Lithium enolate

N-bromosuccinimide (0.56 g, 3.16 mmol) was added to a stirred solution of Methyl N-

tert-butoxycarbonylglycinate (35)27 {0.57 g, 3.02 mmol) in CCI4 (10 ml) under nitrogen

atmosphere. The stirred solution was illuminated with 500 W lamp for 1 h, keeping the

reaction mixture between 10-30 oc using a water bath. The resulting orange reaction mixture was then filtered and the filtrate was concentrated in vacuo to afford the crude

Methyl 2-Bromo-N-tert-blitoxycarbonylglycinate {36) as yellow oil. To the crude

bromide 36 in THF (6 ml) at -78 oc under nitrogen was added anhydrous triethylamine (0.46 ml, 3.30 mmol) with stirring and the reaction mixture was stirred for 45 min at -78

oc to afford a crude imine 3725 solution. Meanwhile to a stirred solution of pyroglutamate 28 {0.67 g, 2.75 mmol) in THF {12 ml) was slowly added LiHMDS {1.0 Min

THF, 3.44 ml, 3.44 mmol) at -78 oc and the reaction mixture was stirred for 1 h. The cold crude enolate solution was then quickly added to crude imine solution via cannula and

stirred for another 2 h at -78 oc. Saturated aqueous ammonium chloride (6 ml) was added and the reaction mixture was allowed to warm to room temperature; water (15

ml) was added and was extracted with ethyl acetate (3 x 15 ml). The combined organic

extracts were washed with brine (15 ml), dried (Na2S04) and concentrated in vacuo to

give a mixture of two diasteroisomers {33 and 34} as yellow foam (0.84 g, 71%) which

was purified by flash column chromatography on silica gel, using ethyl acetate-hexane

152


(40:60} as eluant to afford 33 (0.48 g, 41.3%} as viscous oil (crystallised further from

diethyl ether to a crystalline solid}, and 34 as white foam (0.21 g, 18%}.

Titanium enolate

28 (0.29 g, 1.21 mmol) was dissolved in anhydrous CH2Ch (10 ml) under nitrogen with

stirring, cooled to -78 oc and TiCI4 (1.0 M in CH2CI2, 1.32 ml, 1.32mmol} was added dropwise followed by slow addition of DIPEA (0.25ml, 1.46 mmol) after 5 min, and the

resultant deep violet enol ate solution was stirred for 1.5 h at -78 oc. Meanwhile a fresh imine 37 solution (-78°C} was prepared in anhydrous CH2Ch (6ml) as described above,

quickly added to enolate solution via cannula and the reaction mixture was stirred for

another 2 h at -78°C. The reaction mixture was then quenched with saturated aqueous

ammonium chloride (10 ml), allowed to warm to room temperature, diluted with water

(15 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic extracts

were washed with brine (15 ml), dried (Na2S04), and concentrated in vacuo to give the

crude product as yellowish foam (0.37 g, 71.7%) which was purified by flash column

chromatography on silica using ethyl acetate-hexane as eluant (40:60} to give 34 as a

white foamy solid (0.32g, 62.3%} .

N-tert-para-toluenesulonylamidobenzyl benzaldimine {38)

A solution of TiCI4 (1.0 M in CH2Ch, 9.48 ml, 9.5 mmol,) was added dropwise to a stirred,

ice cooled solution of benzaldehyde (1.92 ml, 19 mmol), p-toluenesulfonamide (3.25 g,

19 mmol) and triethylamine (7.94 ml, 57 mmol) in anhydrous CH2Cb (40 ml) and the

mixture was stirred for 30 min. The titanium dioxide was removed by suction filtration

through celite and washed with CH2CI2 (20 ml). Evaporation of the solvent under

reduced pressure afforded a white solid which was broken up by refluxing in anhydrous

diethyl ether (75 ml) for 15 min. The residual triethylamine hydrochloride salt was

removed by filtration and the filtrate was concentrated under reduced pressure to

afford the crude imine. Purification by crystallization (hexane/ CH2CI2) afforded 38 as

white solid (1.76 g, 72%}.

153


White solid, mp 110 ·c; 1H NMR (300 MHz, CDCI3) S 9.03 (1H, s,

CH=N}, 7.87-7.94 (4H, m, ArH), 7.59-7.64 (1H, t, J = 7.5, ArH), 7.46-

7.51 (2H, t, J = 7.3, ArH}, 7.33-7.36 (2H, d, J = 8.2, ArH), 2.44 (3H, s,

PhCH3); 13C NMR (75 MHz, CDCI3) S 170.2, 144.7, 135.0, 131.3, 129.8,

129.2, 128.1, 21.7; IR (thin film, cm-1) 1602, 1320, 1158, 1088; MS (ESI}: m/z 259, found

260[M+Ht.

Methyi(25,4S}-N-tert-butoxycarbonyl-4-[ ( GRS)-N-para-

toluenesulonylamidobenzyl]pyroglutamate (39 and 40)

Compounds 39 and 40 were obtained following the general procedure for 29, 30 & 31.

Titanium enolate

Purification by flash column chromatography on silica gel, using ethyl acetate-hexane

(40:60) as eluant separated mixture of 39 and 40 (0.526 g, 85%) together with unreacted

tosylamide. The major diastereoisomer 39 was separated and purified by repeated

recrystallisation from diethyl ether which provided distinct crystalline white solid 39

(0.142 g, 23%). The minor isomer 40 could not be obtained pure but the spectrum was

obtained by subtraction from the mixture.

H NHTs

Ph~ 6 -. 4

~ 0 N C02Me I

Methyi(25,4S)-N-tert-butoxycarbonyi-4-[(6R)-N-para-

toluenesulonylamidobenzyl]pyroglutamate (39)

White crystalline solid; mp 171-175 oc; [found: C, 59.70; H,

39

Boc 5.99; N, 5.61. C2sH3oN207S requires C, 59.75; H, 6.02; N,

5.57%]; Rt (40% EtOAc/hexane) 0.32; 1H NMR (300 MHz,

CDCI3) S 7.46-7.49 (2H, d, J 8.1 Hz, ArH), 7.09-7.17 (7H, m, ArH), 6.45-6.47 (1H, d, JNH.G

4.0 Hz, NH}, 4.40-4.44 (1H, d, h,3s 9.5 Hz, H-2), 4.33-4.36 (1H, dd, J6,NH 4.0 Hz, J6,4 6.9 Hz,

H-6), 3.71 (3H, s, C02CH3 ), 3.01-3.10 (1H, m, H-4), 2.35 (3H, s, ArCH3), 2.00-2.12 (1H, m,

H-35), 1.78-1.85 (1H, m, H-3R), 1.74 (9H, s, (CH3)3CO}; 13C NMR (75 MHz, CDCI3) S 173.0,

171.3, 148.8, 143.2, 137.2, 136.8, 129.3, 128.5, 128.1, 127.7, 127.4, 84.2, 59.0, 56.7,

154


52.7, 46.7, 27.9, 25.6, 21.5; IR (thin film, cm-1) 2993, 1749, 1720, 1457, 1328, 1215,

1157, 1092; MS (ESI): m/z 502, found 525 [M+Nat; HRMS (DART): m/z calcd. for

C2oH23N20sS1 [M-CsH1002t: 403.1327; found: 403.1281; [af8o= +77.5 (c 0.6, CHCI3).

H NHTs

Ph~

h 0 N C02Me I Boc

39+40

Methyi(2S,4S)-N-tert-butoxycarbonyi-4-[(6S)-N-para-

toluenesulonylamidobenzyl]pyroglutamate (40 from 39+40)

Rt (40% EtOAc/hexane) 0.32; 1H NMR (300 MHz, CDC13) o 7.42-7.45 (2H, d, J 8.2 Hz, ArH), 7.00-7.17 (7H, m, ArH), 6.75-6.78

(1H, d, JNH.G 9.1 Hz, NH), 4.63-4.68 (1H, dd, J6,NH 9.1 Hz, J6,4 4.8

Hz, H-6), 4.13-4.17 (1H, dd, h,3s 9.1 Hz, J2,3R 2.3 Hz, H-2), 3.73 (3H, s, C02CH3), 3.16-3.24

(1H, m, H-4), 2.30 (3H, s, ArCH3), 1.79-2.12 (2H, m, H-3S+H-3R), 1.43 (9H, s, (CH3hCO);

13C NMR (75MHz, CDCI3) o 173.6, 171.2, 148.6, 142.9, 137.7, 136.4, 129.2, 128.6, 128.0, 127.9, 126.9, 84.1, 57.7, 57.0, 46.5, 27.8, 24.7, 21.4; IR (thin film, cm-1) 2933, 1749,

1720, 1457, 1327, 1263, 1214, 1156, 1092; MS (ESI): m/z 502, found 525 [M+Nat.

tert-butyl phenylsulfonylmethylcarbamate (42)

A mixture of tert-butyl carbamate (1.5 g, 12.8 mmol) and benzenesulfinic acid sodium

salt ( 4.20 g, 25.6 mmol) were suspended in a solution of methanol in water (1:2, 45 ml}

followed by the addition of 30% aqueous formalin (2.56 ml, 25.6 mmol) and formic acid

(98%, 1.5 ml). The reaction was allowed to stir for 3 days at room temperature during

which time the product precipitated as a white solid. The crystalline sulfone 42 was

filtered off with suction, washed with water and diethyl ether, redissolved in

dichloromethane, dried over Na2S04, and concentrated under reduced pressure to

afford the sulfone 42 (3.0 g, 86.4%).

White solid; mp 155-157 oc; 1H NMR (300 MHz, CDCI3) o 7.91-7.94 (1H, d, J 7.4 Hz, ArH), 7.53-7.68 (3H, m, ArH), 5.42 (1H, br, NH), 4.52-4.54

(2H, d, J 7.0 Hz, CH2), 1.26 (9H, s, (CH3hCO); 13C NMR (75 MHz, CDCI3) ()

154.0, 137.0, 134.2, 129.3, 129.1, 81.2, 62.2, 28.1; IR (thin film, cm-1)

155


1703, 1477, 1448, 1421, 1364, 1291, 1142, 1087, 1007; MS (ESI): m/z 271, found 289

[M+NH4t,

Methyl (2S,4RS)-N-tert-butoxycarbonyi-4-(N-tert-

butoxycarbonylaminomethyl)pyroglutamate (44 and 45}

Lithium enolate

UHMDS (1.0 M in THF, 6.14 ml, 6.14 mmol) was added dropwise to a solution of 28 {0.65

g, 2.672 mmol) in anhydrous THF (15 ml) at -78 oc under nitrogen atmosphere with stirring. The reaction mixture was stirred for 1.2 h, a solution of sulfone 42 (0. 79g, 2.93

mmol) in THF (15 ml) was added to it, and the stirring was continued for a further 2 h at

-78 oc. The reaction was quenched with aqueous saturated ammmonium chloride solution (15 ml), allowed to warm to room temperature, diluted with water (25 ml), and

extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were washed

with brine {15 ml) and dried (Na2S04). Removal of the solvent in vacuo gave the product

as a pale yellow foam (0.73 g, 74%) which was purified by flash column chromatography

on silica gel using ethyl acetate-hexane (45:65) as eluant to give 44 (0.34 g, 35%) and 45

(0.33 g, 33.2%) as viscous oils which crystallised to white solid on standing overnight.

Titanium enolate

TiCI4 {1.0 M in CH2CI 2, 3.3 ml, 3.3 mmol) was added dropwise to a solution of 28 (0.35g,

1.43 mmol) in anhydrous CH2CI 2 (10 ml) at -78 oc under nitrogen atmosphere with stirring followed after 5 mins by dropwise addition of DIPEA (0.62 ml, 3.59 mmol)

resulting into a deep violet colored solution. The reaction mixture was stirred for 1.5 h

at -78 oc and a solution of sulfone 42 (0.42 g, 1.58 mmol) in CH2CI2 (10 ml) was added (warm to dissolve). After stirring for 2 h at the same temperature, the reaction was

quenched with aqueous saturated ammonium chloride solution (12 ml) and the mixture

was allowed to warm to room temperature. Water {15 ml) was added and the product

was extracted with dichloromethane (3 x 20 ml). The combined organic extracts were

156


washed with brine (10 ml), dried (Na2504) and concentrated in vacuo to yield the crude

product 44 (0.43 g, 82%) which was purified by flash column chromatography on silica

gel, using ethyl acetate-hexane (45:65) as eluant to give 44 (0.358 g, 67%) as clear oil

which crystallised on standing overnight.

6 BocHN-,,

J:'x. 0 N C02Me I Boc

44

Methyl (25,45)-N-tert-butoxycarbonyi-4-(N-tert-

butoxycarbonylaminomethyl)pyroglutamate (44)

White solid; mp 95-97 OC; [found: C, 54.88; H, 7.45; N, 7.61.

C23H32N201 requires C, 54.83; H, 7.58; N, 7.52%]; Rt (70%

EtOAc/hexane) 0.5;1H NMR {300 MHz, CDCI3) o 5.15 (1H, br, NH), 4.56-4.60 (1H, dd, h,35 8.9 Hz, h,3R 1.7 Hz, H-2), 3.78 (3H, s, C02CH3 ), 3.46-3.52

(1H, m, H-6), 3.30-3.36 (1H, m, H-6), 2. 77-2.85 (1H, m, H-4), 2.06-2.23 (2H, m, H-3R+H-

35), 1.50 {9H, s, (CH3)3CO), 1.42 (9H, s, (CH3)3CO); 13C NMR (75 MHz, CDCI3) 8 174.4,

171.6, 156.3, 83.9, 79.5, 57.0, 52.7, 42.7, 39.5, 28.3, 27.9, 25.6; IR (thin film, cm-1) 2928,

1772, 1707, 1520, 1459, 1374, 1313, 1258, 1217, 1158; MS (ESI): m/z 372, found 395

[M+Nat; HRMS (DART): m/z calcd. for C17H29N20 7 [M+Ht: 373.1974; found: 373.2010;

[a] 220= -40.2 (c 0.28, CHCI3).

6

BocHN~

0 N C~Me I

Methyl (2S,4R)-N-tert-butoxycarbonyi-4-(N-tert-

butoxycarbonylaminomethyl)pyroglutamate (45)

White solid; mp 105-107 OC; [found: C, 54.91; H, 7.53; N,

7.49. C23H32N201 requires C, 54.83; H, 7.58; N, 7.52%]; Rt

(70% EtOAc/hexane) 0.43; 1H NMR {300 MHz, CDCb) o 5.17 (1H, br, NH), 4.47-4.53 (1H, dd (unresolved), H-2}, 3.77 (3H, s, C02CH3 ), 3.46-3.52 (1H,

m, H-6), 3.30-3.38 (1H, m, H-6), 2.70-2.80 (1H, m, H-4), 2.46-2.56 (1H, m, H-3$), 1.74-

Boc

45

1.84 (1H, m, H-3R), 1.49 (9H, s, (CH3)3CO), 1.42 (9H, s, (CH3)3CO); 13C NMR (75 MHz,

CDCI3) o 174.2, 171.7, 156.3, 149.2, 84.1, 79.6, 57.4, 52.6, 43.4, 40.3, 28.4, 27.9, 25.2; IR(thin film, cm-

1) 3020, 1786, 1748, 1710, 1511, 1369, 1308, 1216, 1156; MS (ESI): m/z

372, found 395 [M+Naf; HRMS (DART): m/z calcd. for C11H29N207 [M+Ht: 373.1974;

found: 373.1982; [a] 23 o= -44.1 (c 0.2, CHCI3).

157

I


3.7. Spectral data

J 7.5 7.0

1H NMR, 300 MHz, CD03

yHBoc

Ph:{}.

o ~ C02Me Boc 29

6.5 (d) :')5

~ ~~~§S~~B ~~~~§~~g~~

~~·~vP

5,0 4.5 -tO 3.5 3.0 :15 2.0 1.5

'l~( )~( l:i Is( '~' ):( l§n:l 11:!:1'!!"1 :;:, '-"

:!!'! !OE

\I ~ ~

13C NMR, 75 MHz, CD03

H NHBoc Ph~.

~ 0 ~ C02Me Boc

29


g$~ :!33

\II

I I I I I 135 130 125 120 ll5

I I I I I I I I I U m B W U M D ~ G

Figure 19. 13C-NMR of compound 29 158

Chapter 3

?!•J,::qn:Jiti~r1' l~~~-~4( t> ,:;u;t il.~•m! ~" A~ l,&:tn~~.,.., \'l': >.!1 m V.Hc!


~~E~~i@

~~

1.5

r~1

"' X ~

I 1 H NMR, 400 MHz, CDCI,

H Ph BocHNh o 1;-1 C02Me

Bee __;jj)

5.5 .:.s 40 .L~ .lO

I~( (~I lsl 2JJ

!:\lsi


~~ s " 9!:0::: E~ ~ :! I I

"'c NMR, 75 MHz, CDCI3

BocHNh 0 1;-1 C02Me

Bee 30

., ~s~ ..,

®

~£!5 M

\V

Chapter 3

C'~trJ>:l~ ~~tt l'HUtttn :O..'a! lllll?V~,;:-~;~LNAn~.). ~~!() •

~i'!X!~

f: · lrl:1f:ll.l!~UO!': ~ta~ttnr i!f~- m:.~t.tl Oint t~.~l !ttSlr'..M ~'-"'~t ~ ~ !fa Ml ~~;;,.

;;!re'G ~~~i~ SOIJ


I

~ I

1H NMR. 300 MHz. CDCI3

H. Ph

BocHN_:~A 0 N C02Me

I

Bee 31

;% S£$;~~ ~¥~~~~

f \~P ~1?

Chapter 3

\I\

f;.~,:,."'1~m:n'.t!t $( J.:it.t !::(" ~~- ·~~.:l';:; ~~

~ "'

J __) '-----" '------~

'--------1' ''"-----'! Ll r {

II

i.S 7.0 6.5 6.0 5.S S.O 4.5 4.0 .l5 3.0 2.5 2.0 !.5 1.0 0.5 wm

l~l I;( \§1 lsi I~( Is( l§( is( ~1~

I I \1/

13c NMR, 75 MHz, CDCI3

~h BocHN,h

0 N C02Me I

Bee 31


175 170 16." !flO 15.5 150 l-t-5 '140 135 1~ 11:5 120 11.5 110 105 too 95 90 85 80 75 70 65 60 .55 50 45 .;o ~5 30 25 20 15 10 o prm

Figure 23. 13C-NMR of compound 31

160


7.5

""


Hh.co,Me BocHN 6 4

2

0 ~ C02 Me

Boc __3_2

'1.0 (..5 6.0 5.5

~~~ 5.0 3.0 2.5 2.1)

Is( 1:1 1:1


\I/

170

1'c NMR, 100 MHz, CDCI3 H CO,Me

BocHNh

o ~ co2Me

Boc '----~3.2. ___ ~

I j 160 ISO 140 1:10

1 J 120 110 100 90 70 (I!


40

1.0

1 20

Chapter 3

~l-!:t~! ftt.O ~H~~;J 'fl!:!(. :un·F~ ~~ m w~ l

t' • A::t;::.$i;i~ ~H-"~tUlt r-~u_ x~•~l~ r~ :,_:! i::S.lli"l! lft':(~t P~!ID 1~~wu ra.~ t;l~

·~ ~}!]~ s.:t~m ~l

n m t1 l ~ mt.;a~ r;w,s. MHGJ!:: lil t.:'t.Hlt.'1rt;: ~ .lJJ tl ~-£1-.~ ~ ~-~:!let" 1! ){(;.~ t ;;1 l.tw:~~.o/.:m Be l

- ... ::1W#t: ,. l.m:ut,..

: ~~i.~ ~ :


ISO

1H NMR, 400 MHz, C6 D,;

YHBoc Meo,ch

0 J;'l C02 Me

Boc 33

7.0 (!.0 5.5 5.0 -t5 -1.!1 ]5 3.0 2.5 2.0 1.5 1.0

~~~ f:: " 5::~~ ~ ~

~~

13C N MR, 100 MHz, C60 6

H NHBoc

Me02Ch 0 N C02 Me

I

Boc 33

l:l !:l l:l 1:¥;1~1 l:l ~~~ ~~~


170 160 1:«> 1.:0 no 120 110 100 90 80 70 60


162

Chapter 3

'' .~; f~··

} ~:~YJ;~ ::::.: t,.~~~

~$~~~ ~.0.~ ~~

i*6.UH2t t.i.~J:~!


7.0

\1/

1H NMR, 400 MHz, C6 D6

H co,Me

SocHW~t~

6S

o N/ co,Me I

Soc __3i

I

6.0 5.:-

ls(

I I

13C NMR, 100 MHz, ~6 tyC02Me

SocHN 'h 0 ~ C02 Me

Soc

'------~34--~

§~~§~~~gg,¥~§~~

·~~

I I I

:S.O 4.5 4.0 3.5 .J.O 2.~ ~.0 15 1.0

1~1 1~1 ~~~lsi lsi lsi ~~~


~ ~ II

~~~ \

1 I I I

Chapter 3

f:· ~ J.::l(:HH~(,~ Nz#'R.Hf

""'~ i:~*:a t>M~ i~.;'

~>;:;~ s~t·~ l'!PY>:ii: :t~* n:: ~m' >e:;>;;::;';' ~

~ ;:~ ~ ~!f.Ulll'.: n:at$ ~.m~Pfl II< ~.~!l'l:J) M< . " ~ ,~.me~ ::a u~ ~~#';; ;1 ?.H'-~l u~~~~;; :.: l"Z'~

0.5

l'l.S l'iO IIi. 125 120 115 Ito lOS lt~ 9!1 I'J


~~Ej~~;E~

\\~r;P


'1.5 1.0

1~1 hsl

yHTs Phh 0 t;J C02Me

Boc 39

6.0

~~~~~~ ~

5.0 -1.5 4.0 3.5

lsl~l 1~1

~ft~~~~~~~z~~

~V!l)JJ)

:!..5 20 1.5

1~1 ~~~ lsi 1~1


\I I IV\~

13C NMR, 75 MHz, CDCI3

H NHTs Phh 0 t;J C02Me

Bee

39

q~ ~ ~ " ~.~ " 'C j

fO-$:?) !

e-~ .. :·•~t.:f.lltltl (lt:t .. ' 11.:~.11:: !l'lt ;}.;! !:mill :¥,..,~ W:HO .5~

~i::;~ ~ :i'X! ti !Hl! !'::~"M ~~~li

tl "

~ itt! . .;;;~: r.:at c.~~~m i; fli }.~~}~It: il: ~.S cr t~.!$ :::w~: ~ t$,:-wt ':t m.~l Ci t.~l,t( ~ I

..,..-. .. ~!;, ....... ,.. JtZ:l i3: p; H.~~..: fll .;..re.e f'Cl 3::1).1;;~}.!.1~

fl" • 1:'-£.;.;: '>'u.w!ta S! .• )!1R. 'it ~,!~:!.lf"...::.u~-..,.,. .. ,~ U..",.'>c-T• t: ---••• r:;r~ ..s::r:~B wr: :s IOH II'.~~ nl ·•-~=-rut ~·-:3-}

~f · ~r.t 140 13~ 130 125 120 115 110 105 100 9~ 90 35 SO 75 70 (.._c; 60 55 50 45 40 .'5 ,lO 2.5 20 !;'> 10 ppm



§~~E~E~§~~~i~~~

~~7!JP?P


yHTs Ph'h 0 1)1 C02Me

Boc

39+40

1.•.0 S.5 50 2.5 2.0 1.~

(~i~ 1~n:l ~~~~)

Figure 32. 1H-NMR of compound 39+40

\IV

1'c NMR, 75 MH2, CDC!3

H NHTs

Phh 0 1)1 C02Me

Boc

39+40

1.0

Chapter 3

..,.,..,.,..1.,.,.;.,. »> ~..-


DEPT 135, 75 MHz, CDCI3

H NHTs Phh 0 f:' C02Me

Boc 39+40

Chapter 3

::::::, ~.,.,..).,,.;\""' 0•-N< ..... ,,...,.,.

:;~¥ ""'g·~

.~· .. ~..:rill if....


~& ~.....;

~!:::

l I ~ . .., co -

I I

70 60 50



BocHNb

0 t;J C02Me Boc 45

-c ~~ ,... V"> ..... j o\

""· I I

r---r--f"'iO"'C ~r-.:·n o:'lC'IC'l

\II

Chapter 3

•t:>«>Y"'1:1"""\th J:"t

H.


~ ~, c "' ~\ ,.I-t •r• ,.., :: 3 ~ 0 "' '"" .... ""1:~~ ,... ~ ::! ~o' ,... ~ «:r--v-; "' ..... "' "' ("J -:-~ ':'l I I I I I I I \II

1'c NMR, 75 MHz, CDCI3

6

Boci-IN~

0 N C02Me I

Boc 45

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm


168


3.8. References

1. (a) lkota N. Tetrahedron Lett. 1992, 33, 2553; (b) Rosset S.; Celerier J. P.; Lhommet

G. Tetrahedron Lett. 1991, 51, 7521.

2. (a) Baldwin J. E.; Pritchard G. J.; Williamson D. S. Tetrahedron 2000, 57, 7991; (b)

Campbell A. D.; Raynham T. M.; Taylor R. J. K. J. Chern. Soc. Perkin Trans. 1. 2000,

3194; (c) A. Rubio; J. Ezquerra and A. Escribano, Tetrahedron Lett., 1998, 39, 2171.

3. Ohta T.; Hosoi A.; Nozoe S. Tetrahedron Lett. 1988, 29, 329.

4. Ohfune Y.; Tomita M. J. J. Am. Chern. Soc. 1982, 104, 3511.

5. (a) Van Betsbrugge J.; Van Den Nest W.; Verheyden P.; Tourwe D. Tetrahedron

1998, 54, 1753; (b) Li H.; Sakamoto T.; Kikugawa Y. Tetrahedron Lett. 1997, 38,

6677.

6. Hanessian S.; McNaughton-Smith G.; Lombart H.; Lubell W. Tetrahedron 1997, 53,

12789

7. Menezes, R. F.; Zazza, C. A.; Sheu, J. and Smith, M. B. Tet. Lett. 1989, 30, 3295.

8. (a) Davies, S. G.; Doisneau, G. J. M.; Prodger, J. C. and Sanganee, H. J. Tet. Lett.

1994, 35, 2369 (b) Davies, S. G.; Doisneau, G. J. M.; Prodger, J. C. and Sanganee,

H. J. Tet. Lett. 1994, 35, 2373.

9. (a) li, H.; Sakamoto, T. and Kikugawa, Y. Tet. Lett. 1997, 38, 6677 (b) Escribano, A.;

Carreno, M. C. and Rciano, J. L. G. Tet. Lett. 1994, 53, 2053 (c) Herdeis, C.;

Hubmann, H. P. and Potter, H. Tet. Asymm. 1994, 5, 119 (d) Herdeis, C.;

Hubmann, H. P. and Potter, H. Tet Asymm. 1994, 5, 351 (e) Moody, C. M. and

Young, D. W. J. Chern. Soc. (PT-1} 1997, 3519 (f) Moody, C. M. and Young, D. W.

Tet. Lett. 1994, 35, 7277 (g) Panday, S. K.; Brunet, D. G. and Langlois, N. Tet. Lett.

1994, 35, 6673 (h) Collado, 1.; Ezquerra, J. and Pedregal, C. J. Org. Chern. 1995, 60,

5011.

10. Zhang, X.; Schmitt, A. C.; Jiang, W. Tet. Lett. 2001, 42, 5335.

11. Rosset, S.; Celerier, J. P. and lhommet, G. Tet. Lett. 1992, 51, 7521

12. Honda, T. and Kimura, M. Org. Lett. 2000, 2, 3925.

169


13. (a) Marchalin, S.; Szemes, F.; Bar, N. and Decroix, B. Heterocycles 1999, 110, 8696

(b) Smith, A. l.; Williams, S. F. and Holmes, A. B. J. Am. Chern. Soc. 1988, 110,

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172

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