University of Groningen Novel chiral 1,3,2

University of Groningen

Novel chiral 1,3,2-dioxaphosphorinanesDros, Albert Cornelis

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NOVEL CHIRAL 1,3,2-DIOXAPHOSPHORINANES

This research was sponsored by the Netherlands Orginization for Scientific Research (NWO)

RWKSUNIVERSITEIT GRONINGEN

NOVEL CHIRAL 1,3,2=DIOXAPHOSPHORINANES

Proefschrift

ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus, dr. F. van der Woude,

in het openbaar te verdedigen op vrijdag 4 april 1997

des namiddags te 4.15 uur

door

Albert Cornelis Dros

geboren op 22 januari 1968 te Sneek

Promotor: Prof. dr. R.M. Kellogg

Voonvoord

Hoewel alleen mijn naam op het omslag prijkt, is de inhoud van dit proefschrift mede ge'inspireerd door een aantal mensen in mijn omgeving. Velen hebben bijgedragen aan de resultaten zoals die staan beschreven, enkelen wil ik met name noemen. Ivlijn promotor, professor R.M. Kellogg wil ik danken voor de grote mate van vrijheid in mijn onderzoek. De leden van de leescornmissie, professor Van Leusen, professor Feringa en professor Teuben, voor kritische lezing en correctie van het manuscript. De dagelijkse 'lunchbesprekingen' met Ton Vries waren een belangrijke bron van inspiratie. Henk 'Buurman' van der Worp was er voor de nodige complexe associaties, suggesties voor het avondeten en goed gezelschap tijdens omwegen naar huis. Met zijn muziekkeuze drukte Charon Zondervan zijn stempel op de zo karakteristieke 14-223-Z-sfeer. Ozric Tentacles en Jethro Tull pik ik er nu we1 uit. Marc Veen was er altijd e n dan met name in het weekend- voor koffie, gezelligheid en -uiteraard- computerzaken. Rob Zijlstra liet mij delen in de geheimen van Bridge en Gaussian. Onder werktijd over bridge, en tijdens een stilzit over chemie praten kan zeer verfrissend werken. Ron Hulst heeft rnij wegwijs gemaakt in de fosforchemie en was -ook op afstand- altijd bereid rnee te denken. Esther van den Beuken voorzag rnij van palladium- verbindingen die met haar liganden w61 complexen vormden. Jan Herrema en Wim Kruizinga zorgden ervoor dat mijn NMR-spectra er uitzagen zoals ik ze hebben wilde. Bij Syncom mocht ik ervaren hoe het voelt om ook even 'man van de industrie' te zijn. Als ik dinsdags energie overhad kon ik die ruimschoots kwijt bij het 'ballen'. Voor buitensport was daar 'Transpiractie'. Met name de meerdaagse 'veldtochten' waren altijd erg geslaagd. Mijn ouders bleven a1 die jaren ge'interesseerd in wat ik deed, binnen het lab, maar vooral ook daarbuiten. Papa, mamma, jullie vertrouwen heeft mij altijd erg goed gedaan. Rixt, jij bent voor mij de afgelopen jaren de grootste steun geweest. Vooral de laatste tijd hield jij -ook voor mij- de grote lijnen in het oog.

Contents

Chapter 1 Introduction 1.1 Phosphorus 1.2 Phosphorus: the element 1.3 Structure and bonding 1.4 The organic chemistry of phosphorus 1.5 Phosphorus-based ligands 1.5.1 Tervalent phosphorus in ligands

1.5.2 Pentavalent phosphorus in ligands

1.6 Stereochemistry of organophosphorus compounds 1.7 Dioxaphosphorinanes 1.7.1 Confonnational analysis of 1,3,2-dioxaphosphorinanes

1.7.2 1.3.2-Dioxaphosphorinanes from this laboratory

1.8 Outline of this thesis

Chapter 2 Unusual Stereochemical Aspects of Novel Chiral Pyridinyl-2- phosphonates

2.1 Introduction 2.2 Chiral pyridinyl-2-phosphonates 2.2.1 Synthesis of ch id pyridinyl-2-phosphonates

2.2.2 Characterization

2.2.3 Molecular structure of 2.1k

2.3 Oxidation at nitrogen 2.3.1 Molecular structure of 2.12

2.4 Synthesis of N-methylated pyridinyl phosphonate 2.5 Synthesis and characterization of chiral pyridinyl-2-thiophosphonates 2.6 Borane adduct 2.7 Attempted synthesis of a chirall .lo-phenanthroline-2-phosphonate 2.8 Transition metal complexes and catalysis 2.9 Experimental section

Chapter 3 Novel Enantiomerically Pure Propane-1,3-diols 3.1 Introduction 3.2 Synthesis of the precwsor 3.3 Novel chiral propane-1,3-diols 3.4 Experimental section

Chapter 4 Diphosphites, Diphosphates, and Borane Adducts 4.1 Introduction 4.2 Transition metal complexes 4.3 1,3,2-Dioxaphosphorinanes 4.4 Borane adducts 4.5 Synthesis of chelating diphosphites 4.6 Molybdenum complex 4.7 Borane adducts 4.7.1 Synthesis

4.7.2 Removal of borane

4.8 Oxidation of diphosphites 4.9 Catalysis 4.10 Experimental section

Chapter 5 Chiral Self-Recogniti 5.1 Introduction 5.2 Synthesis of molecules containing two chiral centers 5.3 Diphosphites from racemic diol 5.4 Enantiomeric enrichment 5.4.1 Synthesis of enriched diphosphates

5.5 Labelling experiments 5.5.1 Synthesis of labelled diphosphates

5.5.2 Mass spectrometrical analysis of labelled diphosphates

5.6 Borane adducts 5.7 Origin of recognition 5.8 Conclusions 5.9 Experimental section

Chapter 6 Conformational Analysis of Pyridinyl-2-phosphonates 6.1 Introduction 6.2 The system 6.3 Geometry optimizations. the methods 6.4 Single point energy calculations 6.5 Geometry optimizations, rhe results 6.5.1 Conformations of 6.2s and 6.3s

6.5.2 Conformations of 6.2b and 6.3b

6.5.3 Conformations of N-methylated derivatives 6.5.4 Conformations of thiophosphoryl derivatives

6.5.5 Conformation of the dimethyl derivative

6.6 Experimental section

Samenvatting Inleiding Dit proefschrift

Introduction cm 1 1.1 Phosphorus1 Phosphorus is everywhere. It is present in a multitude of forms in nature and is essential to life. Phosphorus containing materials range from calcium phosphate in bone and teeth via the biochemical energy transfer agent adenosine triphosphate (ATP) to the essence of life itself in the form of the carriers of genetic information, the nucleic acids RNA and DNA. In nature phosphorus is found almost exclusively in the pentavalent oxidation state.

9- -0-p-0 0

- * y o

- * y o 'd" inorganic phosphate ATP part of a DNA strand

Scheme 1.1. Phosphorus in nature

The German Hennig Brand discovered phosphorus in 1669. Upon distillation of urine he obtained a material that glowed in the dark and ignited in air. It was called phosphorus (Greek for light bearing) because of these properties. Phosphorescence, however, is not a characteristic of phosphorus compounds, quite the contrary, most phosphorescent materials do not contain the element.

1 (a) For a detailed discussion on all aspects of phosphorus see: Corbridge, D.E.C. Phosphorus. An Outline of its Chemistry, Biochemistry and Technology. Elsevier Science Publishers, Amsterdam, The Netherlands, 1990. (b) See also: Hartley, F.R. in The Chemistry of Organophosphorus Compounds, Vol. 1, Hartley, F.R., Ed. Wiley: Chicester, England, 1990, p. 1 .

Chapter 1

1.2 Phosphorus: the element Phosphorus, symbol P, atomic number 15, atomic weight 30.9738, exists as a single stable isotope 31P with a nuclear spin of H.l Its relatively high sensitivity (0.066 vs. 1.76.10-4 for l3C, corrected for natural abundance) for nuclear magnetic resonance makes it possible to study reaction kinetics and analyse complex reaction mixtures due to the simplicity of proton- decoupled phosphorus (31P(1H}) NMR spectra compared with lH NMR spectra. The spectral width of phosphorus NMR is large: from -488 ppm for P4 to +277 pprn for PBr3, every class of phosphorus compound having its own region in the spectrum.

1.3 Structure and bondinglb Simple approaches like valence shell electron pair repulsion (VSEPR) do not satisfactorily describe structure and bonding in tervalent organic phosphorus compounds. Walsh diagrams form a more accurate, albeit qualitative, representation of the bonding in phosphines. For quantitative predictions one has to rely upon abstract and time-consuming quantum chemical calculations. The involvement of d-orbitals in bonding to phosphorus still is a disputed issue. Back-donation of transition metal electrons into vacant d-orbitals has often been proposed as the reason for the stability transition metal complexes of tervalent phosphorus. However, it is now accepted that back-bonding plays a role only in complexes of PF3 and phosphites and that not d-orbitals on phosphorus but o*-orbitals are the acceptor orbitals. Another class of compounds where d-orbitals were thought to be involved in bonding, is the pentavalent phosphorus chalcogenides R3P=E (E = 0 , S, Se, Te).2 The generally applied representation of 'pentavalent' phosphoryl compounds as R3P=0 violates the Langmuir octet rule. The representation is also misleading because it implies a double bond between phosphorus and oxygen which suggests the possibility of addition reactions. Numerous alternative models for the phosphoryl PO bond have been put forward.2 Back- donation of oxygen lone pair electrons into anti-bonding orbitals of e symmetry on phosphorus produces two mutually perpendicular half n-bonds (Figure 1.1, left).'

Figure 1.1. Models for the phosphoryl PO bond. Lefi: z-backbond; middle: R-model; right: triple back bond

Gilheany, D.G. in The Chemistry of Organophosphorus Compounds, Vol. 2, Hartley, F.R., Ed. Wiley: Chichcster, England, 1992. p. 1. Knutzelnigg, W. Angew. Chem., Int. Ed. Engl. 1984.23, 272.

Ab initio calculations by different procedures resulted in the a- and triple back bond m ~ d e l s . ~ Although the R3P=O representation is clearly an oversimplification, it is still widely adapted since it reflects the bond strength and interatomic distance in phosphoryl compounds. The nature of the PO bond itself being uncertain, the correct formulation of the coordinative bond to a metal atom seems out of reach. From X-ray diffraction studies it is clear that M-0 bonds have multiple bond chareter with M-O-P angles varying from 113 to 180". In contrast, M-E bonds (E = S, Se, Te) are single bonds with M-E-P angles varying from 96 to 120°.5

1.4 The organic chemistry of phosphorus Synthetic organophosphorus compounds were first reported in the 19th century; alkyl phosphates in 1820 and phosphines in 1840. The organic chemistry of phosphorus is dominated by two oxidation states: PI" and PV. Phosphorus forms strong bonds with oxygen, and formation of this bond is the driving force in many reactions typical of phosphorus, amongst others the Arbuzov reaction and the Wittig reaction.

(Ro)3p + R1CH2X ? + RX R W ~ wR' RO

X= C1, Br, I

Scheme 1.2. The Arbuzov (top) and Wittig reactions

Most tervalent organophosphorus species are sensitive to oxidation by atmospheric dioxygen or hydrolysis, forming pentavalent phosphoryl compounds. A special case is formed by the simple dialkyl phosphites: they exist in equilibrium with tautomeric H-phosphonates and are not readily oxidized.

Scheme 1.3. Tautomerism in dialkyl phosphites/dialkyl H-phosphonates

The spectroscopic data for, and reactivity of these compounds reflect the position of the phosphite/phosphonate equilibrium. Resonances in 3lP NMR for these compounds are found

(a) Schmidt, M.W.; Yabushita, S.; Gordon, M.S. J. Chem. Phys. 1984.88, 382. (b) Messmer, R.P. J . Am. Chem. Soc. 1991,113. 433. Lobana, T.S. in The Chemistry of Organophosphorus Compounds, Vol. 2, Hartley, F.R., Ed. Wiley: Chicester, England, 1990, p. 409.

around 0 ppm, characteristic for pentavalent species. The H-phosphonate hydrogen atom displays a very large coupling constant (JpH = 600-700 Hz), indicative of its being directly bonded to phosphorus. Dialkyl phosphites are not readily oxidized. Contrastingly, alkali metal derivatives of H-phosphonates have dialkyl phosphite character: infrared spectra lack the v(P=O) vibrational band and feature a P-O- band instead. The 31P NMR resonance is found in the phosphite range.6 The anions generally react as P- rather than 0-nucleophiles.

1.5 Phosphorus-based ligands 1.5.1 Tervalent phosphorus in ligands 1 9 7

Tervalent phosphorus has a free electron pair that can be donated to empty metal orbitals to form coordination complexes. Coordination compounds of PF3, phosphines (e.g. PPh3) and phosphites (e.g. P(OEt)3) have all been described, as well as many intermediate forms like phosphinites (e.g. Ph2POEt) and phosphonites (e.g. PhP(OEt)2). Bonding capacity of temalent phosphorus ligands to metals is often described in terms of o- donor ability and x-acceptor ability.7 The ratio between x-acceptor abilitylo-donor ability can be related to carbonyl stretching frequencies in metal carbonyl complexes.8 Generally speaking, phosphines are stronger a-bases whilst phosphites are stronger x-acids. Therefore, phosphines will readily complex electron poor metals in high oxidation states, whereas phosphites prefer electron rich metals in their lower oxidation states. Apart from electronic factors, size of substituents on phosphorus plays a major role in determining the relative stability of the metal phosphorus bond.9

YPh3 CI- R,h- CO

PPh3

ref. 10 ref. 11 ref. 12

Scheme 1.4. Examples of complexes of tervalent phosphorus ligands

Complexes of tervalent phosphorus ligands are known for metals throughout the transition series; examples of PF3,10 PPh311, and P(OMe)312 complexes are depicted in Scheme 1.4.

Nagar, P.N. Phosphorus, Sulfur and Silicon 1993, 79,207. McAuliffe, C.A.; Levason, W. Phosphine, Arsine and Stibine Complexes of the Transition Metals, Elsevier Scientific Publishing Company: Amsterdam, The Netherlands, 1979. Cotton, F.A.; Kraihanzcl, C.S. J. Am. Chem Soc. 1962,84, 4432. Tolman, C.A. Chem Rev. 1977.77, 313. Sikora, D.J.; Rausch, M.D.; Rogers, R.D.; Atwood, J.L. J . Am Chem. Soc. 1981,103, 982. Chen, Y.-J.; Wang, 3.-C.; Wang, Y. Acta Cryst. 1991, C47, 2441. Beevor, R.G.; Green, M.; Orpen, A.G.; Williams, I.D. J. Chem. Soc., Dalton Trans. 1987, 1319.

Introduction

Many complexes have been collected and classified according to the different groups in the Periodic Table.13

1.5.2 Pentavalent phosphorus in ligandsl.5.~ Phosphoryl oxygen, sulfur, selenium, and tellurium can donate electron density to metal atoms, forming coordination compounds. Compounds like trioctylphosphine oxide are efficient extractants for lanthanides and actinides.14 Combination with other donor atoms to give bi- or polydentate ligands enhances the affinity for transition metals. Examples with oxygen,15 nitrogenl6, and tervalent phosphorus17 have been described.

Ph. -R< Ph'P B LP,- ~h

Ph

ref. 15 ref. 16 ref. 17

Scheme 1.5. Examples of complexes of pentavalent phosphorus ligands

1.6 Stereochemistry of organophosphorus compounds With the ever growing importance of asymmetric catalysis,18 synthesis of chiral phosphorus ligands has received much attention in recent years. The 'chiral pool' is a rich source of starting materials for the syntheses of a variety of chiral phosphines, phosphinites, phosphonites, and other derivatives. Typical examples include DIOPl9, derived from tartaric acid, Ph-P-glup- OH,m based on the sugar glucose and ProNOPF1 based on the amino acid proline.

(a) Comprehensive Coordination Chemistry, Wilkinson, G.; Gillard, R.D.; McCleverty, J.A., Eds., Pergamon Press: Oxford, 1987. (b) Comprehensive Orgonometallic Chemistry, Wilkinson, G.; Stone, F.G.A.; Abel, E.W. Eds., Pergamon Press: New York, 1982. Ionic pentavalent phosphorus is left out of consideration. Nicol, M.J.; Fleming, C.A.; Preston, J.S. in reference 13a, Chapter 63. Gahagan, M.; Mackie, R.K.; Cole-Hamilton. D.J.; Cupertino, D.C.; Harman, M.; Hursthouse, M.B. J . Chem. Soc., Dalton Trans. 1990, 2195. Casares, J.A.; Coco, S.; Espinet, P.; Lin, Y.-S. Organometallics 1995, 14, 3058. Baker, M.J.; Giles, M.F.; Orpen, A.G.; Taylor, M.J.; Watt, R.J. J. Chem. Soc., Chern. Comrnun. 1995, 197. Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New York, 1994. Kagan, H.B.; Dang, T.-P. J. Am Chem. Soc. 1972,94, 6429. Kumar, A.; Oehme, G.; Roque, J.P.; Schwarze, M.; Selke, R. Angew. Chem. Int. Ed. Engl. 1994.33, 2197. Agbossou, F.; Carpentier, J.-F.; Hatat, C.; Kokel, N.; Mortreux, A.; Betz, P.; Goddard, R.; Kriiger, C. Organometallics 1995.14, 2480.

DIOP ref. 19

OPh P ~ P '

fi2p /o

Ph-bgl~p-OH ref. 20

ProNOP ref. 21

Scheme 1.6. Tervalent phosphorus ligands derived from naturally occurring chiraI building blocks

The vast majority of tervalent ahd pentavalent phosphorus compounds are tetrahedral. Hence, phosphorus can be, and often is, a stereogenic centre. In contrast with chiral nitrogen, chiral tervalent phosphorus is configurationally stable. Compounds with a stereogenic phosphorus atom are referred to as being P-chiral. A recent review describes the synthesis of a host of P-chiral ligands.22

1.7 Dioxaphosphorinanes This thesis deals with the synthesis of 1,3,2-dioxaphosphorinanes. Dioxaphosphorinanes are six-membered rings containing, apart from carbon, one phosphorus atom and two oxygen atoms. 1,3,2-Dioxaphosphorinanes are generally synthesized from a 1,3-diol and a simple phosphorus compound, e.g. PCl3, P(NMed3, P(OMe)3.

CI

n A 0

7' NMe2

n A 0

7' OMe

Scheme 1.7. General synthesis and numbering scheme of l,3,2-dioxaphosphorinanes

22 Pietrusiewicz, K.M.; Zablocka, M. Chem Rev. 1994,94, 1375.

6

1.7.1 Conformational analysis of 1,3,2-dioxaphosphorinanes The conformations of 1,3,2-dioxaphosphorinanes and 1,3,2-oxazaphosphorinanes have been widely studied over the last decades.23 X-Ray crystallography,24 31P NMR25 and multidimensional 1H NMR studies, and quantum chemical calculations are important tools for conformational analysis. With the ever increasing power of computer systems and refinement of basis sets used, the importance of computational chemistry is growing. Many 1,3,2-dioxaphosphorinanes adopt a chair conformation, slightly flattened at the phosphorus end, due to relatively long P-0 bonds. Unsubstituted and symmetrically 5 3 - disubstituted 1,3,2-dioxaphosphorinanes are highly mobile and undergo rapid chair-chair interconversion.

Scheme 1.8. Chair-chair interconversion in unsubstituted 1,3,2-dioxaphosphorinanes

With the introduction of larger substituents at the 4- or 5-positions, the ring becomes rigid and one of the chair conformations becomes predominantly populated. These systems are referred to as anancomeric.26 The two diastereomers will have reasonable configurational stabilities, but will equilibrate in solution, a process that is accelerated by heating or addition of traces of acid.

Scheme 1.9. Equilibration of anancomeric 1.3.2-dioxaphosphorinanes

With regard to the dioxaphosphorinanes described in this thesis, it is noteworthy that in tervalent systems, chloride and alkoxy groups prefer the axial position at phosphorus. This preference is generally ascribed to the anomeric effect,27 i.e. stabilizing n-o* interactions between lone pair electrons on the ring oxygen and the axial o* P-X orbita1,ZJb in combination with reduced 1,3-syn-axial repulsions due to the relatively long P-O bonds.

23 Maryanoff, B.E.; Hutchins, R.O.; Maryanoff, C.A. in Topics in Stereochemistry, Allinger, N.L.; Eliel, E., Eds.; Wiley: New York, 1979, Vol. 11, p. 187.

24 Corbridge D.E.C. The Structure Chemistry ojPhosphoms, Elsevier: Amsterdam, 1974. 25 (a) Bentrude, W.G.; Setzer, W.N. in Phosphorus-31 NMR Spectroscopy in Stereochemical Analysis,

Verkade, J.G.; Quin, L.D., Eds.; VCH: Deertield Beach, 1987, p. 365. (b) Bentrude,W.G. in Phosphorus- 31 NMR Specrral Properties In Compound Characterizarion and Srructural Analysis, Quin, L.D.; V e r b , J.G., Eds.; VCH: New York, 1994, p. 41.

26 Anteunis, M.; Tavernier, D.; Borremans, F. Bull. Chim. Soc. Belges 1966, 75, 396. 27 Bailey, W.F.; Eliel, E.L. J. Am. Chem. Soc. 1974, 96, 1798.

Chapter 1

Scheme 1.10. Representation of the anomeric effect

1.7.2 1,3,2-Dioxaphosphorinanes from this laboratory In the Organic Chemistry Department of this University, chiral cyclic phosphoric acids have been developed for the classical resolution of chiral amines and amino acids.28 Two P-chiral derivatives of these 1,3,2-dioxaphosphorinanes have been applied as a derivatizing agents for the determination of enantiomeric excesses (e.e.) of amines, amino acids, and alcohols using 31P NMR spectroscopy.29

X = H; 2-C1; 2-Br; 2.4-C12; 2-0Me

ref. 28

ref. 29 ref. 30

Scheme 1.11. Chiral I,3,2-dioxaphosphorinanes studied in this laboratory

Acylphosphonates and isocyanomethylphosphonates were prepared from the methylphosphite as chiral auxilaries for diastereoselective condensation reactions.30

1.8 Outline of this thesis Chapter 2 deals with the synthesis and characterization of novel chiral pyridinyl-2-phosphonates based on the 1,3,2-dioxaphosphorinane fragment. The molecules described exhibit remarkable conformations that have been studied using (multidimensional) NMR spectroscopy and X-ray diffraction. Chapter 3 describes the synthesis of novel chiral diols from a 'universal' chiral starting material. This allows for the synthesis of diols with a variety of steric and electronic characteristics.

28 (a) Ten Hoeve, W.; Wynberg, H. J . Org. Chem. 1985,50, 4508. (b) Van der Haest, A.D. thesis, University of Gmningen, 1992.

29 Hulst, R.; Zijlstra, R.W.J.; De Vries, N.K.; Feringa, B.L. Tetrahedron: Asymmetry 1994,5, 1701. 30 (a) Ebens, R.H.E.; Hulst, A.R.J.L.; Feringa, B.L., unpublished results. (b) Weener, J.-W.; Van Leusen,

A.M., unpublished results.

Introduction

One of these diols is applied in Chapter 4 as structural basis for a number of diphosphites. A diphosphite derived from catechol has been characterized by X-ray diffraction, and a molybdenum complex of this diphosphite has been synthesized. Treatment of oily diphosphites with borane-tetrahydrofuran afforded crystalline, air-stable adducts that were purified by column chromatography. A case of chiral self-recognition, accidentally found during diphosphite synthesis, is examined in Chapter 5. The degree of recognition and its origin were established. In Chapter 6, the conformations of several pyridinyl-2-phosphonates, the synthesis of which is discussed in Chapter 2, are studied using molecular modelling techniques. The calculated optimized geometries correlate favorably with experimental data.

Unusual Stereochemical Aspects of Novel Chiral Pyridinyl-Zphosphonates 2 2.1 Introduction Numerous ligands have been described in which phosphoryl chalcogenide atoms (0, S, Se, Te)

o f pentavalent phosphorus species function as donor atoms.' Structurally simple molecules like

trialkyl phosphine oxides and hexamethylphosphoric triamide (HMPA, 2.1) show high affinity

for lanthanides and actinides and are used to extract heavy metal ions from aqueous solutions by solvat ion . l .2 Bidenta te ligands wi th two oxygen donor a t o m s in 1,3-posit ions l i ke

(carbamoylmethyl)-phosphonates,3 (carbarnoy1methyl)phosphine oxides4 (2.2) and pyridine- N-oxides with phosphoryl groups in ortho-positions5 (2.3) are found to be more effective.

2 1 2 2 R = Ph, MeO, i-PrO 2.3

Scheme 2.1. Ligands with phosphoryl-oxygen donor atoms

Introduction of other donor atoms enhances the affinity for transition metals. Fo r instance,

diphenyl-2-pyridinyl phosphine oxide complexes a variety o f metals, ranging from iron6 to platinum.7 0,O-Dialkyl pyridinyl-2-phosphonates react with first row transition metal halides in an Arbuzov-like fashion, resulting in the extrusion o f alkyl halide and formation of a mono-

Lobana, T.S. in The Chemistry of Organophosphorus Compounds, Vol. 2, Hartley, F.R., Ed., Wiley: Chichestex, England 1992, and references cited therein. Nicol, M.J.; Fleming. C.A.; Preston, J.S. in Comprehensive Coordination Chemistry, Vol. 6 , Wilkinson, G.; Gillard, R.D.; McCleverty, J.A., Eds., Pergamon Press: Oxford, 1987, Chapter 63, and references cited thenin. See for example: Conary, G.S.; Meline, R.L.; Schaeffer, R.; Duesler, E.N.; Paine, R.T. Inorg. Chim. Acta 1992,201, 165. See for example: Caudle, L.J.; Duesler, E.N.; Paine, R.T. Inorg. Chem 1985, 24, 4441. (a) McCabe, D.J.; Russell, A.A.; Kanhikeyan, S.; Paine, R.T.; Ryan, R.R.; Smith, B. Inorg. Chem. 1987,26, 1230. (b) Conary, G.S.; Russell, A.A.; Paine, R.T.; Hall, J.H.; Ryan, R.R. Inorg. Chem. 1988,27, 3242. (c) Rapko, B.M.; Duesler, E.N.; Smith, P.H.; Paine, R.T.; Ryan, R.R. Inorg. Chem. 1993.32, 2164.

ti (a) Damiano, J.-P.; Munyejabo, V.; Postel, M. Polyhedron 1995.14, 1229. (b) Guillaume, P.; Postel, M. Inorg. Chim Acta 1995, 233, 109. Wood, F.E.; Olmstead, M.M.; Farr, J.P.; Balch, A.L. Inorg. Chim Acta 1985, 97, 77.

Chapter 2

anionic 0-alkyl phosphonate ligand (Scheme 2.2).8 Copper(II)nitrates, perchlorates and tetrafluoroborates as well as ruthenium(1II) and rhodium(II1)chlorides. however, give isolable adducts with 0.0-dialkyl-pyridinyl-2-phosphonates.gb~d

Scheme 2.2. 0,O-Diethyl pyridinyl-2-phosphonate and Arbuzov-type reaction

Bond lengths obtained from X-ray diffraction studies show that the metal-phosphoryl-oxygen bonds have multiple bond character with angles varying from 113 to 180". In contrast, M-E-P bonds (E = S, Se, Te) are single with angles varying from 96 to 12W.1

The phosphonates 0,Odiethyl pyridinyl-2-phosphonate (2.4) and 0,O-diethyl pyridinyl-2- thiophosphonate have been studied as pesticides and insecticides, respectively. Their syntheses are based upon nucleophilic attack of a (thio)phosphonate anion at the 2-position of pyridinium N-alkoxide cati~ns.~JOJ

Scheme 2.3. Synthesis of 0,O-diethyl pyridinyl-2-(thio)phosphonate

Subsequent hydrolysis to the phosphonic acid and its conversion to the phosphonyl dichloride 2.6 have been described for 0,0-diethyl pyridinyl-2-phosphonate?J*

(a) Speca, A.N.; Karayannis, N.M.; Pytlewski, L.L. Inorg. Chim. Acta 1972.6, 639. (b) Speca, A.N.; Mink, R.; Karayannis, N.M.; Pytlewski, L.L.; Owens, C. J. Inorg. Nucl. Chem. 1973,35, 1833. ( c ) Brill, T.B.; Landon, S.J. Chem. Rev. 1984 .84 , 577. (d) Huang, Y.-S; Chaudret, B.; Bellan, J.; Mazikres, M.-R. Polyhedron 1991,10, 2229. Redmore, D. J. Org. Chem. 1970,35, 41 14.

O Kraus, W.; Weisert, A. Offenlegungsschrift 2738194, Germany, 1978. Edmundson, R.S. in The Chemistry of Organophosphorus Compounds, Vol. 4 , Hartley, F.R., Ed., Wiley: Chichester, England 1996, Chapter 2. Loran, J.S.; Naylor, R.A.; Williams, A. J. Chem. Soc, Perkin Trans. 11 1976, 1444.

2.2 Chiral pyridinyl-2-phosphonates Phosphonyl dichloride 2.6 can serve as a convenient precursor for chiral derivatives of phosphonate 2.4, which may be candidates for ligands in asymmetric catalysis. Reaction with two equivalents of a chiral alcohol or with one equivalent of a chiral diol in the presence of base furnishes such ligands.

Scheme 2.4. 'Molecular basis of this research'

There is good precedent for such compounds. Cyclic phosphoric acids 2.7 (X = H; 2-C1; 2- OMe, et cetera) have proven to be good resolving agents for a variety of amines and amino alcohols.13 Racemic phosphoric acids of this type are resolved into the enantiomers with chiral amino alcohols or amino acids. The enantiomerically pure phosphoric acids 2.7 are a convenient source of chiral diols 2.9, by hydrolysis or reduction. These diols, in turn, are precursors for a host of chiral molecules, like oxetanesl4 and acetals.15 Moreover, the hydrogen phosphonate 2.8 has been successfully applied as a derivatizing agent for the determination of enantiomeric excesses of alcohols, arnines and amino acids using 31P NMR spectroscopy .I6 The rigid six-membered 1,3,2-dioxaphosphorinane unit could well serve as a backbone for chiral2-pyridinyl-phosphonate ligands.

2.2.1 Synthesis of chiral pyridinyl-2-phosphonates Reaction of pyridinyl-2-phosphonyl dichloride (26) with enantiomerically pure 1-phenyl-2,2- dimethylpropane-l,3-diol (2.9, X = H; Scheme 2.4) is an obvious approach to obtain the desired ligands. The reaction affords a mixture of two epimeric 2-0x0-2-(2-pyridiny1)-4-phenyl- 5,5-dimethyl-1,3,2-dioxaphosphorinanes 2.10a and 2.10b, differing in the relative positions of the pyridinyl and phosphoryl oxygen moieties at phosphorus, in approximately equal amounts.

l 3 (a) Ten Hoeve, W.; Wynberg, H. J. Org. Chem 1985,50, 4508. (b) Van der Haest, A.D. PhD thesis, Univmity of Groningen, 1992.

l4 (a) Hu, X., PhD thesis, University of Groningen, 1995. (b) Hu, X.; Kellogg, R.M. Synthesis 1995, 533. (a) Ebens, R.H.E., PhD thesis, University of Groningen, 1993. (b) Ebens, R.; Kellogg, R.M. Reel. Trav. Chim. Pays-Bas 1992,111, 56. (c) Sjouken, R.; Ebens, R.; Kellogg, R.M. Recl. Trav. Chim. Pays-Bas 1990,109, 552.

l6 Hulst, R.; Zijlstra, R.W.J.; De Vries, N.K.; Feringa, B.L. Tetrahedron: Asymmetry 1994.5, 1701.

Scheme 2.5. Synthesis of pyridinyl-2-phosphonates 2.10~ and b via phosphonyl dichloride 2.6

The epimers were separated by column chromatography (silica gel, ethyl acetate). Crystallization from ethyl acetatelhexanes afforded 2.10a and 2.10b as white crystalline solids in yields of 37% and 24%, respectively. An alternative route involves direct nucleophilic attack of the chiral phosphonate anion16 on pyridinium N-methoxide 2.5 as illustrated in Scheme 2.6. This affords the epimers 2.10a and 2.10b in a 6:l ratio (1H NMR). Epimer 2.10a is easily separated from this mixture by column chromatography.

Scheme 2.6. Synthesis of pyridinyl-2-phosphonates 2.10~ and b via phosphonate 2.8

Alkali metal derivatives of dialkyl phosphonates, like 2.8- are in fact dialkyl phosphite anions. Infrared spectra lack the v(P=O) absorption band and show a strong band around 1050 cm-1 instead, characteristic for P-0- groups.17 The 3lP NMR resonances for these salts are observed in the phosphite range of the spectrum, consistent with the dialkyl phosphite anion formulation. In anancomeric 1,3.2-dioxaphosphorinanes the -0Na group prefers the equatorial position.18 Equilibration of the anions, however, is relatively slow. The kinetically formed anions can be trapped by adding base to a mixture of phosphonate and electrophile.18 Phosphite anions react as P-nucleophiles. Indeed, upon deprotonation of 2.8 in THF solution with potassium tert-butoxide, only one phosphite anion (Scheme 2.7) is observed by 3lP NMR spectroscopy (6 152.2 ppm, attributed to 2.8a-). It is reasonable to assume that this anion reacts with 2.5 to give 2.10a exclusively. Hence, the epimer 2.10b must be formed in a reaction of 2.8b- with 2.5. This suggests a

l 7 Nagar, P.N. Phosphorus, Sulfur and Silicon 1993, 79,207. Lesiak, K.; Uznanski, B.; Stec, W.J. Phosphorus, 1975,6,65.

14

dynamic equilibrium between the two epimeric anions 2.8a- and 2.8b-, with an equilibrium constant of approximately 99.

Scheme 2.7. Equilibrium between dialkyl phosphite anions 2 . 8 ~ - and 2.8b-

Apparently, the epimeric anion 2.8b- is the more reactive. Although it is not detected by 31P NMR spectroscopy, anion 2.8b-contributes up to 15% to the product. By the Curtin-Hammett principle, reaction of 2.8b- to 2.10b is at least 17 times faster than reaction of 2.8a- to 2.lOa.19 The presumed course of events is shown in Scheme 2.7. The advantage of the route depicted in Scheme 2.6 for the preparation of 2.10a is partly lost by the need to synthesize H-phosphonate 2.8. Yields of this compound by the route described by Feringa et al. generally do not exceed 40%.16 A novel general approach to H-phosphonates proved applicable to the synthesis of 2.8 (Scheme 2.8).20

'r\K + HIWl DCC

OH OH THE 0 O C - '"K +

4 0 H 04P; H

Scheme 2.8. Synthesis of H-phosphonate 2.8 from phosphorous acid

k K The equilibrium constant K is at least 99 ( 3 1 ~ NMR). Product ratio = --". Jones, R.A.Y. Physical and

kb

Mechanistic Organic Chemistry, 2"* ed, Cambridge University Press: Cambridge, 1987, pp. 20-21. 20 Munoz, A.; Hubert, C.; Luche, J.-L. J. Org. Chem. 1996.61, 6015.

By this method, both epimers of 2.8 are formed in a clean reaction (Scheme 2.8). The cis- epimer was isolated, essentially pure, in 56% yield by preferential crystallization. Since chromatographic separation of 2.10b can be quite tedious, the route as depicted in Scheme 2.6 is more convenient for the preparation of 2.10a. The overall yield of this epimer, starting from 2.9, however, is slightly lower.

2.2.2 Characterization NMR spectroscopy is an important tool for the assignment of absolute configurations of dioxaphosphorinanes. For the determination of the relative disposition of substituents at the phosphorus atom in epimeric anancomeric phosphonates three parameters are important: the 31P chemical shift, the lJpC coupling constant and the sum of 3 J p ~ coupling constants of the axial and equatorial hydrogen atoms at the 4 and 6 positions on the dioxaphosphorinane ring to the phosphorus atom. Generally, for the epimer having the phosphoryl oxygen atom in axial position, 31P chemical shifts are found at lower field and coupling constants are larger.21.22

8 1.9 ppm

Figure 2.1. Stereochemical assignment of the epimers 2 .10~ and b on basis of NMR data

For the epimeric structures 2.10a and 2.10b. the values shown in Figure 2.3 were found and the absolute configurations were assigned accordingly. One set of experiments failed to rhyme with this stereochemical assignment, however. High resolution NOESY in benzene-& solution did not reveal NOE-interactions between pyridinyl hydrogen atoms and axial hydrogen atoms of the dioxaphosphorinane ring in 2.10a or the axial methyl groups in 2.10b. whereas all other expected intramolecular contacts were visible (Figure 2.2). An important observation is the low field shift for the axial hydrogen atoms for 2.10a: 6 (benzene-d6): 6.03 and 4.93 ppm vs. 5.43 and 4.35 ppm for 2.10b.

21 Maryanoff, B.E.; Hutchins, R.O.; Maryanoff, C.A. in Topics in Stereochemistry Vol. 11, Allinger, N.L.; Eliel, E., Eds.; Wiley: New York, 1979, p. 187.

22 Bentrude, W.G. in Phosphorus-31 NMR Spectml Properties in Compound Characterization and Structural Analysis, Quin, L.D.; Verkade, J.G., Eds.; VCH: New York, 1994, p. 41.

Figure 2.2. NOESY spectrum of 2.10~ in benzene-dg

The lack of NOE interactions suggests that, in the predominant conformation of 2.10a, the pyridine nitrogen atom points towards the dioxaphosphorinane ring, giving rise to the observed dowdeld shift of the axial hydrogen atoms due to the proximity of the nitrogen atom.

Scheme 2.9. Synthesis of a tetramethyl derivative 2.11~

In line with this idea, the downfield shift for the benzylic hydrogen atom is increased upon introduction of two methyl groups at the 6-position of the dioxaphosphorinane ring (Scheme 2.9), forcing the pyridinyl moiety towards the benzylic position (6 (CDC13): 6.16 ppm for 2.11a vs. 5.90 for 2.10a).

2.2.3 Molecular structure of 2.10d To confirm the postulated orientation of the pyridine ring and to study the effect on the conformation of the dioxaphosphorinane ring, the solid-state molecular structure of 2.10a was determined. Crystallization of 2.10a from toluenelpentane mixtures afforded crystals suitable for X-ray analysis. Compound 2.10a crystallizes in the orthorhombic space group P212121 with eight molecules in the unit cell in two slightly different conformations, one of which is depicted in Figure 2.3. Selected bond lengths and angles as well as details on data collection and refinement are listed in the Experimental section. As concluded from the NMR data, the pyridinyl moiety indeed occupies the axial position at the phosphorus atom, with the nitrogen atom pointing towards the dioxaphosphorinane ring (refinement of the structure with part of the nitrogen atoms put in the other position confirmed the given configuration: population of the 'outward' structure decreased to zero). The configuration as found in the solid-state structure is probably dictated by mutual repulsion of the oxygen and nitrogen lone pairs (vide infra). In solid-state molecular structures of Z-phenyl- 1,3,2-dioxaphosphorinanes the axial phenyl groups at phosphorus are oriented perpendicularly with respect to the phosphorus-oxygen double bonds.23

Figure 2.3. Molecular structure of 2.10~ with adopted labelling scheme

The 1,3,2-dioxaphosphorinane ring displays the typical chair conformation, generally observed for this class of compounds. The ring is somewhat flattened at the phosphorus end; dihedral angles P-02-C1-C2 and P-03-C3-C2 are 46.4 (6)" and 50.6 (6)", respectively. These angles

# Molecular structure determination by Dr. H. Kooijman (University of Utrecht). 23 (a) Killean, R.C.G.; Lawrence, J.L.; Magennis, I.M. Acta Cryst. 1971, B27, 189. (b) Craig, D.C.;

Toia, R.F.; Wacher, V.J. Aust. J. Chem. 1989.42, 977.

18

are slightly smaller than those in an 'unstrained' phenyl phosphonate (53.5 (2)" and 55.8 (2)').23b Conformational analysis of 2.10a is described in Chapter 6.

2.3 Oxidation at nitrogen Recently, a paper appeared in which the unexpected in situ oxidation of the nitrogen atom of an amino-phosphineoxide ligand upon treatment with molybdic acid in aqueous hydrogen peroxide was described. The molecular structure of the complex shows the molybdenum atom to be bound to both oxygen atoms of the resulting N,P-dioxide ligand.24 In view of our intention to use 2.10a and b as bidentate ligands, this report drew our immediate interest. However, treatment of pyridinyl phosphonate 2.10a with H2MoO4 does not lead to oxidation of the nitrogen atom and no complex is formed. The N-oxide 2.12 can be prepared, although more forcing conditions are required. Warming an acetic acid solution of 2.10a with excess hydrogen peroxide at 40 "C for two days affords the N-oxide 2.12 (Scheme 2.10). After crystallization from toluenelhexanes white needles of the compound were obtained.

H202, 40 O C *

acetic acid

0'

Scheme 2.10. Synthesis of N-oxide 2.12

The 1H NMR spectrum of 2.12 recorded in CDC13 solution reveals for the pyridine ring overlapping resonances for two hydrogens, whereas the other two are obscured by the phenyl resonances. Changing to benzene-d6 as a solvent allows separate observation of all pyridinyl signals (Figure 2.3). This solvent effect is also observed for compounds 2.10a, 2.10b and 2.15 (vide infra). Resonances for both axial hydrogen atoms in the N-oxide display a downfield shift of over 0.4 ppm relative to the parent compound, 6 (benzene-d6): 6.46 and 5.38 ppm for 2.12 vs. 6.03 and 4.93 ppm for 2.10a, suggesting a close contact with the N-oxygen atom. This information implies that the pyridinyl nitrogen atom is directed towards the dioxaphosphorinane ring, as in 2.10a. The lack of NOE interactions between the axial hydrogen atoms and the 3-pyridinyl hydrogen atom supports this presumption. For this conformation, in which the N-oxygen atom is positioned above the dioxaphosphorinane ring, the structure must be severely distorted.

24 Thiel, W.R.; Priermeier, T.; Bog, T. 3. Chem. Soc., Chem Commun. 1995, 187 1.

Figure 2.3. IH NMR spectra of 2.12 in chloroform-dl (top) and benzene-& (bottom)

20

Unusual Stereochemical Aspects of Novel Chiral Pyridinyl-2-phospho~fes

Nevertheless, the 1H NMR spectra of 2.12 (Figure 2.3) are indicative for chair-like conformation, with no phosphorus coupling at the axial positions and a large phosphorus coupling for the equatorial hydrogen atom (3JpH = 21.5 Hz). Final evidence for the conformation of the dioxaphosphorinane ring was obtained from the molecular structure of 2.12.

2.3.1 Molecular structure of 2.12s Slow crystallization from toluenelhexanes afforded crystals of 2.12 suitable for X-ray diffraction. The compound crystallizes in the orthorhombic space group P212121 with four molecules in the unit cell. Selected bond lengths and angles as well as details on data collection and nfmement are listed in the Experimental section. The molecular structure of 2.12 indeed shows the expected 'inward' orientation of the pyridine ring (Figure 2.4). In order to accommodate the oxygen atom, the flattened chair conformation found in 2.10a is distorted to an envelope-like conformer, with atoms C1, 0 2 , PI, 0 3 and C3 being virtually coplanar. Dihedral angles P-02-C1-C2 and P-03-C3-C2 are 39.0 (4) and -3 1.8 (5). respectively. Conformational analysis of 2.12 is described in Chapter 6 .

Figure 2.4. Molecular structure of N-oxide 2.12 with adopted labelling scheme

Treatment of 2.10b with hydrogen peroxide, under conditions described for 2.10a, fails to produce the corresponding N-oxide. Inspection of a computer generated model of this compound reveals a very close contact between the N-oxygen atom and the axial methyl group in an 'inward' conformation, analogous to the one observed for 2.12 (See also Chapter 6) .

S Structure determination by Dr. A.L. Spek (University of Utrecht).

21

Chapter 2

2.4 Synthesis of N-methylated pyridinyl-2-phosphonate Mutual repulsion between lone pairs of electrons presumably determines the conformations observed for compounds 2.10a and 2.12. Protonation of the nitrogen atom in 2.10a would cancel this repulsion and possibly result in a hydrogen-bridged structure, in which 2.10a acts as a N-P=O chelate ligand. Addition of excess trifluoroacetic acid to a solution of 2.10a, however, does not give a discrete protonated species. Therefore. N-methylation was chosen as an alternative. N-Methylated pyridinyl-2-phosphonate 2.13 was prepared by reaction of 2.10a with excess methyl ~uoromethanesulfonate in dichlorornethane (Scheme 2.11). Although 'magic methyl' is an extremely powerful methylating agent, the reaction proceeds slowly at ambient temperatures, taking several days to go to completion. This low reactivity probably reflects the high bias towards the predominant conformation of 2.10a. N-Methyl pyridinyl phosphonate 2.13 was isolated as a white crystalline solid. Coupling patterns in the 1H NMR spectrum of N-methyl derivative 2.13 are typical for a chair conformer: axial hydrogens show no 3jpH, whereas the equatorial hydrogen atom shows a large 3JpH (24.1 Hz).

Scheme 2.11. N-Methylation of 2.10~. Arrows indicate diagnostic NOE interactions in the product

NOESY analysis shows interactions between the hydrogen atom at the 3-position on the pyridinyl fragment and both axial hydrogen atoms on the dioxaphosphorinane (Figure 2.5) whereas the N-methyl hydrogens lack NOE interactions with the latter, confirming the expected predominance of the 'outward' orientation of the positively charged nitrogen atom.

Figure 2.5. Trace from the NOESY spectrum of 2.13 at 8.28 ppm

The conformation of 2.13 was examined by molecular modelling techniques. Results are described in Chapter 6.

2.5 Synthesis and characterization of chiral pyridinyl-2-thiophosphonates Phosphonates 2.10a and 2.10b are conveniently converted to the respective 2-pyridinyl-2- thio-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinanes 2.14a and 2.14b by treatment with Lawesson's reagent (2,4-bis-(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphetane) in refluxing toluene (Scheme 2.12).

Lawason's reagent

reflux. toluene

Scheme 2.12. Synthesis of chiral pyridinyl-2-thiophosphonates 2.144 and 2.14b

Crystallization from toluenehexanes afforded the thiophosphonates as white crystalline solids. The 1H NMR spectra of 2.14a and b show close resemblance to those of 2.10a and b, respectively, suggesting the same conformations of the 1.3,2-dioxaphosphorinane rings and configurations around phosphorus. The ( lH)3lP NMR spectra of 2.14a and 2.14b show singlets at 70.6 pprn and 79.9 ppm characteristic for phosphorus-sulfur double bonds. Patterns of coupling constants and chemical shifts are in accordance with the assigned configurations (see Figure 2.1 for comparison).

2.6 Borane adduct The borane adduct of 2.10a was prepared by treatment with excess borane-tetrahydrofuran complex (BH3,THF) in THF. The product precipitated from solution and was collected by centrifugation. The white solid can be stored for considerable time without decomposition, but when solutions are exposed to air 2.15 slowly loses borane, regenerating 2.10a.

2.10a

Scheme 2.13. Synthesis of borane adduct 2.15

Chapter 2

The NOESY spectrum shows interaction of borane hydrogen atoms with the benzylic hydrogen atom of the dioxaphosphorinane fragment. No interaction of the other axial hydrogen atom either with borane protons or with the 3-pyridinyl hydrogen atom is observed. This information implies that the pyridine fragment has rotated around the P-C bond, placing the bound borane moiety outside the dioxaphosphorinane ring at the side of the phenyl group (Figure 2.6).

Figure 2.6. Proposed binding mode of borane complex 2.15 based on NOESY (Top view).

2.7 Attempted synthesis of a chiral 1,lO-phenanthrolinyl-2-phosphonate An attempt to synthesize the chiral 1.10-phenanthrolinyl-2-phosphonate from H-phosphonate 2.8 and 1.10-phenanthroline-N-methoxide methosulfate, analogously to the synthesis of pyridinyl-2-phosphonates 2.10, failed.

Scheme 2.14. Attempted synthesis of chiral 1,lO-phenanthroline-2-phosphonate

The unfavorable orientation of the phenanthroline moiety with respect to the 133-dioxaphosphorinane ring in the desired product probably accounts for this failure.

2.8 Transition metal complexes and catalysis Compound 2.10a was tested as a potential ligand in several catalytic asymmetric reactions. In the SN~' reaction of dimethylzinc and cinnamyl chloride racemic 3-phenyl-1-butene was obtained.25 No enantioselectivity was observed in the titanium(1V)isopropoxyde catalyzed

25 This reaction was performed by Dr. H. van der Wotp.

Unusual Stereochemical Aspects o f Novel Chiral Pyridinyl-2-phosphomes

hydrophosphonylation of ben~aldehyde.~~ Attempts to prepare palladium(II)27 complexes of compounds 2.10b and 2.14a and a copper(I1)nitrate complex of compound 2.10a were unsuccessful. Addition of a solution of N-oxide 2.12 to a solution of La(N03)3 did not result in an appreciable heat effecL28 The poor coordinating abilities of the compouds mentioned above are due to the unfavorable orientation of the pyridine nitrogen atom in combination with a high rotational barrier. Although the nitrogen atom in free 2.4 is expected to point away from the phosphoryl oxygen, as in 2.10e, the rotational barrier will be lower owing to the flexibility of the ester groups.

2.9 Experimental section General remarks Optical rotations were measured on a Perkin-Elmer 241 polarimeter at room temperature. 'H NMR spectra were recorded on Varian Gemini-200 BB. VXR-300s or Unity-500 spectrometers at 200,300 and 500 MHz, respectively. 13C and 1H-decoupled 3'P NMR spectra were recorded at 50.3 or 75.5 MHz and 81.0 or 121.4 MHz, respectively. 11B NMR and 19F NMR spectra were recorded at 96.2 and 188 MHz, respectively. Chemical shift values are denoted in ppm and referenced to residual protons in deuterated solvents for 'H NMR (CDCl3: 7.26 ppm; benzene-d6: 7.16 ppm), to solvent resonances for 13C NMR (CDC13: 77.01 ppm; benzene-dg: 128.0 ppm) to external (PhOkPO (-18.0 ppm) for 31P NMR, external BF3.OEt2 (0 ppm) for 11B NMR and external CFC13 (0 ppm) for 19F NMR. Mass spectra were recorded on AEI-MS-902 (EI) and Ribermag R10-1OC (CI) mass spectrometers operated by Mr. A. Kiewiet. Elemental analyses were performed by Mr. H. Draaijer, Mr. J. Ebels, and Mr. J. Hommes. Solvents were distilled prior to use (CHC13, CH2C12, Et2.0, toluene, pentane and hexanes from P205, THF and benzene from Na/benzophenone). Pyridine-N-methoxide methosulfate (2.5),9 pyridinyl-2-phosphonyl dichloride (2.6)?1'2 1- phenyl-2,2-dimethylpropane-1,3-diol (2.9).13a and 1,lO-phenanthroline-N-oxide29 were synthesized according to literature procedures.

(S)-2H-2-0xo-5,5-dimethyl-4-(R)-phenyl-1,3,2-dioxaphosphorinane (2.8) A solution of H3P03 (4.55 g, 55.5 mrnol) in 55 mL of THF was added all at once to a solution of dicyclohexylcarbodiimide (23.0 g, 0.11 mmol) and (R)-(-)-2.9 (10.0 g, 55.5 mmol) in 165 mL of THF, In an exothermic reaction a white precipitate of dicyclohexylurea was formed. After stirring at room temperature for 30 min, the flask was sonicated for 1 h. The solids were removed by filtration and washed three times with ether. The combined filtrates were evaporated to give an off-white solid. 1H NMR spectroscopy revealed the presence of both epimers of 2.8. Crystallization from toluenelether afforded the 2S,4R epimer exclusively, as colorless crystals. Yield: 7.02 g, 31 mrnol, 56%.

26 This reaction was performed by Drs. C. Zondewan. 27 (COD)Pd(Me)CI was kindly provided by Drs. E.K. van den Beuken. 28 Microcalorimetry was performed by Drs. J. Kevelam. 29 Corey, E.J.; Borror, A.L.; Foglia, T. J. Org. Chem. 1965,30, 288.

Spectroscopic data of the product were in accordance with those previously reported.l6

(S)-(-)- and (R)-(+)-2-(2-Pyridinyl)-2-oxo-5,5-dimethyl-4~(R)-phenyI-l,3,2- dioxaphosphorinanes (2.10a and b) Method A. To an ice-cooled solution of (R)-(-)-2.9 (5.59 g, 31.0 mmol) and Et3N (10 mL, 7.3 g, 72 mmol) in 25 mL of chloroform was added dropwise 2.6 (6.25 g, 34.7 mmol) in 5 rnL of chloroform. The resulting suspension was stirred overnight at room temperature. The reaction mixture was washed with 1N HC1 solution and the aqueous layer was extracted three times with chloroform. The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The brown viscous oil contained both epimers of 2.10 in a 1: 1 ratio (1H NMR). Column chromatography (silica gel, EtOAc) and subsequent crystallization from EtOAc/hexanes afforded 3.45 g (11.4 mmol, 37%) of 2.10a and 2.27 g (7.46 -01.24%) of 2.10b as white crystalline solids.

Method B To an ice-cooled solution of (R)-(-)-2.8 (1.26 g, 5.57 mmol) and t-BuOK (0.63 g, 5.61 mmol) in 10 mL of THF was added 2.5 (1.25 g, 5.65 mmol) in THF (25 mL). The resulting suspension was stirred overnight. Saturated aqueous NH4Cl was added and the organic layer was separated. The aqueous layer was extracted twice with chloroform. The combined organic layers were washed with brine, dried over Na2S04 and evaporated to give an oil. 'H NMR showed the presence of both epimers of 2.10 in a 6:l ratio. Column chromatography (silica gel, EtOAc) gave a colorless oil. Trituration with hexanes afforded 2.10a as a white crystalline material (0.93 g, 3.05 mmol, 55%).

(S,R)-(-)-2.lOa Rf = 0.55. [a1578 -129.5 (c = 0.498, CHC13). lH NMR (CDC13): 6 8.75 (m, lH, CsH4N); 8.03 (m, lH, C5H4N); 7.81 (m, lH, CgH4N); 7.44 (m, lH, CgH4N); 7.38-7.31 (m, 5H, C6Hg); 5.90 (s, lH, CHPh); 4.96 (d, 2JAB = 10.6 Hz, lH, CH2); 4.08 (dd, ZJAB = 10.6 Hz, 'JpH = 21.2 Hz, lH, CH2); 1.19 (s, 3H, CH3); 0.87 (s, 3H, CH3). '3C NMR (CDC13): 8 153.39 (d, ' J p c = 220.7 Hz, CgH4N); 149.68 (d, J p c = 23.4 Hz, CgH4N); 136.16 (d, J p c = 11.7 HZ, C5H4N); 135.98 (Cqph); 128.21 (CHph); 127.96 (d, J p c = 25.4 Hz, CsH4N); 127.66 (CHph); 127.28 (CHph); 126.08 (d, J p c = 3.9 Hz, CgH4N); 88.74 (d, J p c = 7.8 Hz, CH); 79.77 (d, J p c = 5.9 HZ, CH2); 36.83 (d, J p c = 5.9 Hz, Cq); 21.13 (CH3); 17.37 (CH3). 31P NMR (CDC13): 6 1.9. Anal. Calcd for C16H18N03P: C, 63.36; H, 5.98; N, 4.62; P, 10.21. Found: C, 63.25; H, 5.93; N, 4.61; P, 10.1 1. HRMS calcd 303.102, found 303.102. IH NMR (C6D6): 6 8.31 (m, lH, 6-CgH4N); 8.10 (m, lH, 3-C5H4N); 7.19 (m, 2H, C6H5); 7.03 (m, 3H, C6Hg); 6.84 (m, lH, 4-CgHqN); 6.50 (m, lH, 5-CsH4N); 6.03 (s, lH, CHPh); 4.93 (d, 2 J ~ ~ = 10.74 Hz, lH, CH2); 3.67 (dd, 2JAB = 10.75 Hz, 3JpH = 21.0 Hz, lH, CH2); 1.04 (s, 3H, CH3); 0.35 (s, 3H, CH3).

Unusual Stereochemical Aspects of Novel Chiral hridinyl-2-phosphomtes

(R,R)-(+)-2.lOb R j = 0.44. [a1578 +46.6 (c = 0.498, CHC13). IH NMR (CDC13): 6 8.90 (m, lH, C5H4N); 8.16 (m, lH, C5H4N); 7.85 (m, lH, C5H4N); 7.51 (m, lH, C5H4N); 7.37-7.31 (m, 5H, C6H5); 5.64 (d, 3 J p ~ = 2.2 HZ, lH, CHPh); 4.66 (dd, 2JAB = 1 1.4 Hz, 3JpH = 2.2 HZ, lH, CH2); 4.05 (dd, 2 J A ~ = 11.4 Hz, 3 J p ~ = 22.0 Hz, lH, CH2); 1.25 (s, 3H, CH3); 0.88 (s, 3H, CH3). I3C NMR (CDC13): 6 150.72 (d, J p c = 24.4 Hz, CsHqN); 149.83 (d, ' J P C = 236.8 HZ, C5H4N); 136.01 (Cqph); 135.99 (d, J p c = 13.43 Hz, C5H4N); 129.00 (d, J p c = 26.9 Hz, C5H4N); 128.27 (CHph); 127.71 (CHph); 127.33 (CHph); 126.64 (d, J p c = 4.9 Hz, C5H4N); 85.13 (d, J p c = 6.1 HZ, CH); 75.98 (d, J p e = 6.1 Hz, CH?); 36.50 (d, J p c = 3.7 Hz, Cq); 21.68 (CH3); 17.44 (CH3). 31P NMR (CDC13): 6 9.8. Anal. Calcd for C16HlgN03P: C, 63.36; H, 5.98; N, 4.62; P, 10.21. Found: C, 63.40; H, 5.91; N, 4.56; P, 10.14. HRMS calcd 303.102, found 303.102. lH NMR (CgDg): 6 8.50 (m, lH, 6-CgH4N); 8.23 (m, lH, 3-CsH4N); 7.22 (m, 2H, C6H5); 7.04 (m, 3H, C6H5); 6.81 (m, lH, 4-CsH4N); 6.48 (m, lH, 5-C5H4N); 5.43 (d, 3JPH = 2 HZ, lH, CHPh); 4.35 (dd, 2 J ~ ~ = 11 HZ, 'JpH = 2 HZ, lH, CH2); 3.58 (dd, 2JAB = 11 HZ, 3 J p ~ = 22 Hz, lH, CH2); 1.27 (s, 3H, CH3); 0.25 (s, 3H, CH3).

(S)-(+)-2-(2-Pyridinyl)-2-oxo-4,4,5,5-tetramethyl-6-(S)-phenyl-l,3,2- dioxaphosphorinane (2.11a) This compound was prepared analogously to 2.10a from 2.6 and (S)-(+)-I6 (see Chapter 3) and purified by means of column chromatography (silica gel, EtOAc). Yield: 24% of 2.11a as a white solid. R j= 0.5. [a1365 +65.0 (c = 0.408, CHC13). IH NMR (CDC13): 6 8.71 (m, lH, CsH4N); 8.01 (m, lH, CsH4N); 7.74 (m, lH, C5H4N); 7.47-7.44 (m, 2H, C6H5); 7.39-7.29 (m, 4H, C6H5, C5H4N); 6.16 (s, lH, CHPh); 1.65 (s, 3H, CH3); 1.48 (d, 4JpH = 1.8 Hz, 3H, CH3); 1.25 (s, 3H, CH3); 0.79 (s, 3H, CH3). I3C NMR (CDC13): 6 153.86 (d, IJpC = 228.3 Hz, C5H4N); 149.83 (d, J p c = 24.4 HZ, C5H4N); 136.60 (d, J p c = 8.6 Hz, CsH4N); 135.85 (d, J p c = 12.2 Hz, Cqph); 128.1 1 (CHph); 128.01 (d, J p c = 25.6 Hz, C5H4N); 127.58 (CHph); 125.67 (d, JPC = 4.9 HZ, C5HqN); 90.89 (d, J p c = 8.6 HZ, Cq); 84.52 (d, J p c = 5.8 Hz, CH); 42.20 (d, J p c = 6.1 HZ, Cg); 26.21. (d, J p c = 6.1 Hz, CH3); 25.18 (CH3); 21.96 (CH3); 15.83 (CH3). 31P NMR (CDC13): 6 1.7. Anal. Calcd for C18H22N03P: C, 65.25; H, 6.69; N, 4.23; P, 9.35. Found: C, 65.22; H, 6.61; N, 4.17; P, 9.21. HRMS calcd 331.134, found 331.134.

2-(R)-(2-Pyridinyl)-2-oxo-S,S-dimethyl-4-(R)-phenyl-1,3,2- dioxaphosphorinane-N-oxide (2.12) A solution of 0.63 g (2.07 mrnol) of 2.10a in 5 mL of acetic acid and 1 mL of 30% H202 in Hz0 was warmed at 40 "C for 48 h. The solution was concentrated on the rotary evaporator, diluted with water and concentrated. The residu was taken up in CHC13 and washed with saturated aqueous NaHC03. The aqueous solution was extracted with CHC13. The combined

organic layers were washed with brine, dried over Na2S04. and evaporated. The yellowish solid was recrystallized from toluenehexanes to afford 2.12 as off-white needles. Yield: 0.39 g (1.22 mmol; 59%). Another recrystallization from the same solvent mixture afforded 2.12 as white needles. Mp = 188.5-188.6 'C (dec.). [a1578 -54.2 (c = 1, CHC13). 'H NMR (CDC13): 6 8.13 (m, 2H, C5H4N); 7.34 (m, 7H, C6H5. CSH~N); 6.17 (s, lH, CHPh); 5.17 (d, 2JAB = 10.0 Hz, lH, CH2); 4.07 (dd, 2 J ~ ~ = 10.0 Hz, 3 J p ~ = 21.5 Hz, lH, CH2); 1.21 (s, 3H, CH3); 0.83 (s, 3H, CH3). '3C NMR (CDC13): 6 141.93 (d, 'JPC = 216 H z , CgHqN); 139.15 (d, J p c = 6.1 HZ, C5H4N); 136.11 (d, J p c = 8.5 HZ, CsH4N); 133.98 (d, J p c = 12.2 Hz, C5H4N); 128.78 (CHm); 128.25 (CHh); 127.70 (CHh); 127.57 (CHA,); 125.39 (d, J p c = 1 1 .O Hz, C5H4N); 90.80 (d, J p c = 7.3 Hz, CH); 81.34 (d, J p c = 6.1 Hz, CH2); 36.85 (d, J p c = 8.5 Hz, Cq); 21.19 (CH3); 18.05 (CH3). 31P NMR (CDC13): 6 -2.6. Anal. Calcd for C16H18N04P: C,

60.19; H, 5.68; P, 9.70. Found: C, 60.06; H, 5.70, P, 9.59. HRMS calcd 319.097, found 3 19.097. lH NMR (CgDg): 6 8.06 (m, lH, 6-CgHqN); 7.41 (m, IH, 3-C5HqN); 7.27 (m, 2H, C6H5); 7.02 (m, 3H, C6H5); 6.46 (s, lH, CHPh); 6.05 (m, lH, 5-CsH4N); 5.95 (m, lH, 4-CgH4N); 5.38 (d, 2JAB = 9.77 Hz, lH, CH2); 3.74 (dd, 2JAB = 9.77 Hz, 3JpH = 21.0 Hz, lH, CH2); 1.15 (s, 3H, CH3); 0.36 (s, 3H, CH3).

N-Methyl-2-(R)-(2-pyridinyl)-2-0~0-5,5-dimethyl-4-(R)-phenyl-l,3,2- dioxaphosphorinane trifluoromethanesulfonate (2.13) A solution of 2.10a (130.7 mg, 0.43 mmol) and CF3S03Me (52 a, 75.4 mg, 0.46 mmol) in CH2C12 was stirred at room temperature for several days. After evaporation of the volatiles, the product was dissolved in methanol and precipitated by addition of ether. The white solid was collected by filtration. Yield: 119 mg, 0.25 mmol. 59%. lH NMR (500 MHz; CDC13): 6 8.95 (m, lH, 6-CgH4N); 8.52 (m, lH, 4-CsH4N); 8.28 (m, lH, 3-C5H4N); 8.13 (m, lH, 5-CsH4N); 7.41 (m, 5H, CgHs); 5.84 (s, lH, CHPh); 4.84 (d, 2JAB = 11.1 Hz, lH, CH2); 4.58 (s, 3H, N-CH3); 4.22 (dd, 2JAB = 11.1 Hz, 'JPH = 24.1 HZ, lH, CH2); 1.21 (s, 3H, CH3); 0.83 (s, 3H, CH3). 13C NMR (CDC13): 6 149.82 (d, J p c = 7.3 Hz, C5H4N); 146.48 (d, 'JpC = 188.0 HZ, C5H4N); 145.53 (d, J p c = 9.8 Hz, CgHqN); 134.24 (d, J p c = 8.5 HZ, C5H4N); 132.33 (d, JPC = 11.0 HZ, C5H4N); 130.60 (CqAr); 129.1 1 (CHA,); 128.13 (CHA,); 127.56 (CHA,); 120.39 (q, JFC = 320 HZ, CF3); 90.28 (d, J p c = 7.3 Hz, CH); 80.60 (d, J p c = 7.3 Hz, CH2); 48.85 (d, J p c = 2.4 Hz, NCH3); 36.92 (d, J P c = 6.1 H z , Cq); 20.33 (CH3); 17.35 (CH3). 31P NMR (CDC13): 6 -6.4. 19F NMR (CDC13): 6 -79.9. Anal. Calcd for ClgH21F3NOgS: C, 46.26; H, 4.53. Found: C, 46.14; H, 4.32.

Unusual Stereochemical Aspects of Novel Chiral Pyridinyl-2-phospho~tes

2-(R)-(2-Pyridinyl)-2.thio-5,5-dimethyl-4-(R)-pheny1-1,3,2- dioxaphosphorinane (2.14a) A toluene solution of 2.10~3 (109.4 mg, 0.361 mmol) and Lawesson's reagent (72.9 mg, 0.18 mmol) was refluxed for 4 h. The reaction mixture was cooled at room temperature and stirred with 3 mL of 1N NaOH solution. The organic layer was separated and the aqueous layer was extracted twice with toluene. The combined organic layers were washed with brine, dried over Na2S04, and concentrated. The resulting white solid was recrystallized from toluene/hexanes to afford 2.14a as white crystals. Yield: 81.0 mg, 0.254 rnmol, 70%. 'H NMR (CDC13): 6 8.75 (m, lH, C5H4N); 8.14 (m, lH, CsH4N); 7.81 (m, IH, C5H4N); 7.45-7.31 (m, 6H, C6H5, C5H4N); 5.74 (d, 3JpH = 1.2 Hz, lH, CHPh); 4.80 (dd, 2JAB = 11 Hz, 3JpH = 4 HZ, lH, CH2); 3.99 (dd, 2JAB = 11 HZ, jJPH = 25 Hz, 1H, CH2); 1.22 (s, 3H, CH3); 0.87 (s, 3H, CH3). 13C NMR (CDC13): 6 157.02 (d, J p c = 170.91 Hz, CsH4N); 149.27 (d, lJpC = 20.8 HZ, C5H4N); 136.52 (d, J p c = 13.4 Hz, C5H4N); 136.06 (d, J p c = 7.3 Hz, Cqph); 128.32 (CHph); 127.84 (d, J p c = 29.3 H z , CsH4N); 127.77 (CHph); 127.54 (CHph); 126.64 (d, J p c = 3.7 Hz, CsH4N); 89.30 (d, J p c = 9.8 Hz, CH); 79.88 (d, J p c = 8.5 Hz, CH2); 36.79 (d, J p c = 6.1 Hz, Cq); 21.43 (CH3); 17.90 (CH3). 31P NMR (CDC13): 6 70.6. Anal. Calcd for C16H18N02PS: C, 60.17; H, 5.68; N, 4.39. Found: C, 60.45; H, 5.67; N. 4.42. HRMS calcd 319.080, found 319.080.

2-(S)-(2-Pyridinyl)-2-thio-5,5-dimethyl-4-(R)-phenyl-l,3,2- dioxaphosphorinane (2.14b) This compound was prepared analogous to 2.14a from 2.10b (11 1.2 mg, 0.367 mmol) and Lawesson's reagent (74.1 mg, 0.182 mmol) to give 58.2 mg (0.182 mmol, 50%) of 2.14b as white crystals. 1H NMR (CDC13): 6 8.90 (m, IH, C5H4N); 8.34 (m, lH, C5H4N); 7.88 (m, IH, C5H4N); 7.50 (m, lH, CsH4N); 7.33-7.28 (m, 5H, C6H5); 5.73 (d, 3 J p ~ = 4 Hz, lH, CHPh); 4.83 (d, 2 J ~ ~ = 10.7 HZ, IH, CH2); 3.99 (dd, 2JAB = 10.7 HZ, jJpH = 23.0 Hz, lH, CH2); 1.20 (s, 3H, CH3); 0.81 (s, 3H, CH3). 13C NMR (CDC13): 6 153.24 (d, J p c = 196.7 Hz, CgHqN); 150.53 (d, l J p c = 22.9 HZ, C5H4N); 136.28 (d, J p c = 13.7 Hz, CsH4N); 135.92 (d, J p c = 9.5 HZ, Cqph); 128.26 (CHph); 128.18 (d, J p c = 31.7 Hz, CsH4N); 127.71 (CHph); 127.57 (CHph); 126.56 (d, J p c = 3.8 HZ, C5H4N); 84.06 (d, J p c = 5.3 Hz, CH); 75.09 (d, J p c = 5.7 Hz, CH2); 37.54 (d, J p c = 3.4 HZ, Cq); 21.56 (CH3); 17.74 (CH3). 31P NMR (CDC13): 6 79.9. HRMS calcd 319.080, found 319.080.

2-(R)-(2-Pyridinyl)-2-0~0-5,5-dimethyl-4-(R)-phenyl-l,3,2- dioxaphosphorinane borane adduct (2.15) To an ice-cooled solution of 0.51 g (1.68 mmol) of 2.10a in 10 mL of TI-IF was added 3 mL of 0.7 M (2.1 mmol) BHyTHF in THF. After several minutes a white precipitate formed. The suspension was stirred at room temperature for another hour. The product was separated from

Chapter 2

the supernatant by centrifugation, washed three times with 5 mL portions of ether, and dried in vacuo to afford 2.15 as a white solid. Yield: 0.32 g (1.01 mmol; 60%). 'H NMR (CgD6): 6 8.46 (m, lH, 3-CsH4N); 8.35 (m, lH, 6-CsH4N); 7.29 (m, 2H, Ph); 7.03 (m, 3H, Ph); 6.48 (m, lH, 4-CsH4N); 6.10 (d, 3JpH = 2.4 Hz, lH, CHPh); 5.99 (m, lH, 5- CsH4N); 5.13 (dd, 2 J ~ ~ = 10.3 Hz, I'JpH = 1.5 Hz, lH, CH2); 3.74 (dd, 2JAB = 10.3 Hz, 3JpH = 18.1 HZ, lH, CH2); 3.56 (d, J = 130 HZ, 3H, BH3); 1.25 (s, 3H, CH3); 0.30 (s, 3H, CH3). 13C NMR (CDC13): 6 151.47 (d, J p c = 12.2 Hz, CgHqN); 139.35 (d, J p c = 11.0 Hz, CsH4N); 135.49 (d, J p c = 7.3 Hz, CsH4N); 133.82 (d, J p c = 15.9 Hz, C5H4N); 128.61 (CHph); 127.95 (CHph); 127.64 (CHph); 89.73 (d, J p c = 7.3 Hz , CH); 79.22 (d, J p c = 6.1 HZ, CH2); 37.22 (d, J p c = 8.5 HZ, Cq); 21.72 (CH3); 18.50 (CH3). 31P NMR (CgD6): 6 -1.7. 'B NMR (CDCl3): 6 -10.9.

Attempted synthesis of 2-(2-l,lO-Phenanthroline)-2-oxo-5,5-dimethyl-4-(R)- phenyl-1,3,2-dioxaphosphorinane A mixture of 1,lO-phenanthroline-N-oxide (1.40 g, 7.14 mmol) and dimethyl sulfate (5 rnL) was heated at 70 "C for 3 h. The excess Me2S04 was removed by distillation and the resulting solid was suspended in 10 mL of THF. To this suspension, a solution of 2.8 (1.66 g, 7.34 mmol) and t-BuOK (0.82 g, 7.31 mrnol) in 30 rnL of THF was added dropwise. Even after refluxing overnight no reaction was observed.

Molecular structures of 2-(R)-(2-pyridinyl)-2-oxo-S,S-dimethyl-4-(R)-phenyl- 1,3,2-dioxaphosphorinane (2.10a) a n d 2- (R) - (2-pyr id iny 1)-2-0x0-5,s- dimethyl-4-(R)-phenyI-1,3,2-dioxaphosphorinane-N-oxide (2.12)

Crystals of 2.10a and 2.12 were obtained from saturated solutions of the respective

compounds in toluenelhexanes. Crystal data for 2.10a: C16H18N03P9 Mr = 303.30, ortho-

rhombic P212121, cell dimensions: a = 8.8425(7) A, b = 11.4530(6) A, c = 30.7161(6) A, V =

3110.7(3) A3 , Z = 8, D = 1.2952(1) g/cm3. Crystal data for 2.12: C I ~ H ~ ~ N O ~ P , Mr =

316.30, orthorhombic P212121, cell dimensions: a = 6.5558(5) A, b = 9.6092(7) A, c = 24.615(2) A, V = 1550.6(2) A3,, Z = 4, D = 1.3678(2) gIcm3.

Table 2.1. Selected bond lengths (&for compound 2.1Oaa p(l)-o(l) 1.460(4)

0(2)-C(l) 1.474(7)

C(l)-C(z) 1.539(8)

C(2)-C(l1) 1.532(8)

C(6)-C(7) 1.37 l(9)

C(13)-C(14) 1.380(8)

Standard deviations in the last decimal are given in parentheses

P(1)-C(12) 1.789(6)

N(1)-C(16) 1.330(8)

C(2)-C(10) 1.522(8)

C(5)-C(6) 1.388(9)

C(12)-C(13) 1.393(9)

P(1)-O(2) 1.575(4)

O(3)-C(3) 1.446(7)

C(1)-C(4) 1.494(8)

C(4)-C(5) 1.385(9)

C(7)-C(8) 1.382(9)

C(14)-C(15) 1.359(8)

P(1)-0(3) 1.581(5)

N(1)-C(12) 1.339(7)

C(2)-C(3) 1.528(9)

C(4)-C(9) 1.390(8)

C(8)-C(9) 1.386(9)

C(15)-C(16) 1.377(9)

a Standard deviations in the last decimal are given in parentheses

Table 2.2. Selected bond angles (deg) for compound 2.ZOaa

O(l)-P(I)-W2) 112.6(2)

O(2)-P(1)-O(3) 105.712)

P(1)-O(2)-C(1) 122.3(3)

O(2)-C(1)-C(2) 109.1(4)

C(1)-C(2)-C(3) 107.4(5)

C(3)-C(2)-C(10) 110.0(5)

O(3)-C(3)-C(2) 1 12.0(5)

C(5)-C(4)-C(9) 1 18.3(6)

C(6)-C(7)-C(8) 1 19.8(6)

P(1)-C(l2)-N(1) 116.9(4)

C(12)-C(13)-C(14) 119.0(5)

N(1)-C(l6)-C(l5) 125.0(5)


Table 2.3. Selected bond lengths (A) for compound 2.Z2a

O(l)-P(1)-0(3) 112.1(2)

O(2)-P(1)-C(12) 107.5(2)

P(1)-O(3)-C(3) 121.3(3)

O(2)-C(1)-C(4) 107.5(4)

C(1)-C(2)-C(I0) 1 13.1(5)

C(3)-C(2)-C(1 I) 106.9(5)

C(1)-C(4)-C(5) 122.2(5)

C(4)-C(5)-C(6) 120.3(5)

C(7)-C(8)-C(9) 1 19.5(6)

P(1)-C(12)-C(13) 120.5(4)

C(13)-C(14)-C(15) 1 19.0(6)

P(l)-O(l) 1.459(3)

0(2)-c(1) 1.4735)

N(1)-C(L6) 1.357(6)

C(2)-C(I0) 1.534(7)

C(5)-C(6) 1.389(6)

C(12)-C(13) 1.368(6)


3 1

O(I)-P(I)-C(12) 112.2(3)

O(3)-P(1)-C(12) 106.3(2)

C(12)-N(1)-C(16) 116.2(5)

C(2)-C(1)-C(4) 115.7(5)

C(1)-C(2)-C(1 I) 109.5(5)

C(l0)-C(2)-C(I I) 109.8(5)

C(1)-C(4)-C(9) 119.6(5)

C(5)-C(6)-C(7) 120.8(6)

C(4)-C(9)-C(8) 121.3(6)

N(1)-C(12)-C(13) 122.6(5)

C(14)-C(15)-C(16) 1 18.2(6)

Table 2.4. Selected bond angles (deg) for compound 2.12a

P(1)-O(2) 1.568(3)

q3)-C(3) 1.461 (6)

C(1)-C(2) 1.542(7)

C(2)-C(I1) 1.530(7)

C(6)-C(7) 1.378(7)

C(13)-C(14) 1.391(7)

O(1)-P(1)-0(2) 1 12.35(17)

O(2)-P(1)-O(3) 107.90(17)

P(1)-O(2)-C(1) 124.3(2)

O(4)-N(1)-C(16) 121.1(4)

O(2)-C(1)-C(4) 106.9(3)

C(1)-C(2)-C(10) 112.6(4)

C(3)-C(2)-C(l I) 106.8(4)

C(1)-C(4)-C(5) 122.2(4)

C(4)-C(5)-C(6) 120.0(5)

C(7)-C(8)-C(9) 120.3(4)

P(1)-C(l2)-C(l3) 121.0(3)

C(13)-C(14)-C(15) 118.9(5)

P(1)-0(3) 1.567(3)

O(4)-N(1) 1.297(5)

C(1)-C(4) 1.507(5)

C(4)-C(5) 1.388(6)

C(7)-C(8) 1.374(7)

C(14)-C(15) 1.382(8)

O(1)-P(1)-O(3) 113.56(18)

O(2)-P(1)-C(12) 110.74(18)

P(1)-O(3)-C(3) 124.4(3)

C(12)-N(1)-C(16) 119.0(4)

C(2)-C(1)-C(4) 115.9(4)

C(1)-C(2)-C(11) 109.8(4)

C(I0)-C(2)-C(11) 1 10.0(4)

C(1)-C(4)-C(9) 1 18.7(3)

C(5)-C(6)-C(7) 120.6(5)

C(4)-C(9)-C(8) 120.4(4)

N(1)-C(12)-C(13) 120.4(4)

C(14)-C(15)-C(16) 1 19.3(5)

P(1)-C(12) 1.805(5)

N(1)-C(12) 1.372(6)

C(2)-C(3) 1.522(5)

C(4)-C(9) 1.383(6)

C(8)-C(9) 1.391(6)

C(15)-C(16) 1.363(7)

O(1)-P(1)-C(12) 106.59(19)

O(3)-P(1)-C(12) 105.48(18)

O(4)-N(1)-C(12) 1 19.9(3)

O(2)-C(1)-C(2) 109.4(3)

C(1)-C(2)-C(3) 106.5(4)

C(3)-C(2)-C(10) 110.9(4)

O(3)-C(3)-C(2) 112.3(4)

C(5)-C(4)-C(9) 119.2(4)

C(6)-C(7)-C(8) 119.5(4)

P(I)-C(I2)-N(1) 118.4(3)

C(12)-C(13)-C(14) 120.2(4)

N(1)-C(16)-C(15) 122.1(4)

Novel Enantiomerically Pure Propane- 1,3-diols -3 3.1 Introduction The experience with 1,3,2-dioxaphosphorinanes based on 1 -aryl-2,2-dimethylpropane- 1,3- diols (3.1)' prompted us to study phosphites based upon this system as ligands in asymmetric catalysis. Variation of steric and electronic properties of the ligand employed can have dramatic influence upon the activity and selectivity of a catalytic system. Diols 3.1 are prepared by an aldol-Cannizzaro sequence from an aromatic aldehyde and isobutyraldehyde.la Hence, the possibility for variation of steric and electronic properties in diols 3.1 is limited to the aromatic ring. Resolution of each substituted phosphoric acid 3.2 requires a specific resolving agent.18

% 1) m 1 3 % 1) resolution

X 2) hydrolysG 0 ,o - 2) hydrolysis

OH OH o ~ - w OH OH

1) resolution b 1-7 Y 7

Y , 2) hydrolysis

Scheme 3.1. Resolution of propane-1,3-diols 3.1 (X = H; 2-Cl; 2-Br; 2,4-Cl2; 2-Me0)

By a different synthetic route, the 3-position of diols 3.1 can be made available for substitution.

Scheme 3.2. 'Locking' of the 1,3,2-dioxaphosphorinane ring by substituent R

(a) Ten Hotve, W.; Wynberg, H. J. Org. Chem 1985,50, 4508. (b) Van der Haest, A.D. PhD thesis, University of Groningen, 1992. (c) Hulst, R.; Zijlstra, R.W.J.; De Vries, N.K.; Feringa. B.L. Tetrahedron: Asymmetry 1994,5, 1701.

To maintain the amncomeric2 nature of the dioxaphosphorinane ring, i.e. the high preference for'a single rigid chair conformer, chiral diols with two equal substituents R' at the 3-position ar? preferred (Scheme 3.2). In the corresponding 1.3.2-dioxaphosphorinanes, the large shtituent R preferentially occupies the equatorial position, thereby locking the ring in one conformer. A general synthetic route was envisaged in which a single optically pure substrate could serve as a precursor for diols with a variety of steric and electronic properties.

Scheme 3.3. Retr~synthetic route to novel enantiomerically pure propane-1,3-diols

Ethyl 2,2-dimethyl-3-hydroxy-3-phenyl propionate (3.3) forms an ideal candidate sisce resolution of the corresponding acid3 has been described and reaction of the racernic ester with phenyllithium gives the corresponding triphenyl diol.4 Asymmetric synthesis of 3.3 via a borane catalyzed aldol reaction with an enantiomeric excess of 91% has recently been reported.5 The higher enantiomeric purity (e.e. > 99%) and cheaper materials make the classical synthesis a viable alternative, especially for large scale preparations.

3.2 Synthesk of the precursor Racemic ethyl 2,2-dimethyl-3-hydroxy-3-phenyl propionate (rac-3.3) was synthesized in a Reformatsky reaction according to a literatun: procedure.6

(8-(+)-33

Ph* OEi Et::20-

I) resolution * +

OH 0 OH 0 2) cat. H2S04. EtOH

rac-3.3 rac-3.4 P ~ ~ & o E ~

OH 0

(R)-(-)3.3

Scheme 3.4. Synthesis of enantiomerically pure hydroxy ester 3.3

Anteunis, M.; Tavernier, D.; Borrernans, F. Bull. Chirn. Soc. Beiges 1966, 75, 396. Matell, M. Arkiv Kemi 1949, 1 , 455. Zimmerrnan, H.E.; Steinrnetz, M.G.; Kreil, C.L. J. Am. Chem. Soc. 1978,100, 4146. Pannee, E.R.; Tempkin, 0.; Masamune, S.; Abiko, A. J. Am. Chern. Soc. 1991,113, 9365. Hauser, C.R; Breslow, D.S. in Organic Syntheses, Coll. Vol. 3, 1955, p. 408.

The resolution of the (+)-acid 3.4 has been described using morphine in aqueous ethanol. The enriched mother liquors were resolved with (+)-a-methylbenzylamine, giving the other enantiomer of the acid? However, using either enantiomer of the cheap a-methylbenzylamine, both enantiomers of acid 3.4 were resolved in three crystallizations from water. In this way, the use of morphine was avoided. The use of aqueous ethanol as a solvent severely diminishes the efficiency of the resolution. For accurate determination of the enantiomeric purity, samples of the acids were esterified in ethanol. HPLC analyses of the resulting esters showed enantiomeric excesses of over 99%. The absolute configuration of 3.3 was established by reduction to 3.1 with lithium aluminum hydride in ether (Scheme 3.5) and comparison of the sense of optical rotation with 1iterature.la

3.3 Novel chiral propane-1,3-diols Reaction of 3.3 with excess phenyllithium in ether affords 2,2-dimethyl- l.l,3-triphenyl- propane-1,3-diol(3.5) in reasonable yield. Contamination of the product with biphenyl makes purification rather sluggish. Several recrystallizations from toluene/hexanes afforded analytically pure samples of the diol. Reaction of 3.3 with methyllithium in ether proceeds smoothly at room temperature to give 1-phenyl-2,2,3-trimethylbutane-1,3-diol (3.6) in good yield. As an attractive alternative, the easily accessible Grignard reagent MeMgI can be applied. Tetrahydrofuran has to be used as a cosolvent in this case, since the initially formed magnesium alkoxide is insoluble in ether.

PhCH2Li

I toluene \

Scheme 3.5. Synthesis of novel chiral diols 3.5-3.7

Treatment of the ester with isobutyllithium in ether affords 3-isobutyl-2,2,5-trimethyl-1- phenylhexane-1.3-diol(3.7) in essentially quantatative yield. The high solubility of this diol in pentane accounts for the moderate yield of purified product. Each of the novel diols is a white crystalline solid. Alkylation or reduction of 3.3 does not lead to detectable racernization; enantiomeric excesses of diols 3.5 and 3.6, from enantiomerically pure 3.3 were higher than 99% by chiral HPLC. Apparently, for diols 3.5-3.7, enolization of the intermediate ketones does not hamper the formation of the products. However, reaction with benzyllithium failed to give the corresponding diol due to the acidity of the benzylic hydrogen atoms of the ketone, 3.3-dimethyl- 1,4-diphenyl-4-hydroxybutan-2-one (3.8). which was isolated as sole product.

3.4 Experimental section For general remarks see Chapter 2. HPLC analyses were performed on a Waters system 600 HPLC, consisting of a Waters 600E system controller and a Waters 991 photodiode array detector, or on a Waters 510 HPLC pump in combination with a Waters 490E programmable muitiwavelength detector. Conditions: hexanes/2-propanol95:5, flow ImUmin, h = 210 nm.

Resolution of 3-hydroxy-2,2-dimethylpropionic acid (3.4) To a suspension of racemic 3.4 (151 g, 0.78 mol) in water (2.5 L) was added (-)-a-methyl benzylamine (1 10 mL, 103 g, 0.85 rnol). The suspension was heated to reflux until a clear, yellow solution was obtained. Upon cooling to room temperature a white precipitate of the n- salt formed, which was collected by filtration. The filtrate was basified, washed with ether to remove (-)-a-methyl benzylamine, and acidified to give the (-)-acid. The combined acid portions from the first two crystallizations were collected (68.8 g, 0.35 mol), resuspended in water and (+)-a-methyl benzylamine (48 mL, 45.1 g, 0.37 mol) was added. Both n-salts were recrystallized from water until the optical rotation was constant at [a1578 f 13.9 (c = 1, MeOH). Usually this required three crystallizations. Since optical rotation was found to be an unreliable measure. for the enantiomeric purity of the salts, at this point samples of the salts were converted to the esters for HPLC analysis. Basification, washing with ether, acidification and filtration afforded the acids as white solids. Yield: (R)-(-)-3.4: 34.8 g, 0.18 mol, 23%. (S)-(+)-3.4: 54.4 g, 0.28 mol, 36%. Acids and amines from mother liquors were recovered.

Enantiomerically pure ethyl 3-hydroxy-2,2-dimethylpropionates (3.3) A suspension of (R)-(-)-3.4 (44.5 g, 0.24 mol) in ethanol was refluxed overnight with a catalytic amount of sulfuric acid. The resulting clear solution was cooled to room temperature, neutralized with saturated NaHC03 solution, and concentrated. The mixture was taken up in etherlwater. The organic layer was separated and the water layer was extracted twice with ether. The combined organic layers were washed with dilute aqueous NaOH, saturated aqueous NH4Cl and brine. Drying over Na2S04, evaporation of the solvent, and bulb-to-bulb distillation under reduced pressure afforded (R)-(+)-3.3 (47.9 g, 0.22 mol, 94%) as a colorless oil. Bp = 100 "C10.01 mrn Hg.

Novel En~tiomerically Pure Propane-1.3-diols

(R)-(+)-3.3: [a1578 0 (C = 1.14, MeOH); [a1365 + 17.6 (c = 1.05, MeOH). HPLC: (Chiralpak AD) Rf= 10.6 min. (5')-(-)-3.3: [a1365 - 17.7 (c = 1.14, MeOH). HPLC: (Chiralpak AD) Rf= 9.2 min.

Reduction of (-)-3.3 A solution of (-)-3.3 (1.00 g, 4.50 mmol) in ether (10 mL) was added dropwise to a suspension of LiAlH4 (0.35 g, 9.2 mmol) in ether (10 mL). After the initial exothermic reaction had subsided, the suspension was heated to reflux for 2 h. The excess LiAlH4 was decomposed with water and the salts were removed by filtration. The organic layer was washed with saturated aqueous NH4C1 and brine. After drying over Na2S04, the solvent was evaporated and the resulting white solid was recrystallized from hexanes to afford (S)-(+)-3.1 (0.69 g, 3.81 mrnol, 85%) as a white crystalline material. [a1578 + 47.7; [a1436 + 91.6 (c = 1, CHC13); lit.: [ a ] ~ + 49.9 (C = 1, CHC13).'a

(S)-(-)-1,1,3-Triphenyi-2,2-dimethylpropane-l,3-diol (3.5) A 1 M solution of PhLi in ether (90 rnL, 90 mrnol) was added dropwise to a solution (S)-(-)- 3.3 (6.0 g, 27 mmol) in ether (50 mL). The brown solution was refluxed overnight and neutralized with saturated aqueous NH4Cl. The organic layer was separated and the water layer was extracted twice with ether.. The combined organic layers were washed with brine, dried over Na2S04 and evaporated. The slightly yellow solid was recrystallized from toluenelhexanes to give 3.5 as off-white needles. Another recrystallization afforded white needles of 3.5. Yield: 2.06 g, 6.2 mmol, 23%. [a1578 - 153.6 (c = 0.53, CHC13). 1H NMR (CDC13): 6 7.98 (m, 2H, C6H5); 7.62 (m, 2H, C6H5); 7.43-7.21 (m, 1 lH, C6H5); 5.42 (S, lH, OH), 5.1 1 (d, 3JHH = 2.4 HZ, CH); 2.50 (d, ~ J H H = 2.4 Hz, OH); 1.10 (s, 3H, CH3); 0.95 (s, 3H, CH3). l3C NMR (CDC13): 6 147.1 (Cq~r) ; 143.8 (CqAr); 141.5 (CqAr); 128.5 (CHAr); 128.2 (CHA,); 128.0 (CHA,); 127.9 (CHA~); 127.6 (CHA,); 127.1 (CHA,); 126.7 (CHA,); 126.4 (CH*,); 83.8 (Cq); 79.6 (CH); 46.1 (Cq); 25.0 (CH3); 17.2 (CH3). Anal. Calcd for C23H2402: C, 83.10; H, 7.28. Found: C, 83.03; H, 7.16. HPLC: (Chiralpak OD) Rf= 14.6 min.

(R)-(-)-1-Phenyl-2,2,3-trimethylbutane-1,3-diol (3.6) A 0.95 M solution of MeMgI in ether (360 rnL, 0.34 mol) was added dropwise to an icecooled solution of (R)-(+)-3.3 (23.4 g, 0.105 mol) in THF (50 mL). A white precipitate formed instantly and methane was liberated. The suspension was stirred at room temperature overnight and carefully neutralized with saturated NH4Cl solution.The organic layer was separated and the water layer was extracted twice with ether. The combined organic layers were washed with saturated Na2S205 solution, brine, dried over Na2S04, and evaporated. The slightly yellow oil was crystallized from hexanes to give 3.6 as white needles. Yield: 16.3 g, 78 mmol, 74%. Mp = 117.7-1 19.0 "C. [a1578 - 36.7 (c = 0.505, CHC13). lH NMR (CDC13): 6 7.33 (m, 5H, C6H5); 4.95 (s, lH, CH); 4.05 (s, 1H, OH); 3.44 (s, lH, OH); 1.44 (s, 3H, CH3); 1.22 (s, 3H, CH3); 0.95 ( s , 3H, CH3); 0.64 (s, 3H, CH3). 13C NMR (CDC13): 6 141.63 (CqAr);

37

--

127.49 (CHA~; 127.38 (~HA,); 127.32 (~HA,); 79.62 (CH); 77.34 (C,); 43.13 (Cq); 26.56 (CH3); 25.39 (CH3); 22.82 (CH3); 14.57 (CH3). Anal. Calcd for C13H2002: C. 74.96; H, 9.68. Found: C, 75.02; H, 9.63. [M+H]+ = 209 (CI; NH3). HPLC (Chiralpak OD): Rf= 17.8 min. The other enantiomer was obtained in the same way starting from (S)-(-)-3.3. [a1578 + 37.1 (c = 0.51, CHC13). HPLC (Chiralpak OD): Rf= 15.9 min.

(S)-(-)-3-Isobutyl-l-phenyl-2,2,5-trimethylhexane-l,3-diol (3.7) To an ice-cooled solution of (S)-(+)-3.3 (2.52 g, 11.3 mmol) in pentane was added isobutyllithium (0.5 M. 75 mL. 37.5 mmol) in pentane. The clear solution was stirred for three h. at room temperature. The reaction was quenched with saturated aqueous NH4Cl. The organic layer was separated and the aqueous layer was extracted with pentane. The combined organic layers were washed with brine, dried over Na2S04, and concentrated. Two recrystallizations from pentane afforded 3.7 as white micmrystals. Concentration of the mother liquor gave a second crop of crystals. Total yield: 1.37 g, 4.70 mmol, 41%. 'H NMR (CDC13): 6 7.37-7.24 (m, SH, CsHs); 5.04 (s, lH, CH); 4.02 (s, lH, OH); 2.83 (s, 1H, OH); 1.99-1.76 (m, 3H. CH, CH2); 1.61-1.31 (m, 3H, CH2); 1.10 (d, 3 ~ H H = 6.4 HZ, 3H, CH3); 1.04 (d, 3 J H ~ = 6.4 HZ, 3H, CH3); 1.03 (d, 3JHH = 6.4 Hz, 3H, CH3); 0.97 (d, 3~~~ = 6.4 HZ, 3H, CH3); 0.96 (s, 3H, CH3); 0.64 (s, 3H, CH3). 13C NMR (CDC1-j): 6 141.93 (CqAr); 128.61 (CHAr); 127.36 (CHA,); 127.20 (CHA,); 81.26 (CH); 79.1 1 (C,); 45.29 (CH2); 45.20 (CH2); 45.00 (C,); 26.82 (CH3); 25.43 (CH3); 24.90 (CH3); 24.47 (CH); 24.16 (CH); 21.91 (CH3); 14.82 (CH3). Anal. Calcd for C19H3202: C, 78.13; H, 11.03. Found: C. 78.05; H. 1 1.21.

rac-3,3-Dimethyl-1,4-diphenyl-4-hydroxybutan-2-one (3.8) A 2.5 M solution of BuLi in hexanes (16 rnL, 40 mmol) was added to a stirred solution of TMEDA (7.2 mL, 5.5 g, 48 mmol) in toluene (25 mL). The red solution was heated to reflux for 30 min., diluted with THF (25 mL) and cooled to -80 'C. A solution of rac-3.3 (2.5 g, 11 mmol) in THF (15 rnL) was added dropwise. The resulting suspension was allowed to warm up to 0 "C and was stirred for 15 rnin at this temperature. The mixture was poured on ice. The organic layer was separated, the aqueous layer was extracted three times with ether. The combined organic layers were washed with brine, dried over NazS04 and evaporated. Residues of TMEDA were pumped off on an oil pump. The resulting solid was recrystallized from etherlpentane to afford 3.8 as off-white needles (2.06 g, 7.7 mmol, 68%). Mp = 81.2-82.3 "C. 'H NMR (CDC13): 6 7.39-7.17 (m, lOH, C6H5); 4.97 (d, 'JHH = ~ H z , CH); 3.86 (s, 2H, CH2); 3.00 (d, 3 ~ H H = 3Hz, OH); 1.23 (s, 3H, CH3); 1.13 (s, 3H, CH3). 13C NMR (CDC13): 6 214.40 (CO); 140.47 (CqAr); 134.34 (CqAr); 129.64 (CHAr); 128.39 (CHA,); 127.77 (CHA,); 126.76 (CHA,); 78.70 (CHOH); 52.42 (C,); 45.22 (CH2); 22.87 (CH3); 18.31 (CH3). Anal. Calcd for C18H2002: C, 80.56; H, 7.51; 0 , 11.92. Found: C, 80.55; H, 7.48; 0, 11.95.

Diphosphites, Diphosphates, and Borane Adducts -'-4 4.1 Introduction Phosphites are compounds in which phosphorus is surrounded by three singly bonded oxygen atoms in a distorted tetrahedron, a lone pair occupying the remaining site at the phosphorus atom. Structure and bonding in tervalent phosphorus compounds has been reviewed by Gilheany. 1

Although phosphites have long been known for their ability to form complexes with transition metals, in comparison to the work on phosphines,2 little research has been done on the development of novel phosphites and their complexes. In the mideighties it was recognized that phosphine-based catalysts suffer from oxidative P-C bond cleavage under hydrogenation and hydroformylation conditions.3 Reports on high activity of rhodium complexes of bulky diphosphites in hydroformylation4 have encouraged renewed efforts to develop novel phosphite ligands for catalysis. With the growing importance of asymmetric catalysis5, development of chiral phosphites and analogs has become increasingly important.

4.2 Transition metal c o m p l e x e s l Phosphite complexes have been described for practically all metals in the transition series.6 The stability of transition metal complexes of tervalent phosphorus compounds has long been ascribed to the back-donation of transition metal electrons into vacant d-orbitals on phosphorus. It is now accepted that back-bonding is virtually absent in phosphines and that it plays a role only in complexes of PF3 and phosphites. In contrast to phosphine complexes, the high stability of PF3 and phosphite complexes is not explained when only ligand basicity is taken into account. Inspection of theoretical bonding models for PH3 and PF3 learns that not d- orbitals on phosphorus but phosphorus-substituent o*-orbitals are the acceptor orbitals.7

I Gilheany, D.G. in The Chemistry of Organophosphorus Compounds, Vol. 1 , Hartley, F.R., Ed. Wiley: Chichester, England, 1990, Chapter 2 and references cited therein. Levason, W. in The Chemistry of Organophosphorus Compounds, Vol. 1 , Hartley, F.R., Ed., Wiley: Chichester, England 1992, p. 567. Gmou, P.E. Chem. Rev. 1985,85, 171. Van Leeuwen, P.W.N.M.; Roobeek, C.F. J. Organomet. Chem. 1983,258, 343. Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New York, 1994. Comprehensive Coordination Chemistry, Wilkinson, G.; Gillard, R.D.; McCleverty, J.A., Eds., Pergamon Press: Oxford, 1987. Marynick, D.S. J. Am. Chem. Soc. 1984,106, 4064.

Chapter 4

Examination of a series of X-ray diffraction data on pairs of transition metal phosphine and phosphite complexes differing only in the oxidation state of the metal confirms this: strengthening of the M-P bond, due to increased back-donation, results in weakening of P-X bonds as measured by bond lengths.8 The bonding abilities of tervalent phosphorus ligands are strongly influenced by the nature of the substituents on phosphorus. Phosphines having electron-rich phosphorus atoms are the stronger o-donors, whereas phosphites having electron-poor phosphorus atoms are the stronger x-acceptors? This is reflected in the different affinities: phosphines prefer high valent, electron- poor transition metals, whereas phosphites prefer low-valent, electron-rich metals. Apart from electronic considerations, as pointed out by Tolman,lo steric effects of substituents on phosphorus are extremely important to chemical behavior of phosphorus ligands and their complexes. Zerovalent molybdenum carbonyl complexes are prepared by thermal or photochemical reactions of Mo(CO)6 with phosphite under extrusion of carbon monoxide or by replacement of diene (norbornadiene) or triene (cycloheptatriene) ligands from molybdenum to give Mo(C0)4Lx or Mo(C0)3Lx complexes.1l Small phosphite ligands can replace all carbonyl ligands from the metal centre. The complexes are stable and can be purified by column chromatography and crystallization in air. Three molecular structures of Mo(C0)4(diphosphite) complexes have recently been described, two of which are based upon 1,3,2- dioxaphosphorinanes.12 In these complexes, the coordination geometry around molybdenum is a slightly distorted octahedron with the phosphorus atoms in a cis-arrangement, as also observed for bis(phosphite) complexes of this type.l3 The cis- and trans- carbonyl ligands show different 13C chemical shifts and different 2JpC coupling constants. As expected, the molybdenum atoms occupy the equatorial positions of the dioxaphosphorinanes. This is also observed in Mo(C0)s complexes of 1,3,2-dioxaphosphorinanes.14 Rhodium complexes of diphosphites have been applied in several catalytic reactions: hydrogenation, hydroformylation, et cetera.15 Rhodium(1) complexes are generally prepared by ligand replacement from dimeric [Rh(C0)2C1]2, [Rh(C2H4)C1]2 or monomeric Rh(acac)(CO)~ (acac = acetylacetonate).

Orpen, A.G.; Connelly, N.G. J. Chem. Soc., Chem. Commun. 1985, 1310. McAuliffe, C.A.; Levason, W. Phosphine, Arsine and Stibine Complexes of the Transition Metals, Elsevier Scientific Publishing Company: Amsterdam, The Netherlands, 1979. Tolman, C.A. Chem Rev. 1977,77, 313. Kirtley, S.W. in Comprehensive Organornetallic Chemistry, Wilkinson, G.; Stone, F.G.A.; Abel, E.W. Eds., Pergamon Press: New York, 1982, Vol. 3, Chapter 26.1, p.783. Gray, G.M.; Fish, F.P.; Srivastava, D.K.; Varshney, A.; Van der Woerd, M.J.; Ealick, S.E. J. Organomer. Chem. 1990,385,49. Gray, G.M.; Watt, W. J. Organomet. Chem. 1992,434, 181. (a) Bartish, C.M.; Kraihanzel, C.S. Inorganic Chemistry 1973, 12, 391. (b) Kraihanzel, C.S.; Bartish, C.M. Phosphorus 1974,4, 271. Applied Homogeneous Catalysis with Organornetallic Compounds, Cornils. B.; Herrmann, W.A., Eds. VCH: Weinheim. 1996.

Diphosphites, Diphosphates, and Borme Adducts

4.3 1,3,2-Dwxaphosphorinanes On tervalent 1,3,2-clioxaphosphorinanes, alkoxy, aryloxy, and chloro substituents prefer an axial disposition at phosphorus. This preference is generally ascribed to the anomeric effect,l6 i.e. stabilizing n-o* interactions between lone pair electrons on the ring oxygen and the axial a* P-X orbital,l7 in combination with reduced 1,3-syn-axial repulsions due to the flattening at the phosphorus end of the ring, and the relatively long P-O bonds. With the introduction of larger substituents at the 4- or 5-positions, the 1,3,2-dioxaphosphorinane ring becomes rigid and only one of the chair conformations is predominantly populated. These systems are referred to as anancorneric.18 Phosphites based on 1,3,2-dioxaphosphorinanes are known to form transition metal complexes with retention of configuration. Numerous examples have been described, several of which are depicted in Scheme 4.1. '9

L in NiL4 R = Me, i - R

ref 19a ref 19b ref 12

Scheme 4.1. Examples of 1,3,2-dioxaphosphorinane-based phosphite ligands

Metal complexes of chelating bidentate ligands show enhanced stabilities due to the chelate effect.20 For application in asymmetric catalysis, this extra stability is desirable. Therefore, this study has been focussed on the synthesis of chiral chelating diphosphite ligands.

4.4 Borane adducts Borane adducts of tervalent phosphorus species are remarkably stable and are generally crystalline solids. They are readily formed by treatment of the phosphorus compound with B2Hg or a labile complex of borane, such as BHyTHF and BHySMe2. The adducts can be decomposed with secondary amines, usually Et2NH or morpholine. Therefore, borane adducts of tewalent phosphorus compounds provide an ideal means of stabilizing otherwise sensitive intermediates in multi-step (ligand) syntheses. The stability of borane adducts of tervalent

l 6 Bailey, W.F.; Eliel, E.L. J. Am Chem. Soc. 1974, 96, 1798. Bentrude,W.G. in Phosphorus-31 NMR Spectral Properties in Compound Characterilation and Structural Analysis, Quin, L.D.; Verkade, J.G., Eds.; VCH: New York, 1994, p. 41.

l 8 Anteunis, M.; Tavernier, D.; Borremans, F. Bull. Chim Soc. Belges 1966, 75, 396. (a) Rodgers, J.; White, D.W.; Verkade, J.G. J. Chem. Soc. A, 1971, 77. (b) McEwen, G.K.; Rix, C.J.; Traynor, M.F.; Verkade, J.G. Inorg. Chem. 1974,13,2800.

20 Huheey, J.E. Inorganic Chemistry, 3ded, Harper: New York, 1983.

phosphorus is illustrated by the reaction conditions used with these compounds. Gaseous hydrogen chloride2l and sec-butyllithium22 are two extremes of reagents tolerated by tewalent phosphorus-borane adducts.

y 3 8H3

HCI BH3 RYT* RZ NMe2 RY$ CI

BH3S P,

4 Rr,+R3 -

R2NH BH3 I 1) s-BuLi, L*

S = THF, S M q P K ~ C H ~ 2) C u ( 0 P i ~ ) ~ *

Me

Scheme 4.2. Borane as protective group in tervalent-phosphorus chemistry

Aqueous workup procedures and column chromatography are an attractive supplement to the purification methods for derivatives of tervalent phosphorus compounds.

4.5 Synthesis of chelating diphosphites Chiral 1,3,2-dioxaphosphorinane-based diphosphites, such as 4.4-4.7, are most conveniently prepared by reaction of the 2-chloro-l,3,2-dioxaphosphorinane 4.2a with a diol in the presence of a base. Phosphochloridite 4.2a is prepared by the reaction of chiral diol 4.1 with phosphorus trichloride in the presence of base.

PC13, base - THF pw O y O + 4 0 OH OH

CI ?' CI

Scheme 4.3. Synthesis of phosphochloridite 4.2

Longeau, A.; Langer, F.; Knochel, P. Tetrahedron Lett. 1996,37,2209. 22 (a) Jugb, S.; Stephan, M.; Merdbs, Genet. I.P.; Halut-Desportes. S. J. Chem. Soc., Chem. Commun.

1993, 531. (b) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J. Am. Chem. Soc. 1990 ,112 , 5244.

Diphosuhites. Diphosphates, and Borane Adducts

Use of triethylamine gives rise to the formation of two epimeric phosphochloridites. In solution, the cis-epimer 4.2b slowly isomerizes to the trans-epimer 4.2a. When pyridine is used only 4.2a is obtained (Scheme 4.3).# Although trans-2-chloro-6-phenyl-4,4.5,5- tetramethyl-l,3,2-dioxaphosphorinanc (4.2a) has been isolated and characterized, for the synthesis of phosphites it is preferable to prepare it in situ to avoid contact with moisture. Hydrolysis of phosphochloridite 4.2 gives epimeric H-phosphonates 4.3. Reaction of 4.2a with catechol affords diphosphite 4.4 (Scheme 4.4) as a white crystalline solid. Reactions of phosphochloridite 4.2~1, prepared in situ from diol 4.1 and PCl3, with resorcinol, 2,2-dimethyl-1.3-propanediol, and fluorene-9.9-dimethanol afford diphosphites 4.5,4.6, and 4.7 respectively, (Scheme 4.4) as colorless oily substances.

Scheme 4.4. Synthesis of chiral diphosphites 4.4-4.7

Phosphorus-31 resonances of all novel diphosphites are found around 120 ppm. Their 1H NMR spectra show small 3JpH coupling constants (2.9-4.4 Hz) for the axial hydrogen atoms, indicative of a chair-like conformation of the 1,3,2-dioxaphosphorinane rings. The methylene groups in diphosphites 4.6 and 4.7 display large 2 ~ p H coupling constants. Evidence for the suggested conformation of the dioxaphosphorinane ring was obtained from the X-ray molecular structure of catechol diphosphite 4.4. Crystals of 4.4 suitable for X-ray diffractions were obtained by recrystallization from benzene by slow diffusion of pentane. Enantiomerically pure (-)-4.4 crystallizes in the orthorhombic space group P212121 with four independent molecules in a unit cell of dimensions a = 8.951(1) A, b = 10.515(1) A, c = 31.850(1) A. Both dioxaphosphorinane rings adopt an elongated chair conformation as generally observed for this class of compounds, with the phenyl groups in

# The higher relative amount of free HC1 in solution when pyridine is used as a base accounts for the exclusive observation of the trm-epimer.

8 Molecular structure determination performed by Drs. A. Meetsma

43

Chapter 4

equatorial positions. The bridging catechol moiety occupies the axial positions at both phosphorus atoms. The axial methyl groups are slightly twisted out of the 'ideal' positions. Torsion angles to phosphorus are 80.6(6)' and 80.0(5)' for the axial methyl groups and -163.1(4)" and -164.7(4)' for the equatorial methyl groups. Some weak intermolecular hydrogen bonds are observed in the crystal. The molecular structure of 4.4 with adopted labelling scheme is depicted in Figure 4.1.

Figure 4.1. Molecular structure of diphosphite 4.4 with adopted labelling scheme

Selected bond lengths and angles are collected in Tables 4.1 and 4.2, respectively, in the Expcrirnental Section.

4.6 Molybdenum complex A molybdenum complex of diphosphite 4.4 was formed by cosolution of 4.4 with an equimolar amount of Mo(C0)4(NBD) (NBD = norbornadiene) in benzene (Scheme 4.5). Progress of the reaction can be monitored by measuring the relative amount of 'free' norbornadiene in solution by 1H NMR spectroscopy. Complex ~ . ~ . M O ( C O ) ~ was purified by column chromatography (Al2O3, ethyl acetatehexanes 1:5). It is a glassy off-white solid which is very soluble in hydrocarbons, even in pentane. The solid is air-stable but solutions gradually turn blue. The molybdenum atom is octahedrally surrounded with the two phosphorus atoms in a cis-orientation, together with two carbonyl groups forming the equatorial plane. The other

Diphosphites, Diphosphates, and Borane Adducts

carbonyls occupy the axial sites. Due to this arrangement, the carbonyl groups are non- equivalent. This is clearly demonstrated in the 13C NMR and infrared spectra of the complex. The infrared spectrum shows four CO vibrations in the 2000 cm-1 region, attributable to two A1 modes, a B 1 mode, and a B2 mode. 19cy23

4.4.M0(C0)~

Scheme 4.5. Synthesis of molybdenum complex 4.4.Mo(C0)4

In the l3C NMR spectrum, the trans-carbonyl groups give rise to a triplet at 206 ppm with a coupling constant 2 ~ p C of 12.7 Hz. The ciscarbonyls are found at 213 ppm with a coupling constant of 15.0 Hz. Reaction of 4.4 with Rh(C0)zCI-dirner in benzene gives rise to instantaneous precipitation of a yellowish solid, accompanied by the evolution of carbon monoxide. The solid was collected by filteration and redissolved in chloroform-dl. From 1H NMR it is clear that the solid is not the expected Rh(diphosphite)Cl complex. An Arbuzov-lie reaction of the rhodium-bound chloride with one of the phosphite functions is probably responsible.

4.7 Borane adducts Only diphosphite 4.4 can be conveniently purified by means of recrystallization, whereas the other diphosphites 4.5-4.7 are oily substances. Due to their sensitivity towards either hydrolysis (4.5) or oxidation (4.6, 4.7), column chromatography is not a viable means of purification. Borane adducts of tervalent phosphorus compounds are air-stable in the solid state, can be conveniently prepared by exchange of a labile ligand (THF, Me2S) and can be purified by column chromatography.

4.7.1 Synthesis Borane adducts 4.4.2BH3-4.7-2BH3 were synthesized by treating benzene solutions of in situ prepared diphosphites 4.4-4.7 with excess borane-THF complex at room temperature. After several minutes excess borane was decomposed with methanol and the solutions were evaporated to dryness, leaving the crude borane adducts. The air-stable products were purified by column chromatography. Recrystallization of 4.4.2BH3, 4.5.2BH3, and 4.7-2BH3 from ethyl acetatelhexanes gave white solids. Propane-13-diol derived 4.6.2BH3 was an oil. Yields

23 Braterman, P.S. Metal Carbonyl Complexes, Academic Press: London, 1975.

were around 45% in each case. 1H NMR spectra of the novel borane adducts show broad doublets around 0.5 pprn for the borane hydrogen atoms. Proton decoupled 31P NMR spectra show broad doublets around 110 ppm due to coupling to 11B nuclei. 11B NMR shows broad singlets around -43 ppm.

Scheme 4.6. Synthesis of borane adducts 4.4.2BHj-4.7.2BH3

Crystals of resorcinol-based borane adduct 4.5.2BH3 were subjected to X-ray diffraction analysis.$ Although severe disorder hampered determination of the space group and refinement of the structure, the crude data show a C2-symmetrical molecule with no unexpected features.

Figure 4.2. Preliminary molecular structure of borane adduct 4.5.2BH3

One of several conformations of 4.5.2BH3 is depicted in Figure 4.2.

S Structure determination by Dr. W.J.J. Smcets

46

4.7.2 Removal of borane Borane adducts of tervalent phosphorus compounds are generally. decomposed by warming for several hours in diethylamine solution. For borane adduct 4.7.2BH3, this method gave unsatisfactory results, Warming with morpholine, however, resulted in complete removal of borane, and regeneration of diphosphite 4.7 (Scheme 4.7).

Scheme 4.7. Decomposition of borane adduct 4.7.2BH3

Although diphosphite 4.7 was the only phosphorus containing compound, the oily product was contaminated with traces ofmorpholiie, which could not be removed in vacuo.

4.8 Oxidation of diphosphites For the investigation of chiral self-recognition during the synthesis of diphosphite 4.4 (see Chapter 5), air-stable derivatives of 4.4 and 4.5 were desirable. Oxidation of the phosphorus atom, to give phosphates or thiophosphates, is an obvious approach. Aliphatic diphosphites 4.6 and 4.7 are smoothly oxidized by elemental sulfur with retention of configuration at phosphorus.23 The resulting thiophosphates, 4.10 and 4.11, respectively, can be purified by column chromatography and subsequent crystallization. Phosphorus-3 1 chemical shifts are found around 60 ppm. In contrast, diphosphites derived from the aromatic diols catechol and resorcinol are not oxidized by sulfur and are very sensitive to hydrolysis. This behavior is similar to that of phosphochloridites, probably due to the leaving group ability of the phenolate-type anions. Treatment of diphosphite 4.4 with m-chloroperbenzoic acid gives the H-phosphonates 4.3 rather than the diphosphate. Oxidation with retention of configuration of this type of diphosphite has been accomplished with anhydrous tert-butylperoxide or bis(trimethylsily1)- peroxide.24 Indeed, diphosphites 4.4 and 4.5 are quantitatively (31P NMR) oxidized with

23 Reagents for retentive oxidation at phosphorus include: N2O4, t-BuOOH, I21H20, OzIAIBN, Sg. See: Bentrude,W.G. in Phosphorus-31 NMR Spectral Properties in Compound Characterization and Structural Analysis, Quin, L.D.; Verkade, J.G., Eds.; VCH: New York, 1994, p. 41, ref 2. For (MegSi0)~ see: Wozniak, L.; Kowalski, W.; Chojnowski, J. Tetrahedron Lett. 1985,26, 4965.

24 (a) Wozniak, L.; Kowalski, J.; Chojowski, J. Tetrahedron Lett. 1985, 26, 4965. (b) Babin. P.; Bennetau, B.; Dunogubs Synth. Commun. 1992,22, 2849.

either peroxide to diphosphates 4.8 and 4.9, respectively. The diphosphates are air-stable, white crystalline solids. Phosphorus31 chemical shifts are found around -15 ppm.

(Me3SiO)z or Ss 4.4-4.7 C

benzene

n

Scheme 4.8. Oxidation of diphosphites 4.4-4.7

The pentavalent dioxaphosphorinanes are more rigid than their tervalent counterparts: methyl groups in the latter all give rise to singlets in IH NMR, whereas in the former, equatorial methyl groups in the 6-positions show coupling with phosphorus.

4.9 Catalysis Diphosphite 4.4 was used as a chiral ligand in two cobalt catalyzed reactions: the [2+2+2] cycloaddition (homo Diels-Alder reaction) of norbomadiene with propargyl acetate (Scheme 4.9)25 and the reduction of a$-unsaturated amide 4.13 (Scheme 4.10).26

Scheme 4.9. Cobalt catalyzed homo Diels-Alder reaction

25 Lautens, M.; Tam, W.; Lautens, J.C.; Edwards, L.G.; Crudden, C.M.; Smith, A.C. J. Am. Chem Soc. 1995,117,6863 and references cited therein.

26 Von Matt, P.; Pfaltz, A Tetrahedron:Asymmctry 1991.2.691.

Although the [2+2+2] cycloaddition proceeded smoothly to give 4.12, the enantiomeric excess of the product, as determined by chiral GC, was only a disappointing 4%.

Scheme 4.10. Cobalt catalyzed reduction of a$-unsaturated amide 4.13

Although conversion was high (91%), the cobalt catalyzed reduction of amide 4.1327 without sigmficant enantioselectivity (3% by chiral HPLC).

4.10 Experimental section For general remarks see Chapter 2. All reactions involving tervalent phosphorus species were performed under dry and oxygen-free nitrogen atmosphere. Standard conditions for HPLC: Chiralpak AD. 30% 2-propanol in hexanes. flow ImWmin, X = 254 nm. Resorcinol and catechol were sublimed before use. Morpholine was distilled from sodiurnlbenzophenone. Molybdenum and rhodium complexes and tert-butylhydroperoxide (5-6 M in nonane) were purchased from Aldrich and used as received. Fluorene-9,9-dimethanol and bis(trimethylsily1)- peroxide were synthesized according to literature procedures.28

trans-(S)-2-Chloro-4,4,5,5-tetramethyl-6-(R)-phenyl-l93,2- dioxaphosphorinane (4.2a) Diol (Rk4.1 (0.57 g, 2.7 mmol) and pyridine (0.5 mL, 0.49 g, 6.2 mmol) were dissolved in ether at 0 "C and PC13 (0.24 mL, 0.37 mg, 2.7 mmol) was added dropwise. The suspension was stirred at room temperature. After 2 h., the volatiles were evaporated and the residu was extracted with ether (3 times 5 mL). Distillation under reduced pressure afforded 4.2a (0.43 g. 1.6 mmol, 58%) as a colorless oil. Bp = 140 "C10.02 rnm Hg. 1H NMR (CDCl3): 6 7.37 (m, 5H, CsH5); 5.78 (d, 3JpH = 6.8 Hz, lH, CH); 1.84 (s, 3H, CH3); 1.36 (s, 3H, CH3), 1.10 (s, 3H, CH3), 0.76 (s, 3H, CH3). '3C NMR (CDCl3): 6 136.71 (Cq*r); 128.11 (CHh); 127.94 (CH*,); 127.52 (CH*,); 88.03 (d, zJCp = 7.3 HZ, Cq); 77.21 (d,,zJcp = 5.5 Hz, CH); 41.89 (d, 3JCP = 3.7 Hz, Cq); 26.31 (CH3); 26.17 (d, 3Jcp = 5.5 Hz. CHfeq); 21.89 (CH3); 15.74 (CH3). 31P NMR (CDC13): 6 148.9.

27 The amide was kindly supplied by Dr. T.R. Vries. 28 (a) Wessl6n. B. Acta Chem. Scand. 1967,21, 718. (b) Babin, P.; Bennetau, B.; Dunoguts, J. Synrh.

Commun. 1992,22, 2849.

49

trans-2H-2-0xo-4,4,5,5-tetramethyl-6.(S)phosphorinane ( 4 . 3 ~ ) A solution of H3P03 (0.39 g, 4.76 rnrnol) in THF (5 mL) was added to an ice-cooled solution of (S)-4.1 (1.0 g, 4.80 mmol) and dicyclohexylcarbodiimide (1.98 g, 9.60 mmol) in THF (15 mL). The resulting white suspension was stirred for 15 min and sonicated for 45 min. The solids were filtered off and washed with small portions of ether. The combined filtrates were evaporated to give a white solid. lH NMR showed the presence of two epimeric H- phosphonates. Crystallization from EtOAcfhexanes afforded 0.36 g (1.42 mmol, 30%) of the S,S-epimer as colorless crystals. Concentration of the mother liquor afforded a second crop of crystals. Total yield: 0.79 g, 3.1 mmol, 65%. [a1578 +25.3 (c = 1.03, CHC13) [a1365 +91.7 (c = 1.03, CHCl3). 1H NMR (CDC13): 6 7.37 (s, 5H, C6H5); 7.16 (d, IJpH = 677 HZ, lH, pH); 5.54 (d, jJpH = 3.6 Hz, lH, CH); 1.71 (s, 3H, CH3); 1.45 (d, ' J ~ H = 2.6 Hz, 3H, CH3); 1.13 (s, 3H, CH3), 0.79 (s, 3H, CH3). 13C NMR (CDC13): 6 135.73 (CqA3; 128.49 ( C H A ~ ; 128.05 (CHA~; 127.76 (CHA,); 90.05 (d, 2JCp = 8.0 HZ, Cq); 83.03 (d, 2Jcp = 4.8 HZ, CH); 41.81 (d, 'JCp = 4.8 HZ, Cq); 25.99 (d, 3JCp r 5.5 HZ, CH3=q); 24.25 (CH3); 21.55 (CH3); 15.52 (CH3). 3'P NMR (CDC13): 6 -3.2. Anal. Calcd for C13Hlg03P: C, 61.41; H, 7.53; P, 12.18. Found: C, 61.39; H, 7.69; P, 12.07.

Catechol diphosphite 4.4 To an ice-cooled stirred solution of (S)-4.1 (251.8 mg. 1.21 mmol) and pyridine (0.35 rnL, 0.34 g, 4.3 mmol) in THF (10 mL) was added dropwise PC13 (0.106 mL, 166 mg, 1.21 rnmol). A white precipitate formed and the suspension was stirred at room temperature for 20 rnin. Catechol(67.0 mg, 6.08 mmol) was added and the reaction mixture was stirred overnight. The volatiles were evaporated and the resulting white solid was stripped with twice 5 mL of benzene. After five extractions with benzene (10 rnL) the extracts were concentrated and the product crystallized by slow diffusion of pentane. Yield: 0.223 g, 0.38 rnrnol, 63% of 4.4 as white crystalline material. lH NMR (C6D6): 8 7.29-7.14 (m, 12H, Ar); 6.69-6.65 (m, 2H, C6H4); 5.91 (d, 3JpH = 2.9 Hz, 2H, CHPh); 1.77 (s, 6H, CH3); 1.20 (s, 6H, CH3); 1.05 (s, 6H, CH3); 0.47 (s, 6H, CH3). I3C NMR (C6Dg): 6 145.03 (m, C+); 138.81 (Cqh); 128.85 (CHh); 127.56 (CHh); 123.80 ( C H A ~ ; 121.54 (CHA~); 121.39 (CHh); 83.89 (d, J p c = 3.7 Hz, Cq); 75.23 (CHPh); 41.76 (Cg); 26.86 (CH3); 26.47 (CH3); 21.95 (CH3); 15.95 (CH3). 31P NMR (CgD6): 6 121. Anal. Calcd for C32H4006P2: C, 65.97; H, 6.92; P, 10.63. Found: C, 66.02; H, 7.07; P, 10.55. HRMS calcd 582.230, found 582.230.

Diphosphites 4.5-4.7. General Procedure. To an ice-cooled solution of 4.1 (1 eq.) and pyridine (3.5 eq.) in THF was added dropwise PC13 (1 eq.). The white suspension was stirred at room temperature for 15 min. Diol (0.5 eq.) was added and the suspension was stirred overnight at room temperature. The volatiles were evaporated and the resulting solid was stripped with benzene. Three extractions with benzene

50

Diphosphites, Diphosphates, and Boranc Adducts

afforded, after evaporation of the solvent, the crude products as white foams in essentially quantitative yields. The diphosphites were contaminated with, inter alia, phosphonates 4.3 (1H NMR, 3lP NMR)

Resorcinol diphosphite 4.5 lH NMR (C6D6): 6 7.24-7.21 (m, 4H, C6H5); 7.14-7.10 (m, 6H, C6H5); 6.96 (m, lH, C6H4); 6.88 (m, 3H, C6H4); 5.76 (d, 3JpH = 4.4 HZ, 2H, CH); 1.58 (s, 6H, CH3); 1.10 (s, 6H, CH3); 1.01 (s, 6H, CH3); 0.39 (s, 6H, CH3). 31P NMR (C6D6): S 122.

Dimethyl propanediol diphosphite 4.6 lH NMR (C6D6): 6 7.34-7.29 (m, 4H, CgH5); 7.14-7.08 (rn, 6H, C6H5); 5.68 (d, 3.IpH = 3.9 Hz, 2H, CH); 1.67 (s, 6H, CH3); 1.16 (s, 6H, CH3); 1.07 (s, 6H, CH3); 0.78 (s, 6H, CH3); 0.47 (s, 6H, CH3). 31P NMR (C6D6): 6 130.0.

Fluorenedimethanol diphosphite 4.7 'H NMR (C6D6): 6 7.59-7.48 (m, 8H, C6H4); 7.34-7.29 (m, 4H, C6H5); 7.28-7.07 (m, 6H, C6H5); 5.58 (d, 3 J p ~ = 3.4 HZ, 2H, CH); 4.21-3.91 (dAB, 4H, CH2); 1.47 (s, 6H, CH3); 1.09 (s, 6H, CH3); 1.01 (s, 6H, CH3); 0.42 (s, 6H, CH3). 1% NMR (C6D6): 6 146.08

141.44 ( C q ~ ) ; 139.06 (G,); 128.87 (CHh); 128.22 (CHA,); 127.82 (CH,); 127.54 (CHk); 127.26 (CHA,); 125.61 (CHA,); 120.12 (CHk); 82.77 (d, J p c = 7.6 Hz, Cq); 74.30 (CHPh); 64.94 (d, JPC = 21.4 H z , CH2); 56.16 (t, Cq); 41.48 (C,); 26.67 (CH3); 26.37 (CH3); 21.81 (CH3); 15.77 (CH3). 3lP NMR (CgD6): 6 128.9.

Synthesis of borane complexes 4.4.2BH3-4.7.2BH3. General procedure Diphosphites were prepared from (5')-4.1 (0.25 g, 1.2 mmol) as described above. To the crude diphosphite in benzene a twofold excess of BH3.THF (0.7 M in THF) was added. After stirring for 1-3 h. at room temperature, the excess BH3 was decomposed by addition of 1 rnL of methanol. The solution was evaporated to dryness and the air-stable residu purified by column chromatography (silica, EtOACmexanes 1 : 1)

Catechol diphosphite borark adduct (4.4.2BH3) White crystalline solid. Rf= 0.69. Yield: 45 %. [a1578 -18.2 (c = 0.516; CHC13). lH NMR (CDC13): 6 7.35 (m, 10H, Ph); 7.17 (m, 2H, C6H4); 7.01 (m, 2H, C6H4); 5.76 (d, ~ J P H = 3.3 Hz, 2H, CHPh); 1.79 (s, 6H, CH3); 1.48 (s, 6H, CH3); 1.12 (s, 6H, CH3); 0.75 (s, 6H, CH3); 0.55 (br. d 6H, BH3). 13C NMR (CDC13): 6 142.1 1 (m, C q d ; 135.85 (d, JPC = 7.3 Hz, Cqh); 128.35 (CH,); 128.16 (CHh); 127.71 (CHA,); 125.42 (CHA,); 121.81 (d, J p c = 2.4 Hz, CHA,); 90.05 (d, J p c = 11.0 Hz, Cq); 80.58 (d, J p c = 8.5 HZ, CHPh); 41.89 (d, J p c = 3.6 Hz, Cq); 26.08 (d, J p c = 8.5 Hz, CH3); 25.44 (CH3); 21.72 (CH3); 15.49 (CH3). 31P NMR (CDC13): 6 103.7 (d, J g p = 106 HZ). "B NMR (CDC13): 6 -43.3. Anal. Calcd ~ O I C32H46B206P2: C, 62.98; H, 7.60; P, 10.15. Found: C, 63.03; H, 7.64; P, 10.01.

Chaprer 4

Resorcinol diphosphite borane adduct (4.5.2BH3) White crystalline solid. Rf= 0.58. Yield: 43 %. [a1578 +20.6 (c = 0.50; CHC13). lH NMR (CDC13): 6 7.38-7.35 (m, 10H, Ph); 7.20 (m, lH, C6H4); 7.00 (m, 1H, C6H4); 6.90 (m, 2H, C6H4); 5.72 (d, 3JpH = 3.6 Hz, 2H, CHPh); 1.72 (s, 6H, CH3); 1.47 (d, 4 J p ~ = 0.8 Hz, 6H, CH3); 1.13 (s, 6H, CH3); 0.77 (s, 6H, CH3); 0.57 (br. d, 4JHp = 122 Hz, 6H, BH3). l3C NMR (CDC13): 6 151.40 (m, CqAr); 135.74 (d, J p c = 8.2 HZ, Cqk); 130.25 (CHk); 128.43 (CHAr); 128.17 (CHA,); 127.75 (CHk); 1 16.75 (d, JPC = 4.1 HZ, CHAr); 112.91 ( C H A ~ ; 89.79 (d, JPC = 10.7 HZ, Cq); 80.68 (d, J p c = 8.2 HZ, CHPh); 41.98 (d, J p c = 4.1 HZ, Cq); 25.99 (d, J p c = 8.2 HZ, CH3); 25.07 (CH3); 21.78 (CH3); 15.47 (CH3). 31P NMR (CDC13): 6 103.1 (d, J g p = 113 Hz). '1B NMR (CDC13): 6 -42.0. Anal. Calcd for C32H46B206P2: C, 62.98; H, 7.60; P, 10.15. Found: C, 62.94; H, 7.58; P. 10.05.

Dimethylpropanediol diphosphite borane adduct (4.6.2BH3) Colorless oil. 'H NMR (CDC13): 6 7.36-7.33 (m, 10H. Ph); 5.56 (d, 2H, 3JpH = 3.6 Hz, 2H, CHPh); 5.72 (d, 3 J p ~ = 2.9 Hz, 2H, CHPh); 3.86-3.71 (m, 4H, CH2); 1.71 (s, 6H, CH3); 1.40 (s, 6H, CH3); 1.06 (s, 6H, CH3); 0.95 (s, 6H, CH3); 0.73 (s, 6H, CH3); 0.6 (br. d, 6H, BH3). 13C NMR (CDC13): 6 136.20 (d, JPC = 8.6 HZ, CqAr); 128.21 (CHAr); 128.16 (CHAr); 127.63 (CHAr); 88.23 (d, JPC = 9.76 HZ, Cq); 79.71 (d, J p c = 8.5 HZ, CHPh); 71.35 (CH2); 41.67 (d, J p c = 4.9 H Z , Cq); 36.35 (in, Cq); 25.95 (d, J p c = 8.6 Hz, CH3); 25.54 (CH3); 21.65 (CH3); 21.15 (CH3); 15.37 (CH3). 31P NMR (CDC13): 6 107.5 (d, J g p = 123 Hz). 11B NMR (CDCl3): 6 -43.1.

Fluorenedimethanol diphosphite borane adduct (4.7.2BH3) White crystalline solid. Rf= 0.65. Yield: 47 %. [a1578 -54.4 (c = 0.502; CHC13). lH NMR (CDC13): 6 7.67-7.21 (m, 18H, Ar); 5.16 (d, 3JpH

= 3.3 Hz, 2H, CHPh); 4.32 (d, j J p ~ = 4.4 Hz, 4H, CH2); 1.27 (s, 12H, CH3); 0.96 (s, 6H, CH3); 0.60 (s, 6H, CH3); 0.5 (br.d, 6H, BH3). 13C NMR (CDC13): 6 143.94 (CqAr); 141.17 (CqAr); 136.03 (d, JPC = 8.6 HZ, CqAr); 128.56 (CHAr); 128.19 (CHA,); 127.53 (CHA,); 127.43 (CHA,); 124.52 (CHk); 120.07 (CHk); 88.54 (d, J p c = 11.0 Hz, Cq); 79.51 (d, J p c

= 8.5 HZ, CHPh); 68.71 (CH2); 55.22 (Cg); 41.56 (d, J p c = 4.9 HZ, Cq); 25.79 (d, J p c = 8.5 Hz, CH3); 24.83 (CH3); 21.57 (CH3); 15.28 (CH3). 31P NMR (CDCl3): 6 107.4 (d, J g p = 120 Hz). 11B NMR (CDCl3): 6 -43.4.

Deprotection of 4.7.2BH3 A solution of 4.7.2BH3 (143 mg, 0.20 mmol) in morpholine (3 mL) was heated at 100 'C overnight. The solvent was evera ted and the resulting oil was stripped twice with benzene (2 mL). Extraction with benzene (5 mL) afforded an impure oily substance. Diphosphite 4.7 was the only phosphorus compound detectable by NMR.

Diphosphites. Diphosphates, and Borane Adducts

Diphosphates and di(thiophosphates). General procedure Diphosphites were prepared as described above. To the crude benzene extract of the diphosphite was added slight excess of oxidant (t-BuOOH, (Me3SiO)z or S8). After standing overnight, the solution was evaporated to dryness and the product was purified by column chromatography and/or crystallization.

Catechol diphosphate (4.8) From (S)-4.1 (0.25 g, 1.20 -01). Oxidation with (Me3Si0)2, crystallization from ethanol. Yield: 191 mg (0.31 mmol, 52%) of 4.9 as a white solid. lH NMR (CDC13): 6 7.37-7.27 (m, 12H, Ar); 7.04-7.00 (m, 2H, C6H4); 5.72 (d, 3JpH = 2.0 Hz, 2H, CHPh); 1.70 (s, 6H, CH3); 1.46 (d, J ~ H = 3.2 Hz, 6H, CH3); 1.09 (s, 6H, CH3); 0.70 (s, 6H, CH3). 13C NMR (CDCl3): 6 141.33 (m, CqAr); 135.74 (d, J p c = 11.0 HZ, CqAr); 128.28 (CHA,); 127.99 (CHA,); 127.63 (CHA,); 125.21 (CHA,); 120.82 (d, J p c = 2.4 Hz, CHh); 9 1.8 1 (d, J p c = 8.5 H Z , Cq); 84.12 (d, J p c = 6.1 Hz, CHPh); 4 1.38 (d, J p c = 3.6 Hz, C,); 25.97 (d, J p c = 10.9 Hz, CH3); 24.15 (CH3); 21.50 (CH3); 15.19 (CH3). 31P NMR (CDC13): 6 -15. Anal. Calcd for C32H4008P2: C, 62.54; H, 6.56; P, 10.08. Found: C, 62.29; H, 6.59; P, 9.95. HPLC: Rf = 8.4 min (SS-enantiomer), Rf = 9.7 rnin (RR-enantiomer).

Resorcinol diphosphate (4.9) From (5')-4.1 (0.25 g, 1.20 -01). Oxidation with (MegSiO)2, crystallization from ethanol. Yield: 185 mg, 0.30 mmol, 50% of 4.9 as a white solid. lH NMR (CDC13): 6 7.36 (s, 10 H, Ph); 7.21-7.02 (m, 4H, C6H4); 5.64 (d, 3JpH = 2.0 Hz, 2H, CHPh); 1.65 (s, 6H, CH3); 1.46 (d, 4JpH = 3.2 Hz, 6H, CH3); 1.10 (s, 6H, CH3); 0.75 (s, 6H, CH3). '3C NMR (CDC13): 6 151.36 (d, JPC = 6 HZ, CqAr); 135.60 (d, J p ~ = 11 HZ, CqAr); 130.43 (CHAr); 128.42 (CHA,); 128.03 (CHA,); 127.7 1 (CHA,); 1 15.73 (d, J p c = 5 HZ, CHh); 11 1.57 (t, J p c = 7 Hz, CHA,); 91.44 (d, J P c = 9 Hz, Cq); 84.17 (d, J p c = 6 H z , CH); 41.33 (d, J p c = 4 Hz, Cg); 25.90 (d, J p c = 11 Hz, CH3); 24.03 (CH3); 21.51 (CH3); 15.11 (CH3). 3lP NMR (CDCl3): 6 -15. HPLC: Rj= 8.4 rnin (RR-enantiomer), Rf= 10.4 min (SS-enantiomer), Rf= 14.8 min (meso).

Dimethylpropanediol di(thiophosphate) (4.10) From (S)-4.1 (269 mg, 1.29 mmol). Oxidation with sulfur, purified by column chromatography (silica, EtOAclhexanes 1:s) and crystallization from EtOAcIhexanes. Yield: 11 1.3 mg, 0.174 mmol, 27%) of 4.10 as white crystals. Rf= 0.37. 1H NMR (CDC13): 6 7.37-7.30 (m, 10H, Ph); 5.60 (d, JpH = 2.9 Hz, 2H, CH); 3.87 (m, 4H, CH2); 1.71 (s, 6H, CH3); 1.43 (d, J ~ H = 2.6 Hz, 6H, CH3); 1.09 (s, 6H, CH3); 0.96 (s, 6H, CH3); 0.72 (s, 6H, CH3). 13C NMR (CDC13): 6 136.07 (d, J p c = 11 HZ, Cq~, ) ; 128.22 (CHh); 127.61 (CHA,); 91.25 (d, J p c = 10 Hz, C,); 83.14 (d, J p c = 7 Hz, CHPh); 72.36 (d, J p c = 5 H Z , CH2); 41.20 (d, J p c = 4 Hz, C,); 35.99 (t, J p c = 9 Hz, C,); 26.23 (d,

Chapter 4

J p c = 11 HZ, CH3); 25.12 (CH3); 21.56 (CH3); 21.46 (CH3); 15.55 (CH3). 31P NMR (cm13): 6 60.2.

Fluorenyldimethanol di(thi0phosphate) (4.11) From (S)-4.1 (255 mg, 1.22 mmol). Oxidation with sulfur, purified by column chromatography (silica, EtOAcIhexanes 1:4) and crystallization from EtOAc/hexanes. Yield: 179.9 mg, 0.234 mrnol, 39%) of 4.11 as a white solid. Rf= 0.38. 'H NMR (CDC13): 6 7.66 (d, 'JHH = 7.3 Hz, 2H, C6H4); 7.50 (d, 3 ~ H H = 7.3 Hz, 2H, C6H4); 7.40-7.23 (m, 14H, Ph); 5.19 (d, J ~ H = 2.9 Hz, 2H, CH); 4.46-4.11 (m, 4H, CH2); 1.30 (d, 4 J p ~ = 2.9 Hz, 6H, CH3); 1.24 (s, 6H, CH3); 0.99 (s, 6H, CH3); 0.59 (s, 6H, CH3). '3C NMR (CDC13): 6 144.17 (CqAr); 141.14 (CqAr); 135.91 (d, JPC = 9.8 HZ, CqAr); 128.52 (CHA,); 128.24 (CHA,); 128.18 (CHA,); 127.5 1 (CHA,); 127.43 (CHA,); 124.58 (CHAr); 120.05 (CHA,); 91.50 (d, JPC = 9.8 HZ, Cq); 82.91 (d, J p c = 8.6 HZ, CH); 69.66 (d, J p c = 4.9 HZ, Cq); 54.85 (t, J p c = 9.8 HZ, Cq); 4 1.07 (d, JPC = 3.7 Hz, Cq); 26.03 (d, J p c = 17.0 HZ, CH3); 24.36 (CH3); 21.46 (CH3); 15.44 (CH3). 31P NMR (CDC13): 6 59.4.

4.4.Molybdenum tetracarbonyl (NBD)Mo(C0)4 (50.2 mg, 0.167 mmol) and 4.4 (97.5 mg, 0.167 mmol) were dissolved in benzene (5 mL). After stirring overnight, the volatiles were removed under reduced pressure and the yellowish foam was purified by column chromatography (A1203 neutral, Act I; EtOAc/hexanes 15). The resulting colorless oil was dissolved in pentane. Slow evaporation of the solvent afforded 4.4.Mo(C0)4 as a glassy solid (105.3 mg, 0.133 mmol, 80%). lH NMR (CDC13): 6 7.46-7.34 (m, 10H, C6H5); 7.05-7.03 (m, 2H, C6H4); 6.99-6.97 (m, 2H, C6H4); 5.79 (s, 2H, CH); 1.75 (s, 6H, CH3); 1.36 (s, 6H, CH3); 1.14 (s, 6H, CH3); 0.75 (s, 6H, CH3). 13C NMR (Cm13): 6 212.75 (dd, 2 ~ p C = 15.0 Hz, CO); 206.12 (t, 2JpC = 12.7 HZ, CO); 143.68 (CqAr); 137.47 ( C q ~ ) ; 128.26 (CHh); 127.79 (CHA,); 127.50 (CHh); 125.87 (CHA,); 124.89 (CHA,); 87.43 (Cq); 78.37 (CH); 41.34 (C,); 25.96 (CH3); 21.90 (CH3); 15.85 (CH3). 31P NMR (CDC13): 6 151.8. IR (nujol): 2043 cm-l, 1958 cm-l (CO, A,); 1941 cm-1 (CO, B1); 1915 cm-1 (CO, B2).

Attempted synthesis of 4.4-Rh(C0)Cl Benzene-dg (0.6 rnL) was added to a mixture of [Rh(C0)2C1]2 (8.1 mg, 20.8 pmol) and 4.4 (24.7 mg, 42.4 pmol). A yellow precipitate (19.5 mg) formed. The solid was dried and dissolved in CDC13. The 1H NMR spectrum was not univocal.

Catalytic homo Diels-Alder reaction To a stirred solution of 4.4 (39.9 mg. 68 pmol), Co(acac)s (24.4 mg. 68 pmol). 4-butynyl- acetate (152 mg, 1.36 mrnol), and norbornadiene (128 mg, 1.39 rnmol) in CH2C12 (1.6 mL) was added Et2AlC1(0.15 rnL, 1.8 M, 0.27 mmol) in toluene. After stirring at room temperature for 16 h., the mixture was treated with water. The organic layer was separated and the aqueous

Diphosphites, Diphosphates, and Bomne Adducts

layer was extracted with CH2C12. The combined organic layers were dried over Na2S04 and concentrated. After filtration over a short pad of silica, the mixture was analyzed by chiral GC. The enantiomeric excess of the product was 4%.

Catalytic reduction of (E)-N-1,3-dimethyl-5-phenylpent-2-enamide A solution of amide (0.61 g, 3.0 mrnol) in ethanoYdiglyme (1: 1,3 rnL) was added to a solution of 4.4 (87.5 mg, 0.15 mmol) and Co(acac)3 (53.4 mg, 0.15 mmol) in THF (5 mL). To this mixture was added NaBH4 (0.1 1 g, 3.0 mmol). The mixture was stirred for two days at room temperature, by which time conversion had reached 91%. Workup with waterldiethyl ether afforded the product. The enantiomeric excess was 3% by chiral HPLC (Chiralpak OJ, 10% 2- propanal in hexanes).

Molecular structure of 4.4

Suitable transparent white block-shaped crystals were obtained by recrystallization from

benzenelpentane. Crystal data for C32H4006P2, Mr = 582.61, orthorhombic P212121, cell

dimensions: a = 8.95 l(1) A, b = 10.5 15(1) A, c = 3 1.85 l(2) A, V = 2997.7(5) A3 , Z = 4, D =

1.291 &m3, T = 130 K, R = 0.052 for 2789 unique observed reflections.

Table 4.1. Selected b

P(1)-O(1) 1.668(4)

P(1)-O(2) 1.604(4)

P(1)-O(3) 1.600(4)

P(2)-O(4) 1.663(4)

P(2)-O(5) 1.603(4)

P(2)-0(6) 1.617(4) O(1)-C(1) 1.388(7)

O(2)-C(7) 1.455(7)

O(3)-C(9) 1.452(6) O(4)-C(6) 1.368(6)

O(5)-C(20) 1.477(6)


Table 4.2. Selected bond angles (deg) for diphosphite 4.4a

O(1 MY Wlo) 103.1(2)

O(l)-P(l)-q3) 96.3(2)

O(2)-P(1)-O(3) 102.3(2)

O(4)-P(2)-O(5) 102.4(2)

a Standard deviations in the last decimal are given in parentheses.

O(4)-P(2)-0(6) 97.99(18)

O(5)-P(2)-q6) 101.7(2)

P(1)-O(1)-C(1) 119.9(3)

P(I )-O(2)-C(7) 127.0(3)

P(1)-O(3)-C(9) 120.1(3)

P(2)-O(4)-C(6) 120.4(3)

P(2)-O(5)-C(20) 126.2(3)

P(2)-O(6)-C(22) 119.1(3)

Molecular Structure determination of 4.5.2BH3 Crystals of borane complex 4.5.2BH3 were obtained from EtOAchxanes. Due to disorder in the lattice, the spacegroup could not be estabLished.

Chiral Self-Recognition 3

5.1 Zniroduction Many chemical processes in living systems depend on chiral recognition. Chiral recognition or stereois'omer discrimination is defined as: 'discrimination between enantiomers, or between enantiotopic ligands, achieved by appropriately structured reagents or catalysts, either natural, such as enzymes, or synthetic." Chiral self-recognition, however, is less general. It describes a process in which a chiral compound reacts preferentially with one of its enantiomers. Complete self-recognition can result in exclusive formation of either the racemic mixture of enantiomeric products, or the achiral meso-product. An example of complete self-recognition is found in the pinacolization of camphor.2 Only one, racemic, product is formed of the possible four racemates and two meso-compounds (Scheme 5.1).

raccamphor mc-endo:endo pinacol

Scheme 5.1. Chiral self-recognition in the pinacolization of camphor

Several other cases of self-recognition during pinacolization of chiral ketones have been described in the literature.3 Two other examples of self-recognition involve organometallic species.4 The principle of chiral self-recognition is similar to that of non-linear effects in asymmetric catalysis.1-5 The presence of diastereomeric catalysts with different reactivities can give rise to

Elial, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic Compounds Wiley: New York, 1994. Radhan, S.K.; Thakkcr, K.R. Tetrahedron Lett. 1987.28, 1813. (a) Touboul, E.; Dana, G. Tetrahedron 1975.31, 1925. (b) Touboul, E.; Dana, G. J. Org. Chem. 1979, 44, 1397. (c) Paquette, L.A.; Itoh, I.; Farnham, W.B. J. Am. Chem. Soc. 1975.97, 7280. (d) Wynberg, H.; Feringa, B. Tetrahedron 1976,32,2831. (a) Memfield, J.H.; Lin, G.-Y.; Kiel, W.A.; Gladysz, J.A. J. Am Chem. Soc. 1983, 105, 5811. (b) Bodwell, G.J.; Davies, S.G.; Preston, S.C. J. Organomet. Chem. 1991,402, C56. Guillaneux, D.; Zhao, S.-H.; Samuel, 0.; Rainford, D.; Kagan, H.B. J. Am. Chem. Soc. 1994,116, 9430.

deviation from the expected linear relationship between enantiomeric excess of the chiral ligand and enantiomeric excess of the product. In the course of investigation of the synthesis of novel chiral diphosphites (see Chapter 4). an unusual case of chiral self-recognition was encountered. Experimental verification of this self- recognition turned out to be a challenge. We describe the approach and argumentation here.

5.2 Synthesis of molecules containing two chiral centers When a molecule contains two chiral centers, there is a maximum of four stereoisomers. However, when the four groups on one chiral center are identical to those on the other, one of the isomers (the meso-form) has a plane of symmetry and hence is optically inactive.' A reaction in which two c h i fragments are connected by an achiral spacer in one molecule is schematically represented in Figure 5.1. Starting from a racemic mixture, two products can be expected: the racemic mixture of the enantiomers and the meso-form. The two meso-forms on the right-hand side in Figure 5. t are identical.

rac meso

Figure 5.1. Fisher projections6 of the possible products. Dashed lines represent mirror

plmtes

When chiral self-recognition is involved, one of these products will predominate, or, when self- recognition is complete, will be the exclusive product. In absence of self-recognition the rac: meso ratio will be 1 : 1. Since the dioxaphosphorinanc moieties are diastereomerically pure, diphosphites 5.4 and 5.6 can be treated as if containing only two chiral centers. The stereochemistries of the chiral 1,3,2-

dioxaphosphorinanes are described by the absolute configurations of the asymmetric carbon atoms.

5.3 Diphosphites from racemic diol Equimolar amounts of meso- and rac-products were expected for the synthesis of diphosphites 5.4 and 5.6 from racemic diol 5.1. Indeed, this is observed for diphosphite 5.4.

Scheme 5.2. Synthesis of diphosphites 5.4 and 5.6 from racemic diol5.1

When racemic diol 5.1 is converted to diphosphite 5.4 (Scheme 5.2), by reaction with PC13 and resorcinol (5.3), both meso- and rac-forms are observed by 1H NMR spectroscopy in

equal amounts.7 However, when racemic diol 5.1 is converted to diphosphite 5.6 (Scheme 5.2), by reaction with PC13 and catechol (5.5). only one set of signals is observed in the 1H NMR spectrum of the purified product. The spectrum is identical to that of the enantiomerically pure compound (see Chapter 4). Although it is possible that either the meso-form is removed during purification or that its NMR spectrum is identical to that of the racform, the possibility of chiral self-recognition cannot be excluded. This recognition should occur during the reaction of the intermediate catechol monophosphite with 5.2. Figure 5.2 represents the assumed course of the reaction.

tr

b

b C

rac (:

Figure 5.2. Schematic representation of the reaction to form the mono-phosphite and consecutive reactions to rac- and meso-diphosphites. For a racemate, thisfigure has a mirror image with the enantiomeric starting material

Chiral self-recognition occurs when one of the pathways in Figure 5.2 is preferred over the other. For the reaction described, in which the rac-product is thought to predominate, this implies that the upper pathway is preferred over the lower. Some dioxaphosphorinanes are believed to form homochiral conglomerates in solution,s i.e. association complexes of dioxaphosphorinanes of alike configuration. This property cannot be the origin of c h i recognition in this system, since recognition is completely absent in the case of diphosphite 5.4 (rac:meso = 1: 1).

Several methods for the determination of enantiomeric excesses rely upon the difference between (spectroscopic) properties of similar coupling products. These methods require complete absence of chiral self-recognition. (a) Feringa, B.L.; Smaardijk, A.; Wynberg, H. J. Am. Chem. Soc. 1985,107, 4798. (b) Vigneron, J.P.; Dhaenens, M.; Horeau, A. Tetrahedron 1973.29, 1055. (a) Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1985.50, 4508. (h) Van der Haest, A.D. PhD thesis. University of Groningen, 1992.

Chiral Self-Reconnition

5.4 Enantiomeric enrichment As stated above, for catechol-derived diphosphite 5.6, synthesized from racemic diol5.1, the meso-compound has not been observed in purified samples by NMR spectroscopy. Several -unsuccessful- attempts were made to independently synthesize the meso-compound. However, detection of the meso-compound is not required for analytical purposes. The amount of meso- compound that is formed can be inferred from the enantiomeric excess of the chiral product when enantiomerically enriched starting materials are used. The degree of self-recognition can be derived from the level of enrichment. Consider the case in which two structurally identical chiral fragments are brought together in one molecule, connected through a non-chiral spacer (Figure 5.1). When non-racemic starting material is used, three products will be observed: two enantiomers and the rneso compound. The molar ratio ql of the enantiomers of the chiral starting material is described by equation 5.1 :

[R] 100+%e.e. q , = = [S] 100-4Rbe.e.

eq. 5.1

where [R] and [SJ are the molar fractions of the respective enantiomers. In this example, the R- enantiomer is present in excess. The molar ratio q2 of the enantiomers of the chiral product is described by equation 5.2:

eq. 5.2

The degree of self-recognition, A, with values between 0 (no recognition; q2 = (q1)2) and 1 (complete recognition; q2 = ql), can be calculated from the observed values for ql and q2 via equation 5.3:

This can be rewritten as equation 5.4:

eq. 5.3

eq. 5.4

This method of determination of the degree of chiral enrichment was used to investigate the chiral recognition occurring during formation of diphosphite 5.6. Diphosphite 5.4 was used as a control, since recognition is absent in that case. For analytical purposes, the diphosphites 5.4 and 5.6 were quantatively transformed to the respective air-stable diphosphates 5.7 and 5.8 by retentive oxidation with bis(trimethylsilyl)pen,xide.~

Wozniak, L.; Kowalski, W.; Chojnowski, J. Tetrahedron Lett. 1985,26, 4965.

Chapter 5

Scheme 5.4. Retentive oxidation of diphosphites 5.4 and 5.6.

5.4.1 Synthesis of enriched diphosphates Dio15.1 of known enantiomeric composition was converted to the diphosphites 5.4 and 5.6 by reaction with PC13 and, respectively, resorcinol (53) and catechol (5.5) as described in Chapter 4, and quantitatively oxidized to diphosphates 5.7 and 5.8 with bis(trimethylsily1)- peroxide. The enantiomeric excesses of the products were determined by chiral HPLC. Unfortunately, by-products hampered accurate determination of enantiomeric excesses and purification of the diphosphates was necessary. The crude catechol diphosphate 5.8 was dissolved in ethyl acetate and precipitated with hexanes to give the pure crystalline compound. Enantiomeric enrichment of 5.8 by preferential crystallization will result in underestimation of the degree of chiral self-recognition. The resorcinol diphosphate was purified by flash column chromatography (ethyl acetatdhexanes 1: 1). Starting from diol of 50% e.e. (ql = 3), catechol diphosphate 5.8 was obtained with 50% e.e. (q2 = 3), and resorcinol diphosphate 5.7 with 84% e.e. (q2 = 11.5). These figures suggest the occurrence of complete recognition in the case of 5.8 (ql = q2) and no recognition in the case of 5.7 (q2 > (q1)2). Given values for the enantiomeric excesses are the averages of three determinations. The obtained value of 84% for 5.7 where a maximum of 80% (q2 = 9) is predicted indicates the rather poor accuracy of this HPLC method. A mass spectrometry method was studied as an alternative.

5.5 Labelling experiments A technique that allows analysis of crude materials is mass spectrometry. Obviously, meso- and rac-forms of one compound, having identical elemental compositions, are not normally distinguished. Selective labelling of one enantiomer (S) of the starting material will result in three different molecular ions for the product. One without labels (enantiomer R,R), one with one set of labels (the meso-compound R,S) and one with two sets of labels (enantiomer S,S). Starting with a quasi-racemate (i.e. an equimolar mixture of R and labelled S enantiomers) the degree of recognition can be inferred from the relative intensities of the three molecular ion peaks of the products in the mass spectrum. It is assumed that the degree of recognition is not

affected hy the remote labelling. Deviation from the statistical ratio (1:2: 1) for the products (R,R), (R,S), and (S,S) reflects the degree of chiral self-recognition during their formation.

5.5.1 Synthesis of labelled diphosphates Deuterium labels were introduced in one of the enantiomers of dio15.1 by reaction of (S)-(+)- ethyl 3-hydroxy-2,2-dimethyl-3-phenyl-propionate (3.3) with methyl-dylithium, analogous to procedures described in Chapter 3 (Scheme 5.5). Deuterium incorporation is higher than 99% in the indicated positions, as judged from the absence of the corresponding methyl resonances in 1H NMR spectra of 5.1-dg.

Scheme 5.5. Synthesis of deuterium-labelled diol (S)-(+)-5.1-dg

Equimolar amounts of unlabelled diol (R)-(5.1) and labelled diol (S)-(5.1-d6) were allowed to react with PC13 and catechol in the usual manner (Scheme 5.6, see also Chapter 4) to give three different products (R,R)-5.8-do, (R,S)-5.8-dg and (S,S)-5.8-d12. After exhaustive extraction with benzene, followed by oxidation to the diphosphates, the extract was evaporated to dryness.

5.5.2 Mass spectrometrical analysis of labelled diphosphates Electron impact (EI-MS) and chemical ionisation mass spectrometry (CI-MS; reactant gas NH3) were found to be unsuitable for determination of product ratios due to extensive fragmentation. 'Softer' ionisation methods like fast atom bombardment (FAB) and electrospray (ES) were tried as alternatives. The latter gave particularly good results. An ES-mass spectrum of a sample from a reaction run at room temperature is depicted in Figure 5.3.

Figure 5.3. ES-mass spectrum of a mixture of (R,R)-5.8-do, (R,S)-5.8-dg and (S,S)- 5.8-dl 2

The (M+H)+-peaks for the (R,R)-5.840 enantiomer (mlz = 615), the (R,S)-5.8-& meso (m/z = 621) and the (S,S)-5.8-d12 enantiomer (mlz = 627) an separated by six mass (mlz) units, due to the different degrees of deuterium labelling. The relative intensities of the (M+H)+-peaks - 1001, SO%, and 1001, respectively - reflect the isomeric composition of the mixture. From Figure 5.3 it is clear that the meso-diphosphate (R,S)-5.8-d6 constitutes only about 20% of total diphosphate 5.8.

Scheme 5.6. Synthesis of labelled diphosphates 5.8 (i: PClj, pyridine, THF; ii: catechol, THF; iii: (MejsiO)~, benzene

The diastereoselectivity D (corresponding A*100% in equations 5.2-5.4) of a reaction is a measure for recognition. It can be obtained from the total amount of rac-products and meso- product via equation 5.5:3a

[ruc] - [meso] D = x 100% [rac] + [meso]

eq. 5.5

The diastereoselectivity for the reaction depicted in Scheme 5.6 is calculated by equation 5.5 to be 60%.

5.6 Borane adducts During the course of this investigation, it was recognized that borane adducts of rac- and meso- diphosphites 5.7 have different lH NMR spectra. Moreover, the meso-borane adduct (meso- 5.7.2BH3) was detected in purified samples of rac-borane adduct (rac-5.7.2BH3). The resonances of the benzylic hydrogen atoms in rac-5.7-2BH3 and meso-5.7-2BH3 are particularly suitable for determination of their relative amounts: they are baseline separated and are found in an otherwise 'silent' region of the spectrum (6 5.82, resp. 5.76 ppm).

i, ii, iii w

OH OH

rac-5.1

Scheme 5.7. Synthesis of rac- and meso-borane adducts 5.6.2BH3 (i: PCl3, pyridine, THF; ii: catechol, THF; iii: BHyTHF, benzene)

To this end, integrated intensities of the benzylic resonances of the two compounds rac- 5.6-2BH3 and meso-5.6.2BH3 were compared (Table 5.1). In order to investigate the influence of temperature upon the degree of chiral self-recognition, coupling reactions were run at three different temperatures: -15 "C, room temperature (ca. 22 'C) and reflux temperature (ca. 80 'C). 1H NMR spectra of crude reaction mixtures were recorded to establish the meso:rac ratios. The observed meso:rac ratios are collected in Table 5.1.

Scheme 5.8. Catechol mono-phosphite borane adduct 5.9.

A third benzylic resonance (6 5,77 ppm) appeared between both 'key'-resonances. Separation of a crude mixture by column chromatography (silica, ethyl acetatehexanes 1:3) afforded a small amount of the responsible compound, which was identified as the borane adduct of the catechol mono-phosphite 5.9 by NMR. The diastereoselectivities, as calculated from eq. 5.5, for the reactions described above are listed in Table 5.1.

Table 5.1. Meso:rac ratios and degrees of recognition for the syntheses of borane adducts 5.6.BH3

Temperature ('C) meso-5.6.BH3 rac-5.6.BH3 diastemselectivity (%)

The diastereoselectivities for the reactions at room temperature obtained from this method and from the labelling method described above show good correlation. As can be seen in Table 5.1, the reaction temperature has a significant influence upon the recognition. Although the reaction temperatures were not accurately determined and only three data points are available, construction of an Arrhenius plot was quite informative. A straight line was obtained when the natural logarithm of the rac:meso-ratio was plotted as a function of the reciprocal temperature. From the slope of the line the difference between activation energies of formation of racemic respectively meso products was calculated to be approximately 2 kcal/mol.lo Even higher values for diastereoselectivity D are expected when the reaction is run at temperatures below -15 "C. According to the Arrhenius plot, the diastereoselectivity will reach 99% when the reaction is performed at approximately -124 "C. However, extremely long reaction times (the reaction takes already several days to go to completion at -15 "C) make a further lowering of the reaction temperature unpractical.

5.7 Origin of recognition To investigate n-n interactions as a possible source of chiral self-recognition, a catechol-derived diphosphate from the aliphatic 2,3,3-trimethyl-2,4-pentanediol5.10" was synthesized., Racemic diol5.10 was converted to diphosphate 5.11 by treatment with, subsequently, PCl3, catechol, and bis(trimethylsilyl)&roxide, by procedures described in Chapter 4. The 31P NMR spectrum of the crude reaction mixture in C g H d C g D g shows two signals at -15.7 and -15.9 ppm with equal intensities for the meso-and rac-products.

Atkins, P.W. Physical Chemistry 3rd ed, Oxford University Press: Oxford, 1986, Chapter 28. Hellier, D.G.; Phillips, A.M. Org. Magn. Reson. 1982, 18, 178.

i, ii, iii -

Scheme 5.9. Synthesis of diphosphate 5.11 (i: PCl3, pyridine, THF; ii: catechol, THF; iii: (MejlSiO)~, benzene)

The 1H NMR spectnun of the purified material shows two sets of signals due to meso- and rac- products in a 1:l ratio. From this result it is clear that the phenyl groups in the parent system must be involved in the self-recognition process.

5.8 Conclusions Chiral self-recognition has indeed been established in the synthesis of diphosphite 5.4. Three methods were tried for determining the degree of recognition. Diphosphates 5.7 and 5.8 were prepared from enantiomerically enriched diol5.1. For precise determination of the enantiomeric excesses of the products by chiral HPLC, purification was unavoidable. Furthermore, the accuracy of HPLC proved insufficient for this purpose. Crude samples can be analyzed by mass spectrometry. To be able to distinguish meso- and rac- products in mass spectra, deuterium labels were introduced selectively. Electrospray proved to be the only mass spectrometry technique by which the molecular ions were observed without fragmentation. Although the meso-diphosphate was observed by this method, a simpler 1H NMR detection of borane complexes of the meso- and rac-diphosphites 5.6 was studied as an alternative. The use of easily accessible racemic dio15.1, together with the simple and accurate analysis by 1H NMR spectroscopy, makes this method preferable over the others described above. The effect of reaction temperature on the degree of recognition was investigated and the involvement of n-n interactions in the self-recognition process was established.

5.9 Experimental section For general remarks see Chapter 2. Ethyl 3-hydroxy-2,2-dimethylbutanoate was prepared according to a literature procedure.'* Electrospray Mass Spectrometry was performed with a R3010 triple-quadrupole mass spectrometer (Delsi-Nermag, Argenteuil, France), equipped with a prototype atmospheric pressure ionization (API) source and an ionspray interface. The stainless steel cappilary of the interface was kept at +3.5 kV for positive ions; the nitrogen

l 2 Cologne, J.; Dumont, P. Bull. Soc. Chim. Fr. 1947, 38.

67

Chapter 5

pressure for nebulization was 3 bar. PE Sciex API3 software was used for data aquisition and data processing. Samples were dissolved in HPLC-grade acetonitrile. Mrs. M. Jeronimus Stratingh and Dr. A.P. Bruins of the Farmaceutical Laboratories of this University are gratefully acknowledged for determination of the ES-MS spectra.

Enantiomerically enriched diphosphates 5.7 and 5.8 Two 0.10 g samples of (S)-5.1 (50% e.e.; HPLC: Chiralpak OD. 3% 2-propanol in hexanes) were converted to the diphosphates 5.7 and 5.8 as described in Chapter 4. Diphosphate 5.7 was purified by column chromatography (silica, ethyl acetatethexanes 1: 1). diphosphate 5.8 was purified by crystallization from ethyl acetate1 hexanes. Enantiomeric compositions of the diphosphates were determined by chiral HPLC (Chiralpak AD, 30% 2-propanol in hexanes). The values given are the averages of three determinations. Diphosphate 5.7: 84% e.e., diphosphate 5.8: 50% e.e.

Borane adducts 5.6.2BH3 Borane complexes were prepared in a typical procedure: 0.10 g of rac-5.1 (0.48 mmol) was dissolved in THF (5 mL). Pyridiie (0.15 mL, 0.15 g. 1.85 mmol) was added and the solution was cooled at 0 "C. PC13 (43 pL, 67.5 mg, 0.49 mmol) was added dropwise and the white suspension was stirred at room temperature for 30 min. Catechol (55 mg, 0.50 mmol) was added and the mixture was stirred at -15 'C (5 days), room temperature (overnight), or 80 "C (5 h). After the indicated periods, the products were extracted with benzene (5 times with 10 mL). Excess BHyTHF was added and the solution was stirred for 1 h at room temperature. Excess borane was decomposed with methanol. Evaporation of the solution gave the crude products as white solids. 1H NMR spectra were recorded to establish the meso:rac ratios. Column chromatography (silica, ethyl acetatehexanes 1:3) of the crude sample from the reaction run at 80 "C afforded pure rac-5.6.2BH3, meso-5.6.2BH3, and catechol mono- phosphite borane adduct 5.9.

rac-Borane adduct (rac-5.6.2BH3) NMR spectral data for the rac-diphosphite borane adduct are identical to those for the enantiomerically pure adduct described in Chapter 4.

meso-Borane adduct (meso-5.6.2BH3) 'H NMR (CDC13): 6 7.38-7.33 (m, 10H, CfjH5); 7.21-7.18 (m 2H, CfjH4); 7.07-7.04'(m ZH, C6H4); 5.82 (d, 3 J p ~ = 3.7 Hz, CH); 1.65 (s, 6H, CH3); 1.11 (s, 6H, CH3); 1.06 (s, 6H, CH3); 0.69 (s, 6H, CH3); 0.6 (br. d, 6H, BH3). 13C NMR (CDC13): 6 142.17 (dd, *JpC = 3.7 HZ, 3 J p ~ = 3.7 HZ, Cqk); 136.1 1 (d, 3JpC = 7.3 HZ, C ~ A ~ ) ; 128.39 (CH*,); 128.31 (CH*,); 127.64 (CHk); 125.25 (CHh); 121.55 (d, J p c = 3.7 Hz, CHA,); 89.87 (d, 2JpC = 11.0 Hz, Cq); 80.60 (d, 2JpC = 8.6 Hz, CH); 41.89 (d, 3Jpc = 4.9 Hz, Cq); 25.45 (d, 3JpC = 8.6 Hz, CH3); 24.95 (CH3); 21.65 (CH3); 15.40 (CH3). 31P NMR (CDC13): 6 104.3.

Chiral SeCRecognition

Cstechol moaophosphite borane adduct (5.9) 'H NMR (CDC13): 6 7.41-7.35 (m, 5H, C6H5); 7.1 1-7.06 (m, lH, C6H4); 7.05-7.03 (m, lH, C6H4); 6.99-6.97 (m, lH, QH4); 6.81-6.78 (m, lH, CbH4); 5.77 (d, 3JpH = 3.4 HZ, lH, CH); 5.40 (s, lH, OH); 1.75 (s, 3H, CH3); 1.50 (d, 4JpH = 1.0 Hz, 3H, CH3); 1.15 (s, 3H, CH3); 0.79 (s, 3H, CH3); 0.6 (br. m, 3H, BH3). 13C NMR (CDC13): 6 146.91 (Cq,+); 135.50 (d, J p c = 7.5 H Z , C q ~ ) ; 128.60 (CHph); 128.10 (CHph); 127.85 (CHph); 125.99 (CHA~); 120.66 (CHh); 120.25 (CHh): 116.96 (CHh); 90.20 (d, J p c = 11.2 H z , CH); 81.11 (d, Jpc = 7.5 Hz, Cq); 41.96 (d, J p c = 3.7 Hz, Cq); 26.00 (d, J p c = 9.3 Hz, CH3); 25.12 (CH3); 21.80 (CH3); 15.49 (CH3).

(S)-l-Phenyl-2,2-dimethyl-3,3-bis(trideuteromethyl)-propane-l,3-diol (5.1-dg) This diol was prepared analogous to diol 3.6 (see Chapter 3) from (S)-(+)-ethyl 3-phenyl-3- hydroxy-2,2-dimethyl propionate (3.3) (1.87 g, 8.4 mmol) and 0.36 M methyllithium-d3 (65 mL, 23.4 rnrnol) to give 0.65 g (3.03 rnrnol, 36%) of 5.1-dg as white crystals. lH NMR (CDC13): 6 7.35-7.26 (m, 5H, Ph); 4.97 (s, lH, CH); 3.87 (s, lH, OH); 3.26 (s, lH, OH); 0.95 (s, 3H, CH3); 0.64 (s, 3H, CH3). 13C NMR (CDC13): 6 141.7 ( C ~ A ~ ) ; 128.55 (CHh); 127.50 (CHh); 127.54 (CHk); 79.96 (CH); 43.08 (Cq); 22.77 (CH3); 14.46 (CH3).

Labelled diphosphates 5.8 A mixture of (R)-5.1 (49.8 mg, 0.239 mmol) and (S)-1-phenyl-2,2,3-trimethylbutane-1,3-diol (5.1-6) (5 1.2 mg, 0.239 mmol) was converted to the diphosphates as described in Chapter 4. The crude products were analyzed using electrospray mass spectrometry (ES-MS).

rac-2,3,3-Trimethyl-2,4-pentanediol (5.10) A 1.85 M solution of MeMgI (70 mL, 0.13 mol) in ether was added dropwise to a stirred solution of ethyl 3-hydroxy-2,2-dimethylbutanoate (5.35 g, 33.4 mmol) in THF (30 mL). The resulting white suspension was stirred overnight. Saturated NH4C1 solution was added carefully and the organic layer was separated. The aqueous layer was extracted with ether and the combined organic layers were washed with Na2S205 solution and brine and were dried over Na~S04. Evaporation of the solvent gave 5.10 as a white solid. Yield 2.95 g (20.2 mmol, 60%). 'H NMR (CDC13): 6 4.09 (q, 'JHH = 6.2 Hz, lH, CH); 3.89 (br s, 2H, OH); 1.28 (s, 3H, CH3); 1.18 (s, 3H, CH3); 1.11 (d, 3 j ~ ~ = 6.2 Hz, 3H, CH3); 0.96 (s, 3H, CH3); 0.71 (s, 3H, CH3). 13C NMR (CDC13): 6 77.50 (Cq); 72.32 (CH); 42.36 (Cq); 26.20 (CH3); 25.21 (CH3); 22.40 (CH3); 18.38 (CH3); 14.03 (CH3). Anal. Calcd for C8H1802: C, 65.71; H, 12.41. Found: C. 65.86; H, 12.47.

rac- and meso-Diphosphates 5.11 To a stirred solution of 5.10 (1 10.2 mg, 0.75 mmol) and pyridine (0.2 mL, 0.2 g, 2.5 mmol) in THF (5 mL) was added PC13 (70 pL, 0.1 1 g, 0.8 mmol) at 0 "C. The white suspension was stirred at room temperature for. 15 min and catechol (45.9 mg, 0.42 mmol) was added. The

Chapter 5

mixture was stirred overnight. The solvent was evaporated and the residue was stripped with twice 5 mL of benzene. The products were extracted five times with benzene (10 mL). To the extract (TMS0)2 was added (0.2 mL, excess) and stimng continued overnight. A sample from the reaction mixture revealed the presence of two equally intense signals attributable to the diphosphates. Evaporation of the volatiles and column chromatography (Al~o3/EtOAc) afforded a mixture of meso- and rac -9.11 as a white foam (77 mg, 0.16 mmol, 42%). 'H NMR (CDC13): 6 7.46-7.37 (m, 2H, C6H4); 7.10-7.05 (m, 2H, C6H4); 4.91-4.85 (m, 2H, CH); 1.5511.54 (s, 3+3N, 6,,-CH3); 1.4111.39 (s, 3+3H, 6,q-CH3); 1.35-1.29 (dd, 3+3H, 4=q-CH3); 1.14 (s, 6H. 5ax-CH3); 0.82 (s, 6H, 5,q-CH3). 31P NMR (CDC13): 6 -15.03, -15.14.

Conformational Analysis of ~yridinyl-2-phosphonates """6 6.1 Introduction1 Conformations of phosphorinanes, 1,3,2-diheterophosphorinanes in particular, have been widely studied.2 1,3,2-Dioxaphosphorinanes and 1.3,2-oxazaphosphorinanes have received most interest since examples of these system are found in physiologically active molecules. Cyclic adenosine mono phosphate (c-AMP) is based on a 1,3,2-dioxaphosphorinane (Scheme 6.1). It is found in all eucariotes and functions as an intracellular 'second' messenger, 'first' messengers b e ' i hormones. Cyclophosphamik is a clinical anti tumor agent based on a 1,3,2- o~azaphosphorinane.3*~

c- AMP cyclophosphamide

Scheme 6.1. Physiologically active 1,3,2-dioxa- and 1,3,2-oxazaphosphorinanes

Three types of conformations are observed for the saturated phosphorinane ring: chair, boat and twist-boat (Scheme 6.2). The rings are always somewhat flattened at the phosphorus end due to the relatively long P a bonds.

A major part of the calculations described in this Chapter were performed by Drs. R.W.J. Zijlstra. Maryanoff, B.E.; Hutchins, R.O.; Maryanoff, C.A. in Topics in Stereochemistry, Vol. 11, Allinger, N.L.; Eliel, E., Eds.; Wiley: New York, 1979, p. 187. Corbridge, D.E.C. Phosphorus. An Outline of its Chemistry, Biochemistry Md Technology. Elsevier Science Publishas, Amsterdam, The Netherlands, 1990. See also: Hartley, F.R. in The Chemistry of Organophosphorus Compoundr, Vol. 1, Hartley, F.R., Ed. Wiley: Chicester, England, 1990, p. 1. Benau&,W.G. in Phosphorus-31 NMR Spectml Properties in Compound Characterization and Siructural Analysis, Quin, L.D.; Verkade, J.G., Eds.; VCH: New York, 1994, p. 41.

Chapter 6

chair boat twist-boat

Scheme 6.2. Conformations of 5,s-dimethyl-1,3,2-dioxaphosphorinanes

When considering the chair conformation, two extreme situations can be distinguished: mobile molecules, in which rapid chair-chair interconversions take place and the ones highly biased towards one conformer, so called anuncomeric molecules (Scheme 6.3).5 Large substituents on the ring show high preferences for the less strained equatorial positions and hence lock the ring in one predominant conformation.

Scheme 6.3. Chair-chair interconversion of a 5,s-dimethyl-1,3,2-dioxaphosphorinane (left) and an ananancomeric 4-phenyl-1,3,2-dioxaphosphorinane

Conformations of phosphorinanes can be studied by a variety of methods, including X-ray diffraction, NMR spectroscopy, and computational chemistry. Many solid-state molecular structures of 13,2-dioxaphosphorinanes have been solved using X- ray diffraction techniques.6 Although absolute configurations within molecules can be readily established, dynamics of the system are frozen out. Crystal packing effects can overcome small energy differences between chair and twist conformations (1-2 kcal/mol)7 of the molecules in the crystal lattice. Hence, crystal structures do not necessarily reflect the minimal energy conformations in solution. NMR spectroscopy allows for the study of molecules in solution, and dynamics on the NMR time scale can be observed. The 1.3,2-dioxaphosphorinane system contains three NMR-active nuclei, 1H, 13C and 31P, which are useful for conformational analyses. Chemical shifts are influenced by changes in the conformation of the ring, for phosphates inter alia depending on the smallest 0-P-O bond angle by the Gorenstein relation.* For conformational analyses, however, coupling constants, both homonuclear and heteronuclear, are more reliable. The

Antcunis, M.; Tavemier, D.; Bommans, F. Bull. Chim Soc. Belges 1966, 75, 3%. Corbridge, D.E.C. The Structure Chemistry of Phosphorus, Elsevier: Amsterdam, 1974. (a) Bentrude, W.G.; Yee, K.C. J. Chem. Soc., Chem Commun. 1972, 169. (b) Bentrude, W.G.; Tan, H.-W. J. Am. Chem Soc. 1973,95, 4666. (c) Bentrude, W.G.; Tan, H.-W.; Yee, K.C. J. Am Chem. SOC. 1975,97, 573. Gorenstdn, D.G. J. Am Chem Soc. 1975,97, 898.

Conformntional Analysis of PYridinyl-2-phospho~fes

development of Fourier-transform NMR techniques has made multidimensional and multi- nuclear experiments available. Increasingly complicated pulse sequences are being developed for the study of increasingly complicated molecules. Homonuclear 1H correlated two- dimensional techniques like COSY and NOESY have become routine in the synthetic organic laboratory. Correlated spectroscopy (COSY) reveals through-bond couplings. In nuclear Overhauser effect spectroscopy (NOESY) intramolecular through-space contacts between nuclear spins can be made visible by magnetization transfer at distances up to 3.5-4 A. Obviously. NOESY is a powerful technique for the conformational analysis of phosphorinancs. Computational chemistry has gained in importance over the last decades, with the ever growing power of computer systems and the development of sophisticated algorithms and programs. Whereas several years ago it was common practice to reduce larger molecules to rudimentary fragments to keep calculation times within limits, today it is possible to consider the complete molecules. Still, for practical reasons, most calculations involve single molecules in vacuo, ignoring solvent-solute and solute-solute interactions in liquid media and packing effects in crystal lattices. For geometry optimizations this implies that calculated minimum energy conformations do not necessarily correspond to solution or solid-state structures of the molecules. Solvation and crystal packing effects can affect the potential energy surface of a molecule. In our Department of Organic Chemistry, phosphochloridate 6.1 (Scheme 6.4) has been studied as a derivatizing agent for the determination of enantiomeric excesses of amines, amino acids, and alcohols using 31P NMR spectroscopy.9 Conformations of several diastereomeric pairs of phosphoric esters and amides were examined with semi-empirical (PM3) methods. The calculations predicted that amines react with phosphochloridate 6.1 with inversion of configuration at phosphorus, whereas alcohols react with retention. The results were in accordance with NOESY and crystal structures of an arnide (R* = (R)-CH(Me)Ph) and an ester (R' = CH2-(R)-CH(Me)Ph) derivative.9

Scheme 6.4. System studied by Hulst et al. (ref: 9)

Although single-bond lengths around phosphorus deviated significantly from experimental values, the PM3 calculations showed that the Gorenstein relation* is also valid for the diastereomers of the phosphoric esters and amides studied.

Hulst, A.I.R.L., PhD thesis, Groningen University, 1994.

6.2 The system This study describes the conformational analyses of several derivatives of 2-(2-pyridiny1)-2- oxo-5,5-dimethyl-4-phenyl-1,3.2-dioxaphosphorinane, syntheses of which have been described in Chapter 2 of this thesis. The aim of this research was to establish the origins of the observed conformations in molecular structures of 6.2a and 6.3a as obtained from X-ray diffraction studies and to calculate the minimal energy conformations of other derivatives depicted in Scheme 6.5, for which only NMR data are available for comparison. Single point energies related to the optimized shuctures were calculated in the 631G* basis set. Furthermore, the thio analogs 6.5a and b were studied to investigate the effect of size of the chalcogcnide on the geometry around phosphorus. Finally, the minimum energy conformation of dimethyl derivative 6.6 was calculated to study the deformation of the dioxaphosphorinane ring as a result of the increased steric requirements at the benzylic position of the ring.

Scheme 6.5. Pyridinyl-2-phosphonates investigated in this Chapter and adopted labelling scheme (only depicted for 6 . 2 ~ )

For N-oxide 6.3b and N-methyl derivative 6.4b, no NMR data are available for comparison. It proved impossible to prepare 6.3b by the procedure applied for the preparation of 63a.

Conformational Analysis of Pyn'dinvl-2-phospho~tes

6.3 Geometry optimizations, the methods Restricted Hartree-Fock geometry opthbations of the compounds depicted in Scheme 6.5 wen performed at the 3-21G level for all atoms except phosphorus and sulfur, for which an additional set of six cartesian d-type polarization functions was included (6-3 lG*). Inclusion of these d-type functions is a requirement for the accurate npduction of experimentally observed bond lengths around phosphorus. Geometry optimization at the 6-31G* level for all atoms would have resulted in unacceptable increase in cpu times. The Hartree-Fock calculations of the compounds described, consisting of 39 (6.2, 6.5) to 45 (6.6) atoms and having C1

symmetry, requires 207 to 260 basisfunctions. Although the use of unbalanced basis sets in geometry optimizations can give rise to substantial BSSE (basis set superposition error) effects on the geometry, the accurate reproduction of two solid-state structures (vide infra) justified this.

6.4 Single point energy calculations The energies related to the minimized geometries for all structures under consideration were calculated in the 6-31G* basis set. Single point calculations of several non-optimized geometries were performed in order to estimate the energy barriers for rotation around the phosphorus-carbon bond. Since non-optimized geometries were used, these energies reflect the upper limits of the rotational barriers.

6.5 Geometry optimizations, the resulkr 6.5.1 Conformations of 6 . 2 ~ and 6 . 3 ~ ; comparison with molecular structures Optimized geometries for 6.2a and 6.3a (Figure 6.1) show good correlations with the solid state structures described in Chapter 2, sections 2.2.3 and 2.3.1, respectively. For comparison, data from solid state structures and RHF calculations are collected in Table 6.1 at the end of this Chapter.

Figure 6.1. RHF 3-21G/6-31G* optimized geometries of 6 . 2 ~ and 6 .3~0

RHF 3-21Gl6-31G* refers to restricted Hartme Fock calculation in a mixed basis set.

Calculated bond lengths around the phosphorus atom are slightly shorter: by 0.003-0.014 A for single bonds and 0.001-0.003 A for the exocyclic 'double' bond. Calculated angles 0 1-P1-02 and 01-P1-03 are larger by 2 degrees, angles 02-P1-C12 and 03-Pl-C12 are smaller by 2-3 and 1 4 degrees, respectively. The deviation in the bond angles is possibly due to the shorter P- O and longer P-C bonds, which are most likely caused by the BSSE effect on the geometries. The very small deviations are acceptably small, probably within zero-point vibrational displacements, and justify the use of this basis. Except for the minor deviations in bond lengths and angles, the RHF optimized geometries of 6.2a and 6.3a are virtually identical to the solid- state structures: the dioxaphosphorinane ring in 6.2a is an elongated chair as generally observed in these systems. In 6.3a. the ring is flattened at the phosphorus end to accommodate the N-oxide function. As stated in Chapter 2, mutual repulsion between the nitrogen lone pair (6.2a). respectively, the N-oxygen lone pair (6.3a), and phosphorus-bound oxygen lone pairs governs the conformations as observed in the crystals. The two gauche conformations, in which the nitrogen or N-oxygen lone pairs are positioned between endocyclic oxygen and phosphoryl oxygen lone pairs, are expected to be local minima on these grounds. However, optimization of 6.2a, 'manually' put in either gauche conformation (Scheme 6.6). does not give local minima: the structure relaxes towards the global minimum instead. Apparently, the rotational barriers between these conformations are sufficiently low to allow for this relaxation to occur.

syn-gauche 6.2a anri-gauche

Scheme 6.6. Relaxation of gauche conformations of 6.2~ towards the global minimum

Energy barriers, associated with rotation around the phosphorus-carbon bond, were estimated from the single point energies of the non-optimized conformations generated from the global minimum energy conformation of 6% For this, dihedral angles 0 1 -P-C 12-N, 02-P-C12-N and 03-P-C12-N were set at 0'. The energy differences of these points with the minimum energy were calculated at: 15.1. 4.1 and 3.9 kcallmol. For estimation of the single point energies of the gauche confomiations of 6.2a, corresponding dihedral angles were adopted from the optimized geometries of gauche conformations of 6.3a (vide infra). Calculated energies are 1 1.1 and 1 1.4 kcallmol higher than the global minimum energy. These energies suggest that, at room temperature, the pyridinyl moiety rotates within 90 degrees from the local minimum orientation to both sides. This explains the lack of NOE interactions observed for this compound.

Conformational Analysis o f firidinyl-2-phosphonates

In contrast, gauche conformations were found to be local minima for N-oxide 6.3s (Figure 6.2). Single point calculations showed these to be higher in energy than the global minimum conformation by 10.16 and 10.91 kcaVmol for the syn- and anti-conformations, respectively.

Figure 6.2. RHF 3-21Gl6-31G* optimized syn- (lefr) and anti-gauche geometries of 6.3~

Dihedral angles 8, defined by phosphoryl oxygen-phosphorus-carbon-nitrogen, associated with these conformations are -75.25" and 72.62", respectively. From the angles 02-PI-C12 (98.51" and 108.01 ") and 03-PI-C12 (108.91' and 98.94") it can be seen that the pyridinyl fragment is tilted backward to minimize repulsions. Single point energies of non-optimized geometries of the N-oxide with dihedral angles 01-P-Cl 2-N, 02-P-C12-N and 03-P-C 12-N 'manually' set at O' were calculated to estimate the rotational barrier.1° Values of 34, 18, and 17, respectively. kcdmol were obtained, starting from the optimized geometry of the global minimum of 63a. Even if a thermodynamical equilibrium exists between the minimal energy conformations, the global minimum conformation will have a time-averaged occupancy of effectively unity. This is in accordance with NMR spectroscopic data, which suggest a single conformation for 63a. An unexpected effect was observed in the syn- and antigauche conformations of 6.3a: the endocyclic P-O bond anti to the N-oxygen atom is elongated (1.600 resp. 1.606 A), whereas the other bond remains unchanged (1.580 resp. 1.576 A). The 02-P-03 bond angles are decreased by 3" relative to the global minimum conformation. This conformational change is probably due to the displacement of electropositive phosphorus towards the electronegative N- oxygen atom.

6.5.2 Conformations of 6.2b and 6.3b As for compounds 6.2a and 6.3a, NOESY of 6.2b also lacks interactions of pyridinyl hydrogen atoms with other hydrogens in the structure. Hence, an 'inward' structure analogous to that of 6.2a and 6.3a was expected for 6.2b. This is indeed what is found. The optimized structure is depicted i~ Figure 6.4. Again, no local minimum energy conformations were found in the gauche orientations for 6.2b.

Attempts to calculate the rotational barriers of 6 . 3 ~ in the semi-empirical AM1 package resulted in gradual change of the ring conformation to a twist-boat.

Figure 6.4. RHF 3-21G/6-3IG* optimized geometries of 6.2b and 6.3b

The dioxaphosphorinane ring retains its chair conformation with bond lengths and angles comparable to those found for 6.2a. The energy calculated for this optimized geometry is higher than that of 6.2a by 0.68 kcaUmo1. The small energy difference between 6.2a and 6.2b is reflected in the product ratio of the mixture prepared from 2-pyridinylphosphonyl dichloride and l-phenyl-2,2-dimethy1propane-1,3-diol (see Chapter 2, section 2.2.1). The nitrogen atom of the equatorial pyridine ring is turned towards the dioxaphosphorinane ring to minimize repulsion. This is in accordance with 1H NMR and NOESY data, which point to a chair conformation with an equatorial pyridinyl group. Both axial hydrogens show small couplings to phosphorus ( 3 ~ p H = 2.2 Hz), the equatorial hydrogen shows a large coupling (3JpH = 22.0 Hz). The phosphoryl oxygen atom does not occupy an 'ideal' axial position in the optimized geometry, it is slightly inclined towards an equatorial orientation. The corresponding N-oxide 6.3b showed a similar minimal energy conformation (Figure 6.4). The single point energy calculated for this structure is higher than that of 6.3a by 4.83 kcal/mol. The higher energy is probably due to the close contact of the N-oxygen atom with the axial methyl group. No NMR data are available for this compound.

6.5.3 Conformations of N-methylated derivatives In Chapter 2 (section 2.2.4) it was established that electrostatic repulsion between oxygen and nitrogen atoms plays an important role in the determination of the minimal energy conformations of 6.2a. The nitrogen atom of compound 6.2a was methylated with methyl trifluoromethanesulfonate to 'neutralize' the lone pair. The 1H NMR spectrum shows upfield shifts for the axial hydrogen atoms on the dioxaphosphorinane ring, indicating that the pyridine nitrogen is no longer positioned above the ring. This was confrnned by NOESY analysis: the 3- pyridinyl hydrogen atom in 6.4a shows significant interactions with the aforementioned axial hydrogens, whereas the N-methyl group does not. Proton-phosphorus coupling constants (3JPWar = 0 Hz; 3JPHe4 = 24.1 Hz) also point towards a single chair conformation for 6.h. RHF calculations for 6.4a reveal two minimal energy conformations: one with the N-methyl and phenyl groups at the same side of the molecule (syn), and the corresponding anti conformation. Both calculated structures show a twist-boat conformation (Figure 6.5).

78

Figure 6.5. RHF 3-21G/6-31G* optimized geometries of 6.4a. Syn- (left) and anti- confonnatiom

The ring deformation is probably caused by the strong electrostatic potential of the system due to the bare positive charge. Intramolecular interaction of the electronegative oxygen atoms with the positive charge forces the endocyclic oxygen atoms towards the pyridinyl moiety, resulting in the twist-boat confomations. Obviously, geometry optimization of charged systems without considering a counter ion can lead to incorrect results. In solution, the charge will be compensated by a counter ion and by the solvent. To mimic this situation as closely as experimentally viable, an iodide counter ion was included in the system. The initial position of the iodide relative to the pyridine ring was obtained from the optimized geometry of a model system, N-methylpyridinium iodide. Iodine was described at the 3-21G* level. The preliminary result of this effort is depicted in Figure 6.6. Although the dioxaphosphorinane ring is flattened at the phosphorus end, the chair-like conformation is retained.

Figure 6.6. Preliminary geometry of the anti-conformation of 6 . 4 ~ with counter ion

Although no counter ion has been included in the calculations, both minimal energy conformations of 6.4b show normal chair conformations for the dioxaphosphorinane ring. The optimized geometries are depicted in Figure 6.7.

Figure 6.7. RHF 3-21G/6-31G* optimized geometries of 6.4b. Syn- (left) and anti- confotmations

6.5.4 Codormations of thiophosphoryl derivatives Comparison of the optimized geometries of 2-thia- l,3,2-dioxaphosphorinanes 6.5a and b with those of 2-oxa- 1.3.2-dioxaphosphorinanes 6.2a and b shows the influence of size of the exo- chalcogenide upon conformation of the ring. Whereas the phosphoryl oxygen atom in 6.2b is inclined towards the equatorial position, the phosphoryl sulfur atom in 6.5b shows a nearly perfect axial disposition (Figure 6.8).

Figure 6.8. RHF 3-21GI6-31G* optimized geometries of 6 . 5 ~ (left) and 6.5b

Sulfur-phosphorus bond lengths are relatively long:" 1.950 A and 1.983 A for 6.5a and 6.5b, respectively when sulfur is described at the 6-31G* level. The larger P=S bond length for 6.5b is explained by anomeric interactions between endocyclic oxygen lone pairs and the antibonding P S a*-orbital.12 Phosphorus-sulfur bond lengths are slightly smaller when sulfur is described at the 3-21G level (1.939 A and 1.947 A, respectively), indicating the minor influence of BSSE on the optimized geometries of 6.5a and 6.5b.

Approximate range of bond lengths: 1.92 f 0.05 A. See reference 6. Van Nuffel, P.; Van Alsenoy, C.; Lenstra, A.T.H.; Geise, H.J. J. Mol. Struct. 1984, 125, 1.

80

6.5.5 Conformation of the dimethyl derivative The 1H NMR spectrum of dimethyl derivative 6.6 is markedly different from the analogous unsubstituted phosphonate 6.2a. The resonance for the benzylic hydrogen atom is shifted to lower field due to closer contact with the nitrogen atom and the phenyl resonances become inequivalent, indicative of hindered rotation. It was expected that the pyridinyl moiety would be rotated towards the benzylic position to relieve repulsion imposed by the axial methyl group. The RHF optimized geometry gives a different picture (Figure 6.9).

Figure 6.9. RHF 3-2IG/6-3IG* optimized geometry of 6.6

According to this picture, strain is mainly relieved by deformation of the dioxaphosphorinane ring, diminishing the difference between axial and equatorial methyl groups. The pyridinyl group is only slightly twisted out of plane; the dihedral angle defined by 01-P-C12-N measures 175.4", a value that compares with the corresponding angle in the X-ray structure of N-oxide 6.3a (174.3"). Although the diagnostic 3 ~ p H coupling constants for axial and equatorial hydrogen atoms are not available in 1H NMR spectra of 6.6, the same trend is observed to a lesser extent in the 4JpC coupling constants for axial and equatorial methyl groups in 13C NMR spectra. No coupling is observed for the axial methyl group, whereas the equatorial methyl group displays a 4JpC coupling constant of 6.1 Hz. This value is significantly lower than observed for equatorial methyl groups in diphosphite-borane complexes and di(thio)phosphates described in Chapter 4 (4JpC = 8.5-1 1 Hz), apparently confirming the deviation from the 'ideal' chair conformation.

6.6 Experimental section Restricted Hartree Fock calculations were performed in the Gaussian-94 package13 on Hewlett Packard 90001735 machines. Initial conformations were generated on a CAChe system.

Gaussian 94. Revision B.3, Frisch. M.J.; Trucks, G.W.; Schlegel, H.B.; Gill, P.M.W.; Johnson, B.G.; Robb, M.A.; Cheeseman. J.R.; Kcith.T.; Petersson, G.A.; Montgomery, J.A.; Raghavachari, K.; Al- Laham, M.A.; W w s k i . V.G.; Ortiz. J.V.; Foresrnan. J.B.; Peng, C.Y.; Ayala, P.Y.; Chen, W.; Wong, M.W.; Andres, J.L.; Replogle, E.S.; Gomperts, R.; Martin, R.L.; Fox, D.J.; Binkley, J.S.; Defrees, D.J.; Baker, J.; Stewart, J.P.; Head-Gordon, M.; Gonzalez. C.; Pople, J.A. Gaussian, Inc., Pittsburgh PA, 1995.

Conformations were optimized at the W3-21G level for C, H, N, 0 at the HF/3-21G* level for I, and at the HFl6-31G* level for P and S,14 using the default Berny gradient minimization algorithms in Gaussian-94. Single point energies were calculated at the W6-31G* level for all atoms.

Tabk 6.1. Geometrical data for 6.2~ and 6.3~. RHF 3-21G/6-31G* vs. X-ray dtTraction

6.3a 6.3a 6.3a anti- syn- gauche

gauche

RHF X-ray RHF X-ray RHF RHF

Energy ( A U P -1236.2078 Bond lengths (A) PI-01 1.457 P1-02 1.589 P 1-03 1.585 PI-C12 1.800 Bond angles (deg) 01-PI-02 114.91 01-P1-03 115.46 01-P1-C12 112.03 02-P1-03 102.48 02-P1 -C 12 105.27 03-PI-C 12 105.58 Dihedral angles (deg) 01-P1-C12-N1 179.72 P 1 -02-C 1 -C2 -51.15 P1-03-C3X2 48.81 a 1AU (atomic unit) = 627.51 k c a h d .

' (a) Pietro, W.S.; Francl, M.M.; Hehre. W.J.; DcFrees, D.J.; Pople, J.A.; Binkley, J.S. J. Am. Chem. Soc. 1982,104, 5039. (b) Francl, M.M.; Pietro, W.S.; Hehre, W.J.; Binkley, J.S.; Gordon, M.S.; DeFrees, DJ.; Pople, J.A. J. Chem Phys. 1982, 77, 3654. (c) Frisch, M.J.; Pople, J.A.; Binkley, J.S. J. Chem Phys. 1984.80, 3265.

Table 6.2. RHF 3-2IG/6-31G* geometrical data for 6.2b, 6.3b,and 6 . 4 ~ *

6.2 b 6.3 b 6.4a-syn 6.4a-anti 6.4a-anti

Energy (AU) -1236.2067 -1310.9739 -1275.6158 -1275.6128 Bond lengths (A) PI-01 1.464 1.465 1.459 1.459 1.454 PI-02 1.587 1.571 1.570 1.563 1.579 P 1-03 1.588 1.582 1.569 1.575 1.575 PI-C12 1.793 1.806 1.829 1.830 1.825 Bond angles (deg) 01-PI-02 116.1 1 116.13 116.78 118.79 116.21 01-PI-03 115.64 115.14 118.56 116.43 116.06 01-PI-C12 113.45 108.64 111.19 110.93 112.58 02-PI-03 102.13 103.40 103.55 103.57 103.98 02-P1-C12 103.33 106.45 102.24 100.95 101.44 03-PI-C12 104.58 106.33 102.41 104.17 104.61 Dihedral angles (deg) 01-PI-C12-N1 -174.33 -172.41 58.54 -58.46 -65.37 PI-02-C1-C2 -49.39 -39.18 13.21 13.61 -39.01 P1-03x3-C2 56.43 63.71 32.68 33.39 32.33 * hliminary results of geometry optimization with iodide counter ion.

Table 6.3. RHF 3-21G/6-3IG* geometrical data for 6.4b, 6.5a, 6.5b, and 6.6

Energy (AU) Bond lengths PI-Sl/Ol PI-02 PI-03 P1-C12 Bond angles (deg) 01-PI-02 01-PI-03 01-PI-C12 02-PI-03 02-PI-C12 03-P1-C12 Dihedral angles (deg) 01-PI-Cl2-Nl P 1-02-C 1-C2 PI-03-C3-C2

Inleiding In dit proefschrift worden de synthese en karakterisatie van nieuwe chirale 1,3,2- dioxafosforinanen beschreven. Een voorwerp is chiraal als het niet met zijn spiegelbeeld tot dekking is te brengen. Chiraliteit is een zeer belangrijk fenomeen in de levende natuur. De overvloedig gememoreerde Softenon-affaire geeft aan wat er kan gebeuren als het belang van chiraliteit niet wordt onderkend. Fosforinanen zijn organische zesringen waarin een fosforatoom aanwezig is. In 1,3,2- dioxafosforinanen wordt het fosforatoom geflankeerd door twee zuurstofatornen. Deze ringen zijn niet vlak en kunnen verscheidene ruimtelijke vormen aannemen, doorgaans aangeduid als stoel, boot en gedraaide boot.

stoel boot gedraaide boot

Figuur 1. Confonnaties van de 1,3,2-dioxafosforimring. Nummering van de posities op de ring is weergegeven voor a2 stoelconfomtie

Door op bepaalde plaatsen op de ring grote groepen in te voeren kan de ring in 66n starre stoelconformatie worden vastgelegd, wat het bestuderen van het molecuul aanmerkelijk vereenvoudigt. Enkele moleculen, zoals die zijn beschreven in de hoofdstukken 2 en 4, zijn gesynthetiseerd met de bedoeling als ligand te dienen voor overgangsmetaalionen. Liganden binden aan een metaalion in een geheel dat wordt aangeduid als een complex. Complexen van zogenaamde overgangsmetalen en lanthaniden kunnen dienst doen als katalysatot. Een katalysator wordt in de Van Dale als volgt gedefmi&rd: 'stof die alleen door haar aanwezigheid, schijnbaar zonder zelf veranderd te worden, een chemisch pmes bespoedigt of vertraagt.' Een chirale katalysator maakt onderscheid tussen de spiegelbeelden van ofwel uitgangsstoffen, ofwel produkten van een bepaalde reactie. Dit leidt tot mengsels van produkten waarin t t n spiegelbeeld (enantiomeer) van een chirale verbinding in grotere hoeveelheid aanwezig is dan het andere. U i t e r d wordt gestreefd naar een zo groot mogelijke enantiomere overmaat. Men spreekt in dit verband van asymmetrische katalyse.

Dit proefschrijt Een korte beschrijving van enkele aspecten van de organische chemie van het element fosfor is te vinden in Hoofdstuk I. Relevante gegevens uit & literatuur worden aangehaald om een kader te vormen voor hetgeen wordt khandeld in de overige hoofdstukken.

In hoofdstuk 2 wordt de synthese van een aantal chirale 2-pyridinylfosfonaten beschreven. Fosfonaten zijn verbindingen waarin een fosforatoom wordt omringd door a n dubbelgebonden en twee enkelgebonden zuurstofatomen en een koolstofatoom. Uit de literatuur is bekend dat eenvoudige 2-pyridinylfosfonaten complexen met metaalionen vorrnen. Tesamen met de expertise, op dit lab aanwezig, op het gebied van chirale 1.3.2-dioxafosforinanen heeft dit geleid tot een studie naar de eigenschappen van 2-pyridinylfosfonaten op basis van het 1,3,2- dioxafosforinaanskelet.

Figuur 2. 2-Pyridinylfosfonaten op basis van de 1,3,2-dioxafosforinaanring

De verrassende voorkeur van enkele van deze 2-pyridinyl-1,3,2-dioxafosforinanen voor een bepaalde conformatie is aanleiding geweest tot bestudering van mogelijke factoren die deze voorkeur dirigeren. Van twee van de pyridinylfosfonaten is de kristalstmctuur bepaald door middel van rontgendiffractie. Het stikstofatoom blijkt zich in beide structuren boven de dioxafosforinaanring te bevinden. Wederzijdse afstoting van vrije electronenparen is tot het minimum beperkt in de conformatie zoals weergegeven in Figuur 2. Deze afstoting kan worden opgeheven door het vrije electronenpaar op stikstof te 'neutraliseren' door methylering. Dit had het gewenste effect: op basis vah NMR spectroscopic kon de verandering van de conformatie worden bevestigd. Als liganden voor asymmetrische katalyse zijn de beschreven verbindingen, mede door de bijzondere conformatie, helaas ongeschikt gebleken. In hoofdstuk 3 wordt de synthese behandeld van chirale diolen (dialcoholen) die als basis kunnen dienen voor nieuwe dioxafosforinanen. Gekozen is voor een universele uitgangsstof die, door reactie met verschillende organolithium- en organomagnesiumverbindingen, omgezet kan worden in diolen met een verscheidenheid aan eigenschappen, bepaald door de groepen R (Figuur 3). Enkele voorbeelden hiewan zijn beschreven.

Figuur 3. Synthese van verschillende chirale 1,3-diolen (R = Me, Ph, i-Bu) uit een enkele uitgangsstof

In hoofdstuk 4 wordt Btn van de diolen uit hoofdstuk 3 toegepast in de synthese van chirale difosfieten en enkele afgeleiden daarvan. Fosfieten zijn verbindingen waarin een fosforatoom

wordt omringd door drie enkelvoudig gebonden zuurstofatomen. Een vrij electronenpaar op het fosforatoom is beschikbaar voor complexatie aan overgangsmetaalionen. Van tbn van de gesynthetiseerde difosfieten is de kristalstructuur bepaald en is een complex met molybdeen gevormd.

Figuur 4. Molybdeencomplex van een difosjiet

Fosfieten zijn vaak gevoelig voor oxidatie met zuurstof uit de lucht. Verwerking en opslag van deze verbindingen gebeurt dan ook in de regel in een atmosfeer van droge, zuurstofvrije stikstof. De luchtgevoeligheid van fosfieten kan belemmerend werken tijdens synthese- procedures. Reactie met boraan (BH3) leidt tot luchtstabiele complexen die na zuivering eventueel weer omgezet kunnen worden in de vrije fosfieten. De synthese van de difosfieten uit racemisch diol (racemisch wil zeggen dat beide spiegelbeeldvormen in gelijke hoeveelheid aanwezig zijn) levert in principe twee produkten in gelijke hoeveelheden: beide enantiomeren van een chirale verbinding (d,l-produkt) en een achirale verbinding, het zogenaamde meso-produkt. In het geval van t t n van de difosfieten uit hoofdstuk 4 werd, na zuivering, slechts CBn van beide produkten waargenomen. Dit lijkt te wijzen op chirale zelf-herkenning: &n proces waarbij een chirale verbinding voorkeur vertoont voor een van zijn enantiomeren, in dit geval hetzelfde enantiomeer. In hoofdstuk 5 wordt de zelf-herkenning nader bestudeerd. Om de zelf-herkenning te bewijzen is het noodzakelijk het produkt te analyseren zonder het te zuiveren. Van de verschillende methoden die hiemoor zijn geprobeerd, is de omzetting tot het boraancomplex het meest praktisch gebleken.

3 reactiestappen

d, 1-produkt meso-produkt

Figuur 5. De synthese aan de hand waarvan de chirale zelf-herkenning is bewezen

87

Met behulp van NMR spectroscopie is de verhouding tussen meso- en 41-produkten bepaald: in alle gevallen was de hoeveelheid d.1-produkt groter dan de hoeveelheid meso-produkt. Ook werd de invloed van de temperatuur op de mate van herkenning bestudeerd: bij lagere temperatuur wordt de herkenning sterker. Tenslotte is aangetoond dat de zelf-herkenning wordt veroorzaakt door de wisselwerking tussen de fenylgroepen (Ph) op de diolen tijdens de reactie. Naast analytische technieken is 'computational chemistry' een belangrijke plaats gaan innemen in de moderne chemie. Met behulp van rekenmethoden en modellen wordt de chemische werkelijkheid gesimuleerd. Dit kan leiden tot een verhoogd begrip van de onderliggende aspecten van een bepaald systeem. In hoofdrtuk 6 worden de pyridinyl-2-fosfonaten uit hoofdstuk 2 onderworpen aan zogenaamde ab-initio-berekeningen. De energetisch meest gunstige conformaties van de moleculen zijn hiermee bepaald. Hoewel is gekozen voor een relatief eenvoudige mathematkche beschrijving van de atomen, is de overeenkomst met de twee kristalstructuren treffend. Voor alle bestudeerde moleculen is de berekende structuur in overeenstemming met gegevens van NMR spectroscopie.

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