Synthesis of Chiral Oxirans

Synthesis of Chiral Oxirans. The recently introduced Katsuki-Sharpless reagent (titanium alkoxide with tartrate) has proved highly effective for the maiden introduction of chirality into prochiral allylic alcohols. An interesting development of this procedure has afforded the possibility of kinetic resolution of racemic allylic alcohols. The basis of the method involves the 

Takaki, M. Yasumura, and K. Negoro, Angew Chem., Int. Ed. Engl., 1981, 20, 

In a series of papers, the application of titanium alkoxide catalysts to the synthesis of sugars has been described. Asymmetric epoxidation and kinetic resolution of (48) afforded (+)-(49) (27% 95%e.e.) and (—)-(48) (33% 72%e.e.). The ring-opening reactions of the chiral epoxides that are produced, for example, from cis- and from trans- 50) provide new routes to saccharides. The reagents also find use in the synthesis of pheromones e.g., (+)-disparlure and (+)-2,6-dimethylhepta-l,5-dien-3-ol acetate via the epoxide (52), which was obtained from the dienol (51) by using D-(—)- 

Leucotrienes are substances that are implicated in asthmatic conditions, and thus their synthesis, or at least the synthesis of their precursors, is of pharmaceutical interest. Two approaches to the synthesis of (56) have been published. The first involves the treatment of the f/ireo-hydroxy-ester lactone 

Highly stereoselective epoxidations of acyclic homoallylic alcohols have been achieved, using the vanadium(v) t-butyl hydroperoxide method. A yield of 90%, with selectivity of 400 1, was achieved in the preparation of 

Synthesis of Chiral Oxirans. This section has been restricted to syntheses in which an enantiomeric excess (e.e.) of one isomer is obtained directly i.e. it excludes syntheses that rely on the resolution of racemic epoxides). 

A method for the production of chiral oxirans from simple unfunctionalized alkenes employs the molybdenum peroxo-complex (51), which has a pentagonal-bipyramidal structure. The oxidations of propene, but-l-ene, and but-2-ene yield e.e. s of around 30% [all of (R) configuration] in PhN02 at 20°C. 

The dioxolan (R)-(52 X = tosyloxy), obtained from di-isopropylidene-mannitol, undergoes substitution reactions with Cul plus XLi (X = Me or Bu) to yield (S)-(52 X - Me) and (5)-(52 X Bu). Sequential treatment of this dioxolan with HBr and HOAc (to form the bromoacetate) and then Me(CH2)40K and Me(CH2)40H gave samples of the (5)-alkyl-oxirans (53 R = H,R = CH2Me) and (53 R = H, R = CH2BU) with high optical purity. 

Racemic halohydrins, on treatment with an insufficient amount of (-)-quinine, underwent dehydrobromination to give the corresponding epoxide with an e.e. of 

12—35%. A distinct advantage of this technique is that the easily recovered unreacted halohydrin mixture is enriched with the less reactive isomer this, on elimination of HBr, gives an e.e. of the other epoxide epimer. Thus racemic [(15,2/ )- and (l/ ,25)-]cry//iro-(54) reacts with (-)-quinine in benzene to give trans- 53, R = — Ph) with (/ ,/ ) prevailing configuration, and the bromo- 

---

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

This remains a developing area for the synthesis of chiral oxiranes and has attracted interest from several research groups. As with the use of dioxiranes (above), it is not necessary to form the reactive oxaziridinium salt rather, the epoxidation reaction can be mediated by the corresponding iminium salt and Oxone. 

Synthesis of Chiral Oxirans. The Katsuki and Sharpless method for... 

Via Halohydrin Cyclisations and Related Reactions 8 From Aldehydes and Ketones 8 Synthesis of Chiral Oxirans 10 Biosynthesis 12... 

Schmid, A., Hofstetter, K., Feiten, H.J., Holhnann, R, Witholt, B. (2001) Integrated Biocatalytic Synthesis on Gram Scale The Highly Enantio Selective Preparation of Chiral Oxiranes with Styrene Monooxygenase. Advanced Synthesis Catalysis, 343(6-7), I il-l il. 

This enantioselective reduction can be used for synthesis of chiral 1-substituted oxiranes.1 2 3 Thus reduction of 2-chloroacetophenone with B2H6 catalyzed by 1 (1 mole %) results in (S)-( + )-(chloromethyl)benzenemethanol, which in the presence of base converts to (S)-( - )-phenyloxirane (styrene oxide). 

Chiral alkenyl and cycloalkenyl oxiranes are valuable intermediates in organic synthesis [38]. Their asymmetric synthesis has been accomplished by several methods, including the epoxidation of allyl alcohols in combination with an oxidation and olefination [39a], the epoxidation of dienes [39b,c], the chloroallylation of aldehydes in combination with a 1,2-elimination [39f-h], and the reaction of S-ylides with aldehydes [39i]. Although these methods are efficient for the synthesis of alkenyl oxiranes, they are not well suited for cycloalkenyl oxiranes of the 56 type (Scheme 1.3.21). Therefore we had developed an interest in the asymmetric synthesis of the cycloalkenyl oxiranes 56 from the sulfonimidoyl-substituted homoallyl alcohols 7. It was speculated that the allylic sulfoximine group of 7 could be stereoselectively replaced by a Cl atom with formation of corresponding chlorohydrins 55 which upon base treatment should give the cycloalkenyl oxiranes 56. The feasibility of a Cl substitution of the sulfoximine group had been shown previously in the case of S-alkyl sulfoximines [40]. 

Scheme 1.3.23 Solid-phase asymmetric synthesis of alkenyl oxiranes by using the chiral sulfonimidoyl linker.

Tetr 39 2323 (1983) (Recent Advances in the Preparation and Synthetic Applications of Oxiranes) 43 3309 (1987) (Synthetic Routes to Tetrahydrofuran, Tetrahydropyran, and Spiroketal Units of Polyether Antibiodcs and a Survey of Spiroketals of Other Natural Products) SO 8885 (1994) (Chemical and Biological Synthesis of Chiral Epoxides)... 

Epoxide formation using biocatalysis is a useful process for the formation of chiral oxiranes (Scheme 29). The synthesis of enantioenriched epoxides using enzymes has been reviewed <1995BCSF769>. Chloroperoxidase has been examined for the oxidation of 2-methyl-l-alkenes, among other alkenes. The yields in some cases can be low, but the enantioselectivities can be high <1995JA6412, 1997JA443>. This enzyme has been used in a synthesis of... 

A. Schmid, K. Hofstetter, H. J. Feiten, F. Hollmann, B. Witholt, Integrated biocatalytic synthesis on gram scale The highly enantioselective preparation of chiral oxiranes with styrene monooxygenase, Adv. Synth. Catal. 343 (2001) 732. 

Otera, J., Niiho, Y. and Nozaki, H. (1991) Oxirane ring-opening with alcohol catalysed by organotin phosphate condensates. Complete inversion at tertiary and henzylic centers. Tetrahedron, 47, IClS-lCiA, Corey, E.J. and Helal, C.J. (1993) A catalytic enantioselective synthesis of chiral monosuhstituted oxiranes. Tetrahedron Letters, 34, 5227-5230. 

Of course, epoxides can also undergo many modes of chemistry in which the heterocyclic ring remains intact. One such example is the addition of lithiated oxazolinyl epoxides (114) onto carbonyl compounds, providing a synthesis of trisubstituted oxiranes (116). In this case the oxazolinyl group not only confers stability to the lithiate, but also provides an opportunity to introduce chiral auxiliaries <01JOC3049>. 

Reaction between a chiral a-sulphinylcarbanion and carbonyl compounds or oxirans forms the basis of a new efficient synthesis of chiral alcohols (Scheme 145) the diastereoisomers formed are separately reduced with Ni-Al. 

Scheme 7.56 Synthesis of vinyl oxiranes catalyzed by chiral sulfide 311a with (a) non-P-substi-tuted vinyl halide (b) P-substituted aUyl halides used...

The second system studied was the separation of the chiral epoxide enantiomers (la,2,7,7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirane Sandoz Pharma) used as an intermediate in the enantioselective synthesis of optically active drugs. The SMB has been used to carry out this chiral separation [27, 34, 35]. The separation can be performed using microcrystalline cellulose triacetate as stationary phase with an average particle diameter greater than 45 )tm. The eluent used was pure methanol. A... 

Durst and coworkers were the first to report the condensation of chiral a-sulphinyl carbanions with carbonyl compounds477. They found that metallation of ( + )-(S)-benzyl methyl sulphoxide 397 followed by quenching with acetone gives a mixture of dia-stereoisomeric /i-hydroxy sulphoxides 398 in a 15 1 ratio (equation 233). The synthesis of optically active oxiranes was based on this reaction (equation 234). In this context, it is interesting to point out that condensation of benzyl phenyl sulphoxide with benzaldehyde gave a mixture of four / -sulphinyl alcohols (40% overall yield), the ratio of which after immediate work-up was 41 19 8 32478. 

Oxidation 205-213 /J-Oximinosulphoxides, chiral 336 Oxiranes 169 reactions of 305 synthesis of 639 2-Oxo-l,2,3-oxathiazolidines 71 /1-Oxosulphones, synthesis of 169 Oxosulphonium ylides, reactions of 219 /3-Oxosulphoxides reduction of 347-349 synthesis of 337-340... 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

---