Sulfoxides, asymmetric reduction

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. 

Chiral sulfoxides are useful both as intermediates and target molecules of synthetic elaboration. The /J-amino-y-hydroxysulfoxidc moiety is one type of chiral sulfoxide which is the intermediate target in the synthesis of (5 )-(+)-sparsomycin. In the key step in this synthesis, the sought after moiety was produced by asymmetric reduction of an oxazoline using DIBAL, in the presence of zinc chloride and at — 78 °C (equation 79)326. 

Stereoselective reduction of -keto sulfoxides. The reduction of the P-keto sulfoxide 1 with NaBH, in CH,OH/aq. NH, (9 1) proceeds with efficient 1,3-asymmetric induction and epimerization at C, (equation 1). Only slight stereoselectivity obtains in a neutral medium. The chirality of the sulfinyl group has no effect. 

Michael additions with 8-phenylmenthyl esters of unsaturated acids Chiral auxiliaries attached elsewhere in asymmetric Michael additions Other Chiral Auxiliaries in Conjugate Addition The Evans oxazolidinones Chiral sulfoxides Asymmetric Birch Reduction Birch reduction of benzene Asymmetric Birch reduction of heterocycles... 

A 1,4-asymmetric reduction of a y-keto sulfoxide has its stereoselectivity reversed on addition of a lanthanide triflate. ... 

Hanlon, S.P., Graham, D.L, Hogan, P.J., Holt, RA., Reeve, C.D., Shad, A.L., and McEwan, A.G. (1998) Asymmetric reduction of racemic sulfoxides by dimethylsulfoxide reductases from Rhodobacter capsulatus, Escherichia coli and Proteus species. Microbiology, 144, 2247-2253. 

It is thought that the asymmetric reduction proceeds through a closed chair transition state 240 in which the horon coordinates to the sulfoxide oxygen delivering hydride in a stereoselective fashion. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

In principle, it should be possible to selectively reduce one of the enantiomers in a racemic sulfoxide mixture that is, an asymmetric kinetic resolution via reduction should... 

Abbott and coworkers229 found that nucleophilic addition of amines to a, p-unsaturated sulfoxide gave asymmetrically induced adducts. For example, treatment of (R)-(—)-cis-propenyl p-tolyl sulfoxide 184 with piperidine in methanol gave a quantitative mixture of the diastereomeric adduct 185. Reduction of this mixture gave (Rs)-(Sc)-2-piperidinopropyl p-tolyl sulfide 186 in 74% optical yield, suggesting that the amines attack from the opposite side of the bulky aryl group at the transition state, as shown above (Figure 6). 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

Pentitol synthesis An asymmetric synthesis of L-arabinitol involves condensation of the (E)-a,fJ-unsaturated ester (2) with the anion of methyl (R)-p-tolyl sulfoxide (1). The resulting p-keto sulfoxide (3) is reduced stereoselectively by ZnCl2/DIBAH (13, 115-116) to 4. Osmylation of 4 with (CH,)3NO and a catalytic amount of 0s04 (13, 224-225) yields essentially a single triol (5). Finally, a Pum-merer rearrangement of the sulfoxide followed by reduction of an intermediate... 

Chiral 2,2-disubstituted cyclobutanones have been obtained by asymmetric rearrangement of chiral sulfinyl- 177,178 and sulfanylcyclopropanes.179 Using readily available cyclopropyl 4-tolyl (/ )-sulfoxide (l),180 the requisite sulfinylcyclopropanes 3 and 3 were obtained by a sequence of lithiation, reaction with carboxylic acid esters and stereoselective addition of Grignard reagents to the ketones 2 thus formed.178 The corresponding sulfanylcyclopropanes 4 and 4 resulted from a sequence of protection, reduction and deprotection.179... 

Many other uses of a-sulfinyl carbanions are found in the literature, and in the recent past the trend has been to take advantage of the chirality of the sulfoxide group in asymmetric synthesis. Various ways of preparation of enantiopure sulfoxides have been devised (see Section 2.6.2) the carbanions derived from these compounds were added to carbonyl compounds, nitriles, imines or Michael acceptors to yield, ultimately, with high e.e. values, optically active alcohols, amines, ethers, epoxides, lactones, after elimination at an appropriate stage of the sulfoxide group. Such an elimination could be achieved by pyrolysis, Raney nickel or nickel boride desulfurization, reduction, or displacement of the C-S bond, as in the lactone synthesis reported by Casey [388]. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolare (29) to the scalemic sulfoxide (30). Direct treatment of the crude Michael adduct with mew-chloroperbeuzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (31) X — a and ftH R = H in over 90% yield. 

An impressive new route to enantiopure syn- and anti- 1,2-diols involves sequential diastereoselective DIBAL reduction of oxalyl-di(/V-iucthyl-/V-methoxyainide) following conversion to a corresponding intermediate / -keto sulfoxide a route that involved control of both reductions by the chiral sulfoxide auxiliary.253 Comparison of / -hydroxy ketone systems with die y-sulfoxide-/ -keto systems used here showed this to be die first example of such asymmetric induction by a y-sulfoxide substituent. 

Asymmetric synthesis of sulfoxides can be achieved by biocatalytic oxidation of sulfides and reduction of sulfoxides (Figure 33). i4-27s One example is the reduction of alkyl aryl sulfoxides by intact cells of Rhodobacter sphaeroides f.sp. denitrificans (Figure 33 (a)). 341 In the reduction of methyl -substituted phenyl sulfoxides, ( S )-cnanliomcrs were exclusively deoxygenated while enantiomerically pure (W)-isomcrs were recovered in good yield. For poor substrates such as ethyl phenyl sulfoxide, the repetition of the incubation after removing the toxic product was effective in enhancing the ee of recovered (f )-enantiomers to 100%. 

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