Sulfoxides, asymmetric reduction chiral

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... 

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. 

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 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. 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

Reduction of sulfoxides to thioethers.1 Use of hydrogen halides for this reduction was first reported in 1909 and is still a viable method. This reduction has assumed importance since chiral sulfinyl groups are valuable in asymmetric syntheses and are eliminated in two steps reduction to the ether followed by catalytic hydrogenation or metal/ammonia reduction. The first step can now be carried out with several reagents, as shown by this comprehensive review (349 references). 

In 1972, Tsuchihashi disclosed that the carbanion (28 Ar = p-tolyl), generated from (/ )-methyl p-tolyl sulfoxide with lithium diethylamide, adds to benzaldehyde or a-tetialone to give an adduct (29) in a dia-stereomeric ratio of 50 50 or 64 36, respectively. Additions of this carbanion to various unsymmetrical ketones are also reported to be poorly diastereoselective (for example, EtCOMe 50 50, Bu COMe 55 45, Bu COPh 70 30). Note that in the case of Ar = 2-pyridyl a chiral sulfinyl group increases the asymmetric induction observed in the addition of the corresponding carbanion to carbonyl compounds (PhCHO 80 20, R-C9H19CHO 70 30). Since diastereomer pairs of (29) are separable, chromatographic separation followed by reductive desulfurization with Raney Ni provides a method for obtaining optically active alcohols (30 Scheme 9). 

Asymmetric sulfinylation. The reaction of ketone enolates with this reagent (1) gives chiral sulfoxides. With the chelation assistance of the sulfinyl group the reduction of the ketones is stereoselective, and a subsequent thermolysis leads to allylic alcohols with an (/ ) configuration. 

However, Lewis bases of this type are less practical than the previously described phoshoramides (Figure 21.1) and ALoxides (Figures 21.2 and 21.3) as they are commonly required in more than stoichiometric amounts. Furthermore, these chiral promoters are rarely recovered due to reduction of the sulfoxide functionality or decomposition during the reaction. A positive nonlinear effect observed in the asymmetric allylation of aldehydes using chiral sulfoxide 21.30 as a promoter suggests a transition state with two molecules of the catalyst coordinated to silicon in the carbon-carbon bond-forming event. - ... 

Chiral sulfoxides have been extensively employed as asymmetric auxiliary group that assist stereoselective reactions. The sulfoxide functional group activates adjacent carbon-hydrogen bonds to allow proton abstraction by bases, and the corresponding anions can be alkylated [1176] oracylated [1177] with high diastereo-selectivity. Similarly, thermal elimination [1178] and reduction of a-keto sulfoxides [1179] can proceed with transfer of chirahty from sulfur to carbon. In spite of... 

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