Chiral sulfinyl

The first report on the addition of carbanions a-substituted by a chiral sulfinyl group to carbonyl functions described the reaction with symmetrical ketones3. It was found that meta-lation of ( + )-(S)-(methylsulfinylmethyl)benzene followed by quenching with acetone gives a mixture of diastereomeric /i-hydroxysulfoxides in a 15 1 ratio. This ratio depends on the presence or absence of extra lithium salts i.c., the source of the mcthyllithium used in deprotonation67. 

Diastereoselective Diels-Alder reactions with chiral sulfinyl derivatives as dienophiles under high pressure [88]... 

A wide variety of chiral sulfinyl substituents have been employed as chiral auxiliaries on both dienes162 and dienophiles163 in asymmetric Diels-Alder reactions. Carreno and colleagues164, for example, used Diels-Alder reactions of (Ss)-2-(p-tolylsulfinyl)-1,4-naphthoquinone (249) to separate racemic mixtures of a wide variety of diene ena-tiomers 250a and 250b via kinetic resolution and to obtain enantiomerically enriched... 

Fernandez de la Pradilla and coworkers167 studied the reactions of chiral sulfinyl and sulfonyl dienes such as 256 and 257 with 7V-phenylmaleimide. They found that the sulfinyl dienes showed facial selectivities opposite to those of the corresponding sulfonyl dienes, indicative of the powerful stereocontrol exerted by the sulfinyl moiety. 

All the chiral sulfinyl compounds discussed above are the derivatives of achiral sulflnic acid 94a. Another class of chiral sulfinyl compounds may be derived from achiral sulfurous acid 94b via replacement of the hydroxy groups by suitable substituents. A brief survey of such chiral sulfinyl compounds is presented next. 

The polarimetric method, in combination with the results of chemical correlation, made it possible to determine the optical purity of a range of chiral sulftnates (105-107), thiosulfinates (35,105), and sulfinamides (83) with the sulfur atom as a sole center of chirality. These compounds were converted by means of Grignard or alkyl-lithium reagents into sulfoxides of known specific rotations. This approach to the determination of optical purity of chiral sulfinyl compounds has at least two limitations. The first is that it cannot be applied to sterically hindered compounds [e.g., t-butyl /-butanethio-sulfinate 72 does not react with Grignard reagents]. Second, this... 

The reaction of tetrahydropyridine 7/-oxide (93) (n = 1) with a chiral sulfinyl maleimide dipolarophile (166) has been reported (Scheme 1.36), but afforded the major product 167 with only modest stereoselectivity, despite the use of a... 

The induced diastereoselectivity is determined by the chiral sulfinyl moiety of the substrate and not by the menthyl chirality, since a similar but opposed d.r. is obtained in sulfoxide 1 (and ee in the oxidized allenylsulfone 2) when the (-)-menthyl (S/ )-sulfinate is used rather than the ( — )-menthyl (SS)-sulfinate. The induced diastereoselectivity is fair to good, as deduced from the optical purity of the sulfones 2, however, inadvertent resolution of the diastereomers during the chromatographic separation of the allenic and acetylenic sulfoxides may have affected the figures. 

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... 

It has been found that F-Teda BF4 (6) transforms chiral and optically pure ft-oxo sulfoxides into the corresponding a-fluoro-substituted compounds 30 without affecting the chiral sulfinyl group.106... 

Fluoro-substituted chiral vinyl sulfoxides such as 103 have been used in 1,3-dipolar cycloadditions with various benzonitrile oxides (Scheme 12.34) (158). The reaction proceeded slowly at room temperature, however, after 5-10 days the isoxazoline (104) was obtained with excellent de in good yield. In some cases, the product tends to eliminate the 5-methoxy substituent of the isoxazoline, thus, after loss of two chiral centers, an isoxazole is obtained (158,159). Other chiral sulfinyl derivatives have also been used in 1,3-dipolar cycloadditions with nitrile oxides (160,161), and in one case a racemic vinyl phosphine was used in reactions with various nitrile oxides, but with moderate selectivities (151). 

A new class of chiral sulfinyl transfer reagents, much more reactive towards Grignard reagents than the Andersen menthyl sulfinate ester, have been introduced by Evans [102] and reacted with a wide range of nucleophiles to afford chiral sulfoxides, sulfinate esters or sulfinamides efficiently. These reagents are shown below ... 

Chiral sulfoximines liganded to copper(II) give highly enantioselective vinylogous Mukaiyama-type aldol reactions under mild conditions.137 A chiral sulfinyl group has been used to achieve 1,5- and 1,6-asymmetric induction in Mukaiyama aldols, using Yb(OTf)3 catalysis.138... 

Sulfinyl dienes and vinyl sulfoxides have rarely been used in asymmetric hete-ro-Diels-Alder reactions [145]. The first example was reported in 1992 and describes an intramolecular cycloaddition using a heterodiene bearing a chiral sulfinyl group [146a]. In this paper, the conversion of a-p-tolylsulfinyl a,ft-unsaturated ketone 176 (prepared by Knoevenagel reaction of 3-methylcitronellal and (S)-p-toluenesulfinylacetone) into the hetero-Diels-Alder adducts 177... 

Reactions of 3,5-dichloro-2,4,6-trimethyl benzonitrile oxide 241 with fluoro-methyl substituted alkenes 242, bearing a chiral sulfinyl group at -position of the double bond, afford diastereoisomeric 4,5-dihydroisoxazoles 243 and 244 [180] with a stereoselectivity lower than 2 1 (Scheme 110). The authors conclude that the efficiency of allyl sulfoxides to control diastereoselectivity of 1,3-dipolar cycloadditions with nitrile oxides is lower than that of vinyl sulfoxides. 

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). 

Thiosulfinate 129 has been used for the synthesis of various chiral sulfinyl derivatives such as sulfoxides, sulfmamides, and sulfinimines in good yield, tert-Butanesulfinyl ketimines have been successfully used for the asymmetric synthesis of a,a-dibranched aminesI09h as well as for the synthesis of o.p. amino acids.109 ... 

The observed change in stereoselectivity can be rationalized by consideration of the conformation of the 2-(arylsulfinyl)-2-cyclopentenone (24) (Fig. 3). The sul-finyl and carbonyl moieties are normally arranged in an anti periplanar orientation (27). The bulky aromatic substituent on the chiral sulfinyl group shields one face of the alkene and thereby controls the facial selectivity of the reaction. In the presence of the Lewis acid the sulfinyl and carbonyl moieties are locked in a syn orientation (28) as a result of chelation between the two moieties and the metal. Thus, the opposite face of the alkene is shielded and (3-addition results in the other diastereoisomer being formed. 

During the past two decades, the asymmetric Diels-Alder reaction has become one of the most powerful tools in asymmetric synthesis as a result of its capacity to create up to four chiral centers in one step, often in a highly stereoselective manner. In the following sections, recent advances in this area using vinyl sulfoxide and vinyl sulfone dienophiles will be considered. It should be noted that, although beyond the scope of this review, many asymmetric Diels-Alder reactions of chiral sulfinyl-1,3-dienes have been reported.111... 

For the epoxidation of y-oxygenated vinyl sulfoxides 260 and 262, with sodium terf-butyl peroxide, an even greater reversal in stereoselectivity was observed. Epoxidation of260 gave the anti isomer 261, whereas 262 gave the syn isomer 263 (Scheme 67).139 This remarkable reversal of facial selectivity may be understood in terms of a mismatched situation and underlines that a chiral sulfinyl functionality is an extremely powerful chiral controller. 

The intramolecular alkylation would occur from the downward side of the chiral sulfinyl group, opposite the bulky p-tolyl group. 

Other chiral sulfinyl transfer reagents include a cyclic sulfite (1) [16] and sulfinamides (2) and (3) [17,18],... 

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