Sulfoxides stereoselective additions

Isomeric (E)- and (Z)-a,/f-unsaturated sulfoxides undergo addition with opposite dia-stereoselectivities. 

Except for the syntheses using terpene-derived starting materials (Schemes 13.7, 13.8, and 13.9), the previous juvabione syntheses all gave racemic products. Some of the more recent juvabione syntheses are enantiospecific. The synthesis in Scheme 13.16 relied on a chiral sulfoxide that undergoes stereoselective addition to cyclohexenone to establish the correct relative and absolute configuration at C(4) and C(7). The origin of the stereoselectivity is a chelated TS that leads to the observed product.20... 

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... 

In contrast, few examples of conjugate additions of nonallylic a-sulfinyl (or a-sulfonyl) carbanions have been reported (for allylic oc-sulfinyl carbanion additions, see Section 1.2.2.5.1). Notable is the dia-stereoselective addition of alkyl f-butyl sulfoxides (245) to a,(3-unsaturated esters (equation 20)187 which is complementary to the diastereoselective addition of enolates to 3-substituted-a,f3-unsaturated sulfoxides (equation 20). 

Reaction of the a-carbanion of an alkyl aryl sulfoxide (RCH2SOAr) with aldehydes may give four dia-stereomers. In general, the reaction is highly diastereoselective with respect to the a-sulEnyl carbon, but poorly diastereofacially selective with respect to attack on the carbonyl component. In fact, the a-carb-anion (31) of benzyl t-butyl sulfoxide adds to an aldehyde to produce only two diastereomers (32a) and (32b). As shown in Scheme 10, the selectivity increases when the counterion is A transition state structure (33) is proposed to account for the anti stereoselection. Addition of the dianion of (/ )-3-(p-to-lylsulfinyOptopionic acid (34) to aldehydes affords two main diasteieoisomeric 3 (p-tolylsulfinyl)-y-lac-tones (35 R = Ph and Bu. ca. 60 40). These isomers (35) were separated by chromatography, and their... 

Phenylsulfinylcarbene, generated from phenyl diazomethyl sulfoxide, undergoes addition to alkenes to form phenylsulfinylcyclopropanes. This reaetion is stereospecific [> 97% of trans-product from ( )-but-2-ene and > 99% cw-product from (Z)-but-2-ene] and highly stereoselective [cisjtrans 34 and > 99 for additions to cyclohexene and (Z)-but-2-ene, respectively]. The sulfinylcarbene reacts with alkenes in the singlet state. 

As in previous cases, the chelated transition state rationale is applicable here. Initially, coordination of the sulfoxide and carbonyl group oxygen atoms to the Lewis acid is believed to occur, allowing the diene to approach the carbonyl function from the least sterically hindered face, leading to the observed cycloadduct. Interestingly, both Danishefsky [116] and Midland [117] have proposed chelated transition states for stereoselective additions of Danishefsky s diene to chiral a-alkoxy aldehydes. 

The intermediate 139 formed following the addition of z-butylmagnesium chloride to the nitrile 138 was then treated with sulfoxide 137 to afford the sulfinyl ketimine 140. " Diastereoselective addition of hydride to the chiral imine 140 in the presence of Ti(0 Pr)4 afforded the chiral amine 142. This reaction may proceed via a closed-transition state (e.g., 141) in which the sulfoxide coordinates to the metal center and directs the stereoselective addition of hydride, as has been proposed for related reactions.Treatment of the sulfoxide 142 with acid and base effected removal of the auxiliary. 

This compilation embraces a wide variety of subjects, such as solid-phase and microwave stereoselective synthesis asymmetric phase-transfer asymmetric catalysis and application of chiral auxiliaries and microreactor technology stereoselective reduction and oxidation methods stereoselective additions cyclizations metatheses and different types of rearrangements asymmetric transition-metal-catalyzed, organocatalyzed, and biocatalytic reactions methods for the formation of carbon-heteroatom and heteroatom-heteroatom bonds like asymmetric hydroamina-tion and reductive amination, carboamination and alkylative cyclization, cycloadditions with carbon-heteroatom bond formation, and stereoselective halogenations and methods for the formation of carbon-sulfur and carbon-phosphorus bonds, asymmetric sulfoxidation, and so on. 

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). 

However, addition of (+ )-(7 )-l-methyl-4-(mcthylsulfinyl)benzene, to aldehydes and ketones proceeds with low stereoselectivity. An improvement of the 3-syn diaslereoselectivity was found with the zinc reagent obtained by transmetalation of the lithiated sulfoxide with anhydrous zinc chloride38. An improvement of the stereoselectivity was also attained by exchange of the 4-methylphenyl substituent for a 2-methoxyphenyl or 2-pyridinyl substituent. Thus, the introduction of an additional complexing site into the aromatic part of the sulfoxide reagent enhances the stereoselectivity35. 

More recently the stereoselectivity of the addition of sulfinyl anions to carbonyl groups was improved by introducing a sulfide group in the a-position30,31. The sulfoxide ( + )-(S)-(4-methylphcnylsulfinyl)(4-methylphenylthio)metliane was added to benzaldehyde to give the adduct 1 as a mixture of three diastereomers [(S5,15,27 )/(SS,17 ,2/J)/(S5,15,25) 55 30 15] which could be transformed into the corresponding a-methoxyaldehydc 4 in 67% yield with 70 % ee. The same reaction, when applied to phenylacetaldehyde, led to a product in 43 % yield with lower ee (46%). 

In addition to the synthetic applications related to the stereoselective or stereospecific syntheses of various systems, especially natural products, described in the previous subsection, a number of general synthetic uses of the reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides are presented below. Several investigators110-113 have employed the allylic sulfenate-to-sulfoxide equilibrium in combination with the syn elimination of the latter as a method for the synthesis of conjugated dienes. For example, Reich and coworkers110,111 have reported a detailed study on the conversion of allylic alcohols to 1,3-dienes by sequential sulfenate sulfoxide rearrangement and syn elimination of the sulfoxide. This method of mild and efficient 1,4-dehydration of allylic alcohols has also been shown to proceed with overall cis stereochemistry in cyclic systems, as illustrated by equation 25. The reaction of trans-46 proceeds almost instantaneously at room temperature, while that of the cis-alcohol is much slower. This method has been subsequently applied for the synthesis of several natural products, such as the stereoselective transformation of the allylic alcohol 48 into the sex pheromone of the Red Bollworm Moth (49)112 and the conversion of isocodeine (50) into 6-demethoxythebaine (51)113. 

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (+ )-cuparenone (39) which involves formation of a quaternary carbon center81, (- )-/ -vetivone (40)8° and steroidal equilenin 4182 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

Parallel to the modification of the catalytic performance in Baeyer-Villiger oxidations, random mutagenesis was successfully applied to improve the stereoselectivity of CHMOAcineto hi cascs of essentially racemic sulfoxide formation. In addition, enantiodivergent clones with >98% ee for both antipodal products were identified (Table 9.5) [205]. However, improvement in stereoselectivity of mutant enzymes was often accompanied by increased formation of sulfone. This effect can also be utilized to resolve racemic sulfoxides. 

No stereoselectivity was observed in the formation of a 1 1 diastereomeric mixture of 2-hydroxy-2-phenylethyl p-tolyl sulfoxide 145 from treatment of (R)-methyl p-tolyl sulfoxide 144 with lithium diethylamide . However, a considerable stereoselectivity was observed in the reaction of this carbanion with unsymmetrical, especially aromatic, ketones The carbanion derived from (R)-144 was found to add to N-benzylideneaniline stereoselectivity, affording only one diastereomer, i.e. (Rs,SJ-( + )-iV-phenyl-2-amino-2-phenyl p-tolyl sulfoxide, which upon treatment with Raney Ni afforded the corresponding optically pure amine . The reaction of the lithio-derivative of (-t-)-(S)-p-tolyl p-tolylthiomethyl sulfoxide 146 with benzaldehyde gave a mixture of 3 out of 4 possible isomers, i.e. (IS, 2S, 3R)-, (IS, 2R, 3R)- and (IS, 2S, 3S)-147 in a ratio of 55 30 15. Methylation of the diastereomeric mixture, reduction of the sulfinyl group and further hydrolysis gave (—)-(R)-2-methoxy-2-phenylacetaldehyde 148 in 70% e.e. This addition is considered to proceed through a six-membered cyclic transition state, formed by chelation with lithium, as shown below . ... 

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