Chiral HWE reagents

Recently, by selection of the appropriate enantiomer of the chiral HWE reagent 31a, the concept of double asymmetric induction in an asymmetric carbonyl olefi-nation step has been applied in controlling the geometry of the alkenic intermediate 103 in the total synthesis of structurally complex macrolides [68, 69] vide infra). 

The usefulness of the Wittig and related reactions in facilitating crucial carbon-carbon bond-formation steps in multi-step chemical syntheses has been demonstrated by many examples of the construction of useful complex molecules such as natural products. Some successfiil constructions of optically active functionalized building blocks with chiral HWE reagents for the total synthesis of natural products have already been discussed in this chapter [12a, 45, 59-61, 78], and additional examples, which have recently been reported, are mentioned here. 

The first example is the stereoselective introduction of the a side chain into 3-oxacarbacyclin and 3-oxaisocarbacydin molecules by reaction with chiral HWE reagents. Reaction of the THP-protected ketone 153 with three equivalents of chiral phosphonate 24 in the presence of LiCl gave an E/Z mixture of the aJS-unsaturated ester (E Z = 95 5) [67] (Scheme 7.26). The desired E-isomer 154 was isolated after deprotection of the THP groups and converted into the 3-oxacarbacyclin 155 as well as 3-oxaisocarbacydin [94]. 

In the total synthesis of bryostatins, chiral HWE reagents have been used for the stereocontrolled transformation of the C13 ketone to the C13-C30-unsaturated enoate [68]. The reaction of macrocyde 102a with chiral phosphonate 31a provided the a,j8-unsaturated ester of Z-stereochemistry, 103a, with a diastereoselectivity of Z/E = 85 15 (75% isolated yield of the Z-isomer, 103a). The obtained Z-isomer 103a was successfully converted into bryostatin by several subsequent chemical... 

Upon initial examination, how one could control chirality in a reaction where the product is an alkene (no new sp centers are formed) which is inherently achiral could be asked. Despite this impression, asymmetric variations of the Wittig reaction have been reported. One approach is to use a chiral auxiliary in the ester moiety of a phosphonate. The first example of a chiral Witting made use of menthol as a chiral auxiliary Reaction of the ketone 86 with the chiral HWE reagent 87 gave rise to 88. However, the levels of chiral induction were not reported. 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

In 2011, Wang and co-workers realized the enantioselective synthesis of Cl-alkylated THIQs 12 by the asymmetrie CDC reaction of Horner-Wadsworth-Emmons (HWE) reagent 11 with Al-aryl THIQs 10 using a chiral Cu complex as the eatalyst. The desired produets were afforded in up to 80% yield, 19 1 dr and 90% ee (Scheme 2.5). A preliminary mechanistic probe indicated that a radical cation intermediate might be involved in the catalytic cycle because a small amount of this species eould be captured by 2,6-di-( Bu)2-4-methylphenol (BHT). 

The concept of desymmetrization through intermoiecuiar HWE reactions using chiral phosphonate reagents was independently demonstrated by two research... 

The reagents most widely applied to the dissymmetrization of ketones are chiral HWE phosphonate reagents possessing an 8-phenyhnenthyl auxiliary on their carboalkoxy portion. Using reagents of this type, high diastereoselectivity has been achieved [58-60] (Scheme 7.14), and this may be due to the presence of the phenyl... 

The anions of the HWE reagents 27a,b were reacted with the chiral monoketone 99 to afford the corresponding Z- and -olefins 100 and 101 with high diastereo-meric excesses, depending upon which enantiomer of the chiral phosphonate was employed. The olefinic products thus obtained served as key intermediates in the synthesis of prostacyclin derivatives [59, 60]. A closely related chiral reagent, 24, bearing 8-phenylnormenthol [67], both enantiomeric forms of which are readily accessible, provided an improved diastereoselectivity in favor of the -isomer 101 (Scheme 7.16). 

It is likely that the initial addition step in the HWE reaction is rate-determining [34] when the Z-isomer is the major product, and energetically favorable approach of an anion of the chiral reagent must be invoked to account for the observed stereochemistry [25, 35], In the planar anionic species of reagent (S)-31a chelated by a metallic cation, the re-face is sterically hindered due to the hydrogen atom at the 3-position of the naphthyl group, and nucleophilic attack on the carbonyl from the exo direction is favored (Scheme 7.7), as has been proven experimentally by sepa-... 

Under PKR conditions, two enantiomeric substrates are simultaneously converted into two structurally and configurationally different chiral products by reaction with chiral reagents or catalysts. It has been shown that to achieve the same selectivity, the selectivity factor s can be significantly lower for PKR than for a traditional kinetic resolution. As yet, there has been only one report of an asymmetric HWE reaction under PKR conditions [88], in which one equivalent of racemic aldehyde 143 was converted into alkene products 144 and 145 by reaction with half an equivalent each of two chiral phosphonates 28 and 20 bearing different chiral auxiliaries (Scheme 7.24). These alkene products, 144 and 145, were readily separable as a result of the difference in polarity between the two auxiliaries. It was clearly shown that the diastereoselectivities of the alkene products were dramatically improved compared to those obtained in the respective individual kinetic resolutions, especially in the case of alkene 145. 

The HWE reactions of 4-tert-butylcydohexanone (la) with reagent 176 in the presence of the alkoxide of chiral amino alcohol 178 as a base resulted in the formation of dissymmetric alkene 179 in good yield with up to 52% ee [100] (Scheme 7.29). In this study, it was suggested that the addition step is reversible and that the... 

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