Simpkins reactions, asymmetric

The potassium enolate generated from 23 is regarded as an enantiomeric atropisomer. Recently non-biaryl atropisomers have been receiving more attention in asymmetric synthesis.19 Most of them employ atropisomers that are configurationally stable at room temperature, while attention in this chapter is focused on asymmetric reactions that proceed via chiral nonracemic enolate intermediates that can exist only in a limited time. An application of configurationally stable atropisomeric amide to a chiral auxiliary for stereoselective alkylation has been reported by Simpkins and co-workers (Scheme 3.10).20... 

Simpkins and co-workers were the first to use an asymmetric catalytic process in (-)-anatoxin-a synthesis (Newcombe and Simpkins, 1995) instead of resorting to the chiral pool strategy. Their total synthesis of (-)-anatoxin-a relied on an enantioselective enolisation reaction of a readily available ( )-3-tropinone (33), by a chiral lithium amide base (34) (Bunn et al. 1993a, 1993b) and subsequent cyclopropanation/ring expansion reaction giving the ketone 37 (Scheme 7.8). 

A dramatic application was the asymmetric synthesis of epibatidine 70 by Simpkins.18 Diels-Alder reaction of the deactivated pyrrole 63 with the alkynyl sulfone 64 gave the bicyclic core 65 of epibatidine. Selective reduction gave the compound 66 needed for epibatidine, but in racemic form. A directed lithiation (chapter 7) and sulfonation led to achiral bis sulfone 67. 

Asymmetric reaction of the sulfides bearing a tricarbonyl(ri -arene)chromi-um complex was shown to be successful by Gibson and Simpkins [48,49]. The benzyhc methylene groups in tricarbonyl(ri -phenylmethyl alkyl sulfide)chro-mium(O) and tricarbonyl(ri -l,3-dihydroisobenzothiophene)chromium(0) were highly asymmetrically functionahzed by deprotonation with a chiral bis-Uthium amide and subsequent electrophihc reactions (Tables 4 and 5). 

Silylation of a-sulfonyl carbanions may proceed through an asymmetric deprotonation pathway [Eqs. (13) and (14)] [57]. Thus, Simpkins has shown that silylated products are obtained with certain enantioselectivities when TMSCl is present in the reaction mixture during the deprotonation reaction with a cam-... 

The enantioselective reaction of a-sulfinyl carbanions involves both desym-metrization of the prochiral alkyl groups and diastereoselection. Simpkins and coworkers have reported the asymmetric induction of a traws-thiane oxide with a camphor-derived chiral lithiiun amide giving products with complete diaster-eoselectivity and with good enantioselectivity (Table 6) [59,60]. 

Aggarwal and Olofsson have developed a direct asymmetric a-arylation of prochiral ketones using chiral lithium amide bases and diaryliodonium salts [881]. In a representative example, the deprotonation of cyclohexanone derivative 684 using chiral Simpkins (/ ,/ )-base followed by reaction with the pyridyl iodonium salt gave the arylated product 685 in 94% ee (Scheme 3.275). This reaction has been employed in a short total synthesis of the alkaloid (-)-epibatidine [881]. 

Stereoselective carbon-carbon bond formations with hypervalent iodine reagents are also prominently described in the literature. Direct asynunetric a-arylation reactions are not easy to perform. Ochiai et al. synthesized chiral diaryliodonium salts such as [l,l -binaphthalen]-2-yl(phenyl)iodonium tetrafluoroborate derivatives 21 via a BFs-catalyzed tin-X -iodane exchange reaction and developed the direct asymmetric a-phenylation of enolate anions derived from cyclic p-ketoesters (Scheme 7) [37]. A beautiful example of direct asymmetric a-arylation of cyclohexanones in the course of a natural product synthesis was presented through the desymmetrization of 4-substituted cyclohexanones using Simpkin s base, followed by coupling with diaryliodonium salts [38]. Other binaphthyl iodonium salts related to 21 have also been reported [39]. 

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