Asymmetric ketoester cyclization

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

Another potential approach towards 1 was reported by Seido et al. utilizing an asymmetric reduction of the ketone (57 Scheme 15) as the key step. Acylation of the lithium enolate of methyl phenylacetate with the imidazolide, obtained by treatment of the acid 56 with A, V -carbonyldiimidazole, gave the ketoester 57 in 66.4% yield. Asymmetric reduction of 57 with [RuI(/7-cymene)(5)-binap]I, tin chloride, and cam-phor-lO-sulfonic acid in methanol at 80 °C afforded the alcohol 58 as a mixture of syn and anti forms in 87.4% yield. The ratio of syn to anti isomers was 76.3 23.7 and the enantiomeric purity of each form was 95.6% ee and 97.8% ee, respectively. Tosylation of 58 with p-toluenesulfonyl chloride and pyridine in the presence of catalytic amounts of DMAP yielded a diastereomeric mixture of tosylate 59 in 61.8% yield. Deprotection of the /V-Cbz group in 59 by hydrogenation over 5% Pd-C followed by cyclization of the resulting amino tosylate 60 with potassium carbonate in methanol furnished methylphenidate as a mixture of erythro and threo isomers in a 7 3 ratio and 77.5% yield. 

Treatment with excess trifluoroacetic acid furnished the (dihydroiminoethano) carbazole 107 in 71% overall yield. Epoxidation of the alkene followed by a two-step protecting group modification gave epoxide 108, which underwent an oxidative epoxide opening followed by silyl protection to give silyl ether 109. Alloc deprotection, alkylation with (Z)-2-iodo-2-butenyl tosylate, followed by an intramolecular Heck reaction delivered pentacyclic diamine 110. A three-step formation of the p-ketoester 111 followed by a three-step reduction process afforded ester 112, which underwent a reduction and deprotection sequence to provide minfien-sine (99). A sequential catalytic asymmetric Heck-(V-acyliminium ion cyclization for the delivery of the enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9//-carbazole is the highlight of the synthesis. 

SCHEME 2.30 Organocatalytic asymmetric FC alkylation/cyclization cascade reaction of 2-naphthols with P,y-unsaturated a-ketoesters. 

Ketoesters could be exploited to generate iminium intermediate employed as hydride acceptor. Gong et al. reported a chiral Brpnsted acid 85-catalyzed asymmetric cascade [1,5]-hydride transfer/cyclization of 2-pyrrolidinyl phenyl ketoesters 82 with anilines 83, which produced the enantio-enriched cyclic aminals 84 (Scheme 29) [113]. The iminium subunit in intermediate I served as hydride acceptor, which was generated in situ through the condensation of o-aminoben-zoketone 82 with aniline 83 in the presence of 85. 

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