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Asymmetric Synthesis of gem-Difluoromethylenated Dihydroxypyrrolizidines and Indolizidines

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journal contribution
posted on 05.10.2012 by Watcharaporn Thaharn, Teerawut Bootwicha, Darunee Soorukram, Chutima Kuhakarn, Samran Prabpai, Palangpon Kongsaeree, Patoomratana Tuchinda, Vichai Reutrakul, Manat Pohmakotr
An asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and indolizidines is described. The fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to chiral imides was achieved in satisfactory yields to provide mixtures of syn- and anti-isomers 69 with moderate to good diastereoselectivities. Reductive cleavage of the phenylsulfanyl group followed by intramolecular radical cyclization of the syn-isomers 69 occurred under refluxing conditions to afford the corresponding gem-difluoromethylenated 1-azabicyclic compounds 1013 in moderate yields as a separable mixture of cis- and trans-isomers. The cis-isomers of compounds 10 and 12 and trans-13 were readily transformed to gem-difluoromethylenated dihydroxypyrrolizidines 20 and 27 and indolizidine 28, respectively, by reductive cleavage of the hydroxyl group and organometallic addition followed by hydrogenolysis.