Convenient new route to piperidines, pyrrolizidines, indolizidines, and quinolizidines by cyclization of acetylenic sulfones with beta- and gamma-chloroamines. Enantioselective total synthesis of indolizidines (-)-167B, (-)-209D, (-)-209B, and (-)-207A

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjuga te additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, fo llowed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl )pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluene sulfony l)pyrrole, respectively. The conjugate additions of a series of acyclic and cyclic secondary beta- and gamma-chloroamines to acetylenic sulfones proce eded similarly under mild conditions. The resulting adducts were deprotonat ed with LI)A in THF at -78 degrees C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sul fones. Thus, acyclic gamma-chloroalkylbenzylamines afforded the correspondi ng 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)pyrrolidines, 2-(2-chloroethyl)-pyrrolidines, 2-(chloromethyl)-piperidines, and 2-(2-chl oroethyl)-piperidines produced the corresponding 3-substituted pyrrolizidin es, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, re spectively. 8-Methyl-5-substituted indolizidines were also prepared from th e appropriate methyl-substituted chloroamine precursor. Enantioselective sy ntheses were achieved by employing chiral chloroamines derived from amino a cids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thu s, reduction of (8aS)-S-n-propyl-6-(p-toluenesulfonyl)-Delta(5,6)-indolizid ine with sodium cyanoborohydride in trifluoroacetic acid, followed by reduc tive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n -hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R,8 aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-Delta(5,6)-indolizidine furni shed (-)-indolizidine 209B. Finally, the similar reduction and debenzylatio n of (-)-(SR, 8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfonyl)-Delt a(5,6)-indolizidine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chlor ide and substitution with a higher order allyl cuprate reagent to afford (- )-indolizidine 207A.