Recently, we reported the first successful chiral alkylation onto 4-acetoxy-2-azetidinones (3 and 6 employing the tin(II) enolates of C4-chiral-3-acyl-1,3-thiazolidine-2-thiones (1a-d and 12) and its application to the chiral synthesis of 1β-substituted carbapenems (11 and 15). Now, we expanded this chiral tactics to alkaloid syntheses. Chiral alkylation of 5-acetoxy-2-pyrrolidinone (18) or 6-acetoxy-2-piperidone (21) with the tin(II) enolates of 3(ω-chloroalkanoyl)-4(S)-isopropyl-1,3-thia-zolidine-2-thiones(22a-d) furnished the corresponding alkylated products 24a-d in a highly diastereoselective manner (≧93 - ≧97%de) and in 57-73% yields. Subsequent reductive annulation of 24a-d with LiAlH4 at 0℃ and then under reflux gave directly the desired bicyclic products 33a-d in 41-69% yields together with the corresponding hydrogenolysis by-products 34a-d. Compounds 33a (≧99%op) and 33d proved to be (-)-trachelanthamidine and (-)-epilupinine, respectively. Naturally occurring (+)-epilupinine (37)(≧97%op) was similarly synthesized. A unified mechanism 30 for the stereochemical outcome of the chiral alkylation and new empirical aspects (Figure 1) for the reductive annulation toward the N-atom-containing bicyclic compounds are also discussed in the text. Thus, we succeeded in developing an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons.
