Enantioselective Synthesis of (-)-Pumiliotoxin C from a Chiral Amino Ester and an Acetylenic Sulfone that Acts as an Alkene Dipole Equivalent.

A new synthesis of the naturally occurring (−)-enantiomer of the dendrobatid alkaloid pumiliotoxin C (1) was achieved by the conjugate addition of methyl (−)-cis-2-amino-trans-6-methylcyclohexanecarboxylate (3) to 1-(p-toluenesulfonyl)-1-pentyne (4), followed by intramolecular acylation to afford (4aS,5R,8aR)-4a,5,6,7,8,8a-hexahydro-5-methyl-2-propyl-3-(p-toluenesulfonyl)-4-quinolinone (2). The acetylenic sulfone thus acts as the synthetic equivalent of an alkene dipole species. The required enantiopure amino ester 3 was obtained by an approach based on pig liver esterase (PLE)-mediated hydrolysis. Thus, the (−)- and (+)-enantiomers of racemic dimethyl trans-3-methylcyclohexane-cis,cis-1,2-dicarboxylate (6) afforded the corresponding half-esters 7 and 8, respectively, when treated with PLE. The desired half-ester 7 was recovered intact after selective conversion of the free carboxylic acid group of the byproduct 8 into its benzyl ester. Half-ester 7 was converted into enantiopure (−)-6 with diazomethane, ...