Asymmetric Synthesis of Fused Bicyclic α-Amino Acids Having a Hexahydro-cyclopenta[c]pyridine Skeleton via Intramolecular Pauson−Khand Reaction of 1-Sulfonimidoyl-Substituted 5-Azaoct-1-en-7-ynes

Abstract

An asymmetric synthesis of fused bicyclic amino acids having a hexahydro-cyclopenta[c]pyridine skeleton and carrying besides an enone structural element a substituent at the β-position is described. The key steps of the synthesis are a highly selective allylation of N-tert-butylsulfonyl imino ester with bis(allylsulfoximine)titanium complexes and a highly diastereoselective Pauson−Khand cycloaddition of sulfonimidoyl-substituted γ,δ-unsaturated α-amino acid esters carrying a substituent at the β-position and a propargyl group at the N-atom. The cyclization is accompanied by a reductive cleavage of the sulfoximine group of the primary cyclization product. Surprisingly, the removal of the sulfoximine group proceeds with inversion of the configuration at the S-atom and gives N-methyl-phenylsulfinamide with ≥98% ee. Deprotection of the bicyclic N-tert-butylsulfonyl-protected amino acid ester was accomplished through treatment with CF₃SO₃H under anhydrous conditions. The enantio- and diastereomerically pure sulfoximine-substituted γ,δ-unsaturated α-amino acid esters used as starting material were obtained through a highly regio- and diastereoselective allylation of N-tert-butylsulfonyl imino ester with acyclic bis(allylsulfoximine)titanium complexes, described previously.