Highly diastereoselective alkylation of chiral tin(II) enolates onto cyclic acyl imines. An efficient asymmetric synthesis of bicyclic alkaloids bearing a nitrogen atom ring juncture

Asymmetric alkylation onto 5-acetoxy-2-pyrrolidinone (5, n = 1) in THF employing chiral tin(II) enolates 4a,b,e,f obtained from treatment of the corresponding 3-acyl-4(S)- or -4(R)-isopropyl-l,3-thiazolidine-2-thiones 3a,b,e,f with Sn(OSO2CF3)2and N-ethylpiperidine in THF afforded the corresponding C (5)-alkylated 2-pyrrolidinones 6, 7,12, and 13 in 67-92% yields and in a highly diastereoselective manner [91-97% diastereomer excess (de)]. Similar alkylation of 4e onto 6-acetoxy-2-piperidinone (5, n = 2) gave the C (6)-alkylated 2-piperidinone 14 in 63% yield and in 96% de. Complete enolization of 3c,d,g was achieved by employing 2 mol equiv of Sn(OSO2CF3)2and 2.2 mol equiv of N-ethylpiperidine at -5 to 0 °C in THF. Subsequently, diastereoselective alkylation onto cyclic acyl imines derived from 5 (n = 1 and 2) in situ using the tin(II) enolates 4c,d,g gave the chiral alkylated lactams 8–11 and 15 in 57-73% yields and in 91-98% de. A six-membered chelated transition state (e.g., 16) is proposed for the highly diastereoselective alkylation with various chiral tin(II) enolates onto 5 (n = 1 and 2). Simplified reductive annulation of 8–11 and 15 with LiAlH4proceeded smoothly to furnish optically pure (-)-trachelanthamidine (17a), two kinds of indolizidine type compounds 17b,c, (-)-epilupinine (17d), and (+)-epilupinine (21) together with the corresponding hydrogenolysis products 19a-d and 23, respectively. Chiral lactam 6 was readily converted to carboxylic acid 26, the synthetic precursor of (S)-homoproline 27, and the chiral diester 31, which could be exploited for the asymmetric synthesis of various chiral pyrrolizidine alkaloids via 32.