Highly enantioselective catalytic dynamic resolution of N-Boc-2-lithiopiperidine: synthesis of (R)-(+)-N-Boc-pipecolic acid, (S)-(-)-coniine, (S)-(+)-pelletierine, (+)-beta-conhydrine, and (S)-(-)-ropivacaine and formal synthesis of (-)-lasubine II and (+)-cermizine C

Abstract

The catalytic dynamic resolution (CDR) of rac-2-lithio-N-Boc-piperidine using chiral ligand 8 or its diastereomer 9 in the presence of TMEDA has led to the highly enantioselective syntheses of both enantiomers of 2-substituted piperidines using a wide range of electrophiles. The CDR has been applied to the synthesis of (R)- and (S)-pipecolic acid derivatives, (+)-beta-conhydrine, (S)-(+)-pelletierine, and (S)-(-)-ropivacaine and the formal synthesis of (-)-lasubine II and (+)-cermizine C.

Figure 1

Dilithio ligands for dynamic resolution.

Scheme 1

DTR of N-Boc-2-lithiopiperidine 2.

Scheme 2

Synthesis of (+)-β-conhydrine i) s-BuLi (1.2 equiv), Et2O, TMEDA (4.0 equiv), –78 °C, 3 h; ii) 8, (10 mol%), –45 °C, 3 h; iii) EtCHO, –78 °C, 2 h; iv) CF3CO2H, CH2Cl2.

Scheme 3

Synthesis of (S)-(+)-pelletierine and (S)-(−)-coniine. Formal synthesis of (−)-lasubine II and (+)-cermizine C. i) Pd(OH)₂ (1.0 eq), H₂ (1 atm), MeOH, rt, 48 h; ii) CF₃CO₂H, CH₂Cl₂, 0 °C, 2 h, then NaOH, pH 10; iii) PdCl₂ (1.0 eq), CuCl (10 mol%), O₂, DMF/H₂O (10:1), rt, 10 h; iv) CF₃CO₂H, CH₂Cl₂, 0 °C, 2 h, then NaOH.

Scheme 4

Synthesis of (S)-(−)-Ropivacaine i) s-BuLi (1.2 eq), Et₂O, TMEDA (4.0 eq), −78 °C, 3 h, then 9, (10 mol%), −45 °C, 3 h, −78 °C, 2,6-dimethylphenyl isocyanate, 2 h, >99:1 er; ii) CF₃COOH, CH₂Cl₂, rt, 10 h, then NaOH; iii) isopropyl alcohol, 1-bromopropane (3.0 equiv), K₂CO₃ (3.0 equiv), H₂O, 100 °C, 6 h.