Enantioselective Syntheses of 2-Substituted Pyrrolidines from Allylamines by Domino Hydroformylation-Condensation: Short Syntheses of (S)-Nicotine and the Alkaloid 225C

Abstract

Short routes to chiral 2-substituted pyrrolidines based on rhodium-catalyzed hydroformylations of allylamines and their N-alkyl and N-acyl derivatives, which were prepared by asymmetric allylic substitutions, are described. The outcome of the hydroformylation reaction was controlled by the substituent at nitrogen, not by the substituent at carbon. In the case of N-alkylallylamines in situ reduction to the pyrrolidines occurred, with N-acyl derivatives hemiaminals and with primary amines cyclic imines were formed. Very short syntheses of (S)-nicotine and the alkaloid 225C are presented.

domino reactions - hydroformylation - pyrrolidines - ­alkaloids - cyclizations

References and Notes

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General Procedure for the Rh-Catalyzed Hydroformylation-Reduction (cf. Conditions B, Scheme 4) A cylindrical glass vessel (2.5 × 7 cm) with a perforated snap on lid was charged with Rh(acac)(CO)₂ (2.3 mg, 9.0 µmol), Biphephos (18 µmol), and a soln of the allylic amine (1.0 mmol) in CHCl₃ (10 mL/mmol). The vessel was placed in an autoclave, which was pressurized (30 bar) with H₂/CO (5:1); oxygen was removed by flushing twice with the gas mixture. The autoclave was then heated for 18-24 h at 50 ˚C. The resulting brown mixture was analyzed by GC-MS. The solvent was removed in vacuo and the residue subjected to flash chromatography on SiO₂.

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