Diastereodivergent strategy to cis or trans-2-phenyl-3-amino/hydroxypiperidine for the total syntheses of (−)-epi-CP-99,994, (+)-CP-99,994 and (+)-L-733,060

Abstract

The total synthesis of alkaloid antagonist CP-99,994 was accomplished in only seven steps, starting from chiral amine (S)-(−)-phenylethylamine. Key steps involve a diastereoselective intramolecular nitro Mannich reaction, followed by a Nef reaction and a diastereodivergent oxime or ketone reduction in which the diastereoselective outcome was explained using the Felkin Anh or Cram-Chelate model depending on the reducing agent employed. Following this methodology, 2,3-disubstituted piperidine derivatives of all four possible configurations can be prepared.