Vanadium( II )‐ and Niobium( III )‐Induced, Diastereoselective Pinacol Coupling of Peptide Aldehydes to Give a C2‐Symmetrical HIV Protease Inhibitor

Peptide aldehydes 15 a–c are prepared without epimerization from enantiomerically pure (S)‐α‐amino acids (Scheme 3). Reductive pinacol homocoupling of 15 a–c, induced by vanadium complex 11 or niobium complex 16 in refluxing THF, yields C2‐symmetrical (S,R,R,S)‐configurated 6a, 6b and 2, respectively, with moderate to high stereoselectivity (Scheme 4). In a novel protocol for the preparation and utilization of THF solutions of 11, the isolation of air‐sensitive intermediates can be avoided and the potent HIV protease inhibitor 2 prepared in enantio‐ and diastereomerically pure form on a kilogram scale without chromatographic purification. The (S,R,R,S) selectivity of the pinacol homocouplings is confirmed by means of an independent, stereochemically unequivocal synthesis of 6 a and 2 from D‐mannitol 4 (Scheme 1).