Synthesis of N-Cbz-fluoropyruvaldehyde N,S-ketals: construction of highly stereoselective and high yielding synthetic reactions using multivariate modelling and design

The synthesis of (R)-fluoropyruvaldehyde-N,S-ketals via a tandem self-immolative Pummerer-type rearrangement of enantiopure (R)-alpha-fluoroalkyl-beta-sulfinylenamines has been studied using statistical experimental design and multivariate modelling. By this study a procedure has been established which simultaneously gives excellent enantioselectivity and synthetically useful yields. The improvement of the ee of the trifluoro derivative was from 69% to 82%. The optimised procedure has been scaled up (10 fold) and extended to the corresponding difluoro and chlorodifluoro derivatives, with similarly good results. The chemometric analysis, along with a crossover experiment, strongly supports the hypothesis of a strictly intramolecular process, according to the previously proposed mechanism. (C) 1997 Published by Elsevier Science Ltd.