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(R)-Trifluoro- and Difluoropyruvaldehyde N,S-Ketals:  Chiral Synthetic Equivalents of β-Trifluoro and β-Difluoro α-Amino Aldehydes

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journal contribution
posted on 19.09.1998, 00:00 by Alessandro Volonterio, Barbara Vergani, Marcello Crucianelli, Matteo Zanda, Pierfrancesco Bravo
A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic γ-tri- and γ-difluoro β-amino alcohols (70% to >95% ee) is described, using tri- and difluoropyruvaldehyde N,S-ketals (R)-1a,b as starting materials. Addition of Grignard reagents to (R)-1 occurs with moderate to excellent anti-stereocontrol, depending on the nature of the organomagnesium halides, providing the β-p-tolylthio β-benzyloxycarbonylamino secondary carbinols 5. The stereochemical outcome of these reactions can be rationalized by means of a chelated Cram's cyclic model, where the NCbz group is the chelating ligand and the p-tolylthio residue acts as the stereocontrolling “large” group. Reductive displacement of the 2-p-tolylthio substituent of 5 efficiently takes places by means of the NaBH4/pyridine system, probably via the corresponding intermediate transient imines 13, providing sulfur-free γ-tri- and γ-difluorinated β-amino alcohols 7 with high levels of anti-stereoselectivity. A considerable shift toward syn-stereoselectivity was obtained performing the reaction on the corresponding phenylacetates 8. Cleavage and reduction of the NHCbz moiety of 7 provided tri- and difluoro analogues of, respectively, norephedrine (11) and ephedrine (12).