A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic ç-tri- and ç-difluoro â-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 â-p-tolylthio â-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 ç-tri- and ç-difluorinated â-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).

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

CRUCIANELLI, MARCELLO;
1998

Abstract

A new, efficient, and stereoselective two-step approach to stereochemically defined chiral nonracemic ç-tri- and ç-difluoro â-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 â-p-tolylthio â-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 ç-tri- and ç-difluorinated â-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).
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11697/11323
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 17
social impact