Enantioselective Synthesis of Fluorinated α-Amino Acids and Derivatives in Combination with Ring-Closing Metathesis:  Intramolecular π-Stacking Interactions as a Source of Stereocontrol

Abstract

[reaction: see text]. Hydride reduction of C=N bonds stereocontrolled by intramolecular pi-stacking interactions of 1-naphthylsulfinyl and N-aryl groups, nonoxidative Pummerer rearrangement, and ring-closing metathesis are efficiently combined in a highly stereoselective entry to enantiomerically pure cyclic and acyclic fluorinated beta-amino alcohols and alpha-amino acid derivatives, respectively.

Facile Synthesis of Chiral α‐Difluoromethyl Amines from N‐(tert‐Butylsulfinyl)aldimines

“…14 The asymmetric hydrogenation of fluorinated imines are usually difficult, and recently Uneyama and co‐workers reported that the palladium‐catalyzed asymmetric hydrogenation of difluoromethyl imino esters proceeded with poor enantioselectivity (30 % ee ) 9. Hydride reduction of the CN bond of chiral difluoromethyl β‐sulfinyl‐ N ‐arylimine only gave 82 % diastereomeric excess 10. Difluoropyruvaldehyde N , S‐ ketal was synthesized in three steps from difluoroacetic esters and chiral methyl p‐ tolyl sulfoxide in only 72 % enantiomeric excess 11.…”

Approaches to Obtaining Fluorinated α-Amino Acids

“…Next, a “non-oxidative” Pummerer reaction was conducted to generate the corresponding aminols 20a – c , which were oxidized to give the (2 S )- N -Cbz-protected amino acids 21a – c (Scheme ). , …”

Nitrogen-Containing Organofluorine Derivatives: An Overview

“…After careful optimization of the reaction conditions, we found that tetrabutylammonium borohydride in methanol at -70 °C provided the best diastereomeric control (dr ranging from 88:12 to 99:1) and nearly quantitative yield in the hydride reduction of enantiopure sulfinyl-containing N-arylimines (S)-35 to give fluorinated b-sulfinylsubstituted amines 36, with a clear predominance of the syn-diastereomers (Scheme 13). 51 The arylsulfinyl group exerted a significant influence on the stereoselectivity, with the 1-naphthyl group affording the best results. Moreover, computational and NMR spectroscopic studies showed an almost parallel (face-to-face) geometry between the 4-methoxyphenyl (PMP) group on the imine moiety and the 1-naphthylsulfinyl ring, which suggested the presence of an attractive p-p interaction (p-stacking).…”