Solution‐, Solid‐Phase, and Fluorous Synthesis of β,β‐Difluorinated Cyclic Quaternary α‐Amino Acid Derivatives: A Comparative Study

Abstract

The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was successfully adapted to solid-phase and fluorous-phase techniques. The reaction times and final deprotection were clearly more favorable in the latter, in which a fluorous trimethylsilylethanol (TMSE) tag was used. The tag was then easily removed upon treatment with TBAF in a high-yield transesterification process.

Recent Advances in the Asymmetric Synthesis of α-(Trifluoromethyl)-Containing α-Amino Acids

“…After separation, removal of the sulfoxide group in 43 by reaction with Raney-nickel -or tert-butyllithium in order to preserve a double-bond side chain -led to amino esters 44. Structurally similar to pyruvate-derived imines, difluoroallyl imino esters 45 were envisioned by Fustero and coworkers as convenient building blocks for the synthesis of difluoromethylene-containing cyclic amino acids 30 (Scheme 10). Addition of allylzinc bromide to 45 proceeded with complete chemo-and diastereoselectivity and was followed by ring-closing metathesis of 46 to render five-and six-membered amino esters 47.…”

Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

“…Cleavage of the benzyl group in 340 under H 2 /Pd(OH) 2 conditions provided the amino ester 341 in almost quantitative yield, which, by treatment with TBAF and subsequent ion-exchange chromatography, furnished the quaternary α-amino acid 342 in 70% yield (Scheme 74). 170…”

Selective Synthesis of New Fluorinated Alicyclic β‐Amino Ester Stereoisomers

“…C 58.93,H 8.12,N 4.91;found C 58.61,H 7.76,N 4.60 13 C NMR (400 MHz, CDCl 3 ): δ = 14. 5,28.7,31.5,39.2,41.7,48.8,50.2,61.7,80.5,155.3,172.1,207.8 ppm. C 14 H 23 NO 5 (285.34): calcd.…”

“…13 C NMR (400 MHz, CDCl 3 ): δ = 14. 5,22.5,28.7,32.6,35.6,46.0,49.6,61.6,80.5,119.4,155.2,172.5 ppm. C 14 H 23 F 2 NO 4 (307.34): calcd.…”