Stereocontrolled Synthesis of ψ[CH(CF₃)NH]Gly-Peptides

Abstract

[reaction: see text] A novel class of peptidomimetics having a stereogenic [CH(CF(3))NH] replacement for a [CONH] peptide bond has been synthesized. The new compounds have been obtained in a stereocontrolled fashion using a kinetically controlled aza-Michael addition of chiral alpha-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. The stereoselectivity is strongly influenced by the solvent, the base, its stoichiometry, and the R side-chain. Diastereomeric ratios higher than 11:1 were achieved using H-Val-OtBu.HCl in toluene with 1.1 equiv of DIPEA.

The Use of N‐Alkyl‐2,2′‐bipyrrolidine Derivatives as Organocatalysts for the Asymmetric Michael Addition of Ketones and Aldehydes to Nitroolefins

“…We just observed a decrease of the diastereoselectivity (syn/anti 73 : 27) with the adduct 13m (entry 8) and a loss of reactivity with the nitroolefin 9n. [126] Indeed, a strong withdrawing group CF 3 does not allow the reaction to take place at À 25 8C (entry 9). But, the adduct 13n was isolated after one day at room temperature in 42% yield, 91% ee and a ratio syn/anti of 77 : 23 (entry 10).…”

“…(2R,3R)-4,4,4-Trifluoro-2-methyl-3-(nitromethyl)butyraldehyde (13n): From propionaldehyde and nitroolefin 9n [126] according to the General Procedure 3 using the diamine (S,S)-iPBP at room temperature for 1 day to give a mixture of inseparable diastereoisomer (syn/anti 77/23) as a yellow oil (yield: 42%, 91% ee). The enantiomeric excess of syn-13n was determined by GC [Hydrodex-B-3P, 90 8C-0-1, R t : 10.3 min (2S,3S) and 10.9 min (2R,3R)]; syn isomer: 1 (38).…”

The Trifluoroethylamine Function as Peptide Bond Replacement

“…Next, we reported a significant advancement of our project, consisting in the stereocontrolled synthesis of a new class of peptidomimetics, much closer to natural peptides, having a fluoroalkyl backbone modification: Y[CHA C H T U N G T R E N N U N G (CF 3 )NH]Gly-Peptides 13 ( Figure 3, R = H). [8] In this case, the trifluoroethylamine function replaces a native peptidic amide-bond [COÀNH]. The stereocontrolled synthesis of these new peptidomimetics is based on another key aza-Michael reaction involving 3,3,3-trifluoro-1-nitropropene 14 (Scheme 3) and an array of a-amino esters, generated in situ from the hydrochlorides 1 with a base.…”

Synthesis and some transformations of alkyl N-(2-aryl-3-nitro-1,1,1-trifluoropropan-2-yl)carbamates

“…В останні два десятиліття пред-метом особливої уваги дослідників стали їх α-фто-роалкіловмісні аналоги -унікальні синтетичні блоки для побудови різноманітних типів фторо-ваних аміносполук [6][7][8]. Описані в літературі під-ходи до їх отримання зазвичай базуються на при-єднанні аміносполук до 3,3,3-трифторо-1-нітро-пропену (реакція аза-Міхаеля) [9][10][11][12][13]. Нещодав-но з'явились перші повідомлення про можливість використання для цієї цілі реакції аза-Генрі за уча-стю фтороалкілованих іміносполук, зокрема, N-за-міщених трифторометилальдімінів [14] та фто-роалкіл-α,β-ненасичених N-трет-бутилсульфініл-кетімінів [15].…”