Trifluoromethyl-modified dipeptides by ZrCl4-promoted aza-Henry reactions

Abstract

Chiral (R)-1-phenylethylamine was successfully employed in a tandem aza-Henry addition-reduction reaction to give chiral β-nitro α-trifluoromethyl amines. A subsequent coupling reaction with N-Boc-protected amino acids leads to obtain optically pure CF3-modified dipeptides carrying two different N-protecting groups. These peptidomimetic units are characterized by the presence of the [CH(CF3)NH] group as mimetic of the natural [CONH] peptidic bond and can be used for the synthesis of more complex CF3-modified peptides after selective deprotection of one of the two amine functions. 2D NMR spectral analyses were employed to determine the absolute configurations of all newly synthesized chiral compounds.

Aza-Henry Reactions on C-Alkyl Substituted Aldimines

“…While only recently, C -CF 3 substituted aldimines [9,10,11] are reported in the aza-Henry reactions as interesting trifluoromethyl nitrogen-containing starting materials; the reactivity of C -aryl analogues has been well documented in the literature, while very few data are reported on the reactivity of C -alkyl substituted aldimines [2]. Classically, non-enantioselective nucleophilic addition of nitro alkanes to C -aryl substituted aldimines usually required the presence of a base as catalyst [12].…”

Selective Synthesis of Trifluoromethyl β‐Lactams by a Zn‐Promoted 2‐Bromo Ester Addition on C‐CF3‐Substituted Aldimines

“…With 2‐bromo esters 2a , 2b , and 2d , trans ‐trifluoromethyl β‐lactams were successfully formed as only products in high yields, but no stereoinduction was observed ( dr = 1:1). However, all diastereomers were easily obtained as optically pure compounds after purification . Instead, by starting from α‐ethyl‐substituted methyl 2‐bromo ester 2c , a different interesting result was obtained.…”

“…In fact, total facial induction was achieved, which suggests once again a key role for the alkyl substituent of 2‐bromo ester. Even in this case, diastereomers were easily obtained as optically pure compounds by flash chromatography with silica gel …”

Trifluoromethyl aldimines: an overview in the last ten years

“…66 The process involves a tandem Zr-catalyzed aza-Henry addition-reduction reaction, aiming at replacing the natural [CONH] peptidic bond with the [CH(CF 3 )NH] mimetic unit (Scheme 36).…”