Efficient asymmetric synthesis of trifluoromethylated β-aminophosphonates and their incorporation into dipeptides

Abstract

Addition of anions derived from dialkyl methylphosphonates to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine afforded (Ss,R) addition adducts in moderate to good yield (53-75%) with excellent diastereoselectivity (94-95% de). After selective removal of the N-sulfinyl group, dipeptides containing enantiomerically pure diethyl 2-amino-3,3,3-trifluoropropylphosphonate were synthesized to investigate the influence of the trifluoromethyl substituent on N-terminal coupling.

Synthesis of (2S,3S)-β-(trifluoromethyl)-α,β-diamino acid by Mannich addition of glycine Schiff base Ni(II) complexes to N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine

“…Thus, it is well established that kinetic control in the alkylation reactions of Ni(II) complex (S)-1 usually affords up to 85:15 diastereoselectivity, favoring the corresponding (S) configuration at the a-carbon [21], and that was also the case in the previously shown example of a Mannich reaction with an achiral imine [6] (Scheme 1). On the other hand, the high facial selectivity displayed by chiral sulfinimine 7 was also demonstrated [9][10][11][12][13][14][15]. Therefore, the reaction of complex (S)-1 with sulfinimine (S S )-7 constituted a perfectly matched case since essentially only one diastereomer (S)(2S,3S)(S S )-11 was observed (Scheme 3).…”

“…This compound has been employed for the expedient synthesis of a wide variety of a-(trifluoromethyl)amines [9]. For instance, several Mannich-type processes have been performed with (S S )-or (R S )-7 by reaction with enolates derived from a-hydroxyesters [10], malonates [11] or indanones [12], as well as with other nucleophiles such as phosphites [13], lithium anions derived from phosphonates [14] or heterocycles [15].…”

Internal chirality descriptors iR and iS and ire and isi. A proposed notation to extend the usefulness of the R/S system by retaining the sense of stereochemistry in cases of ligand ranking changes

“…With the iR / iS descriptors, to firmly circumvent any confusion or ambiguity, the –CF 3 /–CH 3 groups are declared as the rank‐fixed ligand, ie iR / iS CF3/CH3(3) . The situation becomes yet more convoluted in the case of phosphorous analogs of amino acids because in this case the phosphorous substituent is of greater priority than both the –CF 3 and –NH 2 groups. But the amino acid analog 5 has been specifically designed and intended as a stereochemical equivalent of natural alanine ( 3 ).…”

Highly Stereoselective aza‐Baylis–Hillman Reactions of CF3‐Sulfinylimines: Straightforward Access to α‐Methylene β‐CF3 β‐Amino Acids

“…This reaction has been extensively studied in racemic and asymmetric versions and can be extended to various Michael acceptors (mainly acrylates, but also vinyl ketones, cyclic enones, and acroleins) and several activated aldimines (sulfonylimines, sulfinylimines, phosphinylimines) by using different kinds of catalysts (phosphines or tertiary amines). [40,41] Recently, N-tert-butylsulfinylimines [42][43][44] and, in particular, their fluorinated counterparts [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] have received much attention as a result of their potential to undergo various nucleophilic additions in high yields with high diastereoselectivity. Although the corresponding adducts were obtained with good diastereoselectivities [up to 88 % diastereomeric excess (de)], the chemical yields were rather moderate.…”