Memory of Chirality of Tertiary Aromatic Amides: A Simple and Efficient Method for the Enantioselective Synthesis of Quaternary α-Amino Acids

Abstract

A new methodology for the asymmetric synthesis of quaternary alpha-substituted amino acids using memory of chirality has been developed. The strategy utilizes the dynamic axial chirality of tertiary aromatic amides to memorize the initial chirality of an alpha-amino acid during an enolization step. Starting from five different l-amino acids, the corresponding oxazolidin-5-ones containing a tertiary aromatic amide group have been synthesized in one step and then alkylated with various electrophiles, with good yields and enantioselectivities (up to 96% and up to >99% after recrystallization). One-step deprotection affords enantioenriched or enantiopure quaternary alpha-amino acids. We describe here the optimization process, the results obtained in each series and a plausible explanation, based on NMR studies, DFT calculations and crystallographic structures. The methodology presented herein constitutes an efficient synthesis of enantiopure quaternary alpha-amino acids (three steps only) starting from tertiary l-amino acids, without any external source of chirality.

Synthesis of enantiomerically enriched (R)-13C-labelled 2-aminoisobutyric acid (Aib) by conformational memory in the alkylation of a derivative of L-alanine

“…The latter method avoided the presence of yellow impurities in the final amino acid. The alaninate salt was converted to its cyclic naphthamide derivative 3 , following the method of Branca et al [36], resulting in 57% yield and >99.5:0.5 e.r. on a 2.5 g scale (Scheme 1).…”

“…Alkylation through a planar enolate then takes place under the control of the temporary axis or centre in a sequence where the final structure retains a “chiral memory” (in fact a “configurational memory”) of the starting material. The strategy was first developed, in the guise of the “self-regeneration of stereocentres” by Seebach [26–29], but has more recently been shown by Fuji and Kawabata [30–34], by Kouklovsky and coworkers [35–36] and by others [21,37–39] to work effectively when the temporary stereogenic element [40] is a C–N or C–C axis, which retains its configuration at low temperature but becomes conformationally unrestricted as the temperature rises [41–45]. …”

“…In particular, we made use of the method of Kouklovsky [36], which relies on a temporary naphthamide Ar–CO axis as a chiral “aide-mémoire” for translating the configuration of the starting amino acid into the configuration of the product. We have previously employed benzamide and naphthamide Ar–CO axes in “chiral memory” processes [52–53].…”

“…We have previously employed benzamide and naphthamide Ar–CO axes in “chiral memory” processes [52–53]. Kouklovsky reported the enantioselective alkylation of alanine by this method [36], and recently Soai showed that Seebach’s methods can be used to make selectively deuterated Aib [54]. In a previous paper [55], we reported the synthesis and use of a 13 CH 3 -labelled Aib probe made by Kouklovsky’s method [36], to gather evidence of helicity switching in Aib oligomers.…”

“…Kouklovsky reported the enantioselective alkylation of alanine by this method [36], and recently Soai showed that Seebach’s methods can be used to make selectively deuterated Aib [54]. In a previous paper [55], we reported the synthesis and use of a 13 CH 3 -labelled Aib probe made by Kouklovsky’s method [36], to gather evidence of helicity switching in Aib oligomers. We now report in detail a practical method for the enantioselective synthesis and enantiomeric assignment of a derivative of ( R )- 1 *.…”