Asymmetric Synthesis of α-Amino Acids from a Chiral Masked Form of Glyoxal

Abstract

Synthetic works devoted to the synthesis of α-amino acids are simply plethoric. The primary impetus which accounts for such a strong interest clearly is the potential of the target molecules to lead to practical applications associated with their biological interest. On the other hand, and this is a familiar rule in science, research towards this practical objective gave birth to the invention of new important synthetic methodologies and it can be stated that many achievements in this field are unquestionable landmarks in asymmetric synthesis. 1 Among the various methods that give access to optically active α-amino acids, one of the more documented consists in the use of electrophilic glycine equivalents. Fiaud and Kagan, as early as 1970, pioneered this field by reacting Grignard reagents with chiral imines. 2 Since then, this area expanded very rapidly and the syntheses using bis-lactim ethers and oxazinones developed respectively by Schöllkopf's and Williams' groups 3,4 are now considered as classical.In this respect, we have presented a chiral masked form of glyoxal derived from β-amino alcohols. This is another electrophilic glycine equivalent which appeared as an extremely convenient tool for the design of enantiopure acyclic as well as cyclic α-amino acids. This methodology is based on desymmetrization of glyoxal which was transformed into a chiral template. The crucial step of this procedure involves an iminium ion derived from one aldehyde function of glyoxal. This iminium ion was used as a substrate by applying either one of the following processes: (i) intermolecular addition of organozinc reagents or silyl derivatives, (ii) intramolecular ene-iminium reactions entailing an ene moiety linked to the template. Acyclic N-methyl amino acids resulted from the first process whereas the second one afforded proline or pipecolic acid-derived amino acids. In both cases, the reactions between the iminium moiety and its nucleophilic partner occurred with complete stereocontrol. The more significant aspects of this research are presented here. Condensation of glyoxal with chiral β-amino alcoholsWe have been interested for a long time in the stereoselective formation of oxazolidines 1 which result from the condensation of β-amino alcohols with aldehydes. 5 In the case of glyoxal however, it was reported by Le Rouzic et al. 6 , on the basis of X-ray analysis, that similar condensations afforded a 6-membered ring compound 2 (Scheme 1). Treated with thiophenol, heterocycle 2 was cleaved and yielded morpholine derivative 3. Scheme 1This fact strongly attracted our attention because compound 3 can be envisioned as a masked form of glyoxal in which the two original aldehydic functions are now discriminated. We thought that the use of chiral β-amino alcohols would afford a further interesting differentiation, i.e. between the enantiofaces of the glyoxal carbonyl groups.Abstract: Enantiopure acyclic and cyclic α-amino acids were synthesized from glyoxal. This dialdehyde was desymmetrized by condensing it with various (R)-ph...

An Efficient Access to Enantiomerically Pure Substituted Derivatives of Pipecolic Acid

“…The stereoselective formation of the stereocenter at the ring junction corresponds to what was already described on similar iminium ions: , chiral induction by the phenyl-bearing stereocenter leads the addition of the olefinic double bond to occur on the less encumbered face, i.e., the Si face of the cyclic iminium ion. It is worth noting that during this cyclization leading to compounds 8 the integrity of the stereogenic center bearing the R substituent was not altered.…”

Asymmetric Syntheses of Enantiopure 4-Substituted Pipecolic Acid Derivatives

“…As already described, [8,13] this very efficient reaction is completely stereoselective: the attack of the allylsilane moiety onto the intermediate iminium ion 16 occurs on the lessencumbered face i.e. in an anti position relative to the phenyl group (Scheme 4).…”

Efficient 1,3-Asymmetric Inductions during Nucleophilic Additions to Imine and Iminium Ion Derivatives

“…16 In this case however, the diasteroselectivity was dictated by two stereogenic centers already present in the substrate, both providing 1,3-asymmetric induction.…”