An Efficient Synthesis of γ-Aminoacids and Attempts to Drive Its Enantioselectivity

Abstract

Addition of carboxylic acid dianions to bromoacetonitrile lead, in good yields, to the corresponding γ-cyanoacids, which on hydrogenation yielded γ-aminoacids. This two step methodology improves upon previously described results. Poor e.e’s resulted from our attempts to drive the enantioselectivity of this transformation by chiral amide induction.

Structural Chemistry of Peptides Containing Backbone Expanded Amino Acid Residues: Conformational Features of β, γ, and Hybrid Peptides

“…Figure illustrates the substitution pattern for a β amino acid residue. The most commonly used monosubstituted (β 3 ) residues are those derived by Arndt-Eistert homologation of the readily available α amino acid residues that occur in protein structures. − Synthetic routes to β 2 -monosubstituted and multiply substituted β residues − and γ residues − have also been the subject of several investigations. Substitution at backbone carbon atom in the ω amino acids can result in the creation of new chiral centers which can then influence the handedness of folded backbone conformations.…”

“…Conformational energy calculations using semiempirical force fields establish that Gpn residues can be accommodated in a relatively limited region of conformational space. , In the design of folded hybrid peptides, the use of stereochemically constrained ω amino acids permits a biasing of the local conformational choices along the polypeptide backbone. The area of hybrid peptides must undoubtedly benefit from the explosive development of synthetic methodologies directed toward preparation of a wide variety of substituted β and γ amino acids together with methodologies for backbone homologation at the C-terminus residues of α peptides. − …”

Unexplored Nucleophilic Ring Opening of Aziridines

“…In both reactions, only starting material was recovered. Although this was expected from the reactivity of non-activated aziridines with nucleophiles, it was worth testing as enediolates have shown a distinctive reactivity from other nucleophiles [ 9 , 10 , 11 ]. Thus, the more reactive 2-ethyl-1-tosylaziridine ( 3c ), synthesized as described [ 20 ], was used in the rest of the experiments.…”

“…In order to extend our methodology using enediolates from carboxylic acids we wished to complete the study of nucleophilic ring opening with these nucleophiles, which permits direct acces to γ-aminoacids, as a full complement to the efficient synthesis of these compounds from enediolates of carboxylic acids and bromoacetonitrile, described previously by us [ 8 , 9 ].…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…The addition of bromoacetonitrile to the dianions of carboxylic acids has been reported as a two-step process to afford a-substituted amino acids. Although high yielding, the use of chiral bases resulted in only minimal chiral induction [40].…”