Substrate-Controlled and Organocatalytic Asymmetric Synthesis of Carbocyclic Amino Acid Dipeptide Mimetics

Abstract

The asymmetric synthesis of a carbocyclic delta-amino acid representing the P(2)/P(3) subunit of a nonpeptidic truncated peptidomimetic molecule is described relying on two independent approaches.

A hydroxamic-acid-containing nucleoside inhibits DNA repair nuclease SNM1A

“…Due to the acid sensitivity of this molecule, it was used immediately in the next step (carried forward as a mixture of 4′-epimers). We initially attempted to convert the ketene-dithioacetal 16 into the corresponding methyl ester 17 using CuSO 4 •5H 2 O in refluxing methanol, 22 however this resulted in decomposition of the starting material. Switching to AgNO 3 in refluxing methanol 23 for one hour (or rt overnight) did provide product 17, but in very low yield (14%).…”

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

“… 18 We noticed that carbocyclic δ-amino acid ester 16 is a key chiral intermediate to peptidomimetic 17 ( Scheme 7 ), which showed submicromolar activity on β-site amyloid precursor protein cleavage enzyme-1 (BACE-1). 19 However, long synthetic sequences (at least 11 steps) were required to complete the synthesis of such a δ-amino acid and its derivatives. 19 b Our synthetic route started from the asymmetric hydrogenation of 7ag with ( S )- 6b on the multi-gram scale at 0.01 mol% catalyst loading.…”

Syntheses and applications of enantiopure δ-amino acids and their precursors

“…An approach which involves the organocatalytic formation of γ-amino acids followed by Wittig homologation in the generation of cyclic δ-Amino acid precursors as dipeptide mimcs is presented by Hanessian and co-workers, 36 with the ultimate aim of incorporating these into potentially therapeutic peptidomimetics. The group provide several synthetic routes in order to access the target compounds, one of which includes an organocatalytic component.…”