Synthesis of Enantioenriched α-Deuterated α-Amino Acids Enabled by an Organophotocatalytic Radical Approach

Abstract

A mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the well-established two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the long-standing challenge of the installation of sterically demanding side chains into α-amino acids.

Advances in Asymmetric Amino Acid Synthesis Enabled by Radical Chemistry

“…Asymmetric synthesis of the α-deuterated α-AA derivatives 17 by addition of radicals generated from carboxylic acids by organophotoredox catalysis to a chiral substrate 1 b and the isolation of Leu-D (Wang, 2020). [106] Later, the Gómez-Suárez [107] and Schubert [105] groups independently demonstrated that the strategy reported by Wang et al [106] is general and perfectly fits Scheme 11. Asymmetric synthesis of the α-AA derivatives 18 by photocatalytic addition of radicals generated from carboxylic acids to a chiral substrate 1 b and the isolation of α-AA 19 a (Gómez-Suárez, 2020).…”

“…Eco-friendly and green approaches were elaborated by applying readily accessible feedstock carboxylic acids and amines for straightforward radical coupling under mild conditions. [102,103,[105][106][107]166]…”

“…In 1987 Seebach for the first time synthesized a chiral ΔAla derivative 1 a (N-benzoyl-(2S)-methyleneoxazolidinone) [110] which later widely applied as a substrate for the diastereoselective synthesis of different AAs, in particular, by radical chemistry. [86,88,90,92,94,96,98,100,102,103,[105][106][107] For instance, in 1990 Beckwith firstly applied this substrate ((S)-1 a) for the synthesis of a series of non-proteinogenic α-AAs via the radical process (Scheme 2). [86] It was reported that the alkyl radicals generated either by tributylstannane/azobisisobutyronitrile (AIBN) under Scheme 3.…”

“…[103] Quite recently, Wang et al broadened the application of a dehydroalanine derivative (S)-1 b using it as a substrate for the synthesis of enantioenriched αdeuterated α-AAs from readily accessible feedstock carboxylic acids enabled by an organophotocatalytic radical approach under mild conditions (Scheme 10). [106] Starting from various sugar derived carboxylic acids, primary, secondary, tertiary alkyl, αketo carboxylic acids and in the presence of a photosensitizer (Mes-Acr-Me + ClO 4 À ) and deuterium oxide a range of desired unusual AA derivatives were isolated in 46-93% yields with excellent dr (> 20:1) and a high level of deuteration (up to 99%) at the α-carbon centre was reached (Scheme 10). The authors convinced that the carbon radical formed after decarboxylation of acid via a SET mechanism (catalysed by a photosensitiser) are trapped by an electrophilic (S)-1 b and followed by an additional SET, which gives rise to an enolate.…”

Radical‐Based Synthesis and Modification of Amino Acids

“…Recently, the groups of Gómez‐Suárez, [71b] Wang, [71a] and Shubert [71c] independently reported a photoredox‐mediated decarboxylative synthesis of UAAs using 13 as a radical acceptor (Scheme 24). Whereas the procedure developed by Gómez‐Suárez and co‐workers presents a broad scope with a variety of aromatic and aliphatic α‐keto acids, as well as aliphatic carboxylic acids as radical precursors, [71b] the approach developed by Wang and co‐workers allows the synthesis of α‐deuterated UAAs, [71a] and the method developed by the Shubert group facilitates the modification of peptides under metal‐free conditions [71c] . All three methods allow the straightforward synthesis of a wide range of UAAs in good to excellent yields and high diastereoselectivities.…”