Synthesis of Unnatural α‐Amino Acid Derivatives via Light‐Mediated Radical Decarboxylative Processes

Abstract

Unnatural amino acids (UAAs) are key building blocks with widespread application across several scientific fields. Therefore, it is highly attractive to develop straightforward and simple methodologies capable of granting quick access to these species. Herein we report a light‐mediated protocol for the synthesis of UAA via radical decarboxylative processes. This methodology, which employs readily available and abundant starting materials – such as carboxylic and α‐keto acids – proceeds under very mild reaction conditions and shows a high functional group tolerance. In addition, the products of the radical reaction can be readily derivatized to grant rapid access to complex UAAs.

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.…”

“…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). [107] Scheme 12. Asymmetric synthesis of α-AA derivatives 20 by photocatalytic addition of radicals generated from carboxylic acids to a chiral substrate 1 b (Schubert, 2020).…”

Radikal‐basierte Synthese und Modifikation von Aminosäuren

“…Kürzlich berichteten Gómez‐Suárez, [71b] Wang [71a] und Shubert [71c] unabhängig voneinander über eine photoredoxvermittelte decarboxylierende Synthese von UAS unter Verwendung von 13 als Radikalakzeptor (Abbildung 24). Während die Strategie von Gómez‐Suárez ihre große Anwendungsbreite durch Verwendung einer Vielzahl aromatischer und aliphatischer α‐Ketosäuren sowie aliphatischer Carbonsäuren als Radikalvorläufer nachwies, [71b] ermöglicht Wangs Ansatz die Synthese von α‐deuterierten UAS, [71a] und Shuberts Methode erlaubt die Modifikation von Peptiden unter metallfreien Bedingungen [71c] . Alle drei Methoden ermöglichen die einfache Synthese einer Vielzahl von UAS in guten bis ausgezeichneten Ausbeuten und mit hohen Diastereoselektivitäten.…”