Radical-Based Synthesis and Modification of Amino Acids

Abstract

Amino acids (AAs) are key structural motifs with widespread applications in organic synthesis, biochemistry, and material sciences. Recently, with the development of milder and more versatile radical-based procedures, the use of strategies relying on radical chemistry for the synthesis and modification of AAs has gained increased attention, as they allow rapid access to libraries of novel unnatural AAs containing a wide range of structural motifs. In this Minireview, we provide a broad overview of the advancements made in this field during the last decade, focusing on methods for the de novo synthesis of α-, β-, and γ-AAs, as well as for the selective derivatisation of canonical and non-canonical α-AAs.

Keywords: amino acids; peptides; photochemistry; radical reactions; synthetic methods.

Scheme 1

Syntheses of α,β‐diamino esters.

Scheme 2

Synthesis of C‐glyco‐α‐AAs.

Scheme 3

Syntheses of quaternary α‐amino esters.

Scheme 4

Three‐component syntheses of α‐AAs.

Scheme 5

Enantiopure α‐AAs by radical decarboxylations.

Scheme 6

Synthesis of α‐AAs by MHAT.

Scheme 7

α‐AA synthesis by C(sp³)−H amination.

Scheme 8

CO₂ as a C₁ building block to access α‐AAs.

Scheme 9

Asymmetric synthesis of β‐amino‐α‐(aminoxy) esters and amides.

Scheme 10

β‐AA synthesis using xanthates.

Scheme 11

Syntheses of γ‐AAs by radical decarboxylations.

Scheme 12

Syntheses of γ‐AAs by ketimine umpolung or HAT.

Scheme 13

Synthesis of heterocyclic γ‐AAs.

Scheme 14

Asymmetric synthesis of γ‐AAs.

Scheme 15

Syntheses of UAAs using RAEs.

Scheme 16

Asp/Glu derivatisations by reductive cross‐coupling.

Scheme 17

Modification of Asp/Glu residues on peptides.

Scheme 18

Modifications of Dha by decarboxylative strategies.

Scheme 19

Derivatisations of Dha using organoborates.

Scheme 20

Dha modifications by reduction of in situ generated intermediates.

Scheme 21

Modifications of Dha using alkyl halides.

Scheme 22

Diastereoselective syntheses of UAAs.

Scheme 23

Three‐component synthesis of UAAs.

Scheme 24

Decarboxylative functionalisations of 13.

Scheme 25

Ni‐catalysed C−H benzylation of Gly.

Scheme 26

Deaminative Gly modification.

Scheme 27

Gly derivatisations by in situ generated imines.

Scheme 28

C−H functionalisations of Leu.

Scheme 29

C−H fluorination of Phe.

Scheme 30

para‐Selective C−H aminations of Phe.

Scheme 31

Cu‐catalysed trifluoromethylation of Trp residues.

Scheme 32

β‐C(sp³)−H alkylation of Trp.

Scheme 33

Modification of vinyl‐Gly using xanthates.

Scheme 34

Fluorination or azidation of allyl‐Gly derivatives.