Challenges and recent advancements in the synthesis of α,α-disubstituted α-amino acids

Abstract

α,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other types of amino acids. They serve as modifiers of peptide conformation and as precursors of bioactive compounds. Therefore, it has been a long-standing goal to construct this highly valuable scaffold efficiently in organic synthesis and drug discovery. However, access to α,α-disubstituted α-AAs is highly challenging and largely unexplored due to their steric constraints. To overcome these, remarkable advances have been made in the last decades. Emerging strategies such as synergistic enantioselective catalysis, visible-light-mediated photocatalysis, metal-free methodologies and CO₂ fixation offer new avenues to access the challenging synthesis of α,α-disubstituted α-AAs and continuously bring additional contributions to this field. This review article aims to provide an overview of the recent advancements since 2015 and discuss existing challenges for the synthesis of α,α-disubstituted α-AAs and their derivatives.

Fig. 1. General overview on α,α-disubstituted α-AAs.

a Importance of α,α-disubstituted α-amino acid derivates. b Traditional methods to construct α,α-disubstituted α-amino acid scaffolds. c Recent advances of constructing α,α-disubstituted α-AAs.

Fig. 2. Conceptual overview on α,α-disubstituted α-AAs.

Schematic representation of the mentioned strategies for the synthesis of α,α-disubstituted α-AAs classified by the type of bond formation.

Fig. 3. C-N Bond Formation.

a Copper-catalyzed radical addition at nitrosoarenes. b Chiral catalysts used in the electrophilic and nucleophilic amination. c Calculated transition states in Chinchilla’s solvent-free procedure. d Synthesis of α,α-disubstituted α-amino esters via 1,4-acyl transfer. e Nucleophilic approach for the construction of α,α-disubstituted α-amino esters.

Fig. 4. Addition to ketiminoesters.

a Enantioselective addition of styrenes. b Silver-catalyzed Mannich reaction of α-substituted isocyanoacetates and ketimines. c Rhodium-catalyzed alkynylation of α-ketiminoesters. d Direct access to N-unprotected α-tetrasubstituted amino acid esters.

Fig. 5. Recent advances of addition at ketiminoesters.

a Procter’s borylative multi-component coupling using a copper(I) catalyst. b Visible-light-mediated three-component reaction to afford α,α-disubstituted α-amino esters.

Fig. 6. Amino acid schiff bases for unnatural α-amino acid synthesis.

a Synergistic Cu/Pd catalysis. b Synergistic Cu/Ni catalysis. c Synergistic Cu/Ir catalysis. d Aldehyde/Pd catalysis to afford α,α-disubstituted α-amino esters without the preparation of Schiff bases.

Fig. 7. Amino acid schiff bases for unnatural α-AA synthesis via radical coupling.

a Copper-catalyzed radical-radical coupling. b Catalytic cross-dehydrogenative coupling.

Fig. 8. α-Functionalization of general α-AAs.

a Metal-free arylation of amino acids. b Hydroalkylation of alkynes and allenes.

Fig. 9. Direct α-C(sp³)-H bond functionalization.

a Iron-catalyzed C(sp³)-H/C(sp²)-H cross-coupling. b Copper-catalyzed C(sp³)-H direct fluorination.

Fig. 10. Hydrocarboxylation of amines or imines.

a Visible-light-mediated CO₂-fixation; PC: photocatalyst (4-CzIPN). b Visible-light promoted 1,2-acyl migration. c Electrocarboxylation of N-acylimines.