Catalytic asymmetric Tsuji–Trost α−benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives

Abstract

Catalytic asymmetric Tsuji–Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

Chiral aldehyde-nickel dual catalysis enables asymmetric α−propargylation of amino acids and stereodivergent synthesis of NP25302

“…However, most of the reported examples focused on the usage of chiral aldehydes as pure organocatalysts 28 – 35 , and the chiral aldehyde/transition metal combining catalytic systems were very rare (Fig. 1a ) 36 – 38 . Especially, there was only one type of transition metal, the palladium, has been merged with chiral aldehyde catalysts 36 – 38 .…”

“…1a ) 36 – 38 . Especially, there was only one type of transition metal, the palladium, has been merged with chiral aldehyde catalysts 36 – 38 . So, the development of chiral aldehyde/transition metal-involved combining catalytic systems becomes an important way to achieve more challenging α−functionalization reactions of aminomethyl compounds.…”

“…As a continuous work on our discovery of the chiral aldehyde/palladium combined catalysis 36 – 38 , we tried to employ another type of transition metal as a catalyst partner with chiral aldehydes. Palladium is a soft metal that has a large atomic radius and strong electronegative property, while nickel has different chemical properties (harder, smaller atomic radius, and less electronegative) 39 – 42 .…”

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

“…More extensive studies of this ternary catalytic system involving chiral aldehydes are ongoing. In 2022, Guo and co-workers 33 reported the asymmetric -benzylation of more challenging -amino acid esters via an unstable aromaticity-disrupted η 3 -benzyl-palladium complex using the ternary catalytic system comprising of chiral aldehyde, palladium species, and Lewis acid (Schemes 18 and 19). When using the combination of chiral aldehyde C2e/[Pd(C 3 H 5 )Cl] 2 /ZnCl 2 , a variety of polycyclic arylmethanol-derived benzylation reagents 38 reacted smoothly with -amino acid ethyl esters 33 to generate unnatural optically active -benzyl ami-no acids 39 in high yields and enantioselectivities (Scheme 18).…”

Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

“…The unique property of chiral aldehyde catalysis, [21][22][23][24] directly promoting the asymmetric functionalization of Nunprotected amino acid esters, has been demonstrated in alkylation, 25 Michael addition, [26][27][28] Mannich, [29][30] aldol, [31][32][33] allylation, [34][35][36] benzylation, 37 and propargylation 38 reactions. We envisioned that this strategy may be promising for the direct asymmetric hydrocarbylation of amino acid esters with halohydrocarbons.…”