PPubMed28 Mar 2019Cited 49×

The Asymmetric A 3 (Aldehyde–Alkyne–Amine) Coupling: Highly Enantioselective Access to Propargylamines

Jia-Nan Mo, Junqi Su, Jiannan Zhao, Cimarelli Cristina

Abstract

The recent developments in asymmetric A3 (aldehyde-alkyne-amine) coupling has been summarized in this review. Several interesting modifications of the ligands enabled the highly enantioselective synthesis of chiral propargylamines, which are further used in the construction of nitrogen-containing chiral building blocks.

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The review summarizes recent ligand‑enabled, highly enantioselective asymmetric A3 couplings for making chiral propargylamines.

What’s new

i.Summarizes recent ligand modifications that boost enantioselectivity in A3 couplings
ii.Highlights substrate‑scope limitations and the challenge with aliphatic alkynes
iii.Presents catalyst‑recycling data and transition‑state models for stereocontrol

How they did it

The authors performed a literature review of asymmetric A3‑coupling studies, compiling experimental data, tables, and mechanistic proposals from recent papers. They compared ligand structures, yields, and enantiomeric excesses to identify trends and gaps.

What they found

L8 (s‑Bu‑pybox‑diPh) gave 97 % yield and 93 % ee (Table 1, entry 2)
Boysen’s gluco‑pybox L14 afforded 69 % yield and 99 % ee for benzaldehyde‑aniline‑phenylacetylene (2008)
Catalyst recycling gave 99 % yield and 98 % ee in the first run (Table 2)
L20 with i‑Pr/Me3Si gave 84 % yield and 98 % ee (R) (Table 3)

Caveats

✕Aliphatic aldehydes are not tolerated in the L8 catalyst system
✕Three‑component reactions with aliphatic alkynes remain unsolved
✕Catalytic efficiency and substrate scope still need improvement
✕The role of the carboxylate moiety in CuI/thiourea systems is unclear

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