A new synthetic method

21 Jan 2016 NUS chemists reported a new synthetic method of introducing an alkynyl group at β-position of cyclic carbonyl compounds with high enantioselectivity.

One of the most key focus areas in synthetic organic chemistry is to find a new method of synthesising chemicals of practical or potential importance. The chiral acetylene derivatives, which bear a stereogenic centre at propargyl position, are known to be a very important class of compounds because of their high utility in medicinal chemistry and materials science.

A team led by Prof Tamio HAYASHI from the Department of Chemistry in NUS and the Institute of Materials Research and Engineering (IMRE) under A*STAR, has found a new asymmetric reaction which realises asymmetric synthesis of chiral acetylene derivatives, using an asymmetric conjugate alkynylation of cyclic α,β-unsaturated carbonyl compounds in the presence of a rhodium catalyst coordinated with chiral diene ligand (see Figure).

The team has developed catalytic asymmetric conjugate in addition to electron-deficient olefins, typically α,β-unsaturated carbonyl compounds, in the presence of chiral rhodium complexes. Recently, they have found chiral ligands of conceptual novelty, that is, chiral dienes whose basic diene skeleton is norbornadiene or bicyclooctadiene. These were found to be better than the conventional chiral ligands represented by chiral bisphosphines in terms of both catalytic activity and enantioselectivity in many catalytic asymmetric reactions. The nucleophiles used so far for this asymmetric conjugate addition have been limited to sp2 carbon nucleophiles (aryl and alkenyl). In the present report it was discovered that an sp carbon nucleophile (alkynyl) can be introduced with high selectivity by use of a propargyl alcohol as a nucleophile precursor.

Presently, the team is studying the asymmetric synthesis of some other chiral molecules, which is based on the accumulated knowledge and understanding of the rhodium-catalysed asymmetric reactions.


tamio jan full

Asymmetric conjugate alkynylation of cyclic α,β-unsaturated carbonyl compounds (ketone, ester, and amide) was realised by use of diphenyl((triisopropylsilyl)­ethynyl)­methanol as an alkynylating reagent in the presence of a rhodium catalyst coordinated with a new chiral diene ligand (Fc-bod) to give high yields of the corresponding β-alkynyl-substituted carbonyl compounds with 95–98% ee. [Image credit: Tamio HAYASHI]



Dow X, Huang Y, Hayashi T. “Asymmetric Conjugate Alkynylation of Cyclic α,β-Unsaturated Carbonyl Compounds with a Chiral Diene Rhodium Catalyst.” Angew. Chem. Int. Ed. (2015) 54, Early View: DOI: 10.1002/anie.201509778