Week 4 Solution – Mega Chemist Challenge #MegaCC

The solution is of course Ronald Breslow who has been at Columbia University since 1956, and where he now is the Samuel Latham Mitchill Professor of Chemistry.  Despite now being into his 9th decade his passion for research is obviously unabated, and a list of his most recent (and less recent) publications can be found here.

You can see the man in action here for TEDx discussing the development of a drug from his laboratory and taking it all the way to market via Merck.

Breslow has had a prolific career winning numerous awards himself, and as a wonderful honour for his 70th birthday, friends, colleagues and former students established an award in his name, the Ronald Breslow Award for Achievement in Biomimetic Chemistry

Breslow’s early research on traditional reaction mechanism and ‘new molecules with interesting properties’, particularly anti-aromatic compounds, has since given way somewhat – but not completely – to a focus on biomimetic chemistry. His laboratory currently design, synthesise and evaluate artificial enzymes, antibodies and biological receptors that mimic the behaviour of those found in biological systems.

 Today though I would like to have a quick look at a paper from 1958 which takes us all the way back to his seminal work on establishing the mechanism of thiamine (vitamin B1) – an important biological co-enzyme – action. This work of course led to the naming of the so-called ‘Breslow intermediate’, a key feature in the mechanism of many NHC catalysed reactions (Here are two group meeting reviews: Denmark group; Crimmins group.)

Breslow very nicely surmises and discusses previously suggested modes of action of thiamine including reactivity of amino-pyrimidine moiety at A, modes of action that proceed via ring opening of the thiazole B, and as proposed by himself reactivity at the N-methylene carbon C. Breslow then succinctly explains the evidence that refutes these suggestions before walking us gently through his search for an alternative mode of action.

Breslow subsequently suggested the viability of the formation of a zwitterionic thiazole (or NHC) through deprotonation at D and went on to postulate a mechanism for the thiazole catalysed benzoin reaction (scheme 1) analogous to that of the established HCN catalysed condensation.

Despite being unable to isolate the key ‘Breslow intermediate’ from the reaction, he did demonstrate by synthesising 1 independently (methylation of the free NH thiazole with MeI) that it was highly unstable under very mild conditions, providing further support for his mechanism. Breslow demonstrated that not only simple thiazoles (and imidazoles) catalysed this reaction, but also that thiamine itself gave benzoin, suggesting (along with other evidence) that this mode of action for thiamine in biological systems was correct.

This mechanism for the NHC catalysed benzoin reaction is now widely accepted, and is the foundation of a large amount of contemporary NHC organocatalysed chemistry. With this work Breslow showed a long time ago, what we all now know, that nature is a great source of inspiration for the development of new synthetic methodology.


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