Week 2 Mega Chemist Challenge solution

Of course, last weeks star was the one and only Scott E. Denmark of the University of Illinois.  He initially studied at M.I.T before moving to ETH-Zürich where he obtained a D. Sc. Tech under the guidance of the Professor Albert Eschenmoser (my favourite name in chemistry) for work entitled “On the Stereochemistry of the S N’ Reaction”.  The same year he was appointed as an assistant professor at the University of Illinois where he has remained since, and where in 1991 he was named the Reynold C. Fuson Professor of Chemistry.  In addition to life as a chemist, as you may have picked up in the comments he also races cars and you can follow his extremely high-powered journey here.

Denmark’s academic interests are varied, though a fascination with main group chemistry, particularly silicon, has been prevalent throughout his career. Indeed, my introduction to the chemistry of Denmark was watching him command the stage with great aplomb, lecturing on the palladium catalysed coupling of organosilanols as an alternative to boron and tin coupling reagents. You can find an account of this research here.

Despite silicon arguably being the mainstay of his research, I am going to discuss instead two fairly recent papers that do not have a silicon atom anywhere in site, but focus on the enantioselective introduction of chalcogens sulfur and selenium by functionalisation of olefins. This is achieved utilising the “Lewis base activation of Lewis acids”, a concept championed and driven forward by Denmark.

In 2010 Denmark published an extensive full paper article documenting the development of catalytic, enantioselective selenoetherification reactions (scheme 1a).  The detail of the paper is too much for here, but it is a beautiful documentation/lesson in developing new methodology and well worth reading if you have an hour to spare. More recently in 2011 he published a paper utilizing the same underpinning concepts, but for the thiofunctionalisation of alkenes (scheme 1b).

Both reactions utilise in situ generation of a highly active cationic Lewis acid catalyst from a mild Lewis acid electrophile and a Lewis base – “Lewis base activation of Lewis acids” (scheme 2).

Proof of concept was previously established in the analogous Lewis base catalysed selenolactonisation reactions. Denmark showed that a Lewis base and a mild Bronsted acid (in this case the pendant carboxylic acid) were both essential (scheme 3).  Unfortunately though, attempts to induce enantioselectivity in these reactions using chiral Lewis bases failed.

Denmark, subsequently postulated a catalytic cycle (slightly modified for discussions of enantioselectivity, scheme 4) – which is still invoked after mechanistic studies for seleno and thioetherifications – in which I have highlighting the enatio-enriched iranium ion as the key intermediate.  It was suggested that erosion of enantiopurity by either attack on Se by the pendant nucleophile regenerating the olefin and an achiral Nu-SeAr intermediate, or by non-stereocontrolled transfer of the Se ion between olefins led to racemic products. The answer was thus obvious, the generation of iranium ions that were stable under the reaction conditions.

Judicious choice of electrophile (mild Lewis acid), screening of Lewis bases and other reaction parameters gave workable reaction conditions, and the scope and selectivity were explored (scheme 5).

These reactions excitingly present the very first catalytic asymmetric thio/selenium functionalisation of unactivated olefins, and despite the somewhat limiting moderate ee and extended reaction times this is a big step forward in exploring the synthetic utility of less ‘fashionable’ main group elements.  I look forward to seeing where this takes us, with regard to not only how we introduce chalcogens into our molecules, but also the unexplored synthetic utility these can provide us with.

And yes, I was defeated by my own auto schedule.  Generally last weeks solution will come before this weeks challenge.


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