Week 11 Mega Chemist Challenge Solution

This weeks Mega Chemist is the owner of what is probably the most infamous group photo, and definitely the most fiery. Here is Professor M. Christina White (does anybody know what the M stands for?) in all that flaming glory….

You can visit her group page for some brilliant pictures, but I think even better are these posters.

Professor White, as mentioned in the clues, completed her PhD in the group of Professor Gary Posner, initiating the hybrid Vitamin D3 analog program in his group. Following her time with Jacobson working on catalytic epoxidations, she began her independent career at Harvard before moving to the University of Illinois in 2005, where she now holds the position of professor. She has a whole host of awards as you would expect for someone with such a phenomenal background, most recently she was awarded the Roche Excellence in Chemistry Award (2009) and the Cope Scholar Award (2009). A short CV includes all of her  awards.

Professor White hit the ground running after the completion of her PhD. Her paper  “A synthetically useful, self-assembling MMO mimic system for catalytic alkene epoxidation with aqueous H2O2” (DOI 10.1021/ja015884g) published with Jacobson now has 227 citations. Following this her seminal independent publication “A sulfoxide-promoted, catalytic method for the regioselective synthesis of allylic acetates from mono-substituted olefins via C-H oxidation” (DOI 10.1021/ja039107n) was in JACS, and introduced us to the now eponymous White Catalyst.

White’s interest in C-H oxidation resulted in a string of papers in top journals, but new highs were reached with her first Science publication in 2007. This paper demonstrates the selective oxidation of unactivated sp3 C-H bonds in complex molecule synthesis, using only the steric environment and subtle electronic differences in C-H bonds to predictably control the outcome (DOI 10.1126/science.1148597).

Here is a recent perspective on C-H oxidation in synthesis by White.

Today’s paper is not from Science, but a brilliant application of a derivative of the White catalyst (DOI 10.1021/ja2059704) in dehydrogenative Diels-Alder reactions.

We are all aware of the archetypal Pd catalysed allylic functionalisation – the Tsuji-Trost reaction. The attack of a nucleophile on  a Pd-pi-allyl complex formed from an olefin with an appropriate allylic leaving group, allows for the introduction of an extensive range of functionality. Formation of Pd-pi-allyl systems in this manner is obviously a little wasteful, and moreover, wouldn’t fit in with White’s traditionally highly atom economical C-H activation strategies. Instead White uses established contemporary catalytic techniques to form Pd-pi-allyl complexes from terminal olefins, but rather than introduce of a nucleophile as in the Tsuji-Trost reaction, she proposed that direct beta-hydride elimination would generate dienes (dehydrogenation) that could subsequently be exploited in Diels-Alder cycloadditions (scheme 1). This is great because not only is the number of commercial dienes way less than that for termianl olefins, they are far easier to make.

Formation of diene 1 in the absence of a dienophile was initially investigate, though (presumed) polymerisation led to relatively poor isolated yield, despite optimistaion. Conditions that maintained a relatively low concentration of the diene, and the introduction of N-phenylmaleimide to trap the apparently unstable intermediate on formation, proved much more successful (scheme 2) [1][2].

The functional group tolerance of the dehydrogenation conditions is impressive, allowing many ‘synthetic handles’ to be carried through the reaction for later derivatisation. All reactions proceed with greater than 20:1 endo selectivity, and the stereochemical integrity of pre-existing chiral centers is never compromised. Some of the most impressive examples are given (scheme 3).

A number of N-aryl and N-alkyl maleimides were suitable as dienophiles, though less reactive enones and acrylamides yielded poor results in intermolecular reactions. In contrast, White showed tethering of less reactive dienophiles to the terminal olefin permited intramolecular cyclisation under dehydrogenation conditions. White then really began to show off (warranted of course), and using intermolecular reactions with pendant nucleophiles attached to the maleimide was able to derivatise the cycloadducts through intramolecular cyclisations onto the maleimide moiety. The synthesis of isoindoloquinoline in just 4 steps from and 3 is brilliant (scheme 4), and in reality could warrant a little paper of its own! I think this synthesis is another little warning shot across the bows to those who believe organic synthesis is a dying art because it is so time consuming. Challenge us, and we shall rise ;-)!

Keep them coming Professor White.

 [1] 2,6-Me2BQ was employed rather than benzoquinone as the stoichiometric oxidant to avoid competitive DA reactions.

[2] Diene formation gives a 4:1 E/Z selectivity, though experiments support a Pd (II) catalysed dynamic diene isomerisation.


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