Week 5 Solution Mega Chemist Challenge #MegaCC

It was of course Manchester University’s very own Professor Eric J. Thomas.  The picture obviously was not recent, but found on Prof. Ian Fleming’s website.  He has a lovely stash of photos of both his PhD students and post-docs from their time in the group, with a couple of very recognisable faces in there. (US based and industrial scientists may recognise a lot more).

After completing his PhD with Ian Fleming, Professor Thomas moved to Oxford’s Dyson Perrins Laboratory where he undertook post-doctoral research on the synthesis of trans-cyclo-octenes under the supervision of Gordon Whitham. He held academic positions at Kings College, London, and Oxford before moving to Manchester as a Professor of Organic Chemistry in 1988. In 2009 he received the RSC Synthetic Organic Chemistry Award for his synthetic studies on the bryostatins and phomactins. A relatively up to date recent publication list can be found here.

Professor Thomas is a champion of organic chemistry in the UK; he has sat as President of the Perkin Division (now the Organic Division) of the RSC and has been Regional Editor for Tetrahedron Letters and a member of the Executive Board of Tetrahedron Publications for many years.

Today’s paper up for discussion is a well cited article that was published just after Prof. Thomas moved to Manchester.

The paper describes the [3,3]-sigmatropic rearrangement of allylic trifluoroacetimidates as a method for the asymmetric synthesis of L-a-amino acids, and application of this in the synthesis of (+)-polyoxamic acid.  This was the first reported use of trifluoroacetimidates in a synthetic route, and only the second mention in the literature full stop (according to SciFinder).  The earliest mention came two years earlier in a paper on the structure of bis(organosilyl)amides.

Thomas initially intended to use the well established thermally induced Overman rearrangement (Group lit review here) of trichloroacetimidates (scheme 1). Synthesis of stabilized ylide 2 from commercially available ethyl (S)-lactate 1 was facile and generally high yielding. Condensation with an L-tartrate derived aldehyde gave enone 3 as a single diastereoisomer, confirming the enantiomeric purity of the ylide. The steric bulk of the silyl protecting group allowed for stereoselective reduction of 3 using L-selectride, without migration of the silyl group. Treatment of the allylic alcohol with BuLi and trichloroacetonitrile gave trichloroacetimidate 4.

Unfortunately thermal rearrangement to give 5 (scheme 2) proceeded in relatively poor yield (30-40 %), reportedly due to decomposition of material under the prolonged and harsh conditions required – 140 °C for two days. Fear not though, Thomas (or more likely, the student) came back from that gentle kick in the teeth: as [3,3]-sigmatropic rearrangements of allylic imidates were know to be accelerated by electron withdrawing substituents on the imidate carbon, it was proposed that the use of trifluoroacetimidates might be a good idea, with enhanced reactivity hopefully allowing for milder reaction conditions.

Not only did the trifluoroacetimidate 6 rearrange to give a single diastereoisomer 7 (scheme 2), [see below for some handy transition states (scheme 3), c.f. Claisen re-arrangement] in excellent yield (90%) over a comparatively short 20 h, but they were stable at room temperature and could be purified on silica.

Reduction of the trifluoroacetamide with NaBH₄, Boc protection of the amine and ozonolysis of the double bond followed by a harsh RuO₄ oxidation gave free carboxylic acid 8. Global deprotection (a term probably not in existence in 1989?) was mediated with TFA to give (+)-polyoxamic acid (scheme 4).

Thomas importantly demonstrated the stereochemistry of the rearrangement was governed by the configuration of the acetimidate and not the acetal by synthesising the D-tartrate derivative of  6, and observing the same stereoselectivity in the rearrangement.

This is obviously just one of a plethora (see b.r.s.m. for an amusing analysis of scientific language) of methods for the asymmetric synthesis of amino acids but I thought this was a tidy little paper which nicely introduced trifluoracetimidates as a useful tool in synthesis, so was definitely worth a mention.

Some papers:

Ben List’s 2011 paper on enantioselective rearrangements of trifluoracetimidates using counter ion directed Pd catalysis

Overman’s seminal paper and full paper on the rearrangemnet of trichloracetimidates and the first use of mercuric ion catalysis in formal [3,3]sigmatropic rearrangements.