Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 31 October 2009

Total Synthesis of Vinigrol


T. J. Maimone, J. Shi, S. Ashida, P. S. Baran, J. Am. Chem. Soc. 2009, 131, 17066-17067.

DOI: 10.1021/ja908194b

Yes, it’s done. Surprised? This target has been on grant-proposals world-wide for the last twenty years, subsequent to its isolation in 1987, culminating in nearly twenty partial syntheses by big names like Paquette. So what did Baran do to triumph?

The key reaction at the beginning of this terpene synthesis is a Diels-Alder reaction between a diene, which is not commercially available, and (E)-methyl 4-methyl-2-pentenoate, that installed the initial bycycle in a reasonable yield and diastereomeric excess. Baran states that this result is unoptimised, but one would hope that a more exotic Lewis acid might a) confer a higher yield and diastereoselectivity, and b) induce enantioselectivity. A Stille coupling then installed the vinyl side-chain, whilst an oxidation state adjustment gave an aldehyde. Addition of allyl magnesium chloride caused formation of a triene intermediate, which under heating underwent a Diels-Alder reaction again, providing further two rings. That’s an impressive yield for that process, providing much of the vinigrol core in a few convenient steps.

With only some slight modification of conditions and substrates, the chemistry in the new JACS paper follows that of the earlier paper in Angewandte for a few steps here. The main difference is an oxidation, that allows regioselective enolate formation and alkylation. A reduction returns the alcohol with opposed stereochemistry this time, and mesylation sets us up for the centre-piece of this route - a Grob fragmentation, followed by addition of bromonitrile oxide.

Breaking the Grob fragmentation down, it is easier to see what’s going on, and why this is such a smart route. Baran is surmounting here a problem with an extranious carbon-carbon bond. By deprotonating the alcohol, the hydroxide can form a ketone, while mesylate acts as leaving group. A similar Grob fragmentation was used by Steve Ley in his syntheses of the Thapsigargins.

Now, the addition of bromonitrile oxide is interesting, as this is effectively a masked hydroxymethylation. A more familiar method of installing a hydroxyl and a methyl group over a double bond might be epoxidation, followed by addition of methylmetalate. However, this approach was unsuccessful. However the nitrone was easily reduced to the analogous amino alcohol, which features an unwanted primary amine. Baran’s approach now uses a Saegusa deamination sequence.

This seems quite akin to a Barton-McCombie deoxygenation - turning the heteroatom functionalisation into something that can be radically reduced. In this case, the key functional group is a isonitrile. Treatment of this with AIBN and tributyl tinhydride resulted in a fair yield of the desired product.

In a simple, but amazingly selective dihydroxylation / oxidation sequence which confers the correct diastereoselectivity, a desired ketone is formed in high yields. To summarise the rest of the route, a Shapiro reaction with trisylhydrazone provided a vinyl anion, which added to formaldehyde to provide the methanol sidechain.

An awesome total synthesis. Hopefully, the first Diels-Alder will give us an enantioselective route soon…