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Totally Synthetic by SPF, 6 August 2011

Total Synthesis of Omphadiol


G. Liu, D. Romo, Angew. Chem. Int. Ed. 2011, 50, 7537-7540.

DOI: 10.1002/anie.201102289

What if I’d ask you to synthesize this small molecule with six neighbouring stereocenters from biologically available material? Oh, by the way you can’t use any protecting groups and keep it short! Sounds impossible? Not according to Romo et al.. They’ve achieved the total synthesis of this stereo-dense molecule in 10 steps from (R)-carvone (smells like spearmint). (+)-Omphadiol belongs to the africanane family of sesquiterpenes. Its brothers and sisters show some significant bioactivity, but due to insufficient amounts from extraction of natural sources, no further study was possible. There's hope to change that with some synthetic effort. The synthesis starts off with a previously reported, Mn3+ catalyzed, chemo- and regioselective, formal hydration of the enone in (-)-carvone. The resultant mixture of α-hydroxy ketone diastereoisomers was then cleaved to ketoacid with periodic acid.

Activation of carboxylic acid with tosylchloride and use of 4-pyrrolidinopyridine as nucleophilic promoter enabled aldol lactonization to a bicyclic β-lactone. The high diastereocontrol is explained by a chair-like transition state, where pseudo-equatorial is the best position for the isoproprenyl substituent.

They then solve the problem of the required four carbon homologation quite elegantly, by reducing the β-lactone to the diol, converting it to the bromide, employing an intramolecular alkylation and quenching it with methyl iodide.

The original idea was to reduce the lactone, add vinyl magnesium bromide and use of a metathesis reaction to couple both olefins together. A subsequent Simmons-Smith reaction would then give them their product. But surprise, surprise their product didn’t match NMR data. A crystal structure confirmed that they’ve actually made the 5-epi-product. This is due to a magnesium alkoxide on C9 forming an 8-membered metallocycle with the C5 aldehyde, giving the undesired stereochemistry.

So, don’t use the diol? That proved to be troublesome and was only possible by finding a way around the DIBAL reduction/Grignard sequence above. The solution was the addition of an allyllithium which they had to make from transmetallation with allyltriphenyltin before adding the lactone. High yielding tandem isomerization/RCM of the diene, without any unfavoured 8-membered ring formation, afforded the enone.

After that, they regio- and stereoselectively reduced this enone to the right allylic alcohol and a Simmons-Smith cycolopropanation later they finally were holding (+)-omphadiol in their hands.

All in all, they’ve finished this total synthesis in 10 steps, 5 of which are C-C bond forming, from (R)-carvone in 18% yield. Plus, they didn’t use a single protecting group to construct the 6 adjacent stereocenters.