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Totally Synthetic by Paul H. Docherty, 18 June 2008

Total Synthesis of Germanicol


K. Surendra, E. J. Corey, J. Am. Chem. Soc. 2008, 130, 8865-8869.

DOI: 10.1021/ja802730a

Germanicol is actually classed as a ‘pentacyclic triterpenoid’ according to Corey, but it’s still an old-school stereoid target. The synthesis is formal - what we’re targeting here is an intermediate in Johnson and Irelands synthesis way back in ’70. That synthesis is definitely a tour de force, but somewhat lacking in efficiency with 32 steps. Corey reckons that a biomimetic approach, constructing the ring systems like a zip, might be a bit quicker.

The diene starting material can be made easily from farnesyl acetate, using a Corey-Zhang oxidation. 2-Propenyllithium added as expected to the carbonyl, which was followed by a Brook rearrangement to give the corresponding allylic anion which trapped the aryl bromide to give the product. An interesting chain of reactions.

Next up was the key biomimetic cationic cyclisation, promoted by a Lewis acid. This lead to formation of the pseudo A, B and C rings, but they needed two more steps to complete the manoeuvre: protection of the free hydroxyl group and use of acid to complete the final ring. This apparently hydrolysed the freshly installed TBS group too…

Another approach was also developed, using a similar substrate and key step. However, the order in which the rings are formed has been turned over, with the ‘D-ring’ first.

This time, though, the Lewis acid (LA) didn’t work quite as selectively, and they got two products out of the reaction. Unfortunately, more LA didn’t convert between these species, meaning that their origins must be divergent. Corey ascertained that the common parent to both structures is the cation shown below. In the expected pathway, we get addition of the proximal double bond to the cation, forming a new ring and a benzylic cation (nice and stable). However, a different pathway can result in benzylic stabilisation - a [1,5] proton shift. The group proved this by making the deuterated substrate shown and followed the deuterium on its way. If you’re surprised to see this, you’re not the only one; Corey guardedly states that this might be the first example of this rearrangement. Also interesting was the fact that there is no control over the formation of that stereocenter - so the mechanism proceeds on either face of the dihydronaphthalene.

Very interesting work. The synthesis is efficient (relying on the recursive use of similar reactions to build the substrates) and impressive - as is their dissection of the mechanisms. But this is not my favourite Corey total synthesis - that honour goes to his work on the prostaglandins, to which I have a strong personal affinity. I’m also amazed by his Ecteinascidin 743 and Ginkgolide B syntheses.