Enantioselective Total Synthesis of (+)-Conicol via Cascade Three-Component Organocatalysis

Enantioselective Total Synthesis of (+)-Conicol via Cascade

Three-Component Organocatalysis

Bor-Cherng Hong, Prakash Kotame, Chih-Wei Tsai, and Ju-Hsiou Liao

DOI: http://dx.doi.org/10.1021/ol902840x

This time some organocatalysis already published last year by a group based in Taiwan. Though not a spectacular paper I liked the first few steps and so reviewed it.

Conicol belongs to the class of meroterpenoids which were isolated from higher plants and recently from marine organisms. And as usually with these marine stuff it exhibits some cytotoxic effects against human cancer cells .

The key steps of the synthesis are a TMS-prolinol catalyzed enantioselective alkylation/Michael addition reaction followed by another Michael addition/aldol condensation to build the backbone of the whole molecule in almost 2 steps.

Additionally these two single pot sequences can be combined to one protocol giving the product in 55% yield with > 99% ee.

Scheme 1:

Scheme 2:

As mentioned above these sequences were combined to one very successful procedure. If you’re interested in the whole story have a look in here: http://dx.doi.org/10.1016/j.tetlet.2008.11.106

With all stereocenters and the carbon skeleton in hand only a few modifications were needed to give (+)-Conicol:

Scheme 3:

A decarbonylation reaction with Wilkinson catalyst was followed by double bond reduction with palladium on charcoal. Interestingly the nitro function is stable under these conditions.

Next the dimethylacetal was cleaved with hydrochloric acid, which results in elimination of the nitro function too, and an old school Wolff Kishner reduction gave Didehydroconicol.

Going on from the key intermediate the acetal was cleaved under milder conditions without causing elimination of the nitro function. This was done with DABCO, the aldehyde reduced, acetylated and eliminated under Birch conditions to give (+)-Conicol in 5% overall yield over 9 steps in the longest linear sequence.

Scheme 4:

I didn’t manage to publish this in january, sorry for that, but I’m just on the next paper so maybe I finish 3 reviews in February to keep my average of 2 reviews per month.

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