Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Stephen Hanessian, Nicolas Boyer, Gone Jayapal Reddy, and

Benoıˆt Descheˆnes-Simard

DOI: http://dx.doi.org/10.1021/ol901896c

Another sweet paper from the Hanessian group published in August featuring a bunch of nice biological active compounds. Especially Oidiolactone B exhibits an impressive activity against interleukin-1β which could potentially be used for treatment of inflammatory diseases (http://en.wikipedia.org/wiki/Interleukin).

Only a handful of syntheses have been published yet each featuring only one target, this paper disloses the syntheses of 7 members of this class of compounds starting from one common precursor. Pretty amazing I think and very atom economic…

They planned to install the C ring at least and decorating the starting decaline core with some well established methods for example a sweet Reformatzky and Baylis-Hillmann reaction, both a bit underdeveloped in total synthesis.

Scheme 1

scheme_1_061009

So let’s get started with this:

Scheme 2

scheme_2_061009

First some protection and then a nice radical conjugate reduction under Birch conditions quenched with Mander’s reagent to give the methoxycarbonyl side chain in good yield and dr (which is unimportant because it is destroyed in the next step). Triflate formation and Stille like reduction gave them the unsatured ester which was again reduced with single electron transfer as I suppose (or maybe by facial selective hydrogen addition?), followed by alkylation and deprotection. A highly efficient IBX mediated dehydrogenation was followed by deprotection of the ester to give the blue intermediate. Didn’t know the IBX dehydrogenation method, I would have used a Saegusa type reaction but this one seems to be more practical.

With this intermediate in hand they were able to prepare the key intermediate shown above in only 5 more steps:

Scheme 3

scheme_3_061009

A highly efficient phosphine catalysed Baylis-Hillmann reaction with formaldehyde was followed by a bromolactonization to close the D ring lactone through the shown transition state. TES protection and a nice catalytic Reformatzky reaction furnished the key intermediate in an impressive overall yield of 17% over 14 steps.

The biggest problem poses the dehydration to form the exomethylen ester group. This problem was solved employing Burgess reagent to dehydrate the hydroxy function off the ring.

Scheme 4

scheme_4_061009

After having the dehydration problem solved they commenced with HF mediated deprotection/ in situ lactonisation followed by DMDO epoxidation to give Oidiolactone C.

To improve the yield they switched the order of events and got the product in a much better yield. With the epoxidated decaline in hand a mild TES deprotection by CSA, DMP oxidation and strong acid catalysed lactolisation gave then a mixture of epimers of Oidiolactone D.

This was methylated to give Oidiolactone A.

Having these three in hand only 3 more to go:

Scheme 5

scheme_5_061009

Starting with the already employed CSA mediated deprotection and DMP oxidation, followed by Burgess dehydration and acidic lactolisation to give the fourth natural product in this paper. A described access to Nagilactone F through isopropylgrignard addition gave only low yield and moderate diastereoselectivity, so they worked their way through a more commonly isopropylengrignard reaction reaction followed by a modified Wilkinson reduction to give Nagilactone F in a much better yield and diastereoselectivity. Oidiolactone B, the most potent member of this class, was easily accessible by methyl acetal formartion and separation of the desired major isomer.

Overall a nice paper which discloses a bunch of total syntheses in only 4 pages 😉

You are advised to have a look in it. I enjoyed most the smooth preparation of the key intermediate.

Any comments?

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One Response

  1. I like it man. Good job. Thank you

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