A General Approach to the Basiliolide/Transtaganolide Natural Products: Total Syntheses of Basiliolide B, epi-8-Basiliolide B, Transtaganolide C, and Transtaganolide D

A General Approach to the Basiliolide/Transtaganolide Natural Products: Total Syntheses of Basiliolide B, epi-8-Basiliolide B, Transtaganolide C, and Transtaganolide D

Hosea M. Nelson, Kei Murakami, Scott C. Virgil, and Brian M. Stoltz

DOI: http://dx.doi.org/10.1002/anie.201008003

This time a rather short synthesis but with some cool chemistry in it. As can be seen from the papers cited by the Stoltz group, a lot of working groups are currently working on this subject. The main problem of all approaches is the endgame of the synthesis and not the impressive IMDA reaction utilized by most groups to build the core structure.

So here is the subject:

 Scheme 1

 

Because all stereocenters came from one step which is done without any chiral control, the synthesis yields an epimeric mixture of the natural product.

The paper only cites the synthesis of the first fragment so I added it for the sake of completeness.

The synthesis of the green fragment starts from commercially available geranyl acetate. This was oxidized to the ester through a sequence of allylic oxidation and manganese dioxide mediated two step oxidation to give ester 3. Removal of the acetate then yields alcohol 4.

Scheme 2

 

The blue fragment was synthesized from methyl propiolate which was iodinated under acid catalysis to give selectively the Z-product. This was exposed to standard Sonogashira conditions and coupled with butynol to give 7. Lactonization with iodine monochloride and subsequent oxidation furnished crude acid 9 which was used without further purification.

 Scheme 3

 

To test in principle the crucial Claisen/IMDA step, the blue fragment was coupled with geraniol 10 under standard conditions and exposed to well known conditions to form first the enol ester and rearrange this to tricyclic compound 12. Although the yield is pretty good, the reaction took 18 (!) days to reach completeness. Nevertheless Sonogashira coupling under standard conditions after protection of the ester furnished Transganolide C and D in moderate yield.

 Scheme 4

For the preparation of the Basiliolides the synthesis was optimized. First both fragments were coupled in the presence of DCC which set the stage for the Claisen/IMDA reaction as before. By adding two equivalents of BTSA and a catalytic amount of TEA to a solution of 10, tricyclic compound 11 forms in excellent yield and high diastereomeric purity in only 2 (!) days . TBS protection of the acid proved crucial for the final step. Stille coupling with the ethinyl stannane shown produced directly an epimeric mixture of Basiliolide B albeit in low yield.

 Scheme 5

 

So at last here is the cool Claisen/IMDA-reaction step. First BTSA forms the TMS enol ester which undergoes a Claisen-Ireland rearrangement. Now with all double bonds in the right place Diels-Alder reaction forms the remaining two bonds to give the core structure of Basiliolide B.

 Scheme 6

 

I am very busy these days but hopefully I get a second review done this month. THX for reading my stuff.

And THX to Bobby for proofreading in advance.
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