Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B

Temporary Restraints To Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B

John C. Jewett and Viresh H. Rawal

DOI: http://dx.doi.org/10.1002/anie.201003361

Further read: DOI: http://dx.doi.org/10.1002/anie.200701677

and                 DOI: http://dx.doi.org/10.1021/ja050728l

Sorry for the long delay but now I am back into business. This time with a nice synthesis from Rawal et al. who already synthesized this sweety but only in a racemic fashion. Obviously they accomplished the stereoselective synthesis in the last few months by applying an interesting methodology which made it possible to retain the stereochemistry at the carbon center marked with a little star.

Scheme 1

By virtually cutting the molecule into two halves one gets the known natural product pederic acid and the so called mycalamine. Rawal et al. already published a total synthesis of pederic acid which I will refer to later. Mycalamine is not natural product by itself but named after the parent compound.

For the biologists out there: mycalamide B displays some antiproliferative activities against various cancer cell lines which make it an interesting target for many working groups.

I will start this brief review with the synthesis of pederic acid which was published some years ago. It starts with an esterification of the known alcohol shown and protected glyceric acid in the presence of EDC/DMAP. Petasis methylenation then furnished the required exo-methylene group ready for a nice Wacker-type cyclization which closes the THP-ring. The benzylidene protection group was removed under Birch conditions, the more acidic primary alcohol protected as a TES-ether and the remaining one as a benzoylester. PDC oxidation furnished the benzoylpederic acid which was transformed into the acid chloride under standard conditions in quantitative yield.

Scheme 2

Next the second half of the molecule, mycalamine, has to be synthesized. They started with a copper mediated epoxide ring opening, TIPS protection of the free alcohol and oxidative cleavage of the methylene group to the aldehyde. A stereoselective Diels-Alder reaction under Yamamoto’s conditions was done by employing MAD as the catalyst which was prepared in situ from AlMe3 and the corresponding alcohol. During work-up the TIPS was cleaved off and the alcohol methylated. Then my favourite reaction took place:

A Mukaiyama/Michael reaction of the silylketene acetal with the unsaturated ketone in the presence of TBSOTf gave a TBS protected enol which was directly epoxidized with mCPBA (Rubottom oxidation). The MOM group was cleaved, the epoxide opened and both connected in a 1,3-dioxane ring.

Scheme 3

The coupling partner of the above mentioned Diels-Alder reaction is available in two steps from methyl formate and iso-pentanone as showed below.

Scheme 4

Next the ketone was reduced by employing the very old-school Meerwein-Ponndorf-Verley reduction. Other reduction systems gave mainly the alcohol with the wrong stereochemistry. The alcohol was methylated in methyliodide in the presence of silver oxide.

Scheme 5

Debenzylation, saponification and subsequent Curtius rearrangement gave the cyclic carbamate by trapping of the intermediary isocyanate with the free alcohol. And this cyclic carbamate gave the group the opportunity to couple both halves without racemization of the stereocenter marked. The carbamate was deprotonated and reacted with pederic acid chloride to give after selective debenzoylation and carbamtate cleavage mycalamide b in 14 steps in the longest linear sequence and with 3% overall yield.

Dude, what a nice synthesis… And if I counted right 11 named reactions were used… So if you have any questions or suggestions feel free to ask. THX for reading my stuff…


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