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…


Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Joseph D.Panarese and Stephen P.Waters (this review)
DOI: http://dx.doi.org/10.1021/ol902154p

Tomohiro Nagasawa and Shigefumi Kuwahara (last 3 steps)
DOI: http://dx.doi.org/10.1021/ol802803x

Today I will present to you a short formal synthesis of Aspergillide C which makes use of a nice hetero DA followed by a Ferrier-type addition. The last 3 steps were taken from a synthesis published 9 months earlier. You should have a look in it.

I know there’s no KCN-like “never-used-before-in-total-synthesis”-chemistry in it but I were taken with how they accomplished this synthesis in only 9 steps as the longest linear sequence. Efficient and short as expected from a OL paper.

Let’s have a look at the retro:

Scheme 1


(I really like these paper with the retro already in it :))

As you can see they started with commercially available starting materials employing a DA, Ferrier alkylation and Pd(II)-catalysed lactonization. After installation of the side chain via Julia-Kocienski and macrolactonization they furnished Aspergillide C as described in the earlier synthesis from Nagasawa and Kuwahara.

Ok, before I forget it: the biological activity is again really interesting as Aspergillide C displays cytotoxicity against mouse lymphocytic leukaemia cells with a LD50 of 2µg/ml (don’t know why they did not use the IC50 value because as far as I know this is more significant…).

Scheme 2

Starting as mentioned above with a hetero DA catalysed by zinc chloride gave the desired γ-pyrone which was stereoselectively reduced under Luche conditions and acetylated. A lithium perchlorate mediated Ferrier-type alkylation followed by Pinnick oxidation furnished the carboxylic acid which was cyclised to the lactone by a Wacker-type oxidation (take a look at the double bond which moves around the ring; nice). Now we have our red fragment in hand.

The mechanism of the Ferrier-type alkylation might look like this:

Scheme 3


Lithium mediated vinylogue elimination of the acetate followed by anti selective addition of the TBS enol ether yields the product shown.

Next the preparation of the Julia fragment:

Scheme 4


They started with the commercially available hexenol which was protected, hydroborated and oxidised to the satured alcohol shown. Thioether formation under Mitsunobu conditions followed by ammonium heptamolybdate oxidation gave the green fragment in high yield.

The 2 fragments were combined after deprotection and diol cleavage of the red fragment under modified Julia-Kocienski conditions (normally it makes use of KHMDS).

Scheme 5


The rest of the synthesis was taken from the earlier published paper.

Hydrolysis, TBS protection and PMB ether cleavage yields the free acid which was cyclised under Yamaguchi conditions. A bit of TBAF then furnished the desired product in good overall yield.

Scheme 6


As mentioned earlier a very short and efficient synthesis again (17% yield over the longest linear sequence starting from protected glyceraldehyde) but hey, it serves the purpose.

I hope you enjoy reading this review though it is a bit shortspoken.

Ok, and next time I will feature a paper with this KCN-like chemistry, promised 🙂