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…


A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

Fa´tima Churruca, Manolis Fousteris, Yuichi Ishikawa, Margarete von Wantoch Rekowski, Candide Hounsou, Thomas Surrey, and Athanassios Giannis

DOI: http://dx.doi.org/10.1021/ol100579w

As the title suggests it’s time for some sunlight chemistry… Ok only one step but the rest of the synthesis is also worth reading. The Terpendoles are a family of indoleterpenes which show weak activity as acyl-CoA:cholesterol acyltransferase inhibitors. Recently it was discovered that the terpendoles inhibit the kinesin spindle protein (KSP).

In this paper the synthesis of one member of this class is described. The retro is rather short as the paper is, too. We’re starting with some FGI and cut the molecule into two halves by using the above mentioned Nazarov cyclization strategy. As can easily be seen, the molecule should be accessible directly from the known Wieland-Miescher-ketone.


So here we go:

The scheme starts with a selective protection of the unconjugated carbonyl. Phenylthiomethylation (search for Kirk-Petrow-reaction for further information) which was followed by a SET reduction under Birch conditions and subsequent trapping of the anion with allylbromide then yields the allylated/methylated ketone. LAH reduction of the remaining ketone, boronation of the terminal olefin and oxidation results in lactone formation. Oxidation of the ketone lactone to an α-β-unsatured one was achieved under more or less unconventional conditions. Epoxidation with H2O2, epoxide opening with phenylselenide and protection of the resulting alcohol as the MOM ether closes the first scheme.

Scheme 1

Because the phenylthiomethylation looks a bit odd, here is the mechanism:

Mechanism 1

The first few steps should be clear. The Birch reduction step might involve an intermediate radical anion which is trapped by allylbromide and reprotonated under thermodynamic control.

Furthermore the dehydration dehydrogenation step with this to me unknown reagent:

Mechanism 2

This is only a proposal of what I think the mechanism might be… I’m open for better ideas or corrections.

With the blue intermediate in hand we can move on. Selective reduction of the lactone was achieved with DIBAL-H and the aldehyde olefinated. Epoxidation of the alkene with mCPBA was followed by Sc(III) mediated pyran formation, oxidation and epimerization of the isomeric ethers to give one single pyran ring. Grignard reaction with methylmagnesium chloride, PG interconversion and acetal cleavage sets the stage for the final few steps.

Scheme 2

The first step involves an aldol condensation/hydrogenation to link both halves of the molecule together. Methylation of the ketone, benzylic oxidation with DDQ, dehydration of the tertiary alcohol with Burgess reagent to the exocyclic alkene and isomerization of the latter one to the endocyclic alkene prepares the key intermediate for the Nazarov cyclization. This [2+2] cyclization was mediated by UV light and closes the ring in a disrotatory manner.

Scheme 3

Protecting group removal and complete reduction of the ketone then yields Terpendole E.

Scheme 4

Overall a nice synthesis but I would have preferred a bit more details in the paper. The authors only give the used reagents without any more information like conditions or eq’s. Nevertheless nice chemistry but there’s a little mistake in the published paper. Maybe you find it too…

Any comments?

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


So let’s get started with this:

Scheme 2


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


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


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


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?