Identification of an unexpected 2-oxonia[3,3]sigmatropic rearrangement/aldol pathway in the formation of oxacyclic rings – Total synthesis of (+)-Aspergillin PZ

Identification of an unexpected 2-oxonia[3,3]sigmatropic  rearrangement/aldol pathway in the formation of oxacyclic rings – Total synthesis of (+)-Aspergillin PZ

 Stephen M. Canham, Larry E. Overman, Paul S. Tanis


Aspergillin PZ was isolated in 2002 by a Chinese group from a soil fungus and contains an interesting 12-oxatricyclo[]dodecane ring system. Its structure is very similar to that of Aspochalasin D and Cytochalasin D. Aspergillin PZ displays some potential against various cancer cell lines but due to low supply of material an evaluation of the biological profile was not possible.

The retro scheme is shown below:

An obvious disconnection is the opening of the C-ring via an intramolecular Diels-Alder reaction (IMDA). The unsaturated side chain might be installed through a Suzuki cross coupling of a vinyl iodide which arises from Takai-Utimoto olefination of the corresponding aldehyde. Disconnection of the lactam then furnishes an aldehyde which could be produced through a sigmatropic rearrangement/aldol process.

 Scheme 1

The first few steps are only described in the supporting information. Starting from methyl pyruvate the first chiral center was produced using an asymmetric allylation reaction of in situ formed allylstannane. Allylation of the free alcohol in 2 gave ester 3 which was cyclized in the presence of Grubbs I. The resulting double bond was isomerized in the same pot. I am not entirely sure why they add CuCl. Epoxidation and regioselective epoxide opening with methanol was followed by TBS protection and ester reduction to give aldehyde 5.

If anyone has references to the first allylation step I would really like to see them. There is no comment to this reaction in the paper or in the SI. A quick Reaxys® search did not provide any useful information…

 Scheme 2


Stereoselective alkynylation under Carreira’s conditions (I think it is used in every synthesis I posted the last months…) gave alcohol 6 in very good yield. TBS protection and cis selective reduction of the triple bond reproducibly furnished pyran 7 in over 85 % yield. Sigmatropic rearrangement/aldol reaction was accomplished with SnCl4 to give aldehyde 8. Unfortunately the reaction furnished the wrong diastereomer with respect to the aldehyde motif. It was not possible to identify a useful protocol to invert this stereocenter so the group went through a 7 (!) step reaction sequence.

TBDPS removal in the presence of a TBS group was done with TBAF. Pinnick oxidation of the aldehyde to the acid and esterification under standard conditions led to lactone 9. Having the internal anchor in place it was possible to get the inversion done with DBU as the base. Lactone reduction, chemoselective TBDPS protection and Ley oxidation then gave aldehyde 11 with the correct stereochemistry.

 Scheme 3


The group first planned to install the highly unsaturated side chain via some Wittig chemistry but all attempts were unsuccessful. So Takai-Utimoto olefination was chosen and followed by Suzuki cross coupling to give 13. Again TBDPS removal and Swern oxidation gave aldehyde 14 which was reacted with a lactam made from leucine and meldrum’s acid. DMP oxidation of the resulting alcohol furnished 16.

Scheme 4

What remained was the installation of the double bond which was accomplished through selenation/oxidation/elimination under standard conditions. Upon heating the IMDA proceeded to give pentacycle 18 in good yield. Debenzoylation and TBS removal gave at last Aspergillin PZ.

Scheme 5


The crucial rearrangement step is shown below:

Under Lewis acid catalysis the methanol is eliminated to give an oxocarbenium ion. A sigmatropic rearrangement then gave a silyl enol ether which undergoes an aldol reaction to give after hydrolysis aldehyde 8. The stereochemistry of this step should be a consequence of steric hindrance between the bulky protecting groups.

 Scheme 6


All in all a nice synthesis except the unproductive inversion protocol. The authors state that further studies are on the way to get the right stereochemistry in place.

And big thanx to Bobby for proofreading.

5 Responses

  1. Another beautiful write up! Regarding that allylation, it was invented some time ago by Mukaiyama (of aldol/taxol fame; see Chemistry Letters, 1996, 25, 1125), but it hasn’t been used very much. Pretty much the only other time it was applied in a synthesis was in Trost’s route to (-)-ushikulide (see J. Am. Chem. Soc., 2008, 130, 16190–16192), which is another enormous molecule made by a single coworker.

  2. Thanx a lot for the references. How did you find them? Reaxys and Co. didn’t provide any clue regarding invention or use of this method. Btw I am not sure why they used this odd method because a lot of allylation reactions are known… Maybe I add the mechanism later on.

  3. If I recall correctly, and it was a fairly long time ago now, I just searched for all reactions with the catechol-tin compound in. There were not many (only this paper, the Trost example in my last comment and the original paper)

  4. Sadly I cannot access the Chemistry Letters section… Maybe when you got the paper you can forward it to me?

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