Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Allen Y. Hong, Michael R. Krout, Thomas Jensen, Nathan B. Bennett, Andrew M. Harned, and Brian M. Stoltz

DOI: http://dx.doi.org/10.1002/anie.201007814

Recently a very cool methodology was published developed by the Stoltz group for the synthesis of acylcyclopentenes . As given in the paper a lot of natural products are related to this motif so there is a need for an easy and rapid access.

Scheme 1

As can be seen from the structures given these natural products mainly derive from the MVP-pathway. Nevertheless this method should also prove useful in the synthesis of alkaloids or polyketides.

Before I present to you the main part of the paper have a brief look at the synthesis of the main precursor:

Scheme 2

Cyclopentanone 1 was enolized, protected as the TMS ether, and reacted with in situ generated dichloroketene to give cyclobutanone 3. Reductive dechlorination and Grob fragmentation/ether formation produced ketone 5 in good yield on a multigram scale.

This was then decorated with different organic residues in two steps to give ketoester 6 in moderate to good yield. Pd-catalyzed enantioselective decarboxylation/allylation was followed by reduction of the keto group to give 8. Depending on the residues three different reducing conditions are described. At last the critical contraction reaction from 8 to 9 was carried out with LiOH in THF in the presence of TFE in excellent yield.

Scheme 3

A lot of residues are described; I only added just a few to give a brief insight. For detailed information have a look in the more than 250 (!) pages thick supporting information.

The mechanism of the contraction step might look like this: the green proton leaves first and kicks out the red hydroxy group to produce directly the cyclobutanone-intermediate. This opens up with extrusion of the acetyl group to give after reprotonation and tautomerization the expected product.

If you think about the second possibility of first removing the blue proton followed by a Michael-type self-addition of the enolate, generated from deprotonation of the ketone, then you are missing the Baldwin rules (as I did at first sight).

Scheme 4

One of the many special examples which I picked out from the supporting information is the synthesis of the Hamigeran C core structure. Starting from cyclopentene 9 the terminal olefin was elongated with iodophenol in a Heck reaction to give 10. Chemoselective reduction of the styrene double bond and triflate formation was followed by another Heck reaction employing Herrmann’s catalyst to give tricyclic compound 13. First time I have seen Herrmann’s catalyst, funny German name.

Scheme 5

Nice methodology as usual from the Stoltz group. Any comments?

And special thanks to Bobby for proofreading my post in advance!


3 Responses

  1. the reaction mechanism for the 7-membered ring contraction is likely to be ring-opening retro aldol followed by ring closing aldol and dehydratation.

    Hermann catalyst is quite famous in the field of Heck reaction, you can make it simply by heating Pd(OAc)2 with P(o-Tol)3 in benzene. Also Aldrich and Strem sell it, and it is perfectly bench stable.. Hermann was the first chemist to describe usefulness of a palladacycle in Heck and he also has shown that the catalyst loading could be quite small, at the level of ppm. Palladacycles fall apart upon heating irreversibly and leak under-ligated Pd nanoparticle species that are the actual catalysts. (These nanoparticle Pd species die as Pd black, and this aggregation is depencent on the catalyst concentration, so sometimes adding less palladacycle catalyst produces better results…)

  2. hey, thx for the hint: think you’re right with the retro-aldol/aldol step. added it 😉
    btw.: do you think the alternative is completely incorrect? i’m not that sure because it represents essentially the reverse reaction compared to the synthesis of the seven-membered core. It’s maybe some sort of Favorskii rearrangement…

    to the Pd-cat.: I did not run so much Heck reactions so far and I never saw this cat in action before. Maybe one day I have to use it…
    To the Pd-nanoparticles: I ran a lot of Suzuki’s with a mixture of Pd(OAc)2 and MeONa which produces in situ Pd-nanoparticles which areextremely effective in cross coupling reactions.

  3. the ring contraction is just a tandem retro aldol-aldol reaction…..the second alternative is not possible…..an intramolecular Michael addition to produce a [2,0,3] bicycle is energetically unfavorable…by the way I can´t see any Favorskii rearrangement…..or pseudo-Favorskii rearrangement…..nice method: ring-expansions and ring-contractions

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