Guanacastepenes A and E
Sorensen and Shipe. JACS, 2006, ASAP, DOI: 10.1021/ja060847g
Furthering their interest in the synthesis of the Guanacastepenes, Sorensen et al have completed the synthesis of members A and D using an interesting fragmentation strategy. However, before this late-stage event, the A and C rings were constructed and united using a Stille cross-coupling. The required cyclobutane was then implaced via a photo-[2+2] cycloaddition:
With this in place, the cyclobutane was fragmented selectively to provide the seven-member ring, trapping with PhSeBr to facilitate elimination in the next step. A very reasonable explanation for this selectivity is explained in detail in the paper.
This left the core of the guanacastepene series, from which a few simple steps returned guanacastepene A. However, a slight flaw in the synthesis concerns the resolution of an advanced fragment, taken from a racemic model study.
(No Ratings Yet)
Loading ...
Looking at the TLC solvent system they developed, I think it is quite clear why resolution is not tried more often. That’s a lot of leg work!
Where do you suppose the facial selectivity from the 2+2 reaction came from? Seems to me, it would be geometrically predisposed to the top face — i mean, in the end, SOMETHING is going to be bumping into that isopropyl group, right?
These [2+2] photocycloadditions are pretty interesting reactions, in that you can obtain two regioisomers depending on how the olefins line up. In this case, the [3.1.1]bicycloheptane regioisomer is not observed, presumambly because of geometric strain in the requisite transition state. The desired [3.2.0]bicycloheptane is obtained instead.
Facial selectivity at the alpha-olefin is controlled by the allylic methyl group, which should be in a pseudoaxial position in the the transition state. This effectively blocks the bottom face of the alpha-olefin as drawn.
Selectivity at the enone is controlled by the isopropyl group. The isopropyl group should exist in a pseudoaxial position, so as to alleviate 1,2-allylic strain in the cyclopentenone. This effectively blocks the top face of the enone as drawn.
Not the same system, but it’s worth checking out Marc Snapper’s paper on [2+2]‘s in JACS ASAP’s this week.
I happen to know quite a bit about this synthesis. In a model system lacking only the isopropyl group, we observed exclusive diastereofacial selectivity in the [2+2] photocycloaddition. This suggested to me that the selectivity, while perhaps reinforced by the presence of the isopropyl group, was largely dictated by the configuration at the quaternary center. If you build a molecular model of the system, you’ll clearly see that only the desired approach of the olefin to the enone is possible. The angular methyl group has a prohibitive steric interaction with the vinyl methyl group in the undesired approach.
As for the resolution of mandelic esters…yes, it was a lot of leg work. I recall trying over 20 solvent systems before I found the toluene/DCM/ether system that finally resolved the two diastereomers. If I had had more time, there were plans to attempt to carry out an enantioselective Diels-Alder cycloaddition early in the synthesis of the C-ring fragment (2nd step of the whole synthesis). The few things I tried early on failed.
I was quite pleased with our solution to the absolute stereochemistry of the A-ring, however. The idea to ring-contract carvone arose from a Kraus paper (Tet Lett 2000 21-24) I encountered when exploring a route unrelated to the Stille/[2+2]/fragmentation one. If I can find the time in my present position, I plan to follow up on the alpha-acyloxynitrile => 1,2-diketone transformation in a methodology paper.
we should start blogging about big moves, I was surprized to see that Hartwig moves from yale to urbana, McMillan from caltech to princeton. Any other big moves? Anyone is moving from harvard to UCLA?
It’s UKian, but P Andrew Evans is off to Liverpool, and in Germany, Glorious is going to Dortmund (AFAIK).
thanks for the helpful info., Bill.
BTW, alpha-acyloxynitrile from alpha-ketoaldehyde might give 1,2,3-triketones?
marc snapper’s paper (good read, interesting stuff) kinda reminds me of this paper from Germany.
“Catalytic enantioselective reactions driven by photoinduced electron transfer”
nature 436 (2005), 1139.
Editor – the DOI is 10.1038/nature03955
Hey, Bill: Nice paper — I’ll bet you’re very proud.
What made you choose a mandelic ester? I’m not very familiar with resolutions, so maybe this is common?
well, we got Bill Roush to come with his group overe here to Florida but that is pretty old news. Is there any explanation about McMillan? I worked with him briefly when he was a postdoc in Evans group and I liked the guy a lot. Did they annoy him at Caltech?
everyone seems to leave caltech eventually: evans, myers, mcmillan, carreira…may be b/c it is small, inland and has no night life etc…? I do not know, never been there.
Klug, thanks–I’m very happy that the complete story is out there.
Mandelic esters are commonly chosen for this sort of resolution. There was good literature precedent. I can post a reference or two when I have access to that information. For now, I’m just glad it’s Friday!
MacMillan has personal reasons to move to the east. I spoke to him in the uk last year, and i’m not suprised he’s moved. In other news, Steve Clark has left Nottingham. Coupled with Pattenden’s retirement, they’re looking a little short.
That’d be great!
what was the story in pattenden’s synthesis of phorboxazole in angewandte? he just had ONE person as a coauthor. How long did it take him? Like 5 years to make the molecule?;)
In the move news category, Dave Gin is moving from Urbana to Sloan Kettering.
Klug,
With regard to the resolution of mandelic esters, I offer the following two references:
Whitesell, et al. JOC 1983 v48 p3548-3551
Breitholle, et al. JOC 1974 v39 p1311-1312
The second actually deals with O-acetyl mandelic esters, which happened to work better for me on my system.
Sweet. Thanks, dude.
[...] I seemed to miss this one somewhere, probably in the move from my placement back to Cambridge. Anyway, this is a really nice synthesis of the popular guanacastapene targets (see this smart synthesis by Sorensen), using a unusual and funky Heck cyclisation. This reaction forms the main unifying transformation of the separate fragments, along with a 1,4 organocuparate addition. On with the synthesis! [...]