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Totally Synthetic by Paul H. Docherty, 14 May 2007

Total Synthesis of Microcladallene B


J. Park, B. Kim, H. Kim, S. Kim, D. Kim, Angew. Chem. Int. Ed. 2007, 46, 4726-4728.

DOI: 10.1002/anie.200700854

Again medium rings! And what a target - I’m still surprised to see a bromoallene in a natural product, but nature is known for her surprises… This time, however, the focus isn’t really on the eight-ring, but on the six, with a slightly tricky bromide to introduce.

The starting point for the synthesis was a Grignard reaction with an aldehyde, setting up the stereochemistry from a chiral aldehyde. Formation of the ether was followed by enolisation and then addition to the allyl aldehyde. However, they had a little difficulty choosing the correct protecting group for the alcohol in some model studies.

Some work, however, resolved that the best protecting group was an anion, and thus forming the dianion and then adding the electrophile resulted in sucess (6:1 anti/syn). With this material in hand, formation of a second ether with ethyl propiolate, and RCM completed the 8-ring, ready for an interesting samarium mediated annulation. Awesome!

Next came a rather tricky step - displacement of the free hydroxyl with bromide with retention of configuration! Doing this with inversion (SN2 style, normally using CBr4 and P(Oct)3) is a hard reaction, so this now looks like quite a challenge. However Kim, along with many others, has read the NALG work of Lepore with some interest, so they gave it a go:

Nice work! Cleavage of the silyl ether was another benefit of this procedure, leaving them only a few more transformations to complete the synthesis. However, formation of that bromoallene was also nice, so I’ve thrown that in for good measure! A top total synthesis of an appealing target - this is a great read.

Selected Comments

17 May, 2007 at 16:57, neo says:
Anybody, any ideas on how the dianion chemistry works.
17 May, 2007 at 18:39, willyoubemine says:
the more reactive anion, the second one formed, attacks the allyl iodide. thus, the alcohol is protected by the fact that is the less reactive center, as if it were a TBS ether or something.
Also, you might expect some chelation between the alkoxide and enolate giving enhanced diastereoselectivity.
17 May, 2007 at 18:46, HB says:
“neo:” The principle is simple. The most acidic labile proton (alcohol) is deprotonated first, and the least acidic labile proton (pseudo-enolate) is deprotonated second.
Since the pseudo-enolate was formed second, it is less stable than the deprotonated alcohol, and therefore more reactive - so it reacts first and consumes all the allyl iodide before the alkoxide can get to it.
It’s really kind of a misnomer to call it a “protecting group,” but I can see the logic of that as well.
17 May, 2007 at 19:29, Hap says:
How does this manage to go with retention only? The paper doesn’t really suggest a mechanism (the metal and the chelating group accelerate intramolecular delivery of the nucleophile) - since there are neopentyl substrates used, it probably doesn’t go by SN2, and SN1 doesn’t seem to make sense for these substrates. It could be using a radical anion mechanism - if the LG stays close (close ion pair), then the nucleophile will only be delivered from where the LG is and thus with retention - but I don’t know.