D. Kim, Park, B. Kim, H. Kim, and D. Kim. ACIEE, 2006, Early View. DOI: 10.1002/anie.200700854.
Again with the medium rings! And what a target – I’m still surprised to see that bromo-allene 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 addition into an aldehyde, setting up the stereochemistry from a chiral aldehyde. Formation of the ether then left the SM, with which they intended to form an enolate and then add 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 anion1, 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 a funky samarium annulation. Awesome!
Next came a rather tricky step – displacement of the free hydroxyl with bromide with retention of configuration! Doing this with inversion (S N2 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 bromo-allene was also nice, so I’ve thrown that in for good measure! A top synthesis of an appealing target, this is a great read.
1. To me, this is known as the “Foxy protecting group”, as the academic who taught me it’s benefits is one David Fox.