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.
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.