Totally Synthetic by Paul H. Docherty, 2 June 2008
Total Synthesis of Meloscine
P. Selig, T. Bach, Angew. Chem. Int. Ed. 2008, 47, 5082-5084.
Overman completed Meloscine back in ’89. However, Bach uses a smart and original approach to this tightly functionalised natural product. There’s no mention of any biological activity in the paper, so let’s get on with the ‘synthetic challenge’…
The total synthesis starts with an astonishing pair of reactions to build the syn-6,5-fused ring system. A regio- and enatiomerically controlled [2+2] addition in the presence of a chiral complexing agent generates a chiral cyclobutane in excellent yield. The group has been playing with this reaction for some time - and even though they have to use the chiral addivitive in an excess, the result is impressive.
The group initially planned to use a Wagner-Meerwein rearrangement to provide the desired cyclopentenone, but this failed. However, a ‘retro-benzilic ester rearrangement’ did the business in fantastic efficiency, giving them the desired product.
The second cyclopentane required only deprotection of the amine and reductive amination to complete. They then used an interesting approach to provide the quaternary centre - a Johnson-Claisen rearrangement.
Even better, they were able to gain some diastereomeric control, providing that key stereocenter in a decent yield. The final ring was then installed by alkylation of the freed amine with allyl bromide and ring-closing metathesis; only a few functional group transformations were then required to complete the target. A very interesting strategy and implementation (and they even admit that the limiting step is the quantity of chiral complexing agent required early in the synthesis).