Bach and Selig. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800693.
Another Overman target? I should think so; he completed back in ’89. But that doesn’t stop us mere mortals for following in his footsteps. Indeed, Bach seems to be snapping at them with this 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 challange’…
Bach kicks of with an astonishing pair of reactions to build the syn-6,5-fused ring system. First up is regio- and enatiomerically controlled [2+2] addition, using the somewhat strange ‘chiral complexing agent’ to engender asymmetry. It doesn’t come as any surprise that the group has been playing with this bad-boy for some time – and even though they have to use in quite an excess, the result is impressive, generating that cyclobutane in excellent yield. However, I don’t see a quoted e.e. – am I blind?!
The group initially planned to use a Wagnerâ€“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.
Three rings in, the next followed easily, requiring only deprotection of the amine and reductive amination to complete the second cyclopentane. They then used an interesting approach to provide the quaternary centre – a Johnson-Claisen rearrangement. This is a reaction with which I have some experience, and even though it required a fair-old roasting (normally 140 C, 10-18h), I’ve always managed fantastic yields (though I always used propionic acid rather than hydroquinone). The best thing (in my opinion) is the w/o – vac it down, and either do the next reaction or dump it directly onto the column. Nice.
Better still, 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 RCM; only a few functional group transformations were then required to complete the target. Cracking strategy and implementation (and they even admit that the limiting step is the quantity of chiral complexing agent required early in the synthesis).
Selig, P., Bach, T. (2008). Enantioselective Total Synthesis of theMelodinus Alkaloid (+)-Meloscine. Angewandte Chemie International Edition DOI: 10.1002/anie.200800693