Maier and Varseev. Org. Lett., 2007, ASAP. DOI: 10.1021/ol070049a.
Although the biological profile of this zwitterionic target is sparse to say the least, it’s thought that it might have an interesting med-chem role, as the parent compound, symbioimine, has a very interesting activity. Even though it is non-toxic at 100 Î¼g levels, it inhibits differentiation of precursor osteoclast cells (RAW264) into mature osteoclasts, and also slightly inhibits COX-2. However, need I say that the architecture is very appealing? Martin Maier did..
Their synthesis hangs on one particularly effective transformation – creation of a IMDA subrate via a HWE on a conjugated aldehyde, which, after a bit of warming, does it’s thing and out-pops the transdecalin core. Nice, if perhaps not so novel.
So now I’ll take a step back, and do a retro on the HWE-IMDA substrate, which was built pretty quickly, starting with natural citronellol. Most of this is self-explanitory, but the organocatalysis/HWE was done in a pretty fashion.
So, to elaborate, the chemistry they used was taken from MacMillan’s work; Î±-hydroxylation, followed by HWE, then cleavage of the O-N bond all in one pot gave the chiral allylic-alcohol in a respectable 55% yield. Top banana.
From the IMDA-transdecalin, elaboration to the natural product looks straight-forward enough, but when I read homologation I thought we were in for a somewhat messy finish. I couldn’t have been more wrong… Reduction of the ester to an alcohol, mesylation and displacement with cyanide gave the 1-C homologation nitrile, which was methylated with nice substrate-control. Then, reduction of the nitrile and trapping onto a free ketone gave the final ring! Very tasty.