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Totally Synthetic by Paul H. Docherty, 5 April 2007

Total Synthesis of Neosymbioimine


G. N. Varseev, M. E. Maier, Org. Lett. 2007, 9, 1461-1464.

DOI: 10.1021/ol070049a

Although the biological profile of this zwitterionic target is sparse, it might have an interesting role in medicinal chemistry, as the parent compound, symbioimine, has a very interesting activity. Even though it is non-toxic at 100 µg 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 substrate for an intramolecular Diels-Alder reaction (IMDA) via a HWE of a conjugated aldehyde, which, after a bit of warming, generates the transdecalin core. Nice, if perhaps not so novel.

So now I’ll take a step back, and do a retroanalysis on the HWE-IMDA substrate, which was built pretty quickly, starting with natural citronellol. Most of this is self-explanatory, but the organocatalysis/HWE was done in a pretty fashion.

So, to elaborate, the chemistry they used was taken from MacMillan’s work; 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. A very interesting step!

From the IMDA derived transdecalin, elaboration to the natural product looks straightforward. 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 interesting!