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Totally Synthetic by Paul H. Docherty, 20 March 2007

Total Synthesis of GB13 and Himgaline


D. A. Evans, D. J. Adams, J. Am. Chem. Soc. 2007, 129, 1048-1049.

DOI: 10.1021/ja0684996

This brilliant synthesis by Evans it’s a fantastic piece of work on a molecule we have featured a few months back, published by Samuel Chackalamannil at the Schering-Plough Research Institute. As mentioned in the paper, the bark from which this target was isolated has been used by native tribes of Papua New Guinea as a medical treatment, and related compounds have shown potent muscarinic antagonist activity. Evans approach to the molecule is quite diverse. However, the complex architecture of the molecule make a simple retroanalysis rather difficult, so on with the forward synthesis!

The complexity of the polycyclic system was built-up very quickly, using an auxiliary-biased intramolecular Diels-Alder reaction to generate the trans-decalin as a single isomer in great yield. A substrate-controlled dihydroxylation and protection created the material required for the next step, an HWE reaction to append the sidechain, which had to be reduced in the next step to the allylic alcohol to prevent intramolecular cycloaddition.

Reoxidation then allowed them to perform a Roskamp reaction to install the β-ketoester necessary to complete that ring, but they found the reaction went further, doing a conjugate addition to provide the enol ester instead. No matter - the Michael addition with allyldiazoacetate went swimmingly, and the conjugate addition reversed under basic conditions.

The next cyclisation was more simple; deprotection of the amine, dehydration, and treatment with AcOH, caused addition to give the aldol product, isolated as its iminium ion. An interesting discussion about the geometry required of the transdecalin is in the paper, and makes for a good read.

Relatively straight-forward transformations then created GB13, a known precursor to Himgaline, which was efficiently transformed to the target molecule using triacetoxyborohydride.