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Totally Synthetic by Paul H. Docherty, 18 June 2009

Total Synthesis of Haouamine A


N. Z. Burns, I. N. Krylova, R. N. Hannoush, P. S. Baran, J. Am. Chem. Soc. 2009, 131, 9172-9173.

DOI: 10.1021/ja903745s

We covered Weinreb’s synthesis of haouamine back in 2006, but many papers have been published since then. The molecule exhibits an unusual isomerism, which maybe helps to explain the interest. Baran realised after his initial work that there were two isomers of the target, configurationally identical, and sharing the same stereochemistry about the 6,5-ring junction. This meant that the stereochemical divergence must be unusual - with two candidates - atropisomerism of the bent phenol or slow pyramidal inversion at the tetrahydropyran nitrogen. The only way to probe this effectively was to attempt a synthesis of the two atropisomers, and compare with the isolate.

The synthesis, yet again, is racemic, and proceeds from an intermediate in their first synthesis. As we didn’t cover that paper, I try to make the route to this intermediate more transparent: The starting material was produced very quickly, using a standard enolisation and trapping with an alkylating agent to generate the quaternary center. The ketone was then transformed into an oxime, and treated with a source of electrophilic bromine, causing a 5-exo-trig cyclisation and formation of a nitrone. Reduction of the nitrone produced the intermediate shown, which after heating gave an aziridine. Rearrangement caused ring expansion to give a tetrahydropyridine-N-oxide, that was reduced with indium. Some very interesting synthetic steps!

A Suzuki coupling followed by an Appel reaction allowed completion of the macrocyclisation precursor, which was after deprotection treated with base to prompt alkylative cyclisation in a pretty decent yield. Interestingly, a stereochemical bias was found where none would be expect.

The key reaction was the oxidation of this cyclohexenone to a fully aromatic system - a reaction with a wealth of possible reagents. However, some of the more obvious choices, such as manganese dioxide or palladium prove ineffective, so they used a protocol published by Mukaiyama. Initially developed to introduce α,β-unsaturation to ketones, this one-pot procedure oxidised the chiral cyclohexenone to a planar chiral phenol, returning a respectable mass balance.

A few more steps were required to complete the targets, for which also enantiomerically pure starting material was used (maybe they performed chiral HPLC). This gave them both atropisomers, a few crystal structures, and an opportunity to biologically profile both.