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Totally Synthetic by Paul H. Docherty, 28 June 2009

Total Synthesis of Himandrine


M. Movassaghi, M. Tjandra, J. Qi, J. Am. Chem. Soc. 2009, 131, 9648-9650.

DOI: 10.1021/ja903790y

Himandrine is maybe the most exciting total synthesis this year. The sequence starts with a rather nice Suzuki coupling. Taking a standard boronic acid and a vinyl-gem-dibromide, they achieved a selective E,E- product in very high yield. However, they had to use thalium carbonate; which is not a pleasent compound. Quoting directly from the supporting information: ‘Tetrakis(triphenylphosphine)palladium (1.54 g, 1.30 mmol, 8.00 mol%) and thallium carbonate (15.7 g, 33.0 mmol, 2.00 equiv) were added sequentially…’. I’m sure Movassaghi tried several sets of conditions, but would the use of a quantitative amount of Pd(PPh)3)4 maybe not be a better option?

The other, less reactive vinyl bromide was then still avaliable for a copper-mediated coupling with azetidinone developed by Buchwald. Some steps later, a tetraene intermediate was cyclised in a Diels-Alder reaction. Four stereocenters were set in excellent yield and selectivity, followed by a Mukaiyama aldol reaction to complete a third ring, and provide a nice synthetic handle.

Time to construct two more rings: Lithiation of the imine and Michael addition into the enone provided the expected imine intermediate. This tautomerised to the enamine, which added back into the ketone, providing a cyclohexanol in very high yield and efficiency. This follows a hypothesised biosynthetic route, but it’s still pretty inventive!

As can be seen from the tightly caged structure, they had a few more ring junctions to form. Even though they have only got one protecting group in place, the selectivity was remarkable. Addition of Vilsmeier reagent allowed an enolate-type addition into the chloroimine to form a highly activated imine intermediate. The free but highly hindered tertiary alcohol was then able to add into the imine, while dimethyl amine left to give a dihydrofuran (DHF).

This DHF was opened with DDQ to form a hydroxyl group and an aldehyde, which was immediately oxidised to the free acid and then methylated with diazomethane. Removal of the sole protecting group then had them ready for yet another impressive cyclisation. Treatment of the cyclohexenone with NCS promoted addition of the freed piperidine into the ring, and completion of the carbon skeleton.

I do not present details for the mechanism of that transformation, as Movassaghi did quite a bit of work on it. Read the paper instead. Really, one of the best paper so far this year!