Totally Synthetic by Paul H. Docherty, 6 July 2009
Total Synthesis of Haplophytine
H. Ueda, H. Satoh, K. Matsumoto, K. Sugimoto, T. Fukuyama, H. Tokuyama, Angew. Chem. Int. Ed. 2009, 48, 7600-7603.
After many unsuccessful attempts [Corey, Padwa, Nicolaou], the total Synthesis of Haplophytine is finally accomplished. The basic strategy was simple: split the molecule in two fragments about the obvious single bond. As one part is aspidophytine, that has recently been covered, let's start with the other fragment, a bicyclo[3.3.1]skeleton that includes bridged ketone and aminal functionalities. Perhaps the most difficult feature - a chiral quaternary center - was completed at the start of the synthesis of the carbon skeleton. The method was published in a paper in Tet. Lett. by d’Angelo, using a chiral amine to form an imine intermediate of that ketone. Then, conjugate addition to an acrylate allowed highly enantioselective C-C bond formation in good yield. Of course, quantitative amounts of chiral amine were required, but it’s relatively inexpensive, and easy to recover after hydrolysis.
It was quite a few steps to the next scheme - an enolisation and ozonolysis of the resulting cyclopentene allowed opening of the 5-membered ring, whilst the thioester was easily alkylated with a pendant amine. This allowed construction of an eleven-membered cyclic-amine macrocycle, which served as starting material to form three smaller rings via a highly diastereoselective Mannich reaction, and using a method developed by Overman. [As a brief aid: the acid removes the ketal. Then the thiophenol removed the nosyl protecting group, so the molecule was ready for Mannich reaction under acidic conditions . The ethyl ester was removed in the course of these reactions, so TMS-diazomethane was used for the re-esterification.
Moving next to the other half of the target, a relatively simple indole was elaborated to a dihydro-β-carboline using efficient hemistry. A Noyori asymmetric reduction was used to reduce the carboline across the imine, providing asymmetry in high e.e. Addition of NIS to this system caused iodination at the indole C-3 postion, and indolenine formation. Treatment of this with silver triflate caused a Friedel-Crafts alkylation, generating the highly congested quaternary center in a dr of 2.4:1. Note the use of a mesyl group as a phenol protecting group!
A few steps on, mCPBA epoxidises the activated bis-enamine moiety, allowing rearrangement of the 5,6,6-system into the desired bicyclo[3.3.1] ring system, as expected. I’ve shown the product in two representations - one similar to it’s direct precursor in the mechanism, and the other that is used by the authors.
For the coupling of the two fragments, a rather complex and impressive Fischer Indole Synthesis was used. So the last scheme shows a rather late-stage lactonisation, done in a rather interesting way: basic hydrolysis of the ester and then lactone formation using potassium ferricyanide. This chemistry also worked in Nicolaous’s total synthesis of Aspidophytine.
The point is, that Fukuyama, Tokuyama did not use particularly new chemistry, but were able to synthesize 4.2 mg of the target. Given how much effort has gone in from some particularly successful groups, only to be met with failure, this is an astonishing achievement.