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Totally Synthetic by Paul H. Docherty, 1 November 2006

Total Synthesis of Strychnofoline


A. Lechner, E. M. Carreira, Chem. Eur. J. 2006, 12, 8208-8219.

DOI: 10.1002/chem.200600957

A fantastic total synthesis of Strychnofoline by Erick Carreira. This family of alkaloids have been made by a number of research groups, each with a new approach in the interesting 5,5-spiro subunit, and the Carreira group weigh in with their own methodology for this synthesis.

Their work concerns the formal ring expansion of the cyclopropane shown above using a nucleophilic opening with magnesium iodide to form the Mg enolate and alkyl iodide. This is then displaced by the imine, allowing a Mannich reaction to compete the cyclisation. The methodology section explains that they can do this in good yield and excellent diastereoselectivity, so they pushed on for the total synthesis.

The synthesis of the three main fragments is very competent but reasonably well known chemistry that I won’t discuss, save for one particularly nice BOC deprotection using mild conditions, and as they state in the paper, byproducts that are volatile:

With this fragment complete, along with the cyclisation partner, the annulation could be completed - and in good yield, receiving the desired product as a single diastereomer in 55% over two steps - quite impressive. They also noted that the loading of MgI2 could be decreased to 0.5 eq. without dropping the yield at all.

The impressive diastereoselectivity was reasoned by monitoring the change in d.r. versus pH. In acidic media, the protonated tertiary amine could coordinate the amide, whereas in non-acidic media, there was a converse electrostatic repulsion from the lone pairs.

All in, a really nice total synthesis!