Totally Synthetic by Paul H. Docherty, 19 February 2011

Total Synthesis of Strychnine

Vanderwal

D. B. C. Martin, C. D. Vanderwal, Chem. Sci. 2011, 2, 649-651.

Strychnine has a bit of history to it, bound inextricably with the career of one Robert Burns Woodward. Fully characterised by Sir Robert Robinson, he described it thusly: “..for its molecular size it is the most complex substance known..”. Times may well have moved on, but this molecule is still a challenge, and one that the Vanderwal group has solved in only six steps!

The synthetic action starts with a nice cycloaddition, using a class of diene that I never knew was named. It turns out these amino alpha-beta gamma-delta unsaturated aldehydes are known as Zincke aldehydes - and effectively derived from pyridine. Addition of a base and heating was enough to complete the intramolecular reaction and build two carbon-carbon bonds, setting three stereocenters (in a relative sense).

A catalytic amount of palladium removed the allyl protecting group from the amine, allowing addition of a more complex organosilane-based moiety. This group itself was made in only two step from a simple acetylene, using hydrosilylation to append the TMS group. Why all that effort? Well, with one Brooke rearrangement, the group make two more rings, almost completing the natural product! If only they could improve the yield of this reaction. Vanderwal postulates that the problem is protodesilylation, resulting from rather acidic protons in the substrate.

As I said, the group were almost there - in fact, the product of this reaction is the Wieland-Gumlich aldehyde (masquerading as a hemi-acetal). This intermediate is a common feature in Strychnine syntheses, and the transformation is applied like so:

That’s it - all done in six steps (longest linear). Nice paper to return to!