Vanderwal, Martin. Chem. Sci., 2011, Advance Article.DOI: 10.1039/C1SC00009H
Yep, it’s back. However, no promises as to when I write my next total synthesis article! The next blog post will in-fact be an egotistical diatribe – explaining what I’m doing now, and why my life has got a bit busier. But if anything was going to haul my arse back on-line, it’s sweet little syntheses like this one! As I’ve written about before, 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 beast is still a challenge, and one that the Vanderwal group have cracked in only six steps!
The synthetic action kicks-off 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. A little base and a tickling with the bunsen (not that anyone actually uses one these days…) was enough to complete the intramolecular reaction and build two carbon-carbon bonds, setting three stereocentres (in a relative sense).
A little palladium removed the allyl protecting group from the amine (yeah, I kinda missed that too…), 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 neat little 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. Any ideas in the field?
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!