Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies

(+)-Fastigiatine
is a complex alkaloid isolated from the alpine
club moss Lycopodium fastigatum, most commonly found
in New Zealand. It has been the subject of two successful synthetic
campaigns. A second-generation route toward fastigiatine was developed
to resolve two problematic steps from our initial synthesis. Selective
reduction and protection of the C13 ketone improved the yield and
reliability of the dibromocarbene ring expansion step. In the prior
synthesis, cuprate addition to the C10 enone generated a 1:1 mixture
of isomers in an advanced intermediate. Protection of the C13 alcohol
with a large silyl group changed the conformational preference of
the enone and led to a more selective conjugate addition to produce
the desired β-epimer at C10. MacMillan’s decarboxylative
photoredox addition method proved to be more practical than the prior
aminomethyl cuprate addition chemistry. The second-generation synthesis
is longer than the original but improves the selectivity and reproducibility
of the overall route.