Stereodivergent Synthesis of 1‑Hydroxymethylpyrrolizidine Alkaloids

A first
stereodivergent strategy for the asymmetric synthesis of
all stereoisomers of 1-hydroxymethylpyrrolizidine alkaloids is developed
using an asymmetric self-Mannich reaction as a key step. An anti-selective
self-Mannich reaction of methyl 4-oxobutanoate with the PMP-amine
catalyzed by a chiral secondary amine is successfully optimized for
the asymmetric synthesis of (+)-isoretronecanol and (−)-isoretronecanol.
A syn-selective self-Mannich reaction catalyzed by proline is utilized
for the asymmetric synthesis of the diastereomer, (+)-laburnine, and
its enantiomer, (−)-trachelanthamidine.