Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine

(+)-Ryanodine is
a natural product modulator of ryanodine receptors, important intracellular
calcium ion channels that play a critical role in signal transduction
leading to muscle movement and synaptic transmission. Chemical derivatization
of (+)-ryanodine has demonstrated that certain peripheral structural
modifications can alter its pharmacology, and that the pyrrole-2-carboxylate
ester is critical for high affinity binding to ryanodine receptors.
However, the structural variation of available ryanodine analogues
has been limited by the challenge of site-specific functionalization
of semisynthetic intermediates, such as (+)-ryanodol. Here we report
a synthetic strategy that provides access to (+)-ryanodine and the
related natural product (+)-20-deoxyspiganthine in 18 and 19 steps,
respectively. A key feature of this strategy is the reductive cyclization
of an epoxide intermediate that possesses the critical pyrrole-2-carboxylate
ester. This approach allows for the direct introduction of this ester
in the final stage of the synthesis and provides a framework for the
synthesis of previously inaccessible synthetic ryanoids.