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

Abstract

(+)-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.

Concise Unified Access to (−)-8-Deoxy-13-dehydroserratinine, (+)-Fawcettimine, (+)-Fawcettidine, and (−)-8-Deoxyserratinine Using a Direct Intramolecular Reductive Coupling

“…Although several electrochemical approaches were reported for similar intramolecular couplings of aromatic imines and esters, few have been explored on the corresponding aliphatic system, especially a complex aliphatic system that contains multiple continuous stereocenters. As a category of powerful reductants involving single-electron processes, lithium-arenides were employed in some challenging C–C bond formations. , Due to the uncertainty of the reductive C–C coupling between an aliphatic imine and an ester, metal–arene-based conditions were chosen by us as a feasible starting point for the examination. Lithium naphthalenide was first examined, but unfortunately the desired spiro -α-aminocyclopentanone 26 was not observed (Table , entry 1).…”

16-Step Synthesis of the Isoryanodane Diterpene (+)-Perseanol

“…The use of VO(On-Pr)3 61 proved essential to obtain full conversion of alkene 42; the more routinely used VO(acac)2 gave only 5-10% conversion under otherwise identical conditions. Treatment of epoxylactone 43 with LiDBB, 62 the optimal conditions from our (+)-ryanodine synthesis, 25 did produce small quantities of the desired pentacycle 46; however, significant decomposition was observed. Analysis of the side products revealed that reduction of the orthobenzoate was a competing process, prompting a screen of different reductants in order to prevent this undesired reactivity.…”

SYNTHESIS Special Issue in Honor of Professor Sarah Reisman

“…In a subsequent study, Reisman discovered that a key intermediate from the ryanodol synthesis could be esterified to incorporate the pyrrole-3-carboxylate ester directly, allowing the total synthesis of ryanodine in only 18 steps from (S)-pulegone. 10 Reisman's synthetic platform uniquely positions her group to develop synthetic ryanoids that were simply inaccessible through semi-synthesis.…”