Abstract
The structurally complex alkaloid gelsemine was previously thought to have no significant biological activities, but a recent study has shown that it has potent and specific antinociception in chronic pain. While this molecule has attracted significant interests from the synthetic community, an efficient synthetic strategy is still the goal of many synthetic chemists. Here we report the asymmetric total synthesis of (+)-gelsemine, including a highly diastereoselective and enantioselective organocatalytic Diels–Alder reaction, an efficient intramolecular trans-annular aldol condensation furnishing the prolidine ring and establishing the configuration of the C20 quaternary carbon stereochemical centre. The entire gelsemine skeleton was constructed through a late-stage intramolecular SN2 substitution. The enantiomeric excess of this total synthesis is over 99%, and the overall yield is around 5%.
Highlights
The structurally complex alkaloid gelsemine was previously thought to have no significant biological activities, but a recent study has shown that it has potent and specific antinociception in chronic pain
Gelsemine was thought to have no particular biological activities, a recent report indicated that gelsemine exhibited potent and specific antinociception in chronic pain by acting at the three spinal glycine receptors[50]
Gelsemine may be synthesized from intermediate RS-1 and oxindole via the condensation of the hemiacetal with oxindole followed by an intramolecular SN2 displacement (Fig. 3)
Summary
The structurally complex alkaloid gelsemine was previously thought to have no significant biological activities, but a recent study has shown that it has potent and specific antinociception in chronic pain. Gelsemine may be synthesized from intermediate RS-1 and oxindole via the condensation of the hemiacetal with oxindole followed by an intramolecular SN2 displacement (Fig. 3). This equilibrium is shifted to form the desired product after the intramolecular SN2 displacement, which is irreversible under the reaction conditions (Figs 4 and 5).
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