Total Synthesis of (±)-joubertinamine from 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone

Abstract

The sceletium family mesembrine alkaloids as well as their seco-congenors have been the synthetic target of considerable efforts over the past decades (Figure 1). Long been known to the Khoi-khoi and San peoples as a mood enhancer, sedative, analgesic and appetite/thirst suppressant, they have recently proven potentially useful in the treatment of depressive states, psychological or psychiatric disorders with an anxiety component, alcohol and drug dependence, bulimia nervosa and obsessive-compulsive disorders.

Unlike mesembrine 2, there are only a few synthetic studies reported in the literature for joubertinamine 1, with incomplete characterizations. We envisioned that the carbon skeletons including the characteristic quarternary carbon center of sceletium family alkaloids can be readily forged from the cycloadduct of 3,5-dibromo-2-pyrone. As summarized in Scheme 1, 2-pyrone 8 underwent the C3-selective Stille coupling reaction with aryltin 9 to provide 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone 7 in 72% yield. The Diels-Alder cycloaddition reaction with phenyl vinyl sulfide produced bicyclolactone 6 as a mixture of endo/exo isomers (2:1, 82% combined yield). Although not necessary, the endo- and exo-adduct were separated and carried individually through the reaction sequence for the characterization issue. The methanolysis of the cycloadduct 6 furnished the key cyclohexene intermediate 10. Further elaborations including reductive removal of phenylthio group and one-carbon homologation provided a rapid access to joubertinamine (10 steps, 9.6% total yield) as well as mesembrine.

We wish to acknowledge the financial support of Center for Bioactive Molecular Hybrids