Regioselective Synthesis and Diels-Alder Reaction of 3-substituted-5-Bromo-2-pyrones for Total Syntheses of joubertinamine, crinine, crinamine, 6a-epi-crinamine, and aspidospermidine

Abstract

The total synthesis of (±)-joubertinamine has been achieved from 3,5-dibromo-2-pyrone in 9.6% total yield over 10 steps via the regioselective synthesis and Diels-Alder cycloaddition reaction of 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone with phenyl vinyl sulfide. We also devised a new unified synthetic protocol to (±)-crinine, (±)-crinamine, (±)-6a-epi-crinamine from the Diels-Alder cycloadduct of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone with TBS vinyl ether. The requisite 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone was also prepared from the C3-selective Stille coupling reaction of 3,5-dibromo-2-pyrone. The vinyl bromide group can be used as a handle for further derivatization. We have completed total synthesis of (±)-aspidospermidine using the 2-pyrone regioselective coupling / Diels- Alder reaction strategy. The requisite 3-ethyl-5-bromo-2-pyrone was prepared via the C3-selective Suzuki coupling reaction of 3,5-dibromo-2-pyrone.