REACTION OF BENZOCYCLOBUTENOXIDES WITH ALDEHYDES - SYNTHESIS OF PESHAWARINE AND OTHER 3,4-DIHYDROISOCOUMARINS

Deprotonation of benzocyclobutenols 6 in the presence of aromatic alde hydes affords benzopyranols 7 in high yield. In the key step of this p rocess, an o-tolualdehyde anion generated by the known ring-opening of benzocyclobutenoxides adds to the aldehyde to give 7 which is easily oxidized to 3-substituted 3,4-dihydroisocoumarins 8 including intermed iates in some natural product syntheses. For example, reaction of 6-me thoxybenzocyclobutenol (1) with LTMP and p-anisaldehyde gave in 96% yi eld the benzopyranol 16, which subsequently was converted to (+/-)-hyd rangenol (17). Similar treatment of 1 with LDA and isovanillin benzyl ether afforded the benzopyranol 19 (87% yield) which already has been converted to (+/-)-phyllodulcin (21). Finally, reaction of 5,6-(methyl enedioxy)-benzocyclobutenol (10) with LTMP and the aldehyde 26 (from t reatment of hydrastinine with ClCO2-Me) followed by methanolysis produ ced the acetal 28 in 96% yield. The overall yield was 65% for the five -step synthesis of the alkaloid (+/-)-peshawawine (24) from 10 and 26. Extension of the process to aliphatic aldehydes was illustrated by th e preparation of 32 from benzocyclobutenol and isobutyraldehyde in 69% overall yield after oxidation with PCC.