MECHANISTIC INVESTIGATIONS OF A BIOMIMETIC POLYCYCLIZATION PROCESS THAT LEADS TO THE DAPHNIPHYLLUM ALKALOIDS

Synthetic experiments pertaining to a postulated biosynthesis of the Daphniphyllum alkaloids (Fig. 2) have been carried out. The key features of this hypothesis are the postulated cyclizations of 8 to 9 and 9 to 10 (proto-daphniphylline). One question that arises in respect to this biosynthetic hypothesis relates to the regioselectivity of the final ring formation (Fig. 4). This question was addressed by carrying out the synthesis of proto-daphniphylline shown in Fig. 5. Evidence is presented that the selectivity of this ring closure derives from the greater stability of the six-membered ring product, relative to several possible five-membered ring alternatives (Fig. 7). Five-membered ring formation is so heavily disfavored that it does not occur even when the preferred mode of closure is impossible (Fig. 8). The conversion of 8 to 9 could be stepwise or concerted (Fig. 9). This question was addressed by synthesizing the bis-neryl analog 33, which was cyclized to 34. Thus, the conversion of 8 to 9 is concerted. Finally, proto-daphniphylline has been prepared in a straightforward manner from the dihydrosqualene dialdehydes (E)- and (Z)-37 as shown in Figures 16 and 17. © 1990, IUPAC.