Synthetic studies on novel bryostatin analogues and their interaction with the CRD2 of protein kinase C
A fully stereocontrolled asymmetric synthesis of the Southern Hemisphere intermediate 426 for the bryostatin family of antitumour agents is described in this thesis. It details how the strategy evolved from (E)-1,4-hexadiene 450 including a Roush-Masamune coupling between 462 and 507, cyclisation to glycal 505, selective epoxidation and in-situ Fischer glycosidation to 503 and an aldol / dehydration sequence to establish the (E)-exocyclic olefin. We also document a rare example of slow bond rotation in the C(18)- C(19)-bond of 426 and provide an explanation of this phenomenon. In addition, the synthesis of two truncated bryostatin analogs 525 and 526 is described, and the interaction of 525 with the CRD2 of human PKC-α discussed.