I. Concise synthesis of (+)-Sch 642305, a purported bacterial primase inhibitor and II. Rational design of T-shaped potassium channel blockers and III. Studies toward the synthesis of Haouamine B.

摘要

In part I of this manuscript, we present a concise synthesis of the natural product (+)-Sch 642305, a purported bacterial DNA primase inhibitor. The key step of the synthesis is a stereo-selective Mukaiyama-Michael conjugate addition to an enantiopure cyclohexenone, derived from the chiral pool. Because the synthesis was designed to be highly amenable to derivatization, analogues were designed and synthesis begun to conduct SAR studies with the bacterial DNA primase. In collaboration with the Berger lab, cocrystallization of the synthetic material with the primase was attempted to no avail. We have shown through rigorous biochemical studies that (+)-Sch 642305 is not a bacterial DNA primase inhibitor as reported.;Part II describes our efforts toward the rational design of a potent selective potassium channel blocker. Through solid-state NMR studies in collaboration with the Baldus laboratory, we have established that the binding mode of the porphyrin potassium channel blockers, previously reported by our group, is T-shaped rather than cap-like as earlier hypothesized. Prompted by this discovery, we designed and synthesized two novel T-shaped potential potassium channel blockers. The new compounds were evaluated by electrophysiology, in collaboration with the Pongs laboratory, and determined to be moderately potent, but more importantly, selective potassium channel blockers.;Our efforts toward the total synthesis of haouamine B is presented in part III. In particular, my research in this project has been focused on the construction of the highly strained unprecedented 3-aza-[7]-paracylophane core of haouamine B. We have investigated a horseradish peroxidase mediated oxidative enzymatic ring closure of the appropriate biphenyl precursor and a radical closure via the Pschorr reaction without success. We are currently pursuing a pyridazine-alkyne Diels-Alder ring closure strategy for the construction of the paracylophane ring toward the completion haouamine B.