Progress Towards the Total Synthesis of Bengazole A, an Antifungal Natural Product from a Marine Sponge Jaspis sp.

Bengazole A is a highly potent antifungal agent from a marine sponge of the genus Jaspis sp. The structure of bengazole A contains a bis-(oxazolyl)methanol moiety which is an unprecedented motif among natural products. In addition, bengazole A is the only known marine natural product that contains a C5 monosubstituted oxazole. This dissertation research describes work towards the total synthesis of bengazole A and the development of new synthetic methodology.Chapter 2 details the initial work on the synthesis of bengazole A including the attempted synthesis of the undescribed 2-formyloxazoline. While efforts to prepare a 2- formyloxazoline were unsuccessful, a novel oxidative rearrangement of 2-methyloxazoline to a dihydrooxazinone was discovered.Chapter 3 develops the methodology of the oxazoline-dihydrooxazinone oxidative rearrangement, describes the chemistry of 3-unsubstituted dihydrooxazinones, and utilizes the oxidative rearrangement for the synthesis of optically pure (S)-tert-leucine. The mechanism of the oxidative rearrangement was investigated by kinetic studies, isolation of an intermediate, and 13C labeling studies. These studies led to refinement of the proposed mechanism of reaction.Chapter 4 describes the preparation of an advanced intermediate incorporating C1-­C9 of bengazole A by taking advantage of the ambident nucleophilicity of 2-lithiooxazole with preferential C4 addition to aldehydes. The aldehyde used in the synthesis, a precursor to the bengazole side chain, C1-C6, was prepared from the inexpensive sugar D-galactose.Chapter 5 outlines a synthetically useful preparation of C5 monosubstituted oxazoles for incorporation in the last stage of bengazole A synthesis. The methodology allows selective deprotonation-electrophilic addition at C5 of 2-methylthiooxazole for the construction of 5-substituted oxazoles. The methylthio group is then conveniently removed by reductive desulfurization with Raney nickel

Progress Towards the Total Synthesis of Bengazole A, an Antifungal Natural Product from a Marine Sponge Jaspis sp.

Bengazole A is a highly potent antifungal agent from a marine sponge of the genus Jaspis sp. The structure of bengazole A contains a bis-(oxazolyl)methanol moiety which is an unprecedented motif among natural products. In addition, bengazole A is the only known marine natural product that contains a C5 monosubstituted oxazole. This dissertation research describes work towards the total synthesis of bengazole A and the development of new synthetic methodology.Chapter 2 details the initial work on the synthesis of bengazole A including the attempted synthesis of the undescribed 2-formyloxazoline. While efforts to prepare a 2- formyloxazoline were unsuccessful, a novel oxidative rearrangement of 2-methyloxazoline to a dihydrooxazinone was discovered.Chapter 3 develops the methodology of the oxazoline-dihydrooxazinone oxidative rearrangement, describes the chemistry of 3-unsubstituted dihydrooxazinones, and utilizes the oxidative rearrangement for the synthesis of optically pure (S)-tert-leucine. The mechanism of the oxidative rearrangement was investigated by kinetic studies, isolation of an intermediate, and 13C labeling studies. These studies led to refinement of the proposed mechanism of reaction.Chapter 4 describes the preparation of an advanced intermediate incorporating C1-­C9 of bengazole A by taking advantage of the ambident nucleophilicity of 2-lithiooxazole with preferential C4 addition to aldehydes. The aldehyde used in the synthesis, a precursor to the bengazole side chain, C1-C6, was prepared from the inexpensive sugar D-galactose.Chapter 5 outlines a synthetically useful preparation of C5 monosubstituted oxazoles for incorporation in the last stage of bengazole A synthesis. The methodology allows selective deprotonation-electrophilic addition at C5 of 2-methylthiooxazole for the construction of 5-substituted oxazoles. The methylthio group is then conveniently removed by reductive desulfurization with Raney nickel

Ondansetron to Reduce Neonatal Opioid Withdrawal Severity: A Randomized Clinical Trial

ObjectiveTo determine if treatment with a 5-HT3 antagonist (ondansetron) reduces need for opioid therapy in infants at risk for neonatal opioid withdrawal syndrome (NOWS). Study DesignA multicenter, randomized, placebo controlled, double blind clinical trial of ninety (90) infants. The intervention arms were intravenous ondansetron or placebo during labor followed by a daily dose of ondansetron or placebo in infants for five days. ResultsTwenty-two (49%) ondansetron-treated and 26 (63%) placebo-treated infants required pharmacologic treatment (p\u3e0.05). The Finnegan score was lower in the ondansetron-treated group (4.6 vs. 5.6, p=0.02). A non-significant trend was noted for the duration of hospitalization. There was no difference in need for phenobarbital or clonidine therapy, or total dose of morphine in the first 15 days of NOWS treatment. ConclusionsOndansetron treatment reduced the severity of NOWS symptoms; and there was an indication that it could reduce the length of stay

Discovery and Optimization of Novel Pyridines as Highly Potent and Selective Glycogen Synthase Kinase 3 Inhibitors

Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-beta in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.</div