Studies in Natural Product Synthesis and Catalysis of Pericyclic Reactions

我们的研究项目融合了有机化学的基础研究和应用研究。基础研究的重点是开发新的合成方法和天然产物的全合成。我们研究计划的应用部分集中在设计和开发用于癌症治疗的新型杂化分子。在这项提议中描述的基础研究中，我们将继续合成两种天然产物--帕劳胺和病毒碱。帕劳胺是一种具有很强免疫抑制活性的海洋生物碱，由于其官能团的密度和具有挑战性的立体化学，是化学合成的一个极具挑战性的目标。我们正在开发Diels-Alder策略来设置中心碳环和共轭加成/氧化双闭合，以关闭分子中反式熔融的吡咯酰胺/胍缩醛部分。Virosaine是一种新分离的Secounega生物碱，是少数几个被提出通过[3，2]硝酮环加成生物合成的分子之一。我们正在开发一个级联序列，作为我们合成的最后一步，它将测试所提出的[3，2]环加成反应，并将探索其与另一种四叶生物碱--氟尿酸A的关系。除了我们在天然产物全合成方面的工作外，我们还将开发催化Sigmatropic和电环重排以及酰胺键合成的新方法。与另一类主要的周环反应-环加成反应相比，Sigmatrotic和电环重排的催化剂开发明显较少。我们将研究在这些反应中使用亚胺类有机催化剂和光氧化还原催化剂来引发和控制立体化学。最后，开发无水以外无副产物的羧酸与胺偶联催化剂是合成化学中最大的挑战之一。我们将研究使用尿素作为氢键供体来激活羧酸，使其与内部亲核试剂进行酯化反应，然后将酰基从氧转移到外部胺。

Our research program is a blend of fundamental and applied research in organic chemistry. The fundamental research focuses on the development of novel synthetic methods and the total synthesis of natural products. The applied portion of our research program is focused on the design and development of novel hybrid molecules for cancer treatment. In the fundamental research described in this proposal, we will pursue the synthesis of two natural products, palau'amine and virosaine. Palau'amine, a marine alkaloid with potent immunosuppresant activity, is a highly challenging target for chemical synthesis due to its density of functional groups and challenging stereochemistry. We are developing a Diels-Alder strategy to set the central carbocyclic ring and a conjugate addition/oxidative double-closure to close the trans-fused pyrrole amide/guanidine acetal portion of the molecule. Virosaine is a newly isolated Securinega alkaloid that is one of only a few molecules that has been proposed to arise biosyntheticallly by a [3+2] nitrone cycloaddition. We are developing a cascade sequence which will test the proposed [3+2] cycloaddition as the final step of our synthesis and will probe its relation to another Securinega alkaloid, flueggine A.In addition to our work on the total synthesis of natural products, we will also develop novel methods for catalyzing sigmatropic and electrocyclic rearrangements and amide bond synthesis. Sigmatropic and electrocyclic rearrangements have seen significantly less catalyst development when compared to the other major class of pericylic reactions, cycloadditions. We will investigate the use of both iminium based organocatalysts and photoredox catalysts for initiating and controlling stereochemistry in these reactions. Finally, the development of catalysts for coupling carboxylic acids with amines with no by-product other than water is one of the top challenges in synthetic chemistry. We will investigate the use of ureas as hydrogen bond donors to activate carboxylic acids towards esterification with an internal nucleophile and then transfer the acyl group from oxygen to an external amine.