Studies in Natural Product Synthesis and Catalysis of Pericyclic Reactions

我们的研究计划是有机化学基础和应用研究的融合。基础研究侧重于开发新的合成方法和天然产物的全合成。我们的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交分子。在本提案所述的基础研究中，我们将继续合成两种天然产物，帕劳'amine和virosaine。帕劳胺是一种具有免疫抑制活性的海洋生物碱，由于其官能团密度和具有挑战性的立体化学，因此是化学合成的高度挑战性靶标。我们正在开发一种Diels-Alder策略来设置中心碳环和共轭加成/氧化双闭合来闭合分子的反式稠合吡咯酰胺/胍缩醛部分。Virosaine是一种新分离的叶下珠生物碱，是仅有的几种通过[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，这将测试建议的[3+2]环加成作为我们的合成的最后一步，并将探讨其关系到另一个一叶片碱生物碱，flueggine A.除了我们的工作对天然产物的全合成，我们还将开发新的方法催化sigmatropic和电环重排和酰胺键合成。Sigmatropic和电环重排已经看到显着较少的催化剂的发展相比，其他主要类别的周环反应，环加成。我们将研究使用亚胺基有机催化剂和光氧化还原催化剂在这些反应中引发和控制立体化学。最后，开发用于偶联羧酸与胺而除了水之外没有副产物的催化剂是合成化学中的最大挑战之一。我们将研究使用脲作为氢键供体来激活羧酸与内部亲核试剂的酯化反应，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.