New Synthetic Reactions For Active Principles

描述（由申请人提供）：我们最早的项目可以追溯到PI在匹兹堡大学的实验室。起初，它完全是为了描绘有机合成在逻辑和方法论上的进步。随后，耶鲁大学（Yale university）展开了更广泛的努力，寻求利用合成技术的进步来获得小分子天然产物（SMNPs），并利用这种小分子天然产物的全合成。当我们的实验室搬到纽约，并在纪念斯隆-凯特琳癌症中心和哥伦比亚大学化学系之间分岔时，HL 25848被转移到哥伦比亚大学。两笔癌症基金支持我们在MSKCC的工作。我们在哥伦比亚寻求的续期是我们在HL 25848上的最后一次续期。虽然我们的实验室仍保持充分的生产力和竞争力，但我们认识到为新一代科学家让路是适当的，他们将追求令人兴奋的新方向。我们寻求这一复兴的目标有几个。首先，我们相信，它将促进研究，这将是智力上有价值的，也是翻译水平的兴趣。此外，作为我们哥伦比亚大学项目的唯一支持来源，它将使我们在这里的项目有序结束，同时满足对各种研究生和博士后的承诺，无论是他们的研究还是他们的职业发展。该计划分为十个项目，我们认为这些项目可以在指定的时间框架内掌握。D1-D4项目设想了对Diels Alder反应的传统思维的重大新突破。项目D1利用Diels Alder反应得到迄今为止通过羰基缩合反应构建的体系。D2项目将DA反应与其他化学反应结合起来，以达到跨融合连接，而传统的DA反应传统上被视为顺式融合的途径。D3项目在分子内Diels Alder反应（IMDA）的背景下实现了范式转变。D4项目利用D1到D3的进展，完成了一种新的高活性皮质类固醇的全合成。项目D5到D8具有很强的药物相关性。因此，D5项目寻求在具有神经营养活性的SMNPs的背景下寻找开发候选药物，最终目标是应用于神经退行性疾病。D6项目建立在我们合成红参中的一种化合物的基础上。我们已经获得了一种预防癌症的候选结构。项目D7和D8建立在我们最近完成的ET-743和pluraflain A的全合成基础上，这导致了一些有趣和意想不到的SAR发现。D9项目有望在取得重大进展后完成三氯酰胺A的全合成，但仍有许多工作要做。D10计划设想了一种新的（基于新化学的）甲地芬宁的全合成方法，其类似物在未来的发展中似乎非常有希望。公共卫生相关性：我们的项目旨在研究有机合成的潜在进展，并将这些进展应用于小分子天然产物（SMNP）或具有新生物活性的天然产物同源物的细化和研究。在HL 25848中，我们将在三个层面上参与，i)一个针对合成方法的项目；ii)另一项努力将指向药物化学，iii)一个针对生物活性SMNPs全合成中两个具有挑战性的问题的计划。

DESCRIPTION (provided by applicant): Our earliest program goes back to the PI's laboratory at the University of Pittsburgh. At first, it was entirely directed to charting advances in organic synthesis both as to logic and methodology. It then evolved into a broader effort at Yale Univeristy seeking to use advances in synthesis to arrive at small molecule natural products (SMNPs) and to exploit its total syntheses of such SMNPs. When our laboratory moved to NYC and bifurcated between Memorial Sloan-Kettering Cancer Center and the Department of Chemistry at Columbia Univeristy, HL 25848 was transferred to Columbia. Two cancer driven grants support our work at MSKCC. The renewal we seek at Columbia is the last we shall undertake on HL 25848. While our laboratory remains fully productive and competitive, we recognize the appropriateness of making way for a new generation of scientists, who will pursue exciting new directions. Our goals in seeking this renewal are several. First, we are convinced that it will foster research which will be intellectually valuable and also of interest of the translational level. Moreover, being the sole source of support for our Columbia program, it will enable us to bring our program here to an orderly conclusion while meeting commitments to various graduate students and postdoctorals, both for their research and in their career enhancement. The program is distributed among ten projects which, we think, can be mastered in the indicated time frame. Projects D1-D4 envision major new departues from conventional thinking about the Diels Alder reaction. Project D1 utilizes the Diels Alder reaction to reach systems hitherto constructed through carbonyl condensation reactions. Project D2 combines the DA reaction with other chemistry to reach trans fused junctions, whereas the classical DA reaction traditionally is seen as a route to cis fusions. Project D3 achieves the paradigm shift in the context of the intramolecular Diels Alder reaction (IMDA). Project D4 utilizes the advances from D1 through D3 to accomplish a new total synthesis of highly active corticosteroids. Projects D5 through D8 have strong elements of pharmaceutical relevance. Thus, project D5 seeks to find development candidates in the context of SMNPs with neurotrophic activity, the ultimate goal being application to neurodegenerative diseases. Project D6 builds from our synthesis of a compound in red ginseng. We have moved on to obtain a candidate structure for carcinoprevention. Projects D7 and D8 build from our recently completed total syntheses of ET-743 and pluraflavin A which led to some interesting and unexpected SAR findings. Project D9 involves, hopefully, the completion of the total synthesis of tricholomalide A following significant advances, though much remains to be done. Project D10 envisions a fresh total synthesis (based on new chemistry) of jiadifenin, analogs of which seem very promising for future development. PUBLIC HEALTH RELEVANCE: Our program seeks to study potential advances in organic synthesis and to apply such advances to the elaboration and study of small molecule natural products (SMNP) or natural product congeners of novel biological activity. In HL 25848, we will be engaged at three levels, i) a program directed to synthetic methodology; ii) another effort will be directed to medicinal chemistry, and iii) a program directed to two challenging problems in total synthesis of bioactive SMNPs.