Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions

项目摘要/摘要 生物悬浮剂分子与反应的合成、结构与机理 我们由美国国立卫生研究院支持的研究项目包括合成、机械和结构有机化学- 试试看。我们通过研究解决当代悬而未决的问题，这些研究导致了：1)制造鼹鼠的新方法-- CUES，II)具有有价值的生物特性的新分子，III)关于化学如何重新定位的新见解 动作，包括自发的生物合成转换，以及iv)推导结构的新方法- 新的化学实体的结构，通常通过创新地使用核磁共振(核磁共振)方法-- 哎呀。我们计划利用最近在两个专题领域--第一和第二领域取得的成就。 一、天然产物化学：三个分专题。 答：我们经常从事天然产品结构确定的研究。这些挑战往往 要求我们开发新的核磁共振策略来询问复杂的结构。这些研究已经产生了- 条约远远超出了所处理的具体问题。我们的过往记录很好。我们最值得注意的 最近的一个例子向可能是新手的实验者传授了计算化学位移的方法。 冰雪计算学家。早期的贡献包括一阶多重态分析和“No-D”核磁共振光谱学。 B.我们计划利用我们之前在合成极其有效的细胞毒素方面所做的工作。如果他们的 急性细胞毒性可以得到适当的利用，这些药物有可能作为化疗药物非常有用。 肿瘤学中的治疗剂。我们有机会通过合作研究做到这一点，使用：(I) 靶向肿瘤部分的纳米制剂，称为癌症干细胞或(Ii)新型抗体药物 结合物也有可能改善这些强大制剂的治疗窗口。 C.我们仍然有兴趣解开自然产品生物合成的关键步骤，这些步骤将在 没有酶催化--也就是自发的。推动未来工作的具体假设涉及(一) 一种史无前例的COPE重排，从无手性的二芳基六面体塑造了奥特利酮A的独特骨架- 和(Ii)双环烃的高度不饱和线性前体(四炔)的异构化 九元烯二炔类天然产物的核心骨架；这一事件的环化酶仍然难以捉摸。 二、HDDA*-苯化学(*六氢-Diels-Alder)。 我们发现了六氢Diels-Alder(HDDA)反应的广泛范围，这一发现既令人兴奋又令人振奋。 正在启用。这项工作在我们NIGMS赠款的当前资助期内取得了巨大的进展。许多人 我们已有的反应类A.最近发布的或B.正在进行/未来研究的主题 都是革命性的。在许多情况下，这些热诱导的非催化转化不仅仅是 不同寻常，但在这项工作之前，从字面上讲，是不可想象的。这个项目中的机会没有任何迹象表明 减少的可能性。相反，似乎每周左右就会有一个同事带着另一个同事来到我的家门口 新的结果让我产生了这样的感觉：“哇，他们也会这么做的！” (30行)

PROJECT SUMMARY/ABSTRACT Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions Our NIH-supported research program encompasses synthetic, mechanistic, and structural organic chemis- try. We address unresolved contemporary problems through studies that lead to i) new ways to make mole- cules, ii) new molecules with promise of valuable biological properties, iii) new insights about how chemical re- actions, including spontaneous biosynthetic transformations, proceed, and iv) new ways of deducing the struc- tures of novel chemical entities, often through innovative use of nuclear magnetic resonance (NMR) methodol- ogies. We plan to capitalize on recent accomplishments in two topical areas, I. and II. I. Natural Products Chemistry Three subtopics are pursued. A. We frequently engage in natural product structure determination studies. These challenges have often required that we develop new NMR strategies for interrogating complex structures. These studies have had im- pact extending far beyond the specific question being addressed. Our track record is strong. Our most notable recent example teaches methodology for calculation of chemical shifts to the experimentalist who may be a nov- ice computationalist. Earlier contributions include first-order multiplet analysis and “No-D” NMR spectroscopy. B. We plan to capitalize on our previous work in the synthesis of extremely potent cytotoxins. If their acute cytotoxicity could be properly harnessed, these agents have the potential to be quite useful as chemo- therapeutic agents in oncology. We have the opportunity to do just that through collaborative studies using: (i) nanoparticle formulations targeted for portions of tumors called cancer stem cells or (ii) novel antibody-drug conjugates that also have the potential to improve the therapeutic window of these powerful agents. C. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in the absence of enzymatic catalysis—that is, spontaneously. Specific hypotheses driving future work involve (i) an unprecedented Cope rearrangement to fashion the unique skeleton of ottelione A from an achiral diarylhep- tanoid and (ii) an isomerization of a highly unsaturated linear precursor (a tetrayne) to the bicyclic hydrocarbon core skeleton of the 9-membered enediyne family of natural products; a cyclase for this event remains elusive. II. HDDA*-Benzyne Chemistry (*hexadehydro-Diels-Alder). Our discovery of the broad scope of the hexadehydro-Diels–Alder (HDDA) reaction is both exciting and en- abling. This work blossomed tremendously during the current funding period of our NIGMS grant. Many of the reaction classes that we have A. Recently Published or that are the subject of B. Ongoing/Future Research are revolutionary. In a number of instances, these thermally induced, uncatalyzed transformations are not just remarkable, but were, literally, inconceivable prior to this work. The opportunities in this program show no sign of abating. To the contrary, it seems that every week or so a coworker arrives at my doorstep with yet another new result that elicits from me something to the effect of “Wow, they'll also do that!” (30 lines)