Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions

项目总结/摘要 生物相关分子的合成、结构、作用机理及反应 我们的MIRA支持的研究计划包括合成，机械和结构有机化学， - 是的我们通过研究来解决当代未解决的问题，这些研究导致i）推导 新的化学实体的结构，通常通过创新使用NMR方法，ii）新的见解 关于化学反应，包括自发的生物合成转化，如何进行，以及iii）新的方法 以制造具有研究人员感兴趣的结构特征的分子， 逻辑属性。我们将利用最近取得的成就，开展以下新的努力。 I. Natural Products Chemistry A.我们仍然对解开天然产物生物合成的关键步骤感兴趣， 不存在酶催化，也就是说，自发地。两个与起源有关的具体假设 ottelione A独特骨架驱动电流工作：i）前所未有的低势垒科普重排 形成存在于该次级代谢物中的奇怪的脱芳构化的4-亚甲基环己烯酮，和ii）a 简单的非手性二芳基庚烷类化合物被氧化转化为应变的和预组织的科普底物。 一个杰出的合作者参与使用基因组作图方法将是非常有益的。 B。我们经常从事天然产物结构测定研究和 对那些做同样事情的人有价值的方法。这些研究的影响远远超出了 我们提出的具体问题。我们在这方面的记录是强有力的。一个值得注意的例子教methodol- 计算化学位移的ogy给可能是计算新手的实验者。我们的ap- 方法与概率方法的最新发展中所使用的方法相同， 计算的NMR化学位移与实验的NMR化学位移对比，以验证结构归属（DP 4、DP 4+、DP 4-AI、DP 5）。 我们发现一些社区尚未接受这些方法，这是一个差距。我们建议评估 这些方法对各种环肽结构评估的有效性（和局限性）， 如果你愿意的话，这些结果将有利于肽化学家未来的结构研究。 二. HDDA-苄化学 我们发现的六氢-狄尔斯-桤木（HDDA）反应的广泛范围既令人兴奋，又令人兴奋。 abling.自四年前我们的MIRA资助开始以来，这项工作取得了重大进展。机会- 在这个竞技场上的竞争没有减弱的迹象。相反，似乎每个月左右都会有同事来 在我的家门口，又一个新的结果，从我的东西elelections的效果“哇，HDDA- 苯炔也会这样！”无数的新方向在研究策略的第4-6页中提出。许多 将导致含有更大优势的杂原子的产物，从而展示新的应用， 供从事药物发现活动的研究人员考虑和使用。 (30行）

PROJECT SUMMARY/ABSTRACT Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions Our MIRA-supported research program encompasses synthetic, mechanistic, and structural organic chem- istry. We address unresolved contemporary problems through studies that lead to i) new ways of deducing the structures of novel chemical entities, often through innovative use of NMR methodologies, ii) new insights about how chemical reactions, including spontaneous biosynthetic transformations, proceed, and iii) new ways to make molecules that have structural features of interest to researchers pursuing targets with promising bio- logical properties. We will capitalize on recent accomplishments and launch new efforts as follows. I. Natural Products Chemistry A. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in the absence of enzymatic catalysis—that is, spontaneously. Two specific hypotheses related to the origin of the unique skeleton of ottelione A drive current work: i) an unprecedented, low-barrier Cope rearrangement fashions the strange, dearomatized 4-methylenecyclohexenone present in this secondary metabolite and ii) a simple, achiral diarylheptanoid is oxidatively transformed into the strained and preorganized Cope substrate. The engagement of an outstanding collaborator to use genome mapping approaches will be of great benefit. B. We frequently engage in natural product structure determination studies and the development of methodologies of value to those who do the same. These studies have had impact extending well beyond the specific questions that we address. Our record in doing this is strong. One notable example teaches methodol- ogy for calculation of chemical shifts to the experimentalist who may be a novice computationalist. Our ap- proach was the same as that used in the newest developments of probabilistic methods for comparison of computed vs. experimental NMR chemical shifts to validate structure assignments (DP4, DP4+, DP4-AI, DP5). We find a gap in that some communities have yet to embrace these approaches. We propose to evaluate the effectiveness (and limitations) of these methods for structural assessment of various cyclic peptides and then to communicate, advertise if you will, these outcomes to benefit future structural studies by peptide chemists. II. HDDA-Benzyne Chemistry Our discovery of the broad scope of the hexadehydro-Diels–Alder (HDDA) reaction is both exciting and en- abling. This work has advanced significantly since the onset of our MIRA funding four years ago. The opportu- nities in this arena show no sign of abating. To the contrary, it seems that every month or so a coworker arrives at my doorstep with yet another new result that elicits from me something to the effect of “Wow, HDDA- benzynes will also do that!” Myriad new directions are presented in pages 4–6 of the Research Strategy. Many will lead to products containing a greater preponderance of heteroatoms, thereby demonstrating new ap- proaches for consideration and use by researchers engaged in drug discovery activities. (30 lines)