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MIRA支持的研究项目包括合成、机械和结构有机化学- 斯特里特。我们通过研究解决当代悬而未决的问题，这些研究导致了：i)新的推论方法 新化学实体的结构，通常通过创新地使用核磁共振方法，二)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)新方法 为了制造具有研究人员感兴趣的结构特征的分子，他们正在寻找有前途的生物目标 逻辑属性。我们将利用最近取得的成就，开展以下新努力。 一、天然产物化学 答：我们仍然有兴趣解开天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。与宇宙起源有关的两个具体假说 Otelione的独特骨架A驱动当前的工作：i)史无前例的低障碍COPE重排 形成这种次级代谢物中存在的奇怪的、脱芳烃的4-亚甲基环己酮和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和预先组织的COPE底物。 让一位杰出的合作者参与使用基因组图谱方法将是非常有益的。 B.我们经常从事天然产品结构确定的研究和开发 对于那些做同样事情的人来说，这是一种有价值的方法。这些研究的影响远远超出了 我们要解决的具体问题。我们在这方面的记录是很好的。一个值得注意的例子是教人用甲氧西林- 把化学位移的计算交给可能是计算学家新手的实验者。我们的AP- 方法与最新发展的比较概率方法中使用的方法相同 计算与实验的核磁共振化学位移，以验证结构指定(DP4，DP4+，DP4-AI，DP5)。 我们发现了一个差距，一些社区还没有接受这些方法。我们建议评估 这些方法对各种环肽的结构评估的有效性(和局限性)，然后 为了交流，如果你愿意的话，宣传这些结果，以利于多肽化学家未来的结构研究。 二、HDDA-Benzyne化学 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。自从我们四年前开始为米拉提供资金以来，这项工作取得了显着进展。机会-- 这个竞技场的活力丝毫没有减弱的迹象。相反，似乎每个月左右都会有一位同事来上班 在我的家门口，又一个新的结果给了我一些启发，让我产生了这样的感觉：哇，HDDA 比恩斯也会这么做的！在研究战略的第4-6页中提出了无数新的方向。许多 将导致产品包含更多的杂原子优势，从而展示新的AP- 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)