Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions

生物相关分子和反应的合成、结构和机制

基本信息

批准号：
10624523
负责人：
THOMAS R. HOYE
金额：
$ 40.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2028-07-31
项目状态：
未结题

项目摘要

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)

项目概要/摘要生物相关分子和反应的合成、结构和机制我们的 MIRA 支持的研究项目涵盖合成、机械和结构有机化学我们通过研究来解决尚未解决的当代问题，这些研究导致 i) 推论的新方法。新颖化学实体的结构，通常通过 NMR 方法的创新使用，ii) 新见解关于化学反应（包括自发生物合成转化）如何进行，以及 iii）新方法制造具有研究人员感兴趣的结构特征的分子，以追求具有前景的生物目标我们将利用最近取得的成就并开展以下新的努力。一、天然产物化学答：我们仍然对解开天然产物生物合成的关键步骤感兴趣，这些步骤在缺乏酶催化——即自发的。 ottelione A 的独特骨架驱动当前工作：i) 前所未有的低势垒 Cope 重排形成这种次级代谢物中存在的奇怪的脱芳构化 4-亚甲基环己烯酮，并且 ii) a 一种简单的非手性二芳基庚烷被氧化转化为应变且预组织的 Cope 底物。杰出合作者的参与使用基因组作图方法将大有裨益。 B. 我们经常从事天然产物结构测定研究和开发这些研究的方法论对那些从事同样工作的人来说具有价值，其影响远远超出了范围。我们解决的具体问题的记录证明了这一点是强有力的。我们的应用程序为可能是新手计算学家的实验者提供了计算化学位移的科学。 proach 与最新发展的概率方法中使用的相同，用于比较计算与实验 NMR 化学位移以验证结构分配（DP4、DP4+、DP4-AI、DP5）。我们发现一些社区尚未接受这些方法，因此我们建议对这些方法进行评估。这些方法对各种环肽结构评估的有效性（和局限性），然后如果愿意的话，可以交流、宣传这些结果，以利于肽化学家未来的结构研究。 II.HDDA-苯化学我们对广泛的十六氢狄尔斯-阿尔德 (HDDA) 反应的发现既令人兴奋又令人兴奋。自四年前 MIRA 资助开始以来，这项工作取得了显着进展。这种情况并没有减弱的迹象，相反，似乎每个月都会有一位同事来到这里。在我家门口，又一个新结果让我产生了“哇，HDDA- 苯炔也能做到这一点！”《研究策略》第 4-6 页提出了无数新方向。将导致产品含有更多的杂原子，从而证明新的应用供从事药物发现活动的研究人员考虑和使用的方法。（30行）