Asymmetric Synthesis with Strained Molceules

描述（由申请人提供）：有机合成新反应的开发是健康相关领域的核心，如药物发现，工艺化学，天然产物合成和生物启发分子设计。虽然现有技术使得在给予充足的时间和熟练的人员的情况下可以合成非常复杂的分子，但是仍然需要将简单的配偶体偶联以选择性地产生复杂产物的串联反应。 这项研究计划的目标是利用高应变分子的不寻常反应性，快速生成富含立体化学复杂性和结构多样性的分子。这些“应变辅助”反应包括定向亲核加成/捕获序列和环丙烯和双环丁烷的环加成反应。为了使该方法具有广泛的实用性，显然有必要开发不对称和对映选择性的合成和反应。虽然在综合方法学中任何程序的探索阶段都依赖于筛选，但每种方法的细化阶段都将严重依赖于机理分析。这项研究的应用有三个方面：1）开发新的合成方法，因为它们解决了基本的、未解决的问题，因此具有广泛的实用性; 2）开发非天然氨基酸，并将其应用于环境响应性生物材料; 3）应变分子在合成具有全碳季中心的生物碱中的应用，以及在合成Pycnocomandine- a 12-脱氧-16-羟基佛波醇天然产物，是PKC的有效激活剂和作为癌症药物的靶点。计算设计的pycnocomorphin类似物的合成也提出了建议。

DESCRIPTION (provided by applicant): The development of new reactions for organic synthesis is at the core of health related fields such as drug discovery, process chemistry, natural products synthesis and biologically inspired molecular design. While the state of the art is such that remarkably complex molecules can be synthesized given ample time and skilled personnel, there persists a need for tandem reactions that couple simple partners to selectively produce complex products. The goal of this research program is to harness the unusual reactivity of high strain molecules to quickly generate molecules that are rich in stereochemical complexity and structural diversity. These 'strain assisted' reactions include directed nucleophilic addition/capture sequences and cycloaddition reactions of cyclopropenes and bicyclobutanes. In order for the methodology to have broad utility, it is explicitly necessary to develop asymmetric and enantioselective syntheses and reactions. While the exploratory stages of any program in synthetic methodology rely on screening, the refinement stage of each method will rely heavily on mechanistic analysis. The applications of this research are threefold: 1) the development of new synthetic methods that will have broad utility because they address fundamental, unsolved problems; 2) the development of unnatural amino acids with applications in environmentally responsive biomaterials; 3) the use of strained molecules in the syntheses of alkaloids with all-carbon quaternary centers and in the synthesis of pycnocomolide - a 12-deoxy-16-hydroxyphorbol natural product that is a potent activator of PKC and a target as a cancer drug. The syntheses of computationally designed pycnocomolide analogs are also proposed.