Utilizing Non-Functionalized Terpenes to Develop Novel Strategies and Chemoselective Transformations

项目摘要/摘要 作为一类，以萜类为基础的天然产物长期以来一直带来关键的科学发现和进步。 例如，长叶烯的特殊连接性是建立在其基础上的基础。 逆合成分析的力量，而更大的分子，如类固醇，一直是治疗的宝贵工具 并了解疾病以及在其上发展强大的键形成反应的支架，如 亲电泳体诱导的多烯环化和位点特异性官能化。我们相信，有许多人 班级内部仍有进一步发展的机会，在这里，我们特别寻求探索 结构复杂但相对非功能化的成员有潜力为发展做出贡献 具有广泛适用性的新反应、新战略、新战术。我们的目标是开发手段，既能量身定做，又能 提供高度专一性的分子结构，反映了大自然可以通过酶作用完成的化学 以及贡献了新的反应和工具，而这些反应和工具是没有生物对应的。 正如提案中所描述的那样，我们寻求探索可能取得进展的几种途径。第一, 根据先前完成的名为presilphiperfolan-8-ol的应变分子的全合成， 我们设计了一系列基于PD的Heck中继级联，具有各种不同的格式，以生成 原子的关键图案，在几个不同的分子集合中似乎是保守的，尽管 具有独特的植物起源，并且可能是生物起源的。本研究的主要目标是影响这种反应。 在竞争的β-氢化物消除途径可能阻碍成功的情况下，并探索其可行性 在高度受阻的环境中的Heck类型的过程，例如将四取代烯烃作为 接受者。其次，我们寻求利用C-PdII中间体与分子间前所未有的相互作用 氧和氮亲核试剂获得高区域和对映体选择性的GEM-二甲基醚 半个。最后，对如何合成和使用四元中心进行了仔细的考虑 我们认为与合成设计相关的关键见解。这一概念由建议的 在合成中产生两个不同的天然产物家族，这将是唯一可用的 到目前为止的路线，或者在总体步骤经济方面比过去的努力有明显改善的情况。

PROJECT SUMMARY/ABSTRACT As a class, terpene-based natural products have long led to critical scientific discoveries and advances. For instance, the particular connectivity of longifolene served as the inaugural ground upon which to establish the power of retrosynthetic analysis, while larger molecules such as steroids have been valuable tools to treat and understand disease as well as a scaffold upon which to develop powerful bond-forming reactions such as electrophile-induced polyene cyclizations and site-specific functionalizations. We believe that numerous opportunities remain for further development within the class, and here we seek specifically to probe the potential of structurally complex, but relatively non-functionalized, members to contribute to the development of new reactions, strategies, and tactics of broad applicability. Our goal is to develop the means to both tailor and deliver molecular structure with high specificity, mirroring chemistry that Nature can accomplish enzymatically as well as contributing new reactions and tools that have no biological counterpart. As delineated within the proposal, we seek to explore several avenues for possible advances. First, drawing from a previously accomplished total synthesis of a strained molecule known as presilphiperfolan-8-ol, we have designed an array of Pd-based Heck relay cascades, in a variety of different formats, to generate a key patterning of atoms that is seemingly conserved across several different molecular collections despite having distinct plant, and likely biogenetic, origins. Key goals for the present study are to affect such reactions in contexts where competing β-hydride elimination pathways could preclude success, and to probe the viability of Heck-type processes in highly hindered settings, such as ones that would utilize tetrasubstituted olefins as acceptors. Second, we seek to utilize C-PdII intermediates in unprecedented trappings with intermolecular oxygen and nitrogen nucleophiles to access highly regio- and enantioselectively functionalized gem-dimethyl moieties. Finally, careful consideration of both how to synthesize and use quaternary centers has afforded what we believe to be critical insights pertinent to synthetic design. This concept is illustrated by the proposed generation of two different families of natural products in syntheses which either would be the only available route to date or which are marked improvements on past efforts in terms of overall step economy.