Convergent Synthesis via Asymmetric Catalysis

描述（由申请人提供）：该项目的两个目标是发展炔和醛（第1部分）和炔和亚胺（第2部分）的催化偶联反应。这些方法在相同的操作中影响碳-碳键的形成和还原或烷基化，分别产生烯丙醇和烯丙胺。这些反应的产物在制备更复杂的具有治疗作用的分子时是有用的“手性构件”。在第3节中，炔和醛的不对称催化还原偶联被用作大环化或片段偶联的手段，用于terpestacin和fusaproliferin的全合成。特培他星抑制HIV感染的进展，它（或结构相关分子）可能提供一种治疗艾滋病的新手段。David Chan教授（加州理工学院生物学）开发了必要的检测方法，并对研究terpestacin的作用机制表达了浓厚的兴趣。在与第1节相关的初步研究中，已经为某些类型的炔开发了高度对映选择性的炔和醛的催化还原偶联（高达95% ee），并导致设计出可能更具选择性和/或更通用的新型配体。对于其他类型的炔，根据初步结果，另一种新型手性膦配体似乎更优越。与第2节相关的初步研究表明，某些亚胺在分子内和分子间三组分偶联反应中都是有效的偶联伙伴，其中来自有机硼烷试剂的基团也被纳入四取代的烯丙基胺产物中。与第3节相关的初步研究集中在高级合成中间体的制备上，并证明了催化片段偶联反应的可行性。

DESCRIPTION (provided by applicant): Two of the goals of this project are the development of catalytic coupling reactions of alkynes and aldehydes (Section 1) and of alkynes and imines (Section 2). These methods effect a carbon-carbon bond formation and either a reduction or alkylation in the same operation, providing allylic alcohols and allylic amines, respectively. The products of these reactions are useful "chiral building blocks" in the preparation of more complex molecules with therapeutic benefits. In Section 3, asymmetric catalytic reductive coupling of alkynes and aldehydes is used as a means of macrocyclization or fragment coupling in the total synthesis of terpestacin and fusaproliferin. Terpestacin inhibits the progression of HIV infection, and it (or structurally related molecules) may provide a new means with which AIDS can be treated. Prof. David Chan (Caltech Biology) has developed the necessary assays for and has expressed a strong interest in studying terpestacin's mechanism of action. In preliminary studies related to Section l, highly enantioselective catalytic reductive couplings of alkynes and aldehydes (up to 95 percent ee) have been developed for certain types of alkynes and have led to the design of novel ligands that may be more selective and/or more general. For other types of alkynes another novel chiral phosphine ligand appears to be superior based on preliminary results. Initial studies related to Section 2 have shown that certain imines are effective coupling partners in both intramolecular and intermolecular three component coupling reactions, in which a group from an organoborane reagent is also incorporated in the tetrasubstituted allylic amine product. Preliminary studies related to Section 3 have focused on the preparation of advanced synthetic intermediates and have demonstrated the feasibility of the catalytic fragment coupling reactions.