Novel Multiple-Component X-C/C-C Formation Reactions

描述(由申请人提供)：这份NIH R15提案旨在开发使用1-碘-3-硅氧基-L，3-丁二烯(丹尼舍夫斯基类型的二烯)的新型X-C/C-C键形成反应和Diels-Alder环化。这些反应的不对称催化版本将被研究。这些反应可以提供许多化学和生物上重要的化合物的有效途径。例如，根据NCI的测试，由Pl的团队制造的一种新的铅结构被发现对结肠癌、非小细胞肺癌和黑色素瘤具有活性。在过去的几年里，Pi‘s小组在多组分X-C/C-C成键反应方面取得了大量的初步结果。不对称卤代羟醛缩合反应是烯丙醇酸酯与醛的第一次不对称催化羰基加成反应。基于我们的初步结果，新的不对称卤代Aldol反应将通过α，β-烷基酮的1，4-强健活化和1，2-串联官能化来进行。设计了新型手性磷酰胺和聚合物微球固定的手性磷酰胺，并将其合成为Lewis碱催化剂。同时，还将获得一系列手性Lewis酸催化剂，并用于控制卤代Aldol反应和Diels-Alder反应的手性。α，β-乙酰基酮和酯的1，2-二官能化反应将得到多官能化的β-卤代Baylis-Hillman加合物。新的催化剂和催化系统将导致高的区域选择性、立体选择性、化学选择性以及新反应的底物范围。除了不对称催化作用外，手性对甲苯和叔丁基磺亚胺也将被用作新型X-C/C-C键形成反应的手性助剂和亲电体。到目前为止，PI已经培养了21名本科生，其中14人以合著者的身份发表了论文。这些学生中的大多数都成功进入了美国的医学院或研究生院。此外，6名研究生已经或仍在接受派的综合项目的培训。这份R15拨款申请对PI继续他在德克萨斯理工大学的教学和研究活动非常重要。

DESCRIPTION (provided by applicant): This NIH R15 proposal is intended to develop novel X-C/C-C bond formation reactions and Diels-Alder cyclization using 1-iodo-3-siloxy-l,3-butadiene (Danishefsky-type diene). The asymmetric catalytic versions of these reaction will be investigated. These reactions can provide efficient approaches to numerous chemically and biologically important compound. For example, a novel lead structure made by the Pl's group has been found to be active toward colon cancer, non-small cell lung cancer and Melanoma as tested by NCI. In the past few years, the PI's group have obtained a substantial amount of preliminary results for the multiple-component X-C/C-C bond formation reaction. The asymmetric halo aldol reaction is the first asymmetric catalytic carbonyl addition of allenolates to aldehydes. Based on our preliminary results, the new asymmetric halo aldol reactions will be carried out by 1,4-robust activation and 1,2-tandem functionalization of alpha,beta-alkylenic ketones. New chiral phosphoramides and polymer beads-attached chiral phosphoramides are designed and will be synthesized as the Lewis base catalysts. Meanwhile, a series of chiral Lewis acid catalysts will be obtained and utilized to control the chirality for the halo aldol and Diels-Alder reactions. The 1,2-difuctionalization of alpha,beta-acetylenic ketones and esters will result in beta-halo Baylis-Hillman adducts which are multiple functionalized. The new catalysts and catalytic systems will result in high regioselectivity, stereoselectivity, chemoselectivity, as well as the scope of substrates for the new reactions. Besides the asymmetric catalysis, chiral p-toluene and tert-butanesulfinimines will also be utilized as the chiral auxiliaries and electrophiles for the novel X-C/C-C bond formation reactions. So far, the PI has trained 21 undergraduates, and fourteen of them achieved publications as co-authors. Most of these students have successfully entered medical or graduate schools in the US. In addition, 6 graduate students have been or are still being trained by PI's synthesis projects. This R15 grant application is very important for the PI to continue his teaching and research activities at Texas Tech.