b-Lactones: Bioactive Target and Vehicles for Synthesis

该建议旨在利用非对映选择性途径获得双环-β-内酯， 抗肿瘤、抗菌和抗炎剂， 研究基本生物过程的工具。在此资助期内，我们将继续 利用我们小组开发的各种方法的潜力， 多种生物活性天然产物的通用全合成，包括 盐孢菌酰胺类，scabrolides/ineleganalide，恶唑霉素，和 haterumalides/biselides。这些化合物都对各种细胞系表现出有效的作用 因此，该项目也将最终确定其细胞靶点， 这是未知的，或者开发这些蛋白质反应性天然的变体， 产品作为基于活性的细胞探针来识别脱靶。具体目标是： (1)在上一个资助期工作的基础上，优化研究针对 改进的产率和非对映选择性的简明（9步骤从丝氨酸） 有效的蛋白酶体抑制剂salinosporamide A的对映选择性合成是 提出了可能具有增加效力的假设导向衍生物是 基于报告的salino A-和belactosin-20 S的X射线结构提出 蛋白酶体复合物（将在Genzyme进行测试）。(2)在我们努力实现 salinosporamides，我们提出了一种合成恶唑霉素和neooxazolomcyin的方法。 涉及改性双环化的内酰胺核。(3)我们将利用我们最近 开发了酮酸的非对映选择性双环化反应，以获得 环戊基核心，常见于海洋西膜的scabrolide/ineleganalide家族。 为了构建双环-<$-内酯大环核心，我们提出了一个跨环CH 插入，这将是根本利益的综合这一日益扩大的家庭， 双环“-内酯大环化合物和相关的目标。(4)我们建议加倍- 非对映选择性双环化合成戊内酯稠合四氢呋喃 以获取在haterumalides（Hat）/biselides（Bise）中发现的THF。

This proposal seeks to exploit diastereoselective routes to bicyclic-¿-lactones to access antitumor, antibacterial and anti-inflammatory agents of interest for human health and as tools for studying basic biological processes. In this grant period, we will continue to exploit the potential of various methods developed in our group that enable concise and versatile total syntheses of several bioactive natural products including salinosporamides, scabrolides/ineleganolide, oxazolomycins, and haterumalides/biselides. These compounds all exhibit potent effects on various cell lines thus this project will also ultimately target the identification of their cellular targets where this is unknown or alternatively develop variants of these protein-reactive natural products as activity-based cellular probes to identify off-targets. The particular aims are: (1) Building on work from the previous grant period, optimization studies directed toward improved yields and diastereoselectivity of a concise (9 steps from serine) enantioselective synthesis of the potent proteasome inhibitor, salinosporamide A are proposed. Hypothesis-directed derivatives that may have increased potency are proposed based on the reported X-ray structures of the salino A- and belactosin-20S proteasome complexes (to be tested at Genzyme). (2) Building on our work toward the salinosporamides, we propose a synthesis of the oxazolomycin and neooxazolomcyin ¿- lactam core involving modified bis-cyclizations. (3) We will exploit our recently developed, diastereoselective bis-cyclization reaction of keto acids to access the cyclopentyl core common to the scabrolide/ineleganolide family of marine cembranes. To construct, the bicyclic-¿-lactone macrocyclic core, we propose a transannular CH insertion that would be of fundamental interest for the synthesis of this growing family of bicyclic "-lactone macrocycles and related targets. (4) We propose double- diastereoselective, bis-cyclizations for the synthesis of ¿-lactone-fused tetrahydrofurans to access THFs found in the haterumalides(Hat)/biselides(Bise).