Tetrahydrofurans, Tetrahydropyrans and 2H-Furanones

四氢呋喃、四氢吡喃和2H-呋喃酮

• 批准号: 7143366
• 负责人: CHRISTOPHER D SPILLING
• 金额: $ 24.31万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143366
• 关键词: analog; biological products; carbon; chemical synthesis; cyclization; furans; inhibitor /antagonist; lipase; method development; nanotechnology; oxidation; palladium; phosphonate; pyrans; small molecule; stereochemistry; stereoisomer

DESCRIPTION (provided by applicant): The long term objective of this project is the application of allylic hydroxy phosphonates and their derivatives as chiral, nonracemic building blocks for the synthesis of biologically active molecules. The immediate goal is the efficient stereoselective synthesis of tetrahydrofurans, pyrans, and 2H-furanones via the palladium (0)-catalyzed addition of oxygen and carbon nucleophiles to phosphono allylic carbonates. Tetrahydro furans and pyrans are common structural features in a number of important classes of natural product. Preliminary results have demonstrated that oxygen nucleophiles undergo both inter and intra-molecular palladium catalyzed addition to phosphono allylic carbonates with complete chirality transfer. Since the palladium catalyzed cyclization is stereospecific, the stereochemistry of the phosphono allylic carbonates dictates the stereochemistry of new furan ring for a fixed alcohol stereochemistry. Thus, cross metathesis and cyclization with either the R or S phosphonate will yield the cis or trans tetrahydrofurans from a common intermediate. The synthesis of two stereoisomeric lipid furans from a common intermediate will serve as demonstration of the flexibility of the proposed method. A further demonstration of the method will be the synthesis of a series of functionalized thf building which can be used for the synthesis of a wide range of thf containing natural products. In the second aim it is proposed to synthesize the thf containing potent (nanomolar) cytotoxic marine natural product amphidinolide C and confirm structure and the reported biological activity. A convergent synthesis is proposed which will also allow the preparation of side chain derivatives to determine important structural features required for high for activity. The third aim involves the synthesis of selected members of cyclipostin family and some phosphonate analogs. As inhibitors of HSL, the cyclipostins are lead compounds for the treatment of type II diabetes. The planned method of synthesis is flexible will allow variation in the chain and the absolute stereochemistry at C3a. Furthermore, a series of simple acyclic analogs are easily prepared from commercially available acyl butyrolactone. The synthesized compounds will be used to probe the mode of action of the cyclipostins with rat HSL.

描述（由申请人提供）：本项目的长期目标是将烯丙基羟基膦酸酯及其衍生物作为手性、非外消旋结构单元用于生物活性分子的合成。直接的目标是通过钯（0）催化的氧和碳亲核试剂与膦酰基烯丙基碳酸酯的加成，高效立体选择性地合成四氢呋喃、吡喃和2 H-呋喃酮。四氢呋喃和吡喃是许多重要类别的天然产物的共同结构特征。初步研究结果表明，含氧亲核试剂与膦酰基烯丙基碳酸酯发生分子内和分子间钯催化加成反应，并发生完全的手性转移。由于钯催化的环化反应是立体定向的，膦酰基烯丙基碳酸酯的立体化学决定了新呋喃环的立体化学，用于固定的醇立体化学。因此，与R或S膦酸酯的交叉复分解和环化将从共同的中间体产生顺式或反式四氢呋喃。从一个共同的中间体的两个立体异构体的脂质呋喃的合成将作为所提出的方法的灵活性的示范。该方法的进一步证明将是一系列功能化的thf建筑物的合成，其可用于合成广泛的含thf的天然产物。 第二个目标是合成含thf的强（纳摩尔）细胞毒性海洋天然产物amphidinectin C，并确认其结构和已报道的生物活性。提出了一种收敛合成，这也将允许侧链衍生物的制备，以确定高活性所需的重要结构特征。 第三个目标是合成选择性的cyclopostin家族成员和一些膦酸酯类似物。作为HSL的抑制剂，cyclopostins是用于治疗II型糖尿病的先导化合物。计划的合成方法是灵活的，将允许在C3 a的链和绝对立体化学的变化。此外，一系列简单的无环类似物很容易从市售的酰基丁内酯制备。合成的化合物将用于探测cyclopostins与大鼠HSL的作用模式。