Tetrahydrofurans, Tetrahydropyrans and 2H-Furanones

描述(申请人提供)：该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、非外消旋的构建块应用于生物活性分子的合成。目前的目标是通过钯(0)催化的氧和碳亲核试剂与膦基烯丙基碳酸酯的加成反应，高效地立体选择性地合成四氢呋喃、吡喃和2H-呋喃酮。四氢呋喃和吡喃是许多重要的天然产物的共同结构特征。初步结果表明，氧亲核试剂可以通过分子间和分子内的钯催化与膦基烯丙基碳酸盐进行完全的手性转移。由于钯催化的环化反应是立体专一性的，所以膦基烯丙基碳酸酯的立体化学决定了新呋喃环的立体化学是固定的醇立体化学。因此，与R或S膦酸酯的交叉歧化和环化反应将从一个共同的中间体生成顺式或反式四氢呋喃。从一个共同的中间体合成两个立体异构体脂呋喃将证明所提出的方法的灵活性。该方法的进一步演示将是合成一系列功能化的四氢呋喃化合物，这些化合物可用于合成各种含有四氢呋喃的天然产物。 第二个目标是合成具有强细胞毒性(纳米分子)的海洋天然产物四氢呋喃，并确认其结构和生物活性。提出了一种收敛合成方法，它还将允许制备侧链衍生物来确定高活性所需的重要结构特征。 第三个目标是合成环磷酰胺家族的部分成员和一些磷酸酯类似物。作为HSL的抑制剂，环磷酰胺是治疗II型糖尿病的先导化合物。计划中的合成方法是灵活的，将允许链的变化和C3a的绝对立体化学。此外，一系列简单的非环类似物很容易从商业上获得的酰基丁内酯中制备出来。所合成的化合物将用于探索环孢素与大鼠HSL的作用方式。

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.