Synthetic Approaches to Blepharocalyxins D and E

描述（由申请人提供）：本研究的目的是开发从Alpinia blepharocalyx中分离出的抗肿瘤药物blepharocalyxin E和d的立体控制途径，这些天然产物作为治疗人类肿瘤的潜在候选药物显示出特别的希望。Blepharocalyxin D对小鼠结肠26-L5癌细胞的体外抑制活性最强，ED50为3.61 μ M，更显著的是，Blepharocalyxin E对人纤维肉瘤HT-1080细胞的抑制活性为9.02 μ M，与临床使用的5-氟尿嘧啶（ED50为8.00 μ M）相当。为了充分利用这些新型眼睑alyxin阵列作为治疗人类肿瘤的药物的潜力，计划进行合成研究。这些类似物的绝对结构是基于各种光谱数据，并通过与以前分离的白桦的比较确定的。然而，通过全合成对这些结构赋值的验证尚未见报道。因此，这项研究之所以重要，主要有两个原因。除了确定这些天然产物的绝对结构外，这些化合物的大规模途径有望为筛选提供有用的类似物。

DESCRIPTION (provided by applicant): The goal of this research is to develop stereocontrolled routes to the antitumor agents blepharocalyxin E and D. Isolated from Alpinia blepharocalyx, these natural products have shown particular promise as potential drug candidates for the treatment of human tumors. Blepharocalyxin D showed the strongest activity against murine colon 26-L5 carcinoma cells in vitro, with an ED50 of 3.61 mu M. Even more significant, blepharocalyxin E displayed inhibitory activity towards human fibrosarcoma HT-1080 cells with an ED50 of 9.02 mu M, which is comparable in activity to the clinically used 5-fluorouracil (ED50 of 8.00 mu M). In order to exploit the full potential of these novel blepharocalyxin arrays as agents for the treatment of human tumors, synthetic studies are planned. The absolute structures of these analogues were assigned based on a variety of spectroscopic data, and also by comparison with previous isolates of A. blepharocalyx. However, a validation of these structure assignments through total synthesis has not been reported. This research, then, is important for two main reasons. In addition to confirming the absolute structures of these natural products, large-scale routes to these compounds would hopefully provide useful analogues for screening. The main body of this proposal will focus on the stereoselective synthesis of cis-fused dioxabicyclic lactones (6,6- and 6,5-fused) and their subsequent use, through ring opening substitution reactions, in the stereocontrolled construction of C-aryl pyranosides. The purpose of this exercise will be to develop useful models for the synthesis of blepharocalyxins D and E. For the synthesis of the 6,5-fused systems, Mn(lll) acetate mediated radical additions of potassium methyl malonate esters to dihydropyrans will be investigated, while a hetero-Diels-Alder route will used to prepare the corresponding 6,6-fused systems. The in situ generation of oxocarbenium ions from both bicyclic lactone series will be studied for the first time. A postulate to be tested is whether electron-rich aromatic donors consistently add to these oxocarbenium ion intermediates with beta-selectivity.