SYNTHETIC ACTIVE SITES FOR CATALYSIS OF BOND FORMATION

随意构建“人造”酶的能力， 自然界中存在的对应物，会对化学物质产生深远的影响， 合成. 因为这种人工酶可以用来选择性地 催化许多目前化学上或 经济上不可行。 从长远来看，这些合成催化剂可能 也有助于人类医药的药典，不仅用于 在生产新的药物，但也（也许在微- 用于直接治疗各种疾病-疾病 由于患者无法（i）正确处理生物 前体或（ii）代谢/排泄副产物或毒素。 本项目的目标是构建两个完全合成的活性 位点（1/1 '）设计用于催化键的形成。 每一个活跃的网站， 是分子量<1，000的有机分子，含有底物 结合位点和催化单元，并且旨在表现出催化作用， 选择性和周转率。 两个活动站点将采用过渡 状态稳定化以实现其催化活性。 的合成 1/1 "，这充分利用了大型 亚基，应该提供1/1 '的高度收敛的路线，其中 最长的合成序列的长度略多于十几个步骤。 合成酶1/1 '旨在在有机溶剂中操作，因为它们 利用氢键进行识别和结合。 1/1 "的替代方案是 还描述了考虑到意外困难的可能性 1/1 "可以浮出水面。 该提案概述了1/1 '设计中反映的战略， 详细说明了1/1 '概念中的各个元件（包括基底 结合、过渡态稳定、质子转移、柔性与 刚性、产物释放、转化率和选择性）将被并入， 测量和优化。 因为最终的目标是证明 设计概念本质上是通用的，可以很容易地应用于 解决了几乎无限合成和其他实际 问题

The ability to construct, at will, "artificial" enzymes for which no natural counterparts exist, would have a profound effect on chemical synthesis. For such artificial enzymes could be employed to selectively catalyze many reactions that are presently either chemically or economically infeasible. In the long-term, these synthetic catalysts may also contribute to the pharmacopeia of human medicine, being used not only in production of new pharmaceuticals, but also (perhaps in micro- encapsulated form) for directly treating a variety of illnesses - illnesses resulting from a sufferer's inability to (i) properly process biological precursors or (ii) metabolize/excrete by-products or toxins. The objective of this project is to construct two fully synthetic active sites (1/1') designed to catalyze bond formation. Each active site, which is an organic molecule with a molecular weight < 1,000, contains substrate binding sites and a catalytic unit and is intended to exhibit catalysis, selectivity, and turnover. The two active sites will employe transition state stabilization to achieve their catalytic activity. The synthesis of 1/1', which takes advantage of the commercial availability of large subunits, should afford 1/1' by a highly convergent route in which the longest synthetic sequence is little more than a dozen steps in length. Synthetases 1/1' are intended to operate in organic solvents, because they use hydrogen bonding for recognition and binding. Alternatives to 1/1' are also described to allow for the possibility that unexpected difficulties with 1/1' may surface. The proposal outlines the strategies reflected in the design of 1/1' and details how individual elements in the concept of 1/1' (including substrate binding, transition state stabilization, proton transfer, flexibility vs. rigidity, product release, turnover and selectivity) will be incorporated, measured and optimized. For the ultimate goal is to demonstrate that the design concepts are general in nature, and can be easily applied to the solution of a virtually unlimited array of synthetic and other practical problems.