SYNTHETIC ACTIVE SITES FOR CATALYSIS OF BOND FORMATION

随心所欲地构建“人造”酶的能力 天然对应物的存在，会对化学物质产生深远的影响 综合。因为这样的人工酶可以选择性地用于 催化许多反应，这些反应目前要么是化学的，要么是 在经济上是不可行的。从长远来看，这些合成催化剂可能 也有助于人类医学的药典，不仅被使用 在新药物的生产中，但也(可能在微型 包裹式)用于直接治疗各种疾病 由于患者不能(I)适当地处理生物 前体或(Ii)代谢/排泄副产物或毒素。 该项目目标是构建两个完全合成的活性物质 用于催化成键的位置(1/1‘)。每个活动站点，其中 是一种分子质量为1,000的有机分子，含有底物 结合部位和催化单元，并旨在展示催化作用， 选择性和周转率。这两个活跃站点将采用转换 稳定状态以实现其催化活性。双环芳香烃的合成 1/1‘，这利用了大型 亚基，应通过高度收敛的路线提供1/1‘，其中 最长的合成序列的长度只有十几步多一点。 合成酶1/1‘用于在有机溶剂中工作，因为它们 使用氢键进行识别和结合。1/1‘的替代方案有 也被描述为考虑到意外困难的可能性 1/1‘可能浮出水面。 该提案概述了1/1‘和 详细说明1/1‘(包括衬底)概念中的各个元素 结合，过渡态稳定，质子转移，柔韧性与。 刚性、产品发布、周转和选择性)将被纳入， 经过测量和优化。因为最终目标是证明 设计概念本质上是一般性的，可以很容易地应用于 几乎无限阵列的合成和其他实用的解决方案 有问题。

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.