GAP化学用于绿色化学合成与药物生产

The synthesis and production of pharmaceuticals and chemicals in industrial and academic labs generate tons of wastes daily, particularly, the disposal of silica gel wastes and solvents has been imposing significant environmental negative impacts. This proposal is to investigate the new concept: GAP (Group-Assisted Purification) chemistry, the chemistry of utilizing well-engineered functional groups to control the solubility of final products and the reactivity and stereoselectivity of reagents. The pure products from GAP processes can be obtained simply by washing the crude products with certain solvents so as to avoid the traditional purification methods of silica gel chromatography or re-crystallization. Furthermore, the functional auxiliaries of GAP chemistry can be conveniently recovered for re-use. Obviously, the GAP chemistry is anticipated to have a large impact on academic and industry in regard to the decreased use of materials, manpower, energy and processing time in future. The GAP chemistry can not only be utilized for general organic and asymmetric synthesis, it can also be used for amino acids' protection and peptide synthesis to avoid disadvantages of solid-phase-peptide synthesis (SPPS) invented by the Nobel Laureate, Bruce Merrifield and the liquid-phase-peptide synthesis (LPPS). It should noted that the marketed peptides and peptidomimetics are becoming outstanding drugs on market recently, for example, only following three peptide drug, Sandostatin, Kaletra, and Zoladex show annual sales of over 1.0 trillion on worldwide market. The greener GAP synthesis of peptides and peptidomimetics can substantially reduce prices of these drugs as well as many other products. In the meanwhile, it will also accelerate the drug discovery processes.

工业/学术界日常的药品和化学品生产都会伴随着大量的废弃物，其中的硅胶和溶剂对环境有着极坏的影响。本方案将发展一个新概念：GAP(Group-Assisted Purification)化学，利用特定的官能团来控制最终产物的溶解性，通过简单洗涤粗产品即可完成产品纯化。这样就避免使用传统柱层析或重结晶的方法。显然，GAP化学可以大大减少原料，人力、能源和处理时间的需要，将会对学术和工业界的起着非常重大的影响力。GAP化学还可用于合成多肽以避免一些固相多肽合成（SPPS，由诺贝尔奖得主Bruce Merrifield发明）和液相多肽合成（LPPS）的缺点。值得注意的是，最近一些多肽和肽类似物正逐渐成为市场上杰出的药物，比如药物Sandostatin, Kaletra 和Zoladex在世界范围内年销售额都超过10亿美元。GAP化学绿色合成多肽药物不仅可以降低药物的价格还可以加快药物的开发。

数十年来，有机合成和生产总是与环境污染联系在一起，这是由于其低效的合成过程导致了大量副产物和废弃物的产生，比如柱层析纯化产物过程中就需要大量的硅胶和溶剂。与此同时，目前除了离子化和聚合这两种途径外还没有其他有效的方法能使油状的、粘稠的产物转化为固体或者晶体。为了解决这些问题，项目组负责人从概念上提出在有机合成中通过设计新试剂和新辅助基团来实现GAP（官能团辅助纯化）化学/技术。一系列GAP试剂设计合成出来并被用于不对称反应中，反应生成的固体产物可以通过一些常用溶剂或混合溶剂洗涤得到。同样我们也合成了一些GAP催化剂，可用于催化一些不对称反应，并且该催化剂可以通过GAP洗涤回收、重复使用几次而不会使得反应的产率和ee值有明显的下降。GAP多肽合成在避免传统液相和固相多肽合成缺陷的同时却兼具这两者的优势。另外利用具有潜在GAP性质的化合物实现了廉价金属催化C-H键活化官能团化反应、可见光还原型自由基反应、电化学合成和极性翻转反应。一些新的GAP化学官能团参与的反应还在进一步研究中。