GAP Chemistry Approaches to Chiral Amino Acids, Peptides and Peptidomimetics

GAP(基团辅助净化)化学的新概念是最近由 PI‘s基团；GAP化学表明可以实现氨基化合物的有机合成 不需要使用层析和结晶。这份eChem提案计划探索 GAP化学用于不对称合成一系列非天然氨基酸和-氨基 用于神经药物设计和合成的磷酸盐。GAP化学也将使 神经肽和一般多肽的合成及多肽仿生学的研究 传统的固相-多肽合成(SPPS)和溶液-多肽合成。尽管 液相多肽合成(LPPS)是作为一种混合技术发展起来的，这种方法只是 适用于合成肽的简单的酰胺键形成；它的缺点是 模板分子量大，不方便大量生产；长 产生结晶前体和产品通常需要时间(有时，甚至需要一个 周)，通过仔细控制凝固/结晶条件。相比之下，GAP化学工具 由于本项目将具有固相多肽合成(SPPS)、溶液相多肽合成(SPPS)的优点 合成(SoPPS)和液相肽合成(LPPS)，包括过滤快速纯化， 潜在的自动手动选项(用于SPPS)；轻松从mg扩展到kg，并且不需要 过量的试剂或昂贵的仪器(用于SOPPS和LPPS)。到目前为止，一个高效的 一种实现不对称合成的方法，随后不能进行多肽合成 还没有记录在案。在这个eChem项目中，得到的特殊手性氨基酸是由N-键连接的。 来自GAP合成的膦和N-膦部分可用于设计和 神经肽、N-花生四烯酰甘氨酸等重要药物滥用相关靶标的合成 衍生物，N-花生四烯醇胺，血加压素和神经降压素类似物。前景看好 PI小组获得的初步结果表明，这一建议是可行的。在过去的14年里，PI 培养了近60名本科生和18名毕业生(包括5名协作式毕业生 中国，其中一位是中国奥运会化学金牌获得者)在进行有机和 生物有机/医学研究。所有这些毕业生和近30名本科生都完成了研究 作为出版物的合著者，与PI成功地找到了专业职位。

The novel concept of GAP (Group-Assistant-Purification) chemistry has been established recently by the PI's group; the GAP chemistry shows organic synthesis of amino compounds can be achieved without the use of chromatography and crystallization. This ECHEM proposal is planned to explore the GAP chemistry for asymmetric synthesis of a series of unnatural amino acids and - and -amino phosphonates to serve for neuro drug design and synthesis. The GAP chemistry will also benefit the synthesis of neuro and general peptides and peptidomimetics as to avoid the disadvantages of traditional solid-phase-peptide synthesis (SPPS) and solution-phase-peptide synthesis. Although the liquid-phase-peptide synthesis (LPPS) was developed as a hybrid technique, this method was only suitable for simple amide bond formations for peptide synthesis; it suffers from the extremely large molecular weight of template which makes it inconvenient to produce large amounts of products; a long period is often needed to generate crystalline precursors and products (sometimes, it even takes one week) by carefully controlling solidification/crystalization conditions. In contrast, the GAP chemistry tool for this project will have advantages of solid-phase-peptide synthesis (SPPS), solution-phase-peptide synthesis (SoPPS) and liquid-phase-peptide synthesis (LPPS) including quick purification by filtration, a potential automated manual option (for SPPS); easy scale-up from mg to kg, and there is no need for excess amounts of reagents or expensive instrument (for SoPPS and LPPS). So far, an efficient method which enables asymmetric synthesis subsequently followed by peptide synthesis not been documented yet. In this ECHEM project, the resulting special chiral amino acids attached by N- phosphonyl and N-phosphinyl moieties from the GAP synthesis can be utilized for the design and synthesis of important drug abuse related targets, such as neuropeptides,N-arachidonoyl-Gly derivatives, N-arachidonoyl enthanolamines,hemopressin and neurotensin analogs. Promising preliminary results obtained by the PI's group make this proposal feasible. In the past 14 years, the PI has trained nearly 60 undergraduate students and 18 graduates (including 5 collaborative graduates in China, one of them is a Chinese Olympic gold medalist on chemistry) on conducting organic and bioorganic/medicinal research. All of these graduates and nearly 30 undergraduates achieved research publications as co-authors with the PI and successfully found professional positions.