GAP Chemistry Approaches to Chiral Amino Acids, Peptides and Peptidomimetics

GAP（基团辅助纯化）化学的新概念最近已经通过以下方式建立： 差距化学表明氨基化合物的有机合成可以实现 而不使用色谱法和结晶。该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-和-氨基 磷酸盐用于神经药物的设计和合成。差距化学也将使 合成神经肽和一般肽和肽模拟物，以避免 传统的固相肽合成（SPPS）和液相肽合成。虽然 液相肽合成（LPPS）是作为一种混合技术开发的，该方法仅 适用于肽合成的简单酰胺键形成;它具有极大的 模板的分子量，这使得它不方便生产大量的产品;长 通常需要一段时间来产生晶体前体和产物（有时，甚至需要一个 周）通过仔细控制固化/结晶条件。相比之下，差距化学工具 本项目将结合固相肽合成（SPPS）、液相肽合成（SPPS）、液相肽合成（SPPS） 合成（SoPPS）和液相肽合成（LPPS），包括通过过滤的快速纯化， 潜在的自动化手动选项（用于SPPS）;易于从mg放大到kg，并且无需 过量的试剂或昂贵的仪器（用于SoPPS和LPPS）。到目前为止，一个有效的 能够进行不对称合成随后进行肽合成的方法尚未被 记录至今。在这个ECHEM项目中，产生的特殊手性氨基酸通过N- 差距合成的膦酰基和N-氧膦基部分可用于设计， 重要的药物滥用相关靶点，如神经肽、N-花生四烯酸-甘氨酸的合成 衍生物、N-花生四烯酸乙醇胺、加压素和神经降压素类似物。有前途 PI小组获得的初步结果使这一建议可行。在过去的14年里，PI 培养了近60名本科生和18名毕业生（其中5名合作毕业生， 中国，其中一个是中国奥运会化学金牌得主）在进行有机和 生物有机/医学研究。所有这些毕业生和近30名本科生都实现了研究 作为主要研究者的合著者发表了许多出版物，并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.