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.
This proposal is planned to explore novel strategies for the asymmetric synthesis of unnatural amino acids, and -amino phosphonic acids for neuro drug design and synthesis. A new concept of GAP chemistry is also applied to the synthesis of neuro peptides and peptidomimetics to make these syntheses environmentally friendly without tedious work-up. The GAP peptide synthesis can avoid disadvantages of known methods. The preliminary results have been obtained in the PI's lab, which makes this proposal feasible. Thus far, the PI's group has trained nearly 60 undergraduate students and 18 graduates in conducting research in organic/medicinal research including a Chinese Olympic Gold Medalist on Chemistry. All graduates and nearly 30 undergraduates achieved research publications with the PI. All of these students either successfully entered medical schools or found jobs in pharmaceutical companies.
|Sun, Hao; Han, Jianlin; Kattamuri, Padmanabha V et al. (2013) Approach to vicinal t-Boc-amino dibromides via catalytic aminobromination of nitrostyrenes without using chromatography and recrystallization. J Org Chem 78:1171-5|
|Kattamuri, Padmanabha V; Xiong, Yiwen; Pan, Yi et al. (2013) N,N-DIIsopropyl-N-phosphonyl imines lead to efficient asymmetric synthesis of aziridine-2-carboxylic esters. Org Biomol Chem 11:3400-8|
|Pindi, Suresh; Wu, Jianbin; Li, Guigen (2013) Design, synthesis, and applications of chiral N-2-phenyl-2-propyl sulfinyl imines for group-assisted purification (GAP) asymmetric synthesis. J Org Chem 78:4006-12|
|Jiang, Bo; Wang, Xue; Xu, Hai-Wei et al. (2013) Highly selective domino multicyclizations for forming polycyclic fused acridines and azaheterocyclic skeletons. Org Lett 15:1540-3|
|Xiong, Yiwen; Mei, Haibo; Xie, Chen et al. (2013) Asymmetric synthesis of *-alkenyl homoallylic primary amines via 1,2-addition of Grignard reagent to *,*-unsaturated phosphonyl imines. RSC Adv 3:15820-15826|
|Hu, Fang-Le; Wei, Yin; Shi, Min et al. (2013) Asymmetric catalytic aza-Morita-Baylis-Hillman reaction for the synthesis of 3-substituted-3-aminooxindoles with chiral quaternary carbon centers. Org Biomol Chem 11:1921-4|
|Jiang, Bo; Yi, Mian-Shuai; Shi, Feng et al. (2012) A multi-component domino reaction for the direct access to polyfunctionalized indoles via intermolecular allylic esterification and indolation. Chem Commun (Camb) 48:808-10|
|Jiang, Bo; Li, Qiu-Yun; Zhang, Hao et al. (2012) Efficient domino approaches to multifunctionalized fused pyrroles and dibenzo[b,e][1,4]diazepin-1-ones. Org Lett 14:700-3|
|Yuan, Zhiliang; Mei, Liangyong; Wei, Yin et al. (2012) Asymmetric catalytic Mannich-type reaction of hydrazones with difluoroenoxysilanes using imidazoline-anchored phosphine ligand-zinc(II) complexes. Org Biomol Chem 10:2509-13|