The Application Of GAP Chemistry In Asymmetric Aza-MBH Reaction And Synthesis Of Two Functional Molecules

The first section reports a systematic review of the research background and concept of GAP (Group-Assisted Purification) chemistry. During them, studies on auxiliary-imines-involving asymmetric reaction, multi-components reactions and aminohalogenation reactions are representative. By using GAP purification, the pure desired products are rapidly obtained, which only need simple organic solvents to be washed, simplifying operation and advoiding the use of column chromatography and recrystallization. Therefore, this technology has a widespread prospect in organic chemistryand relative industrial applications. Next, the development of aza-Morita-Baylis-Hillman (aza-MBH) reaction in recent five years are also introduced, which focuses on both chiral catalysts induced asymmetric aza-MBH reactions and chiral auxiliaries-mediated aza-MBH reactions. Due to chiral catalysts show poor catalytic activities in gram-scale reactions, their applications are limited whereas the current chiral auxiliaries-mediated aza-MBH reactions suffer from poor stereoselectivity. Therefore, the development of highly stereoselectivechiral auxiliaries-mediated aza-MBH reactionsis desirable.Based on the above studies, herein, we successfully combined GAP chemistry with asymmetric aza-MBH reactions. Under a mild condition (solvent:toluene,10 ℃), phosphoryl imine with cyclohexyl skeleton reacted with vinyl cyanide with triphenylphosphine (20 mol%) as catalyst, affording a series of aza-MBH products β-amino vinyl cyanide with a good diastereoselectivity. A parallel research using phosphoryl imine modified by chiral diphenyl auxiliary also realized asymmetric aza-MBH reaction with three types of acrylates. Among these cases, product derived from benzyl acrylate was found achieving best purification result using GAP method. Based on this phenomenon, chiral cyclohexyl auxiliary was employed in reaction with benzyl acrylate. Under the optimized condition [catalyst:dimethylphenylphosphine (20 mol%), solvent:toluene, room temperature], a library of β-amino acrylates including 19 benzyl acrylate and 1 methyl acrylate had been achieved. Purification of all products was conducted with a convenient GAP chemistry protocol, washing crude product with a mixed solvent (hexane:ethyl acetate=10/1). Neither column chromatography nor recrystallization was required. In all cases, phosphoryl imine with chiral cyclohexyl auxiliaries showed an excellent reactivity. The chiral auxiliary can be recovered and recycled in a high yield. Single crystal of one product from each reaction was obtained and their absolute configuretions were confirmed as (S)-configuretions with single crystal XRD. Referring to previous study, a hypothetic mechanism of this reaction was also proposed and a DFT study was comducted to explain its high disastereoselectivity.In second section, the synthesis of pyrazoline derivatives and their biological activities, such as anti-inflammatory activity, anticonvulsant activity, human MAO inhibitory activity and fluorescent probe and antiallergic activity, are first generalized.Then a brief introduction of the research related to antineoplastic targets EGFR and HER-2 is described, including the overview of EGFR and its signal activation and transduction.On the basis of the above reports, the design and synthesis of a series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been conducted. Furthermore, EGFR/HER-2 inhibitory and anti-proliferation activities of these compounds were also evaluated. Purification of pyrazoline compounds was in line with GAP chemistry, and pure products can be obtained directly by ethanol washing. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (ICso=0.03/μM and GIso=0.15 μM), being slightly more potent than the positive control Erlotinib (ICso=0.16 μM and GIso=1.56 pM) and comparable with Lapatinib (IC50= 0.01 μM and GIso=0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicated that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site.3D QSAR models were built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.In third section, we synthesized BF2-curcumin skeleton compound Probe 2 containing DNBS moiety. It was designed as a high selective fluorescence probe of H2S. Besides the significant turn-on effect caused by H2S, neither 20 equivalents of various amino acids, vitamin B1, DTT, common anions nor 200 equivalents of GSH could cause a certain response. DFT study indicated a peculiar mechanism of Probe 2. That is, only one DNBS moiety was separated during the reaction. Experiment in rat urine suggested the detecting was not disturbed in such a test system.