The Syntheses Of N-Heterocycle Functional Small Molecules And Natural Products Basen On The C-H Activation

N-heterocycles structures are prevalent in natural products and pharmaceutical molecules, especially the a-substituted tetrahydroisoquinolines (THIQs) and quinolines, which not only exhibit good and diverse pharmacological activities, but also serve as the key intermediates in organic synthesis and biosynthesis of complex molecules. For example, tetrahydropalmatine which was isolated from Corydalis has significant analgesic and sedative effect and is used for the treatment of heart disease and liver damage. Palmatine, isolated from the rattan of Caulis Fibraurear, has been used in the clinical treatment with the broad-spectrum antimicrobial effect. Noscapine, acting as the sigma receptor agonist with excellent antitussive effect, has been reported to be effective for the treatment of several cancers and hypoxic ischemia in stroke patients. Methopholine, being the opioid receptor modulator and having lower addiction and higher security, was used in the clinical treatment, which was first obtained through the organic synthesis. Solifenacin, a competitive antagonist preventing acetylcholine from binding to the human muscarinic acetylcholine receptor, is used for the treatment of overactive bladder. Synthetic quinoline alkaloid, namely Mefloquine and Endochin, possess important antimalarial activity, especially the Mefloquine which has been used in the clinical treatment. Kynurenic acid, an antagonist for both Excitatory amino acid and Nicotinic receptors, is a useful agent for the potential control of neurodegerative disorders. Given the importance of these compounds in drug discovery and other applications, a variety of methods have been developed to achieve their syntheses, including the Pictet-Spengler reaction, Bischler-Napieralski reaction and Friedlander-Pfitzinger reaction. In the last decades, the introduction of a carbon unit to the α-position of N-heterocycles based on C-H bond oxidative functionalization has become another option for their syntheses. However, almost all studies have focused on the C-H activation of N-aryl THIQs for their electron-rich features. The difficulty in the deprotection of the aromatic group resulted in poor functional-group tolerance and further limited their synthetic utilities. Only several successful examples have been reported on the functionalization of the C(sp3)-H bond adjacent to readily removable amide or carbamate moieties. Each of these methods only focused on one kind of nucleophile and could not lead to the diversity-oriented synthesis. Moreover, these procedures required harsh reaction conditions. Therefore, the development of practical and efficient methods for the direct C-H functionalization of N-carbamate heterocycles with a wide range of nucleophiles to realize the diversity construction of these kinds of compounds is indeed needed.In the second chapter, a practical, universal and metal-free method was developed for the C-H functionalization of readily removed N-benzyl and N-ally1 carbamates with a wide range of nucleophiles at ambient temperature mediated by Ph3CClO4. The system had good functional-group tolerance and displays a broad scope with both N-carbamate and organoboranes partners. The CDC reactions were smoothly achieved with aldehydes, ketones and electron-rich arenes as the direct nucleophiles. The enantioselective synthesis was achieved through the introduction of chiral auxiliary, which was successfully applied to the synthesis of bioavtive natural products and their analogs. The cytotoxic assay not just demonstrated that some of our products had anti-cancer effect, more importantly proved the validity of this method for the rapid access to a small molecule library of N-heterocycles and drug discovery. Finally, some studies on the reaction mechanism were carried out through the kinetic isotope effect and other experiments.As such THIQs alkaloids with biological activities often possess a specific stereo genic center at the C1 position, many efforts have been devoted to their enantioseletive syntheses. However, the methods based on C-H oxidative functionalization are still rare. Recently, Chi and co-workers have developed the metal/organic cocatalyzed asymmetric cross-dehydrogenative coupling of N-ary1 THIQs with aledhydes. Although the enantiomeric excesses being impressive, the difficulty in the removing the aromatic group limits its synthetic utility.Then in the third chapter, a mild, universal, metal-free organocatalytic enantioselective oxidative coupling between the readily removed N-carbamate THIQs and aldehydes mediated by DDQ has been developed by us. Aldehydes with benzyl group, ester, halo and alkenyl groups all could smoothly give the corresponding products with moderate to good yields and excellent enantiomeric excesses. These products could be converted to β-amino alcohol which could act as the NMDA-NR2B receptor antagonists through simple operations and their relative and absolute configurations were determined by NOESY spectra and modified Mosher’s method.In the forth chapter, we developed a new method for the synthesis of substituted quino lines. The oxidative Povarov reaction of glycin derivatives and olefins was realized with using the copper salt as catalyst and NHPI/O2 as the oxidant, which avoided the use of stoichiometric oxidant and led to less byproduct. The reaction had a broad scope with both glycin derivatives and olefin reagents and a variety of functional groups were compatible. This method provided a simple, efficient and diversity syntheses for quinoline alkaloids.In this thesis, our research work focused on the synthsis of N-heterocycle functional small molecules and natural products through C-H oxidative functionalization. The rapid, diversity and enantioselective synthesis of a-substituted THIQs through C-H bond oxidative activation was achieved in the first two parts of our work. The methods developed allowed rapid access to the construction of functional molecule library and proved to be useful in the drug discovery. A new method on the synthesis of substituted quinolines based on C-H bond activation using O2 as the ultimate oxidant was also developed, which was environmentally friendly and provided a new approach for the synthesis of quinoline alkaloids.