Application Studies Of Chiral Pyrrolidine-quinine Thiourea Based Dual Component Organocatalysts In Asymmetric Biginelli Reaction

With the development of modern chemistry, multicomponent reactions (MCRs) are tools of paramount importance as the central strategy to reach eco-friendly and sustainable transformations. MCRs have many advantages over stepwise linear synthesis such as atom economy, less waste generation,time and energy economies, less human effort, fewer resources required, easy purification issues, and high convergence among others. The Biginelli reaction was initially reported by Italian chemist Pierto Biginelli more than 120 years ago,which is a three-component condensation reaction between benzaldehyde, urea and acetylacetic ether catalyzed by hydrochloric acid, through one-pot successfully synthesised 3,4-dihydropyrimidin-2 (1H)-ones (DHPMs). Nowadays, for human’s thorough research of the Biginelli reaction, mainly four catalytic ways of Biginelli reaction were reported, namely,acid catalytic, ion liquid catalytic, asymmetric catalytic and green catalytic. The products of Biginelli reaction, DHPMs, demonstrated to be promising application values, such as inhibitors of calcium channel, anticancer activity, anti-inflammatory activity, antibacterial activity, antioxidant activity, antimalarial activity, antitubercular activity, fabric dyes and so on.In recent years, rapid development in small organic molecules catalyzed asymmetric field,causing the emergence of a large number of small organic molecule catalysts. For one asymmetric reaction, thus the synergistic effect between different small organic molecules,using dual component organocatalysts always reaching better catalytic performance compared to the classical single component catalyst. Therefore, based on our preliminary work and related literatures at home and abroad, in this paper, we have designed and synthesized a kind of dual component organocatalysts consisted of trans-4, 5-methano-L-proline (A-1) and chiral quinine - thiourea derivatives (B-la). After optimizing the reaction condition, two dozens of new chiral DHPMs were synthesized with excellent catalytic effects(90 - 96 % yield, 92 - 99 % ee). Then the NMR, HPLC and mass spectrometry data characterizations were carried out for all products, and inferred the plausible reaction mechanism for the Biginelli reaction catalyzed by this dual component organocatalysts.Meanwhile, in order to test the anticancer activity of all obtained products, here we chose PC-3 (human prostate cancer) and HepG-2 (human liver cancer) cell lines, after a later cultivation, anti-proliferative acitivity of all compounds were assessed by using the SRB colorimetric assay. The result showed that the product with trifluoromethyl - substituted cinnamic aldehyde portion revealed better anti-proliferative acitivity (4ea, 4eb, 4ec), while the residual part were not very ideal.Chiral epoxides is one of the most important pharmaceutical intermediates, which can be found in mass natural products and biologically active molecules. Seeking for other application of different reactions for dual component organocatalysts consisted of trans-4,5-methano-L- proline (A-1) and chiral quinine - thiourea derivatives (B-la), the dihydropyrimidine derivatives 4aa was subjected to an oxidation with hydrogen peroxide as a green oxygen supply, to afford chiral epoxide 7 in good yield with a maintained enantiomeric excess (87 % yield, 93 % ee), which represents a synthetically challenging family of intermediates due to the presence of three stereogenic centers. This dual component organocatalysts provides a new way to synthesis more active drug moleculars contained chiral epoxides structure.