The synthesis of asymmetric nicotine and proline-based organocatalysts and their applications

The increasing demand from the researchers for the development of cost- and time-effective, environmentally benign synthetic methodologies has resulted in tremendous expansion of the field of the asymmetric catalysis. Since the turn of the millennium, the application of small, chiral molcules as catalysts for a variety of enantioselective transformations -termed organocatalysis- has attracted much attention and has become a complementary method to classical approaches utilized in asymmetric synthesis.Organocatalysts have several advantages over transition-metal catalysts and enzymes. They are usually robust, inexpensive and readily available and non-toxic. Because of their robustness they often do not require demanding reaction conditions like inert atmosphere and absolute solvent.Organocatalysis has played on increasingly prominent role in the design and synthesis of enantioenriched substances. Over the past few years, a number of chiral organocatalysis have been developed for different asymmetric transformations. Among them, chiral secondary amines are probably the most intensively used organocatalysts. Especially, the versatility of proline as an asymmetric catalyst is conspicuous from a broad range C-C or C-heteroatom bond formation reactions.On the other hand, the use of phase transfer catalysts (PTC) for asymmetric synthesis offers further advantages, because it involves mild conditions, simple reaction procedures, safe and inexpensive reagents and solvents, and greatly simplifies product isolation. However, the development of asymmetric phase transfer catalysis based on the use of structurally well defined chiral, nonrasemic catalysis, has progressed rather slowly. Nevertheless, the enarmous efforts that have been made have certainly resulted in notable achievements in this field, making it feasible to perform various bond-formation reactions under phase transfer catalyzed conditions.The stereoselective aldol reaction plays a fundamental role among the carbon-carbon bond forming transformations as a key step in natural product synthesis and for the rapid access to polyoxygenated compounds. Catalytic asymmetric reactions that can be performed in water are of current interest, because water is a desirable solvent with respect to environmental concerns, safety and cost. So, the researches have been continued by the aim of the development of asymmetric reactions in water. One of the important organocatalytic reactions investigated in water is aldol reaction.In this research, the development of new asymmetric organocatalysts for direct asymmetric aldol condensation was aimed. The first part was the synthesis of nicotine based dicationic salt (Compound 1) which can be used as phase transfer catalyst. In the second part, the synthesis of proline based bifunctional asymmetric catalysts (Compound 7, 8 and 9) which were not found in the literature was accomplished. The structures of these compounds were determined by the FTIR, 1H NMR, LC-MS spectral data. In the third part, the organocatalytic asymmetric aldol reactions were succesfully carried out by using the synthesized asymmetric organocatalysts in water without any organic solvent.As a result, enamine-based asymmetric organocatalysts and a nicotine-based dicationic phase transfer catalysis that can be effective for the direct aldol reactions were developed. Especially, reactions using amine-amide bifunctional catalysts afforded the desired products in high yield with moderate enantioselectivities at short reaction times.Keywords: Asymmetric organocatalysis, proline, nicotine, aldol reaction.