Asymmetric Vinylogous Aldol Reaction By Combind Lewis Acid Catalyst

Much attention has been paid to the design and development of effective asymmetric catalyst which is one of the most important aspects of modern organic chemsity. The bifuntional catalytic system incorporates two active centers to work together for simultaneous activation or location of both the electrophilic and nucleophilic reaction partners. Therefore, high efficiency and selectivity are much more easily obtained in this dual activation mode which takes great advantage over the traditional mono activation mode. In recent years, this concept of synergistic effect was applied in the area of asymmetric catalysis and some successful novel bifunctional catalysts were reported by some research groups. Owing to the intrinsic features of bifunctional catalysis and some successful examples, it is promising to development some new catalysts for excellent transformations based on the synergistic effect.The asymmetric vinylogous aldol (AVA) reaction has been one of the versatile C-C bond-forming reactions with extensive application in the synthesis of natural producuts. These adducts contain many functional groups and could further react. The P-hydroxy carboxylic acids,β-hydroxy ketones,8-hydroxy-β-carbonyl esters and six-membered ring lactone derived from the adducts, which are ubiqutious structural subunits in biologically active natural products such as the polyene macrolide antibiotics,HMG-CoA reductase inhibitors and Vitamin D3 analogues. In the last two decades, several asymmetric catalysts have been successfully developed for the AVA reactions between aldehydes and preformed silyl dienol ether donors. However, among most of these successful examples, low-temperature or stoichiometric additives was usually required to obtain high enantioselectivity. Thus, Developing simple and effective methods for the catalytic production of optically active compounds is among the most important tasks in current synthesis of these natural products.In this paper, The combined lewis acid catalytic system (R)-BTHL—(R)-BINOL-Ti-H2O-LiCl (1:1:1:1), generated from (R)-1, 1'-bi-2,2'-naphthol [(R)-BINOL], Ti(O-i-Pr)4, H2O, and lithium chloride, effectively catalyzed the enantioselective vinylogous aldol reaction of benzaldehyde with diene. Then the conditions of the reaction were screened for further optimization. The best reaction condition was obtained after further investigation—1 mL THF as solvent, reacted at 28℃. Under the optimized condition, the scope of the substrate was investigated affording the corresponding products in 75-94% yield and 39-98% ee. We obtained the natural product (5)-(+)-Dihydrokavain (yield 71%, ee 84%) through the method which has been established by the combined lewis acid catalytic system. A lewis acid-lewis acid bifunctional working model was proposed for the catalytic process based on further study of catalyst screening experiments and nonlinear effect.