The Nazarov reaction (cyclization) is one of the most useful synthetic tools for the stereoselective preparation of various cyclopentenone scaffolds. This review summarizes recent applications of this reaction to the synthesis of natural compounds and their usefulness to pharmacology analogs published over 2005-2016. Modern protocols for the facile generation of key cationic intermediates and efficient catalytic, in particular asymmetric, versions of Nazarov cyclization are considered. Available literature data are for the first time classified according to the chemical structures of the products, which include relatively simple non-annulated functionalized cyclopentenoids and complex polynuclear cyclopentenone derivatives annulated with one or more non-aromatic, aromatic or heteroaromatic rings. This classification is convenient for specialists in organic synthesis and for researchers working in the area of medicinal and biomolecular chemistry.

In this review, recent applications of a stereoselective aza-Michael reaction for asymmetric synthesis of naturally occurring N-containing heterocyclic scaffolds and their usefulness to pharmacology are summarized.

The rate of hydrogenation of γ ketoesters MeCOCH 2 CH 2 COOR (R = Et, Pr i , Bu t ) in the presence of the chiral Ru II -BINAP catalyst (BINAP is 2,2´ bis(diphenylphosphino) 1,1´ binaphthyl) greatly increases upon the addition of 5-10 equivalents of HCl with respect to ruthenium. In the hydrogenation of ethyl levulinate, the optically active γ hydroxy ester ini tially formed would cyclize by ~95% to give γ valerolactone with optical purity of 98-99% ee. When the Ru(COD)(MA) 2 -BINAP-HCl catalytic system is used (COD is 1,5 cyclooctadiene, MA is 2 methylallyl), complete conversion of the ketoester (R = Et) in EtOH is attained in 5 h at 60 °C under an H 2 pressure of 60-70 atm.Key words: enantioselective catalytic hydrogenation, ruthenium(II), 2,2´ bis(diphenyl phosphino) 1,1´ binaphthyl (BINAP), esters of levulinic acid, esters of γ hydroxyvaleric acid, optically active γ valerolactone.The asymmetric catalytic hydrogenation of ketoesters is a highly efficient method for the preparation of opti cally active hydroxycarboxylic acids and their derivatives, valuable multi purpose building blocks. The asymmetric hydrogenation of α and β ketoesters catalyzed by chiral ruthenium(II) complexes has been studied rather compre hensively in recent years. 1-5 However, little is known about the asymmetric hydrogenation of γ ketoesters, which are much less reactive than α and β ketoesters. In the presence of the RuCl 2 (BINAP) catalyst (BINAP is 2,2´ bis(diphenylphosphino) 1,1´ binaphthyl), pre pared in situ from Ru(OAc) 2 (BINAP), 6 or the [RuCl 2 (BINAP)(DMF)] n , 7 [RuCl 2 (BINAP)] 2 NEt 3 , 8,9 [RuCl(p MeC 6 H 4 Pr i )(BINAP)]Cl, 10 and [Me 2 NH 2 ]{[RuCl(SEGPHOS)] 2 (µ Cl) 3 } 11 catalysts (SEGPHOS is 5,5´ bis(diphenylphosphino) 4,4´ bi(1,3 benzodioxolyl)), a high conversion of γ ketoesters com bined with a high hydrogenation enantioselectivity can be attained in 2 to 10 days at 30-65 °C and 50-100 atm H 2 .The purpose of this study is to search for a more effi cient catalytic system for the enantioselective hydrogena tion of γ ketoesters. Esters of levulinic acid (1a), com pounds 1b-d, were chosen as model substrates. They were hydrogenated (Scheme 1) in the presence of the Ru 1-Ru 4 catalytic systems (Tables 1 and 2).The plot shown in Fig. 1 indicates that in the presence of the Ru 1 catalytic system, containing only 2 equiv. of HCl (this amount of the acid is required for the formation of RuCl 2 (BINAP)), the conversion of ketoester 1b is less than 5% under the chosen hydrogenation conditions. When HCl is added up to 5 equiv. with respect to ru thenium, hydrogenation occurs much faster and gives γ hydroxy ester 2b, which would cyclize into lactone 3 bỹ 95% under the reaction conditions. Further increase in the amount of HCl induces a gradual increase in the conversion of ketoester, which reaches 100% for the ratio [HCl]/[Ru] = 10. This ratio was chosen as the standard one in the subsequent experiments. It is significant that the growth of the medium acidity does not influence the Scheme 1

No abstract