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

No abstract

A stereoarray isotope labeled (SAIL) lysine, (2S,3R,4R,5S,6R)-[3,4,5,6-(2)H(4);1,2,3,4,5,6-(13)C(6);2,6-(15)N(2)]lysine, was synthesized by the "head-to-tail" conversion of SAIL-Glu, (2S,3S,4R)-[3,4-(2)H(2);1,2,3,4,5-(13)C(5);2-(15)N]glutamic acid, with high stereospecificities for all five chiral centers. With the SAIL-Lys in hand, the unambiguous simultaneous stereospecific assignments were able to be established for each of the prochiral protons within the four methylene groups of the Lys side chains in proteins.

No abstract

Enantioselective hydrogenation of ethyl 4 chloro 3 oxobutyrate in ionic liquid systems containing tetraethylammonium bromide, 1 butyl 3 methylimidazolium hexafluorophosphate, or 1 butyl 3 methylimidazolium trifluoromethanesulfonate in the presence of the chiral cata lyst Ru BINAP ensures a high level of asymmetric induction after at least threefold recycling of the catalyst.Key words: enantioselective hydrogenation, ethyl 4 chloro 3 oxobutyrate, ethyl 4 chloro 3 hydroxybutyrate, chiral ruthenium complexes, (R) and (S) BINAP, ionic liquid, tetraethyl ammonium bromide, recycling of the catalyst.

A comparative study of asymmetric hydrogenation and deuteration of methyl levulinate catalyzed by the Ru II -(S) BINAP-HCl system (BINAP is 2,2´ bis(diphenylphosphino) 1,1´ binaphthyl) in MeOH and MeOD was carried out. The results obtained suggest an impor tant role of the protic solvent in the formation of catalytically active ruthenium complexes.Key words: asymmetric catalytic hydrogenation, deuteration, hydrogen heterolysis, H/D ex change, ruthenium complexes, 2,2´ bis(diphenylphosphino) 1,1´ binaphthyl (BINAP), levulinic acid ester, chiral γ valerolactone.Earlier, 1 we have investigated asymmetric hydroge nation of levulinic acid esters catalyzed by the Ru II -(S) BINAP-HCl system (BINAP is 2,2´ bis(di phenylphosphino) 1,1´ binaphthyl). The resulting (S) γ hydroxy esters underwent in situ transformation into (S) γ valerolactone with up to 99% ee.Here we studied the role of solvent in the aforemen tioned reactions with methyl levulinate (1) as a model substrate (Scheme 1). Scheme 1 R = H (a), D (b) ExperimentalCommercial (S) BINAP, (COD)Ru(H 2 C(Me)C=CH 2 ) 2 (COD is cycloocta 1,5 diene) (Acros), and D 2 and MeOD (pi lot plant Prikladnaya Khimiya, St. Petersburg) were used. Methyl levulinate was prepared from levulinic acid (Acros) ac cording to a standard procedure. 2 Gaseous H 2 and D 2 were purified by passing through columns with a nickel-chromium catalyst and molecular sieves. All solvents were dehydrated be fore use. Catalytic hydrogenation of oxo ester 1 and analysis of the reaction products were carried out as described in the pre ceding paper. 1 Here the catalyst for the asymmetric hydrogena tion and deuteration of oxo ester 1 was prepared in situ without isolating the intermediate complex [((S) BINAP)RuCl 2 ].

A series of new 3-(aminomethyl)pyrazoles and 3-(aminomethyl)isoxazoles was synthesized along a route involving the formation as key intermediates of esters of 5-substituted 1Н-pyrazole-3-carboxylic and 1Н-isoxazole-3-carboxylic acids. All compounds obtained were characterized by physicochemical constants, IR, 1 Н, 13 С NMR, and mass spectra.Many functionally substituted pyrazoles and isoxazoles possess a wide range of pharmacologic activity [1-3]. For instance, 3-pyrazole-and 3-isoxazolecarboxylic acids А and B having alkyl or aryl substituents in the positions 4 and (or) 5 are antagonists of niacinic receptors and analogs of nicotinic acid C (niacin) and of acipimox D used in the medical praxis in the atherosclerosis treatment [4][5][6].Pyrazoles and isoxazoles with substituent of the basic character of E and F type are far less understood. They underlie the synthesis of selective inhibitors of enzymes, like factor Xa, and blood anticoagulants [7]. At the same time the known procedures for the preparation of compounds of E and F type apply diffi cultly available reagents [3,8] or unstable compounds like azides [9] or organometallic derivatives [7]. Therefore the search for more convenient synthetic methods for their preparation is urgent.In this study we performed the synthesis of aminomethyl derivatives of heterocycles of E and F type along a scheme involving the condensation of various ketons I with diethyl oxalate (Claisen reaction) followed by the cyclocondensation of the intermediate α,γ-diketone II with hydrazine or hydroxylamine [1-6].As a result substituted in the ring esters of 3-pyrazoleor 3-isoxazolecarboxylic acids III and IV were obtained. Therewith the cyclocondensation of diketones IIe and IIf with the hydroxylamine proceeded regioslectively. In event of diketones IIa and IIb alongside the 3-ethoxycarbonyl derivatives also 5-ethoxycarbonyl-substituted isoxazoles were obtained in a ratio 9:1. Further compounds III, VI were subjected to ammonolysis or aminolysis with methylamine with the subsequent reduction of amides IV, VII into the corresponding amines V, VIII. Amides IV of the substituted 3-pyrazolecarboxylic acids were reduced with LiAlH 4 , and amides VII of the substituted 3-isoxazolecarboxylic acid, with the help of BH 3 obtained in situ from NaBH 4 and BF 3 ·Et 2 O. The latter procedure was required for the reaction of amides VII with LiAlH 4 occurred nonselectively with the formation of a large number of side products. In both cases THF was used as solvent.