Insight into the solvation and isomerization of 3-halo-1-azaallylic anions from ab initio metadynamics calculations and NMR experiments.
In organic synthesis, it is observed experimentally that the nature of the solvent can influence tremendously the reactivity and overall product selectivity. In this communication, we report on the E/Z isomerization of a typical solvated species, that is, the stable lithiated 3-chloro-3-methyl-1azaallylic anion readily accessible from the N-isopropylACHTUNGTRENNUNGimine of a-chloropropiophenone, from a theoretical and a subsequent NMR study. To date, the configurational properties of these 3-chloro-3-methyl-1-azaallylic anions are poorly understood. Our main emphasis is devoted to the monomeric species as these are believed to be the most important for further reactivity studies (see below). It will be shown that the investigated species is a particular example in which the inclusion of the solvent in the modeling study is of the utmost importance to determine the proper chemical ACHTUNGTRENNUNGbehavior. The 3-chloro-3-methyl-1-azaallylic anion was chosen as a model compound to obtain a deeper insight into the structural features of 3-halo-1-azaallylic anions and to get a better understanding, and eventually a better control, of the stereochemical outcome of the reactions in which these anions are involved. Since their first use in the early 1960s, non-halogenated 1-azaallylic anions have gained a predominant role in organic synthesis due to their ability to form new C C bonds with a lack of side products. The chemistry of 1-azaallylic anions leads to basic heterocyclic systems such as aziridines, azetidines, pyrrolidines, pyrroles, piperidines, oxiranes, oxolanes, and higher functionalized ring systems, currently of interest for pharmaceutical chemistry and agrochemistry. The application of certain halogenated counterparts, that is, the 3-chloro-3-methyl-1azaallylic anions, in particular by the group of De Kimpe and more general by the group of Florio, which incorporated the 3-chloro-3-methyl-1-azaallylic moiety into heterocyclic structures, has led to the synthesis of various important classes of compounds such as cyclopropanes, tetrahydrofurans, tetrahydropyrans, oxiranes, aziridines, chloroimines, pyrroles and pyridines, steroids, alkenylheterocycles, and oxazetidines. As mentioned, 3-chloro3-methyl-1-azaallylic anions can be used for the synthesis of functionalized oxiranes and aziridines since the former anions behave as nucleophiles in Darzensand aza-Darzenstype reactions with carbonyl compounds and imines. One of the determining factors in the stereochemical outcome of these Darzens-type reactions is the E/Z stereochemistry of the starting 1-azaallylic anion. Therefore, it is important to know and understand the configurational properties of 3chloro-3-methyl-1-azaallylic anions in order to perform aldoland Mannich-type reactions with these intermediates in a stereocontrolled manner. NMR investigation and semiempirical calculations on the stereochemistry of (2-(a-chloroethyl)benzothiazolyl)lithium and (4,4-dimethyl-2-(a-chloroethyl)oxazolinyl)lithium have demonstrated that internal coordination between lithium and chlorine stabilizes the corresponding isomer with nitrogen and chlorine at the same side of the C=C double bond. The lack of such structural investigations on 3chloro-3-methyl-1-azaallylic anions in sensu stricto urged us to study their stereochemical properties. The E/Z isomerism for non-halogenated 1-azaallylic anions has been observed and investigated quite frequently. The facile carbon carbon bond rotation in simple lithiated 1-azaallylic anions was investigated using H NMR spectros[a] Dr. R. Declerck, B. De Sterck, T. Verstraelen, Prof. Dr. M. Waroquier, Prof. Dr. V. Van Speybroeck Center for Molecular Modeling, Ghent University Proeftuinstraat 86, 9000 Gent (Belgium) Fax: (+32) 9-264-6697 E-mail : Veronique.VanSpeybroeck@UGent.be [b] Dr. G. Verniest, Dr. S. Mangelinckx, J. Jacobs, Prof. Dr. N. De Kimpe Department of Organic Chemistry, Faculty of Bioscience Engineering Ghent University, Coupure links 653, 9000 Gent (Belgium) Fax: (+32) 9-264-6243 E-mail : Norbert.DeKimpe@UGent.be Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200800948.
Neuere Methoden der präparativen organischen Chemie VI† Über gezielte Aldolkondensationen
In diesem Aufsatz wird gezeigt, wie das neue praparative Verfahren der Aldolkondensation zur Darstellung α,β-ungesattigter Carbonylverbindungen11 entdeckt wurde. Viele Beispiele, auch auf dem Naturstoffgebiet, belegen seine Leistungsfahigkeit, stecken aber auch deren Grenzen ab. Die metallierten Schiff-Basen lassen sich in die Klasse der ambidenten Anionen einordnen, wodurch auch Acylierungen am Stickstoff verstandlich werden. Ein Vergleich der gezielten Aldolkondensation mit der uber Phosphorylide ebenfalls zu ungesattigten Carbonylverbindungen fuhrenden Olefinierung lehrt, das die letzte Methode bei Ketonen als Substrat versagt. Gerade hier bewahrt sich die beschriebene Arbeitsweise mit metallierten Schiff-Basen.
New method for analysis of enzymatic reactions: Thermolysin-catalyzed synthesis of aspartame precursor
Aspartame is an artificial sweetener which is 200 times sweeter than sucrose. A precursor of aspartame, N-(benzyloxycarbonyl)-l-aspartyl-l-phenylalanine methyl ester (Z-APM) was synthesized and hydrolyzed with thermolysin in an aqueous monophasic system. Graphical plotting methods and/or nonlinear regression have been used to analyze enzymatic reactions because of the nonlinearity of enzymatic rate equations. There are, however, problems: the former require accurate measurement of the initial reaction rate and the latter gives no analytical information. The authors proposed a method to solve the nonlinear enzymatic rate equations with respect to the concentration of a product with the Taylor expansion, especially for the reversible Theorell-Chance mechanism (Murakami, Y., Hirata, M., and Hirata, A., J. Ferment. Bioeng., 82, 246–252, 1996). This solution, however, is complex for practical use. In this paper, a simpler solution to explain the thermolysin-catalyzed synthesis of Z-APM is obtained. New methods to determine the kinetic parameters, especially for the reversible Theorell-Chance mechanism, based on the approximated solution are proposed. The results calculated using the obtained kinetic parameters can satisfactorily explain the experimental results, which demonstrates the effectiveness of the proposed analysis. We must know the relation between the concentrations of substrates and a product, and accurately evaluate of the result obtained using Taylor expansion when we determine the kinetic parameters using our newly developed methods. The methods to determine the kinetic parameters of the reversible Theorell-Chance mechanism described in this paper is, however, expected to be applied to general enzymatic reactions.