Alpha-keto esters

Peet, N.P. Burkhart, J.P. Angelastro, M.R. Giroux, E.L. Mehdi, S. Bey, P. Kolb, M. Neises, B. and Schirlin, D. Synthesis of peptidyl fluoromethyl ketones and peptidyl alpha-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G. J Med Chem 33(l) 394-407, 1990. 

Collier P.J., Goulding T., Iggo J.A. and Whyman R. (1995) Studies of the Pt-cinchona alkaloid catalyst for enantioselective alpha-keto esters hydrogenation, in Jannes G. and Dubois V. (eds.). Chiral Reactions in Heterogeneous Catalysis, Plenum Press, N.Y. p. 105-110. 

For C=C hydrogenations the reactions with unmodified catalyst were much faster then those with modified catalyst, such as with Cnd. This is quite different from results reported for the hydrogenation of alpha-keto esters on Pt-alumina, where the addition of the modifier alkaloid leads to chiral products and strongly accelerates the reaction (Bartok et al. Tungler, Nitta et al. 

In kinetic studies zero order was found with respect to the alpha-keto ester and first order with respect to hydrogen Apparent activation energies for hydrogenation on Pt-alumina and Pt-silica were found to be 31 kJ/mol and 38 kJ/mol, respectively (Baiker... 

Niwa, S., Imai, S., Onto, Y. (1980) As5Tnmetric hydrogenation of alpha-keto esters using platinum-alumina catalyst modified with cinchona alkaloid, J. Chem. Soc. Jpn. Nippon Kagaku Kaishi) N4, 670-672. 

Blaser, H.U., Jalett, H.P., Monti, D.M., Wehrli, J.T. (1989) Enantioselective hydrogenation of alpha-keto esters temperature-programmed reduction study of liquid-phase Pt-Alumina hydrogenation catalysts, Appl. 

LeBlond, C., Wang, J., Liu, J., Andrews, A.T., Sun, Y.K. (1999) Highly enantioselective heterogeneously catalyzed hydrogenation of alpha-keto-esters under mild conditions, 121,4920-4921. 

Spindler, F., Pittelkow, U. and Blaser, H.U. (1991) A highly enantioselective Rh-catalyst for the hydrogenation of aliphatic alpha-keto esters. 

Ojima, I., and Kogure, T. (1980) The asymmetric hydrogenation of alpha-keto esters catalyzed by Rh complexes with chiral diphosphine ligands. On the catalytic cycles and the mechanism of asymmetric induction, J. Organomet. Chem., 195,239-248. 

The number of atoms intervening between the central atoms of the two functional groups is given as a prefix to the number of the complex functional group. For example, an alpha keto ester is numbered 0.40, a beta ketoester is numbered 1.40, a gamma ketoester 2.40 etc. 

Shinoda, S. and Osuka, A., Transesterification of the.alpha.-keto ester in methyl pheophorbide-a. Tetrahedron Lett., 37, 4945, 1996. 

AEyl chloride reacts with sodamide in Hquid ammonia to produce benzene when sodamide is in excess, hexadiene dimer is the principal product, with some trimer and tetramer (C24, six double bonds). AEylation at carbon atoms alpha to polar groups is used in the preparation of a-aEyl-substituted ketones and nittiles. Preparation of P-diketone derivatives, methionic acid derivatives, and malonic ester, cyanoacetic ester, and P-keto-ester derivatives, etc, involving substitution on an alpha carbon between two polar carbonyl groups, is particularly facEe. 

Kaluzna, I.A., Feske, B.D., Wittayanan, W. et al. (2005) Stereoselective, biocatalytic reductions of alpha-chloro-beta-keto esters. The Journal of Organic Chemistry, 70 (1), 342-345. 

The base catalyst removes an acidic alpha proton from the starting j8-keto ester to generate a stabilized enolate ion nucleophile. 

The Claisen condensation is a carbanion reaction in which the carbanion produced by alpha hydrogen abstraction on an ester displaces the alkoxy group of another ester molecule the reaction produces keto esters. 

It is of interest that diethyl oxalacetate (Scheme 4.6.), that can be considered both as an alpha- and a fteta-keto ester, caimot be hydrogenated on the RNi-TA catalyst. This demonstrated that small changes in the groups around the carbonyl group may result in difficulties in asymmetric hydrogenation (Tanabe et al. ). 

In general, the reactions of enantioselective hydrogenations of beta-keto esters on modified Ni or of alpha-ksio esters on modified Pt are structure sensitive reactions. In both reactions, enantioselectivities increase with increasing crystallite size of Ni or Pt. 

Another classic method is that known as the Hantzsch pyrrole synthesis (Scheme 9.4). The nitrogen starting material is an enamine (9.2), which is prepared from a beta-keto ester and ammonia. The beta-position of the enamine is electron-rich and is alkylated with an alpha-haloketone. The amino and the carbonyl groups interact in the familiar way to close the ring. 

Collapse of the CTI forms the neutral P-keto ester product that will eventually be isolated, but the reaction mechanism does not stop here. Since the 1,3-dicarbonyl product has a highly acidic alpha proton (a to two EWGs), it becomes deprotonated in the basic reaction conditions to give a stabilized enolate. This deprotonation step is a necessary one, as it drives the equilibrium in the forward direction the Claisen condensation will not occur if there are not at least two alpha protons present in the ester starting material, and the acid-catalyzed Claisen condensation does not exist. Upon treatment with a mild aqueous workup, the enolate is protonated and the neutral P-keto ester product can be isolated. 

The product of this reaction is a P-keto ester that contains a newly formed carbon-carbon bond between the alpha carbon and one of the carbonyl carbons. This is the key bond to be identified in a P-keto ester TM a disconnection at this bond will lead to a Claisen retrosynthesis. 

A typical retrosynthesis of a P-keto ester involves making a disconnection from one of the carbonyls to the alpha carbon between the two carbonyls. The alpha carbon will be introduced as a nucleophilic enolate. The P-keto carbon used to be a carbonyl (E+), but how can it still be a carbonyl after being attacked by a nucleophile The P-keto carbonyl must have had a leaving group attached to it in order for the addition-elimination acyl substitution mechanism to take place. The alkoxy group is the preferred leaving group to select, since esters are stable, easy to work with, and commercially available. 

Addition of an Enolate to Ketones and Aldehydes (a Condensation) 1046 Substitution of an Enolate on an Ester (a Condensation) 1046 Base-Catalyzed Keto-EnolTautomerism 1047 Acid-Catalyzed Keto-EnolTautomerism 1047 Base-Promoted Halogenation 1054 Final Steps of the Haloform Reaction 1056 Acid-Catalyzed Alpha Halogenation 1058 Acid-Catalyzed Aldol Condensation 1063 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

The Knorr Pyrrole Synthesis. In this process, the starting materials are an alpha-amino ketone, or less commonly an alpha-amino aldehyde, and a beta-ketoester. In the latter, the protons on the alpha carbon are activated both by the keto and the ester carbonyls and are especially easily removed. The Knorr process starts with the condensation of the amino group with the keto group in the usual way to tie the two molecules together as in 4.29 of the example shown in Scheme 4.31. This species then undergoes intramolecular aldol-type condensation to form a reduced pyrrole derivative 4.30. 

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