Keto acids, esterification

Oxidation of ecgonine (2) by means of chromium trioxide was found to afford a keto acid (3). This was formulated as shown based on the fact that the compound undergoes ready themnal decarboxylation to tropinone (4)The latter had been obtained earlier from degradative studies in connection with the structural determination of atropine (5) and its structure established independently. Confirmation for the structure came from the finding that carbonation of the enolate of tropinone does in fact lead back to ecgonine. Reduction, esterification with methanol followed by benzoylation then affords cocaine. 

Keto acids can be dehydrated to enol lactones (Section III,A,1). They may also undergo esterification with alcohols e.g., /V-methylhydrasteine (104) in methanol at room temperature gave the expected keto ester 126 (R + R = CH2, R1 = CH3) (5,87). Sodium borohydride reduction of keto acid 104 supplies the saturated y-lactone 132 identical with that obtained from enol lactone 98 (5). 

The synthesis of 6-oxo-2,3,4,6-tetrahydro[l,2,4]triazino[5,6-c]isoquino-line-3-thione 178 was achieved by the reaction of the keto acid 174 with thiosemicarbazide to give azauracil 175. Its esterification gave 176, which was converted to the amide 177 and cyclized (84PHA186 92CCC123) in presence of acetic acid to give 178. 

Reductive Esterification. Organosilane reductions of y- or 5-keto acids and esters provide the corresponding lactones as the final products (Eqs. 226 and 227).69,79,402... 

Aldol reaction of keto-acid 21 with aldehyde 10 and esterification of the resulting acids with alcohol 22 led rapidly to cyclization precursor 23 and its 6S,7R-diastereomer (not shown). RCM using ruthenium initiator 3 (0.1 equiv) in dichloromethane (0.0015 M) at 25 °C afforded macrolactones 24a and 24b in a 1.2 1 ratio. Deprotection and epoxidation of the desired macrolactone, 24a, afforded epothilone A (4) via 25a (epothilone C) (Scheme 5). Varying a number of reaction parameters, such as solvent, temperature and concentration, failed to improve significantly the Z-selectivity of the RCM. However, in the context of the epothilone project, the formation of the E-isomer 24b could actually be viewed as beneficial since it allowed preparation of the epothilone A analog 26 for biological evaluation. 

The cyclobutanone (255) reacted with acid to furnish the keto-acid (259). Upon esterification, ketalization and reduction, (259) was converted to the alcohol (260). Mesylation of the alcohol (260) and then treatment of the mesylate with NaN3 in DMSO provided the azide (261). The azide (261) was then transformed to the urethane (262) by reduction and ethyl chloroformate reaction. The urethane (262) was deketalized by acid, nitrosated by N204—NaOAc and decomposed by NaOEt—EtOH to give the ketone (263) 89). The ketone (263) served as a starting material for the synthesis of veatchine (264)90). 

Conversion of (107) into the dimethyl acetal (108) with trimethyl orthoformate and Rexyn 101, followed by pyrolytic elimination in refluxing o-xylene, gave (109). Treatment of (109) with n-butyl-lithium and C02 in THF, followed by hydrolysis, afforded the keto-acid (110). Reduction of (110) with borohydride, followed by dehydration with phosphoric acid and esterification, gave (111). 

Lactones are cyclic compounds formed through the intramolecular esterification of a hydroxy fatty acid. 7-Lactones and 8-lactones, with fivesided and six-sided rings, respectively have been found in cheese (Jolly and Kosikowski, 1975 Wong et al., 1975 Collins et al., 2004). The origin of the precursor hydroxy fatty acids has been ascribed to a 8-oxidation system in the mammary gland of ruminants (see Fox et al., 2000), the reduction of keto acids (Wong et al., 1975) and/or the action of lipoxygenases and other enzymes present in members of the rumen microflora (Dufosse et al., 1994). Lactones have low flavor thresholds and while their aromas are not specifically cheese-like (their aromas have been described variously as peach, apricot and coconut ), they may contribute to the overall flavor of cheese (see Collins et al., 2004). 

If silylation alone (0.2 ml of BSTFA + 0.05 ml of TMCS) without the preceding methoximation is carried out, TMS enol ether—TMS esters are produced from keto acids. Using the procedure described, methoxime-TMS esters of keto acids and TMS ether—TMS esters of hydroxy acids are produced. Unsubstituted acids give TMS esters. The procedure eliminates possible losses of the derivatives, which can be caused by, e.g., evaporation of the solvent between the esterification and the silylation steps, and is quantitative. SE-30, OV-17 and OV-22 can be used and retention data on these stationary phases have been reported for 15 acids [159]. An example of the separation of the derivatives of some acids prepared by this procedure is illustrated in Fig. 5.12. 

The distribution of metabolites obtained after incubation of pineapple slices with keto acids and keto esters, potential precursors of the corresponding hydroxy compounds, is summarized in Table II. The metabolization steps comprise esterification, reduction to hydroxy compounds, formation of acetoxy esters, and cyclization to the corresponding lactones. Metabolization rate and distribution of formed products strongly depend on the structures of the precursors. The detection of these metabolites proves the enzymatic capability of pineapple tissue to catalyze these conversions, an aspect which might be interesting for future use of pineapple tissue cultures in the production of chiral compounds. 

Our first approach to 1 is based on a retrosynthetic analysis depicted in Fig (8). The crucial step to construct the cw-fused bicyclic ring skeleton of 1 is the intramolecular allylic amination of a cw-allylic carbonate 25. The paUadium-catalyzed allylation takes place with retention of the configuration [76] and requires the c/s-isomer 25 for the ring closure. Compound 25 may be derived from keto acid 24 through a sequence of reactions including esterification, O-methoxycarbonylation, removal of the Boc and benzylidene groups, dehydrative cyclization, reductive alkylation and ureido formation. The last five transformations are to be conducted in a successive manner, i.e., without isolation of the intermediates. The 4-carboxybutyl chain of 1 may be installed by the reaction of O-trimethylsilyl (TMS) cyanohydrin 23 with a di-Grignard... 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

Route A Synthesis and Enantioselective Reduction of Keto Acid 3 with Immobilized Proteus vulgaris Followed by Esterification... 

Simmonds, P. G., Pettitt, B. C., and Zlatkis, A., Esterification, identification, and gas chroihatographic analysis of Krebs cycle keto acids. Anal. Chem. 39, 163-167 (1967). 

The total synthesis of (+ )-dehydroheliotridine (4), a toxic metabolite of the pyrrolizidine alkaloids (e.g. lasiocarpine and heliotrine), has also been described.2 The pyrrole ring was obtained by reaction of l,6-dihydroxy-2,5-dicyanohexa-l,3,5-triene-l,6-dicarboxylic ester (5) with j3-alanine, which afforded the N-substituted pyrrole ester (6), together with the appropriate amide of oxalic acid. Careful hydrolysis of (6) with dilute alkali afforded the related tricarboxylic acid, which was converted, by Dieckmann cyclization, hydrolysis and decarboxylation, into the keto-acid (7). Esterification of (7) with diazomethane, followed by reduction with lithium aluminium hydride, finally afforded ( )-dehydroheliotridine (4), identical, except in optical rotation, with dehydroheliotridine obtained earlier by Culvenor et al.3... 

A new mild and convenient method for esterification of a-keto-acids has been applied to 2-thienylglyoxylic acid. A convenient method for the resolution of j8-(2-thienyl)alanine has been described. ... 

Esterification of thermally unstable carboxylic adds. Bicyclic jS-keto acids can be converted into ethyl esters by diethyl sulfate at 20° or lower with DBN as base. Methyl esters are obtained in the same way. Typical esters and the yields obtained by this procedure are given. ... 

Compounds with keto groups often give more than one derivative on silylation, acylation or esterification because of the possibility of geometrical isomerism, and yields may be unsatisfactory. For oc-keto acids the fonna-... 

These reagents react with carboxylic acids to form Mmc esters by heating in aprotic solvents (benzene, dioxane) at 80 °C [478, 479]. For the derivative formation of (Z-keto acids, hydrazone formation with dimethylhy-drazine and esterification with one of these reagents was suggested. 

Esterification with diazomethane is employed for the profiling of carboxylic acids in body fluids [164, 165]. The mass spectra of organic acid methyl esters show a variety of structurally informative base peaks compared with the corresponding TMS esters. However, artefacts are produced on reaction of diazomethane with 2-keto acids and 2,3-unsaturated acids [166, 167]. The methyl esters also have the disadvantage of providing low molecular weight increments, especially for the low molecular weight volatile acids such as lactic acid. 

This observation led to the proposal of an alternative mechanism similar to the Claisen mechanism involving aUyl enol ethers. They proposed that, in the case of Carroll s observations, the first step was a trans-esterification of the allylic alcohol, catalyzed by NaOAc, to the allyl acetoacetate, followed by a Claisen-type rearrangement to the ) -keto acid, which subsequently decarboxylated under the elevated reaction temperature (Scheme 8.4). 

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