Keto acids, esterification esters

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... 

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). 

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. 

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-... 

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... 

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. ... 

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. 

The alkylation of Hagemann s ester (76) with )S -bromopropionic ester and subsequent decarboxylation and saponification on boiling with hydriodic acid led to the keto acid (77) [894, 895]. This could not be cyclized directly into the hydrindandione (81) [894], and therefore another method of synthesis was tried. The addition of hydrogen cyanide, alkaline hydrolysis, and esterification enabled the cis-diester (78) to be obtained, and this was then converted by Dieckmann cyclization and decarboxylation into the cis-hydrindandione (81) [896]. The same product was obtained by another route, from ethyl y-acetobutyrate (82). Its subsequent condensation with cyano-acetic ester, hydrogen cyanide, and acrylonitrile led to compound (83), which, on acid hydrolysis and esterification, gave the tetraester (84). The Dieckmann cyclization of this with the simultaneous formation of two rings and subsequent decarboxylation yielded the diketone (81) [897]. 

The trifluoromethyl epoxide 150 is an important intermediate in the synthesis of the anti-inflammatory drug lead BI-115 (17, Scheme 2.24). Researchers at Boehringer Ingelheim developed an efficient protocol for the synthesis of the a-trifluoromethyl-a-alkyl epoxide 150 that involved use of (lR,2S)-trans-2-phenylcy-clohexanol 146 as a chiral auxiliary for the asymmetric addition of a trifluoromethyl anion to the a-keto ester 147 153 synthesis of 150 initiated with the esterification of the a-keto acid 145 with (lR,2S)-trans-2-... 

This procedure illustrates a new method for the preparation of 6-alkyl-a,g-unsaturated esters by coupling lithium dialkylcuprates with enol phosphates of g-keto esters. The procedure for the preparation of methyl 2-oxocyclohexanecarboxylate described in Part A Is based on one reported by Ruest, Blouin, and Deslongcharaps. Methyl 2-methyl-l-cyc1ohexene-l-carboxylate has been prepared by esterification of the corresponding acid with dlazomethane - and by reaction of methyl 2-chloro-l-cyclohexene-l-carboxyl ate with lithium dimethylcuprate. -... 

The guanidine 1 can be alkylated more readily than 2, but nevertheless is a very effective proton acceptor. It is preferred to DBU as the base for esterification of carboxylic acids by an alkyl halide. Thus severely hindered tertiary carboxylic acids can be alkylated by isopropyl iodide in about 90% yield in the presence of 1 (1.5 equiv.). Selective C-monoalkylation of a typical /J-keto ester was effected in 80% yield in the presence of I (1.0 equiv.). Preliminary experiments suggest that 1 is not particularly useful for base-promoted elimination reactions, but that the more hindered 2 is superior to collidine or DBN for this purpose. 

In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromide in DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. 

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