Keto acids, esterification preparation

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. 

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 reaction was carried out in a 22 L reactor with EDTA (3.35 g), mercaptoethanol (1.41g), ammonium formate (908 g), and sterile water (18.0 L), which was degassed prior to addition of keto acid sait 58 (800 g). The solution was filtered through a 0.2 p,m filter and transferred to a clean 22-L reactor. NAD+ (23.88 g) was added and the pH adjusted to 6.3 by adding 1 N HCI. This substrate solution was then fed into a membrane reactor with ultrafiltration membrane for enzymatic reduction. The reactor was previously filled with an aqueous mixture of enzymes (d-LDH, 400 units mL-1 with activity 20 units mg-1 and FDH, 20 units mL-1 with activity 76 units mL-1). An appropriate feed rate was used to maintain a conversion of > 90%. The circulation rate was kept between 15 and 30 times that of the feed rate. The aqueous effluent solution thus obtained was adjusted to pH 3.0 with 2 N HCI and extracted with MTBE (5 L). The organic layer was evaporated to obtain 972 g of acid 56 as an off-white solid in a yield of 88%, >90% purity and >99.9% ee. In this process a total of 14.5 kg of 56 was prepared with a productivity of approximately 560 gram per liter per day with good overall 72% yields [113]. To evaluate the optical purity, 56 was converted to methylester by esterification and the ee of methylester was found to be >99.9%. 

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. -... 

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. 

This alcoholysis of carboxylic esters under the influence of alkaline catalysts is important for the preparation of esters of long-chain alcohols with heat-sensitive carboxylic acids, e.g., with /ff-keto carboxylic acids,858-864 and of esters of acid-sensitive alcohols860-863 that cannot be subjected to the usual methods of esterification. For such reactions sodium alkoxides,853 sodium hydroxide,854 855 and potassium carbonate856 have proved useful as catalysts. 

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