Methyl carboxylate

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

At the stage of the ketone 20, or the analogous methyl carboxylate, further substituents can be introduced diastereoselectively by Grignard additions or by enolate methodology4 6. 

Desilylation of the major jjw-isomer, followed by oxidative cleavage with sodium metaperiodate, liberates the 3-hydroxy-2-methyl carboxylic acids. The immolative character of this method, i.e., the destruction of the chiral auxiliary reagent in the final glycol cleavage, is a drawback. 

Table 3. (R)-Cyanohydrins by Enzymatic Formation from Ketones and Hydrocvamic Acid as well as (7 )-a-Hydroxy-a-methyl Carboxylic Acids by Hydrolysis...

Trimethylaluminum, which exhaustively methylates ketones (16-27), also exhaustively methylates carboxylic acids to give tert-butyl compounds (see also 10-99) ... 

N,N-dimethylamides methyl carboxylates propionyl derivatives acetyl ... 

Wong and co-workers have prepared various quaternary cx-nitro-cx-methyl carboxylic acid esters by the palladium-catalyzed allylic alkylation of a-nitropropionate ester (Eq. 5.59). The products can be kinetically resolved by using cx-chymotrypsin and are converted into optical active a-methyl cx-amino acids. Such amino acids are important due to the unique biological activity of these nonproteinogenic a-amino acids.82... 

Effenberger, F., Hoersch, B., Weingart, F. et al. (1991) Enzyme-catalyzed synthesis or (/ )-ketone-cyanohydrins and their hydrolysis to (R)-a-hydroxy-a-methyl-carboxylic acids. Tetrahedron Letters, 32, 2605-2608. 

Further insight into the carbon-oxygen reductive elimination from Pt(IV) and the involvement of five-coordinate Pt(IV) intermediates has been provided recently. The first direct observation of high-yield C-0 reductive elimination from Pt(IV) was described and studied in detail (50,51). Carbon-oxygen coupling to form methyl carboxylates and methyl aryl ethers was observed upon thermolysis of the Pt(IV) complexes ( P2 )PtMe3(OR) ( P2 =bis(diphenylphosphino)ethane or o-bis(diphenyl-phosphino)benzene OR=carboxylate, aryl oxide). As shown in Scheme 47, competitive C-C reductive elimination to form ethane was also observed. 

The oxazoline methodology can be applied in the total synthesis of natural products. For example, in the course of the total synthesis of European pine-saw fly pheromone 47, the key intermediate, chiral a-methyl carboxylic acid 46, was prepared via the reaction of a-lithioethyloxazoline with n-octyl iodide. The product 2-methyl decanoic acid 46 was obtained, after hydrolysis, in 72% ee (Scheme 2-26).51... 

Bis(homoallylic) alkoxides also undergo this 3-cleavage. The substrates (1) are available by reaction of a methyl carboxylate with 2 equiv. of allyl- or methallyl-magnesium chloride. The alcohols when heated at 80° in a slurry of KH in HMPT are converted into 3.7- and a,3-unsaturated ketones (2 and 3) in 75-85% yield. 

Abbreviations SPQ 6-methoxy-N -(sulfopropyl)quinolinium SPA N-(sulfopropyl)acridinium lucigenin bis-N-methylacridinium nitrate MACA 10-methylacridinium-9-carboxamide MAMC N-methylacridinium-9-methyl carboxylate. 

Recent studies with quinoline-4-carboxylic acid angiotensin II receptor antagonists have confirmed the interest of (oxodioxolyl)methyl esters as prodrugs with improved oral bioavailability and efficacy in laboratory animals [79], Olmesartan, another angiotensin II receptor antagonist, has also been derivatized to a (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl carboxylate designated as olmesartan medoxomil [80], In this case, both human serum albumin and arylesterase (presumably EC 3.1.1.2, although paraoxonase cannot be excluded) were shown to be involved in hydrolysis. 

Cleavage Gem-dihalides and monohalides have been dehalogenated to chiral monohalides in the presence of alkaloids [397, 398]. l,l-Diphenyl-2-bromo-2-carboxyl (bromo or methyl carboxylate) cyclopropanes are cathodically debromi-nated in the presence of alkaloid cations with enantioselectivities up to 45% ee. A mechanism is proposed whereby the alkaloid is adsorbed at the Hg cathode, which protonates face selectively the carbanion generated by 2e reduction from the bromide [399]. 

The Bristol group of Christine Willis, in collaboration with Amersham International, developed a procedure for deuterium (or labeling of nonpolar amino acids." In the chemical steps, a selectively methyl-labeled oxazolidinone is converted first into a 2-methyl carboxylic acid and then lengthened by two carbon atoms without racemization to yield an a-keto methyl ester (Scheme 9). 

With this modification the expected a, -nnsaturated methyl carboxylates are obtained in high yields and with complete retention of the C=C bond configuration. In all cases a black precipitate is deposited during the reaction. 

Mix 230 ml of dry ethanol with 32.5 g of sodium methoxide under a nitrogen atmosphere until the methoxide is dissolved. Add 110 g of diethyl malonate and stir for 10 min, then add 75 g of 3-nonene-2-one (or equimolar amount of 5,6-dimethylundec-3-ene-2-one for dimethyl-heptyl) keeping the temp below 49° with external cooling. Stir and reflux for 3 hours, cool to room temp, neutralize with coned HCL add (about 45 ml), and let stand for 8-12 hours. Evaporate in vacuo, and dissolve the residue in 1 N HCl acid and 800 ml ethylacetate. Allow to stand to separate the ethyl acetate, then wash it (the acetate) with two 300 ml portions of water and extract with a saturated solution of NaHCOs until a small sample shows no turbidity upon acidification (it will take at least nine 100 ml portion extractions). Combine the NaHCOs extractions and very carefully acidify them with tiny portions of acid. Extract with three 300 ml portions of ether, and remove the ether by evaporation in vacuo after drying with MgS04 to get the methyl-carboxylate. 

This reaction is also feasible if the benzene ring contains substituents, such as halogens or methyl, carboxyl, and nitro groups. 

The 6-benzylpyrido[4,3-, pyrimidine 145 was prepared by cyclizing the methyl carboxylate 612 with formamidine hydrochloride <2000DEP19900544>. The 2-butyl-6-(2-hydroxy-2-methyl-l-oxopropyl) analogue 615 was also prepared from cyclocondensation of ethyl ester 613 with BuC(NH)NH2 <1994USP5281602>. The trisubstituted analogue 616 was obtained from the reaction of 2-guanidino-4-(4-fluorophenyl)thiazole hydrobromide with iV,3-dibenzoyl-4-piperidone 614 <1995USP5405848>. 

Epoxy-6-methyl[Pg.28]

Relatively stable 2,2,4,6-tetramethyl-2//-pyran (176) exhibited a high regiospecificity toward methyl propargylate to afford [47t + 27t] adduct 561, which spontaneously decomposed to methyl 2,4-dimethylbenzoate (562) in 73% yield.405 Similarly, labile 3-acetyl-2,6-dimethyl-2//-pyran (564) gave with acetylenic methyl carboxylates benzenoid derivatives 565. On the other... 

Enantioselective aldol condensation. Masamtinc et al. have prepared optically pure /Miydroxy-a-methyl carboxylic acids by aldol condensation with the (S)- and (RHsomers of the ethyl ketone I, prepared in three steps from commercially available (S)- and (R>mandelic acid. For example, (SH is converted into the (Z)-boron cnolatc (2), which condenses with propionaldehyde to form a single aldol... 

Aldo/ condensation. The lithium enolate of 1 reacts with aldehydes to form aldols 2 and 3 in all cases the major product is the r/im>-3-hydroxy-2-methyl carboxylic ester (2). In fact with a-hranchcd aldehydes no eryt/iro-product is formed. The esters can be hydrolyzed with KOH in CH3OH. 

Methyl esterification takes place after poly(galacturonic acid) is formed, and Kauss and coworkers315-317 showed that the mung-bean particulate-fraction that contains the galactosyluronic transferase also contains an enzyme responsible for methylating carboxyl groups of poly(galacturonic acid). The methyl donor for this reaction is S-adeno-syl-L-methionine. 

Non-oxidative hydrocarboxylation of alkenes to carboxylic acids with CO and H20 is catalyzed by palladium complexes such as PdCl2(PhCN)2 or PdCl2(PPh3)2, and a-methyl acids predominate in the presence of HC1.374,443 A recent improvement of this reaction consisted of the use of a PdCl2/CuCl2/HCl catalyst under oxidative conditions.377 Almost quantitative yields of a-methyl carboxylic acids and dicarboxylic acids were obtained from terminal alkenes and terminal dialkenes respectively, at room temperature and atmospheric pressure (equation 174).377... 

Alkoxy or 2,2-dialkoxy nitriles.10 Ketals or orthoesters are converted into 2-alkoxy or 2,2-dialkoxy nitriles, respectively, by reaction with cyanotrimethylsilane in the presence of SnCl2 or BF3-0(C2H5)2 as catalyst. A typical reaction is the preparation of dimethoxyacetonitrile (1), which is a useful reagent for conversion of alkyl halides to the homologous methyl carboxylate (equation I). 

METHYL CARBOXYLATES Formaldehyde dimethyl dithioacetal S,S-dioxide. 

---