Esters methoxy formates

Benzocondensed 3,l-oxazin-4-ones are also accessible via an aza-Wittig reaction (Scheme 86) (93T581). Iminophosphorane 230 affords an imidoyl chloride with aroyl chlorides. The electrophilic C atom is attacked by the ester methoxy group, and the formation of a six-membered ring 231 is thermodynamically favored. Extrusion of methyl chloride gives the stable benzoxazinone 232 (93T581). 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Diarylthioketones are converted in good yields into orthometallated complexes by diiron enneacarbonyl.141 These in turn can be transformed oxidatively (Ce4+) or photochemically into isobenzothiophenes (see Section IV,C,2), or by reaction with mercuric trifluoroacetate into isobenzofurans (Scheme 78)142 the formation of methoxy esters is a competing process in... 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

It was Ayusman Sen [8] who discovered in 1982 that the use of weakly coordinating anions and phosphines as the ligands together with palladium yielded much more stable and active catalysts for the formation of polyketone from CO and ethene in alcoholic solvents. Cationic palladium-(triphenylphosphine)2(BF4)2 gave a mixture of oligomers having methoxy ester... 

A more promising approach to a synthesis of vinblastine-type compounds can be derived from the significant observation that reaction of one enantiomer of the carboline ester (-l- )-38 with p-nitrobenzyl chloro-formate and 3-methoxy-A/, A-dimethylaniline, at 25°C, gave a model (-t-)-congener of 39 in 72% yield and 55% enantiomeric excess, thus indicating a conformational retention in the nine-membered cationic intermediate formed on acylation of the carboline ester 38 (37b). 

Chiral synthesis during the coupling reaction betw een an a-methoxy amide and a nucleophile can be achieved. One approach to this problem uses a nucleophile derived from a 2-niethyloxazoIine possessing a chiral centre, for example in the formation of the chiral amine 27 [123], A second approach uses esters of pyroglu-... 

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