Keto amides, hydrolysis

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

Hydrolysis reactions are illustrated by the deacylation of colchicine (10) (amide hydrolysis), olivomycin A (29), Rifamycin B (46) or thymoxamine (52) (ester hydrolysis). The reduction of pentoxyfylline (32), zearalenone (56) or warfarin (65) are examples of the common reduction of keto groups, generally affording, with a high stereospecificity, one of the alcohol stereoisomers. 

A benzazepine that includes the same (3-ketoamide array as piroxicam (Chapter 11) retains NSAID activity. Oxidation of benzothiapinone (5-1), obtainable by cycli-zation of 4-(4-chlorophenylthio)-butyric acid, with hydrogen peroxide gives the corresponding sulfone (5-2). This is then converted to its enamine (5-34) by reaction with pyrrolidine. Condensation of the intermediate with 3,4-dichorophenylisocyanate (5-4) leads to the amide (5-5). Hydrolysis with an aqueous acid cleaves the enamine function to give the keto-amide and thus enolicam (5-6) [6]. 

Carbamate and amide groups have been found to be stable under these coupling conditions73. In the presence of TiCLt or SnCLt, chiral a-keto amides 36 react with allyl-silane to produce, after hydrolysis, optically active tertiary alcohols 37 with extremely high optical selectivity (equation 23)74. The addition reaction appears to occur from the Si face of the carbonyl group. In a similar manner, a high degree of stereoselectivity is obtained from the reactions of A-Boc-a-amino aldehydes 38 with 2-substituted allylsilanes (equation 24)75. 

In this respect, Scheme 27, the ring opening of /V-sulfonyl p-lactam 80 with a dipeptide affords a-keto amide precursor 81. Subsequent elaboration of 81 and final hydrolysis of the ketal moiety affords poststatin 82, a naturally occurring pentapeptide which shows inhibitory activity against prolyl endopeptidase. 

Several c/s-erythrinan derivatives have been synthesized in Mondon s laboratories 17 e.g., the cycloerythrinane (16a) was obtained by heating the bromo-compound (15) with potassium hydroxide in diethylene glycol at 180 °C. On hydrolysis, it yielded the keto-amide (16b), which afforded the amide (16c) and the amine (16d) via the unsaturated amide (17). Bromination of the ketone... 

A striking solvent effect was observed in the reduction of a chiral a-keto amide, C6H5-CO-CO-NR2 (NR2 = (5)-proline methyl ester), with sodium tetrahy-dridoborate, leading to mandelic acid after hydrolysis [704]. When the a-keto amide was reduced in pure tetrahydrofuran or methanol, the resulting enantiomeric excess of (5)-mandelic acid produced was 36% and 4%, respectively. However, when a tetrahydrofuran/methanol (99 1 cL/L) solvent mixture was used, the enantiomeric excess increased to 64% ( ). In other solvent mixtures, a catalytic amount of a protic solvent (CH3OH or H2O) was found to be necessary for good asymmetric induction [704]. 

Another way to form a-aminoketones from a-amino acids is via the Dakin-West reaction, in which amino acids are treated with aliphatic acid anhydrides to give ketone amides. Thus, reaction of ( )-phenylalanine with the appropriate aliphatic acid anhydrides followed by acidic hydrolysis afforded keto-amide 1271. Cyclization of 1272 with potassium cyanate gave 5-alkyl-4-benzyl-l,3-dihydroimidazol-2-ones 1273 (Scheme 322) <2002JHC375>. 

Soon after the discovery of anandamide, enzymatic activities responsible for its degradation (an amidase, also called an amidohydrolase) and s mthesis (synthase) were described (DiMarzo et al. 1994 Desamaud et al. 1995 Ueda et al. 1995 Deutsch and Chin 1993 Kruszka and Gross 1994 Devane and Axelrod 1994). Phenylmethylsulfonyl fluoride (PMSF) was discovered to be a potent inhibitor of the enzymatic breakdown of arachidonoylethanolamide (Deutsch and Chin 1993). A series of anandamide analogs was synthesized (trifluoromethyl ketone, -keto ester, and -keto amide derivatives) and tested in vitro and in intact cells as amidase inhibitors (Koutek et al. 1994). The trifluoromethyl ketones (e.g., arachidonyltrifluoromethyl ketone) were found to be potent inhibitors in the low micromolar (M) range. Most recently, a potent irreversible inhibitor of anandamide hydrolysis (AM 374) has... 

A completely different approach to Y-keto-esters proceeds via Michael additions of carboxylic acid dianions to an a-anilino-acrylonitrile followed by alkylation of the resulting anion and finally acidic hydrolysis (Scheme 13). Overall yields are in the range 47-79% the method is also useful in the synthesis of r-keto-amides. An alternative anion-based route to y-keto-esters utilizes the homoenolate (166) as the interroediate which undergoes smooth acylation by a wide variety of acid chlorides.The homoenolate is obtained from the corresponding iodoester using Zn-Cu couple, and it seems likely that the method can be used to prepare more highly substituted keto-esters although such reactions have not yet been reported. 

More interestingly, however, basic hydrolysis of the amide group in the keto amide 5 leads to the indenobenzazepine 7 which can be taken td the 1,3-indandione 9 ... 

Other electrophiles, such as aromatic and aliphatic aldehydes, alicyclic ketones, or isocyanates, were also used successfully in 1. the second step giving rise to unsymmetrical a-hydroxy ketones 2. and a-keto amides after hydrolysis. Attempts to utilize an ester carbonyl group as an electrophile, however, failed the reactions 3. were low-yielding, and the expected products were accompanied 4. by a number of byproducts. 

The a-keto amides are less susceptible to hydrolysis and preparation of a-keto esters and acids are preferable for synthesizing various derivatives thereof. Various aryl iodides and bromides can be converted into a-keto esters on reactions with alcohols and carbon monoxide in the presence of a base such as tertiary amines or potassium acetate with catalytic amounts of tertiary phosphine-coordinated palladium complexes (Eq. 11).[42]-[46] jjjgjj yields of a-keto esters can be achieved only when iodide substrates are used. Double carbonylation of aryl bromides to a-keto esters can be accomplished with difficulty at much slower rates. Alkyl and benzyl iodides give no double carbonylation products. 

A somewhat related strategy used an a-chloro ketone as a starting material. The ketone moiety in keto-amide 6.34 was reduced quantitatively with sodium boro-hydride and then reacted with ammonia to give 6.35. Aqueous acid hydrolysis led to GABOB, 6.27. An a-bromo ketone is a closely related precursor to 6.20. It is... 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Trichloromethyl keto derivatives 382 (Scheme 78, Section 5.1.1) undergo hydrolysis with sodium hydroxide in aqueous THF to produce acids in overall yields of 60-70%. Coupling of the acids with amines leads directly to amides 383 in 80-90% yield (2000BMCL783). 

Bis(cthylthio)acetic acid (1). This a-keto acid equivalent is converted into the dianion by 2 equivalents of potassium bis(trimethylsilyl)amide in THF at 0°. The dianion is readily alkylated in high yield by a wide variety of electrophiles. The products are converted into a-keto acids by NBS hydrolysis (4, 216) or into methyl 2,2-bismethoxycarboxylatcs by treatment with l2-CH3OH (6, 238). 

N-Benzylamides are recommended when the corresponding acid is liquid and/or water-soluble so that it cannot itself serve as a derivative. The benzyl-amides derived from the simple fatty acids or their esters are not altogether satisfactory since they are often low melting those derived from most hydroxy acids and from polybasic acids or their esters are formed in good yield and are easily purified. The esters of aromatic acids yield satisfactory derivatives but the method must compete with the equally simple process of hydrolysis and precipitation of the free acid, an obvious derivative when the acid is a solid. The procedure fails with esters of keto acids, sulphonic acids and inorganic acids and some halogenated aliphatic esters. 

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