Y-Keto acids

Clearly other combinations of logical and illogical synthons could be used to make 1,4-dioxygenated compounds. How could you use cyanide ion (as the CO2H synthon) to make a y-keto acid such as... 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

Carbonylation of alkynes is a convenient method to synthesize various carbonyl compounds. Alper et al. found that carbonylation of terminal alkynes could be carried out in aqueous media in the presence of 1 atm CO by a cobalt catalyst, affording 2-butenolide products. This reaction can also be catalyzed by a cobalt complex and a ruthenium complex to give y-keto acids (Scheme 4.8).92... 

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

Butenolides are formed in the alkyne-CH3l--Co2(CO)3 phase transfer reaction. When the latter process is effected in the presence of ruthenium carbonyl, a second metal catalyst, y-keto acids are isolated in good yields(17). 

There are many reports describing the preparation of various butyrolac-tones from AAs. When r-butyl 2-dibenzylaminoacetate in the form of its Li-enolate was treated with (5)-0-benzyllactic aldehyde, a mixture of four diastereoisomeric hydroxy-AAs was obtained. After separation and further treatment, three lactones were obtained (Scheme 17) (87T2317). Similar compounds were obtained from a-acylamino-y-keto acids after cycliza-tion (75CC905). 

The cyclization method of Ochiai et al (85CPB989), used for reduced furans 94, affords a mixture of six-membered lactone 243 and the rearranged y-keto acid 244 when acid 242 is the substrate. 

The methodology may also be applicable to the synthesis of pharmacodynamic agents based on the alkoxythiophene core. Such materials should be readily accessible via our new cydization methodology " which utilizes the y-keto acid precursors. 

Anodic oxidation of a carboxylic acid generates a carbenium ion at the a-carbon. This contrapolarization enables a facile fragmentation of y-keto acids [255],... 

Oxazolin-5-ones have also proven to be important intermediates in the homologation of carboxylic acids (71AG(E)655). The IV-acyl-DL-valine derivative (402), prepared from the acid chloride of the carboxylic acid and DL-valine by the Schotten-Baumann procedure, was treated with excess acetic anhydride to afford (403). Reaction of (403) with acrylonitrile and triethylamine led to (404) in good yield. Hydrolysis of (404) with dilute alkali or acid gave the y-keto nitrile or y-keto acid (Scheme 89). 

Generally, acid or base hydrolysis of 2(3//)-furanones gives the corresponding y-keto acids. Refluxing furanones 17 and 19 with aq. sodium hy-... 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

The retrosynthetic disconnection for the y-keto acid shown below generates an acyl anion synthon and a three-carbon carbocation. 

When the alkylidenesuccinic ester is derived from an aldehyde [e.g. (26)], functional group modification provides a route to y-keto acids and the overall process relates to the disconnection strategy outlined above. The required modifications are hydrolysis of the diester to the diacid and photocatalysed... 

The synthesis of bicyclic y-lactam-piperazinone derivatives has been reported by Hulme et al. [8b] as an extension of the UDC strategy. Alternatively, the formation of y-lactams by reacting y-keto acids, amines, and isocyanides [89] has been ex-... 

Further examples of pyran-2-ones obtained from 1,3-dicarbonyl compounds and HC(OEt)3 include several hetero-fused analogues (95H(41)1299) and cyclodehydration of a y-keto acid yields a pyranopyrrole (95JCS(P1)1131). 

Alkylation of cyclohexanone enamines with methyl chloro(methoxy)acetate, followed by alkaline hydrolysis, affords the y-keto acid 30, which readily cyclizes to the unsaturated lactone 31 on treatment with hydrogen chloride in acetic acid (equation 20)40. 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

Subst. phenyl-y-keto acids (1-L25, 3-Mj Subst. phenyl hydrazines (4-L25, 3-L26)... 

Aryl-substituted y keto acids are readily obtained by acylation of aromatic compounds with succinic anhydride, e.g., /S-benzoylpropionic acid (85%). ... 

A general synthesis for y-keto acids involves the oxidation of y-lactones with bromine in the presence of magnesium hydroxide. ... 

Several a-keto acids are easily obtained by hydrolysis of acyl cyanides. An improved procedure using cuprous cyanide in the preparation of the acyl cyanides is described. Hydrolysis of the acyl cyanides by cold concentrated hydrochloric acid is described for pyruvic acid (73%), a-ketobutyric acid, and benzoylformic acid (77%). Isovaleryl cyanide is not hydrolyzed under these conditions. Alkaline hydrolysis has been found to be more successful than acid hydrolysis in the preparation of the y-keto acid, a-phenyl-/S-benzoylpropionic acid (76%). ... 

The introduction of an ester group by the acetoacetic ester synthesis (cf. methods 184 and 213) is possible by alkylation of /S-keto esters with halo esters. Cleavage of the alkylated products by mineral acids furnishes an important route to y-keto acids and es/ers. ... 

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