Keto esters Reformatsky reaction

Two new cephalotaxine esters having significant antileukemic activity, neoharringtonine (11) and anhydroharringtonine (12), were isolated in 1992 by Wang and co-workers (9) from C. fortunei Hook f. These authors also reported their semisynthesis from cephalotaxine and harringtonine, respectively (Scheme 31). On treatment with phenyl pyruvyl chloride in the presence of pyridine, cephalotaxine (1) produced an intermediate a-keto ester. Reformatsky reaction of this cephalotaxyl phenyl pyruvate with methyl bromoacetate yielded a mixture of neoharringtonine (11) and its epimer. 

Reformatsky first introduced electron-withdrawing substituents on the a-carbon of an organozinc halide, leading to the more reactive and thermally stable a-(alkoxycarbonyl)alkylzinc halides (123).107 Typically these reagents react with aldehydes or ketones to afford 3-hydroxy esters while nitriles afford 3-keto esters (Blaise reaction),l07b>c but 1,4-conjugate additions to select a,3 unsaturated ketones are precedented (Section 1.2.2.2.2). 

The Reformatsky reaction provides a method of converting a-bromoesters via the zinc reagent into j3-hydroxy- or j8-keto-esters. The reactions may be carried out either in situ, where zinc, the bromo ester and the carbonyl compound are all warmed together in a solvent (ether, benzene or 1,2-dimethoxyethane), or in two stages by forming the zinc intermediate first. The actual zinc reagent is probably an enolate rather than an organozinc species ... 

Several steroidal spiro-lactones have been prepared by treatment of a 17-keto-steroid, such as 3jS-acetoxyandrost-5-en-17-one (212), in a Reformatsky reaction with a bromo-ester, which gave an isomeric pair of 17-spiro-lactones, such as (213). Similar results have been obtained in the oestratriene series. 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

Ediyl acetoacetate gave only low yields in a Reformatsky reaction but even this is remaikable considering its acidic nature (equation 17). 3 Keto esters that lack acidic hydrogens react in good yield (equation 18). ... 

Reactions of Reformatsky reagents with esters or with acid chlorides generally give only low yields of P-keto esters. Hauser reported that ethyl a-bromoisobutyrate could be acylated in reasonable yields with either the acid chlorides or the phenyl esters of aromatic acids, but the reaction fails with acylating... 

The most successful acylations of Reformatsky reagents have been obtained with nitriles. This reaction, first reported in 1901 by Blaise, was little used until Kagan and Suen reported that slow addition of a benzene solution of a-bromo esters to a refluxing mixture of zinc and the nitrile gave good yields (70-83%) of a,a-disubstituted 3-keto esters. Hannick and Kishl reported that a similar proce-... 

The Reformatsky reaction with A(-acyloxazolidin-2-ones and -thiazolidin-2-thiones provides a route to /3-keto esters. The electrolysis of a-bromoalkanoic esters in acetonitrile on a zinc anode with ZnBr2 and Bu NBEi as supporting electrolytes gives acetoacetic ester derivatives. The acetonitrile solvent is partially consumed. 

Reformatsky reactions. A practical synthesis of P-hydroxy-a,a-difluoroalkanoic esters involves halodifluoroacetic esters and induction by Smij. a-Bromoalkanoic esters undergo self-condensation, and if they are quenched by carbonyl compounds, 5-hydroxy-p-keto esters are formed as products. ... 

This reaction is believed to proceed by a mechanism analogous to that of the Reformatsky Reaction involving an initial condensation of the nitrile with the Reformatsky reagent the intermediate is finally transformed into 0-keto ester via acidic hydrolysis,as illustrated here. 

In that same period, identical problems were encountered when ethyl oxalate was used in Reformatsky reactions [16] with zinc the expected hydroxy acid ester was obtained whereas magnesium yielded the keto acid ester. 

Palladium is a useful catalyst in several reactions which lead to keto-esters. p-Keto-esters react with allylic carbonates, with catalysis by palladium, in a decarboxylative allylation reaction. y-Keto-esters are prepared, in reasonable yield, by the palladium-catalysed regioselective oxidation of Py-unsaturated esters. y-Keto-esters are obtained in good yield by the palladium-catalysed Reformatsky reaction of ethyl bromoacetate and acid chlorides. Derivatives of y-ketopimelic acid are formed by the rhodium-carbonyl-catalysed reaction of derivatives of acrylic acid with carbon monoxide. A mild method for the conversion of propiolic esters into P-keto-esters via thiol addition has been reported (Scheme 63) it has been used in a formal synthesis of ( )-thienamycin. 

Manganese metal (commercial quality) without any special preparation allows Barbier or Reformatsky reactions, respectively, to be performed from allylic bromides and a-halogenoesters. The use of manganese is of real preparative interest since these reactions have a large scope of application and occur under mild conditions to give high yields of 1,2-addition products (16]. It should be noted that numerous functional ketones (keto-esters, keto-acetals, w-chloro-ketones) were converted into the corresponding functional alcohols very efficiently (Schemes 13.13 and 13.15). 

Tetronic acids and P-keto-y-butyrolactones are easily prepared by reaction of an 0-trimethylsilylated cyanohydrin with a-bromo esters in the presence of a Zn- u couple in a Reformatsky-type reaction (Scheme 12). ... 

Keto-y-butyrolactones teironic acids Zinc, activated with Cu(OAc)2, promotes a Reformatsky-type reaction of a-bromo esters with O-silylated cyanohydrins to provide p-keto-y-butyrolactones or tetronic acids. 

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