5-Hydroxy-3-ketoesters

A Idol reactions. The copper comp l> lketene acetals with (benzyloxy )ac< kn approach to 5-hydroxy-3-ketoester es a titanium alkoxide derived from n imino-BINOL complex 15 is effec... 

Xn approach to 5-hydroxy-3-ketoesters by the condensation of diketene with aldehydes n lives a titanium alkoxide derived from the complex Schiff base 14. ... 

The reduction of the pre-fuctionalized, usually through the referred in the previous chapter aldols, asymmetric 5-hydroxy-3-ketoesters (72) can lead directly to functionalized 1,3-diols. This transformation can be achieved either by chemical reduction or by biotransformation. Since the Noyori reduction [72] is not only one of the most prominent and applied catalytic reductions but also highly applicable to P-keto esters, it was investigated by Shao et al. [73]. They used chiral ester 72 and performed Noyori reduction using both enantiomers of DINAR It was realized that the chiral... 

Scheme 12.3. Stereochemical rationalization of syn-reduction of p-hydroxy ketoester 27a.

In the laboratory of FI. Flagiwara, the first total synthesis of the polyketide natural product (-)-solanapyrone E was achieved. The installation of the pyrone moiety required the addition of the b/s(trimethylsilyl) enol ether of methyl acetoacetate to a bicyclic aldehyde precursor in the presence of titanium tetrachloride. The resulting -hydroxy- -ketoester was oxidized with the Jones reagent to afford the corresponding -diketoester in good yield. 

Saicie and eo-workers used olefin metathesis as one of the final steps in their synthesis of ( )-periplahone C, a C-macrolide pheromone. a-Hydroxy ketoester 156, when treated with 3 mol% of 3 in dichloromethane at room temperature over the course of 23 h, gave the desired carbocyle 157 in 81% yield. The authors applied this methodology to access a number of other intermediates in the periplanone family. 

Reaction of a P-ketoestei witii gaseous ammonia (/) gives an enamine, which on treatment with methylhydiazine (2) yields an 85 15 mistuie of 3-hydioxy- and 5-hydioxy-l-substituted pyrazoles (36) (eq. 5). Previously P-ketoesters furnished mainly the 5-hydroxy isomer. 

Coumarin can also be formed by the reaction of phenol with diketene (40). Similarly, diphenols can react with hydroxycarboxyUc acids or beta-ketoesters to give hydroxycoumaria derivatives. The reaction of resorciaol with malic acid produces umbeUiferone (7-hydroxycoumaria) and its reaction with ethyl acetoacetate gives beta-methylumbeUiferone (7-hydroxy-4-methylcoumaria). 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

The Conrad-Limpach reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with the ketone or aldehyde of a 3-ketoester or a-formylester 2 providing enamine 3, and (b) cyclization with loss of alcohol to yield 4-hydroxy-quinoline 4. 

The mercaptals obtained by the acid catalyzed reaction of J3-ketoesters, e.g., ethyl acetoacetate, with methyl thioglycolate (73) undergo the Dieckmann cyclization with alcoholic potassium hydroxide at lower temperatures to give ethyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (74) in 75% yield. ° Besides ethyl acetoacetate, ethyl a-ethylacetoacetate, ethyl benzoyl acetate, and ethyl cyclopentanonecarboxylate were also used in this reaction/ It is claimed that /8-diketones, hydroxy- or alkoxy-methyleneketones, or /8-ketoaldehyde acetals also can be used in this reaction. From acetylacetone and thioglycolic acid, 3,5-dimethyl-2-thiophenecarboxyl-ic acid is obtained. ... 

Several reactions giving rise to hydroxy- and amino-isoxazoles have also been investigated. Thus the reaction of alkoxymethylene-cyanoacetates and hydroxylamine leading to 5-amino- or 5-hydroxy-isoxazoles proved to be rather useful.It is of particular interest that, by changing the reaction conditions, Bauer and Nambury succeeded in obtaining isomeric aminoisoxazolones (24 25 26). It is also possible to prepare isoxazol-3-ones from some /S-ketoesters. ... 

The rhodium-catalyzed conversion of a-diazo-p-hydroxy carbonyl into P-dicarbonyl compounds (Table 23, Entries 6-8) in general seems to be preferable to the acid-catalyzed reaction because of higher yields and absence of side-reactions 37S,377). From a screening of 20 metal salts and complexes, Rh2(OAc)4, RhCl(PPh3)3, PdCl2 and CoCl2 emerged as the most efficient catalysts for the transformation of a-diazo-P-hydroxy esters into P-ketoesters 376). This reaction has become part of... 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

The group of Janda has presented a microwave-mediated oxazole synthesis utilizing /3-ketoestcrs bound to a novel polymeric resin [57]. The desired polymer support was prepared by transesterification reactions of tert-butyl /f-ketoesters and hydroxy-butyl-functionalized JandaJel resin and subsequent standard diazo transfer. The resulting a-diazo /f-ketoesters were employed for the synthesis of an array of oxa-zoles (Scheme 7.41). 

Ojima (43) used the same DIOPRh catalyst earlier to add Et2SiH2, PhMeSiH2, Ph2SiH2 and a-naph-PhSiH2 to a-ketoesters to synthesize optically active a-hydroxy carboxylate esters. With diethyl- or phenyl-methylsilane and propyl pyuvate, a double hydrosilation occurred to chiefly make a cyclic product with double asymmetry. 

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

A closely related reaction of ketones and ketoesters with chiral f-butyl (+)-(i )-p-toluenesulfinylacetate 50 was utilized for the synthesis of chiral (3-hydroxy acids as shown in Scheme 32 (317). The optical purities of the final reaction products varied from 8.5 to 91%. 

Under the conditions of iridium-catalyzed hydrogenation, alkyne-carbonyl and alkyne-imine reductive coupling occurs in the absence of stoichiometric byproducts. For example, iridium-catalyzed hydrogenation of nonconjugated alkynes in the presence of ot-ketoesters delivers the corresponding a-hydroxy esters in... 

Scheme 2 Iridium-catalyzed hydrogenation of alkynes in the presence of a-ketoesters to furnish a-hydroxy esters...

It has been reported that a cationic iridium such as [Ir(cod)2]BARF (BARF = 3,5-(CF3)2C6H3 4B), when combined with l,l -bis(diphenylphosphino)ferrocene (DPPF), catalyzed a hydrogen-mediated reductive carbon-carbon bond formation [68]. Thus, the reaction of alkynes 150 with a-ketoesters 151 produces p.y-unsaturated-a-hydroxy ketones 152 (Equation 10.40). 

Pyrazoles were obtained from corresponding 2-hydroxy(or aIkoxy-)imino-1,3-diketones or related ketoesters and hydrazine . Thus, reaction of oximes 112 with hydrazine in ethanol afforded aminopyrazoles 113 in 48-95% yields (equation 48) . Interaction of... 

Enantioselective hydroxylation of 2-benzyl (3-ketoesters was catalysed by [RuCl(OEt3)(PNNP)]/aq. H O /CH Cy thus ethyl 2-benzyl-3-oxo-butanoate gave ethyl 2-hydroxy-2-benzyl-yoxo-butanoate. Better results were obtained with cumyl hydroperoxide as co-oxidant [14]. The reagent Ru(CO)(TPP) or Ru(CO) (TMP)/(Cl3pyNO)/aq. HBr/C Hy40°C oxidised 5 3-steroids to the corresponding Sp-hydroxy derivatives with retention of configuration [15]. 

Whereas the Markovnikov addition of carboxylic acids to propargylic alcohols produces P-ketoesters, resulting from intramolecular transesterification [30, 31], the addition to propargylic alcohols in the presence of Ru(methallyl)2(dppe) 1 at 65 °C leads to hydroxylated alk-l-en-l-yl esters via formation of a hydroxy vinylidene intermediate [32, 33]. The stereoselectivities are lo ver than those obtained from non-hydroxylated substrates. These esters, which are protected forms of aldehydes, can easily be cleaved under thermal or acidic conditions to give conjugated enals, corresponding to the formal isomerization products of the starting alcohols (Scheme 10.6). 

The succinct synthesis of warfarin starts with condensation of ort/zo-hydroxy-acetophenone (1-2) with ethyl carbonate to give the (3-ketoester (1-3) as the presumed intermediate shown in the enol form. Attack of the phenoxide on the ester grouping will lead to cyclization and the formation of the coumarin (1-4). Conjugate addition of the anion from that product to methyl styryl ketone (1-5) gives the corresponding Michael adduct and thus warfarin (1-6) [1]. 

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