Dicarbonyl substrate systems

Catalytic asymmetric construction of nitrogen-substituted quaternary stereocenter has been another important and challenging task in asymmetric synthesis. The first a-amination using cinchona alkaloids was shown in 1,3-dicarbonyl substrate systems. In 2004, Pihko and coworkers showed enantioselective a-amination of cyclic fi-ketoesters 130, with dibenzyl azodicarboxylate (131) in the presence of... 

In classical Hantzsch procedure, an enaminocarbonyl is formed in sim by condensation of ammonia source onto the 1,3-dicarbonyl substrate. But many groups have used a three-component modified-Hantzsch protocol in which the preformed enamine is introduced as a partner. Thus, utilization of cyclic or acyclic 1,3-dicarbonyl compounds, aldehydes, and acyclic or cyclic enamines has been reported, leading regioselectively to diversely substituted 1,4-DHP derivatives (Scheme 7). The sequence involving such starting materials was performed in numerous efficient systems, and more particularly in the following (1) microwave-assisted reaction in acetic acid [50], DMF [51], or an acetic acid/DMF system [52] (2) sonification in ethylene glycol [53] and (3) use of ionic liquids such as [bmim]BF4 [54]. 

When the 1,3-dicarbonyl substrate reacts twice via its activated methylene due to the presence of heteroatoms blocking the enolization process on other positions, spiranic systems are formed in the presence of two equivalents of aldehyde and an equivalent of urea (Scheme 15) [85]. The reaction can be promoted either in acetic acid as solvent or neat under microwave irradiations or in the presence of H3PW12O40 as catalyst. Finally, this technique for generating spiroheterocyclic products has been transferred to solid-supported methodology by immobilizing the 1,3-dicarbonyl partner onto a resin [86]. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Unsaturated /1-dkarbonyl compounds. This system can be prepared by reaction of enolizable /5-dicarbonyl compounds with C6H5SeCl-pyridine (1 1, 9, 28-29) followed by sclcnoxide elimination. The rate of selenenylation increases with the ease of enolization of the substrate.2... 

Treatment of the substrate 511 with 1,3-dicarbonyl compounds under basic conditions is followed by an acid-induced rearrangement, producing a set of pyrroles, as illustrated by the synthesis of the system 512 via the 2,3-dihydrofuran intermediate 513 (Scheme 67) <2002TL4491, 2003EJO2635>. 

A similar reagent, [hydroxy(tosyloxy)iodo]benzene, has been used to prepare a-tosyloxy ketones, e.g. (14), from the corresponding ketones. A similar mechanism is thought to operate except that here the initially formed a-iodo species decomposes to the a-phenyliodonio ketone (the tosyloxy salt has been isolated in one case), which is displaced directly by tosyloxy anion. The yields are generally good for a range of substrates, including 3-dicarbonyl systems. 

Initial attempts at the direct fluorination of carbonyl compounds such as acetone,72 butane-one,73 and butyric acid74 with elemental fluorine resulted in the formation of complex mixtures, with only low yields of a-monofluorinated carbonyl compounds formed. However, more recently, methyl 3-phenylpyruvate.75,7<1 and other pyruvate derivatives, e.g. I,77 are reported to be selectively monofluorinated with dilute elemental fluorine at — 10"C in moderate yield. The success of this reaction is attributed to the fact that the substrate predominantly exists in the enol form and not the keto form.77 Direct fluorination of acyclic 1,3-dicarbonyl compounds in formic acid or acetonitrile at room temperatures results in the formation of 2-fluoro-1,3-dicarbonyl compounds in good to excellent yield.78,79 Although in these systems the keto form predominates, there are significant concentrations of the enol form which undergoes fluorination (Table 5).78,79 The fluorination of 1,3-dicarbonyl compounds with acetyl hypo-fluorite is only successful when there are significant concentrations of the enol form compounds which have low concentrations of the enol form are successfully fluorinated by preparation of their metal cnolates followed by fluorination with acetyl hypofluorite (see Section 1.1.2.5.).95... 

The radical anions of carbonyl groups can also be generated via PET from activated alkenes, e.g. allylic silanes or stannanes. Triplet excited aromatic ketones, a-dicarbonyls and Michael systems are suitable substrates for oxidizing allylic Group 14 organometallic compounds with subsequent formation of homoallylic alcohols or S-allylated ketones (Scheme 32) [120-122]. 

Copper complexes of the bisoxazoline ligands have been shown to be excellent asymmetric catalysts not only for the formation of carbocyclic systems, but also for the hetero-Diels-Alder reaction. Chelation of the two carbonyl groups of a 1,2-dicarbonyl compound to the metal atom of the catalyst sets up the substrate for cycloaddition with a diene. Thus, the activated diene 20 reacts with methyl pyruvate in the presence of only 0.05 mol% of the catalyst 66 to give the adduct 138 with very high enantiomeric excess (3.99). 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

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