Conjugate addition by carbon nucleophiles

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

A number of highly enantioselective conjugate additions of carbon nucleophiles to a,P-unsaturated substrates mediated by copper Lewis acids have been reported in the past decade. Chiral copper Lewis acids have proven particularly... 

The importance of an -OH group at the C6 position for an organocatalytic reaction was noted by Deng and coworkers in a series of studies of C9 ether derivatives of cupreine and cupreidine [34]. Based on the observation that the C9 0-benzyl and O-phenanthryl ether derivatives (10 and 11, respectively. Figure 6.5) gave similar results for the conjugate addition of carbon nucleophiles to nitroalkenes as obtained with 3 (Scheme 6.18) [34], a transition state model was proposed for this reaction. 

The palladium-catalyzed conjugate addition of carbon nucleophiles generated by suitable precursors such as boronic acids can be conducted in an asymmetric fashion as demonstrated by the Stoltz group. In the presence of the oxazoline ligand shown, high enantiomeric excesses were obtained even for the generation of quaternary stereogenic centers (Scheme 5-44). 

The conjugate addition of a nucleophile to an a,fi-unsaturated aldehyde or ketone is caused by the same electronic factors that are responsible for direct addition. The electronegative oxygen atom of the a,/3-unsaturated carbonyl compound withdraws electrons from the /3 carbon, thereby making it electron-poor and more electrophilic than a typical alkene carbon. 

The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

If a new chiral centre is formed on a saturated six-membered ring, conformational control is a possibility. We have already seen conformational effects in the reduction of ketone 48 and the same kind of arguments apply to attack on ketones by carbon nucleophiles. The alcohol 59, needed to make an analgesic 58, can obviously be made from the ketone 60 and that is the result of conjugate addition to cyclohexenone.12... 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

In accordance with the generally accepted mechanism ofthe MBH reaction, the aza MBH reaction involves, formally, a sequence of Michael addition, Mannich type reaction, and (3 elimination. A commonly accepted mechanism is depicted in Scheme 13.2. A reversible conjugate addition of the nucleophilic catalyst to the Michael acceptor generates an enolate, which can intercept the acylimine to afford the second zvdtterionic intermediate. A proton shift from the a carbon atom to the P amide followed by P elimination then affords the aza M BH adduct with concurrent regeneration of the catalyst [5]. 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

The enantioselective addition of carbon nucleophiles to a,p-unsaturated carbonyls is one of the most studied organic reactions. The diamine catalyst, (S)-l-(2-pyrrolidinylmethyl)pyrrolidine la is effective for conjugate additions. The addition of cyclic ketones to allgrlidene malonate and frans-p-nitroslyrene was demonstrated (Scheme 9.11). Comparable stereochemical results were obtained when the reaction was catalysed by (S)-proline. 

The inone suffers a conjugated addition by the enamine, which attacks by way of its nucleophilic carbon. 

Conjugate Addition. TBDMS triflate has been used to promote the conjugate addition of carbon- and heteroatom-based nucleophiles to a range of a./S-unsaturated carbonyl compounds, in both stoichiometric and catalytic quantities. In some cases, the silyl enol ether is isolated, in other cases, it is implied as an intermediate but hydrolyzed either in situ or by addition of an acid or a reagent known to cleave a carbon-silicon bond e.g., TBAF. Examples of carbon-based nucleophiles are shown in eqs 22-26. 

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