Alkoxides, conjugate addition

Why do stabilized anions undergo 1,4- rather than 1,2-addition to Michael acceptors 1,2-Addition occurs, but is reversible with relatively stable anionic nucleophiles, because it leads to a relatively high-energy alkoxide. Conjugate addition is favored thermodynamically because it produces a resonance-stabilized enolate ion. 

After successful installation of the first two stereocenters, our attention was focused on elaboration of the terminal alkene in 64 (Scheme 6.9). Treatment with disiamylborane followed by oxidative workup afforded primary alcohol 65 in good yield (70-85 %). A side product containing a mixture of two diastereomers (66) was also observed and resulted from conjugate addition of the alkoxide formed during basic workup onto the unsaturated ester. Maintaining the temperature at 0 °C by a slow, dropwise quench during the oxidative workup was necessary to minimize the amount of the undesired cyclization product (66). Subsequent oxidation of the primary alcohol 65 using Dess-Martin periodinane [28] and a Pinnick oxidation afforded carboxylic acid 67 [29]. 

Tanaka et al. (152) demonstrated that a chiral copper alkoxide could be used substoichiometrically to deliver MeLi to an enone in conjugate fashion. The precatalyst is formed from amino alcohol 221, MeLi and Cul, Eq. 123a. Under stoichiometric conditions, this catalyst mediates the conjugate addition of MeLi to the macrocyclic enone, affording muscone in 91% ee. Lower enantioselectivity is observed using a substoichiometric amount of 222 (0.5 equiv), affording a 79% yield of muscone in 76% ee, Eq. 123b. These selectivities are attained by portion-wise addition of the substrate and MeLi to the alkoxy-cuprate. This catalyst also exhibits a complex nonlinear effect (78, 153). 

The Michael-type conjugate addition of an alkoxide such as methoxide to an a,p-unsaturated nitrile or aldehyde proceeds in solution quite readily, being complete in 5—10 minutes. In the gas phase however, it was found that reaction (6a) does not occur there is no evidence of the addition product even at the longest trapping times, nor in the unquenched mode. Rather, the sole product observed is due to proton loss from the nitrile, to form a nominal vinyl anion, reaction (6b). 

Upon fonnation of intermediate LI, conjugate addition to a chalcone and subsequent proton transfer is proposed to lead to enolate LIII (Scheme 37). An intramolecular aldol addition provides activated carboxylate LIV in which alkoxide acylation regenerates the catalyst and delivers p-lactone LVI which, upon decarboxylation, gives rise to a trisubstituted cyclopentene. 

The previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed by an SN2 reaction between the nucleophilic carbanions and the alkylating reagent. Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,/i-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sulfide anions also react similarly, but we will focus on the carbon-carbon bondforming reactions. 

Such an alkoxide-assisted (hydroxyl-assisted) conjugate addition methodology has been exploited in the key step toward ( )-euonyminol (Scheme 72) °. 

Baldwin and co-workers (56, 57) have reported that all attempts to cyclize hydroxy-enones 162 and 164 (R=H or OCH3) under basic conditions failed to give the corresponding furanones 163 and 165 (R=H or 0CH3). The susceptibility of these systems to conjugate addition of alkoxide nucleophile was verified by conducting the attempted cyclization with sodium methoxide in deute-... 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

The conjugate addition of protected pyranose alkoxides to 1-nitro- and 1-nitrosoalkenes gave 2-nitroalkyl and 2-oximinoalkyl glycosides. In several cases, the reaction proceeded with preferential formation of the a-glycoside (a /3 < 4 1).190... 

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