Acceptor-substituted dienes 1,6-addition

Tlianks to tlieir ambident cliaracter, acceptor-substituted dienes can provide seveta isomeric products in copper-mediated Midiael additions, tlierefore making i pariicular impotLant to control not only tlie regiosdectivity but also tlie steteose lectivity of tliese transfotenations iSdieme 4.1). 

In this chapter, nucleophilic l,n-additions (n = 4, 6, 8,. ..) to acceptor-substituted dienes, enynes and polyenes are presented2. Addition reactions which obviously proceed via non-nucleophilic pathways (e.g. catalytic reductions, electrophilic or radical additions3), as well as 1,2-additions to the acceptor group, are not covered. 

Michael additions to acceptor-substituted dienes are often followed by (spontaneous or induced) cyclizations. This was already noted by Vorlander and Groebel4 who obtained a substituted 1,3-cyclohexanedione by treatment of 6-phenyl-3,5-hexadien-2-one with diethyl malonate (equation 5). Obviously, the 1,4-addition product which is formed initially then undergoes cyclization, ester hydrolysis and decarboxylation. Similarly, reaction of methyl sorbate with methyl 4-nitrobutyrate gave the 1,6-adduct which was reductively cyclized to 6-methyl-l-azabicyclo[5.3.0]decane18 (equation 6). 

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

Subsequently, Corey and coworkers40 42 described nucleophilic addition reactions of organocopper reagents and organocuprates to several acceptor-substituted dienes. The... 

Nucleophilic 1,4- and 1,6-additions of cuprates and other organometallic reagents to acceptor-substituted dienes have been utilized extensively in target-oriented stereoselective synthesis52-61. Schollkopf and coworkers55 reported the diastereoselective 1,6-addition of a bislactim ether-derived cuprate to 3,5-heptadien-2-one (90% ds equation 17). The corresponding reactions of dienoates were conducted with the lithiated bislactim ether and proceeded with diastereoselectivities of >99% ds (equation 18)56 the adducts could be converted easily into diastereo- and enantiomerically pure amino acid derivatives. 

Nucleophilic additions of amines to acceptor-substituted dienes were examined as early as 1950. Frankel and coworkers98 found that the reaction of 2,4-pentadienenitrile with various secondary amines proceeded regioselectively to furnish the 1,6-addition products (equation 29). In some cases, these could converted into the 2,4-diamino-substituted pen-tanenitriles by isomerization and 1,4-addition of a second molecule of amine. Analogous results were reported by other groups17,99 100 and extended to hydrazine as nucleophile101 and to vinylcyclobutenones48 and dienoates102-104 as Michael acceptors. 

The number of reports about addition reactions of oxygen nucleophiles to acceptor-substituted dienes is rather limited. Coffman111 and Kurtz17 examined the reaction of 2,4-pentadienenitrile with sodium methoxide and isolated the 2 1 adduct 3,5-dimethoxypen-tanenitrile formed by successive 1,6- and 1,4-additions (equation 34). Analogous treatment... 

Like oxygen nucleophiles, phosphorus and selenium nucleophiles have been employed rarely in Michael additions to activated dienes. The reaction of phosphites with acceptor-substituted dienes was studied by several Russian groups116-118 again, 1,6-adducts and 2 1 addition products were formed (equation 37). The acid-catalyzed reaction of selenourea with sorbic acid was also reported to provide a 1,6-addition product119 (equation 38). 

Structurally rather complicated target molecules can be synthesized with the aid of thi-olate 1,6-addition reactions to acceptor-substituted dienes as well. For example, a richly functionalized proline derivative with a 2,4-pentadienal side chain was converted into the corresponding 6-phenylthio-3-hexen-2-one derivative by 1,6-addition of phenylthiolate, treatment of the adduct with methyl lithium and oxidation (equation 46)127. The product was transformed into acromelic acid A, the toxic principle of clitocybe acromelalga ichimura. Similarly, the 1,6-addition reaction of cesium triphenylmethylthiolate to methyl 2,4-pentadienoate served for the construction of the disulfide bridge of the macrobicyclic antitumor depsipeptide FR-901,228128. 

Thanks to their ambident character, acceptor-substituted dienes can provide several isomeric products in copper-mediated Michael additions, therefore making it particular important to control not only the regioselectivity but also the stereoselectivity of these transformations (Scheme 4.1). 

Scheme 4.1. Regioselectivity in conjugate addition reactions to acceptor-substituted dienes.

The first example of a cuprate addition to an acceptor-substituted diene was reported by Naf et al. [9], who used lithium di-(Z)-l-heptenylcuprate in a Michael addition to dienoate 1 (Eq. 4.2). The reaction proceeded highly regioselectively, furnishing a 1 1 mixture of the two isomeric 1,6-adducts 2, which were converted into the Bartlett pear constituent ethyl (2 ,6Z)-2,6-dodecadienoate (3) by basic isomerization. 

Michael additions of organocopper reagents to acceptor-substituted dienes have found widespread application in target-oriented stereoselective synthesis [12]. For... 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

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