Asymmetric Michael additions nucleophiles

Chen and co-workers utilized the chiral bifunctional catalysts to directly access vinylogous carbon-carbon bonds via the asymmetric Michael addition of a,a-dicy-ano-olefms to nitro-olefms [102]. The scope of the reaction was explored with a variety of substituted a,a-dicyano-olefins and P-substituted nitro-olefms (Scheme 50). The authors propose the catalysf s tertiary amine functionality depro-tonates the cyano-olefm, activating the nucleophile to add to the -face of the pre-coordinated nitro-olefm. 

The conjugate addition of phosphorus nucleophiles of various oxidation states and in neutral or metallated form constitutes an efficient and well-known method for C—P bond formation [30]. In the case of phosphanes as nucleophiles especially, the corresponding phosphane-borane adducts have been used in 1,4-additions to Michael acceptors. Following the idea to use a chirally modified phosphorus nucleophile in asymmetric Michael additions to aromatic nitroalkenes, we synthesized the new enantiopure phospite 45 starting from TADDOL (44) with nearly quantitative yield. Due to the C2 symmetry, of the... 

D.3. CATALYTIC ASYMMETRIC MICHAEL ADDITION OF STABILIZED CARBON NUCLEOPHILES... 

The first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

Treatment of a, -unsaturated carbonyl compounds 18 with nucleophilic selenium species affords -seleno carbonyl compounds 19 in good yields via Michael addition (Scheme 27) [46]. This reaction has been applied to protect a, -unsa-turated lactones [47], in natural product synthesis [48], and in asymmetric Michael additions in the presence of an alkaloid [49]. Michael addition also proceeds with selenolates that are prepared from diphenyl diselenide by cathodic reduction [22], reduction with the Sm-Me3SiCl-H20 system [19], and reduction with tributyl phosphine [25]. 

Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphon-ates (281), a new class of chiral iminodienophiles, and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts (282). Hydrogenation of (282) results in a ring opening that affords the first examples of optically pure quaternary piperidine phosphonates. Two step synthesis of an enantiomeric pure cyclic phosphite (283) and its application as a chiral phosphorus nucleophile in the asymmetric Michael addition to nitroalkenes (284) provides an efficient... 

Heterocyclic compounds as nucleophiles in asymmetric Michael additions to nit-roalkenes 02EJO1877. 

In 2006, Wang and coworkers reported the asymmetric Michael addition of a broad spectrum of nucleophiles to chalcones (25) using the thiourea catalyst 81a [24],... 

A further study of additions of nucleophiles to unsaturated phosphonic diesters confirms reaction (23) The asymmetric Michael addition of a ketone to a dialkyl -(alk-l-enyl)phosphonate has been achieved following the deriva-tization of the carbonyl substrate as a chiral hydrazone (Scheme 77) . 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Subsequent studies demonstrated that the asymmetric Michael addition of trisubstituted carbon nucleophiles promoted by 6 -demethylated Cinchona alkaloids (CPD, CPN, RO-CPD and RO-CPN) could be efficiently achieved using a,p-unsaturated sulfones, enones and enals as Michael acceptors in a highly enantioselective and diastereoselective fashion. 

Scheme 14.2 Asymmetric Michael addition of trisubstituted carbon nucleophiles to nitroalkenes. Phn = 9-phenanthryl.

Since methylenemalonates are known to react readily with amines, the development of a highly efficient asymmetric Michael addition of aldehydes to methylenemalonates catalyzed by amine catalysts is quite challenging. Most recently, Maruoka and co-workers [34] found that the use of less nucleophilic binaphthyl-based secondary amine 27 as organocatalyst could effectively solve the problem, affording the synthetic useful products with good to excellent yields and enantio-selectivities (Scheme 5.16). 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

Boron has been protected from nucleophilic attack by intramolecular coordination in asymmetric Michael additions of organocuprates to acryloyl and vinylsulfonyl dioxazaborocines [20]. With an optically pure aminodiol, the enantiomeric purity was determined after oxidation of the carbon-boron bond. The greatest degree of asymmetric induction observed with a sulfone derivative was rationalized by an exo-approach of the organometaUic reagent (Scheme 9.8). 

On the other hand, a number of asymmetric Michael additions of C-nucleophiles involving acceptors other than a,p-unsaturated aldehydes and catalysed by a proline derivative have recently been reported. As an example. 

The asymmetric Michael addition represents one of the most powerful methods for the formation of C-X (X = C, N, O, S) bonds in organic synthesis. Chiral aluminium complex-catalysed asymmetric Michael additions will be introduced on the basis of different nucleophiles, including carbon-, nitrogen-, ojygen-, sulfur-, and phospha-based nucleophiles. 

Asymmetric Michael Addition with Carhon-hased Nucleophiles... 

As a direct route for the constructing carbon-carbon bonds, catalytic asymmetric Michael additions with various carbon-based nucleophiles including malonic esters, cyanide, electron-deficient nitrile derivatives, a-nitroesters, nitroalkanes, Horner-Wadsworth-Emmons reagent, indoles, and silyl enol ethers have attracted considerable attention. 

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