Enantioselectivity Michael additions

Methods for the catalytic enantioselective Michael addition have been developed using three different approaches ... 

Fig. 32 Proposed cooperative bimetallic intramolecular mechanism for the enantioselective Michael addition of a-cyanoesters 57 to vinylketones...

An enantioselective Michael addition reaction was also accomplished in an inclusion complex with a chiral host compound. Treatment of a 1 1 complex of 10c and 66b with 2-mercaptopyridine (137) in the solid state gave (+)-138 of 80% ee in 51% yield. By a similar method, 3-methyl-3-buten-2-one (139) gave (+)-140 of 49% ee in 76% yield [30]. 

The chiral enamines provide the opportunity for the enantioselective Michael addition to nitroalkenes, as shown in Eq. 4.68, where the ketone is obtained as a single diastereomer with... 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

P. Bako, T. Kiss, L. Toke, Chiral Azacrown Ethers derived from D-Glucose as Catalysts for Enantioselective Michael Addition , Tetrahedron Lett. 1997, 38, 7259-7262. 

To date, hydrogen bond catalysis has been successfully utilized to facilitate enantioselective Michael additions, Baylis-Hillman reactions, Diels-Alder cycloadditions, and additions of 7i-nucleophiles to imines. 

Scheme 6 Enantioselective Michael-addition of acetylacetone to nitrostyrene catalyzed by a bifunctional thiourea catalyst...

Tan also found that guanidine 21, acting as a base to activate the o [3], X [3] tautomers of diaryl phosphine oxides, catalyzes the asymmetric phospha-Michael reachon of aryl nitroalkenes (Scheme 5.42) [76]. He later employed 21 to realize highly enantioselective Michael additions of dithiomalonate and 3-keto thioesters with a range of acceptors, including maleimides, cyclic enones, furanone, and acyclic 1,4-dicarbonylbutenes [77]. 

The same group utilized thiourea 12 (10mol% loading) for the catalysis of the enantioselective Michael addition of thioacetic acid to various chalcones [214]. At room temperature and otherwise unchanged conditions, in comparison to the... 

Scheme 6.67 Products of the 12-catalyzed enantioselective Michael addition of a-alkyl and a-aryl cyanoacetates to alkyl vinyl ketones and aryl vinyl ketones.

In 2007, Chen and co-workers reported the 122-catalyzed (10mol% loading) enantioselective Michael addition [149-152] of ethyl a-cyanoacetate to various electron-rich and electron-deficient trans-chalcones [283]. The reaction was performed for a broad spectrum of chalcones and gave the corresponding adducts in yields of 80-95% and in ee values of 83-95%, but at low sy /a ti-diastereoselectiv-ities as shown for representative products 1-8 in Scheme 6.125. 

Wang and co-workers developed a 121-catalyzed enantioselective Michael addition [149-152] of IH-benzotriazole to a variety of a,P-unsaturated ketones such as the model substrate 3-(4-chloro-phenyl)-l-phenyl-propenone affording the N-1 product 1 (Scheme 6.136) [291]. The evaluation of the reaction medium revealed... 

Scheme 6.150 Proposed mechanistic picture for (S)-favored enantioselective Michael addition of O-benzylhydroxylamine to 2,4-dimethyl pyrazole substituted a,P-unsaturated substrates in the presence of hydrogen-bonding thiourea catalyst 139.

The copper-catalyzed enantioselective Michael addition of organometallic reagents to enones was the first successful application of phosphoramidite chiral ligands in catalysis [4, 43]. Since this early report, substantial enhancement of the enantioselectivity and/or of the substrate scope has been achieved through an untiring effort to optimize the ligand structure [5a, 44]. 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the... 

Table 7.6 Catalytic enantioselective Michael addition using L-tartrate-derived PTCs.

Akiyama s group employed naturally occurring L-quebrachitol 6 to prepare the C2-symmetrical 18-membered chiral crown ether 7 [14]. Compound 7 was found to be an active catalyst for the enantioselective Michael additions of glycine enolates. Thus, deprotonation of ester 8 using potassium tert-butoxide in dichloromethane (DCM) in the presence of crown ether 7 (20 mol %), followed by addition of a Michael acceptor, gave amino-acid derivatives 9 with up to 96% ee, as shown in Scheme 8.4. 

As an extension of this highly enantioselective Michael addition of silyl nitronates with a, p-unsaturated aldehydes, the reactions with cyclic a,p-unsaturated ketones as a Michael acceptor were also tested (Scheme 9.15). Cyclohexenone and cyclohepte-none were employed as a useful Michael acceptor with various silyl nitronates in the presence of catalyst (R,R)-6c, and gave the corresponding enol silyl ethers 28 with excellent stereoselectivities [30]. 

Further applications of the chiral ammonium bifluoride-catalyzed enantioselective Michael addition of silyl nitronates has been shown in the reactions with nitroalkenes as a Michael acceptor (Scheme 9.17). These studies were started by examining the reaction of nitropropane-derived silyl nitronate 23b with P-nitrostyrene, using the chiral quaternary ammonium bifluoride (R,.R)-6d. When P-nitrostyrene was treated with 23b (1.2 equiv.) in the presence of (K,f )-6d (2mol%) in THF at — 78 °C, the... 

Highly enantioselective Michael addition of silyl nitronates (105) to cyclic o /3-unsaturated ketones (106 n = 0-2) has been accomplished by the utilization of N-spiro C2-symmetric chiral quaternary ammonium bifluoride (108) as an organocatalyst, offering a new route to the enol silyl ethers of scalemic y-nitro ketones (107 70-90% ee).156... 

Pyrrolidine-based diamine (136) and triamine derivatives that incorporate the secondary diamine motif have been developed as additional organocatalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to... 

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

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