Enantioselective Michael addition products

When cyclic enones were used as Michael acceptors, both malonates and acetoacetates gave impressive yields and enantioselectivities of the desired Michael addition products (Scheme 5.2Q) NMR spectra and single-crystal X-ray data supported the following ruthenium intermediate (Scheme 5.21) and transition state (Figure 5.8). 

When nitroalkenes were used as Michael acceptors, high yields and enantioselectivities of the desired Michael addition products were also obtained (Scheme 5.22). In these reactions, a well-defined chiral Ru amido complex (Figure 5.9) was an efficient catalyst. The mild reaction conditions and high reactivities and stereoselectivities allowed a large-scale reaction in the presence 1 mol% Ru catalyst. By using a chiral Pd(II) catalyst, an asymmetric allylic arylation was reported by Mikami and coworkers to give the cross-couphng product via the activation of both allylic C H and aryl C H bonds in moderate enantioselectivity (Scheme 5.23). ... 

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... 

An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone-hydrogen bond donor pair affords Michael addition products in <90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172... 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Alexakis et al,231 reported copper-catalyzed enantioselective Michael additions in the presence of various 2-arylcyclohexyl-substituted phosphites. Ligand 279 turned out to be particularly efficient for the 1,4-addition of organozinc reagents to cyclopentadec-2-enone. Whereas Et2Zn gave the addition product with 87% ee, the corresponding reaction of dimethylzinc furnished (R)-(—)-muscone with an enantiomeric excess of 79% ee (Scheme 74). 

An interesting feature the crystals of 1-Cu is that they show triboluminescent behaviour. Compound 1-Cu has been applied successfully as a catalyst in the enantioselective Michael addition reaction involving a variety of substrates and Grignard reagents (eq 6). The addition reaction proceeds with excellent chemical yields, and enantiomeric excesses of up to 70% have been reported. It was shown that the (/ )-catalyst gives rise to the formation of (5)-products. ... 

Enantioselective Michael Additions. Amine 1 has also been used as an effective ligand for enantioselective Michael reactions of ketone lithium enolate donors with various benzylidene acceptors. As representative examples, the lithium enolates of aryl methyl ketones were reacted with dimethyl benzylidene-malonate in the presence of 1 (eq 9). The lithium enolate was generated from the corresponding ketone by treatment with hex-amethyldisilazide in the presence of lithium bromide in toluene. The resulting enolate was then exposed to 1 and allowed to stir for 30 min to form the desired ternary complex. After addition of the benzylidene acceptor, the desired products were isolated in acceptable yields and with high % ee. 

The first total synthesis of barbacenic acid, a bisnorditerpene containing five contiguous stereocenters, was achieved by A. Kanazawa et. al. They started out from a Wieland-Miescher ketone analogue that could be synthesized with high yield and excellent enantioselectivity by the procedure of S. Takahashi. According to this procedure, the Michael addition product 2-methyl-2-(3-oxo-pentyl)-cyclohexane-1,3-dione was cyclized in the presence of (S)-(-)-phenylalanine and D-camphorsulfonic acid. 

Scheme 2.15 Enantioselective Michael addition of aldehydes with functionalized nitroalkenes and an application to the total synthesis of densely functionalized homoprolines and natural product (-)-botryodipIodin.

The Chi group reported in 2011 the enantioselective Stetter reaction between enals and modified chalcones proceeding through a Michael-type addition of NHC-bound enal acyl anions to the Michael acceptors. The Stetter reaction with p-alkyl enals afforded the Michael addition products with good enantioselectivity and yields (14 examples, up to 93% yield, 94% ee). While P-aryl enals were tested in this reaction, up to moderate yield was achieved. This was because the enolate pathway (giving Diels-Alder products)" dominated, which was difficult to suppress under these reaction conditions (Scheme 7.26). 

Moreover, chiral gallium(iii) sodium(i) bis(binaphtholate) 73 effectively catalysed Michael reactions in the presence of NaOt-Bu (Scheme 2.42). For example, the reaction of cyclohexenone with dibenzyl malonate catalysed by 73 provided the corresponding product in 45% yield with 98% ee, while the combined use of 73 and NaOt-Bu provided the Michael addition product in 87% yield with the same enantioselectivity. 

A diastereo- and enantioselective Michael addition combined with a Darzens condensation reaction can be used to form two products of interest in the field of medicinal and natural products chemistry [60]. Additionally, depending on the workup conditions, an optically active epoxycyclohexanone, 92, can be prepared through an Sf 2 reaction, or the ElcB reaction pathway to 91 can be accessed (Scheme 7.17). In the early stages of the proposed mechanism, a planar iminium ion is suggested between the 2-[bis(3,5-bistrifluoromethylphenyl) trimethylsilany-loxymethyljpyrrolidine 61 and the aldehyde moiety of compound 88, which is subsequently attacked by the P-ketoester 89. For the synthesis of the epoxide, a... 

---