Michael addition asymmetric reaction, research

In 1988, Mukaiyama et al. reported the Sn(OTf)2-50d-catalyzed asymmetric Michael reaction of a trimethylsilyl enethiolate, CH2=C(SMe)SSiMej (up to 70% ee) [243]. It was proposed that the catalytic reaction proceeded via an Sn(II) enethiolate. They also demonstrated that a BINOL-derived oxotitaniurn catalyzes the Michael addition of ketene silyl thioacetals to a-enone with high enantioselectivity (up to 90% ee) [244]. After this pioneering work other research groups developed new reaction systems for enantioselective Mukaiyama-Michael reactions. 

Asymmetric Michael additions of the prochiral acceptors using crown ethers are rare. The reaction of 60 and 46 using chiral crown ethers 62,63,64, etc., was reported by Yamamoto and other researchers (Scheme 11) [57, 58]. The phe-nylthio group could be removed under radical conditions giving 61. 

By aiming at BRMs within MBFTs and organocatalysis, this section is limited to a small field of research. Nonetheless, the method is very productive, and the number of interesting examples extends far beyond the number that will be discussed in this section. Therefore, we will start, without further introduction, with the first example by Itoh and coworkers, who reported a proline-catalyzed asymmetric addition reaction for the synthesis of mf-dihydrocomynantheol in 2006 [6]. The reaction commences with activation of methyl vinyl ketone derivative 1 to form the intermediate enamine 4. Simultaneously, the acidic carboxyl group allows activation of the imine 2 and directs the newly formed nucleophile to add stereoselectively on iminium ion 5. The resulting o,p-unsaturated iminium is prone to diastereoselective cyclization by aza-Michael addition of the liberated secondary amine (Scheme 14.1). 

In 2004, Yamamoto and Arvidsson independently reported the catalytic activity of the L-proline tetrazole catalyst 30 in asymmetric aldol reactions of ketones with aldehydes [161-163]. At the same time. Ley and coworkers reached similar conclusions by applying this system to asymmetric Mannich and Michael addition reactions (Scheme 1.8) [164]. Since then, the scope of this chemistry has been expanded by several research groups [165-174]. 

In a related study, the same researchers used guanidine 52 for the enantioselective vinylogous Michael reaction of furanone 53 with various aromatic and aliphatic nitroalkenes (Scheme 10.50) [143]. In addition, several additional asymmetric transformations catalyzed by axially chiral guanidines were reported by Terada and coworkers between 2009-2012 (Schemes 10.51-55) [144-148]. 

Researchers at Merck documented that the N-benzylated cinchonidinium derivative 112 was an excellent phase-transfer catalyst in the Michael addition of 2-propylindanone 111 to 74 (Scheme 12.14) [108]. The reaction is conducted in a biphasic medium (50% aq. NaOH/toluene) with substoichio-metric quantities of the quaternized cinchonidinium salt 112 [109]. The adduct 113 was isolated in 95 % yield and 80 % ee and served as a key intermediate en route to an asymmetric synthesis of the drug candidate 114 [108]. 

Michael reaction. The greatest number of research reports pertaining to methodology development for the asymmetric Michael reaction are based on the addition of ketones to P-nitrostyrene. Among catalysts 2 3 and 4, the first one is the simplest. 

The latter mode of activation, in which a charged tetraaminophosphonium salt acts as a Bronsted acid, was realized by the same research group in 2009. Enanti-oselective aza-Michael reaction of 2,4-dimethoxyaniline with nitroalkenes afforded the conjugate addition products in excellent yields and high enantiomeric excesses (Scheme 10.70) [173, 174]. Similarly, chiral diaminooxaphosphonium salts have been used as Br0nsted acids in the asymmetric protonation reactions of ketene disilyl acetals [175]. 

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