Asymmetric Aza-Michael Additions

Advances and appHcations in organocatalytic asymmetric aza-Michael addition (2010—early 2012) 12CAC917. 

During the last years, organocatalytic asymmetric aza-Michael additions have been thoroughly investigated [62, 63] employing different types of organocatalysis (amine, Brpnsted base, Brpnsted acid, PTC, and enzymatic catalysis). 

Asymmetric aza-Michael addition of purine bases to a,/8-unsaturated aldehydes can be catalysed by the fluorinated proline derivative (123b), giving rise to the corresponding acyclonucleosides with <99% ee. Notably, the simpler derivative (123a), as well as proline itself (124), gave inferior results (< 10% ee). ... 

In 2009, Lin et al. reported an enantioselective synthesis of an important Janus kinase inhibitor, INCBO18424, the key step of which was an asymmetric aza-Michael addition of pyrazoles to an a,p-unsaturated aldehyde catalysed by a chiral diarylprolinol silyl ether. The use of benzoic acid or 4-nitrobenzoic acid as an additive was shown to increase the reaction rate. The highest enantioselectivities of up to 93% ee were observed for the reactions using the more sterically hindered organocatalysts (Scheme 1.68). 

At almost the same time, Ricci and coworkers reported an asymmetric aza-Michael addition of O-benzylhydroxyamines to chalcones catalyzed by a thiourea derived from cinchona alkaloids. The amine derivatives were obtained in good yields but low enantioselectivities (up to 60% ee) [103]. Interestingly, the thiourea moiety has a major role in the catalyst activity. When alkaloids lacking the thiourea moiety were used the reaction resulted in very poor conversions. 

Qu and co-workers have developed organocatalytic asymmetric aza-Michael addition reaction of achiral purine bases (486) to a,p-unsaturated aldehydes (487) followed by reduction of aldehyde group to give optically active products (488) in 82 89% yield and up to 99% ee (Scheme 121). They were readily converted to phosphonic acids (489) in high yields and high enantioselectivities. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

In 2004, Fioravanti, Pellacani, and Tardella reported the asymmetric aza-Michael-initiated ring closure additions of ethyl nosyloxycarbamate to 2-(phenylsulfanyl)-2-cycloalkenones using the cinchona-based PTCs 11 or 29, affording the corresponding aziridines with moderate ee values (Scheme 5.25) [31]. Interestingly, this reaction afforded the same enantiomer, regardless of which pseudoenantiomer of the cinchona-derived catalyst was employed. However, the absolute configuration of the products was not determined in this study. 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

Following the same iminium ion activation mode but with cinchona primary-tertiary diamine bifunctional catalyst 9, Chen and co-workers [108] described the asymmetric intramolecular aza-Michael addition of enone carbamates (Scheme 11.29). The reactions proceed in high yield and with good to excellent stereocontrol (up to 99% ee). 

Shortly afterward, the same group expanded the scope of Brpnsted acid-catalyzed asymmetric intramolecular aza-Michael addition to activated a,(3-unsaturated... 

SCHEME 11 9. Asymmetric organocatalytic intramolecular aza-Michael addition of enone carbamates. 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

The same year, Canesi s group reported an asymmetric s5mthesis of the levoro-tatory enantiomer of the Amaryllidaceae alkaloid fortucine [105]. The L-tyrosine-derived phenol 163 was treated with DIB in HFIP to induce an oxo-spirocyclization into the para-quinolic lactone 164, which was treated with methanolic KOH to mediate both the opening of the lactone unit and an aza-Michael addition of the amide onto the cyclohexa-2,5-dienone moiety in high yield and stereoselectivity. The resulting aza-bicyclic intermediate 165 was then converted in 11 steps into (-)-fortucine (Fig. 41). This first asymmetric synthesis of fortucine led to the correction of the absolute configuration of the natural (+)-fortucine [105]. 

Wang, X.-R, An, J., Zhang, X.-X., Tan, R, Chen, J.-R., Xiao, W.-J. (2011). Catalytic asymmetric aza-Michael-Michael addition cascade enantioselective synthesis of poly-substituted 4-aminobenzopyrans. Organic Letters, 13, 808-811. 

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). 

The high performance of 64 compared to Hantzsch ester 39 was demonstrated by Akiyama and coworkers in the asymmetric transfer hydrogenation of trifluor-omethylacetophenone derivatives (Scheme 11.17a) [31]. Benzothiazoline 64c afforded 68 in 89% yield with 96% ee. In contrast, a significant reduction of reactivity and enantioselectivity was observed when 39 was used (4% yield, 45% ee). Enders and coworkers also reported the superiority of benzothiazoline over Hantzsch ester in a symmetric synthesis of tetrahydroisoquinolines via the reductive amination/aza-Michael addition sequence (Scheme 11.17b) [32]. Benzothiazoline 64d had a beneficial effect on both chemical yield and selectivity (98% yield,... 

Among the few examples of pure acidic activation in Michael addition to nitroalkenes, the recent works of Ooi and coworkers described the aza-Michael addition of aniline [50] by the charged chiral C2 symmetric phosphonium 50 (Scheme 34.16). Indeed, the acidic spirocycUc catalyst 50 was able to asymmetrically activate a Lewis base such as 2,4-dimethoxyaniline, to promote the addition to nitroolefins with excellent yields and selectivity. 

SCHEME 31.28. Asymmetric (J-amino carbonyl compounds synthesis—Aza-Michael addition/... 

Fig. 30 Asymmetric aza-Claisen rearrangement of (Z)-configured trifluoroacetimidates 44 3.1.2 Bispalladium-Catalyzed Michael-Addition of a-Cyanoacetates...

In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

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