Asymmetric Michael addition reaction

Chiral PTC has been used effectively for making intermediates for drugs. Dolling and coworkers have used 8-R, 9-5, N-(p-trifluoromethylbenzyl) cinchonium bromide to carry out an important asymmetric alkylation, giving 95% ee (Starks, 1987). Nucleophilic epoxidations of enones, Darzens reaction, Michael additions, etc. are some examples of reactions rendered asymmetric through chiral PTCs (Nelson, 1999). 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Review. Davies has reviewed use of the chiral iron auxiliary [CpFe-(CO)P(C6H5)3] for effecting asymmetric reactions of an acyl group, including alkylation, aldol reactions, Michael additions. 

The structurally related optically active a-acyl vinyl p-tolyl sulfoxide 269 underwent asymmetric cyclopropanation. Michael addition of the carbanion of bromomalonate to 269 and the subsequent intramolecular alkylation yielded the corresponding optically active a-acyl-cyclopropane 271, with a high degree of diastereoselectivity (Scheme 70).142 It was proposed that the stereochemical outcome of the reaction can be rationalized by transition state 270, in which there is chelation of the oxygen atom of the carbonyl and sulfinyl groups to the metal cation. 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

Iron chiral auxiliary for asymmetric aldol reaction, Michael addition, p-amino acid and p-lactam synthesis. 

In conclusion, chiral heterobimetallic lanthanoid compexes LnMB, which were recently developed by Shibasaki et al., are highly efficient catalysts in stereoselective synthesis. This new and innovative type of chiral catalyst contains a Lewis acid as well as a Bronsted base moiety and shows a similar mechanistic effect as observed in enzyme chemistry. A broad variety of asymmetric transformations were carried out using this catalysts, including asymmetric C-C bond formations like the nitroaldol reaction, direct aldol reaction, Michael addition and Diels-Alder reaction, as well as C-0 bond formations (epoxidation of enones). Thereupon, asymmetric C-P bond formation can also be realized as has been successfully shown in case of the asymmetric hydrophosphonylation of aldehydes and imines. It is noteworthy that all above-mentioned reactions proceed with high stereoselectivity, resulting in the formation of the desired optically active products in high to excellent optical purity. 

Abstract Progress in the field of metal-catalyzed redox-neutral additions of oxygen nucleophiles (water, alcohols, carboxylic acids, and others) to alkenes, alkynes, and allenes between 2001 and 2009 is critically reviewed. Major advances in reaction chemistry include development of chiral Lewis acid catalyzed asymmetric oxa-Michael additions and Lewis-acid catalyzed hydro-alkoxylations of nonacti-vated olefins, as well as further development of Markovnikov-selective cationic gold complex-catalyzed additions of alcohols or water to alkynes and allenes. 

Note at the outset that asymmetric catalysis in the synthesis of fine chemicals is rarely a single-step process that converts a reactant directly to the final product. It is usually one of the steps in a total synthesis but is often the key step. Hence the analysis of the overall yield will be based on the methods described in Chapter 5. There are many types of reactions where asymmetric catalysis can be applied. The most important of these are C-C bond-forming reactions such as alkylation or nucleophilic addition, oxidation, reduction, isomerization, Diels-Alder reaction, Michael addition, deracemization, and Sharpless expoxidation (of allyl alcohols). A few representative examples (homogeneous and heterogeneous) are given in Table 9.6. 

In 2013, Enders and co-workers reported a kinetically controlled asymmetric organocatalytic Michael addition/intramolecular Henry domino reaction, providing a facile access to enantioenriched cis-nitroindanol products 164 in excellent yields (61->99%) with up to 97% ee and 17 1 dr (Scheme 6.77). ... 

Progress in asymmetric organocatalyzed Michael addition/hemi-amino-acetalization/acylimminium-cyclization cascade reactions and application of this type of reactions in the synthesis of alkaloids 13CJ01. Progress in synthesis of benzophenanthridine alkaloids and their derivatives 12CJO1605. 

Recently, an oxidative dearomatization of substituted phenols followed by a desymmetrizing asymmetric intramolecular Michael addition catalyzed by the pro-linol derivative 27 has been described towards the synthesis of highly functionalized polycyclic molecules with excellent enantioselectivities [40]. As shown in Scheme 2.15, the reaction starts with an oxidation of the phenol moiety to the corresponding mera-cyclohexadienones employing PhlCOAc), mild oxidant that does not react with the aldehyde nor with the catalyst. In the presence of different nucleophiles such as, methanol, cyanide, or fluoride, intermediates 26 are formed, which suffer intramolecular Michael addition of the aldehyde moiety to afford the desired chiral products 28 with excellent diastereo- and enantioselectivities. 

Very recently two comprehensive review articles dealing with organocatalytic carbon-sulfur bond-forming reactions and asymmetric sulfa-Michael additions have been published. Historically, the first catalytic enantio-selective sulfenylations of conjugated enones in the presence of Cinchona alkaloids were published in 1977 by Pracejus where acrylamides and... 

S. Oxindole Derivatives. Most recently, Curti et al. [140] disclosed the first example of a direct, organocatalytic asymmetric vinylogous Michael addition of 3-alkylidene oxindole to nitroalkenes. Bifunctional cinchona alkaloid/thiourea catalyst 69 could effectively promote the reaction, solely aHbrding the 7-substituted 3-alkylidene oxindoles 146 with excellent regio-, diastereo-, and enantioselectivities (Scheme 5.71). Importantly, both aromatic and aliphatic substituted nitroalkenes were applicable for such a reaction. 

An asymmetric domino Michael addition-alkylation reaction between aldehydes and ( )-5-iodo-l-nitropent-l-ene was developed by Enders et al. by using this catalyst and following an enamine-enamine mechanism. This method provided an access to cyclic y-nitroaldehydes of the cyclopentane type containing an all-carbon-substituted quaternary stereogenic centre. Enantioselectivities of up to 97% ee could be reached, whereas both yields and dia-stereoselectivities remained moderate, as shown in Scheme 1.62. Furthermore, a novel cyclic y-amino acid of potential pharmaceutical relevance could be synthesised from a domino product. 

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). 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

J. Wang, C. Qi, Z. Ge, T. Cheng, R. li. Efficient direct asymmetric vinylogous Michael addition reactions of y-butenolides to chalcones catalyzed by vicinal primary-diamine salts, Chem. Commun. 46 (2010) 2124-2126. 

SCHEME 5.7 Organocatalyzed asymmetric thia-Michael addition reactions [8],... 

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. 

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