Asymmetric Conjugate Michael Additions

Wang and coworkers synthesised recyclable and reusable pyrrolidine-fluorosulfonamide organocatalysts 3b,c. The fluorous sulfonamide organocatalyst 3b was used for the Michael addition of ketones and aldehydes to nitro-olefins in water, and the reaction gave products with high enantio- and diastereomeric purity. Robust organocatalyst 3b was easily separated from 

Seheme 9.18 Dithioacetal-catalysed enantioselective Michael reactions. 

Chen et al, designed and synthesised a series of chiral pyrrolidinyl-sulfamide derivatives, identifying 3j as an efficient bifunctional organocatalyst for the direct Michael addition of cyclohexanone to a wide range of nitrostyrenes. The desired Michael adducts were obtained in high chemical 

Peng and coworkers reported an example of the Michael addition of aldehydes to ot-substituted nitro-olefins in the presence of sulfonamide-derived organocatalyst 3a. A wide range of y-nitro carbonyl products were 

In 2006, a practical route for the efficient synthesis of (S)-pyrrolidin-2-yl-IH-tetrazole 5a was developed. Ley and coworkers prepared ent-SsL to catalyse the nitrocyclopropanation of cyclohexenone in the presence of 

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Since conjugate (Michael) addition and Diels-Alder reactions use a,p-unsat united carbonyl compounds, asymmetric versions of these reactions could use the auxiliaries that we have seen in aldol reactions in the form of 118 and 119. Diels-Alder reactions work very well with these unsaturated amides and also with amides 121 derived from Oppolzer s chiral sultam14 120, prepared simply from camphorsulfonyl chloride. 

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... 

Several derivatives of cinchona alkaloids 1—4 were prepared and used in the asymmetric sulfa-Michael addition. The first highly efficient method, based on the catalyst (DHQD)2PYR 5, was presented by the Deng group in 2002 [18]. Especially high ees were observed in the conjugated addition of 2-thionaphthol to several six-to nine-membered cyclic enones at low temperature (Scheme 14.3). Although 2-cyclopentenone reacted with moderate enantioselectivity (41% ee), the ee was increased dramatically with 4,4-dimethyl-2-cyclopentenone (92% ee). 

In a manner largely complementary to secondary amine-catalyzed asymmetric conjugate addition to enals with heteroatom nucleophiles, chiral primary amines were recently found to be the catalysts of choice for similar Michael addition to a,p-unsaturated ketones. With their previously developed cinchona-type catalyst 91, Melchiorre and coworkers achieved the asymmetric sulfa-Michael addition to a,p-unsaturated ketones with either benzyl or tert-butyl mercaptane (Scheme 5.30) [58a]. The same catalyst could be further extended to oxa-Michael addition to enones by optimizing the ratio of acidic additive and solvents (Scheme 5.30) [58b]. 

Chiral diaminocarbene complexes of copper were used in asymmetric conjugate addition of diethylzinc to Michael acceptors. Achiral copper carbene complexes derived from imidazolium salts were synthesized and characterized for the first time by Arduengo in 1993 [43]. In 2001, Woodward reported the use of such Arduengo-type carbene in copper-catalyzed conjugate addition and showed their strong accelerating effect [44]. The same year, Alex-... 

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

Silylketene acetals and enolsilanes can also undergo conjugate addition to a,/ -unsaturated carbonyl derivatives. This reaction is referred to as the Mukaiyama-Michael addition and can also be used as a mild and versatile method for C-C bond formation. As shown in Scheme 8-34, in the presence of C2-symmetric Cu(II) Lewis acid 94, asymmetric conjugate addition proceeds readily, giving product with high yield and enantioselectivity.75... 

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

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]. 

The conjugate addition of phosphorus nucleophiles of various oxidation states and in neutral or metallated form constitutes an efficient and well-known method for C—P bond formation [30]. In the case of phosphanes as nucleophiles especially, the corresponding phosphane-borane adducts have been used in 1,4-additions to Michael acceptors. Following the idea to use a chirally modified phosphorus nucleophile in asymmetric Michael additions to aromatic nitroalkenes, we synthesized the new enantiopure phospite 45 starting from TADDOL (44) with nearly quantitative yield. Due to the C2 symmetry, of the... 

Asymmetric Michael additions. In the presence of sodium hydride as base, the /-butyl ester of 1 undergoes conjugate addition to a,/ -unsaturatcd esters (but not to ketones) with 12-24% asymmetric induction. The reaction was used to prepare optically active <5-lactones. 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

Asymmetric Michael addition to enoatesThe known conjugate addition of RCu BF, (8, 324-325) to a,/(-unsaturated carbonyl compounds4 proceeds with high chiral induction to trans- )-8-phenylmenthyl crotonate (2). Addition to the isomeric ei.v-crotonate (5) is less selective, but results mainly in the enantiomeric acid (6). 

Complexes of unsymmetrically substituted conjugated dienes are chiral. Racemic planar chiral complexes are separated into their enantiomers 84 and 85 by chiral HPLC on commercially available /f-cyclodextrin columns and used for enantioseletive synthesis [25]. Kinetic resolution was observed during the reaction of the meso-type complex 86 with the optically pure allylboronate 87 [26], The (2R) isomer reacted much faster with 87 to give the diastereomer 88 with 98% ee. The complex 88 was converted to 89 by the reaction of meldrum acid. Stereoselective Michael addition of vinylmagnesium bromide to 89 from the opposite side of the coordinated Fe afforded 90, which was converted to 91 by acetylation of the 8-OH group and displacement with EtjAl. Finally, asymmetric synthesis of the partial structure 92 of ikarugamycin was achieved [27],... 

The butynoate 14 adds to the chiral enone 3 from the a-surface with asymmetric induction probably rationalized by the chelate model 15. The initial product 16 of the 1,4-conjugate addition is capable of another intramolecular Michael addition to the triple bond resulting in conversion of 16 to 4. 

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... 

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]. 

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