Tandem Michael addition, chiral

Scheme 3.3 Tandem Michael addition and lactonization using chiral ammonium phenoxide.

Recently, Mukaiyama and co-workers prepared cinchona alkaloid-derived chiral quaternary ammonium phenoxide-phenol complex 23 and used it as an efficient organocatalyst for the tandem Michael addition and lactonization between oc,f-unsaturated ketones and a ketene silyl acetal 24 derived from phenyl isobutyrate. This approach permits the highly enantioselective synthesis of a series of 3,4-dihydropyran-2-ones (25), as shown in Scheme 4.11 [17]. 

Node, M., Nishide, K., Shigeta, Y., Shiraki, H., Obata, K. A Novel Tandem Michael Addition/Meerwein-Ponndorf-Verley Reduction Asymmetric Reduction of Acyclic a,P-Unsaturated Ketones Using A Chiral Mercapto Alcohol. J. Am. Chem. Soc. 2000, 122,1927-1936. 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

A 1-phenylethylamino moiety is used for diastereomeric control not only in addition of nucleophiles to A-(l-phenylethyl)imines but also in diasteroselective Michael addition to a,P-unsaturated esters. Thus, lithium A-(l-phenylethyl)-A-benzylamide 148 is employed for a one-pot tandem Michael addition-fluorination reaction (see Scheme 9.32) [58]. The reaction provides a/i/f-3-amino-2-fluoroesters 149 exclusively, whose diastereoselectivi-ties (64-66% de) to the chiral carbon of the 1-phenylethyl-group are good enough. 

Histrionicotoxin (340) and (-)-histrionicotoxin 235A (341) were synthesized from (S)-6-hydroxy-8-nonenoate, using an allylic epoxide cyclization to generate three of the required chiral centers [717]. A recent synthesis of the histrionicotoxin ring system employed a tandem Michael addition-nitrone cyclization [718]. GC-MS, GC-FT1R, and revised i3C NMR spectral data have been reported for a number of histrionicotoxins [719],... 

Several other stereoselective transformations have been presented that afford ehiral eyelohexenones, ° ° cyclohexadienones, or cyclopenta-nones. °° For instanee, tandem Michael addition/Wittig reaction of (3-carbo q -2-oxopropylidene) triphenylphosphorane and a,p-unsaturated aldehydes has been developed by employing catalysis by newly designed bullq chiral secondary amine C10. ° The multifunctional 6-carbo3gr-cyclohex-2-en-l-ones were generally obtained in excellent diastereo- and enantioselectivities (Seheme 8.23). 

The tandem Michael addition-cyclization reaaions of ( )-2-(2-nitrovi-nyl)phenols with malononitrile using a chiral thiophosphonodiamide as catalyst deliver 2-amino-3-cyano-4H-chromenes in high yields (14T181). Other derivatives are obtained from a two-step reaction of benzaldehydes... 

Cyclic (hetero- and carbocyclic) vinyl sulfoxides have been prepared by a tandem Michael addition/Homer olefination reaction of a-phosphorylvinyl sulfoxides and carbonyl compounds bearing a nucleophilic center. Using optically active a-phosphorylvinyl sulfoxides a series of enantiomeric cyclic vinyl sulfoxides in which the chiral sulfinyl group is bonded to a chromene, pyrrazolyne, quinoline or cyclopen-tene ring, has been obtained. The H-W-E reaction of aldehydes with sulfinimine-derived 3-oxo pyrrolidine phosphonates (228) represents a new method for the asymmetric synthesis of ring-functionalized cw-2,5-disubstituted 3-oxo pyrrolidines (229) (Scheme 90). ... 

Guo, S., Xie, Y, Hu, X., Xia, C., Huang, H. (2010). Diastereo- and enantioselective catalytic tandem Michael addition/Mannich reaction Access to chiral isoindohnones and azetidines with multiple stereocenters. Angewandte Chemie International Edition, 49, 2728-2731. 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

The synthesis of the optically active chroman 489 can be achieved by use of a catalytic asymmetric tandem oxa-Michael addition Friedel-Crafts alkylation sequence between 3-methoxyphenol and (/. (-methyl 2-oxo-4-phenylbut-3-enoate. The chiral C2-symmetric box managanese(n)- complex 490 exerts excellent stereocontrol upon the reaction (Equation 200) <20030BC1953>, whereas only moderate enantioselectivity is observed in the presence of a chiral C2-symmetric 2,2 -bipyridyl copper(n)- complex (42% = ee) <20050L901>. 

Despite the importance of the Michael addition in organic synthesis, the tandem conjugate addition/enantioselective protonation has been little explored [14] and only a few publications have involved cinchona alkaloids as bifunctional catalysts B for controlling the configuration of the chiral carbon created during protonation (Scheme 7.9). 

The continued fascination chemists possess with asymmetric synthesis provides the basis for the next four procedures. The synthesis of (R)-(-)-10-METHYL-l(9)-OCTALONE-2 is a nice demonstration of an asymmetric Michael addition by a chiral imine followed by an aldol—in short an asymmetric Robinson annulation. The asymmetric glycolization to STILBENE DIOL (R,R-l,2-DIPHENYL-I,2-ETHANEDIOL) represents an olefin oxidation using catalytic alkaloids in tandem with osmium tetroxide. As reagents for a variety of asymmetric alkylations, the preparation of 2-CYANO-6-PHENYLOXAZOLOPIPERIDINK is pavscnicd as well as another route to... 

Anti stereochemistry in six-membered rings Conformational control from a chiral centre in the cyclohexenone Remote stereochemical control in five-membered rings prostaglandins Regio- and stereochemical control in open chain compounds Asymmetric induction by a chiral auxiliary on the enolate Tandem Michael-Michael Reactions One Conjugate Addition Follows Another Double Michael or Diels-Alder reaction ... 

Mukaiyama et al. have productively employed chiral quaternary ammonium phe-noxides derived from Cinchona alkaloids as catalysts in a new and efficient method for the preparation of optically active 3,4-dihydropyran-2-one derivates via tandem Mukaiyama-Michael addition/lactonization between a, 3-unsaturated ketones and the silyl enolate derived from phenyl isobutyrate (Scheme 2.51) [150]. In this... 

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