Double Michael reaction

The second synthesis follows an entirely different synthetic plan—one dependent upon a double-Michael reaction to establish the spiran junction. Chlorophenol, 7, is reacted with chloro-acetylchloride to give coumaranone, 16. This is treated with methoxyethynyl propenyl ketone (17) (itself prepared by 1,2-... 

Finally, by a diastereoselective intramolecular double Michael reaction of a lithium dieno-late to an a,j6-unsaturated ester moiety, a spiro-fused bicyclo[2.2.2]octane may be prepared. These MIMIRC form the key step in the synthesis of ( )-atisine361 and (-t-)-alisirene362-365. 

Hoashi, Y., Yabuta, T., Takemoto, Y. (2004) Bifunctional Thiourea-Catalyzed Enantioselective Double Michael Reaction of y,5-Unsaturated fS-Ketoesterto Nitroalkene Asymmetric Synthesis of (—)-Epibatidine. Tetrahedron Letters, 45, 9185-9188. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

Reaction of phenyl vinyl ketone with cyclopentanone under thermal conditions resulted in a diastereomeric mixture of 1,5,9-triketones 374 via a double Michael reaction. Treatment of this mixture with ammonium formate in polyethyleneglycol-200 under microwave irradiation conditions led to the very fast and efficient formation of a 2 1 diastereomeric mixture of cyclopental flquinolizidines 375 and 376 <2002T2189>. When this reductive amination-cyclization procedure was carried out starting from the purified /ra r-isomer of 374, the result was identical to that obtained from the cis-trans mixture, showing the operation of thermodynamic control (Scheme 86). 

The mechanistically quite similar double Michael reaction of 2-silyloxy dienes and enones has been shown recently to go via a similar two-step mechanism rather than a Diels-Alder cycloaddition S. Kobayashi, Y. Sagawa, H. Akamatsu and T. Mukaiyama, Chem. Lett., 1988, 1777. 

The double Michael reaction of 18 was first executed with 4-trimeth-ylsilyl-3-butyn-2-one and catalytic KF 2H2O in EtOH, but side products derived from addition of EtOH to the CN groups of the intermediate 23... 

Irie and co-workers (37) have recently observed that the double Michael reaction of dimethyl acetone dicarboxylate on dienone 104 gave the cis decal-in product 106. This result indicates that intermediate 105 underwent a stereoelectronically controlled internal Michael addition to give 106. Without stereoelectronic control in the Michael reaction, there is no apparent reason to prevent the formation of the trans isomer 107. However, if this factor is taken into consideration, examination of molecular models indicates that it seems impossible to obtain isomer 107. 

Table 6.6 Thiourea-catalyzed double Michael reactions of unsaturated /M

M. Ihara, K. Fukumoto, Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction, Angew. Chem. Int. Ed. Engl. 1993, 32, 1010-1022. 

Musso has reported the synthesis of diasterane (tricyclo-[3.1.1.I2 4]octane) 15. For this first member of the series of asteranes, the decarboxylation of 16b -> 16c was best achieved via the photolysis of the Barton ester of 16a in the presence of BuSH, as shown in Scheme 5.14 Fukumoto has accomplished asymmetric total synthesis of atisine 17, where the bridged pentacyclic intermediate 18, a precursor for atisine, was synthesized via an intramolecular double Michael reaction starting with 19, Scheme 6.15 Barton protocol was favored during the late stages of the synthesis and the presence of various functionalities was easily accommodated. 

Asymmetric intramolecular double Michael reaction.3 Treatment of the 8-phenylmenthyl ot,(3-unsaturated amide ester (2) with r-butyldimethylsilyl triflate and triethylamine effects this Michael reaction with almost complete diastereose-lectivity to give the indolizidine 3, which was used for synthesis of (- )tylophorine (4). 

Synthesis of polycyclic alkaloids using an intramolecular double Michael reaction 93AG(E)1010. 

A three-step synthesis of a precursor of paroxetine is described. An aza double Michael reaction was used to form the piperidine ring <03TL7429>. 

The Michael addition of enolates to vinyl sulfones allows one-pot tandem reactions to be devised to achieve cyclisations as illustrated in Scheme 55. In the first reaction, the enolate (131) is transformed into the cyclic p-hydroxy sulfone (132) in good yield. In the second reaction, the enolate (133) yields the tricyclic compound (134) as a result of a double Michael reaction followed by intramolecular elimination of the benzenesulfonyl group. 

From 1988 to 1990, Ihara and co-workers modified the above synthesis approach to develop an asymmetric total synthesis of (-)-tylophorine [(-)- ] via an intramolecular double Michael reaction of a,p-imsaturated esters. Their work proved that the absolute configuration of naturally occurring (-)-tylophorine is (R). Two different chiral auxiliaries, (-)-phenylmenthol [52, 53] or (2R,4S,5R)-(-)-4-(tert-butyldimethylsiloxymethyl)-5-hydroxy-2-phenyl-1,3-dioxane(BDH), were employed [53, 54]. The reactions are summarized in Scheme (2). The resulting (E, E)-esters (26) and (27) underwent a double Michael reaction through proposed transition states (A) (B), respectively, to give a highly enantioselective product (28 and 29, respectively). (-)-... 

Tylophorine [(-)- ] was obtained from 28 and 29 through similar procedures as those in Scheme (1). The high enantioselectivity of the above intramoleeular double Michael reaction achieved by using chiral auxiliaries is notable. 

Zhong et al. also developed a domino double Michael reaction to access multi-substituted cyclopetanes 20 with excellent enantioselectivities (90-99% ee) and high diastereoselectivities (95 5->99 1) catalyzed by 9-amino-9-deoxyepiquinine lo (Scheme 10.24). A similar concerted activation mode was proposed [32],... 

Double Michael reaction in synthesis of N-heterocycles 86YGK96. Electrophilic heterocyclization of unsaturated amino compounds into... 

Conditions for the intermolecular aza-double Michael reaction of acrylamides leading to functionalized 2-piperidones have been developed, as exemplified by the conversion of 225 to 226. Of particular interest was the use of a cross reaction of amide 227 with methyl acrylate to give 228. This 2-piperidone was readily converted to (+)-paroxetine 229 (Scheme 66) <05JOC3957>. 

Twice deprotonated species from a 3-nitropropanoic ester is used in a double Michael reaction on 4,4-dimethoxy-2,5-cyclohexadienone to furnish bridged ring products (for a synthesis of gelsemine). The deprotonation is conveniently carried out with LDA in THF containing HMPA. ... 

Protection of 1,2-diols. Acetal formation with this ester (via a double Michael reaction) at room temperature in the presence of DMAP is limited to 1,2-diols (1,3- and... 

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