Prostaglandin synthesis Michael reaction

Further variations in dienophile have been equally successful (eqs 6 and 7), including applications to the Michael reaction (eq 7) and in the synthesis of a prostaglandin intermediate (eq8).i ... 

Hayashi and Umemiya developed synthesis of prostaglandin methyl ester based on the Michael addition of butanedial to nitroalkene (Scheme 8.9). This synthesis also has noteworthy sustainable features a) it was performed in only three pots, including three isolations and three chromatographic purifications b) the key Michael reaction is a highly selective catal5dic reaction c) the metal-based reagents employed in the synthesis contain only nontoxic metals. 

Michael addition of the reagent to enoates and enones occurs at low temperature (—50 to —78 °C) in the presence of catalytic amounts of various Lewis acids. A catalytic amount of triph-enylmethyl perchlorate (5 mol %) effectively catalyzes the tandem Michael reaction of ethyl acetate-derived silyl ketene acetal to a, -unsaturated ketones and the sequential aldol addition to aldehydes with high stereoselectivity.HgL mediates the Michael addition to chiral enones, followed by Lewis acid-mediated addition to aldehydes. The Michael-aldol protocol has been used for the stereoselective synthesis of key intermediates on the way to prostaglandins, compactin, and ML-236A (eq 19). ... 

The most impressive result of the catalytic Michael-aldol cascade is the kinetic resolution of the racemic cyclopentenone 458 shown in Sch. 64. The reaction is performed with 10 mol % (S)-ALB to give the tandem Michael-aldol adduct 459 in 97 % ee and 75 % yield based on malonate 390f. Asymmetric induction in 459 was measured after dehydration of the hydroxyl group, as was done for 451. Clearly, this demonstrates the viability of this new asymmetric strategy for the synthesis of a variety of fully functionalized prostaglandins. 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

Organometallic reagents are well known for 1,4-additions and can hence be utilized to catalyze domino Michael/aldol reactions. Based on a methodology published by Noyori et al. [24], the group of Feringa estabhshed a catalytic enantios-elective protocol for the synthesis of (—)-prostaglandin Ej methyl ester [25]. There,... 

Exo-methylene ketones like 536 readily undergo addition reactions of various copper-zinc reagents. This methodology has been applied for the synthesis of prostaglandines such as 537 (Scheme 2-152, eq. (a)). Moreover, enantioselective Michael-additions have been pioneered by Feringa et a/. " and Alexakis et Remarkably, only a catalytic amount of the chiral ligand 538 (4 mol%) and Cu(OTf)2 (2 mol%) was required, and the 1,4-addition product 539 was obtained with an enantiomeric excess of 93% ee (Scheme 2-152, eq. This method was used for an... 

I.4.3. Synthesis of Prostaglandin ll-deoxy-PGFj via Tandem Michael-Aldol Reaction (Scheme 9.14f ... 

SCHEME 9.14. The synthesis of prostaglandin 11-deoxy-PGFiaVW tandem Michael-aldol reaction. 

Shibasaki also disclosed an application that incorporates an asymmetric tandem Michael addition-aldol reaction sequence with this family of bimetallic catalysts [117], as shown for the synthesis of the prostaglandin 11-deoxy-PGF (132, Scheme 12.16) [119]. In this route, the first two stereo-genic centers in the cyclopentane ring are installed in the course of an asymmetric Michael addition of malonate 128, followed by trapping of the resulting enolate 129 with aldehyde 130. The sequence provided the trans-cyclo-pentanone 131 in 92% ee. The stereoinduction at Cy was observed to range from dr 6 1 to dr 17 1, although this was inconsequential, as the secondary alcohol at C7 was later excised. 

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