Michael addition prostaglandins

Dithioacetal monoxides undergo Michael addition to acrylonitrile. The addition products are easily converted into y-ketonitriles 382 (equation 221). Benzenesulphinyl allylic carbanions 383 derived from the corresponding allylic sulphoxides react selectively at the y-position with a variety of cycloalkenones to give the l,4-adducts " (equation 222). Recently, Nokami and coworkers have synthesized some prostaglandin analogues via a three-component coupling process involving 1,4-addition of phenylsul-phinyl allylic carbanion (equation 223) . ... 

The Michael addition of nitromethane to cyclopentenone derivatives is used for synthesis of prostaglandins (Scheme 4.20).158 Here, the anion of nitromethane is used as a formyl anion synthon. 

During the last decade, a substantial number of novel (sometimes even stereoselective) strategies for the preparation of allenic prostaglandins have been devised. The approach used by Patterson involves a three-component coupling via a 1,4-addi-tion of the organocopper compound 121 to the enone 120, followed by alkylation of the enolate formed with the bromide 122 (Scheme 18.40) [121]. However, due to the notoriously low reactivity in the alkylation of the mixed copper-lithium enolate formed during the Michael addition [122], the desired product 123 was obtained with only 28% chemical yield (the alkylation was not even stereoselective, giving 123 as a 1 1 mixture of diastereomers). 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

The Michael addition of (+)-(5 )-51 to the aj3-unsaturated ketone 217 constitutes a key step in the asymmetric synthesis of the optically active cyclopentanone 318, which is precursor of the 11-deoxy-prostaglandins (321). 

The second has been used to make prostaglandins from the intermediate aldehyde 186. Note the stereochemistry the obvious trans arrangement of the two substituents in 184 after the Michael addition and the approach of the bulky reducing agent L-selectride Li(s-Bu3BH) from the opposite face to the nearer and larger of the two substituents. Finally, a reductive workup (Me2S) is needed after the oxidation of nitro to ketone with ozone.37... 

In connection with prostaglandin syntheses, Michael additions to cyclopentanones with exo- and endocyclic double bonds have been intensively explored. In all cases protonation of the intermediate occurs in such a way that the side chains end up in the tram position, as exemplified by the following76,78-79 (see also references 77 and 80-83). 

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. 

The Michael addition of the w-chain to a cydopentenone with an a-chain already in place, a synthetic concept developed at Searle, served as the model for a whole series of industrial production processes for synthetic prostaglandins. 

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). ... 

Prior to the work on prostaglandins, Hayashi and coworkers found a new route to effectively produce the dipeptidyl peptidase IV-selective inhibitor ABT-341 (Scheme 14.6) [14]. The strategy also comprised a Michael addition and HWE reaction, but these were in this case used to generate disubstituted cyclohexene carboxylates instead. After a diphenylprolinol silyl ether (10 mol%)-promoted asymmetric Michael addition of acetaldehyde (2.0 equiv) to nitroalkene 38 (97% ee) in 1,4-dioxane in 5 h, another Michael addition was initiated by addition of vinyl phosphonate 40 (1.2 equiv) under basic conditions (CS2CO3, 2.0 equiv) at 0 °C in dichloromethane. The subsequent intramolecular HWE reaction in ethanol at room temperature afforded the cyclohexene in 15 min., which was isomerized in situ by the addition of DiPEA (10 equiv) to yield trans-43. 

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... 

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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