Prostaglandins three component coupling

Scheme 5. Larock s palladium-promoted, three-component coupling strategy for prostaglandin synthesis.

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) . ... 

A short synthesis of prostaglandin derivatives via a three component coupling reaction is reported, in which the enolates are trapped with nitroalkenes. The nitro group is removed via... 

Treating benzaldehyde with diethylzinc in the presence of 2 mol% (—)-DAIB gives (5)-alcohol in 98% ee (Scheme 2-43). When compound 112 is treated in the same manner, compound 113, a chiral building block in the three-component coupling prostaglandin synthesis, is also obtained with high ee (Scheme 2-43). 

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). 

Scheme 18.40 Synthesis of the allenic prostaglandin 123 by three-component coupling [121].

R. Noyori, M. Suzuki, New synthetic methods. (49). Prostaglandin syntheses by three-component coupling, Angew. Chem. Int. Ed. Engl. 23 (1984) 847. 

Suzuki, M. Morita, Y. Koyano, H. Koga, M. Noyori, R. Three-Component Coupling Synthesis of Prostaglandins. A Simplified, General Procedure, Tetrahedron 1990,46,4809. 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

The ultimate in the three-component coupling approach to prostaglandins has now been achieved by Noyori (48). As illustrated in Fig. 15, the cuprate derived from iodide [82] was added to enone [80] in the usual fashion. Then, after addition of hexamethylphosphoramide, triphenyltin chloride was used to effect enolate interchange. As opposed to lithium (or copper) enolates, the tin enolate is cleanly alkylated with allylic iodide [81]. The protected PGE2 [83] was obtained in 78% yield. Two-step deprotection to PGEj was straightforward. 

Three-component coupling of alkenes. Larock and Lee10 have reported an efficient one-step intermolccular coupling of three alkenes to form an intermediate (3) to prostaglandins. The starting material is the chiral cyclopentenol 1, which couples with ethyl vinyl ether and l-octen-3-onc (2) in the presence of Pd(OAc)2, NaOAc, and Nal at room temperature to afford the bicyclic enonc 3 in 72% yield as a 2-3 1 mixture of exo- and endo-isomers, which can be readily separated. A number of analogs of this bicyclic system can be prepared by substitution of 2 by other 1-alkenes. Pure ero-3 was... 

One of the most elegant routes to the formation of prostaglandins is the three-component coupling according to Ryoji Noyori [220], which starts from an... 

Suzuki, M. et al.. Three-component coupling synthesis of prostaglandins. A simphfied, general procedure, Tetrahedron, 46, 4809, 1990. 

A three-component coupling involving three alkenes was employed using a stoichiometric amount of palladium to generate a bicyclic acetal 6.91, which could be converted to an epimer of the prostaglandin, PGF2 (Scheme 6.31). The three-component coupling involves nucleophilic attack of the alcohol 6.89 onto an ethyl vinyl ether-palladium complex 6.93, intramolecular alkene insertion, intermolecular insertion of... 

Overview The utility of combinatorial chemistry within drug discovery is ultimately linked to the ability to rapidly construct complex molecules on polymer supports. With this in mind, a polymer-supported approach to the prostaglandin core was seen as an important benchmark in the progress of this chemistry. First a two-step liquid-phase version of Noyori s (5) three-component coupling strategy was realized. It allowed the successful synthesis of PGE2 methyl ester la (6) and PGF2 (7) lb (Fig. 1). 

The third strategy mentioned on Prostaglandins-13 was the a-methylenecyclopentane strategy. This route was introduced by the Stork group and followed the reaction sequence outlined at the bottom of this page. This is clearly a variation of the three-component coupling approach, but it is less efficient because two carbon-carbon bond-forming reactions are used to transform 139 to the PCs. 

Describe the relevance of this observation to the choice of electrophile for introducing the Cg sidechain in the three-component coupling approach to the prostaglandins. (Prostaglandins-17)... 

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