Three-component coupling, strategy

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

Scheme 2.1 Three-components coupling strategy for 1 by medicinal chemists.

Koh, J. S. Ellman, J. A. Palladium-Mediated Three-Component Coupling Strategy for the Solid-Phase Synthesis of Tropane Derivatives, J. Org. Chem. 1996, 61,4494-4495. 

The scope of the Cu-catalyzed cycloaddition between propargylamines and electron-deficient olefins in the presence of catalytic amounts of a copper salt was subsequently expanded to a one-pot, three-component coupling strategy involving phenols as third components [65]. In this case, reactive Michael acceptors such as ethyl 2-aryl- or alkylsulfonyl cinnamates 57 are involved in the process. This sequence leading to 3(4)-phenoxymethyl pyrrolidines 60 and their isomeric pyrrolidines 61 comprises of the relay process of... 

Several examples have appeared in the literature in which this linker has been employed in combinatorial chemistry strategies. Thus, it has been used in a Pd-mediated three-component coupling strategy for the solid-phase synthesis of tropane derivatives [46], in the solid-phase synthesis of aspartic acid protease inhibitors [47], in the attachment of cholic acid as a template for a combinatorial approach [48] and, more recently, in the solid-phase synthesis of pyrrolidines via 2-aza allyl anion cycloadditions with alkenes [49]. 

Koh, J.S. and Ellman, J.A. (1996) Palladium-mediated three component coupling strategy for the solid-phase synthesis of tropane derivatives. J. Org. Chem., 61, 4494-5. 

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). 

Naresh G, Kant R, Narender T (2014) Copper(II) catalyzed expeditious synthesis of furoquinox-alines through a one-pot three-component coupling strategy. Oig Lett 16 4528-4531. doi 10. 1021/ol502072k... 

J. Azizian, A.R. Karimi, Z. Kazemizadeh, A.A. Mohammadi, M.R. Mohammadizadeh, A synthetic route to ll-(lH-pyrrol-l-yl)-llH-indeno[l,2-i)]quinoxaline derivatives exploiting a three-component coupling strategy under microwave irradiation. Tetrahedron Lett. 46 (2005) 6155-6157. 

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). 

A three component coupling reaction of A-acetyl-2-azetine, aromatic imines and aromatic amines allows a rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines, via fused tricyclic azetidines 1 <02CC444>. Fused heterocycles 1 were formed through an aza Diels-Alder reaction between aromatic imines and A-acetyl-2-azetine, which acts as an enamide substrate. This strategy has been used for the formal synthesis of luotonin A <02TL5469>. 

Promothiocin A was initially synthesised by a three-component coupling approach <1998CC2049>. A Bohlmann-Rahtz pyridine synthesis established the oxazoyl-thiazole-pyridine heterocyclic centerpiece. The thiazole building blocks were obtained by the Hantzsch reaction. Two different strategies for macrocylization were successfully employed, with the dedroalanine side-chain being introduced in the last steps of the synthesis <2000JA3301>. 

Beller and coworkers recently reported a new strategy for the synthesis of poly-substituted anilines based on a three-component-coupling reaction and a domino deprotec-tion/aromatization reaction (equation l)44. A mixture of O-benzyl carbamate, p-toluene-sulfonic acid, aldehyde, AC2O and dienophile in /V-rnclhy I pyrrol idone was allowed to react for 24 h at 120 °C, followed by Pd/C catalyzed dehydrogenation in triglyme at 140 °C. A variety of tri-, tetra- and penta-substituted anilines were efficiently created by this domino process. 

Morimoto successfully used this strategy as a key step in his synthesis of nordehydro-cacalohastine derivates 203 [162]. Trisubstituted furan 202 is available upon the three-component coupling of enynol 201, Michael acceptor 193, and o-iodotohicnc. The desired product, 203, can then be prepared in five to six steps from 202. 

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