Intramolecular cobalt-catalyzed cyclotrimerization

Chang and co-workers developed an intramolecular cobalt-catalyzed cyclotrimerization of both the symmetric and the asymmetric nitrile-diyne... 

A concise synthesis of the cytotoxic alkaloids dehydrotylophorine (127) and (+)-tylophorine (128) has been accomplished by a cascade consisting of a cobalt-catalyzed crossed [2 - - 2 - - 2] cyclotrimerization that is followed by an intramolecular ring annulation reaction (Scheme 7.27) [37],... 

Related co-cyclotrimerizations of two alkyne molecules with limited isocyanates have also been achieved using cobalt and nickel catalysts. With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,m-diynes with isocyanates have been reported to afford bicyclic pyri-dones only in low yields, although 2,3-dihydro-5(lff)-indolizinones were successfully obtained from isocyanatoalkynes and several silylalkynes with the same cobalt catalysis [19]. On the other hand, the ruthenium catalysis using Cp RuCl(cod) as a precatalyst effectively catalyzed the cycloaddition of 1,6-diynes 21 with 4 equiv. of isocyanates in refluxing 1,2-dichloroethane to afford bicyclic pyridones 25 in 58-93% yield (Eq. 12) [20]. In this case,both aryl and aliphatic isocyanates can be widely employed. 

In contrast, the cyclotrimerization catalyzed by the Grubbs catalyst involves consecutive intramolecular ring metathesis through carbene complexes or formation of a ruthenabicy-clo[3.2.0]heptatriene intermediate similar to that formed in the cobalt complex-catalyzed reaction. This mechanism is illustrated in Scheme 2 using acetylene as the alkyne source and CpRuCl[COD] as catalyst. 

Volhardt s tZZ-estrone synthesis was the first application of a transition-metal-catalyzed [2 -1- 2 -I- 2] alkyne cyclotrimerization in natural product synthesis, and the overall beauty of the synthetic sequence is still appealing [4,5]. Undoubtedly, this brilliant synthesis is a classic in its field. Following a D ABCD ring formation approach, the tetracyclic core of estrone was produced in a single reaction step by profiting from a reaction cascade that started with a cobalt-mediated crossed [2 + 2 + 2] alkyne cycloaddifion, which was followed by a benzocyclobutane to o-quinodimethane rearrangement, and was finalized by an intramolecular Diels-Alder reaction (Scheme 7.2). 

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