Macrocyclic enediyne

In the total synthesis of the strained cyclic enediynes 145, the highly substituted macrocyclic enediyne was constructed by intermolecular two-fold Pd-catalzed coupling of the a,ftj-di(iodoalkyne) moietes in 144 with cw-l,2-bis(trimethylstannyl)ethene in 80% yield [Eq. (49)] [70]. 

Enolization of macrocyclic enediyne lactones 11 results surprisingly in the formation of (/ . )-silyl ketene acetals 12 or 13 [lithium hexamethyldisilazanide is usually a lithium diisopropyl-amide/hexamethylphosphoric triamide substitute giving rise to the formation of (Z)-silyl ketene acetals] whereas (Z)-12a,b are obtained in the presence of hexamethylphosphoric triamide. 

In a study on the activation of macrocyclic enediynes by transannular cyclization it was found that the deprotection of the sulfonamide group of ketone 91 triggered the formation of aminol 92 which readily provided the isoquinoline derivative 93 via a Bergman cyclization reaction <04AG(E)132>. 

Scheme 3.111 Reactivity of macrocyclic enediynes with different ring size (Basak).

Scheme 3.115 Structure and synthesis of 19-membered macrocyclic enediynes 3.865 and 3.866. r.t., room temperature.

Scheme 3.116 Structure and synthesis of 14-membered macrocyclic enediynes 3.867, 3.868, and 3.869.

The Bergman cyclization temperature of 18-membered macrocyclic enediyne 3.885 is 130°C, while cyclization of its complex with Ag(I) 3.889 occurs at the lower temperature of 110°C. In the case of complex Ag+-l,8-diazabicyclotriyne 3.891, there was a decrease in the distance between the nitrogen atoms to 4.614 A compared with 5.049 A for the free diamine 3.890 (Scheme 3.123) [24a, 404]. 

Basak, A., Roy, S.K. and Mandal, S. (2005) Activation of macrocyclic enediynes by transannular cyclization. Angewandte Chemie International Edition, 44(1), 132-135. 

An extensive computational analysis expanded the range of the c-d distances for reactive cyclic enediynes to 2.9-3.4 A.38 By comparing unsubstituted enediynes with dialkyl-substituted enediynes, it was found that the activation enthalpy is dependent on factors other than the c-d distance and that reactivity hinges on a subtle interplay of steric and electronic effects that accompany distortion caused by incorporation into a macrocycle. For example, since alkyl substituents stabilize acetylenic bonds to a greater extend than olefinic bonds,39 such substituents stabilize the starting material, thus increasing both the activation barrier and the reaction endothermicity. 

Nitrogen-containing 15-membered trialkyne macrocycles, such as l,6,ll-frw(aiylsulfonyl)-l,6,ll-triazacyclopentadeca-3,8,13-triynes and enediynes as 1,6,11-frw(arylsulfonyl)-1,6,11-triazacyclopentadeca-3-ene-8,13-diynes have been prepared and subjected to a [2+2+2]-cyclotrimerization process catalyzed by transition metal complexes, e.g., RhCl(CO)(PPh3)2 <05JOC2033>. The reaction of pemosylated diethylenetriamine and 2-substituted propan-1,3-... 

In the context of enediyne reactivity, the electronic structure properties and their relationship to the cyclization chemistry of only the porphyrins have been probed in detail to date. Electronic absorption measurements and Raman analysis of the octa(phenylacetylene) derivatives (Scheme 99) show a correlated redshift in the absorption profile of 13nm/alkyne (Fig. 39), as well as a concomitant decrease in the frequency of the porphyrin marker bands between 1300 and 1600 cm as a function of increasing number of alkynes and increasing planarity of the macrocycle (Fig. 40) (584). These compounds also exhibit structure-dependent Bergman cyclization temperatures, but due to the steric crowding and large substituents at the alkyne termini positions,... 

Several examples of the application of Pd/Cu-catalyzed cross-coupling for synthesis of alkynyl ketones, terminal acetylenes, enediyne macrocycles, and enediyne polymers are given. 

Another important application of this protocol for the synthesis of enediynes is its use in the synthesis of natural products containing enediyne macrocycles, such as esperam-icin/calicheamicinf " and dynemicin as discussed in Sect. III.2.18. Some applications to the synthesis of unnatural macrocycles have also been reported (Scheme... 

Despite some uncertainty in the expected olefin geometry, the utility of the RBR is anply demonstrated by its application to the synthesis of many diverse targets. These include dendrimers, cyclophanes, modified carbohydrates such as C-glycosides and exoglycals, alkaloids, terpene derivatives, enediynes, amino acids, stilbenes, and macrocycles.The remainder of this chapter presents examples of the RBR that are pertinent to the strategic considerations oudined previously and illustrate its scope as a versatile and powerful synthetic method. 

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