Strained cyclic enediynes

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]. 

The special fascination of strained cyclic enediynes lies in their intrinsic tendency to undergo thermal cyclisation. This aspect has been stimulating the research activities on enediynes since their beginnings more than 20 years ago, [1] and it is this reactivity of the enediyne structure that brings about the pharmacological effectiveness of natural products, like Dynemicin A. [2]... 

With the mechanistically interesting new approaches described here the spectrum of methods for the synthesis of strained cyclic enediynes could be enlarged markedly. It is to be expected that the search for simple pharmacologically active enediyne derivatives will benefit accordingly. 

As an alternative preparative method of enynes, the highly strained cyclic enediyne moiety 185 was constructed by coupling the dialkynyl diiodide 183 with (Z)-l,2-distarmylethylene (184) in 80% yield in the total synthesis of dyenemicin A [82]. The presence of the epoxide in 183 is important. No coupling took place... 

Strain and antiaromaticity in cyclic enediynes 11 Control of strain through ligand-metal coordination 16 Steric assistance of ortho substituents 17... 

Strain-based systems work the same way as the cyclic enediynes they reduce the c-d distance in the molecule. The first example was provided by Buchwald and coworkers,45 who used metal complexation of a PPh2 substituted enediyne to produce a species with considerably lower activation barrier (compared to the non-coordinated enediyne) (Scheme 10). 

Intramolecular Lewis acid-promoted reaction of coordinated propargylic ether with the silyl enol ether in 158 has been applied successfully to the construction of the highly strained 10-membered cyclic enediyne system 159, present in esperamycin and calicheamycin [39,40]. The enediyne system 157 was prepared by the Pd-catalysed Sonogashira coupling of (Z)-l,2-dichloroethylene (154) with two different terminal alkynes 155 and 156. 

For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition slate this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization ... 

Enediynes amino, 127, 20, 217 antiaromatic region in, 14-15 Bergman cyclization, 3, 18, 25 C1-C5 cyclization of, 5f 25 cyclic, strain and antiaromaticity in, 11-16... 

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