Oxa-Enediynes:  Probing the Electronic and Stereoelectronic Contributions to the Bergman Cycloaromatization

Abstract

Efficient routes to three classes of 10-membered oxa-enediynes are presented. The electronic and stereoelectronic contributions to half-lives are supported by density functional theory calculations. One member of this class cyclizes to give an isochroman which binds to and degrades the aryl hydrocarbon receptor (AhR).

Oxaenediynes through the Nicholas‐Type Macrocyclization Approach

“…The target macrocyclic oxaenediynes 1 and 2 were easily obtained after removing the Co 2 (CO) 6 group by using tetrabutylammonium fluoride hydrate (TBAF · x H 2 O) in THF as mild decomplexation reagent, as previously employed for this purpose. [8a], [9b], [9c]…”

“…Specifically, it was found that the incorporation of either oxygen or nitrogen atoms into an enediyne macrocycle increases the enediyne reactivity in the Bergman cyclization . To date, however, only four examples of 10‐membered oxaenediynes as synthetic analogues of enediyne antibiotics have been obtained (Figure ).…”

“…To date, however, only four examples of 10‐membered oxaenediynes as synthetic analogues of enediyne antibiotics have been obtained (Figure ). [8a],…”

Spin Trapping of 13C‐Labeled p‐Benzynes Generated by Masamune–Bergman Cyclization of Bicyclic Nine‐Membered Enediynes

“…There is clearly a need to study and accurately represent the presumed thermal behavior of the reactive bicyclic cores of natural enediynes, especially those featuring nine‐membered rings 7. 8 We first recognized this need in 1995 after observing the paramagnetic activity of the bicyclic epoxyenediyne core 1 a of the kedarcidin chromophore (Scheme ) 7a. We speculated that a spontaneous equilibration similar to that likely to take place between 1 and the p‐ benzyne biradical 2 at ambient temperatures would occur within other natural chromophores that contain a nine‐membered ring 7b,c.…”

1,2-Dihaloalkenes in Metal-Catalyzed Reactions

“…Enediyne-containing macrocycles have been prepared by several groups. 54,96 For example, Haley and co-workers used a Sonogashira coupling to form silylated dialkyne 186 from (Z)-1,2-dichloroethene [(Z)-8c] and dialkyne 185 (Scheme 53). 96b After removal of the remaining silyl group, autocoupling conveniently led to macrocycle 187.…”