Access to a Guanacastepene and Cortistatin-Related Skeleton via Ethynyl Lactone Ireland–Claisen Rearrangement and Transannular (4 + 3)-Cycloaddition of an Azatrimethylenemethane Diyl

Abstract

Heating a 2,5-furanocyclic (2-azidoethyl)allene initiates a cascade reaction comprising azide-allene cycloaddition, loss of nitrogen, and azatrimethylenemethane (ATMM) diyl-furan transannular (4 + 3)-cycloaddition. The major product of this reaction contains the pentacyclic core common to guanacastepenes D and H and radianspenes J-L; in addition, the central oxa-bridged cycloheptene ring, flanked by two carbocyclic rings, is structurally related to the ABC-ring system found in the cortistatins. This is the first reported synthetic application of a "free" (nonconjugated) ATMM. The cyclization precursors were prepared via the first reported examples of the Ireland-Claisen rearrangement of an ethynyl lactone.

Transannular [4+3] Cycloadditions of Macrocyclic Epoxy Ketones

“…Gung and co‐workers also examined the metal‐catalysed isomerization of several macrocyclic allenes and alkynes which proceeded to transannular cycloadditions to give fused 6‐7‐6, and 6‐7‐5 tricyclic systems, as well as rearrangements to other polycycles . More recently, Robertson and co‐workers reported a transannular cycloaddition of an azatrimethylenemethane diyl intermediate with a furan to synthesize a racemic 5‐7‐6 tricyclic ring system …”

“…Notably,m any of them, including the cortistatin, guanacasptene, dolastane and grayanotoxin families of natural products,p ossess linearly fused polycyclic skeletons featuring ac ycloheptanes ubunit flanked by additional five-, six-or seven-membered rings ( Figure 1). [9] Our group has been exploring an intramolecular [4+ +3] cycloaddition of epoxy enolsilanes such as 2,t oc onstruct bicyclo[5.4.0] undecane frameworks 3 with excellent diastereoselectivity (Scheme1). Ap ossibly equally step-economical, but under-explored approach, is to employ at ransannular cycloaddition to forge the centrally featured seven-membered carbocycle.…”

“…TADA, or the transannular Diels-Alder reaction, has been the cycloaddition most studied in this context, and has been successfully applied to the syntheses of many natural products. [9] Our group has been exploring an intramolecular [4+ +3] cycloaddition of epoxy enolsilanes such as 2,t oc onstruct bicyclo[5.4.0] undecane frameworks 3 with excellent diastereoselectivity (Scheme1). [5] As for [4+ +3] cycloadditions [6] in the transannular context which would be applicable to the synthesis of the frameworks of natural products exemplified in Figure 1, Gung reported a classical oxyallyl cation derived from am acrocyclic chloroketone, that reactedt og ive racemic fused 6-7-7 and 5-7-6 arrays.…”

“…[2] Transannular nitro-olefin [3+ +2] cycloadditions, [3] dipolar [5+ +2] cycloadditions, [4] and other cycloadditionsh ave also been reported. [9] Our group has been exploring an intramolecular [4+ +3] cycloaddition of epoxy enolsilanes such as 2,t oc onstruct bicyclo[5.4.0] undecane frameworks 3 with excellent diastereoselectivity (Scheme1). [7] Gung and co-workersa lso examined the metal-catalysed isomerization of severalm acrocyclic allenes and alkynes which proceeded to transannular cycloadditions to give fused 6-7-6, and 6-7-5 tricyclics ystems, as well as rearrangements to other polycycles.…”

“…[8] More recently,R obertson and co-workers reportedatransannular cycloaddition of an azatrimethylenemethane diyl intermediate with af uran to synthesize ar acemic 5-7-6 tricyclic ring system. [9] Our group has been exploring an intramolecular [4+ +3] cycloaddition of epoxy enolsilanes such as 2,t oc onstruct bicyclo[5.4.0] undecane frameworks 3 with excellent diastereoselectivity (Scheme1). [10] We have also appliedt his reaction to the synthesis of natural products.…”