Gallium(III)‐Catalyzed Cycloisomerization Approach to the Diterpenoid Alkaloids: Construction of the Core Structure for the Hetidines and Hetisines

Abstract

A versatile core structure has been prepared that should provide a foundation for the syntheses of the hetidine and hetisine type of diterpenoid alkaloids. The synthesis of the caged polycyclic core structure, which features nine contiguous stereocenters, utilizes a Ga(III)-catalyzed cycloisomerization of alkynyl indenes as well as a Michael/aldol sequence to build the bicyclo-[2.2.2] framework.

Ongoing Pursuit of Diterpenoid Alkaloids: A Synthetic View

“…[13b, 43] While there are an umber of achievements for the synthesis of atisines, total synthesis of the closely related hetidine alkaloids is still pending. Recently, the groups of Sarponga nd Baran disclosed their efforts towards this goal, [17,18] respectively,s tanding as the only two successfulconstruction of the hetidine skeleton to date.…”

“…[44] This methodh as found furtherapplication in the synthesis of hetidine-type diterpenoid alkaloids. [18] As depicted in Scheme5B, cycloheptadiene 42 was efficiently generated from the precursor 41 catalyzed by GaI 3 .F unctional group manipulations of the former delivered the advancedi ntermediate 43,s etting the stage for the ensuing piperidine ring formation. As ar esult,e xposure of the Boc-protected amino alcohol 43 to thionyl chloride promoted smooth cyclization to provide 44 in 72 %y ield.…”

“…[14] Sarpong and co-workers contributed ac omprehensive review on synthetic strategies towards the hetidine-and hetisine-typed iterpenoid alkaloids in 2014. [15] The past five years have witnessed remarkable achievements in the syntheses of diterpenoid alkaloids, including two new approaches to the atisine alkaloids (1-3), [16,17] two strategies towards the hetidine scaffold, [17,18] the first enantioselective synthesis of denudatine alkaloid (À)-lepenine (8), [19] and the first synthesis of al appaconitine-type alkaloid (AE)-neofinaconitine (12). [20] The purpose of this review is to cover the completed total syntheses or syntheses of the entire skeletons of diterpenoid alkaloids reported since 2010, showcasing the creative solutions through the use of moderno rganic methods.…”

Comparison of homogeneous and heterogeneous Ga(III) catalysis in the cycloisomerization of 1,6-enynes

“…In the field of 1,n-enynes cycloisomerization reactions, the use of heterogeneized gold catalysts was recently reported with gold nanoparticles supported on TiO 2 (36). While homogeneous Ga(III) catalysts have been reported to yield cyclic products (37)(38)(39), no report to our best knowledge deals with heterogeneous Ga catalysts in this field. In the case of 1,6enynes treated by GaCl 3 , a skeletal rearrangement involving the formation of fused cyclobutenes intermediates was invoked in the formation of vinylcyclopentene derivatives but with a limited substrate scope ( Figure 1) (40).…”

Recent applications of gallium and gallium halides as reagents in organic synthesis

“…69,70 Having initially screened several platinum-and ruthenium-based catalyst systems, they discovered that GaCl 3 effected the skeletal reorganisation of a variety of enynes under mild conditions. This approach was successfully applied to the preparation of a key intermediate in the synthesis of The reaction proceeded satisfactorily with arylsubstituted substrates bearing either electron donating (p-Me, o-OMe) or electron withdrawing (p-Cl, p-Br, p-CN, p-NO 2 ) groups (Scheme 40).…”