Divergent and Expeditious Access to Fused Skeletons Inspired by Indole Alkaloids and Transtaganolides

Abstract

We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugi condensations and installation of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the amine building blocks installed at site C.

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

“…This approach allows unified four-step access to a series of indole-alkaloid-like scaffolds. Some of these results were previously reported as a preliminary communication in 2009 [22]. As shown in Fig.…”

“…First, we assembled a linear precursor 24 with installation of a p -methoxybenzyl group and an indole ring at modules 3 and 4, respectively (Scheme 1), according to a procedure previously reported in our preliminary communication [22]. Racemic manifold 6 , indole-3-carbaldehyde derivative ( 20 ), tert -butylisonitrile ( 21 ) and p -methoxybenzylamine ( 22 ) were condensed in methanol under reflux to furnish a dipeptidyl product as a 1:1 diastereomeric mixture in 78% yield.…”

“…To generate skeletal variations by altering the sites of the cycloadditions, we next synthesized a branched precursor 29 bearing a pair of identical indole units at modules 3 and 4 (Scheme 2), as reported previously [22]. Due to the instability of the corresponding amine building block bearing the indole unit, azide 27 was employed as a precursor.…”

Biomimetic Assembly Lines Producing Natural Product Analogs: Strategies from a Versatile Manifold to Skeletally Diverse Scaffolds

“…Thus, the four-step assembly line allowed not only generation of stereochemical variations of the collections, but also efficient access to an alkaloidal scaffold with sufficient quantities (> 100 mg) in high yields (> 30% overall yield for four steps). [16,17] To generate scaffold variations based on the four-step synthetic process, we capitalized on a dynamic conformational equilibrium of the tertiary amide of the branching dipeptidyl moiety of the cyclization precursor ( Figure 13). [17] The tetraketide-like precursor 48 is expected to undergo divergent cycloadditions with the dipolarophiles installed at either module 3 or 4 leading to hexacyclic 49 or tetracyclic 50, respectively.…”

“…[16,17] To generate scaffold variations based on the four-step synthetic process, we capitalized on a dynamic conformational equilibrium of the tertiary amide of the branching dipeptidyl moiety of the cyclization precursor ( Figure 13). [17] The tetraketide-like precursor 48 is expected to undergo divergent cycloadditions with the dipolarophiles installed at either module 3 or 4 leading to hexacyclic 49 or tetracyclic 50, respectively. Whilst the cycloaddition exploiting module 4 (site C) could form 49 reminiscent of terpenoid indole alkaloids such as aspidophytine, [35] the different cyclization mode exploiting the dipolarophile installed at module 3 (site B) would produce a distinct skeleton 50 having a certain degree of structural resemblance to the transtaganolides, [25] a family of sesquiterpenes described in Section 2.1.…”