Diastereoselective Biomimetic Synthesis of Dimeric Tetrahydrocarbazoles via a Copper(II)‐Catalyzed Cycloisomerization‐[3+2] Cyclodimerization Cascade

Abstract

The cyclodimerization (homochiral‐ and heterochiral−) of monomeric units for the construction of stereodefined polycyclic systems is a powerful strategy in both biosynthesis and biomimetic synthesis. Herein we have discovered and developed a CuII‐ catalyzed, biomimetic, diastereoselective tandem cycloisomerization‐[3+2] cyclodimerization of 1‐(indol‐2‐yl)pent‐4‐yn‐3‐ol. This novel strategy operates under very mild conditions, providing access to structurally unprecedented dimeric tetrahydrocarbazoles fused to a tetrahydrofuran unit in excellent yields of the products. Several fruitful control experiments, isolation of the monomeric‐cycloisomerized products and their subsequent conversion into the corresponding cyclodimeric products supported their intermediacy and the possible mechanism as a cycloisomerization‐diastereoselective [3+2] cyclodimerization cascade. The cyclodimerization involves a substituent controlled, highly diastereoselective homochiral [3+2] annulation or heterochiral [3+2] annulation of in situ generated 3‐hydroxytetrahydrocarbazoles. The key and important features of this strategy are: a) construction of three new C−C bonds & one new C−O bond; b) creation of two new stereocenters, and c) construction of three new rings, in a single operation; d) low catalyst loading (1–5 mol %); e) 100 % atom economy; and f) rapid construction of structurally unprecedented natural product like polycyclic frameworks. A chiral pool version using an enantio‐ and diastereopure substrate was also demonstrated.