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

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 Cu-II- 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.

Automated summary

A new Cu-II-catalyzed tandem cycloisomerization-[3+2] cyclodimerization reaction of 1-(indol-2-yl)pent-4-yn-3-ol has been developed, providing access to structurally unprecedented dimeric tetrahydrocarbazoles fused to a tetrahydrofuran unit. This strategy allows for the construction of multiple C-C and C-O bonds, creation of stereocenters, and formation of multiple rings in a single operation. A chiral pool version using enantio- and diastereopure substrate was also demonstrated.