Because benzannulated and indole-fused mediumsized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indolefused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollowshaped C-dtbm ligand for the construction of a ninemembered ring.

Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d -MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure–activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N -methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.

Ag olden compass guides the adventurer's way in an unknown chemical space from the structures with one-and two-dimensional content towards those with an increased three-dimensional character.T hese three-dimensional compounds rise towards uncharted chemical space leaving the flatland behind, based on the cascade cyclization of alkynyl azides generating indole fused medium-sized rings.

In this image, a golden compass guides the adventurer's way in an unknown chemical space. The compass leads the structures with one‐ and two‐dimensional content towards those with an increased three‐dimensional character. These three‐dimensional compounds rise towards uncharted chemical space leaving the flatland behind, based on the cascade cyclization of alkynyl azides generating indole fused medium‐sized rings. More information can be found in the Full Paper by H. Ohno et al. (DOI: 10.1002/chem.202101824).