Authors: Sabine Choppin | Joanna Wencel‐Delord
Source: Accounts of Chemical Research (article, 2023-01-27)
Field: Chemistry — Organic Chemistry

Sulfoxide-Directed or 3d-Metal Catalyzed C–H Activation and Hypervalent Iodines as Tools for Atroposelective Synthesis ConspectusThe expanding applications of atropisomeric compounds combined with the growing diversity of such chiral molecules translate into an urgent need for innovative synthetic strategies allowing their rapid, efficient, and sustainable synthesis. Recently, the C–H activation approach has provided new opportunities for synthesizing axially chiral compounds. The two complementary approaches allowing implementation of the C–H activation methodology toward the synthesis of the chiral molecules imply either ortho-functionalization of the preexisting prochiral or atropo-unstable biaryl substrates or direct C–H arylation of sterically encumbered aromatics. The first approach required the preinstallation of a directing group on a biaryl precursor, which drastically limits the diversity of thus generated products. To tackle this important synthetic limitation, we have envisioned using a chiral sulfoxide as both directing group and chiral auxiliary. Indeed, in addition to efficiently coordinating the Pd-catalyst thus allowing chiral induction, the sulfoxide moiety can be easily removed, via the sulfoxide/lithium exchange, after the C–H activation step, thus guaranteeing an almost unlimited postdiversification of the atropisomeric products. The efficiency and generality of this concept could be illustrated by developing atropo-diastereoselective oxidative Heck reaction, direct acetoxylation, and iodination, as well as direct arylation. Besides, the synthetic utility of this methodology was demonstrated by designing an expedient synthesis of a direct steganone precursor. This unique transformation also allowed us to build up unprecedented triaryl scaffolds with two perfectly controlled chiral axes, original chiral skeletons for new ligand design. While considering the atroposelective direct arylations, the clear antagonism between the harsh reaction conditions frequently required for the coupling of two sterically hindered compounds and the atropo-stability of the new product, resulted in the scarcity of such transformations. To solve this fundamental challenge, we have focused on the application of a low-valent cobalt catalyst, prompted to catalyze C–H activation of indoles at the C2 position under extremely mild reaction conditions (room temperature). Accordingly, atroposelective C2-arylation of indoles could be achieved using an original carbene ligand and delivering the uncommon atropoisomerically pure indoles in excellent yields and enantioselectivities. Detailed combined experimental and theoretical mechanistic studies shed light on the mechanism of this transformation, providing strong evidence regarding the origin of the enantioselectivity. Finally, the antagonism between steric hindrance required to guarantee the atropo-stability of a molecule and harsh reaction conditions required to couple two partners is a strong limitation not only for the development of atroposelective C–H arylation reaction but also for the development of direct synthesis of the C–N axially chiral compounds. Despite the long history and incredible advances achieved in Ullmann–Goldberg and Buchwald–Hartwig couplings, atroposelective versions of such transformations have remained unprecedented until recently. Our idea to tackle this challenging issue consisted in using hypervalent iodines as highly reactive coupling partners, thus allowing the desired N-arylations to occur at room temperature. This hypothesis could be validated by reporting first atropo-diastereoselective Cu-catalyzed N-arylation, using sulfoxide λ3-iodanes as the coupling partners. Subsequently, the enantioselective version of this atroposelective N-arylation was successfully established by using a chiral Cu-complex bearing a BOX ligand. In conclusion, we report herein designing tailored-made solutions to provide new synthetic strategies to construct the atropisomeric molecules, including biaryls and C–N axially chiral molecules. Hypervalent molecule ; Chemistry ; Catalysis ; Sulfoxide ; Metal ; Combinatorial chemistry ; Organic chemistry Axial and Atropisomeric Chirality Synthesis ; Molecular spectroscopy and chirality ; Catalytic C–H Functionalization Methods