Organic synthesis provides opportunities to transform drug discovery

Abstract

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

“…[17] As noted earlier,o ne of the most exciting opportunities regarding cyclic allene chemistry is the possibility of intercepting enantioenriched allenes for the synthesis of enantioenriched cycloadducts.I naseminal study,C hristl and coworkers generated 1-phenyl-1,2-cyclohexadiene in enantioenriched form, as judged by the formation of an enantioenriched cycloadduct, albeit in low yield, likely owing to the necessary use of organolithium reagents. [17] As noted earlier,o ne of the most exciting opportunities regarding cyclic allene chemistry is the possibility of intercepting enantioenriched allenes for the synthesis of enantioenriched cycloadducts.I naseminal study,C hristl and coworkers generated 1-phenyl-1,2-cyclohexadiene in enantioenriched form, as judged by the formation of an enantioenriched cycloadduct, albeit in low yield, likely owing to the necessary use of organolithium reagents.…”

“…[16] Given the potential for heterocyclic allenes to provide af acile means to rapidly assemble stereochemically rich scaffolds, [16] we wondered whether oxacyclica llenes 6 could be employed efficiently in cycloadditions to access oxygencontaining heterocycles. [17] Oxygenated heterocycles are often seen in natural products and drugs [18][19][20][21] and are known bioisosteres for their nitrogen-and sulfur-containing counterparts. [22] Asingle report by Christl and Schreck demonstrated that 6 (R' = H) could be generated using the Doering-Moore-Skattebøl rearrangement, however, this required harsh organolithium-based conditions.…”

Sichtbares Licht ermöglicht Ruthenium‐katalysierte meta‐C‐H‐Alkylierung bei Raumtemperatur

“…[18,19] Inspiriert durch die große Anwendungsbreite der lichtinduzierten Rutheniumkatalyse wollten wir deren Wirkungsmechanismus aufklären (Schema 3). Dem folgend wurden wichtige funktionelle Gruppen wie Imide,E none,P iperidylringe oder Ester als Struktureinheit der Alkylbromide 2 toleriert, und die rutheniumkatalysierte lichtinduzierte meta-C-H-Funktionalisierung erfolgte weiterhin mit hoher Effizienz.…”

Site-Selective Switching Strategies to Functionalize Polyazines

“…6–8 Polyazines are often found in therapeutic compounds (eq 1), and they are also abundant in medicinal chemistry libraries as lead compounds and drug fragments 9. Given the importance of polyazines in pharmaceuticals, site-selective functionalization strategies would be highly desirable 10. We herein report a study that addresses this challenge by selectively installing a phosphonium ion as a generic functional handle in polyazine structures.…”