Organic synthesis provides opportunities to transform drug discovery
Top Cited Papers
- 22 March 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemistry
- Vol. 10 (4), 383-394
- https://doi.org/10.1038/s41557-018-0021-z
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.Keywords
This publication has 150 references indexed in Scilit:
- Nickel-Catalyzed Enantioselective Cross-Couplings of Racemic Secondary Electrophiles That Bear an Oxygen Leaving GroupJournal of the American Chemical Society, 2012
- Catalytic Asymmetric γ-Alkylation of Carbonyl Compounds via Stereoconvergent Suzuki Cross-CouplingsJournal of the American Chemical Society, 2011
- Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl ChloridesJournal of the American Chemical Society, 2011
- Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guideChemical Science, 2010
- Asymmetric Alkyl−Alkyl Cross-Couplings of Unactivated Secondary Alkyl Electrophiles: Stereoconvergent Suzuki Reactions of Racemic Acylated HalohydrinsJournal of the American Chemical Society, 2010
- Diamine ligands in copper-catalyzed reactionsChemical Science, 2010
- Nickel/Bis(oxazoline)-Catalyzed Asymmetric Kumada Reactions of Alkyl Electrophiles: Cross-Couplings of Racemic α-BromoketonesJournal of the American Chemical Society, 2010
- Suzuki−Miyaura Coupling of Aryl Carbamates, Carbonates, and SulfamatesJournal of the American Chemical Society, 2009
- The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as LigandsAccounts of Chemical Research, 2008
- Biaryl Phosphane Ligands in Palladium‐Catalyzed AminationAngewandte Chemie-International Edition, 2008