Synthetic Access to Stable Atropisomers in Drug Discovery via Catalysis

Drug candidates exhibiting atropisomerism are often considered challenging for development by pharmaceutical professionals from synthetic and regulatory perspectives. Molecules that exist as stable atropisomers can be acceptable for development, but are often difficult to synthesize in their isomerically pure form. Modern catalysis, chromatographic separation, and crystallographic resolution methods have made atropisomeric drugs more accessible on scale as single isomers. This minireview highlights recent examples of drug candidates existing as single isomers and approaches to their synthesis.

Examples of Configurationally-Stable Atropisomers Among Drugs and Drug Candidates

Today there are only four FDA-approved drugs that exist as configurationally stable atropisomers: vancomycin (1988), colchicine (2009), lesinurad (2015, discontinued), and most recently, sotorasib (2021). Although sotorasib is the only marketed, synthetic drug today that exists as a stable atropisomer, axially chiral molecules are increasingly common in medicinal chemistry thanks to modern advances in cross-coupling technologies enabling complex C-C, C-N, and C-O bond formations. A selection of recent drug candidates that exist as stable atropisomers are shown below in Figure 1.

How are Stable Atropisomers Synthesized?

Identification and testing of stable atropisomers in medicinal chemistry have also been made simpler by the introduction of chiral HPLC and SFC chromatography, which enable the rapid separation and purification of configurationally stable atropisomers. On a larger scale, alternative methods such as chiral salt resolution, kinetic resolution, or asymmetric catalysis are required. Highlights from the routes to each of the six molecules from Figure 1 are shown below, in Figure 2.

Sotorasib, Amgen’s KRAS^G12C inhibitor, has a C-N stereogenic axis and is prepared on scale via a chiral salt resolution of an intermediate. MRTX1719, Mirati’s PRMT5 inhibitor and a January 2022 Molecule of the Month, has a C-C stereogenic axis and has been prepared by a dynamic kinetic resolution process involving crystallization in a batch-flow process. 

BMS-986142, Bristol Myers Squibb’s reversible BTK inhibitor with two stereogenic axes, has been prepared through an impressive route on kilo-scale involving diastereoselective cross-coupling and diastereoselective heterocycle synthesis. JDQ443, Novartis’s Ph. III KRAS^G12C inhibitor and an April 2022 Molecule of the Month, has a C-C stereogenic axis and was initially prepared by chiral chromatography, though its clinical supply route is undisclosed. RP-6306, Repare’s PKMYT1 inhibitor and a July 2022 Molecule of the Month, has an unusual C-N axis between a phenol and an indole, and was separated by SFC. ZM374979, a neurokinin agonist, has a C-C arylamide stereogenic axis and was isolated by crystallization.

One particularly impressive transformation is explored in more detail below.

Atropselective Cross-Coupling in the Kilo-Scale Synthesis of BMS-986142

In the synthesis of BMS-986142, a palladium-catalyzed cross-coupling was used between a chiral intermediate and a boronic acid. Coupling mediated by an achiral catalyst (Pd(dppf)Cl₂) led to limited selectivity in product formation (atropdiastereomeric ratio of 1.4 : 1). Chiral ligand screening showed improvements in dr using chiral ligands such as (S)-Xyl-SDP and (S)-Ph-SDP (Figure 3), though these are extremely expensive on scale. Optimization with (R)-BINAP was therefore pursued instead. By lowering the reaction temperature to 5 ºC and including a MeOH cosolvent to improve boronic acid solubility, the desired product was formed in 16 : 1 dr. Crystallization from n-BuOH resulted in isolation of the desired compound in 87% yield with a 65 : 1 dr. This example highlights the power of modern catalytic methods in the preparation of single atropisomers as complex as BMS-986142.

Harness the Potential of Atropisomers

As the BMS example shows, catalysts can play a critical role in controlling selectivity and accessing axially chiral molecules. Catalyst control over the selectivity of atropisomer-forming reactions has been an area of significant research and advancement, though commercial access to catalysts has been cited as a barrier to advancement. Interestingly, on the same day this article was first published, Genentech disclosed an atropselective Negishi coupling en route to its KRAS(G12C) clinical candidate, GDC-6036 in JACS, highlighting what is possible with modern catalysts and screening methodologies.

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Further Reading

• Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers
• Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS^G12C: Structural, Analytical, and Synthetic Considerations
• Atropisomerism in medicinal chemistry: challenges and opportunities
• A twist of nature – the significance of atropisomers in biological systems
• Adventures in Atropisomerism: A Case Study from BMS
• The Challenge of Atropisomerism in Drug Discovery
• Synthesis of Atropisomers by Transition-Metal-Catalyzed Asymmetric C−H Functionalization Reactions
• Recent Advances in Catalytic Asymmetric Construction of Atropisomers
• Atropisomers beyond the C–C axial chirality: Advances in catalytic asymmetric synthesis