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. 2023 May 22;14(6):853–859. doi: 10.1021/acsmedchemlett.3c00118

Enabling Deoxygenative C(sp2)-C(sp3) Cross-Coupling for Parallel Medicinal Chemistry

Wei Liu †,*, James Mulhearn †,*, Bo Hao †, Santiago Cañellas ‡, Stefaan Last §, José Enrique Gómez ‡, Alexander Jones §, Alexander De Vera †, Kiran Kumar †, Raquel Rodríguez ‡, Lars Van Eynde §, Iulia I Strambeanu †, Scott E Wolkenberg †
PMCID: PMC10258906  PMID: 37312855

Abstract

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Herein we report the development of an automated deoxygenative C(sp2)-C(sp3) coupling of aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among the most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox deoxygenative coupling is becoming a promising strategy to form C(sp2)-C(sp3) bond, the reaction setup limits its widespread application in library synthesis. To achieve high throughput and consistency, an automated workflow involving solid-dosing and liquid-handling robots has been developed. We have successfully demonstrated this high-throughput protocol is robust and consistent across three automation platforms. Furthermore, guided by cheminformatic analysis, we examined alcohols with comprehensive chemical space coverage and established a meaningful scope for medicinal chemistry applications. By accessing the rich diversity of alcohols, this automated protocol has the potential to substantially increase the impact of C(sp2)-C(sp3) cross-coupling in drug discovery.

Keywords: fraction Csp3, deoxygenative coupling, parallel medicinal chemistry, automation

Small molecule drug candidates with flat structures and high fractions of sp2-hybridized C atoms have increased development attrition, driven by poor pharmaceutical properties and off-target activity.1,2 As a result, an increasing fraction Csp3 has become a widespread strategy to enhance solubility and selectivity (Figure 1).1−4 From a synthetic standpoint, the high aromatic ring count in drug candidates can be partly attributed to the widespread adoption of Suzuki-Miyaura coupling by medicinal chemists.5−9 The robust and uniform conditions of Suzuki-Miyaura coupling and the wide availability of the required building blocks have greatly enabled high-throughput library synthesis and extensive exploration of C(sp2) chemical space. On the contrary, challenges associated with C(sp2)-C(sp3) cross-coupling have resulted in a much slower uptake by pharmaceutical industry,10−15 despite significant advances in last 10 years, particularly in base-metal catalysis16,17 and photoredox chemistry.18,19

Figure 1.

Figure 1

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(A) Evaluation of existing C(sp2)-C(sp3) cross-coupling. (B) Desired C(sp2)-C(sp3) cross-coupling for PMC.

Parallel medicinal chemistry (PMC) enables rapid optimization of a hit or lead compound via high-throughput analogue synthesis and iterative design-make-test-analyze (DMTA) cycle. To enable this approach, a highly robust synthetic method with uniform reaction setup and wide reagent availability is required.20 Several analyses of the synthetic methods used in PMC have shown that C-C bond formation is dominated by the Suzuki-Miyaura coupling.5−9 In contrast, C(sp2)-C(sp3) cross-couplings in PMC have been limited due to lower reaction generality, requiring the development of substrate-specific reaction conditions in multiple rounds of reaction optimization.10−15 In a recent elegant study by Abbvie evaluating state-of-the-art C(sp2)-C(sp3) couplings, seven catalytic conditions with five classes of commercial building blocks were examined for their applicability in medicinal chemistry (Figure 1A).12 While chemical space coverage could be achieved with multiple conditions and building block classes, a uniform condition was not identified to deliver a high synthesis success rate with a single widely available building block class. Therefore, it remains an important goal to develop novel synthetic methods that enable C(sp2)-C(sp3) coupling using a diverse reagent pool with a broad substrate scope (Figure 1B).

In PMC, the diversity of synthesized compounds is directly linked to the chemical space of building blocks being utilized.21−24 Therefore, in considering a synthetic method for library synthesis, the availability and chemical diversity of its reagent pool becomes imperative.21−24 We conducted cheminformatic analysis on common alkyl precursors for C(sp2)-C(sp3) coupling reported in literature including boronates, trifluoroborate salts, alkyl halides (from which organozinc reagents may be derived), carboxylic acids and alcohols (Figure 2A).25,26 Specifically, t-distributed stochastic neighbor embedding (t-SNE) dimensionality reduction of the first 50 principal components using 512-bit Morgan fingerprint descriptors was employed to quantify structural similarities and visualize the commercially accessible chemical space for each sp3 building block.27−29 As shown in Figure 2A, alkyl boronates, including potassium trifluoroborate salts, are commercially available in limited numbers and represent limited chemical diversity. A significant number of alkyl halide building blocks are commercially available, but there are significant gaps in their chemical space coverage. On the contrary, both carboxylic acids and alcohols display high commercial availability (∼14,000 alcohols and ∼17,000 carboxylic acids)30 and wide chemical diversity, rendering both optimal building blocks for introducing chemically diverse Csp3 character.

Figure 2.

Figure 2

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(A) Chemical space and diversity analysis of sp3 building blocks. (B) A recently reported deoxygenative coupling reaction. (C) Automated deoxygenative C(sp2)-C(sp3) cross-coupling.

Recently, the MacMillan group reported a novel metallaphotoredox-enabled deoxygenative C(sp2)-C(sp3) coupling of aryl bromides and alcohols.31 Recognizing the vast number and chemical diversity of alcohol building blocks, the authors developed this innovative method and characterized its performance using uniform conditions, a broad scope of drug-like substrates, and a wide range of primary, secondary, tertiary, benzylic, and basic amine containing alcohol building blocks (Figure 2B).31 Our initial experience applying this methodology in parallel medicinal chemistry confirmed its potential to dramatically improve the synthesis of high Csp3 drug candidates, but the reaction setup proved labor-intensive and time-consuming. In addition, and presenting a greater challenge for high-throughput synthesis, the alcohols need to undergo in situ activation followed by filtration and addition of the filtrate to a stock solution of the remaining reactants. To maximize conversion, these manipulations must be conducted under an inert atmosphere.31

Automated solid-dosing robots and liquid handlers have successfully addressed similar challenges across a range of reactions, performing repetitive tasks and delivering high reproducibility.32−34 We became interested in developing an automated workflow to enable deoxygenative C(sp2)-C(sp3) coupling for parallel medicinal chemistry (Figure 2C).35,36 We envisioned the weighing and dosing of the deoxazole reagent could be achieved by solid-dispensing robotics and the complex sequence of liquid addition/transfer, vortex and filtration could be accomplished by automated liquid handlers. By housing the robotics inside a purge box, the reaction yields would be maximized without the need for manual setup, filtration, liquid transfer or solvent sparging.

Validation studies used methyl 5-bromopicolinate 1 and 1-Boc-3-hydroxypiperidine 2 as model substrates in a 24-well plate format (Table 1). Solid dispensing was performed using the Chronect Quantos and liquid handling and filtration was carried out using an Unchained Laboratories (UL) Junior robotic system housed inside a nitrogen purge box (O2 level <20 ppm). Due to dead volume considerations of liquid transfer by robots, 3.5 equiv of alcohol, which is usually the less costly and more abundant coupling partner, proved optimal. Using the UL Junior to automate the reaction manipulations described in the original deoxygenative coupling publication,31 the 24-well plate delivered highly consistent results with an average 89% yield and standard deviation of 0.7%. This demonstrated the reproducibility of the automated workflow and increased confidence in pursuing subsequent scope studies. Notably, the whole sequence on UL Junior was completed in ∼1 h, whereas manual work to execute a 24-compound library synthesis in the purge box would take ∼3 h, underscoring the efficiency of automation with high precision.

Table 1. Cross-Platform Validation of Automated Workflowa.

graphic file with name ml3c00118_0004.jpg

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a

Yield determined by UPLC analysis on reaction crude.

With a validated automation workflow in hand, we examined the applicability of the deoxygenative coupling in the context of PMC. To benchmark, we selected 24 alcohols that contain the identical alkyl fragments evaluated in the Abbvie study (vide supra) across different C(sp2)-C(sp3) coupling conditions (Table 2).12 Using only one uniform automated deoxygenative coupling condition, 18 out of 24 alcohols yielded satisfactory results (>10% isolated yield). With a larger reagent pool, the deoxygenative coupling provided comparative yields and functional group tolerance as the other cross-coupling reactions, with primary, secondary, and primary benzylic alcohols using a single method. Limitations in substrate scope are consistent with prior reports: for example, basic amines are challenging substrates for nickel photoredox chemistry (A12), α-oxy and α-amino alcohols were low yielding (A22) and tertiary (A24) or secondary benzylic (A10) C(sp3) centers were challenging.

Table 2. A Comprehensive Evaluation of sp3 Space Coverage by Automated Deoxygenative C(sp2)-C(sp3) Cross-Couplinga.

graphic file with name ml3c00118_0005.jpg

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a

Isolated yields. Reaction performed on UL Junior system. See Supporting Information for detailed protocol and reaction condition.

b

17% yield with manual setup.

c

Primary alcohol was reacted.

d

Product isolated as the boronic acid.

e

Secondary alcohol was reacted.

The ease and throughput of our automated protocol prompted us to examine alcohols with more chemical space coverage to establish an expanded scope for medicinal chemistry applications. Using t-SNE analysis, we visualized the chemical space covered by previously examined alkyl fragments (represented as blue dots in Table 2) and mapped out space that has not been explored in C(sp2)-C(sp3) coupling before. Within this space, we selected 48 alcohol building blocks (represented by orange dots in Table 2) based on drug-likeness (heterocycles, hydrogen-bond donors/acceptors, lipophilicity) and functional group diversity (nitrile, ketone, protic groups) to probe the performance of the automated deoxygenative coupling. The synthesis success rate was high, with 32 out of 48 alcohols yielding satisfactory results (>10% isolated yield). A variety of heterocycles and functional groups were successfully tolerated such as pyridine, imidazole, pyrazole, amide, ketone, aldehyde, alcohol, boronate and nitrile. Notably, all secondary benzylic alcohols were unsuccessful coupling partners, despite extensive explorations (B41–B45). Hydroxyl groups that are α to carbonyl groups are also a low-yielding substrate class with the exception of β-lactam (B33). Furthermore, the coupling of tertiary alcohols to form quaternary centers was found to be challenging (B30, B38 and B46).

Because medicinal chemists have access to a variety of automation platforms, we validated the novel automated deoxygenative coupling on multiple systems (Table 1). The results are consistent across platforms: The new automated protocol provides consistent yields, dramatically accelerates the time-consuming manual manipulations, and provides high precision, reproducible data. Our validation study included these configurations: (1) Chronect Quantos (solid dispensing) + UL Junior (liquid handling), inert atmosphere; (2) Chronect Quantos (solid dispensing) + Tecan Freedom (liquid handling), ambient atmosphere; and (3) Chemspeed GDU (solid and liquid dispensing), inert atmosphere. Importantly, Tecan’s automated sequence was conducted outside the inert atmosphere without precautions to exclude moisture or oxygen, which only led to a small compromise of yield (avg. 5% lower). For the Chemspeed, a slow flow rate of liquid aspiration and dispense was found to be critical to ensure consistent distribution of stock solutions (see Supporting Information for detailed description of automation protocols).

To examine these automated protocols under PMC setting, a diverse set of alcohol building blocks encompassing primary, secondary, benzylic and tertiary alcohols was used in the automated deoxygenative coupling in all three automation platforms (Figure 3). Despite the significant differences in their operating environments, highly comparable results were observed across platforms, demonstrating the generality of the automated deoxygenative coupling (see Supporting Information for detailed results).

Figure 3.

Figure 3

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Cross-platform evaluation of the automated deoxygenative C(sp2)-C(sp3) coupling at Jansen Global Discovery Chemistry.

To further demonstrate the utility of the automated protocol, the aryl bromide reactant was varied. Ten complex, drug-like aryl bromides were selected to react with 2 alcohols in library format and automated on the UL Junior system (Table 3).37 Eight of 10 aryl bromides furnished product in synthetically useful yields (average 50% isolated), tolerating a wide range of functional groups and nitrogen-rich heterocycles. These results, along with our experience applying the automated deoxygenative coupling on medicinal programs at Janssen, increase confidence in the wide applicability of the automated protocol. Additionally, we also found that the scale-up of this reaction can be enabled by flow photoreactor, furnishing gram quantity of C(sp3)-coupled product in one run (0.6 mmol/h, see Supporting Information).

Table 3. PMC Library of Aryl Bromide in Automated Deoxygenative C(sp2)-C(sp3) Couplinga.

graphic file with name ml3c00118_0006.jpg

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a

Isolated yields.

To conclude, we have successfully developed an automated protocol to achieve C(sp2)-C(sp3) coupling of aryl bromide with alcohols for PMC. This study establishes the advantage of using automation to achieve operationally challenging synthetic transformations with improved throughput and consistency. Despite differences in automation technologies, our high-throughput protocol is robust and consistent across various robotic platforms. By harnessing the rich diversity of alcohol building blocks, this automated deoxygenative coupling protocol has the potential to dramatically increase the impact of C(sp2)-C(sp3) cross-coupling in drug discovery. For future applications, the consistency of this automated workflow opens the door to conducting high-throughput experimentation on the deoxygenative coupling, which may dramatically accelerate the discovery of new conditions to enable challenging substrates. Furthermore, the high-quality data generated in this fashion could also be utilized in the artificial intelligence/machine learning model for reaction prediction.38−40

Acknowledgments

We thank Dr. Christopher Reiher and Dr. Peter Buijnsters for helpful discussions. We thank Dr. Fan Huang for help in obtaining HRMS data.

Glossary

Abbreviations

DMA

dimethylacetamide

DMTA

design, make, test, analyze

GDU

gravimetric dispensing units

MIDA

methyliminodiacetic acid

PMC

parallel medicinal chemistry

t-SNE

t-distributed stochastic neighbor embedding

UPLC

ultraperformance liquid chromatography

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00118.

  • General information, experimental procedures, and characterization data (PDF)

  • Automation protocol and scripts for Junior, Tecan and Chemspeed (PDF)

Author Contributions

# These authors contributed equally.

The authors declare no competing financial interest.

Dedication

The authors dedicate this work to the memory of our colleague and mentor, Pei-Pei Kung.

Supplementary Material

ml3c00118_si_001.pdf (4.3MB, pdf)
ml3c00118_si_002.pdf (2.8MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Citations

  1. Based on Enamine building block collection. https://enamine.net/building-blocks (accessed October 2022).

Supplementary Materials

ml3c00118_si_001.pdf (4.3MB, pdf)
ml3c00118_si_002.pdf (2.8MB, pdf)

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