Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters

Zhang, Yu An; Palani, Vignesh; Seim, Alexander E.; Wang, Yong; Wang, Kathleen J.; Wendlandt, Alison E.

doi:10.1126/science.add6852

Cited by 47 publications

(21 citation statements)

References 87 publications

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“…LSF has become a loosely defined, catch-all term that is widely used in the chemistry literature. − For the purpose of this Review, we define LSF reactions as those where C–H bonds of structurally complex molecules, which would typically be considered unreactive, are functionalized with an excellent level of chemoselectivity without the need for the introduction of a functional group to enable the transformation. It should be acknowledged that there are recently developed methodologies that could be considered LSF that are not C–H functionalizations; − however, these are beyond the scope of this Review.…”

Section: Introductionmentioning

confidence: 99%

Late-stage Functionalization for Improving Drug-like Molecular Properties

Castellino,

Montgomery,

Danon

et al. 2023

Chem. Rev.

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The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field of organic synthesis. Over the past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for the drug discovery process to become more efficient. Most reported applications of late-stage C–H functionalization of drugs and drug-like molecules have been to rapidly diversify screening libraries to explore structure–activity relationships. However, there has been a growing trend toward the use of LSF methodologies as an efficient tool for improving drug-like molecular properties of promising drug candidates. In this review, we have comprehensively reviewed recent progress in this emerging area. Particular emphasis is placed on case studies where multiple LSF techniques were implemented to generate a library of novel analogues with improved drug-like properties. We have critically analyzed the current scope of LSF strategies to improve drug-like properties and commented on how we believe LSF can transform drug discovery in the future. Overall, we aim to provide a comprehensive survey of LSF techniques as tools for efficiently improving drug-like molecular properties, anticipating its continued uptake in drug discovery programs.

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Section: Introductionmentioning

confidence: 99%

Late-stage Functionalization for Improving Drug-like Molecular Properties

Castellino,

Montgomery,

Danon

et al. 2023

Chem. Rev.

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“…To demonstrate this, we analyzed a reaction recently reported by Wendlandt and colleagues, which focused on the epimerization of unactivated stereogenic methine C−H bonds (Scheme 2). 37 In their original study, the epimerization process was proposed to proceed through a non-degenerate HAT−HAT mechanism facilitated by two distinct HAT catalysts: a photo-excited state of a decatungstate polyanion and 4-chlorothiophenol, which is generated in situ. This non-degenerate HAT/HAT process was proposed to be the exclusive mechanism for epimerization since alternative steps could be discounted on thermochemical grounds.…”

Section: ■ Introductionmentioning

confidence: 99%

Isotopic Fractionation as a Mechanistic Probe in Light-Driven C–H Bond Exchange Reactions

Qiu

Knowles

2023

J. Am. Chem. Soc.

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Here, we report a diagnostic framework for elucidating the mechanisms of photoredox-based hydrogen isotope exchange (HIE) reactions based on hydrogen/deuterium (H/D) fractionation. Traditional thermal HIE methods generally proceed by reversible bond cleavage and bond reformation steps that share a common transition state. However, bond cleavage and bond reformation in light-driven HIE reactions can proceed via multiple, non-degenerate sets of elementary steps, complicating both mechanistic analysis and attendant optimization efforts. Building on classical treatments of equilibrium isotope effects, the fractionation method presented here extracts information regarding the nature of the key bond-forming and bond-breaking steps by comparing the extent of deuterium incorporation into an exchangeable C−H bond in the substrate relative to the H/D isotopic ratio of a solvent reservoir. We show that the extent of fractionation is sensitive to the mechanism of the exchange process and provides a means to distinguish between degenerate and non-degenerate mechanisms for isotopic exchange. In model systems, the mechanisms implied by the fractionation method align with those predicted by thermochemical considerations. We then employed the method to study HIE reactions whose mechanisms are ambiguous on thermodynamic grounds.

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“…Similarly, the alkaloid cyclopamine ( 4 ) promotes the cyclopia phenotype in developing zebrafish embryos, while its skeletal isomer cyclopamine A ( 5 ) is functionally inactive . While methods for the selective late-stage isomerization − of small molecules have become increasingly important in this regard, synthetic processes that enable both the positional and skeletal isomerism of carbocyclic frameworks remain rare and underexplored . Such reactions pose a significant challenge because they often require inert covalent bonds (carbon-carbon) to be selectively broken and reformedeffectively shuffling the connectivity of core atoms in a molecule.…”

Section: Introductionmentioning

confidence: 99%

A Shapeshifting Roadmap for Polycyclic Skeletal Evolution

Sanchez,

Gurajapu,

Guo

et al. 2023

J. Am. Chem. Soc.

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Polycyclic ring systems are ubiquitous three-dimensional (3D) structural motifs central to the function of many biologically active small molecules and organic materials. Indeed, subtle changes to the overall molecular shape and connectivity of atoms in a polycyclic framework (i.e., isomerism) can drastically alter its function and properties. Unfortunately, direct evaluation of these structure−function relationships typically requires the development of distinct synthetic strategies toward a specific isomer. Dynamic, "shapeshifting" carbon cages present a promising approach for sampling isomeric chemical space but are often difficult to control and are largely limited to thermodynamic mixtures of positional isomers about a single core scaffold. Here, we describe the development of a new shapeshifting C9-chemotype and a chemical blueprint for its evolution into structurally and energetically diverse isomeric ring systems. By leveraging the unique molecular topology of π-orbitals interacting through-space (homoconjugation), a common skeletal ancestor evolved into a complex network of valence isomers. This unusual system represents an exceedingly rare small molecule capable of undergoing controllable and continuous isomerization processes through the iterative use of just two chemical steps (light and organic base). Computational and photophysical studies of the isomer network provide fundamental insight into the reactivity, mechanism, and role of homoconjugative interactions. Importantly, these insights may inform the rational design and synthesis of new dynamic, shapeshifting systems. We anticipate this process could be a powerful tool for the synthesis of structurally diverse, isomeric polycycles central to many bioactive small molecules and functional organic materials.

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Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters

Cited by 47 publications

References 87 publications

Late-stage Functionalization for Improving Drug-like Molecular Properties

Late-stage Functionalization for Improving Drug-like Molecular Properties

Isotopic Fractionation as a Mechanistic Probe in Light-Driven C–H Bond Exchange Reactions

A Shapeshifting Roadmap for Polycyclic Skeletal Evolution

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