Visible-Light Photoredox and Energy-Transfer Catalysis: Strategies for C–C Bond Formation and Bioisosteric Scaffold Development for Drug Discovery

Dey, Purusattam (2025) Visible-Light Photoredox and Energy-Transfer Catalysis: Strategies for C–C Bond Formation and Bioisosteric Scaffold Development for Drug Discovery. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Purusattam Dey (19RS071)) 19RS071.pdf - Submitted Version Restricted to Repository staff only Download (27MB)

Abstract

Synthetic chemistry has been at the core of some of the biggest developments in contemporary society, such as agrochemicals and life-saving medications to high-performance materials that power industry and technology. Creating processes that are not just economical and efficient but also environmentally conscious and sustainable is a shared objective among chemists in both academic and industry contexts. With the increasing focus on green chemistry and eco-friendly technology, striking this balance has emerged as one of the field's main problems. Photochemistry has shown to be an effective tool in this endeavour. Researchers may create intricate, highly functional molecules in a mild environment and unlock reactivity that is frequently unavailable through traditional methods by employing light to drive chemical reactions. However, because most organic compounds are unable to directly absorb visible light, photochemistry has mostly relied on ultraviolet (UV) light for a large portion of its history. Despite their effectiveness, UV-driven reactions presented practical challenges, including the requirement for sophisticated photoreactors, high energy consumption, safety issues with high-energy radiation, and challenges with industrial scaling up. The landscape has changed as visible-light photocatalysis has become more prevalent. This method uses safe, low-energy visible light—typically sunlight itself—in conjunction with trace amounts of photocatalysts to initiate chemical reactions rather than harsh UV radiation. As a result, synthetic chemists now have access to a wider range of tools and a cleaner, safer, and more sustainable substitute that adheres to the ideas of green chemistry. This thesis explores the development of photoredox catalysis visible-light-mediated photoredox catalytic strategies for assembling pharmaceutically significant molecular frameworks, with an emphasis on C─C bond formation and design of bioisosteric motifs. This thesis divided into five chapters which are briefly discussed below- Chapter I: Introduction of Photoredox Catalysis This chapter introduces the principles and evolution of visible-light photoredox catalysis, highlighting how it transformed from a niche UV-dependent process into a versatile tool for modern organic synthesis. The fundamental mechanistic pathways, including single-electron transfer (SET) and energy transfer (EnT), are discussed in detail, along with their distinct modes of substrate activation. The chapter also explores recent advances in synergistic systems such as dual photoredox/nickel catalysis and photoredox/Lewis acid catalysis, which have expanded the scope of bond constructions under mild and sustainable conditions. It also focuses on the evolution of EnT catalysis, highlighting its applications in [2+2] photocycloaddition reactions for building strained architectures and strain-release processes for accessing otherwise challenging scaffolds. Chapter II: Dicarbofunctionalizations of an Unactivated Alkene via Photoredox/Nickel Dual Catalysis The 1,2-dicarbofunctionalization of unactivated alkenes has been achieved through dual photoredox/nickel catalysis. Owing to the mild conditions provided by visible-light activation, this method tolerates a wide range of alkyl and aryl electrophiles, even in the presence of sensitive functional groups. The strategy has also been successfully employed for the late-stage modification of pharmaceuticals and bioactive molecules. Mechanistic studies highlighted the crucial roles of photoredox–nickel cooperation and α-amino-radical-driven halogen atom transfer (XAT), while also offering insights into the nickel intermediates formed during the catalytic cycle. Chapter III: Introduction to the Bioisosteres This chapter introduces the concept of bioisosterism, a fundamental strategy in medicinal chemistry applied to fine-tune biological activity and optimize drug-like characteristics. The chapter differentiates between classical bioisosteres, which rely on substituting atoms or functional groups with comparable size, geometry, and electronic properties, and non-classical bioisosteres, which extend beyond traditional replacements by incorporating greater structural and three-dimensional diversity. Particular focus is placed on sp³-enriched frameworks, such as bicyclo[2.1.1]hexanes (BCHs), which are gaining recognition as substitutes for flat aromatic systems like benzene or phthalimide. These rigid, saturated scaffolds are shown to enhance physicochemical profiles, boost metabolic stability, and broaden accessible chemical space in drug discovery. Literature examples are discussed to illustrate the practical value of these motifs in the design of next-generation therapeutic agents. This overview provides the foundation for the thesis, which explores the use of photoredox-catalyzed methods to create novel bioisosteric architectures with pharmaceutical potential. Chapter IV: Energy Transfer Mediated [2π + 2σ] Photocycloaddition of Bicyclo[1.1.0]butanes with Maleimides: Formation of Potential Bioisostere of Phthalimide The replacement of flat aromatic rings with three-dimensional, sp³-enriched cage-like scaffolds has emerged as a powerful approach in medicinal chemistry to enhance the physicochemical characteristics and pharmacokinetic behavior of lead compounds. In this work, a [2π + 2σ] cycloaddition reaction between maleimides and bicyclo[1.1.0]butanes (BCBs) is reported, enabling the construction of succinimide-fused BCHs, which serve as promising bioisosteric alternatives to phthalimides. The visible-light-driven photochemical process proceeds with excellent yields, broad tolerance toward diverse functional groups, and scalability. Furthermore, the straightforward derivatization of the resulting products underscores their value in generating 3D phthalimide mimics. Mechanistic investigations, including cyclic voltammetry, luminescence quenching, and control studies, support a pathway consistent with visible-light energy transfer. Chapter V: Photoredox/Lewis Acid Mediated Enantioselective Synthesis of Bicyclo[2.1.1]hexanes: a Benzene Bioisosteres Increasing the proportion of sp³ carbons together with the introduction of stereocenters contributes to greater molecular complexity, which is frequently linked to improved prospects in drug discovery. Within this framework, three-dimensional (3D) bridged scaffolds have attracted significant interest in medicinal chemistry. In particular, BCHs are emerging as valuable 3D bioisosteres for benzene. However, efficient strategies for accessing enantioenriched, highly substituted BCH derivatives remain limited. Here, we report a synergistic photoredox–Lewis acid catalytic system that enables a [2σ + 2π] cycloaddition between BCBs and olefins, affording BCHs in excellent yields and enantioselectivities (up to 98% yield, 99% ee). The reaction employs a chiral Feng ligand and a lanthanide salt as a Lewis acid. The mild, versatile method tolerates various functional groups, avoids carbocation-related side reactions, and enables easy product transformation. Mechanistic studies reveal the cooperative interplay between photoredox activation and Lewis acid catalysis in generating reactive radical intermediates, underscoring the potential of this strategy for constructing complex, chiral bioisosteres relevant to pharmaceutical development.

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