Cobalt Catalyzed Enantioselective Reductive Cross Coupling of π-Components

Maiti, Mamata (2025) Cobalt Catalyzed Enantioselective Reductive Cross Coupling of π-Components. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Mamata Maiti (20RS038)) 20RS038.pdf - Submitted Version Restricted to Repository staff only Download (35MB)

Abstract

Asymmetric synthesis, where a new stereogenic unit is created in a molecule, resulting in a preference for one enantiomer over another, is one of the most effective ways to meet the growing need for non-racemic small molecules for medicine and pharmacy, nutrition, or materials. It is both thrilling and difficult for a single chiral catalyst molecule to impart its chiral information to thousands of new chiral molecules in organic synthesis. Even though asymmetric catalysis is still developing and emerging field, synthetic chemists are creating more reactive and selective catalysts to satisfy the demands of both industry and academics. In this respect, transition metal-catalysed enantioselective synthesis is one of the extensive research area yet challenging. Specifically, transition metal-catalyzed asymmetric reductive coupling of two π-components has become a new sustainable method for molecular complexity because it enables the construction of densely functionalized sp² and sp³ carbon frameworks in a single step with a high atom economy using readily available and stable feedstocks. Different low-valent transition metals such as rhodium, iridium, palladium, ruthenium, and nickel are employed as catalysts. Recently, there has been a growing application of first-row transition metal specially cobalt in the enantioselective reductive coupling reactions due to its distinct reactivity, availability, low cost, and decreased toxicity. The use of configurationally labile organometallic species, such as organomagnesium and organozinc compounds, was the primary focus of early research into creating enantioselective transition-metal-catalyzed cross-coupling processes. They burden management and the economy by increasing the number of synthetic stages as well as the amount of metallic waste generated. In this regard, an other method for creating different chiral structures is to use reductive cross-coupling reactions that sacrifice a harmless reductant. Therefore, using cheap 3D metal to generate novel catalytic routes for asymmetric synthesis makes a process viable and opens up opportunities on other mechanistic fronts. In this case, alkyne–alkene reductive coupling proceeds through stable metallacyclopentene intermediates and is effective, especially with activated alkenes. The asymmetric reductive coupling between two alkenes, however, is rarely investigated since it involves a less stable non-planar five-membered metallacycle. The mechanism of low valent T.M catalysed reductive coupling of π-components involved light-mediated/reductant mediated/ electricity mediated low-valent cobalt(I) complex generation followed by oxidative ene-yne /ene-ene cyclometallation, and protonation. This thesis's main aim will be to explore cobalt catalysed asymmetric ene-yne and ene-ene reductive coupling in desymmetrization of various meso alkenes with high stereoselectivity. The main focus is to construct new carbon-carbon bonds in complex molecule with multiple stereocenters in a single step using different cobalt complexes in the presence of different chiral diphosphine ligands. This thesis is divided into four chapters, which are briefly discussed below. Chapter -1. Basic Ideas and Challenges in Cobalt-Catalyzed Reductive Cross-Coupling of π-Components This chapter outlines the fundamental principles of low-valent transition-metal-catalyzed reductive coupling of two π-components under reductive conditions. It traces the development of cobalt-catalyzed reductive coupling from its early emergence to the current state-of-the-art, highlighting both mechanistic advances and synthetic scope. Special emphasis is placed on its strategic application in asymmetric synthesis and the key challenges, such as controlling reactivity, selectivity, and stability of intermediates, that continue to drive research in this area. Chapter -2. Cobalt-Catalyzed Regio-, Diastereo-, and Enantioselective Reductive Coupling of Internal Alkynes with Cyclobutenes This chapter describes a cobalt-catalyzed asymmetric ene–yne reductive coupling strategy enabling the regio-, diastereo-, and enantioselective coupling of internal alkynes with nonpolar cyclobutenes, a class of substrates with inherently low reactivity and limited prior exploration. The methodology furnishes densely functionalized chiral vinyl cyclobutanes in high yields, with excellent stereocontrol (>99% ee, >20:1 dr, >20:1 E/Z) and >20:1 regioselectivity. Preliminary mechanistic studies indicate a pathway involving zinc-mediated generation of a low-valent cobalt(I) complex, followed by oxidative ene–yne cyclization and protonation as key steps. Chapter -3. Asymmetric Ene-ene Reductive Cross-coupling Reaction via Visible-light Photoredox/cobalt Dual Catalysis Oxa- and aza-bicyclic alkenes serve as versatile frameworks for constructing highly substituted ring systems with multiple stereocenters in a single transformation, leveraging their intrinsic reactivity. This chapter reports the desymmetrization of meso heterobicyclic alkenes, delivering up to five chiral centers in one step with high yields, diastereoselectivity, and enantioselectivity. The transformation employs a visible-light-mediated photoredox/cobalt dual-catalyzed asymmetric ene–ene reductive coupling of π-components, overcoming longstanding challenges in this domain. Chapter -4. Cobalt-Catalyzed Diastereo-, and Enantioselective Reductive Coupling of Activated Alkenes with Cyclopropenes This chapter presents a diastereo- and enantioselective approach to functionalized cyclopropenes derived from 3,3-disubstituted substrates bearing two diastereotopic faces and two enantiotopic vinylic carbons. Through visible-light-mediated cobalt-catalyzed asymmetric ene–ene reductive coupling, we achieve the desymmetrization of meso cyclopropenes, generating up to two stereocenters with excellent enantio- and diastereoselectivity.

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