Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical Cyclization: Application in the Synthesis of ent‐Tadalafil

Chiu, Wei Jung; Lin, Yan; Barve, Indrajeet J.; Sun, Ching Cherng

doi:10.1002/adsc.202100506

Cited by 3 publications

(2 citation statements)

References 32 publications

(49 reference statements)

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“…The tetrahydroisoquinoline 6‐ cis ( 61.5 ) was ultimately formed by hydrogen atom abstraction from n ‐Bu 3 SnH (Scheme 62). High regio‐ and stereoselectivity towards the synthesis of key tetrahydroisoquinoline structural core marks the admirable translational potential of the discussed synthetic procedure [190] …”

Section: Radical Chemistry In Total Synthesis Of Pharmaceuticalsmentioning

confidence: 99%

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Growing Utilization of Radical Chemistry in the Synthesis of Pharmaceuticals

Gupta

Laha

2023

The Chemical Record

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Our current unhealthy lifestyle and the exponential surge in the population getting affected by a variety of diseases have made pharmaceuticals or drugs an imperative part of life, making the development of innovative strategies for drug discovery or the introduction of refined, cost‐effective and modern technologies for the synthesis of clinically used drugs, a need of the hour. Ever since their discovery, free radicals and radical cations or anions as reactive intermediates have captivated the chemists, resulting in an exceptional utilization of these moieties throughout the field of chemical synthesis, owing to their unprecedented and widespread reactivity. Sticking with the idea of not judging the book by its cover, despite the conventional thought process of radicals being unstable and difficult to control entities, scientists and academicians around the globe have done an appreciable amount of work utilizing both persistent as well as transient radicals for a variety of organic transformations, exemplifying them with the synthesis of significant biologically active pharmaceutical ingredients. This review truly accounts for the organic radical transformations including radical addition, radical cascade cyclization, radical/radical cross‐coupling, coupling with metal‐complexes and radical cations coupling with nucleophiles, that offers fascinating and unconventional approaches towards the construction of intricate structural frameworks of marketed APIs with high atom‐ and step‐economy; complementing the otherwise employed traditional methods. This tutorial review presents a comprehensive package of diverse methods utilized for radical generation, featuring their reactivity to form critical bonds in pharmaceutical total synthesis or in building key starting materials or intermediates of their synthetic journey, acknowledging their excellence, downsides and underlying mechanisms, which are otherwise poorly highlighted in the literature. Despite great achievements over the past few decades in this area, many challenges and obstacles are yet to be unraveled to shorten the distance between the academics and the industry, which are all discussed in summary and outlook.

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Section: Radical Chemistry In Total Synthesis Of Pharmaceuticalsmentioning

confidence: 99%

“…High regio-and stereoselectivity towards the synthesis of key tetrahydroisoquinoline structural core marks the admirable translational potential of the discussed synthetic procedure. [190] Scheme 60. Laha's decarboxylative synthesis of sildenafil from aryl acetic acid.…”

Section: Synthesis Of Sildenafilmentioning

confidence: 99%

Growing Utilization of Radical Chemistry in the Synthesis of Pharmaceuticals

Gupta

Laha

2023

The Chemical Record

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Design, Synthesis, and Biological Evaluation of Tetrahydro‐α‐carbolines as Akt1 Inhibitors That Inhibit Colorectal Cancer Cell Proliferation

Huang

et al. 2022

ChemMedChem

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A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3 + 3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1Hpyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.

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