Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir

Yayla, Hatice G.; Peng, Feng; Mangion, Ian; McLaughlin, Mark; Campeau, Louis Charles; Davies, Ian W.; DiRocco, Daniel A.; Knowles, Robert R.

doi:10.1039/c5sc03350k

Cited by 112 publications

(119 citation statements)

References 83 publications

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“…92–94 This method appears to be the most promising avenue for conducting visible-light reactions at a preparative scale on complex substrates, as shown by a series of pioneering examples by Merck, most notably for the synthesis of elbasvir. 95 Following this general template, we constructed our reactor within the design principles of low cost, easy construction from commercially available parts, and that it should fit within a standard walk-in fume hood. 96 The reactor consisted of blue LED lights contained within a glass beaker wrapped with a single layer of perfluoroalkoxy (PFA) tubing (1.6 mm inner diameter) around the outside, giving a volume of approximately 150 mL (Figure 3A, see also Figures S1 and S2).…”

Section: Resultsmentioning

confidence: 99%

Photochemical Perfluoroalkylation with Pyridine N -Oxides: Mechanistic Insights and Performance on a Kilogram Scale

Beatty

Douglas

Miller

et al. 2016

Chem

243

160

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SUMMARY The direct trifluoromethylation of (hetero)arenes is a process of high importance to the pharmaceutical industry. Many reagents exist for this purpose and have found widespread use in discovery efforts; however, the step-intensive preparation of these reagents and their corresponding cost have resulted in minimal use of these methods in large-scale applications. For the ready transition of direct trifluoromethylation methodologies to large-scale application, the further development of processes utilizing inexpensive CF3 sources available on a metric ton scale is highly desirable. We report the use of pyridine N-oxide derivatives in concert with trifluoroacetic anhydride to promote a high-yielding and scalable trifluoromethylation reaction. Key mechanistic insights include the observation of electron donor-acceptor complexes in solution as well as a high dependence on photon flux. These observations have culminated in the application of this chemistry on a kilogram scale, demonstrating the utility of this reagent combination for preparative applications.

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Section: Resultsmentioning

confidence: 99%

Photochemical Perfluoroalkylation with Pyridine N -Oxides: Mechanistic Insights and Performance on a Kilogram Scale

Beatty

Douglas

Miller

et al. 2016

Chem

243

160

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“…The reaction was also scaled up to 100 g scale in batch and, although the reaction took 62 h, a 35% yield of the desired product was still obtained (vs 57% yield on 18 g scale). More recently, the Knowles group has collaborated with scientists at Merck to develop a photocatalytic dehydrogenation protocol for the synthesis of elbasvir, a NS5A antagonist for the treatment of hepatitis C. 170 Through these studies, a photoredox-mediated method was developed which enabled a high yield of indole 93 to be obtained with no erosion in the enantiopurity of the product (Scheme 36b). Mechanistic studies indicated that this reaction proceeds via a radical chain mechanism.…”

Section: Applications Of Photoredox Catalysismentioning

confidence: 99%

Photoredox Catalysis in Organic Chemistry

2016

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In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon–carbon and carbon–heteroatom bonds.

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“…13,14 Reactors of this type have been applied across academia and industry with excellent success for gram-scale reactions. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] However, extension of these plug flow reactors to kilogram-scale production remains a significant challenge. One approach that has been pursued involves increasing the number of identical reactors operating in parallel, thereby increasing the overall throughput.…”

mentioning

confidence: 99%

A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light

Harper¹,

Moschetta²,

Bordawekar³

et al. 2018

Preprint

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Visible light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multi-kilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer-Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.

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Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir

Abstract: Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C.

Cited by 112 publications

References 83 publications

Photochemical Perfluoroalkylation with Pyridine N -Oxides: Mechanistic Insights and Performance on a Kilogram Scale

Photochemical Perfluoroalkylation with Pyridine N -Oxides: Mechanistic Insights and Performance on a Kilogram Scale

Photoredox Catalysis in Organic Chemistry

A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light

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