Synthesis of an ORL-1 Receptor Antagonist via a Radical Bromination and Deoxyfluorination to Afford a <i>gem</i>-Difluorospirocycle

DeBaillie, Amy C.; Jones, Charles D.; Magnus, Nicholas A.; Mateos, Carlos; Torrado, Alicia; Wepsiec, James P.; Ramachandar, Tokala; Raje, Prasad

doi:10.1021/op5000094

Cited by 12 publications

(16 citation statements)

References 21 publications

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“…The reported route required just three steps to build the spirocyclic core 51 from alcohol 50 , but four additional operations were needed to incorporate the gem -difluoro motif, relying on 2.6 equiv of Deoxo-Fluor (Figure 12). 47 Circumventing this nonoptimal sequence could greatly increase material throughput for lead optimization and evaluation. Toward this end, we designed a photochemical radical Smiles rearrangement to generate difluorinated alcohol 53 , a substrate to be used in lieu of previous intermediate 50 .…”

Section: Targeting Pharmaceutically Relevant Scaffoldsmentioning

confidence: 99%

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

2016

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ConspectusHarnessing visible light as the driving force for chemical transformations generally offers a more environmentally friendly alternative compared with classical synthetic methodology. The transition metal-based photocatalysts commonly employed in photoredox catalysis absorb efficiently in the visible spectrum, unlike most organic substrates, allowing for orthogonal excitation. The subsequent excited states are both more reducing and more oxidizing than the ground state catalyst and are competitive with some of the more powerful single-electron oxidants or reductants available to organic chemists yet are simply accessed via irradiation. The benefits of this strategy have proven particularly useful in radical chemistry, a field that traditionally employs rather toxic and hazardous reagents to generate the desired intermediates.In this Account, we discuss our efforts to leverage visible light photoredox catalysis in radical-based bond-forming and bond-cleaving events for which few, if any, environmentally benign alternatives exist. Mechanistic investigations have driven our contributions in this field, for both facilitating desired transformations and offering new, unexpected opportunities. In fact, our total synthesis of (+)-gliocladin C was only possible upon elucidating the propensity for various trialkylamine additives to elicit a dual behavior as both a reductive quencher and a H-atom donor. Importantly, while natural product synthesis was central to our initial motivations to explore these photochemical processes, we have since demonstrated applicability within other subfields of chemistry, and our evaluation of flow technologies demonstrates the potential to translate these results from the bench to pilot scale.Our forays into photoredox catalysis began with fundamental methodology, providing a tin-free reductive dehalogenation that exchanged the gamut of hazardous reagents previously employed for such a transformation for visible light-mediated, ambient temperature conditions. Evolving from this work, a new avenue toward atom transfer radical addition (ATRA) chemistry was developed, enabling dual functionalization of both double and triple bonds. Importantly, we have also expanded our portfolio to target clinically relevant scaffolds. Photoredox catalysis proved effective in generating high value fluorinated alkyl radicals through the use of abundantly available starting materials, providing access to libraries of trifluoromethylated (hetero)arenes as well as intriguing gem-difluoro benzyl motifs via a novel photochemical radical Smiles rearrangement. Finally, we discuss a photochemical strategy toward sustainable lignin processing through selective C–O bond cleavage methodology. The collection of these efforts is meant to highlight the potential for visible light-mediated radical chemistry to impact a variety of industrial sectors.

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Section: Targeting Pharmaceutically Relevant Scaffoldsmentioning

confidence: 99%

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

2016

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“…Increasing the reaction temperature to 50 °C led to a modest increase in the quantity of 6 to 24% (a/a % HPLC) with limited change to the yield of 5 (Table 1 Entry 4). Previously at small scale (<1 g) the sulfonic acid side product was controlled via the use of high dilution (0.07 M), that 7 reproducibly led to less than 10% of 6 and allowed yields of 5 in the range of 85-95%.…”

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Preparative Scale Demonstration and Mechanistic Investigation of a Visible Light-Mediated Radical Smiles Rearrangement

Douglas

Sevrin

Cole

et al. 2016

Org. Process Res. Dev.

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A visible light-mediated Smiles rearrangement providing the difluoroethanol motif has been shown to reliably operate on preparative scale up to 100 g of starting material. Mechanistic investigation has revealed the reaction proceeds predominantly via a radical chain process that in some instances can be can be initiated via visible light or thermal activation in the absence of a photocatalyst. The reaction was demonstrated in continuous flow, with visible light and thermal initiation using a thiophene substrate relevant to pharmaceutical development.Reactions mediated by visible light 1 have become effective tools for both the preparation and late stage functionalization of pharmaceutically relevant molecules. 2 These methods have demonstrated the unique disconnections enabled by photoredox catalysis, resulting in more efficient synthetic routes, and providing access to previously challenging structural motifs. We recently reported the development of a visible light-mediated radical Smiles rearrangement 3 that proceeded from bromodifluoro sulfonates such as 1 to give the corresponding difluoroethanol motif, following C-Br bond reduction, rearrangement, and loss of SO2 (Scheme 1). 2(e) The reaction was primarily developed to address the synthesis of a challenging intermediate, 4 however the protocol also showed promising generality to a range of other heterocyclic scaffolds. We speculated that the reaction was likely initiated by a C-Br bond reduction mediated by Ru(bpy)3Cl2, of which there is substantial precedent. 5 The possibility of a radical chain process playing a significant role in the product formation was also present, especially given the short reaction time and low catalyst loading (30 minutes, 0.01 mol%) that is atypical of methodologies using visible light. 7 In an isolated instance, the Smiles rearrangement was demonstrated on a 15 g scale; 2(e) however, most examples were performed on a scale more typical of an exploratory investigation i.e. <1 g. Given the limited number of reports applying visible light-mediated methods at moderate scale for example >10 g, 8 combined with the currently unanswered questions concerning the mechanism and its use in manufacture on scale > kg, we further explored the scalability of our methodology. Scheme 1. Visible light-mediated radical Smiles rearrangement The previously published conditions were able to achieve an 89% isolated yield of thiophene 5 by employing high dilution (0.07 M), with scale up conducted at 0.25 M resulting in lower yield of 69%, after hydrolysis of the methyl ester to the carboxylic acid. With the aim of demonstrating this method at preparative scale, the 0.25 M conditions developed for 1 were evaluated further.Due to the poor solubility of tributylamine (NBu3) in DMSO, even following the addition of formic acid, it quickly became apparent that the biphasic reaction showed significant dependency on stir rate at a 5 g scale. A reaction carried out at half the normal stir rate required 45 minutes for full starting material consumption (not shown...

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“…2 Key to the expansion of this mode of catalysis is the demonstration of a strategic benefit when compared to other routes, most likely showcased via the ability of photocatalysis to provide new synthetic disconnections. We aimed to test the potential advantage of photocatalysis in the synthesis of difluorospirocyclic thiophene 1 , 3 a building block in the synthesis of an ORL-1 antagonist currently in development for the treatment of depression and/or obesity. 4 A production campaign demonstrated rapid access to the carbocyclic framework 2 in good yield and on multi-kg scale.…”

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confidence: 99%

“…Inrecent years,there has been an exponential increase in the number of transformations mediated by visible-light photocatalysis; [1] however, there remain to be only few reports detailing its application to agrochemical or pharmaceutical synthesis. [2] Key to the expansion of this mode of catalysis is the demonstration of as trategic benefit when compared to other routes,m ost likely showcased by the ability of photocatalysis to provide new synthetic disconnections.W ea imed to test the potential advantage of photocatalysis in the synthesis of difluoro-substituted spirocyclic thiophene 1, [3] ab uilding block in the synthesis of an opioid receptor-like 1 (ORL-1) antagonist that is currently in development for the treatment of depression and/or obesity (Scheme 1). [4] A production campaign demonstrated rapid access to the carbocyclic framework 2 in good yield and on multi-kilogram scale.H owever,t he benzylic fluorination of 2 proved to be ac hallenge,r equiring four synthetic steps in an overall 25 % yield.…”

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A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist

et al. 2015

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A visible light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of a gem-difluoro group present in an opioid receptor-like 1 (ORL-1) antagonist currently in development. This method led to the direct and efficient introduction of the difluoroethanol motif into a range of aryl- and heteroaryl systems, representing a new disconnection for the synthesis of this versatile functionality. When applied to the target compound, the photochemical step was demonstrated on 15 g scale using industrially relevant catalyst loadings of Ru(bpy)3Cl2 (0.01 mol%). This transformation allowed an overall five-step route that compares favourably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.

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Synthesis of an ORL-1 Receptor Antagonist via a Radical Bromination and Deoxyfluorination to Afford a gem-Difluorospirocycle

Cited by 12 publications

References 21 publications

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

Preparative Scale Demonstration and Mechanistic Investigation of a Visible Light-Mediated Radical Smiles Rearrangement

A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist

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