Dataset Information

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

ABSTRACT: A visible-light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem-difluoro group present in an opioid receptor-like?1 (ORL-1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables 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 moiety. When applied to the target compound, the photochemical step could be conducted on 15?g scale using industrially relevant [Ru(bpy)3Cl2] catalyst loadings of 0.01?mol?%. This transformation is part of an overall five-step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.

SUBMITTER: Douglas JJ

PROVIDER: S-EPMC4725294 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Douglas James J JJ Albright Haley H Sevrin Martin J MJ Cole Kevin P KP Stephenson Corey R J CR

Angewandte Chemie (International ed. in English) 20151016 49

A visible-light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem-difluoro group present in an opioid receptor-like 1 (ORL-1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables 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 moiety. When applied to th ...[more]

PMID: 26474077

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Project description:Harnessing 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.

Dataset Information

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

Publications

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

Similar Datasets

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