Opportunities in Photocatalytic Synthesis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108661/1/2739_ftp.pd

Visible Light Mediated Aryl Migration by Homolytic C−N Cleavage of Aryl Amines

The photocatalytic preparation of aminoalkylated heteroarenes from haloalkylamides via a 1,4‐aryl migration from nitrogen to carbon, conceptually analogous to a radical Smiles rearrangement, is reported. This method enables the substitution of amino groups in heteroaromatic compounds with aminoalkyl motifs under mild, iridium(III)‐mediated photoredox conditions. It provides rapid access to thienoazepinone, a pharmacophore present in multiple drug candidates for potential treatment of different conditions, including inflammation and psychotic disorders.Aminoalkylated heteroarenes are synthesized by a radical Smiles rearrangement of haloalkylamides through a key C−N cleavage under mild, iridium(III)‐mediated photoredox conditions. The method provides rapid access to the pharmaceutically relevant thienoazepinone scaffold.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146419/1/anie201806659_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146419/2/anie201806659.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146419/3/anie201806659-sup-0001-misc_information.pd

Radical Carbon–Carbon Bond Formations Enabled by Visible Light Active Photocatalysts

This mini-review highlights the Stephenson group's contribution to the field of photoredox catalysis with emphasis on carbon–carbon bond formation. The realization of photoredox mediated reductive dehalogenation initiated investigations toward both intra- and intermolecular coupling reactions. These reactions commenced via visible light-mediated reduction of activated halogens to give carbon-centered radicals that were subsequently involved in carbon–carbon bond forming transformations. The developed protocols using Ru and Ir based polypyridyl complexes as photoredox catalysts were further tuned to efficiently catalyze overall redox neutral atom transfer radical addition reactions. Most recently, a simplistic flow reactor technique has been utilized to affect a broad scope of photocatalytic transformations with significant enhancement in reaction efficiency

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

This report details the development of a masked N‐centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1‐aminonorbornanes. This process employs the N‐centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C−C bonds en route to the norbornane core. Achieving bond‐forming reactivity as a function of the N‐centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl‐fused 1‐aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.The N‐centered open‐shell character of photoexcited cyclopropylimines is utilized to initiate a radical fragmentation–cyclization sequence that generates bridgehead‐functionalized norbornanes. This unique mode of reactivity requires only violet light to proceed, and the 1‐aminonorbornane products are valuable building blocks for drug and agrochemical discovery programs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153143/1/anie201909492_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153143/2/anie201909492.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153143/3/anie201909492-sup-0001-misc_information.pd

Arylmigration durch sichtbares Licht unter homolytischer C‐N‐Spaltung in Arylaminen

Die photokatalytische Synthese von aminoalkylierten Heteroaromaten aus Halogenalkylamiden gelingt durch die einer Smiles‐Umlagerung konzeptionell analogen 1,4‐Arylmigration von Stickstoff zu Kohlenstoff. Mit dieser neuartigen Methode kann die Substitution von Aminogruppen in Heteroaromaten durch Aminoalkylmotive unter milden, Iridium(III)‐vermittelten Photoredox‐Bedingungen realisiert werden. Sie bietet einen schnellen Zugang zum Thienoazepinon‐Bicyclus, einem Pharmakophor, der in unterschiedlichen Verbindungen mit potentiellen Anwendungen bei der Behandlung von bestimmten Entzündungen und psychischen Krankheiten vorkommt.Aminoalkylierte Heteroarene werden durch Smiles‐Umlagerung von Halogenalkylamiden über eine C‐N‐Spaltung unter milden, Iridium(III)‐vermittelten Photoredox‐Bedingungen synthetisiert. Das Verfahren bietet einen schnellen Zugang zu dem pharmazeutisch relevanten Thienoazepinon‐Grundgerüst.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146369/1/ange201806659.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146369/2/ange201806659_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146369/3/ange201806659-sup-0001-misc_information.pd

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Chinonmethidâ Dimere wurden durch milde anodische Oxidation vermittelt durch eine preiswerte und leicht verfügbare Aminbase mit exzellenter Ausbeute und Regiokontrolle hergestellt. Diese Strategie ermöglicht raschen Zugang zu Zwischenprodukten für die katalytische Synthese von Phenylpropenoidâ Oligomeren und bietet ein neues Werkzeug für die Totalsynthese dieser komplexen Moleküle.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/1/ange201810870.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/2/ange201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/3/ange201810870-sup-0001-misc_information.pd

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Quinone methide dimers are prepared via mild anodic oxidation mediated by a cheap and readily available amine base with excellent yield and regiocontrol. This strategy provides rapid access to intermediates for the synthesis of phenylpropenoid oligomers in a catalytic fashion, providing a new tool for the total synthesis of these complex molecules.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/1/anie201810870-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/2/anie201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/3/anie201810870.pd

A Scalable Biomimetic Synthesis of Resveratrol Dimers and Systematic Evaluation of their Antioxidant Activities

An efficient synthetic route to the resveratrol oligomers quadrangularin A and pallidol is reported. It features a scalable biomimetic oxidative dimerization that proceeds in excellent yield and with complete regioselectivity. A systematic evaluation of the natural products and their synthetic precursors as radical‐trapping antioxidants has revealed that, contrary to popular belief, this mode of action is unlikely to account for their observed biological activity.Hartnäckigkeit zahlt sich aus: Eine kurze Synthese der Resveratrol‐Oligomere Quadrangularin A und Pallidol macht sich die Stabilität der von 2,6‐Di‐tert‐butylphenol abgeleiteten Radikal‐ und der Chinonmethid‐Zwischenstufe zunutze. Untersuchungen dieser Verbindungen als antioxidative Radikalfänger ergaben, dass diese Eigenschaft höchstwahrscheinlich nicht die Ursache ihrer beobachteten biologischen Aktivität ist.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110868/1/3825_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110868/2/ange_201409773_sm_miscellaneous_information.pd

Understanding the population structure of North American patients with cystic fibrosis

It is generally presumed that the Cystic Fibrosis (CF) population is relatively homogeneous, and predominantly of European origin. The complex ethnic make-up observed in the CF patients collected by the North American CF Modifier Gene Consortium has brought this assumption into question, and suggested the potential for population substructure in the three CF study samples collected from North America. It is well appreciated that population substructure can result in spurious genetic associations

Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio