Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis.

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.R01 GM073855 - NIGMS NIH HHS; R01 GM096129 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HH

NOVEL CASCADE REACTIONS OF ALKENYLZIRCONOCENES AND THEIR APPLICATION TO THE SYNTHESIS OF CYCLOPROPYL PEPTIDE MIMETICS

We have successfully applied to Zr→Zn methodology developed in the Wipf group to the preparation of functionalized allylic amides and alcohols via the 1,2-addition to imines and α-keto esters. During the preparation of allylic amides, concomitant formation of C-cyclopropylalkylamides was observed in CH₂Cl₂. The combination of the Zr→Zn methodology with the Simmons-Smith cyclopropanation reaction has led to the discovery of a novel cascade reaction for the preparation of C,C-dicyclopropylmethylamides from simple, readily available starting materials. These functionalized amides have served as precursors in a diversity-oriented approach for the preparation of 7-, 8-, and 9-membered azaspirocyclic ring structures based on reductive amination, epoxide opening or ring-closing metathesis strategies. Finally, a small library of α,β-cyclopropyl-γ-amino acids were prepared in 6-7 steps from readily available starting materials and evaluated for their potential as peptide mimetics. Simple amide derivatives were found to adopt stable sheet-like structures in the solid state, whereas the structural properties of oligopeptides were not readily assessed using crystallographic techniques. A combination of molecular modeling, circular dichroism and NMR studies was used to ascertain the solution folding preferences of our novel peptides

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

The importance of data issues when comparing cystic fibrosis registry outcomes between countries : are annual review FEV1 in the UK only collected when subjects are well?

Rationale, aims and objective Cross‐country comparisons of cystic fibrosis (CF) outcomes can potentially identify variation in care but are dependent on data quality. An important assumption is that the UK annual review FEV1 is only collected during periods of clinical stability. If this assumption does not hold, results of FEV1 comparisons may be biased in favour of registries with encounter‐based FEV1. We aimed to test the assumption that CF annual reviews in the UK are only performed during periods of clinical stability. Method Prospective encounter‐based data collected in Sheffield (n = 174) was used to establish whether annual review FEV1 were always collected during periods of clinical stability and to determine the group‐level discrepancy between annual review vs best FEV1. We then went on to quantify the group‐level discrepancy between annual review and best annual FEV1 readings within the UK registry (n = 2995) to determine if the differences observed in Sheffield also apply to the wider UK data. Results Sheffield results showed a group‐level discrepancy between best and annual review FEV1 of −2.5% (95% CI −3.95% to −1.2%) for annual reviews performed during periods of clinical stability (n = 50). The group‐level discrepancy is larger at −8.0% (95% CI −11.2% to −4.9%) among annual reviews performed during periods of clinical instability (n = 13). Therefore, the magnitude of this group‐level discrepancy is a surrogate for the proportion of clinically stable annual reviews—smaller discrepancy indicates a higher proportion of clinically stable annual reviews and vice versa. The overall group‐level discrepancy in the UK registry (−5.6%, 95% CI −5.9 to −5.4%) was similar to Sheffield (−6.1%, 95% CI −7.1 to −5.1%). Around 20% of the clinician reviewed, annual reviews in Sheffield were performed during periods of clinically instability. Conclusions Annual review FEV1 underestimates lung health of adults with CF in the UK and may bias cross‐country comparisons

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

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