Visible Light Mediated Photoredox Catalytic Arylation Reactions.

Introducing aryl- and heteroaryl moieties into molecular scaffolds are often key steps in the syntheses of natural products, drugs, or functional materials. A variety of cross-coupling methods have been well established, mainly using transition metal mediated reactions between prefunctionalized substrates and arenes or C-H arylations with functionalization in only one coupling partner. Although highly developed, one drawback of the established sp2-sp2 arylations is the required transition metal catalyst, often in combination with specific ligands and additives. Therefore, photoredox mediated arylation methods have been developed as alternative over the past decade. We begin our survey with visible light photo-Meerwein arylation reactions, which allow C-H arylation of heteroarenes, enones, alkenes, and alkynes with organic dyes, such as eosin Y, as the photocatalyst. A good number of examples from different groups illustrate the broad application of the reaction in synthetic transformations. While initially only photo-Meerwein arylation-elimination processes were reported, the reaction was later extended to photo-Meerwein arylation-addition reactions giving access to the photoinduced three component synthesis of amides and esters from alkenes, aryl diazonium salts, nitriles or formamides, respectively. Other substrates with redox-active leaving groups have been explored in photocatalyzed arylation reactions, such as diaryliodonium and triarylsulfonium salts, and arylsulfonyl chlorides. We discus some examples with their scope and limitations. The scope of arylation reagents for photoredox reactions was extended to aryl halides. The challenge here is the extremely negative reduction potential of aryl halides in the initial electron transfer step compared to, e.g., aryl diazonium or diaryliodonium salts. In order to reach reduction potentials over -2.0 V vs SCE two consecutive photoinduced electron transfer steps were used. The intermediary formed colored radical anion of the organic dye perylenediimide is excited by a second photon allowing the one electron reduction of acceptor substituted aryl chlorides. The radical anion of the aryl halide fragments under the loss of a halide ion and the aryl radical undergoes C-H arylation with biologically important pyrrole derivatives or adds to a double bond. Rhodamine 6G as an organic photocatalyst allows an even higher degree of control of the reaction. The dye is photoreduced in the presence of an amine donor under irradiation with green light (e.g., 530 nm), yielding its radical anion, which is a mild reducing reagent. The hypsochromic shift of the absorption of the rhodamine 6G radical anion toward blue region of the visible light spectrum allows its selective excitation using blue light (e.g., 455 nm). The excited radical anion is highly reducing and able to activate even bromoanisole for C-H arylation reactions, although only in moderate yield. Photoredox catalytic C-H arylation reactions are valuable alternatives to metal catalyzed reactions. They have an excellent functional group tolerance, could potentially avoid metal containing catalysts, and use visible light as a traceless reagent for the activation of arylating reagents.

Direct C-H Phosphonylation of Electron-Rich Arenes and Heteroarenes by Visible-Light Photoredox Catalysis.

The direct transformation of ubiquitous, but chemically inert C-H bonds into diverse functional groups is an important strategy in organic synthesis that improves the atom economy and faclitates the preparation and modification of complex molecules. In contrast to the wide applications of aryl phosphonates, their synthesis via direct C-H bond phosphonylation is a less explored area. We report here a general, mild, and broadly applicable visible-light photoredox C-H bond phosphonylation method for electron-rich arenes and heteroarenes. The photoredox catalytic protocol utilizes electron-rich arenes and biologically important heteroarenes as substrates, [Ru(bpz)3 ][PF6 ]2 as photocatalyst, ammonium persulfate as oxidant, and trialkyl phosphites as the phosphorus source to provide a wide range of aryl phosphonates at ambient temperature under very mild reaction conditions.

Sensitization-Initiated Electron Transfer for Photoredox Catalysis.

Photosynthetic organisms exploit antenna chromophores to absorb light and transfer excitation energy to the reaction center where redox reactions occur. In contrast, in visible-light chemical photoredox catalysis, a single species (i.e., the photoredox catalyst) absorbs light and performs the redox chemistry. Mimicking the energy flow of the biological model, we report a two-center photoredox catalytic approach in which the tasks of light energy collection and electron transfer (i.e., redox reactions) are assigned to two different molecules. Ru(bpy)3 Cl2 absorbs the visible light and transfers the energy to polycyclic aromatic hydrocarbons that enable the redox reactions. This operationally simple sensitization-initiated electron transfer enables the use of arenes that do not absorb visible light, such as anthracene or pyrene, for photoredox applications. We demonstrate the merits of this approach by the reductive activation of chemical bonds with high reduction potentials for carbon-carbon and carbon-heteroatom bond formations.

New fluorinated agonists for targeting the sphingosin-1-phosphate receptor 1 (S1P(1)).

The sphingosine-1-phosphate receptor type 1 (S1P1) is involved in fundamental biological processes such as regulation of immune cell trafficking, vascular barrier function and angiogenesis. This Letter presents multistep syntheses of various fluorine substituted 12-aryl analogues of the drug fingolimod (FTY720) and a seven-steps route to 2-amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol. In vitro and in vivo tests proved all these compounds as potent S1P1 receptor agonists.

Synthesis of new ligands for targeting the S1P1 receptor.

Sphingosine-1-phosphate (S1P) influences various fundamental biological processes by interacting with a family of five G protein-coupled receptors (S1P1-5). FTY720, a sphingosine analogue, which was approved for treatment of relapsing forms of multiple sclerosis, is phosphorylated in vivo and acts as an agonist of four of the five S1P receptor subtypes. Starting from these lead structures we developed new agonists for the S1P1 receptor. The biological activity was tested in vivo and promising ligands were fluorinated at different positions to identify candidates for positron emission tomography (PET) imaging after [(18)F]-labelling. The radioligands shall enable the imaging of S1P1 receptor expression in vivo and thus may serve as novel imaging markers of S1P-related diseases.

Outcomes of Cataract Surgery Complicated by Retained Lens Fragments Requiring Pars Plana Vitrectomy.

OBJECTIVE: To analyze outcomes and complications related to cataract surgery complicated by retained lens fragment (RLF) requiring pars plana vitrectomy (PPV) in a county hospital where procedures are performed by trainees. METHODS: Retrospective study of consecutive patients who met inclusion criteria and underwent PPV for RLF in the vitreous cavity at an urban teaching hospital between January 2010 and January 2016 (N=20). MAIN OUTCOMES/MEASURES: Visual acuity was recorded pre- and post-operatively over a follow-up period of 3 to 12 months. Complications and patient factors contributing to outcomes were assessed using paired and unpaired t-tests and multiple linear regression. RESULTS: The average rate of cataract surgery with RLF requiring PPV was 0.75%. Twenty patients met inclusion criteria. Mean pre-operative visual acuity (VA) was logMAR 1.7 (Snellen 20/1000). Nearly half (8/20) had nuclear cataracts grade 3+ or higher. The majority (14/20) had factors predisposing them to cataract surgery complications. Most patients underwent PPV within 1 week (median 6.5 days). At 12-month follow-up, significant (p=0.001) visual acuity (VA) improvement from initial VA was observed, with final mean logMAR 0.6 (± 0.75; Snellen 20/80) and median logMAR 0.35 (Snellen 20/45). Nearly half of the patients had a final Snellen VA ≥20/40. Factors associated with less VA improvement were older age and greater proportion of lens dropped (p<0.01). Complications following PPV included hypotony (5 patients), corneal edema (4), elevated intraocular pressure (IOP) (3), and cystoid macular edema (3). CONCLUSIONS/RELEVANCE: Despite patients with advanced pathology and trainee surgeons, rates of cataract surgery-associated RLF requiring PPV at a large tertiary care teaching hospital are similar to reported rates in the literature.

Synthesis and evaluation of fluorinated fingolimod (FTY720) analogues for sphingosine-1-phosphate receptor molecular imaging by positron emission tomography.

Sphingosine-1-phosphate (S1P) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G-protein coupled receptors (GPCRs): S1P1-S1P5. S1P and its receptors (S1PRs) play important roles in the immune, cardiovascular, and central nervous systems and have also been implicated in carcinogenesis. Recently, the S1P analogue Fingolimod (FTY720) has been approved for the treatment of patients with relapsing multiple sclerosis. This work presents the synthesis of various fluorinated structural analogues of FTY720, their in vitro and in vivo biological testing, and their development and application as [(18)F]radiotracers for the study of S1PR biodistribution and imaging in mice using small-animal positron emission tomography (PET).