The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

Many boronic acids, including 2-heterocyclic, vinyl, and cyclopropyl derivatives, are inherently unstable, which can limit their benchtop storage and/or efficient cross-coupling. We herein report the first general solution to this problem: in situ slow release of unstable boronic acids from the corresponding air-stable MIDA boronates. This remarkably general approach has transformed all three classes of these unstable boronic acids into shelf-stable and highly effective building blocks for cross-coupling with a wide range of aryl and heteroaryl chlorides.

Small molecule synthesis usually relies on procedures highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block-based synthesis platform to include even Csp3-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small molecule synthesis.

Burke and Gillis S2benzofuranylboronic acid, 4 2-bromo-5-methoxyphenol, 5 4-(methoxymethoxy)benzoic acid. 6 Solutions of n-butyllithium were titrated according to the method of Hoye and coworkers. 7General Experimental Procedures. Suzuki-Miyaura cross-coupling reactions were typically performed under an atmosphere of argon in oven-or flame-dried I-Chem or Wheaton vials sealed with PTFE-lined plastic caps. All other reactions were performed in oven-or flame-dried round-bottom or modified Schlenk flasks fitted with rubber septa under a positive pressure of argon or nitrogen unless otherwise indicated. Organic solutions were concentrated via rotary evaporation under reduced pressure. Reactions were monitored by analytical thin layer chromatography (TLC) performed using the indicated solvent on E. Merck silica gel 60 F254 plates (0.25mm). Compounds were visualized by exposure to a UV lamp (λ = 254 nm), a glass chamber containing iodine, and/or a solution of KMnO 4 , an acidic solution of panisaldehyde, or a solution of ceric ammonium molybdate (CAM) followed by brief heating using a Varitemp heat gun. Flash column chromatography was performed as described by Still and coworkers 8 using EM Merck silica gel 60 (230-400 mesh).Structural analysis. 1 H NMR spectra were recorded at 23 o C on one of the following instruments: Varian Unity 400, Varian Unity 500, Varian Unity Inova 500NB. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane and referenced to residual protium in the NMR solvent (CHCl 3 , δ = 7.26; CD 2 HCN, δ = 1.93, center line) or to added tetramethylsilane (δ = 0.00). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, b = broad, app = apparent), coupling constant (J) in Hertz (Hz), and integration. 13 C NMR spectra were recorded at 23 o C on one of the following instruments: Varian Unity 500 or Varian Unity Inova 500NB. Chemical shifts (δ) are reported in ppm downfield from tetramethylsilane and referenced to carbon resonances in the NMR solvent (CDCl 3 , δ = 77.0, center line; CD 3 CN, δ = 1.30, center line) or to added tetramethylsilane (δ = 0.00). Carbons bearing boron substituents were not observed (quadrupolar relaxation). 11 B NMR were recorded using a General Electric GN300WB instrument and referenced to an external standard of (BF 3 •Et 2 O). High resolution mass spectra (HRMS) were performed by Furong Sun and Dr. Steve Mullen at the

Due to its sensitivity to most synthetic reagents, it is typically necessary to introduce the boronic acid functional group just prior to its utilization. Overcoming this important limitation, we herein report that air- and chromatographically stable MIDA boronates are compatible with a wide range of common reagents which enables the multistep synthesis of complex boronic acid building blocks from simple B-containing starting materials. X-ray and variable temperature NMR studies link the unique stability of MIDA boronates to a kinetic inaccessibility of the potentially reactive boron p-orbital and/or nitrogen lone pair. These findings were collectively harnessed to achieve a short and modular total synthesis of (+)-crocacin C via the iterative cross-coupling of a structurally complex, MIDA-protected haloboronic acid building block.

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A wide range of 2-pyridyl and other difficult-to-access heterocyclic N-methyliminodiacetic acid boronates can be readily prepared from the corresponding bromides via a new method involving direct transligation of trialkoxyborate salts with MIDA at elevated temperatures.

Background. Influenza disproportionately impacts older adults while current vaccines have reduced effectiveness in the older population.Methods. We conducted a comprehensive evaluation of cellular and humoral immune responses of adults aged 50 years and older to the 2008–2009 seasonal trivalent inactivated influenza vaccine and assessed factors influencing vaccine response.Results. Vaccination increased hemagglutination inhibition and neutralizing antibody; however, 66.3% of subjects did not reach hemagglutination inhibition titers ≥ 40 for H1N1, compared with 22.5% for H3N2. Increasing age had a minor negative impact on antibody responses, whereas prevaccination titers were the best predictors of postvaccination antibody levels. Preexisting memory B cells declined with age, especially for H3N2. However, older adults still demonstrated a significant increase in antigen-specific IgG+ and IgA+ memory B cells postvaccination. Despite reduced frequency of preexisting memory B cells associated with advanced age, fold-rise in memory B cell frequency in subjects 60+ was comparable to subjects age 50–59.Conclusions. Older adults mounted statistically significant humoral and cell-mediated immune responses, but many failed to reach hemagglutination inhibition titers ≥40, especially for H1N1. Although age had a modest negative effect on vaccine responses, prevaccination titers were the best predictor of postvaccination antibody levels, irrespective of age.