A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon−carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products. The piperidine ring is widely distributed throughout Nature, e.g., in alkaloids,1 and is an important scaffold for drug discovery, being the core of many pharmaceutically significant compounds.2,3 The syntheses of these type of compounds have been extensively studied in the development of new drugs containing six-membered-ring heterocycles.4 Reactions between N-acyliminium ions and nucleophiles, also described as amidoalkylation or Mannich-type condensations, have been frequently used to introduce substituents at the R-carbon of an amine.5 There are several examples that involve an intramolecular attack of a nucleophilic olefin into an iminium cation for the construction of a heterocyclic ring system.6 Traditionally, the use of hemiaminals or their derivatives as precursors of N-acyliminium intermediates has been a common two-step strategy in these reactions.6a Among this type of cyclization is the aza-Prins cyclization,7 which uses alkenes as intramolecular nucleophile. However, cy† X-ray analysis. E-mail address: malopez@ull.es. (1) (a) Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 23, pp 1-90. (b) Baliah, V.; Jeyarama, R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379-423. (2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681. (3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-930. (4) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729 and references therein. (5) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3187- 3856 and references therein. (6) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, O., Heathcock, C. H., Eds.; Pergamon: New York, 1991; Vol. 2, pp 1047-1081. (b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (7) (a) Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003, 11, 1740-1742. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinove, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. (c) Hanessian, S.; Tremblay, M.; Petersen, F. W. J. Am. Chem. Soc. 2004, 126, 6064-6071 and references therein. (d) Dobbs, A. P.; Guesne, S. J. Synlett 2005, 13, 2101-2103. ORGANIC

Iron-Catalyzed Reactions in Organic Synthesis

L'etude demontre que les radicaux cationiques CH 3 OH +• , CH 3 NH 2 +• et CH 3 Cl +• ont des isomeres stables: • CH 2 OH 2 + , • CH 2 NH 3 + et • CH 2 ClH +

Distonic radical cations in gaseous and condensed phase

Direct Selective Oxidative Cross‐Coupling of Simple Alkanes with Heteroarenes

Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest. Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

Late-stage C-H functionalization offers new opportunities in drug discovery

http://pubs.acs.org/doi/pdf/10.1021/ol503338b

N-Aminopyridinium Salts as Precursors for N-Centered Radicals – Direct Amidation of Arenes and Heteroarenes

Polar effects in free radical reactions. Homolytic aromatic amination by the amino radical cation, .cntdot.+NH3: reactivity and selectivity

Preparation de radicaux carbamoyles et α-N-amidoalkyles. Ces radicaux attaquent selectivement des bases heteroaromatiques protonees, comme la quinoxaline ou la lipidine, en position α. On suggere des mecanismes redox en chaine. On discute de l'importance des effets polaires dans les reactions d'enlevement d'hydrogene, de substitution aromatique et d'oxydation par les sels de Fe(III)

Polar effects in free-radical reactions. Carbamoylation and α-N-amidoalkylation of heteroaromatic bases by amides and hydroxylamine-O-sulfonic acid

Protonated heteroaromatic bases react with formamide, N,N-dimethylformamide, cyclic ethers, and methanol in the presence of hydroxylamine-O-sulphonic acid and catalytic amounts of an iron(II) salt to afford selective substitution by a redox chain process.

Redox-chain decomposition of hydroxylamine-O-sulphonic acid. A novel general source of nucleophilic radicals for the functionalization of heteroaromatic bases

Polar effects in free-radical reactions. A new type of homolytic aromatic alkylation by silver catalyzed oxidation of acetone by peroxydisulphate in the presence of olefins.

Several multi-kinase inhibitors were widely tested as potential first-line or second-line therapy in patients with advanced hepatocellular carcinoma (HCC). However, acquired drug resistance limits their clinical efficacy. Exosomes are microvesicles secreted by tumor and stromal cells that participate in many biological processes, including drug resistance. The current study evaluated the capability of exosomes derived from everolimus (EVE)-resistant HCC cells in inducing drug resistance in parental human HCC cells and the effect of 1,25(OH)2Vitamin D (VitD) treatment in restoring EVE sensitivity. The internalization of exosomes from EVE-resistant (EveR) cells into parental cells conferred the transmission of aggressive phenotype by promoting the transition of epithelial-to-mesenchymal phenotype, as demonstrated by immunofluorescence, and the acquisition of EVE resistance, as demonstrated by cell proliferation and colony formation assays. Moreover, the internalization of exosomes from EveR into parental cells induced deregulation of the mTOR pathway mainly by triggering the activation of the serine/threonine protein kinase Akt, involved in the cellular survival pathway, as demonstrated by Western blot analysis. Interestingly, the treatment with VitD prevented exosome-induced EVE resistance in HCC cells, significantly inhibiting cell proliferation but also partially reducing colony and size number when combined with EVE compared with control. In conclusion, the results of the current study demonstrated that exosomes derived from EveR cells could induce EVE resistance in EVE-sensitive HCC cells and that VitD can revert the exosome-induced EVE resistance by resensitizing to EVE treatment.

/pdf/vitamin-d-reverts-the-exosome-mediated-transfer-of-cancer-2yq11uni.pdf

Anna Gentile

Papers

Polar effects in free radical reactions. Homolytic aromatic amination by the amino radical cation, .cntdot.+NH3: reactivity and selectivity

Polar effects in free-radical reactions. Carbamoylation and α-N-amidoalkylation of heteroaromatic bases by amides and hydroxylamine-O-sulfonic acid

Redox-chain decomposition of hydroxylamine-O-sulphonic acid. A novel general source of nucleophilic radicals for the functionalization of heteroaromatic bases

Polar effects in free-radical reactions. A new type of homolytic aromatic alkylation by silver catalyzed oxidation of acetone by peroxydisulphate in the presence of olefins.

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma