Alfredo Ballesteros

Asymmetric C2-C3 Cyclopentannulation of the Indole Ring

Chiral nonracemic alkynyl(alkoxy)carbene complexes of tungsten(0) undergo the [3 + 2] cyclization toward alpha-methylindoles and 1,6-dimethyl-1,2,3,4-tetrahydropyridine to provide 2,3-indoline-fused cyclopentenone and 2,3-piperidine-fused cyclopentenone skeletons, respectively, with very high enantiomeric purities (96-99% ee).

1,4-Cycloaddition of 1,3-diazabutadienes with enamines: an efficient route to the pyrimidine ring

Abstract [4+2] Cycloaddition reactions of 2-trimethylsilyloxy- and 2-trimethylsilylthio-1,3-diazabutadienes with enamines leading to pyrimidone derivatives are described.

Intramolecular iodoarylation reaction of alkynes : easy access to derivatives of benzofused heterocycles

The iodoarylation reaction of heteroatom-tethered omega-arylalkynes offers an efficient and straightforward entry to heterocycles. As a result, both C-C ring-closing from readily available precursors, and concomitant selective iodination take place. The first related study conducted in water is presented.

Arylation of Phe and Tyr Side Chains of Unprotected Peptides by a Suzuki−Miyaura Reaction in Water

An efficient arylation in water of tyrosine and phenylalanine side chains from unprotected iodopeptides is accomplished by using Suzuki-Miyaura cross-coupling processes. The method is compatible with the hydrophilic and thermolabile nature of biologically active peptides. Also of interest, the arylated tyrosine peptides can be accessed in one-pot mode starting from native peptides.

Gold‐Catalyzed Functionalization of Unactivated C(sp3)H Bonds by Hydride Transfer Facilitated by Alkynylspirocyclopropanes

Transition-metal-catalyzed coupling reactions involving unactivated C(sp) H bonds constitute one of the most active research areas in both industry and academia. 2] In particular, the development of methods that enable C C bond formations through the selective cleavage of ubiquitous C(sp) H bonds is highly desirable as it allows for new retrosynthetic disconnections, thus minimizing the number of steps and the generation of waste. A major drawback of this transformation lies in the control of the selectivity. In general, selective functionalizations are achieved by the assistance of directing groups that bring the catalyst closer to the desired C H bond. Alternatively, good control of the selectivity has been reported by the intramolecular thermal or Lewis acid catalyzed 1,5-hydride transfer reaction (HT). In contrast to hydride transfer to electron-poor alkenes, the use of electronically unbiased alkynes as acceptor partners requires the assistance of platinum or gold catalysts. Thus, a variety of goldor platinum-catalyzed cleavages of C(sp) H bonds through intramolecular HT to alkynes have been described recently by the groups of Sames, Gagosz, and others. As a carbocation is initially generated, this strategy has been limited to C(sp) H bonds bearing a stabilizing functionality at the a position (OR, NR2, aryl; Scheme 1a). Considering this limitation, hydride transfer to alkynes from aliphatic, nonbenzylic, positions constitutes a challenging transformation. As part of our research into the synthesis and reactivity of alkynylcyclopropane derivatives, 10] we have recently reported the synthesis of spiro[2,4]heptane derivatives 1 whose particular structure makes them amenable for use in investigations of new metal-catalyzed processes. These compounds have severe geometrical restrictions that place an inactive methylene group close to the alkyne moiety. We hypothesized that this restricted geometry might facilitate the 1,5-hydride transfer to a metal-activated alkyne (Scheme 1b). Herein, we disclose a new gold-catalyzed hydride transfer from an unactivated C(sp) H bond to an alkyne, and the subsequent selective cyclizations. Initially, we studied the reactivity of spirane 1a in the presence of various gold catalysts. We were pleased to find that a high conversion of 1a was achieved when using cationic gold complex [(IPr)Au(NTf2)] in 1,2-dichloroethane (70 8C, 24 h; Scheme 2), thus yielding a mixture of compounds 2–4a (80 % conv., 2a/3a/4a = 2.5:1:1).

Control of self-assembly of a 3-hexen-1,5-diyne derivative: toward soft materials with an aggregation-induced enhancement in emission.

The supramolecular architectures of a fluorophore are controlled through the design of a conjugated polycatenar molecule, the self-assembly of which can be addressed toward a columnar liquid-crystalline phase and organogels. Thus, depending on the environmental conditions for self-assembly, compound CA9 organizes into an unprecedented hexagonal columnar mesophase in the condensed state, in which half a molecule constitutes the slice of the column, or into a rectangular mesomorphic-like organization in the presence of apolar solvents such as cyclohexane and dodecane, at a concentration in which fibers form and gelling conditions are fulfilled. In this Col(r)-type arrangement, the organization within the columns depends on the solvent. All of the materials prepared show luminescence, and moreover, a remarkable 3-fold increase in fluorescence intensity was observed in going from the solution to the gel state.

Capillary HPLC-ICPMS and Tyrosine Iodination for the Absolute Quantification of Peptides Using Generic Standards

The validity of using tyrosine iodination chemistry for the absolute and generic quantification of peptides by capillary high-performance liquid chromatography (capHPLC) coupled to inductively coupled plasma mass spectrometry (ICPMS) is investigated in detail. In this approach, two iodine atoms are specifically bioconjugated to the meta positions of the aromatic ring of every tyrosine residue. Characterization studies by capHPLC with parallel ICPMS and electrospray ionization tandem mass spectrometry (ESIMS/MS) detection clearly showed that such labeling iodination reaction affords one to obtain most accurate peptide determinations (after translation of the picomoles of iodine, quantified by ICPMS in each chromatographic peak, into picomoles of the corresponding labeled peptide). It is demonstrated that only, but every, tyrosine residue present in the peptide is completely diiodinated. The excellent detection limits for iodine using ICPMS allowed robust and highly sensitive tyrosine-containing peptide quantification (480 pM, 480 amol absolute). Derivatization is easily accomplished in a water/acetonitrile solution in only 2 min. Moreover, since the signal in ICPMS is completely independent from the chemical species containing the detected element, any iodine-containing standard (e.g., iodobenzoic acid) could be used as internal standard for the absolute quantification of every iodine-labeled tyrosine-containing peptide separated and detected along the gradient. The approach was optimized for tyrosine labeling and then validated by application to the absolute quantification of the three standard peptides present in the only reference material for peptide quantity (NIST 8327) commercially available. Identification of the species quantified by ICPMS was carried out by parallel capHPLC-ESI quadrupole time-of-flight (Q/TOF) analysis and corresponded, as expected, to the diiodinated peptides. The collision-induced dissociation (CID) spectra obtained demonstrated unequivocally the specific and complete derivatization of the tyrosine residues. The obtained quantitative results closely matched the reference values reported by the National Institute of Standards and Technology (NIST). In terms of precision, the relative standard deviation was as low as 3% RSD. Finally the approach was tested for the absolute quantification of proteins using a model standard protein (beta-casein). Results agreed again with the value specified showing that this labeling reaction is compatible with tryptic digestion.

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.

New reactions in water: metal-free conversion of alcohols and ketones into α-iodoketones

Using water as the reaction medium, ketones can be transformed into α-iodoketones upon treatment with sodium iodide, hydrogen peroxide and an acid; interestingly, α-iodoketones can be also obtained from secondary alcohols through a metal-free tandem oxidation–iodination approach.

Gold‐Catalyzed Rearrangements: Reaction Pathways Using 1‐Alkenyl‐2‐alkynylcyclopropane Substrates

) allowed to design useful trans-formations based on the cleavage of the cyclopropane ring.Inthisscenario,itseemedtousthatthecatalytictransformationsof substrates containing the alkene–cyclopropane–alkyneconnectivity might be a promising approach. Surprisingly,transformations based on the 1-alkenyl-2-alkynylcyclopro-pane framework (1,5-enyne arrangement) are very rare.