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Dalibor Sames

Publications and source records attributed to Dalibor Sames.

At least 19 recordsLinked to original sources
PubMed2006

sp3 C-H bond arylation directed by amidine protecting group: alpha-arylation of pyrrolidines and piperidines.

A new ruthenium-catalyzed direct sp3 C-H to C-C bond transformation is disclosed. Specifically, a method for the alpha-arylation of cyclic amines, containing either permanent (pyridine, pyrimidine) or removable (amidine) directing groups, is described. This cross-coupling reaction involves heating amine substrates with arylboronate ester at 150 degrees C in a ketone solvent with a catalytic amount of ruthenium carbonyl [Ru3(CO)12]. Arylboronate esters containing either electron-withdrawing or electron-donating substituents could be efficiently coupled. Heteroarene boronates were also effective donors.

Amidines↗
PubMed2006

Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells.

The current arsenal of tools and methods for the continuous monitoring and imaging of redox metabolic pathways in the context of intact cells is limited. Fluorogenic substrates allow for direct measurement of enzyme activity in situ; however, in contrast to proteases and exo-glycosidases, there are no simple guidelines for the design of selective probes for redox metabolic enzymes. Here, we introduce redox probe 1 and demonstrate its high selectivity in living cells for human hydroxysteroid dehydrogenases (HSDs) of the aldo-keto reductase (AKR) superfamily. AKR1C isoforms perform multiple functions among which the metabolism of potent steroid hormones is well documented. Moreover, expression of these enzymes is responsive to cellular stress and pathogenesis, including cancer. Our probe design is based on redox-sensitive optical switches, which couple a ketone-alcohol redox event to a profound change in fluorescence. The high selectivity of phenyl ketone 1 for AKR1C2 over the many endogenous reductases present in mammalian cells was established by a quantitative comparison of the metabolic rates between null control cells (COS-1) and AKR1C2-transfected cells. Phenyl ketone 1 is a cell-permeable fluorogenic probe that permits a direct, real-time, and operationally simple readout of AKR1C2 enzyme activity in intact mammalian cells. Furthermore, it was demonstrated that probe 1 enables the quantitative examination of physiological substrate 5alpha-dihydrotestosterone ("dark substrate") in situ by means of a two-substrate competitive assay. Similarly, inhibitor potency of physiological (ursodeoxycholate) and synthetic inhibitors (flufenamic acid, ibuprofen, and naproxen) was also readily evaluated.

Animals↗
PubMed2006

Phosphorylation state-responsive lanthanide peptide conjugates: a luminescence switch based on reversible complex reorganization.

[reaction: see text] A luminogenic probe for peptide dephosphorylation has been developed. It consists of a serine-/tyrosine-containing peptide modified on the N-terminus with a tryptophan residue and a DTPA chelate capable of binding Tb(3+). We propose a mechanistic model for the luminescence enhancement based on the interconversion of monomeric and dimeric lanthanide species, which is affected by the phosphorylation state of the serine or tyrosine residue. The optical switch reports effectively on phosphatase-catalyzed dephosphorylation in vitro.

Alkaline Phosphatase↗
PubMed2006

Catalytic C-H arylation of SEM-protected azoles with palladium complexes of NHCs and phosphines.

[reaction: see text] The synthesis and catalytic evaluation of palladium complexes containing imidazolyl carbene ligand of varying steric and electronic properties is reported. These complexes catalyze the efficient C-H arylation of SEM-protected azole heteroarenes and thus provide a good method for preparation of a wide range of arylated free (NH)-azoles including pyrroles, indoles, imidazoles, and imidazo[1,2-a]pyridines. The reaction is operationally simple; the complexes are insensitive to moisture.

Journal Article↗
PubMed2006

C-H bond functionalization in complex organic synthesis.

Direct and selective replacement of carbon-hydrogen bonds with new bonds (such as C-C, C-O, and C-N) represents an important and long-standing goal in chemistry. These transformations have broad potential in synthesis because C-H bonds are ubiquitous in organic substances. At the same time, achieving selectivity among many different C-H bonds remains a challenge. Here, we focus on the functionalization of C-H bonds in complex organic substrates catalyzed by transition metal catalysts. We outline the key concepts and approaches aimed at achieving selectivity in complex settings and discuss the impact these reactions have on synthetic planning and strategy in organic synthesis.

Journal Article↗
PubMed2005

Room temperature intramolecular hydro-O-alkylation of aldehydes: sp3 C-H functionalization via a Lewis acid catalyzed tandem 1,5-hydride transfer/cyclization.

[reaction: see text] The scope and limitations of intramolecular hydro-O-alkylation of aldehyde substrates leading to spiroketals and bicyclic ketals and aminals is reported. The direct transformation of tertiary and sterically hindered secondary sp(3) C-H bonds into C-O bonds under the action of a catalytic amount of a variety of Lewis acids is described. The mechanism of these transformations is proposed to involve a tandem hydride transfer/cyclization sequence.

Aldehydes↗
PubMed2005

Room temperature hydroalkylation of electron-deficient olefins: sp3 C-H functionalization via a lewis acid-catalyzed intramolecular redox event.

A practical method for the intramolecular hydroalkylation of electron-deficient olefins has been developed. The direct transformation of benzylic, tertiary, and sterically hindered secondary sp3 C-H bonds into C-C bonds under the action of a catalytic amount of a variety of Lewis acids is described. The mechanism of these transformations is proposed to involve a tandem hydride transfer/cyclization sequence.

Acids↗
PubMed2005

A new fluorogenic transformation: development of an optical probe for coenzyme Q.

[reaction: see text] A new fluorogenic transformation based on a quinone reduction/lactonization sequence has been developed and evaluated as a tool for probing redox phenomena in a biochemical context. The probe presented herein is an irreversible redox probe and is reduced selectively by biologically relevant quinols such as ubiquinol but is inert to reduced nicotinamides (e.g., NADH). The ensuing cyclization is fast and quantitative and provides a measurable optical response.

Fluorescent Dyes↗
PubMed2005

Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity.

We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was observed for both free (NH)-indole and (NR)-indole. To provide a rationale for the observed selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was determined for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addition, the kinetic isotope effect (KIE(H/D)) was determined for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 versus C-3) was achieved by the choice of magnesium base.

Benzene Derivatives↗
PubMed2005

Selective and catalytic arylation of N-phenylpyrrolidine: sp3 C-H bond functionalization in the absence of a directing group.

We herein describe our studies on arylation of N-phenylpyrrolidine, which led to the development of a new transformation for the direct and selective arylation of sp3 C-H bonds in the absence of a directing group. In this method, Ru(H)2(CO)(PCy3)3 4 was used as the catalyst, and preliminary mechanistic studies suggested that Ru(Ph)(I)(CO)(PCy3)2 5 is the key intermediate of the catalytic cycle. A large kinetic isotope effect (kH/kD = 5.4) was observed, which supports the proposal that C-H bond metalation is the slow step. Preliminary examination of the substrate scope showed that in addition to N-phenylpyrrolidine, N-methyl- and N-benzylpyrrolidine, as well as N-benzoylpyrrolidine, were arylated under the reaction conditions.

Benzene Derivatives↗
PubMed2005

Direct C-arylation of free (NH)-indoles and pyrroles catalyzed by Ar-Rh(III) complexes assembled in situ.

Ar-Rh(III) pivalate complexes assembled in situ from the reaction of [RhCl(coe)2]2 (coe = cis-cyclooctene), [p-(CF3)C6H4]3P, and CsOPiv effectively catalyzed the direct C-arylation of free (NH)-indoles and (NH)-pyrroles in good yields and with high regioselectivity. The reaction displayed excellent functional group compatibility and low moisture sensitivity. Kinetics studies support a mechanism involving phosphine displacement by indole in complex 2 (resting state of the catalyst), followed by a rate-limiting C-H bond metalation.

Journal Article↗
PubMed2005

Design of optical switches as metabolic indicators: new fluorogenic probes for monoamine oxidases (MAO A and B).

This study describes the design of sensitive, selective, and fluorogenic reporter substrates for monoamine oxidase (MAO) enzymes. This was achieved by an iterative effort, guided by PET and TICT photophysical concepts, which led to the development of irreversible redox switches based on a facile oxidation-cyclization reporting mechanism. Specifically, enzymatic oxidation of the ethylamino group in probe 9 proceeded via a putative aldehyde intermediate, which subsequently underwent spontaneous and intramolecular condensation with the aniline amino group furnishing an indole product in an irreversible fashion. This overall change resulted in a significant change in the emission intensity. When expressed in terms of brightness, the origins of this emission switch may be rationalized by the changes in quantum yield and absorbance strength. The fluorescence readout directly correlated with the kinetics of the oxidative step (i.e., reporting mechanism was fast, the intermediate aldehyde was not detected). Probe 9 is a good substrate for MAO B (Km = 510 +/- 40 muM, kcat = 21 min-1) with the kinetic parameters comparable to physiological substrates. This probe not only allows for direct and continuous measurement of MAO activity in mitochondria and tissue homogenates, but more importantly sets the stage for future studies in intact cells and organs.

Coumarins↗
PubMed2005

Site-specific phenylation of pyridine catalyzed by phosphido-bridged ruthenium dimer complexes: a prototype for C-H arylation of electron-deficient heteroarenes.

Direct and selective catalytic arylation of alpha-C-H bond in pyridine with iodobenzene was achieved in up to 70% yield. Phosphido-bridged bisruthenium complexes 6a and 6b arising from Ru3(CO)12 and PPh3 were identified as active catalysts. The formation of complexes 6a and 6b was investigated, a sequence of C-H and C-P bond cleavage, cluster fragmentation, and disproportionation was established, and the intermediate ruthenium complexes lying on this pathway were isolated and fully characterized.

Benzene Derivatives↗
PubMed2005

Two-photon induced uncaging of a reactive intermediate. Multiphoton in situ detection of a potentially valuable label for biological applications.

[reaction: see text] Two-photon induced Wolff rearrangement of a terphenyl diazoketone 1 was achieved by using focused laser pulses of 532 nm from a Q-switched Nd:YAG laser. The nonfluorescent terphenyl diazoketone 1 was transformed into a fluorescent ester derivative 4, which can be detected in situ using the focused laser pulses at 532 nm. Laser power dependence studies show that the Wolff rearrangement is induced by two-photon absorption of the terphenyl diazoketone 1, but suggests that more than two photons of 532 nm are involved (a multiphoton process) in excitation of the ester derivative 4.

Diazomethane↗