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Four 3-D coordination polymers of lanthanide with a tetra(amino acid) ligand, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid (H4L, 1), were synthesized. The structure of the Gd(III) complex was characterized. The fluorescence of the Eu(III) complex can be modulated by Ag+.
N-(omega-Bromoalkyl)-amino acid derivatives, readily prepared from natural alpha-amino acids, gave cyclic amino acids with a quaternary stereocenter by treatment with potassium hexamethyldisilazaide in DMF. The chirality of parent amino acids was almost completely preserved during an enolate-formation and cyclization process, giving aza-cyclic amino acids in up to 98% ee in retention of configuration. This method is applicable to the asymmetric synthesis of azetidine, pyrrolidine, piperidine, and azepane derivatives. The asymmetric cyclization seems to proceed via an axially chiral enolate intermediate and not through a concerted SEi process.
A water-soluble turn-on fluorescent sensor for Hg(II) is described. Incorporation of soft thioether donors into an aniline-derived ligand framework that can be linked to a fluorescein platform affords sensor MS1, which shows a approximately 5-fold increase in integrated emission upon addition of 1 equiv of Hg(II). The synthesis and metal-binding properties of MS1 are discussed, and its ability to detect environmentally relevant concentrations of Hg(II) is demonstrated.
Azapeptides, peptide analogues in which the alpha-carbon of one or more of the amino acid residues is replaced with a nitrogen atom, exhibit propensity for adopting beta-turn conformations. A general protocol for the synthesis of azapeptides without racemization on solid phase has now been developed by introducing the aza-amino acid residue as an N-Boc-aza(1)-dipeptide. This approach has been validated by the synthesis of six N-Boc-aza(1)-dipeptides and their subsequent introduction into analogues of the C-terminal peptide fragment of the human calcitonin gene-related peptide (hCGRP). By performing an aza-amino acid scan of such antagonist peptides, a set of aza-hCGRP analogues was synthesized to examine the relationship between turn secondary structure and biological activity.
Catalytic signal enhancement using an organometallic reaction is demonstrated. The reactivity of a Heck cross-coupling reaction that creates a fluorophore is modulated by the addition of a polyazacyclam inhibitor. The inhibitor will complex with Cu(II), which restores the activity of the Pd(II). The addition of Cu(II) therefore leads to the generation of fluorescence, thereby creating a very sensitive assay for Cu(II). The rate of the Heck reaction is followed by monitoring emission as a function of time. The rate is proportional to the Cu(II) concentration and correlates to the affinity of the inhibitor to various metals. This strategy represents a general technique that can be exploited with other catalytic organometallic reactions.
Chlorination-elimination chemistry coupled with three-component Joullié-Ugi reaction and facile deprotection allowed efficient access to an array of polyhydroxylated pyrrolidines through parallel synthesis that may be considered to be a library of imino (aza) sugars (glycomimetics) and/or dihydroxyprolyl peptides (peptidomimetics). The utility of generating such a library was illustrated by screening against 15 different targets that revealed potent and selective inhibition of the Gaucher's disease glycosyltransferase enzyme glucosylceramide synthase and of primary pathogen model for human hepatitis C virus (HCV) and bovine diarrhoeal virus (BVDV). An observed selectivity for this HCV model over hepatitis B virus and remarkably low toxicity suggest a novel mode of action.
We report herein a silver(I)-catalyzed exo-selective synthesis of highly substituted Delta1-pyrroline scaffolds from amino acid-derived münchnones. Silver acetate successfully catalyzed the cycloaddition reaction of azlactones with alkenes, generating Delta1-pyrrolines in very good yields without isomerization to the Delta2-pyrrolines or decarboxylation.
Deamination at C6 of adenosine in RNA catalyzed by the ADAR enzymes generates inosine at the corresponding position. Because inosine is decoded as guanosine during translation, this modification can lead to codon changes in messenger RNA. Hydration of 8-azanebularine across the C6-N1 double bond generates an excellent mimic of the transition state proposed for the hydrolytic deamination reaction catalyzed by ADARs. Here, we report the synthesis of a phosphoramidite of 8-azanebularine and its use in the preparation of RNAs mimicking the secondary structure found at a known editing site in the glutamate receptor B subunit pre-mRNA. The binding properties of analogue-containing RNAs indicate that a tight binding ligand for an ADAR can be generated by incorporation of 8-azanebularine. The observed high-affinity binding is dependent on a functional active site, the presence of one, but not the other, of ADAR2's two double-stranded RNA-binding motifs (dsRBMs), and the correct placement of the nucleoside analogue into the sequence/structural context of a known editing site. These results advance our understanding of substrate recognition during ADAR-catalyzed RNA editing and are important for structural studies of ADAR.RNA complexes.
Chromophores based on a donor-acceptor-donor structure possessing a large two-photon absorption cross section and one or two mono-aza-15-crown-5 ether moieties, which can bind metal cations, have been synthesized. The influence of Mg(2+) binding on their one- and two-photon spectroscopic properties has been investigated. Upon binding, the two-photon action cross sections at 810 nm decrease by a factor of up to 50 at high Mg(2+) concentrations and this results in a large contrast in the two-photon excited fluorescence signal between the bound and unbound forms, for excitation in the range of 730 to 860 nm. Experimental and computational results indicate that there is a significant reduction of the electron donating strength of the aza-crown nitrogen atom(s) upon metal ion binding and that this leads to a blue shift in the position as well as a reduction in the strength of the lowest-energy two-photon absorption band. The molecules reported here can serve as models for the design of improved two-photon excitable metal-ion sensing fluorophores.
Thermolysis of 5-azidoallenes bearing a C(1) methyl group and either an aryl ring or an alkene on C(1) furnishes tricyclic (from the aryl substrates) or bicyclic (from the alkenyl substrates) pyrrolidine products following formal H-CN addition across an intermediate imine. High levels of diastereoselectivity are observed in all cases studied. This reaction cascade presumably passes through unobserved triazoline and azatrimethylenemethane diyl intermediates en route to product.
A process for preparation of amides from unactivated esters and amines has been developed using a catalytic system comprised of group (IV) metal alkoxides in conjunction with additives including 1-hydroxy-7-azabenzotriazole (HOAt). In general, ester-amide exchange proceeds using a variety of structurally diverse esters and amines without azeotropic reflux to remove the alcohol byproduct. Initial mechanistic studies on the Zr(Ot-Bu)4-HOAt system revealed that the active catalyst is a novel, dimeric zirconium complex as determined by X-ray crystallography.
cis-Dioxoruthenium(VI) complex [(Me(3)tacn)(CF(3)CO(2))Ru(VI)O(2)]ClO(4) (1, Me(3)tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane) reacted with alkenes in aqueous tert-butyl alcohol to afford cis-1,2-diols in excellent yields under ambient conditions. When the reactions of 1 with alkenes were conducted in acetonitrile, oxidative C=C cleavage reaction prevailed giving carbonyl products in >90% yields without any cis-diol formation. The alkene cis-dihydroxylation and C=C cleavage reactions proceed via the formation of a [3 + 2] cycloadduct between 1 and alkenes, analogous to the related reactions with alkynes [Che et al. J. Am. Chem. Soc. 2000, 122, 11380]. With cyclooctene and trans-beta-methylstyrene as substrates, the Ru(III) cycloadducts (4a) and (4b) [formula; see text] were isolated and structurally characterized by X-ray crystal analyses. The kinetics of the reactions of 1 with a series of p-substituted styrenes has been studied in acetonitrile by stopped-flow spectrophotometry. The second-order rate constants varied by 14-fold despite an overall span of 1.3 V for the one-electron oxidation potentials of alkenes. Secondary kinetic isotope effect (KIE) was observed for the oxidation of beta-d(2)-styrene (k(H)/k(D) = 0.83 +/- 0.04) and alpha-deuteriostyrene (k(H)/k(D) = 0.96 +/- 0.03), which, together with the stereoselectivity of cis-alkene oxidation by 1, is in favor of a concerted mechanism.
The full details of a catalytic asymmetric aza-Michael reaction of methoxylamine promoted by rare earth-alkali metal heterobimetallic complexes are described, demonstrating the effectiveness of Lewis acid-Lewis acid cooperative catalysis. First, enones were used as substrates, and the 1,4-adducts were obtained in good yield (57-98%) and high ee (81-96%). Catalyst loading was successfully reduced to 0.3-3 mol % with enones. To broaden the substrate scope of the reaction to carboxylic acid derivatives, alpha,beta-unsaturated N-acylpyrroles were used as monodentate, carboxylic acid derivatives. With beta-alkyl-substituted N-acylpyrroles, the reaction proceeded smoothly and the products were obtained in high yield and good ee. Transformation of the 1,4-adducts from enones and alpha,beta-unsaturated N-acylpyrroles afforded corresponding chiral aziridines and beta-amino acids. Detailed mechanistic studies, including kinetics, NMR analysis, nonlinear effects, and rare earth metal effects, are also described. The Lewis acid-Lewis acid cooperative mechanism, including the substrate coordination mode, is discussed in detail.
The synthesis of N-protected allylic amines has been achieved utilizing a palladium(II)-catalyzed, [3,3]-rearrangement of (allyloxy) iminodiazaphospholidines. This [3,3]-aza-phospha-oxa-Cope sigmatropic rearrangement reaction is thermodynamically driven by a P=N to P=O interconversion and is an alternative to the Overman rearrangement. The overall process involves the nucleophilic displacement of an allylic alcohol onto a P(III) precursor, followed by a Staudinger reaction to generate the (allyloxy) iminodiazaphospholidine precursors. Pd(II)-catalyzed [3,3]-aza-phospha-oxa-Cope rearrangement then gives a phosphoramide, which is readily hydrolyzed under acidic conditions to yield allylic amine derivatives. Pd(II) catalysis is believed to occur in a fashion analogous to that of the rearrangement of allylic imidates. The scope of racemic, diastereoselective, and enantioselective variants of this rearrangement is described. The use of chiral diamine auxiliaries in diastereoselective rearrangements is reported. Rearrangement of chiral N,N'-dimethyl cyclohexanediamine derived diazaphospholidines gives rise to phosphoramides with moderate diastereoselectivities (up to 3.5:1 dr). The same major diastereomeric product in these rearrangements was prepared irrespective of the starting allylic alcohol geometry. An enantioselective variant of the reaction was demonstrated for the rearrangement of cis-(allyloxy) iminodiazaphospholidines with cobalt oxazoline palladacycle (COP-X) catalysts (5 mol %) in high yield and enantioselectivity (up to 96% ee).
A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0(2,8)]decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0(2,8)]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0(2,8)]decanone 18, a central intermediate in our total of (+/-)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.
The first detailed study of a room-temperature asymmetric Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadienes is reported enlisting a series of 19 enol ethers bearing chiral auxiliaries, with many providing highly diastereoselective (endo and facial diastereoselection) reactions, largely the result of an exquisitely organized [4+2] cycloaddition transition state. Three new, readily accessible, and previously unexplored auxiliaries rationally emerged from the studies and provide remarkable selectivities (two of these give 49:1 endo:exo and 48:1 facial selectivity) that promise to be useful in systems beyond those detailed.
The cyclization of functionalized aminophosphonates is studied on both experimental and theoretical grounds. In a recently described route to phosphono-beta-lactams [Stevens C. V.; Vekemans, W.; Moonen, K.; Rammeloo, T. Tetrahedron Lett. 2003, 44, 1619], it was found that starting from an ambident allylic anion only four-membered rings were formed without any trace of six-membered lactams. New anion trapping experiments revealed that the gamma-anion is highly reactive in intermolecular reactions. Ab initio calculations predict higher reaction barriers for the gamma-anion due to restricted rotation about the C-N bond and due to highly strained transition states during ring closure. The sodium or lithium counterion, explicit dimethyl ether solvent molecules, and bulk solvent effects were properly taken into account at various levels of theory.
The tandem [4+2]/[3+2] cycloaddition of nitroalkenes has been employed in the synthesis of 1-azafenestranes, molecules of theoretical interest because of planarizing distortion of their central carbon atoms. The synthesis of c,c,c,c-[5.5.5.5]-1-azafenestrane was completed in good yield from a substituted nitrocyclopentene, and its borane adduct was analyzed through X-ray crystallography, which showed a moderate distortion from ideal tetrahedral geometry. The syntheses of two members of the [4.5.5.5] family of 1-azafenestranes are also reported, including one with a trans fusion at a bicyclic ring junction which brings about considerable planarization of one of the central angles (16.8 degrees deviation from tetrahedral geometry). While investigating the [4.5.5.5]-1-azafenestranes, a novel dyotropic rearrangement that converts nitroso acetals into tetracyclic aminals was discovered. Through conformational analysis, a means to prevent this molecular reorganization was formulated and realized experimentally with the use of a bulky vinyl ether in the key [4+2] cycloaddition reaction. Finally, DFT calculations on relative strain energy for the 1-azafenestranes, as well as their predicted central angles, are disclosed.