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The enantiomeric non-natural cyclic amino acids (3R,4R)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid and (3S,4S)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F...

The non-natural cyclic amino acids (1S,3R,4S)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F]9) and (1S,3S,4R)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F]28) have been prepared in 10% and 1.7% decay corrected radiochemical yield, respectively, and in greater than 99% radiochemical purity. Cell assays in rat 9L glio-sarcoma, human U87 ∆EGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells indi-cated that both compounds are substrates for amino acid transport primarily by system L, with some transport taking place via system ASC. In rats with 9L gliosarcoma, [18F]9 and [18F]28 provided high tumor to normal brain tissue ratios, with maximal ratios of 3.5 and 4.1, respectively. Biodistribution studies in healthy rats confirmed that both compounds are BBB permeable, and that bladder accumulation is low until at least 5 minutes post injection.

Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. We describe here a novel class of positive allosteric modulators of N-methyl D-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential roles in learning, memory, cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel open probability, slows receptor deactivation, in addition to decreasing both single channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium influx, and shows that allosteric modulators can act as biased modulators of ion channel permeation., One Sentence Summary A new generation of NMDA receptor modulators control both channel opening and ionic selectivity of the channel pore.

Ortho-functionalized aryl diselenides are catalytic (5.0 mol %) oxidants for the construction of esters from carboxylic acids and alcohols in the presence of stoichiometric triethyl phosphite and dioxygen in air as the terminal redox reagents (redox dehydration conditions). The reaction proceeds through the intermediacy of the anhydride and requires the presence of 10% DMAP to drive the esterification.

[Image: see text] The enantiomeric non-natural cyclic amino acids (3R,4R)-1-amino-3-fluoro-4-(fluoro-(18)F)cyclopentane-1-carboxylic acid and (3S,4S)-1-amino-3-fluoro-4-(fluoro-(18)F)cyclopentane-1-carboxylic acid ([(18)F]5) have been prepared as a racemic mixture in 1.3% decay corrected radiochemical yield and in greater than 99% radiochemical purity. [(18)F]5 is transported primarily via system L with some transport occurring via system ASC, as assessed in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells. In rats bearing intracranial 9L gliosarcoma, [(18)F]5 gave tumor to contralateral brain tissue ratios of up to 2.8. Biodistribution studies in healthy rats demonstrated that bladder accumulation is delayed until 10 min postinjection.

The non-natural cyclic amino acids (1

Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5-36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic "oxidation-reduction condensation" reactions are carried out open to dry air using O2 as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl phosphate is the easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C-N bonds.

At 2.5 mol % loadings using reaction temperatures between 30-55 °C, ortho-functionalized diaryl diselenides are highly effective organocatalytic oxidants for aerobic redox dehydrative amidic and peptidic bond formation using triethyl phosphite as a simple terminal reductant. This simple-to-perform organocatalytic reaction relies on the ability of selenols to react directly with dioxygen in air without recourse to metal catalysts. It represents an important step toward the development of a general, economical, and benign catalytic redox dehydration protocol.

The first organo-catalyzed silylthioesterification of a carboxylic acid and a commercially available mercaptoorganosilane results in the in situ production of an O -silylthionoester. Subsequent amine addition forms amides in an operationally simple one-pot procedure without removal of water. The scope and efficiency of these reactions with respect to the catalyst, carboxylic acid, amine, [Si–S] moiety, and solvent are investigated. A number of functionalities are tolerated in the two-step amidation including alkene, alkyne, alkyl and aryl halides, benzylic ethers, and heterocycles with free coordinating sites.

A novel uncatalyzed reaction between TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyranyl/dihydropyridinyl) complexes and electron-rich arenes/olefins is reported. The reaction proceeds under mild reaction conditions so that a variety of functional groups are tolerated. Combined with a stereospecific annulative demetalation, the new reaction provides a rapid access to polycyclic alkaloid structures. The sequential protocol was used to prepare analogues of the antimalarial agent isofebrifugine.

Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5–36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic “oxidation–reduction condensation” reactions are carried out open to dry air using O2 as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl phosphate is the easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C–N bonds.

The first organo-catalyzed silylthioesterification of a carboxylic acid and a commercially available mercaptoorganosilane results in the in situ production of an O -silylthionoester. Subsequent amine addition forms amides in an operationally simple one-pot procedure without removal of water. The scope and efficiency of these reactions with respect to the catalyst, carboxylic acid, amine, [Si–S] moiety, and solvent are investigated. A number of functionalities are tolerated in the two-step amidation including alkene, alkyne, alkyl and aryl halides, benzylic ethers, and heterocycles with free coordinating sites.

The density functional theory method is used to elucidate the nature of the active species and the mechanism of the aerobic CuI-catalyzed cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids reported previously (J. Am. Chem. Soc.2007, 129, 15734–15735; Angew. Chem., Int. Ed.2009, 48, 1417–1421). The energetically lowest isomer of the proposed active species [LC(O)R1]Cu-(O2)-Cu[LC(O)R1]2+, 2a (where L = thiolatosalicylamide), is found to be I1(OO,OO), with a μ-η2:η2-peroxo Cu2O2 core, while its isomers I2(OO,OO), with a bis(μ-O) Cu2O2 core, and I3(OO,OO), with a (μ-η1:η1) Cu2O2 core, lie only a few kcal/mol higher and are separated by 4–7 kcal/mol energy barriers. In all these isomers, the thiol ester is coordinated to the Cu centers via its two O ends. Isomers with (SO,OO) and (SO,SO) coordination modes of the thiol esters lie slightly higher and are separated with moderate energy barriers. We found the latter isomers to be vital for the reported CuI-templated cross-coupling of S-acyl ...

The novel reactivity of the O-silylthionoesters with amine nucleophiles to generate oxoamides (rather than thioamides) is described. A straightforward first-generation trimethylsilylation protocol using bistrimethylsilylacetamide (BSA) combined with the unique reactivity of the O-silylthionoesters toward 1° and 2° amines to generate oxoamides provides the simplest means of activating a thiol acid for peptide bond formation at neutral pH. Excellent stereoretention is observed.

Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.

We focus our attention here on semisquaric acid, which is known to show high acidity, as a new proton dissociating group for proton exchange membranes (PEMs). The introduction of a squaric acid group into aromatic polymers was conducted by the reaction of lithiated aromatic polymers and diisopropoxy squarate, followed by treatment with hydrochloric acid. A resulting polyphenylsulfone membrane with the squaric acid group introduced (PPSf-SQ, IEC = 4.1 meq·g(-1) ) showed proton conductivity of 1.0 × 10(-1) S·cm(-1) at 80 °C under 95% relative humidity, which indicates that the semisquaric acid has the potential to become an alternative proton-conducting group for PEMs.

A series of acyclic and cyclic 1-alkoxy- and 1-arylsulfonyloxy-substituted TpMo(CO)(2)(η(3)-allyl) complexes was synthesized and characterized, and exchange of the oxygenated substituent was investigated under a variety of reaction conditions. 1-Alkoxy-substituted η(3)-allyl and η(3)-butenyl complexes participated in direct, uncatalyzed exchange of the alkoxy substituent with benzylamine, but required a Lewis acid for exchange with alcohols. The 1-alkoxy-substituted η(3)-cyclohexenyl complex was unreactive towards exchange under all conditions investigated. The corresponding acyclic arylsulfonyloxy-substituted complexes underwent direct, uncatalyzed exchange with both benzylamine and alcohols, while the arylsulfonyloxy-substituted cyclohexenyl compounds participated in direct substitution with benzylamine, but not alcohols. High enantiopurity acyclic and cyclic alkoxy- and arylsulfonyloxy-substituted complexes provided exchange products with predominant, but incomplete, losses in enantiomeric excess in all cases examined. Mechanisms accounting for the observed reactivity trends and for the losses in enantiomeric excess are discussed. Reaction of alkoxy-substituted complexes through an associative mechanism and of arylsulfonyloxy-substituted compounds through a dissociative mechanism is suggested.

Computational studies of the mechanism of the Pd-catalyzed, Cu(I)-carboxylate-mediated desulfitative coupling of thioorganics with boronic acids have determined that the requisite Cu(I)-carboxylate plays multiple important roles. The Cu(I)-carboxylate enhances both the transmetalation and the C-C reductive elimination steps: it acts as a reactive transmetalation center and it provides a vital carboxylate ligand. The carboxylate ligand functions not only as an activator for the boronic acid, but it also displaces a phosphine ligand at the palladium center generating a catalytically competent mono-phosphine-palladium intermediate.

Fumonisin B(1) (FB(1)) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. Inhibition of CerS by FB(1) increases sphinganine (Sa), Sa 1-phosphate, and a previously unidentified metabolite. Analysis of the latter by quadrupole-time-of-flight mass spectrometry assigned an m/z = 286.3123 in positive ionization mode, consistent with the molecular formula for deoxysphinganine (C(18)H(40)NO). Comparison with a synthetic standard using liquid chromatography, electrospray tandem mass spectrometry identified the metabolite as 1-deoxysphinganine (1-deoxySa) based on LC mobility and production of a distinctive fragment ion (m/z 44, CH(3)CH=NH (+)(2)) upon collision-induced dissociation. This novel sphingoid base arises from condensation of alanine with palmitoyl-CoA via serine palmitoyltransferase (SPT), as indicated by incorporation of l-[U-(13)C]alanine into 1-deoxySa by Vero cells; inhibition of its production in LLC-PK(1) cells by myriocin, an SPT inhibitor; and the absence of incorporation of [U-(13)C]palmitate into 1-[(13)C]deoxySa in LY-B cells, which lack SPT activity. LY-B-LCB1 cells, in which SPT has been restored by stable transfection, however, produce large amounts of 1-[(13)C]deoxySa. 1-DeoxySa was elevated in FB(1)-treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK(1) and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB(1), substantial amounts of 1-deoxySa are made and acylated to N-acyl-1-deoxySa (i.e. 1-deoxydihydroceramides). Thus, these compounds are an underappreciated category of bioactive sphingoid bases and "ceramides" that might play important roles in cell regulation.

An efficient synthesis of high enantiopurity N-protected alpha-amino ketones is described. Complementing other studies using boronic acids and thiol esters, this Cu(I) diphenylphosphinate (CuDPP)-mediated, palladium-catalyzed coupling of alpha-amino thiol esters with aryl, heteroaryl, allyl, and alkenyl organostannanes gives N-protected alpha-amino ketones in high yields with high enantiopurity (in almost all cases) under mild and pH-neutral reaction conditions. The viability of pi-deficient heteroarylstannanes is an advantage of this reaction compared to the related boronic acid system.

A general nonoxidative N-amidation of organostannanes and boronic acids has been developed. Under nonbasic conditions a wide variety of aryl, alkenyl, and heteroaryl organostannanes and boronic acids couple efficiently with O-acetyl hydroxamic acids in the presence of Cu(I) sources.

6-Substituted TpMo(CO) 2(eta-2,3,4-pyranyl)- and TpMo(CO) 2(eta-2,3,4-pyridinyl) scaffolds (Tp = hydridotrispyrazolylborato) function as reaction partners in an efficient regio- and stereocontrolled synthesis of functionalized oxa- and azabicyclo[3.2.1]octenes through a novel Brønsted acid catalyzed [5 + 2] cycloaddition reaction. Excellent exo-selectivities are obtained, and the reaction gives products with complete retention of enantiomeric purity when carried out with chiral, nonracemic scaffolds. The substituent at C-6 of the eta (3)-coordinated heterocyclic scaffold not only influences [5 + 2] reactivity but also plays a critical role in the demetalation step directing the reaction to only one of two possible products.

A unified strategy for the high-throughput synthesis of multigram quantities of the eta(3)-oxopyranyl- and eta(3)-oxopyridinylmolybdenum complexes TpMo(CO)(2)(eta(3)-oxopyranyl) and TpMo(CO)(2)(eta(3)-oxopyridinyl) is described (Tp = hydridotrispyrazolylborato). The strategy uses the oxa- and aza-Achmatowicz reaction for the preparation of these organometallic enantiomeric scaffolds, in both racemic and high enantiopurity versions.

Bisarylthiocyclobutenedione 7 reacted smoothly with a variety of both organostannanes and (hetero)arylboronic acids in the presence of a catalytic amount of Pd and a stoichiometric amount of CuTC to produce symmetrical disubstituted cyclobutenediones in yields that range from 37 to 94% (18 examples).

alpha-Amino acid thiol esters derived from N-protected mono-, di-, and tripeptides couple with aryl, pi-electron-rich heteroaryl, or alkenyl boronic acids in the presence of stoichiometric Cu(I) thiophene-2-carboxylate and catalytic Pd(2)(dba)(3)/triethylphosphite to generate the corresponding N-protected peptidyl ketones in good-to-excellent yields and in high enantiopurity. Triethylphosphite plays a key role as a supporting ligand by mitigating an undesired palladium-catalyzed decarbonylation-beta-elimination of the alpha-amino thiol esters. The peptidyl ketone synthesis proceeds at room temperature under nonbasic conditions and demonstrates a high tolerance to functionality.

TpMo(CO)2(5-alkenyl-eta-2,3,4-pyranyl) diene complexes function as excellent chiral scaffolds for the efficient regio- and enantiocontrolled synthesis of highly functionalized 1-oxadecaline derivatives through a novel transition metal-mediated Diels-Alder reaction. Very good to excellent yields and excellent levels of endo selectivity are obtained, and the reaction gives products with complete retention of enantiomeric purity when carried out with chiral, nonracemic scaffolds. A subtle structural modification on the diene (replacement of an H by a trans-CH3 group) leads to a complete change of regiochemistry, which is discussed from a mechanistic point of view. The role of the eta3-coordinated TpMo(CO)2 moiety is also critical to the further functionalization of the [4 + 2] cycloadducts, as illustrated by the preparation of 20 variously functionalized 1-oxadecaline derivatives (98% ee when carried out with high enantiopurity scaffolds).

Bao Gong Teng A, an optically active tropane alkaloid with hypotensive and miotic activity isolated from the Chinese herb Erycibe obtusifolia Benth, was synthesized by an "organometallic chiron" strategy in which single enantiomers of TpMo(CO)(2)(eta(3)-pyridinyl) complexes are produced in quantity and then elaborated easily and efficiently to generate, after demetalation, highly enantiopure advanced synthetic intermediates possessing the tropane core.

[reaction: see text] A general demonstration of orthogonal selectivity of the Liebeskind-Srogl cross-coupling protocol compared to the Suzuki-Miyaura and Stille variants is reported.

[reaction: see text] A new synthesis of thioethers is described. The reaction of boronic acids with aryl, heteroaryl, and alkyl N-thioimides in the presence of catalytic quantities of a Cu(I) carboxylate affords good to excellent yields of thioethers. This reaction takes place in the absence of a base under mild conditions (THF, 45-50 degrees C, 2.5-12 h) and represents an interesting complement to known methods for thioether synthesis.

An efficient and general oxidative demetalation of (eta(3)-allyl)molybdenum complexes using pyridinium dichromate allows the introduction of a carbonyl group at an allylic terminus of the pi-system. The process takes place with high regiocontrol and can lead to the preparation of unsaturated ketones and lactones of high enantiopurity.

Given the stability of the bond between a mercaptide ligand and various redox-active metals, it is of interest that Nature has evolved significant metalloenzymatic processes that involve key interactions of sulfur-containing functionalities with metals such as Ni, Co, Cu, and Fe. From a chemical perspective, it is striking that these metals can function as robust biocatalysts in vivo, even though they are often "poisoned" as catalysts in vitro through formation of refractory metal thiolates. Insight into the nature of this chemical discrepancy is under study in order to open new procedures in synthetic organic and organometallic chemistry.

[reaction: see text] A new protocol for the palladium-catalyzed, copper-mediated coupling of aryl and alkenyl iodides with boronic acids is described. As an alternative to the well-known and widely used Suzuki cross-coupling, this reaction occurs in the absence of a base at room temperature and should be particularly useful for the construction of substrates bearing base-sensitive and thermally sensitive moieties.

The synthesis of meso-linked quinone-porphyrin-porphyrin-quinone tetrads has been accomplished by the simple treatment of a CH2Cl2 solution of zincated 5-substituted-10,20-diphenylporphyrins (where the substituent = 3-cyclobutenyl-1,2-dione, various quinonyl derivatives, and p-anisyl) with 2,3-dichloro-5,6-dicyanoquinone (DDQ). The zincated porphyrinic quinones were synthesized from 5-(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Zn). The meso-linked dimer of 5-(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Zn) was also shown to be a useful precursor to meso-linked quinone-porphyrin-porphyrin-quinone tetrads. This DDQ-based oxidative dimerization appears to be general and effective for various zincated 5-substituted-10,20-diphenylporphyrins bearing both electron-withdrawing and -donating substituents. The oxidative dimerization was very sensitive to the reaction solvent (dimerization occurred in CH2Cl2, not in THF) and required the zincated porphyrins (the corresponding free base porphyrins did not undergo dimerization). When this solvent effect was applied to the reaction of I2/AgO2CCF3 with zincated porphyrins, either the dimeric porphyrins or iodoporphyrins could be selectively prepared simply by selecting methylene chloride or THF as the reaction solvent, respectively.

1,2-Addition of N-Boc-protected α-amino carbanions to cyclobutenediones followed by methylation of the resulting alkoxides generated 4-(1-N-Boc-aminoalkyl)-4-methoxy-3-cyclobutenones. Removal of the Boc protecting group and thermal ring expansion gave dihydro-2-pyridinones in good yields. Treatment of the dihydro-2-pyridinones with NBS/pyridine led to the formation of the corresponding 2-pyridinones. This methodology proved general with regard to both the cyclobutenediones and α-amino carbanions.

2-Unsubstituted hydroquinone monoacetates, quinones, and 3-unsubstituted quinolizinones were synthesized in moderate to high yields via tert-butyl and trimethylsilyl substituted cyclobutenediones. ...

A new method for the synthesis of nitriles is described. As a complement to the classic cyanation of aryl halides using cyanide sources and a transition metal catalyst, the palladium-catalyzed cross-coupling of thiocyanates with boronic acids in the presence of copper(I) thiophene-2-carboxylate (CuTC) affords nitriles in good to excellent yields.

1-BOC-2-lithio-1,4-dihydropyridines were condensed with 3,4-disubstituted cyclobutenediones to produce 1,2-adducts. Neat thermolysis under oxygen-free conditions produced substituted 1,4-dihydroquinoline hydroquinones in which the tert-butoxy residue of the BOC group was displaced by a phenolic residue, generating an oxazolone ring that functioned to protect both rings of the dihydroquinoline hydroquinone from untimely oxidation. Oxidative aromatization with concomitant loss of the oxazolone ring was achieved using 2 equiv of o-chloranil in acetic acid and provided substituted quinoline quinones in good yields. By use of this strategy, a concise synthesis of the pyridoacridine ring system was achieved.

Described in this paper is a new synthetic approach to angularly-fused and simpler substituted xanthones that is based upon the benzannulation of 2-(o-anisoyl)-4-heteroaryl-2-cyclobutenones and 2-(2-(o-anisyl)-1,3-dithian-2-yl)-4-alkenyl-2-cyclobutenones followed by facile intramolecular loss of methanol and cyclization to the xanthone.

The Density Functional Theory (DFT) method is used to elucidate the nature of the active species and the mechanism of the aerobic CuI-catalyzed cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids reported previously (J. Am. Chem. Soc. 2007, 129, 15734–15735; Angew. Chem., Int. Ed. 2009, 48, 1417-1421). The energetically lowest isomer of the proposed active species [LC(O)R1]Cu-(O2)-Cu[LC(O)R1]2+, 2a, (where L = thiolatosalicylamide) is found to be I1(OO,OO) with a μ-η2:η2-peroxo Cu2O2-core, while its isomers I2(OO,OO) with a bis-(μ-O) Cu2O2-core and I3(OO,OO) with a (μ-η1:η1) Cu2O2-core lie only a few kcal/mol higher and separated by 4–7kcal/mol energy barriers. In all these isomers, the thiol ester is coordinated to the Cu-centers via its two O-ends. Isomers with (SO,OO) and (SO,SO) coordination modes of the thiol esters lie slightly higher and are separated with moderate energy barriers. We found the latter isomers to be vital for the reported CuI-templated cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids under aerobic conditions. The presence of an anion (halide, carboxylate modeled as formate) in the reaction medium is found to be necessary. Its coordination to the active catalyst I1(SO,SO) is the first step of the proposed anion-assisted transmetalation by boronic acid. Overall the transmetalation reaction requires 34.0 kcal/mol and is 24.0 kcal/mol exergonic. This conclusion is in reasonable agreement with available experiments. The C-C bond formation in the transmetalation product requires a 6.3 kcal/mol lower energy barrier and is highly exergonic.

From the corresponding TpMo(CO)2(π-allyl) complexes, four symmetrically substituted TpMo(CO)(NO)(π-allyl)+ complexes (π-allyl = propenyl, 2-methylpropenyl, cyclohexenyl, and cyclooctenyl) were prep...