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The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer’s disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD. ispartof: SCIENCE TRANSLATIONAL MEDICINE vol:14 issue:627 ispartof: location:United States status: published

All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition., Various herpesvirus therapeutics target the viral DNA polymerase. Here, the authors present the crystal structure of herpesvirus polymerase in the elongating state with bound primer-template DNA and the broad-spectrum non-nucleoside inhibitor PNU-183792, which is of interest for further drug design.

[Image: see text] By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite 1 lacking structural and binding similarity to known FTase inhibitors. Although multiple lines of evidence established the binding interaction, these ligands exhibited minimal inhibitory activity in a cell-free biochemical FTase inhibition assay. Subsequent modification of the biochemical assay by increasing anion concentration demonstrated FTase inhibitory activity in this novel class. We propose 1 binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed.

Increasing amounts of biological data are accumulating in the pharmaceutical industry and academic institutions. However, data does not equal actionable information, and guidelines for appropriate data capture, harmonization, integration, mining, and visualization need to be established to fully harness its potential. Here, we describe ongoing efforts at Merck & Co. to structure data in the area of chemogenomics. We are integrating complementary data from both internal and external data sources into one chemogenomics database (Chemical Genetic Interaction Enterprise; CHEMGENIE). Here, we demonstrate how this well-curated database facilitates compound set design, tool compound selection, target deconvolution in phenotypic screening, and predictive model building.

Delivery of macromolecular cargos such as siRNA to the cytosol after endocytosis remains a critical challenge. Numerous approaches including viruses, lipid nanoparticles, polymeric constructs, and various peptide-based approaches have yet to yield a general solution to this delivery issue. In this manuscript, we describe our efforts to design novel endosomolytic peptides that could be used to facilitate the release of cargos from a late endosomal compartment. These amphiphilic peptides, based on a chimeric influenza hemagglutinin peptide/cell-penetrating peptide (CPP) template, utilize a pH-triggering mechanism in which the peptides are protonated after acidification of the endosome, and thereby adopt an alpha-helical conformation. The helical forms of the peptides are lytically active, while the non-protonated forms are much less or non-lytically active at physiological pH. Starting from an initial lead peptide (INF7-Tat), we systematically modified the sequence of the chimeric peptides to obtain peptides with greatly enhanced lytic activity that maintain good pH selectivity in a red blood cell hemolysis assay.

An efficient multicomponent orthogonal protocol was developed for post-synthetic oligonucleotide modification using commercially available 2'- O-methyl ester and 2'- O-propargyl nucleoside scaffolds. Amidation of methyl esters with primary amines was achieved in the presence of 2'-propargyl groups which were utilized for subsequent copper catalyzed cycloaddition with GalNAc-azide. The methodology was applied to generate siRNA composed of multiple amide and triazole conjugates. Computational methods were used to illustrate the impact of substitution at the 2'-position. This a powerful post-oligomerization technique for rapidly introducing diversity to oligonucleotide design.

A practical synthesis of a macrocyclic HCV protease inhibitor, MK-1220, is described. The key features are a new synthesis of the trisubstituted isoquinoline, Sonogashira fragment coupling, and a high-yielding, 18-membered macrolactam formation.

The synthesis, computer modeling, and biological activity of an octawalled molecular umbrella short interfacing RNA (siRNA) conjugate is described. This molecular umbrella-siRNA conjugate exhibited mRNA knockdown activity in vitro in the absence of a transfection reagent. Evaluation of this molecular umbrella conjugate in vivo, using the rat eye via intravitreal injection, resulted in sequence specific mRNA knockdown in the retina with no obvious signs of toxicity, as judged by ophthalmic examination.

Design The HIV latent CD4+ T cell reservoir is broadly recognized as a barrier to HIV cure. Induction of HIV expression using protein kinase C (PKC) agonists is one approach under investigation for reactivation of latently infected CD4+ T cells (Beans et al., 2013; Abreu et al., 2014; Jiang et al., 2014; Jiang and Dandekar, 2015). We proposed that an increased understanding of the molecular mechanisms of action of PKC agonists was necessary to inform on biological signaling and pharmacodynamic biomarkers. RNA sequencing (RNA Seq) was applied to identify genes and pathways modulated by PKC agonists. Methods Human CD4+ T cells were treated ex vivo with Phorbol 12-myristate 13-acetate, prostatin or ingenol-3-angelate. At 3 h and 24 h post-treatment, cells were harvested and RNA-Seq was performed on RNA isolated from cell lysates. The genes differentially expressed across the PKC agonists were validated by quantitative RT-PCR (qPCR). A subset of genes was evaluated for their role in HIV reactivation using siRNA and CRISPR approaches in the Jurkat latency cell model. Results Treatment of primary human CD4+ T cells with PKC agonists resulted in alterations in gene expression. qPCR of RNA Seq data confirmed upregulation of 24 genes, including CD69, Egr1, Egr2, Egr3, CSF2, DUSP5, and NR4A1. Gene knockdown of Egr1 and Egr3 resulted in reduced expression and decreased HIV reactivation in response to PKC agonist treatment, indicating a potential role for Egr family members in latency reversal. Conclusion Overall, our results offer new insights into the mechanism of action of PKC agonists, biomarkers of pathway engagement, and the potential role of EGR family in HIV reactivation.

Concentration determination by HPLC analysis is often utilized in pharmaceutical development activities. Traditionally, manual dilutions employing volumetric glassware have to be performed to obtai...

Development of a practical synthesis of MK-7009, a 22-membered macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.

Effective delivery of siRNA (small interfering RNA) into the cells requires the translocation of siRNA into the cytosol. One potential delivery strategy uses cell-delivery peptides that facilitate this step. In the present paper, we describe the characterization of an amphipathic peptide that mediates the uptake of non-covalently bound siRNA into cells and its subsequent release into the cytosol. Biophysical characterization of peptide and peptide/siRNA mixtures at neutral and lysosomal (acidic) pH suggested the formation of α-helical structure only in endosomes and lysosomes. Surprisingly, even though the peptide enhanced the uptake of siRNA into cells, no direct interaction between siRNA and peptide was observed at neutral pH by isothermal titration calorimetry. Importantly, we show that peptide-mediated siRNA uptake occurred through endocytosis and, by applying novel endosomal-escape assays and cell-fractionation techniques, we demonstrated a pH-dependent alteration in endosome and lysosome integrity and subsequent release of siRNA and other cargo into the cytosol. These results indicate a peptide-mediated siRNA delivery through a pH-dependent and conformation-specific interaction with cellular membranes and not with the cargo.

An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor antagonist candidate is described. The synthesis is characterized by a novel intramolecular Friedel−Crafts cyclization of an imino-pyrrole to prepare the azaindole core. Other key steps include a highly selective Horner−Wadsworth−Emmons olefination of a tricyclic ketone intermediate and subsequent catalytic asymmetric hydrogenation of a trisubstituted α,β-unsaturated ester to install the chirogenic center. Finally, a new indole sulfenylation protocol was developed to install the aromatic thioether functionality in good yield.

The development of practical and efficient syntheses of the potent non-nucleoside reverse transcriptase inhibitors 1 and 2 is described. The preparation of 1 proceeded in four synthetic steps and in 48% overall yield from 3. The long-term synthesis of 2 proceeded in nine synthetic steps and in 47% overall yield from commercially available 2,6-diflurorpyridine. The route to 2 was highlighted by the three-step synthesis of intermediate 22 and the high yielding coupling between 18 and phenol 8. The overall sequence required no chromatography and has successfully been utilized for the manufacture of 2 on large scale.

The synthesis of compound 1 by deprotection of the THP, tert-butyl protected amino-pyrazolopyridine (2), is described. The original conditions for this transformation were conducted in a one-pot procedure and necessitated the use of large quantities of either TsOH or benzenesulfonic acid (5 equiv) and trifluoroacetic acid (10−25 equiv) and produced 1 in moderate yield (50−65%). A series of high-throughput screens of Bronstead acids, Lewis acids, and solvents was rapidly performed with the goal of identifying improved efficiency and reaction yield. Through these screens, sulfuric acid was discovered to be a suitable replacement; however, yields of 1 were still unacceptable. A decoupling of the two deprotection steps revealed that the THP byproduct resulting from removal of the THP protecting group was problematic in the subsequent removal of the tert-butyl group. Consequently, a two-step deprotection protocol was developed which, in combination with design of experiment (DOE) optimization, improved the ove...

There are many opportunities to use macromolecules, such as peptides and oligonucleotides, for intracellular applications. Despite this, general methods for delivering these molecules to the cytosol in a safe and efficient manner are not available. Efforts to develop a variety of intracellular drug delivery systems such as viral vectors, lipoplexes, nanoparticles, and amphiphilic peptides have been made, but various challenges such as delivery efficiency, toxicity, and controllability remain. A central challenge is the ability to selectively perturb, not destroy, the membrane to facilitate cargo introduction. Herein, we describe our efforts to design and characterize peptides that form pores inside membranes at acidic pH, so-called pH-switchable pore formation (PSPF) peptides, as a potential means for facilitating cargo translocation through membranes. Consistent with pore formation, these peptides exhibit low-pH-triggered selective release of ATP and miRNA, but not hemoglobin, from red blood cells. Consistent with these observations, biophysical studies (tryptophan fluorescence, circular dichroism, size-exclusion chromatography, analytical ultracentrifugation, and attenuated total reflectance Fourier transformed infrared spectroscopy) show that decreased pH destabilizes the PSPF peptides in aqueous systems while promoting their membrane insertion. Together, these results suggest that reduced pH drives insertion of PSPF peptides into membranes, leading to target-specific escape through a proposed pore formation mechanism.

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.

Two methods are reported for synthesizing a chiral allylic alcohol from the corresponding racemic α,β-unsaturated ketone. Transition metal-based transfer hydrogenation provides the desired allylic alcohol in high enantiomeric purity but low diastereomeric excess. In contrast, an enzymatic dynamic kinetic reduction proceeds with high diastereoselectivity and enantioselectivity.

A novel sulfoxide-directed borane reduction was shown to give a variety of 2-substituted 1,4-dihydrobenzoxathiins. For all substrates evaluated, the reaction is completely stereospecific. Application of this methodology to the chiral synthesis of an artificial sweetener was demonstrated.

The discovery and optimization of the highly enantioselective asymmetric hydrogenation of an α-alkoxy substituted ketone is described. The use of a ruthenium (phosphinoferrocenyl)oxazoline catalyst and the appropriate choice of a solvent and a base is the key to the success of this transformation.

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).

Chemical modification of siRNA is achieved in a high-throughput manner (96-well plate format) by copper catalyzed azide–alkyne cycloadditions. This transformation can be performed in one synthetic operation at up to four positions with complete specificity, good yield, and acceptable purity. As demonstrated here, this approach extends the current synthetic options for oligonucleotide modifications and simultaneously facilitates the systematic, rapid biological evaluation of modified siRNA.

Synthesis and characterization of a set of iridium(III) compounds utilizing the sterically encumbering hydridotris(3,5-dimethylpyrazolyl)borate ligand (TpMe2) has been performed, and a comparison with the corresponding Cp* complexes is presented. TpMe2(PMe3)Ir(Me)OTf (7, OTf = O3SCF3) was synthesized and found to be unreactive toward a variety of C−H bonds, in contrast to the behavior of Cp*(PMe3)Ir(Me)OTf (1). We have rationalized this lack of reactivity in terms of an electronic effect rather than a steric effect imposed by the TpMe2 ligand. Metathesis of the triflate ligand with the BArf (BArf = B[3,5-C6H3(CF3)2]4) anion under a N2 atmosphere produces the dinitrogen complex [TpMe2(PMe3)Ir(N2)(Me)][BArf] (3-N2). Compound 3-N2 is indeed reactive toward dative ligands, H2, and hydrocarbons, activating the C−H bonds of benzene and aldehydes but not those of saturated hydrocarbons. A rationale for the difference in behavior between the Cp* and TpMe2 systems with respect to C−H activation is presented.

The synthesis of the cationic hydridotris(pyrazolyl)borate iridium(III) complex [Tp(PMe3)IrMe(ClCH2Cl)][BArf] (2-CH2Cl2) is reported. Spectroscopic characterization of 2-CH2Cl2 in CH2Cl2 solution indicates that exchange of bound CH2Cl2 with free CH2Cl2 is slow on the NMR time scale. Under 50 atm (1 atm = 101.325 kPa) of N2, the CH2Cl2 in 2-CH2Cl2 is displaced by N2 to yield [Tp(PMe3)IrMe(N2)][BArf] (2-N2). The stronger nucleophile CH3CN reacts rapidly with 2-CH2Cl2 to produce [Tp(PMe3)IrMe(NCCH3)][BArf] (4). A kinetic study was performed on CH2Cl2 substitution in 2-CH2Cl2 by CD3CN. The data are most consistent with dissociative loss of CH2Cl2 to generate the unsaturated species ([Tp(PMe3)IrMe][BArf]) which then reacts with CD3CN to generate [Tp(PMe3)IrMe(NCCD3)][BArf]. Further evidence for a dissociative mechanism was obtained by comparison of ligand substitution rates for the Tp complexes with the analogous TpMe2 complexes (TpMe2 = hydridotris(3,5-dimethylpyrazolyl)borate). The relevance of these substitution experiments to C—H activation by cationic iridium(III) complexes is discussed.Key words: iridium, hydridotris(pyrazolyl)borate, methylene chloride and dinitrogen complexes, dissociative substitution.

A comparison of the electron-donating abilities of the hydridotris(pyrazolyl)borate ligand and cyclopentadienyl ligand toward transition metals is presented. These data demonstrate that there is no definitive trend in donor ability across the periodic table, and consequently generalizations about the relative donating abilities of the two ligands should be discouraged.

Reaction of Cp(PMe(3))IrPh(OH) (1) with nitriles is undetectably slow in benzene solution at room temperature. However, in the presence of Cp(PMe(3))IrPh(OTf) (2) (OTf = O(3)SCF(3)), the reaction is strongly catalyzed, leading to iridium(III) carboxamides Cp(PMe(3))IrPh[NHC(O)R] (6a-d) [R = C(6)H(4)CH(3) (6a), C(6)H(5) (6b), C(6)H(4)CF(3) (6c), CH(3) (6d)]. We propose that these transformations occur by initial displacement of the trifluoromethanesulfonate ("triflate") anion of 2 by a molecule of nitrile, leading to a nitrile-substituted iridium cation, [Cp(PMe(3))IrPh(NCR)](+) (10). Following this, the nucleophilic hydroxide group of 1 attacks the (activated) nitrile molecule bound in 10, leading (after proton transfer) to the iridium carboxamide complex. In the case of nitriles possessing hydrogens alpha to the cyano group, competitive loss of one of these protons is observed, leading to iridium C-bound cyanoenolates such as Cp(PMe(3))(Ph)Ir(CH(2)CN) (7). Protonolysis of carboxamides 6a-d with HCl yields Cp(PMe(3))IrPh(Cl) (9) and the free amides. A pronounced solvent effect is observed when the reaction between 1 and nitriles catalyzed by 2 is carried out in THF solution. The basic hydroxide ligand of 1 induces an overall dehydration/cyclization reaction of the coordinated aromatic nitrile. For example, the reaction of 1 with p-trifluorotolunitrile and a catalytic amount of 2 leads to the formation of 6c, water, [Ph(PMe(3))Ir[C(5)Me(4)CH(2)C(C(6)H(4)CF(3))N]] (12), and [Ph(PMe(3))Ir(C(5)Me(4)CH(2)C(C(6)H(4)CF(3))NH)]OTf (13). A mechanism to explain the formation of both 12 and 13 and the role each compound plays in the formation of the iridium carboxamides is proposed.

Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.

Conditions for facile solution-phase amide conjugation of amine-modified siRNA with a diverse set of carboxylic acid partners using the coupling reagent HATU are described. These conditions eliminate the need for isolated activated esters and allow for rapid access to conjugates with a wide range of lipophilicity and functionality in good yield.

A mild regioselective synthesis of substituted indoles from readily accessible 1-(2-aminophenyl)-2-chloroethanones is described. Addition of a range of carbon nucleophiles to α-chloro acetophenones 1 generates 2-substituted indoles 2 in moderate to excellent yields. A reaction mechanism involving a [1,2]-aryl migration is proposed. This useful transformation is further examined using high throughput experimentation.

A detailed mechanistic study of arene C [bond] H activation in CH(2)Cl(2) solution by Cp(L)IrMe(X) [L = PMe(3), P(OMe)(3); X = OTf, (CH(2)Cl(2))BAr(f); (BAr(f) = B[3,5-C(6)H(3)(CF(3))(2)](4))(-)] is presented. It was determined that triflate dissociation in Cp(L)IrMe(OTf), to generate tight and/or solvent-separated ion pairs containing a cationic iridium complex, precedes C [bond] H activation. Consistent with the ion-pair hypothesis, the rate of arene activation by Cp(L)IrMe(OTf) is unaffected by added external triflate salts, but the rate is strongly dependent upon the medium. Thus the reactivity of Cp(PMe(3))IrMe(OTf) can be increased by almost 3 orders of magnitude by addition of (n-Hex)(4)NBAr(f), presumably because the added BAr(f) anion exchanges with the OTf anion in the initially formed ion pair, transiently forming a cation/borate ion pair in solution (special salt effect). In contrast, addition of (n-Hex)(4)NBAr(f) to [CpPMe(3)Ir(Me)CH(2)Cl(2)][BAr(f)] does not affect the rate of benzene activation; here there is no initial covalent/ionic pre-equilibrium that can be perturbed with added (n-Hex)(4)NBAr(f). An analysis of the reaction between Cp(PMe(3))IrMe(OTf) and various substituted arenes demonstrated that electron-donating substituents on the arene increase the rate of the C [bond] H activation reaction. The rate of C(6)H(6) activation by [Cp(PMe(3))Ir(Me)CH(2)Cl(2)][BAr(f)] is substantially faster than [Cp(P(OMe)(3))Ir(Me)CH(2)Cl(2)][BAr(f)]. Density functional theory computations suggest that this is due to a less favorable pre-equilibrium for dissociation of the dichloromethane ligand in the trimethyl phosphite complex, rather than to a large electronic effect on the C [bond] H oxidative addition transition state. Because of these combined effects, the overall rate of arene activation is increased by electron-donating substituents on both the substrate and the iridium complex.

Pure (Z)-enamines readily prepared from beta-ketoesters and amides using (S)-phenylglycine amide were hydrogenated with very high diastereoselectivities (up to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)-phenylglycine amide afforded the corresponding chiral beta-aminoesters and amides. The high geometrical purity of the (Z)-enamine and a simple activation procedure for the PtO2 catalyst are essential in achieving high selectivity.

The controlled, efficient functionalization of saturated hydrocarbons remains an elusive goal. These workers and others have focused on developing homogeneous transition metal complexes capable of dehydrogenating alkanes. Two Ir(III) compounds, Cp*(PMe{sub 3})Ir(Me)OTf (Cp = C{sub 5}Me{sub 5}, OTf = OSO{sub 2}Cf{sub 3}) and [Cp*(PMe{sub 3})Ir(Me)(ClCH{sub 2}Cl)][BAr{sub f}], BAr{sub f}=B[3,5-C{sub 6}H{sub 3}(CF{sub 3}){sub 2}]{sub 4}, that are capable of cleaving carbon-hydrogen bonds under extremely mild conditions were reported. The hydrotris(3,5-dimethylpyrazolyl)borate (Tp{sup Me{sub 2}}) ligand occupies substantially increased space in the coordination spheres of metals, but otherwise is thought to function as a close analogue of Cp*. The properties of this ligand have also led to the synthesis, characterization, and reactivity toward C-H bonds of [Tp{sup Me{sub 2}}(PMe{sub 3})Ir(Me)N{sub 2}][BAr{sub f}], the first structurally characterized monomeric iridium dinitrogen complex.