The syntheses and preliminary pharmacological characterisation of two novel cyclic phosphinic acid-containing amino acids designed as conformationally restricted analogues of the metabotropic glutamate receptor agonist AP4 (1) are reported.
A concise route to enantiomerically pure 2-substituted indolines 4a-g and a 2-substituted tetrahydroquinoline 4h has been developed by application of the Pd-catalyzed coupling of amino functionalised organozinc reagents with 2-bromoiodobenzene, followed by Buchwald's palladium-catalyzed intramolecular amination reaction. The yields in the initial coupling are modest (36-52%), but the cyclisation yields are satisfactory (63-87%). The stereochemical integrity of a representative example was established by chiral phase HPLC.
Flash vacuum pyrolysis over a bed of freshly sublimed magnesium on glass wool results in efficient coupling of benzyl halides to give the corresponding bibenzyls. Where an ortho halogen substituent is present further dehalogenation gives some dihydroanthracene and anthracene. Efficient coupling is also observed for halomethylnaphthalenes and halodiphenylmethanes while chlorotriphenylmethane gives 4,4'-bis(diphenylmethyl) biphenyl. By using, alpha,alpha'-dihalo-o-xylenes, benzocyclobutenes are obtained in good yield, while the isomeric, alpha,alpha'-dihalo-p-xylenes give a range of high thermal stability polymers by polymerisation of the initially formed p-xylylenes. Other haloalkylbenzenes undergo largely dehydrohalogenation where this is possible, in some cases resulting in cyclisation. Deoxygenation is also observed with haloalkyl phenyl ketones to give phenylalkynes as well as other products. With simple alkyl halides there is efficient elimination of HCl or HBr to give alkenes. For aliphatic dihalides this also occurs to give dienes but there is also cyclisation to give cycloalkanes and dehalogenation with hydrogen atom transfer to give alkenes in some cases. For 5-bromopent-1-ene the products are those expected from a radical pathway but for 6-bromohex-1-ene they are clearly not. For 2,2-dichloropropane and 1,1-dichloropropane elimination of HCl occurs but for 1,1-dichlorobutane, -pentane and -hexane partial hydrolysis followed by elimination of HCl gives E,E-, E,Z- and Z,Z-isomers of the dialk-1-enyl ethers and fully assigned C-13 NMR data are presented for these. With 6-chlorohex-1-yne and 7-chlorohept-1-yne there is cyclisation to give methylenecycloalkanes and -cycloalkynes. The behaviour of 1,2-dibromocyclohexane and 1,2-dichlorocyclooctane under these conditions is also examined. Various pieces of evidence are presented that suggest that these processes do not involve generation of free gas-phase radicals but rather surface-adsorbed organometallic species.
A novel tri(propylene glycol) glycerolate diacrylate cross-linked polystyrene support for solid phase peptide synthesis was prepared by aqueous radical suspension polymerization. The peptides were grown from the hydroxy functionality of the cross-linker in the polymer and this makes it unique among other styrene-based polymer supports that are currently used in polypeptide synthesis. The role of the polymer support in peptide synthesis was established by studies delineating the optimization of synthetic steps involved in solid phase synthesis. The optimization studies include C-terminal amino acid incorporation, Nα-Fmoc and Boc-deprotection, acylation reactions and the removal of the target peptide from the support. The dependence between the nature and extent of cross-linking of the polymer backbone and the reactivity of the attached amino groups was investigated by carrying out a reactivity study on amide bond formation compared with Merrifield resin. The resin-like behavior of the new support was studied by synthesizing a ‘difficult’ sequence of the (34–42) fragment of β-amyloid peptide (1–42) and compared with commercially available Merrifield and Sheppard resins. The synthetic utility of the support was established by synthesizing a 23-residue NR 2B peptide substrate of Ca2+/calmodulin binding peptide in high yield and purity. Better solvation of the resin beads, enhanced coupling efficiency in the peptide synthetic steps and the high yield and purity of the peptides synthesized highlights the positive role of the cross-linker in the new polystyrene support.
1,6-Diiodohexa-1,3,5-triyne (3) and 1,8-diiodoocta-1,3,5,7-tetrayne (5) were prepared in yields of 64 and 75%, respectively, using a new method, allowing easy scale-up. Novel alkyne synthons, viz. 1-triisopropylsilyl-4-iodobuta-1,3-diyne (7) and 1-trimethylsilyl-4-iodobuta-1,3-diyne (8) were obtained in yields of 55 and 40%, respectively, from butadiyne in two-step reactions.
Troger's-base analogues bearing fused pyrazolic or pyrimidinic rings were prepared in acceptable to good yields through the reaction of 3-alkyl-5-amino-1-arylpyrazoles and 6-aminopyrimidin-4(3H)-ones with formaldehyde under mild conditions (i.e., in ethanol at 50 degreesC in the presence of catalytic amounts of acetic acid). Two key intermediates were isolated from the reaction mixtures, which helped us to suggest a sequence of steps for the formation of the Troger's bases obtained. The structures of the products were assigned by H-1 and C-13 NMR, mass spectra and elemental analysis and confirmed by X-ray diffraction for one of the obtained compounds.
Novel enediynyl tripeptides 2(a–c) in fully protected forms have been prepared via a sequence of palladium(0)-based Sonogashira coupling. The thermal reactivity of these peptides was shown to be dependent upon the nature of the side chain in the amino acids. Analysis of the CD-spectra of these peptides as well as the variation of chemical shifts with temperature revealed the presence of a β-sheet nucleating conformation in equilibrium with a conformation induced by H-bond formation between the CO and NH belonging to the enediynyl amino acid.
The synthesis of ABE tricyclic analogues 18 of the alkaloid methyllycaconitine 1 is described. The analogues contain the key pharmacophore reputed to be responsible for the biological activity of methyllycaconitine 1, namely, a homocholine motif formed from a tertiary N-ethylamine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester side chain. The 3-azabicyclo[3.3.1]nonane ring system 10 was assembled via a double Mannich reaction of ethyl 3-(but-3′-enyl)-2-oxocyclohexane-1-carboxylate 9 with ethylamine and formaldehyde. Attempts to append a B ring to this AE ring system via McMurray coupling of dialdehyde 5 were hampered by the inability to effect conversion of the C-9 ketone 10 to vinyl ether 6. Wittig methylenation of ketone 10 afforded diene 7, however, subsequent attempts to effect double hydroboration–oxidation of diene 7 failed to realise diol 11enroute to the key dialdehyde precursor 5 required for the McMurray coupling. Wacker oxidation of the homoallyl group of 10 afforded methyl ketone 12 which underwent intramolecular aldol condensation to form enone 13. After selective reduction of the ketone and methylation, the resultant methyl ethers 15 underwent reduction of the ester sidechain affording neopentyl substituted alcohols 16. Finally, the 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester sidechain was appended by treatment of alcohols 16 with N-(trifluoroacetyl)anthranilic acid followed by fusion of the resultant anthranilates 17 with methylsuccinic anhydride.
A new simple and efficient transformation of various aromatic ketones to the corresponding halo (dihalo) alkenes is described. The reaction proceeds under mild conditions to give the target products in good yields.
Selective fluorination of a range of hydrocarbons was achieved by reaction with either elemental fluorine or Selectfluor(TM), an electrophilic fluorinating reagent of the N-F class. An electrophilic mechanism is envisaged. On prolonged reaction, the strongly acidic reaction medium that is formed upon substitution of hydrogen by fluorine when Selectfluor(TM) is used as the fluorinating reagent, promotes loss of fluoride from the initial fluorinated product. Trapping of the subsequent carbocation by the acetonitrile solvent in a Ritter type process gives overall nitrogen functionalisation of hydrocarbons. Amidation of hydrocarbons could also be achieved in a one-stage process by reaction of the hydrocarbon with fluorine and a Lewis acid, such as boron trifluoride-diethyl ether, in acetonitrile.
A number of boronic acid functionalised azo dye molecules have been prepared using a simple 3-step synthesis and their spectral properties upon complexation with monosaccharides investigated. The dyes undergo visible colour changes in aqueous solution upon addition of monosaccharide.
Tungstophosphoric acid (H3PW12O40) effectively activates hexamethyldisilazane for the selective silylation of primary, secondary, tertiary and phenolic hydroxy groups under solvent-free conditions at 55–60 °C.
6-Nitroquinoline 6 undergoes direct cyclocondensation with aromatic aldehyde hydrazones 9 in the presence of sodium hydride in DMF at low temperature, giving the corresponding 3-aryl-1H-pyrazolo[3,4-f]quinolines 10 and/ or 3-aryl[1,2,4] triazino[6,5-f]quinolines 11 in low to moderate yield. With aromatic keto hydrazones 7, 3,3-disubstituted 2,3-dihydro[1,2,4] triazino[6,5-f]quinoline-4-oxides 8 are obtained in moderate to good yield. The mode of cyclocondensation is considerably dependent on the electronic nature of a ring substituent of the aromatic hydrazones; electron-donating substituents favor the formation of 11, while electron-withdrawing substituents work favorably for the formation of 10. Monocyclic nitroarenes 15 react similarly with 4-nitrobenzaldehyde hydrazone 9a to give another type of cyclocondensation product, 3-aryl-1H-indazoles 16, in moderate yield. In contrast, nucleophilic substitution of a ring hydrogen atom takes place with 4-methylbenzaldehyde hydrazone 9f to yield N-arylated hydrazone 22b, which, however, fails to cyclize to 16 under the conditions employed. The reaction has been suggested to proceed through the initial attack of a hydrazone anion on the position adjacent to the nitro group, followed by migration of an ipso hydrogen atom to the nitro group in the Meisenheimer intermediate 18. The resulting N(2)-arylated hydrazone anion would undergo ring closure via either addition to the nitroso group or displacement of this moiety, eventually leading to the fused aza-arenes 8, 10/11, 13 or 16.
The synthesis of 2-furoic acid derivatives containing both 3-methoxy and 3-TMS groups is described. Reductive alkylation proceeded well to give us access to a series of highly functionalised dihydrofurans with potential for further elaboration. Of the two groups tested at C-3, the TMS derivative was found to be the more useful and gave rise to high levels of stereoselectivity when attached to a furan bearing a chiral auxiliary at C-2. A modi cation of the reaction conditions was made which enabled the TMS group to be cleaved during the reduction reaction without loss of stereoselectivity. Finally, it was also shown that the chiral auxiliary could be removed under acidic conditions to form 2-alkyl-3-TMS substituted dihydrofurans with excellent levels of enantiomeric purity.
Synthetic and spectroscopic details relating to a set of heteroaromatic N-benzyl carboxamides and in particular the corresponding tert-butyl acylcarbamates are reported. These compounds were required to study the postulated effect of various heterocycles (pyridine and pyrazine with and without condensed benzene rings) on the cleavage of acyl-N bonds by reduction. All compounds were initially characterized by cyclic voltammetry (CV) which indicated various degrees of facilitated reduction, reflecting a direct influence of the heterocyclic component. Selected acylcarbamates were studied with respect to acyl-N bond cleavage by mild reducing agents, and selectively deacylated by activated aluminium and sodium borohydride. Conversion to acylcarbamates followed by reduction might therefore be a mild, efficient two-step procedure to effect cleavage of amides, allowing isolation of carbamates and with sodium borohydride also the corresponding alcohols.
The first versatile organometallic reagents derived from azulenes, i.e.. 6-(tri-n-butylstannyl)azulene (1a) and its, 1,3-diethoxycarbonyl derivative (1b), have been prepared by Pd(o)-catalyzed direct stannylation of 6-bromoazulenes, with bis(tri-n-butyltin). We demonstrate the utility of the reagents in the Stille cross-coupling reaction with aryl.acetyl and azulenyl halides to afford 6-aryl-, 6-acyl- and bi-azulenes in good yield. Furthermore. the methodology was applied to the synthesis of poly(azulen-6-yl)benzene derivatives. The reaction of 1b with 1.4-di-, 1,3,5-tri-. 1,2,4,5-tetra- and hexabromobenzenes afforded 1.4-di-, 1,3,5-tri-, 1,2,4,5-tetra-, 1,2,4-tri- and 1,2,3,5-tetra(azulen-6-yl)benzene derivatives (18, 20, 22, 24 and 25). The redox behavior of 18 and 22 was examined by cyclic voltammetry (CV) and compared with those of 20 and 24 reported previously. In contrast to the three-step reduction of 20, the compound 18 exhibited a reversible one-step two-electron reduction wave at - 1.30 V Upon CV, which revealed the formation of a closed-shell dianion. The four azulen-6-yl substituents on benzene in a 1,2,4,5 relationship increased electron-accepting properties because of the formation of a closed-shell dianion stabilized by four azulen-6-yl groups. As expected, the compound 22 exhibited a color change during the electrochemical reduction. However, the reverse oxidation did not regenerate the spectrum of 22 due to the low stability of the presumed dianionic species under the conditions of the UV-vis measurement.
Reaction of the chiral azirine 1a with nucleophiles and dienes is described. Thiols, heteroaromatic nitrogen compounds and phenylmagnesium bromide add to the azirine 1a to give functionalised aziridines 2/3a–h. X-Ray crystal structures for the products 3e and 3g have been obtained. Diastereodifferentiation of the two faces of the azirine 1a is observed in most cases, but only thiophenol gives a single diastereomer (2a). Most mixtures of diastereomers were separated by dry flash chromatography. Benzylamine produced a dimer of the original azirine 1a, compound 9. Representative conjugated dienes (cyclopentadiene, furan and open chain dienes) were added to the chiral azirine 1a. Only poor selectivities were observed. The selectivity was not significantly enhanced in the cycloaddition of cyclopentadiene to the more bulky azirine 1b.
Studies towards a N,N'-bis(p-methoxybenzyl) diketopiperazine asymmetric glycine cation equivalent for the synthesis of homochiral alpha-amino acids are described. The oxidation of enolate 3 with molecular oxygen provides either a mixture of hydroxylated diketopiperazines 7 and 8 or trione 10 depending upon the reaction conditions. The nucleophilic reduction of trione 10 and the reaction of acetoxy N-acyliminium ion precursors 5 and 6, derived from 7 and 8, with allyltrimethylsilane and boron trifluoride etherate is examined and a model for the stereoselectivity observed in these additions is presented.
Synthesis of a series of LNA-type beta-configured C-aryl nucleosides, i.e., 2'- O,4'-C-methylene-beta-D-ribofuranosyl derivatives containing phenyl, 4-fluoro-3-methylphenyl, 1-naphthyl, 1-pyrenyl and 2,4,5-trimethylphenyl groups as aglycons, has been accomplished. The key synthetic step consisted of stereoselective Grignard reactions of the cyclic aldehyde 11 followed by cyclization to give the bicyclic core structure with a locked N-type furanose conformation as confirmed by NOE experiments on the di-O-p-methoxybenzyl derivatives 13a-13e and an X-ray crystallographic study of the phenyl derivative 14a. The phosphoramidite approach was used for automated incorporation of the LNA-type beta-configured C-aryl monomers 17a-17e into short DNA and 2'-OMe-RNA/LNA strands. It is shown that universal hybridization can be obtained with a conformationally restricted monomer as demonstrated most convincingly for the pyrene LNA monomer 17d, both in a DNA context and in an RNA-like context. Increased binding affinity of oligonucleotide probes for universal hybridization can be induced by combining the pyrene LNA monomer 17d with affinity-enhancing 2'-OMe-RNA/LNA monomers.
