Nucleoside Azide-Alkyne Cycloaddition Reactions Under Solvothermal Conditions or Using Copper Vials in a Ball Mill

Novel nucleoside analogues containing photoswitchable moieties were prepared using 'click' cycloaddition reactions between 5 '-azido-5 '-deoxythymidine and mono- or bis-N-propargylamide-substituted azobenzenes. In solution, high to quantitative yields were achieved using 5mol% Cu(I) in the presence of a stabilizing ligand. 'Click' reactions using the monopropargylamides were also effected in the absence of added cuprous salts by the application of liquid assisted grinding (LAG) in metallic copper reaction vials. Specifically, high speed vibration ball milling (HSVBM) using a 3/32('') (2.38mm) diameter copper ball (62mg) at 60Hz overnight in the presence of ethyl acetate lead to complete consumption of the 5 '-azido nucleoside with clean conversion to the corresponding 1,3-triazole.

Synthesis of Piano Stool Complexes Employing the Pentafluorophenyl Substituted Diphosphine (C6F5)2PCH2P(C6F5)2 and the Effect of Phosphine Modifiers on Hydrogen Transfer Catalysis.

Ruthenium, rhodium, and iridium piano stool complexes of the pentafluorophenyl-substituted diphosphine (C6F5)2PCH2P(C6F5)2 (2) have been prepared and structurally characterized by single-crystal X-ray diffraction. The Cp-P tethered complex [{(C5Me4CH2C6F4(C6F5)CH2P(C6F5)2}RhCl2] (9), in which only one phosphorus is coordinated to the rhodium, was prepared by thermolysis of a slurry of [Cp*RhCl(-Cl)]2 and 2 and was structurally characterized by single-crystal X-ray diffraction. The tethering occurs by intramolecular dehydrofluorinative coupling of the pentamethylcyclopentadienyl ligand and P,P-coordinated 2. The geometric changes that occur on tethering force dissociation of one of the phosphorus atoms. The effects of introducing phosphine ligands to the coordination sphere of piano stool hydrogen transfer catalysts have been studied. The complexes of fluorinated phosphine complexes are found to transfer hydrogen at rates that compare favorably with leading catalysts, particularly when the phosphine and cyclopentadienyl functionalities are tethered. The highly chelating Cp-PP complex [(C5Me4CH2-2-C5F3N-4-PPhCH2CH2PPh2)RhCl]BF4 (1) was found to outperform all other complexes tested. The mechanism of hydrogen transfer catalyzed by piano stool phosphine complexes is discussed with reference to the trends in activity observed.

Base free dynamic kinetic resolution of secondary alcohols using ‘piano stool’ complexes of N-heterocyclic carbenes

Piano stool complexes of rhodium and iridium activated by fluorinated and non-fluorinated N-heterocyclic carbene (NHC) ligands were shown to be catalysts for racemization in the one-pot chemoenzymic dynamic kinetic resolution (DKR) of secondary alcohols. Excellent conversions and good enantioselectivities were observed for alkyl aryl and dialkyl secondary alcohols.

Polymer-supported phosphoramidites: highly efficient and recyclable catalysts for asymmetric hydrogenation of dimethylitaconate and dehydroamino acids and esters

Several novel phosphoramidites have been prepared by reaction of the primary amines para-vinylaniline, ortho-anisidine, 2-methoxyphenyl(4-vinylbenzyl)amine, 8-aminoquinoline and 3-vinyl-8-aminoquinoline with (S)-1,1'-bi-2-naphthylchlorophosphite, in the presence of base. Rhodium(l) complexes of these phosphoramidites catalyse the asymmetric hydrogenation of dimethylitaconate and dehydroamino acids and esters giving ee values up to 95%. Soluble non-cross linked polymers of the para-vinylaniline and 3-vinyl-8-aminoquinoline-based phosphoramidites have been prepared by free radical co-polymerisation with styrene in the presence of AIBN as initiator. The corresponding [Rh(COD)](+) complexes serve as recyclable catalysts for the asymmetric hydrogenation dimethylitaconate and dehydroamino acids and esters to give ee values up to 80%. (C) 2003 Elsevier Science Ltd. All rights reserved.

Enzyme-catalysed synthesis and reactions of benzene oxide/oxepine derivatives of methyl benzoates

A series of twelve benzoate esters was metabolised, by species of the Phellinus genus of wood-rotting fungi, to yield the corresponding benzyl alcohol derivatives and eight salicylates. The isolation of a stable oxepine metabolite, from methyl benzoate, allied to evidence of the migration and retention of a carbomethoxy group ( the NIH Shift), during enzyme-catalysed ortho-hydroxylation of alkyl benzoates to form salicylates, is consistent with a mechanism involving an initial arene epoxidation step. This mechanism was confirmed by the isolation of a remarkably stable, optically active, substituted benzene oxide metabolite of methyl 2-( trifluoromethyl) benzoate, which slowly converted into the racemic form. The arene oxide was found to undergo a cycloaddition reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to yield a crystalline cycloadduct whose structure and racemic nature was established by X-ray crystallography. The metabolite was also found to undergo some novel benzene oxide reactions, including epoxidation to give an anti-diepoxide, base-catalysed hydrolysis to form a trans-dihydrodiol and acid-catalysed aromatisation to yield a salicylate derivative via the NIH Shift of a carbomethoxy group.

Ligand differentiated complementary Rh-catalyst systems for the enantioselective desymmetrization of meso-cyclic anhydrides

Two distinct systems for the rhodium-catalyzed enantioselective desymmetrization of meso-cyclic anhydrides have been developed. Each system has been optimized and are compatible with the use of in situ prepared organozinc reagents. Rhodium/PHOX species efficiently catalyze the addition of alkyl nucleophiles to glutaric anhydrides, while a rhodium/phosphoramidite system is effective in the enantioselective arylation of succinic and glutaric anhydrides.

Solventless continuous flow homogeneous hydroformylation of 1-octene

The hydroformylation of 1-octene under continuous flow conditions is described. The system involves dissolving the catalyst, made in situ from [ Rh(acac)(CO)(2)] (acacH = 2,4- pentanedione) and [RMIM][TPPMS] ( RMIM = 1-propyl (Pr), 1-pentyl (Pn) or 1-octyl (O)-3-methyl imidazolium, TPPMS = Ph2P(3-C6H4SO3)), in a mixture of nonanal and 1-octene and passing the substrate, 1-octene, together with CO and H-2 through the system dissolved in supercritical CO2 (scCO(2)). [PrMIM][TPPMS] is poorly soluble in the medium so heavy rhodium leaching (as complexes not containing phosphine) occurs in the early part of the reaction. [PnMIM][ PPMS] affords good rates at relatively low catalyst loadings and relatively low overall pressure (125 bar) with rhodium losses <1 ppm, but the catalyst precipitates at higher catalyst loadings, leading to lower reaction rates. [OMIM][ TPPMS] is the most soluble ligand and promotes high reaction rates, although preliminary experiments suggested that rhodium leaching was high at 5-10 ppm. Optimisation aimed at balancing flows so that the level within the reactor remained constant involved a reactor set up based around a reactor fitted with a sight glass and sparging stirrer with the CO2 being fed by a cooled head HPLC pump, 1-octene by a standard HPLC pump and CO/H-2 through a mass flow controller. The pressure was controlled by a back pressure regulator. Using this set up, [OMIM][ TPPMS] as the ligand and a total pressure of 140 bar, it was possible to control the level within the reactor and obtain a turnover frequency of ca. 180 h(-1). Rhodium losses in the optimised system were 100 ppb. Transport studies showed that 1-octene is preferentially transported over the aldehydes at all pressures, although the difference in mol fraction in the mobile phase was less at lower pressures. Nonanal in the mobile phase suppresses the extraction of 1-octene to some extent, so it is better to operate at high conversion and low pressure to optimise the extraction of the products relative to the substrate. CO and H2 in the mobile phase also suppress the extraction effciency by as much as 80%.

Multi component coupling reactions of N-acetyl-2-azetine

N-Acetyl-2-azetine undergoes Lewis acid catalysed formal [4+2]-cycloaddition with imines derived from aromatic amines to initially give an approximately 1: 1 mixture of exo-endo-diastereoisomeric 1-(2a,3,4,8b-tetrahydro-2H-1,4-diaza-cyclobuta[a]naphthalen-1-yl)-ethanone cycloadducts which were detected by proton NMR spectroscopy. These products, which were too unstable to isolate, and characterise, reacted further with aromatic amines to give 2,3,4-trisubstituted tetrahydroquinolines in good to excellent yield, predominantly as a single diastereoisomer, with the minor diastereoisomer converting to the major diastereoisomer on silica. The cycloaddition was irreversible and a mechanism is presented for the formation of the major diastereoisomer from the mixture of diastereoisomeric intermediates. A range of conditions is described for converting the 2,3,4-trisubsitituted tetrahydroquinolines into 2,3-disubstituted quinolines.

Three component coupling reactions of N-acetyl-2-azetine-rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines

N-Acetyl-2-azetine undergoes Lewis acid catalysed [4 + 2]-cycloaddition with imines derived from aromatic amines and gave a 1:1 mixture of exo-endo diastereoisomeric azetidine cycloadducts which reacted further with aromatic amine, to give 2,3,4-trisubsitituted tetrahydroquinolines in good to excellent yield, predominantly as one diastereoisomer.

Synthesis of the heterocyclic core of the alkaloids martinelline and martinellic acid

The tricyclic core of martinelline and martinellic acid was rapidly assembled utilising an imino Diels-Alder reaction of an imine derived from cinnamaldehyde with a cyclic enamide. The cycloaddition was completely regioselective though the exo endo selectivity was poor. These diastercoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations. (C) 2001 Elsevier Science Ltd. All rights reserved.

Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from L-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)(3)H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from L-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.

The carbenoid approach to peptide synthesis

A different approach to the synthesis of dipeptides is described based on the formation of the (NHCHRCONH)-C-1-(CHRCO)-C-2 bond by carbenoid N-H insertion, rather than the formation of the peptide bond itself. Thus decomposition of triethyl diazophosphonoacetate catalysed by rhodium(Ii) acetate in the presence of N-protected amino acid amides 8 gives the phosphonates 9, Subsequent Wadsworth-Emmons reaction of 9 with aldehydes in the presence of DBU gives dehydro dipeptides 10. The reaction has been extended to a simple two-step procedure, without the isolation of the intermediate phosphonate. for conversion of a range of amino acid amides 11 into dehydro dipepides 12 and to an N-methylamide 11h, and for conversion of a dipeptide: to tripeptide (13-14). Direct conversion, by using methyl diazophenylacetate, of amino acid amides to phenylglycine-containing dipeptides 19 proceeds in good chemical yield, but with poor diastereoselectivity.