Structural control of dithiazolyl radicals: Case studies on 3′- and 4′-cyano-benzo-1,3,2-dithiazolyl, NCC6H3S2N

Dithiazolyl radicals with π-stacking motifs have attracted particular interest because of their ability to exhibit spin-switching between diamagnetic distorted π-stacks and paramagnetic regular π-stacked structures through a solid state phase transition. Previous studies indicate that inclusion of electronegative heteroatoms into the backbone favours lamellar structures. This methodology has been extended to the synthesis and characterisation of the title compound, 4′-cyanobenzo-1,3,2-dithiazolyl (4-NCBDTA). Its electronic structure is probed through DFT calculations, cyclic voltammetry and EPR spectroscopy and its crystal structure determined by X-ray powder diffraction at room temperature. Variable temperature SQUID magnetometry reveals that 4-NCBDTA undergoes two phase transitions, each exhibiting bistability; a high temperature phase transition occurs at room temperature (T_C↓ = 291 K, T_C↑ = 304 K, ΔT = 13 K); whilst the low temperature phase transition occurs below liquid nitrogen temperatures (T_C↓ = 37 K, T_C↑ = 28 K;ΔT = 9 K).     

Spin transitions in a dithiazolyl radical: preparation, crystal structures, and magnetic properties of 3-cyanobenzo-1,3,2-dithiazolyl, C7H3S2N2

The incorporation of the electronegative cyano group into the structure of the title dithiazolyl radical 1 induces a lamellar packing motif that favors spin-transition behavior. Variable-temperature magnetic studies on 1 reveal a reversible phase transition at 250 K between a diamagnetic low-temperature phase and a paramagnetic high-temperature phase. X-ray crystal structures at 180(2) and 300(2) K reveal that both phases crystallize in the space group P2(1)/c, with the phase transition associated with a doubling of the crystallographic a axis. The concomitant change in magnetic properties is associated with a change from a paramagnetic regular pi stack of radicals and a diamagnetic distorted pi stack in which an energy gap opens up at the Fermi level corresponding to a Peierls-like transition.     

Rearrangement of allylic azide and phenylthio groups of 3′-azido- or 3′-phenylthio-4′,5′-didehydro-5′-deoxyarabinofuranosyluridines

The reversible intramolecular [3,3]-sigmatropic rearrangement between 1-(3-azido-3,5-dideoxy-β-d-threo-pent-4-enofuranosyl)uracil (3) and 1-(5-azido-3,5-dideoxy-β-d-glycero-pent-4-enofuranosyl)uracil (4) and irreversible radical rearrangement of 1-(3,5-dideoxy-3-phenylthio-β-d-threo-pent-4-enofuranosyl)uracil (5) and 1-[3,5-dideoxy-3-(4-tolyl)thio-β-d-threo-pent-4-enofuranosyl]uracil (7) into 1-(3,5-dideoxy-5-phenylthio-β-l-glycero-pent-4-enofuranosyl)uracil (6) and 1-[3,5-dideoxy-5-(4-tolyl)thio-β-l-glycero-pent-3-enofuranosyl]uracil (8) were attained at room temperature.     

Oxidative coupling of 2-substituted 1,2-dihydro-1-naphthols using Jones reagent: a simple entry into 3,3′-disubstituted 1,1′-binaphthyl-4,4′-diols

2-Substituted 1,2-dihydro-1-naphthols underwent regioselective oxidative dimerization, when treated with Jones reagent, to furnish 3,3′-disubstituted 1,1′-binaphthyl-4,4′-diols. A series of symmetrical binaphthols were prepared and it was shown that the coupling reaction proceeds via the sequential oxidation of 2-substituted 1,2-dihydro-1-naphthols to 2-substituted 1-naphthols, which oxidatively dehydrodimerized.     

Chiral syntheses of 6′-β-fluoroaristeromycin, 6′-β-fluoro-5′-noraristeromycin and aristeromycin

Carbocyclic nucleosides substituted at the C-6′ position are receiving increasing attention. Chiral synthetic accessibility to the biologically promising 6′-β-fluoroaristeromycin is lacking. Its preparation and that of the 5′-nor analogue are described. Along the way, a new method to aristeromycin arose as an outgrowth of a requisite structure proof.     

Synthesis of 2′-O,3′-O bicyclic adenosine analogues using ring closing metathesis

The synthesis of 2′-O,3′-O bicyclic adenosine derivatives is presented as the first examples of a new family of 13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene intermediate using Grubbs’ catalyst. The Z and E isomers were purified and characterised.     

Enantioselective total synthesis of (2R,3R,6R)-N-methyl-6-(deca-1′,3′,5′-trienyl)-3-methoxy-2-methylpiperidine, an insecticidal alkaloid

An insecticidal piperidine alkaloid, (2R,3R,6R)-N-methyl-6-(deca-1′,3′,5′-trienyl)-3-methoxy-2-methylpiperidine, was efficiently synthesized in a stereoselective manner starting from d-alanine. Chiral center at C-6 was controlled by hydrogenation of imine and side chain was introduced by Julia olefination. The absolute configuration of natural product was determined to be 2R, 3R, 6R.     

Straightforward synthesis of 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes via 2′,3′-O-orthoester group elimination: a simple route to 3′,4′-didehydronucleosides

Straightforward, high-yielding syntheses of 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes and 3′-deoxy-3′,4′-didehydronucleosides starting from 2′,3′-O-orthoester derivatives of ribonucleosides are described.     

Isomers of neplanocin A and 2′-deoxyneplanocin A possessing a C-1′/C-6′ double bond

Missing among the unsaturated carbocyclic nucleosides is the 1′,6′-double bond isomer of neplanocin A. A practical synthesis of this compound and its 2′-deoxy derivative is reported from readily accessible cyclopentenols.     

A versatile reagent for the synthesis of 5′-phosphorylated, 5′-thiophosphorylated or 5′-phosphoramidate-conjugated oligonucleotides

We report the synthesis of a new phosphorylating reagent that is easily accessible and allows not only the chemical synthesis of 5′-phosphorylated and 5′-thiophosphorylated oligonucleotides but also the 5′-conjugation through a phosphoramidate linkage. 5′-Amino-linker and 5′-alkyne oligonucleotides were obtained and the latter was conjugated by a 1,3-dipolar cycloaddition (click chemistry) with a galactosylated azide derivative to afford 5′-galactosyl oligonucleotide with high efficiency.     

Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine

Anti-HIV nucleoside monophosphates have limited cellular uptake due to the presence of negatively-charged phosphate group. Bis-(cycloSaligenyl) derivatives containing two anti-HIV nucleosides, 3′-fluoro-3′-deoxythymidine (FLT) and 3′-azido-3′-deoxythymidine (AZT) were synthesized to increase intracellular delivery of nucleoside monophosphates. 2,5-Bis(hydroxymethylene)benzene-1,4-diol was selected as a monocyclic bidentate scaffold and synthesized by three different methods from bis(hydroxymethylene)cyclohexan-1,4-diene-1,4-diol, or diethyl 2,5-dihydroxyterephthalate. The reaction of the tetraol with diisopropylphosphoramidous dichloride in the presence of 2,6-lutidine, followed by conjugation reactions with nucleosides (i.e., FLT and AZT) and oxidation afforded symmetrical and unsymmetrical bis-(cycloSaligenyl) diphosphate triester products, AZT-AZT, FLT-FLT, and FLT-AZT conjugates, in 63-74% overall yields and modest anti-HIV activities (IC₅₀ = 2.8-69.6 μM).     

Syntheses and structure-activity relationships of novel 3′-difluoromethyl and 3′-trifluoromethyl-taxoids

A series of novel 3′-difluoromethyl-taxoids and 3′-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure-activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3′-difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N₃), while those in the 3′-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps.     

Sterically controlled cyclization of 3′,4′,5,7-tetramethyldihydroquercetin amidophosphites. New synthesis of phostones

A new sterically controlled reaction of α-hydroxyketones with phosphorus acid triamides resulting in new four-membered phostones is reported.     

Cyclization versus oligomerization of SP- and RP-5′-OH-N-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane)s

The S_P-isomer of 5′-OH-N⁴-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane) undergoes DBU-promoted intramolecular cyclization providing as a sole product S_P-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate. Unexpectedly, the R_P-counterpart yields a mixture of products consisting of R_P-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate and macrocyclic oligo(deoxycytidine phosphorothioate)s. The results of molecular modeling indicate that the dychotomy observed for the R_P substrate may result from remarkably higher energy of the corresponding transition states, caused by the presence of bulky ‘spiro’ pentamethylene substituent at the position C4 in the oxathiaphospholane ring.     

Difluorocarbene chemistry: synthesis of gem-difluorocyclopropenylalkynes and 3,3,3′,3′-tetrafluorobicyclopropyl-1,1′-dienes

A series of gem-difluorocyclopropenylalkynes are easily obtained in good yields by the Sonogashira reaction of 3,3-difluoro-1-iodocyclopropenes with terminal alkynes. Onto these new alkynes addition of difluorocarbene, generated from the decomposition of FSO₂CF₂COOTMS in diglme in the presence of 10 mol% anhydrous NaF at 120 °C, gives 3,3,3′,3′-tetrafluorobicyclopropyl-1,1′-dienes. Acid hydrolysis of gem-difluorocyclopropenylalkynes in refluxing CH₃OH affords the corresponding methoxycarbonylenynes.     

Well‐defined polyolefin/poly(ε‐caprolactone) diblock copolymers: New synthetic strategy and application

A new synthetic strategy, the combination of living polymerization of ylides and ring‐opening polymerization (ROP), was successfully used to obtain well‐defined polymethylene‐b‐poly(ε‐caprolactone) (PM‐b‐PCL) diblock copolymers. Two hydroxyl‐terminated polymethylenes (PM‐OH, M_n= 1800 g mol^?1 (PDI = 1.18) and M_n = 6400 g mol^?1 (PDI = 1.14)) were prepared using living polymerization of dimethylsulfoxonium methylides. Then, such polymers were successfully transformed to PM‐b‐PCL diblock copolymers by using stannous octoate as a catalyst for ROP of ε‐caprolactone. The GPC traces and ¹H NMR of PM‐b‐PCL diblock copolymers indicated the successful extension of PCL segment (M_n of PM‐b‐PCL = 5200–10,300 g mol^?1; PDI = 1.06–1.13). The thermal properties of the double crystalline diblock copolymers were investigated by differential scanning calorimetry (DSC). The results indicated that the incorporation of crystalline segments of PCL chain effectively influence the crystalline process of PM segments. The low‐density polyethylene (LDPE)/PCL and LDPE/polycarbonate (PC) blends were prepared using PM‐b‐PCL as compatibilizer, respectively. The scanning electron microscopy (SEM) observation on the cryofractured surface of such blend polymers indicates that the PM‐b‐PCL diblock copolymers are effective compatibilizers for LDPE/PCL and LDPE/PC blends. Porous films were fabricated via the breath‐figure method using different concentration of PM‐b‐PCL diblock copolymers in CH₂Cl₂ under a static humid condition. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Multiple one-electron oxidation and reduction of trinuclear bis(2,4-pentanedionato)ruthenium complexes with substituted diquinoxalino[2,3-a:2′,3′-c]phenazine ligands

The complexes (μ₃-L¹/L²)[Ru(acac)₂]₃, acac⁻ = 2,4-pentanedionato, L¹ = 2,3,8,9,14,15-hexachlorodiquinoxalino[2,3-a:2′,3′-c]phenazine and L² = 2,3,8,9,14,15- hexamethyldiquinoxalino[2,3-a:2′,3′-c]phenazine, undergo stepwise one-electron oxidation involving a total of three electrons and stepwise one-electron reduction with three (L²) or four electrons (L¹). All reversibly accessible states were characterized by UV–Vis–NIR spectroelectrochemistry. Oxidation leads to mixed-valent intermediates {(μ₃-L)[Ru(acac)₂]₃}⁺ and {(μ₃-L)[Ru(acac)₂]₃}²⁺ of which the Ru^IIIRu^IIRu^II combinations exhibit higher comproportionation constants K_c than the Ru^IIIRu^IIIRu^II states – in contrast to a previous report for the unsubstituted parent systems {(μ₃-L³)[Ru(acac)₂]₃}^+/2+, L³ = diquinoxalino[2,3-a:2′,3′-c]phenazine. No conspicuous inter-valence charge transfer absorptions were observed for the mixed-valent intermediates in the visible to near-infrared regions. The monocations and monoanions were characterized by EPR spectroscopy, revealing rhombic ruthenium(III) type signals for the former. Electron addition produces ruthenium(II) complexes of the reduced forms of the ligands L, a high resolution EPR spectrum with ¹⁴N and ^35,37Cl hyperfine coupling and negligible g anisotropy was found for {(μ₃-L¹)[Ru(acac)₂]₃}⁻. DFT calculations of (μ₃-L¹)[Ru(acac)₂]₃ confirm several ligand-centered low-lying unoccupied MOs for reduction and several metal-based high-lying occupied MOs for electron withdrawal, resulting in low-energy metal-to-ligand charge transfer (MLCT) transitions.     

New N-acyl, N-alkyl, and N-bridged derivatives of rac-6,6′,7,7′-tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-bisisoquinoline

The preparation of potential new ligand systems based on the rac-1,1′,2,2′,3,3′,4,4′-octahydro-6,6′,7,7′-tetramethoxy-1,1′-bisisoquinoline skeleton has been investigated. Syntheses of N-(2-bromobenzyl), N-(3-acetoxybenzyl), N-acetyl, N-chloroacetyl, N-chlorocarbonyl, N-ethoxycarbonyl and N-tert-butyloxycarbonyl derivatives and five macrocyclic, polyether containing derivatives are described.     

2′,3′,4′,5′-Tetraacetyl-N(3)-carboxymethylriboflavin derivatives: synthesis and fluorescence studies

The hitherto not described 2′,3′,4′,5′-tetraacetyl-N(3)-carboxymethylriboflavin (1) could be prepared starting from 2′,3′,4′,5′-tetraacetylriboflavin by alkylation with tert-butyl α-bromoacetate and benzyl α-bromoacetate, followed by deprotection reaction. The results of fluorescence studies are described.