Simple route to ferrocenylalkyl nucleobases. Antitumor activity in vivo

Ferrocenylalkyl nucleobases ( 1 – 14 ) were prepared via the reaction of the α‐(hydroxy)alkyl ferrocenes FcCHR(OH) (Fc = ferrocenyl; R = H, Me, Et, Ph) with thymine, cytosine, iodo‐cytosine and adenine in DMSO at 100 °C, yields being 50–80%. The antitumor activities of ferrocenylmethyl thymine ( 1 ) against solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were studied in vivo. Therapeutic synergism of antitumor activity against LLC was demonstrated in the case of combined application of compound 1 with anticancer drug cyclophosphamide. Copyright © 2009 John Wiley & Sons, Ltd.     

Adding a Functional Handle to Nature′s Building Blocks: The Asymmetric Synthesis of β‐Hydroxy‐α‐Amino Acids

β‐Hydroxy‐α‐amino acids are not only used by synthetic chemists but are also found in natural products, many of which show anti‐microbial or anti‐cancer properties. Over the past 30 years, chemists have searched for many asymmetric routes to these useful building blocks. Initial attempts to synthesize these compounds utilized chiral auxiliaries and the reactions of glycine equivalents with aldehydes to form two stereocenters in one step. Other methods with the formation of specific intermediates or that were aimed at a specific amino acid have also been investigated. Asymmetric hydrogenation by dynamic kinetic resolution has emerged as a high‐yielding method for the synthesis of an array of modified amino acids with good stereoselectivity. More recently, amino‐acid functionalization and multicomponent reactions have increased the atom economy and simplified many long and difficult routes. In this Focus Review, many of the elegant syntheses of these compounds are explored. The applications of β‐hydroxy‐α‐amino acids in natural‐product synthesis are also mentioned.     

Ferrocenylalkyl azoles: bioactivity,synthesis, structure

The toxicity of ferrocenylethyl benzotriazole ( 1 ) and other ferrocene compounds including ferrocenylmethyl benzimidazoles ( 4,5,6,11 ), ferricenium salts ( 3,9,10 ) and ferrocenylmethyl adenine ( 7 ), was studied. All ferrocene complexes under investigation showed low or medium toxicities. On the basis of an earlier model of chemical carcinogenesis, the antitumor activity of ferrocenylalkyl azoles 1, 8 and ferricenium salts 9, 10 was studied in vivo in the so‐called sub‐capsular test on human tumors. This effectiveness was compared with that of cisplatin. A series of ferrocenylalkyl azoles were synthesized by interacting azoles either with α‐hydroxyalkyl ferrocenes FcC(OH)R₁R₂ in organic solvent in the presence of aqueous HBF₄ in quantitative yields or with trimethyl(aminomethyl)ferrocene iodide in an aqueous‐basic medium in good yields. The X‐ray determinations of molecular and crystal structures of α‐(1‐benzotriazolyl)ethylferrocene ( 1 ) and α‐(1‐naphthatriazolyl)ethylferrocene ( 12 ) were performed. Copyright © 2008 John Wiley & Sons, Ltd.     

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Fifteen organometallic Ir(III) half‐sandwich complexes ( 1A – 5C ) having the general formula [(η⁵‐Cp^x)Ir(N^N)Cl]PF₆ (Cp^x = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cp^xph) or tetramethyl(biphenyl)cyclopentadienyl (Cp^xbiph); N^N = diamine) have been synthesized and characterized. The molecular structure of 1A was determined using single‐crystal X‐ray diffraction analysis. The hydrolysis of 1A – 5C was monitored using UV–visible spectra. Complexes 3A – 3C showed catalytic activity for the oxidation of NADH to NAD⁺, where 3C showed the highest turnover number of 29.9 within 450 min. Cytotoxicity examination by MTT assay was carried out against two human cancer cell lines (HeLa and A549) after 24 or 48 h drug treatment. The complexes showed high potency, where the most potent complex ( 3C ; IC₅₀ = 3.4 μM) was six times more active than cisplatin against A549 cells after 24 h drug exposure. Cytotoxic potency towards A549 cells increased with phenyl substitution on Cp ring: Cp^xbiph > Cp^xph > Cp*. In addition, the biological studies showed that 3C caused cell apoptosis and cell cycle arrest at G₁ phase in A549 cancer cells. Moreover, 3C increased the level of reactive oxygen species markedly after 24 h, which may provide an important basis for killing cancer cells. Confocal laser scanning microscopy was used to track 3C in A549 cells. The cellular localization experiment showed that 3C targeted lysosomes and caused lysosomal damage.     

A one‐pot,stereoselective synthesis of 2‐ethoxycarbonyl‐substituted 1,3‐dienes and 1,3‐enynes by hydrostannylation–Stille tandem reaction of tributyltin hydride with alkynyl esters and alkenyl or alkynyl halides

2‐Ethoxycarbonyl‐substituted 1,3‐dienes and 1,3‐enynes can be stereoselectively synthesized in one pot under mild conditions, in good yields, by the palladium‐catalyzed hydrostannylation of alkynyl esters, followed by Stille coupling with alkenyl or alkynyl halides, respectively. Copyright © 2009 John Wiley & Sons, Ltd.     

The development and validation of a high‐throughput LC–MS/MS method for the analysis of endogenous β‐hydroxy‐β‐methylbutyrate in human plasma

A high‐throughput, sensitive, and rugged liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the rapid quantitation of β ‐hydroxy‐β ‐methylbutyrate (HMB) in human plasma has been developed and validated for routine use. The method uses 100 μL of plasma sample and employs protein precipitation with 0.1% formic acid in methanol for the extraction of HMB from plasma. Sample extracts were analyzed using LC–MS/MS technique under negative mode electrospray ionization conditions. A ¹³C–labeled stable isotope internal standard was used to achieve accurate quantitation. Multiday validation was conducted for precision, accuracy, linearity, selectivity, matrix effect, dilution integrity (2×), extraction recovery, freeze–thaw sample stability (three cycles), benchtop sample stability (6 h and 50 min), autosampler stability (27 h) and frozen storage sample stability (146 days). Linearity was demonstrated between 10 and 500 ng/mL. Inter‐day accuracies and coefficients of variation (CV) were 91.2–98.1 and 3.7–7.8%, respectively. The validated method was proven to be rugged for routine use to quantify endogenous levels of HMB in human plasma obtained from healthy volunteers.     

Oxidative acylation of α,α‐diarylallylic alcohols: Synthesis of 1,2,4‐triarylbutane‐1,4‐diones

A metal‐free mediated oxidative acylation of α,α‐diarylallylic alcohols with simple aromatic aldehydes for the synthesis of 1,2,4‐triphenylbutane‐1,4‐diones is presented. In the presence of TBPB (tert‐butyl peroxybenzoate), desired products were obtained in good to excellent yields for 28 examples. This protocol features high regioselectivity, wide functional group tolerance and atom economy.     

Asymmetric Synthesis of Chiral α‐Substituted Mercaptoglycine Derivatives via α‐Sulfenylation of Ni(II) Complex of Glycine and S‐Substituted 4‐Methylbenzenesulfonothioate

The asymmetric α ‐sulfenylation of Ni(II ) complex of glycine with S ‐substituted 4‐methylbenzenesulfonothioate is reported. Due to the mild and simple reaction conditions, this asymmetric reaction is compatible with various functional groups.     

A convenient synthesis of α,α′‐ homo‐ and α,α′‐hetero‐bifunctionalized poly(ε‐caprolactone)s by ring opening polymerization: The potentially valuable precursors for miktoarm star copolymers

Two new ring opening polymerization (ROP) initiators, namely, (3‐allyl‐2‐(allyloxy)phenyl)methanol and (3‐allyl‐2‐(prop‐2‐yn‐1‐yloxy)phenyl)methanol each containing two reactive functionalities viz. allyl, allyloxy and allyl, propargyloxy, respectively, were synthesized from 3‐allylsalicyaldehyde as a starting material. Well defined α‐allyl, α′‐allyloxy and α‐allyl, α′‐propargyloxy bifunctionalized poly(ε‐caprolactone)s with molecular weights in the range 4200–9500 and 3600–10,900 g/mol and molecular weight distributions in the range 1.16–1.18 and 1.15–1.16, respectively, were synthesized by ROP of ε‐caprolactone employing these initiators. The presence of α‐allyl, α′‐allyloxy and α‐allyl, α′‐propargyloxy functionalities on poly(ε‐caprolactone)s was confirmed by FT‐IR, ¹H, ¹³C NMR spectroscopy, and MALDI‐TOF analysis. The kinetic study of ROP of ε‐caprolactone with both the initiators revealed the pseudo first order kinetics with respect to ε‐caprolactone consumption and controlled behavior of polymerization reactions. The usefulness of α‐allyl, α′‐allyloxy functionalities on poly(ε‐caprolactone) was demonstrated by performing the thiol‐ene reaction with poly(ethylene glycol) thiol to obtain (mPEG)₂‐PCL miktoarm star copolymer. α‐Allyl, α′‐propargyloxy functionalities on poly(ε‐caprolactone) were utilized in orthogonal reactions i.e copper catalyzed alkyne‐azide click (CuAAC) with azido functionalized poly(N‐isopropylacrylamide) followed by thiol‐ene reaction with poly(ethylene glycol) thiol to synthesize PCL‐PNIPAAm‐mPEG miktoarm star terpolymer. The preliminary characterization of A₂B and ABC miktoarm star copolymers was carried out by ¹H NMR spectroscopy and gel permeation chromatography (GPC). © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 844–860     

Radical‐initiated polymerization of β‐methyl‐α‐methylene‐γ‐butyrolactone

β‐Methyl‐α‐methylene‐γ‐butyrolactone (MMBL) was synthesized and then was polymerized in an N,N‐dimethylformamide (DMF) solution with 2,2‐azobisisobutyronitrile (AIBN) initiation. The homopolymer of MMBL was soluble in DMF and acetonitrile. MMBL was homopolymerized without competing depolymerization from 50 to 70 °C. The rate of polymerization (R_p) for MMBL followed the kinetic expression R_p = [AIBN]^0.54[MMBL]^1.04. The overall activation energy was calculated to be 86.9 kJ/mol, k_p/k_t^1/2 was equal to 0.050 (where k_p is the rate constant for propagation and k_t is the rate constant for termination), and the rate of initiation was 2.17 × 10^?8 mol L^?1 s^?1. The free energy of activation, the activation enthalpy, and the activation entropy were 106.0, 84.1, and 0.0658 kJ mol^?1, respectively, for homopolymerization. The initiation efficiency was approximately 1. Styrene and MMBL were copolymerized in DMF solutions at 60 °C with AIBN as the initiator. The reactivity ratios (r₁ = 0.22 and r₂ = 0.73) for this copolymerization were calculated with the Kelen–Tudos method. The general reactivity parameter Q and the polarity parameter e for MMBL were calculated to be 1.54 and 0.55, respectively. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1759–1777, 2003     

The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

The amount of research activity concerning α‐methylene‐γ‐butyrolactones and α‐alkylidene‐γ‐butyrolactones has increased dramatically in recent years. This Review summarizes the structural types, biological activities, and biosynthesis of these compounds, concentrating on publications from the past 10 years. Traditional approaches to α‐methylene‐γ‐butyrolactones and α‐alkylidene‐γ‐butyrolactones are then reviewed together with novel approaches, including those from our own research group, reported more recently.     

Novel Synthetic Route to α‐Aminophosphonates Containing Benzothiazole Moiety

A novel and ef?cient synthetic route to α‐aminophosphonates containing benzothiazole moiety via a cascade three‐component reaction from conveniently available starting materials has been developed. The target compounds 3a – 3g , 7 and 8a , 8b were evaluated for their anticancer activities against the cancer cell line HL‐60 in vitro by the MTT method. Compound 3g showed good cancer inhibitory activity against the tested cell line. Further study is necessary to find out the potential antitumor activities.     

β‐Cyclodextrin‐Supported,Completely Regioselective Ring Opening of Thiiranes with Thiophenol in Water

Thiolysis of thiiranes I with thiophenols II is performed efficiently in the presence of β‐cyclodextrin in water with high regioselectivity (Scheme, Table).     

Enantiomeric separation of 2‐arylpropionic acid nonsteroidal anti‐inflammatory drugs by HPLC with hydroxypropyl‐β‐cyclodextrin as chiral mobile phase additive

The enantio‐separations of eight 2‐arylpropionic acid nonsteroidal anti‐inflammatory drugs (2‐APA NSAIDs) were established using reversed‐phase high‐performance liquid chromatography with hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as chiral mobile phase additive for studying the stereoselective skin permeation of suprofen, ketoprofen, naproxen, indoprofen, fenoprofen, furbiprofen, ibuprofen and carprofen. The effects of the mobile phase composition, concentration of HP‐β‐CD and column temperature on retention and enantioselective separation were investigated. With 2‐APA NSAIDs as acidic analytes, the retention times and resolutions of the enantiomers were strongly related to the pH of the mobile phase. In addition, both the concentration of HP‐β‐CD and temperature had a great effect on retention time, but only a slight or almost no effect on resolutions of the analytes. Enantioseparations were achieved on a Shimpack CLC‐ODS (150 × 4.6 mm i.d., 5 μm) column. The mobile phase was a mixture of methanol and phosphate buffer (pH 4.0–5.5, 20 mM) containing 25 mM HP‐β‐CD. This method was flexible, simple and economically advantageous over the use of chiral stationary phase, and was successfully applied to the enantioselective determination of the racemic 2‐APA NSAIDs in an enantioselective skin permeation study. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of β‐Hydroxy α‐Sulfanyl Esters by Using Nanocrystalline Magnesium Oxide

Aldol‐type reaction between electron deficient aldehydes and sulfonium salts to afford the corresponding β‐hydroxy α‐sulfanyl esters in moderate‐to‐good yields by using nanocrystalline MgO is described. The sulfanyl group is a useful group for further transformations in organic synthesis. Low R_f‐value isomer is anti‐configured as revealed by X‐ray diffraction study and consistent with the assignment of ¹H‐NMR spectrum.     

Synthesis of α‐(Fluorophenyl)pyridine by Palladium‐Catalyzed Cross‐Coupling Reaction

A series of α‐(fluoro‐substituted phenyl)pyridines have been synthesized by means of a palladium‐catalyzed cross‐coupling reaction between fluoro‐substituted phenylboronic acid and 2‐bromopyridine or its derivatives. The reactivities of the phenylboronic acids containing di‐ and tri‐fluoro substituents with α‐pyridyl bromide were investigated in different catalyst systems. Unsuccessful results were observed in the Pd/C and PPh₃ catalyst system due to phenylboronic acid containing electron‐withdrawing F atom(s). For the catalyst system of Pd(OAc)₂/PPh₃, the reactions gave moderate yields of 55% –80%, meanwhile, affording 10% –20% of dimerisation (self‐coupling) by‐products, but trace products were obtained in coupling with 2,4‐difluorophenylboronic acids because of steric hinderance. Pd(PPh₃)₄ was more reactive for boronic acids with sterically hindering F atom(s), and the coupling reactions gave good yields of 90% and 91% without any self‐coupling by‐product.     

The Stereoselective Synthesis of 2‐Aryl‐2‐hydroxybutanoic Acid via Menthyl Chiral Auxiliaries

In the presence of titanium(IV) tetraethoxide ((EtO)₄Ti), menthyl arylglyoxylates are prepared by transesterification of ethyl arylglyoxylates and natural (−)‐(1R,2S,5R)‐menthol. Using menthyl as a chiral auxiliary, the corresponding novel (R)‐menthyl 2‐aryl‐2‐hydroxybutanoates are synthesized by the addition of Et₂Zn with menthyl arylglyoxylates. The structures of the products are characterized by IR and ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, and elemental analysis. The diastereoselectivities are analyzed by HPLC. The addition reactions are completed with good yields and high diastereoisomeric excess (de up to 95%), and, after hydrolysis, the (R)‐2‐aryl‐2‐hydroxybutanoic acids are obtained with high optical purities.     

Metal‐Free Multicomponent Synthesis of (α‐Aminoalkyl)phosphonates Using 2,4,6‐Trichloro‐1,3,5‐triazine

(α‐Aminoalkyl)phosphonates have efficiently been synthesized by multicomponent reaction of aldehydes, amines, and triethyl phosphite in the presence of 2,4,6‐trichloro‐1,3,5‐triazine at room temperature. The products are formed in high yields (83–91%) within 0.5–1 h.     

A New Route to N‐Aryl 2‐Alkenamides,N‐Allyl N‐Aryl 2‐Alkenamides,and N‐Aryl α,β‐Unsaturated γ‐Lactams from N‐Aryl 3‐(Phenylsulfonyl)propanamides

A series of N‐aryl 2‐alkenamides were produced efficiently by treating N‐aryl 3‐(phenylsulfonyl)‐propanamides with potassium tert‐butoxide in THF at 0°C. With out isolation, it was further treated with an additional equivalent of potassium tert‐butoxide and allyl bromide to give N‐allyl N‐aryl 2‐alkenamides in one pot in good yields. Followed by a ring‐closing metathesis reaction, these N‐allyl N‐aryl 2‐alkenamides were respectively converted into corresponding N‐aryl α,β‐unsaturated γ‐lactams in moderate yields.