Organic & Biomolecular Chemistry (v.8, #18)

Front cover (4029-4029).

Inside front cover (4030-4030).

Contents (4031-4042).

We review recent developments and applications of aldolase-type organocatalytic direct transformations in aqueous media without addition of organic solvent.

Strain-promoted double-click reaction for chemical modification of azido-biomolecules by Isao Kii; Akira Shiraishi; Toshiyuki Hiramatsu; Takeshi Matsushita; Hidehiro Uekusa; Suguru Yoshida; Makoto Yamamoto; Akira Kudo; Masatoshi Hagiwara; Takamitsu Hosoya (4051-4055).
The strain-promoted “double-click” (SPDC) reaction using Sondheimer diyne, a novel convergent method conjugating three molecules spontaneously, has enabled us to readily modify an azido-biomolecule with a small reporter azido-molecule.

An unusual reactivity of BBr3: Accessing tetrahydroisoquinoline units from N-phenethylimides by Jayaraman Selvakumar; Alexandros Makriyannis; Chinnasamy Ramaraj Ramanathan (4056-4058).
Isoindoloisoquinalinone, pyrroloisoquinolinone and benzo[a]quinolizinone units are constructed via intramolecular cyclization of the methoxy substituted N-phenethylimides using BBr3.

Efforts toward elucidating Thalidomide’s molecular target: an expedient synthesis of the first Thalidomide biotin analogue by Scott G. Stewart; Carlos J. Braun; Marta E. Polomska; Mahdad Karimi; Lawrence J. Abraham; Keith A. Stubbs (4059-4062).
Herein we describe the synthesis of the first Thalidomide–biotin analogue in order to initiate investigations into the unknown molecular mode of action of Thalidomide. In this manner we describe the attachment of biotin tether through the Huisgen 1,3-dipolar cycloaddition or “click” synthetic methodology.

A cascade aza-Michael-Henry-dehydration reaction catalyzed by quinidine-derived tertiary amine-thiourea catalyst was developed via installation of suitable electron withdrawing groups at the amino function of aniline. This strategy led to a one-step preparation of chiral 3-nitro-1,2-dihydroquinolines in high yields and with up to 90% enantiomeric excesses.

The design and synthesis of new inhibitor analogues for the Mycobacterium tuberculosis (Mtb) phosphatase PtpB is described. Analogues were synthesized by incorporation of two common and effective phosphate mimetics, the isothiazolidinone (IZD) and the difluoromethylphosphonic acid (DFMP). The basic scaffold of the inhibitor was identified from structure–activity relationships established for a previously published isoxazole inhibitor, while the phosphate mimetics were chosen based on their proven cell permeability and activity when incorporated into previously reported inhibitors for the phosphatase PTP1B. The inhibitory activity of each compound was evaluated, and each was found to have low or submicromolar affinity for PtpB.

A facile direct synthesis of cinnamonitriles from acrylonitriles and benzenes is successfully achieved by using Pd(OAc)2/HPMoV/O2 catalyst system via the direct C–H bond activation of benzenes using molecular oxygen as a terminal oxidant.

Vinyl-substituted (Z)-stilbenes are stereoselectively synthesised on treatment of 4-arylbuta-2,3-dien-1-ols with arylboronic acids in the presence of a rhodium(i) catalyst. The reaction proceeds through the regioselective addition of organorhodium(i) species across the aryl-substituted carbon–carbon double bond of the allene moiety and subsequent δ-elimination of Rh(i)–OH.

Platinum-catalyzed cross-dehydrogenative coupling reaction in the absence of oxidant by Xing-Zhong Shu; Yan-Fang Yang; Xiao-Feng Xia; Ke-Gong Ji; Xue-Yuan Liu; Yong-Min Liang (4077-4079).
A third strategy for cross-dehydrogenative coupling reaction has been reported via platinum-catalyzed sp3 C–H and sp3 C–H coupling reaction in the absence of oxidant. Nitroalkanes as well as dialkyl malonate derivatives, β-keto esters and malononitrile are active participants in this coupling reaction. Both cyclic and acyclic non-activated simple ketones are good reactants in this reaction.

A combination of experimental data [using 18O labelling fragmentation data together with metastable ion studies in a reverse sector mass spectrometer (from a previous study)] and ab initio reaction coordinate studies at the CCSD(T)/6-31++G(d,p)//B3LYP/6-31++G(d,p) level of theory, have provided the following data concerning the formation of PhO in the gas-phase from energized systems PhO(CH2)nO (n = 2–4). All ΔG values were calculated at 298 K. (1) PhO(CH2)2O effects an ipso Smiles rearrangement (ΔGr = +35 kJ mol−1; barrier to transition state ΔG# = +40 kJ mol−1) equilibrating the two oxygen atoms. The Smiles intermediate reverts to PhO(CH2)2O which then undergoes an SNi reaction to form PhO and ethylene oxide (ΔGr = −24 kJ mol−1; ΔG# = +54 kJ mol−1). (2) The formation of PhO from energized PhO(CH2)3O is more complex. Some 85% of the PhO formed originates via a Smiles intermediate (ΔGr = +52 kJ mol−1; ΔG# = +61 kJ mol−1). This species reconverts to PhO(CH2)3O which then fragments to PhO by two competing processes, namely, (a) an SNi process yielding PhO and trimethylene oxide (ΔGr = −27 kJ mol−1; ΔG# = +69 kJ mol−1), and (b) a dissociation process giving PhO, ethylene and formaldehyde (ΔGr = −65 kJ mol−1; ΔG# = +69 kJ mol−1). The other fifteen percent of PhO is formed prior to formation of the Smiles intermediate, occurring directly by the SNi and dissociation processes outlined above. The operation of two fragmentation pathways is supported by the presence of a composite metastable ion peak. (3) Energized PhO(CH2)4O fragments exclusively by an SNi process to form PhO and tetrahydrofuran (ΔGr = −101 kJ mol−1; ΔG# = +53 kJ mol−1). The Smiles ipso cyclization (ΔGr = +64 kJ mol−1; ΔG# = +74 kJ mol−1) is not detected in this system.

A pyridine based 1,2-diamine containing only one stereogenic center has been identified for fast aldol reactions (16–48 h). Using 2–5 mol% of (R)- or (S)-PicAm-2, cyclohexanone (3.3 equiv) readily undergoes aldol reactions with o-, m-, and p-substituted aromatic aldehyde partners (limiting reagent), including the poor electrophile 4-methylbenzaldehyde (95–99% ee). Furthermore, functionalized cyclic ketone substrates have been converted into four aldol products 9–12 using the lowest catalyst loading (5.0 mol%) to date with the highest yield and enantioselectivity.

Gold(i)-catalysed alcohol additions to cyclopropenes by Maximillian S. Hadfield; Jürgen T. Bauer; Pauline E. Glen; Ai-Lan Lee (4090-4095).
Gold(i)-catalysed addition of alcohols to 3,3-disubstituted cyclopropenes occurs in a highly regioselective and facile manner to produce alkyl tert-allylic ethers in good yields. The reaction is tolerant of sterically hindered substituents on the cyclopropene as well as primary and secondary alcohols as nucleophiles. In this full article, we report on the substrate scope and plausible mechanism, as well as the regioselectivity issues arising from subsequent gold(i)-catalysed isomerisation of tertiary to primary allylic ethers.

Azaanthraquinone assembly from N-propargylamino quinone via iodine-induced 6-endo-dig electrophilic cyclization by Na Fei; Qiwen Hou; Shaozhong Wang; Huaqin Wang; Zhu-Jun Yao (4096-4103).
An efficient methodology taking advantage of the excellent nucleophilicity of aminoquinone to assemble the azaanthraquinone framework was developed via an iodine-induced 6-endo-dig electrophilic cyclization. Therefore, starting from N-propargylaminoquinones, various 3-iodo-1-azaanthraquinones were obtained in yields ranging from 45% to 90%. The metal-free protocol features facile installation of an iodine atom on the azaanthraquinone ring and benign functional group compatibility.

Tricarbonyl M(I) (M = Re, 99mTc) complexes bearing acridine fluorophores: synthesis, characterization, DNA interaction studies and nuclear targeting by Teresa Esteves; Catarina Xavier; Sofia Gama; Filipa Mendes; Paula D. Raposinho; Fernanda Marques; António Paulo; João Costa Pessoa; José Rino; Giampietro Viola; Isabel Santos (4104-4116).
New pyrazolyl-diamine ligands with acridine derivatives at the 4-position of the pyrazolyl ring were synthesized and characterized (L1 and L2). Coordination towards the fac-[M(CO)3]+ (M = Re, 99mTc) led to complexes fac-[M(CO)33-L)] (L = L1: M = Re1, Tc1; L = L2: M = Re2, Tc2). The interaction of the novel pyrazolyl-diamine ligands (L1 and L2) and rhenium(i) complexes (Re1 and Re2) with calf thymus DNA (CT-DNA) was investigated by a variety of techniques, namely UV-visible, fluorescence spectroscopy and circular and linear dichroism. Compounds L1 and Re1 have moderate affinity to CT-DNA and bind to DNA by intercalation, while L2 and Re2 have a poor affinity for CT-DNA. Moreover, LD measurements showed that L1 and Re1 act as perfect intercalators. By confocal fluorescence microscopy we found that L1 and Re1 internalize and localize in the nucleus of B16F1 murine melanoma cells. The congener Tc1 complex also targets the cell nucleus exhibiting a time-dependent cellular uptake and a fast and high nuclear internalization (67.2% of activity after 30 min). Plasmid DNA studies have shown that Tc1 converts supercoiled (sc) puc19 DNA to the open circular (oc) form.

Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases by Paola Galletti; Enrico Emer; Gabriele Gucciardo; Arianna Quintavalla; Matteo Pori; Daria Giacomini (4117-4123).
We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto–enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.

Acyclic triaryl olefins possessing a sulfohydroxamic acid pharmacophore: synthesis, nitric oxide/nitroxyl release, cyclooxygenase inhibition, and anti-inflammatory studies by Zhangjian Huang; Carlos Velázquez; Khaled Abdellatif; Morshed Chowdhury; Sarthak Jain; Julie Reisz; Jenna DuMond; S. Bruce King; Edward Knaus (4124-4130).
Nitric oxide (NO) and its reduced form nitroxyl (HNO), effective vasodilation agents that can inhibit platelet aggregation and adhesion, could suppress adverse cardiovascular effects associated with the use of selective COX-2 inhibitors. In this regard, a sulfohydroxamic acid (SO2NHOH) substituent, that can act as a dual NO/HNO donor moiety, was inserted at the para-position of the C2 phenyl ring of acyclic 2-alkyl-1,1,2-triaryl olefins previously shown to be potent and highly selective COX-2 inhibitors. Although this new group of 1,1-diaryl-2-(4-hydroxyaminosulfonylphenyl)alk-1-enes exhibited weak inhibition of the constitutive cyclooxygenase-1 (COX-1) and inducible COX-2 isozymes, in vivo studies showed anti-inflammatory potencies that were generally intermediate between that of the reference drugs aspirin and ibuprofen. All compounds released NO (5.6–13.5% range) upon incubation with phosphate buffer which was increased further (8.3–25.6% range) in the presence of the oxidant K3(FeCN6).The low release of HNO in MeOH-buffer (< 2% at 24 h incubation) was much higher at alkaline pH (11–37% range). The concept of designing better anti-inflammatory drugs possessing either an effective HNO, or dual NO/HNO, donor moiety that are devoid of adverse ulcerogenic and/or cardiovascular side effects warrants further investigation.

Microwave-enhanced synthesis of 2,3,6-trisubstituted pyridazines: application to four-step synthesis of gabazine (SR-95531) by Navnath Gavande; Graham A. R. Johnston; Jane R. Hanrahan; Mary Chebib (4131-4136).
Microwave-enhanced, highly efficient protocols for the synthesis of synthetically and biologically important 2,3,6-trisubstituted pyridazine architectures have been developed by sequential amination/Suzuki coupling/alkylation reactions. This powerful strategy is an economical and highly chemoselective protocol for the synthesis of diversified pyridazines. The total synthesis of gabazine (SR-95531) has been achieved using a versatile strategy in four steps and 73% overall yield.

Rate constants for acid catalysis of the reactions of N-chlorodimethylamine (1), N-chloro-2,2,2-trifluoroethylamine (2) and N,N-dichlorotaurine (3) with iodide ion were determined in H2O at 25 °C and I = 0.5 (NaClO4). The failure to detect significant catalysis by general acids of chlorine transfer from 1 to the nucleophile, together with the observed inverse solvent deuterium isotope effect on the hydronium ion-catalysed reaction (kH/kD = 0.37), indicates that this process occurs by protonation of 1 in a fast equilibrium step, followed by rate determining chlorine transfer to iodide ion. The appearance of general acid catalysis for the reactions of 2 and 3 shows that increasing the leaving group ability leads to a change to a concerted mechanism, which is suggested to be enforced by the absence of a significant lifetime of the protonated chloramine intermediate in the presence of iodide ion.

Rhodamine-based chemosensor for Hg2+ in aqueous solution with a broad pH range and its application in live cell imaging by Yun Zhao; Yue Sun; Xin Lv; Yunlong Liu; Maliang Chen; Wei Guo (4143-4147).
A new fluorescent probe, rhodamine B derivative (1) bearing an 8-hydroxyquinoline group, was synthesized and displayed highly selective and sensitive Hg2+-amplified absorbance and fluorescence emission above 500 nm in aqueous solution with a broad pH range 4–9. It was found that mercury ions coordinate reversibly to 1 and the spirolactam ring of 1 was opened, forming a 1 : 1 metal–ligand complex. Furthermore, this sensor was applied for in vivo imaging in HeLa cells to confirm that 1 can be used as a fluorescent probe for monitoring Hg2+ in living cells.

Through the stoichiometric 2 : 1 coordination of Zn2+ with 4-amino-N-(2-methylquinolin-8-yl)benzenesulfonamide-modified per-methyl-β-cyclodextrin (MQAS-PMCD) and the strong inclusion complexation of permethyl-β-cyclodextrin cavity with meso-tetrakis-(4-sulfonatophenyl)-porphyrin (TSPP), an environment-sensitive Zn2+/cyclodextrin/porphyrin triad supramolecular assembly was constructed, and its structure was fully characterized by UV/vis spectroscopy, fluorescence spectroscopy, powder X-ray diffraction (XRD), scanning tunneling microscopy (STM) and transmission electron microscopy (TEM). Fluorescence spectrometric studies showed that this supramolecular assembly was stable and barely emitted green fluorescence in water due to the energy transfer process, but gave the strong green fluorescence when changing to a hydrophobic environment due to the disruption of the assembly. Further studies on the cell staining experiments by means of fluorescence microscopy showed that this supramolecular assembly was disrupted to release the MQAS-PMCD/Zn2+ and porphyrin components when interacting with the cell membrane. Subsequently, the released MQAS-PMCD/Zn2+ complex remained in the cell membrane, while the porphyrin component entered the cells. This transmembrane dissociation property of the supramolecular assembly will enable its application in the delivery of biological and drug molecules containing the anionic porphyrin skeleton such as β-octaphenyl-meso-tetra(4-carboxyl)-phenylporphyrin and so on.

An efficient route to xanthine based A2A adenosine receptor antagonists and functional derivatives by Paul LaBeaume; Ma Dong; Michail Sitkovsky; Elizabeth V. Jones; Rhiannon Thomas; Sara Sadler; Amy E. Kallmerten; Graham B. Jones (4155-4157).
A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A2A adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

Benzoyl radicals from (hetero)aromatic aldehydes. Decatungstate photocatalyzed synthesis of substituted aromatic ketones by Davide Ravelli; Michele Zema; Mariella Mella; Maurizio Fagnoni; Angelo Albini (4158-4164).
Benzoyl radicals are generated directly from (hetero)aromatic aldehydes upon tetrabutylammonium decatungstate ((n-Bu4N)4W10O32), TBADT) photocatalysis under mild conditions. In the presence of α,β-unsaturated esters, ketones and nitriles radical conjugate addition ensues and gives the corresponding β-functionalized aryl alkyl ketones in moderate to good yields (stereoselectively in the case of 3-methylene-2-norbornanone). Due to the mild reaction conditions the presence of various functional groups on the aromatic ring is tolerated (e.g. methyl, methoxy, chloro). The method can be applied to hetero-aromatic aldehydes whether electron-rich (e.g. thiophene-2-carbaldehyde) or electron-poor (e.g. pyridine-3-carbaldehyde).

Switching from (R)- to (S)-selective chemoenzymatic DKR of amines involving sulfanyl radical-mediated racemization by Lahssen El Blidi; Nicolas Vanthuyne; Didier Siri; Stéphane Gastaldi; Michèle P. Bertrand; Gérard Gil (4165-4168).
Chemoenzymatic dynamic kinetic resolution (DKR) of amines involving sulfanyl radical-induced racemization happened to be the very first switchable DKR process allowing the synthesis of either (R)- or (S)-amides, in good yield and high enantiomeric excess, depending on the nature of the enzyme; the different steps of the development of (S)-selective DKR are discussed.

Substituent effect of group 14 elements on the ring-opening reaction of cyclobutene by Munehiro Hasegawa; Ippei Usui; Soichiro Konno; Masahiro Murakami (4169-4175).
A series of cyclobutenes bearing group 14 elements at the 3-position were synthesized, and their thermal ring-opening reactions were studied. Carbon-substituted cyclobutene underwent the ring-opening reaction through an outward pathway to afford the E-diene exclusively. On the other hand, the ring-opening reaction of the silyl, germyl, and stannyl substituted cyclobutenes occurred in both outward and inward directions giving a mixture of E and Z isomers. The structural features of the calculated transition state and population analysis suggested that the formation of the Z-isomer could be ascribed to the donor/acceptor interaction between the HOMO and the σ* orbital of group 14 elements. Interestingly, the order of inward preference was Si > Sn > Ge. These rotational behaviors of silyl, germyl, and stannyl substituents were explained by taking into account the energy gap and the magnitude of overlap between the σ* orbital and HOMO.

2′,4′-BNA bearing a 2-pyridine nucleobase for CG base pair recognition in the parallel motif triplex DNA by Yoshiyuki Hari; Sachiko Matsugu; Hiroyasu Inohara; Yuri Hatanaka; Masaaki Akabane; Takeshi Imanishi; Satoshi Obika (4176-4180).
We succeeded in the synthesis of triplex-forming oligonucleotides (TFOs) that contain a deoxyribonucleotide (Py) bearing a 2-pyridine nucleobase or the 2′,4′-BNA congener (PyB). By UV melting experiments, it was found that 2-pyridine was a very promising nucleobase for the sequence-selective recognition of a CG base pair within double-stranded DNA (dsDNA) in a parallel motif triplex. Moreover, PyB in TFOs showed stronger affinity to a CG base pair than Py with further increase in the selectivity. Using TFO including multiple PyB units, triplex formation with dsDNA containing three CG base pairs was observed.

Back matter (4181-4182).

Back cover (4183-4184).