Organic & Biomolecular Chemistry (v.12, #24)

Front cover (4033-4033).

Inside front cover (4034-4034).

Contents list (4035-4043).

The development of efficient methods for the synthesis of heteroaromatic compounds is always of great importance for chemists. In this ‘Perspective’, we describe a general approach for the synthesis of functionalized heteroaromatics via intramolecular Wittig reactions. In all cases, the reaction proceeds via in situ generated phosphorus ylides. We especially emphasize the importance of chemoselective intramolecular Wittig reactions using designed Michael acceptors and suitable acyl chloride as trapping reagents, which allows formation of two different classes of heteroaromatics from the same substrates. This metal-free approach is quite general and works in a number of examples, furnishing the corresponding products in moderate to good yields under relatively mild reaction conditions.

This review updates on recent advances in aliphatic sp3 C–H bond oxidation by remote H-radical abstraction with oxygen- and nitrogen-radicals classifying by the type of the radical precursors.

Stereoselective synthesis of hexahydroquinazolin-2(1H)-ones has been achieved through the application of the diene-transmissive hetero-Diels–Alder methodology to 2-vinyl-1-aza-1,3-butadienes. The cross-conjugated 1-azatriene underwent an initial hetero-Diels–Alder reaction on the 1-aza-1,3-butadiene system with tosyl isocyanate to afford the [4 + 2] mono-cycloadduct pyrimidinone. The second Diels–Alder reaction on the electron-rich 1-amino-1,3-diene unit of the mono-cycloadduct with dienophiles provided hexahydroquinazolin-2(1H)-ones with high stereoselectivity.

Versatile post-functionalization of the external shell of cowpea chlorotic mottle virus by using click chemistry by C. A. Hommersom; B. Matt; A. van der Ham; J. J. L. M. Cornelissen; N. Katsonis (4065-4069).
We present the modification of the outer protein shell of cowpea chlorotic mottle virus (CCMV) with linear and strained alkyne groups. These functionalized protein capsids constitute valuable platforms for post-functionalization via click chemistry. After modification, the integrity of the capsid and the reversible disassembly behavior are preserved.

Copper-catalyzed bis-arylations of alkenes leading to oxindole derivatives by Liangliang Shi; Yuyuan Wang; Haijun Yang; Hua Fu (4070-4073).
A simple and practical copper-catalyzed approach to oxindole derivatives by copper-catalyzed bis-arylation of N-alkyl-N-phenylacrylamides with diaryliodonium triflates has been developed under mild conditions, and the method is of tolerance towards some functional groups in the substrates.

Investigating peptide sequence variations for ‘double-click’ stapled p53 peptides by Yu Heng Lau; Peterson de Andrade; Niklas Sköld; Grahame J. McKenzie; Ashok R. Venkitaraman; Chandra Verma; David P. Lane; David R. Spring (4074-4077).
Stapling peptides for inhibiting the p53/MDM2 interaction is a promising strategy for developing anti-cancer therapeutic leads. We evaluate double-click stapled peptides formed from p53-based diazidopeptides with different staple positions and azido amino acid side-chain lengths, determining the impact of these variations on MDM2 binding and cellular activity. We also demonstrate a K24R mutation, necessary for cellular activity in hydrocarbon-stapled p53 peptides, is not required for analogous ‘double-click’ peptides.

The first example of the palladium-catalyzed one-pot synthesis of 2-arylbenzofurans in moderate to excellent yields via a tandem reaction of 2-hydroxyarylacetonitriles with sodium sulfinates is reported. A plausible mechanism for the formation of 2-arylbenzofurans involving desulfinative addition and intramolecular annulation reactions is proposed. Moreover, the present synthetic route to benzofurans could be readily scaled up to the gram quantity without any difficulty. Thus, the method represents a convenient and practical strategy for synthesis of benzofuran derivatives.

A Pd-catalyzed cascade reaction of N–H insertion and oxidative dehydrogenative aromatization: a new entry to 2-amino-phenols by Dong Ding; Xiaobing Lv; Jian Li; Lin Qiu; Guangyang Xu; Jiangtao Sun (4084-4088).
A palladium-catalyzed cascade reaction of N–H insertion (NHI) and oxidative dehydrogenative aromatization (ODA) has been developed, which affords a straightforward and efficient way to access the carbazole precursors (2-arylamino-phenols) as well as to prepare 2-alkylamino-phenols from non-aromatic substrates.

A model study for tethering of (bio)active molecules to biomaterial surfaces through arginine by F. Taraballi; L. Russo; C. Battocchio; G. Polzonetti; F. Nicotra; L. Cipolla (4089-4092).
A new approach for tethering of bioactive molecules via arginine is proposed and validated on collagen 2D matrices. The method involves the introduction of a methyl ketone on arginine side-chains, followed by reaction with model alkoxyamino derivatives.

A simple, fast and efficient method for allylation and propargylation of chlorosilanes through zinc mediation and ultrasound promotion is reported. As a direct application of the resulting bis-allylsilanes, three novel, constrained sila amino acids are prepared for the first time. The design and synthesis of the constrained sila analogue of GABA (γ-amino butyric acid) is a highlight of this work.

Total synthesis of an anticancer norsesquiterpene alkaloid isolated from the fungus Flammulina velutipes by K. Kashinath; Prakash D. Jadhav; D. Srinivasa Reddy (4098-4103).
The first total synthesis of a norsesquiterpene alkaloid (R)-8-hydroxy-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]isoindole-1,3(2H,6H)-dione, isolated from the mushroom-forming fungus Flammulina velutipes, in both racemic and enantiomeric pure forms, is reported. The (−)-enantiomer of the natural product has been synthesized from the d-(−)-pantolactone chiral pool. The synthesis features a one-pot, three-step reaction sequence comprising an enyne RCM/Diels–Alder/aromatization to construct the desired indane skeleton present in the natural product. Our synthesis further confirms the assigned structure and absolute configuration of the natural product.

An efficient gold-catalyzed method to generate the highly reactive cyclic o-QDM species from the enynal/enynone and alkene is reported. This method allows rapid access to a variety of structurally unique propeller-like products through tandem Diels–Alder reactions.

A Rh(iii)-catalyzed oxidative [4 + 1] cycloaddition of benzohydroxamic acids and α-diazoesters is achieved to afford benzolactams in up to 93% yields. With the N-OAc amido moiety as a directing group, the ortho-C–H is selectively functionalized and the catalytic reaction exhibits excellent tolerance to different functional substituents. A notable rhodacyclic complex is isolated and structurally characterized, suggesting that C–H/N–H cyclometallation is a key step in the catalytic cycle.

Synthesis and complexation study of new ExTTF-based hosts for fullerenes by Hassan Iden; Frédéric-Georges Fontaine; Jean-Francois Morin (4117-4123).
A new series of exTTF hosts has been synthesized for supramolecular binding study of fullerenes C60 and C70. Binding constants for C60 in chlorobenzene, toluene, toluene–CH2Cl2 and CS2 have been calculated for different hosts and a direct structure–affinity relationship has been established. As predicted, receptors with two exTTF moieties (1, 3 and 4) have demonstrated higher binding abilities toward C70 than C60. Depending on the linker used to attach the exTTF unit to the core of the host, different binding modes (1 : 1 and 2 : 1) have been obtained.

Conformational analysis of helical aminoisobutyric acid (Aib) oligomers bearing C-terminal ester Schellman motifs by Sarah J. Pike; James Raftery; Simon J. Webb; Jonathan Clayden (4124-4131).
The effect of Schellman motifs on the adoption of stable 310 helical conformations in a series of aminoisobutyric (Aib) oligomers has been studied in the solid state and solution. The destabilising effect of the Schellman motif (a local inversion of helical screw-sense due to a C-terminal ester residue) was quantified in the solid state using X-ray crystallography through analysis of the torsion angles and their deviation from those observed in an ideal 310 helix. Investigation of the intramolecular hydrogen-bonding interactions in the solid state led to the identification of a fully extended C5 conformation in one oligomer, which is a novel folding motif for Aib oligomers. The effect of ester groups with differing steric demands on intermolecular hydrogen-bonding contacts in the solid state was also ascertained. In solution, the adoption of a 310 conformation in Aib oligomers appeared to be more finely tuned, depending on a number of factors, including chain length and the steric demands of the C-terminal destabilising Schellman motif.

Synthesis and antimalarial activity of prodigiosenes by Estelle Marchal; Deborah A. Smithen; Md. Imam Uddin; Andrew W. Robertson; David L. Jakeman; Vanessa Mollard; Christopher D. Goodman; Kristopher S. MacDougall; Sherri A. McFarland; Geoffrey I. McFadden; Alison Thompson (4132-4142).
Several analogues of the natural compound prodigiosin with modified A- and C-rings were synthesised as were some of their tin, cobalt, boron and zinc complexes. The antimalarial activity of these prodigiosenes was evaluated in vitro using the 3D7 Plasmodium falciparum strain. The presence of a nitrogen atom in the A-ring is needed for antimalarial activity but the presence of an alkyl group at the β′-position of the C-ring seems detrimental. Dibutyl tin complexes exhibit IC50 values mostly in the nanomolar range with equal or improved activity compared to the free-base prodigiosene ligand, despite the fact that the general toxicity of such tin complexes is demonstrably lower than that of the free-bases.

At 90–120 °C, in the presence of methylcarbonate and bicarbonate methyltrioctylphosphonium salts as catalysts ([P8881][A]; [A] = MeOCO2 and HOCO2), the transesterification of non-toxic dimethyl- and diethyl-carbonate (DMC and DEC, respectively) with 1,X-diols (2 ≤X≤ 6) proceeds towards the formation of cyclic and linear products. In particular, 1,2-propanediol and ethylene glycol afford propylene- and ethylene-carbonate with selectivity and yields up to 95 and 90%, respectively; while, the reaction of DMC with higher diols such 1,3-butanediol, 2-methyl-1,3-propanediol, 1,3-propanediol, 2,2-dimethyl, 1,3-propanediol, 1,4-butanediol and 1,6-hexanediol produce linear C8–C10 dicarbonates of general formula MeOC(O)O∼∼∼OC(O)OMe as the almost exclusive products. Of note, these dicarbonate derivatives are not otherwise accessible in good yields by other conventional base catalyzed methods. Among 1,3-diols, the only exception was 2-methyl 2,4-pentandiol that yields the corresponding cyclic carbonate, i.e. 4,4,6-trimethyl-1,3-dioxan-2-one. In no one case, polycarbonates are observed. Such remarkable differences of product distributions are ascribed to the structure (branching and relative position of OH groups) of diols and to the role of cooperative (nucleophilic and electrophilic) catalysis which has been proved for onium salts. The investigated carbonate salts are not only effective in amounts as low as 0.5 mol%, but they are highly stable and recyclable.

Improving alkynyl(aryl)iodonium salts: 2-anisyl as a superior aryl group by David J. Hamnett; Wesley J. Moran (4156-4162).
The majority of alkynyl(aryl)iodonium salts reported in the literature are derived from iodobenzene. This article describes the effects of varying this iodoarene building block on the synthesis, reactivity and stability of these salts. Two procedures to synthesize a variety of known and novel alkynyl(aryl)iodonium tosylates directly from the iodoarene are reported. In the reactions of these salts, those derived from 2-iodoanisole gave superior results than the others tested in every reaction. Isothermal microcalorimetry indicated that these novel salts were significantly more stable and less prone to decomposition than all of the other derivatives.

Quantum mechanistic insights on aryl propargyl ether Claisen rearrangement by Venkatesan Srinivasadesikan; Jiun-Kuang Dai; Shyi-Long Lee (4163-4171).
The mechanism of aryl propargyl ether Claisen rearrangement in gas and solvent phase was investigated using DFT methods. Solvent phase calculations are carried out using N,N-diethylaniline as a solvent in the PCM model. The most favorable pathways involve a [3,3]-sigmatropic reaction followed by proton transfer in the first two steps and then deprotonation or [1,5]-sigmatropic reaction. Finally, cyclization yields benzopyran or benzofuran derivatives. The [3,3]-sigmatropic reaction is the rate-determining step for benzopyran and benzofuran with ΔG value of 38.4 and 37.9 kcal mol−1 at M06/6-31+G**//B3LYP/6-31+G* level in gas and solvent phase, respectively. The computed results are in good agreement with the experimental results. Moreover, it is found that the derivatives of aryl propargyl ether proceeded Claisen rearrangement and the rate-determining step may be shifted from the [3,3]-sigmatropic reaction to the tautomerization step. The NBO analysis revealed that substitution of the methyl groups on the aliphatic segment has decreased the stabilization energy E(2) and favors the aryl propargyl ether Claisen rearrangement.

An efficient asymmetric Diels–Alder reaction of 2-vinylindoles with β,γ-unsaturated α-ketoesters has been developed for the construction of functionalized tetrahydrocarbazoles. The products were obtained in high yields (up to 96%) with good stereoselectivities (ee up to 95%, dr up to >99 : 1).

1,2,4,5-Tetrazine fluorophore derivatives with structurally rigid molecular designs were synthesized using Sonogashira and Stille cross-coupling as well as copper-catalyzed azide–alkyne cycloaddition. The synthesized bichromophoric systems exhibit low fluorescence quantum yields due to quenching by the tetrazine. The extent of fluorescence quenching observed for those systems was shown to depend on the distance between the fluorophore and the tetrazine. The decreased fluorescence is “turned on” by conversion of the tetrazine in the inverse electron demand Diels–Alder cycloaddition. Time resolved spectroscopy indicated resonance energy transfer between BODIPY and the tetrazine as the underlying quenching mechanism. The synthesized conjugates were successfully applied in protein labeling experiments.

Organocatalytic asymmetric decarboxylative cyanomethylation of isatins using l-proline derived bifunctional thiourea by V. Pratap Reddy Gajulapalli; Poopathy Vinayagam; Venkitasamy Kesavan (4186-4191).
First asymmetric decarboxylative cyanomethylation of isatins is reported herewith using bifunctional thiourea derived from l-proline in good yields and enantioselectivities. This strategy enables the construction of various 3-cyanomethylene substituted 3-hydroxyoxindoles in enantioselective manner. Enantioselective synthesis of CPC-1 alkaloid has been accomplished in fewer steps.

A domino nitrosation and addition–elimination of nitroacetanilides with NaNO2 and H2SO4 has been developed to synthesize a variety of 1,4,2,5-dioxadiazine-3,6-dicarboxamides in excellent yields. The substrate scope can be extended to aryl nitromethyl ketones. A cascade reaction mechanism is proposed and the conjugated aryl moiety is considered to help stabilize the aci-nitroso species, the key intermediates in the cascade reaction. The methodology is practical and efficient because it avoids the purification of the intermediates. The nitroacetanilides were prepared from nitroacetic acid and various anilines employing DCC–DMAP as coupling reagents, and this protocol also possesses advantages like easy handling and high yields.

Glycosyltransferases are sugar-processing enzymes that require a specific metal ion cofactor for catalysis. In the presence of other ions the catalysis is often impaired. Here, for the first time, the enzymatic catalysis in the presence of various metal ions was modeled for a glycosyltransferase using a large enzymatic model. The catalytic mechanism of α-1,2-mannosyltransferase Kre2p/Mnt1p in the presence of Mn2+ and other ions (Mg2+, Zn2+ and Ca2+) was modeled at the two hybrid DFT-QM/MM (M06-2X/OPLS2005 and B3LYP/OPLS2005) levels. Kinetic and structural parameters of transition states and intermediates, as well as kinetic isotope effects, were predicted and compared with available experimental and theoretical data. The catalysis in the presence of the metal ions is predicted as a stepwise SNi-like nucleophilic substitution reaction (DNint*ANDhAxh) via oxocarbenium ion intermediates. In the rate-determining step the leaving phosphate group of the donor substrate plays a role of the base catalyst. The predicted increased enzymatic reactivity (kcat: Zn2+≈ Mg2+ < Mn2+ < Ca2+) correlated with the metal ion ability to polarize the Kre2p environment (Mg2+ > Zn2+ > Mn2+ > Ca2+). The formation of the retained anomeric configuration in the product is controlled by a strict geometry of the active site of Kre2p. The 6-OH group of the attacking acceptor substrate may assist in protection of the anomeric carbon against unwanted hydrolysis by a through-space interaction with the electron deficient C1O5+ moiety of the oxocarbenium-ion-like transition state.

Improved hemicryptophane hosts for the stereoselective recognition of glucopyranosides by Aline Schmitt; Olivier Perraud; Elina Payet; Bastien Chatelet; Benjamin Bousquet; Marion Valls; Daniele Padula; Lorenzo Di Bari; Jean-Pierre Dutasta; Alexandre Martinez (4211-4217).
Four new enantiomerically and diastereomerically pure hemicryptophane hosts (M-SSS-2/P-SSS-2 and M-RRR-2/P-RRR-2 pairs) were designed for the recognition of sugar derivatives. Their absolute configuration was determined from the circular dichroism spectra and DFT calculations. The host molecules were then used for the stereoselective recognition of glucopyranosides. Binding constants were obtained from 1H NMR titration experiments showing an increase of affinity for this class of receptors, associated with an improved diastereo- and enantio-differentiation.

Non-stoichiometric O-acetylation of Shigella flexneri 2a O-specific polysaccharide: synthesis and antigenicity by Charles Gauthier; Pierre Chassagne; François-Xavier Theillet; Catherine Guerreiro; Françoise Thouron; Farida Nato; Muriel Delepierre; Philippe J. Sansonetti; Armelle Phalipon; Laurence A. Mulard (4218-4232).
Synthetic functional mimics of the O-antigen from Shigella flexneri 2a are seen as promising vaccine components against endemic shigellosis. Herein, the influence of the polysaccharide non-stoichiometric di-O-acetylation on antigenicity is addressed for the first time. Three decasaccharides, representing relevant internal mono- and di-O-acetylation profiles of the O-antigen, were synthesized from a pivotal protected decasaccharide designed to tailor late stage site-selective O-acetylation. The latter was obtained via a convergent route involving the imidate glycosylation chemistry. Binding studies to five protective mIgGs showed that none of the acetates adds significantly to broad antibody recognition. Yet, one of the five antibodies had a unique pattern of binding. With IC50 in the micromolar to submicromolar range mIgG F22-4 exemplifies a remarkable tight binding antibody against diversely O-acetylated and non-O-acetylated fragments of a neutral polysaccharide of medical importance.

Microwave-assisted synthesis of potent PDE7 inhibitors containing a thienopyrimidin-4-amine scaffold by Ana I. Sánchez; Ricardo Meneses; José M. Mínguez; Araceli Núñez; Rafael R. Castillo; Fabiana Filace; Carolina Burgos; Juan J. Vaquero; Julio Álvarez-Builla; Alvaro Cortés-Cabrera; Federico Gago; Emma Terricabras; Víctor Segarra (4233-4242).
A series of novel thienopyrimidin-4-amines have been synthesized and evaluated as phosphodiesterase (PDE) inhibitors. A rationale for the observed selectivity against PDE7 has been obtained from molecular modelling studies on the most active compounds.

Synthesis of 1,4-dihydroquinoline derivatives under transition-metal-free conditions and their diverse applications by Xue-Qiang Chu; You Zi; Hua Meng; Xiao-Ping Xu; Shun-Jun Ji (4243-4251).
A transition-metal-free process for the synthesis of 1,4-dihydroquinoline derivatives starting from simple enaminones with aldehydes via intermolecular cascade cyclization in a one-pot protocol is developed. This methodology affords a variety of products in moderate to good yields. Particularly, the use of the enaminone fragment in 1,4-dihydroquinoline derivatives 3 as a leaving group for further diverse applications with C-nucleophiles is proved to be feasible.

Metal-free (Boc)2O-mediated C4-selective direct indolation of pyridines using TEMPO by Wen-Bing Qin; Jia-Yi Zhu; Yu-Bo Kong; Yun-Hong Bao; Zheng-Wang Chen; Liang-Xian Liu (4252-4259).
Direct metal-free C-4-selective indolation of pyridines is achieved for the first time using TEMPO and (Boc)2O. A variety of substituents on both indoles and pyridines are tolerated to give 3-(pyridin-4-yl)-1H-indole derivatives in moderate to excellent yields. This finding provides a novel approach for developing metal-free C–H functionalization of pyridines.

A versatile synthesis of “tafuramycin A”: a potent anticancer and parasite attenuating agent by Ibrahim M. El-Deeb; Faith J. Rose; Peter C. Healy; Mark von Itzstein (4260-4264).
An improved and versatile synthesis of tafuramycin A, a potent anticancer and parasite-attenuating agent, is reported. The three major improvements that optimized yield, simplified purification and allowed the synthesis of more versatile duocarmycin analogues are: a first-time reported regioselective bromination using DMAP as catalyst; the control of the aryl radical alkene cyclization step to prevent the dechlorination side reaction; and the design of a new protection/deprotection method to avoid furan double bond reduction during the classical O-benzyl deprotection in the final step. This alternative protection/deprotection strategy provides ready access to duocarmycin seco-analogues that carry labile functionalities under reducing reaction conditions. Tafuramycin A (3) was prepared in either 8 steps from intermediate 6 or 7 steps from intermediate 17 in 52% or 37% yield respectively. Our strategy provides a significant improvement on the original procedure (11% overall yield) and greater versatility for analogue development.

Back cover (4265-4266).