Organic & Biomolecular Chemistry (v.11, #17)

Front cover (2731-2731).

Inside front cover (2732-2732).

Contents list (2733-2739).

This review covers uses of bismuth catalysts since 2005 with a special emphasis on the emerging applications of such catalysts. Low toxicity, low catalytic loading, synergistic effects with other catalysts, and some hydrocompatibility properties confer to bismuth salts major advantages. The expanding activity in the field clearly highlights the growing potential of bismuth catalysts. The article is not a comprehensive review on bismuth catalysis but a selection of its most promising uses in challenging synthetic transformations.

A concise and practical Cu-catalyzed protocol for the preparation of chloro- and bromoarenes via C–H bond activation has been developed. The advantages of this strategy are the employment of cheap Cu(NO3)2·3H2O, LiX and O2, and its compatibility with both electron-donating and electron-withdrawing substituents on aryl rings.

Rhodium(iii)-catalyzed oxidative olefination of N-allyl sulfonamides by Shui Hu; Dongqi Wang; Jiexiang Liu; Xingwei Li (2761-2765).
Rhodium(iii)-catalyzed oxidative couplings between N-sulfonyl allylamines and activated olefins have been achieved. Only olefination occurred for acrylates, and the butadiene product can be further cyclized under palladium-catalyzed aerobic conditions. The coupling with N,N-dimethylacrylamide followed a cyclization pathway.

Direct acylation of N-benzyltriflamides from the alcohol oxidation level via palladium-catalyzed C–H bond activation by Jihye Park; Aejin Kim; Satyasheel Sharma; Minyoung Kim; Eonjeong Park; Yukyoung Jeon; Youngil Lee; Jong Hwan Kwak; Young Hoon Jung; In Su Kim (2766-2771).
A palladium-catalyzed ortho-acylation of N-benzyltriflamides from the alcohol oxidation level via C–H bond activation is described. These transformations have been applied to a wide range of substrates, and typically proceed with excellent levels of chemoselectivity and with high functional group tolerance.

N-terminal dual protein functionalization by strain-promoted alkyne–nitrone cycloaddition by Rinske P. Temming; Loek Eggermont; Mark B. van Eldijk; Jan C. M. van Hest; Floris L. van Delft (2772-2779).
Strain-promoted alkyne–nitrone cycloadditon (SPANC) was optimized as a versatile strategy for dual functionalization of peptides and proteins. The usefulness of the dual labeling protocol is first exemplified by the simultaneous introduction of a chloroquine and a stearyl moiety, two endosomal escape-improving functional groups, into the cell-penetrating peptide hLF (human lactoferrin). Additionally, we demonstrate that dual labeling of proteins is feasible by combining metal-free and copper-catalyzed click chemistry. First, SPANC is applied to enhanced green fluorescent protein to introduce both biotin and a terminal alkyne. The terminal acetylene then serves as a convenient anchor point for the CuAAC reaction with azido-containing fluorescein, thereby demonstrating the potential of combined SPANC and CuAAC for the straightforward, dual functionalization of proteins.

Here we describe our studies on solvent-dependent enantiodivergent Mannich-type reactions utilizing conformationally flexible guanidine/bisthiourea organocatalyst (S,S)-1. Our mechanistic investigations revealed that the stereo-determining steps in both the (R)- and (S)-selective Mannich-type reactions are governed by the cooperative effect of guanidine and thiourea in the inherently monomeric structure of (S,S)-1. Based on the mechanistic similarity between the (R)- and (S)-selective Mannich-type reactions, we discovered that (S,S)-1-catalyzed reactions show unique reversibility in mixed solvent systems. We highlight the development of sequential enantiodivergent organocatalysis using (S,S)-1, which allows enantio-switching with single-flask operation and high in situ tunability.

The Ti-BINOLate-catalyzed, enantioselective ring-opening of meso-aziridines with amines by Saravanan Peruncheralathan; Sandra Aurich; Henrik Teller; Christoph Schneider (2787-2803).
The titanium-BINOLate-catalyzed, highly enantioselective ring-opening reaction of meso-aziridines has been developed which furnishes trans-1,2-diamines in typically good yields and excellent enantioselectivities. N-Aryl aziridines attached to a 5- or 6-membered carbocyclic ring are among the best substrates for this process providing the products in up to >99% ee. The chiral catalyst is easily prepared in situ from commercially available components and does not require any laborious ligand synthesis. Structural investigations into the catalyst composition reveal an oligomeric structure of the active Ti-complex.

Concise total syntheses of (±)-noruleine and (±)-uleine by Süleyman Patir; Erkan Ertürk (2804-2810).
The first total synthesis of (±)-noruleine and a concise synthesis of (±)-uleine have been accomplished via the DDQ mediated dehydrogenative cyclization of a tetrahydrocarbazole derivative bearing a non-substituted amide functionality to prepare the key azocino[4,3-b]indole precursor.

Solutions of chloranil (CA) in benzene were irradiated in the presence of Moore's hydrocarbon (MH) and 2-norcarene (NC). These reactions brought about four common products, namely 2,3,5,6-tetrachlorohydroquinone (TCH) and three 1 : 1 cycloadducts, whose C7H10 subunits were reorganised in comparison to the skeletons of MH and NC. As the fifth product, a norcar-3-en-2-yl ether of TCH was formed in the case of NC, whereas MH gave rise to a substance having the structure of the diastereomeric bis(endo-2-norcaryl) ethers of TCH. A control experiment demonstrated that this substance is also produced from MH and TCH without irradiation. In view of the known addition of acids onto MH to give norcaranes substituted in position 2 and the known acid-catalysed isomerisation of MH to NC, it seems obvious that TCH was the only genuine product of the photoreaction of CA with MH. Being an acid, TCH then not only took up two equivalents of MH furnishing the bisethers referred to but also catalysed the rearrangement of MH to NC, which served as a substrate for excited CA to yield the three 1 : 1 cycloadducts mentioned.

Porphyrinogen-like precursors of calix[4]phyrins are presumed to be unstable owing to their auto-oxidation. In contrast to this, the syn and the anti isomers of a calix[4]pyrrole molecule containing pyridine moieties at the meso positions were isolated and their structures were determined by single crystal X-ray diffraction studies. Both the isomers gave the same calix[4]phyrin molecule upon oxidation. The anion binding properties of both the isomers were studied in DMSO-d6 by the EQNMR method, which showed that they have a preference of binding with the F ion over the other large sized halide and oxo anions. In addition, the F ion mediated H/D exchange process was monitored by the 19F NMR method. The solution state structures of the 1 : 1 F ion complexes containing deuterium atoms formed by a random but sequential substitution of NH protons by deuterium atoms were identified from their multiplicity patterns observed in the proton coupled 19F NMR spectrum, which are supported by the proton decoupled 19F NMR spectrum showing one singlet for each type of F ion complex in solution for both the syn and anti isomers, correlating with their solid state structures.

Synthetic approaches are reported to polydentate ligands based on 6-phenyl-6-amino-perhydro-1,4-diazepine. The synthetic route devised averts ring-opening reactions, allowing the exocyclic N-substituent to be introduced separately and involves a nitro-Mannich condensation, prior to chemoselective RANEY® nickel reduction. Comparison of the solid-state structures of four synthetic intermediates reveals that the seven-membered ring adopts a preferred twist-chair conformer in the solid state. Solution state NMR experiments highlight a conformational preference for the bulky aryl groups to adopt an equatorial site, pre-disposing the ligand to metal binding, by adoption of a conformation that creates a facial array of the ligand nitrogen atoms. This ligand conformation averts the formation of less stable metal complexes with differing ligation modes, notably in the binding of Ga3+ to related ligands, where a C-methyl substituent replaces the phenyl group at the quaternary centre.

Low-molecular-weight gelators consisting of hybrid cyclobutane-based peptides by Sergi Celis; Pau Nolis; Ona Illa; Vicenç Branchadell; Rosa M. Ortuño (2839-2846).
Some hybrid tetrapeptides consisting of (1R,2S)-2-aminocyclobutane-1-carboxylic acid and glycine, β-alanine, or γ-aminobutyric acid (GABA) joined in alternation, compounds 1–3, respectively, have been investigated to gain information on the non-covalent interactions responsible for their self-assembly to form ordered aggregates, as well as on parameters such as their morphology and size. All three peptides formed nice gels in many organic solvents and significant difference in their behaviour was not observed. Scanning electron microscopy (SEM) and circular dichroism (CD) pointed out that peptide 1, which contains the shortest C2 linear residue, presented the most defined fibril network and afforded nanoscale helical aggregates. Tetrapeptide 3, with C4 linear residues in its structure, also showed bundles of fibres whereas a homogeneous spherulitic network was observed for tetrapeptide 2, with a C3 spacer between cyclobutane residues. Computational calculations for 1 allowed us to model the self-assembly of the molecules and suggested a head-to-head arrangement to give helical structures corresponding to hydrogen-bonded single chains. These features were corroborated by a high-resolution NMR spectroscopy study of the dynamics of the gelation process in toluene-d8 which evidenced that molecules self-assemble to afford ordered aggregates with a supramolecular chirality.

A stereoselective synthesis of the C9–C19 subunit of (+)-peloruside A by Sadagopan Raghavan; V. Vinoth Kumar (2847-2858).
The stereoselective synthesis of a C9–C19 fragment of the potent antitumor agent peloruside A is disclosed. The C11 stereogenic centre was created by a vinylogous Mukaiyama aldol reaction following Carreira's protocol, with excellent stereocontrol. The C13 stereogenic centre was introduced by a substrate controlled reduction. The C15 stereocentre was fashioned using Noyori's asymmetric transfer hydrogenation while the Z-trisubstituted double bond was formed by a regioselective hydrostannation of an alkyne followed by methylation of the resultant vinyl stannane using Lipshutz's protocol. The C18 chiral centre was introduced by a chemoenzymatic route.

The barriers of torsional isomerization of 13 substituted biphenyls, ranging from 7.4 to 44 kcal mol−1, were calculated using 9 density functionals (the BP86 and B97D GGAs, the meta-GGA TPSS, hybrids B3LYP, PBE0, ωB97XD, BMK and M06-2X, as well as the double-hybrid B2PLYP), some combined with D and D3 corrections for dispersive interactions, and results were compared with experimental data. As attractive dispersive interactions between substituents had a significant impact on the geometries and stabilities of the ground and transition states of the torsional isomerization pathways, the B3LYP-D, B97-D and TPSS-D3 functionals were identified as the most promising methods, and were used to determine the torsional barriers of 33 other substituted biphenyls with known Gibbs energies of activation (6.0 to 45 kcal mol−1). Throughout the 46-member ensemble, results were very accurate relative to experimental values (mean deviation between −0.38 and 0.24 kcal mol−1), and narrow distributions of errors were obtained (root-mean-square deviations between 0.14 and 0.16 kcal mol−1; mean absolute deviations ranging from 0.61 to 0.75 kcal mol−1), as long as (1) large triple-ζ basis sets were used, (2) all conformations were screened at these levels of theory, (3) electronic energies were corrected with zero-point energies and entropic contributions, and (4) solvation effects were taken into account for biphenyl derivatives bearing charged ortho-substituents. With its simple procedures, this study is intended as a benchmark for future determinations of torsional barriers of various biphenyl derivatives.

Molecularly imprinted polymeric films (MIPFs) highly selective to 1R,2S(−)ephedrine (l-ephedrine, EPD) were produced by phase inversion post-polymerization imprinting on poly(acrylonitrile-co-methyl methacrylate-co-acrylic acid) (PAMA) terpolymers. The inclusion of methyl methacrylate (MMA) to the polymer formulation resulted in enhanced EPD selectivity which appears to be dictated by polymer composition to achieve the necessary balance between polymer rigidity and porosity. Substitution of MMA with methyl acrylate, ethyl acrylate and n-butyl acrylate resulted in a loss of EPD selectivity and EPD entrapment within the polymer matrix not observed in PAMA MIPFs. MMA, by virtue of its methyl group, is able to provide the scaffolding and rigidity necessary for stability and preservation of imprinted cavities within the PAMA MIPF leading to high EPD selectivity.

The anomeric effect has been assigned as being due to hyperconjugation, electrostatic/steric interactions or exchange effects; thus, there is no general consensus about its actual origin. The classical hyperconjugation model, usually investigated using natural bond orbital (NBO) analysis, has been arbitrarily refuted because it would not explain some cases of the preferred equatorial anomer over the axial one in polar solution. In this study, hyperconjugation was shown to be dependent on the medium and NBO analysis explains quite well the estimated amounts of axial and equatorial 2-substituted tetrahydropyrans (substituents = F, OH, NH2 and CN) both in the gas phase and aqueous solution. Overall, there is no reason to abandon the hyperconjugation model as it plays a dominating role of the anomeric effect in some systems, while NBO analysis reproduces the energetic profiles on the basis of both hyperconjugative and Lewis-type contributions.

Electrophilic monoiodination of terminal alkenes by Sergiy V. Yemets; Tatyana E. Shubina; Pavel A. Krasutsky (2891-2897).
An excess of elemental iodine in N,N-dimethylacetamide enables effective 3/iodanylium-de-hydronation of terminal alkenes with 3-iodopropene derivatives and hydrogen iodide formation within minutes at room temperature. The optimal molar ratio of iodine to substrate was decreased to 1 : 1 when hydrogen iodide formed was oxidized on a platinum anode. The electrolytic oxidation recovers iodine as a reagent and diminishes the hydrogen iodide inhibitory action to accomplish the monoiodination. The proposed reaction mechanism is based on kinetic measurements and quantum mechanics calculations.

A silver(i)-catalyzed tandem reaction of 2-alkynylbenzaldoximes with ketenes by Hongliang Liu; Gang Liu; Shouzhi Pu; Zhiyong Wang (2898-2902).
A novel and unexpected reaction of 2-alkynylbenzaldoximes with ketenes in the presence of silver triflate (10 mol%) under mild conditions is discovered. This reaction proceeds through 6-endo-cyclization, [3 + 2] cycloaddition, and rearrangement, leading to isoquinoline derivatives in moderate to good yields.

Enzyme-mediated nutrient release: glucose-precursor activation by β-galactosidase to induce bacterial growth by Naama Karton-Lifshin; Uwe Vogel; Eran Sella; Peter H. Seeberger; Doron Shabat; Bernd Lepenies (2903-2910).
Bacteria will gain an advantage if they are able to metabolize nutrients that are inaccessible for other bacteria. To demonstrate this principle, we developed a simple model system, which mimics how bacteria exploit natural carbon sources. A masked glucose precursor that is activated by β-galactosidase was used as a carbon source for bacterial growth in a glucose-deficient medium. No bacterial growth was observed in the presence of control substances in which β-galactosidase mediated cleavage did not lead to glucose release. This study represents a proof-of-principle example in which a bacterium can grow in a nutrient-free medium by inducible, enzyme-mediated nutrient release from a precursor.

Racemization of enantiopure secondary alcohols by Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase by Musa M. Musa; Robert S. Phillips; Maris Laivenieks; Claire Vieille; Masateru Takahashi; Samir M. Hamdan (2911-2915).
Controlled racemization of enantiopure phenyl-ring-containing secondary alcohols is achieved in this study using W110A secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (W110A TeSADH) and in the presence of the reduced and oxidized forms of its cofactor nicotinamide-adenine dinucleotide. Racemization of both enantiomers of alcohols accepted by W110A TeSADH, not only with low, but also with reasonably high, enantiomeric discrimination is achieved by this method. Furthermore, the high tolerance of TeSADH to organic solvents allows TeSADH-catalyzed racemization to be conducted in media containing up to 50% (v/v) of organic solvents.

Back cover (2917-2918).