Organic & Biomolecular Chemistry (v.14, #24)
Front cover (5331-5331).
Inside front cover (5332-5332).
Contents list (5333-5351).
Artificial supramolecular protein assemblies as functional high-order protein scaffolds by Yu-na Kim; Yongwon Jung (5352-5356).
Supramolecular assemblies of protein building blocks potentially offer unique biomaterials with unmatched functionalities as well as atomic level structural accuracy. An increasing number of assembling strategies have been reported for the fabrication of diverse artificial protein assemblies, ranging from rather heterogeneous protein oligomers to computationally designed discrete protein architectures. In this perspective, we discuss these artificial protein supramolecules in terms of their use as highly potent high-order protein scaffolds that can display various functional proteins with precise structural and valency control. Following a brief overview of current approaches for protein assembly, several examples of functional protein assemblies have been introduced, with a particular focus on our recent report of valency-controlled green fluorescent protein nano-assemblies. Our supramolecular protein scaffolds allow building a series of polygonal assemblies of functional binding proteins, which provide unprecedented ways to study multivalent protein interactions. Even with many remaining challenges, there is unlimited potential of artificial protein scaffolds in many fields from nanotechnology to vaccine development.
Enantioselective oxidative boron Heck reactions by A.-L. Lee (5357-5366).
This review highlights the use of the oxidative boron Heck reaction in enantioselective Heck-type couplings. The enantioselective oxidative boron Heck reaction overcomes several limitations of the traditional Pd(0)-catalysed Heck coupling and has subsequently allowed for intermolecular couplings of challenging systems such as cyclic enones, acyclic alkenes, and even site selectively on remote alkenes.
A new generation of chiral phase-transfer catalysts by Shiho Kaneko; Yusuke Kumatabara; Seiji Shirakawa (5367-5376).
Phase-transfer catalysis has long been recognized as a versatile method for organic synthesis. In particular, over more than the past three decades, asymmetric phase-transfer catalysis based on the use of structurally well-defined chiral catalysts has become a topic of great scientific interest. Although various effective chiral catalysts have already been reported and these catalysts were utilized for practical asymmetric transformations, further design and development of new chiral phase-transfer catalysts are still attractive research subjects in organic chemistry due to the high utility and practicability of phase-transfer-catalyzed reactions. This review focuses on the recent examples of newly designed effective chiral phase-transfer catalysts.
Trihaloethenes as versatile building blocks for organic synthesis by Adriana S. Grossmann; Thomas Magauer (5377-5389).
This review highlights the chemistry of trihaloethene building blocks with a special focus on commercially available 1,1,2-trichloroethene. The topics surveyed herein include the use of trihaloethenes as C2-building blocks for transition metal-catalyzed coupling reactions, addition, elimination and cycloaddition reactions as well as natural product syntheses.
Nitropyrrole natural products: isolation, biosynthesis and total synthesis by Xiao-Bo Ding; Margaret A. Brimble; Daniel P. Furkert (5390-5401).
Nitropyrrole-containing natural products are relatively rare in nature. Known examples are limited to the β-nitropyrrole-containing pyrrolomycins and α-nitropyrrole-containing nitropyrrolins and heronapyrroles. Their unique structures and interesting bioactivity are of ongoing interest to the chemistry community. This review describes the isolation, biological activity, biosynthesis and chemical synthesis of nitropyrrole-containing natural products reported to date.
Recent developments in synthetic methods for benzo[b]heteroles by Bin Wu; Naohiko Yoshikai (5402-5416).
Benzo[b]heteroles containing heteroatoms other than nitrogen and oxygen have received considerable attention for their potential applications in materials science. This poses an increasing demand for efficient, selective, and broad-scope methods for their synthesis. This review article summarizes the recent developments in synthetic methods and approaches to access representative members of the benzoheterole family.
Selective chemical labeling of proteins by Xi Chen; Yao-Wen Wu (5417-5439).
Over the years, there have been remarkable efforts in the development of selective protein labeling strategies. In this review, we deliver a comprehensive overview of the currently available bioorthogonal and chemoselective reactions. The ability to introduce bioorthogonal handles to proteins is essential to carry out bioorthogonal reactions for protein labeling in living systems. We therefore summarize the techniques that allow for site-specific “installation” of bioorthogonal handles into proteins. We also highlight the biological applications that have been achieved by selective chemical labeling of proteins.
Palladium catalysed meta-C–H functionalization reactions by Aniruddha Dey; Soumitra Agasti; Debabrata Maiti (5440-5453).
The directing group assisted site selective C–H functionalization approach is having a continuous impact in the field of natural product synthesis, drug discovery and material sciences. While ortho-selective C–H functionalization has been studied extensively, meta-selective C–H functionalization has been less explored. Recent studies have highlighted the efficacy of palladium as a catalyst in activating the meta-C–H bond of arenes. Notably, the introduction of a novel palladium catalysed directing template based approach to activate the remote meta-position has created a revolutionary impact towards seeking a solution to this long standing challenge. In this review we summarize recent advances in palladium catalysed meta-C–H functionalization that have helped in creating a new outlook towards modern organic synthesis.
Enantioselective polyene cyclizations by Chad N. Ungarean; Emma H. Southgate; David Sarlah (5454-5467).
The cyclization of polyolefins represents a powerful tool for the rapid generation of molecular complexity. Within the last decade, significant discoveries have been made in the development of methods for converting prochiral polyene substrates into the corresponding polycyclic products with high levels of enantiocontrol. This review highlights advances in the area of enantioselective polyene cyclizations and their use in the synthesis of complex secondary metabolites.
Site-directed spin labeling of proteins for distance measurements in vitro and in cells by P. Roser; M. J. Schmidt; M. Drescher; D. Summerer (5468-5476).
Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy allows studying the structure, dynamics, and interactions of proteins via distance measurements in the nanometer range. We here give an overview of available spin labels, the strategies for their introduction into proteins, and the associated potentials for protein structural studies in vitro and in the context of living cells.
Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes by E. M. Rigsbee; C. Zhou; C. M. Rasik; A. Z. Spitz; A. J. Nichols; M. K. Brown (5477-5480).
A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold found in several natural product families.
anti-Selective aminofluorination of alkenes with amidines mediated by hypervalent iodine(iii) reagents by Hui Chen; Atsushi Kaga; Shunsuke Chiba (5481-5485).
anti-Selective aminofluorination of alkenes with amidines was enabled by hypervalent iodine(iii) reagents, affording 4-fluoroalkyl-2-imidazolines. Further reductive ring-opening of the 2-imidazoline moiety could deliver highly functionalized 3-fluoropropane-1,2-diamine derivatives.
Copper-catalyzed electrophilic amination using N-methoxyamines by Yutaro Fukami; Takamasa Wada; Tatsuhiko Meguro; Noritaka Chida; Takaaki Sato (5486-5489).
Copper-catalyzed electrophilic amination of a triarylboroxin using an N-methoxyamine to give quick access to a variety of anilines was reported. The reaction was especially useful for syntheses of functionalized anilines when combined with our previously reported nucleophilic addition to N-methoxyamides.
Iron-catalyzed transfer hydrogenation of imines assisted by an iron-based Lewis acid by Hui-Jie Pan; Teng Wei Ng; Yu Zhao (5490-5493).
An iron-catalyzed transfer hydrogenation of N-aryl and N-alkyl imines using isopropanol as the hydrogen donor is reported for the first time. A combination of two iron complexes serving different roles is the key for the success of this catalytic system. As a result, an environmentally friendly and precious metal-free transfer hydrogenation of imines has been developed. The use of a suitable co-catalyst as an activator not only led to efficient transfer hydrogenation, but also showed potential in enantioselective transformation.
Rawal's catalyst as an effective stimulant for the highly asymmetric Michael addition of β-keto esters to functionally rich nitro-olefins by A. Suresh Kumar; T. Prabhakar Reddy; R. Madhavachary; Dhevalapally B. Ramachary (5494-5499).
A general approach to asymmetric synthesis of highly substituted dihydroquinolines was achieved through neighboring ortho-amino group engaged sequential Michael/amination/dehydration reactions on (E)-2-(2-nitrovinyl)anilines with cyclic and acyclic β-keto esters in the presence of a catalytic amount of Rawal's quinidine-NH-benzyl squaramide followed by TFA.
A highly enantioselective Hg(ii)-catalyzed Sakurai–Hosomi reaction of isatins with allyltrimethylsilanes by Zhong-Yan Cao; Jia-Sheng Jiang; Jian Zhou (5500-5504).
A chiral complex derived from (S)-difluorophos and Hg(OTf)2 is identified as a powerful catalyst for the Sakurai–Hosomi reaction of isatins with allyltrimethylsilane, allowing the facile synthesis of valuable building blocks 3-allyl-3-hydroxyoxindoles in up to 97% ee, with only 0.5–1.0 mol% of catalyst loading.
Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1) by L. Chen; P. T. Wilder; B. Drennen; J. Tran; B. M. Roth; K. Chesko; P. Shapiro; S. Fletcher (5505-5510).
Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D 1H–15N HSQC NMR spectroscopy with 15N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.
Palladium-catalyzed β-C(sp3)–H arylation of phthaloyl alanine with hindered aryl iodides: synthesis of complex β-aryl α-amino acids by Xuekai Zhang; Gang He; Gong Chen (5511-5515).
An efficient protocol for palladium-catalyzed β-C(sp3)–H arylation of aliphatic carboxamides equipped with a 2-(2-pyridyl) ethylamine (PE) auxiliary was developed. The PE auxiliary is uniquely effective at facilitating the arylation of primary C(sp3)–H bonds with sterically hindered aryl iodides. A variety of aryl iodides bearing alkoxyl, carbonyl, nitro and halogen groups on the ortho position can react with the PE-coupled phthaloyl alanine substrate in moderate to excellent yield. These reactions offer a useful solution for preparing complex β-aryl α-amino acid products from readily accessible starting materials.
Iron-catalyzed arylation of α-aryl-α-diazoesters by Ji-Min Yang; Yan Cai; Shou-Fei Zhu; Qi-Lin Zhou (5516-5519).
An iron-catalyzed arylation of α-aryl-α-diazoesters with electron-rich benzene rings was developed, which provides an efficient method for the preparation of 1,1-diarylacetates with high yields and excellent chemo- and regio-selectivities.
Direct synthesis of anilines and nitrosobenzenes from phenols by A. H. St. Amant; C. P. Frazier; B. Newmeyer; K. R. Fruehauf; J. Read de Alaniz (5520-5524).
A one-pot synthesis of anilines and nitrosobenzenes from phenols has been developed using an ipso-oxidative aromatic substitution (iSOAr) process. The products are obtained in good yields under mild and metal-free conditions. The leaving group effect on reactions that proceed through mixed quionone monoketals has also been investigated and a predictive model has been established.
3-Component synthesis of α-substituted sulfonamides via Brønsted acid-catalyzed C(sp3)–H bond functionalization of 2-alkylazaarenes by T. Beisel; J. Kirchner; T. Kaehler; J. Knauer; Y. Soltani; G. Manolikakes (5525-5528).
A Brønsted acid-catalyzed addition of 2-alkylazaarenes to in situ generated N-sulfonylimines through selective C(sp3)–H bond functionalization has been developed. This protocol provides an atom- and step-economic approach to α-substituted sulfonamides.
Comparison of boron-assisted oxime and hydrazone formations leads to the discovery of a fluorogenic variant by Cedric J. Stress; Pascal J. Schmidt; Dennis. G. Gillingham (5529-5533).
We use kinetic data, photophysical properties, and mechanistic analyses to compare recently developed high-rate constant oxime and hydrazone formations. We show that when Schiff base formation between aldehydes and arylhydrazines is carried out with an appropriately positioned boron atom, then aromatic B–N heterocycles form irreversibly. These consist of an extended aromatic structure amenable to the tailoring of specific properties such as reaction rate and fluorescence. The reactions work best in neutral aqueous buffer and can be designed to be fluorogenic – properties which are particularly interesting in bioconjugation.
Fluorine-directed 1,2-trans glycosylation of rare sugars by Nuria Aiguabella; Mareike C. Holland; Ryan Gilmour (5534-5538).
To reconcile the urgent need to access well defined β-configured 2,6-di-deoxypyranose analogues for chemical biology, with the intrinsic α-selectivity of the native system, the directing role of fluorine at C2 has been explored. Localised partial charge inversion (C–Hδ+→ C–Fδ−) elicits a reversal of the substrate-based α-stereoselectivity, irrespective of the protecting group electronics.
Phage-displayed macrocyclic glycopeptide libraries by Simon Ng; Ratmir Derda (5539-5545).
In this report, we describe an efficient way to generate libraries of macrocyclic glycopeptides in one step by reacting phage-displayed libraries of peptides with dichloro-oxime derivatives. We showed that the reactions do not interfere with the ability of phage to replicate in bacteria. The reactions are site-selective for phage-displayed peptides and they do not modify any other proteins of phage. The technology described in this report will be instrumental for genetic selection of macrocyclic glycopeptides for diverse glycan-binding proteins.
Some chemical speculation on the biosynthesis of corallidictyals A–D by Adrian W. Markwell-Heys; Jonathan H. George (5546-5549).
The efficient conversion of siphonodictyal B into the spirocyclic natural products corallidictyals A–D has been achieved via oxidative and acid catalyzed cyclizations. The oxidative cyclization of siphonodictyal B occured spontaneously under aerobic oxidation conditions, which suggests that corallidictyals A and B are possibly artefacts of the isolation process. The mechanism of the oxidative cyclization of siphonodictyal B could be described as either an anionic 5-endo-trig cyclization (which is formally disfavoured by Baldwin's rules), or as an electrocyclic reaction, of an ortho-quinone intermediate.
N-Heterocyclic carbene catalysed 1,6-hydrophosphonylation of p-quinone methides and fuchsones: an atom economical route to unsymmetrical diaryl- and triarylmethyl phosphonates by Panjab Arde; Ramasamy Vijaya Anand (5550-5554).
A convenient organocatalytic approach to access unsymmetrical diaryl- and triarylmethyl phosphonates using NHC as a Brønsted base catalyst is described. This atom-economical protocol enables the installation of phosphonate groups on p-quinone methides and fuchsones through a 1,6-conjugate addition of dialkylphosphites, and the corresponding phosphonates were obtained in excellent yields.
Ruthenium photoredox-triggered phospholipid membrane formation by M. D. Hardy; D. Konetski; C. N. Bowman; N. K. Devaraj (5555-5558).
As more methodologies for generating and manipulating biomimetic cellular systems are developed, opportunities arise for combining different methods to create more complex synthetic biological constructs. This necessitates an increasing need for tools to selectively trigger individual methodologies. Here we demonstrate ruthenium tris-bipyridine mediated photoredox triggering of the copper catalyzed alkyne azide cycloaddition reaction (CuAAC), resulting in the synthesis of biomimetic phospholipids in situ, and subsequent membrane assembly. The use of a ruthenium–copper electron transport chain to trigger phospholipid assembly opens up future opportunities for spatiotemporal synthesis of membranes.
Synthesis of 2-diphospho-myo-inositol 1,3,4,5,6-pentakisphosphate and a photocaged analogue by I. Pavlovic; D. T. Thakor; H. J. Jessen (5559-5562).
Diphosphoinositol polyphosphates (inositol pyrophosphates, X-InsP7) are a family of second messengers with important roles in eukaryotic biology. Their chemical synthesis and modification remains a challenging task due to the high density of phosphate groups arranged around the myo-inositol core. Here, a novel approach is presented that facilitates the incorporation of the diphosphate in the 2-position (2-InsP7) and that enables the introduction of a photocage subunit.
One-pot relay catalysis: divergent synthesis of furo[3,4-b]indoles and cyclopenta[b]indoles from 3-(2-aminophenyl)-1,4-enynols by Manisha; Seema Dhiman; Jopaul Mathew; S. S. V. Ramasastry (5563-5568).
Described herein is an efficient divergent strategy for the synthesis of furo[3,4-b]indoles via a sequential Ag(i)/Bi(iii)/Pd(ii) catalysis and cyclopenta[b]indoles via a one-pot Ag(i)/Brønsted acid relay catalysis from 3-(2-aminophenyl)-4-pentenyn-3-ols, accessible in three simple steps from 2-aminobenzaldehydes.
Rhodium-catalyzed pyridannulation of indoles with diazoenals: a direct approach to pyrido[1,2-a]indoles by Sudam Ganpat Dawande; Bapurao Sudam Lad; Sunitkumar Prajapati; Sreenivas Katukojvala (5569-5573).
A novel rhodium catalyzed pyridannulation of 3-substituted indoles with diazoenals furnished privileged pyrido[1,2-a]indoles. The reaction is proposed to involve a [4 + 2]-annulation of the diacceptor rhodium enalcarbenoid via C-2 functionalization of the indole. The utility of the methodology was demonstrated with a short synthesis of the tetrahydropyrido[1,2-a]indole core, present in a large number of biologically important polycyclic indole alkaloids.
Probing the self-assembly and stability of oligohistidine based rod-like micelles by aggregation induced luminescence by Hendrik Frisch; Daniel Spitzer; Mathias Haase; Thomas Basché; Jens Voskuhl; Pol Besenius (5574-5579).
The synthesis and self-assembly of a new C2-symmetric oligohistidine amphiphile equipped with an aggregation induced emission luminophore is reported. We observe the formation of highly stable and ordered rod-like micelles in phosphate buffered saline, with a critical aggregation concentration below 200 nM. Aggregation induced emission of the luminophore confirms the high stability of the anisotropic assemblies in serum.
Facile synthesis of enantioenriched phenol-sulfoxides and their aluminum complexes by Yani Tang; Yuji Sun; Jiyong Liu; Simon Duttwyler (5580-5585).
Chiral phenolic p-tolylsulfoxides and t-butylsulfoxides were prepared by several short synthetic routes starting from readily available starting materials. The key synthetic step was the reaction of lithiated arenes with menthyl sulfinates or enantioselective oxidation of a t-butyl sulfide. Well-defined neutral ligand–AlMe2 complexes were obtained by stoichiometric treatment with AlMe3.
Stereoselective synthesis of thiazino[4,3-a]indoles using the thia-Pictet–Spengler reaction of indoles bearing N-tethered thiols and vinylogous thiocarbonates by Santosh J. Gharpure; Santosh K. Nanda (5586-5590).
An inter- as well as intra-molecular thia-Pictet–Spengler cyclization of N-tethered thiols and vinylogous thiocarbonates is described for the stereoselective synthesis of N-fused thiazinoindole derivatives. The strategy is extended to one-pot, sequential Friedel–Crafts alkylation – Pictet–Spengler cyclization and the synthesis of thiazino-oxepino-indole.
A mild preparation of alkynes from alkenyl triflates by Xiaowen Yang; Dimin Wu; Zhaohong Lu; Hongbin Sun; Ang Li (5591-5594).
We report herein a protocol for preparing alkynes from alkenyl triflates. Stoichiometric LiCl promotes this transformation in DMF at ambient temperature. A range of terminal and internal alkynes were obtained smoothly. A one-pot procedure of alkyne formation/Cu-mediated Huisgen cycloaddition was developed, which may find use in synthesizing natural product-based probes.
First total synthesis of trehalose containing tetrasaccharides from Mycobacterium smegmatis by Manishkumar A. Chaube; Vikram A. Sarpe; Santanu Jana; Suvarn S. Kulkarni (5595-5598).
Total synthesis of three important trehalose containing tetrasaccharides isolated from Mycobacterium smegmatis is reported for the first time, using regioselective opening of benzylidene acetals and stereoselective glycosylations as key steps. The 1,2-cis stereoselectivity in the glycosylation reactions was achieved using anchimeric assistance from a remote participating group, steric effects and solvent participation. The synthetic strategy can also be utilized for the assembly of structurally related oligosaccharides from M. tuberculosis.
Mechanistic studies on intramolecular C–H trifluoromethoxylation of (hetero)arenes via OCF3-migration by Katarzyna N. Lee; Zhen Lei; Cristian A. Morales-Rivera; Peng Liu; Ming-Yu Ngai (5599-5605).
The one-pot two-step intramolecular aryl and heteroaryl C–H trifluoromethoxylation recently reported by our group has provided a general, scalable, and operationally simple approach to access a wide range of unprecedented and valuable OCF3-containing building blocks. Herein we describe our investigations to elucidate its reaction mechanism. Experimental data indicate that the O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives is a radical process, whereas the OCF3-migration step proceeds via a heterolytic cleavage of the N–OCF3 bond followed by rapid recombination of a short-lived ion pair. Computational studies further support the proposed ion pair reaction pathway for the OCF3-migration process. We hope that the current study would provide useful insights for the development of new transformations using versatile N-(hetero)aryl-N-hydroxylamine synthons.
Protein-specific localization of a rhodamine-based calcium-sensor in living cells by Marcel Best; Isabel Porth; Sebastian Hauke; Felix Braun; Dirk-Peter Herten; Richard Wombacher (5606-5611).
A small synthetic calcium sensor that can be site-specifically coupled to proteins in living cells by utilizing the bio-orthogonal HaloTag labeling strategy is presented. We synthesized an iodo-derivatized BAPTA chelator with a tetramethyl rhodamine fluorophore that allows further modification by Sonogashira cross-coupling. The presented calcium sensitive dye shows a 200-fold increase in fluorescence upon calcium binding. The derivatization with an aliphatic linker bearing a terminal haloalkane-function by Sonogashira cross-coupling allows the localization of the calcium sensor to Halo fusion proteins which we successfully demonstrate in in vitro and in vivo experiments. The herein reported highly sensitive tetramethyl rhodamine based calcium indicator, which can be selectively localized to proteins, is a powerful tool to determine changes in calcium levels inside living cells with spatiotemporal resolution.
Synthesis of 4H-chromenes by an unexpected, K3PO4-mediated intramolecular Rauhut–Currier type reaction by Anup Bhunia; Santhivardhana Reddy Yetra; Rajesh G. Gonnade; Akkattu T. Biju (5612-5616).
In an attempt to develop the umpolung of Michael acceptors using chalcones having an enoate moiety under N-heterocyclic carbene (NHC) catalysis, a K3PO4-mediated intramolecular Rauhut–Currier type reaction was observed. This C(sp2)–C(sp2) coupling reaction afforded the biologically important 4H-chromenes in moderate to good yields. It is likely that the enol ether functionality acts as the nucleophilic trigger in this reaction.
Investigation of the dynamic nature of 1,2-oxazines derived from peralkylcyclopentadiene and nitrosocarbonyl species by Victoria K. Kensy; Gregory I. Peterson; Derek C. Church; Neal A. Yakelis; Andrew J. Boydston (5617-5621).
We have investigated the reversible hetero-Diels–Alder reaction of 1,2-oxazines derived from a peralkylcyclopentadiene and a series of nitrosocarbonyl dienophiles. The nature of the dienophile was found to impart broad tunability to the dynamic character of the oxazine adducts. The reversibility was also observed in polymeric systems. The fidelity of the reaction and tunable sensitivity toward elevated temperature and water signify potential applications in the development of dynamic covalent materials or delivery systems for small molecule payloads.
Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins by Marzia Galli; Catherine J. Fletcher; Marc del Pozo; Stephen M. Goldup (5622-5626).
To improve access to a key synthetic intermediate we targeted a direct hydrobromination-Negishi route. Unsurprisingly, the anti-Markovnikov addition of HBr to estragole in the presence of AIBN proved successful. However, even in the absence of an added initiator, anti-Markovnikov addition was observed. Re-examination of early reports revealed that selective Markovnikov addition, often simply termed “normal” addition, is not always observed with HBr unless air is excluded, leading to the rediscovery of a reproducible and scalable initiator-free protocol.
A convenient domino Ferrier rearrangement-intramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines by Paseka T. Moshapo; Mokela Sokamisa; Edwin M. Mmutlane; Richard M. Mampa; Henok H. Kinfe (5627-5638).
The Ferrier rearrangement and the Povarov reaction have proven indispensable tools in carbohydrate chemistry and the synthesis of N-heterocycles, respectively. We hereby report a one-pot cyclization sequence involving the Ferrier and Povarov-like reactions in the synthesis of novel pentacyclic N-heterocycles: benzopyran-fused pyranoquinolines. The reaction entails three component condensation of a glycal with a variety of anilines and 2-hydroxybenzaldehydes under Lewis acid catalysis to yield the title compounds in 4–24 hours of reaction time, in moderate to high yields and excellent diastereoselectivity. Of the Lewis acid catalysts deployed [Sc(OTf)3, Al(OTf)3, Cu(OTf)2, CuOTf, I2, InCl3, and La(OTf)3] in various solvents (acetonitrile, THF, dichloromethane, 1,2-dichloroethane and diethyl ether) at room and elevated temperatures, Sc(OTf)3 (10 mol%) in acetonitrile at 70 °C gave the best results, with excellent diastereoselectivity. CAN-mediated oxidative ring opening of the pentacyclic N-heterocycle gave the corresponding enantiometrically pure chromenoquinoline bearing a pendant sugar moiety.
Conformational diversity and enantioconvergence in potato epoxide hydrolase 1 by P. Bauer; Å. Janfalk Carlsson; B. A. Amrein; D. Dobritzsch; M. Widersten; S. C. L. Kamerlin (5639-5651).
Potato epoxide hydrolase 1 (StEH1) is a biocatalytically important enzyme that exhibits rich enantio- and regioselectivity in the hydrolysis of chiral epoxide substrates. In particular, StEH1 has been demonstrated to enantioconvergently hydrolyze racemic mixes of styrene oxide (SO) to yield (R)-1-phenylethanediol. This work combines computational, crystallographic and biochemical analyses to understand both the origins of the enantioconvergent behavior of the wild-type enzyme, as well as shifts in activities and substrate binding preferences in an engineered StEH1 variant, R-C1B1, which contains four active site substitutions (W106L, L109Y, V141K and I155V). Our calculations are able to reproduce both the enantio- and regioselectivities of StEH1, and demonstrate a clear link between different substrate binding modes and the corresponding selectivity, with the preferred binding modes being shifted between the wild-type enzyme and the R-C1B1 variant. Additionally, we demonstrate that the observed changes in selectivity and the corresponding enantioconvergent behavior are due to a combination of steric and electrostatic effects that modulate both the accessibility of the different carbon atoms to the nucleophilic side chain of D105, as well as the interactions between the substrate and protein amino acid side chains and active site water molecules. Being able to computationally predict such subtle effects for different substrate enantiomers, as well as to understand their origin and how they are affected by mutations, is an important advance towards the computational design of improved biocatalysts for enantioselective synthesis.
Synthesis of polymers and nanoparticles bearing polystyrene sulfonate brushes for chemokine binding by Naatasha Isahak; Julie Sanchez; Sébastien Perrier; Martin J. Stone; Richard J. Payne (5652-5658).
The movement of leukocytes to the site of inflammation in response to injury or infection is orchestrated by chemokines binding and signaling through cognate receptors. The interaction between sulfated tyrosine residues on the flexible N-terminal tail of the receptor with positively charged regions of the chemokine is one of the key recognition features that facilitates binding. In this manuscript we describe the synthesis of polymers and silica nanoparticles bearing polystyrene sulfonate brushes to mimic the sulfated tyrosine residues. We show that both the polymers and nanoparticles possess high binding affinity for the chemokine monocyte chemoattractant protein-1 (MCP-1) in monomeric and dimeric form. We also demonstrate key differences in the relative affinity for the chemokine for the free polymer versus the polymer-derived nanoparticle system.
Catalytic asymmetric formal γ-allylation of deconjugated butenolides by Amit K. Simlandy; Santanu Mukherjee (5659-5664).
A formal γ-allylation of deconjugated butenolides is reported based on a two-step sequence consisting of a catalytic diastereo- and enantioselective vinylogous nucleophilic addition to vinyl sulfones and Julia–Kocienski olefination. This highly modular approach delivers densely functionalized butenolides containing a quaternary stereogenic centre in excellent yield with high enantioselectivity.
A versatile synthesis of chiral β-aminophosphines by Hsin Y. Su; Yixiong Song; Mark S. Taylor (5665-5672).
A method for the preparation of chiral β-aminophosphines having substituted P-aryl groups is described. Ring-opening of cyclic sulfamidates with metal diarylphosphinites yields β-aminophosphine oxides, which are then reduced to the corresponding phosphines. Effects of the diarylphosphinite countercation on the regioselectivity of the ring-opening reaction (P- versus O-alkylation) are discussed. This method enables the introduction of electron-deficient, electron-rich and sterically hindered diarylphosphino groups, as demonstrated by the synthesis of a series of novel, P-aryl-substituted β-aminophosphines derived from tert-leucinol, valinol and phenylglycinol. Access to these derivatives will create new opportunities for steric and electronic tuning of β-aminophosphine-derived chiral ligands and organocatalysts.
Direct conjugate alkylation of α,β-unsaturated carbonyls by TiIII-catalysed reductive umpolung of simple activated alkenes by Plamen Bichovski; Thomas M. Haas; Manfred Keller; Jan Streuff (5673-5682).
The titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique direct conjugate β-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctionalised building blocks without the requirement of stoichiometric organometallic reagents. In this full paper, the development and scope of the titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experiments a refined mechanistic proposal is presented.
I2 mediated synthesis of 5-substituted-3-methyl/benzyl-1,3,4-oxadiazol-2(3H)-ones via sequential condensation/oxidative cyclization and rearrangement by Shyam Sunder Patel; Nisha Chandna; Shreemoyee Kumar; Nidhi Jain (5683-5689).
A simple and efficient iodine-assisted protocol for the synthesis of 5-substituted-3-methyl/benzyl-1,3,4-oxadiazol-2(3H)-ones has been developed. The reaction involves a sequential condensation followed by tandem oxidative cyclization and rearrangement of readily available methyl/benzyl carbazates and aldehydes as starting substrates. The presence of iodine and base promotes intramolecular C–O bond formation, followed by Chapman-like rearrangement at 90 °C of the methyl/benzyl group in the hydrazone intermediate formed during the condensation step. This transition-metal-free approach has been adopted to generate a variety of oxadiazolones under mild conditions in good to excellent yields.
Palladium-catalyzed Suzuki–Miyaura coupling of amides by carbon–nitrogen cleavage: general strategy for amide N–C bond activation by Guangrong Meng; Michal Szostak (5690-5707).
The first palladium-catalyzed Suzuki–Miyaura cross-coupling of amides with boronic acids for the synthesis of ketones by sterically-controlled N–C bond activation is reported. The transformation is characterized by operational simplicity using bench-stable, commercial reagents and catalysts, and a broad substrate scope, including substrates with electron-donating and withdrawing groups on both coupling partners, steric-hindrance, heterocycles, halides, esters and ketones. The scope and limitations are presented in the synthesis of >60 functionalized ketones. Mechanistic studies provide insight into the catalytic cycle of the cross-coupling, including the first experimental evidence for Pd insertion into the amide N–C bond. The synthetic utility is showcased by a gram-scale cross-coupling and cross-coupling at room temperature. Most importantly, this process provides a blueprint for the development of a plethora of metal catalyzed reactions of typically inert amide bonds via acyl-metal intermediates. A unified strategy for amide bond activation to enable metal insertion into N–C amide bond is outlined (Scheme 1).
Green organocatalytic α-hydroxylation of ketones by Errika Voutyritsa; Alexis Theodorou; Christoforos G. Kokotos (5708-5713).
An efficient and green method for the α-hydroxylation of substituted ketones has been developed. This method includes the in situ conversion of various ketones into the corresponding silyl enol ethers and their oxidation to the corresponding α-hydroxy ketones. Two protocols have been established leading either to protected α-hydroxy carbonyls or free α-hydroxy ketones. Both procedures are easy to follow and lead to good to high yields for a variety of ketones.
Reversible morphological changes of assembled supramolecular amphiphiles triggered by pH-modulated host–guest interactions by M. A. Olson; M. S. Messina; J. R. Thompson; T. J. Dawson; A. N. Goldner; D. K. Gaspar; M. Vazquez; J. A. Lehrman; A. C.-H. Sue (5714-5720).
Reversible template-directed micellar-size and shape modulation by virtue of host–guest reversible docking of molecular templates at the micellar–solvent interface was achieved in water. By combining a π-electron deficient bipyridinium-based gemini amphiphile which is capable of binding and aligning with a π-electron rich tri(ethylene glycol)-disubstituted 1,5-diaminonaphthalene, a switchable detergent system which operates through the pH-responsive formation of bisammonium dications was realised. The binding of the 1,5-diaminonaphthalene guest to the bipyridinium-based micellar aggregate superstructure can be actuated by the addition of acid and base. Upon the addition of acid, protonation of the guest forming the dication deactivates molecular recognition with the charged head groups of the micellar aggregate by Coulombic repulsion. This process is completely reversible upon the addition of base, whereby the guest reintercalates into the superstructure –again forming donor–acceptor π–π stacks at the micellar–solvent interface amongst contiguous surfactant head groups. Synchrotron small angle X-ray scattering and dynamic laser light scattering confirm that this form of reversible directionally-templated micellisation results in an oblate spheroid-to-lamellar micelle morphological transition with a stabilising net decrease in the free energy of micellisation of 1.4 kcal mol−1 per hydrophobic tail.
Synthesis and characterization of a highly strained donor–acceptor nanohoop by J. M. Van Raden; E. R. Darzi; L. N. Zakharov; R. Jasti (5721-5727).
A highly-strained, nitrogen-doped cycloparaphenylene (CPP), azaCPP, was synthesized and then converted to a donor–acceptor nanohoop, N-methylazaCPP, via alkylation of the nitrogen center. The energy levels of the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) for both molecules were then probed by cyclic voltammetry (CV), which revealed that the donor–acceptor nanohoop had a significantly lower LUMO energy relative to CPP and azaCPP. Density functional theory (DFT) revealed that the donor–acceptor nanohoop underwent a redistribution of the frontier molecular orbital (FMO) density such that a significant portion of the LUMO density resided upon the electron-deficient nitrogen-containing ring. This localization of LUMO density caused a large lowering in the LUMO energy of nearly a full electron volt, while the HOMO energy was less affected due to a large centralization of the FMO on the electron-rich phenylene backbone. This ultimately resulted in a net lowering of the HOMO–LUMO energy gap which was observed both experimentally and computationally. In addition, N-methylazaCPP has a significantly lower energy LUMO than N-methylazaCPP, illustrating that the FMO levels of donor–acceptor nanohoops can be tuned by adjusting the hoop size.
Synthetic studies towards putative yuremamine using an iterative C(sp3)–H arylation strategy by Matthew B. Calvert; Jonathan Sperry (5728-5743).
An overview of an iterative, 8-aminoquinoline (AQ)-directed C(sp3)–H arylation strategy towards the pyrroloindole structure initially assigned to the alkaloid yuremamine is described. During initial efforts using a model indane system, it was discovered that the iodoresorcinol unit was not a viable C(sp3)–H arylation partner when masked as its dimethyl ether but upon switching to a MOM group, the ether oxygen served to stabilise the high valent Pd intermediate during the reaction, thus promoting reductive elimination and leading to acceptable yields of the C(sp3)–H arylation product. The second C(sp3)–H arylation with an iodopyrogallol gave a 1,3-diarylated model yuremamine system possessing the desired 1,3-cis relationship. When the successful model studies were applied to a pyrroloindole system in pursuit of yuremamine, it became apparent that C9 underwent competing C(sp2)–H arylation if left vacant, but installing a tryptamine side chain at this site prevented the desired C(sp3)–H arylation from occurring altogether. However, a C9-methyl pyrroloindole underwent iterative C(sp3)–H arylation at C1 with an iodoresorcinol followed by C3 with an iodopyrogallol to give a diarylated product with the aryl groups in the undesired 1,3-trans-relationship, arising from epimerisation at C1 during the second C(sp3)–H arylation event. Although the synthesis of putative yuremamine was not accomplished, several findings are disclosed that will serve as useful additions to the burgeoning field of directed C(sp3)–H arylations and related C–H functionalization reactions.
Light-triggered assembly–disassembly of an ordered donor–acceptor π-stack using a photoresponsive dimethyldihydropyrene π-switch by V. Siva Rama Krishna; Mousumi Samanta; Suman Pal; N. P. Anurag; Subhajit Bandyopadhyay (5744-5750).
Self-organization of donor and acceptor π-systems forms alternate D–A stacks of the donor and acceptor molecules. Using a photochromic π-switch as a donor and an electron deficient acceptor dye such stacks were formed. Photomodulation of the donor unit with visible light led to a photoisomerized state having a non-planar structure with reduced donor ability, thereby causing destruction of the alternate D–A π-stacks. The formation and destruction of the stacks were studied by various spectroscopy methods. Both the stacks and the depleted stacks were studied by DLS and SEM experiments. The regeneration of the stacks occurred in solution with the reversal of the photoisomerization process with ultraviolet light. Computational and differential scanning calorimetric studies validated the thermodynamics of the formation of the stacks. This work presents a reversible assembly–disassembly of a donor–acceptor π system devoid of additional auxiliary non-covalent bonding motifs in the donor and acceptor molecules.
Chiral phosphoric acid catalyzed asymmetric addition of naphthols to para-quinone methides by Yuk Fai Wong; Zhaobin Wang; Jianwei Sun (5751-5754).
An asymmetric addition of naphthols to in situ generated para-quinone methides catalyzed by a chiral phosphoric acid is described. A range of useful triarylmethanes can be generated from stable general para-hydroxybenzyl alcohols with good efficiency and enantioselectivity.
In vivo imaging of advanced glycation end products (AGEs) of albumin: first observations of significantly reduced clearance and liver deposition properties in mice by Ayumi Tsutsui; Akihiro Ogura; Tsuyoshi Tahara; Satoshi Nozaki; Sayaka Urano; Mitsuko Hara; Soichi Kojima; Almira Kurbangalieva; Hirotaka Onoe; Yasuyoshi Watanabe; Naoyuki Taniguchi; Katsunori Tanaka (5755-5760).
Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.
Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives by Ajay Chauhan; Sushovan Paladhi; Manish Debnath; Jyotirmayee Dash (5761-5767).
Herein we report the design, synthesis, biophysical and biological evaluation of triazole containing prolinamide derivatives as selective c-MYC G-quadruplex binding ligands. A modular synthetic route has been devised for prolinamide derivatives using a copper(i) catalyzed azide–alkyne cycloaddition (CuAAC). The Förster resonance energy transfer (FRET) melting assay indicates that prolinamide trimers can significantly stabilize G-quadruplex structures over duplex DNA compared to prolinamide dimers. The fluorescent intercalator displacement (FID) assay shows that a trimer with prolinamide side chains at the para-position of the benzene ring can discriminate between different quadruplex structures and exhibits the highest binding affinity towards the c-MYC G-quadruplex structure. Molecular modeling studies reveal that the prolinamide trimer stacks upon the terminal G-quartet of the c-MYC G-quadruplex. Atomic force microscopy (AFM) analysis reveals that the tris-prolinamide ligand can be used to regulate the assembly of novel supramolecular nanoarchitectures. Further, in vitro cellular studies with human hepatocellular carcinoma (HepG2) cells indicate that the tris-prolinamide derivatives can inhibit cell proliferation and reduce c-MYC expression in cancer cells.
Thermodynamic origin of α-helix stabilization by side-chain cross-links in a small protein by Conor M. Haney; Halina M. Werner; James J. McKay; W. Seth Horne (5768-5773).
Peptide cross-linking has been widely explored as a means of constraining short sequences into stable folded conformations, most commonly α-helices. The prevailing hypothesis for the origin of helix stabilization is an entropic effect resulting from backbone pre-organization; however, obtaining direct evidence bearing on this hypothesis is challenging. Here, we compare the folding thermodynamics of a small helix-rich protein domain and analogues containing one of three common cross-linking motifs. Analysis of the folding free energy landscapes of linear vs. cyclized species reveal consistent trends in the effect of cyclization on folding energetics, as well as subtle differences based on the chemistry of the cross link. Stabilization in all three systems arises entirely from a reduction in the entropic penalty of folding that more than compensates for an enthalpic destabilization of the folded state.
Versatile, mild, and selective reduction of various carbonyl groups using an electron-deficient boron catalyst by Katherine M. Lucas; Adam F. Kleman; Luke R. Sadergaski; Caitlyn L. Jolly; Brady S. Bollinger; Brittany L. Mackesey; Nicholas A. McGrath (5774-5778).
A mild and selective new method was discovered to reduce acetanilides and other carbonyl compounds. Unlike sodium borohydride, which is selective in reducing aldehydes and ketones, this new protocol is uniquely selective in reducing acetanilides and nitriles over other carbonyl containing functional groups. Additionally, β-ketoamides were shown to be reduced at the ketone preferentially over the amide.
Benzothiazole hydrazones of furylbenzamides preferentially stabilize c-MYC and c-KIT1 promoter G-quadruplex DNAs by Sushree Prangya Priyadarshinee Pany; Praneeth Bommisetti; K. V. Diveshkumar; P. I. Pradeepkumar (5779-5793).
The stabilization of G-quadruplex DNA structures by using small molecule ligands having simple structural scaffolds has the potential to be harnessed for developing next generation anticancer agents. Because of the structural diversity of G-quadruplexes, it is challenging to design stabilizing ligands, which can specifically bind to a particular quadruplex topology. To address this, herein, we report the design and synthesis of three benzothiazole hydrazones of furylbenzamides having different side chains (ligands 1, 2 and 3), which show preferential stabilization of promoter quadruplex DNAs (c-MYC and c-KIT1) having parallel topologies over telomeric and duplex DNAs. The CD melting study revealed that all the ligands, in particular ligand 2, exhibit higher stabilization toward parallel promoter quadruplexes (ΔTm = 10–15 °C) as compared to antiparallel promoter quadruplex (h-RAS1), telomeric quadruplex and duplex DNAs (ΔTm = 0–3 °C). FID assay and fluorimetric titration results also reveal the preferential binding of ligands toward c-MYC and c-KIT1 promoter quadruplex DNAs over telomeric and duplex DNAs. Validating these results further, Taq DNA polymerase stop assay showed IC50∼ 6.4 μM for ligand 2 with the c-MYC DNA template, whereas the same for the telomeric DNA template was found to be >200 μM. Molecular modeling and dynamics studies demonstrated a 1 : 1 binding stoichiometry in which stacking and electrostatic interactions play important roles in stabilizing the c-MYC G-quadruplex structure. Taken together, the results presented here provide new insights into the design of structurally simple scaffolds for the preferential stabilization of a particular G-quadruplex topology.
Asymmetric nucleophilic dearomatization of diazarenes by anion-binding catalysis by Theresa Fischer; Julia Bamberger; Olga García Mancheño (5794-5802).
The first anion-binding organocatalyzed enantioselective Reissert-type dearomatization of diazarenes has been developed. This reaction represents a synthetic challenge since diazarenes have various reactive sites. The use of a chiral tetrakistriazole as a C–H-based hydrogen-donor catalyst allowed the straightforward highly regio- and enantioselective synthesis of a variety of chiral diazaheterocycles.
Side-chain-to-tail cyclization of ribosomally derived peptides promoted by aryl and alkyl amino-functionalized unnatural amino acids by John R. Frost; Zhijie Wu; Yick Chong Lam; Andrew E. Owens; Rudi Fasan (5803-5812).
A strategy for the production of side-chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Two genetically encodable unnatural amino acids, bearing either an aryl or alkyl amino group, were investigated for their efficiency toward promoting the formation of medium to large-sized peptide macrocycles via intein-mediated side-chain-to-C-terminus cyclization. While only partial cyclization was observed with precursor proteins containing para-amino-phenylalanine, efficient peptide macrocyclization could be achieved using O-2-aminoethyl-tyrosine as the reactive moiety. Conveniently, the latter was generated upon quantitative, post-translational reduction of the azido-containing counterpart, O-2-azidoethyl-tyrosine, directly in E. coli cells. This methodology could be successfully applied for the production of a 12 mer cyclic peptide with enhanced binding affinity for the model target protein streptavidin as compared to the acyclic counterpart (KD: 5.1 μM vs. 22.4 μM), thus demonstrating its utility toward the creation and investigation of novel, functional macrocyclic peptides.
The effect of photoisomerization on the enzymatic hydrolysis of polymeric micelles bearing photo-responsive azobenzene groups at their cores by Assaf J. Harnoy; Gadi Slor; Einat Tirosh; Roey J. Amir (5813-5819).
The design of stable polymeric micelles that can respond to specific stimuli is crucial for the development of smart micellar nanocarriers that can release their active cargo selectively at the target site, thus diminishing the therapeutic limitations due to non-selective damage to healthy tissues. Here we report the design and synthesis of photo- and enzyme-responsive amphiphilic PEG–dendron hybrids bearing one, two or four enzymatically cleavable azobenzene end-groups. These dual-responsive hybrids can respond to light through the reversible isomerization of the azobenzene end-groups from the non-polar trans isomer to the highly polar cis isomer and vice versa, upon UV and visible irradiation, respectively. The high structural precision of these hybrids, which emerges from the dendritic architecture, enabled a detailed study of the photoisomerization of the azobenzene end-groups with high molecular resolution. Remarkably, although the transition from trans-to-cis led to a significant increase in the polarity of the micellar cores, the micelles remained stable. Our kinetic studies show that although the trans isomer is a better substrate for the activating enzyme, the UV induced formation of the cis azobenzene end-groups led to significant acceleration of the enzymatic hydrolysis of the end-groups. These results provide strong indication that the enzyme cannot reach the core of the micelles and instead the end-groups have to leave the hydrophobic core in order to be exposed on the micelle's surface or even leave the micelle in order to allow their cleavage by the activating enzymes.
C2-Alkenylation of N-heteroaromatic compounds via Brønsted acid catalysis by Giacomo E. M. Crisenza; Elizabeth M. Dauncey; John F. Bower (5820-5825).
Substituted heteroaromatic compounds, especially those based on pyridine, hold a privileged position within drug discovery and medicinal chemistry. However, functionalisation of the C2 position of 6-membered heteroarenes is challenging because of (a) the difficulties of installing a halogen at this site and (b) the instability of C2 heteroaryl-metal reagents. Here we show that C2-alkenylated heteroaromatics can be accessed by simple Brønsted acid catalysed union of diverse heteroarene N-oxides with alkenes. The approach is notable because (a) it is operationally simple, (b) the Brønsted acid catalyst is cheap, non-toxic and sustainable, (c) the N-oxide activator disappears during the reaction, and (d) water is the sole stoichiometric byproduct of the process. The new protocol offers orthogonal functional group tolerance to metal-catalysed methods and can be integrated easily into synthetic sequences to provide polyfunctionalised targets. In broader terms, this study demonstrates how classical organic reactivity can still be used to provide solutions to contemporary synthetic challenges that might otherwise be approached using transition metal catalysis.
Towards theory driven structure elucidation of complex natural products: mandelalides and coibamide A by Kevin M. Snyder; Justyna Sikorska; Tao Ye; Lijing Fang; Wu Su; Rich G. Carter; Kerry L. McPhail; Paul H.-Y. Cheong (5826-5831).
The effectiveness of computational tools in determining relative configurations of complex molecules is investigated, using natural products mandelalides A–D and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical NMR chemical shift predictions, and DP4 analyses led to confirmation of the revised structures of mandelalides A–D and coibamide A. All chiral centers in the northern hemisphere of mandelalides A–D are inverted with respect to the originally proposed structures, in agreement with recent total syntheses of mandelalide A by Ye, Fürstner & Carter. In the case of coibamide A, it was found that Fang & Su's revision, in which both the macrocycle [MeAla11] and the side chain [HIV2] residues are inverted from l to d, was consistent with the authentic natural product and computations.
A clickable UTP analog for the posttranscriptional chemical labeling and imaging of RNA by Anupam A. Sawant; Progya P. Mukherjee; Rahul K. Jangid; Sanjeev Galande; Seergazhi G. Srivatsan (5832-5842).
The development of robust tools and practical RNA labeling strategies that would facilitate the biophysical analysis of RNA in both cell-free and cellular systems will have profound implications in the discovery of new RNA diagnostic tools and therapeutic strategies. In this context, we describe the development of a new alkyne-modified UTP analog, 5-(1,7-octadinyl)uridine triphosphate (ODUTP), which serves as an efficient substrate for the introduction of a clickable alkyne label into RNA transcripts by bacteriophage T7 RNA polymerase and mammalian cellular RNA polymerases. The ODU-labeled RNA is effectively used by reverse transcriptase to produce cDNA, a property which could be utilized in expanding the chemical space of a RNA library in the aptamer selection scheme. Further, the alkyne label on RNA provides a convenient tool for the posttranscriptional chemical functionalization with a variety of biophysical tags (fluorescent, affinity, amino acid and sugar) by using alkyne–azide cycloaddition reaction. Importantly, the ability of endogenous RNA polymerases to specifically incorporate ODUTP into cellular RNA transcripts enabled the visualization of newly transcribing RNA in cells by microscopy using click reactions. In addition to a clickable alkyne group, ODU contains a Raman scattering label (internal disubstituted alkyne), which exhibits characteristic Raman shifts that fall in the Raman-silent region of cells. Our results indicate that an ODU label could potentially facilitate two-channel visualization of RNA in cells by using click chemistry and Raman spectroscopy. Taken together, ODU represents a multipurpose ribonucleoside tool, which is expected to provide new avenues to study RNA in cell-free and cellular systems.
Expedient synthesis of densely substituted pyrrolo[1,2-a]indoles by Dattatraya H. Dethe; Raghavender Boda (5843-5860).
Cu(OTf)2 catalyzed [6 + 2] cycloaddition reaction of indolyl-2-carbinols with various dienophiles such as indole derived α,β-unsaturated esters, ketones, nitriles and cinnamates is described. The strategy was further applied for the synthesis of optically active pyrrolo[1,2-a]indoles in >97% de using the chiral auxiliary based approach.
Correction: A convenient domino Ferrier rearrangement-intramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines by Paseka T. Moshapo; Mokela Sokamisa; Edwin M. Mmutlane; Richard M. Mampa; Henok H. Kinfe (5861-5861).
Correction for ‘A convenient domino Ferrier rearrangement-intramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines’ by Paseka T. Moshapo et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c5ob02536b.
Back cover (5863-5864).