Organic & Biomolecular Chemistry (v.17, #42)

Front cover (9259-9260).

Contents list (9261-9266).

Haloperoxidases as catalysts in organic synthesis by Georg T. Höfler; Andrada But; Frank Hollmann (9267-9274).
Haloperoxidases are very active catalysts for the in situ generation of electrophilic halide species for oxidative halogenation reactions. In the synthetic community, these catalysts, however, are not widely used. The aim of this mini-review is to critically summarise the current state-of-the-art of haloperoxidase catalysis for organic synthesis. We hope that the excellent catalytic performance of these catalysts will trigger more chemists to consider them in their synthesis planning.

Rh-Catalyzed domino synthesis of 4-hydroxy-3-methylcoumarins via branch-selective hydroacylation by Maddali L. N. Rao; Boddu S. Ramakrishna; Sachchida Nand (9275-9279).
A Rh-catalyzed domino synthesis of 4-hydroxy-3-methylcoumarins via branch-selective hydroacylation of acrylates and acrylamides using salicylaldehydes is described. This protocol under phosphine-free Rh-catalyzed conditions provided 4-hydroxy-3-methylcoumarins in high yields with excellent functional group tolerance and high selectivity.

Iodine-catalyzed guanylation of amines with N,N′-di-Boc-thiourea by Hao-Jie Rong; Cui-Feng Yang; Tao Chen; Ze-Gang Xu; Tian-Duo Su; Yong-Qiang Wang; Bin-Ke Ning (9280-9283).
Herein, we report that iodine-catalyzed guanylation of primary amines can be accomplished with N,N′-di-Boc-thiourea and TBHP to afford the corresponding guanidines in 40–99% yields. Oxidation of the HI byproduct by TBHP eliminates the need for an extra base to prevent the protonation of substrates and makes the reaction especially useful for both electronically and sterically deactivated primary anilines.

A targeted approach for the synthesis of multi-phosphorylated peptides: a tool for studying the role of phosphorylation patterns in proteins by Mamidi Samarasimhareddy; Daniel Mayer; Norman Metanis; Dmitry Veprintsev; Mattan Hurevich; Assaf Friedler (9284-9290).
Protein phosphorylation barcodes, clusters of several phosphorylation sites within a short unfolded region, control many cellular processes. Existing biochemical methods used to study the roles of these barcodes suffer from low selectivity and provide only qualitative data. Chemically synthesized multiphosphopeptide libraries are selective and specific, but their synthesis is extremely difficult using the current peptide synthesis methods. Here we describe a new microwave assisted approach for synthesizing a library of multiphosphopeptides, using the C-terminus of rhodopsin as a proof of concept. Our approach utilizes multiple protocols for synthesizing libraries of multiphosphopeptides instead of the inefficient single protocol methods currently used. Using our approach we demonstrated the synthesis with up to seven phosphorylated amino acids, sometimes next to each other, an accomplishment that was impractical before. Synthesizing the Rhodopsin derived multiphosphopeptide library enabled dissecting the precise phosphorylation barcode required for the recruitment, activation and modulation of the conformation of Arrestin. Since phosphorylation barcodes modulate the activity of hundreds of GPCRs, synthesizing libraries of multiphosphopeptides is the method of choice for studying their molecular mechanisms of action. Our approach provides an invaluable tool for evaluating how protein phosphorylation barcodes regulate their activity.

Metal-free propargylation/aza-annulation approach to substituted β-carbolines and evaluation of their photophysical properties by Chada Raji Reddy; Mounika Aila; Puppala Sathish; Madoori Mrinalini; Lingamallu Giribabu; Seelam Prasanthkumar; René Grée (9291-9304).
An efficient acid-catalyzed propargylation/aza-annulation sequence was developed under metal-free reaction conditions, thus leading to a one-pot synthesis of a variety of substituted β-carbolines starting from propargylic alcohols and indole 2-carbonyls. This versatile strategy was further extended to the synthesis of 5-azaindoles and 5-azabenzothiazoles. Optical properties suggested that manipulation of electron donor and acceptor moieties on β-carbolines has an impact on their ground and excited state electronic behavior. This leads to blue or green emission and should facilitate the development of organic light emitting diodes (OLEDs). Electrochemical and stability studies revealed that 4a-6 shows ease of redox activity and photostability during illumination.

Primary amine catalyzed diastereo- and enantioselective Michael reaction of thiazolones and α,β-unsaturated ketones by Min Lu; Hong Li; Chuncheng Zou; Jianchang Li; Chengyu Liu; Maolin Sun; Yueyue Ma; Ruihua Cheng; Jinxing Ye (9305-9312).
The chiral primary amine catalyzed asymmetric Michael reaction of thiazolones and α,β-unsaturated ketones was reported. Two different optimal catalytic systems were obtained corresponding to cyclic and linear α,β-unsaturated ketones. By employing chiral primary amines as the catalysts and amino-acid derivatives as the additives, a variety of Michael adducts containing the scaffold of the thiazole ring were prepared in moderate to good yields and with excellent diastereo- and enantioselectivities (up to 95% yield, all up to >19/1 dr, up to 96% ee). The reaction was scaled up to obtain 1.73 grams of the Michael adduct with the maintenance of yield and stereoselectivity.

Driving factors in amiloride recognition of HIV RNA targets by Neeraj N. Patwardhan; Zhengguo Cai; Aline Umuhire Juru; Amanda E. Hargrove (9313-9320).
Noncoding RNAs are increasingly promising drug targets yet ligand design is hindered by a paucity of methods that reveal driving factors in selective small molecule : RNA interactions, particularly given the difficulties of high-resolution structural characterization. HIV RNAs are excellent model systems for method development given their targeting history, known structure–function relationships, and the unmet need for more effective treatments. Herein we report a strategy combining synthetic diversification, profiling against multiple RNA targets, and predictive cheminformatic analysis to identify driving factors for selectivity and affinity of small molecules for distinct HIV RNA targets. Using this strategy, we discovered improved ligands for multiple targets and the first ligands for ESSV, an exonic splicing silencer critical to replication. Computational analysis revealed guiding principles for future designs and a predictive cheminformatics model of small molecule : RNA binding. These methods are expected to facilitate progress toward selective targeting of disease-causing RNAs.

Alginate, an anionic polysaccharide, is an important industrial biomaterial naturally harvested from seaweed. Many of its important physicochemical properties derive from the presence of charged carboxylate groups presented as uronic acids within the polysaccharide backbone. An ability to modify these carboxylates with alternate functional groups would enable the design and implementation of new alginate systems possessing different physicochemical properties. We present herein our approach to the chemical synthesis of alginate disaccharides, modified at the carboxylate C6 position with bioisosteric hydroxamate residues. The synthesis and utilisation of C6-hydroxamate donor and acceptor building blocks enables a first access to protected α- and β-linked hydroxamate-containing disaccharides, additionally equipped with a functional tether at the reducing terminus. The evaluation of these building blocks for chemical glycosylation demonstrates the incorporation of bioisosteric functional groups into an alginate disaccharide backbone and highlights the important contribution of both acceptor and donor reactivity underpinning uronate glycosylations.

A unimolecular nucleophilic substitution reaction that proceeds through a xanthylium carbocation was studied in seven ionic liquid solvents. It was found that the general trend in the rate constant with changing proportion of ionic liquid in the reaction mixture was different to that seen for other unimolecular processes, with the rate constant increasing as more ionic liquid was added to the reaction mixture. A significant correlation was found between the natural logarithm of the rate constant and a combination of the Kamlet–Taft solvent parameters. This relationship indicated that the principal interaction involved hydrogen bonding between the ionic liquid and some species along the reaction coordinate. Further, this correlation enables prediction of the effects that other ionic liquids will have on this, and other, reactions that proceed through a similar intermediate.

An efficient method for the synthesis of structurally diverse 4-aryl-3-(tri/difluoromethyl)-1H-1,2,4-triazol-5(4H)-ones through the cyclization of hydrazinecarboxamides with tri/difluoroacetic anhydride is presented. The method is simple and environmentally benign, providing tri/difluoromethylated 1,2,4-triazol-5(4H)-ones in moderate-to-good yields. A mechanism is proposed to proceed via a tandem reaction of tri/difluoroacetylation, nucleophilic addition and water elimination. Some of these compounds exhibit promising insecticidal activities.

A new and convenient copper-catalysed synthesis of α-ketoamides has been accomplished using readily available cinnamic acids/arylacetic acids and 2° amines in an open atmosphere. The reaction between cinnamic acid and amine involves the formation of enamine followed by its aerobic oxidation, whereas the reaction of arylacetic acid with amine involves amide formation followed by benzylic methylene oxidation.

From ferrocene to fluorine-containing penta-substituted derivatives and all points in-between; or, how to increase the available chemical space by Mehdi Tazi; William Erb; Thierry Roisnel; Vincent Dorcet; Florence Mongin; Paul J. Low (9352-9359).
In spite of the growing interest in fluorine-containing compounds, and the improvements in materials, optical and biological properties that can arise from substitution of a phenyl ring by ferrocene within a molecular scaffold, synthetic strategies that allow the efficient preparation of fluoroferrocene derivatives are scarce. Following conversion of ferrocene to fluoroferrocene, we have developed routes to fluorine-containing di-, tri-, tetra- and penta-substituted ferrocene derivatives to extend the available chemical space. Our approach is based on the identification of suitable reagents and conditions to achieve fluorine-directed deprotometalation, and exploitation of the halogen ‘dance’ rearrangement in the ferrocene series.

An efficient method for the synthesis of unsymmetrical diaryl sulfides has been developed by the C–S cross coupling of aryldithiocarbamates and aryldiazonium salts in the presence of CuI-2,2′-bipyridine and Zn. Aryldithiocarbamate compounds have been used here as thiol substitutes. The protocol shows wide substrate scope and good yields of the products.

A mechanism of alkali metal carbonates catalysing the synthesis of β-hydroxyethyl sulfide with mercaptan and ethylene carbonate by Dongliang Liu; Tiju Thomas; Hong Gong; Fei Li; Qiang Li; Lijuan Song; Tamil Azhagan; Heng Jiang; Minghui Yang (9367-9374).
The reaction of β-hydroxyethylation is essential to the current practice of organic chemistry. Here, we proposed a new and green route to synthesize 2-hydroxyethyl n-alkyl sulfide with n-alkyl mercaptan and ethylene carbonate (EC) in the presence of alkali carbonates as catalysts and revealed the mechanism by experiments and theoretical calculations. The reaction reported proceeds rapidly with high yields when it is performed at 120 °C and the catalytic loading is ∼1 mol%. This protocol is applicable to other mercaptans to synthesize the corresponding β-hydroxyethyl sulfide. Density functional theory-based calculations show the energy profile for the reaction pathway. The rate-determining step is the ring-opening of EC. A negatively charged O atom of alkali carbonates approaches the S atom of –SH under the influence of hydrogen bonds. An activated S atom that carries more negative charge serves as a nucleophilic reagent and assists in the ring-opening of EC by reducing the Mayer bond orders of the C1–O1 bond in EC. Alkali cations also contribute to the C1–O1 bond cleavage. The energy barrier for the ring-opening of EC decreases with the decrease of electronegativity of alkali cations. Subsequent transference of a H atom leads to the formation of β-hydroxyethyl sulfide, the dissociation of CO2 and the reduction of K2CO3.

Enzymatic syntheses of novel carbocyclic scaffolds with a 6,5 + 5,5 ring system by squalene-hopene cyclase by Chiaki Nakano; Takumi Watanabe; Mai Minamino; Tsutomu Hoshino (9375-9389).
Squalene-hopene cyclase (SHC) converts acyclic squalene 1 into the 6,6,6,6,5-fused pentacyclic triterpenes hopene and hopanol. Previously, we reported the polycyclization products 14–17 of 27-norsqualene (13a) and 28-norsqualene (13b) by SHC, and suggested the importance of Me-27 of 1 for the normal polycyclization pathway. To further ensure the theory, (3R,S)-27-noroxidosqualenes (18 and 19) were incubated, and the structures of products 20–25 thus obtained prompted us to reinvestigate the SHC reaction of 13a (13b). One new product 29, composed of a 6,5 + 5,5 ring system with 13α-H and 17α-H, was obtained from 13a in addition to both the previously isolated products 14–17 and the 6,6,6,5-fused tetracyclic dammarenyl compounds, which were overlooked before. We propose the name “nor-allodammarane” for this novel tetracyclic 6,5 + 5,5 ring system and the name “nor-allogammacerane” for the pentacyclic 6,5 + 5,5 + 6 ring system. The stereochemistry of 29 indicated that 13a folded in the following chair-boat-boat-boat conformation: 10α-H, 11β-H; 14α-H, 15β-Me; 18α-H and 19β-Me, which further allowed us to predict the configuration of 20R for 14 and that of 20S for 15. Substrates 18 and 19 were also cyclized only into allodammarane scaffolds 20–25, and all the structures of 20–25 further indicated that 18 and 19 also folded in the same conformation as 13a, providing further evidence that Me-27 groups of 1 and oxidosqualene are essential for the normal polycyclization pathway by SHC.

Highly regio- and diastereoselective [3 + 2]-cycloadditions involving indolediones and α,β-disubstituted nitroethylenes by Madhuri P. Rao; Shubha S. Gunaga; Johannes Zuegg; Rambabu Pamarthi; Madhu Ganesh (9390-9402).
A highly diastereoselective [3 + 2]-cycloaddition strategy involving multiple oxindoles and several α,β-disubstituted nitroethylenes is developed to access tetra-substituted α-spiropyrrolidine frameworks. A variety of α-amino acids were employed for the first time in order to generate azomethine ylides under thermal conditions, affording regioisomers 13 and 14 merely by changing the α-substituents (R = H and substituted carbons) of the α-amino acids. The reaction tolerates various sterically demanding, electron-rich and electron-deficient aryl and nitrogen substituents on glycines, oxindoles and nitroethylenes. The operational simplicity, such as the use of a metal-free and non-inert environment, the utilization of non-halogenated solvents and the ease of isolation, adhering to the principles of green chemistry, makes this process attractive for scale-up opportunities. The reaction delivers good yields (80–94%) and diastereoselectivities (up to 98 : 2) in favor of (cis,cis)-spirooxindoles, with opposite regioselectivity compared to β-nitrostyrenes under identical conditions. Two spiropyrrolidine cycloadducts with unprotected amides exhibited significant activity against Gram-positive MRSA.

Back cover (9403-9404).