Organic & Biomolecular Chemistry Blog

Dirk Menche and co-workers report an efficient procedure for the concise synthesis of highly elaborate polyenes. They have showcased their novel hetero-bis-metallated alkene reagent in the construction of a small library of etnangien side-chain analogues. This has allowed them to establish important structure-activity information about this family of biologically-significant natural products.

Polyketides are a huge class of compounds; the largest group of naturally-occurring secondary metabolites, bearing rich diversity in both structure and biological activity. Because they are beautiful molecules with challenging structures, polyketide synthesis has been a source of inspiration for many an organic chemist.

Dirk Menche and his group at the University of Heidelberg have been investigating the polyketide etnangien, a potent antibiotic that inhibits RNA-polymerase. The molecule is named for Mt. Etna, the soil of which yielded the producing strain of myxobacteria Sorangium cellulosum.

A macrolactone with an extensive polyene sidechain and boasting 12 stereogenic centres, this molecule is no straightforward synthetic target. It is also extremely unstable which adds to the challenge.

Click here to read the rest of this blog

In this HOT article, John C. Vederas and co-workers at University of Alberta report the ring-closing metathesis of unprotected, synthetic analogues of oxytocin (a mammalian hormone) and crotalphine (an analgesic isolated from rattlesnake venom). The replacement of cysteine with S-allylcysteine enables ring-closing metathesis to proceed in water, in the presence of magnesium chloride and tert-butanol co-solvent.

Disulfide bridges are critical for peptide folding, stability and biological activity. This technique enables the replacement of a disulfide bridge with a dicarba linkage, improving stability yet retaining biological activity.

The trick to performing these cyclisations in the aqueous phase is to use tert-butanol or detergent micelles to solubilise the ruthenium catalyst. The addition of magnesium chloride is required to disrupt non-productive chelation between the ruthenium-carbene and unprotected hydroxyl, carboxyl and primary amide functionalities. Low yields with non-sulphur containing peptide analogues indicate that the sulphur atom is a prerequisite for successful ring-closing metathesis in these peptides.

This technique opens up the possibility of performing cyclisations that cannot be achieved on-resin, such as the ring-closing metathesis of crotalphine analogues (due to either complex formation between catalyst and amide backbone and/or hydrophobic peptide protecting groups). Additionally, this method avoids extensive synthetic effort to modify the ruthenium catalyst to optimise aqueous solubility.

Investigation of the ring-closing metathesis of peptides in water
Stephen A. Cochrane, Zedu Huang and John C. Vederas
DOI: 10.1039/C2OB26938D

Published on behalf of Steve Moore, Organic & Biomolecular Chemistry web science writer.

Scientists from Japan report on the use of thionium activation for nucleophilic functionalization of indole derivatives at the 2-alpha position.

In this hot paper Kazuhiro Higuchi and Tomomi Kawasaki and coworkers at Meiji Pharmaceutical University expand on their communication from Chem. Comm. on the aliphatic C–H functionalization at the indole 2α-position mediated by acyloxythionium species generated from sulfoxides, including DMSO, and TFAA.

By using this method the indole ring is transformed into an allyl thionium species, and so is highly activated for nucleophilic attack from a wide variety of nucleophiles. Kawasaki make use of simple and readily available reagents, making the reaction a convenient route to functionalize alpha to the indole ring in a very straightforward fashion, enabling the introduction of O-, N- and C- substituents in a one-pot procedure.

For all the details read this paper for free today.

Sulfoxide-TFAA and nucleophile combination as new reagent for aliphatic C–H functionalization at indole 2α-position
Masanori Tayu, Kazuhiro Higuchi, Masato Inaba and Tomomi Kawasaki
DOI: 10.1039/C2OB26944A

In this HOT paper Didier Boturyn, Jean-Luc Coll and colleagues have designed a probe containing arginine-glycine-aspartic acid (RGD) that can be used for the dual-targeting of αVβ3 integrin and matrix metallopeptidase -9 extracellular proteases in tumours.

Boturyn et al. synthesise the probe via iterative oxime ligations of peptide fragments and use in vitro and in vivo experiments to evaluate it.

To find out more about this dual-targeting probe download the paper for free today!

Integrin and matrix metalloprotease dual-targeting with an MMP substrate–RGD conjugate
Christiane H. F. Wenk, Véronique Josserand, Pascal Dumy, Jean-Luc Coll and Didier Boturyn
DOI: 10.1039/C2OB26926K

In this HOT communication Jian Wang and colleagues at National University of Singapore report an efficient method to construct enantiomeric 2-amino-3-nitrile-chromenes through 2-iminochromenes and malonates. Using a thiourea catalyst Wang et al. rapidly construct the 2-amino-3-nitrile-chromene complexes via a multi-hydrogen-bond cooperative activation model.

For the details of their study download the communication today; it’s free to access for 4 weeks.

Organocatalytic conjugate addition promoted by multi-hydrogen-bond cooperation: access to chiral 2-amino-3-nitrile-chromenes
Wenjun Li, Jiayao Huang and Jian Wang
DOI: 10.1039/C2OB27102H

Cyclodextrins are macrocyclic oligomers of α-D-glucose. Their interaction with guest molecules is largely driven by the hydrophobic effect (the expulsion of water from the lipophilic cavity, into bulk, is entropically favourable).

In this HOT paper Cepeda and co-workers explore the solution phase behaviour of β-cyclodextrin/alkyltrimethylammonium bromide mixtures, varying the surfactant alkyl chain length from hexyl (C₆) to octadecyl (C₁₈).

Cepeda et al. employ the solvolysis of methoxybenzenesulfonyl chloride (MBSC) as a UV ‘handle’ to monitor the interaction between β-cyclodextrin and surfactant guests. In the presence of aggregated cationic surfactants, MBSC hydrolysis is hindered, owing to the reduced polarity of the micelle interior. MBSC solvolysis can be used to monitor the integrity of surfactant micelles and to calculate the concentration of unbound cyclodextrin.

In the presence of aggregated surfactants Cepeda et al. detect a significant concentration of ‘free’ β-cyclodextrin; the highest of which with decyl (C₁₀) and dodecyl (C₁₂) surfactants. This reflects the balance between the hydrophobic effect (smaller surfactant chains displace less water from the cyclodextrin cavity) and surfactant self-assembly (longer surfactant chains favour micelle formation).  The new model created to describe these interactions will aid the further development of commercial applications for these systems.

Competition between surfactant micellization and complexation by cyclodextrin
M. Cepeda, R. Daviña, L. García-Río, M. Parajó, P. Rodríguez-Dafonte and M. Pessêgo
DOI: 10.1039/C2OB26318A

Published on behalf of Steve Moore, Organic & Biomolecular Chemistry web science writer.