Formaldehyde-Extruding Homolytic Aromatic Substitution via C→O Transposition: Selective 'Traceless-Linker' access to Congested Biaryl Bonds.

A new, selective way to form C-C bonds has been developed. In this report, we disclose the homolytic aromatic substitution via C→O transposition coupled with the elimination of formaldehyde (as a traceless linker). Computational analysis indicates the selectivity can be tuned by sterics in the starting materials following an ipso-attack that leads to the C→O transposition.

Formation and stability of gas-phase o-benzoquinone from oxidation of ortho-hydroxyphenyl: a combined neutral and distonic radical study.

Gas-phase product detection studies of o-hydroxyphenyl radical and O2 are reported at 373, 500, and 600 K, at 4 Torr (533.3 Pa), using VUV time-resolved synchrotron photoionisation mass spectrometry. The dominant products are assigned as o-benzoquinone (C6H4O2, m/z 108) and cyclopentadienone (C5H4O, m/z 80). It is concluded that cyclopentadienone forms as a secondary product from prompt decomposition of o-benzoquinone (and dissociative ionization of o-benzoquinone may contribute to the m/z 80 signal at photon energies ≳9.8 eV). Ion-trap reactions of the distonic o-hydroxyphenyl analogue, the 5-ammonium-2-hydroxyphenyl radical cation, with O2 are also reported and concur with the assignment of o-benzoquinone as the dominant product. The ion-trap study also provides support for a mechanism where cyclopentadienone is produced by decarbonylation of o-benzoquinone. Kinetic studies compare oxidation of the ammonium-tagged o-hydroxyphenyl and o-methylphenyl radical cations along with trimethylammonium-tagged analogues. Reaction efficiencies are found to be ca. 5% for both charge-tagged o-hydroxyphenyl and o-methylphenyl radicals irrespective of the charged substituent. G3X-K quantum chemical calculations are deployed to rationalise experimental results for o-hydroxyphenyl + O2 and its charge-tagged counterpart. The prevailing reaction mechanism, after O2 addition, involves a facile 1,5-H shift in the peroxyl radical and subsequent elimination of OH to yield o-benzoquinone that is reminiscent of the Waddington mechanism for ß-hydroxyperoxyl radicals. These results suggest o-hydroxyphenyl + O2 and decarbonylation of o-benzoquinone serve as plausible OH and CO sources in combustion.

Xanthone dimers: a compound family which is both common and privileged.

Covering: up to 2014. Xanthone dimers are a widespread, structurally-diverse family of natural products frequently found in plants, fungi and lichens. They feature an intriguing variety of linkages between the component xanthones (benzannulated chromanones). These synthetically elusive secondary metabolites are of great interest due to their broad array of bioactivities, which has led to the xanthones being designated as 'privileged structures'. We seek herein to give an overview of all reliably-described xanthone dimers, their structures, occurrence, and the bioactivities established to date. The possible biosynthetic pathways leading to members of this family are also discussed in light of our current knowledge.

TMIO-PyrImid hybrids are profluorescent, site-directed spin labels for nucleic acids.

We report the synthesis of a new class of molecules which are hybrids of long-lived tetramethylisoindolinoxyl (TMIO) radicals and the pyrido[1,2-a]benzimidazole (PyrImid) scaffold. These compounds represent a new lead for noncovalently binding nucleic acid probes, as they interact with nucleic acids with previously unreported C (DNA) and C/U (RNA) complementarity, which can be detected by electron paramagnetic resonance (EPR) techniques. They also have promising properties for fluorimetric analysis, as their fluorescent spin-quenched derivatives exhibit a significant Stokes shift.

Double trouble--the art of synthesis of chiral dimeric natural products.

Double or nothing! Recently the total synthesis of secalonic acids A and D was reported. This work and other natural product syntheses with a dimerization step as a common feature are featured in this Highlight. The significant biological activity of the secalonic acids and the fact that their synthesis has fascinated synthetic chemists for the past forty years make this work a milestone in natural product synthesis.

Tethering for selective synthesis of 2,2'-biphenols: the acetal method.

2,2'-Biphenols are a large and diverse group of compounds with exceptional properties both as ligands and bioactive agents. Traditional methods for their synthesis by oxidative dimerisation are often problematic and lead to mixtures of ortho- and para-connected regioisomers. To compound these issues, an intermolecular dimerisation strategy is often inappropriate for the synthesis of heterodimers. The 'acetal method' provides a solution for these problems: stepwise tethering of two monomeric phenols enables heterodimer synthesis, enforces ortho regioselectivity and allows relatively facile and selective intramolecular reactions to take place. The resulting dibenzo[1,3]dioxepines have been analysed by quantum chemical calculations to obtain information about the activation barrier for ring flip between the enantiomers. Hydrolytic removal of the dioxepine acetal unit revealed the 2,2'-biphenol target.

Synthesis of novel inhibitors blocking Wnt signaling downstream of ß-catenin.

Large scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/ß-Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy- and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/ß-Catenin signaling.

ortho-Bromo(propa-1,2-dien-1-yl)arenes: substrates for domino reactions.

o-Bromo(propa-1,2-dien-1-yl)arenes exhibit novel and orthogonal reactivity under Pd catalysis in the presence of secondary amines to form enamines (concerted Pd insertion, intramolecular carbopalladation, and terminative Buchwald-Hartwig coupling) and of amides to form indoles (addition, Buchwald-Hartwig cyclization, and loss of the acetyl group). The substrates for these reactions can be accessed in a reliable and highly selective two-step process from 2-bromoaryl bromides.

An efficient synthesis of (+/-)-frondosin B using a Stille-Heck reaction sequence.

A concise, convergent synthesis of (+/-)-frondosin B has been developed based on the application of a Stille-Heck reaction sequence of 2-chloro-5-methoxybenzo[b]furan-3-yl triflate and 2-(3-butenyl)-3-(trimethylstannyl)cyclohex-2-enone giving the racemic natural product in a 34% overall yield.

A concise approach to the polycyclic scaffold of frondosin D.

In a study directed at developing a concise approach to the polycyclic core of frondosin D, a Stille-Heck sequence has been identified that gives direct access to the trimethylbicyclo[5.4.0]undecane ring system common to all frondosins.