Within 14 years of the seminal experiments of J. D. Roberts
leading to the first proposal of the structure of benzyne (1), synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the total synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon− carbon or carbon−heteroatom bonds in a single operation, often in a regioselective manner. Initially, the scope of synthetic
applications was somewhat limited by the harsh conditions
required to produce the aryne species. Many of these methods required strong bases, such as n-BuLi, or high temperatures (Scheme 1). However, with the development of milder methods for the generation of arynes came increased interest in employing them in the synthesis of more complex polycyclic systems. Most recently, the use of o-silyl aryl triflates as aryne precursors has allowed generation of the reactive intermediate under almost neutral conditions.
To date, over 75 individual natural products have been
prepared using arynes to generate key synthetic intermediates. Herein are recounted the reports of total syntheses that utilize arynes in ways that build complexity or introduce motifs essential to the completion of their targets. The methods by which the authors featured in this review accomplish this task reflect the versatility of arynes as reactive intermediates for synthesis (Scheme 2). For the purposes of organization, the syntheses are divided into subgroups on the basis of the type of aryne transformation: (i) nucleophilic additions or multicomponent reactions, (ii) σ-bond insertion reactions, (iii) [4 + 2]- and [2 + 2]-cycloaddition strategies, and (iv) metal-catalyzed aryne reactions.

A Comprehensive History of Arynes in Natural Product Total Synthesis

2-aminothiophenes by the gewald reaction

Cyclobutarenes and Related Compounds

Acyl Glucuronides: Biological Activity, Chemical Reactivity, and Chemical Synthesis

Cyclic nitriles: tactical advantages in synthesis

Das aus der Cyanpropionsaure (I) erhaltliche Benzocyclobuten (II) reagiert mit dem Jodid (III) (mittels ublicher Methoden aus α-Methylacetessigsauremethylester erhaltlich) zu dem Kondensationsprodukt (IV), das bei Thermolyse regiospezifisch und stereoselektiv in das Octalin (V) ubergeht.

Studies on the syntheses of heterocyclic compounds. 675. A facile regiospecific and stereocontrolled synthesis of a diterpene alkaloid intermediate from benzocyclobutenes

[Studies on anti-inflammatory agents. XXXII. Absorption, excretion, distribution and metabolism of 2-(5H-(1)benzopyrano(2,3-b)pyridin-7-yl)propionic acid (Y-8004) in rats and mice (author's transl)].

[Studies on psychotropic drugs. XXI. Metabolic fate of Y-6047. 1].

Following the oral administration of [14C]pranoprofen to mice, 70-80% of radioactivity was excreted in the urine, and 15-25% in the feces within 3 d at 5, 25, 50, 100 and 200 mg/kg. This showed that no significant change in urinary and fecal excretion was observed among these doses. The radioactivity levels in the blood also increased in proportion to the doses, indicating that no repression of the absorption of pranoprofen was found even at increased doses. The major metabolites in mouse urine were acyl glucuronide and the glucoside of pranoprofen. At low doses acyl glucoside was predominantly excreted in urine, whereas acyl glucoside decreased relative to acyl glucuronide at increased doses. Although 43.2% of the acyl glucoside was recovered in the 24 h urine samples after the intravenous administration of acyl glucuronide, no acyl glucuronide was found in the urine after the intravenous administration of acyl glucoside. These results demonstrated the interesting observation that pranoprofen had a preference for glucosidation rather than glucuronidation in mice at low doses in spite of having a higher capacity of glucuronidation.

Yasuyuki Kato

Papers

Studies on the syntheses of heterocyclic compounds. 675. A facile regiospecific and stereocontrolled synthesis of a diterpene alkaloid intermediate from benzocyclobutenes

Studies on the syntheses of heterocyclic compounds. 675. A facile regiospecific and stereocontrolled synthesis of a diterpene alkaloid intermediate from benzocyclobutenes

[Studies on anti-inflammatory agents. XXXII. Absorption, excretion, distribution and metabolism of 2-(5H-(1)benzopyrano(2,3-b)pyridin-7-yl)propionic acid (Y-8004) in rats and mice (author's transl)].

[Studies on psychotropic drugs. XXI. Metabolic fate of Y-6047. 1].

Dose-Dependent Shift in Acyl Glucuronidation and Glucosidation of Pranoprofen, a 2-Arylpropionic Acid Derivative, in Mice in Vivo