Karl Hemming

Recent developments in the synthesis, chemistry and applications of the fully unsaturated 1,2,4-oxadiazoles

Recent major developments in the synthesis (including solid phase methodologies), chemistry and applications of the fully unsaturated 1,2,4-oxadiazole nucleus are reviewed. The review covers the years 1995–2000.

Pyridines from azabicyclo[3.2.0]hept-2-en-4-ones through a proposed azacyclopentadienone

Pyridines have been formed by heating azabicyclo[3.2.0]hept-2-en-4-ones in toluene. The generation of a 3-azacyclopentadienone intermediate via a [2 + 2]-cycloreversion is proposed as the key step. A Diels-Alder reaction of a styrene, extrusion of carbon monoxide, and loss of hydrogen then gives the pyridine. The process parallels the well-known synthesis of benzenes from cyclopentadienones. The azabicyclo[3.2.0]hept-2-en-4-ones were synthesized from the reaction between readily available cyclopropenones and 1-azetines, in which the cyclopropenones behave as all-carbon 1,3-dipolar equivalents.

An activated sulfonylating agent that undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis.

Activated sulfonyl derivatives, similar to acyl ones, usually undergo aminolysis with amines in water as nucleophilic attack by the amine is preferred to hydrolysis. However, despite being active sulfonyl derivatives, four-membered heterocyclic sulfonamides, beta-sultams, do not undergo aminolysis in aqueous solution but preferentially react to give hydrolysis products only. The rate of the reaction of beta-sultams in buffered solutions of simple primary amines shows a first-order dependence on amine concentrations attributed to general base-catalyzed hydrolysis by the amine. Even N-benzyl-4,4-dimethyl-3-oxo-beta-sultam, which is both a beta-sultam and a beta-lactam, undergoes hydrolysis at the sulfonyl center rather than aminolysis at either the sulfonyl or acyl center. The solvent kinetic isotope effects (SKIE, k(H(2)O)/k(D(2)O)) for the amine-catalyzed hydrolyses are 1.4 and 1.9 for the hydrolysis of N-benzoyl-beta-sultam and N-benzyl-4,4-dimethyl-3-oxo-beta-sultam, respectively, compatible with a general base-catalyzed mechanism. The amine-catalyzed hydrolysis gives a Bronsted beta value of +0.9 for both N-benzoyl beta-sultam and N-benzyl-4,4-dimethyl-3-oxo-beta-sultam, indicating that the general base amine is almost fully protonated in the transition state. A general base-catalyzed mechanism for hydrolysis rather than nucleophilic attack was also deduced for the reaction of N-benzyl-4,4-dimethyl-3-oxo-beta-sultam with carboxylate anions based on a SKIE of 1.7-1.9 and rate constants which fit the Bronsted plot for amines. In contrast to acyl transfer reactions, those for sulfonyl transfer appear to show an inverse reactivity-selectivity relationshipthe most active compounds being the most selective. The lack of reactivity of beta-sultams toward amine nucleophiles appears to be related to the mechanism of ring opening of beta-sultams with a decreased reactivity toward amines relative to hydroxide ion, probably related to the expulsion of the relatively poor leaving group amide anion.

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics.

Synthetic approaches to 1,2,5-benzothiadiazepine 1,1-dioxides - sulfonamide analogues of the 1,4-benzodiazepines

Synthetic approaches to the 1,2,5-benzothiadiazepine 1,1-dioxides, sulfonamide analogues of the 1,4-benzodiazepines, are reviewed. The review incorporates the synthesis of bicyclic, tricyclic and tetracyclic systems, and includes approaches to sulfonamide analogues of the antitumour pyrrolobenzodiazepines, sulfonamide analogues of the tricyclic non-nucleosidic reverse transcriptase inhibiting benzodiazepines (such as nevirapine), and other systems of biological interest. Details of the reactions and biological activity of the 1,2,5-benzothiadiazepines are also given.

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low μM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from 1,2-thiazine 1-oxides

This paper presents a new approach to the synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides, sulfonamide analogues of the ‘privileged’ 1,4-benzodiazepine pharmacophore. The key steps during this synthesis are the hetero Diels-Alder reaction of an N-sulfinylamine dienophile with a diene to give a 1,2-thiazine 1-oxide which is then converted into a N-(o-azidobenzenesulfonyl)-1,2-amino alcohol via a 2 3-sigmatropic rearrangement involving an intermediate allylic sulfoxide and sulfenate ester. Staudinger reaction of the o-azido group and hydrolysis of the intermediate iminophosphorane gave the corresponding N-(o-aminobenzenesulfonyl)-1,2-amino alcohols. Fmoc protection at nitrogen, oxidation of the alcohol, and Fmoc deprotection furnished directly the 1,2,5-benzothiadiazepine 1,1-dioxides in 57–69% yield. An alternative method which uses triazene chemistry is also presented, but was consistently lower yielding. A second route to 1,2,5-benzothiadiazepine 1,1-dioxides using 2-nitrobenzenesulfonamide as the dienophile precursor proceeded without incident to give N-(o-nitrobenzenesulfonyl)-1,2-amino ketones which underwent reductive cyclisation to furnish the target heterocycle.

Effect of plasma surface treatment of poly (dimethylsiloxane) on the permeation of pharmaceutical compounds

This paper addresses the modification of poly(dimethylsiloxane), i.e. PDMS, using plasma surface treatment and a novel application of the membrane created. A set of model compounds were analysed to determine their permeation through PDMS, both with and without plasma treatment. It was found that plasma treatment reduced permeation for the majority of compounds but had little effect on some compounds, such as caffeine, with results indicating that polarity plays an important role in permeation, as is seen in human skin. Most importantly, a direct correlation was observed between plasma-modified permeation data and literature data through calculation of membrane permeability (Kp) values suggesting plasma-modified silicone membrane (PMSM) could be considered as a suitable in vivo replacement to predict clinical skin permeation.

2-Methylsulfanylbenzo[f]isoquinoline

S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate 4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinoline.

Bicyclic 6-6 Systems: Five or More Heteroatoms

This chapter covers the diverse range of heterocycles that have two six-membered rings with five or more heteroatoms at positions other than the ring junctions. The 7-azapteridine nucleus (the pyrimido[5,4-e]-1,2,4-triazines) that is present in natural products such as toxoflavin, fervenulin, and reumycin dominates the chapter, although there are significant contributions from the 6-azapteridines (the pyrimido[4,5-e]-triazines), the pyrazinothiadiazines, the pyrimidothiadiazines, and the recently discovered pyridotetrazines. The organization of the chapter follows reaction type and synthesis type and is not arranged according to ring system. Most of the syntheses covered start with one preexisting heterocycle (commonly a triazine) and are categorized according to the way that the remaining heteroatoms are disposed to the ring junction. Spectroscopic, thermodynamic, and theoretical aspects are dealt with, but concentrate necessarily on the more common heterocycles within this category, or upon interesting or unusual results.