Norman H. Wilson

THROMBOXANE-LIKE ACTIVITY OF PROSTANOIDS WITH AROMATIC SUBSTITUENTS AT C16 AND C17

ABSTRACT Replacement of the C17-C20 unit in PGD 2 , PGF 2α , 9, 11-etheno and 9, 11- ethano PGH 2 with a p-fluorophenoxy moiety markedly increases TXA 2 -like activity. The etheno and ethano analogues show a prolonged contractile action on arterial smooth muscle strips in vitro , which can be correlated with their high oil/water partition coefficients. The relevance of these observations to the nature of the TXA 2 receptor is discussed.

Synthesis of oxabicyclo[2.2.1]heptane prostanoids having thromboxane-like activity at sub-nanomolar concentrations

Abstract Prostanoids with an oxabicyclo[2.2.1]heptane ring system and a 15-hydroxy-16- p -fluorophenoxy ω-chain have been synthesised. One analogue 17d has the highest thromboxane-like agonist activity so far reported. It contracts isolated tracheal smooth muscle and induces platelet shape change at a concentration of 4 × 10 −11 M and is about 100 times more active than the commonly used standard agonist 11,9-epoxymethano PGH 2 , (U-46619) . The 15-oxo precursor of 17d shows high activity on tracheal muscle, but much less activity on platelets; this difference is only partly explained by binding to plasma proteins in the platelet suspension.

A note on three routes to benzyne: decomposition of diphenyliodonium acetate, nitrosation of N-phenylphosphylamidates, and deoxygenation of benzenediazotoluene-p-sulphonate N′-oxide (cupferron tosylate) by phosphorus trichloride

Thermolysis of diphenyliodonium acetate in benzene, nitrosation, via p-chlorobenzoyl nitrite, of diethyl and dipheny N-phenylphosphoramidates, ethyl-NN′-diphenylphosphonodiamidate, and NN′N″-triphenylphosphoric triamide, and deoxygenation of benzenediazotoluene-p-sulphonate N′-oxide by phosphorus trichloride all give benzyne in 4–20% yields, by mechanistically similar pathways, as shown by trapping with tetraphenylcyclopentadienone.

Thromboxane receptor active analogues based on the 6-oxabicyclo[3.2.1]octane ring system

Abstract Prostanoid analogues with a 6-oxabicyclo[3.2.1]octane ring and 3 different types of ω-chain have been synthesized and evaluated for biological activity on thromboxane A 2 (TXA 2 ) receptors and prostaglandin I 2 (PGI 2 ) receptors. The standard ω-chain analogue 34b is a TXA 2 receptor agonist approximately 10-fold less potent than U46619 3 , the standard agonist. The O -diphenylmethyloximino-ω′-chain analogue 32 gives a PGI 2 -like agonist ≈ 5-fold less active than EP 157, the most active molecule in this class. Conversely, 4-arylsemicarbazone ω-chain analogues 35a and 35b show TXA 2 antagonism comparable to that obtained with bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane systems containing this type of ω-chain ( eg EP 092).

Photolytic decomposition of some polycyclic α-diazoketones: generation and reactivity of 1,2-oxocarbenes in benzene with and without tert-butylamine

Irradiation in benzene of the two isomeric 2,3-diazofluoranthenones 11 and 14 results in the formation of only products due to the formal insertion of the intermediate oxocarbenes into the C–H bonds of the solvent, unless the reactions are carried out in the presence of tert-butylamine, whereupon products of an apparent [3 + 2]-cycloaddition of the oxocarbene to the solvent are also obtained, viz. dihydrofurans 13 and 16, respectively. Wolff rearrangement of the generated oxocarbenes to give products derived from direct trapping of the ketene intermediates with tert-butylamine are not observed. The formal insertion product, 2-phenylfluoroanthen-3-ol 12 (from 11) undergoes partial oxidation during chromatographic purification on silica to generate a persistent free radical species 17 which has been detected and characterised by EPR spectroscopy. A reinvestigation of the photolytic decomposition of the related polycyclic α-diazoketone 5 under the same conditions has established that a more likely structure for the isolated dihydrofuran is 8, and not the reported isomeric dihydrofuran 20, which is formed from 8 by hydrogen migration during isolation by repeated thick-layer chromatography.

Tautomerism of the enedione system of 15-oxoprostaglandin D2

Oxidation of prostaglandin F2α methyl ester by chromic acid yielded 15-oxoprostaglandin D2 methyl ester and the Z- and E-tautomers of the isomeric 12-ene, which were separated by partition chromatography and characterized. After equilibration in acidified water the relative proportions of (Z)-12-ene, (E)-13-ene, and (E)-12-ene were 1.0 : 0.88 : 0.89. In contrast, the proportions of the corresponding isomers of the simpler 1-(2-oxocyclopentyl)oct-1-en-3-one were 1.0 : <0.02 : 5.7, indicating that the side chain at C-8 in the prostaglandin merkedly affects the equilibrium position. In both systems the contribution from enolic forms was small.

The reactivity of organophosphorus compounds. Part 31. On the formation of 1,4-diphenylnaphthalene from o-bromophenol and 1,2,5-triphenylphosphole, and related reactions

Attempted synthesis of the 1,2,5-triphenylphospholium betaine (2)via thermolysis at 250 °C of o-bromophenol in the presence of 1,2,5-triphenylphosphole failed, the reaction giving instead bromobenzene (8%), diphenyl phenylphosphonate [(PhO)2P(O)Ph, 7.5%] copious amounts of hydrogen bromide, and 1,4-diphenylnaphthalene (34%). The last-named has been shown to arise via intramolecular rearrangement of 1,2,5-triphenylphosphole, catalysed by hydrogen bromide produced by the thermolysis of o-bromophenol. Diphenyl phenylphosphonate is also formed on thermolysis of 1-phenoxy-1,2,5-triphenylphospholium bromide (8), which may therefore be an intermediate in the reaction of o-bromophenol with 1,2,5-triphenylphosphole. 1-Phenylnaphthalene is also formed in the former reaction and in the hydrogen bromide-catalysed decomposition of 1,2,5-triphenylphosphole oxide. These reactions are interpreted in terms of ring expansion of strained phospholium species.

THE REACTIVITY OF ORGANOPHOSPHORUS COMPOUNDS. PART 31. ON THE FORMATION OF 1,4‐DIPHENYLNAPHTHALENE FROM O‐BROMOPHENOL AND 1,2,5‐TRIPHENYLPHOSPHOLE, AND RELATED REACTIONS

Attempted synthesis of the 1,2,5-triphenylphospholium betaine (2)via thermolysis at 250 °C of o-bromophenol in the presence of 1,2,5-triphenylphosphole failed, the reaction giving instead bromobenzene (8%), diphenyl phenylphosphonate [(PhO)2P(O)Ph, 7.5%] copious amounts of hydrogen bromide, and 1,4-diphenylnaphthalene (34%). The last-named has been shown to arise via intramolecular rearrangement of 1,2,5-triphenylphosphole, catalysed by hydrogen bromide produced by the thermolysis of o-bromophenol. Diphenyl phenylphosphonate is also formed on thermolysis of 1-phenoxy-1,2,5-triphenylphospholium bromide (8), which may therefore be an intermediate in the reaction of o-bromophenol with 1,2,5-triphenylphosphole. 1-Phenylnaphthalene is also formed in the former reaction and in the hydrogen bromide-catalysed decomposition of 1,2,5-triphenylphosphole oxide. These reactions are interpreted in terms of ring expansion of strained phospholium species.