John R. Ferguson

Abnormal Nucleophilic Substitution in 3-Trichloromethylpyridine, its N-Oxide and 3,5-Bis(trichloromethyl)pyridine

Abstract The scope of abnormal reactions of nucleophiles with β-trichloromethylazines is further explored: reactions of 3-trichloromethylpyridine with nucleophiles other than methoxide, and reactions of 3-trichloromethylpyridine N-oxide and 3,5-bis(trichloromethyl)pyridine with methoxide. Attack at a ring carbon, followed by hydrogen migration to the side-chain, occurred in most cases, though attack at the trichloromethyl carbon was also sometimes observed. We now report further studies on this type of interesting, and potentially useful, reaction. These involved reactions of 3-trichloromethylpyridine (1) with nucleophiles other than methoxide, comparative reactios of 3-trichloromethylpyridine-N-oxide (4), and reactions of 3,5-bis(trichloromethyl)pyridine (5) with methoxide.

Glucuronide and sulfate conjugates of ICI 182,780, a pure anti-estrogenic steroid. Order of addition, catalysis and substitution effects in glucuronidation

Abstract The 3-sulfate 4 and 3- and 17-glucuronide conjugates 5 and 6 of the pure anti-estrogenic steroid ICI 182,780 1 , which is expected to be an effective agent for the treatment of breast cancer, have been prepared. The synthesis of 6 could only be satisfactorily achieved using an inverse addition technique, not previously employed in the glucuronic acid series: the value of this technique for some other aglycones is discussed.

Efficient new syntheses of (+)- and (-)-anatoxin-a. Revised configuration of resolved 9-methyl-9-azabicyclo[4.2.1]nonan-2-one

Abstract The bicyclic ketone 2, as either enantiomer, was converted in high yield to the glycidonitrile 4 by successive base-catalysed condensation with 2-chloropropionitrile and N -dealkylation. Opening of the epoxide followed by elimination of HCl from the resulting α-chloroketone gave the enone 7 which was converted to anatoxin-a 1 by mild acidolysis. Maintenance of chiral homogeneity from both (+)- and (-)- 2 was demonstrated by diastereomeric amide formation from (+)- and (-)-1. However, the prior correlation of(+)- 2 with (+)-1 was found to be incorrect: in fact (-)- 2 gives (+)-1.

Structure-activity relationships of some opiate glycosides

A number of analogues of morphine-6-glucuronide 1 have been prepared and evaluated as potential analgesic agents by competitive mu-receptor binding assay and in vivo antinociceptive activity. The analogues show variation in the nature of the carbohydrate residue, the N-substituent, the O(3)-substituent and saturation of the 7,8-double bond compared to 1. In general, only the 6beta-glucoside or beta-glucuronide carbohydrate residues showed potent agonism; other modified carbohydrates were less active or exhibited potential antagonism. Variations in N-substituent led to either reduced agonism (N-H) or potential antagonism [N-allyl, N-(cyclopropyl)methyl]; a polar N-substituent, carboxymethyl, failed to bind. Saturation of the 7,8-double bond led to increased agonism compared to the parent compound in all three examples studied.

Tele Nucleophilic Aromatic Substitutions in 1-Nitro-3- and 1,3-Dinitro-5-trichloromethylbenzene, and 3-Trichloromethylbenzonitrile. A New Synthesis of the 1,4-Benzothiazine-3(4H)-one Ring System from 3-Nitrobenzoic Acid

Abstract 3-Trichloromethylnitrobenzene 2 , 1,3-dinitro-5-trichloromethylbenzene 13 and 3-trichloromethylbenzonitrile 18 react with sodium methoxide to give 4-methoxy-3-nitrobenzaldehyde 6 , 4-methoxy-3,5-dinitrobenzaldehyde 15 and 5-dimethoxymethyl-2-methoxybenzonitrile 19 , respectively. Compounds 2 and 13 react with methyl thioglycolate to afford dichloromethylacetates 7 and 16 , respectively. These products are the result of tele nucleophilic aromatic substitution. Compound 18 reacted with methyl thioglycolate to give acetate 20 resulting from nucleophilic displacement of cyanide. Reductive cyclisation of 7 afforded benzothiazine 11 .

Synthesis of some β-trichloromethyl-azines and -diazines

Syntheses of compounds required as substrates for reactions with nucleophiles are reported: 2-trichloromethylquinoxaline 5, 3-trichloromethylquinoline 6, 3,5-bis(trichloromethyl)pyridine 7, 2,5-bis(trichloromethyl)pyrazine 8 and 5-trichloromethylpyrimidine 9.

Putative metabolites of fulvestrant, an estrogen receptor downregulator. Improved glucuronidation using trichloroacetimidates

Following regioselective protection of the estrogen receptor downregulator fulvestrant (ICI 182,780) 1 as its 17-acetate 2 or 3-benzoate 4, the 3-sulfate 5 and 3- and 17-glucuronide conjugates 8 and 12 were prepared. Satisfactory preparation of 12 required use of the tri-O-isobutyryl imidate derivative 10 in conjunction with an inverse-addition technique not previously employed in glucuronidation. The value of this method for simpler aglycones is discussed together with a study of variations in donor acyl substituent and catalyst. Another putative metabolite, the 17-ketone 19, was prepared by direct oxidation of 1.