Studies related to thietan-2-ones. Part 2. Conversion of a benzylpenicillin-derived thietan-2-one into D- and L-2-methylpenicillamines

Abstract

(3R)- and (3S)-{(1S,5R)-3-Benzyl-7-oxo-4-oxa-2, 6-diazabicyclo[3.2.0]hept-2-en-6-yl}-3,4,4-tri-methylthietan-2-ones (8b) and (9b) were isomerised to (3R)- and (3S)-3-(2-benzyloxazol-5-yl-carbonyl)amino-3,4,4-trimethylthietan-2-ones (10) and (14) by m-chlorobenzoic acid in methanol. Attempts to cleave the amide linkage of compound (10), by the action of phosphorus(V) chloride–methanol, were unrewarding.

In dichloromethane containing boron trifluoride, compound (8b) was converted into (3R)-3-(2-benzyl-5-oxo-2-oxazolin-4-ylidene)amino-3,4,4-trimethylthietan-2-one (16). Ozonolysis of the last-mentioned compound in dichloromethane at –78 °C and addition of ethanol yielded (3R)-3-(formyl)amino-3,4,4-trimethylthietan-2-one (17) and N-(ethoxycarbonyl)phenylacetamide (22a). Removal of the formyl group from compound (17) was achieved by the action of phosphorus(V) trichloride oxide–methanol to give, following addition of toluene-p-sulphonic acid, (3R)-3-amino-3,4,4-trimethylthietan-2-one toluene-p-sulphonate (4c). In boiling water, the thietanone (4c) underwent hydrolysis to give (2S)-2-amino-2,3-dimethyl-3-mercaptobutanoic acid toluene-p-sulphonate (D-2-methylpenicillamine toluene-p-sulphonate)(27b).

Using a similar reaction sequence, the thietanone (9b) was transformed into L-2-methylpenicillamine toluene-p-sulphonate (28b).

D-Penicillamine toluene-p-sulphonate (27a) underwent thiazolidine formation with formaldehyde [to give (4S)-5,5-dimethylthiazolidine-4-carboxylic acid toluene-p-sulphonate (32a)] more rapidly than did compound (27b).