Studies related to cyclopentanoid natural products. Part 2. An improved route to (4R)-4-hydroxy-2-hydroxymethylcyclopent-2-en-1-one and its O-substituted derivatives

Abstract

(3R,4S,5R)-3,4-O-Cyclohexylidene-3,4,5-trihydroxycyclohexan-1-one (11a), prepared from D-quinic acid (4a) by a published three-step sequence, was converted into the 5-O-benzoyl derivative (11b) by the action of benzoyl chloride. Simultaneous protection of the ketonic carbonyl group and removal of the cyclohexylidene moiety occurred when the compound (11b) was treated with ethane-1,2-dithiol and boron trifluoride–diethyl ether. The derived (7R,8R,9R)-9-benzoyloxy-7,8-dihydroxy-1,4-dithiaspiro-[4.5]decane (15a), when treated sequentially with lead(IV) acetate and pyrrolidinium acetate, underwent an oxidative ring contraction to give (8R)-8-benzoyloxy-1,4-dithiaspiro[4.4]non-6-ene-6-carbaldehyde (17a).

The aldehyde (17a) reacted with lithium aluminium hydride to give (8R)-8-hydroxy-6-hydroxymethyl-1,4-dithiaspiro[4.4]non-6-ene (18a) and with sodium cyanoborohydride to yield (8R)-8-benzoyloxy-6-hydroxymethyl-1,4-dithiaspiro[4.4]non-6-ene (18b). Sodium methoxide effected the transformation of the hydroxybenzoate (18b) into the diol (18a) which underwent benzylation with benzyl bromide to give the dibenzyl ether (18c). Benzoylation of the hydroxybenzoate (18b), to give the dibenzoate (18d), was achieved by the action of benzoyl chloride. Removal of the dithiolane moiety from compounds (18a–d), to give the cyclopent-2-en-1-ones (1a–d), was brought about by copper(II) chloride–copper(II) oxide.

The cyclohexanone (11b) also reacted with propane-1,3-dithiol and boron trifluoride–diethyl ether to give (8R,9R,10R)-10-benzoyloxy-8,9-dihydroxy-1,5-dithiaspiro[5.5]undecane (20), which underwent an oxidative ring contraction to (9R)-9-benzoyloxy-1,5-dithiaspiro[5.4]dec-7-ene-7-carbaldehyde (22) when treated with lead(IV) acetate followed by dibenzylamine trifluoroacetate.

The outcome of the reaction of the cyclohexanone (11b) with ethane-1,2-diol depended upon the reaction conditions. In refluxing benzene and in the presence of toluene-p-sulphonic acid, 1-hydroxy-4-(2-hydroxyethoxy)benzene (24) was formed. At room temperature and in the presence of sulphuric acid, (7R,8R,9R)-9-benzoyloxy-7,8-dihydroxy-1,4-dioxaspiro[4.5]decane (15c) was the major product. Although the oxidative ring contraction of the last-mentioned derivative was also effected by the action of lead(IV) acetate followed by dibenzylamine trifluoroacetate, the resultant (8R)-8-benzoyloxy-1,4-dioxaspiro[4.4]non-6-ene-6-carbaldehyde (17c) was an unstable entity.

Compounds (17a) and (22) inhibited the growth of Staphylococcus aureus at concentrations of 2 and 32 µg cm^–3, respectively.