Synthesis of piperazine-2,5-diones related to bicyclomycin: 1,4-dibenzyl-3-hydroxy-3-[1-(2-methoxyethyl)ethenyl]piperazine-2,5-dione. 2. Route via cyclic intermediates

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Abstract
1,4-Dibenzyl-3-hydroxy-3-[1-(2-methoxyethyl)ethenyl]piperazine-2,5-dione (43), which incorporates several of the structural features of the antibiotic bieyclomycin, has been synthesized via a reaction sequence involving early construction of the piperazine-2,5-dione ring. In model studies 3-isopropylidenepiperazine-2,5-dione was di-N-benzylated and epoxidized to give 4,7-dibenzyl-2,2-dimethyl-1-oxa-4,7-diazaspiro[2.5]octane-5,8-dione (10). The opening of the epoxide ring of 10 by several reagents was investigated and it was found that treatment with magnesium isopropylcyclohexylamide (MICA) gives 1,4-dibenzyl-3-hydroxy-3-(1-methylethenyl)piperazine-2,5-dione (23). Treatment of ethyl 3-(2-methoxyethyl)-3-methyl-glycidate (28) with p-toluenesulfonic acid followed by hydrogenation and oxidation gives ethyl 5-methoxy-3-methyl-2-oxopentanoate, which on reaction with chloroacetamide and sulfuric acid followed by treatment of the resulting enamide with ammonia gives (Z)- and (E)-3-(4-methoxybut-2-ylidene)piperazine-2,5-dione. Di-N-benzylation of these followed by epoxidation gives (Z)- and (E)-4,7-dibenzyl-2-(2-methoxyethyl)-2-methyl-1-oxa-4,7-diazaspiro[2.5]octane-5,8-dione (41 and 42). Treatment of 41 with MICA converts it to compound 43. Chromatography of 43 on silica converts it in part to N-benzyl-N-(2-benzylamino-2-oxoethyl)-3-(2-methoxyethyl)-2-oxo-3-butenamide, which on treatment with MICA regenerates 43.

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