- Synthesis of piperazine-2,5-diones related to bicyclomycin: 1,4-dibenzyl-3-hydroxy-3-piperazine-2,5-dione. 2. Route via cyclic intermediates
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1,4-Dibenzyl-3-hydroxy-3-piperazine-2,5-dione (43),which incorporates several of the structural features of the antibiotic bicyclomycin, 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-diazaspirooctane-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-diazaspirooctane-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.
- Yates, Peter,Hoare, John Harold
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p. 1397 - 1404
(2007/10/02)
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