Anodic Amide Oxidations: Total Syntheses of (−)-A58365A and (±)-A58365B

Poh Lee Wong, Kevin D. Moeller

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An anodic amide oxidation-iminium ion cyclization strategy for annulating rings onto amines and amino acid derivatives has been used to synthesize the angiotensin-converting enzyme inhibitors (−)-A58365A and (±)-A58365B. Both syntheses take advantage of the ability of electrochemistry to selectively oxidize an amide in the presence of a disubstituted acetylene nucleophile. In the synthesis of A58365A, an electrolysis substrate (10) derived from proline was oxidized using constant current electrolysis conditions, an undivided cell, a carbon anode, and a 0.03 M tetraethylammonium tosylate in methanol electrolyte solution. An 83% isolated yield of the N-α-methoxyalkyl amide product 11 was obtained. The annulation procedure and formation of the desired 1-aza-2,5-dioxobicyclo[4.3.0]nonane ring skeleton were completed by treatment of the methoxylated amide with titanium tetrachloride followed by ozonolysis of the resulting vinyl chloride product. Keto amide 14 was obtained from this sequence in an 83% yield (69% over the three steps starting from the electrolysis precursor). In the synthesis of A58365B, a nearly identical procedure was used to convert an electrolysis substrate (25) derived from pipecolic acid into the required 1-aza-2,5-dioxobicyclo[4.4.0]decane ring skeleton. In this case, the overall yield of the three-step procedure was 74%. The success of these two annulation procedures serves to highlight the utility of anodic amide-oxidation-based annulation procedures for constructing bicyclic lactam enzyme inhibitors.

Original languageEnglish
Pages (from-to)11434-11445
Number of pages12
JournalJournal of the American Chemical Society
Issue number24
StatePublished - Dec 1 1993


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