ANODIC AMIDE OXIDATIONS - TOTAL SYNTHESES OF (-)-A58365A AND (PLUS-OR-MINUS)-A58365B

An anodic amide oxidation-iminium ion cyclization strategy for annulat ing rings onto amines and amino acid derivatives has been used to synt hesize the angiotensin-converting enzyme inhibitors (-)-A58365A and (/-)-A58365B. Both syntheses take advantage of the ability of electroch emistry to selectively oxidize an amide in the presence of a disubstit uted acetylene nucleophile. In the synthesis of A58365A, an electrolys is substrate (10) derived from proline was oxidized using constant cur rent 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-alpha-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 treatme nt of the methoxylated amide with titanium tetrachloride followed by o zonolysis of the resulting vinyl chloride product. Keto amide 14 was o btained from this sequence in an 83% yield (69% over the three steps s tarting from the electrolysis precursor). In the synthesis of A58365B, a nearly identical procedure was used to convert an electrolysis subs trate (25) derived from pipecolic acid into the required 1-aza-2,5-dio xobicyclo[4.4.0]decane ring skeleton. In this case, the overall yield of the three-step procedure was 74%. The success of these two annulati on procedures serves to highlight the utility of anodic amide-oxidatio n-based annulation procedures for constructing bicyclic lactam enzyme inhibitors.