The development of an amide oxidation method and the enantioselective total synthesis of the Securinega alkaloid (-)-phyllanthine

A convenient amide oxidation method is described. The process involves a cuprous ion promoted decomposition of o-diazobenzamides 48 to give N-acyl-iminium intermediate 51 produces α-methoxy benzamides 57 in good yields and is especially efficient for symmetrical cyclic and acyclic amide systems. The oxidation exhibited good regioselectivities, represented by the methylene/methine extension of this methodology allowed for a series of two sequential amide oxidations using readily prepared 2-amino-nitrobenzamides 70 and 79.; This oxidation method was applied toward the total synthesis of the alkaloid (−) anisomycin 133. Symmetrical o-aminobenzamide pyrrolidine derivative 136 underwent oxidation to give α-methoxy substrate 137 in good yield. Unfortunately, alkylation of the presumed N-acyliminium intermediate 138 gave the undesired anti-compounds 139 as the major product.; The enantioselective total synthesis of the Securinega akaloids (−)-norsecurinine 146 and (−)-phyllanthine 145 have been have been completed starting from trans-4-hydroxy-L-proline 204. Conversion of ketonitrile 214 to the [3.2.1]-azabicyclic compound 227 was accomplished by a samarium diiodide coupling reaction. This bicycle was a key intermediate for the construction of both the (−)-norsecurinine and securinine type alkaloids. Application of our amide oxidation method to o-aminobenzamide 231 provided α-methoxy- and α-chlorobenzamides 233. A stereoselective alkylation of the corresponding N-acyl-iminium ion 232 provided allyl amine 234 which could then be transformed into tricyclic compound 238. Procedures were then developed to 2 convert this intermediate to (−)-norsecurinine 146.; The piperidine containing A-ring of (−)-phyllanthine was assembled by a stereoselective hetero Diels-Alder reaction using the hindered, highly functionalized bicyclic imine 269. This key cycloaddition produced dihydro-pyridone 270 in high yield using either high pressure conditions or catalytic Yb(OTf)₃. The structure of 270 was unambiguously determined by X-ray crystallography. Cycloadduct 270 was conveniently reduced to the desired hydroxyl stereoisomer 279 in a one-pot procedure using L-Selectride. The functionalized A-ring of (−)-phyllanthine was completed by O-methylation. An acid catalyzed α-phenylselenation procedure of tricyclic hydroxy ketone 283 cleanly provided α-phenylselenoenone 296. Vinyl selenide 296 was transformed to tricyclic hydroxy enone 305 and converted to phosphonate 306. Homer-Emmons cyclization of 306 provided (−)-phyllanthine 145 .