First Enantioselective Synthesis of the Diazatricyclic Core of Madangamine Alkaloids

Abstract

En route to madangamines: A unified strategy has been developed for the enantioselective assembly of functionalized diazatricyclic synthetic precursors of madangamines (see scheme; Bn=benzyl, Boc=tert‐butoxycarbonyl, Mbs=para‐methoxybenzenesulfonyl).

Access to Enantiopure Advanced Intermediates en Route to Madangamines

“…Our synthesis of (+)‐madangamine D involved the closure of ring E from an ABCD tetracyclic intermediate. Taking advantage of the previously reported tricyclic intermediate 1 , we envisaged a complementary approach to (+)‐madangamine D, through the ABCE tetracyclic precursor 5 , which bears the C‐9 benzyloxyundecyl substituent required for the final closure of the D ring…”

“…Our approach involved the use of a bridged diazatricyclic platform (rings ABC) containing the appropriate functionality, at C‐3 and the C‐9 substituent, for the subsequent assembly of the peripheral macrocyclic D and E rings (Scheme ). In this context, using a phenylglycinol‐derived oxazolopiperidone lactam as the starting enantiomeric scaffold, we have developed a flexible route for the generation of the aforementioned key diazatricyclic intermediates . We have also developed a straightforward two‐step sequence to build the 11‐membered E ring, in which the skipped ( Z , Z )‐octadienoate chain on C‐3, needed for the final macrolactamization, is incorporated with acceptable stereoselectivity by using a C 8 nonstabilized ylide …”

m‐CPBA‐Mediated IntramolecularAminohydroxylation of N‐Sulfonyl Aminoalkenes to Synthesize β‐Hydroxyl Cyclic Amines

“…The β‐hydroxyl cyclic amine motif is found in a range of bioactive naturally occurring molecules and several synthetic strategies to access this important structural unit have been developed so far . The employment of either toxic or expensive metal salts and the high sensitivity of the requested complexes to air and moisture have limited the metal‐catalyzed intramolecular aminohydroxylation to build up β‐hydroxyl cyclic amine moieties .…”

Total Synthesis of (+)‐Madangamine D

“…By using a phenylglycinol-derived bicyclic lactam [9] as the starting enantiomeric scaffold, [10] our approach involves the initial construction of the bridged diazatricyclic ABC core common to all madangamines, [11] and the subsequent building of the macrocyclic D and E rings ( Figure 2). …”