Total Synthesis of (+)‐Madangamine D

Access to Enantiopure Advanced Intermediates en Route to Madangamines

“…Thus, after N‐tosylation of 1 and Dess–Martin periodinane oxidation of the resulting tricyclic alcohol, Wittig reaction of ketone 2 with the ylide generated from 3 satisfactorily gave the expected ( Z , Z )‐diene 4 in 45 % yield as a 7:1 mixture of Z / E isomers. Remarkably, the stereoselectivity of this reaction was higher than that observed (2.2:1) in a similar Wittig reaction from an ABCD tetracyclic ketone during our synthesis of (+)‐madangamine D . Removal of the N‐tosyl protecting group, followed by alkaline hydrolysis of the ester function and EDCI‐promoted macrolactamization of the resulting crude amino acid, provided tetracyclic lactam 5 , an immediate synthetic precursor of (+)‐madangamine D (Scheme ).…”

“…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…”

“…Although the isolation of madangamines A–E was reported in the 1990s and since then these alkaloids have been the subject of numerous synthetic studies, the first total (enantioselective) synthesis of a member of this group, (+)‐madangamine D, was not reported until 2014 . 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 ).…”

“…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 …”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…226) [595], sculponeatin N [596], vitamin D derivatives [597], ryanodol (e.g. [598], shikimic acids and pinitol [599], carbasugars [600], madangamine D ( a later step forms a macrocyclic amine via RCM) [601], the kaurene core [602], various securinega alkaloids [603], a labyssomicin C derivative (e.g. 228 in a moderately diastereoselective RCM using a substrate featuring diastereotopic vinyl groups) [604], the crotogoudin ring system [605], tetrahydrocannabinol derivatives (e.g.…”