Cross-Metathesis Approach to the Tricyclic Marine Alkaloids (−)-Fasicularin and (−)-Lepadiformine A

Abstract

A cross-metathesis protocol has been developed to provide facile access to highly hindered trisubstituted α-branched olefins, which when coupled with a cationic azaspirocyclization reaction, generates the marine alkaloids (-)-fasicularin 2 and a pro-forma synthesis of (-)-lepadiformine A 1.

Synthesis of 8′,11′-dihydrospiro[cyclohexane-1,2′-oxepino[2,3-h] chromen]-4′(3′H)-ones with ring closing metathesis as a key step

“…In short, electron decient aza spiro cycles are proven to be efficient substrates for RCM compared to those with excess electrons. [20][21][22] The reason is attributed to the fact that the increased basicity on nitrogen is leading to the decomposition of catalyst, thus reducing availability at the site of action. 23 When the reaction was monitored using a standard amount of 2 mol% of G II, carbene transfer must have occurred to a large extent at the basic nitrogen, where the ruthenium metal centre might have been stabilized by chelation.…”

Synthesis of Tricyclic Marine Alkaloids, Cylindricines, Lepadiformines, Fasicularin, and Polycitorols: A Recent Update

“…In 2017, Robinson and co-workers reported asymmetric synthesis of (-)-fasicularin [(-)-17] and (-)-lepadiformine A [(-)-14] using olefin cross-metathesis as the key reaction tool (Scheme 8). 27,28 As cross-metathesis partners, alkenylamine 61 bearing a sterically encumbered trisubstituted olefin and exomethylene cyclohexane 62 were selected. The reaction of 61 and two equivalent of 62 in the presence of the Hoveyda-Grubbs 2nd generation catalyst provided the desired olefin 63.…”

Stereoselective Domino Semipinacol‐Schmidt Reaction: Diastereoselective Synthesis of 7 a‐epi‐(+)‐Lepadiformine C and Formal Synthesis of 7 a‐epi‐(−)‐Lepadiformine A

“…Inspired by the intriguing angularly fused azatricyclic structure of lepadiformine A, several synthetic methods for racemic, [4] epimer [5] as well as for its azatricyclic core [6] and formal synthesis [7] have been reported. Likewise, a number of enantioselective approaches have also been reported, which include N ‐acyliminium‐ion cyclization, [8a] allylsilane spirocyclization, [8b] an aza‐Prins cyclization, [8c] azaspirocyclization, [8d] metal mediated ketimine strategy, [8e] N ‐boc α‐amino nitriles as trianion synthons, [8f] reagent‐controlled diastereoselective reductive amination, [8g] Hg(OTf) 2 ‐catalyzed cycloisomerization reaction, [8h–i] enantioselective desymmetrization protocol, [8j] cross‐metathesis approach [8k] and radical translocation–cyclization reaction [8l] . The simplest alkaloid in the lepadiformine family is the lepadiformine C, which has also attracted the considerable attention from the synthetic community, as a result stereoselective [9,10] as well as enantioselective total synthesis of lepadiformine C [11–13] have been reported [14] …”