Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf)₂‐Catalyzed Cycloisomerization Reaction and their Cytotoxic Activities

Abstract

The enantioselective total syntheses of lepadiformine marine alkaloids, azatricyclic natural products isolated from marine tunicates, were completed. These alkaloids have a unique chemical structure characterized by the trans-1-azadecalin (AB ring system) fused with the spirocyclic ring (AC ring system). Here we found that a cycloisomerization reaction from functionalized linear substrates to a 1-azaspiro[4.5]decane framework corresponding to the AC ring in lepadiformines is promoted by a catalytic amount of mercury(II) triflate (Hg(OTf) ). The total syntheses of (-)-lepadiformines A and B were achieved in 28 % and 21 % overall yields, respectively, through the novel cycloisomerization reaction. The syntheses of (+)- and (-)-lepadiformine C hydrochloride salts also enabled us to determine the absolute configuration of natural lepadiformine C. It has been found that a phenomenon of enantiodivergence occurs in lepadiformine alkaloids from a single species of marine tunicate, Clavelina moluccensis. The cytotoxic activities of synthesized lepadiformine hydrochloride salts and their synthetic intermediates were evaluated.

Marine natural products

“…671 The absolute conguration of (+)-lepadiformine C (Clavelina moluccensis), established by enantioselective synthesis of both enantiomers, has an enantiomeric core to co-metabolites lepadiformines A and B, suggesting that the ascidian is capable of enantiodivergent biosynthesis. 672 Cytotoxic activities were also reported for the NP and related analogues. Rubrolides and analogues were found to inhibit NO production by LPSstimulated macrophages.…”

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

“…Later, this methodology was successfully used for the synthesis of several spiroskeleton structures. Natural products such as histrionicotoxin alkaloids 218 ( Scheme 65 ) [ 127 – 128 ] and lepadoformine [ 129 – 130 ] were being successfully synthesized using this methodology for spirocyclic ring structure synthesis. The proposed mechanism proceeded initially with aminoketal formation by 6- exo -dig intramolecular oxymercuration, followed by Petasis–Ferrier-type cyclization, and finally nucleophilic addition of mercuric enolate to iminium results in the formation of azaspiro structure.…”

‐Aminonitriles: From Sustainable Preparation to Applications in Natural Product Synthesis

“…This disproved the previous assumption that lepadiformine A, B and C were all of the same stereochemistry. A later synthesis of both enantiomers provided further confirmation that lepadiformine C indeed has an enantiomeric core to its congeners, lepadiformines A and B, suggesting that the producing organism is capable of enantiodivergent biosynthesis.…”