Total Synthesis of Stelletins through an Unconventional Annulation Strategy

Abstract

Conspectus Marine ecosystems present the largest source of biodiversity on the planet and an immense reservoir of novel chemical entities. Sessile marine organisms such as sponges produce a wide range of complex secondary metabolites, many of these with potent biological activity engineered for chemical defense. That such compounds exert dynamic effects outside of their native context is perhaps not surprising, and the realm of marine natural products has attracted considerable attention as a largely untapped repository of potential candidates for drug development. Only a handful of the more than 15 000 marine natural products that have been isolated to date have advanced to the clinic, and more are to be expected. The rich chemical information encoded in the intricate three-dimensional structures of many marine natural products facilitates highly discriminating interactions with cell signaling pathways, and especially within cancer cells such nuanced effects offer an exciting opportunity for the development of targeted therapies that lack the side effects and general toxicity of conventional chemotherapeutics. The isomalabaricanes are a rare class of marine triterpenoids that have been hailed as promising cytotoxic lead compounds for the treatment of cancer, and they have attracted a flurry of excitement from researchers because of their potent cytotoxicity in certain human cancer cell lines along with a range of other antineoplastic effects. Most notably, their inhibitory activity is highly cell-selective, characterized by large deviations from their mean GI50 concentrations across 3 orders of magnitude in the NCI-60 Human Tumor Cell Lines screen, suggesting mechanistic specificity rather than general and unbridled toxicity. Despite these auspicious preliminary reports, the isomalabaricane scaffold remains largely unexplored as a potential anticancer lead because of lack of material. This Account describes our recent efforts to develop a general, modular synthesis of the isomalabaricanes, as exemplified by the successful total syntheses of rhabdastrellic acid A, stelletin E, and stelletin A. The unorthodox trans-syn-trans configuration of their perhydrobenz­[e]­indene core severely circumscribes the synthetic methods available for its construction and required several generations of strategy to assemble. Ultimately, a series of unconventional transformations were identified that were capable of building this highly strained motif, and the syntheses of rhabdastrellic acid A and stelletin E were completed in racemic fashion. Subsequently, a second-generation approach to these natural products was developed, rendering the synthesis enantioselective as well as providing access to stelletin A. These synthetic efforts were greatly assisted by computational techniques such as 13C NMR prediction, which enabled structural assignments of hydrocarbon diastereomers, as well as relaxed surface scan conformational analysis, which informed a campaign for directed hydrogenation of an alkene. High-throughput experimentation met...

Unusually cyclized triterpenoids: occurrence, biosynthesis and chemical synthesis

“…Natural Product Reports through cyclizations of 2,3-oxidosqualene (69) via chair−boat−chair (191) transition states (Scheme 8). 57,63,64 Similarly, it has been suggested that the biosynthesis of the basic core skeleton of malabaricane triterpenoids also proceeds through cyclizations of 2,3-oxidosqualene (69) via a chair-chair-chair (193) transition state 57,63,64 and triterpene synthases are responsible to generate the malabaricane basic skeleton 196 (Scheme 8). 64,65 It has been reported that two Arabidopsis thaliana genes including At5g4810 and At4g15340 encode OSCs which furnish arabidiol and thalianol.…”

“…57,63,64 Similarly, it has been suggested that the biosynthesis of the basic core skeleton of malabaricane triterpenoids also proceeds through cyclizations of 2,3-oxidosqualene (69) via a chair-chair-chair (193) transition state 57,63,64 and triterpene synthases are responsible to generate the malabaricane basic skeleton 196 (Scheme 8). 64,65 It has been reported that two Arabidopsis thaliana genes including At5g4810 and At4g15340 encode OSCs which furnish arabidiol and thalianol. 8,66,67 In addition, numerous malabaricanes have been obtained via site-directed mutagenesis of A. acidocaldarius squalene hopene cyclase which in turn comprise point mutants of Tyr420, Phe601 and Ile261.…”

Stellettin B Sensitizes Glioblastoma to DNA‐Damaging Treatments by Suppressing PI3K‐Mediated Homologous Recombination Repair

“…Notably, previous structure‐activity relationship studies have shown that stellettin A (STELA), stellettin B (STELB), and STELE share a singular trans‐syn‐trans perhydrobenz[e]indene core that is indispensable for their anticancer effects. [ 9 ] Therefore, the stellettin compounds represent attractive anticancer drug candidates for in‐depth investigation.…”

Rhabdastrenones A–D from the sponge Rhabdastrella globostellata

“…[4][5][6][7] Of these, rhabdastrellic acid A, stelletin A, and stelletin E have been accomplished through total syntheses, providing materials for studying biological mechanisms. 8,9 To date, over 70 isomalabaricane analogs have been isolated from R. globostellata. 6,7,[10][11][12][13][14][15][16][17][18] It has been shown that chemical structures of isomalabaricanes mostly differ at the side chain by the oxidative degeneration, cyclization, and isomerization of double bonds.…”