Expanding Natural Diversity: Tailored Enrichment of the 8,12-Sesquiterpenoid Lactone Chemical Space through Divergent Synthesis.

The divergent synthesis of a non-natural 8,12-sesquiterpenoid lactone collection is described. The synthesis relies on a rationally designed guaianolide scaffold bearing a tertiary hydroxyl as the pinpoint for inducing its selective diversification. Key reactions include an unprecedented Suarez-type CH lactonization and a highly diastereoselective oxy-Cope/ene cascade that allows the introduction of three stereocenters in a single operation. Selective oxidative/reductive and redox neutral transformations follow to highlight the synthesis of naturally unpresented highly substituted 8,12-guaianolides.

Stereoretentive enantioconvergent reactions.

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.

Short Scalable Route to Apiaceae Sesquiterpene Scaffolds: Total Synthesis of 4-epi-Epiguaidiol A.

The oxy-Cope/ene reaction cascade to form a locked elemane conformer allows the short scalable synthesis of versatile Apiaceae scaffolds. The divergent fate of the obtained macrocyclic germacrane is surveyed under cationic and dioxygen-induced Prins-type reaction conditions to allow the diastereoselective synthesis of oxidized Apiaceae guaiane congeners and the total synthesis of 4-epi-epiguaidiol A. Additionally, the unprecedented reduction of a hydrogen-bond-biased guaiane substrate permits the chemoselective synthesis of desoxo-jungiaguaiane.

A multifunctional divergent scaffold to access the formal syntheses of various sesquiterpenoids.

The development of a divergent scaffold able to access an array of diverse natural sesquiterpenoids is described. The route unifies the scope of previously reported plans of our group to allow the scalable synthesis of 8,12-furo and lactone sesquiterpenoid carbocyclic cores of elemanes, germacranes, guaianes, cadinanes, lindenanes and myliols. The formal syntheses of furogermenone, methyl-curdionolide, zedoarol, qweicurculactone, lindenene and sarcandralactone A are reported.

DFT studies on metal-catalyzed cycloisomerization of trans-1,5-enynes to cyclopropane sesquiterpenoids.

We have recently described the synthesis of strained carbocyclic sesquiterpenoid motifs through a highly regioselective cycloisomerization of common enyne acetates, in the presence of platinum(ii) and gold(i) chlorides as catalysts. In this work, the mechanisms of these cyclization reactions have been studied by means of DFT methods. At the outset of the reactions, the propargyl substrates suffer 1,2- or 1,3-acetate rearrangements, which compete for the formation of a metal-carbene or a vinyl-metal species, respectively. These intermediates are the resting states of the cycles towards the formation of lindenane or myliol core structures. The DFT studies have revealed the energetics of the two migration processes, as well as the reasons for some of the key experimental observations, such as the syn/anti preference in the formation of the cyclopropane rings, the different reactivities of substrates containing furan or lactone moieties, and the different outcomes of the reactions when Pt(ii) and Au(i) salts are used.

Uncovering the pharmacological response of novel sesquiterpene derivatives that differentially alter gene expression and modulate the cell cycle in cancer cells.

The present study aimed to assess the pharmacological anticancer profile of three natural and five synthetic sesquiterpenes developed by total chemical synthesis. To this end, their properties at the cellular and molecular level were evaluated in a panel of normal and cancer cell lines. The results obtained by performing cytotoxicity assays and gene expression analysis by reverse transcription-quantitative polymerase chain reaction showed that: i) Among the sesquiterpene derivatives analyzed, VDS58 exhibited a notable anticancer profile within attached (U-87 MG and MCF-7) and suspension (K562 and MEL-745) cancer cell cultures; however, U-87 MG cells were able to recover their proliferation capacity rapidly after 48 h of exposure; ii) gene expression profiling of U-87 MG cells, in contrast to K562 cells, showed a transient induction of cyclin-dependent kinase inhibitor 1A (CDKN1) expression; iii) the expression levels of transforming growth factor ß1 (TGFB1) increased after 12 h of exposure of U-87 MG cells to VDS58 and were maintained at this level throughout the treatment period; iv) in K562 cells exposed to VDS58, TGFB1 expression levels were upregulated for 48 h and decrease afterwards; and v) the re-addition of VDS58 in U-87 MG cultures pretreated with VDS58 resulted in a notable increase in the expression of caspases (CASP3 and CASP9), BCL2­associated agonist of cell death (BAD), cyclin D1, CDK6, CDKN1, MYC proto-oncogene bHLH transcription factor (MYC), TGFB1 and tumor suppressor protein p53. This upregulation persisted only for 24 h for the majority of genes, as afterwards, only the expression of TGFB1 and MYC was maintained at high levels. Through bioinformatic pathway analysis of RNA-Seq data of parental U-87 MG and K562 cells, substantial variation was reported in the expression profiles of the genes involved in the regulation of the cell cycle. This was associated with the differential pharmacological profiles observed in the same cells exposed to VDS58. Overall, the data presented in this study provide novel insights into the molecular mechanisms of action of sesquiterpene derivatives by dysregulating the expression levels of genes associated with the cell cycle of cancer cells.

Regioselective Ene-Type Allylic Chlorination of Electron-Rich Alkenes by Activated DMSO.

A simple protocol involving the activation of DMSO by chlorotrimethysilane is described for the chemoselective chlorination of polyprenoids. The proposed protocol provides a versatile and scalable alternative to existing routes for accessing useful synthetic synthons for the synthesis of complex terpenoids.

Platinum-catalyzed cycloisomerizations of a common enyne: a divergent entry to cyclopropane sesquiterpenoids. Formal synthesis of sarcandralactone A.

A common enyne scaffold, resembling the structures of natural elemanes was found to be an excellent substrate for highly regioselective cycloisomerizations to produce diverse cyclopropane sesquiterpenoids. Platinum-catalysis was utilized to produce either lindenane or myliol cores, found in natural products, starting from enyne acetate 10 and its corresponding allene 12 respectively. Based on this concept, a second generation strategy allows the formal synthesis of sarcandralactone A.

Divergent pathways to furosesquiterpenes: first total syntheses of (+)-zedoarol and (Rac)-gweicurculactone.

A non-natural hydroxy-elemane was found amenable to divergent transformations, producing either polyunsaturated guaianes under basic, oxygen-free conditions, or oxidized furogermacranes when anionic oxy-Cope reaction quenched by an oxidant is employed. Based on these findings, the first total syntheses of zedoarol and gweicurculactone are reported.