Synthesis and Evaluation of Antimicrobial Activity of the Rearranged Abietane Prattinin A and Its Synthetic Derivatives.

Synthesis of the natural product prattinin A and some new derivatives has been achieved using abietic acid. The final products and a selection of intermediates were evaluated for their antibacterial activity against three human pathogenic bacteria: E. coli, P. aeruginosa, and S. aureus. The results showed that the antibacterial activity varies depending on the chemical structure of the compounds. Notably, compound 27 exhibited the most potent activity against E. coli and P. aeruginosa, with a minimal inhibitory concentration (MIC) of 11.7 µg/mL, comparable to that of the standard antibiotic ciprofloxacin, and strong activity against S. aureus, with an MIC of 23.4 µg/mL. Furthermore, we assessed the stability of these derivative compounds as potential antimicrobial agents and determined their interactions with the crystal structure of the protein receptor mutant TEM-12 from E. coli (pdb:1ESU) using molecular docking via UCSF Chimera software 1.17.3. The results suggest that 27 has potential as a natural antibiotic agent.

Unprecedented Elimination Reactions of Cyclic Aldols: A New Biosynthetic Pathway toward the Taiwaniaquinoid Skeleton.

The acid treatment of 6,7-seco-abietane dialdehydes gives, in high yield, the corresponding derivatives with the 4a-methyltetrahydrofluorene skeleton of taiwaniaquinoids. A mechanism involving the elimination of formic acid from the cyclic aldol intermediate is proposed here. This process can be postulated as a new biogenetic pathway from abietane diterpenes to taiwaniaquinoids. Using this novel reaction, the first enantiospecific synthesis of bioactive natural cupresol and taxodal has been obtained.

Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds.

A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 ± 0.04 µg/mL and 5.71 ± 0.14 µg/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 µg/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.

Deconjugative α-Alkylation of Cyclohexenecarboxaldehydes: An Access to Diverse Terpenoids.

A general and efficient method for the deconjugative α-alkylation of α,ß-unsaturated aldehydes promoted by a synergistic effect between tBuOK and NaH, which considerably increases the reaction rate under mild conditions, is reported. The ß,γ-unsaturated aldehyde, resulting from the α-alkylation, is transformed in high yield into the corresponding allyl acetate via a lead(IV) acetate-mediated oxidative fragmentation. This strategy could be used for the construction of the carbon skeleton of a wide variety of alkyl or arylterpenoids.

Protecting-Group-Free Synthesis of Cassane-Type Furan Diterpenes via a Decarboxylative Dienone-Phenol Rearrangement.

An expeditious route to obtaining cassane-type furan diterpenes starting from (+)-sclareolide, an inexpensive commercially available natural lactone, has been achieved by using a solvent-free Diels-Alder cycloaddition and an unprecedented decarboxylative dienone-phenol rearrangement as key steps. Its applicability is showcased by the first synthesis of (5α)-vouacapane-8(14),9(11)-diene. The synthesis, which requires no protecting group, is efficient and atom- and step-economical (10 steps, 20% global).

Diastereoselective Intramolecular Heck Reaction Assisted by an Acetate Group: Synthesis of the Decahydrobenzofluorene Derivative Dasyscyphin E.

The first synthesis of antifungal sesquiterpene quinol dasyscyphin E was achieved starting from trans-communic acid. The process described involves the first diastereoselective synthesis of this type of compound by cyclization of an aryl bicyclosesquiterpene. The acid was efficiently transformed into a sesquiterpene synthon, which was converted into the corresponding bromoaryl sesquiterpene. The key step of synthetic sequence was the cyclization of the latter under Heck reaction conditions, which yielded the tetracyclic skeleton of the target compound with complete diastereoselectivity. The participation of an acetate group is decisive, both for the course of the Heck reaction and for the stereoselectivity of the process.

Oxidative Coupling of (-)-Sclareol and Related Diols Leading to Oxepane Terpenoids.

Treatment of (-)-sclareol and related compounds with lead tetraacetate affords tetracyclic compounds bearing a 2,8-dioxabicyclo[5.2.0]nonane moiety with complete regio- and stereoselectivity. This process, which is also applicable to 1,5-diols with a similar substitution pattern, facilitates the development of efficient syntheses toward oxepane terpenoids, such as aplysistatin derivatives.

Preparation of oxocene terpenes. The first enantiospecific synthesis of cytotoxic arenaran A.

The first syntheses of cytotoxic marine arenarans A and B starting from commercial (-)-sclareol are reported. The oxocene ring of the target compound is formed via ring-closing metathesis, a process that depends on certain structural requirements. The trans-fused structure of the natural product is confirmed by comparison with the cis-fused isomer, which was synthesized. This synthetic strategy is also applicable to the synthesis of other oxocene terpenes.

Synthesis of the putative structure of 15-oxopuupehenoic acid.

Synthesis of the putative structure of the marine natural 15-oxopuupehenoic acid has been achieved starting from commercial (-)-sclareol. Key steps of the synthetic sequence are the Robinson annulation of a ß-ketoester and methyl vinyl ketone and an unprecedented cyclization of the resulting α,ß-enone, which is mediated by tin(IV) chloride in the presence of N-phenylselenophthalimide. The physical properties of the synthetic compound are somewhat different from those reported for the natural product.

A short synthetic route towards merosesquiterpenes with a benzoxanthene skeleton.

A short synthetic sequence for the preparation of merosesquiterpenes with a benzoxanthene skeleton starting from commercial (-)-sclareol is reported. The D ring of the target compound is obtained through a Diels-Alder cycloaddition, involving a dienoldiether derived from a tricyclic α,ß-enone synthesized in two steps from the starting diterpene. Utilizing this procedure, the preparation of (+)-hongoquercin A and the first synthesis of (+)-cyclospongiaquinone-1 were achieved.

Stereoselective transformations of (+)-abietic acid into (+)-vitedoin B and (+)-negundoin A.

The first synthesis of spirolactone (+)-vitedoin B (14 steps, 8.0% global yield) and spiro enol ether (+)-negundoin A (19 steps, 3.7% global yield), via a nor-labdane acetoxy ester, has been achieved starting from commercial (+)-abietic acid.

The first synthesis of (-)-isoambreinolide, (+)-vitexifolin D and (+)-vitedoin B.

A very efficient method for synthesizing spirolactones is reported. Treatment of δ,ε-unsaturated carboxylic acids with iodine and triphenylphosphine under mild conditions leads to the corresponding spiro γ-lactones in high yield and with complete stereoselectivity. Utilizing this, the first synthesis of the terpene spirolactones (-)-isoambreinolide, (+)-vitexifolin D and (+)-vitedoin B has been achieved.

I2-PPh3 mediated spiroannulation of unsaturated ß-dicarbonyl compounds. The first synthesis of (±)-negundoin A.

An efficient and stereoselective spiroannulation of unsaturated enols is reported. Unsaturated ß-dicarbonyl compounds undergo cyclization by reaction with catalytic I2-PPh3, affording the corresponding spiro enol ether derivatives, with complete regio- and stereoselectivity, under mild conditions. Utilizing this new methodology, the first total synthesis of the anti-inflammatory diterpene negundoin A and a naturally occurring trypanocidal aldehyde is reported.

First synthesis of antitumoral dasyscyphin B.

The first synthesis of dasyscyphin B, an antitumoral metabolite obtained from the ascomycete Dasyscyphus niveus, has been achieved starting from commercial abietic acid. The key steps of the synthetic sequence are the diastereoselective α-methylation of a ketoaldehyde, followed by an intramolecular aldol condensation and the further Diels-Alder cycloaddition of a dienol ester. The procedure reported will allow the synthesis of related metabolites functionalized in the A ring.

NIS-PPh3: a selective reagent for the spiroannulation of o-allyl phenols. Total synthesis of corallidictyal D.

Treatment of o-allyl phenols with catalytic NIS-PPh3 affords the corresponding spirodihydrobenzofuran derivatives in high yield with high regio- and total stereoselectivity under mild conditions. These results were utilized to achieve the first total synthesis of the protein kinase C inhibitor corallidictyal D starting from α-ionone.

General access to taiwaniaquinoids based on a hypothetical abietane C7-C8 cleavage biogenetic pathway.

A new strategy for synthesizing taiwaniaquinoids, a group of terpenoids with an unusual rearranged 5(6→7) or 6-nor-5(6→7)abeo-abietane skeleton, which exhibit promising biological activities, is reported. The procedure, based on the cleavage of the C7-C8 double bond of abietane diterpenes, is the only one yet reported for synthesizing C(20) taiwaniaquinoids bearing a carbon function on the cyclopentane B ring; it is also applicable to the synthesis of the wide variety of existing taiwaniaquinoids. Utilizing this, (-)-taiwaniaquinone A, F, G, and H, (-)-taiwaniaquinol B, and (-)-dichroanone have been synthesized from (+)-abietic acid. The versatility of this strategy allows us to propose the abietane C7-C8 cleavage as a possible biosynthetic pathway to this type of rearranged diterpenes; this proposal seems to be supported by phytochemical evidence.

First enantiospecific synthesis of marine sesquiterpene quinol akaol A.

The first enantiospecific synthesis of akaol A, a marine sesquiterpene quinol, has been achieved. Key steps of the synthetic sequence are the oxidative degradation of (-)-sclareol to a dinorlabdane ketoester, mediated by the ozone-lead(IV) acetate system, the diastereoselective α-methylation of a ketoaldehyde, followed by an intramolecular aldol condensation and the further Diels-Alder cycloaddition of a dienol ether.

Enantioselective total synthesis of cytotoxic taiwaniaquinones A and F.

The first synthesis of cytotoxic (-)-taiwaniaquinone A and (-)-taiwaniaquinone F has been achieved through the intramolecular aldol condensation of a ketoaldehyde and the oxidative cleavage of an isopropylidene ketal.

Enantioselective total synthesis of the selective PI3 kinase inhibitor liphagal.

The enantioselective total synthesis of liphagal, a selective inhibitor of PI3K α isolated from the marine sponge Aka coralliphaga, has been achieved. The novel tetracyclic "liphagane" skeleton is formed in one step, after the hydrogenation of a dihydroxydrimane phenol benzyl ether in the presence of cationic resin.

An enantiospecific route towards taiwaniaquinoids. First synthesis of (-)-taiwaniaquinone H and (-)-dichroanone.

A new methodology for the enantiospecific synthesis of taiwaniaquinoids, based on a thermal 6pi electrocyclization, is reported. Under this procedure, 4a-methylhexahydrofluorene terpenoids bearing an A/B trans-configuration has been prepared for the first time. This methodology also makes it feasible to synthesize taiwaniaquinoids with an A/B cis-configuration and 4a-methyltetrahydrofluorene terpenoids. Accordingly, the first synthesis of (-)-taiwaniaquinone G, (-)-taiwaniaquinone H and (-)-dichroanone has been achieved.