Synthetic study toward the diterpenoid aberrarone

An approach to aberrarone, an antimalarial diterpenoid natural product with tetracyclic skeleton is reported. Key to the stereoselective preparation of the 6-5-5 tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C–H insertion.

Variable temperature NMR spectroscopy was performed at the Northwest A&F University NMR facility.
Mass spectroscopy (MS) experiments were performed in high resolution with an AB SCIEX Triple TOF 5600+ spectrometer (AB SCIEX, Boston, MA, USA). IR spectra were recorded on a Perkin-Elmer Frontier FT-IR spectrometer.
Single-crystal X-ray diffraction data was collected on a Bruker D8-Quest diffractometer equipped with a photon 100 detector by using a graphite monochromator utilizing Mo-K radiation ( = 0.71073 Å). Data integration and absorption correction were processed by the SAINT and SADABS programs. The structures were solved by intrinsic phasing with the SHELXS and refined by full-matrix least-squares methods on F2 by using the SHELXL-2018 program. The hydrogen atoms on C atoms were fixed at the calculated positions and refined by a riding model, with Uiso(H) = 1.2 Ueq(C).

Experimental procedures
Hydrogenation was tried on compounds S1 and S2. To our surprise, hydrogenation of S1 failed in our hand.

S4
Construction the C ring through radical cyclization or [3 + 2] cycloaddition was also tried but failed.

Synthesis of compound 11
To a stirred solution of 12 1 (635 mg, 2.66 mmol) in dry toluene (20 mL) at rt was added Co2(CO)8 (999 mg, 2.93 mmol) under 1 atm of CO, the mixture was stirred at rt for 1 h. After the complete transformation of the starting material, the reaction mixture was added NMO (1.563 g, 13.3 mmol) and heated to 95 °C overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure, the residue was purified by flash column chromatography (EtOAc/petroleum ether = 1:25) to give product 11 (380 mg, 1.43 mmol, 54%) as a yellow oil.

Synthesis of compound 10
Preparation of Nagata reagent: To a solution of Et3Al (1.0 mL, 1.0 mmol, 1.0 M in toluene) was added TMSCN (125 µL, 1.0 mmol) at rt Then the solution was heated to 110 °C. After 1 h, the formed Nagata reagent was cooled down to rt and used for next step.

Synthesis of compound S10
To a solution of alcohol 17 (162 mg, 0.55 mmol) in dry dichloromethane (8 mL) was added DIBAL-H (0.83 mL, 0.83 mmol, 1.0 M in hexanes) at -78 °C under argon. After completing the reaction, the mixture was quenched by MeOH (1 mL) and then saturated Rochelle's salt solution (10 mL) was added, and the mixture was stirred vigorously for 2 h at room temperature until the two layers were clear and the aqueous phase was extracted with t-BuOMe (3 × 10 mL). The combined organic layers was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Afterwards, the residue was purified through flash column chromatography (EtOAc/petroleum ether = 1:8) to yield S10 (100 mg, 0.34 mmol, 62%) as a colorless oil. Aldehyde S10 was directly used for next step.

Synthesis of compound S11
To a stirred solution of trimethylsilylacetylene (0.4 mL, 2.82 mmol) in tetrahydrofuran (6 mL) at -78 °C was added n-BuLi (1.73 mL, 2.77 mmol, 1.6 M in hexanes), the reaction mixture was stirred for 60 min and aldehyde S10 (162 mg, 2.82 mmol) in tetrahydrofuran (5 mL) was added S8 dropwise. After 1 h at -78 °C, the reaction mixture was quenched by saturated aqueous NH4Cl solution (10 mL) and the aqueous layer was extracted with t-BuOMe (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried by Na2SO4. The solvent was removed by rotary evaporation to give crude product, which was purified through flash column chromatography (EtOAc/petroleum ether = 1:80) to yield S11 (198 mg, 0.5 mmol, 90%) as a light yellow oil. Compound S11 was obtained as a single diastereomer and directly used for the next step.

Synthesis of compound 9
To a stirred solution of S11 (51 mg, 0.13 mmol) in CH2Cl2 (3 mL) were added Dess-Martin periodinane (92 mg, 0.2 mmol) at room temperature. After 1 h, the reaction mixture was quenched with saturated aqueous Na2SO3 and extracted with t-BuOMe (3 × 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether = 1:100) to produce 9 (42 mg, 0.11 mmol, 83%) as a light yellow oil.