A unified strategy toward total syntheses of lindenane sesquiterpenoid [4 + 2] dimers

The dimeric lindenane sesquiterpenoids are mainly isolated from the plants of Chloranthaceae family. Structurally, they have a crowded molecular scaffold decorated with more than 11 stereogenic centers. Here we report divergent syntheses of eight dimeric lindenane sesquiterpenoids, shizukaols A, C, D, I, chlorajaponilide C, multistalide B, sarcandrolide J and sarglabolide I. In particular, we present a unified dimerization strategy utilizing a base-mediated thermal [4 + 2] cycloaddition between a common furyl diene, generated in situ, and various types of dienophiles. Accordingly, all the three types of lindenane [4 + 2] dimers with versatile biological activities are accessible, which would stimulate future probing of their pharmaceutical potential.


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concentration (g/100 mL), and solvent. High resolution mass spectra (HRMS) were recorded by using Bruker-FT-MS spectrometers. Infrared (IR) spectra were recorded on a NEXUS 670 FT-IR device and are reported in wavenumbers (cm -1 ).

Experimental Procedures
Procedure for the Preparation of Compound 19 (known procedure 1 In each pot (4 pots in total), to a suspension of CuI (38.1 g, 200 mmol) in THF (380 mL) at -78 °C was added vinyl magnesium bromide (1.0 M in THF, 800 mL, 800 mmol).
The solution was stirred for 50 min at this temperature. A solution of (+)-verbenone (60.1 g, 400 mmol) in THF (380 mL) was added dropwise to this solution and the reaction mixture was stirred at -78 °C for 30 min. A mixture of water (30.0 mL) and THF (300 mL) was added to every pot at -78 °C to quench the reaction. Then the mixture of each pot was combined and poured to water (2.0 L) at rt. Then the mixture was filtered through a pad of silica gel and washed with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (6 × 2.0 L). Then the combined organic layers were dried over Na 2 SO 4

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Step Ⅰ: To a solution of compound 19 (8.0 g, 44.87 mmol) in 1,4-dioxane (409 mL) and H 2 O (40.9 mL) was added SeO 2 (24.905 g, 224.45 mmol) at room temperature. The solution was allowed to stir at 90 °C for 90 h, and then the solution of Na 2 S 2 O 3 (71 g) in water (600 mL) was added to the reaction at 0 °C. After the mixture was filtered through a pad of silica gel and washed with EtOAc, the filtrate was separated and the aqueous layer was extracted with EtOAc (4 × 300 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to get the crude product ii as a yellow oil. The crude compound ii was used for next step without further purification.
Step Ⅱ: Step Ⅰ: Compound 22 (1.73 g, 7.51 mmol) and SeO 2 (834.2 mg, 7.52 mmol) were dissolved in 1,4-dioxane (130 mL) and H 2 O (26 mL). Then the reaction was allowed to stir at 90 °C, and additional SeO 2 (834.2 g, 7.52 mmol) was added per hour. After five-time addition (5.005 g SeO 2 in total), the reaction was allowed to stir at 90 °C for next 3 h. Then the reaction was cooled to room temperature and quenched with saturated aqueous Na 2 S 2 O 3 solution (80 mL). The resulting mixture was extracted with EtOAc (5 × 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (5:1 petroleum ether-EtOAc) to furnish compound iii (1.284  Step Ⅱ: To a solution of compound iii (2.62 g, 10.72 mmol) in absolute MeOH (107 mL) was added pTsNHNH 2 (5.09 g, 27.33 mmol) at room temperature. The solution was allowed to reflux for 0.5 h, and then the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOH (200 mL) again, and the ethanol solvent was removed under reduced pressure to completely remove water in the crude mixture, affording a pale yellow solid without further purification.
Step Ⅲ : To a solution of the above crude compound in absolute methanol (150 mL) at 0 °C was added NaOMe (24.81 mL, 1.0 M in MeOH). After stirring for 10 min at 0 °C, the solution was allowed to stir at 30 °C for additional 30 min. The methanol was removed under reduced pressure to afford tosyl hydrazone sodium salt as a pale yellow solid without further purification. A mixture of this tosyl hydrazone sodium salt and Rh 2 (OAc) 4 (2.417 g, 5.36 mmol) in dry DMF (630 mL) was stirred for 4 h at 50 °C.
After removal of the solvent by vacuum distillation, the residue was purified by flash column chromatography on silica gel (10:1 petroleum ether-EtOAc) to provide compound 23 (1.537 g, 63% for 2 steps) as a white solid. S10 [α] D 22 -16. 1     Known compound 26 can be prepared in a ten-gram scale over six steps from commercially available (+)-verbenone according to our reported procedure 1-3 .
Ozone was generated in the usual fashion by a laboratory ozonator using commercialgrade oxygen (gas flow rate: 5 L / min) as a source. The ozonolysis was carried out in ordinary round-bottomed flasks at -78 °C. Ozone (ozone concentration: 29.8 mg/L) was introduced through a glass tube extended very close to the magnetic stirring bar.
Compound 26 (1.50 g, 6.81 mmol) was dissolved in MeOH (60 mL) and DCM (60 mL), and ozone was passed through the solution at 78 °C for 25 min. Then ozone generation was stopped, but the oxygen was still passed through the solution until there was no peroxide detectable by potassium iodide starch test paper. After removal of the solvent until about 4 mL solution remained, the residue was immediately transferred to the top of a column and purified by flash column chromatography on silica gel (10:1 petroleum ether-EtOAc) to provide compound 32 (1.320 g, 87 %) as a colorless oil.
Causion: normal treatment with dimethyl sulfide or triphenyl phosphine resulted in S17 serious epimerization at C5 to afford compound 33, instead of 32, as the major or sole product. So this workup procedure must be avoided.  Ozone is generated in the usual fashion by a laboratory ozonator using commercialgrade oxygen (gas flow rate: 5.5 L / min) as a source. The ozonolysis was carried out in ordinary round-bottomed flasks. Ozone (ozone concentration: 33.6 mg/L) was introduced through a glass tube extended very close to the magnetic stirring bar.
Step Ⅰ: In every pot (3 pots in total), ozone was passed through a solution of compound 34 (2.38 g, 9.507 mmol) in MeOH (60 mL) and DCM (60 mL) at -78 °C for 15 min. Then NaBH 4 (1.70 g, 44.849 mmol) was added with stirring and the mixture was allowed to stir at -78 °C for 1.5 h. The reaction was quenched with H 2 O (15 mL) and the resulting mixture of every pot was combined. After removal of the solvent, the aqueous layer was extracted with EtOAc (4 × 100.0 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to furnish crude compound 27 as a white solid. The compound 27 was used for next step without further purification.
Step Ⅱ: The above crude compound 27 was divided into 3 parts equally, and every part of 27 S21 was dissolved in dry DCM, 2,2-Dimethoxypropane and PPTS (923.8 mg, 3.674 mmol) were added to the solution in order at 0 °C. The mixture was allowed to stir at 30 °C for 8 h, and then the reaction was quenched with saturated solution of NaHCO 3 (30 mL) and the resulting mixture of every pot was combined. After removal of the solvent, the aqueous layer was extracted with EtOAc (7 × 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to furnish crude product as a colorless oil. This compound was used for next step without further purification.
Step Ⅲ: The above crude compound was divided into 3 parts equally, every part of the compound was dissolved in acetone (105 mL), p-TsOH•H 2 O (904.3 mg, 4.755 mmol) was added to the solution at 0 °C. After stirring for 40 min at 30 °C, the reaction was quenched with saturated aqueous NaHCO 3 solution (20 mL) and the resulting mixture of every pot was combined. After removal of the solvent, the aqueous layer was extracted with EtOAc (5 × 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (6:1 petroleum ether-EtOAc) to furnish compound 35 (6.5 g, 91% for 3 steps) as a white solid.  Step Ⅰ: To a solution of LHMDS, prepared from HMDS (6.19 g, 8.0 mL, 38.37 mmol) and nBuLi (2.5 M in hexane, 14.37 mL, 35.97 mmol) in THF (1000 mL), was added 35 (3.0 g, 11.98 mmol) in THF (23 mL) at -78 °C and the resulting mixture was stirred for 30 min at the same temperature. The mixture of diethyl ketomalonate (2.92 g, 2.56 mL, 16.79 mmol) and ZnCl 2 (2.29 g, 16.79 mmol) in THF (20 mL) was added to the above solution at -78 °C during 10 min. After stirring for another 10 min, saturated aqueous S23 NH 4 Cl solution (50 mL) and NaCl solution (75 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (4 × 100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (6:1 petroleum ether-EtOAc) to furnish compound vii (4.76 g, 94 %) as a white solid.
After stirring at -40 °C for 4 h, MeOH (2 mL) was added to quench the reaction, and then saturated aqueous NaHCO 3 solution (15 mL) was added. The layers were separated S27 and the aqueous layer was extracted with DCM (6× 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc) to give a crude compound ix, which was used in the next reaction without further purification.
An aliquot sample was collected, purified and characterized.  Step Ⅱ:

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To a solution of above compound ix in THF (7.6 mL) was added LiHBEt 3  After the mixture was irradiated with a high voltage sodium lamp (100 W, Galilee ® ) for 5 min, irradiation was discontinued, but oxygen was still passed through the solution for additional 5 minutes. Then the cooling bath was removed, and MeOH (2.7 mL) and TMSCHN 2 (2.0 M in hexane, 0.500 mL) was added in order at 0 °C. The resulting mixture was allowed to stir at room temperature for 5 min, and then the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (20:1, DCM/MeOH) to furnish compound 11 (sarglabolide I, 9.5 mg, 87%) as a pale yellow solid.     Known compound 41can be prepared according to the known procedure 8 .
Step Ⅲ : To a solution of above compound 44 in THF (8 mL) was added aqueous HF•Py (70% in water, 0.4 mL) at 0 °C. Then the reaction was allowed to stir for 1.5 h at 0 °C, before it was added to saturated aqueous NaHCO 3 solution (40 mL) at 0 °C. The mixture was extracted with EtOAc (6 × 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:2 petroleum ether-EtOAc) to furnish 16 (chlorajaponilide C, 6.1 mg, 44% over 3 steps) as a colorless oil.

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Step Ⅰ: p-TsOH•H 2 O (38.0 mg, 0.200 mmol) was added to a solution of 48 (10 mg, 0.020 mmol) in MeOH (4 mL) at 0 °C. Then the reaction was allowed to warm to 40 °C and stir for 5 h, before it was quenched with saturated aqueous NaHCO 3 solution (4 mL) at 0 °C.
The mixture was extracted with DCM (5 × 4 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (5:1 petroleum ether-EtOAc) to furnish compound x (5.1 mg, 55 %) as a colorless oil.

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Step Ⅱ: Oxygen was bubbled through a solution of compound x (6.0 mg, 0.0131 mmol) in DCM (6 mL) containing a catalytic amount of tetraphenylporphyrin (TPP, 1.2 mg, 1.97 μmol) at -20 °C. After the mixture was irradiated with a high voltage sodium lamp (100 W, OSRAM ® ) for 2 min, irradiation was discontinued. After oxygen was bubbled through the solution for additional 5 min, saturated solution of oxalic acid (5 mL) was added.
The mixture was extracted with DCM (5 × 4 mL). The combined organic layers were