9-Step synthesis of (−)-larikaempferic acid methyl ester enabled by skeletal rearrangement

We report here a concise synthesis of the anti-tumor-promoting (−)-larikaempferic acid methyl ester, a novel and rearranged abietane-type diterpene natural product containing a unique tetracyclic skeleton with a trans-hydrindane, an oxabicyclo[3.2.1]octane, and six stereogenic centers. Our synthesis starts with the cheap and abundant abietic acid and features an oxidative C–C bond cleavage followed by a transannular aldol reaction to skeletally rearrange the 6–6–6 tricyclic carbon skeleton of abietic acid to the desired 6–5–7 tricyclic carbon skeleton and an intramolecular oxa-Michael addition to form the oxa bridge. This skeletal rearrangement strategy enabled us to synthesize (−)-larikaempferic acid methyl ester in 9 steps.


S-4
To a flame-dried 50 mL round bottom flask under an argon balloon was added diene 11 1 (200 mg, 0.632 mmol, 1.0 equiv.)followed by a mixture (1:1) of anhydrous methanol (10 mL) and ethyl acetate (10 mL) at room temperature.PtO2 (3.8 mg, 0.0126 mmol) was then added.The mixture was stirred for 5 min before the argon balloon was removed.The reaction mixture was bubbled with H2 gas for 5 min then stirred under H2 atmosphere overnight.After 16 h, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (3 x 15 mL).The resulting solution was concentrated in vacuo to yield a clear yellow oil which was purified via flash column chromatography (hexanes/ethyl acetate, 99:1 to 90:10) to obtain an inseparable mixture of isomers 12a/12b together with over reduced byproducts (71% yield of 12a/12b based on NMR analysis of this mixture).This mixture was not further purified and used directly in the next step.
After the third interval, MeCN was added (45 mL) and subsequently the mixture of 12a/12b (600 mg, 1.88 mmol), dissolved in CCl4 (45 mL) was added dropwise.Once the NaIO4 was added for the fourth time, the flask was fitted with a glass-stopper and left stirring at room temperature overnight.After 16 h, another 5.0 equiv. of NaIO4 (2.01 g) was added in 2-hour intervals as 2.5 equiv.each interval.The reaction was then quenched with ethanol (11 mL), passed through a celite plug and extracted with DCM (70 mL).The organic layers were combined and washed once with sodium thiosulfate (150 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified via flash column chromatography (hexanes/ethyl acetate, 4:1 to 2:1) to give an inseparable mixture of 13a and 13b as a white amorphous solid (322 mg, 49%).13a and 13b were characterized as a 1:1 mixture with different conformers.To a flamed-dried vial was added a 1:1 mixture of diketone 13a/13b (255 mg, 0.728 mmol.) in CH2Cl2 (8.0 mL) via syringe under argon atmosphere.The resulting solution was stirred at 0 °C for 15 min.DBU (0.135 mL, 0.904 mmol.) was added dropwise.The reaction was stirred at 0 °C.After 90 min, the reaction mixture was warmed to room temperature and quenched with saturated NH4Cl (3 mL, dropwise) and extracted with CH2Cl2 (3 x 10 mL).The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain a white foamy solid which was purified via flash column chromatography (pentane/ethyl acetate, 4:1 to 2:1).Two separable isomers 14a and 14b (14a:14b = 1:1, total 216 mg, 85%) were obtained as white solids.

S-9
To a flame dried vial containing alcohol 16 (17 mg, 0.05 mmol, 1.0 equiv.)under argon atmosphere was added CH2Cl2 (0.5 mL).The mixture was stirred at 0 °C for 5 min before p-TsOH (8.4 mg, 0.05 mmol, 1.0 equiv.) in CH2Cl2 (0.5 mL) was added dropwise.The reaction mixture was first stirred at 0 °C for 30 min, then warmed up to room temperature for 1 h until complete consumption of starting material.Reaction mixture was quenched with aqueous sodium bicarbonate (0.5 mL) and extracted with dichloromethane (3 x 2 mL).The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated.The residue was purified via flash column chromatography (hexane/ethyl acetate, 3:1) to afford 17 a yellowish foamy solid (11.3 mg, 70%).A mixture of the diketones 13a/13b (98 mg, 1:1, 0.28 mmol) and basic alumina (1.0 g) in dichloromethane (10 mL) was stirred at room temperature under argon for 16 h.The alumina was removed by filtration and washed with several portions of dichloromethane.The combined filtrates were concentrated under reduced pressure.The resulting oil was purified via flash column chromatography (hexanes/ethyl acetate, 4:1 to 1:1) to give a clear oil which was crystallized to give 19 as a white solid (29.5 mg, 30%; 60% from 13a).Note: 13b decomposed under the conditions.To a flamed-dried vial containing a mixture (1:1) of 13a/13b (95 mg, 0.27 mmol) was added CH2Cl2 (3 mL).The solution was stirred at 0 °C for 5 min, then lithium bis(trimethylsilyl)amide ( 1M in THF, 542 μL, 542 μmol, 2 equiv.)was added dropwise.The reaction was warmed to 23 °C and stirred for 16 h.The reaction mixture was then placed at 0 °C and stirred for 5 min before it was quenched with saturated NH4Cl (1 mL) and extracted with CH2Cl2 (3 x 5 mL).The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated.
To a flamed-dried vial containing alcohol 19 (61.5 mg, 0.175 mmol) under argon atmosphere was added CH2Cl2 (3.5 mL).The solution was stirred at 0 °C for 5 min before triethylamine (978 μL, 7.02 mmol, 40.0 equiv.) was added followed by TMSOTf (637 μL, 3.51 mmol, 20.0 equiv.)dropwise.The reaction mixture was stirred for 1 h at 0 °C before it was quenched with sodium bicarbonate (1.5 mL) and extracted with CH2Cl2 (3 x 2 mL).The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a yellow color oil which was used in the next step without further purification.
The above crude silyl enol ether intermediate was flushed with argon and dissolved in MeCN (3.5 mL).Pd(OAc)2 (43.4 mg, 0.193 mmol) was quickly added.The reaction was stirred overnight at room temperature.The reaction mixture was then filtered through a pad of celite, washed with EtOAc, concentrated, and purified via flash column chromatography (hexanes/ethyl acetate, 4:1 to 1:1) to yield a clear oil 20 (52 mg, 70% over two steps).

Table 1 .
1H and 13 C NMR comparison of natural and synthetic larikaempferic acid methyl ester (2).