Catalytic Asymmetric Formal Total Synthesis of (−)-Triptophenolide and (+)-Triptolide

Abstract Catalytic asymmetric formal synthesis of (−)-Triptophenolide and (+)-Triptolide have been achieved. Key reaction involves Palladium catalyzed asymmetric conjugate addition of aryl boronic acid to 3-methyl cyclohexe-1-none to form quaternary carbon. Claisen rearrangement and subsequent aldol reaction furnished trans-decaline key intermediate, which assured a formal total synthesis of (−)-Triptophenolide and (+)-Triptolide. Graphical Abstract Electronic supplementary material The online version of this article (doi:10.1007/s13659-016-0100-z) contains supplementary material, which is available to authorized users.

pyridine (12 mL) at at 0 °C, then AcCl (12 mL) was injected drop-wise slowly under argon.The mixture was stirred at room temperature for 3 h. The reaction was quenched with H 2 O and extracted with CH 2 Cl 2 (3×100 mL). The combined organic phases were washed with H 2 O, brine, dried over Na 2 SO 4 and concentrated under reduced pressure.
To a solution of the crude acetic 3-bromo benzoate (12.5 g) in dry CH 2 Cl 2 (40 mL) was added AlCl 3 (28 g, 0.21mol) portion-wise at room temperature. The reaction mixture was stirred at 130 °C for 3 h. The resulting mixture was cooled at room temperature and dissolved with CH 2 Cl 2 . the reaction was quenched with H 2 O, the aqueous layer was extracted with CH 2 Cl 2 (3×100 mL). The combined organic phases were washed with H 2 O, brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The product was used directly in the next step.
To a suspension of phenol (25.2 g, 0.1mol), anhydrous Cs 2 CO 3 (47 g ,0.15mol, 1.5eq)) and KI (16.6 g, 0.1 mol, 1.0eq) in CH 3 CN (100 mL) was added BnBr (12 mL, 0.1mol, 1.0eq), and the mixture was stirred at room temperature until the starting phenol was completely consumed. The mixture was filtered and the solvent was removed by rotary evaporation. The crude product was purified by flash column silica gel chromatography (PET: EA = 15:1) to give ketone (24.8 g) as faint yellow solid in 93 % yield.
Methyl iodide (0.68 mL, 78.5 mmol, 1.3 eq) in ether (10 mL) under argon was added drop-wise to a suspension of magnesium turnings (260 mg, 10.86 mmol, 1.3eq) in dry ether (10 mL). After the magnesium turnings disappeared, a solution of methyl aryl ketone (2.55 g, 8.36 mmol) in dry THF (15 mL) was added slowly at 0 °C. The reaction mixture was then allowed to warm to room temperature. The reaction completedin 3 hrs . The reaction was quenched with saturated ammonium chloride, extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
To a stirred solution of crude tertiary alcohol (5.2 g,16.2 mmol) and triethylsilane (5.18 mL，32.5 mmol,2.0 eq) in CH 2 Cl 2 e (20 mL) at 0 °C was added drop-wise BF 3 ·Et 2 O (1.62 mL, 16.2mmol, 1.0 eq). The solution was allowed to warm to room temperature and stirred for 20 minutes. The reaction mixture was quenched with saturated aqueous NaHCO 3 (50 mL) and was extracted with CH 2 Cl 2 (3×15 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash column silica gel chromatography (PET) to give bromobenzene (3.98 g) as colorless oil in 95% yield.
3-methyl-2-cyclohexenone 7 (83 mg, 0.75 mmol, 1.0 eq) and water (68μL, 3.75 mmol, 5.0 eq) were added. The walls of the vial were rinsed with an additional portion of CH 2 Cl 2 (0.5 mL). The mixture was stirred at 60 o C in an oil bath for 24 hrs. Upon complete consumption of the starting material (monitored by TLC, 4:1 hexanes/EtOAc),the mixture was filtrated and the filtrate was further concentrated.