Asymmetric dearomative cyclopropanation of naphthalenes to construct polycyclic compounds

Catalytic asymmetric dearomatization (CADA) reactions is an important synthetic method for constructing enantioenriched complex cyclic systems from simple aromatic feedstocks. However, the CADA reactions of nonactivated arenes, such as naphthalenes and benzenes, have been far less explored than those of electronically activated arenes, such as phenols, naphthols and indoles. Herein, we disclose an asymmetric dearomative cyclopropanation of naphthalenes for the rapid construction of polycyclic compounds. With chiral dirhodium carboxylate as a catalyst, the dearomative cyclopropanation proceeded smoothly under mild conditions and afforded benzonorcaradiene-containing tetracycles in good yield and high enantioselectivity (up to 99% ee). Three stereogenic centers, including two all-carbon quaternary centers, were created in the dearomatization reaction. Moreover, a variety of functional groups are well-tolerated in the reaction. The products could be readily converted into other complex polycycles while maintaining the high ee value.


General Information
All commercial reagents were used as provided without further purification. The substrates 1 were prepared according to the literature. [1][2] The reactions were monitored by thin layer chromatography (TLC) on silica gel GF254 coated 0.2 mm plates (Branch of Qingdao Haiyang Chemical plant). The product spots were visualized with UV and phosphomolybdic acid (PMA). Flash column chromatography were performed using silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical plant) and a gradient solvent system (EtOAc/n-hexane as eluent). 1 H and 13 C NMR spectra were recorded on either a Bruker Avance 300 spectrometer. Chemical shifts (δ) were measured with tetramethylsilane (TMS) as internal reference. High Resolution Mass Spectrometry (HR-MS) data were obtained on AB SCIEX TripleTOF 5600+ mass spectrometer. Enantiomeric excess (ee) was determined using Agilent 1260 Infinity II highperformance liquid chromatography (HPLC) with a UV detector (at appropriate wavelength). [1][2] To a round-bottomed flask containing a Wittig reagent (1.8 equiv.) and sodium hydride (60%, 2.0 equiv.) was added THF/DMSO (4:1) at 0 °C. After stirred at room temperature for 30 mins, 1-naphthaldehydes (1.0 equiv.) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at room temperature until the complete consumption of 1-naphthaldehydes as monitored by TLC analysis. Then the reaction was quenched with H2O, extracted with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound S0.

General procedure for the preparation of substrates 1
A round-bottom flask equipped with a magnetic stir bar was charged with S0, Pd/C (10 mg/1 mmol substrate) and EtOAc (5 mL/mmol). The reaction was stirred for 5 hours under balloonpressure of hydrogen. Then the reaction mixture was filtered through a celite pad with EtOAc, dried with Na2SO4, and concentrated under vacuo. The product S1 was used without chromatographic purification.
A 50-mL schlenk tube containing a magnetic stirring bar was dried with a heat-gun in vacuo and flushed with argon three times after cooling to room temperature. Ester S1 (1.0 equiv.), methyl benzoate (2.0 equiv.) and anhydrous THF were added and the resulting solution was stirred at 0℃ for 5 minutes. Then to the solution was slowly added LiMDS (1.0 M in THF, 2.0 equiv) The solution was stirred for 2 hours and then poured into sat. NH4Cl aq. The resulting mixture was extracted two times with EtOAc, dried over Na2SO4, filtrated, and concentrated in vacuo to afford a yellow oil. The yellow oil was immediately was dissolved in MeCN (0.20 M). To the resulting solution were added p-acetamidobenzenesulfonyl azide (p-ABSA, 1.1 equiv.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.0 equiv.) at 0 ℃. After stirring the mixture for 5 hours at room temperature, the reaction was diluted with EtOAc. The organics were washed with water and brine, dried over Na2SO4, filtrated and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the corresponding product.

General procedure for the intramolecular dearomative cyclopropanation of naphthalenes (1) General procedure for reaction condition screening
Catalyst (2 mol%) was added to a flame-dried 10 mL schlenk tube with a magnetic stir bar. The tube was sealed, evacuated and flushed with argon three times. Then anhydrous solvent (0.5 mL, noted in Table S1) was added and the mixture was stirred under the indicated temperature for 15 minutes. Then substrate 1a or 1b (0.1 mmol, 1.0 equiv.) was dissolved in the same anhydrous solvent (1.5 mL, noted in Table S1). Then the solution was injected into the tube for 30 minutes by using a syringe pump. The reaction mixture was then stirred for the indicated temperature and time in Table S1. Upon completion, the reaction was warmed to ambient temperature. The mixture was concentrated by vacuum and the residue was purified by column chromatography on silica gel to give the corresponding product.
(2) General procedure for Rh2(S-TBPTTL)2-catalyzed intramolecular dearomative cyclopropanation of naphthalenes Rh2(S-TBPTTL)4 (2 mol%) was added to a flame-dried 10 mL Schlenk tube with a magnetic stir bar. The tube was sealed, evacuated and flushed with argon three times. Then 0.5 mL anhydrous toluene was added and the mixture was stirred under -50℃ for 15 minutes. Then substrate 1 (0.1 mmol, 1.0 equiv.) was dissolved in 1.5 mL toluene. Then the solution was injected into the schlenk tube for 30 minutes by using a syringe pump. The reaction mixture was then stirred under -50℃ for 20 hours. Upon completion, the reaction was warmed to ambient temperature. The mixture was concentrated by vacuum and the residue was purified by column chromatography on silica gel to give the corresponding product. A dry 10 mL round-bottom flask equipped with a magnetic stir bar was charged with 2b (30 mg, 0.11 mmol), Pd(OH)2 (2.3 mg, 0.017 mmol) and EtOAc (1 mL). The reaction was stirred for 6 h under balloon-pressure of hydrogen. Then the reaction was filtered through a celite pad with EtOAc, dried with Na2SO4, concentrated under vacuo. The the residue was purified by column chromatography on silica gel to give the corresponding product 4 as colorless liquid (26.2 mg, 88% yield, 94% ee).

Compound 5
A dry 10 mL round-bottom flask equipped with a magnetic stir bar was charged with 2b (30 mg, 0.11 mmol), Pd/C (5.5 mg) and EtOAc (1 mL). The reaction was stirred for 6 h under balloon-pressure of hydrogen. Then the reaction was filtered through a celite pad with EtOAc, dried with Na2SO4, concentrated under vacuo. The the residue was purified by column chromatography on silica gel to give the corresponding product 5 as colorless liquid (25.8 mg, 85%, 95% ee)

Compound 6
To a stirred solution of 2b (28.2 mg, 0.1 mmol, 1.0 equiv.) in CH3OH (3.0 mL) was added NBS (26.7 mg, 0.15 mmol, 1.5 equiv.) at room temperature. After stirring for 2 h at 50 ℃, the reaction was extracted with ethyl acetate (2×20 mL) and then washed with H2O and brine, dried over Na2SO4 and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel to yield product 6 as white solid (28.4 mg, 93%, 95% ee).

NMR Spectra of Compounds
NMR Spectrum for substrates 1 NMR Spectrum for product 49