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The document details the efficient synthesis of a key intermediate for scopolamine using a [4+3] cycloaddition reaction. It includes general information on reagents and experimental procedures, as well as spectroscopic data for various compounds involved in the synthesis. The synthesis steps are outlined with specific conditions and yields for each intermediate compound.

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2 views

Surpporting Information

The document details the efficient synthesis of a key intermediate for scopolamine using a [4+3] cycloaddition reaction. It includes general information on reagents and experimental procedures, as well as spectroscopic data for various compounds involved in the synthesis. The synthesis steps are outlined with specific conditions and yields for each intermediate compound.

Uploaded by

Lázár László
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© © All Rights Reserved
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Supporting Information

Efficient Synthesis of the Key Intermediate of Scopolamine by [4+3] Cycloaddition


Reaction
Xiuyuan Duan, Qian Wang, Muhammad Shahab, Chaoqun Liang, Gudong Li, * and Guojun Zheng, *

State Key Laboratory of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, China

E-mail: [email protected], [email protected]

CONTENTS

Ⅰ General Information S2
Ⅱ Experimental Procedures S2
Ⅲ Spectroscopic Data S5
Ⅳ 1 H and 13C NMR Spectra of Compounds S6
I. General Information

All commercially available reagents were reagent grade and used without further purification. Reactions in-
volving moisture or air sensitive reagents were performed under an argon atmosphere in oven-dried
glassware. Thin layer chromatography (TLC) was carried out on 0.25 mm silica gel plates using UV light as
a visualizing agent and colorized with an iodine fumigation or potassium permanganate and heat as a
developing agent. Flash chromatography was performed using silica gel (35–70 μm) and the indicated
solvent system. NMR spectra were recorded with a 400 MHz spectrometer (400 MHz1H and 100.6
MHz13C). The chemical shifts were referencedto the deuterated solvent (e.g., for CDCl , δ = 7.26 ppm and
3
77.16 ppm for1H and 13C NMR, respectively) and reported in partsper million (ppm, δ) relative to
tetramethylsilane (TMS, δ =0.00 ppm). Data are reported as follows: chemical shift () in ppm, multiplicity
(s = singlet, d = doublet, t = triplet, q= quartet, quin = quintet, and m = multiplet), coupling constant (J) in
Hz, and integration. High resolution mass spectra (HRMS) were recorded in ESI mode using Agilent 6540
Q-TOF at the Center for Instrumental Analysis, Beijing University of Chemical Technology.

Ⅱ. Experimental Procedures

complete synthetic route of 4.

S2
tert-butyl[(3,3-dimethoxyprop-1-en-2-yl)oxy]dimethylsilane (15): To a solution of commercially
available 1,1-dimethoxy-propan2-one 8 (1.21 mL, 10.0 mmol) in dichloromethane (0.5 M) were
added triethylamine (3.34 mL, 24.0 mmol) and TBSOTf (2.76 mL, 12.0 mmol) at 0 ℃ successively.
The mixture was stirred at 0 ℃ for 1 h, and the reaction was quenched with saturated aqueous
NaHCO3. The mixture was extracted with dichloromethane. The combined organic layers were dried
over anhydrous MgSO4, filtered, concentrated under reduced pressure. The residue was purified by
silica gel flash column chromatography (elution with hexane/ethyl acetate =30:1 to 10:1) to give 9
(2.30 g, 99%) as colorless oil.

2-[(tert-butyldimethylsilyl)oxy]acrylaldehyde (1): To a solution of 9 (2.07 g, 8.90 mmol) in


acetone (0.4 M) was added PPTS (2.46 g, 9.8 mmol). The mixture was stirred at 60 ℃ for 1 h and
concentrated under reduced pressure. The residue was purified by silica gel flash column

S3
chromatography (elution with hexane/ethyl acetate: 40:1) to give 1 (1.27 g, 70%) as colorless oil.

2-hydroxy-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (3a): To a mixture of 1 (3.4 g, 18


mmol) and 5a (1.14 g, 9 mmol) in HFIP (20 mL) were added Tf 2NH (170 mg, 0.6 mmol) at 0 ℃.
The mixture was stirred at 0 ℃ for 3 h. The reaction was quenched with saturated aqueous NaHCO 3.
The mixture was extracted with ethyl acetate (×3). The combined organic layers were dried over
anhydrous MgSO4, filtered, concentrated under reduced pressure. The residue was purified by flash
silica gel column chromatography (hexane/ethyl acetate=3:1) to give 3 (1.15 g, 85%) as brown oil.

3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (4) (Barton Deoxygenation Method): To a


mixture of 3 (0.23 g, 1.1 mmol) and DMAP (28 mg, 0.23mmol) in anhydrous acetonitrile (5 mL)
were added TCDI (0.25 g, 1.32 mmol) at r.t. The mixture was stirred at 40 ℃ for 3 h. The reaction
was quenched with ice water. The mixture was extracted with ethyl acetate (×3). The combined
organic layers were dried over anhydrous MgSO 4, filtered, concentrated under reduced pressure.
Crude product without purification. Thiocarbonyl ester 10 (120 mg, 0.32 mmol) and AIBN (96 mg,
0.13 mmol) were added to an oven-dried three-necked flask. And the flask was evacuated and
backfilled with Ar three times. Toluene (9 mL) was added via syringe, followed by nBu3SnH (340
mg, 1.1 mmol) and the reaction flask was placed in an oil bath preheated to 100 °C. After 10h at this
temperature, the reaction mixture was allowed to cool to room temperature and the contents were
concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel
(hexane/ethyl acetate=3:1) to provide 4 (51 mg, 73%) as colorless oil.

S4
3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (4) (SmI2 Method): To a stirred solution of 3
(84.0 mg, 0.4 mmol) in 10 ml THF/t-BuOH (4:1) was added samarium diiodide (0.1 M in THF, 12
ml, 1.2mmol) at r.t. And the flask was evacuated and backfilled with Ar three times, After being
stirred for 10 min, the reaction was opened to air and quenched with addition of saturated aqueous
NaHCO3 solution. The mixture was extracted with ether (20 ml × 3). The combined organic phases
were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel (hexane/ethyl acetate=3:1) to provide 4 (53
mg, 70%) as colorless oil.

Ⅲ. Spectroscopic Data

tert-butyl[(3,3-dimethoxyprop-1-en-2-yl)oxy]dimethylsilane (15):

TLC Rf 0.43 (n-hexane/EtOAc = 30/1).


1
H NMR (400 MHz, CDCl3)  (ppm): 4.59 (d, 2H), 4.34 (d, 1H), 3.34 (s, 6H), 0.98 (s, 9H), 0.20 (s,
6H).
13
C NMR (100 MHz, CDCl3)  (ppm):153.46, 101.90, 92.46, 53.06, 25.57, 18.07, -4.76.
ESI-HRMS calcd. for C11H25O3Si+ [M+H] + 233.1567, found 233.1562.

2-[(tert-butyldimethylsilyl)oxy]acrylaldehyde (1):

TLC Rf 0.43 (n-hexane/EtOAc = 30/1).


1
H NMR (400 MHz, CDCl3) 9.3 (s, 1H), 5.52 (s, 1H), 5.27 (s, 1H), 0.95 (s, 9H), 0.17 (s, 6H).

S5
13
C NMR (100 MHz, CDCl3)  (ppm):189.52, 156.11, 113.57, 25.55, 18.37, -4.73.
ESI-HRMS calcd. for C9H19O2Si+ [M+H] + 187.1149, found 187.1140.

2-hydroxy-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (3a):

TLC Rf 0.35 (n-hexane/EtOAc = 1/1).


1
H NMR (400 MHz, CDCl3) 6.21 (s, 2H), 4.92 (m, 2H), 4.25 (m, 1H), 3.75 (s, 3H), 3.58 (m, 1H),
2.81 (m, 1H), 2.53 (m, 1H).
13
C NMR (100 MHz, CDCl3)  (ppm):206.73, 153.10, 135.02, 132.15, 78.14, 60.69, 57.38, 52.86,
43.74.
ESI-HRMS calcd. for C9H12NO4+ [M+H] + 198.0761, found 198.0765.
3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (4)

TLC Rf 0.50 (n-hexane/EtOAc = 1/1).


1
H NMR (400 MHz, CDCl3)  (ppm): 6.21 (s, 2H), 4.85(m, 2H), 3.76 (s, 3H), 2.72(m, 2H), 2.37 (m,
2H).
13
C NMR (100 MHz, CDCl3)  (ppm):205.51, 153.23, 133.85, 56.12, 52.72, 45.89, 45.44.
ESI-HRMS calcd. for C9H12NO3+ [M+H] + 182.0812, found 182.0810.

Ⅳ 1 H and 13C NMR Spectra of Compounds

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