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S1
Enantioselective, intermolecular [2+2] photocycloaddition
reactions of 3-acetoxyquinolone: Total synthesis of (−−−−)-
pinolinone
Electronic Supplementary Information (ESI)
Florian Mayr, Christian Wiegand and Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstrasse 4,
85747 Garching, Germany
1. Synthetic procedures and analytical data of new compounds .............................................. S2
2. References for the Supporting Information ........................................................................ S32
3. NMR spectra of new compounds ....................................................................................... S33
4. HPLC traces of racemic and enantioenriched products ..................................................... S55
Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2014
S2
1. Synthetic procedures and analytical data of new compounds
General information
All reactions sensitive to air or moisture were carried out in flame-dried glassware under a
positive pressure of argon using standard Schlenk techniques. Dry tetrahydrofuran (THF),
dichloromethane (CH2Cl2) and diethylether (Et2O) were obtained from an MBRAUN MB-SPS
800 solvent purification system. Other dry solvents were obtained from Acros in the highest
purity available and used without further purification. Technical solvents used for aqueous
workup and for column chromatography [n-pentane (pentane), ethyl acetate (EtOAc), diethyl
ether (Et2O), dichloromethane (CH2Cl2), methanol (MeOH)] were distilled prior to use.
Photochemical experiments were performed in Duran tubes (diameter: 1.2 cm, volume 10 mL
or 20 mL each; diameter 2.0 cm, volume 60 mL) in an RPR-100 photochemical reactor
(Southern New England Ultra Violet Company, Branford, CT, USA) equipped with
flourescence lamps: (λ = 366 nm). Prior to irradiation, the mixture was deoxygenated by
purging with argon in an ultrasonicating bath for 15 minutes before alkene were added to the
mixture.
Flash Chromatography was performed on silica gel 60 (Merck, 230-240 mesh) with the eluent
mixtures given for the corresponding procedures. Thin-layer Chromatography (TLC) was
performed on silica-coated glass plates (silica gel 60 F 254). Compounds were detected by
UV (λ = 254 nm, 366 nm) and CAM solution (cerium ammonium molybdate). All solvents
for chromatography were distilled prior to use.
Analytical HPLC was performed using a chiral stationary phase (Daicel ChiralCell, Chemical
Industries, flow rate: 1.0 mL/min, type and eluent is given for the corresponding compounds)
and UV detection (λ = 210 nm or 254 nm) at 20 °C.
IR spectra were recorded on a JASCO IR-4100 (ATR), MS and HRMS measurements were
performed on a Finnigan MAT 8200 (EI). 1H,
13C and
31P NMR spectra were recorded at
300 K either on a Bruker AV-250, a Bruker AV-360 or a Bruker AV-500 spectrometer.
Chemical shifts are reported on parts per million (ppm) relative to residual CDCl3
(δH = 7.26 ppm and δC = 77.0 ppm), DMSO-δ6 (δH = 2.50 ppm and δC = 39.5 ppm). All
coupling constants (J) are reported in Hertz (Hz). Apparent multiplets that occur as a result of
accidental equality of coupling constants those of magnetically non-equivalent protons are
S3
marked as virtual (virt.). Differentiable protons in cyclic systems are signed with Hu = "up"
and Hd = "down". The relative configuration of chiral products and the multiplicity of the
13C-
NMR signals were determined by two-dimensional NMR experiments (COSY, NOESY,
HSQC, HMBC).
2-Chloroquinolin-3-ol
To a solution of di-iso-propylamine (4.29 mL, 3.10 g, 30.6 mmol, 1.0 equiv.) in THF (75 mL)
n-butyllithium (12.2 ml, 2.5 M, 30.6 mmol, 1.0 equiv.) was added slowly at −20 °C. After the
addition the mixture was allowed to warm up to 0 °C. After one hour at this temperature the
mixture was cooled down to −78 °C. 2-Chloroquinoline (5.00 g, 30.6 mmol, 1.0 equiv.)
dissolved in THF (15 mL) was added dropwise. After stirring for two hours at this
temperature trimethyl borate (3.40 mL, 3.21 g, 30.6 mmol, 1.0 equiv.) was added and the
mixture was stirred for two hours at −78 °C. Subsequently the reaction was quenched with
aqueous THF (1 mL H2O in 6 mL THF). Water (100 mL) and Et2O (100 mL) were added. For
the aqueous layer the pH-value was adjusted to pH = 4 by hydrochloric acid (36%). The
aqueous layer was extracted with Et2O (3 × 100 mL). The combined organic layers were
washed with brine, dried over sodium sulfate and filtered. The solvent was removed under
reduced pressure. The residue was dissolved in Et2O (150 mL) and aqueous ammonium
chloride (4.00 g in 160 mL H2O) was added. Under stirring hydrogen peroxide (40 mL, 35%)
was added slowly. The mixture was stirred for four hour at room temperature. The colourless
solid was collected by filtration, washed with water (150 mL) and dried under reduced
pressure. The title compound (3.85 g, 21.4 mmol, 70%) was isolated as colourless solid.
TLC: Rf = 0.89 (EtOAc-MeOH = 9:1) [UV].
S4
1H-NMR (360 MHz, DMSO-d6): δ (ppm) = 7.50-7.58 (m, 2 H, H-6, H-7), 7.67 (s, 1 H,
H-4), 7.82-7.86 (m, 2 H, H-5, H-8), 11.08 (br s, 1 H, OH).
13C-NMR (93 MHz, DMSO-d6): δ (ppm) = 117.7 (d, C-4), 126.3 (d, C-5), 127.0
(d, C-7), 127.1 (d, C-6), 127.4 (d, C-8), 128.4 (s, C-4a), 141.2 (s, C-8a), 142.3 (s, C-2), 147.0
(s, C-3).
Analytical data are in agreement with literature data.[1]
3-Hydroxyquinolin-2(1H)-one
2-Choroquinolin-3-ol (3.85 g, 21.4 mmol, 1.0 equiv.) was suspended in aqueous hydrochloric
acid (6 N, 68 mL) and stirred for 24 hours under reflux. After the reaction was complete, the
mixture was cooled to room temperature and filtered. The residue was washed with water
(100 mL) and dried under reduced pressure. The title compound (2.90 g, 18.0 mmol, 84%)
was isolated as colourless solid.
1H-NMR (250 MHz, DMSO-d6): δ (ppm) = 7.08-7.14 (m, 1 H, H-6), 7.09 (s, 1 H, H-4), 7.24-
7.32 (m, 2 H, H-7, H-8), 7.47-7.50 (m, 1 H, H-5), 9.46 (s, 1 H, OH), 12.01 (s, 1 H, NH).
13C-NMR (63 MHz, DMSO-d6): δ (ppm) = 112.4 (d, C-4), 114.7 (d, C-8), 120.7
(s, C-4a), 122.0 (d, C-6), 125.8 (d, C-5), 126.3 (d, C-7), 133.5 (s, C-8a), 146.2 (s, C-3), 158.6
(s, C-2).
Analytical data are in agreement with literature data.[1]
S5
2-Oxo-1,2-dihydroquinolin-3-yl acetate (4)
3-Hydroxyquinolin-2(1H)-one (2.41 g, 14.5 mmol, 1.0 equiv.) was dissolved in dry pyridine
(60 mL) and acetic anhydride (4.12 mL, 4.45 g, 45.6 mmol, 2.9 equiv.) was added. The
mixture was stirred at room temperature for 24 hours. After the reaction was complete, the
mixture was poured on ice water (250 mL) and filtered. The residue was recrystallised in
ethanol (100 mL) and filtered. The title product 4 (2.13 g, 10.5 mmol, 72%) was isolated as
colourless solid.
TLC: Rf = 0.23 (P/EtOAc = 1/1) [UV, CAM].
1H-NMR (250 MHz, DMSO-d6): δ (ppm) = 2.28 (s, 3 H, OCCH3), 7.22 (ddd,
3J = 8.5 Hz,
3J = 7.2 Hz,
4J = 1.5 Hz, 1 H, H-6), 7.34 (dd,
3J = 8.5 Hz,
4J = 1.5 Hz, 1 H, H-8),
7.51 (ddd, 3J = 8.5 Hz,
3J = 7.2 Hz,
4J = 1.5 Hz, 1 H, H-7), 7.66 (dd,
3J = 8.5 Hz,
4J = 1.5 Hz,
1 H, H-5), 7.81 (s, 1 H, H-4), 12.2 (br s, 1 H, NH).
13C-NMR (63 MHz, DMSO): δ (ppm) = 20.3 (q, C-10), 115.1 (d, C-8), 118.3 (s, C-4a), 122.3
(d, C-6), 127.7 (d, C-5), 128.3 (d, C-4), 129.9 (d, C-7), 136.9 (s, C-8a), 140.6 (s, C-3), 156.6
(s, C-2), 168.3 (s, C-9).
Analytical data are in agreement with literature data.[2]
S6
[2+2] Photocycloaddition of quinolones with alkenes
General procedure for racemic intermolecular [2+2] photocycloadditions:
A solution of quinolone 4 in acetonitrile was purged with argon in an ultrasonicating bath for
15 minutes. The solution was divided in phototubes and the respective alkene 5a-f (20 equiv.)
was added to the solution in each tube. The mixture was irradiated at room temperature at
λ = 366 nm (2-3 hours). The solvent was removed under reduced pressure and the crude
material was subjected to flash column chromatography using an appropriate solvent system,
as described for each individual procedure.
General procedure for enantioselective intermolecular [2+2] photocycloadditions:
A solution of quinolone 4 (49.0 µmol) and template 6 (123 µmol, 2.5 equiv.) in toluene
(10 mL) was purged with argon in an ultrasonicating bath for 15 minutes. The respective
alkene 5a-f (20 equiv.) was added and the solution was transferred in a phototube. The
mixture was irradiated at −70 °C for 3 to 12 hours (described in each individual procedure) at
λ = 366 nm. The solvent was removed under reduced pressure and the crude material was
subjected to flash column chromatography using appropriate solvent system, as described for
each individual procedure.
S7
(2aS,8bS)-3-Oxo-1,3,4,8b-tetrahydrocyclobuta[c]quinoline-1,2a(2H)-diyl diacetate (3a)
Racemic procedure:
Using the general procedure a mixture of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.) and
vinyl acetate 5a (95.0 µL, 85.0 mg, 984 µmol, 20 equiv.) in acetonitrile (10 mL) was
irradiated for three hours. Purification of the crude product by flash column chromatography
on silica (∅ 18 × 1.5 cm) eluting with EtOAc-pentane (3:2) gave the title product 3a
(13.7 mg, 47.0 µmol, 96%) as a 72:28 mixture (by 1
H-NMR spectroscopy) of two
diastereomers as a colourless solid.
Enantioselective procedure:
Following the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.)
and chiral template 6 (44.0 mg, 123 µmol, 2.5 equiv.) in toluene (10 mL) was irradiated after
addition of vinyl acetate 5a (95.0 µL, 85.0 mg, 984 µmol, 20 equiv.) for three hours at
−70 °C. Purification of the crude product by flash column chromatography on silica
(∅ 18 × 1.5 cm) eluting with CH2Cl2-pentane-MeOH (29:70:1) gave the title product 3a
(10.5 mg, 36.4 µmol, 74%) as colourless solid as a 75:25 mixture of two diastereomers (by
1H-NMR spectroscopy).
m.p.: 175 °C.
TLC: Rf = 0.42 (EtOAc-pentane = 3:2) [UV, CAM].
IR (ATR): ν̃ (cm-1
) = 3237 (br), 2928 (w), 1739 (m, C=O), 1681 (br, C=O), 1595 8m), 1490
(m), 1371 (m), 1225 (s, C−O), 1197 (s), 1077 (m), 1028 (br), 755 (m), 733 (m).
S8
Major isomer:
1H-NMR (500 MHz, CDCl3): δ (ppm) = 1.75 (s, 3 H, H-2´), 2.15 (s, 3 H, H-2´´), 2.80 (dd,
2J
= 14.3 Hz, 3J = 5.6 Hz, 1 H, H-2
u), 3.09 (ddd,
2J = 14.3 Hz,
3J = 8.1 Hz,
4J = 3.3 Hz, 1 H, H-
2d), 4.10 (dd,
3J = 7.8 Hz,
4J = 3.3 Hz, 1 H, H-8b), 5.57 (virt. td,
3J = 7.8 Hz,
3J = 5.6 Hz 1 H,
H-1), 6.77 (dd, 3J = 7.5 Hz,
4J = 1.1 Hz, 1 H, H-5), 6.91 (d,
3J = 7.5 Hz, 1 H, H-8), 6.98 (td,
3J = 7.5 Hz,
4J = 1.1 Hz, 1 H, H-7), 7.19 (td,
3J = 7.5 Hz,
4J = 1.1 Hz, 1 H, H-6), 8.26 (s, 1 H,
H-4).
13C-NMR (91 MHz, CDCl3): δ (ppm) = 20.6 (q, C-2´), 21.0 (q, C-2´´), 38.8 (t, C-2), 50.2 (d,
C-8b), 66.7 (d, C-1), 72.6 (s, C-2a), 115.8 (d, C-5), 117.7 (s, C-8a), 123.4 (d, C-7), 128.5 (d,
C-6), 129.5 (d, C-8), 136.9 (s, C-4a), 167.0 (s, C-3), 170.3 (s, C-1´), 170.4 (s, C-1´´).
Minor isomer:
13C-NMR (91 MHz, CDCl3): δ (ppm) = 20.6 (1, C-2´), 21.0 (q, C-2´´), 40.4 (t, C-2), 53.3 (d,
C-8b), 68.6 (d, C-1), 69.9 (s, C-2a), 115.9 (d, C-5), 121.7 (s, C-8a), 124.0 (d, C-7), 127.3 (d,
C-8), 128.5 (d, C-6), 136.1 (s, C-4a), 168.2 (s, C-3), 170.1 (s, C-1´), 170.4 (s, C-1´´).
S9
MS (EI, 70 eV) m/z (%) = 289 (5) [M+], 230 (10) [(C13H12NO3)
+], 188 (80) [(C11H9NO2)
+],
161 (100) [(C9H6NO2)+], 159 (40), 149 (25), 84 (35), 57 (33), 43 (82).
HRMS (EI): C15H15NO5 calc.: [M+]: 289.0945
found: [M+]: 289.0947.
Chiral HPLC: tR [racemate] = 28.4 min, 32.2 min, 39.2 min, 44.5 min; tR [ent-3a] =
31.7 min, 38.6 min, tR [3a] = 28.2 min, 44.0 min; 87% ee, 89% ee (AD-H-250 × 4.6 mm, n-
hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −163.8 (c = 0.53, MeOH).
(2aS,8bR)-1,1-Dichloro-3-oxo-1,3,4,8b-tetrahydrocyclobuta[c]quinolin-2a(2H)-yl acetate
(3b)
Racemic procedure:
Using the general procedure a mixture of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.) and
1,1-dichloroethene 5b (80.0 µL, 94.0 mg, 984 µmol, 20 equiv.) in acetonitrile (10 mL) gave
the crude product. Purification of the crude product by flash column chromatography on silica
(∅ 18 × 1.5 cm) eluting with EtOAc-pentane (2:3) gave the title compound 3b (14.5 mg,
49.0 µmol, quant.) as colourless solid.
Enantioselective procedure:
Following the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.),
template 6 (44.0 mg, 123, µmol, 2.5 equiv.) and 1,1-dichloroethene 5b (80.0 µL, 94.0 mg,
984 µmol, 20 equiv.) in toluene (10 mL) was irradiated for three hours at −74 °C. Purification
of the crude product by flash column chromatography on silica (∅ 18 × 1.5 cm) eluting with
S10
EtOAc-pentane (2:3) gave the title compound 3b (14.8 mg, 49.0 µmol, quant.) as colourless
solid.
m.p.: 178 °C.
TLC: Rf = 0.70 (EtOAc-pentane = 3:2) [UV, CAM].
IR (ATR): ν̃ (cm-1
) = 3368 (w), 2957 (w), 1749 (m, C=O), 1684 (s, C=O), 1483 (m), 1366
(br), 1235 (s, C−O), 1069 (m), 1007 (m), 764 (s).
1H-NMR (500 MHz. CDCl3): δ (ppm) = 2.13 (s, 3 H, H-2´), 3.68 (d,
2J = 15.2 Hz, 1 H, H-2
u),
3.72 (dd, 2J = 15.2 Hz,
4J = 1.6 Hz, 1 H, H-2
d), 4.49 (s, 1 H, H-8b), 6.85 (dd,
3J = 7.5 Hz,
4J = 1.3 Hz, 1 H, H-5), 7.10 (td,
3J = 7.5 Hz,
4J = 1.3 Hz, 1 H, H-7), 7.16 (dd,
3J = 7.5 Hz,
4J = 1.5 Hz, 1 H, H-8), 7.29 (td,
3J = 7.5 Hz,
4J = 1.5 Hz. 1 H, H-6), 8.79 (s, 1 H, H-4).
13C-NMR (91 MHz, CDCl3): δ (ppm) = 20.5 (q, C-2´), 56.5 (t, C-2), 64.7 (d, C-8b), 69.6 (s,
C-2a), 80.3 (s, C-1), 116.1 (d, C-5), 118.4 (s, C-8a), 124.0 (d, C-7), 128.3 (d, C-8), 129.7 (d,
C-6), 137.0 (s, C-4a), 166.8 (s, C-3), 170.2 (s, C-1).
MS (EI, 70 eV) m/z (%) = 299 (2) [M+], 203 (7) [(C11H9NO3)
+], 195 (4), 162 (10), 161 (100)
[(C9H6NO2)+], 124 (15), 109 (15), 86 (20), 84 (33).
HRMS (EI): C13H11NO3Cl2: calc.: [M+]: 299.0111
found: [M+]: 299.0105.
Chiral HPLC: tR [racemate] = 35.5 min, 38.0 min; tR [3b] = 37.7 min, tR [ent-3b] = 40.0 min,
57% ee (AD-H, 250 × 4.6 mm, n-hexane/i-PrOH = 95:5, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −108.8 (c = 0.69, MeOH)
S11
(2aS,8bR)-1,1-Diethyl-3-oxo-1,3,4,8b-tetrahydrocyclobuta[c]quinolin-2a(2H)-yl acetate
(3c)
Racemic procedure:
Using the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.) in
acetonitrile (10 mL) with 2-ethyl-1-butene 5c (120 µL, 83.0 mg, 984 µmol, 20 equiv.) gave
the crude product. Purification by flash column chromatography on silica (∅ 18 × 1.5 cm)
eluting with EtOAc-pentane (2:3) gave the title product 3c (8.70 mg, 30.0 µmol, 62%) as
colourless solid.
Enantioselective procedure:
Following the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.),
template 6 (44.0 mg, 123 µmol, 2.5 equiv.) and 2-ethyl-1-butene 5c (120 µL, 83.0 mg,
984 µmol, 20 equiv.) in toluene (10 mL) gave the crude product. Purification by flash column
chromatography (∅ 18 × 1.5 cm) eluting with CH2Cl2-pentane-MeOH (29:70:1) and a second
flash column chromatography (∅ 18 × 1.5 cm) eluting with EtOAc-pentane (1:1) gave the
title product 3c (4.00 mg, 14.0 µmol, 29%) as colourless solid.
m.p.: 148 °C.
S12
TLC: Rf = 0.50 (EtOAc-pentane = 1:1) [UV, CAM].
IR (ATR): ν̃ (cm-1
) = 2967 (w), 2924 (w), 1746 (m, C=O), 1682 (s, C=O), 1593 (w), 1493
(m), 1391 (m), 1366 (m), 1229 (s, C−O), 1088 (m), 1022 (m), 755 (s).
1H-NMR (500 MHz CDCl3): δ (ppm) = 0.61 (t,
3J = 7.6 Hz, 3 H, H-2´´), 0.93 (t,
3J = 7.3 Hz,
3 H, H-2´), 1.03 (dq, 2J = 15.0 Hz,
3J = 7.6 Hz, 1 H, H-1´´), 1.12 (dq,
2J = 15.0 Hz,
3J = 7.8 Hz, 1 H, H-1´´), 1.63-1.75 (m, 2 H, H-1´), 2.10 (s, 3 H, H-2´´´), 2.38 (d,
2J = 14.0 Hz,
1 H, H-2u), 2.50 (dd,
2J = 14.0 Hz,
4J = 1.2 Hz, 1 H, H-2
d), 3.47 (s, 1 H, H-8b), 6.47 (d,
3J = 7.6 Hz, 1 H, H-5), 6.93-7.01 (m, 2 H, H-7, H-8), 7.14 (td,
3J = 7.6 Hz,
4J = 2.2 Hz, 1 H,
H-6), 8.14 (s, 1 H, H-4).
13C-NMR (91 MHz, CDCl3): δ (ppm) = 7.3 (q, C-2´´), 8.2 (q, C-2´), 20.8 (q, C-2´´´), 25.5 (t,
C-1´´), 32.4 (t, C-1´), 40.4 (s, C-1), 42.5 (t, C-2), 53.2 (d, C-8b), 71.7 (s, C-2a), 115.6 (d, C-
5), 121.4 (s, C-8a), 123.4 (d, C-7), 127.6 (d, C-6), 128.6 (d, C-8), 136.7 (s, C-4a), 169.3 (s, C-
3), 170.7 (s, C-1´´´).
MS (EI, 70 eV) m/z (%) = 287 (1) [M+], 228 (5), 203 (6) [(C11H9NO3)
+], 195 (6), 162 (8), 161
(100) [(C9H6NO2)+], 152 (6), 86 (15), 84 (25), 49 (17).
HRMS (EI): C17H21NO3: calc.: [M+]: 287.1516
found: [M+]: 287.1519.
Chiral HPLC: tR [racemate] = 16.4 min, 21.1 min; tR [3c] = 16.9 min, tR [ent-3c] = 21.8 min,
79% ee (AD-H, 250 × 4.6 mm, n-hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −182.4 (c = 0.21, MeOH).
S13
(2aR,8bR)-1,1,2,2-Tetramethyl-3-oxo-1,3,4,8b-tetrahydrocyclobuta[c]quinolin-2a(2H)-yl
acetate (3d)
Racemic procedure:
Using the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.) and
2,3-dimethyl-2-butene 5d (100 µL, 83.0 mg, 984 µmol, 20 equiv.) in acetonitrile (10 mL) was
irradiated for three hours. Purification of the crude product by flash column chromatography
on silica (∅ 18 × 1.5 cm) eluting with EtOAc-pentane (2:3) gave the title product 3d
(14.5 mg, 49.0 µmol, quant.) as colourless solid.
Enantioselective procedure:
Following the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.),
template 6 (44.0 mg, 123 µmol, 2.5 equiv.) and 2,3-dimethyl-2-butene 5d (100 µL, 83.0 mg,
984 µmol, 20 equiv.) in toluene (10 mL) was irradiated for three hours. Purification of the
crude product by flash column chromatography on silica (∅ 18 × 1.5 cm) eluting with
EtOAc-pentane (2:3) gave the title product 3d (14.2 mg, 49.0 µmol, quant.) as colourless
solid.
S14
m.p.: 182 °C.
TLC: Rf = 0.65 (EtOAc-pentane = 1:1) [UV, CAM].
IR (ATR): ν̃ (cm-1
) = 2991 (w), 1738 (m, C=O), 1677 (s, C=O), 1595 (m), 1495 (m), 1366
(br), 1242 (br, C−O), 1118 (m), 1037 (m), 746 (s).
1H-NMR (500 MHz, CDCl3): δ (ppm) = 0.68 (s, 3 H, H-1´´´), 1.09 (s, 3 H, H-2´´´), 1.22 (s,
3 H, H-1´´), 1.31 (s, 3 H, H-2´´), 2.08 (s, 3 H, H-2´), 3.36 (s, 1 H, H-8b), 6.70 (dd,
3J = 7.5 Hz,
4J = 1.2 Hz, 1 H, H-5), 6.90 (dd,
3J = 7.5 Hz,
4J = 1.5 Hz, 1 H, H-8), 6.98 (td,
3J = 7.5 Hz,
4J = 1.2 Hz, 1 H, H-7), 7.15 (td,
3J = 7.5 Hz,
4J = 1.5 Hz. 1 H, H-6), 7.76 (s, 1 H,
H-4).
13C-NMR (91 MHz, CDCl3): δ (ppm) = 20.9 (q, C-1´´´), 20.9 (q, C-2´), 21.4 (q, C-2´´´), 21.6
(q, C-2´´), 26.6 (q, C-1´´), 41.2 (s, C-1), 46.6 (s, C-2), 53.0 (d, C-8b), 78.2 (s, C-2a), 115.3 (d,
C-5), 122.0 (s, C-8a), 123.3 (d, C-7), 127.5 (s, C-6), 127.9 (d, C-8), 136.5 (s, C-4a), 167.0 (s,
C-3), 170.6 (s, C1).
MS (EI, 70 eV) m/z (%) = 287 (7) [M+], 227 (7) [(M-C2H4O2)
+], 212 (8), 204 (25), 162 (30),
161 (100) [(C9H6NO2)+], 86 (23), 84 (35).
HRMS (EI): C17H21NO3: calc.: [M+]: 287.1516
found: [M+]: 287.1522.
Chiral HPLC: tR [racemate] = 12.6 min, 15.7 min; tR [3d] = 13.1 min, tR [ent-3d] = 16.4 min;
55% ee (AD-H, 250 × 4.6 mm, n-hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −84.2 (c = 0.60, MeOH).
S15
(2aS,8bR)-1,1-Diethoxy-3-oxo-1,3,4,8b-tetrahydrocyclobuta[c]quinolin-2a(2H)-yl acetate
(3e)
Racemic procedure:
Using the general procedure a solution of quinolone 4 (120 mg, 591 µmol, 1.0 equiv.) and
1,1-diethoxyethene 5e (1.56 mL, 1.37 g, 11.8 mmol, 20 equiv.) in acetonitrile (120 mL) was
irradiated for two hours. Purification of the crude product by flash column chromatography on
silica (∅ 25 × 3 cm) eluting with EtOAc-pentane (3:2) gave the title product 3e (133 mg,
416 µmol, 70%) as colourless solid.
Enantioselective procedure:
Following the general procedure a solution of quinolone 4 (10.0 mg, 49.0 µmol, 1.0 equiv.),
template 6 (44.0 mg, 123 µmol, 2.5 equiv.) and 1,1-diethoxyethene 5e (130 µL, 114 mg,
984 µmol, 20 equiv.) in toluene (10 mL) was irradiated for three hours. Purification of the
crude product by flash column chromatography on silica (∅ 18 × 1.5 cm) eluting with
EtOAc-pentane (3:7 → 1:1) gave the title compound 3e (10.5 mg, 33.0 µmol, 67%) as
colourless solid. The mixture of template 6 and quinolone 4 can be separated by a second
flash column chromatography on silica (∅ 20 × 3 cm) eluting with CH2Cl2-pentane-MeOH
(29:70:1).
S16
m.p.: 194 °C.
TLC: Rf = 0.41 (EtOAc-pentane = 1:1) [UV, CAM].
IR (ATR): ν̃ (cm-1
) = 3194 (w), 3059 (w, NH), 2925 (w), 1747 (s, C=O), 1681 (br, C=O),
1595 (m), 1496 (m), 1401 (m), 1263 (m, C−O), 1237 (s), 1090 (m), 1063 (s), 1041 (s),
765 (s).
1H-NMR (250 MHz, CDCl3): δ (ppm) = 0.88 (t,
3J = 7.5 Hz, 3 H, H-2´´´), 1.24 (t,
3J = 7.5 Hz, 3 H, H-2´´), 2.08 (s, 3 H, H-2´), 2.81 (dd,
2J = 13.7 Hz,
4J = 1.5 Hz, 1 H, H-2
d),
2.84 (d, 2J = 13.7 Hz, 1 H, H-2
u), 3.14-3.20 (m, 1 H, H-1´´´), 3.29-3.35 (m, 1 H, H-1´´´), 3.47-
3.53 (m, 1 H, H-1´´), 3.55-3.61 (m, 1 H, H-1´´), 3.85 (s, 1 H, H-8b), 6.75 (d, 3J = 7.5 Hz, 1 H,
H-5), 6.98 (t, 3J = 7.5 Hz, 1 H, H-7), 7.08 (d,
3J = 7.5 Hz, 1 H, H-8), 7.17 (td,
3J = 7.5 Hz,
4J = 1.6 Hz 1 H, H-6), 8.30 (s, 1 H, H-4).
13C-NMR (63 MHz, CDCl3): δ (ppm) = 15.1 (q, C-2´´´), 15.2 (q, C-2´´), 20.6 (q, C-2´), 44.2
(t, C-2), 56.8 (d, C-8b), 57.2 (t, C-1´´), 57.7 (t, C-1´´´), 69.0 (s, C-2a), 97.4 (s, C-1), 115.5 (d,
C-5), 119.4 (s, C-8a), 123.3 (d, C-7), 127.9 (d, C-6), 128.6 (d, C-8), 137.5 (s, C-4a), 168.3 (s,
C-3), 170.5 (s, C-1´).
MS (EI, 70 eV): m/z (%) = 319 (1) [M+], 260 (40) [(C15H18NO3)
+], 232 (10), 186 (65)
[(C11H8NO2)+], 161 (20), 159 (25), 158 (100), 130 (15), 116 (15), 89 (15), 84 (20).
HRMS (EI) C17H21NO5: calc.: [M+]: 319.1414
found: [M+]: 319.1419.
Chiral HPLC: tR [racemate] = 8.56 min, 28.2 min; tR [ent-3e] = 8.91 min, tR [3e] = 27.9 min;
95% ee (AS-H, 250 × 4.6 mm, n-hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −155 (c = 0.53, MeOH).
S17
(2aS,8bR)-1-((tert-Butyldimethylsilyl)oxy)-1-methoxy-3-oxo-1,3,4,8b-tetrahydrocyclo-
buta[c]quinolin-2a(2H)-yl acetate (3f)
Racemic procedure:
Using the general procedure a solution of quinolone 4 (170 mg, 837 µmol, 1.0 equiv.) and
tert-butyl-[(1-methoxyvinyl)oxy]-dimethylsilane 5f (3.40 mL, 16.7 mmol, 20 equiv.) in
acetonitrile (170 mL) was irradiated for three hours. Before purification the residual olefin
should be decomposed by addition of MeOH. Purification of the crude product by flash
column chromatography on silica (∅ 25 × 4 cm) eluting with EtOAc-pentane (1:4) gave the
title compound 3f (193 mg, 492 µmol, 59%) as colourless solid in a diastereomeric mixture
62:38 (by 1H-NMR spectroscopy).
Enantioselective procedure:
Following the general procedure a solution of quinolone 4 (50.0 mg, 246 µmol, 1.0 equiv.),
template 6 (217 mg, 615 µmol, 2.5 equiv.) and tert-butyl-[(1-methoxyvinyl)oxy]-
dimethylsilane 5f (1.00 mL, 492 mmol, 20 equiv.) in toluene (50 mL) was irradiated for
twelve hours at −70 °C. Before purification the residual olefin should be decomposed with
MeOH. Purification of the crude product by flash column chromatography on silica
(∅ 20 × 2 cm) eluting with EtOAc-pentane (2:3) gave the title compound 3f (93.5 mg,
239 µmol, 97%) as colourless solid in a diastereomeric mixture 71:29 (by 1H-NMR
spectroscopy).
m.p.: 98 °C.
TLC: Rf = 0.59 (EtOAc-pentane = 1:1) [UV, CAM].
S18
IR (ATR): ν̃ =3214 (w, NH), 2956 (m), 2928 (m, CH), 1742 (m, C=O), 1671 (s), 1595 (w),
1492 (w), 1372 (w), 1241 (m, C−O), 1197 (w), 1132 (w), 1122 (w), 1093 (w), 1071 (m), 838
(m), 754 (m).
Major isomer:
1H-NMR (360 MHz, CDCl3): δ (ppm) = 0.18 [s, 3 H, Si(CH3)(CH3)], 0.20 [s, 3 H,
Si(CH3)(CH3)], 0.95 [s, 9 H, SiC(CH3)3], 2.09 (s, 3 H, H-2´), 2.87 (dd, 2J = 13.5 Hz,
4J = 2.2 Hz, 1 H, H-2
d), 2.93 (s, 3 H, OCH3) 3.06 (d,
2J = 13.5 Hz, 1 H, H-2
u), 3.82 (s, 1 H,
H-8b), 6.73 (d, 3J = 8.1 Hz, 1 H, H-5), 6.97-7.02 (m, 1 H, H-7), 7.11 (d,
3J = 7.7 Hz, 1 H,
H-8), 7.17-7.21 (m, 1 H, H-6), 7.80 (br s, 1 H, NH).
13C-NMR (63 MHz, CDCl3): δ (ppm) = −3.2 [q, Si(CH3)(CH3)], −2.9
[q, Si(CH3)(CH3)], 18.2 [s, SiC(CH3)3], 20.7 (q, C-2´), 25.8 [q, SiC(CH3)2], 47.6
(t, C-2), 50.2 (q, OCH3), 59.8 (d, C-8b), 68.9 (s, C-2a), 96.3 (s, C-1), 115.7 (d, C-5), 119.2 (s,
C-8a), 123.2 (d, C-7), 128.2 (d, C-6), 128.5 (d, C-8), 137.1 (s, C-4a), 168.1
(s, C-3), 170.5 (s, C-1´).
Minor isomer:
S19
13C-NMR (63 MHz, CDCl3): δ (ppm) = −3.6 [q, Si(CH3)(CH3)], −3.4
[q, Si(CH3)(CH3)], 17.8 [s, SiC(CH3)3], 20.7 (q, C-2´), 25.3 [q, SiC(CH3)3], 48.6
(t, C-2), 49.7 (q, OCH3), 56.7 (d, C-8b), 69.0 (s, C-2a), 96.4 (s, C-1), 115.6 (d, C-5), 119.4 (s,
C-8a), 123.3 (d, C-7), 127.7 (d, C-6), 129.1 (d, C-8), 136.8 (s, C-4a), 168.0 (s, C-3), 170.7 (s,
C-1´).
MS (EI, 70 eV): m/z (%) = 332 (100) [(M-OAc)+], 274 (30) [(C14H12NO5)
+], 216 (30), 185
(81), 158 (59) [(C9H4NO2)+], 129 (43), 89 (73), 75 (75), 43 (97) [(C2H3O)
+].
HRMS (EI): C18H26NO3Si calc.: [(M-OAc)+]: 332.1676
found: [(M-OAc)+]: 332.1673.
Chiral HPLC: tR [racemate] = 10.1 min, 12.1 min, 16.8 min, 22.4 min; tR [3f] = 10.1 min,
16.9 min, tR [ent-3f] = 12.1 min, 22.5 min; 88% ee, 95% ee, (AD-H, 250 × 4.6 mm, n-
hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm, 254 nm).
Specific rotation: [α]D20
= −136 (c = 0.48, CH2Cl2).
For product 3f different conditions were tested (chart 1).
chart 1: Dependence of temperature and solvent for yield, diastereomeric ratio and enantiomeric excess.
entry solvent temp [°C] yield [%] d.r. ee
1a tol r.t. 65 62:38 26%, 27%
2a tol − 74 62 69:31 88%, 89%
3b tol − 70 97 71:29 88%, 95%
4a PhCF3 − 20 58 70:30 56%, 60%
5a MeCN − 40 92 66:34 0%, 0%
6a THF − 70 52 57:43 2%, 6%
7a EtOAc − 70 72 58:42 17%, 18%
8a MeOH − 70 23 67:33 6%, 3%
a: reaction was performed for three hours at λ = 366 nm; b: reaction was performed for twelve hours at λ = 366 nm.
S20
(2aS,8bR)-1-((tert-Butyldimethylsilyl)oxy)-1-methoxy-4-methyl-3-oxo-1,3,4,8b-tetra-
hydrocyclobuta[c]quinolin-2a(2H)-yl acetate (9)
Racemic procedure:
Photoproduct 3f (555 mg, 1.42 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled
to 0 °C. At this temperature sodium hydride (62.3 mg, 60%, 1.55 mmol, 1.1 equiv.) was
added and the mixture was allowed to stir for 30 minutes. After that period of time methyl
iodide (0.44 mL, 1.02 g, 7.08 mmol, 5.0 equiv.) was added dropwise. The mixture was
allowed to warm up to room temperature over night. The solvent was removed under reduced
pressure. Purification by flash column chromatography on silica (∅ 30 × 4 cm) eluting with
EtOAc-pentane (1:9→1:1) gave the title compound 9 (425 mg, 1.05 mmol, 74%) as
colourless oil in a diastereomeric mixture 62:38 (by 1H-NMR spectroscopy).
Enantioselective procedure:
In analogue way photoproduct 3f of enantioselective photoreaction was realized in a scale of
761 µmol. So quinolone 9 (167 mg, 412 µmol, 54%) was isolated as colourless oil in a
diastereomeric mixture 74:26 (by 1H-NMR spectroscopy).
TLC: Rf = 0.69 (EtOAc-pentane = 3:2) [UV, CAM].
IR (ATR): ν̃ = 2953 (m, C-H), 2854 (w, C-H), 1735 (s, C=O), 1644 (br, C=O), 1599 (m),
1472 (m), 1372 (w), 1230 (br, C−O), 759 (m).
S21
Major isomer:
1H-NMR (250 MHz, CDCl3): δ (ppm) = 0.17 [s, 3 H, Si(CH3)(CH3)], 0.18 [s, 3 H,
Si(CH3)(CH3)], 0.95 [s, 9H, Si(CH3)3], 2.05 (s, 3 H, H-2´), 2.88 (s, 3 H, OCH3), 2.89 (d,
2J = 2.1 Hz, 1 H, H-2
u), 3.02 (d,
4J = 13.7 Hz, 1 H, H-2
d), 3.40 (s, 3 H, NCH3), 3.78 (s, 1 H,
H-8b), 6.96-7.00 (m, 1 H, H-5), 7.01-7.05 (m, 1 H, H-7), 7.11 (dd, 3J = 7.4 Hz,
4J = 1.7 Hz, 1
H, H-8), 7.23-7.31 (m, 1 H, H-6).
13C-NMR (63 MHz, CDCl3): δ (ppm) = −3.2 [q, Si(CH3)(CH3)], −3.0 [q, C-Si(CH3)(CH3)],
18.2 [s, SiC(CH3)3], 20.7 (q, C-2´), 25.8 [q, SiC(CH3)3], 30.1 (q, NCH3), 48.2 (t, C-2), 50.3
(q, OCH3), 59.1 (d, C-8b), 68.6 (s, C-2a), 96.0 (s, C-1), 114.8 (d, C-5), 120.5 (s, C-8a), 123.1
(d, C-7), 128.2 (d, C-6), 128.5 (d, C-8), 140.2 (s, C-4a), 167.7 (s, C-3), 170.5 (s, C-1´).
Minor isomer:
u
d1
3
4a
7 1´8b
N O
H
O
O OTBS
O
H
H
13C-NMR (63 MHz, CDCl3): δ (ppm) = −3.6 [q, Si(CH3)(CH3)], −3.5 [q, Si(CH3)(CH3)], 17.8
[s, SiC(CH3)3], 20.7 (q, C-2´), 25.3 [q, SiC(CH3)3], 30.0 (q, NCH3), 49.1 (t, C-2), 49.8 (q,
OCH3), 56.1 (d, C-8b), 68.5 (s, C-2a), 96.0 (s, C-1), 114.7 (d, C-5), 120.6 (s, C-8a), 123.1 (d,
C-7), 127.6 (d, C-6), 129.0 (d,C-8), 139.8 (s, C-4a), 167.6 (s, C-3), 170.7 (s, C-1´).
S22
MS (EI, 70 eV): m/z (%) = 346 (100) [(M-C2H3O2)+], 231 (57), 216 (52) [(C12H10NO3)
3+],
200 (66) [(C12H10NO2)2+
], 199 (77), 175 (54), 172 (96), 89 (44), 75 (66), 73 (36), 57 (20), 44
(36).
HRMS (EI): C19H28O3NSi calc.: [(M-OAc)+]: 346.1833
found: [(M-OAc)+]: 346.1836.
Specific rotation: [α]D20
= −146 (c = 0.64, CH2Cl2).
(2aS,8bR)-1-((tert-Butyldimethylsilyl)oxy)-2a-hydroxy-1-methoxy-4-methyl-2,2a,4,8b-
tetrahydrocyclobuta[c]quinolin-3(1H)-one (10)
Racemic procedure:
Quinolone 9 (458 mg, 1.13 mmol 1.0 equiv.) was dissolved in ethanol (38 mL) and potassium
cyanide (36.7 mg, 569 µmol, 0.5 equiv.) was added. The mixture was stirred for six hours at
80 °C. The solvent was removed under reduced pressure. Purification of the crude product by
flash column chromatography on silica (∅ 25 × 3 cm) eluting with EtOAc-pentane (1:9→1:4)
gave the title compound 10 (398 mg, 1.10 mmol, 97%) as colourless oil in a diastereomeric
mixture 67:33 (by 1H-NMR spectroscopy).
Enantioselective procedure:
In analogue way quinolone 9 was used as starting material in a scale of 354 µmol. On that
way quinolone 10 (129 mg, 354 µmol, quant.) was isolated as colourless oil in a
diastereomeric mixture 70:30 (by 1H-NMR spectroscopy).
S23
TLC: Rf = 0.63 (pentane-EtOAc = 1:1) [UV, CAM].
IR (ATR): ν̃ = 3372 (b, OH), 2926 (m, C-H), 1791 (m, C=O), 1733 (m), 1637 (s, C=O), 1597
(s), 1466 (m), 1383 (w), 1273 (w), 1247 (w, C−O), 1222 (w), 1207 (w), 754 (m).
Major isomer:
1H-NMR (500 MHz, CDCl3): δ (ppm) = 0.18 [s, 6 H, Si(CH3)2] 0.95 [s, 9 H, SiC(CH3)3],
2.58 (dd, 2J = 12.5 Hz,
4J = 1.6 Hz, 1 H, H-2
d), 2.88 (s, 3 H, NCH3), 3.02 (d,
2J = 12.5 Hz,
1 H, H-2u), 3.40 (s, 3 H, OCH3), 3.82 (s, 1 H, H-8b), 6.95-6.99 (m, 1 H, H-5), 7.00-7.05 (m,
1 H, H-7), 7.19 (dd, 3J = 7.5 Hz,
4J = 1.7 Hz, 1 H, H-8), 7.25-7.32 (m, 1 H, H-6).
13C-NMR (126 MHz, CDCl3): δ (ppm) = −3.1 [q, Si(CH3)(CH3)], −3.0 [q, Si(CH3) (CH3)],
18.2 [s, SiC(CH3)3], 25.8 [q, SiC(CH3)3], 29.9 (q, NCH3), 50.4 (q, OCH3), 50.6 (t, C-2), 57.6
(d, C-8b), 65.4 (s, C-2a), 95.5 (s, C-1), 114.8 (d, C-5), 119.9 (s, C-8a), 123.4 (d, C-7), 128.4
(d, C-6), 129.9 (d, C-8), 139.9 (s, C-4a), 171.2 (s, C-3).
Minor isomer:
u
d1
3
4a
7 8b
N O
H
OH
O OTBS
H
H
13C-NMR (126 MHz, CDCl3): δ (ppm) = −3.7 [q, Si(CH3)(CH3)], −3.5 [q, Si(CH3)(CH3)],
17.8 [s, SiC(CH3)3], 25.4 [q, SiC(CH3)3], 29.9 (q, NCH3), 50.0 (q, OCH3), 52.4 (t, C-2), 54.3
S24
(d, C-8b), 65.2 (s, C-2a), 96.4 (s, C-1), 114.6 (d, C-5), 120.2 (s, C-8a), 123.3 (d, C-7), 127.9
(d, C-6), 130.7 (d, C-8), 139.4 (s, C-4a), 171.2 (s, C-3).
MS (EI, 70 eV): m/z (%) = 232 (9) [(M-OTBDMS)+], 231 (19), 216 (23) [(C13H13NO2)
+], 175
(100) [(C10H9NO2)2+
], 172 (13), 147 (26), 118 (9), 89 (6), 77 (6).
HRMS (EI): C13H13NO3 calc.: [(M-C6H16OSi)+]: 231.0895
found: [(M-C6H16OSi)+]: 231.0890.
Chiral HPLC: tR [racemate] = 9.14 min, 10.1 min, 22.0 min, 39.9 min; tR [ent-10] =
9.07 min, 39.8 min, tR [10] = 9.88 min, 21.6 min; 93% ee, 85% ee (AD-H, 250 × 4.6 mm, n-
hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −121 (c = 0.86, CH2Cl2).
(3aS,9bR)-3a-Hydroxy-5-methyl-3,3a,5,9b-tetrahydrofuro[3,2-c]quinoline-2,4-dione (2)
Racemic procedure:
Quinolone 10 (80.0 mg, 0.22 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (6 mL) and cooled
down to 0 °C. At this temperature boron trifluoride diethyl etherate (27.8 µL, 31.2 mg,
0.22 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred for 30 minutes and
afterwards meta-chloroperoxybencoic acid (59.7 mg, 70%, 0.24 mmol, 1.1 equiv.) was added.
The mixture was allowed to warm up to room temperature over night. The solvent was
removed under reduced pressure and purification by flash column chromatography on silica
S25
(∅ 20 × 3 cm) eluting with EtOAc-pentane (3:7) gave the title product 2 (38.9 mg,
0.17 mmol, 76%) as colourless solid.
Enantioselective procedure:
In analogue way quinolone 10 was used as starting material in a scale of 0.22 mmol. Lactone
2 (58.2 mg, 250 µmol, 75%) was isolated as colourless solid. At this step the product was
purified by semipreparative HPLC (n-hexane/i-PrOH = 50:50, 15 mL/min, 70 min,
λ = 215 nm) to get a clean product with an enantiomeric excess of ≥ 99% ee.
m.p.: 191 °C.
TLC: Rf = 0.28 (pentane-EtOAc = 1:1) [UV, CAM].
IR (ATR): ν̃ = 3351 (b, OH), 3075 (w), 2925 (w, C-H), 1785 (s, C=O), 1644 (s, C=O), 1600
(s), 1469 (m), 1382 (m), 1167 (m, C−O), 1085 (m), 1001 (m), 761 (m).
1H-NMR (360 MHz, CDCl3): δ (ppm) = 2.68 (dd,
2J = 17.2 Hz,
4J = 1.2 Hz, 1 H, H-3
d), 2.76
(d, 2J = 17.2 Hz, 1 H, H-3
u), 3.47 (s, 3 H, NCH3), 4.26 (s, 1 H, OH), 5.69 (d,
4J = 1.2 Hz, 1 H,
H-9b), 7.07 (d, 3J = 7.5 Hz, 1 H, H-6), 7.21-7.23 (m, 1 H, H-8), 7.43 (td,
3J = 7.5 Hz,
4J = 0.7 Hz, 1 H, H-7), 7.54 (d,
3J = 7.5 Hz, 1 H, H-9).
13C-NMR (91 MHz, CDCl3): δ (ppm) = 30.5 (q, NCH3), 41.5 (t, C-3), 74.9 (s, C-3a), 82.3 (d,
C-9b), 115.2 (d, C-6), 121.0 (s, C-9a), 125.1 (d, C-8), 129.5 (d, C-9), 130.9 (d, C-7), 136.7 (s,
C-5a), 168.4 (s, C-4), 172.8 (s, C-2).
MS (EI, 70eV): m/z (%) = 233 (25) [M+], 215 (9), 187 (6) [(C11H9NO2)
+], 160 (8), 146 (12)
[(C9H8NO)2+
], 70 (11), 61 (14), 45 (12), 43 (100) [(CO2)2+
].
S26
HRMS (EI): C12H11NO4 calc.: [M+]: 233.0688
found: [M+]: 233.0683.
Chiral HPLC: tR [racemate] = 6.90 min, 9.60 min; tR [ent-2] = 9.60 min, tR [2] = 6.91 min,
87% ee (AD-H, 250 × 4.6 mm, n-hexane/i-PrOH = 50:50, 1mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −137 (c = 0.36, CH2Cl2).
(3aS,9bR)-2,3a-Dihydroxy-5-methyl-3,3a,5,9b-tetrahydrofuro[3,2-c]quinolin-4(2H)-one
(11)
Racemic procedure:
Lactone 2 (40.0 mg, 172 µmol, 1.0 equiv.) was dissolved in CH2Cl2 (6 mL) and cooled down
to −78 °C. At this temperature di-iso-butylaluminium hydride (257 µL, 1 M in CH2Cl2,
257 µmol, 1.5 equiv.) was added dropwise. The mixture was stirred for one hour and
afterwards di-iso-butylaluminium hydride (257 µL, 1 M in CH2Cl2, 257 µmol, 1.5 equiv.) was
added again. After a further hour MeOH (4 mL) was added and the mixture was warmed to
room temperature. At room temperature saturated sodium-potassium-tartrate solution (6 mL)
was added and the mixture was stirred for one hour. Finally saturated sodium chloride
solution (6 mL) was added. The mixture was extracted with CH2Cl2 (4 × 10 mL). The
combined organic phases were dried over sodium sulfate and filtered. The solvent was
removed under reduced pressure. Purification by flash column chromatography on silica
(∅ 12 × 1.5 cm) with a dryload on celite eluting with EtOAc-pentane (3:7→1:1) gave the title
compound 11 (24.6 mg, 105 µmol, 61%) as colourless oil.
S27
Enantioselectiv procedure:
In analogue way lactone 2 was used as starting material in a scale of 126 µmol. Lactole 11
(17.9 mg, 75.9 µmol, 60%) was isolated as colourless oil.
TLC: Rf = 0.14 (P/EtOAc = 1/1) [UV, CAM].
IR (ATR): ν̃ = 3392 (b, OH), 2928 (m, C-H), 1662 (s, C=O), 1604 (s), 1475 (m),
1129 (w).
1H-NMR (360 MHz, CDCl3): δ (ppm) = 2.10-2.27 (m, 2H, H-3), 3.44 (s, 3H, H-NCH3), 4.12
(brs, 1H, H-=H), 4.46 (brs, 1H, H-OH), 5.41-5.44 (m, 2H, H-2, H-9b), 6.99
(dd, 3J = 7.7 Hz,
4J = 1.2 Hz, 1H, H-6), 7.17 (td,
3J = 7.7 Hz,
4J = 1.2 Hz, 1H, H-8), 7.34 (td,
3J = 7.7 Hz,
4J = 1.5 Hz, 1H. H-7), 7.56 (dd,
3J = 7.7 Hz,
4J = 1.5 Hz, 1H, H-9).
13C-NMR (91 MHz, CDCl3): δ (ppm) = 30.3 (q, NCH3), 45.6 (t, C-3), 77.8 (d, C-9b), 81.2 (s,
C-3a), 98.4 (d, C-2), 114.6 (d, C-6), 124.6 (s, C-9a), 125.1 (d, C-8), 128.7
(d, C-9), 129.5 (d, C-7), 136.1 (s, C-5a), 170.3 (s, C-4).
MS (EI,70 eV): m/z (%) = 235 (6) [M+], 146 (6) [(C9H8NO)
2+] , 100 (13), 84 (95), 82 (26), 66
(100), 48 (13), 46 (20).
HRMS (EI): C12H13NO4 calc.: [M+]: 235.0845
found: [M+]: 235.0839.
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(3S,4R)-3,4-Dihydroxy-1-methyl-3-(3-methylbut-2-en-1-yl)-3,4-dihydroquinolin-2(1H)-
one (1)
Racemic procedure:
In a first step triphenyl-iso-propylphosphoniumbromide (167 mg, 434 µmol, 10 equiv.) was
suspended in THF (4 mL) and n-butyllithium (0.17 mL, 2.5 M in hexane, 434 µmol,
10 equiv.) was added slowly and the mixture was stirred for 30 minutes. To that mixture
lactole 11 (10.2 mg, 43.4 µmol, 1.0 equiv.) dissolved in THF (4 mL) was added dropwise at
0 °C. The mixture was stirred for three hours and finally quenched by addition of EtOAc
(4 mL). The crude product was purified by flash column chromatography on silica
(∅ 20 × 1.5 cm) with a dryload on celite eluting with EtOAc-pentane (1:2). So natural
product 1 (5.67 mg, 21.7 µmol, 50%) was isolated as colourless oil.
In analogue way lactole 11 was used as starting material in a scale of 42.5 µmol. Natural
product 1 (6.00 mg, 23.0 µmol, 55%) was isolated as colourless oil.
TLC: Rf = 0.76 (EtOAc) [UV, CAM].
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IR (ATR): ν̃ = 3414 (b, OH), 2960 (m), 2924 (s, C-H), 2850 (m, C-H), 1665 (s, C=O), 1605
(m), 1469 (w), 1376 (w), 1119 (m), 1045 (w), 756 (w).
1H-NMR (360 MHz, CDCl3): δ (ppm) = 1.41 (s, 3H, H-4´
*), 1.64 (s, 3H, H-5´
*), 1.98 (dd,
2J = 14.8 Hz,
3J = 7.3 Hz, 1H, H-1´β), 2.47 (dd,
2J = 14.8 Hz,
3J = 8.2 Hz, 1H, H-1´α), 2.69
(d, 3J = 3.4 Hz, 1H, 4-OH), 3.39 (s, 3H, NCH3), 3.92 (s, 1 H, 3-OH) 4.98-5.06 (m, 2H,H-2´,
H-4), 6.99 (d, 3J = 7.6 Hz, 1H, H-8), 7.19 (td,
3J = 7.6 Hz,
4J = 1.4 Hz, 1H, H-6), 7.34 (t,
3J = 7.6 Hz, 1H, H-7), 7.61 (dt,
3J = 7.6 Hz,
4J = 1.4 Hz, 1H, H-5).
13C-NMR (126 MHz, CDCl3): δ (ppm) = 17.8 (q, C-5´), 26.1 (q, C-4´), 28.8 (t, C-1´), 30.4 (q,
NCH3), 72.8 (d, C-4), 76.1 (s, C-3), 114.4 (d, C-8), 117.0 (d, C-2´), 124.3 (d, C-6), 125.1 (d,
C-5), 127.4 (s, C-4a), 128.7 (d, C-7), 136.5 (s, C-3´), 137.3 (s, C-8a), 172.3 (s, C-2).
* commutable signals.
MS (EI,70 eV): m/z (%) = 261 (4) [M+], 226 (66) [(C15H16NO)
2+], 192 (20)
[(M-C5H9)+], 176 (23), 175 (32), 174 (41) [(M-C5H10O)
+], 146 (58) [(M-C6H14O2)
+], 109 (45),
85 (43), 69 (55) [(C5H9)+], 57 (50), 55 (37), 43 (100) [(C3H6)
+].
HRMS (EI): C15H19NO3 calc.: [M+]: 261.1365
found: [M+]: 261.1359.
Chiral HPLC: tR [racemate] = 11.2 min, 15.1 min; tR [ent-1] = 11.1 min, tR [1] = 15.0 min;
99% ee (AD-H, 250 × 4.6 mm, n-hexane/i-PrOH = 90:10, 1 mL/min, λ = 210 nm).
Specific rotation: [α]D20
= −6.34 (c = 0.16, CHCl3).
The analytical data are in agreement with the literature (see next page).[3]
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Comparison of Analytical Data (natural product/synthetic material)
chart 2: Comparison between literature data and measured data for 1H-NMR in CDCl3.
1H assignment natural product
[3] [ppm] synthetic material [ppm]
H-5 7.61 (d, J = 7.7 Hz) 7.61 (dt, J = 7.6, 1.4 Hz)
H-7 7.34 (t, J = 7.7 Hz) 7.34 (t, J = 7.6 Hz)
H-6 7.19 (t, J = 7.7 Hz) 7.19 (td, J = 7.6, 1.4 Hz)
H-8 6.99 (d, J = 7.7 Hz) 6.99 (d, J = 7.6 Hz)
H-2´ 5.03 (overlapped with H-4) 4.98-5.06 (m, H-2´, H-4)
H-4 5.01 (overlapped with H-2´) 4.98-5.06 (m, H-2´, H-4)
3-OH 3.93 (br s) 3.92 (s)
N-CH3 3.39 (s) 3.39 (s)
4-OH 2.70 (br s) 2.69 (d, J = 3.4 Hz)
H-1´ 2.47 (dd, J = 14.7, 8.1 Hz) 2.47 (dd, J = 14.8, 8.2 Hz, H-1α´)
H-1´ 1.98 (dd, J = 14.7, 7.3 Hz) 1.98 (dd, J = 14.8, 7.3 Hz, H-1β´)
3´-CH3 1.64 (s) 1.64 (s)
3´-CH3 1.41 (s) 1.41 (s)
chart 3: Comparison between literature data and measured data for 13C-NMR in CDCl3.
13C assignment natural product
[3] [ppm] synthetic material [ppm]
C-2 172.2 (s) 172.3 (s)
C-8a 137.2 (s) 137.3 (s)
C-3´ 136.2 (s) 136.5 (s)
C-7 128.5 (d) 128.7 (d)
C-4a 127.3 (s) 127.4 (s)
C-5 125.0 (d) 125.1 (d)
C-6 124.2 (d) 124.3 (d)
C-2´ 116.9 (d) 117.0 (d)
C-8 114.2 (d) 114.4 (d)
C-3 75.9 (s) 76.1 (s)
C-4 72.7 (d) 72.8 (d)
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N-CH3 30.2 (q) 30.4 (q)
C-1´ 28.7 (t) 28.8 (t)
3´-CH3 25.9 (q) 26.1 (q, C-4´)
3´-CH3 17.6 (q) 17.8 (q, C-5´)
chart 4: Comparison between literature data and synthetic data for 1H-NMR in DMSO-d6.
1H assignment natural product
[3] [ppm] synthetic material [ppm]
H-5 7.38 (d, J = 7.8 Hz) 7.39 (d, J = 7.7 Hz)
H-7 7.28 (t, J = 7.8 Hz) 7.29 (td, J = 7.7, 1.6 Hz)
H-8 7.06 (d, J = 7.8 Hz) 7.06 (d, J = 7.7 Hz)
H-6 7.05 (t, J = 7.8 Hz) 7.07 (t, J = 7.7 Hz)
4-OH 5.65 (d, J = 4.8 Hz) 5.68 (d, J = 4.7 Hz)
3-OH 5.15 (br s) 5.20 (s)
H-2´ 5.04 (br t, J = 7.7 Hz) 5.06 (t, J = 7.4 Hz)
H-4 4.54 (d, J = 4.8 Hz) 4.55 (d, J = 4.7 Hz)
N-CH3 3.30 (s) 3.24 (s)
H-1´ 2.30 (dd, J = 15.0, 7.7 Hz) 2.32 (dd, J = 14.9, 7.4 Hz)
H-1´ 2.15 (dd, J = 15.0, 7.7 Hz) 2.16 (dd, J = 14.9, 7.4 Hz)
3´-CH3 1.55 (s) 1.56 (s)
3´-CH3 1.37 (s) 1.38 (s)
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2. References for the Supporting Information
1. F. Marsais, A. Godard, G. Queguiner, Journal of Heterocyclic Chemistry 1989, 26,
1589-1594.
2. K. Kobayashi, M. Suzuki, H. Suginome, The Journal of Organic Chemistry 1992, 57,
599-606.
3. C. Ito, M. Itoigawa, T. Otsuka, H. Tokuda, H. Nishino, H. Furukawa, Journal of
Natural Products 2000, 63, 1344-1348.
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3. NMR spectra of new compounds
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4. HPLC traces of racemic and enantioenriched products
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