Supporting information
For
A rapid three-component MgI2 mediated synthesis of 3,3-pyrollidinyl-spirooxindoles
Victoria Helan, Allie Mills, David Drewry, and Daniel Grant*
Exploratory Chemistry and Biology, GlaxoSmithKline, Five Moore Drive, Research Triangle
Park, NC 27709
[email protected]
Compound
1-methyl-spiro-3,3-cyclopropyl-indole-2-one 1
1-benzyl-5-methoxy-3,3-cyclopropyl-indole-2-one 2
(2'S*)-2’-(4-cyanophenyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'pyrrolidin]-2-one
2’-(4-cyanophenyl)-1-methyl-1'-[(4-methylphenyl)sulfonyl]spiro[indole-3,3'pyrrolidin]-2-one
2'-(3-chlorophenyl)-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'pyrrolidin]-2-one
(2'S*)-2'-(3-chlorophenyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'pyrrolidin]-2-one
2'-(3-chlorophenyl)-1-methyl-1'-[(4-methylphenyl)sulfonyl]spiro[indole-3,3'pyrrolidin]-2-one
2'-(2,2-dimethylpropyl)-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'pyrrolidin]-2-one
2'-(2,2-dimethylpropyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'pyrrolidin]-2-one
2'-phenyl-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'-pyrrolidin]-2one
(2'S*)-2'-phenyl-1-methyl-1'-(1-methylethylspiro [indole-3,3'-pyrrolidin]-2one
2'-phenyl 1-methyl-1'-[(4-methylphenyl)sulfonyl]spiro[indole-3,3'pyrrolidin]-2-one
2'-(3-furanyl)-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'pyrrolidin]-2-one
(2'S*)-2'-(3-furanyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'-pyrrolidin]2-one
(2'S*)-2’-(4-cyanophenyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2’-(4-cyanophenyl)-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2'-(3-chlorophenyl)-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(2'S*)-2'-(3-chlorophenyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2'-(3-chlorophenyl)-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(2'S*)-2'-(2,2-dimethylpropyl)-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
S-1
3
5
4b
Page
S-2
S-2
S-2
4c
S-3
4d
S-3
4e
S-3
4f
S-4
4g
S-4
4h
S-5
4j
S-5
4k
S-6
4l
S-6
4m
S-6
4n
S-7
6b
S-7
6c
S-7
6d
S-8
6e
S-8
6f
S-9
6g
S-9
(2'S*)-2'-(2,2-dimethylpropyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(2'R*)-2'-(2,2-dimethylpropyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2'-phenyl-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(2'S*)-2'-phenyl-1'-(1-methylethyl)-5-(methyloxy)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2'-phenyl-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2'-(3-furanyl)-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(2'S*)-2'-(3-furanyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
2'-(3-furanyl)-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one
References
Spectra
6ha
S-9
6hb
S-10
6j
S-10
6k
S-10
6l
S-11
6m
S-11
6n
S-12
6o
S-12
S-13
S-14-72
Table of reagents:
A
C
2-propanamine
4-methylbenzenesulfonamide
D
F
H
3,3-dimethylbutanal
benzaldehyde
3-chlorobenzaldehyde
Amine
B
4-(methyloxy)aniline
Aldehyde
E 3-furancarbaldehyde
G 4-formylbenzonitrile
General experimental: All monomers and solvents were obtained from commercial sources;
solvent used were anhydrous and stored under nitrogen atmosphere. NMR experiments were
performed at 400 MHz for 1H and 101 MHz for 13C, chemical shifts are reported relative to
residual solvent or TMS. The LCMS analysis was conducted using a 2x50mm 1.7m C18 column
at 40 °C, 0.5µL of sample was injected. The gradient employed was:
Mobile Phase A: Water + 0.20% v/v Formic Acid
Mobile Phase B: Acetonitrile + 0.15% v/v Formic Acid
Time
%A
%B
Flow Rate
0.00 min
95
5
1 ml/min
1.10 min
1
99
1 ml/min
1.50 min
1
99
1 ml/min
UV detection provided by summed absorbance signal from 210 to350nm scanning at 40Hz.
1-methyl-spiro-3,3-cyclopropyl-indole-2-one (3)1 and 1-benzyl-5-methoxy-3,3-cyclopropylindole-2-one (5).2 Both 3,3-cyclopropyl-indole-2-ones were synthesized from 1-methyl-2oxindole and 1-benzyl-6-methoxy-2-oxindole respectively according to the procedure described
by Alper and coworkers.3 Spectral data corresponded with those described in the literature.1,2
(2'S*)-2’-(4-cyanophenyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(4b): 3 (104 mg, 0.60 mmol), A (64 µL, 0.75 mmol), G (98 mg, 0.75 mmol) and magnesium
iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction
S-2
vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture
was analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as a brownyellow solid. (119.2 mg, 0.345 mmol, 57.5%); LCMS retention time: (2’S*,3S*)-diastereoisomer:
0.63 min;1H NMR (400 MHz, CHLOROFORM-d) δ = 7.29 (d, J = 8.8 Hz, 4 H), 7.15 (d, J = 8.2
Hz, 1 H), 7.09 (td, J = 1.2, 7.7 Hz, 1 H), 6.93 (td, J = 0.8, 7.5 Hz, 1 H), 6.54 (d, J = 7.6 Hz, 1 H),
4.36 (s, 1 H), 3.36 (td, J = 7.4, 8.2 Hz, 1 H), 3.22 (td, J = 5.0, 9.7 Hz, 1 H), 3.07 (s, 3 H), 2.89 (dt,
J = 6.6, 13.1 Hz, 1 H), 2.49 (ddd, J = 6.5, 10.2, 12.6 Hz, 1 H), 2.06 - 1.98 (m, 1 H), 1.19 (d, J =
6.8 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 178.1,
144.0, 142.6, 131.4, 131.2, 128.6, 128.1, 128.0, 125.4, 122.3, 122.2, 119.2, 111.0, 107.8, 72.5,
59.6, 47.8, 43.3, 34.2, 26.4, 22.9, 13.2; HMRS (ESI): m/z calcd for C22H23N3O (M+H)+ 346.1921,
found 346.1919.
2’-(4-cyanophenyl)-1-methyl-1'-[(4-methylphenyl)sulfonyl]spiro[indole-3,3'-pyrrolidin]-2one (4c): 3 (150 mg, 0.87 mmol), C (227 mg, 1.30 mmol), G (174 mg, 1.30 mmol) and
magnesium iodide (241 mg, 0.87 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL).
The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the
crude mixture was analyzed by LC-MS. The organic phase was washed with saturated brine
(50mL), dried over sodium sulfate and evaporated in vacuo. The crude compound was then
purified by column chromatography on silica gel (eluent: 30 % AcOEt in hexane). The collected
fraction was evaporated then washed with a sodium hydroxide solution 1.0 N. The organic phase
was extracted with DCM and concentrated to yield the title product as a white solid (138.2 mg,
0.302 mmol, 35%, ratio 3:1); LCMS retention time: (2’S*,3S*)-diastereoisomer (major): 0.90
min, (2’R*,3S*)-diastereoisomer (minor): 0.92 min; 1H NMR (400 MHz, CHLOROFORM-d) δ =
7.74 (d, J = 8.2 Hz, 3 H), 7.39 (dd, J = 2.0, 8.4 Hz, 4 H), 7.30 (td, J = 1.0, 7.7 Hz, 1 H), 7.24 (br.
s., 3 H), 7.15 (td, J = 1.1, 7.7 Hz, 3 H), 7.10 - 7.05 (m, 2 H), 6.90 (d, J = 7.4 Hz, 1 H), 6.89 - 6.84
(m, 3 H), 6.81 - 6.78 (m, 3 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 3 H), 4.97 (s, 1 H),
4.91 (s, 1 H), 4.33 (td, J = 6.0, 11.0 Hz, 1 H), 4.08 - 4.00 (m, 2 H), 3.97 - 3.89 (m, 1 H), 3.09 (s, 3
H), 2.79 (s, 3 H), 2.50 (s., 3 H), 2.49 (s, 3 H), 2.19 - 2.13 (m, 1 H), 2.11 - 1.95 (m, 3 H); 13C NMR
(101 MHz, CHLOROFORM-d) major diastereoisomer: δ = 176.1, 144.7, 143.4, 142.9, 131.7,
130.2, 129.2, 128.4, 127.9, 127.9, 125.0, 122.8, 118.9, 111.6, 108.5, 70.1, 59.4, 48.8, 34.7, 26.7,
21.9, minor diastereoisomer: δ = 175.4, 144.6, 143.6, 142.7, 133.0, 131.7, 129.7, 128.6, 127.8,
127.5, 123.4, 122.4, 119.0, 111.7, 108.6, 71.3, 59.8, 49.3, 35.3, 26.0, 21.9; HMRS (ESI): m/z
calcd for C26H23N3O3S (M+H)+ 458.1538, found 458.1538.
2'-(3-chlorophenyl)-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'-pyrrolidin]-2-one
(4d): 3 (104 mg, 0.60 mmol), B (92 mg, 0.75 mmol), H (85 µL, 0.75 mmol) and magnesium
iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction
vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture
was analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 50%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as orange solid
(250.3 mg, 0.568 mmol, 95%, ratio 3:1), LCMS retention time: (2’S*,3S*)-diastereoisomer
(major): 1.07 min, (2’R*,3S*)-diastereoisomer (minor): 1.05 min; 1H NMR (400 MHz,
CHLOROFORM-d)δ = 7.32 (td, 1 H), 7.23 (d, J = 6.8 Hz, 1 H), 7.16 (d, J = 1.0 Hz, 1 H), 7.14
(dd, J = 1.2, 7.8 Hz, 1 H), 7.11 - 6.98 (m, 3 H), 6.90 (d, J = 6.2 Hz, 1 H), 6.83 (t, J = 7.5 Hz, 1 H),
6.78 - 6.73 (m, 3 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.58 (s., 1 H), 6.47 - 6.42 (m, 1 H), 4.87 (s, 1 H),
4.77 (s, 1 H), 4.36 (dt, J = 7.2, 8.8 Hz, 1 H), 4.17 - 4.11 (m, 1 H), 3.91 (td, J = 6.5, 8.6 Hz, 1 H),
3.71 (s, 3 H), 3.20 (s, 3 H), 2.58 - 2.48 (m, 1 H), 2.37 - 2.29 (m, 1 H); 13C NMR (101 MHz,
CHLOROFORM-d) major diastereoisomer: δ = 178.2, 152.2, 143.3, 141.8, 140.6, 134.1, 129.4,
128.4, 127.7, 127.1, 125.4, 125.3, 122.3, 115.5, 114.7, 108.0, 70.0, 59.1, 55.9, 50.5, 34.2, 26.5;
S-3
minor diastereoisomer: δ = 175.9, 151.8, 143.6, 142.1, 141.4, 134.0, 129.5, 129.1, 128.9, 128.0,
126.8, 123.1, 122.8, 114.9, 114.6, 108.2, 72.0, 59.3, 50.3, 33.8, 26.2; HMRS (ESI): m/z calcd for
C25H23ClN2O2 (M+H)+ 419.1523, found 419.1526.
(2'S*)-2'-(3-chlorophenyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'-pyrrolidin]-2-one
(4e): 3 (104 mg, 0.60 mmol), A (64 µL, 0.75 mmol), H (85 µL, 0.75 mmol) and magnesium
iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction
vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture
was analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as orange solid
(112.5 mg, 317 mmol, 53%); LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.64 min; 1H
NMR (400 MHz, CHLOROFORM-d) δ = 7.33 (d, J = 7.2 Hz, 1 H), 7.09 (dd, J = 1.2, 15.4 Hz, 1
H), 7.10 - 7.05 (m, 1 H), 6.97 (t, J = 2.7 Hz, 1 H), 6.95 (d, J = 2.1 Hz, 1 H), 6.94 (d, J = 1.8 Hz, 1
H), 6.91 (d, J = 7.6 Hz, 1 H), 6.54 (d, J = 7.6 Hz, 1 H), 4.28 (s, 1 H), 3.34 (td, J = 6.3, 8.6 Hz, 1
H), 3.19 (td, J = 14.5, 5.2 Hz, 1 H), 3.08 (s, 3 H), 2.96 (dt, J = 6.6, 13.1 Hz, 1 H), 2.47 (ddd, J =
6.2, 10.1, 12.5 Hz, 1 H), 2.02 (ddd, J = 5.1, 8.0, 12.7 Hz, 1 H), 1.19 (d, J = 6.6 Hz, 3 H), 0.95 (d,
J = 6.2 Hz, 3 H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 178.5, 142.8, 140.3, 133.5, 131.7,
128.7, 128.0, 127.8, 127.4, 126.1, 122.2, 107.6, 72.5, 59.5, 47.5, 43.2, 33.9, 26.4, 22.9, 13.0;
HMRS (ESI): m/z calcd for C21H23ClN2O (M+H)+ 355.1577, found 355.1577.
2'-(3-chlorophenyl)-1-methyl-1'-[(4-methylphenyl)sulfonyl]spiro[indole-3,3'-pyrrolidin]-2one (4f): 3 ( 104 mg, 0.60 mmol), C (128 mg, 0.75 mmol), H (85 µL, 0.75 mmol) and
magnesium iodide (167 mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL).
The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the
crude mixture was analyzed by LC-MS and was purified by column chromatography on silica gel
(eluent: 50 % AcOEt in hexane). The collected fraction was evaporated then washed with a
sodium hydroxide solution 1.0N. The organic phase was extracted with DCM and concentrated to
yield the title product as a pale yellow solid (170.9 mg, 0.322 mmol, 54%, ratio 10:1); LCMS
retention time: (2’S*,3S*)-diastereoisomer (major): 0.98 min, (2’R*,3S*)-diastereoisomer
(minor): 0.98 min;1H NMR (400 MHz, CHLOROFORM-d) major diastereoisomer δ = 7.74 (d, J
= 8.2 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.14 (td, J = 1.1, 7.8 Hz, 1 H), 7.10 - 6.99 (m, 4 H), 6.84
(td, J = 0.8, 7.6 Hz, 1 H), 6.66 (t, J = 6.6 Hz, 2 H), 4.86 (s, 1 H), 4.00 (dd, J = 3.1, 14.8 Hz, 1 H),
4.04 - 3.92 (m, J = 10.7 Hz, 2 H), 3.09 (s, 3 H), 2.47 (s, 3 H), 2.07 - 2.03 (m, 1 H), minor
diastereoisomer: δ = 7.70 (d, J = 8.2 Hz, 4 H), 7.28 (dd, J = 1.1, 7.7 Hz, 2 H), 6.93 (d, J = 7.2 Hz,
2 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.45 (t, J = 7.1 Hz, 2 H), 4.92 (s, 1 H), 4.30 (td, J = 6.2, 10.7 Hz, 1
H), 3.19 (s, 3 H), 2.82 (s, 3 H), 2.51 (dd, J = 3.3, 10.4 Hz, 1 H), 2.22 - 2.15 (m, 1 H), 1.95 (dt, J =
2.2, 10.4 Hz, 1 H); 13C NMR (101 MHz, CHLOROFORM-d) major diastereoisomer δ = 176.6,
144.3, 143.0, 140.2, 133.8, 133.7, 130.0, 129.1, 128.9, 128.3, 128.0, 127.4, 125.5, 125.2, 123.2,
122.6, 108.3, 69.7, 59.1, 48.5, 34.4, 26.6, 21.9, minor diastereoisomer δ = 175.6, 144.3, 143.6,
139.1, 135.3, 130.4, 129.4, 129.1, 128.1, 127.9, 126.9, 125.1, 123.6, 122.4, 108.4, 71.3, 59.6,
49.1, 35.0, 26.0, 21.9; HMRS (ESI): m/z calcd for C25H23ClN2O3S (M+H)+ 467.1198, found
467.1196.
2'-(2,2-dimethylpropyl)-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'-pyrrolidin]-2one (4g): 3 (104 mg, 0.60 mmol), B (92 mg, 0.75 mmol), D (94 µL, 0.75 mmol) and magnesium
iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction
vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture
was analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as a brown
solid (84 mg, 0.222 mmol, 37%, ratio 1:1); LCMS retention time: (2’S*,3S*)-diastereoisomer
S-4
(major): 0.90 min, (2’R*,3S*)-diastereoisomer (minor): 0.90 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.40 (d, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.7 Hz, 2 H), 7.26 (dd, J = 1.1, 15.3
Hz, 1 H), 7.12 (t, J = 7.3 Hz, 1 H), 7.04 - 7.01 (m, 1 H), 6.97 (d, J = 7.0 Hz, 1 H), 6.88 (dd, J =
2.6, 7.9 Hz, 7 H), 6.86 (d, J = 3.3 Hz, 2 H), 6.84 (t, J = 2.6 Hz, 1 H), 6.69 (d, J = 9.0 Hz, 1 H),
4.08 (d, J = 9.0 Hz, 1 H), 3.89 - 3.81 (m, 2 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.71 (td, J = 3.8, 9.0
Hz, 1 H), 3.52 - 3.44 (m, 2 H), 3.22 (s, 6 H), 2.69 (dt, J = 8.4, 12.3 Hz, 1 H), 2.52 - 2.38 (m, 2 H),
2.07 (ddd, J = 3.7, 8.3, 12.4 Hz, 1 H), 1.88 (ddd, J = 2.9, 6.7, 11.7 Hz, 2 H), 1.53 (d, J = 14.8 Hz,
2 H), 1.33 (dd, J = 2.1, 14.8 Hz, 1 H), 1.21 (dd, J = 9.3, 15.3 Hz, 1 H), 0.77 (s, 9 H), 0.59 (s, 9 H);
13
C NMR (101 MHz, CHLOROFORM-d) major diastereoisomer: δ = 177.3, 151.7, 143.3, 142.4,
136.0, 129.0, 128.0, 125.4, 123.2, 123.0, 115.5, 114.9, 114.5, 108.4, 64.6, 58.0, 55.9, 47.0, 41.0,
38.0, 30.1, 29.8, 26.6, minor diastereoisomer: δ = 179.2, 153.6, 142.7, 141.2, 132.3, 128.2, 127.6,
122.7, 120.1, 115.1, 114.3, 107.9, 62.6, 56.0, 52.6, 42.4, 35.5, 30.3, 29.7, 26.5; HMRS (ESI): m/z
calcd for C24H30N2O2 (M+H)+ 379.2286, found 379.2386.
2'-(2,2-dimethylpropyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'-pyrrolidin]-2-one (4h):
3 ( 104 mg, 0.60 mmol), A (64 µL, 0.75 mmol), D (94 µL, 0.75 mmol) and magnesium iodide
(167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction vessel
was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture was
analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as a yellow
solid (20.7 mg, 0.065 mmol, 11%, ratio 3:1); LCMS retention time: (2’S*,3S*)-diastereoisomer
(major): 0.58 min, (2’R*,3S*)-diastereoisomer (minor): 0.59 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.29 (d, J = 1.0 Hz, 1 H), 7.26 (dd, J = 1.1, 7.7 Hz, 3 H), 7.07 (t, J = 7.5
Hz, 2 H), 6.82 (d, J = 7.8 Hz, 2 H), 3.19 (s, 3 H), 3.18 (s, 3 H), 3.09 (t, J = 4.2 Hz, 2 H), 3.01 (t, J
= 7.9 Hz, 2 H), 2.89 (ddd, J = 5.9, 9.0, 10.9 Hz, 1 H), 2.36 (td, J = 7.0, 11.4 Hz, 1 H), 2.29 - 2.21
(m, 3 H), 2.17 (dd, J = 8.2, 15.6 Hz, 1 H), 2.01 - 1.89 (m, 1 H), 1.84 (ddd, J = 1.4, 5.8, 12.0 Hz, 1
H), 1.74 (q, J = 3.8 Hz, 1 H), 1.51 (q, J = 4.1 Hz, 1 H), 1.25 (d, J = 1.6 Hz, 3 H), 1.23 (d, J = 4.5
Hz, 3 H), 1.08 (d, J = 4.3 Hz, 3 H), 1.06 (d, J = 2.5 Hz, 3 H), 0.61 (s, 18 H)
13
C NMR (101 MHz, CHLOROFORM-d) major diastereoisomer δ = 180.1, 143.5, 127.9, 125.9,
122.7, 107.8, 63.8, 57.7, 46.4, 43.4, 42.2, 36.7, 29.9, 29.6, 29.5, 26.4, 23.3, 13.2, minor
diastereoisomer δ = 179.1, 142.9, 127.7, 122.9, 122.7, 108.2, 66.0, 56.6, 46.5, 43.5, 43.0, 38.6,
30.1, 29.9, 29.4, 26.4, 23.4, 13.3; HMRS (ESI): m/z calcd for C20H30N2O (M+H)+ 315.2437,
found 315.2436.
2'-phenyl-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'-pyrrolidin]-2-one (4j): 3 (104
mg, 0.60 mmol), B (92 mg, 0.75 mmol), F (76 µL, 0.75 mmol) and magnesium iodide (167mg,
0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction vessel was
sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture was
analyzed by LC-MS, was purified by column chromatography on silica gel (eluent: 20% AcOEt
in hexane). The collected fraction was evaporated to yield the title product as a brown-yellow
solid (217.3 mg, 0.566 mmol, 94%, ratio 3:1); LCMS retention time: (2’S*,3S*)-diastereoisomer
(major): 1.00 min, (2’R*,3S*)-diastereoisomer (minor): 1.01 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 8.07 (dd, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 1 H), 7.31
(td, J = 1.2, 7.7 Hz, 1 H), 7.20 - 7.11 (m, 1 H), 7.09 (dd, J = 2.6, 3.8 Hz, 1 H), 7.02 - 6.98 (m, 1
H), 6.92 - 6.89 (m, 1 H), 6.79 - 6.76 (m, 1 H), 6.73 (d, J = 9.0 Hz, 1 H), 6.67 (d, J = 7.8 Hz, 1 H),
6.54 - 6.50 (m, 1 H), 6.45 (d, J = 4.7 Hz, 1 H), 6.45 (d, J = 9.0 Hz, 1 H), 4.89 (s, 1 H), 4.83 (s, 1
H), 4.38 (dt, J = 7.3, 8.9 Hz, 1 H), 4.12 (ddd, J = 5.7, 7.8, 8.8 Hz, 1 H), 3.92 (td, J = 6.6, 8.5 Hz, 1
H), 3.85 - 3.78 (m, 1 H), 3.70 (s, 3 H), 3.38 (s, 3 H), 3.19 (s, 3 H), 2.87 (s, 3 H), 2.57 - 2.46 (m, 2
H), 2.39 - 2.28 (m, 2 H); 13C NMR (101 MHz, CHLOROFORM-d) major diastereoisomer: δ =
178.5, 151.9, 143.3, 142.4, 139.5, 134.2, 130.9, 129.5, 128.7, 128.1, 127.7, 127.5, 127.2, 125.4,
S-5
122.1, 115.2, 114.8, 114.7, 107.8, 70.2, 59.1, 56.0, 50.1, 34.2, 26.5; minor diastereoisomer: δ =
176.3, 151.5, 143.8, 141.7, 138.0, 131.8, 129.5, 129.2, 128.1, 127.4, 127.0, 126.7, 125.5, 122.9,
115.5, 114.6, 114.5, 108.1, 72.4, 63.8, 59.5, 50.4, 33.7, 26.0; HMRS (ESI): m/z calcd for
C25H24N2O2 (M+H)+ 385.1914, found 385.1916.
(2'S*)-2'-phenyl-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'-pyrrolidin]-2-one (4k): 3 ( 104
mg, 0.60 mmol), A (64 µL, 0.75 mmol), F (76 µL, 0.75 mmol) and magnesium iodide (83 mg,
0.30 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction vessel was
sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture was
analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20 %
AcOEt in hexane). The collected fraction was evaporated to yield the title product as a brown
solid (61.6 mg, 0.192 mmol, 32%); LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.60 min;
1
H NMR (400 MHz, CHLOROFORM-d) δ = 7.38 (dd, J = 0.7, 7.3 Hz, 1 H), 7.09 - 7.04 (m, 1 H),
7.03 - 6.98 (m, 5 H), 6.93 (td, J = 0.8, 7.5 Hz, 1 H), 6.50 (d, J = 7.6 Hz, 1 H), 4.30 (s, 1 H), 3.33
(td, J = 6.2, 8.6 Hz, 1 H), 3.22 - 3.15 (m, 1 H), 3.05 (s, 3 H), 3.00 (dt, J = 6.6, 13.3 Hz, 1 H), 2.48
(ddd, J = 6.2, 10.3, 12.6 Hz, 1 H), 2.02 (ddd, J = 5.1, 8.0, 12.7 Hz, 1 H), 1.19 (d, J = 6.8 Hz, 3 H),
0.94 (d, J = 6.2 Hz, 3 H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 178.7, 142.8, 137.6,
132.3, 128.0, 127.5, 127.4, 127.2, 125.6, 122.0, 107.3, 73.1, 59.6, 53.7, 47.2, 42.9, 33.9, 26.3,
22.9; HMRS (ESI): m/z calcd for C21H24N2O (M+H)+ 321.1966, found 321.1967.
2'-phenyl-1-methyl-1'-[(4-methylphenyl)sulfonyl]spiro[indole-3,3'-pyrrolidin]-2-one (4l): 3
(104 mg, 0.60 mmol), C (128 mg, 0.75 mmol), F (76 µL, 0.75 mmol) and magnesium iodide
(167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction vessel
was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture was
analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated, then washed with a solution of sodium
hydroxide 1.0N and the desired compound was extracted with DCM. The organic phase was
concentrated to yield the title product as a brown solid (65.9 mg, 0.152 mmol, 25%, ratio 3:1);
LCMS retention time: (2’S*,3S*)-diastereoisomer (major): 0.94 min, (2’R*,3S*)-diastereoisomer
(minor): 0.92 min; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.75 (d, J = 8.2 Hz, 2 H), 7.72
(d, J = 8.2 Hz, 2 H), 7.38 - 7.32 (m, 6 H), 7.28 (dd, J = 1.2, 7.6 Hz, 1 H), 7.15 - 7.03 (m, 7 H),
6.94 (d, J = 7.2 Hz, 1H), 6.80 (td, J = 0.8, 7.6 Hz, 3 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.62 (dd, J =
2.4, 7.7 Hz, 3 H), 4.96 (s, 1 H), 4.88 (s, 1 H), 4.34 (td, J = 6.1, 10.8 Hz, 1 H), 4.09 - 3.90 (m, 1
H), 3.49 - 3.44 (m, 1 H), 3.27 - 3.15 (m, 1 H), 3.08 (s, 3 H), 2.77 (s, 3 H), 2.48 (s, 3 H), 2.47 (s, 3
H), 2.21 - 2.14 (m, 1 H), 2.08 - 2.03 (m, 1 H), 1.93 (dt, J = 2.3, 10.3 Hz, 1 H);13C NMR (101
MHz, CHLOROFORM-d) major diastereoisomer: δ = 176.9, 144.0, 143.1, 138.0, 133.9, 129.9,
129.2, 128.3, 128.0, 127.8, 127.3, 125.4, 122.4, 108.0, 70.2, 59.1, 48.4, 34.4, 25.9, 21.9, , minor
diastereoisomer: δ =175.9, 144.0, 143.8, 136.8, 135.4, 129.9, 129.6, 128.6, 127.9, 127.9, 126.6,
123.0, 122.4, 108.3, 72.0, 59.8, 49.3, 35.0, 26.5, 21.9; HMRS (ESI): m/z calcd for C25H24N2O3S
(M+H)+ 433.1586, found 433.1586.
2'-(3-furanyl)-1-methyl-1'-[4-(methyloxy)phenyl]spiro[indole-3,3'-pyrrolidin]-2-one (4m): 3
(104 mg, 0.60 mmol), B (92 mg, 0.75 mmol), E (63 µL, 0.75 mmol) and magnesium iodide
(167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction vessel
was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture was
analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as a brown
solid (216.7 mg, 0.238 mmol, 90%, ratio 3:1); LCMS retention time: (2’S*,3S*)-diastereoisomer
(major): 0.96 min, (2’R*,3S*)-diastereoisomer (minor): 0.95 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.35 - 7.29 (m, 2 H), 7.21 (td, J = 1.0, 7.7 Hz, 4 H), 7.13 - 6.91 (m, 7 H),
S-6
6.82 - 6.73 (m, 5 H), 6.65 (m., 2 H), 6.01 - 5.90 (m, 2 H), 4.87 (s., 2 H), 4.29 (d, J = 7.8 Hz, 1 H),
4.09 (d, J = 7.2 Hz, 1 H), 3.80 - 3.75 (m, 2 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.21 (s, 6 H); 13C NMR
(101 MHz, CHLOROFORM-d) major diastereoisomer δ = 178.0, 143.4, 142.7, 140.6, 130.1,
129.9, 128.3, 125.3, 124.2, 123.4, 123.0, 122.4, 115.2, 114.6, 111.4, 109.9, 108.7, 108.0, 63.2,
55.9, 55.8, 50.9, 34.2, 26.6, minor diastereoisomer δ = 177.9, 143.4, 142.8, 140.5, 130.2, 129.9,
128.3, 124.4, 124.1, 122.9, 122.8, 115.1, 114.7, 109.8, 109.5, 108.2, 108.1, 58.7, 56.0, 55.9, 45.6,
33.6, 26.5; HMRS (ESI): m/z calcd for C23H22N2O3 (M+H)+ 375.1712, found 375.1709.
(2'S*)-2'-(3-furanyl)-1-methyl-1'-(1-methylethyl)spiro[indole-3,3'-pyrrolidin]-2-one (4n): 3
(104 mg, 0.60 mmol), A (64 µL, 0.75 mmol), E (63 µL, 0.75 mmol) and magnesium iodide
(167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL). The reaction vessel
was sealed and heated in the microwave to 160°C for 10 minutes. Then the crude mixture was
analyzed by LC-MS and was purified by column chromatography on silica gel (eluent: 20%
AcOEt in hexane). The collected fraction was evaporated to yield the title product as a brown
solid (30.2 mg, 0.097 mmol, 16%); LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.47 min;
1
H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 (d, J = 6.6 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H),
7.06 (d, J = 12.5 Hz, 1 H), 7.02 (d, J = 4.9 Hz, 2 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.83 (s., 1 H), 4.17
(s., 1 H), 3.28 - 3.19 (m, J = 6.1 Hz, 1 H), 3.11 (s, 3 H), 3.08 - 2.95 (m, 1 H), 2.44 (ddd, J = 6.0,
10.5, 12.4 Hz, 1 H), 1.74 (q, J = 4.0 Hz, 1 H), 1.51 (q, J = 4.2 Hz, 1 H), 1.17 (d, J = 6.2 Hz, 3 H),
0.91 (d, J = 5.5 Hz, 3 H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 178.5, 143.2, 142.3,
141.0, 127.8, 125.5, 122.2, 118.5, 110.3, 108.2, 107.6, 65.2, 47.0, 42.3, 33.7, 26.5, 22.7, 19.4,
12.5; HMRS (ESI): m/z calcd for C19H22N2O2 (M+H)+ 311.1760, found 311.1760.
(2'S*)-2’-(4-cyanophenyl)-5-(methyloxy)-1'-(1-methylethyl)-1-(phenylmethyl)spiro[indole3,3'-pyrrolidin]-2-one (6b): 5 (168 mg, 0.60 mmol), A (64 µL, 0.75 mmol), G (98 mg, 0.75
mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with
tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the microwave to 160°C for
10 minutes. Then the crude mixture was analyzed by LC-MS and was purified by column
chromatography on silica gel (eluent: 14% AcOEt in hexane with an isocratic gradient). The
collected fraction was evaporated to yield the title product as red-brown solid (106.8 mg, 237
mmol, 39.4%); LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.80 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.28 (s, 1 H), 7.24 (d, J = 1.8 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1 H), 7.23 (d,
J = 14.8, 1 H), 7.21 (d, J = 12.3 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 2 H), 7.05 (d, J = 2.5 Hz, 1 H), 6.93
(dd, J = 2.1, 7.1 Hz, 2 H), 6.53 (dd, J = 2.6, 8.5 Hz, 1 H), 6.33 (d, J = 8.4 Hz, 1 H), 4.98 (d, J =
15.6 Hz, 1 H), 4.55 (d, J = 15.6 Hz, 1 H), 4.42 (s, 1 H), 3.74 (s, 3 H), 3.37 (t, J = 7.50, 8.60, 1 H),
3.22 (td, J = 4.6, 9.9 Hz, 1 H), 2.89 (dt, J = 6.5, 13.1 Hz, 1 H), 2.56 (ddd, J = 6.8, 10.4, 12.5 Hz, 1
H), 2.04 (ddd, J = 4.5, 8.2, 12.5 Hz, 1 H), 1.20 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.4 Hz, 3 H); 13C
NMR (101 MHz, CHLOROFORM-d) δ = 177.6, 155.7, 143.5, 135.8, 135.6, 132.7, 131.6, 129.0,
128.8, 127.8, 127.3, 119.1, 113.8, 111.5, 111.1, 109.0, 72.5, 59.9, 56.0, 47.6, 44.0, 42.9, 34.6,
22.8, 12.9; HMRS (ESI): m/z calcd for C29H29N3O2 (M+H)+ 452.2338, found 452.2338.
2’-(4-cyanophenyl)-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one (6c): 5 ( 168 mg, 0.60 mmol), C (128 mg,
0.75 mmol), G (98 mg, 0.75 mmol) and magnesium iodide (167 mg, 0.60 mmol) were placed in a
5mL vial with tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the
microwave to 160°C for 10 minutes. Then the crude mixture was analyzed by LC-MS and was
purified by column chromatography on silica gel (eluent: 15 % AcOEt in hexane with an isocratic
gradient). The collected fraction was evaporated to yield the title product as an orange solid
(141.4 mg, 0.251 mmol, 42% ratio 1:1); LCMS retention time: (2’S*,3S*)-diastereoisomer
(major): 1.04 min, (2’R*,3S*)-diastereoisomer (minor): 1.04 min; 1H NMR (400 MHz,
S-7
CHLOROFORM-d) δ = 7.81 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 1
H), 7.40 (d, J = 8.2 Hz, 5 H), 7.35 (d, J = 8.2 Hz, 3 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.29 - 7.27 (m, 3
H), 7.22 (d, J = 7.0 Hz, 1 H), 7.18 (d, J = 7.4 Hz, 2 H), 7.03 (dd, J = 3.0, 6.3 Hz, 1 H), 6.69 (dd, J
= 2.4, 8.5 Hz, 2 H), 6.59 (d, J = 2.3 Hz, 1 H), 6.56 (dd, J = 2.5, 8.0 Hz, 2 H), 6.53 (d, J = 2.5 Hz,
1 H), 6.48 (d, J = 8.4 Hz, 1 H), 6.46 (d, J = 8.4 Hz, 1 H), 5.00 (s, 1 H), 4.89 (d, J = 15.8 Hz, 1 H),
4.81 (d, J = 19.9 Hz, 1 H), 4.76 (s., 1 H), 4.59 (d, J = 15.6 Hz, 2 H), 4.41 (td, J = 5.6, 11.6 Hz, 1
H), 4.10 - 4.01 (m, 1 H), 3.97 - 3.90 (m, 1 H), 3.83 - 3.79 (m, 1 H), 3.77 (s, 3 H), 3.65 (s, 3 H),
2.50 (s., 3 H), 2.49 (s, 3 H), 2.12 (dt, J = 9.0, 12.6 Hz, 1 H), 2.00 (dd, J = 3.8, 6.7 Hz, 1 H), 1.96
(dd, J = 3.9, 6.6 Hz, 1 H), 1.92 (dd, J = 3.9, 12.3 Hz, 1 H); 13C NMR (101 MHz,
CHLOROFORM-d) major diastereoisomer δ = 175.6, 155.9, 144.8, 143.7, 143.0, 135.5, 135.2,
132.7, 131.7, 130.2, 129.2, 129.0, 128.4, 128.1, 128.0, 127.4, 126.6, 118.9, 113.0, 111.6, 109.8,
70.3, 59.8, 56.0, 48.9, 44.2, 34.9, 21.9, minor diastereoisomer δ = 175.4, 156.5, 144.7, 142.6,
139.5, 136.2, 134.6, 132.5, 131.9, 129.9, 129.5, 128.9, 128.2, 128.0, 127.9, 127.2, 127.1, 119.1,
113.0, 111.8, 110.1, 71.2, 60.2, 56.0, 49.5, 43.8, 36.3, 21.9; HMRS (ESI): m/z calcd for
C33H29N3O4S (M+H)+ 564.1957, found 564.1957.
2'-(3-chlorophenyl)-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1-(phenylmethyl)spiro[indole3,3'-pyrrolidin]-2-one (6d): 5 (168 mg, 0.60 mmol), B (92 mg, 0.75 mmol), H (85 µL, 0.75
mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with
tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the microwave to 160°C for
10 minutes. Then the crude mixture was analyzed by LC-MS and was purified by column
chromatography on silica gel (eluent: 20% AcOEt in hexane). The collected fraction was
evaporated to yield the title product as a yellow solid (189.4 mg, 0.317 mmol, 53%, ratio 1:1);
LCMS retention time: (2’S*,3S*)-diastereoisomer (major): 1.10 min, (2’R*,3S*)-diastereoisomer
(minor): 1.10 min; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.34 - 7.33 (m, 1 H), 7.31 (d, J =
7.6 Hz, 2 H), 7.21 - 7.05 (m, 8 H), 7.00 (t, J = 7.7 Hz, 2 H), 6.93 (d, 3 H), 6.77 (d, J = 2.9 Hz, 2
H), 6.75 - 6.74 (m, 2 H), 6.71 (d, J = 2.5 Hz, 1 H), 6.69 (d, J = 2.5 Hz, 1 H), 6.58 - 6.53 (m, 5 H),
6.49 (s, 1 H), 6.45 (d, J = 2.9 Hz, 2 H), 6.44 - 6.42 (m, 1 H), 6.36 (d, J = 2.3 Hz, 2 H), 5.00 (d, J =
15.6 Hz, 1 H), 4.97 (s, 1 H), 4.88 (s, 1 H), 4.76 (d, J = 15.8 Hz, 2 H), 4.52 - 4.45 (m, 1 H), 4.25
(d, J = 15.8 Hz, 1 H), 4.20 - 4.13 (m, 1 H), 3.91 (td, J = 5.7, 8.8 Hz, 1 H), 3.78 (s, 3 H), 3.72 (s, 6
H), 3.59 (s, 3 H), 3.23 (t, J = 6.9 Hz, 1 H), 2.60 (ddd, J = 6.4, 8.4, 12.5 Hz, 1 H), 2.29 (ddd, J =
5.7, 7.1, 12.6 Hz, 1 H), 1.94 (quin, J = 7.2 Hz, 1 H), 1.68 (dt, J = 6.5, 14.8 Hz, 1 H). 13C NMR
(101 MHz, CHLOROFORM-d) major diastereoisomer δ = 177.8, 155.7, 152.3, 142.2, 141.6,
135.9, 134.3, 130.6, 129.6, 129.1, 127.8, 127.4, 127.1, 125.6, 115.8, 114.9, 114.7, 112.7, 109.5,
69.9, 59.6, 56.1, 55.9, 50.8, 44.2, 34.9; minor diastereoisomer δ = 176.2, 156.4, 151.8, 141.6,
140.4, 136.5, 135.8, 132.0, 129.8, 128.9, 128.1, 127.6, 127.0, 125.5, 114.8, 113.3, 112.8, 110.6,
109.8, 71.9, 59.9, 56.0, 56.0, 50.9, 43.8, 34.9; HMRS (ESI): m/z calcd for C32H29ClN2O3 (M+H)+
525.1942, found 525.1945.
(2'S*)-2'-(3-chlorophenyl)-5-(methyloxy)-1'-(1-methylethyl)-1-(phenylmethyl)spiro[indole3,3'-pyrrolidin]-2-one (6e): 5 (168 mg, 0.60 mmol), A (64 µL, 0.75 mmol), H (85 µL, 0.75
mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with
tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the microwave to 160°C for
10 minutes. Then the crude mixture was analyzed by LC-MS and was purified by column
chromatography on silica gel (eluent: 20% AcOEt (with 0.5% NH4OH) in hexane). The collected
fraction was evaporated to yield the title product as orange solid (113.8 mg, 0.247 mmol, 41%);
LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.79 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.23 (s, 1 H), 7.21 (d, J = 0.6 Hz, 1 H), 7.18 (s, 1 H), 7.07 (d, J = 2.7 Hz,
1 H), 7.05 (t, J=2.1Hz, 1 H), 7.04 (t, J = 1.9 Hz, 1 H), 6.96 (d, J = 6.6 Hz, 1 H), 6.95 (d, J = 7.2
Hz, 2 H), 6.93 (d, J = 1.6 Hz, 1 H), 6.51 (dd, J = 2.6, 8.5 Hz, 1 H), 6.27 (d, J = 8.4 Hz, 1 H), 5.07
S-8
(d, J = 15.8 Hz, 1 H), 4.52 (d, J = 15.8 Hz, 1 H), 4.36 (s, 1 H), 3.75 (s, 3 H), 3.34 (td, J = 6.4, 8.6
Hz, 1 H), 3.20 (td, J = 4.9, 9.8 Hz, 1 H), 2.96 (dt, J = 6.6, 13.1 Hz, 1 H), 2.54 (ddd, J = 6.4, 10.4,
12.5 Hz, 1 H), 2.08 - 2.01 (m, 1 H), 1.21 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H). 13C NMR
(101 MHz, CHLOROFORM-d) δ = 178.1, 155.7, 140.0, 135.8, 135.7, 133.7, 133.1, 129.0, 128.9,
128.5, 127.6, 127.5, 127.0, 126.6, 113.6, 112.2, 109.0, 72.3, 59.8, 56.2, 47.4, 44.0, 42.8, 34.7,
22.9, 12.9; HMRS (ESI): m/z calcd for C28H29ClN2O2 (M+H)+ 461.1996, found 461.1996.
2'-(3-chlorophenyl)-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one (6f): 5 (168 mg, 0.60 mmol), C (128 mg,
0.75 mmol), H (85 µL, 0.75 mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a
5mL vial with tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the
microwave to 160°C for 10 minutes. Then the crude mixture was analyzed by LC-MS and was
purified by column chromatography on silica gel (eluent: 30% AcOEt in hexane). The collected
fraction was evaporated to yield the title product as a brown solid (146.8 mg, 0.256 mmol, 43%,
ratio 1:1); LCMS retention time: (2’S*,3S*)-diastereoisomer (major): 1.07 min, (2’R*,3S*)diastereoisomer (minor): 1.07 min; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.76 (d, J = 8.4
Hz, 4 H), 7.38 (d, J = 8.0 Hz, 4 H), 7.30 - 7.27 (m, 2 H), 7.19 - 7.08 (m, 7 H), 7.06 - 7.02 (m, 6
H), 6.66 (dd, J = 2.5, 8.6 Hz, 1 H), 6.56 (dd, J = 2.4, 8.3 Hz, 3 H), 6.42 (t, J = 2.8 Hz, 3 H), 6.40 6.39 (m, 1 H), 4.97 (s, 1H), 4.94 (d, J = 15.9 Hz, 1 H ), 4.93 (d, J = 17.5 Hz, 1 H), 4.90 (s, 1H),
4.58 (d, J = 15.6 Hz, 2 H), 4.40 (td, J = 5.7, 11.2 Hz, 1 H), 4.18 - 3.94 (m, 1 H), 3.77 (s, 3 H),
3.62 (s, 3 H), 3.23 (t, J = 6.9 Hz, 1 H), 2.47 (s, 6 H), 2.23 - 2.17 (m, 1 H), 2.14 - 2.06 (m, 1 H),
2.03 - 1.89 (m, 2 H), 1.72 - 1.64 (m, 1 H), 1.34 - 1.23 (m, 1 H), 0.91 - 0.83 (m, 1 H); 13C NMR
(101 MHz, CHLOROFORM-d) major diastereoisomer: δ = 176.3, 155.8, 144.4, 139.9, 135.6,
135.5, 134.0, 130.1, 129.3, 129.1, 128.3, 128.2, 127.9, 127.2, 125.8, 113.9, 112.6, 110.1, 69.7,
59.6, 56.2, 48.6, 44.1, 34.9, 21.9; minor diastereoisomer: 175.6, 156.4, 144.4, 139.0, 135.3,
135.1, 133.4, 129.9, 129.2, 128.9, 128.3, 127.9, 127.6, 126.9, 125.6, 113.3, 110.0, 109.8, 71.3,
60.2, 68.3, 56.0, 49.3, 43.8, 36.2, 21.9; HMRS (ESI): m/z calcd for C32H29ClN2O4S (M+H)+
573.1615, found 573.1615.
(2'S*)-2'-(2,2-dimethylpropyl)-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one (6g): 5 ( 168 mg, 0.60 mmol), B (92 mg,
0.75 mmol), D (94 µL, 0.75 mmol) and magnesium iodide (167 mg, 0.60 mmol) were placed in a
5mL vial with tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the
microwave to 160°C for 10 minutes. Then the crude mixture was analyzed by LC-MS and was
purified by column chromatography on silica gel (eluent: 20 % AcOEt in hexane). The collected
fraction was evaporated to yield the title product as an yellow solid (24.9 mg, 0. 046 mmol, 8%);
LCMS retention time: (2’S*,3S*)-diastereoisomer: 1.00 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.35 - 7.28 (m, 4 H), 7.04 (d, J = 2.3 Hz, 1 H), 6.96 - 6.86 (m, J = 17.4
Hz, 4 H), 6.74 (d, J = 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 6.70 - 6.67 (m, 1 H), 5.16 (d, J =
15.4 Hz, 1 H), 4.61 (d, J = 15.4 Hz, 1 H), 4.10 (d, J = 8.6 Hz, 1 H), 3.80 (s, 3 H), 3.80 (s, 3 H),
3.50 (td, J = 3.5, 9.1 Hz, 1 H), 2.54 (dt, J = 8.7, 12.0 Hz, 1 H), 1.97 - 1.90 (m, 1 H), 1.54 (d, J =
15.2 Hz, 1 H), 1.29 (dd, J = 9.1, 15.1 Hz, 1 H), 0.59 (s, 9 H); 13C NMR (101 MHz,
CHLOROFORM-d) δ = 179.0, 155.9, 153.8, 142.6, 136.2, 136.1, 133.8, 128.9, 127.8, 127.8,
120.7, 114.5, 113.2, 111.8, 109.6, 62.7, 58.4, 56.1, 55.9, 52.5, 44.4, 42.4, 38.5, 29.9; HMRS
(ESI): m/z calcd for C31H36N2O3 (M+H)+ 485.2804, found 485.2804.
(2'S*)-2'-(2,2-dimethylpropyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one (6ha): 5 (168 mg, 0.60 mmol), A (64 µL,
0.75 mmol), D (94 µL, 0.75 mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a
5mL vial with tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the
S-9
microwave to 160°C for 10 minutes. Then the crude mixture was analyzed by LC-MS and was
purified by column chromatography on silica gel (eluent: 50% AcOEt in hexane). The collected
fraction was evaporated to yield the title product as a brown solid (108.5 mg, 0.230 mmol, 38%);
LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.74 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.33 – 7.27 (m, 5 H), 6.89 (d, J = 2.3 Hz, 1 H), 6.71 (dd, J = 2.3, 8.4 Hz,
1 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.00 (d, J = 15.6 Hz, 1 H), 4.71 (d, J = 15.6 Hz, 1 H), 3.79 (s, 3
H), 3.37 - 2.98 (m, 2 H), 2.88 (td, J = 6.3, 9.4 Hz, 1 H), 2.41 (ddd, J = 7.2, 10.2, 12.1 Hz, 1 H),
2.31 (ddd, J = 5.1, 8.0, 12.7 Hz, 1 H), 1.12 (m, 1 H), 1.07 (d, J = 5.2 Hz, 3 H), 0.88 (d, J = 5.1
Hz, 3 H), 0.88 - 0.83 (m, 2 H), 0.62 (s, 9 H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 179.8,
156.1, 136.2, 128.9, 127.8, 127.7, 113.4, 112.4, 111.2, 109.3, 63.7, 57.9, 56.2, 44.2, 43.3, 42.1,
37.4, 30.1, 29.7, 23.1, 13.5; HMRS (ESI): m/z calcd for C27H36N2O2 (M+H)+ 421.2857, found
421.2855.
(2'R*)-2'-(2,2-dimethylpropyl)-5-(methyloxy)-1'-(1-methylethyl)-1(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2-one (6hb): 5 (168 mg, 0.60 mmol), A (64 µL,
0.75 mmol), D (94 µL, 0.75 mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a
5mL vial with tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the
microwave to 160°C for 10 minutes. Then the crude mixture was analyzed by LC-MS and was
purified by column chromatography on silica gel (eluent: 50% AcOEt in hexane). The collected
fraction was evaporated to yield the title product as a brown-yellow solid (20.6 mg, 0.049 mmol,
8.2%); LCMS retention time: (2’S*,3S*)-diastereoisomer: 0.76 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ = 7.32 - 7.28 (m, 5 H), 7.08 (d, J = 2.3 Hz, 1 H), 6.68 (dd, J = 8.5, 2.5 Hz,
1 H), 6.61 (d, J = 8.4 Hz, 1 H), 5.01 (d, J = 15.6 Hz, 1 H), 4.70 (d, J = 15.6 Hz, 1 H), 3.77 (s, 3
H), 3.23 (d, 1 H), 3.05 (dd, J = 2.0, 7.8 Hz, 1 H), 3.01 (d, J = 6.8 Hz, 1 H), 2.34 - 2.26 (m, 1 H),
2.10 (dd, J = 7.6, 15.6 Hz, 1 H), 1.95 (dd, J = 6.6, 12.9 Hz, 1 H), 1.91 - 1.80 (m, 1 H), 1.25 (d, J =
3.7 Hz, 1 H), 1.22 (d, J = 6.6 Hz, 3 H), 1.07 (d, J = 7.4 Hz, 3 H), 0.63 (s, 9 H); 13C NMR (101
MHz, CHLOROFORM-d) δ = 179.9, 156.0, 136.2, 128.9, 127.9, 127.7, 113.4, 112.0, 111.2,
109.2, 109.0, 56.0, 46.4, 44.2, 43.3, 42.0, 37.4, 30.0, 29.9, 29.7, 29.6, 29.5, 23.4, 13.4, 13.4, 13.3;
HMRS (ESI): m/z calcd for C27H36N2O2 (M+H)+ 421.2856, found 421.2855.
2'-phenyl-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1-(phenylmethyl)spiro[indole-3,3'pyrrolidin]-2-one (6j): 5 (168 mg, 0.60 mmol), B (92 mg, 0.75 mmol), F (76 µL, 0.75 mmol)
and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran
(2mL). The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes.
Then the crude mixture was analyzed by LC-MS and was purified by column chromatography on
silica gel (eluent: 50% AcOEt in hexane). The collected fraction was evaporated to yield the title
product as orange solid (227.9 mg, 0.465 mmol, 77%, ratio 1:1); LCMS retention time:
(2’S*,3S*)-diastereoisomer (major): 1.11 min, (2’R*,3S*)-diastereoisomer (minor): 1.11 min; 1H
NMR (400 MHz, CHLOROFORM-d) δ = 7.32 (d, J = 2.1 Hz, 1 H), 7.31 - 7.27 (m, 5 H), 7.25 7.06 (m, 12 H), 6.98 (d, J = 2.3 Hz, 1 H), 6.76 - 6.72 (m, 5 H), 6.68 (dd, J = 2.4, 8.5 Hz, 1 H),
6.54 (dd, J = 2.5, 8.6 Hz, 4 H), 6.45 (d, J = 9.0 Hz, 1 H), 6.46 - 6.43 (m, 2 H), 6.39 (d, J = 8.4 Hz,
1 H), 4.98 (s, 1 H), 5.01 (d, J = 15.8 Hz, 1 H), 4.98 (d, J = 18.0 Hz, 1 H), 4.96 (s, 1H), 4.78 (d, J =
15.6 Hz, 1 H), 4.54 (td, J = 7.3, 8.8 Hz, 1 H), 4.21 (d, J = 15.8 Hz, 1 H), 4.18 - 4.11 (m, 1 H),
3.98 - 3.91 (m, 1 H), 3.79 (s, 3 H), 3.85 - 3.75 (m, 1 H), 3.71 (s, 6 H), 3.53 (s, 3 H), 2.61 - 2.41
(m, 3 H), 2.38 - 2.30 (m, 1 H); 13C NMR (101 MHz, CHLOROFORM-d) δ = 178.3, 176.6, 156.3,
155.5, 136.7, 136.1, 136.0, 135.7, 132.1, 130.8, 128.9, 128.8, 128.5, 128.3, 127.8, 127.7, 127.6,
127.5, 127.4, 127.4, 127.1, 127.0, 115.5, 115.0, 114.7, 113.1, 112.7, 112.6, 110.6, 109.6, 109.2,
72.4, 70.3, 60.1, 59.4, 56.0, 55.9, 51.1, 50.3, 44.0, 43.7, 34.9, 34.8, 22.9, 14.4; HMRS (ESI): m/z
calcd for C32H30N2O3 (M+H)+ 491.2335, found 491.2335.
S-10
(2'S*)-2'-phenyl-5-(methyloxy)-1'-(1-methylethyl)-1-(phenylmethyl)spiro[indole-3,3'pyrrolidin]-2-one (6k): 5 (168 mg, 0.60 mmol), A (64µL, 0.75 mmol), F (76µL, 0.75 mmol) and
magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran (2mL).
The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes. Then the
crude mixture was analyzed by LC-MS and was purified by column chromatography on silica gel
(eluent: 20% AcOEt in hexane). The collected fraction was evaporated to yield the title product as
a yellow solid (64.1 mg, 0.144mmol, 24%); LCMS retention time: (2’S*,3S*)-diastereoisomer:
0.69 min; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.17 (d, J = 2.0 Hz, 1 H), 7.16 (d, J = 1.8
Hz, 1 H), 7.12 (dd, J = 2.1, 11.8 Hz, 3 H), 7.13 (t, J =7.03 Hz, 2 H), 7.08 (d, J = 6.6 Hz, 1 H),
7.08 (d, J = 1.8 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.85 (d, J = 1.8 Hz, 1 H), 6.83 (d, J = 3.9 Hz,
1 H), 6.49 (dd, J = 2.6, 8.5 Hz, 1 H), 6.22 (d, J = 8.4 Hz, 1 H), 5.07 (d, J = 16.0 Hz, 1 H), 4.50 (d,
J = 16.0 Hz, 1 H), 4.38 (s, 1 H), 3.74 (s, 3 H), 3.34 (td, J = 6.5, 8.6 Hz, 1 H), 3.20 (td, J = 4.8, 9.8
Hz, 1 H), 2.99 (dt, J = 13.2, 6.6 Hz, 1 H), 2.55 (ddd, J = 6.3, 10.4, 12.5 Hz, 1 H), 2.05 (ddd, J =
4.8, 8.2, 12.6 Hz, 1 H), 1.20 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.2 Hz, 3 H); 13C NMR (101 MHz,
CHLOROFORM-d) δ = 178.3, 155.6, 137.3, 135.8, 135.7, 133.7, 128.7, 128.6, 127.8, 127.5,
127.4, 127.0, 113.7, 111.6, 108.8, 73.0, 59.9, 56.1, 47.1, 43.8, 42.5, 34.5, 22.8, 12.6; HMRS
(ESI): m/z calcd for C28H30N2O2 (M+H)+ 427.2384, found 427.2386.
2'-phenyl-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)spiro[indole-3,3'pyrrolidin]-2-one (6l): 5 (168 mg, 0.60 mmol), C (128 mg, 0.75 mmol), F (76 µL, 0.75 mmol)
and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran
(2mL). The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes.
Then the crude mixture was analyzed by LC-MS and was purified by column chromatography on
silica gel (eluent: 20% AcOEt in hexane). The collected fraction was evaporated and washed with
a sodium hydroxide solution 1.0 N. The organic phase was extracted with DCM and concentrated
to yield the title product as yellow solid (243.4 mg, 0.443 mmol, 74%, ratio 1:1); LCMS retention
time: (2’S*,3S*)-diastereoisomer (major): 1.03 min, (2’R*,3S*)-diastereoisomer (minor): 1.03
min; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.75 (d, J = 8.0 Hz, 4 H), 7.36 (d, J = 8.0 Hz,
5 H), 7.17 - 7.07 (m, 12 H), 7.02 - 6.98 (m, 3 H), 6.63 (dd, J = 2.4, 8.5 Hz, 1 H), 6.57 (d, J = 2.3
Hz, 1 H), 6.54 (dd, J = 2.5, 8.6 Hz, 1 H), 6.46 (d, J = 7.2 Hz, 1 H), 6.38 (d, J = 8.6 Hz, 1 H), 6.34
(d, J = 8.6 Hz, 1 H), 6.32 (d, J = 2.5 Hz, 1 H), 5.76 (br. s., 2 H), 5.02 (s, 1 H), 4.92 (d, J = 15.8
Hz, 2 H), 4.89 (s, 1 H), 4.58 (d, J = 15.6 Hz, 1 H), 4.44 (td, J = 5.7, 11.4 Hz, 1 H), 4.22 (t, J = 6.1
Hz, 1 H), 4.12 (d, J = 15.6 Hz, 1 H), 4.10 (dt, J = 1.7, 11.2 Hz, 1 H), 4.01 (d, J = 11.7 Hz, 1 H),
3.98 - 3.92 (m, 1 H), 3.77 (s, 3 H), 3.57 (s, 3 H), 2.47 (s., 3 H), 2.46 (s, 3 H), 2.21 - 2.06 (m, 2 H),
1.94 (td, J = 8.2, 12.1 Hz, 1 H); 13C NMR (101 MHz, CHLOROFORM-d) major diastereoisomer
δ = 176.6, 155.7, 144.1, 137.7, 135.7, 135.3, 133.7, 130.0, 129.9, 128.9, 128.4, 128.0, 128.0,
127.7, 127.2, 113.6, 112.6, 109.5, 70.3, 59.4, 56.0, 48.4, 43.9, 34.5, 21.9, minor diastereoisomer δ
= 175.9, 156.3, 144.1, 136.8, 136.4, 135.7, 130.9, 129.5, 128.8, 128.2, 128.0, 128.0, 127.8, 126.9,
113.2, 110.0, 109.9, 72.0, 60.3, 56.0, 49.4, 43.7, 36.2, 21.9; HMRS (ESI): m/z calcd for
C32H30N2O4S (M+H)+ 539.2002, found 539.2005.
2'-(3-furanyl)-5-(methyloxy)-1'-[4-(methyloxy)phenyl]-1-(phenylmethyl)spiro[indole-3,3'pyrrolidin]-2-one (6m): 5 (168 mg, 0.60 mmol), B (92 mg, 0.75 mmol), E (63 µL, 0.75 mmol)
and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran
(2mL). The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes.
Then the crude mixture was analyzed by LC-MS and was purified by column chromatography on
silica gel (eluent: 20% AcOEt in hexane). The collected fraction was evaporated to yield the title
product as a yellow solid (112.8 mg, 0.235 mmol, 39%, ratio 1:1); LCMS retention time:
(2’S*,3S*)-diastereoisomer (major): 1.08 min, (2’R*,3S*)-diastereoisomer (minor): 1.08 min; 1H
NMR (400 MHz, CHLOROFORM-d) δ = 7.31 (t, J = 1.8 Hz, 1 H), 7.29 (d, J = 7.2 Hz, 2 H), 7.27
S-11
- 7.22 (m, 4 H), 7.19 (t, J = 1.6 Hz, 1 H), 7.16 (d, J = 6.6 Hz, 3 H), 7.13 (m., 1 H), 7.11 (d, J = 1.6
Hz, 1 H), 7.05 (s, 1 H), 6.99 (dd, 1 H), 6.89 (d, J = 2.3 Hz, 1 H), 6.86 - 6.83 (m, 1 H), 6.78 (d, J =
9.0 Hz, 4 H), 6.69 (dd, J = 2.5, 8.6 Hz, 2 H), 6.62 (dd, J = 2.5, 8.6 Hz, 1 H), 6.57 (d, J = 8.6 Hz, 1
H), 6.50 (d, J = 8.4 Hz, 1 H), 6.51 (d, J = 8.4 Hz, 3 H), 6.02 (d, J = 1.0 Hz, 1 H), 5.96 (m, 1 H),
5.05 (d, J = 15.6 Hz, 1 H), 4.95 (m., 1 H), 4.97 (d, J = 19.1 Hz, 2 H), 4.87 (s, 1 H), 4.82 - 4.77 (m,
1 H), 4.47 - 4.36 (m, 1 H), 3.92 - 3.83 (m, 1 H), 3.77 (s, 3 H), 3.73 (s, 6 H), 3.70 (s, 3 H), 2.66 2.56 (m, 1 H), 2.50 (dd, J = 3.0, 7.1 Hz, 1 H), 2.47 (dd, J = 3.0, 6.9 Hz, 1 H), 2.38 (dt, J = 8.8,
12.4 Hz, 1 H), 2.30 - 2.20 (m, 1 H), 13C NMR (101 MHz, CHLOROFORM-d) major
diastereoisomer δ = 177.6, 159.7, 155.8, 142.7, 140.8, 136.0, 131.7, 130.2, 128.9, 127.8, 127.5,
127.3, 123.8, 116.3, 115.2, 114.5, 113.1, 112.3, 111.5, 110.2, 109.3, 63.3, 56.0, 55.9, 51.2, 44.1,
34.5, 29.2, minor diastereoisomer δ = 177.4, 156.3, 152.4, 145.9, 142.2, 136.1, 130.0, 129.9,
129.0, 127.5, 127.2, 127.1, 126.1, 115.0, 114.6, 114.4, 112.7, 111.9, 110.3, 110.1, 109.6, 59.2,
56.1, 55.8, 47.8, 44.0, 34.3, 29.9; HMRS (ESI): m/z calcd for C30H28N2O4 (M+H)+ 481.2126,
found 481.2127.
(2'S*)-2'-(3-furanyl)-5-(methyloxy)-1'-(1-methylethyl)-1-(phenylmethyl)spiro[indole-3,3'pyrrolidin]-2-one (6n): 5 (168 mg, 0.60 mmol), A (64 µL, 0.75 mmol), E (63µL, 0.75 mmol)
and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with tetrahydrofuran
(2mL). The reaction vessel was sealed and heated in the microwave to 160°C for 10 minutes.
Then the crude mixture was analyzed by LC-MS and was purified by column chromatography on
silica gel (eluent: 25% AcOEt in hexane with an isocratic gradient). The collected fraction was
evaporated to yield the title product as yellow solid (8.5 mg, 0.02 mmol, 3%); LCMS retention
time: (2’S*,3S*)-diastereoisomer: 0.64 min; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.35 7.27 (m, 2 H), 7.24 (d, J = 2.5 Hz, 1 H), 7.19 (d, J = 1.6 Hz, 1 H), 7.21 - 7.18 (m, 1 H), 7.16 (s, 1
H), 7.08 (t, J = 1.5 Hz, 1 H), 6.87 (dd, J = 2.0, 7.4 Hz, 2 H), 6.60 (dd, J = 2.5, 8.4 Hz, 1 H), 6.36
(d, J = 8.4 Hz, 1 H), 5.84 (d, J = 1.4 Hz, 1 H), 5.11 (d, J = 16.0 Hz, 1 H), 4.52 (d, J = 16.0 Hz, 1
H), 4.23 (s, 1 H), 3.78 (s, 3 H), 3.25 (td, J = 6.2, 8.8 Hz, 1 H), 3.08 (td, J = 4.7, 9.9 Hz, 1 H), 2.99
(dt, J = 6.6, 13.3 Hz, 1 H), 2.51 (ddd, J = 6.1, 10.7, 12.5 Hz, 1 H), 2.03 (ddd, J = 4.7, 8.4, 12.8
Hz, 1 H), 1.18 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.4 Hz, 3 H); 13C NMR (101 MHz,
CHLOROFORM-d) δ = 178.0, 155.7, 142.5, 141.5, 136.0, 135.8, 134.6, 128.7, 128.6, 127.4,
126.8, 121.8, 113.5, 111.6, 111.6, 110.5, 108.9, 65.3, 58.9, 56.0, 46.9, 43.8, 42.0, 33.7, 22.6,
12.4; HMRS (ESI): m/z calcd for C26H28N2O3 (M+H)+ 417.2177, found 417.2178.
2'-(3-furanyl)-5-(methyloxy)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)spiro[indole3,3'-pyrrolidin]-2-one (6o): 5 (168 mg, 0.60 mmol), C (128 mg, 0.75 mmol), E (63 µL, 0.75
mmol) and magnesium iodide (167mg, 0.60 mmol) were placed in a 5mL vial with
tetrahydrofuran (2mL). The reaction vessel was sealed and heated in the microwave to 160°C for
10 minutes. Then the crude mixture was analyzed by LC-MS and was purified by column
chromatography on silica gel (eluent: 50% AcOEt in hexane). The collected fraction was
evaporated and washed with a sodium hydroxide solution 1.0 N. Then the organic phase was
extracted with DCM and concentrated to yield the title product as pale yellow solid (119.0mg,
0.225 mmol, 38%, ratio 1:1); LCMS retention time: (2’S*,3S*)-diastereoisomer (major): 0.99
min, (2’R*,3S*)-diastereoisomer (minor): 0.98 min; 1H NMR (400 MHz, CHLOROFORM-d) δ =
7.73 (d, J = 8.2 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.34 (dd, J = 5.6, 7.7 Hz, 4 H), 7.13 (dt, J =
1.6, 17.8 Hz, 4 H), 6.96 (d, J = 2.5 Hz, 2 H), 6.90 - 6.80 (m, J = 4.7 Hz, 4 H), 6.65 (dd, J = 2.4,
8.5 Hz, 2 H), 6.58 (d, J = 2.3 Hz, 2 H), 6.44 (d, J = 8.6 Hz, 2 H), 6.13 (d, J = 1.0 Hz, 1 H), 5.91 5.84 (m, 3 H), 5.00 (s, 1 H), 4.94 (d, J = 15.4 Hz, 1 H), 4.94 (d, J = 18.4 Hz, 1 H), 4.60 (s, 1 H),
4.54 (d, J = 15.8 Hz, 1 H), 4.36 (d, J = 15.6 Hz, 1 H), 4.36 - 4.29 (m, 2 H), 4.10 - 4.04 (m, 2 H),
3.75 (s, 3 H), 3.75 (s, 3 H), 2.46 (s, 6 H), 2.29 - 2.17 (m, 2 H), 2.07 - 1.92 (m, 2 H); 13C NMR
(101 MHz, CHLOROFORM-d) major diastereoisomer δ = 176.1, 156.1, 144.0, 142.7, 140.4,
S-12
136.4, 135.6, 135.5, 130.8, 129.9, 128.8, 127.9, 127.7, 127.1, 121.9, 113.1, 112.8, 110.3, 110.0,
109.9, 63.5, 59.2, 56.0, 48.9, 43.9, 35.5, 21.9, minor diastereoisomer δ = 175.5, 156.3, 144.3,
142.7, 141.2, 135.8, 135.4, 130.1, 130.0, 128.9, 128.3, 127.7, 126.8, 121.4, 113.1, 110.5, 109.8,
64.4, 59.6, 56.1, 48.2, 43.7, 33.3, 21.8; HMRS (ESI): m/z calcd for C30H28N2O5S (M+H)+
529.1797, found 529.1797.
References:
1. Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann E.; Parr, J.; Storey J. M. D.
Angew Chem Int Ed 2004, 43, 95-98
2. Fischer, C.; Meyers, C.; Carreira, E. M. Helv Chim Acta 2000, 83, 1175-1181
3. Alper, P. B.; Meyers, C.; Siegel, D. R.; Carreira, E. M. Angew Chem Int Ed 1999, 38,
3186-3189
S-13
N10575-8-1AA_56BR_H1
0.45
0.40
O
N
Normalized Intensity
0.35
4
0.30
0.25
0.20
0.15
0.10
0.05
10
9
8
7
6
5
Chemical Shift (ppm)
S-14
4
3
2
1
0
1.0
N10575-18-A1_4X4H_H1
0.9
O
O
N
0.8
Normalized Intensity
0.7
0.6
5
0.5
0.4
0.3
0.2
0.1
10
9
8
7
6
5
Chemical Shift (ppm)
S-15
4
3
2
1
1.0
N10575-18-1C13_BRW3_C13
0.9
O
O
N
0.8
Normalized Intensity
0.7
0.6
5
0.5
0.4
0.3
0.2
0.1
0
180
160
140
120
100
80
Chemical Shift (ppm)
S-16
60
40
20
0
N
O
CN
N
(4b)
S-17
N
O
CN
N
(4b)
S-18
O
O S
N
CN
O
N
(4c)
S-19
O
O S
N
CN
O
N
(4c)
S-20
O
N
O
Cl
N
(4d)
S-21
O
N
O
Cl
N
(4d)
S-22
N
O
Cl
N
(4e)
S-23
N
O
Cl
N
(4e)
S-24
O
O S
N
O
Cl
N
(4f)
S-25
O
O S
N
O
Cl
N
(4f)
S-26
O
N
O
N
(4g)
S-27
O
N
O
N
(4g)
S-28
N
O
N
(4h)
S-29
N
O
N
(4h)
S-30
O
N
O
N
(4j)
S-31
O
N
O
N
(4j)
S-32
N
O
N
(4k)
S-33
N
O
N
(4k)
S-34
S
N
O
O
O
N
(4l)
S-35
S
N
O
O
O
N
(4l)
S-36
O
N
O
O
N
(4m)
S-37
O
N
O
O
N
(4m)
S-38
N
O
N
O
(4n)
S-39
N
O
N
O
(4n)
S-40
O
N
CN
O
N
(4a)
S-41
O
N
CN
O
N
(4a)
S-42
O
N
CN
O
O
N
(6a)
S-43
O
N
CN
O
O
N
(6a)
S-44
N
CN
O
O
N
(6b)
S-45
N
CN
O
O
N
(6b)
S-46
O
O S
N
CN
O
O
N
(6c)
S-47
O
O S
N
CN
O
O
N
(6c)
S-48
O
N
O
O
N
Cl
(6d)
S-49
O
N
O
O
N
Cl
(6d)
S-50
N
O
O
N
Cl
(6e)
S-51
N
O
O
N
Cl
(6e)
S-52
O
O S
N
O
O
Cl
N
(6f)
S-53
O
O S
N
O
O
Cl
N
(6f)
S-54
O
N
O
O
N
(6g)
S-55
O
N
O
O
N
(6g)
S-56
N
O
O
N
(6ha)
S-57
N
O
O
N
(6ha)
S-58
N
O
O
N
(6hb)
S-59
N
O
O
N
(6hb)
S-60
O
N
O
O
N
(6j)
S-61
O
N
O
O
N
(6j)
S-62
N
O
O
N
(6k)
S-63
N
O
O
N
(6k)
S-64
O O
S
N
O
O
N
(6l)
S-65
O O
S
N
O
O
N
(6l)
S-66
O
N
O
O
O
N
(6m)
S-67
O
N
O
O
O
N
(6m)
S-68
N
O
O
O
N
(6n)
S-69
N
O
O
O
N
(6n)
S-70
O
O
S
N
O
O
O
N
(6o)
S-71
O
O
S
N
O
O
O
N
(6o)
S-72