A facile access to enantioenriched isoindolines via one-pot sequential Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition/aromatization

Article abstract of DOI:10.1021/ol302987h

Facile access to enantioenriched isoindolines bearing a quaternary stereogenic center and a tertiary stereogenic center was successfully developed via highly efficient Cu(I)/(S,Rp)-PPFOMe-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylide with quinone derivatives followed by silica-gel-promoted aromatization in a one-pot reaction protocol. The present catalytic system exhibited high diastereoselectivity, excellent enantioselectivity, and a broad substrate scope under mild conditions.

Full text of DOI:10.1021/ol302987h

Supporting Information for
A Facile Access to Enantioenriched Isoindolines via One-Pot
Sequential Cu(I)-Catalyzed Asymmetric 1,3-Dipolar
Cycloaddition/Aromatization
Zhao-Lin He, Tang-Lin Liu, Haiyan Tao, and Chun-Jiang Wang*
Table of Contents
I.
General Remarks..............................................................................................S2
Ligand Screening for one pot and sequential catalytic asymmetric 1,3-DC/
Aromatization reaction...............................................................................S2-S3
II.
III.
p
General Procedure for Cu(I)/(S,R )-PPFOMe-Catalyzed Asymmetric 1,3-
Dipolar Cycloaddition/Aromatization......................................................S3-S16
The Absolute Configuration Determination of (1R,3R)-5b....................S16-S17
Proposed Relative Configuration of Keto-Isomer Intermidiate in This One-Pot
Sequential Catalytic Asymmetric 1,3-DC/ Aromatization.....................S17-S18
The Relative Configuration Determination of Racemic endo-9....................S19
IV.
V.
VI.
VII. References......................................................................................................S19
1
13
VIII. H NMR and C NMR Spectra..............................................................S20-S62
IX.
HPLC Chromatograms.........................................................................S63-S102
S1

I. General Remarks.
1
H NMR spectra were recorded on a VARIAN Mercury 300 MHz or Bruker 400
1
3
MHz spectrometer in CDCl
3
. C NMR spectra were recorded on a VARIAN Mercury
7
5 MHz or Bruker 100 MHz spectrometer in CDCl
3
. Commercially obtained reagents
were used without further purification. All reactions were monitored by TLC with
1
silica gel-coated plates. Diastereomeric ratios were determined from crude H NMR
or HPLC analysis. Enantiomeric excesses were determined by HPLC, using a
chiralpak AD-H column, a chiralpak AS-H column or a chiralcel OD-H column with
hexane and i-PrOH as solvents. (S,R
p
)-L6 were prepared according to the literature
BF /PPh as the
)-PPFOMe was
1
procedure. The racemic adducts were attained by using Cu(CN)
4
4
3
4 4 p
catalyst. The absolute (1R,3R)-5b achieved by Cu(CN) BF /(S,R
determined unequivocally according to the X-ray diffraction analysis, and those of
2
other adducts were deduced on the basis of these results.
II. Ligand Screening for One Pot and Sequential Catalytic Asymmetric
1
,3-DC/Aromatization Reaction
CF3
R
PPh2
PPh2
Fe
PPh2
PPh2
O
O
F3C
F3C
NH2
1
2
NR R
OMe
P N
Fe
NHPPh2
R
1
2
(
(
(
S,R )-L3: R = Me, R = Me (S,R )-L6
p
p
CF3
1
2
S,R )-L4: R = H, R = Me
p
(
S)-TF-BiphamPhos
1
2
(S)-BINAP L7
(S)-Monophos L8
S,R )-L5: R = H, R = H
p
L1: R = H; L2: R = Br
Ph
Ph
Ph
Ph
PPh2
Fe
PPh2
Fe
O
O
O
P N
O
P N
O
P N
O
N
Ph
Ph
Ph
Ph
(
S,R,R)-L9
(R,R,R)-L10
(S,R,R)-L11
(Rp)-L12
(S,Rp)-L13
PPh2
PPh2
OMe
PPh2
NHBn
OEt
Fe
Fe
(
S,R )-L14
(S,R )-L15
(S)-MOP L16
p
p
Scheme 1. Screened chiral ligands.
S2

p
III. General Procedure for Cu(I)/(S,R )-PPFOMe-Catalyzed Asymmetric 1,3-
Dipolar Cycloaddition/Aromatization
p
Under argon atmosphere, (S,R )-PPFOMe (3.1 mg, 0.0072 mmol) and
Cu(CH CN) BF (1.9 mg, 0.006 mmol) were dissolved in toluene (2 mL), and stirred
3
4
4
at room temperature for about 1 h. Then, imine substrate (0.26 mmol), and
naphthoquione (0.2 mmol) were added sequentially, after that the mixture was
o
dropped to -20 C, TEA (3 mg, 0.03 mmol) was added. Once starting material was
S3

consumed (monitored by TLC), The reaction mixture was treated with silica gel for a
short time, then the organic solvent was removed and the residue was purified by
column chromatography to give the product, which was then directly analyzed by
chiral HPLC to determine the enantiomeric excess.
(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-phenyl-2,3-dihydro-1H-benzo[f]isoin-
dole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 86% yield. m.p. 118-121 C; []
3
= +128.2 (c 1.36, CHCl ); H NMR
D
(
CDCl , TMS, 300 MHz)  8.16 (d, J =7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),
3
7
1
1
1
1
1
3
9
.76-7.68 (m, 2H), 7.34-7.15 (m, 10H), 4.88 (s, 1H), 3.85 (s, 3H), 3.63 (d, J = 14.1 Hz,
1
3
H), 3.46 (d, J = 14.1 Hz, 1H); C NMR (CDCl
3
, TMS, 75 MHz)  182.4, 181.6,
72.6, 150.6, 146.4, 141.2, 135.6, 133.8, 132.7, 130.3, 128.4, 128.2, 127.9, 127.7,
13
27.1, 126.4, 126.3, 75.4, 67.1, 52.9, 41.9; C NMR (DMSO-d , TMS, 100 MHz) 
6
82.0, 180.8, 171.8, 149.6, 146.4, 142.2, 135.8, 134.4, 134.3, 131.8, 131.6, 129.7,
27.8, 127.7, 127.1, 126.6, 125.9, 125.8, 74.5, 66.4, 52.3, 40.7; IR (KBr)  3382,
061, 3026, 2957, 2848, 2167, 1740, 1635, 1593, 1494, 1454, 1635, 1297, 1247, 1045,
-
1
+
4
09, 774, 736, 702 cm . HRMS: calcd. for C27H22NO : 424.1543, found 424.1537.
The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee
Chiralpak AS-H, i-propanol/hexane = 20/80, flow rate 1.0 mL/min, λ = 220 nm); t =
(
r
11.59 and 33.88 min.
S4

(
1R,3R)-methyl
1-benzyl-3-(4-chlorophenyl)-4,9-dihydroxy-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
3
above in 89% yield. m.p. 112-115 C; []
= +97.4 (c 1.60, CHCl ); H NMR
D
(CDCl
3
, TMS, 300 MHz)  8.16 (d, J =7.5 Hz, 1H), 7.88 (d, J = 7.5 Hz), 7.79-7.68 (m,
2
1
1
1
1
4
H), 7.31-7.19 (m, 7H), 7.12 (m, 2H ), 4.84 (s, 1H), 3.85 (s, 3H), 3.63 (d, J = 13.8 Hz,
1
3
H), 3.46 (d, J = 13.8 Hz, 1H); C NMR (CDCl , TMS, 75 MHz)  182.3, 181.5,
3
72.5, 150.0, 146.4, 139.8, 135.4, 133.9, 133.6, 132.6, 130.7, 130.2, 129.2, 128.5,
28.3, 127.6, 127.1, 126.5, 126.3, 75.3, 66.3, 52.9, 41.6; IR (KBr)  3380, 1741, 1667,
-
1
+
637, 1594, 1491, 1339, 1219, 1089, 704 cm . HRMS: calcd. for C27
4
H21ClNO :
58.1154, found. 458.1148. The product was analyzed by HPLC to determine the
enantiomeric excess: 95% ee (Chiralpak AS-H, i-propanol/hexane = 40/60, flow rate
.0 mL/min, λ = 220 nm); t = 8.07 and 20.86 min.
1
r
(
1R,3S)-methyl
1-benzyl-3-(2-chlorophenyl)-4,9-dihydroxy-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 87% yield. m.p. 129-132 C; []
D 3
= +75.4 (c 1.54, CHCl ); H NMR
(CDCl
3
, TMS, 300 MHz)  8.18 (d, J =7.5 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H),
7
3
.90-7.71 (m, 2H), 7.35-7.32 (m, 1H), 7.24-7.15 (m, 8H), 5.36 (s, 1H), 3.80 (s, 3H),
1
3
3
.63 (d, J = 14.1 Hz, 1H), 3.47 (d, J = 14.1 Hz, 1H), 2.79 (br, 1H); C NMR (CDCl ,
TMS, 75 MHz)  182.1, 181.1, 172.2, 150.2, 147.3, 138.6, 135.2, 133.7, 133.1, 132.6,
1
4
1
1
32.5, 130.0, 129.3, 129.0, 128.8, 128.2, 127.1, 127.0, 126.4, 126.3, 75.1, 62.6, 52.7,
1
3
1.4; C NMR (DMSO-d , TMS, 100 MHz)  181.9, 180.5, 171.7, 149.4, 147.2,
6
39.6, 135.7, 134.6, 134.5, 132.0, 131.7, 131.6, 129.8, 129.7, 128.8, 128.7, 127.8,
27.2, 126.8, 126.0, 125.9, 74.5, 62.0, 52.4, 40.5; IR (KBr)  3374, 2951, 2168, 1740,
S5

1
637, 1593, 1496, 1474, 1438, 1368, 1340, 1297, 1253, 1050, 906, 798, 755, 742, 705
-1
+
cm . HRMS: calcd. for C27
4
H21ClNO : 458.1154, found. 458.1150. The product was
analyzed by HPLC to determine the enantiomeric excess: 94% ee (Chiralpak AS-H,
r
i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 220 nm); t = 8.79 and 26.77
min.
(
1R,3R)-methyl
1-benzyl-3-(3-chlorophenyl)-4,9-dihydroxy-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 87% yield. m.p. 176-179 C; []
D 3
= +59.0 (c 1.52, CHCl ); H NMR
(CDCl
3
, TMS, 300 MHz)  8.15 (m, 1H), 7.88 (m, 1H), 7.77-7.70 (m, 2H), 7.38 (m,
1
1
1
1
H), 7.21-7.19 (m, 7H), 7.11-7.10 (m, 1H), 4.85 (s, 1H), 3.87 (s, 3H), 3.63 (d, J =
1
3
4.1 Hz, 1H), 3.46 (d, J = 14.1 Hz, 1H); C NMR (CDCl
3
, TMS, 75 MHz)  182.3,
81.4, 172.4, 149.9, 146.5, 143.4, 135.4, 134.2, 133.9, 132.7, 130.2, 129.5, 128.4,
1
3
6
28.1, 128.0, 127.2, 126.5, 126.4, 126.1, 75.3, 66.5, 52.9, 41.6; C NMR (DMSO-d ,
TMS, 100 MHz)  181.9, 180.7, 171.7, 148.9, 146.6, 144.8, 135.7, 134.5, 134.4,
1
5
1
4
9
32.4, 131.7, 131.6, 129.6, 127.8, 127.6, 127.1, 126.6, 126.4, 125.9, 125.8, 74.6, 65.8,
2.2, 40.5; IR (KBr)  3382, 2168, 1741, 1637, 1594, 1433, 1369, 1340, 1297, 1249,
-1
+
4
048, 777, 740, 705, 587 cm . HRMS: calcd. for C27H21ClNO : 458.1154, found.
58.1146. The product was analyzed by HPLC to determine the enantiomeric excess:
4% ee (Chiralpak AS-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 220
r
nm); t = 9.51 and 31.36 min.
S6

(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(4-(trifluoromethyl)phenyl)-2,3-dihy-
dro-1H-benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 87% yield. m.p. 187-190 C; []
3
= +72.6 (c 1.84, CHCl ); H NMR
D
(CDCl
3
, TMS, 300 MHz)  8.17 (d, J =7.5 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H),
7
3
.80-7.68 (m, 2H), 7.55-7.47 (m, 4H), 7.22-7.10 (m, 5H), 4.92 (s, 1H), 3.86 (s, 3H),
13
3
.65 (d, J = 14.1 Hz, 1H), 3.47 (d, J = 14.1 Hz, 1H); C NMR (CDCl , TMS, 100
MHz)  182.3, 181.5, 172.4, 149.8, 146.7, 145.2, 135.3, 134.0, 133.9, 132.7, 130.2,
1
29.9 (JC-F = 32.4 Hz), 128.4, 128.3, 127.3, 126.6, 126.4, 125.3 (JC-F = 3.7 Hz), 124.0
C-F = 270.3 Hz), 75.4, 66.6, 53.0, 41.6; IR (KBr) 3384, 2953, 1742, 1668, 1637,
618, 1594, 1496, 1436, 1369, 1325, 1249, 1219, 1165, 1124, 1067, 1017, 849, 735,
(
J
1
7
-1
+
21 3 4
04, 642, 601 cm . HRMS: calcd. for C28H F NO : 492.1409, found. 492.1417. The
product was analyzed by HPLC to determine the enantiomeric excess: 92% ee
Chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 220 nm); t =
(
r
8
.85 and 10.63 min.
(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(p-tolyl)-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 93% yield. m.p. 176-178 C; []
D 3
= +156.3 (c 1.62, CHCl ); H NMR
3
(CDCl , TMS, 300 MHz)  8.15 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H),
7
.86-7.67 (m, 2H), 7.21-7.07 (m, 9H), 4.85 (s, 1H), 3.84 (s, 3H), 3.62 (d, J = 13.8 Hz,
S7

1
3
1
1
1
2
3
H), 3.44 (d, J = 13.8 Hz, 1H), 2.29 (s, 3H); C NMR (CDCl , TMS, 75 MHz) 
82.4, 181.6, 172.6, 150.7, 146.3, 138.3, 137.5, 135.6, 133.7, 132.7, 130.3, 129.1,
28.1, 127.5, 127.0, 126.4, 126.3, 75.3, 66.8, 52.8, 41.8, 21.1; IR (KBr)  3381, 3029,
-1
951, 1740, 1634, 1593, 1453, 1339, 1297, 1246, 1045, 816, 771, 735, 704 cm .
+
HRMS: calcd. for C28
H24NO
4
: 438.1670, found. 438.1695. The product was analyzed
by HPLC to determine the enantiomeric excess: 95% ee (Chiralpak AS-H,
r
i-propanol/hexane = 30/70, flow rate 1.2 mL/min, λ = 220 nm); t = 7.57 and 20.44
min.
(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(o-tolyl)-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 81% yield. m.p. 135-138 C; []
3
= +107.4 (c 1.50, CHCl ); H NMR
D
(CDCl
3
, TMS, 300 MHz)  8.17 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H),
7
1
1
1
1
.79-7.67 (m, 2H), 7.19-7.12 (m, 9H), 4.92 (s, 1H), 3.82 (s, 3H), 3.58 (d, J = 13.5 Hz,
1
3
H), 3.46 (d, J = 13.5 Hz, 1H), 2.34 (s, 3H); C NMR (CDCl , TMS, 75 MHz) 
3
82.2, 181.4, 172.4, 151.8, 147.2, 139.1, 135.7, 133.7, 132.7, 130.3, 127.9, 127.6,
27.2, 126.9, 126.4, 126.2, 75.1, 62.7, 52.8, 41.9, 19.1; IR (KBr)  3358, 3029, 2950,
-1
+
740, 1667, 1593, 1219, 1050, 735 cm . HRMS: calcd. for C H NO : 438.1670,
2
8
24
4
found. 438.1693. The product was analyzed by HPLC to determine the enantiomeric
excess: 93% ee (Chiralcel OD-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ
=
r
220 nm); t = 6.33 and 15.03 min.
S8

(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(m-tolyl)-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 86% yield. m.p. 179-182 C; []
3
= +113.5 (c 1.48, CHCl ); H NMR
D
(CDCl
3
, TMS, 300 MHz)  8.16 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H),
7
1
1
1
.76-7.69 (m, 2H), 7.19-7.06 (m, 9H), 4.84 (s, 1H), 3.84 (s, 3H), 3.62 (d, J = 14.1 Hz,
1
3
H), 3.45 (d, J = 14.1 Hz, 1H), 2.29 (s, 3H); C NMR (CDCl , TMS, 75 MHz) 
3
82.5, 181.6, 172.6, 150.8, 146.4, 141.2, 138.0, 135.6, 133.8, 133.7, 132.8, 130.3,
28.7, 128.5, 128.3, 128.2, 127.0, 126.4, 126.3, 124.8, 75.4, 67.1, 52.8, 41.9, 21.4; IR
(
KBr)  3383, 3026, 2951, 1741, 1667, 1643, 1593, 1454, 1339, 1296, 1246, 1169,
-1
+
1
4
044, 733, 704 cm . HRMS: calcd. for C28H24NO : 438.1670, found. 438.1695. The
product was analyzed by HPLC to determine the enantiomeric excess: 97% ee
Chiralpak AS-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 220 nm); t =
(
r
7
.95 and 19.35 min.
(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(4-methoxyphenyl)-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 81% yield. m.p. 143-145 C; []
3
= +215.9 (c 1.44, CHCl ); H NMR
D
(CDCl
3
, TMS, 300 MHz)  8.16 (d, J =7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),
7
3
.78-7.66 (m, 2H), 7.23-7.15 (m, 7H), 6.81 (d, J = 8.1 Hz, 2H), 4.85 (s, 1H), 3.85 (s,
1
3
H), 3.76 (s, 3H), 3.61 (d, J = 13.5 Hz, 1H), 3.45 (d, J = 13.5 Hz, 1H); C NMR
S9

(
CDCl
3
, TMS, 75 MHz)  182.5, 181.6, 172.7, 159.1, 150.6, 146.1, 135.6, 133.7,
33.4, 132.7, 130.2, 128.8, 128.2, 127.0, 126.4, 126.3, 113.7, 75.2, 66.5, 55.1, 52.9,
1.8; IR (KBr)  3381, 3029, 2952, 2837, 1740, 1633, 1593, 1511, 1454， 1367, 1338,
1
4
1
-1
301, 1246, 1174, 1034, 915, 833, 771, 736, 712, 641, 586, 554 cm . HRMS: calcd.
+
for C28
H24NO
5
: 454.1649, found. 454.1641. The product was analyzed by HPLC to
determine the enantiomeric excess: 96% ee (Chiralpak AS-H, i-propanol/hexane =
0/70, flow rate 1.2 mL/min, λ = 220 nm); t = 13.51 and 39.34 min.
3
r
(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(2-methoxyphenyl)-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 85% yield. m.p. 149-152 C; []
3
= +49.3 (c 0.93, CHCl ); H NMR
D
3
(CDCl , TMS, 300 MHz)  8.16 (d, J =6.9 Hz, 1H), 7.88 (d, J = 6.9 Hz, 1H),
7
4
1
1
1
1
8
4
9
.87-7.69 (m, 2H), 7.22-7.13 (m, 6H), 6.92-6.89 (m, 2H), 6.77 (d, J = 7.5 Hz, 1H),
.87 (s, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.62 (d, J = 14.1 Hz, 1H), 3.45 (d, J = 14.1 Hz,
1
3
H), 2.69 (br, 1H); C NMR (CDCl , TMS, 75 MHz)  182.4, 181.5, 172.6, 159.6,
3
50.6, 146.3, 142.9, 135.6, 133.8, 133.7, 132.7, 130.3, 129.3, 128.2, 127.1, 126.4,
26.3, 120.1, 113.5, 113.2, 75.4, 67.0, 55.0, 52.9, 41.8; IR (KBr)  3382, 3027, 2950,
740, 1634, 1593, 1508, 1495, 1453, 1434, 1368, 1337, 1296, 1245, 1169, 1045, 860,
-1
+
5
19, 771, 731, 704 cm . HRMS: calcd. for C28H25NO + H : 456.1806, found.
56.1790. The product was analyzed by HPLC to determine the enantiomeric excess:
4% ee (Chiralpak AS-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 220
r
nm); t = 11.87 and 33.47 min.
S10

(
1R,3R)-methyl 1-benzyl-4,9-dihydroxy-3-(naphthalen-2-yl)-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 79% yield. m.p. 198-201 C; []
3
= +43.1 (c 1.46, CHCl ); H NMR
D
(CDCl
3
, TMS, 300 MHz)  8.17 (d, J =7.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H),
7
3
.77-7.67 (m, 5H), 7.47-7.42 (m, 3H), 7.22-7.17 (m, 6H), 5.05 (s, 1H), 3.89 (s, 3H),
1
3
3
.66 (d, J = 14.1 Hz, 1H), 3.49 (d, J = 14.1 Hz, 1H), 2.78 (br, 1H); C NMR (CDCl ,
TMS, 75 MHz)  182.5, 181.6, 172.6, 150.5, 146.4, 138.6, 135.6, 133.7, 133.1, 133.0,
1
7
1
32.7, 130.3, 128.3, 128.0, 127.6, 127.1, 126.9, 126.4, 126.3, 126.0, 125.9, 125.4,
5.4, 67.2, 52.9, 41.9; IR (KBr)  3382, 3060, 2951, 2360, 1741, 1633, 1593, 1496,
-
1
454, 1434, 1336, 1296, 1244, 1169, 1125, 1045, 860, 818, 770, 731, 703, 668 cm .
+
HRMS: calcd. for C31
H24NO
4
: 474.1700, found. 474.1689. The product was analyzed
by HPLC to determine the enantiomeric excess: 97% ee (Chiralpak AS-H,
i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 220 nm); t = 12.75 and 28.66
r
min.
(
1R,3S)-methyl 1-benzyl-3-(furan-2-yl)-4,9-dihydroxy-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
1
above in 76% yield. m.p. 155-158 C; H NMR (CDCl
3
, TMS, 300 MHz)  8.18 (d, J
=
7.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.77-7.71 (m, 2H), 7.17 (s, 5H), 6.28 (m, 1H),
6
.21 (m, 1H), 5.13 (s, 1H), 3.78 (s, 3H), 3.62 (d, J = 13.5 Hz, 1H), 3.45 (d, J = 13.5
S11

1
3
Hz, 1H), 2.79 (br, 1H); C NMR (CDCl
52.9, 148.3, 146.7, 142.2, 135.5, 133.9, 132.6, 130.5, 128.1, 127.0, 126.6, 126.3,
10.6, 107.5, 75.7, 59.4, 42.0; IR (KBr)  3374, 2926, 1736, 1637, 1594, 1436, 1337,
3
, TMS, 75 MHz)  182.2, 181.6, 172.8,
1
1
1
-1
+
293, 1270, 1148, 1046, 770, 732, 702 cm . HRMS: calcd. for C H NO : 414.1336,
2
5
20
5
found. 414.1330. The product was analyzed by HPLC to determine the enantiomeric
excess: 94% ee (Chiralpak AS-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ
=
r
220 nm); t = 11.18 and 14.19 min.
(
1R,3R)-methyl 1-benzyl-3-cyclohexyl-4,9-dihydroxy-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
3
above in 70% yield. m.p. 138-141 C; []
= +83.7 (c 1.28, CHCl ); H NMR
D
3
(CDCl , TMS, 300 MHz)  8.14 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H),
7
3
.77-7.73 (m, 2H), 7.14-7.13 (m, 3H), 7.05-7.03 (m, 2H), 3.81 (s, 1H), 3.77 (s, 3H),
.59 (d, J = 13.8 Hz, 1H), 3.38 (d, J = 13.8 Hz, 1H), 2.23 (m, 1H), 1.94 (m, 1H), 1.70
1
3
(
m, 1H), 1.61 (m, 3H), 1.50-1.47 (m, 1H), 1.23-1.12 (m, 4H); C NMR (CDCl
3
, TMS,
5 MHz)  182.4, 172.9, 151.1, 146.9, 135.6, 133.7, 133.6, 132.9, 132.7, 130.1, 128.2,
27.0, 126.4, 74.8, 68.5, 52.6, 41.6, 41.0, 30.6, 26.5, 26.2, 26.1, 26.0; IR (KBr) 
7
1
3
-1
358, 2977, 1735, 1594, 1424, 1215, 1047, 878, 773, 669, 626 cm . HRMS: calcd.
+
for C27
H28NO
4
: 430.2018, found. 430.2012. The product was analyzed by HPLC to
determine the enantiomeric excess: 94% ee (Chiralcel AS-H, i-propanol/hexane =
0/80, flow rate 1.0 mL/min, λ = 220 nm); t = 7.28 and 10.16 min.
2
r
S12

(
1R,3R)-methyl 4,9-dihydroxy-1-methyl-3-phenyl-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 82% yield. m.p. 95-98 C; [] = +31.5 (c 1.20, CHCl ); H NMR (CDCl ,
D
3
3
TMS, 300 MHz)  8.11 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.74-7.70 (m,
2
1
1

9
H), 7.44 (d, J = 6.9 Hz, 1H), 7.37-7.27 (m, 3H), 5.69 (s, 1H), 3.79 (s, 3H), 2.60 (br,
1
3
H), 1.81 (s, 3H); C NMR (CDCl , TMS, 75 MHz)  182.2, 181.8 172.9, 148.8,
3
48.4, 141.0, 133.7, 132.8, 128.5, 127.9, 127.6, 126.3, 71.0, 66.5, 52.7, 24.4; IR (KBr)
3368, 2951, 1740, 1634, 1593, 1492, 1454, 1372, 1332, 1267, 1171, 1106, 1027,
-1
+
4
01, 776, 730, 716, 704, 641, 554 cm . HRMS: calcd. for C21H18NO : 348.1230,
found. 348.1220. The product was analyzed by HPLC to determine the enantiomeric
excess: 89% ee (Chiralcel OD-H, i-propanol/hexane = 20/80, flow rate 1.0 mL/min, λ
=
220 nm); t
r
= 17.20 and 30.03 min.
OH
CO Me
2
NH (5o)
Ph
OH
(
1R,3R)-methyl 1-ethyl-4,9-dihydroxy-3-phenyl-2,3-dihydro-1H-benzo[f]
isoindole -1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 90% yield. m.p. 102-105 C; []
D 3 3
= +5.5 (c 1.40, CHCl ); H NMR (CDCl ,
TMS, 300 MHz)  8.12 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.74-7.70 (m,
2
1
1
7
1
H), 7.42-7.30 (m, 5H), 5.64 (s, 1H), 3.79 (s, 3H), 2.35-2.31 (m, 1H), 2.22-2.17 (m,
13
H), 0.96-0.91 (t, J = 7.2 Hz, 3H); C NMR (CDCl , TMS, 75 MHz)  182.0, 181.9,
3
73.3, 150.3, 146.4, 141.4, 133.7, 132.9, 132.8, 128.6, 128.0, 127.6, 126.4, 126.3,
5.7, 67.3, 52.7, 29.6, 8.0; IR (KBr)  3374, 2966, 1736, 1632, 1594, 1492, 1456,
-1
368, 1334, 1290, 1261, 1170, 1082, 1026, 772, 742, 715, 701 cm . HRMS: calcd.
+
for C H NO : 362.1387, found. 362.1382. The product was analyzed by HPLC to
2
2
20
4
determine the enantiomeric excess: 94% ee (Chiralpak AS-H, i-propanol/hexane =
0/80, flow rate 1.0 mL/min, λ = 220 nm); t = 17.17 and 33.97 min.
2
r
S13

(
1R,3R)-methyl 4,9-dihydroxy-3-phenyl-1-propyl-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 77% yield. m.p. 91-94 C; []
D 3 3
= +6.3 (c 1.20, CHCl ); H NMR (CDCl ,
TMS, 300 MHz)  8.11 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.77-7.67 (m,
2
2
3
1
1
1
5
H), 7.41-7.29 (m, 5H), 5.63 (s, 1H), 3.78 (s, 3H), 2.61 (br, 1H), 2.39-2.24 (m, 1H),
.15-2.05 (m, 1H), 1.52-1.45 (m, 1H), 1.23-1.14 (m, 1H), 0.98-0.93 (t, J = 7.2 Hz,
1
3
H); C NMR (CDCl , TMS, 75 MHz)  182.0, 181.9, 173.3, 150.0, 146.7, 141.3,
3
33.7, 132.9, 132.8, 128.6, 128.0, 127.6, 126.4, 126.3, 75.2, 67.3, 52.7, 38.9, 17.1,
4.2; IR (KBr)  3375, 3065, 3030, 2958, 2929, 2872, 1736, 1633, 1594, 1493, 1455,
434, 1368, 1333, 1289, 1249, 1170, 1109, 1044, 1028, 941, 777, 747, 715, 701, 645,
-1
+
4
74 cm . HRMS: calcd. for C23H22NO : 376.1530, found. 376.1525. The product
was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralpak
AS-H, i-propanol/hexane = 20/80, flow rate 1.0 mL/min, λ = 220 nm); t = 23.21 and
3.83 min.
r
4
(
1R,3R)-methyl 4,9-dihydroxy-1-isobutyl-3-phenyl-2,3-dihydro-1H-benzo[f]
isoindole-1-carboxylate
The title compound was prepared according to the general procedure as described
o
25
1
above in 74% yield. m.p. 112-115 C; []
3
= +26.5 (c 1.56, CHCl ); H NMR
D
3
(CDCl , TMS, 300 MHz)  8.12 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H),
S14

7
2
3
1
2
1
.77-7.70 (m, 2H), 7.41-7.29 (m, 5H), 5.65 (s, 1H), 3.77 (s, 3H), 2.61 (br, 1H),
.25-2.11 (m, 2H), 1.78-1.74 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz,
1
3
H); C NMR (CDCl , TMS, 75 MHz)  182.1, 173.5, 149.9, 147.2, 141. 3, 133.8,
3
33.7, 133.0, 132.8, 128.6, 128.0, 127.6, 126.5, 126.3, 75.3, 67.0, 52.7, 44.8, 24.5,
4.4, 24.3; IR (KBr)  3380, 2954, 1735, 1668, 1631, 1594, 1492, 1455, 1367, 1329,
-1
+
220, 1169, 1125, 1029, 715, 701 cm . HRMS: calcd. for C H NO : 390.1700,
2
4
24
4
found. 390.1703. The product was analyzed by HPLC to determine the enantiomeric
excess: 93% ee (Chiralpak AS-H, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ
=
220 nm); t
r
= 7.77 and 26.04 min.
OH
Ph
CO Me
2
NH (5r)
Ph
OH
(
1R,3R)-methyl 4,9-dihydroxy-1,3-diphenyl-2,3-dihydro-1H-benzo[f]isoindole-
-carboxylate
The title compound was prepared according to the general procedure as described
1
o
25
1
above in 86% yield. m.p. 120-123 C; []
3
= +48.6 (c 0.42, CHCl ); H NMR
D
(CDCl
3
, TMS, 400 MHz)  8.03 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H),
7
3
1
1
1
4
9
.67-7.64 (m, 4H), 7.45 (d, J = 7.6 Hz, 2H), 7.40-7.24 (m, 8H), 5.84 (s, 1H), 3.85 (s,
1
3
H); C NMR (CDCl , TMS, 100 MHz)  182.3, 182.2, 172.4, 148.7, 147.5, 140.9,
3
40.2, 133.8, 133.6, 132.9, 132.6, 129.7, 128.7, 128.2, 128.0, 127.6, 127.2, 126.5,
26.1, 76.6, 67.3, 53.0; IR (KBr)  3384, 3065, 3030, 2958, 1736, 1669, 1593, 1457,
-1
+
219, 1070, 754, 698 cm . HRMS: calcd. for C H NO : 410.1387, found.
2
6
20
4
10.1377. The product was analyzed by HPLC to determine the enantiomeric excess:
3% ee (Chiralpak AD-H, i-propanol/hexane = 15/85, flow rate 1.0 mL/min, λ = 220
r
nm); t = 31.13 and 34.41 min.
S15

(
1R,3R)-methyl 1-benzyl-4,7-dihydroxy-3-phenylisoindoline-1-carboxylate
The title compound was prepared according to the general procedure as described
2
5
1
above in 82% yield. []
D 3 3
= +53.7 (c 0.48, CHCl ); H NMR (CDCl , TMS, 300
MHz)  7.26 (m, 3H), 7.12 (m, 2H), 6.71 (d, J = 10.2 Hz, 1H), 6.53 (d, J = 10.2 Hz,
1
2
1
4
H), 4.80 (s, 1H), 3.83 (s, 3H), 3.49 (d, J = 14.1 Hz, 1H), 3.37 (d, J = 14.1 Hz, 1H),
1
3
.66 (br, 1H); C NMR (CDCl
3
, TMS, 75 MHz)  184.7, 183.8, 172.5, 148.1, 143.9,
40.8, 136.8, 136.6, 135.4, 130.2, 128.4, 128.2, 127.9, 127.5, 127.1, 75.3, 66.7, 52.9,
-1
1.9; IR (KBr)  2956, 1736, 1669, 1593, 1452, 1215, 1047, 669, cm . HRMS: calcd.
+
for C23
H22NO
4
: 376.1549, found. 376.1530. The product was analyzed by HPLC to
determine the enantiomeric excess: 86% ee (Chiralpak AS-H, i-propanol/hexane =
0/80, flow rate 1.0 mL/min, λ = 220 nm); t = 14.89 and 30.87 min.
2
r
IV. The Absolute Configuration Determination of (1R,3R)-5b
Ph
OH
CO Me
2
NH
*
p-Cl-C H
OH
6
4
(
1R,3R)-5b
Figure 1. X-ray structure of (1R,3R)-5b.
Crystal data for (1R,3R)-5b: C27 , M = 459.91, T = 293 K, tetragonal,
H
22ClNO
4
r
space group P4(3), a = 12.7827(8), b = 12.7827(8), c = 13.7419(18) Å, V = 2245.4(4)
3
Å , Z = 4, 3391 unique reflections, final R
1
= 0.0343 and wR
2
= 0.0908 for 4129
observed [I>2σ(I)] reflections, Flack  = -0.05(6). CCDC 904693 contains the
supplementary crystallographic data for this paper. These data can be obtained free of
S16

charge via www.ccdc.cam.ac.uk/conts/retrieving.htmL (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)
1
223-336-033; or deposit@ccdc.cam.ac.uk).
V. Proposed Relative Configuration of the Labile Keto-Isomer Intermidiate in
This One-Pot Sequential Catalytic Asymmetric 1,3-DC/Aromatization
O
8
Ph
COOMe
Ac
Ac
O
CuBF /L6 (3 mol%)
4
NH
+
o
Et N, PhMe, -20 C
3
Bn
p-Cl-C H
6
4
9
p-Cl-C H
N
COOMe
6
4
9
1% yield,
4b
>
20:1 dr, 86% ee
To further investigate the relative configuration of the labile keto-isomer
intermediate of this one-pot sequential catalytic asymmetric 1,3-DC/Aromatization
reaction, (Z)-hex-3-ene-2,5-dione 8 was employed as the dipolarophile and 4b was
employed as imino ester to study the stereochemistry of the 1,3-dipolar cycloaddition
under the optimized reaction condition. As expected, the normal 1,3-DC adduct 9 was
obtained in 91% yield with excellent diastereoselectivity and 86% ee (Scheme 1), and
the relative configuration of racemic adduct 9 was determined unambiguously to be
endo by single X-ray crystallographic analysis (Figure 2). Hence, the relative
configuration of the labile keto-isomer intermediate in this one-pot sequential
1
,3-DC/Aromatization reaction were tentatively proposed to be endo on the basis of
these results (Scheme 2).
S17

(
2R,3S,4R,5S)-methyl 3,4-diacetyl-2-benzyl-5-(4-chlorophenyl)pyrrolidine-2-
carboxylate
Under argon atmosphere, (S,R
Cu(CH CN) BF (1.9 mg, 0.006 mmol) were dissolved in toluene (2mL), and stirred
p
)-PPFOMe (3.1 mg, 0.0072 mmol) and
3
4
4
at room temperature for about 1 h. Then, imine substrate 4b (78.3 mg, 0.26 mmol),
and (Z)-hex-3-ene-2,5-dione (22.4 mg, 0.2 mmol) were added sequentially, after that
o
the mixture was dropped to -20 C, TEA (3 mg, 0.03 mmol) was added. Once starting
material was consumed (monitored by TLC), the residue was purified by column
chromatography to give 9 in 91% yield, which was then directly analyzed by chiral
1
HPLC to determine the enantiomeric excess. H NMR (CDCl
3
, TMS, 300 MHz) 
7
3
1
1
.38-7.26 (m, 7H), 7.17 (d, J = 8.4 Hz, 2H), 4.16 (d, J = 6.0 Hz, 1H), 3.75 (s, 3H),
.43-3.37 (m, 2H), 3.33 (d, J = 13.5 Hz, 1H), 3.15 (d, J = 13.5 Hz, 1H), 2.48 (s, 3H),
1
3
.66 (s, 3H); C NMR (CDCl , TMS, 75 MHz)  208.4, 205.2, 173.8, 135.9, 135.7,
3
33.7, 130.5, 128.7, 128.4, 128.3, 127.3, 73.4, 64.6, 62.6, 59.1, 52.4, 45.4, 32.3, 31.3;
+
HRMS: calcd. for C23
H
25ClNO
4
: 414.1467, found. 414.1446. The product was
analyzed by HPLC to determine the enantiomeric excess: 86% ee (Chiralpak AD-H,
i-propanol/hexane = 20/80, flow rate 1.0 mL/min, λ = 220 nm); t
r
= 8.16 and 10.99
min.
S18

VI. The Relative Configuration Determination of Racemic endo-9
Figure 2. X-ray structure of racemic endo-9.
4 r
Crystal data for racemic endo-adduct 9: C23H24ClNO , M = 413.88, T = 293 K,
Monoclinic, space group P2(1)/c, a = 8.9427(14), b = 24.682(4), c = 9.8606(16) Å, V
3
=
2156.1(6) Å , Z = 4, 3082 unique reflections, final R = 0.0450 and wR = 0.1077
1
2
for 4233 observed [I>2σ(I)] reflections. CCDC 904694 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.htmL (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or
deposit@ccdc.cam.ac.uk).
VII. References
1
. Hayashi, T; Fukushima, T, M; Kagotani, M; Nagashima, N; Hamada, Y;
Matsumoto, A; Kawakami, S; Konishi, M; Yamamoto, K; Kumada, M. Bull. Chem.
Soc. Jpn., 1980, 53, 1138.
2
. CCDC 904693 (5b) and CCDC 904694 (9) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax:
+44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
(or
from
the
Cambridge
(
S19

1
13
VIII. H NMR and C NMR Spectra
Ph
OH
OH
CO Me
2
NH (5a)
Ph
S20

S21

S22

Ph
OH
OH
CO Me
2
NH (5b)
6
p-Cl-C H4
S23

Ph
OH
OH
CO Me
2
NH (5b)
p-Cl-C H
6
4
S24

Ph
OH
OH
CO Me
2
NH (5c)
o-Cl-C H
6
4
S25

S26

S27

Ph
OH
OH
CO Me
2
NH (5d)
m-Cl-C H
6
4
S28

S29

S30