N-Heterocyclic carbene-catalyzed [3 + 2] annulation of bromoenals with 3-aminooxindoles: Highly enantioselective synthesis of spirocyclic oxindolo-γ-lactams

Article abstract of DOI:10.1039/c5ob02466h

The chiral N-heterocyclic carbene-catalyzed [3 + 2] annulation of α-bromoenals and 3-aminooxindoles was developed, giving the corresponding spirocyclic oxindolo-γ-lactams in good yields with high diastereoselectivities and enantioselectivities.

Full text of DOI:10.1039/c5ob02466h

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DOI: 10.1039/C5OB02466H
Journal Name
RSCPublishing
COMMUNICATION
NꢀHeterocyclic CarbeneꢀCatalyzed [3+2] Annulation
of Bromoenals with 3ꢀAminooxindoles: Highly
Enantioselective Synthesis of Spirocyclic Oxindoloꢀγꢀ
Lactams
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
KunꢀQuan Chen,a,b Yao Li,a,b ChunꢀLin Zhang,a DeꢀQun Sun*b and Song Ye*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
The chiral Nꢀheterocyclic carbeneꢀcatalyzed [3+2] annulation
of αꢀbromoenals and 3ꢀaminooxindoles was developed,
giving the corresponding spirocyclic oxindoloꢀγꢀlactams in
halides,13 acids,8aꢀc and esters,14 usually acts as
biselectrophiles and goes [3+n] annulation with many
bisnucleophiles to afford carboꢀ and heterocycles.15 In 2012,
the NHCꢀcatalzyed [3+2] annulation of enals with oxindoleꢀ
good
yields
with
high
diastereoselectivities
and
enantioselectivities.
derived imines to give spirocyclic oxindoloꢀγꢀlactams was
developed by Jiao and Ye et al. and Chi et al.16 (Scheme 1,
reaction a). Following our previous report on NHCꢀcatalyzed
[3+3] annulation of bromoenals with 1,3ꢀbisnucleophiles and
Introduction
the [3+2] annulation with αꢀamino ketones to give
lactams,8a we are interested in developing the reaction with 3ꢀ
aminooxindoles for the synthesis of spirocyclic oxindoloꢀ
lactams (Scheme 1, reaction b). During the preparation of this
manuscript, Lu and Du et al. published a related paper
majorly focusing on the nonꢀasymmetric reaction.17 In this
paper, we report our enantioselective reaction, which showed
the scope and limitation of 3ꢀaminooxindoles and
bromoenals.
γꢀ
Functionalized spirocyclic oxindolopyrrolidine and its
derivatives are privileged structural building blocks in many
natural and unnatural products with various bioactivities.1
Thus, the synthesis of this motif has been pursued via several
approaches,2 including the typical multiꢀcomponent reaction
of isatin, amine and α,βꢀunsaturated ketones.2fꢀh However, the
enantioselective syntheses of spirocyclic oxindolopyrrolidine
are very rare but highly desired.2d,3
γꢀ
In the last decades, Nꢀheterocyclic carbene (NHC) has
been developed as one of the most powerful organocatalysts4
for a wide variety reactions of aldehydes,5 ketenes,6 esters,7
acids8 and Michael acceptors,9 Among these reactions, the
α,βꢀunsaturated acyl azolium intermediate, catalytically
generated in situ from enals,10 ynals,11 αꢀbromoenals,12 acyl
Scheme1. NHC-catalyzed Enantioselective synthesis of spirocyclic oxindolo-γ-
lactams
Results and discssion
Initially, the model reaction of 3ꢀaminooxindole 1a and αꢀ
bromoenal 2a was investigated under NHC catalysis (Table
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yield
ee
1). We were encouraged to find that the reaction catalyzed by
the preNHC A1 or A2 18
derived from ꢀpyroglutamic acid,
gave the desired spirocyclic oxindoloꢀ ꢀlactam 3a in
moderate yields with high enantioselectivities and
diastereoselectivities (entries 1 and 2). Then the tetracyclic
preNHC catalysts B119 and B2 20
, derived from aminoindanol,
entry cat.
base
solvent
d.r.[c]
(%)[a] (%)[b]
,
L
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
A1
A2
B1
B2
B2
B2
B2
B2
B2
B2
B2
B2
B2
B2
DABCO
DABCO
DABCO
DABCO
Cs2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
24
48
51
50
39
30
32
75
68
85
52
45
57
67
70
60
45
44
trace
ꢀ89
ꢀ92
95
95
96
97
92
92/73
83/65
67/72
97
90
94/45
98
98
98
98
95
/
>20:1
10:1
12:1
15:1
>20:1
>20:1
17:1
3:1
γ
were employed, which resulted in improved yields and better
enantioseletivities (entries 3 & 4). Screening of the bases
revealed that the reaction using inorganic bases, such as
Cs2CO3, K2CO3 and Na2CO3 gave product in low yields but
with high diastereoꢀ and enantioselectivities (entries 5ꢀ7),
while organic bases, such as Et3N, DIPEA and DMAP,
resulted in good to high yields but much low diastereoꢀ
and/or enantioselectivities (entries 8ꢀ10). Considering the two
roles of the base for generation of free NHC from triazolium
salts and removal of the generated hydrobromide, we then
examined the mixed base of DABCO and Cs2CO3, which
gave the balanced results for yield and selectivies (entry 11).
Solvent screening revealed that reactions went well in toluene,
THF, ether and dichloromethane (entries 11ꢀ14). Lowering
the catalyst loading to 15 mol% gave comparable results
(entry 15), but the yields were decreased gradually when 10
and 5 mol% catalyst were used (entries 16 & 17). Further
experiments to clarify the roles of two bases were carried out
by using the free NHC as the catalyst, which was prepared
with KH as the base.21 It were found that the reaction gave
only product in moderate yield using DABCO as the base,
while only trace of product 3a was observed when Cs2CO3
was used (entries 18 & 19)
Na2CO3
Et3N
DIPEA
DMAP
5:1
3:1
DABCO/Cs2CO3[d] toluene
>20:1
12:1
6:1
17:1
16:1
17:1
16:1
>20:1
/
DABCO/Cs2CO3[d]
DABCO/Cs2CO3[d]
DABCO/Cs2CO3[d]
THF
DCM
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
B2[e] DABCO/Cs2CO3[d]
B2[f] DABCO/Cs2CO3[d]
B2[g] DABCO/Cs2CO3[d]
B2
B2
DABCO/KH[h]
Cs2CO3/KH[h]
[a] Isolated yields. [b] Enantiomerical excess of the major isomer, and
followed by minor isomer for entries 8, 9, 10 and 13. [c] Determined by 1H
NMR (300 MHz) of the raw products. [d] The mix base of DABCO (1.0
equiv.) and Cs2CO3 (1.2 equiv.) was used. [e] 15 mol% of preNHC B2. [f]
10 mol% of preNHC B2. [g] 5 mol% of of preNHC B2. [h] The free NHC
was prepared using KH as the base and used immediately
Table 2. Variation of 3ꢀaminooxindoles.
O
B2 (15 mol%)
Cs2CO3 (1.0 equiv.)
DABCO (1.2 equiv.)
NHR
R
N
CHO
Br
Ph
+
X
O
Et2O, rt, 12 h
X
O
Ph
N
N
R'
R'
1
2a
3a-3i
Table 1. Optimization of reaction conditions
O
O
O
R
N
Boc
N
NHBoc
Ph
Ph
cat. A/B (20 mol%)
base (2.2 equiv.)
BocN
CHO
Br
Ph
O
O
+
O
solvent, rt, 12 h
O
N
N
Ph
N
N
N
Bn
R'
Bn
Bn
3a (R = Boc), 70%, 98% ee, 16:1 dr
3a' (R = Ac), trace
3a" (R = Bz), trace
3b (R' = H), 52%, 99% ee, >20:1 dr
3c (R' = Me), 69%, 91% ee, >20:1 dr
3d (R' = ꢀPr), 67%, 99% ee, >20:1 dr
1a
2a
BF4
Ar2
3a
n
O
BF4
N
O
O
Ar1
Ar1
N
N
N
N
Ar
Boc
N
Boc
N
Ph
Ph
X
OH
O
O
A1 (Ar1 = Ph, Ar2 = Mes)
A2 (Ar1 = 3,5ꢀ(CF3)2C6H3, Ar2 = Ph)
B1 (Ar = Ph)
B2 (Ar = Mes)
N
N
Br
Bn
Bn
3e (X = F), 68%, 98% ee, 12:1 dr
3f (X = Cl), 66%,98% ee, 15:1 dr
3g (X = Me), 76%, 98% ee, 17:1 dr
3h (X = MeO), 69%, 97% ee, 17:1 dr
3i, 65%, 99% ee, 15:1 dr
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5OB02466H
The configuration of the compounds 3aꢀc was assigned by
the comparison of its optical rotation with those reported in
the literature.16a
Table 3. Variation of bromoenals.
O
CHO
NHBoc
O
B2 (15 mol%)
Cs2CO3 (1.0 equiv.)
DABCO (1.2 equiv.)
Y
BocN
Br
+
O
N
Et2O, rt, 12 h
N
Y
Bn
Bn
3j-3s
2
1a
O
O
Y
Boc
N
Boc
N
Y
O
O
N
N
Bn
Bn
3j (Y = F), 61%, 99% ee, 15:1 dr
3k (Y = Cl), 72%, 99% ee, 15:1 dr
3l (Y = CN), 76%, 99%ee, >20:1 dr
3m (Y = Me), 65%, 99% ee, >20:1 dr
3n (Y= OMe), 85%, 99% ee, >20:1 dr
3o (Y = Cl), 64%,99% ee, 12:1 dr
3p (Y = OMe), 68%,97% ee, 15:1 dr
O
Y
O
Boc
N
Boc
N
O
O
N
Fig. 1 Plausible catalytic cycle.
N
Bn
Bn
3q (Y = Cl), 62%, 96% ee, 14:1 dr
3r (Y = Me), 58%, 99% ee, >20:1 dr
3s (Y = OMe), 70%, 98% ee, 13:1 dr
The plausible catalytic cycle of the NHCꢀcatalyzed
reaction is depicted in Figure 1. The addition of an NHC
3t, no reaction
catalyst to bromoenal
2
generates the Breslow intermediate
I,
which is tautomerized to
leaving of the bromide gives the corresponding unsaturated
acyl azolium intermediate III. Michael addition of 3ꢀ
α
ꢀbromoacyl azolium anion II. The
Under the optimized reaction conditions, the scope of 3ꢀ
aminooxindole were then briefly investigated (Table 2).
Different substituents on the 3ꢀamino of the oxindoles were
aminooxindole
azolium III gives adduct IV
1
via its enolate 1′ to the α,βꢀunsaturated acyl
which then undergoes
examined, and it was found that although the amine with
Boc worked well for the reaction (3a) ꢀacyl and ꢀbenzoyl
did not (3a′ 3a′′). Then, the protecting groups on the
Nꢀ
,
,
N
N
lactamization to afford the final cycloadduct
regenerates the NHC catalyst.
3 and
&
nitrogen of the oxindole ring were tested. Interestingly, the
oxindole without protecting group resulted in only slight loss
of the yield but with excellent diastereoꢀ and
Conclusions
In summary, the NHCꢀcatalyzed [3+2] annulation of
αꢀ
enantioselectivity (3b), and the ones with
Nꢀmethyl,
Nꢀpropyl
bromoenals and 3ꢀaminooxindoles was developed. The mix
base of inorganic and organic bases benefits the reaction. A
substituents (3c 3d) worked as well as the
&
N
ꢀbenzyl (3a).
Further variation of the substituent on the phenyl ring of the
oxindole revealed that both electronꢀwithdrawing (5ꢀFC6H4,
5ꢀClC6H4) and electronꢀdonating groups (5ꢀMeC6H4, 5ꢀ
MeOC6H4) were well tolerated (3eꢀ3h), and the one with 6ꢀ
substituent (6ꢀBrC6H4) afforded the product 3i in 65% yield
with 99% ee and 15:1 dr.
variety of
α
ꢀbromoenals and 3ꢀamniooxindoles worked well,
ꢀlactams in
giving the corresponding spirocyclic oxindoloꢀ
γ
good yields with excellent enantioselectivities and high
diastereoselectivities. Other related NHCꢀcatalyzed reactions
are underway in our laboratory.
The reaction scope of bromoenals was also investigated
(Table 3). It was found that all the
αꢀbromocinnamic
Acknowledgements
aldehdyes with paraꢀelectronꢀwithdrawing (4ꢀFC6H4, 4ꢀ
ClC6H4, 4ꢀCNC6H4) and electronꢀdonating substituent (4ꢀ
MeC6H4, 4ꢀMeOC6H4) worked well to give the desired
Financial support from National Science Foundation of
China (Nos. 21425207), and the Chinese Academy of
Sciences are greatly acknowledged.
products
enantioselectivities and high diastereoselectivities. The ones
with metaꢀsubstituent (3ꢀClC6H4, 3ꢀMeOC6H4) and ortho
substituent (2ꢀClC6H4, 2ꢀMeC6H4, 2ꢀMeOC6H4) were also
tolerated (3o 3s). Unfortunately, alkyl bromoenals did not
(
3j
ꢀ
3n)
in good yield with excellent
ꢀ
Experimental section
ꢀ
work under current reaction condition.
General information
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Unless otherwise indicated, all reactions were carried out
128.5, 127.4, 126.6, 123.3, 122.2, 109.7, 83.8, 71.7, 49.0,
with N2/Ar protection with magnetic stirring. Anhydrous
THF and toluene were distilled from sodium and
benzophenone. Anhydrous CH2Cl2 was distilled from CaH2.
44.1, 35.1, 27.7, 27.6. IR (KBr) v 3061, 2980, 1723, 1490,
1104 cmꢀ1. HRMS (ESI) [M+Na] calcd for C29H28O4N2Na
491.1932, found 491.1941.
Chiral triazolium salts A1
ꢀ
A2
,
B1ꢀB2 and 3ꢀ
(
2
'
S,3
'
R
)ꢀtertꢀbutyl
2,5'ꢀdioxoꢀ3'ꢀphenylspiro[indolineꢀ
aminooxindoles22 were synthesized according to literatures.
Column chromatograph was performed on silica gel 200~300
mesh. All 1H NMR (400 MHz) or (500 MHz), 13C NMR (101
or 125 MHz) spectra were recorded on a BrukerꢀDMX 400 or
500 pectrometer in CDCl3, with tetramethylsilane as an
internal standard and reported in parts per million (ppm, δ).
1H NMR Spectroscopy splitting patterns were designated as
singlet (s), doublet (d), triplet (t), quartet (q). Splitting
patterns that could not be interpreted or easily visualized
were designated as multiplet (m) or broad (br). Infrared
spectra were recorded on a Nicolet 6700 spectrophotometer
and reported as wave number (cmꢀ1). Optical rotations were
measured on RudolphꢀAutop VI digital polarimeter operating
at the sodium D line with a 100 mm path cell, and are
3,2'ꢀpyrrolidine]ꢀ1'ꢀcarboxylate (3b).16a
Yield: 39.3 mg (52%), white solid, mp 178ꢀ179°C, Rf= 0.1
(petroleum ether/ethyl acetate, 5:1). [α]D +25 (
CH2Cl2); HPLC analysis: 99% ee [Daicel CHIRALPAK ADꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH = 70:30, 1.0
25
c 0.5
1
mL/min, 250 nm, 12.8 min (minor), 30.4 min (major)]. H
NMR (400 MHz, CDCl3) δ 7.38 (t,
7.21 (m, 5H), 6.87 (d, = 8.1 Hz, 2H), 6.66 (d,
1H). 3.74 (dd, = 13.8, 7.5 Hz, 1H), 3.74 (dd,
Hz, 1H), 3.63 – 3.51 (m, 1H), 2.76 (dd,
1.15 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 175.3, 173.5,
148.2, 141.0, 132.5, 129.9, 129.0, 128.5, 128.4, 128.2, 123.3,
122.5, 110.1, 84.2, 72.0, 49.1, 34.9, 27.5. IR (KBr)
2918, 1785, 1384, 1297 cmꢀ1.HRMS (ESI) m/z: [M+Na]Calc.
for C24H15Cl2O3Na, 401.1465, Found 401.1472.
J
= 6.9 Hz, 1H), 7.30 –
= 7.7 Hz,
= 13.8, 7.5
= 16.4, 7.4 Hz, 1H),
J
J
J
J
J
v 3304,
T
reported as follows: [α]D (concentration (g/100 mL),
solvent).
(
2
'
S,3
'
R
)ꢀtertꢀbutyl
1ꢀmethylꢀ2,5'ꢀdioxoꢀ3'ꢀphenylspiro
[indolineꢀ3,2'ꢀpyrrolidine]ꢀ1'ꢀ carboxylate (3c).16a
Yield: 53 mg (69%). white solid mp 188ꢀ190°C, [α]D ꢀ23.5
(c 1.0, CH2Cl2); HPLC analysis: 91% ee [Daicel
CHIRALPAK ODꢀH, 90:10 hexanes/iꢀPrOH, 1.0 ml/min, 8.5
25
[3+2] Annulation of bromoenals with 3ꢀaminooxinꢀ
doles (Table 2 & 3)
Typical procedure: To the a dry Schlenk, aminooxindole
1a (47.8 mg, 0.2 mmol), bromoenal 2a (84.4 mg, 0.4 mmol),
NHC precursor B2 (12.5 mg
1
min(minor), 19.8 min (major)]; H NMR (500 MHz, CDCl3)
δ 7.39 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.19ꢀ7.10
(M Hz, 4H), 6.82 (d, J = 7.5 Hz, 2H), 6.60 (d, J = 7.8 Hz,
1H), δ 3.71 (dd, J = 13.9, 7.1 Hz, 1H), 3.65 – 3.59 (m, 1H), δ
2.76 (dd, J = 16.1, 7.1 Hz, 1H), 2.72 (s, 3H), 1.09 (s, 9H). 13
NMR (126 MHz, CDCl3) δ 173.7, 148.1, 143.8, 132.5, 129.9,
128.7, 128.4, 128.2, 128.1, 128.0, 123.2, 121.9, 108.2, 83.8,
，0.03 mmol), Cs2CO3 (65 mg,
0.2 mmol) and DABCO (27 mg, 0.24 mmol) were added in
toluene (2.0 mL), at room temperature. The reaction mixture
was stirred at room temperature until the full consumption of
the aminooxindole (typically, 12 h). The reaction mixture
was concentrated under reduced pressure, and the
diastereomerical ratio of the raw product was determined by
the 1H NMR (300 MHz). The residue was purified by column
chromatography on silica gel (petroleumether/EtOAc as the
C
72.1, 49.2, 34.8, 27.5, 25.7. IR (KBr)
v 3312, 2908, 1790,
1307, 1152 cmꢀ1.HRMS (ESI) m/z: [M+Na] Calc. for
C23H24O4N2Na, 415.1621, Found 415.1628.
(
2'
S,3
'
R)ꢀtertꢀbutyl
2,5'ꢀdioxoꢀ3'ꢀphenylꢀ1ꢀpropylspiro
eluent, typically 7:1ꢀ5:1) to give 3a
Racemic samples for the chiral phase HPLC analysis were
prepared using NHC precursor under the same conditions.
.
[indolineꢀ3,2'ꢀpyrrolidine]ꢀ1'ꢀ carboxylate (3d).
Yield: 56 mg (67%), white solid, mp 175ꢀ176°C, Rf = 0.35
(petroleum ether/ethyl acetate, 5:1). [α]D ꢀ55.5 (
C
25
c 1.0,
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ADꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH = 85:15, 1.0
1
mL/min, 250 nm, 7.3 min (minor), 15.8 min (major)]. H
NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.3 Hz, 1H), 7.32 (td,
J = 7.8, 1.0 Hz, 1H), 7.19 – 7.10 (m, 4H), 6.83 (d, J = 7.3 Hz,
2H), 6.62 (d, J = 7.8 Hz, 1H), 3.77 – 3.61 (m, 2H), 3.52 (ddd,
J = 14.4, 9.0, 5.8 Hz, 1H), 2.96 – 2.90 (m, 1H), 2.77 (dd, J =
15.8, 6.9 Hz, 1H), 1.08 (s, 9H), 1.06 – 0.86 (m, 2H), 0.56 (t, J
= 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.8, 173.5,
148.0, 143.8, 132.5, 129.78, 128.75, 128.4, 128.3, 128.2,
123.0, 122.1, 108.5, 83.8, 71.7, 49.0, 41.6, 34.8, 27.5, 20.6,
(
2
'
S,3
'
R
)ꢀtertꢀbutyl
1ꢀbenzylꢀ2,5'ꢀdioxoꢀ3'ꢀphenylspiro
[indolineꢀ3,2'ꢀpyrrolidine]ꢀ1'ꢀ carboxylate (3a).16a
Yield: 58 mg (70%), white solid mp 180ꢀ182°C, [α]D +31.1
1.0, CH2Cl2); HPLC analysis: 98% ee [Daicel
CHIRALPAK ODꢀH, 70:30 hexanes/ ꢀPrOH, 1.0 ml/min,
25
(
c
i
9.2min (minor), 22.8min (major)], 1H NMR (500 MHz,
CDCl3) δ 7.43 (d, J = 7.1 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H),
7.20 ꢀ7.14 (m 5H), 7.08 (t, J = 7.5 Hz, 2H), 6.93 (d, J = 7.6
Hz, 2H), 6.40 (t, J = 6.9 Hz, 3H), 5.02 (d, J = 15.9 Hz, 1H),
4.10 (d, J = 15.9 Hz, 1H), 3.84 (dd, J = 13.9, 7.5 Hz, 1H),
3.70 (dd, J = 16.2, 14.2 Hz, 1H), 2.80 (dd, J = 16.4, 7.5 Hz,
1H), 1.09 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 174.0,
173.6, 148.1, 143.5, 134.7, 132.7, 129.9, 128.8, 128.7, 128.6,
11.4. IR (KBr)
v
3421, 1791, 1384, 1100cmꢀ1.HRMS (ESI)
m/z: [M+Na]Calc. for C25H28O4N2Na, 443.1936, Found
443.1941.
(2'S,3'R)ꢀtertꢀbutyl 1ꢀbenzylꢀ5ꢀfluoroꢀ2,5'ꢀdioxoꢀ3'ꢀphenyꢀ
lspiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀ carboxylate (3e).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 8
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5OB02466H
Yield: 62 mg (68%) with 18:1 dr, white solid, mp 159ꢀ163°C,
(2'S, 3'R)ꢀtertꢀbutyl 1ꢀbenzylꢀ5ꢀmethoxyꢀ2,5'ꢀdioxoꢀ3'ꢀpheꢀ
nylspiro[indolineꢀ3,2'ꢀpyrrolidine]ꢀ1'ꢀ carboxylate (3h).
25
Rf= 0.3 (petroleum ether/ethyl acetate, 5:1).[α]D +24 (
c
1.0,
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
Yield: 69 mg (69%),white solid mp 183ꢀ186°C, Rf= 0.22
(petroleum ether/ethyl acetate, 5:1). [α]D +47 (c 1.0,
CH2Cl2), HPLC analysis: 97% ee [Daicel CHIRALPAK ODꢀ
H column, 20oC, 250 nm hexane/iꢀPrOH = 70:30, 1.0
mL/min, 250 nm, 15.1 min (minor) , 31.0 min (major)]. 1H
25
H column, 20 oC, 250 nm hexane/iꢀPrOH = 80:20, 1.0
1
mL/min, 250 nm, 13.4 min (minor) , 27.3 min (major)]. H
NMR (500 MHz, CDCl3) δ 7.33 (t, J = 7.3 Hz, 1H), 7.26ꢀ7.15
(m, 4H), 7.09 (t, J = 7.5 Hz, 2H), 6.97 – 6.88 (m, 3H), 6.38 (d,
J = 7.5 Hz, 2H), 6.31 (dd, J = 8.5, 3.9 Hz, 1H), 4.99 (d, J =
15.9 Hz, 1H), 4.11 (d, J = 15.9 Hz, 1H), 3.79 (dd, J = 13.9,
NMR (500 MHz, CDCl3) δ 7.31 (t,
7.13 (m, 3H), 7.09 – 7.05 (m, 3H), 6.96 (d,
6.71 (dd, = 8.5, 2.2 Hz, 1H), 6.38 (d, = 7.4 Hz, 2H), 6.30
(d, = 8.5 Hz, 1H), 4.99 (d, = 15.9 Hz, 1H), 4.07 (d,
15.9 Hz, 1H), 1H NMR (500 MHz, CDCl3) δ 3.80 (s, 3H)
J
= 7.3 Hz, 1H), 7.20ꢀ
J
= 7.6 Hz, 2H),
7.3 Hz, 1H), δ 3.79 (dd,
J
= 13.9, 7.3 Hz, 1H), 3.72 – 3.66 (m,
J
J
1H), 2.81 (dd, J = 16.2, 7.3 Hz, 1H), 1.16 (s, 9H). 13C NMR
J
J
J =
(126 MHz, CDCl3) δ 173.9, 173.2, δ 159.53 (d, JC, F = 243.0
Hz 1C), 148.1, 139.4 139.4, 134.5, 132.4, 130.29 (d, JC, F
7.7 Hz 1C), 128.9, 128.8, 128.7, 128.6, δ 127.5, 126.6, 116.1
(d, JC, F = 23.3 Hz 1C), 110.37 (t, JC, F = 16.2 Hz), 84.2, 71.8,
=
3.82 – 3.67 (m, 2H), 2.79 (dd, J = 16.2, 7.3 Hz, 1H), 1.13 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 173.8, 173.5, 156.6,
148.1, 136.8, 134.8, 132.7, 129.8, 128.8, 128.71, 128.66,
128.6, 128.5, 126.6, 114.4, 110.2, 109.1, 83.9, 72.0, 56.0,
49.1, 44.3, 35.2, 27.8, 27.7. IR (KBr)
1154cmꢀ1. HRMS (ESI) m/z
C29H27O4N2NaF, 509.1838, Found 509.1847.
S,3 )ꢀtertꢀbutyl 1ꢀbenzylꢀ5ꢀchloroꢀ2,5'ꢀdioxoꢀ3'ꢀphenyꢀ
v
3344, 1793, 1492,
:
[M+Na]+Calc. for
49.1, 44.1, 35.2, 27.6. IR (KBr)
1.HRMS (ESI) m/z
Calc. [M+Na]for C30H30N2NaO5,
521.2040 Found 521.2044.
S,3 )ꢀtertꢀbutyl
v
3329, 1795, 1484, 1288 cmꢀ
:
(
2'
'R
lspiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3f).
(
2'
'
R
1ꢀbenzylꢀ6ꢀbromoꢀ2,5'ꢀdioxoꢀ3'ꢀ
Yield: 65 mg (66%) with 16:1 dr, white solid mp 165ꢀ169°C,
phenylspiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3i).
25
Rf= 0.22 (petroleum ether/ethyl acetate, 5:1). [α]D +35 (
c
Yield: 77 mg (65%), white solid, mp 156ꢀ158°C, Rf = 0.30
25
1.0, CH2Cl2), HPLC analysis: 98% ee [Daicel CHIRALPAK
(petroleum ether/ethyl acetate, 20:1). [α]D +47 (c 1.0,
o
ODꢀH column, 20 C, 250 nm hexane/iꢀPrOH = 70:30, 1.0
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
1
mL/min, 250 nm, 14.5 min (minor) , 26.6 min (major)]. H
H column, 20oC, 250 nm hexane/iꢀPrOH = 90:10, 1.0
1
NMR (500 MHz, CDCl3) δ 7.43 (d, J = 2.0 Hz, 1H), 7.33 (t,
J = 7.4 Hz, 1H), 7.21 (t, J = 7.7 Hz, 2H), 7.19 – 7.15 (m, 2H),
7.09 (t, J = 7.5 Hz, 2H), 6.97 (d, J = 7.6 Hz, 2H), 6.39 (t, J =
7.8 Hz, 2H), 6.31 (d, J = 8.3 Hz, 1H), 4.98 (d, J = 15.9 Hz,
1H), 4.11 (d, J = 16.0 Hz, 1H), 3.80 (dd, J = 13.9, 7.5 Hz,
1H), 3.68 (dd, J = 16.3, 14.0 Hz, 1H), 2.81 (dd, J = 16.4, 7.5
Hz, 1H), 1.16 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 173.7,
173.1, 148.1, 142.0, 134.3, 132.3, 130.4, 129.8, 128.9, 128.8,
128.74, 128.72, 128.6, 127.6, 126.6, 122.6, 110.7, 84.3, 71.6,
mL/min, 250 nm, 10.9min (minor), 29.7min (major),]. H
NMR (500 MHz, CDCl3) δ 7.43 (d,
= 7.4 Hz, 1H), 7.21 – 7.13 (m, 4H), 7.08 (t,
6.93 (d, = 7.7 Hz, 2H), 6.40 (t, = 6.4 Hz, 3H), 5.02 (d,
15.9 Hz, 1H), 4.10 (d, = 15.9 Hz, 1H), 3.83 (dd, = 13.9,
7.5 Hz, 1H), 3.73 – 3.67 (m, 1H), 2.81 (dd, = 16.4, 7.5 Hz,
J
= 7.2 Hz, 1H), 7.30 (t,
J
J
= 7.5 Hz, 2H),
J
J
J =
J
J
J
1H), 1.09 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 174.1,
173.6, 148.1, 143.5, 134.8, 132.7, 129.9, 128.8, 128.7, 128.64,
128.57, 128.5, 127.4, 126.7, 123.3, 122.2, 109.7, 83.9, 71.7,
49.0, 44.2, 35.2, 27.7. IR (KBr)
v
3304, 1791, 1384, 1150 cmꢀ
49.0, 44.1, 35.2, 27.6. IR (KBr) v
3343, 1790, 1467, 1276cmꢀ
1.HRMS (ESI) m/z: [M+Na] Calc. for C29H27O4N2ClNa,
1. HRMS (ESI) m/z: [M+Na]+Calc. for C29H28O4N2Na,
525.1545, Found 525.1552.
491.1932, Found 491.1941.
(
2'S,3
'
R)ꢀtertꢀbutyl 1ꢀbenzylꢀ5ꢀmethylꢀ2,5'ꢀdioxoꢀ3'ꢀphenꢀ
(
2'S,3'R)ꢀtertꢀbutyl
1ꢀbenzylꢀ3'ꢀ(4ꢀfluorophenyl)ꢀ2,5'ꢀ
ylspiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3g).
dioxospiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3j).
Yield: 73 mg (76%), white solid mp 173ꢀ175°C, Rf= 0.22
Yield: 59 mg (61%), white solid, mp 149ꢀ150°C, Rf= 0.31
(petroleum ether/ethyl acetate, 5:1). [α]D +25 (c 1.0,
25
25
(petroleum ether/ethyl acetate, 5:1). [α]D +47 (
c
1.0,
CH2Cl2), HPLC analysis: 98% ee [Daicel CHIRALPAK ADꢀ
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH = 85:15, 1.0
H column, 20 oC, 250 nm hexane/iꢀPrOH = 80:20, 1.0
1
1
mL/min, 250 nm, 15.8 min (minor), 32.9 min (major)]. H
mL/min, 250 nm, 11.2 min (minor) 36.7 min (major)]. H
NMR (500 MHz, CDCl3) δ 7.23 (t,
= 4.4 Hz, 1H), 7.12ꢀ7.05 (m, 3H), 7.00 (t,
6.89 (dd, = 20.2, 7.8 Hz, 3H), 6.30 (d, = 7.5 Hz, 2H), 6.21
(d, = 7.9 Hz, 1H), 4.93 (d, = 15.9 Hz, 1H), 4.00 (d,
15.9 Hz, 1H), 3.75 (dd, = 13.9, 7.5 Hz, 1H), 3.65 – 3.59 (m,
1H), 2.72 (dd, = 16.3, 7.5 Hz, 1H), 2.30 (s, 3H), 1.02 (s,
J
= 7.4 Hz, 1H), 7.19 (d,
J
NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.3 Hz, 1H), 7.26 –
7.12 (m, 4H), 6.85 (dq, J = 17.2, 8.7 Hz, 3H), 6.48 (d, J = 7.0
Hz, 2H), 5.03 (d, J = 15.8 Hz, 1H), 4.12 (d, J = 15.8 Hz, 1H),
3.80 (dd, J = 13.9, 7.6 Hz, 1H), 3.66 – 3.60 (m, 1H), 2.80 (dd,
J = 16.4, 7.6 Hz, 1H), 1.10 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 173.9, 173.2, 163.0 (d, JC, F = 245.1 Hz, 1C) 148.1,
143.5, 134.8, 130.3, 130.2, 130.1, 128.5 (d, JC, F = 7.8 Hz,
J
= 7.5 Hz, 2H),
J
J
J
J
J =
J
J
9H). 13C NMR (126 MHz, CDCl3) δ 174.0, 173.6, 148.1,
141.1, 134.9, 132.9, 132.8, 130.1, 128.71, 128.66, 128.6,
128.54, 128.46, 127.3, 126.6, 122.8, 109.4, 83.8, 71.8, 48.9,
1C), 128.4, 127.7, 126.7, 123.4, 122.2, δ 115.72 (d, JC, F
=
21.4 Hz, 1C), 109.7, 84.0, 71.6, 48.3, 44.1, 35.3, 27.6. IR
44.1, 35.2, 27.5, 21.2. IR (KBr)
v
3459, 1635, 1384, 1088 cmꢀ
(KBr) v :
3389, 1791, 1383, 1152 cmꢀ1. HRMS (ESI) m/z
1.HRMS (ESI) m/z: [M+Na] Calc. for C30H30O4N2Na,
[M+Na]+Calc. for C29H27O4N2NaF, 509.1844, Found
509.1847.
505.2089, Found 505.2098.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Organic & Biomolecular Chemistry
Page 6 of 8
View Article Online
ARTICLE
2'S,3'R)ꢀtertꢀbutyl
Journal Name
DOI: 10.1039/C5OB02466H
(
1ꢀbenzylꢀ3'ꢀ(4ꢀchlorophenyl)ꢀ2,5'ꢀ
Yield: 85 mg (85%), white solid, mp 181ꢀ183°C, Rf= 0.20
(petroleum ether/ethyl acetate, 5:1). [α]D +86 (c 1.0,
25
dioxospiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3k).
Yield: 72 mg (72%), white solid, mp 156ꢀ158°C, Rf= 0.27
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH = 70:30, 1.0
mL/min, 250 nm, 10.4 min (minor) , 24.1 min (major)]. 1H
25
(petroleum ether/ethyl acetate, 5:1). [α]D +51 (
c 1.0,
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ADꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH = 85:15, 1.0
mL/min, 250 nm, 13.2 min (minor), 45.4 min (major)] 1H
NMR (500 MHz, CDCl3) δ 7.41 (d, J = 7.3 Hz, 1H), 7.26ꢀ
7.12 (m, 7H), 6.84 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 7.2 Hz,
3H), 5.07 (d, J = 15.8 Hz, 1H), 4.11 (d, J = 15.8 Hz, 1H),
3.79 (dd, J = 13.9, 7.6 Hz, 1H), 3.63 – 3.60 (m, 1H), 2.79 (dd,
J = 16.4, 7.6 Hz, 1H), 1.10 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 173.9, 173.1, 148.0, 143.5, 134.7, 134.6, 131.3,
130.1, 130.0, 129.0, 128.8, 128.3, 127.7, 126.7, 123.4, 122.2,
NMR (400 MHz, CDCl3) δ 7.41 (d,
7.07 (m, 5H), 6.84 (d, = 8.6 Hz, 2H), 6.69 (d,
2H), 6.49 – 6.05 (m, 3H), 5.10 (d, = 15.9 Hz, 1H), 4.10 (d,
= 15.9 Hz, 1H), 3.7550 (s, 9H), 3.82 – 3.60 (m, 4H), 2.78
J
= 7.0 Hz, 1H), 7.22 –
J
J
= 8.7 Hz,
J
J
(dd,
J
= 16.3, 7.4 Hz, 1H), 1.09 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 174.1, 173.6, 159.8, 148.1, 143.5, 134.7, 129.8,
129.7, 128.7, 128.5, 127.4, 126.7, 124.5, 123.2, 122.1, 114.1,
109.6, 83.8, 71.8, 55.2, 48.3, 44.0, 35.4, 27.6. IR (KBr)
v
3420, 1791, 1467, 1153 cmꢀ1HRMS (ESI) m/z: [MꢀH] Calc.
109.7, 84.0, 71.5, 48.4, 44.2, 35.1, 27.6. IR (KBr)
v
3400,
for C30H30N2NaO5Na, 521.2051 Found 5212054.
1790, 1384, 1089 cmꢀ1. HRMS (ESI) m/z: [MꢀH]+Calc. for
(
2'S,3
'
R)ꢀtertꢀbutyl
1ꢀbenzylꢀ3'ꢀ(3ꢀchlorophenyl)ꢀ2,5'ꢀ
C29H27O4N2ClNa, 525.1544, Found 525.1552.
dioxospiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3o).
(
2'S,3'R)ꢀtertꢀbutyl
1ꢀbenzylꢀ3'ꢀ(4ꢀcyanophenyl)ꢀ2,5'ꢀ
Yield: 64 mg (64%) with 22:1 dr, white solid, mp 179ꢀ181°C,
Rf= 0.32 (petroleum ether/ethyl acetate, 5:1). [α]D +12 (c
25
dioxospiro[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3l).
Yield: 75 mg (76%), white solid, mp 143ꢀ145°C, Rf= 0.15
1.0, CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK
25
o
(petroleum ether/ethyl acetate, 5:1). [α]D ꢀ1.59 (
c
1.0,
ADꢀH column, 20 C, 250 nm hexane/iꢀPrOH = 80:20, 1.0
1
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH =70:30, 1.0
mL/min, 250 nm, 12.6 min (minor), 46,5 min (major)]. 1H
mL/min, 250 nm, 12.1 min (minor), 57.9 min major)]. H
NMR (500 MHz, CDCl3) δ 7.41 (d, J = 7.2 Hz, 1H), 7.23 (dd,
J = 7.8, 0.8 Hz, 2H), 7.20 – 7.12 (m, 4H), 7.06 (t, J = 7.9 Hz,
1H), 6.83 (s, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.52 (dd, J = 17.0,
7.5 Hz, 3H), 4.14 (d, J = 15.8 Hz, 1H), 3.78 (dd, J = 13.9, 7.5
Hz, 1H), 3.64 (dd, J = 16.3, 13.9 Hz, 1H), 2.80 (dd, J = 16.3,
7.5 Hz, 1H), 1.10 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
173.8, 173.0, 148.0, 143.5, 134.9, 134.8, 134.6, 130.2, 129.9,
128.8, 128.7, 128.2, 127.6, 126.8, 126.6, 123.5, 122.1 109.7,
NMR (500 MHz, CDCl3) δ 7.44 (d,
= 8.3 Hz, 2H), 7.30 – 7.25 (m, 2H), 7.21 – 7.17 (m, 3H),
6.98 (d, = 8.3 Hz, 2H), 6.57 (dd, = 12.7, 7.7 Hz, 3H), 4.94
(d, = 15.6 Hz, 1H), 4.15 (d, = 15.6 Hz, 1H), 3.84 (dd,
13.8, 7.6 Hz, 1H), 3.64 (dd, = 16.4, 13.8 Hz, 1H), 2.82 (dd,
= 16.4, 7.6 Hz, 1H), 1.11 (s, 9H). 13C NMR (126 MHz,
J = 7.3 Hz, 1H), 7.37 (d,
J
J
J
J
J
J =
J
J
CDCl3) δ 173.6, 172.5, 147.9, 143.4, 138.2, 134.7, 132.3,
130.4, 129.3, 128.8, 128.0, 127.9, 127.0, 123.6, 122.3, 118.4,
84.1, 71.4, 48.5, 44.2, 34.9, 27.6. IR (KBr) v 3420, 1635,
1384, 1088 cmꢀ1. HRMS (ESI) m/z: [M+Na] Calc. for
112.6, 109.7, 84.3, 71.2, 48.7, 44.2, 34.7, 27.6. IR (KBr)
v
C29H27O4N2ClNa, 525.1544 Found 525.1552.
3314, 1791, 1311, 1028 cmꢀ1. HRMS (ESI) m/z: [M+Na] Calc.
(
2'S,3
'
R)ꢀtertꢀbutyl
1ꢀbenzylꢀ3'ꢀ(3ꢀmethoxyphenyl)ꢀ2,5'ꢀ
for C30H27N3NaO4Na, 516.1888 , Found 516.1894.
dioxospiro[indolineꢀ3,2'ꢀ pyrrolidine]ꢀ1'ꢀcarboxylate (3p).
(
2
'
S,3
'
R
)ꢀtertꢀbutyl
1ꢀbenzylꢀ2,5'ꢀdioxoꢀ3'ꢀ(pꢀtolyl)spiro
Yield: 68 mg (68%), white solid, mp 153ꢀ155°C, Rf= 0.20
(petroleum ether/ethyl acetate, 5:1). [α]D +54 (c 1.0,
25
[indolineꢀ3,2'ꢀpyrrolidine]ꢀ1'ꢀ carboxylate (3m).
Yield: 63 mg (65%), white solid, mp 81ꢀ83°C, Rf= 0.35
CH2Cl2), HPLC analysis: 97% ee [Daicel CHIRALPAK ODꢀ
25
(petroleum ether/ethyl acetate, 5:1). [α]D +53 (
c
1.0,
H column, 20 oC, 250 nm hexane/iꢀPrOH = 70:30, 1.0
1
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
mL/min, 250 nm, 7.1 min (minor), 10.2 min (major)]. H
H column, 20 oC, 250 nm hexane/iꢀPrOH = 80:20, 1.0
NMR (500 MHz, CDCl3) δ 7.48 (d, J = 7.3 Hz, 1H), 7.28 –
7.26 (m, 2H), 7.20 ꢀ7. 09 (m, 6H), 6.67 (dd, J = 8.8, 2.9 Hz,
1H), 6.58 (d, J = 7.5 Hz, 2H), 6.46 (d, J = 7.8 Hz, 1H), 5.15
(d, J = 15.9 Hz, 1H), 4.55 (dd, J = 13.5, 8.2 Hz, 1H), 4.20 (d,
1
mL/min, 250 nm, 16.5 min (minor), 49.9 min (major)]. H
NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.0 Hz, 1H), 7.26 –
7.12 (m, 3H), 7.07 (t, J = 7.4 Hz, 2H), 6.98 (d, J = 7.7 Hz,
2H), 6.82 (d, J = 7.8 Hz, 2H), 6.42 (dd, J = 14.1, 7.5 Hz, 3H),
5.08 (d, J = 15.9 Hz, 1H), 4.10 (d, J = 15.9 Hz, 1H), 3.80 (dd,
J = 13.9, 7.3 Hz, 1H), 3.75 – 3.53 (m, 1H), 2.78 (dd, J = 16.2,
7.3 Hz, 1H), 2.33 (s, 3H), 1.09 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 174.1, 173.7, 148.1, 143.5, 138.2, 134.8, 129.8,
129.7, 129.4, 128.7, 128.53, 128.50, 127.3, 126.8, 123.2,
122.2, 109.6, 83.8, 71.7, 48.7, 44.1, 35.3, 29.8, 27.6, 21.4. IR
J = 16.0 Hz, 1H), 3.60 (s, 3H),
δ3.41 (dd, J = 16.8, 13.6 Hz,
1H), 2.89 (dd, J = 16.9, 8.2 Hz, 1H), 1.10 (s, 9H). 13C NMR
(126 MHz, CDCl3) δ 174.7, 172.9, 159.1, 147.9, 143.2, 135.0,
133.9, 133.7, 130.0, 128.8, 127.6, 127.5, 126.5, 124.2, 123.1,
116.7, 116.4, 115.0, 109.4, 84.0, 71.8, 55.6, 45.6, 44.1, 37.7,
27.6. IR (KBr)
m/z [M+Na] Calc. forC30H30N2NaO5, 521.2043 Found
521.2039.
S,3 )ꢀtertꢀbutyl
v
2925, 1796, 1455, 1035 cmꢀ1. HRMS (ESI)
:
(KBr)
Calc. for C30H30O4N2Na, 505.2103 Found 505.2089.
S,3 )ꢀtertꢀbutyl 1ꢀbenzylꢀ3'ꢀ(4ꢀmethoxyphenyl)ꢀ2,5'ꢀ
v
3466, 1634, 1384, 1088 cmꢀ1HRMS (ESI) m/z: [MꢀH]
(
2'
'
R
1ꢀbenzylꢀ3'ꢀ(2ꢀchlorophenyl)ꢀ2,5'ꢀ
(
2'
'
R
dioxospiro[indolineꢀ3,2'ꢀ pyrrolidine]ꢀ1'ꢀcarboxylate (3q).
dioxospiro[indolineꢀ3,2'ꢀpyrrolidine]ꢀ1'ꢀcarboxylate(3n).
Yield: 62 mg (62%), white solid, mp 140ꢀ143°C, Rf= 0.15
25
(petroleum ether/ethyl acetate, 5:1). [α]D +44 (
c 1.0,
6 | J. Name., 2012, 00, 1-3
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Page 7 of 8
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5OB02466H
CH2Cl2), HPLC analysis: 96% ee [Daicel CHIRALPAK ODꢀ
1 S. Haddad, S. Boudriga, T. N. Akhaja, J. P. Raval, F. Porzio, A.
Soldera, M. Askri, M. Knorr, Y. Rousselin, M. M. Kubicki and D.
Rajani, New J. Chem., 2015, 39, 520.
H column, 20 oC, 250 nm hexane/iꢀPrOH = 70:30, 1.0
1
mL/min, 250 nm, 14.2 min (minor), 24.9 min (major)]. H
NMR (500 MHz, CDCl3) δ 7.63 – 7.61 (m, 1H), 7.45 (d,
7.4 Hz, 1H), 7.20ꢀ7.15 (m, 5H), 7.10ꢀ7.07 (m, 3H), 6.50 (d,
J
=
J
2 (a) B. M. Trost and M. K. Brennan, Synthesis, 2009, 2009, 3003; (b)
A. Millemaggi and R. J. K. Taylor, Eur. J. Org. Chem., 2010,
2010, 4527; (c) G.ꢀS. Wu, L. Ouyang, J. Liu, S. Zeng, W. Huang,
= 7.6 Hz, 2H), 6.42 (d,
J
= 7.8 Hz, 1H), 5.09 (d,
J
J
J
= 15.9 Hz,
= 15.9 Hz,
= 16.8, 8.2
1H), 4.59 (dd,
1H), 3.50 (dd,
J
J
= 13.5, 8.2 Hz, 1H), 4.16 (d,
= 16.8, 13.7 Hz, 1H), 2.86 (dd,
B. Han, F.ꢀB. Wu, G. He and M.ꢀL. Xiang, Mol. Divers., 2013, 17,
271; (d) F. Shi, Z.ꢀL. Tao, S.ꢀW. Luo, S.ꢀJ. Tu and L.ꢀZ. Gong,
Chem. Eur. J., 2012, 18, 6885; (e) A. Kumar, G. Gupta, A. K.
Bishnoi, R. Saxena, K. S. Saini, R. Konwar, S. Kumar and A.
Dwivedi, Bioorg. Med. Chem., 2015, 23, 839; (f) A. S. Girgis, Eur.
J. Med. Chem., 2009, 44, 91; (g) Y. Arun, K. Saranraj, C.
Hz, 1H), 1.09 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 174.4,
173.1, 148.0, 143.0, 135.6, 134.9, 131.3, 130.1, 129.90,
129.88, 129.4, 128.8, 127.9, 127.5, 127.4, 126.7, 123.8, 123.2,
109.5, 84.0, 71.7, 44.1, 42.9, 37.1, 27.6. IR (KBr)
v 3301,
1792, 1384, 1128 cmꢀ1. HRMS (ESI) m/z: [M+Na] Calc. For
Balachandran and P. T. Perumal, Eur. J. Med. Chem., 2014, 74,
C29H27O4N2ClNa, 525.1552 Found 525.1547
50; (h) D. Kathirvelan, J. Haribabu, B. S. R. Reddy, C.
Balachandran and V. Duraipandiyan, Bioorg. Med. Chem., 2015,
25, 389.
(
2'S,3
'
R)ꢀtertꢀbutyl
1ꢀbenzylꢀ2,5'ꢀdioxoꢀ3'ꢀ(oꢀtolyl)spiro
[indolineꢀ3,2'ꢀpyrrolidine] ꢀ1'ꢀcarboxylate (3r).
Yield: 56 mg (58%), white solid, mp 164ꢀ165°C , Rf= 0.20
3 (a) L. Tian, X.ꢀQ. Hu, Y.ꢀH. Li and P.ꢀF. Xu, Chem. Commun., 2013,
49, 7213; (b) B.ꢀD. Cui, J. Zuo, J.ꢀQ. Zhao, M.ꢀQ. Zhou, Z.ꢀJ. Wu,
X.ꢀM. Zhang and W.ꢀC. Yuan, J. Org. Chem., 2014, 79, 5305.
25
(petroleum ether/ethyl acetate, 5:1). [α]D +52 (
c 1.0,
CH2Cl2), HPLC analysis: 99% ee [Daicel CHIRALPAK ODꢀ
H column, 20 oC, 250 nm hexane/iꢀPrOH = 70:30, 1.0
mL/min, 250 nm, 8.7 min (minor), 48.3 min (major)]. 1H
4 (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107
,
5606; (b) J. L. Moore and T. Rovis, in Asymmetric
Organocatalysis, ed. B. List, 2009, pp. 77; (c) X. Bugaut and F.
Glorius, Chem. Soc. Rev., 2012, 41, 3511; (d) M. N. Hopkinson, C.
Richter, M. Schedler and F. Glorius, Nature, 2014, 510, 485.
NMR (500 MHz, CDCl3) δ 7.58 (d,
= 7.3 Hz, 1H), 7.19 – 7.13 (m, 4H), 7.10ꢀ7.06 (m, 3H), 7.01
(d, = 7.1 Hz, 1H), 6.35 (dd, = 19.0, 11.2 Hz, 3H), 5.14 (d,
= 15.9 Hz, 1H), 4.20 (dd,
16.0 Hz, 1H), 3.58 (dd, = 16.9, 13.7 Hz, 1H), 2.84 (dd,
J = 7.6 Hz, 1H), 7.42 (d,
J
J
J
J
J
= 13.6, 8.1 Hz, 1H), 4.07 (d,
J
J
=
=
5 (a) C. Burstein and F. Glorius, Angew. Chem. Int. Ed., 2004, 43,
J
6205; (b) N. T. Reynolds, J. R. de Alaniz and T. Rovis, J. Am.
Chem. Soc., 2004, 126, 9518; (c) S. S. Sohn, E. L. Rosen and J. W.
Bode, J. Am. Chem. Soc., 2004, 126, 14370; (d) G.ꢀQ. Li, Y. Li,
L.ꢀX. Dai and S.ꢀL. You, Adv. Synth. Catal., 2008, 350, 1258.
17.0, 8.1 Hz, 1H), 1.64 (s, 3H), 1.09 (s, 9H). 13C NMR (126
MHz, CDCl3) δ 174.6, 173.6, 148.0, 143.3, 138.0, 134.8,
131.6, 130.8, 129.9, 129.1, 128.8, 128.5, 128.1, 127.3, 126.8,
126.6, 123.0, 122.7, 109.8, 83.9, 72.1, 44.1, 43.6, 37.6, 27.6,
6 (a) Y.ꢀR. Zhang, L. He, X. Wu, P.ꢀL. Shao and S. Ye, Org. Lett.
2008, 10, 277; (b) N. Duguet, C. D. Campbell, A. M. Z. Slawin
and A. D. Smith, Org. Biomol. Chem., 2008, , 1108; (c) X.ꢀL.
,
19.6. IR (KBr)
v
2925, 1606, 1454, 1028 cmꢀ1. HRMS (ESI)
m/z: [M+Na] Calc. For C30H30O4N2Na, 505.2091 Found
6
505.2098.
Huang, L. He, P.ꢀL. Shao and S. Ye, Angew. Chem. Int. Ed., 2009,
48, 192; (d) A. T. Biju, M. Padmanaban, N. E. Wurz and F.
Glorius, Angew. Chem. Int. Ed., 2011, 50, 8412; (e) X. Huang and
S. Ye, Chin. Sci. Bull., 2010, 55, 1753; (f) L.ꢀH. Sun, Z.ꢀQ. Liang
and S. Ye, Acta Chim. Sinica, , 2014, 72, 841.
(
2'S,3
'
R)ꢀtertꢀbutyl
1ꢀbenzylꢀ3'ꢀ(2ꢀmethoxyphenyl)ꢀ2,5'ꢀ
dioxospiro[indolineꢀ3,2'ꢀ pyrrolidine]ꢀ1'ꢀcarboxylate (3s).
Yield 70 mg (70%) with 14:1 dr, white solid, mp 188ꢀ190°C ,
Rf= 0.20 (petroleum ether/ethyl acetate, 5:1). [α]D ꢀ0.94 (
25
c
1.0, CH2Cl2), HPLC analysis: 98% ee [Daicel CHIRALPAK
ODꢀH column, 20 C, 250 nm hexane/iꢀPrOH = 60:40, 1.0
7 (a) L. Hao, Y. Du, H. Lv, X.ꢀK. Chen, H.ꢀS. Jiang, Y.ꢀL. Shao and Y.
R. Chi, Org. Lett., 2012, 14, 2154; (b) S.ꢀJ. Chen, L. Hao, Y.ꢀX.
Zhang, B. Tiwari and Y. R. Chi, Org. Lett., 2013, 15, 5822; (c) Z.ꢀ
Q. Fu, J.ꢀF. Xu, T.ꢀS. Zhu, W. W. Y. Leong and Y. R. Chi, Nat.
o
mL/min, 250 nm, 5.4 min (minor), 9.4 min (major)]. 1H NMR
(500 MHz, CDCl3) δ 7.54 (d, J = 2.3 Hz, 1H), 7.40 – 7.38 (m,
1H), 7.32 (dd, J = 8.7, 2.4 Hz, 1H), 7.20 – 7.08 (m, 6H), 6.62
(d, J = 7.0 Hz, 2H), 6.46 (dd, J = 7.7, 6.4 Hz, 2H), 5.11 (d, J =
15.6 Hz, 1H), 4.46 (dd, J = 13.9, 8.0 Hz, 1H), 4.10 (d, J =
15.7 Hz, 1H), 3.53 (dd, J = 16.5, 14.0 Hz, 1H), 3.10 (s, 3H),
2.73 (dd, J = 16.6, 8.0 Hz, 1H), 1.08 (s, 9H). 13C NMR (126
MHz, CDCl3) δ 174.2, 173.4, 157.2, 148.0, 143.1, 135.2,
132.1, 131.8, 129.3, 129.0, 128.8, 127.5, 126.9, 124.2, 123.1,
122.7, 113.3, 112.4, 109.1, 83.8, 71.4, 55.2, 44.3, 39.7, 35.7,
Chem., 2013, 5, 835; (d) L. He, H. Guo, X.ꢀW. Ma, J. Zhang, C.ꢀZ.
Gu, W. Wang and B. Dai, Chin. Chem. Lett., 2014, 25, 215.
8 (a) X.ꢀY. Chen, Z.ꢀH. Gao, C.ꢀY. Song, C.ꢀL. Zhang, Z.ꢀX. Wang
and S. Ye, Angew. Chem. Int. Ed., 2014, 53, 11611; (b) J.ꢀT.
Cheng, X.ꢀY. Chen and S. Ye, Org. Biomol. Chem., 2015, 13
,
1313; (c) Y.ꢀW. Xie, C.ꢀX. Yu, T.ꢀJ. Li, S.ꢀJ. Tu and C.ꢀS. Yao,
Chem. Eur. J., 2015, 21, 5355; (d) Z. Jin, K. Jiang, Z. Fu, J.
Torres, P. Zheng, S. Yang, B.ꢀA. Song and Y. R. Chi, Chem. Eur.
J., 2015, 21, 9360.
27.6. IR (KBr)
v
3445, 1639, 1384, 1101 cmꢀ1.HRMS (ESI)
m/z: [M+Na] Calc. for C30H30N2O5Na, 521.2052, Found
521.2042
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,
3722; (d) P.ꢀL. Shao, X.ꢀY. Chen and S. Ye, Angew. Chem. Int.
Ed., 2010, 49, 8412; (e) R. L. Atienza, H. S. Roth and K. A.
Notes and references
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ARTICLE
Journal Name
DOI: 10.1039/C5OB02466H
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8 | J. Name., 2012, 00, 1-3
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