Enantioselective Michael addition of 3-aryloxindoles to a vinyl bisphosphonate ester catalyzed by a cinchona alkaloid derived thiourea catalyst

Article abstract of DOI:10.1039/c2ob25966d

A highly enantioselective Michael addition of 3-aryloxindole to vinyl bisphosphonate ester catalyzed by a cinchonidine derived thiourea catalyst has been investigated. The corresponding adducts, containing a chiral quaternary carbon center and geminal bisphosphonate ester fragment at the 3-position of the oxindole, were obtained in moderate to good yields (65-92%) and moderate to good enantioselectivities (up to 92% ee).

Full text of DOI:10.1039/c2ob25966d

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 7970
www.rsc.org/obc
PAPER
Enantioselective Michael addition of 3-aryloxindoles to a vinyl
bisphosphonate ester catalyzed by a cinchona alkaloid derived thiourea
catalyst†
Mei-Xin Zhao,*a Tong-Lei Dai,a Ran Liu,a Deng-Ke Wei,a Hao Zhou,a Fei-Hu Jia and Min Shi*a,b
Received 19th May 2012, Accepted 2nd August 2012
DOI: 10.1039/c2ob25966d
A highly enantioselective Michael addition of 3-aryloxindole to vinyl bisphosphonate ester catalyzed by
a cinchonidine derived thiourea catalyst has been investigated. The corresponding adducts, containing
a chiral quaternary carbon center and geminal bisphosphonate ester fragment at the 3-position of the
oxindole, were obtained in moderate to good yields (65–92%) and moderate to good enantioselectivities
(up to 92% ee).
Introduction
against the in vitro proliferation of several protozoan parasites
Recently, the enantioselective synthesis of oxindoles bearing a
quaternary chiral center at the 3-position has been of crucial
importance and has attracted extensive attention as this structure
motif is widely present in numerous biologically and pharma-
ceutically active natural products and molecules.1 In this context,
various excellent approaches for the asymmetric synthesis of
3,3-disubstituted oxindole derivatives have been reported to
date.2 The most common strategy is through enantioselective
halogenation,3 hydroxylation,4 amination,5 aldol and Mannich
reactions,6 allylic alkylation7 and conjugate addition8 by using
3-substituted oxindoles as nucleophiles. Moreover, synthesis of
optically active 3-acylated oxindoles bearing a quaternary stereo-
center can be achieved through a carboxyl migration of O-acy-
lated oxindoles mediated by a chiral nucleophilic catalyst.9
Geminal bisphosphonates (gem-BPs) are structurally stable
pyrophosphate analogues and constitute an important class of
pharmacologically active compounds due to their high affinity
for hydroxyapatite bone mineral surfaces.10 Some of them have
been used for the prevention and treatment of several bone dis-
eases11 and as carriers for bone-specific therapeutic agents.10
Additionally, gem-BP compounds have also shown activity
that cause African sleeping sickness, malaria, and others.12
These important biological activities and potential clinical utility
of gem-BPs have stimulated intensive interest in their synthesis.
A number of synthetic methods for gem-BPs have been devel-
oped in the past decades.13 Among these, Michael addition of
various nucleophiles to electron-deficient and highly reactive
tetraalkyl ethylidene bisphosphonates has been proven as one of
the most efficient approaches for accessing gem-BPs in good
yields.14 However, catalytic asymmetric approaches for the prep-
aration of optically active gem-BPs are quite limited.15 Organo-
catalyzed Michael addition of nucleophiles to vinylphosphonates
has been underestimated as a valuable tool for the facile syn-
thesis of optically active gem-BPs. Only four examples, includ-
ing chiral secondary amine catalysis for unmodified aldehydes or
ketones15a–c and chiral base-catalysis for β-ketoesters15d with
vinyl bisphosphonates can be found in the literature.
As part of our ongoing interest in the enantioselective syn-
thesis of chiral 3,3-disubstituted oxindoles, we have developed
cinchona alkaloid catalyzed enantioselective chlorination of
3-aryl-N-Boc-oxindoles with N-chlorosuccinimide (NCS)3h and
Michael addition of 3-aryl-N-Boc-oxindoles with phenyl vinyl
sulfone.8j Considering that vinyl phosphonates as valuable and
unique acceptors have been utilized in many asymmetric conju-
gate additions,15,16 we envisioned that cinchona alkaloid cata-
lysts could facilitate the Michael addition of 3-aryl-N-Boc-
oxindoles to vinyl bisphosphonates to afford the desired adducts
bearing a quaternary carbon stereocenter and gem-BP fragment
at the 3-position of the oxindole, which have potential biological
activity and synthetic potential in organic synthesis. To the best
of our knowledge, there are no examples on the organocatalytic
asymmetric Michael addition of simple vinyl bisphosphonates to
3-aryl-N-Boc-oxindoles. Herein, we wish to report our studies
on this subject.
aKey Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology, 130 Mei
Long Road, Shanghai 200237, P.R. China. E-mail: mxzhao@ecust.edu.cn;
Fax: +86-21-34201699
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P.R. China. E-mail: Mshi@mail.sioc.ac.cn;
Fax: +86-21-64166128
†Electronic supplementary information (ESI) available: NMR spectra of
new compounds, HPLC traces for the determination of the enantiomeric
excess for compounds 3, 5, 6, 8 and X-ray crystal data of product 3u.
CCDC 867514. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob25966d
7970 | Org. Biomol. Chem., 2012, 10, 7970–7979
This journal is © The Royal Society of Chemistry 2012

View Online
Table 1 Screening of catalysts for the enantioselective Michael
addition of oxindoles 2a to vinyl phosphatea
Table 2 Optimization reaction conditions using cat. 1i as the catalyst
for enantioselective Michael addition of oxindole 2a to vinyl phosphatea
Entry
Solvent
T (°C)
t [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
CH3CN
Acetone
CH3OH
DMF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t
r.t
r.t
r.t
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
67
77
73
81
81
85
85
83
84
79
78
82
78
83
75
82
84
74
80
84
78
78
64
47
20
73
64
44
46
35
79
72
73
77
81
87
89
88
82
85
88
80
DCM
CHCl3
EtOAc
Et2O
9
THF
10d
11e
12f
13d,g
14d
15d
16d
17d
18d
19d,h
20d,i
21d,j
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Entry
Cat. 1
t [h]
Yieldb [%]
eec [%]
0
−10
−15
−20
−40
−15
−15
−15
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
80
81
79
88
81
80
73
81
67
13
17d
27
50
36
69d
68d
68
a All of reactions were carried out with oxindole 2a (0.2 mmol),
vinyl phosphate (0.1 mmol) and catalyst 1i (20 mol%) in solvent
(1.0 mL). b Yield of isolated product. c Determined by HPLC analysis on
a chiral stationary phase. d 2.0 mL of CH3CN was used. e 3.0 mL of
CH3CN was used. f 4.0 mL of CH3CN was used. g The ratio of oxindole
2a : vinyl phosphate is 1.2 : 1. h 30 mg of 4 Å molecular sieves were
added. i 30 mg of 3 Å molecular sieves were added. j 10 mol% of
catalyst 1i was used.
78
a All of reactions were carried out with oxindole 2a (0.2 mmol), vinyl
phosphate (0.1 mmol) and catalyst 1 (20 mol%) in CH3CN (1.0 mL) at
room temperature. b Yield of isolated product. c Determined by
HPLC analysis on a chiral stationary phase. d Opposite enantiomer was
obtained.
the results are shown in Table 2. In addition to acetonitrile, other
solvents were also examined (Table 2, entries 1–9). To our disap-
pointment, the results were unsatisfactory in all cases except for
using dichloromethane which gave a higher yield, but with a
slightly lower enantioselectivity (Table 2, entry 5). Changing the
concentration from 0.1 to 0.05 M can improve the yield along
with a similar enantioselectivity (Table 2, entries 10 vs. 1).
Further lowering the concentration, the yields did not change but
the ee’s decreased significantly (Table 2, entries 11–12). More-
over, changing the ratio of oxindole 2a : vinyl phosphonate from
2 : 1 to 1.2 : 1, the ee value decreased slightly. Further examin-
ation of the temperature effect revealed that lowering the reaction
temperature could significantly improve the ee’s of 3a without
sacrificing the yields (Table 2, entries 14–18). The best enantio-
selectivity for 3a was obtained in acetonitrile at −15 °C. Further
lowering the temperature, the ee decreased rather than increased.
Studies on the effect of additives suggested that addition of 4 Å
or 3 Å molecular sieves could not further improve the enantio-
selectivities of 3a (Table 2, entries 19–20). However, reducing
catalyst loading to 10 mol% led to a lower yield of 3a along
with lower enantioselectivity (Table 2, entry 21).
Results and discussion
Initial studies were carried out by using the reaction between
3-phenyl-N-Boc oxindole 2a and tetraethyl vinylbisphosphonate in
acetonitrile at room temperature as a model reaction in the pres-
ence of a variety of cinchona alkaloid derived organocatalysts to
determine the optimal conditions and the results of these experi-
ments are summarized in Table 1. Using naturally available
quinine 1a or quinidine 1b as catalyst, the reactions took place
smoothly and the desired product 3a was obtained in good yields
and low enantioselectivities (Table 1, entries 1 and 2). The
cinchona alkaloid derived bifunctional amine-thiourea catalysts
bearing sulfonamide with multiple hydrogen-bonding donors
1c–e, which had shown good catalytic activity in the Michael
addition of N-Boc-3-aryloxindole to phenyl vinyl sulfone,8j only
showed moderate catalytic activity in this reaction, affording 3a
in good yields with moderate enantioselectivities (Table 1, entries
3–5). Further evaluation of cinchona alkaloid derived amine-
thiourea catalysts 1f–i (Table 1, entries 6–9) revealed that cincho-
nidine derived thiourea 1i was the best catalyst for this reaction,
furnishing 3a in 67% yield and 78% ee (Table 1, entry 9).
Having established a catalytic system, extensive screenings for
the improvement of the reaction outcome were carried out and
With the optimized reaction conditions in hand, the substrate
scope of this reaction has been investigated by carrying out a
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7970–7979 | 7971

View Online
Table 3 Enantioselective Michael addition of various oxindoles 2 to vinyl phosphonatea
Entry
2
X
R
3
t [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
H
5-F
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
48
82
85
88
88
72
84
75
84
84
76
92
77
76
79
86
65
75
89
66
82
88(75)
trace
77
89
87
89
89
83
80
84
81
86
85
84
89
83
89
87
90
83
90
92
85
88(99)
n.d.
23
50
5-Me
5-OMe
5-Br
6-MeO
6-Br
6-Cl
H
9
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
2-naphthyl
m-MeC6H4
3,5-Me2C6H3
m-FC6H4
m-MeOC6H4
o-MeC6H4
Me
10
11
12
13
14
15
16
17
18
19
20
21d
22
23
24
5-F
5-Me
5-OMe
H
5-F
5-Me
5-OMe
H
5-F
H
H
H
5-F
H
2t
3t
2u
2v
2w
2x
3u
3v
3w
3x
3.5
10
H
Bn
57
a All of the reactions were carried out with oxindole 2 (0.2 mmol), vinyl phosphate (0.1 mmol) and catalyst 1i (20 mol%) in CH3CN (2.0 mL) at
−15 °C. b Yield of isolated product. c Determined by HPLC analysis on a chiral stationary phase. d The data in parentheses were obtained after
recrystallization.
range of reactions, in which both the X and R in oxindole 2 were
varied (Table 3). For N-Boc-3-phenyl substituted oxindole, sub-
stituents in both 5- and 6-positions were well tolerated and the
corresponding adducts were obtained in good yields (72–88%)
with good enantioselectivities (80–89% ee) (Table 3, entries
1–8). Substrates having substituents at the 6-position gave the
products in slightly lower enantioselectivities than those of the
corresponding substrates without substituent or having substitu-
ents at the 5-position (Table 3, entries 6–8 vs. 1–5). Further
investigation of the substituent at the C-3 position revealed that
the presence of a para-substituted aryl group led to a smooth
reaction, giving adducts in good yields and ee’s (Table 3, entries
8–16). Substrate 2q, bearing a bulky 2-naphthyl group at the C-3
position of the oxindole, also gave the corresponding product 3q
in reasonable yield and good enantioselectivity (Table 3, entry
17). In the case of 3-(meta-substituted aryl group) substituted
oxindoles 2r–2u, the corresponding products were obtained in
the best yields and enantioselectivities (Table 3, entries 18–21).
The enantiopurity of the adduct 3u could be enhanced to 99% ee
by simple recrystallization with petroleum ether–ethyl acetate
(Table 3, entry 21). However, as for 3-(o-tolyl)-substituted oxi-
ndole 2v, the reaction was sluggish and only a trace of desired
product 3v was afforded even after prolonging the reaction time
to 48 h, presumably due to steric hindrance (Table 3, entry 22).
It should be noted that 3-alkyloxindoles 2w and 2x are not
suitable substrates for this Michael addition, affording the corre-
sponding adducts 3w and 3x in moderate yields along with
lower enantioselectivities (Table 3, entries 23 and 24).
In order to investigate the effect of N-protecting group on this
reaction, several 3-phenyl oxindoles with different N-protecting
groups were subjected to this reaction under the standard con-
ditions and the results are summarized in Table 4. Different from
N-Boc oxindole 2a (Table 4, entry 1), using N-unprotected oxi-
ndole 4a, N-methyl substituted oxindole 4b and N-benzyl substi-
tuted oxindole 4c as the corresponding substrates, the reactions
became sluggish (Table 4, entries 2–4). N-Acetyl protected oxi-
ndoles 4d gave the corresponding product 5d in moderate yield
along with a lower ee value (Table 4, entry 5). However,
N-ethoxycarbonyl and N-Cbz protected oxindoles 4e and 4f led
to good yields with moderate enantioselectivities, thus indicating
that the presence of a N-bulky carbonate-protecting group is
crucial for a satisfactory yield and stereochemical outcome
(Table 4, entries 6 and 7).
The absolute configuration was determined to be R by X-ray
crystal structure analysis of the optically active adduct 3u
(Fig. 1, also see the ESI†).17 The configurations of other adducts
were deduced by analogy.
On the basis of the above results and commonly accepted
mechanism, a plausible transition-state model is proposed as
shown in Scheme 1. N-Boc-3-aryl substituted oxindole 2a would
7972 | Org. Biomol. Chem., 2012, 10, 7970–7979
This journal is © The Royal Society of Chemistry 2012

View Online
Table 4 Enantioselective Michael addition of various oxindoles 4 to
vinyl phosphonatea
Entry
2, 4
R
3, 5
t [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
2a
4a
4b
4c
4d
4e
4f
Boc
H
CH3
Bn
Ac
COOEt
Cbz
3a
5a
5b
5c
5d
5e
5f
3.5
48
48
82
89
Trace
Trace
36
70
67
n.d.
n.d.
33
13
69
Scheme 1 Proposed transition-state model.
48
3.5
3.5
3.5
83
57
a All of reactions were carried out with oxindole 2 or 4 (0.2 mmol),
vinyl phosphate (0.1 mmol) and catalyst 1i (20 mol%) in CH3CN
(2.0 mL) at −15 °C. b Yield of isolated product. c Determined by HPLC
analysis on a chiral stationary phase.
Scheme 2 Transformations of Michael adduct 3a.
Conclusions
In conclusion, we have developed the first example of an asym-
metric Michael addition of N-Boc-3-aryloxindole to tetraethyl
vinylbisphosphonate catalyzed by
a cinchonidine derived
thiourea catalyst. High yields (up to 92%) and good enantio-
selectivities (80–92% ee’s) were obtained under optimal con-
ditions for a wide range of N-Boc-3-aryloxindole. Furthermore,
the bisphosphonate adducts can be easily hydrolyzed to the cor-
responding acids, which provided a protocol to easily access a
class of new optically active gem-BP derivatives containing a
tetra-substituted oxindole fragment.
Fig. 1 X-ray crystal structure of compound 3u.
be activated by tertiary amine-thiourea 1i in a bifunctional mode
and the enolized oxindole attacks the vinyl bisphosphonate ester
from Si-face, affording the corresponding adduct with R
configuration.
Our initial attempts to generate functionalized vinyl phospho-
nate 6 by Horner–Wadsworth–Emmons reaction of adduct 3a
with formaldehyde were unsuccessful because retro-Michael
addition/aldol reaction occurred in the presence of various
bases.18 Although after several trials, vinyl phosphonate 6 can
be obtained from adduct 3a in moderate yield in the presence of
DBU and magnesium chloride,19 the ee decreased dramatically
due to an inevitable partial retro-Michael reaction. Considering
the wide applications of bisphosphonic acids in the therapy of
most bone diseases, the tetraethyl ester 3a was converted into
the corresponding bisphosphonic acid 7 through cleavage of the
N-Boc and the tetraethyl group of the BP moiety by treating
with iodotrimethylsilane (TMSI) in good yield with comparable
enantioselectivity. The ee value of bisphosphonic acid 7 was
determined from tetramethyl bisphosphonate 8, which was
obtained by esterification of 7 with trimethylsilyl diazomethane
(TMSCHN2) in good yield (Scheme 2).
Experimental section
General remarks
NMR spectra were recorded with a Bruker AVANCE III 400 and
300 MHz spectrometer with solutions in CDCl3 or d6-DMSO
and tetramethylsilane (TMS) as an internal standard; J values are
reported in Hz. IR spectra were recorded with a Bio-Rad
FTS-185 spectrometer. Chiral HPLC was performed with a
SHIMADZU SPD-10A series instrument with chiral columns.
Optical rotations were determined at 589 nm (sodium D line)
using a Perkin-Elmer-341 MC digital polarimeter; [a]D-values
are given in units of 10−1 deg cm2 g−1. MS and HRMS (EI,
ESI) were measured with a Finnigan MA+ instrument. Flash
column chromatography was performed using silica gel
(300–400 mesh). Melting points are uncorrected. Unless other-
wise noted, all commercially obtained reagents were used
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7970–7979 | 7973

View Online
without further purification. All reactions were carried out under
air in a closed system. Catalysts 1c–e,8j 1f–i,20 substrate 2,3d,h
48h and tetraethyl vinylbisphosphonate21 were prepared using
literature method.
9H), 1.34–1.24 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
175.4, 149.4, 141.8, 138.3, 133.8, 129.5, 128.5, 128.2, 127.6,
126.9, 126.8, 115.2, 83.9, 62.8–62.5 (m), 56.3–56.2 (m), 33.8 (t,
J = 135.0 Hz), 32.7 (t, J = 4.4 Hz), 28.0, 21.1, 16.4–16.3 (m);
31P NMR (162 MHz, CDCl3) δ 24.1, 22.8; IR (film) ν 1792,
1769, 1727, 1489, 1370, 1339, 1264, 1247, 1153, 1021 cm−1
;
General procedure for the Michael addition of 3-aryloxindole to
tetraethyl ethylidene bisphosphonate
HRMS (ESI) Calcd for C30H43NNaO9P2 [M + Na]+: 646.2311;
found: 646.2315.
To a solution of tetraethyl vinylbisphosphonate (0.1 mmol) in
CH3CN (2.0 mL) was added thiourea catalyst 1i (11.3 mg,
0.02 mmol) with stirring. After the mixture was cooled to
−15 °C (bath temperature) for 20 min, oxindole 2 (0.2 mmol)
was added. The resulting mixture was stirred at −15 °C for
3.5–48 h (monitored by TLC until no vinyl bisphosphonate
remained), concentrated, and purified by silica gel column
chromatography to give compound 3.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-methoxy-
2-oxo-3-phenylindoline-1-carboxylate 3d. Yield: 56.7 mg (88%).
Colorless oil. [α]D20 = +55.7 (c = 1.98, CH2Cl2) (89% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 1.0 mL min−1
,
254 nm, tminor = 8.86 min, tmajor = 12.61 min; 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 1H), 7.31–7.23 (m,
5H), 6.99 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.8 Hz, 1H),
4.20–4.00 (m, 8H), 3.84 (s, 3H), 3.41–3.30 (m, 1H), 2.98–2.84
(m, 1H), 2.30–2.14 (m, 1H), 1.59 (s, 9H), 1.35–1.23 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 175.3, 156.6, 149.4, 141.5,
133.9, 129.4, 128.6, 127.6, 126.9, 116.3, 114.4, 112.0, 83.8,
62.9–62.5 (m), 56.7–56.6 (m), 55.6, 33.6 (t, J = 134.9 Hz), 32.5
(t, J = 3.6 Hz), 28.0, 16.4–16.2 (m); 31P NMR (162 MHz,
CDCl3) δ 24.3, 22.9; IR (film) ν 1794, 1770, 1724, 1488, 1369,
1298, 1277, 1245, 1150, 1016 cm−1; MS (EI): m/z 639 (M+,
1%), 539 (11), 288 (43), 239 (100), 210 (33), 171 (27), 163
(33), 135 (16), 57 (16); HRMS (EI) Calcd for C30H43NO10P2
[M]+: 639.2362; found: 639.2366.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-2-oxo-3-
phenylindoline-1-carboxylate 3a. Yield: 49.8 mg (82%). Color-
less oil. [α]2D0 = +57.7 (c = 1.24, CH2Cl2) (89% ee); Chiralpak
AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1, 254 nm,
tminor = 8.07 min, tmajor = 13.15 min; 1H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.42–7.37 (m, 2H),
7.31–7.23 (m, 6H), 4.20–3.95 (m, 8H), 3.40–3.30 (m, 1H),
3.00–2.85 (m, 1H), 2.30–2.18 (m, 1H), 1.59 (s, 9H), 1.34–1.23
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 175.2, 149.3, 141.6,
140.6, 128.9, 128.5, 128.2, 127.6, 126.9, 126.4, 124.2, 115.4,
84.0, 62.9–62.5 (m), 56.2–56.1 (m), 33.8 (t, J = 134.4 Hz), 32.7
(t, J = 4.2 Hz), 28.0, 16.4–16.2 (m); 31P NMR (162 MHz,
CDCl3) δ 24.0, 22.7; IR (film) ν 1793, 1770, 1729, 1348, 1264,
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-bromo-
2-oxo-3-phenylindoline-1-carboxylate 3e. Yield: 49.2 mg (72%).
Colorless oil. [α]D20 = +50.6 (c = 1.07, CH2Cl2) (83% ee);
1247, 1149, 1021 cm−1
;
HRMS (ESI) Calcd for
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
C29H41NNaO9P2 [M + Na]+: 632.2154; found: 632.2155.
254 nm, tminor = 10.13 min, tmajor = 12.69 min; 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 1H), 7.56–7.50 (m,
2H), 7.36–7.25 (m, 5H), 4.21–4.01 (m, 8H), 3.38–3.28 (m, 1H),
2.97–2.82 (m, 1H), 2.24–2.09 (m, 1H), 1.59 (s, 9H), 1.34–1.27
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 174.4, 149.1, 140.8,
139.7, 132.0, 130.6, 129.3, 128.8, 127.9, 126.8, 117.3, 117.0,
84.5, 63.0–62.7 (m), 56.3–56.2 (m), 33.8 (t, J = 134.4 Hz), 32.7
(t, J = 3.5 Hz), 28.0, 16.4–16.3 (m); 31P NMR (162 MHz,
CDCl3) δ 23.6, 22.6; IR (film) ν 1775, 1731, 1473, 1369, 1336,
1294, 1270, 1245, 1152, 1021 cm−1; HRMS (ESI) Calcd for
C29H41BrNO9P2 [M + H]+: 688.1440; found: 688.1441.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-fluoro-2-
oxo-3-phenylindoline-1-carboxylate 3b. Yield: 51.7 mg (85%).
Colorless oil. [α]2D0 = +55.3 (c = 2.4, CH2Cl2) (87% ee); Chiral-
pak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 10.18 min, tmajor = 14.20 min; 1H NMR
(400 MHz, CDCl3) δ 7.94 (dd, J = 8.8, 4.4 Hz, 1H), 7.32–7.24
(m, 5H), 7.14–7.08 (m, 2H), 4.21–4.00 (m, 8H), 3.39–3.29 (m,
1H), 2.97–2.82 (m, 1H), 2.26–2.12 (m, 1H), 1.59 (s, 9H),
1.34–1.26 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 174.8,
159.6 (d, J = 242.7 Hz), 149.2, 140.9, 136.6 (d, J = 2.4 Hz),
130.2 (d, J = 8.0 Hz), 128.7, 127.9, 126.7, 116.7 (d, J = 8.6 Hz),
115.6 (d, J = 22.7 Hz), 113.7 (d, J = 23.6 Hz), 84.3, 63.0–62.6
(m), 56.5–56.4 (m), 33.7 (t, J = 134.5 Hz), 32.7 (t, J = 4.2 Hz),
28.0, 16.3–16.1 (m); 31P NMR (162 MHz, CDCl3) δ 23.6, 22.6;
19F NMR (376 MHz, CDCl3) δ −117.4; IR (film) ν 1793, 1772,
1727, 1482, 1369, 1345, 1296, 1248, 1146, 1019 cm−1; HRMS
(ESI) Calcd for C29H41FNO9P2 [M + H]+: 628.2241; found:
628.2237.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-6-methoxy-
2-oxo-3-phenylindoline-1-carboxylate 3f. Yield: 53.5 mg (84%).
Colorless oil. [α]D20 = +59.6 (c = 1.56, CH2Cl2) (80% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 12.08 min, tmajor = 20.12 min; 1H NMR
(400 MHz, CDCl3) δ 7.59 (d, J = 2.4 Hz, 1H), 7.32–7.22 (m,
6H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 4.21–4.00 (m, 8H), 3.88 (s,
3H), 3.40–3.28 (m, 1H), 2.94–2.80 (m, 1H), 2.31–2.19 (m, 1H),
1.59 (s, 9H), 1.35–1.24 (m, 12H); 13C NMR (100 MHz, CDCl3)
δ 175.7, 160.2, 149.3, 142.0, 141.6, 128.5, 127.6, 127.1, 126.9,
119.7, 110.0, 101.9, 84.0, 62.9–62.5 (m), 55.9–55.8 (m), 55.5,
33.8 (t, J = 134.8 Hz), 32.8 (t, J = 4.1 Hz), 28.0, 16.4–16.2 (m);
31P NMR (162 MHz, CDCl3) δ 24.1, 22.8; IR (film) ν 1797,
1772, 1726, 1614, 1494, 1347, 1245, 1147, 1016 cm−1; HRMS
(ESI) Calcd for C30H44NO10P2 [M + H]+: 640.2440; found:
640.2434.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-methyl-
2-oxo-3-phenylindoline-1-carboxylate 3c. Yield: 50.1 mg (88%).
Colorless oil. [α]2D0 = +56.5 (c = 2.73, CH2Cl2) (89% ee); Chiral-
pak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 8.80 min, tmajor = 12.12 min; 1H NMR
(400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.30–7.23 (m,
5H), 7.20–7.17 (m, 2H), 4.21–3.97 (m, 8H), 3.41–3.28 (m, 1H),
2.97–2.86 (m, 1H), 2.39 (s, 3H), 2.33–2.20 (m, 1H), 1.59 (s,
7974 | Org. Biomol. Chem., 2012, 10, 7970–7979
This journal is © The Royal Society of Chemistry 2012

View Online
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-6-bromo-
2-oxo-3-phenylindoline-1-carboxylate 3g. Yield: 51.6 mg (75%).
Colorless oil. [α]D20 = +47.5 (c = 1.08, CH2Cl2) (84% ee);
136.60 (d, J = 3.6 Hz), 136.56 (d, J = 4.4 Hz), 129.9 (d, J =
7.9 Hz), 128.6 (d, J = 8.9 Hz), 116.8 (d, J = 7.8 Hz), 115.8 (d,
J = 22.5 Hz), 115.5 (d, J = 21.0 Hz), 113.7 (d, J = 23.9 Hz),
84.4, 63.0–62.6 (m), 55.9–55.8 (m), 33.7 (t, J = 135.1 Hz), 33.0
(t, J = 3.5 Hz), 27.9, 16.3–16.1 (m); 31P NMR (162 MHz,
CDCl3) δ 23.6, 22.5; 19F NMR (376 MHz, CDCl3) δ −114.3,
−117.2; IR (film) ν 1794, 1772, 1729, 1507, 1484, 1344, 1297,
1246, 1146, 1015 cm−1; MS (EI): m/z 639 (M+, 1%), 288 (12),
245 (100), 216 (39), 171 (20), 163 (23), 135 (10), 57 (12);
HRMS (EI) Calcd for C29H39F2NO9P2 [M]+: 645.2068; found:
645.2069.
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 9.44 min, tmajor = 12.58 min; 1H NMR
(400 MHz, CDCl3) δ 8.19 (d, J = 1.6 Hz, 1H), 7.42 (dd, J = 8.0,
1.6 Hz, 1H), 7.31–7.25 (m, 6H), 4.22–3.97 (m, 8H), 3.38–3.30
(m, 1H), 2.99–2.88 (m, 1H), 2.26–2.11 (m, 1H), 1.59 (s, 9H),
1.34–1.24 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 174.6,
149.1, 141.7, 140.9, 128.7, 127.9, 127.7, 127.2, 126.7, 122.7,
118.8, 84.6, 63.0–62.5 (m), 56.1–56.0 (m), 33.7 (t, J = 133.4
Hz), 32.6 (t, J = 3.8 Hz), 27.9, 16.4–16.2 (m); 31P NMR
(162 MHz, CDCl3) δ 23.8, 22.6; IR (film) ν 1775, 1729, 1601,
1475, 1343, 1243, 1148, 1017 cm−1; HRMS (ESI) Calcd for
C29H41BrNO9P2 [M + H]+: 688.1440; found: 688.1440.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(4-fluoro-
phenyl)-5-methyl-2-oxoindoline-1-carboxylate 3k. Yield: 58.8 mg
(92%). Colorless oil. [α]2D0 = +66.8 (c = 3.05, CH2Cl2) (84% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 8.95 min, tmajor = 17.46 min; 1H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 1H), 7.29–7.25 (m,
2H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.96 (t, J = 8.8 Hz,
2 H), 4.20–3.97 (m, 8H), 3.37–3.25 (m, 1H), 2.93–2.78 (m, 1H),
2.40 (s, 3H), 2.28–2.15 (m, 1H), 1.59 (s, 9H), 1.34–1.24 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 175.4, 162.2 (d, J =
245.7 Hz), 149.3, 138.2, 137.4 (d, J = 2.7 Hz), 134.0, 129.7,
128.7 (d, J = 7.9 Hz), 127.9, 126.8, 115.32 (d, J = 21.1 Hz),
115.28, 84.1, 62.9–62.5 (m), 55.8–55.6 (m), 33.8 (t, J =
134.9 Hz), 32.9 (t, J = 4.0 Hz), 28.0, 21.1, 16.4–16.2 (m);
31P NMR (162 MHz, CDCl3) δ 24.1, 22.7; 19F NMR (376 MHz,
CDCl3) δ −114.9; IR (film) ν 1793, 1770, 1728, 1506, 1490,
1338, 1245, 1152, 1017 cm−1; HRMS (ESI) Calcd for
C30H42FNNaO9P2 [M + Na]+: 664.2217; found: 664.2220.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-6-chloro-2-
oxo-3-phenylindoline-1-carboxylate 3h. Yield: 54.2 mg (84%).
Colorless oil. [α]D20 = +51.5 (c = 2.71, CH2Cl2) (81% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 8.83 min, tmajor = 12.11 min; 1H NMR
(400 MHz, CDCl3) δ 8.03 (d, J = 1.6 Hz, 1H), 7.33–7.25 (m,
7H), 4.18–3.97 (m, 8H), 3.39–3.30 (m, 1H), 2.98–2.87 (m, 1H),
2.34–2.06 (m, 1H), 1.59 (s, 9H), 1.35–1.24 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 174.7, 149.1, 141.5, 141.0, 134.7, 128.6,
127.8, 127.3, 126.7, 126.6, 124.3, 116.1, 84.6, 63.0–62.5 (m),
56.0–55.9 (m), 33.7 (t, J = 135.2 Hz), 32.7 (t, J = 3.9 Hz), 27.9,
16.4–16.2 (m); 31P NMR (162 MHz, CDCl3) δ 23.8, 22.6; IR
(film) ν 1776, 1729, 1605, 1476, 1344, 1246, 1147, 1016 cm−1
;
HRMS (ESI) Calcd for C29H41ClNO9P2 [M + H]+: 644.1945;
found: 644.1949.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(4-fluoro-
phenyl)-5-methoxy-2-oxoindoline-1-carboxylate 3l. Yield: 50.2 mg
(77%). Colorless oil. [α]2D0 = +45.5 (c = 1.83, CH2Cl2) (89% ee);
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(4-fluoro-
phenyl)-2-oxoindoline-1-carboxylate 3i. Yield: 52.4 mg (84%).
Colorless oil. [α]D20 = +56.8 (c = 2.63, CH2Cl2) (86% ee);
Chiralpak AD-H, hexane–isopropanol = 85 : 15, 1.0 mL min−1
,
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 1.0 mL min−1
,
254 nm, tminor = 7.02 min, tmajor = 12.72 min; 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 1H), 7.29–7.26 (m,
2H), 6.99–6.91 (m, 4H), 4.19–3.99 (m, 8H), 3.84 (s, 3H),
3.38–3.25 (m, 1H), 2.93–2.79 (m, 1H), 2.27–2.12 (m, 1H), 1.59
(s, 9H), 1.35–1.25 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
175.2, 162.2 (d, J = 245.6 Hz), 156.7, 149.3, 137.2 (d, J =
2.9 Hz), 133.8, 129.1, 128.7 (d, J = 7.9 Hz), 116.4, 115.3 (d, J =
20.9 Hz), 114.5, 112.0, 84.0, 62.9–62.5 (m), 56.1–56.0 (m),
55.6, 33.6 (t, J = 134.8 Hz), 32.7 (t, J = 3.8 Hz), 28.0,
16.4–16.1 (m); 31P NMR (162 MHz, CDCl3) δ 24.2, 22.8; 19F
NMR (376 MHz, CDCl3) δ −114.7; IR (film) ν 1791, 1769,
1726, 1507, 1490, 1265, 1247, 1151, 1021 cm−1; HRMS (ESI)
Calcd for C30H42FNNaO10P2 [M + Na]+: 680.2166; found:
680.2169.
254 nm, tminor = 7.72 min, tmajor = 18.17 min; 1H NMR
(400 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 1H), 7.43–7.36 (m,
2H), 7.29–7.24 (m, 3H), 6.96 (t, J = 8.8 Hz, 2H), 4.20–4.08 (m,
8H), 3.36–3.28 (m, 1H), 2.95–2.81 (m, 1H), 2.27–2.14 (m, 1H),
1.60 (s, 9H), 1.37–1.23 (m, 12H); 13C NMR (100 MHz, CDCl3)
δ 175.2, 162.2 (d, J = 245.4 Hz), 149.2, 140.6, 137.3 (d, J = 3.1
Hz), 129.1, 128.7 (d, J = 8.0 Hz), 128.0, 126.3, 124.3, 115.5,
115.3 (d, J = 20.9 Hz), 84.2, 62.9–62.5 (m), 55.7–55.6 (m), 33.8
(t, J = 134.4 Hz), 33.0 (t, J = 3.6 Hz), 28.0, 16.4–16.2 (m);
31P NMR (162 MHz, CDCl3) δ 23.9, 22.6; 19F NMR (376 MHz,
CDCl3) δ −114.8; IR (film) ν 1795, 1771, 1728, 1506, 1480,
1347, 1244, 1148, 1018 cm−1; HRMS (ESI) Calcd for
C29H40FNNaO9P2 [M + Na]+: 650.2060; found: 650.2061.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-fluoro-3-
(4-fluorophenyl)-2-oxoindoline-1-carboxylate 3j. Yield: 49.0 mg
(76%). Colorless oil. [α]2D0 = +60.2 (c = 2.45, CH2Cl2) (85% ee);
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-2-oxo-3-
(p-tolyl)indoline-1-carboxylate 3m. Yield: 47.1 mg (76%).
Colorless oil. [α]D20 = +51.8 (c = 2.56, CH2Cl2) (83% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 9.73 min, tmajor = 21.90 min; 1H NMR
(400 MHz, CDCl3) δ 7.95 (q, J = 4.8 Hz, 1H), 7.29–7.24 (m,
2H), 7.15–7.09 (m, 2H), 6.99 (t, J = 8.8 Hz, 2H), 4.21–4.01 (m,
8H), 3.37–3.25 (m, 1H), 2.93–2.78 (m, 1H), 2.22–2.09 (m, 1H),
1.59 (s, 9H), 1.34–1.26 (m, 12H); 13C NMR (100 MHz, CDCl3)
δ 174.8, 162.3 (d, J = 246.8 Hz), 159.6 (d, J = 242.6 Hz), 149.2,
254 nm, tminor = 8.05 min, tmajor = 17.60 min; 1H NMR
(400 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 1H), 7.40–7.35 (m,
2H), 7.27–7.23 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.08 (d, J =
8.4 Hz, 2H), 4.20–3.95 (m, 8H), 3.38–3.29 (m, 1H), 2.97–2.83
(m, 1H), 2.29–2.18 (m, 1H), 1.59 (s, 9H), 1.32–1.23 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 175.4, 149.4, 140.6, 138.7,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7970–7979 | 7975

View Online
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(naphthalen-
2-yl)-2-oxoindoline-1-carboxylate 3q. Yield: 49.3 mg (75%).
Colorless oil. [α]D20 = +55.7 (c = 2.18, CH2Cl2) (83% ee);
137.4, 129.2, 128.9, 128.5, 126.7, 126.3, 124.2, 115.3, 84.0,
62.9–62.4 (m), 56.0–55.8 (m), 33.8 (t, J = 135.1 Hz), 32.7
(t, J = 3.9 Hz), 28.0, 20.8, 16.4–16.2 (m); 31P NMR (162 MHz,
CDCl3) δ 23.9, 22.7; IR (film) ν 1796, 1772, 1726, 1509, 1480,
1464, 1347, 1299, 1245, 1148, 1018 cm−1; HRMS (ESI) Calcd
for C30H44FNO9P2 [M + H]+: 624.2491; found: 624.2493.
Chiralpak AD-H, hexane–isopropanol = 85 : 15, 1.0 mL min−1
,
254 nm, tminor = 6.16 min, tmajor = 11.14 min; 1H NMR
(400 MHz, CDCl3) δ 7.99 (d, J = 8.8 Hz, 1H), 7.80–7.71 (m,
3H), 7.59 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.46–7.42 (m, 4H),
7.32–7.27 (m, 1H), 4.21–3.97 (m, 8H), 3.55–3.42 (m, 1H),
3.09–2.94 (m, 1H), 2.38–2.24 (m, 1H), 1.59 (s, 9H), 1.33–1.25
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 175.2, 149.3, 140.7,
138.9, 132.9, 132.5, 129.0, 128.5, 128.30, 128.25, 127.3, 126.4,
126.3, 126.1, 125.8, 124.8, 124.3, 115.4, 84.1, 62.9–62.5 (m),
56.4–56.2 (m), 33.8 (t, J = 134.8 Hz), 32.6 (t, J = 4.2 Hz), 28.0,
16.3–16.2 (m); 31P NMR (162 MHz, CDCl3) δ 23.9, 22.7;
IR (film) ν 1794, 1771, 1728, 1480, 1464, 1343, 1299,
1287, 1245, 1148, 1018 cm−1; HRMS (ESI) Calcd for
C33H43NNaO9P2 [M + Na]+: 682.2311; found: 682.2313.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-fluoro-2-
oxo-3-(p-tolyl)indoline-1-carboxylate 3n. Yield: 50.3 mg (79%).
Colorless oil. [α]D20 = +57.2 (c = 2.25, CH2Cl2) (89% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 1.0 mL min−1
,
254 nm, tminor = 7.24 min, tmajor = 17.94 min; 1H NMR
(400 MHz, CDCl3) δ 7.92 (dd, J = 8.8, 4.4 Hz, 1H), 7.14–7.04
(m, 6H), 4.18–3.98 (m, 8H), 3.37–3.25 (m, 1H), 2.92–2.77 (m,
1H), 2.28 (s, 3H), 2.24–2.08 (m, 1H), 1.56 (s, 9H), 1.32–1.23
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 174.9, 159.5 (d, J =
242.5 Hz), 149.3, 138.0, 137.6, 136.5 (d, J = 2.2 Hz), 130.4 (d,
J = 8.2 Hz), 129.3, 126.6, 116.6 (d, J = 7.6 Hz), 115.4 (d, J =
22.6 Hz), 113.7 (d, J = 24.5 Hz), 84.2, 62.9–62.5 (m), 56.2–56.1
(m), 33.7 (t, J = 134.5 Hz), 32.6 (t, J = 3.7 Hz), 27.9, 20.8,
16.3–16.1 (m); 31P NMR (162 MHz, CDCl3) δ 23.6, 22.7;
19F NMR (376 MHz, CDCl3) δ −117.5; IR (film) ν 1772, 1728,
1484, 1345, 1297, 1247, 1146, 1019 cm−1; HRMS (ESI) Calcd
for C30H42FNNaO9P2 [M + Na]+: 664.2217; found: 664.2215.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-fluoro-2-
oxo-3-(m-tolyl)indoline-1-carboxylate 3r. Yield: 56.8 mg (89%).
Colorless oil. [α]D20 = +45.1 (c = 2.73, CH2Cl2) (90% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 7.22 min, tmajor = 9.98 min; 1H NMR
(400 MHz, CDCl3) δ 7.94–7.90 (m, 1H), 7.17–7.04 (m, 5H),
6.98 (d, J = 7.6 Hz, 1H), 4.20–3.99 (m, 8H), 3.36–3.26 (m, 1H),
2.94–2.79 (m, 1H), 2.29 (s, 3H), 2.21–2.08 (m, 1H), 1.57 (s,
9H), 1.33–1.24 (m, 12H); 13C NMR (100 MHz, CDCl3)
δ 174.9, 159.5 (d, J = 242.8 Hz), 149.3, 140.9, 138.4, 136.6 (d,
J = 3.0 Hz), 130.3 (d, J = 8.0 Hz), 128.7, 128.4, 127.4, 123.7,
116.6 (d, J = 7.5 Hz), 115.5 (d, J = 22.5 Hz), 113.8 (d, J =
24.5 Hz), 84.3, 63.0–62.5 (m), 56.4–56.3 (m), 33.7 (t, J =
135.1 Hz), 32.6 (t, J = 3.8 Hz), 28.0, 21.5, 16.4–16.2 (m);
31P NMR (162 MHz, CDCl3) δ 23.7, 22.7; 19F NMR (376 MHz,
CDCl3) δ −117.5; IR (film) ν 1777, 1718, 1483, 1347, 1299,
1246, 1146, 1013 cm−1; HRMS (ESI) Calcd for C30H43FNO9P2
[M + H]+: 642.2397; found: 642.2396.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-methyl-
2-oxo-3-(p-tolyl)indoline-1-carboxylate 3o. Yield: 54.4 mg
(86%). Colorless oil. [α]2D0 = +55.4 (c = 2.51, CH2Cl2) (87% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 8.45 min, tmajor = 16.33 min; 1H NMR
(400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.17–7.14 (m,
4H), 7.07 (d, J = 8.4 Hz, 2H), 4.19–3.95 (m, 8H), 3.36–3.27 (m,
1H), 2.91–2.79 (m, 1H), 2.37 (s, 3H), 2.28 (s, 3H), 2.30–2.16
(m, 1H), 1.57 (s, 9H), 1.32–1.22 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 175.5, 149.4, 138.9, 138.2, 137.3, 133.7,
129.3, 129.2, 128.4, 126.7, 115.1, 83.8, 62.8–62.4 (m),
56.0–55.9 (m), 33.7 (t, J = 135.1 Hz), 32.5 (t, J = 4.1 Hz), 28.0,
21.0, 20.8, 16.3–16.2 (m); 31P NMR (162 MHz, CDCl3) δ 24.1,
22.9; IR (film) ν 1792, 1770, 1727, 1489, 1338, 1264, 1246,
1153, 1021 cm−1; HRMS (ESI) Calcd for C31H45FNNaO9P2
[M + Na]+: 660.2467; found: 660.2463.
(R)-tert-Butyl
3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(3,5-
dimethylphenyl)-2-oxoindoline-1-carboxylate 3s. Yield: 42.1 mg
(66%). White solid. Mp: 56.8–59.1 °C; [α]2D0 = +60.2 (c = 1.87,
CH2Cl2) (92% ee); Chiralpak AD-H, hexane–isopropanol =
90 : 10, 0.8 mL min−1, 254 nm, tminor = 5.95 min, tmajor
=
1
8.41 min; H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz,
1H), 7.41–7.35 (m, 2H), 7.29–7.24 (m, 1H), 6.88 (s, 3H),
4.22–3.95 (m, 8H), 3.38–3.27 (m, 1H), 2.99–2.83 (m, 1H),
2.26–2.12 (m, 1H), 1.60 (s, 9H), 1.35–1.24 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 175.3, 149.3, 141.5, 140.5, 137.9, 129.3,
128.8, 128.4, 126.4, 124.5, 124.1, 115.2, 83.9, 62.9–62.3 (m),
56.1–56.0 (m), 33.7 (t, J = 134.3 Hz), 32.6 (t, J = 3.9 Hz), 28.0,
21.4, 16.4–16.2 (m); 31P NMR (162 MHz, CDCl3) δ 24.1, 22.8;
IR (film) ν 1796, 1771, 1727, 1480, 1346, 1244, 1148,
1020 cm−1; HRMS (ESI) Calcd for C31H46NO9P2 [M + H]+:
638.2648; found: 638.2648.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-5-methoxy-
2-oxo-3-(p-tolyl)indoline-1-carboxylate 3p. Yield: 42.3 mg
(65%). Colorless oil. [α]2D0 = +42.1 (c = 2.04, CH2Cl2) (90% ee);
Chiralpak AD-H, hexane–isopropanol = 85 : 15, 1.0 mL min−1
,
254 nm, tminor = 6.25 min, tmajor = 12.57 min; 1H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 1H), 7.15 (d, J =
8.0 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H),
6.89 (dd, J = 8.8, 2.4 Hz, 1H), 4.19–3.93 (m, 8H), 3.81 (s, 3H),
3.38–3.26 (m, 1H), 2.94–2.79 (m, 1H), 2.27 (s, 3H), 2.28–2.18
(m, 1H), 1.56 (s, 9H), 1.32–1.22 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 175.4, 156.6, 149.4, 138.6, 137.4, 133.9,
129.6, 129.2, 126.7, 116.2, 114.2, 111.9, 83.7, 62.9–62.4 (m),
56.4–56.2 (m), 55.5, 33.6 (t, J = 134.8 Hz), 32.5 (t, J = 4.2 Hz),
28.0, 20.8, 16.4–16.1 (m); 31P NMR (162 MHz, CDCl3) δ
24.3, 22.9; IR (film) ν 1794, 1771, 1723, 1489, 1369, 1275,
1245, 1151, 1064 cm−1; HRMS (ESI) Calcd for C31H46NO10P2
[M + H]+: 654.2597; found: 654.2599.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(3-fluoro-
phenyl)-2-oxoindoline-1-carboxylate 3t. Yield: 51.6 mg (82%).
Colorless oil. [α]D20 = +52.7 (c = 2.13, CH2Cl2) (85% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1
,
254 nm, tminor = 8.50 min, tmajor = 12.96 min; 1H NMR
(400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 1H), 7.44–7.36
7976 | Org. Biomol. Chem., 2012, 10, 7970–7979
This journal is © The Royal Society of Chemistry 2012

View Online
(m, 2H), 7.30–7.22 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03–6.93
(m, 2H), 4.18–3.97 (m, 8H), 3.37–3.25 (m, 1H), 2.97–2.82 (m,
1H), 2.29–2.14 (m, 1H), 1.60 (s, 9H), 1.34–1.24 (m, 12H); 13C
NMR (100 MHz, CDCl3) δ 174.8, 162.6 (d, J = 245.1 Hz),
149.2, 143.9 (d, J = 7.8 Hz), 140.6, 129.9 (d, J = 8.2 Hz), 129.2,
127.6, 126.3, 124.4, 122.6 (d, J = 3.3 Hz), 115.5, 114.6 (d, J =
20.6 Hz), 114.3 (d, J = 23.3 Hz), 84.3, 62.9–62.5 (m), 56.0–55.9
(m), 33.7 (t, J = 135.0 Hz), 32.8 (t, J = 3.7 Hz), 28.0, 16.4–16.2
(m); 31P NMR (162 MHz, CDCl3) δ 23.8, 22.5; 19F NMR
(376 MHz, CDCl3) δ −112.0; IR (film) ν 1795, 1771, 1728,
1480, 1346, 1299, 1244, 1145, 1018 cm−1; HRMS (ESI) Calcd
for C29H41FNO9P2 [M + H]+: 628.2241; found: 628.2244.
1357, 1247, 1150, 1020 cm−1; HRMS (ESI) Calcd for
C30H43NNaO9P2 [M + Na]+: 646.2311; found: 646.2314.
(R)-Tetraethyl (2-(1-benzyl-2-oxo-3-phenylindolin-3-yl)ethane-
1,1-diyl)bis(phosphonate) 5c. Yield: 21.8 mg (36%). White
solid; Mp: 76.3–78.1 °C. [α]2D0 = +21.0 (c = 1.17, CH2Cl2) (33%
ee); Chiralpak AD-H, hexane–isopropanol = 80 : 20, 1.0 mL
1
min−1, 254 nm, tminor = 9.74 min, tmajor = 19.32 min; H NMR
(400 MHz, CDCl3) δ 7.43–7.41 (m, 3H), 7.32–7.17 (m, 9H),
7.07 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.17 (d, J =
15.6 Hz, 1H), 4.67 (d, J = 16.0 Hz, 1H), 4.17–3.89 (m, 8H),
3.33–3.20 (m, 1H), 3.09–2.94 (m, 1H), 2.39–2.25 (m, 1H),
1.33–1.28 (m, 9H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 177.3, 143.5, 141.1, 135.9, 130.0, 128.6,
128.5, 127.35, 127.32, 127.0, 126.9, 126.6, 122.2, 109.2,
62.8–62.3 (m), 56.0–55.9 (m), 44,0, 33.4 (t, J = 133.2 Hz), 32.2
(t, J = 4.0 Hz), 16.3–16.1 (m); 31P NMR (162 MHz, CDCl3) δ
24.2, 23.2; IR (film) ν 1718, 1612, 1489, 1366, 1264, 1163,
1067, 1023 cm−1; HRMS (ESI) Calcd for C31H39NNaO7P2
[M + Na]+: 622.2099; found: 622.2095.
(R)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-(3-methoxy-
phenyl)-2-oxoindoline-1-carboxylate 3u. Yield: 56 mg (88%).
White solid. Mp: 55.6–57.9 °C; [α]2D0 = +61.3 (c = 2.65,
CH2Cl2) (88% ee); Chiralpak AD-H, hexane–isopropanol =
90 : 10, 0.8 mL min−1, 254 nm, tminor = 9.13 min, tmajor
=
1
14.32 min; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz,
1H), 7.41–7.36 (m, 2H), 7.29–7.17 (m, 2H), 6.88 (d, J = 8.0 Hz,
1H), 6.84 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H),
4.20–3.97 (m, 8H), 3.75 (s, 3H), 3.40–3.28 (m, 1H), 2.98–2.84
(m, 1H), 2.30–2.21 (m, 1H), 1.59 (s, 9H), 1.34–1.24 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 175.1, 159.5, 149.2, 143.1,
140.5, 129.4, 128.9, 128.1, 126.3, 124.2, 119.2, 115.3, 113.3,
112.5, 84.0, 62.8–62.4 (m), 56.2–56.0 (m), 55.1, 33.7 (t, J =
135.4 Hz), 32.5 (t, J = 3.8 Hz), 28.0, 16.3–16.2 (m); 31P NMR
(162 MHz, CDCl3) δ 23.9, 22.7; IR (film) ν 1795, 1772, 1727,
1480, 1346, 1244, 1148, 1018 cm−1; HRMS (ESI) Calcd for
C30H44NO10P2 [M + H]+: 640.2440; found: 640.2438.
(R)-Tetraethyl (2-(1-acetyl-2-oxo-3-phenylindolin-3-yl)ethane-
1,1-diyl)bis(phosphonate) 5d. Yield: 38.5 mg (70%). Colorless
oil. [α]2D0 = +4.1 (c = 2.37, CH2Cl2) (13% ee); Chiralpak AD-H,
hexane–isopropanol = 90 : 10, 0.9 mL min−1, 254 nm, tminor
=
1
18.78 min, tmajor = 21.69 min; H NMR (400 MHz, CDCl3) δ
8.35 (d, J = 8.4 Hz, 1H), 7.45–7.39 (m, 1H), 7.33–7.23 (m, 7H),
4.16–3.93 (m, 8H), 3.42–3.31 (m, 1H), 3.01–2.85 (m, 1H), 2.63
(s, 3H), 2.31–2.16 (m, 1H), 1.32–1.24 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 177.9, 171.2, 141.4, 141.1, 129.1, 128.65,
128.61, 127.8, 126.7, 125.7, 124.9, 116.9, 62.8–62.4 (m),
56.2–56.1 (m), 53.4, 33.7 (t, J = 133.9 Hz), 32.7 (t, J = 3.8 Hz),
26.5, 16.3–16.1 (m); 31P NMR (162 MHz, CDCl3) δ 23.6, 22.3;
IR (film) ν 1762, 1708, 1604, 1464, 1370, 1340, 1246, 1161,
1017 cm−1; HRMS (ESI) Calcd for C26H36NO8P2 [M + H]+:
552.1916; found: 552.1919.
(S)-tert-Butyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-3-methyl-
2-oxoindoline-1-carboxylate 3w. Yield: 41.9 mg (77%). Color-
less oil. [α]2D0 = +5.8 (c = 2.07, CH2Cl2) (23% ee); Chiralpak
AD-H, hexane–isopropanol = 90 : 10, 0.8 mL min−1, 254 nm,
tminor = 10.02 min, tmajor = 10.84 min; 1H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.36–7.26 (m, 2H), 7.17 (t,
J = 7.6 Hz, 1H), 4.19–4.01 (m, 8H), 2.71–2.35 (m, 3H), 1.64 (s,
9H), 1.45 (s, 3H), 1.34–1.27 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 177.7, 149.3, 138.9, 131.7, 128.2, 124.3, 123.4, 115.0,
84.0, 62.8–62.4 (m), 47.4–47.2 (m), 32.6 (t, J = 4.3 Hz), 32.2 (t,
J = 134.2 Hz), 28.0, 25.8, 16.3–16.2 (m); 31P NMR (162 MHz,
CDCl3) δ 24.0, 23.3; IR (film) ν 1792, 1771, 1727, 1480, 1351,
1292, 1248, 1151, 1022 cm−1; HRMS (ESI) Calcd for
C24H39NNaO9P2 [M + Na]+: 570.1998; found: 570.2001.
(R)-Ethyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-2-oxo-3-phenyl-
indoline-1-carboxylate 5e. Yield: 38.8 mg (67%). Colorless oil.
[α]2D0 = +20.3 (c = 2.13, CH2Cl2) (69% ee); Chiralpak AD-H,
hexane–isopropanol = 85 : 15, 1.0 mL min−1, 254 nm, tminor
=
1
8.65 min, tmajor = 13.07 min; H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 7.6 Hz, 1H), 7.44–7.23 (m, 8H), 4.45–4.36 (m, 2H),
4.17–3.96 (m, 8H), 3.42–3.32 (m, 1H), 3.01–2.87 (m, 1H),
2.31–2.16 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 1.32–1.24 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 175.2, 151.0, 141.4,
140.4, 129.1, 128.6, 128.3, 127.7, 126.8, 126.3, 124.5, 115.5,
63.1, 62.9–62.5 (m), 56.3–56.2 (m), 33.7 (t, J = 135.2 Hz), 32.7
(t, J = 3.7 Hz), 16.3–16.2 (m), 14.2; 31P NMR (162 MHz,
CDCl3) δ 23.8, 22.6; IR (film) ν 1799, 1774, 1730, 1480, 1465,
1370, 1345, 1234, 1157, 1016 cm−1; HRMS (ESI) Calcd for
C27H38NO9P2 [M + H]+: 582.2022; found: 582.2026.
(S)-tert-Butyl 3-benzyl-3-(2,2-bis(diethoxyphosphoryl)ethyl)-2-
oxoindoline-1-carboxylate 3x. Yield: 35.2 mg (57%). Colorless
oil. [α]2D0 = +6.2 (c = 1.06, CH2Cl2) (50% ee); Chiralpak AD-H,
hexane–isopropanol = 90 : 10, 0.8 mL min−1, 254 nm, tminor
=
1
10.33 min, tmajor = 23.34 min; H NMR (400 MHz, CDCl3) δ
7.52 (d, J = 8.0 Hz, 1H), 7.28–7.14 (m, 3H), 7.06–6.97 (m, 3H),
6.69 (d, J = 6.8 Hz, 2H), 4.18–3.98 (m, 8H), 3.19 (d, J = 12.4
Hz, 1H), 2.96 (d, J = 12.4 Hz, 1H), 2.91–2.82 (m, 1H),
2.72–2.56 (m, 1H), 2.51–2.38 (m, 1H), 1.50 (s, 9H), 1.32–1.22
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 176.4, 148.6, 140.1,
134.4, 129.9, 128.43, 128.39, 127.5, 126.7, 124.2, 123.9, 114.8,
83.5, 62.9–62.5 (m), 54.1–54.0 (m), 47.2, 32.8 (t, J = 132.4 Hz),
31.5 (t, J = 3.5 Hz), 27.9, 16.4–16.2 (m); 31P NMR (162 MHz,
CDCl3) δ 24.0, 22.9; IR (film) ν 1794, 1771, 1727, 1480, 1368,
(R)-Benzyl 3-(2,2-bis(diethoxyphosphoryl)ethyl)-2-oxo-3-phenyl-
indoline-1-carboxylate 5f. Yield: 53.4 mg (83%). Colorless oil.
[α]2D0 = +10.5 (c = 2.56, CH2Cl2) (57% ee); Chiralpak AD-H,
hexane–isopropanol = 80 : 20, 1.0 mL min−1, 254 nm, tminor
9.32 min, tmajor = 14.14 min; H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 6.8 Hz, 2H), 7.43–7.23
(m, 11H), 5.45 (d, J = 12.4 Hz, 1H), 5.31 (d, J = 12.4 Hz, 1H),
=
1
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7970–7979 | 7977

View Online
4.15–3.90 (m, 8H), 3.44–3.32 (m, 1H), 3.01–2.87 (m, 1H),
2.30–2.15 (m, 1H), 1.31–1.12 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 175.1, 150.9, 141.4, 140.2, 134.8, 129.1, 128.6, 128.5,
128.35, 128.30, 128.2, 127.7, 126.7, 126.2, 124.5, 115.5, 68.4,
62.8–62.5 (m), 56.2–56.1 (m), 33.7 (t, J = 134.3 Hz), 32.6 (t,
J = 3.9 Hz), 16.3–16.0 (m); 31P NMR (162 MHz, CDCl3) δ
23.8, 22.4; IR (film) ν 1800, 1773, 1729, 1606, 1480, 1382,
1347, 1244, 1225, 1156, 1016 cm−1; HRMS (ESI) Calcd for
C32H40NO9P2 [M + H]+: 644.2178; found: 644.2180.
of 2.0 M TMSCHN2 in hexane (0.75 mL, 15 equiv.). After stir-
ring overnight at room temperature, the reaction mixture was
concentrated and purified by column chromatography [acetone–
petroleum ether = 2 : 1 to ethyl acetate–methanol = 10 : 1 (1% of
Et3N) as eluent] to afford the corresponding tetramethyl ester 8
as colorless oil (39 mg, 86% yield). [α]2D0 = −3.1 (c = 0.5,
CH2Cl2) (82% ee); Chiralpak AD-H, hexane–isopropanol =
85 : 15, 1.0 mL min−1, 254 nm, tminor = 35.34 min, tmajor
=
1
46.36 min; H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.30 (d,
J = 5.7 Hz, 2H), 7.23–7.16 (m, 5H), 7.02 (t, J = 5.7 Hz, 2H),
6.85 (d, J = 5.7 Hz, 1H), 3.66–3.56 (m, 12H), 3.21–3.14 (m,
1H), 2.89–2.77 (m, 1H), 2.40–2.28 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 179.2, 142.2, 141.0, 130.0, 128.5, 128.2,
127.2, 126.6, 126.0, 121.8, 110.3, 56.1–55.9 (m), 53.33–53.27
(m), 53.0–52.9 (m), 32.3–31.5 (m); 31P NMR (121 MHz,
CDCl3) δ 26.9, 25.5; IR (film) ν 1760, 1713, 1464, 1377, 1263,
1081, 1025 cm−1; MS (EI): m/z 453 (M+, 13%), 232 (100),
209 (9), 180 (9), 124 (18); HRMS (EI) Calcd for C20H25NO7P2
[M]+: 453.1106; found: 453.1107.
HWE reaction for the synthesis of vinyl phosphonate 6
To a solution of adduct 3a (50 mg, 0.082 mmol) in CH3CN
(2 mL) was added MgCl2 (15.6 mg, 0.164 mmol), DBU (24 μL,
0.164 mmol) and (CH2O)n (12.3 mg, 0.411 mmol). The result-
ing mixture was refluxed at 70 °C overnight and monitored by
TLC. After consumption of adduct 3a, the reaction mixture was
concentrated, and purified by flash chromatography (acetone–
petroleum ether = 1 : 10) to give the product 6 as colorless oil
(21.1 mg, 53% yield). [α]2D0 = +8.5 (c = 0.5, CH2Cl2) (23% ee);
Chiralpak AD-H, hexane–isopropanol = 90 : 10, 0.5 mL min−1
,
Acknowledgements
254 nm, tminor = 14.21 min, tmajor = 15.97 min; 1H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 1H), 7.31–7.13 (m,
8H), 5.90 (d, J = 23.6 Hz, 1H), 5.44 (d, J = 49.2 Hz, 1H),
3.93–3.72 (m, 4H), 3.42–3.35 (m, 1H), 3.17 (dd, J = 14.8,
12.0 Hz, 1H), 1.54 (s, 9H), 1.20–1.18 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 176.0, 149.1, 139.8 (d, J = 4.2 Hz), 135.4,
133.7, 132.6 (d, J = 7.5 Hz), 129.2, 128.7 (d, J = 5.2 Hz), 127.8,
126.9, 126.0, 124.2, 115.1, 84.4, 61.9–61.7 (m), 56.3 (d, J =
6.1 Hz), 38.1 (d, J = 11.3 Hz), 29.6, 28.0, 16.3–16.1 (m);
31P NMR (162 MHz, CDCl3) δ 18.3; IR (film) ν 1766, 1729,
1479, 1465, 1347, 1022, 963 cm−1; MS (EI): m/z 485 (M+, 1%),
385 (21), 208 (100); HRMS (EI) Calcd for C26H32NO6P [M]+:
485.1967; found: 485.1966.
We are grateful to the financial support from the National
Natural Science Foundation of China (20772030, 21072056), the
Fundamental Research Funds for the Central Universities, Scien-
tific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry.
Notes and references
1 (a) M. Ochi, K. Kawasaki, H. Kataoka and Y. Uchio, Biochem. Biophys.
Res. Commun., 2001, 283, 1118; (b) P. Hewawasam, M. Erway,
S. L. Moon, J. Knipe, H. Weiner, C. G. Boissard, D. J. Post-Munson,
Q. Gao, S. Huang, V. K. Gribkoff and N. A. Meanwell, J. Med. Chem.,
2002, 45, 1487; (c) X. Z. Wearing and J. M. Cook, Org. Lett., 2002, 4,
4237; (d) G. Gilles and S. L. Claudine, Stress, 2003, 6, 199;
(e) H. Suzuki, H. Morita, M. Shiro and J. I. Kobayashi, Tetrahedron,
2004, 60, 2489; (f) K. Bernard, S. Bogliolo and J. Ehrenfeld,
Br. J. Pharmacol., 2005, 144, 1037; (g) A. H. Abadi, S. M. Abou-Seri,
D. E. Abdel-Rahman, C. Klein, O. Lozach and L. Meijer, Eur. J. Med.
Chem., 2006, 41, 296; (h) S. E. Reisman, J. M. Ready, M. M. Weiss,
A. Hasuoka, M. Hirata, K. Tamaki, T. V. Ovaska, C. J. Smith and
J. L. Wood, J. Am. Chem. Soc., 2008, 130, 2087.
Hydrolysis of the tetraethyl ester 3a to bisphosphonic acid 7 and
subsequent esterification to 8
To a stirred solution of tetraethylbisphosphonate 3a (100 mg,
0.16 mmol) in 1.5 mL of CH3CN was added freshly distilled
TMSI (0.4 mL, 2.81 mmol) dropwise under argon. After being
stirred at room temperature for 24 h, the reaction mixture was
evaporated under reduced pressure. The residue was treated with
4.0 mL MeOH and the resulting mixture stirred overnight. After
evaporation of the solvent, an insoluble brown precipitate was
formed immediately and was washed consecutively with CHCl3
and Et2O, and then dried under vacuum at 65 °C for 8 h afford-
ing bisphosphonic acid 7 as a brown–yellow solid (53.4 mg,
2 (a) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381;
(b) J. J. Badillo, N. V. Hanhan and A. K. Franz, Curr. Opin. Drug Discov-
ery. Dev., 2010, 13, 758.
3 (a) N. Shibata, E. Suzuki, T. Asahi and M. Shiro, J. Am. Chem. Soc.,
2001, 123, 7001; (b) L. Zoute, C. Audouard, J.-C. Plaquevent and
D. Cahard, Org. Biomol. Chem., 2003, 1, 1833; (c) N. Shibata,
T. Ishimaru, E. Suzuki and K. L. Kirk, J. Org. Chem., 2003, 68, 2494;
(d) Y. Hama shima, T. Suzuki, H. Takano, Y. Shimura and M. Sedeoka,
J. Am. Chem. Soc., 2005, 127, 10164; (e) N. Shibata, J. Kohno, K. Takai,
T. Ishimaru, S. Nakamura, T. Toru and S. Kanemasa, Angew. Chem., Int.
Ed., 2005, 44, 4204; (f) T. Toru and T. Shibata, JP 2006290789;
(g) T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura,
T. Toru and M. Shiro, Angew. Chem., Int. Ed., 2008, 47, 4157;
(h) M.-X. Zhao, Z.-W. Zhang, M.-X. Chen, W.-H. Tang and M. Shi,
Eur. J. Org. Chem., 2011, 3001.
4 (a) T. Ishimaru, N. Shibata, J. Nagai, S. Nakamura, T. Toru and
S. Kanemasa, J. Am. Chem. Soc., 2006, 128, 16488; (b) D. Sano,
K. Nagata and T. Itoh, Org. Lett., 2008, 10, 1593; (c) T. Bui,
N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc., 2010, 132, 5574.
5 (a) Z.-Q. Qian, F. Zhou, T.-P. Du, B.-L. Wang, M. Ding, X.-L. Zhao and
J. Zhou, Chem. Commun., 2009, 6753; (b) L. Cheng, L. Liu, D. Wang
and Y.-J. Chen, Org. Lett., 2009, 11, 3874; (c) T. Bui, M. Borregan and
C. F. Barbas III, J. Org. Chem., 2009, 74, 8935; (d) S. Mouri, Z. Chen,
1
82% yield). H NMR (d6-DMSO, 400 MHz) δ 10.31 (s, 1H),
8.24 (s, br., 4H), 7.34–7.22 (m, 7H), 7.03 (t, J = 7.5 Hz, 1H),
6.90 (d, J = 7.5 Hz, 1H), 3.08–2.96 (m, 1H), 2.64–2.49 (m, 1H),
1.78 (td, J = 31.6, 8.8 Hz, 1H); 31P NMR (162 MHz, d6-DMSO)
δ 26.0 (d, J = 4.9 Hz), 25.1 (d, J = 5.3 Hz); MS(EI): m/z 209
{100%, M+ − CH2CH[(PO(OEt)2)]2}, 180 (81), 165 (5),
152 (6); HRMS (ESI) Calcd For C16H17NO7P2 [M]+: 397.0480,
found 397.0471.
To a stirred solution of bisphosphonic acid 7 (40 mg,
0.1 mmol) in 2.0 mL of CH3CN was added dropwise a solution
7978 | Org. Biomol. Chem., 2012, 10, 7970–7979
This journal is © The Royal Society of Chemistry 2012

View Online
H. Mitsunuma, M. Furutachi, S. Matsunaga and M. Shibasaki, J. Am.
Chem. Soc., 2010, 132, 1255.
J. L. Concepción, V. Yardley, S. L. Croft, J. A. Urbina and E. Oldfield,
J. Med. Chem., 2006, 49, 215 and references cited therein.
6 (a) S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru and M. Shiro,
Angew. Chem., Int. Ed., 2007, 46, 8666; (b) X. Tian, K. Jiang, J. Peng,
W. Du and Y.-C. Chen, Org. Lett., 2008, 10, 3583; (c) L. Cheng, L. Liu,
H. Jia, D. Wang and Y.-J. Chen, J. Org. Chem., 2009, 74, 4650;
(d) X.-L. Liu, Y.-H. Liao, Z.-J. Wu, L.-F. Cun, X.-M. Zhang and
W.-C. Yuan, J. Org. Chem., 2010, 75, 4872; (e) K. Shen, X. Liu,
K. Zheng, W. Li, X. Hu, L. Lin and X. Feng, Chem.–Eur. J., 2010, 16,
3736.
7 (a) B. M. Trost and M. U. Frederiksen, Angew. Chem., Int. Ed., 2005, 44,
308; (b) B. M. Trost and Y. Zhang, J. Am. Chem. Soc., 2007, 129, 14548;
(c) K. Jiang, J. Peng, H.-L. Cui and Y.-C. Chen, Chem. Commun., 2009,
3955; (d) B. M. Trost and Y. Zhang, Chem.–Eur. J., 2010, 16, 296.
8 (a) T. Bui, S. Syed and C. F. Barbas III, J. Am. Chem. Soc., 2009, 131,
8758; (b) R. He, C. Ding and K. Maruoka, Angew. Chem., Int. Ed., 2009,
48, 4559; (c) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 9168;
(d) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B. Giannichi,
L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur. J., 2009, 15, 7846;
(e) R. He, S. Shirakawa and K. Maruoka, J. Am. Chem. Soc., 2009, 131,
16620; (f) X. Li, Z.-G. Xi, S. Luo and J.-P. Cheng, Org. Biomol. Chem.,
2010, 8, 77; (g) X. Li, B. Zhang, Z.-G. Xi, S. Luo and J.-P. Cheng, Adv.
Synth. Catal., 2010, 352, 416; (h) Y.-H. Liao, X.-L. Liu, Z.-J. Wu,
L.-F. Cun, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2010, 12, 2896–
2899; (i) S.-W. Duan, J. An, J.-R. Chen and W.-J. Xiao, Org. Lett., 2011,
13, 2290–2293; ( j) M.-X. Zhao, W.-H. Tang, M.-X. Chen, D.-K. Wei,
T.-L. Dai and M. Shi, Eur. J. Org. Chem., 2011, 6078.
13 (a) V. Chaleix and M. Lecouvey, Tetrahedron Lett., 2007, 48, 703;
(b) X. Liu, X. R. Zhang and G. M. Blackburn, Chem. Commun., 1997, 87;
(c) H. J. Cristau, C. Brahic and J. L. Pirat, Tetrahedron, 2001, 57, 9149;
(d) F. H. Ebetino, C. R. Gegenhardt, L. A. Jamison and D. C. Burdsall,
Heterocycles, 1990, 30, 855; (e) Y. Du, K. Y. Jung and D. Wiemer, Tetra-
hedron Lett., 2002, 43, 8665; (f) R. Ruzziconi, G. Ricci, A. Gioiello,
H. Couthon-Gourves and J. P. Gourves, J. Org. Chem., 2003, 68, 736;
(g) P. Moreau and M. Maffei, Tetrahedron Lett., 2004, 45, 743;
(h) F. Gagosz and S. Z. Zard, Synlett, 2003, 387; (i) J. H. Byers,
J. G. Thissel and M. A. Thomas, Tetrahedron Lett., 1995, 36, 6403.
14 For a review on Michael additions to vinyl bisphosphonates, see:
(a) T. Janecki, J. Kędzia and T. Wąsek, Synthesis, 2009, 1227 and refer-
ence cited therein; Forselective papers on Michael additions of various
nucleophiles to vinyl bisphosphonates, see: (b) H. Couthon-Gourves,
G. Simon, J.-P. Haelters and B. Corbel, Synthesis, 2006, 81;
(c) D. Simoni, N. Gebbia, F. P. Invidiata, M. Eleopra, P. Marchetti,
R. Rondanin, R. Baruchello, S. Provera, C. Marchioro, M. Tolomeo,
L. Marinelli, V. Limongelli, E. Novellino, A. Kwaasi, J. Dunford,
S. Buccheri, N. Caccamo and F. Dieli, J. Med. Chem., 2008, 51, 6800;
(d) T. J. Houghton, K. S. E. Tanaka, T. Kang, E. Dietrich, Y. Lafontaine,
D. Delorme, S. S. Ferreira, F. Viens, F. F. Arhin, I. Sarmiento, D. Lehoux,
I. Fadhil, K. Laquerre, J. Liu, V. Ostiguy, H. Poirier, G. Moeck, T. R. Parr
Jr. and A. R. Far, J. Med. Chem., 2008, 51, 6955; (e) P. C. B. Page,
M. J. McKenzie and J. A. Gallagher, J. Org. Chem., 2001, 66, 3704;
(f) G. Bansal, J. E. I. Wright, S. Zhang, R. F. Zernicke and H. Uludag,
J. Biomed. Mater. Res., Part A, 2005, 74A, 618.
9 (a) S. A. Shaw, P. Aleman and E. Vedejs, J. Am. Chem. Soc., 2003, 125,
13368; (b) I. D. Hills and G. C. Fu, Angew. Chem., Int. Ed., 2003, 42,
3921; (c) S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P. Va and
E. Vedejs, J. Am. Chem. Soc., 2006, 128, 925; (d) T. A. Duffey,
S. A. Shaw and E. Vedejs, J. Am. Chem. Soc., 2009, 131, 14.
15 For organocatalytic asymmetric synthesis of optically active gem-BPs,
see: (a) S. Sulzer-Mossé, M. Tissot and A. Alexakis, Org. Lett., 2007, 9,
3749; (b) M. T. Barros and A. M. F. Phillips, Eur. J. Org. Chem., 2008,
2525; (c) S. Sulzer-Mossé, A. Alexakis, J. Mareda, G. Bollot,
G. Bernardinelli and Y. Filinchuk, Chem.–Eur. J., 2009, 15, 3204;
(d) M. Capuzzi, D. Perdicchia and K. A. Jørgensen, Chem.–Eur. J., 2008,
14, 128; For organometallic catalyzed asymmetric synthesis of optically
active gem-BPs, see: (e) Y. Kato, Z. Chen, S. Matsunaga and
M. Shibasaki, Synlett, 2009, 1635; (f) Z.-Y. Xue, Q.-H. Li, H.-Y. Tao and
C.-J. Wang, J. Am. Chem. Soc., 2011, 133, 11757.
16 (a) Ł. Albrecht, B. Richter, H. Krawczyk and K. A. Jorgensen, J. Org.
Chem., 2008, 73, 8337; (b) S. C. Cullen and T. Rovis, Org. Lett., 2008,
10, 3141; (c) D. Enders, Z. Mirjafary and H. Saeidian, Tetrahedron:
Asymmetry, 2009, 20, 2429.
17 CCDC 867514 (3u) contains the supplementary crystallographic data for
this paper.
10 For recent reviews, see: S. Zhang, G. Gangal and H. Uludag, Chem. Soc.
Rev., 2007, 36, 507 and reference cited therein.
11 (a) T. A. Guise, Cancer Treat. Rev., 2008, 34, S19; (b) A. Lipton, Cancer
Treat. Rev., 2008, 34, S25; (c) R. E. Coleman, J.-J. Body, J. R. Gralow
and A. Lipton, Cancer Treat. Rev., 2008, 34, S31; (d) S. C. Fields, Tetra-
hedron, 1999, 55, 12237; (e) Y. Zhang, A. Leon, Y. Song, D. Studer,
C. Haase, L. A. Koscielski and E. Oldfield, J. Med. Chem., 2006, 49,
5804; (f) J. E. Dunford, A. A. Kwaasi, M. J. Rogers, B. L. Barnett,
F. H. Ebetino, R. G. G. Russell, U. Oppermann and K. L. Kavanagh,
J. Med. Chem., 2008, 51, 2187; (g) R. A. Nugent, M. Murphy,
S. T. Schlachter, C. J. Dunn, R. J. Smith, N. D. Staite, L. A. Galinet,
S. K. Shields, D. G. Aspar, K. A. Richard and N. A. Rohloff, J. Med.
Chem., 1993, 36, 134.
18 Various bases, such as LHDMS, NaH, t-BuOK, NaOH had been tried
and no desired product was obtained.
12 (a) E. Kotsikorou, Y. Song, J. M. W. Chan, S. Faelens, Z. Tovian,
E. Broderick, N. Bakalara, R. Docampo and E. Olfield, J. Med. Chem.,
2005, 48, 6128; (b) M. P. Hudock, C. E. Sanz-Rodríguez, Y. Song,
J. M. W. Chan, Y. Zhang, S. Odeh, T. Kosztowski, A. Leon-Rossell,
19 W. Rathke and M. Nowak, J. Org. Chem., 1985, 50, 2624.
20 (a) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005, 4481;
(b) B. Vakulya, S. Varga, A. Csampai and T. Soos, Org. Lett., 2005, 7, 1967.
21 C. R. Degenhardt and D. C. Burdsall, J. Org. Chem., 1986, 51, 3488.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7970–7979 | 7979