Efficient asymmetric synthesis of novel gastrin receptor antagonist AG-041R via highly stereoselective alkylation of oxindole enolates

Article abstract of DOI:10.1021/jo061541v

An efficient method for asymmetric synthesis of the potent Gastrin/CCK-B receptor antagonist AG-041R was developed. Core oxindole stereochemistry was established by asymmetric alkylation of oxindole enolates with bromoacetic acid esters, using l-menthol a

Full text of DOI:10.1021/jo061541v

Efficient Asymmetric Synthesis of Novel Gastrin Receptor
Antagonist AG-041R via Highly Stereoselective Alkylation of
Oxindole Enolates
Takashi Emura,*,† Toru Esaki,† Kazutaka Tachibana,† and Makoto Shimizu‡
Chemistry Research Department 1, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba,
Shizuoka 412-8513, Japan, and Department of Chemistry for Materials, Graduate School of Engineering,
Mie UniVersity, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan
emuratks@chugai-pharm.co.jp
ReceiVed July 25, 2006
An efficient method for asymmetric synthesis of the potent Gastrin/CCK-B receptor antagonist AG-
041R was developed. Core oxindole stereochemistry was established by asymmetric alkylation of oxindole
enolates with bromoacetic acid esters, using l-menthol as a chiral auxiliary. The key alkylation reaction
of the oxindole enolates generated tetrasubstituted chiral intermediates with high diastereoselectivity.
The stereoselective alkylation reactions are described in detail.
SCHEME 1. Retrosynthetic Analysis
Introduction
AG-041R, 2-[(R)-1-(2,2-Diethoxyethyl)-2-oxo-3-(3-p-toly-
lureido)-2,3-dihydro-1H-indol-3-yl]-N-p-tolylacetamide (1), a
novel oxindole derivative, was synthesized as a gastrin/CCK-B
receptor antagonist.1 This compound showed the most potent
activity with an IC50 of 1.1 nmol, the highest bioavailability
among the numerous oxindole derivatives synthesized, and
demonstrated therapeutic efficacy with oral administration in
animal models of gastric ulcer. AG-041R 1 was selected as a
clinical candidate and, for the preclinical study, we investigated
the scalable synthesis of the compound. Here we present
synthesis of the compound based on the stereoselective alkyl-
ation of the oxindole enolates using l-menthyl bromoacetate as
the chiral alkylation reagent. Efficient, chromatography-free
synthesis suitable for the preparation of a large quantity of the
compound was established.
the most straightforward to obtain the basic framework for our
target compound. We soon realized that one of the challenges
of synthesis would be the asymmetric alkylation of oxindole
derivative 2. Therefore, the focus was on identifying an efficient
method for asymmetric alkylation reaction.
Results and Discussion
Retrosynthetic analysis (Scheme 1) revealed that a strategy
based on the alkylation of the oxindole derivatives would be
(1) (a) Chiba, T.; Kinoshita, Y.; Sawada, M.; Kishi, K.; Baba, A.;
Hoshino, E. Yale J. Biol. Med. 1998, 71, 247. (b) Lindstrom, E.; Bjorkqvist,
M.; Hakanson, R. Br. J. Pharm. 1999, 172, 530. (c) Ding, X.-Q.; Lindstrom,
E.; Hakanson, R. Pharmacol. Toxicol. 1997, 81, 232.
† Chugai Pharmaceutical Co., Ltd.
‡ Mie University.
10.1021/jo061541v CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/30/2006
J. Org. Chem. 2006, 71, 8559-8564
8559

Emura et al.
SCHEME 2. Synthesis of Intermediate Urea 2
There are a number of synthetic methods employed to
construct a quaternary stereocenter with high stereoselectivity.2,3
Asymmetric alkylation with a phase transfer catalyst is one of
the choices.4,5 However, this method still requires a relatively
large amount of chiral catalyst, which has a complicated
structure and is difficult to obtain.
Due to availability and ease of control of the reaction process,
we investigated the stoichiometric alkylation of oxindole
enolates with haloacetic acid esters using a commercially
available chiral alcohol such as l-menthol as an auxiliary.
Reactions of this type have rarely been studied to date, even
though a substantial amount of effort to use l-menthol as a chiral
auxiliary has been demonstrated.6,7 To the best of our knowl-
edge, only a single report has been published in which poor
stereoselectivity was shown in the alkylation of oxindole
derivatives with l-menthyl chloroacetate as a chiral electrophile.8
Synthesis of Urea 2. To synthesize the intermediate urea 2,
two possible sequences were considered, as shown in Scheme
2. We first tried alkylation of isatin 3, but the reaction was rather
messy and the yield of the product only moderate, most likely
a result of the instability of both the isatin and the product under
the reaction conditions. The overall yield of urea 2 from isatin
3 was only 23%. We next tried the sequence; the oxime
formation proceeded quantitatively and the following alkylation
was reasonably performed in DMA. The use of t-BuOK or NaH
gave identical results for the alkylation reaction so we selected
t-BuOK because of its ease of handling. Without purification,
the product was hydrogenated in acetonitrile affording the
aminooxindole derivative 8. Product 8 was unstable and readily
oxidized, and was therefore reacted with p-tolylisocyanate
without purification affording urea 2. Compound 2 was purified
by filtration and washing with CH3CN to give a 99% pure
product. The yield of the product was 52% in 3 steps.
and DMSO and the racemic AG-041 was synthesized from the
alkylation of urea 2 with methyl p-bromoacetanilide, and so
we first tried the alkylation reaction with l-menthyl bromoacetate
in DMF. The resulting diastereoselectivity of the reaction was
low (Table 1, entry 1). Even at lower temperatures in DMF,
only a slight degree of improvement in the stereoselectivity was
observed (Table 1, entries 2 and 3). By using solvent THF, the
selectivity showed a slight increase with t-BuOK as the base
(Table 1, entry 4). When the reaction was performed in a less
polar solvent with a lithium cation base, the diastereoselectivity
was greatly increased even at room temperature (Table 1, entry
5). Although dioxane showed the best results in terms of
diastereoselectivity for the reaction (Table 1, entry 6), it is rated
a Class 2 solvent according to the ICH guideline and requires
special handling because of its possible carcinogenic activity.
Therefore, we selected THF for further study. The diastereo-
selectivity increased when the reaction was performed at a lower
temperature (Table 1, entry 8) and was improved by the use of
a slight excess of base (Table 1, entries 9 and 10). We also
confirmed that n-BuLi could be directly used as a base without
a significant side reaction (Table 1, entry 12).
Diastereoselective Alkylation. The alkylation reaction of urea
2 proceeded efficiently in aprotic polar solvents such as DMF
(2) For recent reviews on the asymmetric synthesis of quaternary carbon
centers, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Christoffers,
J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473.
(3) For recent reviews on the asymmetric synthesis of quaternary amino
acids, see: (a) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517. (b) Cativiela, C.; D´ıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645.
(4) For recent reviews on the asymmetric synthesis by chiral phase
transfer catalyst, see: (a) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3.
(b) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (c) O’Donnell, M.
J. Acc. Chem. Res. 2004, 37, 506. (d) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518.
(5) For recent examples of PT catalyst for alkylation of indol-2-on
enolates, see: (a) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56,
872. (b) Pei, X.-F.; Yu, Q.-S.; Lu, B.-Y.; Grieg, N. H.; Brossi, A.
Heterocycles 1996, 42, 229. (c) Yu, Q.-S.; Luo, W.; Holloway, H. W.;
Utsuki, T.; Perry, T. A.; Lahiri, D. K.; Greig, N. H.; Brossi, A. Heterocycles
2003, 61, 529.
Under the same reaction conditions, l-menthyl chloroacetate
did not afford the target product. The stereoselectivity observed
was low (57:43 major/minor, 81% yield) when an isomenthol
derivative was used for the reaction. The borneol ester of
bromoacetic acid also showed unsatisfactory results (66:34
major/minor, 90% yield).
(6) (a) Whitesell, J. K. Chem. ReV. 1992, 92, 953. (b) Chavan, S. P.;
Sharma, P.; Sivappa, R.; Bhadbhade, M. M.; Gonnade, R. G.; Kalkote, U.
R. J. Org. Chem. 2003, 68, 6817. (c) Kigoshi, H.; Imamura, Y.; Mizuta,
K.; Niwa, H.; Yamada, K. J. Am. Chem. Soc. 1993, 115, 3056. (d) Rozema,
M. J.; Kruger, A. W.; Rohde, B. D.; Shelat, B.; Bhagavatula, L.; Tien, J.
J.; Zhang, W.; Henry, R. F. Tetrahedron 2005, 61, 4419. (e) Pollini, G. P.;
Bianchi, A.; Casolari, A.; Risi, C. D.; Zanirato, V.; Bertolasi, V.
Tetrahedron: Asymmetry 2004, 15, 3223. (f) Wei, H.-X.; Chen, D.; Xu,
X.; Li, G.; Pere´, P. W. Tetrahedron: Asymmetry 2003, 14, 971.
(7) (a) Vankar, P. S.; Bhattacharya, I.; Vankar, Y. D. Tetrahedron:
Asymmetry 1996, 7, 1683. (b) Deprez, P.; Royer, J.; Husson, H.-P.
Tetrahedron: Asymmetry 1991, 2, 1189. (c) Takagi, R.; Kimura, J.;
Shinohara, Y.; Ohba, Y.; Takezono, K. J. Chem. Soc., Perkin Trans. 1 1998,
689. (d) Pakulski, Z.; Demchuk, O. M.; Frelek, J.; Luboradzki, R.;
Pietrusiewicz, K. M. Eur. J. Org. Chem. 2004, 18, 3913.
Finally, we selected the reaction conditions shown in Table
1 (entry 9) for further scale-up. We have successfully performed
the reaction on a scale of 100 g with a 92:8 diastereomeric ratio.
Recrystallization of the crude product from a methanol/water
solution gave a diastereomerically pure product in 55% yield.
Confirmation of the Absolute Configuration of the Major
Product. The absolute configuration of the major product of
the reaction was confirmed by X-ray analysis of 12, derived
from the l-menthol ester 9 (Scheme 3). Absolute configuration
of the 3-position was confirmed to be R when the l-menthol
ester of bromoacetic acid was used for the asymmetric reaction.
An ORTEP drawing for the X-ray crystal structure of 12 is
presented in the Supporting Information.
(8) Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetraheron: Asymmetry
1994, 5, 363.
8560 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of NoVel Gastrin Receptor Antagonist AG-041R
TABLE 1. Diastereoselective Alkylation of the Urea 2 with
l-Menthyl Bromoacetate
SCHEME 3. Synthesis of Alcohol Derivative 12
SCHEME 4. Transformation to Target Compound 1
equiv of
base
temp
(°C)
9:10
entrya
solvent
DMF
DMF
DMF-toluene
THF
base
ratioe
1
2
3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
n-BuLi
1.1
1.1
1.1
1.1
1.0
1.0
1.0
1.0
1.1
1.2
1.1
1.1
-10
-60
-78
-10
20
20
20
0
0
60:40f
75:25f
80:20f
75:25f
90:10f
92:8f
g
4
5b
6b,c
7b,c
8
THF
dioxane
t-BuOMe
THF
THF
THF
92:8h
93:7h
94:6h
94:6h
93:7h
9
10d
11
12
0
THF
THF
-15
0
a Unless otherwise noted, the reaction was carried out with 1.2 equiv of
l-menthyl bromoacetate. b 1.1 equiv of l-menthyl bromoacetate was used.
c LiHMDS in hexane was used. d 1.3 equiv of l-menthyl bromoacetate was
used. e The conversion appeared excellent as determined by HPLC analysis,
the products were not isolated, thus only product ratios not yields were
determined. f Determined by 1H NMR analysis of the crude reaction mixture.
g Indeterminate result. h Determined by HPLC analysis of the crude reaction
mixture.
diastereoselectivity increased to a reasonable range with 1.5
equiv of base (Table 2, entry 6). The same trend was observed
in the case of the acyl group for the protective group (Table 2,
entries 8 and 9). The diastereoselectivity of the benzamide was
better than that of acetamide, and therefore, the bulkiness of
the protective group is apparently one of the factors of
stereoselectivity (Table 2, entries 8-11). Not only the bulkiness
of the protective groups but also the basicity order of the
carbonyl group, urea > carbamate > amide, appeared to reflect
the diastereoselectivity. An increase in the electron density of
the carbonyl group in the nitrogen protective group would
facilitate the coordination of the carbonyl group in the N-
protective group with lithium cation and thus lead to high
stereoselection. The use of a slight excess of base would give
partially deprotonated nitrogen and raise the electron density
of the carbonyl group. This would affect efficient chelation,
the probable cause of the high diastereoselectivity observed in
entries 9 and 11.
Stereochemistry of the Reaction. From the results shown
in Table 1 and because the use of a more coordinatable lithium
base gave the best stereoselectivity, the coordination of l-
menthyl bromoacetate with the lithium enolates at its carbonyl
group in the transition state is possible. In the most stable
conformer of the l-menthyl bromoacetate, the carbonyl group
is directed away from the isopropyl group of l-menthol and
bisects the menthol ring, suggesting that the oxindole enolates
approach from the carbonyl group side of the conformer as
depicted in Figure 1 coordinating with the lithium cation, and
thus the approach of the enolates from the upper side would be
eliminated. The results shown in Table 2 indicate that the
Since the final product was not crystalline, clean conversion
from menthol ester 9 to the final compound 1 was required.
Hydrolysis of the menthol ester was efficiently performed by
using KOH in ethanol/H2O under reflux conditions. The
menthol-free carboxylic acid was obtained from basic water
extraction of the intermediate carboxylic acid 13 from hexane
followed by the acidic extraction of the compound. In the
amidation step, we examined EDC-HCl, thionyl chloride,
carbonyl diimidazole, DPPA, and DCC. Among them, EDC-
HCl was selected as the coupling agent because it gave the best
result in terms of purity of the product affording the final product
1 in 99.1% purity and in 91% yield.
Scope of the Asymmetric Alkylation Reaction. To clarify
the generality of the asymmetric reaction, the diastereoselective
alkylation of various N-protected oxindole enolates with l-
menthyl bromoacetate was examined. As shown in Table 2, a
substituent at the 1-position did not affect the diastereoselection
(Table 2, entry 3). The results confirmed that diethylacetal
functionality does not take part in the coordination of the lithium
cation and the substituent at the 1-position does not play a role
in diastereoselection. After exchanging the protective group of
nitrogen at the 3-position for a carbamate, the character of the
reaction significantly changed (Table 2, entries 4-7). Both tert-
butyl and methyl carbamates gave low diastereoselectivity with
1 equiv of base. The selectivity was improved by the use of a
slight excess of base and an electrophile, although only a slight
increase of selectivity was observed in the case of urea. The
J. Org. Chem, Vol. 71, No. 22, 2006 8561

Emura et al.
TABLE 2. Diastereoselective Alkylation of Various N-Protected Oxindole Enolates with l-Menthyl Bromoacetate
LiHMDS
(equiv)
yielde
(%)
ratio
(major:minor)
entrya
substrate
R1
R2
productd
1
2
2
CH2CH(OEt)2
CH2CH(OEt)2
p-TolNH
p-TolNH
p-TolNH
t-BuO
t-BuO
t-BuO
MeO
Ph
Ph
Me
Me
1.0
1.2
1.0
1.0
1.2
1.5
1.0
1.0
1.2
1.0
1.2
9 + 10
83
77
84
74
64
62
58
83
82
57
69
92:8f
2b
3
9 + 10
94:6f
14a
14b
14b
14b
14c
14d
14d
14e
14e
Me
Me
Me
Me
Me
Me
Me
Me
Me
15a + 16a
15b + 16b
15b + 16b
15b + 16b
15c + 16c
15d + 16d
15d + 16d
15e + 16e
15e + 16e
91:9g
4
56:44g
69:31g
85:15g
72:28g
88:12g
95:5g
5b
6c
7
8
9b
10
11b
76:24g
84:16g
a Unless otherwise noted, the reaction was carried out with 1.1 equiv of l-menthyl bromoacetate. b 1.3 equiv of l-menthyl bromoacetate was used. c 1.6
equiv of l-menthyl bromoacetate was used. d Stereochemistry was tentatively assigned on the basis of the results shown in Table 1. e Isolated yield of
1
diastereomixtures. f Determined by HPLC analysis of the crude reaction mixture. g Determined by H NMR analysis of the crude reaction mixture.
was stirred for 2 h at ambient temperature, the solvent was removed
in vacuo. Water (1.0 L) was added to the mixture to give yellow
crystals. The crystals were collected and dried under reduced
pressure over phosphorus oxide to give the title compound 6 as
1
yellow crystals (120 g, 100%): mp 172-173 °C; H NMR (300
MHz, CDCl3) δ 10.04 (s, 1H), 7.88 (dd, J ) 7.5, 0.6 Hz, 1H), 7.29
(ddd, J ) 7.8, 7.8, 1.4 Hz, 1H), 7.00 (ddd, J ) 7.8, 7.5, 0.9 Hz,
1H), 6.92 (d, J ) 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.1,
143.8, 141.9, 132.4, 127.6, 122.8, 116.0, 110.8, 64.7. HRMS m/z
[M + H]+ calcd for C9H9N2O2 177.0664, found 177.0657.
FIGURE 1. Expected direction of the oxindole enolates approach to
the l-menthyl bromoacetate.
1-(2,2-Diethoxyethyl)-1H-indole-2,3-dione 3-(O-Methyloxime)
(7). To a solution of 6 (93.3 g, 0.53 mol) in DMA (370 mL) was
carbonyl group in the nitrogen protective group of the oxindole
enolates participates in the coordination with the lithium cation.
On the basis of these results, two transition states (Figure 2)
are possible. Of the two, transition state A, without the steric
interaction between the isopropyl group in the l-menthyl group
and the nitrogen protective group of transition state B, is
preferable. The relatively lower stereoselectivity observed in
the carbamates as protective groups (Table 2, entries 4 and 7)
would be reasonably explained by the model. The more flexible
nature of the carbamates, compared to the ureas and amides,
would reduce the steric interaction in the undesirable transition
state B and would lead to decreased stereoselectivity.
added potassium tert-butoxide (71.2 g, 0.636 mol) followed by the
addition of bromoacetaldehyde diethylacetal (131 g, 0.665 mol).
The mixture was maintained at 110 °C for 4 h then cooled to
ambient temperature. Aqueous ammonium chloride was added and
extracted with methyl tert-butyl ether (2 × 1 L). The combined
organic layers were washed successively with aqueous potassium
bisulfate and aqueous sodium bicarbonate. The organic layer was
dried over sodium sulfate and concentrated in vacuo to give a yellow
oil. (127 g) The crude product 7 was used without purification for
the next step: mp 72-73 °C; 1H NMR (300 MHz, CDCl3) δ 7.85
(ddd, J ) 7.5, 1.4, 0.8 Hz, 1H), 7.27 (ddd, J ) 8.0, 7.6, 1.4 Hz,
1H), 7.00-6.92 (m, 2H), 4.63 (t, J ) 5.3 Hz, 1H), 4.22 (s, 3H),
3.77 (d, J ) 5.3 Hz, 2H), 3.67 (dq, J ) 9.3, 7.0 Hz, 2H), 3.44 (dq,
J ) 9.3, 7.0 Hz, 2H), 1.07 (t, J ) 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 163.3, 143.9, 143.1, 131.8, 127.2, 122.4, 115.3,
109.8, 100.4, 64.5, 63.5, 43.3, 15.2. HRMS m/z [M + H]+ calcd
for C15H21N2O4 293.1501, found 293.1490.
Conclusion
We have demonstrated a highly efficient asymmetric alkyl-
ation of oxindole derivatives using commercially inexpensive
l-menthol as a chiral auxiliary and found the use of lithium
cation is essential for high diastereoselection. Diastereoselective
alkylation from a six-step chromatography-free synthesis of the
optically pure oxindole derivative 1 was successful and achieved
an overall yield of 26%.
N-[1-(2,2-Diethoxyethyl)-2,3-dihydro-2-oxo-1H-indol-3-yl]-N′-
(4-methylphenyl)urea (2). To a solution of 7 (127 g) in acetonitrile
(2.0 L) was added 5% palladium on carbon (12.7 g). The mixture
was stirred under hydrogen under atmospheric pressure at ambient
temperature for 6 h. After removal of the palladium carbon by
filtration, p-tolyl isocyanate (60.6 g, 0.434 mol) was added at
ambient temperature. The mixture was stirred for 1 h during which
time a solid was generated. The cake was collected, washed with
acetonitrile, and then dried under reduced pressure to yield the title
compound 2 as white crystals (109 g, 52% in 3 steps): mp 175-
Experimental Section
1
1H-Indole-2,3-dione 3-(O-Methyloxime) (6). To a suspension
of isatin (100 g, 0.68 mol) in methanol (1.0 L) were added
O-methylhydroxylamine hydrochloride (59.6 g, 0.714 mol) and
dipotassium hydrogenphosphate (118 g, 0.68 mol). After the mixture
177 °C; H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.38-
7.20 (m, 4H), 7.06 (d, J ) 7.8 Hz, 1H), 7.03-6.95 (m, 3H), 6.91
(d, J ) 7.8 Hz, 1H), 5.05 (d, J ) 7.8 Hz, 1H), 4.69 (t, J ) 5.3 Hz,
1H), 3.82 (dd, J ) 14.2, 5.5 Hz, 1H), 3.70-3.58 (m, 3H), 3.47
8562 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of NoVel Gastrin Receptor Antagonist AG-041R
FIGURE 2. Plausible favored and unfavored transition states for the alkylation reaction.
(dq, J ) 9.5, 7.0 Hz, 2H), 2.19 (s, 3H), 1.05 (t, J ) 7.0 Hz, 3H),
1.04 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 174.6,
154.2, 143.0, 137.1, 129.8, 128.7, 127.7, 127.5, 122.9, 121.6, 117.6,
109.0, 99.4, 62.3, 62.0, 52.3, 43.0, 20.2, 15.2. HRMS m/z [M +
H]+ calcd for C22H28N3O4 398.2080, found 398.2076.
with methanol/water (75/25, 500 mL), and then dried under vacuum
to give diastereomerically pure product 9 as white crystals (82.2 g,
55%). The diastereomeric ratio of the products was >99:1
determined by HPLC assay (YMC-Pack CN 4.6 × 300, n-hexane/
i-PrOH ) 99:1, 0.9 mL/min, major tR ) 19.0 min, minor tR
)
1
21.2 min): mp 153-154 °C; H NMR (300 MHz, CDCl3) δ 7.32
(dd, J ) 7.3, 0.9 Hz, 1H), 7.25 (ddd, J ) 7.8, 7.6, 1.4 Hz, 1H),
7.14-7.05 (m, 4H), 7.02-6.95 (m, 3H), 6.77 (s, 1H), 4.75 (t, J )
4.9 Hz, 1H), 4.62 (ddd, J ) 11.0, 10.8, 4.4 Hz, 1H), 3.94 (dd, J )
14.2, 5.8 Hz, 1H), 3.82 (dd, J ) 14.2, 5.9 Hz, 1H), 3.78-3.65 (m,
2H), 3.62-3.48 (m, 2H), 3.05 (d, J ) 15.3 Hz, 1H), 2.63 (d, J )
15.1 Hz, 1H), 2.25 (s, 3H), 1.90-1.81 (m, 1H), 1.74-1.58 (m,
3H), 1.52-1.32 (m, 1H), 1.30-0.72 (m, 4H), 1.16 (t, J ) 7.0 Hz,
3H), 1.12 (t, J ) 7.0 Hz, 3H), 0.87 (d, J ) 6.4 Hz, 3H), 0.83 (d,
J ) 7.0 Hz, 3H), 0.63 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 176.4, 169.3, 153.8, 142.8, 135.6, 132.7, 129.25, 129.20,
128.7, 122.4, 120.6, 110.1, 100.8, 75.4, 63.7, 63.5, 59.3, 46.7, 44.2,
41.2, 40.7, 34.1, 31.4, 26.1, 23.3, 22.0, 20.9, 20.8, 16.2, 15.44,
15.42. HRMS m/z [M + H]+ calcd for C34H48N3O6 594.3543, found
594.3545.
2-[(R)-1-(2,2-Diethoxyethyl)-2-oxo-3-(3-p-tolylureido)-2,3-di-
hydro-1H-indol-3-yl]-N-p-tolylacetamide (1). To a solution of 9
(12.0 g, 20.2 mmol) in EtOH (240 mL) was added 1 N KOH (24
mL). The mixture was refluxed for 1.5 h, followed by addition of
0.16 N HCl (174 mL). The solvent was removed in vacuo. To the
mixture was added 0.24 N KOH (186 mL) to basify the solution.
The mixture was washed with hexane (4 × 250 mL) to remove the
menthol. The water layer was acidified with 0.2 N HCl (187 mL).
Then the mixture was extracted with ethyl acetate (2 × 100 mL).
The combined organic layers were washed with saturated NaCl,
dried with MgSO4, and then concentrated in vacuo to give 13 (9.7
g). To a solution of 13 were added EDC-HCl (5.03 g, 26.2 mmol)
and p-toluidine (2.82 g, 26.4 mmol) at 0 °C. The mixture was stirred
for 4 h at 0 °C, and then for 1.5 h at room temperature. The mixture
was washed with 1 N HCl (2 × 400 mL), followed by saturated
NaCl solution (400 mL). The organic layer was dried with MgSO4,
and then the solvent was removed in vacuo. The resultant product
was dried under vacuum for 2 days at 30 °C to give the title product
1 (10.0 g, 91%). The purity of the product was 99.1% determined
by HPLC analysis: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H),
7.35-7.19 (m, 5H), 7.14 (s, 1H), 7.08-6.95 (m, 6H), 6.99 (d, J )
General Procedure for the Asymmetric Alkylation Reaction
(Table 1). To a solution of 2 (39.7 mg, 0.10 mmol) in a solvent
(0.40 mL) was added a base at 0 °C followed by the addition of
l-menthyl bromoacetate9 at the indicated temperature. After stirring
until no urea 2 could be detected by TLC, aqueous NH4Cl was
added and the mixture was extracted with methylene chloride (2
× 20 mL). The combined organic layers were dried over Na2SO4
and then concentrated in vacuo. The diastereomeric ratio of the
1
crude products was determined by H NMR analysis or HPLC
assay.
[(R)-1-(2,2-Diethoxyethyl)-2-oxo-3-(3-p-tolylureido)-2,3-dihy-
dro-1H-indol-3-yl]acetic Acid (1R,2S,5R)-2-Isopropyl-5-meth-
ylcyclohexyl Ester (9). (a) For Small Scale. To a suspension of 2
(39.7 mg, 0.10 mmol) in THF (0.40 mL) was added LiHMDS (0.90
M in THF, 0.111 mL, 0.10 mmol) at 0 °C followed by the addition
of l-menthyl bromoacetate (30.5 mg, 0.110 mmol). After stirring
for 5 h, aqueous NH4Cl was added and the mixture was extracted
with methylene chloride (2 × 20 mL). The combined organic layers
were dried over Na2SO4 and then concentrated in vacuo. The crude
mixture was purified by silica gel chromatography to give the title
compound 9 as white crystals (49.4 mg, 83% yield). The diaster-
eomeric ratio of the crude products was 92:8 determined by HPLC
assay (YMC-Pack CN 4.6 × 300, n-hexane/i-PrOH ) 99:1, 0.9
mL/min, major tR ) 19.0 min, minor tR ) 21.2 min).
(b) For Large Scale. To a suspension of 2 (100 g, 0.252 mol)
in THF (500 mL) was added LiHMDS (1 M in THF, 277 mL,
0.277 mol) at 0 °C followed by the addition of l-menthyl
bromoacetate (83.7 g, 0.302 mol). After stirring for 3 h, aqueous
NH4Cl (200 mL) was added and extracted with tert-butyl methyl
ether (500 mL). The organic layer was washed with aqueous NH4-
Cl (2 × 200 mL) and with saturated NaCl solution, dried over Na2-
SO4, and then concentrated in vacuo. To the crude mixture were
added methanol (1.5 L) and water (340 mL) followed by seeding.
After standing for 2 h, the crystals formed were collected, washed
(9) Burgess, K.; Henderson, I. Tetrahedron 1991, 47, 6601.
J. Org. Chem, Vol. 71, No. 22, 2006 8563

Emura et al.
8.4 Hz, 2H), 4.77 (dd, J ) 5.8, 5.2 Hz, 1H), 3.98 (dd, J ) 14.2,
8.2 Hz, 1H), 3.78 (dd, J ) 14.2, 4.3 Hz, 1H), 3.78-3.46 (m, 4H),
2.99 (d, J ) 14.8 Hz, 1H), 2.62 (d, J ) 14.6 Hz, 1H), 2.27 (s, 3H),
2.20 (s, 3H), 1.15 (t, J ) 7.0 Hz, 3H), 1.11 (t, J ) 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 177.3, 167.2, 153.8, 142.3, 135.7,
134.6, 134.4, 132.2, 130.0, 129.3, 129.1, 128.7, 122.8, 122.7, 120.4,
119.8, 110.1, 100.5, 63.4, 59.8, 43.9, 43.8, 20.9, 20.8, 15.3. HRMS
m/z [M + H]+ calcd for C31H37N4O5 545.2764, found 545.2784.
Typical Procedure for the Asymmetric Alkylation of Ureas:
[1-Methyl-2-oxo-3-(3-p-tolylureido)-2,3-dihydro-1H-indol-3-yl]-
acetic Acid (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl Ester
(15a + 16a). To a suspension of 14a (29.5 mg, 0.10 mmol) in
THF (0.40 mL) was added LiHMDS (0.90 M in THF, 0.111 mL,
0.10 mmol) at 0 °C followed by the addition of l-menthyl
bromoacetate (30.5 mg, 0.110 mmol). After stirring for 4 h, aqueous
NH4Cl was added and the mixture was extracted with methylene
chloride (2 × 20 mL). The combined organic layers were dried
over Na2SO4 and then concentrated in vacuo. The diastereomeric
ratio was determined to be 91:9 by comparison of one of the
geminal protons in 1H NMR analysis of the crude product (-CH2-
CO2-l-Menthyl, major δ 2.99 ppm, minor δ 2.97 ppm). The crude
mixture was purified by silica gel chromatography to give the title
compound 15a and 16a as an inseparable mixture of diastereomers
as a colorless oil (41.2 mg, 84% yield): 1H NMR (300 MHz,
CDCl3) δ 7.31 (dd, J ) 7.5, 0.8 Hz, 1H), 7.26 (dd, J ) 7.6, 1.2
Hz, 1H), 7.09 (d, J ) 8.4 Hz, 2H), 7.03 (ddd, J ) 7.6, 7.2, 0.9 Hz,
1H), 6.97 (d, J ) 8.1 Hz, 2H), 6.86 (d, J ) 7.8 Hz, 1H), 6.78 (s,
1H), 4.58 (ddd, J ) 11.0, 10.8, 4.3 Hz, 1H), 3.27 (s, 3H), 2.99 (d,
J ) 15.0 Hz, 1H), 2.63 (d, J ) 15.0 Hz, 1H), 2.24 (s, 3H), 1.91 (br
s, 1H), 1.83-1.76 (m, 1H), 1.69-1.56 (m, 3H), 1.48-1.30 (m,
1H), 1.28-1.16 (m, 1H), 1.05-0.70 (m, 3H), 0.86 (d, J ) 6.6 Hz,
3H), 0.82 (d, J ) 6.9 Hz, 3H), 0.60 (d, J ) 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 176.2, 169.1, 154.0, 143.4, 135.6, 132.6, 129.4,
129.3, 129.1, 123.1, 122.6, 120.4, 108.6, 75.3, 59.3, 46.7, 41.2,
40.7, 34.1, 31.4, 26.8, 26.1, 23.3, 22.0, 20.81, 20.77, 16.2. HRMS
m/z [M + H]+ calcd for C29H38N3O4 492.2862, found 492.2863.
Typical Procedure for the Asymmetric Alkylation of Car-
bamates: (3-tert-Butoxycarbonylamino-1-methyl-2-oxo-2,3-di-
hydro-1H-indol-3-yl)acetic Acid (1R,2S,5R)-2-Isopropyl-5-me-
thylcyclohexyl Ester (15b + 16b). To a solution of 14b (26.2 mg,
0.10 mmol) in THF (0.40 mL) was added LiHMDS (0.90 M in
THF, 0.167 mL, 0.15 mmol) at 0 °C followed by the addition of
l-menthyl bromoacetate (44.4 mg, 0.16 mmol). After stirring for 4
h, aqueous NH4Cl was added and the mixture was extracted with
methylene chloride (2 × 20 mL). The combined organic layers were
dried over Na2SO4 and then concentrated in vacuo. The diastere-
omeric ratio was determined to be 85:15 by comparison of one of
the geminal protons in 1H NMR analysis of the crude product
(-CH2CO2-l-Menthyl: major δ 2.53 ppm, minor δ 2.47 ppm). The
crude mixture was purified by silica gel chromatography to give
the title compound 15b and 16b as an inseparable mixture of
diastereomers as a colorless oil (28.5 mg, 62% yield): 1H NMR
(300 MHz, CDCl3) δ 7.34-7.24 (m, 1H), 7.02 (ddd, J ) 7.6, 7.5,
1.1 Hz, 1H), 6.83 (dd, J ) 7.3, 1.1 Hz, 1H), 6.23 (br s, 1H), 4.66
(ddd, J ) 11.0, 10.8, 4.4 Hz, 1H), 3.25 (s, 3H), 2.96 (d, J ) 14.8
Hz, 1H), 2.53 (d, J ) 15.0 Hz, 1H), 1.96-1.86 (m, 1H), 1.78-
1.58 (m, 3H), 1.54-1.20 (m, 2H), 1.25 (br s, 9H), 1.10-0.70 (m,
3H), 0.88 (d, J ) 6.4 Hz, 3H), 0.84 (d, J ) 7.0 Hz, 3H), 0.68 (d,
J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.2, 169.0, 153.5,
143.1, 129.1, 123.1, 122.8, 122.5, 108.2, 80.2, 75.6, 59.2, 46.8,
41.1, 40.8, 34.1, 31.4, 28.2, 26.7, 26.2, 23.4, 22.1, 20.8, 16.3. HRMS
m/z [M + H]+ calcd for C26H39N2O5 459.2859, found 459.2867.
Acknowledgment. We gratefully thank Mr. Ken-ichiro
Kotake, Ms. Ikumi Tanabe, and Ms. Emi Watanabe for their
analytical support, Dr. Susumu Itoh and Dr. Yoshiharu Nawata
for X-ray data collection and analysis, and Ms. Frances Ford
for proofreading the manuscript.
Supporting Information Available: Complete experimental
procedures, product characterization, and NMR spectra for all
compounds, as well as an ORTEP drawing and a CIF file for the
X-ray structure of 12. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO061541V
8564 J. Org. Chem., Vol. 71, No. 22, 2006