An expedient route to a potent gastrin/CCK-B receptor antagonist (+)-AG-041R

Article abstract of DOI:10.1021/jo901352u

(Chemical Equation Presented) An enantiocontrolled synthesis of (+)-AG-041R (1), a potent gastrin/CCK-B receptor antagonist, has been achieved employing a chiral rhodium(II)-catalyzed, oxidative intramolecular aza-spiroannulation as the key step. 2009 Ame

Full text of DOI:10.1021/jo901352u

pubs.acs.org/joc
asymmetric aza-spirocyclization onto an indole ring catalyzed
An Expedient Route to a Potent Gastrin/CCK-B
Receptor Antagonist (þ)-AG-041R
6
,7
by a chiral rhodium complex. Besides needing to determine
the enantioselectivity of the rhodium-catalyzed asymmetric
process, the novel array of functionalities within the enantio-
merically enriched product inspired us to transform 3 to
AG-041R (1), the potent gastrin/CCK-B receptor anta-
Shigeki Sato, Masatoshi Shibuya, Naoki Kanoh, and
Yoshiharu Iwabuchi*
8
Graduate school of Pharmaceutical sciences, Tohoku
University, 6-3 Aobayama, Sendai 980-8578, Japan
gonist, featuring the quarternary 3-aminooxindole struc-
ture (Scheme 1). We report herein an expedient, asymmetric
synthesis of (þ)-AG-041 (1).
iwabuchi@mail.pharm.tohoku.ac.jp
Received June 25, 2009
SCHEME 1. Synthetic Plan for AG-041R
Synthesis of the metal nitrenoid precursor 6 was initiated
9
by protection of the known indole 4 with a Boc group
followed by reduction with LiAlD to afford the alcohol 5 in
4
9
0% yield: the introduction of two atoms of deuterium was
confirmed to be essential for the efficient promotion of the
An enantiocontrolled synthesis of (þ)-AG-041R (1),
a potent gastrin/CCK-B receptor antagonist, has been
achieved employing a chiral rhodium(II)-catalyzed, oxida-
tive intramolecular aza-spiroannulation as the key step.
10,11
key spirocyclization
(Scheme 2). Installation of a carba-
mate handle was then carried out by a conventional two-step
sequence consisting of trichloroacetyl carbamate formation
12
and the subsequent detrichloroacetylation. Oxidative in-
1
3
tramolecular aza-spiroannulation in 6 under the action of
1
4
7
mol % of Rh (S-TCPTTL) with 1.6 equiv of PhI(OAc)2
2 4
1
5
and 3.0 equiv of MgO afforded 7 in 70% yield with 96% ee,
in which the newly constructed quarternary center was
unambiguously determined to be R by connecting to
Metal nitrenoid complexes in combination with a suitable
chiral ligand offer expeditious access to enantiomerically
1
,2
enriched nitrogen-containing motifs. During endeavors
directed toward the enantiocontrolled synthesis of marine
(
þ)-AG-041R as described in Scheme 3.
3-5
The subsequent transformation was initiated by revealing
the oxindole structure via ozonolysis of the exomethylene
alkaloid chartellines,
we have developed an efficient route
to the spiro β-lactam unit with a chiral quarternary carbon via
a strategy involving a highly enantioselective intramolecular
(6) Liang, J.-L.; Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Tetrahedron
Lett. 2003, 44, 5917.
(7) Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. Chem. Commun.,
DOI: 10.1039/913770j.
(1) Reviews: (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
b) Davies, H. M. L.; Long, M. Angew. Chem., Int. Ed. 2005, 44, 3518. (c)
(
Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VHC: Weinheim, 2005; pp 379-416. (d) M €u ller, P.;
Fruit, C. Chem. Rev. 2003, 103, 2905.
(8) (a) Esaki, T.; Emura, T.; Hoshino, E. WO 9419322. (b) Chiba, T.;
Kinoshita, Y.; Sawada, M.; Kishi, K.; Baba, A.; Hoshino, E. Yale J. Biol. Med.
1998, 71, 247. (c) Lindstrom, E.; Bjorkqvist, M.; Hakanson, R. Br. J. Pharmacol.
1999, 172, 530. (d) Ding, X.-Q.; Lindstrom, E.; Hakanson, R. Pharmacol.
Toxicol. 1997, 81, 232. (e) Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M.
J. Org. Chem. 2006, 71, 8559.
(9) Sengupta, A. K.; Gupta, A. A. Indian J. Chem. 1983, 22B, 263.
(10) In the absence of a Boc group, the reaction gave complex mixtures
after Rh-catalyzed oxidative intramolecular C-N bond formation.
(11) The installation of deuterium is crucial to confer robustness onto the
methylene moiety that is destined to support an acyl nitrenoid moiety
complexed to a rhodium ion. For related observations, see: (a) Kim, M.;
Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006, 8, 1073. (b) Gupta,
R.; Sogi, K. M.; Bernard, S. E.; Decatur, J. D.; Rojas, C. M. Org. Lett. 2009,
11, 1527.
(2) For recent progress, see: (a) Zalatan, D. N.; Du Bois, J. J. Am. Chem.
Soc. 2008, 130, 9220. (b) Anada, M.; Tanaka, M.; Washio, T.; Yamawaki,
M.; Abe, T.; Hashimoto, S. Org. Lett. 2007, 9, 4559. (c) Tanaka, M.;
Nakamura, S.; Anada, M.; Hashimoto, S. Heterocycles 2008, 76, 1633. (d)
Anada, M.; Tanaka, M.; Shimada, N.; Nambu, H.; Yamawaki, M.;
Hashimoto, S. Tetrahedron 2009, 65, 3069.
(3) (a) Chevolot, L.; Chevolot, A. M.; Gajhede, M.; Larsen, C.; Anthoni,
U.; Christophersen, C. J. Am. Chem. Soc. 1985, 107, 4542. (b) Anthoni, U.;
Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org. Chem.
1
987, 52, 4709.
4) Total synthesis of the racemate of chartelline C: Baran, P. S.; Shenvi,
R. A. J. Am. Chem. Soc. 2006, 128, 14028.
5) Synthetic studies of chartellines: (a) Lin, X.; Weinreb, S. M. Tetra-
(
(
(12) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
hedron Lett. 2001, 42, 2631–2633. (b) Nishikawa, T.; Kajii, S.; Isobe, M.
Chem. Lett. 2004, 33, 440. (c) Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004,
(13) (a) Padwa, A.; Stengel, T. Org. Lett. 2002, 4, 2137. (b) Padwa, A.;
Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org. Chem. 2004, 69, 6377.
(14) (a) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimo-
to, S. Tetrahedron Lett. 2002, 43, 9561. (b) Tsutsui, H.; Yamaguchi, Y.;
Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. Tetrahedron: Asym-
metry 2003, 14, 817. (c) Yamawaki, M.; Tanaka, M.; Abe, T.; Anada, M.;
Hashimoto, S. Heterocycles 2007, 72, 709.
11, 2025. (d) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71, 3159–
3166. (e) Baran, P. S.; Shenvi, R. A.; Mitos, C. A. Angew. Chem., Int. Ed.
2005, 44, 3714. (e) Kajii, S.; Nishikawa, T.; Isobe, M. Tetrahedron Lett. 2008,
49, 594–597. (f) Kajii, S.; Nishikawa, T.; Isobe, M. Chem. Commun. 2008,
3121–3123. (g) Black, P. J.; Hecker, E. A.; Magnus, P. Tetrahedron Lett.
2007, 48, 6364–6367.
(15) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598.
7
522 J. Org. Chem. 2009, 74, 7522–7524
Published on Web 08/31/2009
DOI: 10.1021/jo901352u
r 2009 American Chemical Society

Sato et al.
JOCNote
SCHEME 2. Oxidative Asymmetric Intramolecular Aza-spiro-
annulation Reaction
SCHEME 3. Synthesis of AG-041R
portion of 7. The selective and facile cleavage of the cyclic
carbamate moiety in 8 was performed by treatment with
Boc O in the presence of DMAP and Et N followed by
2
3
K CO in methanol to give 9 in 74% yield with concomitant
2
3
deprotection of a Boc group from the indole moiety. The
oxidation of the primary alcohol to a carboxylic acid was
facilely achieved in a one-pot method employing a catalytic
þ
-
amount of 1-MeAZADO Cl in the presence of NaClO2
in MeCN and CH CO H/CH CO Na buffer, which is a
3
2
3
2
1
6
method recently developed in our laboratory. The resulting
carboxylic acid was converted to methyl ester 10 under
CH N in methanol in quantitative yield.
2
2
Removal of the Boc group in 10 under acidic conditions
followed by treatment with p-tolyl isocyanate afforded urea
1
1. When 11 was alkylated with bromoacetaldehyde diethyl
acetal and potassium tert-butoxide, the cyclization between
the methyl ester moiety and the urea moiety occurred to
produce cyclic urea 12 in 23% yield in three steps. Hydrolysis
was stirred vigorously at reflux for 48 h. The mixture was allowed
to cool to rt and filtered through Celite. The filtrate was con-
centrated in vacuo, and the residue was purified by column
chromatography (1:6 AcOEt/hexane) to give cyclic carbamate 7
of 12 was performed using KOH in ethanol/H O to furnish
2
the carboxylic acid, which was finally converted to AG-041R
25
2
5
8a
þ30.6 (c 0.76, CHCl ) [lit. [R]
(
CHCl )]] with p-toluidine in the presence of EDC HCl. The
1) [[R]
þ27.9 (c 3.05,
D
3
D
2
5
as white amorphous solid (1.04 g, 3.28 mmol, 70%): [R]
c 0.93, CHCl ); IR (neat) 3242, 3120, 2979, 1713, 1605 cm ; H
NMR (400 MHz, CDCl ) δ 7.79 (d, J = 8.6 Hz, 1H), 7.34 - 7.30
D
þ52.7
3
3
-
1 1
(
3
absolute configuration was confirmed as R by comparison of
the optical rotation value with the literature value.
3
(
m, 2H), 7.12 (dd, J=7.4, 7.4 Hz, 1H), 5.82 (d, J=1.7 Hz, 1H),
.26 (br, 1H), 5.00 (d, J = 1.6 Hz, 1H), 2.08 (s, 2H), 1.64 (s, 9H);
In conclusion, we have described the stereocontrolled
synthesis of (þ)-AG-041R via a highly enantioselective
oxidative intramolecular aza-spiroannulation reaction cata-
lyzed by a chiral rhodium catalyst. Through the synthesis of
5
13
C NMR (100 MHz, CDCl ) δ 153.4, 151.0, 150.6, 140.2, 132.0,
3
1
MS m/z 318 (M ), 57 (100); HRMS calcd for C17
29.9, 123.9, 122.6, 115.9, 97.2, 83.3, 62.3, 61.6 (br), 35.3, 28.2;
þ
H D O N
18 2 4 2
(
quaternary carbon center was R in the Rh (S-TCPTTL) -
þ)-AG-041R, we confirmed that the stereochemistry of the
3
18.1547, found 318.1538.
0
0
2
4
1,1 -Di-tert-butoxycarbonylspiro[2,3-dihydro-1H-indol-3,6 -
0
0
2
0
0
0
catalyzed reaction. This concise synthesis also provides the
possibility of access to other biologically attractive com-
[4 ,4 - H2][1 ,3 ]oxazinane]-2,2 -dione (8). Cyclic carbamate 7
(1.134 g, 3.56 mmol) was dissolved in CH Cl /MeOH (1:1 178
mL). The solution was cooled at -78 °C, and ozone was
introduced for 5 min and followed by argon gas for 20 min.
2
2
1
7
pounds having 3-aminooxindole core.
2
To the mixture was added Me S (2.62 mL, 35.6 mmol), and the
resulting solution was allowed to warm slowly at rt and stirred
for overnight. The solution was concentrated in vacuo. To the
Experimental Section
0 0 0
2
3R)-1-tert-Butoxy-2-methylenespiro[3H-indol-3,6 -[4 ,4 - H2]-
(
1 ,3 ]oxazinan-2 -one (7). To a solution of carbamate 6 (1.50 g,
0
0
0
[
crude mixture in CH Cl (35.6 mL) were added Boc O (1.23 mL,
2 2 2
4
.68 mmol) in CH
2
Cl
2
(468 mL) at rt were added MgO (566 mg,
4.0 mmol), PhI(OAc)2 (2.43 g, 7.49 mmol), and Rh (S-
5.34 mmol) and DMAP (43.5 mg, 0.356 mmol, 10 mol %). The
reaction mixture was stirred for 10 min. The reaction was
1
TCPTTL)
2
(589 mg, 0.328 mmol, 7 mol %). The reaction mixture
poured onto H
washed with brine, dried over MgSO
2
O (50 mL), extracted with AcOEt (2ꢀ50 mL),
4
4
, and concentrated in
vacuo. The residue was purified by column chromatography
(
009, 1739.
16) Shibuya, M.; Sato, T.; Tomizawa, M.; Iwabuchi, Y. Chem. Commun.
2
(1:2 AcOEt/hexane) to give amide 8 as a white amorphous solid
þ37.2 (c 1.19,
2
9
D
(17) (a) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10,
905. (b) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; K u€ ndig,
(
CHCl
980 mg, 2.33 mmol, 65% for 2 steps): [R]
2
-1
1
); IR (neat) 2982, 1794, 1733, 1608 cm ; H NMR (400
3
E. P. Chem. Commun. 2008, 4040. (c) Hillgren, J. M.; Marsden, S. P. J. Org.
Chem. 2008, 73, 6459. (d) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.;
Silvani, A. J. Org. Chem. 2009, 74, 4537.
MHz, CDCl
3
) δ 7.93 (d, J = 8.2 Hz, 1H), 7.42 (ddd, J=1.2, 7.5,
8.2 Hz, 1H), 7.33 (dd, J=1.2, 7.5 Hz, 1H), 7.24 (ddd, J=1.0, 7.5,
J. Org. Chem. Vol. 74, No. 19, 2009 7523

Sato et al.
JOCNote
7
1
1
8
.5 Hz, 1H), 2.34 (d, J = 14.8 Hz, 1H), 2.24 (d, J = 14.8 Hz, 1H),
.66 (s, 9H), 1.15 (s, 9H) ; C NMR (100 MHz, CDCl ) δ 173.1,
3
(19.7 μL, 0.131 mmol), tetrabutylammonium iodide (10.1 mg,
27.3 μmol, 25 mol %). The mixture was maintained at 80 °C for 4
1
3
49.1, 148.8, 148.6, 138.3, 129.8, 129.1, 125.0, 121.4, 115.4, 85.1,
4.9, 63.4, 61.0 (br), 33.6, 27.9, 26.9; MS m/z 420 (M ), 220
4
h and then cooled to ambient temperature. Saturated NH Cl
þ
(3 mL) was added and the mixture extracted with Et O (2 ꢀ
2
(
4
100); HRMS calcd for C21
20.1862.
H
24
D
2
O
N
7 2
420.1864, found
20 mL). The combined organic layers were washed with brine,
4
dried over MgSO , and concentrated in vacuo. The residue was
2
3R)-3-tert-Butoxycarbonylamino-3-(2-hydroxy[2,2- H2]ethyl)-
(
purified by column chromatography (1:1 AcOEt/hexane) to give
cyclic urea 12 as a yellowish oil (15 mg, 34.3 μmol, 23% for 3
2
8
,3-dihydo-1H-indol-2-one (9). To a solution of cyclic carbamate
(980 mg, 2.33 mmol) in MeOH (23.3 mL) was added K CO
2
4
2
3
steps): [R]
1689, 1614 cm ; H NMR (400 MHz,CDCl
D
þ61.3 (c 1.28, CHCl
3
); IR (neat) 3272, 2977, 1737,
-
1 1
(64.4 mg, 0.466 mmol) at rt and the mixture stirred for 13 h. The
reaction was poured into saturated NH Cl (30 mL), extracted
3
) δ 7.42-7.38 (m,
2H), 7.30-7.23 (m, 4H), 7.18-7.12 (m, 2H), 5.57 (br, 1H), 4.71
(t, J=5.3 Hz, 1H), 4.12 (dd, J=5.3, 14.5 Hz, 1H), 3.39-3.71 (m,
3H), 3.55-3.48 (m, 2H), 3.22 (d, J = 16.4 Hz, 1H), 2.89 (dd, J=
4
with AcOEt (3 ꢀ 70 mL), washed with brine, dried over MgSO ,
4
and concentrated in vacuo. The residue was purified by column
chromatography (2:1 AcOEt/hexane) to give alcohol 9 as a white
1.7, 16.4 Hz, 1H), 2.39 (s, 3H), 1.15 (t, J=7.0 Hz, 3H), 1.15 (t,
2
5
D
13
amorphous solid (554 mg, 1.88 mmol, 81%): [R]
þ15.9 (c 0.60,
J=7.0 Hz, 3H); C NMR (100 MHz, CDCl ) δ 175.3, 167.1,
3
-
1 1
CHCl
MHz, CDCl
J=7.5, 7.5 Hz, 1H), 7.01 (dd, J=7.5, 7.7 Hz, 1H), 6.90 (br, 1H),
.88 (d, J = 7.5 Hz, 1H), 2.10 (d, J=14.7 Hz, 2H), 1.98 (d, J=14.7
3
); IR (neat) 3314, 2979, 1722, 1621 cm ; H NMR (400
154.3, 143.0, 138.6, 132.1, 130.8, 129.9, 128.4, 126.5, 123.7,
123.3, 111.0, 100.2, 63.7, 63.6, 43.6, 39.9, 21.3, 15.3, 15.2; MS
3
) δ 9.23 (br, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.18 (dd,
þ
m/z 437 (M ), 103 (100); HRMS calcd for C24
437.1951, found 437.1940.
H
27
O
5
N
3
6
13
Hz, 1H), 1.26 (br, 9H); C NMR (100 MHz, CDCl
3
) δ 180.1,
2-[(R)-1-(2,2-Diethoxyethyl)-2-oxo-3-(3-p-tolylureido)-2,3-di-
hydro-1H-indol-3-yl]-N-p-tolylacetamide (AG-041R) (1). To a
154.4, 140.4, 131.6 (br), 128.6, 122.7, 122.5, 110.5 (br), 80.4 (br),
62.0 (br), 57.2, 38.6, 28.0 (br); MS m/z 294 (M ), 147 (100);
þ
solution of cyclic urea 12 (15 mg, 34.3 μmol) in EtOH/H O
2
HRMS calcd for C H D O N 294.1547, found 294.1567.
18
(10:1, 1.9 mL) at 0 °C was added KOH (4.8 mg, 85.8 μmol), and
the mixture was allowed to warm to rt and stirred for 10 h. The
15
2
4
2
Methyl (3R)-(3-tert-Butoxycarbonylamino-2-oxo-2,3-dihy-
dro-1H-indoyl-3-yl)acetate (10). To a solution of alchol 9 (147
mg, 0.50 mmol) in MeCN (1.6 mL) and CH CO H/CH CO Na
reaction was poured onto H
2
O (5 mL) and 10% HCl (5 mL),
extracted with CHCl (2 ꢀ 20 mL), washed with brine, dried
3
2
3
2
3
buffer (pH 4.0, 1.6 mL) were added NaClO
mmol) and 1-MeAZADO Cl
2
(80%, 170 mg, 1.50
(3.0 mg, 15 μmol, 3 mol %) at
over MgSO
mixture in CH
4
, and concentrated in vacuo. To a solution of crude
Cl
þ
-16
2
2
(1.0 mL) at 0 °C were added EDC HCl
3
rt, and the solution stirred for 2 h. The reaction was quenched
with 2-methyl-2-butene, water was added, and the resultant
solution was extracted with AcOEt (3 ꢀ 20 mL). The organic
(8.5 mg, 44.6 μmol, 1.3 equiv) and p-toluidine (4.8 mg, 44.6
μmol, 1.3 equiv) at 0 °C. The mixture was stirred for 40 min at
0 °C. The reaction was poured onto H
(5 mL), extracted with CHCl
dried over MgSO , and concentrated in vacuo. The residue was
2
O (5 mL) and 10% HCl
layer was washed with brine, dried over MgSO
4
, and concen-
3
(2 ꢀ 20 mL), washed with brine,
trated in vacuo. To a solution of crude mixture in MeOH (1.0
4
mL) at 0 °C was added a solution of CH N in Et O (2.0 mL).
purified by column chromatography (1:1 AcOEt/hexane) to give
AG-041R 1 as white crystals (15.2 mg, 27.9 mmol, 81% for 2
2
2
2
The reaction was allowed to warm to rt and stirred for 1 h. The
mixture was concentrated in vacuo. The residue was purified by
column chromatography (1:2 AcOEt/hexane) to give methyl
ester 10 as a white amorphous solid (160 mg, 0.50 mmol, 100%
2
5
steps): mp 100;102 °C; [R]
3319, 2974, 2921, 1698, 1686, 1663, 1608 cm ; H NMR (400
D
þ30.6 (c 0.760, CHCl
3
); IR (neat)
-
1 1
MHz, CDCl ) δ 8.51 (s, 1H), 7.29-7.21 (m, 5H), 7.17 (s, 1H),
3
2
9
for two steps): [R]
D
þ46.5 (c 1.38, CHCl
3
); IR (neat) 3285,
979, 1726, 1622 cm ; H NMR (400 MHz, CDCl ) δ 8.63 (br,
H), 7.24-7.19 (m, 2H), 7.00 (dd, J=7.5, 7.5 Hz, 1H), 6.84 (d,
7.07-6.96 (m, 6H), 6.89 (d, J=8.2 Hz, 2H), 4.75 (dd, J = 4.6, 5.5
Hz, 1H), 3.97 (dd, J = 5.9, 14.4 Hz, 1H), 3.78 (dd, J=4.2, 14.5
Hz, 1H), 3.72-3.48 (m, 4H), 2.97 (d, J=14.7 Hz, 1H), 2.63 (dd,
-
1 1
2
1
3
J=7.7 Hz, 1H), 6.45 (br, 1H), 3.71 (s, 3H), 2.93 (d, J=15.1 Hz,
J=14.7 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 1.13 (t, J=7.0 Hz,
1
H), 2.62 (d, J=15.1 Hz, 1H), 1.30 (br, 9H); C NMR (100
3
13
1
MHz, CDCl
3
3H), 1.09 (t, J=7.0 Hz, 3H); C NMR (100 MHz, CDCl ) δ
3
) δ 177.3, 170.3, 153.9, 140.5, 129.9, 129.2, 123.1,
22.6, 110.4, 80.6, 59.5, 52.2, 40.5, 28.0; MS m/z 320 (M ), 264
177.6, 167.3, 154.0, 142.5, 135.9, 134.7, 134.5, 132.3, 130.0,
129.4, 129.2, 128.8, 122.9, 122.8, 120.7, 119.8, 110.2, 100.6,
63.4, 59.7, 43.9, 43.9, 20.9, 20.7, 15.3; MS m/z 544 (M ), 103
þ
1
þ
(
100); HRMS calcd for C16
0
H
20
O
-(4-Methoxyphenyl)-1 -(2,2-diethoxyethyl)spiro[5,6-dihydro-
5
N
2
320.1372, found 320.1349.
3
prymidin-6,3 ;2 ,3 -dihydro-1H-indoyl]-2,2 ,4-trione (12). To a
36 5 4
(100); HRMS calcd for C31H O N 544.2686, found 544.2704.
0
0
0
0
solution of methyl ester 10 (35 mg, 10.9 μmol) in CH Cl (1.0
mL) was added TFA (0.112 mL, 1.51 mmol) at 0 °C, and the
mixture warmed to rt. The reaction was allowed to warm to rt
2
2
Acknowledgment. We thank Dr. Takashi Emura and
Dr. Kazumi Morikawa of Chugai Pharmaceutical Co.,
Ltd. for providing us useful information on AG-041R. This
work was supported by a Grant-in-Aid for the Research
Fellowship for Young Scientists (S.S.) and a Grant-in-Aid
for the Global COE Program for “International Center of
Research & Education for Molecular Complex Chemistry”
from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
and stirred for 2 h. The reaction was poured into H O (5 mL)
2
and washed with Et
was basified with saturated NaHCO
extracted with CHCl
2
O (2 ꢀ 10 mL), and the aqueous solution
3
. The basic solution was
3
(3 ꢀ 20 mL), washed with brine, dried
over MgSO , and concentrated in vacuo. To a solution of crude
4
mixture in MeCN (1.0 mL) was added p-tolyl isocyanate (10.2
μL, 0.120 mmol) at rt. After the reaction was stirred for 1 h, the
precipitation was collected, washed with MeCN, and dried
under reduced pressure. To a solution of the crude mixture in
DMA (1.4 mL) were added potassium tert-butoxide (26.7 mg,
Supporting Information Available: Experimental details and
charachterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
2
1.8 μmol, 2.0 equiv), bromoacetaldehyde diethyl acetal
7
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