Studies directed toward synthesis of the structure proposed for stereocalpin A

Article abstract of DOI:10.1002/cjoc.201190221

Some synthetic efforts directed to the proposed structure of stereocalpin A are disclosed. The stereogenic centers in the aldol unit were installed using the method of Evans and the intermediates obtained through a reliable route helped to reveal that the

Full text of DOI:10.1002/cjoc.201190221

FULL PAPER
Studies Directed toward Synthesis of the Structure Proposed
for Stereocalpin A
Huang, Yixian(黄祎先)
Wu, Yikang*(伍贻康)
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Some synthetic efforts directed to the proposed structure of stereocalpin A are disclosed. The stereogenic centers
in the aldol unit were installed using the method of Evans and the intermediates obtained through a reliable route
helped to reveal that the spectroscopic data reported earlier in the literature for the same structures were either erro-
neous or irrelevant.
Keywords peptide, natural product, aldol reaction, amino acid, condensation
Introduction
was arranged at the amido bond between C-20 and the
amino group at C-12, which related to structure 2. And
this linear intermediate can be further disconnected into
the dipeptide fragment 3 and the aldol subunit 4. The
former 3 is a straightforward condensation product of
phenylalanine derivatives 5 and 6, while the latter 4,
Stereocalpin A was first reported in 2008 by Oh and
1
coworkers as a natural cyclic depsipeptide (1, Figure 1)
with significant antitumoral activity. In an effort to con-
firm the assigned structure, also as a natural extension
of our studies in aldol related synthesis of natural prod-
ucts, we began a synthetic investigation targeting at 1
soon after the Oh’s publication fell to our sight. Then, in
Scheme 1
2
009, while our work was still under going, Ghosh et
2
al. published their synthesis of compound 1 and
showed that the NMR data of the synthetic 1 were not
compatible with those for the natural product. As this in
fact already put an end for compound 1 as a natural
product, we were about to discontinue the work along
3
this line. However, a more recent publication reporting
on the aldol subunit of 1, which gave spectroscopic data
substantially different from ours, prompted us to dis-
close our own results detailed below.
Figure 1 Structure proposed for the natural stereocalpin A (1).
Results and discussion
Our general plan, in a form of retrosynthetic analysis,
is shown in Scheme 1. The initial bond disconnection
*
E-mail: yikangwu@sioc.ac.cn
Received January 14, 2011; revised January 29, 2011; accepted February 24, 2011.
Project supported by the National Basic Research Program of China (973 Program) (No. 2010CB833200), the National Natural Science Foundation
of China (Nos. 21032002, 20921091, 20672129, 20621062, 20772143) and the Chinese Academy of Sciences (“Knowledge Innovation”, No.
KJCX2.YW.H08).
Chin. J. Chem. 2011, 29, 1185— 1191
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Huang & Wu
FULL PAPER
should be possible to be derived from aldol reaction
between 7 and 8.
obtained in 82% isolated yield.
Scheme 3
In execution of the synthetic plan, the commercially
available phenylalanine derivatives 5 and 6 were con-
densed with each other to give the desired dipeptide
fragment 3 (Scheme 2). Initially, this was attempted
under the most traditional conditions using DCC (dicy-
clohexylcarbodiimide) as the condensing agent. How-
ever, the product was very difficult to separate from the
dicyclohexylurea generated in the reaction. Replacing
DCC with EDCI (1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide) and performing the reaction under other-
2 2
wise the same conditions (with CH Cl as the solvent)
did eliminate the separation problem. However, the
yield was still rather low. Using pyBOP [(Benzotria-
zol-1-yl-oxy)tripyrrolidinophosphonium
hexafluoro-
phosphate] gave a higher yield (70%), but the reagent
was substantially more expensive. Finally, we were
4
pleased to observe that addition of some DMF (di-
methylformamide) to the EDCI system in the presence
of HOAt (1-hydroxy-7-azabenzotriazole) could raise the
yield of 9 to 84% and thus provided a satisfactory
means to access the desired dipeptide. Further treatment
of 9 with LiOH in THF led to smooth hydrolysis of the
methyl ester, giving the corresponding acid 3 in 90%
yield.
Oxidation of 12 into 8 was realized with SO -py in
3
8
a,8b
the original report
of Evans et al. However, in our
hands the yield fluctuated significantly from run to run
regardless of the source (from several different com-
mercial suppliers) of the oxidant. This problem later
was solved by using Swern oxidation. Under such con-
ditions the ketone 8 could be obtained in high yields
with high reproducibility. Subjection of ketone 8 to the
Scheme 2
8
a
Evans’ asymmetric aldol reaction conditions led to
formation of fragment 4 in 78% yield.
It should be noted here that in their original report,
8
a
Evans and coworkers mentioned that direct reaction
Scheme 4) of 11 with propionyl chloride could lead to
' (not 8). Therefore, an indirect two-step sequence (i.e.,
(
8
aldol reaction followed by oxidation) was proposed for
the preparation of compound 8. Although a recent pub-
lication claimed acquisition of 8 rather than 8' through
the same reaction under slightly modified conditions (no
1
13
It is noteworthy that both the H and C NMR of 9
contained “additional” signals, which seemingly sug-
gested presence of configurational isomer(s), a problem
occurs from time to time to peptide synthesis in general.
However, repeated careful HPLC separation of 9 failed
to show any isomer(s). Also, when recording at higher
3
MgBr
2
and fast addition of propionyl chloride), the ac-
companying data for the 8' (including optical rotation
1
13
and H as well as C NMR) therein were not only in-
8a
compatible with those of Evans’ 8', but also exactly
the same as those for the 8 reported by Evans. In
temperature (80 ℃ in DMSO-d
6
) complete signals de-
8a
1
13
generation occurred to both the H and C NMR—the
comparison, our 8 was identical to that of Evans’ 8 in all
“
extra” signals in the spectra acquired at ambient tem-
respects, with additional support from single crystal
perature all disappeared. Then we also noticed that
similar phenomena of “extra” signals had been observed
8c
X-ray analysis (Figure 2). All these manifest that the
5
aldol reaction followed by oxidation was (and still is to
date) indeed necessary for the synthesis of 8 and the
structure as well as configuration of the 8 employed in
the present investigation was secured with full confi-
dence.
in some literature cases, where the amido NH in normal
peptides was methylated (NMe).
The aldol fragment 4 was synthesized using the
route shown in Scheme 3. Starting from the commer-
cially available aldehyde 10 and N-acyloxazolidinone
1 through an asymmetric aldol reaction under the con-
ditions developed by Crimmins et al. the aldol 12 was
Then, we were in a position to scrutinize the incom-
patibility between the data for the aldol subunit 4 syn-
1
6
7
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Chin. J. Chem. 2011, 29, 1185— 1191

Studies Directed toward Synthesis of the Structure Proposed for Stereocalpin A
Scheme 4
Figure 3 Configuration of the product 4' that might be derived
from 8' according to the rule in Ref. 7 and three configurational
isomers along with their optical rotations mentioned in Ref. 7.
Figure 2 The ORTEP presentation for 8.
desired coupling product in 40% yield. Having noticed
the great tendency for enolization (and consequently,
racemization) at the C-21, we next opted to reduce the
ketone carbonyl to the corresponding alcohol before
further elaborations on the carboxylic as well as the
amino terminals of the substrate. To this end, the mild
3
thesized in this work and that reported in the literature.
As the identity of our 8 was established beyond any
doubts and the subsequent aldol reaction was performed
exactly under the Evans’ conditions (with the aldehyde
being essentially the same: propionaldehyde in Evans’
case and butyraldehyde in ours), the relative as well as
absolute configuration of our 4 therefore should be the
same as those reported for the congener of 4 (with only
one less CH in the alkyl chain compared with 4) by
2
Evans. Under the same reaction conditions, the corre-
sponding aldol product in the earlier paper (Figure 3),
NaBH(OAc)
any reduction product. NaBH
3
was first examined, which failed to give
was potent enough to
4
reduce the ketone completely, but the chiral auxiliary
was also cleaved with the C-20 concurrently trans-
formed to the corresponding alcohol. Finally,
3
3
NaBH (CN), which was usually unable to reduce ke-
where the starting 8 was reported to have all the spec-
troscopic data identical to those for 8', is expected to
afford the diastereomer 4' (instead of 4) according to the
rule established by Evans. However, while it is impos-
sible to confirm this possibility on the basis of the
tones, was found to be a suitable reductant for the de-
sired transformation, affording a clean reduction of the
C-23 ketone.
9
8
The chiral auxiliary was then cleaved under the clas-
1
0
sic LiOH/H
2
O
2
conditions. The resulting acid (18) was
over Pd-C at ambient tem-
available NMR data, its specific rotation {[α]
D
＋48.2
treated with atmospheric H
2
3
(
c 1.03, CH
Cl
2 2
) } does not seem to be compatible with
perature to cleave the Cbz (benzyloxycarbonyl) pro-
tecting group. The newly formed amino acid 19 was
then cyclized into 20 with the aid of HATU [2-(7-aza-
1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium he-
xafluorophosphate].
a closely related compound {13, [α]
D
－11.0 (c 1.19,
8
a
4
CCl )}. We noticed that all the other possible di-
8
a
astereomers in the literature also showed negative ro-
tations.
The coupling of the aldol fragment and the dipeptide
one was executed as shown in Scheme 5. An initial at-
tempt under the Yamaguchi conditions was unsuccess-
ful, with the ketone carbonyl group apparently enolized.
Then, the union of the two fragments was performed
using DCC as the condensing agent, which led to the
Up to this point, the structure (20) was already very
similar to that of 1. It seems that only one step of oxida-
tion of the C-23 alcohol into the corresponding ketone
would finish the whole synthesis. However, such a usu-
ally rather simple transformation turned out to be ex-
tremely difficult here. We tried several protocols in-
Chin. J. Chem. 2011, 29, 1185— 1191
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Huang & Wu
FULL PAPER
Scheme 5
cluding Swern, SO
3
-py, and Dess-Martin oxidation.
Shimadzu LCMS-2010EV mass spectrometer. HRMS
data were obtained with a Bruker APEXIII 7.0 Tesla
FT-MS spectrometer. Optical rotations were measured
on a Jasco P-1030 polarimeter.
(4R)-3-[(2R,3S)-3-Hydroxy-2-methyl-pentanoyl]-
4-benzyl-oxazolidine-2-one (12) To a solution of the
N-acyl oxazolidinone 11 (4.66 g, 20 mmol) in dry
Unfortunately, they all led to a mixture containing a
component with the C-23 ketone enolized, strongly
suggesting that the structure 1 enolizes very easily. Be-
2
cause by that time Ghosh already published their work,
where the original spectra for the natural product were
disclosed for the first time and the possibility for 1 be-
ing the natural product had been completely excluded,
we did not make any further attempts to convert 20 into
CH
2
Cl
2
(130 mL) stirred at 0 ℃ under N
2
(balloon)
4
were added dropwise TiCl (2.3 mL, 21 mmol) and (5
1
.
min later) (－)-sparteine (7.5 mL, 50 mmol). The dark
red-brown mixture was stirred at the same temperature
for 30 min. Propionaldehyde (2.18 mL, 30 mmol) was
added slowly. Stirring was continued at 0 ℃ for 2 h
Conclusion
In an attempt to synthesize the structure originally
assigned for the natural stereocalpin A, the aldol subunit
of the target structure was constructed efficiently using
the Evans asymmetric aldol reaction, with the absolute
configurations of all stereogenic centers established
without any ambiguity. The present results also show
that the spectroscopic data previously reported for the
corresponding aldol intermediates were either erroneous
or irrelevant.
4
before aqueous saturate NH Cl (20 mL) was added. The
mixture was filtered through Celite. The filtrate was
washed with water and brine and dried over anhydrous
2 4
Na SO . Removal of the solvent by rotary evaporation
and column chromatography (EtOAc/PE, V∶V＝1∶4)
on silica gel gave aldol 12 as a colorless oil (4.77 g,
1
8
1
6.4 mmol, 82%) which solidified on standing. m.p.
7
25
2—83 ℃ (Lit. m.p. 78—79 ℃). [α] －38.9 (c
D
7
25
D
1
.07, CHCl
3
) [Lit. [α] －39.8 (c 1.09, CHCl
3
)]; H
NMR (CDCl
3
, 300 MHz) δ: 7.36—7.19 (m, 5H), 4.70
Experimental
(m, 1H), 4.19 (m, 2H), 3.86 (m, 1H), 3.79 (dq, J＝7.0,
2
.8 Hz, 1H), 3.25 (dd, J＝13.4, 3.3 Hz, 1H), 2.92 (d,
2 2
Dry THF was distilled over Na/Ph CO under N
prior to use. Dry CH
J＝3.2 Hz, 1H), 2.79 (dd, J＝9.4, 13.4Hz, 1H), 1.53 (m,
2
Cl
2
2
and dry DMF were distilled
prior to use. Addition of
2
H), 1.25 (d, J＝7.0 Hz, 3H), 0.98 (t, J＝7.4 Hz, 3H).
over CaH under N
2
(
4R)-3-[(2R)-2-Methyl-3-oxo-pentanoyl]-4-benzyl-
air/moisture sensitive reagents was done using syringe
techniques. PE (for chromatography) stands for petro-
leum ether (b.p. 60—90 ℃). Column chromatography
was performed on silica gel (300—400 mesh) under
slightly positive pressure. NMR spectra were recorded
2
oxazolidine-2-one (8) To a solution of (COCl) (6.76
mL, 8 mmol) in dry CH
under N
2
Cl
2
(20 mL) stirred at －78 ℃
2
(balloon) were added dropwise dry DMSO
(1.1 mL, 16 mmol) and 12 (1.16 g, 4 mmol, added ca. 5
min later). The mixture was stirred at the same tem-
perature for 30 min. Dry i-Pr NEt (2.8 mL, 20 mmol)
on a Varian Mercury Bruker Avance NMR spectrometer
1
2
operating at 300 MHz for H with Me
standard. IR spectra were measured on a Nicolet 380
infrared spectrometer. ESI-MS data were acquired on a
4
Si as the internal
was introduced. The cooling bath was allowed to warm
slowly to ambient temperature. The reaction mixture
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Chin. J. Chem. 2011, 29, 1185— 1191

Studies Directed toward Synthesis of the Structure Proposed for Stereocalpin A
was partitioned between water and CH
layer was washed with aqueous saturated NH
2
Cl
2
. The organic
Cl, aque-
(CDCl
3
, 300 MHz) δ: 7.34—7.12 (m, 15H), 5.92—5.90
4
(m, 1H), 5.18—5.16 (m, 1H), 5.05—4.97 (m, 3H),
ous saturated NaHCO
over anhydrous Na SO
3
and brine before being dried
. Removal of the solvent by ro-
4.95—4.79 (m, 1.5H), 3.68 (s, 3H), 3.36—3.31 (m,
1
3
2
4
15H), 3.05—2.59 (m, 4H); C NMR (CDCl
3
, 75 MHz)
tary evaporation and column chromatography (EtOAc/
PE, V∶V＝1∶8) on silica gel gave ketone 8 as a col-
orless oil (1.04 g, 3.6 mmol, 90%), which solidified on
δ: 173.6, 172.7, 155.6, 136.7, 135.9, 129.4, 129.2, 129.1,
129.0, 128.7, 128.6, 128.4, 127.9, 127.5, 126.9, 126.8,
126.7, 67.2, 66.8, 66.7, 59.3, 52.4, 52.1, 51.0, 38.8, 38.3,
8
a
25
D
standing. m.p. 76—77 ℃ (Lit. 76—77 ℃); [α]
37.5, 34.9, 34.5, 34.3, 33.6, 33.2, 30.2; FT-IR (film) v:
2959, 2865, 1781, 1694, 1683 cm ; ESI-MS m/z: 497.3
8
a
25
－1
－
144 (c 1.2, CH
2
Cl
2
) [Lit. [α] －149 (c 0.97,
D
1
＋
CH
2
Cl
2
)]; H NMR (CDCl
3
, 300 MHz) δ: 7.36—7.18
([M＋H] ); ESI-HRMS calcd for C28
H
30
N
2
O
7
Na ([M＋
＋
(
m, 5H), 4.74 (m, 1H), 4.60 (q, J＝7.5 Hz, 1H), 4.20 (m,
Na] ) 497.2061, found 497.2052.
2
9
H), 3.30 (dd, J＝13.4, 3.2 Hz, 1H), 2.77 (dd, J＝13.4,
.6 Hz, 1H), 2.65 (m, 2H), 1.43 (d, J＝7.3 Hz, 3H), 1.07
(S)-2-[(S)-2-(Benzyloxycarbonylamino)-N-methyl-
3-phenylpropanamido]-3-phenylpropanoic acid (3)
A solution of 9 (4.74 g, 10 mmol) and LiOH (0.50 g, 12
mmol) in water (5 mL) and THF (35 mL) was stirred at
0 ℃ for 2 h. The mixture was acidified to pH 3 with 1
N HCl and extracted with EtOAc (100 mL). The organic
layer was washed with brine and dried over anhydrous
(
t, J＝7.2 Hz, 3H).
(
4R)-3-[(2R,5S)-2,4-Dimethyl-3-oxo-5-hydroxy-
octanoyl]-4-benzyl-oxazolidine-2-one (4) To a solu-
tion of 8 (2.89 g, 10 mmol) in dry Et
2
O (100 mL) stirred
(balloon) were added c-Hex BCl (1.0
NEt
at 0 ℃ under N
2
2
－
1
mol•L , in hexanes, 12 mL, 12 mmol) and Me
2
2 4
Na SO . Removal of the solvent by rotary evaporation
(1.6 mL, 15 mmol). The stirring was continued at the
and column chromatography (EtOAc/PE, V∶V＝2∶1)
same temperature for 1 h and the temperature of the
on silica gel afforded acid 3 as a colorless oil (4.27 g, 9
2
5
1
cooling bath was lowered to －78 ℃. Butyraldehyde
mmol, 90%). [α] ＋16.7 (c 1, CHCl
3
); H NMR
D
(1.35 g, 30 mmol) was added to the milky-yellowish
(CDCl
3
, 300 MHz) δ: 12.1 (br s OH), 7.34—7.12 (m,
mixture. Stirring was continued at －78 ℃ for 3 h and
15H), 5.92—5.90 (m, 1H), 5.18—5.16 (m, 1H), 5.05—
then at －20 ℃ for 14 h. The mixture was diluted with
4.97 (m, 3H), 4.95—4.79 (m, 1.5H), 3.36—3.31 (m,
1
3
Et
2
O (100 mL). A pH 7 buffer (100 mL) was added,
1.5H), 3.05—2.59 (m, 9H); C NMR (CDCl
3
, 75 MHz)
followed by 30% H
2
O
2
(50 mL). The mixture was
δ: 173.6, 172.7, 155.6, 136.7, 135.9, 129.4, 129.2, 129.1,
129.0, 128.7, 128.6, 128.4, 127.9, 127.5, 126.9, 126.8,
126.7, 67.2, 66.8, 66.7, 59.3, 52.4, 52.1, 51.0, 38.8, 38.3,
37.5, 34.9, 34.5, 34.3, 33.6, 33.2, 30.2; FT-IR (film) v:
stirred at ambient temperature for 1 h. The phases were
separated. The organic layer was washed with brine and
2 4
dried over anhydrous Na SO . Removal of the solvent
－
1
by rotary evaporation and column chromatography
3345, 2959, 2865, 1781, 1694, 1683 cm ; ESI-MS m/z:
＋
(
EtOAc/PE, V∶V＝1∶4) on silica gel afforded aldol 4
483.2 ([M＋H] ); ESI-HRMS calcd for C27
28 2 5
H N O Na
2
5
＋
as a colorless oil (2.82 g, 7.8 mmol, 78%). [α] －39.7
([M＋Na] ) 483.1889, found 483.1895.
D
1
(
c 0.97, CHCl
3
); H NMR (CDCl
3
, 300 MHz) δ: 7.34—
(S)-(4S,5S,7R)-8-[(R)-4-Benzyl-oxazolidin-2-on-3-
yl]-5,7-dimethyl-6,8-dioxo-octan-4-yl 2-(S)-2-(ben-
zyloxycarbonylamino)-N-methyl-3-phenylpropana-
mido)-3-phenylpropanoate (16) A solution of acid 3
(460 mg, 1.0 mmol), DCC (466 mg, 2.0 mmol), DMAP
7
1
3
1
.18 (m, 5H), 4.89 (q, J＝7.3 Hz, 1H), 4.76—4.68 (m,
H), 4.27—4.08 (m, 2H), 3.62—3.54 (m, 1H), 3.29—
.26 (m, 1H), 2.85—2.74 (m, 2H), 1.48—1.44 (m, 3H),
.34 (d, J＝6.6 Hz, 1H), 1.18 (d, J＝7.1 Hz, 2H), 1.09 (t,
1
3
J＝7.4 Hz, 1H), 0.96 (t, J＝7.4 Hz, 2H); C NMR
(0.1 mg) in dry CH
Cl
2 2
(5 mL) was stirred at 0 ℃ for 1
(CDCl
3
, 75 MHz) δ: 212.2, 170.5, 153.5, 135.0, 129.3,
h. Aldol 4 (361 mg, 1.0 mmol) was added. The stirring
was continued at ambient temperature for 2 h before
being diluted with EtOAc (20 mL), washed with aque-
ous saturated NaHCO
drous Na SO . Removal of the solvent by rotary evapo-
1
1
1
28.9, 127.4, 73.3, 66.4, 55.3, 52.4, 49.7. 37.9, 36.5,
8.5, 14.1, 13.9, 12.8; FT-IR (film) v: 2959, 2865, 1781,
－
1
＋
694, 1683 cm ; ESI-MS m/z: 362.3 ([M＋H] );
3
and brine, and dried over anhy-
＋
ESI-HRMS calcd for C23
3
H
21
N
3
O
7
Na ([M ＋ Na]
)
2
4
84.1780, found 384.1786.
ration and column chromatography (EtOAc/PE, V∶V＝
Methyl (S)-2-[(S)-2-(benzyloxycarbonylamino)-N-
1∶2) on silica gel afforded 16 as a colorless oil (320
2
5
1
methyl-3-phenylpropanamido]-3-phenylpropanoate
9) A solution of the methyl ester 5 (1.74 g, 9 mmol),
acid 6 (1.8 g, 6 mmol), EDCI (2.3 g, 12 mmol) and
HOAt (1.22 g, 9 mmol) in dry CH Cl (50 mL) and dry
mg, 0.4 mmol, 40%). [α] ＋16.7 (c 0.82, CHCl
3
); H
D
(
NMR (CDCl
3
, 300 MHz) δ: 7.34—7.12 (m, 20H),
5.92—5.90 (m, 1H), 5.18—5.16 (m, 1H), 5.05—4.97
(m, 3H), 4.95—4.79 (m, 3.5H), 4.76—4.68 (m, 1H),
4.27—4.08 (m, 2H), 3.62—3.54 (m, 2H), 3.36—3.26
(m, 2.5H), 3.05—2.59 (m, 6H), 1.48—1.44 (m, 3H),
1.34 (d, J＝6.6 Hz, 1H), 1.18 (d, J＝7.1 Hz, 2H), 1.09 (t,
2
2
DMF (10 mL) was stirred first at 0 ℃ for 2 h then at
ambient temperature for 5 h. EtOAc (100 mL) was
added. The mixture was washed with aqueous saturated
1
3
NaHCO
3
and brine before being dried over anhydrous
J＝7.4 Hz, 1H), 0.96 (t, J＝7.4 Hz, 2H); C NMR
Na SO . Removal of the solvent by rotary evaporation
2
4
3
(CDCl , 75 MHz) δ: 212.2, 173.6, 172.7, 171.5, 152.8,
and column chromatography (EtOAc/PE, V∶V＝1∶3)
155.6, 136.7, 135.9, 129.4, 129.2, 129.1, 129.0, 128.7,
128.6, 128.4, 127.9, 127.5, 126.9, 126.8, 126.7, 67.2,
66.8, 66.7, 59.3, 52.4, 52.1, 51.0, 38.8, 38.3, 37.5, 34.9,
on silica gel afforded dipeptide 9 as a colorless oil (2.38
2
5
1
g, 5 mmol, 84%). [α] ＋19.8 (c 1, CHCl
3
); H NMR
D
Chin. J. Chem. 2011, 29, 1185— 1191
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1189

Huang & Wu
FULL PAPER
5
34.5, 34.3, 33.6, 33.2, 30.2, 14.9, 14.1, 12.2; FT-IR
ture under H (1.01×10 Pa) for 3 h. The solids were
2
－
1
(
film) v: 2959, 2865, 1781, 1694, 1683 cm ; ESI-MS
filtered off. The filtrate was concentrated on a rotary
＋
m/z: 826.3 ([M ＋ H] ); ESI-HRMS calcd for
evaporator to give amino acid 19 as a yellowish oil
＋
1
2
4
C
47
H
53
N
3
O
9
Na ([M＋Na] ) 826.3681, found 826.3679.
(100%). [α] ＋18.8 (c 1.3, CHCl ); H NMR (CDCl ,
D
3
3
(
S)-(4S,5S,7R)-8-[(R)-4-Benzyl-oxazolidin-2-on-3-
300 MHz) δ: 7.28—7.15 (m, 10H), 5.19—5.16 (m, 1H),
5.00—4.97 (m, 1H), 4.95—4.79 (m, 1H), 4.76—4.68
(m, 1H), 3.62—3.54 (m, 3H), 3.36—3.25 (m, 4H),
3.07—2.59 (m, 9H), 1.48—1.44 (m, 3H), 1.35 (d, J＝
6.6 Hz, 1H), 1.20 (d, J＝7.1 Hz, 2H), 1.08 (t, J＝7.4 Hz,
yl]-5,7-dimethyl-6-hydroxy-8-oxo-octan-4-yl 2-(S)-2-
(
benzyloxycarbonylamino)-N-methyl-3-phenylpropa-
namido)-3-phenylpropanoate (17) A solution of ke-
tone 16 (400 mg, 0.5 mmol) and NaBH CN (31 mg, 0.5
3
1
3
mmol) in MeOH (1 mL) and THF (1 mL) was stirred at
ambient temperature for 5 h before being diluted with
EtOAc (30 mL), washed with brine and dried over an-
hydrous Na SO . Removal of the solvent by rotary
1H), 0.98 (t, J＝7.4 Hz, 2H); C NMR (CDCl , 75
3
MHz) δ: 173.6, 172.7, 155.6, 136.7, 135.9, 129.4, 129.2,
129.1, 129.0, 128.7, 128.6, 128.4, 127.9, 127.5, 126.9,
126.8, 126.7, 67.2, 66.8, 66.7, 59.3, 52.4, 52.1, 51.0,
38.8, 38.3, 37.5, 34.9, 34.5, 34.3, 33.6, 33.2, 30.2, 15.9,
14.1, 12.0; FT-IR (film) v: 3345, 2959, 2865, 1781,
2
4
evaporation and column chromatography (EtOAc/PE,
V∶V＝3∶1) on silica gel afforded 17 as a colorless oil
2
5
－1
＋
(
360 mmg, 9 mmol, 90%). [α] ＋25.8 (c 1.56, CHCl );
1694, 1683 cm ; ESI-MS m/z: 535.3 ([M＋Na] );
D
3
1
＋
H NMR (CDCl
3
, 300 MHz) δ: 7.36—7.10 (m, 20H),
ESI-HRMS calcd for C H N O Na ([M ＋ Na]
)
2
9
40
2
6
5
.92—5.90 (m, 1H), 5.18—5.16 (m, 1H), 5.05—4.97
535.2782, found 535.2789.
(
4
m, 3 H), 4.95—4.79 (m, 4H), 4.76—4.68 (m, 1H),
(3S,6S,9R,11R,12S)-3,6-Dibenzyl-10-hydroxy-
4,9,11-trimethyl-12-propyl-1-oxa-4,7-diazacyclodode-
cane-2,5,8-trione (20) A solution of amino acid 19
(460 mg, 1.0 mmol), HATU (766 mg, 2.0 mmol),
.27—4.08 (m, 2H), 3.62—3.54 (m, 2H), 3.36—3.25
(
(
7
3
8
m, 4 H), 3.07—2.59 (m, 6H), 1.48—1.44 (m, 3H), 1.35
d, J＝6.6 Hz, 1H), 1.19 (d, J＝7.1 Hz, 2H), 1.08 (t, J＝
.4 Hz, 1H), 0.96 (t, J＝7.4 Hz, 2H); FT-IR (film) v:
DMAP (0.1 mg), i-Pr NEt (0.28 mL, 2.0 mmol) was
2
－
1
345, 2959, 2865, 1781, 1694, 1683 cm ; ESI-MS m/z:
stirred at 0 ℃ for 5 h before being diluted with EtOAc
＋
28.4 ([M＋Na] ); ESI-HRMS calcd for C47
H
55
N
3
O
9
Na
(30 mL), washed with aqueous saturated NaHCO and
3
＋
(
[M＋Na] ) 828.3681, found 828.3681.
brine, and dried over anhydrous Na SO . Removal of
2
4
(
S)-(4S,5S,7R)-8-Carboxy-5,7-dimethyl-6-hydroxy-
the solvent by rotary evaporation and column chroma-
tography (EtOAc/PE, V∶V＝1∶2) on silica gel af-
forded 20 as a colorless oil (320 mg, 0.4 mmol, 40%).
8
-oxo-octan-4-yl 2-(S)-2-(benzyloxycarbonylamino)-
N-methyl-3-phenylpropanamido)-3-phenylpropano-
ate (18) A solution of 17 (200 mg, 0.25 mmol) and
LiOH (13 mg, 0.3 mmol) in THF (1 mL) and water (0.1
mL) was stirred at 0 ℃ for 2 h. The mixture was acidi-
fied to pH 3 with diluted HCl before being diluted with
EtOAc (30 mL), washed with brine and dried over an-
2
4
1
[α] ＋27.7 (c 1.3, CHCl ); H NMR (CDCl , 300 MHz)
3
3
D
δ: 7.27—7.15 (m, 10H), 5.18—5.16 (m, 1H), 5.00—
4.97 (m, 1 H), 4.95—4.79 (m, 1H), 4.76—4.68 (m, 2H),
3.62—3.54 (m, 3H), 3.36—3.25 (m, 4H), 3.07—2.59
(m, 7H), 1.48—1.44 (m, 3H), 1.36 (d, J＝6.6 Hz, 1H),
1.21 (d, J＝7.1 Hz, 2H), 1.10 (t, J＝7.4 Hz, 1H), 0.98 (t,
J＝7.4 Hz, 2H); FT-IR (film) v: 3326, 2929, 2857, 1702,
2 4
hydrous Na SO . Removal of the solvent by rotary
evaporation and column chromatography (EtOAc/PE,
－
1
＋
V∶V＝8∶1) on silica gel afforded acid 18 as a color-
1698, 1471, 1416 cm ; ESI-MS m/z: 493.2 ([M＋H] );
2
D
4
＋
less oil (145 mg, 0.22 mmol, 90%). [α] ＋23.1 (c 1.02,
ESI-HRMS calcd for C H N O Na ([M ＋ Na]
)
29 38
2
5
1
CHCl
3
); H NMR (CDCl
3
, 300 MHz) δ: 12.1 (br s, 1H),
517.2672, found 517.2669.
7
.36—7.15 (m, 15H), 5.18—5.16 (m, 1H), 5.00—4.97
(
m, 1H), 4.95—4.79 (m, 3H), 4.76—4.68 (m, 1H), 3.62
References and note
—
3.54 (m, 3H), 3.36—3.25 (m, 4 H), 3.07—2.59 (m,
1
Seo, C.; Yim, J. H.; Lee, H. K.; Park, S. M.; Sohn, J. H.; Oh,
H. Tetrahedron Lett. 2008, 49, 29.
7
H), 1.48—1.44 (m, 3H), 1.35 (d, J＝6.6 Hz, 1H), 1.19
(
d, J＝7.1 Hz, 2H), 1.08 (t, J＝7.4 Hz, 1H), 0.96 (t, J＝
1
3
2
3
Ghosh, A. K.; Xu, C. X. Org. Lett. 2009, 11, 1963.
Feng, Y. S.; Dong, W. J.; Zhang, B.; Tang, L.; Tan, W. F.;
Xu, H. J. Chin. J. Appl. Chem. 2010, 27, 240 (in Chinese).
Chen, Y.; Bilban, M.; Foster, C. A. Chin. J. Appl. Chem.
Soc. 2002, 124, 5431.
Wu, X. Y.; Stockdill, J. L.; Wang, P.; Danishefsky, S. J. J.
Am. Chem. Soc. 2010, 132, 4098.
Crimmins, M. T.; King, W. B.; Tabet, E. A. J. Am. Chem.
Soc. 1997, 119, 7883.
7
1
1
1
3
2
3
.4 Hz, 2H); C NMR (CDCl , 75 MHz) δ: 173.6,
72.7, 168.2, 155.6, 136.7, 135.9, 129.4, 129.2, 129.1,
29.0, 128.7, 128.6, 128.4, 127.9, 127.5, 126.9, 126.8,
26.7, 67.2, 66.8, 66.7, 59.3, 52.4, 52.1, 51.0, 34.3, 33.6,
3.2, 30.2, 15.9, 14.1, 12.0; FT-IR (film) v: 3345, 2959,
4
5
6
7
8
－
1
865, 1781, 1694, 1683 cm ; ESI-MS m/z: 647.8
＋
(
(
[M ＋ Na] ); ESI-HRMS calcd for C37
46 2 8
H N O Na
＋
[M＋Na] ) 669.7590, found 669.7581.
(S)-(4S,5S,7R)-8-Carboxy-5,7-dimethyl-6-hydroxy-
Chan, P. C.-M.; Chong, J. M.; Kousha, K. Tetrahedron
8
-oxo-octan-4-yl 2-(S)-2-amino-N-methyl-3-phenyl-
1
994, 50, 2703.
propanamido)-3-phenylpropanoate (19) The above
obtained 18 (145 mg, 0.22 mmol) and Pd-C (10%, 10
mg) were stirred in MeOH (2 mL) at ambient tempera-
(a) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tet-
rahedron 1992, 48, 2127.
1190
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1185— 1191

Studies Directed toward Synthesis of the Structure Proposed for Stereocalpin A
(
b) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J.
Am. Chem. Soc. 2000, 122, 10033.
c) The crystallographic data (CCDC 810138) has be depos-
9
Because the stereogenic center at C-23 was planned to be
eliminated later, no attempt was made to establish the con-
figuration.
(
ited to the Cambridge Crystallographic Data Center, 12
Union Road, Cambridge CB2 1EZ, UK (www.ccdc.cam.ac.
uk); e-mail: deposit@ccdc. cam. ac. uk.
10 Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.
1987, 28, 6141.
(E1101149 Zhao, C.; Fan, Y.)
Chin. J. Chem. 2011, 29, 1185— 1191
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1191