On the Synthesis of Stereocalpin A: Partial Retraction/Correction of Previous Results and Rationalization of the Hidden Difficulties

Article abstract of DOI:10.1002/cjoc.201600884

In continuation/checking of a previous synthesis directed toward the literature structure of stereocalpin A it was found that the data for a substantial part of the intermediates reported before were incorrect. Some of the transformations were not success

Full text of DOI:10.1002/cjoc.201600884

FULL PAPER
DOI: 10.1002/cjoc.201600884
On the Synthesis of Stereocalpin A: Partial Retraction/
Correction of Previous Results and Rationalization of the
Hidden Difficulties
Zhiwei Zhao,a,b Yikang Wu,*,b and Yan Li*,a
a Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials and Ministry-of-Education Key
Laboratory for Synthesis and Application of Organic Functional Molecules, Hubei University,
Wuhan, Hubei 430062, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
In continuation/checking of a previous synthesis directed toward the literature structure of stereocalpin A it was
found that the data for a substantial part of the intermediates reported before were incorrect. Some of the transfor-
mations were not successfully reproduced and the failures were shown to be consequences of the presence of the
N-Me and the particular location of the ester linkage. The origins of the “extra/minor” signals in the NMR for most
of the intermediates, which tend to be mistaken as signs for the presence of impurity/isomers, are also discussed.
Keywords peptide, natural product, aldol reaction, cyclization, condensation
Introduction
obliged[5] to retract part of the previous results to termi-
nate any confusion that might have already been caused
by the previous report and clarify the transformations
involved therein through the new results. Some hidden
difficulties and so far unexplained phenomena in the
synthesis of stereocalpin A will also be discussed.
Stereocalpin A (1) is an antitumor depsipeptide iso-
lated[1] from the MeOH extract of the Antarctic lichen
Stereocaulon alpinum. In 2009, Ghosh (A. Ghosh) and
Xu reported the first synthesis of the assigned structure
using a ring-closure strategy with a macrolactamization
at the -NHMe (Figure 1, disconnection a).[2] In a previ-
ous report[3] (under the title “Studies Directed toward
Synthesis of the Structure Proposed for Stereocalpin A”)
by Huang and Wu (one of us), a different macrolac-
tamization approach (disconnection a, Figure 1) was
also described, where the ring-closure occurred at the
-NH2 rather than the -HNMe group (disconnection b) as
in the Ghosh’s[2] route. S. Ghosh and coworkers also
made extensive efforts in synthesis of 1.[4] Their at-
tempts to employ the strategy of macrolactamization at
the primary -NH2 did not succeed. In the end, their syn-
thesis of 12-epi-1 was completed using the same strate-
gy of ring-closure at the -NHMe developed[2] by A.
Ghosh.
Figure 1 The structure assigned for stereocalpin A (1) and the
two retrosynthetic disconnections for the macrolactamization.
In a recent effort to check the results of the above[3]
mentioned report, it was found that a substantial part of
that study was, regrettably, not reproduced; some phys-
ical and spectroscopic data were proven incorrect, while
the condensation of the aldol subunit with the dipeptide
one and the macrolactamization did not lead to the ex-
pected products as described before. Therefore, we feel
Results and Discussion
The dipeptide subunit was prepared as described be-
fore (Scheme 1). Condensation of the known 4[6] and 5[7]
led to 6, which on saponification gave free acid 7.
*
E-mail: yikangwu@sioc.ac.cn
Received December 13, 2016; accepted January 10, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc. 201600884 or from the author.
Chin. J. Chem. 2017, XX, 1—10
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1

Zhao, Wu & Li
FULL PAPER
Scheme 1
acid 16, but the yield was too low to provide sufficient
quantity for full characterization. The other two isolable
side products appeared to possess the gross structures 17
and 18, while the starting 15 was fully consumed.
NHCbz
Ph
OMe
NH
EDCI, HOAt
HO
+
O
93%
DMF, CH2Cl2
O
Ph
4
5
Scheme 3
OMe
NHCbz
Ph
O
O
OH OH
O
OH
NHCbz
M4NBH(OAc)3
MeCN, 40 C
LiOH, THF
O
O
N
O
N
N
O
O
N
O
92%
O
O
Ph
Ph
75%
Ph
OH
Bn
7
6
Bn
9
13
(Cbz = -C(O)OBn)
CO2H
OH
O
O
The previously published H and 13C NMR data for
7 (compound 3 therein) were more or less compatible
with those for the sample gained in this work. However,
subsequent condensation of 7 with aldol subunit 9 (pre-
pared as described before, Scheme 2) did not occur as
reported[3] before. The reaction mixture was very com-
plex. Although the presence of traces of 10 could not be
excluded, the yield for 10 was definitely impossible to
exceed 10%. In a control experiment using sterically
less hindered/more reactive benzoic acid to replace acid
7 led to mainly 11 (Scheme 2), which suggested that the
failure of direct condensation of 7 and 9 was most likely
caused by the undesired lactonization.
1
Bn
N
Nx
1) DCC
DMAP
5, EDCI, HOAt
4'
Ph
92%
NH
2) H2, Pd/C
O
52% from 13
14
Ph
OH
O
O
OH
O
Nx
O
OH
LiOH
NHCbz
Ph
O
NHCBz
H2O2
19%
N
N
O
O
O
O
Ph
Ph
Ph
15
16
O
O
O
O
NHCbz
Ph
N
Scheme 2
O
O
OH
Ph
O
O
O
O
17
O
O
18
butaldehyde
c-Hex2BCl
24
21
N
O
20
23
N
O
26
Et2O, Me2NEt
78 C, 3 h, 86%
To gain sufficient amounts of 16 for full characteri-
zation, the route in Scheme 4 was then employed. The
chiral auxiliary Nx was cleaved at an earlier stage to
avoid complications encountered in the final step in
Scheme 3. Masking the primary OH and introduction of
two amino acid residues were performed using the sim-
ilar strategy in Scheme 3. And finally, deprotection of
the primary OH followed by oxidation provided acid 16.
Removal of the Cbz protecting group was unexpect-
edly complicated. Treatment of 16 (or 15) with H2 (1
atm) in the presence of 10% Pd/C or Pd (OH)2 (with or
without added NH4CO2H4) could not afford the desired
3 at all. In all runs the only separable products turned
out to be 25－27 (Scheme 5), which presumably oc-
curred via the intramolecular attack of the newly freed
NH2 on the C-1 ester carbonyl group. It is noteworthy
that ketone 10, an intermediate in Scheme 2, was ob-
tained by a Swern oxidation of 15. The spectroscopic
data for 10 were thus made available.
At first sight such unexpected results were hard to
understand, because similar operations had many suc-
cessful precedents in peptide syntheses. However, if one
looks into the particular structural features of this
unique molecule, i.e, a methylated amino group and the
location of the fragile ester bond, the observed phe-
nomenon is still understandable: The presence of the
methyl group on the amino group made the chain more
easily adopt a “bent” conformation than otherwise, so
that the free amino group generated by the cleavage of
OH
9
Bn
Bn
8
PhCO2H
DCC
DMAP
O
O
N
7, DCC, DMAP
cf. text
Nx
O
O
NHCbz
Ph
O
O
O
O
N
O
O
O
Nx =
Ph
11
10
Bn
Ph
O
O
O
N
21
9
Nx
DCC, DMAP
CO2H
Bn
Ph
O
Bn
12
N
Ph
4'
To this end, the C-23 ketone carbonyl group in 9 was
setereoselectively reduced with Me4NB(OAc)3H[8] to
afford 13 (Scheme 3). Treatment of diol 13 with 4' in
the presence of EDCI/HOAt followed by hydrogenoly-
sis over Pd/C under H2 (1 atm) afforded 14 in 52% yield
over 2 steps (from 13). The second amino acid residue
was then introduced by a condensation of 14 with 5.
Without interference of any side reactions leading to
6-membered lactone or lactam, the reaction occurred
smoothly, giving desired 15 in 92% isolated yield. Sub-
sequent cleavage of the Evans auxiliary under the
standard LiOH/H2O2 conditions could afford the desired
2
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On the Synthesis of Stereocalpin A: Partial Retraction/Correction of Previous Results
the Cbz group had better chance to approach the C-1
carbonyl group.
To demonstrate the role of the methyl group on the
amino group we also performed the reactions in Scheme
6, which clearly show the critical influence of the N-Me
on the cyclization and the effects of Cbz on the NMR:
no cyclization (i.e., formation of analogues of 25－27)
occurred and the crude product (without any purifica-
tion/material loss) showed clean 1H and 13C NMR
(without any “redundant” signals).
Scheme 4
O
OH OH
O
OH OH OH
NaBH4
N
O
THF-H2O
93%
19
13
Bn
TBDPSCl DMF
imidazole
Scheme 6
76%
OH OTBDPS
4', DCC
DMAP
OMe
NHCbz
Ph
OH OH OTBDPS
H2, Pd/C
76%
N
25, 26 and/or 27
O
O
76%
OH
O
NBn
Ph
O
20
6
21
OTBDPS
Ph
5, EDCI
H2, Pd/C
O
OMe H
N
NH2
OMe H
N
NHCbz
63%
HOAt
H2, Pd/C
NH
57%
(92% brsm)
O
O
O
OH
22
> 100% (crude)
O
Ph
O
Ph
Ph
Ph
Ph
OTBDPS
NHCbz
28
6'
HO
HF, MeCN
97%
O
OH
Ph
1
It is noteworthy that the H and 13C NMR for 13
N
O
O
were more complicated than one may presume. Some of
the H NMR signals showed similar ones of lower in-
O
Ph
23
1
Ph
O
O
1) TEMPO, KBr
NaHCO3, NaClO
tensity in the close vicinity, seemingly suggesting
co-existence of isomers. However, because raising the
temperature at which the NMR spectra were recorded
clearly showed simplification of the spectra, the com-
plication of the spectra appeared to be mainly caused by
the partial double bond nature of the C-N in the Cbz
group. Indeed, nearly all compounds[9] that contained a
Cbz masked amino group showed similar phenomena in
NMR spectra, including the simplest ones 5 and 6. And
variable temperature NMR did show simplified spectra
at higher temperatures.
N
16
2) NaClO2, Na2HPO4
1-methyl-2-butene
62% from 24
HN
24
Cbz Ph
Scheme 5
Swern
10
OH
O
oxidn.
OH
O
O
X
20
X
O
1
NHCbz
The above rationalization that part of the “minor
species” in the H NMR was caused by the presence of
NH2
N
1
O
(cf. text)
N
O
O
Ph
the Cbz was experimentally proven in the case of 5:
Conversion of 5 into its methyl ester followed by hy-
drogenolysis to remove the Cbz group led to pure phe-
nylglycine methyl ester (without any discernible minor
species in the 1H NMR).
Ph
O
Ph
Ph
15 X = Nx 16 X = OH
3
Ph
Ph
O
Ph
HN
HN
HN
1
12
O
O
O
O
O
11
N
N
2
N
Conclusions
Ph
Ph
25
26
27
Ph
In repetition/continuation of the previously pub-
lished synthesis directed toward stereocalpin A, it was
found that a substantial part of the reported[3] data were
incorrect. The connection of the aldol subunit (corre-
sponding to 9 of this work) with the dipeptide (corre-
sponding to 7 of this work) moiety and the final macro-
lactamization were not successfully reproduced; the
corresponding steps in the previous[3] report (in the pre-
vious report from condensation of 3 with 4 to afford 16
and the subsequent steps) thus must be retracted along
with the reported data. The physical and spectroscopic
data for all attainable intermediates mentioned in the
previous work (i.e., compounds 16, 17 and 18, in the
As cleavage of an ester bond with concurrent for-
mation of a new lactam bond is a thermodynamically
favorable process, the aldol subunit was readily cleaved
regardless what substituent was installed at the C-20
carbonyl group. Indeed, under the same conditions in-
termediate 15 also gave exactly the same results as 16,
proving that formation of 25－27 was an inevitable
outcome. This also explains why only (A.) Ghosh’s[2]
macrolactmization could be accomplished－the possi-
bility to form a similar (undesired) six-memebred lac-
tam or lactone simply did not exist.
Chin. J. Chem. 2017, XX, 1—10
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3

Zhao, Wu & Li
FULL PAPER
previous report, corresponding to 10, 15 and 16) were
carefully acquired through alternative routes to elimi-
nate any potential confusion caused by their counter-
parts in the previous report.[3] The hidden causes for the
failures of those steps that were not successfully repro-
duced in this work were explored and the unexpected
products from these reactions were identified. The ulti-
mate cause for the predominating formation of the
six-membered lactams, which decided no macrolac-
tamization would occur, was attributed to the presence
of the N-methyl group and the particular location of an
ester linkage. This conclusion also explains why
Ghosh’s[2] macrolactamization occurred smoothly. The
almost inevitable complications in the appearance of
NMR spectra for compounds containing Cbz, which
tend to be mistaken for isomers or impurities, were also
explored carefully. Although the previously[1] assigned
target structure 1 had been proven[2] incorrect, the diffi-
culties in the synthetic studies of this compound may
well be encountered in syntheses of other peptides and
related compounds. The knowledge gained herein may
help to avoid undesired side reactions and understand
the “unclean” NMR spectra.
added. The phases were separated. The organic layer
was washed with aq. sat. NaHCO3 (10 mL) and brine (3
×10 mL) and then dried over anhydrous Na2SO4. Fil-
tration and rotary evaporation left a crude oil, which on
purification by column chromatography (2∶1, PE/
EtOAc, V/V) on silica gel gave 6 as a colorless oil (468
mg, 0.986 mmol, 93% from 5). [α]2D5 63.9 (c 0.85,
CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.41－7.26 (m,
5H), 7.25－7.03 (m, 10H), 5.30 (d, J＝9.0 Hz, NH),
5.27 (dd, J＝10.0, 5.9 Hz, 1H), 5.05 (d, J＝12.4 Hz,
1H), 5.03 (d, J＝12.4 Hz, 1H), 4.78 (br q, J＝7.5 Hz,
1H), 3.72, 3.68 and 3.63 (three singlets, with 3.68 being
the main signal, 3H altogether), 3.32 (dd, J＝14.5, 5.8
Hz, 1H), 3.02 (dd, J＝13.4, 7.8 Hz, 1H), 2.93 (dd, J＝
9.9, 4.5 Hz, 1H), 2.88 (dd, J＝13.4, 5.9 Hz, 1H), 2.72 (s,
3H); 13C NMR (125 MHz, CDCl3) δ: 171.83, 170.72,
155.41, 136.59, 136.39, 136.03, 129.53, 128.84, 128.49,
128.44, 128.41, 128.09, 127.89, 126.86, 126.74, 66.73,
58.48, 52.25, 51.96, 39.22, 34.62, 32.53; FT-IR (film) v:
3305, 3030, 2951, 2360, 1739, 1717, 1646, 1497, 1455,
1246, 1048, 750, 699 cm–1. ESI-MS m/z 475.6 ([M＋
H]＋); ESI-HRS calcd for C28H30N2NaO5 ([M＋Na]＋)
497.2047, found 497.2053.
(S)-2-((S)-2-(((Benzyloxy)carbonyl)amino)-N-methyl-
3-phenylpropanamido)-3-phenylpropanoic acid (7)
Experimental
The NMR spectra were recorded on either an Agilent
500/54 NMR spectrometer (operating at 500 MHz for
1H) or an Agilent 400/54 instrument (operating at 400
A mixture of ester 6 (56 mg, 0.118 mmol) and LiOH
(monohydrate, 6.0 mg, 0.14 mmol) in THF (0.41 mL)
and H2O (0.06 mL) was stirred in an ice-water bath for
4 h. The mixture was acidified with 1 mol/L HCl to pH
3 and extracted with EtOAc (10 mL). The organic layer
was washed with brine (3 mL) and dried over anhydrous
Na2SO4. The drying agent and the solvent were removed
by filtration and rotary evaporation. The residue was
purified by column chromatography (1∶5∶0.002, PE/
EtOAc/AcOH, V/V/V) on silica gel to give acid 7 (50
mg, 0.108 mmol, 92%) as a colorless oil. [α]2D5 –62.4 (c
1
MHz for H). IR spectra were measured on a Nicolet
380 Infrared spectrophotometer. ESI-MS data were ac-
quired on a Shimadzu LCMS-2010EV mass spectrome-
ter. ESI-HRMS data were obtained with a Bruker APEX
III 7.0 Tesla FF-MS spectrometer. Optical rotations
were measured on a Jasco P-1030 polarimeter. Melting
points were uncorrected (measured on a hot stage melt-
ing point apparatus equipped with a microscope).
CH2Cl2 was dried with activated 4 Å MS (molecular
sieves). All chemicals were reagent grade and used as
purchased. Column chromatography was performed on
silica gel (300－400 mesh) under slightly positive pres-
sure. Petroleum ether (chromatography eluent) refers to
the fraction boiling between 60 and 90 ℃. EDCI＝
1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hy-
drochloride, HOAt＝3-hydroxytriazolo[4,5-b]pyridine,
HATU ＝ 1-[bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate,
DCC＝dicyclohexylcarbodiimide.
1
0.85, CHCl3). H NMR (500 MHz, CDCl3) δ: 7.34－
7.03 (m, 15H), 6.00, 5.88, 5.84, 5.79 and 5.74 (five
doublets, with 5.74 being the main signal, J＝9.0 Hz,
1H altogether, NH), 5.11 (dd, J＝10.3, 5.3 Hz, 1H), 5.06
－4.96 (m, 2H), 4.80 (br dd, J＝15.4, 7.5 Hz, 1H), 3.35
(br dd, J＝14.5, 5.1 Hz, 1H), 3.02 (dd, J＝13.4, 7.7 Hz,
0.9H), 2.98－2.93 (m, 1H), 2.88 (dd, J＝13.7, 6.7 Hz,
0.9H), 2.77, 2.74 and 2.73 (three singlets of different
intensities, with the most intense line at 2.73, 3H alto-
gether), 2.51 (dd, J＝14.1, 9.3 Hz, 0.1H), 2.00 (dd, J＝
14.1, 4.7 Hz, 0.1H) (because of the co-existence of sev-
eral conformers, the number of protons for each signal
is imprecise, for reference only); 13C NMR (125 MHz,
CDCl3) δ: 173.66, 172.56, 155.65, 136.58, 136.38,
135.99, 129.53, 128.79, 128.52, 128.50, 128.47, 128.05,
127.83, 126.93, 126.78, 66.77, 59.67, 52.17, 38.92,
34.33, 33.51; FT-IR (film) ν: 3307, 3029, 2937, 1718,
1647, 1497, 1454, 1249, 748, 699 cm1. ESI-MS m/z
459.0 ([MH]); ESI-HRS calcd for C27H30N2NaO3
([M＋Na]＋) 483.1890, found 483.1896.
(S)-Methyl 2-((S)-2-(((benzyloxy)carbonyl)-amino)-N-
methyl-3-phenylpropanamido)-3-phenylpropanoate
(6)
EDCI (406 mg, 2.12 mmol) was added to a solution
of amine 4 (226 mg, 1.17 mmol) and acid 5 (317 mg,
1.06 mmol) in dry DMF-CH2Cl2 (1∶5, V/V, 10 mL)
stirred in an ice-water bath under N2 (balloon), followed
by HOAt (159 mg, 1.17 mmol). The mixture was stirred
at ambient temperature for 24 h. EtOAc (20 mL) was
4
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On the Synthesis of Stereocalpin A: Partial Retraction/Correction of Previous Results
(2R,4S,5S)-1-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-5-
81.61, 35.78, 35.01, 18.29, 14.50, 13.83, 10.37. FT-IR
(film) ν: 2961, 2932, 2361, 1736, 1719, 1151, 1058,
1021, 760, 707 cm1; ESI-MS m/z 289.2 [M＋H]＋;
ESI-HRS calcd for C17H20O4Na [M＋Na]＋ 311.1254,
found 311.1260.
hydroxy-2,4-dimethyloctane-1,3-dione (9)
A solution of c-Hex2BCl (1.0 mol/L, in hexanes,
13.33 mL, 13.33 mmol) was added to a solution of 8
(3.211 g, 11.10 mmol) in dry Et2O (40 mL) stirred in an
ice-water bath under N2 (balloon), followed by dry
Me2NEt (1.6 mL, 15 mmol). The resulting green-
ish-yellow mixture was stirred at the same temperature
for 3 h. The ice-water bath was replaced with a –78 ℃
one (acetone-dry ice). Butyraldehyde (4.89 mL g, 55.55
mmol) was introduced dropwise via a syringe. Stirring
was then continued at –78 ℃ for 5 h before sequential
addition of H2O (7 mL), H2O2 (7 mL) and MeOH (7
mL). The mixture was then stirred in an ice-water bath.
Aq. sat. Na2SO3 (25 mL) was added dropwise. The
mixture was extracted with EtOAc (3×50 mL). The
combined organic layers were washed with aq. sat.
Na2SO3 (25 mL) and brine (50 mL), and dried over an-
hydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (3∶1, PE/
EtOAc, V/V) on silica gel afforded aldol 9 as a colorless
oil (3.450 g, 9.55 mmol, 86%). [α]2D5 –58.1 (c 0.97,
CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.38－7.18 (m,
5H), 4.90 (q, J＝7.3 Hz, 1H), 4.79－4.73 (m, 1H), 4.25
(t, J＝8.5 Hz, 1H), 4.18 (dd, J＝9.1, 2.8 Hz, 1H), 3.72
(dt, J＝13.6, 2.5 Hz, 1H), 3.29 (dd, J＝13.4, 3.2 Hz,
1H), 2.82 (dq, J＝7.9, 7.2 Hz, 1H), 2.78 (dd, J＝13.4,
9.6 Hz, 1H), 2.35 (br s, 1H, OH), 1.58－1.50 (m, 2H),
1.47 (d, J＝7.3 Hz, 3H), 1.43－1.32 (m, 1H), 1.19 (d,
J＝7.1 Hz, 3H), 0.92 (t, J＝6.9 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ: 212.10, 170.61, 153.50, 135.09, 129.40,
128.96, 127.39, 73.32, 66.42, 55.35, 52.48, 49.82, 37.92,
36.54, 18.58, 14.14, 13.99, 12.84. FT-IR (film) ν: 3523,
3028, 2959, 2874, 1780, 1717, 1693, 1455, 1391, 1360,
762, 703 cm–1. ESI-MS m/z 362.2 ([M＋H]＋); ESI-HRS
calcd for C20H27NNaO5 ([M＋Na]＋) 384.1781, found
384.1778.
(S)-(4S,5S,7R)-8-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-
5,7-dimethyl-6,8-dioxooctan-4-yl 2-(benzyl(methyl)-
amino)-3-phenylpropanoate (12)
A solution of 4' (112 mg, 0.417 mmol), DCC (87 mg,
0.417 mmol) and DMAP (1.7 mg, 0.014 mmol) in dry
CH2Cl2 (1.8 mL) was stirred in an ice-water bath under
N2 (balloon) for 0.5 h before a solution of 9 (50 mg,
0.138 mmol) in dry CH2Cl2 (1 mL) was introduced
dropwise. The mixture was then stirred at ambient tem-
perature for 4 h. Petroleum ether (PE, 5.6 mL) was
added. The mixture was stirred for 0.5 min. The solids
were filtered off through a short pad of silica gel (wash-
ing with 10∶1 PE/EtOAc, 10 mL). The filtrate was
concentrated on a rotary evaporator. The residue was
purified by column chromatography (10∶1, PE/EtOAc,
V/V) on silica gel to afford 12 as a colorless oil (58 mg,
0.094 mmol, 68%). Data for 12: [α]2D2 –50.0 (c 0.40,
CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.42－7.10 (m,
15H), 5.21－5.09 (an unresolved m, 1H), 4.82 (q, J＝
6.9 Hz, 1H), 4.75 (br tt, J＝8.5, 3.0 Hz, 1H), 4.31 (t, J＝
8.5 Hz, 1H), 4.18 (dd, J＝8.9, 2.6 Hz, 1H), 3.82 (br d,
J＝13.6 Hz, 1H), 3.61 and 3.59 (two unresolved dou-
blets for an AB system, J＜10.5 Hz, 2H altogether),
3.29 (dd, J＝13.4, 3.2 Hz, 1H), 3.06 (dd, J＝13.3, 8.6
Hz, 1H), 3.02－2.94 (m, 1H), 2.89－2.82 (m, 1H), 2.79
(dd, J＝13.4, 9.6 Hz, 1H), 2.32 (s, 3H), 1.52－1.42 (m,
1H), 1.43 (d, J＝7.2 Hz, 3H), 1.41－1.31 (m, 1H), 1.32
－1.22 (m, 2H), 0.92 (br d, J＝6.5 Hz, 3H), 0.89 (br t,
J＝6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 207.04,
171.61, 170.57, 153.62, 139.19, 138.04, 135.11, 129.38,
129.22, 128.95, 128.55, 128.31, 128.17, 127.38, 126.93,
126.44, 73.81, 67.43, 66.46, 58.60, 55.37, 51.48, 51.42,
47.23, 37.98, 36.04, 31.29, 18.81, 13.78, 12.77, 10.46.
FT-IR (film) ν: 3028, 2959, 2874, 1779, 1720, 1359,
(2S,3S)-2-Eethyl-3,5-dimethyl-6-oxo-3,6-dihydro-2H-
pyran-4-yl benzoate (11)
1212, 739, 699 cm1. ESI-MS m/z 613.9 ([M＋H]＋);
＋
A solution of 9 (25 mg, 0.07 mmol), benzoic acid
(9.0 mg, 0.07 mmol) and DCC (29 mg, 0.14 mmol) in
dry CH2Cl2 (0.15 mL) was stirred at ambient tempera-
ture for 1 h. TLC showed that the added 9 was not fully
consumed yet. DMAP (2 mg, 0.02 mmol) was added.
The mixture was stirred for another 3 h and filtered
through a short pad of silica gel (eluting with 4∶1
PE/EtOAc). The filtrate was concentrated and purified
by column chromatography (4∶1, PE/EtOAc, , V/V) on
silica gel to give 11 as a colorless oil (10 mg, 0.035
ESI-HRS calcd for C37H44N2NaO6 ([M ＋ Na]
635.3092, found 635.3087.
)
(R)-4-Benzyl-3-((2R,3S,4S,5S)-3,5-dihydroxy-2,4-di-
methylheptanoyl)oxazolidin-2-one (13)
A mixture of 9 (500 mg, 1.38 mmol) and
Me4NBH(OAc)3 (1.378 g, 5.24 mmol) in AcOH (6.4
mL) and MeCN (6.4 mL) was stirred first in an –40 ℃
(MeCN-liquid N2) bath for 1 h, in an ice-water bath for
1 h and finally at ambient temperature for 1 h. The mix-
ture was partitioned between CH2Cl2 (10 mL) and aq.
sat. NaHCO3 (15 mL). The phases were separated. The
aqueous layer was back-extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were washed with
brine (20 mL) and dried over anhydrous Na2SO4. Re-
moval of the solvent and column chromatography (1∶1,
PE/EtOAc, V/V) on silica gel gave 13 as a white solid
(378 mg, 1.04 mmol, 75%). M.p. 109－110 ℃. [α]D25
1
mmol, 50%): [α]2D5 –14.4 (c 0.60, CHCl3). H NMR
(500 MHz, CDCl3) δ: 8.12 (d, J＝7.4 Hz, 2H), 7.68 (s,
1H), 7.53 (br t, J＝7.7 Hz, 2H), 4.22 (dt, J＝7.8, 4.0 Hz,
1H), 2.89 (d quint, J＝1.5, 7.1 Hz, 1H), 1.83 (d, J＝1.3
Hz, 3H), 1.81－1.72 (m, 2H), 1.66－1.56 (m, 1H), 1.56
－1.45 (m, 1H), 1.18 (d, J＝7.1 Hz, 3H), 0.97 (t, J＝7.4
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 165.94,
163.09, 161.73, 134.27, 130.23, 128.86, 128.14, 116.13,
Chin. J. Chem. 2017, XX, 1—10
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Zhao, Wu & Li
FULL PAPER
1
–55.4 (c 1.05, CDCl3); H NMR (500 MHz,CDCl3) δ:
7.37－7.19 (m, 5H), 4.78－4.70 (m, 1H), 4.31 (dd, J＝
9.7, 1.8 Hz, 1H), 4.22 (d, J＝8.1 Hz, 1H), 4.16 (dd, J＝
9.0, 2.7 Hz, 1H), 4.01 (dq, J＝9.6, 6.9 Hz, 1H), 3.67 (dt,
J＝8.6, 4.2 Hz, 1H), 3.26 (dd, J＝13.4, 3.2 Hz, 1H),
2.79 (dd, J＝13.4, 9.5 Hz, 1H), 2.69－2.50 (a lump, 2H,
including an OH), 1.71－1.65 (m, 1H), 1.64－1.59 (m,
H), 1.59－1.54 (m, 1H), 1.54－1.47 (m, 1H), 1.41－
1.31 (m, 1H), 1.13 (d, J＝6.9 Hz, 3H), 1.05 (d, J＝7.1
Hz, 3H), 0.96 (t, J＝7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ: 176.74, 153.47, 135.25, 129.43, 128.93,
127.35, 76.04, 73.31, 66.24, 55.35, 41.08, 38.02, 37.72,
37.61, 19.32, 14.29, 14.12, 10.54. FT-IR (film of a solu-
tion in CHCl3) ν: 3438 2960, 2933, 2872, 1697, 1451,
1693, 1455, 1389, 1350, 1211, 966, 762, 748, 702 cm–1;
ESI-MS m/z 386.4 ([M＋Na]＋); ESI-HRS calcd for
C20H29NNaO5 ([M＋Na]＋) 386.1938, found 386.1942.
mg, 0.141 mmol, 77%). [α]25 –27.3 (c 0.57, CHCl3). 1H
D
NMR (500 MHz, CDCl3) δ: 7.40－7.11 (m, 15H), 4.89
(ddd, J＝9.1, 5.5, 3.3 Hz, 1H), 4.74－4.64 (m, 1H), 4.24
(t, J＝8.3 Hz, 1H), 4.14 (dd, J＝8.9, 2.2 Hz, 1H), 4.02
(dq, J＝7.2, 7.0 Hz, 1H), 3.73 (dd, J＝7.7, 4.1 Hz, 1H),
3.45 (br t, J＝6.9 Hz, 1H), 3.23 (dd, J＝13.4, 3.1 Hz,
1H), 2.99 (dd, J＝13.7, 6.5 Hz, 1H), 2.93 (dd, J＝13.7,
7.4 Hz, 1H), 2.80 (dd, J＝13.3, 9.5 Hz, 1H), 2.36 (s,
3H), 1.77－1.67 (m, 1H), 1.65－1.54 (m, 1H), 1.52－
1.44 (m, 1H), 1.36－1.23 (m, 2H), 1.21 (d, J＝6.9 Hz,
3H), 0.90 (t, J＝7.4 Hz, 3H), 0.86 (d, J＝6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ: 176.69, 174.68, 153.43,
137.04, 135.34, 129.44, 129.18, 128.90, 128.57, 127.31,
126.81, 76.54, 73.44, 66.31, 64.92, 55.31, 39.82, 39.39,
38.87, 37.95, 34.82, 32.65, 18.79, 14.79, 13.86, 9.59;
FT-IR (film) ν: 3445, 2961, 2932, 2874, 1698, 1604,
1497, 1455, 1388, 1350, 1211, 967, 761, 747, 701 cm–1.
ESI-MS m/z 525.6 ([M＋H]＋ ); ESI-HRS calcd for
C30H41N2O6 ([M＋H]＋) 525.2959, found 525.2964.
(S)-(4S,5S,7R)-8-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-
5,7-dimethyl-6,8-dioxooctan-4-yl 2-(methylamino)-
3-phenylpropanoate (14)
(S)-(4S,5S,6S,7R)-8-((R)-4-Benzyl-2-oxooxazolidin-3-
yl)-5,7-dimethyl-6-hydroxy-8-oxooctan-4-yl 2-((S)-2-
(((benzyloxy)carbonyl)amino)-N-methyl-3-phenyl-
propanamido)-3-phenylpropanoate (15)
A solution of acid 4' (364 mg, 1.35 mmol), DCC
(279 mg, 1.35 mmol) and DMAP (3 mg, 0.024 mmol) in
dry CH2Cl2 (4.4 mL) was stirred at ambient temperature
for 1 h. A solution of 13 (98 mg, 0.27 mmol) in dry
CH2Cl2 (1 mL) was then introduced. The resulting
milky mixture was stirred for another 3 h. Solids were
filtered off through a short pad of silica gel (eluting with
3∶1, PE/EtOAc, 10 mL). The filtrate was concentrated
and purified by column chromatography (3∶1, PE/
EtOAc, V/V) on silica gel to give the N-protected 14
A mixture of 14 (300 mg, 0.572 mmol), 5 (223 mg,
0.744 mmol), HATU (435 mg, 1.144 mmol) and
i-Pr2NEt (0.76 mL, 4.576 mmol) in dry CH2Cl2 (1.5 mL)
was stirred at ambient temperature for 24 h. The mixture
(initially pale yellow but darkened gradually with time;
evetually became yellow-brown) was diluted with
EtOAc (30 mL), washed with aq. KHSO4 (0.5 N, 10 mL)
and brine (10 mL) before being dried over anhydrous
Na2SO4. Removal of the solvent and column chroma-
tography (2∶1, PE/EtOAc, V/V) on silica gel gave 15
as a colorless oil (422 mg, 0.524 mmol, 92% from 14).
(13') as a colorless oil (113 mg, 0.184 mmol, 68%). Da-
1
ta for 13': [α]25 –40.8 (c 0.50, CDCl3). H NMR (500
D
MHz, CDCl3) δ: 7.37－7.14 (m, 15H), 4.90 (ddd, J＝
9.0, 6.1, 3.2 Hz, 1H), 4.77－4.70 (m, 1H), 4.30 (t, J＝
8.3 Hz, 1H), 4.17 (dd, J＝8.8, 2.1 Hz, 1H), 4.02 (dq,
J＝7.2, 6.7 Hz, 1H), 3.84 (br d, J＝11.9 Hz, 1H), 3.70
－3.59 (unresolved m, 3H), 3.25 (dd, J＝13.4, 3.2 Hz,
1H), 3.09 (dd, J＝13.6, 8.4 Hz, 1H), 3.06－3.03 (unre-
solved m, 1H), 2.84－2.80 (m, 2H), 2.35 (br s, 1H),
1.74－1.66 (m, 1H), 1.53－1.44 (m, 2H), 1.41－1.28
(m, 2H), 1.21 (d, J＝6.9 Hz, 3H), 0.91 (t, J＝7.3 Hz,
3H), 0.80 (br d, J＝5.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ: 176.71, 172.53, 153.45, 139.19, 138.15,
135.33, 129.44, 129.17, 128.93, 128.56, 128.36, 128.18,
127.35, 126.94, 126.41, 76.03, 73.58, 67.46, 66.32,
58.63, 55.35, 39.77, 38.79, 38.01, 37.88, 35.96, 32.60,
29.70, 18.80, 14.79, 13.92, 9.34. FT-IR (film) ν: 3430,
[α]25 –67.3 (c 0.44, CDCl3), of 97% pure as shown by
D
HPLC analysis on an Eclipse XDB-C18 (250×4.6 mm,
particle size 5 mol/L) column eluting at 25 ℃ with
MeCN/H2O (85∶15, V/V) at a flow rate of 1.0 mL/min
with the UV detector set to 220 nm. 1H NMR (500 MHz,
CDCl3) δ: 7.37－6.93 (m, 20H), 5.71 and 5.48 (two
doublets, J＝9.0 Hz, 1H altogether), 5.02 (d, J＝12.2
Hz, 1H), 5.01 (d, J＝12.3 Hz, 1H), 4.95－4.86 (m, 2H),
4.79 (dq, J＝7.0 Hz, 1H), 4.71－4.63 (m, 1H), 4.13－
4.02 (m, 3H), 3.90 and 3.76 (two doublets, J＝8.6, 2.6
Hz, 1H altogether), 3.34 (dd, J＝14.4, 5.6 Hz, 1H), 3.21
(br dd, J＝13.0, 1.8 Hz, 1H), 3.08－3.03 (m, 2H), 2.86
(dd, J＝13.6, 6.6 Hz, 1H), 2.82 (s, 3H), 2.81－2.77 (m,
1H), 1.84－1.80 (m, 1H), 1.57－1.53 (m, 2H), 1.33－
1.23 (m, 2H), 1.20 (d, J＝6.9 Hz, 3H), 0.93 (d, J＝6.9
Hz, 3H), 0.88 (t, J＝7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ: 176.56, 171.51, 170.80, 155.51, 153.37,
136.89, 136.34, 136.20, 135.27, 129.53, 129.41, 128.86,
128.79, 128.47, 128.44, 128.43, 128.02, 127.86, 127.28,
126.84, 126.70, 77.10, 72.41, 66.70, 66.11, 60.85, 55.25,
52.03, 40.17, 38.90, 38.40, 37.89, 34.59, 34.37, 33.32,
18.48, 14.50, 13.89, 9.32. FT-IR (film) ν: 3430, 1781,
1697, 1644, 1496, 1454, 1388, 749, 700 cm–1. ESI-MS
2961, 1781, 1636, 1454, 1385, 1350, 737 cm–1. ESI-MS
＋
m/z 614.7 ([M ＋ H]
); ESI-HRS calcd for
C37H46N2NaO6 ([M＋Na]＋) 637.3248, found 637.3242.
The above obtained oil (13', 113 mg) was dissolved
in MeOH (2 mL) and AcOH (0.5 mL). 10% Pd/C (11
mg) was added. The mixture was stirred under H2 (1
atm) at ambient temperature for 6 h. Solids were filtered
off (washing with 15 mL of EtOAc). The filtrate was
concentrated and purified by column chromatography
(1∶1, PE/EtOAc, V/V) to give 14 as a colorless oil (74
6
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—10

On the Synthesis of Stereocalpin A: Partial Retraction/Correction of Previous Results
m/z 806.7 ([M＋H]＋); ESI-HRS calcd for C47H55N3-
NaO9 ([M＋Na]＋) 828.3831, found 828.3836.
4.00 (dd, J＝9.4, 2.1 Hz, 1H), 3.75 (dd, J＝10.2, 4.1 Hz,
1H), 3.67 (dd, J＝10.1, 8.8 Hz, 1H), 3.59 (dt, J＝8.5,
4.3 Hz, 1H), 2.00－1.85 (m, 1H), 1.68－1.59 (m, 1H),
1.59－1.55 (m, 2H), 1.53－1.46 (m, 1H), 1.44－1.29
(m, 1H), 1.05 (s, 9H), 1.04 (d, J＝7.0 Hz, 3H), 0.96 (t, J
＝7.1 Hz, 3H), 0.65 (d, J＝6.9 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ: 135.59, 135.57, 132.71, 132.59, 129.96,
129.93, 127.85, 127.83, 76.47, 75.87, 70.46, 38.24,
38.17, 37.27, 26.79, 19.53, 19.06, 14.25, 12.66, 10.46.
FT-IR (film) v: 3440, 2959, 2930, 2858, 1463, 1427,
1112, 822 cm–1; ESI-MS m/z 451.5 ([M ＋ Na] ＋ );
ESI-HRS calcd for C26H40NaO3Si ([M＋Na]＋) 451.2639,
found 451.2642.
(2R,3S,4R,5S)-5-{[(2S)-2-[(2S)-2-{[(benzyloxy)car-
bonyl]amido}-N-methyl-3-phenylpropanamido]-3-
phenylpropanoyl]oxy}-2,4-dimethyl-3-hydrox-octa-
noic acid (16, obtained by removal of the chiral aux-
iliary in 15)
A mixture of H2O2 (21 L, 0.20 mmol) and LiOH
(monohydrate, 3 mg, 0.075 mmol) in THF-H2O (3∶1,
V/V, 0.3 mL) was stirred in an ice-water bath for 1 h. A
solution of ester 15 (20 mg, 0.025 mmol) in THF-H2O
(3∶1, V/V, 0.3 mL) was added. Stirring was continued
at the same temperature for 3 h. The mixture was diluted
with EtOAc (2 mL). Aq. Na2SO3 (0.5 mol/L, 0.4 mL)
was added. The mixture was then acidified with 1 mol/L
HCl to pH 4 and extracted with EtOAc (3×5 mL). The
organic layer was washed with brine (3 mL) and dried
over anhydrous Na2SO4. The drying agent and the sol-
vent were removed by filtration and rotary evaporation.
The residue was purified by column chromatography
(1∶3, PE/EtOAt, V/V) on silica gel to give acid 16 (3.0
mg, 0.00464 mmol, 19%) as a colorless oil. Data for 16:
Cf below (prepared by oxidation of 24).
(S)-(4S,5R,6R,7S)-8-((tert-Butyldiphenylsilyl)oxy)-6-
hydroxy-5,7-dimethyloctan-4-yl 2-(benzyl(methyl)-
amino)-3-phenylpropanoate (21)
A mixture of 20 (191 mg, 0.446 mmol), acid 4' (235
mg, 0.892 mmol), DCC (276 mg, 1.34 mmol) and
DMAP (11 mg, 0.09 mmol) in dry CH2Cl2 (2.2 mL) was
stirred at ambient temperature for 8 h. Petroleum ether
(PE, 8 mL) was added. Solids were filtered off through
a short pad of silica gel (eluting with 10∶1 PE/EtOAc,
10 mL). The filtrate was concentrated and purified by
column chromatography (12∶1, PE/EtOAc, V/V) on
(2S,3R,4S,5S)-2,4-Dimethyloctane-1,3,5-triol (19)
silica gel to give 21 as a colorless oil (232 mg, 0.341
1
mmol, 76%). [α]25 –9.0 (c 0.72, CDCl3). H NMR (500
A mixture of 13 (41 mg, 0.113 mmol) and NaBH4
(13 mg, 0.344 mmol) in THF (0.38 mL) and H2O (0.08
mL) was stirred at ambient temperature for 3 h. NaOH
(20 mg, 0.50 mmol) was added. The mixture was stirred
for 2 h and concentrated to dryness by rotary evapora-
tion. The residue was purified by column chromatog-
raphy (8∶1, PE/EtOAc, V/V) on silica gel to give triol
19 as a colorless oil (20 mg, 0.105 mmol, 93%). [α]D25
＋22.2 (c 0.65, CDCl3). 1H NMR (500 MHz, CDCl3) δ:
3.95 (dd, J＝9.6, 1.6 Hz, 1H), 3.75－3.58 (m, 3H), 3.24
(br s, 3H, OH), 1.93－1.85 (m, 1H), 1.69－1.61 (m, 1H),
1.60－1.57 (m, 1H), 1.55－1.50 (m, 1H), 1.50－1.43
(m, 1H), 1.40－1.29 (m, 1H), 1.04 (d, J＝7.1 Hz, 3H),
0.96 (t, J＝7.2 Hz, 3H), 0.73 (d, J＝6.9 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ: 77.20, 76.60, 69.27, 38.10,
37.71, 37.10, 19.36, 14.08, 13.13, 10.72. FT-IR (film) v:
3373, 2960, 2932, 2874, 1461, 1027, 967 cm–1; ESI-MS
m/z 191.3 ([M＋H]＋); ESI-HRS calcd for C10H22NaO3
([M＋Na]＋) 213.1461, found 213.1463.
D
MHz, CDCl3) δ: 7.69－7.05 (m, 20H), 4.96 (dt, J＝3.3,
7.9 Hz, 1H), 3.84 (br d, J＝13.2 Hz, 1H), 3.74－3.67 (m,
2H), 3.65 (d, J＝5.2 Hz, 1H), 3.63 (d, J＝5.2 Hz, 1H),
3.30 (d, J＝8.9 Hz, 1H), 3.14－3.08 (m, 1H), 2.98 (s,
2H), 2.34 (s, 3H), 1.78－1.64 (m, 3H), 1.56－1.53 (m,
1H), 1.47－1.26 (m, 2H), 1.06 (s, 9H), 0.93 (t, J＝7.3
Hz, 3H), 0.79－0.76 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ: 170.20, 139.34, 138.30, 135.60, 135.56,
133.35, 133.28, 129.71, 129.31, 129.22, 128.54, 128.20,
128.16, 127.71, 127.69, 126.88, 126.31, 73.41, 68.27,
67.44, 58.64, 38.16, 37.84, 35.74, 33.71, 29.69, 26.86,
19.20, 18.48, 14.05 13.58, 8.84, 8.43. FT-IR (film) v
3504, 2959, 2930, 2857, 1723, 1637, 1455, 1112, 823,
738 cm–1; ESI-MS m/z 680.4 ([M＋H]＋); ESI-HRS
calcd for C43H58NO4Si ([M＋H]＋ ) 680.4130, found
680.4132.
(S)-(4S,5R,6R,7S)-8-((tert-Butyldiphenylsilyl)oxy)-6-
hydroxy-5,7-dimethyloctan-4-yl 2-((S)-2-(((benzyl-
oxy)carbonyl)amino)-N-methyl-3-phenylpropan-
amido)-3-phenylpropanoate (23)
(2S,3R,4S,5S)-1-((tert-Butyldiphenylsilyl)oxy)-2,4-di-
methyloctane-3,5-diol (20)
A solution of triol 19 (135 mg, 0.71 mmol), imidaz-
ole (97 mg, 1.42 mmol) and TBDPSCl (0.22 mL, 0.85
mmol) in dry DMF (1.4 mL) was stirred at ambient
temperature for 5 h. EtOAc (2 mL) was added. The
mixture was washed with H2O (5 mL), aq. HCl (2%, 5
mL) and brine (5 mL) and dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and col-
umn chromatography (10∶1 PE/EtOAc) on silica gel
gave 20 as a colorless oil (233 mg, 0.543 mmol, 76%).
A mixture of 21 (218 mg, 0.321 mmol) and 10%
Pd/C (28 mg) in EtOAc (1 mL) was stirred under H2 (1
atm) at ambient temperature for 18 h. Solids were fil-
tered off. The filtrate was concentrated by rotary evapo-
ration and purified by column chromatography (4∶1,
PE/EtOAc, V/V) to give 22 as a colorless oil (107 mg,
0.182 mmol, 57%) along with recovered 21 (77 mg,
0.113 mmol, 35%).
A mixture of the above obtained 22 (125 mg, 0.212
mmol), 5 (95 mg, 0.317 mmol), EDCI (81 mg, 0.423
mmol) and HOAT (43 mg, 0.316 mmol, addition of
[α]25 ＋18.5 (c 0.55, CDCl3). 1H NMR (500 MHz,
D
CDCl3) δ: 7.74－7.65 (m, 4H), 7.50－7.36 (m, 6H),
Chin. J. Chem. 2017, XX, 1—10
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Zhao, Wu & Li
FULL PAPER
which led to a yellow-green color) in dry DMF (0.15
mL) and dry CH2Cl2 (0.92 mL) was stirred first in an
ice-water bath for 1 h and then at ambient temperature
for 24 h. EtOAc (25 mL) was added. The mixture was
washed with H2O (5 mL) and brine (5 mL) and dried
over anhydrous Na2SO4. Removal of the solvent by ro-
tary evaporation and column chromatography (6∶1,
PE/EtOAc, V/V) on silica gel gave 23 as a colorless oil
(116 mg, 0.133 mmol, 63%). Data for 23: [α]2D4 –35.1 (c
NMR (125 MHz, CDCl3) δ: 171.86, 170.96, 155.60,
136.94, 136.31, 136.12, 129.46, 128.89, 128.58, 128.53,
128.47, 128.06, 127.90, 126.96, 126.86, 77.69, 73.92,
68.17, 66.85, 62.11, 52.15, 38.89, 38.80, 37.08, 35.22,
34.63, 34.28, 18.48, 13.91, 13.59, 9.11. FT-IR (film) v:
3424, 2960, 1716, 1643, 1497, 1455, 1249, 1080, 1029,
749, 699 cm–1. ESI-MS m/z 655.6 ([M＋Na]＋); ESI-
HRS calcd for C37H48N2NaO7 ([M＋Na]＋) 655.3354,
found 655.3356.
1
0.47, CHCl3). H NMR (500 MHz, CDCl3) δ: 7.79－
(5S,8S,11S,12R,13S,14R)-5,8-Dibenzyl-13-hydroxy-7,
12,14-trimethyl-3,6,9-trioxo-1-phenyl-11-propyl-2,10-
dioxa-4,7-diazapentadecan-15-oic acid (16 from 24)
6.96 (m, 25H), 5.38 and 5.28 (two doublets, J＝8.9 Hz,
1H altogether), 5.15 (dd, J＝9.8, 5.7 Hz, 1H), 5.09－
4.93 (m, 3H), 4.75 (dt, J＝8.8, 6.6 Hz, 1H), 3.79 (dd,
J＝10.0, 4.5 Hz, 1H), 3.71 (dd, J＝9.9, 5.9 Hz, 1H),
3.53 and 3.37 (two doublets, J＝9.2, 1.6 Hz, 1H alto-
gether), 3.33 and 3.26 (two doublets, J＝14.5, 5.7 Hz,
1H altogether), 3.01－2.93 (m, 2H), 2.78 (s, 3H), 2.81
－2.76 (m, 1H), 1.82－1.72 (m, 2H), 1.69－1.59 (m,
1H), 1.56－1.45 (m, 1H), 1.32－1.18 (m, 2H), 1.06 (s,
9H), 0.89 (t, J＝7.2 Hz, 3H), 0.88 (d, J＝6.9 Hz, 3H),
0.81 (d, J＝6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ:
171.59, 170.53, 155.39, 136.72, 136.05, 135.56, 125.53,
133.33, 133.20, 129.76, 129.74, 129.49, 128.80, 128.44,
128.40, 128.38, 128.03, 127.87, 127.75, 127.73, 126.83,
126.70, 77.53, 73.02, 68.25, 66.66, 59.27, 51.98, 38.86,
38.56, 37.73, 34.58, 33.93, 26.89, 19.25, 18.39, 14.00,
13.57, 8.74. FT-IR (film) ν: 3502, 2961, 2931, 1781,
A solution of TEMPO (0.05 mol/L, in CH2Cl2, 35
L) was added to a solution of 24 (55 mg, 0.087 mmol)
in dry CH2Cl2 (0.87 mL) stirred in an ice-water bath,
followed by aq. KBr (0.5 mol/L, 17.4 L, 0.0087 mmol)
and KHCO3 (131 mg, 1.31 mmol) and aq. NaOCl
(14.5%, 82 L). The mixture was stirred at the same
temperature for 90 min. H2O (0.5 mL) and aq. Na2SO3
(20%, 5 mL) were added in turn. Phases were separated.
The aqueous layer was extracted with CH2Cl2 (3×10
mL). The combined organic layers were washed with
brine (10 mL) and dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation left a yel-
lowish oil (53 mg, 0.084 mmol, 97%), which was di-
rectly dissolved in t-BuOH (4.35 mL) and H2O (0.44
mL) and stirred at ambient temperature. To this solution
were added in turn a solution of 2-methyl-2-butene
(0.73 mL, 8.7 mmol) in THF (3.65 mL), NaH2PO4 (31
mg, 0.258 mmol) and NaClO (16 mg, 0.177 mmol). The
mixture was stirred at ambient temperature for 30 min.
Et2O (10 mL) and aq. sodium citrate (0.5 mol/L, 6 mL)
were added. Phases were separated. Aqueous layer was
extracted with Et2O (2×10 mL). The combined organic
layers were washed with brine (10 mL) and dried over
anhydrous Na2SO4. Removal of solvents by rotary
evaporation and column chromatography (1∶3∶0.002,
PE/EtOAc/AcOH, V/V/V) on silica gel gave 16 as a col-
1717, 1454, 1388, 1239, 1249, 749, 700 cm1; ESI-MS
＋
m/z: 871.7 ([M ＋ Na] ); ESI-HRS calcd for
C53H66N2O7NaSi ([M＋H]＋) 893.4532, found 893.4533.
(S)-(4S,5R,6R,7S)-6,8-Dihydroxy-5,7-dimethyloctan-
4-yl 2-((S)-2-(((benzyloxy)carbonyl)amino)-N-meth-
yl-3-phenylpropanamido)-3-phenylpropanoate (24)
Aq. HF (48%, 0.16 mL) was added to a mixture of
23 (110 mg, 0.126 mmol) in MeCN (1.26 mL) stirred in
a plastic tube. The mixture was stirred at ambient tem-
perature for 10 h. The excess HF was neutralized with
15% aq. K2CO3. The mixture was diluted with CH2Cl2
(10 mL). Phases were separated. The aq. layer was ex-
tracted with CH2Cl2 (2×5 mL). The combined organic
layers were washed with brine (5 mL) and dried over
anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (1∶1, PE/
EtOAc, V/V) on silica gel gave 24 as a colorless oil (77
orless oil (35 mg, 0.054 mmol, 62% over 2 steps from
1
24). Data for 16: [α]27 –42.4 (c 0.67, CHCl3). H NMR
D
(500 MHz, CDCl3) δ: 7.37－6.94 (m, 15H), 5.70 and
5.52 (two doublets, J＝8.7 Hz, 1H altogether), 5.05 (d,
J＝12.5 Hz, 1H), 4.93 (d, J＝12.3 Hz, 1H), 4.97－4.91
(m, 1H), 4.83－4.71 (m, 2H), 3.88 and 3.61 (two br
doublets, J＝8.7 Hz, 1H altogether), 3.32 and 3.23 (two
doublets, J＝14.2, 5.2 Hz, 1H altogether), 3.06－2.94
(m, 2H), 2.88－2.82 (m, 1H), 2.81 (s, 3H), 2.64－2.56
(m, 1H), 1.85－1.75 (m, 1H), 1.66－1.48 (m, 2H), 1.25
－1.18 (m, 2H), 1.14 (d, J＝6.7 Hz, 3H), 0.91－0.87 (m,
6H); 13C NMR (125 MHz, CDCl3) δ: 176.95, 171.85,
170.83, 155.58, 136.79, 136.23, 136.07, 129.46, 128.83,
128.61, 128.55, 128.47, 128.07, 127.90, 126.98, 126.88,
70.94, 66.86, 62.29, 52.10, 42.19, 38.83, 38.45, 35.45,
34.55, 34.20, 29.70, 18.31, 13.91, 13.66, 8.89. FT-IR
(film) ν: 3430, 2959, 2931, 1716, 1644, 1455, 1253, 750,
699 cm–1. ESI-MS m/z 647.8 ([M＋H]＋); ESI-HRS
calcd for C37H46N2NaO8 ([M＋Na]＋) 669.3146, found
mg, 0.122 mmol, 97%). [α]25 –60.2 (c 0.72, CDCl3). 1H
D
NMR (500 MHz, CDCl3) δ: 7.37－7.28 (m, 6H), 7.26－
7.13 (m, 7H), 7.02 and 6.98 (two doublets, J＝7.0 Hz,
2H altogether), 5.58 and 5.40 (two doublets, J＝9.0 Hz,
1H), 5.07 (d, J＝12.3 Hz, 1H), 4.99 (d, J＝12.3 Hz, 1H),
4.93 (dt, J＝3.2, 8.5 Hz, 1H), 4.88－4.77 (m, 1H), 4.69
(dd, J＝9.2, 6.0 Hz, 1H), 3.76 (dd, J＝10.8, 2.9 Hz, 1H),
3.61－3.55 (m, 2H), 3.35 (dd, J＝14.2, 6.0 Hz, 1H),
3.07－2.98 (m, 2H), 2.84 (dd, J＝13.7, 6.9 Hz, 1H),
2.82 (s, 3H), 2.71 (br s, 2H, OH), 1.86－1.80 (m, 1H),
1.78－1.71 (m, 1H), 1.68－1.59 (m, 1H), 1.59－1.47
(m, 1H), 1.34－1.19 (m, 2H), 0.90 (d, J＝6.9 Hz, 3H),
0.89 (t, J＝7.4 Hz, 3H), 0.80 (d, J＝7.0 Hz, 3H); 13C
8
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—10

On the Synthesis of Stereocalpin A: Partial Retraction/Correction of Previous Results
(S)-(4S,5S,7R)-8-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-
669.3148.
5,7-dimethyl-6,8-dioxooctan-4-yl 2-((S)-2-(((benzyl-
oxy)carbonyl)amino)-N-methyl-3-phenylpropanami-
do)-3-phenylpropanoate (10, by oxidation of 15)
(3S,6S)-3,6-Dibenzyl-1-methylpiperazine-2,5-dione
(25), (3R,6S)-3,6-dibenzyl-1-methylpiperazine-2,5-
dione (26) and/or (3S,6R)-3,6-dibenzyl-1-methyl-
piperazine-2,5-dione (27)
Dry DMSO (0.24 mL, 3.44 mmol) was added slowly
to a solution of (COCl)2 (0.15 mL, 1.72 mmol) in dry
CH2Cl2 (2 mL) stirred at –78 ℃ under argon (balloon).
After completion of the addition the mixture was stirred
at the same temperature for 45 min. A solution of 15 (69
mg, 0.086 mmol) in dry CH2Cl2 (1 mL) was then
introduced. Stirring was continued at –78 ℃ for 1 h
beofre Et3N (0.60 mL, 4.30 mmol) was added slowly.
The mixture was stirred for another 30 min. Water (3
mL) was then added, followed by EtOAc (15 mL). The
phases were saparated. The organic layer was washed
with brine (5 mL) and dried over anhydrous Na2SO4.
The solids were filtered off. The filtrate was
concentrated on a rotary evaporator. The residue was
purified by column chromatography (3∶1, PE/EtOAc,
V/V) on silica gel to give 10 as a colorless oil (53 mg,
0.065 mmol, 76%), along with recovered 15 (6.0 mg,
A mixture of 6 (18 mg, 0.038 mmol) and 10% Pd/C
(3.6 mg) in EtOAc (1 mL) was stirred under H2 (1 atm)
at ambient temperature for 24 h. Solids were filtered off.
The filtrate was concentrated by rotary evaporation and
purified by column chromatography (1∶1, PE/EtOAc,
V/V) to give 25－27 as a white solid (9 mg, 0.029 mmol,
76%). Data for 25: [α]26 –157.4 (c 0.56, CHCl3). M.p.:
D
1
160－161 ℃. H NMR (400 MHz, CDCl3) δ: 7.43－
7.18 (m, 10H), 5.59 (s, 1H), 4.22 (t, J＝3.9 Hz, 1H),
3.87 (d, J＝11.5 Hz, 1H), 3.29 (dd, J＝14.1, 3.6 Hz,
1H), 3.17 (dd, J＝12.9, 3.1 Hz, 1H), 3.14 (s, 3H), 2.91
(dd, J＝13.5, 2.7 Hz, 1H), 0.78 (dd, J＝13.3, 11.7 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ: 165.62, 165.33,
136.08, 134.79, 130.40, 129.13, 129.04, 128.94, 127.76,
127.15. 63.05, 56.77, 40.55, 36.56, 33.16; FT-IR (film
of a solution in CHCl3) ν: 3479, 3226, 2931, 1658, 1454,
1338, 1249, 746, 701 cm–1; ESI-MS m/z 309.3 ([M＋H]
＋ ); ESI-HRS calcd for C19H20N2NaO2 ([M＋Na]＋ )
331.1417, found 331.1419.
0.007 mmol, 9%).
1
Data for 10: [α]22 –62.3 (c 1.0, CHCl3). H NMR
D
(500 MHz, CDCl3) δ: 7.36－7.10 (m, 20H), 5.47 (d, J＝
9.3 Hz, 0.3H), 5.25 (d, J＝9.0 Hz, 0.7H), 5.15 (dt, J＝
3.9, 7.1 Hz, 1H), 5.04－4.97 (four doublets of different
intensities, a part of an AB system from different con-
formers, J＝12.5 Hz, 2H altogether), 4.97 (dd, J＝9.4,
5.5 Hz, 0.1H), 4.85 (q, J＝7.2 Hz, 0.9H), 4.78 (dt, J＝
7.3, 6.8 Hz, 0.8H), 4.74－4.69 (m, 1H), 4.42 (br t, J＝
8.4 Hz, 1H), 4.14 (dd, J＝9.0, 2.7 Hz, 1H), 3.29 (dd,
J＝14.3, 5.6 Hz, 1H), 3.26 (dd, J＝13.5, 3.1 Hz, 1H),
3.05－2.89 (m, 3H), 2.81 (s, 3H), 2.79－2.72 (m, 2H),
1.53－1.42 (m, 5H), 1.33－1.27 (m, 1H), 1.24－1.18
(m, 1H), 1.13 (d, J＝7.1 Hz, 3H), 0.87 (t, J＝7.3 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ: 171.54, 170.47,
169.70, 155.40, 153.58, 136.76, 136.40, 136.08, 135.07,
129.44, 129.39, 128.97, 128.85, 128.48, 128.47, 128.43,
128.07, 127.86, 127.41, 127.30, 126.88, 126.77, 75.33,
66.67, 66.44, 59.68, 55.34, 51.93, 51.63, 47.17, 38.86,
37.95, 34.62, 32.14, 18.24, 13.88, 13.88, 13.85, 12.88,
11.96. FT-IR (film) ν: 3304, 3029, 2690, 1778, 1719,
1649, 1454, 1215, 1050, 753, 700 cm–1. ESI-MS m/z
Data for 26: [α]2D6 –71.8 (c 0.83, CHCl3). M.p.: 210
－211 ℃. 1H NMR (500 MHz, CDCl3) δ: 7.35－6.35 (s,
10H), 5.45 (s, 1H), 4.13 (t, J＝4.0 Hz, 1H), 3.30 (dd,
J＝13.9, 3.1 Hz, 1H), 3.24 (dd, J＝13.9, 3.6 Hz, 1H),
3.14 (dd, J＝13.9, 4.5 Hz, 1H), 3.07 (s, 3H), 2.59 (dd,
J＝10.7, 3.1 Hz, 1H), 2.51 (dd, J＝13.9, 10.7 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ: 167.54, 166.26, 135.63,
134.49, 129.96, 129.08, 128.88, 128.80, 127.78, 127.41,
64.01, 53.74, 38.20, 36.74, 32.94; FT-IR (film of a solu-
tion in CHCl3) ν: 3241, 1680, 1643, 1454, 1444, 1345,
699 cm–1. ESI-MS m/z: 309.1 ([M＋H]＋); ESI-HRS
calcd for C19H20N2NaO2 ([M＋Na]＋) 331.1417 , found
331.1407.
(S)-Methyl 2-((S)-2-amino-3-phenylpropanamido)-3-
phenylpropanoate (28)
A mixture of 6' (10 mg, 0.021 mmol) and 10% Pd/C
(3.6 mg) in EtOAc (0.5 mL) was stirred under H2 (1 atm)
at ambient temperature for 24 h. Solids were filtered off.
The filtrate was concentrated by rotary evaporation to
give 28 as a colorless oil (8 mg, 0.024 mmol, 114%
826.6 ([M＋Na]＋), 804.6 ([M＋H]＋); ESI-HRS calcd
＋
for C47H53N3NaO9 ([M ＋ Na] ) 826.3674, found
826.3677.
crude yield). Data for 28: [α]27 –7.2 (c 0.33, CHCl3). 1H
D
NMR (500 MHz, CDCl3) δ: 7.70－7.04 (m, 10H), 4.87
(dt, J＝8.2, 6.3 Hz, 1H), 3.70 (s, 3H), 3.67 (dd, J＝8.8,
4.4 Hz, 1H), 3.16 (dd, J＝13.9, 4.4 Hz, 1H), 3.12 (dd,
J＝14.4, 6.5 Hz, 1H) 3.06 (dd, J＝13.8, 6.6 Hz, 1H),
2.66 (dd, J＝13.7, 9.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 173.74, 171.89, 137.58, 135.91, 129.29,
129.19, 128.64, 128.40, 126.96, 126.79, 56.13, 52.63,
52.17, 40.67, 38.05. FT-IR (film) ν: 3326, 3028, 2951,
2925, 2360, 2342, 1743, 1670, 1507, 1497, 1213, 1178 ,
745, 701 cm–1. ESI-MS m/z 327.1 ([M＋H]＋); ESI-HRS
calcd for C19H23N2O3 ([M ＋ H] ＋ ) 327.1703, found
327.1707.
References
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[5] One of us (Y.-K. Wu) apologizes for the failure to detect those prob-
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have already been caused by the publication of that work. Those da-
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in this work should be ignored altogether.
Chin. J. Chem. 2017, XX, 1—10
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
9

Zhao, Wu & Li
FULL PAPER
[6] Park, J. D.; Lee, K. J.; Kim, D. H. Bioorg. Med. Chem. 2011, 9, 237.
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(Zhao, X.)
10
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Chin. J. Chem. 2017, XX, 1—10