Total synthesis of reblastatin: Convenient preparation of coupling partners and scaled assembly

Article abstract of DOI:10.1016/j.tet.2014.03.020

Potentially scalable total synthesis of reblastatin was achieved based on Panek's previous study. Novel and convenient synthetic routes were developed for the known C8-C20 and C1-C7 coupling partners. The challenging C8-C20 fragment was prepared from TBS

Full text of DOI:10.1016/j.tet.2014.03.020

Tetrahedron 70 (2014) 2982e2991
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Total synthesis of reblastatin: convenient preparation of coupling
partners and scaled assembly
*
Chuancai Bian, Rui Yan, Xiaoming Yu
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College & Chinese
Academy of Medical Sciences, No. 1 Xiannongtan St., Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 January 2014
Received in revised form 25 February 2014
Accepted 6 March 2014
Available online 14 March 2014
Potentially scalable total synthesis of reblastatin was achieved based on Panek’s previous study. Novel
and convenient synthetic routes were developed for the known C8eC20 and C1eC7 coupling partners.
The challenging C8eC20 fragment was prepared from TBS protected (S)-5-(hydroxymethyl)dihy-
drofuran-2(3H)-one (6) in nine steps (20% overall yield), and the C1eC7 fragment was synthesized from
commercially available 3,4,6-tri-O-acetyl-D-glucal (9) in eight steps (35% overall yield). On a larger scale,
Panek’s eight-step assembly of the target molecule from the two partners was also slightly modified,
giving 45 mg reblastatin (19% overall yield) in the first batch synthesis. Notable feature of our study is the
settlement of the C14 chirality through a diastereoselective a-alkylation of 6 followed by a three-step full
reduction of the lactone carboxyl, making vastly available 6 a universally applicable C11eC14 synthon for
benzenoid/benzoquinone ansamycins.
Keywords:
Benzenoid/benzoquinone ansamycin
Reblastatin
Total synthesis
Hsp90 inhibitor
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
(OSM) mediated pathways in HepG2 B6 cells (IC50 0.16 m
M),2 in-
dicating its potential for treatment of cancer and rheumatoid ar-
thritis. The closely related natural product geldanamycin (2, Fig.1) is
a well-known heat shock protein 90 (Hsp90) inhibitor, and several
of its semisynthetic derivatives are now clinically investigated as
cancer chemotherapeutics.3 Similar to compound 2, reblastatin 1 is
also an ATPase inhibitor of Hsp90,4b but the structural difference
between the two molecules are of great pharmaceutical signifi-
cance. For example, reblastatin 1 should have lower hepatotoxicity
because of the embedment of a redox-inactive phenolic aromatic
core. And secondly, the saturated C4 and C5 in 1, which may account
for its higher molecular affinity to Hsp90,5 also make the compound
more stable. For these reasons, we became interested in a scalable
synthesis of 1 to support in vivo studies on its toxicological profiles
and therapeutic effects, and to this end a sub-gram (0.1e1 g) sample
is usually required.
Benzenoid ansamycin reblastatin (1, Fig. 1) was first isolated
from the culture of Streptomyces hygroscopicus sub sp. hygroscopicus
SANK 61995 by Takatsu,1 and then by Stead from that of Streptomyces
sp. S6699.2 This compound showed considerable anti-proliferative
activity against human histiocytic lymphoma U-937 cells (IC50
0.43 mg/mL or 0.78 m
M)1 and inhibitory effect against Oncostatin M
Panek and co-workers accomplished so far the only total syn-
thesis of reblastatin (Scheme 1),4 which also stands for the first
example of convergent synthesis within the benzenoid/benzoqui-
none ansamycin family.6 Their synthesis started with an enantio-
selective formal [4þ2] cycloaddition of benzaldehyde 3 and a chiral
crotylsilane developed in the authors’ own laboratory.4b This robust
method helped address the challenging C14 configuration with high
efficiency and enabled construction of the four-chiral-centered
C8eC20 fragment 4 in 12 steps. More remarkable to us, however,
is the late stage assembly of the target molecule. Two key steps,
namely a ZrH/Zn mediated highly diastereoselective reductive
Fig. 1. Structures of reblastatin 1 and geldanamycin 2.
* Corresponding author. Tel.: þ86 10 63165259; fax: þ86 10 63017757; e-mail
address: mingxyu@imm.ac.cn (X. Yu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.020

C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
2983
Scheme 1. Panek’s total synthesis of reblasatin.
coupling of alkyne 4 and aldehyde 5, and an unprecedented Hart-
wigeBuchwald type macrolactam ring-closure, were included in
the eight-step sequence that finally delivered reblastatin 1 in 13%
overall yield. These excellent achievements undoubtedly formed
solid foundation for a scalable synthesis, but we were in short of the
supply of Panek’s crotylsilane. We therefore developed an alterna-
tive approach to 4 and 5 that may feature the easy availability of
starting material. In addition, the reported method for assembly 4
and 5 to reblastatin 1 was also slightly modified.
2. Results and discussion
As shownin Scheme 2, weplanned tostartour synthesis of 4 with
a substrate-induced trans-selective a-alkylation of chiral g-lactone
Scheme 2. The retro-synthetic analysis of 4 and 5.

2984
C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
6,7 a compound that is readily prepared from cheap
L
-glutamic acid.
at ꢀ78 ꢁC, trans-substituted lactone 11 could be isolated in 82%
yield. The relative stereochemistry of 11 was confirmed by NOE.
In order to realize a short transformation of the lactone carboxyl
in 11 into the expected C14 methyl group through Caglioti re-
duction,9 the compound was firstly reduced into hemiketal 12 (90%
yield) using DIBAL-H, and then heated with tosylhydrazine (Scheme
4) to form tosylhydrazone 13 (85% yield). Due to its tautomerism
and potential cyclization from the neighboring hydroxyl group, this
compound (a single spot by TLC) was applied to next step without
full characterization. Upon treatment with catecholborane at room
temperature and heating the resulting mixture in THF with
NaOAc$3H2O, the hydrazone functionality was fully reduced to
a methyl group, giving the key intermediate 14 in a delightful 67%
yield. In comparison to a regular transformation through a 1,4-diol
intermediate, this new protocol is advantageous in terms of step-
economy since no hydroxyl protection is needed. More signifi-
cantly in this case is that it enabled the utilization of vastly available
lactone 6 as the C11eC14 synthon, so that the structurally complex
Provided full reduction of the lactone carboxyl could be realized
with ease, such design would be advantageous in its convenience of
settling the C14 chirality. Further establishment of the C10eC11
chirality and introduction of the C8eC9 alkyne tail in 4 was expected
to be achieved by making use of chiral allenylstannane (S)-8,6n
a reagent that is easy to prepare in multi-gram-scale and fairly sta-
ble on storage. The C1eC7 fragment 5 (Scheme 2), on the other hand,
had been synthesized with ease,4 but our retro-synthetic analysis
suggested that commercially available 3,4,6-tri-O-acetyl- -glucal 9
could also be a suitable starting material, and as such a low tem-
perature reduction using DIBAL-H could be circumvented.
According to the synthetic plan, we first prepared benzyl bro-
mide 78 from aldehyde 34 (Scheme 3). Interestingly, both 7 and 10
readily form crystals in ethanol, and therefore could be obtained in
large quantity without chromatography. The anticipated trans-
selective alkylation of 6 with 7 was then carried out using LDA as
base (Scheme 4) in THF at ꢀ78 ꢁC. When the reaction was quenched
D
Scheme 3. Preparation of benzyl bromide 7. Reagents and conditions: (a) NaBH4, MeOH, 0 ꢁC to rt, 91%; (b) PBr3, DCM, 0 ꢁC to rt, 80%.
Scheme 4. Preparation of the C8eC20 fragment 4. Reagents and conditions: (a) LDA, 7, THF, ꢀ78 ꢁC, 82%; (b) DibaleH, toluene, ꢀ78 ꢁC, 90%; (c) H2NeHNTs, 4 A MS, MeOH, 55 ꢁC,
85%; (d) catecholborane, THF, 0 ꢁC to rt, then NaOAc$3H2O, reflux, 67%; (e) Me3Oþ$BF4ꢀ, proton sponge, DCM, 0 ꢁC to rt, 88%; (f) hydrogen fluorideepyridine, pyridine, CH3CN, 0 ꢁC to
rt, 90%; (g) (COCl)2, DMSO, Et3N, DCM, ꢀ78 ꢁC, 95%; (h) 8, BF3$OEt2, DCM, ꢀ78 ꢁC, 78%, dr 10:1; (i) DIPEA, TBAI, DMAP, MOMCl, DCM, 0 ꢁC to rt, then refluxing, 87%.
ꢀ

C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
2985
building block 4 could be produced at low cost. In sense of the
growing number of newly discovered benzenoid/benzoquinone
ansamycins that share a common C8eC14 structural feature,3 this
expedient strategy will find its extended application.
Further elaboration of aldehyde 17 from mono-protected diol 14
was straightforward. Upon O-methylation using Meerwein’s salt
(15), TBS removal using pyridinium hydrogen fluoride (16) and
subsequent Swern oxidation,17 was obtained in 73% yield over three
steps with the spectra data well matching the previous report4a
(Scheme 4).
yield and then oxidized with NaIO4 to give the aldehyde 5. The
spectra data and optical rotation of this compound well matched
the previous report.4
With the above accomplishment in developing the synthesis of
alkyne 4 and aldehyde 5, we literally finished a formal total syn-
thesis of reblastatin. However, we were concerned firstly for the
purity issue of our sample of 4, and secondly the reproducibility of
Panek’s assembly of the target molecule, in particular the yield, as
their late stage synthesis was described on the basis of a series of
10-mg reactions.4 Hence, the one-pot hydrozirconation/trans-
metalation of 4 and its subsequent addition to 5 was performed
according to their procedure, but on a much larger scale (400 mg of
4). As we had expected, the impurity in 4 did not cause problem at
this moment, and pure 25 was obtained in 66% yield. The medium
yield could be attributed to incomplete conversion of 4 since 25% of
cis-olefin 4a (contaminated by its isomers, Scheme 6) was formed
in the reaction. Optimization was attempted by adding extra
dimethylzinc or prolonging the time for Zr/Zn exchange, but the
ratio of isolated 25/4a kept unchanged, indicating that incomplete
Zr/Zn exchange was not the reason.
With enough quantity of 25 in hand, our journey to 1 was
continued following Panek’s route (Scheme 6).4 After smooth TBS
protection of the C7eOH (26) and hydrolysis of the ethyl ester (27),
we were facing the same problem as it was previously noted.4a The
reported amidation method failed to give complete conversion of
acid 27 into 28, and the latter was isolated in <50% yield with re-
covery of >30% of 27. To avoid the tedious recovery and retreatment
procedure, better conditions were sought and finally led to the
isolation of 28 in 80% yield by treating 27 with Boc2O/NH4HCO3 in
dioxane and pyridine.11 More delightfully, the copper(I)-mediated
macrolactam ring-closure of 28 proved well reproducible. Al-
though in our case the use of excessive cuprous iodide seemed
necessary to drive the reaction into completion, the yield of 29 was
nearly identical to that reported by Panek. The remaining steps
from 29 to 1 were straightforward using the known protocols,
giving the target molecule in ca. 60% yield over three steps. These
Similar to that reported by Micalizio,6n the carbon chain elon-
gation from aldehyde 17 was achieved by asymmetric prop-
argylation using S-configured allenylstannane 8 (Scheme 4). A
gram-scale reaction of 17 and 8 was carried out in the presence
of boron trifluorideetherate, affording an approximate 10:1 mixture
of the expected homopropargyl alcohol 18 and its stereoisomer in
78% total yield. Unfortunately, the two isomers were inseparable by
silica gel chromatography, even after protection of the C10 hydroxyl
with a MOM. However, this minor isomer coexisting with 4 may not
affect the assembly of the target molecule and could be possibly
removed during the following sequence. In a word, we were sat-
isfied with the cost efficiency and scalability of this synthetic route
to produce the key intermediate 4, as the yield over the nine steps
(from 6 to 4) was up to 20%.
To prepare the C1eC7 fragment 5 (Scheme 5), commercially
available tri-O-acetyl- -glucal 9 was heated in water as it was de-
D
scribed,10 giving hemiketal 19 in 81% yield. Compound 19 was hy-
drogenated and the saturated hemiketal was subjected without
purification to a Wittig reaction with phosphorus ylide 20. The
resulting a,b-unsaturated ester from the Wittig reaction was then
directly hydrolyzed with K2CO3/EtOH to provide triol 21 in 71%
yield over three steps. Acetonide protection of 21 with 2,2-
dimethoxypropane in the presence of catalytic amount of PPTS
produced a 5:1 mixture of 22 and 22a, with the isolation of the
former in 71% yield. After methylation of 22 with Meerwein’s salt
and subsequent acidic hydrolysis, diol 24 was obtained in good
Scheme 5. Preparation of the C1eC7 fragment 5. Reagents and conditions: (a) H2O, 80 ꢁC, 81%; (b) 10% Pd/C, EtOAc, rt; (c) 20, THF, reflux; (d) K2CO3, EtOH, H2O, 71% over three steps;
(e) 2,2-dimethoxypropane, PPTS, acetone, 71% 22 and 14% 22a; (f) Me3Oþ$BF4ꢀ, proton sponge, DCM, 0 ꢁC to rt, 90%; (g) 1 N HCl, CH3CN, 96%; (h) NaIO4, acetone/H2O (1/1), 98%.

2986
C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
Scheme 6. The assembly of reblastatin. Reagents and conditions: (a) Cp2ZrHCl, 50 ꢁC, ZnMe2 at ꢀ78 ꢁC, then 5 at 0 ꢁC, toluene, 66% for 25 and 25% for 4a; (b) TBSOTf, 2,6-lutidine,
DCM, 0 ꢁC, 80%; (c) LiOH$H2O, THF/MeOH/H2O (2/2/1), 94%; (d) Boc2O, 1,4-dioxane/pyridine (50/1), then NH4HCO3, 80%; (e) N,N0-dimethyl-1,2-ethanediamine, K2CO3, CuI, toluene,
100 ꢁC, 82%; (f) pyridine hydrofluoride/pyridine/THF¼1:1:2.5, 90%; (g) trichloroacetyl isocyanate, DCM, then MeOH, K2CO3, 76%; (h) AlCl3, anisole, DCM, ꢀ78 ꢁC to rt, 86%.
results provided solid experimental evidence that the previous
report was well reproducible, and by modifying the synthesis of
amide 28, the overall yield of the assembly was significantly ele-
vated (from 13% to 19%).
distillation over sodium and benzophenone. Aldehyde 3,4
g-lactone
6,12 and chiral allenylstannane (S)-813 were prepared as previously
reported.
4.2. (3-(Benzyloxy)-5-bromo-2-methoxyphenyl)methanol
(10)8
3. Conclusion
Convenient approaches to the two known coupling partners of
reblastatin, i.e., the C8eC20 fragment 4 and C1eC7 fragment 5,
were described. Notably, our synthesis of 4 features the settlement
To a stirred solution of 3 (9.00 g, 28.0 mmol) in MeOH (95 mL)
was added NaBH4 (2.13 g, 56.0 mmol) in portions at 0 ꢁC. The
resulting mixture was stirred at 0 ꢁC for 1 h, and then at room
temperature overnight. The solution was adjusted to pH 7 using
AcOH and concentrated under reduced pressure. The residue was
dissolved in DCM (100 mL) and washed with saturated aqueous
NaHCO3 (50 mL). The layers were separated and the aqueous phase
was extracted with DCM (3ꢂ50 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated un-
der reduced pressure. The residue was recrystallized from ethanol
to afford the title compound as a white solid in 91% yield (8.25 g,
of the challenging C-14 stereochemistry through
a simple
substrate-induced asymmetric alkylation of inexpensive chiral
g-
lactone 6. By taking advantage of the Caglioti reduction of hemi-
ketal intermediate 12, we successfully realized a fast trans-
formation of the lactone carboxyl into the expected C-14 methyl.
These results suggested that this lactone strategy could be appli-
cable to the synthesis of other benzenoid/benzoquinone ansamy-
cins. In addition, we were able to reproduce the late stage assembly
of reblastatin previously reported by Panek, with one of the steps
improved and on a >20 fold larger scale. Our first run of the eight-
step synthetic sequence from 4 and 5 delivered 45 mg of the final
product in 19% overall yield, indicating sub-gram supply of
reblastatin by chemical synthesis is possible.
24.8 mmol). Mp: 83e85 ꢁC. 1H NMR (400 MHz, CDCl3)
d¼7.47e7.30
(m, 5H), 7.11 (d, J¼1.5 Hz, 1H), 7.06 (d, J¼1.5 Hz, 1H), 5.07 (s, 2H),
4.66 (s, 2H), 3.88 (s, 3H), 2.10 (br, 1H); 13C NMR (100 MHz, CDCl3)
d
¼152.4, 146.6, 136.5, 136.4, 128.9, 128.4, 127.6, 123.9, 117.3, 116.5,
71.3, 61.2, 61.1; IR (neat) 3320, 1476, 1291, 1218, 1028, 748,
699 cmꢀ1; HRMS (EI) m/z calcd for C15H15BrO3 Mþ 322.0205, found
322.0185.
4. Experimental section
4.1. General methods and materials
4.3. 1-(Benzyloxy)-5-bromo-3-(bromomethyl)-2-
methoxybenzene (7)
Unless otherwise indicated, 1H NMR data were recorded in
CDCl3 at 300 and 400 MHz with calibration of spectra to residual
CDCl3 (7.26 ppm), and 13C NMR data were recorded at 75 and
100 MHz with calibration to the central line of CDCl3 (77.00 ppm).
All reactions were conducted in oven-dried glassware under an
argon atmosphere with dry solvents, unless otherwise noted. DCM,
pyridine, and 1,4-dioxane were dried by passing through activated
alumina column. Anhydrous toluene, Et2O, and THF were dried by
To a stirred solution of 10 (8.25 g, 24.8 mmol) in anhydrous DCM
(60 mL) was added PBr3 (2.17 mL, 22.9 mmol) dropwisely at 0 ꢁC.
Once addition completed, the solution was warmed to room tem-
perature and stirred for 4 h before it was quenched with water
(30 mL). The layers were separated and the aqueous layer was
extracted further with DCM (3ꢂ30 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and

C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
2987
concentrated under reduced pressure. The residue was recrystal-
4.6. N0-((2R,4S)-2-(3-(Benzyloxy)-5-bromo-2-
lized from ethanol to afford the title compound as a white solid in
methoxybenzyl)-5-((tert-butyldimethylsilyl)oxy)-4-hydroxy-
pentylidene)-4-methylbenzenesulfonohydrazide (13)
80% yield (7.87 g, 20.4 mmol). Mp: 73e75 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
¼7.50e7.31 (m, 5H), 7.11 (s, 1H), 7.06 (s, 1H), 5.07 (s, 2H),
4.47 (s, 2H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
¼152.7, 147.3,
To a stirred solution of 12 (6.99 g, 13.0 mmol) in anhydrous
MeOH (120 mL) was added p-tosylhydrazine (4.83 g, 26.0 mmol)
136.3, 133.7, 128.9, 128.5, 127.6, 125.7, 118.1, 116.1, 71.3, 61.2, 27.2; IR
(neat) 2942, 1481, 1304, 1233, 1058, 748, 698 cmꢀ1; HRMS (ESI) m/z
calcd for C15H15Br2O2 (MþH)þ 384.9439, found 384.9457.
ꢀ
and powdered 4 A molecular sieve (2.60 g). The suspension was
heated at 55 ꢁC under stirring for 16 h and then filtered through
a pad of Celite. The filtrate was concentrated under reduced pres-
sure, and the residue was purified by flash column chromatography
(1:30 to 1:10, EtOAc/hexanes) to give a pale yellow foam in 85%
4.4. (3R,5S)-3-(3-(Benzyloxy)-5-bromo-2-methoxybenzyl)-5-
(((tert-butyldimethylsilyl)oxy)methyl)dihydrofuran-2(3H)-
one (11)
yield (7.76 g, 11.0 mmol). [
a
]
20 ꢀ15.4 (c 1.45, CHCl3); HRMS (ESI) m/z
D
calcd for C33H46BrN2O6Si (MþH)þ 705.2029, found 705.1983.
An oven-dried three-neck flask was purged with argon and
charged with LDA (15.2 mL, 2.0 M solution in THF, 30.4 mmol) and
anhydrous THF (65 mL) at ꢀ78 ꢁC. A solution of 6 (5.14 g,
22.4 mmol) in THF (15 mL) was added slowly through a syringe
under stirring. The resulting mixture was stirred for 1 h at ꢀ78 ꢁC,
and then 7 (7.87 g, 20.4 mmol) in THF (10 mL) was added drop-
wisely. After stirring was continued at ꢀ78 ꢁC for additional 0.5 h,
the reaction was quenched by slow addition of saturated aqueous
NH4Cl at ꢀ78 ꢁC and gradually warmed to room temperature. The
resulting mixture was extracted with EtOAc (3ꢂ50 mL). The com-
bined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by flash column chromatography (1:100 to 1:20, EtOAc/hexanes) to
4.7. (2S,4R)-5-(3-(Benzyloxy)-5-bromo-2-methoxyphenyl)-1-
((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-ol (14)
Compound 13 (7.30 g, 10.3 mmol) obtained from last step was
dissolved in anhydrous THF (60 mL) under argon and cooled to 0 ꢁC.
Catecholborane (31.0 mL, 31.0 mmol, 1.0 M in THF) was added
dropwisely through a syringe. The solution was stirred for 15 min at
0
ꢁC, and then 2 h at room temperature. NaOAc$3H2O (12.7 g,
93.0 mmol) was then added in one portion and the reaction mix-
ture was heated at reflux for 12 h. After that, the solution was
cooled to room temperature, diluted with Et2O (70 mL), and
washed with 1M NaOH (2ꢂ50 mL). The aqueous washes were
extracted with Et2O (2ꢂ50 mL), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (1:30, EtOAc/hexanes) to afford the desired compound as
yield a light yellow oil in 82% yield (8.97 g, 16.7 mmol). [
a
]
20 þ6.15
D
(c 1.36, CHCl3); 1H NMR (500 MHz, CDCl3)
d¼7.46e7.30 (m, 5H),
7.01 (d, J¼1.9 Hz, 1H), 6.93 (d, J¼1.9 Hz, 1H), 5.05 (s, 2H), 4.48 (m,
1H), 3.83 (s, 3H), 3.81 (d, J¼2.9 Hz, 1H), 3.60 (dd, J¼11.3, 2.8 Hz, 1H),
3.21 (dd, J¼13.6, 4.6 Hz, 1H), 3.12 (m, 1H), 2.66 (dd, J¼10.3, 13.5 Hz,
1H), 2.14 (m, 1H), 2.01 (m, 1H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR
a colorless oil in 67% yield (3.65 g, 6.96 mmol). [
a
]
20 ꢀ4.95 (c 1.01,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d¼7.49e7.29 (m, 5H), 6.96 (d,
J¼2.0 Hz, 1H), 6.93 (d, J¼1.9 Hz, 1H), 5.06 (s, 2H), 3.81(s, 3H),
3.77(m, 1H), 3.62 (dd, J¼9.9, 3.2 Hz, 1H), 3.38 (dd, J¼9.5, 7.7 Hz, 1H),
2.61 (dd, J¼6.3, 13.2 Hz, 1H), 2.47 (dd, J¼8.2, 13.2 Hz, 1H), 2.02 (m,
1H), 1.50 (m, 1H), 1.14 (m, 1H), 0.91 (m, 12H), 0.07 (s, 6H); 13C NMR
(100 MHz, CDCl3)
d
¼179.1, 152.7, 147.3, 136.5, 134.6, 128.9, 128.4,
127.6, 125.4, 116.4, 116.3, 78.4, 71.2, 65.3, 60.9, 40.6, 31.3, 29.9, 26.0,
18.5, ꢀ5.3, ꢀ5.4; IR (neat) 3034, 2931, 1771, 1573, 1479, 1258,
839 cmꢀ1; HRMS (ESI) m/z calcd for C26H35BrNaO5Si (MþNa)þ
557.1335, found 557.1329.
(100 MHz, CDCl3)
d
¼152.7, 147.4, 137.1, 136.7, 128.8, 128.3, 127.6,
126.0, 115.9, 115.5, 71.1, 69.9, 68.0, 60.8, 39.9, 38.0, 30.8, 26.1, 19.6,
18.5, ꢀ5.1, ꢀ5.2; IR (neat) 3472, 3033, 2929, 1573, 1475, 1255, 1092,
837 cmꢀ1; HRMS (ESI) m/z calcd for C26H39BrNaO4Si (MþNa)þ
545.1699, found 545.1711.
4.5. (3R,5S)-3-(3-(Benzyloxy)-5-bromo-2-methoxybenzyl)-5-
(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-furan-2-ol
(12)
4.8. (((2S,4R)-5-(3-(Benzyloxy)-5-bromo-2-methoxyphenyl)-
2-methoxy-4-methylpentyl)oxy)(tert-butyl)dimethylsilane
(15)
To a stirred solution of 11 (7.80 g,14.6 mmol) in dry toluene
(50 mL) was dropwisely added diisobutylaluminum hydride
(14.6 mL, 1.2 M in toluene, 17.5 mmol) at ꢀ78 ꢁC under argon. The
reaction mixture was stirred at ꢀ78 ꢁC for 2 h and quenched by
slow addition of MeOH (10 mL). The solution was allowed to warm
to room temperature, diluted with EtOAc (50 mL), and stirred with
saturated aqueous sodium/potassium tartrate (100 mL) for 2 h. The
resulting clear biphasic solution was separated, and the aqueous
phase was extracted with EtOAc (3ꢂ50 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chro-
To a stirred solution of 14 (3.20 g, 6.1 mmol) in DCM (70 mL) was
ꢀ
added powdered 4 A molecular sieves (1.93 g), proton sponge
(3.92 g,18.3 mmol), and Me3Oþ$BFꢀ4 (2.71 g,18.3 mmol) at 0 ꢁC. The
mixture was stirred for 0.5 h at 0 ꢁC and 8 h at room temperature
(monitored by TLC until total consumption of the starting material).
The resulting mixture was filtered over Celite, and the filtrate was
washed with 1 M aqueous CuSO4 (70 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (1:100 to 1:50, EtOAc/hexanes) to
matography (1:100 to 1:20, EtOAc/hexanes) to yield a clear oil in
20
90% yield (6.99 g, 13.0 mmol). [
a]
ꢀ2.16 (c 1.20, CHCl3). The
afford a colorless oil in 88% yield (2.91 g, 5.43 mmol). [
a
]
20 ꢀ8.61 (c
D
D
spectra of the major isomer: 1H NMR (400 MHz, CDCl3)
1.51, CHCl3); 1H NMR (500 MHz, CDCl3)
d¼7.48e7.32 (m, 5H), 6.97
d
¼7.52e7.31 (m, 5H), 6.99 (d, J¼2.2 Hz, 1H), 6.92 (d, J¼2.0 Hz, 1H),
(s,1H), 6.93 (s,1H), 5.06 (s, 2H), 3.84 (s, 3H), 3.66 (dd, J¼10.6, 5.6 Hz,
1H), 3.56 (dd, J¼10.5, 4.7 Hz,1H), 3.45 (s, 3H), 3.34 (m, 1H), 2.62 (dd,
J¼13.2, 6.1 Hz, 1H), 2.45 (dd, J¼13.2, 8.6 Hz, 1H), 2.01 (m, 1H), 1.53
(m, 1H), 1.30 (m, 1H), 0.97e0.87 (m, 12H), 0.09 (s, 6H); 13C NMR
5.11 (s, 1H), 5.06 (s, 2H), 4.42 (t, J¼7.6 Hz, 1H), 3.94e3.75 (m, 4H),
3.52 (m, 1H), 2.72 (m, 1H), 2.58e2.41 (m, 2H), 2.14 (m, 1H), 1.65 (dd,
J¼12.7, 7.9 Hz, 1H), 0.89 (m, 9H), 0.22 (s, 6H). 13C NMR (100 MHz,
CDCl3)
d¼152.8, 147.4, 136.7, 135.6, 128.9, 128.4, 127.6, 125.7, 116.2,
(100 MHz, CDCl3)
d
¼152.7, 147.4, 137.2, 136.8, 128.9, 128.3, 127.6,
115.9, 102.4, 79.6, 71.2, 65.0, 60.9, 48.7, 32.3, 28.2, 26.1, 18.6, ꢀ5.2,
ꢀ5.4; IR (neat) 3415, 3036, 2929, 1573, 1476, 1256, 839 cmꢀ1; HRMS
(ESI) m/z calcd for C26H37BrNaO5Si (MþNa)þ 559.1491, found
559.1484.
126.1, 115.9, 115.5, 80.1, 71.1, 66.0, 60.8, 58.3, 39.4, 38.1, 30.9, 26.2,
19.7, 18.6, ꢀ5.0, ꢀ5.1; IR (neat) 3033, 2930, 1573, 1475, 1255, 1101,
838 cmꢀ1; HRMS (ESI) m/z calcd for C27H41BrNaO4Si (MþNa)þ
559.1855, found 559.1844.

2988
C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
4.9. (2S,4R)-5-(3-(Benzyloxy)-5-bromo-2-methoxyphenyl)-2-
methoxy-4-methylpentan-1-ol (16)
1:10, EtOAc/hexanes) to afford a light yellow oil in 78% yield (1.08 g,
20
2.21 mmol). [
a
]
ꢀ24.4 (c 1.10, CHCl3); spectra for the major
D
component: 1H NMR (500 MHz, CDCl3)
d
¼7.46e7.30 (m, 5H), 6.95
To a stirred solution of 15 (2.70 g, 5.04 mmol) in MeCN (108 mL)
in a nalgene vial was added premixed solution of [pyridine
hydrofluoride/pyridine/CH3CN (1:1:3) by volume] (75 mL) at 0 ꢁC.
The reaction mixture was stirred for 0.5 h at 0 ꢁC and 2 h at room
temperature before 1 M aqueous HCl (170 mL) and Et2O (170 mL)
were added under stirring. The layers were separated and the
aqueous layer was extracted with Et2O (3ꢂ170 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude compound was purified by flash
column chromatography (1:10 to 1:3, EtOAc/hexanes) to afford
(d, J¼2.0 Hz, 1H), 6.94 (d, J¼2.0 Hz, 1H), 5.05 (s, 2H), 3.81 (s, 3H),
3.69 (dd, J¼9.1, 3.1 Hz, 1H), 3.60 (m, 1H), 3.38 (s, 3H), 2.60 (dd,
J¼13.3, 5.9 Hz, 1H), 2.46 (dd, J¼13.3, 8.9 Hz, 1H), 2.39 (m, 1H), 2.01
(m, 1H), 1.78 (d, J¼2.3 Hz, 3H), 1.62 (m, 1H), 1.25 (m, 1H), 1.25 (d,
J¼6.6 Hz, 3H), 0.89 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
¼152.4, 147.1, 137.0, 136.4, 128.5, 128.0, 127.3, 125.7, 115.6, 115.1,
80.1, 79.8, 77.8, 73.3, 70.8, 60.5, 56.9, 37.9, 34.8, 30.3, 28.7, 18.8, 18.4,
3.4; IR (neat) 3452, 3033, 2933, 2245, 1573, 1477, 1091, 859,
736 cmꢀ1; HRMS (ESI) m/z calcd for C26H33BrNaO4 (MþNa)þ
511.1460, found 511.1447.
a colorless oil in 90% yield (1.94 g, 4.55 mmol). [
a
]
20 þ6.88 (c 0.99,
D
CHCl3); 1H NMR (500 MHz, CDCl3)
d¼7.38 (m, 5H), 6.97 (d, J¼1.9 Hz,
4.12. 1-(Benzyloxy)-5-bromo-2-methoxy-3-((2R,4S,5R,6S)-4-
methoxy-5-(methoxymethoxy)-2,6-dimethylnon-7-yn-1-yl)
benzene (4)
1H), 6.90 (d, J¼1.9 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 3.72 (dd, J¼11.5,
3.4 Hz, 1H), 3.48 (dd, J¼11.5, 5.7 Hz, 1H), 3.40 (m, 1H), 3.40 (s,
3H),2.64 (dd, J¼13.2, 5.8 Hz, 1H), 2.37 (dd, J¼13.1, 8.8 Hz, 1H), 1.92
(m, 1H), 1.66 (m, 1H), 1.24 (m, 1H), 0.89 (d, J¼6.6 Hz, 3H); 13C NMR
MOMCl (1.34 mL,17.7 mmol) was added to the stirred solution of
18 (1.08 g, 2.21 mmol), DIPEA (4.62 mL, 26.5 mmol), TBAI (163 mg,
0.44 mmol), and DMAP (81 mg, 0.66 mmol) in DCM (18 mL) at 0 ꢁC
under argon. The reaction mixture was warmed to room temper-
ature, stirred for 0.5 h, and then heated at reflux for 8 h. After that,
the mixture was cooled to room temperature and saturated aque-
ous NaHCO3 (20 mL) was added. The two layers were separated and
the aqueous layer was extracted with DCM (3ꢂ20 mL). The com-
bined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
by flash column chromatography (1:30 to 1:20, EtOAc/hexanes) to
(100 MHz, CDCl3)
d
¼152.7, 147.3, 136.9, 136.6, 128.8, 128.3, 127.6,
126.0, 115.9, 115.6, 79.8, 71.1, 64.3, 60.8, 57.3, 38.4, 37.8, 31.0, 20.0; IR
(neat) 3426, 3032, 2931, 1573, 1477, 1221, 1094, 739 cmꢀ1; HRMS
(ESI) m/z calcd for
445.0984.
C
21H27BrNaO4 (MþNa)þ 445.0990, found
4.10. (2S,4R)-5-(3-(Benzyloxy)-5-bromo-2-methoxyphenyl)-2-
methoxy-4-methylpentanal (17)
To a stirred solution of oxalyl chloride (1.32 mL, 9.19 mmol) in
DCM (11 mL) at ꢀ78 ꢁC was added dimethyl sulfoxide (1.30
m
L,
afford a light yellow oil in 87% yield (1.02 g, 1.92 mmol). [
a]
20þ8.35
D
18.3 mmol) in DCM (11 mL) under argon. The reaction mixture was
stirred for 15 min before 16 (1.94 g, 4.55 mmol) in DCM (11 mL) was
added dropwisely. After stirring was continued for 1 h, a solution of
triethylamine (2.55 mL, 18.3 mmol) in DCM (11 mL) was added over
a period of 0.5 h. After the solution was stirred at ꢀ78 ꢁC for ad-
ditional 0.5 h, it was allowed to warm to room temperature and
saturated aqueous NaHCO3 (40 mL) was added. The layers were
separated and the aqueous phase was extracted with DCM
(3ꢂ40 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (1:20, EtOAc/hexanes) to
(c 1.03, CHCl3); spectra for the major component: 1H NMR
(500 MHz, CDCl3)
d
¼7.46e7.30 (m, 5H), 6.96 (d, J¼2.0 Hz, 1H), 6.95
(d, J¼2.0 Hz, 1H), 5.05 (s, 2H), 4.83 (d, J¼6.6 Hz, 1H), 4.66 (d,
J¼6.6 Hz, 1H), 3.81 (s, 3H), 3.68 (d, J¼8.7 Hz, 2H), 3.40 (s, 3H), 3.37
(s, 3H), 2.63 (dd, J¼13.4, 5.6 Hz, 1H), 2.47 (m, 2H), 2.01 (m, 1H), 1.77
(d, J¼3.1 Hz, 3H), 1.70 (m, 1H), 1.33 (m, 1H), 1.27 (d, J¼5.2 Hz, 3H),
0.87 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
¼152.7, 147.4,
d
137.4, 136.7, 128.8, 128.3, 127.6, 126.0, 115.9, 115.4, 97.5, 81.3, 80.9,
79.7, 78.2, 71.1, 60.8, 57.2, 56.3, 38.0, 37.0, 30.9, 28.8, 19.1, 18.8, 3.7;
IR (neat) 3033, 2930, 2824,1573, 1477, 1099, 1034,739 cmꢀ1; HRMS
(ESI) m/z calcd for
555.1730.
C
28H37BrNaO5 (MþNa)þ 555.1722, found
afford light yellow oil in 95% yield (1.84 g, 4.37 mmol). [
a
]
20 ꢀ42.6
D
(c 1.72, CHCl3); 1H NMR (400 MHz, CDCl3)
d
¼9.64 (d, J¼5.1 Hz, 1H),
7.49e7.30 (m, 5H), 6.98 (d, J¼2.3 Hz, 1H), 6.90 (d, J¼2.2 Hz, 1H), 5.07
(s, 2H), 3.82 (s, 3H), 3.66 (m, 1H), 3.43 (s, 3H), 2.60 (dd, J¼13.2,
6.5 Hz, 1H), 2.47 (dd, J¼13.2, 8.2 Hz, 1H), 2.05 (m, 1H), 1.67 (m, 1H),
1.41 (m, 1H), 0.92 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.13. (6S,7R,E)-Ethyl 6,7,8-trihydroxy-2-methyloct-2-enoate
(21)
Tri-O-acetyl- -glucal 9 (4.4 g, 16.2 mmol) was added into water
D
d
¼204.2, 152.7, 147.3, 136.6, 136.4, 128.8, 128.3, 127.6, 125.9, 116.0,
(200 mL) under vigorous stirring at 80 ꢁC. The solid melted at once
to give an oil, and then dissolved within minutes. After 1.5 h at
80 ꢁC, the solution was cooled to room temperature, and extracted
with DCM (3ꢂ200 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(1:5 EtOAc/hexanes) to afford 19 as a colorless oil in 81% yield (3.0 g,
13.04 mmol). The H NMR data matched that in the previously
report.10
115.7, 84.3, 71.1, 60.8, 58.6, 37.7, 36.7, 30.5,19.3; IR (neat) 3031, 2932,
2713, 1733, 1573, 1477, 1096, 858, 740 cmꢀ1; HRMS (ESI) m/z calcd
for C21H25BrNaO4 (MþNa)þ 443.0834, found 443.0821.
4.11. (4S,5R,6S,8R)-9-(3-(Benzyloxy)-5-bromo-2-
methoxyphenyl)-6-methoxy-4,8-dimethylnon-2-yn-5-ol (18)
An oven-dried 10 mL flask was charged with (S)-allenylstannane
8 (2.04 g, 5.70 mmol) and DCM (7 mL) at ꢀ78 ꢁC under argon. A
solution of 17 (1.20 g, 2.85 mmol) in DCM (7 mL) was added, fol-
lowed by slow addition of BF3$OEt2 (0.72 mL, 5.7 mmol) through
a syringe. The resulting solution was stirred for 0.5 h at ꢀ78 ꢁC
before saturated aqueous NaHCO3 (20 mL) was added and the
mixture was warmed up to room temperature. The two layers were
separated and the aqueous layer was extracted with Et2O
(3ꢂ20 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (1:15 to
Product from the above step (3.0 g, 13.04 mmol) was dissolved
in EtOAc (50 mL) and stirred under an atmosphere of H2 (1 atm)
overnight in the presence of 10% Pd on charcoal (0.3 g). The reaction
mixture was filtered through Celite, and the filtrate was concen-
trated under reduced pressure. The crude product was then mixed
with ylide 20 (7.02 g, 19.4 mmol) in THF (100 ml). The resulting
yellow solution was heated at reflux overnight and concentrated
under reduced pressure. Upon dissolving the residue (10 g, mixed
with triphenylphosphine oxide) in EtOH (50 mL) and H2O (5 mL),
K2CO3 (8.92 g, 64.6 mmol) was added. The mixture was stirred at

C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
2989
room temperature for 1.5 h, diluted with H2O (20 mL), and
(400 MHz, CDCl3)
d
¼6.75 (t, J¼7.4 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H),
extracted with DCM (5ꢂꢂ80 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (1:30 MeOH/DCM) to afford a white solid (2.67 g, 71% over
3.74 (m, 3H), 3.42 (s, 3H), 3.29 (m,1H), 2.30 (m, 2H),1.85 (s, 3H),1.76
(m, 1H), 1.64 (m, 1H), 1.30 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3)
d
¼168.2, 141.2, 128.4, 82.3, 72.2, 63.5, 60.5, 58.5, 28.9, 24.4,
14.3, 12.4; IR (neat) 3425, 2934, 1709, 1648, 1275, 1098 cmꢀ1; HRMS
three steps). [
a
]
20 ꢀ13.7 (c 2.36, CHCl3); 1H NMR (400 MHz, CDCl3)
(ESI) (m/z) calcd for C12H23O5 [MþH]þ 247.1540, found 247.1539.
D
d
¼6.76 (t, J¼7.5 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.86e3.72 (m, 3H),
3.60 (m, 1H), 2.45 (s, 1H), 2.35 (m, 1H), 1.86 (s, 3H), 1.70e1.60 (m,
4.17. (S,E)-Ethyl 6-methoxy-2-methyl-7-oxohept-2-enoate (5)
2H),1.30 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
¼168.2,141.0,
d
128.7, 73.7, 73.1, 63.3, 60.6, 31.7, 25.1, 14.3, 12.4; IR (neat) 3354, 3179,
1709, 1453, 1282, 1110 cmꢀ1; HRMS (ESI) (m/z) calcd for C11H21O5
[MþH]þ 233.1384, found 233.1381.
Solid NaIO4 (874 mg, 4.06 mmol) was added to a solution of diol
24 (500 mg, 2.03 mmol) in acetone (10 mL) and H2O (10.0 mL). The
reaction mixture was stirred at room temperature for 2 h before it
was diluted with H2O (20 mL) and extracted with EtOAc (3ꢂ40 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
4.14. (S,E)-Ethyl-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-6-
hydroxy-2-methylhex-2-enoate (22)
flash column chromatography (1:12, EtOAc/hexanes) to afford al-
20
2,2-Dimethoxypropane (13.2 mL) and pyridinium p-toluene-
sulfonate (135 mg, 0.54 mmol) were added to a solution of the triol
21 (2.5 g, 10.8 mmol) in acetone (80 mL). The reaction mixture was
stirred for 2.5 h and concentrated under reduced pressure. The
residue was purified by flash column chromatography (1/12 EtOAc/
hexanes) to afford 22 as a colorless oil in 71% yield (2.08 g,
7.65 mmol). A small amount of another regioisomer 22a was also
dehyde 5 as a colorless oil in 98% yield (425 mg, 1.99 mmol). [a]
D
ꢀ60.4 (c 1.68, CHCl3); 1H NMR (400 MHz, CDCl3)
d
¼9.68 (d,
J¼1.5 Hz, 1H), 6.71 (t, J¼7.5 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.56 (m,
1H), 3.46 (s, 3H), 2.31 (m, 2H), 1.84 (s, 3H), 1.80 (m, 2H), 1.30 (t,
J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
¼203.7, 168.0, 140.1,
d
129.3, 85.1, 60.6, 58.4, 28.7, 23.9, 14.4, 12.5; IR (neat) 2935, 2829,
2723, 1733, 1710, 1650, 1447, 1267, 1132, 1092 cmꢀ1; HRMS (ESI) (m/
z) calcd for C11H19O4 [MþH]þ 215.1278, found 215.1278.
isolated in 14% yield (0.42 g, 1.54 mmol). [
a
]
20 þ5.7 (c 1.22, CHCl3);
D
1H NMR (400 MHz, CDCl3)
d
¼6.74 (t, J¼7.5 Hz, 1H), 4.19 (q, J¼7.1 Hz,
2H), 4.03 (m, 1H), 3.97 (m, 1H), 3.90 (m, 1H), 3.78 (m, 1H), 2.36 (m,
2H), 1.86 (s, 3H), 1.59 (m, 1H), 1.50 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H),
4.18. (2E,6S,7S,8E,10S,11R,12S,14R)-Ethyl-15-(3-(benzyloxy)-5-
bromo-2-methoxyphenyl)-7-hydroxy-6,12-dimethoxy-11-
(methoxymethoxy)-2,8,10,14-tetramethylpentadeca-2,8-
dienoate (25)
1.29 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
¼168.1, 140.9,
d
128.7, 109.1, 78.6, 70.1, 64.5, 60.5, 31.4, 26.5, 25.3, 24.9, 14.3, 12.4; IR
(neat) 3485, 2985, 1709, 1649, 1370, 1264, 1067 cmꢀ1; HRMS (ESI)
(m/zm/z) calcd for C14H25O5 [MþH]þ 273.1697, found 273.1691.
To a stirred solution of 4 (420 mg, 0.787 mmol) in toluene (7 mL)
under argon was added Cp2ZrHCl (425 mg, 1.65 mmol). The re-
action mixture was heated at 50 ꢁC for 6 h, and then cooled to
ꢀ78 ꢁC. A solution of dimethylzinc (0.98 mL, 1.20 M in toluene) was
added dropwisely and the solution was warmed to 0 ꢁC. Aldehyde 5
(253 mg, 1.18 mmol) in toluene (1 mL) was added dropwisely and
the resulting mixture was stirred for an additional hour at 0 ꢁC
before it was quenched with saturated aqueous NH4Cl (5 mL). The
two layers were separated and the aqueous layer was extracted
with diethyl ether (3ꢂ5 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash column chromatog-
raphy (1:10 to 1:2, EtOAc/hexanes) to yield firstly Z-alkene 4a as
4.15. (S,E)-Ethyl-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-6-
methoxy-2-methylhex-2-enoate (23)
To a stirred solution of alcohol 22 (1.65 g, 6.07 mmol) in DCM
ꢀ
(60 mL) was added powdered 4 A molecular sieves (3.9 g), proton
sponge (3.9 g, 18.2 mmol) and Me3Oþ$BF4ꢀ (2.69 g, 18.2 mmol)
under an argon atmosphere. The mixture was stirred at room
temperature overnight, filter over Celite and concentrated under
reduced pressure. The residue was dissolved in EtOAc and washed
with 1 N aqueous CuSO4 (40 mL), saturated aqueous NH4Cl (40 mL),
and brine (40 mL). The organic layer was dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (1:20, EtOAc/hexanes) to
a clear oil (105 mg, 0.197 mmol, 25%) and then the title compound 4
20
as a yellow glass (390 mg, 0.521 mmol, 66%). [
a
]
þ10.3 (c 1.04,
D
afford a colorless oil in 90% yield (1.52 g, 5.31 mmol). [
a
]
20 þ3.3 (c
CHCl3); 1H NMR (400 MHz, CDCl3)
d
¼7.49e7.30 (m, 5H), 6.94 (m,
D
2.31, CHCl3); 1H NMR (400 MHz, CDCl3)
d
¼6.75 (t, J¼7.4 Hz,1H), 4.18
2H), 6.68 (t, J¼6.8 Hz, 1H), 5.33 (d, J¼10.0 Hz, 1H), 5.06 (s, 2H), 4.83
(d, J¼6.5 Hz, 1H), 4.62 (d, J¼6.6 Hz, 1H), 4.16 (q, J¼7.1 Hz, 2H), 3.87
(d, J¼6.6 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J¼8.6 Hz, 1H), 3.42 (s, 3H),
3.40 (s, 3H), 3.29 (s, 3H), 3.23 (m, 2H), 2.57 (m, 2H), 2.43 (m, 1H),
2.25 (m, 2H), 1.97 (m, 1H), 1.83 (s, 3H), 1.74 (m, 1H), 1.65 (s, 3H), 1.57
(m, 1H), 1.32e1.15 (m, 5H), 1.08 (d, J¼6.6 Hz, 3H), 0.78 (d, J¼6.5 Hz,
(q, J¼7.1 Hz, 2H), 4.03 (m, 2H), 3.85 (m, 1H), 3.41 (s, 3H), 3.25 (m,
1H), 2.29 (m, 2H), 1.84 (s, 3H), 1.66 (m, 2H), 1.41 (s, 3H), 1.34 (s, 3H),
1.28 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
¼168.2, 141.6,
d
128.2, 109.1, 80.8, 77.2, 66.5, 60.4, 58.5, 29.4, 26.5, 25.3, 24.0, 14.3,
12.4; IR (neat) 2985, 2935, 1712, 1650, 1456, 1369, 1263, 1080 cmꢀ1
;
HRMS (ESI) (m/z) calcd for C15H27O5 [MþH]þ 287.1853, found
3H); 13C NMR (100 MHz, CDCl3)
d
¼168.1, 152.6, 147.4, 141.3, 137.2,
287.1848.
136.7, 134.1, 131.8, 128.8, 128.5, 128.3, 127.6, 125.9, 115.9, 115.4, 97.7,
81.6, 81.5, 80.1, 78.8, 71.1, 60.8, 60.7, 58.7, 57.2, 56.3, 37.9, 37.0, 34.7,
30.7, 29.6, 24.2, 19.3, 17.9, 14.5, 12.8, 12.6; HRMS (ESI) m/z calcd for
4.16. (6S,7R,E)-Ethyl 7,8-dihydroxy-6-methoxy-2-methyloct-
2-enoate (24)
C
39H57BrNaO9 (MþNa)þ 773.3063, found 773.3056.
A solution of 23 (1.34 g, 4.70 mmol) in 1 M HCl (12 mL) and
CH3CN (25 mL) was stirred at room temperature for 1 h. The re-
action mixture was neutralized with solid NaHCO3, diluted with
H2O, and extracted with DCM (3ꢂ80 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chro-
4.19. (2E,6S,7S,8E,10S,11R,12S,14R)-Ethyl-15-(3-(benzyloxy)-5-
bromo-2-methoxyphenyl)-7-((tert-butyldimethylsilyl)oxy)-
6,12-dimethoxy-11-(methoxymethoxy)-2,8,10,14-
tetramethylpentadeca-2,8-dienoate (26)
An oven-dried flask was charged with 25 (390 mg, 0.521 mol)
and DCM (5.9 mL) at 0 ꢁC. The reaction was protected under argon
and 2,6-lutidine (0.24 mL, 2.09 mmol) was added, followed by
matography (1:100, MeOH/DCM) to afford a colorless oil in 96%
20
yield (1.11 g, 4.51 mmol). [
a
]
þ10.35 (c 2.6, CHCl3); 1H NMR
D

2990
C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
TBSOTf (0.24 mL, 1.04 mmol) dropwisely. The reaction mixture was
stirred for 2 h at 0 ꢁC before it was quenched by addition of satu-
rated aqueous NaHCO3 (5 mL). The two layers were separated and
the aqueous layer was extracted with DCM (3ꢂ5 ml). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
concentrated under reduced pressure. The crude product was pu-
rified by flash column chromatography (1:5 to 1:0, EtOAc/hexanes)
to yield a light yellow glass (200 mg, 0.239 mmol, 80%). [
a
]
20 þ13.6
D
(c 1.67, CHCl3); 1H NMR (400 MHz, CDCl3)
d¼7.50e7.30 (m, 5H),
6.94 (dd, J¼6.8, 2.2 Hz, 2H), 6.31 (t, J¼7.2 Hz, 1H), 5.30 (br, 1H), 5.15
(d, J¼9.7, 1H), 5.06 (s, 2H), 4.83 (d, J¼6.6 Hz, 1H), 4.62 (d, J¼6.6 Hz,
1H), 3.95 (d, J¼6.7 Hz, 1H), 3.79 (s, 3H), 3.59 (d, J¼9.3 Hz, 1H), 3.45
(s, 3H), 3.42 (d, J¼3.8 Hz, 1H), 3.40 (s, 3H), 3.28 (s, 3H), 3.20 (d,
J¼10.5 Hz, 1H), 3.09 (m, 1H), 2.60 (dd, J¼5.3, 13.4 Hz, 1H), 2.50 (m,
1H), 2.41 (m, 1H), 2.31e2.10 (m, 2H), 1.96 (m, 1H), 1.81 (s, 3H), 1.73
(m, 1H), 1.59 (s, 3H), 1.46 (m, 1H), 1.37e1.13 (m, 2H), 1.05 (d,
J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.75 (d, J¼6.6 Hz, 3H), 0.07 (s, 3H), 0.01
column chromatography (1:30 to 1:10, EtOAc/hexanes) to yield
20
a yellow glass (360 mg, 0.417 mmol, 80%). [
a]
þ20.7 (c 1.14,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
¼7.50e7.29 (m, 5H), 6.94 (s,
2H), 6.67 (t, J¼7.0 Hz,1H), 5.16 (d, J¼9.8 Hz,1H), 5.05 (s, 2H), 4.84 (d,
J¼6.6 Hz, 1H), 4.62 (d, J¼6.4 Hz, 1H), 4.14 (q, J¼7.1 Hz, 2H), 3.96 (d,
J¼6.6 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J¼9.4 Hz, 1H), 3.46 (s, 3H), 3.40
(s, 3H), 3.28 (s, 3H), 3.20 (d, J¼10.4 Hz, 1H), 3.08 (m, 1H), 2.60 (dd,
J¼13.4, 5.4 Hz, 1H), 2.47 (m, 2H), 2.24 (m, 2H), 1.98 (m, 1H), 1.81 (s,
3H), 1.78 (m, 1H), 1.60 (s, 3H), 1.47 (m, J¼7.0 Hz, 1H), 1.37e1.11 (m,
5H), 1.05 (d, J¼6.4 Hz, 3H), 0.89 (s, 9H), 0.77 (d, J¼6.4 Hz, 3H), 0.07
(s, 3H); 13C NMR (100 MHz, CDCl3)
d
¼171.7, 152.6, 147.3, 137.4, 137.3,
136.6, 135.1, 131.0, 130.4, 128.8, 128.3, 127.6, 125.9, 115.9, 115.3, 97.6,
83.9, 81.4, 80.9, 79.9, 71.1, 60.8, 60.0, 57.1, 56.3, 38.0, 36.9, 34.6, 30.7,
30.5, 26.0, 25.1,19.3,18.3,17.8,12.9,12.7, ꢀ4.4, ꢀ4.7; HRMS (ESI) m/z
calcd for C43H68BrNNaO8Si (MþNa)þ 856.3795, found 856.3764.
(s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
¼167.6,152.1,146.8,
141.2, 136.7, 136.1, 134.6, 130.4, 128.2, 128.1, 127.7, 127.0, 125.3, 115.3,
114.8, 97.1, 83.2, 80.8, 80.4, 79.2, 70.5, 60.2, 60.0, 59.5, 56.4, 55.7,
37.4, 36.2, 34.0, 30.0, 29.8, 25.5, 24.6, 18.7, 17.8, 17.3, 13.9, 12.2, 12.0,
ꢀ5.0, ꢀ5.2; HRMS (ESI) m/z calcd for C45H71BrNaO9 Si (MþNa)þ
885.3948, found 885.3895.
4.22. (4E,8S,9S,10E,12S,13R,14S,16R)-20-(Benzyloxy)-9-(tert-
butyldimethylsilyloxy)-13-(methoxymethoxy)-4,10,12,16-
tetramethyl-,14,19-trimethoxy-2-azabicyclo[16.3.1]docosa-
1(21),4,10,18(22),19-pentaen-3-one (29)
4.20. (2E,6S,7S,8E,10S,11R,12S,14R)-15-(3-(Benzyloxy)-5-
bromo-2-methoxyphenyl)-7-((tert-butyldimethylsilyl)oxy)-
6,12-dimethoxy-11-(methoxymethoxy)-2,8,10,14-
tetramethylpentadeca-2,8-dienoic acid (27)
An oven-dried sealed tube was charged with amide 28 (150 mg,
0.180 mmol), K2CO3 (371 mg, 2.69 mmol), and anhydrous toluene
(12 mL). The mixture was fully degassed by ultrasonic under argon.
Then cuprous iodide (174 mg, 0.916 mmol) and N,N0-dimethyl-1,2-
ethanediamine (191 mL, 1.79 mmol) were added successively and
Ester 26 (350 mg, 0.405 mmol) was dissolved in a mixture of
THF/MeOH/H2O (2:2:1 by volume, 29 mL). Then LiOH$H2O (338 mg,
8.10 mmol) was added and the stirring was continued for 48 h at
room temperature before it was concentrated under reduced
pressure. The residue was diluted with a buffer of NaH2PO4 (30 mL,
pH 4.5) and extracted with DCM (3ꢂ30 ml). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude acid was essentially pure and used in
the suspension turned to deep green. The sealed tube was closed
and the mixture was heated at 100 ꢁC for 36 h. The suspension was
filtered through a plug of silica gel and the filter cake was washed
with ethyl acetate. The combined filtrates were concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (1:5 to 1:1, EtOAc/hexanes) to yield a clear glass
20
(111 mg, 0.147 mmol, 82%). [
(400 MHz, CDCl3)
a
]
D
þ82.6 (c 1.48, CHCl3); 1H NMR
d
¼7.51e7.28 (m, 6H), 6.92 (br, 1H), 6.43 (d,
the next step without further purification (318 mg, 0.381 mmol,
J¼1.9 Hz, 1H), 6.01 (t, J¼6.4 Hz, 1H), 5.11 (m, 1H), 5.09 (s, 2H), 4.81
(d, J¼6.7 Hz, 1H), 4.67 (d, J¼6.7 Hz, 1H), 3.83 (m, 1H), 3.80 (s, 3H),
3.52 (m, 1H), 3.49 (s, 3H), 3.43 (s, 3H), 3.36 (s, 3H), 3.26 (d, J¼8.5 Hz,
1H), 3.04 (m, 1H), 2.69 (dd, J¼13.5, 7.6 Hz, 1H), 2.66e2.49 (m, 2H),
2.35e2.09 (m, 2H), 1.81 (d, J¼6.4 Hz, 1H), 1.71e1.58 (m, 4H), 1.49 (s,
3H), 1.37e1.14 (m, 3H), 1.08 (d, J¼6.6 Hz, 3H), 0.88 (s, 9H), 0.83 (d,
J¼6.6 Hz, 3H), 0.07 (s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3)
20
94%). [
d
a
]
þ15.9 (c 1.42, CHCl3); 1H NMR (300 MHz, CDCl3)
D
¼7.50e7.30 (m, 5H), 6.94 (s, 2H), 6.81 (t, J¼7.2 Hz, 1H), 5.16 (d,
J¼9.7 Hz, 1H), 5.05 (s, 2H), 4.84 (d, J¼6.6 Hz, 1H), 4.61 (d, J¼6.5 Hz,
1H), 3.96 (d, J¼6.5 Hz, 1H), 3.80 (s, 3H), 3.59 (d, J¼9.4 Hz, 1H), 3.46
(s, 3H), 3.40 (s, 3H), 3.28 (s, 3H), 3.20 (d, J¼10.5 Hz, 1H), 3.08 (m,
1H), 2.60 (dd, J¼13.5, 5.7 Hz, 1H), 2.54e2.35 (m, 2H), 2.35e2.15 (m,
2H), 1.98 (m, 1H), 1.81 (s, 3H), 1.72 (m, 1H), 1.60 (s, 3H), 1.49 (m, 1H),
1.39e1.12 (m, 2H), 1.05 (d, J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.76 (d,
J¼6.5 Hz, 3H), 0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
¼172.8, 152.4, 145.5, 137.1, 137.0, 135.4, 134.9, 133.8, 132.6, 132.2,
128.8, 128.2, 127.6, 117.8, 106.0, 97.7, 83.8, 83.7, 82.7, 80.7, 70.8, 61.1,
61.0, 57.6, 56.3, 35.9, 35.5, 34.4, 33.2, 31.5, 26.1, 24.7, 20.2, 18.4, 17.2,
13.7, 11.4, ꢀ4.4, ꢀ4.6; HRMS (ESI) m/z calcd for C43H67NNaO8Si
(MþNa)þ 776.4534, found 776.4522.
d
¼173.0, 152.6, 147.4, 144.7, 137.2, 136.7, 135.1, 130.9, 128.8, 128.3,
127.6, 127.5, 125.9, 115.9, 115.4, 97.6, 83.8, 81.4, 80.8, 79.9, 71.1, 60.8,
60.0, 57.1, 56.3, 38.0, 36.8, 34.6, 30.6, 30.2, 26.1, 25.4, 19.3, 18.4, 17.9,
12.8, 12.3, ꢀ4.4, ꢀ4.6; HRMS (ESI) m/z calcd for C43H67BrNaO9Si
(MþNa)þ 857.3635, found 857.3627.
4.23. (4E,8S,9S,10E,12S,13R,14S,16R)-20-(Benzyloxy)-9-
hydroxy-13-(methoxymethoxy)-4,10,12,16-tetramethyl-14,19-
trimethoxy-2-azabicyclo[16.3.1]docosa-1(21),4,10,18(22),19-
pentaen-3-one (30)
4.21. (2E,6S,7S,8E,10S,11R,12S,14R)-15-(3-(Benzyloxy)-5-
bromo-2-methoxyphenyl)-7-((tert-butyldimethylsilyl)oxy)-
6,12-dimethoxy-11-(methoxymethoxy)-2,8,10,14-
tetramethylpentadeca-2,8-dienamide (28)
Compound 29 (110 mg, 0.145 mmol) was placed in a nalgene vial
and CH3CN (11 mL) was added followed by the premixed solution of
pyridine hydrofluoride/pyridine/CH3CN (1:1:2.5 by volume,
5.0 mL). The reaction mixture was stirred at room temperature for
24 h before it was quenched by addition of saturated aqueous
NaHCO3 (20 mL). The two layers were separated and the aqueous
layer was extracted with ethyl acetate (3ꢂ20 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (1:3 to 1:0, EtOAc/hexanes) to yield a clear
To a stirred solution of acid 27 (250 mg, 0.299 mmol) in a mix-
ture of 1,4-dioxane (10 mL) and pyridine (0.2 mL) was added Boc2O
(1.10 g, 5.05 mmol). The reaction mixture was stirred for 15 min
before addition of NH4HCO3 (400 mg, 5.06 mmol). The stirring was
continued for 18 h at room temperature (monitor by TLC). After
complete consumption of the mixed anhydride, the reaction mix-
ture was extracted with EtOAc (3ꢂ10 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 and brine. The
combined organic layers were dried over Na2SO4, filtered, and
glass (84 mg, 0.131 mmol, 90%). [
(400 MHz, CDCl3)
a
]
20 þ99.1 (c 1.53, CHCl3); 1H NMR
D
d
¼8.00 (br, 1H), 7.53e7.28 (m, 6H), 6.42 (s, 1H),

C. Bian et al. / Tetrahedron 70 (2014) 2982e2991
2991
6.06 (t, J¼6.4 Hz, 1H), 5.39 (d, J¼9.3 Hz, 1H), 5.10 (s, 2H), 4.76 (d,
J¼6.7 Hz, 1H), 4.67 (d, J¼6.7 Hz, 1H), 3.82 (m, 1H), 3.80 (s, 3H), 3.52
(d, J¼6.4 Hz, 1H), 3.45 (s, 3H), 3.43 (s, 3H), 3.38 (m, 1H), 3.38 (s, 3H),
3.21 (m, 1H), 2.81e2.59 (m, 3H), 2.49 (m, 1H), 2.32 (m, 1H), 2.22 (m,
1H), 1.74 (s, 3H), 1.69e1.60 (m, 3H), 1.57 (s, 3H), 1.34 (m, 1H), 1.10 (d,
J¼6.6 Hz, 3H), 0.92 (d, J¼6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1.68 (s, 3H), 1.55 (m, 1H), 1.43 (s, 3H), 1.36 (m, 1H), 1.26 (m, 1H), 1.15
(m, 1H), 0.90 (d, J¼6.6 Hz, 3H), 0.80 (d, J¼5.1 Hz, 3H); 13C NMR
(150 MHz, DMSO)
d
¼170.3, 156.2, 149.9, 142.5, 134.6, 133.5, 133.4,
132.2, 129.7, 114.7, 107.2, 81.1, 80.7, 79.5, 73.7, 59.8, 58.3, 56.5, 35.8,
34.3, 33.7, 31.2, 29.8, 23.6, 19.7, 16.2, 13.1, 11.7; HRMS (ESI) m/z calcd
for C29H44N2NaO8 (MþNa)þ 571.2995, found 571.3001.
d
¼171.2, 152.3, 144.9, 137.1, 135.9, 135.4, 134.2, 133.8, 133.3, 132.7,
128.7, 128.1, 127.6, 116.0, 104.9, 97.5, 83.3, 83.2, 81.1, 79.7, 70.7, 61.0,
59.2, 58.0, 56.2, 36.8, 35.9, 34.2, 33.7, 30.9, 24.5, 20.9,17.3, 13.5,12.2;
HRMS (ESI) m/z calcd for C37H53NNaO8 (MþNa)þ 662.3669, found
662.3664.
Acknowledgements
This project received financial support from National Natural
Science Foundation of China (_501100001809) (21272279). The
authors received valuable advice from Dr. Hanqing Dong (Arvinas
Inc.) during the preparation of the manuscript.
4.24. (4E,8S,9S,10E,12S,13R,14S,16R)-Carbamicacid-20-(benzy-
loxy)-13-(methoxymethoxy)-4,10,12,16-tetramethyl-8,14,19-
trimethoxy-3-oxo-2-azabicyclo[16.3.1]docosa-
Supplementary data
1(21),4,10,18(22),19-pentaen-9-yl ester (31)
1H and C NMR spectra for all new and important known com-
pounds. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2014.03.020.
Trichloroacetyl isocyanate (32 mL, 0.263 mmol) was added to
a stirred solution of 30 (84 mg, 0.131 mmol) in DCM (16.8 mL) and
the reaction mixture was stirred for 15 min. MeOH (21 mL) was
added followed by K2CO3 (84 mg, 0.604 mmol), and stirring was
continued for 0.5 h (monitor by TLC). The solvent was evaporated
under reduced pressure, and the residue was diluted with water
(20 mL) and extracted with EtOAc (3ꢂ20 mL). The combined or-
ganic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (1:1 to 2:1, EtOAc/hexanes) to yield a clear
References and notes
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2000, 53, 657.
3. For recent reviews see: (a) Gorska, M.; Popowska, U.; Sielicka-Dudzin, A.; Ku-
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Chem. 2010, 75, 2820.
glass (68 mg, 0.100 mmol, 76%). [
(400 MHz, CDCl3)
a
]
20 þ66.9 (c 1.40, CHCl3); 1H NMR
D
d
¼8.29 (br, 1H), 7.53e7.27 (m, 5H), 6.42 (s,
J¼2.0 Hz, 1H), 6.09 (t, J¼7.5 Hz, 1H), 5.41 (d, J¼9.7 Hz, 1H), 5.23 (s,
1H), 5.11 (m, 2H), 4.86 (d, J¼6.7 Hz, 1H), 4.64 (d, J¼6.7 Hz, 1H), 3.79
(s, 3H), 3.60 (d, J¼8.7 Hz, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 3.39 (m, 2H),
3.32 (s, 3H), 3.26 (d, J¼5.3 Hz, 1H), 2.71e2.51 (m, 2H), 2.44 (m, 2H),
2.26 (m, 1H), 1.84 (s, 3H), 1.77 (m, 1H), 1.67 (m, 2H), 1.59 (s, 3H), 1.55
(m, 1H), 1.46 (m, 1H), 1.09 (d, J¼6.6 Hz, 3H), 0.89 (d, J¼6.1 Hz, 3H);
5. Onodera, H.; Kaneko, M.; Takahashi, Y.; Uochi, Y.; Funahashi, J.; Nakashima, T.;
Soga, S.; Suzuki, M.; Ikeda, S.; Yamashita, Y.; Rahayu, E. S.; Kanda, Y.; Ichimura,
M. Bioorg. Med. Chem. Lett. 2008, 18, 1577.
13C NMR (75 MHz, CDCl3)
d
¼170.5, 156.8, 152.1, 144.7, 137.3, 136.1,
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(a) Andrus, M. B.; Meredith, E. L.; Simmons, B. L.; Soma Sekhar, B. B. V.; Hicken,
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134.9, 134.6, 133.5, 130.1, 128.7, 128.0, 127.6, 115.0, 110.0, 104.5, 97.4,
84.3, 80.5, 80.2, 77.5, 70.7, 61.1, 59.0, 56.9, 56.3, 37.0, 34.9, 34.5, 30.0,
29.4, 25.9, 20.9, 17.8, 13.7, 13.3; HRMS (ESI) m/z calcd for
C
38H54N2NaO9 (MþNa)þ 705.3727, found 705.3721.
4.25. Reblastatin (1)
Anisole (31 mL) was added to a suspension of aluminum tri-
chloride (360 mg, 2.71 mmol) in DCM (24 mL) at ꢀ78 ꢁC and the
resulting light yellow solution was stirred for additional 5 min.
Then 29 (65 mg, 0.0952 mmol) in DCM (7.5 mL) was added drop-
wisely. The solution was allowed to gradually warm up to 0 ꢁC over
3 h and the stirring was continued for additional 1 h at room
temperature. Aqueous HCl (0.5 M, 15 mL) was added slowly and the
mixture was diluted with saturated aqueous NH4Cl (15 mL). The
two layers were separated and the aqueous layer was extracted
with ethyl acetate (3ꢂ20 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash column chromatog-
ꢁ
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Challis, G. L. J. Am. Chem. Soc. 2010, 133, 1793.
13. (a) Martin, P.; Muller, M.; Flubacher, D.; Boudier, A.; Blaser, H. U.; Spielvogel, D.
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82, 43.
raphy (1:100 to 1:10, MeOH/DCM) to yield reblastatin as a white
20
solid (45 mg, 0.0819 mmol, 86%). [
NMR (600 MHz, DMSO)
a
]
þ59.2 (c 1.13, CHCl3); 1H
D
d
¼9.23 (s, 1H), 9.21 (s, 1H), 6.86 (br, 1H),
6.50 (br, 2H), 6.29 (s, 1H), 5.85 (s, 1H), 5.30 (d, J¼9.1 Hz, 1H), 4.87 (d,
J¼7.4 Hz, 1H), 4.31 (d, J¼5.2 Hz, 1H), 3.63 (s, 3H), 3.33 (s, 3H), 3.33
(m, 1H), 3.27 (m, 1H), 3.21 (s, 3H), 3.01 (m, 1H), 2.57 (dd, J¼13.3,
6.2 Hz, 1H), 2.38 (m, 2H), 2.22 (m, 1H), 2.11 (m, 1H), 1.75 (m, 1H),