Stereoselective total synthesis of cochliomycin A

Article abstract of DOI:10.1016/j.tet.2014.03.001

A convergent and stereoselective synthesis of cochliomycin A, a 14-membered resorcyclic acid lactone, based on chiron approach is described. The key reactions involved olefin cross-metathesis and sodium hydride promoted one-pot intramolecular lactonization. l-Arabinose was used as a chiral pool material for the construction of the key fragment.

Full text of DOI:10.1016/j.tet.2014.03.001

Tetrahedron xxx (2014) 1e5
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Tetrahedron
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Stereoselective total synthesis of cochliomycin A
,
a
a,b,
*
Linlin Wang a, Yangguang Gao b, Jun Liu a , Chao Cai , Yuguo Du
*
a State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences,
Beijing 100085, China
b School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent and stereoselective synthesis of cochliomycin A, a 14-membered resorcyclic acid lactone,
Received 13 January 2014
Received in revised form 24 February 2014
Accepted 2 March 2014
Available online xxx
based on chiron approach is described. The key reactions involved olefin cross-metathesis and sodium
hydride promoted one-pot intramolecular lactonization.
for the construction of the key fragment.
L-Arabinose was used as a chiral pool material
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cochliomycin A
Total synthesis
Resorcylic acid lactones
1. Introduction
new 14-membered resorcyclic acid lactones, together with the
known zeaenol (4), were isolated from the culture broth of
Cochliobolus lunatus in 2011.2
In recent years, resorcylic acid lactones (RALs) have gained
considerable attention, as many of them possess remarkable and
diverse biological activities.1 Cochliomycin AeC (1e3, Fig. 1), three
The cochliomycin A (1) and B (2) comprised similar 14-
membered resorcyclic acid lactone skeleton with a rare natural
acetonide group. The relative configurations of cochliomycin A and
B were established on the basis of extensive spectroscopic analysis
including 1D NOE and 2D NOESY experiments. The only difference
between these two compounds is the acetonide group, which has
never been found before in any natural resorcylic acid lactone. The
absolute configurations of cochliomycin A and B were further
confirmed by treatment of zeaenol (4) with 2,2-dimethoxypropane
in the presence of p-toluenesulfonic acid (PTSA) resulted in a mix-
ture of cochliomycin A and B. Cochliomycin A was found to show
potent antifouling activity against the larval settlement of the
barnacle Balanus amphitrite and moderate antibacterial activity
against Staphylococcus aureus. It is noteworthy that the unusual
acetonide moiety in cochliomycin A probably contributes to the
antifouling activity because cochliomycin A showed better anti-
fouling activity with EC50 value (1.2
fold over zeaenol (4) (5.0 g/mL).
mg/mL), approximately three-
m
Due to its novel structure and potent biological activity,
cochliomycin A constitutes an ideal target for total synthesis. Very
recently, cochliomycin A was firstly synthesized by Nanda’s group
from
L
-(þ)-tartaric acid in 6.5% overall yields employing Keck
allylation, JuliaeKocienski olefination and a late-stage RCM re-
action as the key steps.3 As part of our interest in the total synthesis
of various complex natural products based on carbohydrate skele-
tons,4 we herein report a convergent total synthesis of cochlio-
Fig. 1. Structures of cochliomycin AeC (1e3) and zeaenol (4).
* Corresponding authors. E-mail addresses: junliu@rcees.ac.cn (J. Liu), duyuguo@
rcees.ac.cn (Y. Du).
mycin A using L-arabinose as the chiral pool material.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.001
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L. Wang et al. / Tetrahedron xxx (2014) 1e5
Our retrosynthesis analysis of cochliomycin A is summarized in
1,2-diol 13. Regioselective monotosylation8 of 13 followed by base
treatment gave the epoxide 9 in 78% yield for two steps.9
Scheme 1. To construct the 14-membered macrocyclic core, we
planned to utilize macrolactonization of the precursor 5, which
could be obtained by Stille coupling between the stannane 6 and
the known triflate 7. The key intermediate 6 could be obtained from
the epoxide 8 via an easy reaction sequence. The trans olefin moiety
at C70/C80 in 8 could be installed by olefin cross-metathesis of the
epoxide 9 and the olefinic side chain 10, which could be accessible
The known homoallylic alcohol 10 was prepared by treating
commercially available (S)-(ꢀ)-propylene oxide with vinyl-
magnesium bromide in the presence of CuI.10 Exposure the mixture
of the epoxide 9 and the homoallyl alcohol 10 in 1:1.5 ratio to
Grubbs second generation catalyst in dry DCM under reflux pro-
vided the desired (E)-alkene in 85% yield along with small amounts
of the dimer of 10.11 The ring opening of the epoxide 8 with lithium
acetylide from TMSeacetylene in the presence of BF3$Et2O gave the
corresponding homopropargylic alcohol 15 in 78% yield.12 After
deprotection of the TMS group in 15 with K2CO3 in methanol, the
resulting terminal alkyne was treated with NBS (N-bromosuccini-
mide) in the presence of silver nitrate to afford the 1-bromoalkyne
17 in almost quantitative yield.13 According to the Guibe’s protocol,
Pd-catalyzed hydrostannylation of the bromoalkyne 17 smoothly
yielded the desired (E)-vinyl stannane 6 at room temperature
(Scheme 3).14
readily from
L
-arabinose and (S)-(ꢀ)-propylene oxide, respectively.
This approach was based on the fact that the three desired con-
tinuous stereogenic centers in the cochliomycin A (1) could directly
be mapped onto natural L-arabinose.
Stille cross-coupling of 6 and the known aryl triflate 715 pro-
ceeded smoothly to give the alkene 5 in 81% yield.16 Hydrolysis of 5
with LiOH in a solution of THF/H2O (2:1) afforded an almost
quantitative yield of the free acid 18 (Scheme 4).
However, difficulties were encountered during the attempted
macrocyclization of the resulting carboxylic acid to the corre-
sponding macrolide. The Yamaguchi macrolactonization strategy17
was first explored. Unfortunately, only a trace amount of cochlio-
mycin A was obtained under this condition. Attempts to improve
the yield by changing reaction concentration or going to higher
temperature were fruitless. The CoreyeNicolaou double activation
strategy18 was also examined and no desired product was observed.
Because of the failure of the original strategy for constructing
macrolide from free acid 18, a backup approach was adopted. Fi-
nally, according to De Brabander’s conditions,19 one-pot intra-
molecular lactonization was achieved with excess NaH in dry DMF,
leading to cochliomycin A (1) in reasonable yield (Scheme 4). All the
spectroscopic data and specific rotation data of our synthetic
cochliomycin A are in good agreement with those reported values
for natural product {½a D24
ꢁ
þ10.5 (c 0.6, MeOH); Ref. 3: ½a D30
þ10.6 (c
ꢁ
0.5, MeOH); Ref. 2: ½a D24
þ10.5 (c 0.43, MeOH)}.
ꢁ
Scheme 1. Retrosynthetic analysis of cochliomycin A (1).
3. Conclusions
2. Results and discussion
In conclusion, a convergent and stereoselective synthesis of the
resorcyclic acid lactone, cochliomycin A, has been achieved starting
from readily available chiral pool L-arabinose. The key reactions
involved olefin cross-metathesis, Stille cross-coupling and sodium
hydride promoted one-pot intramolecular lactonization. Further
synthetic studies on other cochliomycins and their biological
evaluation are currently under investigation in our laboratory.
Accordingly, the synthesis of the key intermediate 9 started
from -arabinose and is outlined in Scheme 2. The known aldehyde
11 was prepared from
L
L
-arabinose in three steps according to the
reported procedure.5 Wittig reaction6 of the aldehyde 11 with tri-
phenylphosphonium methylidene followed by selective hydrolysis7
of the terminal acetonide with 75% aqueous acetic acid afforded the
Scheme 2. Reagents and conditions: (a) CH3PPh3Br, t-BuOK, dry THF, rt, overnight; (b) 75% AcOH, rt, overnight, 77% (for two steps); (c) p-toluenesulfonyl chloride, dibutyltin oxide,
dry CH2Cl2, 0 ꢂC to rt, 4 h; (d) K2CO3, MeOH, rt, 3 h, 78% (for two steps).
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L. Wang et al. / Tetrahedron xxx (2014) 1e5
3
Scheme 3. Reagents and conditions: (a) Grubbs second generation catalyst, CH2Cl2, reflux, 24 h, 85%; (b) TMSeacetylene, n-BuLi, BF3$Et2O, THF, ꢀ78 ꢂC, 1 h, 78%; (c) K2CO3, MeOH,
12 h, 86%; (d) NBS, AgNO3, acetone, 1 h, 97%; (e) PdCl2(PPh3)2, Bu3SnH, THF, rt, 30 min, 85%.
Scheme 4. Reagents and conditions: (a) Pd(dba)2, AsPh3, LiCl, DMF, 60 ꢂC, 2 h, 81%; (b) LiOH$H2O, THF/H2O (2:1), 24 h. (c) NaH, dry DMF, 0 ꢂC to rt, 1 h, 46%.
4. Experimental section
4.1. General
cool to 0 ꢂC, a solution of 11 (29.6 g, 129 mmol) in anhydrous THF
(50 mL) was added and the mixture was stirred at room tempera-
ture overnight. To this mixture was carefully added water (200 mL)
and the mixture was extracted with ethyl acetate (800 mL), dried,
filtered, and concentrated under reduced pressure to give a yellow
syrup. This syrup was purified by silica gel column chromatography
(ethyl acetate/petroleum ether 1:20) to give 12 with the contami-
nation of triphenylphosphine oxide, which was used for next re-
action without further purification; 1H NMR (400 MHz, CDCl3):
All anhydrous solvents were purified according to standard
methods. All commercially available reagents were used without
further purification. Reactions were monitored by thin-layer
chromatography (TLC) on gel F254 plates. Flash chromatography
(FC) was performed using silica gel (200e300 mesh) according to
the standard protocol. Optical rotations were recorded in either a 5-
cm microcell or a 2.5-cm microcell. High-resolution mass spec-
trometry data (HRMS) were acquired with a Q-TOF analyzer. 1H and
13C NMR spectra were recorded on a Bruker 400 MHz (100 MHz for
13C) NMR spectrometer.
d
5.91 (ddd, J¼6.0, 10.4, 16.8 Hz, 1H), 5.41 (d, J¼17.2 Hz, 1H), 5.21 (d,
J¼10.4 Hz, 1H), 4.36 (td, J¼1.2, 6.4 Hz, 1H), 4.07e4.15 (m, 2H),
3.93e3.96 (m, 1H), 3.70 (t, J¼7.2 Hz, 1H), 1.41 (s, 6H), 1.40 (s, 3H),
1.34 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 136.3, 117.5, 110.0, 109.8,
81.5, 80.8, 67.4, 27.3, 27.3, 27.0, 25.6; ESI-HRMS calcd for C12H20O4
([MþNa]þ) 251.1253, found 251.1237.
4.1.1. (4R,40S,5S)-2,2,20,20-Tetramethyl-5-vinyl-4, 40-bi(1,3-dioxolane)
(12). To a stirred suspension of methyl triphenylphosphonium
bromide (131 g, 367 mmol) in anhydrous THF (300 mL) was added
potassium tert-butoxide (45.5 g, 405 mmol) at 0 ꢂC under N2 at-
mosphere. The reaction mixture was stirred at 0 ꢂC for 20 min and
then at room temperature for 1 h. After the mixture was allowed to
4.1.2. (S)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethane-
1,2-diol (13). Compound 12 was added to 75% acetic acid (200 mL)
and the mixture was stirred at room temperature overnight. The
reaction mixture was azeotroped with toluene under reduced
pressure below 30 ꢂC to give a yellow syrup. This syrup was purified
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4
L. Wang et al. / Tetrahedron xxx (2014) 1e5
by silica gel column chromatography (ethyl acetate/petroleum
temperature, the reaction mixture was hydrolyzed by adding brine
(30 mL). The aqueous phase was extracted with ethyl acetate
(3ꢃ50 mL) and the combined organic layers were dried over an-
hydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(ethyl acetate/petroleum ether 1:4) to give 15 (554 mg, 78%) as
ether 1:1) to give 13 (18.6 g, 77% from 11) as a colorless oil; ½a D30
ꢁ
ꢀ65.4 (c 0.7, CHCl3); IR (
n ;
): 3308, 2986,1372,1225,1168,1062 cmꢀ1
1H NMR (400 MHz, CDCl3):
d
5.89 (ddd, J¼6.8, 10.0, 16.8 Hz, 1H),
5.43 (d, J¼16.8 Hz, 1H), 5.26 (d, J¼10.4 Hz, 1H), 4.41 (td, J¼0.8,
7.2 Hz, 1H), 3.85e3.88 (m, 1H), 3.79 (dd, J¼5.2, 8.0 Hz, 1H),
3.67e3.75 (m, 2H), 2.25 (br, 2H), 1.43 (s, 3H), 1.42 (s, 3H); 13C NMR
a colorless oil; ½a D
ꢁ
30 50 (c 0.6, CHCl3); IR (
1H NMR (400 MHz, CDCl3):
n): 3415, 2985, 2964, 2932,
(100 MHz, CDCl3):
d
136.3, 118.7, 109.7, 81.3, 79.7, 72.5, 63.8, 27.2,
2901, 2177, 1372, 1250, 1064 cmꢀ1
;
27.2; ESI-HRMS calcd for C9H16O4 ([MþNa]þ) 211.0940, found
d
5.84e5.92 (m, 1H), 5.63 (dd, J¼8.0, 15.6 Hz, 1H), 4.43 (t, J¼8.0 Hz,
211.0917.
1H), 3.85e3.95 (m, 2H), 3.80 (dd, J¼5.6, 8.0 Hz, 1H), 2.51 (dd, J¼1.6,
6.8 Hz, 2H), 2.22e2.26 (m, 2H),1.95 (br, 2H),1.42 (s, 3H),1.41 (s, 3H),
1.20 (d, J¼6.0 Hz, 3H), 0.156 (s, 9H); 13C NMR (100 MHz, CDCl3):
4.1.3. (4R,5S)-2,2-Dimethyl-4-((S)-oxiran-2-yl)-5-vinyl-1, 3-
dioxolane (9). To a stirred solution of 13 (4 g, 21.3 mmol), Bu2SnO
(106 mg, 0.43 mmol), and triethylamine (2.967 mL, 21.3 mmol) in
dry CH2Cl2, p-toluenesulfonyl chloride (4.07 g, 21.3 mmol) was
added at 0 ꢂC under N2 atmosphere. The resulting solution was
stirred for 4 h at room temperature. Water was added and the re-
action mixture was extracted with CH2Cl2. The organic extract was
washed with brine, dried, and concentrated under reduced pres-
sure to afford the crude tosylate 14 as a colorless oil, which was
used for next step without any purification. To a stirred solution of
14 in MeOH (50 mL), anhydrous K2CO3 (8.83 g, 64.0 mmol) was
added under N2 atmosphere. The resulting solution was stirred for
3 h at room temperature and filtered. The residue was washed with
CH2Cl2, and the combined filtrates were concentrated under re-
duced pressure below 30 ꢂC. The residue was redissolved in CH2Cl2,
washed with brine, dried, and concentrated to give the crude
product, which was purified by silica gel column chromatography
(ethyl acetate/petroleum ether 1:40) to give 9 (2.82 g, 78% from 13)
d
132.1, 131.0, 108.9, 102.4, 87.6, 81.7, 78.7, 69.8, 67.0, 42.0, 27.0, 26.9,
25.0, 22.8, 0.0; ESI-HRMS calcd for C17H30O4Si ([MþNa]þ) 349.1805,
found 349.1815.
4.1.6. (S,E)-5-((4S,5S)-5-((S)-1-Hydroxybut-3-ynyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)pent-4-en-2-ol (16). To a solution of 15 (397 mg,
1.22 mmol) in MeOH (10 mL), was added K2CO3 (252 mg,
1.83 mmol). The mixture was stirred for 12 h at room temperature
before water (5 mL) was added. The mixture was extracted with
CH2Cl2. The combined organic layers were dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by silica gel
column chromatography (ethyl acetate/petroleum ether 1:3) to
give 16 (268 mg, 86%) as a colorless oil; ½a D
3301, 2964, 2924, 2856, 2119, 1670, 1374, 1062 cmꢀ1
(400 MHz, CDCl3):
ꢁ
30 45 (c 0.6, CHCl3); IR (
1H NMR
n):
;
d
5.83e5.92 (m, 1H), 5.65 (dd, J¼7.6, 15.6 Hz, 1H),
4.43 (t, J¼7.6 Hz, 1H), 3.92e3.96 (m, 1H), 3.86e3.90 (m, 1H), 3.81
(dd, J¼5.2, 7.6 Hz,1H), 2.48e2.51 (m, 2H), 2.18e2.31 (m, 2H), 2.07 (t,
J¼2.8 Hz,1H),1.69 (br, 2H),1.42 (s, 3H),1.41 (s, 3H),1.20 (d, J¼6.4 Hz,
as a colorless oil; ½a D30
ꢁ
25.1 (c 1.3, CHCl3); IR (n): 2957, 2926, 1653,
1373, 1259, 1218, 1176, 1062, 870 cmꢀ1; 1H NMR (400 MHz, CDCl3):
3H); 13C NMR (100 MHz, CDCl3):
d 132.0, 131.7, 109.4, 81.9, 80.2,
d
5.86 (ddd, J¼6.8, 10.4, 17.2 Hz, 1H), 5.42 (dd, J¼0.8, 17.2 Hz, 1H),
79.1, 71.6, 70.3, 67.4, 42.3, 27.4, 27.3, 23.9, 23.2; ESI-HRMS calcd for
C
5.27 (dd, J¼0.8, 10.4 Hz, 1H), 4.35 (t, J¼7.2 Hz, 1H), 3.59 (dd, J¼5.2,
8.0 Hz, 1H), 3.06e3.09 (m, 1H), 2.81 (dd, J¼4.4, 5.2 Hz, 1H), 2.69 (dd,
J¼2.8, 4.8 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz,
14H22O4 ([MþNa]þ) 277.1444, found 277.1412.
4.1.7. (S,E)-5-((4S,5S)-5-((S)-4-Bromo-1-hydroxybut-3-ynyl)-2,2-di-
methyl-1,3-dioxolan-4-yl)pent-4-en-2-ol (17). To a solution of 16
(218 mg, 0.86 mmol) in acetone (25 mL), was added silver nitrate
(44 mg, 0.26 mmol) and N-bromosuccinimide (183 mg, 1.03 mmol).
The reaction mixture was stirred for 1 h, poured into saturated
NaHCO3 (5 mL) and saturated sodium thiosulfate (5 mL), and
extracted with CH2Cl2. The combined extracts were dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate/pe-
CDCl3):
d 135.3, 119.2, 110.1, 80.6, 80.4, 51.5, 45.0, 27.2, 27.0; ESI-
HRMS calcd for C9H14O3 ([MþNa]þ) 193.0835, found 193.0829.
4.1.4. (S,E)-5-((4S,5R)-2,2-Dimethyl-5-((S)-oxiran-2-yl)-1,3-dioxo-
lan-4-yl)pent-4-en-2-ol (8). To a stirred solution of 9 (1.17 g,
6.9 mmol) and 10 (885 mg, 10.3 mmol) in dry CH2Cl2 (2 mL), 2% mol
of Grubbs second generation catalyst was added under N2 atmo-
sphere. The reaction mixture was stirred for 24 h under reflux. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/petroleum ether 1:6) to give 8 (1.33 g, 85%) as a colorless
troleum ether 1:3) to give 17 (278 mg, 97%) as a colorless oil; ½a D30
ꢁ
73.8 (c 0.9, CHCl3); IR (n): 3374, 2960, 2921, 2853, 2309, 1603, 1376,
1123, 1059 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 5.84e5.91 (m, 1H),
oil; ½a 3D0
ꢁ
64.7 (c 1.3, CHCl3); IR (
n
): 3433, 2985, 2921, 1597, 1454,
;
5.62 (dd, J¼8.0, 15.6 Hz, 1H), 4.41 (t, J¼8.0 Hz, 1H), 3.85e3.94 (m,
2H), 3.77 (dd, J¼5.6, 8.0 Hz, 1H), 2.50 (d, J¼6.4 Hz, 2H), 2.22e2.26
(m, 2H), 2.10 (br, 2H), 1.42 (s, 3H), 1.40 (s, 3H), 1.20 (d, J¼6.4 Hz, 3H);
1376, 1219, 1160, 1112, 1058 cmꢀ1
1H NMR (400 MHz, CDCl3):
d
5.85e5.93 (m, 1H), 5.56e5.62 (m, 1H), 4.37 (t, J¼8.0 Hz, 1H),
3.83e3.91 (m, 1H), 3.51 (dd, J¼5.6, 8.4 Hz, 1H), 3.06 (ddd, J¼2.4, 3.6,
6.4 Hz, 1H), 2.82 (dd, J¼4.0, 4.8 Hz, 1H), 2.70 (dd, J¼2.4, 4.8 Hz, 1H),
2.23e2.25 (m, 2H), 1.67 (br, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.21 (d,
13C NMR (100 MHz, CDCl3):
d 132.4, 131.5, 109.4, 81.9, 79.1, 76.3,
70.2, 67.5, 42.2, 41.3, 27.4, 27.3, 25.1, 23.2; ESI-HRMS calcd for
C
14H21BrO4 ([MþNa]þ) 355.0515, found 355.0514.
J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 132.8, 129.8, 109.8,
80.3, 80.2, 67.2, 51.3, 44.9, 42.2, 27.1, 26.8, 23.0; ESI-HRMS calcd for
4.1.8. (S,E)-5-((4S,5S)-5-((S,E)-1-Hydroxy-4-(tributylstannyl)but-3-
enyl)-2,2-dimethyl-1, 3-dioxolan-4-yl)pent-4-en-2-ol (6). To a solu-
tion of the alkynyl bromide 17 (256 mg, 0.77 mmol) in anhydrous
THF (20 mL), was added Cl2Pd(PPh3)2 (11 mg, 0.0154 mmol) and
tributyltin hydride (0.42 mL, 1.54 mmol). The reaction mixture was
stirred for 30 min, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate/petroleum ether 1:6) to give 6 (357 mg, 85%) as a colorless
C
12H20O4 ([MþNa]þ) 251.1253, found 251.1264.
4.1.5. (S,E)-5-((4S,5S)-5-((S)-1-Hydroxy-4-(trimethylsilyl)but-3-yn-
1-yl)-2, 2-dimethyl-1,3-dioxolan-4-yl)pent-4-en-2-ol (15). To a stir-
red solution of trimethylsilylacetylene (1.24 mL, 8.76 mmol) in
anhydrous THF (20 mL), was added n-BuLi (1.6 M in hexanes,
5.34 mL, 8.54 mmol) dropwise at ꢀ78 ꢂC under N2 atmosphere. The
resulting solution was slowly warmed to 0 ꢂC and stirred at this
temperature for 1 h. The reaction mixture was then cooled to
ꢀ78 ꢂC and BF3$Et2O (0.60 mL, 4.82 mmol) was added dropwise.
After 20 min at ꢀ78 ꢂC, a solution of 8 (500 mg, 2.19 mmol) in THF
(20 mL) was added via cannula. After 1 h of stirring at this
oil; ½a 3D0
ꢁ
28.8 (c 0.8, CHCl3); IR (
n
): 3411, 2957, 2926, 2870, 2850,
1673, 1597, 1457, 1376, 1244, 1165, 1056 cmꢀ1
;
1H NMR (400 MHz,
CDCl3):
d
5.81e6.17 (m, 3H), 5.60 (dd, J¼8.0, 15.6 Hz, 1H), 4.44 (t,
J¼8.0 Hz, 1H), 3.80e3.93 (m, 2H), 3.70 (dd, J¼4.8, 8.0 Hz, 1H),
2.16e2.51 (m, 5H), 2.06e2.10 (m, 1H), 1.46e1.71 (m, 6H), 1.42 (s,
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L. Wang et al. / Tetrahedron xxx (2014) 1e5
5
3H), 1.41 (s, 3H), 1.25e1.36 (m, 6H), 1.20 (d, J¼6.4 Hz, 3H), 0.79e0.96
(m, 15H); 13C NMR (100 MHz, CDCl3):
144.4, 133.5, 132.0, 109.1,
21202193). We thank Min Li and Yuan Li for MS measurements.
We thank Jinshan Li for IR measurements. We also thank Dr. Yi-
Xian Li (CAS Key Laboratory of Molecular Recognition and Func-
tion, Institute of Chemistry, Chinese Academy of Sciences) for
help in measuring the optical rotation of Cochliomycin A.
d
82.8, 78.7, 70.7, 67.4, 42.4, 41.9, 29.5, 27.6, 27.4, 27.3, 23.2, 14.1, 9.8;
ESI-HRMS calcd for
569.2628.
C
26H50O4Sn ([MþNa]þ) 569.2628, found
4.1.9. 5-((S,E)-4-Hydroxy-4-((4S,5S)-5-((S,E)-4-hydroxypent-1-en-1-
yl)-2,2-dimethyl-1, 3-dioxolan-4-yl)but-1-en-1-yl)-7-methoxy-2,2-
dimethyl-4H-benzo[d][1,3]dioxin-4-one (5). To a flame-dried flask
containing triflate 7 (107 mg, 0.301 mmol), Pd(dba)2 (106 mg,
0.184 mmol), AsPh3 (56 mg, 0.183 mmol), and LiCl (29 mg,
0.684 mmol), was added anhydrous DMF 3 mL under N2 atmo-
sphere. The resulting mixture was stirred at room temperature for
30 min before addition of vinyl stannane 6 (126 mg, 0.231 mmol).
The reaction was heated to 60 ꢂC for 2 h, cooled to room temper-
ature, and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (ethyl acetate/
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.001.
References and notes
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petroleum ether 1:1) to give 5 (86 mg, 81%) as a colorless oil; ½a D30
ꢁ
16.7 (c 0.6, CHCl3); IR (n): 3372, 2923, 1726, 1659, 1603, 1460, 1429,
1379 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
7.37 (d, J¼16.0 Hz, 1H),
6.69 (d, J¼2.4 Hz, 1H), 6.34 (d, J¼2.4 Hz, 1H), 6.09e6.16 (m, 1H),
5.85e5.92 (m, 1H), 5.63 (dd, J¼7.6, 15.2 Hz, 1H), 4.47 (t, J¼7.6 Hz,
1H), 3.83e3.93 (m, 5H), 3.73 (dd, J¼5.2, 8.0 Hz, 1H), 2.34e2.56 (m,
3H), 2.10e2.28 (m, 3H), 1.69 (s, 6H), 1.41 (s, 6H), 1.18 (d, J¼6.0 Hz,
2. Shao, C. L.; Wu, H. X.; Wang, C. Y.; Liu, Q. A.; Xu, Y.; Wei, M. Y.; Qian, P. Y.; Gu, Y.
C.; Zheng, C. J.; She, Z. G.; Lin, Y. C. J. Nat. Prod. 2011, 74, 629e633.
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3H); 13C NMR (100 MHz, CDCl3):
d 165.3, 160.7, 159.0, 144.1, 132.2,
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132.2, 131.7, 130.3, 109.1, 109.0, 105.5, 104.0, 100.7, 82.8, 79.1, 71.4,
67.5, 56.0, 42.3, 37.0, 27.4, 27.3, 25.9, 23.2; ESI-HRMS calcd for
C
25H34O8 ([MþNa]þ) 485.2145, found 485.2130.
4.1.10. Cochliomycin A (1). To a stirred solution of 5 (57 mg,
0.123 mmol) in anhydrous DMF (10 mL), was added sodium hydride
(86 mg, 2.15 mmol, 60% oil dispersion) at 0 ꢂC under N2 atmo-
sphere. The mixture was stirred for 1 h. To this mixture was added
saturated aqueous NH4Cl and the mixture was extracted with ethyl
acetate, dried, filtered, and concentrated under reduced pressure.
This residue was purified by silica gel column chromatography
(ethyl acetate/petroleum ether 1:3) to give 1 (23 mg, 46%) as
a white solid (mp 68 ꢂC); ½a D
ꢁ
24 10.5 (c 0.6, MeOH); IR (
n
): 3405, 2921,
11.49 (s,
2372, 2307, 1629, 1378 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
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1H), 7.17 (dd, J¼2.0, 15.2 Hz, 1H), 6.48 (d, J¼2.8 Hz, 1H), 6.40 (d,
J¼2.8 Hz, 1H), 6.00 (ddd, J¼5.2, 8.0, 15.2 Hz, 1H), 5.73 (ddd, J¼2.8,
10.4, 15.2 Hz, 1H), 5.53 (dd, J¼8.8, 15.2 Hz, 1H), 5.42e5.48 (m, 1H),
4.57 (t, J¼8.4 Hz, 1H), 4.21 (ddd, J¼2.0, 4.8, 12.0 Hz, 1H), 3.90 (dd,
J¼2.4, 8.0 Hz, 1H), 3.82 (s, 3H), 2.73e2.80 (m, 1H), 2.18e2.55 (m,
4H), 1.45 (d, J¼6.4 Hz, 3H), 1.44 (s, 3H), 1.38 (s, 3H); 13C NMR
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(100 MHz, CDCl3):
d 170.8, 164.8, 164.0, 142.1, 134.1, 132.7, 129.5,
126.4,108.5,107.2,104.4, 100.1, 81.4, 75.3, 70.6, 68.8, 55.4, 37.9, 36.0,
27.0, 27.0, 19.2; ESI-HRMS calcd for C22H28O7 ([MþNa]þ) 427.1727,
found 427.1728.
Acknowledgements
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This work was supported in partial by the National Basic
Research Program of China (Grants 2012CB822101 and
2011CB936001),
National
Innovative
Drug
Foundation
(2012ZX09502001), and NNSF of China (Projects 21372254 and
Please cite this article in press as: Wang, L.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.001