Asymmetric total synthesis of 5′-epi-cochliomycin C

Article abstract of DOI:10.1016/j.tet.2013.02.033

Asymmetric total synthesis of one of the stereoisomers of naturally occurring chlorine containing 14-membered ring macrolide cochliomycin-F (5′-epi) has been described in this article. The main highlight of the presented synthetic strategy involves a highly regioselective chlorination and Julia-Kocienski olefination with a highly substituted aromatic chloro-aldehyde to create the required E-olefinic unsaturation in the target molecule. Mitsunobu macrolactonization reaction at the late stage enables us to synthesize the target molecule.

Full text of DOI:10.1016/j.tet.2013.02.033

Tetrahedron 69 (2013) 2900e2908
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Tetrahedron
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Asymmetric total synthesis of 50-epi-cochliomycin C
*
Nandan Jana, Debabrata Das, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of one of the stereoisomers of naturally occurring chlorine containing
14-membered ring macrolide cochliomycin-F (50-epi) has been described in this article. The main
highlight of the presented synthetic strategy involves a highly regioselective chlorination and Ju-
liaeKocienski olefination with a highly substituted aromatic chloro-aldehyde to create the required
E-olefinic unsaturation in the target molecule. Mitsunobu macrolactonization reaction at the late stage
enables us to synthesize the target molecule.
Received 27 December 2012
Received in revised form 17 January 2013
Accepted 7 February 2013
Available online 13 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
At first our goal was to synthesize two natural RALs (peacilomycin
F and cochliomycin C) through a common chiral intermediate by
b
-Resorcylic acid lactones (RALs) belong to a unique class of
a divergent approach. As both of the compounds have a common
structural motif with same stereochemical features (except the sub-
stitution pattern at the aromatic ring). Asymmetric dihydroxylation
by Sharpless protocol was initially thought to create the required two
fungal polyketide derived secondary metabolite, which are
b
-resorcylic acid derivatives containing a C11 side chain.1 In ma-
jority of the cases these RALs having a 14-membered ring lactone as
one of its core structural component. Their biological activity spans
from estrogenic, antifungal, cytotoxic, antimalarial and also have
shown to possess inhibitory effect against selective enzymes such
as ATPases and kinases.2 Recently three new 14-membered RALs,
two with an unusual natural acetonide group and one with
a 5-chloro-substituted lactone, named cochliomycins AeC (1e3),
together with four known analogues, zeaenol (4), LL-Z1640-1 (5),
LL-Z1640-2 (6), and paecilomycin F (7), were isolated from the
culture broth of Cochliobolus lunatus, a fungus obtained from the
gorgonian Dichotella gemmacea collected in the South China Sea
(Fig. 1).1c,3 Recently, RAL based fungal metabolites such as
hypothemycin, LL-Z1640-2 and L-783277 have been recognized
new class of protein kinase inhibitors.1e,4 A new family of closely
related resocyclic macrolides isolated from the fermentation of
Pochonia chlamydosporia was recently reported and named
pochonins AeF (8e13), among them five are substituted with
a chlorine atom at the aromatic ring (AeE).1j Whereas radicicol (14)
is one of the well-known chlorine containing RAL, found to be the
most potent inhibitor of HSV (herpes simplex virus). There exist
few synthetic reports for the chloro containing RALs mainly
pochonins AeE and radicicol in the literature.5 We have recently
accomplished the total synthesis of cochliomycin-A, zeaenol, and
50-epi-paecilomycin-F for the first time.6
0
0
hydroxyl stereocenters at C5 and C6 on a Z-substituted
a,b-un-
saturated ester. During our synthetic efforts toward 50-epi-paecilo-
mycin-F we have observed that, the selectivity of asymmetric
dihydroxylation on Z-substituted
was not up to the mark, whereas the selectivity with the corre-
sponding E-olefin was so high, we have decided to carry out the
synthesis with the stereochemically pure diol obtained from E-olefin,
which eventually lead us to 50-epi analogue of the natural product. In
the true sense the synthesis presented here is not a target oriented
synthesis rather it could be better described as a strategy oriented
a,b-unsaturated ester by AD-mix
b
0
0
synthesis as two hydroxyl stereocenters at C5 and C6 have been fixed
by asymmetric dihydroxylation by AD-mix
b
, which lead us to 50-epi-
stereocentre. While our efforts toward the total synthesis of several
RALs are underway, herein we report the asymmetric total synthesis
of 50-epi-cochliomycin-C (15). A detailed structureeactivity re-
lationship (SAR) with in the RAL family indicates that presence of
hydroxyl group at C5 and C6 is essential for increased activity and
solubility.7 As there is no reported relationship between the absolute
configuration of those two stereocenters with its biological activity, it
might be interesting to synthesize all the possible stereoisomers
(variationsatC5 andC6 )andevaluate their biologicalprofileindetail.
Retrosynthetic analysis of compound 15 is shown in Scheme 1.
We envisioned that the double bond between C-10 and C-20 can
be constructed from the ester 16 by adopting ring closing me-
tathesis (RCM) reaction. Whereas the ester 16 can be accessed
from alcohol 17 and highly functionalized aromatic acid 18 con-
taining a pendant vinyl group and required chlorine group by
0
0
0
0
* Corresponding author. Tel.: þ91 3222 283328; fax: þ91 3222 282252; e-mail
address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.033

N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
2901
O
OH
O
OH
OH
R
O
O
O
O
O
MeO
OH
MeO
MeO
OH
OH
OH
O
O
O
OH
1; Cochliomycin A
OH
R = Cl; 3; Cochliomycin C
R = H; 7; Paecilomycin F
2; Cochliomycin B
OH
O
O
O
O
OH
O
HO
MeO
OH
MeO
OH
O
O
O
OH
OH
MeO
OH
OH
4; Zeaenol
6; LL-Z1640-2
5; LL-Z1640-1
OH
O
OH
O
OH
O
O
O
O
O
Cl
HO
HO
HO
HO
Cl
R
Cl
2 O
R1
O
O
R
11: Pochonin D; R1 = H, R2 = Cl
12: Pochonin E; R1 = OH, R2 = Cl
13: Pochonin F; R1 = OH, R2 = H
8; Pochonin A; R = H
9; Pochonin B; R = OH
10: Pochonin C
OH
O
OH
O
O
O
O
MeO
OH
HO
Cl
Cl
OH
O
OH
15: 5'-epi-cochliomycin C
14: Radicicol
Fig. 1. Structures of cochliomycins, pochonins and other related RALs.
Mitsunobu esterification
OH
O
1
OH
Cl
O
9'
3
OH
Cl
O
O
3'
HO
8'
OH
O
1'
OH
7'
6'
OH
MeO
5
+
OP
5'
MeO
OP
Cl
MeO
2'
4'
O
OH
O
18
O
RCM
5'-epi-cochliomycin C; 15
O
17
P = MOM
16
OH
H
OTBDPS
Ref 6b
O
CO2Et
O
2-hydroxy-4-methoxy-6-vinylbenzaldehyde (19, ref 7a)
Scheme 1. Retrosynthetic analysis of 50-epi-cochliomycin C.
a Mitsunobu esterification reaction. The alcohol fragment 17
was earlier synthesized in our group6b for the total synthesis of
50-epi-paecilomycin-F from 1,5-pentane diol by applying stereo-
selective Keck allylation, Sharpless asymmetric dihydroxylation,
and ME-DKR reaction (metaleenzyme combined dynamic kinetic
resolution). The aromatic acid 18 is synthesized by a one-pot
oxidation/chlorination sequence starting from the known alde-
hyde 19.6a

2902
N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
2. Present work
the crucial RCM reaction failed to yield the desired product, we
thought to revise the strategy. The revised strategy was outlined in
Scheme 3, where macrolactonization by Mitsunobu inversion re-
action was thought to construct the macrocycle. The olefinic unsa-
turation (between C-10 and C-20) with E-geometry was planned to
construct by JuliaeKocienski olefination (Scheme 3) between al-
dehyde 23 and sulfone 24. The sulfone 24 was prepared from the
known compound 256b in just three steps as described below.
Whereas aldehyde 23 can be easily accessed from known acid 18.
2.1. Synthesis of aromatic acid 18
We have started our synthetic venture starting from the known
tetrasubstituted aldehyde 19, which on oxidation under Pinnick con-
dition (with H2NeSO3H used as a hypochlorous acid scavenger)
afforded the acid 18 with the incorporation of the required chlorine
group at 3-position (Scheme 2) in 90% yield. The selective in-
corporation of the Cl atom in the 3-position of compound 18 was
proved by NOESY analysis. The acid 20, which is earlier synthesized in
our group6b in its 1He1H NOESY spectrum clearly shows presence of
cross-peaks between HaeHb and HaeHc (Scheme 2; see Supple-
mentary data for the spectrum). Whereas no such cross-peak was
observed in the 1He1H NOESY spectrum ofcompound 18. This is avery
clear indication that incorporation of the ‘Cl’ atom took place in the
required position.
2.3. Revised synthetic strategy
Thus when hydroxy-acid 18 was subjected to treatment with
acetone in presence of (CF3CO)2O it affords the corresponding cyclic
ester 26 in 88% yield.10 The structure of compound 26 was further
confirmed by single crystal X-ray analysis (Fig. 2), which proves that
incorporation of ‘Cl’ atom took place in a regioselective manner.
OH
O
OH
OH
O
HO
CHO
CO2H
a
b
+
O
OR
OR
O
O
Cl
O
O
Cl
19
16
O
O
R = MOM
18
17
c or d
OH
Cl
O
OH
OH
O
H
X
H
X
Hc
Hc
O
O
MeO
20
Hd
MeO
Hd
OR
Ha Hb
Cl
H
O
X = CO2H
O
18; No such NOE
O
OR
Cl
NOE observed between Ha-Hb and Ha-Hc
O
O
O
OH
21
Scheme 2. Reagents and conditions: (a) NaClO2, NH2SO3H, THF/H2O (1:2), 0 ꢀC to rt, 2 h, 90%; (b) DIAD, PPh3, toluene, 1.5 h, 80%; (c) Grubbs-II (7 mol %), DCM, reflux, 40%;
(d) HoveydaeGrubbs-II, DCM, reflux, 32%.
This one-pot oxidation/electrophilic chlorination reaction is
unique as it is very high yielding, affords only one regioisomeric
product and depending on the reaction condition incorporation of
chlorine may or may not take place in the aromatic nucleus. It is
worth mentioning that in our earlier report for the total synthesis
of 50-epi-paecilomycin F,6b we have synthesized a similar acid
without the chlorine atom at 3-position by conducting a Pinnick
oxidation of aldehyde 19, where 2-methyl-2-butene was used as
HOCl scavenger. In general for the total synthesis of chlorine con-
taining RALs, researchers used Ca(OCl)2 or SO2Cl2 at a late stage as a
source of Clþ for the incorporation of chlorine group in the aromatic
nucleus. Chlorination with SO2Cl2 suffers with low regioselectivity
whereas with Ca(OCl)2 yields are usually not good.8
Oxidative cleavage of 26 afforded aldehyde 23 in a single-pot op-
eration in 82% yield.11 Whereas compound 25 upon similar oxida-
tive cleavage followed by reduction of the aldehyde functionality
afforded alcohol 27. Compound 27 was then transformed to sulfone
24 by Mitsunobu reaction and oxidation of the sulfide in 84% yield
over two steps (Scheme 4).
2.4. Fragment coupling and completion of the synthesis
Next JuliaeKocienski olefination of the sulfone 24 with chloro-
aldehyde 23 has been attempted.12 The reaction employing
KHMDS as a base and 18-c-6 as an additive afforded the desired
olefin 22 in 72% yield (E/Z¼12:1). Compound 22 upon treatment
with TBAF afforded the alcohol 28 in 88% yield. Removal of the
cyclic ester functionality was achieved by treating compound 28
with LiOH in THF/water (2:1) solvent system to furnish hydroxy-
acid 29 in 80% yield. Macrolatonization of acid 29 under Mitsu-
nobu inversion condition afforded the desired ring closing lactone
30 in 75% yield.13 Finally deprotection of acetonide and MOM
functionality with 2 N HCl14 afforded the chloro-RAL 50-epi-
cochliomycin C in 90% yield (Scheme 5; overall yield¼2.6% from
1,5-pentane diol).
2.2. Fragment coupling and unsuccessful RCM attempt
Acid 18 is then coupled with the known alcohol 176b under
Mitsunobu condition to afford the ester 16 in 80% yield. Ring closing
metathesis reaction is then attempted on ester 16 under various
conditions.9 But to our dismay the required ring-closing product
was not obtained, instead cross metathesis (CM) product 21 was
obtained in moderate yield (40 and 32%, respectively; Scheme 2). As

N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
2903
Mitsunobu
macrolactonization
OTBDPS
OTBDPS
OR
OH
Cl
O
O
O
O
O
O
O
O
OR
+
O
OR
O
CHO
O
O
TPO2S
O
O
O
Cl
O
Cl
24
O
15
23
R= MOM
JK Olefination
22
OTBDPS
OR
OH OH
O
O
Cl
18
O
O
25
Scheme 3. Revised retrosynthetic strategy involving macrolactonization protocol.
3. Conclusion
In conclusion, we have synthesized new chlorine containing RAL
50-epi-cochliomycin-C in asymmetric fashion. Highlights of our
synthetic strategy involved a highly regioselective electrophilic
chlorination for the synthesis of penta substituted benzaldehyde,
which is then used for JuliaeKocienski olefination. Finally macro-
latonization through Mitsunobu esterification method lead to our
target molecule. Synthetic studies toward several structurally re-
lated RALs (cochliomycins B and C, paecilomycin F) are still under
investigation in our laboratory.
4. Experimental
4.1. General
All moisture and oxygen sensitive reactions were carried out in
flame-dried glassware under a nitrogen atmosphere unless other-
wise stated. Unless otherwise stated, materials were obtained from
commercial suppliers and used without further purification.
Fig. 2. ORTEP presentation (drawn at 50% probability) of compound 26.
OH OH
O
O
O
O
b
a
O
O
O
O
O
O
CHO
23
18
26
Cl
Cl
Cl
OTBDPS
OR
OTBDPS
OR
OTBDPS
OR
c, d
e, f
HO
TPO2S
O
O
O
O
O
O
25
27
24
R = MOM (methoxy methyl)
Scheme 4. Reagents and Conditions: (a) (CF3CO)2O, CH3COCH3, H2SO4 (cat.), ꢁ8 ꢀC, 12 h, 88%; (b) OsO4, NaIO4, THF/H2O (3:1), rt, 2 h, 82%; (c) same as b, 88%; (d) NaBH4, MeOH, rt,
1 h, 96%; (e) PTSH, PPh3, DIAD, THF; (f) (NH4)6Mo7O24$4H2O, H2O2, EtOH (84% in two steps).

2904
N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
OTBDPS
OTBDPS
OR
O
O
O
O
a
O
OR
O
+
O
CHO
23
TPO2S
O
O
O
24
22
Cl
O
Cl
O
PT = 1-phenyl-1H-tetrazol-5-yl
OH
OR
OH
OH OH
O
O
c
b
O
O
OR
O
O
O
O
29
O
Cl
28
O
Cl
OH
O
OH
O
O
d
O
e
O
OH
O
OR
Cl
Cl
OH
30
R = MOM (methoxy methyl)
O
OH
15; 5'-epi-cochliomycin-C
O
Scheme 5. Reagents and conditions: (a) KHMDS, 18-c-6, THF, ꢁ78 ꢀC, 0.5 h, 72%; (b) TBAF, THF, rt, 4 h, 88%; (c) LiOH$H2O, THF/H2O (2:1), 24 h, 80%; (d) DIAD, PPh3, toluene, 1.5 h,
75%; (e) 2 N HCl, THF, 20 h, 90%.
Tetrahydrofuran and diethylether were distilled from sodiumben-
zophenone ketyl. Dichloromethane (DCM), dimethylformamide
(DMF), and dimethylsulfoxide (DMSO) were distilled from calcium
hydride prior to use. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm silica gel plates
(Merck) with UV light, ethanolic anisaldehyde, and phosphomo-
lybdic acid/heat as developing agents. Silica gel 100e200 mesh was
used for column chromatography. Yields refer to chromatographi-
cally and spectroscopically homogeneous materials unless other-
wise stated. NMR spectra were recorded on Bruker 400 and
200 MHz spectrometers at 25 ꢀC in CDCl3 using TMS as the internal
filtered, and concentrated in vacuum to afford the crude acid. The
crude material was then purified by flash column chromatography
with EtOAc/petroleum ether (1:3) to yield the corresponding acid 18
(575 mg) as brown solid in 90% yield. Mp 128e130 ꢀC.
Rf¼0.3 (EtOAc/hexane; 2:1).
IR (n .
): 3400, 2982, 2933, 1710 cmꢁ1
dH (CDCl3, 200 MHz): 11.3 (br, 1H), 6.87 (dd, J¼17.6, 11.6 Hz, 1H),
6.51 (s,1H), 5.61 (d, J¼11.6 Hz,1H), 5.31 (d, J¼17.6 Hz,1H), 3.94 (s, 3H).
dC (CDCl3, 50 MHz): 173.9, 163.5, 160.5, 141.4, 134.0, 120.5, 114.1,
104.2, 99.6, 56.4.
HRMS (ESI) for C10H9ClO4Na [MþNa]þ, calculated: 251.0087,
found: 251.0083.
standard. Chemical shifts are shown in d.
13C NMR spectra were
recorded with a complete proton-decoupling environment. The
chemical shift value is listed as dH and dC for 1H and 13C, re-
spectively. Melting points are uncorrected. Optical rotations were
measured on a JASCO P-1020 digital polarimeter. Mass spectro-
scopic analysis was performed in the IICT, Hyderabad (TOF ana-
lyzer). X-ray data were obtained at IIT-Kharagpur X-ray
Crystallography Facility, Department of Chemistry. One of the
crystal structure reported in the manuscript (compound 26) has
been deposited to Cambridge Crystallographic Data Centre and the
number obtained is CCDC 902974.
4.3. (S)-5-((4R,5R)-5-((S)-1-(Methoxymethoxy)but-3-enyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)pentan-2-yl 2-hydroxy-4-
methoxy-5-chloro-6-vinylbenzoate (16)
OH
O
O
O
OR
Cl
4.2. 3-Chloro-6-hydroxy-4-methoxy-2-vinylbenzoic acid (18)
O
O
OH
R= MOM
CO2H
Triphenylphosphine (Ph3P, 210 mg, 0.8 mmol) and DIAD (0.16 mL,
0.8 mmol) were added sequentially to a stirred solution of acid 18
(92 mg, 0.4 mmol) and alcohol 17 (113 mg, 0.4 mmol) in dry toluene
(4 mL). After completion of the reaction as indicated by TLC analysis,
EtOAc (10 mL) and H2O (5 mL) were added to the reaction solution.
The layers were separated and the aqueous phase was extracted
with EtOAc (2ꢂ15 mL). The combined organic portions were washed
with brine, dried with MgSO4, and concentrated under reduced
pressure to afford the crude residue, which was then purified by
O
Cl
Solution of aldehyde 19 (500 mg, 2.8 mmol) in THF (12 mL) was
sequentially treated at 0 ꢀC with sulfamic acid (545 mg, 5.6 mmol) and
a solution of sodium chlorite (509 mg, 5.6 mmol) in H2O (6 mL). After
2 h stirring at room temperature, the reaction mixture was diluted
with EtOAc. The layers were separated, and it was washed with sat-
urated NH4Cl solution. The organic solvent was dried (MgSO4),

N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
2905
silica gel column chromatography with EtOAc/petroleum ether
(1:20) to afford ester 16 (165 mg) as a colorless syrup (85%).
Rf¼0.4 (EtOAc/hexane, 1:10).
In a 10 mL round-bottomed flask equipped with a magnetic
stirring bar was charged with acid 18 (525 mg, 2.3 mmol), tri-
fluoroacetic anhydride (0.4 mL), and anhydrous acetone (2 mL). The
mixture was then cooled to ꢁ8 ꢀC and catalytic amount of con-
centrated H2SO4 was added to the stirring mixture. The flask was
then kept at ꢁ8 ꢀC for 12 h with stirring. After that time a saturated
solution of aqueous NaHCO3 was poured into the reaction mixture,
and extracted with ethyl acetate (3ꢂ20 mL). The combined organic
extracts were washed with water and brine, dried over anhydrous
MgSO4, filtered, and concentrated to give a brown residue. Chro-
matography of the crude residue over silica using EtOAc/petroleum
ether (1:5) gave acetonide 26 (545 mg, 88%) as white solid.
Rf¼0.7 (EtOAc/hexane, 1:5). Mp 105e107 ꢀC.
IR (n .
): 3440, 2982, 2933, 1705, 1651 cmꢁ1
[
a]
25 ꢁ21.7 (c 0.4, MeOH). dH (CDCl3, 400 MHz): 11.48 (s,1H), 6.81
D
(dd, J¼17.6, 11.6 Hz, 1H), 6.5 (s, 1H), 5.87e5.81 (m, 1H), 5.46 (d,
J¼11.6 Hz,1H), 5.26e5.06 (m, 4H), 4.68 (s, 2H), 3.9 (s, 3H), 3.88e3.86
(m, 1H), 3.71e3.65 (m, 2H), 3.38 (s, 3H), 2.42e2.29 (m, 2H),
1.60e1.32 (m, 6H), 1.42 (s, 3H), 1.40 (s, 3H), 1.22 (d, J¼6.0 Hz, 3H).
dC (CDCl3, 100 MHz): 170.5, 162.6, 159.7, 141.1, 134.8, 134.6, 119.1,
117.8, 113.8, 108.6, 106.1, 99.6, 96.5, 81.9, 77.8, 76.0, 73.3, 56.5, 56.0,
35.9, 33.5, 27.5, 27.1, 22.3, 19.9.
HRMS (ESI) for C26H37ClO8Na [MþNa]þ, calculated: 535.2075,
found: 535.2078.
IR (n .
): 2930, 2372, 1705 cmꢁ1
dH (CDCl3, 200 MHz): 7.0 (dd, J¼17.6, 11.6 Hz, 1H), 6.43 (s, 1H),
5.67 (d, J¼11.6 Hz, 1H), 3.92 (s, 3H), 1.7 (s, 6H).
dC (CDCl3, 50 MHz): 160.9, 159.2, 156.9, 141.6, 132.2, 121.6, 116.9,
105.5, 105.3, 99.2, 56.7, 25.6.
4.4. Dimer 21
HRMS (ESI) for C13H13ClO4Na [MþNa]þ, calculated: 291.0400,
found: 291.0405.
OH
Cl
O
O
4.6. 6-Chloro-7-methoxy-2,2-dimethyl-4-oxo-4H-benzo[d]
[1,3]dioxine-5-carbaldehyde (23)
O
O
OR
O
O
O
O
O
OR
Cl
O
O
O
CHO
O
Cl
O
OH
Dihydroxylation of olefinic compound 26 and consecutive oxi-
dative cleavage were performed in single-pot operation. To a stirring
solution of the olefin 26 (520 mg, 1.94 mmol) in THF/H2O (3:1) at
room temperature NMO (681.8 mg, 5.82 mmol), 0.05 M solution of
OsO4 in toluene (7.76 mL, 0.38 mmol), and NaIO4 (1.24 g, 5.82 mmol)
were added sequentially. The mixture was then stirred vigorously at
room temperature for 3 h, and then quenched by the addition of
saturated aqueous Na2SO3 solution. The solution was extracted then
with EtOAc. The combined organic layers were washed with aqueous
NaHCO3 solution, dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the crude residue was accomplished
by flash column chromatography eluting with EtOAc/petroleum
ether (1:7) to afford the aldehyde 23 (430 mg, 82%) as white solid.
Rf¼0.45 (EtOAc/hexane, 1:5). Mp 110e113 ꢀC.
The ester 16 (152 mg, 0.3 mmol) was taken in anhydrous
degassed DCM (150 mL). The second-generation Grubbs metathesis
catalyst (18 mg, 7 mol %) was then added and the reaction mixture
was allowed to stir at 40 ꢀC for 8 h. The solution was concentrated
and the contents of the flask were directly loaded on a silica gel
column. Flash chromatography with EtOAc/petroleum ether (1:3)
afforded the dimer 21 (119 mg, 40%).
The ester 16 was treated with HoveydaeGrubbs-II (5 mol %)
catalyst in the same manner to afford the dimer 21 (96 mg, 32%).
Rf¼0.2 (EtOAc/hexane, 1:7).
IR (n .
): 3400, 3012, 2935, 2372, 2341, 1698 cmꢁ1
[
a]
25 ꢁ82.5 (c 1.0, MeOH). dH (CDCl3, 400 MHz): 11.5 (s, 2H), 6.88
D
IR (
dH (CDCl3, 200 MHz): 10.4 (s, 1H), 6.57 (s, 1H), 3.96 (s, 3H), 1.75
(s, 6H).
n .
): 2825, 1720, 1700 cmꢁ1
(dd, J¼17.4, 11.2 Hz, 2H), 6.5 (s, 2H), 5.74e5.68 (m, 2H), 5.48
(d, J¼11.2 Hz, 2H), 5.3e5.1 (m, 4H), 4.81e4.77 (m, 4H), 3.95 (s, 6H),
3.94e3.90 (m, 2H), 3.7e3.65 (m, 4H), 3.4 (s, 6H), 2.48e2.40 (m, 4H),
1.62e1.48 (m, 12H), 1.4e1.3 (12H), 1.26 (d, J¼6.0 Hz, 6H).
dC (CDCl3, 100 MHz): 170.3, 162.4, 159.6, 140.9, 134.7, 128.7, 118.9,
113.7, 108.6, 106.0, 99.5, 96.2, 81.4, 78.5, 77.5, 73.1, 56.4, 55.8, 35.7,
34.5, 34.3, 27.4, 27.0, 22.2.19.7.
dC (CDCl3, 50 MHz): 190.8, 161.7, 159.3, 156.9, 140.3, 115.3, 107.2,
104.8, 101.7, 57.2, 25.8.
HRMS (ESI) for C12H11ClO5Na [MþNa]þ, calculated: 293.0193,
found: 293.0198.
HRMS (ESI) for C52H74Cl2O16Na [MþNa]þ, calculated: 1047.4252,
found: 1047.4251.
4.7. (S)-3-(Methoxymethoxy)-3-((4R,5R)-5-((R)-4-tert-butyldi-
phenylsilyloxy-pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)
propan-1-ol (27)
4.5. 6-Chloro-7-methoxy-2,2-dimethyl-5-vinyl-4H-benzo[d]
[1,3]dioxin-4-one (26)
OTBDPS
O
O
MOMO
O
HO
O
O
O
Cl

2906
N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
dC (CDCl3, 50 MHz): 153.5, 135.9, 134.8, 134.6, 133.1, 131.5, 129.7,
The olefin 25 was converted to corresponding aldehyde by
129.5, 129.4, 127.5, 127.4, 125.1, 108.8, 96.8, 82.6, 77.8, 74.1, 69.4,
56.3, 52.8, 39.3, 33.5, 27.5, 27.1, 26.8, 24.7, 23.1, 21.7, 19.3.
HRMS (ESI) for C38H52N4O7SSiNa [MþNa]þ, calculated:
759.3224, found: 759.3229.
dihydroxylation and oxidative cleavage with OsO4/NaIO4 in one-pot
reaction as discussed earlier for compound 23. The aldehyde was
then reduced with NaBH4 as follows.
To a stirring solution of the crude aldehyde (1 g, 1.84 mmol) in
MeOH (10 mL) at 0 ꢀC NaBH4 (105 mg, 2.76 mmol, 1.5 equiv) was
added. Stirring was continued for 1 h at 0 ꢀC after which the reaction
was quenched with the slow addition of saturated aqueous NH4Cl
solution and then it was diluted with EtOAc. The layers were then
separated and the aqueous layer was extracted with EtOAc
(3ꢂ15 mL). The organic layer was washed with water, brine and then
dried over MgSO4. The organic solvent was concentrated under re-
duced pressure to provide the crude alcohol 27. The crude mixture
was then purified by flash column chromatography eluting with
EtOAc/petroleum ether (1:5) to afford the alcohol 27 (930 mg, 93%).
Rf¼0.55 (EtOAc/hexane; 1:5).
4.9. 6-Chloro-7-methoxy-5-((S,E)-4-(methoxymethoxy)-4-
((4R,5R)-5-((R)-4-tert-butyldiphenylsilyloxy-pentyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-1-enyl)-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (22)
OTBDPS
O
O
O
OR
IR (
n
): 3380, 2930 cmꢁ1
.
O
O
25
O
Cl
[a
]
þ11.5 (c 0.6, MeOH). dH (CDCl3, 200 MHz): 7.71e7.68 (m,
D
4H), 7.41e7.32 (m, 6H), 4.77e4.68 (m, 2H), 3.88e3.62 (m, 6H), 3.41
(s, 3H), 3.0 (br, 1H, eOH), 1.81e1.69 (m, 2H), 1.48e1.40 (m, 6H), 1.38
(s, 6H), 1.0 (s, 12H).
To a solution of sulfone 24 (580 mg, 0.786 mmol) and 18-crown-
6-ether (311 mg, 1.18 mmol) in THF (10 mL) was added 0.5 M so-
lution of KHMDS in toluene (1.84 mL, 0.92 mmol) at ꢁ78 ꢀC. The
mixture was stirred at ꢁ78 ꢀC for 30 min, a solution of aldehyde 23
(265 mg, 0.98 mmol) in THF (3 mL) was then added into this so-
lution. The reaction mixture was allowed to warm to room tem-
perature for 2 h and poured into saturated NH4Cl solution. This
mixture was then extracted with ethyl acetate and the organic layer
was washed with saturated NaHCO3 solution and brine. After dry-
ing with anhydrous MgSO4, solvent was removed in vacuo, and the
residue purified by silica gel column chromatography with EtOAc/
petroleum ether (1:5) gave olefin 22 (560 mg) in 75% yield.
Rf¼0.5 (EtOAc/hexane; 1:5).
dC (CDCl3, 50 MHz): 135.9, 134.8, 134.5, 129.5, 129.5, 127.5, 127.4,
108.4, 97.3, 83.1, 77.8, 74.9, 69.4, 58.6, 56.1, 39.3, 34.0, 33.6, 27.4, 27.1,
26.9, 23.1, 21.7, 19.3.
HRMS (ESI) for C31H48O6SiNa [MþNa]þ, calculated: 567.3118,
found: 567.3114.
4.8. 5-((S)-3-(Methoxymethoxy)-3-((4R,5R)-5-((R)-4-tert-bu-
tyldiphenylsilyloxy-pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)
propylsulfonyl)-1-phenyl-1H-tetrazole (24)
OTBDPS
OR
IR (
n
): 2935, 1698 cmꢁ1
þ19.0 (c 2.0, MeOH). dH (CDCl3, 400 MHz): 7.68e7.65 (m,
.
25
[a]
D
4H), 7.4e7.34 (m, 6H), 6.76 (d, J¼18.0 Hz, 1H), 6.43 (s, 1H), 5.97e5.93
(m, 1H), 4.78 (d, J¼6.8 Hz, 1H), 4.68 (d, J¼6.8 Hz, 1H), 3.93 (s, 3H),
3.93e3.88 (m, 1H), 3.86e3.74 (m, 3H), 3.37 (s, 3H), 2.68e2.58 (m,
2H), 1.71e1.5 (m, 6H), 1.42 (s, 3H), 1.38 (s, 3H), 1.0 (12H).
dC (CDCl3, 100 MHz): 160.7, 159.0, 156.8, 141.1, 135.8, 134.8, 134.4,
133.8,129.7,129.4,129.3,128.9,128.1,127.4,127.3,117.0,108.2,105.3,
98.8, 96.3, 81.6, 77.3, 75.7, 69.4, 56.5, 55.8, 39.3, 35.2, 33.4, 27.3, 26.9,
25.5, 25.4, 22.9, 21.7, 19.2.
TPO2S
O
O
Diisopropyl azodicarboxylate (0.42 mL, 2.1 mmol) was added to
a solution of alcohol 27 (880 mg, 1.61 mmol), PPh3 (472 mg,
1.8 mmol), and 1-phenyl-5-mercapto-1H-tetrazole [PT-SH]
(375 mg, 2.1 mmol) in THF (10 mL) at ꢁ20 ꢀC. The solution was
stirred at 0 ꢀC for 30 min, then the reaction mixture was poured
into water and extracted with ethyl acetate. The organic layer was
washed with saturated NaHCO3 solution and brine, dried with
anhydrous MgSO4, and concentrated in vacuum to afford the crude
sulfide. To the solution of the crude sulfide in ethanol (15 mL) were
added (NH4)6Mo7O24$4H2O (299 mg, 0.242 mmol) and 30% H2O2
solution (1.2 mL) at 0 ꢀC. The reaction mixture was stirred at room
temperature for 6 h, and then it was poured into 10% Na2S2O3 so-
lution and extracted with ethyl acetate. The organic layer was
washed with saturated NaHCO3 solution and brine, dried with
MgSO4, and concentrated in vacuo. The residue was purified over
silica gel column chromatography by eluting with EtOAc/petroleum
ether (1:7) to afford the sulfone 24 (1.04 g) as colorless gummy oil
in 88% yield (two steps).
HRMS (ESI) for C43H57ClO9SiNa [MþNa]þ, calculated: 803.3358,
found: 803.3362.
4.10. 6-Chloro-5-((S,E)-4-((4R,5R)-5-((R)-4-hydroxypentyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-4-(methoxymethoxy)but-1-enyl)-
7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (28)
OH
O
O
O
OR
O
O
O
Cl
Rf¼0.6 (EtOAc/hexane; 1:5).
Compound 22 (420 mg, 0.54 mmol) was taken in dry THF
(10 mL). TBAF (1 M in THF, 1.1 mL, 0.11 mmol) was added to it, and
the reaction mixture was stirred for 24 h at room temperature.
After this time, THF was evaporated, and water (2 mL) was added to
it. The reaction mixture was then extracted with EtOAc (25 mL). The
[a
]
25 þ12.45 (c 0.9, MeOH). dH (CDCl3, 400 MHz): 7.73e7.62 (m,
D
9H), 7.43e7.28 (m, 6H), 4.72e4.68 (m, 2H), 4.07e4.03 (m, 1H),
3.96e3.86 (m, 3H), 3.65e3.61 (m, 2H), 3.40 (s, 3H), 2.39e2.33 (m,
1H), 2.20e2.17 (m, 1H), 1.52e1.5 (m, 6H), 1.4 (s, 6H), 1.08 (12H).

N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
2907
organic layer was washed successively with dilute NaHCO3 solution
and brine. The organic solvent was dried with MgSO4 and evapo-
rated in vacuo to afford the crude product, which was purified by
flash chromatography with EtOAc/petroleum ether (1:3) to afford
the compound 28 (258 mg) in 88% yield.
To a solution of PPh3 (209 mg, 0.8 mmol) and DIAD (0.157 mL,
0.8 mmol) in 50 mL of anhydrous toluene under N2 atmosphere at
ꢁ10 ꢀC was added a solution of seco-acid 29 (100 mg, 0.2 mmol)
in 50 mL toluene via syringe pump over 1 h. The resulting mixture
was then slowly allowed to warm at room temperature. After
disappearance of starting material as indicated by TLC, the re-
action mixture was concentrated and the crude material was
purified by flash chromatography on silica gel with EtOAc/petro-
leum ether (1:10) to afford the macrolactone 30 (73 mg) in 75%
yield.
Rf¼0.35 (EtOAc/hexane; 1:5).
IR (n
): 3330, 2920, 2340, 1710 cmꢁ1
.
25
[
a]
þ9.67 (c 0.8, MeOH). dH (CDCl3, 400 MHz): 6.79 (d,
D
J¼16.0 Hz, 1H), 6.44 (s, 1H), 6.0e5.92 (m, 1H), 4.8 (d, J¼6.8 Hz, 1H),
4.71 (d, J¼6.8 Hz, 1H), 4.04e4.0 (m, 1H), 3.95 (s, 3H), 3.91e3.88 (m,
1H), 3.85e3.71 (m, 2H), 3.39 (s, 3H), 2.74e2.59 (m, 2H), 1.51e1.48
(m, 6H), 1.44 (s, 3H), 1.41 (s, 3H), 1.2 (d, J¼6.0 Hz, 3H).
dC (CDCl3, 100 MHz): 160.9, 159.3, 157.2, 141.4, 133.9, 127.7, 117.3,
108.5, 105.6, 105.5, 99.1, 96.6, 81.8, 77.5, 76.0, 69.0, 56.8, 56.1, 39.3,
35.4, 33.4, 27.6, 27.2, 25.8, 25.7, 23.6, 22.5.
Rf¼0.5 (EtOAc/hexane; 1:5).
IR (
n
): 2929, 2365, 2341, 1680 cmꢁ1
.
25
[a
]
þ22.4 (c 0.5, MeOH). dH (CDCl3, 400 MHz): 11.8 (br, 1H,
D
AreOH), 6.56 (d, J¼16.0 Hz, 1H), 6.45 (s, 1H), 6.0 (td, J¼16.0,
6.8 Hz, 1H), 5.25e5.20 (m, 1H), 4.8 (d, J¼6.8 Hz, 1H), 4.73 (d,
J¼6.8 Hz, 1H), 3.94 (s, 3H), 3.88e3.68 (m, 3H), 3.42 (s, 3H),
2.74e2.50 (m, 2H), 1.78e1.52 (m, 6H), 1.43 (s, 3H), 1.41 (s, 3H), 1.1
(d, J¼6.2 Hz, 3H).
HRMS (ESI) for C27H39ClO9Na [MþNa]þ, calculated: 565.2180,
found: 565.2185.
4.11. 3-Chloro-6-hydroxy-2-((S,E)-4-((4R,5R)-5-((R)-4-
hydroxypentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-(methox-
ymethoxy)but-1-enyl)-4-methoxybenzoic acid (29)
dC (CDCl3, 100 MHz): 171.0, 163.1, 160.0, 142.5, 134.0, 128.6, 113.6,
109.0, 104.7, 99.8, 95.9, 82.0, 77.5, 76.3, 70.6, 56.8, 56.0, 35.3, 34.9,
32.8, 27.7, 27.3, 20.9, 20.6.
HRMS (ESI) for C24H33ClO8Na [MþNa]þ, calculated: 507.1762,
found: 507.1766.
OH
OH OH
4.13. 50-epi-Cochliomycin C
O
OR
O
O
OH
Cl
O
O
Cl
O
To a solution of compound 28 (180 mg, 0.33 mmol) in THF (4 mL)
was added LiOH$H2O (54 mg, 1.3 mmol) in H2O (2 mL) at 0 ꢀC. After
completion of the hydrolysis (approximately 20 H), 0.5 N HCl was
slowly added till the solution becomes acidic and it was diluted
with EtOAc. The layers were then separated and the aqueous layer
was extracted with EtOAc (2ꢂ10 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure to give the seco-acid as sticky oil. It was then purified by
flash chromatography with EtOAc/petroleum ether (1:1) to afford
the pure compound 29 (133 mg) in 80% yield.
O
OH
OH
OH
To a solution of compound 30 (50 mg, 0.103 mmol) in THF
(5 mL) was added HCl (2 N, 5 mL) and the mixture was then
stirred for 20 h at room temperature. The reaction was then
quenched with saturated aqueous NaHCO3 solution and
extracted with EtOAc. The organic layer was dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pres-
sure to afford the crude product, which was the purified by
flash column chromatography with EtOAc/petroleum ether
(3:2) to afford 5-epi-Cochliomycin C as a white powder (37 mg,
90%).
Rf¼0.25 (EtOAc/hexane; 1:1).
IR (
n
): 3400, 2930, 2372, 2341, 1690 cmꢁ1
.
25
[
a]
þ19.67 (c 0.4, MeOH). dH (CDCl3, 400 MHz): 11.8 (br, 1H),
D
6.59 (d, J¼16.0 Hz, 1H), 6.44 (s, 1H), 5.70e5.62 (m, 1H), 4.78 (d,
J¼6.8 Hz, 1H), 4.7 (d, J¼6.8 Hz, 2H), 4.1e4.04 (m, 1H), 3.94 (s, 3H),
3.92e3.7 (m, 3H), 3.40 (s, 3H), 2.67e2.52 (m, 2H), 1.65e1.53 (m,
6H), 1.43 (s, 3H), 1.41 (s, 3H), 1.18 (d, J¼6.0 Hz, 3H).
dC (CDCl3, 100 MHz): 173.8, 163.4, 160.1, 140.8, 131.1, 130.0, 114.3,
108.6, 105.3, 99.5, 99.2, 81.7, 77.6, 76.3, 68.4, 56.5, 56.1, 38.5, 35.0,
33.4, 27.6, 27.0, 23.6, 21.7.
Rf¼0.3 (EtOAc/hexane, 2:1).
IR (
n
): 3440, 2930, 2852, 1690, 1598 cmꢁ1
.
25
[a
]
þ41.7 (c 0.5, MeOH). dH (CDCl3, 400 MHz): 12.02 (br, 1H,
D
AreOH), 6.57 (d, J¼16.0 Hz, 1H), 6.47 (s, 1H), 5.95e5.87 (m, 1H),
5.19e5.12 (m, 1H), 3.9 (s, 3H), 3.94e3.9 (m, 1H), 3.7e3.67 (m, 1H),
3.48e3.45 (m, 1H), 2.89e2.85 (m, 1H), 2.52e2.45 (m, 1H), 1.88e1.67
(m, 6H), 1.32 (d, J¼6.2 Hz, 3H). dC (CDCl3, 100 MHz): 171.0, 163.3,
160.3, 140.6, 131.1, 128.8, 114.9, 105.6, 99.8, 73.6, 70.9, 69.8, 67.4,
56.0, 35.8, 34.8, 32.4, 21.5, 21.2. HRMS (ESI) for C19H25ClO7Na
[MþNa]þ, calculated: 423.1187, found: 423.1182.
HRMS (ESI) for C24H35ClO9Na [MþNa]þ, calculated: 525.1867,
found: 525.1862.
4.12. Compound 30
OH
Cl
O
O
Acknowledgements
O
OR
Financial support from CSIR-India is gratefully acknowledged
(grant: 02(0020)/11/EMR-II). We are also thankful to DST-India
(IRPHA) for NMR instrument. One of the authors N.J. is thankful
to CSIR-India for providing research fellowship. One of the authors
D.D. is thankful to UGC-India for providing research fellowship.
O
O

2908
N. Jana et al. / Tetrahedron 69 (2013) 2900e2908
5418e5426; (k) Takehara, K.; Sato, S.; Kobayashi, T.; Maeda, T. Biochem. Biophys.
Supplementary data
Res. Commun. 1999, 257, 19e23; (l) Giese, N. A.; Lokker, N. Int. Pat. WO9613259;
Chem. Abstr. 1996, 457801; (m) Nonomiya-Tsuji, J.; Kajino, T.; Ono, K.; Ohtomo,
T.; Matsumoto, M.; Shiina, M.; Mihara, M.; Tsuchiya, M.; Matsumoto, K. J. Biol.
Chem. 2003, 278, 18485e18490.
Copies of the 1H NMR and 13C NMR spectra for all key in-
termediates and final product. Supplementary data associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.02.033.
3. 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.
4. (a) Liniger, M.; Neuhaus, C.; Hofmann, T.; Fransioli-Ignazio, L.; Jordi, M.;
Drueckes, P.; Trappe, J.; Fabbro, D.; Altmann, K.-H. Med. Chem. Lett. 2011, 2,
22e27; (b) Hofmann, T.; Altmann, K.-H. C.R. Chim. 2008, 11, 1318e1335.
5. (a) Selles, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4621e4625; (b) Selles, P.; Lett,
R. Tetrahedron Lett. 2002, 43, 4627e4631; (c) Agatsuma, T.; Ogawa, K.; Aka-
saka, K.; Asai, A.; Yamashita, Y.; Mizukami, T.; Akinaga, S.; Saitoh, Y. Bioorg.
Med. Chem. 2002, 10, 3445e3454; (d) Barluenga, S.; Lopez, P.; Moulin, E.;
Winssinger, N. Angew. Chem., Int. Ed. 2004, 43, 3467e3470; (e) Moulin, E.;
Zoete, V.; Barluenga, S.; Karplus, M.; Winssinger, N. J. Am. Chem. Soc. 2005,
127, 6999e7004; (f) Grabaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Dani-
shefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903e10908; (g) Barluenga, S.;
Moulin, E.; Lopez, P.; Winssinger, N. Chem.dEur. J. 2005, 11, 4935e4952; (h)
Grabaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 2, 3127e3129; (i) Yang, Z.;
Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc.
2004, 126, 7881e7889.
References and notes
1. (a) Delmotte, P.; Delmotte-Plaquee, J. Nature 1953, 171, 344; (b) Stob, M.;
Baldwin, R. S.; Tuite, J.; Andrews, F. N.; Gillette, K. G. Nature 1962, 196, 1318; (c)
Ellestad, G. A.; Lovell, F. M.; Perkinson, N. A.; Hargreaves, R. T.; McGahren, W. J. J.
Org. Chem. 1978, 43, 2339e2343; (d) Nair, M. S. R.; Carey, S. T. Tetrahedron Lett.
1980, 21, 2011e2012; (e) Winssinger, N.; Barluenga, S. Chem. Commun. 2007,
22e36; (f) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561e1566; (j) Hellwig, V.; Mayer-
Bartschmid, A.; Muller, H.; Greif, G.; Kleymann, G.; Zitzmann, W.; Tichy, H. V.;
Stadler, M. J. Nat. Prod. 2003, 66, 829e837; (h) Shining, H.; Kawamura, Y.; Ikeda,
A.; Aoki, M.; Sakai, N.; Fujimoto, N.; Kawashima, A. Tetrahedron 2009, 65,
3446e3453; (i) Xu, L. X.; He, Z. X.; Xue, J. H.; Chen, X. P.; Wei, X. Y. J. Nat. Prod.
2010, 73, 885e889.
6. (a) Jana, N.; Nanda, S. Eur. J. Org. Chem. 2012, 4313e4320; (b) Jana, N.; Nanda, S.
Tetrahedron: Asymmetry 2012, 23, 802e808.
7. Shinonaga, H.; Noguchi, T.; Ikeda, A.; Aoki, M.; Fujimoto, N.; Kawashima, A.
Bioorg. Med. Chem. 2009, 17, 4622e4635.
8. Green, R. H. Tetrahedron Lett. 1997, 38, 4697e4700.
9. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953e956; (b)
Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746e1787.
10. Dushin, R. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1992, 114, 655e659.
11. Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21,
478e479.
2. (a) Shier, W. T.; Shier, A. C.; Xie, W.; Mirocha, C. J. Toxicon 2001, 39, 1435e1438;
(b) Isaka, M.; Yangchum, A.; Intamas, S.; Kocharin, K.; Jones, E. B. G.; Kong-
saeree, P.; Prabpai, S. Tetrahedron 2009, 65, 4396e4403; (c) Ayer, W. A.; Lee, S.
P.; Tsuneda, A.; Hiratsuka, Y. Can. J. Microbiol. 1980, 26, 766e773; (d) Boettger-
Tong, H.; Murthy, L.; Chiappetta, C.; Kirkland, J. L.; Goodwin, B.; Adlercreutz, H.;
Stancel, G. M.; Makela, S. Environ. Health Perspect. 1998, 106, 369e373; (e)
Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Mordecai, D. Endocrinology
1979, 105, 33e40; (f) Dong, J.; Zhu, Y.; Song, H.; Li, R.; He, H.; Liu, H.; Huang, R.;
Zhou, Y.; Wang, L.; Cao, Y.; Zhang, K. J. Chem. Ecol. 2007, 33, 1115e1126; (g) Abid,
E. S.; Ouanes, Z.; Hassen, W.; Baudrimont, I.; Creppy, E.; Bacha, H. Toxicol.
In Vitro 2004, 18, 467e474; (h) Furstner, A.; Langemann, K. J. Am. Chem. Soc.
1997, 119, 9130e9136; (i) Kwon, H. J.; Yoshida, M.; Abe, K.; Horinouchi, S.;
Beppu, T. Biosci. Biotechnol. Biochem. 1992, 56, 538e539; (j) Chanmugam, P.;
Feng, L.; Liou, S.; Jang, B. C.; Boudreau, M.; Yu, G.; Lee, J. H.; Kwon, H. J.; Beppu,
T.; Yoshida, M.; Xia, Y.; Wilson, C. B.; Hwang, D. J. Biol. Chem. 1995, 270,
12. Aissa, C. Eur. J. Org. Chem. 2009, 1831e1844.
13. (a) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976, 17,
2455e2488; (b) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3,
3149e3152; (c) Marcantoni, E.; Massaccesi, M.; Petrini, M.; Bartoli, G.; Bellucci,
M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 2000, 65, 4553e4559; (d) Liao, X.; Wu,
Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003, 42, 1648e1652.
14. Meyers, A. I.; Durandetta, J. L.; Munavu, R. J. Org. Chem. 1975, 40, 2025e2029.