Stereoselective total synthesis of (-)-cleistenolide

Article abstract of DOI:10.1016/j.tet.2011.03.107

A stereoselective total synthesis of (-)-cleistenolide (1) derived from d-(-)-isoascorbic acid has been described. The new synthetic strategy involves highly diastereoselective reduction, one-pot protection of required benzoyl, acetyl groups, and the RCM

Full text of DOI:10.1016/j.tet.2011.03.107

Tetrahedron 67 (2011) 3815e3819
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective total synthesis of (ꢀ)-cleistenolide
Dokuburra Chanti Babu, Jondoss Jon Paul Selavam, Dorigondla Kumar Reddy, Vanam Shekhar,
*
Yenamandra Venkateswarlu
Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology [IICT], Hyderabad 500 007, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective total synthesis of (ꢀ)-cleistenolide (1) derived from -(ꢀ)-isoascorbic acid has been
D
Received 8 December 2010
Received in revised form 25 March 2011
Accepted 30 March 2011
Available online 7 April 2011
described. The new synthetic strategy involves highly diastereoselective reduction, one-pot protection of
required benzoyl, acetyl groups, and the RCM reaction by using Grubbs catalyst are the key steps with
considerable yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Cleistenolide
Cleistochlamys kirkii
D
-(ꢀ)-Isoascorbic acid
K-Selectride
Oxa-Micheal addition
Grubbs RCM
1. Introduction
The preamble of antibiotics greatly reduced the mortality due to
infectious diseases.1 However, the pathogens developing resistance
to the antibiotics and host toxicity are some commonly encountered
setbacks of recurring or continuous usage of these agents.2 In view of
these shortcomings, there is a constant need and demand for the
identification and development of new antibacterial drugs. Natural
products showing even marginal antibacterial activity are good
source for new leads in drug discovery programs. As a general rule,
the molecular configuration with surrounded functional groups of-
fers the first insight of the pharmacophore entrenched in the com-
pound for itsbiological activity. The biological activityof components
usually depends on their functionality, configuration, and optical
purity. Mainly in the antibacterial drug discovery, the lactone func-
tionality is an important feature for antibacterial agents.3 The te-
nacity needed to preserve the configuration and functionality of
drugs from natural products call for estimable efforts and skills to-
ward their synthesis in enantiomerically pure form.4
extracts of these plants are used in traditional medicine as a rem-
edy for treatment of wound infections, rheumatism, and tubercu-
losis.6 In this backdrop of biomedical significance, recently a couple
of syntheses for (ꢀ)-cleistenolide are reported in the literature.7
Our research interest in the biologically active natural products
and the structural features of
a,b-unsaturated d-lactone moiety
with stereochemically defined tetrolsystem present in 1 gave im-
petus to the synthesis of (ꢀ)-cleistenolide (1). We have been
working in the area of synthesis of biologically active natural
products by using naturally available carbohydrates.8 Out of several
The natural products (ꢀ)-cleistenolide (1) and (ꢀ)-cleistodienol
(2) are isolated from the medicinal plant Cleistochlamys kirkii found
in Tanzania and Mozambique.5 (ꢀ)-Cleistenolide is a six membered
lactone having 2,3-dihydropyranone structure shows in vitro an-
tibacterial activity against Staphylococcus aureus and Bacillus
anthracis and antifungal activity against Candida albicans. The
available carbohydrates, we found that
D
-(ꢀ)-isoascorbic acid is one
of the best chiron source, which has been used for the total syn-
thesis of many bioactive natural products.9 Herein we are reporting
a new approach, where
D
-(ꢀ)-isoascorbic acid is the starting ma-
terial for the synthesis of (ꢀ)-cleistenolide (1).
In our retrosynthetic analysis of compound 1, (Scheme 1) the
intermediate acrylate ester (11) is derived from the compound (9)
by sequel conversions of
diastereoselective reduction and acrylation reactions.
D
-(ꢀ)-isoascorbic acid (3) including highly
* Corresponding author. E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.107

3816
D. Chanti Babu et al. / Tetrahedron 67 (2011) 3815e3819
the fully delocalization of electrons in unsaturated lactonic function
OPMB
of the compound 13.16ꢀ17
O
HO
O
OPMB
O
O
O
HO
With the strategic difficulty in Scheme 3, the isopropylidene
group was deprotected in the compound 11 using DOWEX-50 (Hþ)/
MeOHearly tothe RCM reaction topreventthe oxa-Micheal addition
to afford compound 15 in 95% yield. Here we applied one-pot syn-
thetic strategy for benzoylation and acetylation by the sequential
addition of pyridine and benzoyl chloride to compound 15 in
dichloromethane followed byacetic anhydride to obtain the tri ester
16 in 85% yield. Now the tri ester was subjected to ring closing me-
tathesis using Grubbs second generation catalyst to yield dihy-
dropyranone derivative 17 in 69%. The p-methoxy benzyl group in 17
was removed with DDQ, which was further on acetylation delivered
the natural product 1 in excellent yield as a colorless solid (Scheme
4). Thephysicaland spectroscopic dataof compound 1 werefound to
be identical with natural product (ꢀ) cleistenolide (1).5
O
H
1
O
HO
OH
OTBS
11
9
3
O
Scheme 1. Retrosynthetic analysis of cleistenolide (1).
2. Results and discussion
The synthesis of cleistenolide (1) started from commercially
available sugar -iso-
-(ꢀ)-isoascorbic acid 3 (Scheme 2). Initially
ascorbic acid 3 was converted into -hydroxy ester 4 using the lit-
D
D
a
erature procedure.10 The hydroxyl group in compound 4 was
protected with TBS group followed by the reduction with DIBAL-H to
afford the aldehyde, which was subjected to Grignard reaction with
vinyl magnesium bromideto afford the required allyl alcohol 6 in 73%
yield. In order to obtain the compound 8 with 1,2-syn selectivity at
chiral centers C3 and C4, the allylic alcohol 6 was first oxidized to
allylic ketone 7 with IBX followed by selective reduction. This re-
duction step proved to be unexpectedly troublesome. A collection of
reducing agents were screened, including (R)- and (S)-CBS$BH3,11
NaBH4/CeCl3,12 LiBH4, Red-Al,13 and L-Selectride. However, all these
experiments resulted either in poor diastereoselectivity or no re-
action. The reduction of 7 was next attempted with K-Selectride14
under suitable reaction conditions (ꢀ78 ꢁC, 6 h) to afford selec-
tively diastereomeric alcohol 8 (>95:5) in isolated 91% yield. Ste-
reochemistry of compound 8 was confirmed from the corresponding
diacetonide compound using reported literature.15
OPMB
OH
b
O
O
OPMB
O
O
O
14
a
11
d
OPMB
HO
O
HO
12
O
c
O
13
O
Scheme 3. Reagents and conditions: (a) Grubbs second generation catalyst (5 mol %),
DCM (0.02 mol/L), reflux, 12 h, 70%; (b) p-TSA, MeOH, rt, 2 h, 83%, (c) DOWEX-50 (Hþ),
MeOH, rt, 6 h, 94%; (d) Pyridine, DCM, rt, 30 min, 95%.
OH OPMB
O
OAc OPMB
O
HO
BzO
c
a
b
11
O
O
16
15
OAc OAc
O
OAc OH
O
OAc OPMB
O
BzO
BzO
BzO
e
d
O
O
1
Scheme 2. Reagents and conditions: (a) TBDMSCl, imidazole, DCM, 2 h, rt, 94%; (b) (i)
DIBAL-H, DCM, ꢀ78 ꢁC, 30 min; (ii) Vinyl magnesium bromide, 0 ꢁC to rt, 3 h, 73%;
(c) IBX, DMSO, rt, 3 h; 96% (d) K-Selectride, ꢀ78 ꢁC, 6 h, 91%; (e) PMB/Br, NaH, THF, rt,
1 h, 84%; (f) TBAF, THF, rt, 2 h, 96%; (f) Acryloyl chloride, Et3N, DMAP, rt, 4 h, 86%.
O
18
17
Scheme 4. Reagents and conditions: (a) DOWEX-50 (Hþ), MeOH, rt, 6 h, 95%; (b)
Pyridine, BzCl followed by Ac2O, DCM, 0 ꢁC to rt, 12 h, 85%; (c) Grubbs second gen-
eration catalyst, (5 mol %), DCM (0.01 mol/L), reflux, 12 h, 69%; (d) DDQ, Phosphate
buffer solution: DCM (9:1), rt, 2 h, 88%; (e) Ac2O, pyridine, DCM, rt, 2h, 89%.
The allylic alcohol in 8 was protected with PMB group and
removal of TBS protection using TBAF selectively afforded corre-
sponding alcohol 10 in 96% yield. The secondary alcohol in com-
pound 10 was subjected to acrylation to obtain the intermediate
diene 11 in considerable yield (86%), which was subjected to RCM
reaction successfully using Grubbs second generation catalyst to
obtain the compound 12 in 70% yield. The deprotection of iso-
propylidene group in cyclic compound 12, was unsuccessful with
different acidic catalysts like metal triflates, metal chlorides, CSA,
p-TSA, aq HCl, AcOH etc., in protic solvent media, and afforded
undesirable bicyclic product 14. Finally, the acetonide group was
removed using DOWEX-50 (Hþ) resin in methanol to afford com-
pound 13 (94% yield). Nevertheless, we have faced difficulty to
incorporate the benzoyl group at primary alcohol in compound 13.
With the addition of simple base to compound 13, it is undergoing to
form predominantly bicyclic product 14 and unable to get the re-
quired product. The literature investigations are suggesting that, the
oxa-Micheal addition mechanism may operate predominantly with
3. Conclusions
In summary we are reporting a stereoselective total synthesis of
(ꢀ)-cleistenolide (1) from
D-isoascorbic acid 3 in 18% over all yield.
Our synthetic route is very interesting with sequel reaction analyza-
tions, including high diastereoselective reduction and RCM reactions.
4. Experimental section
4.1. General information
Commercial reagents were used without further purification, all
solvents were purified by standard techniques and Infrared spectra
were recorded on PerkineElmer 683 spectrometer. Optical rota-
tions were obtained on Jasco Dip 360 digital polarimeter. NMR
spectra were recorded in CDCl3 solvent on Brucker 300 and Varian
500 NMR spectrometers. Chemical shifts (d) are quoted in parts per

D. Chanti Babu et al. / Tetrahedron 67 (2011) 3815e3819
3817
million and are referenced to tetramethylsilane (TMS) as an in-
ternal standard. Coupling constants (J) are quoted in Hertz. Column
chromatographic separations were carried out on silica gel
(60e120 mesh) and flash chromatographic separations were car-
ried out using 230e400 mesh, silica gel. ESIMS was recorded on
Agilent Technologies 1100 Series (Agilent Chemistation Software).
HRMS was recorded on Agilent Technologies 6510 Q-TOF LC/MS.
added and extracted into EtOAc (3ꢂ15 mL). The combined EtOAc
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give crude product, which
was purified on silica gel chromatography (5% ethyl acetate in
hexane) to furnish pure compound 7 as a pale yellow color oil
25
(4.65 g, 96% yield). Rf¼0.5 (EtOAc/hexane 1:9). [
CHCl3); IR (neat):
1H NMR (300 MHz, CDCl3):
a
]
þ15.5 (c 2.0,
D
n
2931, 2894, 2858, 1702, 1613, 1256, 1077 cmꢀ1
6.83e6.74 (1H, m, olefin) 6.43e6.37
;
d
4.2. Procedure: general experimental
(1H, dd, J¼1.5, 17.37 Hz, olefin), 5.80e5.76 (1H, dd, J¼1.5, 10.5 Hz,
olefin), 4.22e4.17 (2H, m), 4.0e3.9 (2H, m), 1.41 (3H, s), 1.31 (3H, s),
0.9 (9H, s, terbutyl), 0.08 (3H, s, MeSi), 0.02 (3H, s, MeSi); 13C NMR
4.2.1. (R)-Ethyl2-(tert-butyldimethylsilyloxy)-2-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)acetate (5). To a solution of 4 (5 g, 24.5 mmol) in
dry DCM (50 mL) was added imidizole (2.4 g, 36.75 mmol) followed
by TBSCl (3.95 g, 26.2 mmol). The reaction mixture was stirred for
5 h at room temperature After completion of the reaction as
monitored by TLC, solvent was removed under reduced pressure
and was purified over silica gel column chromatography (5% ethyl
(300 MHz, CDCl3):
d 198.8, 131.4, 129.5, 109.7, 78.1, 76.9, 65.7, 26.4,
25.6 (3C), 25.2, 18.0, ꢀ4.8, ꢀ5.0; ESIMS: 323 [MþNa]þ; HRMS cal-
culated for C15H28O4SiNa is 323.1649, found 323.1642.
4.2.4. (1S,2R)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-3-en-2-ol (8). To a cooled (ꢀ78 ꢁC) solution of
ketone 7 (4.6 g, 15.3 mmol) in toluene (40 mL) was added
K-Selectride (30.4 mL, 1 M in THF, 30.4 mmol) and the reaction
mixture was stirred for 6 h, allowing the temperature to warm
slowly up to ꢀ40 ꢁC. After completion of the reaction, the reaction
was quenched with aq NH4Cl (40 mL) and extracted into EtOAc
(3ꢂ40 mL). The combined organic extract was dried over anhy-
drous MgSO4 and concentrated under reduced pressure to give
crude product, which was purified using silica gel chromatography
(5% ethyl acetate in hexane) to afford allylic alcohol 8 (4.24 g, 91%
acetate in hexane) to furnish a pure compound 5 (7.32 g, 94%) as
25
a colorless liquid. Rf¼0.6 (EtOAc/hexane 1:9). [
CHCl3); IR (neat):
840, 779 cmꢀ1 1H NMR (300 MHz, CDCl3):
a
]
þ24.5 (c 2.04,
D
n
2933, 2859, 1750, 1473, 1371, 1256, 1155, 1074,
4.26e4.12(4H, m),
;
d
3.98e3.96 (2H, d, J¼5.28 Hz, OCH2CH), 1.41 (3H, s), 1.33 (3H, s),
1.32e1.25 (3H, t, J¼7.17 Hz, CH3CH2), 0.89 (9H, s, terbutyl), 0.08 (3H,
s, MeSi), 0.07 (3H, s, MeSi); 13C NMR (300 MHz, CDCl3):
d 171.4,
109.5, 77.1, 72.6, 65.3, 60.9, 26.6, 25.6 (3C), 25.3, 18.1, 14.1, ꢀ5.0,
ꢀ5.1; ESIMS: 341 [MþNa]þ; HRMS calculated for C15H30O5SiNa is
341.1760, found 341.1756.
yields) as a colorless oil. Rf¼0.4 (EtOAc/hexane 1:9). [
CHCl3); IR (neat):
NMR (CDCl3, 300 MHz):
a
]
25 þ37 (c 2.0,
D
n
3473, 2955, 2858, 1627, 1254, 1073 cmꢀ1
;
1H
4.2.2. (1S,2S)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-3-en-2-ol (6). To a cooled (ꢀ78 ꢁC) solution of
compound 5 (7.26 g, 22.7 mmol) in DCM (20 mL) was added DIBAL-
H (22.7 mL of a 1 M soln in toluene, 22.7 mmol) and stirred for 4 h.
After completion of the reaction as monitored by TLC, the reaction
mixture was quenched with saturated aqueous sodium potassium
tartarate solution (20 mL) and extracted into DCM, dried over an-
hydrous Na2SO4, and concentrated under reduced pressure to give
crude aldehyde, which was subjected to next reaction without
further purification. To a solution of crude aldehyde in dry THF
(60 mL) at ꢀ78 ꢁC was added vinyl magnesium bromide (34 mL of
a 1 M soln in THF, 34 mmol) slowly over 20 min. The reaction
mixture was stirred at the same temperature for 1 h and then
slowly warmed to room temperature over 2 h. After completion of
the reaction as monitored by TLC, the reaction was quenched with
saturated NH4Cl (20 mL) and extracted into EtOAc (3ꢂ15 mL). The
combined organic extract was washed with brine, dried over an-
hydrous Na2SO4, concentrated under reduced pressure which upon
silica gel chromatography (5% ethyl acetate in hexane) furnished
a pure compound 6 (5 g, 73%) as a yellow oil. Rf¼0.4(EtOAc/hexane
d
6.01e5.87 (1H, m, olefin), 5.39e5.32 (1H,
td, J¼1.7, 17.1 Hz, olefin), 5.24e5.11 (1H, td, J¼1.7, 10.7 Hz, olefin),
4.13e4.03 (2H, m), 3.99e3.94 (1H, m), 3.76e3.71 (2H, m, OCH2),
2.59e2.53 (1H, br s, OH), 1.40 (3H, s), 1.31 (3H, s), 0.89 (9H, s, ter-
butyl), 0.11 (3H, s, MeSi), 0.08 (3H, s, MeSi); 13C NMR (CDCl3,
100 MHz):
d 137.6, 115.72, 109.12, 76.2, 74.59, 73.82, 66.9, 26.82,
26.03 (3C), 25.47, 18.23, ꢀ3.84, ꢀ4.22; ESIMS: 325 [MþNa]þ; HRMS
calculated for C15H30O4SiNa is 325.1811, found 325.1800.
4.2.5. tert-Butyl((1S,2R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(4-
methoxybenzyloxy)but-3-enyloxy)dimethylsilane (9). To
a
cooled
(0 ꢁC) suspension of NaH (610 mg, 27.8 mmol) in dry THF (30 mL) was
added a solution of alcohol 8 (4.2 g, 13.9 mmol) in dry THF (30 mL)
followed by p-methoxy benzyl bromide (2.25 mL, 15.3 mmol) and
reaction mixture was allowed to stir for 2 h at room temperature.
After completion of the reaction, the reaction was quenched with
saturated NH4Cl (50 mL) and extracted into EtOAc (3ꢂ50 mL). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, and solvent concentrated under reduced pressure to
give crude product, which was purified on silica gel column chro-
1:9); IR (neat):
n
3473, 2955, 2858, 1727, 1254, 1073 cmꢀ1; 1H NMR
matography (5% ethyl acetate in hexane) to furnish pure PMB ether 9
25
(300 MHz, CDCl3): 5.92e5.80 (1H, m, olefin), 5.35e5.28 (1H, td,
J¼15.67, 1.51 Hz, olefin), 5.22e5.18 (1H, td, J¼10.57, 1.51 Hz, olefin),
4.24e4.20 (1H, m, CHOH), 4.06e4.00 (1H, m), 3.97e3.92 (1H,
t, J¼7.93 Hz), 3.89e3.85 (1H, dd, J¼4.72, 3.39 Hz), 3.84e3.79 (1H,
t, J¼7.74 Hz), 2.47e2.38 (1H, br s, OH), 1.37 (3H, s), 1.30 (3H, s), 0.88
(9H, s, terbutyl), 0.10 (6H, s, Me2Si); 13C NMR (300 MHz, CDCl3):
135.8, 116.8, 108.2, 75.8, 75.0, 72.3, 65.7, 26.5, 25.8 (3C), 25.5, 19.6,
ꢀ4.3, ꢀ4.4; ESIMS: 325 [MþNa]þ; HRMS calculated for
C15H30O4SiNa is 325.1811, found 325.1800.
(4.9 g, 84%) as a colorless liquid. Rf¼0.6 (EtOAc/hexane 1:9). [
a]
þ33(c 0.85, CHCl3); IR (neat):
NMR (300 MHz, CDCl3):
n
2954, 2930, 2857,1512,1250 cmꢀ1; 1DH
d
7.30e7.29 (2H, d, J¼8.1 Hz, ArH), 6.89e6.87
(2H, d, J¼8.1 Hz, ArH), 5.97e5.90 (1H, m, olefin), 5.30e5.26 (1H, d,
J¼17.2 Hz, olefin), 5.14e5.12 (1H, d, J¼9.9 Hz, olefin), 4.74e4.61 (2H,
q, J¼11.7, 50.8 Hz, OCH2) 4.32e4.28 (1H, m, OCH), 4.22e4.21 (1H, m),
3.90e3.87 (2H, d, J¼7.2 Hz), 3.8 (3H, s, OMe), 3.72e3.30 (1H, t,
J¼3.6 Hz), 1.43 (3H, s), 1.35 (3H, s), 0.91 (9H, s, terbutyl), 0.02 (6H, s,
Me2Si); 13C NMR (300 MHz, CDCl3):
d 159.0, 137.7, 130.7, 129.2 (2C),
115.0, 113.5 (2C), 81.5, 75.3, 73.7, 72.9, 65.0, 55.1, 26.3, 25.7 (3C), 25.0,
18.1, ꢀ4.8, ꢀ5.1; ESIMS: 445 [MþNa]þ; HRMS calculated for
C23H38O5SiNa is 445.2381, found 445.2407.
4.2.3. (R)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-di-
oxolan-4-yl)but-3-en-2-one (7). To a solution of alcohol (4.9 g,
16.2 mmol) in dimethylsulfoxide (DMSO, 10 mL) was added 2-
iodoxybenzoic acid (9 g, 32.4 mmol) at room temperature and
stirred for 3 h at room temperature. After completion of the re-
action, EtOAc (10 mL) was added to the reaction mixture. The
suspension was filtered. To the filtrate cooled brine solution was
4.2.6. (1S,2R)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(4-methoxy
benzyloxy)but-3-en-1-ol (10). To a cooled (0 ꢁC) solution of 9 (4.8 g,
11.4 mmol) in THF (30 mL) was added tetrabutylammonium fluo-
ride (17 mL of 1 M soln in THF, 17 mmol) and stirred for 4 h at room

3818
D. Chanti Babu et al. / Tetrahedron 67 (2011) 3815e3819
temperature. After completion of the reaction as monitored by TLC,
saturated NaHCO3 was added and extracted into EtOAc (3ꢂ15 mL).
The combined organic layer was washed with saturated NaHCO3,
brine, dried (Na2SO4), concentrated, and the crude residue was
purified by silica gel column chromatography (5% ethyl acetate in
hexane) to afford 10 (3.37 g, 96%) as a colorless liquid. Rf¼0.4
mixture was filtered and the solvent was evaporated to give crude
product that was purified over silica gel column chromatography
(5% ethyl acetate in hexane). Rf¼0.4 (EtOAc/hexane 6:4) to afford
25
compound 13 (206 mg, 94%) as a white solid. [
a
]
þ128(c 0.45,
D
CHCl3); IR (KBr):
n
3451,1750, 1625, 1514, 1255, 1070 cmꢀ1; 1H NMR
7.37 (1H, dd, J¼1.8, 7.2 Hz, olefin), 7.20e7.18
(300 MHz, CDCl3):
d
(EtOAc/hexane 1:9). [
a
]
25 þ33 (c 1.5, CHCl3); IR (neat):
n
3471, 2986,
(2H, d, J¼8.2 Hz, ArH), 6.87e6.86 (2H, d, J¼8.2 Hz, ArH), 6.14e6.12
(1H, m, olefin), 5.36 (1H, m), 4.53e4.45 (2H, q, J¼11.8, 31.9 Hz,
OCH2) 3.86 (1H, m), 3.80 (3H, s, OMe), 3.77 (1H, d, J¼3.6 Hz),
3.71e3.68(1H, m), 3.66e3.64 (1H, m), 2.06e1.56 (2H, br s, 2ꢂ OH);
13C NMR (300 MHz, CDCl3): 173.3, 159.4, 154.0, 129.9 (2C), 129.0,
122.1, 113.8 (2C), 83.6, 77.4, 74.0, 71.1, 63.1, 55.2; ESIMS: 317
[MþNa]þ; HRMS calculated for C15H18O6Na is 317.0996, found
317.1003.
D
2934, 16,121, 1514, 1376, 1248 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
7.25e7.23(2H, d, J¼8.37 Hz, ArH) 6.89e6.86 (2H, d, J¼8.63 Hz,
ArH), 6.04e5.93 (1H, m, olefin), 5.44e5.33 (1H, dd, J¼1.5, 17.1 Hz,
olefin), 5.27e5.23 (1H, dd, J¼1.5, 12.0 Hz, olefin), 4.63e4.57 (2H,
q, J¼10.9, 13.5 Hz, OCH2), 4.23e4.13 (2H, m), 4.05e3.97 (1H, m),
3.88e3.81 (1H, m), 3.80 (3H, s, OMe), 3.59e3.57 (1H, m), 2.70e2.63
(1H, br s, OH), 1.44 (3H, s), 1.34 (3H, s); 13C NMR (300 MHz, CDCl3):
d
159.4, 137.6, 129.8, 129.6 (2C), 116.1, 113.8 (2C), 109.0, 80.5, 75.8,
73.9, 72.0, 66.4, 55.2, 26.6, 25.2; ESIMS: 331 [MþNa]þ; HRMS cal-
4.2.10. (1R,5S,8R,9R)-8-Hydroxy-9-(4-methoxybenzyloxy)-2,6-di-
oxa-bicyclo[3.3.1]nonan-3-one (14). To a solution of 12 (250 mg,
0.74 mmol) in MeOH (20 mL) was added catalytic p-TSA and the
reaction mixture was allowed to stir for 2 h at room temperature.
After completion of the reaction as monitored by TLC, the reaction
mixture was filtered and the solvent was evaporated to give crude
product that was purified silica gel column chromatography (20%
ethyl acetate in hexane) to afford compound 14 (183 mg, 83%) as
culated for C17H24O5Na is 331.1516, found 331.1516.
4.2.7. (1S,2R)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(4-methoxy
benzyloxy)but-3-enyl acrylate (11). To a cooled (0 ꢁC) solution of 10
(3.3 g, 10.7 mmol) in DCM (40 mL) was added Et3N (2.23 mL,
21.4 mmol) followed by acryloyl chloride (1.7 mL, 21.4 mmol) and
stirred for 4 h at room temperature. After completion of the re-
action as monitored by TLC, water (40 mL) was added and extracted
into DCM (3ꢂ15 mL). The combined organic layer was washed with
saturated NaHCO3, brine, dried over Na2SO4, and concentrated
under reduced pressure to give crude product, which was purified
over silica gel column chromatography (10% ethyl acetate in hex-
ane) to afford 11 (3.33 g, 86%) as a colorless liquid. Rf¼0.55 (EtOAc/
a white solid. Rf¼0.4 (EtOAc/hexane 2:3). [
(KBr):
CDCl3):
J¼9.0 Hz, ArH), 4.87e4.86 (1H, d, J¼4.5 Hz), 4.80e4.76 (1H, m),
4.63e4.49(2H, q, J¼11.3, 27.9 Hz, OCH2), 4.06e4.04 (1H,
d, J¼5.3 Hz), 3.98e3.93 (1H, m), 3.80 (3H, s, OMe), 3.77e3.76(1H,
d, J¼3.0 Hz), 3.65e3.59 (1H, m), 2.71 (2H, m, CH2CO), 2.16e2.07
a
]
25 ꢀ3.5(c 0.5, CHCl3); IR
D
n
3465, 2927, 2859,1737,1237,1169 cmꢀ1; 1H NMR (300 MHz,
d
7.28e7.23 (2H, d, J¼9.0 Hz, ArH), 6.90e6.86 (2H, d,
hexane 2:8). [
a
]
25 þ66 (c 0.4, CHCl3); IR (neat):
n
3441, 2988, 2936,
7.27e7.23
D
1727, 1513, 1250, 1186 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
(1H, br s, OH); 13C NMR (300 MHz, CDCl3):
d 174.8, 159.5, 129.6 (2C),
(2H, d, J¼8.3 Hz, ArH), 6.88e6.85 (2H, d, J¼8.3 Hz, ArH), 6.48e6.40
(1H, dd, J¼1.5, 17.3 Hz, olefin), 6.20e6.11 (1H, m, olefin), 5.95e5.84
(2H, m, olefin), 5.48e5.45 (1H, m, OCH), 5.36e5.24 (2H, m, olefin),
4.66 (2H, s, OCH2), 4.19e4.08 (1H, m, OCH), 3.94e3.91 (2H, m), 3.82
(1H, m), 3.80 (3H, s, OMe), 1.41 (3H, s), 1.32 (3H, s); 13C NMR
128.6, 113.9 (2C), 87.8, 84.9, 82.7, 77.5, 72.4, 62.1, 55.2, 35.7; ESIMS:
317 [MþNa]þ; HRMS calculated for C15H18O6Na is 317.0996, found
317.1023.
4.2.11. (2R,3R,4R)-1,2-Dihydroxy-4-(4-methoxybenzyloxy)hex-5-en-
3-yl acrylate (15). To a solution of 11 (1.5 g, 4.1 mmol) in MeOH
(35 mL) was added DOWEX-50 resin and the reaction mixture was
allowed to stir for 6 h at room temperature. After completion of the
reaction as monitored by TLC, the reaction mixture was filtered and
the solvent was evaporated to give crude product that was purified
by column chromatography (25% ethyl acetate in hexane) to afford
compound 15 (1.26 g, 95%) as a colorless liquid. Rf¼0.4 (EtOAc/
(300 MHz, CDCl3):
d 164.9, 159.2, 133.0, 131.3, 129.9, 129.6 (2C),
128.1, 118.6, 113.7 (2C), 108.6, 79.4, 75.8, 74.3, 74.2, 65.4, 55.2, 26.4,
25.2; ESIMS: 385 [MþNa]þ; HRMS calculated for C20H26O6Na is
385.1622, found 385.1620.
4.2.8. (5R,6S)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-methoxy
benzyloxy)-5,6-dihydropyran-2-one (12). To a degassed solution of
acryl ester 11 (1 g, 2.76 mmol) in anhydrous DCM (100 mL) was
added Grubbs second generation catalyst (117 mg, 5 mol %) and
refluxed for 24 h. After completion of the reaction as monitored by
TLC, the reaction mixture was filtered and the solvent was evapo-
rated to give crude product that was purified by column chroma-
hexane 1:1). [
a
]
D
25 þ58 (c 1.8, CHCl3); IR (neat):
n
3430, 2929, 1722,
7.27e7.23
1613,1514, 1407, 1249 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
(2H, d, J¼8.6 Hz, ArH), 6.88e6.85 (2H, d, J¼8.6 Hz, ArH), 6.50e6.44
(1H, d, J¼17.3 Hz, olefin), 6.24e6.14 (1H, m, olefin), 6.03e5.91 (1H,
m, olefin), 5.90e5.86 (1H, d, J¼10.3 Hz, olefin), 5.67e5.64 (1H, m,
OCH), 5.42e5.36 (1H, d, J¼17.1 Hz, olefin), 5.30e5.27 (1H,
d, J¼10.5 Hz, olefin), 4.67e4.52 (2H,q, J¼10.9, 2.6 Hz, OCH2), 3.79
(3H, s, OMe), 3.74e3.33 (4H, m), 3.16e2.56 (2H, br s, 2ꢂ OH); 13C
tography (15% ethyl acetate in hexane) to afford compound 12
25
(645 mg, 70%) as colorless liquid. Rf¼0.3 (EtOAc/hexane 3:7). [
þ63 (c 0.48, CHCl3); IR (neat):
1076 cmꢀ1 1H NMR (300 MHz, CDCl3):
a]
D
n
2926, 1754, 1611, 1513, 1250,
7.47e7.45 (1H, dd, J¼1.5,
;
d
NMR (300 MHz, CDCl3): d 165.9, 159.3, 133.3, 131.8, 129.7 (2C),127.9,
6.0 Hz, olefin), 7.22e7.19 (2H, d, J¼9.0 Hz, ArH), 6.88e6.85 (2H, d,
J¼9.0 Hz, ArH), 6.14 (1H, m, olefin) 5.19 (1H, m, OCH), 4.65e4.60
(1H, d, J¼11.3 Hz), 4.53e4.49 (1H, d, J¼11.3 Hz), 4.19 (1H, m), 4.06
(1H, m), 3.82 (1H, m), 3.80 (3H, s, OMe), 3.56 (1H, m), 1.39 (3H, m),
117.9, 113.7 (2C), 80.4, 74.4, 74.3, 70.4, 63.0, 55.1; ESIMS: 345
[MþNa]þ; HRMS calculated for C17H22O6Na is 345.1309, found
345.1325.
1.34 (3H, m); 13C NMR (300 MHz, CDCl3):
d
173.3, 159.5, 153.3, 129.8
4.2.12. (2R,3S,4R)-2-Acetoxy-3-(acryloyloxy)-4-(4-methoxybenzyl-
oxy) hex-5-enyl benzoate (16). To a cooled (0 ꢁC) solution of diol 15
(1.1 g, 3.4 mmol) in DCM (15 mL) was added pyridine (1.10 mL,
13.6 mmol) followed by benzoyl chloride (0.4 mL, 3.4 mmol) and
the reaction mixture stirred at the same temperature for 3 h. Acetic
anhydride (0.3 mL, 3.4 mmol) was added to the reaction mixture at
(2C), 129.6, 122.2, 113.8 (2C), 110.1, 84.2, 79.0, 75.3, 74.4, 66.9, 55.6,
26.6, 25.1; ESIMS: 357[MþNa]þ; HRMS calculated for C18H22O6Na is
357.1309, found 357.1301.
4.2.9. (5R,6R)-6-((R)-1,2-Dihydroxyethyl)-5-(4-methoxy benzyloxy)-
5,6-dihydropyran-2-one (13). To
a
solution of 12 (250 mg,
0
ꢁC and stirred at room temperature for additional 4 h. Water
0.74 mmol) in MeOH (20 mL) was added DOWEX-50 resin and the
reaction mixture was allowed to stir for 6 h at room temperature.
After completion of the reaction as monitored by TLC, the reaction
(10 mL) was added to the reaction mixture and extracted with DCM
(3ꢂ15 mL). The combined organic layer was washed with saturated
NaHCO3, water, brine, dried (Na2SO4), concentrated, and the

D. Chanti Babu et al. / Tetrahedron 67 (2011) 3815e3819
3819
residue was purified by column chromatography (7% ethyl acetate
in hexane) to afford 16 (1.35 g, 85%) as a viscous liquid Compound.
the reaction mixture and stirred at room temperature for 4 h. After
completion of the reaction, water (10 mL) was added to the reaction
mixture and extracted with DCM (3ꢂ15 mL). The combined organic
layer was washed with saturated NaHCO3, water, brine, dried
(Na2SO4), concentrated, and the residue was purified over silica gel
column chromatography (15% ethyl acetate in hexane) to afford 1
(100 mg, 90%) as a white solid. Rf¼0.5 (EtOAc/hexane 3:7). Mp
Rf¼0.3 (EtOAc/hexane 1:9). Compound 16 [
IR (KBr):
(300 MHz, CDCl3):
(1H, t, J¼7.36 Hz, ArH), 7.48e7.39 (2H, t, J¼7.74 Hz, ArH), 7.28e7.22
(2H, d, J¼8.68 Hz, ArH), 6.87e6.80 (2H, d, J¼8.68 Hz, ArH),
6.50e6.41 (1H, m, olefin), 6.23e6.11 (1H, m, olefin), 6.05e5.83 (2H,
m, olefin), 5.64e5.58 (1H, m, OCH), 5.47e5.45(1H, m, OCH)
541e5.25 (2H, m, olefin), 4.72e4.54 (3H, m), 4.48e4.39 (1H, m),
3.95e3.89 (1H, m), 3.77 (3H, s, OMe), 2.02 (3H, s, CH3CO); 13C NMR
a
]
25 þ27.3 (c 0.9, CHCl3);
D
n
2927, 1726, 1611, 1513, 1183, 1072 cmꢀ1
;
1H NMR
d
8.02e7.95 (2H, d, J¼7.74 Hz, ArH), 7.61e7.52
132e134 ꢁC. [
a
]
25 ꢀ142 (c 0.4, CHCl3); IR (KBr):
n
2963, 1725, 1452,
8.02 (2H,
D
1372, 1224, 1099, 1070 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d
d, J¼7.7 Hz), 7.57 (1H, t, J¼7.5 Hz), 7.45 (2H, t, J¼7.6 Hz), 7.00 (1H, dd,
J¼9.6, 6.1 Hz), 6.29 (1H, d, J¼9.7 Hz), 5.52 (1H, ddd, J¼9.5, 4.0,
2.3 Hz), 5.42 (1H, dd, J¼6.0, 2.5 Hz), 4.93 (1H, dd, J¼12.5, 2.0 Hz),
4.80 (1H, dd, J¼9.6, 2.5 Hz), 4.53 (1H, dd, J¼12.5, 4.4 Hz), 2.09 (3H,
(300 MHz, CDCl3):
d 169.8, 166.1, 165.1, 159.4, 133.1, 132.5, 131.5,
129.8 (2C), 129.7, 129.6 (2C), 129.2, 128.4 (2C), 128.0, 118.8, 113.8
(2C), 77.7, 74.1, 73.4, 70.2, 62.9, 55.2, 20.9; ESIMS: 491 [MþNa]þ;
HRMS calculated for C26H28O8Na is 491.1676, found 491.1701.
s, CH3CO), 2.04 (3H, s, CH3CO); 13C NMR (300 MHz, CDCl3):
d 169.9,
169.5, 166.0, 161.1, 139.7, 133.3, 129.7 (2C), 129.6 (2C), 128.5, 125.4,
75.5, 67.7, 62.0, 59.7, 20.7, 20.5; ESIMS: 385 [MþNa]þ; HRMS cal-
culated for C18H18O8Na is 385. 1002, found 385.0992.
4.2.13. (R)-2-Acetoxy-2-((2S,3R)-3-(4-methoxybenzyloxy)-6-xo-
3,6-dihydro-2H-pyran-2-yl)ethyl benzoate (17). To a degassed so-
lution of diene ester 16 (500 mg, 1.06 mmol) in anhydrous DCM
(100 mL) was added Grubbs second generation catalyst (44 mg,
5 mol %) and refluxed for 24 h. After completion of the reaction as
monitored by TLC, the reaction mixture was filtered and the solvent
was evaporated to give crude product that was purified by column
Acknowledgements
Authors are thankful to UGC, CSIR New Delhi, India, for financial
assistance and to the Director of Indian Institute of Chemical
Technology, for his encouragement.
chromatography (15% ethyl acetate in hexane) to afford 17 (320 mg,
25
69%) as a viscous liquid. Rf¼0.4 (EtOAc/hexane 3:7). [
1.32, CHCl3); IR (neat):
NMR (300 MHz, CDCl3):
a
]
þ61.8(c
D
n
2924, 2853, 1751, 1724, 1514,1275 cmꢀ1
8.05e7.97 (2H, d, J¼8.3 Hz, ArH),
;
References and notes
d
1. (a) Livermore, D. M. Clin. Infect. Dis. 2003, 36, 1058e4838; (b) Ohno, A. Infect.
Control 2004, 13, 1012e1017; (c) McDaniel, R.; Welch, M.; Hutchinson, C. R.
Chem. Rev. 2005, 105, 543e558.
7.61e7.56 (1H, t, J¼7.5 Hz, ArH), 7.48e7.42 (2H, t, J¼7.5 Hz, ArH),
7.42e7.39 (1H, dd, J¼1.5, 6.0 Hz, olefin), 7.22e7.19 (2H, d, J¼8.3 Hz,
ArH), 6.85e6.82 (2H, d, J¼8.3 Hz, ArH), 6.21e6.18 (1H, dd, J¼2.2,
6.0 Hz, olefin), 5.26e5.20 (1H, m, OCH), 5.12e510 (1H, m, OCH),
4.79e4.74 (1H, dd, J¼3.0, 12.0 Hz), 4.61e4.53 (2H, m, OCH2),
4.47e4.41 (1H, dd, J¼5.2, 12.8 Hz), 3.98e3.95 (1H, d d, J¼3.7, 6.7 Hz,
OCH), 3.76 (3H, s, OMe), 2.04 (3H,s, CH3CO); 13C NMR (300 MHz,
2. (a) Hunt, E. Drugs Future 2000, 25, 1163e1168; (b) Walsh, C. T.; Wright, G. Chem.
Rev. 2005, 105, 391e394.
3. Siedle, B.; Pineres, A. J. G.; Murillo, R.; Schulte-Monting, J.; Castro, V.; Rungeler,
€
P.; Klaas, C. A.; Da Costa, F. B.; Kisiel, W.; Merfort, I. J. Med. Chem. 2004, 47,
6042e6054.
4. Nair, V.; Prabhakaran, J.; George, T. G. Tetrahedron 1997, 53, 15061e15068.
5. Samwel, S.; Mdachi, S. J. M.; Nkunya, M. H. H.; Irungu, B. N.; Moshi, M. J.;
Moulton, B.; Luisi, B. S. Nat. Prod. Commun. 2007, 2, 737e741.
CDCl3):
d 169.8, 166.0, 164.6, 159.6, 152.3, 133.2, 130.0 (2C), 129.8,
129.5 (2C), 128.5 (2C), 124.9, 123.2, 113.9 (2C), 82.6, 75.4, 74.0, 71.3,
62.3, 55.2, 20.8; ESIMS: 463 [MþNa]þ; HRMS calculated for
C24H24O8Na is 463.1363, found 463.1379.
6. Nkunya, M. H. H. Pure Appl. Chem. 2005, 77, 1943e1955.
7. (a) Schmidt, B.; Kunz, O.; Biernat, A. J. Org. Chem. 2010, 75, 2389e2394; (b) Cai,
C.; Liu, J.; Du, Y.; Linhardt, R. J. J. Org. Chem. 2010, 75, 5754e5756.
8. (a) Suresh, V.; Jon Paul Selvam, J.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron:
Asymmetry 2008, 19, 1509e1513; (b) Jon Paul Selvam, J.; Rajesh, K.; Suresh, V.;
Chanti Babu, D.; Venkateswarlu, Y. Tetrahedron: Asymmetry 2009, 20,
1115e1119; (c) Rajesh, K.; Suresh, V.; Jon Paul Selvam, J.; Venkateswarlu, Y.
Synthesis 2010, 8, 1381e1385; (d) Kumar Reddy, D.; Rajesh, K.; Shekhar, V.;
Chanti Babu, D.; Venkateswarlu, Y. Tetrahedron Lett. 2010, 51, 5440e5442; (e)
Prbhakar, P.; Rajaram, S.; Kumar Reddy, D.; Shekar, V.; Venkateswarlu, Y. Tet-
rahedron: Asymmetry 2010, 21, 216e221.
9. (a) Shen, X.; Wu, Y.-L.; Wu, Y. Helv. Chim. Acta 2000, 83, 943e953; (b) Hirata, Y.;
Nakamura, S.; Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.; Kitagaki, S.;
Shiro, M.; Hashimoto, S. Chem.dEur. J. 2006, 12, 8898e8925; (c) Dahlgren, A.;
Kvarnstroem, I.; Vrang, L.; Hamelink, E.; Hallberg, A.; Rosenquist, A.; Sa-
muelsson, B. Bioorg. Med. Chem. 2003, 11, 827e842.
10. Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu,
D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598e2602.
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A. L.; Luche, L. J. Am. Chem. Soc. 1981, 103, 5454e5459.
13. (a) Takahashi, T.; Miyazawa, M.; Tsuji, J. Tetrahedron Lett. 1985, 26, 5139e5142;
(b) Overman, L. E.; McCready, R. J. Tetrahedron Lett. 1982, 23, 2355e2358.
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4.2.14. (R)-2-Acetoxy-2-((2S,3R)-3-hydroxy-6-oxo-3,6-dihydro-2H-
pyran-2-yl)ethyl benzoate (18). To a solution of allyl ester (250 mg,
0.56 mmol) in CH2Cl2/phosphate buffer solution (9:1, 10 mL, pH 7.2)
at ambient temperature was added DDQ (161 mg, 0.7 mmol). The
reaction mixture was stirred for 1 h and the reaction mixture was
diluted with CH2Cl2, filtered and the organic layer was washed with
H2O, dried over Na2SO4, and concentrated under reduced pressure.
The crude residue was purified over silica gel column chromatog-
raphy (18% ethyl acetate in hexane) to afford (160 mg, 88%) of 18 as
a white solid. Rf¼0.2 (EtOAc/hexane 3:7). [
a
]
D
25 ꢀ29.5(c 0.45, CHCl3);
IR (KBr): 3427, 2924, 2854, 1724, 1277, 1229 cmꢀ1
;
1H NMR
(300 MHz, CDCl3):
d
8.05e8.01 (2H, d, J¼8.0 Hz, ArH), 7.63e7.58
(1H, t, J¼7.7 Hz, ArH), 7.49e7.47 (1H, d, J¼2.37 Hz, olefin), 7.46e7.43
(2H, t, J¼7.6 Hz, ArH), 6.24e6.21 (1H, dd, J¼2.2, 6.0 Hz, olefin),
5.25e5.20 (1H, m, OCH), 5.25e5.15 (1H, m, OCH), 4.78e4.65 (2H,
qd, J¼3.7 Hz, 12.0 Hz, 16.6 Hz,), 4.08e4.02 (1H, td, J¼3.02 Hz, OCH),
2.06 (3 H, s, CH3CO), 2.03e1.56 (1H, br s, OH); 13C NMR (300 MHz,
CDCl3):
d 169.8, 166.7, 164.3, 153.3, 133.4, 129.7 (2C), 128.5 (2C),
123.1, 82.2, 71.9, 68.9, 68.9, 62.5, 20.9; ESIMS: 343 [MþNa]þ; HRMS
calculated for C16H16O7Na is 343.0788, found 343.0803.
4.2.15. Cleistenolide (1). To a cooled (0 ꢁC) solution of alcohol 18
(100 mg, 0.31 mmol) in DCM (15 mL) was added pyridine (0.03 mL,
0.38 mmol) followed by acetic anhydride (0.03 mL, 0.31 mmol) to