Total synthesis of clavosolide A

Article abstract of DOI:10.1016/j.tet.2008.03.039

For the total synthesis of (-)-clavosolide A described herein, a Schmidt glycosidation reaction was used to attach the sugar moiety at an early stage in the synthesis to the 4-hydroxy group of the substituted tetrahydropyran unit of the molecule, which itself was built following a Ti(III)-mediated method developed by us earlier, and at the end, it was the Yamaguchi reaction that was successfully employed for the cyclodimerization of the two halves of the molecule leading to its total synthesis.

Full text of DOI:10.1016/j.tet.2008.03.039

Tetrahedron 64 (2008) 5162–5167
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Tetrahedron
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Total synthesis of clavosolide A
*
Tushar Kanti Chakraborty , Vakiti Ramkrishna Reddy, Praveen Kumar Gajula
Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
For the total synthesis of (ꢀ)-clavosolide A described herein, a Schmidt glycosidation reaction was used
to attach the sugar moiety at an early stage in the synthesis to the 4-hydroxy group of the substituted
tetrahydropyran unit of the molecule, which itself was built following a Ti(III)-mediated method
developed by us earlier, and at the end, it was the Yamaguchi reaction that was successfully employed for
the cyclodimerization of the two halves of the molecule leading to its total synthesis.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 February 2008
Received in revised form 12 March 2008
Accepted 13 March 2008
Available online 15 March 2008
Keywords:
Clavosolides
Clavosolide A
Epoxide opening
2-Methyl-1,3-diol
Diolide
1. Introduction
structure and established that this was indeed the naturally
occurring (ꢀ)-clavosolide A (5). Subsequently, we also reported the
There are many instances where the structures of the natural
products, isolated from various sources, were first wrongly
assigned, but corrected later on by chemical synthesis.1 Clavo-
solides A–D (1–4), isolated from extracts of the marine sponge
Myriastra clavosa collected in Philippines,2 are some of the recent
examples. Crude extracts of Myriastra clavosa displayed promising
cytotoxic and antiproliferative effects in antitumor screens. How-
ever, thorough evaluation of the cytotoxic properties of the clavo-
solides was not possible due to the limited natural abundance of
these compounds. The symmetric structure of the 16-membered
core diolide ring in these molecules, with highly substituted
tetrahydropyran units, disubstituted cyclopropyl rings, and per-
methylated xylose moieties, attracted the attention of many
synthetic chemists leading to their successful syntheses.3–9 Syn-
theses of the originally assigned structure of clavosolide A3a,b
revealed that it was actually an isomer of the natural product and
Willis et al.3b proposed a revised structure 5 for the molecule based
on NMR and molecular modeling. Subsequently, a total synthesis of
the revised structure for clavosolide A was accomplished by Lee
et al.4 Unfortunately, an error, which was subsequently corrected by
them,5 in the sign of the optical rotation led them mistakenly to
conclude that the compound synthesized by them was the anti-
pode of the natural product. This error was revealed by Willis et al.,6
as well as by Smith and Simov,7 who had synthesized the revised
total synthesis of the revised structure of (ꢀ)-clavosolide A.8
Recently, the total synthesis of (ꢀ)-clavosolide B was also accom-
plished by Lee et al.9 (Fig. 1).
One unsatisfactory aspect, in all the reported syntheses of
clavosolide A,3–8 was the forcible wastage of the invaluable aglycon
in the glycosidation step that resulted in the formation of unwanted
isomers along with the requisite target. To rectify this problem of
OMe
O
OMe
O
MeO
O
OMe
H
R''O
O
OR'
R
O
O
H
H
H
O
O
H O
H
H O
H
O
H
O
H
O
O
H
H
O
O
O
O
O
O
MeO
OMe
MeO
OMe
OMe
OMe
Clavosolides (originally reported structure)
Clavosolide A (5)
(Revised structure)
(1) A: R = R' = R'' = Me
(2) B: R = R' = Me, R'' = H
(3) C: R = R'' = Me, R' = H
(4) D: R = H, R' = R'' = Me
* Corresponding author. Tel.: þ91 40 2719 3154; fax: þ91 40 2719 3275/3108.
E-mail address: chakraborty@iict.res.in (T.K. Chakraborty).
Figure 1. Structures of clavosolides.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.039

T.K. Chakraborty et al. / Tetrahedron 64 (2008) 5162–5167
5163
loosing the priceless material at the final step, we decided to carry
out the glycosidation at an early stage10 and use O-glycoside as the
protecting group during the entire synthesis. The detail account of
this modified approach to (ꢀ)-clavosolide A is described in this
paper.
We needed the 9R-stereoisomer 11 to give the requisite (R,R)-
cyclopropane ring, since the cyclopropanation reaction is pre-
dominantly syn-selective.14 It was envisaged that inversion of the
C9–OH would re-establish the S-configuration in the product. In
order to generate more of the requisite propargylic alcohol 11, the
major isomer 12 was subjected to Mitsunobu inversion15 followed
by benzoate deprotection under basic conditions to provide 11 in
92% overall yield from 12.
2. Results and discussions
The remaining steps of the synthesis are shown in Scheme 2.
Red-Al reduction of 11 gave an E-allylic alcohol, in 80% yield, which
under modified Simmons–Smith cyclopropanation conditions16
furnished the expected syn-product 13 as the major isomer (de
>96%) in 91% yield. The stereochemistry of the major product was
assigned based on earlier reports.14 It now remained to invert the
C9-stereocentre. However, Mitsunobu reaction failed to provide the
inverted product. Therefore, an oxidation–reduction sequence was
contemplated as there are many methods known for diaster-
eoselective hydride reduction of cyclopropyl ketones.17
Our synthesis started with the tetrahydropyranyl compound 6
(Scheme 1), which was synthesized earlier by us3a applying
a methodology developed for the synthesis of highly substituted
tetrahydropyrans by a Ti(III)-mediated opening of trisubstituted
epoxy alcohols.11
OH
OH
O
Me
BnO
Me
BnO
i
Oxidation of 13 with Dess–Martin periodinane (DMP)18 pro-
vided the 9-keto intermediate, which was subjected to hydride
reduction using lithium aluminum hydride (LAH) in THF at 0 ꢁC to
give the required 9S-isomer 14 as the major product in 5:1 ratio.
The minor isomer could be separated easily by silica gel column
chromatography to give 14 in 54% overall yield after two steps.
Silylation of 14 gave the intermediate 15 in 89% yield. Deben-
zylation of 15 was followed by DMP oxidation to give an aldehyde,
which was subjected to olefination to furnish 16 in 67% yield in two
steps from the alcohol. Hydroboration of 16 gave, exclusively, the
primary alcohol 17, in 91% yield, which was oxidized to the
corresponding acid in two steps and 87% overall yield from 17.
Acid-catalyzed desilylation of the resulting acid furnished the hy-
OTBDPS
O
OH
6
OMe
7
MeO
NH
OMe
ii
iii
Cl3C
OMe
O
O
8
OMe
O
OMe
O
MeO
MeO
O
OMe
O
+
Me
BnO
Me
BnO
O
OTBDPS
O
OTBDPS
OMe
9
10
iv-vi
OMe
OMe
OMe
O
OMe
O
MeO
O
OMe
MeO
O
OMe
MeO
O
OMe
MeO
O
i-ii
11
O
O
Me
BnO
Me
BnO
Me
BnO
iii, iv
Me
BnO
OH
OH
OH
OH
+
O
O
11
O
O
Me
Me
12
13
14
vii
OMe
O
OMe
Scheme 1. Synthesis of compound 11. Reagents and conditions: (i) TBDPSCl, Et3N,
DMAP (cat), CH2Cl2, 0 ꢁC to rt, 4 h, 85%; (ii) 8, TMSOTf, 4 Å MS, CH2Cl2, rt, 2 h, 84%; (iii)
HF-Py (60–70%), rt, 6 h, 89%; (iv) TBAF, THF, 0 ꢁC to rt, 3 h, 95%; (v) (COCl)2, DMSO,
Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h, 96%; (vi) LDA, propyne, THF, ꢀ78 ꢁC, 0.5 h, then the aldehyde,
1 h, 90%; (vii) (a) DEAD, Ph3P, p-nitrobenzoic acid, 1 h; (b) K2CO3, MeOH, rt, 30 min,
92% in two steps.
MeO
O
OMe
vi-viii
MeO
O
OMe
v
ix
O
Me
BnO
Me
OTBS
OTBS
O
O
The primary hydroxyl group of 6 was selectively protected as
tert-butyldiphenylsilyl ether in the presence of the secondary
hydroxyl group, using 1.1 equiv of TBDPSCl, 1.5 equiv of TEA, and
0.1 equiv of DMAP in CH2Cl2 at 0 ꢁC to room temperature for 4 h, to
give the desired compound 7 in 85% yield. Schmidt glycosidation12
15
16
OMe
O
OMe
O
MeO
OMe
MeO
O
OMe
xiii
x-xii
of 7 with 2,3,4-tri-O-methyl-D-xylopyranosyl trichloroacetimidate
O
5
83a using TMSOTf in the presence of 4 Å MS in CH2Cl2 furnished, as
expected, a mixture (w1:1) of two products, which could be sep-
arated easily to give the unwanted a-product 9 along with the
desired b-product 10. The unwanted a-product 9 was subjected to
deglycosidation using HF-py,13 to recover the material as tetrahy-
dropyran 6, which was recycled to afford more quantities of the
desired b-product 10. Desilylation of 10 gave an alcohol that was
oxidized to the corresponding aldehyde and treated with Li-pro-
pynilide, generated from propyne and LDA, to furnish a mixture of
propargylic alcohols 11 and 12 in 90% overall yield and in 1:2 ratio.
The isomers could be separated easily by standard silica gel column
chromatography. The stereochemistries of the isomers were
assigned based on methods described earlier.3a
Me
Me
OTBS
O
OH
HO
O
HO
O
17
18
Scheme 2. Synthesis of clavosolide A (5). Reagents and conditions: (i) Red-Al, Et2O,
0 ꢁC, 4 h, 80%; (ii) CH2I2, Et2Zn, CH2Cl2, ꢀ20 ꢁC to 0 ꢁC, 5 h, 91%; (iii) DMP, CH2Cl2, 0 ꢁ
C
to rt, 30 min, 85%; (iv) LAH, THF, ꢀ78 ꢁC, 20 min, 63%; (v) TBSOTf, 2,6-lutidine, CH2Cl2,
0 ꢁC to rt, 4 h, 89%; (vi) H2, Pd–C, EtOAc, 1 h, 91%; (vii) DMP, CH2Cl2, 0 ꢁC to rt, 20 min;
(viii) Ph3P]CH2, Et2O, 0 ꢁC, 10 min, 67% in two steps; (ix) (chex)2BH, THF, 0 ꢁC, 1 h,
then 30% H2O2, NaOH, 2 h, 91%; (x) DMP, CH2Cl2, 0 ꢁC to rt, 20 min; (xi) NaClO2,
NaH2PO4$2H2O, 2-methyl-2-butene, rt, t-BuOH, 1 h, 87% in two steps; (xii) CSA, MeOH-
CH2Cl2 (1:1), 0 ꢁC to rt, 1 h, 85%; (xiii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, 3 h;
the mixed anhydride was then added to DMAP, toluene, 10ꢀ3 M, 80 ꢁC, 5 h, then 12 h at
rt, 71%.

5164
T.K. Chakraborty et al. / Tetrahedron 64 (2008) 5162–5167
droxy-acid 18, in 85% yield, which was subjected to cyclo-
dimerization reaction under Yamaguchi conditions.19 Following an
inverse-addition protocol, the mixed anhydride from 18, dissolved
in toluene, was slowly added using a syringe pump over ca. 5 h to
a solution of DMAP in toluene (final concentration 10ꢀ3 M) at 80 ꢁC
followed by stirring at room temperature for 12 h to furnish the
desired diolide 5 in 71% yield. The 1H and 13C NMR spectra and
optical rotation, [a]D ꢀ42.4 (c 0.125, CHCl3), of our synthetic
product 5 matched with those reported for the natural clavosolide
A (literature: [a]D ꢀ48.5 (c 1, CHCl3)).2a
127.5, 127.4, 80.7, 73.7, 73.3, 72.3, 70.6, 60.2, 40.9, 40.1, 38.7, 26.8,
19.2, 12.6; HRMS (ESIMS) calcd for
541.2750, found: 541.2738.
C
32H42O4NaSi [MþNa]þ:
3.1.2. Synthesis of 10
A
solution of the aglycon 7 (3.0 g, 5.79 mmol) and tri-
chloroacetimidate 8 (1.90 g, 5.79 mmol) in CH2Cl2 (15 mL) was
stirred with 4 Å MS (75 mg) for 15 min at room temperature and
then treated with TMSOTf (5.79 mL, 0.0579 mmol, 0.01 M solution
CH2Cl2) at room temperature. After being stirred for 2 h at room
temperature, the reaction mixture was quenched with Et3N (2
drops), washed with water (10 mL), brine (10 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by column chromatography
(SiO2, 18–26% EtOAc in petroleum ether eluant) eluted first the
desired b-product 10 (1.72 g, 43%) along with unwanted a-product
9 (1.64 g, 41%) as colorless oils.
In summary, we achieved the total synthesis of clavosolide A by
carrying out the glycosidation reaction in the early part of the
synthesis and used the O-glycosylated product in the remaining
steps. The overall yield calculated from the desilylated product
from 10 to the final product was 8.6% as compared to 1.93% from the
corresponding C4-OTBDPS protected intermediate reported in our
earlier synthesis.8
Analytical data for 10: Rf¼0.55 (SiO2, 40% EtOAc in petroleum
ether); [a]2D5 ꢀ6.18 (c 1.7, CHCl3); IR (neat): nmax 3016, 1471, 1426,
1364, 1213, 1161, 1089, 984, 927, 750, 702 cmꢀ1; 1H NMR (300 MHz,
3. Experimental section
CDCl3):
d 7.68–7.25 (m, 15H, aromatic protons), 4.55 (ABq,
3.1. General experimental procedures
J¼12.3 Hz, 2H, OCH2Ph), 4.31 (d, J¼7.4 Hz, 1H, anomeric proton),
3.96 (dd, J¼11.5, 5.1 Hz, 1H, OCH–), 3.87 (m, 1H, OCH–), 3.77 (m, 1H,
OCH–), 3.63 (s, 3H, OMe), 3.61 (s, 3H, OMe), 3.59–3.53 (m, 3H,
OCH2–, OCH–), 3.48 (s, 3H, OMe), 3.33–3.23 (m, 2H, OCH–), 3.15–
3.09 (m, 3H, OCH–), 3.01 (m, 1H, OCH–), 2.11 (dd, J¼11.9, 4.3 Hz, 1H,
CH), 1.86 (m, 1H, CH), 1.80–1.86 (m, 2H, CH), 1.46 (q, J¼11.5 Hz, 1H,
CH), 1.05 (s, 9H, tert-butyl protons), 0.99 (d, J¼6.4 Hz, 3H, Me pro-
tons); 13C NMR (75 MHz, CDCl3): d 138.4, 135.5, 134.0, 134.0, 129.5,
129.5, 128.2, 127.7, 127.6, 127.5, 127.4, 105.4, 85.6, 83.9, 83.7, 81.1,
79.4, 73.4, 72.3, 70.8, 63.2, 60.7, 60.7, 60.3, 58.7, 40.2, 38.8, 38.7, 26.9,
19.2, 12.6; MS (ESIMS) m/z (%): 715 (96) [MþNa]þ; HRMS (ESIMS)
calcd for C40H56O8NaSi [MþNa]þ: 715.3642, found: 715.3631.
Analytical data for compound 9: Rf¼0.52 (SiO2, 40% EtOAc in
petroleum ether); [a]D25 þ28.0 (c 0.43, CHCl3); IR (neat): nmax 2929,
All reactions were carried out in oven or flame-dried glassware
with magnetic stirring under nitrogen atmosphere using dry,
freshly distilled solvents, unless otherwise noted. Reactions were
monitored by thin layer chromatography (TLC) carried out on
0.25 mm silica gel plates with UV light, I2, 7% ethanolic phospho-
molybdic acid–heat and 2.5% ethanolic anisaldehyde (with 1%
AcOH and 3.3% concd H2SO4)–heat as developing agents. Silica gel
finer than 200 mesh was used for flash column chromatography.
Yields refer to chromatographically and spectroscopically homo-
geneous materials unless otherwise stated. Melting points are
uncorrected. IR spectra were recorded as neat liquids or KBr pellets.
Mass spectra were obtained under electron impact ionization (EI),
liquid secondary ion mass spectrometric (LSIMS) technique, elec-
tron spray ionization (ESI), and MALDI techniques. Optical rotations
were measured with a digital polarimeter. NMR spectra were
recorded on 500, 300, and 200 MHz spectrometers at 30 ꢁC with
2–10 mM solutions in appropriate solvents using TMS as internal
standard or the solvent signals as secondary standards and the
chemical shifts are shown in d scales. Multiplicities of NMR signals
are designated as s (singlet), d (doublet), t (triplet), q (quartet), br
(broad), m (multiplet, for unresolved lines), etc. 13C NMR spectra
were recorded on 150, 100, 75, and 50 MHz spectrometers with
complete proton decoupling.
2856, 1739, 1464, 1429, 1369, 1161, 1101, 1037, 822, 740, 702 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.68–7.29 (m, 15H, aromatic protons),
5.07 (d, J¼3.7 Hz, anomeric proton), 4.55 (ABq, J¼12.1 Hz, 2H,
OCH2Ph), 3.93–3.79 and 3.76–3.67 (m, 3H, OCH), 3.64 (s, 3H, OMe),
3.63–3.55 and 3.53–3.37 (m, 3H, OCH), 3.50 (s, 3H, OMe), 3.46 (s,
3H, OMe), 3.33–3.22 and 3.21–3.10 (m, 6H, OCH2– and OCH–), 2.07
(m, 1H, CH), 1.96–1.69 (m, 3H, CH), 1.25 (q, J¼11.6 Hz, 1H, CH), 1.04
(s, 9H, tert-butyl protons), 0.95 (d, J¼6.8 Hz, 3H, Me protons); 13C
NMR (75 MHz, CDCl3): d 138.4, 135.5, 135.5, 134.0, 129.5, 128.2,
127.7, 127.6, 127.4, 98.7, 83.2, 82.3, 82.2, 81.1, 80.0, 73.4, 72.2, 71.0,
60.5, 60.3, 59.8, 59.0, 58.8, 39.8, 38.8, 26.9,19.2,12.6; HRMS (ESIMS)
calcd for C40H56O8NaSi [MþNa]þ: 715.3642, found: 715.3650.
3.1.1. Synthesis of 7
To a stirred solution of 6 (2.0 g, 7.14 mmol) in CH2Cl2 (20 mL),
Et3N (1.48 mL, 10.71 mmol) and TBDPSCl (2.01 mL, 7.85 mmol)
were added sequentially at 0 ꢁC under nitrogen atmosphere. Next,
a catalytic amount of DMAP (87 mg, 0.71 mmol) was added to the
reaction mixture. The reaction mixture was warmed to room
temperature and stirred for 3 h. It was quenched with saturated
aqueous NH4Cl solution (20 mL) and extracted with CH2Cl2
(2ꢂ10 mL), washed with brine (10 mL), dried (Na2SO4), and con-
centrated in vacuo. Purification by column chromatography (SiO2,
20–22% EtOAc in petroleum ether eluant) afforded pure compound
7 (3.14 g, 85%) as colorless liquid. Rf¼0.52 (SiO2, 40% EtOAc in
3.1.3. Synthesis of 6 from 9
A polypropylene reaction vial was charged with compound 9
(158 mg, 0.23 mmol) and HF-py (4 mL, 60–70%), and the mixture
was stirred at 25 ꢁC for 6 h. The mixture was diluted with 10 mL of
MeOH and concentrated under a stream of nitrogen. The residue
was washed with 15 mL of EtOAc followed by decanting the solvent
and this was repeated three times. The crude product was further
purified by column chromatography (SiO2, 55–60% EtOAc in
petroleum ether eluant) to afford pure diol 6 (58 mg, 89%) as col-
orless liquid. Rf¼0.4 (SiO2, 80% EtOAc in petroleum ether); [a]D25
þ3.42 (c 1.43, CHCl3); IR (neat): n
3348, 3016, 1421, 1368, 1213,
max
petroleum ether); [a]D25 þ1.2 (c 0.5, CHCl3); IR (neat): n
3430,
1082, 1045, 1028, 876, 748, 702 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
max
3068, 2927, 2856, 1725, 1620, 1457, 1428, 1384, 1109, 822, 738,
702 cmꢀ1; 1H NMR (200 MHz, CDCl3): d 7.67–7.24 (m,15H, aromatic
protons), 4.53 (ABq, J¼12.6 Hz, 2H, OCH2Ph), 3.91–3.47 (m, 5H,
O–CH2– and O–CH–), 3.33 (m, 1H, O–CH–), 3.07 (m, 1H, O–CH–),
1.96–1.62 (m, 2H, CH), 1.50 (m, 1H, CH), 1.36–1.18 (m, 2H, CH), 1.04
(s, 9H, tert-butyl protons), 0.94 (d, J¼6.0 Hz, 3H, Me protons); 13C
NMR (50 MHz, CDCl3): d 138.3, 133.8, 135.4, 129.5, 128.2, 127.7,
d 7.38–7.25 (m, 5H, aromatic protons), 4.55 (ABq, J¼11.9 Hz, 2H,
OCH2Ph), 3.81 (t, J¼6.0 Hz, 2H, OCH2), 3.64 (dd, J¼10.6, 2.3 Hz, 1H,
OCH), 3.63 (m, 1H, OCH), 3.51 (dd, J¼10.6, 6.0 Hz, 1H, OCH), 3.36 (dt,
J¼10.6, 4.5 Hz, 1H, OCH), 3.23 (ddd, J¼10.6, 6.0, 2.3 Hz, 1H, OCH),
3.02 (br s, 1H, OH), 2.16 (br s, 1H, OH), 1.94 (ddd, J¼12.1, 4.5, 2.3 Hz,
1H, CH), 1.84 (m, 1H, CH), 1.76–1.66 (m, 1H, CH), 1.50–1.37 (m, 2H,
CH), 0.95 (d, J¼6.8 Hz, 3H, Me protons); 13C NMR (75 MHz, CDCl3):

T.K. Chakraborty et al. / Tetrahedron 64 (2008) 5162–5167
5165
d 138.0, 128.3, 127.7, 127.6, 80.5, 75.7, 73.4, 73.1, 71.0, 61.1, 40.9, 40.2,
37.6, 12.6; HRMS (ESIMS) calcd for C16H24O4Na [MþNa]þ: 303.1572,
found: 303.1565.
benzoate ester (762 mg, 96%) as a clear oil, which was directly used
for the next reaction without further characterization.
To the above prepared ester (762 mg, 1.188 mmol) in dry MeOH
(4 mL), dry K2CO3 (180 mg, 1.306 mmol) was added at 0 ꢁC under
nitrogen atmosphere. The reaction mixture was allowed to come
reach temperature and stirred for 30 min. Aqueous NH4Cl solution
(5 mL) was added to it and extracted with EtOAc (2ꢂ5 mL), washed
with water (5 mL), brine (5 mL), dried (Na2SO4), and concentrated
in vacuo. Purification by column chromatography (SiO2, 18–20%
EtOAc in petroleum ether eluant) afforded pure propargylic alcohol
11 (561 mg, 96%) as colorless liquid.
3.1.4. Synthesis of 11
To a stirred solution of 10 (1.70 g, 2.45 mmol) in dry THF (7 mL),
TBAF (1 M in THF, 2.7 mL, 2.7 mmol) was added at 0 ꢁC. The reaction
mixture was warmed to room temperature and stirred for 3 h. It
was quenched with saturated aqueous NH4Cl solution (10 mL),
extracted with EtOAc (2ꢂ10 mL), washed with brine (10 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by column
chromatography (SiO2, 35–40% EtOAc in petroleum ether eluant)
afforded pure primary alcohol (1.05 g, 95%) as colorless oil, which
was used directly in the next step.
To a solution of oxalyl chloride (0.29 mL, 3.37 mmol) in dry
CH2Cl2 (3 mL) at ꢀ78 ꢁC, DMSO (0.51 mL, 7.2 mmol) was added
slowly in dropwise manner, with stirring under nitrogen atmo-
sphere. After 15 min stirring, the alcohol prepared above (1.0 mg,
2.25 mmol) dissolved in dry CH2Cl2 (10 mL) was added to the
reaction mixture. After 0.5 h of stirring at ꢀ78 ꢁC, Et3N (1.56 mL,
11.25 mmol) was added and stirred for another 0.5 h at ꢀ78 ꢁC and
then for 0.5 h at 0 ꢁC. The reaction mixture was then quenched with
saturated aqueous NH4Cl solution (10 mL) and extracted
with CHCl3 (2ꢂ10 mL). The combined organic layers were washed
with water (10 mL), brine (10 mL), dried (Na2SO4), and concen-
trated in vacuo. The aldehyde, thus obtained, was directly used after
flash chromatography (955 mg, 96%) for the next reaction without
further characterization.
3.1.6. Synthesis of 13
To a stirred solution of 11 (829 mg, 1.684 mmol) in dry ether
(5 mL), Red-Al (1.92 mL, 6.736 mmol, 3.5 M solution in toluene)
was added slowly in dropwise manner at 0 ꢁC. The reaction mixture
was allowed to reach room temperature and stirred for 4 h. It was
re-cooled to 0 ꢁC, quenched with saturated aqueous NH4Cl solution
(5 mL), extracted with ether (2ꢂ5 mL), washed with water (5 mL),
brine (5 mL), dried (Na2SO4), and concentrated in vacuo. Purifica-
tion by column chromatography (SiO2, 30–35% EtOAc in petroleum
ether eluant) afforded pure E-allylic alcohol intermediate (666 mg,
80%) as colorless liquid.
To
a stirred solution of the E-allylic alcohol (665 mg,
1.346 mmol) in dry CH2Cl2 (4 mL), Et2Zn (6.73 ml, 6.73 mmol) and
CH2I2 (1.085 mL, 13.46 mmol) were added slowly in dropwise
manner at ꢀ20 ꢁC. The reaction mixture was warmed to 0 ꢁC and
stirred for 5 h. It was quenched with saturated aqueous NH4Cl
solution (5 mL), extracted with EtOAc (2ꢂ5 mL), washed with 10%
aqueous NaHCO3 (5 mL), water (5 mL), brine (5 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by column chromatography
(SiO2, 30–35% EtOAc in petroleum ether eluant) afforded pure
compound 13 (622 mg, 91%) as colorless liquid. Rf¼0.48 (SiO2, 50%
EtOAc in petroleum ether); [a]2D5 ꢀ36.0 (c 2.69, CHCl3); IR (neat):
nmax 3446, 3017,1519,1420,1213,1046, 927, 750, 702 cmꢀ1; 1H NMR
(200 MHz, CDCl3): d 7.27–7.19 (m, 5H, aromatic protons), 4.49 (ABq,
J¼11.8 Hz, 2H, OCH2Ph), 4.31 (d, J¼7.4 Hz, 1H, anomeric proton),
3.98 (dd, J¼11.0, 5.1 Hz, 1H, OCH), 3.72 (m, 1H, OCH), 3.64–3.40 (m,
3H, OCH), 3.55 (s, 3H, OMe), 3.52 (s, 3H, OMe), 3.40 (s, 3H, OMe),
3.35–3.17 (m, 3H, OCH), 3.13–2.91 (m, 3H, OCH), 2.52 (br s, 1H, OH),
2.04 (ddd, J¼12.5, 4.4, 1.5 Hz, 1H, CH), 1.88 (m, 1H, CH), 1.80 (m, 1H,
CH), 1.56 (m, 1H, CH), 1.40 (m, 1H, CH), 0.95 (d, J¼5.1 Hz, 3H, CHMe),
0.90 (d, J¼6.6 Hz, 3H, CHMe), 0.52 (m, 3H, cyclopropane CH), 0.22
(m, 1H, cyclopropane CH); 13C NMR (75 MHz, CDCl3): d 138.2, 128.3,
127.6, 127.5, 100.5, 85.2, 83.3, 81.0, 79.4, 78.6, 73.4, 73.1, 72.2, 70.9,
63.2, 60.6, 60.6, 58.6, 42.2, 37.7, 36.8, 26.1, 18.4, 12.9, 11.2, 10.0; MS
(ESIMS) m/z (%): 531 (100) [MþNa]þ; HRMS (ESIMS) calcd for
Under nitrogen atmosphere, a solution of n-butyl lithium in
hexane (1.6 M solution, 2.4 mL, 3.83 mmol) was added to a solution
of DIPA (0.56 mL, 4.01 mmol) in THF (5 mL) at 0 ꢁC and the mixture
was stirred for 15 min. It was then added to a solution of propyne
(0.27 mL, 4.77 mmol) in THF (5 mL) at ꢀ78 ꢁC and the mixture was
stirred for 1 h. Then,
a solution of the aldehyde (955 mg,
1.91 mmol), prepared above, in dry THF (6 mL) was added to the
reaction mixture. After stirring for 1 h at ꢀ78 ꢁC, the reaction
mixture was quenched by adding saturated aqueous NH4Cl solution
(10 mL), extracted with EtOAc (2ꢂ10 mL), washed with water
(10 mL), brine (10 mL), dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (SiO2, 30–35% EtOAc in
petroleum ether eluant) first eluted compound 11 (329 mg, 31%)
followed by compound 12 (627 mg, 59%) as colorless oils.
Data for 11: Rf¼0.42 (silica gel, 50% EtOAc in petroleum ether).
[a]2D5 ꢀ51.0 (c 2.55, CHCl3). IR (neat): n
3444, 3017, 1420, 1213,
max
1161, 1089, 928, 750, 702 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 7.34–
7.23 (m, 5H, aromatic protons), 4.55 (ABq, J¼12.1 Hz, 2H, OCH2Ph),
4.59 (m, 1H, propargylic CHOH), 4.30 (d, J¼7.6 Hz, 1H, anomeric
proton), 3.96 (dd, J¼11.3, 5.3 Hz, 1H, OCH), 3.87 (dt, J¼11.3, 2.3 Hz,
2H, OCH), 3.65–3.58 (m, 1H, OCH), 3.60 (s, 3H, OMe), 3.54 (s, 3H,
OMe), 3.52–3.42 (m, 1H, OCH), 3.46 (s, 3H, OMe), 3.30–3.22 (m, 2H,
OCH), 3.13–3.05 (m, 2H, OCH), 2.95 (m, 1H, OCH), 2.06–1.96 (m, 2H,
CH), 1.83 (d, J¼2.3 Hz, 3H, propargylic Me), 1.75 (ddd, J¼14.4, 6.0,
2.3 Hz, 1H, CH), 1.61 (m, 1H, CH), 1.39 (m, 1H, CH), 0.94 (d, J¼6.0 Hz,
3H, Me protons); 13C NMR (75 MHz, CDCl3): d 138.0, 128.2, 127.5,
127.4, 100.4, 85.1, 83.2, 80.6, 80.4, 80.1, 79.2, 78.2, 73.2, 73.0, 70.7,
63.1, 60.4, 60.4, 60.4, 58.5, 42.2, 37.6, 36.5, 12.7, 3.4; HRMS (ESI)
calcd for C27H40O8Na [MþNa]þ, 515.2620; found, 515.2624.
C
28H44O8Na [MþNa]þ: 531.2933, found: 531.2947.
3.1.7. Synthesis of 14
To a stirred solution of 13 (620 mg, 1.22 mmol) in CH2Cl2 (4 mL),
Dess–Martin periodinane (DMP) (621 mg, 1.464 mmol) was added
at 0 ꢁC and the reaction mixture was allowed to reach room
temperature and stirred for 20 min under nitrogen atmosphere.
Saturated Na2S2O3 (10 mL) and NaHCO3 (2 mL) were then added,
and the biphasic mixture was stirred for 15 min and extracted with
EtOAc. The organic phase was washed with water (5 mL), brine
(5 mL), dried (Na2SO4), and concentrated in vacuo. Purification by
column chromatography (SiO2, 15–18% EtOAc in petroleum ether
eluant) afforded pure ketone (525 mg, 85%) as colorless liquid,
which was used in the next step without further characterization.
To a stirred solution of the ketone (525 mg, 1.037 mmol) in dry
THF (5 mL), LAH (79 mg, 2.074 mmol) was added at ꢀ78 ꢁC. After
being stirred for 30 min at the same temperature, it was quenched
with saturated aqueous Na2SO4 (5 mL) at 0 ꢁC and stirred for
another 15 min. Precipitated solid was filtered through a short pad
3.1.5. Synthesis of 11 from 12
To a stirred solution of 12 (610 mg, 1.239 mmol) in dry THF
(8 mL), PPh3 (1.138 g, 4.34 mmol), p-nitrobenzoic acid (869 mg,
5.2 mmol), and DEAD (0.683 mL, 4.34 mmol) were added sequen-
tially at 0 ꢁC under nitrogen atmosphere. The reaction mixture was
allowed to reach room temperature and stirred for 1 h. It was then
concentrated in vacuo. Purification by column chromatography
(SiO2, 15–16% EtOAc in petroleum ether eluant) afforded the

5166
T.K. Chakraborty et al. / Tetrahedron 64 (2008) 5162–5167
of Celite and the filter cake was washed with ether (2ꢂ5 mL). The
filtrate and the washings were combined, washed with brine
(5 mL), dried (Na2SO4), and concentrated in vacuo. Purification by
column chromatography (SiO2, 28–30% EtOAc in petroleum ether
eluant) afforded compound 14 (332 mg, 63%) as colorless oil.
Rf¼0.50 (SiO2, 50% EtOAc in petroleum ether); [a]2D5 ꢀ34.5 (c 1.53,
CHCl3); IR (neat): nmax 3440, 3017, 1522, 1423, 1213, 1045, 928, 750,
702 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 7.35–7.25 (m, 5H, aromatic
protons), 4.55 (ABq, J¼12.8 Hz, 2H, OCH2Ph), 4.29 (d, J¼6.8 Hz, 1H,
anomeric proton), 3.96 (dd, J¼11.1, 5.1 Hz, 1H, OCH), 3.70–3.57 (m,
2H, OCH), 3.60 (s, 3H, OMe), 3.54 (s, 3H, OMe), 3.50–3.37 (m, 3H,
OCH), 3.46 (s, 3H, OMe), 3.30–3.16 (m, 2H, OCH), 3.15–3.04 (m, 2H,
OCH), 2.96 (m, 1H, OCH), 2.06 (m, 1H, C3–H), 1.82 (m, 1H, CH), 1.72
(m, 1H, CH), 1.58 (m, 1H, CH), 1.35 (m, 1H, CH), 1.06 (d, J¼5.3 Hz, 3H,
CHMe), 0.93 (d, J¼6.0 Hz, 3H, CHMe), 0.78 (m, 1H, cyclopropane
CH), 0.61 (m, 1H, cyclopropane CH), 0.30 (m, 1H, cyclopropane CH),
0.18 (m, 1H, cyclopropane CH); 13C NMR (75 MHz, CDCl3): d 138.1,
128.3, 127.7, 127.6, 100.5, 85.5, 85.2, 83.3, 80.9, 79.3, 78.3, 76.3, 76.0,
73.5, 71.0, 63.2, 60.6, 58.7, 42.3, 37.8, 37.1, 26.1, 18.7, 12.8, 11.1, 10.1;
MS (ESIMS) m/z (%): 531 (100) [MþNa]þ; HRMS (ESIMS) calcd for
dried (Na2SO4), and concentrated in vacuo. The aldehyde thus
obtained was directly used after flash chromatography for the next
reaction without further characterization.
Sodamide (160 mg, 4.088 mmol) was added to a suspension of
methyltriphenylphosphonium iodide (620 mg, 1.533 mmol) in dry
ether (10 mL) at 0 ꢁC. The mixture was allowed to reach room
temperature and stirred for 6 h. The resulting methylene-
triphenylphosphorane was added to a solution of the aldehyde,
prepared above and dissolved in ether (5 mL), at 0 ꢁC. After 10 min,
the reaction mixture was quenched with saturated aqueous NH4Cl
solution (5 mL). The layers were separated. The aqueous layer was
extracted with ether (2ꢂ5 mL), washed with water (5 mL), brine
(5 mL), dried (Na2SO4), and concentrated. Purification by column
chromatography (SiO2, 15–18% EtOAc in petroleum ether eluant)
afforded pure compound 16 (181 mg, 67% in two steps) as colorless
liquid. Rf¼0.45 (silica gel, 25% EtOAc in petroleum ether). [a]D25
ꢀ35.8 (c 0.83, CHCl3). IR (neat): n
3017, 2924, 1213, 1090, 928,
max
750, 702 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 5.81 (ddd, J¼17.4, 10.6,
6.8 Hz, 1H, olefinic proton), 5.25 (d, J¼17.4 Hz, 1H, olefinic proton),
5.17 (d, J¼10.6 Hz, 1H, olefinic proton), 4.32 (d, J¼7.6 Hz, 1H,
anomeric proton), 3.98 (dd, J¼11.3, 4.5 Hz, OCH), 3.61 (s, 3H, OMe),
3.58 (m, 1H, OCH), 3.55 (s, 3H, OMe), 3.47 (s, 3H, OMe), 3.45–3.35
(m, 2H, OCH), 3.32–3.18 (m, 2H, OCH), 3.14–3.04 (m, 2H, OCH), 2.96
(dd, J¼9.1, 7.6 Hz, 1H, C3–H), 2.11 (m, H, CH), 1.94 (m, 1H, CH), 1.68–
1.58 (m, 2H, CH), 1.40 (m, 1H, CH), 1.03 (d, J¼5.3 Hz, 3H, CHMe), 0.94
(d, J¼6.0 Hz, 3H, CHMe), 0.88 (s, 9H, tert-butyl protons), 0.64 (m,1H,
cyclopropane CH), 0.57 (m, 1H, cyclopropane CH), 0.31 (m, 1H,
cyclopropane CH), 0.18 (m, 1H, cyclopropane CH), 0.06 (s, 3H, SiMe),
0.03 (s, 3H, SiMe); 13C NMR (75 MHz, CDCl3): d 137.2, 117.0, 100.2,
85.3, 83.4, 82.9, 79.4, 78.5, 73.4, 72.5, 63.3, 60.6, 60.5, 58.7, 44.5,
41.3, 36.8, 26.1, 25.9,18.7,18.1,13.3,11.4,10.6, ꢀ4.0, ꢀ4.5. HRMS (ESI)
calcd for C28H52O7NaSi [MþNa]þ, 551.3380; found, 551.3394.
C
28H44O8Na [MþNa]þ: 531.2933, found: 531.2925.
3.1.8. Synthesis of 15
To a stirred solution of 14 (330 mg, 0.649 mmol) in CH2Cl2
(3 mL), 2,6-lutidine (0.226 mL, 1.948 mmol) and TBSOTf (0.223 mL,
0.97 mmol) were added sequentially at 0 ꢁC under nitrogen atmo-
sphere. The reaction mixture was warmed to room temperature
and stirred for 4 h. It was quenched with saturated aqueous
NaHCO3 solution (5 mL) and extracted with EtOAc (2ꢂ5 mL). The
organic extracts were combined, washed with water (5 mL), brine
(5 mL), dried (Na2SO4), and concentrated in vacuo. Purification by
column chromatography (SiO2, 18–20% EtOAc in petroleum ether
eluant) gave pure compound 15 (360 mg, 89%) as clear oil. Rf¼0.51
(SiO2, 35% EtOAc in petroleum ether); [a]2D5 ꢀ29.8 (c 2.83, CHCl3);
1H NMR (300 MHz, CDCl3): d 7.35–7.25 (m, 5H, aromatic protons),
4.58 (ABq, J¼12.1 Hz, 2H, OCH2Ph), 4.31 (d, J¼7.6 Hz, 1H, anomeric
proton), 3.97 (dd, J¼11.3, 4.5 Hz, 1H, OCH), 3.67–3.50 (m, 3H, OCH),
3.61 (s, 3H, OMe), 3.55 (s, 3H, OMe), 3.47 (s, 3H, OMe), 3.42 (dt,
J¼10.6, 4.5 Hz, 1H, OCH), 3.31–3.19 (m, 2H, OCH), 3.15–3.03 (m, 3H,
OCH), 2.98–2.93 (m, 1H, OCH), 2.09 (m, 1H, CH), 1.95 (m, 1H, CH),
1.67–1.58 (m, 2H, CH), 1.23 (m, 1H, CH), 1.02 (d, J¼6.0 Hz, 3H,
CHMe), 0.94 (d, J¼6.8 Hz, 3H, CHMe), 0.88 (s, 9H, tert-butyl
protons), 0.67–0.53 (m, 2H, cyclopropane CH), 0.30 (m, 1H,
cyclopropane CH), 0.18 (m, 1H, cyclopropane CH), 0.06 (s, 3H, SiMe),
0.03 (s, 3H, SiMe); 13C NMR (75 MHz, CDCl3): d 138.5, 128.2, 127.6,
127.4, 100.3, 85.2, 83.3, 81.2, 79.4, 78.6, 73.4, 73.4, 72.7, 71.1, 63.2,
60.6, 60.6, 58.7, 44.5, 37.8, 36.6, 26.0, 25.9, 18.6, 18.1, 13.0, 11.3, 10.6,
ꢀ4.1, ꢀ4.5.
3.1.10. Synthesis of 17
(cHex)2BH (2.076 mmol) was freshly prepared from cyclohexene
(0.436 mL, 4.15 mmol) and BH3$DMS (0.19 mL, 2.076 mmol) in dry
THF (2 mL) at room temperature. To the above prepared (chex)2BH
solution, olefinic compound 16 (180 mg, 0.34 mmol) in THF (5 mL)
was added at 0 ꢁC under nitrogen atmosphere. After being stirred
for 4 h at the same temperature, dry MeOH (0.168 mL, 4.152 mmol),
NaOH (3 N aqueous solution,1.038 mL, 3.114 mmol), and H2O2 (30%,
w/v, 0.823 mL, 7.266 mmol) were added sequentially. Then, the
reaction mixture was slowly warmed to 55 ꢁC and stirred at that
temperature for 1 h, during which time the turbid solution became
clear. It was cooled to room temperature and extracted with EtOAc
(2ꢂ10 mL). The combined organic layer was washed with water
(5 mL), brine (5 mL), dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (SiO2, 30–33% EtOAc in
petroleum ether eluant) afforded compound 17 (168 mg, 91%) as
colorless liquid. Rf¼0.52 (SiO2, 60% EtOAc in petroleum ether); [a]D25
ꢀ33.2 (c 0.25, CHCl3); IR (neat): nmax 3480, 1462, 1213, 1089, 1213,
3.1.9. Synthesis of 16
To a solution of the silyl ether 15 (350 mg, 0.56 mmol) in EtOAc
(3 mL), 10% Pd–C (78 mg) was added and the mixture was hydro-
genated using a H2-filled balloon for 1 h. It was then filtered
through a short pad of Celite and the filter cake was washed with
EtOAc (2ꢂ5 mL). The filtrate and washings were combined and
concentrated in vacuo. Purification by column chromatography
(SiO2, 28–30% EtOAc in petroleum ether eluant) furnished the
debenzylated intermediate (272 mg, 91%) as colorless oil, which
was used directly in the next step.
The debenzylated product (272 mg, 0.511 mmol) in CH2Cl2
(3 mL) was oxidized with Dess–Martin periodinane (DMP, 325 mg,
0.766 mmol) under nitrogen atmosphere at 0 ꢁC, then allowed to
reach room temperature and stirred for 30 min. Saturated Na2S2O3
(10 mL) and NaHCO3 (2 mL) were then added, and the biphasic
mixture was stirred for 15 min and extracted with EtOAc (2ꢂ5 mL).
The organic phase was washed with water (5 mL), brine (5 mL),
1089, 928, 750, 702 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.31 (d,
;
J¼7.2 Hz, 1H, anomeric proton), 3.98 (dd, J¼11.3, 5.3 Hz, 1H, OCH),
3.82–3.72 (m, 2H, OCH), 3.65–3.51 (m, 2H, OCH), 3.61 (s, 3H, OMe),
3.56 (s, 3H, OMe), 3.47 (s, 3H, OMe), 3.40 (dd, J¼11.3, 4.5 Hz, 1H,
OCH), 3.32–3.18 (m, 2H, OCH), 3.16–3.02 (m, 2H, OCH), 2.96 (m, 1H,
OCH), 2.12 (br s, 1H, OH), 2.09–1.82 (m, 2H, CH), 1.78–1.54 (m, 2H,
CH), 1.46 (m, 1H, CH), 1.30 (m, 1H, CH), 1.03 (d, J¼5.6 Hz, 3H, CHMe),
0.97 (d, J¼6.0 Hz, 3H, CHMe), 0.89 (s, 9H, tert-butyl protons), 0.66
(m, 1H, cyclopropane CH), 0.58 (m, 1H, cyclopropane CH), 0.33 (m,
1H, cyclopropane CH), 0.22 (m, 1H, cyclopropane CH), 0.06 (s, 3H,
SiMe), 0.02 (s, 3H, SiMe); 13C NMR (75 MHz, CDCl3): d 100.3, 85.2,
83.3, 82.2, 79.4, 78.0, 73.5, 72.9, 63.3, 61.5, 60.7, 60.7, 58.8, 44.7, 41.3,
36.8, 34.7, 26.0, 25.9, 18.6, 18.1, 13.1, 11.5, 10.8, ꢀ4.1, ꢀ4.6; HRMS
(ESIMS) calcd for
569.3498.
C
28H54O8NaSi [MþNa]þ: 569.3485, found:

T.K. Chakraborty et al. / Tetrahedron 64 (2008) 5162–5167
5167
3.1.11. Synthesis of 18
petroleum ether). [a]2D5 ꢀ42.4 (c 0.13, CHCl3); IR (neat): n
3016,
max
Compound 17 (165 mg, 0.3 mmol) in CH2Cl2 (3 mL) was oxidized
with Dess–Martin periodinane (DMP, 189 mg, 0.45 mmol) under
the same conditions followed for the synthesis of 16. The resulting
aldehyde was directly used after flash chromatography in the next
reaction.
To a stirred solution of the aldehyde in t-BuOH/2-methyl-
2-butene (2:1, 3 mL) at room temperature, NaClO2 (67.83 mg,
0.75 mmol) and NaH2PO4$2H2O (117 mg, 0.75 mmol), dissolved in
minimum amount of water, were added. After being stirred for 1 h,
the solvent was removed in rotary evaporator and the residue was
extracted with EtOAc (2ꢂ5 mL). The combined organic extracts
were washed with brine (5 mL), dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography (SiO2, 60–65%
EtOAc in petroleum ether eluant) afforded the acid (123 mg, 87% in
two steps) as colorless liquid, which was used directly in the next
step.
1728, 1213, 1088 cmꢀ1 1H NMR (500 MHz, CDCl3, proton number-
;
ing as in Ref. 2a): d 4.42 (dt, J¼9.0, 1.0 Hz, 2H, –CHOCO–), 4.26 (d,
J¼7.5 Hz, 2H, anomeric proton), 3.95 (dd, J¼11.5, 5.0 Hz, 2H, C19–H),
3.61 (s, 6H, OMe), 3.57 (s, 6H, OMe), 3.48–3.43 (m, 4H, OCH), 3.46 (s,
6H, OMe), 3.27–3.21 (m, 4H, OCH), 3.09 (t, J¼8.0 Hz, 2H, C17–H),
3.08 (dd, J¼11.5, 8.0 Hz, 2H, C19–H0), 2.95 (t, J¼8.0 Hz, 2H, C16–H),
2.54 (dd, J¼17.0, 3.5 Hz, 2H, C2–H), 2.41 (dd, J¼17.0, 6.5 Hz, 2H,
C2–H0), 2.04 (dd, J¼11.5, 5.0 Hz, 2H, C6–H), 1.88 (dt, J¼15.7, 9.0 Hz,
2H, C8–H), 1.67 (ddd, J¼15.7, 2.4, 1.0 Hz, 2H, C6–H0), 1.37 (q,
J¼11.5 Hz, 2H, C6–H0), 1.37 (m, 2H, C4–H), 0.96 (two d, J¼6.5 Hz,
12H, methyls), 0.83 (m, 2H, C11–H), 0.72 (tt, J¼9.0, 5.0 Hz, 2H,
C10–H), 0.33 (dt, J¼8.0, 5.0 Hz, 2H, C13–H), 0.22 (dt, J¼8.0, 5.0 Hz,
2H, C13–H0); 13C NMR (75 MHz, CDCl3): d 171.1, 105.5, 85.5, 83.8,
83.2, 79.3, 77.2, 77.0, 74.8, 63.2, 60.8, 60.8, 58.8, 42.5, 41.2, 40.7, 39.2,
24.7, 18.5, 12.6, 12.0, 10.9. HRMS (ESI) calcd for C44H72O16Na
[MþNa]þ, 879.4718; found, 879.4687.
To a stirred solution of the acid (120 mg, 0.215 mmol) in dry
CH2Cl2/MeOH (2:1, 3 ml), CSA (25 mg, 0.107 mmol) was added at
0 ꢁC under nitrogen atmosphere. The reaction mixture was warmed
to room temperature and stirred for 1 h. Then, it was quenched
with water (3 mL), extracted with EtOAc (2ꢂ5 mL), washed with
brine (5 mL), dried (Na2SO4), and concentrated in vacuo. Purifica-
tion by column chromatography (SiO2, 90–95% EtOAc in petroleum
ether eluant) furnished compound 18 (81 mg, 85%) as colorless
liquid. Rf¼0.35 (silica gel, EtOAc). [a]2D5 ꢀ23.1 (c 0.23, CHCl3). IR
Acknowledgements
The authors wish to thank DST, New Delhi for a Ramanna
Fellowship (SR/S1/RFOC-06/2006; T.K.C.), CSIR (V.R.R) and UGC
(P.K.G), New Delhi for research fellowships.
References and notes
(neat): n
3448, 2924, 2853, 2361, 1631, 1459, 1380, 1093,
max
759 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 4.28 (d, J¼7.4 Hz, 1H,
1. Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012–1044.
2. (a) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386–388; (b) Erickson, K. L.;
Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.; Boyd, M. R. J. Nat. Prod. 2002, 65,
1303–1306.
3. For total syntheses of the first reported structure of clavosolide A see: (a)
Chakraborty, T. K.; Reddy, V. R. Tetrahedron Lett. 2006, 47, 2099–2102; (b) Barry,
C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding, J. R.; Willis, C. L.
Chem. Commun. 2005, 5097–5099; For synthesis of the monomeric unit see: (c)
Yakambram, P.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,
3781–3783.
4. Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D.-H. Org. Lett. 2006, 8, 661–664.
5. Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D.-H. Org. Lett. 2006, 8, 3411.
6. Barry, C. S.; Elsworth, J. D.; Seden, P. T.; Bushby, N.; Harding, J. R.; Alder, R. W.;
Willis, C. L. Org. Lett. 2006, 8, 3319–3322.
7. Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315–3318.
8. Chakraborty, T. K.; Reddy, V. R.; Chattopadhyay, A. K. Tetrahedron Lett. 2006, 47,
7435–7438.
anomeric proton), 3.97 (dd, J¼11.7, 5.0 Hz, 1H, OCH), 3.68–3.37 (m,
1H, OCH), 3.60 (s, 3H, OMe), 3.54 (s, 3H, OMe), 3.51–3.38 (m, 2H,
OCH), 3.47 (s, 3H, OMe), 3.26 (ddd, J¼5.2, 8.6, 9.4 Hz, 1H, OCH), 3.17
(dd, J¼2.4, 8.9 Hz, 1H, OCH), 3.14–3.03 (m, 2H, OCH), 3.01 (br s, 1H,
OH), 2.94 (dd, J¼7.3, 9.0 Hz, 1H, OCH), 2.69 (dd, J¼2.6, 15.2 Hz, 1H,
CH), 2.40 (dd, J¼4.8, 12.8 Hz, 1H, CHCO–), 2.05 (dd, J¼4.8, 12.8 Hz,
1H, CHCO–), 1.89–1.55 (m, 2H, CH), 1.47–1.16 (m, 2H, CH), 1.01 (d,
J¼5.9 Hz, 3H, CHMe), 0.98 (d, J¼6.5 Hz, 3H, CHMe), 0.76 (m, 1H,
cyclopropane CH), 0.58 (m, 1H, cyclopropane CH), 0.24 (m, 1H,
cyclopropane CH), 0.17 (m, 1H, cyclopropane CH); 13C NMR
(75 MHz, CDCl3): d 173.1, 100.5, 85.2, 83.3, 79.3, 78.3, 77.0, 76.9,
63.3, 60.6, 60.6, 58.7, 52.3, 41.8, 41.1, 38.5, 37.2, 25.8, 25.2, 22.7, 18.5,
13.0, 11.7, 10.2; HRMS (ESI) calcd for C22H38O9NaSi [MþNa]þ,
469.2413; found, 469.2409.
9. Son, J. B.; Hwang, M.-H.; Lee, W.; Lee, D.-H. Org. Lett. 2007, 9, 3897–3900.
10.
A
similar approach was adopted by Lee et al. in their recently reported
synthesis of clavosolide B (Ref. 9).
11. Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J. Tetrahedron 2003, 59, 8613–8622.
12. Schimdt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212–235.
13. Wanner, J.; Tang, D.; McComas, C. C.; Crowley, B. M.; Jiang, W.; Moss, J.; Boger,
D. L. Bioorg. Med. Chem. Lett. 2003, 13, 1169–1173.
14. (a) Charette, A. B.; Label, H. J. Org. Chem. 1995, 60, 2966–2967; (b) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–1050.
15. (a) Dembinski, R. Eur. J. Org. Chem. 2004, 2763–2772; (b) Ahn, C.; Correia, R.;
DeShong, P. J. Org. Chem. 2002, 67, 1751–1753; (c) Mitsunobu, O.; Yamada, M.
Bull. Chem. Soc. Jpn. 1967, 40, 2380–2382.
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Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53–58.
17. (a) Kazuta, Y.; Abe, H.; Yamamoto, T.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003,
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3.1.12. Synthesis of clavosolide A (5)
2,4,6-Trichlorobenzoyl chloride (0.17 mL, 1.1 mmol) was added
to a stirred solution of the seco acid 18 (50 mg, 0.11 mmol) and
triethyl amine (0.3 mL, 2.2 mmol) in dry THF (3 mL) at room tem-
perature under nitrogen atmosphere. After being stirred for 3 h, the
TEA$HCl salt was filtered off and the filtrate was diluted with dry
toluene (5 mL). This solution was then added slowly to a stirred
solution of DMAP (134 mg, 1.1 mmol) in dry toluene (110 mL) at
90 ꢁC through a syringe pump over 5 h. Then it was cooled to room
temperature and stirred for further 12 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution (5 mL), extracted
with EtOAc (2ꢂ5 mL), washed with brine (5 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by column chromatography
(SiO2, 55–60% EtOAc in petroleum ether eluant) afforded clavo-
solide A (5) (34 mg, 71%). Rf¼0.55 (silica gel, 70% EtOAc in
18. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
19. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.