A flexible and unified strategy for syntheses of cladospolides A, B, C, and iso-cladospolide B

Article abstract of DOI:10.1039/c1ob05787a

A simple, efficient and flexible strategy for the syntheses of cladospolides A-C and iso-cladospolide B is reported here. This strategy involves Julia-Kocienski olefination and Yamaguchi macrolactonization as key steps, starting from either d-ribose or suitable tartaric acid esters. Although our initial efforts towards cladospolide A involving a ring closing metathetic approach were not successful, changing the mode of ring closure and the use of Julia-Kocienski olefination for the construction of the key intermediate solved this issue and paved the way for the completion of total syntheses of this class of natural products.

Full text of DOI:10.1039/c1ob05787a

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PAPER
A flexible and unified strategy for syntheses of cladospolides A, B, C, and
iso-cladospolide B†‡
Debjani Si, Narayana M. Sekar and Krishna P. Kaliappan*
Received 19th May 2011, Accepted 22nd June 2011
DOI: 10.1039/c1ob05787a
A simple, efficient and flexible strategy for the syntheses of cladospolides A–C and iso-cladospolide B is
reported here. This strategy involves Julia–Kocienski olefination and Yamaguchi macrolactonization as
key steps, starting from either D-ribose or suitable tartaric acid esters. Although our initial efforts
towards cladospolide A involving a ring closing metathetic approach were not successful, changing the
mode of ring closure and the use of Julia–Kocienski olefination for the construction of the key
intermediate solved this issue and paved the way for the completion of total syntheses of this class of
natural products.
Introduction
Marine fungi, being a potential source of new biologically
active secondary metabolites, are a topic of growing interest.
Cladospolides (A–D) (Fig. 1) are such secondary metabolites,
responsible for the host plant’s growth, and were isolated1–4 from
different Cladosporium sp. Structurally this class of natural prod-
ucts differ in the position, number and stereochemistry of hydroxyl
groups as well as the double bond and these trivial differences in
functionality affect their biological profiles significantly. The first
two members, cladospolides A1 and B2 were first isolated from
the culture filtrate of Cladosporium cladosporioides FI-113 in 1985
by Isogai and co-workers. Later in 2000, Ireland and co-workers
isolated cladospolide B as well as g-butenolide iso-cladospolide B
Fig. 1 Cladospolide family.
from the sponge-derived fungus Cladosporium herbarum and ma-
of total synthesis by various groups.5–9 As a part of our ongoing
research program on the synthesis of biologically active natural
and unnatural products using a metathetic approach,10 we became
interested in developing a general strategy for syntheses of this
class of natural products. As an outcome of our synthetic voyage,
we had earlier reported an expedient route to the total synthesis of
(-)-cladospolide A 1.5b Herein, we discuss in detail our cumulative
rine fungal species I962S215 respectively,3b whereas, cladospolide
C was isolated from the metabolites of the soil fungus Cladospo-
rium tenuissimum by Fukuda and co-workers in 1995.3a Although
isolated from the same species, (-)-cladospolide A 1 is found to
inhibit root growth of lettuce seedlings, while cladospolide B 2
promotes the growth. Likewise, cladospolide C 4 was also found to
inhibit shoot elongation of rice seedlings.2 Unlike other congeners,
efforts to the total synthesis of (-)-cladospolide A and other family
members.
cladospolide D 5, the recently isolated species from Cladosporium
sp. FT-0012 by Omura and co-workers, shows antimicrobial
activity with IC50 values of 0.1 and 29 mg mL-1 against Mucor
racemosus and Pyricularia oryazae respectively.4
Results and discussion
The promising biological profiles of the cladospolide family
of natural products have attracted the interest of the synthetic
community since their isolation and they have been the subject
First generation strategy: (-)-cladospolide A
According to our first strategy a ring closing metathesis was
planned as the key step for the synthesis of cladospolide A (Fig.
2). We envisaged that 1 could be derived from 6 in a couple
of steps involving selective hydrogenation and removal of the
protecting group. The diene lactone 6 could be obtained from 7 via
a regioselective RCM. The RCM precursor 7 could be synthesized
from alcohol 8 and acid 9. The carboxylic acid 9 could be traced
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai 400076, India; Fax: +91(22)25723480
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05787a
‡ Dedicated to my colleague, Professor V. K. Singh, on the occasion of his
60th birthday.
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After the successful synthesis of RCM precursor 7 the stage
was set for the key ring closing metathesis reaction17 but, to our
dismay, all our attempts to carry out the ring closing metathesis
reaction of triene 7 failed to provide the required product 6.
Various substrate concentrations in refluxing CH2Cl2 or toluene
were examined, however, only unidentified products and unreacted
starting material were isolated in all the cases. Our observed results
were found to be in accordance with the results observed later by
Hou and co-workers in their total synthesis of (+)-cladospolide
C,8d where a similar ring closing metathesis reaction provided the
desired product only in nominal yield.
On the basis of our earlier experience in our laboratory,10m we
anticipated that the presence of acetonide in the vicinity of the
RCM site might hinder the progress of the reaction. Accordingly,
the acetonide group was deprotected under mild conditions18
using CuCl2 to afford a trienediol which was further acetylated
to provide the diacetate 14 (Scheme 2). Yet again, the diacetate
14 also failed to undergo the ring closing metathesis reaction and
similar results were observed under a variety of conditions.
Fig. 2 Retrosynthetic analysis.
to D-ribose and the known alcohol 8 could be derived from chiral
epoxide 10 in good quantity.
So, our initial synthetic journey towards cladospolide A began
with the synthesis of acid 9 involving Wittig reaction of ribose
monoacetonide 11 using triphenylphosphonium methylidene to
afford diol 1211 (Scheme 1). The diol was then oxidatively cleaved
12
with silica supported NaIO4 and the resultant aldehyde was
subjected to Horner–Wadsworth–Emmons reaction13 to afford
the (E)-a,b-unsaturated ester 13 in 87% yield. The other coupling
partner, alcohol 8 was obtained by the ring opening of enan-
tiomerically pure R-propylene oxide 10, derived from the racemic
counterpart through Jacobsen’s hydrolytic kinetic resolution,14
with 4-butenylmagnesium bromide in the presence of Li2CuCl4.15
Exposure of ester 13 to an aqueous solution of lithium hydroxide
provided the acid 9, which under Yamaguchi conditions16 was
coupled with alcohol 8 to provide the ring closing metathesis
precursor 7 in moderate yield.
Scheme 2 Reagents and conditions: (a) i) CuCl2·2H2O, CH3CN; ii) Ac2O,
Py, DMAP, 79% (for two steps).
This unexpected failure of the ring closing metathesis reaction
forced us to think that the presence of an extra double bond in
the form of the a,b-unsaturated ester could perhaps increase the
complicacy during the ring closing metathesis reaction. Hence,
attempts were initiated to synthesize ring closing metathesis pre-
cursor 17 lacking the conjugated double bond. Thus, regioselective
reduction of the conjugated double bond in ester 13 was achieved
by a mixture of NaBH4 and Cu2Cl2 (Scheme 3).19 Saponification
of 16 followed by esterification of the resultant acid with alcohol
8 provided the diene 17. This whole process also didn’t solve the
problem, as the diene 17 failed to undergo RCM. Moving a step
further, compound 17 was converted into diacetate 18 using a two
step sequence, removal of acetonide and formation of diacetate,
and then subjected to the ring closing metathesis reaction, but
all our efforts once again failed to produce the required cyclised
product.
Scheme 1 Reagents and conditions: (a) Ph3PCH3Br, KOtBu, THF, 0 ◦C,
80%; (b) i) silica supp. NaIO4, CH2Cl2; ii) (OEt)2P(O)CH2CO2Et, NaH,
THF, 0 ◦C, 87% (for two steps); (c) LiOH, THF/MeOH/H2O; (d)
8, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, DMAP, 46% (for two
steps).
We had observed that during the RCM reaction, the sterically
less hindered olefin reacts with Grubbs’ catalyst much faster and
further rearranges to afford undesired products (Fig. 3). In order to
succeed in our ring closing metathesis approach, we felt that it was
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Wittig reaction with ethyl(triphenylphosphoranylidene) acetate,
and then protection of the diol as a bis-silyl ether (Scheme 4).
DIBAL-H reduction of ester 24 provided alcohol 25 which on
allylation gave the diene 26 in 89% yield. Removal of vicinal silyl
ether was accomplished with tetrabutyl ammonium fluoride in
THF to give the diol 27 which on oxidative cleavage with silica
supp. NaIO4 followed by Horner–Wadsworth–Emmons reaction
afforded the a,b-unsaturated ester 28 in good yield. Hydrolysis
of ester 28 and subsequent esterification with alcohol 8 furnished
the relay RCM precursor 21 in moderate yield. Nonetheless, the
tetraene 21 also failed to undergo RCM reaction in the presence
of either Grubbs’ first (G-I) or second generation (G-II) catalyst
under various substrate concentrations (0.002–0.02 M).
Scheme 3 Reagents and conditions: (a) NaBH4, Cu2Cl2, THF–EtOH,
-20 ◦C, 94%; (b) i) LiOH, THF–MeOH–H2O; ii) 8, DCC, DMAP, CH2Cl2,
42% (for two steps); (c) i) CuCl2·2H2O, CH3CN; ii) Ac2O, Py, 78% (for two
steps).
Fig. 3 Relay ring closing metathesis approach.
imperative to force the other alkene to react with the ruthenium
catalyst faster.
Therefore, a relay approach was planned, wherein an allyl ether
could be tethered to the less reactive alkene, which should then
generate the Ru-carbene on the required side selectively and the
key relay RCM reaction17c,20 could be carried out on substrate
21 (Fig. 4). The relay RCM precursor 21 could be synthesized
from acid 22 which in turn could be achieved starting from the
commercially available D-ribose.
Scheme 4 Reagents and conditions: (a) i) Ph3P CHCO2Et, PhCOOH,
CH2Cl2, rt; ii) TBSCl, DMF, rt, 2 h, 76% (for two steps); (b) DIBAL-H,
CH2Cl2, 0 ◦C, 70%; (c) NaH, allylbromide, THF, rt, 12 h, 89%; (d)
TBAF, THF, rt, 96%; (e) i) silica supp. NaIO4, CH2Cl2; ii) NaH,
(OEt)2P(O)CH2CO2Et, THF, rt, 63% (for two steps); (f) i) LiOH,
THF–MeOH–H2O; ii) 8, DCC, DMAP, CH2Cl2, 35% (for two steps).
Second generation strategy: (-)-cladospolide A
After spending much of our time in troubleshooting RCM and
relay RCM reactions toward cladospolide A, we modified our
strategy and planned a variation on the site of macrolide closure.
A Yamaguchi macrolactonization was planned to construct the
macrolide and we envisioned that the macrolide 1 could be
easily synthesised from the precursor 29, which in turn could
be constructed from hydroxy acid 30 through macrolactonization
(Fig. 5). We chose alkene 32 to be a good substrate to convert to
the hydroxy acid 30 in a sequence of steps. The alkene 32 could,
in turn, be assembled through a cross-metathetic route between
Fig. 4 Retrosynthetic analysis.
Accordingly, our revised synthetic expedition towards cla-
dospolide A commenced with the synthesis of a,b-unsaturated
ester 24 from ribose monoacetonide 11 in a two step sequence, first
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40 in overall 42% yield from alkene 37. The low yield in the
cross-metathesis reaction made us think about an alternative
strategy to increase the efficiency of the coupling step. Our prior
experience in applying Julia–Kocienski olefination22 in the formal
total synthesis of palmerolide A10b came in handy to be utilized in
the construction of the key intermediate 39.
Thus, the alcohol 36 was converted into the sulfone 42, required
for the key Julia–Kocienski olefination, in a couple of steps using
a Mitsunobu reaction with 1-phenyl-1H-tetrazole-5-thiol23 41,
followed by oxidation of the resultant sulfide (Scheme 6). We were
delighted to see the smooth proceeding of the Julia–Kocienski
olefination between sulfone 42 and the known aldehyde 4324 to
furnish the key intermediate 39 in high yield. Having the alkene
39 in appreciable quantity, we then looked at the hydrogenation
and lactonization. Hydrogenation and selective removal of vicinal
silyl ethers proceeded to afford the diol 44, which on oxidative
cleavage in the presence of silica supported NaIO4 followed by
Horner–Wadsworth–Emmons reaction furnished the trans a,b-
unsaturated ester 45 in 64% yield along with the minor cis-isomer.
The trans a,b-unsaturated ester 45, on hydrolysis as well as removal
of the secondary silyl ether with tetrabutyl ammonium fluoride at
elevated temperature, provided the hydroxy acid 30 thereby setting
the stage for the key lactonisation step. The lactonisation of the hy-
droxy acid 30 was accomplished efficiently utilizing the Yamaguchi
protocol to afford the macrolactone, which upon cleavage of the
acetonide with trifluoroacetic acid6f furnished (-)-cladospolide A
1. The spectral data of synthetic (-)-cladospolide A 1 matched with
Fig. 5 Retrosynthetic analysis of cladospolide A.
alkenes 33 and 34 and the alkene 33 might well be obtained from
commercially available D-ribose-derived ester 35 in a few steps.
Thus, the revised synthesis of cladospolide A commenced with
the hydrogenation of a,b-unsaturated ester 24 and subsequent
reduction with LAH afforded the alcohol 36 in good yield
(Scheme 5). The primary alcohol 36 was then oxidized and
subjected to Wittig reaction to furnish one of the cross-metathesis
precursors 37 in excellent yield. Delightfully, exposure of the
alkene 37 to the key cross-metathesis reaction with known
alkene partner 3821 in the presence of Grubbs’ second generation
catalyst (G-II) delivered our desired intermediate 39 as the
major isomer along with some undesired dimerised product.
Hydrogenation of intermediate 39 gave the saturated intermediate
Scheme 6 Reagents and conditions: (a) 41, DIAD, PPh3, THF, -20 ◦C,
92%; (b) (NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, rt, 88%; (c) 43,
LiHMDS, THF, -78 ◦C, 83%; (d) H2, Pd/C, EtOH, rt, 2 h, 84%; (e) TBAF
(1 M soln in THF), THF, 0 ◦C, 2 h, 80%; (f) i) silica supp. NaIO4, CH2Cl2,
Scheme 5 Reagents and conditions: (a) H2, Pd/C, EtOH, rt, 2 h, 89%;
0
◦C, 1 h; ii) (OEt)2P(O)CH2COOEt, LiCl, DIPEA, THF, 6 h, 64% (for
◦
two steps); (g) LiOH, THF–MeOH–H2O, 4 h, 93%; (h) TBAF (1 M soln in
THF), THF, 55 ◦C, 81%; (i) 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
2 h, then DMAP, toluene, reflux, 8 h, 71%; (j) TFA, CH3CN–H2O, 0 ◦C,
1 h, 65%.
˚
(b) LiAlH4, Et2O, 0 C, 15 min, 82%; (c) i) PCC, CH3COONa, 4 A MS,
CH2Cl2, 0 ◦C; ii) Ph3PCH3Br, KOtBu, THF, 0 ◦C, 78% (for two steps); (d)
38, G-II 5 mol%, toluene, 110 ◦C, 6 h; (e) H2, Pd/C, EtOH, rt, 2 h, 42%
(for two steps).
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that of the natural isomer in all aspects and thus a total synthesis
of (-)-cladospolide A 1 has been successfully accomplished.
Synthesis of (-)-cladospolide B and iso-cladospolide B
After the successful synthesis of (-)-cladospolide A 1, we planned
to synthesize other members of this family and decided to imple-
ment this general strategy for the syntheses of this class of natural
products. Therefore, taking the different stereochemical aspects of
the congeners of this family into consideration, we anticipated that
cladospolide B 2 could be synthesized utilizing a similar strategy
involving Julia–Kocienski olefination and macrolactonization as
pivotal reactions starting from commercially available L-(+)-
tartrate. As per our retrosynthetic analysis, the macrolide 2 could
be easily obtained from the hydroxy acid 46 through Yamaguchi
macrolactonization (Fig. 6). The seco acid 46 could be traced
back to compound 47 involving Wittig reaction and compound
47 is expected to be obtained from the intermediate 48. Here, we
visualized that the key intermediate 48 could be constructed by
Julia–Kocienski olefination between sulfone 49 and aldehyde 50.
Sulfone 49 could be easily derived from commercially accessible
L-(+)-tartaric acid ester in a few steps.
Scheme 7 Reagents and conditions: (a) H2/Pd-C, EtOH, 95%; (b)
LiAlH4, Et2O, 0 ◦C, 88%; (c) 41, PPh3, DIAD, THF, -20 ◦C, 95%; (d)
(NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, rt, 72%; (e) 43, LiHMDS, THF,
-78 ◦C, 84%; (f) H2/Pd-C, EtOH, 93%; (g) TBAF, THF, 0 ◦C, 94%; (h)
i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 ◦C; ii) Ph3PCHCOOEt, MeOH,
-78 ◦C, 65% (for two steps); (i) LiOH, THF–MeOH–H2O, 75%; (j) TBAF,
THF, 55 ◦C, 83%; (k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then
DMAP, toluene, reflux, 60%; (l) TFA, CH3CN–H2O, 62%.
isomer in 65% yield. The saponification of the cis ester 55 with
LiOH afforded the free acid, which upon deprotection of the
secondary TBS ether resulted in the key hydroxy acid 46 in
moderate yield. The seco acid 46 was successfully cyclised using
Yamaguchi protocol to lactone, which upon deprotection afforded
cladospolide B 2 in 62% yield. The spectral data of synthetic
2 matched with that reported earlier,6b thus confirming the
completion of a total synthesis of cladospolide B. Accomplishment
of total synthesis of iso-cladospolide B 3 was achieved in one step
from cis a,b-unsaturated ester 55, by acidic treatment (Scheme 8).
Fig. 6 Retrosynthetic analysis of cladospolide B.
Our journey for the synthesis of (-)-cladospolide B began
with the conversion of L-(+)-diethyltartrate to the known a,b-
unsaturated ester 50 in a sequence of steps (Scheme 7).25 Ester
50, upon catalytic hydrogenation and LAH reduction, afforded
alcohol 51 in good yield. Subsequently, alcohol 51 was converted
into the sulfone 52 in a couple of steps using Mitsunobu reaction
with 1-phenyl-1H-tetrazole-5-thiol 41, followed by oxidation of
the resultant sulfide. The pivotal Julia–Kocienski olefination
between sulfone 52 and the aldehyde 43 in the presence of
LiHMDS proceeded smoothly to provide 53 as an inseparable
mixture of E and Z isomers in the ratio of 2.7 : 1 in 84% yield.
However, the mixture of alkenes 53 was easily transformed into
alcohol 54 as a single isomer, by catalytic hydrogenation and
selective removal of the primary silyl ether with TBAF at 0 ◦C.
Oxidation of the alcohol 54 followed by Wittig reaction with
ethyl(triphenylphosphoranylidene) acetate at lower tempetature6f
furnished the desired cis a,b-unsaturated ester 55 as the major
Scheme 8 Synthesis of iso-cladospolide B.
Synthesis of (+)-cladospolide C
Successful exploitation of our designed strategy to the total
synthesis of cladospolide B 2 and iso-cladospolide B 3, took us to
extending the same strategy toward the synthesis of cladospolide
C 4 as well. Hence, following our unified strategy, we anticipated
that the twelve membered macrolide cladospolide C 4 could
be obtained from open precursor 56 by involving Yamaguchi’s
protocol (Fig. 7). The hydroxy acid 56 could in turn be synthesised
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Fig. 7 Retrosynthetic analysis of cladospolide C.
from compound 57 by involving Horner–Wadsworth–Emmons
reaction and accordingly, intermediate 58 was expected to deliver
compound 57 in a few steps. The key intermediate 58 was thought
to be constructed by Julia–Kocienski olefination between sulfone
59 derived from commercially available D-(-)-tartrate and known
aldehyde 60.
Scheme 9 Reagents and conditions: (a) H2/Pd–C, EtOH, 82%; (b)
LiAlH4, Et2O, 0 ◦C, 95%; (c) 41, PPh3, DIAD, THF, -20 ◦C, 92%; (d)
(NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, rt, 76%; (e) 43, LiHMDS, THF,
-78 ◦C, 72%; (f) H2/Pd–C, EtOH, 90%; (g) TBAF, THF, 0 ◦C, 94%; (h) i)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 ◦C; ii) (OEt)2P(O)CH2COOEt, LiCl,
DIPEA, THF, 54% (for two steps); (i) LiOH, THF–MeOH–H2O, 79%; (j)
TBAF, THF, 55 ◦C, 83%; (k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
then DMAP, toluene, reflux, 63%; (l) TFA, CH3CN–H2O, 67%.
So, for the total synthesis of cladospolide C, we embarked on
the construction of the required sulfone from D-(-)-diethyltartrate,
which in a few steps was converted into a,b-unsaturated ester
61 following the known protocol (Scheme 9).25 Ester 61, on
hydrogenation followed by reduction with LAH, furnished alcohol
62 which was subsequently transformed into the corresponding
sulfone 63 utilizing the well established two step sequence.
Exposure of the sulfone 63 to the known aldehyde 43 in the
presence of LiHMDS resulted in the formation of the key
intermediate 64 in 72% yield as an inseparable mixture of E and
Z isomers favoring E in a 2.5 : 1 ratio. Pleasingly, the mixture
of alkenes 64, on hydrogenation followed by deprotection of the
primary TBS ether, afforded the alcohol 65 as a single isomer.
Oxidation of alcohol 65 under Swern conditions followed by
Horner–Wadsworth–Emmons reaction resulted in the trans a,b-
unsaturated ester 66 in 54% yield along with a small amount of
its cis isomer. Saponification of the ester 66 and the cleavage
of the secondary TBS ether went efficiently to furnish the seco
acid 56 in excellent yield. The acid 56 was pleasingly cyclised
under Yamaguchi conditions to the desired lactone, which upon
deprotection under TFA conditions afforded cladospolide C 4 in
67% yield.
Experimental
General experimental section is provided in the ESI.†
Experimental procedures and spectral data for selected compounds
(E)-((R)-Hept-6-en-2-yl) 3-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-
dioxolan-4-yl)acrylate (7). To a stirred solution of ester 13
(0.2 g, 0.88 mmol) in a mixture of THF (12 mL), MeOH (3 mL)
and water (3 mL) was added 1 M solution of lithium hydroxide
(1.8 mL). The reaction mixture was stirred for 1 h at rt. The
aqueous phase was washed with Et2O, acidified with 10% aq.
citric acid and extracted with EtOAc (3 ¥ 10 mL). The combined
organic phase was washed with brine solution, dried over Na2SO4
and concentrated in vacuo. The crude acid was used for the next
step without further purification.
To a stirred solution of crude acid 9 (0.140 g, 0.71 mmol)
in toluene (5 mL) was added DMAP (0.097 g, 0.78 mmol),
(R)-hept-6-en-ol 8 (0.097 g, 0.85 mmol) and Et3N (0.12 mL,
0.852 mmol). Then 2,4,6-trichloroacetylchloride (0.173 g, 0.71
mmol) was added at 0 ◦C and the resulting mixture was stirred
at room temperature for 1 h. The mixture was filtered through
a pad of Celite, the insoluble residue was carefully washed with
Et2O, the combined organic parts were concentrated and purified
by flash column chromatography (3% ethyl acetate in hexanes) to
afford the triene ester 7 (0.12 g, 46% for two steps). Rf 0.7 (3%
ethyl acetate in hexanes); [a]2D0 +20.7 (c 0.30, CHCl3); IR (neat):
3080, 2984, 2936, 1719, 1378, 1216, 1050, 987, 862 cm-1; 1H NMR
Conclusions
In conclusion, we have successfully achieved the total syntheses of
cladospolides A, B, C and iso-cladospolide B utilising a unified
and efficient strategy. The strategy involves a Julia–Kocienski
olefination between either a sugar or a tartaric acid ester-derived
sulfone and a siloxy aldehyde to construct the pivotal alkene
intermediate and a Yamaguchi lactonization to make the twelve-
membered cycle.
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(400 MHz, CDCl3): d 6.76 (dd, J = 15.5, 5.8 Hz, 1H), 6.04 (dd,
J = 15.5, 1.5 Hz, 1H), 5.88–5.62 (m, 2H), 5.36 (d, J = 17.4, 1H),
5.27 (d, J = 10.7, 1H), 5.14–4.9 (m, 3H), 4.76–4.70 (m, 2H), 2.06
(q, J = 7.3, 2H), 1.56 (s, 3H), 1.42 (s, 3H), 1.24 (d, J = 6.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 165.7, 143.3, 138.6, 133.6, 123.4,
119.4, 114.9, 109.7, 79.9, 77.7, 71.2, 35.5, 33.6, 27.9, 25.5, 24.8,
20.1; HRMS (ESI) calcd. for C17H26O4SiNa m/z 317.1729, found
m/z 317.1730
77.1, 70.8, 35.2, 33.4, 31.1, 28.1, 26.0, 25.5, 24.6, 19.9; HRMS
(ESI) calcd. for C17H28O4Si Na m/z 319.1885, found m/z 319.
1899.
(3S,4R)-7-((R)-Hept-6-en-2-yloxy)-7-oxohept-1-ene-3,4-diyl di-
acetate (18). To a solution of diene ester 17 (0.1 g, 0.34 mmol) in
CH3CN (10 mL) was added cupric chloride (0.58 g, 0.68 mmol).
After stirring for 2 h at RT, the reaction mixture was diluted
with water and extracted with ethyl acetate. The organic layer was
separated, dried over anhydrous Na2SO4, concentrated and used
for the next step without further purification.
A solution of crude trienediol in pyridine (1 mL) was treated
with acetic anhydride (0.122 g, 1.33 mmol) and a catalytic amount
of DMAP. After 2 h the reaction mixture was evaporated to make
a slurry and it was purified (3% ethyl acetate in hexanes) to afford
the diacetate 18 (78% for two steps). Rf 0.2 (10% ethyl acetate in
hexanes); [a]2D0 +5.2 (c 0.50, CHCl3); IR (neat): 2928, 2256, 1736,
1641, 1446, 1229, 1050, 911, 735, 649 cm-1; 1H NMR (300 MHz,
CDCl3): d 5.84–5.74 (m, 2H), 5.42–5.30 (m, 3H), 5.07–4.87 (m,
4H), 2.39–2.23 (m, 2H), 2.08 (s, 3H), 2.06 (s, 3H) 2.12–2.03 (m,
1H), 1.64–1.35 (m, 2H), 1.20 (d, J = 6.1 Hz, 3H); 13C NMR (100
MHz, CDCl3): d 172.4, 170.5, 170.0, 138.4, 131.8, 119.6, 114.8,
74.9, 73.0, 71.2, 35.3, 33.5, 30.6, 29.7, 24.7, 24.5, 21.1, 21.0, 20.0;
HRMS (ESI) calcd. for C18H28O6Si Na m/z 363.1784, found m/z
363.1794.
(3S,4R,E)-7-((R)-Hept-6-en-2-yloxy)-7-oxohepta-1,5-diene-3,4-
diyl diacetate (14). A solution of triene ester 7 (0.02 g, 0.068
mmol) in CH3CN (5 mL) was treated with cupric chloride
(0.023 g, 0.136 mmol). After stirring for 3 h at rt, the reaction
mixture was diluted with water and extracted with ethyl acetate (3
¥ 20 mL). The organic layer was separated, dried over anhydrous
Na2SO4, concentrated and without further purification was
carried through to the next step.
To a stirred solution of the trienediol 7a (0.045 g, 0.18 mmol) in
pyridine (1 mL) was added acetic anhydride (0.05 g, 0.53 mmol)
and a catalytic amount of DMAP. After 2 h, the solvent was
evaporated in vacuo and was purified to afford (1% ethyl acetate
in hexanes) trienediacetate 14 as a colorless liquid (0.48 g, 79%).
Rf 0.5 (6% ethyl acetate in hexanes); [a]2D0 +24.0 (c 0.25, CHCl3);
IR (neat): 3026, 2936, 1747, 1716, 1374, 1221, 1126, 1031, 758
cm-1; 1H NMR (400 MHz, CDCl3): d 6.82 (dd, J = 15.9, 5.5 Hz,
1H), 6.01 (dd, J = 15.9, 1.8 Hz, 1H), 5.84–5.74 (m, 2H), 5.61–
5.89 (m, 1H), 5.50–5.46 (m, 1H), 5.39–5.32 (m, 2H), 5.04–4.95
(m, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.09–2.04 (m, 2H), 1.69–
1.37 (m, 2H), 1.25 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 170.0, 169.9, 165.4, 140.1, 138.5, 131.2, 124.7, 120.2,
114.4, 74.4, 72.8, 71.6, 35.5, 33.6, 24.8, 21.1, 21.0, 20.1; HRMS
(ESI) calcd. for C18H26O6SiNa m/z 361.1627, found m/z 361.
1605.
(E)-((R)-Hept-6-en-2-yl) 3-((4R,5S)-5-((Z)-3-(allyloxy)prop-1-
enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (21). To a stirred
solution of a,b-unsaturated ester 28 (0.5 g, 1.7 mmol) in a mixture
of THF (34 mL), MeOH (8.5 mL) and water (8.5 mL) was
added 1 M solution of lithium hydroxide (3.5 mL). The reaction
mixture was stirred for 1 h at room temperature. The aqueous
phase was washed with Et2O, acidified with 10% aq. citric acid
and extracted with EtOAc (3 ¥ 20 mL). The combined organic
phase was washed with brine solution, dried over Na2SO4 and
concentrated in vacuo. The crude acid was used for the next step
without further purification.
(R)-Hept-6-en-2-yl 3-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-diox-
olan-4-yl)propanoate (17). To a stirred solution of ester 16 (0.2
g, 0.884 mmol) in a mixture of THF (12 mL), MeOH (3 mL) and
water (3 mL) was added 1 M solution of lithium hydroxide (1.8
mL). The reaction mixture was stirred for 1 h at rt. The aqueous
phase was washed with Et2O, acidified with 10% aq. citric acid
and extracted with EtOAc (3 ¥ 15 mL). The combined organic
phase was washed with brine solution, dried over Na2SO4 and
concentrated in vacuo. The crude acid was used for the next step
without further purification.
To a stirred solution of the above crude acid (0.11 g) in CH2Cl2
(10 mL) was added DMAP (0.216 g, 1.77 mmol), (R)-hept-6-
en-ol 8 (0.101 g, 0.884 mmol). Then DCC (0.273 g, 1.33 mmol)
was added at rt and the resulting mixture was stirred at room
temperature for 3 h. The mixture was filtered through a Celite
pad, the insoluble residue was carefully washed with CH2Cl2, the
combined organic washings were concentrated and purified by
flash column chromatography (5% ethyl acetate in hexanes) to
afford diene ester 45 (0.11 g, 42% for two steps). Rf 0.5 (6% ethyl
acetate in hexanes); [a]2D0 +11.7 (c 0.41, CHCl3); IR (neat): 2984,
2938, 1724, 1380, 1251, 1176, 1059, 925, 867 cm-1; 1H NMR (400
MHz, CDCl3): d 5.86–5.79 (m, 2H), 5.35–5.27 (m, 2H), 5.29–
4.89 (m, 3H), 4.52 (t, J = 7.2 Hz, 1H), 4.21–4.12 (m, 1H), 2.65–
2.33 (m, 2H), 2.05 (q, J = 6.3 Hz, 2H), 1.78–1.58 (m, 6H), 1.48
(s, 3H), 1.36 (s, 3H), 1.20 (d, J = 6.1 Hz, 3H); 13C NMR (100
MHz, CDCl3): d 172.8, 138.3, 133.9, 118.5, 114.7, 108.3, 79.5,
To the mixture of above crude acid (1.7 mmol), (R)-hept-6-
en-ol 8 (0.194 g, 1.7 mmol) and DMAP (0.207 g, 1.7 mmol)
in CH2Cl2 (15 mL) was added a solution of DCC (0.421 g, 1.2
mmol) in CH2Cl2 (5 mL) at room temperature. The resulting
mixture was stirred for 5 h. The mixture was filtered through a
pad of Celite, the insoluble residue was carefully washed with
CH2Cl2, the combined organic washings were concentrated and
purified by flash column chromatography (5% ethyl acetate in
hexanes) to afford ester 21 (0.180 g, 35% for two steps). Rf 0.5 (5%
ethyl acetate in hexanes); [a]2D0 +38.2 (c 0.57, CHCl3); IR (neat):
1
2926, 1718, 1380,1164, 916 cm-1; H NMR (400 MHz, CDCl3):
d 6.76 (dd, J = 15.9, 6.1 Hz, 1H), 6.23 (dd, J = 15.8, 1.2 Hz,
1H), 5.96–5.86 (m, 1H), 5.84–5.74 (m, 2H), 5.54–5.48 (m, 1H),
5.32–5.19 (m, 2H), 5.08–5.04 (m, 1H), 5.04–4.93 (m, 3H), 4.75–
4.71 (m, 1H), 4.07–4.06 (m, 2H), 3.99–3.96 (m, 2H), 2.60 (q, J =
7.3 Hz, 2H), 1.68–1.48 (m, 2H), 1.46–1.37 (m, 2H), 1.55 (s, 3H),
1.41 (s, 3H), 1.23 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 165.7, 143.4, 138.6, 134.6, 128.4, 123.5, 117.5, 114.9,
109.7, 77.8, 74.7, 71.4, 71.2, 66.0, 35.5, 33.6, 28.0, 25.5, 24.8, 20.1;
HRMS (ESI) calcd. for C21H32O5Na m/z 387.2147, found m/z 387.
2126.
6994 | Org. Biomol. Chem., 2011, 9, 6988–6997
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General procedure for Julia–Kocienski olefination reaction
(complex m, 10H), 1.39 (s, 3H), 1.30 (s, 3H), 1.09 (d, J = 6.1 Hz,
3H), 0.90 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.10 (s, 3H), 0.07 (s,
3H), 0.05 (s, 6H), 0.037 (s, 3H), 0.033(s, 3H); 13C NMR (100 MHz,
CDCl3): d 107.7, 76.6, 72.6, 68.5, 65.3, 39.6, 30.0, 29.8, 28.4, 26.1,
26.0, 25.96, 25.90, 23.8, 18.4, 18.2, 18.1, -3.5, -4.4, -4.7, -4.8,
-5.3,-5.4; HRMS (ESI): calcd for C32H70O5Si3Na m/z 641.4429,
found m/z 641.4412.
To a solution of sulfone (1 mmol) and aldehyde (1.4 mmol) in
anhydrous THF (13 mL) was added a 0.5 M solution of freshly
prepared LiHMDS (3 mmol) [prepared by adding 1.6 M solution
of n-BuLi (3 mmol) in hexane dropwise over a period of 5 min
to a pre cooled solution of HMDS (3.1 mmol) in THF at -20 ◦C
and then stirring at -10 ◦C for 30 min] dropwise at -78 ◦C. After
stirring for 20 min at the same temp., the reaction was quenched
with water and the aqueous part was extracted with ethyl acetate.
The combined organic phase was washed with brine, dried over
Na2SO4 and concentrated in vacuo. The crude residue was purified
by silica gel column chromatography.
(R)-1-((4R,5S)-5-((R)-6-(tert-Butyldimethylsilyloxy)heptyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (44). Following
the general procedure for the removal of TBS protection, a
solution of compound 40 (300 mg, 0.48 mmol) in THF (15 mL)
at 0 ◦C was treated with tetrabutyl ammonium fluoride (1.9 mL,
1 M soln in THF). Silica gel column chromatography (35% ethyl
acetate in hexanes) afforded the diol 44 (153 mg, 80%) as a thick
liquid. Rf 0.32 (50% ethyl acetate in hexanes); [a]2D0 -9.4 (c 0.50,
CHCl3); IR (neat): 3431, 2931, 1461, 1374, 1256, 1047, 911 cm-1;
1H NMR (400 MHz, CDCl3): d 4.20–4.15 (m, 1H), 3.94 (dd,
J = 8.2, 5.8 Hz, 1H), 3.83–3.68 (m, 4H), 2.69 (bs, 2H), 1.69–1.65
(m, 1H), 1.59–1.42 (m, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 1.37–1.24
(complex m, 8H), 1.09 (d, J = 6.1 Hz, 3H), 0.86 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): d 108.2, 78.1,
77.9, 69.7, 68.8, 64.8, 39.8, 29.9, 29.5, 28.2, 26.8, 26.0, 25.9, 25.7,
23.9, 18.3, -4.2, -4.5; HRMS (ESI): calcd for C20H42O5SiNa m/z
413.2699, found m/z 413.2714.
General procedure for hydrogenation of alkene
To a solution of alkene (1 mmol) in EtOH (11 mL) was added 5%
Pd–C (30 mg) and the resulting mixture was stirred for 2 h. The
reaction mixture was filtered through a pad of celite, the filtrate
was concentrated in vacuo and was purified by silica gel column
chromatography.
General procedure for the removal of TBS protection
To a solution of TBS ether (1 mmol) in THF (30 mL) at 0 ◦C was
added tetrabutyl ammonium fluoride (2 mmol, 1 M soln in THF)
and the mixture was stirred at the same temperature for 2 h. The
solvent was evaporated, the residue was adsorbed into silica gel
and purified by column chromatography.
tert - Butyl(((4S,5S) - 5 - ((R) - 6 - (tert - butyldimethylsilyloxy)-
heptyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)dimethylsilane
(53a). Following the general procedure for the Julia–Kocienski
olefination, to a solution of sulfone 52 (2.4 g, 4.90 mmol) and
aldehyde 43 (1.6 g, 8.33 mmol) in anhydrous THF (50 mL) was
added a 0.5 M solution of freshly prepared LiHMDS (25.5 mL,
12.74 mmol) dropwise at -78 ◦C. The crude material was purified
by silica gel column chromatography (1% ethyl acetate in hexanes)
to afford compound 53 (1.9 g, 84%) as a colourless oil as an
inseparable mixture of E and Z isomers in a 2.7 : 1 ratio. Rf 0.28
(2% ethyl acetate in hexanes); IR (neat): 2985, 1742, 1374, 1242,
(R)-5-((4S,5S)-5-((R,E)-6-(tert-Butyldimethylsilyloxy)hept-3-
enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,3,3,8,8,9,9-octamethyl-
4,7-dioxa-3,8-disiladecane (39). Following the general procedure
for the Julia–Kocienski olefination, to a solution of sulfone 42
(100 mg, 0.15 mmol) and aldehyde 43 (44 mg, 0.21 mmol) in
anhydrous THF (2 mL) was added a 0.5 M solution of freshly
prepared LiHMDS (0.81 mL, 0.45 mmol) dropwise at -78 ◦C. The
crude residue was purified by silica gel column chromatography
(1% ethyl acetate in hexanes) to afford compound 39 (80 mg, 83%)
as a colourless oil. Rf 0.28 (2% ethyl acetate in hexanes); [a]2D0 -27.6
(c 0.50, CHCl3); IR (neat): 3020, 2931, 1657, 1045 cm-1; 1H NMR
(400 MHz, CDCl3): d 5.45–5.42 (m, 2H), 4.09–4.05 (m, 3H), 3.80–
3.74 (m, 1H), 3.66 (dd, J = 11.3, 4.8 Hz, 1H), 2.13–2.03 (m, 4H),
1.63–1.53 (m, 2H), 1.40 (s, 3H), 1.31 (s, 3H), 1.10 (d, J = 6.1 Hz,
3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.11(s, 3H), 0.08 (s,
3H), 0.06 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 132.0, 127.2, 107.8, 77.4, 76.4, 72.6, 68.8, 65.3, 43.0,
30.1, 29.1, 28.4, 26.0, 25.96, 25.90, 23.3, 18.4, 18.1, -3.5, -4.5,
-4.6, -4.7, -5.3, -5.4.
1
1047 cm-1; H NMR (400 MHz, CDCl3): d 5.44–5.40 (m, 2H),
3.91–3.86 (m, 1H), 3.82–3.72 (m, 2H), 3.69–3.65 (m, 2H), 2.21–
2.04 (m, 4H), 1.69–1.63 (m, 2H), 1.39 (s, 3H), 1.36 (s, 3H), 1.09
(d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s,
3H), 0.036 (s, 6H), 0.034 (s, 3H).
Following the general procedure for hydrogenation of alkene, a
solution of compound 53 (170 mg, 0.35 mmol) in EtOH (10 mL)
was treated with 10% Pd–C (10 mg). Purification by silica gel
column chromatography (2% ethyl acetate in hexanes) resulted in
compound 53a (160 mg, 93%) as a colourless oil. Rf 0.26 (2% ethyl
acetate in hexanes); [a]2D0 -21.1 (c 0.66, CHCl3); IR (neat): 2932,
2859, 2640, 1378, 1255, 1086 cm-1; 1H NMR (400 MHz, CDCl3):
d 3.90–3.85 (m, 1H), 3.76–3.72 (m, 2H), 3.70–3.64 (m, 2H), 1.54–
1.22 (complex m, 10H), 1.40 (s, 3H), 1.37 (s, 3H), 1.10 (d, J =
6.1 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.06 (s, 6H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): d 108.2,
81.1, 78.7, 68.6, 63.7, 39.6, 33.4, 29.8, 27.3, 26.9, 26.0, 25.8, 25.6,
23.7, 18.3, 18.1, -4.4, -4.7, -5.40, -5.46; HRMS (ESI): calcd for
C25H54O4Si2Na m/z 497.3458, found m/z 497.3466.
(R)-5-((4S,5S)-5-((R)-6-(tert-Butyldimethylsilyloxy)heptyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,3,3,8,8,9,9-octamethyl-4,7-
dioxa-3,8-disiladecane (40). Following the general procedure for
hydrogenation of alkene, a solution of compound 39 (2.25 g, 3.64
mmol) in EtOH (60 mL) was treated with 5% Pd–C (110 mg). The
crude material was purified by silica gel column chromatography
(2% ethyl acetate in hexanes) resulting in saturated compound
40 (1.90 g, 84%) as a colourless oil. Rf 0.26 (2% ethyl acetate in
hexanes); [a]2D0 -29.7 (c 0.66, CHCl3); IR (neat): 3021, 2930, 2858,
((4S,5S)-5-((R)-6-(tert-Butyldimethylsilyloxy)heptyl)-2,2-dime-
thyl-1,3-dioxolan-4-yl)methanol (54). Following the general pro-
cedure for removal of TBS protection, a solution of compound
1
2640, 1380, 1044 cm-1; H NMR (400 MHz, CDCl3): d 4.08–
4.04 (m, 2H), 3.79–3.73 (m, 3H), 3.68–3.64 (m, 1H), 1.65–1.24
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53a (150 mg, 0.31 mmol) in THF (5 mL) at 0 ◦C was treated
with TBAF (0.28 mL, 1 M soln in THF). Purification by silica gel
column chromatography (30% ethyl acetate in hexanes) provided
alcohol 54 (110 mg, 94%) as a thick liquid. Rf 0.32 (50% ethyl
acetate in hexanes); [a]2D0 -22.0 (c 0.83, CHCl3); IR (neat): 3435,
3019, 2934, 2862, 1216, 1020 cm-1; 1H NMR (400 MHz, CDCl3): d
3.89–3.84 (m, 2H), 3.81–3.71 (m, 2H), 3.61–3.57 (m, 1H), 1.97 (t,
1H), 1.58–1.25 (complex m, 10H), 1.59–1.42 (m, 1H), 1.41 (s, 3H),
1.41 (s, 3H), 1.10 (d, J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H);
13C NMR (100 MHz, CDCl3): d 108.5, 81.4, 77.3, 68.5, 62.0, 39.5,
33.0, 29.7, 27.3, 26.9, 25.9, 25.8, 25.6, 23.7, 18.1, -4.4, -4.7; HRMS
(ESI): calcd for C19H41O4Si m/z 361.2774, found m/z 361.2780.
18.0, -4.4, -4.7; HRMS (ESI): calcd for C19H41O4Si m/z 361.2774,
found m/z 361.2779.
Acknowledgements
KPK thanks DST for the award of Swarnajayanti fellowship.
DS and NMS thank CSIR, New Delhi and IIT Bombay for
fellowships, respectively. We thank SAIF, IIT Bombay for financial
support and the use of spectral facilities.
References
1 (a) A. Hirota, A. Isogai and H. Sakai, Agric. Biol. Chem., 1981, 45,
799–800; (b) A. Hirota, H. Sakai, A. Isogai, Y. Kitano, T. Ashida, H.
Hirota and T. Takahashi, Agric. Biol. Chem., 1985, 49, 903–904; (c) H.
Hirota, A. Hirota, H. Sakai, A. Isogai and T. Takahashi, Bull. Chem.
Soc. Jpn., 1985, 58, 2147–2148; (d) A. Hirota, H. Sakai and A. Isogai,
Agric. Biol. Chem., 1985, 49, 731–735.
tert - Butyl( ( ( 4R , 5R) - 5 - ((R) - 6 - (tert - butyldimethylsilyloxy)-
heptyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)dimethylsilane
(64a). Following the general procedure for the Julia–Kocienski
olefination, to a solution of sulfone 63 (520 mg, 1.04 mmol) and
aldehyde 43 (356 mg, 1.76 mmol) in anhydrous THF (11 mL) was
added a 0.5 M solution of freshly prepared LiHMDS (5.4 mL,
2 A. Hirota, H. Sakai and A. Isogai, Agric. Biol. Chem., 1985, 49, 731–
735.
3 (a) Y. Fujii, A. Fukuda, T. Hamasaki, I. Ichimoto and H. Nakajima,
Phytochemistry, 1995, 40, 1443–1446; (b) C. J. Smith, D. Abbanat, V. S.
Bernan, W. M. Maiese, M. Greenstein, J. Jampa, A. Tahir and C. M.
Ireland, J. Nat. Prod., 2000, 63, 142–145.
4 H. Zhang, H. Tomoda, N. Tabata, H. Miura, M. Namikoshi, Y.
Yamaguchi, R. Masuma and S. Omura, J. Antibiot., 2001, 54, 635–
641.
◦
2.70 mmol) dropwise at -78 C. The crude residue was purified
by silica gel column chromatography (1% ethyl acetate in hexanes)
to afford compound 64 (350 mg, 72%) as a colourless oil as an
inseparable mixture of E and Z isomers in a 2.5 : 1 ratio. Rf 0.28
(2% ethyl acetate in hexanes); IR (neat): 2930, 2858, 1737, 1378,
1
1256, 1125 cm-1; H NMR (400 MHz, CDCl3): d 5.44–5.40 (m,
5 For earlier synthesis of cladospolide A, see: (a) K. Rajesh, V. Suresh, J.
J. P. Selvam, C. B. Rao and Y. Venkateswarlu, Synthesis, 2010, 1381–
1385; (b) K. P. Kaliappan and D. Si, Synlett, 2009, 2441–2444; (c) M. G.
Banwell and D. T. J. Loong, Org. Biomol. Chem., 2004, 2, 2050–2060;
(d) M. G. Banwell, K. A. Jolliffe, D. T. J. Loong, K. J. McRae and F.
Vounatsos, J. Chem. Soc., Perkin Trans. 1, 2002, 22–25; (e) G. Solladie´
and A. Almario, Tetrahedron: Asymmetry, 1995, 6, 559–576; (f) G.
Solladie´ and A. Antonio, Pure Appl. Chem., 1994, 66, 2159–2162; (g) I.
Ichimoto, M. Sato, M. Kirihata and H. Ueda, Chem. Express, 1987,
2, 495–498; (h) S. Maemoto and K. Mori, Chem. Lett., 1987, 109–112;
(i) K. Mori and S. Maemoto, Liebigs Ann. Chem., 1987, 863–869.
6 For earlier synthesis of cladospolide B, see: (a) Y. Xing, J. H. Penn
and G. A. O’Doherty, Synthesis, 2009, 2847–2854; (b) Y. Xing and G.
A. O’Doherty, Org. Lett., 2009, 5, 1107–1110; (c) W.-K. Wang, J.-Y.
Zhang, J.-M. He, S.-B. Tang, X.-L. Wang, X.-G. She and X.-F. Pan,
Chin. J. Chem., 2008, 26, 1109–1113; (d) G. V. M. Sharma, J. J. R. Reddy
and K. L. Reddy, Tetrahedron Lett., 2006, 47, 6535–6540; (e) G. V. M.
Sharma, J. J. R. Reddy and K. L. Reddy, Tetrahedron Lett., 2006, 47,
6531–6535; (f) S. K. Pandey and P. Kumar, Tetrahedron Lett., 2005, 46,
6625–6627; (g) K. A. B. Austin, M. G. Banwell, D. T. J. Loong, D. Rae
and A. C. Willis, Org. Biomol. Chem., 2005, 3, 1081–1088.
7 For earlier synthesis of iso-cladospolide B, see: (a) K. R. Prasad and V.
R. Gandi, Tetrahedron: Asymmetry, 2010, 21, 275–276; (b) L. Ferrie´, S.
Reymond, P. Capdevielle and J. Cossy, Synlett, 2007, 2891–2893; (c) P.
Srihari, E. V. Bhasker, S. J. Harshavardhan and J. S. Yadav, Synthesis,
2006, 4041–4045; (d) X. Franck, M. E. V. Araujo, J.-C. Jullian, R.
Hocquemiller and B Figade`re, B., Tetrahedron Lett., 2001, 42, 2801–
2803.
8 For earlier synthesis of cladospolide C, see: (a) Y. Xing, J. H. Penn and
G. A. O’Doherty, Synthesis, 2009, 2847–2854; (b) Y. Xing and G. A.
O’Doherty, Org. Lett., 2009, 5, 1107–1110; (c) C. R. Reddy and N. N.
Rao, Tetrahedron Lett., 2009, 50, 2478–2480; (d) C.-Y. Chou and D.-R.
J. Hou, J. Org. Chem., 2006, 71, 9987–9890; (e) G. V. M. Sharma, J. J. R.
Reddy and K. L. Reddy, Tetrahedron Lett., 2006, 47, 6535–6540; (f) G.
V. M. Sharma, J. J. R. Reddy and K. L. Reddy, Tetrahedron Lett., 2006,
47, 6531–6535; (g) M. G. Banwell, D. T. J. Loong and A. C. Willis,
Aust. J. Chem., 2005, 58, 511.
2H), 3.88 (dt, J = 7.3, 4.0 Hz, 1H), 3.83–3.72 (m, 2H), 3.69–3.65
(m, 2H), 2.20–2.03 (m, 4H), 1.68–1.61 (m, 2H), 1.40 (s, 3H), 1.36
(s, 3H), 1.10 (d, J = 5.8 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.06 (s,
3H), 0.04 (s, 3H), 0.037 (s, 6H), 0.034 (s, 3H).
Following the general procedure for hydrogenation of alkene, a
solution of compound 64 (350 mg, 0.74 mmol) in EtOH (20 mL)
was treated 10% Pd–C (53 mg). The crude material was purified
by silica gel column chromatography (2% ethyl acetate in hexanes)
resulting in compound 64a (320 mg, 90%) as a colourless oil. Rf
0.26 (2% ethyl acetate in hexanes); [a]2D0 -17.0 (c 0.88, CHCl3); IR
1
(neat): 2931, 2858, 1472, 1377, 1255, 1085 cm-1; H NMR (400
MHz, CDCl3): d 3.87 (dt, J = 7.5, 2.9 Hz, 1H), 3.76–3.72 (m,
2H), 3.70–3.65 (m, 2H), 1.59–1.26 (complex m, 10H), 1.40 (s, 3H),
1.37 (s, 3H), 1.10 (d, J = 5.8 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H),
0.85 (s, 9H), 0.06 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 108.2, 81.1, 78.7, 68.5, 63.7, 39.6, 33.5, 29.8,
27.3, 26.9, 26.1, 25.8, 25.7, 23.7, 18.3, 18.1, -4.4, -4.7, -5.40, -5.46;
HRMS (ESI): calcd for C25H54O4Si2Na m/z 497.3458, found m/z
497.3474.
((4R,5R)-5-((R)-6-(tert-Butyldimethylsilyloxy)heptyl)-2,2-dime-
thyl-1,3-dioxolan-4-yl)methanol (65). Following the general pro-
cedure for removal of TBS protection, to a solution of compound
64a (320 mg, 0.67 mmol) in THF (11 mL) at 0 ◦C was added
tetrabutyl ammonium fluoride (0.60 mL, 1 M soln in THF). The
crude material was purified by column chromatography (35% ethyl
acetate in hexanes) to provide alcohol 65 (230 mg, 94%) as a thick
liquid. Rf 0.32 (50% ethyl acetate in hexanes); [a]2D0 10.4 (c 0.83,
1
CHCl3); IR (neat): 3403, 3018, 2932, 2857, 1216, 1020 cm-1; H
9 For earlier synthesis of cladospolide D, see: (a) K.-J. Lu, C.-H. Chen
and D.-R. Hou, Tetrahedron, 2009, 65, 225–231; For synthesis of ent-
cladospolide D, see: (b) Y. Xing, J. H. Penn and G. A. O’Doherty,
Synthesis, 2009, 2847–2854; (c) Y. Xing and G. A. O’Doherty, Org.
Lett., 2009, 5, 1107–1110.
10 (a) A. V. Subrahmanyam, K. Palanichamy and K. P. Kaliappan, Chem.–
Eur. J., 2010, 16, 8545–8556; (b) P. Gowrisankar, S. A. Pujari and K. P.
Kaliappan, Chem. Eur. J., 2010, 16, 5858–5862; (c) R. S. Nandurdikar,
NMR (400 MHz, CDCl3): d 3.88 (dt, J = 7.9, 3.9 Hz, 1H), 3.80
(ddd, J = 5.1, 3.0 Hz, 1H), 3.76–3.70 (m, 2H), 3.61–3.55 (m, 1H)
1.88 (dd, J = 5.1, 5.1 Hz, 1H), 1.57–1.25 (complex m, 10H), 1.41
(s, 3H), 1.40 (s, 3H), 1.10 (d, J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.039
(s, 3H), 0.035 (s, 3H); 13C NMR (100 MHz, CDCl3): d 108.5, 81.5,
77.3, 68.5, 61.9, 39.5, 33.0, 29.7, 27.3, 26.9, 25.9, 25.8, 25.6, 23.7,
6996 | Org. Biomol. Chem., 2011, 9, 6988–6997
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A. V. Subrahmanyam and K. P. Kaliappan, Eur. J. Org. Chem., 2010,
2788–2799; (d) K. P. Kaliappan and P. Das, J. Org. Chem., 2009, 74,
6266–6274; (e) K. P. Kaliappan and V. Ravikumar, J. Org. Chem., 2007,
72, 6116–6126; (f) K. P. Kaliappan and V. Ravikumar, Synlett, 2007,
0977–0980; (g) K. P. Kaliappan and A. V. Subrahmanyam, Org. Lett.,
2007, 9, 1121–1124; (h) K. P. Kaliappan, R. S. Nandurdikar and M.
M. Shaikh, Tetrahedron, 2006, 62, 5064–5073; (i) K. P. Kaliappan, V.
Ravikumar and S. A. Pujari, Tetrahedron Lett., 2006, 47, 981–984;
(j) K. P. Kaliappan and R. S. Nandurdikar, Org. Biomol. Chem., 2005,
3, 3613–3614; (k) K. P. Kaliappan and N. Kumar, Tetrahedron, 2005,
61, 7461–7469; (l) K. P. Kaliappan and V. Ravikumar, Org. Biomol.
Chem., 2005, 3, 848–851; (m) K. P. Kaliappan and R. S. Nandurdikar,
Chem. Commun., 2004, 2506–2507; (n) K. P. Kaliappan and N. Kumar,
Tetrahedron Lett., 2003, 44, 379–381.
H. Hoveyda, D. G. Gillingham, J. J. V. Veldhuizen, O. Kataoka, S. B.
Garber, J. S. Kingsbury and J. P. Harrity, Org. Biomol. Chem., 2004,
2, 8–23; (g) R. H. Grubbs, Tetrahedron, 2004, 60, 7117–7140; (h) J.
Prunet, Angew. Chem., 2003, 115, 2932–2936; J. Prunet, Angew. Chem.,
Int. Ed., 2003, 42, 2826–2830; (i) Handbook of Metathesis, Vol. 1–3
(Ed.: R. H. Grubbs), Wiley-VCH, Weinheim, 2003; (j) T. M. Trnka
and R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18–29; (k) S. Kotha
and N. Sreenivasachary, Indian J. Chem., 2001, 39, 763–780; (l) A.
Fu¨rstner, Angew. Chem., 2000, 112, 3140–3172; A. Fu¨rstner, Angew.
Chem., Int. Ed., 2000, 39, 3012–3043; (m) R. Roy and S. Das, Chem.
Commun., 2000, 519–529; (n) M. E. Maier, Angew. Chem., 2000, 112,
2153–2157; M. E. Maier, Angew. Chem., Int. Ed., 2000, 39, 2073–2077;
(o) L. Yet, Chem. Rev., 2000, 100, 2963–3007; (p) M. L. Randall and
M. L. Snapper, Strem. Chem., 1998, 17, 1–9; (q) A. J. Phillips and A. D.
Abell, Aldrichimica Acta, 1999, 32, 75–85; (r) D. L. Wright, Curr. Org.
Chem., 1999, 3, 211–240; (s) S. K. Armstrong, J. Chem. Soc., Perkin
Trans. 1, 1998, 371–388; (t) R. H. Grubbs and S. Chang, Tetrahedron,
1998, 54, 4413–4450; (u) M. Schuster and S. Blechert, Angew. Chem.,
1997, 109, 2124–2144; M. Schuster, Angew. Chem., Int. Ed. Engl., 1997,
36, 2036–2056.
11 W. J. Choi, H. R. Moon, H. L. Kim, B. N. Yoo, J. A. Lee, D. H. Shink
and L. S. Jeong, J. Org. Chem., 2004, 69, 2634–2636.
12 Y. L. Zhong and T. K. M. Shing, J. Org. Chem., 1997, 62, 2622–
2624.
13 M. A. Blanchette, W. Chey, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25, 2183–
2186.
18 P. M. Saravanan, R. Chandrasekhar, A. Vijaya and V. K. Singh,
Tetrahedron Lett., 1998, 39, 3091–3092.
19 M. Narisada, I. Horibe, F. Watanabe and K. Takeda, J. Org. Chem.,
1989, 54, 5308–5313.
20 (a) T. R. Hoye, C. S. Jeffrey, M. A. Tennakoon, J. Wang and H. Zhao,
J. Am. Chem. Soc., 2004, 126, 10210–10211; (b) E. C. Hansen and D.
Lee, Org. Lett., 2004, 6, 2035–2038.
21 P. Kumar, P. Gupta and S. V. Naidu, Chem. Eur. J., 2006, 12, 1397–1402.
22 (a) P. R. Blakemore, J. Chem. Soc. Perkin Trans.1, 2002, 2563–2585;
(b) P. R. Blakemore, W. J. Cole, P. J. Kocienski and A. Morley, Synlett,
1998, 26–28; (c) P. J. Kocienski, B. Lythgoe and I. Waterhouse, J. Chem.
Soc. Perkin Trans. 1, 1980, 1045–1050; (d) P. J. Kocienski, B. Lythgoe
and S. Ruston, J. Chem. Soc. Perkin Trans. 1, 1979, 1290–1293; (e) P. J.
Kocienski, B. Lythgoe and D. A. Roberts, J. Chem. Soc. Perkin Trans.
1, 1978, 834–837; (f) P. J. Kocienski, B. Lythgoe and S. Ruston, J. Chem.
Soc. Perkin Trans. 1, 1978, 829–834.
14 (a) S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B.
Hansen, A. E. Gould, M. E. Furrow and E. N. Jacobsen, J. Am. Chem.
Soc., 2002, 124, 1307–1315; (b) E. N. Jacobsen and K. Hinterding, J.
Org. Chem., 1999, 64, 2164–2165; (c) E. N. Jacobsen, M. E. Furrow and
S. E. Schaus, J. Org. Chem., 1998, 63, 6776–6777; (d) E. N. Jacobsen, M.
Tokunaga, J. F. Larrow and F. Kakiuchi, Science, 1997, 277, 936–938.
15 (a) D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin Trans. 1,
2000, 2385–2394; (b) A. Fu¨rstner, O. R. Thiel and L. Ackermann, Org.
Lett., 2001, 3, 449–451.
16 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi, Bull.
Chem. Soc. Jpn., 1979, 52, 1989–1993.
17 For selected recent reviews on metathesis, see: (a) A. Gradillas and
J. Pe´rez-Castells, Angew. Chem., 2006, 118, 6232–6247; A. Gradillas
and J. Pe´rez-Castells, Angew. Chem., Int. Ed., 2006, 45, 6086–6101;
(b) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., 2005,
117, 4564–4601; K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew.
Chem., Int. Ed., 2005, 44, 4490–4527; (c) D. J. Wallace, Angew. Chem.,
2005, 117, 1946–1949; D. J. Wallace, Angew. Chem., Int. Ed., 2005,
44, 1912–1915; (d) A. Giessert and S. T. Diver, Chem. Rev., 2004, 104,
1317–1382; (e) B. Schmidt, Eur. J. Org. Chem., 2004, 1865–1880; (f) A.
23 E. Leiber and J. Ramachandran, Can. J. Chem., 1959, 37, 101–109.
24 A. J. Duplantier and S. Masamune, J. Am. Chem. Soc., 1990, 112,
7079–7081.
25 P. Davoli, A. Spaggiari, L. Castagnetti and F. Prati, Org. Biomol. Chem.,
2004, 3, 38–47.
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