Alkyne-mediated approach for total syntheses of cladospolides A, B, C and iso-cladospolide B

Article abstract of DOI:10.1002/ejoc.201300022

A general strategy for the stereoselective total syntheses of cladospolides A, B, and C and iso-cladospolide B has been accomplished. The key steps provide easy access to the target molecules and include an alkyne-zipper reaction, a Sharpless asymmetric e

Full text of DOI:10.1002/ejoc.201300022

FULL PAPER
DOI: 10.1002/ejoc.201300022
Alkyne-Mediated Approach for Total Syntheses of Cladospolides A, B, C and
iso-Cladospolide B
Chada Raji Reddy,*[a] Devatha Suman,[a] and Nagavaram Narsimha Rao[a]
Keywords: Natural products / Total synthesis / Lactones / Alkynes / Epoxidation / Dihydroxylation
A general strategy for the stereoselective total syntheses of
cladospolides A, B, and C and iso-cladospolide B has been
accomplished. The key steps provide easy access to the tar-
get molecules and include an alkyne-zipper reaction, a
Sharpless asymmetric epoxidation/dihydroxylation, and a
Yamaguchi macrolactonization. The feasibility of the alkyne-
mediated approach to construct the required carbon frame-
work as well as to create the diol functionality and the olefin
geometry is successfully demonstrated.
Introduction
Cladospolides A–D and iso-cladospolide B (see Figure 1)
comprise a family of fungal secondary metabolites isolated
from the fermented broth of cultures that were obtained
from either marine fungi or soil fungus.[1–4] Among these,
cladospolides A (1) and B (2) were first isolated from the
culture filtrate of the fungus Cladosporium cladosporiolides
FI-113 by Isogai and co-workers.[1] In 1995, Fukada et al.
isolated cladospolide C (4) along with cladospolides A and
B from Cladosporium tenuissium.[2] Later in 2000, Ireland
and co-workers isolated 2 from Cladosporium herbarum to-
gether with iso-cladospolide B (3) from the fungal strain
I96S215.[3] Cladospolide D (5) was isolated in 2001 from
the fermentation broth of Cladosporium sp. FT0012.[4]
Structurally, cladospolides A–C are γ,δ-dihydroxy-α,β-un-
saturated 12-membered macrolides, whereas cladospolide D
is a δ-hydroxy-γ-oxo-α,β-unsaturated 12-membered lactone.
Furthermore, cladospolides A and C possess an (E)-olefin
geometry, whereas cladospolides B and D have a (Z)-olefin
geometry. In contrast to cladospolides A–D, iso-cladospol-
ide B is a butenolide that is γ-substituted by an aliphatic
group. Although the cladospolides are fungal metabolites,
they are plant-growth regulators. For example, cladospol-
ides A–C inhibit the shoot elongation of rice seedlings and,
interestingly, cladospolides A and B have the opposite ef-
fect. The biological properties of cladospolide C suggest
that it is a gibberellin synthesis inhibitor. Unlike the other
members, cladospolide D shows antimicrobial activity
against Mucor recemosus and Pyricularia oryzae.
Figure 1. Structures of cladospolides A–D and iso-cladospolide B.
Given their fascinating structural diversities and bio-
logical profiles, the cladospolide family members have gen-
erated considerable interest in the synthetic community. Ac-
cordingly, various strategies have been developed that uti-
lize diverse key reactions.[5–9] In continuation of our interest
in the synthesis of bioactive macrolides through alkyne-as-
sisted approaches,[10] we herein report a general strategy for
the syntheses of dihydroxylated cladospolides 1–4 by using
an alkyne-based strategy.
In this present approach, we plan to construct the desired
carbon chain of these molecules with the assistance of the
alkyne functionality by using: (i) an epoxide ring-opening
reaction followed by alkyne-zipper reaction, (ii) a Pd-cata-
lyzed coupling reaction, and (iii) a partial reduction reac-
tion. Furthermore, the required asymmetric diol function-
ality as well as the olefin geometry was envisioned from
the alkyne functionality by using a Sharpless asymmetric
epoxidation or a dihydroxylation and reduction of the alk-
yne, respectively.
[a] Division of Natural Products Chemistry, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91-40-27160512
E-mail: rajireddy@iict.res.in
Homepage: www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300022.
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Alkyne-Mediated Approach for Syntheses of Cladospolides
isopropylidene derivative.[17] The benzoate was removed un-
der basic hydrolysis conditions (K2CO3, MeOH) to give
triol 13 (89%), to which the tert-butyldimethylsilyl (TBS)
group was selectively installed at the primary hydroxy group
with ease (TBSCl/imidazole/CH2Cl2) to lead to the corre-
sponding silylated diol 14 (73%). Diol 14 was treated with
2,2-dimethoxypropane (2,2-DMP) in the presence of cam-
phorsulfonic acid (CSA) in dichloromethane to obtain the
isopropylidene derivative 15 in 94% yield. Then, a tetra-n-
butylammonium fluoride (TBAF) mediated desilylation of
both of the silyl groups was carried out to yield diol 16 in
92% yield. The primary hydroxy group of 16 was selectively
oxidized with 2,2,6,6-tetramethylpiperidine-1-oxyl/(di-
acetoxyiodo)benzene (TEMPO/BAIB) to the corresponding
Results and Discussion
Synthesis of Cladospolide A
For the approach towards cladospolide A (see Scheme 1),
we began by synthesizing alkynol 7 from epoxide 6 through
a two-step sequence[7a,11] that involved: (i) an epoxide ring-
opening reaction with 1-hexyne and nBuLi/hexameth-
ylphosphoramide (HMPA) and (ii) a KH-mediated alkyne-
zipper reaction.[12] The spectroscopic data of alkynol 7 was
in agreement with the reported data, and the specific rota-
tion was comparable with the literature value.[13] Further-
more, the optical purity was measured at the next stage,
that is, after protection of the secondary alcohol as the tert-
butyldiphenylsilyl (TBDPS) ether 8, which was carried out
in 82% yield.[14] Extending the molecule by one carbon
atom to give the allylic alcohol was accomplished through
the formylation (HCHO, nBuLi) of terminal alkyne 8 to
afford propargylic alcohol 9 in 78% yield. Reduction of 9
by using sodium bis(2-methoxyethoxy)aluminum hydride/
tetrahydrofuran (Red-Al/THF) reaction conditions pro-
vided allylic alcohol 10 in 95% yield. Next, the introduction
of the desired chiral anti-diol functionality was achieved by
using Sharpless protocols, which involved an asymmetric
epoxidation followed by a Lewis acid mediated regioselec-
tive 2,3-epoxide ring-opening reaction.[15,16] The Sharpless
asymmetric epoxidation of 10 with (–)-diisopropyl tartrate/
titanium tetraisopropoxide/tert-butyl hydroperoxide [(–)-
DIPT/Ti(iPrO)4/TBHP] gave epoxy alcohol 11 in 78% yield
with good diastereoselectivity (dr Ͼ95:5). The enantiopure
epoxy alcohol 11 underwent a ring-opening reaction with
PhCOOH as the nucleophile and Ti(iPrO)4 as the acidic
catalyst to furnish diol benzoate 12 in 91% yield with excel-
aldehyde,
which
upon
Wittig
olefination
with
Ph3P=CHCO2Et afforded α,β-unsaturated ester 17 in 94%
yield in a one-pot reaction.[18] The hydrolysis of the ester 17
by using LiOH/THF/H2O conditions produced the hydroxy
acid, which was subjected to lactonization according to the
Yamaguchi protocol[19] with 2,4,6-trichlorobenzoyl chloride
to obtain macrolactone 18 in 87% yield. Finally, deprotec-
tion of the acetonide group of 18 with trifluoroacetic acid
(TFA, 88% yield) furnished cladospolide A (1, see
Scheme 1). The spectroscopic data (1H and 13C NMR, MS,
and IR) of synthetic 1 were in good agreement with those
reported for the natural product. The specific rotation ob-
served for 1 {[α]2D0 = –35.5 (c = 0.6, MeOH)} was compar-
able with that of the natural product {ref.[1b,1d] [α]D18 = –30.0
(c = 0.4, MeOH)}.
Synthesis of Cladospolide B and iso-Cladospolide B
lent regioselectivity (no trace of the other isomer was de-
tected in the H NMR spectrum). The anti stereochemistry began with the TBDPS-protected terminal alkyne 8, which
of the diol was determined after it was converted into an was initially converted into (E)-vinyl iodide 19 through a
As outlined in Scheme 2, the synthesis of cladospolide B
1
Scheme 1. Synthesis of cladospolide A. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 °C to r.t., 6 h, 82%; (b) (i) nBuLi,
THF, –78 °C, 30 min, (ii) HCHO, r.t., 6 h, 78%; (c) Red-Al, THF, 0 °C to r.t., 1 h, 95%; (d) (–)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, –20 °C,
4 h, 78%; (e) PhCOOH, Ti(OiPr)4, CH2Cl2, r.t., 1 h, 91%; (f) K2CO3, MeOH, 0 °C, 1 h, 89%; (g) TBSCl, imidazole, DMAP, CH2Cl2,
0 °C to r.t., 1 h, 73%; (h) 2,2-DMP, CSA, CH2Cl2, 1 h, r.t., 94%; (i) TBAF, THF, r.t., 12 h, 92%; (j) (i) TEMPO, BAIB, CH2Cl2, r.t., 2 h,
(ii) Ph3P=CHCO2Et, CH2Cl2, 0 °C to r.t., 2 h, 94% (one pot); (k) (i) LiOH, THF/H2O (1:1), r.t., 12 h, (ii) 2,4,6-trichlorobenzoyl chloride,
Et3N, 0 °C, 2 h, DMAP, toluene, 100 °C, 8 h, 87%; (l) TFA, CH3CN/H2O, 0 °C to r.t., 2 h, 88%.
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Scheme 2. Synthesis of cladospolide B and iso-cladospolide B. Reagents and conditions: (a) (i) NBS, AgNO3, acetone, 0 °C to r.t., 1 h,
(ii) Bu3SnH, PPh3, Pd2(dba)3, THF, 0 °C to r.t., 45 min, (iii) NIS, THF, –78 °C, 15 min, 72% (over three steps); (b) I, Pd(PPh3)2Cl2, CuI,
Et3N, 0 °C to r.t., 1 h, 79%; (c) K3Fe(CN)6, K2CO3, CH3SO2NH2, (DHQ)2PHAL, OsO4, tBuOH/H2O (1:1), 0 °C, 24 h, 71%; (d) 2,2-
DMP, CSA, CH2Cl2, 1 h, 0 °C, 79%; (e) TBAF, THF, r.t., 1 h, 98%; (f) H2, Pd/CaCO3, quinoline, EtOAc, r.t., 1 h, 98%; (g) TEMPO,
BAIB, CH2Cl2/H2O (1:1), 1 h, 0 °C to r.t., 72%; (h) TBAF, THF, r.t., 6 h, 80%; (i) 2,4,6-trichlorobenzoyl cloride, Et3N, THF, 0 °C, 2 h,
DMAP, toluene, 100 °C, 8 h, 84%; (j) TiCl4, CH2Cl2, 0 °C, 2 h, 86%; (k) TFA, CH3CN/H2O, 0 °C to r.t., 2 h, 89%.
three-step reaction sequence[20] that involved: (i) the (89% yield) from macrolactone 27 by the treatment with
bromination of the 1-alkyne to a bromo-substituted alkyne, an excess amount of trifluoroacetic acid in a mixture of
(ii) the Pd-catalyzed hydrostannation of the bromoalkyne to acetonitrile/water (see Scheme 2).[24] The spectroscopic data
an (E)-vinylstannane, and (iii) the iodination of the vinyl- (1H and 13C NMR, IR, and MS) of the obtained target
stannane to give vinyl iodide 19 (72% yield). Derivative 19 molecules were in full agreement with those of the reported
was treated with TBS-protected propargylic alcohol (I) un- natural product data. The specific rotations observed for 2
der Sonogashira coupling reaction[21] conditions to provide {[α]2D0 = +21.2 (c = 0.6, MeOH); ref.[1d] [α]D22 = +26.9 (c =
enyne 20 (79%). Having the required carbon chain for the 0.4, MeOH)} and 3 {[α]2D0 = –98.0 (c = 0.70, MeOH); re-
target molecule, we next focused on the formation of the f.[3,7a–7c] [α]D = –90.0 (c = 0.23, MeOH)} were comparable
asymmetric syn-diol and (Z)-olefin functionalities. Thus, with the reported values.
enyne 20 was subjected to Sharpless asymmetric dihydrox-
ylation[22] with K3Fe(CN)6, K2CO3, CH3SO2NH2, hydro-
quinine 1,4-phthalazinediyl diether [(DHQ)2PHAL], OsO4,
tBuOH/H2O (1:1) to obtain diol 21 (71% yield) as a separa-
Synthesis of Cladospolide C
ble diastereomeric mixture (95:5). The major isomer was
After successful utilization of the proposed alkyne-as-
separated by column chromatography in pure form without sisted strategy to the total syntheses of cladospolides A, B,
1
a trace of the other isomer as detected by H NMR spec- and iso-caldospolide B, we extended a similar approach to
troscopy. Protection of the newly created 1,2-diol by treat- the total synthesis of cladospolide C (see Scheme 3). The
ment with 2,2-DMP/CSA (cat.) in dichloromethane (79% structural differences of cladospolide C in comparison to
yield) gave acetonide 22, which upon removal of the TBS cladospolide B are that it is an (E)-olefin and has the oppo-
group with TBAF in THF gave propargylic alcohol 23 in site stereochemistry at the diol functionality. Thus, we
98% yield. The catalytic hydrogenation of 23 with Lindlar’s started the synthesis of cladospolide C from the same enyne
catalyst offered (Z)-olefin 24 in 98% yield. For the ap- intermediate 20 that was used in the synthesis of cladospol-
proach towards the macrolactonization, allylic alcohol 24 ide B. Initially, the dihydroxylation of enyne 20 through a
was oxidized by using BAIB/TEMPO in CH2Cl2/H2O (1:1) Sharpless asymmetric dihydroxylation[22] with K3Fe(CN)6,
to yield acid 25 (72% yield). This was followed by the re- K2CO3, CH3SO2NH2, (DHQD)2PHAL, OsO4, tBuOH/
moval of the TBDPS group by using TBAF in THF to pro- H2O (1:1) furnished diol 28 with the requisite stereochemis-
vide hydroxy acid 26 in 80% yield. The macrolactonization try in 72% yield (as a separable 95:5 diastereomeric mix-
of 26 under Yamaguchi conditions [2,4,6-trichlorobenzoyl ture). Pure diol 28 was transformed into propargylic
chloride/Et3N/4-(dimethylamino)pyridine
(DMAP), alcohol 30 in a two-step reaction sequence that involved:
100 °C] gave lactone 27 in 84% yield. Exposing 27 to tita- (i) acetonide protection of the diol to give 29 (78%) and
nium tetrachloride in dichloromethane provided for the (ii) removal of the TBS group to afford 30 (98%). Now,
cleavage of the acetonide and furnished cladospolide B (2) the desired (E)-olefinic funtionality was accomplished by
in 86% yield.[23] iso-Cladospolide B (3) was also obtained reduction of propargylic alchol 30 with Red-Al in THF to
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Alkyne-Mediated Approach for Syntheses of Cladospolides
Scheme 3. Synthesis of cladospolide C. Reagents and conditions: (a) K3Fe(CN)6, K2CO3, CH3SO2NH2, (DHQD)2PHAL, OsO4, tBuOH/
H2O (1:1), 0 °C, 24 h, 72%; (b) 2,2-DMP, CSA, CH2Cl2, 1 h, 0 °C, 78%; (c) TBAF, THF, r.t., 1 h, 98%; (d) Red-Al, THF, 0 °C to r.t.,
1 h, 92%; (e) TEMPO, BAIB, CH2Cl2/H2O (1:1), 0 °C to r.t., 2 h, 71%; (f) TBAF, THF, r.t., 6 h, 83%; (g) 2,4,6-trichlorobenzoyl cloride,
Et3N, THF, 0 °C, 2 h, DMAP, toluene, 100 °C, 8 h, 85%; (h) TFA, CH3CN/H2O, 0 °C to r.t., 2 h, 91%.
grade ethyl acetate and hexanes that were used for column
chromatography were distilled prior to use. When used as a reac-
tion solvent, THF was freshly distilled from sodium benzophenone
ketyl. All the moisture-sensitive reactions were performed under
nitrogen in flame-dried or oven-dried glassware, and magnetic
stirring was used. Column chromatography was carried out with
silica gel (60–120 mesh and 100–200 mesh) packed in glass col-
umns. The 1H NMR spectroscopic data were recorded at 300 or
500 MHz, and the chemical shifts are referenced to TMS (δ =
0.0 ppm). The 13C NMR spectroscopic data were recorded at
give the (E)-alcohol 31 (92% yield). Next, for the comple-
tion of the synthesis of cladospolide C, allylic alcohol 31
was successfully converted into macrolactone 34 through 32
and 33 according to the similar sequence of reactions that
was used for the conversion of 24 into 27 (three steps).
Lastly, removal of the acetonide group in 34 by treatment
with trifluoroacetic acid (91% yield) provided the cladospo-
lide C (4). All the spectroscopic data (1H and 13C NMR,
MS, and IR) of 4 was in full agreement to the literature
data. The specific rotation observed for 4 {[α]2D0 = +48.9 (c 75 MHz, and the chemical shifts are referenced to CDCl3 (δ =
77.0 ppm) as an internal standard. FTIR spectra were recorded by
using KBr pellets or neat. Optical rotations were measured with a
digital polarimeter by using a 2 mL cell with a 1 dm path length.
= 0.45, MeOH)} was comparable with the natural product
data {ref.[2] [α]D22 = +59.7 (c = 0.4, MeOH)}.
(R)-tert-Butyl(non-8-yn-2-yloxy)diphenylsilane (8): To
a stirred
solution of alcohol 7 (600 mg, 4.28 mmol), imidazole (514 mg,
8.56 mmol), and a catalytic amount of DMAP in dry CH2Cl2
(5 mL) was added dropwise TBDPSCl (1.29 g, 4.69 mmol) at 0 °C.
The reaction mixture was warmed to room temperature and stirred
for 6 h. Water (15 mL) was added, and the reaction mixture was
extracted with CH2Cl2 (2ϫ15 mL), dried with Na2SO4, and con-
centrated under reduced pressure to obtain the crude product,
which was purified by using silica gel flash chromatography (hex-
anes/EtOAc) to give TBDPS-protected alcohol 8 (1.32 g, 82%).
Conclusions
We have demonstrated the accomplishment of the stereo-
selective total syntheses of cladospolides A, B, and C and
iso-cladospolide B by using an alkyne-assisted approach.
The key features of the synthesis are the following: (i) a
common strategy for the target molecules and (ii) the ex-
ploitation of the Sharpless asymmetric epoxidation or d-
ihydroxylation to create the desired diol stereochemistry.
This approach relies on the use of the alkyne functionality,
which allows for a straightforward strategy to extend the
carbon chain and provides the necessary platform to install
the desired functionalities during the course of the synthe-
sis. The present alkyne-assisted strategy that involves an al-
kyne-zipper reaction, a Sonogashira coupling reaction, and
a Yamaguchi macrolactonization is a useful route in the
synthesis of macrolides.
[α]2D0 = +14.8 (c = 1.92, CHCl ). IR (KBr): νmax = 2934, 2858, 2080,
˜
3
1428, 1106, 1051, 703 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.71–
7.65 (m, 4 H), 7.45–7.32 (m, 6 H), 3.88–3.77 (m, 1 H), 2.18–2.04
(m, 2 H), 1.93 (t, J = 2.2 Hz, 1 H), 1.52–1.23 (m, 8 H), 1.06 (d, J
= 6.7 Hz, 3 H), 1.05 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 135.8, 134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 84.6, 69.4, 68.0,
39.2, 28.7, 28.3, 27.0, 24.6, 23.2, 19.2, 18.2 ppm. MS (ESI): m/z =
379 [M + H]+.
(R)-9-(tert-Butyldiphenylsilyloxy)dec-2-yn-1-ol (9): A solution of
nBuLi (1.6 m in hexanes, 0.45 mL, 0.72 mmol) was added dropwise
to the solution of alkyne 8 (250 mg, 0.66 mmol) in dry THF (5 mL)
at –78 °C under argon. After 30 min, paraformaldehyde (40 mg,
1.3 mmol) was added at the same temperature. The resulting solu-
tion was warmed to room temperature and stirred for 6 h. Next,
the reaction mixture was diluted with ethyl acetate (5 mL) followed
Experimental Section
General Methods: All the reagents and solvents were reagent grade
and used without purification unless otherwise specified. Technical
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C. R. Reddy, D. Suman, N. N. Rao
FULL PAPER
by the addition of saturated aqueous NH4Cl (10 mL). The aqueous
phase was separated and extracted with ethyl acetate (2ϫ10 mL).
The combined organic layers were washed with brine (10 mL),
dried with Na2SO4, and concentrated under reduced pressure. The
crude residue was purified by silica gel flash chromatography (hex-
zoic acid (490 mg, 4.0 mmol) was added, and the stirring was con-
tinued for another 1 h. Aqueous tartaric acid solution (15% w/v,
25 mL) was added, and the stirring was continued until the distinct
phases were separated (30 min). The aqueous phase was extracted
with CH2Cl2 (2ϫ20 mL), and the combined organic phases were
washed with a saturated aqueous solution of NaHCO3 (2ϫ20 mL)
and brine (30 mL), dried with Na2SO4, and concentrated. The resi-
due was purified by column chromatography (hexanes/EtOAc) to
anes/EtOAc) to give propargylic alcohol 10 (210 mg, 78%). [α]2D0
=
+10.1 (c = 2.60, CHCl ). IR (KBr): νmax = 3321, 3067, 2988, 2926,
˜
3
2075, 1476, 1217, 1081, 742 cm–1. H NMR (300 MHz, CDCl3): δ
1
= 7.71–7.65 (m, 4 H), 7.45–7.32 (m, 6 H), 4.23 (d, J = 2.0 Hz, 2 yield diol 12 (2.21 g, 91%) as an oil. [α]2D0 = +2.1 (c = 2.00, CHCl3).
H), 3.85–3.76 (m, 1 H), 2.19–2.05 (m, 2 H), 1.52–1.23 (m, 8 H),
1.06 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 135.8, 134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 86.5,
78.2, 69.4, 51.3, 39.2, 28.7, 28.4, 27.0, 24.6, 23.2, 19.2, 18.6 ppm.
MS (ESI): m/z = 408 [M + H]+.
IR (KBr): ν
= 3410, 2932, 2858, 1717, 1453, 1274, 1109, 1070,
˜
max
772 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.07–8.02 (m, 2 H),
7.71–7.56 (m, 5 H), 7.52–7.30 (m, 8 H), 5.09–5.01 (m, 1 H), 3.86–
3.75 (m, 1 H), 3.75–3.56 (m, 3 H), 2.66–2.59 (m, 1 H), 2.53–2.42
(m, 1 H), 1.92–1.66 (m, 2 H), 1.53–1.17 (m, 8 H), 1.04 (d, J =
6.7 Hz, 3 H), 1.03 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.3, 135.8, 134.8, 134.5, 133.4, 129.7, 129.5, 129.4, 129.3, 128.4,
127.4, 127.3, 74.9, 73.0, 69.4, 62.4, 39.2, 30.7, 29.3, 27.0, 25.3, 25.0,
23.2, 19.2 ppm. HRMS: calcd. for C33H44O5SiNa [M + Na]+
571.7768; found 571.7759.
(R,E)-9-(tert-Butyldiphenylsilyloxy)dec-2-en-1-ol (10): To a solution
of progargylic alcohol 9 (500 mg, 1.2 mmol) in THF (10 mL) at
0 °C was added a solution of Red-Al (65% in toluene, 1.14 mL,
3.6 mmol). The mixture was warmed to room temperature and
stirred for 1 h. The reaction mixture was quenched with water
(2 mL) at 0 °C, and the resulting mixture was extracted with ethyl
acetate (3ϫ10 mL). The combined organic layers were washed
with brine (10 mL), dried with Na2SO4, and concentrated in vacuo
to give a residue, which was purified by silica gel column
chromatography (hexanes/EtOAc) to afford pure allylic alcohol 10
(2R,3S,9R)-9-(tert-Butyldiphenylsilyloxy)decane-1,2,3-triol (13): To
a solution of benzoate 12 (840 mg, 1.53 mmol) in methanol
(10 mL) was added potassium carbonate (416 mg, 3.05 mmol) at
0 °C. The resulting solution was maintained at room temperature
for 1 h and then quenched with water (2 mL). The resulting solu-
tion was extracted with ethyl acetate (3ϫ5 mL). The combined or-
(512 mg, 95%). [α]2D0 = +14.2 (c = 0.90, CHCl ). IR (KBr): ν
=
˜
3
max
3326, 2930, 2856, 1465, 1427, 1107, 1001, 703 cm–1. 1H NMR ganic phases were washed with brine (10 mL), dried with Na2SO4,
(300 MHz, CDCl3): δ = 7.70–7.65 (m, 4 H), 7.43–7.33 (m, 6 H), and concentrated. The residue was purified by column chromatog-
5.70–5.57 (m, 2 H), 4.18–4.06 (m, 2 H), 3.87–3.70 (m, 1 H), 1.19
raphy (hexanes/EtOAc) to yield triol 13 (605 mg, 89%) as an oil.
(q, J = 6.6 Hz, 2 H), 1.52–1.15 (m, 8 H), 1.06 (d, J = 6.7 Hz, 3 H),
[α]2D0 = +11.8 (c = 0.80, CHCl ). IR (KBr): νmax = 3371, 2932, 2858,
˜
3
1.05 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8, 134.8, 1589, 1428, 1376, 1109, 1068, 703 cm–1
.
1H NMR (300 MHz,
134.5, 133.4, 129.4, 129.3, 128.7, 127.4, 127.3, 69.5, 63.8, 39.3, 32.1,
CDCl3): δ = 7.72–7.64 (m, 4 H), 7.45–7.31 (m, 6 H), 3.88–3.67 (m,
29.1, 29.0, 27.0, 25.0, 23.2, 19.2 ppm. HRMS: calcd. for C26H38O2- 4 H), 3.60–3.52 (m, 1 H), 1.52–1.15 (m, 10 H), 1.05 (d, J = 6.7 Hz,
SiNa [M + Na]+ 433.2533; found 433.2523.
3 H), 1.04 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8,
134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 73.9, 73.6, 69.5, 63.1, 39.3,
32.8, 29.5, 27.0, 25.8, 25.0, 23.2, 19.2 ppm. HRMS: calcd. for
C26H40O4SiNa [M + Na]+ 467.2588; found 467.2579.
{(2R,3R)-3-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]oxiran-2-yl}-
methanol (11): To a stirred mixture of powdered molecular sieves
(4 Å, 4.0 g) and titanium tetraisopropoxide (0.29 mL, 0.97 mmol)
in CH2Cl2 (15 mL) was added (–)-diisopropyl tartrate (0.25 mL,
(6R,7S,13R)-2,2,3,3,13,16,16-Heptamethyl-15,15-diphenyl-4,14-di-
1.21 mmol) in CH2Cl2 (3 mL) at –20 °C. The mixture was stirred oxa-3,15-disilaheptadecane-6,7-diol (14): To a stirred solution of
at –20 °C for 10 min, and then tert-butyl hydroperoxide (4 m solu-
tion in toluene, 4.87 mL, 19.4 mmol) was added. After 30 min, a
solution of allylic alcohol 10 (2.0 g, 4.87 mmol) in CH2Cl2 (8 mL)
was added. The resulting mixture was stirred at –20 °C for 4 h and
then quenched with H2O (2.9 mL) and a 20% aqueous solution
of NaOH (2.9 mL). After the mixture had been stirred at room
triol 13 (585 mg, 1.31 mmol) in dry CH2Cl2 (10 mL) were added
imidazole (134 mg, 1.97 mmol), tert-butyldimethylsilyl chloride
(238 mg, 1.57 mmol), and a catalytic amount of DMAP at 0 °C.
The reaction mixture was stirred at room temperature for 1 h.
Then, the reaction mixture was diluted with CH2Cl2 (25 mL), and
the resulting solution was washed with water (20 mL), dried with
temperature for 45 min, it was filtered, and the filtrate was ex- Na2SO4, filtered, and concentrated under reduced pressure. The
tracted with CH2Cl2 (2ϫ 15 mL). The combined organic layers crude residue was purified by column chromatography (hexanes/
were washed with brine (10 mL), dried with Na2SO4, filtered, and
concentrated. The residual oil was purified by column chromatog-
raphy (hexanes/EtOAc) to give epoxy alcohol 11 (1.65 g, 78 %).
EtOAc) on silica gel to afford silyl ether 14 (557 mg, 73%). [α]2D0
=
+11.4 (c = 1.20, CHCl ). IR (KBr): νmax = 3440, 3070, 2931, 2858,
˜
3
1466, 1376, 1255, 1107, 703 cm–1. H NMR (300 MHz, CDCl3): δ
1
[α]2D0 = +19.0 (c = 2.3, CHCl ). IR (KBr): νmax = 3423, 2932, 2858,
= 7.71–7.64 (m, 4 H), 7.45–7.32 (m, 6 H), 3.88–3.73 (m, 3 H), 3.72–
˜
3
1
1465, 1428, 1108, 1048, 772 cm–1. H NMR (300 MHz, CDCl3): δ 3.63 (m, 1 H), 3.56–3.48 (m, 1 H), 2.77 (d, J = 5.4 Hz, 1 H), 2.36
= 7.71–7.66 (m, 4 H), 7.44–7.34 (m, 6 H), 3.93–3.81 (m, 2 H), 3.65–
(d, J = 5.4 Hz, 1 H), 1.52–1.16 (m, 10 H), 1.05 (d, J = 6.7 Hz, 3
3.58 (m, 1 H), 2.94–2.84 (m, 2 H), 1.55–1.17 (m, 10 H), 1.06 (d, J H), 1.04 (s, 9 H), 0.91 (s, 9 H), 0.10 (s, 6 H) ppm. 13C NMR
= 6.7 Hz, 3 H), 1.05 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ
(75 MHz, CDCl3): δ = 135.8, 134.8, 134.5, 129.4, 129.3, 127.4,
= 135.8, 134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 69.4, 61.6, 58.4,
127.3, 73.2, 73.0, 69.5, 63.8, 39.3, 32.9, 29.6, 27.0, 25.8, 25.1, 23.2,
55.9, 39.1, 31.3, 29.2, 26.9, 25.7, 24.9, 23.1, 19.1 ppm. HRMS: 19.2, –5.4, –5.5 ppm. HRMS: calcd. for C32H54O4Si2Na [M +
calcd. for C26H38O3SiNa [M + Na]+ 449.2482; found 449.2474. Na]+ 581.3452; found 581.3466.
(2R,3S,9R)-9-(tert-Butyldiphenylsilyloxy)-1,2-dihydroxydec-3-yl tert-Butyl[(R)-7-{(4S,5R)-5-[(tert-butyldimethylsilyloxy)methyl]-2,2-
Benzoate (12): To a stirred solution of epoxy alcohol 11 (1.9 g,
4.45 mmol) in dry CH2Cl2 (20 mL) were sequentially added benzoic
dimethyl-1,3-dioxolan-4-yl}heptan-2-yloxy]diphenylsilane (15): To
silyl ether 14 (525 mg, 0.93 mmol) in CH2Cl2 (5 mL) was added
acid (490 mg, 4.0 mmol) and Ti(iPrO)4 (1.73 mL, 5.77 mmol) at camphorsulfonic acid (catalytic amount) followed by 2,2-dimeth-
room temperature. The mixture was stirred for 15 min. Then, ben- oxypropane (0.85 mL, 2.34 mmol) at 0 °C. The mixture was stirred
3790
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3786–3796

Alkyne-Mediated Approach for Syntheses of Cladospolides
at room temperature for 1 h, and a saturated aqueous solution of
NaHCO3 (5 mL) was added. The mixture was extracted with
was added at a rate of 3 mL/h to a solution of DMAP (1.15 g,
9.41 mmol) in toluene (80 mL) that was heated at reflux. The reac-
CH2Cl2 (3ϫ15 mL). The combined organic layers were dried with tion mixture was then heated at reflux for an additional 8 h. The
Na2SO4, and the solvents were evaporated under reduced pressure.
The residue was purified by column chromatography (hexanes/
EtOAc) to give the fully protected alcohol 15 (528 mg, 94%). [α]2D0
resulting mixture was cooled to room temperature and then
quenched with a saturated aqueous solution of NaHCO3 (20 mL).
The aqueous layer was extracted with ethyl acetate (3ϫ25 mL).
= +5.9 (c = 0.84, CHCl ). IR (KBr): νmax = 2927, 2857, 1626, 1464, The combined organic layers were washed with brine (15 mL),
˜
3
1374, 1217, 1103, 770 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.71– dried with Na2SO4, and concentrated in vacuo. The residue was
7.64 (m, 4 H), 7.45–7.32 (m, 6 H), 4.14–4.01 (m, 2 H), 3.89–3.77
(m, 1 H), 3.70–3.52 (m, 2 H), 1.40–1.18 (m, 16 H), 1.06–1.02 (m, 12
purified by silica gel column chromatography (hexanes/EtOAc) to
afford lactone 18 (73 mg, 87%) as a viscous liquid. [α]2D0 = –5.0 (c
H), 0.88 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 0.22, CHCl ). IR (KBr): ν
= 2929, 2857, 1717, 1374,
˜
3
max
= 135.8, 134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 107.5, 77.9, 77.6,
69.5, 62.0, 39.4, 29.7, 29.0, 28.2, 27.0, 26.6, 25.8, 25.5, 25.1, 19.2,
18.2, –5.4, –5.5 ppm. HRMS: calcd. for C35H58O4Si2Na [M +
Na]+ 621.3765; found 621.3766.
1053 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.99 (dd, J = 9.0,
15.8 Hz, 1 H), 6.07 (d, J = 15.8 Hz, 1 H), 5.20–5.10 (m, 1 H), 4.71
(dd, J = 6.7, 9.0 Hz, 1 H), 4.13 (ddd, J = 1.5, 6.0, 8.3 Hz, 1 H),
1.76–1.64 (m, 2 H), 1.57–1.23 (m, 7 H), 1.51 (s, 3 H), 1.37 (s, 3 H),
1.30 (d, J = 6.7 Hz, 3 H), 1.02–0.93 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.0, 145.1, 124.4, 109.5, 79.5, 76.4, 72.7,
33.4, 30.7, 28.1, 28.0, 25.4, 21.8, 20.1, 18.3 ppm. HRMS: calcd. for
C15H26O5Na+ [M + Na]+ 291.1572; found 291.1569.
(R)-7-[(4S,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-
heptan-2-ol (16): To a solution of 15 (475 mg, 0.79 mmol) in THF
(3 mL) at 0 °C was added TBAF (1.0 m solution in THF, 3.17 mL,
2.37 mmol) dropwise. The resulting brown solution was stirred at
room temperature for 12 h. The solvent was removed in vacuo, and
the crude residue was purified by flash column chromatography
(hexanes/EtOAc) to afford diol 16 (180 mg, 92%). [α]2D0 = +8.5 (c
Cladospolide A (1): To a solution of macrolactone 18 (60 mg,
0.22 mmol) in acetonitrile/water (2:1 v/v, 5 mL) was added tri-
fluoroacetic acid (1.6 mL, 22 mmol) at 0 °C, and the reaction mix-
ture was stirred at room temperature for 2 h and then diluted with
ethyl acetate (5 mL). The resulting mixture was washed with a satu-
rated aqueous solution of NaHCO3 (5 mL), dried with Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (hexanes/EtOAc) on silica gel to afford the clados-
polide A (1, 44 mg, 88%). [α]2D0 = –35.5 (c = 0.60, MeOH); ref.[1d]
= 2.48, CHCl ). IR (KBr): ν
= 3392, 2931, 2859, 1374, 1244,
˜
3
max
1218, 1103, 1045, 771 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.20–
4.10 (m, 2 H), 3.86–3.74 (m, 1 H), 3.61 (d, J = 5.2 Hz, 2 H), 1.61–
1.23 (m, 18 H), 1.19 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 107.9, 77.9, 76.9, 67.8, 61.5, 39.0, 29.5, 28.8, 28.2,
26.5, 25.5, 23.3 ppm. HRMS: calcd. for C13H26O4Na [M + Na]+
269.3354; found 269.3361.
[α]1D8 = –30.0 (c = 0.4, MeOH). IR (KBr): νmax = 3448, 2922, 2853,
˜
1717, 1638, 1459, 1259, 1218, 1100, 1022 cm–1
.
1H NMR
Ethyl (E)-3-{(4R,5S)-5-[(R)-6-Hydroxyheptyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}acrylate (17): To diol 16 (175 mg, 0.71 mmol) in
CH2Cl2 (3 mL) at 0 °C were added BAIB (263 mg, 0.81 mmol) and
TEMPO (10 mg, 0.06 mmol). After stirring at room temperature
for 2 h, the mixture was cooled to 0 °C, and (ethoxycarbonylmethy-
lene)triphenylphosphorane (320 mg, 0.92 mmol) was added. The
stirring was continued for another 2 h at room temperature. After
completion of the reaction, the mixture was concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (hexanes/EtOAc) to afford α,β-unsaturated ester 17 (210 mg,
94%) as a yellow liquid. [α]2D0 = –2.3 (c = 0.64, CHCl3). IR (KBr):
(300 MHz, CDCl3): δ = 6.80 (dd, J = 5.6, 15.8 Hz, 1 H), 6.20 (dd,
J = 1.5, 15.8 Hz, 1 H), 5.08–5.16 (m, 1 H), 4.58–4.53 (m, 1 H), 3.67
(ddd, J = 1.1, 1.7, 9.0 Hz, 1 H), 1.83–1.13 (complex m, 9 H), 1.27
(d, J = 6.7 Hz, 3 H), 0.92–0.84 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.8, 145.5, 122.3, 74.7, 72.9, 72.8, 32.5, 30.6, 28.1,
25.0, 22.5, 18.9 ppm. HRMS: calcd. for C12H20O4Na+ [M + Na]+
251.1253; found 251.1252.
(R,E)-tert-Butyl(9-iodonon-8-en-2-yloxy)diphenylsilane (19): A solu-
tion of alkyne 7 (1.24 g, 3.27 mmol) in acetone (10 mL) was treated
with AgNO3 (55 mg, 0.32 mmol) and N-bromosuccinimide (NBS,
640 mg, 3.59 mmol) at room temperature. After 1 h, hexanes
(10 mL) were added, and the mixture was filtered through a pad
of Celite®. The pad was rinsed with ethyl acetate (10 mL), and
the combined filtrates were concentrated. Purification by column
chromatography on SiO2 (hexanes/EtOAc) afforded the bromo-
alkyne (1.0 g). To a solution of the bromoalkyne (1.0 g, 2.18 mmol)
and Pd2(dba)3 (10 mg, 0.01 mmol, dba = dibenzylideneacetone) in
THF (10 mL) was added nBu3SnH (1.29 mL, 2.2 mmol) in one por-
tion at 0 °C under nitrogen. The mixture was stirred at room tem-
perature for 45 min. To this mixture at –78 °C was added a solution
ν
= 3442, 2924, 2865, 1723, 1352, 1245, 1148, 1027, 857 cm–1.
˜
max
1H NMR (300 MHz, CDCl3): δ = 6.84 (dd, J = 1.5, 15.8 Hz, 1 H),
6.06 (d, J = 15.8 Hz, 1 H), 4.64 (dt, J = 1.5, 7.5 Hz, 1 H), 4.26–
4.16 (m, 3 H), 3.84–3.72 (m, 1 H), 1.56–1.24 (m, 22 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 160.0, 143.7, 122.9, 108.7, 78.2, 68.0,
60.5, 39.1, 30.3, 29.4, 27.9, 26.1, 25.5, 25.4, 23.4, 14.1 ppm. HRMS:
calcd. for C17H30O5Na [M + Na]+ 337.4132; found 337.4129.
(3aR,8R,13aS,E)-2,2,8-Trimethyl-9,10,11,12,13,13a-hexahydro-
3aH-[1,3]dioxolo[4,5-e][1]oxacyclo-dodecin-6(8H)-one (18): To a
solution of ester 17 (110 mg, 0.35 mmol) in THF/H2O (1:1, 2 mL) of N-iodosuccinimide (NIS, 640 mg, 2.84 mmol) in THF (5 mL),
was added LiOH (30 mg, 0.71 mmol) at 0 °C. The reaction mixture
was stirred at room temperature for 12 h and then diluted with
H2O (2 mL). The resulting solution was acidified to pH ≈ 7 with
HCl (1 n solution), and the solution was extracted with EtOAc
(2ϫ3 mL). The combined organic phases were dried with Na2SO4
and concentrated in vacuo. The resulting crude seco-acid (99 mg)
was used in the next step without further purification. To a stirred
solution of the seco-acid (90 mg, 0.31 mmol) and Et3N (0.26 mL,
1.88 mmol) in anhydrous THF (12 mL) was added 2,4,6-tri-
chlorobenzoyl chloride (0.33 mL, 1.58 mmol) at 0 °C, and the re-
sulting mixture was stirred for 2 h. The reaction mixture was then
diluted with anhydrous toluene (15 mL), and the resulting mixture
and the reaction mixture was stirred at the same temperature for
15 min. The mixture was quenched by the addition of saturated
aqueous NaHCO3 (5 mL) and saturated aqueous Na2S2O3 (5 mL)
solutions. The resulting mixture was extracted with ethyl acetate
(3ϫ15 mL). The combined organic layers were washed with brine
(20 mL), dried with Na2SO4, filtered, and concentrated. Purifica-
tion of the crude product by chromatography on SiO2 (hexanes/
EtOAc) gave vinyl iodide 19 (1.18 g, 72%) as a colorless liquid.
[α]2D0 = +11.8 (c = 1.44, CHCl ). IR (KBr): νmax = 2929, 2856, 1629,
˜
3
1464, 1428, 1053, 1106, 702 cm–1. H NMR (300 MHz, CDCl3): δ
1
= 7.70–7.66 (m, 4 H), 7.44–7.34 (m, 6 H), 6.51–6.44 (m, 1 H), 5.94
(d, J = 14.7 Hz, 1 H), 3.87–3.80 (m, 1 H), 2.02–1.95 (m, 2 H), 1.42–
Eur. J. Org. Chem. 2013, 3786–3796
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3791

C. R. Reddy, D. Suman, N. N. Rao
FULL PAPER
1.12 (m, 8 H), 1.06 (d, J = 5.9 Hz, 3 H); 1.05 (s, 9 H) ppm. 13C chromatography (hexanes/EtOAc, 95:5) to give 22 (152 mg, 79%).
NMR (75 MHz, CDCl3): δ = 146.7, 135.8, 134.8, 134.5, 129.4, [α]2D0 = +3.0 (c = 3.04, CHCl ). IR (KBr): νmax = 2930, 2857, 2252,
˜
.
3
129.3, 127.4, 127.3, 74.2, 69.4, 39.2, 35.9, 28.8, 28.2, 27.0, 24.8,
23.2, 19.2 ppm. MS (ESI): m/z = 507 [M + H]+. C25H35IOSi
(506.53): calcd. C 59.28, H 6.96; found C 59.80, H 7.42.
1633, 1464, 1430, 1252, 1102, 703 cm–1
1H NMR (300 MHz,
CDCl3): δ = 7.70–7.66 (m, 4 H), 7.43–7.34 (m, 6 H), 4.36 (br. s, 2
H), 4.22 (d, J = 7.9 Hz, 1 H), 3.99–3.93 (m, 1 H), 3.88–3.79 (m, 1
H), 1.61–1.16 (m, 10 H), 1.45 (s, 3 H), 1.40 (s, 3 H), 1.06 (d, J =
6.7 Hz, 3 H), 1.05 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 135.8, 134.8, 134.5, 129.4, 129.3,
127.4, 127.3, 104.5, 85.1, 81.4, 81.3, 70.5, 69.4, 51.7, 39.3, 32.2,
29.6, 27.1, 27.0, 26.1, 25.7, 25.0, 23.1, 19.2, 18.2, –5.1 ppm. HRMS:
(R,E)-2,2,3,3,15,18,18-Heptamethyl-17,17-diphenyl-4,16-dioxa-
3,17-disilanonadec-8-en-6-yne (20): To a solution of vinyl iodide 19
(1.17 g, 2.31 mmol) and silyl-protected propargylic alcohol I
(590 mg, 3.46 mmol) in triethylamine (10 mL) was added bis(tri-
phenylphosphane)palladium(II) dichloride (162 mg, 0.23 mmol) at
0 °C. The mixture was stirred at 0 °C for 15 min, and then cop-
per(I) iodide (88 mg, 0.46 mmol) was added. After stirring at 0 °C
for 10 min, the reaction mixture was warmed to room temperature
and stirred for another 1 h. After completion, the mixture was con-
centrated under reduced pressure. The residue was purified by flash
column chromatography (hexanes/EtOAc) to afford enyne 20
(1.1 g, 79%) as a light yellow liquid. [α]2D0 = +14.3 (c = 0.48,
calcd. for C37H58O4Si2NH4 [M + NH4]+ 640.4212; found
+
640.4243.
3-{(4S,5S)-5-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}prop-2-yn-1-ol (23): To a solution of 22 (80 mg,
0.13 mmol) in THF (3 mL) was added TBAF (1.0 m solution in
THF, 0.13 mL, 0.13 mmol) at 0 °C, and the resulting brown solu-
tion was stirred at room temperature for 1 h. Then, the mixture
CHCl ). IR (KBr): νmax = 2929, 2856, 2246, 1615, 1464, 1252, 1087, was cooled to 0 °C and quenched with a saturated aqueous solution
˜
3
836 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.71–7.64 (m, 4 H), of NH4Cl (5 mL). The aqueous layer was extracted with ethyl acet-
7.46–7.32 (m, 6 H), 6.15–6.03 (m, 1 H), 5.45 (d, J = 15.8 Hz, 1 H), ate (3 ϫ5 mL), and the combined organic layers were washed with
4.38 (s, 2 H), 3.88–3.71 (m, 1 H), 2.08–1.98 (m, 2 H), 1.53–1.10 (m,
8 H), 1.05 (d, J = 5.2 Hz, 3 H), 1.04 (s, 9 H), 0.91 (s, 9 H), 0.12 (s,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 145.0, 135.8, 134.9,
134.5, 129.4, 129.3, 127.4, 127.3, 109.0, 85.7, 78.4, 69.4, 52.0, 39.2,
32.9, 28.9, 28.5, 25.8, 25.7, 24.9, 23.2, 19.2, 19.1, –5.1, –5.2 ppm.
MS (ESI): m/z = 571 [M + Na]+.
brine (15 mL), dried with Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexanes/
EtOAc) to afford primary alcohol 23 (63 mg, 98%). [α]2D0 = +1.8 (c
= 1.76, CHCl ). IR (KBr): ν
= 3419, 3067, 2931, 2859, 2252,
˜
3
max
1648, 1462, 1376, 1225, 1108, 1040, 702 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.70–7.65 (m, 4 H), 7.44–7.34 (m, 6 H), 4.31 (s, 2 H),
4.23 (d, J = 6.9 Hz, 1 H), 4.00–3.94 (m, 1 H), 3.87–3.81 (m, 1 H),
1.54–1.17 (m, 10 H), 1.45 (s, 3 H), 1.41 (s, 3 H), 1.06 (d, J = 6.7 Hz,
3 H), 1.05 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8,
134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 84.8, 82.3, 81.3, 70.4, 69.4,
51.0, 39.2, 32.1, 29.6, 29.5, 27.1, 27.0, 26.2, 25.6, 25.0, 19.2 ppm.
HRMS: calcd. for C31H44O4SiNa [M + Na]+ 531.2901; found
531.2906.
(8S,9S,15R)-2,2,3,3,15,18,18-Heptamethyl-17,17-diphenyl-4,16-di-
oxa-3,17-disilanonadec-6-yne-8,9-diol (21): Into a round-bottomed
flask were added tBuOH (5 mL), water (5 mL), K3Fe(CN)6
(934 mg, 2.83 mmol), K2CO3 (392 mg, 2.84 mmol), MeSO2NH2
(90 mg, 0.94 mmol), (DHQ)2PHAL (15.5 mg, 0.02 mmol), and
OsO4 (4.7 mg, 0.02 mmol). The reaction mixture was stirred at
room temperature for approximately 15 min and then cooled to
0 °C. To this solution was added enyne 20 (520 mg, 0.94 mmol),
and the reaction mixture was stirred at 0 °C for 24 h. The reaction
was quenched with a saturated aqueous solution of sodium sulfite
(10 mL) at room temperature, and the resulting mixture was ex-
tracted with ethyl acetate (2ϫ10 mL). The combined organic layers
were washed with NaOH (2 n aqueous solution, 10 mL) and brine
(10 mL). After the evaporation of the solvents in vacuo, flash
chromatography on silica gel (hexanes/EtOAc) of the residue gave
diol 21 (391 mg, 71%). [α]2D0 = +12.2 (c = 0.48, CHCl3). IR (KBr):
(Z)-3-{(4S,5S)-5-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}prop-2-en-1-ol (24): To a solution of the
alcohol 23 (135 mg, 0.36 mmol) in ethyl acetate (5 mL) was added
quinoline (0.2 mL diluted in EtOAc) followed by Pd/CaCO3 cata-
lyst (30 mg) at room temperature under hydrogen. The reaction
mixture was stirred at room temperature for 1 h, and the solution
was diluted with additional EtOAc (5 mL). The mixture was fil-
tered through Celite® and dried with Na2SO4, and the solvent was
evaporated under reduced pressure. The crude product was purified
by silica gel column chromatography (hexanes/EtOAc) to furnish
ν
max = 3424, 2929, 2856, 2250, 1633, 1465, 1427, 1256, 1107, 1084,
˜
836 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.70–7.66 (m, 4 H), cis-olefin 24 (130 mg, 98%) as a colorless liquid. [α]2D0 = +9.6 (c =
7.44–7.33 (m, 6 H), 4.35 (d, J = 2.2 Hz, 2 H), 4.17 (d, J = 5.5 Hz, 2.16, CHCl ). IR (KBr): νmax = 3449, 3069, 2931, 2857, 1650, 1427,
˜
3
1 H), 3.87–3.80 (m, 1 H), 3.62–3.56 (m, 1 H), 1.55–1.14 (m, 10 H), 1374, 1236, 1108, 1042, 703 cm–1. H NMR (300 MHz, CDCl3): δ
1
1.06 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8, 134.9, 134.6, 129.4,
129.3, 127.4, 127.3, 85.1, 83.0, 74.7, 69.5, 66.1, 39.3, 32.3, 29.5,
27.0, 25.7, 25.5, 23.1, 19.2, 18.2, –5.1 ppm. HRMS: calcd. for
C34H54O4Si2Na [M + Na]+ 605.3452; found 605.3448.
= 7.70–7.65 (m, 4 H), 7.44–7.33 (m, 6 H), 5.92–5.82 (m, 1 H), 5.51
(t, J = 8.9 Hz, 1 H), 4.36–4.28 (m, 2 H), 4.21–4.11 (m, 1 H), 3.86–
3.79 (m, 1 H), 3.67–3.61 (m, 1 H), 1.51–1.15 (m, 10 H), 1.42 (s, 3
H), 1.41 (s, 3 H), 1.05 (s, 9 H), 1.04 (d, J = 6.7 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 135.8, 134.0, 134.8, 134.5, 129.4,
129.3, 128.5, 127.4, 127.3, 108.6, 80.8, 69.4, 58.6, 39.3, 31.6, 29.6,
27.2, 27.0, 25.9, 25.0, 23.1 ppm. HRMS: calcd. for C31H46O4SiNa
[M + Na]+ 533.3058; found 533.3054.
tert-Butyl[(R)-7-{(4S,5S)-5-[3-(tert-butyldimethylsilyloxy)prop-1-
ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}hept-2-yloxy]diphenylsilane
(22): To diol 21 (180 mg, 0.3 mmol) in CH2Cl2 (5 mL) was added
camphorsulfonic acid (catalytic amount) followed by 2,2-dimeth-
oxypropane (0.09 mL, 0.76 mmol) at 0 °C, and the reaction mixture
was stirred at room temperature for 1 h. After completion of the
reaction (monitored by TLC), a saturated solution of NaHCO3
(5 mL) was added to the reaction mixture at 0 °C. The resulting
mixture was extracted with CH2Cl2 (3ϫ5 mL). The combined or-
ganic layers were dried with Na2SO4, and the solvents were evapo-
rated under reduced pressure. The residue was purified by column
(Z)-3-{(4S,5S)-5-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}acrylic Acid (25): To a solution of allylic
alcohol 24 (200 mg, 0.39 mmol) in H2O/CH2Cl2 (1:1, 2 mL) were
added TEMPO (17 mg, 0.11 mmol) and BAIB (378 mg,
1.17 mmol) at 0 °C. After stirring at room temperature for 1 h, the
reaction mixture was diluted with CH2Cl2 (5 mL), and the resulting
solution was washed with a saturated aqueous solution of Na2S2O3
(5 mL). The organic layer was dried with Na2SO4 and filtered, and
3792
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3786–3796

Alkyne-Mediated Approach for Syntheses of Cladospolides
the filtrate was concentrated under reduced pressure. The crude
carboxylic acid was purified by flash column chromatography (hex-
quenched with a saturated aqueous solution of NaHCO3 (5 mL).
The resulting solution was extracted with CH2Cl2 (2ϫ5 mL). The
anes/EtOAc) to afford acid 25 (148 mg, 72%) as a colorless oil. combined organic extracts were washed with brine (5 mL), dried
[α]2D0 = +15.5 (c = 2.80, CHCl ). IR (KBr): νmax = 3448, 2927, 2856,
with Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexanes/EtOAc) to afford
cladospolide B (2, 36 mg, 86%) as a white solid. [α]2D0 = +21.2 (c =
˜
3
1702, 1433, 1374, 1238, 1108, 1048, 702 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.70–7.65 (m, 4 H), 7.45–7.32 (m, 6 H), 6.23 (dd, J =
8.4, 11.8 Hz, 1 H), 5.96 (d, J = 11.8 Hz, 1 H), 5.19 (t, J = 8.3 Hz,
0.6, MeOH); ref.[1d] [α]2D2 = +26.9 (c = 0.4, MeOH). IR (KBr): ν
˜
max
1H NMR
1 H), 3.88–3.77 (m, 1 H), 3.77–3.66 (m, 1 H), 1.49–1.16 (m, 10 H), = 3323, 2927, 2855, 1711, 1634, 1127, 1050 cm–1
.
1.44 (s, 3 H), 1.43 (s, 3 H), 1.03 (d, J = 6.7 Hz, 3 H), 1.04 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9, 147.9, 135.8, 134.9,
134.7, 129.4, 129.3, 127.6, 127.4, 127.3, 109.4, 80.9, 76.0, 69.5, 39.3,
31.9, 29.6, 29.3, 27.0, 25.8, 25.1, 23.1, 22.6, 19.2 ppm. HRMS:
calcd. for C31H44O5Si Na [M + Na]+ 547.285; found 547.2894.
(500 MHz, CDCl3): δ = 6.24 (dd, J = 7.7, 12.1 Hz, 1 H), 5.77 (d,
J = 12.1 Hz, 1 H), 5.28–5.23 (m, 1 H), 4.92–4.85 (m, 1 H), 3.76
(ddd, J = 1.1, 2.2, 9.9 Hz, 1 H), 2.32 (br. s, 1 H), 2.02 (br. s, 1 H),
1.84–1.71 (m, 2 H), 1.67–1.52 (m, 2 H), 1.50–1.38 (m, 2 H), 1.29
(d, J = 6.7 Hz, 3 H), 1.27–1.23 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.8, 148.5, 121.7, 74.4, 73.8, 67.3, 31.9, 30.5, 25.6,
24.1, 21.2, 19.6 ppm. HRMS: calcd. for C12H20O4Na [M + Na]+
251.1253; found 251.1257.
(Z)-3-{(4S,5S)-5-[(R)-6-Hydroxyheptyl]-2,2-dimethyl-1,3-dioxolan-
4-yl}acrylic Acid (26): A solution of acid 25 (140 mg, 0.26 mmol)
in THF (3 mL) was cooled to 0 °C, and TBAF (1.0 m solution in
THF, 0.8 mL, 0.80 mmol) was added dropwise. The resulting solu-
tion was warmed to room temperature and stirred for 6 h. The
reaction mixture was then cooled to 0 °C and quenched by the
addition of a saturated aqueous solution of NH4Cl (3 mL). The
aqueous layer was extracted with ethyl acetate (3 ϫ 5 mL). The
combined organic layers were washed with brine (10 mL), dried
with Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexanes/EtOAc) to afford
seco-acid 26 (61 mg, 80%). [α]2D0 = –4.2 (c = 0.60, CHCl3). IR
iso-Cladospolide B (3): To a solution of lactone 27 (47 mg,
0.17 mmol) in acetonitrile/water (2:1 v/v, 5 mL) was added tri-
fluoroacetic acid (1.25 mL, 17 mmol) at 0 °C. The reaction mixture
was stirred at room temperature for 2 h and then diluted with ethyl
acetate (5 mL). The resulting solution was washed with a saturated
aqueous solution of NaHCO3, dried with Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
(hexanes/EtOAc) on silica gel to give iso-cladospolide B (3, 34 mg,
89%). [α]2D0 = –98.0 (c = 0.7, MeOH); ref.[3,7a–7c] [α]D = –90.0 (c =
(KBr): νmax = 3449, 2928, 2857, 1711, 1648, 1374, 1220, 1046 cm–1. 0.23, MeOH). IR (KBr): νmax = 3402, 2923, 2853, 2510, 2025, 1725,
˜
˜
1H NMR (300 MHz, CDCl3): δ = 6.19 (dd, J = 9.0, 12.0 Hz, 1 H),
5.93 (d, J = 12.0 Hz, 1 H), 5.27 (dd, J = 8.3, 8.3 Hz, 1 H), 3.85–
1108 cm–1. H NMR (300 MHz, CDCl3): δ = 7.45 (d, J = 5.8 Hz,
1
1 H), 6.19 (dd, J = 1.8, 5.8 Hz, 1 H), 5.00–4.96 (m, 1 H), 3.83–3.71
3.69 (m, 2 H), 1.41 (s, 3 H), 1.40 (s, 3 H), 1.48–1.20 (m, 10 H), 1.18 (m, 2 H), 1.63–1.52 (m, 2 H), 1.48–1.24 (m, 8 H), 1.19 (d, J =
(d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.2,
6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172, 153.5,
147.5, 122.4, 109.3, 80.7, 75.8, 68.3, 38.7, 31.2, 29.1, 27.3, 26.9,
122.7, 86.0, 71.8, 68.0, 39.0, 33.1, 29.3, 25.5, 25.3, 23.5 ppm.
25.1, 24.6, 23.3 ppm. HRMS: calcd. for C15H25O5 [M – H]+ HRMS: calcd. for C12H20O4Na [M + Na]+ 251.1253; found
285.1701; found 285.1710.
251.1260.
(3aS,8R,13aS,Z)-2,2,8-Trimethyl-9,10,11,12,13,13a-hexahydro- (8R,9R,15R)-2,2,3,3,15,18,18-Heptamethyl-17,17-diphenyl-4,16-di-
3aH-[1,3]dioxolo[4,5-e][1]oxacyclododecin-6(8H)-one (27): To a
stirred solution of seco-acid 26 (60 mg, 0.21 mmol) and Et3N
(0.17 mL, 1.25 mmol) in anhydrous THF (8 mL) was added 2,4,6-
trichlorobenzoyl chloride (0.16 mL, 1.04 mmol) at 0 °C, and the
resulting mixture was stirred for 2 h. The reaction mixture was then
diluted with anhydrous toluene (10 mL), and the resulting mixture
was added at a rate of 3 mL/h to a solution of DMAP (768 mg,
6.29 mmol) in toluene (50 mL) that was heated at reflux. The reac-
tion mixture was then heated at reflux further for an additional
8 h. The mixture was cooled to room temperature and quenched
with a saturated aqueous solution of NaHCO3 (20 mL). The aque-
ous layer was extracted with ethyl acetate (3ϫ25 mL). The com-
bined organic fractions were washed with brine (20 mL), dried with
Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexanes/EtOAc) to afford lac-
tone 27 (47 mg, 84%) as a viscous liquid. [α]2D0 = +10.8 (c = 0.65,
oxa-3,17-disilanonadec-6-yne-8,9-diol (28): Into a round-bottomed
flask were added tBuOH (12.5 mL), water (12.5 mL), K3Fe(CN)
(2.51 g, 7.62 mmol), K2CO3 (1.05 mg, 7.60 mmol), MeSO2NH2
6
(242 mg, 2.54 mmol), (DHQD)2PHAL (41 mg, 0.05 mmol), and
OsO4 (12 mg, 0.05 mmol). The reaction mixture was stirred at
room temperature for approximately 15 min and then cooled to
0 °C. To this solution was added enyne 20 (1.4 g, 2.55 mmol), and
the reaction mixture was stirred at 0 °C for 24 h and then quenched
with a saturated aqueous solution of sodium sulfite (10 mL) at
room temperature. The resulting solution was extracted with ethyl
acetate (2 ϫ 10 mL), and the combined organic extracts were
washed with NaOH (2 n aqueous solution, 10 mL) and brine
(10 mL). After removal of the solvent in vacuo, flash chromatog-
raphy of the crude residue on silica gel (hexanes/EtOAc) gave diol
28 (1.07 g, 72%). [α]2D0 = +15.4 (c = 1.40, CHCl ). IR (KBr): ν
˜
3
max
= 3415, 2930, 2857, 2240, 1628, 1465, 1427, 1255, 1107, 1083,
836 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.72–7.64 (m, 4 H),
7.46–7.35 (m, 6 H), 4.35 (s, 2 H), 4.17 (br. s, 1 H), 3.88–3.78 (m, 1
H), 3.62–3.55 (m, 1 H), 2.35–2.23 (m, 2 H), 1.53–1.16 (m, 10 H),
1.06 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H)
CHCl ). IR (KBr): ν
= 2926, 2856, 1714, 1630, 1462, 1213,
˜
3
max
1046 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.15 (dd, J = 8.5,
12.4 Hz, 1 H), 5.85 (d, J = 12.4 Hz, 1 H), 5.31 (dd, J = 8.5, 8.5 Hz,
1 H), 4.93–4.84 (m, 1 H), 3.92–3.84 (m, 1 H), 1.77–1.65 (m, 2 H),
1.54–1.19 (m, 8 H), 1.45 (s, 3 H), 1.43 (s, 3 H), 1.27 (d, J = 6.7 Hz, ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8, 134.9, 134.6, 129.4,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8, 144.7, 123.7,
129.3, 127.4, 127.3, 84.9, 83.1, 74.7, 69.5, 66.1, 51.6, 39.3, 32.3,
29.6, 27.0, 25.7, 25.5, 23.1, 19.2, 18.2, –5.1 ppm. HRMS: calcd. for
109.2, 79.5, 74.1, 73.9, 32.5, 27.2, 26.9, 26.5, 24.3, 20.8, 20.1,
17.0 ppm. HRMS: calcd. for C15H26O5Na [M + Na]+ 291.1572; C34H54O4Si2Na [M + Na]+ 605.3452; found 605.3445.
found 291.1575.
tert-Butyl[(R)-7-{(4R,5R)-5-[3-(tert-butyldimethylsilyloxy)prop-1-
Cladospolide B (2): To a solution of lactone 27 (50 mg, 0.18 mmol) ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}heptan-2-yloxy]diphenylsilane
in CH2Cl2, was added TiCl4 (1 m solution in CH2Cl2, 0.18 mL,
(29): To diol 28 (860 mg, 1.46 mmol) in CH2Cl2 (5 mL) was added
0.18 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h and
CSA (catalytic amount) followed by 2,2-dimethoxypropane
Eur. J. Org. Chem. 2013, 3786–3796
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3793

C. R. Reddy, D. Suman, N. N. Rao
FULL PAPER
(0.45 mL, 3.68 mmol) at 0 °C. After stirring at room temperature
for 1 h, a saturated aqueous solution of NaHCO3 (5 mL) was
added at 0 °C. The resulting solution was extracted with CH2Cl2
(3ϫ5 mL). The combined organic layers were dried with Na2SO4,
and the solvent was evaporated to dryness under reduced pressure.
The residue was purified by column chromatography (hexanes/
EtOAc) to give 29 (718 mg, 78%). [α]2D0 = +15.4 (c = 1.64, CHCl3).
added TEMPO (15 mg, 0.1 mmol) and BAIB (331 mg, 1.02 mmol)
at 0 °C. After stirring at room temperature for 1 h, the reaction
mixture was diluted with CH2Cl2 (3 mL). The resulting solution
was washed with a saturated aqueous solution of Na2S2O3 (5 mL).
The organic layer was dried with Na2SO4 and filtered, and the fil-
trate was concentrated under reduced pressure to give the crude
carboxylic acid. The crude residue was purified by flash column
chromatography (silica gel, EtOAc/hexanes) to yield acid 32
IR (KBr): ν
= 2933, 2859, 2240, 1629, 1464, 1429, 1253, 1102,
˜
max
836 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.71–7.65 (m, 4 H), (127 mg, 71%) as a colorless oil. [α]2D0 = +17.1 (c = 2.52, CHCl3).
7.46–7.32 (m, 6 H), 4.36 (d, J = 1.5 Hz, 2 H), 4.22 (td, J = 1.5, 6.4, IR (KBr): ν = 3448, 3067, 2931, 2858, 1701, 1658, 1425, 1375,
˜
max
7.9 Hz, 1 H), 4.01–3.92 (m, 1 H), 3.88–3.77 (m, 1 H), 1.45 (s, 3 H),
1224, 1108, 1052, 703 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.75–
1.40 (s, 3 H), 1.60–1.17 (m, 10 H), 1.06 (d, J = 6.7 Hz, 3 H), 1.05 7.63 (m, 4 H), 7.48–7.32 (m, 6 H), 6.97 (dd, J = 4.5, 15.1 Hz, 1 H),
(s, 9 H), 0.90 (s, 9 H), 0.11 (s, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 135.8, 134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 109.5,
85.2, 81.4, 81.3, 70.5, 69.4, 51.7, 39.1, 32.2, 29.6, 27.1, 27.0, 26.2,
6.15 (d, J = 15.1 Hz, 1 H), 4.23–4.09 (m, 1 H), 3.89–3.77 (m, 1 H),
3.77–3.64 (m, 1 H), 1.59–1.16 (m, 10 H), 1.44 (s, 3 H), 1.41 (s, 3
H), 1.05 (d, J = 6.7 Hz, 3 H), 1.04 (s, 9 H) ppm. 13C NMR (CDCl3,
25.7, 25.0, 23.2, 19.2, 18.2, –5.1 ppm. HRMS: calcd. for 75 MHz): δ = 171.1, 146.7, 135.8, 134.8, 134.5, 129.4, 129.3, 127.4,
C37H58O4Si2 [M + NH4]+ 640.4212; found 640.4241.
127.3, 121.7, 109.4, 80.5, 80.0, 69.4, 39.2, 32.0, 29.5, 27.2, 27.0,
25.8, 25.0, 23.2, 22.6, 19.2 ppm. HRMS: calcd. for C31H44O5Si Na
[M + Na]+ 547.2850; found 547.2882.
3-{(4R,5R)-5-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]-2,2-dimeth-
yl-1,3-dioxolan-4-yl}prop-2-yn-1-ol (30): To a solution of 29
(610 mg, 0.98 mmol) in THF (5 mL) was added TBAF (1.0 m solu-
tion in THF, 0.98 mL, 0.98 mmol) at 0 °C, and the resulting solu-
tion was stirred at room temperature for 1 h. The resulting mixture
was cooled to 0 °C and quenched with a saturated aqueous solution
of NH4Cl (5 mL). The aqueous layer was extracted with ethyl acet-
ate (3 ϫ5 mL). The combined organic layers were washed with
brine (15 mL), dried with Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexanes/
(E)-3-{(4R,5R)-5-[(R)-6-Hydroxyheptyl]-2,2-dimethyl-1,3-dioxolan-
4-yl}acrylic Acid (33): To a solution of acid 32 (100 mg, 0.19 mmol)
in THF (3 mL) was added TBAF (1.0 m solution in THF, 0.57 mL,
0.57 mmol,) at 0 °C, and the resulting solution was stirred at room
temperature for 6 h. The mixture was cooled to 0 °C and quenched
with a saturated aqueous solution of NH4Cl (3 mL). The aqueous
layer was extracted with ethyl acetate (3ϫ5 mL). The combined
organic layers were washed with brine (10 mL), dried with Na2SO4,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexanes/EtOAc) to afford seco-acid 33
EtOAc) to afford propargylic alcohol 30 (488 mg, 98%). [α]2D0
=
+17.5 (c = 1.00, CHCl ). IR (KBr): νmax = 3424, 2933, 2858, 2250,
˜
3
1628, 1464, 1375, 1223, 1108, 1044, 704 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.71–7.65 (m, 4 H), 7.46–7.32 (m, 6 H), 4.31 (d, J =
7.5 Hz, 2 H), 4.23 (td, J = 1.5, 6.0, 7.5 Hz, 1 H), 4.01–3.93 (m, 1
H), 3.88–3.77 (m, 1 H), 1.66–1.17 (m, 10 H), 1.46 (s, 3 H), 1.41 (s,
3 H), 1.06 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 135.8, 134.8, 134.6, 129.4, 129.3, 127.4,
127.3, 109.6, 84.8, 82.4, 81.3, 70.4, 69.5, 51.0, 39.3, 32.1, 29.5, 29.3,
27.1, 27.0, 26.2, 25.6, 25.0, 19.2 ppm. HRMS: calcd. for C31H44O4-
SiNa [M + Na]+ 531.2901; found 531.2904.
(45 mg, 83%). [α]2D0 = +5.8 (c = 0.68, CHCl ). IR (KBr): ν
=
˜
3
max
3447, 2929, 2854, 1707, 1642, 1429, 1374, 1212, 1043 cm–1
.
1H
NMR (300 MHz, CDCl3): δ = 6.95 (dd, J = 5.9, 15.9 Hz, 1 H),
6.13 (dd, J = 1.0, 15.9 Hz, 1 H), 4.17 (ddd, J = 1.0, 6.9, 15.9 Hz,
1 H), 3.88–3.70 (m, 2 H), 1.44 (s, 3 H), 1.41 (s, 3 H), 1.51–1.15 (m,
10 H), 0.88 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.3, 145.6, 122.3, 109.3, 80.4, 79.9, 68.0, 38.7, 31.8, 29.3,
27.0, 26.4, 25.7, 25.3, 22.9 ppm. HRMS: calcd. for C15H25O5 [M –
H]+ 285.1701; found 285.1705.
(E)-3-{(4R,5R)-5-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}prop-2-en-1-ol (31): To a solution of prop-
argylic alcohol 30 (100 mg, 0.19 mmol) in THF (5 mL) was added
a solution of Red-Al (65 % in toluene, 0.18 mL, 0.58 mmol,
3 equiv.) at 0 °C, and the mixture was stirred at room temperature
for 1 h. After completion, the reaction was quenched with water
(2 mL) at 0 °C, and the resulting solution was extracted with ethyl
acetate (3 ϫ 15 mL). The combined organic layers were washed
with brine (5 mL), dried with Na2SO4, and concentrated in vacuo
to give a residue, which was purified by silica gel column
(3aR,8S,13aR,E)-8-Hydroxy-2,2-dimethyl-9,10,11,12,13,13a-hexa-
hydro-3aH-[1,3]dioxolo[4,5-e][1]oxacyclododecin-6(8H)-one (34): To
a stirred solution of seco-acid 33 (50 mg, 0.17 mmol) and Et3N
(0.14 mL, 1.04 mmol) in anhydrous THF (7 mL) was added 2,4,6-
trichlorobenzoyl chloride (0.13 mL, 0.87 mmol) at 0 °C, and the
resulting mixture was stirred for 2 h. The reaction was then diluted
with anhydrous toluene (9 mL), and the resulting mixture was
added at a rate of 3 mL/h to a solution of DMAP (640 mg,
5.24 mmol) in toluene (50 mL) that was heated at reflux. The reac-
tion mixture was then heated at reflux for an additional 8 h. Then,
the mixture was cooled to room temperature and quenched with a
saturated aqueous solution of NaHCO3 (20 mL), and the aqueous
layer was extracted with ethyl acetate (3ϫ25 mL). The combined
organic layers were washed with brine (25 mL), dried with Na2SO4,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexanes/EtOAc) to afford macrolactone
34 (39 mg, 85%) as a viscous liquid. [α]2D0 = +10.1 (c = 1.00,
chromatography to afford allylic alcohol 31 (92 mg, 92%). [α]2D0
+15.2 (c = 2.68, CHCl ). IR (KBr): νmax = 3420, 2932, 2858, 1650,
=
˜
3
1427, 1373, 1219, 1107, 1049, 703 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.70–7.65 (m, 4 H), 7.44–7.34 (m, 6 H), 6.61–5.93 (m,
1 H), 5.73–5.66 (m, 1 H), 4.18 (d, J = 4.9 Hz, 2 H), 4.0 (t, J =
7.9 Hz, 1 H), 3.87–3.80 (m, 1 H), 3.68–3.63 (m, 1 H), 1.54–1.15 (m,
10 H), 1.41 (s, 6 H), 1.05 (s, 9 H), 1.04 (d, J = 6.7 Hz, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 135.8, 134.8, 134.5, 134.1, 129.4,
129.3, 127.7, 127.4, 127.3, 108.3, 81.6, 80.7, 69.4, 62.5, 39.2, 31.7,
29.6, 27.2, 26.9, 26.0, 25.0, 23.1, 19.2 ppm. HRMS: calcd. for
C31H46O4SiNa [M + Na]+ 533.3058; found 533.3051.
CHCl ). IR (KBr): ν
= 2925, 2856, 1712, 1627, 1412, 1217,
˜
3
max
1043 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.78 (dd, J = 9.5,
15.8 Hz, 1 H), 6.23 (d, J = 15.8 Hz, 1 H), 5.05–4.93 (m, 1 H), 4.04
(dd, J = 8.5, 9.3 Hz, 1 H), 3.90 (ddd, J = 4.2, 8.3, 11.0 Hz, 1 H),
2.10–1.90 (m, 1 H), 1.70–1.50 (m, 3 H), 1.48–1.35 (m, 8 H), 1.30
(d, J = 6.7 Hz, 1 H), 1.26–1.15 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.6, 143.8, 125.9, 109.2, 80.3, 75.3, 35.3, 29.7, 27.8,
(E)-3-{(4R,5R)-5-[(R)-6-(tert-Butyldiphenylsilyloxy)heptyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}acrylic Acid (32): To a solution of allylic
alcohol 31 (175 mg, 0.34 mmol) in H2O/CH2Cl2 (1:1, 3 mL) were
3794
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Eur. J. Org. Chem. 2013, 3786–3796

Alkyne-Mediated Approach for Syntheses of Cladospolides
Tetrahedron Lett. 2006, 47, 6531–6535; g) S. K. Pandey, P. Ku-
mar, Tetrahedron Lett. 2005, 46, 6625–6627; h) K. A. B. Austin,
M. G. Banwell, D. T. J. Loong, D. Rae, A. C. Willis, Org. Bi-
omol. Chem. 2005, 3, 1081–1088, and ref.[5a]
27.2, 26.8, 25.1, 24.9, 20.6 ppm. HRMS: calcd. for C15H26O5Na
[M + Na] 291.1572; found 291.1577.
Cladospolide C (4): To a solution of lactone 34 (30 mg, 0.11 mmol)
in acetonitrile/water (2:1, 5 mL) was added trifluoroacetic acid
(0.8 mL, 11 mmol) at 0 °C, and the reaction mixture was stirred at
room temperature for 2 h and then diluted with ethyl acetate
(3 mL). The resulting solution was washed with a saturated aque-
ous solution of NaHCO3 (3 mL), dried with Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
on silica gel to give cladospolide C (4, 22 mg, 91%). [α]2D0 = +48.9
(c = 0.45, MeOH); ref.[2] [α]2D2 = +59.7 (c = 0.4, MeOH). IR (KBr):
[7]
For the synthesis of (4S,5S,11R)-iso-cladospolide B, see: a)
C. R. Reddy, N. N. Rao, P. Sujitha, C. G. Kumar, Synthesis
2012, 44, 1663–1666; b) B. M. Trost, A. Aponick, J. Am. Chem.
Soc. 2006, 128, 3931–3933; c) P. Srihari, E. V. Bhasker, S. J.
Harshavardhan, J. S. Yadav, Synthesis 2006, 4041–4045; d) X.
Franck, M. E. V. Araujo, J.-C. Jullian, R. Hocquemiller, B. Fi-
gadere, Tetrahedron Lett. 2001, 42, 2801–2803; and ref.[5a,6f,6g]
;
for other isomers of iso-cladospolide B, see: e) K. R. Prasad,
V. R. Gandi, Tetrahedron: Asymmetry 2010, 21, 275–276; f) L.
Ferrie, S. Reymond, P. Capdevielle, J. Cossy, Synlett 2007,
2891–2893; and ref.[6a,6b]
For the synthesis of cladospolide C, see: a) C. R. Reddy, N. N.
Rao, Tetrahedron Lett. 2009, 50, 2478–2480; b) C.-Y. Chou, D.-
R. J. Hou, J. Org. Chem. 2006, 71, 9987–9890; c) M. G.
Banwell, D. T. J. Loong, A. C. Willis, Aust. J. Chem. 2005, 58,
511–516; and ref.[5a,6a,6b]
For synthesis of cladospolide D, see: a) D. Si, K. P. Kaliappan,
Synlett 2012, 19, 2822–2826; b) K.-J. Lu, C.-H. Chen, D.-R.
Hou, Tetrahedron 2009, 65, 225–231; c) Y. Xing, J. H. Penn,
G. A. O’Doherty, Synthesis 2009, 2847–2854; d) Y. Xing, G. A.
O’Doherty, Org. Lett. 2009, 11, 1107–1110.
ν
= 3425, 2931, 2860, 1701, 1641, 1457, 1348, 1260, 1162,
˜
max
1037 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.81 (dd, J = 8.9,
15.8 Hz, 1 H), 6.05 (d, J = 15.8 Hz, 1 H), 5.01–4.92 (m, 1 H), 3.98
(dd, J = 7.9, 8.9 Hz, 1 H), 3.57 (t, J = 7.9 Hz, 1 H), 2.73–2.53 (br.
s, 1 H), 2.51–2.32 (br. s, 1 H), 1.30 (d, J = 6.7 Hz, 3 H), 1.77–1.05
(m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 124.4, 77.2, 76.4,
74.3, 33.9, 32.0, 27.2, 24.5, 24.0, 20.8 ppm. HRMS: calcd. for
C12H20O4Na [M + Na]+ 251.1253; found 251.1256.
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of all compounds.
[10]
a) C. R. Reddy, N. N. Rao, P. Sujitha, C. G. Kumar, Eur. J.
Org. Chem. 2012, 1819–1824; b) C. R. Reddy, D. Suman, N. N.
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[11]
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D. S. and N. N. R. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for the research fellowships.
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=
19.75 min (0.62%), 25.8 min (99.38%).
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Eur. J. Org. Chem. 2013, 3786–3796
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C. R. Reddy, D. Suman, N. N. Rao
FULL PAPER
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group to give 3 from compound 27. (After hydrolysis of the
acetonide, the formation of five-membered lactone is favorable
through a translactonization reaction.) However, when 1 equiv.
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be responsible for the activation of the carbonyl group through
protonation of the carbonyl oxygen atom followed by nucleo-
Received: January 7, 2013
Published Online: May 5, 2013
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Eur. J. Org. Chem. 2013, 3786–3796