Stereoselective total synthesis of cladospolide A

Article abstract of DOI:10.1055/s-0029-1219236

A simple and highly efficient stereoselective total synthesis of cladospolide A, a polyketide natural product, has been achieved. The synthesis involves stereoselective zinc-mediated allylation, pivotal aldol coupling, and ring-closing metathesis. The pivotal aldol coupling is used for the first time for macrolide construction and provides an effective alternative to Yamaguchi macrolactonization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1219236

PAPER
1381
Stereoselective Total Synthesis of Cladospolide A
S
K
ynthesis of Clado
a
spolide
A
ruturi Rajesh, Vangaru Suresh, Jondoss Jon Paul Selvam, Chitturi Bhujanga Rao, Yenamandra Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division – I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: luchem@iict.res.in
Received 2 December 2009; revised 8 December 2009
The first total synthesis of (–)-cladospolide A (1) was de-
scribed in 1987 by Mori and co-workers, who prepared it
from ethyl (R)-3-hydroxybutyrate. The hydroxy groups at
C4 and C5 were introduced by a Katsuki–Sharpless asym-
Abstract: A simple and highly efficient stereoselective total syn-
thesis of cladospolide A, a polyketide natural product, has been
achieved. The synthesis involves stereoselective zinc-mediated al-
lylation, pivotal aldol coupling, and ring-closing metathesis. The
6
pivotal aldol coupling is used for the first time for macrolide con- metric epoxidation, and the macrolide ring was estab-
struction and provides an effective alternative to Yamaguchi mac- lished by use of the Yamaguchi macrolactonization
rolactonization.
procedure. A closely related synthesis was reported in the
7
Key words: stereoselective synthesis, zinc mediator, allylations, same year by Ichimoto and co-workers. Another synthe-
aldol coupling, ring-closing metathesis
sis of (–)-cladospolide A was reported in 1994 by Solladié
8
and Almario, and was based on chiral sulfoxide asym-
metric induction. Recently, a chemo-enzymatic synthesis
Terrestrial as well as marine fungi are attracting increas- of cladospolide A (1) was detailed by Banwell and co-
9
ing attention as potential sources of new pharmaceutically workers. In all the approaches, the macrocyclic ring with-
interesting compounds of various structures. Clado- in target 1 was constructed by late-stage Yamaguchi lac-
spolide A (1) and B (2) (Figure 1) were first isolated from tonization. Despite the great number of reports regarding
the culture filtrate of the fungus Cladosporium cladospo- the synthesis of these macrolides, no effort was made to
1
rioides FI-113 by Isogai and co-workers. Subsequently, construct the macrocyclic framework by using aldol cou-
2
other groups reported the isolation of cladospolide C (3), pling.
as well as congeners 1 and 2, from Cladosporium tenuis-
Because of the unique biological properties and syntheti-
3
simum and cladospolide D (4) (Figure 1) from the fer-
cally challenging structures of macrolides, the develop-
mentation broth of Cladosporium sp. FT-0012.
Cladospolide A (1) was found to inhibit root growth in let-
ment of new methods for their preparation has received
much synthetic attention during the past decades. We
10
tuce seedlings, while cladospolide B (2) displays the op-
found that aldol coupling for macrolide construction pro-
vides an effective alternative route to Yamaguchi macro-
lactonization. In continuation of our interest in the
1
posite effect. Cladospolides A (1) and B (2), together
4
with patulolides, have been patented as allergy and in-
5
flammation inhibitors. The potential biological impor-
11
synthesis of biologically active natural products, we
tance as well as unique structural features of these
molecules have led to interest in the syntheses of these
molecules.
have developed an efficient and practical total synthesis of
(
–)-cladospolide A (1), which we report here.
Our planned approach to (–)-cladospolide A (1) involved
stereoselective zinc-mediated allylation, pivotal aldol
coupling, and ring-closing metathesis as key steps from
commercially available D-mannitol as a chiral starting
material. The retrosynthesis is summarized in Scheme 1.
OH
OH
O
O
OH
O
As depicted in Scheme 2, the zinc-mediated allylation of
(R)-2,3-O-isopropylidineglyceraldehyde (5)12 in aqueous
medium was carried out by following the operationally
O
OH
cladospolide B (2)
cladospolide A (1)
13
simple procedure of Luche to afford anti-homoallylic al-
OH
OH
14
cohol 6 in high diastereoselectivity (syn/anti = 5:95).
The acetonide protection group in 6 was removed by treat-
ment with aqueous trifluoroacetic acid to afford triol 7,
which was selectively protected with pivaloyl chloride to
afford 8. The 1,2-diol in 8 was protected with 2,2-
dimethoxypropane to afford fully protected compound 9.
The pivaloyl group in compound 9 was removed by using
potassium carbonate in methanol, to afford primary alco-
hol 10. The primary alcohol in 10 was oxidized by using
2-iodoxybenzoic acid (IBX) in dimethyl sulfoxide, to af-
ford the corresponding aldehyde in 92% yield; aldol
O
O
OH
O
O
O
cladospolide C (3)
cladospolide D (4)
Figure 1
SYNTHESIS 2010, No. 8, pp 1381–1385
x
x
.
x
x
.2
0
1
0
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219236; Art ID: Z26209SS
Georg Thieme Verlag Stuttgart · New York
15
18
coupling of the aldehyde with ester 16 by use of lithi-
©

1
382
K. Rajesh et al.
PAPER
OH
OH
O
O
O
O
O
O
O
OH
O
O
O
OH
11
1
12
O
O
OAc
O
O
+
O
O
CHO
15
16
5
Scheme1 Retrosynthetic approach to (–)-cladospolide A (1)
um hexamethyldisilazide as base furnished aldol product In conclusion, an efficient and straightforward total syn-
1 as a diastereomeric mixture, in 60% yield. We also ex- thesis of (–)-cladospolide A has been achieved. The initial
1
amined other bases, such as lithium diisopropylamide and zinc-mediated allylation of the aldehyde for the introduc-
potassium hexamethyldisilazide, but they gave poor tion of chirality, and the subsequent aldol coupling and
yields (<30%). Unfortunately, we were not able to sepa- ring-closing metathesis constitute the key reactions for
rate these isomers, and therefore decided to carry forward constructing the macrolide. The synthetic strategy de-
the remaining three steps. The diene adduct 11 was sub- scribed here has significant potential for the synthesis of a
jected to ring-closing metathesis in the presence of the variety of other biologically important macrolides con-
1
6
Grubbs first-generation catalyst, to afford macrolide 12. taining natural products.
The double bond in 12 was hydrogenated in the presence
of palladium on carbon, to afford 13. The diastereomeric
Solvents were dried over standard drying agents and freshly dis-
tilled prior to use. The reagents were purchased from Aldrich and
hydroxy group at C3 in compound 13 was mesylated by
1
7
using mesyl chloride and pyridine; treatment with 1,8- Acros and were used without further purification unless otherwise
diazabicyclo[5.4.0]undec-7-ene followed, to furnish stated. All moisture-sensitive reactions were carried out under N2.
Organic solns were dried over anhyd Na SO and concentrated in
enone 14 in 80% yield. Finally, the acetonide protecting
group in 14 was removed in hot aqueous acetic acid to af-
ford (–)-cladospolide A (1) in 82% yield. The physical
and spectral data of compound 1 were found to be identi-
2
4
vacuo below 40 °C. All column chromatographic separations were
1
performed on silica gel (Acme, 60–120 mesh). H NMR (200 and
1
3
3
00 MHz) and C NMR (50 and 75 MHz) spectra were recorded on
Varian Gemini FT-200 and Bruker Avance 300 instruments, with
1
cal with those reported for the natural product.
OH
O
a
b
c
O
HO
O
O
CHO
OH
OH
5
6
7
OH
PivO
HO
d
e
f, g
PivO
O
O
O
O
OH
8
9
10
O
h
O
O
i
O
O
O
O
O
O
OH
O
O
12
OH
O
O
OH
11
13
j
k
O
OH
OH
O
O
O
O
14
1
Scheme 2 Reagents and conditions: (a) Zn, AllBr, THF, sat. aq NH Cl (cat.), 6 h, 78%; (b) TFA–H O, r.t., 5 h, 90%; (c) PvCl, Et N, CH Cl ,
4
2
3
2
2
0
°C to r.t., 4 h, 90%; (d) 2,2-dimethoxypropane, PTSA (cat.), CH Cl , r.t., 5 h, 95%; (e) K CO , MeOH, r.t., 3 h, 95%; (f) IBX, DMSO, CH Cl ,
2
2
2
3
2
2
5
h, 92%; (g) 16, LiHMDS, anhyd THF, –78 °C, 6 h, 60%; (h) Grubbs I cat., CH Cl , reflux, 24 h, 72%; (i) H , Pd/C, MeOH, 24 h, 92%; (j)
2 2 2
MsCl, Et N; DBU, 4 h, 80%; (k) AcOH–H O, 70 °C, 1 h, 82%.
3
2
Synthesis 2010, No. 8, 1381–1385 © Thieme Stuttgart · New York

PAPER
Synthesis of Cladospolide A
1383
1
TMS as internal standard in CDCl . IR spectra were recorded on a
H NMR (300 MHz, CDCl ): d = 5.93–5.79 (m, 1 H), 5.22–5.15 (m,
3
3
Perkin-Elmer IR-683 spectrophotometer with NaCl optics. Optical
rotations were measured on a Horiba high-sensitive polarimeter
SEPA-300 at 25 °C. Mass spectra were recorded on an Agilent
Technologies 1100 Series (Agilent Chemistation Software) spec-
trometer.
2 H), 4.28–4.25 (m, 2 H), 3.80–3.75 (m, 1 H), 3.70–3.64 (m, 1 H),
2.41 (br s, 2 H), 2.48–2.22 (m, 2 H), 1.20 (s, 9 H).
13
C NMR (75 MHz, CDCl ): d = 179.33, 134.2, 118.6, 72.66, 71.07,
3
6
5.6, 38.7, 37.11, 27.19.
[
(4R,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl Piv-
alate (9)
,2-Dimethoxypropane (1.3 mL, 11.52 mmol) and PTSA (5 mg)
were added to a stirred soln of 8 (2 g, 9.25 mmol) in anhyd CH Cl .
(
S)-1-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]but-3-en-1-ol (6)
Sat. aq NH Cl (5 mL) was added dropwise over 30 min to a cooled
4
2
(0 °C) and well-stirred mixture of 5 (2 g, 15.3 mmol), Zn dust (2 g,
2
2
3
0.5 mmol), and AllBr (3.6 g, 30 mmol) in THF (30 mL). The mix-
The mixture was stirred at r.t. for 5 h. After completion of the reac-
tion, H O (15 mL) was added, the mixture was extracted into
ture was stirred for 6 h at r.t. until the aldehyde was totally con-
sumed (by TLC). The mixture was filtered, and the precipitate was
thoroughly washed with CHCl . The aqueous layer was separated
and treated with 5% HCl to dissolve the suspended turbid material.
The clear soln was extracted with CHCl (3 × 20 mL). The com-
bined organic layer was washed successively with 10% NaHCO
2
CH Cl (3 × 50 mL), and the combined organic layer was washed
2
2
3
with brine (2 × 15 mL), dried (Na SO ), and concentrated to give
2
4
the crude material, which was purified by column chromatography
silica gel, EtOAc–hexane, 1:9); this gave 9.
3
(
3
Y
i
e
l
d
:
2
.
2
5
g
(
9
5
%
)
;
c
o
l
o
r
l
e
s
s
o
i
l
;
[
a
]
2
0
+
8
(
c
0
.
4
,
C
H
C
l
)
.
(
15 mL), H O (15 mL), and brine (15 mL). After removal of the sol-
D
3
2
vent under reduced pressure, the residue was purified by column
chromatography (silica gel, EtOAc–hexane, 1:9), resulting in the
isolation of the diastereomers in pure form. The minor isomer
IR (neat): 2980, 2875, 1733, 1642, 1478, 1373, 1281, 1219, 1157,
–1
1
077, 993, 917 cm .
1
H NMR (300 MHz, CDCl ): d = 5.93–5.78 (m, 1 H), 5.18–5.10 (m,
3
(
2R,3R) eluted first, followed by the major isomer (2R,3S).
2
H), 4.28–4.21 (m, 2 H), 4.12–4.10 (m, 1 H), 2.37–2.25 (m, 2 H),
2
0
Yield: 1.98 g (75%) [(2R,3S)-6], 0.07 g (3%) [(2R,3R)-6]; [a]D +14
1.46 (s, 3 H), 1.35 (s, 3 H), 1.20 (s, 9 H).
(
c 0.8, CHCl3).
13
C NMR (75 MHz, CDCl ): d = 134.23, 118.7, 117.37, 76.48,
3
IR (neat): 3423, 3077, 2986, 2929, 1722, 1641, 1253, 1215, 1156,
7
5.15, 62.8, 33.8, 28.0, 27.17, 25.5.
–1
1
065, 917 cm .
1
[(4S,5S)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (10)
K CO (3.0 g, 21.9 mmol) was added to a cooled soln of 9 (2.25 g,
H NMR (300 MHz, CDCl ): d = 5.09–5.75 (m, 1 H), 5.16–5.06 (m,
H), 3.99–3.83 (m, 3 H), 3.73–3.66 (m, 1 H), 2.35–2.31 (m, 2 H),
.93 (1 H, OH), 1.39 (s, 3 H), 1.32 (s, 3 H).
3
2
1
2
3
8
.7 mmol) in anhyd MeOH (8 mL), and the mixture was stirred for
3
h at r.t. After completion of the reaction, the mixture was filtered
1
3
C NMR (75 MHz, CDCl ): d = 134.5, 118.6, 109.5, 78.6, 70.5,
3
and the MeOH was evaporated; the residue was washed with H O
2
6
5.7, 38.1, 27.0, 25.7.
(
10 mL) and extracted into EtOAc (2 × 40 mL). The combined or-
MS (EI): m/z = 172 [M+].
ganic phase was dried (Na SO ) and then concentrated to give the
2
4
crude material, which was purified by column chromatography (sil-
(
2R,3S)-Hex-5-ene-1,2,3-triol (7)
ica gel, EtOAc–hexane, 2:8); this gave 10.
Compound 6 (1.98 g, 0.015 mol) was taken in 90% aq TFA (5 mL)
and stirred for 3 h at 0 °C. After completion of the reaction, the mix-
ture was diluted with CHCl (20 mL) and H O (10 mL). The aque-
ous layer was extracted with CHCl (3 × 15 mL). The combined
organic layer was washed successively with 2% NaHCO (15 mL)
and H O (15 mL) and the solvent was removed under reduced pres-
sure to give the crude triol, which was purified by column chroma-
tography (silica gel, EtOAc–hexane, 8:2); this gave 7.
20
Yield: 1.43 g (95%); viscous liquid; [a]D +3 (c 0.4, CHCl3).
–
1
IR (neat): 3346, 2933, 2864, 1465, 1254, 1102 cm .
3
2
1
3
H NMR (300 MHz, CDCl ): d = 5.91–5.77 (m, 1 H), 5.22–5.13 (m,
3
3
2 H), 4.04–3.91 (m, 2 H), 3.80–3.70 (m, 1 H), 3.66–3.58 (m, 1 H),
2.63 (br s, 1 H), 2.38–2.19 (m, 2 H), 1.43 (s, 3 H), 1.36 (s, 3 H).
2
1
3
C NMR (75 MHz, CDCl ): d = 134.23, 118.2, 78.03, 73.43, 65.13,
3
3
4.8, 27.17.
2
0
Yield: 1.36 g (90%); colorless oil; [a]D +5 (c 0.2, MeOH).
MS (EI): m/z = 172 [M+].
–
1
IR (neat): 3388, 2922, 2852, 1647, 1382, 1217, 1071, 922 cm .
1
(R)-Hex-5-en-2-yl 3-[(4S,5S)-5-Allyl-2,2-dimethyl-1,3-dioxolan-
H NMR (300 MHz, CDCl ): d = 5.9–5.76 (m, 1 H), 5.16–5.09 (m,
3
4
-yl]-3-hydroxypropanoate (11)
2
1
H), 4.52 (br s, 3 H), 3.70–3.53 (m, 4 H), 2.36–2.17 (m, 2 H).
A soln of 10 (0.5 g, 2.9 mmol) in anhyd CH Cl (20 mL) was added
3
2
2
C NMR (75 MHz, CDCl ): d = 134.55, 117.68, 74.01, 72.06,
3
to a stirred soln of IBX (1.22 g, 4.3 mmol) in anhyd DMSO at r.t.,
and the mixture stirred for 5 h at r.t. After completion of the reac-
6
2.85, 37.27.
tion, the mixture was filtered and diluted with H O (20 mL) and ex-
2
(
2R,3S)-2,3-Dihydroxyhex-5-enyl Pivalate (8)
tracted into CH Cl (2 × 30 mL). The combined organic layer was
2
2
To a stirred soln of triol 7 (1.36 g, 10.3 mmol) in anhyd CH Cl (20
mL) at 0 °C, Et N (2.08 g, 20.5 mmol) was added slowly followed
2
2
washed with brine (20 mL) and dried (Na SO ), and the solvent was
2
4
3
evaporated to afford the crude aldehyde. The residue was purified
by column chromatography (silica gel, EtOAc–hexane, 1:9); this
furnished the aldehyde.
by PvCl (1.1 g, 9.1 mmol). The mixture was stirred at r.t. for 4 h.
After completion of the reaction, the mixture was extracted into
CH Cl (3 × 50 mL) and the combined organic layer was washed
with brine (2 × 15 mL), dried (Na SO ), and concentrated to give the
crude material, which was purified by column chromatography (sil-
2
2
Yield: 0.45 g (92%); colorless liquid.
2
4
The aldehyde was directly used for the next reaction. A 1 M soln of
LiHMDS in THF (3.2 mL, 3.2 mmol, 1.2 equiv) was added to a soln
of ester 16 (0.45 g, 3.16 mmol, 1.2 equiv) in anhyd THF (20 mL) at
ica gel, EtOAc–hexane, 2:3); this gave 8.
2
0
Yield: 2.0 g (90%); colorless oil; [a]D +12 (c 0.8, CHCl3).
–
78 °C, and the soln was stirred for 1 h. Then the previously pre-
IR (neat): 3447, 3078, 2972, 1702, 1642, 1579, 1399, 1287, 1232,
1
pared aldehyde (0.45 g, 2.6 mmol) in THF was added slowly, and
the resulting mixture was stirred for 6 h at –78 °C. After completion
–
1
166, 1069, 993, 917 cm .
of the reaction, the mixture was quenched with sat. aq NH Cl soln
4
(5 mL) and stirred for an additional 30 min, and was then extracted
Synthesis 2010, No. 8, 1381–1385 © Thieme Stuttgart · New York

1
384
K. Rajesh et al.
PAPER
2
0
into EtOAc (3 × 50 mL). The organic phase was washed with H O
Yield: 45 mg (80%); [a]D –13 (c 1, CHCl3).
IR (neat): 2930, 2859, 1710, 1651, 1454, 1371, 1268, 1172, 1119,
2
(
15 mL) and dried (Na SO ), the solvent was evaporated, and the
2 4
residue was purified by column chromatography (silica gel,
EtOAc–hexane, 2:8); this afforded an inseparable diastereomeric
mixture of aldol product 8.
–1
1
043, 988 cm .
1
H NMR (300 MHz, CDCl ): d = 6.99 (dd, J = 15.7, 8.7 Hz, l H),
3
6
.07 (d, J = 15.7 Hz, l H), 5.15 (m, 1 H), 4.72 (dd, J = 8.7, 6.1 Hz, l
H), 4.13 (m, 1 H), 1.52 (s, 3 H), 1.38 (s, 3 H), 1.31 (d, J = 6.7 Hz, 3
H), 1.80–1.00 (m, 10 H).
2
0
Yield: 0.495 g (60%); clear liquid; [a]D +4 (c 1, CHCl3).
–
1
IR (neat): 3388, 2930, 2880, 1762, 1642, 1270, 1105 cm .
1
ESI-MS: m/z = 559 [2M + 23]+.
H NMR (300 MHz, CDCl ): d = 5.98–5.72 (m, 2 H), 5.18–4.96 (m,
3
4
2
1
H), 4.29–4.23 (m, 1 H), 4.10–4.03 (m, 1 H), 3.94–3.89 (m, 1 H),
.83–2.69 (m, 2 H), 2.62–2.26 (m, 2 H), 2.12–2.06 (m, 2 H), 1.78–
.48 (m, 2 H), 1.42 (s, 3 H), 1.32 (s, 3 H), 1.25 (d, 3 H).
(2E,4R,5S,11R)-4,5-Dihydroxydodec-2-en-11-olide (Clado-
spolide A, 1)
ESI-MS: m/z = 335 [M + 23]+.
A soln of 14 (45 mg) in AcOH–H O (3:1; 3 mL) was heated at 70 °C
for 1 h. After completion of the reaction, EtOAc (15 mL) was add-
2
ed, and the mixture was washed with sat. aq NaHCO (3 × 5 mL).
3
(
3aR,8R,13aS,Z)-4-Hydroxy-2,2,8-trimethyl-4,5,9,10,13,13a-
The aqueous layer was extracted with EtOAc (3 × 20 mL). The or-
hexahydro-3aH-[1,3]dioxolo[4,5-e][1]oxacyclododecin-6(8H)-
one (12)
ganic phase was washed with H O (15 mL) and dried (Na SO ), the
2
2
4
solvent was evaporated under reduced pressure, and the crude resi-
due was purified by column chromatography (silica gel, EtOAc–
hexane, 4:6); this afforded cladospolide A (1) as a white solid.
The Grubbs I ruthenium catalyst (79 mg, 0.096 mmol) was added to
a degassed soln of diene 11 (0.1 g, 0.32 mmol) in CH Cl (10 mL),
and the mixture was refluxed for 24 h. After completion of the reac-
tion, the solvent was removed under vacuum and the crude residue
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 3:7); this afforded macrolide 12.
2
2
Yield: 31 mg (82%); colorless needles (benzene); mp 92.0–92.6 °C.
IR (neat): 3415, 2931, 2858, 1706, 1656, 1457, 1359, 1277, 1179,
–1
1
128, 1053 cm .
2
0
Yield: 65 mg (72%); [a]D +16 (c 0.1, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 6.81 (dd, J = 16.0, 5.8 Hz, 1 H),
3
–
1
IR (neat): 3432, 2923, 2855, 1761, 1638, 1190, 1076, 761 cm .
6.21 (dd, J = 16.0, 1.6 Hz, 1 H), 5.13 (m, 1 H), 4.56 (m, 1 H), 3.67
(m, 1 H), 1.80–1.20 (m, 10 H), 1.24 (d, J = 6.4 Hz, 3 H).
1
H NMR (300 MHz, CDCl ): d = 5.70–5.36 (m, 2 H), 5.0–4.92 (m,
3
1
3
1
1
3
H), 4.34–3.91 (m, 3 H), 2.85–2.63 (m, 2 H), 2.17–2.00 (m, 2 H),
.83–1.52 (m, 2 H), 1.42 (s, 3 H), 1.32 (s, 3 H), 1.21 (d, J = 6.04 Hz,
H).
C NMR (75 MHz, CDCl ): d = 167.9, 145.8, 122.3, 74.7, 73.0,
3
72.5, 32.5, 30.6, 28.2, 25.1, 22.6, 19.0.
ESI-MS: m/z = 457 [2M + 1]+.
ESI-MS: m/z = 569 [2M + 1]+.
References
(
[
3aR,8R,13aS)-4-Hydroxy-2,2,8-trimethyloctahydro-3aH-
1,3]dioxolo[4,5-e][1]oxacyclododecin-6(8H)-one (13)
(
1) (a) Hirota, A.; Isogai, A.; Sakai, H. Agric. Biol. Chem. 1981,
5, 799. (b) Hirota, A.; Sakai, H.; Isogai, A.; Kitano, Y.;
Ashida, T.; Hirota, H.; Takahashi, T. Agric. Biol. Chem.
985, 49, 903. (c) Hirota, H.; Hirota, A.; Sakai, H.; Isogai,
A.; Takahashi, T. Bull. Chem. Soc. Jpn. 1985, 58, 2147.
d) Hirota, A.; Sakai, H.; Isogai, A. Agric. Biol. Chem. 1985,
9, 731. (e) Smith, C. J.; Abbanat, D.; Bernan, V. S.;
A soln of 12 (45 mg, 0.228 mmol) in MeOH (4 mL) was added to a
suspension of Pd/C (5% Pd, 25 mg) in MeOH (8 mL). The reaction
mixture was allowed to stir at r.t. for 24 h under H (4 atm). After
completion of the reaction as indicated by TLC, the reaction mix-
ture was filtered and concentrated in vacuum. The crude residue
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 3:7); this afforded 13.
4
2
1
(
4
Maiese, W. M.; Greenstein, M.; Jompa, J.; Tahir, A.; Ireland,
C. M. J. Nat. Prod. 2000, 63, 142.
2
0
Yield: 60 mg (92%); [a]D +4 (c 0.1, CHCl3).
(
(
2) Fujii, Y.; Fukuda, A.; Hamasaki, T.; Ichimoto, I.; Nakajima,
H. Phytochemistry 1995, 40, 1443.
3) Zhang, H.; Tomoda, H.; Tabata, N.; Miura, H.; Namikoshi,
M.; Yamaguchi, Y.; Masuma, R.; Omura, S. J. Antibiot.
IR (neat): 3422, 2923, 2854, 1753, 1636, 1460, 1375, 1167, 1070,
–1
7
60 cm .
1
H NMR (300 MHz, CDCl ): d = 5.10–4.95 (m, 1 H), 4.20–4.13 (m,
3
1
H), 4.00–3.92 (m, 2 H), 2.80–2.73 (m, 1 H), 2.52–2.44 (m, 1 H),
2001, 54, 635.
1
.86–1.45 (m, 10 H), 1.40 (s, 3 H), 1.32 (s, 3 H), 1.25 (d, J = 6.04
(
4) (a) Sekiguchi, J.; Kuroda, H.; Yamada, Y.; Okada, H.
Tetrahedron Lett. 1985, 26, 2341. (b) Rodphaya, D.;
Sekiguchi, J.; Yamada, Y. J. Antibiot. 1986, 39, 629.
5) Hansske, F.; Wilhelms, O. H.; Anke, H. Ger. Offen. DE
3906214, 1990.
Hz, 3 H).
ESI-MS: m/z = 595 [2M + 23]+.
(
(
(
2E,4R,5S,11R)-4,5-(Isopropylidenedioxy)dodec-2-en-11-olide
14)
(6) (a) Mori, K.; Maemoto, S. Liebigs Ann. Chem. 1987, 863.
(b) Maemoto, S.; Mori, K. Chem. Lett. 1987, 109.
(7) Ichimoto, I.; Sato, M.; Kirihata, M.; Ueda, H. Chem. Express
1987, 2, 495; Chem. Abstr. 1988, 108, 167.
To a soln of alcohol 13 (60 mg, 0.2 mmol) in py (1 mL) was added
MsCl (36 mg, 0.33 mmol) and the mixture was stirred for 2 h at r.t.
After completion of the reaction, the mixture was diluted with H O
2
(
5 mL) and extracted with CH Cl (3 × 5 mL). The organic layer
(8) (a) Solladié, G.; Almario, A.; Carmen, D. Pure Appl. Chem.
1994, 66, 2159. (b) Solladié, G.; Almario, A. Tetrahedron:
Asymmetry 1995, 6, 559.
(9) Banwell, M. G.; Jolliffe, K. A.; Loong, D. T. J.; McRae, K.
J.; Vounatsos, F. J. Chem. Soc., Perkin Trans. 1 2002, 22.
(10) Tadashi, N. In Macrolide Antibiotics: Chemistry, Biology
and Practice, 2nd ed.; Omura, S., Ed.; Academic Press: San
Diego, 2002, 181–284.
2
2
was dried (Na SO ), and evaporation of the solvent gave the mesyl-
ated product. This mesylated product was reacted with DBU (51
mg, 0.33 mmol) in CH Cl (1 mL) for 4 h at r.t. After completion of
2
4
2
2
the reaction, H O was added, and the mixture was extracted with
2
CH Cl2 (3 × 15 mL). The combined organic layer was dried
2
(Na SO ), the solvent was removed under reduced pressure, and the
2 4
crude residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:9); this afforded 14.
Synthesis 2010, No. 8, 1381–1385 © Thieme Stuttgart · New York

PAPER
Synthesis of Cladospolide A
1385
(
11) (a) Rajesh, K.; Suresh, V.; Jon Paul Selvam, J.;
(17) Poppe, L.; Recseg, K.; Novak, L. Synth. Commun. 1995, 25,
3993.
Bhujanga Rao, Ch.; Venkateswarlu, Y. Helv. Chim. Acta
2
009, 92, 1866. (b) Jon Paul Selvam, J.; Rajesh, K.; Suresh,
(18) Acetyl fragment 16 was synthesized (Scheme 3) from
commercially available epoxide 15, which was subjected to
copper(I) cyanide promoted regioselective nucleophilic ring
opening with allylmagnesium chloride to provide the
corresponding alcohol in 87% yield; acetylation of the
alcohol by use of acetic anhydride and pyridine yielded 16.
V.; Chanti Babu, D.; Venkateswarlu, Y. Tetrahedron:
Asymmetry 2009, 20, 1115. (c) Suresh, V.;
Jon Paul Selvam, J.; Rajesh, K.; Venkateswarlu, Y.
Tetrahedron: Asymmetry 2008, 19, 1509. (d) Suresh, V.;
Rajesh, K.; Jon Paul Selvam, J.; Venkateswarlu, Y.
Tetrahedron Lett. 2008, 49, 7358.
(
(
12) Praveen Kumar, S.; Nagaiaha, K.; Chorghade, M. S.
Tetrahedron Lett. 2006, 47, 7149.
13) (a) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910.
O
a, b
O
O
(
b) Einhorn, C.; Luche, J. L. J. Organomet. Chem. 1987,
322, 177.
15
16
(
(
(
14) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
15) Lorenz, M.; Kalesse, M. Org. Lett. 2008, 10, 4371.
16) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
Scheme 3 Reagents and conditions: (a) allyl chloride, Mg, CuCN,
THF, 0 °C to r.t., overnight; (b) Ac O, py, 0–25 °C, 3 h, 98%.
2
(b) Du, Y.; Chen, Q.; Linhardt, R. J. J. Org. Chem. 2006, 71,
8446.
Synthesis 2010, No. 8, 1381–1385 © Thieme Stuttgart · New York