Synthesis of the C7-C23 fragment related to iriomoteolide-1a via B -alkyl suzuki-miyaura cross-coupling and indium-mediated aldehyde allylation

Article abstract of DOI:10.1055/s-0030-1258507

Synthesis of the C7-C23 fragment and its 18R,19S-diastereomer of iriomoteolide-1a has been accomplished from the C7-C12 allyl bromide, the C13-C16 vinyl iodide, and the C17-C23 alkyl iodide fragments. These fragments were assembled first by the B-alkyl Suzuki-Miyaura cross-coupling to give the C13-C23 intermediate. The latter, after being transformed into the C13 aldehyde, was coupled to the C7-C12 allyl bromide in the presence of indium powder in THF-H₂O (1:1) at 70deg;C to the fully functionalized C7-C23 fragment with orthogonal protecting groups at C19 (PMB ether), and C9, C14, and C22 (TBS, TES, and TBS ethers, respectively). Formation of the characteristic six-membered C9/C13-hemiacetal ring has been demonstrated after global desilylation using pyridine-buffered HF.

Full text of DOI:10.1055/s-0030-1258507

2184
LETTER
Synthesis of the C7–C23 Fragment Related to Iriomoteolide-1a via B-Alkyl
Suzuki–Miyaura Cross-Coupling and Indium-Mediated Aldehyde Allylation
Synthesis of the
C
u
F
ragm
a
ent Relate
n
x
olide-1a in Liu,a Jian Wang,a Huoming Li,a Jinlong Wu,a Gaofeng Feng,b Wei-Min Dai*a,b
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Center for Cancer Research and Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax +85223581594; E-mail: chdai@ust.hk
Received 17 May 2010
preparation of the C1–C12 (or C1–C9) fragment while
Zhao,2e Loh,2f,g and Paterson2h have accomplished the
synthesis of the C13–C23 fragment. The advanced C7–
C23 fragment 3¢ and the proposed structure of iriomo-
Abstract: Synthesis of the C7–C23 fragment and its 18R,19S-dia-
stereomer of iriomoteolide-1a has been accomplished from the C7–
C12 allyl bromide, the C13–C16 vinyl iodide, and the C17–C23
alkyl iodide fragments. These fragments were assembled first by the
B-alkyl Suzuki–Miyaura cross-coupling to give the C13–C23 inter- teolide-1a were constructed by Horne1c,2d using Sakurai
reaction3 of the allylsilane 4¢,2c B-alkyl Suzuki–Miyaura
mediate. The latter, after being transformed into the C13 aldehyde,
was coupled to the C7–C12 allyl bromide in the presence of indium
powder in THF–H2O (1:1) at 70 °C to the fully functionalized C7–
C23 fragment with orthogonal protecting groups at C19 (PMB
cross-coupling4 of the alkyl iodide 6¢¢, and RCM reaction
at C6–C7 (Scheme 1).
ether), and C9, C14, and C22 (TBS, TES, and TBS ethers, respec-
Me
18
OH
22
OH
tively). Formation of the characteristic six-membered C9/C13-
hemiacetal ring has been demonstrated after global desilylation us-
ing pyridine-buffered HF.
Me
13
16
12
19
O
23
Me
17
O
21
OH
O
7
Me
Me
Key words: allylation, B-alkyl Suzuki–Miyaura cross-coupling,
indium, iriomoteolide, macrolide
9
H
esterification
O
OH
Me
OH Me
1: iriomoteolide-1a
6
CM or RCM
Up to date, three 20-membered iriomoteolide-1a, -1b, and
-1c have been reported.1 These macrolides are produced
by the marine dinoflagellate Amphidinium sp. (HYA024
strain) which was monoclonally separated from sea sand
collected off Iriomote Island, Japan. The structures of iri-
omoteolide-1a (1, Scheme 1)1a,c and -1b have been pro-
posed while the absolute configurations at C22 and C23 of
the side chain of iriomoteolide-1c have not been deter-
mined.1b Both iriomoteolide-1a and -1c share the same
macrolactone core possessing the characteristic C11 exo-
cyclic methylene, six-membered C9/C13-hemiacetal (tet-
rahydropyran) ring, and C2–C3 trisubstituted Z-double
bond,1c in addition to the C14 tertiary alcohol and two E-
endogenous double bonds. Preliminary studies showed
that iriomotolide-1a and -1c exhibited potent cytotoxicity
against human B lymphocyte DG-75 cells (IC50 value of
0.002 mg/mL for both macrolides) and Epstein–Barr virus
(EBV)-infected human B lymphocyte Raji cells (IC50 val-
ues of 0.003–0.004 mg/mL).1 It was suggested that the C9/
C13-hemiacetal ring and/or the C11 exocyclic methylene
are essential for the observed potent cytotoxicity of irio-
moteolide-1a and -1c.1b The intriguing molecular archi-
tecture and potent biological activity of iriomotolide-1a
have attracted considerable attention for its total synthe-
sis.1c,2 Yang,2a Ghosh,2b and Paterson2h have reported the
TBSO
Me
2: C1–C6 fragment
B-alkyl Suzuki–Miyaura
indium-mediated allylation
+
Me
OR4
OR2
Me
12
19R
23
Me
21
16
22
18S
13
17
R1O
O
R3O
Me
9
7
3: R1 = R4 = TBS, R2 TES, R3 = PMB
3': R1 = R3 = TES, R2 = H, R4 = PMB
12
X
Me
18
OR2
OTES
Me
13
TBSO
19
23
Me
I
+
21
+
16
I
22
9
17
R1O
Me
7
RO
4: X = Br
5: R = TES
5': R = PMB
6: R1 = PMB, R2 = TBS
6': R1 = TES, R2 = TBS
6": R1 = TES, R2 = PMB
4': X = TMS
Scheme 1 Retrosynthetic bond disconnections of iriomoteolide-1a
(1) leading to the fragments 2–6 along with some known analogues
Moreover, Xu and Ye’s team has accomplished the core
of 1 via RCM at the C15–C16 E-double bond.2i We envis-
aged synthesis of iriomoteolide-1a from the four small
fragments 2 and 4–6 according to the critical bond discon-
nections shown in Scheme 1. Some related fragments 4¢,2c
5¢,2h 6¢,2h and 6¢¢2d appeared recently in the literature, we
SYNLETT 2010, No. 14, pp 2184–2188
x
x
.x
x
.2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258507; Art ID: W07610ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the C7–C23 Fragment Related to Iriomoteolide-1a
2185
focused on a strategic choice of the orthogonal protecting
groups, which should allow selective release of the C19–
OH at a later stage, and the method/sequence for the frag-
ment assembly. Our strategy is flexible and it allows quick
access to structural analogues. We report here on synthe-
sis of the C7–C23 fragment 3 and its 18R,19S-diaste-
reomer via B-alkyl Suzuki–Miyaura cross-coupling2d,h,4
and the indium-mediated aldehyde allylation,5 which is
the first demonstration in the total synthesis of iriomo-
teolide-1a.
1. Me2CH(OMe)2
PPTS, CH2Cl2
30 °C (94%)
Me
OMe
Me
O Me
HO Me
O
OH
HO
O
2. KOH, MeOH
30 °C (81%)
O
11
10
1. DMP, NaHCO3
CH2Cl2, r.t. (85%)
2. CrCl2, CHI3, THF
0 °C, 1 h; r.t., 2 h
(70%)
Me
1. PPTS, MeOH
45 °C, 16 h
We prepared the allyl bromide 4 from the known aldehyde
72a as shown in Scheme 2. Reaction of 7 with (–)-B-
allyldiisopinocampheylborane6 gave the chiral homoallyl
alcohol 8 in 82% yield. Protection of 8 as the bis-TBS
ether (92%) was followed by selective removal of the pri-
mary TBS group, affording the allyl alcohol 9 (90%).
Treatment of 9 with p-TsCl and Et3N in the presence of
DMAP formed the corresponding tosylate which was
transformed into the allyl bromide 47 (LiBr, refluxing
acetone) in 95% overall yield for the two steps.
Me OTES
Me
O Me
TESO
O
2. TESOTf, 2,6-lutidine
CH2Cl2, 0 °C, 3 h
(84% for 2 steps)
14
I
I
5
12
Scheme 3 Synthesis of the C13–C16 vinyl iodide 5
Paterson2h obtained 14 from the crotylation of acetalde-
hyde with (Z)-crotyldiisopinocamphenylborane. Alterna-
tively, Horne2d synthesized the PMB-protected 14¢¢ from
(3S)-methyl hydroxybutyrate via anti-selective allylation.
In our recent work on total synthesis of marine buteno-
lides,12 we used the THP-protected dithiane 13a obtained
from the syn-selective aldol reaction of acetaldehyde with
the norephedrine-derived chiral propionate.13 We pre-
pared the TBS-protected 13b in the same manner and
found that the minor anti-diastereomer could be separated
by column chromatography. Removal of the dithiane moi-
ety in 13b gave the aldehyde 14 in 88% yield. The latter
was subjected to Wittig olefination with the stabilized
ylide and the resultant a,b-unsaturated ester was reduced
to the allyl alcohol 15 in excellent overall yield. For intro-
ducing 18R,19S-configuration, the epoxide 16 was ob-
tained in 87% yield in a single diastereomer as confirmed
by 1H NMR analysis. Treatment of 16 with
Me2Cu(CN)Li2 in THF at –78 °C gave the 1,3-diol which
was transformed into the cyclic acetal 17 in excellent ste-
reoselectivity and overall yield. After regioselective re-
ductive ring opening of the cyclic acetal the resultant
primary alcohol was converted into the iodide 187 which
is the 18R,19S-diastereomer of 6.
(–)-Ipc2BCH2CH=CH2
Et2O, –78 °C to r.t.
TBSO
CHO
TBSO
NaOH, H2O2
OH
reflux, 1 h (82%)
7
8
1. TBSOTf, 2,6-lutidine
CH2Cl2, r.t., 2 h (92%)
2. AcOH–TBAF (1:1)
r.t., 8 h (90%)
1. p-TsCl, Et3N
DMAP, CH2Cl2
Br
HO
0 °C to r.t. (100%)
2. LiBr, acetone
reflux, 8 h (95%)
OTBS
OTBS
4
9
Scheme 2 Synthesis of the C7–C12 allyl bromide 4
The chiral diol 10 is readily available by using the modi-
fied Sharpless asymmetric dihydroxylation (AD) of the
corresponding para-methoxybenzoate.8 In our previous
total synthesis of amphidinolide X and Y,9 we used 10 and
its antipodal for construction of the stereogenic oxygenat-
ed quaternary carbons at C7 and C18(C19), respectively.
In the current work, we applied this versatile chiral build-
ing block for assembling the vinyl iodide 52d,h possessing
the C14-oxygenated quaternary carbon (Scheme 3). Pro-
tection of the diol 10 as the acetonide followed by alkaline
hydrolysis of the ester produced the alcohol 11 in 76%
overall yield. Oxidation of 11 using Dess–Martin period-
inane (DMP) gave the volatile aldehyde, which was then
subjected to the Takai olefination10 using CrCl2 and CHI3,
affording the vinyl iodide 12 in good overall yield.11 Fi-
nally, the acetonide moiety in 12 was replaced to give the
bis-TES-protected vinyl iodide 52d in 84% overall yield
for the two steps.
With the fragments 4, 5, and 18 in hand, we investigated
the sequence for their assembly (Scheme 5). In order to
minimize protection–deprotection operations at C13, we
first coupled the vinyl iodide 5 with the alkyl iodide 18.
Treatment of 18 with t-BuLi formed the corresponding
alkyllithium, which reacted with MeO-9-BBN to afford
the B-alkyl boronate. The latter was then subjected to the
coupling with the vinyl iodide 5 in the presence of
PdCl2(dppf) (5 mol%), AsPh3, and Cs2CO3 in mixed DMF
and H2O at room temperature to furnish 1914 in 85%
yield.2d,h,4 The C13-TES ether in 19 was selectively
cleaved, and the resultant primary alcohol was oxidized to
20 in 66% overall yield for the two steps. We initially tried
the indium-mediated allylation of the aldehyde 20 with
the allyl bromide 4 at room temperature but no reaction
was detected. We rationalized the failure as the result of
steric hindrance imposed by the bulky substitutions at the
The aldehyde 14 and the related 14¢ and 14¢¢, containing
the syn-aldol moiety, have been reported (Scheme 4). Loh
and Zhao prepared the TBS-protected 142f and the
TBDPS-protected 14¢2e,g from (S)-lactates while
Synlett 2010, No. 14, 2184–2188 © Thieme Stuttgart · New York

2186
Y. Liu et al.
LETTER
OR
OR
Me
Me OTES
TESO
S
18, t-BuLi, THF–Et2O, MeO-9-BBN
–78 °C to r.t.; 5, PdCl2(dppf) (5 mol%)
AsPh3, Cs2CO3, DMF–H2O, r.t., 4 h
MeI, K2CO3
Me
Me
I
OHC
5
MeCN–H2O (10:1)
45 °C, 5 h
S
Me
+
13a: R = THP
13b: R = TBS
(85%)
14: R = TBS
14': R = TBDPS
14": R = PMB
(14, 88%)
Me
OTBS
Me
I
Me
OTBS
Me OTES
1. Ph3P=CHCO2Me
PMBO
Me
19S
TESO
PhMe, reflux (95%)
2. DIBAL-H, CH2Cl2
0 °C, 1 h (98%)
18R
from 14
18
Me
Me
13
PMBO
19
OTBS
Me
OTBS
Ti(Oi-Pr)4
1. PPTS, CH2Cl2–MeOH (3:1)
r.t., 15 min (81%)
L-(+)-DIPT
HO
HO
Me
TBHP, CH2Cl2
–20 °C, 20 h
(87%)
O
2. DMP, NaHCO3, CH2Cl2
r.t., 1 h (82%)
Me
Me
16
15
Me
OTBS
Me OTES
OHC
4, In (1.2 equiv)
19S
1. Me2Cu(CN)Li2, THF
–78 °C to r.t. (98%)
2. p-MeOC6H4CH(OMe)2
PPTS, r.t., 5 h (96%)
22
18R
Me
THF–H2O (1:1)
70 °C, 16 h
PMBO
Me
20
Me
OTBS
Me
OTBS
Me
OTBS
Me
OR
Me
1. DIBAL-H, CH2Cl2
–78 °C to r.t. (96%)
19S
13
Me
I
22
14
18R
Me
O
O
Me
2. I2, Ph3P, imidazole
THF, 0 °C to r.t. (93%)
TBSO
OH
PMBO
Me
PMBO
Me
9
PMP
18
21a: R = TES (57%)
21b: R = H (20%)
17
Scheme 4 Synthesis of the diastereomeric C17–C23 alkyl iodide 18
DMP, NaHCO3
CH2Cl2, r.t., 2 h (61%)
from 21a
a-carbon of the aldehyde. By running the allylation at
70 °C, we were pleased to find that the expected allylation
took place smoothly to give a mixture of two epimers of
the C13-alcohol 21a (57% combined yield) along with a
C14-desilylated diol 21b (20% combined yield of two
epimers). Oxidation of the epimeric 21a using DMP gave
the ketone 22a15 in 61% yield (not optimized). Finally, we
carried out global desilylation of 22a using pyridine-
buffered HF (r.t., 23 h) to form the C9/C13-hemiacetal
2316 (50% yield) along with a partially desilylated com-
pound, the C14-alcohol 22b (9%).
Me
OTBS
OR
Me
19S
18R
13
14
22
Me
TBSO
O
PMBO
Me
HF⋅py
9
(50%)
Me
r.t., 23 h
22a: R = TES
22b: R = H
OH
OH
Me
13
19S
18R
Me
22
OH
O
PMBO
Me
9
H
Finally, we synthesized the C7–C23 ketone fragment 3 of
iriomoteolide-1a (Scheme 6). In order to shorten the reac-
tion sequence an anti-selective aldol reaction of (1R,2S)-
2413 with 14 was performed to give, after LiAlH4 reduc-
tion, the 1,3-diol 25 in 76% overall yield and in an excel-
lent diastereomer ratio. By following the same procedures
used in Scheme 4, the diol 25 was transformed into the
chiral iodide 6.7 The latter was then sequentially assem-
bled with the vinyl iodide 5 and the allyl bromide 4 ac-
cording to the established procedures in Scheme 5,
furnishing the ketone 3.7 Exposure of 3 upon pyridine-
buffered HF at room temperature for about 10 hours gave
a major product, the C9/C13-hemiacetal 27, according to
TLC analysis.17 A minor product of low polarity was also
found and was thought to be a partial desilylation interme-
diate. However, after stirring for 40 hours, the minor prod-
uct increased significantly, and it was tentatively assigned
as the isomerized byproduct 26 (27% yield) by 1H NMR
analysis: (a) disappearance of the two exocyclic methyl-
23
Scheme 5 Synthesis of the C7–C23 ketone fragment 22a and the
corresponding hemiacetal 23
ene protons at C11; and (b) appearance of a new singlet vi-
nyl proton and a new singlet methyl group at d = 6.10 and
2.04 ppm, respectively. Nevertheless, it should be possi-
ble to suppress formation of 26 by controlling the reaction
time. A related hemiacetal was prepared by Horne2d from
the corresponding C9-TES-protected ketone 3¢ (see
Scheme 1). Our results on successful cleavage of the C9-
TBS ether in 22a and 3 using pyridine-buffered HF are
different from those observed in Horne’s model study.2c
Our findings indicate that the C9-TBS-protected ketone 3
is the suitable advanced intermediate which should enable
further manipulation of the functional groups for complet-
ing the total synthesis of iromoteolide-1a.
Synlett 2010, No. 14, 2184–2188 © Thieme Stuttgart · New York

LETTER
Synthesis of the C7–C23 Fragment Related to Iriomoteolide-1a
2187
Masuda, A.; Kitaya, Y.; Omasa, K. J. Org. Chem. 2007, 72,
4469. (b) Tsuda, T.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.;
Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A. J. Nat.
Prod. 2007, 70, 1661. After submission of this
1. c-Hex2BOTf, Et3N
CH2Cl2, –78 °C;
then 14, –78 °C
Ph
Bn
O
Me
OTBS
Me
Me
O
2. LiAlH4, Et2O, 0 °C
(76% for 2 steps;
dr = 97:3)
N
Me
OH OH Me
MesSO2
communication, the proposed structure of iriomoteolide-1a
was confirmed incorrect via total synthesis, see: (c) Xie, J.;
Ma, Y.; Horne, D. A. Chem. Commun. 2010, 46, 4770.
(2) For synthesis of fragments of iriomoteolide-1a, see:
(a) Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4645.
(b) Ghosh, A. K.; Yuan, H. Tetrahedron Lett. 2009, 50,
1416. (c) Xie, J.; Horne, D. A. Tetrahedron Lett. 2009, 50,
4485. (d) Xie, J.; Ma, Y.; Horne, D. A. Org. Lett. 2009, 11,
5082. (e) Ye, Z.; Deng, L.; Qian, S.; Zhao, G. Synlett 2009,
2469. (f) Chin, Y.-J.; Wang, S.-Y.; Loh, T.-P. Org. Lett.
2009, 11, 3674. (g) Wang, S.-Y.; Chin, Y.-J.; Loh, T.-P.
Synthesis 2009, 3557. (h) Paterson, I.; Rubenbauer, P.
Synlett 2010, 571. (i) Li, S.; Chen, Z.; Xu, Z.; Ye, T. Chem.
Commun. 2010, 46, 4773.
25
(1R,2S)-24
see Scheme 4
Me
OTBS
Me
see Scheme 5
I
PMBO
Me
6
Me
OTBS
OTES
Me
19R
13
14
22
18S
Me
TBSO
O
PMBO
Me
9
(3) Hosomi, A.; Sakarai, H. Tetrahedron Lett. 1976, 17, 1295.
(4) For a review on B-alkyl Suzuki–Miyaura coupling, see:
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 4544.
3
HF⋅py, r.t., 40 h
(5) (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53,
1831. (b) Li, C. J.; Chan, T. H. Tetrahedron Lett. 1991, 32,
7017. (c) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999,
121, 3228. (d) Moral, J. A.; Moon, S.-J.; Rodriguez-Torres,
S.; Minehan, T. G. Org. Lett. 2009, 11, 3734.
(6) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
2092. (b) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown,
H. C. J. Org. Chem. 1986, 51, 432. (c) Ramachandran,
P. V. Aldrichimica Acta 2002, 35, 23.
Me
OH
OH
OH
Me
13
Me
13
19R
18S
Me
Me
22
OH
OH
O
O
PMBO
Me
+
9
9
H
H
26 (27%)
27 (41%)
Scheme 6 Synthesis of the C7–C23 ketone fragment 3 and the cor-
responding hemiacetal 27
(7) Full characterization data are found in Supporting
Information.
(8) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem.
Soc. 1995, 117, 10805.
(9) (a) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2006, 1177.
(b) Jin, J.; Chen, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9,
2585. (c) Dai, W.-M.; Chen, Y.; Jin, J.; Wu, J.; Lou, J.; He,
Q. Synlett 2008, 1737.
In summary, we have accomplished synthesis of the C7–
C23 fragment and its 18R,19S-diastereomer of iriomo-
teolide-1a in both forms of the C13-ketone 3/22a and the
C9/C13-hemiacetal 23/27. Our synthesis highlights a se-
quence of B-alkyl Suzuki–Miyaura cross-coupling and in-
dium-mediated aldehyde allylation for formation of the
C16–C17 sp2–sp3 and the C12–C13 sp3–sp3 bonds, re-
spectively. Our work offers the first demonstration of the
indium-mediated aldehyde allylation (70 °C, THF–H2O)
and cleavage of the C9-TBS ether (HF·py, r.t.) in the syn-
thesis of the advanced intermediates related to iriomo-
teolide-1a.
(10) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408.
(11) Due to the volatile nature of the aldehyde obtained from
alcohol 11, lower yields for the Takai olefination were noted
in the scale-up synthesis.
(12) (a) Wang, Y.; Dai, W.-M. Tetrahedron 2010, 66, 187.
(b) Dai, W.-M.; Shi, L.; Li, Y. Tetrahedon: Asymmetry 2008,
19, 1549.
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A. J. Org. Chem. 2002, 67, 5250.
(14) Procedure for the Synthesis of Alkene 19
A flame-dried 50 mL two-neck flask was charged with the
alkyl iodide 18 (680.0 mg, 1.31 mmol). The loaded flask was
evacuated and backfilled with nitrogen for five times. A
solution of 9-MeO-BBN (1 M in hexanes, 5.0 mL, 5.00
mmol) and dry Et2O (12.0 mL) were then added successively
at ambient temperature (about 18 °C). The resultant
colorless solution was cooled to –78 °C and kept at the same
temperature for 5 min. A solution of t-BuLi (1.6 M in
heptane, 2.0 mL, 3.20 mmol) was rapidly added in one
portion at –78 °C. The resultant yellow suspension was
stirred for 10 min at the same temperature. Dry THF (12.0
mL) was added and the mixture turned clear. After stirring
for an additional 10 min, the cold bath was removed
followed by stirring at ambient temperature for 1.5 h to give
a pale yellow homogeneous solution of the B-alkyl boronate.
A separate 50 mL two-neck flask was charged with
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The Laboratory of Asymmetric Catalysis and Synthesis is esta-
blished under the Cheung Kong Scholars Program of The Ministry
of Education of China. This work is supported by Zhejiang Univer-
sity, Zhejiang University Education Foundation, and Department of
Chemistry, HKUST.
References and Notes
(1) For isolation and structures of iriomoteolide-1a, -1b, and -1c,
see: (a) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.;
Kobayashi, J.; Fukushi, E.; Kawabata, J.; Ozawa, T.;
Synlett 2010, No. 14, 2184–2188 © Thieme Stuttgart · New York

2188
Y. Liu et al.
LETTER
PdCl2 (dppf)·CH2Cl2 (40.0 mg, 4.9×10–2 mmol), AsPh3 (44.0
mg, 0.14 mmol), and Cs2CO3 (1.04 g, 3.2 mmol). The loaded
flask was evacuated and backfilled with nitrogen for five
times. A solution of the vinyl iodide 5 (360.0 mg, 0.79
mmol) in degassed DMF (12.0 mL) was added through a
syringe followed by adding degassed H2O (0.36 mL, 20
mmol). Some blocky solid in the resultant yellow suspension
was crushed with ultrasonication. After stirring at ambient
temperature for 5 min, the above solution of the B-alkyl
boronate was added via a syringe followed by stirring for
another 4 h at ambient temperature. The reaction was
quenched with sat. aq NH4Cl solution. The resultant mixture
was extracted with EtOAc (3 × 30 mL). The combined
organic layer was washed with brine, dried over anhyd
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica
gel, first with PE and then with 2% EtOAc in PE) to afford
the coupling product 19 (485.0 mg, 85%).
(m, 2 H), 4.96 (s, 1 H), 4.83 (s, 1 H), 4.48 and 4.33 (ABq,
J = 11.2 Hz, 2 H), 3.82–3.75 (m, 1 H), 3.80 (s, 3 H), 3.71–
3.64 (m, 1 H), 3.43 and 3.38 (ABq, J = 18.0 Hz, 2 H), 3.36–
3.31 (m, 1 H), 2.30–1.49 (m, 10 H), 1.44 (s, 3 H), 1.18 (br
dd, J = 12.4, 11.6 Hz, 1 H), 1.07 (d, J = 6.0 Hz, 3 H), 0.97 (t,
J = 8.4 Hz, 9 H), 0.87–0.84 (m, 21 H), 0.78 (d, J = 6.4 Hz, 3
H), 0.68–0.60 (m, 6 H), 0.05–0.01 (m, 12 H). 13C NMR (100
MHz, CDCl3): d = 210.2, 159.0, 140.8, 135.1, 133.9, 131.2,
130.3, 129.2 (2×), 117.0, 116.5, 113.7 (2×), 82.4, 79.9, 72.6,
71.0, 70.8, 55.3, 43.7, 43.5, 41.8, 36.1 (2×), 35.4, 33.7, 25.9
(6×), 24.4, 20.8, 18.1, 18.1, 14.2, 13.4, 7.1 (3×), 6.6 (3×),
–4.3, –4.5 (2×), –4.8. HRMS (+ESI): m/z [M + Na+] calcd for
C48H88O6Si3Na: 867.5781; found: 867.5781.
(16) Procedure for the Synthesis of Hemiacetal 23
To a solution of the ketone 22a (7.8 mg, 9.2×10–3 mmol) in
dry THF (1.0 mL) was added pyridine-buffered HF (0.15
mL, prepared from 0.5 mL of HF·pyridine, 0.7 mL of
pyridine, and 1.6 mL of THF) at r.t. After stirring at the same
temperature for 1 h, no reaction had taken place according to
TLC analysis. Additional HF·pyridine (0.25 mL) was added
followed by stirring at r.t. for 23 h. The reaction was
quenched by adding sat. aq NaHCO3. The mixture was
extracted with EtOAc (3 × 5 mL). The combined organic
layer was washed with brine, dried over anhyd Na2SO4,
filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica
gel, 33% EtOAc in hexane) to give the hemiacetal 23 (2.3
mg, 50%) along with the hydroxy ketone 22b (0.6 mg, 9%).
Characterization Data for Hemiacetal 23
Characterization Data for Alkene 19
Colorless oil. [a]D20 –18.1 (c 2.50, CHCl3). Rf = 0.21 (100%
PE). 1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 7.6 Hz, 2
H), 6.86 (d, J = 7.6 Hz, 2 H), 5.60 (dt, J = 16.0, 6.4 Hz, 1 H),
5.51 (d, J = 16.0 Hz, 1 H), 4.50 and 4.32 (ABq, J = 11.2 Hz,
2 H), 3.80 (s, 3 H), 3.73–3.64 (m, 1 H), 3.41–3.34 (m, 1 H),
3.37 (s, 2 H), 2.10–1.80 (m, 3 H), 1.71–1.60 (m, 1 H), 1.51
(br dd, J = 12.8, 10.8 Hz, 1 H), 1.28 (s, 3 H), 1.20 (br dd,
J = 12.8, 12.0 Hz, 1 H), 1.07 (d, J = 6.0 Hz, 3 H), 1.00–0.90
(m, 18 H), 0.88 (br s, 12 H), 0.78 (d, J = 6.4 Hz, 3 H), 0.58
(q, J = 8.0 Hz, 12 H), 0.02 (br s, 6 H). 13C NMR (100 MHz,
CDCl3): d = 159.0, 136.7, 131.3, 129.2 (2×), 127.5, 113.6
(2×), 79.7, 75.6, 72.7, 71.4, 70.7, 55.3, 36.3, 36.0, 35.3, 33.6,
25.9 (3×), 24.5, 20.9, 18.1, 14.1, 13.1, 7.1 (3×), 6.8 (3×), 6.7
(3×), 4.4 (3×), –4.3, –4.8. HRMS (+ESI): m/z [M + Na+]
calcd for C40H78O5Si3Na: 745.5049; found: 745.5013.
Pale yellow oil. [a]D20 –17.6 (c 0.23, CHCl3). IR (film):
3459, 2924, 1613, 1514, 1264, 1035 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.25 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8
Hz, 2 H), 5.88–5.70 (m, 3 H), 5.11–5.03 (m, 2 H), 4.87 (d,
J = 2.0 Hz, 1 H), 4.83 (d, J = 2.0 Hz, 1 H), 4.53 and 4.32
(ABq, J = 11.0 Hz, 2 H), 3.95–3.84 (m, 1 H), 3.80 (s, 3 H),
3.79–3.70 (m, 1 H), 3.42–3.33 (m, 1 H), 3.03 (d, J = 1.6 Hz,
1 H), 2.40 (s, 1 H), 2.36–2.20 (m, 4 H), 2.17–1.84 (m, 5 H),
1.71–1.50 (m, 2 H), 1.35–1.17 (m, 2 H), 1.31 (s, 3 H), 1.12
(d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 3 H), 0.83 (d, J = 7.0
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 159.2, 141.5,
134.4, 133.9, 129.5 (2×), 129.3, 117.2, 113.8 (3×), 111.3,
99.2, 80.3, 77.1, 70.8, 70.7, 70.5, 55.3, 40.2, 39.3, 37.8, 36.7,
36.5, 34.9, 32.5, 21.0, 19.6, 14.5, 13.7. MS (+TOF LD):
m/z (%) = 525 (100) [M + Na+], 467 (55) [M+ – H2O – OH].
HRMS (+TOF CI): m/z [M+ – H2O – OH] calcd for
(15) Procedure for the Synthesis of Ketone 22a
A mixture of the allyl bromide 4 (63.0 mg, 0.20 mmol), the
aldehyde 20 (100.0 mg, 0.16 mmol), and indium powder
(24.0 mg, 0.20 mmol) in THF–H2O (1:1, 0.4 mL) was stirred
at 70 °C for 16 h in a sealed pressurized vial. After cooling
to r.t., the reaction mixture was diluted with 10% aq
NaHCO3 (2 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic layer was washed with brine, dried over
anhyd Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column
chromatography (silica gel, 9% EtOAc in hexane) to provide
the alcohol 21a (79.0 mg, 57%) along with the diol 21b (24.2
mg, 20%).
+
C30H43O4 : 467.3161; found: 467.3158.
(17) Characterization Data for Hemiacetal 27
To a suspension of the alcohol 21a (69.0 mg, 8.1×10–2
mmol) and solid NaHCO3 (68.0 mg, 0.81 mmol) in CH2Cl2
(1 mL) cooled at 0 °C was added Dess–Martin periodinane
(0.3 M in CH2Cl2, 0.83 mL, 0.25 mmol) followed by stirring
at 25 °C for 2 h. The reaction was quenched by adding sat.
aq Na2S2O3 and sat. aq. NaHCO3. The resultant mixture was
extracted with EtOAc (3 × 5 mL), and the combined organic
layer was washed with brine, dried over anhyd Na2SO4,
filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica
gel, 9% EtOAc in hexane) to provide the ketone 22a (42.0
mg, 61%).
Pale yellow oil. [a]D20 –2.3 (c 0.28, CHCl3). IR (film): 3445,
2967, 2919, 1613, 1513, 1248, 1036 cm–1. 1H NMR (500
MHz, CDCl3): d = 7.25 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8
Hz, 2 H), 5.85–5.70 (m, 3 H), 5.12–5.03 (m, 2 H), 4.87 (s, 1
H), 4.83 (s, 1 H), 4.47 and 4.38 (ABq, J = 11.5 Hz, 2 H),
3.95–3.85 (m, 1 H), 3.80 (s, 3 H), 3.74–3.66 (m, 1 H), 3.42–
3.35 (m, 1 H), 3.09 (s, 1 H), 2.45 (br s, 1 H), 2.35–2.14 (m,
5 H), 2.07–1.93 (m, 3 H), 1.90 (dd, J = 12.5, 12.5 Hz, 1 H),
1.75–1.60 (m, 2 H), 1.45–1.32 (m, 2 H), 1.29 (s, 3 H), 1.09
(d, J = 7.0 Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H), 0.88 (d, J = 7.0
Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = 159.3, 141.6,
134.4, 133.8, 129.5 (2×), 129.3, 117.1, 113.9, 113.9 (2×),
111.2, 99.2, 80.0, 77.1, 70.7, 70.6, 70.0, 55.3, 40.2, 39.4,
37.9, 36.0, 36.0, 35.0, 32.7, 21.1, 20.1, 14.8, 14.6. HRMS
Characterization Data for Ketone 22a
Colorless oil. [a]D20 +16.4 (c 1.13, CHCl3). IR (film): 2956,
1722, 1514, 1465, 1251, 1083 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.24 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 2
H), 5.87–5.68 (m, 2 H), 5.44 (d, J = 15.2 Hz, 1 H), 5.07–4.99
+
(+TOF EI): m/z [M+] calcd for C30H46O6 : 502.3294; found:
502.3316.
Synlett 2010, No. 14, 2184–2188 © Thieme Stuttgart · New York