Synthesis of two diastereomers of iriomoteolide-1a via a tunable four-module coupling approach using ring-closing metathesis as the key step

Article abstract of DOI:10.1055/s-0030-1260822

A tunable four-module coupling approach has been established for assembling the 20-membered macrolactone core related to the proposed structure of iriomoteolide-1a by using ring-closing metathesis as the key step. Two C1-C6 (2E)-diene acid fragments with (4R,5S)- and (4S,5R)-stereogenic centers, respectively, were synthesized via anti-selective aldol reaction and E-selective conjugate addition of Me₂CuLi with an alkynoic ester in the presence of TMSCl. The ring-closing metathesis reaction was carried out in the presence of 10 mol% Grubbs second-generation initiator at room temperature to give exclusively the (6E)-cycloalkenes. Our four-module coupling strategy enables efficient synthesis of two diastereomers of the proposed iriomoteolide-1a with opposite chirality at C4 and C5. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260822

1774
LETTER
Synthesis of Two Diastereomers of Iriomoteolide-1a via a Tunable Four-
Module Coupling Approach Using Ring-Closing Metathesis as the Key Step
Synthesis of
T
w
o
uiastereome
a
s
of Iriomo
n
teolide-1a xin Liu,a Gaofeng Feng,b Jian Wang,a Jinlong Wu,a 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 24 March 2011
and C19 via B-alkyl Suzuki–Miyaura cross-coupling7 of 5
and 6 followed by indium-mediated allylation of 4 with a
C13–C23 aldehyde.3i The latter provided an alternative to
the Sakurai reaction of allylsilane 4¢ and an analogue used
Abstract: A tunable four-module coupling approach has been es-
tablished for assembling the 20-membered macrolactone core relat-
ed to the proposed structure of iriomoteolide-1a by using ring-
closing metathesis as the key step. Two C1–C6 (2E)-diene acid
fragments with (4R,5S)- and (4S,5R)-stereogenic centers, respec- by Horne3c,d and Ghosh.2c,3b We report here on syntheses
tively, were synthesized via anti-selective aldol reaction and E-se-
lective conjugate addition of Me2CuLi with an alkynoic ester in the
of (2Z)-diene acid 3a (PG = TBS), two enantiomeric
(2E)-diene acids 3b and 3c, and two diastereomers of the
presence of TMSCl. The ring-closing metathesis reaction was car-
proposed iriomoteolide-1a possessing 2E,4R,5S- and
ried out in the presence of 10 mol% Grubbs second-generation ini-
2E,4S,5R-stereochemistry.
tiator at room temperature to give exclusively the (6E)-
cycloalkenes. Our four-module coupling strategy enables efficient
synthesis of two diastereomers of the proposed iriomoteolide-1a
with opposite chirality at C4 and C5.
indium-mediated
allylation
Me
*
6
*
B-alkyl
Suzuki–Miyaura
CO2H
CO2H
Key words: iriomoteolide, macrolide, modular synthesis, ring-
closing metathesis, stereoisomers
TBSO
Me
(4R,5S)-3b
(4S,5R)-3c
Me
OH
Me
OH
16
12
23
19
21
13
22
18
Me
17
or
OH
O
O
O
Me
The structures of three 20-membered ring macrolides, iri-
omoteolide-1a, -1b, and -1c, remain mysterious after sev-
eral total syntheses of the proposed structures 1 and 2 have
been disclosed (Scheme 1).1–3 Horne and coworkers as-
sembled the macrolide 1 from the (2Z)-diene acid 3a¢ and
a C7–C23 fragment3d via ring-closing metathesis (RCM),4
affording a mixture of (6E)- and (6Z)-cycloalkenes in
2.5:1 ratio.2a Alternatively, Xu and Ye’s team utilized
RCM to construct the C15=C16 E-double bond within the
macrolactone core which does not incorporate with the
C9/C13-hemiacetal moiety (tetrahydropyran).2b Yang and
coworkers employed a similar RCM reaction for synthe-
sizing an 18-membered ring diolide intermediate which
was then transformed into the 2E-isomer of 1 by installa-
tion of the C9/C13-hemiacetal subunit via SmI2-mediated
intramolecular reductive addition of an allyl iodide with
an ester functionality.2d Moreover, two diastereomers
with different chirality at C9, C13, C14, C18, C19, and
Me
Me
9
H
6
6
R
5S
4R
5S
ester bond
formation
4R
7
PGO
Me
OH Me
RCM
3a: R = H; 3a': R = Me
iriomoteolide-1a (1)
(proposed structure)
+
PGO
7
X
9
12
4: X = Br; 4': X = TMS
Me
OH
Me
+
OH
16
12
9
OTES
Me
23
21
Me
19
13
18
16
22
Me
17
TESO
I
O
O
O
Me
5
+
Me
HO
6
5S
Me
OTBS
4R
7
23
Me
I
21
19
OH Me
18
22
17
RCM
iriomoteolide-1b (2)
(proposed structure)
TBSO
Me
6
C21 were synthesized, but unfortunately none of them Scheme 1 Four-module coupling approach to stereoisomers of the
proposed iriomoteolide-1a (1) and -1b (2). PG = protecting group
matched with the naturally occurring iromoteolide-1a by
comparison of their NMR spectral data.2d We envisaged a
four-module coupling approach2a,3i,5 toward total synthe-
sis of iromoteolide-1a and -1b using RCM as the key step
(Scheme 1).6 We reported the synthesis of two diastereo-
meric C7–C23 fragments with opposite chirality at C18
Our synthesis of the MOM-protected diene esters (E)-11
and (Z)-11 is illustrated in Scheme 2. An anti-selective al-
dol reaction8 of the chiral propionate (1S,2R)-7 with ac-
rolein afforded, after silylation of the hydroxy group, the
chiral TBS ether 8 in excellent diastereomeric ratio (dr)8
and overall yield. Reduction of 8 using DIBAL-H to the
primary alcohol (91%) was followed by DMP oxidation to
furnish the aldehyde (88%). The latter was then converted
into the 1,1-dibromoalkene 9 in 82% yield. A modified
SYNLETT 2011, No. 12, pp 1774–1778
x
x
.x
x
.2
0
1
1
Advanced online publication: 28.06.2011
DOI: 10.1055/s-0030-1260822; Art ID: W07911ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Two Diastereomers of Iriomoteolide-1a
1775
Corey–Fuchs protocol9 was used to obtain the known The results of conjugate addition of 10b are summarized
alkynoic ester 10a.3b Since 10a could not be separated in Table 1. Reaction of 10b with Me2CuLi in THF at –78
from excess ClCO2Me, it was desilylated using HF·pyri- °C for 6 hours afforded the known diene ester (Z)-11 ex-
dine (THF, r.t.) to give the alcohol 10c. Treatment of 10c clusively in 98% isolated yield (entry 1, Table 1).2a,b,3b
with TBSOTf and 2,6-lutidine afforded pure 10a in 82% Our result is consistent with that reported by Ghosh and
overall yield from 9 (data not shown in Scheme 2). Unfor- Yuan.3b When TMSCl2d was added to the same conjugate
tunately, we found that 10a failed in the conjugate addi- addition at –78 °C followed by warming the reaction mix-
tion with Me2CuLi. Therefore, the known MOM ether ture to 0 °C during 2 hours, an inseparable mixture of (E)-
10b3b was prepared from 10c using MOMCl–i-Pr2NEt in 11 and (Z)-11 was obtained in 91% combined yield and in
92% yield.
75:25 E/Z ratio (entry 2, Table 1). We found that the E/Z
ratio is temperature-dependent and a 60:40 mixture of ent-
(E)-11 and ent-(Z)-11 was generated from the reaction of
ent-10b at 0 °C (entry 3, Table 1).
1. c-Hex2BOTf, Et3N
CH2Cl2, –78 °C;
Ph
O
Ph
O
OTBS
Me
O
Me
Bn
CH2=CHCHO (95%)
O
2. TBSOTf, Et3N
r.t., 1 h (96%)
N
Me
N
Me
(Z)-11
(E)-11
+
(Z)-11
Bn
SO2Mes
SO2Mes
(1S,2R)-7
8
concd HCl–MeOH
(v/v = 1:2.4)
60 °C, 5 h
concd HCl–MeOH
(v/v = 1:4)
(E/Z = 3:1)
60 °C, 5 h (91%)
1. DIBAL-H, –78 °C to r.t. (91%)
2. DMP, NaHCO3, r.t. (88%)
3. CBr4, Ph3P, 0 °C, 10 h (82%)
Me
O
Me
OR
Me
MeO2C
12
+
MeO2C
OR
OTBS
1. n-BuLi, ClCO2Me
–78 °C to r.t.
Me
Br
O
13a: R = H; 13b: R = TBS
12
2. concd HCl–MeOH
Me
Br
Me
(v/v = 1:6.7), r.t.
(10c, 78% from 9)
3. MOMCl, i-Pr2NEt
(10b, 92%)
1. 1 N LiOH, MeOH, r.t.
2. TBSOTf, 2,6-lutidine
–78 °C, 2 h
3. K2CO3, MeOH, r.t.
(78% from 12)
1. TBSOTf, Et3N
10a: R = TBS
10b: R = MOM
10c: R = H
9
[91% from (E)-11]
2. LiOH, MeOH (90%)
Me
OTBS
Me2CuLi
(see Table 1)
HO2C
4R
5S
Me
OTBS
Me
3b
4R
5S
Me
OMOM
Me
OMOM
MeO2C
HO2C
Me
3a
1 N LiOH, MeOH, r.t.;
+
TBSOTf, Et3N, 0 °C, 4 h
12
MeO2C
Me
(Z)-11
Me
(E)-11
(54%)
Scheme 3 Synthesis of (Z)- and (E)-diene acids 3a and 3b
Scheme 2 Synthesis of diene esters (E)-11 and (Z)-11
Scheme 3 outlines the synthesis of the (Z)- and (E)-diene
acids 3a,b. First, the MOM ether in (Z)-11 was cleaved
using methanolic HCl at 60 °C for 5 hours to form the lac-
tone 12 in 91% isolated yield. Hydrolysis of 12 using
aqueous LiOH in MeOH gave the acyclic hydroxy car-
boxylic acid which was then protected as the bis-TBS de-
rivative at –78 °C using 2,6-lutidine as the base. When
Et3N3a was used as the base for the silylation at 0 °C,
isomerization of the Z-double bond occurred to give (2E)-
diene acid 3b10 (Scheme 3) presumably mediated by trace
amount of triflic acid contaminated in TBSOTf. More-
over, the above bis-TBS intermediate was found to be
quite stable, and it could be purified by column chroma-
tography over silica gel. Thus, the crude bis-TBS interme-
diate formed from 12 was treated with K2CO3 in MeOH at
room temperature for 20 minutes to furnish the (2Z)-diene
acid 3a10 in 78% overall yield from 12.
Table 1 Results of Conjugate Addition of Alkynoic Ester 10b
Entry Additive Temp (°C) Time (h) (E)-11/(Z)-11 Yield (%)a
1
–
–78
6
2
2
0:100
75:25
60:40d
98
2
TMSCl
TMSCl
–78 to 0
0
91b
95b
3c
a Isolated yield.
b Combined yield of the inseparable mixture of E- and Z-isomers.
c The enantiomer ent-10b was used.
d The enantiomers ent-(E)-11 and ent-(Z)-11 were obtained.
We found that desilylation of the crude 10a could be con-
veniently achieved using methanolic HCl solution instead
of HF·pyridine in a scale-up operation without causing de-
hydration of 10c. Attempt was made to use 10c directly in
the conjugate addition with Me2CuLi but without success.
By following the same sequence outlined in Scheme 2, the
enantiomer ent-10b was synthesized starting from
(1R,2S)-7.
Alternatively, the (2E)-diene acid 3b could be synthesized
from the mixture of (E)-11 and (Z)-11 as shown in
Scheme 3. Acidic cleavage of the MOM ether in (E)-11
and (Z)-11 formed an inseparable mixture of 12 and the
Synlett 2011, No. 12, 1774–1778 © Thieme Stuttgart · New York

1776
Y. Liu et al.
LETTER
hydroxy ester 13a. The latter was then silylated as the HF·pyridine in THF at room temperature. After 38 hours,
TBS ether 13b, being separable from 12, in 91% yield cal- the starting material was consumed to give the desired C9/
culated from (E)-11. After hydrolysis of the methyl ester C13-hemiacetal 17 in 40% isolated yield along with the
13b, the desired (2E)-diene acid 3b was obtained in 90% C11 double-bond migration and C9 alcohol-dehydration
yield. By following the same procedures, the (2E)-diene byproducts 18 and 1911 in various amounts. Optimization
acid 3c10 was generated from the mixture of ent-(E)-11 on the global desilylation was carried out but formation of
and ent-(Z)-11.
the byproducts could not be eliminated.2c,12 Finally, the
RCM reaction of 17 took place smoothly at room temper-
ature in the presence of 10 mol% Grubbs second-genera-
tion initiator, furnishing the macrolide (2E,4R,5S)-20 in
68% yield as the sole product.13,14 In a preliminary trial,
we found that the RCM reaction of the conjugate ketone
18 proceeded successfully to form the 2E,4R,5S-diastereo-
mer of the proposed iriomoteolide-1b (2). The detail re-
sults will be disclosed in due course after optimization.
We previously reported the synthesis of the advanced C7–
C23 intermediate 14 from three small fragments 4–6.3i
With the enantiomeric (2E)-diene acid 3b and 3c in hand,
we moved forward for synthesis of two new diastereomers
of the proposed iriomoteolide-1a (1). Scheme 4 illustrates
the synthesis of the diastereomer (2E,4R,5S)-20. Thus, the
PMB ether 14 was cleaved with DDQ to form the alcohol
15 (95%), which was condensed with the acid 3b under
the standard Yamaguchi esterification conditions, afford- Synthesis of the macrolide (2E,4S,5R)-23 is depicted in
ing the ester 16 in 93% yield.
Scheme 5. Esterification of the alcohol 15 with the acid 3c
afforded the ester 21 in 93% yield. Global desilylation
transformed 21 into the C9/C11-hemiacetal 22 (37%)
which was then subjected to the RCM reaction to give the
expected macrolide (2E,4S,5R)-23 as the sole product in
Global desilylation was performed according to our previ-
ously established protocol using pyridine-buffered
Me
OTBS
OTES
Me
9
13
19R
14
22
18S
Me
Me
OTBS
Me
OTES
Me
TBSO
O
OR Me
19R
13
9
14
18S
14: R = PMB
15: R = H (95%)
DDQ, pH 7
TBSO
O
OH Me
15
Me
Me
5S
3b, 2,4,6-Cl3C6H2COCl, Et3N, PhMe, r.t.;
then 15, DMAP, r.t., 18 h (93%)
5R
4R
CO2H
3c, 2,4,6-Cl3C6H2COCl, Et3N, PhMe, r.t.;
then 15, DMAP, r.t., 18 h (93%)
4S
CO2H
TBSO
Me
TBSO
Me
3b
Me
OTBS
Me
OTES
Me
3c
Me
OTBS
Me
OTES
Me
13
19R
9
14
18S
13
19R
9
14
18S
O
TBSO
O
O
Me
O
TBSO
O
O
Me
Me
Me
5R
HF⋅py, py, THF
HF⋅py, py, THF
4R
r.t., 38 h
5S
r.t., 37 h
4S
Me
Me
TBSO
TBSO
16
Me
OH
OH
Me
14
21
Me
OH
OH
Me
19R
14
18S
Me
19R
13
OH
OH
18S
Me
13
Me
13
O
O
O
Me
OH
9
O
O
O
Me
9
14
H
9
Me
+
+
H
OH
Me
18
O
Me
+
byproducts
4R
5S
4S
Me
5R
OH
Me
Me
OH
N
13
14
OH
N
17 (40%)
9
22 (37%)
Me
19
O
N
Mes
Mes
Me
OH
Me
N
Me
OH
Me
Me
14
Me
OH
OH
OH
OH
Mes
Mes
Cl
14
Ru
19R
19R
Cl
Cl
18S
18S
13
13
Ru
Ph
PCy3
(10 mol%)
Cl
O
O
O
O
Me
Ph
O
O
Me
PCy3
(10 mol%)
9
9
H
H
CH2Cl2, r.t., 1.5 h
(68%)
Me
Me
5R
CH2Cl2, r.t., 4 h
(71%)
4R
4S
5S
Me
Me
OH
OH
(2E,4R,5S)-20
(2E,4S,5R)-23
Scheme 4 Synthesis of the diastereomer (2E,4R,5S)-20
Scheme 5 Synthesis of the diastereomer (2E,4S,5R)-23
Synlett 2011, No. 12, 1774–1778 © Thieme Stuttgart · New York

LETTER
Synthesis of Two Diastereomers of Iriomoteolide-1a
1777
(4) For our three-module coupling approach in the synthesis of
butenoilde stereomers, see: (a) Dai, W.-M.; Shi, L.; Li, Y.
Tetrahedron: Asymmetry 2008, 19, 1549. (b) Wang, Y.;
Dai, W.-M. Tetrahedron 2010, 66, 187.
(5) For selected reviews on use of RCM in total synthesis, see:
(a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4490. (b) Gradillas, A.; Pérez-Castells, J.
Angew. Chem. Int. Ed. 2006, 45, 6086. (c) Hoveyda, A. H.;
Malcolmson, S. J.; Meek, S. J.; Zhugralin, A. R. Angew.
Chem. Int. Ed. 2010, 49, 34.
(6) For our previous total synthesis using RCM strategy, see:
(a) Jin, J.; Chen, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9,
2585. (b) Dai, W.-M.; Chen, Y.; Jin, J.; Wu, J.; Lou, J.; He,
Q. Synlett 2008, 1737. (c) Sun, L.; Feng, G.; Guan, Y.; Liu,
Y.; Wu, J.; Dai, W.-M. Synlett 2009, 2361. (d) Li, H.; Wu,
J.; Luo, J.; Dai, W.-M. Chem. Eur. J. 2010, 16, 11530.
(e) Wu, D.; Li, H.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2011,
895.
71% yield. As compared to the seco-substrate 17, the
RCM reaction of 22 required a longer reaction time (4 h
vs. 1.5 h), suggesting that the macrolide (2E,4S,5R)-23
should have higher ring strain than (2E,4R,5S)-20.
In summary, we have demonstrated that our tunable four-
module coupling approach provides an efficient access to
the 20-membered ring macrolide related to the proposed
structure of iriomoteolide-1a. Although our two synthe-
sized diastereomers (2E,4R,5S)-20 and (2E,4S,5R)-23 do
not match with the naturally occurring iriomoteolide-1a,
our work concurs with the early report2a for using RCM
reaction to construct the 20-membered ring macrolide
core with spontaneous formation of the 6E-double bond.
Moreover, the flexibility provided by our modular-cou-
pling strategy allows us accessing other diastereomers
from the 18R,19S-C7–C23 fragment3i and various diene
acids such as 3a–c in a collective effort with other labora-
tories to reveal the mysterious structure of the biologically
potent natural iriomoteolide-1a. Detail of these results
will be reported in due course.
(7) 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.
(8) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. (b) Inoue, T.; Liu, J.-F.; Buske, D.; Abiko,
A. J. Org. Chem. 2002, 67, 5250.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(10) Characterization Data for (2Z,4R,5S)-Diene Acid 3a
A pale yellow oil. [a]D20 –72.2 (c 2.85, CHCl3). Rf = 0.28
(17% EtOAc–PE). IR (film): 2957, 2925, 2858, 1695, 1632,
1254, 1184, 1084 cm–1. 1H NMR (400 MHz, CDCl3):
d = 5.78 (d, J = 0.8 Hz, 1 H), 5.74 (ddd, J = 17.6, 10.0, 7.0
Hz, 1 H), 5.20–5.14 (m, 2 H), 4.03 (dd, J = 7.6, 7.6, 1 H),
3.65 (quin, J = 7.2 Hz, 1 H), 1.84 (d, J = 1.2 Hz, 3 H), 0.97
(d, J = 6.8 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.03 (s, 3 H);
CO2H not observed. 13C NMR (100 MHz, CDCl3):
d = 169.5, 159.4, 139.4, 119.2, 116.6, 77.2, 41.2, 25.7 (3×),
20.4, 18.2, 14.7, –4.1, –5.0. HRMS (+TOF EI): m/z [M+]
calcd for C15H28O3Si: 284.1808; found: 284.1812.
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 The National Na-
tural Science Foundation of China (grant no. 21072165), Zhejiang
University, Zhejiang University Education Foundation, and Depart-
ment of Chemistry, HKUST.
Characterization Data for (2E,4R,5S)-Diene Acid 3b
A pale yellow oil. [a]D20 –5.3 (c 3.90, CHCl3). Rf = 0.26
(17% EtOAc–PE). IR (film): 2958, 2925, 2858, 1693, 1643,
1253, 1087 cm–1. 1H NMR (500 MHz, CDCl3): d = 5.73 (s,
1 H), 5.69 (ddd, J = 17.5, 10.0, 7.0 Hz, 1 H), 5.15 (d, J = 17.5
Hz, 1 H), 5.12 (d, J = 11.0 Hz, 1 H), 4.04 (dd, J = 7.0, 7.0
Hz, 1 H), 2.33 (quin, J = 7.0 Hz, 1 H), 2.17 (s, 3 H), 1.00 (d,
J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H);
CO2H not observed. 13C NMR (125 MHz, CDCl3):
d = 172.3, 164.8, 139.5, 116.6, 116.0, 76.9, 50.6, 25.7 (3×),
18.1, 17.4, 14.9, –4.1, –5.1. HRMS (+TOF EI): m/z [M+]
calcd for C15H28O3Si: 284.1808; found: 284.1812.
References and Notes
(1) For isolation and proposed 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.; 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.
(2) For total synthesis of the proposed structures and stereomers
of iriomoteolide-1a and -1b, see: (a) Xie, J.; Ma, Y.; Horne,
D. A. Chem. Commun. 2010, 46, 4770. (b) Li, S.; Chen, Z.;
Xu, Z.; Ye, T. Chem. Commun. 2010, 46, 4773. (c) Ghosh,
A. K.; Yuan, H. Org. Lett. 2010, 12, 3120. (d) Fang, L.;
Yang, J.; Yang, F. Org. Lett. 2010, 12, 3124.
(3) 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) Liu, Y.; Wang, J.; Li, H.; Wu, J.; Feng,
G.; Dai, W.-M. Synlett 2010, 2184.
Characterization Data for (2E,4S,5R)-Diene Acid 3c
A pale yellow oil. [a]D20 +4.5 (c 1.65, CHCl3). Other
spectroscopic data are identical to those of 3b.
(11) We obtained an analogous byproduct to 19 from global
desilylation of 14 in 27% yield but its structure (compound
26 in Scheme 6 in ref. 3i) was wrongly assigned due to error
in its 1H NMR analysis. A corrected structure based on the
newly obtained 1H NMR and other spectroscopic data is
found in Supporting Information of this article.
(12) Desilylation of an analogous substrate to 14 under the
pyridine-buffered HF·pyridine conditions was reported in
ref. 3d without migration of the C11 double bond.
(13) Representative Procedure for the RCM Reaction
To a stirred solution of 17 (13.8 mg, 2.6×10–2 mmol) in dry
CH2Cl2 (25 mL) at r.t. was added Grubbs second-generation
initiator (2.4 mg, 2.8×10–3 mmol) followed by stirring at the
same temperature for 1.5 h. The reaction mixture was
condensed under reduced pressure, and the residue was
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Y. Liu et al.
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purified by flash column (silica gel, 35–45% EtOAc in PE) to
afford (2E,4R,5S)-20 (8.9 mg, 68%).
Characterization Data for (2E,4R,5S)-20
m/z [M+] calcd for C29H46O7: 506.3244; found: 506.3235.
For 1H NMR and 13C NMR, see Supporting Information.
(14) Yang and co-workers reported in ref. 2d that (2E,4R,5S)-20
exits as a 5:1 equilibrating mixture with its keto form in
CDCl3. However, we did not observe this phenomenon for
our sample. For comparison of the 1H NMR and 13C NMR
spectra, see Figures S1 and S2 of Supporting Information.
The 13C NMR signal for the hemiacetal carbon (C13) of their
sample is observed at d = 96.8 ppm as compared with 99.7
(natural iriomoteolide-1a), 99.5 (our sample 20), and 99.7
(our sample 23) ppm, suggesting that their sample might be
a 13R-epimer.
A pale yellow oil. [a]D20 +9.5 (c 0.16, CHCl3); Rf = 0.39
(60% EtOAc–PE). IR (film): 3444 (br), 2969, 2936, 1693,
1651, 1455, 1372, 1218, 1009 cm–1. HRMS (+TOF ESI):
m/z [M + Na+] calcd for C29H46O7Na: 529.3141; found:
529.3141. For 1H NMR and 13C NMR spectra, see in
Supporting Information.
Characterization Data for (2E,4S,5R)-23
A pale yellow oil. [a]D20 –24.7 (c 1.33, CHCl3); Rf = 0.39
(60% EtOAc–PE). IR (film): 3446 (br), 2926, 1688, 1635,
1456, 1372, 1232, 1163, 1009 cm–1. HRMS (+TOF EI):
Synlett 2011, No. 12, 1774–1778 © Thieme Stuttgart · New York

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