Asymmetric total synthesis of (+)-brefeldin A: Intramolecular epoxide-opening/RCM strategy

Article abstract of DOI:10.1055/s-0029-1216723

A highly efficient asymmetric total synthesis of (+)-brefeldin A was accomplished by using intramolecular epoxide opening of an epoxy allylsilane and RCM reaction for the constructions of the cyclopentane and macrocyclic lactone rings of (+)-brefeldin A,

Full text of DOI:10.1055/s-0029-1216723

LETTER
1303
Asymmetric Total Synthesis of (+)-Brefeldin A: Intramolecular Epoxide-
Opening/RCM Strategy
Asymmetric
T
otal Syn
y
thesis of (+)-
u
B
refeldin Ang-Yeol Kim, Hyemi Kim, Jinsung Tae*
Department of Chemistry and Center for Bioactive Molecular Hybrids (CBMH), Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received 6 February 2009
OH
OTBS
Abstract: A highly efficient asymmetric total synthesis of (+)-
brefeldin A was accomplished by using intramolecular epoxide
opening of an epoxy allylsilane and RCM reaction for the construc-
tions of the cyclopentane and macrocyclic lactone rings of (+)-
brefeldin A, respectively.
H
H
H
H
O
O
HO
PMPO
O
O
RCM
2
Key words: (+)-brefeldin A, cyclizations, epoxides, metathesis,
(+)-brefeldin A (1)
total synthesis
LA
O
O
H
O
Li
PMPO
PMPO
Since the structural establishment of (+)-brefeldin A1
(BFA, 1) in 1971,2 it has been an active synthetic target for
several decades.3 The bicyclic structure of BFA possesses
a cyclopentane and a 13-membered macrolactone rings.
Synthetic approaches for BFA are mainly focused on the
stereoselective construction of the cyclopentane ring sys-
tem possessing three stereogenic centers and the efficient
synthesis of the macrocyclic lactone ring. Although nu-
merous synthetic methods for the stereoselective con-
struction of the cyclopentane ring have been reported,
development of more efficient asymmetric methods is
still required. The macrocyclic lactone ring system of BFA
was typically synthesized by using macro-lacto-
nization3a,d,e,h,i and intramolecular Horner–Wadsworth–
Emmons (HWE) olefination methods.3c,j And intramolec-
ular nitrile oxide cycloaddition strategy has also been de-
veloped.3f,g Two ring-closing metathesis (RCM)4
approaches have been reported for the synthesis of the
macrolactone derivatives of BFA. For example, an inter-
molecular nitrile oxide cycloaddition/RCM strategy3g and
an RCM-mediated synthesis of 12-membered b-keto lac-
tone analogue of BFA3b have been reported. However, the
RCM reaction of trans-alkenoic ester-tethered dienes (2
in Scheme 1) has not been examined up to now. Herein,
we report a concise asymmetric total synthesis of BFA
based on an intramolecular epoxide-opening/RCM strate-
gy.
+
O
H
SiMe3
5
3
4
Scheme 1 Retrosynthetic analysis of (+)-brefeldin A (1)
Allylsilane 5 was prepared from the known epoxy alcohol
(–)-6 that we have synthesized previously6,7 by using
Jacobsen’s hydrolytic kinetic resolution (HKR) method.8
Cross-metathesis9 of
6 with four equivalents of
allylsilane10 catalyzed by the Grubbs second-generation
catalyst (7) in refluxing dichloromethane followed by
Mitsunobu inversion of the secondary alcohol by 4-
MeOC6H4OH generated the epoxy allylsilane 5 efficiently
(Scheme 2).
With the compound 5 in hand, we then attempted Lewis
acid mediated intramolecular epoxide-opening reaction of
the epoxy allylsilane11 to yield the cyclopentane structure
of BFA.12 When the cyclization reaction was conducted
using TiCl4, cis isomer was formed as the major product
(see Table 1, entries 4 and 5). And SnCl4-mediated cy-
clization produced only ca. 1:1 mixture of cis and trans
products (see Table 1, entries 6 and 7). The production of
the required trans cyclopentane 8 was optimized using
BF3·OEt2 in toluene solution (see Table 1, entries 2 and 3).
Under the slow addition conditions of BF3·OEt2, the trans
cyclopentane 8 was produced in ca. 7.3:1 (trans/cis) ratio
as shown in entry 3 in Table 1. The relative stereochemis-
tries of 8 was confirmed by comparisons of NMR data and
optical rotation value of the known compound 9,3b which
was synthesized from 8 in four steps (Scheme 3).
We have devised an intramolecular cyclization strategy
for the stereoselective synthesis of the five-membered
ring of BFA using the epoxy allylsilane 5 (Scheme 1).
Then the 13-membered macrocyclic lactone could be syn-
thesized from 2 by using RCM-mediated macrocycliza-
tion method.5 Compound 2 could be readily prepared
from 3 and 4 as shown in Scheme 1.
After setting up the proper stereochemistries of the cyclo-
pentane ring of BFA, we then elaborated the alcohol 8 to
the RCM substrate 2. The required compound 11 was pre-
pared from commercially available epoxide 10 in two
steps.13 Thus, reaction of 10 with H2C=CHCH2CH2MgBr
in the presence of Cu(I) catalyst followed by DCC cou-
SYNLETT 2009, No. 8, pp 1303–1306
x
x.
x
x.
2
0
0
9
Advanced online publication: 17.04.2009
DOI: 10.1055/s-0029-1216723; Art ID: U01309ST
© Georg Thieme Verlag Stuttgart · New York

1304
M.-Y. Kim et al.
LETTER
N
N
Mes
Cl
Mes
1.
7 (10 mol%)
Ph
Ru
Cl
PCy3
CH2Cl2 (0.01 M), reflux
SiMe3
(59%)
O
OH
O
PMPO
(4 equiv)
6
SiMe3
5
4-MeOC6H4OH
2.
ref. 6
Ph3P, DIAD, THF
(73%)
Scheme 2 Synthesis of epoxy allylsilane 5
Table 1 Lewis Acid Mediated Intramolecular Epoxide Opening of 5
OH
H
Lewis acid
PMPO
diastereoisomeric
center
5
H
8
Entry
1
Lewis acid
Solvent
CH2Cl2
Conditions
Yield (%)a
33
cis/transb
BF3·OEt2 (2 equiv)
BF3·OEt2 (2 equiv)
BF3·OEt2 (2 equiv)
TiCl4 (1 equiv)
0.05 M
–78 °C, 1 h
51:49
25:75
12:88
83:17
78:22
51:49
52:48
2
3c
4
5
6
7
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
0.05 M
–78 °C, 1 h
49
72
86
63
55
55
0.005 M
–78 °C, 2 h
0.05 M
–78 °C, 1 h
TiCl4 (1 equiv)
0.05 M
–78 °C, 1 h
SnCl4 (1 equiv)
SnCl4 (1 equiv)
0.005 M
–78 °C to 0 °C, 2 h
0.005 M
–78 °C to 0 °C, 2 h
a Cyclization total yields (cis + trans).
b Ratios were determined by HPLC.
c Lewis acid was added slowly over 2 h.
OH
H
as an inseparable diastereomeric mixture (dr ca. 1:1).
1. CAN, MeCN–H2O (85%)
2. TBDMSCl, Imidazole
DMF (42%)
Next, trans-selective conjugate hydride addition on the g-
15
16
hydroxy-a,b-alkynoic esters using LiAlH4 or NaBH4
MOMO
25
8
as the hydride source was examined. Conjugate hydride
additions to 12 using LiAlH4 (50%) and NaBH4 (65%)
yielded the trans-alkenoic esters 13. The resulting alco-
hols were protected with TBSOTf to give the dienes 2 and
4-epi-2 (Scheme 4).
3. MOMCl, i-Pr2NEt
CH2Cl2 (88%)
4. TBAF, THF (85%)
H
9
[α]
[α]
= –45 (c 0.001, CHCl3)
D
25
D
= –39 (c 0.001, CHCl3)
Next, we attempted ring-closing metathesis to construct
the macrocyclic lactone ring. While the RCM reaction of
alcohols 13 proved to be unsatisfactory, the TBS-protect-
ed substrates 2 and 4-epi-2 yielded the desired macro-
cyclic lactones in 81% yield when the reaction was
catalyzed by 7 in refluxing dichloromethane solution
(Scheme 5). After deprotection of the TBS group, two dia-
stereomers were readily separated to give 14 and 4-epi-14
Scheme 3 Confirmation of relative stereochemistries of 8
pling of the resulting alcohol with propynoic acid6c,14
yielded 11 (Scheme 4).
The alcohol 8 was oxidized under Swern oxidation condi-
tions to give aldehyde 3 which was immediately coupled
with the lithium anion 4 derived from 11 at low tempera-
ture. The g-hydroxy-a,b-alkynoic ester 12 was obtained
Synlett 2009, No. 8, 1303–1306 © Thieme Stuttgart · New York

LETTER
Asymmetric Total Synthesis of (+)-Brefeldin A
1305
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
O
O
CO2H
MgBr
CuCN, THF
–78 °C to r.t.
(89%)
DCC, cat. DMAP
O
CH2Cl2 (1 M)
–20 °C to r.t., 4 h
(65%)
Acknowledgment
10
11
This work was supported by the Center for Bioactive Molecular
Hybrids (CBMH).
(COCl)2, DMSO
Et3N, CH2Cl2
1.
OH
H
O
NaBH4
THF
References and Notes
–78 °C to r.t. (94%)
PMPO
O
8
(1) Singleton, V. L.; Bohonos, N.; Ullstrup, A. J. Nature
(London) 1958, 181, 1072.
(2) Weber, H. P.; Hauser, D.; Sigg, H. P. Helv. Chim. Acta 1971,
–30 to 0 °C
(65%)
2.
11, n-BuLi
H
THF–HMPA (6:1)
–78 °C (55%)
12 (dr ~ 1:1)
54, 2763.
(3) For the representative recent syntheses of BFA and related
references, see the following references: (a) Wu, Y.; Gao, J.
Org. Lett. 2008, 10, 1533. (b) Lin, W.; Zercher, C. K.
J. Org. Chem. 2007, 72, 4390. (c) Seo, S.-Y.; Jung, J.-K.;
Paek, S.-M.; Lee, Y.-S.; Kim, S.-H.; Suh, Y.-G. Tetrahedron
Lett. 2006, 47, 6527. (d) Wu, Y.-K.; Shen, X.; Yang, Y.-Q.;
Hu, Q.; Huang, J.-H. J. Org. Chem. 2004, 69, 3857. (e)Wu,
Y.-K.; Shen, X.; Yang, Y.-Q.; Hu, Q.; Huang, J.-H.
Tetrahedron Lett. 2004, 45, 199. (f) Kim, D.; Lee, J.; Shim,
P. J.; Lim, J. I.; Jo, H.; Kim, S. J. Org. Chem. 2002, 67, 764.
(g) Kim, D.; Lee, J.; Shim, P. J.; Lim, J. I.; Doi, T.; Kim, S.
J. Org. Chem. 2002, 67, 772. (h) Suh, Y. G.; Jung, J.-K.;
Seo, S.-Y.; Min, K.-H.; Shin, D.-Y.; Lee, Y.-S.; Kim, S.-H.;
Park, H.-J. J. Org. Chem. 2002, 67, 4127. (i) Trost, B. M.;
Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328.
(j) Wang, Y.; Romo, D. Org. Lett. 2002, 4, 3231. See also
the following pioneering works on brefeldin A synthesis:
(k) Corey, E. J.; Wollenberg, R. H. Tetrahedron Lett. 1976,
4705. (l) Bartlett, P. A.; Green, F. R. J. Am. Chem. Soc.
1978, 100, 4858. (m) Baudouy, R.; Crabbé, P.; Greene, A.
E.; Le Drian, C.; Orr, A. F. Tetrahedron Lett. 1977, 2973.
(n) Kitahara, T.; Mori, K.; Matsui, M. Tetrahedron Lett.
1979, 3021.
OH
H
O
TBSOTf
PMPO
O
2,6-lutidine
CH2Cl2
H
OTBS
H
(90%)
13
O
O
PMPO
H
2 + 4-epi-2
Scheme 4 Synthesis of RCM precursor 2
in ca. 1:1 ratio.17 The 4-epi-14 was converted into 14 in
two steps by Mitsunobu inversion using 4-O2NC6H4CO2H
followed by hydrolysis.3j Finally, deprotection of the p-
methoxyphenyl (PMP) group using ceric ammonium
nitrate (CAN) in aqueous acetonitrile solution completed
the total synthesis of (+)-brefeldin A {[a]22 +86.6 (c =
D
0.9, MeOH)}.
(4) For recent reviews on olefin metathesis, see: (a) Diver,
S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317.
(b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4490.
1. 4-O2NC6H4CO2H
DIAD, Ph3P, THF (78%)
2. K2CO3, MeOH–H2O
0 °C (90%)
(5) Gradillas, A.; Perez-Castells, J. Angew. Chem. Int. Ed. 2006,
1. 7 (10 mol%)
45, 6086.
OH
CH2Cl2
H
(6) (a) Kim, Y.-J.; Tae, J. Synlett 2006, 61. (b) Lee, J.; Jung,
Y.-H.; Tae, J. Bull. Korean Chem. Soc. 2007, 28, 513.
(c) Jung, Y.-H.; Lee, J.; Tae, J. Chem. Asian J. 2007, 2, 656.
(7) For an asymmetric desymmetrization method, see: Li, Z.;
Zhanh, W.; Yamamoto, H. Angew. Chem. Int. Ed. 2008, 47,
7520.
(8) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen,
E. N. Science 1997, 277, 936. (b) Brandes, B. D.; Jacobsen,
E. N. Tetrahedron: Asymmetry 1997, 8, 3927.
(0.001 M)
reflux (81%)
O
4
4-epi-14
PMPO
+
2 + 4-epi-2
O
2.
TBAF
THF (78%)
H
14
CAN
MeCN–H2O
(4:1)
(84%)
(9) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42,
1900.
(+)-brefeldin A (1)
Scheme 5 Completion of total synthesis of (+)-brefeldin A (1)
(10) (a) Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5,
4891. (b) Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E.
Org. Lett. 2001, 3, 2209. (c) Taylor, R. E.; Engelhardt,
C. E.; Schmitt, M. J.; Yuan, H. J. Am. Chem. Soc. 2001, 123,
2964.
(11) (a) Molander, G. A.; Andrews, S. W. J. Org. Chem. 1989,
54, 3114. (b) Procter, G.; Russell, A. T.; Murphy, P. J.; Tan,
T. S.; Mather, A. N. Tetrahedron 1988, 44, 3953.
(12) For the synthesis of BFA by intramolecular cyclization
reactions using allylsilanes, see: (a) Epoxide opening:
Hatakeyama, S.; Sugawara, K.; Kawamura, M.; Takano, S.
Synlett 1990, 691. (b) b-Lactone opening: ref 3j
In summary, we have completed the asymmetric total syn-
thesis of (+)-brefeldin A starting from the known epoxy
alcohol 6 in ten steps.18 The cyclopentane ring of BFA
was constructed using intramolecular cyclization of an
epoxy allylsilane 5 and the macrocyclic lactone was syn-
thesized by RCM reaction. This asymmetric total synthe-
sis of BFA is highly efficient and one of the most concise
synthetic routes reported up to date.
Synlett 2009, No. 8, 1303–1306 © Thieme Stuttgart · New York

1306
M.-Y. Kim et al.
LETTER
(13) (a) Jastrzebska, I.; Scaglione, J. B.; DeKoster, G. T.; Rath,
N. P.; Covey, D. F. J. Org. Chem. 2007, 72, 4837.
(b) Fürstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett.
2001, 3, 449. (c) Takahata, H.; Yotsui, Y.; Momose, T.
Tetrahedron 1998, 54, 13505.
(14) (a) Rao, K. S.; Mukkanti, K.; Reddy, D. S.; Pla, M.; Iqbal, J.
Tetrahedron Lett. 2005, 46, 2287. (b) Meta, C. T.; Koide,
K. Org. Lett. 2004, 6, 1785. (c) Zhu, G.; Lu, X.
14: mp 178–179 °C; Rf 0.26 (hexane–EtOAc, 2:1); [a]20
D
+42.6 (c 0.9, CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.38
(dd, J = 15.7, 3.2 Hz, 1 H), 6.81 (m, 4 H), 5.91 (dd, J = 15.6,
1.8 Hz, 1 H), 5.70 (ddt, J = 16.4, 11.4, 5.8 Hz, 1 H), 5.29 (dd,
J = 15.2, 9.2 Hz, 1 H), 4.81–4.91 (m, 1 H), 4.63–4.71 (m, 1
H), 4.10–4.18 (m, 1 H), 3.76 (s, 3 H), 2.25–2.48 (m, 3 H),
2.00 (q, J = 9.3 Hz, 2 H), 1.80–1.91 (m, 2 H), 1.70–1.80 (m,
3 H), 1.63–1.70 (m, 1 H), 1.47–1.55 (m, 1 H), 1.26 (d, J =
6.2 Hz, 3 H), 0.90–1.00 (m, 1 H). 13C NMR (100 MHz,
CDCl3): d = 166.31, 154.02, 151.69, 136.72, 130.67, 117.76,
116.94, 114.81, 78.49, 76.39, 71.89, 55.90, 52.60, 44.50,
40.31, 39.00, 34.33, 31.93, 26.85, 21.01. IR (film, neat):
3496, 2925, 2851, 1709, 1681, 1506, 1443, 1377, 1268,
1227, 1032, 969, 824 cm–1. HRMS: m/z [M]+ calcd for
C23H30O5: 386.2093; found: 386.2090.
4-epi-14: mp 105–106 °C; Rf 0.31 (hexane–EtOAc, 2:1);
[a]20D +40.3 (c 0.65, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 7.10 (dd, J = 15.6, 8.4 Hz, 1 H), 6.81 (s, 4 H), 5.78 (d,
J = 16.0 Hz, 1 H), 5.66 (ddt, J = 14.9, 10.2, 4.6 Hz, 1 H), 5.28
(dd, J = 14.9, 9.6 Hz, 1 H), 4.89–4.99 (m, 1 H), 4.63–4.70
(m, 1 H), 4.42–4.48 (m, 1 H), 3.76 (s, 3 H), 2.86 (q, J = 4.8
Hz, 1 H), 2.18–2.28 (m, 1 H), 2.11–2.18 (m, 1 H), 2.02–2.11
(m, 1 H), 1.92–2.02 (m, 2 H), 1.75–1.87 (m, 2 H), 1.61–1.75
(m, 3 H), 1.48–1.53 (m, 1 H), 1.26 (d, J = 6.4 Hz, 3 H), 0.89–
1.00 (m, 1 H). 13C NMR (100 MHz, CDCl3): d = 166.43,
153.91, 151.97, 151.09, 137.78, 130.17, 119.89, 116.89,
114.80, 79.08, 72.04, 71.91, 55.87, 50.24, 40.33, 39.72,
35.63, 34.58, 32.01, 26.51, 20.93. IR (film, neat): 3475,
2929, 2846, 2364, 1714, 1506, 1457, 1355, 1260, 1228,
1038, 974, 825 cm–1. HRMS: m/z [M]+ calcd for C23H30O5:
386.2093; found: 386.2090.
Synthesis of (+)-Brefeldin A (1): To a solution of 14 (8 mg,
0.02 mmol) in MeCN–H2O (4:1, 0.2 mL) was added CAN
(ceric ammonium nitrate; 22 mg, 0.040 mmol) in MeCN–
H2O (4:1, 0.1 mL) at 0 °C. The reaction mixture was warmed
to r.t. and stirred for 1 h. A solution of sat. aq NH4Cl (2.5
mL) was added. The layers were separated and the aqueous
layer was extracted with EtOAc (2 × 10 mL). The combined
organic layers were dried over MgSO4, filtered, concentrated
in vacuo, and the residue was purified by silica gel chroma-
tography (CH2Cl2–MeOH, 20:1) to give 1 (4.8 mg, 84%) as
a white solid; mp 202–204 °C; Rf 0.23 (CH2Cl2–MeOH,
10:1); [a]22D +86.6 (c 0.9, MeOH). 1H NMR (400 MHz,
CD3OD): d = 7.49 (dd, J = 15.6, 3.0 Hz, 1 H), 5.85 (dd, J =
15.6, 1.9 Hz, 1 H), 5.79 (ddd, J = 15.2, 10.2, 4.7 Hz, 1 H),
5.20 (dd, J = 15.0, 9.6 Hz, 1 H), 4.75–4.83 (m, 1 H), 4.18–
4.25 (m, 1 H), 4.01–4.07 (m, 1 H), 2.39 (q, J = 8.7 Hz, 1 H),
2.12 (ddd, J = 13.6, 8.6, 5.4 Hz, 1 H), 1.96–2.06 (m, 3 H),
1.72–1.92 (m, 6 H), 1.52–1.63 (m, 2 H), 1.40–1.48 (m, 1 H),
1.27 (d, J = 6.3 Hz, 3 H), 0.85–1.00 (m, 1 H). 13C NMR (100
MHz, CD3OD): d = 168.38, 155.12, 138.13, 131.41, 117.78,
76.63, 73.21, 72.98, 53.18, 45.46, 44.09, 41.85, 34.99,
32.97, 28.01, 21.06. IR (film, neat): 3364, 2972, 2927, 2857,
1715, 1442, 1255, 1111, 1077, 1000, 975 cm–1. HRMS: m/z
[M]+ calcd for C16H24O4: 280.1675; found: 280.1681.
Tetrahedron: Asymmetry 1995, 6, 1657.
(15) Rao, K. S.; Mukkanti, K.; Reddy, D. S.; Pal, M.; Iqbal, J.
Tetrahedron Lett. 2005, 46, 2287.
(16) Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785.
(17) We were not able to isolate the minor Z-isomers. Only
E-isomers were isolated after column chromatography.
(18) Lewis Acid Mediated Intramolecular Epoxide Opening:
To a solution of 5 (365 mg, 1.14 mmol) in toluene (230 mL)
was added BF3·OEt2 (0.21 mL, 2.3 mmol) at –78 °C for 2 h
using a syringe pump. The reaction mixture was treated with
sat. aq NaHCO3 (20 mL) at –78 °C and the layers were
separated. The aqueous layer was extracted with EtOAc (2 ×
20 mL) and the combined organic layers were dried over
MgSO4, filtered, concentrated in vacuo, and the residue was
purified by silica gel chromatography (hexane–EtOAc, 6:1)
to give 8 and the cis isomer (trans/cis = 88: 12, 203 mg,
72%) as a colorless oil. The ratios were determined by
HPLC.
8: Rf 0.29 (hexane–EtOAc, 3:1); [a]24D –51 (c 0.125, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.76–6.86 (m, 4 H), 5.78–
5.89 (m, 1 H), 4.94–5.09 (m, 2 H), 4.65–4.72 (m, 1 H), 3.76
(s, 3 H), 3.68–3.75 (m, 1 H), 3.55–3.63 (m, 1 H), 2.26–2.42
(m, 2 H), 2.12–2.22 (m, 1 H), 2.03–2.12 (m, 1 H), 1.69–1.79
(m, 2 H), 1.36 (t, J = 5.5 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 154.06, 152.42, 142.55, 116.70, 114.81, 65.19,
55.88, 46.18, 40.30, 36.33. IR (film, neat): 3447, 3066, 2923,
2353, 1735, 1631, 1584, 1497, 1463, 1436, 1355, 1221,
1177, 1104, 1035, 992, 905, 823, 737 cm–1. HRMS: m/z [M]+
calcd for C15H20O3: 248.1412; found: 248.1417.
cis-Isomer of 8: Rf 0.29 (hexane–EtOAc, 3:1). 1H NMR (400
MHz, CDCl3): d = 6.76–6.86 (m, 4 H), 5.85–5.97 (m, 1 H),
5.04–5.16 (m, 2 H), 4.74–4.81 (m, 1 H), 3.77 (s, 3H), 3.65
(dd, J = 11.2, 7.0 Hz, 1 H), 3.55 (dd, J = 11.2, 6.0 Hz, 1 H),
3.03 (q, J = 4.2 Hz, 1 H), 2.47–2.58 (m, 1 H), 2.00–2.13 (m,
2 H), 1.88–1.97 (m, 1 H), 1.78–1.88 (m, 1 H). 1.40 (t, J = 5.5
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 139.13, 116.77,
115.62, 114.82, 78.52, 64.06, 55.08, 43.73, 43.70, 38.39,
35.39.
Macrolactone Synthesis by Ring-Closing Metathesis: A
solution of 2 and 4-epi-2 (32 mg, 0.060 mmol) and 7 (10
mol%) in CH2Cl2 (60 mL) was refluxed at 55 °C for 8 h
under N2. The solvent was removed in vacuo and the residue
was purified by silica gel chromatography (hexane–EtOAc,
30:1) to give the macrocyclic lactones (25 mg, 81%) as a
colorless oil. These lactones (22.6 mg, 0.045 mmol) in THF
(0.5 mL) were treated with 1 M TBAF in THF (2.19 mL,
2.19 mmol) at r.t. for 3 h. The solvent was removed in vacuo
and the residue was purified by silica gel chromatography
(hexane–EtOAc, 5:1) to give 14 (7 mg) and 4-epi-14 (7 mg)
in 78% yield.
Synlett 2009, No. 8, 1303–1306 © Thieme Stuttgart · New York

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