Total synthesis of amphidinolide X and its 12Z-isomer by formation of the C12-C13 trisubstituted double bond via ring-closing metathesis

Article abstract of DOI:10.1055/s-2008-1077885

Amphidinolide X, a 16-membered cytotoxic macro-diolide, and its 12Z-isomer have been synthesized via ring-closing metathesis (RCM) for assembling the C12-C13 trisubstituted double bond. A 29:71 E/Z mixture was obtained from the seco substrate appended with a bulky C8-ODPS group in 50-65% combined yields by using 20 mol% of the second-generation Grubbs initiator and the corresponding indenylidene ruthenium complex. Amphidinolide X and 12Z-isomer exhibit similar cytotoxicity (IC₅₀: 7.6-13.9 μg/mL) against A549, KB, and HL60 cell lines. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1077885

LETTER
1737
Total Synthesis of Amphidinolide X and Its 12Z-Isomer by Formation of the
C12–C13 Trisubstituted Double Bond via Ring-Closing Metathesis
Total
Synthesis of
Amp
e
X
i
and
1
-
2
Z
-Isom
M
er in Dai,*a,b Yile Chen,a Jian Jin,a Jinlong Wu,*a Jianshu Lou,c Qiaojun Hec
a
b
c
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
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
Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University,
Zi-Jin-Gang Campus, Hangzhou 310058, P. R. of China
Received 27 March 2008
double bond according to RCM gave three fragments 3–5,
of which the tetrahydrofuran fragment 5 has been synthe-
sized in our previous study.7,9 The fragment 3 would be
prepared by anti-selective aldehyde crotylation using
Abstract: Amphidinolide X, a 16-membered cytotoxic macro-
diolide, and its 12Z-isomer have been synthesized via ring-closing
metathesis (RCM) for assembling the C12–C13 trisubstituted dou-
ble bond. A 29:71 E/Z mixture was obtained from the seco substrate
appended with a bulky C8-ODPS group in 50–65% combined chiral boron10a,b and silicon11 reagents. The hydroxyl
yields by using 20 mol% of the second-generation Grubbs initiator
and the corresponding indenylidene ruthenium complex. Amphidi-
group in the chiral ester (R)-6 was selected as a masked
C8-ketone. The bisacid fragment 4 could be obtained
nolide X and 12Z-isomer exhibit similar cytotoxicity (IC50: 7.6–
from the chiral alcohol (S)-7 by homologation at C5 and
13.9 mg/mL) against A549, KB, and HL60 cell lines.
the Wittig olefination at C3. We report here on total syn-
Key words: anti-selective aldehyde crotylation, macrodiolide,
thesis of amphidinolide X (1) and its 12Z-isomer via RCM
ring-closing metathesis, microwave, trisubstituted olefin
and preliminary cytotoxicity of both macrodiolides.
Scheme 2 describes the synthesis of the C7–C12 fragment
3. The reaction of (S,S)-diisopropyl tartrate (E)-crotylbor-
Amphidinolide X1 (1, Scheme 1) belongs to a family of bi-
ologically significant secondary metabolites featured with
versatile macrocyclic lactones of 12- to 29-membered
onate (S,S)-1010c with the known aldehyde (R)-812 derived
from (R)-3-hydroxybutyric acid methyl ester (R)-6 gave a
83:17 mixture of the two anti-homoallyl alcohols 3 and 3¢
in favor of the desired stereomer 3.10d We used the chiral
silicon reagent (S,S)-9 developed by Leighton et al.11,13 for
the same crotylation of the chiral aldehyde (R)-8. The de-
sired homoallyl alcohol 3 was obtained in 59% yield and
in a diastereomeric ratio of >99:1. The results suggest a
nearly complete stereocontrol by the chiral silicon reagent
without influence arising from the stereogenic b-carbon of
the aldehyde.
The acid 11 was prepared from the known alcohol (S)-714
in 73% overall yield in three steps (Scheme 3). Condensa-
tion of 11 with the chiral homoallyl alcohol 3 was per-
formed under the Yamaguchi conditions15 to afford the
ester 12 in 90% yield. Removal of the PMB group in 12
by DDQ (82%) and oxidation of the resultant alcohol 13
by DMP (80%) afforded the aldehyde 14. The latter was
then subjected to the Wittig olefination with the ylide,
Ph3P=CHCO2Me, to form the methyl ester 15 in 90%
yield. Selective cleavage of a methyl ester in the presence
of other esters could be effected by using LiI in pyridine
at heating temperatures for more than 24 hours.16 We used
a modified procedure by treating 15 with LiI (10 equiv) in
pyridine at 180 °C for one hour under microwave
heating16b to afford the acid 16 in 85% isolated yield. Con-
densation of the acid 16 with the known fragment 57 af-
forded the seco intermediate 17 (90%) which was treated
with HF·pyridine to remove the tert-butyldiphenylsilyl
(DPS) group, affording the C8-free alcohol 18 in 65%
rings.2 Compound 1 is a unique 16-membered macro-
diolide and was isolated from cultures of marine di-
noflagellates Amphidinium sp. (strain Y-42), exhibiting
cytotoxicity against murine lymphoma L1210 and human
epidermoid carcinoma KB cell lines with IC50 values of
0.6 and 7.5 mg/mL, respectively.1 It was proposed that 1
may be biogenetically related to the 17-membered amphi-
dinolide Y3 (2, Scheme 1), which exists as an equilibrium
mixture of 6-keto and 6(9)-hemiacetal forms (2a/2b = 5:1
to 9:1) in CDCl3. Exposure of 2 to Pb(OAc)4 formed 1 as
the oxidative cleavage product.1 These two molecules
possess a common trans-fused tetrasubstituted tetrahy-
drofuran ring, and trisubstituted and conjugated E-double
bonds. Fürstner and co-workers have completed the first
total syntheses of amphidinolide X and Y4 by using the
classic macrolactonization as the ring-forming operation.5
We have recently accomplished the second total synthesis
of amphidinolide Y by ring-closing metathesis (RCM)6 of
the densely functionalized alkenes for assembling the
trisubstituted E-double bond at C11–C12 (Scheme 1).7,8 It
was found that the remote endocyclic appendages at C6
and C9 exerted a profound influence on the reactivity to-
ward RCM. We took a similar strategy for construction of
the 16-membered macrodiolide 1 as outlined in Scheme 1.
Disconnection of the two ester bonds and the C12–C13
SYNLETT 2008, No. 11, pp 1737–1741
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1077885; Art ID: W05008ST
© Georg Thieme Verlag Stuttgart · New York

1738
W.-M. Dai et al.
LETTER
HO
Me
R
21
11
(R)-6
10R
12
Me
8R
S
Me
9S
H
O
18R
10R
9S
Me
Me
15S
HO
7R
DPSO
OH
25
ref. 12
24
Me
6
16R
O
26
HO
Me
Me
(S,S)-9 (1.2 equiv)
CH2Cl2, 0 °C, 24 h
(59%, dr >99:1)
7R
Me
3 (major)
4S
23
1
O
H
6
2a/2b =
5:1–9:1
O
Me
DPSO
(R)-8
H
O
Me
HO
2b
Pb(OAc)4
22
O
+
or (S,S)-10 (2 equiv)
PhMe, 4 Å MS, –78 °C, 24 h
(90%, dr = 83:17)
Me
amphidinolide Y (2a)
8R
R
Me
S
7
Me
DPSO
OH
RCM
8
9
22
3' (minor)
12
Me
13
11R
O
10S
p-BrC6H4
H
O
O
Me
19R
CO2i-Pr
16S
N
Me
25
Me
24
4S
17R
Me
26
Si
6
O
Cl
O
ester
N
1
O
CO2i-Pr
H
cleavage
Me
B
Me
O
p-BrC6H4
23
O
ester cleavage
1
(S,S)-9
(S,S)-10
Scheme 2 Synthesis of the C7–C12 fragment 3
anti aldol or
crotylation
22
Me
Wittig
Me
HO
+
O
phidinolide X [(12Z)-1] in 85% yield (Table 1, entries 5
and 6).19 Finally, the mixture of 20/21 was subjected to
desilylation (HF·pyridine, 75%) and oxidation (DMP,
85%),20 giving pure (12Z)-amphidinolide X {[a]D17 –16.0
(c 1.00, CHCl3)} and amphidinolide X (1) {[a]D17 –26.8
(c 1.00, CHCl3)}. The latter agrees with the reported
Me
O
O
19R
6
7
Me
13
11R
16S
17R
8R
4S
14
Me
1
+
OH
10S
12
DPSO
OH
Me
HO
3
4
5
17
[a]D values of –12 (c 1.00, CHCl3)1 and –25.6 (c 1.00,
CHCl3).4a
HO
7
3
Table 2 shows our preliminary assay results of synthetic
amphidinolide X (1) and the 12Z-isomer using A549, KB,
and HL60 cancer cell lines. The data reveal that 1 and
(12Z)-1 exhibit similar cytotoxicity (IC50: 7.6–13.9 mg/
mL), indicating that the geometry of the trisubstituted alk-
ene is not essential for cytotoxic activity.
Me
10 OMe
O
8R
5
4S
OPMB
Me
HO
(R)-6
(S)-7
Scheme 1 Structures of amphidinolide X (1) and Y (2) and retro-
synthetic bond disconnections of amphidinolide X
In summary, we have accomplished total synthesis of am-
phidinolide X (1) and its 12Z-isomer via formation of the
trisubstituted double bond by RCM. A bulky DPSO group
at the remote exocyclic C8 position is found helpful in for-
yield. Finally, oxidation of 18 using DMP19 furnished the
ketone 19 in 93% yield.
In our total synthesis of amphidinolide Y (2),7 we found
that the second-generation Grubbs initiator 23 promoted
formation of the trisubstituted E-C11–C12 double bond
while Schrock’s molybdenum catalyst was inactive with
only recovered starting materials. We examined the RCM
reactions of 17–19 using three initiators 22–24 (Scheme
4) and the results are summarized in Table 1. In the pres-
ence of 20 mol% of the first-generation Grubbs initiator
22, the substrate 17 did not form any RCM product with
Table 1 Results of RCM Reactions of 17–19 in Refluxing CH2Cl2
Entry Substrate Cat.a Time (d) Yield (%)(%)b
Ratio (Z/E)c
1
2
3
4
5
6
17
17
17
17
18
19
22
22
23
24
23
23
3
NRd
–
4e
6
NRd
–
20 + 21: 50
20 + 21: 65
71:29
71:29
–
17
or without added Ti(Oi-Pr)4 (Table 1, entries 1 and 2).
6
When the second-generation Grubbs initiator 23 was
used, the substrate 17 furnished the RCM products 20 and
21 in 50% combined yield as a 71:29 (Z/E) mixture (Table
1, entry 3). It is interesting to find that the indenylidene ru-
thenium complex 2418 could promote RCM of 17 to afford
a 65% yield of 20 and 21 and in the same Z/E ratio (Table
1, entry 4). In contrast to the C8-protected 17, the C8-free
alcohol 18 decomposed upon exposure to the initiator 23
while the C8-ketone 19 afforded exclusively (12Z)-am-
f
3
–
4
(12Z)-1: 85
100:0
a The catalyst was added in portions.
b Isolated yield.
c Estimated values based on 1H NMR spectra of the reaction mixtures.
d No reaction with recovery of 17.
e Ti(Oi-Pr)4 (30 mol%) was added.
f Decomposed to give unidentified byproduct(s).
Synlett 2008, No. 11, 1737–1741 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Amphidinolide X and 12Z-Isomer
1739
TsO
Cl
1. NaCN, DMSO
60 °C (90%)
TsCl, Et3N
17
(S)-7
OPMB
DMAP (90%)
2. KOH, MeOH
reflux (90%)
Me
20 mol% Ru
(see Table 1)
CH2Cl2, reflux
Me
Cl
COCl
CO2H
Me
Cl
Me
13
Me
RO
OPMB
12
DPSO
O
O
Et3N, PhMe;
3, DMAP
(90%)
Me
11
Me
O
OR
Me
O
Me
Me
O
O
12: R = PMB
13: R = H
DDQ, pH 7
(82%)
Me
O
(12Z)-1
1. HF•py
(75%)
20: R = DPS
(80%)
Me
DMP, NaHCO3
+
+
Me
RO
2. DMP
(85%)
12
13
1
Me
Me
O
O
O
Me
Me
Me
DPSO
Me
Ph3P=CHCO2Me
CH2Cl2, r.t.
Me
O
O
DPSO
O
O
OR
(90%)
O
Me
O
O
O
Me
Me
21: R = DPS
14
15: R = Me
16: R = H
LiI, py, 180 °C
MW, 1 h (85%)
N
N
N
N
Mes
Mes
Mes
Mes
PCy3
Ph
Cl
Cl
Cl
Cl
Cl
Ru
Ru
Ru
Me
Cl
Cl
Ph
Ph
PCy3
PCy3
PCy3
Me
13
Cl
COCl
Me
O
12
24
Me
22
23
Cl
Me
Et3N, PhMe;
then 5, DMAP
(90%)
R1
R2
Scheme 4 The RCM reaction of 17 and synthesis of (12Z)-1 and 1
O
O
O
O
mation of the 12E-alkene as compared to the exclusive
formation of the 12Z-isomer from the C8-ketone sub-
strate.21 The preference for trisubstituted Z-alkene in as-
sembling the skeleton of amphidinolide X via RCM seems
the synergetic effect of a smaller ring system and the mac-
rodiolide moiety.
Me
17: R1 = ODPS, R2 = H
HF•py, THF,
r.t., 24 h (65%)
18: R1 = OH, R2 = H
19: R1, R2 = O
DMP, NaHCO3
(93%)
Scheme 3 Synthesis of the seco intermediates 17–19
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 in part by the re-
search grants from The National Natural Science Foundation of
China (Grant No. 20432020), Zhejiang University, and Zhejiang
University Education Foundation.
Table 2 The IC50 (mg/mL) Data of Amphidinolide X (1) and (12Z)-1
Compound
1
IC50 (A549)a
10.93 1.55
13.85 1.06
0.013 0.002
IC50 (KB)b
IC50 (HL60)c
11.31 0.84
7.61 1.01
<0.003
8.53 0.92d
12.86 1.32
0.003 0.0004
(12Z)-1
taxol
References and Notes
(1) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.;
Kawabata, J.; Katsumata, K.; Horiguchi, T.; Kobayashi, J.
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a Non-small-cell lung cancer cell line.
b Human epidermoid carcinoma cell line.
c Human leukemia cell line.
d A value of 7.5 mg/mL was reported for natural 1 (see ref. 1).
Synlett 2008, No. 11, 1737–1741 © Thieme Stuttgart · New York

1740
W.-M. Dai et al.
LETTER
(3) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.;
Kawabata, J.; Kobayashi, J. J. Org. Chem. 2003, 68, 9109.
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(13) We used noncrystallized form of the reagent. An 85:15
mixture of (S,S)-9 and its Z-isomer was prepared from an
85:15 mixture of E- and Z-crotyl chloride obtained from
Aldrich according to the literature procedure (ref. 11). The
Z-isomer of (S,S)-9 reacted with (R)-8 to produce a syn-
homoallyl alcohol which is different from 3¢. The diaste-
reomeric ratio of >99:1 was estimated according to the 1H
NMR spectrum of the product mixture.
(14) (a) Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857.
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(h) Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed.
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assisted cleavage of aromatic methyl esters, see: Sheppard,
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Erickson, S. A.; Barnes, D. M.; Tedrow, J. S.;
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Wiley-VCH: Weinheim, 2003.
(7) For the second total synthesis of amphidinolide Y, see: Jin,
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2585.
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Org. Lett. 2001, 3, 449. (b) Nicolaou, K. C.;
Kolaczkowski, L.; Vasudevan, A.; Park, D. C.; Wang, G. T.;
Sanders, W. J.; Mantei, R. A.; Palazzo, F.; Tucker-Garcia,
L.; Lou, P.; Zhang, Q.; Park, C. H.; Kim, K. H.; Petros, A.;
Olejniczak, E.; Nettesheim, D.; Hajduk, P.; Henkin, J.;
Lesniewski, R.; Davidsen, S. K.; Bell, R. L. J. Med. Chem.
2006, 49, 3832.
Vassilikogiannakis, G.; Montagnon, T. Angew. Chem. Int.
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Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc.
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Ring-Closing Metathesis of the seco Ketone 19 Using
Second-Generation Grubbs Initiator 23
Rheingold, A. L.; Burkart, M. D. Chem. Commun. 2006,
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To a degassed, refluxing solution of the seco ketone 19 (30.0
mg, 6.3⋅10–2 mmol) in anhyd CH2Cl2 (100 mL) under a
nitrogen atmosphere was added the second-generation
Grubbs initiator 23 (2.7 mg, 0.3⋅10–2 mmol). The resulting
clear, pale pink solution changed to a clear yellow color after
refluxing for 24 h. Three additional portions of 23 (2.7 mg,
0.3⋅10–2 mmol; a total of 1.2⋅10–2 mmol) were added after 24,
48, and 72 h, respectively. After refluxing for a total of 4 d,
the reaction mixture was concentrated to <1 mL on a rotary
evaporator, and the remaining mixture was purified directly
by flash column chromatography over SiO2 [eluting with 3%
EtOAc in PE (bp 60–90 °C)] to give (12Z)-amphidinolide X
[(12Z)-1, 24.0 mg, 85%]. (12Z)-Amphidinolide X [(12Z)-1]:
colorless oil; [a]D17 –16.0 (c 1.00, CHCl3). IR (film): 2964,
1731, 1655, 1454, 1377, 1315, 1269, 1215, 1167, 1049 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.92 (dd, J = 16.0, 6.4 Hz,
1 H), 5.81 (dd, J = 16.0, 1.6 Hz, 1 H), 5.18 (dt, J = 8.8, 4.0
Hz, 1 H), 4.88 (d, J = 10.4 Hz, 1 H), 4.82 (dt, J = 8.8, 7.2 Hz,
1 H), 3.74 (ddd, J = 10.0, 7.6, 2.8 Hz, 1 H), 2.96–2.89 (m, 1
H), 2.85–2.80 (m, 1 H), 2.66–2.58 (m, 2 H), 2.53 (dd,
J = 14.8, 4.8 Hz, 1 H), 2.42–2.33 (m, 2 H), 2.26–2.19 (m, 1
H), 2.16 (s, 3 H), 1.89–1.82 (m, 2 H), 1.70 (s, 3 H), 1.64 (dd,
(9) (a) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2006, 1177.
(b) For an alternative synthesis, see: Rodríguez-Escrich, C.;
Olivella, A.; Urpí, F.; Vilarrasa, J. Org. Lett. 2007, 9, 989.
(10) (a) Brown, H. C.; Bhat, K. J. Am. Chem. Soc. 1986, 108,
293. (b) Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc.
1986, 108, 294. (c) Roush, W. R.; Ando, K.; Powers, D. B.;
Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990,
112, 6339. (d) Benowitz, A. B.; Fidanze, S.; Small, P. L. C.;
Kishi, Y. J. Am. Chem. Soc. 2001, 123, 5128.
Synlett 2008, No. 11, 1737–1741 © Thieme Stuttgart · New York

LETTER
J = 13.2, 7.2 Hz, 1 H), 1.49–1.47 (m, 2 H), 1.36–1.30 (m, 2
Total Synthesis of Amphidinolide X and 12Z-Isomer
1741
To a solution of the above mixture (34.0 mg, 7.5⋅10–2 mmol)
in CH2Cl2 (1 mL) at r.t. was added NaHCO3 (19 mg, 0.225
mmol) followed by carefully adding a solution of Dess–
Martin periodinane in CH2Cl2 (0.3 M, 0.5 mL, 0.15 mmol).
The resultant mixture was stirred at r.t. for 4 h followed by
treating with sat. aq Na2S2O3. The reaction mixture was
extracted with CH2Cl2. The organic layer was washed with
brine, dried over anhyd Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography over SiO2 [eluting with 15%
EtOAc in PE (bp 60–90 °C)] to give amphidinolide X (1, 8.0
mg, 23%) and (12Z)-amphidinolide X [(12Z)-1, 21.0 mg,
62%].
H), 1.26 (s, 3 H), 1.15 (d, J = 7.6 Hz, 3 H), 1.05 (d, J = 6.8
Hz, 3 H), 0.91 (t, J = 7.6 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): d = 206.4, 171.3, 166.0, 151.7, 137.3, 126.3, 120.0,
81.9, 79.5, 78.0, 72.8, 44.8, 43.8, 43.1, 40.0, 35.9, 33.9, 31.4,
30.1, 27.3, 26.7, 23.5, 19.6, 17.8, 14.7, 14.6. MS (+ESI):
m/z (rel. int.) = 471 (100) [M + Na+]. HRMS (+ESI): m/z
calcd for C26H40O6Na+ [M + Na+], 471.2717; found:
471.2719.
(20) Procedure for the Synthesis of Amphidinolide X via
Ring-Closing Metathesis of 17 Using Second-Generation
Grubbs Initiator 23 as the Key Step
To a degassed, refluxing solution of 17 (150.0 mg, 0.21
mmol) in anhyd CH2Cl2 (150 mL) under a nitrogen
atmosphere was added the second-generation Grubbs
initiator 23 (8.9 mg, 1.1⋅10–2 mmol). The resulting clear, pale
pink solution changed to a clear yellow color after refluxing
for 24 h. Three additional portions of 23 (8.9 mg, 1.1⋅10–2
mmol; a total of 4.4⋅10–2 mmol) were added after 24, 48, and
72 h, respectively. After refluxing for a total of 6 d, the
reaction mixture was concentrated to <1 mL on a rotary
evaporator and the remaining mixture was purified directly
by flash column chromatography over SiO2 [eluting with
3% EtOAc in PE (bp 60–90 °C)] to give a 71:29 mixture of
the Z and E RCM products 20 and 21 (70.0 mg, 50%) as a
colorless oil. The Z/E ratio was determined by the
Amphidinolide X (1): colorless oil; [a]D17 –26.8 (c 1.00,
CHCl3). IR (film): 2963, 1717, 1654, 1453, 1377, 1265,
1186, 1039 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.12 (dd,
J = 15.8, 7.2 Hz, 1 H), 5.79 (dd, J = 15.8, 1.6 Hz, 1 H), 5.20
(m, 2 H), 4.95 (d, J = 10.3 Hz, 1 H), 3.96 (dt, J = 11.2, 3.6
Hz, 1 H), 2.78 (m, 1 H), 2.69 (dd, J = 16.6, 6.1 Hz, 1 H), 2.69
(m, 1 H), 2.58 (dd, J = 13.6, 3.9 Hz, 1 H), 2.58 (dd, J = 16.5,
7.5 Hz, 1 H), 2.41 (dd, J = 13.3, 6.3 Hz, 1 H), 2.18 (m, 1 H),
2.17 (m, 1 H), 2.14 (s, 3 H), 2.12 (m, 1 H), 1.94 (tt, J = 13.5,
3.3 Hz, 1 H), 1.75 (dd, J = 13.9, 2.4 Hz, 1 H), 1.55 (s, 3 H),
1.54 (m, 1 H), 1.50 (m, 2 H), 1.35 (m, 2 H), 1.30 (s, 3 H),
1.14 (d, J = 6.9 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H), 0.91 (d,
J = 7.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = 205.5,
170.7, 165.8, 153.2, 135.6, 126.1, 120.3, 83.0, 80.6, 78.5,
74.3, 47.2, 44.3, 43.6, 41.5, 35.6, 35.4, 33.1, 30.5, 30.5, 24.7,
18.2, 17.9, 17.6, 15.5, 14.7. MS (+ESI): m/z (rel. int.) = 471
(100) [M + Na+]. HRMS (+ESI): m/z calcd for C26H40O6Na+
[M + Na+]: 471.2717; found: 471.2699.
integration of the corresponding signals in the 1H NMR
spectrum. An pure sample of isomer 20 was obtained by
flash column chromatography [eluting with 3% EtOAc in PE
(bp 60–90 °C)] of the product mixture.
Compound 20: colorless oil; [a]D17 –35.9 (c 2.0, CHCl3).
IR (film): 2929, 1733, 1653, 1456, 1428, 1379, 1268, 1167,
1112, 1086 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.68–
7.65 (m, 4 H), 7.42–7.32 (m, 6 H), 6.93 (dd, J = 16.0, 6.0 Hz,
1 H), 5.75 (dd, J = 16.0, 1.6 Hz, 1 H), 5.02–5.00 (m, 1 H),
4.86 (d, J = 10.8 Hz, 1 H), 4.78 (dt, J = 8.4, 7.2 Hz, 1 H),
3.82–3.78 (m, 1 H), 3.74–3.70 (m, 1 H), 2.97–2.89 (m, 1 H),
2.74–2.67 (m, 1 H), 2.43–2.36 (m, 2 H), 2.30–2.22 (m, 2 H),
1.91–1.71 (m, 4 H), 1.67 (s, 3 H), 1.64–1.61 (m, 2 H), 1.48–
1.44 (m, 2 H), 1.36–1.30 (m, 2 H), 1.25 (s, 3 H), 1.14 (d,
J = 6.8 Hz, 3 H), 1.02 (d, J = 6.0 Hz, 3 H), 1.00 (s, 9 H), 0.96
(d, J = 7.2 Hz, 3 H), 0.91 (t, J = 7.2 Hz, 3 H). 13C NMR (125
MHz, CDCl3): d = 171.3, 166.2, 151.8, 136.3 (2×), 136.1
(2×), 135.7, 135.3, 134.2, 129.7, 129.6, 127.7 (2×), 127.6
(2×), 127.4, 119.9, 81.7, 79.8, 77.8, 74.3, 67.6, 44.8, 44.0,
40.1, 38.5, 36.1, 33.4, 31.3, 27.2 (3×), 27.1, 26.8, 24.2, 23.3,
19.5, 19.3, 17.9, 14.8, 14.4. MS (+ESI): m/z (rel. int.) = 711
(100) [M + Na+]. HRMS (+ESI): m/z calcd for
(21) Remote control of alkene geometry by endocyclic groups in
ring-closing metathesis has been reported. For examples of
formation of disubstituted macrocyclic alkenes, see:
(a) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen,
E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.;
Horwitz, S. B. J. Am. Chem. Soc. 1997, 119, 2733.
(b) Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2,
3731. (c) Fürstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G.
Chem. Eur. J. 2001, 7, 5286. (d) Aïssa, C.; Riveiros, R.;
Ragot, J.; Fürstner, A. J. Am. Chem. Soc. 2003, 125, 15512.
(e) Couladouros, E. A.; Mihou, A. P.; Bouzas, E. A. Org.
Lett. 2004, 6, 977. (f) Castoldi, D.; Caggiano, L.; Panigada,
L.; Sharon, O.; Costa, A. M.; Gennari, C. Angew. Chem. Int.
Ed. 2005, 44, 588. (g) Matsumura, T.; Akiba, M.; Arai, S.;
Nakagawa, M.; Nishida, A. Tetrahedron Lett. 2007, 48,
1265. (h) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M.
A.; Chorghade, M. S.; Gurjara, M. K.; Grubbs, R. H.
Tetrahedron Lett. 2007, 48, 2621. (i) For examples of
formation of trisubstituted macrocyclic alkenes, see: Meng,
D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.;
Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997,
119, 10073. (j) Nicolaou, K. C.; Vassilikogiannakis, G.;
Montagnon, T. Angew. Chem. Int. Ed. 2002, 41, 3276.
(k) Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.;
Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872.
(l) Vassilikogiannakis, G.; Margaros, I.; Tofi, M. Org. Lett.
2004, 6, 205. (m) Alhamadsheh, M. M.; Gupta, S.; Hudson,
R. A.; Perera, L.; Tillekeratne, L. M. V. Chem. Eur. J. 2008,
14, 570. (n) Trost, B. M.; Dong, G.; Vance, J. A. J. Am.
Chem. Soc. 2007, 129, 4540. (o) Ramírez-Fernández, J.;
Collado, I. G.; Hernández-Galán, R. Synlett 2008, 339; see
also ref. 7.
C42H60O6SiNa+ [M + Na+], 711.4051; found: 711.4054.
A plastic tube was charged with the 71:29 mixture of 20 and
21 (50.0 mg) in THF (2 mL) followed by adding 70%
hydrogen fluoride pyridine (2 mL) at r.t. The resultant
mixture was stirred for 24 h at r.t. and the reaction was
quenched carefully with sat. aq Na2CO3. The reaction
mixture was extracted with Et2O and the combined organic
layer was dried over anhyd Na2SO4, filtered, and
concentrated under reduced pressure. The residue was
purified by flash column chromatography over SiO2 [eluting
with 20% EtOAc in PE (bp 60–90 °C)] to give a mixture of
the alcohol (34.0 mg, 75%) as a colorless oil. The structure
of the alcohol was confirmed by mass spectrometry data. MS
(+ESI): m/z (rel. int.) = 473 (100) [M + Na+]. HRMS (+ESI):
m/z calcd for C26H42O6Na+ [M + Na+]: 473.2874; found:
473.2880.
Synlett 2008, No. 11, 1737–1741 © Thieme Stuttgart · New York