Influence of appended groups on the formation of 16-membered macrolactone core related to the plecomacrolides via diene-ene ring-closing metathesis

Article abstract of DOI:10.1055/s-0029-1217720

A 1,3-diene-ene ring-closing metathesis (RCM) strategy was investigated for assembling the 16-membered macrolactone core of the plecomacrolides. It was found that the desired (10E,12E)-diene unit could be constructed from the fully functionalized C13-C17

Full text of DOI:10.1055/s-0029-1217720

LETTER
2361
Influence of Appended Groups on the Formation of 16-Membered
Macrolactone Core Related to the Plecomacrolides via Diene–Ene
Ring-Closing Metathesis
F
ormationof th
i
Macr
a
olactone Co
n
re of Plecom
g
acrolides Sun,a,b Gaofeng Feng,a,b Yucui Guan,a,b Yuanxin Liu,a Jinlong Wu,a,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
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
b
Fax +85223581594; E-mail: chdai@ust.hk
Received 22 May 2009
diene functionality between C10–C13 was constructed by
formation of the C11–C12 bond via palladium-catalyzed
cross-coupling reactions of vinyl tin10,11,13,15,16,18 or
boron12 derivatives with vinyl iodides. Alternatively, a
Abstract: A 1,3-diene–ene ring-closing metathesis (RCM) strategy
was investigated for assembling the 16-membered macrolactone
core of the plecomacrolides. It was found that the desired
(10E,12E)-diene unit could be constructed from the fully function-
alized C13–C17 homoallyl alcohol fragment and the C1–C12 acid Sonogashira reaction has been used to form the enyne in-
fragment possessing one E double bond at C2–C3 or C3–C4. The
termediate, which was subsequently reduced to the 1,3-di-
ene.14 We envisaged a different approach to the assembly
functional groups at C2 and C3 resulted in preferential formation of
the undesired (12Z)-macrolactone, while additional appended
of the 16-membered tetraene macrolactone core by em-
groups at C6–C8 furnished the (12Z)-macrolactone as the sole RCM
ploying 1,3-diene–ene ring-closing metathesis (RCM).22–24
product.
Here, we report on the construction of the 16-membered
Key words: alkene, 1,3-diene, macrolactone, plecomacrolide, ring-
macrolactone core and on the finding that the appended
closing metathesis
groups influence the geometry of the forming C12–C13
double bond.
Bafilomycin A1 (1, Figure 1)1 is a representative member
Pd-catalyzed
1,3-diene–ene
of the 16-membered plecomacrolide family,2,3 which are
best known for possessing a folding hemiacetal subunit on
the side chain. The macrolactone core is connected to the
hemiacetal via a three-carbon linker (C16–C18 for 1).
Formation of an intramolecular hydrogen bonding net-
work among the lactone/linker/hemiacetal motif was sug-
gested to play an important role in the biological
functions,4 although non-supportive findings were ob-
tained from a study on synthetic analogues.5 Most of the
plecomacrolides deliver antifungal and antibacterial ac-
tivity. Moreover, bafilomycin A1 is known to be a specific
inhibitor of vacuolar H+-ATPase (V-ATPase) and it holds
some promise for treating osteoporosis.5–8 24-Demethyl-
bafilomycin A2 (2)9a is produced together with 24-deme-
thylbafilomycin C1 (3) by a commensal microbe
Streptomyces sp. CS associated with Maytenus hookeri.9
It was reported that the macrolide 2 exerts strong cytotox-
icity, with IC50 values of 1.13 and 0.01 mM against P388
and A549 tumor cell lines, respectively. The complex
structure of 1 has attracted much synthetic effort. After the
first total synthesis of bafilomycin A1 was accomplished
by Evans and Calter in 1993,10 several total syntheses of 1
were developed by Toshima,11 Roush,12 Hanessian,13 and
Carreira,14 along with studies on the fragment syntheses
by many other research groups.15–21 In general, the 1,3-
cross-couplings
ring-closing metathesis
R3
Me
OMe Me
Me
O
12
10
15
O
R2
19
21
22
11
13
O
OH
O
Me
Me
23
HO
O
25
Me
R1
24
Me
Me
OMe
bafilomycin A1 (1): R1 = Me, R2 = R3 = H
24-demethylbafilomycin A2 (2): R1 = R2 = H, R3 = Me
24-demethylbafilomycin C1 (3): R1 = R3 = H, R2
O
=
OH
O
Figure 1 Structures of bafilomycin A1 (1), 24-demethylbafilomycin
A2 (2), and 24-demethylbafilomycin C1 (3) and the strategic bond dis-
connections between C11–C12 and C12–C13
According to the early findings by Yang and co-work-
ers,25 the non-functionalized 16-membered tetraene mac-
rolactone could not be constructed directly via the 1,3-
diene–ene RCM, presumably due to high ring-strain
caused by the two sets of 1,3-diene moieties. We con-
firmed this result with the RCM reaction of a fully func-
tionalized seco substrate, which decomposed in the
presence of the RCM initiator. In order to alleviate the ri-
gidity of the RCM substrate, we decided to first construct
a triene macrolactone followed by the installation of the
fourth double bond.
SYNLETT 2009, No. 14, pp 2361–2365
x
x
.x
x
.2
0
0
9
Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217720; Art ID: W07709ST
© Georg Thieme Verlag Stuttgart · New York
As shown in Scheme 1, the fully functionalized homoallyl
alcohol 5,26 bearing the required stereotriad, was con-

2362
L. Sun et al.
LETTER
densed with the triene acid 4 under Yamaguchi esterifica- firmed to possess the (E)-geometry according to the cou-
tion conditions in toluene at 60 °C for 20 hours, to provide pling constant (J = 15.0 Hz) for the C12 and C13 vinyl
the seco ester 6 in 71% yield. When the condensation was protons at d = 6.32 and 5.36 ppm, respectively. The rela-
performed at room temperature, a b,g-unsaturated ester tively lower yield of 11, as compared to the macrolactone
was formed (vide infra). After screening the RCM initia- 7, is an indication that there might be competing side-re-
tors, solvents, and reaction temperatures, we found that 6 action(s), such as formation of smaller rings resulting
smoothly underwent the 1,3-diene–ene RCM in toluene at from cleavage of the trisubstituted double bond at C3–C4.
80 °C after four hours in the presence of 10 mol% Grubbs’ Alternatively, the less efficient RCM reaction of 10 might
2nd generation initiator 8;27 the 16-membered triene mac- arise from an increase in the ring-strain associated with
rolactone 7 was isolated in 73% yield.28 The 12E geome- the RCM transition state.
try in 7 was assigned on the basis of the large coupling
constant (J = 15.3 Hz) between the C12 and C13 vinyl
protons at d = 6.32 and 5.31 ppm, respectively. When the
RCM reaction of 6 was carried in refluxing dichlo-
romethane, using Grubbs’ 1st generation initiator,25 no
desired product was detected and the starting 6 was par-
tially recovered. These results imply that the presence of
an allylic methoxy group at C14 and the bulky appendage
at C15 render the RCM reaction more difficult to achieve,
and a much more robust initiator 8 and higher reaction
temperatures are required.
OH
OMe Me
O
+
Me
Me
OH ODPS
9
5
2,4,6-Cl3C6H2COCl,
Et3N, THF, r.t., 2 h;
DMAP, PhMe, r.t., 24 h
80%
OMe Me
O
ODPS
OMe Me
OH
O
O
+
Me
Me
OH ODPS
Me
10
5
4
(DPS = t-BuPh2Si)
8 (10 mol%)
PhMe, 80 °C, 4 h
52%
2,4,6-Cl3C6H2COCl,
Et3N, THF, r.t., 30 min;
DMAP, PhMe, 60 °C, 20 h
71%
Me
OMe Me
OMe Me
O
ODPS
3
4
O
ODPS
O
Me
11
O
Me
Me
6
8 (10 mol%)
Scheme 2 Synthesis of 16-membered triene macrolactone core 11
via 1,3-diene–ene RCM
73%
PhMe, 80 °C, 4 h
With the successful formation of the triene macrolactones
7 and 11, we examined the aldol–RCM–b-elimination se-
quence for assembling the tetraene core (Scheme 3). An
aldol reaction of the a,b-unsaturated aldehyde 1225 with
the lithium enolate derived from the methoxyacetate 1326
and LiHMDS was carried out. Two major syn-diastereo-
mers (2S*,3R*)-14 are expected to form preferentially
from the (Z)-enolate of 13. Indeed, a 60:40 inseparable
mixture of (2S*,3R*)-14 was obtained in 81% yield, while
another 50:50 inseparable mixture of the minor anti-dia-
stereomers (2S*,3S*)-14 was isolated in 12% yield. The
syn-diastereomers (2S*,3R*)-14 were then protected as
the TES ether 15. The latter was subjected to the same
RCM reaction conditions (10 mol% 8, toluene, 80 °C, 4
h)27 to furnish three inseparable macrolactones in 62%
combined yield. Upon removal of the TES-ether, the three
macrolactones 16a (55%), 16b (28%), and 17 (12%) were
obtained in diastereomerically pure form. The (12Z)-
geometry of 16a and 16b was deduced from the C12–C13
OMe Me
N
N
Mes
12
Mes
15
14
Cl
Cl
13
Ru
PCy3
8: Grubbs II
O
ODPS
Ph
O
7
Scheme 1 Synthesis of 16-membered triene macrolactone core 7
via 1,3-diene–ene RCM
In order to tackle the reactivity of the seco substrates with
an (E)-double bond located at different positions, we de-
signed the b,g-unsaturated ester 10, which could be pre-
pared from the condensation of 5 with the a,b-unsaturated
carboxylic acid 9 at room temperature in 80% yield
(Scheme 2). Upon exposing the seco substrate 10 to the
same RCM conditions used for the preparation of 6, the
expected RCM product 11 was formed in 52% isolated
yield.27,29 The C12–C13 double bond was again con-
Synlett 2009, No. 14, 2361–2365 © Thieme Stuttgart · New York

LETTER
Formation of the Macrolactone Core of Plecomacrolides
2363
At this stage, we went on one step further to investigate
the influence of the C6–C8 stereotriad on the RCM reac-
tion (Scheme 4). The fully functionalized aldehyde 20
was derived from the ester 1931 in 75% overall yield. In
order to enhance the diastereoselectivity, the dicyclohex-
ylboron enolate32 of 13 was used for the aldol reaction
with 20. Since the aldol product could not be directly sep-
arated from the starting ester 13 in the reaction mixture, it
was then protected as the TES-ether 21, which was ob-
tained in 34% overall yield from the aldehyde 20. No op-
timization was attempted at improving the aldol reaction
yield. The obtained seco intermediate 21 was found to be
a 78:19:3 mixture of two major (syn) and one minor (anti)
diastereomers. The RCM reaction of 21 was executed
with 13 mol% 8 in toluene at 80 °C for 11 hours, to afford
an 82:18 mixture of two diastereomers of the macrolac-
tone 22 in 89% combined yield. It was again confirmed
that the RCM reaction of 21 exclusively produced the
(12Z)-macrolactone 22, having a coupling constant of J =
11.2 Hz for both the C12 and C13 vinyl protons. Accord-
ing to the diastereomeric ratio of 22, both syn-diastereo-
mers of 21 (dr = 80:20) efficiently underwent the RCM
reaction, implying that the stereochemistry at C2 and C3,
and the C6–C8 stereotriad in 21 are compatible with the
macrocyclization. We found that selective removal of the
C3-TES ether from the major isomer of 22 was possible
by careful control of the reaction temperature and time,
and the major syn-isomer 23 could be obtained in a dia-
stereomerically pure form in 77% yield. The other minor
syn-isomer of 22 was recovered. The C3-OH of 23 was
mesylated [(MeSO2)2O, Et3N, –10 to 0 °C] and the result-
ant mesylate was eliminated (DBU, CDCl3, r.t.; reaction
OMe Me
O
CHO
+
Me
Me
ODPS
12
O
OMe
13
LiHMDS, THF; –78 °C, 2 h
(93%; dr = 52:35:6.5:6.5)
OMe Me
O
R
O
ODPS
2S*
3R*
O
Me
Me
OMe
TESOTf, 2,6-lutidine
–78 °C, 30 min (87%)
14: R = H
15: R = TES
1. 8 (10 mol%)
PhMe, 80 °C, 4 h (62%)
2. THF–TFA–H2O (20:1:1),
r.t., 9 h
12
13
Me
Me
Me
OMe Me
15
MeO
ODPS
+
HO
O
O
ODPS
HO
2S*
2S*
O
3R*
3R*
O
Me OMe
16a (55%); 16b (28%)
Me
OMe
17 (12%; one isomer)
1. MsCl, Et3N, CH2Cl2
2. DBU (40% for 2 steps)
for 16a
12
13
Me
Me
1
monitored by H NMR spectroscopy), to furnish the
15
tetraene 24 in 51% overall yield from 23. Finally, global
desilylation of 24 afforded the (12Z)-isomer 2533,34 of the
known (12E)-7,17-diol10b,35 in 63% yield. The measured
MeO
ODPS
O
O
25
specific optical rotation of 25 {[a]577 –89.1 (c 0.43,
Me OMe
CH2Cl2)} was close to that reported10b for the correspond-
18
ing (12E)-isomer {[a]57725 –86.4 (c 0.49, CH2Cl2)}.
Scheme 3 Synthesis of 16-membered triene macrolactones 16a,
16b, and 17 via 1,3-diene–ene RCM
In summary, we have investigated 1,3-diene–ene ring-
closing metathesis for assembling the C10–C13-diene
subunit embedded in the 16-membered macrolactone core
related to the plecomacrolides such as bafilomycin A1 and
24-demethylbafilomycin C1. The results described in this
work have confirmed the early findings25 that the 16-
membered macrolactone core can be constructed with
only one (E)-double bond located between the C2–C5 po-
sitions. Moreover, the C14-allylic methoxy group and the
C15-bulky appendage are tolerated in the RCM reaction
when Grubbs’ second generation initiator 8 is used. Al-
though the oxygen functionalities at C2 and C3 (including
the stereochemistry) and the C6–C8 stereotriad deliver
minimal deactivation toward the RCM reaction, these ap-
pended groups collectively favor formation of the (12Z)-
geometric isomer. Finally, we have demonstrated that the
fourth double bond can be installed onto the C2–C3 posi-
tions with the desired (E)-geometry via b-elimination of
the mesylate. Our findings are valuable for general appli-
vinyl proton coupling constants (J = 11.1 Hz) for both 16a
and 16b. In the same manner, the C12–C13 double bond
of 17 was assigned the (12E)-geometry, since the cou-
pling constant J = 15.0 Hz was similar to those observed
for 7 and 11. Moreover, we can assume that 16b and 17
were formed from the same syn-diastereomer of 15, while
16a was produced from the other syn-diastereomer of 15.
These results suggest that the two syn-oxygen functional-
ities introduced to the C2 and C3 positions in 15, includ-
ing their stereochemistry, are not significantly detrimental
to the RCM reactivity but do alter the geometry of the
forming C12–C13 double bond, leading to preferential
formation of the (12Z)-macrolactones. Among the three
triene macrolactones, only 16a could be converted into
the tetraene macrolactone 1830 (40% yield) by mesylation
of 16a followed by DBU-mediated b-elimination
(Scheme 3).
Synlett 2009, No. 14, 2361–2365 © Thieme Stuttgart · New York

2364
L. Sun et al.
LETTER
grants from The National Natural Science Foundation of China
(Grant No. 20432020), Zhejiang University, and Zhejiang Univer-
sity Education Foundation, and by the Department of Chemistry,
HKUST. The authors thank Granberg K. L. of AstraZeneca R&D
Mölndal, Sweden for providing a copy of the 1H NMR spectrum of
the (12E)-isomer of 25 as reported in ref. 35.
1. TBAF, THF, r.t., 20 h
2. TESOTf, 2,6-lutidine
3. DIBAL-H, THF, –78 °C
OTBS
CO2Et
4. DMP, NaHCO3
(75% for 4 steps)
Me
Me
Me
Me
Me
Me
19
1. 13, c-Hex2BOTf
Et3N, CH2Cl2,
–78 to 0 °C, 2 h
OTES
CHO
References and Notes
2. TESOTf
2,6-lutidine
CH2Cl2, –78 °C
1.5 h (34%)
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OTES
TESO
O
ODPS
2S*
3R*
O
Me
Me
Me
Me
OMe
21 (dr = 78:19:3)
12
13
Me
Me
TFA–H2O–THF
(1:3:50), 0 °C,
4.5 h (77%)
15
MeO
ODPS
Me
TESO
O
2S*
TESO
3R*
O
Me OMe
22 (dr = 82:18)
Me
12
13
Me
Me
O
15
MeO
ODPS
1. (MeSO2)2O, Et3N
CH2Cl2, –10 to 0 °C
Me
HO
O
2S*
TESO
(7) Bowman, B. J.; McCall, M. E.; Baertsch, R.; Bowman, E. J.
3R*
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(51% for 2 steps)
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23 (one isomer)
Me
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Me
Me
Shen, Y. J. Antibiot. 2003, 56, 415.
15
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MeO
OR2
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R1O
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O
Me OMe
Me
24: R1 = TES, R2 = DPS
25: R1 = R2 = H
TBAF–AcOH, THF
r.t., 3 d (63%)
Scheme 4 Synthesis of fully functionalized 16-membered tetraene
macrolactone core 25 via 1,3-diene–ene RCM
cations of the RCM reaction to the total synthesis of com-
plex macrolides. We are working toward alternative
approaches to construct the tetraene macrolactone core of
the plecomacrolides via the 1,3-diene–ene RCM and these
results will be reported in due course.
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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 research
Synlett 2009, No. 14, 2361–2365 © Thieme Stuttgart · New York

LETTER
Formation of the Macrolactone Core of Plecomacrolides
2365
20
(19) Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett.
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(29) Physical and spectroscopic data for 11: Colorless oil; [a]D
+32.8 (c 0.25, CHCl3); Rf = 0.50 (EtOAc–hexane, 5%); IR
(film): 2929, 1741, 1463, 1111 cm–1; 1H NMR (300 MHz,
CDCl3): d = 7.70–7.62 (m, 4 H), 7.43–7.30 (m, 6 H), 6.32
(dd, J = 15.0, 10.8 Hz, 1 H), 5.80 (d, J = 11.1 Hz, 1 H), 5.36
(dd, J = 15.0, 9.3 Hz, 1 H), 5.25–4.17 (m, 2 H), 3.58 (dd,
J = 9.6, 9.3 Hz, 1 H), 3.52–3.38 (m, 2 H), 3.25 (s, 3 H), 2.82
(d, J = 6.6 Hz, 2 H), 2.43–2.32 (m, 1 H), 2.20–2.09 (m, 1 H),
2.05–1.92 (m, 3 H), 1.69 (s, 3 H), 1.51 (s, 3 H), 1.55–1.40
(m, 2 H), 1.40–1.10 (m, 4 H), 1.04 (s, 9 H), 0.91 (d, J = 7.2
Hz, 3 H); 13C NMR (75 MHz, CDCl3): d = 171.4, 138.7,
136.5, 135.6 (×2), 135.5 (×2), 133.7, 133.6, 131.3, 129.4,
129.3, 128.8, 127.4 (×4), 125.7, 117.2, 82.1, 72.6, 65.7, 56.1,
39.1, 38.4, 35.7, 33.6, 26.9 (×3), 26.0, 25.5, 25.4, 19.3, 16.4,
16.1, 10.3; HRMS (+ESI): m/z [M + Na+] calcd for
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Chang, S. Tetrahedron 1998, 54, 4413. (b) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012. (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42,
4592. (e) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199. (f) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem. Int. Ed. 2005, 44, 4490. (g) Gradillas, A.; Pérez-
Castells, J. Angew. Chem. Int. Ed. 2006, 45, 6086.
(h) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40,
45. (i) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450,
243. (j) Handbook of Metathesis, Vol. 1-3; Grubbs, R. H.,
Ed.; Wiley-VCH: Weinheim, 2003.
(23) For selected examples of 1,3-diene–ene RCM in the
synthesis of macrocycles, see: (a) Hayashi, Y.; Shoji, M.;
Ishikawa, H.; Yamaguchi, J.; Tamura, T.; Imai, H.;
Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew.
Chem. Int. Ed. 2008, 47, 6657. (b) Wang, L.; Gong, J.;
Deng, L.; Xiang, Z.; Chen, Z.; Wang, Y.; Chen, J.; Yang, Z.
Org. Lett. 2009, 11, 1809; see also the early references cited
in ref. 26.
C37H52O4SiNa+: 611.3527; found: 611.3533.
(30) Physical and spectroscopic data for 18: Colorless oil; [a]D
20
–63.3 (c 0.50, CHCl3); Rf = 0.54 (EtOAc–hexane, 10%); IR
(film): 2931, 1721, 1646, 1428, 1246, 1108 cm–1; 1H NMR
(300 MHz, CDCl3): d = 7.70–7.61 (m, 4 H), 7.44–7.30 (m,
6 H), 6.67 (s, 1 H), 6.46 (dd, J = 11.4, 11.4 Hz, 1 H), 6.18 (d,
J = 11.1 Hz, 1 H), 5.52 (dd, J = 9.9, 6.0 Hz, 1 H), 5.19 (dd,
J = 9.9, 1.8 Hz, 1 H), 5.11 (dd, J = 10.2, 10.2 Hz, 1 H), 4.28
(dd, J = 9.6, 9.6 Hz, 1 H), 3.62 (dd, J = 9.6, 6.9 Hz, 1 H),
3.46 (s, 3 H), 3.39 (d, J = 9.6, 7.8 Hz, 1 H), 3.27 (s, 3 H),
2.50–2.18 (m, 5 H), 1.97 (s, 3 H), 1.67 (s, 3 H), 1.60–1.20
(m, 4 H), 1.05 (s, 9 H), 1.04 (d, J = 7.2 Hz, 3 H); 13C NMR
(75 MHz, CDCl3): d = 162.5, 144.7, 140.4, 136.0, 135.5
(×2), 135.5 (×2), 133.7, 133.7, 129.9 (×2), 129.4, 129.3,
127.5 (×2), 127.4 (×2), 126.8, 120.7, 120.4, 75.1, 73.6, 66.2,
59.4, 56.4, 37.8, 36.6, 27.4, 27.3, 26.9 (×3), 25.0, 22.7, 19.3,
15.0, 10.5; HRMS (+ESI): m/z [M + Na+] calcd for
C38H52O5SiNa+: 639.3476; found: 639.3468.
(24) For our recent work on the use of RCM in total synthesis,
see: (a) Jin, J.; Chen, Y.; Li, 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) Dai, W.-M.; Shi, L.;
Li, Y. Tetrahedron: Asymmetry 2008, 19, 1549.
(25) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z.
Org. Lett. 2006, 8, 1193.
(31) Dai, W.-M.; Feng, G.; Wu, J.; Sun, L. Synlett 2008, 1013.
(32) (a) Andrus, M. B.; Soma Sekhar, B. B. V.; Turner, T. M.;
Meredith, E. L. Tetrahedron Lett. 2001, 42, 7179.
(26) Guan, Y.; Wu, J.; Sun, L.; Dai, W.-M. J. Org. Chem. 2007,
72, 4953.
(27) General procedure for the 1,3-diene–ene RCM reaction. To
a solution of the seco substrate (4.6 × 10–2 mmol) in
degassed toluene (46 mL), was added Grubbs’ second
generation initiator 8 (3.9 mg, 4.6 × 10–3 mmol) followed by
stirring at 80 °C for 4 h. After cooling to r.t., the reaction
mixture was concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica
gel; EtOAc–hexane, 2%) to provide the RCM product. For
the RCM reaction of 21 (Scheme 4), the loading of 8 was 13
mol% and the reaction time was 11 h instead of 4 h.
(b) Andrus, M. B.; Meredith, E. L.; Simmons, B. L.;
Soma Sekhar, B. B. V.; Hicken, E. J. Org. Lett. 2002, 4,
3549.
25
(33) Physical and spectroscopic data for 25: Colorless oil; [a]577
–89.1 (c 0.43, CH2Cl2); Rf = 0.22 (EtOAc–hexane, 33%); IR
(film): 3444, 2927, 1715, 1641, 1456, 1247, 1105 cm–1; 1H
NMR (400 MHz, CDCl3): d = 6.64 (d, J = 0.4 Hz, 1 H), 6.43
(dd, J = 12.0, 12.0 Hz, 1 H), 6.03 (d, J = 12.8 Hz, 1 H), 5.91
(d, J = 10.4 Hz, 1 H), 5.01 (d, J = 10.4 Hz, 1 H), 4.96 (dd,
J = 9.6, 2.4 Hz, 1 H), 4.18 (dd, J = 9.6, 9.6 Hz, 1 H), 3.64 (d,
J = 2.4 Hz, 1 H), 3.62 (s, 3 H), 3.53–3.28 (m, 3 H), 3.25 (s,
3 H), 2.77 (dd, J = 16.4, 2.8 Hz, 1 H), 2.63–2.53 (m, 1 H),
2.40–2.30 (m, 1 H), 1.92 (d, J = 1.2 Hz, 3 H), 1.67 (s, 3 H),
1.60–1.50 (m, 2 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.8
Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H) (one OH signal not seen);
13C NMR (100 MHz, CDCl3): d = 165.3, 141.9, 141.0, 140.9,
133.5, 131.4, 130.7, 126.8, 120.3, 80.4, 75.2, 74.9, 64.5,
60.3, 56.3, 40.7, 39.9, 35.8, 35.7, 25.3, 17.0, 14.9, 13.4, 9.9;
HRMS (+CI): m/z [M+] calcd for C24H38O6: 422.2668;
found: 422.2662.
20
(28) Physical and spectroscopic data for 7: Colorless oil; [a]D
+74.5 (c 0.85, CHCl3); Rf = 0.33 (EtOAc–hexane, 5%); IR
(film): 2930, 1723, 1654, 1428, 1110 cm–1; 1H NMR (300
MHz, CDCl3): d = 7.75–7.63 (m, 4 H), 7.45–7.28 (m, 6 H),
6.81 (ddd, J = 15.0, 10.8, 4.2 Hz, 1 H), 6.32 (dd, J = 15.3,
11.1 Hz, 1 H), 5.79 (d, J = 10.2 Hz, 1 H), 5.63 (dd, J = 15.6,
2.4 Hz, 1 H), 5.31 (dd, J = 15.3, 9.6 Hz, 1 H), 5.20 (dd,
J = 9.6, 2.4 Hz, 1 H), 3.65 (dd, J = 9.6, 9.0 Hz, 1 H), 3.57,
3.46 (ABqd, J = 9.9, 7.2 Hz, 2 H), 3.26 (s, 3 H), 2.40–1.90
(m, 5 H), 1.71 (s, 3 H), 1.60–1.37 (m, 4 H), 1.37–1.10 (m,
4 H), 1.05 (s, 9 H), 0.97 (d, J = 6.9 Hz, 3 H); 13C NMR (75
MHz, CDCl3): d = 166.0, 150.7, 139.3, 135.6 (×2), 135.5
(×2), 133.8, 133.7, 131.6, 129.3 (×2), 128.5, 127.4 (×4),
125.0, 121.6, 83.3, 72.6, 66.1, 56.4, 39.2, 36.1, 31.4, 28.2,
27.8, 27.6, 26.9 (×3), 26.1, 19.3, 15.6, 10.7; HRMS (+ESI):
m/z [M + Na+] calcd for C36H50O4SiNa+: 597.3376; found:
597.3352.
(34) We attempted the isomerization of the (12Z)-double bond in
25 by treatment with CSA in toluene-d8 at room temperature
for 1 day, resulting in no visible change. When 25 was
exposed to I2 in toluene-d8 at 40 °C overnight, no clear
conclusion could be drawn from the 1H NMR spectrum of
the reaction mixture.
(35) Granberg, K. L.; Edvinsson, K. M.; Nilsson, K. Tetrahedron
Lett. 1999, 40, 755.
Synlett 2009, No. 14, 2361–2365 © Thieme Stuttgart · New York