Novel branched ether formation via conjugate reduction of an unsaturated cyanohydrin derivative and its synthetic application to the EF-ring segment of ciguatoxin

Article abstract of DOI:10.1016/j.tetlet.2004.08.117

A novel branched ether formation reaction was developed and applied to the synthesis of the EF-ring segment of ciguatoxin.

Full text of DOI:10.1016/j.tetlet.2004.08.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7567–7571
Novel branched ether formation via conjugate reduction of
an unsaturated cyanohydrin derivative and its synthetic
application to the EF-ring segment of ciguatoxin
Atsushi Takemura, Kenshu Fujiwara,* Akio Murai,ꢀ Hidetoshi Kawai and
Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 29 July 2004; revised 18 August 2004; accepted 20 August 2004
Abstract—A synthetic method for a branched ether system was developed. The method was based on Lewis-acid-promoted c-posi-
tion selective reduction of a c-alkoxy b,c-unsaturated a-silyloxy nitrile, prepared through a process including intermolecular hetero-
Michael reaction of a 2-butynoate ester derivative with an alcohol. The method was efficiently applied to the synthesis of fused
medium-ring ethers involving the EF-ring segment (2) of ciguatoxin (1).
Ó 2004 Elsevier Ltd. All rights reserved.
Since medium-sized cyclic ethers are often seen in
potently bioactive natural products,1 such as ciguatoxin
(1),1a,b,e,2–4 they attract significant synthetic attention.
So far, many approaches have been studied for their effi-
cient construction.5 Among these approaches, a ring-
closing olefin metathesis reaction (RCM) has currently
attracted great interest, because it is a catalytic reaction,
which achieves efficient closure of medium cycles under
cyclic ethers. In this context, we have explored new
methods for construction of the branched ether sys-
tem.12 Here, a new entry of the methods based on
Lewis-acid-promoted c-position selective reduction of
a c-alkoxy b,c-unsaturated a-silyloxy nitrile group and
its application to the synthesis of fused medium-ring
ethers involving the EF-ring segment (2) of ciguatoxin
(1) are described (Fig. 1).
mild conditions and tolerates a wide variety of func-
5,6
tionalgroups in its substrates.
However, application
Our generalsynthetic strategy for a fused-bicycilc ether
system involving medium rings, shown in Scheme 1, was
based on the following four processes: (i) construction
of the medium-membered ether ring of 4 by RCM of
precursor 5 using Grubbsꢁ method;6,13 (ii) introduction
of a hydroxy group to the b-position of the branched
ether part of 6; (iii) reduction of the 3-alkoxy-2-buteno-
ate part of 7 and (iv) hetero-Michaelreaction of 2-but-
ynoate ester 9 with alcohol 8 according to Paintnerꢁs
procedure.14 The success of this synthesis strongly relied
on the achievement of the third process, which would
construct the branched ether system.15 Therefore, a
reductive transformation reaction shown in Scheme 2
was newly designed. We expected that c-alkoxy b,c-
unsaturated a-silyloxy nitrile 10 would be activated by
an appropriate Lewis acid to generate oxonium ion 11,
which would be selectively reduced at the c-position into
c-alkoxy a,b-unsaturated nitrile 12 by a proper reducing
agent. The nitrile group would be available for further
synthesis toward 5.
of RCM to the syntheses of cyclic ethers involves a cru-
cialchaellnge in the preparation of the substrates for
RCM, namely, the stereoselective construction of an
acyclic branched ether part in each substrate. Recently,
severalsuccessfulmethods based on an akl yal tion or an
aldol reaction of a glycolate ester derivative,7,8 allyl9 or
hydride10 addition to an acetalgroup, an addition reac-
tion of an a-alkoxy carbon radical to a b-alkoxy pro-
penoate ester,11 or ring cleavage of C-glycosides,12
have been developed to solve the challenge. Neverthe-
less, the number of methods is insufficient to meet the
requirements for the synthesis of varied and complex
Keywords: Fused medium-ring ether; Ciguatoxin; Branched ether
synthesis; Hetero-Michaeladdition.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
ꢀ
Present address: 6-14-44, Asabu-cho, Kita-ku, Sapporo 001-0045,
Japan.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.117

7568
A. Takemura et al. / Tetrahedron Letters 45 (2004) 7567–7571
Me
Me
H
H
OH
H
H
O
Me
G
I
O
HO
H
H
H
H
O
J
RO
RO
O
H
OR
OR
K
H
H
O
O
O
E
H
O
H
H
L
H
M
OR
OR
H
Me
H
H
O
O
F
O
O
H
H
H
H
H
H
H
H
H
OH
H
Me
O
O
B
E
F
2
3
A
C
O
D
O
H
O
H
OH
HO
Ciguatoxin CTX1B (1)
OH
Figure 1.
Ring Closing
Olefin Metathesis
( )n
Hydroxy Group
Introduction
( )n
O
H
H
H
( )m
O
H
a
b, c
( )m
O
H
O
OMe
OH
O
OH
O
O
O
OH
( )k
( )
O
H
H R
l
H
( )k
( )
l
H
H R
OTBS
TBSO
OMe
13
14
15
4
5
k, l, m, n = 0 or 1
O
CN
OTMS
Reduction of
the Enol Ether Part
H
H
H
O
O
d
( )m
( )m
H
H
O
R
O
O
O
O
H
O
O
( )
lH
OR
OR
( )k
( )k
( )
OTBS
OTBS
H
H R
l
16
17
7
6
Scheme 3. Preparation of reduction precursor 17. Reagents and
conditions: (a) PMe3 (1.0equiv), 14 (2.8equiv), CH2Cl2–THF, 25°C,
24h, 74% (only E), 20% recovery of 13; (b) DIBAH (4.0equiv),
CH2Cl2, ꢀ78°C, 10min, ꢁ100%; (c) TPAP (0.1equiv), NMO
Hetero Michael
Addition
O
OR
OR
( )m
H
O
˚
(2.0equiv), MS 4A, CH2Cl2, 24°C, 50min, 88%; (d) Me3Al(1.1equiv),
OH
( )
lH
TMSCN (2.5equiv), benzene, 24°C, 1h, 71%.
( )k
8
9
Table 1. BF3ÆOEt2 promoted reduction of 17 with severalreducing
reagents
Scheme 1. Synthetic plan for fused-bicyclic ether 4.
.
CN
OTMS
BF3 OEt2 (3.0 eq)
CH2Cl2-R3MH (1 : 1)
-18 oC, Time
H
H
O
CN
CN
CN
OTMS
Lewis
acid
R MH
3
O
OTBS
R
R
R
O
R
17
O
R
O
R
H
CN
CN
OTBS
H
O
H
H
10
11
H MR
12
O
3
M = Si or Sn
O
R1
R2
O
H
18
19
Scheme 2. Lewis-acid-promoted c-position selective reduction of a c-
alkoxy b,c-unsaturated a-silyloxy nitrile system.
18a : R1 = CH2OTBS, R2 = H
18b : R1 = H, R2 = CH2OTBS
First, we planned to synthesize fused 6/8 cyclic ether 3,
which has a side chain and a hydroxylgroup with proper
stereochemistry available for further construction of a
trans-fused ether ring, from 1316 and 14 according to
the above strategy. Reduction precursor 17 was synthe-
sized according to Scheme 3. Hetero-Michaeladdition
of 13 to butynoate 14 in the presence of Me3P afforded
15 in 74% yield and gave 13 in 20% recovery.17 The ester
15 was converted to aldehyde 16 through reduction and
oxidation reactions in 88% yield. Treatment of 16 with
TMSCN (2.5equiv) in the presence of Me3Alin benzene
at ambient temperature gave 17 as a 1:1 mixture of dia-
stereomers in 71% yield.
Entry
R3MH
Time (min)
Yield (%)
18a:18b:19
1
2
2
4
5
Et3SiH
17
10
10
10
10
71
65
74
61
64
1.9:3.8:1.0
1.8:3.9:1.0
1.4:3.5:1.0
2.0:4.2:1.0
1.0:1.3:0
Et2MeSiH
EtMe2SiH
Me2PhSiH
Bu3SnH
at ꢀ18°C.18 All organosilanes afforded a mixture of nit-
riles 18a, 18b, and 19 in 61–74% yield (entries 1–4). It
was noted that the ratio of 18a to 18b increased with
increasing bulkiness of the organosilane. On the other
hand, the reaction with Bu3SnH gave the best result,
in which only the desired nitriles 18a and 18b were
produced as an inseparable 1.0:1.3 mixture in 64% yield
(entry 5). The stereochemistry at the newly formed
stereocenters of 18a and 18b was determined after trans-
Next, reduction of 17 with several organometallic hy-
dride reagents was examined (Table 1). All reactions
were carried out in a 1:1 (v/v) mixture of a hydride rea-
gent and CH2Cl2 in the presence of BF3ÆOEt2 (3.0equiv)

A. Takemura et al. / Tetrahedron Letters 45 (2004) 7567–7571
7569
ring closure in the synthesis of a trans-fused-bicyclic
ether system.
OH
CN
H
H
H
H
O
a, b
2
c
O
1
1
O
R
2
O
R
2
Then, we examined the synthesis of the EF-ring segment
(2) of ciugatoxin (1) according to the above considera-
tions (Scheme 5). Hetero-Michaeladdition of the F-ring
part 2424 to 2-butynoate ester 14 gave 25 in good yield
(90%),14 which was converted to a-silyloxy nitrile 27
through reduction, oxidation, and addition of TMSCN.
R
R
1
1
2
18a : R = CH OTBS, R = H 20a : R = CH OTBS, R = H
2
2
1
2
1
2
18b : R = H, R = CH OTBS 20b : R = H, R = CH OTBS
2
2
OH
H
H
O
O
d
e
O
1
OH
1
O
R
2
O
H
H
1
R
2
R
R
2
1
2
21a : R = CH OTBS, R = H 22a : R = CH OTBS, R = H
OBn
OBn
OBn
OBn
2
2
O
O
F
1
2
1
2
21b : R = H, R = CH OTBS 22b : R = H, R = CH OTBS
2
2
a
b, c
O
HO
H
O
1
O
J
= 4.6 Hz
H
H9-H10
4
9
MeO OTBS
24
25
10
OH
O
H
11
OTBS
H
OBn
OBn
OBn
O
O
H
23
H
NOE
d
O
O
OBn
O
NC
Scheme 4. Synthesis of bicyclic ether 23. Reagents and conditions: (a)
DIBAH (2.5equiv), CH2Cl2, ꢀ78°C, 10min, 68%; (b) DIBAH
(3.0equiv), CH2Cl2, ꢀ78°C, 8min, ꢁ100%; (c) D-(ꢀ)-DET (0.8equiv),
OTBS
TMSO OTBS
26
27
OBn
OBn
OBn
OBn
O
O
Ti(OiPr)4 (0.7equiv), TBHP (5.0equiv), MS 4A, CH2Cl2, ꢀ40°C,
˚
e
f, g
O
O
30min!ꢀ25°C, 24h, ꢁ100%; (d) Ph3P (5.0equiv), imidazole
(5.0equiv), I2 (4.0equiv), THF, 25°C, 45min, 61%; (e) [{CH2-
(Mes)N}2C](Cl)2(PCy3)Ru@CHPh (10mol%), CH2Cl2 (5mM), reflux,
6h, 44%.
NC
OTBS
HO
OTBS
28
29
HO
OBn
OBn
h, i, j
k, l
O
TBSO
formation of 18b into bicyclic ether 23 (vide infra).
Thus, efficient conditions for the c-selective reduction
of a-silyloxy nitrile 17 were found.
O
30
O
O
3
OBn
OBn
OBn
Synthesis of a 6/8 bicyclic system from 18a and 18b is
shown in Scheme 4. A ca. 1:2 mixture of 18a and 18b
was converted to a mixture of allyl alcohols 20a and
20b (68%) by repeated reduction with DIBAH. The allyl
alcohols were subjected to Katsuki–Sharpless asymmet-
ric epoxidation19 using (ꢀ)-DET to produce a mixture
of epoxides 21a and 21b (ꢁ100%), which was treated
with PPh3 and I2 in the presence of imidazole at ambient
temperature to give allyl alcohols 22a and 22b (61%) as a
1:2 mixture.20,21 Ring closure of dienes 22a and 22b in
refluxing CH2Cl2 by Grubbsꢁ second-generation cata-
lyst22 gave a mixture of products, in which only 23
was isolated as a bicyclic product (44%), and the desired
3 was not detected.23 Stereochemistry of 23 was con-
firmed by the presence of NOE between H4 and H11
as well as the small J value between H9 and H10
(4.6Hz). From the fact that the 1:2 ratio of the diastereo-
mers was maintained throughout the transformation
process from 18 to 22, and that the yield of 23 (44%)
was apparently higher than the ideal yield (33%) of the
cyclization product from minor diastereomer 22a, it
was concluded that 23 was produced from 22b and orig-
inated from 18b.
3
O
O
2
2
1
+
1
O
O
OBn
O
O
31a
31b
J
= 9.5Hz
J
= 1.8 Hz
H2-H3
H2-H3
m
H
H
14
O
OBn
OBn
H
OBn
OBn
3
H
O
O
E
7
2
O
O
+
1
O
H
O
F
H
O
2
32
NOE
J
= 9.4 Hz
H2-H3
Scheme 5. Synthesis of the EF-ring segment (2) of ciguatoxin CTX1B
(1). Reagents and conditions: (a) PMe3 (1.5equiv), 14 (3.0equiv),
CH2Cl2, 0!24°C, 1h, 90% (only E); (b) DIBAH (4.0equiv), CH2Cl2,
˚
ꢀ78°C, 10min, 99%; (c) TPAP (0.1equiv), NMO (2.0equiv), MS 4A,
CH2Cl2, 24°C, 1.5h, 75%; (d) Me3Al(1.1equiv), TMSCN (2.5equiv),
benzene, 24°C, 1h, 79%; (e) BF3ÆOEt2 (3.0equiv), CH2Cl2–Bu3SnH
(1:1), ꢀ18°C, 15min, 55%, 18% recovery of 27; (f) DIBAH (2.5equiv),
CH2Cl2, ꢀ78°C, 10min; (g) DIBAH (6.0equiv), CH2Cl2, ꢀ78°C,
20min, 72% for two steps; (h) L-(+)-DET (1.5equiv), Ti(OiPr)4
˚
(1.3equiv), TBHP (10equiv), MS 4A, CH2Cl2, ꢀ40°C, 30min!
ꢀ25°C, 26h; (i) Ph3P (5.0equiv), imidazole (5.0equiv), I2 (4.0equiv),
THF, 25°C, 35min; (j) Zn (7.0equiv), EtOH–satd NH4Claq (40:1),
25°C, 2.5h, 68% for three steps; (k) TBAF (1.5equiv), THF, 25°C,
11.5h, 68%; (l) 2,2-dimethoxypropane (4.0equiv), CSA (0.5equiv),
CH2Cl2, 24°C, 3h then acetone (5.0equiv), 11.5h, 31a: 50%, 31b: 46%;
(m) (Cy3P)2Cl2Ru@CHPh (25mol%), CH2Cl2 (3mM), 24°C, 15h,
31a:2:32 = 1:1:0.5; (Cy3P)2Cl2Ru@CHPh (30mol%), CH2Cl2 (3mM),
24°C, 24h, 2: 67%, 32: 24%, after two cycles.
The results from the final RCM step suggested that the
vinylgroups of 22a were apart from each other in the
stable conformation of 22a, and such orientation of
the vinylgroups was inappropriate for the cycilzation
of 22a. Therefore, we decided to prepare a bicyclic
RCM precursor, of which the vinylgroup woudl be
placed in close proximity to each other, for successful

7570
A. Takemura et al. / Tetrahedron Letters 45 (2004) 7567–7571
Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J. Am.
Chem. Soc. 1997, 119, 11325; For a review on ciguatera,
see: (h) Lewis, R. L. Toxicon 2001, 39, 97.
The reduction of 27 with Bu3SnH in CH2Cl2 in the pres-
ence of BF3ÆOEt2 (3equiv) at ꢀ18°C smoothly produced
nitrile 28 as a 1:1 mixture of diastereomers in 55% yield
and gave 27 in 18% recovery. Conversion of nitrile 28 to
allyl alcohol 29 followed by a three-step transformation
3. For the bioactivities of ciguatoxin and related compounds,
see: (a) Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.;
Chungue, E.; Legrand, A.-M.; Bagnis, R.; Lazdanski, M.
J. Biol. Chem. 1984, 259, 8353; (b) Lombet, A.; Bidard, J.
N.; Lazdanski, M. FEBS Lett. 1987, 219, 355; For a
review, see: (c) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.;
Legrand, A.-M. Toxicon 1999, 37, 125. See also the
references cited in Ref. 2h.
4. For the totalsynthesis of ciguatoxin CTX3C, see (a)
Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama,
M.; Oguri, H.; Satake, M. Science 2001, 294, 1904; (b)
Inoue, M.; Uehara, H.; Maruyama, M.; Hirama, M. Org.
Lett. 2002, 4, 4551; (c) Inoue, M.; Hirama, M. Synlett
2004, 577.
5. Recent reviews for synthesis of medium cyclic ethers, see:
(a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127; (b) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2002,
2301; (c) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin
Trans. 1 2001, 2303; (d) Yet, L. Chem. Rev. 2000, 100,
2963; (e) Hoberg, J. O. Tetrahedron 1998, 54, 12631; (f)
Alverz, E.; Candenas, M.-L.; Perez, R.; Ravelo, J. L.;
[(i) Katsuki–Sharpless asymmetric epoxidation19 using
20
(+)-DET; (ii) iodation of the hydroxylgroup
and
(iii) reduction of the resulting epoxy iodide with Zn]
gave the corresponding allyl alcohol 30 as a 1:1 mixture
of diastereomers in 68% yield. In order to facilitate the
closure of the trans-fused medium ring by RCM and
to confirm the stereochemistry of each diastereomer,
acetonides 31a and 31b were synthesized from 30
through removal of the TBS group followed by protec-
tion of the resulting diol. Diastereomers 31a and 31b
were easily separated by silica gel column chromatogra-
phy, and the stereochemistry of each compound was
determined by the J value between H2 and H3.
RCM6,13 of 31a with Grubbsꢁ first-generation catalyst
in CH2Cl2 at ambient temperature successfully produced
the desired trans-fused EF-ring segment 2 of ciguatoxin
(1) in 67% yield along with 32 in 24% yield.25 The stereo-
chemistry of 2 was confirmed by the presence of NOE
between H2 and H7 as well as the large J value between
H2 and H3 (9.4Hz).26
´
Martın, J. D. Chem. Rev. 1995, 95, 1953.
6. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinhem, 2003.
7. Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653.
Thus, we have developed a novel branched ether forma-
tion reaction based on Lewis-acid-promoted c-position
selective reduction of a c-alkoxy b,c-unsaturated a-silyl-
oxy nitrile group. The reaction has been employed for
the construction of fused-bicyclic ether 23 and the EF-
ring segment (2) of ciguatoxin (1).
8. (a) Oishi, T.; Tanaka, S.-i.; Ogasawara, Y.; Maeda, K.;
Oguri, H.; Hirama, M. Synlett 2001, 952; (b) Maruyama,
M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara, Y.;
Shindo, Y.; Hirama, M. Tetrahedron 2002, 58, 1835.
9. (a) Inoue, M.; Sasaki, M.; Tachibana, K. Tetrahedron
Lett. 1997, 38, 1611; (b) Kadota, I.; Ohno, A.; Matsuda,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 3562; (c)
´
Alvarez, E.; Diaz, M. T.; Hanxing, L.; Martın, J. D. J.
Am. Chem. Soc. 1995, 117, 1437.
Acknowledgements
10. (a) Oishi, T.; Nagumo, Y.; Hirama, M. Synlett 1997, 980;
See also: (b) Oishi, T.; Watanabe, K.; Murata, M.
Tetrahedron Lett. 2003, 44, 7315.
11. (a) Sasaki, M.; Inoue, M.; Noguchi, T.; Takechi, A.;
Tachibana, K. Tetrahedron Lett. 1998, 39, 2783; (b)
Sasaki, M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett.
1999, 40, 1337; (c) Inoue, M.; Wang, G. X.; Wang, J.;
Hirama, M. Org. Lett. 2002, 4, 3439.
12. (a) Fujiwara, K.; Souma, S.-i.; Mishima, H.; Murai, A.
Synlett 2002, 1493; (b) Fujiwara, K.; Koyama, Y.; Doi, E.;
Shimawaki, K.; Ohtaniuchi, Y.; Takemura, A.; Souma,
S.-i.; Murai, A. Synlett 2002, 1496.
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS & NMR Laboratory, Graduate Schoolof
Agriculture, Hokkaido University) for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
References and notes
1. Reviews for naturalcycilc ethers, see: (a) Yasumoto, T.
Chem. Rec. 2001, 3, 228; (b) Yasumoto, T.; Murata, M.
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H. G.; Northcore, P. T.; Prinsep, M. R. Nat. Prod. Rep.
2004, 21, 1; (g) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1.
2. For isolation and structure determination of ciguatoxin,
see: (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.;
Yoshida, T. Science 1967, 155, 1267; (b) Tachibana, K.
Ph.D. Thesis; University of Hawaii, 1980; (c) Nukina, M.;
Koyanagi, L. M.; Scheuer, P. J. Toxicon 1984, 22, 169; (d)
Tachibana, K.; Nukai, M.; Joh, Y. G.; Scheuer, P. J. Biol.
Bull. 1987, 172, 122; (e) Murata, M.; Legrand, A.-M.;
Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc.
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shi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990,
112, 4380; (g) Satake, M.; Morohashi, A.; Oguri, H.;
13. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856; (b) Zuercher, W. J.; Hashimoto, M.;
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15. Several attempts to reduce selectively the a,b-unsaturated
ester part of 15 were unsuccessful.
16. Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A. Synlett
1999, 1037.
17. Hetero-Michaeladdition of 13 to butynoate 14 with a
catalytic amount of Me3P according to Paintnerꢁs procedure14
often stopped without completion. The incomplete reaction
was due to the oligomerization of 14. A stoichiometric
amount of Me3P and excess 14 (2.8equiv) were required to
accelerate the reaction rate and to improve the yield.
18. When TMSOTf was used in stead of BF3ÆOEt2, complex
products were obtained. On the other hand, Me3Alwas
ineffective in activating the substrate.

A. Takemura et al. / Tetrahedron Letters 45 (2004) 7567–7571
7571
19. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
20. Classon, B.; Liu, Z.; Samuelsson, B. J. Org. Chem. 1988,
53, 6126.
21. Under the reaction conditions, epoxides 21a and 21b
were directly converted to allyl alcohols 22a and 22b,
respectively. There were several reports for conver-
sion of 2,3-epoxypropanolderivatives to the correspond-
ing 1-propen-3-ol derivatives under Classon–Samuelsson
conditions. For examples: (a) Aziz, M.; Rouessac, F.
Tetrahedron 1988, 44, 101; (b) Hayashi, N.; Mine, T.;
Fujiwara, K.; Murai, A. Chem. Lett. 1994, 2143; (c)
Reagents and conditions: (a) H3O+, 68%; (b) Swern oxid.;
(c) Ph3P@CH2; (d) HSCH2CH2SH, NaHCO3, Zn(OTf)2,
58% for three steps; (e) NaH, BnBr, TBAI; (f) TBAF,
ꢁ100% for two steps.
25. Since the RCM reaction of 31a often stopped without
completion, this step was repeated once in order to
consume 31a completely. Optimization of the step is
currently under way.
23
26. Spectraldata of 2: a colorless oil; ½aꢂD +13.0 (c 0.20,
1
CHCl3); H NMR (300MHz, (CD3)2C@O, CHD2C(@O)-
CD3 as 2.04ppm), d 7.34–7.24 (10H, m, Bn), 6.00 (1H, dt,
J = 12.4, 2.6Hz, H4 or H5), 5.78–5.67 (2H, m, H9, H10),
5.40 (1H, dt, J = 12.4, 2.6Hz, H4 or H5), 4.68 (1H, d,
J = 11.6Hz, Bn), 4.49 (2H, s, Bn), 4.41 (1H, d, J = 11.6Hz,
Bn), 4.30 (1H, br dqn, J = 9.4, 2.6Hz, H3), 3.88–3.83 (1H,
m, H6), 3.72 (1H, dd, J = 11.3, 5.7Hz, H1eq), 3.70–3.61
(3H, m, H12, H14a,b), 3.58–3.50 (1H, m, H7), 3.55 (1H,
dd, J = 11.3, 9.4Hz, H1ax), 3.29 (1H, ddd, J = 8.5, 5.7,
2.6Hz, H13), 3.18 (1H, td, J = 9.4, 5.7Hz, H2), 2.89–2.78
(1H, m, H8), 2.66–2.58 (1H, m, H11), 2.39 (1H, m, H11),
2.07–1.98 (1H, m, H8), 1.42 (3H, s, Me), 1.28 (3H, s, Me);
IR (film) mmax 3087, 3063, 3027, 2991, 2922, 2855, 1496,
1454, 1372, 1336, 1311, 1292, 1267, 1221, 1200, 1100, 1027,
988, 945, 893, 866, 779, 767, 735, 697, 680cmꢀ1; LR-
FDMS, m/z 506 (22.4%, [M]+), 491 (47.9%, [MꢀMe]+), 91
(bp); HR-FDMS, calcd for C31H38O6 [M]+: 506.2669,
found: 506.2650.
´
Dorta, R. L.; Rodrıguez, M. S.; Salazar, J. A.; Suarez, E.
Tetrahedron Lett. 1997, 38, 4675.
´
22. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
23. In the RCM reaction, 22a was not recovered, and an
oligomer that would be resulted from 22a was detected.
24. The F-ring derivative 24 could be synthesize in six steps
from the reported compound 33.12b
TBSO
HO
O
O
O
O
Ph
a
Ph
TBSO
O
TBSO
O
33
34
OH
OH
OBn
OBn
O
O
b, c, d
e, f
TBSO
HO
35
24