Syntheses of the D-, E-, F-, and I-ring parts of ciguatoxin by a common strategy starting from tri-O-acetyl-D-glucal

Article abstract of DOI:10.1055/s-2002-33527

Chiral medium-sized monocyclic ethers corresponding to the D-, E-, F-, and I-ring parts of ciguatoxin have been synthesized from tri-O-acetyl-D-glucal through a common synthetic route involving ring-closing olefin metathesis.

Full text of DOI:10.1055/s-2002-33527

1496
LETTER
Syntheses of the D-, E-, F-, and I-Ring Parts of Ciguatoxin by a Common
Strategy Starting from Tri-O-acetyl-D-glucal
S
ynthese
s
of the
D
e
-, E-, F-, an
n
d
I
-Ring Par
s
ts of Cigu
h
atoxin u Fujiwara,*a Yasuhito Koyama,a Eriko Doi,a Ken Shimawaki,a Yuko Ohtaniuchi,a Atsushi Takemura,
Shin-ichiro Souma,a Akio Murai*a,b
a
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax +81(11)7062714; E-mail: fjwkn@sci.hokudai.ac.jp
b
Present address: 6-14-44 Asabu-cho, Kita-ku, Sapporo 001-0045, Japan
Fax +81(11)7476963; E-mail: amurai@rmail.plala.or.jp
Received 29 May 2002
Me
Abstract: Chiral medium-sized monocyclic ethers corresponding
to the D-, E-, F-, and I-ring parts of ciguatoxin have been synthe-
sized from tri-O-acetyl-D-glucal through a common synthetic route
Me
H
H
H
OH
O
Me
G
HO
H
I
O
J
H
O
L
K
O
H
H
O
O
M
H
H
H
involving ring-closing olefin metathesis.
H
H
O
O
H
H
H
H
H
H
H
H
O
O
B
Me
E
OH
F
Me
Key words: Heterocycles, stereoselective synthesis, natural prod-
ucts, ethers, metathesis
A
C
O
D
O
H
H
Ciguatoxin (1)
O
HO
H
OH
OH
Me
5
5
4
Ciguatoxin (1), isolated as one of the causative toxins of
ciguatera sea food poisoning, has attracted much attention
of synthetic chemists from its unique ladder-shaped poly-
ether structure and strong bioactivity.1–4 In the course of
our studies toward the total synthesis of 1,5 we planned to
construct the D-, E-, F-, and I-ring parts as the key syn-
thetic intermediates. Here, the syntheses of oxepene 2 as
the D- or E-ring part, oxonene 3 as the F-ring part, and
oxocane 4 as the I-ring part by a common strategy starting
from tri-O-acetyl-D-glucal (8) are described.
6
O
8
HO
8
F
HO
O
TBSO
O
O
I
Ph
D/E
7
Ph
2
2
2
Ph
O
O
O
10
O
9
O
1
1
1
2
3
4
PivO
RCM
n=m=0
TBSO
TBDPSO
RCM
n=m=1
RCM and
Hydrogenation
Me
m
O
n
RO
O
RO
Ph
Ph
O
O
O
O
5
6
R'O
R'O
n=1
n=0
OH
Our strategy for the syntheses of 2, 3, and 4 is outlined in
Scheme 1. Oxepene 2 and oxonene 3 would be construct-
ed readily from diene 5 by a ring-closing olefin metathesis
(RCM) reaction.6 On the other hand, oxocane 4 should be
synthesized through a 2-step process [(i) a RCM reaction
between vinyl and propen-2-yl groups of 67 and (ii) the
stereoselective reduction of the resultant trisubstituted
olefin part]. The dienes 5 and 6 would be provided from
C-glycoside 7, having all requisite stereocenters, through
a cleavage at the cis-diol part of the hexose ring.8 Stereo-
chemistry of 7 would be set up from tri-O-acetyl D-glucal
(8) via diastereoselecive introduction of a 1-hydroxy-2-
propenyl or 1-hydroxy-3-butenyl side chain.
O
O
O
OAc
n
R"O
O
Ph
OAc
OR"
7
OAc
8
Scheme 1
to afford 12. Nitrile 12 was reduced with DIBALH and the
resulting imine was hydrolyzed under acidic conditions to
produce aldehyde 13. Stereoselective vinylation of 13 was
succeeded with vinyl lithium prepared in situ from vinyl
bromide and t-BuLi to give 14 in 79% isolated yield (dr
11:1).11 On the other hand, 16 was obtained selectively by
allylation of 13 with 2-allyl-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane12 in 79% isolated yield (dr 3.8:1).11 These
alcohols 14 and 16 were converted to the corresponding
cyclic phenyl boronates 20 and 21 in good yields by a 4-
step sequence [(i) removal of TBS groups with TBAF; (ii)
oxidative cleavage of 1,2-diol parts; (ii) reduction with
NaBH4; (iv) treatment with PhB(OH)2].13
Syntheses of intermediates 20 and 21 are shown in
Scheme 2. Tri-O-acetyl-D-glucal (8) was converted to 109
in 52% overall yield through a 3-step process [(i) treat-
ment with TMSCN and SnCl4,10 (ii) removal of acetyl
groups by methanolysis with Amberlyst 15, and (iii) ben-
zylidene acetal formation]. In the latter two steps, no sig-
nificant isomerization of a double bond at C3 to a
conjugate system was observed. Olefin 10 was oxidized to
diol 11 stereoselectively, which was protected with TBS
The D/E-ring part 2 was synthesized from 20 as shown in
Scheme 3. Firstly, we examined a concise route. Alcohol
20 was converted to diene 24 in only three steps [(i) Swern
oxidation, (ii) Wittig olefination, and (iii) removal of cyc-
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1496,1499,ftx,en;U01602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Syntheses of the D-, E-, F-, and I-Ring Parts of Ciguatoxin
1497
O
X
NC
O
NC
O
b, c
OAc
a
OAc
OAc
d
O
a
f
c
e
O
O
R1O
R2O
2
20
O
O
O
O
OAc
O
Ph
PhB
Ph
Ph
O
O
OAc
9
10
8
22: X=O
24: R1=R2=H
b
d
OH
23: X=CH2
25: R1=H, R2=Piv
R1
O
O
j, k
g or h
O
O
l
n
R2O
OAc
O
X
R2O
O
Ph
O
Ph
OR2
OR2
TBSO
O
O
Ph
k
PhB
Ph
11: R1=CN, R2=H
12: R1=CN, R2=TBS
13: R1=CHO, R2=TBS
14: n=0, R2=TBS
15: n=0, R2=H
16: n=1, R2=TBS
17: n=1, R2=H
O
O
e
i
i
TBSO
j
O
O
O
f
OR2
g
30: X=O
26
31: X=CH2
R1O
R1O
O
Ph
O
OH
O
n
O
OH
O
27: R1=H, R2=Ac
28: R1=TBS, R2=Ac
29: R1=TBS, R2=H
l
O
n
h
i
O
PhB
Ph
HO
O
Ph
O
O
O
OH
18: n=0
19: n=1
20: n=0
21: n=1
Scheme 3 Reagents and conditions. a) TPAP (0.06 equiv), NMO
(1.5 equiv), MS 4Å, CH2Cl2, 12 min; b) Ph3PCH3Br (10 equiv),
NaHMDS (10 equiv), THF, 22 °C, 1 h, then 22, –78 →22 °C, 9 h, 46%
for 2 steps; c) 30% H2O2, EtOAc, 20 °C, 1 h, 84%; d) PivCl (1.1
equiv), pyridine, 25 °C, 2.5 h, 80%; e) (Cy3P)2Cl2Ru=CH2Ph (0.05
equiv), ClCH2CH2Cl (5 mM of 25), reflux, 4 h, 90%; f) AcCl (1.1
equiv), pyridine (2.2 equiv), CH2Cl2, 25 °C, 1 h, ~100%; g) 30%
H2O2, EtOAc, 20 °C, 6 h, 92%; h) TBSOTf (2.6 equiv), 2,6-lutidine
(5.2 equiv), CH2Cl2, 25 °C, 18 h, ~100%; i) DIBALH (1 equiv),
CH2Cl2, –78 °C, 8 min, ~100%; j) (COCl)2 (3 equiv), DMSO (4.8
equiv), CH2Cl2, –78 °C, 20 min, then Et3N (10 equiv), –20 °C, 5 min;
k) Ph3PCH3Br (2 equiv), NaHMDS (2 equiv), THF, 25 °C, 1 h, then
30, –78 °C, 6 min, 83% for 2 steps; l) TBAF (2.1 equiv), THF, 25 °C,
2 h, ~100%
Scheme 2 Reagents and conditions. a) TMSCN (1.5 equiv), SnCl4
(1.0 equiv), CH2Cl2, –78 °C, 10 min, then –20 °C, 10 min, 61%; b)
Amberlyst 15, MeOH, reflux, 24 h; c) PhCHO (3 equiv), Amberlyst
15, CHCl3, 23 °C, 19 h, then reflux with Dean–Stark trap, 3.5 h, 85%
(2 steps); d) OsO4 (0.01 equiv), NMO (1.4 equiv), 1,4-dioxane–H2O
(3:1), 20 °C, 4 d, ~100%; e) TBSOTf (3 equiv), 2,6-lutidine (6 equiv),
CH2Cl2, 0 →22 °C, 72 h, ~100%; f) DIBALH (1 equiv), CH2Cl2, –78
°C, 12 min; 1 M HCl aq–CH2Cl2 22 °C, 16 h, 95%; g) CH2=CHBr (6
equiv), t-BuLi (12 equiv), THF, –78 °C, 20 min, then 13, –78 °C, 1 h,
14: 79%; h) 2-allyl-4,4,5,5-tetramethyl-1,3-dioxo-2-borolane (6.5
equiv), CH2Cl2, –78 °C, 3.5 h, then –20 °C, 20 min, 16: 79%; i) TBAF
(3–3.5 equiv), THF, 22 °C, 25–41 h, 15: ~100%, 17: 95%; j) NaIO4
(1.1–1.3 equiv), 1,4-dioxane–H2O (3:1), 22 °C, 6–48 h; k) NaBH4 (2–
3.7 equiv), MeOH, 0 °C, 1–2 h, 18: 99% (2 steps), 19: 96% (2 steps);
l) PhB(OH)2 (1 equiv), PhH, reflux with Dean–Stark trap, 2.5–4.5 h,
20: 95%, 21: 98%
subjected to Wittig olefination to produce diene 42. The
diene 42 was transformed into the F-ring part 319 in 98%
yield by the RCM reaction with (Cy3P)2Cl2Ru=CH2Ph.15
On the other hand, 38 was reduced to aldehyde 40, which
was subjected to addition of MeMgBr followed by oxida-
tion to give ketone 44. Treatment of 44 with Tebbe
reagent20 and the subsequent deprotection and protection
process produced dienes 45–47. After several endeavors
using these dienes, we found that the RCM reaction of di-
ene 47 with Grubbs’ second generation catalyst 4821 in
CH2Cl2 (5 mM of 47) under refluxed conditions afforded
cyclized compound 49 in 97% yield.7 Stereoselective re-
duction of 49 was achieved only by homogeneous hydro-
genation conditions using Crabtree’s catalyst22 to give the
I ring part 423 in 88% yield (dr 19:1). Stereochemistry of
C5 was confirmed by the existence of NOEs between H5/
H3 and between H5/H7 in NOESY of 4. It is noted that
this step showed unusual face selectivity which did not re-
sult from the coordination of the catalyst with the allylic
hydroxy group of 49.22b Interestingly, hydrogenation of 49
under heterogeneous conditions using PtO2 gave the op-
posite selectivity (50% yield, dr 1:8).
lic boronate part],14 though the instability of cyclic bor-
onate part caused the low yield (39% overall). Since 24 is
not a good precursor for RCM reaction, the primary hy-
droxy group was protected as pivaloate ester. The result-
ing 25 was readily cyclized with (Cy3P)2Cl2Ru=CH2Ph15
to produce 216 in 80% yield. Next, we also explored an al-
ternative route to 24 in order to avoid the trouble owing to
instability of the cyclic boronate group. Protection of al-
cohol 20 with acetyl group and subsequent removal of cy-
clic boronate afforded diol 27, which was protected with
TBS group and hydrolyzed to give 29. Alcohol 29 was
converted to diene 24 by Swern oxidation17 followed by
Wittig olefination and desilylation. The D/E-ring part 2
was eventually obtained from 20 in 26% total yield in 5
steps via 23 and in 51% total yield in 9 steps via 31.
The I- and F-ring parts were synthesized from the corre-
sponding substrates 20 and 21 (Scheme 4). Conversion of
hydroxy group in 20 or 21 to chloromethanesulfonate
ester18 followed by a 3-step transformation [(i) removal of
cyclic boronate,14 (ii) protection with TBS, and (iii) sub-
stitution with cyanide] gave the corresponding nitrile 38
or 39. For the F-ring construction, the nitrile group of 39
was reduced with DIBALH to an aldehyde, which was
Thus, chiral medium-sized monocyclic ethers corre-
sponding to the D-, E-, F-, and I-ring parts of ciguatoxin
have been synthesized from tri-O-acetyl-D-glucal through
a common synthetic route involving ring-closing olefin
metathesis. Further studies toward the total synthesis of 1
are currently under way in this laboratory.
Synlett 2002, No. 9, 1496–1499 ISSN 0936-5214 © Thieme Stuttgart · New York

1498
K. Fujiwara et al.
LETTER
References
OMc
n
OMc
O
20
or
a
b
d
n
(1) 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;
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(d) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.;
Yasumoto, T. J. Am. Chem. Soc. 1989, 111, 8929.
O
O
RO
RO
O
PhB
Ph
Ph
21
O
O
O
O
32: n=0
33: n=1
34: n=0, R=H
c
35: n=0, R=TBS
36: n=1, R=H
37: n=1, R=TBS
Mc = -SO2CH2Cl
c
(e) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.;
Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380.
X
CN
g
e
(f) Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama,
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n
n
3
TBSO
TBSO
TBSO
TBSO
O
O
n=1
Ph
O
Ph
O
O
O
38: n=0
39: n=1
40: n=0, X=O
41: n=1, X=O
42: n=1, X=CH2
f
(2) 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. (c) For a review,
see: Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M.
Toxicon 1999, 37, 125; see also the references cited in ref.1i.
(3) For the total synthesis of CTX3C, a congener of ciguatoxin,
see: Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.;
Me
Me
OH
O
X
h
i
TBSO
TBSO
R1O
O
40
Ph
Ph
R2O
44: X=O, R1=R2=TBS
O
O
O
O
43
j
k
l
45: X=CH2, R1=R2=TBS
46: X=CH2, R1=R2=H
47: X=CH2, R1=H, R2=TBDPS
N
N
Mes
Cl
Mes
Maruyama, M.; Oguri, H.; Satake, M. Science 2001, 294,
1904.
Ru=CHPh
PCy3
Cl
NOEs
48
Me
(4) For recent synthetic studies on ciguatoxins, see: (a) Sasaki,
M.; Noguchi, T.; Tachibana, K. J. Org. Chem. 2002, 67,
3301. (b) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183.
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Ogasawara, Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002,
58, 1835. (e) Kira, K.; Hamajima, A.; Isobe, M. Tetrahedron
2002, 58, 1875. (f) Sasaki, M.; Ishikawa, M.; Fuwa, H.;
Tachibana, K. Tetrahedron 2002, 58, 1889. (g) Candenas,
M. L.; Pinto, F. M.; Cintado, C. G.; Morales, E. Q.; Brouard,
I.; Díaz, M. T.; Rico, M.; Rodríguez, E.; Rodríguez, R. M.;
Pérez, R.; Pérez, R. L.; Martín, J. D. Tetrahedron 2002, 58,
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K. Angew. Chem. Int. Ed. 2001, 40, 1090. (i) Oishi, T.;
Tanaka, S.-I.; Ogasawara, Y.; Maeda, K.; Oguri, H.; Hirama,
M. Synlett 2001, 952. (j) Imai, H.; Uehara, H.; Inoue, M.;
Oguri, H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42,
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(l) Oguri, H.; Tanaka, S.; Oishi, T.; Hirama, M. Tetrahedron
Lett. 2000, 41, 975. (m) Sasaki, M.; Noguchi, K.; Fuwa, H.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 1425. (n) Kira,
K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951. (o) Liu, T.-
Z.; Isobe, M. Tetrahedron 2000, 56, 5391. (p) Liu, T.-Z.;
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M. A.; Kulker, C.; Overkleeft, H. S.; van der Marel, G. A.;
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(v) Eriksson, L.; Guy, S.; Perlmutter, P.; Lewis, R. J. Org.
Chem. 1999, 64, 8396. (w) Sasaki, M.; Inoue, M.;
H
Me
5
I
H
m
n
H
HO
HO
O
O
7
3
Ph
Ph
O
O
9
O
O
1
49
4
TBDPSO
TBDPSO
Scheme 4 Reagents and conditions. a) ClCH2SO2Cl (1–1.5
equiv), 2,6-lutidine (2–3 equiv), CH2Cl2, 21–23 °C, 2–2.5 h, 32:
~100%, 33: 98%; b) 30% H2O2, EtOAc, 21–23 °C, 2 h; c) TBSOTf
(3–4.3 equiv), 2,6-lutidine (6–10 equiv), CH2Cl2, 21–25 °C, 2–7 h,
35: 97% from 32, 37: 88% from 33; d) KCN (6 equiv), DMSO, 23–
25 °C, 12–15 h, 38: 95%, 39: 96%; e) DIBALH (1 equiv), CH2Cl2,
–78 °C, 30–40 min, 40: 97%, 41: 88%; f) Ph3PCH3Br (5 equiv),
NaHMDS (4.8 equiv), THF, 22 °C, 2 h, then 41, –78 °C →23 °C, 4
h, 99%; g) (Cy3P)2Cl2Ru=CH2Ph (0.16 equiv), CH2Cl2 (3 mM of
42), reflux, 3 h, 98%; h) MeMgBr (2 equiv), Et2O, 0 °C, 1.5 h, 89%;
i) DMPI (2 equiv), NaHCO3 (2 equiv), CH2Cl2, 0 →23 °C, 1 h,
~100%; j) Tebbe reagent (5 equiv), THF, 0 °C, 5 min, 88%; k)
TBAF (3.5 equiv), THF, 23 °C, 14 h, ~100%; l) TBDPSCl (2 equiv),
imidazole (6 equiv), DMF, 23 °C, 17 h, 77%; m) 48 (0.1 equiv),
CH2Cl2 (5 mM of 47), reflux,
4
h, 97%; n) H2,
[(cod)(py)(Cy3P)Ir]PF6 (0.3 equiv), CH2Cl2, –20 °C, 4.5 h, 88% (dr
19:1)
Acknowledgement
The authors are grateful to Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC-MS & NMR Laboratory, Graduate School of Agriculture,
Hokkaido University) for the measurements of mass spectra.
Takamatsu, K.; Tachibana, K. J. Org. Chem. 1999, 64,
9399. (x) Inoue, M.; Sasaki, M.; Tachibana, K. J. Org.
Chem. 1999, 64, 9416. (y) Inoue, M.; Sasaki, M.;
Tachibana, K. Tetrahedron 1999, 55, 10949.
Synlett 2002, No. 9, 1496–1499 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Syntheses of the D-, E-, F-, and I-Ring Parts of Ciguatoxin
1499
(5) For synthetic studies on ciguatoxin in this laboratory, see:
(a) Oka, T.; Murai, A. Chem. Lett. 1994, 1611. (b) Oka, T.;
Fujiwara, K.; Murai, A. Tetrahedron 1996, 52, 12091.
(c) Atsuta, H.; Fujiwara, K.; Murai, A. Synlett 1997, 307.
(d) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron Lett. 1997,
38, 8053. (e) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1.
(f) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1998, 54,
21. (g) Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A.
Synlett 1999, 1037. (h) Fujiwara, K.; Tanaka, H.; Murai, A.
Chem. Lett. 2000, 610. (i) Fujiwara, K.; Takaoka, D.;
Kusumi, K.; Kawai, K.; Murai, A. Synlett 2001, 691.
(6) For recent reviews on olefin metathesis, see: (a) Grubbs, R.
H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2067. (c) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (d) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371. (e) Blechert, S. Pure Appl. Chem. 1999,
71, 1393. (f) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39,
3013.
(7) For the construction of an 8-membered cyclic trisubstituted
alkene by the RCM reaction using Grubbs’ second
generation catalyst 48,21 see: (a) Fürstner, A.; Thiel, O. R.;
Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem.
2000, 65, 2204. (b) See also: Fürstner, A.; Thiel, O. R.;
Ackermann, L. Org. Lett. 2001, 3, 449.
(8) The similar ring cleavage of a C-glycoside for the
preparation of a RCM precursor having a chiral dialkyl ether
part has been applied for the total synthesis of prelaureatin in
this laboratory: Fujiwara, K.S.; Souma, S.; Mishima, H.;
Murai, A. Synlett 2002, 1493.
H, d, J = 5.7 Hz, 6-OH), 1.24 (9 H, s, t-Bu); IR (film): 3487,
2971, 2860, 1729, 1481, 1456, 1399, 1287, 1167, 1115,
1032, 977, 752, 698 cm–1; HR-EIMS, calcd for C20H26O6
(M)+: 362.1729, found: 362.1722.
(17) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(b) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480. (c) Mancuso, A. J.; Swern, D. Synthesis
1981, 165.
(18) (a) Shimizu, T.; Hiranuma, S.; Nakata, T. Tetrahedron Lett.
1996, 37, 6145. (b) Shimizu, T.; Ohzeki, T.; Hiramoto, K.;
Hori, N.; Nakata, T. Synthesis 1999, 1373.
(19) Representative data for 3: a colorless oil; [α]D21 –9.2 (c 0.29,
CHCl3); 1H NMR (400 MHz, CDCl3, 55 °C), δ 7.28–7.48 (5
H, m, Ph), 5.74–5.82 (2 H, m, H5, H6), 5.40 (1 H, s, acetal),
4.52 (1 H, dd, J = 4.3, 10.3 Hz, H1eq), 3.77 (1 H, dd, J = 1.8,
10.6 Hz, H10a), 3.62–3.70 (2 H, m, H3, H8), 3.57 (1 H, dt, J
= 4.3, 10.3 Hz, H2), 3.50 (1 H, t, J = 10.3 Hz, H1ax), 3.44 (1
H, dd, J = 7.7, 10.6 Hz, H10b), 3.32 (1 H, dt, J = 1.8, 7.7 Hz,
H9), 2.68–2.80 (1 H, m, H4a), 2.44–2.58 (2 H, m, H7a,
H4b), 2.28–2.43 (1 H, m, H7b), 0.91 (9 H, s, TBS), 0.90 (9
H, s, TBS), 0.098 (3 H, s, TBS), 0.070 (3 H, s, TBS), 0.066
(3 H, s, TBS), 0.049 (3 H, s, TBS); IR(film): 2955, 2928,
2856, 1471, 1462, 1389, 1361, 1294, 1258, 1213, 1148,
1103, 1027, 977, 836, 811, 776, 747, 665 cm–1; HR-FDMS,
calcd for C29H51O5Si2 (M + H)+: 535.3298, found: 535.3275.
(20) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem.
Soc. 1978, 100, 3611. (b) Tebbe, F. N.; Parshall, G. W.;
Reddy, G. S. J. Am. Chem. Soc. 1979, 101, 5074. (c) Pine,
S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem.
Soc. 1980, 102, 3270. (d) Pine, S. H.; Kim, G.; Lee, V. Org.
Synth. 1990, 69, 72.
(9) Tulshian, D. B.; Fraser-Reid, B. J. Org. Chem. 1984, 49,
518.
(21) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(22) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Chem. Soc.,
Chem. Commun. 1976, 716. (b) Crabtree, R. H.; Felkin, H.;
Fellebeen-Khan, T.; Morris, G. E. J. Organometal. Chem.
1979, 168, 183. (c) Crabtree, R. H.; Davis, M. W.
(10) Cyanation of 8 was performed by the modified method of the
following report: De Las Heras, F. G.; San Felix, A.;
Fernández-Resa, P. Tetrahedron 1983, 39, 1617.
(11) Stereochemistry of the allylic hydroxy group in 14 or the
homoallylic one in 16 was confirmed by 1H NMR using
modified Mosher’s method. See: Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
(12) Hoffmann, R. W.; Endesfelder, A.; Zeiß, H.-J. Carbohydr.
Res. 1983, 123, 320.
(13) Ferrier, R. J. Methods Carbohydr. Chem. 1972, 6, 419.
(14) Evans, D. A.; Polniaszek, R. P. Tetrahedron Lett. 1986, 27,
5683.
Organometallics 1983, 2, 681. (d) Stork, G.; Kahne, D. E. J.
Am. Chem. Soc. 1983, 105, 1072.
(23) Representative data for 4: a colorless oil; [α]D25 +13.3 (c
0.15, CHCl3); 1H NMR [400 MHz, C6D6–CDCl3 (1:1)], δ
7.66–7.72 (4 H, m, Ph), 7.51–7.47 (2 H, m, Ph), 7.33–7.15
(9 H, m, Ph), 5.29 (1 H, s, acetal), 4.08–4.17 (1 H, m, H1eq),
3.75 (1 H, dd, J = 10.5, 5.4 Hz, H9a), 3.69 (1 H, dd, J = 10.5,
5.9 Hz, H9b), 3.50–3.59 (1 H, m, H7), 3.42–3.50 (1 H, m,
H3), 3.35–3.41 (2 H, m, H1ax, H2), 3.26 (1 H, brdt, J = 8.9,
5.5 Hz, H8), 2.28 (1 H, m, 7-OH), 1.91 (1 H, brdd, J = 13.8,
3.5 Hz, H4a), 1.62–1.64 (1 H, m, H5), 1.53–1.62 (3 H, m,
H4b, H6), 1.09 (9 H, s, t-Bu), 1.00 (3 H, d, J = 7.1 Hz, 5-Me);
IR(film): 3490, 3071, 3047, 2928, 2857, 1589, 1455, 1428,
1391, 1372, 1292, 1215, 1112, 1029, 916, 823, 744, 701, 615
cm–1; HR-EIMS, calcd for C29H33O5Si (M – t-Bu)+:
489.2097, found: 489.2105.
(15) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856.
(16) Representative data for 2: a colorless oil; [α]D22 +23.3 (c,
0.06, CHCl3); 1H NMR (300 MHz, CDCl3), δ 7.48 (2 H, m,
Ph), 7.36 (3 H, m, Ph), 5.77 (2 H, m, H4, H5), 5.30 (1 H, s,
acetal), 4.53 (1 H, dd, J = 12, 4.3 Hz, H8a), 4.31–4.17 (4 H,
m, H1eq, H3, H6, H8b), 3.64 (1 H, t, J = 10 Hz, H1ax), 3.60–
3.56 (1 H, m, H7), 3.52 (1 H, dt, J = 10, 4.8 Hz, H2), 2.92 (1
Synlett 2002, No. 9, 1496–1499 ISSN 0936-5214 © Thieme Stuttgart · New York