Synthesis of the C42-C52 part of ciguatoxin CTX3C

Article abstract of DOI:10.1016/j.tetlet.2005.09.163

The C42-C52 part of ciguatoxin CTX3C (1) was synthesized from tri-O-acetyl d-glucal. The synthetic segment had a tetrahydropyran ring corresponding to the 'C49-reduced' L-ring of 1, designed to avoid side reactions due to acid-labile C49 acetal carbon dur

Full text of DOI:10.1016/j.tetlet.2005.09.163

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8279–8283
Synthesis of the C42–C52 part of ciguatoxin CTX3C
Daisuke Domon, Kenshu Fujiwara,* Yuko Ohtaniuchi, Akihiro Takezawa,
Sayaka Takeda, Hidekazu Kawasaki, Akio Murai, Hidethoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 2 September 2005; revised 22 September 2005; accepted 28 September 2005
Available online 17 October 2005
Abstract—The C42–C52 part of ciguatoxin CTX3C (1) was synthesized from tri-O-acetyl D-glucal. The synthetic segment had a tetra-
hydropyran ring corresponding to the ꢀC49-reducedꢁ L-ring of 1, designed to avoid side reactions due to acid-labile C49 acetal car-
bon during acidic reductive conditions planned in further synthesis toward 1. The vicinal dimethyl part at C47–C48 was constructed
by a stepwise conjugate addition/methylation procedure. The C50–C52 unit was installed by Grignard addition of the C3 unit fol-
lowed by spirocyclization and reductive cleavage of the spirocyclic acetal. Stereoselective assembly of the C42–C44 part was
achieved by Brownꢁs asymmetric crotylboration.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Ciguatoxin CTX3C (1) (Fig. 1), isolated as a causative
toxin of ciguatera fish poisoning from cultured dinofla-
gellate Gambierdiscus toxicus by Yasumoto, has potent
neurotoxicity and a complex trans-fused polycyclic ether
structure.1–3 The remarkable features of 1 prompted us
to start our program toward total synthesis of 1.4 Here,
the synthesis of the C42–C52 part (5) of 1 is described.
the synthesis of 2, the predictable instability of its spiro-
cyclic acetal part (C49) under the reductive conditions
during the JK ring formation compelled us to revise
the design of the C42–C52 part.5 Therefore, tetrahydro-
pyran 5 was selected as a stable C42–C52 part and was
envisaged to be synthesized from spirocyclic acetal 6,
which would be prepared from 7 via a stepwise Grignard
addition/spiroacetalization process, by an asymmetric
aldol or crotylboration reaction constructing the C42–
C44 part and by reductive cleavage of the spirocyclic
acetal part. Tri-O-acetyl D-glucal (9) was selected as
the starting material for the preparation of 7, where
inversion of stereochemistry at C46 and C47, lactone
formation, and introduction of two methyl groups at
C47 and C48 were intended.
In our program, the C42–C52 part was planned to be
connected with the C32–C41 part (3) to construct the
IJKLM-ring part (2) of 1 by our method based on
anion-coupling and reductive etherification reactions
(Scheme 1).4g Although spirocyclic acetal 4 was initially
designed as a straightforward synthetic intermediate for
First, spirocyclic acetal 6 was synthesized as shown in
Scheme 2. After the starting 9 was transformed into 10
by known procedure,6 the alcohol 10 was treated with
3,4-dimethoxybenzyl (DMB) alcohol and t-BuOK to
give 11 (80%) in accordance with Crottiꢁs method.6 Pro-
tection of 11 as a TBS ether followed by removal of the
DMB group provided hemiacetal 13 (overall 79%),
which was oxidized with TEMPO under basic condi-
tions to afford a,b-unsaturated lactone 8 (93%).7 The
lactone 8 was reacted with Me2CuLi to produce 14 as
a single isomer (98%). Deprotonation of 14 with
NHMDS followed by the addition of MeI resulted in
the exclusive formation of 15 (98%).8 The trityl group
of 15 was detached with BCl3 in CH2Cl2 to afford 16
in good yield (86%).9 After mesylation of the alcohol
Me
HO
H
Me
H
O
Me
I
O
H
42
H
H
H
H
J
G
O
OH
H
H
H
H
H
H
O
O
H
O
B
E
H
H
O
K
H
F
D
H
C
O
H
O
H
A
O
O
O
52
H
L
O
M
H
Me
OH
Me
Ciguatoxin CTX3C (1)
Figure 1.
Keywords: Ciguatoxin CTX3C; Natural product synthesis; Reductive
ring-opening; Oxidative cyclization.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.163

8280
D. Domon et al. / Tetrahedron Letters 46 (2005) 8279–8283
TrO
TrO
Me
Me
H
Me
OBn
O
O
OR1
OBn
H
O
L
H
H
43
ref. 6
O
J
O
a
d
44
52
42
O
O
52
O
K
I
9
R2O
49
M
BnO
BnO
MsO
TBSO
Me
O
O
H
H
11: R1=DMB, R2=H
OH
Me
Me
b
c
Me
32
10
12: R1=DMB, R2=TBS
13: R1=H, R2=TBS
4
2
DMB: 3,4-Dimethoxybenzyl
RO
TBDPSO
Me
Me
OBn
52
OR
41
O
TrO
TrO
42
O
O
O
e
O
O
O
O
49
+
f
i
BnO
BnO
TBSO
SMe
O
48
MeS
O
47
47
Me
TBSO
TBSO
TBSO
Me
Me
32
3
5
Me
14
Me
8
15: R=Tr
16: R=H
17: R=Ms
g
h
52
O
O
O
O
EEO
HO
HO
45
49
47
52
50
TBSO
48 Me
RO
TESO
TBSO
Me
O
HO
Me
Me
6
O
OH
Me
O
O
O
j
l
7
TBSO
TBSO
k
Me TBSO
Me
Me
Me
7: R=H
19: R=TES
Me
O
O
O
TrO
AcO
AcO
18
20
TBSO
OAc
52
52
52
OH
OR
OR
8
Tri-O-acetyl D-glucal (9)
O
O
O
O
O
O
m
TBSO
n
49
49
49
Scheme 1.
+
Me TBSO
Me TBSO
Me
Me
Me
Me
16 followed by basic treatment, the resulting epoxide 18
was cyclized by a catalytic amount of CSA into lactone 7
(overall 91%), which was protected with TESCl to give
19 (98%). Installation of an ethoxyethyl-protected
three-carbon unit10 corresponding to the C50–C52 part
as a Grignard reagent at C49 of 19 produced 20
(100%). When the hemiacetal 20 was treated with CSA
in CH2Cl2, detachment of the ethoxyethyl and TES
groups as well as the subsequent spirocyclization took
place to give 6 as an inseparable 3:1 mixture of diaste-
reomers (89%). After pivaloate ester formation from 6,
the resulting diastereomers 21a and 21b were separated
(21a: 67%, 21b: 22%) and transformed into 6a (98%)
and 6b (100%), respectively. Stereochemistry of 6a was
determined by X-ray crystallographic analysis of its
crystalline TBDPS ether 22 (colorless needles, mp 83–
84 ꢁC) (Fig. 2).11 Thus, the spirocyclic acetal 6a having
the same stereochemistry at C49 as 1 was obtained as
a major product.
6
21a: R=Piv
6a: R=H
22: R=TBDPS
21b: R=Piv
6b: R=H
p
o
q
Scheme 2. Reagents and conditions: (a) t-BuOK, DMBOH, PhH,
23 ꢁC, 2 h, 80%; (b) TBSCl, imidazole, DMF, 23 ꢁC, 2 h, 99%; (c)
DDQ, CH2Cl2–pH 7 buffer (10:1), 23 ꢁC, 30 min, 80%; (d) TEMPO,
Bu4NCl, NCS, CH2Cl2–pH 8.6 buffer (1:1), 23 ꢁC, 2 h, 93%; (e)
Me2CuLi, Et2O, ꢀ40 ꢁC, 2 h, 98%; (f) NaHMDS, MeI, THF, ꢀ78 ꢁC,
30 min, 98%; (g) BCl3, CH2Cl2, ꢀ20 ꢁC, 2 h, 86%; (h) MsCl, Et3N,
CH2Cl2, ꢀ20 ꢁC, 1 h; (i) 1 M LiOH, THF, 23 ꢁC, 3 h; (j) CSA, CH2Cl2,
23 ꢁC, 7 h, 91% from 16; (k) TESCl, imidazole, DMF, 23 ꢁC, 30 min,
98%; (l) EEO(CH2)3MgBr, THF, ꢀ20 ꢁC, 30 min, 100%; (m) CSA,
CH2Cl2, 23 ꢁC, 30 min, 89%; (n) PivCl, pyridine, DMAP, CH2Cl2,
23 ꢁC, 12 h, 21a: 67%, 21b: 22%; (o) DIBALH, CH2Cl2, ꢀ78 ꢁC, 1 h,
98%; (p) DIBALH, CH2Cl2, ꢀ78 ꢁC, 30 min, 100%; (q) TBDPSCl,
imidazole, DMAP, DMF, 23 ꢁC, 15 min, 50%.
presence of NOE between H44 and H42ax in 28 display-
ing the axial orientation of these protons and by the
small values of JH43–H44, JH42ax–H43, and JH42eq–H43 in
28 exhibiting the equatorial orientation of H43.
Next, stereoselective construction of the C44–C42 part
was examined. After several attempts to apply aldol or
crotylboration reaction to aldehyde 23, prepared from
6a by Swern oxidation,12 we found that Brownꢁs asym-
metric crotylboration using 24, prepared from (ꢀ)-B-
methoxydiisopinocampheylborane,13 exclusively gave
25 in good yield (90% from 6a) (Scheme 3).14 Stereo-
chemistry of 25 was determined by NMR analysis of
its acetonide derivatives 26 and 28 as follows: the rela-
tionship between C45 and C44 was confirmed by large
JH44–H45 (9.5 Hz) of 26 showing diaxial coupling; the rela-
tive configurations at C44 and C43 were verified by the
During the search for appropriate conditions for direct
benzyl protection of the hydroxy group at C44 of 25,
we encountered a problem of TBS migration from O46
to O44. Since the strong basic conditions with K+ were
found to accelerate and complete the migration, a three-
step protection/deprotection sequence [(i) the TBS
migration to O44 and (2-naphthyl)methyl (NAP)15 pro-
tection at O46, (ii) removal of the TBS group from O44
(overall 71%), and (iii) Bn protection at O44 (ꢁ100%)]

D. Domon et al. / Tetrahedron Letters 46 (2005) 8279–8283
Me
8281
Me
O
O
44
44
O
O
a
c
RO
BnO
25
46
46
NAPO
Me
NAPO
Me
Me
Me
31a
29: R=TBS
30: R=H
b
NAP: (2-Naphthyl)methyl
Scheme 4. Reagents and conditions: (a) NAPBr, t-BuOK, Bu4NI,
THF, 23 ꢁC, 30 min; (b) Bu4NF, THF, 23 ꢁC, 20 h, 71% from 25; (c)
BnBr, t-BuOK, Bu4NI, THF, 23 ꢁC, 30 min (ꢁ100%).
5). Although several Brønsted acids did not induce the
isomerization, Et2OÆBF3 promoted the inversion at
C49 with detachment of the NAP group to give an
inseparable ꢁ3:1 mixture of 32a and 32b, which was
protected again with NAPBr to provide the desired
31a (overall 53%) and recovered 31b (overall 19%).
Thus, the minor component 6b was converted to the nat-
ural type spiroacetal 31a in overall 23% yield in seven
steps.
Figure 2. ORTEP diagram of 22.
42
43
Me
O
O
44
45
R
O
O
b
HO
Me TBSO
Then, reduction of the spirocyclic acetals 31a and 31b
was examined (Scheme 6). Treatment of 31a with large
excess of Et3SiH in the presence of TMSOTf at
ꢀ78 ꢁC in CH2Cl2 exclusively produced 33 (99%).16,17
The configuration at C49 of 33 was determined by the
presence of NOE between H45 and H49. On the other
Me
TBSO
Me Me
Me
Me
)2B
Me
Me
24
6a: R=CH2OH
23: R=CHO
25
a
e, f
c, d
Me
42
52
HO
O
Me
H
45 O
O
O
Me
Me
HO
O 44
O
O
O
Me
Me
O
O
a-e
f
TBSO
Me
BnO
BnO
RO
H
6b
49
49
Me
46
46
Me
27
g
Me
H
NAPO
Me
Me
26
JH44-H45 = 9.5 Hz
Me
Me
31b
32: R=H
31a: R=NAP
g
Me
52
Heq
43 H
42
H
O
O
Scheme 5. Reagents and conditions: (a) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 ꢁC, 10 min; (b) 24, THF, ꢀ78 ꢁC, 2 h, then 2 N NaOH,
H2O2, THF, 23 ꢁC, 12 h, 58% for two steps; (c) NAPBr, t-BuOK,
Bu4NI, THF, 23 ꢁC, 30 min; (d) Bu4NF, THF, 23 ꢁC, 24 h, 74% for
two steps; (e) BnBr, t-BuOK, Bu4NI, THF, 23 ꢁC, 30 min, ꢁ100%; (f)
Et2OÆBF3, CH2Cl2, 0 ꢁC, 3 h, (32a:32b = ꢁ3:1); (g) NAPBr, NaH,
Bu4NI, DMF, 23 ꢁC, 5 h, 31a: 53% for two steps, 31b: 19% for two
steps.
45
O
Hax
Me
44
O
TBSO
Me
JH43-H44 = 2.2 Hz
JH42ax-H43 = 1.7 Hz
JH42eq-H43 = 2.6 Hz
Me
H
Me
NOE
H
28
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 ꢁC, 10 min; (b) 24, THF, ꢀ78 ꢁC, 2 h, then 2 N NaOH,
H2O2, THF, 23 ꢁC, 12 h, 90% from 6a; (c) Bu4NF, THF, 23 ꢁC, 1 h,
69%; (d) 2,2-dimethoxypropane, PPTS, DMF, 23 ꢁC, 2 h, 85%; (e)
OsO4, NMO, 1,4-dioxane–H2O (1:1), 23 ꢁC, 6 h, then NaIO4, 12 h; (f)
NaBH4, MeOH, 23 ꢁC, 20 min; (g) 2,2-dimethoxypropane, PPTS,
DMF, 23 ꢁC, 5 h, 51% from 25.
NOE
H
Me
H
OH
O
a
c
b
BnO
45
49
31a
31b
31a
31b
+
NAPO
Me
1.3 : 1
was performed for the benzyl protection of O44 to pro-
duce 31a in good yield (Scheme 4).
Me
33
At this stage, conversion of 6b to a natural type spiro-
cyclic acetal was investigated. Since 6b could not be
isomerized into 6a even after several attempts, advanced
synthetic intermediate 31b, prepared from 6b in a similar
manner as 31a (overall 43%), was examined for the
isomerization into 31a under acidic conditions (Scheme
side products
33
+
Scheme 6. Reagents and conditions: (a) TMSOTf, Et3SiH–CH2Cl2
(1:1), ꢀ78 ꢁC, 15 h, 33: 99%; (b) iodobenzene diacetate, I2, hm (a 500 W
tungsten lamp), cyclohexane, 23 ꢁC, 1 h, 70% (31a:31b = 1.3:1); (c)
TMSOTf, Et3SiH–CH2Cl2 (1:1), ꢀ78 ꢁC, 5 h, 33: 16%.

8282
D. Domon et al. / Tetrahedron Letters 46 (2005) 8279–8283
ments of mass spectra. This work was supported by a
Me
H
Me
H
TBDPSO
TBDPSO
X
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
H
H
O
O
a
c
BnO
RO
BnO
TBSO
33
Me
Me
Me
Me
34: R=NAP
35: R=H
36: X=CH2
5: X=O
b
d
References and notes
1. Isolation: Satake, M.; Murata, M.; Yasumoto, T. Tetra-
hedron Lett. 1993, 34, 1975.
Scheme 7. Reagents and conditions: (a) TBDPSCl, imidazole, DMF,
23 ꢁC, 30 min, 96%; (b) DDQ, CH2Cl2–pH 7 buffer (10:1), 23 ꢁC,
10 min, 93%; (c) TBSOTf, 2,6-lutidine, CH2Cl2, 23 ꢁC, 10 h, 91%; (d)
OsO4, NMO, 1,4-dioxane–H2O (1:1), 23 ꢁC, 20 h, then NaIO4, 1 h,
88%.
2. Total synthesis of CTX3C: (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)
Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasa-
wara, Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002, 58,
1835; (d) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.;
Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.; Hirama, M.
Tetrahedron 2002, 58, 6493; (e) Kobayashi, S.; Takahashi,
Y.; Komano, K.; Alizadeh, B. H.; Kawada, Y.; Oishi, T.;
Tanaka, S.-i.; Ogasawara, Y.; Sasaki, S.-y.; Hirama, M.
Tetrahedron 2004, 60, 8375; (f) Inoue, M.; Yamashita, S.;
Tatami, A.; Miyazaki, K.; Hirama, M. J. Org. Chem.
2004, 69, 2797; Reviews: (g) Inoue, M.; Hirama, M.
Synlett 2004, 57; (h) Inoue, M.; Miyazaki, K.; Uehara, H.;
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2004, 101, 12013; (i) Inoue, M.; Hirama, M. Acc. Chem.
Res. 2004, 37, 961.
3. Recent synthetic studies on ciguatoxins by other groups:
(a) Kobayashi, S.; Alizadeh, B. H.; Sasaki, S.-y.; Oguri,
H.; Hirama, M. Org. Lett. 2004, 6, 751; (b) Baba, T.;
Takai, S.; Sawada, N.; Isobe, M. Synlett 2004, 603; (c)
Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59,
6851; (d) Fuwa, H.; Fujikawa, S.; Tachibana, K.; Taka-
kura, H.; Sasaki, M. Tetrahedron Lett. 2004, 45, 4795; (e)
Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org.
Lett. 2002, 4, 2771; (f) Bond, S.; Perlmutter, P. Tetrahe-
dron 2002, 58, 1779; (g) Candenas, M. L.; Pinto, F. J.;
hand, reduction of 31b under the same conditions gave
33 in low yield (16%) along with unknown side products.
The alcohol 33 could return to 31 by a photo-induced
radical process using iodobenzene diacetate and I2
(70%, 31a:31b = 1.3:1),18 thereby establishing the final
M-ring forming process, planned in the synthesis of 2.
The final process in the synthesis of 5 is illustrated in
Scheme 7. Protection of 33 with TBDPSCl followed by
removal of the NAP group with DDQ and protection
of the resulting hydroxy group with TBSOTf produced
36 (overall 81%), which was converted to 519 through
a two-step dihydroxylation/oxidative cleavage process
(88%). Thus the C42–C52 part 5 was synthesized from
known alcohol 10 in 25 steps in 11% overall yield.20
In conclusion, the C42–C52 part (5) of 1 was synthesized
from 10, prepared from tri-O-acetyl D-glucal by Crottiꢁs
method. The tetrahydropyran ring of 5 corresponding to
the ꢀC49-reducedꢁ L-ring of 1 was designed to avoid side
reactions due to acid-labile C49 acetal carbon during
acidic reductive conditions planned in further synthesis
toward 1. The vicinal dimethyl part at C47–C48 was
constructed by a stepwise conjugate addition/methyla-
tion procedure. The C50–C52 unit was installed by
Grignard addition of the C3 unit followed by spirocycli-
zation and reductive cleavage of the resulting spirocyclic
acetal. Stereoselective assembly of the C42–C44 part
was achieved by Brownꢁs asymmetric crotylboration.
Further studies toward total synthesis of 1 are in pro-
gress in this laboratory.
´
Cintada, C. G.; Morales, E. Q.; Brouard, I.; Dıaz, M. T.;
´
´
´
Rico, M.; Rodrıguez, E.; Rodrıguez, R. M.; Perez, R.;
´
´
Perez, R. L.; Martın, J. D. Tetrahedron 2002, 58, 1921.
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(i) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.;
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5. Hirama reported the reductive etherification reaction
forming the C41–O(C46) bond in 2, where the spirocyclic
LM-ring remained intact.2d,f However, our preliminary
experiments toward the construction of 2 via our original
route, shown in Scheme 1, displayed significant problems
due to the spirocyclic acetal part. The details will be
described elsewhere.
Supplementary data
Crystallographic data (excluding structure factors) of 22
have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication num-
bers CCDC 282747. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS and NMR Laboratory, Graduate School of
Agriculture, Hokkaido University), for the measure-

D. Domon et al. / Tetrahedron Letters 46 (2005) 8279–8283
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´ ´
18. (a) Concepcion, J. I.; Francisco, C. G.; Hernandez, R.;
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Salazar, J. A.; Suarez, E. Tetrahedron Lett. 1984, 25, 1953;
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9. Jones, G. B.; Chapman, B. J.; Huber, R. S.; Beaty, R.
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´
55, 7661; See, also: (d) Cekovic, Z. Tetrahedron 2003, 59,
10. (a) Descoins, C.; Samain, D.; Lalanne-Casson, B.; Gollois,
M. Bull. Soc. Chim. Fr. 1977, 941; (b) Leyendecker, F.;
Drouin, J.; Debegge, J. J.; Conia, J. M. Tetrahedron Lett.
1977, 18, 1591; (c) Shea, K. J.; Wise, S.; Burke, L. D.;
Davis, P. D.; Gilman, J. W.; Greeley, A. C. J. Am. Chem.
Soc. 1982, 104, 5708.
8073.
23
1
19. Selected spectral data of 5: ½aꢂD ꢀ3.1 (c 0.48, CHCl3); H
NMR (300 MHz, C6D6, C6HD5 as 7.15 ppm): d 0.02 (6H,
s), 0.58 (3H, d, J = 6.4 Hz), 0.84 (3H, d, J = 6.2 Hz), 0.91
(9H, s), 0.95–1.34 (3H, m), 1.10 (9H, s), 1.25 (3H, d,
J = 7.2 Hz), 1.56–1.74 (2H, m), 1.77–1.85 (1H, m), 2.55
(1H, m), 2.74 (1H, br dt, J = 2.2, 8.4 Hz), 2.98 (1H, t,
J = 9.4 Hz), 3.47 (1H, br d, J = 9.4 Hz), 3.65 (2H, br dd,
J = 6.1, 5.9 Hz), 4.14 (1H, br d, J = 4.4 Hz), 4.41 (1H,
d, J = 11.9 Hz), 4.52 (1H, d, J = 11.9 Hz), 7.04–7.24
(11H, m), 7.69–7.72 (4H, m), 9.80 (1H, br s); 13C NMR
(75 MHz, C6D6, 13CC5D6 as 128.0 ppm): d ꢀ3.1 (CH3),
ꢀ2.3 (CH3), 10.9 (CH3), 14.5 (CH3), 16.6 (CH3), 18.7 (C),
19.5 (C), 26.4 (CH3) · 3, 27.1 (CH3) · 3, 28.6 (CH2),
29.7 (CH2), 41.3 (CH), 45.5 (CH), 47.5 (CH), 64.2 (CH2),
71.4 (CH2), 74.3 (CH), 77.5 (CH), 82.0 (CH), 83.3
(CH),127.56 (CH) · 2, 127.59 (CH), 128.0 (CH) · 4,
128.5 (CH) · 2, 129.9 (CH) · 2, 134.5 (C) · 2, 136.0
(CH) · 4, 139.3 (C), 202.9 (CH); IR (film) mmax 3070,
2929, 2857, 2711, 1725, 1589, 1472, 1462, 1428, 1388, 1361,
1258, 1216, 1187, 1111, 1028, 1006, 939, 921, 867, 835, 775,
757, 738, 701, 665, 614 cmꢀ1; LR-EIMS, m/z 659 (6.2%,
[M ꢀt-Bu]+), 551 (47%, [Mꢀ(t-Bu+BnOH)]+), 91 (bp);
HR-EIMS, calcd for C39H55O5Si2 [Mꢀt-Bu]+: 659.3588,
found: 659.3594.
11. Crystal data of 22: C33H52O4Si2, M 568.94, monoclinic
˚
˚
P21
(No.
4),
a = 12.136(4) A,
b = 10.699(3) A,
3
˚
˚
c = 12.758(4) A, b = 96.935(4), U = 1644.4(9) A , Dc
(Z = 2) = 1.149 g/cm3, T = 153 K, l = 1.41 cmꢀ1
. The
final R value is 0.028 for 5469 independent reflections
with I > 2rI and 353 parameters.
12. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2048.
13. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1990, 108,
5919.
14. Although both Evansꢁ asymmetric aldol reaction and
Roushꢁs crotylboration gave excellent selectivities in this
system, both production yields were modest, cf. Ref. 4g
and 2d.
15. (a) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998,
63, 4172–4173; (b) Xia, J.; Abbas, S. A.; Locke, R. D.;
Piskorz, C. F.; Alderfer, J. L.; Matta, K. L. Tetrahedron
Lett. 2000, 41, 169–173; (c) Wright, J. A.; Yu, J.; Spencer,
J. B. Tetrahedron Lett. 2001, 42, 4033–4036.
16. When the reduction was performed at 0 ꢁC, the yield of 33
decreased and considerable amounts of unknown side
products were given.
20. The total yield was based on the linear route from
10 to 5 excluding the isomerization process from 6b to
31a.