Synthesis of a common key intermediate for (-)-tetrodotoxin and its analogs

Article abstract of DOI:10.1016/S0040-4020(01)00258-7

A key intermediate for tetrodotoxin and its analogs such as (-)-5,11-dideoxytetrodotoxin was stereoselectively synthesized from a chiral starting material, levoglucosenone, via Diels-Alder reaction and the Overman rearrangement as key steps. The Overman r

Full text of DOI:10.1016/S0040-4020(01)00258-7

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 3875±3883
Synthesis of a common key intermediate for ꢀ2)-tetrodotoxin
and its analogs
Toshio Nishikawa, Masanori Asai, Norio Ohyabu, Noboru Yamamoto, Yoshio Fukuda
and Minoru Isobep
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 5 February 2001; accepted 27 February 2001
AbstractÐA key intermediate for tetrodotoxin and its analogs such as )2)-5,11-dideoxytetrodotoxin was stereoselectively synthesized from
a chiral starting material, levoglucosenone, via Diels±Alder reaction and the Overman rearrangement as key steps. The Overman rearrange-
ment of the precursor bearing hydroxy group of C-8 was also described. q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
these questions, labeled tetrodotoxin derivatives have been
highly desirable;11 however, derivatization of naturally
occurring tetrodotoxin was so dif®cult due to the unusual
chemical properties. In spite of many synthetic efforts,12
only one total synthesis of the racemate was reported by
Kishi±Goto and co-workers in 1972.13 The novel structure
including contiguous asymmetric centers, polyhydroxylated
cyclohexane ring, a novel zwitter ion structure between
cyclic guanidine and ortho ester still present a challenge
for total synthesis. Recently, we achieved stereocontrolled
synthesis of )2)-5,11-dideoxytetrodotoxin )5).14 In this
paper, we describe a practical synthesis of a versatile inter-
mediate for tetrodotoxin and its analogs as shown in Fig. 1.
Tetrodotoxin )1) is one of the most famous marine natural
products because of its frequent involvement in fatal poison-
ing and the unique chemical structure.1 The structure was
elucidated in 1964 by three groups including Hirata±Goto,
Tsuda and Woodward.2 As the speci®c inhibition of sodium
ion in¯ux through voltage dependent channel proteins,
tetrodotoxin has been served as an important biochemical
tool in neurophysiological area.3 Tetrodotoxin and its
analogs )Fig. 1)4 have been isolated not only from puffer
®sh, but also from other animals such as frog, newt,
octopus;5 farm-raised puffer ®sh lacked the toxin, but
accumulated it when fed the toxic puffer ®sh livers.6 In
1986, tetrodotoxin producing bacteria were reported.7
These studies strongly suggested the food chain for accu-
mulation of the toxin into puffer ®sh from microorganisms.
Biologically interesting issues have been reported such as
biosynthesis of tetrodotoxin,8 detoxication, molecular
mechanism for accumulation of tetrodotoxin in puffer
®sh,9 actual biological function,10 etc. In order to answer
2. Results and discussion
2.1. Synthetic plan
Our synthetic plan for the tetrodotoxins is illustrated in
Scheme 1. Tetrodotoxin and its analogs A could be
Figure 1. Structures of tetrodotoxin and its analogs.
Keywords: tetrodotoxin; Diels±Alder reaction; Overman rearrangement; levoglucosenone; A-strain.
Corresponding author. Tel.: 181-52-789-4109; fax: 181-52-789-4111; e-mail: isobem@agr.nagoya-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00258-7

3876
T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
Scheme 1. Retrosynthetic plan for tetrodotoxin and its analogs.
synthesized from the corresponding lactone intermediate B
having all the requisite functionalities of a cyclohexane ring
for a tetrodotoxin molecule. The lactone B was retrosynthe-
sized into C, in which a hydroxy group at C-8 is a common
functionality found in all the naturally occurring tetrodo-
toxins. For introduction of the hydroxy group, two routes
were explored. The ®rst route is oxygenation at C-8 of D
)D!C), which could be synthesized from the Overman
rearrangement15 of E. The second one is to introduce a
hydroxy group into the precursor E followed by the
Overman rearrangement )E!C). The former route was
ultimately adopted in our synthesis of )2)-5,11-dideoxy-
tetrodotoxin )5) through a novel neighboring group partici-
pation of the trichloroacetamide because of the total
ef®ciency.14 The latter approach will also be disclosed in
this paper. The nitrogen functionality of D or C would be
introduced by the so-called Overman rearrangement from
exo-allylic alcohol E )RˆH or OR) via allylic trichloro-
acetimidate15 in which an allylic strain16 could be operative
with high stereoselectivity. The precursor E could arise
from the Diels±Alder reaction between halo-levoglucose-
none F as a chiral starting material and butadiene derivative.
This paper deals with: )i) the details of the practical synthe-
sis of versatile key intermediate D and )ii) an attempt to
introduce a requisite hydroxy group of the C-8 position
before the Overman rearrangement.17
2.2. Diels±Alder reaction
Levoglucosenone 6 has been selected as a chiral starting
material for our tetrodotoxin synthesis )Scheme 2).18
Bromination of levoglucosenone was followed by elimina-
tion of hydrogen bromide with Et3N to give bromolevo-
glucosenone 719 in 91% yield. According to our initial
study using butadiene as the simplest diene for the Diels±
Alder cycloaddition20 to synthesize D )R1ˆH),21 bromo-
levoglucosenone 7 was heated with isoprene in a sealed
tube at 1208C to give an inseparable mixture )7:3) of 8a
and b. The resulting mixture could not be separated even
in the later stages, which prompted us to examine conditions
promoted by Lewis acid in order to improve the selectivity.
Representative results are shown in Table 1. In the presence
Scheme 2. Diels±Alder reaction between 7 and isoprene.
Table 1. Diels±Alder reaction between 7 and isoprene
Entry
Conditions
Solvent
Products
Lewis acid )equiv.)
Temperature
CH 1208Cb
Yield )%)
Ratio )8a/8b)a
1
2
3
4
5
6
±
BF3´OEt2 )0.2)
LiClO4 )5 M)
Sc)OTf)3 )0.3)
BF3´OEt2 )1)
SnCl4 )1)
2Cl2
CH2Cl2
Et2O
CH2Cl2
CH3CN
CH3CN
80
±
7:3
10:1
8:1
10:1
15:1
10:1
c
08C±rt
rt
rt
08C±rt
08C±rt
82
50
76
64
a
1
The ratios were determined by the integration values of H NMR.
The reaction was conducted in a sealed tube.
The yield could not be determined because of inseparable polymer.
b
c

T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
3877
of cat. Lewis acid such as BF3´OEt2, SnCl4, in CH2Cl2, the
product was obtained along with a considerable amount of
polymer, which was dif®cult to remove )entry 2). The
Diels±Alder reaction in LiClO4±ether solution22 gave a
better result )entry 3). Scandium tri¯ate catalyzed reaction23
gave the desired product in moderate yield with better
regioselectivity )entry 4). Further examinations led us to
®nd that the conditions with Lewis acid such as BF3´OEt2,
SnCl4, in acetonitrile were superior in respect to the yield
and the regioselectivity )entries 5 and 6). In particular, a
stoichiometric amount of BF3´OEt2 in acetonitrile24 was
the best condition to give the desired adduct 8a in good
yield with the highest regioselectivity )entry 5). Acetonitrile
as a solvent prevented polymerization to result in good
yield, probably because the solvent attenuated the acidity
of the Lewis acid.
)TFA) in Ac2O25 to afford triacetate 10 in good overall yield.
To introduce an exo-double bond whose Z ole®n geometry
was indispensable for the next stereoselective Overman
rearrangement, the bromoacetate was reduced with Zn±Cu
couple26 to give 11. The pyranose ring of 11 was cleaved
with LiAlH4 to give a triol, in which 1,2-glycol was
protected as acetonide to afford an allylic alcohol 12 as a
precursor for the Overman rearrangement.
The trichloroacetimidate 13 was prepared from the allylic
alcohol 12 with 1,8-diazabicyclo[5,4,0]undec-7-ene )DBU)
and trichloroacetonitrile in CH2Cl2 at 08C. In a large-scale
preparation of imidate from 12 )over 10 g), a lower tempera-
ture around 2208C was recommended. The preferred
conformation of this intermediate 13 is shown in Scheme
3. That is, the acetonide side chain occupies the pseudo-
axial position because of A-strain16 between the exo-allyl
trichloroacetimidate and the acetonide side chain. Conse-
quently, we predicted that nitrogen group should be intro-
duced from the upper face as shown in 13. In fact, the
rearrangement proceeded at a xylene-re¯ux temperature in
the presence of K2CO3 to give the product 14 as a single
2.3. Synthesis of the precursor for the Overman
rearrangement
The ketone 8a was reduced with NaBH4 in methanol to give
the b-alcohol 9, which was treated with tri¯uoroacetic acid
Scheme 3. Synthesis of key intermediate 14.
Scheme 4. Hydroxylation of C-8 and the Overman rearrangement.

3878
T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
stereoisomer in over 90% yield from 12 on a 20 g scale.
Addition of K2CO3 was indispensable to keep the high
yield with high reproducibility.27 The stereochemistry was
con®rmed by comparison to the model compound 15, whose
structure was unambiguously determined by X-ray crystal-
lographic analysis.21
are reported in wave number )cm21). Proton nuclear
magnetic resonance )1H NMR) spectra were recorded on
Brucker ARX-400 )400 MHz) and Varian Gemini-2000
)300 MHz) spectrometers. Carbon nuclear magnetic reso-
nance )13C NMR) spectra were recorded on Brucker
ARX-400 )100 MHz) and Varian Gemini-2000 )75 MHz)
spectrometers. Optical rotations were measured on a
JASCO DIP-370 digital polarimeter. Low resolution mass
spectra were recorded on a JEOL JMS-D 100 )EI), JEOL
DX-705L )FAB) and JEOL Mstation )FAB) spectrometers.
High resolution mass spectra )HRMS) were recorded on
JEOL DX-705L and JEOL Mstation spectrometers, and
reported in m/z. Elemental analyses were performed by
the Analytical Laboratory at the School of Bioagricultural
Sciences, Nagoya University. Reactions were monitored by
thin-layer chromatography carried out on 0.25 mm silica gel
coated glass plates 60F-254 )Merck, Art 5715) using UV
light as visualizing agent and 7% ethanolic phospho-
molybdic acid, or p-anisaldehyde solution and heated as
developing agents. Cica-Merck silica gel )60, particle size
0.063±0.2 mm A STM) was used for open-column chroma-
tography. Preparative thin-layer chromatography separa-
tions were carried out on 0.5 mm silica gel plates 60F-254
)Merck, Art 5774) or prepared silica gel 60 FP-254 )Merck,
Art 7747), layer thickness 2.0 mm. Non-aqueous reactions
were carried out under nitrogen or argon atmosphere unless
otherwise stated. Anhydrous ethyl ether was purchased from
Kanto Chemical Co., Inc. in a bottle as ethyl ether
anhydrous. Dry CH2Cl2 was distilled from CaH2 under
nitrogen atmosphere. Pyridine and triethylamine were
dried over anhydrous KOH. BF3´OEt2 was distilled from
CaH2. All other commercially available reagents were
used as received.
2.4. Overman rearrangement of hydroxylated allylic
imidate
In order to synthesize naturally occurring tetrodotoxin
analogs )Fig. 1), a hydroxy group must be introduced into
the C-8 position. We describe another approach to introduce
the hydroxy group at the C-8 position prior to the rearrange-
ment, while the hydroxy group was introduced by neigh-
boring group participation of 14 in the synthesis of )2)-
5,11-dideoxytetrodotoxin.14 The precursor 20 bearing the
hydroxyl group at the C-8 position was synthesized from
16 as shown in Scheme 4. Allylic oxidation of the C-8
position in 16 was best accomplished with CrO3±pyridine28
in CH2Cl2 to give 17 in moderate yield. The ketone was then
reduced with NaBH4 and CeCl329 to give an alcohol 18 as a
single isomer. The con®guration of C-8 could not be deter-
mined at this stage )vide infra). Protection of the alcohol 18
as t-butyldimethylsilyl )TBS) ether was followed by de-
acetylation to afford the allylic alcohol 20 as a precursor
of the Overman rearrangement. The corresponding imidate
underwent the Overman rearrangement under our modi®ed
conditions )at xylene-re¯ux temperature in the presence of
K2CO3) to afford the desired product 21 in about 60% yield.
We found that K2CO3 prevented the imidate from aromati-
zation under the conditions.27 The reaction proceeded
slower than the Overman rearrangement of 13. Desilylation
of the product 21 with tetra-n-butylammonium ¯uoride
)TBAF) in THF gave a cyclic carbamate 22. The structure
including stereochemistry of the C-8 position was estab-
lished by analysis of the NOESY spectra of 22 as depicted
in Scheme 4. Unfortunately, the con®guration was opposite
to that of naturally occurring tetrodotoxins.
4.1.1. Bromolevoglucosenone 7.19 Levoglucosenone )6)
)60.5 g, 0.479 mol) was dissolved in CH2Cl2 )1.20 L). To
the cooled )at 08C) solution was added bromine )ca. 24 mL.
0.48 mmol) dropwise until the color of the mixture turned
brown. Et3N )134 mL, 0.958 mmol) was added at the same
temperature. After stirring for 30 min, the mixture was
®ltered through the pad of Super-Cel, the ®ltrate was diluted
with CH2Cl2 )1.20 L) and water )600 mL) and partitioned.
The aqueous layer )1.5 L) was extracted with CH2Cl2 )£6).
The combined organic layer was dried over anhydrous
Na2SO4, concentrated under reduced pressure. The residue
was puri®ed by column chromatography )silica gel 650 g,
Et2O/hexaneˆ1:4!1:2!1:1!2:1) to afford 7 )98.0 g,
91%).
3. Conclusion
We established a highly ef®cient and stereocontrolled synth-
esis of a key intermediate for tetrodotoxin. The synthesis
described here is capable of preparing the key intermediate
14 on 50 g scale with high reproducibility. The compound
14 was eventually transformed into )2)-5,11-dideoxytetro-
dotoxin )5).14 This study also indicated that the alcohol such
as 20 could be served as a precursor for the Overman
rearrangement to afford more functionalized nitrogen
containing cyclohexane product. The syntheses of other
tetrodotoxin analogs as shown in Fig. 1from the common
intermediate 14 are currently underway in our laboratory.
4.1.2. Bromoketone 8a. To an ice-cold solution of bromo-
levoglucosenone 7 )70.1g, 0.342 mol) in CH 3CN )1.00 L)
was added BF3´OEt2 )46.0 mL, 0.359 mol) dropwise over
20 min. After stirring at 08C for 20 min, isoprene
)171 mL, 1.71 mol) was added dropwise over 25 min.
After stirring at 08C for 10 min and at rt for additional
1.5 h, the reaction mixture was cooled to 08C, and quenched
with sat. NaHCO3 solution )1L). The mixture was extracted
with AcOEt )1L £1, 0.5 L£2), and the combined organic
extract was washed with water )1L £2) and brine )1L £1).
The solution was dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was puri®ed
by column chromatography )silica gel 1300 g, ether/
hexaneˆ1:10!1:5) to give a bromoketone 8a )75.4 g,
4. Experimental
4.1. General
Melting points were recorded on a Yanaco MP-S3 melting
point apparatus and are not corrected. Infrared spectra were
recorded on a JASCO FT/IR-8300 spectrophotometer and

T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
3879
76%). Mp 90±918C )as colorless prisms from Et2O±
)1H, brd, Jˆ17 Hz, CHAHB±CMevCH), 2.11 )3H, s,
OAc), 2.12 )3H, s, OAc), 2.20 )3H, s, OAc), 2.54±2.76
)3H, m, CHAHB±CMevCH, MeCvCH±CHAHB and
±CH±), 3.57 )1H, brd, Jˆ20 Hz, MeCvCH±CHAHB),
3.96 )1H, ddd, Jˆ10, 4, 3 Hz, O±CH2±CH±O), 4.20 )1H,
dd, Jˆ12, 3 Hz, O±CHAHB±CH±O), 4.26 )1H, dd, Jˆ12,
4 Hz, O±CHAHB±CH±O), 5.07 )1H, brs, AcO±CH), 5.36
)1H, m, MeCvCH), 6.04 )1H, d, Jˆ1Hz, AcO±C H±O).
13C NMR )75 MHz, CDCl3) d 20.7, 20.8, 21.0, 23.2, 28.8,
34.4, 39.1, 64.6, 65.3, 70.0, 71.7, 92.0, 116.5, 130.5, 168.1,
169.4, 170.8. MS )FAB) m/z 359 )M2OAc). HRMS )FAB)
calcd for C15H20O5Br )M2OAc) 359.0494, found 359.0472.
23
hexane). [a]D ˆ21.06 )c 15.3, CHCl3). IR )KBr) nmax
2967, 2921, 2853, 1735, 1625, 1120 cm21 1H NMR
.
)300 MHz, CDCl3) d 1.77 )3H, s, CH3±CvCH), 2.16
)1H, dd, Jˆ16, 5.5 Hz, CHAHB±CMevCH), 2.47 )1H, dd,
Jˆ16, 8 Hz, CHAHB±CMevCH), 2.59 )1H, brd, Jˆ16 Hz,
MeCvCH±CHAHB), 2.88 )1H, brdd, Jˆ8, 5.5 Hz, ±CH±),
2.99 )1H, dd, Jˆ16, 5.5 Hz, MeCvCH±CHAHB), 3.88 )1H,
dd, Jˆ7.5, 5.5 Hz, O±CHAHB±CH±O), 4.48 )1H, brd,
Jˆ5.5 Hz, O±CH2±CH±O), 4.56 )1H, d, Jˆ7.5 Hz,
O±CHAHB±CH±O), 5.27 )1H, s, O±CH±O), 5.47 )1H, m,
MeCvCH). 13C NMR )75 MHz, CDCl3) d 22.7, 34.4, 36.9,
48.2, 56.0, 67.1, 79.2, 100.1, 119.2, 137.4, 195.3. EI-MS m/z
274 )M1), 272 )M1). HRMS )EI) calcd for C11H13O379Br
)M1) 272.0048, found 272.0029. Anal. calcd for
C11H13O3Br: C, 48.53; H, 4.82. Found: C, 48.53; H, 4.98.
10b: Mp 164±1658C )as colorless crystals from Et2O±
26
hexane). [a]D ˆ125.6 )c 1.53, CHCl3). IR )KBr) nmax
2978, 2932, 2889, 1771, 1751, 1736, 1442, 1374, 1229,
1074, 1031 cm21 1H NMR )300 MHz, CDCl3) d 1.73
.
4.1.3. Bromohydrin 9. To an ice-cold solution of bromo-
ketone 8a )22.1g, 81.1mmol) in MeOH )300 mL) was
added NaBH4 )1.53 g, 40.5 mmol) portionwise over
30 min. After stirring at 08C for 10 min, the reaction mixture
was carefully quenched with small amount of AcOH, and
concentrated. The residue was dissolved in CH2Cl2 and
water, and partitioned. The aqueous layer was further
extracted with CH2Cl2 )£2). The combined organic extract
was dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give a crude alcohol 9 )21.9 g) as a dark
brown foam. This material was used for the next reaction
without puri®cation. A portion of this material was puri®ed
by column chromatography )ether/hexaneˆ1:3) to afford
)3H, s, CH3±CvCH), 1.94 )1H, br d, Jˆ18 Hz, CHAHB±
CMevCH), 2.08 )3H, s, OAc), 2.11 )3H, s, OAc), 2.24 )3H,
s, OAc), 2.51±2.65 )2H, m, ±CH± and CHAHB±
CMevCH), 2.81H)1, brd,
Jˆ20 Hz, MeCvCH±
CHAHB), 3.03 )1H, brd, Jˆ20 Hz, MeCvCH±CHAHB),
3.73 )1H, ddd, Jˆ10.5, 5, 2.5 Hz, O±CH2±CH±O), 4.23
)1H, dd, Jˆ12.5, 5 Hz, O±CHAHB±CH±O), 4.29 )1H, dd,
Jˆ12.5, 2.5 Hz, O±CHAHB±CH±O), 5.27 )1H, brs, AcO±
CH), 5.33 )1H, brs, MeCvCH), 6.09 )1H, d, Jˆ1.5 Hz,
AcO±CH±O). 13C NMR )100 MHz, CDCl3) d 20.7, 20.8,
23.4, 28.3, 34.6, 38.7, 64.6, 64.7, 72.0, 3.4, 89.5, 114.8,
131.2, 168.6, 169.9, 170.7. MS )FAB) m/z 359 )M2OAc).
Anal. calcd for C17H23O7Br: C, 48.70; H, 5.53. Found: C,
48.69; H, 5.57.
25
the analytically pure sample. [a]D ˆ268.3 )c 0.98,
CHCl3). IR )KBr) nmax 3442, 2963, 2898, 1475, 1439,
.
1389, 1325, 1239, 1078 cm21
1H NMR )300 MHz,
4.1.5. Hemiacetal 11. A solution of 10a,b )29.4 g,
68.6 mmol) in DMF )500 mL) was mixed with H2O
)100 mL) at 08C and then allowed to warm to rt. An acti-
vated zinc±copper couple )30 g) was added to the reaction
mixture and the reaction vessel was immersed in an oil bath
)at 558C). After vigorous stirring for 1h, the mixture was
cooled to an ice bath temperature. Prolonged reaction time
over 2 h at ca. 608C provided considerably reduced yields
because of product decomposition. The mixture was then
®ltered through a pad of Super-Cel, and the precipitate was
washed with AcOEt. The combined ®ltrate was extracted
with AcOEt )£3). The combined organic extract was
washed with water )£2) and brine )£1), and dried over
anhydrous Na2SO4. The solution was concentrated under
reduced pressure. The residue was puri®ed by column
chromatography )silica gel 350 g, ether/hexaneˆ1:2!1:1)
to give a hemiacetal 11 )13.2 g, 81%) as a light yellow
amorphous solid.
CDCl3) d 1.69 )3H, brs, CH3±CvCH), 2.31±2.38 )2H, m,
CH2±CMevCH), 2.48 )1H, d, Jˆ12.5 Hz, OH), 2.73 )1H, d
quintet, Jˆ17, 2.5 Hz, MeCvCH±CHAHB), 2.92±3.02
)2H, m, MeCvCH±CHAHB and ±CH±), 3.20 )1H, dd,
Jˆ12.5, 2 Hz, HO±CH), 3.74 )1H, dd, Jˆ7.5, 5 Hz,
O±CHAHB±CH±O), 4.27 )1H, dd, Jˆ5, 1.5 Hz, O±CH2±
CH±O), 4.71)1H, d, Jˆ7.5 Hz, O±CHAHB±CH±O), 5.23
)1H, m, MeCvCH), 5.36 )1H, d, Jˆ2 Hz, O±CH±O). 13C
NMR )75 MHz, CDCl3) d 22.6, 33.8, 40.6, 44.6, 67.0, 70.3,
74.0, 78.3, 101.8, 118.0, 133.4. MS )EI) m/z 274 )M1), 272
)M1). HRMS )EI) calcd for C11H15O3Br )M1) 274.0205,
found 274.0201. Anal. calcd for C11H15O3Br: C, 48.02; H,
5.50. Found: C, 47.93; H, 5.76.
4.1.4. Triacetate 10. To an ice-cold solution of the crude
bromohydrin 9 )21.9 g) in Ac2O )220 mL) was added TFA
)22 mL) dropwise over 5 min. After stirring at 08C for
30 min, the reaction mixture was evaporated to remove
TFA. The solution was diluted with toluene )250 mL) and
concentrated in vacuo. The residue was puri®ed by column
chromatography )silica gel 450 g, ether/hexaneˆ1:2!2:1)
to give a triacetate 10 )29.4 g, 85% in 2 steps from 8a) as a
diastereo mixture )10a,bˆ9:1by 1H NMR). Further puri®-
cation by careful column chromatography )ether/hex-
aneˆ1:2) afforded 10a as a white amorphous solid and
10b as colorless crystals )from ether±hexane).
Major isomer: IR )KBr) nmax 3432, 2963, 2908, 1741, 1437,
1368, 1236 cm21. 1H NMR )300 MHz, CDCl3) d 1.68 )3H,
brs, CH3±CvCH), 1.70±1.85 )1H, m, CHAHB±
CMevCH), 2.12 )3H, s, OAc), 2.12±2.21 )1H, m,
CHAHB±CMevCH), 2.42 )1H, m, ±CH±), 2.68±2.98
)2H, m, MeCvCH±CH2), 3.97 )1H, ddd, Jˆ10, 6, 2 Hz,
O±CH2±CH±O), 4.22 )1H, dd, Jˆ12, 6 Hz, O±CHAHB±
CH±O), 4.35 )1H, dd, Jˆ12, 2 Hz, O±CHAHB±CH±O),
5.36 )1H, m, MeCvCH), 5.44 )1H, brs, O±CH±OH),
5.65 )1H, m, HO±CH±CHvC). 13C NMR )75 MHz,
CDCl3) d 20.7, 23.3, 31.4, 32.8, 33.3, 64.5, 70.7, 89.1,
119.0, 119.1, 131.1, 138.7, 171.3. MS )EI) m/z 238 )M1).
26
10a: [a]D ˆ147.8 )c 1.63, CHCl3). IR )KBr) nmax 2969,
2932, 2857, 1748, 1439, 1371, 1232 cm21 1H NMR
)300 MHz, CDCl3) d 1.72 )3H, brs, CH3±CvCH), 1.93
.

3880
T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
HRMS )EI) calcd for C13H18O4 )M1) 238.1205, found
238.1187.
)3H, s, CH3 of acetonide), 1.41 )3H, s, CH3 of acetonide),
1.64 )3H, brs, CH3±CvCH), 1.72 )1H, brd, Jˆ18 Hz,
CHAHB±CMevCH), 2.33 )1H, brd, Jˆ18 Hz, CHAHB±
CMevCH), 2.67 )1H, brd, Jˆ19 Hz, MeCvCH±
CHAHB), 2.94±3.10 )2H, m, MeCvCH±CHAHB and
±CH±), 3.71)1H, dd, Jˆ8, 6.5 Hz, O±CHAHB±CH±O),
4.10 )1H, dd, Jˆ8, 6 Hz, O±CHAHB±CH±O), 4.23 )1H,
dt, Jˆ10, 6.5 Hz, O±CH2±CH±O), 4.77 )1H, ddd, Jˆ12,
6, 2 Hz, O±CHAHB±CHvC), 5.00 )1H, ddd, Jˆ12, 8, 1 Hz,
O±CHAHB±CHvC), 5.38 )1H, brs, MeCvCH), 5.71)1H,
ddd, Jˆ8, 6, 2 Hz, O±CH2±CHvC), 8.25 )1H, brs, NH).
13C NMR )75 MHz, CDCl3) d 23.2, 25.3, 26.7, 32.3, 33.3,
39.8, 65.3, 68.6, 75.7, 91.5, 109.0, 118.2, 120.2, 131.1,
142.5, 162.7. MS )FAB) m/z 382 )M1H), 384 )M1H),
386 )M1H). HRMS )FAB) calcd for C16H23NO3Cl3
)M1H), calcd 382.0743, found 382.0749.
4.1.6. Allylic alcohol 12. LiAlH4 )6.40 g, 0.169 mol) was
placed in a 1L three-necked round-bottomed ¯ask equipped
with a magnetic stirrer, a dropping funnel and nitrogen inlet,
and anhydrous Et2O )400 mL) was added. After cooling to
08C, the hemiacetal 11 )16.0 g, 67.6 mmol) in ether )40 mL)
was added by use of dropping funnel over 30 min. The
suspension was re¯uxed for 5 h, and then cooled to
2788C. The reaction was carefully quenched with water
and aqueous potassium sodium tartrate. The resulting
mixture was stirred for 2 h and then extracted with AcOEt
)£10). The combined organic extract was dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to
give crude triol )14.4 g) as a colorless oil. To a solution of
the crude triol in acetone )325 mL) and 2,2-dimethoxy-
propane )16.3 mL, 0.133 mol) was added dl-camphor-
sulfonic acid )CSA) )3.13 g, 13.5 mmol). After stirring at
rt for 15 min, the reaction mixture was quenched with sat.
NaHCO3 solution, and extracted with CH2Cl2 )£3). The
combined organic extract was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
residue was puri®ed by column chromatography )silica gel
300 g, ether/hexaneˆ1:3!1:2!1:1!2:1) to give an allylic
alcohol 12 )11.8 g, 74%, 2 steps from 11) as a colorless oil.
4.1.8. Trichloroacetamide 14. The crude imidate 13 was
dissolved in p-xylene )600 mL) and powdered anhydrous
K2CO3 )1.2 g) was added. The mixture was heated at re¯ux
temperature for 20 h with vigorous stirring. After cooling to
rt, the mixture was ®ltered through a pad of Super-Cel, and
the precipitate was washed with toluene. The combined
®ltrate was evaporated in vacuo. The residue was puri®ed
by column chromatography )silica gel 550 g, ether/
hexaneˆ1:10!1:5) to give
27
a trichloroacetamide 14
)27.4 g, 92% from 12). Mp 100±1028C )as white crystals
26
[a]D ˆ18.78 )c 1.11, CHCl3). IR )KBr) nmax 3440, 2984,
1
2912, 1436, 1380, 1212, 1069 cm21. H NMR )300 MHz,
from hexane). [a]D ˆ170.2 )c 0.97, CHCl3). IR )KBr)
1
CDCl3) d 1.34 )3H, s, CH3 of acetonide), 1.43 )3H, s, CH3 of
acetonide), 1.63±1.72 )1H, m, CHAHB±CMevCH), 1.64
)3H, brs, CH3±CvCH), 2.26±2.38 )1H, m, CHAHB±
CMevCH), 2.33 )1H, dd, Jˆ9, 2 Hz, CH2OH), 2.67 )1H,
brd, Jˆ20 Hz, MeCvCH±CHAHB), 2.92±3.08 )2H, m,
MeCvCH±CHAHB and ±CH±), 3.66 )1H, t, Jˆ7.5 Hz,
nmax 3313, 2987, 2924, 1727, 1542, 1261, 1067 cm21. H
NMR )400 MHz, CDCl3) d 1.39 )3H, s, CH3 of acetonide),
1.42 )3H, s, CH3 of acetonide), 1.64±1.71 )5H, m, CH2±
CMevCH), 2.08 )1H, td, Jˆ9, 7.5 Hz, ±CH±), 2.27 )1H, d
quintet, Jˆ17.5, 2.5 Hz, MeCvCH±CHAHB), 3.37 )1H,
ddq, Jˆ17.5, 6, 1.5 Hz, MeCvCH±CHAHB), 3.63 )1H,
dd, Jˆ9, 7.5 Hz, O±CHAHB±CH±O), 4.03 )1H, td, Jˆ9,
5.5 Hz, O±CH2±CH±O), 4.10 )1H, dd, Jˆ7.5, 5.5 Hz, O±
CHAHB±CH±O), 5.30 )1H, dd, Jˆ17, 1 Hz, CHvCHAHB),
5.32 )1H, dd, Jˆ11, 1 Hz, CHvCHAHB), 5.39 )1H, m,
MeCvCH), 5.82 )1H, dd, Jˆ17, 11 Hz, CHvCH2), 9.21
)1H, brs, NH). 13C NMR )75 MHz, CDCl3) d 22.5, 26.2,
26.5, 30.0, 35.8, 44.3, 59.9, 68.8, 76.3, 93.8, 109.9, 116.0,
119.0, 130.8, 133.7, 160.4. MS )FAB) m/z 382 )M1H), 384
)M1H), 386 )M1H). HRMS )FAB) calcd for
C16H23NO3Cl3 )M1H), calcd 382.0743, found 382.0721.
Anal. calcd for C16H22O3NCl3: C, 50.08; H, 6.04; N, 3.65.
Found: C, 50.25; H, 5.97; N, 3.59.
O±CHAHB±CH±O), 3.91)H1, ddd,
Jˆ11.5, 9, 7.5 Hz,
HO±CHAHB), 4.13 )1H, dd, Jˆ7.5, 6 Hz, O±CHAHB±
CH±O), 4.16±4.24 )1H, m, O±CH2±CH±O), 4.26 )1H,
brdd, Jˆ11.5, 7.5 Hz, HO±CHAHB), 5.39 )1H, brs,
MeCvCH), 5.85 )1H, td, Jˆ7.5, 2 Hz, HO±CH2±
CHvC). 13C NMR )75 MHz, CDCl3) d 23.3, 25.3, 26.4,
31.6, 32.7, 39.0, 56.8, 69.0, 75.2, 109.2, 120.1, 124.4,
130.7, 139.9. MS )EI) m/z 238 )M1), 223 [)M2CH3)1],
178 [)M260)1]. HRMS )EI) calcd for C14H22O3 )M1)
238.1569, found 238.1558. Anal. calcd for C14H22O3: C,
70.56; H, 9.30. Found: C, 70.42; H, 9.56.
4.1.7. Trichloroacetimidate 13. To a solution of allylic
alcohol 12 )18.5 g, 77.7 mmol) in dry CH2Cl2 )370 mL)
cooled at 2358C was added DBU )13.9 mL, 93.2 mmol).
To this solution was added CCl3CN )9.35 mL, 93.2 mmol)
dropwise over 10 min. After stirring at 2358C for 1h, the
reaction mixture was quenched with sat. NH4Cl solution
)300 mL) and extracted with CH2Cl2 )300 mL£2,
200 mL£1). The combined organic extract was washed
with sat. NH4Cl solution )1L £1), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resi-
due was dissolved in Et2O and passed through a short
column packed with anhydrous Na2SO4 and silica gel )to
remove polymeric products). The eluent was evaporated to
give the crude trichloroacetimidate 13 as a light yellow oil.
This material was used for the subsequent step without any
puri®cations. IR )KBr) nmax 3345, 2983, 2931, 1661, 1455,
1370, 1289, 1072 cm21. 1H NMR )300 MHz, CDCl3) d 1.33
4.1.9. Allyl acetate 16. A solution of the allylic alcohol 12
)2.37 g, 9.95 mmol) in pyridine )10 mL) and Ac2O )10 mL)
was stirred at rt for 1h. The reaction mixture was diluted
with toluene )20 mL), and concentrated in vacuo. The
residue was puri®ed by column chromatography )silica gel
100 g, ether/hexaneˆ1:1!2:1!3:1) to give the acetate 16
27
)2.69 g, 97%) as a colorless oil. [a]D ˆ179.1) c 0.98,
CHCl3). IR )KBr) nmax 2987, 1735, 1438, 1370, 1231,
1157, 1073 cm21 1H NMR )300 MHz, CDCl3) d 1.32
.
)3H, s, CH3 of acetonide), 1.39 )3H, s, CH3 of acetonide),
1.62 )3H, s, CH3±CvCH), 1.70 )1H, brd, Jˆ19 Hz,
CHAHB±CMevCH), 2.04 )3H, s, OAc), 2.30 )1H, brd,
Jˆ19 Hz, CHAHB±CMevCH), 2.62 )1H, brd, Jˆ21Hz,
MeCvCH±CHAHB), 2.93 )1H, dd, Jˆ10, 6.5 Hz, ±CH±),
3.20 )1H, brd, Jˆ21Hz, MeC vCH±CHAHB), 3.70 )1H, dd,
Jˆ8.5, 6.5 Hz, O±CHAHB±CH±O), 4.10 )1H, dd, Jˆ8.5,

T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
3881
6.5 Hz, O±CHAHB±CH±O), 4.20 )1H, dt, Jˆ10, 6.5 Hz,
O±CH2±CH±O), 4.74 )1H, ddd, Jˆ12.5, 6.5, 2 Hz, AcO±
CHAHB), 4.77 )1H, dd, Jˆ12.5, 8.5 Hz, AcO±CHAHB), 5.37
)1H, brs, MeCvCH), 5.58 )1H, ddd, Jˆ8.5, 6.5, 2 Hz,
AcO±CH2±CHvC). 13C NMR )75 MHz, CDCl3) d 21.0,
23.2, 25.3, 26.7, 32.4, 33.4, 39.7, 60.3, 68.7, 75.7, 109.1,
118.9, 120.3, 131.2, 141.6, 171.1. EI-MS m/z 265 )M215).
Anal. calcd for C16H24O4: C, 68.55; H, 8.63. Found: C,
68.54; H, 8.69.
Jˆ8.5, 6.5, 2 Hz, AcO±CH2±CHvC). 13C NMR
)75 MHz, CDCl3) d 20.9, 22.8, 25.3, 26.7, 33.6, 40.3,
60.4, 67.1, 68.9, 76.0, 109.3, 117.3, 125.3, 135.2, 143.5,
171.1. EI-MS m/z 296 )M1), 281)M 215). Anal. calcd for
C16H24O5: C, 64.85; H, 8.16. Found: C, 64.86; H, 8.31.
4.1.12. TBS ether 19. To a solution of the allyl alcohol 18
)151 mg, 0.509 mmol) in DMF )4.5 mL) were added
imidazole )177 mg, 4.07 mmol) and TBSCl )153 mg,
1.02 mmol). After stirring at rt for 1 h, the reaction mixture
was quenched with sat. NaHCO3 solution and extracted with
AcOEt )£3). The combined organic extract was washed
with H2O )£2) and brine )£1), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give
crude product 19 )232 mg) as a colorless oil. This material
was used for next reaction without puri®cation. A portion of
this material was puri®ed by column chromatography
)ether/hexaneˆ1:3!1:2!1:1) to afford the analytically
4.1.10. Dienone 17. CrO3 )4.82 g, 48.2 mmol, dried over
P2O5 prior to use) was suspended in dry CH2Cl2 )4 mL)
and pyridine )7.8 mL, 96.4 mmol) was added at 08C. After
stirring at 08C for 5 min, the acetate 16 )900 mg,
3.24 mmol) in dry CH2Cl2 )2 mL) was added and the
mixture was stirred for 5 h 30 min. Et2O and Super-Cel
were then added, the mixture was ®ltered through a pad of
Super-Cel. The precipitate was washed with Et2O, and the
®ltrate was concentrated under reduced pressure. The
residue was dissolved in Et2O and the solution was passed
through a column packed with anhydrous Na2SO4 and silica
gel )to remove chromium residue). The eluent was evapo-
rated and the residue was puri®ed by column chromato-
graphy )silica gel 25 g, ether/hexaneˆ1:1!2:1!3:1) to
give dienone 17 )381mg, 40%) as a colorless oil.
25
pure sample. [a]D ˆ182.9 )c 1.28, CHCl3). IR )KBr)
nmax 2930, 1741, 1379, 1232, 1082 cm21 1H NMR
.
)300 MHz, CDCl3) d 0.11 )3H, s, CH3±Si), 0.12 )3H, s,
CH3±Si), 0.95 )9H, s, t-Bu±Si), 1.29 )3H, s, CH3 of
acetonide), 1.35 )3H, s, CH3 of acetonide), 1.65 )3H, brs,
CH3±CvCH), 1.69 )1H, brd, Jˆ19 Hz, CHAHB±
CMevCH), 2.02 )3H, s, ±OAc), 2.26±2.38 )1H, m,
CHAHB±CMevCH), 3.06 )1H, brdd, Jˆ9, 6.5 Hz, ±CH±
), 3.62 )1H, dd, Jˆ7.5, 6 Hz, O±CHAHB±CH±O), 4.40 )1H,
dd, Jˆ7.5, 6 Hz, O±CHAHB±CH±O), 4.12 )1H, dt, Jˆ9,
6 Hz, O±CH2±CH±O), 4.58 )1H, ddd, Jˆ12.5, 6.5, 2 Hz,
AcO±CHAHB), 4.79 )1H, dd, Jˆ12.5, 8.5 Hz, AcO±
CHAHB), 4.86 )1H, brs, TBSO±CH), 5.34 )1H, brs,
MeCvCH), 5.82 )1H, ddd, Jˆ8.5, 6.5, 2 Hz, AcO±CH2±
CHvC). 13C NMR )75 MHz, CDCl3) d 25.1, 25.0,
18.4, 21.0, 22.8, 25.4, 25.9, 26.7, 34.0, 39.6, 60.2, 67.9,
68.9, 76.3, 109.0, 116.4, 126.2, 134.4, 143.1, 171.1.
EI-MS m/z 410 )M1) 395 )M215), 350 )M260). Anal.
calcd for C22H38O5Si: C, 64.35; H, 9.33. Found: C, 64.29;
H, 9.60.
26
[a]D ˆ151.7 )c 1.19, CHCl3). IR )KBr) nmax 2986,
1
1740, 1675, 1373, 1229, 1064 cm21. H NMR )300 MHz,
CDCl3) d 1.28 )3H, s, CH3 of acetonide), 1.38 )3H, s, CH3 of
acetonide), 1.98 )3H, t, Jˆ1Hz, C H3±CvCH), 2.08 )3H, s,
OAc), 2.10 )1H, brd, Jˆ19 Hz, CHAHB±CMevCH), 2.69
)1H, m, CHAHB±CMevCH), 3.24 )1H, brt, Jˆ7 Hz, ±CH±
), 3.61)1H, ddd, Jˆ10, 7, 3.5 Hz, O±CH2±CH±O), 3.99±
4.09 )2H, m, O±CH2±CH±O), 4.69 )1H, dd, Jˆ14.5, 5 Hz,
AcO±CHAHB), 4.95 )1H, dd, Jˆ14.5, 8.5 Hz, AcO±
CHAHB), 6.05 )1H, dq, Jˆ2.5, 1Hz, MeC vCH), 6.80
)1H, dd, Jˆ8.5, 5 Hz, AcO±CH2±CHvC). 13C NMR
)75 MHz, CDCl3) d 20.8, 24.6, 25.2, 26.3, 32.2, 39.7,
61.0, 68.1, 76.8, 109.4, 127.2, 133.8, 135.7, 159.0, 170.9,
186.3. EI-MS m/z 294 )M1), 279 )M215). Anal. calcd for
C16H22O5: C, 65.29; H, 7.53. Found: C, 65.30; H, 7.73.
4.1.13. Allyl alcohol 20. To a solution of the crude acetate
19 )232 mg) in MeOH )6 mL) was added anhydrous K2CO3
)300 mg). After vigorous stirring at rt for 15 min, sat. NH4Cl
solution was added and the mixture was extracted with
CH2Cl2 )£3). The combined organic extract was dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was puri®ed by column chromato-
graphy )silica gel 6 g, ether/hexaneˆ1:1) to give the allyl
alcohol 20 )147 mg, 79%, 2 steps from 18) as a colorless oil.
4.1.11. Allyl alcohol 18. The dienone 17 )242 mg,
0.823 mmol) and CeCl3´)H2O)7 )307 mg, 0.823 mmol)
were dissolved in MeOH )7.5 mL) and the solution was
cooled to 08C. To this solution was added NaBH4 )31mg,
0.82 mmol) portionwise. After stirring at 08C, sat. NH4Cl
solution and sat. potassium sodium tartrate solution were
added, and the mixture was extracted with CH2Cl2 )£3).
The combined organic extract was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
residue was puri®ed by column chromatography )silica gel
12 g, ether/hexaneˆ2:1) to give the allyl alcohol 18
27
[a]D ˆ168.3 )c 2.75, CHCl3). IR )KBr) nmax 3457, 2931,
2858, 1256, 1159, 1075 cm21. 1H NMR )300 MHz, CDCl3)
d 0.12 )3H, s, CH3±Si), 0.14 )3H, s, CH3±Si), 0.95 )9H, s,
t-Bu±Si), 1.31 )3H, s, CH3 of acetonide), 1.40 )3H, s, CH3 of
acetonide), 1.56±1.69 )1H, m, CHAHB±CMevCH), 1.66
)3H, brs, CH3±CvCH), 2.02 )1H, m, OH), 2.34 )1H,
m, CHAHB±CMevCH), 3.08 )1H, brt, Jˆ7.5 Hz, ±CH±),
3.60 )1H, m, O±CHAHB±CH±O), 3.94±4.15 )3H, m,
O±CHAHB±CH±O and HO±CHAHB), 4.25 )1H, dd, Jˆ12,
8 Hz, HO±CHAHB), 4.84 )1H, brs, TBSO±CH), 5.37 )1H,
brs, MeCvCH), 6.11 )1H, td, Jˆ8, 2 Hz, HO±CH2±
CHvC). 13C NMR )75 MHz, CDCl3) d 25.0, 24.9, 18.4,
22.8, 25.4, 25.9, 26.5, 33.3, 39.4, 57.2, 67.5, 69.3, 76.0,
109.3, 122.2, 126.2, 133.9, 141.9. MS )FAB) m/z 369
)M1H). HRMS )FAB) calcd for C20H37O4Si )M1H),
26
)151 mg, 62%) as a colorless oil. [a]D ˆ192.6 )c 0.59,
CHCl3). IR )KBr) nmax 3445, 2933, 1736, 1372, 1237,
1070, 1029 cm21 1H NMR )300 MHz, CDCl3) d 1.31
.
)3H, s, CH3 of acetonide), 1.39 )3H, s, CH3 of acetonide),
1.67 )3H, brs, CH3±CvCH), 1.67±1.73 )1H, m, CHAHB±
CMevCH±), 2.05 )3H, s, OAc), 2.32 )1H, m, CHAHB±
CMevCH), 3.04 )1H, dd, Jˆ8.5, 6.5 Hz, ±CH±), 3.65
)1H, ddd, Jˆ13, 6, 5 Hz, O±CHAHB±CH±O), 4.05±4.16
)2H, m, O±CHAHB±CH±O), 4.62 )1H, ddd, Jˆ13, 6.5,
2 Hz, AcO±CHAHB), 4.79±4.86 )2H, m, AcO±CHAHB
and HO±CH), 5.45 )1H, brs, MeCvCH), 5.91)1H, ddd,

3882
T. Nishikawa et al. / Tetrahedron 57 ,2001) 3875±3883
26
needles from Et2O±hexane). [a]D ˆ144.2 )c 0.21,
1067 cm21. H NMR )300 MHz, CDCl3) d 1.33 )3H, s,
369.2461, found 369.2440. Anal. calcd for C20H36O4Si: C,
65.17; H, 9.84; Found: C, 65.18; H, 9.87; N.
CHCl3). IR )KBr) nmax 3406, 2916, 1760, 1372,
1
4.1.14. Trichloroacetamide 21. To an ice-cold solution of
allylic alcohol 20 )76 mg, 0.21mmol) in dry CH 2Cl2 )5 mL)
were added DBU )49 mL, 0.32 mmol) and CCl3±CN
)39 mL, 0.39 mmol) successively. The mixture was stirred
at 08C for 45 min. The reaction mixture was diluted with
CH2Cl2 and washed with sat. NH4Cl solution )£2), dried
over anhydrous Na2SO4, and evaporated under reduced
pressure.
CH3 of acetonide), 1.42 )3H, s, CH3 of acetonide), 1.62±
1.83 )2H, m, CH2±CMevCH), 1.82 )3H, s, CH3±CvCH)
1.98 )1H, td, Jˆ10, 8 Hz, ±CH±), 3.60 )1H, t, Jˆ8 Hz,
O±CHAHB±CH±O), 3.95 )1H, ddd, Jˆ10, 8, 6 Hz,
O±CH2±CH±O), 4.08 )1H, dd, Jˆ8, 6 Hz, O±CHAHB±
CH±O), 4.48 )1H, brd, Jˆ4.5 Hz, Me±CvCH±CH±O),
5.34 )1H, dd, Jˆ11, 1 Hz, CHvCHAHB), 5.40 )1H, dd,
Jˆ17.5, 1 Hz, CHvCHAHB), 5.66 )1H, m, MeCvCH),
5.84 )1H, dd, Jˆ17.5, 11 Hz, CHvCH2), 5.98 )1H, brs,
NH). 13C NMR )100 MHz, CDCl3) d 23.5, 25.7, 26.6,
29.4, 43.4, 62.8, 68.9, 76.9, 78.5, 109.9, 116.6, 117.3,
133.3, 140.8, 158.5. MS )FAB) m/z 280 )M1H). HRMS
)FAB) calcd for C15H22O4N )M1H), 280.1549, found
280.1535. Anal. calcd for C15H21O4N: C, 64.50; H, 7.58;
N, 5.01. Found: C, 64.48; H, 7.55; N, 4.84.
Trichloroacetimidate of 20. IR )KBr) nmax 2932, 1664,
.
1380, 1287, 1256, 1085 cm21 1H NMR )300 MHz,
CDCl3) d 0.11 )3H, s, CH3±Si), 0.13 )3H, s, CH3±Si),
0.95 )9H, s, t-Bu±Si), 1.29 )3H, s, CH3 of acetonide), 1.37
)3H, s, CH3 of acetonide), 1.66 )3H, brs, CH3±CvCH), 1.72
)1H, br d, Jˆ18 Hz, CHAHB±CMevCH±), 2.34 )1H, brd,
Jˆ18 Hz, CHAHB±CMevCH), 3.08 )1H, m, ±CH±),
3.62 )1H, dd, Jˆ8, 6 Hz, O±CHAHB±CH±O), 4.05 )1H,
dd, Jˆ8, 6 Hz, O±CHAHB±CH±O), 4.14 )1H, dt, Jˆ9,
6 Hz, O±CH2±CH±O), 4.86 )1H, m, O±CHAHB±CHvC),
4.88 )1H, d, Jˆ6 Hz, TBSO±CH) 4.95 )1H, ddd, Jˆ13, 7,
1.5 Hz, O±CHAHB±CHvC) 5.36 )1H, brs, MeCvCH),
5.95 )1H, td, Jˆ7, 2 Hz, O±CH2±CHvC), 8.25 )1H, brs,
NH). MS )FAB) m/z 512 )M1H). The crude imidate was
dissolved in xylene )10 mL) and powder of K2CO3 )20 mg)
was added. The mixture was heated at a re¯ux temperature
for 36 h. After cooling to rt, the mixture was ®ltered through
a pad of Super-Cel, washed with toluene. The combined
®ltrate was evaporated in vacuo. The residue was puri®ed
by column chromatography to give the trichloroacetamide
21 )65 mg, 62%) and unreacted imidate )11 mg, 10%).
Acknowledgements
We are grateful to Mr S. Kitamura )analytical laboratory in
this school) for elemental analyses and measurements of
HR-MS. A part of levoglucosenone was supplied from
Japan Tobacco Inc. and Yuki Gousei Yakuhin Co. Ltd.,
whom we thank. This work was ®nancially supported by
JSPS-RFTF, a Grant-in-Aid for Scienti®c Research from
the Ministry of Education, Science, Sports, and Culture
of Japan, Iyakushigen Kenkyushinkoukai )Fujisawa
Foundation) and Mitsubishi Chemical Corporation Fund.
References
Trichloroacetamide 21. Mp 130±1328C. )as white prisms
27
from Et2O±hexane) [a]D ˆ1133 )c 0.40, CHCl3). IR
1. Review: )a) In Tetrodotoxin, Saxitoxin, and the Molecular
Biology of the Sodium Channel; Kao Y.; Lovinson S.; Eds.
Ann. NY Acad. Sci., 1986, vol. 479, pp. 1±355. )b)
Kobayashi, J.; Ishibashi, M. In Comprehensive Natural
Products Chemistry, Pergamon: New York, 1999; pp 480±
489.
1
)KBr) nmax 3327, 2930, 1727, 1533, 1256 cm21. H NMR
)300 MHz, CDCl3) d 0.05 )6H, s, )CH3)2±Si), 0.85 )9H, s,
t-Bu±Si), 1.39 )3H, s, CH3 of acetonide), 1.41 )3H, s, CH3 of
acetonide), 1.51±1.62 )1H, m, CHAHB±CMevCH), 1.69
)3H, brs, CH3±CvCH), 1.75 )1H, dd, Jˆ18.5, 6 Hz,
CHAHB±CMevCH), 2.48 )1H, ddd, Jˆ11.5, 9.5, 6 Hz,
±CH±), 3.68 )1H, m, O±CHAHB±CH±O), 4.01±4.11 )2H,
m, O±CHAHB±CH±O), 4.87 )1H, d, Jˆ6 Hz, TBSO±CH),
5.33 )1H, dd, Jˆ11, 1 Hz, CHvCHAHB), 5.38 )1H, dd,
Jˆ17.5, 1 Hz, CHvCHAHB), 5.56 )1H, brd, Jˆ6 Hz,
MeCvCH), 5.68 )1H, dd, Jˆ17.5, 11 Hz, CHvCH2),
8.91)1H, brs, N H). 13C NMR )100 MHz, CDCl3) d 24.5,
23.7, 18.1, 22.7, 25.9, 26.3, 26.5, 30.6, 38.6, 64.4, 66.2,
68.7, 75.6, 94.0, 109.9, 116.0, 123.1, 132.4, 135.4, 159.3.
HRMS )FAB) calcd for C22H37O4NCl3Si )M1H), 512.1557,
found 512.1540. Anal. calcd for C22H36O4NCl3Si: C, 51.51;
H, 7.07; N, 2.73. Found: C, 51.47; H, 7.07; N, 2.62.
2. For the structure: )a) Goto, T.; Kishi, Y.; Takahashi, S.; Hirata,
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2345.
4.1.15. Carbamate 22. To a solution of the trichloro-
acetamide 21 )14.5 mg, 23.8 mmol) in THF )0.5 mL) was
added n-Bu4NF )1M in THF, 12 mL, 12 mmol). After stir-
ring at rt for 1h, the mixture was quenched with sat. NH 4Cl
solution and extracted with AcOEt )£3). The combined
organic extract was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was
puri®ed by silica gel TLC )ether/hexaneˆ3:1) to give the
carbamate 22 )7.6 mg, 92%). Mp 106±1088C )as colorless
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