Scalable synthesis of a new dihydroxylated intermediate for tetrodotoxin and its analogues

Article abstract of DOI:10.1055/s-0029-1218747

The synthesis of a novel intermediate for tetrodotoxin and its analogues, possessing two hydroxy groups at C-8 and C-11, is described. The procedure involves a Diels-Alder reaction between bromolevoglucosenone and a tert-butyldiphenylsilyl-protected isoprenol during which the C-11 group hydroxy is installed. Subsequent transformations, including an Overman rearrangement, affords a cyclohexene intermediate containing a trichloroacetamide moiety as a requisite amino functionality for installation of the guanidine unit present in tetrodotoxin. Hydroxylation at C-8 is carried out via neighboring group participation of the trichloroacetamide to furnish the desired diol intermediate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218747

1992
PAPER
Scalable Synthesis of a New Dihydroxylated Intermediate for Tetrodotoxin
and Its Analogues
Scalable
S
ynthesis
o
of
a
Ne
w
D
s
ihydroxyl
h
a
tedIntermed
i
iate ki Satake, Toshio Nishikawa,* Takeshi Hiramatsu, Hiroshi Araki, Minoru Isobe*
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894111; E-mail: nisikawa@agr.nagoya-u.ac.jp
Received 26 January 2010; revised 8 March 2010
H
H
N
+
+
N
Abstract: The synthesis of a novel intermediate for tetrodotoxin
and its analogues, possessing two hydroxy groups at C-8 and C-11,
is described. The procedure involves a Diels–Alder reaction be-
tween bromolevoglucosenone and a tert-butyldiphenylsilyl-protect-
ed isoprenol during which the C-11 group hydroxy is installed.
Subsequent transformations, including an Overman rearrangement,
affords a cyclohexene intermediate containing a trichloroacetamide
moiety as a requisite amino functionality for installation of the
guanidine unit present in tetrodotoxin. Hydroxylation at C-8 is car-
ried out via neighboring group participation of the trichloroacet-
amide to furnish the desired diol intermediate.
HO
HO
NH2
NH2
NH
NH
5
R2
O
OH
OH
HO
R1
8
11
Me
11
O–
O
O
OH
O
OH
5,11-dideoxytetrodotoxin (4)
tetrodotoxin (1)
R
R
R
1 = R2 = OH
1 = H, R2 = OH
11-deoxytetrodotoxin (2)
8,11-dideoxytetrodotoxin (3) 1 = R2 = H
Key words: tetrodotoxin, Diels–Alder reaction, hydroxylation,
neighboring group participation, Overman rearrangement
O
O
O
O
COCCl3
NH
Boc
Our research has led to the synthesis of tetrodotoxin (1),1
a well-known natural product, and several of its analogues
including 11-deoxytetrodotoxin (2),2 8,11-dideoxytetro-
dotoxin (3),3 and 5,11-dideoxytetrodotoxin (4),4 from
common intermediate 55 (Figure 1). Since compound 5
has no hydroxy groups on the cyclohexene ring, its regio-
selective and stereoselective hydroxylation was a major
issue in the above synthetic studies. Hydroxylation at C-8
has been established via neighboring group participation
of a trichloroacetamide;4 however, introduction of the hy-
droxy group at C-11 still remains problematic, despite the
fact that we were able to hydroxylate at C-11 by allylic ox-
idation with selenium dioxide during our total synthesis of
tetrodotoxin.1 Hence, a general route to prepare tetrodo-
toxin analogues hydroxylated at C-11 is still required, as
these are necessary for biochemical research associated
with tetrodotoxin. Recently, we reported the synthesis of
compound 6, a newly designed intermediate possessing
hydroxy groups at C-11 and C-8, starting from the com-
NH
8
R1
HO
R2
OH
11
5 R1 = R2 = H
6
7 R1 = R2 = OH
Figure 1 Structures of tetrodotoxin, its analogues and synthetic in-
termediates
mon intermediate 5.6 Herein, we report a new and scalable
synthesis of the dihydroxylated intermediate 7.7
Since common intermediate 5 had been prepared via a
Diels–Alder reaction between bromolevoglucosenone
(10) and isoprene 11 (R1 = H),5 we planned to synthesize
new intermediate 7 starting with the Diels–Alder reaction
between 10 and isoprenol 11 (R1 = OH) as the diene
(Scheme 1). The resulting cycloadduct could be trans-
formed into cyclohexene 8 via Overman rearrangement of
allylic alcohol 9, and finally into the new intermediate 7
O
O
O
O
O
O
O
O
OH
COCCl3
NH
COCCl3
NH
Overman
rearrangement
Diels–Alder
reaction
hydroxylation
at C-8
O
8
Br
8
10
11
OH
R1
OH
OR
OR
7
11
8
9
Scheme 1 Synthetic plan for intermediate 7
SYNTHESIS 2010, No. 12, pp 1992–1998
x
x.
x
x
.
2
0
1
0
Advanced online publication: 19.04.2010
DOI: 10.1055/s-0029-1218747; Art ID: F02010SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Scalable Synthesis of a New Dihydroxylated Intermediate
1993
according to the method developed previously in our lab- ether complex (LiClO4·OEt2)11 did not improve the regio-
oratory.4
selectivity (Table 1, entry 4). The reaction in the presence
of the Lewis acids, ytterbium(III) triflate [Yb(OTf)3] and
scandium(III) triflate [Sc(OTf)3]12 gave similar results
(Table 1, entries 5 and 6). In the event, the use of boron
trifluoride–diethyl ether complex in dichloromethane as
solvent, at 0 °C, proved to be the optimum conditions for
this Diels–Alder reaction, providing an 89% yield of the
products with high regioselectivity (14a:14b, >20:1)
(Table 1, entry 7).
Our preliminary studies on the Diels–Alder reaction of
compound 10 with isoprenol and its derivatives 11
(R1 = OH or R1 = OR) indicated that isoprenol was unsta-
ble under Lewis acid conditions, and so we instead em-
ployed tert-butyldiphenylsilyl-protected isoprenol 13 as
the diene. It was anticipated that the tert-butyldiphenylsi-
lyl group of isoprenol 13 would be compatible with the re-
action conditions throughout the synthesis of intermediate
7. Of the several syntheses of isoprenol 11 (R1 = OH) re-
ported to date,8 we chose the method of Silverstein,9 be-
ginning from isoprene, because of its simple procedure
and the low cost of the starting material and reagents
(Scheme 2). Thus, isoprene was treated with N-bromosuc-
cinimide in water to give an intermediate bromohydrin
which was exposed to aqueous sodium hydroxide to af-
ford isoprene monoxide 12 in good yield. When base-pro-
moted isomerization of 12 was carried out with lithium
diisopropylamide in accord with the literature,9 a low
yield (ca. 30%) of product 13 was obtained after silylation
with tert-butyldiphenylsilyl chloride and imidazole in
O
O
O
O
O
O
O
O
O
+
Br
Br
Br
10
OTBDPS
OTBDPS
14b
OTBDPS
13
14a
Equation 1
Table 1 Diels–Alder Reaction between Bromolevoglucosenone
N,N-dimethylformamide. Extensive examination of the (10) and Diene 13
reaction conditions revealed that the use of lithium hexa-
methyldisilazide, at reflux in diethyl ether, improved the
yield giving 66% of 13 after protection with tert-butyl-
diphenylsilyl chloride. This modified method is practical
for the synthesis of isoprenol derivatives, and made it pos-
sible to prepare over 100 grams of 13 with good reproduc-
ibility.
Entry Lewis acid and/
Temp
Time
5 h
Yield 14a/14ba
(%)
or solvent
1
BF3·OEt2 (1 equiv),
MeCN
0 °C
complex mixture
2
3
4
5
toluene
110 °C 21 h
48
63
46
70
2:1
4:1
4:1
4:1
neat
r.t.
r.t.
5 d
18 h
9 d
1) NBS, H2O
5 °C
1) LiHMDS
Et2O, reflux
5 M LiClO4·Et2O
2) 30% NaOH
H2O, 5 °C
2) TBDPS-Cl
imidazole
DMF, r.t.
Yb(OTf)3 (0.1 equiv), r.t.
CH2Cl2
O
OTBDPS
(82%)
isoprene
12
13
(66% in 2 steps)
6
7
Sc(OTf)3 (0.1 equiv), r.t.
CH2Cl2
8 d
82
89
4:1
Scheme 2 Synthesis of tert-butyldiphenylsilyl-protected isoprenol
13
BF3·OEt2 (2 equiv),
CH2Cl2
0 °C
15 h
>20:1
a The ratio was determined by 1H NMR spectroscopy.
With a sufficient amount of diene 13 in hand, the Diels–
Alder reaction with bromolevoglucosenone (10) was ex-
amined (Equation 1 and Table 1). In our synthesis of com-
pound 5, the Diels–Alder reaction between 10 and
isoprene was best carried out using boron trifluoride–di-
ethyl ether complex in acetonitrile as the solvent, to give
the desired product in high yield and with excellent regio-
selectivity (76% yield, 15:1).5 To our surprise, the Diels–
Alder reaction between 10 and protected isoprenol 13, un-
der identical conditions, gave a complex mixture of prod-
ucts (Table 1, entry 1). We therefore investigated the
conditions for this Diels–Alder reaction further. Heating
the reaction in toluene at reflux temperature without a
Lewis acid gave a 2:1 mixture of the products 14a and 14b
(Table 1, entry 2),10 while the same reaction without sol-
vent, proceeded at room temperature to give the same
products, but with improved regioselectivity (ca. 4:1)
(Table 1, entry 3). The use of lithium perchlorate–diethyl
The product 14a was transformed into trichloroacetamide
20 according to the reported procedure for the synthesis of
5.5 Although all the reactions shown in Scheme 3 pro-
ceeded smoothly to give the desired products in good
yields, two comments are worthwhile. We did not encoun-
ter any difficulties in preparing bicyclic compound 16
from bromohydrin 15 on a 65 gram scale. However, when
ca. 150 grams of 15 was used for the same reaction, the
desired product 16 was obtained in 60% yield along with
a significant amount of by-product 17 (36% yield). This
was due to the prolonged time required for removal of the
reaction medium, which led to acetolysis of the silyl ether
group of 16. Therefore, the work-up procedure was mod-
ified in order to neutralize the reaction with triethylamine
before concentration. This modified procedure enabled us
to prepare compound 16 on a 150 gram scale without
Synthesis 2010, No. 12, 1992–1998 © Thieme Stuttgart · New York

1994
Y. Satake et al.
PAPER
forming the undesired product 17. For the reduction of bi-
cyclic 16 with the zinc–copper couple in N,N-dimethyl-
formamide–water, a temperature of 50 °C and a short
reaction time (about 10 min; it was necessary to quench
the reaction by addition of cold aqueous sodium bicarbon-
ate solution), were found to be critical. Longer reaction
times resulted in decreased yields of product 18. Since the
transformation of 18 into trichloroacetamide 20, including
the Overman rearrangement, was successful, on ca. 50
gram scale, we were able to obtain 20 on a 40 gram scale
in a single batch.
O
O
O
O
COCCl3
NH
COCCl3
NH
Br3PyH
K2CO3
DBU
DMF
r.t.
CH2Cl2
10 °C
(99%)
8
11
Br
OR
Br
22
OH
20 R = TBDPS
21 R = H
TBAF
THF, r.t.
(94%)
O
O
O
O
COCCl3
NH
O
O
p-TsOH
O
O
TFA, Ac2O
0 °C to r.t.;
N
O
NaBH4
pyridine, H2O
70 °C
CCl3
8
O
OH
MeOH
CH2Cl2
0 °C
Et3N
OH
Br
Br
(64% in 2 steps)
OH
OH
(86% in 2 steps)
23
7
OTBDPS
OTBDPS
14a
15
Scheme 4 Procedure for hydroxylation at C-8
OAc
OAc
O
OAc
OAc
O
OH
1) LiAlH4, Et2O
Zn–Cu
0 °C
Melting points were recorded on a Yanaco MP-S3 melting point ap-
paratus and are uncorrected. Infrared spectra were obtained using a
Jasco FT/IR-8300 spectrophotometer and are reported in wavenum-
bers (cm–1). Proton nuclear magnetic resonance (1H NMR) spectra
were recorded with Bruker ARX-400 (at 400 MHz) or Varian Gem-
ini-2000 (at 300 MHz) spectrometers. Carbon nuclear magnetic res-
onance (13C NMR) spectra were recorded with Bruker ARX-400 (at
100 MHz) or Varian Gemini-2000 (at 75 MHz) spectrometers. Op-
tical rotations were measured on a JASCO DIP-370 digital polarim-
eter. Elemental analyses were performed by the Analytical
Laboratory at the Graduate School of Bioagricultural Sciences,
Nagoya University. Reactions were monitored by thin layer chro-
matography on 0.25 mm silica gel coated glass plates 60F-254
(Merck, Art 5715) using UV light as visualizing agent and 7% eth-
anolic phosphomolybdic acid or p-anisaldehyde soln as developing
agents. Cica-Merck silica gel (60, particle size 0.063–0.2 mm A
STM) was used for column chromatography. Unless otherwise not-
ed, non-aqueous reactions were carried out under N2 or Ar. Anhyd
CH2Cl2 and Et2O were purchased from Kanto Chemical Co., Inc.
Et3N and py were dried over anhyd KOH. BF3·OEt2 was distilled
from CaH2. All other commercial reagents were used as received.
DMF–H2O
50 °C
2) Me2C(OMe)2
dl-CSA,
acetone, r.t.
Br
OR
OTBDPS
(75% in 3 steps)
16 R = TBDPS
17 R = Ac
18
O
O
1) CCl3CN
DBU, CH2Cl2
–40 °C
O
O
OH
COCCl3
NH
2) K2CO3
xylene, reflux
(84% in 2 steps)
OTBDPS
OTBDPS
19
20
Scheme 3 Synthesis of trichloroacetamide 20
Hydroxylation at C-8 of compound 20 was carried out us-
ing the neighboring group participation effect of the
trichloroacetamide moiety according to the method devel-
oped in our laboratory (Scheme 4).4 Attempted bromina-
tion of 20 gave a complex mixture, while bromination of
21, prepared by desilylation of 20 with tetrabutylammoni-
um fluoride, proceeded at 10 °C to afford dibromide 22,
quantitatively.13 Treatment of 22 with 1,8-diazabicyc-
lo[5.4.0]undec-7-ene in N,N-dimethylformamide then
gave oxazoline 23. Finally, hydrolysis of 23 using p-tolu-
enesulfonic acid in aqueous pyridine afforded the desired
dihydroxylated intermediate 7 in 69% yield over two
steps.
1-Methyl-1-ethenylcyclopropane (Isoprene Monoxide) (12)
A three-necked flask (1 L), equipped with a mechanical stirrer, a
dropping funnel and a thermometer was charged with H2O (190
mL) and cooled in an ice-bath. Isoprene (82 mL, 0.840 mol) was
added and the mixture stirred for 15 min. Powdered NBS (313 g,
1.76 mol) was added portionwise, with vigorous stirring over 30
min whilst maintaining the internal temperature <5 °C. After stir-
ring for 1 h, 30% aq NaOH soln (100 mL) was added dropwise over
30 min and stirring was continued for 1 h. The mixture was parti-
tioned and the aq layer extracted with Et2O (3 × 20 mL). The com-
bined organic layer was washed with brine (100 mL) and then
transferred to a distillation apparatus. The solvent was removed un-
der vacuum (760 mmHg) with oil-bath heating at 50 °C, and the re-
maining material was distilled at 760–230 mmHg with oil-bath
heating at 75 °C to give 12 (38.7 g, 82%) as a colorless liquid.
In conclusion, we have established a scalable route for the
preparation of new advanced intermediate 7 for the syn-
thesis of tetrodotoxin and its analogues. This compound is
expected to play an important role in expeditious synthe-
ses of various tetrodotoxin derivatives possessing hy-
droxy groups at C-11 and C-8 for biochemical
investigations, and efforts in this direction are in progress.
tert-Butyl-(2-methylenebut-3-enyloxy)diphenylsilane (13)
A three-necked flask (2 L), equipped with a dropping funnel, a re-
flux condenser and a gas inlet adapter was purged with argon.
Freshly distilled hexamethyldisilazane (135 mL, 0.639 mol) and an-
hyd Et2O (350 mL) were added, and the soln was cooled to –78 °C.
Synthesis 2010, No. 12, 1992–1998 © Thieme Stuttgart · New York

PAPER
Scalable Synthesis of a New Dihydroxylated Intermediate
1995
n-BuLi (1.60 M in hexanes, 368 mL, 0.589 mol) was added via the
dropping funnel over 50 min. The resulting suspension was stirred
for 30 min at r.t., isoprene monoxide (12) (41.3 g, 0.491 mol) was
added via cannula over 15 min at r.t., and the mixture then heated at
reflux for 24 h. After cooling in an ice-bath, the mixture was slowly
poured onto ice-cold 2 M HCl (800 mL), and stirred vigorously for
1.5 h. The organic layer was separated, and the aq layer extracted
with Et2O (500 mL, then 2 × 400 mL). The combined organic phase
was washed with sat. aq NaHCO3 soln (200 mL) and brine (200
mL), dried over anhyd Na2SO4 and concd under reduced pressure
(ca. 500 mmHg at 30 °C) to give the crude isoprenol (674 g) as a
yellow oil. To a soln of the crude isoprenol (674 g) and imidazole
(100 g, 1.47 mol) in DMF (1.0 L) was added TBDPSCl (158 mL,
0.614 mol) at r.t. After being stirred for 30 min, the reaction mixture
was quenched with sat. aq NaHCO3 soln (250 mL) and H2O (750
mL), and then extracted with Et2O (500 mL then 400 mL). The com-
bined organic extract was washed with H2O (2 × 1.5 L) and brine
(200 mL), and dried over anhyd Na2SO4. The solvent was concen-
trated under reduced pressure and the residue was purified by col-
umn chromatography [silica gel (1.2 kg), Et2O–hexane,
0:1→1:100→1:75→1:50] to give TBDPS ether 13 (105 g, 66%
over 2 steps) as a colorless oil.
13C NMR (75 MHz, CDCl3): d = 19.2, 26.7, 30.0, 36.6, 48.4, 55.9,
66.1, 67.2, 79.0, 100.1, 119.1, 127.8, 129.8, 133.5, 135.6, 140.2,
195.2.
Anal. Calcd for C27H31BrO4Si: C, 61.47; H, 5.92. Found: C, 61.46;
H, 5.95.
(1S,4R,5R,5aS,9aR)-5a-Bromo-8-[(tert-butyldiphenylsily-
loxy)methyl]-1,2,4,5,5a,6,9,9a-octahydro-1,4-epoxy-3-benz-
oxepin-5-ol (15)
To an ice-cold soln of bromoketone 14a (101 g, 191 mmol) in
CH2Cl2 (150 mL) and MeOH (1.5 L) was added NaBH4 (2.89 g,
76.5 mmol) portionwise. After stirring for 15 min, AcOH (20 mL)
was added and the reaction mixture evaporated. The residue was
dissolved in H2O (600 mL) and Et2O (600 mL), and the organic lay-
er separated. The aq layer was extracted with Et2O (3 × 350 mL),
and the combined organic layer washed with brine (500 mL), dried
over Na2SO4 and concentrated under reduced pressure to give crude
bromohydrin 15 (99.9 g) as a yellow oil. This material was used in
the next step without further purification. A small quantity was pu-
rified by column chromatography (silica gel, EtOAc–hexane,
1:10→1:5) to give an analytically pure sample.
[a]D24 –43.2 (c 1.38, CHCl3).
IR (NaCl, film): 3072, 2931, 2858, 1597, 1473, 1428, 1391, 1113,
902 cm–1.
IR (NaCl, film): 3528, 3071, 2957, 2857, 1473, 1428, 1391, 1238,
1078, 988, 823 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.07 (s, 9 H, t-Bu), 4.38 (m, 2 H,
CH2OTBDPS), 4.98 (d, J = 11 Hz, 1 H, CHAHB=CH), 5.05 (d,
J = 18 Hz, 1 H, CHAHB=CH), 5.17 (m, 1 H, CHAHB=C), 5.50 (m, 1
H, CHAHB=C), 6.38 (dd, J = 18, 11 Hz, 1 H, CHAHB=CH), 7.35–
7.48 (m, 6 H, Ph), 7.67–7.73 (m, 4 H, Ph).
13C NMR (75 MHz, CDCl3): d = 19.2, 26.7, 63.0, 113.2, 114.9,
127.8, 129.7, 133.6, 135.6, 136.6, 144.6.
1H NMR (300 MHz, CDCl3): d = 1.06 (s, 9 H, t-Bu), 2.33 (br d,
J = 8 Hz, 2 H, CH2C=CH), 2.49 (d, J = 12.5 Hz, 1 H, OH), 2.75 (dq,
J = 17, 2.5 Hz, 1 H, C=CHCHAHB), 2.95 (td, J = 8, 1.5 Hz, 1 H,
CH), 3.02 (dd, J = 17, 6 Hz, 1 H, C=CHCHAHB), 3.11 (dd, J = 12.5,
2 Hz, 1 H, CHOH), 3.73 (dd, J = 7.5, 5 Hz, 1 H, OCHACHBCHO),
4.07 (s, 2 H, CH2OTBDPS), 4.25 (dd, J = 5, 1.5 Hz, 1 H,
OCH2CHO), 4.68 (d, J = 7.5 Hz, 1 H, OCHAHBCHO), 5.34 (d,
J = 2 Hz, 1 H, OCHO), 5.53 (m, 1 H, C=CH), 7.34–7.47 (m, 6 H,
Ph), 7.63–7.74 (m, 4 H, Ph).
Anal. Calcd for C21H26OSi: C, 78.21; H, 8.13. Found: C, 78.35; H,
8.40.
13C NMR (75 MHz, CDCl3): d = 19.2, 26.7, 29.3, 40.2, 44.4, 66.6,
67.2, 70.5, 73.8, 78.3, 101.7, 117.8, 127.7, 129.8, 133.5, 135.6,
136.4.
(1S,4R,5aS,9aR)-5a-Bromo-8-[(tert-butyldiphenylsilyl-
oxy)methyl]-1,2,5a,6,9,9a-hexahydro-1,4-epoxy-3-benzoxepin-
5(4H)-one (14a)
Anal. Calcd for C27H33BrO4Si: C, 61.24; H, 6.28. Found: C, 61.24;
H, 6.02.
Bromolevoglucosenone (10) (65.9 g, 0.321 mol, dried by azeotropic
removal of H2O with toluene) in a three-necked flask (3 L),
equipped with a mechanical stirrer, was dissolved in anhyd CH2Cl2
(800 mL) under Ar. The mixture was cooled to 0 °C, and BF3·OEt2
(81.4 mL, 0.642 mol) and a soln of diene 13 (125 g, 0.386 mol, dried
by azeotropic removal of H2O with toluene) in anhyd CH2Cl2 (200
mL) were added dropwise via cannula over 30 min. After stirring
for 15 h, sat. aq NaHCO3 soln (700 mL) was added slowly. The or-
ganic layer was separated and the aq layer extracted with CH2Cl2 (2
× 500 mL). The combined organic layer was dried over anhyd
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography [silica gel (1.2 kg), EtOAc–
hexane, 1:25→1:15→1:10] to afford bromoketone 14a (152 g,
89%) as a colorless oil.
Diastereomers (16)
To a soln of crude bromohydrin 15 (99.9 g) in Ac2O (1 L), at 0 °C,
was added TFA (50 mL) over 10 min. The mixture was allowed to
warm to r.t. and stirring was continued for 1.5 h. Et3N (69.0 mL, 491
mmol) was added at 0 °C and the resulting mixture stirred for 30
min, and then concentrated in vacuo. The residue was dissolved in
H2O (500 mL) and EtOAc (500 mL) and partitioned. The aq layer
was extracted with Et2O (3 × 300 mL) and the combined organic
layer washed with H2O (2 × 300 mL) and brine (3 × 200 mL), dried
over anhyd Na2SO4 and concentrated in vacuo. The residue was pu-
rified by column chromatography [silica gel (750 g), EtOAc–hex-
ane, 1:10→1:5→1:2) to afford triacetate 16 (110 g, 86% over 2
steps) as a diastereomeric mixture (16a:16b = 10:1 by 1H NMR). A
small quantity of the mixture was separated by flash column chro-
matography (silica gel, EtOAc–hexane, 1:5) to give diastereomers
16a and 16b as yellow amorphous solids.
[a]D24 –11.1 (c 0.904, CHCl3).
IR (NaCl, film): 2931, 2857, 1736, 1473, 1428, 1113, 998, 924, 824
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.05 (s, 9 H, t-Bu), 2.13 (dd,
J = 16, 6 Hz, 1 H, CHAHBCH), 2.41 (dd, J = 16, 8 Hz, 1 H, CHA-
HBCH), 2.67 (br d, J = 16 Hz, 1 H, CHAHBCBr), 2.83 (dd, J = 8, 6
Hz, 1 H, CH), 3.02 (dd, J = 16, 5.5 Hz, 1 H, CHACHBCBr), 3.85 (dd,
J = 7.5, 5.5 Hz, 1 H, OCHAHBCHO), 4.14 (br s, 2 H, CH2OTBDPS),
4.41 (d, J = 5.5 Hz, 1 H, OCHAHBCHO), 4.51 (d, J = 7.5 Hz, 1 H,
OCH2CHO), 5.25 (s, 1 H, OCHO), 5.78 (m, 1 H, C=CH), 7.34–7.40
(m, 6 H, Ph), 7.62–7.74 (m, 4 H, Ph).
(1S,3R,4R,4aS,8aR)-1-[(Acetyloxy)methyl]-4a-bromo-7-[(tert-
butyldiphenylsilyloxy)methyl]-3,4,4a,5,8,8a-hexahydro-1H-2-
benzopyran-3,4-diol 3,4-Diacetate (16a)
[a]D31 +38.7 (c 1.02, CHCl3).
IR (NaCl, film): 3072, 2932, 2858, 1748, 1473, 1428, 1370, 1232,
1154, 1112, 1047, 1015, 965, 824 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.07 (s, 9 H, t-Bu), 1.99 (br d,
J = 20 Hz, 1 H, CHAHBC=CH), 2.06 (s, 3 H, OAc), 2.15 (s, 3 H,
Synthesis 2010, No. 12, 1992–1998 © Thieme Stuttgart · New York

1996
Y. Satake et al.
PAPER
OAc), 2.20 (s, 3 H, OAc), 2.56 (br d, J = 20 Hz, 1 H, CHAHB-
C=CH), 2.68 (dd, J = 11, 6 Hz, 1 H, CH), 2.75 (br d, J = 20 Hz, 1
H, C=CHCHAHB), 3.60 (br d, J = 20 Hz, 1 H, C=CHCHAHB), 3.90
(ddd, J = 11, 4, 3 Hz, 1 H, OCH2CHO), 4.05 (d, J = 15 Hz, 1 H,
CHAHBOTBDPS), 4.10 (d, J = 15 Hz, 1 H, CHAHBOTBDPS), 4.15
(dd, J = 12, 3 Hz, 1 H, OCHAHBCHO), 4.20 (dd, J = 12, 4 Hz, 1 H,
OCHAHBCHO), 5.08 [d, J = 1 Hz, 1 H, C(Br)CHOAc], 5.63 (br s, 1
H, C=CH), 6.04 (d, J = 1 Hz, 1 H, OCHOAc), 7.34–7.47 (m, 6 H,
Ph), 7.64–7.70 (m, 4 H, Ph).
Hz, 1 H, OCHAHBCHO), 4.30 (dd, J = 12.5, 2.5 Hz, 1 H, OCHAH-
BCHO), 5.45 (br s, 1 H, OCHOH), 5.66 (br s, 2 H, C=CHCH2C=CH,
C=CHCH2C=CH), 7.34–7.47 (m, 6 H, Ph), 7.63–7.70 (m, 4 H, Ph).
13C NMR (75 MHz, CDCl3): d (major isomer) = 19.2, 20.8, 26.8,
28.2, 31.0, 33.2, 64.4, 67.1, 70.7, 89.3, 119.1, 119.4, 127.7, 129.7,
133.6, 134.2, 135.6, 139.2, 171.1.
Anal. Calcd for C29H36O5Si: C, 70.70; H, 7.37. Found: C, 70.70; H,
7.48.
13C NMR (100 MHz, CDCl3): d = 19.2, 20.7, 20.8, 21.1, 24.4, 26.8,
34.1, 38.5, 64.3, 65.4, 66.8, 69.8, 71.6, 91.9, 116.4, 127.6, 129.67,
129.70, 133.2, 133.4, 135.46, 135.52, 168.0, 169.3, 170.5.
(Z)-2-{(6S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-6-[(4S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-3-cyclohexen-1-ylidene}ethanol
(19)
Anal. Calcd for C33H41BrO8Si: C, 58.84; H, 6.13. Found: C, 58.99;
H, 6.04.
LiAlH4 (8.13 g, 214 mmol) was placed in a three-necked flask (2 L),
equipped with a mechanical stirrer and an inlet adapter. Anhyd Et2O
(560 mL) was added under an Ar atm, the resulting suspension
cooled to 0 °C and a soln of crude hemiacetal 18 (55.2 g) in Et2O
(100 mL) was added via cannula over 5 min. After stirring for 20
min at 0 ºC, H2O was carefully added dropwise until evolution of H2
gas ceased. H2O (300 mL) and sat. aq tartaric acid soln (300 mL)
were added and the mixture stirred for 5 min. Sat. aq potassium so-
dium tartrate soln (200 mL) was added, and vigorous stirring was
continued for a further 20 min. The resulting suspension was fil-
tered, the solid added to EtOAc (300 mL), and the suspension
stirred vigorously and filtered again. The filtrate was partitioned
and the aq layer extracted with EtOAc (2 × 400 mL). The combined
organic layer was washed with brine (300 mL), dried over anhyd
Na2SO4, and concentrated under reduced pressure to give the crude
intermediate triol (47.4 g) as a pale-yellow oil. The crude triol (47.2
g) was dissolved in acetone (711 mL), and Me2C(OMe)2 (13.1 mL,
107 mmol) and dl-CSA (330 mg, 1.42 mmol) were added. The re-
sulting soln was stirred at r.t. for 40 min, and then sat. aq NaHCO3
soln (30 mL) and H2O (500 mL) were added. The reaction mixture
was extracted with EtOAc (500 mL, then 300 mL) and the com-
bined organic layer washed with brine (200 mL), dried over anhyd
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography [silica gel (500 g), EtOAc–
hexane, 1:10→1:6→1:3] to afford allylic alcohol 19 (39.6 g, 75%
over 3 steps) as a pale-yellow oil.
(1S,3S,4R,4aS,8aR)-1-[(Acetyloxy)methyl]-4a-bromo-7-[(tert-
butyldiphenylsilyloxy)methyl]-3,4,4a,5,8,8a-hexahydro-1H-2-
benzopyran-3,4-diol 3,4-Diacetate (16b)
[a]D31 +20.5 (c 0.58, CHCl3).
IR (NaCl, film): 2932, 2858, 1751, 1473, 1428, 1369, 1232, 1158,
1112, 1071, 823 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.06 (s, 9 H, t-Bu), 2.01 (br d,
J = 18 Hz, 1 H, CHAHBC=CH), 2.06 (s, 3 H, OAc), 2.08 (s, 3 H,
OAc), 2.24 (s, 3 H, OAc), 2.54 (br d, J = 18 Hz, 1 H, CHA-
HBC=CH), 2.59 (dd, J = 11, 6 Hz, 1 H, CH), 2.89 (br d, J = 19.5 Hz,
1 H, C=CHCHAHB), 3.06 (br d, J = 19.5 Hz, 1 H, C=CHCHAHB),
3.65 (ddd, J = 11, 4.5, 3 Hz, 1 H, OCH2CHO), 4.04 (d, J = 14 Hz, 1
H, CHAHBOTBDPS), 4.10 (d, J = 14 Hz, 1 H, CHAHBOTBDPS),
4.20 (d, J = 4.5 Hz, 1 H, OCHAHBCHO), 4.21 (d, J = 3 Hz, 1 H,
OCHAHBCHO), 5.29 [d, J = 1 Hz, 1 H, C(Br)CHOAc], 5.60 (br s, 1
H, C=CH), 6.09 (d, J = 1 Hz, 1 H, OCHOAc), 7.34–7.47 (m, 6 H,
Ph), 7.63–7.70 (m, 4 H, Ph).
13C NMR (100 MHz, CDCl3): d = 19.2, 20.8, 23.8, 26.8, 34.4, 38.2,
64.5, 64.8, 66.7, 71.9, 73.2, 89.4, 114.9, 127.7, 129.72, 129.73,
133.4, 133.4, 134.0, 135.47, 135.51, 168.6, 169.9, 170.5.
Anal. Calcd for C33H41BrO8Si: C, 58.84; H, 6.13. Found: C, 58.82;
H, 6.04.
[a]D24 +4.52 (c 1.15, CH2Cl2).
(1S,8aS)-1-[(Acetyloxy)methyl]-7-[(tert-butyldiphenylsilyl-
oxy)methyl]-3,5,8,8a-tetrahydro-1H-2-benzopyran-3-ol (18)
A flask (5 L), equipped with a mechanical stirrer, was charged with
a soln of triacetate 16 (72.0 g, 107 mol) in DMF (400 mL). A mix-
ture of DMF (860 mL) and H2O (200 mL) was added followed im-
mediately by zinc–copper couple (70 g). The reaction vessel was
immersed into an oil-bath at 50 ºC, and following vigorous stirring
for 10 min, ice-cold EtOAc (700 mL), sat. aq NaHCO3 soln (100
mL) and ice (500 g) were added sequentially. The mixture was fil-
tered through a pad of Super-Cel, and the solid rinsed with EtOAc.
The filtrate was separated and the aq layer was extracted with
EtOAc (1 L, then 0.8 L). The combined organic layer was washed
with H2O (2 × 2.5 L, then 2 L) and brine (200 mL), dried over anhyd
Na2SO4 and evaporated to give crude hemiacetal 18 (55.2 g) which
was used in the next step without further purification. A small quan-
tity of this material was purified by column chromatography (silica
gel, Et2O–hexane, 1:2→1:1) to afford an analytically pure sample
of 18 as a diastereomeric mixture (ca. 1:10).
IR (NaCl, film): 3440, 2932, 2858, 1473, 1428, 1371, 1212, 1156,
1112, 1067, 824 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.06 (s, 9 H, t-Bu), 1.34 (s, 3 H,
CH3), 1.42 (s, 3 H, CH3), 1.81 (d, J = 18 Hz, 1 H, CHCHAHB-
C=CH), 2.23 (br d, J = 18 Hz, 1 H, CHCHAHBC=CH), 2.32 (d, J = 8
Hz, 1 H, OH), 2.73 (br d, J = 20 Hz, 1 H, C=CHCHAHBC=CH),
2.98 (dd, J = 10, 6 Hz, 1 H, CH), 3.04 (br d, J = 20 Hz, 1 H,
C=CHCHAHBC=CH), 3.61 (t, J = 8 Hz, 1 H, OCHAHBCHO), 3.91
(dt, J = 11.5, 8 Hz, 1 H, CHAHBOH), 4.00 (m, 2 H, CH2OTBDPS),
4.02 (dd, J = 8, 6 Hz, 1 H, OCHAHBCHO), 4.11 (ddd, J = 10, 8, 6
Hz, 1 H, OCH2CHO), 4.27 (dd, J = 11.5, 8 Hz, 1 H, CHAHBOH),
5.64 (br s, 1 H, C=CHCH2C=CH), 5.86 (td, J = 8, 2 Hz, 1 H,
C=CHCH2OH), 7.34–7.48 (m, 6 H, Ph), 7.62–7.69 (m, 4 H, Ph).
13C NMR (75 MHz, CDCl3): d = 19.2, 25.4, 26.4, 26.8, 28.1, 31.2,
38.8, 56.9, 67.2, 69.0, 75.0, 109.3, 120.6, 124.7, 127.7, 129.8,
133.6, 133.8, 135.6, 140.1.
Anal. Calcd for C30H40O4Si: C, 73.13; H, 8.18. Found: C, 73.11; H,
8.26.
[a]D22 +19.8 (c 0.84, CH2Cl2).
IR (NaCl, film): 3431, 3072, 2931, 2858, 1744, 1590, 1473, 1428,
1365, 1236, 1157, 1113, 824 cm–1.
N-{(1R,6S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-6-[(4S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-1-ethenyl-3-cyclohexen-1-
yl}trichloroacetamide (20)
To a soln of allylic alcohol 19 (44.9 g, 91.1 mmol) in anhyd CH2Cl2
(673 mL) at –40 °C were added DBU (16.0 mL, 114 mmol) and
trichloroacetonitrile (Cl3CCN) (11.4 mL, 114 mmol). After stirring
at –40 °C for 90 min, the cold-bath was removed, and sat. aq NH4Cl
1H NMR (300 MHz, CDCl3): d (major isomer) = 1.06 (s, 9 H, t-Bu),
1.72 (m, 1 H, CHCHAHBC=CH), 2.10 (s, 3 H, OAc), 2.19 (dd,
J = 17, 6.5 Hz, 1 H, CHCHAHBC=CH), 2.39 (m, 1 H, CH), 2.75–
2.99 (m, 2 H, C=CHCH2C=CH), 3.96 (ddd, J = 10, 5.5, 2.5 Hz, 1 H,
OCH2CHO), 4.05 (br s, 2 H, CH2OTBDPS), 4.19 (dd, J = 12, 5.5
Synthesis 2010, No. 12, 1992–1998 © Thieme Stuttgart · New York

PAPER
Scalable Synthesis of a New Dihydroxylated Intermediate
1997
soln (300 mL) was added. The organic layer was separated and the
aq layer extracted with CH2Cl2 (2 × 200 mL). The combined organic
layer was dried over anhyd Na2SO4 and concentrated under reduced
pressure. The residue was suspended in Et2O and passed through a
short column [neutral silica gel (150 g), eluting with Et2O]. The fil-
trate was concentrated to give the crude intermediate trichloroacet-
imidate (57.6 g) as a yellow oil which was used in the next step
without further purification. A small quantity of the material was
purified by column chromatography (neutral silica gel, EtOAc–hex-
ane, 1:25) to give an analytically pure sample. A suspension of the
crude trichloroacetimidate (57.6 g) and K2CO3 (5.8 g) in xylene (1.2
L) was heated at reflux for 15 h. The reaction mixture was cooled to
r.t. and then filtered through a pad of Super-Cel. The filtrate was di-
luted with toluene (500 mL) and concentrated in vacuo. The residue
was purified by column chromatography [silica gel (500 g),
EtOAc–hexane, 1:50→1:25→1:15] to afford trichloroacetamide 20
(48.5 g, 84% over 2 steps) as a colorless oil.
N-{(1R,6S)-6-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-4-hy-
droxymethyl-1-ethenylcyclohex-3-en-1-yl}trichloroacetamide
(21)
To a soln of TBDPS ether 20 (8.16 g, 12.8 mmol) in THF (150 mL)
was added TBAF (1 M in THF, 14.7 mL, 14.7 mmol). After stirring
at r.t. for 70 min, sat. aq NH4Cl soln (50 mL) and H2O (50 mL) were
added and the reaction mixture was extracted with EtOAc (150 mL,
then 2 × 200 mL). The combined organic layer was washed with
brine (200 mL), dried over anhyd Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy [silica gel (150 g), EtOAc–hexane, 1:3→1:1→1:0] to afford
allylic alcohol 21 (4.82 g, 94%) as a colorless oil.
[a]D31 +57.7 (c 1.84, CHCl3).
IR (NaCl, film): 3308, 2986, 2904, 1725, 1640, 1531, 1437, 1412,
1373, 1341, 1259, 1159, 1066, 1004, 924, 846, 822 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 1.41 (s, 3 H,
CH3), 1.73 (m, 1 H, CHAHBC=CH), 1.91 (dd, J = 18, 5 Hz, 1 H,
CHAHBC=CH), 2.07 (ddd, J = 12, 9.5, 5 Hz, 1 H, CH), 2.31 (d,
J = 18 Hz, 1 H, C=CHCHAHB), 3.46 (dd, J = 18, 5 Hz, 1 H,
C=CHCHAHB), 3.64 (t, J = 8 Hz, 1 H, OCHAHBCHO), 3.94–4.14
(m, 4 H, CH2OH, OCHAHBCHO, OCHAHBCHO), 5.29 (dd,
J = 17.5, 1 Hz, 1 H, CH=CHAHB), 5.33 (dd, J = 10.5, 1 Hz, 1 H,
CH=CHAHB), 5.69 (br d, 1 H, C=CH), 5.80 (dd, J = 17.5, 10.5 Hz,
1 H, CH=CHAHB), 9.27 (br s, 1 H, NH).
Data for the Intermediate Trichloroacetimidate
[a]D30 +47.6 (c 0.67, CH2Cl2).
IR (NaCl, film): 3343, 3072, 2932, 2858, 1661, 1473, 1428, 1370,
1289, 1212, 1156, 1112, 1071, 973, 824 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.06 (s, 9 H, t-Bu), 1.33 (s, 3 H,
CH3), 1.40 (s, 3 H, CH3), 1.85 (d, J = 17.5 Hz, 1 H, CHCHAHB-
C=CH), 2.25 (br d, J = 17 Hz, 1 H, CHCHAHBC=CH), 2.73 (br d,
J = 20 Hz, 1 H, C=CHCHAHBC=CH2), 2.99 (dd, J = 9.5, 6 Hz, 1 H,
CH), 3.08 (br d, J = 20 Hz, 1 H, C=CHCHAHBC=CH2), 3.66 (dd,
J = 8, 6.5 Hz, 1 H, OCHAHBCHO), 4.02 (dd, J = 8, 6.5 Hz, 1 H,
OCHAHBCHO), 4.01 (m, 2 H, CH2OTBDPS), 4.16 (dt, J = 9.5, 6.5
Hz, 1 H, OCH2CHO), 4.77 (ddd, J = 12.5, 6, 1.5 Hz, 1 H,
C=CHCHAHBO), 5.01 (ddd, J = 12.5, 8, 1 Hz, 1 H, C=CHCHA-
HBO), 5.63 (m, 1 H, C=CH), 5.72 (ddd, J = 8, 6, 2 Hz, 1 H,
C=CHCH2O), 7.34–7.48 (m, 6 H, Ph), 7.62–7.69 (m, 4 H, Ph), 8.26
(br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 25.6, 26.2, 35.5, 44.1, 60.0, 66.3,
68.9, 76.3, 93.7, 110.1, 116.4, 120.8, 133.4, 134.6, 160.6.
Anal. Calcd for C16H22Cl3NO4: C, 48.20; H, 5.56; N, 3.51. Found:
C, 48.11; H, 5.56; N, 3.46.
N-{(1R,2S,4R,5S)-4,5-Dibromo-2-[(4S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-4-hydroxymethyl-1-ethenylcyclohexyl}trichloro-
acetamide (22)
Allylic alcohol 21 (4.69 g, 11.8 mmol) was dissolved in anhyd
CH2Cl2 (120 mL), cooled to 10 °C, and K2CO3 (3.20 g, 23.5 mmol)
and pyridinium tribromide (PyHBr3) (7.52 g, 23.5 mmol) were add-
ed. The reaction mixture was stirred at 10 °C for 35 min, and then
treated with sat. aq NH4Cl soln (100 mL) and H2O (50 mL). The re-
action mixture was extracted with CH2Cl2 (3 × 100 mL) and the
combined organic layer washed with aq 3% CuSO4 soln (2 × 150
mL), dried over anhyd Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography [sil-
ica gel (50 g), EtOAc–hexane, 1:10→1:5→1:1] to afford dibromide
22 (6.48 g, 99%) as a white amorphous solid.
13C NMR (100 MHz, CDCl3): d = 19.2, 25.4, 26.80, 26.84, 28.8,
32.1, 39.7, 65.3, 67.2, 68.6, 75.6, 91.6, 109.1, 118.5, 120.6, 127.6,
129.7, 133.5, 133.6, 134.1, 135.5, 142.5, 162.7.
Anal. Calcd for C32H40Cl3NO4Si: C, 60.33; H, 6.33; N, 2.20. Found:
C, 60.33; H, 6.27; N, 2.22.
Data for Trichloroacetamide 20
[a]D25 +37.8 (c 1.89, CHCl3).
IR (NaCl, film): 3315, 3072, 2932, 2858, 1728, 1526, 1473, 1428,
1373, 1261, 1159, 1113, 1069, 925, 822 cm–1.
[a]D29 +33.4 (c 0.77, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.06 (s, 9 H, t-Bu), 1.38 (s, 3 H,
CH3), 1.42 (s, 3 H, CH3), 1.59 (m, 1 H, CHAHBC=CH), 1.77 (dd,
J = 17, 5 Hz, 1 H, CHAHBC=CH), 2.01 (ddd, J = 12, 10, 5 Hz, 1 H,
CH), 2.28 (br d, J = 18 Hz, 1 H, C=CHCHAHB), 3.41 (dd, J = 18, 5
Hz, 1 H, C=CHCHAHB), 3.56 (m, 1 H, OCH2CHO), 3.96–4.08 (m,
2 H, OCH2CHO), 4.06 (br s, 2 H, CH2OTBDPS), 5.28 (dd, J = 17,
1 Hz, 1 H, CHAHB=CH), 5.32 (dd, J = 11, 1 Hz, 1 H, CHAHB=CH),
5.62 (br d, J = 5 Hz, 1 H, C=CH), 5.74 (dd, J = 17, 11 Hz, 1 H,
CH2=CH), 7.33–7.48 (m, 6 H, Ph), 7.62–7.69 (m, 4 H, Ph), 9.23 (br
s, 1 H, NH).
IR (NaCl, film): 3494, 3318, 2988, 2935, 1724, 1522, 1456, 1435,
1373, 1247, 1222, 1160, 1067, 960, 928, 846, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.34 (s, 3 H, CH3), 1.44 (s, 3 H,
CH3), 1.56 (ddd, J = 15, 3, 2.5 Hz, 1 H, CHCHAHB), 1.83 (dd,
J = 15, 12.5 Hz, 1 H, CHCHAHB), 2.28 (t, J = 7 Hz, 1 H, OH), 2.55
(ddd, J = 12.5, 9.5, 3 Hz, 1 H, CH), 2.97 [dd, J = 16, 4.5 Hz, 1 H,
CH(Br)CHAHB], 3.60 (m, 1 H, OCHAHBCHO), 3.62 [dd, J = 16, 2.5
Hz, 1 H, CH(Br)CHAHB], 3.93 (dd, J = 12.5, 7 Hz, 1 H, CHAH-
BOH), 4.03 (dd, J = 12.5, 7 Hz, 1 H, CHAHBOH), 4.05–4.12 (m, 2
H, OCHAHBCHO, OCHAHBCHO), 4.82 (dt, J = 4.5, 2.5 Hz, 1 H,
CHBr), 5.35 (d, J = 17 Hz, 1 H, CH=CHAHB), 5.37 (d, J = 11 Hz, 1
H, CH=CHAHB), 6.72 (dd, J = 17, 11 Hz, 1 H, CH=CHAHB), 8.78
(br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 19.2, 25.4, 26.2, 26.5, 26.8, 35.5,
44.0, 60.2, 66.8, 68.8, 76.3, 93.8, 110.1, 116.2, 119.6, 127.7, 129.8,
133.6, 134.0, 135.6, 160.5.
Anal. Calcd for C32H40Cl3NO4Si: C, 60.33; H, 6.33; N, 2.20. Found:
C, 60.12; H, 6.40; N, 2.06.
13C NMR (75 MHz, CDCl3): d = 25.8, 26.5, 30.0, 39.2, 44.9, 50.5,
61.4, 69.0, 72.1, 75.5, 76.1, 93.6, 110.3, 116.0, 134.0, 160.7.
Anal. Calcd for C16H22Br2Cl3NO4: C, 34.41; H, 3.97; N, 2.51.
Found: C, 34.49; H, 3.91; N, 2.54.
Synthesis 2010, No. 12, 1992–1998 © Thieme Stuttgart · New York

1998
Y. Satake et al.
PAPER
{(3aR,4S,7aS)-4-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3a-eth-
enyl-2-trichloromethyl-3a,4,5,7a-tetrahydrobenzooxazol-6-
yl}methanol (23)
References
(1) (a) Nishikawa, T.; Urabe, D.; Isobe, M. Angew. Chem. Int.
Ed. 2004, 43, 4782. (b) Urabe, D.; Nishikawa, T.; Isobe, M.
Chem. Asian J. 2006, 1, 125.
To a soln of dibromide 22 (6.48 g, 11.6 mmol) in DMF (115 mL)
was added DBU (5.19 mL, 34.8 mmol). After stirring at r.t. for 30
min, the reaction vessel was cooled in an ice-bath and sat. aq NH4Cl
soln (50 mL) and H2O (20 mL) were added. The mixture was ex-
tracted with EtOAc (3 × 300 mL), and the combined organic layer
washed with H2O (3 × 300 mL) and brine (100 mL), dried over an-
hyd Na2SO4, and concentrated under reduced pressure to give crude
oxazoline 23. The crude material was used in the next reaction with-
out further purification.
(2) Nishikawa, T.; Asai, M.; Isobe, M. J. Am. Chem. Soc. 2002,
124, 7847.
(3) (a) Nishikawa, T.; Urabe, D.; Yoshida, K.; Iwabuchi, T.;
Asai, M.; Isobe, M. Org. Lett. 2002, 4, 2679.
(b) Nishikawa, T.; Urabe, D.; Yoshida, K.; Iwabuchi, T.;
Asai, M.; Isobe, M. Chem. Eur. J. 2004, 10, 452.
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Isobe, M. Angew. Chem. Int. Ed. 1999, 38, 3081. (b) Asai,
M.; Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M.
Tetrahedron 2001, 57, 4543.
(5) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.;
Fukuda, N.; Isobe, M. Tetrahedron 2001, 57, 3875.
(6) Nishikawa, T.; Koide, Y.; Adachi, M.; Isobe, M. Bull. Chem.
Soc. Jpn. 2010, 83, 66.
(7) Tetrodotoxin possesses an a configured hydroxy group at
C-8, however, a b-hydroxy group was important in the
synthesis of 11-deoxytetrodotoxin (2) and tetrodotoxin (1),
as the b configuration was crucial for further transformation
of the corresponding epoxide into an allylic alcohol, see ref.
2.
(8) For examples of the preparation of isoprenol, see:
(a) Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem.
2003, 68, 3. (b) Smulik, J. A.; Diver, S. T. Org. Lett. 2000,
2, 2271. (c) Bailey, W. J.; Carpenter, W. G.; Hermes, M. E.
J. Org. Chem. 1962, 27, 1975. (d) Bailey, W.; Hermes, M.
J. Org. Chem. 1962, 27, 2732. (e) Kondo, K.; Dobashi, S.;
Matsumoto, M. Chem. Lett. 1976, 1077. (f) Nunomoto, S.;
Yamashita, Y. J. Org. Chem. 1979, 44, 4788. (g) Thomas,
A. F. J. Am. Chem. Soc. 1969, 91, 3281. (h) Tanaka, J.;
Suzuki, T.; Takabe, K.; Katagiri, T. A. Nippon Kagaku
Kaishi 1973, 2, 292.
N-{(1R,2S,6S)-6-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-eth-
enyl-2-hydroxy-4-(hydroxymethyl)-3-cyclohexen-1-yl}tri-
chloroacetamide (7)
To a soln of crude oxazoline 23 (4.36 g) in py (100 mL) and H2O
(20 mL) was added p-TsOH·H2O (2.53 g, 13.0 mmol). After stirring
at 70 ºC for 2 h, ice and sat. aq NaHCO3 soln (20 mL) were added.
The mixture was extracted with EtOAc (4 × 100 mL) and the com-
bined organic layer washed with brine, dried over anhyd Na2SO4,
and concentrated under reduced pressure. The residue was dis-
solved in EtOAc and passed through a short column [silica gel (10
g), eluting with EtOAc], and then concentrated. Repeated crystalli-
zation of the crude product (from EtOAc–hexane) afforded diol 7
(2.93 g, 64% over 2 steps) as white needles.
Mp 171.0–172.5 °C; [a]D29 +99.4 (c 1.08, CHCl3).
IR (KBr): 3305, 2986, 2920, 1722, 1637, 1541, 1411, 1373, 1227,
1161, 1064, 931, 855, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 1.41 (s, 3 H,
CH3), 1.66 (dd, J = 18, 12 Hz, 1 H, CHAHBC=CH), 1.94 (dd, J = 18,
5.5 Hz, 1 H, CHAHBC=CH), 2.11 (br s, 1 H, CH2OH), 2.35 (ddd,
J = 12, 9.5, 5.5 Hz, 1 H, CH), 2.76 (br d, J = 5 Hz, 1 H, CHOH),
3.66 (t, J = 8 Hz, 1 H, OCHAHBCHO), 3.97–4.15 (m, 4 H, CH2OH,
OCHAHBCHO, OCHAHBCHO), 4.99 (br t, J = 5 Hz, 1 H, CHOH),
5.36 (dd, J = 10.5, 1 Hz, 1 H, CHAHB=CH), 5.38 (dd, J = 17.5, 1 Hz,
1 H, CHAHB=CH), 5.65 (dd, J = 17.5, 10.5 Hz, 1 H, CHAHB=CH),
5.91 (br d, J = 5.5 Hz, 1 H, C=CH), 9.26 (br s, 1 H, NH).
(9) Riley, R. G.; Silverstein, R. M.; Katzenellenbogen, J. A.;
Lenox, R. S. J. Org. Chem. 1974, 39, 1957.
(10) The structure of the major compound 14a was determined by
comparison with a similar compound reported previously
(see ref. 5); the structure of the minor product 14b was not
verified because of the difficulties experienced in separating
it from the major product.
(11) Grieco, P. A.; Nunes, J.; Gaul, M. D. J. Am. Chem. Soc.
1990, 112, 4595.
13C NMR (100 MHz, CDCl3): d = 25.8, 26.3, 26.6, 38.3, 65.3, 65.6,
65.7, 68.9, 75.9, 93.5, 110.3, 117.9, 121.4, 132.2, 139.4, 161.3.
Anal. Calcd for C16H22Cl3NO5: C, 46.34; H, 5.35; N, 3.38. Found:
C, 46.33; H, 5.25; N, 3.37.
(12) Yb(OTf)3: (a) Kobayashi, S.; Hachiya, I.; Takahori, T.;
Arali, M.; Ishitani, H. Tetrahedron Lett. 1992, 33, 6815.
Sc(OTf)3: (b) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani,
H. Tetrahedron Lett. 1993, 34, 3755.
(13) The configurations of the bromo substituents in 22 have not
been determined due to a lack of conclusive spectroscopic
data. However, the structure of a similar dibromide was
discussed earlier in ref. 4b.
Acknowledgment
We are grateful to Mr. S. Kitamura (analytical laboratory of this
school) for elemental analyses. This work was supported financially
by a Grant-in-Aid for Scientific Research (B) and G-COE from
MEXT, and the Naito Foundation.
Synthesis 2010, No. 12, 1992–1998 © Thieme Stuttgart · New York