128 J . Org. Chem., Vol. 67, No. 1, 2002
Inagaki et al.
and CH2Cl2 (70 mL) was refluxed for 5 h. The reaction was
cooled to room temperature, and insoluble materials were
removed by filtration. The filtrate was concentrated to give a
crude form of the title compound (8.16 g), which was used in
the next reaction without further purification. 1H NMR
(CDCl3): δ 1.28 (s, 9H), 1.32 (s, 9H), 6.81 (s, 1H), 6.83 (d, J )
2.4 Hz, 1H), 7.42 (d, J ) 2.4 Hz, 1H).
(E)-5-(3,5-Di-ter t-bu tyl-4-h yd r oxyben zylid en e)-2-eth yl-
1,2-isoth ia zolid in e-1,1-d ioxid e (S-2474; 1). A solution of 6
(8.21 g, 55 mmol) in toluene (10 mL) was added to LHMDS (1
M in toluene, 115 mL, 115 mmol) with ice-cooling, and the
mixture was stirred for 30 min under the same conditions.
Next, to this solution was added a solution of 9 (12.42 g, 50
mmol) in THF (30 mL) and toluene (25 mL) over 30 min with
ice-cooling. The reaction was stirred for an additional 4 h under
the same conditions and then quenched with cold diluted HCl.
The organic layer was separated and washed with water twice.
Drying and removal of the solvents gave a residual solid (the
purity by HPLC analysis was determined to be 97.31%, with
2 (1.40%) and 8 (1.29%) as impurities of more than 0.1%.). It
was crystallized from 2-propanol to give the title compound
(14.7 g, 80%) as colorless crystals. The purity was over 99.9%
as determined by HPLC analysis; mp 135-137 °C.
E-selectivity, which is the first example of a relatively
stable R-methoxyquinone methide being used as an
equivalent of the protected p-hydroxy benzaldehyde. This
procedure resolves the problems arising from protection/
deprotection procedures of the formyl group and the
dehydration/deprotecion reaction with p-TsOH described
in the Introduction and gives S-2474 of high quality after
a single crystallization.
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR spectra were
determined at 200 or 300 MHz. 13C NMR spectra were
determined at 75.5 MHz. IR spectra were recorded on a Nicolet
20SXB FT-IR spectrometer. Mass spectra were measured on
a J EOL J MS-SX/S102A or a HITACHI M-90 mass spectrom-
eter. Unless otherwise stated, all reactions were carried out
under a nitrogen atmosphere with guaranteed grade solvents
that had been dried over type 3A or 4A molecular sieves.
Drying of organic extracts over anhydrous sodium sulfate is
simply indicated by the word “dried”. Column chromatography
using Merck silica gel 60 (70-230 or 230-400 mesh) or a
Merck Lobar column is referred to “chromatography on silica
gel”.
HPLC analysis was performed on a Cosmosil 5C18-AR
column (4.6 × 150 mm) with UV detection at 230 nm. The
mobile phase flow rate was 1 mL/min with a gradient for which
solvent A was MeOH/H2O/AcOH (50:50:1) and B was MeOH/
AcOH (100:0.1). Time program: 0-10 min, A:B ) 50:50; 10-
20 min, A:B ) 50:50-30:70; 20-30 min, A:B ) 30:70.
Retention times: 10a , 4.9 min; 8, 5.8 min; 2, 6.1 min; 1, 6.8
min.
2,6-Di-ter t-b u t yl-4-m et h oxym et h ylen ecycloh exa -2,5-
d ien on e (9). A mixture of 3,5-di-tert-butyl-4-hydroxybenzal-
dehyde (2) (23.4 g, 0.10 mol), NH4Cl (1.0 g), trimethyl
orthoformate (50 mL, 0.46 mol), xylene (50 mL), and absolute
MeOH (50 mL) was refluxed for 2 h. Excess trimethyl ortho-
formate, methyl formate formed during the reaction, and
MeOH were removed by distillation. To the residue was added
xylene (50 mL), and the mixture was cooled to room temper-
ature. NH4Cl was removed by filtration, and the filtrate was
heated at 160 °C to remove xylene and MeOH formed during
the thermal decomposition reaction over 2 h and an additional
2 h under reduced pressure (20-100 mmHg). The reaction was
cooled to 50 °C, and then hexane (50 mL) was added. The
crystalline product was collected and washed with a small
amount of hexane to afford yellow crystals of the title
compound (9) (22.1 g, 89%); mp 137-139 °C (lit.4a mp 136-
138 °C). 1H NMR (acetone-d6): δ 1.27 (s, 9H), 1.29 (s, 9H),
4.08 (s, 3H), 7.02 (d, J ) 2.5 Hz, 1H), 7.41 (dd, J ) 0.9, 2.5
Hz, 1H), 7.54 (brs, 1H). 13C NMR (acetone-d6): δ 29.68, 30.24,
35.42, 35.82, 63.03, 114.83, 124.58, 132.42, 145.39, 147.27,
162.62, 186.30. IR (Nujol): 1637, 1558, 1454, 1358, 1290, 1269,
1153, 1088, 1020 cm-1. Anal. Calcd for C16H24O2: C, 77.38; H,
9.74. Found: C, 77.15; H, 9.75.
2,6-Di-ter t-bu t yl-4-et h oxym et h ylen ecycloh exa -2,5-d i-
en on e. The title compound was prepared from 2 (23.4 g, 0.10
mol), NH4Cl (2.0 g), triethyl orthoformate (60 mL), absolute
EtOH (60 mL), and xylene (60 mL) in 84% yield by the same
procedure described above; mp 114-117 °C. 1H NMR (acetone-
d6): δ 1.27 (s, 9H), 1.30 (s, 9H), 1.41 (t, J ) 7.1 Hz, 3H), 4.40
(q, J ) 7.1 Hz, 2H), 7.03 (d, J ) 2.4 Hz, 1H), 7.44 (dd, J ) 0.7,
2.4 Hz, 1H), 7.46 (brs, 1H). 13C NMR (acetone-d6): δ 15.60,
29.67, 29.70, 35.34, 35.74, 72.24, 114.64, 124.64, 132.56,
145.05, 146.98, 161.58, 186.15. IR (Nujol): 1633, 1560, 1450,
1358, 1252, 1149, 1088, 1022 cm-1. HR-FABMS: m/z 263.2005
[M + H]+ (calcd for C17H27O2, 263.2011).
(5R*, 1′R*)-5-[(3,5-Di-ter t-bu tyl-4-h ydr oxyp h en yl)m eth -
oxym eth yl]-2-eth yl-1,2-isoth ia zolid in e-1,1-d ioxid e (10a ;
th r eo) a n d (5S*, 1′R*)-5-[(3,5-Di-ter t-bu tyl-4-h yd r oxy-
p h en yl)m eth oxym eth yl]-2-eth yl-1,2-isoth ia zolid in e-1,1-
d ioxid e (10b; er yth r o). To a stirred solution of diastereo
mixture of 5-((3,5-di-tert-butyl-4-methoxymethyloxyphenyl)-
hydroxymethyl)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (7) (2.64
g, 6.17 mmol) in MeOH (25 mL), which was prepared by a
previously reported method,1 was added 10 N HCl/MeOH (2.5
mL, 25 mmol) at 0 °C. The resulting mixture was stirred for
15 h at room temperature. The reaction was poured into water,
and the product was extracted with diisopropyl ether. The
organic layer was washed with water and then brine, dried,
and evaporated. The residue was carefully purified by column
chromatography on silica gel, eluting with hexane/AcOEt (4:
1). The erythro 10b (1.00 g, 41%) and the threo 10a (0.30 g,
12%) were obtained as colorless solids from the less polar and
polar fractions, respectively. Compound 10a : mp 204-206 °C.
1H NMR (CDCl3): δ 1.22 (t, J ) 7.2 Hz, 3H), 1.43 (s, 18H),
1.65-1.90 (m, 2H), 2.93-3.23 (m, 4H), 3.27 (s, 3H), 3.36-3.48
(m, 1H), 4.34 (d, J ) 9.9 Hz, 1H), 5.25 (s, 1H), 7.09 (s, 2H). 13
C
NMR (CDCl3): δ 13.20, 22.99, 30.30, 34.37, 39.68, 43.90, 56.67,
63.18, 82.66, 123.82, 127.79, 136.25, 154.09. IR (KBr): 3547,
2948, 1434, 1287, 1233, 1198, 1113 cm-1. Anal. Calcd for
C
21H35NO4S: C, 63.44; H, 8.87; N, 3.52; S, 8.06. Found: C,
63.17; H, 8.74; N, 3.55; S, 8.07. Compound 10b: mp 90-92
°C. 1H NMR (CDCl3): δ 1.23 (t, J ) 7.2 Hz, 3H), 1.44 (s, 18H),
2.21-2.35 (m, 1H), 2.42-2.56 (m, 1H), 3.08-3.34 (m, 5H), 3.27
(s, 3H), 4.65 (d, J ) 4.2 Hz, 1H), 5.21 (s, 1H), 7.10 (s, 2H). 13C
NMR (CDCl3): δ 13.56, 20.61, 30.27, 34.34, 40.04, 45.03, 57.05,
63.21, 79.49, 122.99, 128.33, 135.89, 153.49. IR (KBr): 3585,
2953, 1431, 1358, 1299, 1234, 1106, 1086 cm-1. Anal. Calcd
for C21H35NO4S: C, 63.44; H, 8.87; N, 3.52; S, 8.06. Found: C,
63.16; H, 8.77; N, 3.48; S, 8.09.
Ack n ow led gm en t. The authors thank Drs. Mit-
suaki Ohtani, Kenji Kawada, Toshiro Konoike, and
Saichi Matsumoto for their encouragement and helpful
discussions throughout this study, and Mr. Hiroshi
Nakai for the X-ray crystallography of compound 10a .
Su p p or tin g In for m a tion Ava ila ble: Tables 4 and 5 and
tables of X-ray crystallographic data of compound 10a and a
figure showing an ORTEP diagram of 10a . This material is
2,6-Di-ter t-b u t yl-4-ch lor om et h ylen ecycloh exa -2,5-d i-
en on e. A mixture of 2 (7.02 g, 30 mmol), triethylamine (8.36
mL, 60 mmol), methansulfonyl chloride (4.7 mL, 60 mmol),
J O0106795