the threo-isomer 12a (63.39 g). The filtrate included the erythro-
isomer 12b. It was evaporated to a residue (66.39 g) from which
58 g was crystallized from hexane to give crude 12b (42.5 g).
The crude crystals (30 g) were purified by silica gel chroma-
tography (70-230 mesh, 240 g, dichloromethane as eluent).
Crystallization with diethylether gave 12b (23.35 g). Compound
12a: mp 160-162 °C. 1H NMR (500 MHz, (CDCl3 δ) 1.25 (t,
J ) 7.3 Hz, 3H), 1.43 (s, 18H), 1.84 (m, 1H), 1.94 (m, 1H),
3.03 (ddd, J ) 9.1, 8.2, 7.2 Hz, 1H), 3.08 (dq, J ) 13.4, 7.2
Hz, 1H), 3.18 (ddd, J ) 9.1, 8.0, 3.5 Hz, 1H), 3.23 (dq, J )
13.4, 7.2 Hz, 1H), 3.53 (m, 1H), 4.84 (d, J ) 9.7 Hz 1H), 5.27
(s, 1H), 7.16 (s, 2H). 13C NMR (150 MHz, (CDCl3 δ) 13.18,
23.09, 30.24, 34.41, 39.42, 43.92, 63.67, 74.64, 123.58, 129.99,
136.38, 154.22. Elemental analysis: Calcd for C20H33O4NS: C;
62.63, H; 8.67, N; 3.65, S; 8.36, Found: C; 62.58, H; 8.62, N;
3.66, S; 8.32. Compound 12b: mp 78-96 °C. 1H NMR (500
MHz, (CDCl3 δ) 1.25 (t, J ) 7.3 Hz, 3H), 1.44 (s, 18H), 2.08
(m, 1H), 2.60 (dq, J ) 13.0, 8.5 Hz, 1H), 3.07 (m, 1H), 3.08
(m, 1H), 3.21 (dq, J ) 13.3, 7.2 Hz, 1H), 3.28 (m, 1H), 3.31
(d, J ) 2.6 Hz, 1H), 3.38 (td, J ) 8.5, 2.1 Hz 1H), 5.21 (s,
1H), 5.40 (brs, 1H), 7.15 (s, 2H). 13C NMR (150 MHz, (CDCl3
δ) 13.18, 18.30, 30.28, 34.43, 39.46, 44.56, 63.21, 69.19,
122.41, 129.94, 136.14, 153.54. Elemental analysis: Calcd for
C20H33O4NS: C; 62.63, H; 8.67, N; 3.65, S; 8.36, Found. C;
62.19, H; 8.63, N; 3.62, S; 8.10.
Into the residue, acetone (15 mL) and 1 N HCl (5 mL) were
added for hydration of acetal. The reaction mixture was
extracted with ethyl acetate, and then the organic layer was
evaporated to give 3,5-di-tert-butyl-4-methoxybenzaldehyde 14
(3.25 g).
Aldol-type condensation of 14 and 6 and dehydration were
tried according to the “Procedure for a One-Pot Process to
S-2474”. However, no dehydration was detected with HPLC.
The reaction mixture was extracted with toluene, and evapora-
tion gave white crystals of 15 as a diastereomer mixture (the
1
threo-isomer was the major product). H NMR (600 MHz,
(CD3)2SO δ) 1.10 (t, J ) 7.2 Hz, 3H), 1.38 (s, 18H), 1.61 (m,
1H), 1.69 (m, 1H), 2.95 (m, 2H), 2.98 (m, 2H), 3.38 (minor)
and 3.43 (major) (ddd, J ) 11.9, 9.7, 8.4 Hz, 1H), 3.61 (s, 3H),
4.65 (major) and 4.80 (minor) (dd, J ) 9.7, 4.8 Hz, 1H), 5.65
(minor) and 5.72 (major) (d, J ) 4.8 Hz, 1H), 7.26 (major)
and 7.28 (minor) (s, 2H). 13C NMR (150 MHz, (CD3)2SO δ)
13.0 (major) and 13.1 (minor), 21.7 (minor) and 22.7 (major),
31.8, 35.3, 39.2, 43.4 (major) and 44.2 (minor), 63.2 (major)
and 62.9 (minor), 63.9 (minor) and 64.0 (major), 70.1 (minor)
and 72.3 (major), 124.7 (minor) and 125.0 (major), 135.8
(major) and 136.1 (minor), 142.2 (minor) 142.7 (major), 158.3.
HRMS (FAB+) Calcd for C21H35NO4S: ([M + Na]+), 420.2185:
Found. m/z 420.2183.
Examination of Reaction Mechanism Study (Scheme 5).
3,5-Di-tert-butyl-4-hydroxybenzaldehyde (7.0 g, 29.9 mmol),
ethylene glycol (2.8 g, 45.2 mmol), toluene (70 mL), and
p-toluene sulfonic acid monohydrate (113 mg, 0.59 mmol) were
stirred and heated. The water formed during the reaction was
removed azeotropically over the 7 h. The reaction mixture was
poured into saturated NaHCO3, and a product was extracted
with ethyl acetate. The organic layer was separated and washed
with water. This organic layer was dried and concentrated to
give 6.1 g of (3,5-di-tert-butyl-4-hydroxybenzaldehyde)-1,3-
dioxolane as white crystals. The crystals (5.0 g) were dissolved
with THF (5 mL) and DMF (5 mL), and this solution was
slowly added dropwise to a stirred suspension of NaH (60% in
mineral oil, 0.80 g, 20 mmol) in THF (5 mL) with ice-cooling
and stirred for 15 min at 0 °C. Iodomethane (10.2 g, 71.9 mmol)
was added to the reaction mixture at 0 °C, and stirring was
continued for 1 h. The reaction mixture was poured into
saturated NaHCO3 and extracted with ethyl acetate. The organic
layer was separated and concentrated under reduced pressure.
Acknowledgment
We thank Dr. Hideki Tsujisita, Dr. Yasuyuki Hiramatsu, and
Mr. Yusuke Sakou for helpful discussions on the molecular
mechanical calculation.
Supporting Information Available
1
HPLC chart of S-2474 1; copies of H NMR spectra of
S-2474 1; copies of H and 13C NMR spectra of (5R*,1′R*)-
1
5-[3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-ethyl-
1,2-isothiazolidine-1,1-dioxide 12a (threo), (5S*,1′R*)-5-[3,5-
di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-ethyl-1,2-
isothiazolidine-1,1-dioxide 12b (erythro), 5-[(3,5-di-tert-butyl-
4-methoxyphenyl)hydroxymethyl]-2-ethyl-1,2-isothiazolidine-
1,1-dioxide 15. This material is available free of charge via the
Received for review January 15, 2008.
OP800008W
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Vol. 12, No. 3, 2008 / Organic Process Research & Development