3028
S. V. Narina, A. Sudalai / Tetrahedron 63 (2007) 3026–3030
measured using sodium D line on a JASCO-181 digital
polarimeter. Infrared spectra were recorded on a Shimadzu
FTIR-8400 spectrometer. H NMR and C NMR spectra
were recorded on Bruker AC-200 spectrometer. Elemental
analysis was carried out on a Carlo Erba CHNS-O analyzer.
Enantiomeric excess was determined by chiral HPLC.
bicarbonate solution (50 mL), dried over Na SO , and then
2 4
concentrated in vacuo to give Mosher’s ester of the alcohol
7 (53 mg, 70%) as a colorless thick syrup. [a] ꢁ4.8 (c
1
13
25
D
1
0.8, MeOH); H NMR (CDCl ) d: 7.32–7.49 (m, 5H),
3
4.65–4.45 (m, 1H), 3.98–3.55 (m, 4H), 3.52 (s, 3H), 1.38
(s, 9H).
4
(
.1.1. (S)-(L)-N-Boc-3-tert-butylamino-1,2-propane diol
6). A mixture of K Fe(CN) (2.1 g, 6.4 mmol), K CO
3
4.1.4. (S)-5-((4-Morpholino-1,2,5-thiadiazol-3-yloxy)-
methyl)-3-tert-butyloxazolidin-2-one (9). To a mixture of
2-oxazolidinone 7 (0.432 g, 2.5 mmol) and 3-chloro-4-mor-
3
6
2
(
0.89 g, 6.4 mmol), and (DHQ) -PHAL (0.038 g,
2
1
1
0
1
.04 mmol) in t-BuOH/H O (1:1, 40 mL) was stirred for
2
pholino-1,2,5-thiadiazole (0.512 g, 2.5 mmol) in tert-butyl
ꢂ
ꢂ
of OsO (50 mL, 0.02 mmol, 0.5 M solution in toluene) was
ꢂ
0 min at 25 C. It was then cooled to 0 C and a solution
alcohol (5 mL) at 25 C was added potassium tert-butoxide
(0.336 g, 3 mmol). The mixture was stirred for 12 h. The sol-
vent was evaporated in vacuo and the residue was neutralized
by 6 N HCl. Work-up (extraction with 30 mL of EtOAc) and
purification by column chromatography (40% EtOAc/petro-
leum ether) gave oxazolidinone 9 (0.641 g, 75%) as a white
4
ꢂ
min and then the olefin 5 (0.450 g, 2.1 mmol) was added.
added. The resulting reaction mixture was stirred at 0 C for
5
ꢂ
The reaction mixture was stirred at 25 C for 18–24 h (mon-
itored by TLC). It was quenched with sodium sulfite (2.0 g)
and extracted with ethyl acetate (4ꢃ20 mL). Combined or-
ganic layers were washed with brine (15 mL), dried over an-
hydrous Na SO , and evaporated in vacuo to give the crude
ꢂ
25
solid. Mp 86–87 C; [a]D ꢁ3.4 (c 2, EtOH); R (40%
f
EtOAc/petroleum ether) 0.39; IR: (CHCl ) n : 472, 685,
3
max
ꢁ
1
1
782, 1227, 1760, 3046 cm
CDCl ): d 4.80–4.65 (m, 1H), 4.54 (br s, 2H), 3.91–3.40
;
H NMR (200 MHz,
2
4
product, which was purified by column chromatography
(
3
1
3
30% EtOAc/petroleum ether) to give pure diol 6 (0.482 g,
(m, 10H), 1.36 (s, 9H); C NMR (50 MHz, CDCl3):
d 155.8, 152.9, 149.7, 70.3, 69.2, 66.3, 53.5, 47.8, 44.9,
27.3. Anal. Calcd for C H N O S (342.41): C, 49.11; H,
2
5
93%) as a colorless thick syrup. [a] ꢁ2.90 (c 2, EtOH);
R (30% EtOAc/petroleum ether) 0.43; IR: (CHCl ) n
f 3 max
D
:
43, 749, 861, 920, 953, 1285, 1393, 1452, 1688, 1710,
14 22 4 4
4
2
3
9
6
6.48; N, 16.36; S, 9.36%. Found: C, 49.25; H, 6.31; N,
16.42; S, 9.31%.
1
902, 2977, 3396; H NMR (200 MHz, CDCl ): d 3.81–
3
.32 (m, 5H), 2.99–2.75 (br s, 2H), 1.48 (s, 9H), 1.37 (s,
H); C NMR (50 MHz, CDCl ): d 157.7, 80.6, 72.4,
1
3
4.1.5. (2S)-1-(tert-Butylamino)-3-[(4-morpholin-4-yl-
1,2,5-thiadiazol-3-yl)oxy]propan-2-ol (1, (S)-timolol). To
a stirred solution of oxazolidinone 9 (0.684 g, 2 mmol) in
methanol (20 mL) was added 1 N NaOH (10 mL). The reac-
tion mixture was stirred for 8 h, the residue filtered off, and
the solvent removed in vacuo to give the crude product,
which was purified by column chromatography (20%
3
3.3, 55.8, 46.9, 29.9, 28.5. Anal. Calcd for C H NO
4
1
2
25
(247.33): C, 58.27; H, 10.19; N, 5.66%. Found: C, 58.20;
H, 10.26; N, 5.70%.
4.1.2. (S)-3-tert-Butyl-5-(hydroxymethyl)oxazolidin-2-
one (7). A mixture of diol 6 (0.988 g, 4 mmol) and K CO
2
3
(
5
0.828 g, 6 mmol) in dry MeOH (10 mL) was refluxed for
h. The resulting reaction mixture was cooled to room tem-
MeOH/Et O) to give timolol 1 (0.569 g, 90%) as a colorless
2
2
5
thick syrup. [a]D ꢁ1.93 (c 1, CHCl ); R (30% MeOH/Et O)
3
f
2
perature and the solvent was evaporated in vacuo. Work-up
extraction with 30 mL of EtOAc) and purification by col-
umn chromatography (30% EtOAc/petroleum ether) gave
0.52; IR (neat) nmax: 768, 957, 1122, 1228, 1311, 1497, 2855,
2964, 3295 (br), 3412 (br) cm ; H NMR (200 MHz,
ꢁ
1
1
(
CDCl ): d 4.48 (dd, J¼11.1, 4.1 Hz, 1H), 4.37 (dd, J¼11.1,
3
2
5
2
-oxazolidinone 7 (0.657 g, 95%) as a colorless oil. [a]
2.5 (c 2, EtOH); R (30% EtOAc/petroleum ether) 0.46;
f
5.6 Hz, 1H), 3.94 (m, 1H), 3.79–3.83 (t, J¼4.9 Hz, 4H),
D
ꢁ
3.50–3.55 (t, J¼5.4 Hz, 4H), 2.82 (dd, J¼4.0, 12.1 Hz,
13
IR: (CHCl ) nmax: 491, 677, 919, 1066, 1227, 740,
3
1H), 2.59 (dd, J¼7.9, 12.1 Hz, 1H), 2.09 (br s, 1H), 1.10
ꢁ1
1
3
1
9
5
5
8
026 cm ; H NMR (200 MHz, CDCl ): d 4.50–4.39 (m,
3
(s, 9H); C NMR (50 MHz, CDCl ): d 153.7, 150.0, 72.7,
3
H), 3.85–3.50 (m, 4H), 3.40–3.31 (br s, 1H), 1.36 (s,
H); C NMR (50 MHz, CDCl ): d 157.0, 72.4, 62.4,
68.0, 66.3, 50.3, 47.8, 44.3, 28.9. Anal. Calcd for
C H N O S (316.41): C, 49.35; H, 7.65; N, 17.71; S,
10.13%. Found: C, 49.48; H, 7.53; N, 17.79; S, 10.01%.
1
3
3
13 24 4 3
3.2, 44.5, 27.2. Anal. Calcd for C H NO (173.2): C,
3
8
15
5.47; H, 8.73; N, 8.09%. Found: C, 55.54; H, 8.60; N,
.14%.
4.1.6. (S)-(L)-3-(3-tert-Butylamino-2-hydroxypropoxy)-
4
-(N-morpholino)-1,2,5-thiadiazole ((S)-1 hemimaleate
4
.1.3. Preparation of Mosher’s ester of (S)-3-tert-butyl-5-
hydroxymethyl)oxazolidin-2-one (14). A two-neck 10 mL
salt, 10). To a stirred solution of timolol 1 (0.418 g,
1.3 mmol) in THF (5 mL) was added a solution of maleic
acid (0.151 g, 1.3 mmol) in THF (3 mL). The mixture was
(
flask with septum was charged with N,N -dicyclohexylcar-
0
bodiimide (DCC) (44 mg, 0.21 mmol), catalytic amount of
ꢂ
seeded and aged for 1 h at 25 C. The resulting salt was fil-
tered, washed with THF (3 mL), and dried at 50 C in vacuo
ꢂ
to give hemimaleate salt 10 (0.477 g, 85%) as a white solid.
4
-dimethylaminopyridine (DMAP), and CH Cl (2 mL) un-
2
2
ꢂ
der argon atmosphere. The flask was allowed to cool at 0 C
for 10 min and a solution of alcohol 7 (31 mg, 0.18 mmol) in
CH Cl (2 mL) was introduced through a syringe. It was
allowed to stir for additional 10 min, followed by dropwise
addition of (R)-a-methoxy-a-trifluoromethylphenyl acetic
acid (46 mg, 0.196 mmol) in CH Cl (2 mL). This reaction
mixture was then stirred at 0 C for additional 1 h and then
at room temperature overnight. The reaction mixture was di-
luted with CH Cl (50 mL), washed with saturated sodium
ꢂ
5g
ꢂ
25
Mp 198–201 C {lit. mp 201–202 C}; [a] ꢁ6.45 (c 4,
D
5
g
25
1 N aq HCl), 56% ee {lit. [a]D ꢁ11.52 (c 4, 1 N aq
HCl)}; HPLC: 56% ee, Chiracel OD-H, l¼297 nm, diethyl
amine/2-propanol/hexane (1:40:960), 1 mL/min, retention
time: (R)-enantiomer 9.07 min, (S)-enantiomer 11.33 min;
IR (neat) nmax: 443, 749, 861, 920, 953, 1285, 1393, 1452,
2
2
2
2
ꢂ
ꢁ1
1
1562, 1688, 1710, 2902, 2977, 3396 cm
(200 MHz, DMSO-d ): d 8.36 (br s, 1H), 6.01 (s, 2H,
;
H NMR
2
2
6