H.-F. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 1630–1635
1633
atmosphere. The reaction mixture was stirred at ꢀ78 °C for 30 min
J = 10.5 Hz), 3.91 (1H, d, J = 10.5 Hz), 4.58 (1H, s); 13C NMR (CDCl
,
3
under an argon atmosphere. Compound 5 (207 mg, 1.0 mmol) in
dry THF (10 mL) was added dropwise over a period of 10 min into
the above freshly prepared LDA solution via a syringe, and the
resulting solution was stirred at ꢀ78 °C for 30 min 0.35 mL DMPU
75 MHz): d 10.0, 18.4, 19.4, 20.0, 25.7, 28.9, 47.7, 48.3, 52.8, 63.1,
+
68.8, 78.8, 173.3, 181.6; MS: m/z 251 (M , 1.94), 223 (1.18), 220
(13.3), 207 (54.7), 192 (100.0), 179 (59.6), 164 (13.8), 148 (24.7),
124 (60.0), 91 (39.3), 84 (36.1), 77 (27.7), 69 (29.9), 55 (28.1), 41
(
3 equiv) was then added to the reaction mixture. A solution of
(66.6); HRMS (ESI): m/z calcd for C14H21NO
3
: [M+H]+ 252.1594,
3
CH I (1.2 mmol, 1.2 equiv) in dry THF (10 mL) was then added to
found 252.1595.
the reaction mixture via a syringe with the needle contacting the
wall of the neck over 10 min. The solution was stirred at ꢀ78 °C
for 1 h. Subsequently, aqueous ammonium chloride (10%, 2 mL)
was added to the mixture to quench the reaction. The reaction mix-
ture was warmed up to room temperature, washed with saturated
4.4. (1S,4S,7S,8R)-4,8,11,11-Tetramethyl-4-hydroxymethyl-6-
oxa-3-aza-tricyclo[6.2.1.0 ]undec-2-en-5-one 20
2
,7
4.4.1. (1S,4R,7S,8R)-1,4,11,11-Tetramethyl-4-hydroxymethyl-6-
2
,7
aqueous NaHSO
3
(3 ꢂ 5 mL), NaHCO
3
, and water; dried (MgSO
4
),
oxa-3-aza-tricyclo[6.2.1.0 ]undec-2-en-5-one 20a
Diisopropylamine (156 L, 1.1 mmol, 1.1 equiv) was added to a
solution of dry THF (3 mL) and n-BuLi (2.1 M, 520 L, 1.1 mmol,
and concentrated to give the crude product. The crude product
was purified by column chromatography to yield desired com-
l
l
2
D
2
pound 6 (432 mg, 98%, dr >99:1). ½
a
ꢁ
¼ þ100:7 (c 1.08, CHCl
3
),
): d 4.63 (d, J = 7.6 Hz, 1H),
.59 (s, 1H), 2.24 (d, J = 4.8 Hz, 1H), 2.16–2.04 (m, 1H), 1.82–1.73
m, 1H), 1.62–1.54 (m, 1H), 1.44 (d, J = 7.6 Hz, 3H), 1.42–1.38 (m,
H), 1.06 (s, 3H), 0.98 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz,
CDCl ): d 181.1, 171.9, 78.5, 57.6, 52.6, 48.4, 47.9, 29.1, 25.8, 20.1,
1.1 equiv) at ꢀ78 °C in flame-dried modified flasks under an argon
atmosphere. The reaction mixture was then stirred at ꢀ78 °C for
30 min under an argon atmosphere. Compound 19 (221 mg,
1.0 mmol) in dry THF (10 mL) was added dropwise over a period
of 10 min into the above freshly prepared LDA solution via a syr-
inge, and the resulting solution was stirred at ꢀ78 °C for 30 min
after which 0.35 mL DMPU (3 equiv) was added to the reaction
mixture. A solution of saturated HCHO (gas) in dry THF (10 mL)
was then added to the reaction mixture via a syringe with the nee-
dle contacting the wall of the neck over 10 min. The solution was
then stirred at ꢀ78 °C for 2 h. Subsequently, aqueous ammonium
chloride (10%, 2 mL) was added to the mixture to quench the reac-
tion. The reaction mixture was warmed up to room temperature,
1
mp 78–80 °C; H NMR (400 MHz, CDCl
3
4
(
1
3
+
1
1
6
9.5, 16.3, 10.0; MS: m/z 221 (M , 26.4), 193 (47.9), 177 (100.0),
62 (91.1), 149 (46.4), 124 (38.8), 110 (14.1), 96 (55.7), 69 (14.5),
3
8 (15.3), 55 (14.1). IR (NaCl, CHCl ): 2968 (m), 1744 (s), 1691
ꢀ1
+
(
m) cm . HRMS (ESI): m/z calcd for C13
H19NO
2
M 221.1410, found
+
M 221.1416. Anal. Calcd for C13
Found: C, 70.54; H, 8.56; N, 6.24.
H19NO : C, 70.56; H, 8.65; N, 6.33.
2
4
.3. (1R,4S,7R,8S)-1,4,11,11-Tetramethyl-4-hydroxymethyl-6-
washed with saturated aqueous NaHSO
3
(3 ꢂ 5 mL), NaHCO
3
, and
2,7
oxa-3-aza-tricyclo[6.2.1.0 ]undec-2-en-5-one 7
water; dried over MgSO ; and concentrated to give the crude prod-
4
uct. The crude product was purified by column chromatography to
4
.3.1. (1R,4R,7R,8S)-1,4,11,11-Tetramethyl-4-hydroxymethyl-6-
yield desired compounds 20 and 20a (228 mg, 91%, 20:20a = 1:2).
2,7
1
oxa-3-aza-tricyclo[6.2.1.0 ]undec-2-en-5-one 7a
Diisopropylamine (156 L, 1.1 mmol, 1.1 equiv) was added to a
solution of dry THF (3 mL) and n-BuLi (2.1 M, 520 L, 1.1 mmol,
Compound 20: H NMR (CDCl
3
, 300 MHz): d 0.82 (3H, s), 0.96
l
(3H, s), 1.07 (3H, s), 1.36 (3H, s), 1.36–1.43 (1H, m), 1.52–1.60
(1H, m), 1.73–2.08 (2H, m), 2.42 (1H, d, J = 4.8 Hz), 2.83 (1H, br
s), 3.83 (1H, d, J = 10.8 Hz), 3.94 (1H, d, J = 10.8 Hz), 4.41 (1H, s);
l
1
.1 equiv) at ꢀ78 °C in flame-dried modified flasks under an argon
+
atmosphere. The reaction mixture was stirred at ꢀ78 °C for 30 min
under an argon atmosphere. Compound 6 (221 mg, 1.0 mmol) in
dry THF (10 mL) was added dropwise over a period of 10 min into
the above freshly prepared LDA solution via a syringe, and the
resulting solution was stirred at ꢀ78 °C for 30 min after which
MS: m/z 251 (M , 1.2), 223 (1.4), 220 (3.2), 207 (60.0), 192
(100.0), 179 (61.2), 164 (16.8), 148 (25.0), 124 (74.0), 91 (40.2),
84 (39.4), 77 (33.7), 69 (47.3), 55 (38.2), 41 (88.6); Compound
1
20a: H NMR (CDCl
3
, 300 MHz): d 0.83 (3H, s), 0.97 (3H, s), 1.05
(3H, s), 1.36–1.43 (1H, m), 1.54 (3H, s), 1.59–1.68 (1H, m), 1.80–
1.96 (1H, m), 1.97–2.09 (1H, m), 2.41 (1H, d, J = 3.9 Hz), 3.73 (1H,
d, J = 10.8 Hz), 4.00 (1H, d, J = 10.8 Hz), 4.62 (1H, s); MS: m/z 251
0
.35 mL DMPU (3 equiv) was added to the reaction mixture. A
solution of saturated HCHO (gas) in dry THF (10 mL) was then
added to the reaction mixture via a syringe with the needle con-
tacting the wall of the neck over 10 min. The solution was stirred
at ꢀ78 °C for 2 h. after which aqueous ammonium chloride (10%,
+
(M , 1.93), 223 (1.20), 220 (13.3), 207 (54.7), 192 (100.0), 179
(59.6), 164 (13.8), 148 (24.7), 124 (60.0), 91 (39.3), 84 (36.1), 77
(27.7), 69 (30.0), 55 (28.0), 41 (66.5).
2
mL) was added to the mixture to quench the reaction. The reac-
tion mixture was warmed up to room temperature, washed with
saturated aqueous NaHSO , and water; dried
(3 ꢂ 5 mL), NaHCO
over MgSO and concentrated to give the crude product. The crude
4.5. (S)-Methylserine 8 and (R)-methylserine 15
3
3
4
Compound 7 (7a) (100 mg, 0.4 mmol) was treated with 6 M HCl
(2 mL) in THF (2 mL) at 90 °C for 4 h and then concentrated under
reduced pressure. The mixture was extracted with diethyl ether.
The aqueous layer was evaporated under reduced pressure. The
residue was dissolved in EtOH (4 mL), after which propylidene
oxide (3 mL) was added, and the mixture was stirred at room tem-
perature for 30 min during which time, fine white solids precipi-
tated. The precipitate was collected by filtration, washed
product was purified by column chromatography to yield the de-
sired compounds 7 and 7a (236 mg, 94%, 7:7a = 7:1). Compound
1
D
5
1
7
3
: ½
aꢁ
¼ þ86 (c 0.40, CHCl
3 3
); mp 156–157 °C; H NMR (CDCl ,
00 MHz): d 0.79 (3H, s), 0.95 (3H, s), 1.06 (3H, s), 1.35–1.42 (1H,
m), 1.54 (3H, s), 1.64–1.80 (2H, m), 1.99–2.05 (1H, m), 2.17 (1H,
d, J = 4.8 Hz), 3.74 (1H, d, J = 10.8 Hz), 3.99 (1H, d, J = 10.8 Hz),
1
3
4
2
2
3
.79 (1H, s); C NMR (CDCl , 75 MHz): d 10.3, 19.4, 20.2, 24.6,
6.0, 29.2, 47.8, 48.3, 52.9, 65.3, 69.0, 80.7, 174.2, 181.2; MS: m/z
51 (M , 1.0), 223 (1.3), 220 (3.2), 207 (54.8), 192 (100.0), 179
2
successively with cold EtOH and Et O, and dried to afford the de-
sired (S)-methylserine 8 or (R)-methylserine 15 (44 mg, 92%). Com-
+
1
D
5
1
(
(
C
59.9), 164 (16.8), 148 (25.0), 124 (74.0), 91 (40.2), 84 (39.4), 77
pound 8: ½
aꢁ
¼ þ6:0 (c 1.0, H,O); mp 237–239 °C; H NMR (D
2
O,
33.7), 69 (47.3), 55 (38.2), 41 (87.6); HRMS (ESI): m/z calcd for
300 MHz): d 1.23 (3H, s), 3.47 (1H, d, J = 11.7 Hz), 3.72 (1H, d,
: [M+H]+ 252.1594, found 252.1595. Compound 7a:
J = 11.7 Hz); C NMR (D
HRMS (ESI): m/z calcd for C
13
14
H
21NO
3
2
O, 75 MHz): d 18.6, 62.6, 64.9, 175.6;
1
5
1
+
½
a
ꢁ
¼ þ124 (c 0.30, CHCl
3
); mp 123–124 °C; H NMR (CDCl
3
,
4
H
9
NO
3
: [M+H] 120.0655, found
D
1
5
3
1
2
00 MHz): d 0.76 (3H, s), 0.94 (3H, s), 1.01 (3H, s), 1.33 (3H, s),
.35–1.41 (1H, m), 1.51–1.61 (1H, m), 1.71–1.80 (1H, m), 2.00–
.10 (1H, m), 2.22 (1H, d, J = 4.8 Hz), 2.84 (1H, br s), 3.81 (1H, d,
120.0651. Compound 15: ½ ꢁ
a
¼ ꢀ6:0 (c = 1.0, H,O); mp 237–
D
1
239 °C; H NMR (D
2
O, 300 MHz): d 1.23 (3H, s), 3.47 (1H, d,
1
3
J = 11.7 Hz), 3.72 (1H, d, J = 11.7 Hz); C NMR (D
2
O, 75 MHz): d