6
K. HE ET AL.
ꢀ
give 2.20 g (80%) 7 as a white solid. mp. 102-103 C; R ¼ 0.33 (silica gel, petroleum
f
2
D
0
1
ether/EtOAc 2/1); [a]
¼ -88.5 (c ¼ 1.0, CHCl ); H NMR (500 MHz, CDCl ) d 7.66
3
3
(
dd, J ¼ 5.2, 3.3 Hz, 2H), 7.40-7.34 (m, 4H), 7.31-7.28 (m, 4H), 6.35 (s, 2H), 5.17 (t,
J ¼ 7.8 Hz, 1H), 3.92 (dd, J ¼ 7.7, 4.7 Hz, 1H), 3.34 (s, 2H), 3.28 (dd, J ¼ 13.6, 7.5 Hz,
1
1
H), 2.90-2.84 (m, 1H), 2.65 (d, J ¼ 9.4 Hz, 1H), 2.34 (d, J ¼ 24.7 Hz, 1H), 1.99 (s, 6H),
.83 (dd, J ¼ 12.7, 5.3 Hz, 2H), 1.76 (t, J ¼ 3.8 Hz, 1H), 0.91-0.85 (m, 6H), 0.70 (s, 3H).
1
3
C NMR (125 MHz, CDCl ) d 173.1, 169.8, 154.1, 140.1, 139.5, 135.7, 130.1, 128.8,
3
1
2
28.1, 127.9, 114.8, 65.2, 64.4, 53.3, 48.2, 47.6, 44.6, 38.1, 34.2, 32.8, 26.4, 20.2, 20.1,
þ
0.0, 19.8. HRMS (ESI): calcd. for C H N O S [M þ H] 571.2625; found 571.2630.
3
4
39 2 4
Anal. Calcd for C H N O S: C, 71.55; H, 6.71; N, 4.91; S, 5.62. Found: C, 71.45; H,
3
4
38 2 4
6.63; N, 4.97; S, 5.50.
(2S)-2-Amino-1-((6R,7aR)-8,8-dimethyl-2,2-dioxidotetrahydro-3H-3a,6-methanobenzo
[c]isothiazol-1(4H)-yl)-3-(4-hydroxy-2,6-dimethylphenyl)propan-1-one (8)
To a solution of 7 (1.68 g, 2.96 mmol) in THF (20 mL) was added aqueous 1.0 mol/L HCl
ꢀ
ꢀ
(
4.5 mL) at 0 C. The reaction was stirred at 0 C for 4 h. After adding 20 mL of H O, the
2
two phases were separated, the aqueous layer was washed with ethyl acetate (20 mL), then
was basified with saturated sodium bicarbonate and extracted with ethyl acetate (3 x 50 mL).
The combined organic phase was dried with Na SO , filtered and evaporated to dryness.
2
4
The residue was purified by flash column chromatography on silica gel eluting with petrol-
ꢀ
1
eum ether/EtOAc to give 1.04 g 8 (86%) as a white solid. m.p. 208-209 C; R ¼ 0.23 (silica
f
20
D
gel, petroleum ether/EtOAc 1/1); [a]
¼ þ23.5 (c ¼ 1.0, MeOH); H NMR (500 MHz,
DMSO) d 6.34 (s, 2H), 3.72 (d, J¼ 14.1 Hz, 2H), 3.06 (q, J¼ 14.0 Hz, 1H), 2.89 (dd,
J¼ 13.8, 8.7 Hz, 1H), 2.70 (dd, J¼ 13.8, 6.6 Hz, 1H), 2.26 (s, 2H), 2.19 (s, 6H), 1.84-1.70 (m,
1
3
6
H), 1.64 (s, 1H), 1.23-1.13 (m, 1H), 1.04 (s, 1H), 0.85 (s, 6H). C NMR (125 MHz,
DMSO) d 167.4, 155.4, 138.0, 124.3, 114.8, 62.0, 54.2, 49.9, 47.0, 44.2, 35.3, 31.5, 26.4, 20.4,
þ
2
0.3, 20.1, 20.0. HRMS (ESI): calcd. for C H N O S [Mþ H] 407.1999; found 407.2012.
2
1 31 2 4
Anal. Calcd for C H N O S: C, 62.04; H, 7.44; N, 6.89; S, 7.89. Found: C, 61.98; H,
2
1
30 2 4
7.35; N, 6.94; S, 7.74.
10
(S)-2,6-Dimethyltyrosine (S-DMT)
Lithium hydroxide solution (2.7 mL, 6.64 mmol, 2.5 mol/L) was added to a stirred solu-
ꢀ
tion of 8 (0.90 g, 2.22 mmol) in THF (15 mL) at 0 C. The resulting mixture was stirred
at this temperature for an additional 1.0 h. THF was evaporated, the aqueous solution
was acidified with 1.0 mol/L hydrochloric acid to pH 2 and the mixture was extracted
with ethyl acetate (3 ꢂ 20 mL). The aqueous phase was neutralized with saturated
sodium bicarbonate solution to pH 6-7. At this point, precipitation of a white solid
occurred. The precipitate was filtered and dried under vacuum to afford white solid
ꢀ
10
ꢀ
product (S)-DMT (300 mg, 82%). mp. 247-248 C (lit. 247-249 C); R ¼ 0.28 (silica
f
2
D
0
10
25
D
gel, EtOAc/MeOH 2/1); [a]
¼ þ43.3 (c ¼ 1.0, MeOH), lit. [a]
¼ þ39.41(c ¼
1
1
.017, MeOH); H NMR (500 MHz, D O) d 6.38 (s, 2H), 3.88 (t, J ¼ 8.2 Hz, 1H), 3.01
2
13
(
(
dd, J ¼ 14.7, 8.5 Hz, 1H), 2.86 (dd, J ¼ 14.7, 7.9 Hz, 1H), 2.01 (s, 6H). C NMR
125 MHz, D O) d ¼171.8, 154.2, 139.3, 123.3, 115.0, 52.5, 29.6, 19.2.
2