alumina, 1:1:18 Et2O–MeOH–PE) yielded 29 (33 mg, 28%) as
a yellow solid; νmax (thin film)/cmϪ1 3360s (NH), 2927s (CH),
1716s (C᎐O), 1456m, 1260m, 1155m, 801m; δ (200 MHz,
CDCl3) 1.44 (9H, s, C(CH3)3), 1.47 (9H, s, C(CH3)3), 1.93–2.19
(2H, m, CH2), 2.60–2.68 (2H, m, CH2), 4.21–4.25 (1H, m, CH),
5.08 (2H, br s, NH2), 5.40 (1H, d, J 7.5, NH), 6.50 (1H, d, J 5.0,
ArH), 8.17 (1H, d, J 5.0, ArH); δC (500 MHz, CDCl3) 27.98
(C(CH3)3), 28.30 (C(CH3)3), 31.37 (CH2), 33.42 (CH2), 53.75
(CH), 79.61 (C(CH3)3), 81.98 (C(CH3)3), 110.52 (Ar-CH),
131.25 (4 × Ar-CH), 136.56 (Ar-C, ipso), 155.71, 164.19,
167.31, 170.72, 172.67 (3 × Ar-C, ipso; 2 × C᎐O); m/z
᎐
(APCIϩ), 446 (MHϩ, 100%), 390 (MHϩ Ϫ (C4H8), 60); HRMS
᎐
H
found MHϩ 446.2114. C23H32N3O4S requires 446.2114.
(S)-á-tert-Butoxycarbonylamino-â-(2-p-chlorophenyl-6-
phenylpyrimidin-4-yl)propanoic acid á-tert-butyl ester 33. Pre-
pared from 22 (163 mg, 0.44 mmol), ethyl acetate (2 ml), water
(16 µl), 4-chlorobenzamidine hydroiodide (170 mg, 0.60 mmol)
and sodium carbonate (127 mg, 1.20 mmol). Purification by
flash column chromatography (SiO2, 1:1 Et2O–PE) yielded 33
(198 mg, 89%) as pale yellow oil; [α]D22 ϩ26.9 (c 0.28 in CHCl3)
(Found C, 65.97; H, 6.37; N, 8.23. C28H32ClN3O4 requires C,
65.94; H, 6.32; N, 8.24%); νmax (thin film)/cmϪ1 3436w, 3361w
155.44 (HNC᎐O), 157.98 (Ar-CH), 162.86, 170.74, 171.59
᎐
(2 × Ar-C, ipso; C᎐O); m/z (APCIϩ) 353 (MHϩ, 100%), 297
᎐
[MHϩ Ϫ (C4H8), 25].
(S)-á-tert-Butoxycarbonylamino-ã-(2-methylthio-6-propyl-
pyrimidin-4-yl)butyric acid á-tert-butyl ester 30. Prepared from
21 (88 mg, 0.25 mmol), ethyl acetate (1.5 ml), water (9 µl), 2-
methyl-2-thiopseudourea sulfate (104 mg, 0.37 mmol) and
sodium carbonate (159 mg, 1.50 mmol). Purification by flash
column chromatography (SiO2, 5:2 Et2O–PE) yielded 30 (101
mg, 95%) as a colourless oil; [α]D22 ϩ17.3 (c 0.48 in CHCl3); νmax
(thin film)/cmϪ1 3368w (NH), 2975m, 2931m, 2874w (CH),
(NH), 2979m, 2932w (CH), 1714s (C᎐O), 1590s, 1495s, 1369s,
᎐
1252m, 1155s, 1015m; δH (200 MHz, CDCl3) 1.35 (9H, s,
C(CH3)3), 1.43 (9H, s, C(CH3)3), 3.36 (1H, dd, J 5.0, 16.0,
CH(H)), 3.45 (1H, dd, J 5.0, 16.0, CH(H)), 4.70–4.74 (1H,
m, CH), 5.81 (1H, d, J 7.0, NH), 7.39–7.62 (6H, m, Ar-H),
8.17–8.21 (2H, m, Ar-H), 8.54 (2H, d, J 8.5, Ar-H); δC (50.3
MHz, CDCl3) 27.84 (C(CH3)3), 28.24 (C(CH3)3), 39.24 (CH2),
52.27 (CH), 79.83 (C(CH3)3), 82.04 (C(CH3)3), 114.54, 127.39,
128.87, 129.14, 130.05, 131.22 (6 × Ar-CH), 136.39, 136.99,
137.15 (3 × Ar-C, ipso), 155.79, 163.30, 164.34, 167.31, 171.00
1714s (C᎐O), 1577s, 1534s, 1259m, 1154s, 849w; δH (200 MHz,
᎐
CDCl3) 0.95 (3H, t, J 7.0, CH3), 1.43 (9H, s, C(CH3)3), 1.46 (9H,
s, C(CH3)3), 1.62–1.81 (2H, m, CH2), 1.99–2.25 (2H, m, CH2),
2.55 (3H, s, SCH3), 2.60 (2H, t, J 7.0, CH2), 2.66–2.75 (2H, m,
CH2), 4.22–4.25 (1H, br m, CH), 5.22 (1H, d, J 8.0, NH), 6.68
(1H, s, ArH); δC (125.8 MHz, CDCl3) 13.66, 13.89 (2 × CH3),
21.81 (CH2), 27.86 (C(CH3)3), 28.18 (C(CH3)3), 31.20 (CH2),
33.16 (CH2), 39.50 (CH2), 53.68 (CH), 79.72 (C(CH3)3), 82.05
(C(CH3)3), 114.59 (Ar-CH), 155.64, 169.40, 171.15, 171.88,
(3 × Ar-C, ipso; 2 × C᎐O); m/z (APCIϩ) 512 (37MH, 50%), 510
᎐
(35MHϩ, 100).
(S)-á-tert-Butoxycarbonylamino-â-(2-methylthiopyrimidin-4-
yl)propanoic acid á-tert-butyl ester 34. Prepared from 23 (45 mg,
0.15 mmol), ethyl acetate (1.5 ml), water (6 µl), 2-methyl-2-
thiopseudourea sulfate (56 mg, 0.20 mmol) and sodium
carbonate (85 mg, 0.80 mmol). Purification by flash column
chromatography (SiO2, 1:1 Et2O–PE) yielded 34 (48 mg, 87%)
as a colourless oil; [α]D22 ϩ20.7 (c 0.85 in CHCl3); νmax (thin film)/
172.03 (3 × Ar-C, ipso; 2 × C᎐O); m/z (APCIϩ) 426 (MHϩ,
᎐
100%), 370 [MHϩ Ϫ (C4H8), 97]; HRMS found MHϩ 426.2427.
C21H36N3O4S requires 426.2426.
cmϪ1 3370br w (NH), 2978m, 2931w (CH), 1716s (C᎐O), 1568s,
(S)-á-tert-Butoxycarbonylamino-ã-(2-methyl-6-propyl-
᎐
pyrimidin-4-yl)butyric acid á-tert-butyl ester 31. Prepared from
21 (100 mg, 0.28 mmol), ethyl acetate (1.5 ml), water (10 µl),
acetamidine hydrochloride (40 mg, 0.42 mmol) and sodium
carbonate (178 mg, 1.7 mmol). Purification by flash column
chromatography (SiO2, 3:1 Et2O–PE) yielded 31 (91 mg, 83%)
as a colourless oil; [α]D22 ϩ9.8 (c 0.53 in CHCl3); νmax (thin film)/
1548m, 1496m, 1367s, 1154s, 1056w; δH (200 MHz, CDCl3) 1.38
(9H, s, C(CH3)3), 1.44 (9H, s, C(CH3)3), 2.60 (3H, s, SCH3),
3.13–3.29 (2H, m, CH2), 4.57–4.61 (1H, m, CH), 5.68 (1H, d,
J 8.0, NH), 6.84 (1H, d, J 5.0, ArH), 8.40 (1H, d, J 5.0, ArH);
δC (50.3 MHz, CDCl3) 13.88 (SCH3), 27.76 (C(CH3)3), 28.18
(C(CH3)3), 38.97 (CH2), 52.42 (CH), 79.77 (C(CH3)3), 82.13
cmϪ1 3350w (NH), 2975m, 2933m, 2874w (CH), 1714s (C᎐O),
᎐
(C(CH ) ), 116.30 (Ar-CH), 155.61 (HNC᎐O), 157.17 (Ar-CH),
᎐
3
3
1588s, 1547m, 1454w, 1397m, 1250m, 1155s, 849w; δH (200
MHz, CDCl3) 0.96 (3H, t, J 7.0, CH3), 1.43 (9H, s, C(CH3)3),
1.45 (9H, s, C(CH3)3), 1.62–1.80 (2H, m, CH2), 1.94–2.28 (2H,
m, CH2), 2.66 (3H, s, CH3), 2.60–2.78 (4H, m, 2 × CH2), 4.16–
4.26 (1H, br m, CH), 5.47 (1H, d, J 8.0, NH), 6.82 (1H, s,
ArH); δC (125.8 MHz, CDCl3) 13.67 (CH3), 22.21 (CH2), 25.85
(CH3), 27.85 (C(CH3)3), 28.17 (C(CH3)3), 31.42 (CH2), 33.44
(CH2), 39.73 (CH2), 53.76 (CH), 79.58 (C(CH3)3), 81.94
(C(CH3)3), 116.11 (Ar-CH), 155.70, 167.76, 169.16, 170.92,
166.94, 170.60, 172.76 (2 × Ar-C, ipso; C᎐O); m/z (APCIϩ)
᎐
370 (MHϩ, 100%), 314 [MHϩ Ϫ (C4H8), 40]; HRMS found
MHϩ 370.1801. C17H28N3O4S requires 370.1801.
General procedure for methylthio derivative oxidation
Typically to a stirred solution of the 2-thiomethyl pyrimidine
functionalised amino acids in dichloromethane was added
m-chloroperbenzoic acid (50%, 2 equiv.). The reaction mixture
was stirred for two hours at room temperature and then washed
with 1 M sodium thiosulfate solution before being taken into
ethyl acetate. The organic extract was washed with saturated
aqueous sodium bicarbonate solution and brine before being
dried over MgSO4 and concentrated in vacuo afforded the crude
product.
171.87 (3 × Ar-C, ipso; 2 × C᎐O); m/z (APCIϩ) 394 (MHϩ,
᎐
100%), 338 [MHϩ Ϫ (C4H8), 30]; HRMS found MHϩ 394.2706.
C21H36N3O4 requires 394.2706.
(S)-á-tert-Butoxycarbonylamino-â-(2-methylthio-6-phenyl-
pyrimidin-4-yl)propanoic acid á-tert-butyl ester 32. Prepared
from 22 (162 mg, 0.43 mmol), ethyl acetate (2 ml), water (16 µl),
2-methyl-2-thiopseudourea sulfate (167 mg, 0.60 mmol) and
sodium carbonate (254 mg, 2.40 mmol). Purification by flash
column chromatography (SiO2, 2:3 Et2O–PE) yielded 32 (175
mg, 91%) as a pale yellow oil; [α]D22 ϩ26.8 (c 1.66 in CHCl3);
νmax (thin film)/cmϪ1 3370w (NH), 2978m, 2930w (CH), 1715s
(C᎐O), 1574s, 1496s, 1225s, 1154s, 1026w; δ (200 MHz,
(S)-á-tert-Butoxycarbonylamino-ã-(2-methylsulfonyl-
pyrimidin-4-yl)butyric acid á-tert-butyl ester 35. Prepared from
28 (255 mg, 0.66 mmol), MCPBA (460 mg at 50%, 1.33 mmol)
and DCM (3 ml). Purification by flash column chromatography
(SiO2, 3:17 ethyl acetate–DCM) yielded 35 (238 mg, 86%) as a
colourless oil; [α]D22 13.5 (c 3.11 in CHCl3); νmax (thin film)/cmϪ1
᎐
H
CDCl3) 1.39 (9H, s, C(CH3)3), 1.43 (9H, s, C(CH3)3), 2.64 (3H,
s, SCH3), 3.15–3.39 (2H, m, CH2), 4.11–4.65 (1H, m, CH), 5.75
(1H, d, J 8.5, NH), 7.26 (1H, s, ArH), 7.47–7.51 (3H, m, ArH),
8.06–8.11 (2H, m, ArH); δC (50.3 MHz, CDCl3) 14.06 (SCH3),
27.81 (C(CH3)3), 28.21 (C(CH3)3), 39.17 (CH2), 52.57 (CH),
79.75 (C(CH3)3), 82.16 (C(CH3)3), 111.86, 127.38, 129.04,
3374w (NH), 2979m, 2934w (CH), 1711s (C᎐O), 1581s, 1534m,
᎐
1452w, 1368s, 1155s, 847w; δH (200 MHz, CDCl3) 1.42 (9H, s,
C(CH3)3), 1.45 (9H, s, C(CH3)3), 2.01–2.31 (2H, m, CH2), 2.92–
3.01 (2H, m, CH2), 3.35 (3H, s, SO2CH3), 4.11–4.25 (1H, br m,
CH), 5.15 (1H, d, J 8.0, NH), 7.43 (1H, d, J 5.0, ArH), 8.77
(1H, d, J 5.0, ArH); δC (125.8 MHz, CDCl3) 27.81 (C(CH3)3),
862
J. Chem. Soc., Perkin Trans. 1, 1999, 855–866