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Helvetica Chimica Acta ± Vol. 84 (2001)
(Æ)-(2R*,3R*)-2-Hydroxy-3-[[(4-methylphenyl)sulfonyl]amino]-N-{3-{[(4-methylphenyl)sulfonyl]ami-
no}propyl}-3-phenylpropanamide (12). A soln. of 11 (1.146 g, 4.835 mmol) in H2O (15 ml) was diluted with
dioxane (30 ml), Na2CO3 (1.025 g, 9.67 mmol) added, and the mixture allowed to cool in an ice/water bath. TsCl
(1.90 g, 9.92 mmol) was added by portions and the mixture stirred at 08, then slowly warming to 208 until no
primary amine could be detected by TLC (SiO2, CHCl3/MeOH/25% aq. NH3 soln. 10 :4 :1; Fluram). After 7 h,
the mixture was evaporated to a small volume (238/25 mbar) and quenched with H2O (70 ml). The crude
product was separated by filtration (1.97 g) and crystallized from MeOH/H2O (75 and 100 ml, resp.): 1.657 g
(62.9%) of 12 as white crystalline solid, after washing with H2O and drying in vacuo for 9 h. The product was
hardly soluble in all org. solvents, except DMSO and DMF. The combined supernatants were extracted with
CHCl3 to give 560 mg of a residue, which contained no 12 according to TLC and NMR. 12: Rf (5% MeOH/
CHCl3) 0.1. M.p. 1508 (dec.) FT-IR (KBr): 3432s, 3331s, 3303s, 3256m, 3065w, 3038w, 2923m, 2872w, 1910w,
1807w, 1756w, 1658s (CO), 1599w, 1533m, 1495w, 1457m, 1419m, 1322s, 1251w, 1210w, 1184w, 1158s, 1091s,
1065w, 1034w, 1020w, 937w, 809m, 776w, 750w, 703s, 661s, 565s, 550s. 1H-NMR (300 MHz, 10 mg in 0.6 ml of
(D6)DMSO, d((D5)DMSO) 2.69): 8.27 (d, J 9.2, TsNHCH); 7.80 (d, J 8.2, 2 H of Ts); 7.67 (d, J 8.3, 2 H
of Ts); 7.58 (overlapping d, J 7.9, 2 H of Ts); 7.55 (overlapping t, J 6.6, NHCO); 7.50 (t, J 6.1, TsNHCH2);
7.34 (d, J 8.0, 2 H of Ts); 7.15 ± 7.25 (unres. m, Ph); 6.11 (d, J 5.8, OH); 4.79 (dd, J(CH,CH) 3.5,
J(CH,NH) 9.2, H C(3)); 4.22 (dd, J(CH,CH) 3.6, J(CH,OH) 5.8, H C(2)); 3.08, 2.92 (2 sext. (ddt), J
6.5, CH2NHCO); 2.58, 2.47 (2 overlapping s, 2 Me); 2.58, 2.47 (2 overlapping m, OH2NHTs); 1.38 (oct., J 6.8,
CH2CH2). 13C-NMR (75 MHz, (D6)DMSO, d((D6)DMSO) 39.41): 170.57 (CONH); 142.36, 141.90, 138.32,
137.57, 136.60 (5 C); 129.44, 128.92, 128.02, 126.92 (4 arom. CH); 126.57 (of Ph); 126.28 (2 overlapping arom.
CH); 74.56 (C(2)); 59.14 (C(3)); 39.56 (CH2NHCO); 35.12 (CH2NHTs); 28.70 (CH2); 20.72 (2 Me). ESI-MS
(MeCN/CH2Cl2): 584 (10, [M K] ), 568 (50, [M Na] ), 546 (100, [M H] ), 375 (53, [M TsNH] ), 255
(24, [OCNH(CH2)3NHTs] ), 229 (15, [H3N(CH2)3NHTs] ). Anal. calc. for C26H31N3O6S2 (545.67): H 5.73, C
57.23, N 7.70, S 11.75; found: H 5.56, C 57.01, N 7.59, S 11.59.
Reaction of 12 with an Excess of 1,4-Dibromobutane (Table 1, Entry 2). A suspension of Cs2CO3 (144 mg,
0.44 mmol, 1.2 equiv.) and 12 (200 mg, 0.367 mmol) in anh. DMF (1 ml) was stirred under N2 for 20 min. Then
1,4-dibromobutane (313 ml, 570 mg, 2.64 mmol, 6 equiv.) was added. After 22 h at 238, the mixture was
partitioned between H2O (10 ml) and CH2Cl2 (3 Â 10 ml), dried (Na2SO4), and evaporated under h.v. FC (silica
gel (25 ml), gradient CHCl3 ! 4% MeOH/CHCl3) gave disubstituted 18 (39 mg, 12.3%; with 1% MeOH),
monosubstituted 16 (81 mg; with 1 ± 2% MeOH), 16/17 3 :1 (63 mg; with 2% MeOH), and unreacted 12 (62 mg,
31%; with 4% MeOH). Yields of 16, 128 mg (51.3 %) and of 17, 15.7 mg (6.3%).
Data of (Æ)-(2R*,3R*)-N-{3-{(4-Bromobutyl)[(4-methylphenyl)sulfonyl]amino}propyl}-2-hydroxy-3-{[(4-
methylphenyl)sulfonyl]amino}-3-phenylpropanamide (16): White foam. Rf (5% MeOH/CHCl3) 0.26. M.p. 57 ±
598. FT-IR (KBr): 3000 ± 3700 (br.), 3385s, 3299s, 3064w, 3028w, 2927m, 2870w, 1648s (CO), 1599m, 1540s,
1495m, 1456s, 1437m, 1331s, 1307m, 1255w, 1185w, 1159s, 1091s, 1063w, 1019w, 973w, 935w, 814m, 703s, 655s,
563s, 549s. 1H-NMR (300 MHz, 81 mg in 1.3 ml of CDCl3): 7.59 (overlapping d, J 8.1, 2 H of Ts); 7.56
(overlapping d, J 8.1, 2 H of Ts); 7.29 (d, J 8.1, 2 H of Ts); 7.11 ± 7.18 (m, 2 H of Ph); 7.00 ± 7.11 (m, 2 H of Ts,
3 H of Ph, NHCO); 6.32 (br. d, J 8.1, TsNHCH); 4.82 (unres. dd, H C(3)); 4.55 (d, J(CH,CH) 3.6,
H
C(2)); 4.4 (very br. s, OH); 3.34 (t, J 6.5, CH2Br); 3.24 (quint., 1 H, CH2NHCO); 2.9 ± 3.1 (m, 3 H,
CH2NHCO, CH2NTs); 2.71 (br. t, J 6.5, Br(CH2)3CH2NTs); 2.41, 2.29 (2 s, 2 Me); 1.76 (quint., J 6.7, CH2);
1.5 ± 1.6 (overlapping m, CH2); 1.42 ± 1.55, 1.3 ± 1.42 (2 m, CH2). 13C-NMR (75 MHz, d(CDCl3) 76.92): 170.79
(CONH); 143.37, 143.00 (2 Cp of 2 Ts); 136.98 (Cipso of Ph); 136.06, 135.77 (2 Cipso of 2 Ts); 129.66, 129.23,
128.17, 127.76 (Co and Cm of Ph, Cm of 2 Ts); 127.45 (Cp of Ph); 127.0 (overlapping, Co of 2 Ts); 74.51 (C(2));
59.67 (C(3)), 47.92, 45.53, 35.31, 32.85, 29.51, 28.01, 27.06 (7 CH2), 21.36, 21.27 (2 Me). ESI-MS: 702, 704 (98,
100, [M Na] ), 680, 682 (17, 17, [M H] ).
Data of (Æ)-(2R*,3R*)-3-{(4-bromobutyl)[(4-methylphenyl)sulfonyl]amino}-2-hydroxy-N-{3-{[(4-methyl-
phenyl)sulfonyl]amino}propyl}-3-phenylpropanamide (17): Rf (5% MeOH/CHCl3) 0.23. 1H-NMR (300 MHz,
CDCl3; data from 16/17, selected resonances): 7.69 (d, J 8.3, 2 H of Ts); 7.64 (d, J 8.4, 2 H of Ts); 5.55 (br. t,
TsNH); 5.16 (d, J(CH,CH) 3.9, H C(3)); 4.93 (d, J(CH,CH) 3.8, H C(2)). 13C-NMR (75 MHz,
d(CDCl3) 76.90; selected resonances): 172.22 (CONH); 75.13 (C(2)); 63.68 (C(3)).
Data of (Æ)-(2R*,3R*)-3-{(4-Bromobutyl)[(4-methylphenyl)sulfonyl]amino}-N-{3-{(4-bromobutyl)[(4-
methylphenyl)sulfonyl]amino}propyl}-2-hydroxy-3-phenylpropanamide (18): Rf (5% MeOH/CHCl3) 0.49.
1H-NMR (300 MHz, 37 mg in 1.0 ml of CDCl3): 7.66 (overlapping d, J 8.3, 2 H of Ts); 7.64 (overlapping d,
J 8.4, 2 H of Ts); 7.31 (d, J 8.0, 2 H of Ts); 7.15 ± 7.29 (m, Ph, NHCO, 2 H of Ts); 5.14 (d, J(CH,CH) 3.8,
CHNTs); 4.84 (d, J(CH,CH) 3.8, H C(2)); 3.2 ± 3.4 (overlapping m, 4 CH2: 3.37 (t, J 6.5, CH2Br); 3.29 (t,
J 6.5, CH2); 3.22 (t, J 6.5, CH2); 3.07 (t, J 7.3, CH2); 2.96 (t, J 6.6, CH2); 2.43, 2.40 (2 s, 2 Me); 1.76 ± 1.86