The Journal of Organic Chemistry
Article
(d, J = 3.3 Hz, 3H), 2.25−2.41 (m, 1H), 2.64−2.91 (m, 2H), 3.15 (d, J
= 6.8 Hz, 1H), 3.56 (s, 3H), 3.82 (m, 1H), 3.99 (s, 2H), 4.37 (m, 1H),
5.23 (s, 2H), 5.81 (s, br, 1H),7.45−7.67 (m, 10H), 8.12 (s, br, 1H),
8.34−8.6 (2s, br, 2H); 13C NMR (75 MHz, CDCl3) δ 10.5, 14.9, 17.0,
27.5, 34.0, 39.1, 42.8, 46.6, 51.5, 52.1, 59.1, 66.9, 122.0, 124.2, 125.6,
127.6, 128.1, 128.3, 128.7, 139.5, 141.9, 156.0, 170.9, 171.5, 171.8, 212.
Anal. Calcd for C29H38N4O6Se: C, 56.40; H, 6.20; N, 9.07; O, 15.54;
Se, 12.79. Found: C, 56.01; H, 5.67; N, 8.13; O, 15.11; Se, 12.81.
8.2. (S)-(9H-Fluoren-9-yl)methyl 2-(((S)-1-((S)-1-(Benzyloxy)-4-
methyl-1-oxopentan-2-ylamino)-3-phenyl-1-selenoxopropan-2-yl)-
C33H37N3O5Se: C, 62.45; H, 5.88; N, 6.62; O, 12.61; Se, 12.44. Found:
C, 61.67; H, 5.23; N, 6.41; O, 12.19; Se, 12.39.
8.6. (S)-Benzyl 2-((S)-2-((S)-2-(Benzyloxycarbonyl)-3-phenylpro-
panamido)-4-methylpentaneselenoamido)-3-methylbutanoate
25
(4f). [α]D +187.6 (c, 1.0 CHCl3); Rf 0.44 (n-hexane/EtOAc, 6:4);
yellow solid, mp 107−109 °C; ESI-MS Calcd for C35H43N3O5Se m/z
688.1 (M + Na)+, found 688.2; IR (Neat) υmax 3249, 1755, 1748, 1642,
1
1525, 1228, 1159 cm−1; 77Se NMR (75 MHz, CDCl3) δ 531.549; H
NMR (300 MHz, CDCl3) δ 0.87 (d, J = 5.8 Hz, 6H), 0.94 (d, J = 4.9
Hz, 6H), 1.27−1.43 (m, 2H), 1.62−1.85 (m, 1H), 2.51−2.62 (m, 1H),
2.74 (d, J = 7.2 Hz, 1H), 2.83 (d, J = 5.5 Hz, 1H), 3.25 (d, J = 6.3 Hz,
1H), 3.41 (t, J = 9.1 Hz, 1H), 4.39−4.61 (m,1H), 5.19 (s, 4H), 5.41 (s,
br, 1H), 6.89−7.55 (m, 15H), 8.19 (s, br, 1H), 8.71 (s, br, 1H); 13C
NMR (75 MHz, CDCl3) δ 17.5, 21.0, 22.8, 30.9, 37.7, 41.2, 42.8, 53.1,
62.7, 64.1, 67.0, 127.1, 128.1, 128.3, 128.6, 128.9, 129.2, 139.9, 140.0,
155.7, 170.1, 170.7, 213.0. Anal. Calcd for C35H43N3O5Se: C, 63.24; H,
6.52; N, 6.32; O, 12.04; Se, 11.88. Found: C, 62.94; H, 6.11; N, 5.89;
O, 11.74; Se, 11.69.
9. General Procedure for the Synthesis of Diselenoxo
Tripeptides 6. To a stirred suspension of protected tripeptide ester
(1.0 mmol) in dry benzene (10 mL) was added crystalline PCl5 (615
mg, 3.0 mmol) and DMF (0.062 mL). A clear solution was formed
after 30 min at rt. A THF solution of LiAlHSeH (386.7 mg, 3.2 mmol)
was added. The flask was protected from light and was stirred at the
same temperature for another 30 min. After the reaction was complete
(TLC analysis), solvent was evaporated under vacuum and diluted
with EtOAc (10 mL). Organic phase was washed with 1 N NaHCO3
(3 × 10 mL), 1 N citric acid (2 × 10 mL), H2O (2 × 10 mL), and
brine (10 mL) solution followed by drying over Na2SO4. The solvent
was filtered and evaporated under reduced pressure. The crude
reaction mixture was purified under column chromatography using
hexane/ethyl acetate (8:2) as the eluent.
25
carbamoyl)pyrrolidine-1-carboxylate (4b). [α]D +154.5 (c, 1.5
CHCl3); Rf 0.21 (n-hexane/EtOAc, 6:4); gum; HRMS (ESI) Calcd for
C42H45N3O5Se m/z 752.2603 (M + H)+, found 752.2601; IR (Neat)
υmax 3456, 1765, 1752, 1669, 1535, 1219, 1105 cm−1; 77Se NMR (75
MHz, CDCl3) δ 510.732; 1H NMR (300 MHz, CDCl3) δ 0.91 (d, J =
4.1 Hz, 6H), 1.31−1.45 (m, 2H), 1.49−1.61 (m, 2H), 1.62−1.81 (m,
3H), 2.62 (d, J = 5.2 Hz, 1H), 2.77 (d, J = 5.3 Hz, 1H), 3.15−3.29 (m,
2H), 3.33 (t, J = 3.3 Hz, 1H), 3.75−3.83 (m, 1H), 4.21 (m, 1H), 4.39
(t, J = 5.4 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 5.29 (s, 2H), 5.79 (s, br,
1H), 6.45 (s, br, 2H), 7.11−7.82 (m, 18H); 13C NMR (75 MHz,
CDCl3) δ 22.9, 23.7, 24.5, 29.3, 38.7, 40.5, 46.9, 47.3, 54.9, 60.1, 66.6,
67.5, 68.1, 120.0, 124.8, 127.1, 127.6, 127.7, 128.6, 128.7, 129.2, 130.8,
141.3, 143.7, 143.8, 155.8, 170.1, 170.8, 213.8. Anal. Calcd for
C42H45N3O5Se: C, 67.19; H, 6.04; N, 5.60; O, 10.66; Se, 10.52. Found
C, 67.02; H, 5.71; N, 5.15; O, 10.34; Se, 10.43.
8.3. (S)-3-(2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-3-
phenylpropanamido)acetamido)-4-((S)-1-(benzyloxy)-3-methyl-1-
oxobutan-2-ylamino)-4-selenoxo benzoate (4c). [α]D25 +78.1 (c, 1.5
CHCl3); Rf 0.25 (CHCl3:MeOH, 9:1); Yellow Solid, mp 144−145 °C;
ESI-MS Calcd for C49H50N4O8Se m/z 903.2 (M + H)+, found 903.2;
IR (Neat) υmax 3365, 1755, 1749, 1623, 1534, 1251, 1125 cm−1; 77Se
1
NMR (75 MHz, CDCl3) δ 521.463; H NMR (300 MHz, CDCl3) δ
0.91 (d, J = 5.8 Hz, 6H), 2.36 (m, 1H), 2.52 (m, 2H), 2.92 (d, J = 3.5
Hz, 1H), 3.04 (d, J = 4.9 Hz, 1H), 3.29 (d, J = 6.3 Hz, 1H), 3.95 (s,
2H), 4.12 (m, 1H), 4.38 (t, J = 5.9 Hz, 1H), 4.59 (d, J = 10.2 Hz, 2H),
4.74 (m, 1H), 5.32 (s, 4H), 6.01 (s, br, 1H), 7.01−7.75 (m, 23H), 8.29
(s, br, 1H), 8.52 (s, br, 1H), 9.49 (s, br, 1H); 13C NMR (75 MHz,
CDCl3) δ 17.5, 18.9, 30.9, 35.9, 37.8, 38.0, 43.1, 47.0, 53.3, 59.9, 66.9,
67.1, 125.0, 127.0, 127.1, 127.7, 128.2, 128.3, 128.4, 128.5, 128.7,
129.1, 135.3, 136.3, 141.2, 143.6, 156.2, 170.1, 171.3, 171.5, 171.8,
211.1. Anal. Calcd for C49H50N4O8Se: C, 65.25; H, 5.59; N, 6.21; O,
14.19; Se, 8.75. Found: C, 64.01; H, 5.18; N, 5.93; O, 14.01; Se, 8.88.
8.4. (S)-Methyl 2-((S)-2-((S)-2-(Benzyloxycarbonyl)-4-
methylpentanamido)propaneselenoamido)-3-phenylpropanoate
9.1. (S)-Methyl 2-((S)-2-(2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-
ethaneselenoamido)-3-phenylpropaneselenoamido)-4-methylpen-
25
tanoate (6a). [α]D +9.8 (c, 1.5 CHCl3); Rf 0.34 (CHCl3/MeOH,
9:1); Pale Yellow solid, mp 143−144 °C; HRMS (ESI) Calcd for
C33H37N3O4Se2 m/z 722.1012 (M + Na)+, found 722.1002; IR (KBr)
υmax 3157, 1747, 1738, 1551, 1548, 1287, 1159 cm−1; 77Se NMR (75
1
MHz, CDCl3) δ 534.106, 534.545; H NMR (300 MHz, CDCl3) δ
0.92 (d, J = 5.4 Hz, 6H), 1.45−1.71 (m, 3H), 2.52−2.63 (m, 2H), 2.79
(m, 1H), 2.97 (s, 2H), 3.31 (t, J = 4.2 Hz, 1H), 3.69 (s, 3H), 4.32 (t, J
= 2.9 Hz, 1H), 4.49 (d, J = 7.2 Hz, 2H), 5.69 (s, br, 1H), 6.2 (s, br,
1H), 7.09−7.81 (m, 13H), 8.82 (s, br, 1H); 13C NMR (75 MHz,
CDCl3) δ 21.8, 22.5, 38.4, 41.1, 44.2, 46.9, 50.8, 52.0, 54.3, 67.2, 119.8,
125.0, 126.8, 126.9, 127.6, 128.3, 129.2, 136.2, 141.1, 143.7, 156.6,
170.7, 209.7, 210.0. Anal. Calcd for C33H37N3O4Se2: C, 56.82; H, 5.35;
N, 6.02; O, 9.17; Se, 22.64. Found: C, 56.19; H, 5.04; N, 5.91; O, 9.00;
Se, 22.17.
25
(4d). [α]D +87.6 (c, 1.0 CHCl3); Rf 0.31 (n-hexane/EtOAc, 6:4);
gum; HRMS (ESI) Calcd for C27H35N3O5Se m/z 584.1640 (M +
Na)+, found 584.1613; IR (Neat) υmax 3451, 1749, 1738, 1665, 1590,
1
1210, 1150 cm−1; 77Se NMR (75 MHz, CDCl3) δ 523.321; H NMR
(300 MHz, CDCl3) δ 0.91 (d, J = 5.2 Hz, 6H),1.13 (d, J = 4.8 Hz, 3H)
1.41−1.69 (m, 3H), 2.82 (d, J = 3.6 Hz, 1H), 2.78 (d, J = 7.1 Hz, 1H),
3.59 (s, 3H), 3.69−3.81 (m, 2H), 4.43 (t, J = 3.9 Hz, 1H), 5.24 (s,
2H), 6.18 (s, br, 1H), 7.23−7.62 (m, 10H), 8.38 (s, br, 2H); 13C NMR
(75 MHz, CDCl3) δ 18.4, 22.6, 24.8, 38.8, 40.0, 41.1, 51.3, 52.9, 58.2,
66.7, 127.1, 127.5, 128.1, 128.4, 128.8, 129.2, 139.2, 140.8, 156.4,
170.7, 171.1, 209.1. Anal. Calcd for C27H35N3O5Se: C, 57.85; H, 6.29;
N, 7.50; O, 14.27; Se, 14.09. Found: C, 57.05; H, 6.10; N, 6.19; O,
13.97; Se, 13.79.
9.2. (S)-4-Benzyl 1-Methyl 2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)-
m e t h o x y ) c a r b o n y l ) p r o p a n e s e l e n o a m i d o ) - 3 -
25
methylbutaneselenoamido)succinate (6b). [α]D +208.5 (c, 1.5
CHCl3); Rf 0.41 (CHCl3:MeOH, 7:3); yellow solid, mp 155−157 °C ;
HRMS (ESI) Calcd for C35H39N3O6Se2 m/z 780.1067 (M + Na)+,
found 780.1054; IR (KBr) υmax 3257, 1758, 1750, 1741, 1590, 1584,
1200, 1190 cm−1; 77Se NMR (75 MHz, CDCl3) δ 561.932, 563.311;
1H NMR (300 MHz, CDCl3) δ 0.89 (d, J = 3.7 Hz, 6H), 1.17 (d, J =
6.4 Hz, 3H), 2.12 (m, 1H), 2.41 (d, J = 4.8 Hz, 1H), 2.82 (d, J = 7.1
Hz, 1H), 2.89 (d, J = 11.2 Hz, 1H), 3.52 (s, 3H), 3.63 (m, 1H), 3.85
(m, 1H), 4.51 (t, J = 6.6 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 5.38 (s,
2H), 6.12 (s, br, 1H), 6.93 (s, br, 1H), 7.12−7.75 (m, 13H), 8.91 (s,
br, 1H); 13C NMR (75 MHz, CDCl3) δ 18.0, 18.9, 30.9, 37.1, 42.7,
46.9, 49.4, 55.4, 57.9, 66.6, 66.9, 119.7, 124.9, 126.8, 127.5, 128.0,
128.3, 135.4, 141.0, 143.6, 143.7, 156.6, 170.1, 171.6, 211.1, 211.9.
Anal. Calcd for C35H39N3O6Se2(%): C, 55.63; H, 5.20; N, 5.56; O,
12.70; Se, 20.90. Found: C, 55.28; H, 5.07; N, 5.19; O, 12.48; Se,
20.77.
8.5. (R)-Methyl 2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)-
carbonyl)-3-methylbutanamido)propaneselenoamido)-3-phenyl-
25
propanoate (4e). [α]D +79.5 (c, 1.0 CHCl3); Rf 0.41 (n-hexane/
EtOAc, 6:4); yellow solid, mp 128−129 °C; HRMS (ESI) Calcd for
C33H37N3O5Se m/z 658.1796 (M + Na)+, found 658.1702; IR (KBr)
υmax 3452, 1748, 1740, 1650, 1549, 1390, 1196 cm−1; 77Se NMR (75
MHz, CDCl3) δ 521.153; 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J =
4.7 Hz, 6H), 1.09 (d, J = 7.2 Hz, 3H), 2.49 (m, 1H), 3.12 (d, J = 2.5
Hz, 1H), 3.27 (d, J = 4.4 Hz, 1H), 3.49 (s, 3H), 3.71−3.83 (m, 2H),
4.28 (d, J = 6.6 Hz, 1H), 4.42 (t, J = 11.1 Hz, 1H), 4.70 (d, J = 3.9 Hz,
9.3. (S)-Methyl 2-(2-((S)-2-(Benzyloxycarbonyl)-3-
2H)̧ 5.81 (s, br, 1H), 7.12−7.78 (m, 13H), 8.49 (s, br, 1H),9.45 (s, br,
methylbutaneselenoamido)ethaneselenoamido)propanoate (6c).
1H); 13C NMR (75 MHz, CDCl3) δ 17.4, 18.3, 31.2, 37.7, 41.1, 47.1,
52.3, 58.8, 60.3, 67.0, 119.9, 125.0, 127.0, 127.1, 127.6, 128.5, 128.6,
129.2, 135.5, 141.3, 143.7, 156.3, 171.4, 171.5, 212.4. Anal. Calcd for
[α]D +69.7 (c, 1.5 CHCl3); Rf 0.38 (CHCl3/MeOH, 9:1); gum;
25
HRMS (ESI) Calcd for C19H27N3O4Se2 m/z 544.0230 (M + Na)+,
found 544.0217; IR (Neat) υmax 33316, 1747, 1729, 1575, 1548, 1254,
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dx.doi.org/10.1021/jo2024703 | J. Org. Chem. 2012, 77, 2689−2702