Short Total Synthesis of Aspartyl Protease Inhibitors L-685,434, L-682,679 and L-685,458

Abstract

Hydroxyethylene dipeptide isosteres L-685,434, L-682,679 and L-685,458 were synthesized in a few steps by a sequence involving an allyltrichlorostannane coupling with an α-aminoaldehyde followed by hydroboration of the corresponding 1,2-syn and 1,2-anti aminoalcohols to give the diols, lactonization under TPAP conditions, lactone opening and peptide coupling with the desired amine or dipeptide amide.

amino aldehydes - HIV - peptides - total synthesis - lactones

References

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32

New compounds and the additional isolatable intermediates gave satisfactory ¹H and ¹³C NMR, IR, HRMS and analytical data. Yields refer to chromatographically and spectroscopically homogeneous materials.

33

L-685,434(1): N -[(2 R )-Hydroxy-(1 S )-indanyl]-(5 S )-{[ tert -butoxycarbonyl]-amino-(4 S )-hydroxy-6-phenyl-(2 R )-benzyl}-hexanamide: IR (KBr) 3447, 3365, 3061, 3022, 2917, 2849, 1665, 1645, 1537, 1392, 1278, 1158, 1058, 899, 862, 733, 703, 649 cm^-1. ¹H NMR (500 MHz, DMSO): δ = 1.37 (s, 9 H), 1.80-1.96 (m, 2 H), 2.72-2.95 (m, 6 H), 3.02 (dd, J = 5.1, 16.8 Hz, 1 H), 3.45 (m, 1 H), 3.68 (m, 1 H), 3.81 (m, 1 H), 4.22 (t, J = 4.8 Hz, 1 H), 4.81 (d, J = 9.5 Hz, 1 H), 5.23 (dd, J = 6.1, 8.4 Hz, 1 H), 5.87 (d, J = 8.4 Hz, 1 H), 7.05 (brs, 1 H), 7.05-7.30 (m, 14 H). ¹³C NMR (125 MHz, DMSO): δ = 28.5, 37.5, 39.0, 39.1, 39.6, 47.1, 57.4, 57.6, 69.3, 73.1, 79.6, 124.1, 125.1, 126.4, 126.5, 127.0, 128.0, 128.4, 128.5, 129.0, 129.3, 138.4, 139.8, 140.1, 140.3, 156.2, 175.4. TLC: R_f = 0.21 (60% EtOAc:hexanes).
L-682,679(2): {(1 S )-benzyl-4 R -[1-((1 S )-carbamoyl-2-phenyl-ethylcarbamoyl)-(1 S )-3-methyl-butyl-carbamoyl]-(2 S )-hydroxy-5-phenyl-pentyl} Carbamic Acid tert -Butyl Ester: IR (KBr) 3377, 3341, 3190, 2955, 2924, 2872, 2853, 1667, 1649, 1621, 1531, 1451, 1365, 1273, 1250, 1172, 1080, 743, 698 cm^-1. ¹H NMR (500 MHz, DMSO): δ = 0.77 (d, J = 6.4 Hz, 3 H), 0.84 (d, J = 6.4 Hz,
3 H), 1.28 (s, 9 H), 1.20-1.35 (m, 2 H), 1.49 (m, 1 H), 1.60 (m, 2 H), 2.45 (dd, J = 8.2, 13.4 Hz, 1 H), 2.53 (dd, J = 9.5, 13.7 Hz, 1 H), 2.70 (dd, J = 5.0, 13.6 Hz, 1 H), 2.78-2.87 (m, 3 H), 3.00 (dd, J = 5.2, 3.7 Hz, 1 H), 3.51-3.57 (m, 1 H), 4.21 (q, J = 6.7 Hz, 1 H), 4.42 (q, J = 5.5 Hz, 1 H), 4.48 (d, J = 6.1 Hz, 1 H), 6.36 (d, J = 9.0 Hz, 1 H), 7.09 (brs, 1 H), 7.12-7.25 (m, 15 H), 7.34 (brs, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 23.1, 24.2, 28.0, 28.4, 35.1, 36.3, 37.7, 38.9, 40.9, 43.7, 51.5, 53.5, 56.5, 69.4, 77.6, 125.9, 126.0, 126.4, 128.1, 128.2, 128.3, 129.1, 129.2, 129.4, 137.9, 139.8, 140.0, 155.5, 171.8, 172.8, 174.7. TLC: R_f = 0.18 (70% EtOAc:hexanes).
L-685,458(3): {(1 S )-benzyl-(4 R )-[1-((1 S )-carbamoyl-2-phenyl-ethylcarbamoyl)-(1 S )-3-methyl-butyl-carba-moyl]-(2 R )-hydroxy-5-phenyl-pentyl} Carbamic Acid tert -Butyl Ester: White solid. Mp 212-213 °C. [α]_D ²⁵ =
-26.8 (c 0.5, CHCl₃). IR (KBr): 3375, 3338, 3197, 2960, 2930, 2872, 2856, 1666, 1647, 16231, 1535, 1451, 13675, 1271, 1251, 1174, 1086, 743, 698 cm^-1. ¹H NMR (500 MHz, DMSO): δ = 0.74 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz,
3 H), 1.24 (s, 9 H), 1.25-1.40 (m, 2 H), 144-1.70 (m, 3 H), 2.40-3.00 (m, 7 H), 3.42 (m, 2 H), 4.16 (m, 1 H), 4.40 (m,
1 H), 4.70 (brs, 1 H), 6.48 (d, J = 9.0 Hz, 1 H), 7.05-7.27
(m, 17 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 23.9, 25.4, 26.1, 30.4, 37.6, 38.0, 39.8, 39.9, 42.8, 46.6, 53.7, 55.8, 58.9, 73.5, 79.7, 127.9, 128.0, 128.6, 130.0, 130.2, 130.4, 131.1, 131.4, 140.0, 142.0, 142.3, 157.4, 174.0, 174.8, 175.2. TLC:
R_f = 0.21 (60% EtOAc:hexanes).