Aminodiol HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 10 2003
removed in vacuo and the residue was purified by flash
chromatography (CH2Cl2-MeOH-NH4OH, 98:2:0 to 90:10:1)
to afford, after trituration with Et2O overnight, 10e (103 mg;
27%) as a white solid: 1H NMR (CD3OD) δ 1.29 (s, 18H), 2.55
(m, 2H), 2.78 (m, 4H), 3.03 (m, 1H), 3.11 (m, 1H), 3.61 (m,
4H), 4.20 (t, J ) 4.5, 5 Hz, 2H), 4.39 (t, J ) 4.5, 5 Hz, 2H),
6.80 (d, J ) 8.5 Hz, 2H), 6.96 (s, 1H), 7.12 (d, J ) 8 Hz, 2H),
7.21 (m, 6H), 7.71 (s, 1H). 13C NMR (CD3OD) δ 28.8, 37.0,
37.9, 47.7, 52.9, 56.9, 57.0, 68.7, 72.7, 80.1, 115.5, 121.1, 127.2,
129.0, 130.5, 131.6, 133.0, 138.9, 140.2, 158.2, 158.3 (two
carbons unresolved). Anal. (C35H51N5O7) C, H, N.
[1S-[1R*,2S* (2S*, 3R*)]]-[3-[[3-[[(1,1-Dim eth yleth oxy)-
ca r b on yl]a m in o]-2-h yd r oxy-4-[4-[2-(3-p yr id in yloxy)-
eth oxy]p h en yl]bu tyl]a m in o]-2-h yd r oxy-1-(p h en ylm eth -
yl)p r op yl]ca r ba m ic Acid , 1,1-Dim eth yleth yl Ester (10f).
Epoxide 12f (0.160 g; 0.400 mmol) was reacted with amino
alcohol 5 in DMF at 100 °C for 5 h. Volatiles were removed
in vacuo, and the residue was purified by chromatography
(CH2Cl2-MeOH-NH4OH, 99:1:0.1 to 90:10:1) to afford a white
solid (0.125 g, 46%). This material was further purified by
preparative HPLC (using as eluent a stepwise gradient from
50:50 to 75:25 A:B; A ) 90:10:0.05 MeOH-H2O-TFA; B )
90:10:0.05 H2O-MeOH-TFA) to furnish 91 mg (34%) of
aminodiol 10f as a white solid: 1H NMR (CD3OD; 50 °C) δ
1.29 (broad s, 9 H), 2.56-2.81 (m, 6 H), 3.03-3.10 (m, 2 H),
3.61-3.78 (m, 4 H), 4.28-4.31 (m, 2 H), 4.35-4.38 (m, 2 H),
6.86 (d, J ) 8.5 Hz, 2 H), 7.14 (d, J ) 8.4 Hz, 2 H), 7.21-7.28
(m, 5 H), 7.33 (m, 1 H), 7.43 (m, 1 H), 8.12 (d, J ) 4.6 Hz, 1
H), 8.26 (d, J ) 2.7 Hz, 1 H); 13C NMR (CD3OD; 50 °C) δ 28.7,
37.0, 37.8, 46.0, 53.2, 56.9, 68.1, 68.7, 71.1, 73.2, 80.1, 115.8,
123.6, 125.7, 127.1, 129.2, 130.5, 131.5, 133.0, 138.9, 140.3,
142.6, 157.1, 158.0, 158.7 (four carbons unresolved). Anal.
(C37H52N4O8) C, H, N.
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dim et h ylet h oxy)-
ca r bon yl]a m in o]-2-h yd r oxy-4-[4-[2-h yd r oxy-2-(3-p yr id i-
n yl)et h oxy]p h en yl]b u t yl]a m in o]-2-h yd r oxy-1-(p h en yl-
m eth yl)p r op yl]ca r ba m ic Acid , 1,1-Dim eth yleth yl Ester
(10g). Epoxide 12g (0.030 g; 0.075 mmol) and amino alcohol
5 (0.025 g; 0.090 mmol) were heated in MeOH (0.20 mL) at 60
°C for 4 h. Volatiles were removed in vacuo, and the residue
was purified by chromatography (CH2Cl2-MeOH-NH4OH, 99:
1:0.1 to 92:8:0.8) to afford a white solid (0.026 g, 52%). This
was further purified by preparative HPLC (Waters Delta Prep
4000 HPLC; Polymer Labs PLRP-S column, 25 × 300 mm, 10
mm particle size, stepwise gradient from 70:30 to 40:60 A:B;
A ) 90:10:0.2 H2O-MeCN-NH4OH; B ) 90:10:0.2 MeCN-
H2O-NH4OH; flow rate 25 mL/min) and then lyophilized from
dioxane-H2O to give 10g (0.021 g; 41%) as a white solid: 1H
NMR (CD3OD; 55 °C) δ 1.28 (br s, 9 H), 2.51-2.78 (m,6 H),
2.96-3.08 (m, 2 H), 3.58-3.76 (m, 4 H), 4.08-4.14 (m, 2 H),
5.04 (dd, J ) 5.3, 5.9 Hz, 1 H), 6.82 (d, J ) 8.8 Hz, 2 H), 7.11
(d, J ) 8.7 Hz, 2 H), 7.13-7.25 (m, 5 H), 7.40 (m, 1 H), 7.91
(m, 1 H), 8.43 (dd, J ) 1.6, 4.9 Hz, 1 H), 8.61 (d, J ) 1.7 Hz,
1 H); 13C NMR (CD3OD; 55 °C) δ 28.7, 37.0, 37.8, 53.0, 56.9,
71.2, 72.8, 74.0, 80.3, 115.8, 116.2, 124.9, 127.1, 129.2, 130.4,
131.5, 132.8, 136.4, 139.5, 140.2, 148.8, 149.3, 158.1, 158.7
(three aliphatic carbons unresolved); accurate mass measure-
ment (M + H)+ calcd for [C37H53N4O8]+ 681.3863, found
681.3872 (∆ppm ) 1.3).
white solid: 1H NMR (CD3OD, 60 °C) δ 1.23 (d, 3H), 1.30
(broad s, 18H), 2.52-2.81 (m, 6H), 2.98-3.12 (m, 2H), 3.61-
3.78 (m, 4H), 3.82 (d, J ) 5.3 Hz, 2H), 4.07 (m, 1H), 6.83 (d, J
) 8.6 Hz, 2H), 7.12 (d, J ) 8.6 Hz, 2H), 7.21-7.25 (m, 5H);
13C NMR (CD3OD, 60 °C) δ 18.3, 27.2, 35.5, 36.4, 51.8, 55.4,
55.5, 65.6, 71.8, 73.2, 78.5, 114.2, 125.5, 127.7, 129.0, 130.0,
131.1, 138.8, 156.5, 157.5. Anal. (C33H51N3O8) C, H, N.
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3[[(1,1-Dim et h ylet h oxy)-
ca r b on yl]a m in o]-2-h yd r oxy-4-[4-(2-h yd r oxy-2-m et h yl-
p r op oxy)p h en yl]b u t yl]a m in o]-2-h yd r oxy-1-(p h en ylm e-
th yl)pr opyl]car bam ic Acid, 1,1-Dim eth yleth yl Ester (10i).
Epoxide 12i (85 mg; 0.242 mmol) was reacted with amino
alcohol 5 (68 mg; 0.242 mmol) using the same general
procedure as described above. The crude product was purified
by chromatography (CH2Cl2-MeOH-NH4OH, 99:1:0.1 to 92:
8:0.8) to give a white solid (45 mg; 30%). This was further
purified by preparative HPLC as described in the synthesis
of 10h and finally lyophilized from dioxane-water to give 10i
(20 mg; 18%) as a white lyophilate: 1H NMR (CD3OD; 55 °C)
δ 1.38 (broad s, 18 H), 1.40 (s, 6H), 2.48-2.82 (m, 6H), 2.95-
3.15 (m, 2H), 3.58-3.80 (m, 4H), 3.73 (s, 2H), 6.84 (d, J ) 8.7
Hz, 2H), 7.12 (d, J ) 8.7 Hz, 2H), 7.20-3.28 (m, 5H). 13C NMR
(CD3OD, 55 °C) δ 25.0, 27.1, 27.2, 36.3, 51.8, 55.3, 69.4, 71.8,
114.1, 125.5, 127.4, 129.0, 129.9, 131.0, 138.7, 156.5, 157.7;
accurate mass measurement (M + H)+ calcd for [C34H54N3O8]+
632.3911, found 632.8887 (∆ppm ) -3.8).
[1S-[1R*,2S*(2S*,3R*)]]-[4-[4-(Car boxym eth oxy)ph en yl]-
3-[[3-[[(1,1-d im eth yleth oxy)ca r bon yl]a m in o]-2-h yd r oxy-
1-(p h en ylm eth yl)p r op yl)ca r ba m ic Acid , 1,1-Dim eth yl-
et h yl E st er (10j). Epoxide 12j (0.037 g; 0.102 mmol) and
amino alcohol 5 (0.029 g; 0.102 mmol) were heated in DMF
(0.20 mL) for 4 h as described above. Volatiles were removed
in vacuo, and the residue was purified by chromatography
(CH2Cl2-MeOH-NH4OH, 99:1:0.1 to 92:8:0.8) to afford amino-
diol ester (0.028 g, 43%) as a white solid: 1H NMR (CD3OD) δ
1.26 (t, J ) 7.1 Hz, 3 H), 1.29 (s, 9 H), 1.30 (s, 9 H), 2.50-2.69
(m, 2 H), 2.73-2.92 (m, 4 H), 3.01-3.17 (m, 2 H), 3.63-3.78
(m, 4 H), 4.22 (q, J ) 7.1 Hz, 2 H), 4.61 (s, 2 H), 6.83 (d, J )
8.7 Hz, 2 H), 7.14 (d, J ) 8.7 Hz, 2 H), 7.21-7.24 (m, 5 H).
The above aminodiol ester (0.010g; 0.0156 mmol) was
hydrolyzed using aqueous LiOH (82 µL of a 0.2 M solution) in
THF (0.10 mL) for 24 h at 0 °C. More aqueous LiOH (90 mL
of a 0.2 M solution) was added, and the reaction mixture was
stirred for an additional 24 h. Aqueous HCl (35 mL of a 1 M
solution) was added and the pH adjusted to 5.5 with aqueous
LiOH. EtOAc (2 mL) was added, and the aqueous layer was
further extracted with EtOAc (3 × 2 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in
vacuo to give a white solid, which was lyophilized from
dioxane-water to furnish 10j (7.1 mg; 74%) as a white solid:
1H NMR (CD3OD) δ 1.31 (s, 9 H), 1.33 (s, 9 H), 2.57-2.63 (m,
4 H), 3.02-3.30 (m, 4 H), 3.62-3.77 (m, 2 H), 3.80-3.89 (m, 2
H), 4.59 (s, 2 H), 6.88 (d, J ) 8.7 Hz, 2 H), 7.16 (d, J ) 8.7 Hz,
2 H), 7.20-7.25 (m, 5 H); accurate mass measurement (M +
H)+ calcd for [C32H48N3O9]+ 618.3391, found 618.3386 (∆ppm
-0.8).
)
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[4-[4-[2-[[(Dim eth yla m in o)-
ca r bon yl]oxy]et h oxy]p h en yl]-3-[[(1,1-d im et h ylet h oxy)-
ca r b on yl]a m in o]-2-h yd r oxyb u t yl]a m in o]-2-h yd r oxy-1-
(p h en ylm eth yl)p r op yl]ca r ba m ic Acid (10k ). A solution
of epoxide 12k (155 mg, 0.39 mmol) and amino alcohol 5 (132
mg, 0.47 mmol) in DMF (1 mL) was stirred at 100 °C for 4 h.
Volatiles were removed in vacuo, and the crude product was
purified by chromatography (CH2Cl2-MeOH-NH4OH, 98:1.8:
0.2 to 94:5.4:0.6) to afford 10k (88 mg; 33%) as a white solid:
1H NMR (CD3OD) δ 1.29 and 1.31 (two singlets) with 1.18 (s,
minor rotamer) and 1.21 (s, minor rotamer, 18H), 2.54 (m, 2H),
2.72 (m, 4H), 3.08 (m, 2H), 3.61 (m, 4H), 4.14 (t, J ) 4.7 Hz,
2H), 4.35 (t, J ) 4.7 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H), 7.13 (d,
J ) 8.6 Hz, 2H), 7.22 (m, 5H); 13C NMR (CD3OD) δ 28.8, 36.2,
36.6, 37.0, 37.9, 53.1, 56.9, 57.0, 65.4, 67.6, 73.0, 73.2, 79.9,
115.5, 127.1, 129.2, 130.5, 131.5, 132.7, 140.3, 158.1, 158.3,
158.7 (4 carbons unresolved). Anal. (C35H54N4O9) C, H, N.
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dim et h ylet h oxy)-
car bon yl]am in o]-2-h ydr oxy-4-[4-[2-(2-oxo-3-oxazolidin yl)-
eth oxy]p h en yl]bu tyl]a m in o]-2-h yd r oxy-1-(p h en ylm eth -
yl)p r op yl]ca r ba m ic Acid , 1,1-Dim eth yleth yl Ester (10l).
[1S-[1R*, 2S* (2S*, 3R*)]-[3-[[3-[[(1,1-Dim eth yleth oxy)-
car bon yl]am in o]-2-h ydr oxy-4-[4-(2-h ydr oxypr opoxy)ph e-
n yl]bu tyl]am in o]-2-h ydr oxy-1-(ph en ylm eth yl)pr opyl]car -
ba m ic Acid , 1,1-Dim eth yl Ester (10h ). The epoxide 12h
(190 mg; 0.44 mmol) was reacted with amino alcohol 5 (124
mg; 0.44 mmol) using the general procedure as described for
10e. The crude product was chromatographed (CH2Cl2-
MeOH-NH4OH, 98:2:0.2 to 92:8:0.8) to yield O-benzyl-10h
(140 mg; 63%) as a beige solid.
To a suspension of 10% Pd/C (60 mg) in MeOH (2.5 mL)
was added O-benzyl-10h (64 mg; 0.09 mmol) followed by
aqueous HCl (900 µL of a 0.1 N solution), and the reaction
mixture was stirred under an atmosphere of H2 for 1 h. The
reaction mixture was neutralized with aqueous NaOH (900
µL of a 0.1 M solution), filtered through Celite and concen-
trated in vacuo. The crude product was purified by chroma-
tography (CH2Cl2-MeOH-NH4OH, 98:2:0.2 to 92:8:0.8) to
yield 10h (35 mg; 65%, 1:1 mixture of diastereomers) as a