Journal of Medicinal Chemistry
Article
45.1, 35.4, 31.2, 27.8, 27.3, 27.2, 20.1, 19.8, 15.2; LRMS-ESI (m/z)
617.80 (M + H)+. HRMS-ESI (m/z) [M + Na]+ calcd for
(C32H44N2O8SNa), 639.2716; found, 639.2719.
1H), 2.08−2.04 (m, 2H), 1.73−1.59 (m, 2H), 0.97 (d, J = 6.4 Hz,
3H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, d-MeOH) δ
164.6, 158.0, 140.2, 131.9, 130.7, 130.6, 129.3, 127.1, 115.4, 110.8,
75.0, 74.4, 69.2, 69.1, 68.2, 68.0, 59.0, 57.2, 56.2, 54.1, 46.8, 45.6, 37.3,
31.2, 28.0, 20.5; HRMS-ESI (m/z) [M + H]+ calcd for
(C31H42N2O9S), 619.2689; found, 619.2679.
(3aS,3bR,4S,7aR,8aS)-6,6-Dimethyldecahydrofuro[2,3-b]-
benzofuran-4-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphe-
nylsulfonamido)-1-phenylbutan-2-yl)carbamate (16c). The indi-
cated inhibitor was obtained following the general procedure outlined
above for inhibitor 16a. The product was obtained as a mixture of
diastereomers (16c/16d) (61% yield, 16c/16d). Rf = 0.33, (50%
hexanes/ethyl acetate). 16c/16d were separated by HPLC with
column YMC-Pack-ODS-A (250 × 10 mm) and a solvent/flow rate of
2.5 mL/min (CH3CN/H2O, 65:35). Retention time: 16c = 18.31 min
and 16d = 18.99 min. For 16c: [α]D23 −19.0 (c 0.6, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 8.9 Hz, 2H), 7.28 (s, 2H), 7.25−
7.18 (m, 3H), 6.99 (d, J = 8.9 Hz, 2H), 5.57 (d, J = 5.0 Hz, 1H), 5.01−
4.94 (m, 1H), 4.82 (d, J = 8.9 Hz, 1H), 4.26−4.15 (m, 1H), 4.05 (q, J
= 8.1 Hz, 2H), 3.94 (s, 1H), 3.88 (s, 4H), 3.83 (s, 1H), 3.24−3.10 (m,
2H), 3.01−2.95 (m, 1H), 2.87 (d, J = 8.3 Hz, 2H), 2.80 (d, J = 13.2
Hz, 2H), 2.15−2.05 (m, 1H), 2.03−1.90 (m, 2H), 1.89−1.80 (m, 2H),
1.75−1.55 (m, 3H) 0.97−0.94 (m, 6H), 0.90−0.86 (m, 6H); 13C
NMR (125 MHz, CDCl3) δ 163.0, 155.7, 137.7, 129.6, 129.4, 129.2,
128.4, 127.7, 126.5, 114.3, 113.8, 109.7, 73.1, 71.0, 68.4, 58.8, 55.6,
54.7, 53.7, 44.6, 42.4, 41.3, 40.7, 35.6, 32.6, 31.2, 27.7, 27.2, 24.6, 20.1,
19.8. HRMS-ESI (m/z) [M + H]+ calcd for (C34H48N2O8S),
645.3209; found, 645.3210.
(3aS,3bS,4S,7aR,8aR)-Octahydro-2H-furo[3′,2′:4,5]furo[2,3-c]-
pyran-4-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-yl)carbamate (16g). The indicated in-
hibitor was obtained following the general procedure outlined above
for inhibitor 16a (70% yield). Rf = 0.27 (80% ethyl acetate/hexanes);
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[α]D −11.5 (c 1.7, CHCl3); H NMR (400 MHz, d-MeOH) δ 7.79
(d, J = 8.8 Hz, 2H), 7.30−7.24 (m, 4H), 7.21−7.17 (m, 1H), 7.11(d, J
= 8.8 Hz, 2H), 5.72 (d, J = 5.0 Hz, 1H), 4.70 (d, J = 5.2 Hz, 1H),
4.14−3.97 (m, 2H), 3.90 (s, 4H), 3.76−3.81 (m, 2H), 3.70 (dd, J =
10.7, 7.1 Hz, 1H), 3.61 (dd, J = 13.4, 2.4 Hz, 1H), 3.57−3.43 (m, 2H),
3.26−3.13 (m, 1H), 3.10−2.98 (m, 2H), 2.92 (dd, J = 13.6, 7.1 Hz,
1H), 2.73 (dt, J = 10.0, 4.8 Hz, 1H), 2.65 (dd, J = 13.7, 10.9 Hz, 1H),
2.43 (t, J = 4.9 Hz, 1H), 2.25−2.10 (m, 1H), 2.06−1.97 (m, 2H),
1.86−1.69 (m, 1H), 1.05−0.83 (m, 6H); 13C NMR (100 MHz, d-
MeOH) δ 164.5, 158.0, 140.2, 132.3, 130.6, 130.5, 129.2, 127.2, 115.4,
110.8, 79.5, 75.0, 74.0, 69.0, 68.3, 68.1, 58.6, 57.6, 56.2, 53.8, 47.1,
45.5, 37.1, 31.3, 28.0, 20.5; HRMS-ESI (m/z) [M + Na]+ calcd for
(C31H42N2O9SNa), 641.2509; found, 641.2501.
(3aS,3bR,4R,7aS,8aS)-6,6-Dioxidooctahydro-2H-furo[2,3-b]-
thiopyrano[4,3-d]furan-4-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-me-
thoxyphenylsulfonamido)-1-phenylbutan-2-yl)carbamate (16h).
The indicated inhibitor was obtained following the general procedure
outlined above for inhibitor 16a. The product was obtained as a
mixture of diastereomers (16h/16i) (61% yield). 16h/16i were
separated was separated by chiral HPLC, and titled inhibitor 16h was
determined to be >95%. Column ChiralPak IC, hexanes/IPA (52−
48%, 20 min), 2.5 mL/min, 24 °C, retention time 16h = 6.38 min. Rf =
3aS,3bS,4R,7aS,8aR)-6,6-Dimethyldecahydrofuro[2,3-b]-
benzofuran-4-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphe-
23
nylsulfonamido)-1-phenylbutan-2-yl)carbamate (16d). [α]D
1
+21.5 (c 0.6, CHCl3); H NMR (500 MHz, CDCl3) δ 7.70 (d, J =
8.3 Hz, 2H), 7.43−7.13 (m, 5H), 6.98 (d, J = 8.6 Hz, 2H), 5.69 (s,
1H), 5.10−4.98 (m, 1H), 4.93 (d, J = 8.3 Hz, 1H), 4.27 (s, 1H), 4.09
(d, J = 6.5 Hz, 1H), 3.87 (s, 6H), 3.64 (s, 1H), 3.13 −3.08 (m, 1H),
3.02 (d, J = 14.3 Hz, 2H), 2.96−2.91 (m, 2H), 2.79 (dd, J = 13.4, 6.7
Hz, 1H), 2.68 (s, 1H), 2.08−2.05 (m, 1H), 1.90−1.54 (m, 1H), 1.86−
1.80 (m, 1H), 1.75−1.71 (m, 1H), 1.64−1.61 (s, 1H), 1.55−1.51 (s,
1H), 0.95 (s, 3H), 0.91−0.86 (m, 9H); 13C NMR (125 MHz, CDCl3)
δ 163.1, 156.13, 137.7, 129.7, 129.4, 128.5, 126.5, 114.3, 113.9, 109.8,
72.6, 71.1, 68.5, 58.8, 55.6, 55.2, 53.6, 45.3, 42.4, 41.3, 35.1, 32.7, 31.9,
31.3, 27.8, 27.3, 24.8, 22.7, 20.1, 19.9; HRMS-ESI (m/z) [M + Na]+
calcd for (C34H48N2O8SNa), 667.3209; found, 667.3040.
(4aR,4bR,5S,8aR,9aS)-Decahydro-2H-pyrano[2,3-b]benzofuran-
5-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonami-
do)-1-phenylbutan-2-yl)carbamate (16e). The indicated inhibitor
was obtained following the general procedure outlined above for
inhibitor 16a (80% yield). Rf = 0.31 (ethyl acetate/hexanes); 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 8.9 Hz, 2H), 7.32−7.19 (m, 5H),
6.98 (d, J = 8.9 Hz, 2H), 5.12 (d, J = 3.9 Hz, 1H), 5.01 (dd, J = 18.6,
4.5 Hz, 1H), 4.96−4.86 (m, 1H), 4.86−4.72 (m, 1H), 4.41−4.30 (m,
1H), 3.87 (s, 3H), 3.86−3.73 (m, 2H), 3.67 (d, J = 12.2 Hz, 1H), 3.41
(t, J = 10.7 Hz, 1H), 3.18−3.07 (m, 1H), 3.07−2.99 (m, 2H), 2.99−
2.70 (m, 2H), 2.58 (dd, J = 15.0, 7.4 Hz, 1H), 2.06 (ddd, J = 16.0,
10.5, 6.4 Hz, 1H), 1.88−1.68 (m, 2H), 1.53 (s, 4H), 1.53−1.37 (m,
4H), 1.35−1.16 (m, 2H), 0.91 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 163.0, 155.8, 137.6, 129.5,
129.4, 128.4, 126.5, 114.3, 100.9, 74.5, 73.0, 72.6, 61.0, 58.7, 55.5, 54.7,
53.7, 41.2, 36.6, 35.4, 30.9, 29.6, 28.6, 27.2, 23.8, 23.3, 21.9, 20.1, 19.8;
HRMS-ESI (m/z) [M + H]+ calcd for (C33H46N2O8S), 631.3053;
found, 631.3047.
1
0.28 (50% ethyl acetate/hexanes); H NMR (400 MHz, CDCl3) δ
7.75 (d, J = 5.4 Hz, 2H), 7.27−7.25 (m, 5H), 6.99 (d, J = 6.0 Hz, 2H),
5.69 (d, J = 5.5 Hz, 1H), 5.58 (d, J = 5.5 Hz, 1H), 5.43 (d, J = 9.1 Hz,
1H), 5.37 (d, J = 9.3 Hz, 1H), 5.19−5.10 (m, 2H), 4.08−3.98 (m,
1H), 3.95−3.88 (m, 1H), 3.86 (s, 3H), 3.83−3.71 (m, 3H), 3.68−3.49
(m, 1H), 3.40−3.30 (m, 1H), 3.28−3.18 (m, 2H), 3.20−3.05 (m, 2H),
3.05−2.91 (m, 1H), 2.91−2.69 (m, 1H), 2.50 (dd, J = 13.4, 9.7 Hz,
1H), 2.21−2.10 (m, 1H), 1.92−1.87 (m, 1H), 1.83−1.73 (m, 1H),
1.72−1.51 (m, 1H), 0.92 (d, J = 8.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 164.2, 156.4, 143.3, 129.7, 128.5,
128.4, 127.9, 114.4, 109.1, 74.9, 72.6, 71.8, 68.7, 57.7, 55.9, 50.2, 43.0,
41.4, 37.1, 32.0, 29.2, 29.0, 27.3, 27.1, 23.9, 20.1, 19.8;HRMS (m/z)
[M + Na]+ calcd for (C31H42N2O10S2Na), 689.2178; found, 689.2169.
(3aS,3bS,4S,7aR,8aR)-6,6-Dioxidooctahydro-2H-furo[2,3-b]-
thiopyrano[4,3-d]furan-4-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-me-
thoxyphenylsulfonamido)-1-phenylbutan-2-yl)carbamate (16i). Re-
1
tention time = 8.02 min. Rf = 0.28 (50% ethyl acetate/hexanes); H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 5.1 Hz, 2H), 7.28−7.26 (m,
5H), 6.98 (d, J = 8.3 Hz, 2H), 5.69 (d, J = 5.5 Hz, 1H), 5.58 (d, J = 5.5
Hz, 1H), 5.43 (d, J = 9.1 Hz, 1H), 5.37 (d, J = 9.3 Hz, 1H), 5.19−5.10
(m, 2H), 4.08−3.98 (m, 1H), 3.95−3.88 (m, 1H), 3.86 (s, 3H), 3.83−
3.71 (m, 3H), 3.68−3.49 (m, 1H), 3.40−3.30 (m, 1H), 3.28−3.18 (m,
2H), 3.20−3.05 (m, 2H), 3.05−2.91 (m, 1H), 2.91−2.69 (m, 1H),
2.50 (dd, J = 13.4, 9.7 Hz, 1H), 2.21−2.10 (m, 1H), 1.89 (dq, J = 13.9,
7.2, 6.7 Hz, 1H), 1.83−1.73 (m, 1H), 1.72−1.51 (m, 1H), 0.92 (d, J =
4.5 Hz, 3H), 0.87 (d, J = 2.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
164.3, 156.4, 143.3, 129.7, 128.4, 128.3, 127.9, 113.8, 109.1, 74.9, 72.6,
71.8, 68.5, 57.7, 55.9, 50.2, 43.0, 41.4, 37.2, 32.1, 31.8, 30.9, 29.2, 28.9,
27.3, 27.1, 23.8, 20.1, 19.8; HRMS (m/z) [M + Na]+ calcd for
(C31H42N2O10S2Na), 689.2178; found, 689.2170.
Determination of the X-ray Structure of the Inhibitor 16a−HIV-1
Protease Complex. The HIV-1 protease was expressed and purified as
previously described.29,30 The protease−inhibitor complex was
crystallized at room temperature by the hanging-drop vapor-diffusion
method with well solutions of 1.15 M ammonium chloride and 0.1 M
sodium acetate buffer (pH 5.5). Diffraction data were collected on a
single crystal cooled to 90 K at the SER-CAT BM beamline 22,
(3aS,3bR,4R,7aS,8aS)-Octahydro-2H-furo[3′,2′:4,5]furo[2,3-c]-
pyran-4-yl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-yl)carbamate (16f). The indicated inhib-
itor was obtained following the general procedure outlined above for
inhibitor 16a (82% yield). Rf = 0.42 (80% ethyl acetate/hexanes);
23
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[α]D +12.8 (c 1.0, CHCl3); H NMR (400 MHz, d-MeOH) δ 7.79
(d, J = 8.8 Hz, 2H), 7.29−7.26 (m, 4H), 7.22−7.16 (m, 1H), 7.11 (d, J
= 8.8 Hz, 2H), 5.51 (d, J = 4.8 Hz, 1H), 4.67 (d, J = 5.2 Hz, 1H),
4.05(d, J = 8.0 Hz, 1H), 3.98 (s, 1H), 3.89 (s, 4H), 3.81−3.84 (m,
3H), 3.71 (d, J = 12.0 Hz, 1H), 3.61 (dd, J = 13.2, 2.0 Hz, 1H), 3.47−
3.39 (m, 2H), 3.26−3.23 (m, 1H), 3.11 (dd, J = 13.5, 8.4 Hz, 1H),
2.95 (dd, J = 14.8, 8.1 Hz, 1H), 2.86 (dd, J = 13.5, 6.6 Hz, 1H), 2.63−
2.46 (dd, J = 13.6, 2.8 Hz, 1H), 2.32 (t, J = 4.9 Hz, 1H), 2.16−2.09 (m,
I
dx.doi.org/10.1021/jm400768f | J. Med. Chem. XXXX, XXX, XXX−XXX