A Novel, Picomolar Inhibitor of HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 395
2-[[(ter t-Bu tyloxy)ca r bon yl]a m in o]-(4R)-h yd r oxy-(5R)-
[[(b en zyloxy)ca r b on yl]a m in o]-1,6-d ip h en yl-2-a za h ex-
a n e (4). To a solution of 1.2 g of compound 3 in 36 mL of
2-propanol was added 1.07 g (1.2 equiv) of N1-[(tert-butyloxy)-
carbonyl]-N2-benzylhydrazine. The solution was heated at
reflux for 24 h, cooled to room temperature, and concentrated
in vacuo. Silica gel column chromatography (20% EtOAc/80%
hexane) provided 1.5 g (72%) of 4: 1H NMR (CDCl3) δ 1.33 (s,
9H), 2.43 (m, 1H), 2.78 (m, 1H), 2.96 (d, J ) 7.5 Hz, 2H), 3.57
(m, 2H), 3.70-4.00 (m, 3H), 5.48 (s, 2H), 5.19 (br s, 1H), 5.37
(m, 1H), 7.18-7.36 (m, 15H); MS (M + H)+ ) 520. Anal.
(C30H37N3O5) C, H, N.
2-[[(Ben zyloxy)car bon yl]am in o]-(4R)-[[(tr im eth ylsilyl)-
eth oxy]m eth oxy]-(5R)-[[(ben zyloxy)ca r bon yl]a m in o]-1,6-
d ip h en yl-2-a za h exa n e (5). The (tert-butyloxy)carbonyl pro-
tecting group of compound 4 was exchanged to a (benzyl-
oxy)carbonyl protecting group by deprotection with trifluoro-
acetic acid and methylene chloride, and then reaction of the
resulting amino compound with N-[[(benzyloxy)carbonyl]oxy]-
succinimide provided the di-Cbz compound in 90% yield. To
1.5 g of di-Cbz compound in 12 mL of dimethylformamide were
added to 1.8 mL of diisopropylethylamine and then 1.14 mL
of [(trimethylsilyl)ethoxy]methyl chloride. The reaction mix-
ture was stirred at room temperature for 19 h. The solvent
was removed in vacuo. The residue was extracted with EtOAc
(3 × 80 mL) and washed with saturated NaCl solution. The
organic layer was dried with anhydrous sodium sulfate and
filtered and the solvent evaporated in vacuo. Purification of
the crude product by silica gel column chromatography (20%
acetone/80% hexane) provided 1.23 g (83%) of compound 5: 1H
NMR (CDCl3) δ 0.05 (s, 9H), 0.95 (t, J ) 9 Hz, 2H), 2.80 (m,
3H), 3.10 (m, 1H), 3.65 (m, 3H), 3.97 (m, 1H), 4.26 (m, 1H),
4.70 (ABq, J ) 7.5 Hz, 2H), 5.0 (m, 4H), 5.30 (br d, 1H), 7.25
(m, 20H); MS (M + H)+ ) 684. Anal. (C39H49N3O6Si) C, H,
N.
(5R,6R)-1,5-Diben zyl-3-oxo-6-[[(tr im eth ylsilyl)eth oxy]-
m eth oxy]-1,2,4-tr ia za cycloh ep ta n e (6). To a suspension
of 100 mg of 10% Pd/C in 20 mL of methanol was added 1.2 g
of compound 5. The mixture was stirred vigorously under a
hydrogen atmosphere (balloon filled with hydrogen) for 1 h.
The catalyst was filtered off, and the filtrate was concentrated
in vacuo to give a colorless oil which was dissolved in 120 mL
of dichloromethane. To this solution was added 300 mg of 1,1′-
carbonyldiimidazole. The solution was kept at room temper-
ature for 72 h and then concentrated in vacuo and the crude
product purified by silica gel column chromatography (20%
EtOAc/80% CH2Cl2) to provide 617 mg of compound 6 (80%,
two steps): 1H NMR (CDCl3) δ 0.02 (s, 9H), 0.90 (t, J ) 9.0
Hz, 2H), 2.96 (m, 2H), 3.17 (m, 2H), 3.70 (m, 3H), 3.97 (m,
1H), 4.05 (ABq, J ) 13.5 Hz, 2H), 4.45 (br s, 1H), 4.73 (ABq,
J ) 7.5 Hz, 2H), 5.62 (br s, 1H), 7.30 (m, 10H); MS (M + H)+
) 442. Anal. (C24H35N3O3Si) C, H, N.
1-(Hydroxymethyl)-4-[[[(trimethylsilyl)ethoxy]methoxy]-
m eth yl]ben zen e. To 3.08 g (21.7 mmol) of 1,4-benzene-
dimethanol in 5 mL of DMF/200 mL of dichloromethane were
added 4.6 mL (1.2 equiv) of diisopropylethylamine and 4.0 mL
of SEM-Cl. After 3 h at room temperature, solvent was
removed in vacuo and the residue taken up in 150 mL of
EtOAc and washed with saturated NaHCO3 (50 mL). The
organic layer was dried and concentrated in vacuo. The crude
product was purified by silica gel column chromatography (10%
EtOAc/90% CH2Cl2) to give 2.98 g (51%) of product: 1H NMR
(CDCl3) δ 0.01 (s, 9H), 0.95 (t, J ) 10 Hz, 2H), 1.60 (br s, 1H),
3.65 (t, J ) 10 Hz, 2H), 4.58 (s, 2H), 4.67 (s, 2H), 4.72 (s, 2H),
7.32 (s, 4H); MS (M + NH4)+ ) 286.
(5R,6R)-2,4-Bis[(h yd r oxym eth yl)ben zyl]-1,5-d iben zyl-
6-h yd r oxy-3-oxo-1,2,4-tr ia za cycloh ep ta n e (7a )sGen er a l
P r oced u r e for Alk yla tion of Ur ea 6 a n d Dep r otection
of th e SEM Gr ou p s. To a solution of 180 mg of urea 6 (0.41
mmol) in 3 mL of DMF was added 165 mg of NaH (60% oil
dispersion, 10 equiv). After 15 min at room temperature and
the evolution of hydrogen stopped, a solution of 680 mg (5
equiv) of the mesylate described above was added. After 3 h
at room temperature, the reaction was quenched carefully with
saturated NH4Cl at 0 °C and the mixture extracted with ether
(3 × 50 mL). The combined organic layer was washed with
saturated NaCl solution and dried with anhydrous Na2SO4.
Concentration and purification by silica gel column chroma-
tography (10% EtOAc/90% hexane) provided 285 mg (73%) of
the SEM-protected product. To a solution of 280 mg of this
product in 2.8 mL of methanol was added 0.28 mL of chloro-
trimethylsilane. The solution was stirred at room temperature
for 1.25 h. The sovlent was removed in vacuo, and the crude
product was purified by silica gel column chromatography (5%
MeOH/95% CH2Cl2) to give 150 mg (88%) of compound 7a : 1H
NMR (CDCl3) δ 1.55 (br s, 3H), 2.70 (d, J ) 9.0 Hz, 2H), 2.92
(m, 2H), 3.08 (m, 1H), 3.40 (m, 1H), 3.80 (m, 1H), 4.06 (ABq,
J ) 9 Hz, 4H), 4.70 (s, 4H), 4.90 (m, 2H), 7.06-7.50 (m, 18H);
MS (M + H)+ ) 552. Anal. (C34H37N3O4) C, H, N.
(5R,6R)-1-(3-F u r a n ylm et h yl)-5-b en zyl-3-oxo-6-[[(t r i-
m et h ylsilyl)et h oxy]m et h oxy]-1,2,4-t r ia za cycloh ep t a n e.
The synthesis of this urea followed the same sequence of
reactions leading to 6, except the N1-[(tert-butyloxy)carbonyl]-
N2-benzylhydrazine was replaced by N1-[(tert-butyloxy)carbon-
yl]-N2-(3-furanylmethyl)hydrazine: 1H NMR (CDCl3) δ 0.02 (s,
9H), 0.92 (ABq, J ) 7 Hz, 2H), 2.95 (d, J ) 7.0 Hz, 2H), 3.10
(dd, J ) 4, 7 Hz, 1H), 3.20 (dd, J ) 4, 7 Hz, 1H), 3.65 (m, 3H),
3.95 (m, 3H), 4.45 (br s, 1H), 4.72 (ABq, J ) 7.5 Hz, 2H), 5.65
(d, J ) 1.5 Hz, 1H), 6.48 (t, J ) 1.5 Hz, 1H), 7.20 (m, 5H),
7.38 (d, J ) 1.5 Hz, 1H); MS (M + H)+ ) 431. Anal.
(C22H33N3O4Si) C, H, N.
(5R,6R)-2,4-Bis[4-(h yd r oxym eth yl)ben zyl]-1-(3-fu r a n -
ylm eth yl)-5-ben zyl-6-h ydr oxy-3-oxo-1,2,4-tr ia za cycloh ep -
ta n e (7b). The above-described urea was alkylated and the
SEM group deprotected using the identical procedures de-
scribed for 7a to give 7b in 89% yield: 1H NMR (CDCl3) δ 1.55
(br s, 3H), 2.70-3.00 (m, 5H), 3.40 (m, 1H), 3.80 (m, 1H), 3.90
(ABq, J ) 13.5 Hz, 2H), 4.10 (m, 1H), 4.66 (s, 2H), 4.68 (s,
2H), 4.85 (m, 2H), 6.83 (d, J ) 1.5 Hz, 1H), 7.05-7.48 (m, 15H);
MS (M + H)+ ) 542. Anal. (C32H35N3O5‚0.25H2O) C, H, N.
(5R,6R)-1,2,4,5-Tetr a ben zyl-6-h yd r oxy-3-oxo-1,2,4-tr i-
a za cycloh ep ta n e (7c). Alkylation of the urea 6 with benzyl
bromide and deprotection of the SEM group using identical
procedures described for 7a provided 7c in 91% yield: 1H NMR
(CDCl3) δ 1.18 (d, J ) 6 Hz, 1H), 2.71 (d, J ) 10 Hz, 1H), 2.91
(dd, J ) 3, 10 Hz, 1H), 2.96 (d, J ) 3 Hz, 1H), 3.10 (dd, J )
10, 15 Hz, 1H), 3.46 (m, 1H), 3.82 (m, 1H), 4.05 (m, 3H), 4.92
(d, J ) 15 Hz, 1H), 7.10-7.50 (m, 20H); MS (M + H)+ ) 504.
Anal. (C32H33N3O2‚0.5H2O) C, H, N.
(5R,6R)-2,4-Bis(4-h yd r oxyb en zyl)-1,5-d ib en zyl-6-h y-
d r oxy-3-oxo-1,2,4-tr ia za cycloh ep ta n e (7d ). Alkylation of
the urea 6 with 4-[[(trimethylsilyl)ethoxy]methoxy]benzyl
chloride and deprotection of the SEM groups using identical
procedures described for 7a provided 7d in 85% yield: 1H NMR
(DMSO-d6) δ 2.64 (d, J ) 13.5 Hz, 1H), 2.87 (m, 2H), 3.48 (m,
3H), 3.60 (m, 1H), 3.77 (d, J ) 13.5 Hz, 1H), 3.90 (ABq, J )
10 Hz, 2H), 4.57 (dd, J ) 3, 12, Hz, 2H), 4.90 (d, J ) 4.5 Hz,
1H), 6.72 (d, J ) 9 Hz, 4H), 6.90 (d, J ) 9 Hz, 2H), 7.04 (d, J
) 9 Hz, 2H), 7.25 (m, 10H), 9.27 (s, 1H), 9.38 (s, 1H); MS (M
+ H)+ ) 524. Anal. (C32H33N3O4‚0.25H2O) C, H, N.
(5R,6R)-2,4-Bis(3-m et h oxyb en zyl)-1,5-d ib en zyl-6-h y-
d r oxy-3-oxo-1,2,4-tr ia za cycloh ep ta n e (7e). Alkylation of
urea 6 with 3-methoxybenzyl bromide and deprotection of the
SEM group using identical procedures described for 7a pro-
vided 7e in 75% yield: 1H NMR (CDCl3) δ 1.20 (d, J ) 6 Hz,
1H), 2.72 (m, 2H), 2.93 (m, 2H), 3.10 (dd, J ) 12, 13.5 Hz,
1H), 3.47 (dt, J ) 4, 13.5 Hz, 1H), 3.78 (s, 3H), 3.80 (s, 3H),
3.86 (m, 2H), 4.0 (m, 1H), 4.08 (s, 2H), 4.90 (d, J ) 13.5 Hz,
2H), 6.75 (m, 4H), 7.10 (m, 4H), 7.30 (m, 10H); MS (M + H)+
) 552. Anal. (C34H37N3O4) C, H, N.
1-[[(Meth ylsu lfon yl)oxy]m eth yl]-4-[[[(tr im eth ylsilyl)-
eth oxy]m eth oxy]m eth yl]ben zen e. To 622 mg (2.32 mmol)
of the hydroxymethyl compound described above in 25 mL of
dichloromethane were added at 0 °C 0.404 mL of triethylamine
(1.25 equiv) and 0.183 mL of methanesulfonyl chloride (1.0
equiv). After 0.5 h at 0 °C, the solvent was removed in vacuo
and the crude product purified directly by silica gel column
chromatography (5% EtOAc/95% CH2Cl2) to give 638 mg (79%)
of product: 1H NMR (CDCl3) δ 0.02 (s, 9H), 0.95 (t, J ) 9.0
Hz, 2H), 2.88 (s, 3H), 3.65 (t, J ) 9.0 Hz, 2H), 4.60 (s, 2H),
4.72 (s, 2H), 5.20 (s, 2H), 7.38 (s, 2H); MS (M + NH4)+ ) 364.