IrreVersible Inhibition of the HIV-1 Protease
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5855
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1431, 1295, 1215, 1116 cm-1; H NMR (CDCl3) 7.25-7.42 (m, 8 H,
DMF to initiate the reaction. After 30 min a solution of 4-(p-
chlorophenyl)-4-hydroxypiperidine (338 mg, 1.6 mmol) in CH2Cl2 was
added, and the reaction mixture was stirred at ∼25 °C for 1.5 h. The
solution was sequentially washed with 5% NaHCO3, water, and brine
before it was dried and the solvent removed. Purification of the crude
residue by flash chromatography on silica gel (hexane/ethyl acetate,
aromatic), 7.6 (d, 2 H, J ) 7.3 Hz, aromatic), 7.77 (d, 2 H, J ) 7.3
Hz, aromatic), 6.03 (br s, 1 H, NCH2CH), 4.47 (d, 2 H, J ) 6.78 Hz,
FMOC-CH2), 4.27 (t, 1 H, J ) 6.5 Hz, FMOC-CH), 4.13 (br s, 2 H,
NCH2CH), 3.68 (br s, 2 H, NCH2CH2), and 2.49 (br s, 2 H, NCH2CH2)
ppm; 13C NMR (CDCl3) 174.9, 144.4, 141.3, 138.9, 133.09, 128.54,
127.66, 127.01, 126.18, 124.94, 119.96, 67.3, 47.36, 43.72, 42.67, 40.47,
and 27.13 ppm; MS (LSIMS) m/z (%) 416 (MH+, 100), 238 (78);
HRMS for C26H22ClNO2, calcd 415.1339, found 415.1329.
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6:4) provided 172 mg of product (30% yield): mp 138-140 °C; H
NMR (CDCl3) 7.2-7.5 (m, 8 H, aromatic), 6.6-6.7 (dd, 1 H, J )
10.9 Hz, J ) 17.6 Hz, vinyl H), 5.79 (d, 1 H, J ) 17.6 Hz, vinyl
CHCHcisCHtrans), 5.32 (d, 1 H, J ) 10.9 Hz, vinyl CHCHcisCHtrans),
4.6 (br, 1 H, OH), 3.2-3.7 [br m, 4 H, (CH2)2N)], and 1.8-2.8 [br m,
4 H, (CH2CH2)2N] ppm; 13C NMR (CDCl3) 38.17, 38.95, 43.80, 71.39,
115.30, 125.96, 126.23, 127.23, 128.63, 135.10, 136.04, 138.98, 146.08,
and 170.19 ppm; MS (HREI) m/z (%) 341 (15), 323 (15), 131 (100);
HRMS for C20H20ClNO2, calcd 341.1183, found 341.1179.
N-FMOC-4-(p-chlorophenyl)-3,4-epoxypiperidine (5). To a solu-
tion of N-FMOC-4-(p-chlorophenyl)-1,2,5,6-tetrahydropyridine (200
mg, 0.48 mmol) in CH2Cl2 was added a solution of 80% mCPBA (126
mg, 0.7 mmol) in CH2Cl2, and the reaction mixture was stirred for 18
h. A few drops of methyl ethyl sulfide were added to destroy excess
peroxide. The solution was then washed sequentially with 5% NaHCO3,
water, and brine. Drying over Na2SO4 and evaporation of the solvent
provided a crude solid that was purified by flash chromatography on
silica gel (hexane/ethylacetate, 6:4). The desired product (163.7 mg,
79% yield) was thus obtained: IR (CHCl3) 3024, 1697, 1456, 1431,
4-(p-Chlorophenyl)-4-hydroxy-N-[4-(1,2-epoxyethyl)benzoyl]pi-
peridine (4). 4-(p-Chlorophenyl)-4-hydroxy-N-(4-ethenylbenzoyl)-
piperidine (102 mg, 0.29 mmol) was epoxidized as described above.
Flash chromatography provided 41.5 mg (40%) of the product: mp 90
1339, 1246, 1221, 1123, 1098, 1018 cm-1; H NMR (CDCl3) 7.77-
1
1
°C; H NMR (CDCl3) 7.2-7.45 (m, 8 H, aromatic), 4.64 (br s, 1 H,
7.30 (m, 12 H, aromatic), 4.47 (d, 2 H, J ) 6.5 Hz, OCH2CH), 4.26 (t,
1 H, J ) 6.4 Hz, OCH2CH), 3.8-4.2 (br m, 2 H, CH2NCH2), 3.6-3.8
(br d, 1 H, NCH2CHOC), 3.1-3.3 (br m, 2 H, CH2NCH2), and 2.0-
2.5 (br m, 2 H, NCH2CH2) ppm; 13C NMR (CDCl3) 143.94, 141.33,
133.84, 128.64, 127.67, 127.03, 126.66, 124.83, 119.94, 67.36, 58.52,
and 47.53 ppm; MS (LSIMS) m/z (%) 432 (MH+, 90), 391 (54); HRMS
for C12H11NClO3, calcd 252.0427, found 252.0418. Anal. Calcd for
C26H22ClNO3: C, 73.3; H, 5.13; N, 3.24. Found: C, 73.78; H, 5.37;
N, 3.24.
1-(4′-Fluorophenyl)-4-iodobutane. To a solution of 850 mg (5.18
mmol) of p-fluorophenyl cyclopropyl ketone in CHCl3 were added 4.6
g (31 mmol) of NaI and a catalytic amount of tetrabutylammonium
iodide followed by 1.6 g (15.5 mmol) of (CH3)3SiCl.36 The solution
was stirred for 18 h and was then poured into a solution of NaHCO3.
The excess iodide was removed by the addition of a saturated solution
of sodium thiosulfate. The organic layer was separated and washed
with water and brine. Evaporation of the solvent after drying over
anhydrous Na2SO4 yielded a crude product that was dissolved in hexane/
ethyl acetate (9:1) and filtered through a short column of silica gel.
Evaporation of the solvent yields a dark brown liquid, 1.41 g (94%
yield), that is best stored at 0 °C because it decomposes at room
temperature: 1H NMR (CDCl3) 8.00 (m, 2 H, aromatic), 7.14 (m, 2 H,
aromatic), 3.32 (t, 2 H, J ) 6.7 Hz, CH2I), 3.11 (m, 2 H, CH2CO), and
2.25 (m, 2 H, CH2CH2I) ppm; 13C NMR (CDCl3) 196.56, 130.41,
130.29, 115.56, 115.27, 38.57, 27.25 and 6.58 ppm.
CHHN), 3.88 (br t, 1 H, PhCHOCHcisHtrans), 3.2-3.7 (br m, 3 H,
piperidine H), 3.17 (t, 1 H, J ) 4.6 Hz, PhCHOCHcisHtrans), 2.7 (dd, 1
H, J ) 2.3 Hz, J ) 5.3 Hz, PhCHOHcisHtrans), and 1.6-2.2 (br m, 4
H, piperidine H) ppm; 13C NMR (CDCl3) 169.97, 146.07, 139.36,
135.77, 133.21, 128.58, 127.16, 125.94, 125.6, 71.27, 51.95, 51.26,
43.81, 38.87, 38.29, and 37.72 ppm.
N-FMOC-1,2,5,6-tetrahydropyridine. To a solution of 455 mg
(5.4 mmol) of 1,2,5,6-tetrahydropyridine in CH2Cl2 was added 668 mg
(5.4 mmol) of 4-(dimethylamino)pyridine, and the resulting solution
was cooled to 0 °C. A solution of 1.41 g (5.4 mmol) of 9-fluorenyl-
methyl chloroformate in CH2Cl2 was slowly added, after which the
cooling bath was removed and the mixture was stirred for 2 h. The
solution was washed with 1 N hydrochloric acid, water, and brine.
Evaporation of solvent after drying over anhydrous Na2SO4 leaves a
residue that upon recrystallization from CHCl3/CH3OH gave 1.3 g (77%
yield) of fine yellow needles: mp 94 °C; IR (CHCl3) 3024, 1696, 1455,
1431, 1283, 1239, 1215, 1116, and 1029 cm-1; 1H NMR (CDCl3) 7.31-
7.75 (m, 8 H, aromatic), 5.6-5.8 (br d, 2 H, HCCH), 4.41 (m, 2 H,
OCH2), 4.24 (m, 1 H, OCH2CH), 3.96 (br s, 2 H, NCH2CH), 3.56 (br
s, 2 H, NCH2CH2), and 2.15 (br s, 2 H, NCH2CH2) ppm; 13C NMR
(CDCl3) 174.69, 144.10, 141.31, 127.61, 126.99, 124.98, 119.93, 67.29,
47.37, 43.44, 40.57, 33.68, and 24.94 ppm; MS (LSIMS) m/z 306 (MH+,
100). Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59.
Found: C, 78.48; H, 6.35; N, 4.51.
N-FMOC-3,4-epoxypiperidine (6). To a solution of 300 mg (0.98
mmol) of N-FMOC-1,2,5,6-tetrahydropyridine in CH2Cl2 was added a
solution of 700 mg (3.2 mmol) of mCPBA in CH2Cl2 and 10 mL of
0.5 M NaHCO3. The reaction mixture was stirred for 18 h at ∼25 °C.
Excess peroxide was destroyed by the addition of a few drops of methyl
ethyl sulfide (starch-iodide paper test). The organic phase was washed
sequentially with aqueous NaHCO3, water, and brine and was then dried
over anhydrous Na2SO4. Solvent removal and purification by flash
chromatography on silica gel with hexane/ethyl acetate (6:4) gave 280
mg (89% yield) of crystalline material: mp 110 °C; IR (CHCl3) 3018,
1703 1481, 1450, 1431, 1339, 1289, 1252, 1215, 1110, 1055, 962, and
N-(4-p-Fluorophenyl-4-oxobutyl)-4-(p-chlorophenyl)-3,4-epoxypi-
peridine (3). To a solution of 138 mg (0.32 mmol) of N-FMOC-4-
(p-chlorophenyl)-3,4-epoxypiperidine in 1.5 mL of DMF was added
0.1 mL of piperidine. The solution was stirred for 0.5 h at ∼25 °C
before the solvent was removed on a rotary evaporator. The solid
residue was redissolved in 10 mL of DMF before 44 mg (0.32 mmol)
of K2CO3 and 93.4 mg (0.32 mmol) of 1-(4′-fluorophenyl)-4-iodobutane
were sequentially added. The reaction mixture was gently refluxed
for 0.5 h. The solvent was then evaporated, and the residue was
redissolved in CHCl3 and washed with 5% NaHCO3, water, and brine.
The solution was dried over anhydrous Na2SO4. Filtration and
evaporation of solvent gave a dark brown residue that, after flash
chromatography on silica gel with ethyl acetate, provided 76.8 mg (64%
yield) of the desired product: IR (neat) 3018, 2950, 1684, 1604, 1221,
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752 cm-1; H NMR (CDCl3) 7.2-7.8 (m, 8 H, aromatic), 4.41 (m, 2
H, OCH2), 4.24 (m, 1 H, OCH2CH), 3.70-4.00 (m, 2 H, NCHHCHO),
3.18-33.6 (m, 4 H, CH2NCHHCHOCH), and 1.8-2.2 (m, NCH2CH2)
ppm; 13C NMR (CDCl3) 155.28, 143.92, 141.27, 127.61, 126.98,
124.87, 119.90, 67.31, 50.44, 47.28, 42.39, 37.30, and 24.10 ppm; MS
(LSIMS) m/z (%) 322 (MH+, 35), 179 (99), 178 (100). Anal. Calcd
for C20H19NO3: C, 74.10; H, 5.96; N, 4.29. Found: C, 74.10; H, 5.98;
N, 4.29.
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1160, and 1098 cm-1; H NMR (CDCl3) 7.0-8.1 (m, 8 H, aromatic),
3.18 (m, 1 H, epoxide), 3.12 (m, 1 H, CHCHaxHeqN), 2.98 (t, 2 H,
NCH2CH2CH2CO), 2.55 (d, 1 H, J ) 11.2 Hz, CHCHaxHeqN), 2.3-
2.55 (m, 5 H, CHHCHHNCH2CH2CH2CO), 2.08 (m, 1 H, CHHCH2N),
and 1.95 (m, 2 H, NCH2CH2CH2CO) ppm; 13C NMR (CDCl3) 133.42,
130.57, 130.68, 128.46, 126.85, 115.76, 115.46, 60.54, 58.56, 56.98,
52.15, 46.52, 36.06, 29.07, and 21.56 ppm; MS (HREI) m/z (%) 373
(5), 356 (12), 235 (100), and 222 (52); HRMS for C21H21ClFNO2, calcd
373.1235, found 373.1245.
FMOC-4,5-epoxy-Leu Methyl Ester (7). A methanol solution of
FMOC-4,5-dehydro-Leu-OH (100 mg, 0.28 mmol) was treated with
an excess of diazomethane in ether. Evaporation of the solvent gave
a quantitative yield of the ester: 1H NMR (CDCl3) 7.25-7.7 (m, 8 H,
aromatic), 5.27 (d, 1 H, J ) 7.8 Hz, NH), 4.7-4.8 (d, 2 H, J ) 30 Hz,
vinyl H), 4.52 (m, 1 H, NHCHCOOH), 4.38 (d, 2 H, J ) 7.2 Hz,
CHCH2O), 4.22 (m, 1 H, J ) 7.2 Hz, CHCH2O), 3.74 (S, 3 H, OCH3),
2.55 (dd, 1 H, J ) 5.2 Hz, J ) 13.2 Hz, CHCHHC), 2.40 (dd, 1 H, J
) 8.3 Hz, J ) 13.2 Hz CHCHHC), and 1.75 (s, 3 H, -CH3) ppm; MS
(HREI) m/z (%) 365.2 (M+, 12), 178.1 (100). The crude FMOC-4,5-
4-(p-Chlorophenyl)-4-hydroxy-N-(4-ethenylbenzoyl)piperidine. To
a CH2Cl2 solution of 4-ethenylbenzoic acid (340 mg, 2.3 mmol) was
added 2.3 mmol of oxalyl chloride at 0 °C followed by a few drops of
(36) Olah, G. A.; Narang, S. C.; Field, L. D., Salem, G. F. J. Org. Chem.
1980, 45, 4792-4793.