3440 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18
Moore et al.
[[4(S)-[(N-ter t-Bu toxycar bon yl)am in o]-2,2-diflu or o-3(R)-
h ydr oxypen tan oyl]-L-valyl]-L-isoleu cin e ben zyl ester (4g):
68%; 1H NMR (CDCl3) δ 0.86 (6H, m), 1.00 (6H, m), 1.30 (3H,
d), 1.46 (9H, s), 2.30 (1H, br), 3.71 (1H, br), 4.02 (2H, m), 4.36
(1H, dd), 4.69 (1H, dd), 5.16 (3H, q), 7.09 (1H, br), 7.36 (5H,
m), 7.46 (1H, br).
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
fluoro-5-cyclohexyl-3(R)-hydroxypentanoyl]-L-valyl]-L-isoleu-
cin e m eth yl ester (5e): 88%; mp 164-165 °C; 1H NMR
(CDCl3) δ 0.78-1.27 (26H, m), 1.46 (9H, s), 1.61-2.01 (9H,
m), 2.28 (1H, m), 3.20 (1H, br), 3.60 (1H, dd J ) 9 and 9 Hz),
3.78 (3H, s), 4.12 (2H, br dd J ) 9 and 9 Hz), 4.64 (1H, dd J
) 9 and 9 Hz), 5.04 (1H, d J ) 9 Hz), 6.33 (1H, d J ) 11 Hz),
6.66 (1H, d J ) 9 Hz), 8.21 (1H, d J ) 7 Hz), 8.34 (1H, d J )
8 Hz); MS m/z 700 (M+ + Na+). Anal. (C33H58F2N4O8) C,H,N.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-3(R)-h yd r oxyp en ta n oyl]-L-va lyl]-L-isoleu cin e eth -
yl ester (5f): 87%; 1H NMR (CDCl3) δ 1.02 (18 H, m), 1.32 (2
H,m), 1.41 (3H, d J ) 7.0 Hz), 1.45 (9H, s), 1.90 (1H, m), 2.26
(1H, m), 3.28 (1H, m), 3.60 (1H, dd J ) 9.0 Hz), 4.11 (1H, m),
4.25 (2H, m), 4.67 (1H, dd J ) 9.0 Hz), 5.03 (1H, d J ) 9.0
Hz), 6.33 (1H, d J ) 10.9 Hz), 6.67 (1H, d J ) 8.9 Hz), 8.26
(1H, d J ) 6.3 Hz), 8.39 (1H, d J ) 6.7 Hz).
[[4(S)-[(N-ter t-Bu toxycar bon yl)am in o]-2,2-diflu or o-3(R)-
h yd r oxyp en ta n oyl]-L-va lyl]-L-isoleu cin e d im eth yla m id e
(4i): 68%; 1H NMR (CDCl3) δ 0.89 (6H, m), 1.00 (6H, m), 1.36
(3H, d J ) 6.7 Hz), 1.46 (9H, s), 1.67 (3H, br), 1.80 (1H, m),
2.06 (1H, s), 2.35 (1H, m), 2.97 (3H, s), 3.15 (3H, s), 4.04 (2H,
m), 4.29 (1H, m), 4.87 (1H, dd J ) 7.4 Hz), 5.21 (1H, d J ) 8.7
Hz), 7.23 (1H, br), 7.35 (1H, br).
[[4(S)-[(N-ter t-Bu toxyca r bon yl)a m in o]-2,2-d iflu or o-5-
cycloh e xyl-3(R )-h yd r oxyp e n t a n oyl]-L-va lyl]-L-isole u -
cin e ben zyl ester (4j): mp 60-61 °C; 84%; 1H NMR (CDCl3)
δ 0.80-0.92 (6H, m), 0.93-1.02 (6H, dd J ) 6.6 and 6.6 Hz),
1.03-1.35 (11 H, m), 1.44 (9H,s), 1.92 (2 H, m), 2.22 (1H, m),
3.74 (1H, br), 4.04 (1H, dd J ) 14 and 13 Hz), 4.24 (1H, dd J
) 9 and 8 Hz), 4.64 (1H, dd J ) 9 and 9 Hz), 5.11 (1H, d 12
Hz), 5.22 (1H, d 12 Hz), 6.53 (1H, d J ) 8 Hz), 7.16 (1H, br),
7.35 (5H, m); MS m/z 677 (M+ + Na+). Anal. (C34H53F2N3O7)
C,H,N.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-3(R)-h yd r oxyp en ta n oyl]-L-va lyl]-L-isoleu cin e ben -
1
zyl ester (5g): 84%; H NMR (CDCl3) δ 0.94 (16H, m), 1.09
(2H, d J ) 6.5 Hz), 1.39 (3H, d J ) 7.0 Hz), 1.45 (9H, s), 1.91
(3H, br), 2.28 (1H, br), 3.26 (1H, br), 3.58 (1H, t), 4.08 (2H,
m), 4.74 (1H, dd), 5.03 (1H, d), 5.20 (2H, q J ) 15 Hz), 6.29
(1H, br), 6.66 (1H, d), 7.38 (5H, m), 8.18 (1H, d), 8.37 (1H, d).
Gen er a l Meth od Tow a r d Com p ou n d s 5. Compounds of
general structure 4 were deprotected using TFA/CH2Cl2 1:1
at ambient temperature for 1 h. The TFA/CH2Cl2 layer was
evaporated, and the residue was partitioned between CH2Cl2
and saturated NaHCO3 solution. The aqueous layer was
extracted with additional CH2Cl2. The organic layers were
combined, dried over Na2SO4, and concentrated. To a 0.5 M
solution of the free amine in CH2Cl2 were added N-Boc-L-valine
(1.25 equiv), HOBT (1.4 equiv) and EDC (1.4 equiv). After
overnight reaction, the mixture was diluted with more CH2-
Cl2, washed with 4× saturated NaHCO3 solution, dried over
Na2SO4, filtered, and concentrated. Column chromatography
with either ethyl acetate/hexanes 2:1 or CH2Cl2/MeOH 99:1
provided purified products.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-3(R)-h yd r oxyp en ta n oyl]-L-va lyl]-L-isoleu cin e Me-
th yla m id e (5h ). To a 0 °C solution of methyl ester 5a (85
mg, 0.143 mmol) in 16 mL MeOH was bubbled in methylamine
to saturation. After overnight reaction at ambient tempera-
ture, 5h had precipitated from the solution and was isolated
by filtration: 80%; 1H NMR (CDCl3) δ 0.96 (18 H, m), 1.85
(2H, m), 1.18 (2H, m), 1.40 (3H, d J ) 7 Hz), 1.47 (9H, s), 2.21
(1H, m), 2.84 (3H, d J ) 4.7 Hz), 3.38 (1 H, br), 3.83 (1H, m),
4.18 (3H, m), 5.07 (1H, d J ) 8.7 Hz), 5.90 (1H, br), 6.41 (1H,
br), 7.31 (1H, br), 7.94 (1H, br), 8.48 (1H, br).
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-3-h yd r oxyp en ta n oyl]-L-va lyl]-L-isoleu cin e d im e-
th yla m id e (5i): 29% (purified by filtration from CH2Cl2); 1H
NMR (CDCl3) δ 0.90 (8H, m), 1.02 (12H, m), 1.39 (3H, d J )
7.0 Hz), 1.46 (9H, s), 1.83 (3H, m), 2.06 (1H, s), 2.20 (1H, m),
2.98 (3H, s), 3.22 (3H, s), 3.62 (1H, m), 3.91 (1H, dd J ) 9.4
Hz), 4.28 (1H, dd J ) 9.2 Hz), 4.81 (1H, dd J ) 8.3 Hz), 5.07
(1H, d J ) 9.1 Hz), 5.32, 6.59 (1 H, d J ) 11.1 Hz), 7.35 (1H,
d J ) 8.5 Hz), 7.96 (1H, d J ) 8.3 Hz), 8.78 (1H, d J ) 5.8 Hz).
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
fluoro-5-cyclohexyl-3(R)-hydroxypentanoyl]-L-valyl]-L-isoleu-
cin e ben zyl ester (5j): mp 140-141 °C; 87%; 1H NMR
(CDCl3) δ 0.75-1.04 (26H, m), 1.42 (9H, s), 1.59-1.77 (7H,
m), 1.85 (3H, br), 2.21 (1H, br), 3.15 (1H, br), 3.55 (1H, dd J )
9 and 9 Hz), 4.09 (2H, br), 4.64 (1H, dd J ) 9 and 9 Hz), 5.00
(1H, d J ) 9 Hz), 5.13 (1H, m), 5.21 (1H, m), 6.28 (1H, d J )
11 Hz), 6.57 (1H, d J ) 9 Hz), 7.34 (5H, m), 8.17 (1H, d J ) 7
Hz), 8.35 (1H, d J ) 7 Hz); MS m/z 776 (M+ + Na+). Anal.
(C39H62F2N4O8) C,H,N.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-3(R)-h ydr oxypen tan oyl]-L-valyl]-L-isoleu cin e m eth -
yl ester (5a ): 81%; mp 142 °C; 1H NMR (CDCl3) δ 1.01 (18H,
m aliphatic H, 1.41 (3H, d J ) 7.1 Hz), 1.46 (9H, s), 1.92 (2H,
m), 2.29 (1H, m), 3.29 (1H, m), 3.59 (1H, m), 3.79 (3H, s), 4.13
(2H, m), 4.70 (1H, dd J ) 5.5 and 3.4 Hz), 5.01 (1H, br), 6.30
(1H, br), 6.68 (1H, br), 8.21 (1H, br), 8.36 (1H, br); MS (MALDI-
TOF) m/z 617 (M + Na). Anal. (C27H48F2N4O8‚H2O) C,H,N.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-5-m eth yl-3(R)-h yd r oxyh exa n oyl]-L-va lyl]-L-isoleu -
cin e m eth yl ester (5b): 88%; mp 90-91 °C; 1H NMR (CDCl3)
δ 0.87-1.11 (25H, m), 1.45 (9H, s), 1.98 (2H, m), 2.27 (1H, m),
2.46 (1H, m), 2.62 (1H, m), 3.73 (1H, br), 3.75 (1H, s), 4.18-
4.39 (3H, br), 4.66 (1H, dd J ) 8 and 9 Hz), 5.44 (1H, d J ) 9
Hz), 6.35 (1H, br), 7.40 (1H, d J ) 8 Hz), 8.25 (1H, d J ) 7
Hz), 8.46 (1H, d J ) 8 Hz); Anal. (C29H52F2N4O8) C,H,N.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-5-ph en yl-3(R)-h ydr oxypen tan oyl]-L-valyl]-L-isoleu -
cin e m eth yl ester (5c): 72%; mp 159-161 °C; 1H NMR
(CDCl3) δ 0.80 (6H, m), 0.91 (6H, m), 1.05 (6H, m), 1.18 (2H,
m), 1.45 (9H, s), 2.00 (2H,m), 2.33 (1H, m), 3.20 (2H, br), 3.74
(3H, s), 3.78 (1H, br), 3.90 (1H, br), 4.24 (1H, br), 4.38 (2H,
br), 4.63 (1H, m), 4.84 (1H, br), 6.73 (2H, br), 7.21 (5H, m),
7.44 (1H, br); MS m/z 694 (M+ + Na+). Anal. (C33H52F2N4O8‚
H2O) C,H,N.
Gen er a l P r oced u r e for Oxid a tion of Diflu or o Alcoh ols
5 to Diflu or o Keton es 6. To a stirred solution of difluoro
alcohol 5 in CH2Cl2 (10 mM) was added 7 equiv of Dess-
Martin periodinane. After 3 h, the reaction mixture was added
to Na2S2O3 (49 equiv based on 5) in saturated NaHCO3
solution. After an additional 10 min, the mixture was parti-
tioned between Et2O and saturated NaHCO3 solution. The
organic layer was washed several times with saturated aque-
ous NaHCO3, dried over MgSO4, filtered, and concentrated to
give difluoro ketones 6. Further purification was usually not
necessary. However, if needed, purification was accomplished
by either recrystallization from ether/pentane or column
chromatography with ethyl acetate/hexanes 2:1 or CH2Cl2/
MeOH 99:1.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
fluoro-5(S)-methyl-3(R)-hydroxyheptanoyl]-L-valyl]-L-isoleu-
cin e m eth yl ester (5d ): 74%; mp 153-155 °C; 1H NMR
(CDCl3) δ 0.77-1.29 (24 H, m), 1.46 (9H, s), 1.67 (1H, m), 1.90
(3H, br), 2.26 (3H, br), 2.65 (1H, br), 3.67 (1H, dd J ) 9 and 9
Hz), 3.78 (3H, s), 4.11 (1H, dd J ) 9 and 9 Hz), 4.36 (2H, br),
4.66 (1H, dd J ) 8 and 9 Hz), 5.07 (1H, d J ) 9 Hz), 6.42 (1H,
d J ) 11 Hz), 6.71 (1H, d J ) 9 Hz), 8.22 (1H, d J ) 6 Hz),
8.42 (1H, d J ) 8 Hz); MS m/z 660 (M+ + Na+). Anal.
(C30H54F2N4O8) C,H,N.
[4(S)-[[(N-ter t-Bu t oxyca r b on yl)-L-va lyl]a m in o-2,2-d i-
flu or o-3-oxop en ta n oyl]-L-va lyl]-L-isoleu cin e m eth yl es-
1
ter (6a ): 86%; mp 75 °C; H NMR (CDCl3) δ 0.85 (18 H, m),
1.26 (3H, d J ) 7.1 Hz), 1.38 (9H, s), 1.78 (1H, m), 1.90 (1H,
m), 2.07 (1H, m), 3.62 (3H, s), 3.82 (1H, dd), 4.22 (1H, m), 4.72