7620 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Kahnberg et al.
7.78 (d, J ) 7.6 Hz, 2H), 7.60-7.62 (m, 2H), 7.41 (dd, J ) 7.5
Hz, 2H), 7.33 (dd, J ) 7.4 Hz, 2H), 5.91-5.93 (m, 1H), 5.27-
5.37 (m, 2H), 4.66 (br s, 2H), 4.41-4.42 (m, 3H), 4.24 (t, J ) 7.0
Hz, 1H), 2.35 (t, J ) 7.4 Hz, 2H), 1.86-1.88 (m, 1H), 1.63-1.70
(m, 3H), 1.26 ) 7-1.42 (m, 4H); 13C NMR (DMSO, 125 MHz) δ
179.1, 172.3, 155.9, 143.8, 143.7, 141.3, 131.4, 127.7, 127.0, 125.0,
119.9, 118.9, 67.0, 65.9, 53.8, 47.1, 33.7, 32.4, 28.5, 24.8, 24.3.
Coupling of Acid to Resin (12). Commercially available
N-Fmoc hydroxylamine 2-chlorotrityl resin (0.77 mmol/g, 7.54 g,
5.81 mmol) was shaken gently with 1:1 piperidine/DMF (20 mL)
overnight and then washed through with DMF 10 times. In a
separate flask, HATU (2.26 g, 6.10 mmol) was added to a solution
of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-octanedioic acid 1-al-
lyl ester (3.14 g, 7.0 mmol) and DIPEA (5.06 mL, 29.0 mmol)
dissolved in DMF (10 mL), and the resulting solution was stirred
gently for 10 min. The HATU-activated acid was then added in
one portion to the deprotected resin, and the resin was shaken gently
for 1 h. After washing the resin well with DMF, the resin loading
of 12 was determined to be 0.522 mmol/g (91%; LRMS m/e calcd
for C26H30N2O6 (MH+), 467.2; found, 467.2). The unreacted resin
was then acylated by addition of a solution of acetic anhydride
(842 mg, 7.8 mmol) and DIPEA (5.3 mL, 31.2 mmol) in DMF (20
mL) with shaking for 2 min, followed by thorough washing with
DMF.
Removal of the Allyl Ester: The resin was flow washed with
DCM for 2 min and then shaken in DCM (30 mL) for a further 10
min. A nitrogen stream was introduced, and the resin and DCM
were degassed for 5 min. DMBA (0.80 g, 5.12 mmol) was added,
and bubbling was continued for a further minute to ensure thorough
mixing. Pd(Ph3)4 (493 mg, 0.43 mmol) was added to the resin and
the flask was wrapped in aluminum foil, and after a further 30 s of
degassing, the nitrogen stream was removed, and the resin was
shaken gently for 1 h. The resin was flow washed successively
with DCM, DMF, and DCM before drying under high vacuum.
(LRMS m/e calcd for C23H26N2O6 (MH+), 427.2; found, 427.1).
Coupling of Amines General Procedure (13): The resin was
shaken in DMF for 10 min, and then DIPEA (5 equiv) and 0.5 M
HBTU in DMF (1.1 equiv) were introduced and shaking continued
for a further 5 min. The desired amine (1 equiv) was then added,
and shaking was continued for a further 1 h. After washing the
resin well with DMF, cleavage of a small portion of resin, and
analysis by mass spectroscopy generally indicated 40-85% conver-
sion to the amide. Repeating the coupling provides increased
conversion.
2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.4-1.3 (m, 4H); 13C NMR
(DMSO-d6, 75 MHz) δ 171.9, 169.1, 161.1, 139.5, 136.4, 131.3,
128.2, 127.0, 126.7, 123.4, 121.5, 119.7, 112.2, 109.5, 53.1, 42.0,
32.2, 31.6, 28.3, 25.5, 25.0; HRMS calcd for C29H33N3O4 (MH+),
488.2544; found, 488.2527.
1
Hydroxamic Acid 25. H NMR (acetone-d6, 500 MHz) δ 9.92
(s, 2H), 7.88 (d, J ) 8.5 Hz, 2H), 7.84 (d, J ) 6.5, Hz, 2H), 7.65
(d, J ) 8.5 Hz, 2H), 7.28 (m, 3H), 7.21 (m, 1H), 4.62 (m, 1H),
4.42 (d, J ) 6 Hz, 2H), 2.72 (s, 1H), 1.94 (m, 2H), 1.79 (m, 2H),
1.58 (m, 2H), 1.4-1.3 (m, 4H); 13C NMR (DMSO-d6, 75 MHz) δ
171.8, 169.1, 165.6, 139.5, 133.3, 131.2, 129.7, 128.2, 127.0, 126.7,
125.0, 53.7, 42.0, 32.2, 31.5, 28.3, 25.5, 25.0; HRMS calcd for
C22H26BrN3O4 (MH+), 476.1179; found, 476.1200.
1
Hydroxamic Acid 28. H NMR (acetone-d6, 500 MHz) δ 9.91
(s, 1H), 7.80 (s, 1H), 7.68 (m, 2H), 7.64 (d, J ) 7.5 Hz, 2H), 7.57
(d, J ) 8.2 Hz, 2H), 7.46-7.38 (m, 5H), 7.35-7.20 (5H), 4.44
(m, 1H), 4.37 (d, J ) 6.0 Hz, 2H), 3.62 (d, J ) 4.2 Hz, 2H), 1.81
(m, 2H), 1.62 (m, 2H), 1.53 (m, 2H), 1.30 (m, 4H); 13C NMR
(DMSO-d6, 75 MHz) δ 171.7, 170.0, 169.1, 140.0, 139.4, 138.2,
135.8, 129.6, 128.9, 128.2, 127.3, 127.0, 126.7, 127.1, 126.7, 126.5,
126.4, 52.6, 41.9, 41.7, 32.2, 32.1, 28.3, 25.1, 25.0; HRMS calcd
for C29H33N3O4 (MH+), 488.2544; found, 488.2527.
Hydroxamic Acid 31. 1H NMR (DMSO-d6, 600 MHz) δ 10.31
(s, 1H), 8.40 (s, 1H), 7.41 (d, J ) 8.1 Hz, 2H), 7.36-7.29 (m,
6H), 7.23 (d, J ) 7.5 Hz, 2H), 5.02 (d, J ) 3.5 Hz, 2H), 4.27 (dd,
J ) 5.6, 3.7 Hz, 2H), 3.97 (m 1H), 3.44 (br s, 1H), 1.91 (t, J ) 7.4
Hz, 2H), 1.69 (m, 1H), 1.56 (m, 1H), 1.45 (m, 2H), 1.31-1.23 (m,
4H); 13C NMR (DMSO-d6, 75 MHz) δ 172.0, 169.0, 168.1, 139.4,
137.1, 128.3, 128.2, 127.8, 127.7, 127.0, 127.7, 65.3, 54.7, 42.0,
32.2, 31.8, 28.3, 25.2, 25.0; HRMS calcd for C23H29N3O5 (MH+),
428.2180; found, 428.2209.
Hydroxamic Acid 32. 1H NMR (DMSO-d6, 600 MHz) δ 10.31
(s, 1H), 8.52 (t, J ) 7.2 Hz, 1H), 8.1 (d, J ) 8.1 Hz, 2H), 7.85 (d,
J ) 8.2 Hz, 2H), 7.64 (br s, 1H), 7.32-7.22 (m, 5H), 4.40 (m,
1H), 4.28 (d, J ) 7.2 Hz, 2H), 1.91 (t, J ) 7.5 Hz, 2H), 1.77 (m,
2H), 1.47 (m, 2H), 1.37-1.26 (m, 4H); 13C NMR (DMSO-d6, 75
MHz) δ 171.7, 169.0, 165.4, 139.5, 137.9, 128.5, 128.2, 127.0,
126.7, 125.2, 125.1, 53.8, 42.0, 32.2, 31.4, 28.3, 25.5, 25.0; HRMS
calcd for C23H26F3N3O4 (MH+), 466.1948; found, 466.1968.
Hydroxamic Acid 50. 1H NMR (DMSO-d6, 600 MHz) δ 10.31
(s, 1H), 8.25 (d, J ) 8.4 Hz, 1H), 8.16 (d, J ) 7.2 Hz, 1H), 7.35
(m, 2H), 7.29 (m, 2H), 7.13 (m, 3H), 5.03 (m, 2H), 4.94 (m, 1H),
3.97 (m, 1H), 2.71 (m, 2H), 1.91 (t, J ) 7.5 Hz, 2H), 1.84 (m,
2H), 1.69-1.54 (m, 4H), 1.45 (m, 2H), 1.31-1.23 (m, 4H); HRMS
calcd for C26H31N5O4 (MH+), 478.2456; found, 478.2449.
Hydroxamic Acid 51. 1H NMR (DMSO-d6, 600 MHz) δ 10.54
(s, 1H), 10.32 (s, 1H), 8.78 (d, J ) 4.3 Hz, 1H), 8.65 (m, 3H),
8.42 (dd, J ) 8.3, 1.6 Hz, 1H), 7.86 (d, J ) 9.0 Hz, 1H), 7.66 (dd,
J ) 8.3, 1.2 Hz, 1H), 7.60 (dd, J ) 8.3, 4.2 Hz, 1H), 7.58 (t, J )
8.0 Hz, 1H), 6.7 (d, J ) 9.0 Hz, 2H), 4.61 (m, 1H), 1.93 (t, J )
7.5 Hz, 2H), 1.49 (m, 2H), 1.48-1.45 (m, 2H), 1.31-1.23 (m, 4H);
HRMS calcd for C26H31N5O4 (MH+), 478.2456; found, 478.2449.
Hydroxamic Acid 52. 1H NMR (DMSO-d6, 600 MHz) δ 11.65
(s, 1H), 10.52 (s, 1H), 10.32 (s, 1H), 8.99 (d, J ) 7.4 Hz, 1H),
8.78 (m, 1H), 8.65 (dd, J ) 7.9, 1.1 Hz, 1H), 8.64 (s, 1H), 8.39
(dd, J ) 8.3, 1.6 Hz, 1H), 7.69-7.66 (m, 2H), 7.60-7.57 (m, 2H),
7.43 (d, J ) 8.3 Hz, 1H), 7.39 (s, 1H), 7.20 (t, J ) 7.9 Hz, 1H),
7.06 (t, J ) 7.8 Hz, 1H), 4.72 (m, 1H), 1.93 (t, J ) 7.3 Hz, 2H),
1.50 (m, 4H), 1.48-1.30 (m, 4H); 13C NMR (DMSO-d6, 125 MHz)
δ 170.8, 169.0, 161.7, 148.8, 137.8, 136.5, 133.9, 130.8, 127.7,
126.9, 126.9, 123.5, 122.1 121.9, 121.6, 119.7, 116.0, 112.2, 107.5,
103.7, 54.5, 32.2, 30.6, 28.3, 25.5, 24.9; HRMS calcd for
C26H27N5O4 (MH+), 474.2148; found, 474.2136.
Coupling of Acids General Procedure (14): The resin was
shaken in DMF for 10 min, the DMF removed, and then 1:1
piperidine/DMF added. After shaking for 5 min, the piperidine/
DMF was removed, and the resin was washed well with DMF.
This procedure was repeated two more times. In a separate flask,
0.5 M HBTU (4 equiv) in DMF was added to a solution of the
desired acid (4 equiv) and DIPEA (16 equiv) in DMF (1 mL), and
the resulting solution was stirred for 5 min before being added in
one portion to the resin. The resin was shaken for 1 h, and then
washed well with DMF. Cleavage of a small portion of resin and
analysis by mass spectroscopy generally indicates 100% conversion
to the amide.
General Procedure for Cleavage of the Product from Resin:
The resin was washed well with DCM and then drained. TFA/
DCM (95:5) with a drop of water (per 50 mL) was added, and the
resin was shaken for 20 min. The TFA was collected, and the
procedure was repeated 1-2 more times. The solvent was removed
by evaporation. Purification was performed by rpHPLC, and
hydroxamates were confirmed to be greater than 95% pure by
1
Hydroxamic Acid 53. 1H NMR (DMSO-d6, 600 MHz) δ 10.46
(s, 1H), 10.31 (s, 1H), 8.86 (dd, J ) 4.3, 1.7 Hz, 1H), 8.64 (dd, J
) 7.7, 1.3 Hz, 1H), 8.41 (dd, J ) 8.3, 1.7 Hz, 1H), 8.31 (dd, J )
8.5, 3.6 Hz, 1H), 7.69 (dd, J ) 8.3, 1.3 Hz, 1H), 7.59-7.55 (m,
2H), 7.50 (d, J ) 15.8 Hz, 1H), 7.65 (dd, J ) 8.3, 4.2 Hz, 1H),
7.59 (t, J ) 8.0 Hz, 1H), 7.44-7.7.39 (m, 3H), 6.84 (d, J ) 15.8
Hz, 1H), 4.11 (m, 1H), 1.93 (t, J ) 7.5 Hz, 2H), 1.64-1.58 (m,
2H), 1.46 (m, 2H), 1.34-1.27 (m, 4H); 13C NMR (DMSO-d6, 125
analytical rpHPLC and H NMR spectroscopy. All hydroxamic
acids displayed high field 1H NMR spectral and HRMS parameters
consistent with their proposed structures, with nine relevant
examples shown.
Hydroxamic Acid 24. 1H NMR (acetone-d6, 500 MHz) δ 10.76
(s, 2H), 9.93 (s, 1H), 7.87 (t, J ) 6.0 Hz, 1H), 7.81 (d, J ) 8.0 Hz,
1H), 7.61 (d, J ) 8.0 Hz, 1H), 7.3-7.1 (m, 5H), 7.06 (t, J ) 8 Hz,
1H), 4.64 (m, 1H), 4.42 (d, J ) 6 Hz, 2H), 4.39 (s, 1H), 1.96 (m,