4960 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 26
Natchus et al.
8.3, 8.3 Hz, 1H), 2.90-3.02 (m, 1H), 3.61 (dd, J ) 8.1, 7.0 Hz,
1H), 3.98 (d, J ) 9.2 Hz, 1H), 7.12-7.21 (m, 2H), 7.29 (dd, J
) 7.3, 7.3 Hz, 1H), 7.49 (dd, 7.7, 7.7 Hz, 2H), 7.85 (dd, J )
8.8, 1.5 Hz, 2H), 8.97 (s, 1H), 10.70 (s, 1H). ESI MS: m/z (rel
intensity) 446.1 ([M + H]+, 100). Analysis: C, H, N for
synthetic sequence described for compound 48 and recrystal-
lized from EtOAC:methanol to white crystals. 1H NMR:
(DMSO-d6, 300 MHz) δ 1.62 (ddd, J ) 12.6, 9.3, 9.3 Hz, 1H),
1.91-1.99 (m, 1H), 2.72-2.78 (m, 4H), 2.83 (dd, J ) 8.4, 8.4
Hz, 1H), 2.94-2.99 (m, 4H), 3.29-3.39 (m, 1H), 3.62 (dd, J )
8.8, 7.2 Hz, 1H), 3.88 (s, 3H), 3.99 (dd, J ) 9.0, 2.4 Hz, 1H),
7.16 (br d, J ) 8.6 Hz, 2H), 7.82 (ddd, J ) 8.6 Hz, 2H), 9.00 (s,
1H), 10.71 (s, 1H). ESI MS: m/z (rel intensity) 434.0 ([M +
H]+, 100), 456.0 ([M + Na]+, 32). Analysis: C, H, N for
C
22H27N3O5S‚0.3H2O.
1N-(4-Meth oxyp h en ylsu lfon yl)-2(R)-N-h yd r oxyca r box-
a m id o-4(S)-(m or p h olin -1N-yl)p yr r olid in e (48). The start-
ing methyl ester 10 (310 mg, 0.86 mmol) was treated with
NH2OK (2 mL, 1.25 M in methalol) in 4 mL of methanol and
stirred overnight at room temperature. The material was then
condensed and partitioned between EtOAC and dilute NaH-
CO3. The organic layer was then dried over MgSO4, filtered
and evaporated. The residue was adsorbed onto silica and
eluted through a flash silica column with EtOAC:MeOH (1:0
to 4:1) to give 205 mg (66%) of material which was puffed to
C
16H23N3O7S2.
1N-(4-n -Bu t oxyb en zen esu lfon yl)-2(R)-N-h yd r oxyca r -
b oxa m id o-4(S)-(4,4-d ioxyt h iom or p h olin -1N-yl)p yr r oli-
d in e (54). The compound was prepared according to the
synthetic sequence described for compound 48 to give material
which was puffed to a white solid under vacuum and not
1
recrystallized. H NMR: (DMSO-d6, 300 MHz) δ 0.96 (t, J )
1
a white solid under vacuum and not recrystallized. H NMR:
7.3 Hz, 3H), 1.39-1.53 (m, 2H), 1.55-1.67 (m1H), 1.69-1.79
(m, 2H), 1.89-2.00 (m, 1H), 2.72-2.87 (m, 5H), 2.93-3.03 (m,
4H), 3.30-3.40 (m, 1H), 3.61 (dd, J ) 8.6, 6.2 Hz, 1H), 3.99
(br d, J ) 7.0 Hz), 4.09 (t, J ) 6.4 Hz, 2), 7.15 (br d, J ) 8.6
Hz, 2H), 7.79 (br d, J ) 8.6 Hz, 2H). ESI MS: m/z (rel
intensity) 476.1 ([M + H]+, 100), 498.1 ([M + Na]+, 22).
Analysis: C, H, N for C19H29N3O6S2.
(DMSO-d6, 300 MHz) δ 1.53 (ddd, J ) 12.5, 8.8, 8.8 Hz, 1H),
1.88-1.96 (m, 1H), 2.17-2.31 (m, 4H), 2.78 (dd, J ) 8.4, 8.4
Hz, 1H), 2.90-3.00 (m, 1H), 3.41-3.46 (m, 4H), 3.59 (dd, J )
9.0, 6.4 Hz, 1H), 3.88 (s, 3H), 3.98 (d, J ) 6.78 Hz, 1H), 7.16
(br d, J ) 9.0 Hz, 2H), 7.81 (br d, J ) 9.0 Hz, 2H). ESI MS:
m/z (rel intensity) 408.1 ([M + NH4]+, 7), 386.1 ([M + H]+,
100). Analysis: C, H, N for C16H23N3O6S‚0.6H2O.
1N-(4-n -P r op oxyben zen esu lfon yl)-2(R)-N-h yd r oxyca r -
boxa m id o-4(S)-(1-p yr r olid in -1N-yl)p yr r olid in e (55). The
compound was prepared according to the synthetic sequence
described for compound 57 to give a white solid. 1H NMR:
(DMSO-d6, 300 MHz) δ 0.99 (t, J ) 7.3 Hz, 3H), 1.46-1.56
(m, 4H), 1.63 (ddd, J ) 12.1, 8.4, 8.4 hz, 1H), 1.69-1.82 (m,
2H), 1.88 (ddd, J ) 13.1, 4.0, 4.0 Hz, 1H), 2.25-2.34 (m, 4H),
2.76-2.70 (m, 2H), 3.46-3.55 (m, 1H), 3.96 (dd, J ) 8.4, 4.0
Hz, 1H), 4.03 (t, J ) 6.4 Hz, 2H), 7.12 (d, J ) 8.8 Hz, 2H),
7.78 (d, J ) 8.8 Hz, 2H), 8.97 (br s, 1H), 10.69 (s, 1H). ESI
MS: m/z (rel intensity) 398.1 ([M + H]+, 100). Analysis: C,
H, N for C18H27N3O5S‚0.2H2O.
1N-(4-Flu or oph en oxyben zen esu lfon yl)-2(R)-N-h ydr oxy-
ca r boxa m id o-4(S)-(p yr r olid in -1N-yl)p yr r olid in e (56). The
compound was prepared according to the synthetic sequence
described for compound 57. 1H NMR: (DMSO-d6, 300 MHz) δ
1.48-1.58 (m, 4H), 1.73 (ddd, J ) 12.5, 7.9, 7.9 Hz, 1H), 1.91
(ddd, J ) 12.5, 4.9 Hz, 1H), 2.18-2.36 (m, 4H), 2.80-2.88 (m,
1H), 2.95 (dd, J ) 9.3, 6.4 Hz, 1H), 3.53 (dd, J ) 9.2, 5.3 Hz,
1H), 3.98 (dd, J ) 8.2, 4.4 Hz, 1H), 7.13 (d, J ) 8.4 Hz, 2H),
7.23 (dd, J ) 8.2, 4.8 Hz, 2H), 7.33 (dd, J ) 8.2, 8.2 Hz, 2H),
7.85 (d, J ) 7.84 Hz, 2H), 8.97 (s, 1H), 10.71 (s, 1H). ESI MS:
m/z (rel intensity) 449.9 ([M + H]+, 100). Analysis: C, H, N
for C21H24FN3O5S‚0.4H2O.
1N-(4-n -P r op oxyben zen esu lfon yl)-2(R)-N-h yd r oxyca r -
boxa m id o-4(S)-(m or p h olin -1N-yl)p yr r olid in e (49). The
compound was prepared according to the synthetic sequence
1
described for compound 48. H NMR: (DMSO-d6, 300 MHz) δ
1.01 (t, J ) 7.3 Hz, 3H), 1.55 (ddd, J ) 12.6, 6.1, 6.1 Hz,
1H),1.72-1.84 (m, 2H),), 1.93 (ddd, J ) 12.5, 6.6, 2.4 Hz, 1H),
2.17-2.32 (m 4H), 2.78 (dd, J ) 8.5, 8.5, Hz, 1H), 2.89-3.00
(m, 1H), 3.41-3.48 (m, 4H), 3.60 (dd, J ) 8.8, 6.2 Hz, 1H),
3.97 (dd, J ) 8.8, 2.2 Hz, 1H), 4.06 (t, J ) 6.6 Hz, 2H), 7.16 (d,
J ) 9.0 Hz, 2h), 7.79 (d, J ) 9.0 Hz, 2H), 8.98 (d, J ) 1.5 Hz,
1H), 10.71 (d J ) 1.5 Hz, 1H). ESI MS: m/z (rel intensity)
414.1 ([M + H]+, 100). Analysis: C,H,N for C18H27N3O6S.
1N-(4-n -Bu t oxyb en zen esu lfon yl)-2(R)-N-h yd r oxyca r -
boxa m id o-4(S)-(m or p h olin -1N-yl)p yr r olid in e (50). The
compound was prepared according to the synthetic sequence
described for compound 48 to give material which was puffed
to a white solid under vacuum and not recrystallized. 1H
NMR: (DMSO-d6, 300 MHz) δ 0.96 (t, J ) 7.4 Hz, 3H), 1.39-
1.59 (m, 3H), 1.69-1.77 (m, 2H), 1.87-1.95 (m, 1H), 2.16-
2.31 (m, 4H), 2.77 (dd, J ) 8.4, 8.4 Hz, 1H), 2.89-3.00 (m,
1H), 3.40-3.46 (m, 4H), 3.58 (dd, J ) 8.6, 6.0 Hz, 1H), 3.97
(dd, J ) 8.5, 2.5 Hz, 1H), 4.08 (t, J ) 6.4 Hz, 2H), 7.14 (br d,
J ) 8.8 Hz, 2H), 7.78 (br d, J ) 8.9 Hz, 2H). ESI MS: m/z (rel
intensity) 428.08 ([M + H]+, 100), 450.07 ([M + Na]+, 8), 465.99
([M + K]+, 15). Analysis: C, H, N for C19H29N3O6S‚0.1H2O.
1N-(4-n -P en t ylb en zen esu lfon yl)-2(R)-N-h yd r oxyca r -
boxa m id o-4(S)-(m or p h olin -1N-yl)p yr r olid in e (51). The
compound was prepared according to the synthetic sequence
described for compound 48. 1H NMR: (DMSO-d6, 300 MHz) δ
0.87 (t, J ) 6.3 Hz, 3H), 1.22-1.37 (m, 4H), 1.49-1.67 (m, 3H),
1.91 (br d, J ) 12.5 Hz, 1H), 2.14-2.29 (m, 4H), 2.69 (dd, J )
7.5, 7.5 Hz, 1H), 2.80-2.99 (m, 2H), 3.36-3.44 (m, 4H), 3.60
(dd, J ) 8.2, 6.2 Hz, 1H), 3.98 (d, J ) 7.3 Hz, 1H), 7.46 (d, J
) 7.2 Hz, 2H), 7.77 (d, J ) 7.0 Hz, 2H), 8.98 (s, 1H), 10.71 (s,
1H). ESI MS: m/z (rel intensity) 426.1 ([M + H]+, 100).
Analysis: C, H, N for C20H31N3O5S.
1N-(4-P h en yloxyben zen esu lfon yl)-2(R)-N-h yd r oxyca r -
boxa m id o-4(S)-(p yr r olid in -1N-yl)p yr r olid in e (57). The
starting methyl ester 16 (752 mg, 1.75 mmol) was converted
to the title hydroxamic acid as described for compound 48 and
purified by recrystallizing from EtOAc:MeOH (∼10:1) to give
320 mg (43%) of white powder. 1H NMR: (DMSO-d6, 300 MHz)
δ 1.50-1.58 (m, 4H), 1.69-1.80 (m, 1H), 1.87-1.75 (m, 1H),
2.19-2.37 (m, 4H), 2.80-2.90 (m, 1H), 2.76 (dd, J ) 9.3, 6.2
Hz, 1H), 3.53 (dd, J ) 9.5, 6.2 Hz, 1H), 3.88 (dd, J ) 7.7, 4.8
Hz, 1H), 7.10-7.19 (m, 4H), 7.29 (ddd, J ) 7.3, 7.3, 1.3 Hz,
1H), 7.50 (dd, J ) 7.1, 7.1 Hz, 2H), 7.86 (dd, J ) 8.6, 1.7 Hz,
2H), 8.99 (br s, 1H), 10.71 (br s, 1H). ESI MS: m/z (rel
intensity) 432.2 ([M + H]+, 100). Analysis: C, H, N for
C
21H25N3O5S‚0.2H2O.
1N-(4-P h en yloxyben zen esu lfon yl)-2(R)-N-h yd r oxyca r -
boxa m id o-4(S)-(m or p h olin -1N-yl)p yr r olid in e (52). The
compound was prepared according to the synthetic sequence
described for compound 48. 1H NMR: (DMSO-d6, 300 MHz) δ
1.57-1.72 (m, 1H), 1.87-1.98 (m, 1H), 2.16-2.34 (m, 4H),
2.82-3.00 (m, 2H), 3.38-3.50 (m, 4H), 3.56-3.64 (m, 1H),
3.94-4.01 (m, 1H), 7.11-7.20 (m, 4H), 7.28 (ddd, J ) 6.9, 6.9,
0.9 Hz, 1H), 7.49 (ddd, J ) 7.6, 7.6, 1.1 Hz, 1H), 7.86 (dd, J )
8.6 Hz, 2H), 8.99 (s, 1H), 10.71 (s, 1H). ESI MS: m/z (rel
intensity) 448.0 ([M + H]+, 100). Analysis: C, H, N for
1N-(4-Met h oxyb en zen esu lfon yl)-2(R)-N-h yd r oxyca r -
b oxa m id o-4(S)-(γ-su lt a m -1N-yl)p yr r olid in e (58). Com-
pound 24 was prepared as described for compound 23 to give
a white solid. 1H NMR: (DMSO-d6, 300 MHz) δ 1.83-2.17 (m,
4H), 2.91-3.03 (m, 2H), 3.06 (dd, J ) 9.5, 8.1 Hz, 1H), 3.12-
3.22 (m, 2H), 2.79-3.89 (m, 2H), 3.59 (dd, J ) 9.7, 6.8 Hz,
1H), 3.87 (s, 3H), 3.92-4.03 (m, 1H), 4.05 (dd, J ) 8.4, 2.7 Hz,
1H), 7.17 (br d, J ) 9.0 Hz, 2H), 7.82 (br d, J ) 9.0 Hz, 2H),
9.02 (s, 1H), 10.81 (s, 1H). ESI MS: m/z (rel intensity) 420.0
([M + H]+, 100), 437 ([M + NH4]+, 20). Analysis: C, H, N for
C
19H29N3O6S‚0.2H2O.
C
15H21N3O7S2.
1N-(4-Met h oxyb en zen esu lfon yl)-(2R )-N-h yd r oxyca r -
b oxa m id o-4(S)-(4,4-d ioxyt h iom or p h olin -1N-yl)p yr r oli-
d in e (53). The compound was prepared according to the
1N-(4-n -P r op oxyben zen esu lfon yl)-2(R)-N-h yd r oxyca r -
b oxa m id o-4(S)-(γ-su lt a m -1N-yl)p yr r olid in e (59). Com-