Synthesis of Pantocin B Analogues
J. Am. Chem. Soc., Vol. 123, No. 41, 2001 9943
172.97; IR (Nujol mull) 3352, 3302, 1710, 1646, 1538 cm-1; HRMS-
FAB+ (C24H30N3O6S, M+ + 1) Calcd: 488.1855 found: 488.1860.
170.89, 172.69; IR (Nujol mull) 3314, 1710, 1700, 1646, 1532, 1304
cm-1; HRMSFAB+ (C24H30N3O6S, M+ + 1) Calcd: 488.1855 found:
488.1860.
N-[(2-R-Benzyloxycarbonylamino-3-methylpentanoylamino)me-
thyl] 2-R-methanesulfanyl succinamic benzyl ester (14h): 88 mg
(0.27 mmol) of 8h, 15 mL of dichloromethane, 71 mg (0.27 mmol) of
13a, 6 mL of dichloromethane, 62 mg (0.32 mmol) of EDAC, 60 mg
(0.35 mmol) of HOBT, 50 µL (0.40 mmol) of N-ethylmorpholine; yield
93 mg (66%) of a white solid; mp ) 164-165 °C. 1H NMR (400 MHz,
DMSO-d6, partial data) δ 0.78 (m, 6 H), 1.07 (m, 1 H), 1.38 (m, 1 H),
1.66 (m, 1 H), 2.05 (s, 3 H), 2.74 (dd, 1 H, J ) 6.8, 9.4 Hz), 3.62 (dd,
1 H, J ) 5.8, 9.4 Hz), 3.87 (t, 1 H, J ) 8.0 Hz), 4.37 (m, 2 H), 5.01
(ab quart, 2 H, J ) 12.8, 4.0 Hz), 5.13 (q, 2 H, J ) 12.7 Hz), 7.24 (d,
1 H, J ) 9.2 Hz), 7.35 (m, 10 H), 8.53 (t, 1 H, J ) 5.9 Hz), 8.79 (t,
1 H, J ) 5.9 Hz); 13C NMR (100 MHz, DMSO-d6) δ 10.89, 13.36,
15.26, 24.29, 36.19, 36.48, 42.18, 43.09, 58.88, 65.35, 65.86, 127.64,
127.70, 127.98, 128.29, 128.38, 136.01, 137.03, 155.90, 169.52, 170.87,
171.79; IR (Nujol mull) 3310, 1731, 1650, 1543, 1162 cm-1; HRMS-
FAB+ (C27H36N3O6S, M+ + 1) Calcd: 530.2326 found: 530.2325.
Scheme A: General Procedure to Synthesize Sulfone (15). In a
dried flask under argon, 1 equiv of 14 was suspended in anhydrous
dichloromethane. The suspension was chilled to approximately 0 °C.
In a second dried flask under argon 2.2 equiv of m-chloroperbenzoic
acid (mCPBA) was dissolved in anhydrous dichloromethane. The
solution of mCPBA was added in portions to the suspension of 14.
The reaction mixture was stirred for 3-4 h at 0 °C. When the oxidation
was complete, 2-4 mL of a saturated sodium thiosulfate solution was
added to the reaction mixture to quench the residual mCPBA. The
reaction mixture was then stirred vigorously for 10-20 min at which
time the reaction mixture was partitioned between dIH2O and chloro-
form. The organics were washed three times with saturated aqueous
NaHCO3 solution and one time with brine. The organics were then
dried over MgSO4 and concentrated under partial vacuum. The resultant
solid was dried in vacuo to give the sulfone 15 cleanly.
N-[(2-S-Benzyloxycarbonylamino-3-phenylpropanoylamino)me-
thyl] 2-methanesulfonyl succinamic acid benzyl ester (15c): 403
mg (0.700 mmol) of 14c, 15 mL of dichloromethane, 461 mg (1.50
mmol) of mCPBA, 15 mL of dichloromethane; yield 284 mg (68%) of
N-[1-S-(2-S-Benzyloxycarbonylamino-propanoylamino)-ethyl] 2-R-
methanesulfanyl succinamic acid benzyl ester (14i): 61 mg (0.20
mmol) of 8i, 50 mg (0.20 mmol) of 13a, 5 mL of dichloromethane, 54
mg (0.28 mmol) of EDAC, 50 mg (0.32 mmol) of HOBT, 40 µL (0.30
mmol) of N-ethylmorpholine; yield 74 mg (74%) of a white solid
(NOTE: Change in workup, the reaction mixture was partitioned
between ethyl acetate and 1 N HCl. The organics were washed with a
saturated aqueous NaHCO3 solution and dried over MgSO4. After
filtration, the organics were concentrated in vacuo, giving 14i cleanly.);
1
a white solid; mp ) 145-147 °C. H NMR (400 MHz, DMSO-d6) δ
2.71 (t, 1 H, J ) 10.8 Hz), 2.92 (m, 3 H), 3.14 (s, 3 H), 4.23 (m, 1 H),
4.41 (m, 2 H), 4.67 (m, 1 H), 4.92 (ab quart, J ) 12.8, 4.4 Hz), 5.21
(m, 2 H), 7.00-7.40 (m, 16 H), 8.71 (q, 1 H, J ) 5.8 Hz), 8.80 (q, 1
H, J ) 5.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 30.55, 37.53, 43.44,
50.16, 55.98, 64.16, 65.16, 67.15, 126.21, 127.42, 127.64, 127.91,
127.98, 128.26, 128.41, 128.80, 129.21, 130.64, 135.19, 136.98, 138.01,
138.07, 155.76, 165.28, 168.42, 168.48, 172.05; IR (Nujol mull) 3295,
1741, 1697, 1652, 1538 cm-1; HRMSFAB+ (C30H34N3O8S, M+ + 1)
Calcd: 596.2067 found: 596.2075.
1
mp ) 143-144 °C. H NMR (400 MHz, DMSO-d6, partial data) δ
1.15 (d, 3 H, J ) 7.2 Hz), 1.22 (d, 3 H, J ) 6.4 Hz), 2.05 (s, 3 H),
2.70 (dd, 1 H, J ) 6.4, 8.8 Hz), 3.60 (dd, 1 H, J ) 8.8, 6.0 Hz), 3.99
(m, 1 H), 5.00 (ab quart, 2 H, J ) 6.4, 12.2 Hz), 5.12 (ab quart, 2 H,
J ) 6.0, 13.0 Hz), 5.40 (m, 1 H) 7.20-7.34 (m, 11 H), 8.08 (d, 1 H,
J ) 7.4 Hz), 8.23 (d, 1 H, J ) 7.4 Hz); 13C NMR (100 MHz, DMSO-
d6) δ 13.42, 18.18, 20.72, 42.35, 49.79, 52.27, 65.30, 65.87, 66.15,
127.69, 127.75, 127.94, 128.04, 128.30, 128.38, 128.47, 136.02, 137.00,
155.57, 168.07, 170.90, 171.36; IR (Nujol mull) 3290, 1722, 1664,
1565, 1144 cm-1; HRMSFAB+ (C25H32N3O6S, M+ + 1) Calcd:
502.2012 found: 502.2012.
N-[(2-S-Benzyloxycarbonylamino-3-methylbutrylamino)meth-
yl] 2-methanesulfonyl succinamic acid benzyl ester (15d): 194 mg
(0.390 mmol) of 14d, 10 mL of dichloromethane, 253 mg (0.850 mmol)
of mCPBA, 10 mL of dichloromethane; yield 109 mg (53%) of a white
1
solid; mp ) 116-117 °C. H NMR (400 MHz, DMSO-d6) δ 0.89 (t,
6 H, J ) 6.4 Hz), 1.91 (sextet, 1 H, J ) 6.4 Hz), 2.78-2.97 (m, 2 H),
3.13 (s, 3 H), 3.85 (m, 1 H), 4.93 (m, 2 H), 4.65 (dd, 2 H, J ) 3.6,
10.8 Hz), 5.01 (ab quart, 2 H, J ) 12.6, 6.4 Hz), 5.20 (d of ab quarts,
2 H, J ) 2.4, 12.4, 6.0 Hz), 7.22 (d, 1 H, J ) 8.8 Hz), 7.36 (m, 10 H),
8.52 (t, 1 H, J ) 6.0 Hz), 8.79 (t, 1 H, J ) 6.0 Hz); 13C NMR (100
MHz, DMSO-d6) δ 18.07, 19.12, 30.33, 30.48, 43.28, 59.91, 64.16,
65.37, 67.14, 127.66, 127.95, 128.21, 128.31, 135.18, 137.04, 156.03,
165.24, 168.38, 171.76; IR (Nujol mull) 3302, 1735, 1691, 1640, 1540
cm-1; HRMSFAB+ (C26H34N3O8S, M+ + 1) Calcd: 548.2067 found:
548.2065.
N-[1-R-(2-S-Benzyloxycarbonylamino-propanoylamino)-ethyl] 2-R-
methanesulfanyl succinamic acid benzyl ester(14j): 172 mg (0.570
mmol) of 8j, 155 mg (0.610 mmol) of 13a, 20 mL of dichloromethane,
156 mg (0.800 mmol) of EDAC, 131 mg (0.860 mmol) of HOBT, 130
µL (1.00 mmol) of N-ethylmorpholine; yield 202 mg (71%) of a white
solid (NOTE: Change in workup, the reaction mixture was partitioned
between ethyl acetate and 1 N HCl. The organics were washed with a
saturated aqueous NaHCO3 solution. The organics were dried over
MgSO4. After filtration, the reaction was concentrated in vacuo, giving
14j cleanly.); mp ) 123-125 °C. 1H NMR (400 MHz, DMSO-d6,
partial data) δ 1.17 (m, 6 H), 2.07 (s, 3 H), 2.75 (dd, 1 H, J ) 5.6,
10.2 Hz), 3.63 (dd, 1 H, J ) 5.0, 10.2 Hz), 4.01 (m, 1 H), 5.00-5.18
(m, 4 H), 5.40 (m, 1 H), 7.32-7.40 (m, 11 H), 8.05 (d, 1 H, J ) 7.4
Hz), 8.22 (d, 1 H, J ) 7.4 Hz); 13C NMR (100 MHz, DMSO-d6) δ
14.04, 18.98, 21.16, 36.99, 42.64, 50.34, 52.83, 65.83, 66.34, 128.17,
128.45, 128.52, 128.79, 128.85, 128.97, 136.52, 137.48, 156.00, 168.36,
N-[(2-S-Benzyloxycarbonyl-3-methylpentanoylamino)methyl]
2-methanesulfonyl succinamic acid benzyl ester (15e): 252 mg
(0.470 mmol) of 14e, 8 mL of dichloromethane, 314 mg (1.03 mmol)
of mCPBA, 8 mL of dichloromethane; yield 246 mg (93%) of a white
solid. [Note: a precipitate was observed in the organic layer so the
organics were concentrated directly under partial vacuum. The resultant
residue was triturated with a dichloromethane: hexanes mixture to give
15e]; mp ) 189 °C (dec). 1H NMR (400 MHz, DMSO-d6) δ 0.76 (m,
6 H), 1.06 (m, 1 H), 1.37 (m, 1 H), 1.64 (m, 1 H), 2.78-2.90 (m, 2
H), 3.13 (s, 3 H), 3.86 (t, 1 H, J ) 8.4 Hz), 4.38 (t, 2 H, J ) 6.0 Hz),
4.64 (dd, 1 H, J ) 3.2, 10.8 Hz), 5.00 (ab quart, 2 H, J ) 5.2, 13.6
Hz), 5.20 (ab quart, 2 H, J ) 6.0, 12.4 Hz), 7.24-7.39 (m, 11 H), 8.53
(m, 1 H), 8.79 (t, 1 H, J ) 6.0 Hz); 13C NMR (100 MHz, DMSO-d6)
δ 10.92, 15.31, 24.35, 28.27, 30.52, 36.35, 36.49, 43.34, 58.91, 61.11,
62.89, 64.16, 65.39, 67.17, 126.41, 126.62, 127.69, 127.78, 127.97,
127.98, 128.04, 128.25, 128.34, 128.46, 135.21, 137.06, 142.53, 155.96,
165.29, 168.43, 171.42, 171.89; IR (Nujol mull) 3295, 1729, 1691,
1646, 1545 cm-1; HRMSFAB+ (C27H36N3O8S, M+ + 1) Calcd:
562.2223 found: 562.2229.
171.42, 171.86; IR (Nujol mull) 3300, 1728, 1664, 1529, 1259 cm-1
;
HRMSFAB+ (C25H32N3O6S, M+ + 1) Calcd: 502.2012 found: 502.2012.
N-[(2-S-Benzyloxycarbonylamino-propanoylamino)methyl] 2-S-
methanesulfanyl succinamic acid benzyl ester (14k): 505 mg (1.70
mmol) of 8a, 30 mL of dichloromethane, 438 mg (1.70 mmol) of 13b,
10 mL of dichloromethane, 394 mg (2.00 mmol) of EDAC, 346 mg
(2.20 mmol) of HOBT, 330 µL (2.60 mmol) of N-ethylmorpholine;
1
yield 523 mg (62%) of a white solid; mp ) 141-143 °C. H NMR
(400 MHz, DMSO-d6, partial data) δ 1.16 (d, 3 H, J ) 7.2 Hz), 2.06
(s, 3 H), 2.74 (dd, 1 H, J ) 10.0, 5.6 Hz), 3.64 (dd, 1 H, J ) 6.0, 10.0
Hz), 4.02 (quintet, 1 H, J ) 7.2 Hz), 4.37 (m, 2 H), 5.00 (ab quart, 2
H, J ) 12.4, 6.8 Hz), 5.13 (ab quart, 2 H, J ) 12.4, 14.4 Hz), 7.35 (m,
11 H), 8.44 (t, 1 H, J ) 6.0 Hz), 8.58 (t, 1 H, J ) 6.0 Hz); 13C NMR
(100 MHz, DMSO-d6) δ 13.42, 18.16, 36.25, 42.18, 43.31, 49.80, 65.32,
65.85, 127.69, 127.97, 128.30, 128.38, 136.01, 136.99, 155.54, 169.56,
Scheme A: General Procedure to Synthesize Final Zwitterions:
A 5% formic acid in methanol solution was degassed with argon. Under
a positive argon flow, the Pd-black catalyst (1:1 by weight) was slowly
added to the vigorously stirring degassed solution. 15 was dissolved
in a minimal amount of formic acid and was added to the suspension