2
308
B. G. Davis et al. / Bioorg. Med. Chem. 7 (1999) 2303±2311
1
:9 to 1:3) to give 5,5-bis(aminomethyl)-1-O-tert-butyl-
LiBr (860 mg, 9.89 mmol) was added to a solution of 9
(245 mg, 0.62 mmol) in acetone (25 mL) under N and
dimethylsilyl-N,N'-di-tert-butoxycarbonyl-3-oxo-hexan-1-
ol (7). (1.04 g, 72% over 2 steps) as a colorless oil; IR
2
heated under re¯ux. After 8 h the reaction mixture was
cooled and the solvent removed. The residue was parti-
tioned between ether (150 mL) and water (50 mL). The
aqueous layer was reextracted with ether (50 mLÂ2). The
�
1
(
®lm) 3360 (NH), 1701, (amide I), 1508 (amide II) cm ;
H NMR (CDCl , 400 MHz) d � 0.02 (s, 6H, Si(CH ) ),
1
3
3 2
0
.75 (s, 3H, H-6), 0.81 (s, 9H, SiC(CH ) ), 1.34 (s, 18H,
3 3
OC(CH ) Â2 ), 2.83 (dd, 2H, JH,NH=5.3 Hz, JH,H'
=
organic fractions were combined, dried (MgSO ), ®ltered
3
3
4
1
J
2
4.0 Hz, -CHH N-Â2), 3.00 (dd, 2H, JH',NH=7.9 Hz,
and the solvent removed to give 5,5-bis(aminomethyl)-1-
bromo-N,N'-di-tert-butoxycarbonyl-3-oxo-hexane (10)
(769 mg, 93%) as a yellow oil which was used directly in
the next step.
=14.1 Hz, -CHH'N-Â2), 3.16 (s, 2H, H-4), 3.39 (t,
H,H'
H, J=4.9 Hz, H-2), 3.65 (t, 2H, J=4.9 Hz, H-1), 5.30
13
(
1
br t, 2H, J=6.8 Hz, NHÂ2); C NMR (CDCl3,
00 MHz) d 5.4 (Si(CH ) ), 18.2 (SiC(CH )), 18.8 (C-6),
3
2
3
2
5.7 (SiC(CH ) ), 28.3 (OC(CH ) Â2), 40.2 (C-5), 44.4
NaSSO CH (315mg, 2.35mmol) was added to a solution
2
3
3
3 3
3
(
-CH N-), 62.3, 72.8, 76.3 (C-1, C-2, C-4), 78.7
2
of 10 (769mg, 1.81mmol) in DMF (30mL) and the
resulting solution warmed to 50 C under N . After 20h
ꢀ
TLC (EtOAc:hexane, 1:1) showed the conversion of
(OC(CH ) Â2), 156.7 (-NH(CO)O-Â2); MS m/z (FAB
+
3
3
2
+
+
): 351 (M+Na , 3), 329 (M+H , 45).
starting material (R 0.8) to a major product (R 0.35). The
f
f
A solution of TBAF in THF (1M, 3.7 mL, 3.7 mmol)
was added dropwise to a solution of 7 (1.04 g,
solvent was removed and the residue puri®ed by ¯ash
chromatography to give (EtOAc:hexane, 1:1) 5,5 - bis
(aminomethyl)-N,N'-di-tert-butoxycarbonyl-3-oxo-hexyl
methanethiosulfonate (11) (720 mg, 87%) as a colorless
oil; IR (®lm) 3385 (NH), 1700 (amide I), 1508 (amide II)
2.18 mmol) in THF (17 mL) under N . After 3 h, the
2
solvent was removed. The residue was dissolved in
EtOAc (200 mL) and washed with water (100 mLÂ2).
The aqueous layer was reextracted with EtOAc
�
1 1
1320, 1167 (S-SO ) cm ; H NMR (CDCl , 400 MHz)
2
3
(
dried (MgSO ), ®ltered and the solvent removed. The
residue was puri®ed by ¯ash chromatography (EtOAc:
hexane, 1:1) to give 5,5-bis(aminomethyl)-N,N'-di-tert-
butoxycarbonyl-3-oxo-hexan-1-ol (8) (735 mg, 93%) as a
colorless oil; IR (®lm) 3355 (OH, NH), 1700 (amide I),
100 mLÂ2). The organic fractions were combined,
d 0.83 (s, 3H, H-6), 1.42 (s, 18H, OC(CH ) Â2), 2.95 (dd,
3
3
2H, J
=6.1Hz, J
H,NH H,H'
(dd, 2H, JH',NH=7.2 Hz, J
=14.2 Hz, -CHH'N-Â2), 3.05
H,H'
4
=14.2 Hz, -CHH'N-Â2),
3 2
3.24 (s, 2H, H-4), 3.34 (s, 3H, CH SO ), 3.35 (t, 2H,
J=4.9Hz, H-2), 3.71 (t, 2H, J=4.9Hz, H-1), 5.20 (br s,
1
3
2H, NHÂ2); C NMR (CDCl , 100 MHz) d 18.7 (C-6),
3
�
1 1
1
0
2
520 (amide II) cm ; H NMR (CDCl , 400 MHz) d
28.4 (OC(CH ) Â2), 36.2 (C-1), 40.5 (C-5), 44.2 (-CH N-),
3
3 3
2
.80 (s, 3H, H-6), 1.39 (s, 18H, OC(CH ) Â2), 2.93 (dd,
50.6 (CH SO ), 69.6, 76.2 (C-2, C-4), 79.2 (OC (CH ) Â2),
3
3
3
2
3 3
+
H, J
=5.6 Hz, J
=14.0 Hz, -CHH'N-Â2), 3.01
156.7 (-NH(CO)O-Â2); MS m/z (FAB+): 479 (M+Na ,
H,NH
H,H'
+
(
dd, 2H, JH',NH=8.0 Hz, JH,H'= 13.9ÂHz, -CHH'N-
8), 457 (M+H , 10%).
Â2), 3.14 (s, 2H, H-4), 3.29 (s, 1H, OH), 3.47 (t, 2H,
J=4.5 Hz, H-2), 3.65 (t, 2H, J=4.3 Hz, H-1), 5.30 (br s,
Compound 11 (720 mg, 1.58 mmol) was dissolved in
DCM (20 mL) under N and TFA (20 mL) was added.
1
3
2
2
7
H, NHÂ2); C NMR (CDCl , 100 MHz) d 18.8 (C-6),
3
2
8.3 (OC(CH ) Â2), 40.3 (C-5), 44.0 (-CH N-), 61.3,
After 1 h the solvent was removed. The residue was pur-
i®ed by ion exchange chromatography (Dowex
3
3
2
2.7, 74.7 (C-1, C-2, C-4), 79.2 (OC(CH ) Â2), 156.7
3
3
+
+
(
-NH(CO)O-Â2); MS m/z (FAB+): 385 (M+Na , 45),
50W(H ), 4Â3 cm, eluant aq HCl, concave gradient 0.5±
+
1
363 (M+H , 95%). MsCl (0.24 mL, 3.1 mmol) was
added dropwise to a solution of 8 (735 mg, 2.03 mmol)
2.5 M) to give 1c as a white foam (348 mg, 67%); H
NMR (D O, 400 MHz) d 0.91 (s, 3H, H-6), 2.89 (d, 2H,
2
and Et N (0.57 mL, 4.09 mmol) in DCM (5 mL) under
3
N at 0 C. After 1 h the solution was warmed to room
2
temperature. After a further 16 h the solution was dilu-
ted with DCM (100 mL), washed with sat. NaHCO3
JH,H'=13.5 Hz, -CHH' N-Â2), 2.99 (d, 2H, JH,H'=
13.2 Hz, -CHH N-Â2), 3.28 (t, 2H, J=5.6 Hz, H-1),
3.31 (s, 3H, CH SO ), 3.42 (s, 2H, H-4), 3.63 (t, 2H,
ꢀ
3
2
13
J=5.9 Hz, H-2); C NMR (D O, 100 MHz) d 17.8 (C-
2
(
(
aq, 30 mL), water (30 mL), brine (30 mL), dried
MgSO ), ®ltered and the solvent removed. The residue
6), 36.4, 37.1, 45.2 (C-1, C-5, -CH N-), 50.6 (CH SO ),
2
3
2
+
70.1, 75.4 (C-2, C-4); MS m/z (FAB+): 289 (M+Na ,
4
+
was puri®ed by ¯ash chromatography (MeOH:CHCl3,
:25) to give 5,5-bis(aminomethyl)-N,N'-di-tert-butoxy-
carbonyl-1-O-methanesulfonyl-3-oxo-hexan-1-ol (9)
880 mg, 99%) as a colorless oil; IR (®lm) 3360 (NH),
700 (amide I), 1520 (amide II) 1362, 1173 (O-SO )
15), 257 (M+H , 65%). HRMS m/z (FAB+). Found
+
1
257.1000 (M+H ); C H N O S requires 257.0994.
8
21
2
3 2
(
1
2,2-Bis(aminomethyl)-3-aminopropyl methanethiosulfo-
nate trihydrochloride (1d)
2
�
1 1
cm ; H NMR (CDCl , 400 MHz) d 0.83 (s, 3H, H-6),
3
1
.41 (s, 18H, OC(CH ) Â2), 2.94 (dd, 2H, JH,NH=5.9
Pentaerythritol (12) (12.8 g, 94 mmol) was dissolved in
glacial AcOH:40% HBr (aq) (1:5 v/v, 60 mL) and heated
under re¯ux. After 24 h 40% HBr (aq) (50 mL) and c.
H SO (23 mL) were added and the resulting solution
3
3
Hz, J
CH SO ), 3.06 (dd, 2H, J
= 14.2 Hz, -CHH N-Â2), 3.05 (s, 3H,
H',NH H,H'
H,H'
=7.7 Hz, J
=13.9 Hz,
3
2
-
4
CHH N-Â2), 3.24 (s, 2H, H-4), 3.65±3.67 (m, 2H, H-2),
2
4
.33±4.35 (m, 2H, H-1), 5.27 (br t, 2H, J=6.4 Hz,
heated under re¯ux. After a further 24 h the reaction
mixture was cooled. The lower liquid layer from the
resulting mixture was separated and dissolved in CHCl3
(50 mL), washed with water (20 mL), dried (anhyd.
K CO ), ®ltered and the solvent removed. The residue
1
3
NHÂ2); C NMR (CDCl , 100 MHz) d 18.8 (C-6), 28.4
3
(
CH2N-), 68.6, 69.2, 76.3 (C-1, C-2, C-4), 79.2
OC(CH ) Â2), 37.7 (CH SO ), 40.5 (C-5), 44.1 (-
3
3
3
2
(
(
OC(CH ) Â2), 156.8 (-NH(CO)O-Â2); MS m/z
3
3
2
3
+
FAB+): 441 (M+H , 10%).
was puri®ed by ¯ash chromatography (EtOAc:hexane,