S. K. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 1273–1280
1277
Anal. Calcd for C13H21N3O2ꢁ0.33CH2Cl2 (279.35): C, 57.31; H, 7.82;
the product containing fractions by rotary evaporation. The
residue was dried by oil pump vacuum to give (S)-7L2 (3.42 g,
10.2 mmol, 85%) as a white solid, mp 126–129 °C (open
capillary). Anal. Calcd for C15H29N3O5 (331.41): C, 54.36; H, 8.82,
N, 15.04. Found: C, 57.00; H, 7.44; N, 14.97. [
a]
589 = ꢀ5.3 0.2
24
(c 1.15, CH3OH). NMR (CDCl3, d in ppm): 1H (400 MHz): 7.32–7.25
(m, 5H, Ph), 5.34 (br s, 1H, NH), 5.06 (m, 2H, OCH2Ph), 3.65–3.64
2
3
(m, 1H, CHNHCbz), 2.83 (dd, JHH = 13.2 Hz, JHH = 4.4 Hz, 1H,
N, 12.68. Found: C, 54.33; H, 8.71; N, 12.54. NMR (DMSO-d6, d in
2
3
3
CHH0NH2), 2.73 (dd, JHH = 13.2 Hz, JHH = 4.4 Hz, 1H, CHH0NH2),
ppm): 1H (500 MHz) 7.21 (br s, 1H, CHNH), 7.04 (t, JHH = 5.5 Hz,
2
3
2.33 (dd, JHH = 11.8 Hz, JHH = 8.2 Hz, 1H, CHH0N(CH3)2), 2.22 (dd,
1H, CONHH0), 6.83 (m, 1H, CONHH0), 6.68 (br s, 1H, CH2NH), 3.70
2JHH = 12.2 Hz, JHH = 6.6 Hz, 1H, CHH0N(CH3)2), 2.18 (s, 6H,
(d, JHH = 7.0 Hz, 4H, 2ꢂ OCH2CH(CH3)2), 3.44 (br s, 1H, CHNH),
3
3
N(CH3)2), 1.37 (br s, 2H, NH2); 13C{1H} (100.6 MHz) 156.2 (s, (C@O)O),
Ph at 136.2 (s, i), 128.0 (s, m),22 127.6 (s, p), 127.5 (s, o); 66.1
(s, OCH2Ph), 60.3 (s, CH2N(CH3)2), 53.1 (s, CH2Cl2), 50.8 (s, CHNHCbz),
45.3 (s, N(CH3)2), 43.8 (s, CH2NH2). IR ((powder film, cmꢀ1): 3358
2.98 (t, JHH = 6.0 Hz, 2H, CH2NH), 2.09–1.93 (m, 2H, CH2CONH2),
3
1.87–1.73 (m, 2H, 2ꢂ CH(CH3)2), 1.69–1.57 (m, 1H, CHCHH0CH2),
1.50–1.37 (m, 1H, CHCHH0CH2), 0.94–0.77 (m, 12H, 2ꢂ CH
(CH3)2); 13C{1H} (125 MHz) 174.0 (s, CONH2), 157.6 and 156.2
(2ꢂ s, 2ꢂ (C@O)O), 69.7 and 69.6 (2ꢂ s, 2ꢂ OCH2CH(CH3)2), 50.6
(s, CHNH), 44.2 (s, CH2NH), 31.7 (s, CH2CONH2), 27.68 and 27.65
(2ꢂ s, 2ꢂ CH(CH3)2), 27.5 (s, CHCHH0CH2), 19.0 and 18.9 (2ꢂ s,
(m,
m
NH), 2995, 2822, and 2771 (3 ꢂ m,
m
CH), 1693 (vs,
mC@O),
1531 (s, dNH), 1247 (vs,
m
(C@O)OC); MS:23 252 (95) [22+H]+, 180
(100) [22+H–C3H8N2]+.
2ꢂ CH(CH3)2). IR (powder film, cmꢀ1): 3414 (m,
mNH), 3352 and
mCH), 1690, 1678, and 1663
5.1.5. (S)-N1,N1-Dimethylpropane-1,2,3-triamine or (S)-NH2CH2-
CH(CH2NMe2)NH2 (S)-L1
3312 (m,
m
NH), 2959 and 2876 (2ꢂ m,
(3ꢂ vs, 3ꢂ
m
C@O), 1539 (s, dNH).
A Schlenk flask was charged with (S)-8L1 (5.08 g, 18.18 mmol),
CH3OH (60 mL), and Pd/C (10%, 0.795 g). The solution was sparged
with H2 and stirred under an H2 atmosphere (balloon). After 14 h,
the mixture was filtered through a plug of Celite and the solvent
was removed under reduced pressure (17 mbar) at 0 °C to give (S)-
5.1.8. (S)-N1,N2-Di-i-butoxycarbonyl-1,2,4,-triaminobutane or
(S)-(i-BuOC(O))NHCH(CH2CH2NH2)CH2NH(C(O)Oi-Bu) (S)-8L2
A
round bottom flask was charged with (S)-7L2 (3.0 g,
8.96 mmol), CH3CN (25 mL), EtOAc (25 mL), H2O (12 mL), and PhI
(OAc)2 (4.2 g, 13 mmol) with stirring. After 15 h, the solvents were
removed by rotary evaporation. The residue was chromatographed
on a silica gel column (3 ꢂ 8 cm, 100:0 to 80:20 v/v CH2Cl2/CH3-
OH). The solvent was removed from the product containing frac-
tions to give (S)-8L2 (1.55 g, 5.05 mmol, 57%)17b as a colorless
sticky liquid. NMR (CDCl3, d in ppm): 1H (500 MHz) 5.57 (br s,
1H, CHNH), 5.43 (br s, 1H, CH2NH), 3.89–3.70 (m, 5H, 2ꢂ
OCH2CH(CH3)2 and CHNH), 3.26 (br s, 2H, CH2NH), 2.81 (t,
3JHH = 5 Hz, 2H, CH2NH2), 2.36 (br s, 2H, NH2), 1.94–1.79 (m, 2H,
2ꢂ CH(CH3)2), 1.73–1.63 (m, 1H, CHCHH0CH2), 1.60–1.47 (m, 1H,
L1 as a colorless oil (1.90 g, 16.3 mmol, 90%). [
a
]
589 = ꢀ9.3 0.1 (c
24
0.1081 CH3OH). NMR (CDCl3, d in ppm): 1H (400 MHz): 2.90–2.85
2
3
(m, 1H, CHNH2), 2.72 (dd, JHH = 12.4 Hz, JHH = 4.0 Hz, 1H,
2
3
CHH0NH2), 2.52 (dd, JHH = 12.6 Hz, JHH = 7.0 Hz, 1H, CHH0N
(CH3)2), 2.21 (s, 6H, N(CH3)2, partly overlapped by CHH0N(CH3)2),
2.16 (m, 1H, CHH0N(CH3)2, partly overlapped by N(CH3)2), 2.10 (dd,
3
2JHH = 12.0 Hz, JHH = 4.4 Hz, 1H, CHH0NH2); 13C{1H} (75.5 MHz)
64.1 (s, CH2N(CH3)2), 50.1 (s, CHNH2), 46.1 (s, CH2NH2), 45.5 (s, N
(CH3)2). IR (powder film, cmꢀ1): 3280 (m,
m
NH), 2949 and 2831 (2ꢂ
m,
m
CH), 1571 (s, dNH), 1461 (s, dCH ); MS:24 118 (100) [23+H]+.
2
3
CHCHH0CH2), 0.89 (d, JHH = 5 Hz, 12H, 2ꢂ CH(CH3)2); 13C{1H}
(125 MHz) 157.6 and 157.4 (2ꢂ s, 2ꢂ (C@O)O), 71.1 and 71.0 (2ꢂ
s, 2ꢂ OCH2CH(CH3)2), 49.9 (s, CHNH), 45.1 (s, CH2NH), 38.2 (s,
CH2NH2), 35.1 (s, CHCHH0CH2), 28.0 (s, 2ꢂ CH(CH3)2), 19.0 (s, 2ꢂ
CH(CH3)2).
5.1.6. Tris(hydrochloric acid) salt of (S)-N1,N1-dimethylpropane-
1,2,3-triamine or (S)-H3NCH2CH(CH2NMe2H)NH3]3+ 3Clꢀ (S)-L1ꢁ
(HCl)3
A Schlenk flask was charged with (S)-L1 (1.90 g, 16.3 mmol) and
CH3OH (10 mL). A solution of HCl in Et2O (2.0 M, 12 mL) was then
added dropwise to form a precipitate. The supernatant was dec-
anted and the precipitate was washed with Et2O (2 ꢂ 10 mL) and
dried by oil pump vacuum to give (S)-L1ꢁ(HCl)3ꢁH2O as a white
powder (3.95 g, 16.1 mmol, 99%), dec pt 213 °C (capillary). Anal.
Calcd for C5H18Cl3N3ꢁH2O (244.59): C, 24.55; H, 8.24; N, 17.18.
5.1.9. (S)-N1,N2-Di-i-butoxycarbonyl-N4,N4-dimethyl-1,2,4-triam
inobutane or (S)-(i-BuOC(O))NHCH(CH2CH2NMe2)CH2NH(C(O)O-
i-Bu) (S)-9L2
A
Fischer Porter bottle was charged with (S)-8L2 (1.80 g,
5.863 mmol), CH3OH (50 mL), distilled H2O (15 mL), and 37%
aqueous HCHO (1.6 mL). The mixture was stirred for 1 h, then
10% Pd/C (1.2 g, 0nominally 50% water wet0) was added, and
50 psi of H2 were introduced. After 24 h, the mixture was filtered
through a plug of Celite and washed with CH3OH/distilled H2O
(1:1 v/v). The solvent was removed by rotary evaporation and
Found: C, 24.58; H, 8.00; N, 16.96. [
a
]
589 = ꢀ8.7 0.4 (c 0.116,
24
H2O). NMR (D2O, d in ppm): 1H (400 MHz): 4.20–4.13 (m, 1H,
CHNH3), CH2N(CH3)2H and CH2NH3 at 3.68–3.57 (m, 2H) and
3.54–3.42 (m, 2H), 3.06 (s, 6H, N(CH3)2H+); 13C{1H} (100.6 MHz)
59.4 (s, CH2N(CH3)2H), 47.7 (s, N(CH3)2H), 46.6 (s, CHNH3), 42.4
the residue was chromatographed on
a silica gel column
(s, CH2NH3). IR (powder film, cmꢀ1): 3479 and 3424 (2ꢂ m,
mOH),
(3 ꢂ 8 cm, 100:0 to 80:20 v/v CH2Cl2/CH3OH). The solvent was
removed from the product containing fractions by rotary evapora-
tion and oil pump vacuum to give (S)-9L2 (1.02 g, 2.87 mmol, 50%)
as a colorless oil that often solidified upon storage, mp 47–50 °C
(open capillary). Anal. Calcd for C16H33N3O4ꢁ0.75CH3OH, (355.48):
C 56.59, H 10.21, N 11.82; Calcd for C16H33N3O4ꢁ0.33CH3OH,
(342.02, corresponding to 1H NMR integration): C 57.35, H 10.11,
N 12.29; found C 56.26, H 9.95, N 12.22. NMR (CDCl3, d in ppm):
1H (500 MHz) 5.98 (br s, 1H, CHNH), 5.53 (br s, 1H, CH2NH),
3.87–3.78 (m, 4H, 2ꢂ OCH2CH(CH3)2), 3.77–3.70 (m, 1H, CHNH),
3.47 (s, 1H, CH3OH), 3.37–3.30 (m, 1H, CHH0NH), 3.29–3.19 (m,
1H, CHH0NH), 2.57–2.39 (m, 2H, CH2N(CH3)2), 2.30 (s, 6H, N
(CH3)2), 1.96–1.82 (m, 2H, 2ꢂ CH(CH3)2), 1.82–1.72 (m, 1H,
CHCHH0CH2), 1.71–1.57 (m, 1H, CHCHH0CH2), 1.02–0.83 (m, 12H,
2ꢂ CH(CH3)2); 13C{1H} (125 MHz) 157.5 and 157.2 (2ꢂ s, 2ꢂ
(C@O)O), 71.1 and 71.0 (2ꢂ s, 2ꢂ OCH2CH(CH3)2), 56.0 (s, CH2N
þ
2902 and 2816 (2ꢂ s,
mCH), 2708 and 2627 (2ꢂ s, mNH ), 1625 (w,
3
dNH), 1481 (vs, dCH ).
2
5.1.7. (S)-N4,N5-Di-i-butoxycarbonyl-4,5-diaminopentamide or
(S)-(i-BuOC(O))NHCH(CH2CH2CONH2)CH2NH(C(O)Oi-Bu) (S)-7L2
A round bottom flask was charged with (S)-6L2 (4.010 g,
12.078 mmol)17b and THF (130 mL). Next, N-methyl morpholine
(1.70 mL, 1.565 g, 15.49 mmol) was added with stirring and the
solution was cooled to ꢀ20 °C. Isobutyl chloroformate (2.0 mL,
2.091 g, 15.30 mmol) was slowly added. After 0.5 h, aqueous
NH4OH (30%, 8.8 mL) was added. The cold bath was allowed to
warm to 0 °C over the course of 6 h. The solvent was removed by
rotary evaporation and the residue was chromatographed on a
silica gel column (3 ꢂ 14 cm, 93:7 v/v CH2Cl2/(85:15 v/v
CH3OH/30% aqueous NH4OH)). The solvent was removed from