8
Tetrahedron
4
3.5, 36.8, 28.7; mass spectrum (ESI+) calc
A
d.
C
C
C
H
EP
N
3
T
O +
2
E
D
H: MA4.
NU
4.1
diphenylheptan-2-yl)-2-(3,3-dibenzylureido)-3-methylbutanamide
4)
4.
S
(S
C
)-
R
N-
I
((
P
2S,4S,5R)-5-Benzyl-4-hydroxy-6-imino-7-oxo-1,7-
T
2
0
25
M+H (theory), 340.2020; M+H (found), 340.2028.
(
4
.4.9. N-Benzyl-4-(3-methyl-3-phenylureido)butanamide (8i)
i was prepared from 7i and benzylamine according to the
To slurry of benzyl tert-butyl ((2S,3S,5S)-3-hydroxy-1,6-
8
19
diphenylhexane-2,5-diyl)dicarbamate 9 (6.7 g, 12.8 mmol) in
EtOAc (50 ml) was added excess conc. HCl (5.6 ml, 64.1 mmol)
and the reaction was stirred until judged complete by HPLC
analysis. The resulting slurry was slowly quenched into a rapidly
stirred solution of aq. K CO (10% w/w) (106 g, 77 mmol) and
general ureidoacetamide formation procedure in 78% yield as a
waxy off-white solid; H NMR (700 MHz, CDCl ) δ 7.51 – 7.22
1
3
(m, 10H), 7.12 (t, J = 6.1 Hz, 1H), 4.63 (t, J = 6.0 Hz, 1H), 4.43
(d, J = 6.1 Hz, 2H), 3.38 – 3.09 (m, 5H), 2.26 (t, J = 7.2 Hz, 2H),
13
2
3
1
1
4
.77 (p, J = 6.9 Hz, 2H); C NMR (176 MHz, CDCl ) δ 172.8,
57.7, 143.3, 138.7, 130.1, 128.6, 127.7, 127.4, 127.3, 127.2,
3.5, 40.1, 37.2, 33.6, 26.7; mass spectrum (ESI+) calcd.
3
the phases were separated. The organics were washed with aq.
NaCl (5% w/w), dried (MgSO ), and concentrated in vacuo and
4
the resulting crude amine 10 was taken up in EtOAc:water (100
mL:3 mL) and heated to reflux. In a separate flask, a slurry of
C H N O +H:
M+H (theory), 326.1863; M+H (found),
19
23
3
2
3
26.1866.
.4.10. N-Benzyl-5-(3-methyl-3-phenylureido)pentanamide (8j)
j was prepared from 7j and benzylamine according to the
(S)-2-(3,3-dibenzylureido)-3-methylbutanoic acid (7l, 4.8 g, 14.1
mmol) in EtOAc (23 mL) was treated with 1,1’-
carbonyldiimidazole (2.4 g, 14.8 mmol) and this mixture was
stirred at rt for 1h. This solution was added to the pre-heated
solution of the free-base in EtOAc, and the resulting mixture was
stirred for 1h at reflux then cooled to rt. Water (50 mL) was
added and the phases were separated. The organics were washed
with 10% citric acid, 5% NaHCO , and brine then dried
(MgSO ), filtered, and purified using silica gel chromatography
eluting with EtOAc/hexanes. The resulting purified material was
recrystallized from EtOAc/hexanes to give 5.5 g (60% yield) of 4
4
8
general ureidoacetamide formation procedure in 73% yield as a
waxy off-white solid; H NMR (700 MHz, CDCl ) δ 7.48 – 7.19
1
3
(
=
1
2
1
2
m, 10H), 6.72 – 6.61 (m, 1H), 4.47 (t, J = 5.9 Hz, 1H), 4.43 (d, J
6.1 Hz, 2H), 3.37 – 3.00 (m, 5H), 2.26 (t, J = 7.6 Hz, 2H),
.63 (dddd, J = 7.5, 7.5, 7.6, 7.6 Hz, 2H), 1.46 (dddd, J = 7.1 Hz,
H); C NMR (176 MHz, CDCl ) δ 173.0, 157.5, 143.4, 138.7,
30.1, 128.6, 127.8, 127.4, 127.3, 127.3, 43.4, 39.9, 37.1, 35.8,
3
13
4
3
9.8, 22.9; mass spectrum (ESI+) calcd. C H N O +H: M+H
20
25
3
2
23
as a white solid: m.p. 158-160 ºC; [α] -3.7 (c 1.28, DMSO);
D
(theory), 340.2020; M+H (found), 340.2025.
1
H NMR (600 MHz, DMSO-d , 60 ºC) δ 7.49 (d, J = 8.4 Hz,
6
4
.4.11. N-Benzyl-6-(3-methyl-3-phenylureido)hexanamide (8k)
k was prepared from 7k and benzylamine according to the
1
H), 7.38 – 7.02 (m, 25H), 6.52 (s, 1H), 5.60 (d, J = 8.4 Hz, 1H),
8
4.91 (t, J = 14.8 Hz, 2H), 4.57 – 4.34 (m, 5H), 4.15 (q, J = 7.3
Hz, 1H), 4.03 (dd, J = 6.4, 8.4 Hz, 1H), 3.82 (dddd, J = 2.3, 5.6,
9.0, 9.0 Hz, 1H), 3.60 (dddd, J = 2.4, 6.6, 6.6, 6.7 Hz, 1H), 3.12
(s, 2H), 2.81 – 2.58 (m, 4H), 2.49 (p, J = 1.9 Hz, 2H), 1.84 (h, J
= 6.7 Hz, 1H), 1.52 (m, 2H), 0.70 (d, J = 6.7 Hz, 3H), 0.61 (d, J
general ureidoacetamide formation procedure in 64% yield as a
waxy off-white solid; H NMR (700 MHz, CDCl ) δ 7.50 – 7.21
1
3
(
=
2
m, 10H), 6.37 – 6.24 (m, 1H), 4.45 (d, J = 5.9 Hz, 2H), 4.39 (t, J
5.9 Hz, 1H), 3.26 (d, J = 1.9 Hz, 3H), 3.17 (q, J = 6.7 Hz, 2H),
.24 (t, J = 7.6 Hz, 2H), 1.67 (dddd, J = 7.7 Hz, 2H), 1.45 (dddd,
13
= 6.7 Hz, 3H); C NMR (151 MHz, DMSO-d ) δ 170.9, 157.2,
6
13
J = 7.3 Hz, 2H), 1.31 (dddd, J = 7.8 Hz, 2H); C NMR (176
MHz, CDCl ) δ 172.9, 157.4, 143.5, 138.6, 130.1, 128.7, 127.8,
155.9, 139.4, 138.7, 138.3, 137.4, 129.2, 129.0, 128.4, 128.2,
127.9, 127.8, 127.5, 127.1, 127.1, 126.9, 126.5, 125.7, 125.7,
69.0, 64.8, 59.4, 55.5, 49.4, 47.0, 38.2, 37.2, 30.5, 19.3, 17.9;
mass spectrum (ESI+) calcd. C H N O +H: M+H (theory),
3
1
27.4, 127.3, 127.3, 43.5, 40.6, 37.2, 36.5, 30.0, 26.4, 25.3; mass
spectrum (ESI+) calcd. C H N O +H: M+H (theory),
21
27
3
2
46 52
4
5
3
54.2176; M+H (found), 354.2172.
741.4010; M+H (found), 741.4028.
4
.4.12. (S)-N-Benzyl-2-(3,3-dibenzylureido)-3-methylbutanamide
4.4.15. Benzyl-((2S,3S,5S)-3-hydroxy-5-((S)-3-methyl-2-(3-
methyl-3-phenylureido)butanamido)-1,6-diphenylhexan-2-
yl)carbamate (11)
(8l)
8
l was prepared from 7l and benzylamine according to the
general ureidoacetamide formation procedure in 63% yield as a
To slurry of benzyl tert-butyl ((2S,3S,5S)-3-hydroxy-1,6-
diphenylhexane-2,5-diyl)dicarbamate 9 (3.3 g, 6.3 mmol) in
23
1
20
white solid: m.p. 92-95 ºC; [α]
+29.0 (c 1.27, CH Cl ); H
D
2
2
NMR (400 MHz, CDCl ) δ 7.45 – 6.85 (m, 15H), 6.47 (t, J = 5.8
Hz, 1H), 4.85 (d, J = 8.0 Hz, 1H), 4.48 (d, J = 16.3 Hz, 2H), 4.41
EtOAc (50 mL) was added excess conc. HCl (2.5 ml, 28.4 mmol)
and water (1 mL) and the reaction was stirred until judged
complete by HPLC analysis. The resulting slurry was slowly
3
–
1
4.21 (m, 4H), 4.12 (dd, J = 6.2, 8.1 Hz, 1H), 1.96 (dq, J = 6.7,
3.3 Hz, 1H), 0.72 (d, J = 6.7 Hz, 3H), 0.56 (d, J = 6.8 Hz, 3H);
quenched into a rapidly stirred solution of aq. K
(22 g, 32 mmol) and the phases were separated. The organics
were washed with aq. NaCl (5% w/w), dried (MgSO ), and
CO (10% w/w)
2
3
1
3
C NMR (101 MHz, CDCl ) δ 172.0, 158.0, 138.2, 137.4, 128.9,
3
1
28.6, 127.6, 127.3, 127.2, 60.0, 50.7, 43.4, 30.5, 19.4, 17.7;
4
mass spectrum (ESI+) calcd. C H N O +H: M+H (theory),
concentrated in vacuo to give the crude amine 10 that was taken
27
33
3
2
4
30.2489; M+H (found), 430.2485.
up in EtOAc:water (50 mL:2 mL) and heated to reflux. In a
separate flask,
a
slurry of (S)-3-methyl-2-(3-methyl-3-
4
.4.13. (S)-N-Benzyl-3-methyl-2-(3-methyl-3-phenylureido)
phenylureido)butanoic acid (7m, 1.7 g, 6.6 mmol) in EtOAc (20
mL) was treated with 1,1’-carbonyldiimidazole (1.1 g, 6.9 mmol)
and this mixture was stirred at rt for 1h. This solution was added
to the pre-heated solution of the free-base in EtOAc, and the
resulting mixture was stirred for 1h at reflux then cooled to rt.
Water (50 mL) was added and the phases were separated. The
organics were washed with 10% citric acid, 5% NaHCO , and
brine then dried (MgSO ), filtered, and purified using silica gel
chromatography eluting with EtOAc/hexanes. The resulting
purified material was recrystallized from EtOAc/hexanes to give
butanamide (8m)
m was prepared from 7m and benzylamine according to the
general ureidoacetamide formation procedure in 93% yield as an
8
23
1
oil; [α] +22.7 (c 8.75, CH Cl ); H NMR (400 MHz, CDCl ) δ
D
2
2
3
7
8
1
2
.50 – 7.21 (m, 10H), 7.12 (dt, J = 3.1, 7.1 Hz, 1H), 4.90 (d, J =
.6 Hz, 1H), 4.52 (dd, J = 6.0, 14.9 Hz, 1H), 4.37 (dd, J = 5.6,
4.9 Hz, 1H), 4.24 (ddd, J = 1.5, 6.9, 8.3 Hz, 1H), 3.17 (s, 3H),
.03 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H);
3
4
13
C NMR (101 MHz, CDCl ) δ 172.0, 157.1, 142.8, 138.3, 130.0,
3
1
1
28.5, 127.6, 127.5, 127.2, 127.14, 59.9, 43.3, 37.1, 30.7, 19.5,
8.1; mass spectrum (ESI+) calcd. C H N O +H: M+H
23
2
.48 g (60% yield) of 15 as a white solid: m.p. 116-119 ºC; [α]
D
1
20
25
3
2
+
9.9 (c 1.27, ACN); H NMR (600 MHz, DMSO-d , 60 ºC) δ
6
(theory), 340.2020; M+H (found), 340.2035.
7
6
.60 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.19 (m, 18H),
.53 (s, 1H), 5.05 (d, J = 8.6 Hz, 1H), 4.92 (q, J = 12.5 Hz, 2H),