-
1
recorded in CDCl on a Bruker AC250/400
A
/5
C
00
C
s
E
pe
P
ct
T
ro
E
me
D
terMA303
N
4,US
1
C
69
R
2,IP
1553 cm ; HRMS(CI) found 269.1134,
T
3
+
unless otherwise stated. Mass spectra data were obtained at the C H N O ([M+H] ) requires 269.1132.
1
2
17
2
5
EPSRC Mass Spectrometry Service Centre at the University of Benzyl (4-di-Boc-guanidino-3-hydroxybutyl)carbamate 11
.
Wales, Swansea. Infrared spectra were recorded as thin films
NiCl 6H O (5.3 g, 149 mmol, 3 equiv.) dissolved in
2 2
(
oils) on a Bruker Tensor 27 series instrument. Melting points methanol (400 mL) was cooled (0 °C) and NaBH (2.5 g, 67
4
were performed on a Stuart SMP10 apparatus and are mmol, 9 equiv.) was added slowly in small portions in such a
uncorrected.
way as to prevent excessive foaming and following this the
mixture was stirred for 45 mins. Alcohol (2.00 g, 7.45 mmol)
dissolved in methanol (25 mL), was then added followed by the
9
4
Benzyl (3-hydroxypropyl)carbamate 7
A stirred solution of 1-aminopropan-3-ol
6
(12.0 g, 133 careful addition of further NaBH (5.6 g, 149 mmol, 20 equiv.)
4
mmol) and NaOH (aqueous, 1 M) (40 mL, 3.0 equiv.) was in small portions over 30 mins. After 2 h the mixture was
©
cooled (0 °C) and benzyl chloroformate (22.5 g, 133 mmol, 1 filtered through a pad of Celite which was washed with
equiv.) was added drop-wise over 10 min. After warming to rt methanol (2 x 80 mL). Triethylamine (66 g, 92 mL, 0.65 mol,
the mixture was stirred for 1 h and CH Cl (100 mL) was added 88 equiv.) was added to the filtrate and the mixture stirred for 1
2
2
and stirring continued for 16 h. The layers were separated and h. N,N′-Di-Boc-1
H-pyrazole-1-carboxamidine 10 (2.77 g, 8.94
the aqueous layer extracted with CH Cl (2 x 50 mL) and mmol, 1.2 equiv.) was then added and the mixture stirred for 3
2
2
EtOAc (2 x 50 mL). The combined organic layers were dried days. The methanol was evaporated under reduced pressure and
MgSO ) and evaporated under reduced pressure to yield the the resulting viscous oil dissolved in water (400 mL), which
(
4
crude product as a pale yellow solid. The solid was dissolved in was then extracted with EtOAc (3 x 100 mL). The combined
warm EtOAc (ca. 50 mL) and cooled (–20 °C) overnight to give organic extracts were dried (MgSO ) and evaporated under
4
crystals which were filtered and washed with petrol to give
white crystals (22.5 g, 117 mmol) 88% yield.
7
as reduce pressure to give crude
9 (4.6 g) as a viscous purple oil.
Purification by column chromatography (35% EtOAc in PE)
Mp. 49-50 °C (Lit 50-51 °C); R 0.13 (50 % EtOAc in PE, gave 11 (2.9 g, 6.0 mmol) in an 81% yield as a glassy solid
f
PMA); δH 1.68–1.74 (2H, m, CH ), 2.59 (1H, br. s, OH), 3.34 containing trace amounts of EtOAc.
2
(
(
2H, apparent q,
J
6.2, CH ), 3.67 (2H, t,
J
5.8 Hz, CH ), 5.08
R 0.19 (40% EtOAc in PE, PMA); δH 1.46 (9H, s, 3 x Me),
2
2
f
1H, br. s, 1H, NH), 5.11 (2H, s, CH ), 7.30–7.39 (5H, m, Ph); 1.48 (9H, s, 3 x Me), 1.53–1.66 (2H, m, CH ), 3.20–3.39 (2H,
2
2
δC 32.6, 37.7, 59.6, 66.9, 128.1, 128.2, 128.6, 136.5, 157.3.
m, 2 x CH), 3.40–3.60 (2H, m, 2 x CH), 3.75–3.85 (1H, m,
CH), 5.08 (2H, s, CH ), 5.41 (1H, br s, NH), 7.27–7.34 (5H, m,
2
5
Benzyl (3-oxopropyl)carbamate 8
Ph), 8.68 (1H, br s, NH), 11.44 (1H, br s, NH); δ 28.1, 28.3,
C
PCC (8.75 g, 40.6 mmol, 1.7 equiv.) and Celite© (9 g) were 34.9, 38.0, 47.6, 66.8, 69.5, 79.7, 83.6, 128.2, 128.2, 128.6,
stirred in CH Cl (50 mL) for 5 min whereupon alcohol (5.0 136.7, 153.1, 157.1, 157.3, 162.9; vmax 3681, 3415, 3331, 2984,
7
2
2
-
1
g, 24 mmol) dissolved in CH Cl (30 mL) was added. After 4 h 2935, 1725, 1638+ cm ; HRMS(CI) found 481.2644,
2
2
the reaction was diluted with Et O (100 mL) and passed C H N O ([M+H] ) requires 481.2657.
2
23 37
4
7
©
through a short pad of layered silica and Celite . The remaining
solids were suspended in CH Cl (25 mL) and precipitated with
2
2
(E)-tert-butyl-5-(2-(((benzyloxy)carbonyl)amino)ethyl)-2-
Et O (50 mL) and this mixture passed through the same pad. ((tert-butoxycarbonyl)imino)imidazolidine-1-carboxylate 12
2
This process was repeated a further three times and the filtrate
Dppe (1.24 g, 3.12 mmol, 1.5 equiv.) and imidazole (0.5 g,
evaporated under reduced pressure to give a yellow oil (5.0 g). 7.3 mmol, 3.5 equiv.) were added to a cooled (–20 °C) solution
Column chromatography (40% EtOAc in PE) gave
colourless viscous oil (3.0 g, 14.5 mmol) in 60% yield.
8 as a of 11 (1.00 g, 2.08 mmol) in anhydrous CH Cl (20 mL) and
2 2
the mixture stirred to ensure dissolution. At this point finely
J 5.7 powdered iodine (0.8 g, 3.1 mmol, 1.5 equiv.) was added and
R 0.4 (50% EtOAc in petrol, PMA); δH 2.75 (2H, t,
f
Hz, CH ), 3.49 (2H, apparent q,
J 6.0 Hz, CH ), 5.09 (2H, s, the mixture stirred for 2 h. The reaction mixture was diluted
2
2
CH ), 5.15 (1H, br s, HN), 7.30-7.39 (5H, m, Ar), 9.81 (1H, s, with CHCl3 (200 mL) then washed with NH Cl solution
2
4
CHO); δC 34.6, 44.2, 66.9, 128.2, 128.3, 128.7, 136.5, 165.4, (aqueous, saturated, 200 mL) and brine (200 mL). The organic
-
1
2
01.3; vmax 3445, 1704, 1645 cm .
layer was dried (MgSO ) and evaporated under reduced
4
pressure to give the crude product (2.7 g). This was dissolved in
Benzyl (3-hydroxy-4-nitrobutyl)carbamate 9
Aldehyde (2.2 g, 10.2 mmol) and nitromethane (18.7 g, effected the precipitation of phosphine oxide by products. After
6.5 mL, 0.31 mol, 30 equiv.) were dissolved in CH Cl (20 storage at –20 °C for 12 h, the solution was filtered and the
CH Cl (10 mL) and diethyl ether (100 mL) was added which
2 2
8
1
2
2
mL) and cooled (0°C). DIPEA (3.7 g, 5 mL, 28.6 mmol, 2.8 filtrate evaporated to give crude 12 (1.06 g) which was used in
equiv.) was added to the solution in a drop-wise manner and the the next step without further purification.
mixture stirred for 5 days. NH Cl solution (aqueous, saturated,
R 0.18 (40% EtOAc in PE, PMA); δH (partial data, NH not
f
4
2
50 mL) was added and stirring continued for 10 min. The observed) 1.46 (9H, s, Boc), 1.49 (9H, s, Boc), 1.71–1.84 (1H,
organic layer was separated and the aqueous layer extracted m, CH), 1.85–1.95 (1H, m, CH), 3.15–3.29 (2H, m, CH ), 3.51
2
with CH Cl (3 x 100 mL). The combined organic layers were (1H, br d,
J
12.3 Hz, CH), 3.88 (1H, dd,
J 8.9, 12.3 Hz, CH),
2
2
dried (MgSO ), evaporated under reduced pressure and the 4.19–4.29 (1H, m, CH), 5.06 (2H, s, CH ), 5.25 (1H, br s, NH)
4
2
crude product (4.8 g) purified by column chromatography in 7.25–7.35 (5H, m, Ph); δC (partial data, 2 x quaternary C not
5
0% EtOAc in petrol to give
9
(2.5 g, 9.2 mmol) in 90% yield observed) 28.1, 34.3, 36.9, 51.2, 54.5, 66.7, 81.4, 84.0, 128.1,
as a clear colourless oil.
128.1, 128.5, 136.5, 150.7, 156.5, 166.1; vmax 3332, 2982,
-
1
R 0.29 (50% EtOAc in PE, PMA); δH 1.56–1.73 (2H, m, 2933, 1712, 1645+ cm ; HRMS(CI) found 463.2545,
f
CH ), 3.22–3.29 (1H, m, CH), 3.54–3.66 (1H, m, CH), 3.85 C H N O ([M+H] ) requires 463.2551.
2
23 35
4
6
(
1H, br s, OH), 4.36–4.47 (3H, m, CH CH), 5.05 (1H, br s,
2
,
NH), 5.12 (2H, s, CH ), 7.30–7.40 (5H, m, Ph); δC 34.3, 37.1, 2-(2-iminoimidazolidin-4-yl)ethanamine hydrochloride 13
2
6
6.0, 67.4, 80.4, 128.3, 128.5, 128.8, 136.3, 157.7; vmax 3404,
4