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Organic & Biomolecular Chemistry
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OH), 4.38 - 4.33 (1H, m, A part of a CHH-OH AB system), 4.30 (1H, d, 83.2 (CH-O), 77.7 (CH-O), 73.3 (CH2-Ph), 71.9 (CH2-Ph), 67.1 (CH-O
DOI: 10.1039/C5OB00532A
J = 8.2 Hz, CH-O (2)), 4.11 - 4.06 (1H, m, CH-O (4)), 4.02 -3.95 (1H, m, (3)), 62.3 (CH2-OH), 44.6 (2CH-N), 39.8 (CH-CH2OH), 25.2 (CH3), 19.0
B part of a CHH-OH AB system), 3.43 (1H, dd, J = 7.9, 2.6 Hz, CH-N (CH3); HRMS calculated for C24H31N2O4: 411.2284 [M+H]+; found:
(6)), 3.40 (1H, dd, J = 8.3, 2.3 Hz, CH-O (3)), 3.02 (1H, br d, J = 8.2 Hz, 411.2288.
CH-OH (4)), 2.98 - 2.87 (1H, m, A part of a CHH-CH3 AB system), 2.77
(1R,2S,3S,4S,5R,6R)-5-(hydroxymethyl)-7-
azabicyclo[4.1.0]heptane-2,3,4-triol (1a)
- 2.68 (1H, m, B part of a CHH-CH3 AB system), 2.66 (1H, d, J = 7.9
Hz, CH-N (1)), 2.19 - 2.14 (1H, m, CH-CH2OH), 1.24 (3H, t, J = 7.3 Hz,
CH3);C (126 MHz; CDCl3) 159.9 (C=O), 156.0 (C=N), 145.8 (Car (4a’)),
137.8 (Car (phenyl)), 137.7 (Car (phenyl)), 134.3 (CHar (6’)), 128.7
(CHar), 128.6 (CHar), 128.5 (2CHar), 128.2 (CHar), 128.1 (2CHar), 128.0
(CHar), 127.9 (CHar), 127.8 (CHar), 127.0 (CHar (5’)), 126.8 (CHar (7’)),
126.4 (CHar (8’)), 120.8 (Car (8a’)), 83.8 (CH-O (3)), 74.9 (CH-O (2)),
74.3 ((CH2-Ph (2)), 71.5 ((CH2-Ph (3)) , 67.5 (CH-O (4)), 62.3 (CH2-
OH), 52.1 (CH-N (1)), 47.5 (CH-N (6)), 40.9 (CH-CH2OH), 27.7 (CH2-
CH3), 10.6 (CH3); HRMS calculated for C31H33N3O5: 550.2318
[M+Na]+; found: 550.2316.
A suspension of sodium (50.0 mg, 2.18 mmol) in dry THF (6 mL) was
cooled to -78 ºC and it was treated with liquid ammonia for 5
minutes until the starting suspension became a dark blue solution.
Then, a solution of (1R,2R,3S,4S,5S,6R)-7-amino-4,5-bis(benzyloxy)-
2-(hydroxymethyl)-7-azabicyclo[4.1.0]heptan-3-ol (5) (19.2 mg,
0.052 mmol) in THF (4 mL) was added. The resulting mixture was
stirred at -78 ºC for 1 hour. After that, MeOH was added dropwise
until the blue color disappeared and then, the reaction mixture was
allowed to reach room temperature and concentrated in vacuo to
give a residue that was purified by ion-exchange chromatography
with Dowex 50W X8 (729.0 mg) after adsorption with water (10 mL)
and desorption by 30% aq ammonia (100 mL) to afford N-amino
aziridine 1a as a white waxy solid (9.0 mg, 91%). H (400 MHz;
CD3OD) 3.90 (1H, d, J = 8.2 Hz, CH-O (2)), 3.82 (2H, d, J = 7.3 Hz, CH2-
O), 3.71 - 3.67 (1H, m, CH-O (4)), 3.15 (1H, dd, J = 8.2, 2.1 Hz, CH-O
(3)), 2.25 - 2.20 (1H, br d, J = 7.0 Hz, CH-N (6)), 2.03 (1H, d, J = 7.1
Hz, CH-N (1)), 2.03 - 1.97 (1H, m, CH-CH2OH); C (101 MHz; CD3OD)
77.9 (CH-O (3)), 71.9 (CH-O (4)), 71.5 (CH-O (2)), 62.2 (CH2-O), 48.3
(CH-N (1)), 46.0 (CH-N (6)), 41.9 (CH-CH2OH); HRMS calculated for
C7H14N2NaO4: 213.0851 [M+Na]+; found: 213.0838. The following
hydrazone 1b was isolated as reaction by-product in the same
reaction (0.9 mg, 8%). In addition, the treatment of compound 1a
(1.4 mg, 7.36 mol) with an excess of acetone (2 mL) at room
temperature overnight afforded pure compound 1b (1.7 mg, 100%)
after removal of the solvent under reduced pressure. The purity of
the compound 1a determined by HPLC-ELS (see Supporting
Information) is 100%. The HPLC-MS confirms the identity of the
compound.
(1R,2R,3S,4S,5S,6R)-7-amino-4,5-bis(benzyloxy)-2-
(hydroxymethyl)-7-azabicyclo[4.1.0] heptan-3-ol (5)
A mixture of 3-((1R,2S,3S,4S,5R,6R)-2,3-bis(benzyloxy)-4-hydroxy-5-
(hydroxymethyl)-7-azabicyclo[4.1.0]heptan-7-yl)-2-ethylquinazolin-
4(3H)-one (4) (172.4 mg, 0.327 mmol) and hydrazine (6.5 mL, 132
mmol) was heated to 120 ºC for 20 min. Then, the reaction mixture
was concentrated under reduced pressure to give a residue, which
was purified by flash chromatography (silica gel, MeOH-EtOAc
0.5:9.5 + 1% aq NH3) to afford pure product 5 as a pale yellow oil
20
(111.9 mg, 78%). []D +74.8 (c 2.1 in MeOH); max /cm-1 3311,
3085, 3062, 3029, 2919, 2879, 1682-1600, 1454, 1101, 1062; H
(400 MHz; CDCl3) 7.43 - 7.22 (10H, m, 2Ph), 4.77 (2H, s, CH2 benz),
4.73 (1H, d, JAB = 12.0 Hz, A part of a CHH-Ph AB system), 4.63 (1H,
d, JAB = 12.0 Hz, B part of a CHH-Ph AB system), 4.02 (1H, d, J = 8.1
Hz, CH-O), 4.01 - 3.98 (1H, m, CH-O), 3.98 - 3.89 (2H, m, CH2-OH),
3.42 (4H, br s, 2OH and NH2), 3.26 (1H, dd, J = 8.0, 2.3 Hz, CH-O),
2.15 (1H, dd, J = 7.3 Hz, 1.0 Hz, CH-N (1)), 2.10 (1H, d, J = 7.3 Hz, CH-
N (6)), 1.99 - 1.96 (1H, m, CH (2)). );C (101 MHz; CDCl3) 138.4 (Car),
138.1 (Car), 128.6 (CHar), 128.4 (CHar), 128.2 (CHar), 128.0 (CHar),
128.0 (CHar), 127.7 (CHar), 82.8 (CH-O), 77.6 (CH-O), 73.3 (CH2-Ph),
71.9 (CH2-Ph), 67.6 (CH-O), 62.5 (CH2-OH), 45.6 (CH-N (1)), 45.3 (CH-
N (6)), 39.7 (CH (2)); HRMS calculated for C21H27N2O4: 371.1971
[M+H]+; found: 371.1968. The following hydrazone 8 was isolated as
trace by-product in the same reaction. It could also be obtained
quantitatively by treatment of compound 5 with an excess of
acetone at room temperature overnight and after removal of the
solvent under reduced pressure. (1R,2R,3S,4S,5S,6R)-4,5-
bis(benzyloxy)-2-(hydroxymethyl)-7-(propan-2-ylideneamino)-7-
aza bicyclo[4.1.0]heptan-3-ol (8)
(1R,2S,3S,4S,5R,6R)-5-(hydroxymethyl)-7-(propan-2-
ylideneamino)-7-azabicyclo[4.1.0]heptane-2,3,4-triol (1b)
H (400 MHz; D2O) 4.10 (1H, d, J = 8.7 Hz, CH-O), 3.92 - 3.90 (1H, m,
CH-O), 3.89 (2H, d, J = 7.4 Hz, CH2O), 3.45 (1H, dd, J = 8.7, 2.4 Hz,
CH-O), 2.69 (1H, ddd, J = 7.2, 3.0, 1.1 Hz, CH-N), 2.31 (1H, d, J = 7.2
Hz, CH-N), 2.30 - 2.25 (1H, m, CH-CH2O), 2.08 and 2.07 (3H, s, CH3
invertomer), 1.98 and 1.94 (3H, s, CH3 invertomer); C (101 MHz;
D2O) 174.7 (C=N), 77.7 (CH-O), 71.9 (CH-O), 71.4 (CH-O), 62.7
(CH2O), 48.4 (CH-N), 45.8 (CH-N), 41.6 (CH-CH2OH), 26.1 (CH3), 21.0
(CH3); HRMS calculated for C10H19N2O4: 231.1345 [M+H]+; found:
231.1334. The purity of the compound 1b determined by HPLC-ELS
(see Supporting Information) is 96%. The HPLC-MS confirms the
identity of the compound.
H (400 MHz; CDCl3) δ 7.41 - 7.24 (10H, m, 2Ph), 4.82 - 4.62 (4H, m,
2CH2-Ph), 4.12 (1H, d, J = 8.1 Hz, CH-O), 4.12 - 4.07 (1H, m, CH-O
(3)), 3.96 (2H, ddd, J = 17.3, 11.0, 7.3 Hz, CH2-OH), 3.89 - 3.80 (1H,
br s, OH (3)), 3.37 (1H, dd, J = 8.0, 2.3 Hz, CH-O), 2.60 - 2.55 (1H, m,
CH-N (1)), 2.37 (1H, d, J = 7.2 Hz, CH-N (6)), 2.13 - 2.06 (1H, m, CH-
CH2OH), 1.94 (3H, s, CH3), 1.91 (3H, s, CH3), 1.61 (1H, br s, OH); C
(101 MHz; CDCl3) 168.1 (C=N), 138.4 (Car), 138.1 (Car), 128.6 (CHar),
128.5 (CHar), 128.2 (CHar), 128.1 (CHar), 128.0 (CHar), 127.8 (CHar),
(1R,2S,3S,4S,5R,6R)-5-(acetoxymethyl)-7-acetyl-7-
azabicyclo[4.1.0]heptane-2,3,4-triyl triacetate (7)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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