5602
H. Li et al. / Bioorg. Med. Chem. 17 (2009) 5598–5604
(100.6 MHz, D2O) d = 173.9 (C@O), 71.1 (C-4), 67.4 (C-3), 65.1
(C-6), 60.0 (C-8), 57.8 (C-2), 53.7 (C-5), 49.3 (C-7), 22.0 (COCH3);
HRMS (CIMS) m/z: [M+H]+ calcd for C9H19O5N2: 235.1294; found:
235.1286.
Purification by flash column chromatography (cyclohexane/EtOAc
1:10) afforded the azido azepane 20 (29 mg, 80%) as an oil.
[a]
D = +5.8 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.29–7.05
(m, 40H, aromatic H), 5.14–5.01 (m, 4H, 4 ꢀ NCOOCHPh), 4.71 (d,
J = 12.0 Hz, 1H, CHPh), 4.54–4.42 (m, 9H, 9 ꢀ CHPh), 4.39 (d,
J = 12.0 Hz, 1H, CHPh), 4.34 (d, J = 12.0 Hz, 1H, CHPh), 3.91 (dt,
3J(6,7a) = 2.0 Hz, 3J(6,5) = 3J(6,7b) = 8.0 Hz, 1H, H-6), 3.85 (dt,
5.1.4. Spectroscopic data for (3R,4S,5R,6R,7S),N-(3,5,6-
trihydroxy-7-hydroxymethyl-azepan-4-yl)-acetamide 16
3
[a
]
D = +8.5 (c 0.2, CH3OH); 1H NMR (400 MHz, D2O): d = 4.00 (dt,
3J(60,70a) = 1.6 Hz, J(60,50) = 3J(60,70b) = 7.6 Hz, 1H, H-60), 3.80–3.67
3J(6,7a) = 2.3 Hz, 3J(5,6) = 3J(6,7b) = 9.8 Hz, 1H, H-6), 3.86 (app. d,
3J(3,4) = 5.6 Hz, 1H, H-3), 3.79–3.74 (m, 2H, H-4, H-5), 3.60–3.47
(m, 3H, H-2, H-8a, H-8b), 3.21 (dd, 3J(7a,6) = 2.3 Hz, 3J(7a,7b) =
13.6 Hz, 1H, H-7a), 3.12 (dd, 3J(7b,6) = 9.8 Hz, 3J(7b,7a) = 13.6 Hz,
1H, H-7b), 1.79 (s, 3H, COCH3); 13C NMR (100 MHz, D2O):
d = 173.0 (C@O), 72.9 (C-4), 68.5 (C-3), 67.4 (C-6), 60.4 (C-8), 60.2
(C-5), 57.0 (C-2), 48.4 (C-7), 21.0 (COCH3); HRMS (CIMS) m/z:
[M+H]+ calcd for C9H19O5N2: 235.1294; found: 235.1291.
(m, 5H, H-2a, H-30, H-4, H-40, H-20a), 3.65–3.60 (m, 3H, H-70a, H-
7a, H-3), 3.58–3.55 (m, 2H, H-5, H-50), 3.50–3.45 (m, 3H, H-2b,
3
3
H-20b, H-7b), 3.39 (dd, J(70b,60) = 7.6 Hz, J(70b,70a) = 14.8 Hz, 1H,
H-70b); 13C NMR (100 MHz, CDCl3): d = 156.2, 156.1 (2 ꢀ C@O),
138.4, 138.1, 137.9, 137.8, 137.7, 137.6, 136.5, 136.4 (8 ꢀ Cipso),
128.6–127.4 (40 ꢀ aromatic CH), 83.0, 82.4 (C-50, C-5), 81.7, 81.1
(C-4, C-40), 79.4, 78.5 (C-3, C-30), 73.3, 73.1, 73.0, 72.9, 71.7, 71.6
(6 ꢀ CH2Ph), 67.8, 67.5 (2 ꢀ NCOOCH2Ph), 64.0, 63.3 (C-60, C-6),
46.1, 46.0 (C-7, C-70), 44.8, 44.4 (C-20, C-2); HRMS (CIMS) m/z:
[M+H]+ calcd for C35H37O5N4: 593.2764; found: 593.2763.
5.1.5. Spectroscopic data for (3S,4R,5R,6R,7R),N-(4,5,6-
trihydroxy-7-hydroxymethyl-azepan-3-yl)-acetamide 17
[a]
D = +62.8 (c 1.3, CH3OH); 1H NMR (400 MHz, D2O): d = 4.42
5.1.8. (3S,4R,5R,6S) 3-Acetylamino-4,5,6-tris-benzyloxy-
azepane-1-carboxylic acid benzyl ester 21
(ddd, 3J(6,7a) = 4.8 Hz, 3J(5,6) = 9.6 Hz, 3J(6,7b) = 11.2 Hz, 1H, H-6),
4.30 (dd, 3J(4,5) = 1.3 Hz, 3J(3,4) = 6.7 Hz, 1H, H-4), 4.19 (dd,
3J(4,5) = 1.3 Hz, 3J(5,6) = 9.6 Hz, 1H, H-5), 4.10 (dd, 3J(2,3) = 3.9 Hz,
3J(3,4) = 6.7 Hz, 1H, H-3), 3.97 (dd, 3J(2,8a) = 4.4 Hz, 3J(8a,8b) =
12.3 Hz, 1H, H-8a), 3.83 (dd, 3J(2,8b) = 8.5 Hz, 3J(8a,8b) = 12.3 Hz,
1H, H-8b), 3.57 (dd, 3J(6,7a) = 4.8 Hz, 3J(7a,7b) = 13.8 Hz, 1H, H-
7a), 3.40 (m, 3J(2,3) = 3.9 Hz, 3J(2,8a) = 4.4 Hz, 3J(2,8b) = 8.5 Hz,
1H, H-2), 3.12 (dd, 3J(6,7b) = 11.2 Hz, 3J(7a,7b) = 13.8 Hz, 1H, H-
7b), 1.89 (s, 3H, COCH3); 13C NMR (100 MHz, D2O): d = 174.8
(C@O), 74.6 (C-4), 70.3 (C-5), 67.2 (C-3), 66.6 (C-2), 61.2 (C-8),
48.7 (C-6), 46.0 (C-7), 22.4 (COCH3); HRMS (CIMS) m/z: [M+H]+
calcd for C9H19O5N2: 235.1294; found: 235.1292.
Triphenyl phosphine (16 mg, 61 lmol) was added to a solution
of the azido azepane 20 (24 mg, 0.040 mmol) in a 3:1 mixture of
THF–H2O (2 mL) under argon. The reaction mixture was stirred
at 50 °C for 18 h, by which time TLC revealed no trace of starting
material. The reaction mixture was concentrated under reduced
pressure and the crude amine was directly engaged in the next
step. The crude amine was dissolved in anhydrous pyridine
(1.5 mL) and acetic anhydride (0.5 mL) was added under argon.
The reaction mixture was stirred at rt for 2 h and was then co-
evaporated with toluene and concentrated. Purification by flash
column chromatography (cyclohexane/ethyl acetate, 10:1 then
3:1 then 1:1) afforded the corresponding acetamido azepane 21
5.1.6. Spectroscopic data for (3S,4R,5R,6R,7R),N-(3,5,6-
(18 mg, 72%) as a colorless oil. [
a]
D = ꢁ1.2 (c 0.25, CHCl3); 1H
trihydroxy-7-hydroxymethyl-azepan-4-yl)-acetamide 18
NMR (400 MHz, CDCl3): d = 7.32–7.08 (m, 30 H, aromatic H),
6.57–6.55 (m, 2H, NH, NH’), 5.07–4.98 (m, 4H, 4 ꢀ NCOOCHPh),
4.71 (d, J = 11.7 Hz, 1H, CHPh), 4.59–4.24 (m, 10 H, 4 ꢀ CH2Ph, H-
6, H-60), 4.20–4.12 (m, 3 H, H-2a, H-7a, H-70a), 4.00–3.87 (m, 5 H,
H-20a, H-4, H-40, H-3, H-50), 3.80–3.72 (m, 2 H, H-30, H-5), 3.29–
3.21 (m, 4H, H-2b, H-20b, H-7b, H-70b), 1.68 (s, 3H, CH3CO), 1.36
(s, 3H, CH3CO); 13C NMR (100 MHz, CDCl3): d = 170.0, 169.7
(2 ꢀ C@O, Ac), 156.5, 156.2 (2 ꢀ C@O, Z), 138.2, 138.1, 137.7,
137.5, 137.4, 137.3, 136.6, 136.5 (8 ꢀ Cipso), 128.6–127.6
(40 ꢀ aromatic CH), 83.7, 83.4 (C-4, C-40), 81.3, 81.1 (C-30, C-3),
76.0, 75.8 (C-5, C-50), 72.7, 72.5, 72.3, 71.9, 71.8 (6 ꢀ CH2Ph),
67.5, 67.2 (2 ꢀ NCOOCH2Ph), 51.9, 51.5 (C-60, C-6), 47.8 (C-20 or
C-70), 47.7 (C-20 or C-70), 47.6 (C-2 or C-7), 46.8 (C-2 or C-7), 22.8
(2 ꢀ CH3CO); HRMS (CIMS) m/z: [M+H]+ calcd for C37H41O6N2:
609.2965; found: 609.2961.
[a]
D = +72.7 (c 1.3, CH3OH); 1H NMR (400 MHz, D2O): d = 4.39
(dd, 3J(4,5) = 1.6 Hz, 3J(5,6) = 9.6 Hz, 1H, H-5), 4.21 (ddd,
3J(6,7a) = 4.1 Hz, 3J(1,7b) = 10.6 Hz, 3J(5,6) = 9.6 Hz, 1H, H-6), 4.18
(dd, 3J(3,4) = 6.6 Hz, 3J(4,5) = 1.6 Hz, 1H, H-4), 4.08 (dd,
3J(2,3) = 3.0 Hz, 3J(3,4) = 6.6 Hz, 1H, H-3), 3.96 (dd, 3J(8a,2) =
4.5 Hz, 3J(8a,8b) = 12.2 Hz, 1H, H-8a), 3.83 (dd, 3J(8b,2) = 9.0 Hz,
3J(8a,8b) = 12.2 Hz, 1H, H-8b), 3.62 (dd, 3J(6,7b) = 4.1 Hz, 3J(7a,
7b) = 13.6 Hz, 1H, H-7b), 3.49 (ddd, 3J(2,3) = 3.0 Hz, 3J(2,8a) =
4.5 Hz, 3J(2,8b) = 9.0 Hz, 1H, H-2), 3.24 (dd, 3J(7a,6) = 10.6 Hz,
3J(7a,7b) = 13.6 Hz, 1H, H-7a); 13C NMR (100.6 MHz, D2O):
d = 174.5 (C@O), 72.9 (C-4), 67.6 (C-3), 66.3 (C-6), 66.1 (C-2), 61.4
(C-8), 53.8 (C-5), 48.0 (C-7), 22.4 (COCH3); HRMS (CIMS) m/z:
[M+H]+ calcd for C9H19O5N2: 235.1294; found: 235.1290.
5.1.7. (3S,4R,5R,6S) 3-Azido-4,5,6-tris-benzyloxy-azepane-1-
carboxylic acid benzyl ester 20
5.1.9. (3S,4R,5R,6S),N-(4,5,6-Trihydroxy-azepan-3-yl)-
acetamide 22
To a solution of the protected acetamido azepane 21 (18 mg,
0.030 mmol) in CH3OH (3 mL) was added 10% Pd/C (20 mg) and a
Methanesulfonyl chloride (17.4
dropwise at 0 °C under argon to a solution of alcohol 19 (41 mg,
72.2 mol) and a catalytic amount of DMAP (3.5 mg, 29 mol) in
lL, 0.23 mmol) was added
l
l
dry pyridine (1 mL). The ice bath was removed and the reaction
mixture was stirred for 2 h at rt, co-evaporated with toluene and
concentrated. The residue was dissolved in CH2Cl2 (10 mL) and
washed with a 1 M HCl aq solution (5 mL). The organic layer was
then dried (MgSO4), filtered, and concentrated under reduced pres-
sure. The crude mesylate was used directly without further purifi-
cation. To a solution of crude mesylate in DMF (2 mL) was added
NaN3 (28 mg, 0.43 mmol) and the reaction mixture was heated at
90 °C for 60 h. The solvent was removed and the residue was dis-
solved in CH2Cl2 (15 mL) and washed successively with water
(10 mL) and brine (10 mL). The organic layer was dried (MgSO4),
filtered and the solvent evaporated under reduced pressure.
1 M HCl aq solution (30
and air was replaced by H2. After stirring for 7 h at rt, the reaction
mixture was filtered through a RotilaboÒ Nylon 0.45
m filter
eluted with CH3OH, and concentrated to afford the acetamido aze-
pane 22 (6.1 mg, quantitative yield) as a colorless oil. [ D = +14.8
lL). The solution was degased three times
l
a
]
(c 0.4, CH3OH); 1H NMR (400 MHz, D2O): d= 4.18 (dt,
3J(3,2a) = 2.7 Hz, 3J(3,4) = 3J(3,2b) = 9.7 Hz, 1H, H-3), 4.03 (dt,
3J(6,7a) = 2.4 Hz, 3J(5,6) = 3J(6,7b) = 6.6 Hz, 1H, H-6), 3.76 (t,
3J(5,6) = 3J(4,5) = 6.6 Hz, 1H, H-5), 3.65 (dd, 3J(4,5) = 6.6 Hz,
3J(3,4) = 9.7 Hz, 1H, H-4), 3.33–3.22 (m, 3H, H-2a, H-2b, H-7a),
3.15–3.07 (m, 1H, H-7b), 1.95 (s, 3H, CH3CO); 13C NMR