R. F. G. Fröhlich et al. / Carbohydrate Research 346 (2011) 1592–1598
1597
at ambient temp. for 90 min. The mixture was brought to pH 5 by
addition of aqueous HCl (5%) and the solvent was removed under
reduced pressure to give crude 5c. Mono-N-dansyl-1,6-diamino-
hexane (A, 200 mg, 0.57 mmol) in dichloromethane (5 mL) was
added to this crude 5c and the solvent was again removed under
reduced pressure. The residue was dissolved in DMF (4.5 mL),
Et N (125 lL, 0.9 mmol) and TBTU (96%, 130 mg, 0.40 mmol) were
3
added. After it completed conversion (TLC, ca. 90 min), the mixture
was concentrated under reduced pressure. Chromatography of the
(CHCl
3
/MeOH/concd NH
4
OH = 40:10:1 v/v/v) to give syrupy sec-
ondary amine 11 (127 mg, 47%) and less polar tertiary amine 12
(38 mg, 9%).
1
5
20
D
2 2
Cl
); 1H NMR (500 MHz,
Compound 11: ½
aꢂ
ꢁ3.7 (c 1.9, CH
CDCl
3
): d = 4.27 (m, 1H, H-4), 3.91 (dd, 1H, J = 3.6 Hz, J = 11.8 Hz,
H-6a), 3.86–3.78 (m, 3H, H-2, H-3, H-6b), 2.94 (m, 1H), 2.89–2.82
(m, 8H), 2.72 (m, 1H, H-1eq), 2.64–2.46 (m, 6H), 2.08 (m, 1H, H-
1
3
1ax), 1.56–1.20 (m, 18H), 1.19–1.08 (m, 4H); C NMR (125 MHz,
CDCl ): d = 109.9 (isopropylidene), 81.0, 70.6, 61.8, 60.8, 54.9,
52.9 (C-1, C-2, C-3, C-4, C-5, C-6), 49.8, 49.6, 45.7, 43.4 (C-1 , C-6 ,
3
0
0
residue (CHCl
3 4
/MeOH/concd NH OH = 10:4:1 v/v/v) gave com-
20
00
00
pound 8 (267 mg, 86%) as a pale yellow syrup. ½
a
ꢂ
ꢁ7.7 (c 2.7,
2
C-1 , C-6 , NMe ), 29.7, 29.5, 29.3, 28.7, 27.5, 27.4, 26.8, 26.7,
D
1
+
MeOH); H NMR (500 MHz, MeOH-d
4
): d = 3.99 (br s, 1H, H-4),
26.4, 24.4. MS: Calcd for [C33
Found: [M+H] 635.3897.
H
54
N
O
4 6
SH]: m/z 635.3842 [M+H] ;
+
3
.87–3.76 (m, 3H, H-2, H-3, H-6a), 3.24 (dd, 1H, J = 2.5 Hz,
2
D
0
2 2
Cl
); 1H NMR (500 MHz,
J = 9.1 Hz, H-6b), 3.04–2.95 (m, 3H, incl. H-1eq), 2.92 (br s 1H, H-
Compound 12: ½
aꢂ
ꢁ2.8 (c 1.9, CH
0
5
1
1
1
6
5
3
), 2.88–2.77 (m, 8H), 2.77–2.67 (m, 1H, H-1 a), 2.57–2.49 (m,
CDCl ): d = 4.29 (m, 1H, H-4), 3.92 (dd, 1H, J = 5.1 Hz, J = 11.9 Hz,
3
0
H, H-1 b), 2.46–2.39 (m, 1H, H-5), 2.20–2.10 (m, 3H, incl. H-
ax), 1.65–1.55 (m, 2H), 1.55–1.45 (m, 2H), 1.34–1.20 (m, 6H),
.15–1.01 (m, 4H); C NMR (125 MHz, MeOH-d
), 77.0, 72.1, 68.8, 65.2, 62.2, 57.8 (C-1, C-2, C-3, C-4, C-5, C-6),
H-6a), 3.89–3.81 (m, 3H, H-2, H-3, H-6b), 2.96 (m, 1H, H-1eq),
2.90–2.81 (m, 16H), 2.73 (m, 1H, H-1 a), 2.64 (m, 1H, H-5), 2.55
(m, 1H, H-1 b), 2.32–2.21 (m, 6H), 2.18–2.07 (m, 2H, incl. H-
1ax), 1.52 (s, 3H), 1.49–1.30 (m, 12H), 1.30–1.05 (m, 14H);
NMR (125 MHz, CDCl ): d = 110.1 (isopropylidene), 80.9, 77.8,
70.9, 61.7, 60.6, 54.7 (C-1, C-2, C-3, C-4, C-5, C-6), 54.0 (2 C-6 ),
52.9 (C-1 ), 45.8 (2 NMe
0
1
3
0
4
): d = 175.9 (C-
0
13
C
0
00
00
0
3.8, 45.8, 43.7, 40.1 (C-1 , C-1 , C-6 , NMe
2
), 37.0 (C-5 ), 30.4,
SH]:
3
00
0.1, 28.0, 27.2, 27.0, 26.9, 24.7. MS: Calcd for [C30
H
48
N
4
O
7
+
+
0
m/z 609.3322 [M+H] ; Found: [M+H] 609.3340.
2
), 43.6 [N–(CH
2
–)
3
], 29.8, 28.6, 27.5,
2
7.4, 27.1, 26.8, 26.75 (3 C), 26.7 (3 C), 24.4 (2 C). MS: Calcd
3
.5. N-Bis(dansylaminohexyl)aminocarbonylpentyl-1,5-
for [C51
H
78
N
6
O
S
8 2
H]: m/z 967.5401 [M+H] ; Found: [M+H]+
+
dideoxy-1,5-imino- -galactitol (9)
D
967.5460.
To an aqueous solution (1.5 mL) of N-methoxycarbonylpentyl-
-deoxynojirimycin (5b, 32 mg, 0.11 mmol), 0.5 M aqueous NaOH
3.7. N-Bis(dansylaminohexyl)aminohexyl-1,5-dideoxy-1,5-
imino- -galactitol (13)
1
D
(
0.30 mL, 0.15 mmol) was added and the mixture was kept at
ambient temp for 60 min. The mixture was brought to pH 5 by
addition of aqueous HCl (5%) and the solvent was removed under
To compound 12 (36 mg, 0.037 mmol), aqueous HCl (6%, 2 mL)
was added and the mixture was stirred at ambient temp for 3 h.
Removal of the solvent under reduced pressure provided a slightly
yellow glass which was triturated with dichloromethane and again
dried under reduced pressure to provide inhibitor 13 as the tetra-
15
reduced pressure. Bis(6-dansylamino)hexylamine
.15 mmol) in dichloromethane (3 mL) was added to the residue
and the solvent was again removed under reduced pressure. The
residue was dissolved in DMF (1.5 mL), Et N (30 L, 0.22 mmol)
(B, 100 mg,
0
2
0
+2.3 (c 2.0, MeOH); 1H NMR
3
l
hydrochloride (40 mg, 100%). ½
(500 MHz, D O) d = 4.10 (br s, 1H, H-4), 3.87 (ddd, 1H, J1eq,2 = 5 Hz,
1ax,2 = J2,3 = 10.6 Hz, H-2), 3.77 (m, 2H, H-6a, H-6b), 3.40 (m, 2H),
3.35–3.20 (m, 14H), 3.15–2.95 (m, 3H), 2.86–2.80 (m, 7H), 2.80–
2.55 (m, 4H), 1.70–0.38 (m, 24H). MS: Calcd for [C48 H]:
aꢂ
D
and TBTU (96%, 39 mg, 0.12 mmol) were added. After it completed
conversion (TLC, ca. 10 min), the mixture was concentrated under
2
J
reduced pressure and the residue was chromatographed (CHCl
MeOH/concd NH OH, 50:10:1 v/v/v) providing compound
90 mg, 87%) as a fluorescent yellow syrup. ½
3
/
9
4
74 6 8 2
H N O S
2
D
0
+
+
(
a
ꢂ
ꢁ6.0 (c 2.8,
m/z 927.5088 [M+H] ; Found: [M+H] 927.5034.
1
4
MeOH); H NMR (500 MHz, MeOH-d ): d = 3.99 (m, 1H, H-4),
3
1
2
.87–3.77 (m, 3H, H-2, H-3, H-6a), 3.64–3.57 (m, 2H), 3.24 (dd,
3.8. N-[(Dansylaminohexyl)-N-octanoylamino]hexyl-3,4-O-
isopropylidene-1,5-dideoxy-1,5-imino- -galactitol (14)
H, J = 2.9 Hz, J = 9.2 Hz, H-6b), 3.10–2.97 (m, 5H, incl. H-1eq),
D
0
.89–2.66 (m, 16H), 2.59–2.49 (m, 1H, H-1 a), 2.49–2.38 (m, 1H,
0
H-1 b), 2.27–2.11 (m, 3H, incl. H-1ax), 1.63–1.43 (m, 4H), 1.34–
To a solution of compound 11 (123 mg, 0.194 mmol) in dichlo-
romethane (6 mL) containing pyridine (25 L, 0.31 mmol), a solu-
tion of octanoic chloride (37 L, 0.21 mmol) in dichloromethane
1
3
1
.14 (m, 14H), 1.14–1.04 (m, 4H), 1.03–0.93 (m, 4H); C NMR
l
0
(
125 MHz, MeOH-d
4
): d = 174.8 (C-6 ), 78.3, 75.9, 71.0, 67.7, 64.0,
l
6
1.1 (C-1, C-2, C-3, C-4, C-5, C-6), 57.1, 52.7, 48.7, 46.5, 45.7, 44.8
(3 mL) was added at 0 °C over 30 min. The reaction was then
quenched with MeOH (1 mL) and the mixture was concentrated
under reduced pressure. The residue was purified on silica gel
0
00
00
(
C-1 , 2 C-1 , 2 C-6 , 2 NMe
2
), 42.6, 42.5, 32.7, 29.3, 29.2, 28.6,
2
7.2, 27.1, 26.1, 26.0, 25.4, 23.7. Caused by the nature of the amide
00
bond, some signals of carbons of the X sections appear at slightly
different parts per million values. MS: Calcd for [C48 H]:
m/z 941.4880 [M+H] ; Found: [M+H] 941.4921.
(CHCl
3 4
/MeOH/concd NH OH = 150:10:1 v/v/v) to provide com-
2
0
H
72
N
6
O
S
9 2
pound 14 (105 mg, 71%) as a faintly yellow syrup. ½
aꢂ
ꢁ3.5 (c
D
+
+
1
1.4, MeOH); H NMR (500 MHz, CDCl
3
): d = 4.29 (br s, 1H, H-4),
3
.92 (m, 1H, H-2), 3.88–3.81 (m, 3H, H-3, H-6a, H-6b), 3.29–3.11
3
1
.6. N-(Dansylaminohexylamino)hexyl-3,4-O-isopropylidene-
,5-dideoxy-1,5-imino- -galactitol (11) and N-bis(dansylamino
(m, 3H), 3.08 (dd, 1H, J = 7.4 Hz, J = 8 Hz), 2.98 (m, 1H), 2.90–2.81
0
D
(m, 8H), 2.74 (m, 1H, H-1 a), 2.63 (m, 1H, H-5), 2.54 (m, 1H, H-
0
hexyl)aminohexyl-3,4-O-isopropylidene-1,5-dideoxy-1,5-
imino- -galactitol (12)
1 b), 2.23 (t, 1H, J = 7.5 Hz), 2.19 (t, 1H, J = 7.5 Hz), 2.08 (m, 1H,
1
3
D
H-1ax), 1.65–1.05 (m, 32H), 0.88–0.82 (t, 3H); C NMR (125
MHz, CDCl ): d = 173.2/173.1, 110.0/109.9 (isopropylidene), 81.0/
80.9, 77.8/77.7, 70.9/70.8, 61.8/61.7, 60.9/60.8, 54.7, 52.8/52.7,
3
16
To a solution of known compound 10 (128 mg, 0.42 mmol)
1
5
0
0
00
and mesylate C (185 mg, 0.43 mmol) in dry N,N-dimethylform-
amide, sodium carbonate (271 mg, 2.54 mmol) was added and
48.2/48.1 (C-1, C-2, C-3, C-4, C-5, C-6, C-1 , C-6 ), 45.9 (C-1 ), 45.8
0
0
3
(NMe ), 43.4/43.3 (C-6 ), 33.5/33.4, 32.1, 29.9, 29.8/29.7, 29.5,
the mixture was stirred at 60 °C for 44 h when TLC (CHCl
3
/
29.2, 28.7/28.6, 27.7/27.6, 27.5/27.2, 27.0/26.9, 26.7, 26.5/26.4,
25.9/25.8, 23.0, 14.4. Due to the amide bond, double signals are ob-
MeOH/NH OH concd = 12:4:1 v/v/v) indicated complete conver-
4
sion of the starting material. The mixture was concentrated under
reduced pressure and the remaining residue was chromatographed
68 4 7
served for several carbon atoms. MS: Calcd for [C41H N O SH]: m/
z 761.4887 [M+H] ; Found: [M+H] 761.4835.
+
+