Synthesis of Azepane and Nojirimycin Analogues
(s, 3H), 3 0.72 (dd, J ) 11.4, 4.5 Hz, 1H), 3.77-3.79 (m, 1H),
3.98 (dd, J ) 11.7, 2.7 Hz, 1H), 4.19-4.24 (m, 2H), 4.30 (d, J
) 2.0 Hz, 1H), 4.53 (d, J ) 3.6 Hz, 1H), 5.11 (ABq, J ) 11.0
Hz, 2H), 5.98 (d, J ) 3.9 Hz, 1H), 7.32 (broad s, 5H); 13C NMR
(75 MHz, CDCl3) δ 26.3, 26.9, 53.9, 61.8, 67.2, 72.1, 76.0, 79.6,
85.2, 104.8, 111.9, 128.0 (s), 128.2, 128.4 (s), 135.8, 156.8. Anal.
Calcd for C18H25NO8: C, 56.57; H, 6.18. Found: C, 56.48; H,
6.25.
1,6-Dideoxy-1,6-im in o-(2S,3R,4R,5R,6R)-L-glycer o-D-glu -
co-h ep titol (1c) Hyd r och lor id e. A solution of 7a (0.10 g,
0.269 mmol) in TFA-H2O (3 mL, 2:1) was stirred at 25 °C for
2.5 h. Trifluroacetic acid was coevaporated with benzene to
furnish a thick liquid. To a solution of the above product in
methanolic hydrochloric acid (5 mL, 9:1) was added 10% Pd/C
(0.05 g). The solution was hydrogenated at 80 psi for 24 h.
The catalyst was filtered through Celite and washed with
methanol. The filtrate was concentrated to obtain a semisolid
of 1c (0.045 g, 75%). Rf 0.20 (chloroform/methanol 8/2); [R]D
+15.9 (c 1.26, MeOH); IR (Nujol) 3200-3600 (broad band)
cm-1; 1H NMR (300 MHz, D2O) δ 3.19 (broad dd, J ) 12.6, 7.2
Hz, 1H), 3.26-3.35 (m, 1H), 3.38-3.48 (m, 1H), 3.72 (dd, J )
12.4, 6.0 Hz, 1H), 3.80-3.92 (m, 4H), 4.02 (broad d, J ) 7.2
Hz, 1H); 13C NMR (75 MHz, D2O) δ 45.3, 59.7, 60.2, 67.6, 70.5,
72.3, 75.1. Anal. Calcd for C7H16ClNO5: C, 36.61; H, 7.02.
Found: C, 36.68; H, 7.25.
50.6, 62.2, 67.1, 70.9, 77.5, 83.7, 104.3, 112.4, 128.1 (s), 128.2,
128.5 (s), 136.1, 155.6, 170.2 (s), 170.5 (s). Anal. Calcd for
C24H31NO11: C, 56.58; H, 6.13. Found: C, 56.65; H, 6.20.
1,5-Dideoxy-1,5-im in o-(2R,3S,4R,5R)-D-altr itol (1-Deoxy-
a ltr on ojir im ycin ) Hyd r och lor id e (2c‚HCl) a n d 2c. A
solution of 8a (0.20 g, 0.393 mmol) in TFA-H2O (2:1, 3 mL)
was stirred at 25 °C for 2.5 h. Trifluroacetic acid was
coevaporated with benzene to furnish a thick liquid. To a
cooled solution of hemiacetal (0.162 g, 0.38 mmol) in acetone:
water (10 mL, 5:1) was added sodium metaperiodate (0.099 g,
0.46 mmol). After the reaction was stirred for 1.5 h ethylene
glycol (0.2 mL) was added and the reaction mixture was
concentrated and residue extracted with chloroform (3 × 15
mL). Workup and column purification (n-hexane/ethyl acetate
) 8/2) afforded an aldehyde that was directly subjected to
hydrogenation in methanol (8 mL) and 10% Pd/C (0.10 g)
under 80 psi for 12 h. The catalyst was filtered and washed
with methanol and the filtrate was concentrated to get a
gummy solid that was directly subjected to deacetylation by
MeOH:HCl (3 mL, 9:1) under reflux for 6 h. Then reaction
mixture was cooled to room temperature,and on freeze-drying
afforded a semisolid of 2c as hydrochloride (0.042 g, 54%
overall). Rf 0.24 (chloroform/methanol ) 5/5); [R]D +31.0 (c 2.0,
MeOH) [lit.4o [R]589 +33.2 (c 0.5, MeOH)]; IR (neat) 3200-3600
1
(broad band) cm-1; H NMR (300 MHz, D2O) δ 3.09 (dd, J )
13.5, 2.7 Hz, 1H), 3.19-3.30 (m, 2H), 3.70 (dd, J ) 12.6, 6.7
Hz, 1H), 3.84 (dd, J ) 12.6, 3.6 Hz, 1H), 3.87-3.92 (m, 2H),
3.99-4.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 43.8, 55.8,
58.1, 63.5, 66.1, 68.3. Anal. Calcd for C6H14ClNO4: C, 36.10;
H, 7.07. Found: C, 35.95; H, 7.25.
1,6-Did eoxy-1,6-im in o-(2S,3R,4R,5S,6S)-D-glycer o-L-id o-
h ep titol (1d ) Hyd r och lor id e. A solution of 7b (0.10 g, 0.269
mmol) in TFA-H2O (3 mL, 2:1) was stirred at 25 °C for 2.5 h,
and following the procedure described in the synthesis of 1c
afforded 1d as a sticky gum (0.040 g, 80%). Rf 0.18 (chloroform/
methanol 8/2); [R]D -4.8 (c 3.35, MeOH); IR (neat) 3200-3600
(broad band) cm-1; 1H NMR (300 MHz, D2O) δ 3.27-3.36 (m,
2H), 3.56-3.74 (m, 2H), 3.76-3.87 (m, 2H), 3.88-3.96 (m, 1H),
3.98-4.16 (m, 2H); 13C NMR (75 MHz, D2O) δ 45.9, 58.9, 60.5,
67.5, 68.4, 75.1, 75.6. Anal. Calcd for C7H16ClNO5: C, 36.61;
H, 7.02. Found: C, 36.63; H, 7.10.
3,5,7-Tr i-O-acetyl-6-(N-ben zoxycar bon ylam in o)-6-deoxy-
1,2-O-isop r op ylid e n e -r-D -glycer o-D -glu co-h e p t ofu r a -
n ose (8a ). To an ice-cooled solution of 7a (0.50 g, 1.30 mmol)
in dry pyridine (1.5 mL) was added acetic anhydride (2.65 g,
26.11 mmol). After the mixture was stirred for 8 h at room
temperature, ice water was added and extracted with chloro-
form (3 × 15 mL). Usual workup and chromatographic
purification (n-hexane/ethyl acetate ) 9/1) afforded triacetate
8a as a thick liquid (0.524 g, 79%). Rf 0.54 (n-hexane/ethyl
acetate 7/3); [R]D +2.0 (c 1.0, CHCl3); IR (Nujol) 3346, 1747
(broad), 1668 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 3H),
1.55 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 4.10-4.21
(m, 1H), 4.30-4.46 (m, 2H), 4.43 (dd, J ) 9.6 and 2.7 Hz, 1H),
4.49 (d, J ) 3.6 Hz, 1H), 5.10 (d, J ) 12.0 Hz, 1H), 5.17 (dd,
J ) 9.6 and 2.7 Hz, 1H), 5.18 (d, J ) 12.0 Hz, 1H), 5.28 (bd,
J ) 8.7 Hz, 1H, exchanges with D2O), 5.33 (d, J ) 2.7 Hz,
1H), 5.94 (d, J ) 3.6 Hz, 1H), 7.39 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 20.7, 20.8 (s), 26.2, 26.7, 51.8, 62.6, 66.9, 69.6, 74.9,
82.9 (s), 105.1, 112.5, 128.1 (s), 128.5 (s), 136.3, 156.0, 169.6,
169.9, 170.8 (s). Anal. Calcd for C24H31NO11: C, 56.58; H, 6.13.
Found: C, 56.45; H, 6.25.
A solution of 2c‚HCl (0.042 g, 0.21 mmol) in methanol and
25% aqueous ammonia (2:1, 3 mL) was stirred at room
temperature for 15 min. The solvent was evaporated on a
rotary evaporator and the crude mixture was loaded on Dowex
50W × 8 (100-200 mesh) resin. Elution with methanol-25%
aq ammonia (19:1) afforded 2c (0.028 g, 82%) as a semisolid.
Rf 0.30 (chloroform/methanol ) 5/5); [R]D +21.0 (c 0.92, H2O)
[lit.8a [R]D +19.1 (c 0.74, H2O)]; IR (neat) 3200-3600 (broad
band) cm-1; 1H NMR (300 MHz, D2O) δ 2.68 (dd, J ) 14.1, 2.1
Hz, 1H), 2.75 (dt, J ) 9.6, 4.5 Hz, 1H), 2.87 (dd, J ) 13.8, 2.1
Hz, 1H), 3.62 (d, J ) 4.5 Hz, 2H), 3.69 (dd, J ) 9.6, 2.7 Hz,
1H), 3.75-3.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 44.3,
55.6, 60.3, 65.7, 68.8, 70.3. Anal. Calcd for C6H13NO4: C, 44.16;
H, 8.03. Found: C, 44.35; H, 8.25.
1,5-Dideoxy-1,5-im in o-(2R,3S,4S,5S)-L-glu citol (1-Deoxy-
L-n ojir im ycin ) Hyd r och lor id e (2d ‚HCl) a n d 2d . The reac-
tion of 8b (0.19 g, 0.373 mmol) with TFA:H2O (2:1, 3 mL), then
with NaIO4 (0.094 g, 0.44 mmol) and hydrogenolysis in the
presence of 10% Pd/C (0.10 g), followed by deacetylation in
methanolic hydrochloric acid (3 mL, 9:1) with the same
reaction conditions as used for 8a afforded 2d ‚HCl as a
semisolid (0.070 g, 48.6% overall). Rf 0.20 (chloroform/methanol
) 5/5); [R]D -46.0 (c 1.26, H2O); IR (neat) 3200-3600 (broad
band) cm-1 1H NMR (300 MHz, D2O) δ 2.84 (dd, J ) 12.3,
;
12.0 Hz, 1H), 3.08 (ddd, J ) 10.2, 5.2, 3.4 Hz, 1H), 3.38 (dd, J
) 12.3, 5.4 Hz, 1H), 3.41 (t, J ) 9.3 Hz, 1H), 3.47 (dd, J )
10.2, 9.3 Hz, 1H), 3.66 (ddd, J ) 12.0, 9.3, 5.4 Hz, 1H), 3.74
(dd, J ) 12.6, 5.2 Hz, 1H), 3.81 (dd, J ) 12.6, 3.4 Hz, 1H); 13
C
3,5,7-Tr i-O-acetyl-6-(N-ben zoxycar bon ylam in o)-6-deoxy-
1,2-O-isopr opyliden e-â-L-glycer o-L-ido-h eptofu r an ose (8b).
The reaction of 7b (0.55 g, 1.44 mmol) with acetic anhydride
(2.93 g, 28.72 mmol) and dry pyridine (1.6 mL) under the same
conditions used for 7a followed by column chromatography (n-
hexane:ethyl acetate ) 8/2) afforded 8b as a white solid (0.56
g, 77%). Mp 141-143 °C; Rf 0.48 (n-hexane/ethyl acetate )
7/3); [R]D -3.9 (c 1.03, CHCl3); IR (Nujol) 3375, 1738 (broad),
NMR (75 MHz, CDCl3) δ 43.8, 55.8, 58.1, 63.5, 66.1, 68.3. Anal.
Calcd for C6H14ClNO4: C, 36.10; H, 7.07. Found: C, 36.05; H,
7.18.
The reaction of 2d ‚HCl (0.058 g, 0.29 mmol) in methanol
and 25% aqueous ammonia as described for 2c and resin
column purification afforded 2d as a solid (0.045 g, 95%). Mp
192-194 °C (lit.9b mp 193-195 °C); Rf 0.10 (chloroform/
1689, 1524, 1460, 1377 cm-1
;
1H NMR (300 MHz, CDCl3) δ
methanol ) 5/5); [R]D -45.5 (c 0.81, H2O) [lit.9b [R]25 -46°
589
1.34 (s, 3H), 1.53 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.13 (s,
3H), 4.10-4.22 (m, 3H), 4.50 (dd, J ) 7.2, 3.3 1H), 4.56 (d, J
) 3.9 Hz, 1H), 5.12 (ABq, J ) 12.0 Hz, 2H), 5.26 (d, J ) 3.3
Hz, 1H), 5.33 (broad s, exchanges with D2O, 1H), 5.36 (dd, J
) 7.2, 3.3 Hz, 1H), 5.94 (d, J ) 3.9 Hz, 1H), 7.32-7.42 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 20.7 (s), 21.0, 26.2, 26.7,
(c 0.3 H2O)]; IR (neat) 3200-3600 (broad band) cm-1; 1H NMR
(300 MHz, D2O) δ 2.46 (dd, J ) 12.0, 11.0 Hz, 1H), 2.56 (ddd,
J ) 9.0, 6.3, 3.0 Hz, 1H), 3.11 (dd, J ) 12.0, 5.4 Hz, 1H), 3.21
(t, J ) 9.0 Hz, 1H), 3.29 (t, J ) 9.0 Hz, 1H), 3.47 (ddd, J )
11.0, 9.0, 5.4 Hz, 1H), 3.60 (dd, J ) 11.7, 6.3 Hz, 1H), 3.79
(dd, J ) 11.7, 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 48.3,
J . Org. Chem, Vol. 69, No. 14, 2004 4765