Manpadi et al.
JOCArticle
64.0, 61.7, 56.4, 47.8, 27.1, 20.0, 19.3, 14.3; HRMS m/z (ESI) calcd
for C33H41N3O7SiNa (M þ Na)þ 642.2610, found 642.2611.
Ethyl (2RþS,3R)-2-Azido-3-(1,3-benzodioxol-5-yl)-3-[(4R,5R)-
2,2,5-trimethyl-1,3-dioxolan-4-yl]propanoate (16a). Yield 77%
(anti:syn = 1:2.5); Rf 0.61 (20% EtOAc/hexanes); [R]22D þ27.86
(c 0.05, CHCl3); 1H NMR (CDCl3) δ 6.67-6.89 (m, 3H), 5.94 (m,
2H), 4.69 (d, J = 4.9 Hz, 1H), 4.07-4.29 (m, 3H), 3.91 (m, 1H),
3.77 (m, 1H), 3.31 (dd, J=9.6, 3.6 Hz, 1H), 3.17 (dd, J=9.9, 4.6
Hz, 1H), 1.42 (m, 6H), 1.29 (t, J = 7.2 Hz, 3H), 1.18 (t, J=7.2Hz,
3H), 0.77 (d, J = 6.1 Hz, 3H), 0.72 (d, J=6.1 Hz, 3H); 13C NMR
(CDCl3) δ 169.4, 169.3, 148.1, 147.7, 147.5, 131.1, 128.5, 123.0,
122.4, 109.6, 109.1, 108.5, 108.3, 108.2, 101.3, 101.2, 81.6, 65.6,
64.3, 61.9, 61.8, 51.3, 27.5, 27.2, 26.8, 19.1, 19.0, 14.2; HRMS m/z
(ESI) calcd for C18H23N3O6Na (M þ Na)þ 400.1486, found
400.1485.
(m, 1H), 1.42 (s, 6H), 0.76 (d, J =5.8Hz, 3H);13C NMR(CDCl3)
δ 156.7, 148.0, 147.1, 122.3, 122.2, 109.2, 108.6, 108.0, 101.3, 82.7,
64.1, 56.1, 52.3, 50.9, 27.4, 27.1, 18.9; HRMS m/z (ESI) calcd for
C18H25NO7Na (M þ Na)þ 390.1528, found 390.1529.
Methyl N-(1RþS,2R)-1-(Hydroxymethyl)-2-(7-methoxy-1,3-
benzodioxol-5-yl)-2-[(4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl]ethy-
lcarbamate (17b). Yield 71%; Rf 0.47 (10% MeOH/CHCl3); H
1
NMR (CDCl3) δ 6.37 (m, 2H), 5.93 (s, 2H), 4.07-3.41 (m, 13H),
2.84 (m, 1H), 1.38 (m, 6H), 0.73 (d, J=6.0 Hz, 3H); 13C NMR
(CDCl3) δ 156.9, 149.3, 143.7, 134.8, 132.4, 108.4, 108.0, 103.1,
101.6, 83.3, 82.7, 64.0, 56.9, 52.3, 50.9, 27.4, 27.1, 18.7; HRMS m/z
(ESI) calcd for C19H27NO8Na (M þ Na)þ 420.1634, found
420.1644.
General Procedure for Isopropylidene Deprotection. Dowex-
50 acid resin (450 mg) was added to a solution of the corre-
sponding carbamate (1.06 mmol) in MeOH (40 mL). The
reaction mixture was refluxed for 10 h. The resin was
removed from the mixture and washed with methanol (3 ꢀ
30 mL). The combined organic fractions were evaporated
under reduced pressure to yield corresponding pure triol as
a semisolid.
Ethyl (2RþS,3R)-2-Azido-3-(7-methoxy-1,3-benzodioxol-5-yl)-
3-[(4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propanoate (16b).
Yield 74% (anti:syn = 1:1); Rf 0.28 (20% EtOAc/hexanes);
1
selected H NMR (CDCl3) data for the anti-isomer δ 6.52 (d,
J=1.6 Hz, 1H), 6.40 (d, J=0.8 Hz, 1H), 5.92 (s, 2H), 4.63 (d, J =
5.2 Hz, 1H), 4.11-3.72 (m, 4H), 3.84 (s, 3H), 3.10 (dd, J = 10.5,
5.2 Hz, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 1.15 (t, J = 6.9 Hz, 3H),
0.72 (d, J = 5.8 Hz, 3H); selected 1H NMR (CDCl3) data for the
syn-isomer δ 6.46 (m, 2H), 5.90 (m, 2H), 4.28-3.91 (m, 5H), 3.87
(s, 3H), 3.26 (dd, J = 9.9, 3.6 Hz, 1H), 1.36 (s, 3H), 1.32 (s, 3H),
Methyl N-[(1R,2R,3R,4R)-2-(1,3-Benzodioxol-5-yl)-3,4-dihy-
droxy-1-(hydroxy-methyl)pentyl]carbamate (18a). Yield 56%; Rf
1
0.26 (60% EtOAc/hexanes); [R]22 þ9.41 (c 0.26, CHCl3); H
D
NMR (CDCl3) δ 6.59-6.74 (m, 3H), 5.92 (s, 2H), 5.16 (m, 1H),
4.28 (m, 1H), 3.69 (s, 3H), 3.42 (m, 3H), 3.07 (m, 1H). 1.11 (d,
J=5.5 Hz, 3H); 13C NMR (CDCl3) δ 158.8, 148.1, 146.9, 131.6,
122.3, 109.1, 108.8, 101.2, 73.9, 67.0, 64.6, 53.0, 50.0, 21.4;
HRMS m/z (ESI) calcd for C15H21NO7Na (M þ Na)þ
350.1216, found 350.1217.
1.26 (t, J = 7.7 Hz, 3H), 0.76 (d, J = 6.0 Hz, 3H); selected 13
C
NMR (CDCl3) δ 169.4, 149.1, 143.6, 135.1, 131.5, 129.2, 109.3,
108.4, 103.5, 102.9, 81.6, 65.6, 64.3, 61.9, 56.8, 51.5, 27.4, 19.3,
14.3; HRMS m/z (ESI) calcd for C19H25N3O7Na (M þ Na)þ
430.1590, found 430.1588.
General Procedure for Carbamate Formation. To a suspension
of LiAlH4 (2.5 mmol) in anhydrous ether (20 mL) at 0 ꢀC was
added a solution of the azide (1 mmol in 5 mL) dropwise. The
reaction mixture was stirred for 2.5 h at room temperature.
After the completion of the reaction, monitored by TLC, 20 mL
of ether was added to the reaction mixture and recooled to 0 ꢀC.
Saturated NaSO4 (15 mL) was added slowly, and the reaction
was stirred for 30 min at room temperature. Fifteen milliliters of
water was added and extracted with EtOAc (3 ꢀ 25 mL).
Combined organic layers were washed with brine, dried
(MgSO4), and evaporated under reduced pressure to yield the
respective aminoalcohol, which was used without further pur-
ification. To the amine (1.03 mmol) in dioxane (12 mL) and
water (12 mL) were added K2CO3 (2.06 mmol) and methyl-
chloroformate (1.24 mmol) at room temperature. The solution
was stirred for 2 h, dioxane was evaporated under vacuum, and
the aqueous layer was extracted with EtOAc (3 ꢀ 10 mL). The
combined organic layers were washed with brine, dried, and
evaporated under reduced pressure. The residual oil was pre-
sorbed on silica gel and purified by column chromatography
(15-30% EtOAc/hexanes) to yield corresponding carbamate.
Methyl-(2R,3R,4R,5R)-3-(benzo[d][1,3]dioxol-5-yl)-5-(tert-
butyldiphenylsilyloxy)-1-hydroxy-4-(methoxymethoxy)hexan-
2-ylcarbamate (13). Yield 65%, Rf 0.52 (60% EtOAc/hexanes);
1H NMR (CDCl3) δ 7.26-7.50 (m, 10H), 6.68 (d, J=8.0 Hz,
1H), 6.49 (m, 2H), 5.90 (d, J = 19.0 Hz, 2H), 4.75 (m, 3H), 4.31
(m, 1H), 3.86 (m, 1H), 3.71(d, J=10.0 Hz, 1H), 3.64 (s, 3H),
3.43 (m, 1H), 3.39 (s, 3H), 3.35 (m, 1H), 1.00 (m, 3H), 0.96 (s,
9H); 13C NMR (CDCl3) δ 147.8, 146.7, 135.9, 135.8, 134.8,
134.1, 129.5, 127.5, 127.3, 122.9, 109.9, 108.4, 101.1, 98.9,
83.1, 70.1, 64.8, 56.4, 52.3, 46.1, 27.1, 19.9, 19.2; HRMS m/z
(ESI) calcd for C33H43NO8SiNa (M þ Na)þ 632.2650, found
632.2656.
Methyl N-[(1R,2R,3R,4R)-3,4-Dihydroxy-1-(hydroxymethyl)-
2-(7-methoxy-1,3-benzodioxol-5-yl)pentyl]carbamate (18b). Yield
50%; Rf 0.51 (20% MeOH/CHCl3); [R]22D þ9.6 (c 0.062, CHCl3);
1H NMR (CDCl3) δ 6.34 (br s, 2H), 5.94 (s, 2H), 5.09 (m, 1H),
4.29 (m, 1H), 3.88 (s, 3H), 3.72-3.30 (m, 6H), 3.68 (s, 3H), 3.08
(m, 1H). 1.13 (m, 3H); 13C NMR (CDCl3) δ 158.8, 149.3, 143.8,
134.5, 132.4, 109.2, 102.5, 101.7, 73.9, 67.0, 64.3, 57.0, 53.0, 50.3,
21.2; HRMS m/z (ESI) calcd for C16H23NO8Na (M þ Na)þ
380.1321, found 380.1326.
General Procedure for Acetyl Protection. To a mixture of the
corresponding triol (0.61 mmol) and DMAP (3 mg, 0.024 mmol)
in dry pyridine (5 mL) at 0 ꢀC was added acetic anhydride (1.87
g, 18.44 mmol). The reaction mixture was stirred at room
temperature for 12 h and diluted with water (50 mL). The
aqueous layer was extracted with ether (5 ꢀ 20 mL). The
combined organic layers were washed with water (4 ꢀ 15 mL)
and brine, dried (MgSO4), and evaporated under reduced
pressure. The oily residue was presorbed on silica gel and
purified by column chromatography (2-5% MeOH/CHCl3)
to yield corresponding triacetate.
(1R,2R,3R)-4-(Acetyloxy)-1-[(1R)-1-(acetyloxy)ethyl]-2-(1,3-
benzodioxol-5-yl)-3-[(methoxycarbonyl)amino]butyl Acetate (19a).
Yield 88%; Rf 0.47 (50% EtOAc/hexanes); [R]22D þ58.33 (c 0.02,
CHCl3); 1H NMR (CDCl3) δ 6.76 (d, J = 7.8 Hz, 1H), 6.58 (s,
1H), 6.52 (d, J=7.8 Hz, 1H), 5.96 (s, 2H), 4.63 (m, 1H), 4.46 (m,
2H), 3.85 (dd, J = 11.0, 5.5 Hz, 1H), 3.65 (m, 3H), 3.19 (dd, J=
11.2, 0.4 Hz, 1H), 2.22 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.07 (d,
J = 6.3 Hz, 3H); 13C NMR (CDCl3) δ 170.9, 169.8, 156.8, 148.6,
147.6, 128.6, 121.9, 109.2, 108.5, 101.5, 72.8, 69.4, 65.5, 52.6, 48.7,
46.6, 21.1, 20.8, 16.8; HRMS m/z (ESI) calcd for C21H27NO10Na
(M þ Na)þ 476.1538, found 476.1533.
(1R,2R,3R)-4-(Acetyloxy)-1-[(1R)-1-(acetyloxy)ethyl]-2-(7-me-
thoxy-1,3-benzodi-oxol-5-yl)-3-[(methoxycarbonyl)amino]butyl
Methyl N-(1RþS,2R)-2-(1,3-Benzodioxol-5-yl)-1-(hydroxyme-
thyl)-2-[(4R,5R)-2,2, 5-trimethyl-1,3-dioxolan-4-yl]ethylcarbama-
te (17a). Yield 86%; Rf 0.50 (60% EtOAc/hexanes); [R]22D -5.24
(c 0.56, CHCl3); 1H NMR (CDCl3) δ 6.54-6.82 (m, 3H), 5.94 (s,
2H), 4.12 (m, 1H), 3.78 (m, 2H), 3.64 (m, 3H), 3.54 (s, 3H), 2.82
Acetate (19b). Yield 96%; Rf 0.73 (8% MeOH/CHCl3); [R]22
D
þ60.0 (c 0.02, CHCl3); 1H NMR (CDCl3) δ 6.26 (d, J=1.6 Hz,
1H), 6.15 (d, J=1.4 Hz, 1H), 5.93 (s, 2H), 5.32 (dd, J=11.3, 1.6
Hz, 1H), 4.62 (qd, J=6.3, 1.6 Hz, 1H), 4.52 (d, J = 11.0 Hz,
1H), 4.36 (m, Hz, 1H), 3.85 (m, 3H), 3.66-3.64 (m, 1H), 3.61 (s,
J. Org. Chem. Vol. 74, No. 18, 2009 7129