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W. Schönemann et al. / Bioorg. Med. Chem. 18 (2010) 2645–2650
3.1.2. General procedure for the addition of Grignard reagents
Crude 6 was dissolved in dry THF (0.1 M) and treated with a
solution of Grignard reagent (5 or 10 equiv). After 2 days of stirring
at room temperature, the reaction was quenched with saturated
NH4Cl. The organic layer was diluted with CH2Cl2, washed with
5% aqueous HCl, saturated NaHCO3, and water. The organic phase
was dried over MgSO4. The solid was filtered and the filtrate was
concentrated under vacuum. The crude product was purified by
column chromatography (PE/EA 4:1).
and the filtrate was concentrated under vacuum and co-evapo-
rated with toluene.
3.1.3.1. b-1-C-Allyl-N-benzyl-2,3,4,6-tetra-O-benzyl-1,5-dideoxy-
1,5-imino-L-iditol (8a). The reaction was carried out on 520 mg
(0.774 mmol) of 7a. Purification was performed by column chroma-
tography (PE/EA 9:1) affording 8a (362 mg, 72%). Analytical data are
in accordance with the literature data.27
3.1.3.2. N-Benzyl-2,3,4,6-tetra-O-benzyl-b-1-C-butyl-1,5-dideoxy-
3.1.2.1. (1R)-1-C-Allyl-2,3,4,6-tetra-O-benzyl-1-benzylamino-1-
1,5-imino-L-iditol (8b). The reaction was carried out on 207 mg
deoxy-
D
-glucitol (7a). The reaction was carried out on 3.31 g
(0.301 mmol) of 7b. Purification was performed by column chroma-
tography (PE/EA 95:5) affording 8b (93 mg, 46%) as a colorless oil.
(5.25 mmol) of 6 and commercial allylmagnesium bromide (1 M
in Et2O, 5 equiv) was used. Compound 7a (2.54 g, 72%) was ob-
tained as a colorless oil. Analytical data are in accordance with
the literature data.27
½
a 2D0
ꢂ
ꢃ7.8 (c 1.10, CHCl3). 1H NMR (CDCl3) d 7.34–7.21 (m, 25H,
HAr), 4.81, 4.78 (2d, J = 10.9 Hz, 2H, PhCH2O), 4.61, 4.60, 4.55, 4.54
(4d, J = 11.6 Hz, 4H, PhCH2O), 4.45 (s, 2H, PhCH2O), 4.09, 4.00 (2d,
J = 14.9 Hz, 2H, PhCH2N), 3.81 (dd, J = 5.3, 9.6 Hz, 1H, H6b), 3.73–
3.67 (m, 3H, H3, H4, H6a), 3.65–3.61 (m, 1H, H2), 3.50–3.45 (m,
1H, H5), 3.01 (q, J = 6.2 Hz, 1H, H1), 1.73–1.64 (m, 1H, H7b), 1.58–
1.49 (m, 1H, H7a), 1.39–1.17 (m, 4H, H8, H9), 0.83 (t, J = 6.8 Hz,
3H, H10). 13C NMR (CDCl3) d 141.2, 138.2, 138.8, 138.8, 138.7 (CAr),
128.4–126.8 (CHAr), 80.9 (C2), 80.1, 78.9 (C3, C4), 75.2, 73.3, 72.9,
72.7 (PhCH2O), 71.1 (C6), 59.3, 59.2 (C1, C5), 58.5 (PhCH2N), 31.2
3.1.2.2. (1R)-2,3,4,6-Tetra-O-benzyl-1-benzylamino-1-C-butyl-1-
deoxy-
D
-glucitol (7b). The reaction was carried out on 196 mg
(0.312 mmol) of
6
and commercial butylmagnesium chloride
(20% (wt) in THF/toluene, 10 equiv) was used. Compound 7b
(143 mg, 67%) was obtained as a colorless oil. ½a D20
ꢃ5.7 (c
ꢂ
0.92, CHCl3). 1H NMR (CDCl3) d 7.32–7.18 (m, 25H, HAr), 4.85,
4.81, 4.70 (3d, J = 11.4 Hz, 3H, PhCH2O), 4.57–4.50 (m, 4H,
PhCH2O), 4.37 (d, J = 11.4 Hz, 1H, PhCH2O), 4.29 (dd, J = 2.9,
7.6 Hz, 1H, H3), 4.10–4.06 (m, 1H, H5), 3.87 (d, J = 13.0 Hz, 1H,
PhCH2N), 3.83 (dd, J = 2.4, 7.6 Hz, 1H, H2), 3.65–3.55 (m, 3H,
H6a, H6b, PhCH2N), 3.50 (dd, J = 2.9, 6.7 Hz, 1H, H4), 2.49–2.45
(m, 1H, H1), 1.65–1.56 (m, 1H, H7b), 1.46–1.37 (m, 1H, H7a),
1.26–1.04 (m, 4H, H8, H9), 0.81 (t, J = 7.2 Hz, 3H, H10). 13C
NMR (CDCl3) d 141.1, 139.0, 138.6, 138.3 (CAr), 128.6–126.9
(CHAr), 80.4 (C2), 79.9 (C3), 78.0 (C4), 74.9, 74.7, 73.6, 72.8
(PhCH2O), 71.8 (C6), 70.8 (C5), 57.3 (C1), 51.2 (PhCH2N), 30.2
(C8), 29.1 (C7), 23.3 (C9), 14.3 (C10). IR (neat)
m 3029, 2927, 2867,
1495, 1453, 1089, 1071 cmꢃ1. MS (ESI+) m/z = 670.5 [M+H]+. HRMS
(ESI) [M+H]+ calcd for C45H52NO4 m/z = 670.3896; found m/
z = 670.3879.
3.1.3.3. N-Benzyl-2,3,4,6-tetra-O-benzyl-b-1-C-hexyl-1,5-dideoxy-
1,5-imino-L-iditol (7c). The reaction was carried out on 261 mg
(0.365 mmol) of 6c. Purification was performed by column chroma-
tography (PE/EA 95:5) affording 8c (181 mg, 71%) as a yellowish oil.
½
a 2D0
ꢂ
ꢃ9.4 (c 1.18, CHCl3). 1H NMR (CDCl3) d 7.34–7.21 (m, 25H, HAr),
(C7), 29.0 (C8), 23.2 (C9), 14.3 (C10). IR (neat)
m
3029, 2940,
4.82, 4.77 (2d, J = 10.9 Hz, 2H, PhCH2O), 4.61, 4.60, 4.55, 4.54 (4d,
J = 11.6 Hz, 4H, PhCH2O), 4.45 (s, 2H, PhCH2O), 4.09, 4.00 (2d,
J = 14.8 Hz, 2H, PhCH2N), 3.81 (dd, J = 5.3, 9.7 Hz, 1H, H6b), 3.75–
3.67 (m, 3H, H3, H4, H6a), 3.62 (dd, J = 5.9, 8.8 Hz, 1H, H2), 3.49–
3.45 (m, 1H, H5), 3.00 (q, J = 5.9 Hz, 1H, H1), 1.72–1.63 (m, 1H,
H7b), 1.57–1.48 (m, 1H, H7a), 1.37–1.15 (m, 8H, H8, H9, H10,
H11), 0.85 (t, J = 6.8 Hz, 3H, H12). 13C NMR (CDCl3) d 141.2, 139.2,
138.8, 138.8, 138.7 (CAr), 128.4–126.8 (CHAr), 80.9 (C2), 80.1, 78.9
(C3, C4), 75.1, 73.2, 72.9, 72.6 (PhCH2O), 70.9 (C6), 59.2, 59.0 (C1,
C5), 58.5 (PhCH2N), 31.9, 29.8, 29.0, 22.8 (C8, C9, C10, C11), 29.3
2866, 1495, 1453, 1085, 1067 cmꢃ1
. MS (ESI+) m/z = 688.5
[M+H]+. HRMS (ESI) [M+H]+ calcd for C45H54NO5 m/
z = 688.4002; found m/z = 688.4012.
3.1.2.3. (1R)-2,3,4,6-Tetra-O-benzyl-1-benzylamino-1-deoxy-1-
C-hexyl-
(1.09 mmol) of
D
-glucitol (7c). The reaction was carried out on 689 mg
and commercial hexylmagnesium chloride
6
(2 M in THF, 10 equiv) was used. Compound 7c (416 mg, 53%)
was obtained as a colorless oil. ½a D20
ꢂ
ꢃ10.6 (c 1.21, CHCl3). 1H
NMR (CDCl3) d 7.33–7.19 (m, 25H, HAr), 4.85, 4.80, 4.70 (3d,
J = 11.4 Hz, 3H, PhCH2O), 4.56–4.50 (m, 4H, PhCH2O), 4.37 (d,
J = 11.4 Hz, 1H, PhCH2O), 4.28 (dd, J = 2.9, 7.6 Hz, 1H, H3), 4.10–
4.06 (m, 1H, H5), 3.86 (d, J = 13.2 Hz, 1H, PhCH2N), 3.83 (dd,
J = 2.2, 7.6 Hz, 1H, H2), 3.65–3.55 (m, 3H, H6a, H6b, PhCH2N),
3.50 (dd, J = 2.9, 6.7 Hz, 1H, H4), 2.49–2.45 (m, 1H, H1), 1.64–
1.55 (m, 1H, H7b), 1.46–1.36 (m, 1H, H7a), 1.26–1.11 (m, 8H,
H8, H9, H10, H11), 0.86 (t, J = 7.1 Hz, 3H, H12). 13C NMR (CDCl3)
d 141.2, 139.0, 138.6, 138.3, 138.3 (CAr), 128.6–127.0 (CHAr),
80.5 (C2), 79.9 (C3), 77.9 (C4), 74.9, 74.8, 73.6, 72.9 (PhCH2O),
71.8 (C6), 70.8 (C5), 57.4 (C1), 51.3 (PhCH2N), 32.0, 29.9, 26.8,
(C7), 14.2 (C12). IR (neat) m 3029, 2922, 2855, 1495, 1453, 1089,
1071 cmꢃ1. MS (ESI+) m/z = 698.5 [M+H]+. HRMS (ESI) [M+H]+ calcd
for C47H56NO4 m/z = 698.4209; found m/z = 698.4195.
3.1.4. General procedure for hydrogenolysis
Protected compounds 8a–c were dissolved in ethanol (0.1 M) in
the presence of 1 M HCl (5 equiv). After few minutes of stirring Pd/
C (10%) (125 g/mol) and Pd black (125 g/mol) were added. The
reaction was carried out under a hydrogen atmosphere at room
temperature for 16 h. The mixture was filtered through membrane,
and the residual solid was then washed with methanol. The crude
solution was introduced on a DOWEX 50W-X8-100 (H+) ion ex-
change column. The column was washed with methanol and
water. The product was then eluted with 0.5 M NH4OH and the
eluted fractions were concentrated under reduced pressure afford-
ing final pure compounds.
22.8 (C8, C9, C10, C11), 30.6 (C7), 14.3 (C12). IR (neat)
m 3029,
2925, 2855, 1495, 1453, 1080, 1068 cmꢃ1. HRMS (ESI) [M+H]+
calcd for C47H58NO5 m/z = 716.4315; found m/z = 716.4310.
3.1.3. General procedure for the cyclization
Open-chain compounds 7a–c were dissolved in pyridine (0.1 M)
in the presence of activated 4 Å molecular sieves. After 10 min of
stirring at room temperature, methanesulfonyl chloride (2.5 equiv)
was added. The mixture was stirred at 100 °C for 3–6 h, then fil-
tered through Celite and concentrated under vacuum. The crude
product was diluted with ethyl acetate. The organic phase was
washed with water and dried over MgSO4. The solid was filtered
3.1.4.1. b-1-C-Propyl-1,5-dideoxy-1,5-imino-
L
-iditol
(3d). The
reaction was carried out on 128 mg (0.196 mmol) of 8a, affording
3d (43 mg, 100%) as a yellow oil. ½a D20
ꢂ
ꢃ16.8 (c 1.20, MeOH). 1H
NMR (D2O) d 4.07 (br s, 1H, H3), 3.86 (br s, 1H, H4), 3.79 (br s,
1H, H2), 3.76–3.70 (m, 2H, H6), 3.22 (t, J = 5.8 Hz, 1H, H5), 3.13–
3.10 (m, 1H, H1), 1.70–1.59 (m, 1H, H7b), 1.50–1.47 (m, 1H,