Probing Intestinal a-Glucosidase Enzyme Specificities
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(t,
J
1,2 =J2,3 =9.6 Hz, 1H; H-2), 3.44 (ddd,
J
5,6a =2.2,
J
5,6b =3.7, J5,4
=
(500 mg, 4.5 mmol) in MeOH (15 mL) and the reaction was stirred at
room temperature, overnight. The solvent was removed under vacuum to
give the crude product, which was used directly in the next step without
further purification. The crude product was dissolved in DMF (20 mL),
and NaH (130 mg, 5.4 mmol) and BnBr (0.5 mL, 4 mmol) were added at
08C. The reaction mixture was stirred for 2 h at room temperature, then
quenched with ice, and extracted with ether (3ꢂ50 mL). The organic so-
lution was washed with water (30 mL) and brine (30 mL), dried (Na2SO4)
and concentrated and the residue was purified by flash chromatography
9.4 Hz, 1H; H-5), 3.29, 3.27 (2s, 6H; 2OMe), 2.53 (br, 1H; OH), 1.33,
1.29 (2s, 6H; 2Me), 0.90 (s, 9H; 3Me), 0.10, 0.08 ppm (2s, 6H; 2Me);
13C NMR (CDCl3): d=137.0–127.9 (m, Ar), 101.9 (C-1), 99.5, 99.0
(2MeOCMe), 74.7 (C-5), 71.9 (C-3), 71.2 (C-2), 70.7 (CH2Ph), 65.1 (C-4),
61.3 (C-6), 48.0, 47.9 (2OMe), 25.8 (3Me), 18.3 (CMe3), 17.6 (2Me),
ꢁ5.0, ꢁ5.4 ppm (2Me); HRMS calcd for C25H42NaO8Si [M+Na]:
521.2541, found: 521.2546.
Benzyl
2,3,4,6-tetra-O-acetyl-a-d-glucopyranosyl-(1!4)-2,3,6-tri-O-
(EtOAc/hexanes 1:5) to yield 16 as white foam (475 mg, 73%). [a]D23
=
acetyl-b-d-glucopyranosyl-(1!4)-6-O-tert-butyldimethylsilyl-2,3-O-
ꢁ15 (c=0.8, CH2Cl2); 1H NMR (CDCl3): d=7.40–7.11 (m, 40H; Ar),
5.73 (d, J1’’,2’’ =3.7 Hz, 1H; H-1’’), 4.96–4.52 (m, 14H; 7CH2Ph), 4.63 (m,
1H; H-1’), 4.60 (m, 1H; H-1), 4.45, 4.26 (2d, JA,B =12.1 Hz, 2H; CH2Ph),
4.18 (t, J3’’,4’’ =J4’’,5’’ =8.9 Hz, 1H; H-4’’), 4.01 (t, J3’,4’ =J4’,5’ =9.5 Hz, 1H;
H-4’), 3.95–3.77 (m, 8H; H-6a, H-3’’, H-4’, H-6’’a, H-3, H-6b, H-6b’’, H-
3’), 3.66 (m, 2H; H-5’, H-2), 3.54–3.49 (m, 3H; H-5’’, H-6’a, H-2’’), 3.46
[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-b-d-glucopyranoside
(15):
BF3·Et2O (0.02 mL, 0.2 equiv) was added to a solution of the acceptor
glycoside 14 (0.7 g, 1.4 mmol) and maltosyl trichloroacetimidate 12 (1.3 g,
1.68 mmol) in dry CH2Cl2 (10 mL) under N2, at room temperature. After
being stirred for 30 min, the mixture was quenched with NEt3 (0.2 equiv)
with vigorous stirring. The mixture was concentrated and purified by
column chromatography (hexanes/EtOAc 1:1) to give the coupled prod-
uct 15 as white foam (0.7 g, 45%). [a]2D3 =ꢁ9 (c=0.7, CH2Cl2); 1H NMR
(CDCl3): d=7.39–7.28 (m, 5H; Ar), 5.42 (d, J1’’,2’’ =4.1 Hz, 1H; H-1’’),
5.38 (t, J2’’,1’’ =J2’’,3’’ =10.4 Hz, 1H; H-2’’), 5.19 (t, J3’,4’ =J2’,3’ =7.7 Hz, 1H;
(dd,
J2’,1’ =8.0, J2’,3’ =9.0 Hz, 1H; H-2’), 3.38 (dd, J6’a,6’b =1.8, J5’,6’b =
10.9 Hz, 1H; H-6’b), 3.33 (ddd, J5,6a =1.8, J5,6b =3.5, J4,5 =5.3 Hz, 1H; H-
5), 3.31, 3.28 (2s, 6H; 2OMe), 1.34, 1.32 (2s, 6H; 2Me), 1.32, 1.21 (2s,
6H; 2Me), 0.91 (s, 9H; 3Me), 0.07, 0.06 ppm (2s, 6H; 2Me); 13C NMR
(CDCl3): d=138.3–126.1 (m, Ar), 101.3 (C-1’), 99.2 (C-1), 99.1, 99.0
(2MeOCMe), 96.2 (C-1’’), 84.6 (C-3’), 82.3 (C-2’), 81.6 (C-4’), 78.8 (C-
5’’), 77.3 (C-5’), 76.3 (C-5), 75.0, 74.5, 74.2, 73.6, 73.2, 73.0, 72.8, 69.8
(8CH2Ph), 74.4 (C-2“), 72.5 (C-4), 71.6 (C-3’’), 70.4 (C-3), 70.3 (C-4”),
69.4 (C-2), 68.1 (C-6’’), 67.7 (C-6’), 61.2 (C-6), 47.5, 47.4 (2OMe), 25.5
(3Me), 17.93 (CMe3), 17.2, 17.1 (2Me), ꢁ5.4, ꢁ5.6 ppm (2Me); HRMS
calcd for C86H104NaO18Si [M+Na]: 1477.6941, found: 1477.6941.
H-3’), 5.08 (t,
J3’’,4’’ =J4’’,5’’ =9.9 Hz, 1H; H-4’’), 4.90, 4.66 (2d, JA,B =
12.0 Hz, 2H; CH2Ph), 4.87 (t, J3’’,4’’ =J2’’,3’’ =4.1 Hz, 1H; H-3’’), 4.83 (m,
2H; H-1’, H-2’), 4.55 (d, J1,2 =7.8 Hz, 1H; H-1), 4.42 (dd, J6’a,6’b =3.1,
J
5’,6’a =12.5 Hz, 1H; H-6’a), 4.29 (dd, J6’a,6’b =3.6, J5’,6’b =12.2 Hz, 1H; H-
6’b), 4.24 (dd, J6’’a,6’’b =3.6, J5’’,6’’a =12.5 Hz, 1H; H-6’’a), 4.06 (m, 2H; H-
6’’b, H-4’), 3.94 (ddd, J5’’,6a’’ =3.1, J5’’,6b’’ =2.6, J4’’,5’’ =10.0 Hz, 1H; H-5’’),
3.88 (dd, J6a,6b =1.5, J5,6a =11.5 Hz, 1H; H-6a), 3.82 (t, J3,4 =J2,3 =9.6 Hz,
1H; H-3), 3.71 (m, 2H; H-4, H-6b), 3.67 (ddd, J5’,6a’ =3.2, J5’,6b’ =3.0,
Benzyl
2,3,4,6-tetra-O-benzyl-a-d-glucopyranosyl-(1!4)-2,3,6-tri-O-
benzyl-b-d-glucopyranosyl-(1!2)-6-O-tert-butyldimethylsilyl-3,4-O-
[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-b-d-glucopyranoside (21): The
compound was obtained as white solid (585 mg, 76%) from 20 (592 mg,
0.53 mmol) by using the same procedure that was used to obtain 16. M.p.
J
4’,5’ =9.5 Hz, 1H; H-5’), 3.59 (dd, J1,2 =7.8, J2,3 =10.0 Hz, 1H; H-2), 3.34
(ddd, J5,6a =1.5, J5,6b =5.1, J4,5 =6.8 Hz, 1H; H-5), 3.32, 3.30 (2s, 6H;
2OMe), 2.14, 2.12, 2.06, 2.05, 2.04, 2.02, 2.01 (7s, 21H; 7OAc), 1.34, 1.32
(2s, 6H; 2Me), 0.94 (s, 9H; 3Me), 0.11, 0.10 ppm (2s, 6H; 2Me);
13C NMR (CDCl3): d=170.4–169.3 (m, CO), 137.4–127.4 (m, Ar), 100.0
(C-1’), 99.4, 99.3 (2MeOCMe), 99.2 (C-1), 95.4 (C-1’’), 76.1 (C-5), 75.5
(C-3’), 75.4 (C-4), 72.8 (C-2’), 72.3 (C-4’), 71.9 (C-5’), 71.4 (C-3), 70.3
(CH2Ph), 69.8 (C-3’’), 69.4 (C-2), 69.2 (C-2“), 68.3 (C-5”), 67.8 (C-4“),
62.9 (C-6’), 61.9 (C-6), 61.2 (C-6”), 47.8, 47.7 (2OMe), 25.8 (3Me), 20.7–
20.4 (m, OAc), 18.22 (CMe3), 17.5, 17.4 (2Me), ꢁ5.1, ꢁ5.3 ppm (2Me);
HRMS calcd for C51H76NaO25Si [M+Na]: 1139.4337; found: 1139.4330.
90–928C; [a]2D3 = +76.8 (c=1.0, CH2Cl2); H NMR (CDCl3): d=7.43–7.17
1
(m, 40H; Ar), 5.77 (d, J1’’,2’’ =3.6 Hz, 1H; H-1’’), 5.05–4.84 (m, H-1’, 8H;
7CH2Ph), 4.71–4.51 (m, H-1, 9H; 8CH2Ph), 4.40 (d, JA,B =12.1 Hz, 1H;
CH2Ph), 4.24 (t,
J4’,3’ =J4’,5’ =9.2 Hz, 1H; H-4’), 4.18 (t, J4’’,3’’ =J4’’,5’’ =
8.9 Hz, 1H; H-4’’), 4.13–3.80 (m, 8H; H-6a, H-6b, H-3, H-3’, H-3’’, H-4,
H-6’a, H-6’’a), 3.76–3.66 (m, 4H; H-6’’b, H-6’b, H-2, H-5’’), 3.58–3.48 (m,
4H; H-2’’, H-2’, H-5’, H-5), 3.35, 3.17 (2s, 6H; 2OMe), 1.33, 1.30 (2s,
6H; 2Me), 0.98 (s, 9H; 3Me), 0.18, 0.16 ppm (2s, 6H; 2Me); 13C NMR
(CDCl3): d=138.8–126.5 (m, Ar), 101.9 (C-1’), 101.2 (C-1), 99.5, 99.4
(2MeOCMe), 96.7 (C-1’’), 84.8 (C-5’’), 83.0 (C-2’), 81.9 (C-3’’), 79.2 (C-
2’’), 77.7 (C-4’’), 75.4, 74.9, 74.6 (3CH2Ph), 74.4 (C-5, C-5’), 73.8, 73.4
(CH2Ph), 73.3 (C-3), 73.1 (CH2Ph), 72.3 (C-4’), 70.8 (C-3’), 70.9 (C-2),
69.7 (CH2Ph), 68.2 (C-6’’), 68.1 (C-6’), 65.1 (C-4), 61.4 (C-6), 48.0
(2OMe), 25.8, 25.5 (3Me), 18.3 (CMe3), 17.8, 17.6 (2Me), ꢁ5.0,
ꢁ5.4 ppm (2Me); HRMS calcd for C86H104NaO18Si [M+Na]: 1477.6941,
found: 1476.6938.
Benzyl
2,3,4,6-tetra-O-acetyl-a-d-glucopyranosyl-(1!4)-2,3,6-tri-O-
acetyl-b-d-glucopyranosyl-(1!2)-6-O-tert-butyldimethylsilyl-3,4-O-
[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-b-d-glucopyranoside (20): The
compound was obtained as white solid (1.7 g, 52%) from 19 (1.5 g,
2.95 mmol) by using the same procedure that was used to obtain 15. M.p.
95–988C; [a]2D3 = +64.4 (c=0.1, CH2Cl2); H NMR (CDCl3): d=7.40–7.29
1
(m, 5H; Ar), 5.37 (d, J1’’,2’’ =4.0 Hz, 1H; H-1’’), 5.32 (t, J3’’,2’’ =J3’’,4’’
9.5 Hz, 1H; H-3’’), 5.16 (t, J3’,2’ =J3’,4’ =9.1 Hz, 1H; H-3’), 5.03 (t, J4’’,3’’
=
=
J
J
4’’,5’’ =10.1 Hz, 1H; H-4’’), 4.94–4.91 (m, 2H, H-1’, CH2Ph), 4.85 (dd,
2’’,1’’ =7.5, J2’’,3’’ =4.0 Hz, 1H; H-2’’), 4.81 (dd, J2’,1’ =7.5, J2’,3’ =2.1 Hz, 1H;
Benzyl
2,3,4,6-tetra-O-benzyl-a-d-glucopyranosyl-(1!4)-2,3,6-tri-O-
benzyl-b-d-glucopyranosyl-(1!4)-6-O-trifluoromethanesulfonyl-2,3-O-
[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-b-d-glucopyranoside (17): TBAF
(1.0m solution in THF, 0.28 mL, 0.28 mmol) was added to a solution of
16 (205 mg, 0.14 mmol) in THF (15 mL) and the reaction mixture was
stirred at room temperature. After 12 h it was concentrated and further
dried under high vacuum for 1 h. The crude product was dissolved in
CH2Cl2 (10 mL) and pyridine (0.013 mL, 1.2 equiv) was added. The mix-
ture was cooled to ꢁ108C, and Tf2O (0.036 mL, 1.5 equiv) was added
under N2. After 30 min the reaction was quenched by the addition of
cold saturated NaHCO3 (1.5 mL). The organic layers were washed with
1N HCl (5 mL), water (5 mL) and brine (5 mL), dried (Na2SO4), and
concentrated, in vacuo. Chromatographic purification of the crude prod-
uct (EtOAc/hexanes 1:10) gave 17 as a foam (85 mg, 41%). [a]2D3 =ꢁ5.5
(c=0.2, CH2Cl2); 1H NMR (CDCl3): d=7.38–7.11 (m, 40H; Ar), 5.62 (d,
H-2’), 4.62 (d, JAB =11.7 Hz, 1H; CH2Ph), 4.50 (d, J1,2 =6.9 Hz, 1H; H-1),
4.28 (dd, J6’b,6’a =12.2, J6’b,5’ =2.6 Hz, 1H; H-6’b), 4.23 (dd, J6’’a,6’’b =12.6,
J
6’’a,5’’ =3.8 Hz, 1H; H-6’’a), 4.08–3.96 (m, 3H; H-6’a, H-6’’b, H-4’), 3.89
(ddd, J5’’,4’’ =10.1, J6’’a,5’’ =3.3, J6’’b,5’’ =2.3 Hz, 1H; H-5’’), 3.86–3.84 (m, 2H;
H-6a, H-6b), 3.75–3.64 (m, 3H; H-2, H-4, H-5), 3.49 (ddd, J5’,4’ =9.7,
J
5’,6’a =3.7, J5’,6’b =2.4, 1H; H-5’), 3.37 (dd, J3,2 =3.4, J3,4 =1.8, 1H; H-3),
3.24, 3.20 (2s, 6H; 2OMe), 2.07–2.00 (7s, 21H; 7OAc), 1.26, 1.25 (2s,
6H; 2Me), 0.88 (s, 9H; 3Me), 0.07, 0.05 ppm (2s, 6H; 2Me); 13C NMR
(CDCl3, 100 MHz): d=170.5–169.4 (m, CO), 137.6–127.4 (m, Ar), 101.8
(C-1), 99.9 (C-1’), 99.6, 99.4 (2MeOCMe), 95.6 (C-1’’), 77.9 (C-2), 75.8
(C-3’), 74.4 (C-3), 73.3 (C-2’), 72.6 (C-4’), 72.2 (C-5’), 71.2 (C-5), 70.7
(CH2Ph), 69.9 (C-2’’), 69.4 (C-3’’), 68.4 (C-5’’), 68.0 (C-4’’), 65.2 (C-4),
63.0 (C-6’), 61.4 (C-6’’), 61.3 (C-6), 48.0, 47.9 (2OMe), 25.8 (3Me), 21.0–
20.6 (m, OAc), 18.4 (CMe3), 17.6, 17.5 (2Me), ꢁ5.0, ꢁ5.4 ppm (2Me);
HRMS calcd for C51H76NaO25Si [M+Na]: 1139.4337, found: 1139.4325.
J
1’’,2’’ =3.7 Hz, 1H; H-1’’), 4.91–4.32 (m, 16H; 8CH2Ph), 4.85 (m, 1H; H-
6a), 4.60 (m, 1H; H-6b), 4.59 (m, 1H; H-1’), 4.53 (m, 1H; H-1), 4.05 (m,
2H; H-5’’, H5’), 3.91 (t, J3,4 =J4,5 =9.7 Hz, 1H; H-4), 3.85 (t, J3’,4’ =J4’,5’
Benzyl
2,3,4,6-tetra-O-benzyl-a-d-glucopyranosyl-(1!4)-2,3,6-tri-O-
=
benzyl-b-d-glucopyranosyl-(1!4)-6-O-tert-butyldimethylsilyl-2,3-O-
[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-b-d-glucopyranoside (16): A cat-
alytic amount of NaOMe (1m) was added to a solution of compound 15
9.6 Hz, 1H; H-4’), 3.76 (m, 4H; H-4’’, H-6’a,b, H-3’), 3.66 (m, 2H; H-2,
H-3), 3.56–3.48 (m, 4H; H-6’’a, H-5, H-2’, H-2’’), 3.42 (dd, J6’’a,6’’b =1.8,
J
5’’,6’’b =10.5 Hz, 1H; H-6’’b), 3.30, 3.29 (2s, 6H; 2OMe), 1.32, 1.23 ppm
Chem. Eur. J. 2011, 17, 14817 – 14825
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14823