Biological Activity of Synthetic b-1,4 Disaccharides
FULL PAPER
recorded at 300 and 75.5 MHz, respectively, on a Bruker AC300 spec-
trometer at 600 and 150 MHz, respectively, on a Bruker AC600 spec-
trometer. The chemical shifts are reported in parts per million (ppm) rel-
ative to tetramethylsilane (TMS) or a residual solvent peak (CHCl3: d=
7.26 and 77.2 ppm for 1H and 3C, respectively). Peak multiplicity is re-
ported as singlet (s), doublet (d), triplet (t), quartet (q), pentet (p), mul-
tiplet (m), and broad (br). High-resolution mass spectrometry (HRMS)
with electrospray ionization (ESI) was carried out on a Micromass-
Waters Q-TOF Ultima Global instrument. Optical rotations were mea-
sured on a 343 PerkinElmer instrument at 2088C in a cell (1 cm) in the
stated solvent. [a]D values are given in 10ꢀ1 cmꢀ1 gꢀ1 (concentration
c given as g100 mLꢀ1).
(COCCl3), 139.1 (Ph), 133.5 (CH2CH=CH2), 128.1–127.3 (Ph), 117.5
(CH2CH=CH2), 99.7 (C1’), 94.8 (C1), 92.2 (COCCl3), 78.0 (C4), 76,1
(C3), 74.9 (CH2Ph), 72.9 (C2), 71.9 (C5’), 71.7 (C3’), 70.8 (C5), 68.1
(OCH2CHCH2), 68.0 (C4’), 61.7 (C6’), 61.5 (C6), 56.6 (C2’), 25.8 (C-
A
R
AHCTUNGTRENNUNG
Disaccharide 1: This compound was obtained as a white solid (95 %
yield from 24, quantitative form 26). M.p. 128–1318C; [a]D20 = +88.5 (c=
0.5 in MeOH); 1H NMR (600 MHz, CD3OD): d=4.97 (d, J1,2 =3.7 Hz,
1H; H1), 4.64 (dd, J2,3 =10.1 Hz, 1H; H2), 4.54 (d, J1’,2’ =8.5 Hz, 1H;
H1’), 3.98 (dd, J3,4 =8.4 Hz, 1H; H3), 3.94 (dd, J6a’,5’ =2.2 Hz, J6’a,6’b
11.8 Hz, 1H; H6a’), 3.77 (dd, J6a,6b =10.0 Hz, 1H; H6a), 3.73 (dd, J2’,3’
=
Synthesis of disaccharide 10: A mixture of 1-(phenylsulfinyl)piperidine
=
(62.8 mg,
0.30 mmol),
2,6-di-tert-butyl-4-methylpyridine
(61.6 mg,
10.4 Hz, 1H; H2’), 3.67 (m, 4H; H6b, H5’, H6’b, CHCH2CH3), 3.59 (dd,
4,5 =9.7 Hz, 1H; H4), 3.49 (dd, J3’,4’ =8.6 Hz, 1H; H3’), 3.67 (m, 1H;
H5), 3.36 (dt, Jgem =9.7 Hz, J=6.5 Hz, 1H; CHCH2CH3), 3.34 (dd, J4’,5’
0.30 mmol), and molecular sieves 4 ꢄ (400 mg) in anhydrous CH2Cl2
(2 mL) was stirred 30 min at room temperature in an Ar atmosphere.
After cooling at ꢀ608C, Tf2O (50 mL, 0.30 mmol) was added, and the stir-
ring was continued for another 30 min. A solution of 9[12] (111.0 mg,
0.23 mmol) in anhydrous CH2Cl2 (2 mL) was added, and the reaction
mixture was stirred at ꢀ608C for 15 min. A solution of acceptor 8a
(141.6 mg, 0.30 mmol) in anhydrous CH2Cl2 (2 mL) was added to the re-
action mixture, which was allowed to reach 108C in 12 h. After the addi-
tion of methanol (10 mL), the mixture was filtered through Celite and
concentrated to a syrup. Flash chromatography on silica gel (EtOAc/cy-
clohexane 20:80) gave the disaccharide fraction (130.1 mg, 67%, a/b=
1:2). Further purification gave pure b-disaccharide 10 as a colourless
syrup. [a]D20 =ꢀ68.0 (c=0.1 in acetone); 1H NMR (300 MHz, CDCl3):
d=7.38 (m, 15H; Ph), 5.92 (m, 1H; CH2CH=CH2), 5.56 (s, 1H; CHPh),
J
=
9.8 Hz, 1H; H4’), 2.10, 2.04 (2 s, 6H; 2ꢅCOCH3), 1.62 (m, 2H;
CH2CH2CH3), 0.96 ppm (t, J=7.4 Hz, 3H; CH2CH2CH3); 13C NMR
(75 MHz, CD3OD): d=173.8, 172.4 (2ꢅCOCH3), 103.0 (C1’), 96.8 (C1),
81.4 (C4), 78.1 (C5’), 75.7 (C3’), 74.4 (C2), 72.0 (C4’), 71.7 (C5), 71.0
(C3), 70.7 (CH2CH2CH3), 62.6 (C6’), 61.6 (C6), 57.4 (C2’), 23.6
(CH2CH2CH3), 23.1, 20.8 (2ꢅCOCH3), 10.9 ppm (CH2CH2CH3); HRMS
(ESI): m/z calcd for C19H33NO12 +Na+: 490.1900 [M+Na]+; found:
490.1896.
Disaccharide 2: This compound was obtained as a white solid (86 %
yield from 28, quantitative from 26). M.p. 191–1938C; [a]D20= +68.5
(c=0.5 in MeOH); 1H NMR (600 MHz, CD3OD): d=4.97 (d, J1,2
=
3.7 Hz, 1H; H1), 4.67 (dd, J2,3 =10.0 Hz, 1H; H2), 4.65 (d, J1’,2’ =8.4 Hz,
1H; H1’), 4.29 (dd, J6a,5 =3.2 Hz, J6a,6b =10.9 Hz, 1H; H6a), 4.14 (dd,
5.34 (dd, Jgem =1.7, Jtrans =17.1 Hz, 1H; CH2CH=CH), 5.23 (dd, Jcis
10.1 Hz, 1H; CH2CH=CH), 5.06 (d, J1,2 =3.9 Hz, 1H; H1), 4.97 (d, Jgem
11.1 Hz, 1H; CHaPh), 4.93 (d, Jgem =11.2 Hz, 1H; CHbPh), 4.84 (d, 1H;
CHaPh), 4.82 (dd, J2,3 =9.6 Hz, 1H; H2), 4.68 (d, 1H; CHbPh), 4.66 (d,
=
=
J
6b,5 =2.0 Hz, 1H; H6b), 3.95 (dd, J3,4 =8.7 Hz, 1H; H3), 3.95 (dd, J6a’,5’ =
2.3 Hz, J6a,6b =11.9 Hz, 1H; H6a’), 3.86 (dd, J2’,3’ =10.1 Hz, 1H; H2’), 3.84
(m, 1H; H5), 3.72 (dd, J6b’,5’ =6.1 Hz, 1H; H6b’), 3.71 (dd, J4,5 =9.8 Hz,
J
1’,2’ =7.9 Hz, 1H; H1’), 4.21 (m, 2H; H6a, CHCH=CH2), 4.06 (m, 3H;
1H; H4), 3.69 (dt, J=6.5, Jgem =9.8 Hz, 1H; CHCH2CH3), 3.45 (dd, J3’,4’
=
H6’a, H6b, CHCH=CH2), 4.05 (dd, J3,4 =9.2 Hz, 1H; H3), 3.98 (dd, J3’,4’
8.8 Hz, 1H; H3’), 3.88 (m, 1H; H6’b), 3.76 (m, 1H; H5’), 3.71 (dd, J4’,5’
9.2 Hz, 1H; H4’), 3.54 (dd, J4,5 10.5 Hz, 1H; H4), 3.46 (dd, J2’,3’ =9.2 Hz,
1H; H2’), 3.30 (m, 1H; H5), 2.07 (s, 3H; COCH3), 0.94 (s, 9H; C(CH3)3),
0.12 ppm (s, 6H; Si
(CH3)2); 13C NMR (75 MHz, CDC13): d=170.7
(COCH3), 139.4, 138.1, 137.5 (Ph), 134.02 (CH2CH=CH2), 129.5–126.4
(Ph), 118.1 (CH2CH=CH2), 101.6 (CHPh, C1’), 95.3 (C1), 82.2 (C4’), 80.0
(C3’), 79.5 (C3), 76.9 (C4), 75.7 (CH2Ph), 75.4 (CH2Ph), 73.4 (C2), 71.5
(C5’), 68.9 (C6’), 68.6 (CH2CH=CH2), 67.1 (C2’), 66.4 (C5), 61.6 (C6),
=
8.6 Hz, 1H; H3’), 3.46 (m, 1H; H5’), 3.39 (dd, J4’,5’ =9.5 Hz, 1H; H4’),
3.38 (dt, J=6.5 Hz, 1H; CHCH2CH3), 2.12, 2.11 (2 s, 6H; 2ꢅCOCH3),
1.64 (m, 2H; CH2CH2CH3), 0.97 ppm (t, J=7.4 Hz, 3H; CH2CH2CH3);
13C NMR (75 MHz, CD3OD): d=174.1, 172.3 (2ꢅCOCH3), 103.0 (C1’),
96.9 (C1), 81.2 (C4), 78.1 (C5’), 76.4 (C3’), 74.5 (C2), 71.8 (C4’), 70.9
(C3), 70.8 (CH2CH2CH3), 69.6 (C5), 66.6 (C6), 62.4 (C6’), 56.8 (C2’), 23.6
(CH2CH2CH3), 23.1, 20.7 (2ꢅCOCH3), 10.8 ppm (CH2CH2CH3); HRMS
(ESI): m/z calcd for C19H32NO15Sꢀ: 546.1498 [M]ꢀ; found: 546.1493.
=
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Disaccharide 3: This compound was obtained as a white solid (80 %
yield from 29). M.p. 129–1328C; [a]D20 = +76.6 (c=0.5 in MeOH);
1H NMR (CD3OD, 600 MHz): d=4.78 (d, J1,2 =3.8 Hz, 1H; H1), 4.51 (d,
26.3 (C
(CH3)3), 21.3 (COCH3), 18.7 (C
E
ACHTUGNRTNE(NUNG CH3)2);
HRMS (ESI): m/z calcd for C44H57N3O11Si+Na+: 854.3660 [M+Na]+;
found: 854.3653.
J
1’,2’ =8.5 Hz, 1H; H1’), 3.93 (dd,
J6a’,5’ =2.1 Hz, J6a’,6b’ =11.8 Hz, 1H;
Procedure for the glycosylation with NHTCA trichloroacetimidates:
BF3·OEt2 (55 mL, 0.43 mmol) was added to a mixture of acceptor 8a
(200 mg, 0.43 mmol), donor 17[29] (511 mg, 0.86 mmol), and molecular
sieves 4 ꢄ (1 g) in anhydrous dichloromethane (5 mL) at ꢀ408C. The re-
action mixture was slowly allowed to warm to ꢀ208C over 4 h. N,N-Di-
H6a’), 3.78 (dd, J3,4 =8.7 Hz, 1H; H3), 3.75 (m, 1H; H6a), 3.71 (dd, J2’,3’
=
10.3 Hz, 1H; H2’), 3.67 (dd, J6b’,5’ =6.5 Hz, 1H; H6b’), 3.66 (dt, Jgem =9.5,
J=7.0 Hz, 1H; CHCH2CH3), 3.63 (dd, J6b,5 =4.5, J6b,6a =11.6 Hz, 1H;
H6b), 3.61 (m, 1H; H5), 3.48 (dd, J3’,4’ =8.3 Hz, 1H; H3’), 3.46 (dd, J4,5
=
9.5 Hz, 1H; H4), 3.44 (dd, J2,3 =9.8 Hz, 1H; H2), 3.42 (dt, J=6.5 Hz, 1H;
CHCH2CH3), 3.37 (m, 1H; H5’), 3.35 (dd, J4’,5’ =10.0 Hz, 1H; H4’), 2.03
(s, 3H; COCH3), 1.66 (m, 2H; CH2CH2CH3), 0.96 ppm (t, J=7.4 Hz,
3H; CH2CH2CH3); 13C NMR (75 MHz, CD3OD): d=173.8 (COCH3),
103.1 (C1’), 99.6 (C1), 81.8 (C4), 78.0 (C5’), 75.7 (C3’), 73.5 (C3), 73.0
(C2), 71.9 (C4’), 71.8 (C5), 70.8 (CH2CH2CH3), 62.5 (C6’), 61.6 (C6), 57.4
(C2’), 23.7 (CH2CH2CH3), 23.1 (COCH3), 11.0 ppm (CH2CH2CH3);
HRMS (ESI): m/z calcd for C17H31NO11 +Na+: 448.1795 [M+Na]+;
found: 448.1809.
ACHTUNGTRENNUNGisopropylethylamine (213 mL) was added to the reaction mixture, which
was warmed to room temperature, filtered through Celite, and concen-
trated to a syrup. Flash chromatography on C18 RP column (9:1 to 0:1
H2O/CH3CN) afforded 19 as a white solid (287 mg, 75%). M.p. 104–
1068C; [a]D20 = +32.4 (c=0.5 in CHCl3); 1H NMR (600 MHz, CDCl3):
d=7.32 (m, 5H; Ph), 6.75 (d, JNH,2’ =9.0 Hz, 1H; NH), 5.85 (m, 1H;
CH2CH=CH2), 5.27 (dd, Jtrans =17.2, Jgem =1.6 Hz, 1H; CH2CH=CH), 5.23
(dd,
J3’,2’ =10.8, J3’,4’ =9.4 Hz, 1H; H3’), 5.20 (dd, Jcis =10.4 Hz, 1H;
CH2CH=CH), 5.13 (dd, J4’,5’ =9.7 Hz, 1H; H4’), 5.01 (d, Jgem =11.7 Hz,
1H; CHPh), 5.00 (d, J1,2 =3.9 Hz, 1H; H1), 4.92 (d, J1’,2’ =8.3 Hz, 1H;
H1’), 4.74 (dd, J2,3 =9.7 Hz, 1H; H2), 4.66 (d, 1H; CHPh), 4.23 (ddd,
Disaccharide 4: This compound was obtained as a white solid (70 %
yield from 30). M.p. m.p. 197–2008C; [a]D20 = +60.6 (c=0.5 in MeOH);
1H NMR (600 MHz, CD3OD): d=4.77 (d, J1,2 =3.8 Hz, 1H; H1), 4.61 (d,
J
6a’,5’ =4.6, J6a’,6b’ =12.3 Hz, 1H; H6a’), 4.11 (dd, J=5.2 Hz, Jgem =13.2 Hz,
1H; CHCH=CH2), 4.03 (dd, J2’,3’ =10.8 Hz, 1H; H2’), 4.02 (dd, J6b’,5’
2.3 Hz, 1H; H6b’), 4.00 (dd, J3,4 =9.1 Hz, 1H; H3), 3.97 (dd, J=5.9 Hz,
1H; CHCH=CH2), 3.96 (dd, J4,5 =9.5 Hz, 1H; H4), 3.81 (dd, J6a,5
J
1’,2’ =8.8 Hz, 1H; H1’), 4.27 (dd, J6a,5 =3.0 Hz, J6a,6b =10.8 Hz, 1H; H6a),
=
4.10 (dd, J6b,5 =1.9 Hz, 1H; H6b), 3.93 (dd, J6a’,5’ =2.1, J6a’,6b’ =11.9 Hz,
1H; H6a’), 3.84 (dd, J2’,3’ =9.5 Hz, 1H; H2’), 3.78 (m, 1H; H5), 3.75 (dd,
=
J
3,4 =9.4 Hz, 1H; H3), 3.71 (dd, J6b’,5’ =5.7 Hz, 1H; H6b’), 3.66 (dt, J=
2.9 Hz, J6a,6b =12.3 Hz, 1H; H6a), 3.80 (dd, J6b,5 =1.8 Hz, 1H; H6b), 3.62
(m, 1H; H5), 3.60 (m, 1H; H5’), 2.05–2.00 (4 s, 12H; 4ꢅCOCH3), 0.95 (s,
9H; C
(75 MHz, CDCl3): d=170.8, 170.5, 170.2, 169.2 (4ꢅCOCH3), 161.7
6.9 Hz, Jgem =9.6 Hz, 1H; CHCH2CH3), 3.59 (dd, J4,5 =9.5 Hz, 1H; H4),
3.47 (dd, J2,3 =9.7 Hz, 1H; H2), 3.43 (dd, J3’,4’ =8.5 Hz, 1H; H3’), 3.42 (m,
1H; H5’), 3.41 (m, 1H; CHCH2CH3), 3.38 (dd, J4’,5’ =9.3 Hz, 1H; H4’),
ACHTUNGTRENNUNG
(CH3)3), 0.13 (s, 3H; SiCH3), 0.12 ppm (s, 3H; SiCH3); 13C NMR
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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