A. Titz et al. / Bioorg. Med. Chem. 16 (2008) 1046–1056
1055
2
Extensively dried CsF (50 mg, 0.33 mmol) was added
and the reaction mixture was stirred for 25 min at rt.
Then, a solution of dry (R)-14 (134 mg, 300 lmol) in
dry DME (6 mL) was added to the reaction, which
turned turbid upon addition, but cleared again after
2.5 h. After stirring for 4 d at rt, the reaction mixture
was concentrated and the residue was purified by two
consecutive column chromatographies on silica (1:
PE/EE 10/1 to 2/1, 2: DCM/MeOH 50/1) to yield 22
as a white solid (58 mg, 21%) and, as a byproduct,
of A0B0, J = 12.9 Hz, 1H, PhCH2), 4.67 (B00 of A00B00,
2J = 12.1 Hz, 1H, PhCH2), 4.61 (B of AB, J = 11.6 Hz,
1H, PhCH2), 4.56–4.50 (m, 2H, Gal-H1, Lac-H2), 4.49
2
3
(s, 2H, PhCH2), 4.44 (q, J = 7.1 Hz, 1H, Fuc-H5), 4.37
3
(t, J = 9.7 Hz, 1H, Gal-H2), 4.15 (s, 1H, Gal-H4), 4.03
(dd, 3J = 3.5, 3J = 10.1 Hz, 1H, Fuc-H2), 3.97 (dd,
3
3J = 2.7, J = 10.1 Hz, 1H, Fuc-H3), 3.78–3.75 (m, 2H,
Cy-CH, Gal-H6a), 3.68–3.59 (m, 4H, Cy-CH, Fuc-H4,
Gal-H5/6b), 3.49 (dd, 3J = 2.9, 3J = 9.7 Hz, 1H, Gal-
H3), 2.36 (br s, 1H, OH), 2.00–1.98 (m, 5H, 2· Cy-CH2,
2
3
(S)-benzyl 3-(1-adamantyl)-2-fluoro-propionate (23,
3· Ad-H3), 1.84 (dd, J = 14.8, J = 2.0 Hz, 1H, Lac-
H3a), 1.73–1.51 (m, 15H, 2H of Cy-CH2, 12H of Ad-
CH2, Lac-H3b), 1.49–1.17 (m, 4H, 4H of Cy-CH2), 1.11
(d, 3J = 6.5 Hz, 3H, Fuc-H6); 13C NMR (CDCl3): d
169.6 (Lac-C1), 139.2, 138.9, 138.7, 137.5 (4C, Bn-Ci),
128.5–127.2 (Ar–C), 98.1 (Gal-C1), 94.5 (Fuc-C1), 79.7
(Fuc-C3), 78.5 (Cy-CH), 78.2 (Cy-CH), 76.7 (Fuc-C2),
76.4 (Gal-H2), 76.0 (Fuc-H4), 75.7 (Lac-C2), 74.82
(Gal-H3), 74.79 (PhCH2), 73.7 (CH), 73.0 (2C, PhCH2),
72.9 (PhCH2), 68.4 (Gal-C6), 66.9 (Gal-C4), 66.0 (Fuc-
C5), 46.9 (Lac-C3), 42.6 (3C, Ad-C3), 36.8 (3C, Ad-C2),
32.4 (Ad-C1), 29.5 (Cy-CH2), 28.7 (Cy-CH2), 28.5 (3·
Ad-C4), 23.0 (2C, Cy-CH2), 16.6 (Fuc-C6); ESI-MS
Calcd for C59H72NaO12 [M+Na]+: 995.5; Found:
995.7.
20
D
48 mg, 51%). 22: Rf (PE/EE 2/1) 0.50; ½aꢁ ꢀ48.3 (c
1
1.05, CHCl3); H NMR (CDCl3): d 7.37–7.20 (m, 25
H, Ar–H), 5.18, 5.11 (A, B of AB, J = 12.2 Hz, 2H,
2
2
PhCH2), 4.94 (A0 of A0B0, J = 11.6 Hz, 1H, PhCH2),
3
4.91 (d, J = 2.5 Hz, 1H, Fuc-H1), 4.80 (A00 of A00B00,
2J = 11.6 Hz, 1H, PhCH2), 4.75 (A000 of A000B000,
2J = 12.0 Hz, 1H, PhCH2), 4.68 (m, 2H, PhCH2),
4.60 (B0 of A0B0, 2J = 11.6 Hz, 1H, PhCH2), 4.54–
4.46 (m, 3H, 2H of PhCH2, Lac-H2), 4.43–4.40 (m,
1H, Fuc-H5), 4.28 (d, 3J = 7.7 Hz, 1H, Gal-H1),
3
4.04–3.94 (m, 2H, Fuc-H2), 3.85 (d, J = 2.8 Hz, 1H,
Gal-H4), 3.79–3.63 (m, 6H, 1H of Cy-CH, Fuc-H3/4,
Gal-H2/6a,b), 3.59–3.53 (m, 1H, Cy-CH), 3.48 (t,
3J = 6.0 Hz, 1H, Gal-H5), 3.27 (dd, 3J = 3.2,
3J = 9.2 Hz, 1H, Gal-H3), 2.89 (br s, 1H, OH), 2.48
(br s, 1H, OH), 1.97 (br s, 2H, Cy-CH2), 1.91 (br s,
3H, Ad-H3), 1.72–1.40 (m, 16H, 1H of Cy-CH2, 12H
of Ad-CH2, Lac-H3a,b), 1.38–1.09 (m, 4H, 4H of
Cy-CH2), 1.06 (d, 3J = 6.5 Hz, 3H, Fuc-H6); 13C
NMR (CDCl3): d 174.9 (Lac-C1), 139.2, 138.9, 138.8,
138.2, 135.3 (5C, Bn-Ci), 128.7–126.6 (Ar–C), 100.0
(Gal-C1), 94.9 (Fuc-C1), 81.2 (Gal-C3), 79.7 (CH),
78.1 (CH), 77.2 (CH), 76.32 (CH), 76.28 (CH), 76.1
(PhCH2), 74.9 (CH), 73.6 (PhCH2), 73.3 (Gal-C5),
73.0 (PhCH2), 71.4 (CH), 69.1 (CH2), 67.1 (Gal-C4),
66.9 (Ph-CH2–O–CO–), 66.1 (Fuc-C5), 47.8 (Lac-C3),
42.5 (3· Ad-C3), 36.8 (3· Ad-C2), 32.5 (Ad-C1),
29.9 (Cy-CH2), 29.3 (Cy-CH2), 28.5 (3· Ad-C4), 23.3
(2· Cy-CH2), 16.6 (Fuc-C6); ESI-MS Calcd for
C66H80NaO13 [M+Na]+: 1103.6; Found: 1103.8.
4.12. Sodium (2S) 3-(1-adamantyl)-2-O-{1-O-[(1R,2R) 2-
O -(a-L-fucopyranosyl) cyclohexyl] b-D-galactopyranos-3-
yl}-propionate ((S)-7)
Compound 22 (26.3 mg, 24 lmol) and Pd(OH)2/C
(20 mg) were suspended in dioxane/water (4/1, 3 mL).
This suspension was hydrogenated at rt for 3 d. The sol-
vents were removed in vacuo and the residue taken up
in MeOH. Filtration over Celite and evaporation of the
solvent gave the crude product (22 mg). Purification by
column chromatography on silica (DCM/MeOH/H2O
10/4/0.8), Dowex 50 · 8 ion exchange chromatography
(Na+ form), Sephadex G-15 size exclusion chromatogra-
phy, and microfiltration afforded (S)-7 (14.8 mg, 92%)
t
as white solid after a final lyophilization from BuOH/
20
D
H2O. Rf (DCM/MeOH/H2O 10/4.8/0.5) 0.34; ½aꢁ ꢀ64.5
20
D
1
Benzyl (S)-3-(1-adamantyl)-2-fluoro-propionate (23). ½aꢁ
(c 0.74, MeOH); H NMR (MeOH-d4): d 4.86 (m, 1H,
Fuc-H1), 4.58 (q, 1H, 3J = 6.2 Hz, Fuc-H5), 4.32 (d,
1H, 3J = 7.8 Hz, Gal-H1), 3.96 (d, 1H, 3J = 8.9 Hz, Lac-
ꢀ6.4 (c 2.3, CHCl3); 1H NMR (CDCl3): d 7.39–7.33 (m,
2
5H, Ar–H), 5.23, 5.19 (A, B of AB, J = 12.2 Hz, 2H,
PhCH2), 5.09 (ddd, 2J(H–F) = 50.2, 3J = 2.3,
3J = 9.6 Hz, 1H, H2), 1.97 (br s, 3H, H6), 1.75–1.53 (m,
14H, H3a,b, 12H of Ad-CH2); ESI-MS Calcd for
C20H25FNaO2 [M+Na]+: 339.2; Found: 339.2.
H2), 3.89 (dd, 1H, J = 3.3, J = 10.1 Hz, Fuc-H3), 3.84
(d, 1H, J = 2.3 Hz, Gal-H4), 3.76 (m, 1H, Gal-H6a),
3
3
3
3.73–3.65 (m, 4H, 1· Cy-CH, Fuc-H2/4, Gal-H6b),
3.58–3.52 (m, 2H, Gal-H2, 1· Cy-H), 3.47 (t, 1H,
3J = 6.1 Hz, Gal-H5), 3.23 (dd, 1H, 3J = 3.0,
3J = 9.4 Hz, Gal-H3), 2.09–2.03 (m, 2H, Cy-CH2), 1.93
(br s, 3H, Ad-H3), 1.74–1.61 (m, 14H, 2· Cy-CH2, 12·
Ad-CH2), 1.60–1.41 (m, 2H, Lac-H3a,b), 1.39–1.25 (m,
4.11. Lactone derivative of benzyl (2R) 3-(1-adamantyl)-
2-O-{1-O-[(1R,2R) 2-O-(2,3,4-tri-O-benzyl-a-L-fucopyr-
anosyl) cyclohexyl] 6-O-benzyl-b-D-galactopyranos-3-yl}-
propionate (24)
4H, 4· Cy-CH2), 1.18 (d, 3H, 3J = 6.5 Hz, Fuc-H6); 13
C
NMR (MeOH-d4): d 184.00 (Lac-C1), 102.6 (Gal-C1),
97.0 (Fuc-C1), 84.5 (Gal-C3), 80.2 (Lac-C2), 79.2 (CH),
77.2 (CH), 75.9 (Gal-C5), 73.8 (CH), 71.7 (CH), 71.5
(Fuc-C3), 69.9 (CH), 67.7 (Gal-C4), 67.4 (Fuc-C5), 63.2
(Gal-C6), 50.1 (Lac-C3), 43.9 (3· Ad-C3), 38.2 (3· Ad-
C2), 33.5 (Ad-C1), 30.9 (Cy-CH2), 30.3 (3· Ad-C4),
30.0 (Cy-CH2), 24.5 (2· Cy-CH2), 16.6 (Fuc-C6); HR-
MS Calcd for C31H49O13 [MꢀH]ꢀ: 629.3173; Found:
629.3195.
Compound 24 was prepared in analogy to 22 starting
from 21 (51 mg, 65 lmol). Purification by column chro-
matography (PE/EE 9/1 > 0/10) yielded the pure lactone
20
1
24 (62 mg, 25%): ½aꢁ ꢀ62.4 (c 0.25, CHCl3); H NMR
D
(CDCl3): d 7.39–7.26 (m, 20 H, Ar–H), 4.95 (A of AB,
2J = 13.0 Hz, 1H, PhCH2), 4.93 (d, 3J = 3.6 Hz, 1H,
2
Fuc-H1), 4.84 (A0 of A0B0, J = 11.7 Hz, 1H, PhCH2),
4.76 (d, A00 of A00B00, 2J = 11.9 Hz, 1H, PhCH2), 4.70 (B0