M. Adinolfi, D. Giacomini, A. Iadonisi, A. Quintavalla, S. Valerio
FULL PAPER
3
2
4
-CH2CH=CHcisHtrans), 5.19 (dq, J = 10.2, J = J = 1.8 Hz, 1 H, 67.6, 43.2, 25.3, 22.3 ppm. C40H42F3NO7 (705.77): calcd. C 68.07,
-CH2CH=CHcisHtrans), 4.96 (d, J1,2 = 1.6 Hz, 1 H, 1-H), 4.75–4.59 H 6.00; found C 67.96, H 5.94.
(6 H, benzyl CH2), 4.28–3.92 (m, 3 H, -CH2CH=CH2 and 5-H),
Allyl 2,3,6-Tri-O-benzyl-4-O-isovaleryl-α-
D-mannopyranosyl-(1Ǟ4)-
3.88–3.70 (5 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 138.1 (ϫ3),
133.7, 128.3–127.5, 117.2, 97.1 (C-1), 79.6, 73.9, 73.4, 72.5, 71.8,
71.5, 70.3, 67.8 ppm. C30H34O6 (490.59): calcd. C 73.45, H 6.99;
found C 73.20, H 7.05.
2,3,6-tri-O-benzyl-α-D-mannopyranoside (8): Donor 3 (58 mg,
0.082 mmol) and acceptor 2 (32 mg, 0.065 mmol) were coevapo-
rated three times in anhydrous toluene and dried under vacuum for
one hour. The mixture was then dissolved under argon in toluene/
DME (2:1, 1 mL) in the presence of freshly activated 4 Å AW mo-
lecular sieves and cooled to – 60 °C. After the system had been
Allyl 2,3,6-Tri-O-benzyl-4-O-isovaleryl-α-D-mannopyranoside (6):
Isovaleryl chloride (45 µL, 0.35 mmol) was added at 0 °C to a solu-
tion of 2 (130 mg, 0.27 mmol) in anhydrous pyridine (3 mL). The
mixture was stirred for 2 hour, and methanol was then added to
quench the reaction. The mixture was concentrated, and the residue
was purified by silica gel flash chromatography (eluent: petroleum
ether/ethyl acetate, 9:1) to yield pure 6 as an oil (139 mg, yield
91%).
stirred for 15 minutes,
a solution of Bi(OTf)3 in dioxane
(18 mgmL–1, 115 µL, 0.003 mmol) was added. The mixture was
warmed up to 0 °C over 50 minutes, and the reaction was then
quenched with pyridine. The mixture was filtered through a short
plug of silica gel, concentrated and purified by silica gel flash
chromatography (eluent: petroleum ether/acetone, 9:1) to yield di-
saccharide 8 as an oil (47 mg, 73% yield).
Compound 6 [α]2D5 = +23.0 (c = 1.0, CHCl3). H NMR (200 MHz,
1
Compound 8: [α]2D5 = +10.4 (c = 1.0, CHCl3). H NMR (500 MHz,
1
CDCl3): δ = 7.10–7.30 (benzyl aromatic protons), 6.02–5.80 (m, 1
H, -CH2=CH-CH2), 5.46 (t, J3,4 = J4,5 = 10.0 Hz, 1 H, 4-H), 5.29
CDCl3): δ = 7.20–6.95 (aromatic protons), 5.95–5.85 (m, 1 H,
-CH2CH=CH2), 5.35 (t, J3,4 = J4,5 = 10.0 Hz, 1 H, 4Ј-H), 5.31 (d,
3
2
4
(dq, J = 18.0, J = J = 1.6 Hz, 1 H, -CH2CH=CHcisHtrans), 5.19
3
2
4
J1,2 = 2.0 Hz, 1 H, 1Ј-H), 5.28 (dq, J = 17.0, J = J = 1.5 Hz, 1
3
2
4
(dq, J = 9.8, J = J = 1.6 Hz, 1 H, -CH2CH=CHcisHtrans), 4.97
(d, J1,2 = 1.6 Hz, 1 H, 1-H), 4.82–4.45 (6 H, benzyl CH2), 4.30–
3.80 (5 H), 3.72–3.58 (m, 2 H, H2-6), 2.18–2.00 (3 H), 0.96–0.86
(m, 6 H, isovaleryl CH3) ppm. 13C NMR (50 MHz, CDCl3): δ =
171.8, 138.1 (ϫ3), 133.6, 128.2–127.4, 117.2, 97.3 (C-1), 77.3, 74.2,
73.3, 72.6, 71.7, 70.6, 69.9, 68.5, 67.9, 43.2, 25.3, 22.3 ppm.
C35H42O7 (574.71): calcd. C 73.15, H 7.37; found C 73.04, H 7.48.
3
2
4
H, -CH2CH=CHcisHtrans), 5.21 (dq, J = 10.5, J = J = 1.5 Hz, 1
H, -CH2CH=CHcisHtrans), 4.94 (d, J1,2 = 2.0 Hz, 1 H, 1-H), 4.70–
4.20 (benzyl CH2), 4.24 (m, 1 H), 4.07 (t, J3,4 = J4,5 = 10.0 Hz, 1
H, 4-H), 4.00 (m, 1 H), 3.91–3.84 (m, 2 H), 3.84–3.76 (m, 5 H), 3.69
(dd, J2,3 = 2.5 Hz, 1 H, 2Ј-H), 3.49 (dd, J5,6a = 6.5, 2J = 11.0 Hz, 1
H, 6aЈ-H), 3.43 (dd, J5,6b = 3.0 Hz, 1 H, 6bЈ-H), 2.20–1.92 (m, 3 H,
isovaleryl CH2 and CH), 0.87–0.83 (2ϫd, 6 H, isovaleryl methyl
groups) ppm. 13C NMR (50 MHz, CDCl3): δ = 171.8, 138.7, 138.5,
138.4, 138.2, 138.1, 138.0, 133.8, 128.4–127.2, 117.3, 100.1 (C-1Ј),
96.0 (C-1), 80.0, 75.2, 75.0, 73.6, 73.5, 73.1, 72.4, 72.1, 71.6, 71.5,
71.4, 71.0, 70.4, 70.0, 68.4, 68.0, 43.4, 25.4, 22.4 ppm. C62H70O12
(1007.23): calcd. C 73.93, H 7.01; found C 73.82, H 6.98.
2,3,6-Tri-O-benzyl-4-O-isovaleryl-α-D-mannopyranose (7): PdCl2
(4 mg, 0.02 mmol) was added at room temperature to a solution of
6 (125 mg, 0.22 mmol) in methanol (1 mL). The mixture was kept
whilst stirring for 5 hours and was then concentrated under vac-
uum. The residue was re-suspended in DCM/methanol (19:1), fil-
tered through a short silica gel plug and concentrated under vac-
uum to yield 7 with a satisfactory purity (TLC, NMR) for direct
subjection to the following step. H NMR (200 MHz, CDCl3): δ =
7.10–7.30 (benzyl aromatic protons), 5.46 (t, J3,4 = J4,5 = 9.8 Hz, 1
H, 4-H), 5.26 (br. s, 1 H, 1-H), 4.80–4.44 (6 H, benzyl CH2), 4.14
2,3,6-Tri-O-benzyl-4-O-isovaleryl-α-D-mannopyranosyl-(1Ǟ4)-2,3,6-
tri-O-benzyl-α- -mannopyranosyl
D
(N-Phenyl)trifluoroacetimidate
1
(9): Disaccharide donor 9 (anomeric mixture β/α ca. 8:1, 34 mg,
75% overall yield) was prepared from 8 (40 mg) by a deallylation/
trifluoroacetimidoylation sequence analogous to that adopted in
the synthesis of 3 from 6.
(m, 1 H, 5-H), 3.91 (dd, J2,3 = 2.8 Hz, 1 H, 3-H), 3.80 (dd, J1,2
=
1.8 Hz, 1 H, 2-H), 3.69–3.44 (m, 2 H, 6-H2), 2.16–1.96 (m, 3 H,
isovaleryl CH2 and CH), 0.89 and 0.87 (2ϫd, 3J = 6.2 Hz, 6 H,
isovaleryl methyl groups) ppm. 13C NMR (50 MHz, CDCl3): δ =
172.0, 138.1 (ϫ2), 137.4, 128.2–127.3, 92.6 (C-1), 76.7, 74.3, 73.2,
72.6, 71.6, 69.9, 68.6, 43.3, 25.3, 22.3 ppm.
1
Compound 9: β-Anomer. H NMR (200 MHz, CDCl3): δ = 7.50–
6.70 (aromatic protons), 5.74 (br. s, 1 H, 1-H), 5.36 (t, J3,4 = J4,5
= 10.0 Hz, 1 H, 4Ј-H), 5.32 (d, J1,2 = 2.0 Hz, 1 H, 1Ј-H), 4.96–4.20
(benzyl CH2), 4.14–4.05 (m, 2 H, 2-H and 4-H), 3.98 (dd, J5,6
=
1.6 Hz, 2J = 11.0 Hz, 1 H, 6-H), 3.95–3.60 (m, 6 H), 3.58–3.40 (m,
2 H, 6Ј-H2), 2.20–1.92 m, (3 H, isovaleryl CH2 and CH), 1.00–0.87
(2ϫd, 6 H, isovaleryl methyl groups). 13C NMR (50 MHz, CDCl3):
δ = 171.8, 143.4, 138.4, 138.3 (ϫ2), 138.2, 137.9, 137.4, 128.7–
127.3, 124.3, 120.5, 119.3, 100.0 (C-1Ј), 95.7 (C-1), 81.7, 75.3, 74.0,
73.7, 73.5, 73.2, 72.2, 71.7, 71.6, 71.4, 70.2, 69.9, 68.4, 43.4, 25.4,
22.4 ppm. C67H70F3NO12 (1138.28): calcd. C 70.70, H 6.20; found
C 70.56, H 6.24.
2,3,6-Tri-O-benzyl-4-O-isovaleryl-D-mannopyranosyl (N-Phenyl)tri-
fluoroacetimidate (3): (N-Phenyl)trifluoroacetimidoyl chloride
(45 µL, 0.35 mmol) and sodium hydride (60% in oil, 12 mg,
0.29 mmol) were sequentially added at –10 °C to a solution of 7 in
anhydrous dichloromethane (2 mL). The mixture was then allowed
to warm to room temp., and after 4 hours the solvent was removed
under vacuum. The residue was purified by column chromatog-
raphy on neutral aluminium oxide (Brockman grade 2, eluent: pe-
troleum ether/ethyl acetate, 9:1) to yield 3 (anomeric mixture) as
an oil (129 mg, yield 83% over two steps).
Ethyl ((2Z,3S)-3-{(1R)-1-[2,3,6-Tri-O-benzyl-4-O-isovaleryl-α-
mannopyranosyl-(1Ǟ4)-2,3,6-tri-O-benzyl-α- -mannopyranosyl-
oxy]ethyl}-4-oxoazetidin-2-ylidene)acetate (10): Disaccharide donor
Compound 3: β/α ca. 1.5:1. 1H NMR (200 MHz, CDCl3): δ = 7.50– 9 (20 mg, 17 µmol) and β-lactam acceptor 2 (6 mg, 30 µmol) were
D-
D
6.70 (aromatic protons), 6.28 (br. s, 1 H, α 1-H), 5.82 (br. s, 1 H,
β 1-H), 5.51 (t, J3,4 = J4,5 = 10.0 Hz, 1 H, β 4-H), 5.45 (t, J3,4
coevaporated three times in anhydrous toluene and dried under
vacuum for one hour. The mixture was then dissolved under argon
in toluene/DME (2:1, 0.7 mL) in the presence of freshly activated
4 Å AW molecular sieves and cooled to –70 °C. After the system
had been stirred for 15 minutes a solution of Bi(OTf)3 in dioxane
(17 mgmL–1, 27 µL, 0.7 µmol) was added. The mixture was allowed
to warm gradually to –55 °C over 50 minutes, and the reaction was
=
J4,5 = 10.0 Hz, 1 H, α 4-H), 4.98–4.44 (α/β benzyl CH2), 4.16–4.00
(m, α/β 2-H and α 5-H), 3.92–3.56 (m, α/β 3-H and 6-H2, and β 5-
H), 2.20–1.92 (m, isovaleryl CH2 and CH), 1.00–0.87 (m, isovaleryl
methyl groups) ppm. 13C NMR (50 MHz, CDCl3): δ = 171.8,
143.3, 137.6 (ϫ2), 137.5, 129.2–127.3, 126.1, 120.6, 119.3, 95.3 (C-
1), 78.6, 76.0, 75.4, 73.6, 73.4, 72.7, 72.2, 71.9, 69.6, 69.4, 68.0, quenched with some drops of pyridine. The mixture was filtered
2898
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Eur. J. Org. Chem. 2008, 2895–2899