M. Ousmer, V. Boucard, N. Lubin-Germain, J. Uziel, J. Augé
compounds 9 and 9Ј as a 77:23 mixture of diastereomers as a color-
FULL PAPER
reduced pressure. Purification of the residue over silica gel
(30:70Ǟ100% EtOAc/cyclohexane) provided 0.83 g (86%) of 7 as
a white solid. M.p. 138–140 °C. [α]2D5 = +28.9 (c = 1, EtOH), Rf =
less oil. R = 0.28 (EtOAc/cyclohexane: 2:3). IR (ATR): ν = 2979,
˜
f
1747, 1706, 1608, 1500, 1451, 1369, 1212, 1153, 1047, 960 cm–1. 1H
NMR (250 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 2 H, CHarom.),
7.22 (d, J = 8.2 Hz, 2 H, CHarom.), 6.05 (d, J2,3 = 5.2 Hz, 0.77 H,
0.24 (pure EtOAc). IR (ATR): ν = 3422, 3367, 2971, 2925, 1731,
˜
1707, 1664, 1517, 1252, 1172, 1070, 1049, 1022, 1011, 986 cm–1. 1H
NMR (250 MHz, MeOD): δ = 7.62 (d, J = 8.2 Hz, 2 H, Harom.), 2-H for 9), 5.98 (d, J2,3 = 2.3 Hz, 0.23 H, 2-H for 9Ј), 5.68 (dd, J3,4
7.23 (d, J = 8.2 Hz, 2 H, Harom.), 5.32 (d, J2,3 = 2.7 Hz, 1 H, 2-H),
4.32 (dd, J3,4 = 5.3 Hz, 1 H, 3-H), 4.26 (br. dd, J = 8.4, J = 6.3 Hz,
= 4.1 Hz, 0.77 H, 3-H for 9), 5.61 (dd, J3,4 = 8.5 Hz, 0.23 H, 3-H
for 9Ј), 5.46 (dd, J4,5 = 7.1 Hz, 0.77 H, 4-H for 9), 5.44 (dd, J4,5
=
1 H, CHNH), 4.08–3.85 (m, 3 H, 5-H, 6-H), 3.70 (br. t, J4,5
=
3.3 Hz, 0.23 H, 4-H for 9Ј), 5.32–5.25 (m, 0.23 H, 5-H for 9Ј), 5.14–
5.08 (m, 0.77 H, 5-H for 9), 5.15 (br. d, J = 7.6 Hz, 1 H, NH),
4.50–4.40 (m, 1 H, CHNH), 4.30 (d, J6,6Ј = 12.4, J5,6Ј = 3.2 Hz,
0.77 H, 6Ј-H for 9), 4.29 (dd, J6,6Ј = 11.9, J5,6Ј = 3.9 Hz, 0.23 H,
8.4 Hz, 1 H, 4-H), 3.07 (dd, J = 13.8 Hz, 1 H, CH2), 2.93 (dd, J =
13.8 Hz, 1 H, CH2), 1.45–1.33 (m, 18 H, CH3 Boc) ppm. 13C NMR
(62.5 MHz, MeOD): δ = 173.73 (CO), 158.59 (CO), 154.02 (C-1),
139.84, 135.31 (Cquat. arom.), 131.03, 127.04 (CHarom.), 100.97 (C- 6Ј-H for 9Ј), 4.14 (dd, J5,6 = 7.3 Hz, 0.23 H, 6-H for 9Ј), 4.09 (dd,
2), 83.62 (Cquat. tBu), 81.70 (C-5), 81.37 (Cquat. tBu), 72.41 (C-3),
71.85 (C-4), 63.24 (C-6), 57.89 (CHNH), 39.35 (CH2), 29.54, 29.07
(CH3 tBu) ppm. C24H35NO8 (465.54): calcd. C 61.92, H 7.58, N
3.01; found C 61.81, H 7.67, N 3.03.
J5,6 = 5.7 Hz, 0.77 H, 6-H for 9), 3.18–2.98 (m, 2 H, CH2), 2.15–
1.90 (m, 15 H, CH3 acet), 1.45–1.25 (m, 18 H, CH3 Boc) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 192.92 (CO-1), 170.57, 170.41,
169.79, 169.65, 169.56, 169.48 (CO), 154.98 (CO), 143.18, 133.67
(Cquat. arom.), 129.99, 128.47 (CHarom.), 82.45 (Cquat. tBu), 79.88
(Cquat. tBu), 72.27 (C-2), 69.13 (C-4), 68.58 (C-5), 68.50 (C-3),
61.68 (C-6), 54.47 (CHNH), 38.46 (CH2), 28.26, 27.91 (CH3 tBu),
20.74, 20.66, 20.52, 20.40, 20.32 (CH3 Ac) ppm. HRMS (CI) calcd.
for C34H53N2O15 [M + NH4]+: 727.3289; found 727.3285.
N-[(1,1-Dimethylethoxy)carbonyl]-4-(3,4,6-tri-O-acetyl-1,2-dideoxy
-
D
-arabino-hexenopyranosyl)- -phenylalanine 1,1-Dimethylethyl Es-
L
ter (8): A solution of TBAF·3H2O (1.10 g, 3.5 mmol) in THF
(3 mL) was added dropwise, with a cannula, to a solution of com-
pound 4b (0.381 g, 0.5 mmol) in THF (4 mL) at 0 °C. The mixture
was stirred for 2 h at 0 °C and then it was warmed to room tem-
perature and stirred for 20 h. The mixture was quenched with water
and extracted with EtOAc, then the solvent was dried (Na2SO4)
and evaporated under reduced pressure. The crude product was
acetylated under standard conditions [pyridine (2.37 g, 30 mmol),
acetic anhydride (3.06 g, 30 mmol), DMAP (73.3 mg, 0.6 mmol),
room temperature, overnight stirring]. The solution was diluted
with EtOAc and washed with 0.1 HCl and brine. The organic
layer was dried (Na2SO4) and concentrated. Chromatography of
the residue (0%Ǟ60% EtOAc/cyclohexane) afforded 0.24 g (81%
over two steps) of 8 as a colorless foam. [α]2D5 = –17.5 (c = 1,
N-[(Fluoren-9-ylmethoxy)carbonyl]-4-(2,3,4,6-tetra-O-acetyl-β-D-glu-
copyranosyl)-L-phenylalanine (1): Trifluoroacetic acid (13.68 g,
120 mmol) was added dropwise, at 0 °C, under argon, to a solution
of compound 6 (0.782 g, 1.2 mmol) in distilled dichloromethane
(12 mL). The mixture was warmed to room temperature and stirred
for 5 h. Toluene (3×40 mL) was then added, and the solvent was
removed in vacuo. The resultant foam was immediately dissolved
in water (10 mL) and acetonitrile (10 mL) and stirred at room tem-
perature. FmocOSu (0.486 g, 1.44 mmol) was then added, followed
by the dropwise addition of triethylamine (0.36 g, 3.6 mmol) in or-
der to maintain the pH equal to 9. The solution was stirred for 3 h
at room temperature. The mixture was then acidified to pH 2–3
with 1 HCl. The aqueous layer was extracted with EtOAc
(3×20 mL). The combined extracts were washed with brine and
dried (Na2SO4) and the solvent was evaporated. Chromatography
of the residue (0%Ǟ10% MeOH/CHCl3) afforded 1 (0.760 g, 88%
over two steps) as a white solid. M.p. 126–128 °C. Rf = 0.2 (MeOH/
CHCl ), R = 0.55 (EtOAc/cyclohexane, 1:1). IR (ATR): ν = 3398,
˜
3
f
2977, 2933, 1734, 1693, 1657, 1524, 1448, 1367, 1220, 1157, 1096,
1035, 963 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.49 (d, J =
8.2 Hz, 2 H, CHarom.), 7.14 (d, J = 8.2 Hz, 2 H, CHarom.), 5.49 (dd,
J3,4 = 5.3, J2,3 = 3.7 Hz, 1 H, 3-H), 5.35 (d, J = 3.7 Hz, 1 H, 2-H),
5.28 (dd, J4,5 = 7.2 Hz, 1 H, 4-H), 4.96 (br. d, J = 8.0 Hz, 1 H,
NH), 4.48–4.26 (m, 4 H, CHNH, 5-H, 6-H), 3.07–3.01 (m, 2 H,
CH2), 2.14–2.00 (m, 9 H, CH3 Ac), 1.42–1.31 (m, 18 H, CH3 Boc)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 170.63, 170.53, 170.45,
169.59 (CO), 154.94 (CO), 153.34 (C-1), 137.80, 132.04 (Cquat.
arom.), 129.43, 125.15 (CHarom.), 94.07 (C-2), 82.08, 79.60 (Cquat.
tBu), 74.32 (C-5), 68.60 (C-3), 67.31 (C-4), 61.32 (C-6), 54.60
(CHNH), 38.02 (CH2), 28.21, 27.90 (CH3 tBu), 21.00, 20.76, 20.67
(CH3 Ac) ppm. C30H41NO11 (591.65): calcd. C 60.90, H 6.98, N
2.37; found C 61.12, H 7.05, N 2.34.
CHCl3, 1:9). [α]2D5 = +4.1 (c = 1, CHCl ). IR (ATR): ν = 2927,
˜
3
1744, 1517, 1370, 1220, 1038 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.74 (d, J = 7.3 Hz, 2 H, CHarom. Fmoc), 7.55 (d, J = 7.3 Hz,
2 H, CHarom. Fmoc), 7.38 (t, J = 7.3 Hz, 2 H, CHarom. Fmoc), 7.29
(d, J = 7.8 Hz, 2 H, CHarom. Fmoc), 7.23 (d, J = 7.8 Hz, 2 H,
CHarom.), 7.10 (d, J = 7.8 Hz, 2 H, CHarom.), 5.4 (d, J = 8.2 Hz, 1
H, NH), 5.32 (t, J2,3 = J3,4 = 9.6 Hz, 1 H, 3-H), 5.22 (t, J4,5
=
9.6 Hz, 1 H, 4-H), 5.10 (t, J2,1 = 9.6 Hz, 1 H, 2-H), 4.70–4.63 (m,
1 H, CHNH), 4.42 (dd, J = 10.1, JЈ = 6.9 Hz, 2 H, CH2 Fmoc),
Dihydroxylation: Pyridine (0.5 mL), H2O (1 mL), NMO (94 mg,
0.8 mmol), and OsO4 (0.05 solution in tBuOH, 0.8 mL,
0.2 equiv.) were added sequentially to a solution of glucal interme-
diate 8 (0.118 g, 0.2 mmol) in THF (2 mL) and tBuOH (2 mL). The
mixture was heated to reflux for 3 h, cooled to room temperature,
and quenched by addition of 10% NaHSO3 (4 mL). The resulting
mixture was stirred for 5 h and extracted with EtOAc. The com-
bined extracts were washed with brine, dried (Na2SO4), and the
solvent was evaporated. The crude product was acetylated under
standard conditions [pyridine (1.02 g, 10 mmol), acetic anhydride
(0.79 g, 10 mmol), DMAP (12.2 mg, 0.1 mmol), room temperature,
overnight stirring]. The solution was diluted with EtOAc and
washed with HCl (0.1 ⁾ and brine. The organic layer was dried
(Na2SO4) and concentrated. Purification of the residue over silica
gel (10%Ǟ50% EtOAc/cyclohexane) provided 0.04 g (28%) of
4.29 (d, J1,2 = 9.6 Hz, 1 H, 1-H), 4.27 (dd, J6,6Ј = 12.8, J5,6 =
4.6 Hz, 1 H, 6-H), 4.18 (d, J = 6.9 Hz, 1 H, CH Fmoc), 4.12 (t,
J6Ј,6 = J6Ј,5 = 12.8 Hz, 1 H, 6Ј-H), 3.82–3.72 (m, 1 H, 5-H), 3.16
(dd, J = 13.8, J = 5.1 Hz, 1 H, CH2), 3.05 (dd, J = 13.8, J = 6.5 Hz,
H, CH2), 2.07–1.97 (m, 9 H, CH3 Ac), 1.75 (s, 3 H, CH3 Ac) ppm.
13C NMR (100 MHz, CDCl3): δ = 174.64 (CO acid), 171.13,
170.65, 169.84, 169.36 (CO Ac), 155.89 (CO Fmoc), 143.87, 143.76,
141.38 (Cquat. arom. Fmoc), 136.75, 135.08 (Cquat. arom.), 129.66
(CHarom.), 127.86, 127.56, 127.19(CHarom. Fmoc), 127.19
(CHarom.), 125.25, 125.15, 120.12 (CHarom. Fmoc), 80.04 (C-1),
76.17 (C-5), 74.24 (C-3), 72.71 (C-2), 68.61 (C-4), 67.08 (CH2
Fmoc), 62.44 (C-6), 54.57 (CHNH), 47.19 (CH Fmoc), 37.62
(CH2), 20.91, 20.80, 20.46 (CH3 Ac) ppm. C38H39NO13 (717.72):
HRMS (CI) calcd. for C38H43N2O13 [M + NH4]+: 735.2765; found
735.2759.
1220
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Eur. J. Org. Chem. 2006, 1216–1221