Conjugate addition of phenols to 2-nitrogalactal - Synthesis of O-(2-acetamido-2-deoxygalactosyl) tyrosine

Article abstract of DOI:10.1002/ejoc.200200712

2-Nitrogalactal derivative 1 afforded 2-deoxy-2-nitrogalactopyranosides on treatment with phenol and substituted derivatives under base catalysis. Transformation of the nitro group into the amino and the acetamido groups and O-deprotection could readily be performed, thus providing aryl 2-acetamido2-deoxygalactopyranosides 5 and 6 in high yields and with good stereoselectivities. The same reaction sequence could also be successfully applied to N-Boc-protected tyrosine methyl ester, to afford the O-galactopyranonsyl tyrosine derivative 10. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200712

FULL PAPER
Conjugate Addition of Phenols to 2-Nitrogalactal ؊ Synthesis of
O-(2-Acetamido-2-deoxygalactosyl)tyrosine
Ahmed I. Khodair,[a][‡] Gottfried A. Winterfeld,[a] and Richard R. Schmidt*[a]
Keywords: Carbohydrates / Galactosamine / Glycals / Glycosidation / Glycosides / Glycosylamino acid / Michael
additions / Phenol
2-Nitrogalactal derivative 1 afforded 2-deoxy-2-nitrogalacto-
pyranosides on treatment with phenol and substituted deriv- also be successfully applied to N-Boc-protected tyrosine
atives under base catalysis. Transformation of the nitro group methyl ester, to afford the O-galactopyranonsyl tyrosine de-
into the amino and the acetamido groups and O-deprotection rivative 10.
good stereoselectivities. The same reaction sequence could
could readily be performed, thus providing aryl 2-acetamido-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
2-deoxygalactopyranosides 5 and 6 in high yields and with Germany, 2003)
Introduction
O)Tyr],[10Ϫ13] it was also of interest to investigate tyrosine
addition.
The low nucleophilicity of phenols has often been the
cause of low yields in acid-promoted glycosidation reac-
tions.[1] Because of the occurrence of quite a variety of aryl
glycosides in nature,[2] the base-catalysed addition of phen-
ols (i.e., the addition of more nucleophilic phenolates[3]) to
2-nitrogalactal was now investigated. This fundamentally
new approach to glycoside bond formation, as outlined in
Scheme 1, was shown to be a convenient method for the
highly stereoselective syntheses of α- and β-O-glycosides
with alcohols and also sugars as O-nucleophiles,[4] of β-nu-
cleosides with heterocyclic bases as nucleophiles,[5] and of β-
Results and Discussion
3,4,6-Tri-O-benzyl-2-nitro--galactal (Scheme 2, 1), read-
ily available through nitration of the corresponding galac-
tal,[4] was treated with phenol in toluene as solvent in the
presence of a catalytic amount of potassium tert-butoxide,
thus affording a 13:1 ratio of α-anomer 2aα and β-anomer
2bβ in 92% yield.
The two compounds could be separated and structurally
3
2
assigned by their NMR data (2aα: J1,2 ϭ 4.1, J2,3
ϭ
3
3
10.7 Hz; 2bβ: J1,2 ϭ 8.1, J2,3 ϭ 10.6 Hz). The kinetically
and thermodynamically preferred α-attack of phenolate and
the thermodynamically preferred protonation from the β-
side prevailed in this reaction, and so two new stereogenic
centres were generated with high stereocontrol. Under the
same conditions, o-cresol and resorcin monomethyl ether
afforded α-anomers 2bα and 2cα, respectively; the corre-
sponding β-anomers were not detected. With p-cresol, α-
anomer 2dα (84%) was also preferentially found, with only
8% of the β-anomer 2dβ being isolated. Thus, as expected
from previous investigations on O-nucleophiles,[4,7Ϫ9] ad-
dition of phenolates gave mainly α-anomers in high yields.
Reduction of the 2-nitro group in 2aαϪ2dα with hydrogen
in the presence of platinised Raney nickel T4[14] as catalyst
afforded amino derivatives 3aϪd in high yields, and these,
on acetylation with acetic anhydride in pyridine, furnished
aryl glycosides of N-acetylgalactosamine 4aϪd. Finally, hy-
drogenolytic O-debenzylation (Ǟ 5a-d) and then O-acety-
lation under standard conditions provided the desired tar-
get molecules 6aϪd in high yields.
Scheme 1. Base-catalysed addition of nucleophiles to 2-nitroglycals
C-glycosides with CH-acidic compounds as nucleophiles.[6]
This method was also successfully extended to the syn-
thesis of important GalNAcα(1-O)-Ser and GalNAcα(1-O)-
Thr building blocks required for mucin O-glycopeptide
synthesis.[7Ϫ9] If phenolates would also act as nucleophiles,
aryl glycosides would then become readily available. Be-
cause of the frequent occurrence of O-glycosyl tyrosine con-
stituents in nature [particularly Glcα(1-O)Tyr and Galβ(1-
[a]
Fachbereich Chemie, Universität Konstanz,
Fach M725, 78457 Konstanz, Germany
Fax: (internat.) ϩ 49-7531/883135
E-mail: richard.schmidt@uni-konstanz.de
[‡]
On leave from the Chemistry Department, Faculty of
The excellent reactivity of phenols with 2-nitrogalactal 1
was reason also to investigate tyrosine addition. To this end,
Education, Tanta University, Kafr El-Sheikh Branch, Kafr El-
Sheikh, Egypt
Eur. J. Org. Chem. 2003, 1847Ϫ1852
DOI: 10.1002/ejoc.200200712
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1847

A. I. Khodair, G. A. Winterfeld, R. R. Schmidt
FULL PAPER
3
(1H NMR: 7α: δ ϭ 5.84, J1,2 ϭ 4.1 Hz; 7β: δ ϭ 5.27,
3J1,2 ϭ 8.0 Hz). In addition, no racemisation of the tyrosine
moiety was observed. Selective reduction of the nitro group
in 7α with platinised Raney nickel[14] afforded 2-amino de-
rivative 8, which on acetylation gave acetylamino derivative
9. Hydrogenolytic O-debenzylation and then O-acetylation
gave the desired O-acetyl-N-Boc-protected O-(α--galactos-
yl)tyrosine 10. Acid-catalysed removal of the Boc protecting
group with trifluoroacetic acid (TFA) in dichloromethane
did not affect the glycosidic bond; ensuing N-acetylation
furnished N,O-diacetyl derivative 11 in high yield.
In conclusion, base-catalysed addition of phenol and
phenol derivatives to 2-nitrogalactal derivative 1 afforded
mainly α-adducts with galacto configurations, two stereo-
genic centres thus being generated with high stereocontrol.
Transformation of the adducts into the corresponding gal-
actosamine target molecules could be readily performed
with high yields.
Experimental Section
General Remarks: Solvents were removed under reduced pressure
while the water bath temperature was maintained below 40 °C.
Chromatography was performed on silica gel for flash chromatog-
raphy (40 µm; J. T. Baker) at 3 bar pressure. For thin layer chroma-
tography, TLC plastic sheets (60 F254 silica gel) were used and the
compounds were viewed by illumination under UV light at 253 nm
and by treatment with 5% (NH4)2MoO4, 0.1% Ce(SO4)2 in 10%
H2SO4 and heating to 160 °C. Optical rotations were measured at
25 °C with a PerkinϪElmer 241/MS polarimeter at the sodium D
line. NMR: Bruker AC-250 Cryospec, Bruker DR-600; TMS or the
Scheme 2. Synthesis of phenyl 2-acetylamino-2-deoxy--galactopy-
ranosides: (a) toluene, tBuOK; (b) Ra-Ni T4-Pt, H2, EtOH; (c)
Ac2O, Pyr; (d) Pd/C, H2, MeOH, HOAc; (e) Ac2O, Pyr
commercially available N-Boc-protected tyrosine methyl es-
ter was selected (Scheme 3).
3
solvent residual peak were used as internal standard. JC,4 coup-
lings were observed in gradient-selected heteronuclear multi-bond
correlations (HMBC). MALDI-MS: Kratos Kompact Maldi 1; 2,5-
dihydroxybenzoic acid was used as matrix. FAB-MS: Finnigan
MAT 312/AMD-5000, 790 eV, 70 °C. Calculated yields are based
on consumed starting material where its recovery is stated.
Phenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-α-
(2aα) and Its β-Anomer 2aβ: tBuOK (200 µL of a 1  solution in
THF) was added to solution of nitrogalactal (1.00 g,
D-galactopyranoside
a
1
2.16 mmol) and phenol (0.41 g, 4.33 mmol) in toluene (30 mL), and
the solution was stirred at room temp. for 30 min. The reaction
mixture was quenched with acetic acid (200 µL) and concentrated.
The crude product was purified by flash chromatography on silica
gel, eluting with toluene/ethyl acetate (98:2), to give 2aα (1.03 g,
86%) as a white foam and 2aβ (72 mg, 6%) as a colourless oil.
Compound 2aα: TLC (toluene/ethyl acetate, 95:5) Rf ϭ 0.50. [α]D ϭ
ϩ90.5 (c ϭ 0.18, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ
3
3.54Ϫ3.69 (m, 2 H, 6-H, 6Ј-H), 4.12 (d, J4,3 ϭ 2.9 Hz, 1 H, 4-H),
3
3
4.23 (dd, J5,6 ϭ 6.7, J5,6Ј ϭ 6.6 Hz, 1 H, 5-H), 4.35 (d, 2J ϭ
Scheme 3. Synthesis of O-(2-acetylamino-2-deoxy-α--galactopyr-
anosyl)tyrosine derivatives: (a) toluene, tBuOK; (b) Ra-Ni, T4-Pt,
EtOH; (c) Ac2O, Pyr; (d) Pd/C, H2, MeOH, HOAc, Ac2O, Pyr; (e)
TFA, CH2Cl2, Ac2O, Pyr
11.6 Hz, 1 H, CHHPh), 4.42 (d, 2J ϭ 11.7 Hz, 1 H, CHHPh), 4.48
(d, 2J ϭ 11.1 Hz, 1 H, CHHPh), 4.67 (dd, J3,4 ϭ 3.0, J3,2
ϭ
3
3
2
10.6 Hz, 1 H, 3-H), 4.77 (d, J ϭ 11.5 Hz, 1 H, CHHPh), 4.80 (d,
2J ϭ 11.5 Hz, 1 H, CHHPh), 4.90 (d, 2J ϭ 11.2 Hz, 1 H, CHHPh),
3
3
3
5.18 (dd, J2,1 ϭ 4.2, J2,3 ϭ 10.7 Hz, 1 H, 2-H), 5.93 (d, J1,2
ϭ
Treatment under the conditions described above afforded
practically only the α-anomers 7α (80% yield), with only 2%
of the corresponding β-anomer 7β being found. The two
4.1 Hz, 1 H, 1-H), 6.99Ϫ7.41 (m, 20 H, Ar-H) ppm. 13C NMR
(62.8 MHz, CDCl3): δ ϭ 68.2 (C-6), 70.4 (C-5), 73.7 (C-4,
CHHPh), 73.5 (CHHPh), 75.1 (CHHPh), 75.2 (C-3), 84.1 (C-2),
compounds could be separated and structurally assigned 96.0 (C-1), 115.3, 117.4, 123.5, 127.8, 127.9, 128.1, 128.38, 128.42,
1848  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 1847Ϫ1852

Conjugate Addition of Phenols to 2-Nitrogalactal
FULL PAPER
128.5, 129.6, 137.3, 137.7, 137.9, 156.2 (C-Ar) ppm. MS (MALDI): from o-cresol (468 µL, 4.33 mmol) in the manner described for 2aα;
calcd. 555 ϩ 23 [Na] ϭ 578; found 578 [M ϩ Na]ϩ. C33H33NO7 the product was chromatographed on silica gel (toluene/ethyl acet-
(555.6): calcd. C 71.34, H 5.99, N 2.52; found C 71.59, H 6.15,
N 2.47.
ate, 98:2) to give 1.03 g (84%) of 2dα as a white foam and 0.10 g
(8%) of 2dβ as a white foam.
Compound 2aβ: TLC (toluene/ethyl acetate, 95:5) Rf ϭ 0.45. [α]D ϭ
ϩ10.5 (c ϭ 0.58, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 3.61 ϩ94.5 (c ϭ 0.11, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 2.29
Compound 2dα: TLC (toluene/ethyl acetate, 95:5) Rf ϭ 0.60. [α]D ϭ
1
1
3
3
3
(m, 2 H, 6-H, 6Ј-H), 3.74 (dd, J5,6 ϭ 6.4, J5,6Ј ϭ 6.5 Hz, 1 H, 5-
(s, 3 H, CH3), 3.55Ϫ3.67 (m, 2 H, 6-H, 6Ј-H), 4.11 (d, J4,3 ϭ
H), 4.00 (d, 3J4,3 ϭ 2.5 Hz, 1 H, 4-H), 4.12 (dd, 3J3,4 ϭ 2.5, 3J3,2 ϭ 2.7 Hz, 1 H, 4-H), 4.23 (dd, 3J5,6 ϭ 6.7, 3J5,6Ј ϭ 6.6 Hz, 1 H, 5-H),
2
2
2
10.6 Hz, 1 H, 3-H), 4.36Ϫ4.47 (m, 3 H, 3 CHHPh), 4.54 (d, J ϭ 4.40 (d, J ϭ 11.7 Hz, 1 H, CHHPh), 4.45 (d, J ϭ 11.7 Hz, 1 H,
11.4 Hz, 1 H, CHHPh), 4.62 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.86 CHHPh), 4.52 (d, J ϭ 11.1 Hz, 1 H, CHHPh), 4.65 (dd, J3,4
ϭ
2
3
(d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 5.10 (dd, J2,1 ϭ 8.2, J2,3
ϭ
3.0, J3,2 ϭ 10.7 Hz, 1 H, 3-H), 4.80 (d, 2J ϭ 11.8 Hz, 1 H,
3
3
3
10.6 Hz, 1 H, 2-H), 5.27 (d, J1,2 ϭ 8.1 Hz, 1 H, 1-H), 6.93Ϫ7.35 CHHPh), 4.85 (d, 2J ϭ 11.8 Hz, 1 H, CHHPh), 4.90 (d, 2J ϭ
3
(m, 20 H, Ar-H) ppm. MS (MALDI): calcd. 555 ϩ 23 [Na] ϭ 578;
found 578 [M ϩ Na]ϩ. C33H33NO7 (555.6): calcd. C 71.34, H 5.99,
N 2.52; found C 71.25, H 5.99, N 2.52.
11.2 Hz, 1 H, CHHPh), 5.15 (dd, 3J2,1 ϭ 4.1, 3J2,3 ϭ 10.6 Hz, 1 H,
3
2-H), 5.86 (d, J1,2 ϭ 4.1 Hz, 1 H, 1-H), 6.89Ϫ7.34 (m, 19 H, Ar-
H) ppm. 13C NMR (62.8 MHz, CDCl3): δ ϭ 20.1 (CH3), 67.7 (C-
6), 69.9 (C-5), 72.7 (C-4), 72.8 (CHHPh), 73.0 (CHHPh), 74.68
(CHHPh), 74.71 (C-3), 83.7 (C-2), 95.8 (C-1), 116.9, 127.3, 127.4,
127.6, 127.7, 127.88, 127.92, 128.0, 129.6, 132.5, 136.8, 137.2,
137.5, 153.6 (C-Ar) ppm. MS (MALDI): calcd. 569 ϩ 23 [Na] ϭ
592; found 592 [M ϩ Na]ϩ. C34H35NO7 (569.6): calcd. C 71.69, H
6.19, N 2.46; found C 71.43, H 5.96, N 2.59.
2-Methylphenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-α-D-galactopyr-
anoside (2bα): This compound was prepared from o-cresol (468 µL,
4.33 mmol) in the manner described for 2aα; the product was chro-
matographed on silica gel (toluene/ethyl acetate, 98:2) to give 1.01 g
(82%) of 2bα as a colourless oil. TLC (toluene/ethyl acetate, 95:5)
1
Rf ϭ 0.48. [α]D ϭ ϩ98.4 (c ϭ 0.25, CHCl3). H NMR (250 MHz,
CDCl3): δ ϭ 2.15 (s, 3 H, CH3), 3.52Ϫ3.67 (m, 2 H, 6-H, 6Ј-H), Compound 2dβ: TLC (toluene/ethyl acetate, 95:5) Rf ϭ 0.55. [α]D ϭ
3
3
3
4.11 (d, J4,3 ϭ 2.7 Hz, 1 H, 4-H), 4.17 (dd, J5,6 ϭ 6.8, J5,6Ј
ϭ
ϩ8.9 (c ϭ 0.18, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 2.19
2
3
6.6 Hz, 1 H, 5-H), 4.39 (d, J ϭ 11.6 Hz, 1 H, CHHPh), 4.43 (d, (s, 3 H, CH3), 3.58 (m, 2 H, 6-H, 6Ј-H), 3.65 (dd, J5,6 ϭ 5.7,
2J ϭ 11.7 Hz, 1 H, CHHPh), 4.52 (d, 2J ϭ 11.1 Hz, 1 H, CHHPh),
3J5,6Ј ϭ 5.8 Hz, 1 H, 5-H), 3.96 (d, J4,3 ϭ 2.7 Hz, 1 H, 4-H), 4.07
3
4.68 (dd, J3,4 ϭ 3.0, J3,2 ϭ 10.7 Hz, 1 H, 3-H), 4.79 (d, 2J ϭ (dd, 3J3,4 ϭ 2.7, 3J3,2 ϭ 10.5 Hz, 1 H, 3-H), 4.37 (m, 3 H, CHHPh),
3
3
11.6 Hz, 1 H, CHHPh), 4.80 (d, 2J ϭ 11.5 Hz, 1 H, CHHPh), 4.90 4.50 (d, J ϭ 11.4 Hz, 1 H, CHHPh), 4.56 (d, J ϭ 11.6 Hz, 1 H,
2
2
(d, 2J ϭ 11.1 Hz, 1 H, CHHPh), 5.16 (dd, J2,1 ϭ 4.1, J2,3
ϭ
CHHPh), 4.84 (d, J ϭ 11.4 Hz, 1 H, CHHPh), 5.04 (dd, J2,1 ϭ
3
3
2
3
3
3
3
10.7 Hz, 1 H, 2-H), 5.92 (d, J1,2 ϭ 4.1 Hz, 1 H, 1-H), 6.92Ϫ7.37 7.9, J2,3 ϭ 10.4 Hz, 1 H, 2-H), 5.20 (d, J1,2 ϭ 7.8 Hz, 1 H, 1-H),
(m, 19 H, Ar-H) ppm. 13C NMR (62.8 MHz, CDCl3): δ ϭ 15.4
6.78Ϫ7.31 (m, 19 H, Ar-H) ppm. MS (MALDI): calcd. 569 ϩ 23
(CH3), 67.6 (C-6), 69.8 (C-5), 72.6 (C-4, CHHPh), 72.7 (CHHPh), [Na] ϭ 592; found 592 [M ϩ Na]ϩ. C34H35NO7 (569.6): calcd. C
73.0 (CHHPh), 74.7 (C-3), 83.7 (C-2), 95.1 (C-1), 114.3, 122.5, 71.69, H 6.19, N 2.46; found C 71.37, H 6.00, N 2.48.
126.5, 127.1, 127.27, 127.34, 127.4, 127.56, 127.62, 127.7, 127.87,
Phenyl 2-Amino-3,4,6-tri-O-benzyl-2-deoxy-2-nitro-α-D-galactopyr-
127.90, 128.0, 130.5, 136.7, 137.1, 137.4, 153.7 (C-Ar) ppm. MS
(MALDI): calcd. 569 ϩ 23 [Na] ϭ 592; found 592 [M ϩ Na]ϩ.
C34H35NO7 (569.6): calcd. C 71.69, H 6.19, N 2.46; found C 71.08,
H 6.51, N 2.27.
anoside (3a): Compound 2aα (0.50 g, 0.90 mmol) was dissolved in
ethanol (15 mL) and transferred to a hydrogenation vessel. Platin-
ised Raney nickel T4 catalyst was freshly prepared as described
in ref.[14], and the material obtained from 2.70 g of Raney nickel/
aluminium alloy was suspended in ethanol (15 mL). From a homo-
geneous suspension of this catalyst, 15 mL was added to the reac-
tion vessel and the suspension was shaken under H2 for 48 h at
ambient temp. and pressure. The catalyst was filtered off and the
3-Methoxyphenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-α-D-galacto-
pyranoside (2cα): This compound was prepared from 3-meth-
oxyphenol (468 µL, 4.33 mmol) in the manner described for 2aα;
the product was chromatographed on silica gel (toluene/ethyl acet-
ate, 98:2) to give 1.16 g of 2cα as a colourless oil. TLC (toluene/ solvent was evaporated. The residue was purified by column chro-
ethyl acetate, 95:5) Rf ϭ 0.52. [α]D ϭ ϩ60.7 (c ϭ 0.15, CHCl3). 1H
matography (CH2Cl2/MeOH, 95:5) to furnish 3a (0.37 g, 78%) as
NMR (250 MHz, CDCl3): δ ϭ 3.51Ϫ3.65 (m, 2 H, 6-H, 6Ј-H), 3.71 a colourless oil. TLC (CH2Cl2/MeOH, 95:5) Rf ϭ 0.30. [α]D
ϭ
(s, 3 H, OCH3), 4.10 (d, 3J4,3 ϭ 2.3 Hz, 1 H, 4-H), 4.19 (dd, 3J5,6 ϭ ϩ91.7 (c ϭ 0.30, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ
3
6.7, J5,6Ј ϭ 6.5 Hz, 1 H, 5-H), 4.37 (d, 2J ϭ 11.7 Hz, 1 H,
3.45Ϫ3.56 (m, 3 H, 6-H, 6Ј-H, 2-H), 3.65Ϫ3.74 (m, 2 H, 4-H, 5-
CHHPh), 4.45 (d, 2J ϭ 11.7 Hz, 1 H, CHHPh), 4.50 (d, 2J ϭ H), 4.08 (m, 3 H, NH2, 3-H), 4.37 (d, 2J ϭ 11.5 Hz, 1 H, CHHPh),
11.2 Hz, 1 H, CHHPh), 4.65 (dd, 3J3,4 ϭ 2.9, 3J3,2 ϭ 10.7 Hz, 1 H, 4.44 (d, J ϭ 11.7 Hz, 1 H, CHHPh), 4.56 (d, J ϭ 11.6 Hz, 1 H,
2
2
3-H), 4.79 (d, J ϭ 10.7 Hz, 1 H, CHHPh), 4.83 (d, J ϭ 11.3 Hz, CHHPh), 4.60 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 4.80 (d, 2J ϭ
2
2
1 H, CHHPh), 4.89 (d, 2J ϭ 11.2 Hz, 1 H, CHHPh), 5.14 (dd, 11.6 Hz, 1 H, CHHPh), 4.90 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 5.57
3J2,1 ϭ 4.1, J2,3 ϭ 10.6 Hz, 1 H, 2-H), 5.90 (d, J1,2 ϭ 4.1 Hz, 1
(d, 3J1,2 ϭ 3.6 Hz, 1 H, 1-H), 6.97Ϫ7.42 (m, 20 H, Ar-H) ppm. MS
3
3
H, 1-H), 6.56Ϫ7.36 (m, 19 H, Ar-H) ppm. 13C NMR (62.8 MHz, (MALDI): calcd. 525 ϩ 23 [Na] ϭ 548; found 548 [M ϩ Na]ϩ.
CDCl3): δ ϭ 55.3 (OCH3), 68.2 (C-6), 70.4 (C-5), 73.2 (C-4, C33H35NO5 (525.6): calcd. C 75.40, H 6.71, N 2.66; found C 74.91,
CHHPh), 73.5 (CHHPh), 75.1 (CHHPh), 75.2 (C-3), 84.1 (C-2), H 6.80, N 2.62.
95.9 (C-1), 103.5, 109.3, 109.4, 127.8, 127.9, 128.1, 128.2, 128.40,
2-Methylphenyl 2-Amino-3,4,6-tri-O-benzyl-2-deoxy-2-nitro-α-D-ga-
128.42, 128.5, 130.0, 137.3, 137.6, 137.9, 157.3 (C-Ar) ppm. MS
(MALDI): calcd. 585 ϩ 23 [Na] ϭ 608; found 608 [M ϩ Na]ϩ.
C34H35NO8 (585.6): calcd. C 69.73, H 6.02, N 2.39; found C 69.73,
H 5.87, N 2.52.
lactopyranoside (3b): This compound was prepared from 2bα
(512 mg, 0.90 mmol) in the manner described for 3a; the product
was chromatographed on silica gel (CH2Cl2/MeOH, 95:5) to give
442 mg (82%) of 3b as a pale yellow oil. TLC (CH2Cl2/MeOH,
95:5) Rf ϭ 0.38. [α]D ϭ ϩ117.3 (c ϭ 0.33, CHCl3). 1H NMR
4-Methylphenyl 3,4,6-Tri-O-benzyl-2-deoxy-2-nitro-α-D-galactopyr-
anoside (2dα) and Its β-Anomer 2dβ: This compound was prepared (250 MHz, CDCl3): δ ϭ 2.17 (s, 3 H, CH3), 3.46Ϫ3.57 (m, 3 H, 6-
Eur. J. Org. Chem. 2003, 1847Ϫ1852
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1849

A. I. Khodair, G. A. Winterfeld, R. R. Schmidt
H, 6Ј-H, 2-H), 3.67Ϫ3.74 (m, 2 H, 4-H, 5-H), 4.05Ϫ4.12 (m, 3 H, (259 mg, 0.48 mmol) in the manner described for 4a; the product
FULL PAPER
NH2, 3-H), 4.40 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.45 (d, 2J ϭ
was chromatographed on silica gel (CH2Cl2/MeOH, 98:2) to give
11.6 Hz, 1 H, CHHPh), 4.55 (d, 2J ϭ 11.7 Hz, 1 H, CHHPh), 4.64 256 mg (92%) of 4b as a white solid; m.p. 153Ϫ155 °C. TLC
(d, 2J ϭ 11.5 Hz, 1 H, CHHPh), 4.83 (d, 2J ϭ 11.7 Hz, 1 H, (CH2Cl2/MeOH, 95:5) Rf ϭ 0.58. [α]D ϭ ϩ94.3 (c ϭ 0.28, CHCl3).
3
CHHPh), 4.93 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 5.60 (d, J1,2
ϭ
1H NMR (250 MHz, CDCl3): δ ϭ 1.86 (s, 3 H, Ac), 2.06 (s, 3 H,
3
3
3.4 Hz, 1 H, 1-H), 6.90Ϫ7.43 (m, 19 H, Ar-H) ppm. MS (MALDI):
CH3), 3.53 (dd, J6,5 ϭ 5.5, J6,6Ј ϭ 9.1 Hz, 1 H, 6-H), 3.66Ϫ3.74
calcd. 539 ϩ 23 [Na] ϭ 562; found 562 [M ϩ Na]ϩ. C34H37NO5 (m, 1 H, 6Ј-H), 3.86 (dd, J3,4 ϭ 2.4, J3,2 ϭ 11.2 Hz, 1 H, 3-H),
3
3
(539.7): calcd. C 75.67, H 6.91, N 2.60; found C 75.28, H 7.05,
N 2.60.
4.00 (m, 1 H, 5-H), 4.13 (br. s, 1 H, 4-H), 4.35Ϫ4.53 (m, 3 H,
CHHPh), 4.67 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.81 (d, 2J ϭ
12.2 Hz, 1 H, CHHPh), 4.93 (m, 1 H, 2-H), 5.00 (d, J ϭ 11.4 Hz,
2
3-Methylphenyl 2-Amino-3,4,6-tri-O-benzyl-2-deoxy-2-nitro-α-D-ga-
1 H, CHHPh), 5.10 (d, 3JNH,2 ϭ 8.4 Hz, 1 H, NH), 5.61 (d, 3J1,2 ϭ
3.4 Hz, 1 H, 1-H), 6.88Ϫ7.40 (m, 19 H, Ar-H) ppm. MS (MALDI):
calcd. 581 ϩ 23 [Na] ϭ 604; found 604 [M ϩ Na]ϩ. C36H39NO6
(581.7): calcd. C 74.33, H 6.76, N 2.41; found C 73.89, H 7.01,
N 2.44.
lactopyranoside (3c): This compound was prepared from 2cα
(526 mg, 0.90 mmol) in the manner described for 3a; the product
was chromatographed on silica gel (CH2Cl2/MeOH, 95:5) to give
400 mg (80%) of 3c as a pale yellow foam. TLC (CH2Cl2/MeOH,
95:5) Rf ϭ 0.40. [α]D ϭ ϩ121.3 (c ϭ 0.15, CHCl3). 1H NMR
(250 MHz, CDCl3): δ ϭ 3.44Ϫ3.55 (m, 3 H, 6-H, 6Ј-H, 2-H),
3.64Ϫ3.70 (m, 2 H, 4-H, 5-H), 3.72 (s, 3 H, OCH3), 4.07 (m, 3 H,
NH2, 3-H), 4.38 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.45 (d, 2J ϭ
11.6 Hz, 1 H, CHHPh), 4.53 (d, 2J ϭ 11.7 Hz, 1 H, CHHPh), 4.59
3-Methoxyphenyl
2-Acetylamino-3,4,6-tri-O-benzyl-2-deoxy-α-D-
galactopyranoside (4c): This compound was prepared from 3c
(266 mg, 0.48 mmol) in the manner described for 4a; the product
was chromatographed on silica gel (petroleum ether/ethyl acetate,
80:20) to give 269 mg (94%) of 4c as a white foam. TLC (petroleum
ether/ethyl acetate, 50:50) Rf ϭ 0.50. [α]D ϭ ϩ92.9 (c ϭ 0.14,
CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.92 (s, 3 H, Ac),
3.51Ϫ3.72 (m, 2 H, 6-H, 6Ј-H), 3.74 (s, 3 H, OCH3), 3.86 (dd,
3J3,4 ϭ 2.5, 3J3,2 ϭ 11.0 Hz, 1 H, 3-H), 4.04Ϫ4.13 (m, 2 H, 5-H, 4-
(d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 4.80 (d, 2J ϭ 11.6 Hz, 1 H,
3
CHHPh), 4.90 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 5.55 (d, J1,2
ϭ
3.6 Hz, 1 H, 1-H), 6.57Ϫ7.38 (m, 19 H, Ar-H) ppm. MS (MALDI):
calcd. 555 ϩ 23 [Na] ϭ 578; found 578 [M ϩ Na]ϩ. C34H37NO6
(555.7): calcd. C 73.49, H 6.71, N 2.52; found C 73.19, H 6.73,
N 2.42.
2
2
H), 4.37 (d, J ϭ 11.5 Hz, 1 H, CHHPh), 4.45 (d, J ϭ 11.5 Hz, 1
2
2
H, CHHPh), 4.50 (d, J ϭ 12.3 Hz, 1 H, CHHPh), 4.62 (d, J ϭ
11.6 Hz, 1 H, CHHPh), 4.80 (d, 2J ϭ 12.1 Hz, 1 H, CHHPh), 4.86
(m, 1 H, 2-H), 5.01 (d, 2J ϭ 11.5 Hz, 1 H, CHHPh), 5.41 (d,
4-Methylphenyl 2-Amino-3,4,6-tri-O-benzyl-2-deoxy-α-D-galacto-
pyranoside (3d): This compound was prepared from 2dα (512 mg,
0.90 mmol) in the manner described for 3a; the product was chrom-
atographed on silica gel (CH2Cl2/MeOH, 95:5) to give 407 mg
(84%) of 3d as a white foam. TLC (CH2Cl2/MeOH, 95:5) Rf ϭ
0.30. [α]D ϭ ϩ138.5 (c ϭ 0.13, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 2.27 (s, 3 H, CH3), 3.43Ϫ3.56 (m, 3 H, 6-H, 6Ј-H, 2-
H), 3.67Ϫ3.73 (m, 2 H, 4-H, 5-H), 4.08 (m, 3 H, NH2, 3-H), 4.37
(d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.44 (d, 2J ϭ 11.6 Hz, 1 H,
CHHPh), 4.55 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.60 (d, 2J ϭ
11.4 Hz, 1 H, CHHPh), 4.80 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.90
3JNH,2 ϭ 8.7 Hz, 1 H, NH), 5.62 (d, J1,2 ϭ 3.5 Hz, 1 H, 1-H),
3
6.56Ϫ7.40 (m, 19 H, Ar-H) ppm. 13C NMR (62.8 MHz, CDCl3):
δ ϭ 23.3 (Ac), 49.0 (C-2), 55.2 (OCH3), 68.7 (C-6), 70.5 (C-5), 71.4
(C-4), 72.5 (CHHPh), 73.4 (CHHPh), 74.6 (CHHPh), 77.0 (C-3),
96.9 (C-1), 103.1, 108.1, 109.0, 127.6, 127.66, 127.73, 127.8, 128.0,
128.16, 128.23, 128.3, 128.5, 129.9, 137.8, 138.0, 138.4, 160.7 (C-
Ar), 169.8 (Ac) ppm. MS (MALDI): calcd. 597 ϩ 23 [Na] ϭ 620;
found 620 [M ϩ Na]ϩ. C36H39NO7 (597.7): calcd. C 72.34, H 6.58,
N 2.34; found C 72.08, H 6.70, N 2.49.
2
3
(d, J ϭ 11.4 Hz, 1 H, CHHPh), 5.51 (d, J1,2 ϭ 3.6 Hz, 1 H, 1-
H), 6.93Ϫ7.40 (m, 19 H, Ar-H) ppm. MS (MALDI): calcd. 539 ϩ
23 [Na] ϭ 562; found 562 [M ϩ Na]ϩ. C34H37NO5 (539.7): calcd.
C 75.67, H 6.91, N 2.60; found C 75.81, H 6.83, N 2.36.
4-Methylphenyl 2-Acetylamino-3,4,6-tri-O-benzyl-2-deoxy-α-D-ga-
lactopyranoside (4d): This compound was prepared from 3d
(259 mg, 0.48 mmol) in the manner described for 4a; the product
was chromatographed on silica gel (petroleum ether/ethyl acetate,
80:20) to give 260 mg (93%) of 4d as a white foam. TLC (petroleum
ether/ethyl acetate, 50:50) Rf ϭ 0.48. [α]D ϭ ϩ117.5 (c ϭ 0.16,
Phenyl 2-Acetylamino-3,4,6-tri-O-benzyl-2-deoxy-α-D-galactopyr-
anoside (4a): Compound 3a (252 mg, 0.48 mmol) was treated with
pyridine/acetic anhydride (6:4, 10 mL) and the mixture was stirred
at room temp. for 12 h. All volatiles were evaporated under reduced
pressure and the product was purified by flash chromatography
(CH2Cl2/MeOH, 98:2) to give 4a (262 mg, 96%) as a colourless oil.
TLC (CH2Cl2/MeOH, 95:5) Rf ϭ 0.60. [α]D ϭ ϩ127.7 (c ϭ 0.13,
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 1.93 (s, 3 H, Ac), 2.31
(s, 3 H, CH3), 3.52 (dd, 3J6,5 ϭ 5.5, 3J6,6Ј ϭ 9.2 Hz, 1 H, 6-H), 3.68
3
3
3
(dd, J6Ј,5 ϭ 7.1, J6Ј,6 ϭ 9.2 Hz, 1 H, 6Ј-H), 3.83 (dd, J3,4 ϭ 2.4,
3J3,2 ϭ 11.2 Hz, 1 H, 3-H), 4.10 (m, 2 H, 5-H, 4-H),), 4.40 (d, 2J ϭ
11.6 Hz, 1 H, CHHPh), 4.42 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.52
(d, 2J ϭ 12.2 Hz, 1 H, CHHPh), 4.62 (d, 2J ϭ 11.6 Hz, 1 H,
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 1.91 (s, 3 H, Ac), 3.52
3
3
3
2
(dd, J6,5 ϭ 5.5, J6,6Ј ϭ 9.2 Hz, 1 H, 6-H), 3.67 (dd, J6Ј,5 ϭ 7.6,
CHHPh), 4.78 (d, J ϭ 12.1 Hz, 1 H, CHHPh), 4.92 (m, 1 H, 2-
3J6Ј,6 ϭ 9.1 Hz, 1 H, 6Ј-H), 3.84 (dd, J3,4 ϭ 2.4, J3,2 ϭ 11.1 Hz,
1 H, 3-H), 4.05 (dd, J5,6 ϭ 6.7, J5,6Ј ϭ 6.8 Hz, 1 H, 5-H), 4.10
3
3
H), 5.00 (d, 2J ϭ 11.5 Hz, 1 H, CHHPh), 5.38 (d, 3JNH,2 ϭ 8.6 Hz,
3
3
3
1 H, NH), 5.58 (d, J1,2 ϭ 3.6 Hz, 1 H, 1-H), 6.90Ϫ7.40 (m, 19 H,
2
2
Ar-H) ppm. 13C NMR (62.8 MHz, CDCl3): δ ϭ 20.5 (CH3), 23.4
(Ac), 49.0 (C-2), 68.7 (C-6), 70.4 (C-5), 71.4 (C-4), 72.6 (CHHPh),
73.4 (2 ϫ CHHPh), 74.6 (C-3), 97.1 (C-1), 116.8, 127.5, 127.7,
127.8, 127.9, 128.1, 128.2, 128.3, 128.5, 130.0, 132.0, 137.9, 138.1,
138.5, 154.5 (C-Ar), 169.8 (Ac) ppm. MS (MALDI): calcd. 581 ϩ
23 [Na] ϭ 604; found 604 [M ϩ Na]ϩ. C36H39NO6 (581.7): calcd.
C 74.33, H 6.76, N 2.41; found C 74.53, H 6.55, N 2.54.
(m, 1 H, 4-H), 4.37 (d, J ϭ 11.6 Hz, 1 H, CHHPh), 4.42 (d, J ϭ
11.5 Hz, 1 H, CHHPh), 4.50 (d, 2J ϭ 12.3 Hz, 1 H, CHHPh), 4.62
(d, 2J ϭ 12.5 Hz, 1 H, CHHPh), 4.80 (d, 2J ϭ 12.3 Hz, 1 H,
CHHPh), 4.85 (m, 1 H, 2-H), 5.00 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh),
5.35 (d, JNH,2 ϭ 8.8 Hz, 1 H, NH), 5.60 (d, J1,2 ϭ 3.6 Hz, 1 H,
1-H), 6.96Ϫ7.39 (m, 20 H, Ar-H) ppm. MS (MALDI): calcd. 567
ϩ 23 [Na] ϭ 590; found 590 [M ϩ Na]ϩ. C35H37NO6 (567.7): calcd.
C 74.05, H 6.57, N 2.47; found C 73.67, H 6.64, N 2.55.
3
3
Phenyl 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-
side (6a): Compound 4a (0.20 g, 0.35 mmol) was dissolved in meth-
lactopyranoside (4b): This compound was prepared from 3b anol/acetic acid (9:1; 10 mL), and Pd/C (0.126 g, 10% Pd) was sus-
D-galactopyrano-
2-Methylphenyl 2-Acetylamino-3,4,6-tri-O-benzyl-2-deoxy-α-D-ga-
1850
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1847Ϫ1852

Conjugate Addition of Phenols to 2-Nitrogalactal
FULL PAPER
pended in the solution. This mixture was stirred under H2 for 3 h.
After complete disappearance of the starting material (TLC:
CH2Cl2/MeOH, 90:10), the catalyst was filtered off and all solvents
were removed to afford phenyl 2-acetamido-2-deoxy-α--galactop-
yranoside (5a) as a white solid, which was used in the next step
without purification. Compound 5a was treated with pyridine/
acetic acid (2:1, 10 mL) and the mixture was stirred at room temp.
for 12 h. All volatiles were evaporated and the product was purified
by column chromatography on silica gel with CH2Cl2/MeOH (98:2)
to give 6a (127 mg, 86%) as a white foam. TLC (CH2Cl2/MeOH,
(98%) of 6d as a yellow oil. TLC (CH2Cl2/MeOH, 95:5) Rf ϭ 0.38.
[α]D ϭ ϩ125.7 (c ϭ 0.35, CHCl3). H NMR (250 MHz, CDCl3):
δ ϭ 1.91, 1.95, 2.01, 2.16 (4s, 12 H, 4 ϫ Ac), 2.28 (s, 3 H, CH3),
1
3
4.00 (dd, 3J6,5 ϭ 7.2, 3J6,6Ј ϭ 11.3 Hz, 1 H, 6-H), 4.10 (dd, J6Ј,5
ϭ
ϭ
ϭ
3
3
3
6.0, J6Ј,6 ϭ 11.2 Hz, 1 H, 6Ј-H), 4.27 (dd, J5,6 ϭ 6.4, J5,6Ј
3
3
3
6.7 Hz, 1 H, 5-H), 4.72 (ddd, J2,1 ϭ 3.6, J2,NH ϭ 9.6, J2,3
3
3
11.3 Hz, 1 H, 2-H), 5.37 (dd, J3,4 ϭ 3.3, J3,2 ϭ 11.2 Hz, 1 H, 3-
H), 5.42 (d, 3J4,3 ϭ 3.4 Hz, 1 H, 4-H), 5.52 (d, 3J1,2 ϭ 3.6 Hz, 1 H,
3
1-H), 5.73 (d, JNH,2 ϭ 9.6 Hz, 1 H, NH), 6.93, 7.24 (2d, J ϭ
8.7 Hz, 4 H, Ar-H) ppm. 13C NMR (62.8 MHz, CDCl3): δ ϭ 20.5,
95:5) Rf ϭ 0.25. [α]D ϭ ϩ139.2 (c ϭ 0.50, CHCl3). 1H NMR 20.67, 20.73 (4 ϫ Ac), 23.3 (CH3), 48.0 (C-2), 61.7 (C-6), 67.3 (C-
(250 MHz, CDCl3): δ ϭ 1.87, 1.94, 1.99, 2.13 (4s, 12 H, 4 ϫ Ac), 5), 67.5 (C-4), 68.3 (C-3), 96.7 (C-1), 116.6, 130.1, 132.6, 153.9 (C-
3
3.97 (dd, 3J6,5 ϭ 7.3, 3J6,6Ј ϭ 11.3 Hz, 1 H, 6-H), 4.06 (dd, J6Ј,5
ϭ
ϭ
ϭ
Ar), 170.1, 170.3, 171.0 (4 ϫ Ac) ppm. MS (MALDI): calcd. 437
ϩ 23 [Na] ϭ 460; found 460 [M ϩ Na]ϩ. C21H27NO9 (437.4): calcd.
C 57.66, H 6.22, N 3.20; found C 57.69, H 6.06, N 3.05.
3
3
3
5.8, J6Ј,6 ϭ 11.2 Hz, 1 H, 6Ј-H), 4.25 (dd, J5,6 ϭ 6.4, J5,6Ј
3
3
3
6.7 Hz, 1 H, 5-H), 4.72 (ddd, J2,1 ϭ 3.5, J2,NH ϭ 9.5, J2,3
13.1 Hz, 1 H, 2-H), 5.33Ϫ5.40 (m, 2 H, 3-H, 4-H,), 5.56 (d, 3J1,2 ϭ
Methyl (2S)-2-tert-Butoxycarbonylamino-3-[4-(3,4,6-tri-O-benzyl-2-
deoxy-2-nitro-α-D-galactopyranosyloxy)phenyl]propionate (7α) and
3
3.6 Hz, 1 H, 1-H), 6.00 (d, JNH,2 ϭ 9.4 Hz, 1 H, NH), 7.00Ϫ7.05
(m, 3 H, Ar-H), 7.24Ϫ7.30 (m, 2 H, Ar-H) ppm. 13C NMR
(62.8 MHz, CDCl3): δ ϭ 20.4, 20.5, 20.6, 23.1 (4 ϫ Ac), 47.8 (C-
2), 60.2 (C-6), 61.6 (C-5), 67.1 (C-4), 67.4 (C-3), 96.4 (C-1), 116.7,
123.0, 129.6, 156.0 (C-Ar), 170.1, 170.8 (4 ϫ Ac) ppm. MS
(MALDI): calcd. 423 ϩ 23 [Na] ϭ 446; found 446 [M ϩ Na]ϩ.
C20H25NO9 (423.4): calcd. C 56.73, H 5.95, N 3.31; found C 56.64,
H 5.45, N 3.25.
Its β-Anomer 7β: This compound was prepared from N-tert-butoxy-
carbonyl--tyrosine methyl ester (590 mg, 2 mmol) in the manner
described for 2aα; the product was chromatographed on silica gel
(toluene/ethyl acetate, 90:10) to give 1.21 g (80%) of 7α as a colour-
less oil and 0.03 g (2%) of 7β as a white foam.
Compound 7α: TLC (toluene/ethyl acetate, 80:20) Rf ϭ 0.60. [α]D ϭ
1
ϩ50.0 (c ϭ 0.10, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 1.39
2-Methylphenyl 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-galac-
(s, 9 H, CMe3), 3.00 (m, 2 H, 2m, 3a-H, 3b-H), 3.51Ϫ3.64 (m, 2
topyranoside (6b): This compound was prepared from 4b (203 mg,
0.35 mmol) in the manner described for 6a; the product was chrom-
atographed on silica gel (CH2Cl2/MeOH, 98:2) to give 142 mg
(93%) of 6b as a colourless oil. TLC (CH2Cl2/MeOH, 95:5) Rf ϭ
0.40. [α]D ϭ ϩ68.4 (c ϭ 0.50, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 1.92, 1.95, 2.03, 2.17 (4s, 12 H, 4 ϫ Ac), 2.26 (s, 3 H,
3
H, 6Ј-H, 6ЈЈ-H), 3.67 (s, 3 H, OMe), 4.09 (d, J4Ј,3Ј ϭ 2.5 Hz, 1 H,
3
3
4Ј-H), 4.17 (dd, J5Ј,6Ј ϭ 6.7, J5Ј,6ЈЈ ϭ 6.5 Hz, 1 H, 5Ј-H), 4.35 (d,
2J ϭ 11.6 Hz, 1 H, CHHPh), 4.45 (d, 2J ϭ 12.2 Hz, 1 H, CHHPh),
2
4.48 (d, J ϭ 11.3 Hz, 1 H, CHHPh), 4.53 (m, 1 H, 2-H), 4.63 (dd,
3J3Ј,4Ј ϭ 2.8, 3J3Ј,2Ј ϭ 10.6 Hz, 1 H, 3Ј-H), 4.78 (d, J ϭ 11.5 Hz, 1
2
2
2
3
3
H, CHHPh), 4.80 (d, J ϭ 11.5 Hz, 1 H, CHHPh), 4.86 (d, J ϭ
CH3), 4.03 (dd, J6,5 ϭ 7.2, J6,6Ј ϭ 11.2 Hz, 1 H, 6-H), 4.12 (dd,
3
3J6Ј,5 ϭ 5.9, J6Ј,6 ϭ 11.3 Hz, 1 H, 6Ј-H), 4.26 (dd, J5,6 ϭ 6.2,
3
3
11.2 Hz, 1 H, CHHPh), 4.92 (d, JNH,2 ϭ 8.2 Hz, 1 H, NHBoc),
5.10 (dd, 3J2Ј,1Ј ϭ 4.2, 3J2Ј,3Ј ϭ 10.7 Hz, 1 H, 2Ј-H), 5.84 (d, 3J1Ј,2Ј
ϭ
3J5,6Ј ϭ 5.8 Hz, 1 H, 5-H), 4.74 (ddd, J2,1 ϭ 3.5, J2,NH ϭ 9.5,
3
3
4.1 Hz, 1 H, 1Ј-H), 6.89Ϫ7.36 (m, 19 H, Ar-H) ppm. 13C NMR
(150.8 MHz, CDCl3): δ ϭ 28.3 (CMe3), 37.5 (C-3), 52.2 (OMe),
54.4 (C-2), 68.0 (C-6Ј), 70.3 (C-5Ј), 73.0 (C-4Ј), 73.1 (CHHPh), 73.5
(CHHPh), 75.0 (CHHPh), 75.2 (C-3Ј), 80.1 (CMe3), 84.0 (C-2Ј),
96.0 (C-1Ј), 117.4, 127.8, 127.9, 128.15, 128.22, 128.38, 128.44,
128.5, 130.5, 131.1, 137.2, 137.6, 137.9, 155.0 (C-Ar), 155.2 (CO-
OMe), 172.2 (NHBoc) ppm. MS (MALDI): calcd. 756 ϩ 23 [Na] ϭ
779; found 779 [M ϩ Na]ϩ. C42H48N2O11 (756.8): calcd. C 66.65,
H 6.39, N 3.70; found C 66.86, H 6.60, N 3.38.
3J2,3 ϭ 13.1 Hz, 1 H, 2-H), 5.39 (dd, J3,4 ϭ 3.3, J3,2 ϭ 11.3 Hz,
3
3
1 H, 3-H), 5.45 (dd, J4,5 Ͻ 1.1, 3J4,3 ϭ 3.2 Hz, 1 H, 4-H), 5.59 (d,
3
3J1,2 ϭ 3.6 Hz, 1 H, 1-H), 5.70 (d, JNH,2 ϭ 9.4 Hz, 1 H, NH),
3
6.93Ϫ7.24 (m, 4 H, Ar-H) ppm. MS (MALDI): calcd. 437 ϩ 23
[Na] ϭ 460; found 460 [M ϩ Na]ϩ. C21H27NO9 (437.4): calcd. C
57.66, H 6.22, N 3.20; found C 57.69, H 5.58, N 2.94.
2-Methoxyphenyl 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-ga-
lactopyranoside (6c): This compound was prepared from 4c
(209 mg, 0.35 mmol) in the manner described for 6a; the product
was chromatographed on silica gel (CH2Cl2/MeOH, 98:2) to give
140 mg (88%) of 6c as a colourless oil. TLC (CH2Cl2/MeOH, 95:5)
Rf ϭ 0.43. [α]D ϭ ϩ127.5 (c ϭ 0.32, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 1.89, 1.94, 1.99, 2.14 (4s, 12 H, 4 ϫ Ac), 3.75 (s, 3 H,
Compound 7β: TLC (toluene/ethyl acetate, 80:20) Rf ϭ 0.52. [α]D ϭ
Ϫ4.0 (c ϭ 0.30, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.40
(s, 9 H, CMe3), 3.00 (m, 2 H, 3a-H, 3b-H), 3.67 (m, 5 H, 6Ј-H, 6ЈЈ-
3
3
H, OMe), 3.78 (dd, J5Ј,6Ј ϭ 6.7, J5Ј,6ЈЈ ϭ 6.5 Hz, 1 H, 5Ј-H), 4.04
3
3
3
3
(d, J4Ј,3Ј ϭ 2.7 Hz, 1 H, 4Ј-H), 4.12 (dd, J3Ј,4Ј ϭ 2.8, J3Ј,2Ј
ϭ
OCH3), 3.98Ϫ4.07 (m, 2 H, 6-H, 6Ј-H), 4.24 (dd, J5,6 ϭ 6.4,
3J5,6Ј ϭ 6.5 Hz, 1 H, 5-H), 4.72 (ddd, J2,1 ϭ 3.5, J2,NH ϭ 9.5,
3
3
10.5 Hz, 1 H, 3Ј-H), 4.44Ϫ4.60 (m, 6 H, CHHPh, 2-H), 4.88 (d,
3
2J ϭ 11.4 Hz, 1 H, CHHPh), 4.92 (d, JNH,2 ϭ 8.2 Hz, 1 H,
3J2,3 ϭ 13.1 Hz, 1 H, 2-H), 5.31Ϫ5.39 (m, 2 H, 3-H, 4-H), 5.53 (d,
3
3
3J1,2 ϭ 3.5 Hz, 1 H, 1-H), 5.90 (d, JNH,2 ϭ 9.5 Hz, 1 H, NH),
3
NHBoc), 5.12 (dd, J2Ј,1Ј ϭ 8.0, J2Ј,3Ј ϭ 10.5 Hz, 1 H, 2Ј-H), 5.27
3
6.56Ϫ7.24 (m, 4 H, Ar-H) ppm. 13C NMR (62.8 MHz, CDCl3):
δ ϭ 20.4, 20.6, 20.7, 23.2 (4 ϫ Ac), 47.8 (C-2), 55.3 (OCH3), 61.7
(C-6), 67.2 (C-5), 67.5 (C-4), 68.2 (C-3), 96.5 (C-1), 103.3, 108.5,
108.8, 130.1, 157.2, 160.8 (C-Ar), 170.1, 170.21, 170.21, 170.1 (4 ϫ
Ac) ppm. MS (MALDI): calcd. 453 ϩ 23 [Na] ϭ 476; found 476
[M ϩ Na]ϩ. C21H27NO10 (453.4): calcd. C 55.62, H 6.00, N 3.09;
found C 55.14, H 6.39, N 2.76.
(d, J1Ј,2Ј ϭ 8.0 Hz, 1 H, 1Ј-H), 6.87Ϫ7.32 (m, 19 H, Ar-H) ppm.
MS (MALDI): calcd. 756 ϩ 23 [Na] ϭ 779; found 779 [M ϩ Na]ϩ.
C42H48N2O11 (756.8): calcd. C 66.65, H 6.39, N 3.70; found C
66.92, H 6.60, N 3.23.
Methyl (2S)-3-[4-(2-Amino-3,4,6-tri-O-benzyl-2-deoxy-α-D-galacto-
pyranosyloxy)phenyl]-2-(tert-butoxycarbonylamino)propionate (8):
This compound was prepared from 7α (680 mg, 0.90 mmol) in the
manner described for 3a; the product was chromatographed on sil-
ica gel (CH2Cl2/MeOH, 95:5) to give 575 mg (88%) of 8 as a white
foam. TLC (CH2Cl2/MeOH, 95:5) Rf ϭ 0.32. [α]D ϭ ϩ7.1 (c ϭ
0.17, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.39 (s, 9 H,
4-Methylphenyl 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-galac-
topyranoside (6d): This compound was prepared from 4d (203 mg,
0.35 mmol) in the manner described for 6a; the product was chrom-
atographed on silica gel (CH2Cl2/MeOH, 98:2) to give 150 mg
Eur. J. Org. Chem. 2003, 1847Ϫ1852
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1851

A. I. Khodair, G. A. Winterfeld, R. R. Schmidt
FULL PAPER
CMe3), 2.98 (br. s, 2 H, 3a-H, 3b-H), 3.43Ϫ3.71 (m, 8 H, 6Ј-H, 6ЈЈ-
H, 2Ј-H, 4Ј-H, 5Ј-H, OMe), 4.07 (s, 3 H, NH2, 3Ј-H), 4.38 (d, 2J ϭ
11.4 Hz, 1 H, CHHPh), 4.53 (d, 2J ϭ 11.5 Hz, 1 H, CHHPh), 4.58
Methyl O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-
D-galactopyr-
anosyl)-N-acetyl- -tyrosinate (11): Compound 10 (12.50 mg,
L
0.02 mmol) was dissolved in trifluoroacetic acid/CH2Cl2 (1:1,
(d, 2J ϭ 11.5 Hz, 1 H, CHHPh), 4.75 (d, 2J ϭ 11.6 Hz, 1 H, 2 mL) and the solution was stirred at room temp. for 12 h. All
CHHPh), 4.85 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 4.90 (d, 2J ϭ solvents were then evaporated, and the residue was treated with
3
11.2 Hz, 1 H, CHHPh), 4.92 (m, 1 H, 2-H), 5.50 (d, J1Ј,2Ј
ϭ
pyridine/acetic anhydride (2:1, 3 mL) and stirred at room temp. for
3
3.4 Hz, 1 H, 1Ј-H), 6.70 (d, JNH,2 ϭ 8.4 Hz, 1 H, NHBoc), 12 h. All volatiles were evaporated and the product was purified by
6.91Ϫ7.37 (m, 19 H, Ar-H) ppm. MS (MALDI): calcd. 726 ϩ 23
column chromatography (CH2Cl2/MeOH, 98:2) to give 10 mg
[Na] ϭ 749; found 749 [M ϩ Na]ϩ. C42H50N2O9 (726.8): calcd. C (88%) of 11 as a pale yellow foam. TLC (CH2Cl2/MeOH, 95:5)
1
69.40, H 6.93, N 3.85; found C 69.31, H 6.87, N 3.52.
Rf ϭ 0.20. [α]D ϭ ϩ50.0 (c ϭ 0.10, CHCl3). H NMR (250 MHz,
CDCl3): δ ϭ 1.92, 1.96, 1.98, 2.01, 2.16 (5s, 3 H, 5 ϫ Ac), 3.06 (m, 2
Methyl O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-
D-galacto-
H, 3a-H, 3b-H), 3.72 (s, 3 H, OMe), 4.01 (dd, 3J6Ј,5Ј ϭ 7.0, 3J6Ј,6ЈЈ
ϭ
pyranosyl)-N-tert-butoxycarbonyl)- -tyrosinate (9): This compound
L
11.3 Hz, 1 H, 6Ј-H), 4.08 (dd, 3J6ЈЈ,5Ј ϭ 6.0, 3J6ЈЈ,6Ј ϭ 11.2 Hz, 1 H,
was prepared from 8 (348 mg, 0.48 mmol) in the manner described
for 4a; the product was chromatographed on silica gel (petroleum
ether/ethyl acetate, 80:20) to give 320 mg (87%) of 9 as a white
foam. TLC (petroleum ether/ethyl acetate, 60:40) Rf ϭ 0.25. [α]D ϭ
3
3
6ЈЈ-H), 4.23 (dd, J5Ј,6Ј ϭ 7.0, J5Ј,6ЈЈ ϭ 6.0 Hz, 1 H, 5Ј-H), 4.72
(ddd, 3J2Ј,1Ј ϭ 3.6, 3J2Ј,NH ϭ 9.4, 3J2Ј,3Ј ϭ 13.2 Hz, 1 H, 2Ј-H), 4.84
3
3
(dd, J2,3 ϭ 5.1, J2,NH ϭ 8.5 Hz, 1 H, 2-H), 5.33Ϫ5.41 (m, 2 H,
3Ј-H, 4Ј-H), 5.54 (d, 3J1Ј,2Ј ϭ 3.6 Hz, 1 H, 1Ј-H), 5.80 (d, 3JNH,2Ј
ϭ
1
ϩ59.6 (c ϭ 0.25, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 1.40
3
9.4 Hz, 1 H, NHAc), 5.98 (d, JNH,2 ϭ 8.6 Hz, 1 H, NHAc), 6.96,
6.98 (2d, J ϭ 8.9 Hz, 4 H, Ar-H) ppm. MS (MALDI): calcd. 566
ϩ 23 [Na] ϭ 587; found 589 [M ϩ Na]ϩ. C26H34N2O12 (566.6):
calcd. C 55.12, H 6.05, N 4.94; found C 55.10, H 5.75, N 4.71.
(s, 9 H, CMe3), 1.90 (s, 3 H, Ac), 2.98 (m, 2 H, 3a-H, 3b-H), 3.49
(dd, 3J6Ј,5Ј ϭ 5.6, 3J6Ј,6ЈЈ ϭ 9.1 Hz, 6Ј-H), 3.62 (m, 1 H, 6ЈЈ-H), 3.68
(s, 3 H, OMe), 3.80 (dd, 3J3Ј,4Ј ϭ 2.5, 3J3Ј,2Ј ϭ 11.1 Hz, 1 H, 3Ј-H),
3.98Ϫ4.09 (m, 2 H, 5Ј-H, 4Ј-H), 4.36 (d, 2J ϭ 11.6 Hz, 1 H,
CHHPh), 4.38 (d, 2J ϭ 1106 Hz, 1 H, CHHPh), 4.54 (d, 2J ϭ
12.2 Hz, 1 H, CHHPh), 4.57 (d, 2J ϭ 11.6 Hz, 1 H, CHHPh), 4.63
(m, 1 H, 2-H), 4.76 (d, 2J ϭ 12.2 Hz, 1 H, CHHPh), 4.85 (m, 2 H,
2Ј-H, NHBoc), 4.95 (d, 2J ϭ 11.4 Hz, 1 H, CHHPh), 5.26 (d,
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinsch-
aft, the European Community (Grant No. HRPN-CT-2000-00001/
GLYCOTRAIN) and the Fonds der Chemischen Industrie. A. I.
K. is grateful for an Alexander von Humboldt Fellowship. We are
grateful to Ms. Anke Friemel for her help in the structural assign-
ments by NMR experiments.
3
3JNH,2Ј ϭ 8.7 Hz, 1 H, NHAc), 5.55 (d, J1Ј,2Ј ϭ 3.6 Hz, 1 H, 1Ј-
H), 6.85Ϫ7.38 (m, 19 H, Ar-H) ppm. 13C NMR (62.8 MHz,
CDCl3): δ ϭ 23.3 (Ac), 28.2 (CMe3), 37.4 (C-3), 49.0 (C-2Ј), 52.1
(OMe), 54.4 (C-2), 68.5 (C-6Ј), 70.4 (C-5Ј), 71.3 (C-4Ј), 72.4
(CHHPh), 73.4 (CHHPh), 74.5 (CHHPh), 76.7 (C-3Ј), 79.8
(CMe3), 96.9 (C-1Ј), 116.9, 127.5, 127.7, 127.9, 128.0, 128.2, 128.3,
128.5, 130.1, 130.3, 137.8, 138.0, 138.4, 155.0 (C-Ar), 155.7 (CO-
OMe), 169.8 (Ac), 172.2 (NHBoc) ppm. MS (MALDI): calcd. 769
ϩ 23 [Na] ϭ 792; found 792 [M ϩ Na]ϩ. C44H52N2O10 (768.9):
calcd. C 68.73, H 6.82, N 3.64; found C 68.79, H 6.85, N 3.40.
[1]
R. R. Schmidt, W. Kinzy, Adv. Carbohydr. Chem. Biochem.
1994, 50, 21Ϫ123; and references therein.
J. B. Harborne, T. J. Mabry, The Flavanoids, Advances in Re-
[2]
search, Chapman and Hall, London, 1982.
For work on direct anomeric O-arylation, see: U. Huchel, C.
[3]
Methyl
O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-
D-galacto-
Schmidt, R. R. Schmidt, Tetrahedron Lett. 1995, 36,
pyranosyl)-N-tert-butoxycarbonyl)-L-tyrosinate (10): This com-
9457Ϫ9460.
pound was prepared from 9 (269 mg, 0.35 mmol) in the manner
described for 6a; the product was chromatographed on silica gel
(CH2Cl2/MeOH, 98:2) to give 179 mg (82%) of 10 as a colourless
oil. TLC (CH2Cl2/MeOH, 95:5) Rf ϭ 0.30. [α]D ϭ ϩ56.2 (c ϭ 0.16,
CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.38 (s, 9 H, CMe3),
1.91, 1.94, 2.00, 2.15 (4s, 3 H, 4 ϫ Ac), 3.01 (m, 2 H, 3a-H, 3b-H),
[4]
J. Das, R. R. Schmidt, Eur. J. Org. Chem. 1998, 1609Ϫ1613.
G. A. Winterfeld, J. Das, R. R. Schmidt, Eur. J. Org. Chem.
[5]
2000, 3047Ϫ3050.
K. Pachamuthu, A. Gupta, J. Das, R. R. Schmidt, Y. D. Van-
[6]
kar, Eur. J. Org. Chem. 2002, 1479Ϫ1483.
G. A. Winterfeld, Y. Ito, T. Ogawa, R. R. Schmidt, Eur. J. Org.
[7]
Chem. 1999, 1167Ϫ1171.
G. A. Winterfeld, Y. Ito, T. Ogawa, R. R. Schmidt, Angew.
3
3
3.69 (s, 3 H, OMe), 3.99 (dd, J6Ј,5Ј ϭ 6.8, J6Ј,6ЈЈ ϭ 11.2 Hz, 1 H,
[8]
3
3
6Ј-H), 4.08 (dd, J6ЈЈ,5Ј ϭ 6.1, J6ЈЈ,6Ј ϭ 11.3 Hz, 1 H, 6ЈЈ-H), 4.24
Chem. 2001, 113, 2718Ϫ2721; Angew. Chem. Int. Ed. 2001,
(dd, 3J5Ј,6Ј ϭ 6.8, 3J5Ј,6ЈЈ ϭ 6.8 Hz, 1 H, 5Ј-H), 4.51 (dd, 3J2,3 ϭ 6.0,
40, 2654Ϫ2657.
G. A. Winterfeld, A. I. Khodair, R. R. Schmidt, Eur. J. Org.
3J2,NH ϭ 8.2 Hz, 1 H, 2-H), 4.72 (ddd, J2Ј,1Ј ϭ 3.6, J2Ј,NH ϭ 9.6,
3
3
[9]
3J2Ј,3Ј ϭ 11.1 Hz, 1 H, 2Ј-H), 4.96 (d, JNH,2 ϭ 8.2 Hz, 1 H,
3
Chem., submitted.
M. D. Alonso, J. Lomako, W. M. Lomako, W. J. Whelan, FA-
3
3
[10]
NHBoc), 5.36 (dd, J3Ј,4Ј ϭ 3.3, J3Ј,2Ј ϭ 11.2 Hz, 1 H, 3Ј-H), 5.40
(dd, J4Ј,5Ј Ͻ 1.0, J4Ј,3Ј ϭ 3.3 Hz, 1 H, 4Ј-H), 5.53 (d, J1Ј,2Ј
3
3
3
ϭ
SEB J. 1995, 9, 1126.
K. Bock, J. Schuster-Kolbe, E. Altman, G. Allmaier, B. Stahl,
[11]
3
3.5 Hz, 1 H, 1Ј-H), 5.78 (d, JNH,2Ј ϭ 9.5 Hz, 1 H, NHAc), 6.94,
7.00 (2d, J ϭ 8.7 Hz, 4 H, Ar-H) ppm. 13C NMR (62.8 MHz,
CDCl3): δ ϭ 20.5, 20.7, 23.2 (4 ϫ Ac), 28.2 (CMe3), 37.4 (C-3),
47.9 (C-2Ј), 52.2 (OMe), 54.4 (C-2), 61.6 (C-6Ј), 67.1 (C-5Ј), 67.5
(C-4Ј), 68.1 (C-3Ј), 80.0 (CMe3), 96.5 (C-1Ј), 116.6, 130.5, 130.7,
155.1 (C-Ar), 170.1, 170.2, 171.0, 172.2, 172.7 (5 ϫ CO) ppm. MS
(MALDI): calcd. 624 ϩ 23 [Na] ϭ 647; found 647 [M ϩ Na]ϩ.
C29H40N2O13 (624.6): calcd. C 55.76, H 6.45, N 4.48; found C
55.49, H 6.72, N 4.89.
R. Christian, U. B. Sleytr, P. Messner, J. Biol. Chem. 1994,
269, 7137Ϫ.
[12]
P. Messner, R. Christian, C. Neuninger, G. Schulz, J. Bacteriol.
1995, 177, 2188.
V. Wittmann in Glycoscience: Chemistry and Chemical Biology
[13]
(Eds.: B. Fraser-Reid, K. Tatsuta, J. Thiem), Springer Verlag,
Heidelberg, 2001, vol. III, chapter 8.1, p. 2.34.
S. Nishimura, Bull. Chem. Soc. Jpn. 1959, 32, 61Ϫ64.
[14]
Received December 20, 2002
1852
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1847Ϫ1852