β-selective C-mannosylation of electron-rich phenols

Article abstract of DOI:10.1055/s-0029-1218772

The reaction of tetra-O-benzylmannosyl trichloroacetimidate with electron-rich phenols in the presence of TMSOTf surprisingly leads to the exclusive formation of aryl β-C-glycosides while a preference for the -anomer could be observed with other Lewis aci

Full text of DOI:10.1055/s-0029-1218772

PAPER
2393
b-Selective C-Mannosylation of Electron-Rich Phenols
b
-Selective C-
t
Manno
e
sylationof
f
E
lectron
a
-RichPhen
nols Weck, Till Opatz*
Universität Hamburg, Institut für Organische Chemie, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax +49(40)428383834; E-mail: opatz@chemie.uni-hamburg.de
Received 11 February 2010; revised 24 March 2010
conditions in combination with TMSOTf as the promot-
er.19,21 The O/C-rearrangement appears to be sensitive to
the electronic properties of the protecting groups since tet-
ra-O-acetyl-a-mannosyl trichloroacetimidate gave only
the O-glycoside22 while the tetra-O-benzyl derivative 4
smoothly yielded the desired C-glycosides.19 Glycosyl
donor 4 was prepared from D-mannose in five steps ac-
cording to known procedures23–27 in 75% overall yield
(Scheme 1).
Abstract: The reaction of tetra-O-benzylmannosyl trichloroacet-
imidate with electron-rich phenols in the presence of TMSOTf sur-
prisingly leads to the exclusive formation of aryl b-C-glycosides
while a preference for the a-anomer could be observed with other
Lewis acids such as ZnCl2.
Key words: glycosylation, phenols, C-glycosides, Lewis acids,
anomers
Due to the cooperation between the anomeric effect and
steric hindrance or neighboring group participation, the
synthesis of b-O-mannosides remains a challenging task
that has attracted considerable attention.1 Most notably,
indirect methods, for example, via intramolecular agly-
cone delivery2–4 or via inversion of configuration at C-2,
for example, by intramolecular SN2 reaction have been de-
veloped.1,5 Successful direct syntheses either use Königs–
Knorr type reactions6 or dehydrative mannosylation,7,8
but they are often limited to certain types of glycosyl ac-
ceptors. While the preference for a-O-mannoside forma-
tion is notorious, the C-mannosylation of electron-rich
phenols using tetra-O-benzylmannosyl trichloroacetimi-
date surprisingly produced pure b-C-mannosides when
trimethylsilyl trifluoromethanesulfonate was used as the
activating agent. C-Glycosides are inherently inert against
degradation by acid or hydrolytic enzymes and have fre-
quently been employed as metabolically stable mimetics
for O-glycosides. C-Glycosides with an aromatic or het-
eroaromatic aglycone have been isolated from natural
sources and some of these compounds have been found to
exhibit potent antibacterial and antiproliferative activity.9
A prominent and useful method for their preparation is the
ortho-C-glycosylation of electron-rich phenols,10–16
which has been suggested to proceed in a stepwise fashion
through intermediate formation of the O-glycoside fol-
lowed by a Fries-type O/C-rearrangement induced by the
Lewis acidic reaction conditions.13,17,18 In addition to the
high regioselectivity, a high b-selectivity is typically ob-
served in the gluco and galacto series.10,16,19
OH
OH
1. AllOH, AcCl
O
HO
HO
80%
2. BnBr, NaH, DMF
OH
OBn
1
OBn
O
BnO
BnO
1. Rh(PPh3)3Cl
O
toluene–EtOH–H2O
(20:10:1), reflux
2
94%
2. I2, THF–H2O (4:1)
OBn
OBn
O
Cl3CCN
BnO
BnO
DBU, CH2Cl2
quant
OH
OBn
3
OBn
O
BnO
BnO
O
CCl3
4
NH
Scheme 1 Synthesis of 2,3,4,6-tetra-O-benzyl-a-D-mannopyrano-
syl trichloroacetimidate (4) from D-mannose
The reaction of 4 with 2-naphthol (5) and TMSOTf fur-
nished a single product in 63% yield, which could be iden-
tified as the C-mannoside 6 (Scheme 2). Since the
determination of the configuration at the anomeric center
in O-mannosides can not be based on the vicinal coupling
constant of H-1, a NOESY NMR experiment was per-
formed to elucidate the relative configuration.
In an attempt to prepare aryl C-mannosides as precursors
for metabolically stable trisaccharide mimetics, several
mannosyl donors were prepared and tested in the ortho-
mannosylation of phenols. The trichloroacetimidates in-
troduced by Schmidt20 exhibited a favorable reactivity
and permitted the C-glycosylation under relatively mild
As expected for the b-anomer, there were NOE interac-
tions between H-1, H-3, and H-5 of about the same inten-
sity as the H-1/H-2 interaction.28 This result had to be
verified for other C-mannosides. Therefore, mannosyl do-
nor 4 was coupled with different electron-rich phenols un-
der identical conditions to furnish the corresponding C-
glycosides (Table 1). In every case, only a single product
was obtained. The NOESY spectra of the products
showed the same H-1/H-3/H-5 triaxial arrangement found
SYNTHESIS 2010, No. 14, pp 2393–2398
x
x.
x
x
.
2
0
1
0
Advanced online publication: 05.05.2010
DOI: 10.1055/s-0029-1218772; Art ID: T03510SS
© Georg Thieme Verlag Stuttgart · New York

2394
S. Weck, T. Opatz
PAPER
for glycoside 6. Thus, mannose surprisingly behaves sim-
ilar to glucose19 and galactose16 with respect to the stereo-
chemical preference in this type of C-glycosylation.
OBn
OBn
O
HO
BnO
BnO
+
With a reliable protocol for a b-selective ortho-C-manno-
sylation in hand, we sought for an a-selective counterpart.
By applying conditions, which gave poor anomeric selec-
tivities in other C-glycosylations to the mannosylation of
2-naphthol (5),10 BF3·OEt2 was found to produce a mix-
ture of the a-O-mannoside (25%) and the b-C-mannoside
6 (10%) along with 30% of the a-C-mannoside 15. The
latter compound exhibited an unusual coupling pattern in
its 1H NMR spectrum, which can be attributed to an inver-
sion of the ring conformation.29 Presumably, the steric re-
pulsion of the aryl substituent with H-3 and H-5 in the 4C1
conformation accounts for this behavior. In agreement
with an inverted ring conformation, the NOESY spectrum
of 15 showed a remarkably strong NOE contact between
H-1 and H-6a. When applied to 3,5-dimethoxyphenol (9),
the BF3·OEt2-catalyzed mannosylation led, however, ex-
clusively to the b-C-mannoside 10 (Scheme 3).
O
CCl3
4
5
NH
TMSOTf
CH2Cl2
4 Å MS, 0 °C
66%
OBn
HO
OBn
O
5
BnO
BnO
1
3
6
Scheme 2 Selective b-C-glycosylation of 2,3,4,6-tetra-O-benzyl-a-
D-mannopyranosyl trichloroacetimidate (4)
Table 1 Synthesis of Aryl b-C-Mannosides
OBn
OBn
OBn
HO
OBn
O
HO
O
TMSOTf
BnO
BnO
R
R
BnO
BnO
+
CH2Cl2
4 Å MS
0 °C
O
CCl3
NH
Donor
Acceptor
Product
Yield (%)
OBn
OBn
O
OBn
HO
OBn
O
HO
BnO
BnO
66
BnO
BnO
O
CCl3
5
NH
6
4
4
OBn
HO
OBn
O
HO
OH
BnO
BnO
53
57
7
OH
8
OBn
HO
OMe
HO
OMe
OBn
O
4
BnO
BnO
OMe
OMe
9
10
OBn
OBn
HO
OMe
OMe
HO
HO
OMe
OMe
OBn
O
4
4
49
45
BnO
BnO
11
12
HO
OMe
OMe
OBn
O
BnO
BnO
13
14
Synthesis 2010, No. 14, 2393–2398 © Thieme Stuttgart · New York

PAPER
b-Selective C-Mannosylation of Electron-Rich Phenols
2395
HO
formed in 31% yield showing the same ring inversion as
15 (Scheme 4).
4
+
BF3⋅OEt2, CH2Cl2
In summary, C-glycosylation of various electron-rich
phenols with 2,3,4,6-tetra-O-benzyl-a-D-mannopyrano-
syl trichloroacetimidate (4) using TMSOTf as the promot-
er gave exclusively the corresponding b-C-mannosides.
The reaction of 2-naphthol (5) with donor 4 in the pres-
ence of BF3·OEt2 or ZnCl2 mainly furnished the corre-
sponding a-C-mannoside 15, which showed an inversion
of the pyranose ring. The latter promoter also permits the
preparation of a-C-galactosides.
5
4 Å MS, 0 °C
BnO
OBn
6
OBn
H
1
OH
OBn
O
O
BnO
BnO
+
OBn
O
OBn
15
30%
16
25%
+
6
10%
The trichloroacetimidates 4 and 17 were prepared according to
known procedures.15–18 Moisture sensitive reactions were carried
out under argon atmosphere in dried glassware sealed by rubber
septa. Unless otherwise specified, chemicals were obtained from
commercial suppliers and used without further purification. CH2Cl2
was dried over CaH2 and distilled under argon atmosphere prior to
use. Flash chromatography was performed on silica gel 60 (0.035–
0.070 mm, Acros). Chromatography solvents (cyclohexane,
EtOAc) were distilled prior to use. For analytical TLC, Merck glass
plates (60 F254) were used. Visualization was accomplished by UV
(254 nm) and sugar reagent (1 M ethanolic H2SO4/0.2% ethanolic
3-methoxyphenol solution, 1:1).30 1H and 13C NMR spectra were re-
corded on a Bruker AV 400 or DRX 500 in CDCl3 or CD3OD using
the residual solvent peak as internal reference (CDCl3, dH = 7.26,
dC = 77.16, CD3OD, dH = 3.31, dC = 49.0). Optical rotations were
measured at r.t. on a Krüss P8000 polarimeter at 589 nm. IR spectra
were recorded on a ThermoNicolet Avatar 370 FT-IR spectrometer.
FAB mass spectrometry was carried out on with a VG70S (Xe-FAB
ionization) with m-nitrobenzyl alcohol as matrix. For exact mass
determination (FAB-HRMS), PEG 300 or PEG 600 was used as the
internal standard.
BF3⋅OEt2, CH2Cl2
4 Å MS, 0 °C
HO
OMe
52%
4
+
OMe
OBn
HO
OMe
9
OBn
O
BnO
BnO
OMe
10
Scheme 3 C-Mannosylations with BF3·OEt2
Further screening of Lewis acids for the C-mannosylation
of 2-naphthol (5) and optimization of the conditions
showed the highest a-selectivity for ZnCl2 (Scheme 4),
which gave 15 in 42% isolated yield. To prove that this
phenomenon is not only limited to mannosylation of
naphthols, the same reaction was applied to the benzyl-
ated galactosyl donor 17.27 a-C-Galactoside 18 was
b-C-Arylmannosides from Trichloroacetimidate 4 with
TMSOTf as Promoter; General Procedure
A mixture of 2,3,4,6-tetra-O-benzylmannopyranosyl trichloroacet-
imidate (4), phenol, and activated 4 Å molecular sieves (1 g) in an-
hyd CH2Cl2 (8 mL) was stirred at 0 °C for 20 min under argon to
remove traces of H2O from the reactants. Then, TMSOTf in anhyd
CH2Cl2 (2 mL) was added and the mixture was stirred until TLC-
monitoring showed no further progress. The reaction was quenched
by the addition of sat. aq NaHCO3 (20 mL). The organic layer was
separated and the aqueous phase extracted with CH2Cl2 (20 mL).
The combined organic extracts were dried (Na2SO4) and concentrat-
ed in vacuo. The crude residue was purified by flash chromatogra-
phy (cyclohexane–EtOAc) (Table 1).
HO
4
+
ZnCl2, r.t.
CH2Cl2
4 Å MS
5
BnO
OBn
6
H
OH
OBn
O
OBn
O
1
BnO
BnO
OBn
+
O
OBn
15
16
14%
42%
1-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-b-D-mannopyranosyl)naphthalen-
2-ol (6)
OBn
OBn
The title compound was prepared according to the general proce-
dure from 4 (54.2 mg, 79.1 mmol, 1 equiv), 2-naphthol (5; 13.4 mg,
95.7 mmol, 1.2 equiv), and TMSOTf (17.6 mg, 79.1 mmol, 1 equiv)
within a reaction time of 3 h. Purification by flash chromatography
(cyclohexane–EtOAc, 10:1) afforded 6 as a colorless oil (35 mg,
HO
O
+
BnO
ZnCl2, r.t.
CH2Cl2
4 Å MS
BnO
31%
O
CCl3
17
5
20
52.5 mmol, 66%); [a]D +45.1 (c = 1.0, CHCl3); Rf = 0.40 (cyclo-
NH
hexane–EtOAc, 10:1).
BnO
OH
H
IR (film): 3345, 3029, 3866, 1622, 1453, 1406, 1228, 1102, 1026,
735, 697 cm–1
OBn
O
.
BnO
1H NMR (500 MHz, CDCl3): d = 9.14 (s, 1 H, OH), 7.76 (d,
3
3J5,6 = 8.0 Hz, 1 H, H-5), 7.70 (d, J3,4 = 8.9 Hz, 1 H, H-4), 7.45–
BnO
18
7.19 (m, 18 H, H-7, H-6, H-8, Ph-H), 7.14 (d, 3J3,4 = 8.9 Hz, 1 H, H-
3), 7.11–7.02 (m, 3 H, Ph-H), 6.97 (br d, 3J = 6.6 Hz, 2 H, Ph-H),
5.39 (br s, 1 H, H-1¢) 4.95 (d, 2J = 10.8 Hz, 1 H, CH2aPh), 4.72 (d,
Scheme 4 a-C-glycosylation with ZnCl2
Synthesis 2010, No. 14, 2393–2398 © Thieme Stuttgart · New York

2396
S. Weck, T. Opatz
PAPER
2
2J = 11.7 Hz, 1 H, CH2aPh), 4.69 (d, J = 11.7 Hz, 1 H, CH2bPh),
CH2aPh), 4.68 (s, 2 H, CH2Ph), 4.63 (d, 2J = 12.3 Hz, 1 H, CH2aPh),
2
2
2
4.68 (d, J = 12.2 Hz, 1 H, CH2aPh), 4.58 (d, J = 10.8 Hz, 1 H,
CH2bPh) 4.54 (d, 2J = 12.2 Hz, 1 H, CH2bPh), 4.40 (d, 2J = 11.6 Hz,
1 H, CH2aPh), 4.28 (pseudo t, 3J3¢,4¢ ≈ 3J4¢,5¢ ≈ 9.5 Hz, 1 H, H-4¢), 4.22
(d, 2J = 11.6 Hz, 1 H, CH2bPh), 4.12 (d, 3J2¢,3¢ = 2.7 Hz, 1 H, H-2¢),
3.86 (dd, 3J3¢,4¢ = 9.5 Hz, 3J2¢,3¢ = 2.7 Hz, 1 H, H-3¢), 3.84–3.78 (m, 2
H, H-6a¢, H-6b¢), 3.70–3.64 (m, 1 H, H-5¢).
13C NMR (125.8 MHz, CDCl3): d = 156.0 (C-2), 138.5, 138.3,
138.2, 138.0 (C-1¢¢), 131.1 (C-8a), 130.2 (C-4), 129.2 (C-5), 128.6,
128.6, 128.5, 128.2, 128.0, 127.8, 127.7, 127.3 (20 CH Ph), 126.8
(C-8), 122.6 (C-6), 121.8 (C-4a), 120.4 (C-3), 120.3 (C-7), 111.5
(C-1), 84.0 (C-3¢), 79.9 (C-5¢), 79.1 (C-1¢), 76.4 (C-2¢), 75.5
(CH2Ph), 74.9 (CH2Ph), 74.3 (C-4¢), 73.6 (CH2Ph), 72.4 (CH2Ph),
68.6 (C-6¢).
4.57–4.50 (m, 3 H, CH2Ph), 4.45 (d, J = 11.8 Hz, 1 H, CH2bPh),
4.15 (pseudo t, 3J3,4,5 = 9.7 Hz, 1 H, H-4¢), 3.94 (pd, 3J2,3 = 1.9 Hz,
1 H, H-2¢), 3.78 (s, 3 H, OCH3), 3.75–3.69 (m, 3 H, H-3¢, H-6a¢, H-
6b¢), 3.67 (s, 3 H, OCH3), 3.54 (ddd, 3J4,5 = 9.7 Hz, 3J5,6a = 3.4 Hz,
3J5,6b = 2.2 Hz, 1 H, H-5¢).
13C NMR (100.6 MHz, CDCl3): d = 160.9 (C-5), 158.9 (C-1), 157.0
(C-3), 138.5, 138.4, 138.3, 138.2 (C-1¢¢), 128.4, 128.3, 128.2, 128.0,
127.9, 127.7, 127.4, 127.2 (20 CH Ph), 103.2 (C-2), 94.4 (C-6), 90.2
(C-4), 84.0 (C-3¢), 79.5 (C-5¢), 76.7 (C-1¢), 76.0 (C-2¢), 75.3, 74.5
(2 CH2Ph), 74.3 (C-4¢), 73.4, 72.2 (2 CH2Ph), 68.6 (C-6¢), 55.4, 55.3
(OCH3).
FAB-MS: m/z (%) = 677.2 (25, [M + H]+), 195.0 (43), 181.1 (100,
matrix).
FAB-HRMS: m/z calcd for [C42H44O8 + H]+: 677.3109; found:
677.3129.
FAB-MS: m/z (%) = 666.5 (33, [M]+), 181.1 (100, matrix).
FAB-HRMS: m/z calcd for [C44H42O6]+: 666.2981; found:
666.3008.
2-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-b-D-mannopyranosyl)-4,5-
dimethoxyphenol (12)31
1-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-b-D-mannopyranosyl)naph-
thalene-2,7-diol (8)
The title compound was prepared according to the general proce-
dure from 4 (150.1 mg, 0.219 mmol, 1.1 equiv), 3,4-dimethoxyphe-
nol (11; 30.8 mg, 0.200 mmol, 1.1 equiv), and TMSOTf (56.3mg,
0.253 mmol, 1.2 equiv) within a reaction time of 2 h. Purification
by flash chromatography (cyclohexane–EtOAc, 3:1) afforded 12 as
The title compound was prepared according to the general proce-
dure from 4 (134.0 mg, 0.196 mmol, 1.0 equiv), 2,7-dihydroxy-
naphthalene (7; 84.1 mg, 0.525 mmol, 2.5 equiv), and TMSOTf (52
mg, 0.234 mmol, 1.2 equiv) within a reaction time of 2.5 h. Purifi-
cation by flash chromatography (cyclohexane–EtOAc, 4:1) afford-
26
a colorless oil (66.0 mg, 98 mmol, 49%); [a]D +10.1 (c = 1,
23
ed 8 as a colorless oil (70.2 mg, 103 mmol, 53%); [a]D +68.1
CHCl3); Rf = 0.20 (cyclohexane–EtOAc, 3:1).
(c = 1, CDCl3); Rf = 0.24 (cyclohexane–EtOAc, 4:1).
IR (film): 3385, 3029, 2864, 1631, 1518, 1453, 1202, 1117, 737,
698 cm–1.
IR (film): 3372, 3247, 2869, 1693, 1453, 1218, 1109, 834, 751 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.65 (d, 3J5,6 = 8.8 Hz, 1 H, H-
1H NMR (500 MHz, CDCl3): d = 7.95 (s, 1 H, OH), 7.40–7.10 (m,
20 H, Ph-H), 6.49 (s, 1 H, H-3), 6.34 (s, 1 H, H-6), 4.92 (d, 2J = 10.8
Hz, 1 H, CH2aPh), 4.75–4.68 (m, 2 H, CH2Ph), 4.66–4.62 (m, 2 H,
3
5), 7.64 (d, J3,4 = 8.9 Hz, 1 H, H-4), 7.41–7.20 (m, 15 H, Ph-H),
7.13–7.03 (m, 4 H, H-8, 3 Ph-H), 6.93 (d, J = 8.7, 3 H, H-6, 2 Ph-
H), 6.88 (d, 3J3,4 = 8.8 Hz, 1 H, H-3), 5.42 (br s, 1 H, H-1¢), 4.89 (d,
2J = 11.0 Hz, 1 H, CH2aPh), 4.66 (s, 2 H, CH2Ph), 4.63 (d, 2J = 12.1
2
CH2Ph), 4.58 (d, J = 10.8 Hz, 1 H, CH2bPh), 4.56–4.48 (m, 2 H,
CH2Ph), 4.47 (br s, 1 H, H-1¢), 4.18 (pseudo t, 3J3,4 ≈ 3J3,5 ≈ 9.6 Hz,
1 H, H-4¢), 3.96 (d, 3J2,3 = 1.8 Hz, 1 H, H-2¢), 3.87 (s, 3 H, OCH3),
3.79–3.71 (m, 3 H, H-3¢, H-6a¢, H-6b¢), 3.75 (s, 3 H, OCH3), 3.59–
3.53 (m, 1 H, H-5¢).
2
Hz, 1 H, CH2aPh), 4.58 (d, J = 11.0 Hz, 1 H, CH2bPh), 4.51 (d,
2
2J = 12.1 Hz, 1 H, CH2bPh), 4.27 (d, J = 11.3 Hz, 1 H, CH2aPh),
4.23 (m, 2 H, H-2¢, H-4¢), 4.11 (d, 2J = 11.3, 1 H, CH2bPh), 3.95 (dd,
3
2
3J3¢,4¢ = 9.5 Hz, J2¢,3¢ = 2.9 Hz, 1 H, H-3¢), 3.83 (dd, J6a¢,6b¢ = 10.7
13C NMR (125.8 MHz, CDCl3): d = 151.5 (C-1), 150.1, 142.2 (C-4,
C-5), 138.6, 138.5, 138.1 (4 C-1¢¢), 128.8, 128.7, 128.5, 128.3,
128.1, 128.0, 127.9, 127.8, 127.8 (20 CH Ph), 112.9 (C-2), 111.6
(C-3), 102.2 (C-6), 84.5 (C-3¢), 82.6 (C-1¢), 79.1 (C-5¢), 78.0 (C-2¢),
75.4, 74.9 (CH2Ph), 74.6 (C-4¢), 73.8, 72.6 (CH2Ph), 69.0 (C-6¢),
57.0, 56.2 (OCH3).
Hz, J5,6a = 3.4 Hz, 1 H, H-6a¢), 3.77 (dd, 2J6a¢,6b¢ = 10.7 Hz,
3
3J5¢,6b¢ = 2.1 Hz, 1 H, H-6b¢), 3.66 (ddd, 3J4¢,5¢ = 9.8 Hz, 3J5¢,6a¢ = 3.2
Hz, 3J5¢,6b¢ = 2.4 Hz, 1 H, H-5¢).
13C NMR (100.6 MHz, CD3OD): d = 158.1 (C-7), 157.7 (C-2),
140.7, 140.6, 140.3, 140.1 (C-1¢¢), 135.1 (C-8a), 132.3, 138.6 (C-4,
C-5), 130.3, 130.2, 130.1, 130.0, 129.8, 129.7, 129.6, 129.5 (20 CH
Ph), 129.2 (C-8), 125.8 (C-4a), 118.2 (C-3), 116.5 (C-6), 112.8 (C-
1), 85.9 (C-3¢), 81.5 (C-5¢), 80.9 (C-1¢), 78.0 (C-2¢). 77.0, 76.6
(CH2Ph), 76.2 (C-4¢), 75.2, 74.1 (CH2Ph), 70.5 (C-6¢).
FAB-MS: m/z (%) = 676.2 (92 [M]+), 195.0 (47), 181.1 (100, ma-
trix).
FAB-HRMS: m/z calcd for C42H44O8: 676.3036; found: 676.3014.
FAB-MS: m/z (%) = 683.5 (8, [M + H]+), 181.1 (100, matrix).
FAB-HRMS: m/z calcd for [C44H42O7 + H]+: 683.3003; found:
2-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-b-D-mannopyranosyl)-5-methoxy-
phenol (14)
683.3002.
The title compound was prepared according to the general proce-
dure from 4 (150.1 mg, 0.219 mmol, 1.1 equiv), 3-methoxyphenol
(13) (24.8 mg, 0.200 mmol, 1.0 equiv), and TMSOTf (56.3 mg,
0.253 mmol, 1.2 equiv) within a reaction time of 2.5 h. Purification
by flash chromatography (cyclohexane–EtOAc, 6:1) afforded 14 as
a colorless oil (57.7 mg, 89 mmol, 45%); [a]D23 –1.3 (c = 1, CDCl3);
Rf = 0.18 (cyclohexane–EtOAc, 5:1).
2-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-b-D-mannopyranosyl)-3,5-
dimethoxyphenol (10)31
The title compound was prepared according to the general proce-
dure from 4 (95.2 mg, 0.139 mmol, 1.0 equiv), 3,5-dimethoxyphe-
nol (9; 23.6 mg, 0.153 mmol, 1.1 equiv), and TMSOTf (38 mg, 0.17
mmol, 1.2 equiv) within a reaction time of 1.5 h. Purification by
flash chromatography (cyclohexane–EtOAc, 15:1) afforded 10 as a
colorless oil (53.2 mg, 79 mmol, 57%); [a]D26 +19.6 (c = 1, CHCl3);
Rf = 0.24 (cyclohexane–EtOAc, 15:1).
IR (film): 3346, 2864, 1529, 1453, 1359, 1211, 1106, 736, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.68 (s, 1 H, OH), 7.37–7.12 (m,
20 H, Ph-H), 6.11 (d, J4,6 = 2.4 Hz, 1 H, H-6), 5.93 (d, J4,6 = 2.4
IR (film): 3355, 3029, 2866, 1596, 1511, 1453, 1149, 1107, 1038,
737, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.27 (s, 1 H, OH), 7.37–7.14 (m,
4
20 H, Ph-H), 6.78 (d, 3J3,4 = 8.5 Hz, 1 H, H-3), 6.47 (d, J4,6 = 2.5
3
4
Hz, 1 H, H-6), 6.36 (dd, J3,4 = 8.5 Hz, J4,6 = 2.5 Hz, 1 H, H-4),
4.91 (d, 2J = 10.8 Hz, 1 H, CH2aPh), 4.69 (m, 2 H, CH2Ph), 4.65 (d,
2J = 12.3 Hz, 1 H, CH2aPh), 4.61 (d, J = 11.5 Hz, 1 H, CH2aPh),
4
4
2
2
2
2
Hz, 1 H, H-4), 4.93 (br s, 1 H, H-1¢), 4.91 (d, J = 10.9 Hz, 1 H,
4.58 (d, J = 10.8 Hz, 1 H, CH2bPh), 4.53 (d, J = 12.3 Hz, 1 H,
Synthesis 2010, No. 14, 2393–2398 © Thieme Stuttgart · New York

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b-Selective C-Mannosylation of Electron-Rich Phenols
2397
CH2bPh), 4.51 (br s, 1 H, H-1¢), 4.48 (d, 2J = 11.5 Hz, 1 H, CH2bPh),
(cyclohexane–EtOAc, 4:1) afforded 10 as a colorless oil (74 mg, 98
mmol, 52%).
3
3
4.16 (pseudo t, J3,4 ≈ J3,5 ≈ 9.5 Hz, 1 H, H-4¢), 3.96 (pseudo d,
3J2,3 = 1.7 Hz, 1 H, H-2¢), 3.79 (s, 3 H, OCH3), 3.77 (m, 2 H, H-6¢),
3
3
3.73 (dd, J3,4 = 9.5 Hz, J2,3 = 2.6 Hz, 1 H, H-3¢), 3.55 (ddd,
a-C-Arylglycosides from Trichloroacetimidates with ZnCl2 as
Promoter; 1-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-a-D-mannopyrano-
syl)naphthalen-2-ol (15)
3J4,5 = 9.5 Hz, 3J5,6a = 3.6 Hz, 3J5,6b = 2.3 Hz, 1 H, H-5¢).
13C NMR (125.8 MHz, CDCl3): d = 161.0 (C-5), 158.3 (C-1),
138.6, 138.5, 138.2 (4 C-1¢¢), 128.8 (C-3), 128.7, 128.6, 128.4,
128.1, 128.0, 127.9, 127.8, (20 CH Ph), 115.2 (C-2), 106.0 (C-4),
102.8 (C-6), 84.4 (C-3¢), 82.7 (C-1¢), 79.9 (C-5¢), 78.6 (C-2¢), 75.7,
75.0 (CH2Ph), 74.6 (C-4¢), 73.8, 72.5 (CH2Ph), 69.0 (C-6¢), 55.6
(OCH3).
FAB-MS: m/z (%) = 646.4 (15, [M]+), 181.1 (100, matrix).
FAB-HRMS: m/z calcd for [C41H42O7]+: 646.2931; found:
A mixture of 4 (260.0 mg 380 mmol, 1 equiv), 2-naphthol (5; 65.1
mg, 460 mmol, 1.2 equiv), ZnCl2 (110.3 mg, 760 mmol, 2 equiv), and
dried 4 Å molecular sieves (1.5 g) in anhyd CH2Cl2 (4 mL) was
stirred at r.t. under argon for 2 h. The mixture was quenched with
sat. aq NaHCO3 (10 mL). The organic layer was separated and the
aqueous phase extracted with CH2Cl2 (10 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated in vacuo. Puri-
fication by flash chromatography (cyclohexane–EtOAc, 20:1)
afforded 15 as a colorless oil (107.1 mg, 160 mmol, 42%).
646.2934.
1-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-a-D-galactopyranosyl)naphthalen-
2-ol (18)
C-Arylmannosides from Trichloroacetimidate 4 with BF3·OEt2
as Promoter; 1-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-a-D-mannopyrano-
syl)naphthalen-2-ol (15)
A mixture of 2,3,4,6-tetra-O-benzyl-a-D-galactopyranosyl trichlo-
roacetimidate (17; 106 mg, 0.154 mmol, 1 equiv), 2-naphthol (5;
28.3 mg, 0.196 mmol, 1.2 equiv), ZnCl2 (52.0 mg, 0.381 mmol, 2.2
equiv), and 4 Å dried molecular sieves (1 g) in anhyd CH2Cl2 (4
mL) was stirred at r.t. under argon for 1.5 h. The reaction was
quenched by the addition of sat. aq NaHCO3 (10 mL). The organic
layer was separated and the aqueous phase extracted with CH2Cl2
(10 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. Purification by flash chromatography (cy-
clohexane–EtOAc, 20:1) afforded 18 as a colorless oil (32.3 mg,
48.2 mmol; 31%); [a]D23 +24.4 (c = 0.71, CDCl3); Rf = 0.38 (cyclo-
hexane–EtOAc, 12:1).
A mixture of 2,3,4,6-tetra-O-benzylmannopyranosyl trichloroace-
timidate (4; 51.3 mg, 75 mmol, 1 equiv), 2-naphthol (5; 13.0 mg, 90
mmol, 1.2 equiv), and dried 4 Å molecular sieves (1 g) in anhyd
CH2Cl2 (4 mL) was stirred at 0 °C for 20 h under argon. Then,
BF3·OEt2 (27.9 mL, 31.5 mg, 222 mmol, 3 equiv) in anhyd CH2Cl2
(1 mL) was added and the mixture was stirred for 3 h. The reaction
was quenched with sat. aq NaHCO3 (10 mL). The organic layer was
separated and the aqueous phase extracted with CH2Cl2 (10 mL).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. Purification by flash chromatography (cyclohexane–
EtOAc, 4:1) afforded 15 as a colorless oil (14.8 mg, 22 mmol, 30%);
[a]D26 –22.9 (c = 1.0, CHCl3); Rf = 0.45 (cyclohexane–EtOAc, 9:1).
IR (film): 3332, 3029, 2924, 1622, 1453, 1226, 1085, 820, 737, 697
cm–1.
IR (film): 3373, 2360, 1658, 1629, 1495, 1453, 1091, 1070, 1028
cm–1.
1H NMR (500 MHz, CDCl3): d = 8.77 (s, 1 H, OH), 7.94 (d,
3J7,8 = 8.6 Hz, 1 H, H-8), 7.77 (d, 3J5,6 = 8.3 Hz, 1 H, H-5), 7.75 (d,
3J3,4 = 8.8 Hz, 1 H, H-4), 7.41 (m, 1 H, H-7), 7.37–7.20 (m, 15 H,
Ph-H), 7.32 (m, 1 H, H-6), 7.16 (d, 3J3,4 = 8.8 Hz, 1 H, H-3), 7.11
1H NMR (400 MHz, CDCl3): d = 9.14 (s, 1 H, OH), 7.77 (mc, 1 H,
H-5), 7.73–7.70 (m, 1 H, H-4), 7.46–7.07 (m, 22 H, H-3, H-6, H-7,
H-8, 18 Ph-H), 6.85–6.80 (m, 2 H, Ph-H), 5.94 (br s, 1 H, H-1¢), 4.74
(d, 2J = 12.2 Hz, 1 H, CH2aPh), 4.73–4.66 (m, 1 H, H-5¢), 4.63 (d,
2J = 11.8 Hz, 1 H, CH2aPh), 4.60–4.51 (m, 4 H, CH2Ph), 4.38 (dd,
2J6a,6b = 12.1 Hz, 3J5,6a = 8.9 Hz, 1 H, H-6a¢), 4.27 (dd, 3J = 6.6, 2.8
Hz, 1 H, H-4¢), 4.03 (d, 2J = 11.8 Hz, 1 H, CH2bPh), 3.94–3.89 (m,
2 H, H-6b¢, CH2Ph), 3.88–3.84 (m, 1 H, H-3¢), 3.77 (pseudo d,
3J2,3 = 3.3, 1 H, H-2¢).
13C NMR (125.8 MHz, CDCl3): d = 156.5 (C-2), 138.6, 138.4,
137.7 (4 C-1¢¢), 131.6 (C-8a), 130.2 (C-4), 129.3 (C-5), 128.9,
128.8, 128.7, 128.5, 128.4, 128.2, 128.1, 128.9, 127.9, 127.8 (20
CH-phenyl, C-4a), 126.9 (C-8), 122.8 (C-6), 121.0 (C-7), 120.3 (C-
3), 111.5 (C-1), 77.6 (C-2¢), 76.7 (C-5¢), 75.1 (C-3¢), 73.9, 73.8
(CH2Ph), 73.4 (C-4¢), 73.2, 72.1 (CH2Ph), 69.5 (C-1¢), 64.8 (C-6¢).
3
2
(app d, J = 7.4 Hz, 1 H, Ph-H), 7.06 (t, J = 7.4 Hz, 2 H, Ph-H),
6.60 (d, 2J = 7.3 Hz, 2 H, Ph-H), 5.91 (d, 3J1,2 = 10.1 Hz, 1 H, H-1¢),
2
4.79 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.62–4.49 (m, 4 H, CH2Ph),
4.43 (m, 2 H, CH2Ph, H-5¢), 4.27 (dd, 3J1,2 = 10.1 Hz, 3J2,3 = 2.6 Hz,
1 H, H-2¢), 4.19–4.10 (m, 1 H, H-6a¢), 3.94 (br s, 1 H, H-3¢), 3.84
(d, 2J = 11.3 Hz, 1 H, CH2Ph), 3.79–3.72 (m, 2 H, H-6b¢, H-4¢), 3.67
(d, 2J = 11.3 Hz, 1 H, CH2Ph).
13C NMR (125.8 MHz, CDCl3): d = 155.2 (C-2), 138.5, 138.2,
137.8 (4 C-1¢¢), 133.3 (C-8a), 130.3 (C-4), 128.7 (C-4a), 128.6,
128.5 (5 CH Ph), 128.3 (C-5), 128.0, 127.8, 127.7, 127.4 (15 CH
Ph), 126.4 (C-7), 123.2 (C-8), 123.0 (C-6), 119.3 (C-3), 115.1 (C-
1), 76.3 (C-5¢), 75.2 (C-2¢), 75.1 (C-4¢), 75.0 (C-3¢), 73.8, 73.2, 73.0,
71.7 (CH2Ph), 67.9 (C-1¢), 66.9 (C-6¢).
FAB-MS: m/z (%) = 666.4 (19, [M]+), 181.1 (100, matrix).
FAB-HRMS: m/z calcd for [C44H42O6]+: 666.2981; found:
666.2999.
FAB-MS: m/z (%) = 666.4 (17, [M]+), 181.1 (100, matrix).
FAB-HRMS: m/z calcd for C44H42O6: 666.2981; found: 666.3008.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
2-(2¢,3¢,4¢,6¢-Tetra-O-benzyl-b-D-mannopyranosyl)-3,5-
dimethoxyphenol (10)
A mixture of 4 (128.1 mg 187 mmol, 1 equiv), 3,5-dimethoxyphenol
(9; 31.7 mg, 206 mmol, 1.2 equiv), and dried 4 Å molecular sieves
(1.5 g) in anhyd CH2Cl2 (3 mL) was stirred at 0 °C for 20 h under
argon. Then, BF3·OEt2 (52.0 mL, 58.7 mg, 414 mmol, 2.2 equiv) in
anhyd CH2Cl2 (1 mL) was added and the mixture was stirred for 2
h. The reaction was quenched with sat. aq NaHCO3 (10 mL). The
organic layer was separated and the aqueous phase extracted with
CH2Cl2 (10 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. Purification by flash chromatography
Acknowledgment
This work was supported by the Bundesministerium für Bildung,
Forschung und Technologie (BMBF, Grant no. 0315139).
References
(1) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans.
1 2000, 1471.
Synthesis 2010, No. 14, 2393–2398 © Thieme Stuttgart · New York

2398
S. Weck, T. Opatz
PAPER
(18) Kometani, T.; Kondo, H.; Fujimori, Y. Synthesis 1988,
(2) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113,
9376.
1005.
(3) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087.
(4) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33,
1765; Angew. Chem. 1994, 106, 1843.
(5) Kunz, H.; Günther, W. Angew. Chem., Int. Ed. Engl. 1988,
27, 1086; Angew. Chem. 1988, 100, 1118.
(6) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155;
Angew. Chem. 1982, 94, 184.
(19) Mahling, J. A.; Schmidt, R. R. Synthesis 1993, 325.
(20) Schmidt, R. R.; Michel, J. Angew. Chem., Intl. Ed. Engl.
1980, 19, 731; Angew. Chem. 1980, 92, 763.
(21) Schmidt, R. R.; Hoffmann, M. Tetrahedron Lett. 1982, 23,
409.
(22) Ješelnik, M.; Plavec, J.; Polanc, S.; Kočevar, M. Carbohydr.
Res. 2000, 328 , 591.
(7) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435.
(8) Codee, J. D. C.; Hossain, L. H.; Seeberger, P. H. Org. Lett.
2005, 7, 3251.
(23) Lindhorst, T. K. Essentials of Carbohydrate Chemistry and
Biochemistry, 3rd ed.; Wiley-VCH: Weinheim, 2007.
(24) Lönn, H. Carbohydr. Res. 1985, 139, 105.
(25) Grathwohl, M.; Schmidt, R. R. Synthesis 2001, 2263.
(26) Eichler, E.; Jennings, H. J.; Gilbert, M.; Whitfield, D. M.
Carbohydr. Res. 1999, 319, 1.
(9) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep.
2005, 22, 742.
(10) Jaramillo, C.; Knapp, S. Synthesis 1994, 1.
(11) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54,
9913.
(27) Schmidt, R. R.; Michel, J.; Roos, M. Liebigs Ann. Chem.
1984, 1343.
(12) Schmidt, R. R.; Effenberger, G. Carbohydr. Res. 1987, 171,
59.
(13) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett.
1988, 29, 6935.
(14) Palmacci, E. R.; Seeberger, P. H. Org. Lett. 2001, 3, 1547.
(15) Ben, A.; Yamauchi, T.; Matsumoto, T.; Suzuki, K. Synlett
2004, 225.
(28) Compound 6 was first reported by Palmacci and Seeberger,
who suggested the a-configuration. See ref. 14.
(29) The measured vicinal coupling constants are in accordance
with the values expected for the 1C4 conformer. See:
(a) Paulsen, H.; Györgydeák, Z.; Friedmann, M. Chem. Ber.
1974, 107, 1590. (b) Finch, P.; Nagpurkar, A. G.
Carbohydr. Res. 1976, 49, 275.
(16) Li, Y.; Wei, G.; Yu, B. Carbohydr. Res. 2006, 341, 2717.
(17) Matsumoto, T.; Hosoya, T.; Suzuki, K. Synlett 1991, 709.
(30) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883.
(31) Compounds 10 and 12 were first reported by Li et al. who
suggested the a-configuration. See ref. 16.
Synthesis 2010, No. 14, 2393–2398 © Thieme Stuttgart · New York