Toward fluorinated aminoglycosides: Structural studies of phenylhydrazine condensation with carbohydrate derivatives

Article abstract of DOI:10.1055/s-0032-1317783

The reaction of phenylhydrazine with a sugar dialdehyde in water, as a key step for the synthesis of the 3-amino-3-deoxy-d-glucose moiety contained in kanamycin, has been revisited. Structural studies (IR and NMR as well as a simple theoretical model base

Full text of DOI:10.1055/s-0032-1317783

LETTER
▌249
letter
Toward Fluorinated Aminoglycosides: Structural Studies of Phenylhydrazine
Condensation with Carbohydrate Derivatives
Phenylhydrazine Condensation with Carbohydrate Derivatives
Antonio Franconetti,* Pastora Borrachero, Manuel Gómez-Guillén, Francisca Cabrera-Escribano*
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado de Correos No. 1203, 41071 Sevilla, Spain
Fax +34(95)4624960; E-mail: afranconetti@us.es; E-mail: fcabrera@us.es
Received: 28.10.2012; Accepted: 15.11.2012
commonly used for the direct replacement of a hydroxyl
Abstract: The reaction of phenylhydrazine with a sugar dialdehyde
group by fluorine under very mild conditions.3,4
in water, as a key step for the synthesis of the 3-amino-3-deoxy-D-
glucose moiety contained in kanamycin, has been revisited. Struc-
tural studies (IR and NMR as well as a simple theoretical model
based on energy-minimization calculations and MD calculations)
reported herein support the observed stereo- and regioselectivity.
Efforts to improve the reproducibility and viability of the process as
part of a convenient approach towards fluorinated kanamycin are
also now presented.
With the aim of developing a potentially efficient route to
fluorinated kanamycin, we set out to synthesize the 3-ami-
no-3-deoxy-D-glucose moiety and study its subsequent
fluorination with DAST at position 2. Therefore, as a pre-
vious step of kanamycin synthesis, the formation of 3-
amino-3-deoxy-D-glucose from commercial available
products has to be carried out. Condensation of phenylhy-
drazine with the sugar-derived dialdehyde 2 in water, as a
key step, has been used5 as an elegant and simple synthetic
strategy (Scheme 1).
Key words: carbohydrates, condensation, phenylhydrazine, stereo-
and regioselectivity, green chemistry
We have revisited this process and we report herein new
structural NMR and IR data of compounds 2 and 4 as well
as a simple theoretical model for explaining the result of
the key condensation process. In addition to this, we de-
scribe novel improved reaction conditions and our recent
progress toward 2-fluorinated 3-amino-3-deoxy-D-glu-
cose.
Aminoglycosides are the most commonly used antibiotics
worldwide thanks to the combination of their high effica-
cy with low cost. These compounds act on gram-positive
and gram-negative bacteria as protein synthesis inhibi-
tors.1 However, they are nephrotoxic and ototoxic in some
cases, thus limiting their use. Kanamycin is a representa-
tive member of the aminoglycoside antibiotic family that
shows multiple therapeutic applications and contains a
3-amino-3-deoxy-D-glucose moiety as a structural unit
(Scheme 1).
The synthesis of methyl 4,6-O-benzylidene-3-deoxy-3-
phenylazo-α-D-glucopyranoside (4) was carried out in
water by using phenylhydrazine.5 It has been proposed
that, in aqueous solution, an equilibrium (Scheme 2) ex-
ists between the dialdehyde 2 and the hemialdal 3, ob-
tained by periodate oxidation of methyl 4,6-O-
benzylidene-α-D-glucopyranoside (1). This reaction was
carried out for a week at room temperature (Table 1, meth-
od A) in aqueous solution to obtain the oxidized product
in 70% yield, but this proved irreproducible. When we
used sodium periodate in a MeOH–H2O mixture to accel-
erate the reaction (Table 1, method B), a white solid, oxi-
dized product was obtained in 98% yield.6
In general, substitution of an OH group by a fluorine atom
is an important resource in medicinal chemistry.2 In addi-
tion to the bioavailability issue, the fluorination of bioac-
tive molecules can increase their biological activity and
improve their lipid permeability and metabolic stability.
Furthermore, it is known that the presence of fluorine in
the carbohydrate moiety contained in aminoglycoside an-
tibiotics reduces their toxicity, especially when the fluo-
rine atom is adjacent to the amino group. Among a large
number of strategies or agents to introduce fluorine into
carbohydrates, diethylaminosulfur trifluoride (DAST) is
NH2
protecting group
O
HO
HO
H2N
O
O
Ph
O
H2N
Ph
O
O
O
O
NH2
OH
HO
PhN2
O
O
HO
O
OMe
OMe
NH2
OH
reduction
to amine
O
2
4
kanamycin B
HO
Scheme 1
SYNLETT 2013, 24, 0249–0253
Advanced online publication: 11.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317783; Art ID: ST-2012-D0925-L
© Georg Thieme Verlag Stuttgart · New York

250
A. Franconetti et al.
LETTER
O
O
O
O
O
Ph
O
Ph
O
Ph
O
O
NaIO4
OMe
OH
OMe
OMe
H2O–MeOH
O
HO
O
O
HO
OH
1
2
3
Scheme 2
135.5–126.4 ppm (aromatic carbons), 101.2 ppm (PhCH),
96.6 ppm (C-1), and 48.9 ppm (CH3)], confirming the
presence of the dialdehyde 2 in the sample.
Table 1 Reaction Conditions to Obtain Dialdehyde 2 or Hemialdal 3
Method Solvent
Time Other conditions
Yield (%)
Next, we have investigated the condensation reaction of
phenylhydrazine with dialdehyde 2 to obtain compound 4
(Scheme 3). We have tried different reaction conditions as
indicated in Table 2.
A
B
H2O
1 w darkness
70
98
MeOH–H2O
20 h darkness, cooling
We have performed IR spectra of compounds obtained by
using both methods (Scheme 2, Table 1) and we did not
observe a carbonyl absorption (ca. 1600 cm–1) in either
case. This indicates that the periodate oxidation product of
compound 1 has the structure of the hemialdal 3. Further-
more, the product obtained by the periodate method
Under the conditions studied, the results were not repro-
ducible. Regarding compound 4, the best results were ob-
tained using conditions A and E (Table 2).7 From the 1H
NMR spectrum we realized that the crude product ob-
tained under conditions A (Table 2) was a 3:1 mixture of
compounds 4 and 4a. The presence of both regioisomers
could be inferred from the two diagnostic signals for the
anomeric OMe groups at δ = 3.50 and 3.52 ppm, and two
singlets corresponding to H-7 of the benzylidene groups at
δ = 5.77 and 5.74 ppm.
1
showed H NMR and 13C NMR spectra (in DMSO-d6)
with no signals for the aldehydic protons nor carbonyl car-
bons, respectively. This information reinforced the hemi-
aldal structure 3 assigned to the periodate oxidation
product of compound 1, not only in the solid state as de-
duced from the IR spectrum, but also in solvents other
than water, since the equilibrium between 2 and 3 occurs
only in aqueous solution.
Recrystallization of the crude solid product obtained un-
der conditions E (Table 2),7 which was carried out under
argon atmosphere and absence of light, afforded highly
pure 4. Its 1H NMR spectrum (300 MHz, CDCl3) included
aromatic proton signals (10 H) at δ = 7.74–7.29 ppm, two
singlets at δ = 5.77 and 3.50 ppm, respectively, assigned
to the benzylic (H-7) and OMe protons, a broad singlet at
δ = 4.72 ppm (anomeric proton), two triplets at δ = 5.48
(10.2 Hz) and 4.10 ppm (10.0 Hz, H-3 and H-4), and a
Therefore, we used D2O as the solvent for recording the
1H NMR spectrum of compound 3 under presaturation
conditions; in this case, the aldehydic proton signal was
clearly observed at δ = 9.97 ppm. Analogously, the alde-
hydic carbonyl signal appeared in the 13C NMR spectrum
(in D2O) at δ = 196.8 ppm [other relevant signals: δ =
O
O
O
O
Ph
O
Ph
O
Ph
O
PhNHNH2
Table 2
O
OMe
OMe
N2Ph
O
OMe
+
O
O
PhN2
OH
HO
4a
2
4
Scheme 3
Table 2 Reaction of Phenylhydrazine with Dialdehyde 2
Conditions
Temp (°C)
Reagent
Reagent (equiv) Other conditions
Products (yield, %)a
A
B
C
D
E
85
80
70
83
92
PhNHNH2
1.5
2.5
2
–
4 (15) + 4a (7)
5 (78)
PhNHNH2
not cooling
PhNHNH3Cl/NaOAc
PhNHNH2
darkness, ice (0 °C)
ice/NaCl (–15 °C)
5 (–b)
2.5
2
5 (68)
NaOAc/PhNHNH3Cl
darkness, ice/NaCl (–15 °C), argon
4 (16)
a After recrystallization.
b Not quantified, only detected by TLC.
Synlett 2013, 24, 249–253
© Georg Thieme Verlag Stuttgart · New York

LETTER
Phenylhydrazine Condensation with Carbohydrate Derivatives
251
double doublet at δ = 4.75 ppm (3J1,2 = 4.5 Hz), assigned get temperature was held at 300 K, and the step and frame
to H-2.
intervals were 2.0 and 10 fs, respectively. With this infor-
mation, we could build a model for isomer interaction to
check that aromatic stacking is not broken (Figure 3).
Nevertheless, compound 4 [Rf = 0.88 (49:1 CH2Cl2–ace-
tone)], was unstable, and its rapid decomposition into
products of lower Rf was observed by TLC. Additionally,
the low yields obtained for this compound could be ex-
plained by a competitive acid hydrolysis of 2 at the ano-
meric position in the aqueous medium to give 2,4-O-
benzylidene-D-erythrose and glyoxal, which subsequently
reacted with excess phenylhydrazine to afford glyoxal bi-
sphenylhydrazone 5 (Figure 1). This compound, a useful
product as promoter for metal-catalyzed cross-coupling
reactions,8 was isolated in most conditions (conditions B,
C, and D, Table 2) as an orange solid and identified ac-
cording to the literature.5
Figure 3 (a) Model of isomer 4, and (b) model of isomer 4a based
on MD calculations
Crude compound 4 obtained under conditions E (Table 2)
was reduced in MeOH by hydrogen in the presence of Ad-
am’s catalyst (PtO2) to give methyl 3-amino-4,6-O-ben-
zylidene-3-deoxy-α-D-glucopyranoside (6) in quantitative
yield pure enough to be used for further transformation,
but too unstable to be purified by column chromatography
(Scheme 4).
HN
N
N NH
5
Figure 1
To justify the higher proportion of isomer 4, we used a
simple theoretical model with ChemBio3D and Discovery
Studio 3.1. First, we applied an energy-minimization cal-
culation using MM2 field force. Aromatic stacking inter-
actions are widespread in nature, generally in
biomolecules (e.g., DNA). In this context, two aromatic
residues are considered to interact if the distance between
phenyl centroids is less than 7 Å.9 From our calculations,
a stacking interaction between the two phenyl groups
present in the molecule of 4 was indicated (Figure 2). By
using the same conditions to minimize energy, we ob-
served an increased theoretical energy in the isomer 4a,
since the additional stabilization (–12.1 kJ mol–1) of an ar-
omatic stacking interaction is not possible in this case.
O
O
Ph
O
H2, PtO2
MeOH
OMe
Ph
O
O
O
OMe
quant. yield
PhN2
OH
H2N
OH
6
4
Ac2O–Py
Ac2O–EtOH
0 °C
r.t.
(20%)
O
O
O
Ph
O
Ph
O
O
OMe
OAc
OMe
+
AcHN
AcHN
OH
7 (traces)
8 (15%)
Scheme 4
Prior to the 2-OH fluorination of compound 6, we consid-
ered the possibility of selective protection of the 3-amino
group by acetylation under the mild conditions described
by Sharma et al.11 for related compounds. Under these
conditions (Ac2O–EtOH, 0 °C, Scheme 4), only trace
amounts of the 3-acetamido compound 7 were obtained
along with the 2,3-N,O-diacetate 8 in poor yield (15%).
Moreover, conventional acetylation in Ac2O–pyrdine of
compound 6 also turned out to be ineffective, with 8 being
isolated in 20% yield.
Figure 2 Modeling results: (a) isomer 4 showing aromatic interac-
tion between aromatic ring residues, and (b) isomer 4 showing integ-
rity of carbohydrate chair; (c) isomer 4a where aromatic interaction is
not observed
1
All these compounds presented characteristic H NMR
features; the anomeric protons displayed a coupling con-
stant 3J1,2 = 4.5 Hz, in agreement with that expected for α
anomers, and a singlet was observed at δ = ca. 4.5 ppm
corresponding to the anomeric OMe.
Additionally, molecular-dynamics calculations10 were
performed for isomers 4 and 4a. In our simulation, the tar-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 249–253

252
A. Franconetti et al.
LETTER
O
O
O
O
Ph
O
Ph
O
O
O
O
O
i. HCl/MeOH, reflux 48 h
OMe
OMe
+
ii. PhCHO, ZnCl2
80%
O
N3
OH
N3
OH
N3
2:1
9
10
11
DAST
MeCN, reflux
3J1,F = 7.8 Hz
MeO
O
O
F
F
O
Ph
Ph
O
O
HO
O
H
O
H1
+
N3
OMe
3J3,F = 29.0 Hz
H2
H3
N3
OMe
2J2,F = 48.2 Hz
N3
F
F
13 + 14 (63%)
12 (25%)
Scheme 5 Alternative synthetic route to fluorinated aminoglycoside derivatives and coupling constants of compound 12
While these reactions constitute a highly stereo- and regi- Compound 12, having the backbone of an important moi-
oselective route toward aminoglycosides that can be con- ety of kanamycin and a fluorine atom at C-2, presents a
sidered an example of a green chemistry strategy12 the suitable feature to potentially reduce the toxicity of this
lack of reproducibility and low yields made it necessary to aminoglycoside antibiotic. This compound has a latent
seek alternative synthesis routes to 3-amino-3-deoxy-D- amino functionality, the azide group, reduction of which
glucose13 (Scheme 5).
Accordingly, hydrolysis of the diacetal 914 (HCl–MeOH,
would lead to the desired amine after hydrolysis of the
benzylidene group (Figure 4).
reflux, 7 h) followed by the conventional protection of the The azide group could be readily reduced with hydrogen
4- and 6-OH functions as a benzylidene acetal gave the in the presence of Pd/C catalyst or by Staudinger reaction
anomeric 2:1 mixture of 10/11, whose spectroscopic data with triphenylphosphine, and the benzylidene group could
were identical to those previously described in the litera- be hydrolyzed in a mixture AcOH–H2O (7:3)17 or p-tolu-
ture.13a After separation by column chromatography, the enesulfonic acid.18
major α-D-anomer 10 was dissolved in MeCN and treated
In summary, the aqueous condensation of phenylhydra-
with DAST under reflux for six hours. Workup and puri-
zine and the dialdehyde obtained by periodate oxidation
fication by column chromatography on silica gel led to the
of methyl 4,6-O-benzylidene-α-D-glucopyranoside (1),
described in the literature as an elegant and easy synthesis
of the corresponding 3-amino-3-deoxy derivative 6, has
poor reproducibility in our hands. Spectroscopic studies
desired pure 2-fluorinated compound 12 (25%),15 along
with a diastereomeric mixture of rearranged, ring-con-
tracted products 13 and 14 (63%)4 and unreacted starting
material 10 (9%).
and a simple theoretical model based on energy-minimi-
1
Usually, in H NMR spectra of fluorinated sugars, the zation and molecular-dynamics calculations support the
geminal coupling constants (2JF,H) are 43–59 Hz in pyra- stereo- and regioselectivity of the process in favor of the
noses and 46–66 Hz in furanose rings.16 The vicinal cou- 3-phenylazo isomer 4. In view of our unsuccessful efforts
pling constants (3JF,H) depend on the electronegativity of to improve the reproducibility and viability of this ap-
neighboring substituents. In our case, the observed 2J2,F
=
proach toward fluorinated kanamycin, we present the
48.2 Hz and 3J3,F = 29.0 Hz values are in agreement with preparation of fluorinated precursor subunit 12 starting
the proposed structure 12. The required disposition of the from commercially available diacetone-D-glucose, via the
4
hydrogen atoms on the C1 pyranose conformation for 3-azido-3-deoxy derivative 9.
these coupling constants is shown in Scheme 5.
Acknowledgment
We thank the AECID (Projects A/023577/09 and A/030422/10) and
the ‘Junta de Andalucía’ (FQM 142 and Project P09-AGR-4597)
for financial support. We also thank D. Lara for invaluable collabo-
ration.
O
O
HO
HO
Ph
O
O
OMe
O
toxicity
reduction
N3
F
H2N
OH
References and Notes
facile reduction
to amino group
kanamycin moiety
(1) (a) Li, J.; Chang, T. Anti-Infect. Agents Med. Chem. 2006, 5,
255. (b) Corey, E. J.; Czakó, B.; Kürti, L. Molecules and
Medicine; John Wiley and Sons: Hoboken, 2007.
Figure 4
Synlett 2013, 24, 249–253
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LETTER
Phenylhydrazine Condensation with Carbohydrate Derivatives
253
(2) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(3) Ferret, H.; Déchamps, I.; Gomez Pardo, D.; Van Hijfte, L.;
Cossy, J. ARKIVOC 2010, (viii) 1, 26.
(4) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.;
Carmona-Asenjo, A.; Gómez-Guillén, M. Tetrahedron:
Asymmetry 2004, 15, 429; and references cited therein.
(5) Patroni, J.; Stick, R. Aust. J. Chem. 1985, 38, 947; and
references cited therein.
Larina, L. I.; Klyba, L. V.; Sukhanov, G. T.; Sakovich, G. V.
Russ. J. Org. Chem. 2009, 45, 1683.
(9) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J.
J. Chem. Soc., Perkin Trans. 2 2001, 651.
(10) (a) Rode, M. B.; Hofer, S. T.; Kugler, D. M. The Basics of
Theoretical and Computational Chemistry; Wiley-VCH:
Weinheim, 2007. (b) Young, D. Computational Chemistry;
John Wiley and Sons: New York, 2001.
(6) Synthesis of Compound 2 (Method B)
(11) Sharma, M.; Bernacki, R. J.; Hillman, M. J.; Korytnyk, W.
Carbohydr. Res. 1993, 240, 85.
NaIO4 (7.7 g, 36 mmol) was dissolved in H2O (95 mL). After
cooling at 5 °C, a solution of methyl 4,6-O-benzylidene-α-D-
glucopyranoside (5 g, 17.73 mmol) in MeOH (95 mL) was
added. The mixture was stirred in the dark for 20 h at r.t.
EtOH was added to precipitate iodates, and the filtered
solution was evaporated under vacuum and dried to obtain
dialdehyde 2 (98% yield). 13C NMR (125.7 MHz, D2O): δ =
196.8 (CHO), 135.5–126.4 (Ph), 101.2 (CHPh), 96.6 (C-1),
75.9 (C-4), 71.3 (C-6), 64.6 (C-5), 48.9 (OCH3) ppm. HRMS
(CI): m/z calcd for C13H15O5 [M–CHO]: 251.0919; found:
251.0913; and m/z calcd for C13H13O5 [M–OMe]: 249.0763;
found 249.0766.
(12) Anastas, Y.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998.
(13) (a) Albert, R.; Dax, K.; Pleschko, R.; Stutz, A. E.
Carbohydr. Res. 1985, 137, 282. (b) Faghih, R.; Cabrera-
Escribano, F.; Castillon, S.; Garcia, J.; Olesker, A.; That
Thang, T. J. Org. Chem. 1986, 51, 4558.
(14) Brimacombe, J. S.; Bryan, J. G. H.; Husain, A.; Stacey, M.;
Tolley, M. S. Carbohydr. Res. 1967, 3, 318.
(15) Preparation of Compound 12
A solution of compound 10 (109 mg, 0.355 mmol) in dry
MeCN (6.5 mL) was treated with DAST (236 μL, 1.785
mmol) at 0 °C under argon. After several minutes, the
cooling bath was removed, and the mixture was heated to
reflux for 6 h, monitoring the reaction by TLC. On
completion, after evaporation of the solvent, the residue was
treated with CH2Cl2 (20 mL) and cold sat. aq NaHCO3 (50
mL). The aqueous layer was extracted with CH2Cl2 (3 × 20
mL), and the combined organic layers were washed with sat.
aq NaCl (50 mL), dried (Na2SO4), filtered, and concentrated.
The residue was purified by column chromatography on
silica gel (1:5 to 1:3 gradient hexane–Et2O with 1% Et3N) to
give unreacted 10 (9%), compound 12 (25 mg,
(7) Preparation and Most Relevant Data of Compound 4
Conditions A5
Phenylhydrazine (250 μL, 2.59 mmol) was added to a
solution of compound 2 (0.5 g, 1.79 mmol) in H2O (125 mL)
at 85 °C. On shaking the yellow mixture rapidly with ice-
water, a yellow solid precipitated. This crude product was
filtered off and purified by recrystallization from a small
volume of butan-1-ol to give a yellow solid, identified as a
mixture of 4 (95.2 mg, 15%) and 4a (27.7 mg, 7%).
Attempted column chromatography on silica gel resulted in
rapid decomposition.
Conditions E
corresponding to 25% yield from converted substrate) and
the epimeric mixture 13/14 [63% yield, characterized by
transformation into the corresponding (1R and 1S)-2,5-
anhydro-3-azido-6-O-tert-butyl-diphenylsilyl-3,4-dideoxy-
1,4-difluoro-1-O-methyl-D-talitols.4]
A solution of compound 2 (0.33 g, 1.18 mmol) in H2O (100
mL) was heated at 92 °C, under argon in darkness. The
solution was cooled, then NaOAc (0.39 g, 4.73 mmol) was
added followed by slow addition of phenylhydrazine
hydrochloride (0.34 g, 2.36 mmol). After rapid cooling to –
15 °C and shaking of the mixture, a yellow solid
precipitated. This product was filtered off, washed with cool
H2O, recrystallized from butan-1-ol and dried under vacuum
to give a yellow solid which was identified as pure methyl
4,6-O-benzylidene-3-deoxy-3-phenylazo-α-D-
Selected Analytical Data
Compound 12: solid; mp 56–60 °C; Rf = 0.44 (Et2O–hexane
= 1:3). 1H NMR (300 MHz, CD3COCD3): δ = 7.49–7.36 (m,
5 H, Ph), 5.81 (s, 1 H, CHPh), 4.91 (dd, 1 H, 3J1,F = 7.8 Hz,
J1,2 = 1.7 Hz, H-1), 4.78 (ddd, 1 H, 2J2,F = 48.2 Hz, J2,3 = 2.3
Hz, H-2), 4.27 (dd, 1 H, J6,6′ = 11.7 Hz, J5,6 = 1.7 Hz, H-6),
4.12 (ddd, 1 H, J3,4 = 10.6 Hz, J4,5 = 9.0 Hz, 4J4,F = 1.6 Hz,
H-4), 3.92 (ddd, 3J3,F = 29.0 Hz, H-3), 3.89–3.83 (m, 2 H, H-
5 and H-6′), 3.44 (s, 3 H, OCH3) ppm. 13C NMR (75.8 MHz,
CD3COCD3): δ = 138.8–127.2 (Ph), 102.5 (CHPh), 99.5 (d,
2JC1,F = 31.0 Hz, C-1), 89.8 (d, 1JC2,F =180.0 Hz, C-2), 74.6
(C-4), 69.2 (C-6), 64.9 (C-5), 59.7 (d, 2JC3,F = 16.6 Hz), 55.7
(OCH3) ppm. HRMS (CI): m/z calcd for C14H16FN3O4 + H:
310.1203; found: 310.1207.
glucopyranoside (4, 68.6 mg, 16%). Rf = 0.88 (CH2Cl2–
acetone = 49:1).
1H NMR (300 MHz, CDCl3): δ = 7.74–7.29 (m, 10 H, Ph),
5.77 (s, 1 H, H-7), 5.48 (t, 1 H, H-3, J3,4 = J3,2 = 10.2 Hz),
4.75 (dd, 1 H, H-2, J2,1 = 4.5, J2,3 = 10.6 Hz), 4.72 (br s, 1 H,
H-1), 4.46 (dd, 1 H, J6ec,5 = 4.6 Hz, J6ec,6ax = 10.2 Hz, H-6eq),
3.32 (m, 2 H, H-5 and H-6ax), 4.10 (t, 1 H, H-4, J4,3 = J4,5
10.0 Hz), 3.50 (s, 3H, OCH3) ppm. HRMS (CI): m/z calcd
for C20H22N2O5: 370.1529; found: 370.1522.
=
(16) Michalik, M.; Hein, M.; Frank, M. Carbohydr. Res. 2000,
327, 185.
(17) Baer, H. H.; Gan, Y. Carbohydr. Res. 1991, 210, 233.
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(8) (a) Liu, Y.-H.; Li, G.; Yang, L.-M. Tetrahedron Lett. 2009,
50, 343. (b) Trofimov, B. A.; Myachina, G. F.; Ermakova, T.
G.; Kuznetsova, N. P.; Volkova, L. I.; Sultangareev, R. G.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 249–253