Efficient Two-Step Multifunctionalization of Substituted 2-Hydro-xyglycopyranosides

Article abstract of DOI:10.1055/s-0036-1588624

A straightforward route to diversely functionalized glycopyranosides is reported. 2,3-Enopyranosides, 2- and/or 3-azido-, 2-halopyranosides, and a hex-3-ulose, among other α- and β-glycopyranosides are easily obtained in good to excellent yields from 2-hydroxyglycopyranosides by means of a two-step process involving trifluoromethanesulfonation and subsequent treatment with the appropriate nucleophilic agent.

Full text of DOI:10.1055/s-0036-1588624

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
A. Franconetti et al.
Letter
Synlett
Efficient Two-Step Multifunctionalization of Substituted 2-Hydro-
xyglycopyranosides
Antonio Franconetti*a
Eleuterio Álvarezb
Francisca Cabrera-Escribano*a
a Departamento de Química Orgánica, Facultad de Química,
Universidad de Sevilla, C/Profesor García González 1, 41012
Sevilla, Spain
afranconetti@us.es
fcabrera@us.es
b Instituto de Investigaciones Químicas, C.S.I.C.-Universidad
de Sevilla, Avda. Américo Vespucio 49, Isla de la Cartuja,
41092 Sevilla, Spain
Received: 11.07.2016
Accepted after revision: 20.09.2016
Published online: 11.10.2016
side-based building blocks by means of an interesting rear-
rangement, promoted by diethylamiosulfur trifluoride
(DAST), of equatorial-2-OH methyl hexopyranosides.8 Re-
cently, metallic catalysts and organocatalysts have been re-
ported as selective glycosylation tools.9
Unsaturated glycopyranosides are often found as chiral
intermediates in the synthesis of numerous biologically ac-
tive natural products.10 These compounds are also a com-
mon structural unit in many medicinally significant mole-
cules such as antibiotics.11 In order to induce functionalization
on unsaturated pyranoside rings (i.e., 2,3 enopyranosides),
anomeric C-glycosylation from D-glycals by acid-catalyzed
Ferrier rearrangement is required.12 Another possibility in-
cludes a tandem Tebbe–Claisen approach involving multiple
steps.13
Searching for new simple and selective routes to func-
tionalized carbohydrate derivatives useful in synthesis and
as privileged scaffolds in pharmacological studies, we have
found that substituted 2-hydroxyglycopyranosides can be
efficiently multi- and diversely functionalized by means of
a two-step process involving trifluoromethanesulfonation
and subsequent treatment with the appropriate nucleo-
philic agent. Furthermore, DFT calculations have been ap-
plied to corroborate the results obtained.
DOI: 10.1055/s-0036-1588624; Art ID: st-2016-d0448-l
Abstract A straightforward route to diversely functionalized glycopy-
ranosides is reported. 2,3-Enopyranosides, 2- and/or 3-azido-, 2-ha-
lopyranosides, and a hex-3-ulose, among other α- and β-glycopyrano-
sides are easily obtained in good to excellent yields from 2-
hydroxyglycopyranosides by means of a two-step process involving tri-
fluoromethanesulfonation and subsequent treatment with the appro-
priate nucleophilic agent.
Key words functionalized glycopyranosides, 2-hydroxyglycopyrano-
sides, 2,3-enopyranosides, 2-halopyranosides, DFT calculations, confor-
mational analysis
Carbohydrates are of interest due to their role in a num-
ber of biological processes.1 In general, carbohydrates are
present in different macromolecules such as glycoproteins,2
glycolipids,3 oligosaccharides, and polymers.4 Since carbo-
hydrates are conformationally restricted structures with
added hydrogen-bond capability and enantiopure diversity
they have demonstrated their capability to construct the
backbone of novel structures with unique properties, in
particular foldamers,5 nanotubes,6 and self-assembling
nanostructured LC phases.7
However, one of the major difficulties in using these
polyhydroxylated molecules as starting materials, or as in-
termediates in synthesis, is to achieve their selective func-
tionalization in ways that no protection and deprotection
steps are required. Different methodologies have been ex-
plored for generating new configurations at different posi-
tions of both pyranoside and furanoside rings. In this con-
text, we have described an easy access to configurationally
controlled formyl C-glycofuranoside and C-glycofurano-
Reaction of methyl 4,6-O-benzylidene-α-D-glucopyra-
noside 1 with trifluoromethanesulfonic anhydride (triflic
anhydride) led to the corresponding 2,3-di-O-triflate 214
under mild conditions in good yield, thus providing the
starting material. Compound 2 having two recognized leav-
ing groups constitutes an excellent candidate for multifunc-
tionalization processes. For this purpose, reaction of 2 with
several nucleophiles was investigated (Table 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
A. Franconetti et al.
Letter
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Table 1 Multifunctionalization of 2,3-di-O-triflate 2
ido groups at C-2 and C-3 have the trans-diaxial relation-
ship. In its 13C NMR spectrum the resonances at δ = 61.0 and
58.5 ppm were assigned to C-2 and C-3, respectively.
X-ray data for compound 4 permitted unambiguous
confirmation of the proposed structure (Figure 1). However,
preliminary attempts for crystallizing compound 5 have
thus far been unsuccessful.
O
OMe
O
OMe
nucleophile
O
O
Tf2O/Py
3–7
CH2Cl2, 20 min, r.t.
Ph
O
OH
Ph
O
OTf
OH
OTf
1
2 (80%)
Entry Nucleophile and reaction Products
conditions
Yield (%)
O
OMe
O
Bu4NI (5 equiv), DMF,
1
27
60 °C, 15 h
Ph
Ph
O
3
O
OMe
N3
O
4
5
O
Bu4NN3 (4 equiv), THF,
r.t., 1 week
+
2
3
47 + 12
O
OMe
N3
O
O
Ph
Ph
O
O
N3
O
OMe
ethylenediamine
(excess), MeCN, 40 °C,
15 h
quant.
6
O
Notwithstanding the low yield (27%), compound 315 was
obtained under very mild conditions with Bu4NI in different
solvents. Firstly, the use of THF at room temperature in the
absence of light did not provide any reaction. After reflux
for 20 hours, a 6% yield of compound 3 resulted. Secondly,
by changing solvent (MeCN) and conditions (60 °C, 25 h),
the yield reached 15%. When compound 2 was dissolved in
DMF at reflux, the addition of Bu4NI gave the desired com-
pound 3 (27%, Table 1, entry 1) after 15 hours. No starting
material was recovered in any case and a darkening of the
mixture, probably due to decomposition of 2 in the reaction
conditions, was systematically observed. Characteristic ole-
finic protons were observed at δ = 6.08 (d, J2,3 = 10.5 Hz) and
5.75 ppm (J3,2 = 10.5, J3,4 = 2.5 Hz) and assigned to H-2 and
H-3, respectively.
Figure 1 ORTEP plots for compound 4. Hydrogen atoms are omitted.
Selected bond lengths (Å) and angles (°) are: O(4)–C(7) 1.415(3), N(1)–
N(2) 1.240(3), C(1)–C(2) 1.510(4), C(2)–C(3) 1.326(3), C(3)–C(4)
1.487(3), C(4)–C(5) 1.513(3), C(5)–C(6) 1.509(3), C(7)–O(4)-C(6)
111.71(19), N(3)–N(2)-N(1) 173.7(3), O(2)–C(1)–C(2) 112.4(2), C(3)–
C(2)–N(1) 126.5(3), C(3)–C(2)–C(1) 123.9(2), C(2)–C(3)–H(3) 120.7,
C(4)–C(3)–H(3) 120.7 (CCDC-1444060).
Reaction of 2 with ethylenediamine gave the unexpect-
ed 2-deoxy-3-oxo hexulose 617 in quantitative yield. Syn-
theses of 3-hexuloses often involve several steps as well as
an oxidation step. In this context, very simple reaction con-
ditions in only one step provides compound 6, a very useful
building block for accessing highly modified carbohydrate
derivatives. The formation of compound 6 is explained by
the amino derivative’s basic properties. Thus, ethylenedi-
amine promotes E2 elimination instead of a substitution
process. Subsequently, hydrolysis of triflate at C-3 and SiO2-
catalyzed keto-enol tautomerism would lead to 6. Further-
more, when the enol intermediate (detected by 1H NMR
spectroscopy) was purified by silica gel column chromatog-
raphy, quantitative transformation into the keto form oc-
curred. The structure is supported by spectroscopic data.18
In order to get a better insight into the role of the MeCN we
examined whether the rate of our reaction might be in-
creased under solvent-free conditions. In the absence of
MeCN the same results were achieved.
Reaction of the 2,3-di-O-triflate 2 with Bu4NN3 in THF at
room temperature gave 4 (47%)16 accompanied by the dia-
zide 5 (12%, Table 1, entry 2), easily separable by recrystalli-
1
zation from MeOH. The H NMR spectrum of unsaturated
azide 4 shows a very small coupling constant, J3,4 = 1.5 Hz
for H-3, resonating at δ = 5.67 ppm in CDCl3. Additionally,
an allylic small coupling constant J3,1 = 0.5 Hz was observed
in acetone-d6.
For D-altro diazide 5, the configuration was readily as-
signed from the low H-1–H-2 coupling constant (J1,2 = 0.5
Hz). Another noteworthy characteristic in the spectroscop-
ic data was that H-2 appeared as a double doublet with J2,1
=
0.5 Hz and J2,3 = 2.5 Hz. Thus, we concluded that the two az-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
A. Franconetti et al.
Letter
Synlett
For compounds 2–6, chemical stabilities have been eval-
uated by using the B3LYP hybrid functional at 6-31G (d,p)
level of theory.19 In addition, solvent effects have been con-
sidered with the IEPCM model. Different stabilities were
observed for compound 2 in different solvents studied. For
example, this compound is –1.6 kcal mol–1 more stable in
MeCN than in THF. Furthermore, based on charge distribu-
tion of compound 2, the C-2 position proved to be more
electrophilic than C-3. Arguably, C-2 in compound 2 could
react initially followed by the C-3 position. This characteris-
tic is the same for all solvents considered (DMF, MeCN, and
THF).
Table 2 Synthesis of Compounds 11–13
O
OMe
nucleophile
O
OMe
O
O
Tf2O/Py
CH2Cl2, 20 min, r.t.
11–13
Ph
O
OTf
Ph
O
OH
OBn
OBn
7
9 (89%)
Entry
1
Conditions
Products
Yield (%)
80
O
OMe
N3
O
Bu4NN3 (4 equiv),
THF, r.t., 1 week
Ph
O
OBn
11
In this context, evaluating the calculated energy of com-
pound 3 against starting compound 2 shows that 2 is more
stable than compound 3. In the case of compound 4, the ge-
ometry obtained by B3LYP 6-31G (d,p) is in agreement with
the X-ray diffraction data. A consideration of the energy dif-
ference, ΔE (E5 – E4) –103.4 kcal mol–1, permits an under-
standing the course of the reaction. The strained elimina-
tion product is less stable than compound 5 even though
the yield is higher for compound 4, probably due to attack
initially occurring at C-2 by SN2 reaction, followed by E2
elimination. As far as compound 3 is concerned, a presum-
ably trans-diaxial diiodide intermediate can directly elimi-
O
OMe
HO
Bu4NBr (3 equiv),
MeCN, reflux, 14 h
HO
Br
2
3
84
26
OBn
12
O
OMe
I
O
Bu4NI (3 equiv),
MeCN, reflux, 6 h
Ph
O
OBn
13
–
nate iodine by attack of an iodide ion forming I3 . In order to
investigate the structural and electronic requirements for
the above-described multifunctionalization, we have tested
tetrabutylammonium nucleophiles on compound 9 in
which the C-3 hydroxyl is blocked as a benzyl ether.
Compound 9 was obtained from 720 in 89% yield by
treatment with trifluoromethanosulfonic anhydride in a
pyridine–dichloromethane mixture. Triflate 9 was dis-
solved in THF under the same experimental conditions
used to obtain compounds 4 and 5. In this case, only the
substitution product 11 (80%)21 was obtained (Table 2).
Synthesis of compound 12 (84%, Table 2, entry 2)22 with
Bu4NBr is an example of a one-pot reaction involving two
steps: (a) bromination and (b) 4,6-O-benzylidene deprotec-
tion. The formation of the 2-bromo derivative was evi-
denced by two isotopes in the mass spectrum. Conforma-
tional analysis was realized in order to ensure the substitu-
tion pattern had the D-manno configuration. A 2D NOESY
experiment showed contacts for H-3/H-5 as expected (Fig-
ure 2, a). The position of the bromine is suggested based on
the absence of any H-2/H-4 NOE enhancement and a trans-
diaxial J2,3 value. In addition, the hydroxymethyl group is
now capable of free rotation around C-5/C-6 following
deprotection. The lack of the H-7 proton corresponding to
the CH of the benzylidene group, the H-5 multiplicity, and
respective lack of the H-4/H-6 NOE enhancement were di-
agnostic. Consequently in Figure 2 (b), on the basis of cou-
pling constant values, NOE enhancements and MM2 force
field calculations we suggest a possible conformation for
compound 12.
Figure 2 (a) NOE enhancements for compound 12. Theoretic distance
(Å) calculated for these protons are: 2.572 (H-3/H-5), 2.768 (H-5/H′),
2.233 (H-3/CHPh), 2.810 (H-2/CH′Ph). (b) Suggested conformer of
compound 12 from MM2 force field minimization energy, coupling con-
stant value, and NOEs observed.
Reaction of compound 9 with Bu4NI (3 equiv) in MeCN,
under reflux for six hours gave compound 1323 in poor yield
(26%), which is probably due to decomposition of the start-
1
ing triflate 9 under the reaction conditions. The H NMR
spectrum shows a resonance at δ = 5.68 ppm corresponding
to H-7. In summary, an SN2 process occurs in all cases using
tretabutylammonium nucleophiles when a benzyl ether is
used to block the C-3 hydroxyl as in compound 9.
Based on our previous experience,24 fluorination using
Et3N·3HF of the epimeric mixture of 9/10 obtained from re-
action of α+β diastereoisomers 7/8 with trifluoromethane-
sulfonic anhydride was carried out. An antiperiplanar dis-
position between C–OTf and C–O is required to enable the
oxygen exocyclic attack to C-2 position.
NMR analysis after column chromatography of the reaction
mixture showed that methyl β-D-glycoside 10 reacts selective-
ly with the fluorinating agent, while the α anomer 925 (26%
overall yield) is recovered after purification (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
A. Franconetti et al.
Letter
Synlett
O
OMe
OTf
O
OMe
OH
Tf2O/Py
O
O
CH2Cl2, 20 min
r.t.
Ph
O
Ph
O
OBn
OBn
9α + 10β (98%)
7α + 8β
Et3N⋅3HF
EtOAc
48 h., r.t.
O
F
O
OMe
O
OMe
F
O
O
O
+
complex
mixture
+
+
Ph
O
OMe
Ph
O
OTf
Ph
O
OBn
OBn
OBn
9 (26%)
15 (4%)
14 (7%)
Scheme 1 Fluorination reaction for epimeric mixture 9/10
Nucleophilic attack on C-2 of the β anomer by fluorine gives
1426 (7% overall yield; 14% from converted anomer) with
characteristic values of J1,F = 18.9, J2,F = 50.4, and J3,F = 26.4
Hz for D-manno fluorocompounds. A D-mannopyranosyl
fluoride product 15 (4% overall yield; 1% from converted
anomer) was detected showing a rearranged substitution
pattern. Anchimeric assistance of the methoxy group may
be proposed to explain this result from the α anomer. The
coupling-constant value J1,F = 49 Hz for H-1 (at δ = 5.29
the mild fluorinating agent employed may be efficiently
used to transform the 3-azido derivative 1728 into the 3-azi-
do-2-enopyranoside 19 (Scheme 2). Additionally, com-
pound 19 was obtained by reaction of 18 with tetrabu-
tylammonium fluoride in MeCN for one hour at room tem-
perature with a 78% yield.27 Noteworthy, in product 19, the
double bond formed becomes conjugated with the azido
group, that presumably being the reason of a ready elimina-
tion process. It has been argued that the strain associated
with the bicyclic systems, the less ready chair inversion and
possible torsion towards the unsaturated system, are key
aspects in this type of processes.29 In order to investigate
the intrinsic features which involve the participation of
group at C-3 position, 3-acetamide-D-allopyranoside
(22)27,30 was synthesized (Scheme 3).
ppm) is in the range for a pyranose ring. Moreover, the J1,2
=
0.7 Hz value is consistent with a trans-diequatorial disposi-
tion of H-1 and H-2 in this α-D-hexapyranosyl fluoride as
well as an inverted configuration at C-2.27 Other compounds
were obtained in the reaction mixture, but their spectra
were too complex to be analyzed.
The poor result of this reaction leads us to regard fluo-
rine as a nonselective nucleophile for stereocontrolled syn-
thesis of selectively functionalized products. Nevertheless,
Synthesis of compound 22 from the known methyl 3-
azido-2-O-benzoyl-4,6-O-benzylidene-3-deoxy-α-D-allopy-
ranoside (16)23 was performed in three steps involving pal-
O
OMe
OH
O
OMe
OTf
O
OMe
Tf2O/Py
Et3N⋅3HF
O
O
O
Et3N, EtOAc
30 h, 70 °C
10 min, 0 °C
Ph
O
Ph
O
Ph
O
N3
N3
N3
18 (88%)
19a (87%)
17
NaOMe
MeOH, 30 min, r.t.
O
OMe
O
OMe
OH
O
O
Ph
O
OBz
Ph
O
N3
NHAc
16
22 (85%)
NaOMe
MeOH, 30 min, r.t.
H2,Pd/C
MeOH, 30 min, r.t.
O
OMe
O
OMe
OBz
Ac2O
O
O
Py, DMAP
24 h, 4 °C
Ph
O
OBz
Ph
O
NH2
NHAc
20 (quant.)
21 (90%)
Scheme 2 Efficient transformation of 3-azido-α-D-allopyranoside 18 into the unsaturated 3-azido derivative 19 and synthesis of 3-acetamide allopyra-
noside 22 in three steps. a Compound 19 (78%) was also obtained by reaction of 18 with Bu4NF in MeCN for 1 h at r.t.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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A. Franconetti et al.
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O
OMe
OH
O
OMe
OTf
O
OMe
Tf2O/Py
O
Et3N⋅3HF
O
O
Et3N, EtOAc
30 h, 70 °C
CH2Cl2, 20 min, 0 °C
Ph
O
Ph
O
Ph
O
NHAc
NHAc
NHAc
22
23 (91%)
24 (90%)
Scheme 3 Preparation of unsaturated 3-acetamido derivative 24 by reaction with Et3N·3HF
ladium-catalyzed hydrogenation in MeOH followed by
acetylation with acetic anhydride and deprotection of the
2-O-benzoyl group with 1 M NaOMe in MeOH (Scheme 2).
Reaction of this 3-acetamide-2-hydroxyglycopyrano-
side 22 with trifluoromethanosulfonic anhydride in a pyri-
dine–dichloromethane mixture gave the triflate 23 in good
yield (91%). This was dissolved in EtOAc and treated with
Et3N·3HF under the same experimental conditions used to
obtain compound 19. In this case, the elimination product,
methyl 3-acetamide-4,6-O-benzylidene-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (24),21,27 was obtained in 90%
yield. These results can be rationalized by taking into ac-
count that β-elimination occurs when the triflate on C-2
can adopt an antiperiplanar disposition with the hydrogen
at position 3, as in compounds 18 and 23, but not in 9/10.
In conclusion, diverse functionalizations of substituted
2-hydroxyglycopyranosides can be carried out by means of
a two-step process involving trifluoromethanesulfonation
and subsequent treatment with an appropriate nucleophile.
The 2,3-enopyranosides, 2- and/or 3-azido-, 2-halopyrano-
sides, and even a hex-3-ulose, among other α- and β-glyco-
pyranosides are readily obtained in good to excellent yields.
These transformations could be considered as ‘adaptable
sequence tools’ suitable to facilitate access to further syn-
thetic targets.
(5) Franconetti, A.; Jatunov, S.; Borrachero, P.; Gómez-Guillén, M.;
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(18) Preparation and More Relevant Data of Compound 6
Compound 2 (100 mg, 0.18 mmol) was dissolved in MeCN (5
mL). Large excess of ethylenediamine (1.04 mL, 15.51 mmol)
was added. The mixture was heated to 40 °C for 15 h. The solu-
tion was diluted with CH2Cl2 (20 mL). The organic layer was
successively extracted with iced H2O (3 × 20 mL), sat. NaHCO3 (2
× 20 mL), dried over Na2SO4, and concentrated to afford, after
column chromatography (EtOAc–hexane, 1:2), the uloside 6 in
The authors thank to Dr. S. Jatunov for his contribution to the synthe-
sis of compound 24. The authors also thank the Junta de Andalucía
(FQM 142 and Project P09-AGR-4597) for financial support.
References and Notes
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Romero, A.; Roy, R.; Smetana, K. Jr.; Gabius, H. J. Biochim. Bio-
phys. Acta 2015, 1850, 186. (b) Cabezas, Y.; Legentil, L.; Robert-
Gangneux, F.; Daligault, F.; Belaz, S.; Nugier-Chauvin, C.;
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Biomol. Chem. 2015, 13, 8393.
quantitative yield. Rf = 0.18 (EtOAc–hexane, 1:2). IR: νmax
2918, 1732 (CO), 1455 cm–1 1H NMR (500 MHz, CDCl3): δ =
7.52–7.35 (m, 5 H, Ph), 5.59 (1 H, s, H-7), 5.14 (1 H, d, J1,2 = 4.7
Hz, H-1), 4.38 (1 H, dd, J6eq 5 = 4.8 Hz, J6eq 6ax = 10.3 Hz, H-6eq),
4.31 (1 H, dd, J4,2′ = 0.7 Hz, J4,5 = 9.9 Hz, H-4), 4.16 (1 H, dt, J5,6eq
4.9 Hz, J5,6ax = 10.1 Hz, H-5), 3.92 (1 H, t, J6ax 6eq = J6ax,5 =10.2 Hz,
=
.
,
,
=
,
H-6ax), 3.87 (3 H, s, OMe), 2.84 (1 H, ddd, J2′,1 = 5.0 Hz, J2′,2 = 14.6,
J2′,4 = 1.0 Hz, H-2′), 2.68 (1 H, d, J2,2′ = 14.6 Hz, H-2). 13C NMR
(125.7 MHz, CDCl3): δ = 197.5 (CO), 136.7, 129.5, 128.4, 126.6
(4) Jatunov, S.; Franconetti, A.; Prado-Gotor, R.; Heras, A.;
Mengíbar, M.; Cabrera-Escribano, F. Carbohydr. Polym. 2015,
123, 288.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
A. Franconetti et al.
Letter
Synlett
(Ph), 102.4 (C-7), 100.8 (C-1), 83.3 (C-4), 69.7 (C-6), 65.3 (C-5),
55.1 (OCH3), 46.7 (C-2). HRMS (CI): m/z calcd for C14H17O5 [M +
H]+: 265.1076; found: 265.1071.
3.57 (3 H, s, OMe), 3.39 (1H, dt, J5,6eq = 4.9 Hz, J5,6ax = 9.6 Hz, H-
5). 13C NMR (125.7 MHz, CDCl3): δ = 134.6, 129.9, 129.2, 128.9,
128.6, 128.4, 128.1, 126.2 (Ph), 101,8 (C-7), 101.6 (J1,F = 16 Hz,
C-1), 86.2 (J2,F = 188.7 Hz, C-2), 78.5 (C-4), 75.8 (J3,F = 25.7 Hz, C-
3), 71.7 (CH2Ph), 68.7 (C-6), 67.3 (C-5), 57.6 (OCH3), 50.1 (C-2).
HRMS (CI): m/z calcd for C21H23O5F [M]+: 374.1530; found:
374.1527.
(19) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A. Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam,
J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision C.01; Gaussian, Inc: Wallingford CT, 2009.
Compound 15: Rf = 0.67 (EtOAc–hexane, 1:4). 1H NMR (500
MHz, CDCl3): δ = 7.49–7.34 (10 H, m, Ph), 5.60 (1 H, s, H-7), 5.29
(1 H, dd, J1,F = 49.3, J1,2 = 0.8 Hz, H-1), 4.89 and 4.75 (2 H, 2 d,
JH,H′ = 12.4 Hz, CH2Ph), 4.36 (1 H, dd, J6eq,5 = 5.0 Hz, J6eq 6ax
Hz, H-6eq), 4.16 (1 H, t, J4,3 = J4,5 = 9.6 Hz, H-4), 3.93 (1 H, t, J6ax 6eq
= J6ax,5 = 10.3 Hz, H-6ax), 3.76 (1 H, m, H-2), 3.67 (4 H, s and m,
,
= 10.5
,
OMe and H-3, respectively), 3.39 (1 H, dt, J5,6eq = 4.9 Hz, J5,6ax
=
9.6 Hz, H-5).
Compound 18: Rf = 0.47 (EtOAc–hexane, 3:1). IR: νmax = 2114
(N3), 1375, 1141 (SO2), 974 (CF) cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.49–7.27 (5 H, m, Ph), 5.58 (1 H, s, H-7), 4.90 (1 H, d,
J1,2 = 4.1 Hz, H-1), 4.86 (1 H, dd, J2,3 = J2,1 = 4.1 Hz, H-2), 4.47 (1
H, dd, J3,4 = 3.5 Hz, H-3), 4.37 (1 H, dd, J6ax 6eq
5.2 Hz, H-6eq), 4.25 (1 H, ddd, J4,5 = J5,6ax = 9.9 Hz, H-5), 3.78 (1 H,
dd, J4,3 = 3.5 Hz, J4,5 = 9.9 Hz, H-4), 3.74 (1 H, dd, J6ax 6eq = 10.3 Hz,
J6ax 5
= 9.9 Hz, H-6ax), 3.51 (3 H, s, OMe). 13C NMR (125.7 MHz,
,
= 10.3 Hz, J6eq,5 =
(20) Fleet, G. W.; Gough, M. J.; Shing, T. K. M. Tetrahedron Lett. 1984,
25, 4029.
(21) Walvoort, M. T. C.; Lodder, G.; Overkleeft, H. S.; Codée, J. D. C.;
van der Marel, G. A. J. Org. Chem. 2010, 75, 7990.
,
,
CDCl3): δ = 136.5–126.3 (Ph), 118.5 (q, JC,F = 319.7, CF3), 102.2
(C-7), 97.2 (C-1), 78.3 (C-2), 77.5 (C-4), 68.8 (C-6), 59.4 (C-3),
58.1 (C-5), 56.8 (OCH3). HRMS (CI): m/z calcd for C15H17F3N3O7S
[M + H]+: 440.0739; found: 440.0748.
Compound 19: Rf = 0.47 (EtOAc–hexane, 1:4). IR: νmax = 2116
(N3), 1651 (C=C) cm–1. 1H NMR (500 MHz, acetone-d6): δ = 7.51–
7.34 (5 H, m, Ph), 5.77 (1 H, s, H-7), 5.31 (1 H, dd, J2,1 = 3.0 Hz, J2,4
= 2.0 Hz, H-2), 5.03 (1 H, dd, J1,2 = 3.0 Hz, J1,4 = 1.0 Hz, H-1),
(22) Preparation of Compound 12
To a solution of compound 9 (109 mg, 0.22 mmol) in MeCN (10
mL) was added Bu4NBr (310 mg, 0.65 mmol) at r.t. The mixture
was heated to reflux for 14 h, and then the solvent was removed
under reduced pressure. The residue was purified by column
chromatography (EtOAc–hexane, 3:1) to afford compound 12
(64 mg, 84%) as a syrup.
Rf = 0.69 (EtOAc–hexane, 3:1). IR: νmax = 3412 (OH), 2929, 2358,
4.58–4.55 (1 H, m, H-5), 4.29 (1 H, dd, J6eq,6ax = 8.7 Hz, J6eq,5 = 3.2
1
740 (CBr) cm–1. H NMR (500 MHz, CDCl3): δ = 7.40–7.32 (5 H,
Hz, H-6eq), 3.96–3.89 (2 H, m, H-4 and H-6ax), 3.39 (3 H, s, OMe).
13C NMR (125.7 MHz, acetone-d6): δ = 138.8 (C-3), 138.5-127.0
(Ph), 111.9 (C-2), 102.6 (C-7), 97.3 (C-1), 75.8 (C-5), 69.5 (C-6),
65.0 (C-4), 55.8 (OCH3). HRMS–FAB: m/z calcd for C14H15N3O4 +
Na [M]+: 312.0960; found: 312.0955.
m, Ph), 4.98 (1 H, d, J1,2= 1.2 Hz, H-1), 4.71 and 4.46 (2 H, 2d, JH,H′
= 11.3 Hz, CH2Ph), 4.38 (1 H, dd, J2,1 = 1.3 Hz, J2,3 = 3.8 Hz, H-2),
3.99 (1 H, t, J4,3 = J4,5 = 9.4 Hz, H-4), 3.85 (2 H, dt, J6eq 6ax
11.8 Hz, J6eq,5 = 3.6 Hz, H-6eq and H-6ax), 3.75 (1 H, dd, J3,2 = 3.8
Hz, J3,4 = 9.0 Hz, H-3), 3.70 (1 H, m, H-5), 3.38 (3 H, s, OMe). 13
,
= J6ax,5 =
1
C
Compound 22: Yield 85% (112 mg). H NMR (500 MHz, CDCl3):
NMR (125.7 MHz, CDCl3): δ = 137.4, 128.7, 128.3, 128.2 (Ph),
101.6 (C-1), 76.8 (C-3), 72.5 (CH2Ph), 71.0 (C-5), 67.1 (C-4), 62.7
(C-6), 54.4 (OCH3), 50.1 (C-2). HRMS (CI): m/z calcd for calcd for
δ = 7.63–7.33 (5 H, m, Ph), 6.32 (1 H, d, JH,3 = 9.1 Hz, NH), 5.56 (1
H, s, H-7), 4.92 (1 H, m, H-3), 4.74 (1 H, d, J1,2 = 3.5 Hz, H-1), 4.33
(1 H, dd, J4,3 = 4.2 Hz, J4,5 = 9.7 Hz, H-4), 3.87 (1 H, t, J2,1 = J2,3 =
C
14H19O5Br79 and C14H19O5Br81 [M]+: 346.0416 and 348.0395;
4.0 Hz, H-2), 3.80 (1 H, m, H-5), 3.76 (1 H, t, J6ax 6eq
Hz, H-6ax), 3.66 (1 H, dd, J6eq 5 = 4.0 Hz, J6eq 6ax = 9.4 Hz, H-6eq),
3.49 (3 H, s, OMe), 2.06 (3 H, s, COMe).
,
= J6ax,5 = 10.1
found: 346.0413 and 348.0397, respectively.
(23) Vatèle, J.-M.; Hanessian, S. Tetrahedron 1996, 52, 10557.
(24) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Gómez-
Guillén, M. Tetrahedron: Asymmetry 2005, 16, 889.
(25) Cumpstey, I.; Ramstadius, C.; Akhtar, T.; Goldstein, I. J.; Winter,
H. C. Eur. J. Org. Chem. 2010, 10, 1951.
,
,
Compound 24: Rf = 0.58 (EtOAc–hexane, 2:1). 1H NMR (500
MHz, CDCl3): δ = 8.21 (1 H, br s, NHAc), 7.52–7.37 (5 H, m, Ph),
5.46 (1 H, t, J2,1 = J2,4 = 2.3 Hz, H-2), 5.67 (1 H, s, H-7), 5.03 (1 H,
dd, J1,2 = 3.0 Hz, J1,4 = 0.7 Hz, H-1), 4.23 (2 H, m, H-4 and H-6eq),
3.90 (1 H, dt, J5,6eq = 4.4 Hz, J5,6ax = 10.4 Hz, H-5), 3.84 (1 H, t,
(26) Luxen, A.; Satyamurthy, N.; Vida, G. T.; Barrio, J. R. Int. J. Radiat.
Appl. Instrum. A 1986, 37, 409.
J6ax 6eq = J6ax,5 = 10.4 Hz, H-6ax), 3.38 (3 H, s, OMe). HRMS (CI):
,
(27) Representative Analytical Data
m/z calcd for C16H19NO5 [M]+: 305.1263; found: 305.1260.
(28) Baer, H. H.; Gan, Y. Carbohydr. Res. 1991, 210, 233.
(29) (a) Oberg, C. T.; Noresson, A. L.; Delaine, T.; Larumbe, A.; Tejler,
J.; von Wachenfeldt, H.; Nilsson, U. J. Carbohydr. Res. 2009, 344,
1282. (b) Dong, H.; Zhou, Y.; Pan, X.; Cui, F.; Liu, W.; Liu, J.;
Ramström, O. J. Org. Chem. 2012, 77, 1457.
Compound 14: Rf = 0.46 (EtOAc–hexane, 1:4).
In agreement with literature data.26 1H NMR (500 MHz, CDCl3):
δ = 7.51–7.29 (10 H, m, Ph), 5.67 (1 H, s, H-7), 4.87 and 4.78 (2
H, 2d, JH,H′ = 12.3 Hz, CH2Ph), 4.79 (1 H, dd, J2,F = 50.4 Hz, J2,3
2.5 Hz, H-2), 4.42 (1 H, d, J1,F = 18.9 Hz, H-1), 4.36 (1 H, dd,
J6eq,5 = 5.0 Hz, J6eq 6ax = 10.5 Hz, H-6eq), 4.11 (1 H, dt, J4,F = 1.8 Hz,
J4,3 = J4,5 = 9.8 Hz, H-4), 3.91 (1 H, t, J6ax 6eq = J6ax,5 = 10.3 Hz, H-
ax), 3.67 (1 H, ddd, J3,F = 26.4 Hz, J3,2 = 2.5 Hz, J3,4 = 9.9 Hz, H-3),
=
,
(30) Komarova, B. S.; Maryasina, S. S.; Tsvetkov, Y. E.; Nifantiev, N. E.
Synthesis 2013, 45, 471.
,
6
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F