Approach to the valorization of carbohydrates as raw materials by microwave-assisted neat 1,3-dipolar cycloaddition

Article abstract of DOI:10.1080/00397910903019959

By reaction of C,N-diphenylnitrone and carbohydrates with a crotonyl side chain at their primary or anomeric carbon position, we explore the application of sugar derivatives as raw materials and chiral inducers in microwave-assisted neat 1,3-dipolar cycloadditions.

Full text of DOI:10.1080/00397910903019959

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Approach to the Valorization of
Carbohydrates as Raw Materials by
Microwave-Assisted Neat 1,3-Dipolar
Cycloaddition
Marta M. Andrade a , Maria Teresa Barros a & Rui C. Pinto a
a REQUIMTE, CQFB, Departamento de Química, Faculdade de
Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica,
Portugal
Version of record first published: 22 Feb 2010.
To cite this article: Marta M. Andrade, Maria Teresa Barros & Rui C. Pinto (2010): Approach to the
Valorization of Carbohydrates as Raw Materials by Microwave-Assisted Neat 1,3-Dipolar Cycloaddition,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:6, 855-860
To link to this article: http://dx.doi.org/10.1080/00397910903019959
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Synthetic Communications1, 40: 855–860, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903019959
APPROACH TO THE VALORIZATION OF
CARBOHYDRATES AS RAW MATERIALS BY
MICROWAVE-ASSISTED NEAT 1,3-DIPOLAR
CYCLOADDITION
Marta M. Andrade, Maria Teresa Barros, and Rui C. Pinto
´
REQUIMTE, CQFB, Departamento de Quımica, Faculdade de Ciencias
e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal
ˆ
By reaction of C,N-diphenylnitrone and carbohydrates with a crotonyl side chain at their
primary or anomeric carbon position, we explore the application of sugar derivatives as
raw materials and chiral inducers in microwave-assisted neat 1,3-dipolar cycloadditions.
Keywords: Carbohydrate; chiral auxiliary; 1,3-dipolar cycloaddition; microwave; neat reaction
INTRODUCTION
Cycloaddition reactions employing conventional methodologies usually
require the use of harsh reaction condition. Consequently, these reactions rapidly
became suitable candidates for studies using microwave (MW) irradiation.[1–3] In
particular, 1,3-dipolar cycloaddition (1,3-DC) is one of the most important methods
for the construction of five-membered heterocyclic rings.[4] Several dipolarophiles
have been used, such as nitrones, azides, and nitrile oxides, among many others.[5,6]
By the application of chiral starting materials, it is often possible to control
regioselectivity, endo=exo selectivity, and diasterofacial selectivity in these reactions.
Carbohydrates are good candidates in this practice[7–12] because they are highly
functionalized molecules with complex stereochemistry resulting from the presence
of several chiral centers. Sugars also constitute a suitable renewable source in organic
synthesis: antibiotics, nucleotides, and several other optically pure noncarbohydrate
natural products can be synthesized from these natural precursors.
RESULTS AND DISCUSSION
During our previous studies,[13] we applied MW-assisted neat procedures for
the synthesis of a library of open-chain nitrones and isoxazolidines. As a continu-
ation of our interest in the selective derivatization of sugars with unsaturated
Received April 9, 2009.
Address correspondence to Maria Teresa Barros, REQUIMTE, CQFB, Departamento de
´
Quımica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica,
Portugal. E-mail: mtbarros@dq.fct.unl.pt
ˆ
855

856
M. M. ANDRADE, M. T. BARROS, AND R. C. PINTO
moieties,[14] we envisaged the possibility of applying 1,3-DC for the construction of
asymmetric isoxazolidines using carbohydrates as chiral auxiliaries. The presence of
the optically pure carbohydrate moiety has also the advantage of producing only
diastereoisomers, which we are able to distinguish by analytical and spectroscopical
analyses.
With this purpose, some crotonyl sugars were synthesized by applying
the methodology described previously,[14] which were then reacted with C,N-
diphenylnitrone under MW irradiation in neat conditions, producing optically active
isoxazolidines.
Cycloaddition to the crotonyl moiety located at the primary carbon position of
glucose derivative 1 (Scheme 1) afforded two major diastereoisomeric products, 3
and 4, in yields of more than 90%; cycloadducts 3 show a 3,4-trans-4,5-trans relation-
ship at the heterocyclic ring, whereas 4 are 3,4-cis-4,5-trans. The ratio observed was
1
3=4 of 87:13. The H NMR spectrum indicated the presence of two diasteriomeric
products 3a and 3b, but their ratio could not be measured because of overlapping
peaks.
Similar results were obtained at the a-anomeric position of glucose (2,
Scheme 1) with the ratio 5=6 of 90:10. For this derivative, it was possible to measure
the ratio of the endo products 5a=5b as 66:44. In terms of yield and 3,4-trans-4,5-
trans:3,4-cis-4,5-trans ratio, these results are similar to those found for analogous
cycloaddition without the carbohydrate moiety,[15] but the sugar does seem to confer
some facial selectivity to the reaction.
For xylose derivatives, different results were achieved when comparing both a
and b anomers (Scheme 2). For the b-anomer (7), the ratio obtained for 9=10 could
not be accurately determined because of some overlapping of signals. The two dia-
stereoisomers, 9a and 9b, show a ratio of 57:43, denoting a minor facial selectivity
when compared to the analogous anomer of glucose. However, when the a-anomer
of xylose (8) was treated with C,N-diphenylnitrone, we could only detect the
Scheme 1. MW-neat cycloadditon using crotonyl-glucose derivatives.

1,3-DIPOLAR CYCLOADDITION APPLIED TO SUGARS
857
Scheme 2. MW-neat cycloaddition using crotonyl-xylose derivatives.
presence of isoxazolidine isomers 11, and the facial selectivity is improved to the
ratio 11a=11b of 81:19. This result is promising for further exploration the chiral
assistance of the a-isomers of monosaccharides.
The previous sugar derivatives can also be interesting for biological studies
after removal of all protecting groups, producing isoxazolidines linked to a hydro-
philic moiety.
Furthermore, the results obtained are promising for the use of carbohydrates
as chiral assistants in the asymmetric synthesis of isoxazolidines. By changing the
unsaturated side chain in the carbohydrate moiety, we can synthesize a library of
novel isoxazolidines linked to sugars at different carbon positions. Disaccharides,
such as sucrose, are also excellent candidates for these reactions.[14]
In summary, the present study represents a potential and efficient methodology
for obtaining optically active isozazolidines, by MW-assisted synthesis, in the
absence of catalyst or solid supports.
EXPERIMENTAL
General Procedures
All solvents were purified before use. All reactions were monitored by
thin-layer chromatography (TLC), which was performed on aluminium-backed
silica-gel Merck 60 F254 plates, and compounds were detected by ultraviolet (UV)
light or by staining with 10% solution of H2SO4 in ethanol followed by heating.
Flash chromatography was carried out using silica gel from Macherey-Nagel
(Kieselgel 60 M). Preparative-layer chromatography was performed on glass plates
coated with 1 mm of silica gel (Mackerey-Nagel, Kieselgel DGF254). Elemental
analyses were performed on a Thermo Finnigan-CE Flash EA 1112 CHNS series
analyzer. NMR spectra were recorded on a Bruker AMX 400-MHz apparatus in
CDCl3, using tetramethylsilane (TMS) as internal standard, with chemical shift
values (d) in parts per million (ppm). Structural assignment of all new compounds

858
M. M. ANDRADE, M. T. BARROS, AND R. C. PINTO
was made by bi-dimensional NMR techniques (correlation spectroscopy 45, hetero-
nuclear multiple quantum correlation, nuclear overhauser effect spectroscopy, total
correlation spectroscopy). Microwave experiments were conducted in a Milestone
MicroSynth apparatus. Temperatures were measured at the surface of the vessel with
a built-in contactless infrared (IR) sensor which provides a ꢀ1ꢁC precision (accord-
ing to the manufacturer).
Synthesis of Carbohydrate-Derived Isoxazolidines—General Method
Glucose and xylose derivatives were synthesized as described in a previous
work.[14] Then 0.1 g (1 equiv.) of sugar derivative and 1.2 equiv. of nitrone were
placed in an open flask. The heterogeneous solid mixture was positioned in the center
of the MW cavity, over a Weflon-made support provided by the manufacturer, and
irradiated for 30 min at 300 W. Reactions were monitored by thin-layer chromato-
graphy (TLC). After completion, products were purified by preparative-layer
chromatography with the eluent indicated for each case.
Methyl 2,3,4-Tri-O-acetyl-6-O-[30RS-(30Rꢂ,40Sꢂ,50Rꢂ)-20,30-di-phenyl-
50-methyl-isoxazolidin-40-yl]-a-D-glucopyranoside (3) and Methyl
2,3,4-Tri-O-acetyl-6-O-[30RS-(30Rꢂ,40Rꢂ,50Sꢂ)-20,30-di-phenyl-50-methyl-
isoxazolidin-40-yl]-a-D-glucopyranoside (4)
Eluent: ether–hexane 2:1, 135.7 mg, 90%, colorless oil. Ratio 3:4 ¼ 87:13. Anal.
calcd. for C30H35NO11: C, 61.53; N, 2.39; H, 6.02. Found: C, 61.58; N, 2.28; H, 6.20.
1
Compound 3: H NMR (400 MHz, CDCl3): d 1.54 (‘‘fake’’ t, J ¼ 5.9 Hz, 3H,
CH3(isox)), 2.00, 2.02, 2.08 (3 s, 3 ꢃ 3H, 3 ꢃ CH3), 3.21–3.27 (m, 1H, H-40), 3.29 (s,
3H, OCH3), 3.93 (td, J ¼ 10.2, 3.5 Hz, 1H, H-5), 4.18 (t, J ¼ 4.8 Hz, 2H, H-6),
4.41–4.52 (m, 1H, H-50), 4.77 (dd, J ¼ 10.2, 3.5 Hz, 1H, H-2), 4.85–4.91 (m, 2H,
H-1, H-4), 5.20 (d, J ¼ 6.7 Hz, 1H, H-30), 5.44 (t, J ¼ 9.8 Hz, 1H, H-3), 6.92 (t,
J ¼ 7.3 Hz, 1H, NPh-H), 7.00 (dd, J ¼ 7.8, 4.1 Hz, 2H, NPh-H), 7.29 (m, 4H, NPh-
H, Ph-H), 7.39 (t, J ¼ 7.6 Hz, 2H, Ph-H), 7.56 (t, J ¼ 8.2 Hz, 2H, Ph-H). 13C
NMR (100 MHz, CDCl3): d 17.4 (CH3(isox)), 20.5, 20.6 (CH3), 55.3 (OCH3), 62.7
(C-6), 65.4 (C-40), 66.8 (C-5), 68.5 (C-4), 69.8 (C-3), 70.6 (C-2), 73.2 (C-30), 77.5
(C-50), 96.5 (C-1), 113.9, 121.4, 127.6, 128.8, 128.9, 141.7, 151.4 (C-Ar), 169.4,
=
169.9 (C O(Ac)), 170.0, 170.1 (isox-C O).
=
1
Compound 4: Detected in the isomeric mixture by H NMR analysis (only
some peaks are distinguishable). 1H NMR (400 MHz, CDCl3): d 1.48 (d, J ¼ 6.1 Hz,
Hz, 3H, CH3(isox)), 4.79–4.85 (m, 2H, H-30, H-50).
1-O-[30RS-(30Rꢂ,40Sꢂ,50Rꢂ)-20,30-Di-phenyl-5-methyl-isoxazolidin-40-yl]-
2,3,4,6-tetra-O-acetyl-b-D-glucopyranose (5) and 1-O-[30RS-
(30Rꢂ,4’Rꢂ,50Sꢂ)-20,30-Di-phenyl-50-methyl-isoxazolidin-40-yl]-
2,3,4,6-tetra-O-acetyl-b-D-glucopyranose (6)
Eluent: ether–hexane 1:2, 132.6 mg, 90%, colorless oil. Ratio 5:6 ¼ 90:10. Anal.
calcd. for C31H35NO12: C, 60.68; N, 2.28; H, 5.75. Found: C, 60.49; N, 2.12; H, 5.96.

1,3-DIPOLAR CYCLOADDITION APPLIED TO SUGARS
859
Compound 5: 1H NMR (400 MHz, CDCl3): d 1.52 (d, J ¼ 6.0 Hz, 3H, CH3(isox
minor)), 1.55 (d, J ¼ 5.9 Hz, 3H, CH3(isox major)), 1.90 (s, 3H, CH3(major)), 1.93 (s, 3H,
CH3(minor)), 2.01 (s, 6H, 2 ꢃ CH3(Ac)), 2.03 (s, 6H, 2 ꢃ CH3(Ac)), 2.04 (s, 3H, CH3(Ac,
major)), 2.05 (s, 3H, CH3(Ac, minor)), 3.24 (dd, J ¼ 8.8, 6.8 Hz, 1H, H-40(major)), 3.30 (dd,
J ¼ 8.6, 6.3 Hz, 1H, H-40(minor)), 3.77–3.85 (m, 2H, H-5), 4.17 (ddd, J ¼ 12.6, 10.1,
4.7 Hz, 2H, H-6(major)), 4.21–4.37 (m, 3H, H-50(minor), H-6(minor)), 4.51 (dq, J ¼ 8.9,
5.9 Hz, 1H, H-50(major)), 5.04–5.28 (m, 8H, H-3, H-30, H-2, H-4), 5.70 (d, J ¼ 8.2 Hz,
Hz, 1H, H-1(major)), 5.71 (d, J ¼ 8.0 Hz, 1H, H-1(minor)), 6.88–7.03 (m, 6H, NPh-H),
7.19–7.34 (m, 6H, Ph-H), 7.34–7.42 (m, 4H, NPh-H), 7.47–7.55 (m, 4H, Ph-H). 13C
NMR (100 MHz, CDCl3): d 17.6, 17.7, (CH3(isox)), 20.4, 20.5, 20.7 (CH3), 61.3 (C-6),
65.1 (C-40), 67.7 (C-4), 70.0 (C-2), 72.6, 72.8, 73.2 (C-3, 30, 5), 77.3 (C-50), 92.2 (C-1),
114.0, 114.11, 115.8 121.7, 126.4, 127.8, 129.0, 141.3, 141.4, 151.0, 151.2 (C-Ar),
=
168.8, 168.9, 169.3 (C O(Ac)), 170.0, 170.5 (isox-C O).
=
1
Compound 5: Detected in the isomeric mixture by H NMR analysis (only
some peaks are distinguishable). 1H NMR (400 MHz, CDCl3): d 1.46 (d, J ¼ 6.0 Hz,
Hz, 3H, (CH3(isox)), 3.33 (t, J ¼ 9.7 Hz, 1H, H-40(minor)), 3.39 (t, J ¼ 9.57 Hz, 1H,
H-40(major)).
1-O-[30RS-(30Rꢂ,40Sꢂ,50Rꢂ)-20,30-Di-phenyl-50-methyl-isoxazolidin-
40-yl]-2,3,4-tri-O-benzoyl-b-D-xylopyranose (9) and 1-O-[30RS-
(30Rꢂ,40Rꢂ,50Sꢂ)-20,30-Di-phenyl-50-methyl-isoxazolidin-40-yl]-2,3,4-tri-
O-benzoyl-b-D-xylopyranose (10)
Eluent: ether–hexane 1:2, colorless oil, 116.6 mg, yield 85%. Anal. calcd. for
C43H37NO10: C, 70.97; N, 1.92; H, 5.12. Found: C, 70.99; N, 1.81; H, 5.44.
Compound 9: 1H NMR (400 MHz, CDCl3): d 1.31 (d, J ¼ 5.0 Hz, 3H, CH3(isox,
minor)), 1.45 (d, J ¼ 5.1 Hz, 3H, CH3(isox, major)), 3.18 (t, J ¼ 7.2 Hz, 2H, H-40), 3.80 (dd,
J ¼ 11.7, 7.2 Hz, 1H, H-5(major)), 4.33 (m, 2H, H-5(minor), H-50), 4.48 (m, 1H, H-50),
5.09 (d, J ¼ 6.1 Hz, 1H, H-30(major)), 5.16 (d, J¼6.3 Hz, 1H, H-5(minor)), 5.33 (m, 2H,
H-4), 5.46 (m, 2H, H-2), 5.79 (m, 2H, H-3), 6.07 (d, J ¼ 5.2 Hz, 2H, H-1), 6.89 (t,
J ¼ 8.4 Hz, 6H, 6 ꢃ NPh-H), 7.22 (m, 10H, 4 ꢃ NPh-H, 6 ꢃ Ph-H), 7.38 (m, 16H,
4 ꢃ Ph-H, 12 ꢃ Bz-H), 7.52 (m, 6H, 6 ꢃ Bz-H), 7.95 (2d, J ¼ 7 and J ¼ 7.4 Hz, 12H,
12 ꢃ Bz-H). 13C NMR (100 MHz, CDCl3): d 17.3, 17.5 (CH3), 62.6 (C-5), 62.2
(C-40(major)), 65.5 (C-40(minor)), 68.6 (C-4), 69.1 (C-2(minor)), 69.2 (C-2(major)), 69.9
(C-3(minor)), 70.1 (C-3(major)), 77.5 (C-50(major)), 77.7 (C-50(minor)), 97.7 (C-1), 113.9,
114.1, 121.7, 126.1, 126.3, 127.7, 127.8, 128.5, 128.7, 128.8, 129.0, 129.8, 130.0,
=
133.6, 141.3, 151.1 (C-Ar), 164.9, 165.2, 165.5 (C O(Ac)), 169.0, 169.1 (isox-C O).
=
1-O-[30RS-(30Rꢂ,40Sꢂ,50Rꢂ)-20,30-Di-phenyl-50-methyl-isoxazolidin-
40-yl]-2,3,4-tri-O-benzoyl-a-D-xylopyranose (11)
Eluent: ether–hexane 1:2, colorless oil, 123.5 mg, yield 90%. Anal. calcd. for
1
C43H37NO10: C, 70.97; N, 1.92; H, 5.12. Found: C, 70.78; N, 1.93; H, 5.34. H NMR
(400MHz, CDCl3): d 1.53 (d, J ¼ 6.0 Hz, 3H, CH3(isox major)), 1.57 (d, J ¼ 6.0 Hz, 1H,
CH3(isox minor)), 3.33 (m, 2H, H-40), 3.47 (m, 1H, H-5a(minor)), 3.57 (t, J ¼ 10.9Hz,
1H, H-5a(major)), 4.13 (m, 2H H-5b), 4.38 (qd, J ¼ 9.4, 6.0 Hz, 1H, H-50(minor)), 4.54
(qd, J ¼ 8.8, 6.0 Hz, 1H, H-50(major)), 5.07 (d, J ¼ 6.4 Hz, 1H, H-30(major)), 5.24

860
M. M. ANDRADE, M. T. BARROS, AND R. C. PINTO
(d, J ¼ 6.6 Hz, 1H, H-30(minor)), 5.43 (m, 4H, H-2, H-4), 6.00 (t, J ¼ 10.0Hz, 1H,
H-3(minor)), 6.06 (t, J ¼ 9.9 Hz, 1H, H-3(major)), 6.58 (d, J ¼ 3.8 Hz, 1H, H-1(minor)),
6.59 (d, J ¼ 3.6 Hz, 1H, H-1(major)), 7.03–6.78 (m, 6H, 6 ꢃ NPh-H), 7.66–7.11 (m,
32H, 4 ꢃ NPh-H, 10ꢃ Ph-H, 18ꢃ Bz-H), 7.92 (m, 12H, 12 ꢃ Bz-H). 13C NMR
(100MHz, CDCl3): d 17.2 (CH3), 60.9 (C-5), 65.5 (C-40), 68.7 (C-4), 69.0 (C-2), 69.9
(C-3), 73.4 (C-50), 89.9 (C-1), 113.4, 121.3, 126.0, 128.0, 128.1, 128.2, 128.7, 129.3,
=
129.4, 133.0, 133.2 (C-Ar), 165.0, 165.3 (C O(Ac)), 168.6 (isox-C O).
=
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