Coupling radical and ionic processes: an unusual rearrangement affords sugar and c-glycoside derivatives

Article abstract of DOI:10.1002/ejoc.200900427

An unusual scission-rearrangement process, which couples radical and ionic reactions, was observed with galactofuranose derivatives. This one-pot procedure afforded, in good yields, highly functionalized. 1,4-dioxanes, which could be considered as six-mem

Full text of DOI:10.1002/ejoc.200900427

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900427
Coupling Radical and Ionic Processes: An Unusual Rearrangement Affords
Sugar and C-Glycoside Derivatives
Alicia Boto,*[a] Dácil Hernández,[a] Rosendo Hernández,*[a] and Eleuterio Álvarez[b]
Keywords: Radical reactions / Rearrangement / Carbohydrates / Sequential processes / Photochemistry
An unusual scission–rearrangement process, which couples
radical and ionic reactions, was observed with galacto-
furanose derivatives. This one-pot procedure afforded, in
good yields, highly functionalized 1,4-dioxanes, which could
be considered as six-membered-ring sugar analogues. The
synthesis of C-glycoside analogues is also possible with this
methodology.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The development of sequential processes,[1] which reduce
the number of steps, avoid the isolation of intermediates
and reduce waste, is a hot research area in sustainable
chemistry. The application of such processes to the prepara-
tion of high-profit products from relatively inexpensive sub-
strates is particularly interesting.
In this line, we have been studying sequential processes[2]
(which combine radical with ionic reactions[3] and take
place in mild conditions) that are compatible with most
functional groups. These processes are very versatile and
allow the conversion of carbohydrates, amino alcohols or
α-amino acid derivatives into a variety of products (substi-
Scheme 1. Sequential processes that combine radical and ionic pro-
tuted cyclic ethers, unusual sugars, nucleoside analogues, al- cesses.
kaloid precursors, unnatural amino acids and modified
peptides).
For instance, the ribose derivative 1 (Scheme 1) was con-
When secondary alkoxyl radicals are generated, both α,β-
verted into the 2,4-diacetals 2a and 2b, by using a one-pot
fragmentation–oxidation-Ritter process.[4] Thus, when sub-
strate 1 was treated with iodosylbenzene and iodine under
visible light, a primary 5-alkoxyl radical was formed, which
underwent β-scission to give the intermediate 3. The latter
reacted with iodine to yield an α-iodoacetal 4.[5] Extrusion
of iodine generated an oxycarbenium intermediate 5, which
was trapped by the solvent to afford compounds 2a/2b
(81% global yield) after aqueous workup.[4]
C–C bonds could be cleaved. To study the regioselectivity
of the scission, we prepared different substrates with sec-
ondary hydroxy groups. In this preliminary communication,
we report that galactofuranose derivatives 6 (Scheme 2) un-
dergo a regioselective C2–C3 scission, followed by a re-
arrangement process, to give new sugar or C-glycoside ana-
logues 7.
[a] Instituto de Productos Naturales y Agrobiología del CSIC,
Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna,
Tenerife, Spain
Fax: +34-922-260135
E-mail: alicia@ipna.csic.es
rhernandez@ipna.csic.es
[b] Instituto de Investigaciones Químicas (CSIC-USe),
Isla de la Cartuja, Avda. Américo Vespucio 49, 41092 Sevilla,
Spain
Scheme 2. Unusual scission–rearrangement process yielding six-
membered-ring sugar analogues.
Eur. J. Org. Chem. 2009, 3853–3857
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A. Boto, D. Hernández, R. Hernández, E. Álvarez
SHORT COMMUNICATION
The stereochemistry of compounds 13–16 was deter-
mined with the use of the experimental H NMR coupling
Results and Discussion
1
The galactofuranose substrates were prepared from com-
mercial -galactopyranose 8 (Scheme 3). Silylation with
TBSCl, followed by methylation with NaH and MeI, af-
forded the galactofuranose 9. This synthetic intermediate
was desilylated to give diol 10. The primary hydroxy group
was protected by acetylation to yield compound 11, as well
as the diacetylated compound 12.
constants (Table 1) and NOESY experiments (Figure 1).
Further, X-ray analysis of product 15 (Figure 2) confirmed
the proposed structure and configuration.
1
Table 1. Experimental H NMR coupling constants [Hz].
J
13
14
15
16
J1,2
J3,4
J4,5
4.3
7.0
3.0
1.6
8.3
3.0
3.7
3.7
2.1
1.4
3.5
1.5
Scheme 3. Preparation of galactofuranose substrates.
Figure 1. NOESY experiments of products 13–16 (weak interaction
for 15).
When compound 11 (Scheme 4) was treated with (di-
acetoxyiodo)benzene (DIB) and iodine in dichloromethane,
under irradiation with visible light, two unexpected scis-
sion–rearrangement products were obtained, which were as-
signed the structures 13 and 14. On the other hand, when
the dihydroxy substrate 10 was subjected to the same condi-
tions, two related rearrangement products 15 and 16 were
obtained.
Figure 2. ORTEP representation of 15 with thermal displacement
ellipsoids drawn at the 50% probability level.
These results can be explained according to the mecha-
nism shown in Scheme 5. Thus, the radical scission of sub-
strates 10 or 11 generated C-radical 17,[6] which underwent
oxidation to an oxycarbenium ion 18.[7] The oxygen atom
from the carbonyl group at C3 acts as a nucleophile, and
the resulting ion was trapped either by acetate from DIB
(route [a]) or by the hydroxyl group on C6 (route [b]).[8]
Route [a] affords compounds 13 and 14, while route [b]
yields the bicyclic products 15 and 16. It should be noted
that in the scission of the dihydroxylated substrate 10, frag-
mentation of the secondary O-radical (which generates 15
and 16) is much faster than the scission of the primary radi-
cal (no products derived from C5–C6 fragmentation were
detected).[9] The formation of (2S) and (2R) derivatives in
almost 1:1 ratio implies that the rotation of the C1–C2 bond
in intermediates 17 or 18 is also fast.
Scheme 4. Scission–rearrangement processes.
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Eur. J. Org. Chem. 2009, 3853–3857

Coupling Radical and Ionic Processes
irradiated with visible light. The scission–rearrangement
process generated, in good yield, C-glycoside analogue 21,
whose configuration was assigned as (1R, 2S) (Table 2).
Table 2. Experimental and theoretical[12] 1H NMR coupling con-
stants [Hz] for the possible isomers.
J
21
(1R,2R)
(1R,2S)
(1S,2R)
(1S,2S)
J1,2 7.5
J3,4 2.8
J4,5 0.0
1.5
3.0
1.1
7.3
2.6
1.2
1.0
3.4
1.1
3.1
2.8
1.2
The formation of product 21 is remarkable, since several
side reactions (such as the abstraction of 1Ј-H) could have
taken place. However, the reaction was clean and no side-
products were isolated. Therefore, this methodology would
allow the efficient preparation of analogues of C-glycosides.
The synthesis of other rigid C-glycoside analogues (as po-
tential antiviral or cytotoxic compounds) is currently under
way and will be reported in due time.
Scheme 5. Possible mechanisms for the scission–rearrangement
process.
Conclusions
An unusual scission–rearrangement process, which cou-
ples radical and ionic reactions, was observed with galacto-
furanose derivatives. This one-pot procedure afforded six-
membered-ring sugar analogues in good yields, which were
characterized by spectroscopic methods and X-ray analysis.
A possible mechanism for the process is discussed. The
method can also be applied to prepare C-glycoside ana-
logues.
Finally, the addition of acetate to C3 (route [a]) occurs
on the face opposite the alkyl chain on C4 to give the 3,4-
trans products 13 and 14. On the contrary, when the hy-
droxyl group on C6 acts as the nucleophile (route [b]), the
3,4-cis products 15 and 16 were formed.
Products 13–16 are analogues of six-membered-ring
sugars. In order to assess if this process could also afford
analogues of C-glycosides,[10] 2-alkyl galactofuranose 20
(Scheme 6) was prepared from the diacetate 12 by alky-
lation of the anomeric position (to afford phenone 19), fol-
lowed by hydrolysis of the acetate groups (to yield alcohol
20).[11] Substrate 20 was treated with DIB and iodine and
Experimental Section
General Procedure for the Scission–Rearrangement Process: To a
solution of the carbohydrate substrate (0.1 mmol) in dry dichloro-
methane (2 mL) was added iodine (25 mg, 0.1 mmol) and DIB
(39 mg, 0.12 mmol). The resulting mixture was stirred for 2 h at
26 °C, under irradiation with visible light (80 W tungsten-filament
lamp, available in DIY shops). The mixture was poured into 10%
aqueous Na2S2O3 and extracted with CH2Cl2. The organic layer
was dried on sodium sulfate and filtered, and the solvents evapo-
rated under vacuum. The residue was purified by column
chromatography on silica gel (hexanes/EtOAc).
13: isolated (44%) as a syrup. 1H NMR (500 MHz, CDCl3): δ =
2.09 (s, 3 H), 2.12 (s, 3 H), 3.45 (s, 3 H), 3.46 (s, 3 H), 3.51 (s, 3
H), 3.52 (ddd, J = 2.9, 5.8, 5.9 Hz, 1 H, 5-H), 3.73 (dd, J = 3.0,
7.0 Hz, 1 H, 4-H), 4.28 (d, J = 5.9 Hz, 2 H, 6-Ha, 6-Hb), 4.40 (d,
J = 4.3 Hz, 1 H, 1-H), 4.51 (d, J = 4.3 Hz, 1 H, 2-H), 6.11 (d, J =
7.0 Hz, 1 H, 3-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 20.8
(CH3, Ac), 20.9 (CH3, Ac), 56.3 (CH3, OMe), 56.6 (CH3, OMe),
59.4 (CH3, OMe), 62.4 (CH2, C6), 72.9 (CH, C4), 76.5 (CH, C5),
88.0 (CH, C3), 99.6 (CH, C2), 100.6 (CH, C1), 169.1 (C, CO),
170.7 (C, CO) ppm. HMRS (EI): calcd. for C12H19O8 [M+ – OMe]
291.1080; found 291.1102.
14: isolated (31%) as a syrup. 1H NMR (500 MHz, CDCl3): δ =
2.09 (s, 3 H), 2.13 (s, 3 H), 3.43 (s, 3 H), 3.54 (s, 3 H), 3.56 (m, 1
H, 5-H), 3.57 (s, 3 H), 3.74 (dd, J = 3.0, 8.4 Hz, 1 H, 4-H), 4.27
(dd, J = 6.0, 11.5 Hz, 1 H, 6-Ha), 4.31 (dd, J = 6.0, 11.5 Hz, 1 H,
6-Hb),4.57 (d, J = 1.7 Hz, 1 H, 1-H), 4.62 (d, J = 1.6 Hz, 1 H, 2-
Scheme 6. Formation of a C-glycoside analogue.
Eur. J. Org. Chem. 2009, 3853–3857
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Boto, D. Hernández, R. Hernández, E. Álvarez
SHORT COMMUNICATION
H), 6.16 (d, J = 8.3 Hz, 1 H, 3-H) ppm. 13C NMR (125.7 MHz,
C3), 128.2 (2ϫCH, Ph), 128.6 (2ϫCH, Ph), 133.3 (CH, Ph), 137.0
CDCl3): δ = 20.9 (2ϫCH3, Ac), 55.7 (CH3, OMe), 57.1 (CH3, (C, Ph), 196.5 (C, CO) ppm. HMRS (EI): calcd. for C15H17O5
OMe), 59.1 (CH3, OMe), 62.2 (CH2, C6), 75.5 (CH, C4), 76.3 (CH, [M+ – OMe] 277.1076; found 277.1053.
C5), 84.7 (CH, C3), 97.3 (CH, C2), 99.0 (CH, C1), 168.7 (C, CO),
170.7 (C, CO) ppm. HMRS (EI): calcd. for C12H19O8 [M+ – OMe]
291.1080; found 291.1081.
Acknowledgments
15: isolated (41%) as a crystalline solid. M.p. 72–73 °C (from
This work was supported by the Plan Nacional de Investigación
1
EtOAc/n-hexane). H NMR (500 MHz, CDCl3): δ = 3.40 (s, 3 H),
Científica, Desarrollo e Innovación Tecnológica, and Ministerio de
3.50 (s, 3 H), 3.53 (s, 3 H), 3.93 (dd, J = 1.7, 9.9 Hz, 1 H, 6-Ha),
4.04 (ddd, J = 1.9, 1.9, 4.9 Hz, 1 H, 5-H), 4.10 (dd, J = 2.1, 3.6 Hz,
1 H, 4-H), 4.24 (d, J = 3.7 Hz, 1 H, 1-H), 4.29 (dd, J = 4.9, 9.9 Hz,
Educación y Ciencia, Spain (Research Program CTQ2006-14260/
PPQ). We also acknowledge financial support from FEDER funds.
D. H. thanks the Gobierno de Canarias (Consejería de Industria) –
CSIC for a research contract.
1 H, 6-Hb), 4.58 (d, J = 3.7 Hz, 1 H, 2-H), 5.39 (d, J = 3.7 Hz, 1
H, 3-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 56.0 (CH3,
OMe), 56.5 (CH3, OMe), 57.1 (CH3, OMe), 70.9 (CH2, C6), 77.7
[1] a) L. F. Tietze, G. Brasche, K. Gericke, Domino reactions in
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X-Ray Analysis of 15: C9H16O6, Mr = 220.22, colourless needle
crystal (0.50ϫ0.21ϫ0.06 mm) from EtOAc/n-hexane, monoclinic,
space group C2 (no. 5), a = 14.892(8) Å, b = 4.395(2) Å, c =
16.651(9) Å, V = 1063.6(9) Å3, Z = 4, ρcalcd. = 1.375 gcm–3, F(000)
= 472, µ = 0.116 mm–1. 3841 measured reflections, of which 1251
were unique (Rint = 0.0866). The asymmetric unit of the structure
is formed by one molecule of 15. Because of a large su on the
Flack parameter, the Friedel pairs were averaged in the refinement
(MERG 4 command). Thereby, the absolute configuration of new
chiral centres has been assigned by reference to other unchanging
chiral centres of known absolute configuration in the synthetic pro-
cedure. Refined parameters: 139, final R1 = 0.0588, for reflections
with IϾ2σ(I), wR2 = 0.1351 (all data), GOF = 1.019. The max/
min residual electron density: +0.263/–0.262 eÅ–3. CCDC-725226
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[3] a) For a review on the modification of amino acids and carbo-
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26, 157–167.
16: isolated (32%) as a syrup. 1H NMR (500 MHz, CDCl3): δ =
3.39 (s, 3 H), 3.54 (s, 3 H), 3.56 (s, 3 H), 3.83 (d, J = 9.6 Hz, 1 H,
6-Ha), 4.00 (dd, J = 1.0, 3.9 Hz, 1 H, 5-H), 4.21 (dd, J = 1.4,
3.1 Hz, 1 H, 4-H), 4.35 (dd, J = 4.0, 9.6 Hz, 1 H, 6-Hb), 4.48 (d, J
= 1.3 Hz, 1 H, 1-H), 4.52 (d, J = 1.4 Hz, 1 H, 2-H), 5.27 (d, J =
3.5 Hz, 1 H, 3-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 55.9
(CH3, OMe), 56.8 (CH3, OMe), 57.1 (CH3, OMe), 70.1 (CH2, C6),
77.0 (CH, C4), 84.4 (CH, C5), 94.6 (CH, C2), 96.6 (2ϫCH, C1 +
C3) ppm. HMRS (EI): calcd. for C8H13O5 [M+ – OMe] 189.0763;
found 189.0770.
21: isolated (71%) as a syrup. 1H NMR (500 MHz, CDCl3): δ =
3.22 (d, J = 7.5 Hz, 1Ј-Ha), 3.23 (d, J = 4.5 Hz, 1Ј-Ha), 3.33 (s, 3
H), 3.49 (s, 3 H), 3.73 (d, J = 4.1 Hz, 1 H, 5-H), 3.84 (d, J = 9.8 Hz,
1 H, 6-Ha), 3.96 (ddd, J = 4.5, 7.4, 7.5 Hz, 1 H, 1-H), 4.08 (d, J =
2.8 Hz, 1 H, 4-H), 4.26 (dd, J = 4.2, 9.7 Hz, 6-Ha), 4.70 (d, J =
7.5 Hz, 1 H, 2-H), 5.47 (d, J = 2.8 Hz, 1 H, 3-H), 7.47 (dd, J =
7.6, 7.9 Hz, 2 H, Ph), 7.58 (dd, J = 7.4, 7.4 Hz, 1 H, Ph), 7.95 (d,
[4] A. Boto, D. Hernández, R. Hernández, E. Suárez, J. Org.
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[5] a) For the isolation of α-iodoacetals derived from carbo-
hydrates, see: C. G. Francisco, C. González, E. Suárez, J. Org.
Chem. 1998, 63, 8092–8093; b) For examples of the reactivity
of α-iodoacetals towards nucleophiles, see: M. H. El-Badry, J.
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hedron Lett. 2003, 44, 7863–7866.
1
J = 7.39 Hz, 2 H, Ph) ppm. H NMR (500 MHz, C6D6): δ = 2.76
(s, 3 H), 2.95 (d, J = 4.5 Hz, 1Ј-Ha), 2.96 (d, J = 7.5 Hz, 1Ј-Hb),
3.26 (s, 3 H), 3.44 (d, J = 4.6 Hz, 1 H, 5-H), 3.75 (d, J = 9.6 Hz, 1
H, 6-Ha), 3.80 (d, J = 2.7 Hz, 4-H), 4.14 (dd, J = 4.3, 9.6 Hz, 6-
Ha), 4.20 (ddd, J = 4.4, 7.4, 7.6 Hz, 1 H, 1-H), 4.78 (d, J = 7.5 Hz,
1 H, 2-H), 5.58 (d, J = 2.7 Hz, 1 H, 3-H), 7.01 (dd, J = 7.3, 7.8 Hz,
2 H, Ph), 7.09 (dd, J = 7.4, 7.4 Hz, 1 H, Ph), 7.79 (d, J = 7.1 Hz,
2 H, Ph) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 40.3 (CH2,
C1Ј), 56.3 (CH3, OMe), 57.1 (CH3, OMe), 71.0 (CH2, C6), 72.0
(CH, C1), 76.2 (CH, C4), 83.9 (CH, C5), 98.0 (CH, C2), 98.8 (CH,
[6] Only products derived from scission of the C2–C3 bond were
isolated. The cleavage of the C3–C4 bond was not detected.
Since both scissions would give radical intermediates of similar
stability (secondary C radicals stabilized by alkoxy groups) and
aldehyde derivatives as products, the causes for the regioselec-
tivity are not clear. A possible explanation would be a better
stabilization of the developing radical on C2 by the 2-alkoxy
group, since good orbital overlapping is possible. In contrast,
the developing radical on C4 would be less stabilized by the
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Coupling Radical and Ionic Processes
nonbonding orbitals of the ring oxygen atom, since proper or-
bital alignment is not possible until bond cleavage is complete.
[7] The addition of the C radical to the carbonyl oxygen atom,
followed by oxidation of the resulting radical on C4 to a cyclic
oxycarbenium ion is less probable. For a discussion on related
processes see: A. L. J. Beckwith, D. Crich, P. J. Duggan, Q.
Yao, Chem. Rev. 1997, 97, 3273–3312.
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[9] a) The stability of the scission products or the radical interme-
diates determines the course of the process. For example, frag-
mentations generating RCORЈ (R, RЈ = alkyl, aryl) are ther-
modynamically more favoured than those affording aldehydes
RCHO. The latter, in turn, are more favoured than scissions,
to yield HCHO. Thus, the scission of secondary O radicals pre-
dominates over the scission of primary alkoxyl radicals. b) For
reviews discussing β-scissions, see: E. Suárez, M. S. Rodríguez
in Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi),
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[10] a) For a review on the use of related cyclic 1,2-diacetals as
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Lehmann, L. Ziser, Carbohydr. Res. 1996, 286, 189–196; d)
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1791–1795.
[11] The phenone 19 was obtained as an optically pure product.
However, an isomerization process took place with time (ob-
servable by NMR spectroscopy) to afford a mixture of epimers
at C1. The same happened with the phenone 20. Thus, to pre-
serve the optical purity, product 19 was hydrolyzed and then
immediately treated under the scission–rearrangement condi-
tions to afford compound 21, which was quite resistant to epi-
merization.
[12] Calculations were made using an AMBER force field model
implanted in the Macromodel 7.0 program. The calculations
were also performed with an MMFF force field, by using high-
quality parameters. Similar results were obtained in both cases.
The theoretical coupling constants were calculated over the
minimized structures for all possible isomers, by using the
Karplus–Altone equation implemented in Macromodel.
Received: April 17, 2009
Published Online: June 29, 2009
Eur. J. Org. Chem. 2009, 3853–3857
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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