1,8-hydrogen atom transfer promoted by N-radicals in (1→4)-O- disaccharide models

Article abstract of DOI:10.1002/ejoc.201101146

The nitrogen-centered radical generated by reaction of an N-sulfonamidate, attached to C-6 of a hexopyranose in a disaccharide model, with (diacetoxyiodo)benzene (DIB) andiodine undergoes a novel regio- and stereoselective intramolecular 1,8-hydrogen atom

Full text of DOI:10.1002/ejoc.201101146

FULL PAPER
DOI: 10.1002/ejoc.201101146
1,8-Hydrogen Atom Transfer Promoted by N-Radicals in
(1Ǟ4)-O-Disaccharide Models
Elisa I. León,[a] Ángeles Martín,*[a] Inés Pérez-Martín,*[a] and Ernesto Suárez[a]
Keywords: Carbohydrates / Radical reactions / Hydrogen transfer / Radicals
The nitrogen-centered radical generated by reaction of an
N-sulfonamidate, attached to C-6 of a hexopyranose in a di-
saccharide model, with (diacetoxyiodo)benzene (DIB) and
iodine undergoes a novel regio- and stereoselective intramo-
lecular 1,8-hydrogen atom transfer (HAT) reaction to pro-
mote the functionalization of remote positions.
Introduction
Intramolecular hydrogen atom transfer (HAT) is one of
the most interesting radical processes, because it allows the
completely regioselective functionalization of remote posi-
tions.[1] In recent years our laboratory has devoted its atten-
tion to the application of this process, promoted by O-[2] or
N-radicals,[3] to sugar templates. In these studies, intramo-
lecular 1,5- and 1,6-HAT reactions were initiated by alkoxyl
or aminyl radicals derived from an alcohol or suitably pro-
tected amine, respectively, by treatment with a hypervalent
iodine reagent in the presence of iodine. The results demon-
strated the synthetic potential of this methodology for the
preparation of different five- or six-membered heterocyclic
compounds. As a consequence of these results, and con-
sidering the lack of reported examples in sugars,[4] we envi-
sioned that an intramolecular HAT reaction via a higher-
than-seven-membered transition state might be possible.
The results of these investigations revealed a successful and
highly unusual 1,8-HAT reaction promoted by an alkoxyl
Scheme 1. 1,8-HAT reaction promoted by an O-radical.
Results and Discussion
The question that immediately arises is whether, and to
radical.[5] This process occurs between the two monosac- what extent, this methodology can be applied to N-radical-
charide units in a (1Ǟ4)-O-disaccharide suitably substi- promoted reactions considering that to the best of our
tuted to meet the required geometrical and stereoelectronic knowledge this kind of process has never been described
conditions via a nine-membered transition state (Scheme 1). previously (Scheme 2). That was the aim of this work, and
In this process, if a 1,3,5-trioxocane ring I could be formed we report herein the results obtained, which include the first
in a stable boat–chair conformation, the abstraction would long-distance aminyl-promoted intramolecular HAT reac-
occur preferentially at C-5Ј, whereas if the process is ener- tion and remote functionalization without modification of
getically disfavored, in conformations similar to a boat– the remainder of the molecule.
boat or crown ether, the abstraction would take place
mainly at C-1Ј.
The greater part of the required N-sulfonamidate precur-
sors was prepared according to a well-established general
protocol by starting from suitably protected disaccharides,
as described in the Supporting Information; C-6 primary
unprotected alcohols, described in previous articles,[5] were
used as starting materials and submitted to a general four-
step protocol. First, conversion into the mesyl derivatives
and subsequent nucleophilic substitution with an azide ion
took place, then the azides were hydrogenated to the corre-
[a] Instituto de Productos Naturales y Agrobiología del C.S.I.C.,
Carretera de la Esperanza 3, 38206 La Laguna, Tenerife, Spain
Fax: +34-922-260-135
E-mail: angelesmartin@ipna.csic.es
ines@ipna.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101146.
Eur. J. Org. Chem. 2011, 7339–7345
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7339

E. I. León, Á. Martín, I. Pérez-Martín, E. Suárez
FULL PAPER
Scheme 2. 1,8-HAT reaction promoted by N-radicals.
sponding amines, and finally the resulting crude free amines the HAT reaction. In addition, they have been successfully
were all treated with the corresponding sulfonyl chloride in used under our radical conditions to give an assortment of
the presence of TEA to give the required sulfonamides.
pyrrolidines, as shown by Fan and co-workers.[9] Note also
Sulfonamidates were chosen as protecting groups, on the that the carbohydrate structures were selected on the basis
basis of their certain application in amino and amino acid of the conclusions drawn from the stereochemical and con-
chemistry,[6–8] to avoid oxidation of the amino group during formational study of the intramolecular 1,8-HAT reaction
the formation of the iodoamide intermediate and, at the when promoted by a primary 6-O-yl radical.[5b] Based on
same time, to control the stability of the N-radical during these data, we initially prepared the α-l-Rhap-(1Ǟ4)-α-d-
Table 1. Intramolecular HAT of C-6 sulfonamidyl α-l-Rhap-(1Ǟ4)-α-d-Galp.[a]
[a] The sulfonamidyl derivative (1 mmol) in CH2Cl2 (20 mL) containing (diacetoxyiodo)benzene (DIB; 2.5 mmol) and iodine (1.2 mmol)
was irradiated with an 80 W tungsten filament lamp at room temp.
7340
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Eur. J. Org. Chem. 2011, 7339–7345

1,8-Hydrogen Atom Transfer in Disaccharide Models
Galp disaccharide, which gave the best results in the alk- and CSA to promote the intramolecular cyclization to give
oxyl-promoted abstraction. Derivatives 1, 4, 7, and 10 were the 1,3,5-dioxazocane ring, but no changes were observed
successfully prepared and submitted to the intramolecular in the outcome of the process, and only the acetylated deriv-
HAT reaction under the oxidative conditions previously de- atives were obtained.
veloped by our group (Table 1) with (diacetoxyiodo)ben-
zene and iodine in CH2Cl2 at room temperature under irra- enhance the nucleophilicity of the amino group with the
diation with an 80 W tungsten filament lamp. purpose of obtaining a 1,3,5-dioxazocane substructure,
Next we modified the protecting group in an attempt to
We started our study with the radical reactions of the which would constitute a new tricyclic system not pre-
nosyl and tosyl derivatives 1 and 4, which proceeded viously described in the literature. We then studied the HAT
smoothly to give, in both cases, a mixture of two com- reactions of the (p-methoxyphenyl)sulfonylamine 7 and the
pounds with global yields of 45 and 62%, respectively 2-pyridinylsulfonylamine 10, which gave 1,8-hydrogen ab-
(Table 1, Entries 1 and 2) as a result of the 1,8-HAT reac- straction with global yields of 58 and 73%, respectively
tion. The formation of the acetate derivatives 2 and 5 shows (Table 1, Entries 3 and 4). Also in these cases, the corre-
that the 1,8-HAT reaction occurred, but no cyclization sponding acetyl products 8 and 11, deriving from intermo-
product 1,3,5-dioxazocane was formed, as was reported lecular attack, were obtained as the major products in a
previously for the O-radical counterpart in which a 1,3,5- mixture of two, in the case of Entry 3, and as the only prod-
trioxocane ring I (Scheme 1) was achieved.[5b] Apparently, uct in the case of 2-pyridinylsulfonylamine 11 (Entry 4).
a lower nucleophilicity of the sulfonamidate group is re- Unfortunately, the improvement in the nucleophilicity of
sponsible for the competitive intermolecular attack of the the amine with these sulfonyl protecting groups was not suf-
acetate anion deriving from the reagent. The (R) configura- ficient to promote the intramolecular closure, but neverthe-
tion at C-5Ј in both products was assigned by the NOE less remote functionalization of C-5Ј through a 1,8-HAT
correlations observed between 6Ј-Me and 4Ј-H in a 1C4 con- reaction was successful. Again in these cases, the stereo-
formation. Product 3, also derived from the 1,8-HAT reac- chemistry at C-5Ј was established according to the NOE
tion, was obtained with 2 as an inseparable mixture on ordi- interactions observed between 6Ј-Me and 4Ј-H. The minor
nary chromatography columns, and may have occurred by product 9 was tentatively formed from the radical fragmen-
a subsequent radical fragmentation of the pyranose ring of tation of the pyranose in II followed by oxidation to an
II to give, after oxidation of the corresponding C-radical, oxycarbenium ion III, which could be trapped by H2O mo-
an oxycarbenium ion III, which is trapped by acetate from lecules to give a hemiacetal intermediate that could be oxid-
the reagent (Scheme 3). Otherwise, probably due to the ized in the medium to the corresponding δ-keto ester 9
higher nucleophilicity of the tosylamine relative to the nosyl (Table 1, Entry 3; Scheme 3).
derivative, in this case, the oxycarbenium ion III was
Encouraged by these initial results, which may lead to a
trapped intramolecularly by the tosylamine group to yield synthetically useful methodology for the remote function-
a 1,3-oxazolidine cycle in product 6. The (S) configuration alization of the C-5Ј carbon atom, we decided to investigate
at C-1Ј in 6 was assigned on the basis of the NOE corre- whether this protocol is exclusive to α-l-Rhap-(1Ǟ4)-α-d-
lation observed between 1Ј-H and 4-H. In both cases the Galp or, on the contrary, can be extended to other disacchar-
radical reaction was also tested in the presence of BF3·Et2O ides that fulfill the stereochemical and conformational
requirements for that purpose. With this aim we synthesized
α-d-Manp-(1Ǟ4)-α-d-Glcp derivatives 12 and 14 (Table 2,
Entries 1 and 2), which were submitted to the oxidative
HAT reaction conditions. The results for 12 showed direct
C-5Ј functionalization via a nine-membered transition state,
as observed previously in Table 1, to give exclusively the
acetate derivative 13 in 52% yield. The (S) configuration at
C-5Ј was determined on the basis of the NOE interactions
observed between 4Ј-H and 6Ј-Ha. However, the reaction of
the acetate-substituted counterpart 14 was not successful.
Apparently, the electron-withdrawing acetyl groups at C-4Ј
and C-6Ј can inhibit hydrogen abstraction at C-5Ј, and no
reaction was observed, although long reaction times re-
sulted in decomposition of the starting material.
Next, the question arises as to whether the substituent at
C-5Ј in hexopyranose disaccharide models could hinder the
intramolecular closure of the amine group and thereby
favor intermolecular acetate attack. As a consequence, we
prepared α-d-Lyxp-(1Ǟ4)-α-d-Glcp 15, a pentopyranose
derivative with no substitution at C-5Ј, and submitted it to
the HAT reaction conditions (Table 2, Entry 3). An insepa-
Scheme 3. N-radical-promoted 1,8-HAT and β-fragmentation.
rable mixture of epimers of 16 was obtained in only 25%
Eur. J. Org. Chem. 2011, 7339–7345
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E. I. León, Á. Martín, I. Pérez-Martín, E. Suárez
FULL PAPER
Table 2. Intramolecular HAT of C-6 nosyl α-d-Manp-(1Ǟ4)-α-d- to 18, which can be attributed to the acidity of the reaction
Glcp, α-d-Lyxp-(1Ǟ4)-α-d-Glcp, and α-d-Araf-(1Ǟ4)-α-d-Glcp.[a]
medium. The configuration at C-4Ј was established on the
basis of the NOE correlation between 1Ј-H and 5Ј-H2.
Conclusions
To the best of our knowledge, with these examples, we
have performed a novel and previously unknown radical
1,8-HAT reaction promoted by N-sulfonamidyl radicals.
The yields achieved are slightly lower than those previously
obtained in the O-centered radical studies, and no intramo-
lecular cyclized products were obtained, but the novelty of
the process and the ability to promote the remote function-
alization of the molecule without modifying the remainder
of the disaccharide are highly remarkable and encouraging.
The polarity of the amino protecting group may be very
important, because the nitrogen atom could act with umpo-
lung reactivity during the reaction, first as an electrophilic
N-radical and then as a nucleophile, if the cyclization step
was to occur. Further investigations employing more elec-
tron-donating protecting groups to support the intramolec-
ular amino cyclization, such as sulfoxides, sulfonamidates,
or carbamates, are underway.
Experimental Section
General Methods: Melting points were determined with a hot-plate
apparatus. Optical rotations were measured with a Perkin-Elmer
Polarimeter PE-241 at the sodium line at ambient temperature in
CHCl3. IR spectra were recorded with a Perkin Elmer 1600/FTIR
instrument in CCl4. NMR spectra were recorded with a Bruker
AMX 400 spectrometer at 400 MHz for 1H and 100.6 MHz for 13
C
in CDCl3 in the presence of TMS as internal standard. Mass spec-
tra were recorded with a Waters LCT Premier XE spectrometer
by using electrospray ionization (ESI+). Elemental analyses were
performed with a Leco TrueSpec Micro instrument. Merck silica
gel 60 PF (0.063–0.2 mm) was used for column chromatography.
Circular layers of 1 mm of Merck silica gel 60 PF254 were used
with a Chromatotron for centrifugally assisted chromatography.
Commercially available reagents and solvents were analytical grade
or were purified by standard procedures prior to use. All reactions
involving air- or moisture-sensitive materials were carried out un-
der nitrogen. TLC analysis was conducted with a spray of 0.5%
vanillin in H2SO4/EtOH (4:1) and heating until the development of
color.
[a] The sulfonamidyl derivative (1 mmol) in CH2Cl2 (20 mL) con-
taining (diacetoxyiodo)benzene (DIB; 2.5 mmol) and iodine
(1.2 mmol) was irradiated with an 80 W tungsten filament lamp at
room temp.
yield. Destabilization of the oxycarbenium intermediate ion
due to the absence of substituents at C-5Ј could be responsi-
ble for the low yield.
Until now, pento- and hexopyranose models have been
studied, and the same conclusions as drawn from alkoxyl
radicals have been reached, that is, the 1,8-HAT reaction
takes place, although lower yields were obtained in these
cases.
To complete the study, the pentofuranose models should
be revised. Apparently, the sulfonamide group has greater
difficulty than the hydroxy group in trapping the oxycar-
benium ion, probably due to a combination of steric and
electronic factors. It would be worthwhile researching the
HAT reaction of a pentofuranose derivative that has less
steric hindrance. α-d-Araf-(1Ǟ4)-α-d-Glcp 17 was thus
submitted to the standard HAT conditions and amino
alcohol 18 was obtained after chromatotron chromatog-
raphy as the sole product in 46% yield (Table 2, Entry 4).
Traces of the corresponding unstable acetate derivative
General Procedure for the Oxidative HAT: A solution of N-sulfona-
midate (1 mmol) in dry CH2Cl2 (20 mL) containing DIB
(2.5 mmol) and iodine (1.2 mmol) under nitrogen was irradiated
with one 80 W tungsten filament lamp at room temperature for 1–
6 h. The reaction mixture was then poured into 10% aqueous
Na2S2O3 and extracted with CH2Cl2, dried with Na2SO4, concen-
trated, and purified by chromatography (hexanes/EtOAc).
Methyl 5-Acetoxy-2,3,4-tri-O-acetyl-α-
6-deoxy-2,3-di-O-methyl-6-(4-nitrophenylsulfonylamino)-α-
topyranoside (2) and 2,3,4-Tri-O-acetyl-6-deoxy- -lyxo-hexos-5-
ulose [Methyl 6-Deoxy-2,3-di-O-methyl-6-(4-nitrophenylsulfon-
ylamino)-α- -galactopyranoside-4-yl] Acetyl Acetal (3): By starting
from 1 (91 mg, 0.13 mmol), an inseparable mixture of compounds
L-rhamnopyranosyl-(1Ǟ4)-
D-galac-
L
D
show that this product was almost completely hydrolyzed 2 and 3 was obtained as a colorless oil (43 mg, 2/3 = 1.4:1) after
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1,8-Hydrogen Atom Transfer in Disaccharide Models
1
2 h. H NMR: δ = 1.59 (s, 3 H), 2.02 (s, 3 H), 2.03 (s, 6 H), 2.08 (CH3), 57.7 (CH3), 59.4 (CH3), 67.4 (CH), 68.5 (CH), 69.7 (CH),
(s, 3 H), 2.12 (s, 3 H), 2.14 (s, 3 H), 2.15 (s, 3 H), 2.17 (s, 3 H),
2.19 (s, 3 H), 2.93 (ddd, J = 7.2, 7.2, 7.2 Hz, 1 H), 3.06 (ddd, J =
70.1 (CH), 75.3 (CH), 76.6 (CH), 77.2 (CH), 77.6 (CH), 98.1 (CH),
127.0 (2 CH), 129.8 (2 CH), 137.2 (C), 143.6 (C), 166.7 (C), 169.3
7.4, 7.4, 6.1 Hz, 1 H), 3.24–3.53 (m, 8 H), 3.35 (s, 3 H), 3.36 (s, 3 (C), 169.8 (C), 201.4 (C) ppm. IR (CCl ): ν = 3389, 2932, 1757,
˜
4
H), 3.40 (s, 3 H), 3.44 (s, 6 H), 3.50 (s, 3 H), 3.59 (ddd, J = 10.1, 1216 cm–1. MS (ESI+): m/z (%) = 668 (100) [M + Na]+. HRMS
3.2, 0 Hz, 1 H), 3.65 (ddd, J = 8.7, 6.4, 0 Hz, 1 H), 3.99 (m, 2 H), (ESI+): calcd. for C28H39NNaO14S 668.2004 [M + Na]+; found
4.71 (d, J = 3.2 Hz, 1 H), 4.80 (d, J = 3.7 Hz, 1 H), 5.06 (d, J = 668.1989. C28H39NO14S (645.68): calcd. C 52.09, H 6.09, N 2.17,
8.5 Hz, 2 H), 5.14 (dd, J = 8.2, 3.4 Hz, 1 H), 5.23 (m, 3 H), 5.41 S 4.97; found C 52.16, H 6.39, N 2.38, S 5.03.
(d, J = 3.2 Hz, 1 H), 5.73 (dd, J = 7.0, 3.0 Hz, 1 H), 6.27 (dd, J =
Methyl 5-Acetoxy-2,3,4-tri-O-acetyl-α-
6-deoxy-2,3-di-O-methyl-6-(4-methoxyphenylsulfonylamino)-α-
lactopyranoside (8): By starting from 7 (184.2 mg, 0.28 mmol), com-
pound 8 (67 mg, 0.09 mmol, 32%) was obtained as a white crystal-
L
-rhamnopyranosyl-(1Ǟ4)-
-ga-
8.5, 5.6 Hz, 1 H), 8.05 (d, J = 9.3 Hz, 2 H), 8.10 (d, J = 9.0 Hz, 2
H), 8.35 (d, J = 6.6 Hz, 2 H), 8.36 (d, J = 6.6 Hz, 2 H) ppm; signal
of 1 H from NH is missing. An NOE correlation was observed
between 6Ј-Me and 4Ј-H in product 2. The stereochemistry at C-
1Ј in 3 could not be elucidated. 13C NMR: δ = 20.2 (CH3), 20.3
(CH3), 20.4 (2 CH3), 20.6 (CH3), 20.7 (2 CH3), 20.9 (CH3), 22.0
(CH3), 26.7 (CH3), 41.9 (CH2), 42.6 (CH2), 55.5 (CH3), 55.7 (CH3),
57.8 (CH3), 58.2 (CH3), 59.0 (CH3), 59.4 (CH3), 66.3 (CH), 67.5
(CH), 68.0 (CH), 68.3 (CH), 68.6 (CH), 68.7 (CH), 69.8 (CH), 70.2
(CH), 74.4 (CH), 75.2 (CH), 77.2 (CH), 77.3 (CH), 77.6 (CH), 78.9
(CH), 96.9 (2 CH), 97.9 (CH), 98.2 (CH), 103.9 (C), 124.2 (2 CH),
124.4 (2 CH), 128.0 (2 CH), 128.3 (2 CH), 145.7 (C), 147.2 (C),
149.9 (C), 150.1 (C), 167.0 (C), 168.7 (C), 168.9 (C), 169.2 (C),
D
line solid after 2 h. M.p. 68.5–69.1 °C (n-hexane/EtOAc). [α]D
=
1
–47.5 (c = 0.040, CHCl3). H NMR: δ = 1.61 (s, 3 H), 2.01 (s, 3
H), 2.10 (s, 3 H), 2.12 (s, 3 H), 2.14 (s, 3 H), 3.21 (dd, J = 7.1,
7.1 Hz, 2 H), 3.35 (s, 3 H), 3.39 (dd, J = 4.9, 2.8 Hz, 2 H), 3.44 (s,
6 H), 3.66 (dd, J = 7.7, 7.7 Hz, 1 H), 3.85 (s, 3 H), 4.03 (br. s, 1
H), 4.73 (d, J = 2.9 Hz, 1 H), 5.09 (dd, J = 8.3, 3.8 Hz, 1 H), 5.14
(d, J = 8.5 Hz, 1 H), 5.27 (dd, J = 3.4, 3.4 Hz, 1 H), 5.3 (d, J =
3.2 Hz, 1 H), 5.80 (dd, J = 7.2, 7.2 Hz, 1 H), 6.95 (d, J = 9.0 Hz,
2 H), 7.83 (d, J = 9.0 Hz, 2 H) ppm. An NOE correlation was
observed between 6Ј-Me and 4Ј-H. 13C NMR: δ = 20.5 (CH3), 20.6
(2 CH3), 21.1 (CH3), 21.9 (CH3), 41.8 (CH2), 55.4 (CH3), 55.6
(CH3), 58.0 (CH3), 59.0 (CH3), 66.5 (CH), 67.9 (CH), 68.3 (CH),
68.5 (CH), 73.5 (CH), 77.6 (CH), 79.2 (CH), 96.4 (CH), 97.9 (CH),
103.9 (C), 114.1 (2 CH), 129.0 (2 CH), 132.9 (C), 162.8 (C), 168.7
169.3 (C), 169.4 (2 C), 169.7 (C), 201.7 (C) ppm. IR (CCl ): ν =
˜
4
2928, 1759, 1215 cm–1. MS (ESI+): m/z (%) = 759 (100) [M +
Na]+. HRMS (ESI+): calcd. for C29H40N2NaO18S 759.1895 [M +
Na]+; found 759.1890.
Methyl 5-Acetoxy-2,3,4-tri-O-acetyl-α-
6-deoxy-2,3-di-O-methyl-6-(4-methylphenylsulfonylamino)-α-
L
-rhamnopyranosyl-(1Ǟ4)-
-ga-
(2 C), 168.9 (C), 169.3 (C) ppm. IR (CCl ): ν = 3327, 2932, 1760,
˜
4
1214 cm–1. MS (ESI+): m/z (%) = 744 (100) [M + Na]+. HRMS
(ESI+): calcd. for C30H43NNaO17S 744.2149 [M + Na]+; found
744.2149. C30H43NO17S (721.73): calcd. C 49.93, H 6.01, N 1.94,
S 4.44; found C 49.90, H 6.12, N 1.77, S 4.09.
D
lactopyranoside (5): By starting from 4 (88.5 mg, 0.14 mmol), com-
pound 5 (38 mg, 0.05 mmol, 39%) was obtained as a white crystal-
line solid after 2.5 h. M.p. 55.7–56.0 °C (n-hexane/EtOAc). [α]D
=
1
–38.0 (c = 0.050, CHCl3). H NMR: δ = 1.61 (s, 3 H), 2.01 (s, 3
H), 2.11 (s, 3 H), 2.13 (s, 3 H), 2.15 (s, 3 H), 2.42 (s, 3 H), 3.20–
3.25 (m, 2 H), 3.35 (s, 3 H), 3.38 (m, 1 H), 3.43 (m, 1 H), 3.44 (s,
3 H), 3.45 (s, 3 H), 3.66 (m, 1 H), 4.03 (br. s, 1 H), 4.73 (d, J =
2.6 Hz, 1 H), 5.09 (dd, J = 8.5, 3.7 Hz, 1 H), 5.14 (d, J = 8.5 Hz,
1 H), 5.27 (dd, J = 3.4, 3.4 Hz, 1 H), 5.33 (d, J = 3.2 Hz, 1 H),
5.85 (dd, J = 7.7, 6.4 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 7.79 (d,
J = 8.2 Hz, 2 H) ppm. An NOE correlation was observed between
6Ј-Me and 4Ј-H. 13C NMR: δ = 20.6 (CH3), 20.7 (2 CH3), 21.1
(CH3), 21.5 (CH3), 21.9 (CH3), 41.8 (CH2), 55.4 (CH3), 58.0 (CH3),
59.0 (CH3), 66.5 (CH), 67.8 (CH), 68.3 (CH), 68.4 (CH), 73.5 (CH),
77.5 (CH), 79.1 (CH), 96.4 (CH), 97.8 (CH), 103.9 (C), 126.9 (2
CH), 129.6 (2 CH), 138.3 (C), 143.2 (C), 168.7 (C), 168.9 (2 C),
Methyl 4-O-(2,3,4-Tri-O-acetyl-6-deoxy-
deoxy-2,3-di-O-methyl-6-(4-methoxyphenylsulfonylamino)-α-
lactopyranoside (9): By starting from 7 (184.2 mg, 0.28 mmol), com-
pound 9 (50.4 mg, 0.07 mmol, 26%) was obtained as a white crys-
L
-lyxo-hex-5-ulosonoyl)-6-
D
-ga-
talline solid after 2 h. M.p. 56.4–57.0 °C (n-hexane/EtOAc). [α]D
=
1
+40.0 (c = 0.030, CHCl3). H NMR: δ = 2.00 (s, 3 H), 2.07 (s, 3
H), 2.17 (s, 3 H), 2.21 (s, 3 H), 2.86 (ddd, J = 6.9, 6.9, 6.9 Hz, 1
H), 3.02 (ddd, J = 13.7, 7.8, 6.1 Hz, 1 H), 3.33 (s, 3 H), 3.39 (s, 3
H), 3.40 (dd, J = 9.9, 3.6 Hz, 1 H), 3.49 (s, 3 H), 3.54 (dd, J =
10.1, 3.2 Hz, 1 H), 3.86 (s, 3 H), 3.95 (dd, J = 7.3, 7.3 Hz, 1 H),
4.80 (d, J = 3.7 Hz, 1 H), 4.94 (dd, J = 6.9, 6.9 Hz, 1 H), 5.29 (d,
J = 7.4 Hz, 1 H), 5.36 (d, J = 2.6 Hz, 1 H), 5.38 (d, J = 3.2 Hz, 1
H), 5.76 (dd, J = 7.3, 3.0 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 2 H), 7.79
(d, J = 9.0 Hz, 1 H) ppm. 13C NMR: δ = 20.2 (CH3), 20.3 (CH3),
20.4 (CH3), 26.7 (CH3), 42.4 (CH2), 55.6 (2 CH3), 57.7 (CH3), 59.4
(CH3), 67.4 (CH), 68.6 (CH), 69.8 (CH), 70.1 (CH), 75.4 (CH),
77.1 (CH), 77.6 (CH), 98.1 (CH), 114.3 (2 CH), 129.1 (2 CH), 131.8
(C), 163.0 (C), 166.7 (C), 169.2 (2 C), 169.7 (C), 201.3 (C) ppm.
169.4 (C) ppm. IR (CCl ): ν = 3312, 2933, 1754, 1219 cm–1. MS
˜
4
(ESI+): m/z (%) = 728 (100) [M + Na]+. HRMS (ESI+): calcd. for
C3 0 H4 3 NNaO1 6 S 728.2200 [M + Na]+ ; found 728.2196.
C30H43NO16S (705.73): C 51.06, H 6.14, N 1.98, S 4.54; found C
51.12, H 6.23, N 2.22, S 4.61.
Methyl (1S)-4-O,6-N-(2,3,4-Tri-O-acetyl-6-deoxy-
ulosylidene)-6-deoxy-2,3-di-O-methyl-6-(4-methylphenylsulfonyl-
amino)-α- -galactopyranoside (6): By starting from 4 (88.5 mg,
L-lyxo-hexos-5-
IR (CCl ): ν = 3392, 2930, 1757, 1214, 1112 cm–1. MS (ESI+): m/z
˜
4
(%) = 700 (100) [M + Na]+ . HRMS (ESI+ ): calcd. for
C28H39NNaO16S: 700.1887 [M + Na]+; found 700.1891.
C28H39NO16S (677.77): calcd. C 49.63, H 5.80, N 2.07, S 4.73;
found C 49.82, H 5.98, N 1.76, S 4.67.
D
0.14 mmol), compound 6 (20 mg, 0.03 mmol, 23%) was obtained
1
as a colorless oil after 2.5 h. [α]D = +16.0 (c = 0.050, CHCl3). H
NMR: δ = 2.00 (s, 3 H), 2.07 (s, 3 H), 2.17 (s, 3 H), 2.22 (s, 3 H),
2.42 (s, 3 H), 2.89 (m, 1 H), 3.05 (m, 1 H), 3.33 (s, 3 H), 3.40 (s, 3
H), 3.42–3.55 (m, 2 H), 3.50 (s, 3 H), 3.95 (ddd, J = 7.3, 7.3, 0 Hz,
1 H), 4.81 (d, J = 3.4 Hz, 1 H), 4.95 (dd, J = 6.1, 6.1 Hz, 1 H),
5.29 (d, J = 7.4 Hz, 1 H), 5.37 (dd, J = 11.7, 2.6 Hz, 1 H), 5.38 (d,
J = 2.6 Hz, 1 H), 5.76 (dd, J = 7.4, 2.9 Hz, 1 H), 7.31 (d, J =
7.9 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 2 H) ppm. An NOE correlation
was observed between 1Ј-H and 4-H. 13C NMR: δ = 20.2 (CH3),
20.3 (CH3), 20.4 (CH3), 21.5 (CH3), 26.8 (CH3), 42.4 (CH2), 55.7
Methyl 5-Acetoxy-2,3,4-tri-O-acetyl-α-
6-deoxy-2,3-di-O-methyl-6-(2-pyridinylsulfonylamino)-α-
pyranoside (11): By starting from 10 (95.3 mg, 0.15 mmol), com-
pound 11 (75.8 mg, 0.11 mmol, 73%) was obtained as a white crys-
L
-rhamnopyranosyl-(1Ǟ4)-
-galacto-
D
talline solid after 5 h. M.p. 57.1–58.3 °C (n-hexane/EtOAc). [α]D
=
+4.6 (c = 0.130, CHCl3). 1H NMR: δ = 1.63 (s, 3 H), 2.02 (s, 3 H),
2.10 (s, 6 H), 2.13 (s, 3 H), 3.33–3.59 (m, 4 H), 3.36 (s, 3 H), 3.45
(s, 3 H), 3.46 (s, 3 H), 3.80 (dd, J = 7.5, 7.5 Hz, 1 H), 4.15 (br. s,
Eur. J. Org. Chem. 2011, 7339–7345
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7343

E. I. León, Á. Martín, I. Pérez-Martín, E. Suárez
FULL PAPER
1 H), 4.75 (d, J = 3.4 Hz, 1 H), 5.14 (s, 1 H), 5.14 (m, 1 H), 5.28
(m, 1 H), 5.36 (d, J = 3.4 Hz, 1 H), 6.22 (dd, J = 7.0, 7.0 Hz, 1 H),
7.47 (ddd, J = 7.7, 4.8, 1.1 Hz, 1 H), 7.89 (ddd, J = 7.7, 7.7, 1.8 Hz,
1 H), 8.00 (ddd, J = 8.0, 1.0, 1.0 Hz, 1 H), 8.65 (ddd, J = 4.8, 1.8,
1.0 Hz, 1 H) ppm. An NOE correlation was observed between 6Ј-
Me and 4Ј-H. 13C NMR: δ = 20.5 (CH3), 20.7 (2 CH3), 21.0 (CH3),
21.9 (CH3), 42.2 (CH2), 55.5 (CH3), 58.0 (CH3), 59.0 (CH3), 66.5
(CH), 68.3 (2 CH), 68.4 (CH), 73.8 (CH), 77.6 (CH), 79.1 (CH),
96.5 (CH), 97.8 (CH), 103.9 (C), 121.9 (CH), 126.4 (CH), 137.9
J = 4.8 Hz, 1 H), 3.82 (dd, J = 4.6, 2.5 Hz, 1 H), 4.60 (d, J =
3.7 Hz, 1 H), 5.37 (d, J = 2.4 Hz, 1 H), 6.03 (dd, J = 6.8, 6.8 Hz,
1 H), 8.11 (d, J = 9.0 Hz, 2 H), 8.33 (d, J = 9.0 Hz, 2 H) ppm; the
signal of 1 H from OH is missing. An NOE correlation was ob-
served between 1Ј-H and 5Ј-H2. 13C NMR: δ = 44.4 (CH2), 55.3
(CH3), 57.9 (CH3), 58.6 (CH3), 59.0 (CH3), 59.6 (CH3), 60.8 (CH3),
68.7 (CH), 75.0 (CH2), 76.2 (CH), 82.4 (CH), 82.7 (CH), 83.9 (CH),
88.6 (CH), 97.1 (CH), 103.7 (C), 106.4 (CH), 124.0 (2 CH), 128.5
(2 CH), 147.1 (C), 149.8 (C) ppm. IR (CCl ): ν = 3489, 3290, 2934,
˜
4
(CH), 149.8 (CH), 158.2 (C), 168.7 (C), 168.6 (C), 168.9 (C), 169.4 1534, 1348 cm–1. MS (ESI+): m/z (%) = 619 (100) [M + Na]+.
(C) ppm. IR (CCl ): ν = 3315, 2931, 1757, 1215 cm–1. MS (ESI+): HRMS (ESI+): calcd. for C23H36N2NaO14S 619.1785 [M + Na]+;
˜
4
m/z (%) = 715 (100) [M + Na]+. HRMS (ESI+): calcd. for
C28H40N2NaO16S 715.1996 [M + Na]+; found 715.1987.
C28H40N2O16S (692.69): calcd. C 48.55, H 5.82, N 4.04, S 4.63;
found C 48.35, H 5.62, N 4.31, S 4.42.
found 619.1793. C23H36N2O14S (596.60): calcd. C 46.30, H 6.08, N
4.70, S 5.37; found C 46.42, H 6.37, N 4.91, S 5.09.
Supporting Information (see footnote on the first page of this arti-
cle): Complete description of the experimental details of precursors
and analytical data for all new compounds.
Methyl 5-Acetoxy-2,3,4,6-tetra-O-methyl-α-
D-mannopyranosyl-
(1Ǟ4)-6-deoxy-2,3-di-O-methyl-6-(4-nitrophenylsulfonylamino)-α-
D-
glucopyranoside (13): Starting from 12 (43.8 mg, 0.07 mmol), com-
pound 13 (25 mg, 0.04 mmol, 52%) was obtained as an amorphous
solid after 4 h. [α]D = +2.2 (c = 0.09, CHCl3). H NMR: δ = 2.16
Acknowledgments
1
This work was supported by the Gobierno de Canarias (Research
Program SolSubC200801000192) and the Ministerio de Ciencia e
Innovación (Research Program CTQ2010-18244), co-financed by
the Fondo Europeo de Desarrollo Regional (FEDER). I. P.-M.
thanks the Ministerio de Ciencia e Innovación for support (Re-
search Program PIE 200930I138).
(dd, J = 9.5, 3.4 Hz, 1 H), 2.16 (s, 3 H), 3.12 (dd, J = 10.1, 9.0 Hz,
1 H), 3.24 (s, 3 H), 3.27 (s, 3 H), 3.27–3.35 (m, 3 H), 3.42 (s, 3 H),
3.46 (s, 3 H), 3.47 (s, 3 H), 3.48 (s, 3 H), 3.52 (s, 3 H), 3.56–3.60
(m, 2 H), 3.74–3.78 (m, 3 H), 4.02 (d, J = 3.7 Hz, 1 H), 4.09 (d, J
= 8.7 Hz, 1 H), 5.15 (d, J = 8.2 Hz, 1 H), 6.66 (dd, J = 6.5, 6.5 Hz,
1 H), 8.20 (d, J = 9.0 Hz, 2 H), 8.29 (d, J = 9.0 Hz, 2 H) ppm. An
NOE correlation was observed between 4Ј-H and 6Ј-Ha. 13C NMR:
δ = 22.3 (CH3), 42.9 (CH2), 55.3 (CH3), 58.1 (CH3), 58.6 (CH3),
59.4 (2 CH3), 59.6 (CH3), 61.2 (CH3), 68.9 (CH), 70.2 (CH2), 74.0
(CH), 76.1 (CH), 76.8 (CH), 77.2 (CH), 81.7 (CH), 82.2 (CH), 96.7
(CH), 98.4 (CH), 104.4 (C), 123.3 (2 CH), 128.5 (2 CH), 149.3 (C),
[1] For recent reviews, see: a) J. M. Tanko, Annu. Rep. Prog. Chem.,
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ceed via eight- or higher-membered transition states have been
reported, limiting their applications to appropriate skeletons
such as steroids; for example, see: a) K. Orito, M. Ohto, N.
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149.4 (C), 170.3 (C) ppm. IR (film): ν = 3301, 2933, 1733,
˜
1347 cm–1. MS (ESI+): m/z (%) = 705 (100) [M + Na]+. HRMS
(ESI+): calcd. for C27H42N2NaO16S 705.2153 [M + Na]+; found
705.2157. C27H42N2O16S (682.69): calcd. C 47.50, H 6.20, N 4.10,
S 4.70; found C 47.52, H 6.09, N 3.83, S 4.54.
Methyl 5-Acetoxy-2,3,4-tri-O-acetyl-α-
deoxy-2,3-di-O-methyl-6-(4-nitrophenylsulfonylamino)-α-
D
-lyxopyranosyl-(1Ǟ4)-6-
-glucopyr-
D
anoside (16): By starting from 15 (44.2 mg, 0.07 mmol), compound
16 (12.1 mg, 0.02 mmol, 25%, 5ЈS/5ЈR, 4.3:1) was obtained as a
1
mixture of epimers and as a colorless oil after 3 h. H NMR [only
the major (5ЈS) isomer is described]: δ = 2.04 (s, 3 H), 2.09 (s, 3
H), 2.13 (s, 3 H), 2.15 (s, 3 H), 2.81 (dd, J = 9.5, 3.4 Hz, 1 H),
3.31–3.64 (m, 5 H), 3.37 (s, 3 H), 3.39 (s, 3 H), 3.55 (s, 3 H), 4.55
(d, J = 3.4 Hz, 1 H), 5.26 (m, 1 H), 5.29 (d, J = 7.4 Hz, 1 H), 5.30–
5.32 (m, 2 H), 5.85 (d, J = 6.9 Hz, 1 H), 8.13 (d, J = 8.7 Hz, 2 H),
8.34 (d, J = 8.7 Hz, 2 H) ppm; the signal of 1 H from NH is
missing. 13C NMR [only the major (5ЈS) isomer is described]: δ =
20.6 (CH3), 20.7 (2 CH3), 21.0 (CH3), 43.9 (CH2), 55.6 (CH3), 58.7
(CH3), 61.1 (CH3), 67.8 (CH), 67.9 (CH), 68.4 (CH), 68.6 (CH),
78.0 (CH), 82.2 (CH), 82.3 (CH), 89.9 (CH), 97.0 (CH), 98.6 (CH),
123.9 (2 CH), 128.6 (2 CH), 146.9 (C), 149.9 (C), 169.3 (C), 169.6
(2 C), 169.9 (C) ppm. IR (CCl ): ν = 3357, 2933, 1759, 1219 cm–1.
˜
4
MS (ESI+): m/z (%) = 745 (100) [M + Na]+. HRMS (ESI+): calcd.
for C28H38N2NaO18S 745.1738 [M + Na]+; found 745.1736.
Methyl 4-Hydroxy-2,3,5-tri-O-methyl-α-
6-deoxy-2,3-di-O-methyl-6-(4-nitrophenylsulfonylamino)-α-
D
-arabinofuranosyl-(1Ǟ4)-
-gluco-
[6] a) T. Greene, P. G. M. Wuts, Protective Groups in Organic Syn-
thesis, 4th ed., Wiley, Hoboken, NJ, 2007, pp. 851–868; b) P. J.
Kocienski, Protecting Groups, 3rd ed., Georg Thieme, Stutt-
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J. Synth. Org. Chem., Jpn. 2001, 59, 779–789; b) T. Kan, T.
Fukuyama, Chem. Commun. 2004, 353–359, and references
D
pyranoside (18): By starting from 17 (48.7 mg, 0.08 mmol), com-
pound 18 (24 mg, 0.04 mmol, 46%) was obtained as colorless oil
after 3 h. [α]D = +96.3 (c = 0.320, CHCl3). 1H NMR: δ = 2.88 (dd,
J = 9.5, 3.4 Hz, 1 H), 3.30–3.58 (m, 7 H), 3.35 (s, 3 H), 3.41 (s, 3
H), 3.54 (s, 3 H), 3.46 (s, 3 H), 3.53 (s, 3 H), 3.54 (s, 3 H), 3.72 (d,
7344
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7339–7345

1,8-Hydrogen Atom Transfer in Disaccharide Models
cited therein; c) for nosyl as a protecting group in peptides, see:
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2007, 63, 8164–8173.
pentamethylchromanyl-6-sulfonyl (Pmc) group, see: J. Green,
O. M. Ogunjobi, R. Ramage, A. S. J. Stewart, S. McCurdy, R.
Noble, Tetrahedron Lett. 1988, 29, 4341–4344.
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8997; b) for intermolecular HAT promoted by N-radicals un-
der these conditions, see: R. Fan, W. Li, D. Pu, L. Zhang, Org.
Lett. 2009, 11, 1425–1428.
[8] a) For the 2-(1,3-dioxan-2-yl)ethylsulfonyl group (Dios), see: I.
Sakamoto, N. Izumi, T. Yamada, T. Tsunoda, Org. Lett. 2006,
8, 71–74; b) for the β-trimethylsilylethylsulfonyl group (SES),
see: P. Ribière, V. Declerck, J. Martinez, F. Lamaty, Chem. Rev.
2006, 106, 2249–2269; c) for the ortho-anisylsulfonyl group, see:
R. R. Milburn, V. Snieckus, Angew. Chem. 2004, 116, 910; An-
gew. Chem. Int. Ed. 2004, 43, 892–894; d) for the 2,2,5,7,8-
Received: August 4, 2011
Published Online: October 25, 2011
Eur. J. Org. Chem. 2011, 7339–7345
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7345