Intramolecular 1,8- Versus 1,6-hydrogen atom transfer between pyranose units in a (1→4)-disaccharide model promoted by alkoxyl radicals. Conformational and stereochemical requirements

Article abstract of DOI:10.1021/ol070496q

The stereochemical and conformational factors controlling the intramolecular hydrogen atom transfer (HAT) reaction between the two pyranose units in a (1→4)-disaccharide when promoted by a primary 6-0-yl radical are studied. Models with α-D-Glcp-(1→4)-β-D

Full text of DOI:10.1021/ol070496q

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1785-1788
Intramolecular 1,8- versus 1,6-Hydrogen
Atom Transfer between Pyranose Units
in a (1f4)-Disaccharide Model
Promoted by Alkoxyl Radicals.
Conformational and Stereochemical
Requirements
Angeles Mart´ın, Ine´s Pe´rez-Mart´ın, Luis M. Quintanal, and Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C.,
Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain
esuarez@ipna.csic.es
Received February 27, 2007
ABSTRACT
The stereochemical and conformational factors controlling the intramolecular hydrogen atom transfer (HAT) reaction between the two pyranose
units in a (1 4)-disaccharide when promoted by a primary 6-O-yl radical are studied. Models with -Glcp-(1 4)- -Glcp or -Rhamp-
(1 4)- -Galp skeletons lead exclusively to the abstraction of H C-5 and the formation, through a nine-membered transition state, of a
1,3,5-trioxocane ring system in a stable boat-chair conformation. Notwithstanding, derivatives of -Rhamp-(1 4)- -Glcp abstract exclusively
C-1 through a seven-membered transition state and therefore lead to an interglycosidic spiro ortho ester.
f
r
-D
f
â
-
D
r-L
f
r-
D
−
′
r-L
f r-D
H
−
′
In a previous paper from this laboratory, we described a most
unusual 1,8-hydrogen atom transfer (HAT) between the two
glucopyranose units of a R-D-Glcp-(1f4)-â-D-Glcp disac-
charide (D-maltose) (1) through a nine-membered transition
state.1 The hydrogen abstraction from C-5′ is promoted, in
a highly efficient and completely regioselective manner, by
the 6-O-yl radical (A) generated in situ from the photolysis
of the primary alcohol in the presence of (diacetoxyiodo)-
benzene and iodine (Scheme 1). The C-radical (B) evolves
to a final 1,3,5-trioxocane cyclized derivative (2), presumably
via oxidation to an oxonium ion intermediate. The process
may also be accomplished under reductive conditions by
reaction of the 6-O-phthalimide derivative with tri-n-butyltin
hydride and AIBN. In this case, the C-radical reduction gave
predominant inversion of the configuration at C-5′. In
principle, this may be a synthetically useful protocol for the
remote functionalization of the C-5′ carbon atom or for the
inversion of configuration at this center and consequent
transformation of this D-glucose moiety in L-idose. None of
these synthetic processes is a trivial task under more classical
conditions.2
A question that immediately arises is whether and to what
extent this methodology can be applied to other (1f4)-
(2) (a) Ermolenko, L.; Sasaki, N. A. J. Org. Chem. 2006, 71, 693-703.
(b) Takahashi, H.; Shida, T.; Hitomi, Y.; Iwai, Y.; Miyama, N.; Nishiyama,
K.; Sawada, D.; Ikegami. S. Chem.-Eur. J. 2006, 12, 5868-5877. (c)
Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Chirality 2000, 41, 338-341.
(d) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K.
B.; Walker, F. J. Tetrahedron 1990, 46, 245-264.
(1) Francisco, C. G.; Herrera, A. J.; Kennedy, A. R.; Melia´n, D.; Sua´rez,
E. Angew. Chem., Int. Ed. 2002, 41, 856-858.
10.1021/ol070496q CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/04/2007

would be energetically disfavored, the HAT reaction could
alternatively take place at C-1′ through a seven-membered
transition state. This last reaction should give an interesting
spiro ortho ester (such as 12, Scheme 3), which is a sub-
structure present in several antibiotics of the orthosomycin5
and erythromycin6 families and consequently has attracted
considerable attention from synthetic organic chemists.7
This may be the case of the fifth-lowest-energy structural
arrangement E which is approximately 3 kcal/mol more
energetic than the arrangement of D-maltose A and where
the 1,3,5-trioxocane ring adopts a theoretically less-stable
boat-boat conformation (Table 1).
Scheme 1. HAT Reaction of D-Maltose
To address these issues, we decided to prepare disaccha-
rides R-L-Rhamp-(1f4)-R-D-Galp 3 and R-L-Rhamp-(1f4)-
R-D-Glcp 11 which, after HAT, could hypothetically lead to
structural arrangements C and E, respectively. The selection
of 3 was also made considering that arrangement C belongs
to a pseudoenantiomeric pair different from that of D-maltose
and slightly more energetic.
disaccharides or whether it is exclusive to D-maltose. As can
be easily determined by molecular mechanics calculations,
the 1,3,5-trioxocane ring in 2 adopts a constrained, stable,
boat-chair conformation.3 We therefore analyzed the con-
formation of the ring for all 16 possible disaccharide
diastereoisomers of the four chiral centers involved in the
cyclization step (C-5′, C-1′, C-4, and C-5).4 Only four
structural arrangements (A-D) were found that can easily
accommodate 1,3,5-trioxocane rings in stable boat-chair
conformations of similar minimized energies (∆E e 1.5 kcal/
mol), as depicted in Table 1. Among the four structures, two
Compounds 3 and 11 were effectively synthesized by
TMSOTf-mediated glycosylation of suitably protected
D-
galactopyranose and D-glucopyranose derivatives, respec-
tively, using 2,3,4-tri-O-acetyl-R-L-rhamnopyranosyl trichlo-
roacetimidate as the glycosyl donor, as described in the
Supporting Information.8
The alkoxyl radicals were generated by oxidation of the
primary alcohol with (diacetoxyiodo)benzene in the presence
(3) To the best of our knowledge, studies on the conformation of the
1,3,5-trioxocane ring are scarce: (a) McCullough, K. J.; Masuyama, A.;
Morgan, K. M.; Nojima, M.; Okada, Y.; Satake, S.; Takeda, S.-y. J. Chem.
Soc., Perkin Trans. 1 1998, 2353-2362. For the conformation of a related
1,3,6-trioxocane derivative, see: (b) Buchanan, G. W.; Driega, A. B.; Laister,
R. C.; Bourque, K. Magn. Reson. Chem. 1999, 37, 401-406. See also: (c)
Anet, F. A. L. In Conformational Analysis of Medium-Sized Heterocycles;
Glass, R. S., Ed.; VCH: New York, 1988; pp 35-95. (d) McGuire, R. R.;
Pflug, J. L.; Rakowsky, M. H.; Shackelford, S. A.; Shaffer, A. A.
Heterocycles 1994, 38, 1979-2004. (e) Burkert, U. Z. Naturforsch 1980,
35b, 1479-1481.
Table 1. Conformations of 1,3,5-Trioxocane Rings
(4) Molecular mechanics calculations were carried out by using CS
Chem3D, version 10.0. For the purpose of simplification, substituents at
C-2, C-3, C-2′, C-3′, and C-4′ in the carbohydrate skeleton were not
considered in the calculation.
(5) (a) Ganguly, A. K. Oligosaccharide Antibiotics. In Topics in Antibiotic
Chemistry; Sammes, P. G., Ed.; Ellis Horwood: Chichester, 1978; Vol. 2,
Part B, p 49. (b) Wright, D. E. Tetrahedron 1979, 35, 1207-1237. (c) Ollis,
W. D.; Smith, C.; Wright, D. E. Tetrahedron 1979, 35, 105-127.
(6) (a) Martin, J. R.; Egan, R. S.; Goldstein, A. W.; Collum, P.
Tetrahedron 1975, 31, 1985-1989. (b) Mikami, Y.; Yazawa, K.; Nemoto,
A.; Komaki, H.; Tanaka, Y.; Grafe, U. J. Antibiot. 1999, 52, 201-202.
(7) (a) Ohtake, H.; Ichiba, N.; Ikegami, S. J. Org. Chem. 2000, 65, 8164-
8170. (b) Ohtake, H.; Ichiba, N.; Ikegami, S. J. Org. Chem. 2000, 65, 8171-
8179. (c) Ohtake, H.; Ikegami, S. Org. Lett. 2000, 2, 457-460. (d) Nicolaou,
K. C.; Mitchell, H. J.; Fylaktakidou, K. C.; Suzuki, H.; Rodr´ıguez, R. M.
Angew. Chem., Int. Ed. 2000, 39, 1089-1093. (e) Nicolaou, K. C.;
Fylaktakidou, K. C.; Mitchell, H. J.; van Delft, F. L.; Rodr´ıguez, R. M.;
Conley, S. R.; Jin, Z. Chem.-Eur. J. 2000, 6, 3166-3185. (f) Trumtel,
M.; Tavecchia, P.; Veyrieres, A.; Sinay¨, P. Carbohydr. Res. 1990, 202,
257-275. (g) Tamura, J.; Horito, S.; Hashimoto, H.; Yoshimura, J.
Carbohydr. Res. 1988, 174, 181-199. (h) Beau, J.-M.; Jaurand, G.; Esnault,
J.; Sinay¨, P. Tetrahedron Lett. 1987, 28, 1105-1108. (i) Yoshimura, J.;
Horito, S.; Tamura, J.; Hashimoto, H. Chem. Lett. 1985, 1335-1338. (j)
Asano, K.; Horito, S.; Saito, A.; Yoshimura, J. Carbohydr. Res. 1985, 136,
1-11. (k) Asano, K.; Horito, S.; Yoshimura, J.; Nakazawa, T.; Ohya, Z.-
I.; Watanabe, T. Carbohydr. Res. 1985, 138, 325-328.
arrangement C-5′ C-1′ C-4 C-5 conformation ∆Ea
Ab
B
C
D
E
S
R
R
S
R
S
R
R
S
R
S
R
R
S
S
R
S
R
S
R
boat-chair
boat-chair
boat-chair
boat-chair
boat-boat
0
0.3
1.1
1.5
3.3
a
b
In kcal/mol. D-Maltose arrangement.
(8) (a) Schmidt, R. R.; Jung, K.-H. In PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 283-
312. For the use of 2,3,4-tri-O-acetyl-R-L-rhamnopyranosyl trichloroace-
timidate as a glycosyl donor, see: (b) Wang, J.; Li, J.; Tuttle, D.; Takemoto,
J. Y.; Chang, C.-W. T. Org. Lett. 2002, 4, 3997-4000. (c) Gurjar, M. K.;
Mainkar, A. S. Tetrahedron 1992, 48, 6729-6738.
pairs of pseudoenantiomers, A and B and C and D, with
very similar energies (∆∆E e 0.4 kcal/mol) can be identified.
Another question that now arises is whether, in those
compounds where the formation of the 1,3,5-trioxocane ring
1786
Org. Lett., Vol. 9, No. 9, 2007

of iodine, under either thermal or visible light irradiation
conditions. To acquire additional insight into the HAT
reaction mechanism, the alkoxyl radicals were also pre-
pared under reductive conditions by treatment of the 6-O-
phthalimido derivatives 6 and 13 with n-Bu3SnH/AIBN and
n-Bu3SnD/AIBN in benzene solutions.9 The synthesis of 6-O-
phthalimido derivatives was readily achieved from the
corresponding alcohol and N-hydroxyphthalimide under
Mitsunobu conditions.10
of configuration at C-5′, simply by reduction of the O-radical
prior to the abstraction reaction, or by a combination of these
two mechanisms; and finally the olefin 8 formed by reductive
elimination of the acetate group at C-4′.
The structure of 7, where the original R-L-rhamnopyra-
nosyl moiety has been transformed into a 6-deoxy-â-D-
gulopyranosyl derivative and, consequently, the pyranose ring
1
4
has been changed from a C4 to a C1 conformation, was
easily established by analyzing the coupling constants of the
1
ring hydrogens by H NMR spectroscopy.11
The results of the HAT reaction for the disaccharide R-L-
Rhamp-(1f4)-R-D-Galp 3 are outlined in Scheme 2. Under
To confirm the structures and to shed light on the HAT
mechanism, the reduction of the phthalimide 6 was also made
with n-Bu3SnD (Scheme 2). Analysis of the isotopic distribu-
tion in compound 9 showed a complete substitution of
deuterium at C-5′.12 On the other hand, only 30% of
deuterium labeling was found in compound 10, and therefore
the reduction of the O-radical is responsible for the unlabeled
molecules. It can thus be concluded that the abstraction at
C-5′ occurs with an inversion-retention ratio of approxi-
mately 9:1. The formation of unlabeled olefin 8 supports
the mechanism of free-radical reductive â-elimination pro-
posed.
Scheme 2. HAT Study of Arrangement Ca
The results pertaining to the reactivity of alkoxyl radicals
generated from alcohol 11 and phthalimide 13 are depicted
in Scheme 3. The reaction of disaccharide R-L-Rhamp-
Scheme 3. HAT Study of Arrangement Ea
a PhtN ) phthalimide.
oxidative conditions, the alcohol 3 was transformed into the
trioxocane 4 in good yield. A small amount (10%) of methyl
ketone 5 was also formed, in which the NOE interaction
observed between H-1′ and H-4 corroborates the assignment
of the (S)-configuration at C-1′. Because the ketone 5 was
presumably formed by partial acid-catalyzed rearrangement
of 4 under the reaction conditions, the HAT reaction
proceeded with absolute regioselectivity by abstraction of
the hydrogen at C-5′ in almost quantitative yield.
The phthalimide 6 by reaction with n-Bu3SnH/AIBN was
transformed into three compounds: disaccharide 7 formed
by hydrogen abstraction at C-5′ and radical quenching by
the stannane with inversion of configuration; the precursor
alcohol 3 which, evidently, arises by abstraction and retention
a PhtN ) phthalimide.
(1f4)-R-D-Glcp 11 under oxidative conditions gave rise to
the spiro ortho ester 12 in good yield. Complete regio- and
(9) (a) Crich, D.; Huang, X.; Newcomb, M. J. Org. Chem. 2000, 65,
523-529. (b) Crich, D.; Huang, X.; Newcomb, M. Org. Lett. 1999, 1, 225-
227. (c) Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471-472. (d) Okada,
K.; Okamoto, K.; Oda, M. J. Chem. Soc., Chem. Commun. 1989, 1636-
1637. (e) Barton, D. H. R.; Blundell, P.; Jaszberenyi, J. Cs. Tetrahedron
Lett. 1989, 30, 2341-2344. (f) Okada, K.; Okamoto, K.; Oda, M. J. Am.
Chem. Soc. 1988, 110, 8736-8738.
(11) Assignments were made by DEPT and 2D COSY, HMBC, and
HSQC experiments.
(12) The deuterium position was determined by the coupling with the
geminal carbon atom and also by the small yet significant displacement of
the adjacent carbon signals in the 13C NMR spectra. See: Berger, S. In
Encyclopedia of Nuclear Magnetic Resonance; Grant, D. M., Harris, R.
K., Eds.; John Wiley: Chichester, 1996; Vol. 2, pp 1168-1172.
(10) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Grochowski, E.;
Jurczak, J. Synthesis 1976, 682-684.
Org. Lett., Vol. 9, No. 9, 2007
1787

stereoselectivity was observed; the abstraction occurred
exclusively at C-1′, and no compounds resulting from
abstraction at C-5′ could be detected in the crude reaction
mixture. The stereochemistry at the spiro center was tenta-
tively assigned as R on the basis of the NOE interaction
observed between H-C-3′ and the methoxy group at C-3.13
The situation changed, however, when the HAT reaction
was performed under reductive conditions. The expected
compound 16, formed by abstraction at C-1′ and radical
reduction by the stannane with inversion of configuration,
was obtained in only 9% yield.14 The main reaction product
was the ester 14, originated also by abstraction at C-1′ but
where the radical was stabilized by â-fragmentation of the
C-5′-O bond prior to the stannane quenching. A small
amount of transesterified ester 15 was also obtained, where
the ester group had evidently migrated from the 4- to the
6-position.15
that the abstraction at C-1′ occurred with total inversion of
configuration.
These results reassured us that the modeling procedure is
reliable and that if a 1,3,5-trioxocane ring is formed in a
stable boat-chair conformation the abstraction would occur
preferentially at C-5′. Contrarily, if this process is energeti-
cally disfavored, the abstraction should occur preferentially
at C-1′. Nevertheless, we are aware that the cyclization step
may also be influenced by the nature and stereochemistry
of all the substituents of the sugar molecule, not only by the
stereochemistry of the trioxocane ring carbons (C-5′, C-1′,
C-4, and C-5), and that generalizations are difficult at this
stage of the research.
Acknowledgment. This work was supported by Research
programs CTQ2004-06381/BQU and CTQ2004-02367/BQU
of the Ministerio de Educacio´n y Ciencia, Spain, cofinanced
by the Fondo Europeo de Desarrollo Regional (FEDER). I.P.-
M. and L.M.Q. thank the Program I3P-CSIC for fellowships.
NMR spectral analysis of deuterated compounds 17 and
18 confirmed the structures and the mechanism proposed.12
The complete deuteration of 19 and the isolation of a small
amount of the undeuterated alcohol precursor 11 implicate
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) The three methoxy groups can be easily distinguished by 2D HSQC
and HMBC correlations. Furthermore, the observed coupling constants for
the hydrogens at C-4 and C-6 (J4,5 ) 9.5 Hz, J5,6e ) 5.1 Hz, and J5,6a
)
10.4 Hz) are consistent with a chair conformation for the 1,3-dioxane ring.
Ikegami et al. (ref 7a) have demonstrated, in a closely related L-rhamno-
D-glucosylidene ortho ester, that the 1,3-dioxane ring adopts a chair
conformation in the R-isomer, whereas in the S-isomer, a skew boat
conformation is preferred.
(14) The high propensity of pyranosyl radicals for quenching by stannanes
along the axial direction and formation of equatorial glycosides is well
established. See, for example: Crich, D.; Sun, S.; Brunckova, J. J. Org.
Chem. 1996, 61, 605-615 and references therein.
OL070496Q
(15) The intramolecular migration of esters from 4 to 6 positions of the
glucopyranose skeletons is well-documented: (a) Zhang, S.-Q.; Li, Z.-J.;
Wang, A.-B.; Cai, M.-S.; Feng, R. Carbohydr. Res. 1997, 299, 281-285.
(b) Morales, J. C.; Penade´s, S. Tetrahedron Lett. 1996, 37, 5011-5014.
(c) Zhang, Z.; Magnusson, G. J. Org. Chem. 1996, 61, 2383-2393. (d)
Machida, K.; Kikuchi, M. Chem. Pharm. Bull. 1993, 41, 248-251.
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