Synthesis of postulated molecular probes: Stereoselective free-radical-mediated C-glycosylation in tandem with hydrogen transfer

Article abstract of DOI:10.1021/ja046389y

Reported herein is a strategy employing an addition reaction in tandem with a hydrogen-transfer reaction for the elaboration of C-glycoside-based sialyl Lewis X (sLe^X) analogues. Significant stereocontrol was noted when alkyl radicals were reacted with a series of alkoxytaconates. Transition states were proposed to explain the obtained selectivity. Further reaction between an anomeric-centered fucosyl-derived radical and a galactosylated hydroxytaconate provided easy access to C,O-diglycosides as mimics of sLe^X. In this case, two 1,3-distant stereocenters were created with high diastereoselectivity using free radical intermediates in a tandem process.

Full text of DOI:10.1021/ja046389y

Published on Web 12/21/2004
Synthesis of Postulated Molecular Probes: Stereoselective
Free-Radical-Mediated C-Glycosylation in Tandem with
Hydrogen Transfer
Yvan Guindon,* Mohammed Bencheqroun, and Abderrahim Bouzide
Contribution from the Bio-organic Chemistry Laboratory, Institut de recherches cliniques de
Montre´al (IRCM), 110 aVenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7,
Department of Chemistry and Department of Pharmacology, UniVersite´ de Montre´al, C.P. 6128,
succursale Centre-Ville, Montre´al, Que´bec, Canada H3C 3J7, and Department of Chemistry,
McGill UniVersity, 801 Sherbrooke Street West, Montre´al, Que´bec, Canada H3A 2K6
Received June 18, 2004; E-mail: guindoy@ircm.qc.ca
Abstract: Reported herein is a strategy employing an addition reaction in tandem with a hydrogen-transfer
reaction for the elaboration of C-glycoside-based sialyl Lewis X (sLeX) analogues. Significant stereocontrol
was noted when alkyl radicals were reacted with a series of alkoxytaconates. Transition states were proposed
to explain the obtained selectivity. Further reaction between an anomeric-centered fucosyl-derived radical
and a galactosylated hydroxytaconate provided easy access to C,O-diglycosides as mimics of sLeX. In
this case, two 1,3-distant stereocenters were created with high diastereoselectivity using free radical
intermediates in a tandem process.
The present study stems from our interest in what could
appear to be unrelated scientific issues: the discovery of new
synthetic methodologies that allow for diastereoselective
modifications1-3 of acyclic free radical intermediates, and the
development of sialyl Lewis X (sLeX) mimetics as antagonists
of E- and P-selectins. The latter originates from our interest in
altering the biological effects mediated by the interaction
between posttranslationally modified proteins (e.g., glycopro-
teins) and their receptors.4
The selectin-dependent vascular adhesion of neutrophils, in
response to pro-inflammatory stimuli, is an example of such.
Disrupting the interactions between E- and P-selectins and their
respective ligands, ESL-1 (E-selectin ligand-1) and PSGL-1 (P-
selectin glycoprotein ligand-1), which are located at the surface
of neutrophils and malignant cells, is believed to be promising
as a new treatment for inflammatory diseases5 or certain forms
of invasive cancer.6
At the molecular level, recent X-ray diffraction analysis of
sLeX (alone as well as attached to the PSGL-1 N-terminus)
bound to P-selectin clearly established7 the main pharmaco-
phores to be the sialylated galactose (NeuAc-Gal) and fucose
(Fuc) subunits through electrostatic attraction and H-bonding,
the N-acetylglucosamine (GlcNAc) only acting as a tether.
Similar conclusions were empirically reached through structure-
activity relationship studies, aimed at preventing the interactions
between E- and P-selectins and their sLeX-containing ligands,
as the replacement of the GlcNAc subunit of sLeX, while
unattached to the protein, by different tethers (cyclic as well as
acyclic) led to potent antagonists in competition-based assays.8
(1) For reviews on the synthetic usefulness of free-radical-mediated reactions
see: (a) Radicals in Organic Synthesis, Volume 1: Basic Principles;
Renaud, P., Sibi, M. P., Eds/; Wiley-VCH: Weinheim, Germany, 2001.
(b) Stereochemistry of Radical Reactions: Concepts Guidelines, and
Synthetic Applications; Curran, D. P., Porter, N. A., Giese, B., Eds.; Wiley-
VCH: New York, 1996.
(2) For stereoselective free-radical-based hydrogen-transfer reactions, see: (a)
Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S. R.; Jung, G.; Bencheqroun,
M.; Faucher, A.-M.; Gue´rin, B. J. Org. Chem. 2001, 66, 5427. (b) Bouvier,
J.-P.; Jung, G.; Liu, Z.; Gue´rin, B.; Guindon, Y. Org. Lett. 2001, 3, 1391.
(c) Guindon, Y.; Faucher, A.-M.; Bourque, EÄ .; Caron, V.; Jung, G.; Landry,
S. R. J. Org. Chem. 1997, 62, 9276. (d) Guindon, Y.; Rancourt, J. J. Org.
Chem. 1998, 63, 6554. (e) Guindon, Y.; Liu, Z.; Jung, G. J. Am. Chem.
Soc. 1997, 119, 9289. (f) Guindon, Y.; Slassi, A.; Rancourt, J.; Bantle, G.;
Bencheqroun, M.; Murtagh, L.; Ghiro, E.; Jung, G. J. Org. Chem. 1995,
60, 288. (g) Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme,
D.; Renaud, J.; Robinson, G.; Lavalle´e, J.-F.; Slassi, A.; Jung, G.; Rancourt,
J.; Durkin, K.; Liotta, D. J. Org. Chem. 1994, 59, 1166. (h) Giese, B.;
Damm, W.; Wetterich, F.; Zeitz, H. G.; Rancourt, J.; Guindon, Y.
Tetrahedron Lett. 1993, 34, 5885. (i) Guindon, Y.; Lavalle´e, J.-F.; Llinas-
Brunet, M.; Horner, G.; Rancourt, J. J. Am. Chem. Soc. 1991, 113, 9701.
(3) For stereoselective free-radical-based allylation reactions, see: (a) Guindon,
Y.; Houde, K.; Pre´vost, M.; Cardinal-David, B.; Landry, S. R.; Daoust,
B.; Bencheqroun, M.; Gue´rin, B. J. Am. Chem. Soc. 2001, 123, 8496. (b)
Gue´rin, B.; Chabot, C.; Mackintosh, N.; Guindon, Y. Can. J. Chem. 2000,
78, 852. (d) Guindon, Y.; Jung, G.; Gue´rin, B.; Ogilvie, W. W. Synlett
1998, 213. (e) Guindon, Y.; Gue´rin, B.; Chabot, C.; Ogilvie, W. W. J. Am.
Chem. Soc. 1996, 118, 12528. (f) Guindon, Y.; Gue´rin, B.; Chabot, C.;
Mackintosh, N.; Ogilvie, W. W. Synlett 1995, 449.
(4) (a) Bhunia, A.; Jayalakshmi, V.; Benie, A. J.; Schuster, O.; Kelm, S.; Rama
Krishna, N.; Peters, T. Carbohydr. Res. 2004, 339, 259. (b) Ideo, H.; Seko,
A.; Ishizuka, I.; Yamashita, K. Glycobiology 2003, 13, 713R. (c) Thomas,
B. E.; Kaila, N. Med. Res. ReV. 2002, 22, 566. (d) Beum, P. V.; Cheng, P.
W. AdV. Exp. Med. Biol. 2001, 491, 279.
(5) Alper, J. Science 2003, 301, 159.
(6) Hopfner, M.; Alban, S.; Schumacher, G.; Rothe, U.; Bendas, G. J. Pharm.
Pharmacol. 2003, 55, 697.
(7) Somers, W. S.; Tang, J.; Shaw, G. D.; Camphausen, R. T. Cell 2000, 103,
467.
9
554
J. AM. CHEM. SOC. 2005, 127, 554-558
10.1021/ja046389y CCC: $30.25 © 2005 American Chemical Society

Synthesis of Postulated Molecular Probes
A R T I C L E S
Scheme 2
Figure 1. Tartrate-derived O,O- and C,O-diglycosides as GlcNAc mimics.
Scheme 1
Scheme 3. Addition of 1-Fucosyl Radical to â-Alkoxytaconate 2 in
Tandem with a Hydrogen-Transfer Reaction
In this regard, we became interested in testing the value of
O,O-diglycosides derived from dimethyl tartrate (Figure 1, X
) O) as sLeX analogues, for both theoretical and practical
reasons.
On one hand, previous studies by our group have shown that
the preferred conformation of tartrate derivatives involves both
esters being anti-oriented, to minimize electrostatic repulsion,
and the ethereal oxygens (Figure 1, X ) O) gauche to each
other.9 This led us to hypothesize that the tartrate moiety could
be an acceptable surrogate to GlucNAc. Indeed, if fucose and
galactose subunits were attached to it, they could adopt a
conformation similar to the sLeX bioactive one.7 On the other
hand, apart from being crucial for the conformational bias
described above, the presence of ester functionalities should
enable the coupling of members of this “trisaccharide” family
to other chemical entities (e.g., proteins, peptides, polymer
support, etc.). These “postulated molecular probes” could be
of use in various biochemical techniques: affinity chromatog-
raphy, cell sorting, etc.
A number of studies were launched to prepare these tartrate
derivatives (O,O-diglycosides) to test these hypotheses. It
quickly became obvious that efforts also had to be directed
toward the synthesis of derivatives with intrinsic gain in stability
against acid- and glycosidase-mediated hydrolysis. This led us
to look at mixed C,O-diglycosides (Figure 1, X ) CH2) in which
one of the oxygens is replaced by a methylene. A new chemical
strategy to the synthesis of this series of molecules first had to
be designed and tested, which is the object of the study reported
herein.
From the beginning of this project, we were interested by
the use of free radical intermediates to establish the relative
stereochemistry of the acyclic tether, as illustrated in Scheme
1. In fact, we were inspired by a number of reports on the
stereoselective free-radical-mediated synthesis of â-alkoxy
esters.
Indeed, we and others1-3,10,11 have shown that free-radical-
based hydrogen-transfer processes can be used to produce
R-alkyl-â-alkoxy esters with high stereocontrol. As described
in Scheme 2, high anti selectivity was obtained when R-bromo
or R-(phenylselenyl) esters reacted with tributyltin hydride and
a free radical initiator (e.g., Et3B; see eq 1). The addition of
bidentate Lewis acids in such reactions was found to reverse
the sense of stereoselectivity (coined the endocyclic effect;2d,i
see eq 2), the syn compounds being predominant.
Interestingly, replacing the â-alkoxy substituent by an ester
was reported12 to lead to a syn stereochemistry, as shown in eq
3. Indeed, good stereoselectivity was noted when hindered
radicals were added on diethyl 2-methylfumarate. The synthesis
of our proposed targets, as described in Scheme 3, would involve
the addition of radicals to â-alkoxytaconates, in which both an
ester and an alkoxy group are present at the stereodeterminant
center. Thus, the first question: What would be the combined
effects of these functionalities on the stereoselectivity of the
hydrogen-transfer reaction? A second, and perhaps even more
interesting question arose: Could an anomeric-based free
radical, generated from a glycosyl halide, be a suitable reactive
species for the addition to an R-alkoxytaconate as a radical trap?
One could then envisage controlling two new noncontiguous
(9) (a) Guindon, Y.; Ogilvie, W. W.; Bordeleau, J.; Cui, W.; Durkin, K.; Gorys,
V.; Juteau, H.; Lemieux, R.; Liotta, D.; Simoneau, B.; Yoakim, C. J. Am.
Chem. Soc. 2003, 125, 428. (b) Drouin, M.; Michel, A. G.; Guindon, Y.;
Ogilvie, W. W. Acta Crystallogr., Sect. C 1993, C49, 75. (c) Labelle, M.;
Morton, H. E.; Guindon, Y.; Springer, J. P. J. Am. Chem. Soc. 1988, 110,
4533.
(10) (a) Eastwood, F. W.; Mifsud, R. D.; Perlmutter, P. Aust. J. Chem. 1994,
12, 2187. (b) Erdmann, P.; Schaefer, J.; Springer, R.; Zeitz, H.-G.; Giese,
B. HelV. Chim. Acta 1992, 75, 638. (c) Bulliard, M.; Zehnder, M.; Giese,
B. HelV. Chim. Acta 1991, 7, 1600.
(11) (a) Hartung, J.; Gottwald, T.; Spehar, K. Synthesis 2002, 1469. (b) Hartung,
J. Eur. J. Org. Chem. 2001, 4, 619. (c) Hartung, J.; Kneuer, R. Eur. J.
Org. Chem. 2000, 1677. (d) Guindon, Y.; Gue´rin, B.; Landry, S. R. Org.
Lett. 2001, 3, 2293. (e) Hartung, J.; Schwarz, M.; Svoboda, I.; Fuess, H.;
Duarte, M. T. Eur. J. Org. Chem. 1999, 6, 1275. (f) Guindon, Y.; Denis,
R. C. Tetrahedron Lett. 1997, 39, 339. (g) Hartung, J.; Gallou, F. J. Org.
Chem. 1995, 60, 6706.
(8) See for example: (a) Kolb, H. C.; Ernst, B. Chem.sEur. J. 1997, 1571. (b)
Jahnke, W.; Kolb, H. C.; Blommers, M. J. J.; Magnani, J. L. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2603. (c) Kolb, H. C.; Ernst, B. Pure Appl. Chem.
1997, 69, 1879.
(12) Bulliard, M.; Zeitz, H.-G.; Giese, B. Synlett 1991, 423.
9
J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 555

A R T I C L E S
Scheme 4a
Guindon et al.
Table 1. Addition of Alkyl-Derived Free Radicals in Tandem with
a Diastereoselective Hydrogen-Transfer Reactiona
ratiob
yield
(%)
entry
radical trap
R
products
(syn:anti)
a Reagents and conditions: (a) HIO4, THF; (b) DABCO, methyl acrylate,
THF, 68%; (c) Ag2O, MeI, CH2Cl2, 75%; (d) (TBS)Cl, imidazole, CH2Cl2,
82%; (e) TBDPSCl, imidazole, CH2Cl2, 83% (f) Ac2O, 2,6-lutidine, CH2Cl2,
-50 °C, 82%.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5 (P ) H)
Me
i-Pr
c-Hex
t-Bu
Me
10a,b
11a,b
12a,b
13a,b
14a,b
15a,b
16a,b
17a,b
18a,b
19a,b
20a,b
21a,b
22a,b
23a,b
24a,b
25a,b
1:2
1:3
1:2.5
1:1.5
1:2.5
1:1
77
68
64
68
75
70
80
86
59
84
91
83
63
68
67
81
5 (P ) H)
5 (P ) H)
5 (P ) H)
6 (P ) Me)
6 (P ) Me)
i-Pr
stereogenic centers in this novel tandem process, as illustrated
in Scheme 3.
6 (P ) Me)
c-Hex
t-Bu
Me
1:2
5:1
6 (P ) Me)
The first stereocenter would result from a selective R-C-
glycosylation under stereoelectronic control, as pioneered by
Giese and others.13 The second stereocenter would result from
a hydrogen-transfer reaction involving the intermediate free
radical adduct 2, to give the “syn” isomer 3. These are the
hypotheses we seek to test in this first study.
7 (P ) TBS)
7 (P ) TBS)
7 (P ) TBS)
7 (P ) TBS)
8 (P ) TBDPS)
8 (P ) TBDPS)
8 (P ) TBDPS)
8 (P ) TBDPS)
2.5:1
4.5:1
6:1
11:1
7:1
9:1
11:1
17:1
i-Pr
c-Hex
t-Bu
Me
i-Pr
c-Hex
t-Bu
Results and Discussion
a Conditions: to a solution of the olefin and the halide (0.05M) in toluene
was slowly added (0.5 mL/h) Bu3SnH (2 equiv, 1 M) in toluene. Initiation
was accomplished using Et3B (0.2 equiv) every 20 min. b Ratios of crude
A Baylis-Hillman condensation was used to synthesize our
target radical traps, as illustrated in Scheme 4. The reaction
between methyl acrylate and methyl glyoxylate, obtained from
HIO4-mediated oxidative cleavage of dimethyl tartate, gave the
alcohol 5 in good yield, which was subsequently converted to
the various ethers 6, 7, and 8 as well as to the acetate 9.
To these substrates were added various alkyl radicals, all
generated from their corresponding iodides, using Et3B/O2 as
the initiator. As seen in Table 1, only modest anti14 selectivity
was noted when the free alcohol 5 was used as the substrate
(entries 1-4). Similar results were obtained for the methyl ether
6 when primary and secondary alkyl radicals were added (entries
5-7). Interestingly, a reversal of diastereoselectivity was
observed when the tert-butyl radical was added (entry 8). With
the silyl ethers 7 and 8, the results were much more consistent
in terms of syn preference. In both cases, the diastereocontrol
increased with the steric encumbrance of the alkyl radical (Me
< i-Pr < c-Hex < t-Bu), the TBDPS series giving a better ratio
(entries 13-16) than their TBS counterparts (entries 9-12). Of
particular importance, bearing in mind the planned tandem
sequence, is the 11:1 syn:anti ratio obtained using cyclohexyl
radical in conjunction with the TBDPS ether 8 (entry 15).
Figure 2 illustrates the importance of the ester group on the
stereogenic center for the hydrogen-transfer reaction to proceed
with syn selectivity. Indeed, compounds 17 and 18 (R ) CO2-
1
product mixtures were determined by H NMR.
Figure 2. Importance of the â-positioned ester functionality on the syn
selectivity during the hydrogen-transfer reaction.
Figure 3. Proposed transition states.
Me) were obtained in a syn-selective manner,2d whereas 26 and
27 (R ) Me) were produced with no (or even slightly anti)
selectivity.
(13) (a) Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700. (b)
Giese, B. Angew. Chem., Int. Ed. Engl. 1989, 28, 969. (c) Giese, B.; Linker,
T.; Muhn, R. Tetrahedron 1989, 45, 935. (d) Giese, B.; Hoch, M.; Lamberth,
C.; Schmidt, R. R. Tetrahedron Lett. 1988, 29, 1375. (e) Giese, B. Pure
Appl. Chem. 1988, 60, 1655. (f) Giese, B.; Dupuis, J.; Nix, M. Org. Synth.
1987, 65, 236. (g) Giese, B.; Dupuis, J. Angew. Chem., Int. Ed. Engl. 1983,
22, 622.
(14) The configuration of the syn and anti alcohols 10 and 11 was previously
assigned; see: (a) Bhat, K. S.; Dixit, K. N.; Rao, A. S. Indian J. Chem.
Sect. B 1985, 24, 509 (b) Wasmuth, D.; Arigoni, D.; Seebach, D. HelV.
Chim. Acta 1982, 65, 344. (c) Nakata, M.; Ishiyama, T.; Hirose, Y.;
Maruoka, H.; Tatsuta, K. Tetrahedron Lett. 1993, 34, 8439. (d) Nakata,
M.; Ishiyama, T.; Akamatsu, S.; Hirose, Y.; Maruoka, H. Bull. Chem. Soc.
Jpn. 1995, 68, 967. These known alcohols were subsequently derived in
the corresponding methyl and silylated ethers and their NMR data compared.
In all cases the chemical shifts of the hydrogens on the carbons bearing
the ethers of the anti isomers were upfield of those of the anti compounds,
and the constant couplings (H2-H3) of the anti compounds greater than
their syn counterparts. This assignment was confirmed by X-ray analysis
of compound 33a.
These results could be rationalized using variants of transition
states that we and others have previously suggested2,3 to explain
the experimental results obtained in a hydrogen-transfer reaction
involving carbon-centered free radicals flanked on one side by
a stereogenic center bearing an oxygen and on the other side
by an ester (Scheme 2, eqs 1 and 3). Minimization of
intramolecular dipole-dipole interactions and of the allylic 1,3-
strain in these π-delocalized radicals prompted us to propose
two transition states: A leading to the anti and B leading to
the syn products (Figure 3). The product distribution of any
specific reaction of this type would be dictated by the difference
9
556 J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005

Synthesis of Postulated Molecular Probes
A R T I C L E S
Scheme 5a
Scheme 6a
a Reagents and conditions: (a) Ac2O, pyridine, DMAP; (b) HBr, AcOH,
quantitative.
a Reagents and conditions: (a) Candida rugosa lipase, toluene, pH 7
buffer.
Table 2. Diastereoselective C-Glycosylation in Tandem with
Hydrogen Transfer Involving Free Radical Intermediates
in energy between these transition states. As reported before,2
anti products were prevalent when P was small (e.g., methyl or
benzyl) and R2 significant from a steric standpoint (isopropyl
or higher alkanes). The ratios dropped when the steric encum-
brance of P or R1 increased (see Figure 2, formation of 26 and
27). In those cases, minimization of the now important allylic
1,2-strain, by increasing the angle θA (Figure 3), placed OP in
the trajectory of the incoming hydride reagent in A, thus raising
the energy of this anti-leading transition state. In the case of
hydroxytaconate-derived radicals, the presence of an additional
electron-withdrawing group on the oxygen-bearing stereogenic
center would change the delicate balance between steric and
electronic factors by affecting the latter. Indeed, the dipole
moment is no longer defined solely by the C-O bond in these
cases, due to the presence of the additional ester functionality.
We therefore suggest that, as seen in transition state C, the
resulting angle θC, between R and OP, is greater than the
corresponding θA for transition state A, thus impeding the
approach of the incoming reagent in the case of transition state
C. Similarly, since θD is thought to be greater than θB, by
invoking the same electronic argument, the top face attack
should be facilitated in D. Thus, having increased the energy
of transition state C and decreased that of D, one would expect
the anti preference to be lower in the present cases. In this
particular situation, increasing the steric encumbrance of R and
OP should further increase θC and θD, so far facilitating the
top face attack of the reagent, at the expense of the bottom face,
thus allowing the syn products to be favored as experimentally
noted. ESR studies15 to evaluate the ground-state conformation
of such radicals are planned to support the aforementioned
hypothesis.
a Conditions: to a solution of the olefin and the halide (0.05 M) in toluene
was slowly added (0.5 mL/h) Bu3SnH (2 equiv, 1 M) in toluene. Initiation
was accomplished using Et3B (0.2 equiv) every 20 min. b Ratios of crude
product mixtures were determined by 1H NMR. c Products were not isolated.
Scheme 7a
Knowing the controlling factors of the free radical addition-
hydrogen-transfer sequence, we then turned our attention to the
second objective of our study aiming at the synthesis of our
pseudo-trisaccharides: the addition of an anomeric-centered free
radical to a chiral taconate-derived radical trap. Kinetically
controlled enzyme-based resolution (Scheme 5) of the racemic
acetate 9, using Candida rugosa lipase,16 afforded the enan-
tiopure alcohol (R)-5, which was converted to the TBDPS ether
(R)-8.
To a toluene solution containing the silyl ether (R)-8 and the
known17 peracetylated bromofucoside 28 (see the preparation
in Scheme 6) was slowly added tributyltin hydride in the
presence of Et3B and O2.
a Reagents and conditions: (a) (R)-5, NIS, TfOH, CH2Cl2, -30 °C, 48%.
trap occurred on the R face of the anomeric-centered free radical,
no â-anomer being detected in the crude reaction mixture.
Second, the reduced products 31a and 31b were obtained in a
12:1 ratio, favoring the 2,3-syn stereochemistry.
Substituting the silyl-derived protecting group by a â-galac-
tosyl moiety was then accomplished. Reaction between the
alcohol 5 and the peracetylated 1-ethylthiogalactose 2918
(Scheme 7) afforded the â-galactoside 30, the anomeric con-
figuration resulting from the well-known anchimeric participa-
tion19 of the C-2 acetate group.
The tert-butyl radical was then added to the new radical trap
30 to verify if the steric encumbrance of the sugar moiety would
be sufficient to provide stereocontrol during the hydrogen-
transfer step. As seen in entry 2, high stereocontrol was
achieved, as only 32a was observed by NMR. The addition of
As illustrated by entry 1 (Table 2), exciting results were
observed. First, as expected, stereoselective attack of the radical
(15) (a) Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G. Tetrahedron Lett.
1992, 33, 1863. (b) Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G.;
Rancourt, J.; Guindon, Y.; Tetrahedron Lett. 1993, 34, 5885.
(16) (a) Iding, H.; Wirz, B.; Sarmiento, R.-M. R. Tetrahedron: Asymmetry 2003,
14, 1541. (b) Warwel, S.; Borgdorf, R. Biotechnol. Lett. 2000, 22, 1151.
(c) Kapeller, H.; Jary, W. G.; Hayden, W.; Griengl, H. Tetrahedron:
Asymmetry 1997, 8, 245.
(18) Mu¨ller, D.; Vic, G.; Critchley, P.; Crout, D. H. G.; Lea, N.; Roberts, L.;
Lord, J. M. J. Chem. Soc., Perkin Trans. 1 1998, 15, 2287.
(19) (a) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. Engl. 2001,
40, 1576. (b) Lemieux, R.; Hayami, J. Can. J. Chem. 1965, 43, 2162.
(17) Koto, S.; Yoshida, T.; Takenaka, K.; Zen, S. Bull. Chem. Soc. Jpn. 1982,
55, 3667.
9
J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 557

A R T I C L E S
Guindon et al.
suggests a conformational bias different from the one observed
with di-O-tartrate-derived diethers, consequences of which will
be further evaluated in relevant biological systems.
Conclusion
The present study illustrated the use of an anomeric carbon-
centered free radical in an addition reaction to R,â-unsaturated
esters, followed by a hydrogen-transfer reaction. Two 1,3-distant
stereogenic centers were formed in good yield and ratio, attesting
to the potential usefulness of free radical intermediates in the
synthesis of highly functionalized molecules. In particular, this
approach offers an original route to the synthesis of new families
of pseudo-trisaccharides. The impact of such molecules and their
derivatives as putative receptor antagonists, or as molecular
probes, remains to be evaluated. The results of those studies
will be reported in due course.
Figure 4. Structure of 33a as determined by X-ray diffraction analysis.
the fucosyl radical derived from 28 was then performed, as
described in entry 3. Once again, exclusive formation of the
R-anomers was observed; 33a/b being obtained in a 7:1 ratio
as the result of the hydrogen-transfer reaction. Though the
selectivity was slightly less than what we observed in the case
of the addition of “secondary” radicals in the pilot study, this
is nonetheless an impressive result.
X-ray crystal diffraction analysis of the desired compound
33a confirmed the absolute and relative configurations of the
newly formed stereocenters, as depicted in Figure 4. One should
note the gauche orientation, not only between the two sugar
counterparts, but also between both carboxylic ester groups. This
Acknowledgment. We thank NSERC for its financial support
as well as Dr. Daniel Chapdelaine and Ms. Georgia Bizoglou
for their assistance in the preparation of this manuscript.
Supporting Information Available: Experimental procedures
and characterization data of new compounds (PDF, CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA046389Y
9
558 J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005