Mirror-Image Carbohydrates: Synthesis of the Unnatural Enantiomer of a Blood Group Trisaccharide

Article abstract of DOI:10.1021/jo035789l

Methyl D-glucoside and D-glucose pentaacetate are transformed, respectively, into methyl α-O-glucuronide 3 and hydroxymethyl β-C-glucuronide 9, which undergo decarboxylative elimination efficiently to produce 4-deoxypentenoside 4 and L-glucal 10. These unsaturated pyranosides provide an expeditious entry into mirror-image oligosaccharides, as demonstrated in the synthesis of the unnatural enantiomer of the H-type II blood group determinant trisaccharide (D-Fuc-(α1-2)-L-Gal-(β 1-4)-L-GlcNAc-β-OMe). This work illustrates that D-glucose, a common starting material in the synthesis of naturally occurring carbohydrates, can also be used to prepare their mirror-image analogues.

Full text of DOI:10.1021/jo035789l

Mir r or -Im a ge Ca r boh yd r a tes: Syn th esis of th e Un n a tu r a l
En a n tiom er of a Blood Gr ou p Tr isa cch a r id e
Fabien P. Boulineau and Alexander Wei*
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084
alexwei@purdue.edu
Received December 6, 2003
Methyl D-glucoside and D-glucose pentaacetate are transformed, respectively, into methyl R-O-
glucuronide 3 and hydroxymethyl â-C-glucuronide 9, which undergo decarboxylative elimination
efficiently to produce 4-deoxypentenoside 4 and L-glucal 10. These unsaturated pyranosides provide
an expeditious entry into mirror-image oligosaccharides, as demonstrated in the synthesis of the
unnatural enantiomer of the H-type II blood group determinant trisaccharide (D-Fuc-(R1f2)-L-
Gal-(â1f4)-L-GlcNAc-â-OMe). This work illustrates that D-glucose, a common starting material in
the synthesis of naturally occurring carbohydrates, can also be used to prepare their mirror-image
analogues.
In tr od u ction
tiospecificity, while important in very many situations,
is not a universal trait of biomolecular recognition.
A dichotomy in this paradigm is that the building
blocks of the three main classes of biopolymersspeptides,
nucleic acids, and carbohydratessare essentially homo-
chiral. The basic set of amino acids which comprise most
proteins share the same R-carbon stereochemistry com-
monly referred to as the L configuration, whereas nucle-
otides and most pyranosidic polysaccharides are derived
from carbohydrates having a D configuration, as defined
by the chiral center most remote from the reducing end.13
To further probe this fundamental aspect of biomolecular
chirality, a number of research groups have engaged in
the synthesis and evaluation of mirror-image biopoly-
mers. Proteins and polypeptides comprised solely of
D-amino acids have been synthesized and shown to be
intriguing compounds in mirror-image receptor binding,
as these are likely to resist enzymatic degradation.14-17
A similar line of thinking has been applied to nucleic
acids: oligomers composed of nucleotides derived from
2-deoxy-L-ribofuranose have been synthesized and suc-
cessfully assembled into mirror-image DNA duplexes,18
and efforts toward mirror-image RNA oligonucleotides
are being pursued.19
The role of chirality at the chemistry-biology interface
is a topic of enormous fascination and importance.1-3
Organic structures have an intrinsic capacity for chiral
discrimination, but the relationships between molecular
stereochemistry and biological function are not always
predictable. While it is often assumed that biomolecular
recognition processes are stereospecific, there are many
notable exceptions. A well-known example in which chiral
specificity is completely absent is the mammalian taste
bud receptor, which recognizes D-sugars and L-sugars
with equal avidity.4 The biological activities of various
natural products versus that of their antipodes also
provide numerous instances in which activity is not
exclusively determined by molecular chirality.5-10 Indeed,
there are cases in which signaling can be modulated by
varying the enantiomeric excess of the pheromone,11 and
there is at least one example in which the potency of the
unnatural enantiomer is superior to that of the natural
product itself.12 It is therefore apparent that enan-
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Morissette, C.; Tremblay, N.; Boule, M.; Sarazin, P.; Stea, D.; Lacombe,
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10.1021/jo035789l CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004
J . Org. Chem. 2004, 69, 3391-3399
3391

Boulineau and Wei
In comparison, oligosaccharides and glycoconjugates
based on mirror-image pyranosides have received less
attention. This is partly due to the synthetic challenge
and high cost of using L-pyranosides as synthetic precur-
sors but also to the knowledge base still being developed
for the various biological roles of carbohydrates. Mirror-
image carbohydrates may be useful for addressing the
significance of molecular chirality in glycobiology, par-
ticularly in situations where the biomolecular interac-
tions are not well defined, such as carbohydrate-
carbohydrate interactions.20 In addition, it is worth
noting that compounds containing L-sugars often have
biological activities of medicinal or agricultural value
which are superior to that of their D-sugar analogues.21-23
This suggests that mirror-image oligosaccharides and
glycoconjugates may present untapped opportunities for
the discovery and development of compounds with potent
biological activity.
F IGURE 1. H-type II blood group determinant and its
unnatural enantiomer 1.
SCHEME 1. Syn th esis of 4-Deoxyp en ten osid e 4a
The synthesis of mirror-image carbohydrates requires
a general but expeditious route to L-pyranosides and
other rare sugars. To address this, we have developed
methodologies based on the degradation of D-glucuronic
acid (GlcA) derivatives to unsaturated pyranosides, in
which the C4 and C5 substituents have been removed.24
For example, R- and â-O-GlcA derivatives can be trans-
formed in good yields into 4-deoxypentenosides (4-DPs)
by decarboxylative elimination, a method originally
described by Zˇemlicˇka and co-workers.25 We have recently
demonstrated that the same approach can also be applied
to â-C-GlcA intermediates to obtain L-glycals.26 These
dihydropyrans can be epoxidized and reacted with nu-
cleophiles with high levels of stereocontrol and provide
a novel entry into L-sugars and mirror-image oligosac-
charides.
a
Reagents and conditions: (a) p-MeOC6H4CH(OMe)2, CSA,
THF, 85 °C; (b) NaH, BnBr, DMF, rt; (c) 8:1:1 AcOH/THF/H2O,
45 °C (60% over three steps); (d) NaOCl, TEMPO (5 mol %), satd
aq NaHCO3, CH2Cl2, 0 °C; (e) DMFDNA, toluene, 120 °C (70%
over two steps).
Resu lts a n d Discu ssion
Syn th esis of 4-Deoxyp en ten osid es a n d L-Glyca ls.
Given the successful application of D-glycals as building
blocks in organic chemistry and oligosaccharide synthe-
sis,28 we considered that other chiral dihydropyrans could
be similarly useful as synthons for exploring uncharted
areas of structural or chiral space. In particular, 4-DPs
(4,5-unsaturated pentopyranosides) were attractive be-
cause of their structural resemblance to glycals. Such
derivatives have been prepared by the degradation of
common pyranosides such as D-glucose25 and D-xylose,29
but to the best of our knowledge no synthetic applications
of 4-DPs had been reported prior to our work.
We elected to synthesize 4-DP derivative 4 from
D-glucose, based on the route described by Zˇemlicˇka and
co-workers (see Scheme 1).25 2,3-Di-O-benzyl glucoside
2 was prepared in multigram quantities from methyl R-D-
glucoside in three steps and 60% yield30, then oxidized
to GlcA derivative 3 and refluxed in toluene with N,N-
dimethylformamide dineopentyl acetal (DMFDNA), a
reagent developed by Eschenmoser for the decarboxyla-
tive elimination of â-hydroxy acids.31 In their original
protocol, Zˇemlicˇka and co-workers oxidized 4,6-diol 2 with
Pt/C and O2, followed by treatment with DMFDNA in
DMF at 40 °C; however, in our hands this sequence did
not produce high yields. Replacing the first step with a
In this paper, we describe an efficient synthesis of
trisaccharide 1, the unnatural enantiomer of the H-type
II blood group determinant (see Figure 1).27 The H-type
II trisaccharide is characterized by an N-acetyllac-
tosamine unit which is R-fucosylated at the C2 position
of the galactosyl moiety. The synthesis of mirror-image
trisaccharide 1 (R-D-Fuc(1f2)-â-L-Gal-(1f4)-â-L-GlcNAc-
OMe) is achieved by constructing the D-fucosyl and
N-acetyl-L-lactosaminyl units from 4-DP and L-glycal
derivatives, respectively, both of which are ultimately
derived from D-glucose.
(20) (a) Rojo, J .; Morales, J . C.; Penade´s, S. In Host-Guest Chem-
istry; Penade´s, S., Ed.; Topics in Currrent Chemistry Vol. 218;
Springer: Berlin, 2002; p 45. (b) Burger, M. M.; Spillmann, D. J . Cell.
Biochem. 1996, 61, 562.
(21) Berkowitz, D. B.; Danishefsky, S. J .; Schulte, G. K. J . Am.
Chem. Soc. 1992, 114, 4518.
(22) Anzeveno, P. B.; Green, F. R., III. In Synthesis and Chemistry
of Agrochemicals VI; Baker, D. R., Fenyes, J . G., Lahm, G. P., Selby,
T. P., Stevenson, T. M., Eds.; ACS Symposium Series 800; American
Chemical Society: Washington, DC, 2002; p 262.
(23) Flekhter, O. B.; Baltina, L. A.; Tolstikov, G. A. J . Nat. Prod.
2000, 63, 992.
(24) Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281.
(25) Philips, K. D.; Zemlicka, J .; Horwitz, J . P. Carbohydr. Res. 1973,
30, 281.
(26) Boulineau, F. P.; Wei, A. Org. Lett. 2004, 6, 119.
(27) Examples of blood group determinant syntheses: (a) Lemieux,
R. U.; Driguez, H. J . Am. Chem. Soc. 1975, 97, 4063. (b) J acquinet,
J .-C.; Sinay¨, P. Tetrahedron Lett. 1976, 32, 1693. (c) Petrakova, E.;
Spohr, U.; Lemieux, R. U. Can. J . Chem. 1992, 70, 233. (d) Danishef-
sky, S. J .; Behar, V.; Randolph, J . T.; Lloyd, K. O. J . Am. Chem. Soc.
1995, 117, 5701. (e) Routenberg, K.; Andrade, R. B.; Seeberger, P. H.
J . Org. Chem. 2001, 66, 8165.
(28) Danishefsky, S. J .; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380.
(29) Ferrier, R. J .; Tyler, P. C. J . Chem. Soc., Perkin Trans. 1 1980,
2767.
(30) Bako´, P.; Bajor, Z.; La´szlo´, T. J . Chem. Soc., Perkin Trans. 1
1999, 3651.
(31) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35, 1675.
3392 J . Org. Chem., Vol. 69, No. 10, 2004

Mirror-Image Carbohydrates
SCHEME 2. Syn th esis of L-Glu ca l 1a
a
PMP ) p-methoxyphenyl. Reagents and conditions: (a) PhSH, BF3‚OEt2, CH2Cl2, rt; (b) NaOMe, MeOH/CH2Cl2, 0 °C; (c)
p-MeOC6H4CH(OMe)2, CSA, THF, 85 °C; (d) NaH, BnBr, DMF, rt; (e) lithium naphthalenide, THF, -78 °C (47% over five steps); (f)
DMDO, acetone/CH2Cl2, 0 °C; (g) Me2(i-PrO)SiCH2MgCl (3.5 equiv), CuI (0.5 equiv), THF, -10 °C; (h) H2O2, KOH, MeOH/THF, rt (66%
over three steps); (i) Bu2SnO, toluene, reflux then Bu4NI, BnBr, reflux (94%); (j) AcOH, THF/H2O, 45 °C (96%); (k) NaOCl, TEMPO (5
mol %), satd aq NaHCO3, CH2Cl2, 0 °C; (l) DMFDNA, xylenes, 150 °C (60% over two steps).
TABLE 1. Cu I-Med ia ted Ad d ition s of r-Silyl Gr ign a r d
hypochlorite oxidation catalyzed by tetramethyl-1-pi-
Rea gen ts to Ep oxyglyca l 6
peridine oxide (TEMPO)32 and raising the temperature
of the decarboxylative elimination afforded compound 4
from diol 2 in 70% yield.
The decarboxylative elimination approach was then
applied toward the synthesis of L-glucal 10 from the
corresponding â-C-glycoside intermediate (see Scheme
entry
equiv of CuI
yield (%)
2).26 D-Glucal 5 was obtained on a multigram scale from
commercially available â-D-glucose pentaacetate in five
steps and 47% overall yield, using the procedure reported
by Sinay¨ and co-workers.33,34 Treatment with dimethyl-
dioxirane (DMDO) gave R-epoxyglycal 6, followed by CuI-
mediated addition of Me2(i-PrO)SiCH2MgCl and Tamao-
Kumada oxidation35 to afford hydroxymethyl â-C-glycoside
7 in three steps and 66% overall yield from 5. A brief
survey of reaction conditions with a similar R-silyl
Grignard reagent (Me2PhSiCH2MgCl) demonstrated the
importance of CuI for efficient addition: whereas high
yields were observed with 0.5 equiv of CuI, the yields
decreased with 0.1 equiv and the absence of CuI did not
provide any conversion at all (see Table 1).
1
2
3
0.5
0.1
0
80
66
0
SCHEME 3. Syn th esis of L-Ga la cta l 11a
a
Reagents and conditions: (a) Dess-Martin periodinane, NaH-
CO3, 4A molecular sieves, CH2Cl2, rt; (b) NaBH4, CH3OH/CH2Cl2,
-5 °C; (c) NaH, BnBr, DMF, rt (80% over three steps).
Regioselective benzylation and deacetalization trans-
formed unsymmetrically protected meso C-glycoside 7
into triol 8 in 90% yield, which was converted into â-C-
GlcA 9 by TEMPO oxidation (see Scheme 2). Decarboxy-
lative elimination using DMFDNA in refluxing xylenes
yielded 3*,6*-O-dibenzyl-L-glucal 10 in 60% yield.36 Higher
temperatures were needed for efficient decarboxylative
elimination of the â-C-glucuronide, indicative of a greater
activation barrier imposed by the anomeric alkyl sub-
stituent.26 This strongly suggests that decarboxylative
elimination proceeds by an E2 mechanism, in which the
conformations with trans-diaxial C4 and C5 substituents,
rather than by the concerted fragmentation of a cyclic
orthoamide intermediate.32,37,38
L-Galactal was obtained in a straightforward manner
from L-glucal 10 by epimerization of C4* (see Scheme 3).
Oxidation using the Dess-Martin periodinane39 produced
an unstable ketone, which was reduced immediately with
NaBH4 in 1:1 CH3OH/CH2Cl2 to afford 3*,6*-O-dibenzyl-
L-galactal (L-galacto/L-gluco > 30:1); benzylation yielded
tri-O-benzyl-L-galactal 11 in high overall yields. With
L-glucal 10, L-galactal 11, and 4-deoxypentenoside 4 in
hand, a variety of mirror-image oligosaccharides were
now synthetically accessible.
1
intermediate glucuronides must adopt C4 or twist-boat
(32) (a) Hara, S.; Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahe-
dron Lett. 1975, 19, 1545. (b) Davis, N. J .; Flitsch, S. L. Tetrahedron
Lett. 1993, 34, 1181.
(33) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrie`res,
A.; Sinay¨, P. Carbohydr. Res. 1989, 188, 81.
(37) Mulzer, J .; Bru¨ntrup, G. Chem. Ber. 1982, 115, 2057.
(38) In addition to the E2 pathway, it is possible that fragmentation
may proceed by intramolecular SN2 displacement of the activated C4
hydroxyl to form an intermediate â-lactone, prior to thermal decar-
boxylation. However, no direct evidence of such intermediates has been
observed.
(34) This process is highly scalable, as no column chromatography
is required for this sequence. See the Supporting Information for
details.
(35) Tamao, K.; Ishida, N.; Kumada, M. J . Org. Chem. 1983, 48,
2120.
(36) To maintain a consistent nomenclature, the carbons of L-glycals
and derivatives thereof have been numbered 1* through 6*.
(39) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
J . Org. Chem, Vol. 69, No. 10, 2004 3393

Boulineau and Wei
SCHEME 4. Syn th esis of L-La ctosa m in e Der iva tivesa
a
Reagents and conditions: (a) DMDO, CH2Cl2/acetone, -55 °C; (b) EtSLi, THF, 0 °C; (c) Ac2O, pyridine, rt (69% over three steps); (d)
donor 12 (1.0 equiv), acceptor 10 (1.5 equiv), MeOTf, 2,6-di-tert-butyl-4-methylpyridine, 4A molecular sieves, CH2Cl2, 0 °C (73%); (e)
I(collidine)2ClO4, PhSO2NH2, 4A molecular sieves, 0 °C; (f) NaOMe, MeOH, rt (84% over two steps); (g) LiHMDS, EtSH, DMF, -40 °C to
rt (72% over two steps); (h) Ac2O, Et3N, DMAP, CH2Cl2, rt (96%); (i) PMBOCH2CH2OH, MeOTf, 2,6-di-tert-butyl-4-methylpyridine, 4A
molecular sieves, CH2Cl2, 0 °C (68%).
SCHEME 5. Red u ctive Clea va ge of
N-a cetylsu lfon a m id es
Syn th esis of Mir r or -Im a ge Ca r boh yd r a tes. We
chose to couple L-galactal with L-glucal to produce L-
lactal, a precursor for N-acetyl-L-lactosamine and L-
lactose (see Scheme 4). The natural enantiomers of both
disaccharides are common to the blood group oligosac-
charides; in the latter case, a â-lactosyl spacer separates
the carbohydrate antigen from the cell-surface anchor.40
Tribenzyl-L-galactal 11 was treated with anhydrous
DMDO to yield the corresponding R-epoxide and then
reacted with EtSLi and acetylated to produce thioethyl
â-L-galactoside donor 12 in 69% yield. It is worth noting
that all traces of acid must be assiduously removed to
avoid the competitive formation of the 1,2-cis-isopropyl-
idene acetal.41 L-Galactosyl donor 12 was coupled with
1.5 equiv of L-glucal 10 using the activation conditions
described by Danishefsky and co-workers to furnish
protected L-lactal 13 in 73% yield.42
N-Phenylsulfonyl-L-lactosamine derivatives 14 and 15
indeed observed in the case of methyl glycoside 16, which
was transformed cleanly into N-acetyl-L-lactosaminoside
were obtained using the sulfonamidoglycosylation pro-
tocol developed by Griffith and Danishefsky.43 Treatment
18 in 81% yield using sodium naphthalenide (see Scheme
of L-lactal 13 with iodonium dicollidine perchlorate and
5). However, reductive cleavage of glycol-linked disac-
subsequent reaction with sodium methoxide yielded
charide 17 did not result in the desired N-acetyllac-
tosamine, but instead produced oxazoline 19 in 94% yield
plus recovery of the PMB-protected ethylene glycol linker.
One possible explanation for this unexpected observation
methyl N-phenylsulfonyl-â-L-lactosaminoside 14, whereas
quenching with lithium ethanethiolate afforded the thio-
ethyl â-glycoside 15. Acetylation of 14 yielded N-acetyl-
N-phenylsulfonyl derivative 16; an L-lactosaminoside
may be attributed to the chelating properties of the
with an extended glycosyl linkage was also prepared by
ethylene glycol linker: coordination of the sodium coun-
terion could promote nucleophilic attack on the anomeric
carbon by the acetamido oxygen. This provides an
interesting alternative to 1,2-oxazolines from N-acetyl-
coupling thioglycoside 15 with PMB-protected ethylene
glycol44 after N-acetylation to afford 17 as a single
stereoisomer. Coupling this linker to 15 without prior
N-acetylation resulted in a lower yield and a 4:1 â/R ratio
glucosamines, which are more typically obtained from
of stereoisomers.
their corresponding R-glycosyl halides.46
The reductive cleavage of the acetylated N-phenylsul-
The rare sugar D-fucose was synthesized from 4-DP
fonamido groups was expected to yield the corresponding
derivative 4.47 Stereoselective epoxidation using DMDO
acetamides under relatively mild conditions.45 This was
(40) Unger, F. M. Adv. Carbohydr. Chem. Biochem. 2001, 57, 207.
(41) Lohman, G. J . S.; Seeberger, P. H. J . Org. Chem. 2003, 68, 7541.
(42) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky,
S. J . J . Am. Chem. Soc. 1997, 119, 10064.
(43) Griffith, D. A.; Danishefsky, S. J . J . Am. Chem. Soc. 1990, 112,
5811.
(45) Danishefsky, S. J .; Hu, S.; Cirillo, P. F.; Eckhardt, M.; See-
berger, P. H. Chem. Eur. J . 1997, 3, 1617.
(46) Shoda, S.-I.; Izumi, R.; Suenaga, M.; Saito, K.; Fujita, M. Chem.
Lett. 2002, 2, 150.
(47) D-Fucose has also been synthesized by C6 deoxygenation of
D-galactose: Roush, W. R.; Harris, D. J .; Lesur, B. M. Tetrahedron
Lett. 1983, 24, 2227.
(44) Huang, H.; Wong, C.-H. J . Org. Chem. 1995, 60, 3100.
3394 J . Org. Chem., Vol. 69, No. 10, 2004

Mirror-Image Carbohydrates
SCHEME 6. Syn th esis of Mir r or -Im a ge
Tr isa cch a r id e 1a
sumably via in situ regeneration of fucopyranoside 22a .
Last, global debenzylation afforded mirror-image trisac-
charide 1, whose optical activity was opposite that of the
naturally occurring enantiomer.51
In summary, we have demonstrated an efficient and
straightforward synthesis of the unnatural enantiomer
of a blood group antigen using 4-deoxypentenosides and
L-glycals, derived from readily available D-glucose deriva-
tives. An important benefit provided by this approach is
the generation of L-pyranosides in differentially protected
forms; a similar synthesis starting from unprotected
L-hexoses would be far less practical and efficient. This
synthetic methodology can be extended to a diverse range
of oligosaccharide structures for investigating the role of
chirality in carbohydrate recognition and biological func-
tion.
Exp er im en ta l Section
Meth yl 2,3-Di-O-ben zyl-4-deoxy-â-L-th r eo-pen t-4-en opy-
r a n osid e (4-Deoxyp en ten osid e) (4). A solution of methyl
2,3-di-O-benzyl-R-D-glucopyranoside 2 (0.993 g, 2.652 mmol)
in CH2Cl2 was stirred at 0 °C and treated with TEMPO (20
mg, 0.132 mmol), followed by satd aq NaHCO3 (10 mL) and
the dropwise addition of commercial bleach (∼0.7 M, 9 mL).
After 45 min, aqueous 1.0 M HCl was added (30 mL), and the
mixture was stirred for an additional 5 min. EtOAc (150 mL)
was added, and the mixture was separated, dried over Na2-
SO4, and concentrated. The resulting yellow oil was evaporated
four times with toluene (30 mL) under reduced pressure and
kept under high vacuum for 24 h to afford methyl 2,3-di-O-
benzyl-R-D-glucuronic acid 3. The crude oil was dissolved in
toluene (10 mL) and treated with N,N-dimethylformamide
dineopentyl acetal (4.0 mL, 14.33 mmol). The resulting mixture
was stirred and heated to 120 °C for 1 h under argon, cooled
to 40 °C, and evaporated to a brown oil. Silica gel chromatog-
raphy using a 5:95 to 10:90 EtOAc-hexanes gradient contain-
ing 0.1% of Et3N yielded 4-deoxypentenoside 4 as a clear oil
a
Reagents and conditions: (a) DMDO, CH2Cl2/acetone, -55 °C;
(b) AlMe3, toluene, -78 °C; (c) NaH, BnBr, DMF, rt (74% over
three steps); (d) BF3‚OEt2 (1.1 equiv), EtSH (5.0 equiv), CH2Cl2,
rt (1:2 R/â, 77%); (e) BF3‚OEt2 (3.3 equiv), EtSH (5.0 equiv),
CH2Cl2, rt (75%); (f) NaOMe, MeOH, 45 °C (99%); (g) D-fucosyl
donor (2.5 equiv), acceptor 23 (1.0 equiv), DMTST, 2,6-di-tert-butyl-
4-methylpyridine, 4A molecular sieves, CH2Cl2, -78 °C to room
temperature (5:1 R/â, 71%); (h) H2, Pd(OH)2/C, MeOH, rt (99%).
at low temperatures afforded epoxypyranoside 20 in a
10:1 â/R ratio, which was treated with trimethylalumi-
num in toluene at -78 °C and protected as a C4 benzyl
ether to yield D-fucoside 21 in three steps and 74%
isolated yield from 4 (see Scheme 6). The stereocontrolled
methylation of the 4,5-â-epoxypyranoside is analogous to
the syn addition of trialkylaluminum compounds to
R-epoxyglycals, which is considered to proceed via an
oxocarbenium ion to produce R-C-glycosides in good
yields.48 Methyl R-D-fucoside 21 was then converted into
thioethyl D-fucoside 22a in 77% yield as a mixture of
diastereoisomers. This reaction was found to be sensitive
to reagent stoichiometry; using 2 or more equiv of
ethanethiol and BF3‚Et2O produced acyclic dithioacetal
22b instead.49
Methyl N-acetyl-â-L-lactosaminoside 18 was deacety-
lated at O2′ to yield glycosyl acceptor 23 (see Scheme 6).
Attempts to couple this with glycosyl donor 22a using
MeOTf (cf. Scheme 4) did not produce any trisaccharide,
even after long reaction times at room temperature.
However, activation by dimethyl(methylthio)sulfonium
triflate (DMTST)50 afforded trisaccharide 24 as the major
product in 59% isolated yield (R/â ) 5:1). It is worth
mentioning that coupling disaccharide acceptor 23 with
acyclic dithioacetal 22b produced identical results, pre-
1
(0.607 g, 70% over two steps): [R]D +148 (c ) 1, CHCl3); H
NMR (C6D6, 300 MHz) δ 7.31-7.05 (m, 10 H, Ar-H), 6.12 (dd,
1 H, J 3,5 ) 1.2 Hz, J 4,5 ) 6.0 Hz, H-5), 4.83 (dd, 1 H, J 3,4 ) 3.0
Hz, H-4), 4.81 (d, 1 H, J 1,2 ) 2.4 Hz, H-1), 4.62 (s, 2 H, CH2-
Ph), 4.45 (s, 2 H, CH2Ph), 4.32 (ddd, 1 H, J 2,3 ) 6.0 Hz, H-3),
3.85 (dd, 1 H, H-2), 3.20 (s, 3 H, OCH3); 13C NMR (C6D6, 125
MHz) δ 144.22, 141.28, 141.18, 128.57, 128.55, 127.87, 127.81,
127.59, 127.52, 97.45, 95.16, 68.60, 64.20, 63.81, 61.36, 44.18;
HR-ESIMS calcd for C20H23O4 [M + H]+ 327.1596, found
327.1598.
Hyd r oxym eth yl (3-O-Ben zyl-4,6-O-p-m eth oxyben zyli-
d en e)-â-C-glu cop yr a n osid e (7). D-Glucal 5 (2.98 g, 8.41
mmol) was dissolved in CH2Cl2 (8 mL) and treated with freshly
prepared DMDO (140 mL, 0.1 M in acetone) at 0 °C for 30
min. The resulting epoxide was concentrated to dryness,
dissolved in anhydrous THF (35 mL), and treated with (i-PrO)-
Me2SiCH2MgCl (30 mL, 1.0 M in THF) and CuI (800 mg, 4.2
mmol) at -10 °C for 20 min under an argon atmosphere. After
aqueous workup and extraction with Et2O (150 mL), the crude
oil was dissolved in 1:1 THF/CH3OH (120 mL) and treated with
15% aqueous KOH (90 mL), followed by the slow addition of
30% aqueous H2O2 (90 mL) at 0 °C. The reaction mixture was
stirred at rt for 18 h, carefully quenched with saturated
aqueous Na2S2O3 (60 mL), and extracted with Et2O (150 mL).
Diol 7 was recrystallized from 25% EtOAc in hexanes to afford
a white crystalline solid (2.25 g, 66% yield over 3 steps): mp
147 °C; [R]D -13.3 (c ) 1 in CHCl3); 1H NMR (C6D6) δ 7.53
(48) Rainier, J . D.; Cox, J . M. Org. Lett. 2000, 2, 2707.
(49) Lehmann, J .; Petry, S.; Scheuring, M.; Schmidt-Schuchardt, M.
Carbohydr. Res. 1994, 264, 199.
(50) Wacowich-Sgarbi, S. A.; Bundle, D. R. J . Org. Chem. 1999, 64,
9080.
(51) The specific rotation of 1 ([R]20 ) +101.3; c ) 0.37, MeOH) is
D
opposite in sign but nearly equal in magnitude to that reported for
the natural enantiomer ([R]20 ) -94.3; c ) 0.9, H2O): Cromer, R.;
D
Spohr, U.; Khare, D. P.; LePendu, J .; Lemieux, R. U. Can. J . Chem.
1992, 70, 1511.
J . Org. Chem, Vol. 69, No. 10, 2004 3395

Boulineau and Wei
(m, 2H, Ar-H), 7.26 (m, 2 H, Ar-H), 7.09 (m, 3 H, Ar-H), 6.82
(m, 2 H, Ar-H), 5.29 (s, 1 H, CH-acetal), 5.02 (d, 1 H, J ) 11.7
Hz, CH-Ph), 4.63 (d, 1 H, J ) 11.7 Hz, CH-Ph), 4.10 (dd, 1 H,
J 5,6 ) 5.1 Hz, J 6a,6b ) 10.2 Hz, H-6a), 3.64-3.80 (m, 3 H), 3.55
(dt, 1 H, J OH,2 ) 2.7 Hz, J 1,2 ) J 2,3 9.3 Hz, H-2), 3.36-3.46 (m,
2 H), 3.26 (s, 3 H, OMe), 3.14-3.23 (m, 2 H), 2.07 (d, 1 H, J )
2.7 Hz, OH), 1.52 (t, 1 H, J ) 5.7 Hz, OH); 13C NMR (CDCl3)
δ 160.01, 138.28, 129.73, 128.54, 128.03, 127.93, 127.26,
113.59, 101.15, 82.09, 81.93, 79.77, 74.56, 70.55, 70.41, 68.68,
62.60, 55.26; HR-EIMS calcd for C22H26O7 [M]+ 402.1679, found
402.1684.
of Et3N yielded 3*,6*-di-O-benzyl-L-galactal as a colorless oil
(102 mg, 84%, 30:1 l-galacto/l-gluco).
A solution of di-O-benzyl-L-galactal (102 mg, 0.312 mmol)
in dry DMF (5 mL) was treated at -5 °C with NaH (60% in
mineral oil, 75 mg, 1.875 mmol), stirred for 5 min under argon,
and then treated with BnBr (0.11 mL, 0.937 mmol). After being
stirred for 1.5 h at rt, the reaction mixture was diluted at 0
°C with satd aq NH4Cl (6 mL) and Et2O (40 mL), extracted,
and concentrated. Silica gel chromatography using a 19:1 to
9:1 hexanes-EtOAc gradient containing 0.1% of Et3N yielded
L-galactal 11 as a colorless oil: [R]20D ) +42.0 (c ) 1 in CHCl3);
1H NMR (C6D6) δ 7.06-7.30 (m, 15 H, Ar-H), 6.25 (dd, 1 H,
J 1,3 ) 1.5 Hz, J 1,2 ) 6.3 Hz, H-1*), 4.78 (d, 1 H, J ) 11.7 Hz,
CH-Ph), 4.72 (ddd, 1 H, J 1,4 ) 1.5 Hz, J 2,3 ) 3.0 Hz, H-2*),
4.45 (d, 1 H, J ) 11.7 Hz, CH-Ph), 4.36 (AB system, 2 H, J AB
) 12.0 Hz,CH2-Ph), 4.30 (AB system, 2 H, J AB ) 12.0 Hz, CH2-
Ph), 4.24 (m, 1 H, H-3*), 3.81-3.91 (m, 4 H, H-4*,5*,6a*,6b*);
13C NMR (C6D6) δ 144.23, 139.22, 138.93, 128.49, 128.42,
128.39, 127.99, 127.86, 127.60, 127.57, 127.49, 100.11, 76.02,
73.33, 73.29, 72.19, 71.28, 70.94, 68.73; HR-ESIMS calcd for
3*,6*-Di-O-ben zyl-L-glu ca l (10).36 Diol 7 (2.25 g, 5.59
mmol) was refluxed in toluene (110 mL) with (n-Bu)2SnO (1.95
g, 7.83 mmol) for 2 h, with azeotropic distillation of water using
a Dean-Stark apparatus. TBAI (2.50 g, 6.76 mmol), Et3N (35
µL, 0.27 mmol), and BnBr (2.32 mL, 19.5 mmol) were succes-
sively added, and the reaction mixture was refluxed for an
additional 18 h before being concentrated and passed through
a silica gel plug (hexanes/EtOAc) to afford the primary benzyl
ether as a wax (2.58 g, 94%): [R]20 ) -12.4 (c ) 1 in CHCl3);
D
C
27H28O4 [M]+ 416.1988, found 416.1996.
1H NMR (C6D6) δ 7.53 (m, 2H, Ar-H), 7.34 (m, 2 H, Ar-H), 7.28
(m, 2 H, Ar-H), 7.07-7.18 (m, 6 H, Ar-H), 6.82 (m, 2 H, Ar-H),
5.29 (s, 1 H, CH-acetal), 5.05 (d, 1 H, J ) 12.0 Hz, CH-Ph),
4.73 (d, 1 H, J ) 12.0 Hz, CH-Ph), 4.37 (AB system, 2 H, J AB
E t h yl 2*-O-Acet yl-3*,4*,6*-t r i-O-b en zyl-1-t h io-â-L-ga -
la ctop yr a n osid e (12). A solution of l-galactal 11 in CH2Cl2
(1 mL, 0.17 m solution) was added dropwise to a solution of
DMDO (5 mL, 0.1 m in acetone) at -55 °C under argon and
stirred for 3 h. The reaction mixture was warmed to rt,
concentrated, and dried under high vacuum. The highly acid-
sensitive R-epoxy-L-galactal was used without further purifica-
tion.
) 12.3 Hz, CH2-Ph), 4.19 (dd, 1 H, J 5,6a ) 4.8 Hz, J 6a,6b
)
10.5 Hz, H-6), 3.76 (t, 1 H, J 1,2 ) J 2,3 9.0 Hz, H-2), 3.68 (d, 2
H, CH2-Ph), 3.22-3.58 (m, 8 H), 2.54 (bs, 1 H, OH); 13C NMR
(C6D6) δ 160.47, 139.42, 138.82, 130.86, 128.59, 128.55, 128.16,
127.86, 127.80, 127.78, 127.73, 127.68, 113.77, 101.45, 82.69,
82.20, 79.71, 74.52, 73.65, 71.40, 70.88, 70.44, 68.99, 54.73.
CIMS m/z 493 [M + H]+. The partially benzylated intermediate
was redissolved in 8:1:1 AcOH/THF/H2O (60 mL) and stirred
at 45 °C for 2 h, concentrated, and purified by silica gel
chromatography (hexanes/EtOAc) to afford triol 8 as a colorless
oil (1.89 g, 96%), which was used without further purification.
A stirring solution of EtSH (0.5 mL, 6.75 mmol) in dry THF
(4 mL) at 0 °C was treated with n-BuLi (0.1 mL, 2.6 M in
hexanes) under an argon atmosphere. The resulting mixture
was treated with R-epoxy-L-galactal (0.168 mmol, in 4 mL of
THF) at 0 °C and stirred for 18 h. The reaction was diluted
with satd aq NaHCO3 (15 mL) and EtOAc (80 mL), extracted,
dried over Na2SO4, and concentrated. Silica gel chromatogra-
phy using a 9:1 to 4:1 hexanes-EtOAc gradient yielded the
corresponding thioethyl â-L-galactoside as a colorless oil.
The galactoside C2* alcohol was dissolved in dry pyridine
(4 mL) and treated with acetic anhydride (2 mL). After being
stirred at rt for 18 h, the reaction was quenched at 0 °C with
satd aq NaHCO3 (50 mL), diluted with CHCl3 (80 mL),
extracted, washed with brine (10 mL), dried with Na2SO4, and
azeotroped with dry toluene (15 mL) under high vacuum to
Triol 8 (1.89 g, 5.04 mmol) was dissolved in CH2Cl2 (50 mL)
and treated with TEMPO (39 mg, 0.25 mmol), saturated
aqueous NaHCO3 (50 mL), and NaOCl (28 mL, 0.7 m in H2O)
at 0 °C for 30 min. The reaction mixture was diluted with satd
aq NH4Cl until pH ) 5 and then thoroughly extracted with
EtOAc (3 × 75 mL) and concentrated to yield C-glucuronide 9
as a clear oil. This was dissolved in degassed xylenes (50 mL)
and N,N-dimethylformamide dineopentyl acetal (7 mL, 25.0
mmol) and heated to 70 °C for 15 min and then to 150 °C for
45 min under an argon atmosphere. The crude mixture was
concentrated and purified by gradient silica gel chromatogra-
phy (hexanes/EtOAc) to afford 3*,6*-di-O-benzyl-L-glucal 10
afford 2*-O-acetyl-L-galactoside 12 as a colorless oil (63 mg,
1
69% over three steps): [R]20 ) +2.4 (c ) 0.63 in CHCl3); H
D
NMR (C6D6) δ 7.06-7.30 (m, 15 H, Ar-H), 5.39 (dd, 1 H, J )
9.0, 9.9 Hz, H-2*), 4.62-4.75 (m, 3 H, CH-Ph), 4.31-4.51 (m,
3 H, CH-Ph), 4.21 (d, 1 H, J ) 9.9 Hz, H-1*), 3.54-3.66 (m, 4
H, H-3*,4*,6a*,6b*), 3.29 (dt, 1 H, J ) 2.7, 9.3 Hz, H-5*), 2.66
(m, 2 H, CH2S), 1.72 (s, 3 H, OAc), 1.11 (t, 3 H, J ) 7.5 Hz,
SCH2-CH3); 13C NMR (CDCl3) δ 169.95, 138.91, 138.31, 138.13,
128.74, 128.72, 128.48, 128.28, 128.24, 128.14, 128.04, 127.77,
127.74, 83.96, 81.78, 77.77, 74.71, 73.85, 73.22, 72.25, 69.95,
68.83, 23.85, 21.37, 15.13; HR-CIMS calcd for C31H37O6S [M
+ H]+ 537.2311, found 537.2318.
as a colorless oil (0.99 g, 58% yield over three steps): [R]20
)
D
+35.0 (c ) 1 in CHCl3); 1H NMR (C6D6) δ 7.06-7.30 (m, 10 H,
Ar-H), 6.19 (dd, 1 H, J 1,3 ) 1.2 Hz, J 1,2 ) 6.0 Hz, H-1*), 4.66
(dd, 1 H, J 2,3 ) 2.1 Hz, H-2*), 4.06 (dd, 1 H, J ) 6.6, 9.0 Hz,
H-4*), 3.97 (m, 1 H, H-3*), 3.86 (m, 1 H, H-5*), 3.70 (dd, J 5,6a
) 4.8 Hz, J 6a,6b ) 10.8 Hz, H-6a*), 3.65 (dd, J 5,6b ) 3.6 Hz,
J 6a,6b ) 10.5 Hz, H-6b*), 2.22 (bs, 1 H, OH); 13C NMR (C6D6) δ
144.61, 139.38, 138.69, 128.55, 128.53, 127.81, 127.76, 127.72,
127.65, 100.37, 77.28, 76.49, 73.27, 70.54, 69.34, 69.03; HR-
ESIMS calcd for C20H22O4 [M]+ 326.1518, found 326.1520.
P r otected L-La cta l (13). A mixture of thioethyl-L-galac-
tosyl donor 12 (63 mg, 0.117 mmol) and L-glucal acceptor 10
(53 mg, 0.162 mmol) were azeotroped with toluene (3 × 10
mg) and dried under high vacuum. 4A molecular sieves (200
mg), di-tert-butyl-4-methylpyridine (96 mg, 0.468 mmol), and
CH2Cl2 (2 mL) were added under an argon atmosphere. The
suspension was stirred at rt for 30 min, cooled to 0 °C, and
treated dropwise with MeOTf (53 µL, 0.468 mmol). The
reaction mixture was stirred at 0 °C for 18 h, warmed to rt
for 30 min, and then treated with Et3N (0.1 mL). EtOAc (50
mL) was added, and the mixture was filtered, diluted with satd
aq NaHCO3 (15 mL), extracted, dried with Na2SO4, and
concentrated. Silica gel chromatography using a 9:1 to 4:1
hexanes-EtOAc gradient containing 0.1% of Et3N gave a
mixture of L-lactal 13 and L-glucal acceptor 10 as a colorless
oil. Size-exclusion liquid chromatography (J AI LC-908, CHCl3)
3*,4*,6*-Tr i-O-ben zyl-L-ga la cta l (11). A solution of 3*,6*-
di-O-benzyl-L-glucal 10 (121 mg, 0.370 mmol), 4A molecular
sieves (80 mg), and NaHCO3 (180 mg) in dry CH2Cl2 (4.5 mL)
was stirred at rt under argon atmosphere and treated with
Dess-Martin periodinane (280 mg, 0.660 mmol). The mixture
was vigorously stirred under complete disappearance of the
starting material (1 h), filtered, and rinsed with CH2Cl2 (2 ×
3 mL). The filtrate was quickly diluted with CH3OH (11 mL),
cooled to -5 °C, and treated with NaBH4 (52 mg, 1.374 mmol,
added in three portions). After 1.5 h, the reaction was diluted
with acetone (5 mL), satd aq Na2S2O3 (15 mL), satd aq NH4Cl
(15 mL), and CHCl3 (80 mL). The mixture was extracted, dried
with Na2SO4, and concentrated. Silica gel chromatography
using a 9:1 to 4:1 hexanes-EtOAc gradient containing 0.1%
3396 J . Org. Chem., Vol. 69, No. 10, 2004

Mirror-Image Carbohydrates
afforded pure L-lactal 13 as a clear oil (67 mg, 73% yield), as
138.18, 138.10, 138.03, 137.96, 132.22, 128.67, 128.54, 128.49,
128.44, 128.32, 128.21, 128.13, 128.05, 127.94, 127.81, 127.78,
127.65, 127.43, 127.36, 100.32, 83.55, 79.91, 79.58, 74.91,
74.79, 73.67, 73.58, 73.45, 72.81, 72.67, 71.99, 69.42, 67.98,
56.54, 24.92, 21.10, 14.75; ESIMS m/z 1040 [M + Na]+.
well as recovered L-glucal acceptor 10 (15 mg): [R]20 ) -2.5
D
(c ) 1 in CHCl3); IR (thin film) 3030, 2868, 1750, 1649, 1496,
1367, 1232, 1075, 1027, 735, 697, 478; 1H NMR (C6D6) δ 7.40-
7.05 (m, 25 H, ArH), 6.24 (dd, 1 H, J 1,3 ) 0.9 Hz, J 1,2 ) 6.3 Hz,
H-1a), 5.85 (dd, 1 H, J ) 8.1, 10.5 Hz, H-2b), 4.92 (d, 1 H, J )
11.4 Hz, CH-Ph), 4.72 (m, 2 H, CH-Ph, H-2a), 4.60-4.15 (m,
11 H), 4.09 (m, 1 H), 3.92 (dd, 1 H, J ) 4.5, 10.8 Hz), 3.81 (d,
1 H, J ) 2.4 Hz), 3.70 (m, 2 H), 3.49 (dd, 1 H, J ) 5.4, 9.0 Hz),
3.36 (dd, 1 H, J ) 7.2, 6.0 Hz), 3.25 (dd, 1 H, J ) 2.7, 10.2
Hz), 1.80 (s, 3 H, OAc); 13C NMR (CDCl3) δ 169.39, 144.32,
138.69, 138.44, 138.04, 137.90, 137.73, 128.36, 128.34, 128.29,
128.17, 128.11, 127.87, 127.76, 127.69, 127.67, 127.57, 127.45,
127.36, 127.31, 127.25, 100.30, 99.81, 80.17, 75.83, 74.43,
73.80, 73.53, 73.46, 73.44, 73.34, 72.36, 71.75, 71.51, 70.48,
68.28, 68.02, 20.92; HR-ESIMS calcd for C49H52O10Na [M +
Na]+ 823.3458, found 823.3457.
Meth yl 2-Aceta m id o-4-O-(2-a cetyl-3,4,6-tr i-O-ben zyl-â-
L-ga la ctop yr a n osyl)-3,6-d i-O-ben zyl-2-d eoxy-â-L-glu cop y-
r a n ose (18). A solution of N-phenylsulfonamide 14 (63 mg,
0.066 mmol), DMAP (2 mg), and Et3N (0.45 mL) in CH2Cl2
(2.0 mL) was treated with acetic anhydride (0.2 mL, 2.11
mmol) and stirred for 18 h at rt. Aqueous workup (CHCl3, 20
mL) followed by silica gel chromatography using 4:1 hexanes-
EtOAc afforded N-acetylsulfonamide 16 as an oil (64 mg, 95%).
Compound 16 was azeotroped twice with toluene, dissolved
in THF (2 mL) at -78 °C under an argon atmosphere, and
treated dropwise with a freshly prepared solution of sodium
naphthalenide (1.5 mL, 0.23 M in THF) until a green color
persisted. Aqueous workup (CHCl3, 20 mL) followed by silica
gel chromatography using a 2:1 to 0:100 hexanes-EtOAc
Meth yl 3,6-Di-O-ben zyl-4-O-(3,4,6-tr i-O-ben zyl-â-L-ga -
la ct op yr a n osyl)-2-d eoxy-2-p h en ylsu lfon a m id o-â-L-glu -
cop yr a n osid e (14). A suspension of L-lactal 13 (62 mg, 0.077
mmol), benzenesulfonamide (49 mg, 0.309 mmol), and 4A
molecular sieves (60 mg) in CH2Cl2 (4 mL) at 0 °C was treated
with I(sym-collidine)2ClO4 (145 mg, 0.309 mmol) under an
argon atmosphere. After 30 min, the mixture was filtered,
rinsed with Et2O (40 mL), washed with satd aq Na2S2O3 (20
mL), satd aq CuSO4 (10 mL), and brine (20 mL), dried with
Na2SO4, and concentrated. Silica gel chromatography using a
9:1 to 4:1 hexanes-EtOAc gradient afforded the corresponding
2-iodo-1-phenylsulfonamide as an oil (76 mg, 90%). The
resulting iodosulfonamide (76 mg, 0.070 mmol) was treated
with a 0.3 M solution of NaOMe in MeOH (3 mL) at rt under
argon and stirred for 18 h. The mixture was treated with satd
aq NH4Cl (20 mL) and CHCl3 (60 mL), extracted, dried over
Na2SO4, and concentrated to give 14 as clear oil (63 mg,
gradient afforded N-acetyl-L-lactosamine 18 as an oil (45 mg,
1
81%): [R]20 ) +29.5 (c ) 1.0 in CHCl3); H NMR (CDCl3) δ
D
7.22-7.33 (m, 25 H, Ar-H), 6.15 (d, 1 H, J ) 9.0 Hz, NH), 5.29
(dd, 1 H, J ) 7.8, 9.9 Hz, Hb-2), 4.91 (d, 1 H, J ) 11.7 Hz,
CH-Ph), 4.32-4.68 (m, 11 H), 3.92-4.03 (m, 3 H), 3.70-3.82
(m, 4 H), 3.42-3.59 (m, 4 H), 3.41 (s, 3 H, OCH3), 2.01 (s, 3 H,
Ac), 1.95 (s, 3 H, Ac); HR-ESIMS calcd for C52H59NO12Na [M
+ Na]+ 912.3935, found 912.3941.
2-Am in o-4-O-(2-O-a cetyl-3,4,6-tr i-O-ben zyl-â-L-ga la cto-
p yr a n osyl)-3,6-d i-O-ben zyl-2-d eoxy-1-O,2-N-(eth a n -1-yl-
1-ylid en e)-R-L-glu cop yr a n osid e (19). A solution of N-phe-
nylsulfonamide 15 (52 mg, 0.051 mmol), DMAP (2 mg), and
Et3N (0.45 mL) in CH2Cl2 (2.0 mL) was treated with acetic
anhydride (0.2 mL, 2.11 mmol) and stirred for 18 h at rt.
Aqueous workup (CHCl3, 20 mL) followed by silica gel chro-
matography using 4:1 hexanes-EtOAc afforded the N-acetyl-
sulfonamide as an oil (51.4 mg, 95%). A mixture of the
resulting N-acetylsulfonamide donor (51.4 mg, 0.048 mmol)
and PMB-protected ethylene glycol43 (30 mg, 0.164 mmol) was
azeotroped with toluene (3 × 10 mL) and dried under high
vacuum. Molecular sieves (4A, 50 mg), di-tert-butyl-4-meth-
ylpyridine (40 mg, 0.192 mmol), and CH2Cl2 (1 mL) were added
under an argon atmosphere. The suspension was stirred at rt
for 30 min, cooled to 0 °C, and treated dropwise with MeOTf
(22 µL, 0.192 mmol). The reaction mixture was stirred at 0 °C
for 18 h, warmed to rt for 30 min, treated with Et3N (0.1 mL),
and diluted with EtOAc (50 mL). The mixture was filtered,
diluted with satd aq NaHCO3 (15 mL), washed with H2O (8
mL), dried with Na2SO4, and concentrated. Preparative TLC
using 2:1 hexanes-EtOAc yielded compound 17 as a clear oil
(39.5 mg, 68%): 1H NMR (CDCl3) δ 7.87 (m, 2 H, Ar-H), 7.18-
7.48 (m, 30 H, Ar-H), 6.86 (m, 2 H, Ar-H), 5.39 (d, 1 H, J )
5.7 Hz, Ha-1), 5.32 (dd, 1 H, J ) 8.1, 10.2 Hz, Hb-2), 4.96 (d,
1 H, J ) 12.0 Hz, CH-Ph), 4.83 (AB system, 2 H, J AB ) 11.7
Hz, CH2-Ph), 4.26-4.70 (m, 10 H), 3.80-3.95 (m, 5 H), 3.79
(s, 3 H, OCH3), 3.33-3.72 (m, 10 H), 1.97 (s, 3 H, Ac), 1.86 (s,
3 H, Ac).
1
95%): [R]20 ) +12.5 (c ) 0.2 in CHCl3); H NMR (CDCl3) δ
D
7.83 (m, 2 H, Ar-H), 7.21-7.47 (m, 28 H, Ar-H), 4.94 (d, 1 H,
J 1a,2a ) 6.9 Hz, H-1a), 4.48-4.89 (m, 8 H, 4CH2Ph), 4.43 (d, 1
H, J 1b,2b ) 7.8 Hz, H-1b), 4.32 (AB system, 2 H, J AB ) 11.7
Hz, CH2Ph), 4.05 (d, 1 H, J NH,2a ) 7.2 Hz, NH), 4.03 (t, 1 H,
J 2a,3a ) J 3a,4a ) 7.8 Hz, H-3a), 3.90 (m, 3 H, H-2b,4b,5b), 3.70
(dd, 1 H, J ) 3.0, 10.8 Hz, H-6b), 3.60 (t, 1 H, J 4a,5a ) 8.1 Hz,
H-4a), 3.34-3.58 (m, 6 H), 3.29 (dd, 1 H, J 3b,4b ) 2.7 Hz, J 2b,3b
) 9.6 Hz), 2.97 (s, 3 H, OCH3); ESIMS m/z 968 [M + Na]+.
Eth yl 4-O-(2-Acetyl-3,4,6-tr i-O-ben zyl-â-L-ga la ctop yr a -
n osyl)-3,6-d i-O-b en zyl-2-d eoxy-2-p h en ylsu lfon a m id o-1-
th io-â-L-glu cop yr a n osid e (15). A suspension of L-lactal 13
(62 mg, 0.077 mmol), benzenesulfonamide (49 mg, 0.309
mmol), and 4A molecular sieves (60 mg) in CH2Cl2 (4 mL) at
0 °C was treated with I(sym-collidine)2ClO4 (145 mg, 0.309
mmol) under an argon atmosphere. After 30 min, the mixture
was filtered, rinsed with Et2O (40 mL), washed with satd aq
Na2S2O3 (20 mL), satd aq CuSO4 (10 mL), and brine (20 mL),
dried with Na2SO4, and concentrated. Silica gel chromatogra-
phy using a 9:1 to 4:1 hexanes-EtOAc gradient afforded the
2-iodo-1-phenylsulfonamide as an oil (76 mg, 90%).
LiHMDS (0.95 M in THF) was added to a stirred solution
of EtSH (0.15 mL, 2.02 mmol) in DMF (2 mL) at -40 °C,
followed by the dropwise addition of the iodosulfonamide (2
mL, 0.032 mM in DMF). The reaction mixture was stirred at
-40 °C for 1 h and then at room temperature for 3 h, diluted
with satd aq NH4Cl (10 mL) and Et2O (80 mL), extracted, dried
over Na2SO4, and concentrated. Silica gel chromatography
using a 9:1 to 4:1 hexanes-EtOAc gradient afforded disac-
A solution of N-acetylsulfonamide 17 (39.5 mg, 0.033 mmol)
in THF (3 mL) at -78 °C was treated dropwise with a freshly
prepared solution of sodium naphthalenide (1.0 mL, 0.23 M
in THF) under an argon atmosphere until the green color
persisted. Aqueous workup (CHCl3, 20 mL) followed by silica
gel chromatography using a 2:1 to 0:100 hexanes-EtOAc
gradient afforded the oxazoline derivative 19 as a crude oil
(27 mg, 94%): IR (thin film) 2866, 1750, 1671, 1513, 1496,
1454, 1367, 1235, 1071, 736, 698; 1H NMR (CDCl3) δ 7.24-
7.42 (m, 25 H, Ar-H), 6.01 (d, 1 H, J ) 7.5 Hz, Ha-1), 5.35 (dd,
1 H, J )7.8, 9.9 Hz, Hb-2), 4.97 (d, 1 H, J )12.0 Hz, CH-Ph),
4.50-4.75 (m, 7 H, CH-Ph), 4.43 (d, 1 H, J )7.8 Hz, Hb-1),
4.37 (s, 2 H, CH2-Ph), 4.27 (t, J )2.1 Hz, Hb-3), 4.20 (m, 1 H,
Ha-2), 3.97 (m, 2 H, Hb-4, Ha-3), 3.41-3.68 (m, 7 H, Ha-4,5,-
6a,6b, Hb-5,6a,6b), 2.07 (d, 3 H, J 1.8 Hz, NdC-CH3), 1.94 (s,
3 H, OAc); ESIMS m/z 880 [M + Na]+.
charide 15 as a white solid (52.7 mg, 80%): [R]20 ) +32.0 (c
D
) 1 in CHCl3); IR (thin film) 2869, 1749, 1453, 1367, 1328,
1
1231, 1157, 1089, 735, 697; H NMR (CDCl3) δ 7.95 (m, 2 H,
SO2Ph), 7.25-7.45 (m, 28 H, Ar-H), 5.34 (m, 2 H, NH, H-2),
4.98 (d, 1 H, J 11.7 Hz, CH-Ph), 4.72 (d, 1 H, J ) 12.0 Hz,
CH-Ph), 4.37-4.63 (m, 10 H), 4.00 (m, 2 H), 3.43-3.76 (m, 9
H), 2.56 (m, 2 H, SCH2), 2.04 (s, 3 H, OAc), 1.19 (t, 3 H, J )
7.5 Hz, SCH2CH3); 13C NMR (CDCl3) δ 170.03, 141.79, 138.54,
J . Org. Chem, Vol. 69, No. 10, 2004 3397

Boulineau and Wei
Meth yl 2,3,4-Tr i-O-ben zyl-R-D-fu cosid e (21). A solution
of 4-deoxypentenoside 4 (0.433 g, 1.326 mmol) in CH2Cl2 (2
mL) was stirred at -55 °C and treated with a freshly prepared
solution of DMDO (27 mL, 0.1 M in acetone). The resulting
mixture was stirred at -55 °C under argon for 2 days and then
warmed to 0 °C over a period of 4 h. The mixture was
concentrated to an oil to afford the â-epoxypyranoside 20 as a
10:1 â/R mixture (0.452 g, 99%). The crude epoxide was
evaporated with toluene (10 mL) under reduced pressure, kept
under high vacuum for 24 h, and then used without further
purification.
Performing the above reaction with an excess of BF3‚OEt2
(21 µL, 0.132 mmol) yielded instead the corresponding acyclic
dithioacetal 22b (18 mg, 75%): [R]20 ) -5.4 (c ) 0.5 in
D
1
CHCl3); H NMR (CDCl3) δ 7.27-7.36 (m, 15 H, Ar-H), 4.82
(m, 4 H, 2CH2-Ph), 4.75 (d, 1 H, J ) 11.7 Hz, CH-Ph), 4.60 (d,
1 H, J ) 11.7 Hz, CH-Ph), 4.29 (dd, 1 H, J ) 4.5, 6.0 Hz, H-3),
4.03 (m, 1 H, H-5), 3.96 (m, 2 H, H-1,2), 4.48 (dd, 1 H, J ) 3.0,
4.5 Hz, H-4), 2.68 (m, 2 H, SCH2), 1.22 (m, 6 H, SCH2CH3,
CH3); 13C NMR (CDCl3) δ 138.40, 138.06, 137.85, 128.28,
128.13, 128.00, 127.96, 127.73, 127.68, 127.62, 127.39, 82.68,
81.78, 80.93, 75.07, 74.48, 73.22, 67.08, 53.63, 25.24, 25.10,
19.83, 14.30; HR-ESIMS calcd for C31H40O4S2Na [M + Na]+
563.2266, found 563.2258.
A solution of the epoxide (15 mg, 0.044 mmol) in anhydrous
toluene (1.5 mL) was treated with AlMe3 (0.1 mL, 2.0 M in
hexanes) at -78 °C under an argon atmosphere. The reaction
mixture was stirred for 15 min, quenched with satd aq NH4Cl
(10 mL) at -78 °C, and allowed to reach rt. The mixture was
diluted with EtOAc (20 mL), extracted, dried over Na2SO4, and
concentrated. Silica gel chromatography using a 4:1 hexanes-
Meth yl 2-Aceta m id o-4-O-(3,4,6-tr i-O-ben zyl-â-L-ga la c-
t op yr a n osyl)-3,6-d i-O-b e n zyl-2-d e oxy-â-L -glu cop yr a -
n ose (23). Acetate 18 (45 mg, 0.050 mmol) was diluted in a
0.3 M solution of NaOMe in MeOH and stirred for 18 h at 45
°C. Aqueous workup (CHCl3, 25 mL) afforded the glycosyl
acceptor 23 as a clear wax (43 mg, 99%): [R]20 ) +9.6 (c )
EtOAc gradient afforded methyl 2,3-di-O-benzyl-R-D-fucoside
D
0.5 in CHCl3); 1H NMR (CDCl3) δ 7.23-7.36 (m, 25 H, Ar-H),
5.74 (d, 1 H, J ) 7.8 Hz, NH), 4.89 (d, 1 H, J ) 11.7 Hz, CH-
Ph), 4.87 (d, 1 H, J ) 11.7 Hz, CH-Ph), 4.53-4.74 (m, 8 H),
1
as a clear oil (15 mg, 95%): [R]20 ) +48 (c ) 1 in CHCl3); H
D
NMR (C6D6) δ 7.05-7.39 (m, 10 H, Ar-H), 4.70 (d, 1 H, J 1,2
)
3.3 Hz, H-1), 4.43-4.60 (m, 4 H, 2CH2-Ph), 3.94 (dd, 1 H, J 2,3
) 9.6 Hz, H-2), 3.86 (dd, 1 H, J 3,4 ) 3.0 Hz, H-3), 3.64 (dq, 1
H, J 4,5 ) 1.8 Hz, J 5,6 ) 6.6 Hz, H-5), 3.53 (dd, 1 H, H-4), 3.13
(s, 3 H, OCH3), 2.26 (bs, 1 H, OH), 1.34 (d, 3 H, CH3); 13C NMR
(C6D6) δ 139.52, 139.06, 128.57, 128.53, 128.51, 128.00, 127.87,
127.79, 127.58, 98.79, 78.00, 76.78, 72.91, 72.60, 70.50, 65.63,
54.92, 16.53.
4.48 (d, 1 H, J ) 7.5 Hz, Ha-1), 4.32 (AB system, 2 H, J AB
)
12.0 Hz, CH2-Ph), 3.89-4.04 (m, 6 H), 3.81 (dd, 1 H, J ) 2.7
Hz, 11.1 Hz), 3.30-3.63 (m, 10 H), 3.01 (bs, 1 H, OH), 1.85 (s,
3 H, NAc); HR-ESIMS calcd for C50H58NO11 [M + H]+ 848.4010,
found 848.4007.
Meth yl 2-Acetam ido-2-deoxy-3,6-di-O-ben zyl-4-O-[3,4,6-
tr i-O-ben zyl-2-O-(2,3,4-tr i-O-ben zyl-R-D-fu cop yr a n osyl)-
â-L-ga la ctop yr a n osyl]-â-L-glu cop yr a n osid e (24). A mix-
ture of L-glycosyl acceptor 23 (9.5 mg, 0.0106 mmol) and
D-fucosyl donor 22 (13 mg, 0.027 mmol) was azeotroped three
times with toluene (15 mL) and then dissolved in anhydrous
CH2Cl2 (0.5 mL). The solution was added dropwise to a stirring
mixture of dimethyl(methylthio)sulfonium triflate (DMTST)54
(11 mg, 0.042 mmol), di-tert-butyl-4-methylpyridine (DTBMP)
(13 mg, 0.063 mmol), and 4A molecular sieves (15 mg) in dry
CH2Cl2 (0.5 mL) at -78 °C under argon. The reaction mixture
was stirred and slowly warmed to room temperature over a
period of 14 h. The mixture was treated with Et3N (0.1 mL),
diluted with CHCl3 (15 mL), filtered, washed with CHCl3 (10
mL), and concentrated to afford the desired trisaccharide as
a 5:1 mixture of diastereomers (10 mg, 71%). The mixture was
further separated by preparative TLC using 96:4 CHCl3:MeOH
A solution of methyl 2,3-di-O-benzyl-R-D-fucoside (185 mg,
0.516 mmol) in anhydrous DMF (6 mL) was treated with NaH
(60% in mineral oil, 103 mg, 2.58 mmol) at 0 °C under an argon
atmosphere. The reaction mixture was stirred for 5 min,
treated with BnBr (0.185 mL, 1.55 mmol), and warmed to rt.
After being stirred for 1 h, the reaction was diluted at 0 °C
with satd aq NH4Cl (6 mL) and Et2O (40 mL), extracted, and
concentrated. Silica gel chromatography using a 19:1 to 9:1
hexanes-EtOAc gradient containing 0.1% of Et3N yielded the
perbenzylated methyl D-fucoside 21 (182 mg, 79%): [R]20
)
D
+22.0 (c ) 1.0 in CHCl3); IR (thin film): 2896, 1496, 1453,
1355, 1193, 1133, 1099, 1049, 734, 696; 1H NMR (CDCl3) δ
7.35-7.47 (m, 15 H, Ar-H), 5.08-4.71 (m, 7 H, H-1, 3CH2-
Ph), 4.12 (dd, 1 H, J 1,2 ) 3.6 Hz, J 2,3 ) 9.9 Hz, H-2), 4.01 (dd,
J 3,4 ) 3.3 Hz, H-3), 3.91 (q, 1 H, J 5,6 ) 6.6 Hz, H-5), 3.71 (m,
1 H, H-4), 3.43 (s, 3 H, OCH3), 1.19 (d, 3 H, CH3); 13C NMR
(CDCl3) δ 138.86, 138.53, 138.47, 128.32, 128.27, 128.21,
128.08, 127.99, 127.55, 127.46, 127.38, 98.71, 79.31, 77.75,
76.23, 74.71, 73.37, 73.26, 65.97, 55.18, 16.50; HR-CIMS calcd
for C27H29O4 [M - CH3OH]+ 417.2066, found 417.2071.
to yield major isomer 24 as a clear oil: [R]20 ) +35.0 (c )
D
1
0.84 in CHCl3); H NMR (CDCl3) δ 7.14-7.39 (m, 40 H, Ar-
H), 5.86 (d, 1 H, J ) 7.8 Hz, NH), 5.79 (d, 1 H, J 1c,2c ) 3.6 Hz,
H-1c), 4.39-5.04 (m, 19 H, H-1,1b,5c 8CH2Ph), 4.27 (dd, 1 H,
J 1b,2b ) 7.8 Hz, J 2b,3b ) 9.3 Hz, H-2b), 4.11 (dd, 1 H, J 2c,3c
)
Eth yl 2,3,4-Tr i-O-ben zyl-1-th io-D-fu cop yr a n ose (22a ).
A solution of D-fucoside 21 (20 mg, 0.044 mmol) and EtSH (15
µL, 0.22 mmol) in CH2Cl2 (1 mL) was treated at 0 °C with
BF3‚OEt2 (7 µL, 0.048 mmol) and stirred for 1 h. Aqueous
workup (CHCl3, 25 mL) and preparative TLC using 4:1
hexanes-EtOAc yielded thioglycoside 22a as a separable 2:1
mixture of anomers (16 mg, 77%). Eth yl 2,3,4-tr i-O-ben zyl-
1-th io-R-D-fu copyr an ose (m in or isom er ):52 1H NMR (CDCl3)
δ 7.22-7.42 (m, 15 H, Ar-H), 5.47 (d, 1 H, J 1,2 ) 5.4 Hz, H-1),
5.01-5.64 (m, 6 H, 3CH2Ph), 4.29 (dd, 1 H, J 2,3 ) 10.0 Hz,
H-2), 4.20 (q, 1 H, J 5,6 ) 6.0 Hz, H-5), 3.79 (dd, 1 H, J 3,4 ) 1.8
Hz, H-3), 3.64 (m, 1 H, H-4), 2.55 (m, 2 H, CH2S), 1.28 (t, 3 H,
J ) 7.5 Hz, CH3CH2S), 1.14 (d, 3 H, CH3). Eth yl 2,3,4-tr i-O-
ben zyl-1-th io-â-D-fu cop yr a n ose (m a jor isom er ):53 1H NMR
(CDCl3) δ 7.22-7.42 (m, Ar-H), 4.68-5.02 (m, 6 H, 3CH2Ph),
4.40 (d, 1 H, J 1,2 ) 9.6 Hz, H-1), 3.83 (t, 1 H, J 2,3 ) 9.3 Hz,
H-2), 3.61 (m, 1 H, H-4), 3.56 (dd, 1 H, J 3,4 ) 1.8 Hz, H-3),
3.49 (q, 1 H, J ) 6.0 Hz, H-5), 2.73 (m, 2 H, CH2S), 1.30 (t, 3
H, J ) 7.5 Hz, CH3CH2S), 1.21 (d, 3 H, CH3); HR-CIMS calcd
for C29H35O4S [M + H]+ 479.2256, found 479.2259.
9.6 Hz, H-2c), 3.80-4.07 (m, 6 H), 3.68 (dd, 1 H, J 3b,4b ) 1.8
Hz, H-3b), 3.49-3.64 (m, 8 H), 1.94 (s, 3 H, Ac), 1.31 (d, 3 H,
J 5c,6c ) 6.3 Hz, H-6c); 13C NMR (CDCl3) δ 170.24, 138.87,
138.77, 138.63, 138.54, 138.46, 138.22, 138.01, 137.85, 128.44,
128.36, 128.27, 128.15, 128.00, 127.91, 127.81, 127.72, 127.51,
127.46, 127.39, 127.34, 127.28, 127.23, 126.19, 101.31, 100.83,
97.38, 84.01, 79.28, 77.95, 76.55, 76.06, 75.64 (2), 74.82, 74.60,
74.01, 73.54, 73.34, 73.02 (2), 72.65, 72.41, 72.21, 70.98, 68.84,
68.12, 66.43, 56.61, 55.07; ESIMS m/z 1286 [M + Na]+.
Meth yl 2-Aceta m id o-2-d eoxy-4-O-[2-O-(R-D-fu cop yr a -
n osyl)-â-L-ga la ctop yr a n osyl]-â-L-glu cop yr a n osid e (1). A
solution of trisaccharide 24 (14 mg, 0.011 mmol) in EtOAc (5
mL) was treated with activated charcoal (10 mg), stirred for
15 min at rt, passed through a short column of silica gel with
EtOAc (60 mL), and concentrated to dryness. Trisaccharide
24 was dissolved in MeOH (3.5 mL) with Pd(OH)2 (30 mg,
∼20% Pd) and stirred under an H2 atmosphere for 18 h at rt.
The mixture was then filtered over a pad of Celite, rinsed with
MeOH (20 mL), and concentrated to afford trisaccharide 1 as
1
a wax (6 mg, 99%): [R]20 ) +101.3 (c ) 0.37 in CH3OH); H
D
(52) Murphy, P. V.; Hubbard, R. E.; Manallack, D. T.; Wills, R. E.;
Montana, J . G.; Taylor, R. J . K. Bioorg. Med. Chem. 1998, 6, 2421.
(53) Zhang, Z. Y.; Magnusson, G. Carbohydr. Res. 1994, 262, 79.
(54) Ravenscroft, M.; Roberts, R. M. G.; Tillett, J . G. J . Chem. Soc.,
Perkin Trans. 2 1982, 1569.
3398 J . Org. Chem., Vol. 69, No. 10, 2004

Mirror-Image Carbohydrates
NMR (CD3OD) δ 4.50 (bd, 1 H, H-1c), 4.32 (d, 1 H, J 1b,2b ) 8.5
Hz, H-1), 4.19 (d, 1 H, J 1a,2a ) 6.6 Hz, H-1a), 3.36-3.56 (m, 16
H), 3.47 (s, 3 H, OCH3), 1.98 (s, 3 H, NHCOCH3), 1.22 (d, 3 H,
J 5c,6c )6.5 Hz, CH3); 13C NMR (CD3OD) δ 176.35, 103.83,
102.69, 101.97, 79.09, 78.28, 77.21, 77.09, 75.41, 74.42, 73.71,
71.81, 70.85, 68.44, 62.77, 61.69, 57.24, 56.67, 23.06, 16.89;
HR-ESIMS calcd for C21H37NO15Na [M + Na]+ 566.2061, found
566.2068.
(CDD-106244), the American Heart Association (30399Z),
and the National Institutes of Health (EB-001777-01).
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and characterization of intermediates leading to D-
1
glucal 5 and H NMR spectra of selected intermediates leading
to mirror-image trisaccharide 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the American Cancer Society
J O035789L
J . Org. Chem, Vol. 69, No. 10, 2004 3399