The stereodirecting effect of the glycosyl C5-carboxylate ester: Stereoselective synthesis of β-mannuronic acid alginates

Article abstract of DOI:10.1021/jo8020192

(Chemical Equation Presented) Glycosylations of mannuronate ester donors proceed highly selectively to produce the 1,2-cis-linked products. We here forward a mechanistic rationale for mis counterintuitive selectivity, based on the remote stereodirecting e

Full text of DOI:10.1021/jo8020192

The Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester:
Stereoselective Synthesis of ꢀ-Mannuronic Acid Alginates
Jeroen D. C. Code´e,* Leendert J. van den Bos, Ana-Rae de Jong, Jasper Dinkelaar,
Gerrit Lodder, Herman S. Overkleeft, and Gijsbert A van der Marel*
Leiden Institute of Chemistry, Leiden UniVersity, P.O. Box 9502, 2300 RA Leiden, The Netherlands
jcodee@chem.leidenuniV.nl; marel_g@chem.leidenuniV.nl
ReceiVed September 12, 2008
Glycosylations of mannuronate ester donors proceed highly selectively to produce the 1,2-cis-linked
products. We here forward a mechanistic rationale for this counterintuitive selectivity, based on the remote
stereodirecting effect of the C5-carboxylate ester, which has been demonstrated using pyranosyl uronate
ester devoid of ring substituents other than the C5- carboxylate ester. It is postulated that the C5-carboxylate
ester prefers to occupy an axial position in the oxacarbenium intermediate, thereby favoring the formation
of the 3H4 half-chair over the 4H3 conformer. Nucleophilic attack on the 3H4 half-chair intermediate occurs
in a ꢀ-fashion, providing the 1,2-cis-mannuronates with excellent stereoselectivity. The potential of the
mannuronate ester donors in the formation of the ꢀ-mannosidic linkage has been capitalized upon in the
construction of a mannuronic acid alginate pentamer using a convergent orthogonal glycosylation strategy.
Introduction
chemistry is explained by the intermediacy of relatively stable
anomeric R-triflates, which are substituted in a SN2-like manner
to provide the ꢀ-mannosides. Collapse of the anomeric triflate
into the mannosyl oxacarbenium ion, which is presumed to give
R-selective condensations, is thought to be disfavored because
of the electronically and conformationally disarming effect of
the 4,6-O-benzylidene group in combination with unfavorable
torsional interactions of the C2 and C3 substituents in going
from the R-triflate to the oxacarbenium ion.5,6 On the basis of
these results, we reasoned that electron-withdrawing substituents
in the mannose core also guide the corresponding mannosyla-
tions to give the 1,2-cis product. Indeed, we recently showed
that glycosylations with disarmed 1-thio-2-azidomannosides7
and, in particular, 1-thiomannuronate ester donors8 led to the
predominant formation of the 1,2-cis products. We here report
that the ꢀ-selectivity of the mannuronate esters results from the
stereodirecting effect of the C5-carboxylate ester and postulate
that the observed stereocontrol originates from the oxacarbenium
The stereoselective introduction of glycosidic bonds is the
most important transformation in glycochemistry. In spite of
enormous efforts, a general procedure for the stereoselective
formation of 1,2-cis linkages is not available, and their introduc-
tion often requires special glycosylation strategies and careful
tuning of the reaction parameters.1,2 Among the several types
of 1,2-cis linkages, the construction of the ꢀ-mannosidic linkage
is considered to be one of the greatest challenges3 since its
formation is disfavored on both steric (repulsion by the axial
C2-substituent) and electronic (lack of the anomeric effect,
destabilization by the ∆-2 effect) grounds. A breakthrough in
the formation of ꢀ-mannosides was reported by Crich and co-
workers, who showed that 4,6-O-benzylidene-protected man-
nosyl sulfoxide and thiomannoside donors preferentially form
1,2-cis products in glycosidations.4 This remarkable stereo-
(1) (a) ComprehensiVe Glycoscience; Kamerling, J. P., Ed.; Elsevier: Oxford,
2007; Vol. 1. (b) The Organic Chemistry of Sugars; Levy, D. E., Fu¨gedi, P.,
Eds.; CRC Press, Boca Raton, FL, 2006. (c) Garegg, P. J. AdV. Carbohydr. Chem.
Biochem. 2004, 59, 69. (d) Code´e, J. D. C.; Litjens, R. E. J. N.; van den Bos,
J. L.; Overkleeft, H. S.; van der Marel, G. A. Chem. Soc. ReV. 2005, 34, 769.
(2) Demchenko, A. V. Synlett 2003, 1225.
(3) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000,
1471.
(4) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506. (b) Crich, D.; Sun,
S. J. Org. Chem. 1997, 62, 1198. (c) Crich, D.; Sun, S. Tetrahedron 1998, 54,
8321. (d) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435. (e) Crich, D.
J. Carb. Chem. 2002, 21, 667.
(5) (a) Crich, D.; Vinogradova, O. J. Org. Chem. 2006, 71, 8473–8480. (b)
Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681.
(6) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 116, 5500.
(7) van den Bos, L. J.; Duivenvoorden, B. A.; De Koning, M. C.; Filippov,
D. V.; Overkleeft, H. S.; van der Marel, G. A. Eur. J. Org. Chem. 2007, 116.
(8) (a) van den Bos, L. J.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel,
G. A. J. Am. Chem. Soc. 2006, 128, 13066. (b) van den Bos, L. J.; Code´e, J. D. C.;
Litjens, R. E. J. N.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel, G. A. Eur.
J. Org. Chem. 2007, 3963.
38 J. Org. Chem. 2009, 74, 38–47
10.1021/jo8020192 CCC: $40.75 2009 American Chemical Society
Published on Web 11/26/2008

Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester
SCHEME 1. Intermediates in the Condensation of
Mannuronate Ester 1
mational flexibility of these donors readily allows flattening of
the pyranose ring,14 we reasoned that the putative R-anomeric
triflates are not the (sole) intermediate responsible for the
observed ꢀ-selectivity in the glycosidations of mannuronate
esters and that the ꢀ-selectivity can also arise from the oxac-
arbenium intermediate 4. It is well-established that the nature
and orientation of the substituents on the pyranose core have a
profound influence on the stability and reactivity of the
oxacarbenium ion.15,16 The effect of both alkyl and heteroatom
substituents at C2, C3, and C4 on the stability of pyranosyl
cations has been investigated in detail using both experimental15
and computational techniques.17 In the most favorable half-chair
conformations,18 alkyl groups prefer to adopt equatorial positions
for steric reasons, whereas electron-withdrawing substituents
at C3 and C4 preferentially take up axial positions to allow
through-space stabilization of the anomeric cation. Hypercon-
jugative effects are at the basis for the preference of C2-alkoxy
groups to assume an equatorial position. For C5, only the effect
of alkyl substituents19 has been examined and little is known
about the stereodirecting effects of electron-withdrawing (or
donating) groups at this position.
To establish the stereodirecting effect of the C5-carboxylate
ester, we “isolated” this substituent and investigated the stere-
ochemical preferences of the stripped pyranosyl uronate ester
16 (Scheme 2 and Table 2). A range of alcohols of increasing
size was condensed with 16 and with its “non-oxidized”
counterpart 17, using our standard glycosylation conditions
(Scheme 2).20 The stereodirecting effect of the C5-carboxylate
ester is immediately clear from Table 2: uronate ester 16 reacts
in a highly 1,5-cis-selective fashion when compared to its
benzyloxymethyl counterpart 17. This holds true for all exam-
ined nucleophiles. Although the selectivity depends on the steric
demands of the nucleophile, the C5 carboxyl ester in 16 is highly
1,5-cis-directing. The ꢀ-linked products are preferentially formed
with both primary and secondary alcohols, and also tert-butanol
reacts in a 1,5-cis-selective fashion. Only with the bulky
1-adamantanol no selectivity is found.21 In the C5 benzyloxym-
ethylene series (17), the same trend is observed: increased steric
bulk of the nucleophile leads to a stronger trans preference.15
The stereochemical outcome of these condensations can be
explained with the two diasteromeric half-chair oxacarbenium
ion intermediate. Furthermore, we demonstrate that this reliable
stereocontrol can be capitalized upon in the construction of
higher mannuronic acid alginate oligomers using a block
coupling glycosylation strategy.1d
Results and Discussion
To rationalize the ꢀ-selectivities observed in the glycosida-
tions of R-(S)-phenyl mannuronate ester 1, we initially reasoned
that the equilibrium between the covalent triflate (or the
corresponding tight ion pair) 3 and the solvent separated ion
pair 4 is shifted toward the covalent triflate because of the strong
electron-withdrawing capacity of the C5-carboxylate ester
(Scheme 1). To substantiate this hypothesis, we tried to detect
thetransientintermediate3bylow-temperatureNMRexperiments.4,9
When 1-thiomannuronate ester 1 was treated with diphenylsul-
foxide (Ph2SO, 1.2 equiv) and trifluoromethanesulfonic anhy-
dride (Tf2O, 1.2 equiv) in CD2Cl2 at -50 °C, the temperature
required for full activation of 1-thiouronic acids, the starting
material disappeared completely. However, several species were
formed that did not converge into a single product in time or
upon warming. The presence of the C5-carboxylate ester
function apparently does not induce the formation of a single
triflate species.10
To probe whether direct SN2-like displacement of the
activated anomeric R-thiophenyl moiety in 2 is at the basis of
the observed selectivity, we examined the glycosylation proper-
ties of ꢀ-(S)-phenyl mannuronate ester 8. As recorded in Table
1 (entries 1 and 2), this thioglycoside performed identical to
R-mannoside 1 in the glycosidation with glucoside 6, disproving
the latter line of thought. Furthermore, the carboxylbenzyl11
donor 10 and the N-phenyl trifluoroacetimidate 1312,13 proved
equally capable to stereoselectively form the ꢀ-mannosidic bond
(Table 1, entries 3 and 4), indicating that the stereoselectivity
in these mannosylations is independent of the type of donor
used and does not rely on the preactivation protocol.
(14) Even in the condensation of the rigid 4,6-O-benzylidene mannosides,
in which R-anomeric triflates have convincingly been demonstrated to be
intermediates, substantial oxacarbenium ion character developed in the transition
state, leading to the coupled products. See ref 6.
(15) (a) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 1552. (b) Chamberland, S.; Ziller, J. W.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 5322. (c) Lucero, C. G.; Woerpel,
K. A. J. Org. Chem. 2006, 71, 2641.
(16) (a) Jensen, H. H.; Bols, M. Acc 2006, 39, 259, and references therein. (b)
Boutureira, O.; Rodr´ıguez, M. A.; Benito, D.; Matheu, M. I.; D´ıaz, Y.; Castillo´n,
S. Eur. J. Org. Chem. 2007, 3564.
(17) (a) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859. (b) Miljkovic´, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L.
J. Org. Chem. 1997, 62, 7597. (c) Nukada, T.; Be´rces, A.; Wang, L.; Zgierski,
M. Z.; Whitfield, D. M. Carbohydr. Res. 2005, 340, 841.
(18) Although the developing double bond character between O5 and C1
can also be accommodated in the pyranose ring by adopting a 2,5B or B2,5 boat
conformation, these conformers will be substantially higher in energy: Shinskina,
S. V.; Shishkin, O. V.; Leszczynski, J. Chem. Phys. Lett. 2002, 354, 428. Also
see refs 15 and 22.
(19) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53, 8837–
8852.
(20) (a) Code´e, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1947. (b) Van
den Bos, L. J.; Litjens, R. E. J. N.; van den Berg, R. J. B. H. N.; Overkleeft,
H. A.; van der Marel, G. A. Org. Lett. 2005, 7, 2007.
(21) In contrast, 1-adamantanol very reliably provides the ꢀ-linked products
when used as an acceptor in the benzylidene mannose system, featuring anomeric
triflates. See for example ref 4.
Given the fact that no single anomeric triflate of the
mannuronate ester was detected by NMR and that the confor-
(9) (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217. (b) Nokami,
T.; Shibuya, A.; Tsuyama, H.; Suga, S.; Bowers, A. A.; Crich, D.; Yoshida, J.
J. Am. Chem. Soc. 2007, 129, 10922.
(10) Although no single R-anomeric triflate was observed, it cannot be
excluded that the reaction proceeds via such an intermediate and/or an exploded
SN2-like transition state. See ref 6.
(11) (a) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem.
Soc. 2001, 123, 8477. (b) Code´e, J. D. C.; Kro¨ck, L.; Castagner, B.; Seeberger,
P. H. Chem.sEur. J. 2008, 14, 3987.
(12) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405.
(13) The corresponding R/ꢀ-anomeric acetate and R-trichloroacetimidate were
also assessed in the coupling with allylTMS. The former donor proved completely
unreactive toward the activation with BF3 · OEt2 and was recovered after the
reaction. The latter donor stereoselectively provided mannuronate 15, but showed
substantial self-condensation, leading to the formation of the anomeric trichlo-
roacetamide.
J. Org. Chem. Vol. 74, No. 1, 2009 39

Code´e et al.
TABLE 1. ꢀ-Mannosylations Using Various Donors and Promoters
a Isolated yields. b TTBP ) tri-tert-butylpyrimidine. c The R-anomer could not be detected by TLC analysis and isolated by column chromatography.
d
The stereochemistry of the newly formed glycosidic bond was deduced from the value of the JC-H coupling of H-1′ and C-1′. e CB ) carboxylbenzyl.
1
f DTBMP ) 2,6-di-tert-butyl-4-methyl pyridine. g The stereochemistry of the anomeric center was established using NOESY experiments.
SCHEME 2. Oxacarbenium Ions of “Stripped” Uronate Ester 16 and its Benzyloxymethyl Counterpart 17
ions 16-I/17-I and 16-II/17-II as product-forming intermediates.
TABLE 2. Condensations of 16 and 17a
An incoming nucleophile will attack these cations with a facial
selectivity to form the lower-energy chair product as opposed
to the twist-boat adduct.22 If no destabilizing interactions
develop in the transition state, oxacarbenium ions 16-I/17-I will
provide the 1,5-cis products, where ions 16-II/17-II lead to the
corresponding trans products. The formation of the 1,5-cis
products 18a-c arises from the 3H4 oxacarbenium ion 16-I, in
which the carboxylate ester occupies an axial position. The
diminished ꢀ-selectivity of the bulky alcohols results from
destabilizing interactions between the axially oriented carboxy-
late and the incoming acceptor, making attack on the 3H4
oxacarbenium ion 16-I (and 17-I) less favorable for sterically
demanding nucleophiles.23 The C5-carboxylate ester thus pref-
erentially occupies a pseudo axial position in the half-chair
oxacarbenium ion intermediate. As such, the positively charged
a Condensations were performed as described in Scheme 2.
b Determined by NMR spectroscopy of the isolated compounds.
c Isolated yields.
(22) (a) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289. (b) Deslongschamps,
P. Stereoelectronic Effects in Organic Chemistry; Pergamon: New York, 1983.
(23) Seeman, J. I. Chem. ReV. 1983, 83, 83.
40 J. Org. Chem. Vol. 74, No. 1, 2009

Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester
donors 8 and 21, respectively.30 Preactivation of the donors 20
and 8 was effected using the Ph2SO/Tf2O reagent combination
and ensuing addition of alcohol 11 led to the formation of the
(S)-phenyl dimers. Unfortunately, several side products were
formed during these reactions, presumably due to activation of
the thiomannosyl acceptor and/or the dimer products. Addition
of triethylphosphite to scavenge any thiophilic side products of
the activator system did not lead to cleaner reactions, and the
desired products could only be obtained in moderate yield.30,31
We therefore switched to an orthogonal glycosylation approach
and transformed (S)-phenyl mannosides 8 and 20 into carboxy-
lbenzyl (CB) donors 10 and 22, respectively.11 Activation of
these CB mannuronate esters in the presence of acceptor 11
was achieved using Tf2O and di-tert-butyl methyl pyridine
(DTBMP), and the desired dimers 12 and 21 were both obtained
in 65% yield, with excellent ꢀ-selectivity.
FIGURE 1. Mannuronate ester oxacarbenium ion conformers.
oxacarbenium ion can be stabilized by the through-space
interaction with the electron-rich carbonyl function.24 In addi-
tion, the electron-withdrawing effect of the carboxylate ester is
minimized in this constellation.25
When we now reconsider the mannuronate ester oxacarbe-
nium ions 4-I and 4-II, it is clear that all substituents occupy a
26
3
preferred position in the H4 conformer 4-I (Figure 1). The
4H3 conformer on the other hand has all substituents in
disfavored positions, thereby destabilizing this intermediate.
Although 1,3-pseudo-diaxial interactions of the substituents at
C3 and C5 and the incoming nucleophile develop upon attack
of the acceptor on 4-I, the cooperative stabilization of the ring
substituents suffices to allow the stereoselective formation of
the ꢀ-mannuronic acid bond. It is of interest to note that Woerpel
and co-workers have previously established that the mannosyl
oxacarbenium also prefers to adopt the 3H4 conformation, having
all ring substituents but the C5 group in the most favorable
orientation.15c A Curtin-Hammet kinetic scenario, in which
product formation arises from the higher ground state 4H3
conformer, has been proposed to account for the R-selectivity
generally observed in mannosylations. The additional stabiliza-
tion of the C5-carboxylate ester in oxacarbenium ion 4-I
prevents such a Curtin-Hammet reaction scheme to occur.
Next, we turned to the assembly of 1,4-linked ꢀ-D-mannuronic
alginate oligomers. Alginates are linear, anionic polysaccharides
composed of 1,4-linked ꢀ-D-mannuronic and R-L-guluronic
acids.27 Small oligomers of these polymers have been shown
to have immunomodulating activity by binding to Toll-like
receptors (TLRs) 2 and 4.28 With the dual goal to establish an
efficient synthetic route toward these oligomers8,26 and to
explore how the stereochemistry of the mannosylations develops
when larger coupling partners are involved,29 we envisaged a
convergent assembly route using both monomer (8 and 20) and
dimer building blocks (12 and 21) as depicted in Scheme 3.
The levulinoyl group was selected to temporarily mask the C4
hydroxyl of the oliogomannuronates to be elongated.
With the monomers (8 and 20) and dimer building blocks
(12 and 21) in hand, we set out to assemble the target oligomers.
First, monomeric donor 8 was condensed with azidopropanol
at -78 °C to provide the terminal mannuronate ester 23, carrying
an azidopropanol spacer in 76% yield. Hydrazine treatment of
23 liberated the C4-OH, to give the reducing end mannuronate
ester 24 in near quantitative yield. Acceptor 24 was then
mannosylated with 20 and 8 using our standard Ph2SO/Tf2O
activation protocol to give the dimers 25 and 26, in somewhat
reduced yields (52 and 46%, respectively). When dimeric donors
21 and 12 were employed in the condensation with 25, a further
drop in yield was observed: trimers 28 and 29 were isolated in
29 and 28%, respectively. In all these condensations, TLC
analysis showed complete consumption of the thio donors 8,
20, 12, and 21 in the preactivation step, but incomplete
conversion into the coupled products. In our previous studies
toward the synthesis of heparin oligosaccharides, we observed
a similar behavior of (S)-phenyl glucuronate ester donors.32 This
setback was overcome by replacing the Ph2SO/Tf2O system with
the closely related 1-benzenesulfinyl piperidine (BSP)/Tf2O
couple.33 Application of the latter activator system in the present
case gave a significant improvement in the outcome of the
glycosylations, and now the dimers and trimers were obtained
in satisfactory yields (25: 67%, 26: 62%, 28: 74%, and 29: 51%).
To elongate the di- (26) and trimannoside (29), the levulinoyl
groups were removed and the resulting alcohols 27 and 30 were
glycosylated with dimer donor 22. Gratifyingly, both the [2 +
2] and [2 + 3] coupling proceeded efficiently to provide the
tetra- and pentamer mannuronate esters 31 and 32 in 67 and
69% yields, respectively. Importantly, the excellent ꢀ-selectivity
was maintained in all condensations and was not affected by
the size of the coupling partners, underscoring the strength of
mannuronate ester donors in the construction of the ꢀ-manno-
sidic bond. To complete the synthesis of the set of mannuronic
acid alginates, the oligomers were deprotected by saponification
and ensuing hydrogenolysis (Scheme 4).
To maximize efficiency, we explored the possibility to
construct the thiophenyl mannuronic acid dimer building blocks
12 and 21 from thiomannosyl acceptor 11 and thiomannoside
(24) Full neighboring group participation of the C5-carboxylate does not
occur. See also: Schmidt, R. R.; Ru¨cker, E. Tetrahedron Lett. 1980, 21, 1421.
(25) Jensen, H. H.; Lyngbye, L.; Bols, M. Angew. Chem., Int. Ed. 2001, 40,
3447.
3
(26) Analogously, in the H4 oxacarbenium ion of L-gulose, the C5 epimer
of D-mannose, all ring substituents take up their most favorable orientation, and
glycosydations of L-gulose proceed with an unusual high preference for the
R-anomer: Dinkelaar, J.; van den Bos, L. J.; Hogendorf, W. F. J.; Lodder, G.;
Overkleeft, H. S.; Code´e, J. D. C.; van der Marel, G. A. Chem.sEur. J. 2008,
14, 9400.
(27) Moe, S. T.; Draget, K. I.; Skjåk-Bræk, G.; Smidsrød, O. Food
Polysaccharides and Their Applications; Stephen, A. M., Eds.; Marcel Dekker,
Inc.: New York, 1995; pp 245-286.
(28) (a) Flo, T. H.; Ryan, L.; Latz, E.; Takeuchi, O.; Monks, B. G.; Lien, E.
Ø.; Halaas, Ø.; Akira, S.; Skjåk-Bræk, G.; Golenbock, D. T.; Espevik, T. J. Biol.
Chem. 2002, 38, 35489. (b) Iwamoto, M.; Kurachi, M.; Nakashima, T.; Kim,
D.; Yamaguchi, K.; Oda, T.; Iwamoto, Y.; Muramatsu, T. FEBS Lett. 2005,
579, 4423.
(30) (a) Code´e, J. D. C.; van den Bos, J. L.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; van der Marel, G. A. Tetrahedron
2004, 60, 1057. (b) Crich, D.; Hongmei, L. J. Am. Chem. Soc. 2004, 126, 15081.
(31) Sliedrecht, L. A. J. M.; van der Marel, G. A.; Van Boom, J. H.
Tetrahedron Lett. 1994, 35, 4015–4018.
(32) Code´e, J. D. C.; Stubba, B.; Schiattarella, M.; Overkleeft, H. S.; van
Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A. J. Am. Chem. Soc.
2005, 127, 3767.
(29) Crich, D.; Wu, B.; Jayalath, P. J. Org. Chem. 2007, 72, 6806.
(33) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
J. Org. Chem. Vol. 74, No. 1, 2009 41

Code´e et al.
SCHEME 3. Assembly of the Mannuronate Ester Oligomers
Conclusion
agrees well with this postulate.34,16b In concert with the other
substituents on the ring, the axial C5-carboxylate ester favors
In conclusion, the outcome of the sulfonium ion mediated
condensations of pyranosyl uronate 16 indicate that the C5-
carboxylate ester exerts a strong stereodirecting effect, promot-
ing the formation of 1,5-cis glycosidic bonds. This remote
stereodirecting effect can be rationalized with the most stable
oxacarbenium ion, having an axially oriented carboxylate ester,
as product forming intermediate. The stereocontrol of mannu-
ronate esters is independent of the type of donor employed and
3
4
the formation of the H4 half-chair over the H3 conformer.
3
Incoming nucleophiles attack the H4 half-chair oxacarbenium
ion in a ꢀ-fashion, leading to the formation of the counterin-
tuitive 1,2-cis-mannosidic bond. The value of the stereodirecting
(34) See for some recent examples of oxacarbenium ion directed stereose-
lective glycosylations: Zhu, X.; Kawathar, S.; Rao, Y.; Boons, G.-J. J. Am. Chem.
Soc. 2006, 128, 11948. Also see ref 16b.
42 J. Org. Chem. Vol. 74, No. 1, 2009

Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester
SCHEME 4. Deprotection of the Mannuronic Acid
Oligomers
for Ph2SO-Tf2O mediated glycosylations (93%): [R]D ) +10 (c )
0.019, DCM); IR (neat) ν (cm-1) 737, 1713, 1744; 1H NMR (400
MHz) δ 2.53 (m, 2H, CH2 Lev), 2.71 (t, 2H, J ) 6.8 Hz, CH2
Lev), 3.31 (s, 3H, OCH3), 3.40 (m, 3H, H-3′, H-6, H-4), 3.50 (dd,
1H, J ) 3.6 Hz, J ) 9.6 Hz, H-2), 3.70 (m, 4H, CO2Me, H-5′),
3.77 (m, 2H, H-5, H-5′), 4.01 (t, 1H, J ) 9.6 Hz, H-3), 4.13 (m,
2H, H-6, H-1′), 4.29 (d, 1H, J ) 12.4 Hz, CHHPh), 4.49 (d, 2H,
J ) 11.6 Hz, 2 × CHHPh), 4.57 (d, 1H, J ) 3.2 Hz, H-1), 4.66 (d,
1H, J ) 12 Hz, CHHPh), 4.74-4.89 (m, 4H, 4 × CHHPh), 4.91
(d, 1H, J ) 8.0 Hz, CHHPh), 5.02 (d, 1H, J ) 10.8 Hz, CHHPh),
5.51 (t, 1H, J ) 9.6 Hz, H-4′), 7.17-7.39 (m, 25H, Harom); 13C
NMR (100 MHz) δ 27.8 (CH2 Lev), 29.8 (CH3 Lev), 37.7 (CH2
Lev), 52.5 (CH3 CO2CH3), 55.0 (OCH3), 68.6 (C-6), 69.1 (C-4′),
69.7 (C-5), 71.6 (CH2 Bn), 72.9 (C-2′), 73.2 (CH2 Bn), 73.5 (C-
5′), 73.5 (CH2 Bn), 74.6 (CH2 Bn), 75.6 (CH2 Bn), 77.5 (C-4),
78.1 (C-3′), 79.8 (C-2), 82.1 (C-3), 97.7 (C-1), 101.5 (JC-1′,H-1′
)
156 Hz, C-1′), 127.4-128.4 (Carom), 137.7 (Cq Bn), 138.0 (Cq Bn),
138.2 (Cq Bn), 138.7 (Cq Bn), 167.8, 171.4 (CdO), 206.1 (CdO);
HRMS: [M + Na+] calcd for C54H60O14Na 955.3875, found
955.3883.
effect of the C5-glycuronate ester has been demonstrated in the
construction of a set of mannuronic acid alginate oligomers.
Also when larger coupling partners are involved the mannur-
onate esters reliably produce the 1,2-cis linkage. Current research
is aimed at further validation of the mechanistic rationale put
forth, the identification of the intermediates observed by NMR,
and the role of the counterion in the glycosylations.
(Carboxylbenzyl 2,3-di-O-benzyl-4-O-levulinoyl-ꢀ-mannopy-
ranosyluronic acid) methyl ester (10). Thiomannuronic acid 8
(914 mg, 1.58 mmol) and 2-hydroxymethyl benzoic acid benzyl
ester (1.14 g, 4.73 mmol) were coupled as described in the general
procedure for Ph2SO-Tf2O mediated glycosylations. The resulting
(benzyl carboxylbenzyl 2,3-di-O-benzyl-4-O-levulinoyl-ꢀ-man-
nopyranosyluronic acid) methyl ester was purified by column
chromatography (100% PE to 98/2 toluene/EtOAc) and taken up
in EtOAc/MeOH (0.05 M, 1/3). NH4OAc (3 equiv) and Pd/C
(catalytic amount) were added, and the mixture was degassed and
purged with H2. The mixture was stirred overnight under a H2
atmosphere, after which the Pd/C was filtered off and the mixture
was concentrated. The product was purified by column chroma-
tography (100% PE to 80/20/1 PE/EtOAc/AcOH) to provide the
title compound (66% over 2 steps): [R]D ) -36 (c ) 0.75, CHCl3);
Experimental Section
General Procedure for Ph2SO/BSP-Tf2O Mediated Glycosy-
lations: The thiodonor, TTBP (3 equiv), and Ph2SO (1.2 equiv) or
BSP (1.2 equiv) were dissolved in DCM (0.05 M donor in DCM)
and stirred over molecular sieves (3 Å) for 30 min before being
cooled to -60 °C. Tf2O (1.1 equiv) was added, and the mixture
was warmed to -45 °C in 15 min, after which the solution was
brought back to -60 °C, and the acceptor was added (0.1 M in
DCM). The mixture was allowed to very slowly reach 0 °C (several
hours), and Et3N (5 equiv) was added. The molecular sieves were
filtered off, and the mixture was washed with saturated aqueous
NaHCO3. The aqueous layer was extracted twice with DCM, and
the combined organic layers were dried (MgSO4), filtered, and
concentrated. The resulting mixture was purified by silica gel
column chromatography and size exclusion chromatography to
provide the target compounds.
General Procedure for Levulinoyl Cleavage: The levulinoyl
ester was dissolved in pyridine/HOAc (4/1, 0.05 M), and
H2NNH2 ·H2O (5 equiv) was added. The reaction was stirred for
20 min, after which a few drops of acetone were added. The mixture
was diluted with EtOAc, washed with aqueous HCl (1 M), saturated
aqueous NaHCO3, dried (MgSO4), and concentrated. Column
chromatography yielded the pure alcohols.
Low-Temperature NMR Experiment: Thiomannuronic acid
1 (13 mg, 0.025 mmol) and Ph2SO (6 mg, 1.2 equiv) were dissolved
in CD2Cl2 (0.5 mL), and the solution was transferred to an argon-
flushed NMR tube. The NMR sample was immersed in the NMR
probe, which was cooled to -50 °C. After a spectrum was recorded,
the sample was removed from the probe and immersed in an acetone
bath (-78 °C). Tf2O (5 µL) was added; the NMR tube was quickly
shaken to ensure complete mixing, and the tube was reimmersed
in the cold NMR probe (-50 °C). The probe was maintained at
this temperature for 30 min and then gradually warmed to -10 °C
(steps of 10 °C).
Methyl 2,3,4-tri-O-benzyl-6-O-(methyl 2,3-di-O-benzyl-4-O-
acetyl-ꢀ-D-mannopyranosyl uronate)-r-D-glucopyranoside) (7):
The synthesis of the title compound has been reported previously.8a
Methyl 2,3,4-tri-O-benzyl-6-O-(methyl 2,3-di-O-benzyl-4-O-
levulinoyl-ꢀ-D-mannopyranosyluronate)-r-D-glucopyranoside (9):
The title compound was synthesized from 8 (98 mg, 0.17 mmol)
and 6 (118 mg, 0.26 mmol) as described by the general procedure
1
IR (neat) ν (cm-1) 729, 1271, 1686, 1714, 1734; H NMR (400
MHz) δ 2.15 (s, 3H, CH3 Lev), 2.54 (m, 2H, CH2 Lev), 2.71 (m,
2H, CH2 Lev), 3.61 (m, 4H, CH3 CO2Me, H-3), 3.96 (s, H-2), 3.99
(d, 1H, J ) 8.0 Hz, H-5), 4.47 (d, 1H, J ) 12.0 Hz, CHHPh), 5.53
(d, 1H, J ) 12.0 Hz, CHHPh), 4.69 (s, 1H, H-1), 4.83 (d, 1H, J )
12.4 Hz, CHHPh), 4.93 (d, 1H, J ) 12.4 Hz, CHHPh), 5.06 (d,
1H, J ) 13.2 Hz, CHHPh), 5.36 (d, 1H, J ) 13.2 Hz, CHHPh),
5.63 (t, 1H, J ) 8.4 Hz, H-4), 7.22-7.49 (m, 12H, Harom), 7.66 (d,
1H, J ) 7.6 Hz), 8.05 (d, 1H, J ) 7.6 Hz), 9.9 (br s, 1H, CO2H);
13C NMR (125 MHz) δ 27.8 (CH2 Lev), 29.7 (CH3 Lev), 37.7 (CH2
Lev), 52.4 (CH3 CO2Me), 69.1 (C-4), 69.9 (CH2 Bn), 71.7 (CH2
Bn), 73.1, 73.2 (C-2 and C-5), 73.4 (CH2 Bn), 77.3 (C-3), 100.5
(JC1-H1 ) 158 Hz, C-1), 126.8 (Cq CB), 127.1, 127.2, 127.4, 127.5,
127.6, 127.7, 127.9, 128.1, 128.2, 131.2, 133.1 (CHarom), 137.7 (Cq
Bn), 138.1 (Cq Bn), 140.4 (Cq CB), 168.0 (CdO), 171.5 (CdO),
171.7 (CdO), 206.4 (CdO, Lev); HRMS [M + Na+] calcd for
C34H36O11NNa 643.2155, found 643.2155.
Phenyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-O-benzyl-
4-O-levulinoyl-ꢀ-D-mannopyranosyl uronate)-1-thio-ꢀ-D-man-
nopyranosyl uronate) (12): CB-Mannoside 10 (800 mg, 1.29
mmol), thiomannoside 11 (929 mg, 1.93 mmol), and di-tert-
butylmethylpiridine (DTBMP, 662 mg, 3.35 mmol) were dissolved
in DCM (0.05 M, 25 mL) and stirred over molecular sieves (3 Å)
for 30 min before being cooled to -60 °C. Tf2O (0.24 mmol, 1.43
mmol) was added, and the mixture was allowed to very slowly
reach 0 °C (several hours). Et3N (5 equiv) was added; the molecular
sieves were filtered off, and the mixture was washed with saturated
aqueous NaHCO3. The aqueous layer was extracted twice with
DCM, and the combined organic layers were dried (MgSO4),
filtered, and concentrated. The resulting mixture was purified by
silica gel column chromatography to provide the thiodisaccharide
(65%): [R]D ) -68 (c ) 1, DCM); IR (neat) ν (cm-1) 729, 1060,
1
1361, 1717, 1744; H NMR (400 MHz) δ 2.14 (s, 3H, CH3 Lev),
2.54 (m, 2H, CH2 Lev), 2.67 (m, 2H, CH2 Lev), 3.46 (dd, 1H, J )
J. Org. Chem. Vol. 74, No. 1, 2009 43

Code´e et al.
2.8 Hz, J ) 9.6 Hz, H-3′), 3.51 (s, 3H, CH3 CO2Me), 3.64 (m, 4H,
CH3 CO2Me, H-3), 3.72 (d, 1H, J ) 10.0 Hz, H-5′), 3.81 (d, 1H,
J ) 2.8 Hz, H-2′), 3.85 (d, 1H, J ) 9.6 Hz), 4.06 (d, 1H, J ) 2.0
Hz, H-2), 4.40-4.52 (m, 3H, H-4, CH2 Bn), 4.66-4.80 (m, 7H,
H-1, H-1′, 5 × CHHPh), 4.97 (d, 1H, J ) 12.0 Hz, CHHPh), 5.43
(t, 1H, J ) 9.6 Hz, H-4′), 7.19-7.54 (m, 25H, Harom); 13C NMR
(100 MHz) δ 27.8 (CH2 Lev), 29.8 (CH3 Lev), 37.7 (CH2 Lev),
52.3 (CH3 CO2Me), 52.4 (CH3 CO2Me), 68.9 (C-4′), 73.1 (CH2
Bn), 73.3 (C-5′), 74.3 (CH2 Bn), 74.9 (C-2′), 75.1 (CH2 Bn), 77.5
(C-2), 77.7 (C-4, C-5), 78.4 (C-3′), 81.2 (C-3), 81.2 (JC1-H1 ) 154
Hz, C-1), 102.5 (JC1′-H1′ ) 159 Hz, C-1′), 127.2, 127.3, 127.5, 127.7,
127.9, 128.1, 128.2, 128.3, 128.9, 130.7 (CHarom), 135.2 (Cq SPh),
137.8 (Cq Bn), 138.0 (Cq Bn), 138.6 (Cq Bn), 138.7 (Cq Bn), 167.7
(CdO), 168.3 (CdO), 171.5 (CdO), 206.1 (CdO, Lev); HRMS
[M + Na+] calcd for C53H56O14NaS 971.3289, found 971.3293.
(2,3,4-Tri-O-benzyl-r/ꢀ-mannopyranosyluronic acid methyl
ester)-1-(N-phenyl)-2,2,2-trifluoroacetimidate (13): 2,3,4-Tri-O-
benzyl-R-mannopyranosyluronic acid methyl ester (20)8 (3.0 g, 5.3
mmol) was dissolved in DCM/H2O (0.2 M, 10/1) and treated with
N-iodosuccinimide (NIS) (1.2 g, 5.3 mmol) and TFA (0.41 mL,
5.3 mmol) for 15 min, after which the reaction was quenched by
the addition of saturated aqueous NaHCO3 and Na2S2O3. The layers
were separated, and the aqueous layer was extracted once with
DCM. The combined organic layers were dried (MgSO4), filtered,
and concentrated. Purification of the crude oil by column chroma-
tography (80/20 PE/EtOAc 75/25 PE/EtOAc) gave the pure lactol
(1.55 g, 3.23 mmol 61%). The lactol (330 mg, 0.690 mmol) was
dissolved in acetone (4 mL), containing 5 drops of water. Trifluo-
roacetimidoyl chloride35 and K2CO3 (190 mg, 1.38 mmol) were
added, and the reaction mixture was stirred until TLC analysis
indicated complete cenversion of the starting material. The reaction
mixture was filtered and concentrated. Purification of the crude oil
by column chromatography (100% toluene to 92.5/7.5 toluene/
EtOAc) gave the pure imidate (R/ꢀ ) 5:1, 434 mg, 0.668 mmol,
(d, 1H, J ) 2.8 Hz, H-2), 3.81 (d, J ) 10.0 Hz, H-5), 4.23 (t, 1H,
J ) 9.2 Hz, H-4), 4.66 (2H, CH2Ph), 4.73 (d, 1H, J ) 11.6 Hz,
CHHPh), 4.77 (d, 1H, J ) 11.6 Hz, CHHPh), 4.85 (d, 1H, J )
12.4 Hz, CHHPh), 5.01 (m, 3H, CH2CHdCH2, CHHPh), 5.63 (m,
1H, CH2CHdCH2), 7.21-7.38 (m, 15H, Harom); 13C NMR (100
MHz) δ 35.4 (CH2CHdCH2), 52.3 3 (CH3 CO2Me), 72.6 (CH2
Bn), 74.4 (CH2 Bn), 74.4 (C-2), 75.2 (CH2 Bn), 76.3 (C-4), 79.1
(C-5), 79.3 (C-1), 84.5 (C-3), 117.5 (CH2CHdCH2), 127.4, 127.6,
127.7, 128.0, 128.2, 128.3, 128.5 (CHarom), 134.1 (CH2CHdCH2),
138.2 (Cq Bn), 138.5 (Cq Bn), 169.2 (CdO); HRMS [M + Na+]
calcd for C31H34O7Na 525.2253, found 525.2240.
Couplings of 16 and 17. 16 and 17 were condensed with benzyl
alcohol (BnOH, 4 equiv), isopropanol (4 equiv), tert-butanol (4
equiv), and 1-adamantanol (4 equiv) as described by the general
procedure for Ph2SO-Tf2O mediated glycosylations. The acceptor
alcohols were added as a stock solution (5 M in DCM), which were
dried over molecular sieves. Activation of the thiopyranosides was
achieved at -78 °C for 5 min. The reactions were quenched after
15 min at -78 °C to prevent possible anomerization. Purification
of the products was achieved by column chromatography. If
complete separation of both anomers was achieved, they were
separately isolated. If separation was not possible, the R/ꢀ-mixtures
were isolated and analyzed.
6-Benzyloxy tetrahydropyran-2-carboxylic acid methyl ester
(18a): The product was obtained from 16 (37 mg, 0.15 mmol) and
benzylalcohol as an R/ꢀ-mixture (R/ꢀ ) 1:7.7, 74%): IR (neat) ν
1
(cm-1) 997, 1738; H NMR (400 MHz) δ 1.51-2.12 (m, 6.8 H,
H-3, 4, 5 R+ꢀ), 3.77 (s, 3.1 H, CH3 CO2Me R+ꢀ), 4.08 (dd, 1H,
J ) 2.4 Hz, J ) 10.0 Hz, H-6 ꢀ), 4.46 (dd, 0.13H, J ) 2.4 Hz, J
) 10.0 Hz, H-6 R), 4.52 (d, 1H, J ) 9.2 Hz, H-2 ꢀ), 5.53 (d, 0.13
H, J ) 12.0 Hz, CHHPh R), 4.62 (d, 1H, J ) 12.0 Hz, CHHPh ꢀ),
4.76 (d, 0.13 H, J ) 12.0 Hz, CHHPh R), 4.95 (d, 1 H, J ) 12.0
Hz, CHHPh ꢀ), 5.08 (s, 0.13H, H-2 R); 7.26-7.35 (m, 5.7H, Harom);
13C NMR (125 MHz) δ 17.7 (R), 21.2 (ꢀ), 27.7 (ꢀ), 28.2 (R), 29.1
(R), 30.5 (ꢀ) (C-3, C-4, C-5), 52.1 (CH3 CO2Me R+ꢀ), 68.5 (C-6
R), 69.0 (CH2 Bn R), 70.0 (CH2 Bn ꢀ), 74.4 (C-6ꢀ), 97.0 (C-1R),
100.8 (C-1ꢀ), 127.6, 127.8, 127.9, 128.3, 128.4 (CHarom R+ꢀ), 137.7
(Cq Ph ꢀ), 138.4 (Cq Ph R), 171.3 (CdO, ꢀ), 172.3 (CdO, R);
HRMS [M + Na+] calcd for C14H18O4Na 273.1103, found
273.1098.
1
98%): IR (neat) ν (cm-1) 736, 1101, 1708, 1749; H NMR (400
MHz) major anomer (R) δ 3.66 (s, 3H, CH3 CO2Me), 3.81 (br s,
1H, H-2), 3.88 (dd, 1H, J ) 3.2 Hz, J ) 8.4 Hz, H-3), 4.29 (t, 1H,
J ) 8.4 Hz, H-4), 4.38 (d, 1H, J ) 8.4 Hz, H-5), 4.53-4.83 (m,
6H, 3 × CH2 Bn), 6.34 (br s, 1H, H-1), 6.75 (d, 2H, J ) 8.0 Hz,
CHaromNPh), 7.06 (t, 1H, J ) 8.8 Hz, CHaromNPh), 7.25-7.33 (17H,
CHarom); 13C NMR (125 MHz) major anomer (R) δ 52.5 (CH3
CO2Me), 72.7 (2 × CH2 Bn), 73.2 (C-2), 73.8 (C-5), 74.6 (CH2
Bn), 75.8 (C-4), 77.4 (C-3), 94.8 (JC1-H1 ) 178 Hz, C-1), 115.8
(q, 1JC-F ) 285 Hz, CF3), 119.3 (CHaromNPh), 124.3 (CHaromNPh),
126.9, 127.3, 127.5, 127.7, 127.8, 127.9, 128.2, 128.3, 128.6, 128.8,
129.1, 129.2, 129.7, 129.9 (CHarom), 137.4 (Cq Bn), 137.6 (Cq Bn),
6-Isopropyloxy tetrahydropyran-2-carboxylic acid methyl
ester (18b): The product was obtained from 16 (87 mg, 0.35 mmol)
and isopropanol as an R/ꢀ-mixture (R/ꢀ ) 1:3.8, 48%): IR (neat)
ν (cm-1) 1037, 1755; 1H NMR (400 MHz) δ 1.12 (d, 0.78H, CH3
iPr R), 1.14 (d, 3H, CH3 iPr ꢀ), 1.21 (d, 0.78H, CH3 iPr R), 1.26
(d, 3H, CH3 iPr ꢀ), 1.38-1.95 (m, 7.6H, H-3, 4, 5 R+ꢀ), 3.75 (3.8
H, CH3 CO2Me R+ꢀ), 3.93 (m, 0.26H, CH iPr R), 4.06 (m, 2H,
CH iPr ꢀ, C-6 ꢀ), 4.46 (d, 0.26H, J ) 11.6 Hz, H-6 R), 4.53 (d,
1H, J ) 9.2 Hz, H-2 ꢀ), 5.07 (s, 0.26H, H-1R); 13C NMR (125
MHz) δ 17.7 (R), 21.9 (ꢀ), 27.7 (ꢀ), 28.3 (R), 29.6 (R), 31.0 (ꢀ)
(C-3, 4, 5), 21.3 (CH3 iPr R), 21.6 (CH3 iPr ꢀ), 23.3 (CH3 iPr R),
23.5 (CH3 iPr ꢀ), 52.0 (CH3 CO2Me R+ꢀ), 68.1 (C-6R), 68.4 (CH3
iPr R), 70.0 (CH3 iPr ꢀ), 74.7 (C-6ꢀ), 95.0 (C-2R), 100.1 (C-2R),
171.2 (CdO); HRMS [M + Na+] calcd for C10H18O4Na 225.1103,
found 225.1099.
6-tert-Butyloxy tetrahydropyran-2-carboxylic acid methyl
ester (18c): The products were obtained from 16 (62 mg, 0.25
mmol) and tert-butanol as pure anomers (R/ꢀ ) 1:2.9, 52%); IR
(neat) ν (cm-1) 1038, 1740; R-anomer, 1H NMR (400 MHz) δ 1.24
(s, 9H, tBu), 1.51-1.95 (m, 6H, H-3, 4, 5), 3.75 (s, 3H, CH3
COOMe), 4.57 (d, 1H, J ) 10.4 Hz, H-6), 5.25 (s, 1H, Hz, H-2);
13C NMR (125 MHz) δ 17.9, 28.2, 31.0 (C-3, C-4, C-5), 28.4 (CH3
tBu), 52.0 (CH3 CO2Me), 68.7 (C-6), 74.5 (Cq tBu), 91.9 (C-2),
172.9 (CdO); ꢀ-anomer, 1H NMR (400 MHz) δ 1.27 (s, 9H, tBu),
1.49-1.96 (m, 6H, H-3, 4, 5), 3.75 (s, 3H, CH3 COOMe), 4.04
(dd,1H, J ) 2.4 Hz, J ) 10.8 Hz, H-6), 4.63 (dd, 1H, J ) 2.0 Hz,
J ) 10.8 Hz, H-2); 13C NMR (125 MHz) δ 22.2, 27.5, 31.8 (C-3,
C-4, C-5), 28.7 (CH3 tBu), 52.0 (CH3 CO2Me), 74.6 (C-6), 75.2
2
137.7 (Cq Bn), 143.2 (Cq NPh), 142.4 (q, JC-F ) 36 Hz, C)N),
168.7 (CdO); ꢀ-anomer 1H NMR (400 MHz) diagnostic peaks 3.63
(s, CH3 CO2Me), 5.93 (br s, 1H, H-1); 13C NMR (125 MHz)
diagnostic peaks 52.2 (CH3 CO2Me), 94.4 (JC1-H1 ) 166 Hz, C-1);
HRMS [M + Na+] calcd for C36H34F3O7NNa 672.2185, found
672.2191.
(Allyl 1-deoxy-2,3,4-tri-O-benzyl-ꢀ-mannopyranosyluronic acid)
methyl ester (15): (2,3,4-Tri-O-benzyl-R/ꢀ-mannopyranosyluronic
acid methyl ester)-1-(N-phenyl)-2,2,2-trifluoroacetimidate (13) (110
mg, 0.169 mmol) and allylTMS (0.11 mL, 0.68 mmol) were
dissolved in DCM (3.4 mL) and cooled to -60 °C. TMSOTf (6
µL, 3.4 µmol) was added, and the mixture was allowed to warm to
-20 °C in 2 h, after which the reaction was quenched by the
addition of Et3N. The mixture was concentrated and the product
purified by column chromatography (95/5 toluene/EtOAc to 90/10
toluene/EtOAc) to give the pure C-mannoside 15 (62 mg, 0.122
mmol, 73%): [R]D ) -36 (c 1); IR (neat) ν (cm-1) 736, 1101,
1
1749; H NMR (400 MHz) δ 2.29 (m, 1H, CHHCHdCH2), 2.48
(m, 1H, CHHCHdCH2), 3.35 (t, 1H, J ) 6.8 Hz, H-1), 3.60 (dd,
1H, J ) 2.8 Hz, J ) 9.2 Hz, H-3), 3.70 (s, 3H, CH3 CO2Me), 3.76
(35) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama, K. J.
Org. Chem. 1993, 58, 32–35.
44 J. Org. Chem. Vol. 74, No. 1, 2009

Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester
(Cq tBu), 96.8 (C-2), 171.2 (CdO); HRMS [M + Na+] calcd for
6-Benzyloxymethyl-2-adamantyloxytetrahydropyran (19d):
The products were obtained from 17 (94 mg, 0.30 mmol) and
1-adamantanol as pure anomers (R/ꢀ ) 1:0.33, 74%): IR (neat) ν
C10H18O4Na 239.1254, found 239.1254.
6-Adamantyloxy tetrahydropyran-2-carboxylic acid methyl
ester (18d): The product was obtained from 16 (48 mg, 0.19 mmol)
and 1-adamantanol as an R/ꢀ-mixture (R/ꢀ ) 1:1.2, 52%), contain-
ing Ph2SO and 1-adamantanol: 1H NMR (400 MHz) δ 1.33-2.13
(m, 46.2H, H-3, 4, 5, CH and CH2 adamantanol, R+ꢀ), 3.73 (s,
3H, CH3 CO2Me R), 3.74 (s, 3.6H, CH3 CO2Me ꢀ), 4.05 (dd, 1.2H,
J ) 2.4 Hz, J ) 10.8 Hz, H-6 ꢀ), 4.60 (dd, 1H, J ) 2.4 Hz, J )
10.8 Hz, H-6 R), 4.75 (d, 1.2H, J ) H2 ꢀ), 5.39 (s, 1H, H-2 R);
13C NMR (100 MHz) δ 17.8 (R), 22.1 (ꢀ), 27.5 (ꢀ), 28.3 (R), 30.8
(R), 31.7 (ꢀ) (C-3, 4, 5), 30.5 (CH Ada), 36.3 (CH2 Ada), 42.4
(CH2 Ada), 51.9 (CH3 CO2Me R+ꢀ), 68.5 (C-6 R), 73.5 (Cq Ada
R), 74.4 (Cq Ada ꢀ), 74.5 (C-6 ꢀ), 90.2 (C-2 R), 94.5 (C-2 R),
171.2 (CdO ꢀ), 172.8 (CdO R); HRMS [M + Na+] calcd for
C17H26O4Na 317.1729, found 317.1724.
1
(cm-1) 736, 1078, 1439; R-anomer, H NMR (400 MHz) δ 1.33
(m, 1H), 1.50-1.69 (m, 10H), 1.79-1.95 (m, 7H, H-3, 4, 5 + 6 ×
CH2 Ada), 2.10 (br s, 3H, 3 × CH Ada), 3.39-3.48 (m, 2H, 2 ×
H-7), 4.17 (m, 1H, H-6), 4.53 (d, 1H, J ) 12.4 Hz, CHHPh), 4.57
(d, 1H, J ) 12.4 Hz, CHHPh), 5.30 (d, 1H, J ) 2.8 Hz, H-1),
7.22-7.36 (m, 5H, Harom); 13C NMR (100 MHz) δ 17.7, 27.9, 31.3
(C-3, C-4, C-5), 30.6 (CH Ada), 36.4 (CH2 Ada), 42.7 (CH2 Ada),
67.4 (C-6), 73.3, 73.9 (C-7, CH2 Bn), 90.0 (C-1), 127.3, 128.2
1
(CHarom), 138.6 (Cq Ph); ꢀ-anomer, H NMR (400 MHz) δ 1.26
(m, 1H), 1.41-1.65 (m, 10H), 1.79-1.89 (m, 7H, H-3, 4, 5 + 6 ×
CH2 Ada), 2.10 (br s, 3H, 3 × CH Ada), 3.47 (dd, 1H, J ) 4.4 Hz,
J ) 9.6 Hz, H-7), 3.55 (d, 1H, J ) 6.4 Hz, J 10.0 Hz, H-7), 3.64
(m, 1H, H-6), 4.53 (d, 1H, J ) 12.0 Hz, CHHPh), 4.59 (d, 1H, J
) 12.4 Hz, CHHPh), 4.72 (dd, 1H, J ) 2.8 Hz, J ) 8.8 Hz, H-1),
7.24-7.35 (m, 5H, Harom); 13C NMR (100 MHz) δ 22.4, 27.4, 32.5
(C-3, C-4, C-5), 30.7 (CH Ada), 36.3 (CH2 Ada), 42.7 (CH2 Ada),
73.4 (CH2 Bn), 73.7 (C-7), 76.7 (C-6), 94.8 (C-2), 127.4, 127.5,
128.3 (CHarom), 138.5 (Cq Ph); HRMS [M + Na+] calcd for
C23H32O3Na 379.2249, found 379.2244.
6-Benzyloxymethyl-2-benzyloxytetrahydropyran (19a): The
product was obtained from 17 (94 mg, 0.30 mmol) and benzylal-
cohol as an R/ꢀ-mixture (R/ꢀ ) 1:1.4, 82%): IR (neat) ν (cm-1
)
1
739, 1037, 1454; H NMR (400 MHz) δ 1.23-1.89 (m, 14.1H,
H-3, 4, 5, R+ꢀ), 3.44-3.53 (m, 3.35H, 2 × H-7R, H-7ꢀ), 3.59
(m, 2.7H, H-6ꢀ, H-7ꢀ), 4.03 (m, 1H, H-6R), 4.78 (m, 2.35H, H-1ꢀ,
CHHPh R), 4.53-4.65 (m, 6.05H, 2 × CHHPh R, 3 × CHHPh ꢀ),
4.76 (d, 1H, J ) 12.0 Hz,CHHPh R), 4.76 (d, 1.35H, J ) 12.0
Hz,CHHPh ꢀ), 4.96 (m, 1H, H-1R), 7.22-7.37 (m, 23.5H, Harom);
13C NMR (100 MHz) δ 17.7 (R), 21.7 (ꢀ), 27.4 (ꢀ), 27.5 (R), 29.5
(R), 31.0 (ꢀ) (C-3, C-4, C-5), 68.1 (C-6 R), 68.3 (CH2 Bn R), 69.8
(CH2 Bn ꢀ), 73.2, 73.3, 73.4, 73.5 (C-7R, C-7ꢀ,CH2 Bn R, CH2Bn
ꢀ), 75.4 (C-6 ꢀ), 96.5 (C-2 R), 100.9 (C-2 ꢀ), 126.9, 127.4, 127.5,
127.6, 127.8, 127.9, 128.3, 128.4 (CHarom R+ꢀ), 137.9, 138.4 (Cq
Ph R+ꢀ); HRMS [M + Na+] calcd for C20H24O3Na 335.1623, found
335.1618.
Phenyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3,4-tri-O-ben-
zyl-ꢀ-D-mannopyranosyl uronate)-1-thio-ꢀ-D-mannopyranosyl
uronate) (21): The title compound was synthesized form CB-
Mannoside 22 (800 mg, 1.29 mmol) and thiomannoside 11 (929
mg, 1.93 mmol) as described for 12: [R]D ) -55 (c 1, DCM); IR
(neat) ν (cm-1) 737, 1063, 1749; 1H NMR (400 MHz) δ 3.49 (dd,
1H, J ) 2.8 Hz, J ) 9.6 Hz, H-3′), 3.53 (s, 3H, CH3 CO2Me), 3.64
(m, 4H, CH3 CO2Me, H-3), 3.79 (d, 1H, J ) 10.0 Hz, H-5′), 3.83
(d, 1H, J ) 2.8 Hz, H-2′), 3.86 (d, 1H, J ) 9.6 Hz), 4.05 (d, 1H,
J ) 2.0 Hz, H-2), 4.19 (t, 1H, J ) 9.6 Hz, H-4′), 4.51 (t, 1H, J )
9.6 Hz, H-4), 4.56 (s, 2H, CH2 Bn), 4.60-4.64 (m, 2H, 2 ×
CHHPh), 4.64 (s, 1H, H-1′), 4.73 (d, 1H, J ) 10.8 Hz, CHHPh),
4.78-4.86 (m, 4H, H-1, 3 × CHHPh), 4.96 (d, 1H, J ) 12.0 Hz,
CHHPh), 4.98 (d, 1H, J ) 12.0 Hz, CHHPh), 7.20-7.46 (m, 30H,
6-Benzyloxymethyl-2-isopropyloxytetrahydropyran (19b):
The product was obtained from 17 (101 mg, 0.32 mmol) and
isopropanol as an R/ꢀ-mixture (R/ꢀ ) 1:0.6, 61%): IR (neat) ν
1
(cm-1) 741, 1037, 1454; H NMR (400 MHz) δ 1.12 (m, 4.8H,
H
arom); 13C NMR (100 MHz) δ 52.5 (CH3 CO2Me), 52.9 (CH3
CH3 iPr R+ꢀ), 1.23 (m, 4.8H, CH3 iPr R+ꢀ), 1.32-1.92 (m, 9.6H,
H-3, 4, 5, R+ꢀ), 3.40-3.50 (m, 2.6H, 2 × H-7R, H-7ꢀ), 3.57 (m,
0.6H, H-7ꢀ), 3.66 (m, 0.6H, H-6ꢀ), 3.91-4.07 (m, 2.6H, H-6R,
CH iPr R+ꢀ), 4.50 (d, 0,6H, J ) 8.4 Hz, H-1ꢀ), 4.54-4.62 (m,
3.2H, 2 × CHHPh R, 2 × CHHPh ꢀ), 4.99 (s, 1H, H-1R),
7.14-7.33 (m, 8H, Harom); 13C NMR (100 MHz) δ 17.7 (R), 21.4
(CH3 iPr R), 21.8 (CH3 iPr ꢀ), 22.0 (ꢀ), 27.5 (ꢀ), 27.6 (R), 30.0
(R), 31.6 (ꢀ) (C-3, C-4, C-5), 67.5 (CH iPr ꢀ), 67.8 (CH iPr ꢀ),
69.8 (C-6 R), 73.2, 73.4, 73.6 (C-7R, C-7ꢀ,CH2 Bn R, CH2Bn ꢀ),
75.4 (C-6 ꢀ), 94.7 (C-2 R), 100.1 (C-2 ꢀ), 127.4, 127.5, 128.2,
128.3 (CHarom R+ꢀ), 138.5 (Cq Ph R+ꢀ); HRMS [M + Na+] calcd
for C16H24O3Na 287.1623, found 287.1619.
CO2Me), 72.3 (CH2 Bn), 73.8 (CH2 Bn), 74.9 (CH2 Bn), 77.5 (2 ×
CH2Bn), 75.6 (C-5′), 75.8 (C-2′), 76.1 (C-4′), 77.8 (C-4), 77.9 (C-
2),78.3 (C-5), 81.7 (C-3), 81.9 (C-3′), 89.4 (JC1-H1 ) 154 Hz, C-1),
103.3 (JC1′-H1′ ) 156 Hz, C-1′), 127.2, 127.3, 127.4, 127.5, 127.6,
127.7, 128.0, 128.1, 128.2, 128.3, 128.5, 128.9, 129.0, 129.2, 130.2,
130.7, 130.8 (CHarom), 135.3 (Cq SPh), 137.8 (Cq Bn), 138.0 (2xCq
Bn), 138.1 (Cq Bn), 138.3 (Cq Bn), 138.6 (Cq Bn), 138.8 (Cq Bn),
168.8 (CdO), 169.1 (CdO); HRMS [M + NH4+] calcd for
C55H60O12NS 958.3831, found 958.3841.
(Carboxylbenzyl 2,3,4-tri-O-benzyl-ꢀ-mannopyranosyluronic
acid) methyl ester (22): The title compound was synthesized from
208 (1.72 g, 3.0 mmol) and 2-hydroxymethyl-benzoic acid benzyl
ester (2.2 g, 9.1 mmol) as described for 10 (R/ꢀ ) 1:6, 65% over
2 steps): IR (neat) ν (cm-1) 731, 1278, 1680, 1715, 1734; ꢀ-anomer,
1H NMR (400 MHz) δ 3.57 (dd, 1H, J ) 2.4 Hz, J ) 9.2 Hz,
H-3), 3.66 (s, 3H, CH3 CO2Me), 3.92 (d, 1H, J ) 8.8 Hz, H-5),
3.98 (s, 1H, H-2), 4.30 (t, 1H, J ) 8.8 Hz), 4.48 (d, 1H, J ) 11.6
Hz, CHHPh), 4.64 (m, 2H, H-1, CHHPh), 4.86 (m, 2H, 2 ×
CHHPh), 5.00 (d, 1H, J ) 12.4 Hz, CHHPh), 5.07 (d, 1H, J )
14.4 Hz, CHHPh), 5.34 (d, 1H, J ) 14.0 Hz, CHHPh), 7.21-7.60
(m, 17H, Harom), 7.65 (d, 1H, J ) 7.6 Hz), 8.05 (d, 1H, J ) 8.0
Hz), 9.0 (br s, 1H, CO2H); 13C NMR (100 MHz) δ 52.3 (CH3
CO2Me), 70.0 (CH2 Bn), 61.6 (CH2 Bn), 73.7 (C-2), 73.9 (CH2
Bn), 74.9 (CH2 Bn), 75.0 (C-5), 75.8 (C-4), 80.9 (C-3), 101.5
(JC1-H1 ) 159 Hz, C-1), 126.9 (Cq CB), 127.1, 127.4, 127.5, 127.6,
127.7, 127.8, 127.9, 128.1, 128.2, 129.7, 131.3, 133.1 (CHarom),
137.9 (Cq Bn), 138.0 (Cq Bn), 138.3 (Cq Bn), 140.5 (Cq CB), 168.9
(CdO), 171.9 (CdO); HRMS [M + Na+] calcd for C36H36O9Na
635.2251, found 635.2248.
6-Benzyloxymethyl-2-tert-butyloxytetrahydropyran (19c): The
products were obtained from 17 (94 mg, 0.30 mmol) and tert-
butanol as pure anomers (R/ꢀ ) 1:0.38, 60%): IR (neat) ν (cm-1
)
1
741, 1101, 1479; R-anomer, H NMR (400 MHz) δ 1.25 (s, 9H,
CH3 tBu), 1.40 (m, 1H), 1.50-1.68 (m, 4H), 1.87 (m, 1H, H-3, 4,
5), 3.38-3.46 (m, 2H, 2 × H-7), 4.13 (m, 1H, H-6), 4.53 (d, 1H,
J ) 12.4 Hz, CHHPh), 4.57 (d, 1H, J ) 12.4 Hz, CHHPh), 5.17
(d, 1H, J ) 2.8 Hz, H-1), 7.24-7.32 (m, 5H, Harom); 13C NMR
(100 MHz) δ 17.7, 27.9, 31.3 (C-3, C-4, C-5), 28.8 (CH3 tBu),
67.4 (C-6), 73.2, 73.8 (C-7, CH2 Bn), 91.5 (C-1), 127.3, 127.4,
1
128.2 (CHarom), 138.6 (Cq Ph); ꢀ-anomer, H NMR (400 MHz) δ
1.27 (s, 9H, CH3 tBu), 1.21 (m, 1H), 1.42-1.61 (m, 4H), 1.87 (m,
1H, H-3, 4, 5), 3.47 (dd, 1H, J ) 5.2 Hz, J ) 10.0 Hz, H-7), 3.55
(d, 1H, J ) 6.0 Hz, J ) 10.0 Hz, H-7), 3.64 (m, 1H, H-6), 4.53 (d,
1H, J ) 12.0 Hz, CHHPh), 4.59 (d, 1H, J ) 12.4 Hz, CHHPh),
4.61 (dd, 1H, J ) 2.4 Hz, J ) 9.6 Hz, H-1), 7.25-7.32 (m, 5H,
H
arom); 13C NMR (100 MHz) δ 22.4, 27.4, 32.5 (C-3, C-4, C-5),
28.8 (CH3 tBu), 73.4 (CH2 Bn), 73.6 (C-7), 75.3 (C-6), 96.6 (C-2),
127.4, 127.5, 128.3 (CHarom), 138.5 (Cq Ph); HRMS [M + Na+]
calcd for C17H26O3Na 301.1780, found 301.1775.
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-levulinoyl-ꢀ-D-
mannopyranosyl uronate) (23): The title compound was synthe-
sized from 8 (3.2 g, 5.6 mmol) and 3-azidopropanol (1.13 g, 11.2
J. Org. Chem. Vol. 74, No. 1, 2009 45

Code´e et al.
mmol) as described by the general procedure for Ph2SO-Tf2O
mediated glycosylations at -78 °C (R/ꢀ ) 1:10, 72%): [R]D
CO2Me), 3.73 (m, 3H, H-2, 2 × H-5), 3.78-3.84 (m, 3H, 2 ×
H-2, H-5), 4.01 (m, 1H, O-CHHCH2), 4.16 (t,1H, J ) 9.6 Hz, H-4),
4.32 (t, 1H, J ) 9.5 Hz, H-4), 4.41 (t, 1H, J ) 9.5 Hz, H-4), 4.44
(s, 1H, H-1), 4.49-4.61 (m, 7H, H-1, 6 × CHHPh), 4.69-4.85
(m, 10H, H-1, 9 × CHHPh), 7.18-7.40 (m, 35H, Harom); 13C NMR
(100 MHz) δ 29.0 (CH2 CH2CH2CH2), 48.2 (CH2N3), 52.0 (2 ×
CH3 CO2Me), 52.3 (CH3 CO2Me), 66.7 (O-CH2CH2), 71.7 (CH2
Bn), 72.3 (CH2 Bn), 72.7 (CH2 Bn), 73.8 (CH2 Bn), 74.3 (CH2
Bn), 74.4 (CH2 Bn), 75.0 (CH2 Bn), 74.2, 74.4, 74.4, 75.0, 75.1,
75.2, 75.6 (3 × C-2 and 3 × C-5), 76.0 (C-4), 77.2 (C-4), 77.4
(C-4), 79.2 (C-3), 79.6 (C-3), 81.3 (C-3), 101.6 (JC1-H1 ) 155 Hz,
C-1), 102.3 (JC1-H1 ) 157 Hz, C-1), 102.7 (JC1-H1 ) 155 Hz, C-1),
127.2, 127.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3
(CHarom), 138.0 (Cq Bn), 138.2 (Cq Bn), 138.4 (Cq Bn), 138.7 (Cq
Bn), 138.8 (Cq Bn), 138.9 (Cq Bn), 168.6 (3 × CdO); HRMS [M
+ NH4+] calcd for C73H83O19N4 1319.56460, found 1319.56664,
[M + Na+] calcd for C73H79O19N3 1324.5200, found 1324.5217.
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-4-O-(methyl 2,3-di-O-benzyl-4-O-levulinoyl-ꢀ-D-man-
nopyranosyl uronate)-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-man-
nopyranoside uronate) (29): The title compound was synthesized
from 21 (362 mg, 0.38 mmol) and 24 (225 mg, 0.48 mmol) as
described by the general procedure for BSP-Tf2O mediated gly-
cosylations (51%). Spectroscopic data were identical to those
reported previously.8
)
-56 (c 1); IR (neat) ν (cm-1) 741, 1153, 1719, 1755, 2097; H
NMR (400 MHz) δ 1.88 (m, 2H, CH2CH2CH2), 2.16 (s, 3H, CH3
Lev), 2.54 (m, 2H, CH2 Lev), 2.71 (m, 2H, CH2 Lev), 3.38 (t, 2H,
J ) 6.8 Hz, CH2N3), 3.53 (m, 2H, H-3, O-CHHCH2), 3.71 (s, 3H,
CO2Me), 3.87 (m, 2H, H-2, H-5), 4.03 (m, 1H, O-CHHCH2), 4.41
(d, 1H, J ) 12.4 Hz, CHHPh), 4.43 (s, 1H, H-1), 4.53 (d, 1H, J )
12.4 Hz, CHHPh), 4.80 (d, 1H, J ) 12.8 Hz, CHHPh), 4.91 (d,
1H, J ) 12.4 Hz, CHHPh), 5.53 (t, 1H, J ) 9.6 Hz), 7.24-7.42
(m, 10H, Harom); 13C NMR (100 MHz) δ 27.9 (CH2 Lev), 29.0 (CH2
CH2CH2CH2), 29.8 (CH3 Lev), 37.7 (CH2 Lev), 48.2 (CH2N3), 52.6
(CO2CH3), 66.9 (O-CH2CH2), 69.1 (C-4), 73.1, 73.5 (C-2 and C-5),
73.8 (CH2 Bn), 78.0 (C-3), 101.5 (JC1-H-1 ) 158 Hz, C-1), 127.5,
127.7, 128.0, 128.3 (Carom), 137.7 (Cq Ph), 138.2 (Cq Ph), 167.9
(CdO), 171.5 (CdO), 206.2 (CdO Lev); HRMS [M + Na+] calcd
for C29H35O9N3Na 592.2271, found 592.2261.
1
3-Azidopropyl (methyl (2,3-di-O-benzyl-ꢀ-D-mannopyranosi-
de)uronate) (24): Mannuronic acid 23 (2.28 g, 4.0 mmol) was
delevulinoylated as described by the general procedure for levuli-
noyl cleavage (99%). Spectroscopic data were identical to those
reported previously.8a
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3,4-tri-
O-benzyl-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranoside
uronate) (25): The title compound was synthesized from 20 (106
mg, 0.19 mmol) and 24 (70 mg, 0.15 mmol) as described by the
general procedure for BSP-Tf2O mediated glycosylations (67%):
[R]D ) -33 (c 1, DCM); IR (neat) ν (cm-1) 739, 1064, 1747, 2097;
1H NMR (400 MHz) δ 1.84 (m, 2H, CH2CH2CH2), 3.32 (t, 1H, J
) 6.8 Hz, CH2N3), 3.48 (m, 2H, O-CHHCH2, H-3), 3.55 (s, 3H,
CH3 CO2Me), 3.61 (m, 4H, H-3, CH3 CO2Me), 3.75 (d, 1H, J )
9.5 Hz, H-5), 3.82 (d, 1H, J ) 3.0 Hz, H-2), 3.85 (d, 1H, J ) 2.4
Hz, H-2), 3.88 (d, 1H, J ) 8.4 Hz, H-5), 3.99 (m, 1H, O-CHHCH2),
4.18 (t, 1H, J ) 9.6 Hz, H-4), 4.42 (t, 1H, J ) 9.5 Hz, H-4), 4.46
(s, 1H, H-1), 4.52-4.62 (m, 4H, 2 × CH2 Bn), 4.69 (s, 1H, H-1),
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-4-O-(methyl 2,3-di-O-benzyl-ꢀ-D-mannopyranosyl ur-
onate)-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranoside ur-
onate) (30): Trimannuronic acid 29 (71 mg, 0.054 mmol) was
delevulinoylated as described by the general procedure for levuli-
noyl cleavage (78%): [R]D ) -67 (c 1, DCM); IR (neat) ν (cm-1
)
727, 1055, 1747, 2097; 1H NMR (500 MHz) δ 1H NMR (400 MHz)
1.85 (m, 2H, CH2CH2CH2), 2.98 (br s, 1H, 3′′-OH), 3.27 (dd, 1H,
J ) 2.5 Hz, J ) 9.5 Hz, H-3), 3.34 (t, 1H, J ) 6.5 Hz, CH2N3),
3.47 (s, 3H, CH3 CO2Me), 3.50-3.62 (m, 10H, 2 × H-3, H-5,
O-CHHCH2, 2 × CH3 CO2Me), 3.73-3.88 (m, 5H, 3 × H-2, 2 ×
H-5), 4.01 (m, 1H, O-CHHCH2), 4.17 (t, 1H, J ) 9.5 Hz, H-4),
4.36 (t, 1H, J ) 9.0 Hz, H-4), 4.42 (t, 1H, J ) 9.0 Hz, H-4), 4.45
(s, 1H, H-1), 4.52-4.58 (m, 4H, 4 × CHHPh), 4.62 (s, H-1), 4.64
(d, 1H, J ) 13.5 Hz, CHHPh), 4.72 (s, 1H, H-1), 4.72-4.83 (m,
7H, 7 × CHHPh), 7.18-7.38 (m, 30H, Harom); 13C NMR (125 MHz)
δ 29.0 (CH2 CH2CH2CH2), 48.2 (CH2N3), 52.1 (CH3 CO2Me), 52.2
(CH3 CO2Me), 52.3 (CH3 CO2Me), 66.8 (O-CH2CH2), 68.1 (C-4),
71.7 (CH2 Bn), 72.3 (CH2 Bn), 73.8 (CH2 Bn), 74.5 (CH2 Bn),
74.1, 74.4, 74.7, 75.0, 75.1, 75.7, (3 × C-2 and 3 × C-5), 77.1
(C-4), 77.2 (C-4), 79.3 (C-3), 79.7 (C-3), 80.3 (C-3), 101.7 (C-1),
102.3 (C-1), 102.5 (C-1), 127.1, 127.2, 127.3, 127.4, 127.6, 127.7,
127.8, 127.9, 128.0, 128.1, 128.2, 128.4 (CHarom), 137.9 (Cq Bn),
138.3 (Cq Bn), 138.6 (Cq Bn), 138.7 (Cq Bn), 168.5 (CdO), 168.6
(CdO), 169.8 (CdO); HRMS [M + NH4+] calcd for C66H77O19N4
1229.51765, found 1229.51990, [M + Na+] calcd for C66H73O19N3
1234.4730, found 1234.4753.
4.71-4.85 (m, 6H, 3 × CH2 Bn), 7.19-7.40 (m, 25H, Harom); 13
C
NMR (100 MHz) δ 28.9 (CH2 CH2CH2CH2), 48.1 (CH2N3), 52.0
(CH3 CO2Me), 52.2 (CH3 CO2Me), 66.7 (O-CH2CH2), 71.7 (CH2
Bn), 72.3 (CH2 Bn), 73.7 (CH2 Bn), 74.0 (C-2), 74.3 (C-5), 74.4
(CH2 Bn), 75.0 (C-5), 75.0 (CH2 Bn), 75.2 (C-2), 75.6 (C-4), 77.3
(C-4), 79.1 (C-3), 81.3 (C-3), 101.6 (JC1-H1 ) 156 Hz, C-1), 102.5
(JC1-H1 ) 155 Hz, C-1), 127.2, 127.3, 127.4, 127.5, 127.6, 127.7,
127.9, 128.0, 128.1, 128.3 (CHarom), 137.9 (Cq Bn), 138.0 (Cq Bn),
138.3 (Cq Bn), 138.5 (Cq Bn), 138.8 (Cq Bn), 168.6 (2 × CdO);
HRMS [M + NH4+] calcd for C52H610O13N4 949.4230, found
949.4241.
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-4-O-levulinoyl-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-
mannopyranoside uronate) (26): The title compound was syn-
thesized from 20 (80 mg, 0.14 mmol) and 24 (83 mg, 0.18 mmol)
as described by the general procedure for BSP-Tf2O mediated
glycosylations (62%). Spectroscopic data were identical to those
reported previously.8a
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranoside
uronate) (27): Dimannuronic acid 26 (65 mg, 0.069 mmol) was
delevulinoylated as described by the general procedure for levuli-
noyl cleavage (95%). Spectroscopic data were identical to those
reported previously.8a
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-4-O-(methyl 2,3,4-tri-O-benzyl-ꢀ-D-mannopyranosyl
uronate)-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranoside
uronate) (28): The title compound was synthesized from 21 (100
mg, 0.11 mmol) and 24 (75 mg, 0.16 mmol) as described by the
general procedure for BSP-Tf2O mediated glycosylations (74%):
[R]D ) -55 (c 1, DCM); IR (neat) ν (cm-1) 739, 1059, 1749, 2095;
1H NMR (400 MHz) δ 1.86 (m, 2H, CH2CH2CH2), 3.33 (t, 1H, J
) 6.8 Hz, CH2N3), 3.44 (m, 4H, H-3, CH3 CO2Me), 3.47-3.55
(m, 5H, H-3, O-CHHCH2, CH3 CO2Me), 3.57 (m, 4H, H-3, CH3
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-4-O-(methyl 2,3-di-O-benzyl-4-O-(methyl 2,3,4-tri-O-
benzyl-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranosyl ur-
onate)-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranoside
uronate) (31): The title compound was synthesized from 21 (124
mg, 0.13 mmol) and 27 (74 mg, 0.088 mmol) as described by the
general procedure for BSP-Tf2O mediated glycosylations (67%):
[R]D ) -56 (c 1, DCM); IR (neat) ν (cm-1) 738, 1057, 1747, 2096;
1H NMR (400 MHz) δ 1.86 (m, 2H, CH2CH2CH2), 3.42 (t, 1H, J
) 6.8 Hz, CH2N3), 3.40 (s, 3H, CH3 CO2Me), 3.41 (s, 3H, CH3
CO2Me), 3.41-3.58 (m, 11H, 4 × H-3, O-CHHCH2, 2 ×
CH3CO2Me), 3.69-3.75 (m, 5H, 2 × H-2, 3 × H-5), 3.80-3.84
(m, 3H, 2 × H-2, H-5), 4.02 (m, 1H, O-CHHCH2), 4.15 (t,1H, J )
9.6 Hz, H-4), 4.30 (m, 2H, 2 × H-4), 4.40 (t, 1H, J ) 9.6 Hz,
H-4), 4.44 (s, 1H, H-1), 4.49-4.54 (m, 5H, 5 × CHHPh),
4.58-4.60 (m, 3H, 2 × H-1, CHHPh), 4.68-4.83 (m, 12H, H-1,
11 × CHHPh), 7.22-7.40 (m, 45H, Harom); 13C NMR (100 MHz)
46 J. Org. Chem. Vol. 74, No. 1, 2009

Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester
δ 29.0 (CH2 CH2CH2CH2), 48.2 (CH2N3), 52.0 (2 × CH3 CO2Me),
52.1 (CH3 CO2Me), 52.3 (CH3 CO2Me), 66.8 (O-CH2CH2), 71.7
(CH2 Bn), 72.3 (CH2 Bn), 72.5 (CH2 Bn), 73.9 (CH2 Bn), 74.4
(CH2 Bn), 74.5 (CH2 Bn), 75.0 (CH2 Bn), 74.2, 74.4, 74.5, 74.5,
75.0, 75.2, 75.9, 76.0 (4 × C-2 and 4 × C-5), 75.6 (C-4), 77.1
(C-4), 77.3 (C-4), 77.4 (C-4), 79.2 (C-3), 79.6 (C-3), 79.7 (C-3),
81.4 (C-3), 101.7 (JC1-H1 ) 155 Hz, C-1), 102.3 (JC1-H1 ) 157
Hz, C-1), 102.5 (JC1-H1 ) 158 Hz, C-1), 102.7 (JC1-H1 ) 155 Hz,
C-1), 127.2, 127.3, 127.4, 127.5, 127.6, 127.7, 127.9, 128.0, 128.1,
128.2, 128.3 (CHarom), 138.0 (Cq Bn), 138.2 (Cq Bn), 138.3 (Cq
Bn), 138.6 (Cq Bn), 138.8 (Cq Bn), 138.9 (Cq Bn), 168.6 (CdO),
168.6 (CdO), 168.7 (CdO); HRMS [M + NH4+] calcd for
C94H105O25N4 1689.7096, found 1689.7075.
compound was synthesized from 26 (70 mg, 0.077 mmol) as
described above and isolated as its monotriethyl ammonium salt
1
(21 mg, 0.045 mmol, 59%): H NMR (400 MHz) δ 1.26 (t, 9H, J
) 7.6 Hz, CH3, Et3N), 1.97 (m, 2H, CH2CH2CH2), 3.11 (m, 2H,
CH2NH3), 3.28 (q, 6H, J ) 7.6 Hz, CH2, Et3N), 3.64-3.76 (m,
5H), 3.81-3.97 (m, 4H), 4.03 (d, 1H, J ) 2.8 Hz), 4.62 (s, 1H,
H-1), 4.71 (s, 1H, H-1); 13C NMR (100 MHz) δ 8.2 (CH3, Et3N),
26.7 (CH2 CH2CH2CH2), 37.7 (CH2NH2), 46.7 (CH2 Et3N), 67.5
(O-CH2-CH2), 68.5, 69.8, 70.1, 70.8, 71.5, 72.6, 75.9, 76.0, 78.3,
99.9 (C-1), 100.1 (C-1), 175.5 (CdO), 175.8 (CdO); HRMS [M
+ H+] calcd for C15H26O13N 428.1401, found 428.1397.
3-Aminopropyl (4-O-(4-O-(ꢀ-D-mannopyranosyluronate)-ꢀ-
D-mannopyranosyluronate)-ꢀ-D-mannopyranosideuronate)tri-
ethylammonium salt (34): The target compound was synthesized
from 29 (50 mg, 0.038 mmol) as described above and isolated as
3-Azidopropyl (methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-
O-benzyl-4-O-(methyl 2,3-di-O-benzyl-4-O-(methyl 2,3-di-O-
benzyl-4-O-(methyl 2,3,4-tri-O-benzyl-ꢀ-D-mannopyranosyl
uronate)-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranosyl
uronate)-ꢀ-D-mannopyranosyl uronate)-ꢀ-D-mannopyranoside
uronate) (32): The title compound was synthesized from 21 (116
mg, 0.12 mmol) and 30 (100 mg, 0.082 mmol) as described by the
general procedure for BSP-Tf2O mediated glycosylations (69%):
[R]D ) -63 (c 1, DCM); IR (neat) ν (cm-1) 735 1057, 1747, 2097;
1H NMR (500 MHz) δ 1.86 (m, 2H, CH2CH2CH2), 3.37 (t, 1H, J
) 7.0 Hz, CH2N3), 3.41 (s, 3H, CH3 CO2Me), 3.43 (s, 3H, CH3
CO2Me), 3.45 (s, 3H, CH3 CO2Me), 3.43-3.62 (m, 6H, 5 × H-3,
O-CHHCH2), 3.56 (s, 3H, CH3 CO2Me), 3.61 (s, 3H, CH3 CO2Me),
3.70-3.79 (m, 6H), 3.84-3.87 (m, 3H, 5 × H-2, 5 × H-5), 4.04
(m, 1H, O-CHHCH2), 4.18 (t, 1H, J ) 9.0 Hz, H-4), 4.30 (m, 3H,
3 × H-4), 4.44 (t, 1H, J ) 8.5 Hz, H-4), 4.47 (s, 1H, H-1),
4.52-4.63 (m, 10H, 3 × H-1, 7 × CHHPh), 4.71-4.80 (m, 10H,
H-1, 9 × CHHPh), 4.83-4.86 (m, 6H, 6 × CHHPh), 7.23-7.43
(m, 55H, Harom); 13C NMR (150 MHz) δ 28.9 (CH2 CH2CH2CH2),
48.1 (CH2N3), 52.0 (3 × CH3 CO2Me), 52.1 (CH3 CO2Me), 52.3
(CH3 CO2Me), 66.7 (O-CH2CH2), 71.6 (CH2 Bn), 72.3 (CH2 Bn),
72.4 (CH2 Bn), 72.5 (CH2 Bn), 73.8 (CH2 Bn), 74.4 (CH2 Bn),
74.5 (CH2 Bn), 75.1 (CH2 Bn), 75.0 (CH2 Bn), 74.2, 74.4, 75.0,
75.2, 75.9, 75.9, 76.0, (5 × C-2 and 5 × C-5), 75.6 (C-4), 77.2 (3
1
its monotriethyl ammonium salt (20 mg, 0.033 mmol, 86%): H
NMR (400 MHz) δ 1.26 (t, 18H, J ) 7.6 Hz, CH3, Et3N), 1.90 (m,
2H, CH2CH2CH2), 3.05 (m, 2H, CH2NH3), 3.11 (q, 12H, J ) 7.6
Hz, CH2, Et3N), 3.55-3.69 (m, 7H), 3.75-3.90 (m, 5H), 3.95 (br
s, 2H), 4.54 (s, 1H, H-1), 4.58 (s, 1H, H-1), 4.65 (s, 1H, H-1); 13
C
NMR (100 MHz) δ 8.24 (CH3 Et3N), 26.7 (CH2CH2CH2), 37.7
(CH2NH2), 46.7 (CH2 Et3N), 67.5 (O-CH2-CH2), 68.5, 69.8, 70.0,
70.4, 71.4, 72.6, 75.9, 76.0, 78.1, 78.2, 99.9 (C-1), 100.0 (C-1),
100.1 (C-1), 175.2 (CdO), 175.4 (CdO), 176.0 (CdO); HRMS
[M + H+] calcd for C21H34O19N 604.1725, found 604.1717.
3-Aminopropyl (4-O-(4-O-(4-O-(ꢀ-D-mannopyranosyluronate)-
ꢀ-D-mannopyranosyluronate)-ꢀ-D-mannopyranosyluronate)-ꢀ-
D-mannopyranosideuronate)triethylammonium salt (35): The
target compound was synthesized from 32 (40 mg, 0.024 mmol)
as described above to give the title compound (17 mg, 0.016 mmol):
1H NMR (400 MHz) δ 1.26 (t, 27H, J ) 7.6 Hz, CH3, Et3N), 1.90
(m, 2H, CH2CH2CH2), 3.07 (m, 2H, CH2NH3), 3.10 (q, 18H, J )
7.6 Hz, CH2, Et3N), 3.48-3.69 (m, 10H), 3.74-3.92 (m, 7H), 3.95
(brs, 3H), 4.55 (s, 1H, H-1), 4.57 (s, 1H, H-1), 4.58 (s, 1H, H-1),
4.65 (s, 1H, H-1); 13C NMR (100 MHz) δ 26.6 (CH2CH2CH2),
37.7 (CH2NH2), 67.5 (O-CH2-CH2), 68.5, 69.8, 69.9, 70.4, 71.3,
71.4, 75.9, 77.8, 78.0, 78.2, 99.8 (C-1), 100.0 (2 × C-1), 100.1
(C-1), 175.2 (CdO), 175.3 (CdO); HRMS [M + H+] calcd for
C27H42O25N 780.2046, found 780.2044.
× C), 79.2 (C-3), 79.7 (3 × C-3), 81.4 (C-3), 101.7 (JC1-H1
1565 Hz, C-1), 102.3 (JC1-H1 ) 157 Hz, C-1), 102.5 (JC1-H1
)
)
155 Hz, 2 × 1), 102.7 (JC1-H1 ) 154 Hz, C-1), 127.1, 127.2, 127.3,
127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3
(CHarom), 138.0 (Cq Bn), 138.2 (Cq Bn), 138.3 (Cq Bn), 138.6 (Cq
Bn), 138.8 (Cq Bn), 138.9 (Cq Bn), 168.5 (CdO), 168.6 (CdO);
HRMS [M + 2NH4+] calcd for C115H131O31N5 1039.4425, found
1039.4438.
3-Aminopropyl (4-O-(4-O-(4-O-(4-O-(ꢀ-D-mannopyranosylu-
ronate)-ꢀ-D-mannopyranosyluronate)-ꢀ-D-mannopyranosylur-
onate)-ꢀ-D-mannopyranosyluronate)-ꢀ-D-mannopyranosideur-
onate)triethylammonium salt (36): The target compound was
synthesized from 33 (54 mg, 0.026 mmol) as described above, and
passed through a small Amberlite Na+ column to give the title
1
compound (27 mg, 0.020 mmol): H NMR (400 MHz) δ 1.26 (t,
General Procedure for Deprotection of the Mannuronic
Acid Oligomers: The fully protected mannuronic acid oligomers
were dissolved in THF (0.025 M) and aqueous KOH (0.45 M, (n
+ 1) equiv, in which n is the number of ester groups). The biphasic
mixture was homogenized by the addition of a little extra THF
(<half the total volume). The mixture was stirred for 1 h, before
being quenched by the addition of Amberlite-H+. The resin was
filtered off and the solvent evaporated. The crude product was taken
up in MeOH/HOAc (10/1, ∼0.01 M for 25 and 28) or MeOH/
tBuOH/H2O/HOAc (6/5/4/0.15, ∼0.01 M, for 31 and 32) and Pd/C
(catalytic amount) was added. The heterogeneous mixture was
degassed, purged with H2, and stirred (48 h) under a H2 atmosphere,
after which the Pd/C was filtered off and the mixture was
concentrated. The product was purified by gel filtration (HW-40,
0.15 M Et3NHOAc in H2O) to provide the fully deprotected
products (33: 59% over 2 steps; 34: 86% over 2 steps; 35: 65%
over 2 steps; 36: 76% over 2 steps).
6H, J ) 7.6 Hz, CH3, residual Et3N), 1.91 (m, 2H, CH2CH2CH2),
3.14 (m, 2H, CH2NH3), 3.18 (q, 4H, J ) 7.6 Hz, CH2, residual
Et3N), 3.56-4.02 (m, 22H), 4.62-4.72 (m, 5H, 5xH-1); 13C NMR
(100 MHz) δ 26.6 (CH2CH2CH2), 37.7 (CH2NH2), 67.5 (O-CH2-
CH2), 68.5, 69.8, 69.9, 70.4, 71.3, 72.6, 75.9, 77.8, 78.0, 78.1, 99.8
(C-1), 99.9 (3 × C-1), 100.1 (C-1); HRMS [M + H+] calcd for
C33H50O31N 956.2361, found 956.2360.
Acknowledgment. We thank The Netherlands Organisation
for Scientific Research (NWO) for Financial support (VENI
fellowship to J.D.C.C.)
Supporting Information Available: Additional experimental
details for the synthesis of 8, 11, 16, and 17 and NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
3-Aminopropyl (4-O-(ꢀ-D-mannopyranosyluronate)-ꢀ-D-man-
nopyranoside uronate)triethylammonium salt (33): The target
JO8020192
J. Org. Chem. Vol. 74, No. 1, 2009 47