Convergent synthesis of a β-(1→3)-mannohexaose

Article abstract of DOI:10.1021/jo071009n

(Chemical Equation Presented) An as yet unknown β-(1→3)- mannohexaose has been synthesized by a block route involving the coupling of two trisaccharides. Comparison of three closely related attempted mannohexaose syntheses reinforces the influence of subt

Full text of DOI:10.1021/jo071009n

Convergent Synthesis of a â-(1f3)-Mannohexaose
David Crich,*,† Baolin Wu,† and Prasanna Jayalath
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@chem.wayne.edu
ReceiVed May 12, 2007
An as yet unknown â-(1f3)-mannohexaose has been synthesized by a block route involving the coupling
of two trisaccharides. Comparison of three closely related attempted mannohexaose syntheses reinforces
the influence of subtle matching and/or mismatching interactions on the outcome of convergent
oligosaccharide synthesis.
Introduction
by Mallet and co-workers,15-20 and the general approach to
â-mannosides has been applied widely to the synthesis of other
complex oligosaccharides.21-30
In this paper, we turn our attention to the â-(1f3)-mannan
which, to our knowledge, and in contrast to the closely related
â-(1f3)-D-rhamnan,30,31 has yet to be found in Nature. We do
so because the synthesis and provision of samples to glycomics
databases should assist in the future identification of such
substances in Nature, and because of the challenge this particular
mannan presents to our chemistry, especially when considered
Insofar as the â-mannopyranosides have traditionally been
considered to be one of the more challenging classes of
glycosidic bond to synthesize in a stereocontrolled manner,1-6
the â-mannans are the ultimate proving ground for methodology
development in this area. Over the course of the past decade,
we have developed in our laboratory a direct stereocontrolled
route to the synthesis of the â-mannopyranosides,7 based on
the in situ generation and coupling of 4,6-O-alkylidene-protected
R-mannosyl triflates,8-11 and have applied it successfully to the
synthesis of the â-(1f2)-mannan from Candida albicans,12 to
the â-(1f4)-mannan from hard and soft woods, and guar gum,12
and to the alternating â-(1f3)-â-(1f4)-mannan from Rhodo-
torula glutinis and mucilaginosa and Leptospira biflexa.13,14 An
analogous synthesis of the â-(1f2)-mannan was also reported
(13) Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold,
A. L. J. Am. Chem. Soc. 2001, 121, 5826-5828.
(14) Crich, D.; Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126, 15081-
15086.
(15) Dromer, F.; Chevalier, R.; Sendid, B.; Improvisi, L.; Jouault, T.;
Robert, R.; Mallet, J. M.; Poulain, D. Antimicrob. Agents Chemother. 2002,
46, 3869-3876.
(16) For the synthesis of â-mannans by less direct routes, see refs 17-
20.
† Current address: Chemistry Department, Wayne State University, 5101 Cass
Avenue, Detroit, MI 48202.
(17) Nitz, M.; Bundle, D. R. J. Org. Chem. 2001, 66, 8411-8423.
(18) Mathew, F.; Mach, M.; Hazen, K. C.; Fraser-Reid, B. Synlett 2003,
1319-1322.
(1) Barresi, F.; Hindsgaul, O. In Modern Methods in Carbohydrate
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ers: Amsterdam, 1996; pp 251-276.
(19) Wu, X.; Bundle, D. R. J. Org. Chem. 2005, 70, 7381-7388.
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Chem. 2003, 1, 623-628.
(2) Ito, Y.; Ohnishi, Y. In Glycoscience: Chemistry and Chemical
Biology; Fraser-Reid, B., Kuniaki, T., Thiem, J., Eds.; Springer-Verlag:
Berlin, 2001; Vol. 2, pp 1589-1619.
(21) Shao, N.; Guo, Z. W. Pol. J. Chem. 2005, 79, 297-307.
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2003, 44, 1791-1793.
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Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, pp
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10.1021/jo071009n CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/01/2007
6806
J. Org. Chem. 2007, 72, 6806-6815

ConVergent Synthesis of a â-(1f3)-Mannohexaose
from a convergent or block synthesis standpoint. In effect, the
size and nature of the O-3 substituent in 4,6-O-benzylidene-
protected mannosyl donors has been found to influence critically
the stereochemical outcome of these reactions, with the benzyl
ether being ideal and both smaller and larger groups detri-
mental.14,32-38
the coupling of the disaccharide donor 10 to acceptor 11 when
trisaccharide 12 was obtained in 80% yield with 5.2:1 â/R ratio.39
Results and Discussion
Background. The negative influence of sterically bulky
protecting groups on O-3 of the mannosyl donors was first
noticed with the 3-O-tert-butyldimethylsilyl protected system
1, which was less selective than the corresponding regioisomer
2.36,38 Subsequently, the phenomenon reared its head in the
convergent synthesis of the alternating â-(1f3)-â-(1f4)-
mannan when coupling of 3 with 4 resulted in the formation of
the trisaccharide 5, but with only a 1:1 â/R ratio,14 and that of
trisaccharides 6 and 7 to give hexasaccharide 8 with a dis-
appointing 0.67:1 â:R ratio.14 We rationalized the influence of
the size of the O-3 protecting group in terms of a steric
buttressing effect between the O-2 and O-3 protecting groups,
which causes undue hindrance of the â-face of the glycosyl
donor and leads to the observed reduction in selectivity.36,37,39
First Approach to the â-(1f3)-Mannohexaose. With this
in mind, we embarked on a convergent synthesis of the â-(1f3)-
mannohexaose featuring extensive use of the 2-O-propagryl
ether protecting system. Accordingly, phenyl 4,6-O-benzylidene-
R-D-thiomannopyranoside was converted first to the 3-O-
naphthylmethyl ether 13, by means of the stannylene acetal
formed in situ with dibutyltin oxide, and then to the corre-
sponding 2-O-propargyl ether 14. Removal of the naphthylm-
ethyl ether from 14 with DDQ afforded the key building block
15 in 93% yield.42-44 Activation of 14 with BSP11,45 and triflic
anhydride in the presence of TTBP46 at -60 °C in dichlo-
romethane followed by quenching with methanol afforded the
â-mannoside 16 in 85% yield (Scheme 1). Removal of the
naphthylmethyl ether with DDQ then provided the acceptor 17
in 89% yield (Scheme 1).
SCHEME 1. Synthesis of 15 and 17
Taking a hint from the highly â-selective coupling observed
by the van Boom group with the 2-azido-2-deoxy donor 9 we
developed the propargyl ethers as sterically minimal protecting
groups for O-2 capable of overcoming the influence of the bulky
group on O-3.40,41 On this basis, we were able to demonstrate
(32) Crich, D.; Vinogradova, O. J. Org. Chem. 2006, 71, 8473-8480.
(33) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681-1690.
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(35) Crich, D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232-8236.
(36) Crich, D.; Dudkin, V. Tetrahedron Lett. 2000, 41, 5643-5646.
(37) Crich, D.; Jayalath, P.; Hutton, T. K. J. Org. Chem. 2006, 71, 3064-
3070.
(42) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; L., A. J.; Matta,
K. L. Tetrahedron Lett. 2000, 41, 169-173.
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7, 3251-3254.
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2000, 41, 4949-4953.
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(40) Code´e, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft, H.
S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519-1522.
(41) Code´e, J. D. C.; van den Bos, L. J.; 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, 1057-1064.
(44) Csa´va´s, M.; Szabo´, Z. B.; Borba´s, A.; Lipta´k, A. In Handbook of
Reagents for Organic Synthesis: Reagents for Glycoside, Nucleotide, and
Peptide Synthesis; Crich, D., Ed.; Wiley: Chichester, 2005; pp 459-460.
(45) Crich, D.; Banerjee, A.; Li, W.; Yao, Q. J. Carbohydr. Chem. 2005,
24, 415-424.
J. Org. Chem, Vol. 72, No. 18, 2007 6807

Crich et al.
SCHEME 2. Synthesis of Trisaccharide Donor 20 and Acceptor 22
Activation of donor 14 with the BSP/triflic anhydride/TTBP
combination followed by addition of acceptor 15 at -78 °C
and then, before warming to room temperature, triethyl phos-
phite to quench any extraneous thiophiles and prevent premature
activation of the new thioglycoside41,47 afforded disaccharide
18 in 91% yield and 25:1 â/R selectivity (Scheme 2). Treatment
with DDQ then provided the alcohol 19 (Scheme 2). In the same
manner, coupling of donor 14 to acceptor 19 provided trisac-
charide 20 in 82% yield as a single â-anomer (Scheme 2). Under
the same conditions coupling of donor 18 with acceptor 17 gave
the trisaccharide 21 in 84% yield with 7:1 â:R ratio (Scheme
2), from which removal of the naphthylmethyl group afforded
acceptor 22 (Scheme 2). In contrast, activation of donor 18
followed by reaction with acceptor 15 gave trisaccharide 20 in
88% yield but with the unexpected â:R ratio of 1:20 (Scheme
2). The complete reversal of selectivity in going from acceptor
15 to acceptor 17 in coupling to donor 18 is remarkable and
draws attention to the still poorly understood influence of
acceptor structure on the outcome of glycosylation reactions.48-50
Unfortunately, despite repeated attempts, we were unable to
realize the coupling of trisaccharide 20 with trisaccharide
acceptor 22 and, thus, were forced to reconsider our approach.
Synthesis of the â-(1f3)-Mannohexaose. In redesigning our
approach to the target mannan we elected to incorporate the
use of the naphthylpropargyl ethers, developed in the interim,51
as sterically minimal protecting groups cleavable in a single
step with DDQ. On the basis of the developmental work, it was
known that these ethers afford excellent selectivity when used
as O-3 protecting groups for donors in conjunction with 2-O-
benzyl ethers. Additionally, because the more electron-rich
naphthylpropargyl system is susceptible to electrophilic attack
by the activated Ph2SO/triflic anhydride combination,51 the use
of glycosyl sulfoxides52-55 as donors was recommended.51 Thus,
the previously described sulfoxide 2351 was activated with triflic
anhydride in the presence of TTBP and 1-octene at -78 °C in
dichloromethane before addition of methanol, resulting in the
formation of the â-mannoside 24 as a single anomer (Scheme
3). In this and subsequent coupling reactions 1-octene serves
as a sacrificial alkene for the trapping of electrophilic species
that otherwise diminish the overall yields by reaction with one
or other of the naphthylpropargyl ethers or the thioglycoside
(50) Fraser-Reid, B.; Lo´pez, J. C.; Go´mez, A. M.; Uriel, C. Eur. J. Org.
Chem. 2004, 1387-1395.
(51) Crich, D.; Wu, B. Org. Lett. 2006, 8, 4879-4882.
(52) For a previous use of sacrificial alkenes in sulfoxide glycosylations,
see: Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc.
1989, 111, 6881-6882.
(46) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
(47) Sliedregt, L. A. J. M.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 1994, 35, 4015-4018.
(48) Paulsen, H. In SelectiVity a Goal for Synthetic Efficiency; Bartmann,
W., Trost, B. M., Eds.; Verlag Chemie: Weinheim, 1984; pp 169-190.
(49) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. 1991,
30, 180-183.
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Kahne, D. E. J. Am. Chem. Soc. 2007, 129, 3080-3081.
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Chem. Soc. 2006, 128, 15084-15085.
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6808 J. Org. Chem., Vol. 72, No. 18, 2007

ConVergent Synthesis of a â-(1f3)-Mannohexaose
SCHEME 3. Synthesis of Trisaccharide Acceptor 29
SCHEME 4. Convergent Synthesis of Trisaccharide Donor
34 and Acceptor 29
containing acceptors.56 Removal of the naphthylpropargyl group
from 24 with DDQ gave 25 (Scheme 3) which, on coupling to
23 gave disaccharide 26 as a single anomer (Scheme 3). A
sequence of treatment with DDQ, coupling to 23, and fur-
ther treatment with DDQ gave the trisaccharide mono-ol 29
(Scheme 3).
Structure of the â-(1f3)-Mannohexaose. Inspection of the
13C NMR spectrum of 37 at 125 MHz revealed the presence of
only three anomeric carbon signals at δ 100.8 (1JCH ) 157.9),
δ 96.6 (1JCH ) 158.6), and δ 96.4 (1JCH ) 159.4) indicative of
a highly regular open polymer. In this, 37 resembles the
â-(1f4)-mannohexaose synthesized previously,12 but is distinct
from the â-(1f2)-mannooctaose in which all eight anomeric
carbons were discernible owing to its disordered, collapsed
helical structure.12,59 The 13C NMR of spectrum of 38 exhibited
The second trisaccharide required for the convergent synthesis
was assembled by activation of donor 23 in the presence of
1-octene, and introduction of the known acceptor 30,14 when
disaccharide 31 was obtained as a single anomer in 76% yield
(Scheme 4). Removal of the naphthylpropargyl group from 31
gave 32, and coupling to a second aliquot of 23 then afforded
the trisaccharide 33 as a â only isomer in 78% yield (Scheme
4). Oxidation of 33 with mCPBA gave sulfoxide 34 as a single
diastereomer at sulfur, which is assigned the (R)-configuration
on the basis of previous crystallographic work.57,58 Coupling
of 34 with methanol and subsequent removal of the naphthyl-
propargyl protecting group provided a second more convenient
entry into the acceptor trisaccharide 29 (Scheme 4). The ability
to prepare the trisaccharide acceptor 29 from the donor 34 in
this manner considerably enhances the efficiency of the overall
protocol.
Finally, activation of 34 (1.2 equiv) with triflic anhydride in
the presence of 1-octene and TTBP at -78 °C in dichlo-
romethane, followed by the addition of 29 (1.0 equiv) smoothly
afforded the hexasaccharide 35 as an approximately 1:1 mixture
of anomers in 61% yield, Although the two anomers of 35 could
be separated with difficulty by reversed-phase HPLC, it was
found to be more convenient to process the mixture with DDQ,
giving the mono-ols 36, which were much more amenable to
separation. Hydrogenolysis of each anomer over Pearlman’s
catalysis gave the mannans 37 and 38, respectively (Scheme
5). In this manner the synthesis of the â-(1f3)-mannohexaose
37 was completed in 8% overall yield in a highly convergent
manner from two monosaccharide building blocks 23 and 30,
with only four glycosidic bond forming steps required, which,
with the exception of the joining of 29 and 34 were all
completely â-selective.
two well resolved anomeric carbon signals at δ 102.1 (1JCH
)
165.0) and 100.8 (1JCH ) 155.0), indicative of R and â
configured anomeric positions respectively; the remaining four
anomeric signals resonated between δ 96.5 and 96.9 but were
insufficiently resolved to permit determination of the one bond
C-H coupling constants.
Influence of the 3-O-Naphthylpropargyl Protecting on
â-Mannosylation. In addition to the preliminary results de-
scribed previously,51 the coupling reactions summarized in
Schemes 3 and 4 highlight the excellent â-selectivities obtained
with the mannosyl donor 23, which are comparable to those
provided by corresponding 3-O-benzyl and naphthylmethyl
ethers.55 More noteworthy, however, is the contrast between
the highly â-selective 23 and the somewhat unselective 3-O-
propargyl system 39,37 which again highlights the sensitivity
of these coupling reactions to substitution at the 3-position.
By means of the standard low-temperature NMR methods,60
we determined the steric A value of the 1-naphthylpropargyloxy
group in the cyclohexyl ether 40 to be 1.21, which is somewhat
larger than of the simple propargyloxy group (1.10),37 compa-
rable to the allyloxy group (1.25),37 a little smaller than the
benzyloxy group (1.39),37 and substantially smaller than the tert-
butyldimethylsilylether group (1.50).37 Taking into account the
lack of selectivity seen with each of the 3-deoxy system 41,32
the 3-deoxy-3-fluoro system 4233 (A value for fluoride )
0.27),60-65 and the 3-azido-3-deoxy system 4366 (A value for
azide ) 0.75),61,67 but the excellent selectivity for the 3-ben-
zylideneimino-3-deoxy system 44,66 we are led to the conclusion
that there is a relatively narrow window for the steric bulk of
the group at the 3-position, centered around the benzyloxy group,
in which excellent â-selectivity is observed. As we have
previously discussed,32,33 groups that are significantly smaller
than the benzyloxy ether function result in a loss of selectivity
due to minimization of the developing torsional interaction
(56) Gildersleeve, J.; Smith, A.; Sakurai, D.; Raghavan, S.; Kahne, D.
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J. Org. Chem, Vol. 72, No. 18, 2007 6809

Crich et al.
SCHEME 5. Synthesis of the Mannans 37 and 38 and Completion of the Synthesis
between the O2 and O3 groups as the covalent triflate10 flattens
to the oxacarbenium ion,68 thereby facilitating oxacarbenium
ion formation and ultimately leading to a loss of selectivity.
Larger groups than the benzyloxy ether result in the buttressing
interaction discussed above, which also results in a loss of
selectivity.
Experimental Section
Phenyl 4,6-O-Benzylidene-3-O-(2-naphthylmethyl)-1-thio-R-
D-mannopyranoside (13). A stirred solution of phenyl 4,6-O-
benzylidene-1-thio-R-D-mannopyranoside69 (5.25 g, 14.6 mmol) in
toluene (500 mL) was treated with Bu2SnO (5.43 g, 21.8 mmol).
The reaction mixture was refluxed for 4 h followed by removal of
the solvent, affording a residue which was dissolved in DMF (50
mL). CsF (4.43 g, 29.1 mmol) and 2-bromomethylnaphthalene (4.83
g, 21.8) were then successively added into the reaction mixture,
which then was stirred at 95 °C for 6 h. DMF was then removed
by rotary evaporation under reduced pressure. The residue was
redissolved in CH2Cl2 (200 mL), washed with saturated aq
Na2CO3 and brine, dried over anhydrous Na2SO4, and concentrated.
The crude product was purified by flash chromatography on silica
gel (hexane:ethyl acetate; 4:1) to give 13 (6.76 g, 94%): [R]22
+176.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.80 (br. s,
1H), 3.89 (t, J ) 10.0 Hz, 1H), 4.04 (dd, J ) 3.5, 9.5 Hz, 1H),
4.23-4.27 (m, 2H), 4.33 (dd, J ) 1.0, 3.5 Hz, 1H), 4.37 (dt, J )
4.5, 9.5 Hz, 1H), 4.93 (d, J ) 12.0 Hz, 1H), 5.04 (d, J ) 12.5 Hz,
1H), 5.62 (d, J ) 1.5 Hz, 1H), 5.66 (s, 1H), 7.26-7.37 (m, 13H),
7.76-7.86 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 64.7, 68.6,
71.4, 73.2, 75.8, 79.0, 87.8, 101.8, 125.7, 126.1, 126.2, 126.3, 126.4,
127.7, 128.0, 128.3, 128.4, 128.5, 129.1, 129.2, 129.3, 131.7, 133.1,
133.3, 135.2, 137.5; ESIHRMS calcd for C30H28O5SNa [M + Na]+
523.1555, found 523.1545.
Conclusion
Trisaccharide donor 34 was successfully coupled to trisac-
charide acceptor 29 to give hexasaccharide 35 in 61% yield as
a 1:1 â:R mixture of anomers, whereas the closely related pair
of 20 and 22 failed to give any appreciable amount of
hexasaccharide under comparable conditions. As previously
reported,14 trisaccharide donor 6 was coupled to trisaccharide
acceptor 7 to give hexasaccharide 8 in 88% yield but only 0.67:1
â:R ratio. These three reactions, which all involved the attempted
coupling of closely related 3-O-glycosyl-4,6-O-benzylidene
protected mannopyranosyl donors to the non-reducing 3-OH of
mannotrioses, serve to highlight the continuing difficulty in
predicting the outcome of block approaches to oligosaccharide
synthesis. As the molecular weight of the donors and acceptors
increase with chain length (e.g., the MW of 29 and 34 are
1053.15 and 1310.47 Da, respectively), and the concentration
of the reaction mixture inevitably decreases, subtle steric and
matching/mismatching effects play increasingly important roles
and influence the outcome considerably.
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6810 J. Org. Chem., Vol. 72, No. 18, 2007

ConVergent Synthesis of a â-(1f3)-Mannohexaose
Phenyl 4,6-O-Benzylidene-3-O-(2-naphthylmethyl)-2-O-(prop-
2-ynyl)-1-thio-R-D-mannopyranoside (14). To a stirred solution
of compound 13 (4.66 g, 9.3 mmol) in dry DMF (25 mL) at 0 °C
was added NaH (60% in oil, 0.93 g, 18.6 mmol). The reaction
mixture was stirred for 15 min before propargyl bromide (1.97 mL,
18.6 mmol) was added dropwise to the mixture, and the stirring
was continued for 3 h. The reaction mixture was then quenched by
addition of methanol, diluted with CH2Cl2 (75 mL), and washed
with satd NaHCO3. The organic layer was separated, dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography on silica gel (hexane/ethyl
NaHCO3 was added, and the mixture was extracted with CH2Cl2.
The extract was washed several times with satd NaHCO3, dried
over Na2SO4, and concentrated on a rotary evaporator. The crude
product was purified by chromatography on silica gel (hexane/ethyl
acetate; 7:3) to give 17 (51 mg, 89%) as a white solid: mp 126
°C; [R]27D -119.9 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ
2.5 (t, J ) 2.4 Hz, 1H), 3.31-3.36 (m, 1H), 3.5 (s, 3H), 3.76-
3.83 (m, 2H), 3.87 (t, J ) 10.3 Hz, 1H), 4.0 (dd, J ) 0.5, 3.2 Hz,
1H), 4.3 (dd, J ) 4.9, 10.5 Hz, 1H), 4.46 (dd, J ) 2.4, 16.1 Hz,
1H), 4.48 (s, 1H), 4.6 (dd, J ) 2.4, 16.1 Hz, 1H), 5.5 (s, 1H),
7.26-7.38 (m, 3H), 7.48-7.5 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 57.5, 60.6, 67.0, 68.4, 70.3, 75.5, 77.2, 79.1, 79.7, 102.0,
103.0, 126.3, 128.2, 129.1, 137.2; ESIHRMS calcd for C17H21O6
[M + H]+ 321.1338, found 321.1347.
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-3-O-(2-naph-
thylmethyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
(prop-2-ynyl)-1-thio-R-D-mannopyranoside (18). To a stirred
solution of donor 14 (270 mg, 0.50 mmol), BSP (126 mg, 0.6
mmol), TTBP (187 mg, 0.8 mmol), and 4 Å molecular sieves in
CH2Cl2 (5 mL), at -60 °C under an Ar atmosphere, was added
Tf2O (110 µL, 0.65 mmol). After 30 min, the temperature was
brought down to -78 °C, and then acceptor 15 (240 mg, 0.60
mmol) in CH2Cl2 (3 mL) was slowly added. The reaction mixture
was stirred for 2 h at -78 °C and then quenched by the addition of
triethyl phosphite (255 µL, 1.5 mmol) and stirred for 1 h at -78
°C before it was allowed to reach room temperature. The reaction
mixture was diluted with CH2Cl2 (10 mL), and the molecular sieves
were filtered off and washed with saturated NaHCO3. The organic
layer was separated, dried, and concentrated. The crude product
was purified by column chromatography on neutral alumina
(hexane/ethyl acetate; 7:3) to give 18 (380 mg, R:â; 1:25, 91%).
For â-anomer: [R]27D +51.1 (c 2.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 2.28 (t, J ) 2.4 Hz, 1H), 2.56 (t, J ) 2.3 Hz, 1H), 3.24-
3.29 (m, 1H), 3.67 (dd, J ) 3.1, 9.8 Hz, 1H), 3.85-3.90 (m, 2H),
4.16-4.21 (m, 3H), 4.23 (t, J ) 4.8, 10.2 Hz, 1H), 4.27-4.31 (m,
3H), 4.34 (dd, J ) 1.5, 3.0 Hz, 1H), 4.37 (dd, J ) 2.4, 16.3 Hz,
1H), 4.47 (dd, J ) 2.4, 16.3 Hz, 1H), 4.65 (dd, J ) 2.4, 16.0 Hz,
1H), 4.69 (dd, J ) 2.4, 16.0 Hz, 1H), 4.80 (s, 1H), 4.95 (d, J )
12.8 Hz, 1H), 4.98 (d, J ) 13.7 Hz, 1H), 5.57 (s, 2H), 5.63 (s,
1H), 7.26-7.53 (m, 18H), 7.80-7.86 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 58.3, 59.8, 65.2, 67.7, 68.4, 68.6, 72.5, 75.0, 75.2, 75.5,
77.9, 78.4, 79.3, 80.5, 86.6, 100.0, 101.3, 101.7, 125.7, 125.9, 126.1,
126.2, 126.4, 127.7, 127.8, 127.9, 128.1, 128.2, 128.3, 128.9, 129.1,
129.3, 131.7, 132.9, 133.5, 137.3, 137.6; ESIHRMS calcd for
C49H46O10SNa [M + Na]+ 849.2710, found 849.2729
acetate; 5:1) to give 14 (5.01 g, 91%): [R]24 +124.8 (c 2.0,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 2.45 (t, J ) 2.3 Hz, 1H),
3.89 (t, J ) 10.0 Hz, 1H), 4.07 (dd, J ) 3.1, 9.5 Hz, 1H), 4.22-
4.32 (m, 3H), 4.35 (dd, J ) 1.4, 3.2 Hz, 1H), 4.4 (dd, J ) 2.3,
16.1 Hz, 1H), 4.49 (dd, J ) 2.3, 16.1 Hz, 1H), 4.93 (dd, J ) 12.4
Hz, 1H), 5.03 (d, J ) 12.4 Hz, 1H), 5.63 (d, J ) 1.4 Hz, 1H), 5.67
(s, 1H), 7.26-7.45 (m, 3H), 7.42-7.58 (m, 10H), 7.84-7.89 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 58.8, 65.4, 68.5, 73.2, 75.4,
76.2, 77.5, 79.1, 79.4, 87.3, 101.6, 125.7, 125.0, 126.1, 126.2, 126.4,
127.7, 128.0, 128.2, 128.9, 129.2, 131.6, 133.0, 133.3, 133.6, 135.6,
137.6; ESIHRMS calcd for C33H30O5SNa [M + Na]+ 561.1712,
found 561.1722.
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-1-thio-R-D-man-
nopyranoside (15). To a stirred solution of compound 14 (1.25 g,
2.3 mmol) in CH2Cl2 (40 mL) and water (2 mL) was added DDQ
(1.05 g, 4.6 mmol) at rt. After the reaction mixture was stirred for
3 h, satd NaHCO3 was added, and the mixture was extracted with
CH2Cl2. The extracts were washed several times with satd NaHCO3
and dried over Na2SO4. Evaporation of the solvent in vacuo gave
an oil, which was chromatographed on silica gel (hexane/ethyl
acetate 4:1) to give 15 (852 mg, 93%) as a white solid: mp 128
1
°C; [R]27 +119 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
D
2.49 (t, J ) 2.4 Hz, 1H), 2.5 (bs, 1H), 3.84 (t, J ) 10.2 Hz, 1H),
3.9 (t, J ) 9.6 Hz, 1H), 4.16 (dd, J ) 3.6, 10.0 Hz, 1H), 4.21-
4.24 (m, 2H), 4.27-4.32 (m, 1H), 4.34 (dd, J ) 2.4, 16.1 Hz, 1H),
4.42 (dd, J ) 2.4, 16.1 Hz, 1H), 5.59 (s, 1H), 5.68 (s, 1H), 7.32-
7.53 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 58.6, 64.7, 68.4,
68.9, 75.7, 78.9, 79.3, 79.4, 86.4, 102.2, 126.3, 127.7, 128.3, 129.2,
131.7, 133.8, 137.2; ESIHRMS calcd for C22H22O5SNa [M + Na]+
421.1086, found 421.1095.
Methyl 4,6-O-Benzylidene-3-O-(2-naphthylmethyl)-2-O-(prop-
2-ynyl)-â-D-mannopyranoside (16). To a stirred solution of donor
14 (122 mg, 0.23 mmol), BSP (57 mg, 0.27 mmol), TTBP (84.6
mg, 0.34 mmol), and 4 Å molecular sieves in CH2Cl2 (6 mL), at
-60 °C under an Ar atmosphere, was added Tf2O (50 µL, 0.29
mmol). After 30 min of stirring at -60 °C, dry methanol (28 µL,
0.68 mmol) was added. The reaction mixture was stirred for further
2 h at -60 °C, and then allowed to warm to room temperature.
The reaction mixture was diluted with CH2Cl2 (10 mL), the
molecular sieves were filtered off and washed with saturated
NaHCO3. The organic layer was separated, dried, and concentrated.
The crude product was purified by chromatography on silica gel
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-â-D-mannopy-
ranosyl-(1f3)-4,6-O-benzylidene-2-O-(prop-2-ynyl)-1-thio-R-D-
mannopyranoside (19). To a stirred solution of 18â (72 mg, 0.09
mmol) in CH2Cl2 (10 mL) and water (0.5 mL) was added DDQ
(49.4 mg, 0.22 mmol) at room temperature. After 3 h, satd NaHCO3
was added, and the mixture was extracted with CH2Cl2. The extracts
were washed several times with satd NaHCO3 and dried over
Na2SO4. Evaporation of the solvent in vacuo gave an oil, which
(hexane/ethyl acetate; 5:1) to give 16 (89 mg, 85%) as a colorless
was chromatographed on silica gel (hexane/ethyl acetate; 3:2) to
1
1
oil: [R]27 -29.8 (c 2.0, CHCl3); H NMR (500 MHz, CDCl3) δ
give 19 (55 mg, 94%): [R]22 +27.8 (c 1.0, CHCl3); H NMR
D
D
2.53 (t, J ) 2.4 Hz, 1H), 3.30-3.35 (m, 1H), 3.52 (s, 3H), 3.67
(dd, J ) 3.1, 9.9 Hz, 1H), 3.93 (t, J ) 10.3 Hz, 1H), 4.17 (t, J )
9.6 Hz, 1H), 4.21 (d, J ) 3.0 Hz, 1H), 4.34 (dd, J ) 4.9, 10.4 Hz,
1H), 4.39 (s, 1H), 4.61 (dd, J ) 2.4, 16.1 Hz, 1H), 4.65 (dd, J )
2.4, 16.1 Hz, 1H), 4.98 (d, J ) 12.9 Hz, 1H), 5.0 (d, J ) 12.9 Hz,
1H), 5.64 (s, 1H), 7.40-7.54 (m, 8H), 7.71-7.87 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 50.5, 60.0, 67.5, 68.6, 72.5, 74.9, 75.0,
78.4, 80.0, 101.5, 102.9, 125.7, 125.9, 126.0, 126.4, 127.7, 127.9,
128.1, 128.2, 128.9, 132.9, 133.2, 135.7, 137.6; ESIHRMS calcd
for C28H28O6Na [M + Na]+ 483.1784, found 483.1805.
(500 MHz, CDCl3) δ 2.5 (t, J ) 2.4 Hz, 1H), 3.31-3.34 (m, 1H),
3.78 (t, J ) 10.0 Hz, 1H), 3.82-3.89 (m, 3H), 4.19-4.26 (m, 2H),
4.31-4.37 (m, 3H), 4.36 (dd, J ) 2.5, 16.5 Hz, 1H), 4.47 (dd, J )
2.5, 16.5 Hz, 1H), 4.55 (dd, J ) 2.0, 16.0 Hz, 1H), 4.58 (dd, J )
2.0, 16.0 Hz, 1H), 4.94 (s, 1H), 5.37 (s, 1H), 5.57 (s, 1H), 5.66 (s,
1H), 7.26-7.41 (m, 9H), 7.44-7.52 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 57.8, 59.9, 65.3, 67.1, 68.5, 70.2, 74.1, 75.6, 75.8, 76.1,
76.5, 77.4, 79.0, 79.5, 79.8, 86.1, 98.9, 101.8, 126.2, 126.3, 127.9,
128.3, 129.1, 129.3, 131.7, 133.5, 137.2, 137.3; ESIHRMS calcd
for C38H38O10SNa [M + Na]+ 709.2084, found 709.2068.
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-3-O-(2-naph-
thylmethyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
(prop-2-ynyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-
O-(prop-2-ynyl)-1-thio-R-D-mannopyranoside (20R). To a stirred
Methyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-â-D-mannopy-
ranoside (17). To stirred solution of 16 (82 mg, 0.18mmol) in
CH2Cl2 (5 mL) and water (0.1 mL) was added DDQ (81 mg, 0.36
mmol) at rt. After the reaction mixture was stirred for 3 h, satd
J. Org. Chem, Vol. 72, No. 18, 2007 6811

Crich et al.
solution of donor 18â (179 mg, 0.22 mmol), BSP (54.4 mg 0.26
mmol), TTBP (80.5 mg, 0.32 mmol), and 4 Å molecular sieves in
CH2Cl2 (3 mL), at -60 °C under an Ar atmosphere, was added
Tf2O (47 µL, 0.28 mmol). After 30 min, the temperature was
brought down to -78 °C, and then acceptor 15 (103 mg, 0.26
mmol) in CH2Cl2 (2 mL) was slowly added. The reaction mixture
was stirred for 2 h at -78 °C, quenched by the addition of triethyl
phosphite (72 µL, 0.43 mmol), and stirred for 1 h at -78 °C before
it was allowed to reach room temperature. The reaction mixture
was diluted with CH2Cl2 (10 mL), and the molecular sieves were
filtered off and washed with saturated NaHCO3. The organic layer
was separated, dried, and concentrated. The crude product was
purified by column chromatography on neutral alumina (hexane/
ethyl acetate; 3:1) to give 20 (210 mg, R:â; 20:1, 88%). For
of donor 18â (124 mg, 0.15 mmol), BSP (37.6 mg 0.18 mmol),
TTBP (55.8 mg, 0.23 mmol), and 4 Å molecular sieves in CH2Cl2
(3 mL), at -60 °C under an Ar atmosphere, was added Tf2O (32.8
µL 0.19 mmol). After 30 min of stirring at -60 °C, acceptor 17
(72 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added slowly. The
reaction mixture was stirred for a further 2 h at -60 °C, and then
allowed to reach room temperature. The reaction mixture was
diluted with CH2Cl2 (10 mL), and the molecular sieves were filtered
off and washed with saturated NaHCO3. The organic layer was
separated, dried, and concentrated. The crude product was purified
by chromatography on silica gel (toluene/ethyl actate/CH2Cl2; 7:2:
1) to give 21 (130 mg, R:â; 1:7, 84%). For â-anomer: [R]22D -82.2
(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.94 (t, J ) 2.3 Hz,
1H), 2.48-2.52 (m, 2H), 3.29-3.40 (m, 3H), 3.55 (s, 3H), 3.61
(dd, J ) 3.0, 10.0 Hz, 1H), 3.84-3.93 (m, 3H), 3.97 (t, J ) 10.0
Hz, 1H), 4.0-4.05 (m, 2H), 4.08 (dd, J ) 3.0, 10.0 Hz, 1H), 4.17
(t, J ) 10.0 Hz, 1H), 4.21 (d, J ) 3.0 Hz, 1H), 4.23-4.28 (m,
3H), 4.35 (dd, J ) 4.5, 10.0 Hz, 1H), 4.47 (dd, J ) 2.5, 16.0 Hz,
1H), 4.49 (s, 1H), 4.55 (dd, J ) 2.5, 17.0 Hz, 1H), 4.61 (dd, J )
2.5, 16.5 Hz, 1H), 4.65 (dd, J ) 2.5, 16.0 Hz, 1H), 4.93 (s, 1H),
4.97 (s, 2H), 5.03 (s, 1H), 5.48 (s, 1H), 5.54 (s, 1H), 5.59 (s, 1H),
7.26-7.46 (m, 18H), 7.62-7.71 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 57.6, 59.4, 59.5, 60.0, 67.5, 67.8, 68.5, 72.0, 72.1, 72.8,
73.7, 73.8, 74.7, 74.8, 75.2, 75.3, 76.2, 76.4, 76.6, 78.2, 80.4, 80.6,
97.6, 97.8, 101.4, 101.5, 103.4, 125.8, 125.9, 125.99, 126.0, 126.1,
126.5, 127.6, 127.8, 128.1, 128.2, 128.3, 128.9, 129.9, 132.9, 133.1,
135.6, 137.2, 137.5; ESIHRMS calcd for C60H60O16Na [M + Na]+
1059.3779, found 1059.3792.
R-anomer: [R]20 +37.6 (c 1.0, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 1.62 (t, J ) 2.0 Hz, 1H), 2.53 (t, J ) 2.5 Hz, 1H), 2.57
(t, J ) 2.0 Hz, 1H), 3.21-3.26 (m, 1H), 3.64 (dd, J ) 3.5, 10.0
Hz, 1H), 3.81-3.89 (m, 3H), 4.0-4.07 (m, 1H), 4.09-4.31 (m,
15H), 4.41 (dd, J ) 2.5, 16.0 Hz, 1H), 4.63 (dd, J ) 2.5, 16.0 Hz,
1H), 4.68 (dd, J ) 2.5, 16.5 Hz, 1H), 4.73 (s, 1H), 4.94 (d, J )
12.5 Hz, 1H), 4.98 (d, J ) 13.0 Hz, 1H), 5.31 (s, 1H), 5.50 (s,
2H), 5.65 (s, 1H), 7.26-7.53 (m, 23H), 7.80-7.89 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 57.9, 58.6, 59.8, 64.2, 64.5, 65.2, 67.7,
68.5, 68.7, 72.2, 72.4, 74.9, 75.1, 75.2, 75.3, 76.6, 77.2, 77.8, 78.4,
79.0, 79.1, 79.2, 80.5, 86.4, 99.6, 100.5, 101.5, 101.6, 102.0, 125.7,
125.9, 126.2, 126.3, 126.5, 127.7, 127.9, 128.2, 128.3, 128.4, 128.9,
129.0, 129.3, 129.4, 131.7, 133.0, 133.2, 133.4, 134.5, 134.6, 135.7,
137.3, 137.5, 137.6; ESIHRMS calcd for C65H62O15SNa [M + Na]+
1137.3702, found 1137.3699.
Methyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-â-D-mannopy-
ranosyl-(1f3)-4,6-O-benzylidene-2-O-(prop-2-ynyl)-â-D-man-
nopyranosyl-(1f3)-4,6-O-benzylidene-2-O-(prop-2-ynyl)-â-D-
mannopyranoside (22). To a stirred solution of 21â (72 mg, 0.069
mmol) in CH2Cl2 (10 mL) and water (0.5 mL) was added DDQ
(40 mg, 0.18 mmol) at room temperature. After 3 h, satd NaHCO3
was added, and the mixture was extracted with CH2Cl2. The extracts
were washed several times with satd NaHCO3 and dried over
Na2SO4. Evaporation of the solvent in vacuo gave an oil, which
was purified by column chromatographed on neutral alumina
(hexane/ethyl acetate; 2:1) to give 22 (51 mg, 81%): [R]20D -116.1
(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.05 (t, J ) 2.0 Hz,
1H), 2.48-2.50 (m, 2H), 2.59 (br. s, 1H), 3.35-3.45 (m, 3H), 3.56
(s, 3H), 3.76-3.86 (m, 3H), 3.91 (t, J ) 10.0 Hz, 1H), 4.0 (t, J )
10.0 Hz, 1H), 4.0-4.05 (m, 2H), 4.09-4.13 (m, 2H), 4.25-4.30
(m, 4H), 4.36 (dd, J ) 4.5, 10.5 Hz, 1H), 4.50 (s, 1H), 4.53 (dd,
J ) 2.5, 16.0 Hz, 1H), 4.55 (dd, J ) 2.5, 16.0 Hz, 1H), 4.57 (dd,
J ) 2.5, 16.0 Hz, 1H), 4.63 (dd, J ) 2.5, 16.0 Hz, 1H), 4.69 (dd,
J ) 2.5, 16.0 Hz, 1H), 4.70 (dd, J ) 2.5, 16.0 Hz, 1H), 5.07 (s,
2H), 5.47 (s, 1H), 5.49 (s, 1H), 5.57 (s, 1H), 7.26-7.48 (m, 15H);
13C NMR (125 MHz, CDCl3) δ 57.7, 59.4, 59.5, 60.5, 67.2, 67.7,
68.4, 68.5, 70.2, 72.1, 72.8, 73.8, 73.9, 75.1, 75.2, 76.6, 77.2, 79.3,
80.0, 80.4, 80.6, 97.6, 97.8, 101.4, 101.6, 101.9, 103.4, 126.0, 126.2,
128.1, 128.18, 128.2, 128.3, 128.9, 129.0, 129.1, 137.1, 137.2;
ESIHRMS calcd for C49H52O16Na [M + Na]+ 919.3148, found
919.3143.
Standard Procedure for Coupling Reactions of the Sulfoxide
Donor 23 with the Corresponding Sugar Acceptors Using TTBP
and Tf2O. To a stirred solution of sulfoxide donor 23 (0.05 M in
mixed solvent, 1.2 equiv), TTBP (1.6 equiv), and 4 Å molecular
sieves in a mixed solvent of CH2Cl2 and 1-octene (v/v, 4/1), at
-78 °C under argon atmosphere, was added Tf2O (1.2 equiv). After
the reaction mixture was stirred at -78 °C for 30 min, a solution
of sugar acceptors (0.1 M, 1.0 equiv) in CH2Cl2 was added. Stirring
was maintained for another 30 min at -78 °C before the reaction
temperature was allowed to warm to -20 °C slowly. The reaction
mixture was poured into aq NaHCO3 solution, diluted with CH2-
Cl2, and filtered through Celite. The organic layer was separated
from the filtrate, washed with brine, dried over anhydrous
Na2SO4, and concentrated. The residue was purified by chroma-
tography on silica gel to give the coupled products.
Phenyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-3-O-(2-naph-
thylmethyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
(prop-2-ynyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-
O-(prop-2-ynyl)-1-thio-R-D-mannopyranoside (20â). To a stirred
solution of donor 14 (400 mg, 0.074 mmol), BSP (18.6 mg 0.09
mmol), TTBP (27.6 mg, 0.11 mmol), and 4 Å molecular sieves in
CH2Cl2 (2.5 mL), at -60 °C under an Ar atmosphere, was added
Tf2O (16 µL, 0.65 mmol). After 30 min, the temperature was
brought down to -78 °C, and then acceptor 19 (55 mg 0.081 mmol)
in CH2Cl2 (2 mL) was slowly added. The reaction mixture was
stirred for 2 h at -78 °C and then quenched by the addition of
triethyl phosphite (24 µL, 0.15 mmol) and stirred for 1 h at -78
°C before it was allowed to reach room temperature. The reaction
mixture was diluted with CH2Cl2 (10 mL) and molecular sieves
were filtered off and washed with saturated NaHCO3. The organic
layer was separated, dried, and concentrated. The crude product
was purified by column chromatography on neutral alumina
(hexane/ethyl acetate; 7:3) to give 20â (69 mg, 82%): [R]27D -10.7
(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.08 (t, J ) 2.5 Hz,
1H), 2.47 (t, J ) 2.5 Hz, 1H), 2.51 (t, J ) 2.5 Hz, 1H), 3.25-3.34
(m, 2H), 3.62 (dd, J ) 3.0, 10.0 Hz, 1H), 3.84 (t, J ) 11.0 Hz,
1H), 3.86 (t, J ) 10.0 Hz, 1H), 3.90 (t, J ) 10.0 Hz, 1H), 4.03-
4.04 (m, 2H), 4.14 (t, J ) 10.0 Hz, 1H), 4.17 (t, J ) 10.0 Hz, 1H),
4.21-4.25 (m, 5H), 4.30-4.35 (m, 2H), 4.36-4.37 (m, 2H), 4.46
(dd, J ) 2.5, 16.5 Hz, 1H), 4.51 (dd, J ) 2.5, 16.0 Hz, 1H), 4.62
(dd, J ) 3.0, 15.0 Hz, 1H), 4.65 (dd, J ) 2.5, 16.5 Hz, 1H), 4.87
(s, 1H), 4.91 (s, 1H), 4.95 (d, J ) 13.5 Hz, 1H), 4.99 (d, J ) 14.0
Hz, 1H), 5.43 (br. s, 1H), 5.58 (s, 1H), 5.59 (s, 1H), 5.64 (d,
J ) 1.5 Hz, 1H), 7.26-7.54 (m, 23H), 7.76-7.87 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 57.1, 59.5, 60.0, 65.3, 67.8, 68.5,
68.6, 72.2, 73.2, 73.9, 74.8, 74.9, 75.2, 75.3, 75.8, 75.9, 76.5, 76.9,
77.6, 78.3, 79.3, 80.3, 80.7, 86.2, 98.6, 99.1, 101.5, 101.8, 125.8,
125.9, 126.1, 126.2, 126.5, 127.7, 127.9, 128.2, 128.2, 128.3, 128.9,
129.2, 129.3, 131.7, 132.9, 133.2, 133.4, 135.7, 137.3, 137.6;
ESIHRMS calcd for C65H62O15SNa [M + Na]+ 1137.3702, found
1137.3698.
Methyl 4,6-O-Benzylidene-2-O-(prop-2-ynyl)-3-O-(2-naph-
thylmethyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
(prop-2-ynyl)-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-
O-(prop-2-ynyl)-â-D-mannopyranoside (21). To a stirred solution
6812 J. Org. Chem., Vol. 72, No. 18, 2007

ConVergent Synthesis of a â-(1f3)-Mannohexaose
Methyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)prop-2-ynyl]-â-D mannopyranoside (24). To a stirred solution
of sulfoxide 23 (0.15 g, 0.23 mmol), TTBP (0.094 g, 0.38 mmol),
and 4 Å molecular sieves in a mixed solvent of CH2Cl2 and 1-octene
(5 mL, v/v, 4:1), at -78 °C under argon atmosphere, was added
Tf2O (48 µL, 0.28 mmol). After the reaction mixture was stirred at
-78 °C for 30 min, 1 mL of anhydrous methanol was added. The
reaction mixture was stirred at -78 °C for another 30 min before
being poured into aq NaHCO3 solution and then diluted with
CH2Cl2 and filtered through Celite. The organic layer was washed
with brine, dried over Na2SO4, and concentrated. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate; 4:1)
to give the â-coupled product 24 (0.087 g, 68%): [R]20D -33.8 (c
Removal of the naphthylpropargyl protecting group from 26 (0.135
g, 0.15 mmol) by the standard protocol gave deprotected compound
27 (0.091 g, 1.28 mmol) in 77% yield: [R]21 -113.4 (c 1.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.41-7.46 (m, 6H), 7.21-
7.7.38 (m, 10H), 7.17-7.20 (m, 4H), 5.05 (d, J ) 11.0 Hz, 1H),
5.00 (d, J ) 12.5 Hz, 1H), 4.53 (d, 11.0 Hz, 1H), 4.52 (s, 1H),
4.38 (dd, J ) 4.5, 10.5 Hz, 1H), 4.18 (dd, J ) 5.0, 10.5 Hz, 1H),
4.07-4.15 (m, 3H), 4.02 (d, J ) 2.5 Hz, 1H), 3.96 (t, J ) 10.5
Hz, 1H), 3.71-3.76 (m, 2H), 3.62 (s, 3H), 3.57 (d, J ) 4.0 Hz,
1H), 3.41-3.48 (m, 2H), 2.98 (dt, J ) 4.5, 9.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 138.2, 137.4, 137.2, 129.1, 129.0, 128.5,
128.4, 128.2, 127.8, 126.2, 103.8, 101.84, 101.80, 97.0, 79.5, 77.6,
75.1, 74.4, 73.3, 72.6, 70.2, 68.7, 68.5, 67.8, 67.0; ESIHRMS calcd
for C41H44O11Na [M + Na]+ 735.2782, found 735.2761.
1
1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 8.30 (d, J ) 8.0 Hz,
1H), 7.85 (t, J ) 8.0 Hz, 2H), 7.64 (d, J ) 7.0 Hz, 1H), 7.48-7.54
(m, 6H), 7.41-7.44 (dd, J ) 7.0, 8.0 Hz, 1H), 7.33-7.36 (m, 5H),
7.28-7.29 (m, 1H), 5.65 (s, 1H), 5.03(d, J ) 12.0 Hz 1H), 4.91
(d, J ) 12.0 Hz, 1H), 4.60-4.68 (m, 2H), 4.48 (s, 1H), 4.36 (dd,
J ) 4.5, 10.5 Hz, 1H), 4.24 (t, J ) 9.5 Hz, 1H), 4.09 (d, J )
3.0 Hz, 1H), 3.95-4.00 (m, 2H), 3.56 (s, 3H), 3.44 (dt, J ) 5.0,
10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.5, 137.5, 133.4,
133.1, 130.7, 129.0, 128.9, 128.4, 128.32, 128.25, 128.2, 127.5,
126.9, 126.5, 126.2, 126.1, 125.2, 120.2, 103.3, 101.6, 90.2, 84.5,
78.6, 76.3, 75.1, 68.7, 67.6, 59.0, 57.5; ESIHRMS calcd for
C34H32O6Na [M + Na]+ 559.2097, found 559.2094.
Standard Procedure for Removal of the 1-Naphthylpropargyl
Protecting Group with DDQ. To a stirred solution of the
1-naphthylpropargyl-protected saccharide (0.06 M) in CH2Cl2 and
water (CH2Cl2/water, v/v, 20:1) was added DDQ (1.5 equiv). The
resulting mixture was stirred at rt for 2-3 h. When the reaction
was over as monitored by TLC, the reaction mixture was quenched
by adding aq NaHCO3 solution and then diluted with CH2Cl2. The
organic layer was separated, and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layer was washed with
brine, dried and concentrated. The residue was purified by chro-
matography on silica gel to give the deprotected product.
Methyl 4,6-O-Benzylidene-2-O-benzyl-â-D-mannopyranoside
(25). Removal of the naphthylpropargyl protecting group from 24
(0.42 g, 0.78 mmol) by the standard protocol gave compound 25
(0.21 g, 0.56 mmol) in 74% yield: [R]20D -122.3 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.48-7.50 (m, 2H), 7.30-7.42 (m,
8H), 5.55 (s, 1H), 5.08 (d, J ) 12.0 Hz, 1H), 4.65 (d, J ) 12.0 Hz,
1H), 4.49 (s, 1H), 4.34 (dd, J ) 5.0, 10.5 Hz, 1H), 3.76-3.93 (m,
4H), 3.59 (s, 3H), 3.35 (dt, J ) 5.0, 9.5 Hz, 1H), 2.31 (br. s, 1H);
13C NMR (125 MHz, CDCl3) δ 138.3, 137.3, 129.1, 128.6, 128.3,
128.24, 128.15, 128.0, 126.3, 103.5, 102.0, 79.4, 78.4, 75.7, 70.8,
68.6, 67.1, 57.6; ESIHRMS calcd for C21H24O6Na [M + Na]+
395.1471, found 395. 1486.
Methyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)prop-2-ynyl]-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-
2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
benzyl-â-D-mannopyranoside (28). Method 1. Coupling of sulfoxide
23 (0.095 g, 0.15 mmol) with donor 27 (0.09 g, 0.13 mmol) by the
standard coupling protocol gave trisaccharide 28 (0.12 g, 0.10
mmol) in 78% yield. Method 2. Coupling of sulfoxide donor 34
(0.07 g, 0.05 mmol) with methanol (1 mL, excess) by standard
coupling protocol gave trisaccharide 28 (0.061 g, 0.05 mmol) in
1
94% yield: [R]24 -100.8 (c 1.0, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 8.35 (d, J ) 8.0 Hz, 1H), 7.84 (t, J ) 8.0 Hz, 2H),
7.64 (d, J ) 7.0 Hz, 1H), 7.28-7.53 (m, 25H), 7.17-7.20 (m,
5H), 7.11-7.12 (m, 3H), 5.60 (s, 1H), 5.57 (s, 1H), 5.51 (s, 1H),
5.04 (d, J ) 12.5 Hz, 1H), 5.01 (d, J ) 12.0 Hz, 1H), 4.92 (d,
12.0 Hz, 1H), 4.80 (d, J ) 13.0 Hz, 1H), 4.77 (d, J ) 12.0 Hz,
1H), 4.60-4.70 (m, 3H), 4.52-4.54 (m, 1H), 4.38 (dd, J )
4.5, 10.0 Hz, 1H), 3.72-4.25 (m, 17H), 3.62 (s, 3H), 3.44 (dt, J )
4.5, 9.5 Hz, 1H), 3.12 (dt, J ) 4.5, 9.5 Hz, 1H), 3.02 (dt, J ) 4.5,
9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8, 138.3, 138.2,
137.5, 137.43, 137.38, 133.4, 133.2, 130.7, 129.0, 128.9, 128.6,
128.44, 128.39, 128.2, 128.11, 128.08, 127.8, 127.3, 126.9, 126.5,
126.23, 126.18, 126.15, 125.2, 120.3, 103.8, 101.72, 101.67, 101.5,
97.7, 97.3, 90.4, 84.4, 78.4, 76.97, 76.93, 76.2, 74.9, 74.2, 74.1,
73.8, 73.3, 73.0, 72.7, 68.7, 68.6, 67.8, 58.7, 57.7; ESIHRMS calcd
for C74H72O16Na [M + Na]+ 1239.4713, found 1239.4680.
Methyl 4,6-O-Benzylidene-2-O-benzyl-â-D-mannopyranosyl-
(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-mannopyranosyl-(lf3)-
4,6-O-benzylidene-2-O-benzyl-â-D-mannopyranoside (29). Re-
moval of protecting group from compound 28 (0.094 g, 0.08 mmol)
by the standard deprotection protocol gave trisaccharide 29 (0.065
1
g, 0.06 mmol) in 77% yield: [R]29 -120.8 (c 1.0, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.43-7.47 (m, 9H), 7.19-7.36 (m,
21H), 5.60 (s, 1H), 5.47 (s, 1H), 5.37 (s, 1H), 5.03-5.07 (m, 2H),
4.97 (d, J ) 12.0 Hz, 1H), 4.81 (d, J ) 12.5 Hz, 1H), 4.72 (d, J )
11.0 Hz, 1H), 4.55 (d, J ) 12.5 Hz, 1H), 4.54 (s, 1H), 4.38 (dd, J
) 5.0, 10.5 Hz, 1H), 4.30 (s, 1H), 4.10-4.23 (m, 5H), 4.00-4.04
(m, 2H), 3.96 (t, J ) 10.0 Hz, 1H), 3.75-3.86 (m, 5H), 3.70 (d, J
) 4.0 Hz, 1H), 3.63 (s, 3H), 3.60-3.63 (m, 1H), 3.42-3.48 (m,
1H), 3.01-3.12 (m, 2H), 2.47 (d, J ) 9.0 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 138.3, 138.2, 137.4, 137.4, 129.1, 129.0, 128.60,
128.55, 128.4, 128.2, 128.1, 127.9, 127.8, 126.3, 126.22, 126.16,
103.8, 101.80, 101.75, 101.7, 97.4, 97.2, 79.6, 77.6, 77.3, 75.1,
74.3, 73.6, 73.3, 72.9, 72.7, 70.2, 68.7, 68.6, 67.8, 67.1, 57.7;
ESIHRMS calcd for C61H64O16Na [M + Na]+ 1075.4087, found
1075.4090.
Methyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)prop-2-ynyl]-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-
2-O-benzyl-â-D-mannopyranoside (26). Coupling of sulfoxide 23
(0.16 g, 0.25 mmol) with donor 25 (0.08 g, 0.21 mmol) by the
standard coupling protocol gave disaccharide 26 (0.17 g, 0.19 mmol)
1
in 93% yield: [R]20 -81.8 (c 1.0, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 8.34 (d, J ) 8.0 Hz, 1H), 7.85 (t, J ) 7.5 Hz, 2H), 7.65
(d, J ) 7.0 Hz, 1H), 7.18-7.54 (m, 23H), 5.62 (s, 1H), 5.53 (s,
1H), 4.98 (d, J ) 12.0, Hz, 1H), 4.93 (d, J ) 12.5 Hz, 1H), 4.74
(t, J ) 12.5 Hz, 2H), 4.58-4.66 (m, 2H), 4.48 (s, 1H), 4.36 (dd,
J ) 4.5, 10.5 Hz, 1H), 4.20 (dd, J ) 5.0, 10.5 Hz, 1H), 4.07-4.15
(m, 4H), 3.94-3.98 (m, 2H), 3.86 (t, J ) 10.5 Hz, 1H), 3.76 (d, J
) 3.0 Hz, 1H), 3.60 (s, 4H), 3.41 (dt, J ) 5.0, 10.0 Hz, 1H), 3.02
(dt, J ) 5.0, 9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8,
138.1, 137.5, 137.4, 133.4, 133.2, 130.7, 129.1, 128.9, 128.8, 128.4,
128.3, 128.2, 128.1, 127.3, 127.0, 126.5, 126.3, 126.2, 125.2, 120.3,
103.7, 101.8, 101.5, 97.4, 90.5, 84.4, 78.3, 77.0, 76.0, 74.8, 74.3,
73.5, 72.9; ESIHRMS calcd for C54H52O11Na [M + Na]+ 899.3408,
found 899.3444.
Phenyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)prop-2-ynyl]-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-
2-O-benzyl-1-thio-R-D-mannopyranoside(31). Coupling of sul-
foxide donor 23 (0.105 g, 0.17 mmol) with thioglycoside 30 (0.050
g, 0.11 mmol) by the standard coupling protocol gave disaccharide
31 (0.081 g, 0.085 mmol) as a colorless syrup in 76% yield: [R]24
D
+37.6 (c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J )
8.5 Hz, 1H), 7.85 (t, J ) 7.5 Hz, 2H), 7.67 (d, J ) 7.0 Hz, 1H),
7.20-7.53 (m, 28H), 5.64 (s, 1H), 5.63 (s, 1H), 5.56 (s, 1H), 5.02
(d, J ) 11.5 Hz, 1H), 4.83 (d, J ) 11.5 Hz, 1H), 4.65-4.72 (m,
Methyl 4,6-O-Benzylidene-2-O-benzyl-â-D-mannopyranosyl-
(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-mannopyranoside (27).
J. Org. Chem, Vol. 72, No. 18, 2007 6813

Crich et al.
3H), 4.48 (d, J ) 12.5 Hz, 1H), 4.41(dd, J ) 3.0, 10.0 Hz, 1H),
4.24-4.36 (m, 5H), 4.18 (t, J ) 9.5 Hz, 1H), 4.07-4.08 (m, 1H),
3.95 (d, J ) 3.0 Hz, 1H), 3.91 (t, J ) 10.0 Hz, 2H), 3.77 (dd, J )
3.5, 10.0 Hz, 1H), 3.12 (dt, J ) 4.5, 9.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 138.8, 137.6, 137.5, 137.1, 133.8, 133.4, 133.2,
131.8, 130.7, 129.3, 129.1, 129.0, 128.9, 128.61, 128.55, 128.4,
128.2, 128.1, 127.9, 127.3, 127.0, 126.5, 126.3, 126.2, 126.1, 125.2,
120.3, 101.9, 101.5, 98.4, 90.5, 86.0, 84.5, 78.4, 77.4, 76.6, 75.7,
75.0, 72.7, 72.1, 68.64, 68.56, 67.7, 65.5, 58.8; ESIHRMS calcd
for C59H54O10SNa [M + Na]+ 977.3336, found 977.3380.
Phenyl 4,6-O-Benzylidene-2-O-benzyl-â-D-mannopyranosyl-
(1f3)-4,6-O-benzylidene-2-O-benzyl-1-thio-R-D-mannopyrano-
side (32). Removal of the naphthylpropargyl group from compound
31 (1.30 g, 1.36 mmol) by the standard protocol gave product 32
(0.95 g, 1.20 mmol) in 88% yield: [R]25D -2.2 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.45-7.49 (m, 6H), 7.24-7.38 (m,
19H), 5.68 (s, 1H), 5.64 (s, 1H), 5.33 (s, 1H), 5.06 (d, J ) 11.0
Hz, 1H), 4.77 (d, J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H),
4.55 (d, J ) 12.0 Hz, 1H), 4.42 (dd, J ) 3.0, 10.0 Hz, 1H), 4.35-
4.40 (m, 2H), 4.22-4.30 (m, 3H), 4.12-4.13 (m, 1H), 3.92 (t, J )
10.0 Hz, 1H), 3.83 (t, J ) 9.0 Hz, 1H), 3.74-3.78 (m, 2H), 3.58-
3.66 (m, 1H), 3.10 (dt, J ) 4.5, 9.5 Hz, 1H), 2.53 (d, J ) 9.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 138.1, 137.44, 137.36, 137.1,
133.7, 131.8, 129.3, 129.08, 129.05, 128.7, 128.6, 128.5, 128.4,
128.2, 127.9, 127.8, 126.3, 102.0, 101.8, 97.8, 86.1, 79.8, 77.5,
77.30, 77.25, 75.4, 74.9, 72.4, 72.2, 70.2, 68.7, 68.6, 67.0, 65.6;
ESIHRMS calcd for C46H46O10SNa [M + Na]+ 813.2704, found
813.2694.
J ) 5.0, 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 141.6, 138.8,
138.3, 137.5, 137.1, 136.6, 133.4, 133.2, 131.9, 130.7, 129.6, 129.2,
129.0, 128.9, 128.7, 128.5, 128.3, 128.23, 128.19, 128.1, 127.8,
127.4, 127.0, 126.5, 126.3, 126.2, 125.2, 124.4, 120.3, 101.9, 101.7,
101.5, 98.4, 97.9, 96.3, 90.4, 84.4, 78.4, 77.3, 77.0, 76.4, 76.1, 74.9,
74.3, 73.9, 73.7, 72.7, 72.1, 70.7, 70.2, 68.6, 68.2, 67.8, 58.6;
ESIHRMS calcd for C79H74O16SNa [M + Na]+ 1333.4590, found
1333.4589.
Methyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)prop-2-ynyl]-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-
2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
benzyl-R-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-
â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranoside (35R) and Methyl 4,6-O-Benzylidene-2-O-
benzyl-3-O-[3-(naphthalen-1-yl)-prop-2-ynyl]-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-
mannopyranoside (35â). To a stirred solution of sulfoxide donor
34 (120 mg, 0.09 mmol), TTBP (40 mg, 0.16 mmol), and 4 Å
molecular sieves in a mixed solvent of CH2Cl2 and 1-octene (7.5
mL, v/v, 4:1), at -78 °C under argon atmosphere, was added Tf2O
(15 µL, 0.09 mmol). After the reaction mixture was stirred at -78
°C for 30 min, a solution of acceptor 29 (80 mg, 0.075 mmol) in
CH2Cl2 (1.5 mL) was added. The stirring was maintained for
30 min at -78 °C, and the reaction temperature was allowed to
warm to -20 °C slowly over 30 min. The resultant mixture
was stirred for another 30 min at -20 °C before it was quenched
by pouring into aq NaHCO3 solution. The mixture was diluted
with CH2Cl2 and filtered through Celite. The organic layer was
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by chromatography on silica gel (hexane/ethyl
acetate; 2:1f 1.5:1) to give a mixture of hexasaccharides 35R,
35â (103 mg, 61%) in 1:1 ratio as estimated by 1H NMR
spectroscopy of the mixture. Separation of 30 mg of the mixture
by RP HPLC using a gradient of 90% A to 100% A over 144 min
(A: CH3CN, B: H2O; Varian Microsorb C18 250 × 21.4 mm;
flow rate: 5 mL/min; UV detection: 215 nm) gave pure samples
Phenyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)-prop-2-ynyl]-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-
2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
benzyl-1-thio-R-D-mannopyranoside (33). Coupling of sulfoxide
donor 23 (0.063 g, 0.10 mmol) with thioglycoside 32 (0.062 g,
0.08 mmol) by the standard coupling protocol gave trisaccharide
33 (0.074 g, 0.06 mmol) as a colorless syrup in 73% yield: [R]27
D
-40.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J )
8.0 Hz, 1H), 7.84 (t, J ) 7.5 Hz, 2H), 7.63 (d, J ) 7.0 Hz, 1H),
7.44-7.52 (m, 10H), 7.28-7.40 (m, 20H), 7.18-7.23 (m, 5H),
7.11-7.12 (m, 3H), 5.66 (s, 1H), 5.60 (s, 1H), 5.56 (s, 1H), 5.49
(s, 1H), 4.99 (d, J ) 12.0 Hz, 1H), 4.93 (d, J ) 12.0 Hz, 1H), 4.77
(t, J ) 12.0 Hz, 2H), 4.53-4.70 (m, 4H), 4.43 (dd, J ) 3.0, 10.0
Hz, 1H), 4.06-4.35 (m, 10H), 3.85-3.94 (m, 6H), 3.71 (dd, J )
3.0, 10.0 Hz, 1H), 3.08-3.14 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 138.8, 138.2, 137.5, 137.4, 137.0, 133.7, 133.4, 133.2, 131.9,
130.7, 129.3, 129.0, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1,
127.9, 127.8, 127.3, 126.9, 126.5, 126.3, 126.2, 125.2, 120.3, 101.8,
101.7, 101.5, 98.0, 90.4, 85.8, 84.4, 78.4, 76.1, 75.4, 74.9, 74.2,
73.9, 73.4, 72.3, 71.9, 68.6, 67.8, 65.5, 58.7; ESIHRMS calcd for
C79H74O15SNa [M + Na]+ 1317.4641, found 1317.4630.
of 35R, 35â.
1
Hexasaccharide 35R: [R]20 -127.7 (c 0.5, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 8.33 (d, J ) 8.5 Hz, 1H), 7.82 (t, J ) 8.0
Hz, 2H), 7.62 (d, J ) 7.0 Hz, 1H), 7.05-7.50 (m, 61H), 6.97 (d,
J ) 7.5 Hz, 2H), 5.63 (s, 1H), 5.57 (s, 1H), 5.56 (s, 1H), 5.55 (s,
1H), 5.45 (s, 1H), 5.39 (s, 1H), 4.45-5.07 (m, 15H), 4.39 (dd, J )
3.5, 9.0 Hz, 2H), 3.68-4.25 (m, 33H), 3.63 (s, 3H), 3.60-3.65
(m, 1H), 3.45 (dt, J ) 4.5, 9.0 Hz, 1H), 3.05-3.12 (m, 3H), 3.01
(dt, J ) 4.5, 9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8,
138.29, 138.27, 138.2, 137.9, 137.7, 137.5, 137.4, 137.3, 133.4,
133.2, 130.7, 129.5, 129.00, 128.96, 128.91, 128.85, 128.7, 128.6,
128.47, 128.45, 128.4, 128.34, 128.29, 128.24, 128.21, 128.16,
128.1, 128.0, 127.88, 127.85, 127.8, 127.3, 126.9, 126.5, 126.3,
126.2, 125.2, 120.3, 103.9, 102.2, 101.8, 101.69, 101.65, 101.5,
98.8, 98.5, 97.6, 97.3, 90.4, 84.4, 78.8, 78.3, 77.3, 76.9, 76.1, 76.0,
75.1, 74.8, 74.24, 74.16, 74.1, 73.9, 73.8, 73.7, 73.5, 73.3, 73.2,
72.6, 72.4, 72.1, 71.8, 68.7, 68.6, 67.8, 67.7, 67.5, 64.6, 58.6, 57.7;
ESIHRMS calcd for C134H132O31Na [M + Na]+ 2259.8645, found
Phenyl 4,6-O-Benzylidene-2-O-benzyl-3-O-[3-(naphthalen-1-
yl)-prop-2-ynyl]-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-
2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-benzylidene-2-O-
benzyl-1-thio-R-D-mannopyranoside S-Oxide (34). To a stirred
solution of 33 (0.98 g, 0.76 mmol) in CH2Cl2 (40 mL) was added
a solution of m-CPBA (77%, 0.17 g, 0.76 mmol) in CH2Cl2 (2
mL) dropwise at -78 °C. The resultant mixture was stirred for 1
h during which time the temperature was allowed to warm up to
-20 °C slowly. The reaction mixture was then quenched by pouring
into aq NaHCO3 solution and was diluted with CH2Cl2. The organic
layer was separated, washed with 1 M aq NaOH solution and brine,
dried over anhydrous Na2SO4, and concentrated. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate;
1.5:1) to give the title compound 34 (0.98 g, 98%): [R]25D -103.9
2259.8513.
1
Hexasaccharide 35â: [R]20 -132.2 (c 0.5, CHCl3); H NMR
D
1
(c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 8.34 (d, J ) 8.0
(500 MHz, CDCl3) δ 8.33 (d, J ) 8.0 Hz, 1H), 7.83 (t, J ) 7.5
Hz, 2H), 7.63 (d, J ) 7.0 Hz, 1H), 7.09-7.51 (m, 63H), 5.62 (s,
1H), 5.55 (s, 1H), 5.53 (s, 1H), 5.51 (s, 1H), 5.50 (s, 1H), 5.48 (s,
1H), 4.98-5.08 (m, 5H), 4.89 (d, J ) 12.0 Hz, 1H), 4.66-4.83
(m, 7H), 4.59-4.63 (m, 2H), 4.53-4.54 (m, 1H), 4.39 (dd, J )
4.5, 10.5 Hz, 2H), 3.78-4.24 (m, 30H), 3.68 (dd, J ) 3.0, 9.5 Hz,
Hz, 1H), 7.84 (t, J ) 8.0 Hz, 2H), 7.11-7.65 (m, 39H), 5.58 (s,
2H), 5.48 (s, 1H), 5.01 (d, J ) 12.0 Hz, 1H), 4.93 (d, J ) 12.0 Hz,
1H), 4.58-4.77 (m, 7H), 4.43-4.52 (m, 2H), 4.11-4.31 (m, 8H),
4.08 (t, J ) 9.5 Hz, 1H), 3.94 (t, J ) 10.0 Hz, 1H), 3.85-3.88 (m,
4H), 3.71-3.78 (m, 2H), 3.15 (dt, J ) 5.0, 10.0 Hz, 1H), 3.08 (dt,
6814 J. Org. Chem., Vol. 72, No. 18, 2007

ConVergent Synthesis of a â-(1f3)-Mannohexaose
1H), 3.63 (m, 4H), 3.45 (dt, J ) 5.0, 9.5 Hz, 1H), 3.13 (dt, J )
5.0, 9.5 Hz, 1H), 3.01-3.08 (m, 4H); 13C NMR (125 MHz, CDCl3)
δ 138.8, 138.3, 138.2, 138.1, 137.5, 137.43, 137.37, 137.3, 133.4,
133.2, 130.6, 128.99, 128.95, 128.91, 128.8, 128.7, 128.5, 128.42,
128.35, 128.3, 128.21, 128.19, 128.1, 127.93, 127.87, 127.3, 126.9,
126.5, 126.24, 126.17, 126.1, 125.2, 120.3, 103.9, 101.8, 101.70,
101.63, 101.5, 97.5, 97.3, 90.4, 84.4, 78.4, 76.9, 76.1, 74.9, 74.2,
73.9, 73.8, 73.5, 73.3, 73.2, 72.5, 72.4, 72.1, 72.0, 68.7, 68.5, 67.8,
58.6, 57.7; ESIHRMS calcd for C134H132O31Na [M + Na]+
2259.8645, found 2259.8560.
â-D-mannopyranosyl-(1f3)-â-D-mannopyranosyl-(1f3)-â-D-
mannopyranoside (37). A mixture of hexasaccharide 36â (19 mg,
0.01mmol) and 10% Pd(OH)2/C (30 mg) in a mixed solvent of
methanol (2.0 mL) and ethyl acetate (0.5 mL) was shaken under
50 psi of H2 for 40 h. The mixture was filtered through Celite,
followed by removal of the solvent under reduced pressure to give
mannohexose 37 (10 mg, 100%): [R]19 -68.9 (c 0.25, MeOH:
D
1
H2O, 1:1); H NMR (500 MHz, D2O) δ 4.65-4.74 (m, 6H), 4.42
(s, 1H), 4.13 (s, 3H), 4.04 (s, 1H), 3.92 (s, 1H), 3.79-3.85 (m,
11H), 3.40-3.43 (m, 1H), 3.40 (s, 3H), 3.26-3.29 (m, 6H); 13C
NMR (500 MHz, D2O) δ 100.8 (1JCH ) 157.9), 96.6 (1JCH ) 158.6),
Methyl 4,6-O-Benzylidene-2-O-benzyl-â-D-mannopyranosyl-
(1f3)-4,6-O-benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-
4,6-O-Benzylidene-2-O-benzyl-R-D-mannopyranosyl-(1f3)-4,6-
O-benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranoside (36R) and Methyl
4,6-O-Benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-
O-benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-ben-
zylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranosyl-(1f3)-4,6-O-
benzylidene-2-O-benzyl-â-D-mannopyranoside (36â). Removal
of the naphthylpropargyl group from a 1:1 mixture of 35R and
35â (85 mg, 0.038 mmol) by the standard deprotection pro-
tocol gave 36 as a mixture of anomers (55 mg, 70%). Separation
by RP HPLC using a gradient of 80% A to 100% B over 144 min
(A: CH3CN, B: H2O; Varian Microsorb C18 250 × 21.4 mm;
flow rate: 10 mL/min; UV detection: 215 nm) gave pure samples
96.4 (1JCH
) 159.4), 81.7, 78.9, 78.8, 78.7, 76.3, 76.0,
75.8, 72.8, 70.7, 67.7, 67.6, 67.1, 66.8, 65.2, 65.1, 61.0, 56.8;
ESIHRMS calcd for C37H64O31Na [M + Na]+ 1027.3324, found
1027.3334.
Methyl â-D-Mannopyranosyl-(1f3)-â-D-mannopyranosyl-
(1f3)-R-D-mannopyranosyl-(1f3)-â-D-mannopyranosyl-(1f3)-
â-D-mannopyranosyl-(1f3)-â-D-mannopyranosyl-(1f3)-â-D-
mannopyranoside (38). A mixture of hexasaccharide 36R (23 mg,
0.01mmol) and 10% Pd(OH)2/C (30 mg) in a mixed solvent of
methanol (2.0 mL) and ethyl acetate (0.5 mL) was shaken under
50 psi of H2 for 21 h until the reaction was over as monitored by
TLC. The mixture was filtered through Celite followed by removal
of the solvent under reduced pressure to give mannohexose 38 (12
mg, 100%): [R]19D -40.0 (c 0.5, MeOH/H2O, 1:1); 1H NMR (500
MHz, D2O) δ 5.03 (s, 1H), 4.43 (s, 1H), 4.05-4.12 (m, 5H), 3.93
(s, 1H), 3.80-3.81 (m, 7H), 3.53-3.68 (m, 12H), 3.39-3.44 (m,
4H), 3.20-3.30 (m, 7H); 13C NMR (500 MHz, D2O) δ 102.1 (1JCH
) 165.0), 100.8 (1JCH ) 155), 96.9, 96.7, 96.54, 96.49, 80.2, 79.0,
77.2, 76.4, 76.2, 76.1, 76.0, 75.9, 73.1, 72.9, 72.1, 70.8, 70.5, 67.83,
67.78, 67.2, 66.9, 66.3, 65.3, 65.2, 62.5, 61.1, 61.0, 57.4, 56.9, 48.9;
ESIHRMS calcd for C37H64O31Na [M + Na]+ 1027.3324, found
1027.3338.
1-Naphthylpropargylcyclohexyl Ether (40). A mixed solution
of propargyl cyclohexyl ether70 (0.94 g, 6.8 mmol) and 1-bro-
monaphthalene (1.05 mL, 7.5 mmol) in triethylamine (20 mL) was
degassed by bubbling Ar gas for 30 min, and then PdCl2(PPh3)2
(0.24 g, 0.34 mmol) and CuI (0.064 g, 0.34mmol) were successively
added into the reaction mixture. The resulting mixture was stirred
at 50-55 °C overnight under Ar and then was filtered through
Celite. The filter cake was washed with CH2Cl2, and the filtrate
was concentrated under vacuum and residue was purified by
chromatography on silica gel (hexane/ethyl acetate; 20:1) to afford
the title compound 40 (0.80 g, 44%) as a colorless oil: 1H NMR
(500 MHz, CD2Cl2) δ 1.25-1.42 (m, 5H), 1.55-1.60 (m, 1H),
1.78-1.79 (m, 2H), 2.00-2.03 (m, 2H), 3.62-3.66 (m, 1H), 4.55
(d, J ) 2.5 Hz, 2H), 7.43-7.47 (m, 1H), 7.54-7.61 (m, 2H), 7.69-
7.70 (m, 1H), 7.86-7.90 (m, 2H), 8.33 (d, J ) 8.0 Hz, 1H); 13C
NMR (125 MHz, CD2Cl2) δ 24.1, 25.8, 32.1, 55.8, 76.7, 83.0, 91.4,
91.4, 120.5, 125.2, 126.0, 126.4, 126.8, 128.3, 128.8, 130.5, 133.2,
133.3; ESIHRMS (EI) calcd for C19H20O[M]+ 264.1514, found
264.1521.
of 36R, 36â respectively. Hexasaccharide 36R: [R]21 -122.7
D
1
(c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.43-7.52 (m,
11H), 7.12-7.41 (m, 47H), 7.01 (d, J ) 7.5 Hz, 2H), 5.64 (s, 1H),
5.59 (s, 1H), 5.55 (s, 2H), 5.41 (s, 1H), 5.36 (s, 1H), 4.81-5.08
(m, 7H), 4.76 (d, J ) 3.5 Hz, 1H), 4.73 (d, J ) 3.5 Hz, 1H),
4.48-4.55 (m, 2H), 4.41 (dt, J ) 4.5, 10.0 Hz, 2H), 3.74-4.32
(m, 30H), 3.70 (d, 3.5 Hz, 1H), 3.66-3.68 (m, 1H), 3.64 (s,
3H), 3.57-3.58 (m, 1H), 3.45 (dt, J ) 5.0, 10.0 Hz, 1H), 3.00-
3.16 (m, 4H), 2.47 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 138.3,
138.2, 138.1, 137.9, 137.7, 137.4, 137.34, 137.30, 137.2, 129.5,
129.1, 128.94, 128.90, 128.7, 128.6, 128.43, 128.38, 128.3,
128.23, 128.18, 128.15, 128.1, 128.0, 127.94, 127.90, 127.8, 126.24,
126.21, 126.1, 103.8, 102.1, 101.8, 101.7, 101.6, 98.8, 98.2, 97.5,
97.3, 79.6, 78.7, 77.6, 77.2, 76.9, 76.0, 75.0, 74.23, 74.19, 74.1,
73.9, 73.72, 73.67, 73.5, 73.1, 72.5, 72.3, 72.0, 71.8, 70.2, 68.7,
68.6, 68.5, 67.7, 67.6, 67.5, 67.0, 64.6, 64.2, 57.7; ESIHRMS calcd
for C121H124O31Na [M + Na]+ 2095.8019, found 2095.7938.
1
Hexasaccharide 36â: [R]21 -152.5 (c 1.0, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.44-D7.47 (m, 14H), 7.22-7.36 (m, 49H),
5.63 (s, 1H), 5.49-5.53 (m, 4H), 5.37 (s, 1H), 4.97-5.08 (m, 6H),
4.75-4.84 (m, 5H), 4.53-4.55 (m, 2H), 4.40 (dd, J ) 4.5, 10.0
Hz, 1H), 3.70-4.26 (m, 33H), 3.64 (s, 3H), 3.55-3.58 (m, 1H),
3.45 (dt, J ) 4.5, 9.0 Hz, 1H), 3.01-3.17 (m, 5H), 2.47 (br. s,
1H); 13C NMR (125 MHz, CDCl3) δ 138.3, 138.22, 138.16, 137.4,
137.3, 129.1, 129.0, 128.72, 128.66, 128.5, 128.4, 128.3, 128.2,
128.1, 128.0, 127.8, 126.3, 126.2, 126.1, 103.9, 101.81, 101.79,
101.7, 101.6, 97.5, 97.4, 97.3, 79.6, 77.7, 75.1, 74.2, 74.0, 73.9,
73.5, 73.3, 73.2, 72.5, 72.4, 72.0, 70.2, 68.7, 68.6, 67.8, 67.7, 67.1,
57.7; ESIHRMS calcd for C121H124O31Na [M + Na]+ 2095.8019,
found 2095.7932.
Acknowledgment. We thank the NIH (GM57335) for
support of this work and Professors Shin-ichiro Nishimura and
Masaki Kurogochi, Hokkaido University, for mass spectrometry
of the hexaose.
Supporting Information Available: Copies of spectra of all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
Methyl â-D-Mannopyranosyl-(1f3)-â-D-mannopyranosyl-
(1f3)-â-D-mannopyranosyl-(1f3)-â-D-mannopyranosyl-(1f3)-
(70) Wardrop, D. J.; Fritz, J. Org. Lett. 2006, 8, 3659-3662.
JO071009N
J. Org. Chem, Vol. 72, No. 18, 2007 6815