Block synthesis of tetra- and hexasaccharides (β-D-glycero-D-manno- hepp-(1→4)-[α-L-rhap-(1→3)-β-D-glycero-D-manno-hepp- (1→4)]n-α-L-rhap-OMe (n = 1 and 2)) corresponding to multiple repeat units of the glycan from the surface-layer glycoprotein from Bacillus thermoaerophilus

Article abstract of DOI:10.1021/jo801414c

(Chemical Equation Presented) A fully stereocontrolled block synthesis of the title tetra- and hexasaccharides has been achieved taking advantage of the ability of the 4,6-O-benzylidene acetal to control the stereochemistry of the β-D-glycero-D-mannoheptopyranoside unit and of a 2,3-O-diphenylmethylene acetal to install the α-L-rhamnopyranosidic linkages. Comparison of the spectral data for the hexasaccharide with that of the natural isolate confirms the structure of this very unusual and structurally challenging glycan.

Full text of DOI:10.1021/jo801414c

Block Synthesis of Tetra- and Hexasaccharides (ꢀ-D-Glycero-D-manno-
Hepp-(1f4)-[r-L-Rhap-(1f3)-ꢀ-D-glycero-D-manno-Hepp-(1f4)]n-r-L-Rhap-
OMe (n ) 1 and 2)) Corresponding to Multiple Repeat Units of the
Glycan from the Surface-Layer Glycoprotein from Bacillus
thermoaerophilus
David Crich* and Ming Li
Chemistry Department, Wayne State UniVersity, 5101 Cass AVenue, Detroit, Michigan 48202
dcrich@chem.wayne.edu
ReceiVed June 28, 2008
A fully stereocontrolled block synthesis of the title tetra- and hexasaccharides has been achieved taking
advantage of the ability of the 4,6-O-benzylidene acetal to control the stereochemistry of the ꢀ-D-glycero-
D-mannoheptopyranoside unit and of a 2,3-O-diphenylmethylene acetal to install the R-L-rhamnopyranosidic
linkages. Comparison of the spectral data for the hexasaccharide with that of the natural isolate confirms
the structure of this very unusual and structurally challenging glycan.
Introduction
Results and Discussion
Although our previous approach to the synthesis of the key
D-glycero-D-mannothioheptopyranoside donor was successful
and has subsequently been adopted by others,6 it suffered from
a low yield at the level of the homologation step in which a
six-carbon thiomannopyranoside was extended to a seven-carbon
system by Swern oxidation and Wittig olefination owing to
competing elimination of a benzyloxy group from the 4-position
In 1995, Kosma and co-workers described the characterization
of the surface-layer glycoprotein from Bacillus thermoaerophilus
and proposed the very unusual disaccharide motif f4)-[R-L-
rhamnopyranosyl-(1f3)-ꢀ-D-glycero-D-mannoheptopyranosyl-
(1f as the repeating unit of the glycan chain, with the
stereochemistry of the ꢀ-D-glycero-D-mannoheptopyranoside
assigned on the basis of comparison of spectral data with
synthetic methyl ꢀ-L-glycero-D-mannoheptopyranoside.1 Having
recently described the first stereocontrolled route to ꢀ-D-glycero-
D-mannoheptopyranosides and their 6-deoxy analogues2 and
applied this chemistry to a linear synthesis of methyl R-L-
rhamnopyranosyl-(1f3)-ꢀ-D-glycero-D-mannoheptopyranosyl-
(1f3)-6-deoxy-ꢀ-glycero-D-mannoheptopyranosyl-(1f4)-R-L-
rhamnopyranoside, a tetrasaccharide subunit from the Plesi-
monas shigelloides lipopolysaccharide,3 we selected this oli-
gomer as a proving ground for a block synthesis approach to
glycans containing the unusual ꢀ-D-glycero-D-mannoheptoside
structure.4,5
(4) For reviews expounding the difficulties of ꢀ-mannoside synthesis and
presenting classical and indirect solutions to the problem, see: (a) Barresi, F.;
Hindsgaul, O. In Modern Methods in Carbohydrate Synthesis; Khan, S. H.;
O’Neill, R. A., Eds.; Harwood Academic Publishers: Amsterdam, 1996, pp 251-
276. (b) Demchenko, A. V. Synlett 2003, 1225–1240. (c) Pozsgay, V. In
Carbohydrates in Chemistry and Biology; Ernst, B.; Hart, G. W.; Sinay¨, P., Eds.;
Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, pp 319-343. (d) Gridley, J. J.;
Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000, 1471–1491. (e) Ito, Y.;
Ohnishi, Y. In Glycoscience: Chemistry and Chemical Biology; Fraser-
Reid, B.; Tatsuta, K.; Thiem, J., Eds.; Springer: Berlin, 2001; Vol. 2, pp 1589-
1619.
(5) For the direct approach to ꢀ-mannopyranoside synthesis and its mech-
anism, see: (a) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198–1199. (b) Crich,
D.; Sun, S. Tetrahedron 1998, 54, 8321–8348. (c) Crich, D.; Smith, M. J. Am.
Chem. Soc. 2001, 123, 9015–9020. (d) Crich, D.; Banerjee, A.; Li, W.; Yao, Q.
J. Carbohydr. Chem. 2005, 24, 415–424. (e) Crich, D.; Sun, S. J. Am. Chem.
Soc. 1997, 119, 11217–11223. (f) Crich, D.; Chandrasekera, N. S. Angew. Chem.,
Int. Ed. 2004, 43, 5386–5389. (g) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am.
Chem. Soc. 2004, 126, 9205–9213.
(1) (a) Kosma, P.; Wugeditsch, T.; Christian, R.; Zayni, S.; Messner, P.
Glycobiology 1995, 5, 791–796. (b) Kosma, P.; Wugeditsch, T.; Christian, R.;
Zayni, S.; Messner, P. Glycobiology 1996, 6, 5.
(2) Crich, D.; Banerjee, A. Org. Lett. 2005, 7, 1935–1938.
(3) Crich, D.; Banerjee, A. J. Am. Chem. Soc. 2006, 128, 8078–8086.
(6) Jaipuri, F. A.; Collet, B. Y. M.; Pohl, N. L. Angew Chem., Int. Ed. 2008,
47, 1707–1710.
10.1021/jo801414c CCC: $40.75
Published on Web 08/27/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7003–7010 7003

Crich and Li
TABLE 1. Osmoylation of Alkene 4
entry
1
oxidant/ligand
solvent
T/°C
6/8 (yield)
7/9 (yield)
OsO4/NMO
acetone/H2O
22
2.2/1
1.2/1
(86%)
1/1.2
(97%)
1.2/1
(93%)
1.5/1
(96%)
2.5/1
(8.40%)
not detected
2
3
4
5
AD- ꢀ-mix
t-BuOH/H2O
22
0
AD-R-mix
t-BuOH/H2O
not detected
not detected
not detected
K3Fe(CN)6/OsO4/(DHQ)2Pry
K3Fe(CN)6/OsO4/(DHQ)2Pry
t-BuOH/H2O
22
0
t-BuOH/H2O/PhCH3
(96%)
SCHEME 1. Improved Homologation Procedure
compounds (Table 1). Some minor overoxidation to the corre-
sponding sulfones 7 and 9 was also observed in these reactions.14
Selective monobenzylation with dibutyltin oxide and benzyl
bromide15 of 6 and 8 afforded the corresponding 7-O-benzyl-
6-ols 10 and 11 in excellent yield. Attempted inversion of the
unwanted L,D-alcohol 11 to the desired D,D-isomer 10 by the
Mitsunobu protocol16 was stymied by poor yields, but the
desired effect was achieved by recourse to displacement of the
6-O-triflate with potassium nitrite with in situ hydrolysis of the
corresponding nitroso ester.17 Hydrolysis of the biacetal function
in 10 to give a triol was followed by selective benzylidene acetal
formation across the 1,3-diol functionality and introduction of
a naphthylmethyl ether18 onto the remaining alcohol, thereby
providing the known glycosyl donor 133 and, incidentally,
confirming the D,D-stereochemistry of 6 (Scheme 2).
Two L-rhamnopyranosyl acceptors 16 and 17 were prepared
by protection of the corresponding triols as the benzophenone
acetals19 in moderate yield (Scheme 3). Somewhat better yields
of 16 and 17 have been reported in the literature for alkylation
of 14 and 15 with dichlorodiphenylmethane in pyridine.19a
A first glycosidic bond forming reaction involved activation
of donor 13 with 4-nitrophenylsulfenyl chloride and silver triflate
in the course of the Wittig reaction.2,3 We began, therefore, by
seeking to improve the homologation step and were attracted
to the use of the Ley bisacetal function7 for protection of the
3,4-diol functionality on the grounds that elimination would be
retarded by the confinement of the putative alkoxide leaving
group within a fused bicyclic ring system. Thus, treatment of
the bisacetal 18 with sodium hydride and benzyl bromide in
DMF from -40 to 10 °C, according to the method described
by Ley and others,9 afforded the 2-O-benzyl derivative 2 with
good selectivity alongside a minor amount of the 2,6-di-O-
benzyl system 3.10 Swern oxidation followed by standard Wittig
homologation then afforded alkene 4 in 84% yield along with
a minor amount of a methylthioalkene 5,11 representing a distinct
improvement over the earlier protocol (Scheme 1).
(13) (a) Denmark, S. E.; Cottell, J. J. J. Org. Chem. 2001, 66, 4276–4284.
(b) Guzlek, H.; Graziani, A.; Kosma, P. Carbohydr. Res. 2005, 340, 2808–2811.
(c) Dong, L.; Roosenberg, J. M.; Miller, M. J. J. Am. Chem. Soc. 2002, 124,
15001–15005. (d) Gurjar, M. K.; Talukdar, A. Tetrahedron 2004, 60, 3267–
3271.
(14) (a) Kaldor, S. W.; Hammond, M. Tetrahedron Lett. 1991, 32, 5043–
5046. (b) Aucagne, V.; Tatibouet, A.; Rollin, P. Tetrahedron 2004, 60, 1817–
1826.
(15) (a) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643–663. (b) David,
S. In PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Dekker: New
York, 1997; pp 69-86.
(16) (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) Hughes, D. L. Org. React.
1992, 42, 335–656. (c) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32,
3017–3020.
Catalytic osmoylation of 4 took place with excellent yield
but poor selectivity for the formation of 6 and 8,12 whatever
the conditions employed, in keeping with our previous observa-
tions3 and those of other workers13 with closely related
(7) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53–80.
(8) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291–1297.
(9) Regioselective monobenzylation of the 2-methoxyphenyl thioglycoside
analogue of: Ley, S. V.; Humphries, A. C.; Eick, H.; Downham, R.; Ross, A. R.;
Boyce, R. J.; Pavey, J. B. J.; Pietruszka, J. J. Chem. Soc., Perkin Trans. 1 1998,
3907–3912.
(10) The regioselectivity of the benzylation reaction was assigned according
to the work of Ley with a direct analogue9 and was confirmed by the subsequent
reaction sequence.
(17) Adapted from (a) Crich, D.; Vinogradova, O. J. Am. Chem. Soc. 2007,
129, 11756–11765. (b) Lattrell, R.; Lohaus, G. Liebigs Ann. Chem. 1974, 901–
920. (c) Moriarty, R. M.; Zhuang, H.; Penmasta, R.; Liu, K.; Awasthi, A. K.;
Tuladhar, S. M.; Rao, M. S. C.; Singh, V. K. Tetrahedron Lett. 1993, 34, 8029–
8032. (d) Binkley, R. W. J. Org. Chem. 1991, 56, 3892–3896. (e) Binkley, R. W.
J. Carbohydr. Chem. 1994, 13, 111–123. (f) Dong, H.; Pei, Z.; Ramstroem, O.
J. Org. Chem. 2006, 71, 3306–3309. (g) Albert, R.; Dax, K.; Link, R. W.; Stuetz,
A. E. Carbohydr. Res. 1983, 118, C5–C6.
(18) (a) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.;
Matta, K. L. Tetrahedron Lett. 2000, 41, 169–173. (b) Liao, W.; Locke, R. D.;
Matta, K. L. Chem. Commun. 2000, 369–370. (c) 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.
(11) Shi, M.; Shen, Y.-M. J. J. Chem. Res. (S) 2002, 422–427.
(12) The stereochemistry of diols 6 and 8 can be determined based on
comparison of the double doublet representing H5 with literature values Thus,
3
3
the L,D-series (8) has a the smaller J5,6 of 2.0 Hz when compared to the J5,6
coupling of 6.0 Hz observed in the D,D-series (6). In addition the 6- and 7-OH
signals for 6 resonate downfield (δ 3.16 and 2.20, respectively) relative to those
for 8 (δ 2.66 and 1.85, respectively). Read, J. A.; Ahmed, R. A.; Tanner, M. E.
Org. Lett. 2005, 7, 2457–2460.
(19) (a) Borba´s, A.; Hajko´, J.; Kajta´r-Peredy, M.; Lipta´k, A.; Lipta´k, A.
J. Carbohydr. Chem. 1993, 12, 191–200. (b) Borba´s, A. Carbohydr. Res. 1993,
241, 99–116. (c) Hajko´, J.; Borba´s, A.; Szabovik, G.; Kajta´r-Peredy, M.; Lipta´k,
A. J. Carbohydr. Chem. 1997, 16, 1123–1144.
7004 J. Org. Chem. Vol. 73, No. 18, 2008

Block Synthesis
SCHEME 2. Synthesis of Heptosyl Donor 13
SCHEME 3. Rhamnosyl Acceptor Preparation
SCHEME 4. Upstream Disaccharide Synthesis
in dichloromethane at -78 °C to give the corresponding glycosyl
triflate followed by addition of the acceptor 16 when disaccha-
ride 18 was obtained in 81% yield and exquisite ꢀ-selectivity,
in keeping with our previous observations in the benzylidene
protected D-glycero-D-mannoheptoside series. The 4-nitrophe-
nylsulfenyl chloride/silver triflate protocol20 is a convenient
variant on benzenesulfenyl triflate activation protocol21 that
employs a commercial, stable sulfenyl chloride. The anomeric
stereochemistry of the newly formed glycosidic bond is readily
assigned on the basis of the shielded, upfield nature of the
heptoside H5 resonance (δ 2.63), something that is highly
characteristic of 4,6-O-benzylidene-protected ꢀ-mannosides and
which carries over to corresponding benzylidene acetals of the
ꢀ-D-glycero-D-mannoheptosides. Confirmation of this anomeric
SCHEME 5. Disaccharide Donor Synthesis
1
stereochemistry derives from the anomeric 159.7 Hz JH1,C1
coupling constant.22 Removal of the naphthylmethyl ether with
dichlorodicyanoquinone in wet dichloromethane gave the gly-
cosyl acceptor 19 in good yield (Scheme 4).
An analogous protocol was then applied to the coupling of
donor 13 with the thioglycoside-containing acceptor 17 to give
the thiodisaccharide 20, again with exquisite ꢀ-selectivity (for
the heptopyranoside: δH5 2.60, 1JH1,C1 159.0 Hz). Unfortunately,
yields were lower with acceptor 17 than with the corresponding
methyl glycoside 16, maximizing at 54% when 1.2 equiv of
the sulfenyl chloride was employed. However, the 1-benzene-
sulfinyl piperidine (BSP)/trifluoromethanesulfonic anhydride
protocol proved superior when the activation was conducted in
the presence of 1-octene as a sacrificial olefin, resulting in a
73% yield of the desired disaccharide (Scheme 5).
silver triflate in excellent yield and R-selectivity. The 4-nitro-
phenylsulfenyl chloride/silver triflate protocol was also at-
tempted but only gave the target compound in 26% yield. In
addition to the two anomeric resonances characterizing the
preinstalled ꢀ-mannoheptoside linkages, the 13C NMR spectrum
of the tetrasaccharide contained resonances at δ 93.9 and 98.1
with 1JCH of 168.7 and 172.3 Hz, indicative of the R-nature for
the two rhamnoside linkages. Finally, global deprotection of
21 was achieved cleanly by hydrogenolysis over palladium on
charcoal leading to the isolation of the target tetrasaccharide
22 in 85% yield (Scheme 6).
The synthesis of the hexasaccharide 25 began with removal
of the naphthylmethyl protecting group from tetrasaccharide 21
to give the acceptor 23 and was followed by NIS/AgOTf-
mediated coupling with the disaccharide donor 20 to give the
hexasaccharide 24 in 64% yield as a single anomer. The
R-nature of the rhamnopyranosidic linkage formed in this
glycosylation again rested on the one-bond CH coupling constant
The tetrasaccharide 21, comprising two iterations of the
Bacillus thermoaerophilus glycan repeating unit was then
assembled by coupling of the disaccharide acceptor 19 with the
disaccharide donor 20 on activation with N-iodosuccinimide and
(20) Crich, D.; Cai, F.; Yang, F. Carbohydr. Res. 2008, 343, 1858–1862.
(21) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435–436.
(22) (a) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293–
297. (b) Tvaroska, I.; Taravel, F. R. AdV. Carbohydr. Chem. Biochem. 1995,
51, 15–61. (c) Duus, J. O.; Godfredsen, C. H.; Bock, K. Chem. ReV. 2000, 100,
4589–4614.
J. Org. Chem. Vol. 73, No. 18, 2008 7005

Crich and Li
SCHEME 6. Tetrasaccharide Synthesis
Phenyl 2-O-Benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-
1-thia-r-D-mannopyranoside (2) and Phenyl 2,6-Di-O-benzyl-
3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-1-thia-r-D-mannopyr-
anoside (3). To a cooled (-40 °C) solution of diol 18 (12.24 g,
31.67 mmol) in dry DMF (140 mL) was added benzyl bromide
(4.20 mL, 35.4 mmol) followed by 60% NaH in mineral oil (2.57
g, 64.3 mmol). The resultant mixture was stirred for 1 h at -40
°C, then for 16 h at -10 °C. The reaction mixture was poured into
water and extracted with CH2Cl2. The collected organic phase was
further washed with brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by silica gel chromatography
(AcOEt/hexane ) 1/4 to 1/3, then AcOEt/CH2Cl2 ) 1/3 to 1/2) to
afford the monobenzylated ether 2 (12.21 g, 25.6 mmol, 81%):
1
[R]24 ) +221.3 (c 1.2, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.43-7.41 (m, 4 H), 7.35-7.26 (m, 6 H), 5.48 (s, 1 H), 4.93 (d, 1
H, J ) 11.5 Hz), 4.68 (d, 1 H, J ) 11.5 Hz), 4.29 (t, 1 H, J ) 10.0
Hz), 4.25-4.22 (m, 1 H), 4.08 (dd, 1 H, J ) 2.5, 9.5 Hz), 3.99 (br
s, 1 H), 3.85-3.77 (m, 2 H), 3.33 (s, 3 H), 3.30 (s, 3 H), 1.90 (br
s, 1 H), 1.37 (s, 3 H), 1.34 (s, 3 H); 13C NMR (125 MHz, CDCl3)
δ 138.6, 134.2, 132.0, 129.3, 128.5, 128.2, 127.8, 100.3, 99.9, 87.8,
77.7, 73.4, 72.2, 69.6, 64.1, 61.7, 48.3, 48.1, 18.0; HRMS m/z calcd
for C25H32O7NaS, 499.1766 [M + Na+]; found C25H32O7NaS,
SCHEME 7. Hexasaccharide Synthesis
499.1761; and 38 (1.51 g, 3.90 mmol, 12%): [R]23 ) +172.2 (c
D
1
1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.51-7.46 (m, 4 H),
7.36-7.24 (m, 11 H), 5.59 (s, 1 H), 4.94 (d, 1 H, J ) 12.5 Hz),
4.74 (d, 1 H, J ) 12.0 Hz), 4.66 (d, 1 H, J ) 11.5 Hz), 4.55 (d, 1
H, J ) 11.5 Hz), 4.50-4.48 (m, 1 H), 4.36-4.32 (m, 1 H),
4.13-4.10 (m, 1 H), 4.03 (s, 1 H), 3.88-3.84 (m, 2 H), 3.58 (s, 3
H), 3.25 (s, 3 H), 1.40 (s, 3 H), 1.36 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 138.83, 138.81, 134.6, 132.0, 129.2, 128.5, 128.4, 128.0,
127.74, 127.71, 127.67, 127.5, 100.3, 99.9, 87.6, 77.9, 73.6, 73.0,
72.0, 69.8, 69.0, 64.2, 48.3, 48.2, 18.12, 18.09; HRMS m/z calcd
for C32H42NO7NaS, 584.2682 [M + NH4+]; found C32H42NO7NaS,
584.2674; calcd for C32H38O7NaS, 589.2236 [M + Na+]; found
C32H38O7NaS, 589.2238.
Phenyl 2-O-Benzyl-6,7-dideoxy-3,4-O-(2′,3′-dimethoxybutane-
2′,3′-diyl)-1-thia-r-D-mannohepto-6-enopyranoside (4) and Phen-
yl 2-O-Benzyl-6,7-dideoxy-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-
1-thia-r-D-mannohepto-(E)-7-methylthio-6-enopyranoside (5). To
a cooled (-75 °C) solution of oxalyl chloride (1.07 mL, 12.46
mmol) in dry CH2Cl2 (30 mL) was added a solution of DMSO
(1.80 mL, 25.34 mmol) in dry CH2Cl2 (3 mL). After stirring for
10 min at -75 °C, a solution of alcohol 2 (2.95 g, 6.19 mmol) in
CH2Cl2 (10 mL + 1 mL rinse) was added dropwise. The mixture
was stirred for 15 min at -75 °C, then for 45 min at -60 °C, and
then for 45 min at -45 °C. At this stage, Et3N (6.80 mL, 48.92
mmol) was added dropwise, after which stirring was continued for
45 min at -45 °C, before the reaction mixture was allowed to warm
to 0 °C over 2 h. The reaction mixture was diluted with CH2Cl2
and washed with saturated aqueous NaHCO3 and brine. The organic
layer was dried over MgSO4, filtered, and concentrated, and the
residue was dried for 12 h at -20 °C in vacuum before it was
taken up in THF (9 mL + 2 mL rinse) and added to a -40 °C
stirred solution of the Wittig reagent formed by addition of n-BuLi
in hexane (1.80 M, 7.5 mL, 13.50 mmol) at 0 °C to a suspension
of Ph3PCH3Br (5.00 g, 14.00 mmol) in THF (30 mL) and cooling
to -40 °C. The resulting mixture was stirred for 1.5 at -40 °C,
then warmed to 10 °C over 2.5 h before it was poured into water
and extracted with CH2Cl2. The collected organic phase was further
washed with brine, dried over anhydrous Na2SO4, and concentrated.
The residue was purified by silica gel chromatography (AcOEt/
at the anomeric center of the newly formed glycosidic bond
(167 Hz). Global deprotection was again achieved by hydro-
genolysis, affording the target hexasaccharide in 60% yield
(Scheme 7).
The spectral data for the central residues in hexasaccharide
25 were compared to those reported for the natural isolate and
were found to show a very high degree of concordance
(Supporting Information), thereby confirming the structure
proposed by Kosma and co-workers.
Conclusion
A block synthesis of the target hexasaccharide has been
achieved and confirms the very rare ꢀ-D-glycero-D-mannohep-
topyranoside linkage at the heart of this glycan.
hexane ) 1/15) to furnish alkene 4 (2.45 g, 5.17 mmol, 84%): [R]24
D
) +251.7 (c 1.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.45-7.41
(m, 4 H), 7.35-7.25 (m, 6 H), 6.02-5.95 (m, 1 H), 5.52 (s, 1 H),
5.45-5.42 (m, 1 H), 5.27-5.24 (m, 1 H), 4.91 (d, 1 H, J ) 12.0
Hz), 4.71 (d, 1 H, J ) 12.0 Hz), 4.63 (t, 1 H, J ) 7.5 Hz),
4.09-4.03 (m, 2 H), 3.99 (m, 1 H), 3.33 (s, 3 H), 3.26 (s, 3 H),
1.38 (s, 3 H), 1.34 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 138.7,
134.8, 134.0, 131.6, 129.2, 128.5, 128.2, 127.8, 127.6, 118.1, 100.2,
Experimental Section
General Experimental. Peak assignments in the NMR spectra
were made in the usual manner with the assistance of phase-
sensitive COSY-45 and phase-sensitive NOESY experiments.
7006 J. Org. Chem. Vol. 73, No. 18, 2008

Block Synthesis
100.0, 87.6, 77.8, 73.2, 72.3, 69.8, 67.8, 48.2, 48.1, 18.1, 18.0;
OH), 1.37 (s, 3 H), 1.33 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ
138.1, 136.9, 134.7, 129.6, 128.9, 128.6, 128.5, 128.1, 100.1, 100.0,
93.2, 76.8, 74.7, 71.9, 69.2, 68.9, 64.6, 62.0, 48.4, 48.3, 17.9; HR-
ESI m/z calcd for C26H34O10NaS, 561.1770 [M + Na+]; found
C26H34O10NaS, 561.1746.
HR-ESI m/z calcd for C26H32O6NaS, 495.1817 [M + Na+]; found
C26H32O6NaS, 495.1826; and alkene 5 (58.1 mg, 112 µmol, 1.8%):
1
[R]23 ) +218.3 (c 0.97, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.43-7.38 (m, 4 H), 7.34-7.24 (m, 6 H), 6.45 (dd, 1 H, J ) 1.0,
15.0 Hz), 5.47 (s, 1 H), 5.45 (dd, 1 H, J ) 6.5, 15.5 Hz), 4.89 (d,
1 H, J ) 12.5 Hz), 4.70 (d, 1 H, J ) 12.0 Hz), 4.65 (t, 1 H, J )
7.5 Hz), 4.05-4.00 (m, 2 H), 3.96 (m, 1 H), 3.32 (s, 3 H), 3.25 (s,
3 H), 2.24 (s, 3 H), 1.36 (s, 3 H), 1.33 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 138.6, 134.8, 131.6, 129.8, 129.3, 128.5, 128.2,
127.8, 127.6, 120.4, 100.2, 100.0, 87.7, 77.8, 73.3, 72.4, 69.7, 68.0,
48.2, 48.0, 18.1, 18.0, 14.6; HR-ESI m/z calcd for C27H34O6NaS2,
541.1695 [M + Na+]; found C27H34O6NaS2, 541.1675.
Method 2: To a mixture of alkene 4 (1.52 g, 3.2 mmol) in 1/1
t-BuOH/H2O (32 mL) were added toluene (2.5 mL), K2CO3 (1.31
g, 9.7 mmol), and K3Fe(CN)6 (3.29 g, 10.0 mmol). After stirring
for 10 min, the mixture was cooled to 0 °C followed by addition
of (DHQ)2Pyr (29.1 mg, 0.033 mmol) and a solution of OsO4 in
t-BuOH (2.5 wt %, 161 µL). After the mixture was stirred for 24 h,
additional t-BuOH/H2O (8 mL, 1/1), K2CO3 (344 mg, 2.5 mmol),
and K3Fe(CN)6 (832 mg, 2.5 mmol) were added. Stirring was
continued for another 24 h before the reaction mixture was diluted
with CH2Cl2, washed with saturated aqueous NaSO3, and brine.
The organic phase was dried over Na2SO4, filtered, and concen-
trated. The residue was subjected to silica gel chromatography
(AcOEt/CH2Cl2 ) 1/4) to give 6 (1.12 g, 2.2 mmol, 68%) and 8
(455 mg, 0.9 mmol, 28%).
Phenyl 2,7-Di-O-benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-
diyl)-D-glycero-1-thia-r-D-mannoheptopyranoside (10). To a
solution of diol 6 (1.69 g, 3.33 mmol) in anhydrous toluene (80
mL) was added Bu2SnO (957 mg, 3.84 mmol) after which the
reaction mixture was heated to reflux in a Dean-Stark apparatus.
After 2 h, the resulting clear solution was cooled to room
temperature and concentrated under reduced pressure. The residue
was dissolved in DMF (30 mL) under N2, and benzyl bromide (0.48
mL, 4.04 mmol) and CsF (1.07 g, 7.06 mmol) were added. The
resulting mixture was stirred for 16 h at room temperature under
N2, diluted with CH2Cl2, and washed with aqueous KF and brine.
The organic phase was collected, dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel chromatography
Phenyl 2-O-Benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-
D-glycero-1-thia-r-D-mannoheptopyranoside (6), Phenyl 2-O-
Benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-D-glycero-1-sul-
fonyl-r-D-mannoheptopyranoside (7), Phenyl 2-O-Benzyl-3,4-
O-(2′,3′-dimethoxybutane-2′,3′-diyl)-L-glycero-1-thia-r-D-
mannoheptopyranoside (8), and Phenyl 2-O-Benzyl-3,4-O-(2′,3′-
dimethoxybutane-2′,3′-diyl)-L-glycero-1-sulfonyl-r-D-
mannoheptopyranoside (9). Method 1: To a solution of alkene 4
(345 mg, 730 µmol) in 8/1 acetone/H2O (9 mL), chilled in an
ice-water bath, were added NMO (139 mg, 1.2 mmol) and OsO4
(13.0 mg, 5 µmol). After stirring for 7 h, the reaction was quenched
with a solution of sodium sulfite and extracted with AcOEt. The
collected organic phase was further washed with brine, dried over
Na2SO4, and concentrated. The residue was subjected to silica gel
chromatography (AcOEt/CH2Cl2 ) 1/4, then AcOEt/hexane ) 1/1
and AcOEt/CH2Cl2 ) 2/5) to afford 6 (219.3 mg, 433 µmol, 59%):
1
[R]24 ) +240.3 (c 0.94, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.43-7.40 (m, 4 H), 7.35-7.26 (m, 6 H), 5.43 (s, 1 H), 4.91 (d, 1
H, J ) 12.0 Hz), 4.67 (d, 1 H, J ) 12.0 Hz), 4.37 (t, 1 H, J ) 10.0
Hz), 4.26 (dd, 1 H, J ) 6.0, 10.0 Hz), 4.07 (dd, 1 H, J ) 3.0, 10.0
Hz), 3.96-3.93 (m, 2 H), 3.70-3.63 (m, 2 H), 3.33 (s, 3 H), 3.31
(s, 3 H), 3.16 (d, 1 H, OH, J ) 3.0 Hz), 2.20 (t, 1 H, OH, J ) 6.5
Hz), 1.36 (s, 3 H), 1.33 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ
138.5, 133.7, 132.2, 129.4, 128.5, 128.2, 128.1, 127.9, 100.3, 100.2,
87.8, 77.5, 73.5, 73.4, 71.2, 69.4, 67.1, 63.2, 48.6, 48.3, 18.1, 18.0;
HR-ESI m/z calcd for C26H34O8NaS, 529.1872 [M + Na+]; found
(AcOEt/hexane ) 1/6) to yield ether 10 (1.90 g, 3.19 mmol, 96%):
1
[R]24 ) +186.5 (c 1.2, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.41-7.36 (m, 4 H), 7.34-7.23 (m, 11 H), 5.47 (s, 1 H), 4.89 (d,
1 H, J ) 12.5 Hz), 4.67 (d, 1 H, J ) 12.0 Hz), 4.53 (d, 1 H, J )
12.0 Hz), 4.48 (d, 1 H, J ) 12.5 Hz), 4.36 (t, 1 H, J ) 10.0 Hz),
4.20 (dd, 1 H, J ) 5.0, 10.0 Hz), 4.13-4.10 (m, 1 H), 4.03 (dd, 1
H, J ) 3.0, 10.5 Hz), 3.93-3.92 (m, 1 H), 3.57 (d, 2 H, J ) 5.0
Hz), 3.30 (s, 3 H), 3.23 (s, 3 H), 2.84 (d, 1 H, OH, J ) 2.5 Hz),
1.33 (s, 3 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 138.6,
138.5, 134.3, 131.6, 129.3, 128.6, 128.2, 128.1, 127.9, 127.8, 127.7,
100.3, 100.0, 87.5, 77.5, 73.6, 73.3, 72.8, 71.0, 69.6, 65.9, 48.5,
48.3, 18.1, 18.0; HR-ESI m/z calcd for C33H40O8NaS, 619.2342
[M + Na+]; found C33H40O8NaS, 619.2323.
C26H34O8NaS, 529.1859; 7 (18.3 mg, 34 µmol, 4.6%): [R]23
)
D
+148.7 (c 0.78, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.93 (d, 2
H, J ) 7.5 Hz), 7.69 (t, 1 H, J ) 7.5 Hz), 7.58 (t, 2 H, J ) 7.5
Hz), 7.44 (d, 2 H, J ) 7.0 Hz), 7.37-7.31 (m, 3 H), 5.00 (d, 1 H,
J ) 11.5 Hz), 4.72 (s, 1 H), 4.67 (d, 1 H, J ) 11.0 Hz), 4.61 (d,
1 H, J ) 3.0 Hz), 4.52-4.49 (m, 2 H), 4.35 (t, 1 H, J ) 9.0 Hz),
3.79-3.75 (m, 1 H), 3.57-3.52 (m, 2 H), 3.35 (s, 3 H), 3.33 (s, 3
H), 3.27 (br s, 1 H, OH), 2.23 (br s, 1 H, OH), 1.37 (s, 3 H), 1.35
(s, 3 H); 13C NMR (125 MHz, CDCl3) δ 138.1, 136.7, 134.6, 129.5,
129.3, 128.6, 128.4, 128.1, 100.3, 100.1, 93.0, 74.7, 74.1, 73.9,
71.9, 69.1, 66.1, 62.4, 48.6, 48.4, 18.0, 17.9; HR-ESI m/z calcd for
C26H34O10NaS, 561.1770 [M + Na+]; found C26H34O10NaS,
561.1748; 8 (101.0 mg, 199 µmol, 27%): [R]24D ) +232.2 (c 1.1,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.43 (d, 2 H, J ) 7.5 Hz),
7.38-7.28 (m, 8 H), 5.52 (s, 1 H), 4.95 (d, 1 H, J ) 12.0 Hz),
4.67 (d, 1 H, J ) 11.5 Hz), 4.42 (t, 1 H, J ) 10.0 Hz), 4.14 (dd,
1 H, J ) 2.0, 10.0 Hz), 4.08 (dd, 1 H, J ) 3.0, 10.0 Hz), 3.97-3.95
(m, 1 H), 3.94-3.90 (m, 1 H), 3.50 (br s, 2 H), 3.33 (s, 3 H), 3.32
(s, 3 H), 2.66 (d, 1 H, OH, J ) 6.0 Hz), 1.85 (br s, 1 H, OH), 1.36
(s, 3 H), 1.33 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 138.5, 133.3,
132.1, 129.5, 128.6, 128.2, 127.9, 100.3, 100.0, 87.6, 77.3, 73.5,
72.9, 69.7, 68.8, 65.1, 63.4, 48.3, 18.1, 18.0; HR-ESI m/z calcd for
C26H34O8NaS, 529.1872 [M + Na+]; found C26H34O10NaS, 529.1874;
9 (15.1 mg, 28 µmol, 3.8%): [R]23D ) +135.8 (c 0.67, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.85 (d, 2 H, J ) 8.0 Hz), 7.70 (t, 1 H,
J ) 7.5 Hz), 7.59 (t, 2 H, J ) 8.0 Hz), 7.44 (d, 2 H, J ) 7.0 Hz),
7.37-7.30 (m, 3 H), 5.03 (d, 1 H, J ) 11.0 Hz), 4.81 (s, 1 H),
4.67 (d, 1 H, J ) 11.0 Hz), 4.60 (d, 1 H, J) 3.0 Hz), 4.49-4.45
(m, 1 H), 4.41-4.37(m, 2 H), 3.89 (m, 1 H), 3.51-3.44 (m, 2 H),
3.35 (s, 3 H), 3.32 (s, 3 H), 2.10 (br s, 1 H, OH), 1.72 (br s, 1 H,
Phenyl 2,7-Di-O-benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-
diyl)-L-glycero-1-thia-r-D-mannoheptopyranoside (11). Follow-
ing the protocol for 10, diol 8 (1.16 g, 2.29 mmol) gave rise to
ether 11 (1.24 g, 2.08 mmol, 91%): [R]24 ) +198.7 (c 0.97,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.43 (d, 2 H, J ) 7.5 Hz),
7.36-7.22 (m, 13 H), 5.56 (s, 1 H), 4.92 (d, 1 H, J ) 12.0 Hz),
4.69 (d, 1 H, J ) 11.5 Hz), 4.48-4.40 (m, 3 H), 4.15-4.13 (m, 2
H), 4.06 (dd, 1 H, J ) 2.5, 10.0 Hz), 3.95 (br s, 1 H), 3.38 (t, 1 H,
J ) 10.5 Hz), 3.31-3.29 (m, 7 H), 2.15 (br s, 1 H, OH), 1.36 (s,
3 H), 1.31 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 138.6, 138.3,
134.1, 131.5, 129.2, 128.6, 128.5, 128.2, 127.9, 127.8, 127.6, 100.3,
99.9, 87.3, 77.3, 73.5, 73.3, 71.8, 71.3, 69.9, 67.6, 63.1, 48.2, 18.0;
HR-ESI m/z calcd for C33H40O8NaS, 619.2342 [M + Na+]; found
C33H40O8NaS, 619.2333.
Formation of Phenyl 2,7-Di-O-benzyl-3,4-O-(2′,3′-dimethoxy-
butane-2′,3′-diyl)-D-glycero-1-thia-r-D-mannoheptopyrano-
side (10) by Stereochemical Inversion of 11. Method 1: To a
solution of alcohol 11 (267.9 mg, 450 µmol), 4-nitrobenzoic acid
(155 mg, 924 µmol), and triphenylphosphine (238 mg, 910 µmol),
cooled at 0 °C, in THF (125 mL) was added diisopropyl azodi-
carboxylate (177 µL, 899 µmol). The reaction mixture was allowed
to reach ambient temperature and was stirred for 12 h before it
was diluted with CH2Cl2 and washed with saturated aqueous
NaHCO3 and brine. The residue was subjected to silica gel
J. Org. Chem. Vol. 73, No. 18, 2008 7007

Crich and Li
chromatography to give ester (73.1 mg, 98 µmol, 22%), which was
treated with K2CO3 (45.8 mg, 331 µmol) in 2/1 MeOH/THF (3
mL). The resulting mixture was stirred for 16 h at ambient
temperature under N2, then concentrated under reduced pressure.
The solid was diluted with CH2Cl2 and washed with saturated
aqueous NaHCO3 and brine. The organic phase was dried over
Na2SO4, filtered, concentrated, and purified by silica gel chroma-
tography (AcOEt/hexane ) 1/5) to afford 10 (55.4 mg, 93 µmol,
95%).
Hz), 4.76 (d, 1 H, J ) 12.5 Hz), 4.57 (d, 1 H, J ) 12.5 Hz), 4.51
(d, 1 H, J ) 13.0 Hz), 4.42 (t, 1 H, J ) 8.5 Hz), 4.19-4.12 (m, 2
H), 4.09-4.04 (m, 2 H), 3.63 (d, 1 H, J ) 11.0 Hz), 3.57 (dd, 1 H,
J ) 5.5, 12.0 Hz); 13C NMR (125 MHz, CDCl3) δ 138.6, 137.9,
136.1, 133.8, 133.6, 133.2, 131.8, 129.3, 129.1, 128.7, 128.5, 128.4,
128.2, 127.9, 127.8, 127.7, 126.6, 126.3, 126.1, 125.9, 101.4, 86.8,
78.8, 78.4, 77.9, 76.7, 73.7, 73.4, 73.3, 69.5, 66.4; HR-ESI m/z:
calcd for C45H42O6NaS, 733.2600 [M+Na+]; Found C45H42O6NaS,
733.2561.
Method 2: To a chilled (-40 °C) solution of alcohol 11 (478.7
mg, 802 µmol) in CH2Cl2 (12 mL) were added anhydrous pyridine
(163 µL, 2.0 mmol) and Tf2O (240 µL, 1.45 mmol, 1.8 equiv) after
which the reaction mixture was stirred for 10 min at -40 °C, then
warmed to -5 °C over 80 min, then was poured into cold 0.2 N
HCl and extracted with CH2Cl2. The collected organic phase was
further washed with cold aqueous NaHCO3 and brine. The organic
phase was dried over Na2SO4, filtered, and concentrated. The
resulting residue was dissolved in dry DMF (10 mL), and 18-C-6
(57 mg, 0.22 mmol) and KNO2 (460 mg, 5.4 mmol) were added.
After stirring for 13 h, more 18-C-6 (256.3 mg, 0.97 mmol) and
KNO2 (324 mg, 3.8 mmol) were added. Stirring was continued for
71 h before the reaction mixture was poured into 1 N aqueous
K2CO3 and stirred for 2 h and extracted with CH2Cl2. The organic
phase was washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel chromatography (AcOEt/
hexane ) 1/5) to afford alcohol 10 (331 mg, 556 µmol, 69%).
Phenyl 2,7-Di-O-benzyl-4,6-O-benzylindene-D-glycero-1-thia-
r-D-mannoheptopyranoside (12). To a solution of 1,2-diacetal 10
(2.21 g, 3.7 mmol) in CH2Cl2 (30 mL) was added a 10/1 mixture
of TFA/H2O (15 mL). The resulting mixture was stirred for 40
min at ambient temperature under N2 before the volatiles were
removed under reduced pressure and residue was purified by silica
gel chromatography (AcOEt/CH2Cl2 ) 1/1 to 3/2) to give triol (1.60
g, 3.3 mmol, 89%), which was dissolved in dry CH2Cl2 (36 mL)
and treated with camphorsulfonic acid (52.2 mg, 0.23 mmol) and
benzaldehyde dimethyl acetal (2.4 mL, 16 mmol). After stirring
for 14 h at room temperature under N2, the mixture was diluted
with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine.
The organic phase was dried over Na2SO4, filtered, and concen-
trated. The residue was subjected to flash chromatography on silica
Methyl 2,3-O-Diphenylmethylene-r-L-rhamnopyranoside (16).
Triol 1423 (1.43 g, 8.0 mmol), benzophenone dimethyl acetal24 (3.65
g, 16.0 mmol), and camphorsulfonic acid (308.4 mg, 1.39 mmol)
were dissolved in dry DMF (20 mL). The mixture was stirred in a
50 °C water bath in a rotary evaporator for 8 h under the reduced
pressure (27 mmHg) to remove methanol formed during the
reaction, then was poured into a saturated solution of NaHCO3 in
H2O, and extracted with AcOEt. The organic phase was washed
with brine, dried over Na2SO4, and concentrated. The residue was
purified by flash chromatography on silica gel (AcOEt/hexane )
1/5to1/4) to afford 1619a (1.29 g, 3.8 mmol, 47%): [R]24D ) -71.6
1
(c 0.65, CHCl3); H NMR (500 MHz, CDCl3) δ 7.53-7.51 (m, 4
H), 7.34-7.27 (m, 6 H), 5.02 (s, 1 H), 4.28 (t, 1 H, J ) 6.5 Hz),
4.06 (d, 1 H, J ) 5.5 Hz), 3.71-3.66 (m, 1 H), 3.42-3.39 (m, 1
H), 3.38 (s, 3 H), 2.28 (br s, 1 H, OH), 1.27 (d, 3 H, J ) 6.0 Hz);
13C NMR (125 MHz, CDCl3) δ 143.1, 142.7, 128.4, 128.3, 126.3,
126.2, 109.8, 98.3, 79.1, 76.1, 74.1, 66.2, 55.2, 17.3; HR-ESI m/z
calcd for C20H22O5Na, 365.1365 [M + Na+]; found C20H22O5Na,
365.1353.
Phenyl 2,3-O-Diphenylmethylene-1-thia-r-L-rhamnopyrano-
side (17). Following the protocol for 16, treatment of thioglycoside
1525 (1.60 g, 6.2 mmol) with benzophenone dimethyl acetal24 (2.84
g, 12.5 mmol) and camphorsulfonic acid (81 mg, 0.35 mmol)
furnished alcohol 1719a (1.03 g, 2.4 mmol, 39%): [R]24D ) -191.0
1
(c 1.2, CHCl3); H NMR (500 MHz, CDCl3) δ 7.54-7.47 (m, 6
H), 7.46-7.25 (m, 9 H), 5.91 (s, 1 H), 4.34 (dd, 1 H, J ) 5.5, 7.0
Hz), 4.29 (d, 1 H, J ) 6.0 Hz), 4.14-4.09 (m, 1 H), 3.45-3.40
(m, 1 H), 2.14 (br s, 1 H), 1.19 (d, 3 H, J ) 6.5 Hz); 13C NMR
(125 MHz, CDCl3) δ 143.2, 142.9, 133.6, 132.3, 129.3, 128.5,
128.4, 127.9, 126.2, 126.0, 109.8, 83.8, 79.3, 77.1, 74.9, 67.2, 17.3;
HR-ESI m/z calcd for C25H24O4NaS, 443.1293 [M + Na+]; found
C25H24O4NaS, 443.1277.
gel to afford benzylidene 12 (1.64 g, 2.9 mmol, 87%): [R]23
)
D
+144.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.54-7.53
(m, 2 H), 7.41-7.24 (m, 18 H), 5.68 (s, 1 H), 5.62 (s, 1 H), 4.77
(d, 1 H, J ) 11.5 Hz), 4.66 (d, 1 H, J ) 11.5 Hz), 4.53 (d, 1 H, J
) 12.5 Hz), 4.48 (d, 1 H, J ) 12.0 Hz), 4.14-4.01 (m, 5 H),
3.58-3.51 (m, 2 H), 2.44 (d, 1 H, OH, J ) 7.5 Hz); 13C NMR
(125 MHz, CDCl3) δ 138.4, 137.5, 137.4, 133.7, 131.9, 129.3,
128.9, 128.5, 128.4, 128.3, 127.8, 127.7, 126.7, 101.9, 86.0, 79.9,
78.8, 78.7, 73.7, 73.5, 69.4, 65.7; HRMS m/z calcd for
C34H34O6NaS, 593.1974 [M + Na+]; found C34H34O6NaS, 593.1962.
Phenyl 2,7-Di-O-benzyl-4,6-O-benzylindene-3-O-(2-naphtha-
lenylmethyl)-D-glycero-1-thia-r-D-mannoheptopyranoside (13).
To a solution of alcohol 12 (1.60 g, 2.8 mmol) in dry DMF (24
mL), cooled in an ice-water bath, was added 60% NaH in mineral
oil (230 mg, 5.8 mmol). After stirring for 20 min, tetrabutylam-
monium iodide (106 mg, 0.29 mmol) and 2-(bromomethyl)naph-
thalylene (843 mg, 3.7 mmol) were added, and the resulting mixture
was stirred for 12.5 h in the dark at room temperature under N2.
At this point, MeOH (2.0 mL) was added, followed by neutralization
with acidic resin to pH 6.0. The solid was filtered off, and the filtrate
was concentrated under vacuum. The residue was dissolved in
CH2Cl2 and washed with aqueous NaHCO3 and brine. The organic
phase was dried over Na2SO4, filtered, and concentrated. The residue
was purified by silica gel chromatography (AcOEt/hexane ) 1/8
to 1/6) to yield ether 133 (1.94 g, 2.7 mmol, 91%): [R]24D ) +110.0
Methyl 2,7-Di-O-benzyl-4,6-O-benzylindene-3-O-(2-naphtha-
lenylmethyl)-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-2,3-O-
(diphenylmethylene)-r-L-rhamnopyranoside (18). A flask, charged
with thioheptoside 13 (206.4 mg, 290 µmol), TTBP (240.1 mg,
967 µmol), silver triflate (232 mg, 903 µmol), and 4 Å molecular
sieves (500 mg), was dried under vacuum for 1 h with the exclusion
of light. Then dry CH2Cl2 (7 mL) was added, and the resulting
mixture was stirred for 0.5 h at -78 °C before 4-nitrobenzene-
sulfenyl chloride (112.0 mg, 591 µmol) was added in one portion
as a solid. After stirring for 10 min at -78 °C, the mixture was
warmed to -45 °C, and stirring continued for 15 min before the
reaction mixture was recooled to -78 °C. A solution of methyl
rhamnoside 16 (130 mg, 380 µmol) in CH2Cl2 (1 mL + 0.5 mL
rinse) then was added dropwise. The reaction mixture was stirred
for 30 min at -78 °C, then warmed to -45 °C, and stirring
continued for 3 h. Saturated aqueous NaHCO3 was added, and after
filtration of the solid, the filtrate was further washed with aqueous
NaHCO3 and brine. The organic phase was dried over Na2SO4 and
concentrated. The residue was purified by flash chromatography
on silica gel (AcOEt/PhCH3 ) 1/40 to 1/30) to afford disaccharide
18 (221.1 mg, 234 µmol, 81%) as a white foam: [R]24 ) -59.5
D
(23) Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. Bull.
Chem. Soc. Jpn. 1985, 58, 1699–1706.
(24) Irurre, J.; Alonso-Alija, C. Tetrahedron: Asymmetry 1992, 3, 1591–
1596.
(25) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl,
W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C.
J. Am. Chem. Soc. 1993, 17, 7593–7611.
1
(c 0.80, CHCl3); H NMR (500 MHz, CDCl3) δ 7.87-7.82 (m, 3
H), 7.76-7.74 (m, 1 H), 7.62-7.60 (m, 2 H), 7.49-7.46 (m, 3 H),
7.44-7.22 (m, 18 H), 5.80 (s, 1 H), 5.60 (s, 1 H), 4.98 (d, 1 H, J
) 12.0 Hz), 4.84 (d, 1 H, J ) 12.5 Hz), 4.80 (d, 1 H, J ) 12.5
7008 J. Org. Chem. Vol. 73, No. 18, 2008

Block Synthesis
1
(c 0.63, CHCl3); H NMR (500 MHz, CDCl3) δ 7.80-7.78 (m, 3
H), 7.68-7.56 (m, 1 H), 7.52-7.27 (m, 25 H), 7.07-7.05 (m, 3
H), 5.71 (s, 1 H), 5.02 (s, 1 H), 4.97 (d, 1 H, J ) 12.5 Hz), 4.88
(d, 1 H, J ) 12.0 Hz), 4.85 (d, 1 H, J ) 13.0 Hz), 4.78 (d, 1 H, J
) 13.0 Hz), 4.54 (d, 1 H, J ) 12.5 Hz), 4.50 (d, 1 H, J ) 12.0
Hz), 4.38 (s, 1 H), 4.23 (dd, 1 H, J ) 6.0, 7.5 Hz), 4.18 (t, 1 H, J
) 9.5 Hz), 4.10 (t, 1 H, J ) 8.0 Hz), 4.03-4.02 (m, 2 H),
3.65-3.60 (m, 1 H), 3.53-3.50 (m, 2 H), 3.39 (s, 3 H), 3.34 (dd,
1 H, J ) 7.5, 11.5 Hz), 3.27 (dd, 1 H, J ) 7.5, 10.0 Hz), 2.63 (t,
1 H, J ) 9.5 Hz), 1.19 (d, 3 H, J ) 6.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 143.2, 143.1, 138.8, 138.5, 137.9, 133.5, 133.2, 129.0,
128.9, 128.7, 128.6, 128.4, 128.1, 127.9, 127.8, 126.6, 126.4, 126.3,
126.2, 126.1, 125.8, 109.4, 102.3 (JC1-H1 ) 159.7 Hz), 101.2, 98.0
(JC1-H1 ) 174.6 Hz), 80.8, 79.1, 78.9, 78.0, 77.8, 76.5, 76.2, 75.0,
73.6, 72.5, 69.5, 68.7, 64.6, 55.2, 17.8; HR-ESI m/z calcd for
C59H58O11Na, 965.3877 [M + Na+]; found C59H58O11Na, 965.3904.
Methyl 2,7-Di-O-benzyl-4,6-O-benzylindene-D-glycero-ꢀ-D-
mannoheptopyranosyl-(1f4)-2,3-O-(diphenylmethylene)-r-L-
rhamnopyranoside (19). To a heterogenerous mixture of 18 (252.2
mg, 267 µmol) in 9/1 CH2Cl2/H2O (6.6 mL) was added DDQ (96.0
mg, 423 µmol). The reaction mixture was stirred for 3 h at ambient
temperature under N2, diluted with CH2Cl2, and washed with
aqueous NaHCO3 and brine. The organic phase was dried over
Na2SO4 and concentrated. The residue was purified by flash
chromatography on silica gel (AcOEt/hexane ) 1/4 to 1/3) to
128.07, 127.96, 127.90, 127.86, 126.6, 126.5, 126.4, 126.1, 125.8,
125.6, 109.4, 102.3 (JC1-H1 ) 159.0 Hz), 101.2, 83.9 (JC1-H1
167.2 Hz), 81.2, 78.9, 78.8, 78.0, 77.9, 77.0, 76.1, 75.0, 73.6, 72.6,
69.5, 68.6, 66.3, 17.6; HR-ESI m/z calcd for C64H60O10NaS,
1043.3805 [M + Na+]; found C64H60O10NaS, 1043.3755.
)
Method 2: A mixture of thioheptoside 13 (535.6 mg, 753 µmol),
TTBP (298.1 mg, 1.2 mmol), and BSP (168.5 mg, 805 µmol) in
CH2Cl2 (15 mL) in the presence of 4 Å molecular sieves (500 mg)
was stirred for 0.5 h at ambient temperature. Then the mixture was
cooled to -60 °C, and Tf2O (156 µL, 940 µmol) was added
dropwise. After stirring for 6 min at -78 °C, 1-octene (2.0 mL,
12.7 mmol) was added, and stirring continued for 5 min. The
reaction mixture was cooled to -78 °C followed by the addition
of a solution of thiorhamnoside 17 (480.0 mg, 1.1 mmol) in CH2Cl2
(3 mL + 0.5 mL rinse). The resulting mixture was stirred for 1 h
at -78 °C before saturated aqueous NaHCO3 was added to quench
the reaction, and the solid was filtered off. The filtrate was washed
with saturated aqueous NaHCO3 and brine. The organic phase was
dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel chromatography (AcOEt/PhCH3 ) 1/50) to
afford disaccharide 20 (561.0 mg, 549 µmol, 73%).
Methyl 2,7-Di-O-benzyl-4,6-O-benzylindene-3-O-(2-naphtha-
lenylmethyl)-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-2,3-O-
(diphenylmethylene)-r-L-rhamnopyranosyl-(1f3)-2,7-di-O-benzyl-
4,6-O-benzylindene-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-
2,3-O-(diphenylmethylene)-r-L-rhamnopyranoside (21). A mixture
of alcohol 19 (90.0 mg, 112 µmol) and thioheptoside 20 (135.3
mg, 132 µmol) in CH2Cl2 (6 mL) in the presence of 4 Å molecular
sieves (320 mg) was stirred for 50 min at ambient temperature under
N2 atmosphere. Then the mixture was cooled to -15 °C, and NIS
(38.4 mg, 170 µmol) and AgOTf (16.9 mg, 66 µmol) were
subsequently added. The reaction mixture was stirred for 2.5 h,
while the reaction temperature was increased to 5 °C. The solids
were filtered off, and the filtrate was washed with saturated aqueous
Na2S2O3 containing NaHCO3 and brine. The organic phase was
dried over Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (AcOEt/PhCH3 )
furnish alcohol 19 (185.2 mg, 231 µmol, 86%) as a white foam:
[R]24 ) -88.1 (c 0.1.1, CHCl3); H NMR (500 MHz, CDCl3) δ
1
D
7.52-7.48 (m, 6 H), 7.41-7.22 (m, 18 H), 7.15 (t, 1 H, J ) 7.5
Hz), 5.60 (s, 1 H), 5.05 (s, 1 H), 5.02 (d, 1 H, J ) 11.5 Hz), 4.68
(d, 1 H, J ) 12.0 Hz), 4.58 (s, 1 H), 4.55 (d, 1 H, J ) 12.5 Hz),
4.52 (d, 1 H, J ) 12.5 Hz), 4.35 (dd, 1 H, J ) 6.0, 7.5 Hz),
4.06-3.99 (m, 3 H), 3.77 (t, 1 H, J ) 9.5 Hz), 3.68-3.62 (m, 2
H), 3.49 (dd, 1 H, J ) 1.5, 11.5 Hz), 3.39 (s, 3 H), 3.72-3.32 (m,
2 H), 2.60 (t, 1 H, J ) 9.0 Hz), 2.37 (br s, 1 H, OH), 1.21 (d, 3 H,
J ) 6.0 Hz); 13C NMR (125 MHz, CDCl3) δ 143.2, 138.5, 138.4,
137.5, 129.2, 128.7, 128.6, 128.5, 128.4, 128.2, 127.9, 126.6, 126.2,
126.1, 125.9, 109.5, 102.1, 101.6, 98.0, 80.6, 79.2, 79.0, 78.6, 78.5,
76.5, 75.8, 73.6, 71.1, 69.5, 68.3, 64.5, 55.2, 17.9; HR-ESI m/z
calcd for C48H50O11Na, 825.3251 [M + Na+]; found C48H50O11Na,
825.3207.
1/20 to 1/15) to afford tetrasaccharide 21 (164.2 mg, 96 µmol, 85%):
1
[R]23 ) -86.6 (c 1.2, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.80-7.76 (m, 3 H), 7.68-7.66 (m, 1 H), 7.57-7.19 (m, 46 H),
7.15-7.01 (m, 7 H), 5.70 (s, 1 H), 5.60 (s, 1 H), 5.07 (s, 1 H),
5.01 (s, 1 H), 4.85 (d, 1 H, J ) 12.0 Hz), 4.83 (d, 1 H, J ) 12.0
Hz), 4.77-4.64 (m, 4 H), 4.56-4.48 (m, 5 H), 4.34 (dd, 1 H, J )
5.5, 7.0 Hz), 4.30 (t, 2 H, J ) 6.5 Hz), 4.14 (t, 1 H, J ) 9.5 Hz),
4.11-4.04 (m, 3 H), 4.02-3.92 (m, 4 H), 3.91-3.86 (m, 1 H),
3.83 (dd, 1 H, J ) 6.0, 9.5 Hz), 3.70-3.66 (m, 1 H), 3.52 (d, 1 H,
J ) 9.5 Hz), 3.47 (d, 1 H, J ) 10.0 Hz), 3.43-3.41 (m, 4 H),
3.37-3.33 (m, 2 H), 3.28 (dd, 1 H, J ) 7.5, 11.0 Hz), 3.23 (dd, 1
H, J ) 7.5, 10.0 Hz), 2.67 (t, 1 H, J ) 9.5 Hz), 2.46 (t, 1 H, J )
2,7-Di-O-benzyl-4,6-O-benzylindene-3-O-(2-naphthalenylm-
ethyl)-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-2,3-O-diphe-
nylmethylene-1-thia-r-L-rhamnopyranoside (20). Method 1: A
mixture of thioheptoside 13 (90.1 mg, 127 µmol), TTBP (70.9 mg,
285 µmol), and AgOTf (81.6 mg, 318 µmol) in CH2Cl2 (3 mL) in
the presence of 4 Å molecular sieves (290 mg) was stirred for 0.5 h
at -78 °C before 4-nitrobenzenesulfenyl chloride (29.6 mg, 156
µmol) was added as a solid. After stirring for 10 min, the reaction
mixture was warmed to -45 °C and stirred for 10 min before it
was recooled to -78 °C followed by the addition of a solution of
thiorhamnoside 17 (64.8 mg, 154 µmol) in CH2Cl2 (1 mL + 0.5
mL rinse). The resulting mixture was stirred for 4 h at -78 °C,
and then saturated aqueous NaHCO3 was added to quench the
reaction, and the solid was filtered off. The filtrate was washed
with saturated aqueous NaHCO3 and brine. The organic phase was
dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel chromatography (AcOEt/PhCH3 ) 1/40) to
afford disaccharide 20 (70.1 mg, 69 µmol, 54%): [R]23D ) -115.5
9.5 Hz), 1.23 (d, 1 H, J ) 6.5 Hz), 1.03 (d, 1 H, J ) 6.5 Hz); 13
C
NMR (100 MHz, CDCl3) δ 143.19, 143.15, 143.11, 143.04, 143.07,
138.5, 138.4, 138.1, 138.0, 137.6, 136.1, 133.5, 133.1, 129.2, 129.0,
128.66, 128.63, 128.6, 128.5, 128.45, 128.41, 128.39, 128.35, 128.2,
128.12, 128.09, 127.98, 127.90, 127.8, 126.6, 126.44, 126.38, 126.3,
126.0, 125.9, 125.82, 125.77, 109.6, 109.3, 102.5 (JC1-H1 ) 161.8
Hz), 102.4 (JC1-H1 ) 160.5 Hz), 101.6, 101.1, 98.1 (JC1-H1 ) 172.3
Hz), 93.9 (JC1-H1 ) 168.7 Hz) 81.0, 80.3, 79.2, 79.1, 78.96, 78.92,
77.9, 77.7, 76.5, 76.4, 75.6, 75.1, 74.9, 74.5, 74.0, 73.9, 73.5, 72.2,
69.6, 69.4, 69.1, 68.7, 65.0, 64.6, 55.2, 17.9, 17.5; ESI-HRMS m/z
calcd for C106H104O21Na, 1735.6968 [M + Na+]; found 1735.7017.
Methyl D-Glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-r-L-rham-
nopyranosyl-(1f3)-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-
r-L-rhamnopyranoside (22). To a solution of tetrasaccharide 21
(37.5 mg, 22 µmol) in 4/4/1 MeOH/THF/H2O (4.5 mL) were added
AcOH (13.0 µL, 227 µmol) and 10% Pd/C (84.6 mg). The mixture
was purged with H2 six times and stirred for 84 h at ambient
temperature under 1 atm of H2. The catalyst was filtered off, and
the filtrate was concentrated. The residue was dissolved in H2O
and washed with AcOEt. The aqueous layer was concentrated to
1
(c 0.74, CHCl3); H NMR (500 MHz, CDCl3) δ 7.83-7.80 (m, 3
H), 7.73-7.70 (m, 1 H), 7.54-7.28 (m, 30 H), 7.06-7.04 (m, 3
H), 5.89 (s, 1 H), 5.72 (s, 1 H), 4.99 (d, 1 H, J ) 12.5 Hz), 4.94
(d, 1 H, J ) 12.5 Hz), 4.90 (d, 1 H, J ) 13.0 Hz), 4.83 (d, 1 H, J
) 12.5 Hz), 4.54 (d, 1 H, J ) 12.0 Hz), 4.50 (d, 1 H, J ) 12.5
Hz), 4.31 (s, 1 H), 4.26 (d, 1 H, J ) 5.5 Hz), 4.22-4.18 (m, 2 H),
4.11-4.04 (m, 2 H), 4.04 (d, 1 H, J ) 2.5 Hz), 3.52 (dd, 1 H, J )
3.0, 10.0 Hz), 3.49 (d, 1 H, J ) 10.0 Hz), 3.59-3.29 (m, 2 H),
2.60 (t, 1 H, J ) 10.0 Hz), 1.14 (d, 3 H, J ) 6.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 143.12, 143.07, 138.8, 138.5, 137.9, 136.1,
133.5, 133.2, 132.3, 129.4, 129.1, 128.6, 128.5, 128.4, 128.13,
J. Org. Chem. Vol. 73, No. 18, 2008 7009

Crich and Li
give tetrasaccharide 22 (13.2 mg, 19 µmol, 85%): [R]23D ) -104.0
The residue was purified by flash chromatography on silica gel
1
(c 0.45, MeOH); H NMR (500 MHz, D2O) δ 4.83 (d, 1 H, J )
(AcOEt/PhCH3 ) 1/18) to afford hexasaccharide 24 (124.2 mg,
1
50 µmol, 64%): [R]23 ) -92.0 (c 0.44, CHCl3); H NMR (500
1.5 Hz), 4.72 (s, 1 H), 4.71 (s, 1 H), 4.55 (d, 1 H, J ) 1.5 Hz),
4.13 (d, 1 H, J ) 1.8 Hz), 3.94-3.83 (m, 5 H), 3.78 (dd, 1 H, J )
2.0, 4.0 Hz), 3.71-3.47 (m, 13 H), 3.30 (dd, 1 H, J ) 3.0, 9.5
Hz), 3.26-3.24 (m, 4 H), 1.22 (d, 3 H, J ) 6.0 Hz), 1.18 (d, 3 H,
J ) 6.0 Hz); 13C NMR (125 MHz, D2O) δ 100.98 (JC1-H1 ) 172.1
Hz), 100.86 (JC1-H1 ) 161.5 Hz), 100.78 (JC1-H1 ) 161.3 Hz),
96.3 (JC1-H1 ) 173.0 Hz),, 79.5, 79.2, 77.1, 76.2, 76.1, 73.4, 72.5,
70.8, 70.6, 70.5, 70.4, 68.3, 67.7, 67.3, 66.4, 66.2, 62.2, 54.9, 17.1;
ESI-HRMS m/z calcd for C27H48O21Na, 731.2586 [M + Na+]; found
C27H48O21Na, 731.2585.
D
MHz, CDCl3) δ 7.80-7.75 (m, 3 H), 7.68-7.66 (m, 1 H),
7.57-7.09 (m, 76 H), 6.93 (t, 2 H, J ) 8.0 Hz), 5.69 (s, 1 H), 5.58
(s, 2 H), 5.07 (s, 1 H), 5.01 (s, 1 H), 4.88-4.81 (m, 3 H), 4.76-4.62
(m, 5 H), 4.55-4.42 (m, 8 H), 4.38-4.34 (m 3 H), 4.30-4.26 (m,
2 H), 4.15-4.01 (m, 7 H), 3.98-3.82 (m, 8 H), 3.74-3.65 (m, 2
H), 3.51-3.33 (m, 9 H), 3.30-3.25 (m, 3 H), 3.18 (dd, 1 H, J )
7.5, 10.0 Hz), 2.67 (t, 1 H, J ) 9.5 Hz), 2.48 (t, 1 H, J ) 9.0 Hz),
2.42 (t, 1 H, J ) 9.5 Hz), 1.23 (d, 3 H, J ) 6.5 Hz), 1.04 (d, 3 H,
J ) 6.5 Hz), 1.00 (d, 3 H, J ) 6.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 143.22, 143.18, 143.12, 143.08, 138.6, 138.5, 138.4,
138.06, 137.98, 137.8, 137.63, 137.60, 136.1, 133.5, 133.2, 129.2,
129.1, 129.0, 128.7, 128.65, 128.60, 128.53, 128.5, 128.45, 128.41,
128.4, 128.33, 128.30, 128.27, 128.2, 128.1, 128.0, 127.9, 127.86,
127.84, 126.6, 126.5, 126.4, 126.3, 126.04, 125.98, 125.83, 125.79,
109.6, 109.5, 109.3, 102.6, 102.5, 102.4, 101.7, 101.6, 101.1, 98.1
Methyl 2,7-Di-O-benzyl-4,6-O-benzylindene-D-glycero-ꢀ-D-man-
noheptopyranosyl-(1f4)-2,3-O-(diphenylmethylene)-r-L-rham-
nopyranosyl-(1f3)-2,7-di-O-benzyl-4,6-O-benzylindene-D-glycero-
ꢀ-D-mannoheptopyranosyl-(1f4)-2,3-O-(diphenylmethylene)-r-L-
rhamnopyranoside (23). To a mixture of tetrasaccharide 21 (180.1
mg, 106 µmol) in 15/3/5 CH2Cl2/H2O/phosphate buffer (pH ) 7.4)
(9.2 mL) was added DDQ (38.6 mg, 170 µmol). The mixture was
stirred for 2.5 h at ambient temperature under N2, before another
portion of DDQ (34.5 mg, 152 µmol) was added. After the mixture
was stirred for another 2 h, it was diluted with CH2Cl2 and washed
with saturated aqueous NaHCO3 and brine. The collected organic
phase was dried over Na2SO4, filtered, and concentrated. The residue
was subjected to silica gel chromatography to furnish alcohol 23
(123.6 mg, 79 µmol, 74%) as white foam: [R]23D ) -96.5 (c 0.71,
(JC1-H1 ) 169.5 Hz), 93.86 (JC1-H1 ) 168.5 Hz), 93.79 (JC1-H1
)
167.0 Hz), 81.2, 80.5, 80.3, 79.2, 79.1, 79.0, 78.9, 77.9, 77.7, 76.6,
76.5, 76.4, 75.6, 75.1, 74.9, 74.5, 74.3, 73.9, 73.8, 73.7, 73.65,
73.62, 73.55, 72.9, 72.2, 69.7, 69.6, 69.4, 69.2, 69.1, 68.8, 64.9,
64.6, 55.3, 17.9, 17.5; ESI-HRMS m/z calcd for C153H150O31Na,
2506.0059 [M + Na+]; found 2506.0273.
Methyl D-Glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-r-L-rham-
nopyranosyl-(1f3)-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-
r-L-rhamnopyranosyl-(1f3)-D-glycero-ꢀ-D-mannoheptopyranosyl-
(1f4)-r-L-rhamnopyranoside (25). To a solution of hexasaccharide
24 (58.3 mg, 23 µmol) in 3/1 MeOH/THF (6 mL) was added AcOH
(100 µL, 1.7 mmol) and 10% Pd/C (100 mg). The mixture was
purged with H2 six times and stirred for 24 h under H2 at 50 psi.
The solid was filtered off, and the filtrate was concentrated to
dryness. The resulting residue was dissolved in water and washed
with CHCl3 (5 mL × 3). The aqueous phase was concentrated under
reduced pressure and dried under vacuum to afford hexamer 25
(14.9 mg, 14 µmol, 60%): [R]23D ) -84.6 (c 0.71, H2O); 1H NMR
(500 MHz, D2O, 330 K, referenced to an external standard sodium
3-trimethylsilyl-(2,2,3,3-2H) propionate (δ ) 0.00) in D2O) δ 4.96
(s, 2 H), 4.84 (s, 2 H), 4.83 (s, 1 H), 4.68 (s, 1 H), 4.24 (br. s, 2
H), 4.05-3.96 (m, 8 H), 3.92-3.90 (m, 1 H), 3.83-3.60 (m, 19
H), 3.44-3.41 (m, 2 H), 3.38-3.35 (m, 4 H), 1.33 (d, 3 H, J )
6.5 Hz), 1.31 (d, 6 H, J ) 6.5 Hz); 13C NMR (125 MHz, D2O, 330
K, referenced to an external standard 1,4-dioxane (δ ) 67.40) in
D2O) δ 101.63 (JC1-H1 ) 174.5 Hz), 101.48 (JC1-H1 ) 160.5 Hz),
101.36 (JC1-H1 ) 161.4 Hz), 97.09 (JC1-H1 ) 170.2 Hz), 80.27,
80.10, 77.99, 76.84, 76.71, 74.08, 73.29, 73.25, 71.52, 71.28, 71.17,
69.10, 68.34, 67.92, 67.29, 67.14, 63.03, 62.98, 55.59, 17.78; ESI-
HRMS m/z calcd for C40H70O31Na, 1069.3799 [M + Na+]; found
1069.3762; calcd for C40H70O31Na2, 546.1848 [M + 2Na]2+; found,
546.1837.
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.53-7.45 (m, 10 H),
7.40-7.02 (m, 40 H), 5.59 (s, 1 H), 5.58 (s, 1 H), 5.07 (s, 1 H),
5.02 (s, 1 H), 4.85 (d, 1 H, J ) 12.0 Hz), 4.84 (d, 1 H, J ) 12.0
Hz), 4.68 (d, 1 H, J ) 12.0 Hz), 4.53-4.44 (m, 7 H), 4.41 (dd, 1
H, J ) 5.5, 7.5 Hz), 4.35 (dd, 1 H, J ) 5.5, 7.0 Hz), 4.09-3.99
(m, 5 H), 3.95 (t, 1 H, J ) 10.0 Hz), 3.92-3.88 (m, 2 H), 3.83
(dd, 1 H, J ) 3.5, 10.5 Hz), 3.81-3.64 (m, 2 H), 3.60-3.56 (m,
1 H), 3.52 (dd, 1 H, J ) 1.5, 11.0 Hz), 3.44 (dd, 1 H, J ) 1.5, 11.0
Hz), 3.41 (s, 3 H), 3.37-3.26 (m, 4 H), 2.67 (t, 1 H, J ) 9.5 Hz),
2.44 (t, 1 H, 9.5 Hz), 2.30 (d, 1 H, J ) 9.0 Hz, OH), 1.23 (d, 1 H,
J ) 6.5 Hz), 1.03 (d, 1 H, J ) 6.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 143.23, 143.19, 143.15, 143.13, 138.5, 138.4, 138.3,
138.1, 137.6, 129.2, 129.1, 128.8, 128.7, 128.62, 128.59, 128.56,
128.52, 128.49, 128.45, 128.41, 128.2, 128.1, 128.0, 127.94, 127.89,
126.7, 126.5, 126.4, 126.3, 126.0, 109.6, 109.4, 102.6, 102.2, 101.6,
98.1, 93.9, 81.1, 80.2, 79.2, 79.1, 79.03, 78.96, 78.6, 78.0, 76.6,
76.4, 75.6, 75.3, 74.9, 73.9, 73.8, 73.64, 73.60, 71.0, 69.7, 69.4,
69.1, 68.4, 64.9, 64.6, 55.3, 17.9, 17.6; ESI-HRMS m/z calcd for
C95H96O21Na, 1595.6342 [M + Na+]; found 1595.6427.
Methyl 2,7-Di-O-benzyl-4,6-O-benzylindene-3-O-naphthale-
nylmethyl)-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-2,3-O-
(diphenylmethylene)-r-L-rhamnopyranosyl-(1f3)-2,7-di-O-benzyl-
4,6-O-benzylindene-D-glycero-ꢀ-D-mannoheptopyranosyl-(1f4)-
2,3-O-(diphenylmethylene)-r-L-rhamnopyranosyl-(1f3)-2,7-di-
O-benzyl-4,6-O-benzylindene-D-glycero-ꢀ-D-mannoheptopyranosyl-
(1f4)-2,3-O-(diphenylmethylene)-r-L-rhamnopyranoside (24).
A solution of thioglycoside 20 (106.2 mg, 104 µmol) and alcohol
23 (121.6 mg, 77 µmol) in CH2Cl2 (8 mL) was stirred for 30 min
in the presence of 4 Å molecular sieves at ambient temperature
under N2 before it was cooled to -15 °C and treated with NIS
(29.9 mg, 133 µmol) and AgOTf (27.4 mg, 106 µmol). The resulting
mixture was stirred for 1.5 h, while the temperature was increased
to 10 °C. The solid was filtered off, and the filtrate was washed
with saturated aqueous Na2S2O3 containing NaHCO3 and brine. The
organic phase was dried over Na2SO4, filtered, and concentrated.
Acknowledgment. We thank the NIH (GM57335) for support
of this work.
Supporting Information Available: Comparison of spectral
data of glycan 25 with that of the natural isolate, and copies of
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801414C
7010 J. Org. Chem. Vol. 73, No. 18, 2008