Synthesis of a nonavalent mannoside glycodendrimer based on pentaerythritol

Article abstract of DOI:10.1021/jo052045u

A nonavalent glycodendrimer bearing terminal α-D-mannopyranoside units has been synthesized with a convergent approach. Terminal trivalent mannoside dendrons bearing p-halophenyl ethers were prepared by glycosylation of pentaerythritol derivatives having

Full text of DOI:10.1021/jo052045u

Synthesis of a Nonavalent Mannoside Glycodendrimer Based on
Pentaerythritol
Hussein Al-Mughaid and T. Bruce Grindley*
Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia, B3H 4J3 Canada
bruce.grindley@dal.ca
ReceiVed September 29, 2005
A nonavalent glycodendrimer bearing terminal R-D-mannopyranoside units has been synthesized with a
convergent approach. Terminal trivalent mannoside dendrons bearing p-halophenyl ethers were prepared
by glycosylation of pentaerythritol derivatives having three 2-hydroxyethyl ether substituents. Two efficient
routes were developed for the synthesis of the pentaerythritol-based core (17), which has three terminal
propargyl ethers. Conditions were found under which the triple Sonogashira coupling reaction of the
dendron and the tri-O-propargyl ether (17) proceeded efficiently. The product was deprotected and it
and precursors were fully characterized by NMR spectroscopy and FT-ICR mass spectrometry.
Introduction
are commensal inhabitants of the human intestinal tract and
extraintestinal sites, particularly the urinary tract, but also cause
a variety of infectious diseases. The vast majority of E. coli
express Type 1 fimbriae that recognize terminal R-D-mannopy-
ranoside residues present on cell surfaces via the lectin FimH.7,8
The binding of E. coli to R-D-mannopyranoside residues has
been recognized for some time,9,10 and a number of dendrimers
have been designed to evaluate the utility of antibacterial
strategies involving this type of compound.11-16 There is
considerable variation in the binding strengths observed for E.
Terminal R-D-mannopyranoside residues on cell surfaces are
recognized by a number of protein receptors of different types.
In general, the strengths of the interactions of single monosac-
charides or oligosaccharides with their protein receptors are
weak; usually the dissociation constants are in the millimolar
to micromolar range.1 Multivalent presentation of the carbohy-
drate allows the binding strength to become sufficiently
stronger2-5 that synthetic ligands can compete with the natural
polyvalent ligands.
One of the medically most significant carbohydrate-protein
interactions involves the initial attachment of pathogenic bacteria
to target tissues. Bacteria express lectins termed adhesins on
their surfaces to attach themselves to cell surface carbohydrates
from a variety of tissues. In Gram negative bacteria, these
adhesins often are on pili or fimbriae protruding from the cell
surface.6 Strains of the Gram negative bacteria Escherichia coli
(6) Remaut, H.; Waksman, G. Curr. Opin. Struct. Biol. 2004, 14, 161-
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(7) Berglund, J.; Knight, S. D. Glycobiol. Med. 2003, 535, 33-52.
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Hultgren, S. J. Mol. Microbiol. 2002, 44, 903-915.
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Chem. Soc., Perkin Trans. 1 1998, 2193-2200.
* Address correspondence to this author. Phone: 902-494-2041. Fax: 902-
494-1310.
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Eur. J. Org. Chem. 2000, 2027-2034.
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10.1021/jo052045u CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/21/2006
1390
J. Org. Chem. 2006, 71, 1390-1398

Synthesis of a NonaValent Mannoside Glycodendrimer
coli strains,17,18 although the actual binding site is thought to
be strongly conserved. The binding of R-D-mannopyranoside
residues to the FimH lectin from both an E.coli uropathogenic
strain J96 and a K-12 laboratory strain MG1655 were shown
recently to be very strong, in the micromolar to nanomolar range
depending on the structure of the aglycon.19
design, the R-D-mannopyranoside units were linked via their
anomeric centers to expose the maximal number of hydroxyl
groups so as to aid water solubility. Aromatic groups were
incorporated to aid binding to the two tyrosine units located
outside the mannose binding site in the FimH lectin.19,33 The
synthetic route to the glycodendrimer allows extension to higher
order dendrimers later via the hydroxyl group that can be
unveiled by selective removal of the single p-methoxybenzyl
group. The design also allows the incorporation of variable
length spacer arms in later syntheses if this feature is considered
desirable. This paper reports the synthesis of the glycodendrimer
resulting from these considerations.
A second type of important receptor is the C-lectin DC-SIGN
(dendritic cell-specific ICAM-grabbing nonintegrin), present on
dendritic cells which sample the microenvironment of every
tissue for foreign antigens.20-23 A number of different pathogens
utilize this lectin to gain access to specific cell types: HIV-1,
HIV-2, Ebola virus, hepatitis C virus, Dengue virus, cyctoma-
galovirus; bacteria such as Mycobacterium tuberculosis, Helio-
bacter pylori, and Klebsiella pneumoniae; yeasts such as
Candida albicans; and parasites such as Leishmania and
Schistosoma.21 DC-SIGN is a calcium-dependent lectin, present
as a tetramer,24-26 that binds the blood group determinants
containing terminal fucose, Lewisx and Lewisa, as well as
structures containing both internal and terminal mannose.27-29
The closely related C-lectin DC-SIGNR only binds mannose-
containing structures.29 It has been suggested that pathogens
use closely spaced glycans for multivalent binding with the
multiple carbohydrate recognition domains (CRDs) in the DC-
SIGN tetramer, because clusters of either mannose-type or
fucose-type ligands are uncommon on endogenous cell surfaces
and glycoproteins.29 Rojo and co-workers have found that
mannose-terminal glycodendrimers based on the Boltorn den-
drimers were able to inhibit DC-SIGN mediated cell entry by
Ebola virus at nanomolar concentration.30,31 Other dendrimers
have also been found to be active against HIV.32
Results and Discussion
The synthetic plan followed a convergent route where
dendritic trimannoside clusters were designed to be coupled to
a central propargylated pentaerythritol core via Sonagashira
coupling as outlined in Scheme 1.
Synthesis of the Dendritic Clusters. The synthetic route to
the dendritic clusters is shown in Schemes 2 and 3. Pentaeryth-
ritol tri-O-allyl ether (1), chromatographically purified from
commercial technical product, was converted to the correspond-
ing tosylate 2 by using tosyl chloride and pyridine in 84% yield.
Treatment of tosylate 2 with p-bromophenol and p-iodophenol
according to the method reported by Laliberte´ et al.,34 used
during the synthesis of pentaerythritol tetra-O-phenyl ether,
provided precursors 3 and 4 in yields of 70% and 68%,
respectively. Ozonolysis of tri-O-allyl ethers 3 and 4 in methanol
and dichloromethane at -78 °C followed by reductive workup
with sodium borohydride in ethanol afforded triols 5 and 6 in
yields of 81% and 71%, respectively.
These observations encouraged us to design a glycodendrimer
with clustered terminal R-D-mannopyranoside units. In this
As depicted in Scheme 3, the benzoylated imidate 9 was
obtained in three steps from mannose, starting with 1,2,3,4,6-
penta-O-benzoyl-R,â-D-mannopyranoside (7) prepared according
to the standard procedure reported by Fletcher et al.,35 followed
by anomeric de-O-benzoylation. Anomeric de-O-benzoylation
of perbenzoylated mannose suffers from low yields and/or long
reaction times of up to several days.36 Dubber and Lindhorst37
have examined several alternative conditions for anomeric de-
O-benzoylation and found that the commercially available
solution of Et2NH in EtOH (5.6 M) with THF as a solvent was
effective for both anomeric de-O-benzoylations and de-O-
acetylations. However, in the case of perbenzoylated mannose,
pyridine was reported to be superior to THF; the reaction was
completed within 1.5 h in yields up to 78%. Here, it was found
that the commercially available solution of MeNH2 in ethanol
(33%) in THF effected the anomeric de-O-benzoylation of 7
faster, in less than 30 min, and afforded an R/â-mixture of 8 in
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S. L. M.; KewalRamani, V. N.; Littman, D. R.; Figdor, C. G.; van Kooyk,
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J. Org. Chem, Vol. 71, No. 4, 2006 1391

Al-Mughaid and Grindley
SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Synthesis of the Cluster Corea
a Reagents and conditions: (a) TsCl (2 equiv), Py, 0 °C to room temperature, 12 h; (b) p-halophenol (1.25 equiv), DMF, NaOH (1.25 equiv), reflux, 12
h; (c) O3 (g), CH2Cl2, MeOH (1:1), -78 °C; Me2S, -78 °C; (d) NaBH4, EtOH, 0 °C to room temperature, 24 h.
SCHEME 3. Synthesis of Trivalent Cluster Mannosides 10
and 11a
no decomposition was detected after it was stored at room
temperature for more than one month.
Coupling of the glycosyl donor 9 with triol 5 or 6 in the
presence of TMSOTf as catalyst in dichloromethane as solvent
at room temperature furnished the desired tris-R-D-mannopy-
ranoside dendrons 10 and 11, in yields of 86% and 85%,
respectively, after column chromatography. No benzoyl group
transfer products, ortho esters, or mono- and divalent clusters
were observed. The expected R-stereochemistries of the D-
1
mannosides 10 and 11 were established from their H and 13C
NMR spectra. The signals of the anomeric protons appeared in
1
the H NMR spectra at 5.15 and 5.17 ppm, respectively, as
3
doublets with identical J1,2 values of 1.6 Hz. This value is
consistent with an equatorial-equatorial relationship between
a Reagents and conditions: (a) MeNH2 (33%) in EtOH, THF, 30 min;
(b) Cl3CCN, DBU; (c) 9 (3.75 equiv), CH2Cl2, TMSOTf, 10 h.
H-1 and H-2.39,40 The R-configurations were confirmed from
(38) Bien, F.; Ziegler, T. Tetrahedron: Asymmetry 1998, 9, 781-790.
(39) Duus, J. Ø.; Gotfredsen, C. H.; Bock, K. Chem. ReV. 2000, 100,
77% yield. Base-catalyzed addition of 8 to trichloroacetonitrile
according to the procedure reported by Ziegler and Bien38
yielded 9. The benzoylated glycosyl imidate 9 was quite stable;
4589-+.
(40) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-
297.
1392 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of a NonaValent Mannoside Glycodendrimer
SCHEME 4. Syntheses of the Tri-O-propargyl Ether 17a
a Reagents and conditions: (a) Et3SiH (1.2 equiv), EtAlCl2 (3.3 equiv), CH2Cl2, -78 °C, 35 min; (b) NaOMe, MeOH, 1 h; (c) NaH (4.6 equiv), DMF,
propargyl bromide (4.0 equiv), 0 °C to room temperature, 5 h; (d) NaH (3.3 equiv), DMF, propargyl bromide (2.8 equiv), 0 °C to room temperature, 4 h;
(e) Et3SiH (1.2 equiv), EtAlCl2 (1.7 equiv), CH2Cl2, -78 °C, 40 min; (f) NaH (1.2 equiv), DMF, propargyl bromide (1.2 equiv), -10 °C to room temperature,
8 h.
the magnitudes of the one bond 13C-1H coupling constants.
The JC1-H1 coupling of 10 and 11 was found to be 173.7 and
173.4 Hz, respectively, from the 13C undecoupled HSQC
experiment. Values of 160 Hz are typical of â-anomers while
those of ∼170 Hz are typical of R-anomers.39,40 The molecular
masses of clusters 10 and 11 were established from their mass
spectra. The ESI mass spectrum of cluster 10, a bromo derivative
with the formula C119H105BrO34, was recorded on an ion trap
mass spectrometer. The resolution at m/z 2180, where M + Na+
occurs, was >1 Da and the peak at this mass extended from
m/z 2179.6 to 2186.6 with a maximum at m/z 2181.6. The
relative intensities of the various unit mass peaks were calculated
with the program ISOMABS,41 and it was found that the most
intense peak in this cluster should occur at m/z 2181.6, exactly
matching the observed position, and the general shape of the
molecular ion peak matched that calculated. In contrast, the mass
spectrum of cluster 11 was recorded with a MALDI FT-ICR
mass spectrometer, which had a resolution of <0.01 Da at this
mass. The individual peaks in this cluster were very well
resolved, separated by about 30 line widths. The mass-to-charge
ratio for the [M + Na]+ peak was calculated to be m/z 2227.542,
and was observed at 2227.546, in excellent agreement, and the
intensities of the M + 1 + Na, M + 2 + Na, M + 3 + Na, and
M + 4 + Na peaks also fit the intensities calculated with
ISOMABS41 well.
were unable to repeat this procedure. Two alternatives were
developed. As outlined in Scheme 4 (top), the diacetate 14,
prepared (87% yield) in two straightforward steps from pen-
taerythritol,43 was reductively cleaved by addition of EtAlCl2-
Et3SiH44 in CH2Cl2 to produce the corresponding alcohol 15 in
72% yield. Removal of the acetyl groups with sodium methoxide
in MeOH gave triol 16 in 90% yield that yielded the tri-O-
propargyl ether 17 in 78% yield on treatment with propargyl
bromide and NaH in DMF.
Initial difficulties with the reduction of p-methoxybenzylidene
acetal (13), ultimately overcome through the use of the diacetate
14 as outlined above, led to the development of a second
approach (Scheme 4, bottom) to tri-O-propargyl ether 17. Diol
13 was treated with propargyl bromide in the presence of sodium
hydride in DMF to give di-O-propargyl ether 18 in 91% yield.
Reductive opening of the p-methoxybenzylidene acetal as for
14 gave the desired alcohol 19 in 72% yield. Alkylation of
alcohol 19 was then achieved with propargyl bromide in the
presence of sodium hydride in DMF to give the tri-O-propargyl
ether 17 in 81% yield. This synthesis is shorter (3 steps from
13) and higher yielding than the previous route (53% vs 44%).
With the key intermediates 11 and 17 in hand, we were able
to focus on combining them via triple Sonogashira coupling
reactions. In a series of papers, Roy et al.45-49 demonstrated
the usefulness of the Sonogashira reaction in the construction
of divalent glycoclusters and high-order glycoclusters having
different geometries and shapes. It was found that the reaction
of propargyl glycosides and phenyl halides could be performed
at high temperature in DMF as a solvent and Et3N as a base,
using either Pd(PPh3)2Cl2 or Pd(PPh3)4 as catalyst in the absence
Synthesis of the Core Molecule. Pentaerythritol mono-p-
methoxybenzyl ether (16) was selected as a core to allow future
extension by selective deprotection and further reaction of the
exposed alcohol. Burns et al.42 described a procedure of the
synthesis of triol 16, involving the reductive opening of the
pentaerythritol mono-p-methoxybenzylidene acetal (13) with
DIBAL in toluene at room temperature in good yield, but we
(43) El Ashry, E. S. H.; El Kilany, Y.; Hamid, H. A.; El-Zemity, S. R.;
Boghdady, S. J. Chem. Res. (S) 2003, 111-128.
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Dam, T. K.; Brewer, C. F. Chem. Eur. J. 2000, 6, 1757-1762.
(46) Gan, Z.; Roy, R. Tetrahedron Lett. 2000, 41, 1155-1158.
(47) Liu, B.; Roy, R. Chem. Commun. 2002, 594-595.
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(49) Liu, B.; Roy, R. Tetrahedron 2001, 57, 6909-6913.
(41) Grossert, J. S. ISOMABS, version 4c, A program for assisting in
the correlation of isotopic abundances and molecular formulae with mass
spectral measurements, 2004
(42) Burns, C. J.; Culshaw, P.; Field, L. D.; Islam, M.; Morgan, J.;
Raguse, B.; Ridley, D. D.; Wieczorek, L.; Wilkinson, M.; Vignevich, V.
Aust. J. Chem. 1999, 52, 1071-1075.
J. Org. Chem, Vol. 71, No. 4, 2006 1393

Al-Mughaid and Grindley
SCHEME 5. Preparation of the Model Di-O-propargyl
SCHEME 6. Synthesis of Mannoside Glycodendrimer 23a
Ether 20 and Its Coupling Reactiona
a Reagents and conditions: (a) NaH (3.3 equiv), DMF, propargyl bromide
(2.5 equiv), 0 °C to room temperature; (b) Pd(PPh3)4 (5 mol %), CuI (20
mol %), DMF-Et3N (1:1), room temperature, 6 h.
of CuI.48-50 This latter point was significant because in the
absence of CuI, the oxidative homodimerization of the alkynyl
moiety was not observed.
Initially, Sonogashira coupling between the dendron 11 and
the tri-O-propargyl ether 17 was attempted at high temperature
and in the absence of CuI, following Roy’s observations. No
cross product was formed. The dendron 11 was recovered and
the tri-O-propargyl ether was consumed during the course of
the reaction. It is noteworthy to mention that the tri-O-propargyl
ether 17 is not stable, decomposing after being stored for 2 days
at 5 °C in the dark. Therefore, a model reaction was employed
to develop conditions under which Sonogashira coupling of this
type of propargyl ethers was viable. As a starting point of
investigation, the di-O-propargyl ether 20 was prepared in 92%
yield by reacting monobenzylidene pentaerythritol with prop-
argyl bromide and NaH in DMF. 4-Iodoanisole (21) was chosen
as the coupling partner.
To find optimal reaction conditions for coupling, the reaction
between the di-O-propargyl ether 20 and p-iodoanisole 21 was
performed under a variety of reaction conditions. Unfortunately,
all attempts to accomplish the coupling under copper-free
condition were unsuccessful. On the other hand, the reaction
was found to be successful on the addition of CuI. In the
presence of 5 mol % of Pd(PPh3)4 and 20 mol % of CuI the
reaction proceeded at room temperature in a mixture of DMF
and Et3N (1:1) to give the cross coupling product 22 in 81%
yield after column chromatography (Scheme 5).
Surprisingly, when the same conditions were applied to couple
compounds 11 and 17, no cross product formed. Krause and
Thorand51 observed that the rate of the palladium-catalyzed
coupling of terminal alkynes with aryl bromides increased
markedly when the coupling was performed in THF, rather than
DMF. Using THF as a solvent led to the isolation of the
glycodendrimer 23 in good yield. Indeed, the dendron 11 reacted
smoothly with 17 in the presence of Pd(PPh3)4, CuI, and HN-
(i-Pr)2 in THF at room temperature to afford the desired coupling
product, the 9-mer 23 in 74% yield after column chromatog-
raphy (Scheme 6). No mono- and disubstituted products were
observed. The side reaction, the homocoupling of the tri-O-
propargyl ether 17, was prevented almost completely by adding
17 in THF slowly to keep its concentration in the reaction
mixture very low. The optimized conditions were found to be
10 mol % of Pd(PPh3)4, 30 mol % of CuI, and HN(i-pr)2 (4.5
a Reagents and conditions: (a) Pd(PPh3)4 (10 mol %), CuI (30 mol %),
HN(i-Pr)2, THF, room temperature, 9 h.
equiv). Pd(PPh3)4) was the best catalyst for this reaction while
PdCl2(PPh3)2 was less effective. Both bases (Et3N and HN(i-
pr)2) can be used in this reaction.
The 1H and 13C NMR spectra were consistent with the
proposed structure depicted in Scheme 6. The mass spectrum,
recorded on an FT-ICR mass spectrometer, with MALDI
ionization, contained well resolved M + Na, M + 1 + Na, M
+ 2 + Na, M + 3 + Na, etc. peaks of appropriate intensities
as calculated by the ISOMABS program.41 The m/z value
calculated for the M + Na peak, 6623.1, agreed with the
observed value within 0.3.
Due to the poor solubility of the benzoylated glycoclusters
in methanol, Lindhorst et al. reported that elongated reaction
times of up to two weeks were necessary to make the de-O-
benzoylation reaction go to completion.13 Here, it was found
that a mixture of THF and methanol (2:1, v/v) is an excellent
solvent system for the de-O-benzoylation of benzoylated gly-
coclusters. Before attempting the de-O-benzoylation of the
9-mer, cluster 11, dissolved in a 2:1 mixture of THF and
methanol, was treated with 0.5 M NaOMe/methanol solution
for 4 h. The corresponding de-O-benzoylated cluster 24 was
obtained in 93% yield (Scheme 7).
In the case of the 9-mer, it was dissolved in a mixture of
THF and methanol (1:2, v:v) and treated as for cluster 11. The
(50) Liu, B.; Roy, R. Tetrahedron 2001, 57, 6909-6913.
(51) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553.
1394 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of a NonaValent Mannoside Glycodendrimer
SCHEME 7. De-O-benzoylation of Mannoside Cluster 11a
Experimental Section
1,3-Bis(allyloxy)-2-allyloxymethyl-2-[(p-toluenesulfonyloxy)-
methyl]propane (2). To a cold (0 °C, ice-water bath) solution of
tri-O-allyl pentaerythritol (1, 0.73 g, 2.85 mmol) in dry pyridine
(13 mL) was added p-toluenesulfonyl chloride (1.1 g, 5.7 mmol)
and the resulting reaction mixture was stirred at room temperature
for 12 h and concentrated. The residue was dissolved in dichlo-
romethane (50 mL) and the resulting solution was washed with
saturated NaHCO3 (50 mL). The organic layer was separated and
the aqueous layer was extracted with dichloromethane (2 × 25 mL).
The combined organic extracts were dried (MgSO4) and concen-
trated to a residue that was purified by flash column chromatography
(hexanes-EtOAc (7:1), Rf 0.32) to give the title compound as a
a Reagents and conditions: (a) 0.5 M NaOMe, THF-MeOH (2:1), room
temperature, 4 h.
1
colorless oil (0.98 g, 84%). H NMR δ 7.79-7.30 (m, 4H, PhH),
corresponding de-O-benzoylated 9-mer was obtained in 91%
yield in 8 h at room temperature (Scheme 8).
3
2
5.79 (m, 3H, 3 × CHd), 5.20 (dq, 3H, Jtrans ) 17.4 Hz, JH,H
)
4Jtrans ) 1.7 Hz, dCHHtrans), 5.13 (dq, 3H, Jcis ) 10.4 Hz,
3
Water-insoluble clusters will be biologically inactive and
solubility has been a problem for some clusters prepared
previously.14 The compounds synthesized here, trivalent cluster
24 and the 9-mer 25, were found to exhibit good solubilities in
water.
3
dCHHcis), 4.07 (s, 2H, CH2OTs), 3.86 (dt, 6H, JH,H ) 5.5 Hz,
4Jcis ) Jtrans ) 1.4 Hz, 3 × allylic CH2), 3.38 (s, 6H, 3 × CH2-
4
OAll), 2.43 (CH3); 13C NMR δ 144.6, 132.8, 129.8, 128.0 (PhC),
134.7 (3 × CHdCH2), 116.4 (3 × CHdCH2), 72.2 (3 × allylic
CH2), 69.7 (CH2OTs), 68.1 (3 × CH2OAll), 44.8 (qC), 21.6 (CH3).
LR ESI MS: m/z calcd for C21H30O6S + Na 433.17, found 433.1.
1,3-Bis(allyloxy)-2-allyloxymethyl-2-[(p-bromophenoxy)meth-
yl]propane (3). To a stirred solution of compound 2 (1.3 g, 3.2
mmol) and p-bromophenol (0.69 g, 4 mmol, 1.25 equiv) in dry
DMF (50 mL) was added powdered NaOH (0.16 g, 4 mmol, 1.25
equiv) and the resulting reaction mixture was heated at reflux for
12 h, then concentrated. Water (40 mL) was added and the reaction
mixture was extracted with dichloromethane (3 × 35 mL), dried
(MgSO4), and concentrated. The residue was purified by flash
column chromatography (hexanes:EtOAc, 6:1, Rf 0.72) to give the
Conclusions
A nonavalent glycodendrimer bearing terminal R-D-man-
nopyranoside units has been synthesized by using a convergent
approach. The terminal trivalent mannoside dendron bearing a
p-halophenyl ether was prepared by glycosylation of a pen-
taerythritol derivative having three 2-hydroxyethyl ether sub-
stituents. Two efficient routes were developed for the synthesis
of the pentaerythritol-based core (17), which has three terminal
propargyl ethers. Conditions were found under which the triple
Sonogashira coupling reaction of the dendron and the tri-O-
propargyl ether (17) proceeded efficiently. The product was
deprotected and it and precursors were fully characterized by
NMR spectroscopy and FT-ICR mass spectrometry.
1
title compound as a syrup (0.91 g, 70%). H NMR δ 7.36-6.78
3
(m, 4H, PhH), 5.86 (m, 3H, 3 × CH), 5.20 (dq, 3H, Jtrans ) 17.1
Hz, 2JH,H ) 4Jtrans ) 1.7 Hz, dCHHtrans), 5.11 (dq, 3H, 3Jcis ) 10.4
3
Hz, dCHHcis), 3.97 (s, 2H, CH2OPh), 3.96 (dt, 6H, JH,H ) 5.2
Hz, 4Jcis ) 4Jtrans )1.4 Hz, 3 × allylic CH2), 3.54 (s, 6H, 3 × CH2-
OAll); 13C NMR δ 158.6, 132.3, 116.7, 112.8 (PhC), 135.2 (3 ×
CHdCH2), 116.6 (3 × CHdCH2), 72.5 (3 mtmex allylic CH2),
SCHEME 8. De-O-benzoylation of 9-Mer 23a
a Reagents and conditions: (a) 0.5 M NaOMe, THF-MeOH (1:2), room temperature, 8 h.
J. Org. Chem, Vol. 71, No. 4, 2006 1395

Al-Mughaid and Grindley
69.0 (3 × CH2OAll), 67.5 (CH2OPh), 45.4 (qC). LR ESI MS: m/z
calcd for C20H27BrO4 + Na 433.10, found 433.1.
OH), 45.2 (qC). EI HRMS: m/z calcd for C17H27IO7 470.0801,
found 470.0812.
2,3,4,6-Penta-O-benzoyl-r,â-D-mannopyranoside (8). A solu-
tion of methylamine in ethanol (33%, 30 mL) was added to a
solution of 1,2,3,4,6-penta-O-benzoyl-R,â-D-mannopyranoside (7)35
(25 g, 36 mmol) in THF (250 mL) at room temperature and the
reaction mixture was stirred for 30 min. The reaction mixture was
concentrated and the resulting residue was purified by column
chromatography (hexane:EtOAc, 2:1 f 1:1) to give the title
compound as a white solid (16.5 g, 77%). Rf 0.70 (hexane:EtOAc,
1,3-Bis(allyloxy)-2-allyloxymethyl-2-[(p-iodophenoxy)methyl]-
propane (4). To a stirred solution of compound 2 (13.0 g, 32 mmol)
and p-iodophenol (8.80 g, 40 mmol, 1.25 equiv) in dry DMF (120
mL) was added powdered NaOH (1.60 g, 40 mmol, 1.25 equiv)
and the resulting reaction mixture was heated at reflux for 12 h,
then concentrated. Water (100 mL) was added and the reaction
mixture was extracted with dichloromethane (3 × 50 mL), dried
(MgSO4), and concentrated. The residue was purified by flash
column chromatography (hexanes-EtOAc (7:1), Rf 0.58) to give
the title compound as a pale yellow oil (9.97 g, 68%). 1H NMR δ
7.51-6.66 (m, 4H, PhH), 5.79 (m, 3H, 3 × CHd), 5.20 (dq, 3H,
1
1:1); mp 191-193 °C (lit.52 mp 181-182 °C); H and 13C NMR
data were consistent with those reported previously.53
1,9-Bis(2,3,4,6-tetra-O-benzoyl-r-D-mannopyranosyloxy)-5-(4-
[2,3,4,6-tetra-O-benzoyl-r-D-mannopyranosyloxy]-2-oxabutyl)-
5-(p-bromophenoxymethyl)-3,7-dioxanonane (10). A two-necked
round-bottomed flask (flame-dried), equipped with a magnetic stirrer
bar, was charged with triol 5 (0.22 g, 0.52 mmol) and 2,3,4,6-
tetra-O-benzoyl-R-D-mannopyranosyl trichloroacetimidate 938 (1.45
g, 1.95 mmol). The flask was evacuated and backfilled with argon.
Dry dichloromethane (15 mL) was added via a syringe and the
reaction mixture was stirred at room temperature for 25 min.
TMSOTf (0.1 mL) was added to the reaction mixture dropwise
via a syringe. The reaction mixture was stirred at room temperature
for 10 h, neutralized with NaHCO3 (1 g), and filtered and the filtrate
was concentrated. The resulting residue was purified by flash
column chromatography (hexanes:EtOAc, 3:1 f 2:1 f 1:1, Rf 0.49
(hexanes:EtOAc, 1:1)) to give the title compound as a white
2
4
3Jtrans ) 17.8 Hz, JH,H ) Jtrans ) 1.8 Hz, dCHHtrans), 5.10 (dq,
3
3H, Jcis ) 11.8 Hz, dCHHcis), 3.98 (s, 2H, CH2OPh), 3.90 (dt,
3
4
4
6H, JH,H ) 5.2 Hz, Jcis ) Jtrans )1.4 Hz, 3 × allylic CH2), 3.54
(s, 6H, 3 × CH2OAll,); 13C NMR δ 159.2, 138.1, 117.1, 82.7 (PhC),
135.1 (3 × CHdCH2), 116.4 (3 × CHdCH2), 72.3 (3 × allylic
CH2), 68.8 (3 × CH2OAll), 67.2 (CH2OPh), 45.2 (qC). LR ESI
MS: m/z calcd for C20H27IO4 + Na 481.18, found 481.0.
5-[(p-Bromophenoxy)methyl]-5-[(2-hydroxyethoxy)methyl]-
3,7-dioxa-1,9-nonanediol (5). Ozone was bubbled through a
solution of compound 3 (2.82 g, 6.88 mmol) in dichloromethane-
methanol (150 mL, 1:1) at -78 °C until the reaction mixture turned
blue, and the complete consumption of the olefin was then verified
by TLC. After the removal of residual ozone by bubbling nitrogen
through the solution for 25 min, excess dimethyl sulfide was added
at -78 °C and the resulting solution was then allowed to warm to
room temperature and then concentrated. The oily residue was
dissolved in ethanol (100 mL) and cooled to 0 °C (ice-water bath).
Sodium borohydride (3.90 g, 100 mmol) was added in portions.
After the reaction mixture was allowed to reach room temperature,
it was stirred for a further 24 h. Water (50 mL) was added and the
reaction mixture was acidified with 20% HCl to pH 6 (pH paper),
then filtered. The filtrate was concentrated and the residue was
extracted with dichloromethane (3 × 30 mL). The combined
extracts were dried (MgSO4) and concentrated. Purification of the
residue by flash column chromatography (pure EtOAc, Rf 0.28)
afforded the title compound as a viscous colorless oil (2.35 g, 81%).
1H NMR δ 7.36-6.78 (m, 4H, PhH), 3.93 (s, 2H, CH2OPh), 3.67
(t, 6H, J ) 4.2 Hz, 3 × CH2OH), 3.58 (s, 6H, 3 × CCH2O), 3.53
(t, 6H, J ) 4.2 Hz, 3 × CH2OCH2); 13C NMR δ 158.2-113.0
(PhC), 72.7 (3 × CH2OCH2), 69.9 (3 × CCH2O), 67.4 (CH2OPh),
61.4 (3 × CH2OH), 45.3 (qC). EI HRMS: m/z calcd for C17H27-
BrO7 422.0940, found 422.0941.
1
crystalline powder (0.96 g, 86%). [R]D -44.7 (c 1.0, CHCl3); H
NMR δ 7.91-6.79 (complex m, 64H, PhH), 6.12 (t, 3H, J3,4 ) J4,5
) 10 Hz, 3 × H-4man), 5.94 (dd, 3H, J2,3 ) 3.3 Hz, J3,4 ) 10.1 Hz,
3 × H-3man), 5.71 (dd, 3H, J1,2 ) 1.8 Hz, J2,3 ) 3.2 Hz, 3 × H-2man),
5.15 (d, 3H, J1,2 ) 1.6 Hz, 3 × H-1man), 4.67 (m, 3H, 3 × H-6aman),
4.50-4.45 (m, 6H, 3 × H-6bman, 3 × H-5man), 4.07, 4.03 (AB q,
2H, J ) 9.2 Hz, CH2OPh), 3.90, 3.77 (m, 6H, OCH2CH2O), 3.75-
3.71 (m, 6H, OCH2CH2O), 3.72 (s, 6H 3 × CCH2O); 13C NMR δ
166.3, 165.7, 165.6, 165.5 (12 × CO), 158.5-112.8 (PhC), 97.9
(3 × C-1man), 70.8 (3 × OCH2CH2O), 70.7 (3 × C-2man), 70.3 (3
× C-3man), 70.0 (3 × CCH2O), 69.0 (3 × C-5man), 67.5 (CH2OPh),
67.4 (3 × OCH2CH2O), 67.2 (3 × C-4man), 63.0 (3 × C-6man), 45.8
(qC). ESI MS on Agilent ion trap m/z calcd for C119H105BrO34
Na 2179.56, found 2179.6. Calcd for the tallest mass peak of the
M + Na cluster (M + 2 + Na) 2181.6, found 2181.6.
+
1,9-Bis(2,3,4,6-tetra-O-benzoyl-r-D-mannopyranosyloxy)-5-(4-
[2,3,4,6-tetra-O-benzoyl-r-D-mannopyranosyloxy]-2-oxabutyl)-
5-(p-iodophenoxymethyl)-3,7-dioxanonane (11). A two-necked
round-bottomed flask (flame-dried), equipped with a magnetic stirrer
bar, was charged with triol 6 (0.4 g, 0.85 mmol) and compound
938 (2.36 g, 3.2 mmol). The flask was evacuated and backfilled
with argon. Dry dichloromethane (20 mL) was added with a syringe
and the reaction mixture was stirred at room temperature for 30
min. TMSOTf (0.2 mL) was added to the reaction mixture dropwise
via a syringe. The reaction mixture was stirred at room temperature
for 10 h, neutralized with NaHCO3 (2 g), and filtered and the filtrate
was concentrated. The resulting residue was purified by flash
column chromatography (hexanes:EtOAc, 3:1 f 2:1 f 1:1, Rf 0.65
(hexanes:EtOAc, 1:1)) to give the title compound as a white foamy
5-[(p-Iodophenoxy)methyl]-5-[(2-hydroxyethoxy)methyl]-3,7-
dioxa-1,9-nonanediol (6). Ozone was bubbled through a solution
of compound 4 (4.23 g, 9.2 mmol) in dichloromethane-methanol
(120 mL, 1:1) at -78 °C until the reaction mixture turned blue,
and complete consumption of the olefin was then verified by TLC.
After nitrogen was bubbled through the solution for 30 min, excess
dimethyl sulfide was added at -78 °C and the resulting solution
was allowed to warm to room temperature and then concentrated.
The oily residue was dissolved in ethanol (100 mL) and cooled to
0 °C (ice-water bath). Sodium borohydride (3.14 g, 83 mmol) was
added in portions. After the reaction mixture had been allowed to
reach room temperature, it was stirred for a further 18 h. Water
(50 mL) was added and the reaction mixture was acidified with
20% HCl to pH 6 (pH paper) then filtered. The filtrate was
concentrated and the residue was extracted with dichloromethane
(3 × 50 mL). The combined extracts were dried (MgSO4) and
concentrated. Purification of the residue by flash column chroma-
tography (EtOAc-MeOH (95:5), Rf 0.30) afforded the title
1
solid (1.59 g, 85%). [R]D -41 (c 1.0, CHCl3); H NMR δ 8.01-
6.6.13 (complex m, 64H, PhH), 6.13 (t, 3H, J3,4 ) J4,5 ) 10.0 Hz,
3 × H-4man), 5.91 (dd, 3H, J2,3 ) 3.3 Hz, J3,4 ) 10.1 Hz, 3 ×
H-3man), 5.73 (dd, 3H, J1,2 ) 1.7 Hz, J2,3 ) 3.2 Hz, 3 × H-2man),
5.17 (d, 3H, J1,2 ) 1.6 Hz, 3 × H-1man), 4.69 (m, 3H, 3 × H-6aman),
4.52-4.46 (m, 6H, 3 × H-6bman, 3 × H-5man), 4.09, 4.06 (AB q,
2H, J ) 9.1 Hz, CH2OPh), 3.92, 3.76 (m, 6H, 3 × OCH2CH2O),
3.82-3.72 (m, 6H, 3 × OCH2CH2O), 3.72 (s, 6H, 3 × CCH2O);
1
compound as a viscous yellow oil (3 g, 71%). H NMR δ 7.54-
6.67 (m, 4H, PhH), 3.93 (s, 2H, CH2OPh), 3.66 (t, 6H, J ) 3.7
Hz, 3 × CH2OH), 3.57 (s, 6H, 3 × CCH2O), 3.52 (t, 6H, J ) 3.9
Hz, 3 × CH2OCH2); 13C NMR δ 158.9-82.9 (PhC), 72.7 (3 ×
CH2OCH2), 69.8 (3 × CCH2O), 67.2 (CH2OPh), 61.3 (3 × CH2-
(52) Nikolaev, A. V.; Ivanova, I. A.; Shibaev, V. N.; Kochetkov, N. K.
Carbohydr. Res. 1990, 204, 65-78.
(53) Mbadugha, B. N. A.; Menger, F. M. Org. Lett. 2003, 5, 4041-
4044.
1396 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of a NonaValent Mannoside Glycodendrimer
13C NMR δ 166.3, 165.7, 165.6, 165.5 (12 × CO), 138.3-117.3
(PhC), 97.9 (3 × C-1man), 70.8 (3 × OCH2CH2O), 70.7 (3 ×
C-2man), 70.3 (3 × C-3man), 70.0 (3 × CCH2O), 69.0 (3 × C-5man),
67.4 (CH2OPh), 67.4 (3 × OCH2CH2O), 67.2 (3 × C-4man), 63.0
(3 × C-6man), 45.8 (qC). MALDI FTICR MS: m/z calcd for
under nitrogen was added Et3SiH (9.1 mmol, 1.45 mL) and the
reaction mixture was cooled to -78 °C. EtAlCl2 (1.8 M in toluene,
13 mmol, 7 mL) was added dropwise and the reaction mixture was
stirred at -78 °C for 40 min and quenched with saturated NaHCO3
(100 mL). The resulting mixture was extracted with dichlo-
romethane (5 × 50 mL) and the combined extracts were dried
(MgSO4) and concentrated. The residue was purified by flash
column chromatography (EtOAc-hexane (1:3), Rf 0.32) to afford
the title compound as a pale yellow oil (1.12 g, 72%). 1H NMR δ
7.23-6.85 (m, 4H, PhH), 4.42 (s, 2H, OCH2Ph), 4.10 (d, 4H, J )
2.4 Hz, 2 × propargylic CH2), 3.78 (s, 3H, OCH3), 3.69 (d, 2H, J
) 6.2 Hz, CH2OH), 3.55 (s, 4H, 2 × CCH2O), 3.49 (s, 2H, CH2-
OBn), 2.67 (t, 1H, J ) 6.3 Hz, OH), 2.43 (t, 2H, J ) 2.4 Hz, 2 ×
acetylenic H); 13C NMR δ 159.3-113.9 (PhC), 79.9, 74.6 (acety-
lenic carbons), 73.3 (OCH2Ph), 70.5 (CH2OBn), 70.2 (2 × CCH2O),
65.2 (CH2OH), 58.8 (2 × propargylic CH2), 55.3 (OCH3), 44.9
(qC). EI HRMS: m/z calcd for C19H24O5 332.1624, found 332.1616.
1-(p-Methoxybenzyloxy)-3-(prop-2-ynyloxy)-2,2-bis(prop-2-
ynyloxy)methyl]propane (17). Method A: To a stirred solution
of 2-hydroxymethyl-2-[3-p-methoxyphenyl-2-oxapropyl)]-1,3-pro-
panediol (16, 0.29 g, 1.1 mmol) in dry DMF (50 mL) was added
NaH (0.20 g, 5.1 mmol, 60% in mineral oil) in portions at 0 °C.
After 30 min, propargyl bromide (0.65 g, 4.5 mmol, 80% in toluene)
was added and the reaction mixture was allowed to stir for 5 h at
room temperature. Water (25 mL) was added and the product was
extracted with Et2O (4 × 40 mL). The combined organic extracts
were dried (MgSO4) and concentrated. The crude product was
purified by flash column chromatography on silica gel (EtOAc-
hexane (1:3), Rf 0.74) to yield the title compound as a yellow oil
C
119H105 IO34 + Na 2227.542, found 2227.546.
2,2-Bis(acetoxymethyl)-3-(p-methoxybenzyloxy)propanol (15).
To a stirred solution 5,5-bis(acetoxymethyl)-2-(p-methoxyphenyl)-
1,3-dioxane (14)43 (2.5 g, 7.4 mmol, dried by coevaporation with
dry toluene) in dry dichloromethane (60 mL) under nitrogen was
added Et3SiH (8.9 mmol, 1.2 equiv, 1.4 mL) and the reaction
mixture was cooled to -78 °C. EtAlCl2 (1.8 M in toluene, 24.4
mmol, 3.3 equiv, 13.3 mL) was added dropwise and the reaction
mixture was stirred at -78 °C for 35 min and quenched with
saturated NaHCO3 (100 mL), extracted with dichloromethane (5
× 50 mL), dried (MgSO4), and concentrated. The residue was
purified by flash column chromatography (EtOAc-hexane (1:1),
Rf 0.48) to afford the title compound as a colorless oil (1.82 g,
1
72%). H NMR δ 7.23-6.85 (m, 4H, PhH), 4.42 (s, 2H, OCH2-
Ph), 4.10 (s, 4H, 2 × CH2OAc), 3.79 (s, 3H, OCH3), 3.58 (d, 2H,
J ) 6.4 Hz, CH2OH), 3.44 (s, 2H, CCH2O), 2.85 (t, 1H, J ) 5.5
Hz, OH), 2.01 (s, 6H, 2 × CH3); 13C NMR δ 171.1 (2 × CO),
159.3-113.8 (PhC), 73.2 (OCH2Ph), 69.1 (CCH2O), 62.9 (2 × CH2-
OAc), 62.4 (CH2OH), 55.2 (OCH3), 43.8 (qC), 20.8 (2 × CH3). EI
HRMS: m/z calcd for C17H24O7 340.1522, found 340.1517.
2-Hydroxymethyl-2-[3-p-methoxyphenyl-2-oxapropyl]-1,3-
propanediol (16).42 2,2-Bis(acetoxymethyl)-3-(p-methoxybenzyl-
oxy)propanol (15, 2.88 g, 8.5 mmol) was dissolved in dry methanol
(50 mL). A catalytic amount of sodium metal (15 mg) was added
and the reaction mixture was stirred for 1 h. The reaction mixture
was neutralized with Amberlite IR-120 (H+), then filtered. The ion-
exchange resin was washed with methanol (2 × 15 mL) and the
combined filtrate and washings were concentrated. The crude
product was purified by flash column chromatography (pure
EtOAc), Rf 0.47) to afford the title compound 16 (1.96 g, 90%) as
a white solid. Mp 57-58 °C; 1H NMR δ 7.23-6.86 (m, 4H, PhH),
4.42 (s, 2H, OCH2Ph), 3.80 (s, 6H, 3 × CH2OH), 3.66 (s, 3H,
OCH3), 3.44 (s, 2H, CCH2O); 13C NMR δ 159.6-114.1 (PhC),
73.7 (OCH2Ph), 72.2 (CCH2O), 64.4 (3 × CH2OH), 55.5 (OCH3),
45.2 (qC). EI HRMS: m/z calcd for C13H20O5 256.1311, found
256.1317.
1
(0.32 g, 78%). H NMR δ 7.28-6.87 (m, 4H, PhH), 4.43 (s, 2H,
OCH2Ph), 4.10 (d, 6H, J ) 2.4 Hz, 3 × propargylic CH2), 3.80 (s,
6H, 3 × CCH2O), 3.54 (s, 3H, OCH3), 3.46 (s, 2H, CH2OBn), 2.40
(t, 3H, J ) 2.1 Hz, 3 × acetylenic H); 13C NMR δ 159.1-113.7
(PhC), 80.2, 74.3 (acetylenic carbons), 73.0 (OCH2Ph), 69.2
(CCH2O), 68.9 (CH2OBn), 58.8 (3 × propargylic CH2), 55.3
(OCH3), 45.1 (qC). EI HRMS: m/z calcd for C22H26O5 370.1780,
found 370.1775.
Method B: To a stirred solution of 3-(p-methoxybenzyloxy)-
2,2-bis[(prop-2-ynyloxy)methyl]propanol (19, 0.76 g, 2.3 mmol)
in dry DMF (20 mL) was added NaH (0.11 g, 2.8 mmol, 60% in
mineral oil) in portions at -10 °C. After the reaction mixture had
been stirred for 20 min, propargyl bromide (0.43 g, 2.9 mmol, 80%
in toluene) was added and the reaction mixture was allowed to warm
and then was stirred for 8 h. Water (10 mL) was added and the
product was extracted with Et2O (3 × 35 mL). The combined
organic extracts were dried (MgSO4) and concentrated. The crude
product was purified as in method A, yield 0.69 g, 81%.
2-Phenyl-5,5-bis(prop-2-ynyloxymethyl)-1,3-dioxane (20). To
a stirred solution of 5,5-bis(hydroxymethyl)-2-phenyl-1,3-dioxane55
(2.5 g, 11.2 mmol) in dry DMF (150 mL) was added NaH (1.34 g,
33.6 mmol, 60% in mineral oil) in portions at 0 °C. After 30 min,
propargyl bromide (4.17 g, 28 mmol, 80% in toluene) was added
and the reaction mixture was allowed to stir for 4 h at room
temperature. Water (15 mL) was added and the product was
extracted with Et2O (3 × 50 mL). The combined organic extracts
were dried (MgSO4) and concentrated. The crude product was
purified by flash column chromatography (EtOAc-hexane (1:4),
Rf 0.53) to yield the title compound as a pale yellow oil (3.1 g,
92%). 1H NMR δ 7.49-7.32 (m, 5H, PhH), 5.39 (s, 1H, acetal H),
4.16, 4.06 (2d, 4H, J ) 2.4 Hz, 2 × propargylic CH2), 4.08, 3.84
(AB q, 4H, J ) 11.6 Hz, dioxane CH2), 4.07, 3.83 (2s, 4H, 2 ×
exocyclic CH2), 2.44, 2.43 (2 overlapping triplets, 2H, 2 ×
acetylenic H); 13C NMR δ 138.3-126.2 (PhC), 101.7 (acetal C),
79.9, 79.6, 74.9, 74.5 (4 × acetylenic carbons), 69.8 (C-4 and C-6,
dioxane), 69.8, 68.6 (2 × exocyclic CH2), 58.7 (2 × propargylic
2-(p-Methoxyphenyl)-5,5-bis[(prop-2-ynyloxy)methyl]-1,3-di-
oxane (18). To a stirred solution of 5,5-bis(hydroxymethyl)-2-(p-
methoxyphenyl)-1,3-dioxane (13)54 (2.5 g, 8.9 mmol) in dry DMF
(70 mL) was added NaH (1.17 g, 29.4 mmol, 60% in mineral oil)
in portions at 0 °C. After 30 min propargyl bromide (3.46 g, 24.5
mmol, 80% in toluene) was added and the reaction mixture was
allowed to stir for 4 h at room temperature. Water (35 mL) was
added and the product was extracted with Et2O (3 × 50 mL). The
combined organic extracts were dried (MgSO4) and concentrated.
The crude product was purified by flash column chromatography
(EtOAc-hexane (1:4), Rf 0.53) to yield the title compound as a
pale yellow oil (2.9 g, 91%). 1H NMR δ 6.85-7.40 (m, 4H, PhH),
5.35 (s, 1H, acetal H), 4.18, 4.08 (2d, 4H, J ) 2.4 Hz, 2 ×
propargylic CH2), 4.08, 3.33 (2s, 4H, 2 × exocyclic CH2), 4.07,
3.84 (AB q, 4H, J ) 12.1 Hz, dioxane CH2), 3.75 (s, 3H, OCH3),
2.45, 2.44 (2 overlapping triplets, 2H, 2 × acetylenic H); 13C NMR
δ 160.1-113.7 (PhC), 101.7 (acetal C), 80.1, 79.7, 74.8, 74.5
(acetylenic carbons), 69.9 (C-4 and C-6, dioxane), 69.8, 68.7 (2 ×
exocyclic CH2), 58.8 (2 × propargylic CH2), 55.3 (OCH3), 38.5
(qC). EI HRMS: m/z calcd for C19H22O5 330.1467, found 330.1460.
3-(p-Methoxybenzyloxy)-2,2-bis[(prop-2-ynyloxy)methyl]pro-
panol (19). To a stirred solution of 2-(p-methoxyphenyl)-5,5-bis-
[(prop-2-ynyloxy)methyl]-1,3-dioxane (18, 2.5 g, 7.6 mmol, dried
by coevaporation with dry toluene) in dry dichloromethane (50 mL)
(54) Aguilera, B.; Romero-Ram´ırez, L.; Abad-Rodr´ıguez, J.; Corrales,
G.; Nieto-Sampedro, M.; Ferna´ndez-Mayoralas, A. J. Med. Chem. 1998,
41, 4599-4606.
(55) Issidorides, C. H.; Gulen, R. C. Monobenzalpentaerythritol. In
Organic Syntheses; Rabjohn, N., Ed.; John Wiley and Sons: New York,
1963; Collect. Vol. IV, pp 679-681.
J. Org. Chem, Vol. 71, No. 4, 2006 1397

Al-Mughaid and Grindley
CH2), 38.5 (qC). EI HRMS: m/z calcd for C18H20O4 300.1361,
found 300.1360.
1,9-Bis(r-D-mannopyranosyloxy)-5-(4-[r-D-mannopyranosy-
loxy]-2-oxabutyl)-5-(p-iodophenoxymethyl)-3,7-dioxanonane (24).
To a stirred solution of cluster 11 (100 mg, 0.045 mmol) in THF
(50 mL) and MeOH (25 mL) was added sodium methoxide (0.5 M
in MeOH, 5 mL). After the solution was stirred for 4 h, TLC
(EtOAc-MeOH-H2O, 10:5:1) showed complete conversion to a
product (Rf 0.43), and the reaction mixture was neutralized with
Amberlite IR-120 (H+), filtered, and concentrated. The resulting
residue was dissolved in H2O (2 mL) and extracted with CH2Cl2
(3 × 4 mL), and the aqueous portion was evaporated. The resulting
residue was purified by size exclusion chromatography on a
Sephadex G-25 column (elution H2O) to afford the completely de-
O-benzoylated dendron (24) as a glassy solid (40 mg, 93%). [R]D
5,5-Bis[5-(p-methoxyphenyl)-2-oxapent-4-ynyl]-2-phenyl-1,3-
dioxane (22). A two-necked round-bottomed flask (flame-dried),
equipped with a magnetic stirrer bar, was charged with p-
iodoanisole (21, 0.19 g, 0.81 mmol, 2.2 equiv), CuI (31 mg, 0.16
mmol, 20 mol %), and Pd(PPh3)4 (93.5 mg, 0.081 mmol, 10 mol
%). The flask was evacuated and argon was bubbled through the
reaction mixture for 30 min. This process was repeated two times.
Anhydrous DMF (1 mL) was added via a syringe followed by
anhydrous triethylamine (0.5 mL) and the reaction mixture was
stirred at room temperature for 5 min under argon. To the reaction
mixture was added di-O-propargyl ether 20 (111 mg, 0.37 mmol)
in DMF (1 mL) drop by drop over a 20 min period. The reaction
mixture was stirred at room temperature for 6 h under argon. The
solvent and triethylamine were removed under reduced pressure
and the resulting residue was purified by flash column chroma-
tography (hexanes:EtOAc, 4:1, Rf 0.28) to give the title compound
as a viscous orange oil (153 mg, 81%). 1H NMR δ 6.76-7.46 (m,
13H, PhH), 5.44 (s, 1H acetal H), 4.41, 4.32 (2s, 4H, 2 ×
propargylic CH2), 4.16, 3.92 (AB q, 4H, J ) 11.9 Hz, dioxane
CH2), 3.96, 3.45 (2s, 4H, 2 × exocyclic CH2), 3.78, 3.77 (2s, 6H,
2 × OCH3); 13C NMR δ 160.0-114.1 (PhC), 102.0 (acetal C), 86.5,
86.3, 84.2, 83.8 (4 × acetylenic carbons), 70.2 (C-4 and C-6,
dioxane), 70.0, 68.8 (2 × exocyclic CH2), 59.9, 59.8 (2 ×
propargylic CH2), 55.5 (OCH3), 38.9 (qC). LS ESI MS: m/z calcd
for C32H32O6 + Na 535.21, found 535.2.
1
+37.1 (c 1.0, CH3OH); H NMR (methanol-d4, 500.13 MHz) δ
7.56-6.76 (m, 4H, PhH), 4.85 (d, 3H, J1,2 ) 1.7 Hz, 3 × H-1man),
3.95 (s, 2H, CH2OPh), 3.84-3.72 (m, 12H, 3 × H-3man, 3 ×
H-6aman, 3 × H-6bman, 3 × H-2man), 3.79-3.62 (m, 6H, OCH2-
CH2O), 3.64-3.59 (m, 12H, 3 × H-5man, 3 × H-4man, 3 × OCH2-
CH2O), 3.61 (s, 6H, CCH2O); 13C NMR (methanol-d4,125.77 MHz)
δ 160.7-118.4 (PhC), 101.6 (3 × C-1man), 74.5 (3 × C-5man), 72.7
(3 × C-3man), 72.2 (3 × C-2man), 72.0 (3 × OCH2CH2O), 70.7 (3
× CCH2O), 68.3 (CH2OPh), 67.7 (3 × OCH2CH2O), 67.2 (3 ×
C-4man), 62.9 (3 × C-6man), 46.6 (qC). MALDI FTICR MS: m/z
calcd for C35H57IO22 + Na 979.2, found 979.3.
De-O-benzoylated 9-Mer (25). To a stirred solution of the 9-mer
23 (25 mg, 0.0038 mmol) in THF (25 mL) and MeOH (50 mL)
was added sodium methoxide (0.5 M in MeOH, 5 mL). The reaction
mixture was stirred for 8 h and neutralized with Amberlite IR-120
(H+), filtered, and concentrated. The resulting residue was dissolved
in H2O (1 mL) and extracted with CH2Cl2 (3 × 2 mL), and the
aqueous portion was evaporated. The resulting residue was purified
by size exclusion chromatography on a Sephadex G-25 column
(elution H2O) to afford the completely de-O-benzoylated dendron
(25) as a film (10 mg, 91%). [R]D +23.8 (c 1.0, CH3OH); 1H NMR
(methanol-d4, 500.13 MHz) δ 8.01-6.88 (m, 16H, PhH), 4.82 (d,
9H, J1,2 ) 1.7 Hz, 9 × H-1man), 4.42 (s, 2H, OCH2Ph), 4.31 (s,
6H, 3 × propargylic CH2), 3.98, (s, 6H, 3 × CH2OPh), 3.84-3.70
(m, 36H, 9 × H-3man, 9 × H-6aman, 9 × H-6bman, 9 × H-2man),
3.79-3.56 (m, 54H, 9 × OCH2CH2O, 9 × H-5man, 9 × H-4man),
3.62 (s, 24H, 12 × CCH2O), 3.58 (s, 3H, OCH3), 3.50 (s, 2H, CH2-
OBn); 13C NMR (methanol-d4,125.77 MHz) δ 134.5-116.0 (PhC),
101.8 (9 × C-1man), 86.5, 84.6 (6 × acetylenic carbons), 74.7 (9 ×
C-5man), 72.8 (9 × C-3man), 72.3 (9 × C-2man), 72.1 (9 × OCH2-
CH2O), 70.8 (12 × CCH2O), 68.8 (CH2OBn), 68.1 (3 × CH2OPh),
67.8 (9 × OCH2CH2O), 68.8 (9 × C-4man), 63.1 (9 × C-6man), 58.6
(3 × propargylic CH2), 55.3 (OCH3), 46.3 (4 × qC). MALDI
FTICR MS: m/z calcd for C127H194O71 + Na 2878.1, found 2877.8.
9-Mer (23). A two-necked round-bottomed flask (flame-dried),
equipped with a magnetic stirrer bar, was charged with mannoside
cluster 11 (364 mg, 0.165 mmol), CuI (9.5 mg, 30 mol %), and
Pd(PPh3)4 (19 mg, 10 mol %). The flask was evacuated and argon
was bubbled through the reaction mixture for 30 min. THF (3 mL)
was added via a syringe followed by N,N-diisopropylamine (0.1
mL) and the reaction mixture was stirred at room temperature for
10 min. To the reaction mixture was added tri-O-propargyl ether
(17) (18 mg, 0.05 mmol) in THF (1 mL) drop by drop over a 20
min period. The reaction mixture was stirred at room temperature
for 9 h under argon. The solvent and N,N-diisopropylamine were
removed under reduced pressure and the resulting residue was
purified by flash column chromatography (hexanes:EtOAc, 3:1 f
2:1 f 1:1 f 1:2, Rf 0.65 (hexanes:EtOAc, 1:2)) to give the title
compound as a pale yellow powder (244 mg, 74%). [R]D -39.7 (c
1.0, CHCl3); 1H NMR δ 8.09-6.70 (complex m, 196H, PhH), 6.12
(t, 9H, J3,4 ) J4,5 ) 10.0 Hz, 9 × H-4man), 5.95 (dd, 9H, J2,3 ) 3.3
Hz, 9 × H-3man), 5.80 (br s, 9H, 9 × H-2man), 5.17 (br s, 9H, 9 ×
H-1man), 4.69 (br d, 9H, J6a,6b ) 11.7 Hz, 3.3 Hz, 9 × H-6bman),
4.48-4.38 (m, 18H, 9 × H-6bman, 9 × H-5man), 4.38 (s, 2H, OCH2-
Ph), 4.31 (s, 6H, 3 × propargylic CH2), 4.17, 3.76 (m, 18H, OCH2-
CH2O), 4.01 (br s, 6H, CH2OPh), 3.90-3.72 (m, 18H, OCH2CH2O),
3.72 (s, 24H, 12 × CCH2O), 3.66 (s, 3H, OCH3), 3.60 (s, 2H, CH2-
OBn); 13C NMR δ 166.3, 165.7, 165.6, 165.5 (36 × CO), 159.5-
113.8 (PhC), 97.9 (9 × C-1man), 86.0, 84.2 (6 × acetylenic carbons),
73.2 (OCH2Ph), 70.8 (9 × OCH2CH2O), 70.7 (9 × C-2man), 70.4
(9 × C-3man), 70.0 (12 × CCH2O), 69.6 (CH2OBn), 69.0 (9 ×
C-5man), 67.4 (9 × OCH2CH2O), 67.4 (3 × CH2OPh), 67.2 (9 ×
C-4man), 63.1 (9 × C-6man), 59.9 (3 × propargylic CH2), 55.3
Acknowledgment. We thank the NSERC for financial
support and ARMRC for NMR time. We are very grateful to
Drs. D. Volmer and J. S. Grossert and M. Forbes for recording
the FT-ICR mass spectra.
Supporting Information Available: 1H and 13C NMR spectra
of all products and partial FT-ICR mass spectra of the 23 and 25.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(OCH3), 45.8, 45.5 (4 × qC). MALDI FTICR MS: m/z calcd for
12
C
13C1H338O107 + Na 6624.093, found 6624.13.
JO052045U
378
1398 J. Org. Chem., Vol. 71, No. 4, 2006