Synthesis, aggregation, and chiroptical properties of chiral, amphiphilic dendrimers

Article abstract of DOI:10.1021/jo010423z

The syntheses of amphiphilic dendrimers based on 3,5-dihydroxybenzyl alcohol containing tri-or tetrafunctional chiral central cores and allyl ester termini are described. Water solubility is imparted to the dendrimers via a palladium-catalyzed deprotection of the peripheral allyl esters. This method affords complete deprotection of the carboxylate surface because, in contrast to the basic hydrolysis of methyl ester termini, the solubility of partially hydrolyzed intermediates is maintained throughout the course of the deprotection, thereby avoiding precipitation during the reaction. Chiroptical analysis indicates that the structure of the dendrimers collapses in water, resulting in an increased steric effect upon the central core that is manifested by lower optical rotatory power. However, contributions to the chiroptical properties from the dendron branch segments were not evident in water or organic media, suggesting that chiral substructures were not developing in the branch segments of the dendrimers. Multiangle light scattering studies revealed that the dendrimers experienced significant aggregation in aqueous media that decreased at higher generations. This behavior could be rationalized by a change in conformational preference from a disklike conformation at low generations to a more globular conformation at higher generations.

Full text of DOI:10.1021/jo010423z

6440
J . Org. Chem. 2001, 66, 6440-6452
Syn th esis, Aggr ega tion , a n d Ch ir op tica l P r op er ties of Ch ir a l,
Am p h ip h ilic Den d r im er s
Matthew J . Laufersweiler,† J ason M. Rohde,† J ean-Louis Chaumette,†
Dominique Sarazin,‡ and J on R. Parquette*,†
The Ohio State University, Department of Chemistry, Columbus, Ohio 43210, and
Institut Charles Sadron, Strasbourg, France
parquett@chemistry.ohio-state.edu
Received April 23, 2001
The syntheses of amphiphilic dendrimers based on 3,5-dihydroxybenzyl alcohol containing tri- or
tetrafunctional chiral central cores and allyl ester termini are described. Water solubility is imparted
to the dendrimers via a palladium-catalyzed deprotection of the peripheral allyl esters. This method
affords complete deprotection of the carboxylate surface because, in contrast to the basic hydrolysis
of methyl ester termini, the solubility of partially hydrolyzed intermediates is maintained throughout
the course of the deprotection, thereby avoiding precipitation during the reaction. Chiroptical
analysis indicates that the structure of the dendrimers collapses in water, resulting in an increased
steric effect upon the central core that is manifested by lower optical rotatory power. However,
contributions to the chiroptical properties from the dendron branch segments were not evident in
water or organic media, suggesting that chiral substructures were not developing in the branch
segments of the dendrimers. Multiangle light scattering studies revealed that the dendrimers
experienced significant aggregation in aqueous media that decreased at higher generations. This
behavior could be rationalized by a change in conformational preference from a disklike conformation
at low generations to a more globular conformation at higher generations.
In tr od u ction
dritic interior and the end groups in a manner that
prevents backfolding.6 Similarly, placement of polar end
groups such as carboxylates on the periphery of an
otherwise hydrophobic dendrimer creates a water-
soluble, amphiphilic structure that superficially re-
sembles the Hartley model of the micelle.7 This structural
model segregates the polar end groups from the nonpolar
interior by surrounding the dendritic interior with a shell
In contrast to linear polymers, dendritic polymers are
constructed with monomers containing multiple branch-
ing points. The presence of a branch at every stage of
growth creates a structure that contains a large number
of terminal groups and affords a globular shape at high
molecular weights.1 Due to this globular morphology, the
terminal groups would be expected to reside near the
surface of the polymer; however, the location of the
terminal groups in relation to the central core has been
the subject of recent debate and appears to be highly
structure dependent.2 For example, the presence of
secondary interactions at the periphery such as hydrogen-
bonding3 and π-stacking4 force the peripheral groups to
reside at the periphery while in dendrimers containing
flexible, noninteracting subunits, the end groups tend to
fold back toward the dendrimer interior.5 Percec has
shown that amphiphilic polyaryl ether dendrimers con-
taining perfluorinated or aliphatic terminal chains as-
semble into mesogenic phases that segregate the den-
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† The Ohio State University.
‡ Institut Charles Sadron.
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10.1021/jo010423z CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/21/2001

Synthesis of Chiral, Amphiphilic Dendrimers
J . Org. Chem., Vol. 66, No. 19, 2001 6441
of hydrophilic carboxylate end groups thereby obviating
backfolding. This putative unimolecular micelle model of
amphiphilic dendrimers in water is supported by several
photophysical8 and EPR9 studies. Two-dimensional dif-
fusion-ordered NMR spectroscopy (DOSY NMR) indicates
that the hydrodynamic radii of amphiphilic dendrimers
are highly dependent on environmental factors such as
pH due to repulsions that occur between charged surface
carboxylates.10 Similarly, both theoretical11 and experi-
mental12 studies suggest that the molecular dimensions
of dendrimers expand in good solvents and collapse in
poor solvents13 because much of their inner volume is
accessible to solvent.14 Unlike micelles, however, the
structure of an amphiphilic dendrimer is unimolecular
and therefore stable to changes in pH, concentration, and
the nature of the medium.
There has been considerable interest in dendrimers
composed of chiral subunits because their well-defined
structure and homogeneity permits studies to be under-
taken that probe whether the local chirality of a subunit
can be cooperatively transmitted to distal portions of the
molecule.15 However, several reports suggest that such
cooperative transmission of asymmetry rarely occurs due
to the conformational mobility of these systems.16 Fur-
thermore, these systems were studied in good solvents
that afford a fully expanded conformation that likely
exhibits backfolding and maximum flexibility. Our inter-
est in studying chiral, amphiphilic dendrimers17 stems
from the potential of aqueous media to reduce backfolding
and impose a hydrophobic effect that compresses the
dendrimer into a more compact conformation to minimize
interactions of the aqueous medium with the nonpolar
interior. This solvent-induced compression should create
a compact globular structure that is more structurally
rigid, and hence, conformational order should be optimal
in water.18 Seebach observed a variation in the sign and
shape of the CD spectra with dendrimer generation that
occurred in a poor solvent, acetonitrile, but not in a good
solvent such as dichloromethane.19 Although this obser-
vation could not be explicitly rationalized, the origin of
the chiroptical anomalies is likely due to a collapse of
the dendrimer structure in acetonitrile that perturbs the
conformational equilibria of the molecule. Similarly, we
have observed conformational order in intramolecularly
hydrogen-bonded dendrimers that was optimal in poor
solvents.20 Chiral, amphiphilic dendrimers may be useful
as enantioselective phase-transfer catalysts in aqueous
media especially if conformational order can be induced
throughout the dendritic branches. The goal of this work
is directed at developing a strategy to prepare am-
phiphilic dendrimers elaborated from a chiral, nonrace-
mic central core and to explore the effect of aqueous
media on the conformational and chiroptical properties
of dendrimers constructed with highly flexible polyaryl
ether branch units.
Resu lts a n d Discu ssion
Syn th esis. (1R,2S)-1-Phenyl-2-amino-1,3-propanediol,
1, and 2,5-anhydro-D-mannitol, 4,21 were selected to be
tri- and tetrafunctional chiral central core units, respec-
tively. Polyfunctional cores 1 and 4 were acylated with
4-benzyloxybenzoyl chloride and subsequently hydroge-
nated, giving 3 and 6 to provide phenolic hydroxyls to
simplify the convergent dendron attachment to the
central cores by O-alkylation22 (Scheme 1). Use of an acyl
linkage to the central core posed potential selectivity
issues in the final terminal ester hydrolysis that would
be necessary to render the dendrimers amphiphilic;
however, efforts to introduce other linkages were unsuc-
cessful.
Since methyl esters can be readily cleaved by non-
hydrolytic, dealkylative methods, we briefly investigated
the selective hydrolyis of methyl ester terminated den-
drimers. Accordingly, trialkylation of 3 with the first-
((CH3O2C)2[G-1]-Br), second- (CH3O2C)4[G-2]-Br), or third-
(16) (a) Seebach, D.; Lapierre, J . M.; Skobridis, K.; Greiveldinger,
G. Angew. Chem., Int. Ed. Engl. 1994, 33, 440. (b) Seebach, D.;
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77, 1673. (c) Peerlings, H. W. I.; Meijer, E. W. Eur. J . Org. Chem. 1998,
573, 3. (d) Chen, Y.-M.; Chen, C.-F.; Xi, F. Chirality 1998, 10, 661. (e)
Peerlings, H. W. I.; Trimbach, D. C.; Meijer, E. W. Chem. Commun.
1998, 497. (f) Peerlings, H. W. I.; Struijk, M. P.; Meijer, E. W. Chirality
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M.; McGrath, D. V. Macromolecules 1996, 29, 8979. (k) Chang, H.-T.;
Chen, C.-T.; Kondo, T.; Siuzdak, G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 182. (l) Kress, J .; Rosner, A.; Hirsch, A. Chem.
Eur. J . 2000, 6, 247. (m) Chow, H.-F.; Mak, C. C. J . Chem. Soc., Perkin
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Chow, H.-F.; Mak, C. C. Tetrahedron Lett. 1996, 37, 5935. (q) Lartigue,
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8, 2697. (r) Issberner, J .; Boehme, M.; Grimme, S.; Nieger, M.; Paulus,
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Recl. Trav. Chim. Pays-Bas. 1995, 114, 225. (v) Murer, P.; Seebach,
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Lapierre, J . M.; Greiveldinger, G.; Seebach, D. Helv. Chim. Acta 1997,
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1990, 112, 8515. (b) Gopidas, K. R.; Leheny, A. R.; Caminati, G.; Turro,
N. J .; Tomalia, D. A. J . Am. Chem. Soc. 1991, 113, 7335.
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Romanelli, M.; Turro, N. J .; Tomalia, D. A. J . Phys. Chem. 1996, 100,
11033.
(10) (a) Young, J . K.; Baker, G. R.; Newkome, G. R.; Morris, K. F.;
J ohnson, C. S., J r. Macromolecules 1994, 27, 3464. (b) Newkome, G.
R.; Young, J . K.; Baker, G. R.; Potter, R. L.; Audoly, L.; Cooper, D.;
Weis, C. D.; Morris, K.; J ohnson, C. S. J . Macromolecules 1993, 26,
2394.
(11) (a) Murat, M.; Grest, G. S. Macromolecules 1996, 29, 1278. (b)
Welch, P.; Muthukumar, M. Macromolecules 1998, 31, 5892.
(12) (a) De Backer, S.; Prinzie, Y.; Verheijen, W.; Smet, M.; Desmedt,
K.; Dehaen, W.; De Schryver, F. C. J . Phys. Chem. A 1998, 102, 5451.
(b) Gitsov, I.; Frechet, J . M. J . J . Am. Chem. Soc. 1996, 118, 3785. (c)
Stechemesser, S.; Eimer, W. Macromolecules 1997, 30, 2204.
(13) We use the terms “good” and “poor” solvent to mean compatible
or incompatible with the molecule in the usual polymer chemistry
sense; see: Flory, P. J . Principles of Polymer Chemistry; Cornell
University Press: Ithaca, 1953 p 424.
(17) For an example of
a water-soluble dendrimer containing
peripheral glucose units, see: (a) Schmitzer, A.; Perez, E.; Rico-Lattes,
I.; Lattes, A. Tetrahedron Lett. 1999, 40, 2947. (b) Schmitzer, A.; Perez,
E.; Rico-Lattes, I.; Lattes, A.; Rosca, S. Langmuir 1999, 15, 4397.
(18) Tanford, C. The Hydrophobic Effect: Formation of Micelles and
Biological Membranes, 2nd ed.; J ohn Wiley and Sons: New York, 1980.
(19) Murer, P.; Seebach, D. Helv. Chim. Acta 1998, 81, 603.
(20) Recker, J .; Tomcik, D. J .; Parquette, J . R. J . Am. Chem. Soc.
2000, 122, 10298.
(14) Naylor, A. M.; Goddard, W. A. I.; Kiefer, G. E.; Tomalia, D. A.
J . Am. Chem. Soc. 1989, 111, 2339.
(15) (a) For some reviews of chiral dendrimers, see: (a) Seebach,
D.; Rheiner, P. B.; Greiveldinger, G.; Butz, T.; Sellner, H. Top. Curr.
Chem. 1998, 197, 125. (b) Peerlings, H. W. I.; Meijer, E. W. Chem.
Eur. J . 1997, 3, 1563. (c) Thomas, C. W.; Tor, Y. Chirality 1998, 10,
53.
(21) The preparation of this compound was adapted from the
following report: Horton, D.; Philips, K. D. Carbohydr. Res. 1973, 30,
367.
(22) Hawker, C. J .; Frechet, J . M. J . J . Am. Chem. Soc. 1990, 112,
7638.

6442 J . Org. Chem., Vol. 66, No. 19, 2001
Sch em e 1. Syn th esis of Tr i- a n d Tetr a fu n ction a l Cen tr a l Cor esa
Laufersweiler et al.
a
Key: (a) 4-BnOC6H4COCl, DMAP, pyr, 64%; (b) H2/Raney Ni CH3OH/EtOAc, 52%; (c) NaNO2-HOAc, 0 °C; (d) NaBH4, H2O, pH <8;
(e) Ac2O, pyr, DMAP, 51% from 4; (f) NaOCH3, CH3OH, 81%; (g) 4-BnOC6H4COCl, DMAP, pyr, 85%; (h) H2/Pd-C CH3OH/EtOAc, 100%.
generation (CH3O2C)8[G-3]-Br) Fre´chet-type dendritic
wedge using K2CO3/18-C-6 in THF/DMF (4:1) at 70 °C
provided the first-, second-, and third-generation den-
drimers.23 Conversion of dendrimers with methyl esters
on the periphery to the corresponding carboxylic acids
required selective hydrolysis of the peripheral groups in
the presence of the core benzoate linkages. Therefore,
basic hydrolysis of the third-generation dendrimer was
investigated first because the increased steric encum-
brance of the internal ester linkages was expected to
decrease the rate of hydrolysis relative to the terminal
esters. However, exposure to a stoichiometric amount of
KOH in THF/water at 60 °C resulted in cleavage of the
ester linkages to the core leaving only the amide intact
as determined by electrospray mass spectrometry. De-
alkylative hydrolysis using NaCN in HMPA at 70 °C
promoted hydrolysis of the methyl ester termini without
generated in this process tend to be soluble in THF, this
method should prevent precipitation from occurring
during hydrolysis. Accordingly, synthesis of the allyl
ester-terminated dendron bromides was accomplished by
bis-alkylation of 3,5-dihydroxybenzyl alcohol with methyl
4-bromomethyl benzoate7b followed by transesterification
of the methyl esters with allyl alcohol/sodium allyloxide
in THF (Scheme 2). Conversion of the dendritic benzyl
alcohols to the corresponding bromides was carried out
using phosphorus tribromide for each generation and was
found to be superior to PPh3/CBr4, which afforded un-
reproducible yields. Synthesis of the second- and third-
generation bromides proceeded by repetition of the al-
kylation and bromination steps.
Trialkylation of the central core, 3, with the first-
((allylO2C)2[G-1]-Br, 9), second- ((allylO2C)4[G-2]-Br, 11),
and third-generation ((allylO2C)8[G-3]-Br, 13) dendron
monobromides was accomplished using K2CO3/18-C-6 in
THF/DMF (3:1) at 70 °C. Purification over silica gel
afforded monodisperse dendrimers with molecular weights
of 1937 (14a , 63%), 3714 (15a , 74%), and 7267 (16a , 99%)
with 6, 12, and 24 terminal allyl esters, respectively
(Figure 1). The six protons ortho to the hydroxyl group
of the benzoate linkage to the central aminodiol core were
observed as a multiplet at 6.9 ppm in the 1H NMR
spectrum of all three dendrimers and were clearly
distinguishable from the multiple resonances of the
dendritic wedge even in the third-generation dendrimer
16a . Integration of the areas of these protons and the
peripheral allyl esters confirmed that complete alkylation
of the central core had occurred for each generation.
Tetrafunctional dendrimers 17a -19a were prepared in
an analogous fashion to 14a -16a affording after purifi-
cation over silica gel dendrimers with molecular weights
of 2526 (17a , 72%), 4897 (18a , 72%), and 9638 (19a , 38%)
with 8, 16, and 32 terminal allyl esters, respectively
(Figure 2). Proton NMR was also useful in ascertaining
1
core hydrolysis affording 16b in 90% yield. However, H
NMR analysis indicated that only ca. 90% of the methyl
esters had been hydrolyzed. This was, in part, a conse-
quence of the decreasing solubility of the carboxylate-
terminated dendrimer in HMPA as the hydrolysis pro-
ceeded. Efforts to extend the reaction time to afford
complete hydrolysis led ultimately to decomposition,
possibly due to cleavage of the benzyl ether linkages
present in the dendrons.
To exhaustively deprotect the peripheral esters, a
method capable of maintaining the solubility of the
dendrimer throughout hydrolysis was necessary to avoid
precipitation of partially hydrolyzed intermediates. There-
fore, we turned to preparation of the allyl ester-
terminated dendrimers as precursors since allyl esters
can be readily deprotected using catalytic Pd(0) and
HCO2H/(C4H9)3N,24 thereby circumventing the possibility
of core hydrolysis or degradation of the benzyl linkages.
Further, since the tributylammonium carboxylate salts
(23) (a) Chaumette, J .-L.; Laufersweiler, M. J .; Parquette, J . R. J .
Org. Chem. 1998, 63, 9399. (b) Rohde, J . M.; Parquette, J . R.
Tetrahedron Lett. 1998, 39, 9161.
(24) Hayakawa, Y.; Wakabayashi, S.; Kato, H.; Noyori, R. J . Am.
Chem. Soc. 1990, 112, 1691.

Synthesis of Chiral, Amphiphilic Dendrimers
J . Org. Chem., Vol. 66, No. 19, 2001 6443
Sch em e 2. Syn th esis of Allyl Ester Ter m in a ted Den d r itic Wed gesa
a
Reagents: (a) K2CO3, 18-C-6, 3,5-dihydroxybenzyl alcohol, acetone, reflux; (b) allyl alcohol, Na0 (cat.) THF; (c) PBr3, toluene, 0 °C.
that complete alkylation of 6 with the dendrons had
CH2Cl2 separated the PPh3 from the dendrimers. The
dendrimers were finally isolated by adjusting the pH of
the aqueous solution to 2-3, causing precipitation to
occur and thereby permitting isolation of the dendrimers
by filtration. This procedure afforded dendrimers from
14a -16a with 6 (HO2C)6[G-1] (14b), 12 (HO2C)12[G-2]
(15b), and 24 (HO2C)24[G-3] (16b) terminal acids in 90%,
66%, and 81% yields, respectively. Similarly, deprotection
of 17a -19a afforded dendrimers with 8 (HO2C)8[G-1]
(17b), 16 (HO2C)16[G-2] (18b), and 32 (HO2C)32[G-3] (19b)
terminal acids in 70%, 92%, and 62% yields, respectively.
occurred. The magnetic equivalence of the C-2,5 methine
and C-1,6 methylene protons of the core caused these
resonances to be observed in 17a -19a as a singlet (or
slightly broadened singlet) (6H) at 4.6 ppm and the C-3,4
methine protons to also be observed as a broad singlet
at 5.7 ppm. These eight core protons were clearly
distinguishable from the resonances arising from the
wedges even in the third generation dendrimer 19a .
Integration of the respective areas of these protons and
the peripheral allyl esters confirmed that complete al-
kylation of the central core had occurred for each genera-
tion.
All the dendrimers were obtained as white solids or
glasses that were readily soluble in aprotic solvents such
as CH2Cl2, acetone, ethyl acetate, and THF but were
completely insoluble in methanol. MALDI-TOF mass
spectrometry revealed molecular masses for 14a -15a
and 17a -19a consistent with the expected structures;
however, it was not possible to observe ions for third-
generation dendrimer 16a using several matrixes (Table
1). However, SEC analysis revealed the expected increase
in Mw with generation for all dendrimers and the poly-
dispersity values (Mw/ Mn) were close to unity, indicating
the high purity of these materials.
Deprotection of the allyl esters of 14a -19a was effected
by exposure to 2.5 mol % Pd2(dba)3CHCl3/25 mol % PPh3
and HCO2H/(C4H9)3N in THF at 55 °C for 12 h (Figures
1 and 2).24 In all cases, homogeneity was maintained
throughout the course of the deprotection, ultimately
affording the poly-tributylammonium salt of the den-
drimers. The tributylammonium salts of 14b-19b were
sufficiently soluble in organic media such that CH2Cl2
solutions of the crude salts could be washed with water
to remove the excess tributylammonium formate used in
the deprotection. Subsequent exchange of the tributyl-
ammonium counterion for sodium by washing the organic
layer with aqueous sodium bicarbonate imparted water
solubility to the dendrimers so that washing with
Rigorous characterization of carboxylic acid terminated
dendrimers was hampered by the propensity of these
materials to aggregate in organic and aqueous solution.25
1H and 13C NMR analysis indicated that all of the allyl
esters had been hydrolyzed without core hydrolysis;
however, the proton resonances became significantly
broadened with increasing generation in acetone-d6 and
to a lesser degree in DMSO-d6. In D2O (pH 9, Na2DPO4),
extreme broadening was observed at all generations
resulting in indecipherable spectra. Increasing the tem-
perature from 22 to 70 °C in any of these solvents only
slightly reduced the broadening in the spectra. Similarly,
GPC analysis revealed broad, ill-defined peaks presum-
ably due to the aggregation that occurred in the carrier
solvent, THF. Polystyrene-equivalent molecular weights
were significantly higher than the calculated molecular
weights and some displayed varying amounts of an
extremely broadened peak at very high molecular weight
in the range of 18 000-45 000 Da. Negative-ion electro-
spray mass spectrometry in basic water (water/2-pro-
panol, (C2H5)3N) showed a peak at m/e ) 1696 for 14b;
m/e ) 3236 for 15b; m/e ) 2206 for 17b; and m/4e ) 1066
for 18b, verifying that the deprotection protocol pro-
ceeded without core hydrolysis or cleavage of the benzylic
linkages (Table 1). However, we have been unable to
(25) Aggregation of dendrimers with hydrophilic carboxylate termini
has been observed previously in organic solvents, see ref 7j,k.

6444 J . Org. Chem., Vol. 66, No. 19, 2001
Laufersweiler et al.
F igu r e 1. Trifunctional amphiphilic dendrimers: (a) 2.5 mol % Pd2(dba)3CHCl3/25 mol % PPh3, 1.2 M HCO2H/(C4H9)3N (1:1) in
THF, 55 °C.

Synthesis of Chiral, Amphiphilic Dendrimers
J . Org. Chem., Vol. 66, No. 19, 2001 6445
F igu r e 2. Tetrafunctional amphiphilic dendrimers: (a) 2.5 mol % Pd2(dba)3CHCl3/25 mol % PPh3, 1.2 M HCO2H/(C4H9)3N (1:1)
in THF, 55 °C.
observe distinct ions with dendrimers 16b and 19b,
possibly as a consequence of the aggregation.
Differ en tia l Sca n n in g Ca lor im etr y. The glass tran-
sition temperatures of trifunctional dendrimers 14a /b-
16a /b and the corresponding methyl ester analogues were
measured by differential scanning calorimetry (DSC)
(Table 1). Interestingly, whereas all the allyl ester
terminated dendrimers (14a -16a ) and (MeO2C)6-[G1]

6446 J . Org. Chem., Vol. 66, No. 19, 2001
Laufersweiler et al.
Ta ble 1. GP C,a MS,b a n d DSC Da ta for Tr i- a n d Tetr a fu n ction a l Den d r im er s 14-19
dendrimer
M (calcd)
Mw (SEC)
Mn (SEC)
M (ms)
Tg (°C)
Tm (°C)
+64
(MeO2C)6-[G1]
1782
3402
6643
1937
3714
7267
1697
3235
6306
2524
4893
9638
2208
4261
8366
1941
3540
5671
2477
3422
6399
2560
6455
14 928
2407
4951
9614
2819
7781
9144
1865
3405
5492
2426
3174
6089
2504
5799
5373
2095
4711
9264
2576
6238
6147
1783 (MH)
(MeO2C)12-[G2]
3426 (M + Na)
6683 (M + K)
1964 (M + Na)
3738 (M + Na)
+67
+45
(MeO2C)24-[G3]
(allylO2C)6-[G1] (14a )
(allylO2C)12-[G2] (15a )
(allylO2C)24-[G3] (16a )
(HO2C)6-[G1] (14b)
(HO2C)12-[G2] (15b)
(HO2C)24-[G3] (16b)
(allylO2C)8-[G1] (17a )
(allylO2C)16-[G2] (18a )
(allylO2C)32-[G3] (19a )
(HO2C)8-[G1] (17b)
(HO2C)16-[G2] (18b)
(HO2C)32-[G3] (19b)
+45
+45
+43
1696 (M - H)
3234 (M - H)
+133
+123
+132
2547 (M + Na)
4916 (M + Na)
4842 (M + 2Na)
2206 (M - H)
1066 (M - 4H)
a
b
Molecular weights determined by comparison to polystyrene standards. Determined by MALDI-TOF MS; 14b-19b determined by
negative-ion electrospray MS.
Ta ble 2. Ch ir op tica la Da ta for 14-19
b
c
compd
[R]22
[Φ]22
365
365
(allylO2C)6-[G1] (14a )
(allylO2C)12-[G2] (15a )
(allylO2C)24-[G3] (16a )
(HO2C)6-[G1] (14b)
(HO2C)12-[G2] (15b)
(HO2C)24-[G3] (16b)
(allylO2C)8-[G1] (17a )
(allylO2C)16-[G2] (18a )
(allylO2C)32-[G3] (19a )
(HO2C)8-[G1] (17b)
(HO2C)16-[G2] (18b)
(HO2C)32-[G3] (19b)
141.5
57.0
2743
2118
1483
192.9
203.9
328.2
20.4
11.3
6.3
5.2
-65.1
-26.7
-10.8
-41.4
-18.8
-11.0
-1644
-1307
-1041
-916
-800
-918
a
Rotations measured in CHCl3 for 14a -19a ; 14b-19b in THF.
Specific rotations in 10-1 deg cm2 g-1 c Molar rotations in 10-1
deg cm2 mol-1
b
.
.
F igu r e 3. Molar rotations of 14b-16b in water (pH 9, 5%
phosphate).
exhibited melting transitions (Tm), (MeO2C)12-[G2],
(MeO2C)24-[G3], and the acid-terminated dendrimers
(14b-16b) displayed glass transitions (Tg). Glass transi-
tion temperatures of dendrimeric molecules have been
previously shown to increase with increasing polarity of
the terminal groups because of the large proportion of
end-groups in these systems.26 The significantly increased
glass transition temperatures for the acid-terminated
dendrimers relative to the corresponding methyl esters
are consistent with these reports.
Ch ir op tica l P r op er ties. The allyl ester-terminated
dendrimers (14a -16a ) exhibited positive molar rotations
in CHCl3 that decreased going from the first- to the third-
generation dendrimers (Table 2). Similarly, the molar
rotations in CHCl3 of tetrafunctional dendrimers 17a -
19a became less negative going from the first- to the
third-generation dendrimer. We have previously observed
this behavior with the methyl ester dendrimers derived
from this central core and allyl ester dendrimers derived
from 2,5-anhydro-D-mannitol.23 By comparison to a series
of model compounds, this effect was correlated with a
change in conformational equilibrium brought about by
the increase in steric congestion developing around the
central core as the dendrimers increased in size.23
F igu r e 4. Molar rotations of 17b-19b in water (pH 9, 5%
NaHCO3).
However, the ORD curves became stable when measured
after equilibrating for 1 h following dissolution. Interest-
ingly, both series of dendrimers exhibited rotations that
varied in sign and magnitude as a function of generation.
Although deviations of the dendrimer optical activity
with generation from that of the chiral central core
suggest the presence of chiral substructures within the
achiral dendritic branches,27 the dynamic nature of the
In contrast to the ORD curves observed in THF or
CHCl3, the value of the rotations of acid-terminated
dendrimers 14b-19b in water were extremely fluxional
and difficult to reproduce within the first hour following
dissolution in the aqueous buffer (Figures 3 and 4).
1
rotation values and the broadening observed in the H
NMR spectra also suggest that the chiroptical variation
arises from aggregation that occurs in water and reaches
(27) For
a discussion of the relationship of optical activity to
(26) (a) Wooley, K. L.; Hawker, C. J .; Pochan, J . M.; Frechet, J . M.
J . Macromolecules 1993, 26, 1514. (b) Hawker, C. J .; Frechet, J . M. J .
J . Chem. Soc., Perkin Trans. 1 1992, 2459.
conformation in linear polymers, see: (a) Farina, M. Top. Stereochem.
1987, 171. (b) Pino, P.; Salvadori, P.; Chiellini, E.; Luisi, P. L. Pure
Appl. Chem. 1968, 16, 469.

Synthesis of Chiral, Amphiphilic Dendrimers
J . Org. Chem., Vol. 66, No. 19, 2001 6447
F igu r e 6. CD of 17b in water (pH 9) as a function of
temperature.
F igu r e 5. CD of 14b in water (pH 9).
a state of equilibrium within 1 h for each of the den-
drimers. Changes in aggregation state can give rise to
large variations in optical rotatory power.28 The simul-
taneous presence of several different equilibrating ag-
gregation states likely contributes significantly to the
dynamic optical rotatory behavior that is observed in
water. Multiangle light scattering studies (vide infra)
support this interpretation of the chiroptical variation
with dendrimer generation.
In aqueous solution, the first-generation dendrimer
14b exhibited a weak excitonically coupled29 Cotton effect
centered at 264 nm (Figure 5); however, the second- (15b)
and third-generation (16b) dendrimers did not exhibit
any observable Cotton effects. This is in contrast to the
CD spectra recorded in CHCl3 for the methyl ester
derivatives that displayed excitonically coupled Cotton
effects at this wavelength for all generations.23 The
intensity of CD observed for 14b in water was also
decreased by an order of magnitude in water relative to
the CD of the corresponding methyl ester measured in
CHCl3. To increase the extent of the hydrophobic effect,
the CD spectrum was recorded for the dendrimers in
aqueous media saturated with LiCl. However, this de-
stroyed the Cotton effect observed for 14b resulting in
flat lines for 14b-16b. A decrease in the amplitude of
this Cotton effect with increasing generation was previ-
ously observed for the methyl ester derivatives in CHCl3
and was correlated with an increasing steric effect that
perturbed the conformational equilibrium of the chiral
central core.23 The low intensity of the Cotton effect at
264 nm observed for 14b and the lack of any CD observed
for 15b and 16b are also consistent with a solvent-
induced structural collapse that increases the effective
steric bulk of the dendritic wedges.
F igu r e 7. Zimm plot of 14b in water with buffer at pH ) 9.
Mw ) 9.1 106 g mol-1, RG ) 911 nm, A2 ) 4.5 10-5 cm3 mol
Z
g-2. Vv is the excess Raleigh ratio for the vertically polarized
incident beam detected through a vertically positioned ana-
lyzer placed before the photomultiplier. C ) concentration of
the solution; K ) the optical constant; Q ) wave vector (Å-1 ).
exhibit a Cotton effect in aqueous medium. The CD curve
was also sensitive to temperature becoming maximal at
-3 °C and smoothly decreasing upon heating to 77 °C.
Similar to 14b, saturating the solution with LiCl resulted
in a loss of the Cotton effect at 264 nm and did not change
the spectra of 18b or 19b. The transition at 264 nm is
due to a π f π* transition (1La) associated with the
4-alkoxylbenzoate linkages connecting the central core
to the dendritic wedges. Therefore, we conclude that the
variations of the optical rotations and CD spectra of 14b-
19b in water reflect a solvent induced aggregation of the
dendrimers that is accompanied by a shift in conforma-
tional state that increases the steric effect of the dendritic
wedges on the central core rather than to the presence
of chiral conformations present in the dendritic branches.
Ligh t Sca tter in g Stu d ies. Multiangle laser light
scattering (MALLS) was used to determine the degree
of aggregation that occurs when the carboxylic acid
terminated dendrimers were dissolved in aqueous media.
Solutions were prepared by dissolving the dendrimers in
aqueous buffer (glycine/NaOH; pH 9) and the static light
scattering measurements were carried out using a Se-
matech instrument equipped with a He-Ne laser.
The MALLS measurements confirmed that the acid-
terminated dendrimers were significantly aggregated in
aqueous media (Tables 3 and 4). The molecular dimen-
Neither the allyl ester or the acid-terminated tet-
rafunctional dendrimers 17a /b-19a /b exhibited any
detectable CD in CHCl3 or THF, respectively, in the
range of 230-350 nm. Although the second- (18b) and
third-generation (19b) dendrimers did not show any
Cotton effects in aqueous solution, the first-generation
dendrimer, 17b, exhibited an excitonically coupled Cotton
effect at 264 nm similar to the curve seen for 14b (Figure
6). It is noteworthy that even the central core 6 did not
(28) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p 1076.
(29) (a) Circular Dichroism: Principles and Applications; Nakanishi,
K. L., Berova, N., Woody, R., Eds.; VCH: New York, 1994. (b) Harada,
N.; Nakanishi, K. O. Circular Dichroic Spectroscopy: Exciton Coupling
in Organic Stereochemistry; University Science Books: Mill Valley, CA,
1983.

6448 J . Org. Chem., Vol. 66, No. 19, 2001
Ta ble 3. Molecu la r Dim en sion s in Wa ter (p H ) 9.0) by MALLS
Laufersweiler et al.
b
concentration
A2
THF
water (pH ) 9)
a
c
d
dendrimer
(× 10-3 g/mL)
Mw (g/mol)
RG (nm)
(mol‚mL‚g-2)
FV
QR
dn/dce mL‚g-1
dn/dc mL‚g-1
G1(CO2H)6 (14b)
G2(CO2H)12 (15b)
G3(CO2H)24 (16b)
G1(CO2H)8 (17b)
G2(CO2H)16 (18b)
G3(CO2H)32 (19b)
3.69
3.62
2.63
3.40
1.22
0.91
9.1 106
1.9 106
3.5 105
1.6 107
1.9 105
4.6 105
911
539
395
480
217
352
4.5 10-5
-2.5 10-4
5.3 10-3
0.04
0.015
0.06
0.02
0.07
0.023
4 ... 11
2.4...7
1.8...5
2...6
0.9...2.8
1.6...4.5
0.184
0.182
0.187
0.122
0.160
0.150
0.228
0.227
0.230
0.173
0.201
0.196
-1.3 10-4
5.4 10-3
1.6 10-3
a
b
d
Radius of gyration. Second virial coefficient. c Depolarization ratio. Scattering windows: QR < 1 (Guinier domain) and QR > 1
(asymptotic domain). e dn/dc ) refractive index increment.
Ta ble 4. Molecu la r Dim en sion s in Wa ter (p H ) 9.0) by MALLS
porod slope
small Q (shape)
porod slope
high Q (shape)
ML
starlike fit:
no. of branches
b
dendrimer
ba (Å)
g (mol Å)-1
Naggr
G1(CO2H)6 (14b)
G2(CO2H)12 (15b)
G3(CO2H)24 (16b)
G1(CO2H)8 (17b)
G2(CO2H)16 (18b)
G3(CO2H)32 (19b)
-2 disc
-1 rod
2700
2040
75
42
5360
587
55
6900
45
55
6
4
-2 disc
-2 disc
-1.1 rod
-3 aggregated
-1 rod
-1.1 rod
2
-2.2 branched
-0.3 globular
-0.33 globular
2000
280
10
5
8
-1 rod
a
b
Persistence length. Degree of aggregation.
sions of the aggregates were determined from a Zimm
plot30 as shown in Figure 7 for 14b as an example. The
linearity of the lines indicate low polydispersity and the
validity of the extrapolation for the mean weight molec-
ular weight (Mw) determination. The extent of aggrega-
tion was highly dependent on dendrimer generation and
the branching multiplicity of the central core, each of
which altered the conformational preference of the den-
drimers. First-generation dendrimers 14b and 17b de-
veloped very high molecular weight aggregates in water
displaying aggregation numbers (Nagg) of 5360 (Mw ) 9.1
× 106) and 6900 (Mw ) 1.6 × 107), respectively. The
molecular dimensions (Mw, Nagg, and Rg ) decreased for
each generational step up to the third generation for both
series of dendrimers. Although the aggregation number
(Nagg) of the trifunctional dendrimers (14b-16b) de-
creased by a factor of 10 for each generational step, the
tetrafunctional series (17b-19b) experienced a 150-fold
decrease in Nagg upon going from the first to the second
generation, and only a small change in aggregation
number occurred upon increasing to the third generation.
The value of the second virial coefficient, A2, generally
increased in value at higher dendrimer generation for
both dendrimer series. This indicates that the dendrimer-
solvent interaction becomes more favorable at higher
generations as would be expected for a more globular
conformation.
The shape of the aggregates was estimated by measur-
ing the fractal dimensions (D) at large scattering win-
dows (QR > 1) in the asymptotic regime as shown for
14b in Figure 8 as an example.31 The trifunctional first-
and second-generation dendrimers, 14b and 15b, exhib-
ited a fractal dimension of 2, suggesting that the ag-
gregates resembled a smooth two-dimensional shape such
as a disk morphology. At the third generation (16b), D
decreased to 1.1, which is characteristic of a smooth
rodlike morphology. The tetrafunctional first-generation
dendrimer 17b had D ) 3, indicating that a highly
irrregular three-dimensional aggregate was formed con-
sistent with the high molecular weight of the aggregate.
The fractal D value decreased to 1 for the second- (18b)
and third-generation (19b) dendrimers in contrast to the
trifunctional series, which remained disklike at the
second generation. AFM images obtained for 17b-19b
showed that aggregates of 17b exhibited spherical shapes
while fiberlike aggregates were formed for 18b-19b in
agreement with the MALLS studies (Figure 9).
The flexibility of polyaryl ether dendritic branches
likely affords dendrimers that exhibit highly dynamic
structural morphologies. Accordingly, the observed de-
crease in the degree of aggregation (Nagg) with increasing
dendrimer generation can be rationalized by considering
a conformational equilibrium interconverting two limit-
ing dendrimer conformations such as a disklike shape
at one extreme and a globular shape at the other (Figure
10). If this conformational equilibrium favors the disklike
shape with a large hydrophobic surface exposed to
solvent, as would be expected at lower dendrimer genera-
tion, aggregation would occur to minimize unfavorable
interactions with the aqueous phase. At higher genera-
tions, the position of the conformational equilibrium
shifts in the direction of the globular morphologies
exposing the hydrophilic carboxylates to solvent thereby
segregating the hydrophobic interior segments of the
dendrimer from the aqueous phase. Consequently, the
degree of aggregation would decrease at higher genera-
tions because the need to avoid the unfavorable interac-
tions of the solvent with the hydrophobic dendrimer
interior would decrease. That the tetrafunctional den-
drimers experienced a more pronounced decrease in the
(30) Zimm, B. H. J . Chem. Phys. 1948, 16, 1093.
(31) Higgins, J . S.; Benoit, H. C. Polymers and Neutron Scattering;
Oxford Science: Oxford, 1994.
F igu r e 8. Porod slope or fractal determination of 14b in water
with buffer at pH ) 9 (c ) 3.7 10-3 g/mL).

Synthesis of Chiral, Amphiphilic Dendrimers
J . Org. Chem., Vol. 66, No. 19, 2001 6449
F igu r e 9. Atomic force micrographs (AFM) for G1(CO2H)8, 17b (left); G2(CO2H)16, 18b (middle); and G3(CO2H)32, 19b (right).
AFM films were prepared by dissolving the dendrimers in water (pH ) 9) and then allowing them to dry slowly in an inert
atmosphere at 80 °C for 24 h. The films were then washed with distilled water and dried again at 80 °C for 24 h affording
crack-free wafers. The wafers were then scanned in contact mode using a cantilever spring constant of 0.58 N m-1. The z scale
representation is achieved by using a gray scale for which a lower value of z is indicated by darker gray and, conversely, lighter
gray indicates a higher z value. These images show that the aggregation of 18b and 19b form rodlike structures resembling a
linear necklace of spherical particles, whereas 17b forms a more globular aggregate.
F igu r e 10. Notional depiction of generation-dependent dynamic conformational equilibrium of amphiphilic dendrimers in water
interconverting between disklike and spherical morphologies.
spectra were recorded on a Perkin-Elmer model 1600 instru-
ment. 1H NMR spectra were recorded at 300, 400, or 500 MHz
and 13C NMR spectra at 75, 100, or 125 MHz on a Bruker AC-
300, AC-400, or AC-500 instrument as indicated. EI or FAB
mass spectra were recorded at The Ohio State University
Chemical Instrument Center. MALDI-TOF spectrometry was
performed with a Kratos Kompact III spectrometer using
indoleacrylic acid as the matrix in tetrahydrofuran (THF).
Electrospray mass spectrometry was performed on a PE Sciex
API300 triple quadrupole mass spectrometer, with negative
ion electrospray at a concentration of 2 mg/mL in a 10% NH4-
OH solution in 1:1 H2O/i-PrOH. Ultraviolet spectroscopy was
performed on a Hewlett-Packard 8452 A diode array spectro-
photometer. Optical rotations were measured on a Perkin-
Elmer 241 MC polarimeter. Optical rotations were performed
in chloroform, THF or 5% aqueous sodium phosphate solution
(pH 9.0). Concentrations are given in g/100 mL. Circular
dichroism measurements were performed on a J ASCO J -500C
spectrapolarimeter. Gel permeation chromatography (gpc) was
carried out using a Waters 6000A pump, a Waters 410
differential refractometer detector, and three divinylbenzene
columns arranged in series (103, 104, and 105 Å). All runs were
carried out using THF as the carrier solvent at 40 °C. All
reactions were performed under an argon or nitrogen atmo-
sphere. Dimethylformamide (DMF) was dried by distillation
from barium oxide; THF was distilled from sodium/benzophe-
none ketyl; acetone was distilled from CaSO4 and dichlo-
romethane was distilled from calcium hydride. Chromato-
graphic separations were performed on silica gel 60 (230-400
mesh, 60 Å) using the indicated solvents.
degree of aggregation upon progressing from the first to
second generations than observed in the trifunctional
series is consistent with this interpretation since a higher
core multiplicity would be expected to create a more
globular shape at lower generations.
Con clu sion s
A convenient strategy to prepare chiral, amphiphilic
dendrimers displaying peripheral carboxylates has been
described. A palladium-catalyzed deprotection of the
peripheral allyl esters circumvents precipitation of par-
tially hydrolyzed intermediates, thereby permitting ac-
cess to homogeneous amphiphilic dendrimers. Chiroptical
analysis of these materials in aqueous media revealed
that the dendrimer structures experience a structural
collapse that increases the effective steric bulk of the
dendritic wedges. However, the associated increase in
structural rigidity does not create stable chiral substruc-
tures in the achiral dendritic branches as evidenced by
circular dichroism. Further, to avoid interactions with
the aqueous media, the dendrimers experience a genera-
tion dependent aggregation that can be rationalized by
a change in conformational equilibria that accompanies
the increase in dendrimer generation.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined in open
capillaries and are uncorrected. Elemental analyses were
carried out at Atlantic Microlab, Inc., Norcross, GA. Infrared
2,5-An h yd r o-[r]-D-m a n n itol.21 A. 1,3,4,6-Tetr a -O-a cetyl-
2,5-a n h yd r o-D-m a n n itol. A solution of D-glucosamine hy-

6450 J . Org. Chem., Vol. 66, No. 19, 2001
Laufersweiler et al.
136.2, 162.6, 163.0, 165.3, 165.9; IR (neat) 1715, 1605 cm-1
drochloride (10 g, 0.05 mol) in water (116 mL) was stirred for
5 h at room temperature to attain mutarotational equilibrium.
The solution was cooled to 0 °C, and sodium nitrite (9.6 g, 0.14
mol) was added followed by the dropwise addition of glacial
acetic acid (5.6 g, 5.3 mL, 0.09 mol). After being stirred at 0
°C for 2 h, the solution was allowed to warm to ambient
temperature. After the mixture was sparged with nitrogen for
30 min, the solvent was removed by lyophilization. Methanol
(75 mL) was repeatedly added to and evaporated from the solid
residue until the insoluble salts in the solution became
sufficiently granular to remove by filtration. The filtercake was
then washed with methanol (2 × 10 mL), and the combined
methanol fractions were concentrated in vacuo giving a yellow
oil. The yellow oil was dissolved in water (116 mL), and sodium
borohydride (1.75 g, 0.05 mol) was added slowly at 0 °C
maintaining the pH at 8 by the addition of several portions of
dry ice. After the solution was stirred for an additional 1 h at
0 °C, the solution was brought to pH 7 with acetic acid and
the water was removed by lyophilization. Borate salts were
converted to trimethylborate by repeatedly adding methanol
(3 × 75 mL) to the residue and then concentrating in vacuo to
evaporate the methanol-trimethyl borate azeotrope. Further
desalting was achieved by dissolving the residue in methanol
(75 mL) and adding IR-120 Amberlite H+ resin. Removal of
the resin by filtration followed by evaporation of the methanol
afforded a yellow oil that was dispersed in dry pyridine (50
mL), cooled to 0 °C, and treated with excess acetic anhydride
(46.2 g, 50 mL, 0.43 mol). After the mixture was stirred at
ambient temperature for 24 h, methanol (50 mL) was added
dropwise at 0 °C, and then the mixture was concentrated in
vacuo. The resultant oil was partitioned between water (50
mL) and dichloromethane (50 mL), and the aqueous layer was
extracted with dichloromethane (2 × 50 mL). The combined
organic layers were washed with a 1.2 M HCl (50 mL), 5%
NaHCO3 (50 mL), and saturated NaCl (50 mL) and then dried
over Mg2SO4 and concentrated. Chromatography over silica
gel (1:1/ ethyl acetate/hexanes) afforded 1,3,4,6-tetra-O-acetyl-
2,5-anhydro-D-mannitol as a yellow oil (8.46 g, 0.026 mol, 51%):
;
HRMS for C62H53O13 (FAB) (MH) calcd 1005.35, obsd 1005.60.
Anal. Calcd for C62H52O13: C, 74.09; H, 5.21. Found: C, 73.95;
H, 5.16.
1,3,4,6-Tetr a-O-(4-h ydr oxyben zoyl)-2,5-an h ydr o-D-m an -
n itol (6). 1,3,4,6-Tetra-O-(4-benzyloxybenzoyl)-2,5-anhydro-
D-mannitol, 5 (1.29 g, 1.28 mmol), was dispersed in 100 mL of
methanol/ethyl acetate (1:1). The solution was degassed by
sparging with argon for 5 min, charged with Pd/C (0.23 g),
and then hydrogenated at 50 psi. After 24 h, the reaction
mixture was filtered through a short plug of Celite and the
resultant filtrate was concentrated, affording 6 (0.83 g, 1.28
mmol, 100%) as a white solid: mp ) 131-134 °C (CH3OH/
1
EtOAc); H NMR (250 MHz, acetone-d6) δ 4.67 (m, 6H), 5.78
(bd, J ) 2.0 Hz, 2H), 6.86 (d, J ) 8.8 Hz, 4H), 6.92 (d, J ) 8.8
Hz, 4H), 7.94 (d, J ) 8.5 Hz 4H), 7.95 (d, J ) 8.5 Hz, 4H); 13
C
NMR (62.5 MHz, CDCl3) δ 64.2, 80.1, 82.3, 115.8, 115.9, 121.3,
121.9, 132.4, 132.6, 162.5, 162.8; IR (neat) 3448, 1694, 1609
cm-1; HRMS for C34H28O13 (FAB) (MH) calcd 645.1608, obsd
645.1610.
(AllylO2C)2[G1]-OH (8). Allyl alcohol (1.5 mL) was treated
with sodium metal (50 mg, 2.2 mmol) and was allowed to stir
for ca. 5 min until all the sodium metal was consumed. This
solution was added to (CH3O2C)2[G1]-OH (7)7b (10.43 g, 24
mmol) in 1:1 THF/allyl alcohol (80 mL) and was then heated
to 50 °C. After 24 h, the solvents were evaporated in vacuo,
and the residue was dissolved in dichloromethane (80 mL) and
washed with 1.2 N aqueous HCl (80 mL). The organic layer
was dried over Mg2SO4 and evaporated to dryness. Purification
by flash chromatography (SiO2) with (0-5%) diethyl ether/
dichloromethane afforded 8 (9.04 g, 18.5 mmol, 77%) as a pale
yellow oil: 1HNMR (300 MHz, CDCl3) δ 4.61 (s, 2H), 4.81 (dt,
J ) 1.3, 5.6 Hz, 4H), 5.07 (s. 4H), 5.29 (dd, J ) 1.3, 10.4 Hz,
2H), 5.39 (dd, J ) 1.3, 16.1, Hz, 2H), 5.97-6.08 (m, 2H), 6.49
(t, J ) 2.2 Hz, 1H), 6.60 (d, J ) 2.2 Hz, 2H), 7.47 (d, J ) 8.3
Hz, 4H), 8.06 (d, J ) 8.3 Hz, 4H); 13C NMR (75 MHz, CDCl3)
δ 65.0, 65.5, 69.25, 101.3, 105.7, 118.2, 126.8, 129.8, 132.1,
142.0, 143.7, 159.7, 165.9; IR (CHCl3) 3504, 1714, 1596 cm-1
;
32
1H NMR (300 MHz, CDCl3) δ 5.03 (bd, 2.35 Hz, 2H), 4.12
HRMS for C29H28O7 (EI) (M+) calcd 488.1835, obsd 488.1853.
(AllylO2C)2[G1]-Br (9). Phosphorus tribromide (1.48 g, 0.52
mL, 5.5 mmol) was added dropwise to a stirred solution of 8
(8.58 g, 17.6 mmols) in toluene (40 mL) at 0 °C. The mixture
was allowed to warm to room temperature over 2 h. The
solvent was then evaporated in vacuo, and the yellow residue
was partitioned between water (100 mL) and dichloromethane
(100 mL). The aqueous layer was extracted with dichlo-
romethane (2 × 100 mL), and the combined organic layers
were dried over Mg2SO4 and evaporated to dryness. Purifica-
tion by flash chromatography (SiO2) with 5% diethyl ether/
dichloromethane afforded 9 (6.19 g, 11.3 mmol, 64%) as a white
solid: mp ) 79-81 °C ((C2H5)2O, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 4.40 (s, 2H), 4.83 (dt, J ) 1.6, 5.6 Hz, 4H), 5.09 (s,
4H), 5.29 (dq, J ) 1.6, 10.4 Hz, 2H), 5.41 (dq, J ) 1.6, 17.2
Hz, 2H), 5.95-6.14 (m, 2H), 6.51 (t, J ) 2.2 Hz, 1H), 6.63 (d,
J ) 2.2 Hz, 2H), 7.48 (d, J ) 8.4 Hz, 4H), 8.08 (d, J ) 8.4 Hz,
4H); 13C NMR (75 MHz, CDCl3) δ 33.3, 65.5, 69.3, 102.1, 108.2,
118.2, 126.9, 129.8, 132.1, 139.9, 141.7, 159.7, 165.8; IR
(CHC;3) 3024, 1718, 1596. cm-1; HRMS for C29H27BrO6 (EI)
(M) calcd 550.1035, obsd 550.0976. Anal. Calcd for C29H27BrO6;
C, 63.17; H, 4.94. Found: C, 63.52; H, 5.04.
(bm, 6H), 1.97 (s, 12H).
B. 2,5-An h yd r o-D-m a n n itol. To a solution of the 1,3,4,6-
tetra-O-acetyl-2,5-anhydro-D-mannitol from part A (3.66 g, 11.0
mmol) in dry methanol (30 mL) was added 1 M NaOMe in
methanol (1 mL). After 24 h at room temperature, the solution
was neutralized with Amberlite IR 120 H+ resin (10 g), which
was then removed by filtration. Evaporation of the methanol
in vacuo afforded 2,5-anhydro-D-mannitol. To remove the last
traces of methanol, pyridine (5 × 20 mL) was repeatedly added
to the solid and evaporated in vacuo affording 2,5-anhydro-D-
mannitol as a white solid (1.46 g, 8.9 mmol, 81%).
1,3,4,6-Tet r a -O-(4-b en zyloxyb en zoyl)-2,5-a n h yd r o-D-
m a n n itol (5). A stirred suspension of 4-benzyloxybenzoic acid
(6.45 g, 28.3 mmol) in dichloromethane (25 mL) was charged
with oxalyl chloride (3.66 mL, 5.33 g, 41.9 mmol) and DMF (5
drops). After the mixture was stirred for 24 h at ambient
temperature, the solvent was removed in vacuo affording a
light yellow solid. A mixture of 2,5-anhydro-D-mannitol (0.58
g, 3.53 mmol) and DMAP (43 mg, 0.35 mmol) in pyridine (10
mL) was added, and the resulting solution was heated at 50
°C for 24 h. The reaction was then cooled to room temperature
and concentrated. The resultant solid was dissolved in dichlo-
(AllylO2C)4[G2]-OH (10). Compound
9 (6.19 g, 11.25
romethane (40 mL) and washed with
a 1.2 N aqueous
mmol), 3,5-dihydroxybenzyl alcohol (0.7 g, 5.0 mmol), finely
powdered potassium carbonate (3.52 g, 25.5 mmol), and 18-
crown-6 (0.13 g, 0.5 mmol) were suspended in 25 mL of dry
acetone. The mixture was heated at reflux for 18 h, at which
time the solvent was removed in vacuo and the resultant
residue was partitioned between water (100 mL) and dichlo-
romethane (100 mL). The aqueous layer was extracted with
dichloromethane (2 × 100 mL), and the combined organic
layers were dried over Mg2SO4 and then evaporated to dryness.
Purification via flash chromatography (SiO2) with (0-5%)
diethyl ether/dichloromethane afforded 10 (4.42 g, 4.08 mmol,
73%) as a clear glass: 1H NMR (300 MHz, CDCl3) δ 4.58 (s,
2H), 4.80 (dt, J ) 1.4, 5.6 Hz, 8H), 4.94 (s, 4H), 5.07 (s, 8H),
5.24 (dq, J ) 1.54, 10.53 Hz, 4H), 5.39 (dq, J ) 1.54, 17.25
hydrochloric acid (50 mL) and 5% aqueous sodium bicarbonate
(50 mL). The organic layer was then dried over Mg2SO4 and
concentrated to a brown solid. Purification by flash chroma-
tography (SiO2) with 0-2.5% diethyl ether/dichloromethane
afforded 5 (3.0 g, 2.98 mmol, 85%) as a white solid: 1H NMR
(200 MHz, CDCl3) δ 4.65 (bm, 6H), 5.05 (s, 4H), 5.1 (s, 4H),
5.7 (bs, 2H), 6.9 (d, J ) 8.7 Hz, 4H), 6.95 (d, J ) 8.7 Hz, 4H),
7.4 (bs, 20H), 7.92 (d, J ) 8.7 Hz, 4H), 8.05 (d, J ) 8.7 Hz,
4H); 13C NMR (62.5 MHz, CDCl3) δ 63.8, 70.1, 70.2, 79.5, 82.1,
114.5, 114.6, 122.4, 127.4, 128.2, 128.6, 131.9, 132.0, 136.0,
(32) Kozlowski, J . S.; Marzabadi, C. H.; Rath, N. P.; Spilling, C. D.
Carbohydr. Res. 1997, 300, 301.

Synthesis of Chiral, Amphiphilic Dendrimers
J . Org. Chem., Vol. 66, No. 19, 2001 6451
Hz, 4H), 5.95-6.12 (m, 4H), 6.44 (t, J ) 2.1 Hz, 1H), 6.51 (t,
J ) 2.1 Hz, 2H), 6.54 (d, J ) 2.1 Hz, 2H), 6.63 (d, J ) 2.1 Hz,
4H), 7.44 (d, J ) 8.4 Hz, 8H), 8.03 (d, J ) 8.4 Hz, 8H); 13C
NMR (75 MHz, CDCl3) δ 64.9, 65.5, 69.3, 69.6, 101.0, 101.5,
105.5, 106.3, 118.2, 126.9, 129.6, 129.8, 132.1, 139.5, 141.9,
143.7, 159.8, 165.8; MS for C65H60O15 (MALDI-TOF) (MH) calcd
1081.2, obsd 1081.0; IR (neat) 3512, 1720, 1597 cm-1. Anal.
Calcd for C65H60O15; C, 72.21; H, 5.59. Found: C, 72.31; H, 5.
64.
(AllylO2C)4[G2]-Br (11). (AllylO2C)4[G2]-OH (10) (4.67 g,
4.3 mmol) was treated with PBr3 (0.4 g, 0.14 mL, 1.5 mmol)
in toluene (14 mL) at 0 °C as described for 9. Purification by
flash chromatography (SiO2) with 5% diethyl ether/dichlo-
romethane afforded 11 (2.91 g, 2.54 mmol, 60%) as a clear
glass: 1H NMR (300 MHz, CDCl3) δ 4.39 (s, 2H), 4.82 (dt, J )
1.4, 5.6 Hz, 8H), 4.96 (s, 4H), 5.10 (s, 8H), 5.30 (dq, J ) 1.6,
10.5, Hz, 4H), 5.42 (dq, J ) 1.6, 17.2, Hz, 4H), 5.98-6.11 (m,
4H), 6.48 (t, J ) 2.2 Hz, 1H), 6.54 (t, J ) 2.2 Hz, 2H), 6.59 (d,
J ) 2.2 Hz, 2H), 6.65 (d, J ) 2.2 Hz, 4H), 7.48 (d, J ) 8.4 Hz,
8H), 8.07 (d, J ) 8.4 Hz, 8H); 13C NMR (75 MHz, CDCl3) δ
33.5, 65.5, 69.3, 69.8, 101.6, 102.1, 106.4, 108.1, 118.2, 126.9,
129.7, 129.8, 130.2, 132.1, 139.2, 139.7, 141.9, 159.8, 165.8;
IR (CHCl3) 1717, 1597 cm-1; MS for C65H59BrO14Na (MALDI-
TOF) (M + Na) calcd 1167.08, obsd 1167.92
solution of N(Bu)3/HCO2H (1:1) in THF (4 equiv/allyl ester).
The mixture was then heated to 55 °C for 12 h, and the solvent
was removed in vacuo. The oily residue was dissolved in CH2-
Cl2 (10 mL) and washed with water (10 mL). The CH2Cl2 layer
was concentrated in vacuo, and the resultant yellow solid was
dissolved in 20 mL of 5% aqueous NaHCO3 and washed with
20 mL of diethyl ether. The aqueous layer was diluted to 50
mL with water and acidified with concentrated hydrochloric
acid to pH 2, causing a precipitate to form that was filtered,
washed with two portions of deionized water, and dried for at
least 12 h in a vacuum desiccator over P2O5. The dried solid
was dissolved in 3 mL of THF, and to this solution was added
1 mL of chlorotrimethylsilane. The solution was allowed to stir
for 15 min and was then poured into 6 mL of deionized water
resulting in a white precipitate. The water was decanted, and
the white solid was dried for at least 12 h in a vacuum
desiccator over P2O5.
(AllylO2C)6[G1] Den d r im er 14a . (AllylO2C)2[G1]-Br (9)
(0.35 g, 0.63 mmol), 3 (0.1 g, 0.19 mmol), K2CO3 (0.15 g, 1.1
mmol), and 18-crown-6 (0.01 g, 0.038 mmol) were reacted in
THF/DMF (6 mL/2 mL) following general procedure A. Puri-
fication by flash chromatography (SiO2) with 5-10% diethyl
ether/dichloromethane afforded dendrimer 14a (0.23 g, 0.12
1
mmol, 63%) as a white solid: mp ) 66-71 °C; H NMR (300
(AllylO2C)8[G3]-OH (12). (AllylO2C)4[G2]-Br (11) (2.86 g,
2.4 mmol) was converted to (allylO2C)8[G3]-OH (12) using 3,5-
dihydroxybenzyl alcohol (0.15 g, 1.1 mmol), potassium carbon-
ate (0.76 g, 5.5 mmol) and 18-crown-6 (0.029 g, 0.11 mmol) in
10 mL of dry acetone as described for 10. Purification via flash
chromatography (SiO2) with (0-5%) diethyl ether/dichlo-
romethane afforded 12 (2.26 g, 1.0 mmol, 90%) as a clear
glass: 1H NMR (300 MHz, CDCl3) δ 4.59 (s, 2H), 4.8 (dt, J )
1.29, 6.84 Hz, 16 H), 4.9 (s, 12 H), 5.1 (s, 16 H), 5.28 (dq, J )
1.28, 9.15 Hz, 8 H), 5.40 (dq, J ) 1.28, 17.1 Hz, 8 H), 5.95-
6.05 (m, 8H), 6.49-6.65 (m, 21 H), 7.43 (d, J ) 8.3 Hz, 16 H),
8.03 (d, J ) 8.3 Hz, 16 H); 13C NMR (75 MHz, CDCl3) δ 65.5,
69.3, 69.7, 101.1, 106.4, 118.2, 126.8, 129.4, 129.8, 132.1, 139.3,
141.9, 159.8, 165.8; IR (neat) 3462, 1715, 1597 cm-1; MS for
MHz, CDCl3) δ 4.25 (dd, J ) 5.3, 11.3 Hz, 1H), 4.50 (dd, J )
2.5, 11.3 Hz, 1H), 4.81 (d, J ) 5.5 Hz, 12H), 4.96-5.1 (m, 19H),
5.27 (d, J ) 10.5 Hz, 6H), 5.38 (d, J ) 17.2 Hz, 6H), 5.94-
6.13 (m, 6H), 6.34 (d, J ) 8.6 Hz, 1H), 6.53-6.64 (m, 9H),
6.83-6.96 (m, 7H), 7.35-7.54 (m, 17H), 7.65 (d, J ) 8.6 Hz,
2H), 7.96-8.08 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 52.0,
63.0, 65.5, 69.35, 69.7, 69.8, 75.0, 101.6, 101.7, 106.3, 106.4,
114.5, 118.2, 122.2, 126.0, 126.9, 127.2, 128.7, 128.8, 129.7,
129.8, 129.9, 131.7, 131.8, 132.1, 138.8, 139.0, 141.8, 159.8,
162.5, 165.8, 166.0; IR (neat) 1719, 1605 cm-1; UV (CHCl3)
λmax 248 (ꢀ ) 113 301), 264 (ꢀ ) 71 223) nm; [φ]23
(c 0.6,
578
CHCl3) 537; MS for C117H103NO26Na (M + Na) (MALDI-TOF)
calcd 1962, obsd 1964. Anal. Calcd for C117H103NO26: C, 72.47;
H, 5.35; N, 0.72. Found: C, 72.31; H, 5.36; N, 0.75.
C
137H124O31 (MH) (MALDI-TOF) calcd 2264.8, obsd 2263.2.
(HO2C)6[G1] Den d r im er 14b. Following procedure B for
allyl ester deprotection, (allylO2C)6[G1] dendrimer 14a (95 mg,
0.05 mmol) in 2 mL of THF was converted to (HO2C)6[G1] 14b
using 0.18 mL of the Pd(0) solution and 1 mL of the 1.2 M
solution of N(Bu)3/HCO2H in THF. This afforded 14b as a
Anal. Calcd for C137H124O31: C, 72.6; H, 5.51. Found: C, 72.39;
H, 5.60.
(AllylO2C)8[G3]-Br (13). (AllylO2C)8[G3]-OH (12) (2.1 g,
0.92 mmol) was converted to (allylO2C)8[G3]-Br (13) by treat-
ment with PBr3 (0.8 g, 28.2 µL, 0.31 mmol) in toluene (5 mL)
at 0 °C as described for 9. Purification by flash chromatography
(SiO2) with 5% diethyl ether/dichloromethane afforded 13 (1.1
g, 0.47 mmol, 51%) as a white solid: mp ) 53-56 °C; 1H NMR
(300 MHz, CDCl3) δ 4.38 (s, 2H), 4.81 (bd, J ) 5.6 Hz, 16H),
4.95 (bs, 12 H), 5.10 (bs, 16 H), 5.30 (dd, J ) 2.3, 10.52 Hz, 8
H), 5.4 (dd, J ) 1.4, 16.7 Hz, 8 H), 5.98-6.87 (m, 8 H), 6.51-
6.66 (m, 21 H), 7.45 (d, J ) 8.3 Hz, 16H), 8.05 (d, J ) 8.3 Hz,
16H); 13C NMR (75 MHz, CDCl3) 32.7, 65.5, 69.3, 69.7, 102.1,
106.3, 118.2, 126.8, 129.6, 129.8, 132.0, 139.3, 141.9, 159.9,
165.8; IR (CHCl3) 1720, 1596 cm-1; MS for C137H123O30Br (MH)
(MALDI-TOF) calcd 2327.7, obsd 2328.3. Anal. Calcd for
1
white solid (77 mg, 0.045 mmol, 90%): mp) 147 °C dec; H
NMR (500 MHz, DMSO-d6) δ 4.19 (br s, 1H), 4.34 (br s, 1H),
4.90 (bm, 1H), 5.04-5.26 (m, 18H), 6.14 (d, J ) 6.65 Hz, 1H),
6.63-6.73 (m, 9H), 7.00-7.10 (m, 6H), 7.27-7.35 (m, 3H), 7.44
(d, J ) 7.8 Hz, 2H), 7.50-7.53 (m, 12 H), 7.70 (d, J ) 8.6 Hz,
2H), 7.84-7.87 (m, 2H), 7.93 (d, J ) 8.1 Hz, 12 H), 8.02 (d, J
) 8.6 Hz, 2H), 8.58 (d, J ) 7.85 Hz, 1H); 13C NMR (125 MHz,
DMSO-d6) 52.0, 63.3, 67.0, 68.7, 69.1, 69.3, 74.9, 101.2, 101.3,
106.7, 106.8, 114.2, 114.7, 121.8, 126.7, 127.0, 127.3, 128.2,
128.4, 129.1, 129.4, 130.1, 131.3, 131.6, 137.9, 138.9, 139.2,
141.9, 159.4, 160.5, 162.3, 164.5, 165.0, 166.4, 167.0; IR (KBr)
3422, 3058, 1695, 1594 cm-1; MS for C99H78NO26 (negative ion
electrospray) (M - H) calcd 1697, obsd 1696; UV (0.6 M aq
NaHCO3) λmax 238 nm (ꢀ ) 104 830).
C
137H123O30Br: C, 70.64; H, 5.32. Found: C, 70.73; H, 5.29.
A. Gen er a l P r oced u r e for Allyl E st er Den d r im er
Syn th esis. Central core 3 or 6 (100 mol %), finely powdered
potassium carbonate (excess), 18-crown-6 (20 mol %), and
dendron monobromide (9, 11, or 13) were suspended in THF/
DMF (3:1) (0.2 M in 3 or 6) and heated at 65 °C. After 18 h,
the solvents were removed in vacuo, and the resultant residue
was partitioned between water and dichloromethane. The
aqueous layer was extracted three times with dichloromethane,
and the combined organic layers were dried over Mg2SO4 and
evaporated to dryness. Final purification was achieved by flash
chromatography (SiO2) as indicated below.
B. Gen er a l P r oced u r e for Dep r otection of Allyl Ester
Ter m in a ted Den d r im er s. Pd2(dba)3‚CHCl3 (25.8 mg, 0.025
mmol) and triphenylphosphine (65 mg, 0.25 mmol) were mixed
in THF (1 mL) and stirred at ambient temperature until the
solution became bright yellow and homogeneous (ca. 5 min).
To a solution of the allyl ester terminated dendrimer (100 mol
%) in THF was added a portion of the aforementioned solution
corresponding to 5 mol % Pd followed by a preformed 1.2 M
(AllylO2C)12[G2] Den d r im er 15a . (AllylO2C)4[G2]-Br (11)
(0.715 g, 0.625 mmol), 3 (0.1 g, 0.19 mmol), K2CO3 (0.15 g, 1.1
mmol), and 18-crown-6 (0.01 g, 0.14 mmol, 0.0378 mmol) were
reacted in THF/DMF (6 mL/2 mL) following general procedure
A. Purification by flash chromatography (SiO2) with 5% diethyl
ether/dichloromethane afforded 15a (0.52 g, 0.14 mmol, 74%)
as a white solid: mp ) 69-74 °C; 1H NMR (300 MHz, CDCl3)
δ 4.23 (br m, 1H), 4.5 (br m, 1H), 4.8 (bs, 24 H), 4.9-5.15 (m,
42 H), 5.25 (d, J ) 10.32, 12 H), 5.97-6.03 (m, 12H), 6.32 (d,
J ) 8.3 Hz, 1H), 6.50-6.63 (m, 27H), 6.81-6.97 (m, 6H), 7.26-
7.48 (m, 29H), 7.60 (d, J ) 8.4 Hz, 2H), 7.94-8.05 (m, 28H);
13C NMR (75 MHz, CDCl3) δ 65.5, 69.2, 69.7, 83.4, 83.8, 101.5,
106, 114.5, 118.2, 126.9, 129.7, 132, 139.3, 141.9, 159.7, 159.9,
165.8; IR (CHCl3) 1720, 1598 cm-1; MS for C225H199NO50Na
(M + Na) (MALDI-TOF) calcd 3737.3, obsd 3737.9; UV (CHCl3)
λmax 246 (ꢀ ) 183 945), 276 (ꢀ ) 55 211)nm; [φ]23
(c 0.6,
578
CHCl3) 439. Anal. Calcd for C225H199NO50: C, 72.71; H, 5.40;
N, 0.38. Found: C, 72.57; H, 5.41; N, 0.28.

6452 J . Org. Chem., Vol. 66, No. 19, 2001
Laufersweiler et al.
(HO2C)12[G2] Den d r im er 15b. Following procedure B for
allyl ester deprotection, (allylO2C)12[G2] dendrimer 15a (210
mg, 0.056 mmol) in 2 mL of THF was converted to (HO2C)12-
[G1] 15b using 0.18 mL of the Pd(0) solution and 1 mL of the
1.2 M solution of N(Bu)3/HCO2H in THF. This afforded 15b
as a white solid (119 mg, 0.036 mmol, 66%): mp ) 151 °C
159.4, 162.5, 165.1, 167.1; IR (neat) 1713, 1601 cm-1; UV (THF)
λmax 234 nm (ꢀ ) 151 639); UV (0.1M Na2HPO4) λmax 210 nm
(ꢀ ) 208 813); MS for C126H99O37 (M - H) (negative ion
electrospray) calcd 2206.2, obsd 2206.4.
(AllylO2C)16[G2] Den d r im er 18a . (AllylO2C)4[G2]-Br (11)
(0.220 g, 0.192 mmol), 6 (28.8 mg, 0.0447 mmol), K2CO3 (49
mg, 0.358 mmol), and 18-crown-6 (2.36 mg, 0.0089 mmol) were
reacted in THF/DMF (3 mL/1 mL) following general procedure
A. Purification by flash chromatography (SiO2) with 5-10%
diethyl ether/dichloromethane afforded 18a (157 mg, 0.032
mmol, 72%) as a glass: 1H NMR (250 MHz, CDCl3) δ 4.68 (bs,
6H), 4.81 (bd, J ) 4.6 Hz, 24H), 4.90 (bd, J ) 6.1 Hz, 8H),
4.95-5.09 (m, 56H), 5.28(d, J ) 10.5 Hz, 16H), 5.40 (d, J )
17.4 Hz, 16H), 5.69 (s, 2H), 6.05 (bm, 16H), 6.52 (bs, 12 H),
6.65 (bs, 24H), 6.86 (d, J ) 8.9 Hz, 4H), 6.95 (d, J ) 8.9 Hz,
4H), 7.45 (m, 32H), 7.95-8.06 (m, 40H); 13C NMR (62.5 MHz,
CDCl3) δ 65.5, 69.3, 103.9, 104.0, 106.3, 106.6, 118.2, 126.9,
129.7, 129.9, 132.3 (mult carbons), 138.5, 139.3, 141.9, 159.8,
160.0, 162.8, 165.8; IR (neat) 1721, 1598 cm-1; MS for
C294H260O69Na (MALDI-TOF) (M + Na) calcd 4916, obsd 4916.
Anal. Calcd for C294H260O69: C, 72.11; H, 5.35. Found: C, 72.20;
H, 5.37.
(HO2C)16[G2] Den d r im er 18b. Following procedure B for
allyl ester deprotection, (allylO2C)16[G2] dendrimer 18a (0.16
g, 0.033 mmol) in 1 mL of 1.2 M solution of (C4H9)3N/HCO2H
(1:1) in THF was converted to (HO2C)16[G2] 18b using 65 µL
of the Pd(0) solution. This afforded 18b as white solid (0.13 g,
0.030 mmol, 92%): mp ) 120 °C dec; 1H NMR (500 MHz,
DMSO-d6) δ 4.58-4.69 (m, 6H), 4.88-5.17 (br m, 56H), 5.66
(br s, 2H), 6.55-6.62 (br m, 36H), 6.99 (br s, 4H), 7.12 (br s,
4H), 7.43 (br s, 32H), 7.85 (br s, 40H), 12.84 (br s, 16H); 13C
NMR (125 MHz, DMSO-d6) δ 66.7, 104.6, 125.3, 127.4, 128.1,
139.9, 157.4, 165.0; IR (neat) 3271, 1713, 1596 cm-1; UV (THF)
λmax 232 nm (ꢀ ) 366 638); UV (0.1 M Na2HPO4) λmax 210 nm
(ꢀ ) 494 468); MS for C246H200O69 (M - 4H) (negative ion
electrospray) calcd 1065, obsd 1066 (m/4e).
1
dec; H NMR (500 MHz, DMSO-d6) δ 4.15 (br s, 1H), 4.35 (br
s, 1H), 4.80 (bm, 1H), 4.99 (br s, 24H), 5.12 (br s, 18H), 6.16
(d, J ) 6.05 Hz, 1H), 6.61 (br s, 9H), 6.68 (br s, 19H), 6.98-
7.05 (m, 5H), 7.24-7.53 (m, 30H), 7.70 (d, J ) 8.3 Hz, 1H),
7.82-8.01 (m, 28H), 8.56 (d, J ) 7.4 Hz, 1H); 13C NMR (125
MHz, DMSO-d6) δ 67.0, 68.7, 69.1, 69.3, 101.1, 106.6, 114.2,
114.7, 121.8, 126.7, 127.3, 128.4, 129.1, 129.4, 130.1, 131.3,
138.7, 139.4, 141.9, 159.3, 159.4, 167.1; IR (KBr) 3425, 3047,
1690, 1592 cm-1; UV (0.6 M aq NaHCO3) λmax 222 nm (ꢀ )
130 583); MS for C189H150NO50 (M - H) (negative ion electro-
spray) calcd 32354, obsd 3234.
(AllylO2C)24[G3] Den d r im er 16a . (AllylO2C)8[G3]-Br (13)
(0.800 g, 0.343 mmol), 3 (53 mg, 0.101 mmol), K2CO3 (70 mg,
0.505 mmol), and 18-crown-6 (3 mg, 0.010 mmol) were reacted
in THF/DMF (3 mL/1 mL) following general procedure A.
Purification by flash chromatography (SiO2) with 5% diethyl
ether/dichloromethane afforded 16a (0.75 g, 0.100 mmol 99%)
as a white solid: mp ) 65-70 °C; 1H NMR (300 MHz, CDCl3)
δ 4.12 (br s, 1H), 4.5 (br s, 1H), 4.79-5.01 (m, 139H), 5.24-
5.40 (m, 48H), 5.97-6.02 (m, 24H), 6.34 (br s, 1H), 6.56-6.63
(m, 63H), 6.83-6.91 (m, 7H), 7.31-7.42 (m, 53H), 7.65 (br s,
2H), 7.91-8.01 (m, 54H); 13C NMR (75 MHz, CDCl3) δ 65.4,
69.3, 69.7, 101, 106, 118, 126.8, 126.9, 129.6, 129.7, 132, 139.3,
141.9, 159.7, 159.9, 165.7; IR (neat) 1720, 1597 cm-1; UV
(CHCl3) λmax 246 (ꢀ ) 426 624), 276 (ꢀ ) 130 299) nm; [φ]23
578
(c 0.6, CHCl3) 291. Anal. Calcd for C441H391NO98; C, 72.83; H,
5.42; N, 0.19. Found: C, 72.57; H, 5.40; N, 0.27.
(HO2C)24[G3] Den d r im er 16b. Following procedure B for
allyl ester deprotection, (allylO2C)24[G3] dendrimer 16a (200
mg, 0.027 mmol) in 2 mL of THF was converted to (HO2C)24-
[G2] 16b using 55 µL of the Pd(0) solution and 1 mL of the 1.2
M solution of N(Bu)3/HCO2H in THF. This afforded 16b as a
white solid (136 mg, 0.022 mmol, 81%): mp ) 152 °C dec; 1H
NMR (500 MHz, DMSO-d6) δ 4.12 (br s, 1H), 4.50 (br s, 1H),
4.94 (br s, 31 H), 5.07 (br s, 60H), 6.15 (br s, 1H), 6.58-7.10
(m, 69H), 7.4-7.6 (m, 53H), 7.89 (bs, 53H); 13C NMR (125 MHz,
DMSO-d6) 67.0, 68.7, 69.0, 101.0, 106.6, 127, 128.7, 129, 130,
131.4, 131.5, 132, 139.4, 141.8, 159.3, 159.4, 167; IR (KBr)
3419, 3066, 1692, 1598 cm-1; UV (0.6 M aq NaHCO3) λmax 230
nm (ꢀ ) 305 340).
(AllylO2C)32[G3] Den d r im er 19a . (AllylO2C)8[G3]-Br (13)
(0.350 g, 0.150 mmol), 6 (23 mg, 0.036 mmol), K2CO3 (40 mg,
0.286 mmol), and 18-crown-6 (1.9 mg, 0.0072 mmol) were
reacted in THF/DMF (3 mL/1 mL) following general procedure
A. Purification by flash chromatography (SiO2) with 5-10%
diethyl ether/dichloromethane afforded 19b (0.130 g, 0.0135
mmol, 38%) as a glass: 1H NMR (200 MHz, CDCl3) δ 4.60 (s,
ca. 6H), 4.69-5.06 (m, 184H), 5.26 (d, J ) 9.6 Hz, 32H), 5.37
(d, J ) 17.1 Hz, 32H), 5.69 (bs, ca. 2H), 6.05 (m, 32H), 6.48-
6.65 (m, 84 H), 6.8 (bd, ca. 4H), 6.9 (bd, ca. 4H), 7.33-7.48 (m,
64 H), 7.91-8.13 (m, 72H); 13C NMR (75 MHz, CDCl3) δ 65.5,
65.6, 69.3, 69.6, 101.5, 106.4, 118.2, 126.9, 127.1, 129.6, 129.7,
129.8, 132.1, 138.4, 139.3, 139.4, 141.9, 159.8, 165.7, 165.8;
IR (neat) 1719, 1597 cm-1; MS for C582H516O133Na2 (MALDI-
TOF) (M + 2Na) calcd (m/2e) 4842, obsd 4842. Anal. Calcd for
(AllylO2C)8[G1] Den d r im er 17a . (AllylO2C)2[G1]-Br (9)
(0.980 g, 1.78 mmol), 6 (0.255 g, 0.396 mmol), K2CO3 (0.44 g,
3.2 mmol), and 18-crown-6 (0.021 g, 0.079 mmol) were reacted
in THF/DMF (3 mL/1 mL) following general procedure A.
Purification by flash chromatography (SiO2) with 5-10%
diethyl ether/dichloromethane afforded 17a (0.710 g, 0.281
C
582H516O133: C, 72.53; H, 5.59. Found: C, 72.24; H, 5.59.
1
(HO2C)32[G3] Den d r im er 19b. Following procedure B for
mmol, 72%) as a white solid: mp ) 63-65 °C; H NMR (200
allyl ester deprotection, (allylO2C)32[G3] dendrimer 19a (90 mg,
9.3 × 10-3 mmol) in 0.5 mL of 1.2 M solution of (C4H9)3N/
HCO2H (1:1) in THF was converted to (HO2C)32[G3] 19b using
65 µL of the Pd(0) solution. This afforded 19b as white solid
MHz, CDCl3) δ 4.67 (bs, 6H), 4.81 (bd, 16H), 5.02 (m, 24H),
5.28 (dd, J ) 10.3, 1.3 Hz, 8H), 5.39 (dd, J ) 15.8, 1.3 Hz,
8H), 5.67 (bs, 2H), 6.04 (m, 8H), 6.50 (t, J ) 2.4 Hz, 4H), 6.62
(bs, 8H), 6.86 (d, J ) 8.92 Hz, 4H), 6.93 (d, J ) 9.0 Hz, 4H),
7.45 (m, 16H). 7.9-8.1 (m, 24H); 13C NMR (62.5 MHz, CDCl3)
65.6, 69.4, 69.4, 69.8, 101.8, 106.4, 114.5, 114.6, 118.2, 121.7,
122.5, 126.9, 128.5, 128.9, 129.7, 129.9, 131.9, 132.0, 132.2,
138.7, 138.8, 141.9, 159.9, 162.4, 162.8, 165.2, 165.9; IR (neat)
1718, 1604. cm-1; MS for C150H132O37Na (MALDI-TOF) (M +
Na) calcd 2547, obsd 2547. Anal. Calcd for C150H132O37: C,
71.31; H, 5.27. Found: C, 71.55; H, 5.32.
(HO2C)8[G1] Den d r im er 17b. Following procedure B for
allyl ester deprotection, (allylO2C)8[G1] dendrimer 17a (0.40
g, 0.16 mmol) in 3 mL of 1.2 M solution of (C4H9)3N/HCO2H
(1:1) in THF was converted to (HO2C)8[G1] 17b using 0.32 mL
of the Pd(0) solution. This afforded 17b as white solid (0.25 g,
0.11 mmol, 70%): mp ) 130 °C dec; 1H NMR (250 MHz,
DMSO-d6) δ 4.58-4.69 (m, 6H), 5.09-5.13 (m, 24H), 5.66 (br
s, 2H), 6.65-6.73 (m, 12H), 6.99 (d, J ) 8.8 Hz, 4H), 7.12 (d,
J ) 8.9 Hz, 4H), 7.52 (m, 16H), 7.94 (m, 24H), 12.98 (br s,
8H); 13C NMR (62.5 MHz, DMSO-d6) 68.5, 68.8, 106.7, 114.7,
121.3, 121.8, 127.3, 127.4, 129.4, 130.1, 131.4, 138.8, 141.9,
1
(48 mg, 5.74 × 10-3 mmol, 62%): mp ) 120 °C dec; H NMR
(500 MHz, DMSO-d6) δ 4.63 (barely visible br s, 6H), 4.93-
5.06 (br m, 121H), 5.66 (barely visible br s, 1H), 6.62 (br s,
84H), 6.99 (barely visible br s, 4H), 7.12 (barely visible br s,
4H), 7.43 (br s, 64H), 7.85 (br s, 72H), 12.83 (br s, 32H); 13C
NMR (125 MHz, DMSO-d6) δ 66.7, 104.6, 125.3, 127.4, 128.1,
139.9, 157.4, 165.0; IR (neat) 3307, 1719, 1596 cm-1; UV (THF)
λmax 234 nm (ꢀ ) 739 065); UV (0.1 M Na2HPO4) λmax 208 nm
(ꢀ ) 609 682).
Ack n ow led gm en t. This work was supported by the
National Science Foundation CAREER program (CHE-
98-75458), and acknowledgment is made to the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
work.
J O010423Z