3796
J . Org. Chem. 1999, 64, 3796-3797
Therefore, to restrict mobility and create the potential in a
dendritic wedge to coil helically toward the focal point, we
modified the symmetrical 3,5-disubstitution pattern of a
Fre´chet-type wedge to an unsymmetrical 2,3-branched pat-
tern.10 We describe herein the synthesis of unsymmetrically
branched dendrons based on 2,3-dihydroxybenzyl alcohol.
Syn th esis of Un sym m etr ica lly Br a n ch ed
Den d r im er ic Wed ges u p to th e F ou r th
Gen er a tion Ba sed on 2,3-Dih yd r oxyben zyl
Alcoh ol
J acob G. Weintraub and J on R. Parquette*
Department of Chemistry, The Ohio State University,
Columbus, Ohio 43210
The synthesis progressed in a convergent fashion starting
with 2,3-dihydroxybenzaldehyde, 1, as the branching subunit
(Scheme 1). Generational growth was accomplished by
O-alkylation of the phenolic hydroxyl groups, and focal point
activation was achieved by a reduction/bromination sequence
on the focal aldehyde. Because our intention was to develop
a method to construct amphiphilic dendrimers with the 2,3-
branching pattern, potentially hydrophilic methyl esters
were introduced in the first step; these groups ultimately
become the termini of the dendrimer. Accordingly, treatment
of 1 with methyl-4-bromomethylbenzoate in the presence of
potassium carbonate and 18-C-6 in THF-DMF (4:1) at 70
°C afforded the first-generation dendron (CH3O2C)2-[G-1]-
CHO, 2a . We found that alkylation occurred most effectively
by removing the solvent at ca. 60 mmHg during the course
of the reaction. In this manner, the reaction proceeded to
completion in 30-60 min, affording pure 2a in 99% yield
without the need for chromatographic purification. Conse-
quently, this protocol was employed to increase the rate of
the alkylation step for each ensuing generation. Subsequent
reduction of the aldehyde with NaBH4 in refluxing methanol
generated the corresponding alcohol (CH3O2C)2-[G-1]-OH,
2b. Conversion to the bromide, 2c, was accomplished by
exposure of the alcohol to PBr3 in CH2Cl2 at 0 °C. Reaction
of 2 equiv of 2c with 1 as above gave the second-generation
aldehyde (CH3O2C)4-[G-2]-CHO, 3a . Although the first-
generation materials (2a -c) were quite soluble in CH2Cl2,
THF, and methanol, beginning with the second generation,
the dendrons exhibited poor solubility in methanol and were
only sparingly soluble in THF.11 Therefore, reduction of 3a
with NaBH4 in THF at reflux provided unreliable yields.
Performing the reduction in CH2Cl2 using BH3-THF cir-
cumvented the problems associated with solubility and
reproducibly provided alcohol 3b in g85% yield. Surpris-
ingly, bromination of second-generation alcohol 3b with PBr3
generated significant amounts of the first-generation bro-
mide 2c as a side product as a result of selective cleavage of
the more electron-rich inner shell benzyl linkages. Fortu-
itously, recourse to a CBr4/PPh3 bromination method fur-
nished bromide 3c without significant cleavage of the
benzylic linkages. Subsequent condensation of 3c with 1
gave third-generation aldehyde (CH3O2C)8-[G-3]-CHO 4a in
g99% yield. Reduction of 4a to alcohol (CH3O2C)8-[G-3]-OH
4b was similarly accomplished using BH3-S(CH3)2 in CH2-
Cl2. Focal activation of 4b with CBr4/PPh3 and alkylation
with 1 provided the fourth-generation dendron (CH3O2C)16-
[G-4]-CHO, 5, in 98% yield.12
Received March 11, 1999
Dendrimers, in contrast to linear polymers, maintain a
highly branched primary structure that creates a spherical
morphology with internal cavities and a densely packed
surface at higher generations.1 These structural character-
istics are expected to be useful in designing highly ordered
materials for applications in molecular recognition and
catalysis.2 Symmetrically branched subunits are commonly
employed to facilitate generational growth by minimizing
steric interactions that develop as the dendrimer grows in
size. This approach permits synthetic access to high molec-
ular weight materials; however many of these systems
appear to maintain a relatively flexible structure so that
conformational rigidity can be observed only at high molec-
ular weights. Moreover, several theoretical3 and experimen-
tal4 studies suggest that significant inward folding of the
chain termini occurs in these systems, resulting in a density
maximum near the core rather than at the periphery. As a
consequence of this conformational mobility, Meijer observed
that an enantiomerically pure dendrimer constructed using
three constitutionally different wedges attached to a central
carbon atom exhibited no optical activity.5 However, attach-
ment of “backfolding” wedges to restrict flexibility in the
branch segments permitted the expression of a small tem-
perature-dependent optical rotation.6 The presence of stable
chiral conformations in dendrimers constructed with enan-
tiomerically pure subunits appears to be uncommon in many
of the relatively flexible systems that have been studied.7-9
(1) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic Molecules-
Concepts-Synthesis-Perspectives; VCH: New York, 1996.
(2) For a recent review, see: Matthews, O. W.; Shipway, A. N.; Stoddart,
J . F. Prog. Polym. Sci. 1998, 23, 1.
(3) (a) Lescanec, R. L.; Muthukumar, M. Macromolecules 1990, 23, 2280.
(b) Mansfield, M. L.; Klushin, L. I. Macromolecules 1993, 26, 4262. (c)
Meltzer, A. D.; Tirrell, D. A.; J ones, A. A.; Inglefield, P. T.; Hedstrand, D.
M.; Tomalia, D. A. Macromolecules 1992, 25, 4541. (d) Murat, M.; Grest,
G. S. Macromolecules 1996, 29, 1278.
(4) (a) Karakaya, B.; Claussen, W.; Gessler, K.; Saenger, W.; Schlu¨ter,
A.-D. J . Am. Chem. Soc. 1997, 119, 3296. (b) Wooley, K. L.; Klug, C. A.;
Tasaki, K.; Schaefer, J . J . Am. Chem. Soc. 1997, 119, 53. (c) Scherrenberg,
R.; Coussens, B.; van Vliet, P.; Edouard, G.; Brackman, J .; de Brabander,
E. Macromolecules 1998, 31, 456.
(5) (a) Kremers, J . A.; Meijer, E. W. J . Org. Chem. 1994, 59, 4262. (b)
Peerlings, H. W. I.; Strunk, M. P.; Meijer, E. W. Chirality 1998, 10, 46.
(6) Peerlings, H. W. I.; Trimbach, D. C.; Meijer, E. W. Chem. Commun.
1998, 497.
(7) For some recent reviews, see: (a) Peerlings, H. W. I.; Meijer, E. W.
Chem. Eur. J . 1997, 3, 1563. (b) Thomas, C. W.; Tor, Y. Chirality 1998, 10,
53. (c) Seebach, D.; Rheiner, P, B.; Greiveldinger, G.; Butz, T.; Sellner, H.
Top. Curr. Chem. 1998, 197, 125.
(8) (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, 50, 9161.
(9) McElhanon, J . R.; McGrath, D. V. J . Am. Chem. Soc. 1998, 120, 1647.
(10) For synthesis of 3,5-branched polyether dendrimers, see: (a) Fre´chet,
J . M. J .; Hawker, C. J .; Wooley, K. L. J . Macromol. Sci., Pure Appl. Chem.
1994, A31(11), 1627. (b) Hawker, C. J .; Wooley, K. L.; Fre´chet, J . M. J . J .
Chem. Soc., Perkin Trans. 1 1993, 1287.
The synthesis of these desymmetrized analogues of the
3,5-branched Fre´chet-type dendrons affords a capability to
explore the effect of monomer structure on the global
morphology of the dendrimers. The lack of symmetry of these
1
materials is apparent in the 500 MHz H NMR spectrum of
third-generation aldehyde 4a , in which both the benzylic
methylene and methyl ester proton resonances appear as
partially resolved singlets (Figure 1). Furthermore, inspec-
tion of the lowest energy conformer of 3b suggests that the
(11) This is in contrast to dendritic wedges based on 3,5-dihydroxybenzyl
alcohol, which exhibit good solubility in THF from generation one to four.
(see ref 10b).
(12) Molecular weights for 3-5, determined by MALDI-TOF, were
consistent with the expected structures (see Supporting Information).
(13) The lowest energy conformation was generated by employing a
Monte Carlo conformational search using the MM2* force field and the GB/
SA model for CHCl3 implemented on Macromodel 5.0. This afforded a single
conformation within 1 kcal/mol of the global energy minimum.
(14) For a comparison of the hydrodynamic volumes of 3,5-branched
polyaryl ether dendrons with their exact linear analogues, see: Hawker,
C. J .; Malmstro¨m, E. E.; Frank, C. W.; Kampf, J . P. J . Am. Chem. Soc.
1997, 119, 9903.
10.1021/jo990438l CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/08/1999
Weintraub, Jacob G.
