Chiral dendrimers with backfolding wedges

Article abstract of DOI:10.1039/a708158h

Dendritic wedges with a substitution pattern that forces the growth inwards are introduced and the use of this new building strategy is exemplified in the synthesis and chiroptical properties of a chiral dendrimer.

Full text of DOI:10.1039/a708158h

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Chiral dendrimers with backfolding wedges
H. W. I. Peerlings, D. C. Trimbach and E. W. Meijer*†
Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven,
The Netherlands
Dendritic wedges with a substitution pattern that forces the
growth inwards are introduced and the use of this new
building strategy is exemplified in the synthesis and
chiroptical properties of a chiral dendrimer.
modification of the Fre´chet-type poly(benzylether) wedges by
changing from a 3,5- to a 2,6-dibenzyloxy substitution pat-
tern.
2,6-Dihydroxybenzoic acid was used as a starting material
for the synthesis of both desired backfolding dendritic wedges.
The first generation was synthesized starting from a reaction of
2,6-dihydroxybenzoic acid with 3 equiv. of benzylbromide,
yielding benzyl 2,6-dibenzyloxybenzoate 2, which was reduced
by a reaction with LiAlH4 to 2,6-dibenzyloxybenzyl alcohol 3
(Scheme 1). Bromination of 3 was accomplished by a reaction
with PBr3, yielding 2,6-dibenzyloxybenzyl bromide 4, the first
generation bromide backfolding dendrimer. For the synthesis of
the second generation of bromide backfolding dendritic wedge,
first 2,6-dihydroxybenzoic acid was converted into methyl
2,6-dihydroxy benzoate 5 via reaction with methyl iodide in
DMF in the presence of NaHCO3. In our first approach to
backfolding, the normal Fre´chet-type dendritic wedge of the
first generation was brought into reaction with 5, yielding 6.
After reduction to the corresponding benzyl alcohol 7, the
desired benzyl bromide 8 was obtained via reaction with PBr3.
The crystalline benzyl bromides 4 and 8 proved to be rather acid
sensitive and compound 8 even decomposes on standing in a
CHCl3 solution.
The first reports on the synthesis and properties of dendrimers1
initiated many studies towards this new class of highly branched
macromolecules. A wide variety of synthetic routes have led to
the production of a large number of new dendritic structures,
even leading to structures that are now commercially available.2
The branching pattern of many, if not all, of these dendrimers is
designed to facilitate the growth of each next generation
outwards. As a result, dendrimers can be obtained that possess
a highly packed periphery and cavities in the interior, making
for example, encapsulation of guest molecules possible.3
Recently, however, it has been indicated that many of the
structures studied so far have a rather flexible conformation,
leading to an average density that is not different for interior and
periphery. So far, conformational rigidity in these structures has
only been found at higher generations of dendrimers.3–6
Restricted flexibility at lower generations, however, has not
been observed before and is of interest for many applications
foreseen for dendrimers, e.g. molecular recognition and cataly-
sis.7 Also our search for an optically active chiral dendritic
object, which owes its chirality to the presence of constitution-
ally different wedges attached to a central carbon atom, is
hampered by this flexibility.8 Recently, the enantiomerically
pure dendrimer (S)-1 was described (Fig. 1); however, no
detectable optical activity was observed.9 Here, we present the
concept of backfolding wedges in the synthesis of dendrimers
with restricted flexibility at lower generations. The effect of
these wedges is exemplified in a chiroptical study based on the
The effect of the backfolding dendritic wedges was tested in
the synthesis of (S)-9, the conformationally more rigid analogue
of (S)-1 (Fig. 1). The assigned conformational flexibility in
(S)-1 is based on the chiroptical study, as there is no detectable
optical activity in terms of optical rotatory dispersion (ORD),
circular dichroism (CD) or optical rotation,9 and therefore this
compound can be referred to as being cryptochiral.10
O
OH
CO2H
OH
O
O
O
O
O
O
i
ii
iii
CO2
O
OH
Br
O
O
O
O
O
O
O
O
O
O
*
O
2
3
4
O
O
O
O
O
O
O
H
O
*
O
O
O
O
O
O
O
(S)-1
(S)-9
OH
CO2H
OH
OH
O
O
O
O
iv
v
vi
vii
CO2Me
CO2Me
OH
Br
OH
5
O
O
O
O
O
O
O
O
6
7
8
Scheme 1 Reagents and conditions: i, BnBr, K2CO3, 18-crown-6, acetone;
ii, LiAlH4, Et2O, 65% for two steps; iii, PBr3, Et2O, 96%; iv, MeI, NaHCO3,
DMF, 77%; v, [G-1]Br, K2CO3, 18-crown-6, acetone, 67%; vi, LiAlH4,
THF, 75%; vii, PBr3, Et2O–THF, 74%
Fig. 1 Modelling study of (S)-1 and (S)-9
Chem. Commun., 1998
497

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In conclusion, we present the concept of a backfolding
dendritic wedge by modifying the branching pattern of Fre´chet-
type dendritic wedges. The backfolding character of this new
type of dendrimers is illustrated in chiral dendrimer (S)-9, which
exhibits optical activity. The chiroptical properties show that
when introducing these conceptually new wedges an overall
conformationally more rigid structure is obtained. The use of
this new type of wedge enables us create more conformational
rigidity at low generations, which up to now was only possible
at very high generations.
O
O
HO OH
ButMe2SiO OH
iii
O
O
O
O
O
O
O
O
O
i
ii
O
O
OH
10
11
12
iv
The authors thank The Netherlands Foundation for Chemical
Research (SON) and The Netherlands Organization for Scien-
tific Research (NWO) for financial support. DSM Research is
gratefully acknowledged for an unrestricted research grant.
Sergey Nepogodiev and Peter Ashton are acknowledged for the
LSIMS measurement of chiral dendrimer (S)-9.
O
O
ButMe2SiO
v
O
HO
vi
O
O
O
O
O
O
O
O
O
O
O
O
O
*
Notes and References
O
14
13
O
† E-mail: tgtobm@chem.tue.nl
‡ Selected data for (S)-9: dH(CDCl3) 3.58–3.69 (m, 4 H, C*HCH2), 3.79 (q,
J 5.5, 1 H, C*H), 4.51 and 4.67 (2*s, 4 H, CH2OCH2OAr), 4.71 and 4.73
(S)-9
(2d,
J 10.3, C*HOCH2Ph), 4.89 and 4.90 (2s, 8 H, ArOCH2Ph,
ArOCH2ArA), 4.91 (s, 8 H, ArAOCH2Ph), 6.44 and 6.48 (2d, J 8.4, 4 H, ArH-
3,5), 6.51 (t, J 2.2, 2 H, ArAH-4), 6.64 (d, J 2.2, 4 H, ArAH-2,6), 7.03–7.35
(m, 37H, ArH-4 and PhH); dc(CDCl3) 61.4, 69.8, 70.1, 70.9, 71.0, 71.8
(CH2), 77.4 (C*H), 101.3 (ArAC-4), 105.4 and 105.6 (ArC-3,5), 105.8
(ArAC-2,6), 115.4, 115.5 (ArC-1), 126.8, 126.9, 127.2, 127.4, 127.5, 127.8,
128.3, 128.4, 129.3, 129.4 (PhCH), 129.3, 129.4 (ArC-4), 136.7 (ArA-
OCH2PhC-ipso), 137.1 (ArOCH2PhC-ipso), 139.1 (C*HOCH2PhC-ipso),
139.7 (ArAC-1), 158.4 (ArC-2,6), 159.9 (ArAC-3,5); nmax(KBr)/cm21 3031
(NC–H), 2927 and 2872 (–CH2–), 1596 and 1497 (CNC), 1452 (CH2); 1115
(CH2OCH2). [a]2D0 +0.8 (c 2.2, CH2Cl2). m/z 1233 (M + Na+), 1249 (M +
K+), 1343 (M + Cs+).
Scheme 2 Reagents and conditions: i, 4, NaH, THF, 98%; ii, TsOH, MeOH,
75%; iii, NaH, ButMe2SiCl, THF, 54%; iv, NaH, BnBr, THF, 77%; v,
Bu4NF, THF, 77%; v, 8, NaH, THF, 68%.
The synthetic approach to chiral dendrimer (S)-9 is similar to
the synthesis of (S)-1, with normal Fre´chet-type wedges, as
reported before.9 However, due to the acid-sensitivity of the
dendritic wedges the use of strong acidic conditions in the
synthetic route had to be circumvented. Enantiomerically pure
(S)-2,2-dimethyl-1,3-dioxolane-4-methanol [[a2D0] +15.2 (neat,
25 °C)] was used as a starting material for the synthesis of the
backfolding dendrimer (S)-9. The free alcohol functionality was
brought into reaction with the first generation of backfolding
bromide 4, yielding 10. Deprotection of the acetal protecting
group was performed under mild acidic conditions, making use
of a catalytic amount of toluene-p-sulfonic acid in MeOH,
leading to diol 11, which could be obtained as a white
crystalline solid. In order to differentiate between the two
alcohol functionalities a bulky protecting group was introduced
via a reaction with NaH and ButMe2SiCl. Only the desired
monosubstituted product 12 and unreacted product 11 could be
obtained after the reaction, which could be separated by
washing with hexane (in which only the product dissolved). The
free secondary alcohol functionality was reacted with benzyl
bromide (the zeroth generation of dendrimer), yielding 13.
Subsequently, the ButMe2Si group was removed by reaction
with Bu4NF to yield precursor molecule 14. In the final step the
free primary alcohol functionality of 14 was reacted with the
second generation of backfolding bromide 8 in a Williamson
synthesis, leading to target molecule (S)-9. Except for 11, all
chiral compounds were oils that had to be purified using column
chromatography. All spectroscopic data are in full agreement
with the compounds obtained.‡
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Backfolding dendrimer (S)-9 exhibited, in sharp contrast to
(S)-1, an optical activity of [a]2D0 +0.8 (c = 2.2, CH2Cl2). A
more thorough study was performed using ORD, UV and CD
measurements. For the CD measurements, destilled CH2Cl2 was
used and spectra were measured at l = 320–220 nm. A very
weak signal was found at l = 280 nm, at a temperature of
15 °C, indicative of an induced chiral effect. However, at more
elevated temperatures (30 °C) this signal vanished, indicating
that the conformational flexibility/rigidity can be triggered by
temperature. The difference in chiroptical effects for (S)-1 and
(S)-9 are proposed to be the result of more conformational
rigidity in the latter.
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Received in Liverpool, UK, 12th November 1997; 7/08158H
498
Chem. Commun., 1998