A divergent synthesis of modular dendrimers via sequential C-C bond fragmentation thio-Michael addition

Article abstract of DOI:10.1039/c0cc02289f

The C-C bond fragmentation of carbocycles has been developed as a new method for the divergent synthesis of dendrimers. The scope of this reaction was examined with the preparation of six first generation dendrimers from structurally diverse and readily available fragmentation precursors. By pairing the fragmentation with a thio-Michael reaction, the preparation of a [G4]-ene₂₄ dendrimer has been achieved.

Full text of DOI:10.1039/c0cc02289f

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A divergent synthesis of modular dendrimers via sequential C–C bond
fragmentation thio-Michael additionw
Judith Hierold, Angus Gray-Weale and David W. Lupton*
Received 1st July 2010, Accepted 28th July 2010
DOI: 10.1039/c0cc02289f
The C–C bond fragmentation of carbocycles has been developed
as a new method for the divergent synthesis of dendrimers. The
scope of this reaction was examined with the preparation of six
first generation dendrimers from structurally diverse and readily
available fragmentation precursors. By pairing the fragmentation
with a thio-Michael reaction, the preparation of a [G4]-ene24
dendrimer has been achieved.
To explore these ideas b-ketoester 3 was exposed to methanol
and K2CO3 at room temperature in a trial reaction. Remarkably,
complete C–C bond cleavage occurred in less than 5 minutes,
providing a,b-unsaturated ester 4 quantitatively (eqn (2)). The
facile nature of this test reaction, ready availability of
the starting material (ESIw), and the range of carbocycles
potentially suited to this reaction proved ample incentive for
further investigation. In this communication the use of a
Grob/Eschenmoser fragmentation to prepare a range of first
generation alkenes, and the fourth generation dendrimer 11a,
is reported.
The success of hyperbranched monodisperse macromolecules
3
in fields spanning nanotechnology1a–e to medicine1f,g, has
driven the development of efficient strategies for the synthesis
and functionalisation of dendrimers.2 Recent synthetic
highlights include the development of methods for internal
functionalisation,2d,e,g,j,n accelerated growth,2h–j degradability,2k,m
and bifunctionality.2f Remarkably, these discoveries have been
achieved using only a handful of powerful organic reactions.
Herein, we report the first example of a divergent dendrimer
synthesis using the C–C bond fragmentation of carbocyclic
b-ketoesters.
Recently, we commenced studies aimed at tackling the
preparation of dendrimers with tuneable physical properties
and the prediction of those properties.3,4 Inspired by the broad
utility of CQC ring opening in ROMP polymerisation5 we
decided to explore a strategy based around the C–C bond
fragmentation6,7 of cycloalkanones. The strength of this
approach lies in the ubiquity of the substrates, providing a
broad, and untapped resource for polymer synthesis.
While Grob-fragmentations are known, simple cycloalkanones
require ring strain and/or forcing conditions to be viable
(eqn (1)).6a To overcome this lack of reactivity we identified
the fragmentation of b-ketoesters as worth investigating
(i.e. 3). It was postulated that the ester group would weaken
the C–C bond thereby favouring fragmentation, a hypothesis
supported by the observation that related materials undergo
ring opening as a minor side reaction.8 Alternately, 3 can
be viewed as a substrate that can open by a retro-Dieckmann9/
elimination sequence to provide the same product.10
ð1Þ
ð2Þ
Studies commenced with the assembly of a number of first
generation dendrimers from polyol cores and b-ketoesters
3a–e (Table 1). Fragmentation precursors 3a–e were chosen
to examine the scope of the reaction, while modulating
physical properties (vide infra). In addition, these substrates
are readily prepared in one or two steps, from known or
commercial materials.
During initial experiments, triol 5 was reacted with 3
equivalents of b-ketoester 3a, under conditions analogous to
those in eqn (2). Unfortunately, triol 5 was sparingly miscible
with b-ketoester 3a, and little conversion was achieved after
24 hours. Various solvents increased miscibility, however they
did not provide a serviceable yield of [G1]-ene3 7a. In contrast
increasing the stoichiometry of monomer 3a (2 equiv. per
alcohol group) and raising the temperature to 70 1C allowed
[G1]-ene3 7a to be prepared in 93% isolated yield after 72 hours
(Table 1, entry 1). In an attempt to accelerate the reaction,
microwave irradiation at 70 1C was trialled. Using these
conditions 92% conversion of triol 5 was achieved after
60 minutes, while extended heating introduced decomposition
products (Table 1, entry 1b). Although the reaction time is
long under conventional heating, the high purity of the
product meant that these conditions were used. Next the tetrol
core 6 was subjected to four fold fragmentation with
b-ketoesters 3a, providing [G1]-ene4 8a in 87% isolated yield
(Table 1, entry 2). The use of fragmentation precursor 3b met
In addition to facilitating C–C bond fragmentation the ester
group in starting material 3 provides an a,b-unsaturated
ester motif in product 4. This functionality was considered
useful for either chain extension, as developed herein, or as a
malleable chemical handle for the attachment of materials to
the interior of the dendrimer.11
Monash University, Clayton Victoria 3800, Australia.
E-mail: david.lupton@monash.edu; Fax: +61 3 9905 4597;
Tel: +61 3 9902 0327
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for new materials and 1H NMR
spectra. See DOI: 10.1039/c0cc02289f
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6789–6791 6789

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Table 1 Scope of modified Grob/Eschenmoser fragmentation
Entry Core
b-Ketoester Producta
% Yieldb
1a
1b
93
92c
2
3
87
87
4
5
98
Fig. 1 (A) 1H NMR Expansion of [G1]-ene3 to [G4]-ene24 between
91
88
d 6.2 and 4.5 ppm. (B) GPC trace of alkenes [G1]-ene3 to [G4]-ene24
.
1
(C) H NMR of [G4]-ene24
.
purity (ESIw). Diagnostic signals in the 1H NMR for con-
sumption of the alkene in the thio-Michael, and the benzylic
alcohol in the fragmentation allowed the reaction progress to
be analysed (Fig. 1A and C).
6
a
b
2 equiv. 3a–e and K2CO3/alcohol, 70 1C, 72 h. Isolated yield following
flash column chromatography. Conversion judged by 1H NMR.
c
GPC analysis of the olefin terminating materials, [G1]-ene3
7a to [G4]-ene24 11a, was also conducted demonstrating
narrow dispersion (PDI o 1.2, see ESIw), and a predictable
increase in molecular size (Fig. 1B). ESI HRMS was possible
on all compounds up to [G2]-ene6, providing the expected
results, while at higher generations the materials were analysed
by MALDI-TOF. The alkene terminating materials failed to
ionize using various matrices and methods, while [G3]-ol24
provided a positive analysis within the expected mass range.
Access to a range of macromolecules allowed us to test
theories for the prediction of dendrimer size. When Random
Branching Theory (RBT) was used to reproduce the hydro-
dynamic radii of [G1]-ene3 7a to [G4]-ene24 11a, as obtained
from GPC analysis, the predictions were qualitatively correct,
however they failed to reproduce the sharp increase in size
relative to mass (ESIw). These studies highlight the need for
improved theoretical models13 for modelling dendrimer size.
Ongoing investigations aim to address this topic, using small
angle scattering data of the dendrimers presented herein.
In summary, we have developed a divergent synthesis of
[G4]-ene24 11a using the fragmentation of readily available
carbocycles. This reaction proceeds in excellent yields, using a
range of b-ketoesters, prepared in either one or two steps from
commercial materials. The use of C–C bond fragmentation
reactions in dendrimer synthesis is new. While the Grob/
Eschenmoser fragmentation explored in these studies performed
exceptionally well, we believe that a host of related fragmentation
reactions are equally well suited to applications in dendrimer and
polymer synthesis. These are the subjects of ongoing studies. In
addition, we are developing improved models to predict the
physical properties of dendrimers bearing internal branching.
with similar success, providing [G1]-ene3 7b in 87% yield
(Table 1, entry 3). This product contains key functionality,
useful for internal modification, or switchable dendrimer
decomposition.12 Monomer length was explored with pentanone
3c and heptanone 3d providing chain-contracted, and -extended,
first generation dendrimers 7c and 7d (Table 1, entries 4 and 5).
The latter example demonstrates that while the reaction
reported by Eschenmoser is highly sensitive to ring size,6a
our substrates are far less so. Finally the introduction of
forced turns was explored using indanone 3e and providing
[G1]-ene3 7e, in 88% isolated yield (Table 1, entry 6). In all
cases the outcome of the reaction was determined using
conventional means (ESIw), while with [G1]-ene3 7a, in addi-
tion, GPC analysis was used to confirm the outcome of the
reaction (Fig. 1B).
Having established the viability of the Grob/Eschenmoser
fragmentation, a phosphine catalysed thio-Michael addition
was investigated to introduce a branching diol.2l We found
that the threefold reaction of [G1]-ene3 7a with thiol 9
proceeded rapidly, either solvent free or more conveniently,
in acetonitrile, to afford [G1]-ol6 10a in full conversion.
Repeating the Grob/Eschenmoser fragmentation and thio-
Michael reactions furnished [G4]-ene24 11a in five subsequent
steps (Scheme 1). Each step reached greater than 95% com-
pletion as judged by 1H NMR analysis. Trituration of the
crude reaction mixtures gave high yields with few impurities,
although for analytical purposes flash column chromato-
graphy was performed, giving lower isolated yields but greater
c
6790 Chem. Commun., 2010, 46, 6789–6791
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Scheme 1 Synthesis of [G4]-ene24 11a: (a) 2 equiv. 3a and K2CO3/alcohol, 70 1C, 72 h; (b) 10 mol% Me2PPh, 1 equiv. 9/alkene, CH3CN, rt, 1 h.
We thank the ARC for financial support (DP0881137),
Monash University for a research fellowship (AGW), Dr Kei Saito
and Priscilla Johnston for help with GPC and Dr David Steer
for MALDI-TOF.
G. Franc, A. Castonguay and A. Kakkar, Chem. Commun., 2010,
46, 1875; (n) T. Kang, R. J. Amir, A. Khan, K. Ohshimizu,
J. N. Hunt, K. Sivanandan, M. I. Montanez, M. Malkoch,
M. Ueda and C. J. Hawker, Chem. Commun., 2010, 46,
1556.
3 For a review of polymer structure and therapeutic utility see:
´
M. E. Fox, F. C. Szoka and J. M. J. Frechet, Acc. Chem. Res.,
2009, 42, 1141.
4 (a) D. Konkolewicz, R. G. Gilbert and A. Gray-Weale, Phys. Rev.
Lett., 2007, 98, 238301; (b) D. Konkolewicz, O. Thorn-Seshold and
A. Gray-Weale, J. Chem. Phys., 2008, 129, 054901.
5 For a recent example see: Y. Xia, B. D. Olsen, J. A. Kornfield and
R. H. Grubbs, J. Am. Chem. Soc., 2009, 131, 18525.
6 (a) A. Eschenmoser and A. J. Frey, Helv. Chim. Acta, 1952, 35,
1660; (b) F. Nerdel, D. Frank and H. Marschall, Chem. Ber., 1967,
100, 720. For review: (c) C. A. Grob, Angew. Chem., Int. Ed. Engl.,
1969, 8, 535.
7 For recent fragmentation reactions see: (a) A. Bayir, C. Draghici
and M. Brewer, J. Org. Chem., 2010, 75, 296; (b) J. Tummatorn
and G. B. Dudley, J. Am. Chem. Soc., 2008, 130, 5050.
8 For example: (a) Y. Tsuda, A. Ishiura, S. Takamura, S. Hosoi,
K. Isobe and K. Mohri, Chem. Pharm. Bull., 1991, 39, 2797;
(b) E. Hasegawa, T. Kitazume, K. Suzuki and E. Tosaka, Tetrahedron
Lett., 1998, 39, 4059; (c) E. Charonnet, M.-H. Filippini and
J. Rodriguez, Synthesis, 2001, 5, 788.
9 For retro-Dieckmann of related substrates: S. Sano, H. Shimizu
and Y. Nagao, Tetrahedron Lett., 2005, 46, 2883.
10 Kinetic studies support a Grob/Eschenmoser fragmentation over a
retro-Dieckmann elimination sequence.
Notes and references
1 For recent examples, in catalysis: (a) K. Yamamoto, T. Imaoka,
W.-J. Chun, O. Enoki, H. Katoh, M. Takenaga and A. Sonoi, Nat.
Chem., 2009, 1, 397; (b) K. Mitsui, S. A. Hyatt, D. A. Turner,
C. M. Hadad and J. R. Parquette, Chem. Commun., 2009, 3261;
in light harvesting: (c) K. R. J. Thomas, A. L. Thompson,
A. V. Sivakumar, C. J. Bardeen and S. Thayumanavan, J. Am.
Chem. Soc., 2005, 127, 373; (d) W. R. Dichtel, S. Hecht and J. M. J.
´
Frechet, Org. Lett., 2005, 7, 4451; (e) U. Hahn, M. Gorka,
F. Vogtle, V. Vicinelli, P. Ceroni, M. Maestri and V. Balzani,
¨
Angew. Chem., Int. Ed., 2002, 41, 3595; in medicine:
(f) R. K. Tekade, P. V. Kumar and N. K. Jain, Chem. Rev., 2009,
109, 49; (g) S. H. Medina and M. E. H. El-Sayed, Chem. Rev., 2009,
109, 3141.
2 For recent reviews see: (a) G. Franc and A. K. Kakkar, Chem. Soc.
Rev., 2010, 39, 1536; (b) R. Hourani and A. Kakkar, Macromol.
Rapid Commun., 2010, 31, 947; (c) A. Carlmark, C. Hawker,
A. Hult and M. Malkoch, Chem. Soc. Rev., 2009, 38, 352. For
synthetic highlights see: (d) M. E. Piotti, F. Rivera Jr., R. Bond,
C. J. Hawker and J. M. J. Frechet, J. Am. Chem. Soc., 1999, 121,
´
9471; (e) L. G. Schultz, Y. Zhao and S. C. Zimmerman, Angew.
Chem., Int. Ed., 2001, 40, 1962; (f) P. Wu, M. Malkoch, J. N. Hunt,
R. Vestberg, E. Kaltgrad, M. G. Finn, V. V. Fokin,
K. B. Sharpless and C. J. Hawker, Chem. Commun., 2005, 5775;
(g) C. O. Liang and J. M. J. Frechet, Macromolecules, 2005, 38,
6276; (h) P. Antoni, D. Nystrom, C. J. Hawker, A. Hult and
M. Malkoch, Chem. Commun., 2007, 2249; (i) K. L. Killops,
L. M. Campos and C. J. Hawker, J. Am. Chem. Soc., 2008, 130,
11 By growth through the ester an AB2C dendrimer synthesis can be
achieved with an internal alkene. Studies to this end are ongoing.
12 Deprotection of TBS alcohols in compounds related to [G1]-ene37b
results in lactonisation, a reaction that could provide a switch for
removal of the outer generation of a dendrimer.
¨
5062; (j) P. Antoni, Y. Hed, A. Nordberg, D. Nystrom, H. von
¨
13 (a) A. Gray-Weale and R. G. Gilbert, J. Polym. Sci., Part A:
Polym. Chem., 2009, 47, 3914; (b) M. Gaborieau, R. G. Gilbert,
A. Gray-Weale, J. M. Hernandez and P. Castignolles, Macromol.
Theory Simul., 2007, 16, 13.
Holst, A. Hult and M. Malkoch, Angew. Chem., Int. Ed., 2009, 48,
2126; (k) R. E. Kohman and S. C. Zimmerman, Chem. Commun.,
2009, 794; (l) J. W. Chan, C. E. Hoyle and A. B. Lowe, J. Am.
Chem. Soc., 2009, 131, 5751; (m) A. Vieyres, T. Lam, R. Gillet,
c
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Chem. Commun., 2010, 46, 6789–6791 6791