Novel synthesis of amphiphilic dendrons by the double-stage convergent method

Article abstract of DOI:10.1021/ol901765f

A serles of amphophilic dendrons (G1-G4) have been designed and synthesized, which have a highly branched aliphatic hydrocarbon skeleton and a hydrophilic hydroxyl functionality to enable conjugation with other substrates. The higher generation dendrons (G3 and G4) were synthesized by a double-stage convergent method, which shortened the synthetic route significantly and provided the products In an efficient manner. The key branching step involved a double alkyl-metal addition to an ester functionality followed by deoxygenation of a resulting tertiary alcohol by triethylsilane.

Full text of DOI:10.1021/ol901765f

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4394-4397
Novel Synthesis of Amphiphilic
Dendrons by the Double-Stage
Convergent Method
Zi-Fa Shi, Wen-Yu Chai, Peng An, and Xiao-Ping Cao*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou UniVersity, Lanzhou, Gansu 730000, China
caoxplzu@163.com
Received July 31, 2009
ABSTRACT
A series of amphiphilic dendrons (G1-G4) have been designed and synthesized, which have a highly branched aliphatic hydrocarbon skeleton
and a hydrophilic hydroxyl functionality to enable conjugation with other substrates. The higher generation dendrons (G3 and G4) were
synthesized by a double-stage convergent method, which shortened the synthetic route significantly and provided the products in an efficient
manner. The key branching step involved a double alkyl-metal addition to an ester functionality followed by deoxygenation of a resulting
tertiary alcohol by triethylsilane.
Amphiphilic dendrimers, due to their unusual structural
architecture, possess many interesting and unique properties.
These compounds have been used as novel agents in self-
assembling,1 gene transfection,2 catalyst,3 and other applica-
tions.4 They were generally synthesized either by grafting
hydrophilic chains to the surface sector of a hydrophobic
dendrimer5 or by linking linear aliphatic hydrocarbon chains
to the surface sector of a hydrophilic core.6 However, few
papers reported the synthesis of hydrophobic dendrimers
based on a highly branched aliphatic hydrocarbon skeleton.7
The earliest report was by Newkome, in which a G3 aliphatic
dendrimer with multiple hydrophilic hydroxyl surface was
prepared by a divergent method.7a Later, Chow disclosed a
(4) (a) Svenson, S.; Tomalia, D. A. AdV. Drug DeliVery ReV. 2005, 57,
2106. (b) Meyers, S. R.; Juhn, F. S.; Griset, A. P.; Luman, N. R.; Grinstaff,
M. W. J. Am. Chem. Soc. 2008, 130, 14444.
(1) (a) Vutukuri, D. R.; Basu, S.; Thayumanavan, S. J. Am. Chem. Soc.
2004, 126, 15636. (b) Gomez-Escudero, A.; Azagarsamy, M. A.; Theddu,
N.; Vachet, R. W.; Thayumanavan, S. J. Am. Chem. Soc. 2008, 130, 11156.
(2) (a) Joester, D.; Losson, M.; Pugin, R.; Heinzelmann, H.; Walter,
E.; Merkle, H. P.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1486.
(b) Guillot-Nieckowski, M.; Joester, D.; Sto¨hr, M.; Losson, M.; Adrian,
M.; Wagner, B.; Kansy, M.; Heinzelmann, H.; Pugin, R.; Diederich, F.;
Gallani, J.-L. Langmuir 2007, 23, 737.
(5) (a) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders,
M. J.; Grossman, S. H. Angew. Chem., Int. Ed. 1991, 30, 1178. (b) Pan,
Y.; Ford, W. T. Macromolecules 2000, 33, 3731.
(6) (a) Cho, B.-K.; Jain, A.; Nieberle, J.; Mahajan, S.; Wiesner, U.;
Gruner, S. M.; Tu¨rk, S.; Ra¨der, H. J. Macromolecules 2004, 37, 4227. (b)
Luman, N. R.; Grinstaff, M. W. Org. Lett. 2005, 7, 4863.
(7) (a) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Johnson, A. L.;
Behera, R. K. Angew. Chem., Int. Ed. 1991, 30, 1176. (b) Newkome, G. R.;
Arai, S.; Fronczek, F. R.; Moorefield, C. N.; Lin, X.; Weis, C. D. J. Org.
Chem. 1993, 58, 898. (c) Chow, H.-F.; Ng, K.-F.; Wang, Z.-Y.; Wong,
C.-H.; Luk, T.; Lo, C.-M.; Yang, Y.-Y. Org. Lett. 2006, 8, 471.
(3) (a) Helms, B.; Liang, C. O.; Hawker, C. J.; Fre´chet, J. M. J.
Macromolecules 2005, 38, 5411. (b) Hecht, S.; Fre´chet, J. M. J. J. Am.
Chem. Soc. 2001, 123, 6959.
10.1021/ol901765f CCC: $40.75
Published on Web 08/31/2009
 2009 American Chemical Society

Figure 1. Structure of amphiphilic dendrons.
convergent way to obtain a series of G1-G3 aliphatic
dendrons with a polar hydrophilic carboxylic acid core7c and
used them in polymer chemistry and catalytic reaction.8 The
advantages of the divergent approach are the rapid growth
of the dendrimer series, the rapid increase of the size of the
dendritic species, and the better overall yield of the dendrimer
products. However, the limiting features of this method are
the possibility of generating molecular imperfection at higher
generations and the difficulty in selectively modifying the
peripheral functionality. On the other hand, the convergent
approach offers attractive features such as greater control of
the dendrimer growth and easy placement of specific
peripheral functionality. Nonetheless, the inherent limitations
of this approach are: the dendritic growth is slow, the
branching reaction is highly susceptible to steric inhibition
at the focal point, and there is a generally lower overall yield
of the target products due to the increasing number of
synthetic operations.9 In this paper, we report the synthesis
of aliphatic hydrocarbon dendrons 1-4 (Figure 1) with a
hydroxyl focal point using a double-stage convergent ap-
proach to overcome the problem of steric inhibition in
preparation of the higher generation G3 and G4 dendrons.
The growth cycle in this present method involves only four
operations, and the G4 dendron could be prepared in an
overall yield of 12% from readily available starting materials
in 13 steps.
In our synthetic scheme, we chose the addition reaction
of ester with alkyl-metal reagent as the pivotal step in the
branching growth of such dendrons. First, two key branching
intermediates, ester 610 and diester 11, used separated on
the convergent growth and the double-stage convergent
growth, respectively, were prepared (Scheme 1). Ester 6 was
prepared from commerically available alcohol 5 by Jones
oxidation followed by esterification with ethanol (cat. H2SO4)
in 75% yield in 50 g scale. On the other hand, brancher 11
was prepared in six steps in 31% overall yield from the
known dibromide 7. Hence, the monobromide 811 was
obtained in 80% yield by reaction of 4-methoxybenzyl
alcohol (PMBOH) with 1,4-dibromobutane in the presence
of NaOH. The bromide was converted into the correspondng
Grignard reagent and reacted with the ester 6 to afford a
tertiary alcohol 9 in 87% yield. Then, removal of two PMB
protecting groups in 9 with ammonium ceric nitrate (CAN)
furnished the synthesis of triol 10 in 79% yield. Subse-
quently, oxidation of the two primary hydroxyl groups in
10 to the corresponding diacid with Jones reagent followed
by esterification with ethanol (cat. H2SO4) gave a mixture
of isomeric unsaturated diesters due to the elimination of
the tertiary hydroxyl group. The isomeric mixture of unsatur-
ated diesters was then hydrogenated in the presence of 10%
(8) (a) Lau, K.-N.; Chow, H.-F.; Chan, M.-C.; Wong, K.-W. Angew.
Chem., Int. Ed. 2008, 47, 6912. (b) Lo, C.-M.; Chow, H.-F. J. Org. Chem.
2009, 74, 5181.
(9) (a) Carlmark, A.; Hawker, C.; Hulta, A.; Malkoch, M. Chem. Soc.
ReV. 2009, 38, 352, and references cited therein. (b) Xu, Z.; Kahr, M.;
Walker, K. L.; Wilkins, C. L.; Moore, J. S J. Am. Chem. Soc. 1994, 116,
4537.
(10) Charette, A. B.; Chua, P. Synlett 1998, 163.
(11) Acharya, H. P.; Kobayashi, Y. Tetrahedron 2006, 62, 3329.
Org. Lett., Vol. 11, No. 19, 2009
4395

completed by three steps, and the G1 dendron was obtained
in 69% yield from 12.
Scheme 1. Synthesis of 6 and 11
For the synthesis of the G2 dendron, compound 1 was
brominated with NBS and PPh3 in CH2Cl2 at -78 °C to
produce bromide 1413 in 88% yield. The bromide 14 was
found to react smoothly with Mg in ether to produce the
corresponding Grignard reagent, followed by addition with
ester 6 to produce tertiary alcohol 15 in 81% yield. It was
noteworthy to comment that Grignard formation could only
be initiated when the concentration of the bromide 14 was
higher than 1 M. The tertiary hydroxyl group in 15 was then
subjected to the same deoxygenation protocol (Et3SiH/TFA
followed by hydrogenation) to produce the G2 dendron 2 in
85% yield from 15. Again, dendritic growth could be
completed in four synthetic steps from 1. Each of them was
efficient, and all of the products formed could be purified
by column chromatography.
For the synthesis of G3 and G4 dendrons, diester 11 was
used as a starting material by an accelerated double-stage
convergent method (Scheme 3). Hence, diester 11 was
Pd-C and Et3N under H2 atmosphere (1 atm)12 to give
diester 11 in 56% overall yield in three steps.
Scheme 3. Synthesis of G3 and G4 Dendrons
With the requisite 6 in hand, we began to accomplish the
synthesis of G1 and G2 dendrons 113 and 2 (Scheme 2). First,
Scheme 2. Synthesis of G1 and G2 Dendrons
1-bromobutane 12 was converted into the corresponding
Grignard reagent and then reacted with ester 6 to form
tertiary alcohol 13 in 81% yield. The hydroxyl group in 13
was then treated with Et3SiH and trifluoroacetic acid (TFA)
in CH2Cl2 at room temperature to give a mixture of
deoxygenation as well as elimination products,14 which could
not be separated by column chromatography. The mixture
was then hydrogenated in the presence of 10% Pd-C under
H2 atmosphere (1 atm) to produce 1 in 85% yield from 13.
During this transformation, the hydrogenation of the double
bond and the removal of the benzyl group were carried out
simultaneously. Thus, the first iterative synthetic cycle was
reacted with 5.2 equiv of the Grignard reagent generated in
situ from 14 to afford the desired diol 16 in 82% yield. The
two tertiary hydroxyl groups in 16 were then deoxygenated
4396
Org. Lett., Vol. 11, No. 19, 2009

smoothly with Et3SiH/TFA followed by the hydrogenation
and concomitant removal of the focal point benzyl group to
produce the G3 dendron 3 in 86% yield from 16. Likewise,
the fourth synthetic cycle began with the same G2 alcohol
2, which was first converted to the corresponding bromide
17 (80% yield) in the presence of NBS and PPh3. Unfortu-
nately, the Grignard reagent from bromide 17 could not be
obtained as the reaction could not be initiated despite many
attempts, and only unreacted bromide 17 was recovered.
Hence, alcohol 2 was converted to corresponding iodide 18
in 90% yield by treatment with I2, Ph3P, and imidazole in
dichloromethane. Subsequently, diester 11 was reacted with
18 (6.0 equiv) in the presence of SmI2 (12.0 equiv) and NiI2
(cat.) according to the method reported by Namy15 to produce
desired diol 19 (50% yield) together with an incomplete
addition product 20 (10% yield). Compound 20 could be
converted to 19 in 60% yield by further treatment with 18
(3.0 equiv) in the presence of SmI2 (6.0 equiv) and NiI2 (cat.).
Finally, the tertiary hydroxyl groups in 19 were cleanly
converted to the target G4 dendron 4 in 84% yield from 19.
All synthesized compounds were characterized by 1H and
13C NMR, DPET spectroscopy, mass spectrometry, and exact
mass measurement (Table 1). 1H NMR spectra were proved
Figure 2.
1H NMR spectra of 1 (G1-OH), 2 (G2-OH), 3 (G3-OH),
and 4 (G4-OH).
3 (G3-OH), and 24.2:1 (theoretical 24:1) in 4 (G4-OH),
respectively.
In conclusion, we have synthesized a series of amphiphilic
dendrons (G1-G4), which possess a highly branched
hydrophobic aliphatic hydrocarbon skeleton and a hydrophilic
hydroxyl focal point group. The synthesis of the G3 and G4
was highly efficient by a double-stage convergent method.
Hence, the G4 dendron could be prepared only in 13 steps
from alcohol 5 in 12% overall yield. The key reaction steps
involved are a metal-mediated double alkylation to an ester
functionality and an Et3SiH-mediated deoxygenation reaction.
This method allowed the straightforward and rapid construc-
tion of such dendritic species for their structural and
properties investigations. Furthermore, the presence of the
hydroxyl or halogen functional group in these dendrons
enables their conjugations to other functional moieties to
modify their self-assembly properties. These works are
currently underway in our laboratory.
Table 1. Mass Spectral Data of Synthesized Compounds
compound
found
calculated
1a
2
3
4
9
10
11
13
15
16
19
168 [M - H2O]+
186.1984
449.4119
881.9388
1778.9404
582.3789
325.2373
393.2636
275.2369
499.4873
1003.9756
1900.9772
449.4122b [M + K]+
881.9407b [M + Na]+
1778.9 [M + Na]+
582.3779b [M + NH4]+
325.2371b [M + H]+
393.2633b [M + H]+
275.2368b [M - H2O + H]+
499.4884b [M - H2O + H]+
1003.9760b [M + Na]+
1900.9 [M + Na]+
Acknowledgment. The authors are grateful to the National
Basic Research Program (973 Program) of China (Grant No.
2010CB833203) and the National Natural Science Founda-
tion of China (Grant No. 20872055 and 20621091) and the
111 Project for continuing financial support. We thank Prof.
Hak-Fun Chow, the Chinese University of Hong Kong, for
his helpful discussions and guidance in the preparation of
the manuscript.
a Known compound. b High-resolution mass spectral result.
to be very useful in the characterization of the various
products. Thus, the chemical shift patterns and relative
integration values obtained from 1H NMR spectra were very
useful to ascertain the generation as well as the focal point
functional group identity of all compounds (Figure 2). Hence,
the diagnostic integration ratio of the surface methyl protons
(δ 0.89) to the R-methylene protons (δ 3.64) adjacent to the
oxygen atom was 3.0:1 (theoretical 3:1) in 1 (G1-OH), 6.0:1
(theoretical 6:1) in 2 (G2-OH), 12.2:1 (theoretical 12:1) in
Supporting Information Available: Experimental pro-
cedure, characterization for compounds 1-4, 6, 8-11, and
13-20, and 1H, 13C NMR, and DEPT 135 spectra of
compounds 1-4, 9-11, 13, and 15-20. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901765F
(14) Hallgren, J. E.; Lucas, G. M. Tetrahedron Lett. 1980, 21, 3951.
(15) Machrouhi, F.; Hamann, B.; Namy, J.-L.; Kagan, H. B. Synlett 1996,
633.
(12) Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981.
(13) Nusselder, J. J. H.; Engberts, J. B. F. N. Langmuir 1991, 7, 2089.
Org. Lett., Vol. 11, No. 19, 2009
4397