AB3 building blocks for the synthesis of polyester dendrimers

Article abstract of DOI:10.1016/j.tetlet.2014.04.073

Syntheses of several examples of a new type of trivalent building blocks for the preparation of aliphatic polyester dendrimers are presented. Starting from the well-known mono-O-benzylidenepentaerythritol, AB₃ type acid dendrons can be obtained

Full text of DOI:10.1016/j.tetlet.2014.04.073

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AB3 building blocks for the synthesis of polyester dendrimers
Jean-d’Amour K. Twibanire a,b, , Malcolm P. Huestis a,c, T. Bruce Grindley a,
⇑
⇑
a Department of Chemistry, Dalhousie University, Halifax, NS B3H 4J3, Canada
b CanAm Bioresearch Inc., Winnipeg, MB R3T 0P4, Canada
c Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of several examples of a new type of trivalent building blocks for the preparation of aliphatic
polyester dendrimers are presented. Starting from the well-known mono-O-benzylidenepentaerythritol,
AB3 type acid dendrons can be obtained in high yield in only two steps. Other triprotected bis-2,2-
(hydroxymethyl)-3-hydroxypropanoic acid derivatives with varying protecting groups were also synthe-
sized readily. This type of dendron was used in combination with 2,20-bis(hydroxymethyl) propanoic acid
(bis-HMPA) divalent dendrons to produce low generation mixed polyester dendrimers with increased
number of branching points.
Received 27 March 2014
Revised 17 April 2014
Accepted 21 April 2014
Available online xxxx
Keywords:
Dendrons
Polyester dendrimers
Mono-O-benzylidenepentaerythritol
Tribranched dendrons
Ó 2014 Elsevier Ltd. All rights reserved.
Polyester dendrimers are of particular interest because they are
easily synthesized, non-toxic, and they have been shown to have
applications in many fields.1 They are particularly useful for
biomedical applications including as smart carriers for drug deliv-
ery.1,2 However, the synthesis of polyester dendrimers has largely
relied on the use of the 2,20-bis(hydroxymethyl) propanoic acid
(bis-HMPA) dendrons.1,3 Since the 1990s, this aliphatic building
block has continued to be the dendron of choice. The use of bis-
HMPA has allowed easy preparation of higher generation polyester
dendrimers because it is not sterically hindered, and most
importantly, the resulting polyester dendrimers are non-toxic
and biodegradable, which make them attractive for biological
and drug delivery applications.2a,d,g,3c,4
The field of polyester dendrimers is still in its infancy. Conse-
quently, dendritic architectures, properties, and applications are
still essentially unexplored. The preparation of different types of
polyester dendrimers with new properties and new potential
applications depends largely on the ability of researchers to syn-
thesize dendrimers with increasing structural diversity. The use
of new building blocks is one way of achieving this goal. Herein
we report the design and preparation of dendrons derived from
pentaerythritol that have three branching points. Dendrons with
three branching points can allow the synthesis of polyester dendri-
mers that are more highly branched (per generation) than previ-
ously reported polyester dendrimers. Such dendrimers should
have the advantage that they are less easily hydrolyzed in vivo
than previously synthesized polyester dendrimers, but share the
advantages of synthesis under mild conditions of other polyester
dendrimers and potential biological release of bioactive molecules
either trapped or conjugated.
Dibutylstannylene acetals have shown to be useful for selective
chemical manipulations of diols and polyols.5 They are formed
readily from diols6 and have served as convenient intermediates
for the formation of monobenzyl ethers from diols or polyols by
reacting with benzyl bromide in benzene or toluene in the
presence of tetrabutylammonium bromide6a,7 or in DMF in the
presence of cesium fluoride.6b,8 Issidorides and Gulen9 described
an efficient procedure for the synthesis of 5,5-bis(hydroxy-
methyl)-2-phenyl-1,3-dioxane, also known as mono-O-ben-
zylidenepentaerythritol 1. Following the procedure developed
earlier in this laboratory,10 1 was refluxed with one equivalent of
dibutyltin oxide in toluene followed by the subsequent benzylation
in situ, to give isomers
2 and 3 as thick colorless syrups
(Scheme 1). When p-methoxybenzaldehyde is employed as in
Scheme 2, the resulting isomers 5 and 6 are colorless crystalline
solids.
These isomers were separated as previously described,10 char-
acterized using 1H NMR and 13C NMR spectroscopy, and their
structures were assigned. While clean NMR spectra for 2, 3, and
5 could be obtained in chloroform-d, pure samples of 6 equili-
brated whenever dissolved in chloroform-d to give 3:2 mixtures
of 5 to 6. The same ratio was observed independent of the amount
of time the sample was left in chloroform-d (e.g., 0, 2, or 36 h after
dissolving the sample in chloroform-d). It is known that
⇑
Corresponding authors.
E-mail addresses: twibanire@dal.ca (J. K. Twibanire), bruce.grindley@dal.ca (T.B.
Grindley).
http://dx.doi.org/10.1016/j.tetlet.2014.04.073
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Twibanire, J. K.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.073

2
J. K. Twibanire et al. / Tetrahedron Letters xxx (2014) xxx–xxx
OBn
OBn
Bu
Sn
OBn
Bu
O
O
O
Ph
Ph
O
Ph
HO
49%
O
OH
O
79%
O
O
2
OH
OH
OH
OH
O
7
2
OH
OH
BnBr
NaClO2
Bu2SnO
O
Bu4NBr
+
O
TEMPO, NaClO
toluene
- H2O
toluene
O
O
Ph
Ph
76%
O O
Ph
Scheme 1. Mono-O-benzylation.
O
O
Ph
35%
O
O
O
Ph
H2O, CH3CN
3
OBn
OBn
8
NaH2PO4, Na2HPO4
1
3
OBn
OBn
OH
OBn
O
O
O
O
40%
MeO
MeO
O
9
OH
5
chloroform-d decomposes slowly on standing to release dichloro-
carbene and HCl. When acetone-d6 was used for NMR experiments
on 6, no equilibration was observed (see Supporting information).
Scheme 3 shows the likely mechanism of the equilibrium in chlo-
roform-d. Presumably, 6 equilibrates more readily than 5 because
of the greater bulk of the axial CH2OBn group in 6. In addition, iso-
mer 5 is likely stabilized by hydrogen bonding between the down-
ward pointing 1,3-dioxane ring oxygen(s) and the axially-oriented
hydroxymethyl group.
Oxidation is a fundamental transformation in organic synthesis
and numerous methods have been reported for the desired trans-
formation.11 When the starting alcohols have labile functional
groups that can cleave under acidic conditions as it is the case here
for 2, 3, 5, and 6, fewer methods exist for the transformation to car-
boxylic acids. Here, we found that Zhao’s method, the so-called
‘Merck oxidation’,12 worked efficiently either on the individual iso-
mers or the mixture of isomers. The reaction between the primary
alcohol and a stoichiometric amount of sodium chlorite in the
presence of catalytic TEMPO and bleach at 38 °C for 12 h in a buf-
fered solution, gave the corresponding acid dendrons in good yield
(Scheme 4).
Scheme 4. Merck oxidation of primary alcohols.
Ph
Ph
O
O
O
O
O
O
OBn
OH
DCC
DCM
O
Ph
Ph
O
O
10
O
89%
BnO
OBn
OBn
O
7
O
O
BnO
OH
DCC
DCM
O
11
91%
O
O
O
O
O
O
OBn
8
Ph
Ph
Scheme 5. Dendron activation.
The activated anhydride dendrons were synthesized from the
respective individual isomeric carboxylic acids (7 and 8) using
DCC as illustrated in Scheme 5. Anhydrides 10 and 11 are crystal-
line products and they remained stable over a period of several
months at room temperature. It is important to mention that for
H
O
OH
O
HO
HO
HCl
H2O
O
78%
OH
+
MeO
OH
4
HO
OMe
OBn
HO
O
OH
Bu
48%
36%
O
O
Sn
MeO
MeO
Bu
HO
O
5
O
BnBr
Bu2SnO
O
O
O
Bu4NBr
+
toluene
- H2O
toluene
OH
O
O
OMe
MeO
4
OBn
6
Scheme 2. Mono-O-benzylation.
OBn
OH
OH
O
O
O
O
O
O
+
CDCl3
MeO
MeO
MeO
H
57%
OBn
O
OBn
6
5
6
43%
OH
OH
OH
O
O
O
resonance
O
+
O
contributors
HO
MeO
MeO
MeO
H+
OBn
OBn
OBn
H
6
OBn
H
HO
OBn
OBn
OH
+ H+
- H+
O
O
O
O
OH
O
MeO
MeO
OH
5
MeO
Scheme 3. Acid-catalyzed equilibrium of 5/6.
Please cite this article in press as: Twibanire, J. K.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.073

J. K. Twibanire et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
OBn
O
O
O
O
O
CoCl2, BH3.THF
OH
OH
NaH, MeI
DMF, 0 - rt
O
O
THF, rt
93%
HO
O
13
12
82%
1
Jones reagent
acetone
87%
O
O
O
BnO
OBn
DCC
DCM
O
BnO
OH
O
O
O
O
O
15
14
88%
O
Scheme 6. Preparation of anhydride 15.
Jones
AllO
AllO
AllO
AllO
O
O
O
reagent
acetone
AllO
AllO
AllO
OAll
OAll
AllO
AllO
AllO
DCC
DCM
AllO
AllO
O
OH
OH
OH
67%
OAll
16
18
93%
17
70% tech. grade
Scheme 7. Preparation of allyl-protected anhydride 18.
the purpose of polyester dendrimer synthesis, the separation of the
isomeric alcohols (2 and 3), precursors to the carboxylic acids (7
and 8) is not necessary, because the deprotection step, involving
removal of the benzylidene acetal, eliminates the cis/trans
isomerism.
We have previously reported the synthesis of an AB3 symmetri-
cal dendron prepared by selective reduction of known13 di-O-ben-
zyl-O-benzylidenepentaerythritol to tri-O-benzylpentaerythritol
followed by Jones oxidation and dendron activation with DCC.14
A similar approach using methyl iodide (see Scheme 6) leads to a
new dendron 14 in good yield. Dendrons such as compound 14
O
S
O
O
O
Ph
O
O
O
OH
Ph
O
DMAP
DCM
HO
19
O
S
O
+
O
O
Ph
pyridine
O
OBn
O
O
O
O
O
O
O
86%
O
20
O
O
Ph
BnO
BnO
OBn
10
Scheme 8. Preparation of second generation mixed polyester dendron 20.
HO
HO
OH
OBn
O
Ph
O
O
BnO
OBn
O
OH
O
O
O
O
O
DMAP
DCM
DMAP
DCM
1.
O
1.
2.
O
O
O
O
O
O
pyridine
pyridine
O
S
O
+
+
94%
O
O
93%
HO
Ph
O
O
S
DBU
DCM
97%
O
2.
Pd/ C, H2
98%
O
Ph Ph
O
O
O
O
O
BnO
23
OBn
OBn
Ph
24
21
22
Scheme 9. Preparation of second generation mixed acid dendron 24.15
O
O
HO
OH
OH
OH
O
O
HO
HO
O
OH
O
O
O
O
HO
O
OH
O
HO
OBn
O
BnO
OBn
DMAP
DCM
1.
O
O
O
O
DMAP
DCM
O
O
O
1.
2.
O
pyridine
pyridine
O
O
+
97%
+
94%
O
O
2.
Pd/ C, H2
96%
26
O
O
Pd/ C, H2
96%
Ph Ph
O
23
BnO
OBn
HO
OBn
O
OH
HO
25
21
O
O
O
O
OH
HO
O
HO
OH
OH
O
OH
HO
O
O
Scheme 10. Preparation of second generation mixed polyester dendrimer 26.14
Please cite this article in press as: Twibanire, J. K.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.073

4
J. K. Twibanire et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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which could be important for alleviating steric hindrance at
higher dendrimer generations and/or for dendrimer surface
functionalization.
Another tribranched dendron was obtained when technical-
grade tri-O-allylpenterythritol, the commercially available
tri-O-allylpenterythritol (stated to have 70% purity, containing
both monoallylpentaerythritol and diallylpentaerythritol, easily
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corresponding acid anhydride with DCC (Scheme 7).
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investigating how versatile they are in the preparation of polyester
dendrimers. This new type of building blocks will allow dendrimer
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Please cite this article in press as: Twibanire, J. K.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.073