Synthesis of dissymmetric phosphorus dendrimers using an unusual protecting group

Article abstract of DOI:10.1039/c8nj01229f

The presence of an azido group directly linked to phosphorus functionalized monomeric species allows the synthesis of neutral or polycationic original phosphorus dendrimers of reduced symmetry bearing branches of different generations on the core.

Full text of DOI:10.1039/c8nj01229f

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The role of atropisomers on the photo-reactivity and fatigue of
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Synthesis of dissymmetric phosphorus dendrimers using an unusual protecting group
Evgeny K. Apartsina*, Alya G. Venyaminovaa, Serge Mignanib,c, AnneꢀMarie Caminaded,e, Jeanꢀ
Pierre Majorald,e*
a
Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev ave.,
Novosibirsk, 630090, Russian Federation.
b
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Université Paris
Descartes, PRES Sorbonne Paris Cité, CNRS UMR 8601, 75006 Paris, France;
c
Centro de Química da Madeira, MMRG, Universidade da Madeira, 9000-390 Funchal,
Portugal;
d
Laboratoire de Chimie de Coordination du CNRS, 205, route de Narbonne, 31077 Toulouse
Cedex 04, France.
e LCC-CNRS, Université de Toulouse, CNRS, Toulouse, France
* E-mail: eka@niboch.nsc.ru (E. K. Apartsin), jean-pierre.majoral@lcc-toulouse.fr (J.-P.
Majoral)
Abstract
The presence of an azido group directly linked to phosphorus functionalized monomeric species
allows the synthesis of neutral or polycationic original phosphorus dendrimers of reduced
symmetry bearing branches of different generations on the core.
Keywords: phosphorus dendrimers; dissymmetric dendrimers; azides; functionalization.
Introduction
Design and applications of dendrimers represent some of the most important developments in
macromolecular chemistry, as a new class of highly branched polymers for which, size, internal
and external topologies, molecular weight, shape, and charges can be precisely controlled1. They
are generally prepared via stepꢀbyꢀstep procedures (divergent synthesis from a core or
convergent ones).2 Physicochemical and biological properties of the dendrimers are related to
their structure and anatomy such as generations and surface characteristics. Within numerous
dendrimer types described upꢀtoꢀdate, phosphorus dendrimers are among the most useful
3
architectures which can be tailored at will for various uses . Indeed, the rich organophosphorus
chemistry allows the development of sophisticated ways of preparation of phosphorus
dendrimers or related macromolecular species, and consequently a number of applications in
1

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different fields ranging from biology, nanomedicine, nanosciences in general and nanomaterials
4
in particular as well as in the field of catalysis . Some examples of the synthesis of topological
subclasses of phosphorus dendrimers by blocking partially the branches growth sites of the core 5
or by modifying stepwise their functionalization were reported 6.
It is also possible to modify the dendrimer topology by growing branches of different
7
generations on the core . The potential consequence of the topology alteration is the change of
the distribution and density of functional groups on the periphery of dendrimers8 resulting in
drastic changes in dendrimer interactions with various biological systems such as cells, proteins,
blood serum, DNA, etc.9 As an example, the influence of the dendrimers topology on their
activity towards immune cells was recently reported by Caminade et al.10 Interestingly, there are
also evidences of the smaller toxicity of lowꢀgeneration of dissymmetric dendrimers in
comparison with symmetric ones11. Consequently, obtaining dissymmetric phosphorus
dendrimers represents an interesting objective for pharmaceutical applications by developing
new synthetic procedures of preparation of phosphorus dendrimers with potential lower toxicity
issue.
Dissymmetric dendrimers are generally obtained by using classical protecting groups, often at
the level of the core, which need additional reagents for the deprotection and further purification
step 12. The synthesis can be simplified by introducing a temporary protecting group resistant to
one of the reactions comprising typical dendrimer synthesis.13 In particular, azido group linked to
a phosphorus atom can be considered as a pseudoꢀhalogen when reacted with phenols,14 thus this
function could be considered also as a protecting group, easily removed by phenols, without
adding any deprotecting agent. Despite its potential utility, this method has never been used for
the synthesis of dendrimers. In this study, we report the useful and tunable phosphorus azidesꢀ
based synthesis of original dissymmetric phosphorus dendrimers bearing branches of different
generations on the core.
Results and discussion
The synthesis of phosphorus dendrimers15,16 consists of two orthogonal reactions repeating
consecutively: (a) the reaction of dichlorothiophosphate fragments on the periphery of the
growing branch with 4ꢀhydroxybenzaldehyde (intermediate generation); (b) the reaction of
aldehydes with dichlorothiophosphomethylhydrazide to form the Schiff base stabilized by the
aromatic and thiophosphate fragments in vicinity (increasing generation).
Herein, our simple strategy is based on the functionalization of the thiophosphate unit –P(S)<
as a core, which allows to conduct iterative synthesis of three structurally independent branches
2

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for the construction, for instance, of dissymmetric dendrimers. One of the branch growth sites
was temporarily blocked by an azido group to make it unavailable for the generation increasing
reaction. The strong advantage of the proposed strategy is the specific nucleophilic substitution
of N3 of >P(S)ꢀN3 with phenol groups and its stability towards the reaction with amines and
hydrazides allowing the construction of tunable dissymmetric assemblages. All further reactions
at the branches proceeded identically with the same conversion efficiency, independently of the
branch generation. In order to exemplify this approach, we decided to construct dissymmetric
phosphorus dendrimers bearing two branches of the generation N and one branch of the
generation (Nꢀ1) from the –P(S)< core.
Scheme 1
i) NaN3, acetone; ii) H2NꢀN(CH3)ꢀP(S)Cl2, THF; iii) 4ꢀhydroxybenzaldehyde, Cs2CO3, THF.
As shown in the Scheme 1, the synthesis of dissymmetric dendrimers (7) began from the
disubstituted core (1) which has been prepared in one step synthesis by reacting P(S)Cl3 with two
equivalents of 4ꢀhydroxybenzaldehyde.17 Then, the remaining >PꢀCl fragment of (1) was
substituted to the PꢀN3 by the action of NaN3 to form the derivative (2) quantitatively.17 Next is
the condensation of amino group of dichlorothiophosphomethylhydrazide (2 eq.) with (2) (1 eq.)
to
afford
the
Schiff
base
(3)
in
95%
yield.
No
condensation
of
dichlorothiophosphomethylhydrazide with >PꢀN3 has been observed. This strategy prevents the
fast reaction of (1) with the amino group of dichlorophosphomethylhydrazide that does not allow
3

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the construction of tunable dissymmetric dendrimers: both >PꢀCl and the two aldehyde groups
react with dichlorothiophosphomethylhydrazide.
Topologically, the compound (3) is a dendron of the generation 1 (G1) bearing azide group in
the focal point. The phosphorus atoms in the core (P0) and on the periphery (P1) are clearly
discerned in the 31P NMR spectra (chemical shifts of 58.9 and 63.0 ppm, respectively). The next
step is the reaction of (3) with 4ꢀhydroxybenzaldehyde (3 eq.) leading to (4) in 97% yield by the
substitution of the both PꢀCl fragments on the periphery (63.0 to 60.2 ppm) and PꢀN3 fragment in
the focal point (58.9 to 51.5 ppm), as expected. Thus, in the structure of the dendrimer (4), there
1
appear two types of aldehyde groups. The H NMR signals of these aldehydes (9.99 and 10.03
ppm) have the ratio of the integral intensities of 4:1, as it is expected from the structure of (4)
(Fig S1 in the ESI). It is clear from these data that the azide group linked to the phosphorus atom
plays the role of a protecting group, directly removed by a phenolate. With the objective to
obtain the next generation of (4), the reaction of phosphorohydrazide (5 eq.) was carried out to
form dissymmetric dendrimer (5) with 90.4 % yield bearing one branch of generation 1 and two
branches of generation 2 (G1ꢀP(S)ꢀ(G2)2). The P0 atom in the structure of (5) behaves as a
dendrimer core by analogy with fully symmetric phosphorus dendrimers,15 with its chemical
shift (52.2 ppm) being not drastically changed in the course of further reactions. Repeating these
two reactions – condensation of 4ꢀhydroxybenzaldehyde (10 eq.) with (5) leading to the
dissymmetric dendrimers (6, 75% yield) and addition of H2NꢀN(CH3)ꢀP(S)Cl2 (10 eq.) ꢀ affords
(7) bearing one branch of the generation 2 and two branches of the generation 3 (G2ꢀP(S)ꢀ(G3)2,
98% yield). Chemical shifts of the peripheral phosphorus atoms depend on the nature of the
terminal groups (aldehyde or P(S)Cl2) and alternate upon iterative synthesis, as described for
fully symmetric analogs.15 The evolution of 31P{1H} signals of the dissymmetric dendrimers
through the synthetic stages is presented in the Fig. S2 (ESI). The dissymmetric dendrimers (5)
and (7) have 10 and 20 PꢀCl fragments, respectively, on the periphery. These fragments are
available for further chemical modifications. In order to exemplify the functionalization of
dendrimers (5) and (7) the corresponding cationic aminoꢀterminated dendrimers under nonꢀ
protonated and protonated forms (8a,b) and (9a,b) have been prepared (Scheme 2). The
protonated dendrimers (8b) and (9b) have been prepared in order to increase the water solubility
of these nanoparticles and to study their complexation with therapeutic nucleic acids (vide infra).
4

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Scheme 2
i) 1ꢀ(2ꢀAminoethyl)piperidine, DIPEA, THF; ii) HCl/Et2O, THF.
Aminoꢀderivatives of the dissymmetric phosphorus dendrimers were obtained by the reaction
of the dendrimers (5) and (7) with a primary amine in the presence of an organic base
(diisopropylethylamine, DIPEA). As an example, 1ꢀ(2ꢀaminoethyl)piperidine has been chosen
for the modification of the dendrimers’ periphery. Recently, we have shown that cationic
phosphorus dendrimers bearing tertiary amines on the periphery are biocompatible and highly
efficient carriers for the delivery of nucleic acids into cells 18–21. The grafting of amines onto the
periphery of dendrimers resulted in the shifting of the 31P NMR signals corresponding to the
peripheral phosphorus atoms from 63.0 to 68.2 ppm (Fig. S3 in the ESI). Neutral aminoꢀ
modified dendrimers (8a) and (9a) have been obtained in high yields (83ꢀ85%). Waterꢀsoluble
cationic dendrimers (8b) and (9b) were obtained by the protonation of neutral dendrimers (8a)
and (9a) in the organic medium with HCl solution in Et2O. The quantity of HCl used was
calculated to protonate 90% of amines on the dendrimer periphery. Nevertheless, despite of
being incompletely protonated, cationic dendrimers are well soluble in water. Considering the
pK values of ethylpiperidine (~11.3), we can assume that immediately after dissolving in water,
remaining amino groups are ionized by water protons. Thus, cationic dendrimers can be
5

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31
considered fully protonated. P NMR data confirmed the integrity of the dendrimer architecture
after the protonation. The full chemical structure of the compound (9b) is shown in Figure 1.
Fig. 1. Chemical structure of the aminoꢀmodified dissymmetric dendrimer G2ꢀP(S)ꢀ(G3)2,
protonated form (9b).
Conclusions
In summary, an original strategy of the synthesis of dissymmetric phosphorus dendrimers was
reported, using an azide group as unusual protecting group. On one side, the core has an
aminothiophosphate, and on the other side a thiophosphate, both functions being linked through
a methylhydrazinophenol. This work is a new facet of the use of phosphorus azides. Up to now,
two major reactions of phosphorus azides were outlined. The first one consists on the use of
active synthons bearing phosphorus azide unit for the preparation, via Staudinger reaction, of
monomers, macrocycles, dendrimers etc. bearing P=NꢀP=S, or P=NꢀP=NꢀP=S linkages6,22 within
6

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their structures. The second one illustrated the possibility via irradiation of PꢀN3 units to form
transient phosphorus nitrenes via a Curtius type rearrangement23 or unprecedented P≡N triple
bond species which afford unusual cyclodiphosphazene four membered rings24.
Despite the fact that azides display a versatile reactivity, their use as a protecting group
sensitive to phenols but not to hydrazines opens new perspectives in the synthesis domain, as
illustrated here with the design of original dissymmetric dendrimers. The first species of this
topological group bearing two branches of generation 2 or 3 and one branch of generation 1 or 2
at the core and dichlorohydrazidothiophosphate fragments on the periphery were synthesized.
Using these dendrimers as precursors, waterꢀsoluble polycationic dissymmetric dendrimers were
obtained with good overall yield. It should be noted that the reported approach can be extended
to another phosphorus core with different branching degree (cyclotriphosphazene). For example,
a pentaꢀsubstituted core, penta(4ꢀformylphenoxy)chlorocyclo(triphosphazene)5, can be also
converted into an azide derivative25 that would lead to dissymmetric dendrimers.
Dissymmetric phosphorous dendrimers can be used in molecular biology and
nanomedicine26,27 as therapeutics per se or as carriers of biologically active molecules (i.e.,
nucleic acids) into cells. The future research will help to investigate the potential of the reported
synthetic methodology and the use of these phosphorus dendrimers for organic chemistry and
nanomedicine28.
Experimental
All manipulations were carried out using standard dry argonꢀhigh vacuum technique. Organic
solvents were dried and distilled prior to use. Dichlorothiophosphomethylhydrazine was obtained
as described elsewhere15,16 and used without further purification as 0.2 M solution on CHCl3.
Compounds (1) and (2) were synthesized according to published procedures17, as well as
compound (3)29 [Caution: It is strongly recommended to apply standard safety precautions while
1
treating phosphorus azides because of their explosive nature]. H, 13C{1H}, and 31P{1H} NMR
spectra were recorded using AV300PAS, AV400PAS, AV400LIQ spectrometers (Bruker,
Germany). The attribution of the NMR signals of the dendrimer branches was made by analogy
with Refs. 15,16, the attribution of the NMR signals of the amines on the periphery was made by
analogy with Refs.21,30. To assign the 13C NMR signals, Jmod, HMBC, HBQC NMR
experiments were additionally done, if necessary. The atom numbering used for the signals
attribution is given in Fig. 2. Protonated dendrimers were characterized only by 31P{1H} NMR to
ensure the integrity of structure. Unfortunately, mass spectrometry could not be used to prove the
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purity of these dendrimers because of spontaneous rearrangements in the phosphorhydrazone
structure during the analysis.31
Fig. 2. Atom numbering used for the NMR signals attribution.
O,Oꢀbis(4ꢀ((2ꢀ(bis(formylphenyloxy)phosphorothioyl)ꢀ2ꢀ
(methylhydrazono)methyl)phenyl)ꢀOꢀ(4ꢀformylphenyl)ꢀphosphorothioate
(dissymmetric
dendrimer G0′ꢀP(S)ꢀ(G1′)2 (4). 4ꢀHydroxybenzaldehyde (805.2 mg, 6.6 mmol) was stirred with
Cs2CO3 (2 g, 9 mmol) in THF (40 mL) overnight at room temperature. Then, the solution of (3)
(700 mg, 1.04 mmol) in 10 mL THF was added dropwise at 0 °C, the reaction mixture was
stirred for 4 h at room temperature. The reaction mixture was filtered, the filtrate was evaporated
to oil, and the product (4) was purified by the silica gel column chromatography (eluent 25%
1
THF/CH2Cl2, Rf 0.9), reꢀprecipitated in 60 mL pentane as white powder. Yield 97%. H NMR
3
(400 MHz, CDCl3) δ 3.44 (d, J = 10.8, 6 H, CH3NNP1), 7.30 (dd, J = 8.7, 1.5, 4 H, C0 H), 7.41
3
3
4
(dd, J = 8.4, 1.2, 8 H, C1 H), 7.45 (dd, J = 8.5, 1.4, 2 H, C0′ H), 7.69 (c, 2 H, C0 ꢀCH), 7.73 (d, J
2
2
2
4
= 8.5, 4 H, C0 H), 7.91 (d, J = 8.5, 8 H, C1 H), 7.97 (d, J = 8.4, 2 H, C0′ H), 9.99 (s, 4 H, C1 ꢀ
CHO), 10.03 (s, 1H, C0′ ꢀCHO). 13C{1H} NMR (101 MHz, CDCl3) δ 32.3 (d, J = 13.5, CH3NP1),
4
3
3
3
2
121.6 (d, J = 5.0, C0 ), 121.8 (d, J = 5.1, C0′ ), 122.0 (d, J = 5.0, C1 ), 128.5 (m, C0′ ), 131.5 (m,
2
2
4
4
4
C1 ) 131.7 (m, C0 ), 132.5 (m, C0′ ), 133.7 (m, C1 ), 134.1 (m, C0 ), 139.2 (d, J = 13.9,
1
1
1
4
CH=NNP1), 151.2 (d, J = 8.0, C0 ), 154.8 (d, J = 7.5, C0′ ), 155.1 (d, J = 8.0, C1 ), 190,6 (s, C0′ ꢀ
4
CHO), 190.7 (s, C1 ꢀCHO). 31P{1H} NMR (162 MHz, CDCl3) δ 51.5 (m, P0), 60.2 (s, P1).
Dissymmetric dendrimer G1ꢀP(S)ꢀ(G2)2 (5). Dissymmetric dendrimer (4) (0.9 g, 0.825
mmol) was dissolved in THF (30 mL), then 2 g anhydrous Na2SO4 was added, the reaction
mixture was cooled to 0 °C, and the solution of dichlorothiophosphomethylhydrazine (0.2 M in
CHCl3, 4.13 mmol, 20.6 mL) was added dropwise. The reaction mixture was stirred for 10 min
at 0 °C, then 30 min at room temperature. The reaction was followed by the disappearance of the
1
aldehyde signal in the H NMR. The solution of the product was recovered by filtration,
evaporated to oil, the product (5) was precipitated in 60 mL pentane as white powder. Yield
90.4%. 1H NMR (400 MHz, CDCl3) δ 3.49 (d, J = 13.5, 3 H, CH3NNP1′), 3.50 (d, J = 13.8, 6 H,
3
CH3NNP1), 3.53 (d, J = 13.7, 12 H, CH3NNP2), 7.30 (d, J = 1.5, 2 H, C0 H), 7.32 (dd, J = 3.1,
3
3
1.5, 4 H, C1 H), 7.35 (d, J = 1.7, 1 H, C0′ H), 7.68 (br. s, 6 H, CH=NNP1, CH=NNP2), 7.72 (m, 5
8

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H, C0′ H, C1 H), 7.75 (br. s, 1 H, CH=NNP2), 7.80 (m, 2 H, C0 H). 13C{1H} NMR (101 MHz,
2
2
2
3
CDCl3) δ 31.8 (d, J = 19.1, CH3NNP2), 33.1 (d, J = 19.1, CH3NNP1, CH3NNP1′), 121.8 (m, C0 ,
3
3
2
2
2
4
4
C1 , C0′ ), 128.4 (d, J = 18.1, C0′ ), 128.8 (m, C0 , C1 ), 131.4ꢀ132.8 (m, C0 , C0′4 C1 ), 140.3 (d, J
1
1
1
= 19.1, CH=NNP2), 140.6 (m, CH=NNP1, CH=NNP1′), 151.9 (m, C0 , C1 , C0′ ). 31P{1H} NMR
(162 MHz, CDCl3) δ 52.2 (m, P0), 61.8 (s, P1), 62.96 (s, P2), 63.04 (s, P1′).
Dissymmetric dendrimer G1′ꢀP(S)ꢀ(G2′)2 (6). 4ꢀHydroxybenzaldehyde (350 mg, 2.9 mmol)
was stirred with Cs2CO3 (1.3 g, 4 mmol) in THF (30 mL) overnight at room temperature. Then,
the solution of (5) (500 mg, 0.26 mmol) in 10 mL THF was added dropwise at 0 °C, the reaction
mixture was stirred for 2 h at room temperature. The reaction mixture was filtered, the filtrate
was evaporated to oil, and the product (6) was precipitated in 60 mL pentane as white powder.
1
Yield 75%. H NMR (400 MHz, CDCl3) δ 3.38 (m, 21 H, CH3NNP1, CH3NNP1′, CH3NNP2),
3
3
3
3
7.25 (d, J = 8.7, 5 H, C1 H, C0′ H), 7.30 (d, J = 7.6, 2 H, C0 H), 7.36 (d, J = 8.7, 10 H, C2 H,
3
C1′ H), 7.63 (m, 6 H, CH=NNP1, CH=NNP2), 7.70 (s, 1 H, CH=NNP1′), 7.77 (d, J = 8.7, 3 H,
2
2
2
2
2
4
C0 H, C0′ H), 7.85 (d, J = 8.7, 14 H, C1 H, C1′ H, C2 H), 9.93 (s, 2 H, C1′ ꢀCHO), 9.94 (s, 8 H,
C2 ꢀCHO). 13C{1H} NMR (101 MHz, CDCl3) δ 33.1 (d, J = 3.2, CH3NP1′), 32.9 (d, J = 3.1,
4
3
3
CH3NP1), 33.0 (d, J = 3.1, CH3NP2), 121.6 (d, J = 3.5, C0 ), 121.8 (d, J = 4.8, C0′ ), 121.9 (d, J =
3
3
3
2
2
2
2
2
4
5.0, C1 ), 122.0 (m, C1′ , C2 ), 128.4 (m, C0 , C0′ , C1′ ), 131.4 (m, C1 , C2 ), 131.8 (s, C1 ), 132.4
4
4
4
4
(s, C0′ ), 132.7 (s, C0′ ), 133.7 (m, C1′ , C2 ), 138.8 (d, J = 14.2, CH=NNP1), 139.3 (d, J = 14.2,
1
1
CH=NNP1′), 139.5 (d, J = 14.2, CH=NNP2), 151.2 (d, J = 8.0, C0 ), 151.3 (d, J = 7.9, C0′ ), 151.6
1
1
1
4
4
(d, J = 7.1, C1 ), 155.1 (m, C1′ , C2 ), 190.6 (s, C1′ ꢀCHO), 190.7 (s, C2 ꢀCHO). 31P{1H} NMR
(162 MHz, CDCl3) δ 52.5 (s, P0), 60.17 (s, P1), 60.22 (s, P2), 62.1 (s, P1′).
Dissymmetric dendrimer G2ꢀP(S)ꢀ(G3)2) (7). Dissymmetric dendrimer (6) (0.4 g, 0.145
mmol) was dissolved in THF (30 mL), then 2 g anhydrous Na2SO4 was added, the reaction
mixture was cooled to 0 °C, and the solution of dichlorothiophosphomethylhydrazine (0.2 M in
CHCl3, 1.45 mmol, 7.36 mL) was added dropwise. The reaction mixture was stirred for 10 min
at 0 °C, then 30 min at room temperature. The reaction was followed by the disappearance of the
1
aldehyde signal in the H NMR. The solution of the product was recovered by filtration,
evaporated to oil, the product (7) was precipitated in 60 mL pentane as white powder. Yield
1
98%. H NMR (400 MHz, CDCl3) δ 3.34ꢀ3.42 (m, 21 H, CH3NNP1, CH3NNP1′, CH3NNP2),
3
3
3
3
3
3.42ꢀ3.51 (m, 30 H, CH3NNP2′, CH3NNP3), 7.23ꢀ7.26 (m, 17 H, C0 H, C1 H, C0′ H, C2 H, C1′ H
3
3
C2′ H, C3 H), 7.63ꢀ7.68 (m, 17 H, CH=NNP1, CH=NNP1′, CH=NNP2, CH=NNP2′, CH=NNP3),
2
2
2
2
2
2
2
7.68ꢀ7.82 (m, 17 H, C0 H, C1 H, C0′ H, C2 H, C1′ H C2′ H, C3 H). 13C{1H} NMR (101 MHz,
CDCl3) δ 31.8 (d, J = 13.2, CH3NNP1, CH3NNP1′, CH3NNP2), 33.1 (d, J = 13.0, CH3NNP2′,
3
3
3
3
3
3
3
4
CH3NNP3), 128.3 (m, C0 , C0′ ), 128.5 (m, C1 , C2 , C1′ ), 128.7 (m, C2′ , C3 ), 131.5 (m, C2′ ,
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4
4
4
4
4
4
C3 ), 132.1 (m, C1 , C1′ , C2 ), 132.7 (s, C0′ , C0 ), 138.7 (d, J = 11.1, CH=NNP1), 138.8 (d, J =
11.4, CH=NNP1′), 139.0 (d, J = 11.8, CH=NNP2), 140.7 (d, J = 18.8, CH=NNP2′, CH=NNP3),
1
1
1
1
1
1
1
151.2 (m, C0 , C0′ , C1 ), 151.5 (m, C1′ , C2 ), 151.9 (d, J = 7.3, C2′ , C3 ). 31P{1H} NMR (162
MHz, CDCl3) δ 52.4 (m, P0), 61.7 (s, P1), 61.8 (s, P2), 62.1 (s, P1′), 63.0 (s, P2′, P3).
Aminomodification of the periphery of the dissymmetric dendrimers
To the iceꢀcooled solution of the dendrimer (5) or (7) (0.1 mmol) in 10 mL THF, DIPEA (2.5
eq. per PꢀCl fragment, 2.5 or 5 mmol, respectively) and 1ꢀ(2ꢀaminoethyl)piperidine (1.05 eq. per
PꢀCl, 1.05 or 2.1 mmol, respectively) were added dropwise. The reaction mixture was stirred for
3 h at room temperature, and then evaporated to dryness. The solid residue was dissolved in 20
mL CH2Cl2, 10 mL 1M K2CO3 was added, and the product was extracted 3 times 20 mL CH2Cl2.
Organic fractions were mixed, dried over MgSO4 and evaporated to oil. The product (8a) or (9a)
was precipitated in 70 mL pentane as white powder which was recovered by filtration and dried.
To obtain the protonated forms (8b) or (9b), 1M HCl in Et2O (0.9 mmol or 1.8 mmol,
respectively) was added dropwise to the iceꢀcooled solution of dendrimer (8a) or (9a) in 20 mL
THF (0.1 mmol). Protonated dendrimers were recovered by filtration as white powders, washed
2 times with 20 mL THF and dried.
1
Aminomodified dissymmetric dendrimer G1ꢀP(S)ꢀ(G2)2 (8а). Yield 85%. H NMR (400
MHz, CDCl3) δ 1.39 (s, 20 H, CeH2), 1.51 (m, 40 H, CdH2), 2.35 (s, 40 H, CcH2), 2.42 (t, J = 5.9,
10 H, CbH2), 2.87–3.11 (m, 20H, CaH2), 3.16 (m, 15 H, CH3NNP1′, CH3NNP2), 3.34 (d, J = 10.2,
3
3
6 H, CH3NNP1), 4.00 (m, 10 H, NH), 7.20 (d, J = 8.8, 8 H, C1 H), 7.24 (d, J = 8.5, 4 H, C0 H),
3
7.28 (d, J = 9.0, 2 H, C0′ H), 7.45 (s, 4 H, CH=NNP2), 7.49 (s, 2 H, CH=NNP1), 7.60 (m, 8 H,
2
2
2
C1 H), 7.65 (m, 5 H, C0 H, CH=NNP1′), 7.75 (m, 2 H, C1 H). 31P{1H} NMR (162 MHz, CDCl3)
δ 52.5 (m, P0), 62.6 (m, P1), 68.2 (m, P2, P1′).
Aminomodified dissymmetric dendrimer G1ꢀP(S)ꢀ(G2)2, protonated form (8b). 31P{1H}
NMR (162 MHz, CD3OD) δ 53.3 (m, P0), 62.5 (m, P1), 69.8 (m, P2), 69.9 (m, P1′).
1
Aminomodified dissymmetric dendrimer G2ꢀP(S)ꢀ(G3)2 (9а). Yield 83%. H NMR (400
MHz, CDCl3) δ 1.37 (s, 40 H, CeH2), 1.52 (m, 80 H, CdH2), 2.36 (s, 80 H, CcH2), 2.42 (t, J = 5.7,
20 H, CbH2), 2.88–3.10 (m, 40H, CaH2), 3.14 (d, J = 9.5, 30 H, CH3NNP2′, CH3NNP3), 3.33 (m,
3
21 H, CH3NNP1, CH3NNP1′, CH3NNP2), 4.03 (m, 20 H, NH), 7.18 (d, J = 7.7, 20 H, C1′ H,
3
3
3
3
C2 H), 7.26 (d, J = 7.6, 10 H, C0′ H, C1 H), 7.31 (d, J = 6.9, 4 H, C0 H), 7.45 (s, 12 H,
2
2
CH=NNP2, CH=NNP2′, CH=NNP3), 7.60 (dd, J = 7.8, 3.4, 20 H, C1′ H, C1 H), 7.65 (s, 4 H,
2
2
2
CH=NNP1), 7.65 (m, 5 H, C0 H, CH=NNP1′), 7.72 (d, J = 6.7, 10 H, C0′ H, C1 H), 7.77 (d, J =
10

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6.9, 2 H, C0 H), 7.82 (s, 2 H, CH=NNP1′). 31P{1H} NMR (162 MHz, CDCl3) δ 52.3 (m, P0), 62.6
(m, P1, P1′, P2), 68.14 (s, P3), 68.17 (s, P2′).
2
Aminomodified dissymmetric dendrimer G2ꢀP(S)ꢀ(G3)2, protonated form (9b). 31P{1H}
NMR (162 MHz, CD3OD) δ 52.7 (m, P0), 61.8 (m, P1), 62.5 (s, P1′, P2), 69.74 (s, P3), 69.78 (s,
P2′).
Acknowledgements
This work was supported by RFBR grant 16ꢀ33ꢀ60152_mol_a_dk, by Russian State funded
budget project (VI.62.1.4, 0309ꢀ2016ꢀ0004), by the Scholarship of the President of the Russian
Federation (grant 882.2016.4), by the 7th European Community Framework Program project
PIRSESꢀGAꢀ2012ꢀ316730 NANOGENE, and by CNRS (France).
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Synthesis of dissymmetric phosphorus dendrimers using an unusual protecting group
Evgeny K. Apartsina*, Alya G. Venyaminovaa, Serge Mignanib,c, Anne-Marie Caminaded, Jean-
Pierre Majorald*
a
Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev ave.,
Novosibirsk, 630090, Russian Federation.
b
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Université Paris
Descartes, PRES Sorbonne Paris Cité, CNRS UMR 8601, 75006 Paris, France;
c
Centro de Química da Madeira, MMRG, Universidade da Madeira, 9000-390 Funchal,
Portugal;
d
Laboratoire de Chimie de Coordination du CNRS, 205, route de Narbonne, 31077 Toulouse
Cedex 04, France.
* E-mail: eka@niboch.nsc.ru (E. K. Apartsin), jean-pierre.majoral@lcc-toulouse.fr (J.-P.
Majoral)
Table of contents entry :
We report the synthesis of neutral and polycationic dissymmetric phosphorus dendrimers bearing
branches of different generations on the core.