Efficient and accelerated growth of multifunctional dendrimers using orthogonal thiol-ene and SN2 reactions

Article abstract of DOI:10.1039/c3cc46633g

An orthogonal coupling strategy was developed by combining thiol-ene and S_N2 reactions, which was subsequently applied to the accelerated synthesis of multifunctional dendrimers using carbohydrate building blocks. In surface plasmon resonance (

Full text of DOI:10.1039/c3cc46633g

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Efficient and accelerated growth of
multifunctional dendrimers using orthogonal
thiol–ene and SN2 reactions†
Cite this: Chem. Commun., 2014,
50, 1983
Received 29th August 2013,
Accepted 10th December 2013
Naresh Kottari, Yoann M. Chabre, Tze Chieh Shiao, Rabindra Rej and Rene Roy*
´
DOI: 10.1039/c3cc46633g
www.rsc.org/chemcomm
An orthogonal coupling strategy was developed by combining thiol–ene
and SN2 reactions, which was subsequently applied to the accelerated
synthesis of multifunctional dendrimers using carbohydrate building
blocks. In surface plasmon resonance (SPR) studies, the b-D-galacto-
pyranoside-coated dendrimer exhibited nM binding affinity with the
bacterial LecA lectin extracted from Pseudomonas aeruginosa.
Scheme 1 Orthogonal thiol–ene and SN2 reactions of bifunctional monomer
3 with various thiols. Reagents and conditions: (i) K2CO3, ClCH2COCl, acetone–
H2O, rt, 1 h, 70%; (ii) K2CO3, AllBr, DMF, 50 1C, 3 h, 71%; (iii) RSH, K2CO3, THF, rt,
12 h; (iv) DMPAP, 365 nm, MeOH, rt, 2 h (see ESI† for details).
Dendrimers are hyperbranched globular shape macromolecules, with
significant applications in fields ranging from nanomaterials to
biology.1 The syntheses of dendrimers via classical convergent and
divergent approaches generally require deprotection or activation
steps between each generation, leading to a large number for
synthetic manipulations. Various methods have been developed for sugar-based AB4 monomer 8, a new family of multifunctionalized G(1)
the rapid and accelerated synthesis of these fascinating dendritic and G(2) dendrimers has been synthesized. The details of the synthesis
macromolecules in fewer steps, out of which, the efficient orthogonal are presented herein. In order to optimize the orthogonality of the
coupling strategy2 disclosed by Zimmerman stands out.2a The concept thiol–ene vs. SN2 reactions, a bifunctional monomer model 3 decorated
of orthogonality has been extensively applied in the synthesis of with allyl and chloroacetyl groups was prepared from p-aminophenol 1
complex organic molecules and biomolecules.3,4 The orthogonal according to Scheme 1.
chemical coupling strategy consists of using bifunctional monomers
The coupling of 1 with chloroacetyl chloride led to the
containing complementary functional groups (AxBy) with the ability to formation of intermediate 2,6 which upon subsequent allylation with
undergo selective group manipulations without the necessity for excess allyl bromide and K2CO3 afforded bifunctional compound 3.
deprotection or activation steps, which will in turn dramatically The exclusive reactivity of 3 towards the thiol–ene vs. the SN2 reaction
reduce the number of required synthetic steps.
conditions was first demonstrated using common thiols and the
We describe herein an under exploited combination of orthogonal optimized conditions (see ESI† for yields and details). The nucleophilic
coupling reactions based on thiol functionality; namely thiol–ene substitutions of the N-chloroacetamide group of 3 using a variety of
(radical mediated addition of thiol across double bonds) and nucleo- thiols were accomplished (4) in the presence of K2CO3–THF, keeping
philic substitution (SN2) reactions toward the rapid assembly of the allyl group entirely intact. Alternatively, the chemoselective photo-
dendrimers. The thiol–ene reaction shares the many attributes of click lytic addition of thiols to the allyl group of 3 was achieved in the
chemistry that has been copiously employed for the synthesis of presence of a radical initiator a,a-dimethoxy-a-phenylacetophenone
polymers, dendrimers, and other macromolecules.5 We have designed (DMPAP, 10 mol%) under UV irradiation at 365 nm and room
the monomers with the mutually tolerable N-chloroacetamide and allyl temperature (5). All products were unambiguously characterized by
1
functionalities (3 and 8) and optimized the conditions for the chemo- 1H- and 13C-NMR spectroscopy and MS. Conspicuously, the H-NMR
selective thiol–ene or SN2 reactions. By using the orthogonality of a spectrum of the crude products clearly showed complete disappearance
of olefinic protons that have undergone the thiol–ene reactions while
the up-field shift of the chloroacetyl protons remained entirely intact.
Conversely, the latter protons unambiguously moved from d 4.18 ppm
Department of Chemistry, University of Quebec a Montreal, C.P. 8888, Succ. Centre-
Ville, Montreal, Quebec, Canada H3C 3P8. E-mail: roy.rene@uqam.ca
(COCH2Cl) to d 3.30–3.70 ppm (COCH2S) in the SN2 reactions, thus
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc46633g
confirming the perfect orthogonality of the system.
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of the reactions were unambiguously supported by 1H-NMR analysis
of 11, which showed the disappearance of a singlet at d 4.01 ppm
corresponding to the –COCH2Cl group together with the appearance
of the signal at d 3.20 ppm of the newly formed –COCH2S– linkages,
while the characteristic allylic patterns at d 5.20 and 5.90 ppm showed
the expected integration. In addition, the presence of only one signal
in the 13C-NMR spectrum for 17 at d 136.3 ppm, corresponding to
central Car, indicated full hexakis substitution. The full chemical
integrity of 11 and 17 was further confirmed by HRMS analysis,
Scheme 2 Synthesis of AB4-type building block 8 from glucose.
Having established the complete orthogonality of the thiol–ene vs. which displayed the expected molecular ion adducts. Subsequently,
SN2 reactivity of model derivative 3, a glucose based AB4 monomer (8), the thiol–ene reaction of 11 with thioacetic acid in the presence of
possessing four allyl appendages and a N-(2-(glucosyloxy)ethyl)-2- DMPAP under UV radiation at 365 nm led to the formation of
chloroacetamide group as the aglycon, was synthesized (Scheme 2).
intermediate 12 en route to the next dendrimer generation and
The synthesis was initiated using the known 2-azidoethyl having sixteen thioacetyl termini. As expected and besides satis-
b-D-glucopyranoside 6.7 Direct allylation of 6 with allyl bromide factory HRMS data, the complete disappearance of allylic signals
(NaH, DMF, rt, 12 h) afforded derivative 7. Staudinger reduction in the 1H-NMR spectra supported the complete thiol–ene coupling
of azide 7 with PPh3 (aq. THF, rt, 12 h) and in situ treatment with reactions, together with the desired integration for the methyl
chloroacetyl chloride in the presence of Hunig’s base led to the protons of the SAc groups (48H) compared with those of amides
formation of the desired AB4 monomer 8, in a 64% overall yield. (4H, d 7.20 ppm), anomeric (4H, d 4.20 ppm) and CqCH2S internal
Thiol–ene reaction of monomer 8 with thioacetic acid under the (8H, d 2.75 ppm) protons. Our optimized SN2 conditions between 8
conditions described above led to the formation of 9, thus (2.5 eq. per site) and 12 (G1) subsequently afforded G(2) dendrimer
confirming the complete orthogonality of the strategy towards 13 harbouring 64-allyl functions in 73% yield (Scheme 3). Once
multifunctional monomers.
again, the total absence of SAc signals in the 1H-NMR spectra
This approach was next extended to the accelerated synthesis of conjugated with the presence of the newly formed allylic signals
polyallylated dendrimers 11, 13 and 17 to demonstrate its efficiency in confirmed the complete transformation of peracetylated G(1)
the construction of complex architectures (Schemes 3 and 4). To this dendrimer 12. Moreover, the precise integration of the allylic
end, the previously reported A4 and A6 thioacetylated monomers 10 protons compared nicely with those of the methylene linker at
and 168 have been used as precursors for the SN2 reaction with d 1.90 ppm (OCH2CH2CH2S) further confirming complete conver-
monomer 8. Hence, S-alkylation of 8 with thioacetates 10 and 16 in sion which also discarded the possibility of thiol oxidation to
the presence of a slight excess of 1 M MeONa–MeOH solution cross-linked materials. Another strong evidence of the structure’s
(see ESI†) led to the formation of 16-, 64- and 24-allyl functionalized uniformity was provided by Gel Permeation Chromatography
dendrimers 11, 13 and 17 in excellent yields, regardless of aliphatic or (GPC) that clearly showed a symmetrical Gaussian pattern with
aromatic thioacetylated precursors. Completion and chemoselectivity a low PDI of 1.064 (see ESI†).
Scheme 3 Synthesis of polyol-terminated dendrimers 14 (G(1)) and 15 (G(2)) harbouring 32- and 128-OH groups.
1984 | Chem. Commun., 2014, 50, 1983--1985
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with monovalent galactosides (in the order of 10À4 M)11 that can be
explained on the basis of the ‘‘multivalency effect’’.
In conclusion, we developed an efficient orthogonal coupling
strategy based on the combination of thiol–ene and SN2 reactions.
By using an orthogonal approach, multifunctional dendrimers were
synthesized without the necessity for carrying out protection–
deprotection steps and hence the approach is applicable to the
construction of complex organic molecules. For the synthesis of
dendrimers 14, 15 and 19, unexplored carbohydrate AB4 building
blocks were used. Interestingly, glycodendrimer 19 exhibited high
affinity with the LecA lectin, highlighting the fact that globular
dendritic systems with a low number of generations could efficiently
serve as potent anti-adhesive agents against bacterial infections and
biofilm formation. The strategy clearly pinpoints the high efficiency
of sugars for the accelerated growth of multifunctional dendrimers
within limited generation.
This work was supported by NSERC Canada.
Notes and references
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Chem. Commun., 2014, 50, 1983--1985 | 1985