A programmable "build-couple" approach to the synthesis of heterofunctionalized polyvalent molecules

Article abstract of DOI:10.1039/c1ob05606a

A maximally divergent "build-couple" synthesis of heterofunctionalized polyvalent molecules is described. This strategic approach enables the synthesis of highly diverse polyvalent structures from a pre-programmed combinatorial set of modules. The Royal S

Full text of DOI:10.1039/c1ob05606a

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COMMUNICATION
A programmable “build–couple” approach to the synthesis of
heterofunctionalized polyvalent molecules†
Ritwik Burai,a Jaruwan Chatwichiena and Brian R. McNaughton*a,b
Received 14th April 2011, Accepted 26th May 2011
DOI: 10.1039/c1ob05606a
A maximally divergent “build–couple” synthesis of het-
erofunctionalized polyvalent molecules is described. This
strategic approach enables the synthesis of highly diverse
polyvalent structures from a pre-programmed combinatorial
set of modules.
Polyvalent interactions play a critical role in a large number of
biochemical processes, including protein–nucleic acid and protein–
protein interactions.1 Traditional small molecules (MW < 800
Daltons) regulate a small number of such interactions. In contrast,
the overwhelming majority of polyvalent biochemical processes,
which utilize large surface areas and “flat” topologies, are largely
resistant to traditional small molecule-dependent regulation.2
Fig. 1 A programmable and convergent “build–couple” strategy yielding
In an effort to expand beyond the traditional small molecule
paradigm, researchers have begun to synthesize and evaluate
new materials and molecules designed to interact with polyvalent
targets. Various molecular architectures, including dendrons and
dendrimers, have recently emerged as a potential solution to
recognizing polyvalent systems.3 While the large surface area
spanned by these molecules is a critical component for rec-
ognizing complex polyvalent surfaces, highly selective binding
typically requires spatially-defined interactions involving diverse
functional groups. For example, heterofunctionalized polyvalent
molecules that display functional groups precisely matching
the electrostatic signature of their polyvalent target would be
expected to have higher target affinity, binding selectivity and
therapeutic utility, in comparison to polyvalent molecules that
display a single functional group. However, in comparison to
homofunctionalized polyvalent molecules, general approaches
for the programmed synthesis of heterofunctionalized polyvalent
molecules are limited.4
a hetero-functionalized dendrimer.
of highly diverse polyvalent structures from a combinatorial set of
modules. In order to avoid the generation of racemic molecules,
our approach focuses on modules that contain a programmable
combination of two identical and one different functional group.
As a proof-of-concept, we prepared a small library of het-
erofunctionalized modules, beginning with the preparation of
triol 1 from pentaerythritol, which proceeded in 91% overall
yield, over three steps. Triol 1 was then reacted with propargyl
bromide to generate di- and tri-propargylated compounds 2 and
3, respectively. The highest yield (55%) of di-propargyl compound
2 was obtained when six equivalents of propargyl bromide were
used.6 Unlike compound 3, the primary alcohol and terminal
alkynes in compound 2 can be orthogonally functionalized. In
order to utilize tri-yne 3, it was converted into a ~1 : 2 ratio of
mono- (29%) and di-TMS (52%) alkynes 4 and 5, by addition of
trimethylsilyl trifluoromethansulfonate and zinc triflate.7,8 Taken
together, three module precursors (2, 4 and 5) were synthesized in
83% overall yield from 1 in either one or two steps (Scheme 1).
We next prepared six azide or alkyne building blocks 6–9b9
(Scheme 2A), which contain protein-compatible hydrophobic,
anionic (protected as the t-butyl ester) or cationic groups (Boc
protected). As a proof-of-concept, we prepared four hetero-
functionalized modules from precursors 2, 4 and 5 and building
blocks 6–9b, (Scheme 2B). Module precursor 2 was first reacted
with two equivalents of azide 6 using Huisgen–Sharpless 1,3-
dipolar cycloaddition conditions.9 The remaining primary alcohol
was next converted to the mesylate, then to the corresponding azide
Unlike strategies that rely on iterative steps to grow or diversify
a polyvalent molecule, we envisaged a “build–couple” approach,
wherein pre-programmed heterofunctionalized modules are first
synthesized, then selectively coupled to a multi-podal core. The
general “build–couple” concept is illustrated in Fig. 1.5 This
maximally divergent strategic choice allows for the preparation
aDepartment of Chemistry, Colorado State University, Fort Collins, Colorado
80523-1872, USA. E-mail: brian.mcnaughton@colostate.edu
bDepartment of Biochemistry and Molecular Biology, Colorado State
University, Fort Collins, Colorado 80523-1872, USA
† Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and spectral data. See DOI: 10.1039/c1ob05606a
◦
by reacting with sodium azide at 110 C for 72 h. A 1,3-dipolar
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Scheme 1 Synthesis of module precursors 2, 4 and 5. a = MeC(OEt)3,
PTSA (0.1 equiv.), toluene, 100 ◦C, 3 days, 95% yield; b = p-iodobenzyl
bromide, NaH/DMF, 25 ◦C, 2 h, 98% yield; c = HCl (0.1 equiv.)/MeOH,
50 ◦C, 4 h, 98% yield; d = propargyl bromide (6 equiv.), NaOH,
DMSO/H2O, 25 ◦C, 18 h; e = TMS-OTf, Zn(OTf)2, Et3N, DCM, 25 ◦C,
20 h.
cycloaddition between the newly formed azide and terminal alkyne
on 9b was used to generate heterofunctionalized module 10 in 67%
overall yield, in four steps from 2. Heterofunctionalized module 11
was prepared similarly in 69% overall yield from 2, using building
blocks 7 and 9a. A synthetic sequence involving a 1,3-dipolar
cycloaddition, removal of TMS from the remaining alkyne(s),
and an additional 1,3-dipolar cycloaddition was employed to
synthesize heterofunctionalized modules 12 and 13, in three steps,
from precursors 4 and 5 in 48% and 46% overall yield, respectively.
An orthogonal coupling strategy10 was used to chemoselectively
attach modules to a core scaffold. We envisaged utilizing either a
palladium-catalyzed Sonogashira reaction between the iodoben-
zene moiety present on modules 10–13 and a pendant terminal
alkyne on a core structure, or a Huisgen–Sharpless 1,3-dipolar
cycloaddition reaction between a module equipped with a terminal
alkyne and pendant azide on a core structure. In order to test the
latter approach, p-ethynyl module 14 was prepared in two steps
from 10 in 66% overall yield (Scheme 2B, steps e–f).
With this orthogonal coupling strategy in mind we prepared
two previously unreported di- and tri-podal cores 1511 and 16,12
respectively (Scheme 3), which can be programmably decorated
with modules 10–14. The synthesis of a heterofunctionalized
dendron was initiated by coupling module 10 to di-podal core
15 using a Sonogoshira reaction, which proceeded in 95% yield.
Removal of the TMS group on the remaining alkyne was next
achieved by the addition of cesium fluoride. The resulting terminal
alkyne was then coupled to module 12 in 62% yield, using an
additional Sonogashira reaction.13
Scheme 2 (A) Azide and alkyne building blocks. (B) Synthesis of
heterofunctionalized modules. a = azide building block, CuI (10 mol%),
DIPEA, THF, 25 ◦C, 15 h; b = MsCl, Et3N, DCM, 25 ◦C, 4 h; c = NaN3,
DMF, 110 ◦C, 72 h; d = alkyne building block, CuI (10 mol%), DIPEA,
THF, 70 ◦C, 15 h; e = ethynyltrimethylsilane, PdCl2(PPh3)2 (10 mol%), CuI
(20 mol%), NEt3, DMF, 25 ◦C, 8 h; f = CsF, MeCN, 25 ◦C, 3 h; g = K2CO3,
MeOH, 25 ◦C, 1.5 h.
ful. However, a recently reported variation14 on the Mitsunobu
reaction, which employs DDQ as the activating reagent, was used
to successfully install an azide in 65% yield. A subsequent 1,3-
dipolar cycloaddition between the newly generated core azide and
alkyne on module 14 was achieved in 74% yield. Following removal
of the TMS group from the remaining alkyne, module 13 was
attached via a Sonogashira reaction. For both the di- and tri-podal
molecules, global deprotection of t-butyl ester and Boc groups
A tri-podal heterofunctionalized dendrimer was prepared by
first performing a Sonogashira reaction between core 16 and
module 11. Our initial efforts to convert the benzyl alcohol on
the Sonogashira reaction product to the corresponding azide by
mesylation and displacement with sodium azide were unsuccess-
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was assessed by 1H NMR spectroscopy by the disappearance of t-
butyl protons at 1.48–1.49 ppm (Boc) and 1.41 ppm (t-butyl ester)
for 17, and 1.48 ppm (Boc) and 1.42 ppm (t-butyl ester) for 18.
Conclusions
In conclusion, we have developed a programmable “build–
couple” method for the synthesis of heterofunctionalized poly-
valent molecules. This approach was used to prepare a diverse
heterofunctionalized dendron and dendrimer. We demonstrated
the effectiveness of pairing the Huisgen–Sharpless 1,3-dipolar
cycloaddition and Sonogashira coupling reaction with pre-
programmed modular components to synthesize these complex
molecules. While the functional groups we chose to utilize herein
are inspired by amino acid side chains, the functional group
tolerance demonstrated by these coupling reactions15 likely makes
this approach well suited for the synthesis functional group diverse
heterofunctionalized polyvalent molecules.
Scheme 3 Synthesis of di- and tri-podal cores 15 and 16.
Notes and references
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6 Order of addition, speed of addition, reactant concentration and
temperature had little impact on the ratio of 2 and 3.
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8 Compounds
4 and 5 were easily separable. Using 1 : 9 ethyl
Scheme 4 Programmed synthesis of di- and tri- hetero-functionalized
polyvalent compounds. a = 10, PdCl2(PPh3)2 (10 mol%), CuI, (20 mol%),
NEt3, DMF, 25 ◦C 12 h (95% yield); b = CsF, MeCN, 25 ◦C, 14 h (77%
yield); c = 12, PdCl2(PPh3)2 (10 mol%), CuI, (20 mol%), NEt3, DMF, 25 ◦C
14 h (62% yield); d = 11, PdCl2(PPh3)2 (10 mol%), CuI, (20 mol%), NEt3,
DMF, 25 ◦C 12 h (98% yield); e = Bu4NN3, DDQ, PPh3, DCM, 25 ◦C,
1 h (65% yield); f = 14, CuI (20 mol%), DIPEA, 25 ◦C, 8 h (74%); g =
CsF, MeCN, 25 ◦C, 3 h (99% yield); h = 13, PdCl2(PPh3)2 (10 mol%), CuI,
(20 mol%), NEt3, DMF, 25 ◦C, 14 h (52% yield); i = 20% TFA/1% TES,
DCM, 25 ◦C, 1 h.
acetate : hexanes, tri-TMS Rf 0.62; compound 5 Rf 0.55; compound
4 Rf 0.46; starting material 3 Rf 0.33.
9 See the ESI for experimental details†.
10 Orthogonal coupling strategies applied to homofunctional dendrimer
synthesis, see: (a) R. Spindler and J. M. J. Fre´chet, J. Chem. Soc., Perkin
Trans. 1, 1993, 913; (b) F. Zeng and S. C. Zimmerman, J. Am. Chem.
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13 Increasing the amount of p-iodobenzyl module, palladium catalyst or
reaction temperature did not significantly change the yield of the second
Sonogashira reaction.
14 N. Iranpoor, H. Firouzabadi, B. Akhlaghinia and N. Nowrouzi,
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15 Functional group tolerance of the Sonogashira Reaction, see: K.
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was performed at room temperature with 20% trifluoroacetic
acid/1% triethylsilane in dichloromethane. The fully deprotected
compounds were then precipitated by the addition of cold diethyl
ether (summarized in Scheme 4). Precipitated products 17 and 18
were obtained as TFA salts in ~95% yield from the t-butyl ester
and Boc-protected precursors. The completeness of deprotection
5058 | Org. Biomol. Chem., 2011, 9, 5056–5058
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The Royal Society of Chemistry 2011
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