Functionalizable Stereocontrolled Cyclopolyethers by Ring-Closing Metathesis as Natural Polymer Mimics

Article abstract of DOI:10.1002/anie.201805113

Whereas complex stereoregular cyclic architectures are commonplace in biomacromolecules, they remain rare in synthetic polymer chemistry, thus limiting the potential to develop synthetic mimics or advanced materials for biomedical applications. Herein we

Full text of DOI:10.1002/anie.201805113

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Title: Functionalizable Stereocontrolled Cyclopolyethers by Ring-
Closing Metathesis as Natural Polymer Mimics
Authors: Mohammed Alkattan, Joelle Prunet, and Michael Shaver
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10.1002/anie.201805113
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Functionalizable Stereocontrolled Cyclopolyethers by Ring-
Closing Metathesis as Natural Polymer Mimics
Mohammed Alkattan,[a,b] Joëlle Prunet*[b] and Michael P. Shaver*[a]
Abstract: While complex stereoregular cyclic architectures are
commonplace in biomacromolecules, they remain rare in synthetic
polymer chemistry, limiting the potential to develop synthetic mimics
or advanced materials for biomedical applications. Herein we
disclose the formation of a stereocontrolled 1,4-linked six-membered
cyclopolyether prepared by ring-closing metathesis (RCM). Ru-
mediated RCM, with careful control of catalyst, concentration and
the configuration of all the stereogenic centers present in these
polymers is controlled (Figure 1). While the broad functional
group tolerance of metathesis catalysts suggests a broad
reaction scope, poly(ethylene glycol) backbones are especially
interesting given their role as gold standard stealth polymers in
drug delivery.11 We thus envisaged a sequence of ring-opening
polymerization (ROP), ring-closing metathesis (RCM) and
temperature, selectively affords the six-membered ring cyclopolymer. dihydroxylation (DH), as shown in Figure 1. ROP of 3,4-epoxy-1-
Under optimized reaction conditions, no metathetical degradation,
macrocycle or crosslinking was observed. Post-polymerization
modification by dihydroxylation afforded a novel polymer family
encompassing a poly(ethylene glycol) backbone and sugar-like
functionalities (“PEGose”). This strategy also paves the way for
using RCM as an efficient method to synthesize other
stereocontrolled cyclopolymers.
butene (EB) would afford polyepoxybutene (PEB), with the
chirality of the parent epoxide leading to stereogenic control in
the linear polymer. Ring-closing metathesis would then give a
1,4-linked functionalizable cyclopolyether (FCPE). Further
functionalization, specifically diatereoselective dihydroxylation
(DH), would produce a new stereocontrolled polymer that we
have called "PEGose", as it has the structural features of both
sugars and PEG, replacing the glycosidic bond of amylose with
a strong ether link.
Control over the absolute configuration of a synthetic polymer
main chain remains a significant challenge,1,2 especially in light
of the importance of this regularity in natural polymers.3 This
stereoregularity of the main chain plays a significant role in
shaping the three-dimensional structure, and in-turn influencing
the biological function of the natural macromolecules. In addition,
rings are embedded in the backbones of many natural polymers,
which restricts the bond rotation around the stereogenic
centers.4 These local conformational restrictions result in a
specific compact structure along the polymer backbone: i.e. the
six membered cyclic structures of cellulose and amylose
backbones (Figure 1) form linear and helical structures,
respectively. However, synthetic polymers that are made of
similar 1,4-linked six-membered rings that would mimic these
secondary structures, present a unique challenge to synthetic
chemists, especially if conventional polymerization techniques
are employed.5
Ring-closing metathesis (RCM) has been predominantly used to
prepare cyclic small molecules, including phosphine-boranes,
sulfides, amines, phenols, and oxazolines.6 The use of RCM in
polymer synthesis, however, remains rare,7 with a few examples
for the preparation of polymeric nanoparticles,8 cyclic-9 and
cyclo-polymers.10 We hypothesized that this underutilized post-
polymerization technique could be employed for the synthesis of
cyclopolyethers to mimic the topology of polysaccharides, where
Figure 1. Biopolymers serving as inspiration for stereocontrolled polymer
synthesis, and a strategy to target the desired cis-PEGose cyclopolymer.
For this structural control, it is imperative to start with
enantiopure EB. Atactic PEB would lead to
a
non-
stereocontrolled cyclopolymer, where the 1,4-links would be
indiscriminately cis (amylose-like) or trans (cellulose-like) (Figure
2). Furthermore, the subsequent dihydroxylation reaction would
not be diastereoselective on the trans 1,4-disubstituted six-
membered rings. On the other hand, dihydroxylation of the cis
cyclopolymer will occur exclusively from the top face, which is
not hindered by the two substituents.
[a]
[b]
Mr. M. Alkattan, Prof. M. P. Shaver
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph
Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK
E-mail: michael.shaver@ed.ac.uk
Mr. M. Alkattan, Dr. J. Prunet
WestCHEM, School of Chemistry, University of Glasgow, Joseph
Black Building, University Avenue, Glasgow, G12 8QQ, UK
E-mail: joelle.prunet@glasgow.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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Table 1. RCM of a-PEB.
b
b
d
b
Entrya
[Olefin]
0.2
Mn,st
Ðst
Conv. %c Mn,th
Mn
Ðb
1
2
3200
3200
1.19
1.19
99
99
2540 2500 1.21
2540 2900 1.3
0.4
a Reactions performed in 1,2-DCE at reflux with 5 mol% of HG2 catalyst for 72
h. bMn and Ð determined by GPC vs uncorrected PS standards. c Determined
by 1H-NMR spectroscopy of olefin peaks integration of the produced polymer.
d Mn,th = PEB Mn,GPC × 0.8 due to expected loss of one C2H4 per monomer unit.
When concentrations were kept at 0.2 M (Table 1, entry 1), no
cross-linking was observed, and polymer dispersity and viscosity
remained similar. However, at higher concentrations (0.4 M),
competing ring-closing and polymer cross-linking occurs,
evidenced by the formation of a high molecular shoulder in GPC
traces (see SI-Figure S1).16 This new polymer represents the
first synthetic cyclo-polyether prepared, yet its inherent atacticity
prevents any overall topological control. Thus, isotactic-rich PEB
(i-PEB) was synthesized by ROP of the R-enantiomer of EB
(95:5 er), which was prepared from racemic EB by Jacobsen’s
hydrolytic kinetic resolution (see SI-Page 3).17 The behavior of
the isotactic polymer towards RCM was directly compared to
that of its atactic derivative under the previously optimized
conditions (Table 2).
Figure 2. Influence of polymer tacticity on RCM and resultant polymer
stereochemistry in cis- and atactic-FCPE.
Ring-opening and ring-closing reactions were first explored with
the commercially available racemic 3,4-epoxy-1-butene mon-
omer. While PEB has been prepared via a number of routes
from the EB monomer,12,13 our optimized reaction conditions
used tetraphenylporphyrin aluminium chloride [(TPP)AlCl] as an
initiator14 for the bulk polymerization of EB at ambient tem-
perature (Equation 1, see SI-Table S1).
Table 2. RCM of PEB with HG2 catalyst.
(1)
The 13C-NMR spectrum of the resultant PEB showed two peaks
for the stereogenic carbon, confirming the expected atacticity of
the produced PEB (a-PEB), as the catalyst is not stereoselective.
Low, controlled molecular weight polymers were produced, with
Mn,GPC of 2100 and 3200 respectively, and Ð < 1.2. Although
RCM on a-PEB will not give a stereocontrolled cyclopolyether, it
was used to establish optimum RCM conditions. While little
difference in molecular weight was observed by gel permeation
chromatography (GPC) with the lowest molecular weight PEB
samples, due to overlap with eluent peaks, the higher molecular
weight samples (Mn,GPC 3200) showed a clear molecular weight
loss on ring closing, correlating well with the loss of a single
ethylene molecule per repeat unit (Table 1). Optimal ring-closing
conditions for PEB included the use of 5 mol% of the second-
generation Hoveyda-Grubbs (HG2) catalyst, at high
concentrations of polymer (≥ 0.2 M respective to monomer unit)
in 1,2-dichloroethane (1,2-DCE) (Table 1). Note that poor
conversions were achieved with the first-generation Grubbs
catalyst, likely due to lower reactivity and thermal stability (see
SI-Table S2).15
FCPE
PEB
Mn
Time
(days)
Entrya
Ðb Tg °Cc
Ðb Tg °Cc
b
d
b
Mn,th
Mn
rac
R
4380
3940
1.18 -56
1.15 -54
5
7
3500
3150
2700 1.22 -26
2600 1.19 -11
a[Olefin] = 0.2 M; the reaction conversion was monitored daily until >99% by
1H-NMR spectroscopy using 1,2-DCE at reflux with 5 mol% HG2 catalyst. b Mn
c
and Ð determined by GPC vs uncorrected PS standards. Determined by
differential scanning calorimetry. d Mn,th = PEB Mn,GPC × 0.8.
The kinetics of cyclization of the enantiomerically pure monomer
were significantly slower than for the racemic monomer. Plotting
reaction kinetics (Figure 3 and SI-Figure S2) showed that the
cyclization reaction progressed quickly in the beginning, with
94% of the pendant vinyl groups forming cross-links within 30
min for both atactic and isotactic derivatives. The metathesis
reaction then significantly slowed down, especially for the more
conformationally rigid isotactic derivative. This profile suggests a
mechanism originally proposed by Coates and Grubbs:10 (i) a
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fast stage when the catalyst randomly closes adjacent olefins
until only isolated olefins remain, and (ii) a slow stage when the
rings rearrange along the chain until all olefins are cyclized. This
requires that the cyclized olefins can undergo further metathetic
reactions, enabling a re-opening and exchange of the product
rings.18 The two-stage reactivity is showcased through the RCM
optimization, with the first stage completed in a similarly short
time regardless of the solvent used (1,2-DCE, DCM, THF,
CHCl3) or catalyst loading (2-5%) (see SI-Tables S3-S6).
Most of these cyclic olefin peaks were not observed at the end
of the reaction (after 7 days), which purports that in the initial
metathesis stage when the catalyst randomly closes olefins,
different ring sizes were formed (Figure 5). In the subsequent
slow stage, rings rearrange along the chain until only the most
thermodynamically stable 6-membered rings are present.
Figure 3: The RCM of iso-PEB, Mn,GPC 3940 and Đ 1.15, kinetic profile at 0.2
M using 5% of 2nd H-G catalyst in 1,2 DCE under reflux monitored by 1H-
NMR spectroscopy.
Figure 5: Proposed kinetic mechanism of RCM of i-PEB.
An illustration of this mechanism can be observed in 13C-NMR
spectra of both atactic and isotactic FCPE and PEB (Figure 4),
which demonstrate that greater than 99% of the olefins of PEB
are cyclized (Figure 4, B and E). In the atactic FCPE (Figure 4,
B), the new olefin peaks appear as broad, overlapping
resonances (d 125-132), reflecting the different ring
configurations along the polymer backbone. On the other hand,
i-FCPE showed only two sharp olefin resonances (Figure 4, E),
confirming the stereocontrolled structure of the polymer (Figure
2, cis-cyclopolymer). However, the spectrum of i-FCPE after
94% conversion (Figure 4, D), which was taken after 30 min,
showed the 6% of uncyclized isolated olefin peaks (d 118.3 and
135.6) and several cyclic olefin peaks (d 125-132).
Fixing the free rotation of the pendent olefins through RCM
impacts the glass transition temperature (Tg) in both a- and i-
PEB. The organized structure of i-FCPE has a significantly
higher Tg vs. a-FCPE (-11 °C from -26 °C). This is consistent
with the presence of cycles hindering segmental chain mobility
in both structures.
To prepare the PEGose polymer, i-FCPE was dihydroxylated
under mild conditions using N-methylmorpholine N-oxide (NMO)
and OsO4 as catalyst. This second post-polymerization
functionalization was diastereoselective, as OsO4 attacks on the
less hindered side of the ring (Figure 2), as demonstrated by
13C-NMR spectroscopy (Figure 6). The dihydroxylation produces
a unique stereocontrolled polymer structure, with a hydrophilic
surface (cis-diols) opposite of a hydrophobic backbone. This
distinctive structure could have potential applications in
biomaterials, blood storage or drug delivery, with face polarity
shaping surface chemistry and self-assembly.19,20 While amylose,
(C6H10O5)n, and PEGose, (C6H10O4)n, have similar monomer
units, PEGose is connected with an additional methylene bridge,
giving more flexibility to the polymer backbone. Circular
dichroism (CD) was used to determine the influence of this CH2
unit on the secondary structure of PEGose. Indeed, PEGose
and amylose have the same prominent negative bands at 182
nm (SI Figure S25), showing that this new PEGose has an
extended pseudo-helical structure similar to amylose.21 Efforts to
gain complementary X-ray characterization of this self-assembly
is ongoing.
While excess NMO affords complete dihydroxylation of the
double bonds, the reaction also offers the ability to adjust
polymer polarity by limiting this co-oxidizing reagent. Reducing
the NMO loading from 1.1- 0.8 equivalents dramatically alters
Figure 4: 13C-NMR of olefin region in CDCl3 of: (A) a-PEB, (B) a-FCPE, (C) i-
PEB, (D) metathesis product of i-PEB after 30 min (94% conversion) and (E)
metathesis product of i-PEB after 7 days (˃99% conversion).
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the polarity and solubility of the resultant polymer (Table 3),
offering a secondary tuning for biomedical applications and
leaving sites remaining for further functionalization or drug
conjugation.22 While the parent polymer is soluble in organic
solvents and the fully dihydroxylated polymer is freely soluble in
water and DMSO, this strategy allows for a broad range of
polymer polarities to be accessed.
Acknowledgements
This work was supported by the University of Edinburgh and
EaStCHEM, the University of Glasgow and WestCHEM, and
EPSRC (Doctoral Training Allocation EP/M506539/1 for M.A.).
Keywords: Polyethylene glycol • Ring-closing metathesis •
Post-polymerization modification • Cyclopolymers •
Stereocontrolled synthesis
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Con. (%)a
Soluble in
Insoluble in
[NMO]
1:1.1
1:0.9
1:0.8
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1
2
3
>99
91
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DMF, MeOH
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80
EtOAc, CH2Cl2
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In conclusion, we have shown that RCM of linear, stereoregular
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provides sugar-like structures with
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backbone, leading to a new PEGose architecture. The isotactic
linear PEB leads, after RCM, to a cyclic polymer with well
defined cis substitution patterns. By taking advantage of the
diastereoselectivity of the subsequent dihydroxylation reaction,
we were able to create a cyclopolymer where the configuration
of all the stereogenic centers is controlled, and which mimics the
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future functionalization, drug conjugation and biomedical
mimicry, and is a significant focus of our future work, as is
expanding this idea to other polymer backbones.
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Mohammed Alkattan,[a,b]
Joëlle Prunet*[b] and Michael
P. Shaver*[a]
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Title: Functionalizable
Stereocontrolled
Cyclopolyethers via Ring-
Closing Metathesis as
Natural Polymer Mimics
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