Base- A nd Catalyst-Induced Orthogonal Site Selectivities in Acylation of Amphiphilic Diols

Article abstract of DOI:10.1021/acs.orglett.0c00830

Seeking to selectively functionalize natural and synthetic amphiphiles, we explored acylation of model amphiphilic diols. The use of a nucleophilic catalyst enabled a remarkable shift of the site selectivity from the polar site, preferred in background noncatalyzed or base-promoted reactions, to the apolar site. This tendency was significantly enhanced for organocatalysts comprising an imidazole active site surrounded by long/branched tails. An explanation of these orthogonal modes of selectivity is supported by competitive experiments with monoalcohol substrates.

Full text of DOI:10.1021/acs.orglett.0c00830

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Letter
Base- and Catalyst-Induced Orthogonal Site Selectivities in
Acylation of Amphiphilic Diols
Natali Ashush, Reut Fallek, Amit Fallek, Roman Dobrovetsky, and Moshe Portnoy*
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ABSTRACT: Seeking to selectively functionalize natural and
synthetic amphiphiles, we explored acylation of model amphiphilic
diols. The use of a nucleophilic catalyst enabled a remarkable shift
of the site selectivity from the polar site, preferred in background
noncatalyzed or base-promoted reactions, to the apolar site. This
tendency was significantly enhanced for organocatalysts comprising
an imidazole active site surrounded by long/branched tails. An
explanation of these orthogonal modes of selectivity is supported
by competitive experiments with monoalcohol substrates.
ite-selective organic transformations, one of the emerging
synthetic methodology advances, enable selective mod-
ifications of natural products, which otherwise necessitate more
long peripheral hydrocarbon or oligoether tails enabled a
substantial improvement of the chemoselectivity in certain
1
S
12
Morita−Baylis−Hillman reactions. Since site selectivity is
13
tedious methods, e.g., total synthesis with a heavy use of
sometimes considered as an extension of chemoselectivity,
2
protective groups. Furthermore, such methodology enables
we decided to capitalize on our previous findings and apply a
similar design to acylation catalysts designated to site-
selectively promote butyrylation of model amphiphiles. The
proposed catalysts were based on the layout depicted in Figure
1a, while N-benzylimidazole (BnIm) was chosen as our
reference catalyst.
last-step diversification of synthetic products. Focusing their
study of site-selective methods on functionalities abundantly
present in natural products, a number of research groups have
demonstrated nonenzymatic site-selective modifications of
alcohols in natural product substrates as well as in entirely
3
−5
synthetic molecules.
Mostly, the selectivity in these cases
Among the synthesized benzylimidazole-cored catalysts
originated from highly specific intermolecular substrate−
(
Figure 1b and Scheme S1), the catalyst G1(C12)
6
catalyst interactions. Occasionally, it originated from subtle
incorporates three long linear hydrocarbon tails around the
catalytic core. In the second-generation catalyst G2(C12), five
long linear lipophilic tails and two aromatic branching units
surround the imidazole-bearing core. Finally, in the second-
generation dendritic catalyst G2(C5), branching points are
incorporated into the three aliphatic peripheral groups,
providing tighter lipophilic shielding of the catalytically active
unit.
differences in the reactivities of the reagents or their match
with the respective alcohol functionalities, catalysts, or auxiliary
4
b,7
14
bases.
In the past years we became interested in selective
functionalization of natural and synthetic amphiphilic mole-
cules, particularly site-selective acylation of amphiphilic diols
a method that can be highly useful in facilitating the
construction of various building blocks for supramolecular
In order to study selective functionalization of diol
amphiphiles, the model substrate 1 comprising two primary-
alcohol-terminated arms (one hydrocarbon, another oli-
goether) and an aromatic resorcinol-derived core was prepared
by stepwise alkylation (Scheme S2). The two monobutyrate
8
assemblies, e.g., amphiphilic dendrons and Janus dendrimers.
Furthermore, a great number of natural products are
amphiphilic, and in many of them hydroxyl groups are situated
9
in both polar and apolar regions of the molecule. While site-
selective acylation of various di- and polyols, particularly
3
a−d,4,6c
glycoside derivatives, has been described,
those studies
1
0
Received: March 4, 2020
did not include such amphiphilic substrates. Herein we
report our approach to site-selective acylation of alike
amphiphiles.
N-Alkylimidazoles are known, readily modifiable acylation
1
1
catalysts. Recently we demonstrated that using dendron-like
catalysts with an active imidazole unit near a focal point and
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00830
A
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Table 1. Acylation of the Model Primary Diol with a
a
Catalyst and a Base
entry
catalyst
reaction time (min)
2:3 ratio
1
2
3
4
BnIm
80
40
60
50
1.05:1
1.48:1
1.24:1
1.50:1
G1(C12)
G2(C12)
G2(C5)
a
Reaction conditions: 0.1 mmol of 1, 0.4 mmol of butyric anhydride,
0
.3 mmol of DIPEA, and 0.005 mmol of a catalyst in 1 mL of benzene
at room temperature. The reactions were followed by HPLC, and the
time and 2:3 ratio were interpolated for 50% consumption.
Table 2. Acylation of the Model Diols without a Catalyst
a
and/or a Base
entry
1
2
substrate
catalyst
reaction time (h)
2:3 or 6:7 ratio
1
1
1
1
1
1
5
5
5
5
5
−
−
12
2
2
1.33
3
1.5
23
14.3
11.5
8
1:2.17
1:11.1
1.49:1
1.86:1
1.84:1
2.30:1
1:2.00
1:16.7
1.90:1
1.94:1
2.21:1
b
Figure 1. (a) Catalyst design and (b) the actual structures.
3
4
5
6
7
BnIm
G1(C12)
G2(C12)
G2(C5)
−
esters 2 and 3 and the dibutyrate 4 derived from 1 were
isolated in the subsequently described experiments (Scheme
1
a) and fully characterized. HPLC characterization of 1 and its
butyrate derivatives enabled easy monitoring of all acylation
experiments.
b
8
−
9
BnIm
G1(C12)
G2(C5)
1
1
0
1
Scheme 1. Acylation of the (a) Primary and (b) Secondary
Diol Model Substrates
15
a
Reaction conditions: 0.1 mmol of substrate, 0.4 mmol of butyric
anhydride, and 0.005 mmol of a catalyst in 1 mL of benzene at room
temperature. The reactions were followed by HPLC, and the time and
b
the 2:3 or 6:7 ratio were interpolated for 50% consumption. In the
presence of 0.3 mmol of DIPEA.
in the absence of a catalyst and a base and that the acylation on
the polar arm of the substrate is preferred under these
conditions, with an approximate ratio of 1:2.2 between the
formed monoesters (2:3 ratio). Furthermore, when the
reaction is performed in the presence of DIPEA as the base
(
3 equiv) but without the catalyst, the rate is comparable to
that of the catalyzed reactions, but the 2:3 ratio is lowered to
:11, thus bringing the amount of 3 in the mixture of the
1
monoacylated products to 92%.
This dramatic influence of the base enabled highly selective
acylation of the alcohol on the oligoether arm. At the same
time, it hinted that the limited selectivity for 2 in the catalyzed
experiments may originate from the opposing preferences for
the acylation site imparted by the base and the catalyst.
Accordingly, we repeated the catalytic experiments without the
stoichiometric base in the reactions (Table 2, entries 3−6).
Remarkably, the reaction rates were only slightly reduced
compared with the parallel base-including experiments, while
the 2:3 ratio was now influenced much more by the catalyst
design, spanning between 1.5:1 and 2.3:1 (BnIm and G2(C5),
respectively). Though the highest 2-favoring selectivity leads at
the moment only to 70% of this product in the mixture of the
two monoacylated products at 50% consumption, the latter set
of experiments clearly demonstrates that the catalyst
modifications strongly affect the site selectivity and could be
further explored for enlarging the percentage of the product of
the monoesterification on the apolar arm in the reaction
mixture. Furthermore, while under optimal conditions favoring
one of the monoesters, a 30 or 43% absolute yield of the
preferred monoacylated product (2 or 3, respectively) is
The new catalysts were examined in the model reaction
Scheme 1a), with a particular emphasis on determining the
(
ratio between the two monoester products at 50% con-
sumption of the starting diol 1. This consumption ensured that
the amount of the diacylated product did not exceed 10%.
These experiments (Table 1) revealed that the reaction
promoted by BnIm is almost nonselective (the ratio between
the products of the monoacylation at the apolar arm (2) and
the polar arm (3) is 1.05:1), while all of the catalysts that we
prepared demonstrate a higher preference for the acylation at
1
5
the apolar arm. However, the highest 2:3 ratio was only 1.5:1
(
catalyst G2(C5)).
While attempting to achieve better selectivity, we examined
the noncatalyzed reaction more thoroughly (Table 2, entries 1
and 2). We found that the background reaction of 1 with
butyric anhydride in benzene at room temperature is very slow
B
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produced at 50% consumption (chosen for examination in
order to minimize the influence of diacylation), prolonging the
reaction time could substantially improve these yields, to 39%
(
at 80% consumption) or 69% (at 90% consumption)
16,17
respectively.
An additional model substrate 5 with the same resorcinol-
derived core but harboring secondary alcohol sites on the
hydrocarbon and oligoether arms was prepared via a
convergent synthesis (Scheme S3). When this substrate was
examined under various conditions described above, the
reactivity and selectivity patterns of the acylation (Scheme
1
b and Table 2, entries 7−11) followed the same trend as with
the primary diol model substrate. Thus, the reaction with
DIPEA only and without a catalyst led to a 6:7 ratio of ca. 1:17
(
94% of 7 in the mixture of the monoacylated products). On
the other hand, in the reaction catalyzed by G2(C5) in the
absence of base, a 6:7 ratio of 2.2:1 was achieved, producing
6
9% of the product 6 in the mixture of the monoacylated
products at 50% consumption.
In an attempt to understand the origins of the results
described above, we conducted a series of experiments with
truncated substrates 9 and 10 incorporating only one alcohol-
decorated site of diol 1, a hydrocarbon arm or an oligoether
18
arm, respectively (Scheme 2 and Figure 2). When a mixture
Figure 2. (a) Base- and catalyst-free or (b) base-induced acylation of
truncated substrates (9 and 10). Red lines/markers show the
formation of 11, and blue lines/markers show the formation of 12;
square markers (■) are for single-substrate experiments, and triangle
Scheme 2. Acylation with the Truncated Model Substrates
markers (▲) are for mixture-of-substrates experiments. For reaction
conditions, see the Supporting Information.
of these two substrates was subjected to the acylation under
base- and catalyst-free conditions (Scheme 2b and Figure 2a,
triangle-marked lines), the rate of the transformation of 9 was
only slightly decreased while the rate of the transformation of
10 was substantially increased compared with the equivalent
experiments with pure substrates 9 and 10 (Scheme 2a and
Figure 2a, square-marked lines). It seems that the acylation of
the alcohol on the oligoether chain (10) is assisted by the
apolar alcohol 9, but not vice versa. The reason for this may be
the hydrogen-bond activation of the electrophile (anhydride)
exerted by the apolar alcohol, while such activation by the
alcohol of the oligoether substrate is negligible because of the
internal hydrogen bond of the latter. In the case of the diol
substrate 1, the activation of the electrophile by the
hydrocarbon arm of the diol will enable an intramolecular
mode of reaction (along with the intermolecular pathways)
that will place the alcohol of the other arm in a suitable
position to attack the activated electrophile (Figure 3a), thus
amplifying the effect observed with the mixture of the single-
site substrates and providing the aforementioned 2:3 ratio of
Figure 3. Rationalization of the (a) substrate-controlled and (b) base-
controlled selectivities.
the reaction to occur at another alcohol site of the substrate,
was implicated as the rationale behind the site selectivity in
6c,19
acylations of diols and carbohydrates.
Moreover, stabiliza-
tion of transition states and intermediates by hydrogen
bonding was proposed in a number of computational studies
20
that analyzed acylations by carboxylic anhydrides.
The addition of DIPEA as the base (but not any imidazole-
based catalyst) had a profound accelerating effect on the
acylation of 10 when it was tested as the only substrate (blue
1
:2.2. Intermolecular hydrogen bonding of sterically un-
hindered primary alcohols to the acylating agents, directing
C
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square-marked lines, Figure 2b vs Figure 2a), and even more so
when it was used in a mixture with 9 (blue triangle-marked
lines, Figure 2b vs Figure 2a). At the same time, the base did
not have any substantial effect on the acylation of 9 when it
was tested separately or in a mixture with 10 (compare red
lines, Figure 2b vs Figure 2a). The most likely explanation for
these observations is the difference in the acidities of the two
alcohols. Although we lack pK data in benzene or similar
a
2
1
apolar solvents, in water β-alkoxy substituents usually lower
the acidity constants of alcohols by approximately an order of
2
2
magnitude. It is conceivable that the base strength of DIPEA
is sufficient to promote acylation of 10 through specific- or
23
general-base catalysis but too low to affect the acylation of 9.
In the acylation of diol 1, such base catalysis reinforces the pre-
existing preference for the acylation at the polar site, thus
bringing the site selectivity to the remarkable 11:1 value
(Figure 3b).
In the case of imidazole-based catalysts applied in the
acylation experiments with substrates 9 and 10 in the absence
of DIPEA, the transformation of 9 was always faster than that
of 10, both in the experiments with a single substrate and in
the experiments with the mixture of substrates. This finding
correlates with the preference for the acylation on the apolar
arm in the corresponding experiments with diol 1. Moreover,
these experiments with the catalysts and without the
stoichiometric base demonstrated that the N-alkylimidazole
moiety is only weakly basic in benzene. The rates of these
acylations are only slightly lower than those of acylations
carried out with the same catalysts in the presence of base, i.e.,
protonation of the catalyst by the stoichiometric amount of
butyric acid generated during the reaction is negligible. Hence,
the N-alkylimidazole group in the catalysts is not basic enough
to fully or partially deprotonate even the oligoether-arm
alcohol (as DIPEA does), while it is nucleophilic enough to
promote the alternative catalytic pathway proceeding through
Figure 4. Rationalization of the catalyst-controlled selectivity.
Scheme 3. Orthogonal Selectivities in the Acylation of Diol
Model Substrates
2
4
the acylimidazolium intermediate. The latter, being an
activated electrophile, can react with both alcohol function-
alities even in the absence of the hydrogen-bond activation and
prefers to react with the apolar alcohol, presumably since the
product and thus the transition state for such acylation are
25
lower in energy (Figure 4a).
The combination of the various acylation mechanisms that
are active in a given experiment according to its conditions
defines the overall selectivity and the rate of the reaction. In
the experiments with the imidazole-based catalysts, we
attribute the enhanced preference of the new catalysts to
acylate the site at the apolar arm (compared to BnIm) to the
1
1a
combination of their increased nucleophilicity,
which
channels more of the reaction via the pathway with the
cationic intermediate (Figure 4b), and the more lipophilic
environment around the catalytic center, which encourages the
access of the amphiphilic substrates to the catalytic center in an
ASSOCIATED CONTENT
■
*
sı Supporting Information
“apolar arm first” mode (Figure 4c).
In conclusion, we identified two sets of conditions that
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00830.
encourage site-selective acylation of the model amphiphilic
substrates with a carboxylic anhydride in benzene (Scheme 3).
While one set directed the acylation to the alcohol site situated
at the polar oligoether part of the molecule, the other set,
involving a specially designed catalyst, boosted the acylation at
the alcohol site of the apolar hydrocarbon-based part.
Synthetic schemes, experimental procedures, character-
ization data, results of additional catalytic experiments,
preliminary DFT calculation data, NMR spectra, and
HPLC monitoring of the catalytic experiments (PDF)
D
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pubs.acs.org/OrgLett
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(
5) For enzymatic site-selective modifications of polyol compounds,
AUTHOR INFORMATION
■
see: (a) Park, H. G.; Do, J. H.; Chang, H. N. Biotechnol. Bioprocess
Eng. 2003, 8, 1−8. (b) Gonzalez-Sabin, J.; Moran-Ramallal, R.;
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Corresponding Author
Moshe Portnoy − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
(6) (a) Giuliano, M. W.; Miller, S. J. Site-Selective Reactions with
Peptide-Based Catalysts. In Site-Selective Catalysis; Kawabata, T., Ed.;
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Yoshida, U.; Sato, M.; Shigeta, T.; Yoshida, K.; Furuta, T.; Kawabata,
T. J. Org. Chem. 2015, 80, 3075−3082. (c) Imayoshi, A.; Yamanaka,
M.; Sato, M.; Yoshida, K.; Furuta, T.; Ueda, Y.; Kawabata, T. Adv.
Synth. Catal. 2016, 358, 1337−1344.
6
997801, Israel; orcid.org/0000-0002-0174-0815;
Email: portnoy@tauex.tau.ac.il
Authors
Natali Ashush − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
(7) (a) Wilcock, B. C.; Uno, B. E.; Bromann, G. L.; Clark, M. J.;
Anderson, T. M.; Burke, M. D. Nat. Chem. 2012, 4, 996−1003.
(b) Kattnig, E.; Albert, M. Org. Lett. 2004, 6, 945−948.
6
997801, Israel
Reut Fallek − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
(8) For examples of amphiphilic dendritic molecules, including Janus
dendrimers, see: (a) Ramireddy, R. R.; Raghupathi, K. R.; Torres, D.
A.; Thayumanavan, S. New J. Chem. 2012, 36, 340−349. (b) Roche,
C.; Percec, V. Isr. J. Chem. 2013, 53, 30−44. (c) Raghupathi, K. R.;
Guo, J.; Munkhbat, O.; Rangadurai, P.; Thayumanavan, S. Acc. Chem.
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Malkoch, M. Prog. Polym. Sci. 2015, 48, 85−110. (e) Amir, R. Synlett
6
997801, Israel
Amit Fallek − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
6
997801, Israel
̈
m, A. M.;
Roman Dobrovetsky − School of Chemistry, Raymond and
Beverly Sackler Faculty of Exact Sciences, Tel Aviv University,
Tel Aviv 6997801, Israel; orcid.org/0000-0002-6036-
2
015, 26, 2617−2622. (f) d’Arcy, R.; Burke, J.; Tirelli, N. Adv. Drug
Delivery Rev. 2016, 107, 60−81. (g) Cao, Y.; Liu, X.; Peng, L. Front.
Chem. Sci. Eng. 2017, 11, 663−675. (h) Taabache, S.; Bertin, A.
Polymers 2017, 9, 280.
4
709
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00830
(
̈
9) (a) Furstner, A. Eur. J. Org. Chem. 2004, 2004, 943−958.
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The authors declare no competing financial interest.
(
10) In the case of an amphiphilic amphotericin B derivative (ref
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a), only hydroxy groups in the polar region were targeted.
ACKNOWLEDGMENTS
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Pharm. Bull. 1983, 31, 3724−3727. (b) Kosugi, Y.; Akakura, M.;
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Y.-s.; Shibuno, M.; Shishido, T.; Sakai, Y.; Kosaki, Y.; Susa, K.;
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2
(
This research was supported by the Israel Science Foundation
(
Grant 955/10) and the United States−Israel Binational
Science Foundation (BSF) (Grant 2012193). We thank Dr.
Maria Kramer (Tel Aviv University) for assistance in the
characterization of one of the intermediates.
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016, 358, 3541−3554.
13) Site selectivity, i.e., differentiation between the same functional
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(
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23) The base catalysis may occur in concert with the hydrogen-
(
bond activation of the electrophile or in parallel to the above-
described hydrogen-bond-induced base-free acylation.
(24) For this frequently invoked pathway, see: Connors, K. A.;
Pandit, N. K. Anal. Chem. 1978, 50, 1542−1545. (b) Jarvo, E. R.;
Copeland, G. T.; Papaioannou, N.; Bonitatebus, P. J.; Miller, S. J. J.
Am. Chem. Soc. 1999, 121, 11638−11643. (c) Ishihara, K.; Kosugi, Y.;
Akakura, M. J. Am. Chem. Soc. 2004, 126, 12212−12213.
(25) The preferred product possesses intramolecular hydrogen bond
at the polar alcohol site and a more stable ester at the apolar site (due
to the lack of the electron-withdrawing inductive effect of the β-
oxygen). Preliminary DFT calculations at the BP86(D3)/def2-SVP
level of theory show that the difference in the free energy of the esters
alone is ca. 0.5 kcal/mol (see the Supporting Information).
F
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Org. Lett. XXXX, XXX, XXX−XXX