Phosphorylation Organocatalysts Highly Active by Design

Article abstract of DOI:10.1021/acs.orglett.0c01226

The activity of nucleophilic organocatalysts for alcohol/phenol phosphorylation was enhanced through attaching oligoether appendages to a benzyl substituent on imidazole- or aminopyridine-based active units, presumably because of stabilizing n-cation interactions of the ethereal oxygens with the positively charged aza-heterocycle in the catalytic intermediates, and was substantially higher than that of known benchmark catalysts for a range of substrates. Density functional theory calculations and the study of analogues having a lower potential for such stabilizing interactions support our hypothesis.

Full text of DOI:10.1021/acs.orglett.0c01226

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Letter
Phosphorylation Organocatalysts Highly Active by Design
Amit Fallek, Mor Weiss-Shtofman, Maria Kramer, Roman Dobrovetsky,* and Moshe Portnoy*
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ABSTRACT: The activity of nucleophilic organocatalysts for
alcohol/phenol phosphorylation was enhanced through attaching
oligoether appendages to a benzyl substituent on imidazole- or
aminopyridine-based active units, presumably because of stabilizing
n−cation interactions of the ethereal oxygens with the positively
charged aza-heterocycle in the catalytic intermediates, and was
substantially higher than that of known benchmark catalysts for a
range of substrates. Density functional theory calculations and the
study of analogues having a lower potential for such stabilizing
interactions support our hypothesis.
been only scarcely reported, although they are presumably
hosphate is a functional group ubiquitously present in
1
Pvarious chemical components of living organisms. more efficient, more economical, and easy to handle.
Organocatalytic phosphorylation methods, originally limited
to DMAP and N-alkylylimidazoles,14,15 were later expanded to
π-methylhistidine-incorporating peptides by Miller and pyr-
idine-N-oxide derivatives by Spivey.16,17 Although the two
latter types of catalysts benefited from enhanced activity and
selectivity, the broad gap in the performance between synthetic
phosphorylation catalysts and kinase enzymes provides much
room for improvement in phosphorylation organocatalysis.
The generally accepted mechanism of phosphorylation of
alcohols with phosphorochloridates by a nucleophilic organo-
catalyst, proposed by Miller (Scheme 1),16a involves a cationic
intermediate, which is higher in energy than both the starting
material and the product. Lowering the energy of this
intermediate and the adjacent transition states will facilitate
the entire catalytic process. One way to do so is by
introduction of secondary noncovalent interactions of the
remote parts of the catalyst with its positively charged
phosphoryl-substituted aza-heterocyclic part. Such stabilization
of transition states is well-known in metal-less enzymes and
artificial enzyme mimics,19 and is similar to some of the
stabilizing second coordination sphere effects in metal-
oenzymes.20 Thus, we hypothesized that properly located
electron-rich moieties, e.g., ether oxygens with their lone-pair
electrons, could stabilize the electron-deficient aza-heterocycle
Reversible phosphorylation/dephosphorylation of hydroxyl-
bearing side chains in proteins serves as a fundamental
component of signal transduction pathways in biological
systems,2 while disruption of these mechanisms is frequently
associated with pathological disorders.2c Phosphates of small
biomolecules also bear important biological functions.3,4
Furthermore, a rising number of phosphorylated prodrugs
are introduced in order to increase the water solubility and,
accordingly, bioavailability of the parent alcohol-bearing
therapeutic agents.5
While the scope of biomimetic phosphorylation of alcohols/
phenols by kinase enzymes6 in chemical synthesis is rather
limited, organic synthesis of phosphorylated molecules opens
new avenues, particularly when “artificial” compounds are the
target. Accordingly, a number of synthetic methods for the
conversion of alcohols or phenols to phosphate esters have
been developed.7 Along with the approach based on
phosphytilation with P(III) reagents followed by oxidation,
which use sensitive reagents and is limited to substrates that
can tolerate an oxidative environment,8 several more
straightforward and step- and reagent-economical phosphor-
ylation schemes utilizing P(V) reagents (mostly phosphoro-
chloridates) were established.9 However, these methods suffer
from lower reactivity of phosphorus-introducing reagents and,
thus, were performed with preformed alkoxides/pheno-
lates,10,11 or with a base, used in large excess or as a solvent
and acting as a nucleophilic catalyst, a proton scavenger, or
both.5a,12 Surprisingly, catalytic methods of phosphorylation
with P(V) reagents, whether based on Lewis acids,13 or on
organic nucleophiles in a catalytic amount, in conjunction with
a base (which acts then as a proton scavenger only)14−18 have
Received: April 6, 2020
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© XXXX American Chemical Society
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methylimidazole (MeIm) and DMAP catalysts (Figures 1a and
1b). As is evident from the HPLC-assisted monitoring of the
reaction, all new catalysts were more active that the parent N-
benzylimidazole (BnIm), despite the increased steric hindrance
around the catalytic unit. Particularly remarkable was the
activity of the oligoethers-including Cat(Im,TEG), which
surpassed that of MeIm and closely approached the activity of
DMAP.
Scheme 1. Proposed Mechanism of Organocatalytic
Phosphorylation
a
The increased activity of the new catalysts, relative to BnIm,
seems to reflect, first and foremost, the higher electron-
donating nature of the o,o-dialkoxybenzyl group, as compared
to the unsubstituted benzyl. In these cases, the activating
electronic effect overpowers the deactivating steric. While the
inductive electron-donating ability of Bn is lower than that of
Me25and, hence, both the electronic and steric effects are
responsible for the lower activity of BnIm, compared to
MeImit is not clear whether this is the situation causing the
higher activity of the latter versus that of Cat(Im,OMe) and
Cat(Im,OC12). Furthermore, the extraordinary activity of
Cat(Im,TEG) cannot be explained by a simple electron-
donating effect or by the sterics. The former must be stronger
in Cat(Im,OMe) and Cat(Im,OC12), because of the electron-
withdrawing influence of the β-oxygens in the ortho-
substituents of Cat(Im,TEG). The deactivating steric
hindrance, on the other hand, is obviously lower in
Cat(Im,OMe), compared to Cat(Im,OC12) or Cat(Im,TEG),
and should be similar for the latter two. Thus, there must be
another effect that is responsible for the outstandingly high
activity of Cat(Im,TEG), with the most likely candidate being
the n−cation interactions, stabilizing the catalytic intermediate
and the adjacent transition states.
Encouraged by these results, we decided to construct 4-
aminopyridine-derived catalysts, analogous to the imidazole-
based catalysts described above and possessing a stronger
nucleophile as a core. The catalysts Cat(BMAP,OMe),
Cat(BMAP,OC12), Cat(BMAP,TEG), as well as the reference
core catalytic unit 4-(benzyl(methyl)amino)pyridine (BMAP),
were prepared (Scheme 2b) and examined in the model
phosphorylation, while being compared between themselves
and to DMAP (Figure 1c).
The comparison demonstrated that, consistent with BnIm
being inferior to MeIm, BMAP was less active than DMAP.
However, all tail-incorporating BMAP-derived catalysts were
more active than the latter, with the particularly high reactivity
displayed by Cat(BMAP,TEG). Notably, both Cat-
a
Adopted from ref 16a.
in the cationic catalytic intermediate. Recently, n−cation
interactions between an oxygen lone pair and a positively
charged heterocyclic moiety of an organocatalytic intermediate
were implicated by Tang and co-workers as the key selectivity-
determining factor in site-selective acylation of carbohydrates
and enantioselective dynamic kinetic acylation of 2-chroma-
nols.21 Furthermore, a recent review22 demonstrated that this
paradigm of directing n−cation noncovalent interactions was
also responsible for inducing diastereoselectivity in dynamic
kinetic acylation of anomeric hydroxyls in carbohydrates and
their precursors, reported earlier by the same group.23
To verify our assumption, we slightly simplified the layout of
the imidazole-based multibranched and dendritic nucleophilic
organocatalysts, recently found by our group to be effective in
inducing chemo- and site-selectivity,24 and prepared the
catalyst Cat(Im,TEG) (Scheme 2a), i.e., N-benzylimidazole
catalytic core flanked by long linear oligoether tails attached via
ether linkage in the ortho positions of the benzyl aromatic ring.
In parallel, we prepared catalysts Cat(Im,OMe) and Cat-
(Im,OC12), which both, similar to Cat(Im,TEG), bear alkoxy
substituents in the ortho positions of the benzyl aromatic ring,
but unlike the latter lack the oxygen donors with the correct
spatial location for the interaction with the cation.
Furthermore, the hydrocarbon tails of Cat(Im,OC12) imitate
the steric bulk of the oligoether tails of Cat(Im,TEG).
We tested the new catalysts in phosphorylation of a model
substrate, 8-phenoxyoctan-1-ol (1), comparing them to the
parent BnIm structure, as well as to the benchmark N-
Scheme 2. Synthesis of the (a) Imidazole-Based and (b) BMAP-Based Series of Catalysts
B
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Figure 1. (a) Model phosphorylation reaction; (b) the comparison of the new imidazole-based catalysts to BnIm, MeIm, and DMAP and (c) the
comparison of the new BMAP-based catalysts to DMAP, using HPLC-assisted monitoring. Reaction conditions: 0.2 mmol of 1, 0.25 mmol
ClP(O)(OPh)2, 0.25 mmol EtNiPr2, and 0.005 mmol of a catalyst in 10 mL benzene at room temperature (rt).
Figure 2. (a) Analogues of Cat(BMAP,TEG) with shorter oligoether
Figure 3. DFT calculation results of the effect of different substituents
substituents and (b) the comparison of the BMAP-based catalysts
(R) on the stabilization of [(PhO)2P(O)−Cat(BMAP,R)]+ cation,
with oligoether tails using HPLC-assisted monitoring of the model
based on isodesmic substitution reaction of Cat(BMAP,R).
reaction (see Figure 1 for reaction conditions).
(BMAP,OMe) and Cat(BMAP,OC12) are substantially more
active than DMAP, while the analogous imidazole-based
catalysts were less active, compared to MeIm. This difference
between the two series of catalysts indicates that, while the
electron-donating inductive effect of the o,o-dialkoxybenzyl
group is probably stronger than that of methyl, it is
outbalanced, in the case of the Im series, by the deactivating
steric hindrance of the o,o-disubstituted benzyl group. In the
case of the BMAP-series, the net balance of the two effects is
shifted toward the enhancement of the catalytic activity,
probably since the steric bulk of the disubstituted benzyl group
is situated farther from the catalytic center, compared to the
imidazole-based catalysts. Again, the remarkable activity of
Cat(BMAP,TEG) cannot be explained by the activating
electron-donating inductive effect, which should be weaker
than that in Cat(BMAP,OC12), because of the β-oxygen
electron-withdrawing influence, as explained above. Deactivat-
ing steric interference in Cat(BMAP,TEG) should be similar
to that in Cat(BMAP,OC12) and stronger than those in
Cat(BMAP,OMe), BMAP, or DMAP. Thus, the intermediate/
transition state-stabilizing n−cation interactions remain the
most likely explanation for the superiority of Cat-
(BMAP,TEG).
In order to further support this conclusion, we prepared two
analogues of Cat(BMAP,TEG) with shorter oligoether tails
substituting the ortho positions of the benzyl aromatic ring,
Cat(BMAP,DEG) and Cat(BMAP,MEG) (Figure 2a), via the
similar synthetic pathway. While the steric hindrance in the
C
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(BMAP,TEG) to the n−cation interaction, the catalyst
Cat(BMAP,MEG)and, possibly, Cat(BMAP,DEG)were
expected to be less active than their triethylene glycol-derived
analogue. This prediction was, indeed, confirmed by the
comparison of the (oligo)ethylene glycol-incorporating cata-
lysts in the model reaction (Figure 2b). The activity of
Cat(BMAP,DEG) was slightly lower, and that of Cat-
(BMAP,MEG) substantially lower, than the activity of
Cat(BMAP,TEG), reflecting the respective length, number
of oxygens and, accordingly, the expected potential of the
ethylene glycol-derived tails to participate in the stabilizing
interactions.
To understand this phenomena better, we performed density
functional theory (DFT) calculations at BP86-D3/def2SVP
level of theory in gas phase in which we compared the stability
of the formed [(PhO)2P(O)−Cat(BMAP,R)]+ (R = H, OMe,
OCH2CH2OMe (MEG), (OCH2CH2)2OMe (DEG) and
(OCH2CH2)3OMe (TEG)) cationic intermediates, based on
the isodesmic substitution reaction of Cat(BMAP,R) in
[(PhO)2P(O)−Cat(BMAP,R)]+ (Figure 3).26 The computa-
tional results clearly show the stabilization of the [(PhO)2P-
(O)−Cat(BMAP,R)]+ intermediate when R = H is replaced
by R = OMe (ΔH = −6.2 kcal mol−1 and ΔG = −6.4 kcal
mol−1). Longer ethereal tails further increase the stability of
the [(PhO)2P(O)−Cat(BMAP,R)]+ intermediate. Similarly to
the experimental observation, Cat(BMAP,TEG) provides the
most stabilized cationic intermediate.
Figure 4. Electron density surfaces with color-coded electrostatic
potentials obtained from DFT calculations using optimized structures
of [(PhO)2P(O)−Cat(BMAP,R)]+ with (a) R = H and (b) R = TEG
(blue, low electron density; red, high electron density).
While the difference between Cat(BMAP,H) and Cat-
(BMAP,OMe) in stabilizing the [(PhO)2P(O)−Cat-
(BMAP,R)]+ cation can be mostly rationalized by the donating
nature of OMe substituents, the explanation for the
stabilization effect of the longer ethereal appendages is not
that intuitive. To understand the cause of the effect of these
tails on the stability of [(PhO)2P(O)−Cat(BMAP,R)]+, we
extracted the electron density surfaces with electrostatic
potentials (ESP) obtained from DFT calculations of optimized
structures of [(PhO)2P(O)−Cat(BMAP,R)]+ (R = H and
TEG) (see Figure 4). The electron density surface of
[(PhO)2P(O)−Cat(BMAP,H)]+ reveals that the electron
density at the amino pyridinyl moiety is very low, i.e., the
positive charge is delocalized heavily into this moiety (Figure
4a). This positive charge is stabilized by Coulombic attraction
interactions with the electronegative oxygen atoms of the
ethereal tails in [(PhO)2P(O)−Cat(BMAP,TEG)]+, which are
wrapped around the amino pyridinyl moiety, as seen from the
electron density surface (Figure 4b).
The outstanding activity of Cat(BMAP,TEG) was further
emphasized, when the model reaction was repeated with 4
equiv of the phosphorylating agent and DIPEA each (see Table
S1 in the Supporting Information). Under conditions
otherwise equivalent to those in Figure 1, 90% yield of the
product was obtained in just 5 min when using Cat-
(BMAP,TEG), while the use of DMAP or BMAP afforded,
in the same time, only 14% or 6%. Cat(BMAP,DEG) imparted
a yield only slightly inferior to that of Cat(BMAP,TEG)
(84%), while the use of other catalysts of the BMAP-series
produced under these conditions substantially lower yields
(30%−72%). Furthermore, the pseudo-first-order rate con-
stants for all catalysts, measured under these conditions of
excess reagent and base, matched the outcome of all former
experiments (see Table S3 in the Supporting Information).
Finally, we demonstrated that Cat(BMAP,TEG) is superior
to the benchmark DMAP catalyst in phosphorylation of other
Figure 5. Conversion of the various alcohol/phenol substrates into
the corresponding phosphates achieved with Cat(BMAP,TEG) vs
that with DMAP under the conditions of the model reaction (Figure
1).
proximity of the catalytic center should be lower in the new
catalysts, compared to Cat(BMAP,TEG), their oligoether tails
may be too short for the optimal alignment of the oxygen lone
pairs and the heterocyclic cation in the catalytic intermediate
and, in addition, incorporate fewer oxygen atoms, available for
such interactions (particularly in the case of Cat-
(BMAP,MEG)). Since we attribute the strongest contribution
to the enhancement of the catalytic activity of Cat-
D
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Notes
primary alcohols (beyond the model substrate), as well as
secondary alcohols and phenols, under conditions identical to
those in the model reaction (Figure 5). At reaction times
chosen to ensure above 50% conversion of substrates with
Cat(BMAP,TEG), the conversions observed with DMAP were
30%−50% lower for most substrates, and 15%−20% lower for
sterically hindered secondary alcohols and a serine derivative.
In conclusion, we prepared two series of nucleophilic
organocatalysts for alcohol phosphorylation, with N-benzyli-
midazole or 4-(benzyl(methyl)amino)pyridine active units. For
both families, the catalysts equipped with triethylene glycol-
derived tails attached to the ortho position in the benzyl
moiety, Cat(Im,TEG) and Cat(BMAP,TEG), respectively,
exhibited extraordinary activity, which cannot be explained by
simple electronic or steric effects. Instead, stabilizing n−cation
interactions between the ethereal oxygens lone pairs and the
electron-deficient cationic heterocycle in the catalytic inter-
mediate and the adjacent transition states are presumed to
induce this activity enhancement. The activity trends observed
within the extended BMAP series, as well as DFT calculations,
support this explanation of the cause of the outstanding activity
of Cat(Im,TEG) and Cat(BMAP,TEG). Remarkably, the
latter catalyst exceedingly outperforms the benchmark DMAP
catalyst for all examined substrates.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Israel Science Foundation
(Grant No. 955/10) and the United States−Israel Binational
Science Foundation (BSF) (Grant No. 2012193).
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ASSOCIATED CONTENT
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Tables with comparative yields and pseudo-first-order
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1
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(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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-
4709; Email: rdobrove@tauex.tau.ac.il
Moshe Portnoy − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
6997801, Israel; orcid.org/0000-0002-0174-0815;
Email: portnoy@tauex.tau.ac.il
Authors
Amit Fallek − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
6997801, Israel
Mor Weiss-Shtofman − School of Chemistry, Raymond and
Beverly Sackler Faculty of Exact Sciences, Tel Aviv University,
Tel Aviv 6997801, Israel
Maria Kramer − School of Chemistry, Raymond and Beverly
Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv
6997801, Israel
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01226
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