Kinetic resolution of phosphoric diester by: Cinchona alkaloid derivatives provided with a guanidinium unit

Article abstract of DOI:10.1039/c5cy01208b

Cinchona alkaloid derivatives featuring a guanidinium group in diverse positions efficiently catalyze the cleavage of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). Their high catalytic efficiency as phosphodiesterases and the pote

Full text of DOI:10.1039/c5cy01208b

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Kinetic resolution of phosphoric diester by
Cinchona alkaloid derivatives provided with a
guanidinium unit†
ab
Cite this: DOI: 10.1039/c5cy01208b
Mauro Moliterno,a Dario Caramelli,a Luca Pisciottani,a
*
Riccardo Salvio,
Achille Antenucci,a Melania D'Amicoa and Marco Bellaa
Cinchona alkaloid derivatives featuring a guanidinium group in diverse positions efficiently catalyze the
cleavage of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). Their high cata-
lytic efficiency as phosphodiesterases and the potentiometric and kinetic investigations indicate the exis-
tence of a high degree of cooperation between the guanidinium group and the quinuclidine moiety with
the operation of a general acid/general base mechanism. The performance of these compounds was
investigated and compared in the kinetic resolution of HPNP. These data were also compared with the
results of DFT calculations on the transition states of the transesterification reaction that, in part, predict
and rationalize the experimental data.
Received 29th July 2015,
Accepted 11th November 2015
DOI: 10.1039/c5cy01208b
www.rsc.org/catalysis
In artificial phosphodiesterases, as in all supramolecular
catalysts, a primary role is played by the molecular scaffold
Introduction
The relevance of phosphodiester bonds in biology and chem-
istry and their reluctance towards hydrolysis1 have encour-
aged many scientists to design and synthesize artificial cata-
lysts able to cleave DNA, RNA and their model compounds2–4
with the idea of using these systems in health-related targets,
such as antisense therapy.4a,5
Most bifunctional small-molecule enzyme-mimics contain
metal cations as catalytically active groups, typically CuII and
ZnII.2,3 In addition or alternatively to metal ions several artifi-
cial catalysts feature other functions as active components.
These moieties play the role of anchoring sites, activators
and general bases. Among these components the
guanidinium group has a noteworthy importance because it
has been successfully employed in the design of enzyme
mimics.2b,4 This group can interact, due to its planar and
rigid structure and its geometrical complementarity, with the
phosphate anion through the formation of a two-point hydro-
gen bonding chelate motif.6 In nature this guanidinium–oxa-
nion interaction is frequently observed in enzymes and
antibodies.2b,7
that must be a compromise between preorganization and
flexibility, keeping the active functions at the proper dis-
tance and in a favourable orientation. Diverse non chiral
spacers have been used in the design of these artificial cat-
alysts such as terpyridine,4i 2,2′-dipyridyl,4j the xylylene
unit,4c,g,h calix[4]arene8 and diphenylmethane4b derivatives.
Another promising and emerging strategy in the prepara-
tion of artificial phosphodiesterases is the use of nanostruc-
tured supports, i.e. gold monolayer protected clusters2a,9
(Au MPC) and polymer brushes,10 as spacers for the active
units.
In the present study we designed and developed
guanidinium-based artificial phosphodiesterases derived
from quinine, one of the naturally occurring Cinchona alka-
loids. These compounds have attracted exceptional attention
in the field of asymmetric catalysis11 because of their ability
to efficiently mediate a number of asymmetric reactions
together with their commercial availability as enantiopure
compounds. In their underivatized form, they can act as chi-
ral Brønsted bases due to their quinuclidine moiety. They can
be easily modified in order to improve their catalytic effi-
ciency in enantioselective synthesis. In particular, the most
common derivatives are amino derivatives12 capable of acti-
vating carbonyl compounds via enamine or iminium ion for-
mation, quaternary ammonium salts acting as phase-transfer
catalysts13 and bifunctional catalysts equipped with an addi-
tional H-bond donor moiety.14
a Dipartimento di Chimica, Università di Roma – Sapienza, Italy.
E-mail: riccardo.salvio@uniroma1.it; Tel: +39 06 4969 3656
b IMC-CNR Sezione Meccanismi di Reazione, Università di Roma – Sapienza, Italy
† Electronic supplementary information (ESI) available: 1H and 13C spectra of
compounds, distribution diagrams, titrations, kinetic experiments, energies and
coordinates of DFT calculations. See DOI: 10.1039/c5cy01208b
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Scheme 1 Synthesis of quinine derivative 1b starting from 9-aminoIJ9-
deoxy)epi quinine 4. Reagents and conditions: (a) BocNHCIJS)NHBoc,
HgCl2, Et3N, DMF, 12 h, rt, yield: 53%; (b) 0.1 M HCl, 1,4-dioxane, 12 h,
rt, yield: 97%.
In the present study we have synthesized and investigated
compounds 1b, 2b and 3, featuring a guanidinium unit and a
tertiary amine in different relative positions and orientations
on a Cinchona alkaloid scaffold, as catalysts in the trans-
esterification of the RNA model compound 2-hydroxypropyl
p-nitrophenyl phosphate (HPNP, eqn (1)).
(1)
Scheme
2 Synthesis of catalyst 2b starting from epiquinine 6.
Reagents and conditions: a) MsCl, Et3N, THF, 3.5 h, rt, yield: 40%; b)
NaN3, DMF, 80 °C, 3 h, yield: 69%; c) PPh3 in H2O/THF 80 °C, 3 h, yield
48%; and d, e) as in steps a and b in Scheme 1, yields: 86% and 73%.
Compounds 1b and 2b differ in the configuration at C9,
which can be crucial for catalyst performance as observed by
Connon et al. with the urea-substituted Cinchona alkaloid
derivatives 1a and 2a which exhibit dramatically different
yields and enantioselectivity as bifunctional catalysts in the
addition of malonate to nitroalkenes.15
Potentiometric and kinetic evidence are presented to eval-
uate the catalytic efficiency and propose a catalytic mecha-
nism. The different performances of the three catalysts are
also compared in the kinetic resolution of HPNP. DFT calcu-
lations on the transition states of the transesterification reac-
tion complement kinetic investigation, providing a useful
rationalization of the experimental results. In the present
paper we have highlighted the importance and the unique-
ness of using a chiral spacer such as quinine derivatives for
the synthesis of artificial phosphodiesterases, considering
the fact that DNA and RNA are chiral molecules.
compound in low yield. For this reason the synthesis was car-
ried out by converting the alcohol 6 into its mesylate followed
by substitution with NaN3 and reduction with PPh3 (steps
a–c, Scheme 2). The guanidinylation on the 5′ position
affording compound 3 was carried out starting from the
dihydroquinine derivative 1018 with the same guanidinylation
method used for the synthesis of 1b and 2b.
Results and discussion
Synthesis of the catalysts
Potentiometric titrations
The guanidine derivative 1b was synthesized starting from
9-aminoIJ9-deoxy)epi quinine (4)14a using N,N'-di-Boc-thiourea
and HgCl2,16 followed by the removal of protecting groups to
afford the product as trihydrochloride 1b·3HCl (Scheme 1).
The preparation of compound 2b was carried out starting
from the 9-epiquinine 617 through steps a–e illustrated in
Scheme 2. Direct synthesis of compound 9 from 9-epiquinine
through the Mitsunobu reaction afforded the desired
Determination of the acidity constants of the investigated
compounds is a prerequisite for the kinetic study of their cat-
alytic properties. The potentiometric titrations were carried
out in 80 : 20 DMSO : H2O v/v, hereafter referred to as 80%
DMSO. In this polar and protic solvent mixture, which is
known to be suitable for the investigation of phosphoryl
transfer reactions4b,8,19 and for potentiometric measure-
ments,20 the autoprotolysis of water is strongly suppressed,
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substituted compounds (1b and 2b) due to the higher acidity
of aromatic guanidiniums compared to aliphatic ones.4g,8,19
Amino derivatives 4 and 9 show similar acidity constants
(entries 4 and 5, Table 1). The least acidic proton (pK3) can
be attributed, in this case, to the quinoline unit. Conse-
quently pK2 is the constant associated with the deprotonation
of the primary amine that is expected to be less basic than a
tertiary amine. For comparison the dihydrochloride of qui-
nine was also titrated in this set of experiments showing only
two titratable protons with the acidity constants pK1 and pK2
indicated in entry 6 of Table 1.
Fig. 1 Potentiometric titrations of trihydrochlorides of 1b, 2b and 3 (2
mM) with Me4NOH in 80% DMSO at 25 °C in the presence of 10 mM
NMe4ClO4. Data points are experimental and the lines are calculated.
Kinetic measurements
The catalytic activity of 1b, 2b and 3 in the transesterification
of the RNA model compound HPNP (eqn (1)) was investi-
gated in the same solvent mixture and conditions used for
the titrations (80% DMSO, 10 mM Me4NClO4, 25.0 °C).
A first set of kinetic experiments were carried out to evalu-
ate the best pH value to carry out the measurements. Partial
neutralization of 5.0 mM solutions of 1b·3HCl with different
amounts of Me4NOH afforded a number of buffer solutions
with pH values in the range of around 8–12, which were used
for catalytic rate measurements of HPNP transesterification
using the initial rate method. Pseudo-first-order rate con-
stants (kobs) for the cleavage of HPNP, corrected for back-
ground contributions8 whenever appropriate (pH > 11), are
reported in Fig. 2. The pH rate profile shows a maximum of
activity around pH 10–12. If we assume that 1bH+, the mono-
protonated form of the catalyst, is the only catalytically active
species (eqn (2)), kobs can be given by eqn (3), where K2 and
K3 are the acidity constants as defined in Table 1 and Ccat is
the total catalyst concentration.
pKw = 18.4 at 25 °C,21 and this implies that a neutral solution
corresponds to pH 9.2. The results of the elaboration of the
titration plots in Fig. 1 are summarized in Table 1, together
with the acidity constants of aminoquinines 4 and 9 and the
underivatized quinine (6b) reported for comparison.
Titrations showed three titratable protons for all the inves-
tigated compounds, except for 6b that features only two
acidic groups. 1b and 2b show a very similar potentiometric
behavior, whereas the curve of the trihydrochloride of 3 sig-
nificantly differs from that of the other two at higher pH
values. The most acidic proton (pK1 <2) can be attributed to
the nitrogen atom of the quinoline unit. Acidity constants in
that range cannot be accurately determined for titration car-
ried out at millimolar concentration. This high acidity com-
pared to that of quinolinium ion (pKa = 4.90)22 is probably
due to the marked electrostatic repulsion between the posi-
tively charged units, which facilitates the departure of a pro-
ton from the quinoline moiety. pK2 is similar for compounds
1b, 2b and 3, ranging from 8.4 to 8.7, and can be attributed
to the quinuclidine moiety.
v = kcat[1bH+][HPNP] = kobs[HPNP]
(2)
(3)
The least acidic protons (pK3) in entries 1–3 belong to the
guanidinium unit. The curve relative to the quinine derivative
3IJH+)3 reveals a significantly higher acidity constant (pK3,
entry 3, Table 1) compared to the other two guanidine-
Table 1 Acidity constants of Cinchona alkaloid derivatives in 80% DMSO
at 25 °Ca
Entry
Species
pK1
pK2
pK3
1
2
3
4
5
6
1bIJH+)3
2bIJH+)3
3IJH+)3
<2
<2
8.7
8.9
8.4
7.9
8.0
8.6
13.5
13.7
11.6
9.0
8.9
—
<2
4IJH+)3
2.1b
2.2b
3.5
9IJH+)3
6bIJH+)2
a
pKi data measured from potentiometric titration plots in Fig. 1 and
4S–6S in the ESI. The titrations were carried out on 6 mL of 2 mM
Fig. 2 kobs versus pH for the cleavage of 0.10 mM HPNP catalyzed by
5.0 mM 1b in 80% DMSO, 25.0 °C, 10 mM Me4NClO4. The rate
constants measured at pH >11 were corrected for background
hydrolysis at the given pH.
substrate solutions in the presence of NMe4ClO4. Experimental error
b
=
0.1 pK units unless otherwise stated. Experimental error = 0.3
pK units.
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The data in Fig. 2 can be fitted to a good precision to eqn
Furthermore the straight line resulting from the fitting
procedure shows an intercept close to zero, confirming that
the contribution of background hydrolysis to the overall rate
is negligible.
(3). The acidity constants (K2, K3) and kcat were treated as
adjustable parameters in a nonlinear least-squares fitting
procedure. The following values of best fit parameters were
obtained: pK2 = 8.45 0.12, pK3 = 13.58 0.13, and kcat = (9.2
0.4) × 10−3 M−1 s−1.
The nice fit of data points to eqn (3) and the good agree-
ment of the kinetically determined acidity constant values
with the potentiometrically determined ones (pK2 and pK3 of
entry 1 in Table 1) are clearly consistent with the idea that
1bH+ is the sole active species and indicate the operation of a
bifunctional mechanism in which the guanidinium is acting
as an electrophilic activator and the quinuclidine moiety is
acting as a general base (Fig. 3).
In a second set of kinetic experiments a number of buff-
ered solutions (pH = 8.7) of catalyst 1b at different concentra-
tions were used for the transesterification of HPNP. The
results of the kinetic experiments are graphically shown in
Fig. 7S (pag. 13S, ESI†) as plots of pseudo-first-order rate con-
stants (kobs, s−1) of HPNP cleavage versus total catalyst con-
centration (Ccat). Data points could be fitted to a straight line
with the following value of best fit parameter: k2 = (7.6 0.5)
× 10−3 s−1 M−1. This finding indicates that the catalysts do
not significantly bind to the substrate in the investigated con-
centration range. This evidence is in agreement with the fact
that the guanidinium–phosphate interaction has a weak
binding constant in water and water/DMSO mixtures (K <20
M−1).2b,19
The phosphodiesterase activity of the other two catalysts
(2b and 3) was also investigated and the results of the kinetic
experiments are reported in Table 2 together with the results
obtained in the presence of the catalysts lacking the
guanidinium unit (4, 9 and 6b) that were tested in control
experiments. Solutions of trihydrochloride precatalysts were
partially neutralized with 1.5 molar equivalents of Me4NOH.
In the resulting buffer solutions the predominant species are
the di- and monoprotonated forms of the catalysts (see distri-
bution diagrams calculated using the acidity constants in
Table 1 and Fig. 1S–3S, ESI†). These buffer solutions were
used for the transesterification of HPNP with the initial rate
method.
HPNP transesterification in the presence of 5.0 mM cata-
lysts were in all cases much faster than background trans-
esterification (kbg). The rate enhancements (kobs/kbg) cluster
around 5 × 103-fold and reach four orders of magnitude in
the case of the guanidine derivative 1b (entries 1–3 in
Table 2). The three catalysts also exhibit a different catalytic
activity towards the two enantiomers of HPNP. For the gen-
eral case in which the pseudo-first-order rate constants of the
R
two HPNP enantiomers, kobs and kobsS, are different the inte-
grated kinetic equation for the formation of p-nitrophenol is
given by (4).23 For the particular case in which there is no
R
S
kinetic resolution (kobs = kobs = kobs) the concentration of
p-nitrophenol is given by the well-known simpler eqn (5).
(4)
[pNPhOH] = [HPNP]o(1 − e−k t)
(5)
obs
The full time-course profile of the HPNP trans-
esterification in the presence of catalyst 1b significantly devi-
ates from the ordinary first-order behavior of eqn (5) (see Fig.
Fig. 3 Proposed bifunctional mechanism for the cleavage of RNA
models catalyzed by guanidine-substituted quinine derivatives involv-
ing the synergic action of a general base and an electrophilic activator.
Table 2 Transesterification of HPNP catalyzed by the listed catalysts (80% DMSO, 25 °C)a
106 × kobsIJS)b (s−1
)
106 × kobsIJR)b (s−1
)
kobsIJS)/kobsIJR)
106 × kobs (s−1
)
1010 × kbg (s-1)
kobs/kbg
d
e
Entry
Precatalyst
pH
1
2
3
4
5
6
1bIJH+)3
2bIJH+)3
3IJH+)3
8.7
8.9
8.4
7.9
8.0
8.6
62
11.6
6.0
5.2
3.0
2.4
—
—
—
34
12
8.7
0.08
0.12
0.10
32
50
16
5.0
6.3
25
10 600
2400
5400
160
190
40
18.3
13.5
3.9
c
c
4IJH+)3
—
—
9IJH+)3
—
—
c
c
6bIJH+)2
—
—
c
c
a
b
5 mM, [HPNP]i = 0.1 mM, 10 mM NMe4ClO4. Determined by UV-vis measurements using the full time-course method by fitting to eqn (4)
c
and confirmed by HPLC separation with a chiral column (see ref. 23, Experimental section and the ESI for details), error limit = 12%. Too
slow to be measured with the full time-course method. Pseudo-first-order specific rates kobs measured with the initial rate method and calcu-
d
lated as vo/[HPNP], where vo is the spectrophotometrically determined rate of p-nitrophenol liberation. Error limit = 5% unless otherwise
stated. e The spontaneous transesterification rate at the given pH is calculated by the following equation: kbg = 10(pH- 17.2), see ref. 8.
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8S, ESI†), but it can be fitted to good precision to eqn (4).
R
S
The values of kobs and kobs were treated in the fitting proce-
dure as adjustable parameters obtaining the values reported
in Table 2. The data about the kinetic resolution were con-
firmed by chiral HPLC chromatography of reaction mixtures
quenched with acidic solutions at proper time intervals (see
the Experimental section and ESI†).
The compounds which are not provided with the
guanidinium unit exhibit a dramatically lower activity in the
HPNP transesterification (entries 4–6 of Table 2). This experi-
mental evidence proves that the presence of the guanidinium
unit is a key requisite to obtain high catalytic efficiency
and confirm the postulated mechanism depicted in Fig. 3.
On the basis of kinetic data reported by Yatsimirsky et al. on
the cleavage of HPNP catalyzed by amines and guanidine
derivatives19 it was possible to evaluate the effectiveness of
the investigated catalytic scaffold in terms of effective molar-
ity (EM). The EM values for compounds 1b, 2b and 3 are esti-
mated to be in the range 1–5 M.
Fig.
4
Transition state structure (DFT calculations) for the
transesterification of (R)-HPNP catalyzed by 1bH+. Some of the
hydrogen atoms are omitted for clarity.
phosphate group of a phosphodiester. These findings suggest
the operation of an ANDN concerted mechanism rather than
an AN + DN,2a,b also labeled by Kirby as SN2IJP),25 consistent
with the presence of a good leaving group such as the
p-nitrophenolate.26
Ab initio calculations
The mechanism proposed on the basis of the kinetic mea-
surements and schematically depicted in Fig. 3 was also
quantitatively investigated by in silico experiments. DFT cal-
culations were carried out with the Gaussian 09 package24 at
the b3lyp/6–31 gIJd,p)//b3lyp/6–31 g(d,p) level of theory. The
Berny optimization using the GEDIIS algorithm was used for
the optimization procedure of the transition states of the
HPNP transesterification catalyzed by catalysts 1bH+, 2bH+
and 3H+ (see the Experimental section and ESI† for further
details and for the coordinates of all the optimized struc-
tures). The polarized continuum model was used to take into
account the solvent effect, setting a dielectric constant value
of 72, that is the experimental value measured in bulk for a
DMSO : H2O 80 : 20 mixture.19 All the TS structures feature a
single imaginary frequency. The animation of the normal
mode of vibration with a negative spring constant confirms
that the saddle points obtained from the optimization proce-
dure are actually the transition states of the HPNP trans-
esterification. Fig. 4 shows as an example the TS structure of
1bH+·(R)-HPNP. The geometry of the guanidinium-phosphate
group and the H2–O3 and H3–O4 distances (average value =
1.72 Å) indicate the presence of a chelate hydrogen bonding
and not only a mere electrostatic interaction. The bond
between the hydrogen atom H1 of the HPNP hydroxyl group
and the oxygen atom O1 is breaking and a new bond is
forming between the hydrogen and the quinuclidine nitrogen
N1. The distances of the bonds involved in the proton
transfer (O1–H1 = 1.42 Å, H1–N1 = 1.15 Å) indicate a late tran-
sition state. The distances O1–P (2.08 Å) and O2–P (1.86 Å),
compared with the average P–O distance of phosphodi-
esters,2b indicate the forthcoming formation of a sigma bond
and the breaking of the oxygen–phosphorus bond of the leav-
ing group. In addition, the O3–P–O4 angle is 121,3°, therefore
significantly different from the tetrahedral geometry of the
The results of the calculations on the transition states of
HPNP transesterification catalyzed by the investigated com-
pounds are reported in Table 3. The difference in the ener-
gies of the transition states for the two enantiomers is signifi-
cantly higher in the presence of catalyst 1bH+. In the case of
the other two catalysts the energy difference is much lower
and does not reach 1 kcal mol−1. On the basis of this energy
difference the ratio between the observed rate constants of
the two enantiomers was calculated using the Eyring equa-
tion. These values are in fair agreement with the experimen-
tal data in the last column of Table 2. (S)-HPNP turns out to
be more reactive than the (R) enantiomer in all cases. This is
probably due to the repulsive interaction of the (R)-HPNP
methyl group with the bulky quinine scaffold, specifically
with the quinuclidine moiety (see Fig. 4). The largest energy
difference is predicted in the presence of 1bH+, as observed
in the kinetic measurements, even though a larger rate con-
stant ratio is calculated for a difference of 2.1 kcal mol−1.
Table 3 Differences in the transition state energies (DFT calculations) for
the transesterification of the two HPNP enantiomers catalyzed by the
listed species and corresponding calculated ratio of the rate constants of
the reactions
a
Catalyst
ΔE≠ (E≠R – E≠
)
S
(kcal mol−1
)
k
obsIJS)/kobsIJR) calcdb
1bH+
2bH+
3H+
2.11
0.13
0.81
36
1.2
3.9
a
Differences between the energies of the transition states corrected
for the zero-point vibrational energy determined by frequency calcu-
lation; DFT b3lyp/6 31 gIJd,p)//b3lyp/6 31 g(d,p), PCM, ε = 72.0. See
the ESI and the Experimental section for further details and for the
b
coordinates of all the optimized structures. Ratio of the trans-
esterification rate constants kobsIJS) and kobsIJR), calculated with the
Eyring equation, on the basis of the energy differences obtained by
ab initio calculations.
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Conclusions
argon atmosphere. The reaction flask was cooled down to
0 °C and HgCl2 (354 mg, 1.31 mmol) was added to the solu-
tion. The mixture was stirred for 12 h at room temperature.
Then 10 mL of ethyl acetate were added and the HgS was
eliminated by filtration through a pad of Celite. A pure sam-
ple of 5 was obtained by flash column chromatography (SiO2,
AcOEt/hexane 3 : 2) as a colorless sticky solid (395 mg, 53%
Here we have presented the design, synthesis and inves-
tigation on the catalytic activity of quinine-derived guani-
dines as phosphodiesterases. These compounds feature a
guanidinium unit in diverse positions on the molecular scaf-
fold. Potentiometric and kinetic investigations at different
pH and catalyst concentrations demonstrate the operation of
a general acid/general base mechanism (Fig. 3 and 4). Species
1bH+, 2bH+ and 3H+ turn out to be very effective catalysts of
HPNP transesterification with rate enhancements relative to
the background hydrolysis, approaching four orders of mag-
nitude in the case of 1bH+. These data suggest that the con-
figuration of C9 plays a crucial role in modulating the activity
of the catalysts. Interestingly the same compound is slightly
stereoselective in the kinetic resolution of HPNP. This experi-
mental evidence is supported by DFT calculations on the
transition states of transesterification which confirm the pos-
tulated mechanism. The calculations show geometrical com-
plementarity between the catalysts and the substrate and
quantitatively predict, with fairly good agreement with experi-
mental data, the ratio between the observed rate constants of
the transesterification reaction. These results provide a useful
comparison between experimental and in silico data which
are potentially useful in the design of artificial ribonucleases,
and, in general, in catalysis by design.
1
yield). H NMR (300 MHz, CDCl3): δ 1.39 (s, 9H), 1.44 (s, 9H),
1.55–1.85 (m, 6H), 2.35 (bs, 1H), 2.70–3.05 (m, 2H), 3.21–3.59
(m, 3H), 4.0 (s, 3H), 5.04 (m, 2H), 5.81 (m, 1H), 7.33–7.42 (m.
2H), 7.83 (s, 1H), 8.03 (d, 1H, 12 Hz), 8.75 (s, 1H), 8.77 (s,
1H), 11.32 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 26.9, 27.5,
27.8, 28.1, 28.2, 39.5, 41.3, 55.8, 56.1, 59.3, 78.5, 82.9, 102.1,
114.5, 119.7, 122.3, 128.5, 131.3, 161.6, 144.4, 144.8, 147.4,
152.8, 155.4, 157.9, 163.3. HR ES-MS: m/z calcd for
C31H44N5O5 (M+H)+: 566.3342, found 566.3336.
9-GuanidineIJ9-deoxy)epi quinine tris-hydrochloride (1b·3HCl).
A solution of compound 5 (136 mg, 0.240 mmol) in 20 mL of
a 1 : 1 v/v mixture of dioxane and 0.5 M hydrochloric acid was
stirred for 12 hours at room temperature. Evaporation of the
solvent gave compound 1·3HCl as a white sticky solid (111
mg, 0.234 mmol, 97% yield). 1H NMR (300 MHz, D2O): δ
1.26–1.44 (m, 1H), 1.63–1.77 (tr, 1H, J = 12 Hz), 1.97–2.20 (m,
3H), 2.81–2.96 (m, 2H), 3.41–3.56 (m, 2H), 3.67–3.80 (tr, 1H, J
= 14 Hz), 3.90–4.02 (m, 1H), 4.08 (s, 3H), 4.13–4.25 (m, 1H),
5.08–5.25 (m, 2H), 5.70–5.88 (m, 1H), 7.79–7.93 (m, 2H),
8.12–8.28 (m, 2H), 9.00 (d, 1H, 6 Hz). 13C NMR (75 MHz,
D2O): δ 23.4, 24.0, 26.1, 30.2, 36.3, 43.0, 54.1, 57.5, 60.7,
103.4, 117.3, 121.7, 124.0, 128.6, 130.1, 134.7, 137.8, 141.4,
150.9, 157.3, 161.8. HR ES-MS: m/z calcd for C21H28N5O (M
+H)+ 366.2294, found 366.2289.
9-MethanesulfonateIJ9-deoxy)epi quinine (7). 2.71 g of 6
(8.35 mmol) and 4.6 mL of triethylamine were dissolved in
dry THF under a nitrogen atmosphere. The reaction flask was
cooled down to 0 °C and mesyl chloride (1.33 ml, 17.2 mmol)
was added dropwise to the solution. The mixture was stirred
for 30 minutes at 0 °C and then 3.5 hours at room tempera-
ture. After that the solvent was evaporated under reduced
pressure. The residue was dissolved in dichloromethane (400
mL) and washed with a 3.5% NaHCO3 aqueous solution (3 ×
200 mL). The organic phase was dried over Na2SO4 and evap-
orated. The crude material was purified by column chroma-
tography (SiO2; CH2Cl2/MeOH 14 : 1) giving a pale yellow
amorphous solid (1.351 g, 3.36 mmol, 40% yield). 1H NMR
(300 MHz, CDCl3): δ 0.63–0.75 (m, 1H), 1.27–1.48 (m, 1H),
1.49–1.58 (m, 2H), 1.60–1.67 (m, 1H), 2.20–2.32 (bs, 1H),
2.72–2.85 (m, 2H), 2.88–3.07 (bs, 3H), 3.15–3.28 (m, 1H),
3.25–3.50 (br, 2H), 3.94 (s, 3H), 4.90–5.05 (m, 2H), 5.62–5.87
(m, 1H), 6.30 (bs, 1H), 7.37 (d, 1H, J = 3 Hz), 7.40 (d, 1H, J =
3 Hz), 7.46 (m, 1H), 8.03 (d, 1H, 9 Hz), 8.76 (s, 1H). 13C NMR
(75 MHz, CDCl3): δ 24.9, 27.2, 27.6, 39.0, 39.2, 41.0, 55.5,
59.6, 76.6, 100.4, 114.5, 119.6, 122.1, 127.2, 131.9, 139.6,
141.2, 144.8, 147.3, 158.3. HR ES-MS: m/z calcd for
C21H27N2O4S (M+H)+: 403.1692, found 403.1685.
Experimental section
Instruments and general methods
1H and 13C NMR spectra were recorded on a Bruker 300 MHz
spectrometer. Chemical shifts are reported as δ values in
ppm. In some cases small amounts of TMS or dioxane were
used as an internal standard. High-resolution mass-spectro-
metric analysis was performed on an electrospray ionization
time-of-flight spectrometer. Ab initio calculation were carried
out with the Gaussian 09 (Revision D.01) package24 using
Narten Cluster – Dipartimento di Chimica - Sapienza. Chiral
HPLC separation was performed employing a CHIRALPAK IA
column.
Materials
HPNP,27 9-aminoIJ9-deoxy)epi quinine (4,)14a 9-epiquinine
(6),17 and 5′-aminodihydro quinine (10)18 were prepared as
reported in the literature. DMSO was purged for 30 min with
argon to eliminate volatile sulphide impurities and mQ water
was used in the preparation of 80 : 20 DMSO : H2O v/v. Anhy-
drous dichloromethane was obtained by distillation over
CaCl2. Triethylamine was distilled over KOH. Anhydrous THF
was obtained by distillation over Na. Other reagents and sol-
vents were commercially available and used without any fur-
ther purification.
9-Bisij4-(N,N-diIJtert-butoxycarbonyl)guanidineIJ9-deoxy)epi
quinine (5). 507 mg of 9-aminoIJ9-deoxy)epi quinine (4, 1.57
mmol), N,N'-di-Boc-thiourea (362 mg, 1.31 mmol) and 0.50
mL of triethylamine were dissolved in dry DMF under an
9-AzidoIJ9-deoxy) quinine (8). 1.35 g of 9-methanesulfonate-
IJ9-deoxy)epi quinine (7, 3.36 mmol) were dissolved in DMF
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under a nitrogen atmosphere. Sodium azide (0.813 g, 12.5
mmol) was added to the solution. The mixture was stirred for
3 hours at 80 °C and then one night at room temperature.
After that the mixture was evaporated under reduced pres-
sure. 400 mL of a 1 M NaOH aqueous solution and
dichloromethane (400 mL) were added to the residue. The
organic phase was separated, washed with a 1 M NaOH aque-
ous solution (3 × 200 mL), and dried over Na2SO4. The sol-
vent was evaporated and the crude material was purified by
column chromatography (SiO2; CH2Cl2/MeOH 100 : 1). Com-
pound 8 was obtained as a white amorphous solid (0.813 g,
2.33 mmol, 69% yield). 1H NMR (300 MHz, CDCl3): δ 1.45–
1.80 (m, 3H), 1.80–1.99 (m, 2H), 2.23–2.37 (m, 1H), 2.57–2.75
(m, 2H), 3.01–3.35 (m, 3H), 3.97 (s, 3H), 4.96–5.05 (m, 2H),
5.17–5.37 (bs, 1H), 5.70–5.89 (m, 1H), 7.30–7.36 (m, 1H),
7.36–7.43 (m, 2H), 8.06 (d, 1H, J = 9 Hz), 8.79 (d, 1H, J = 3
Hz). 13C NMR (75 MHz, CDCl3): δ 24.7, 27.2, 27.5, 39.4, 42.1,
55.8, 56.5, 58.4, 65.0, 101.0, 114.7, 119.5, 121.8, 127.0, 132.0,
141.3, 141.7, 144.9, 147.5, 158.2. HR ES-MS: m/z calcd for
C20H24N5O (M+H)+: 350.1981, found 350.1992.
9-AminoIJ9-deoxy) quinine (9). 2.46 g of 9-azidoIJ9-deoxy)epi
quinine (8, 7.04 mmol) and triphenylphosphine (4.14 mg,
15.8 mmol) were dissolved in dry THF under a nitrogen
atmosphere. The mixture was stirred for 3 hours at 80 °C.
After cooling 1 mL of water was added and the reaction mix-
ture was stirred for 12 h at room temperature. Afterward the
solvent was evaporated under reduced pressure and the resi-
due was dissolved in 10% aqueous HCl (400 mL) and washed
with dichloromethane (3 × 200 mL). 1 M NaOH aqueous solu-
tion was added to the water phase until alkaline pH was
reached. The mixture was extracted with dichloromethane
and the organic phase was dried over Na2SO4. The crude
material was purified by column chromatography (SiO2,
CH2Cl2/MeOH 30:1). Compound 9 was obtained as a pale yel-
low oil (1.10 g, 3.41 mmol; 48% yield). 1H NMR (300 MHz,
CDCl3): δ 1.45–1.63 (m, 2H), 1.64–1.78 (m, 2H), 1.83–1.95 (m,
2H), 2.08–2.21 (m, 1H), 2.24–2.35 (m, 1H), 2.47–2.75 (m, 2H),
2.95–3.12 (m, 2H), 3.13–3.26 (m, 1H), 3.96 (s, 3H), 4.65 (d,
1H, J = 9 Hz), 5.00–5.13 (m, 2H), 5.84–6.00 (m, 1H), 7.32–7.39
(m, 2H), 7.43 (d, 1H, J = 3 Hz), 8.02 (d, 1H, J = 12 Hz), 8.73
(d, 1H, J = 3 Hz). 13C NMR (75 MHz, CDCl3): δ 26.3, 27.7,
39.6, 41.9, 53.6, 55.6, 56.1, 60.5, 101.1, 114.4, 118.2, 121.1,
127.6, 131.9, 141.7, 144.7, 147.8, 149.1, 157.7. HR ES-MS: m/z
calcd for C20H26N3O (M+H)+: 324.2076, found 324.2089.
86% yield): mp 150–152 °C. 1H NMR (300 MHz, CDCl3): δ
1.10–1.30 (m, 1H), 1.45 (s, 9H), 1.47 (s, 9H), 1.65–2.05 (m,
3H), 2.21–2.41 (m, 1H), 2.55–2.88 (m, 3H), 2.90–3.15 (m, 2H),
3.40–3.58 (m, 1H), 3.99 (s, 3H), 4.98–5.14 (m, 2H), 5.81–6.05
(m, 1H), 6.21–6.35 (m, 1H), 7.32–7.43 (m, 2H), 7.81 (s, 1H),
8.98 (d, 1H, J = 9 Hz), 8.71 (bs, 1H), 8.75 (d, 1H, J = 6 Hz),
11.43 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 25.1, 27.6, 28.0,
28.2, 39.5, 42.1, 46.1, 51.0, 56.1, 56.4, 58.3, 79.3, 83.7, 101.8,
114.6, 118.8, 122.4, 128.1, 131.5, 141.6, 144.3, 145.0, 147.5,
153.1, 156.3, 158.1, 163.3. HR ES-MS: m/z calcd for
C31H44N5O5 (M+H)+: 566.3342, found 566.3329.
9-GuanidineIJ9-deoxy) quinine tris-hydrochloride (2b·3HCl). A
solution of compound 9b (100 mg, 0.18 mmol) in 0.41 mL
of TFA and 1 mL of dichloromethane was stirred for 2 hours
at room temperature. The solution was evaporated, dried
under vacuum, and the solid dissolved in 10 mL of 1 M HCl.
Evaporation of the solvent gave the compound as a sticky
white solid (142 mg, 0.142 mmol, 73% yield). 1H NMR (300
MHz, D2O): δ 1.91–2.49 (m, 4H), 2.65–2.75 (m, 1H), 2.80–2.98
(m, 1H), 3.05–3.55 (m, 3H), 3.58–3.78 (m, 1H), 4.11 (s, 3H),
4.28–4.48 (m, 1H), 5.15–5.38 (m, 2H), 5.85–5.95 (m, 1H), 5.95–
6.10 (m, 1H), 7.83 (d, 1H, J = 12 Hz), 7.90–8.00 (m, 1H), 8.15–
8.35 (m, 2H), 9.00–9.15 (m, 1H). 13C NMR (75 MHz, D2O): δ
23.7, 24.3, 25.9, 36.3, 43.5, 54.8, 57.4, 60.3, 63.1, 67.2, 102.3,
117.8, 121.5, 124.9, 128.7. HR ES-MS: m/z calcd for C21H28N5O
(M+H)+: 366.2294, found 366.2286.
5′-[(N,N-DiIJtert-butoxycarbonyl)guanidine dihydroquinine
(11). 252 mg of compound 10 (0.74 mmol), N,N′-di-Boc-
thiourea (328 mg, 1.19 mmol) and 0.30 mL of triethylamine
were dissolved in dry DMF under a nitrogen atmosphere. The
reaction flask was cooled down to 0 °C and HgCl2 (525 mg,
1.93 mmol) was added to the solution. The mixture was
stirred for 24 h at room temperature and then 10 mL of ethyl
acetate were added and the precipitated HgS was eliminated
by filtration through Celite. A pure sample of 11 was obtained
by flash column chromatography (SiO2, AcOEt/MeOH 100 : 1)
as a yellow sticky solid (151 mg, 0.26 mmol, 35% yield). 1H
NMR (300 MHz, CDCl3): δ 0.87 (tr, 3H, J = 6 Hz), 1.34–1.48
(m, 4H), 1.53 (s, 18H), 1.58–1.75 (m, 2H), 1.77–1.87 (bs, 1H),
2.05–2.21 (m, 1H), 2.41 (d, 1H, J = 15 Hz), 2.57–2.72 (m, 1H),
2.91–3.13 (m, 2H), 3.47–3.67 (m, 1H), 4.08 (s, 3H), 5.49 (d,
1H, J = 9 Hz), 7.39 (d, 1H, J = 3Hz), 7.51 (d, 1H, J = 9Hz), 7.90
(d, 1H, J = 9 Hz), 8.71 (d, 1H, J = 3 Hz), 12.09 (bs, 1H). 13C
NMR (75 MHz, CDCl3): δ 12.8, 25.4, 26.2, 28.8, 29.0, 38.1,
42.5, 57.9, 58.1, 58.5, 80.9, 82.6, 116.3, 119.5, 120.6, 121.5,
121.8, 127.0, 142.6, 144.7, 146.1, 149.2. HR ES-MS: m/z calcd
for C31H46N5O6+ (M+H)+: 584.3448, found 584.3474.
5′-Guanidine dihydroquinine tris-hydrochloride (3·3HCl).
A solution of compound 11 (26 mg, 0.044 mmol) in 4 mL of a
1 : 1 v/v mixture of dioxane and 0.1 M hydrochloric acid was
stirred for 24 hours at room temperature. Evaporation of the
solvent gave compound 3·3HCl as a sticky white solid (16.1
mg, 0.042 mmol, 96% yield), mp 128–129 °C. 1H NMR (300
MHz,): δ 0.87 (tr, 3H, J = 9 Hz), 1.25–1.43 (m,1H), 1.50–1.78
(m, 3H), 1.95–2.17 (m, 3H), 2.81–2.96 (m, 1H), 3.39–3.64 (m,
3H), 3.65–3.80 (m, 1H), 3.88–4.03 (m, 1H), 4.08 (s, 3H), 5.04
9-Bisij4-(N,N-diIJtert-butoxycarbonyl)guanidineIJ9-deoxy) qui-
nine (9b). 600 mg of 9-aminoIJ9-deoxy) quinine (9, 1.86
mmol), N,N'-di-Boc-thiourea (513 mg, 1.86 mmol) and 0.8 mL
of triethylamine were dissolved in dry DMF under a nitrogen
atmosphere. The reaction flask was cooled down to 0 °C and
HgCl2 (1.25 g, 4.62 mmol) was added portionwise. The mix-
ture was stirred for one night at room temperature and then
50 mL of ethyl acetate were added and the HgS precipitate
was eliminated by filtration through Celite. After solvent
removal at reduced pressure a pure sample of 9b was
obtained by flash column chromatography (SiO2, CH2Cl2/
MeOH/Et3N 100 : 0.5 : 0.25) as a colorless white solid (904 mg,
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(d, 1H, J = 9 Hz), 7.65 (d, 1H, 9 Hz), 7.83 (d, 1H, 6 Hz), 8.42
(d, 1H, 9Hz), 8.97 (d, 1H, 6 Hz). 13C NMR (75 MHz,): δ 10.8,
22.6 24.1, 26.3, 26.9, 36.1, 41.3, 55.9, 56.7, 58.2, 69.6, 114.0,
117.8, 121.2, 113.3, 133.4, 142.1, 143.9, 148.0, 148.4, 155.1,
157.1. HR ES-MS: m/z calcd for C21H30N5O2 (MH+): 384.2394,
found 384.2403.
input section to place an individual sphere on the two
guanidinium hydrogen atoms involved in the interaction with
the phosphate and on the hydrogen atom of the HPNP
hydroxyl. Energies and coordinates of the calculations are
reported in the ESI.†
Acknowledgements
Potentiometric titrations
The authors thank Chiesa Valdese Italiana and Sapienza Uni-
versity – “Progetti di Ateneo 2014” for financial support. Pro-
fessor Luigi Mandolini and Dr. Roberta Cacciapaglia are
acknowledged for the fruitful discussions. The authors also
acknowledge Prof. Ruggero Caminiti for providing computing
time on the NARTEN Cluster HPC Facility.
Potentiometric titrations were performed on an automatic
titrator equipped with a glass pH microelectrode. Experimen-
tal details and procedure for the electrode calibration in 80%
DMSO were the same as previously reported.4b,8
Potentiometric titrations were carried out under an argon
atmosphere, on 6 mL of 2 mM solutions of the investigated
compounds, in the presence of 10 mM Me4NClO4 (80%
DMSO, 25 °C). A 50–70 mM Me4NOH solution in 80% DMSO Notes and references
was automatically added to the titration vessel in small incre-
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gram HYPERQUAD 2000.28 Distribution diagrams of the spe-
cies were calculated using the acidity constants determined
by potentiometric titrations.
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Kinetic measurements of HPNP cleavage were carried out by
UV-vis monitoring of p-nitrophenol liberation at 400 nm on a
diode array spectrophotometer. Rate constants reported in
Table 2 were obtained by an initial rate method or full time-
course experiments, with error limits on the order of 5%
unless otherwise stated. The kobsIJS)/kobsIJR) ratio and the abso-
lute configuration were confirmed by HPLC separation of the
unreacted HPNP enantiomers by quenching the reaction mix-
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equation was used: kobsIJS)/kobsIJR) = ln[(1 − c)(1 − ee)]/ln[(1 − c)
(1 + ee)], see ref. 23 and pag. 15S, ESI† for further details.
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