The Anancomeric Character of the Pharmacophore 1,3,4-Thiadiazoline Framework in Chiral Spiro-Cyclohexyl Derivatives: Effects on Stereochemistry and Spiro-Junction Lability. Thermodynamic Aspects

Article abstract of DOI:10.1021/acs.joc.5b01635

Three new and easily accessible chiral compounds, containing the pharmacophore 1,3,4-thiadiazoline nucleus joined by a spiro center to a monoalkyl (methyl or t-butyl) substituted cyclohexyl fragment, have been synthesized and fully characterized from the structural and stereochemical point of view. The formation of a spiro-cyclohexyl-thiadiazoline system (sCT) offered the rare opportunity to generate at room temperature both anancomeric structures, displaying alkyl groups bound to the cyclohexyl ring in equatorial position, and other quite stable stereoisomers in which the same alkyl moieties are, instead, inserted in axial position, even for the extreme case represented by the really bulky t-butyl group. DFT calculations led to a clear rationalization of such stereochemical behaviors, pointing out that in all cases they arise from the unexpected strong anancomeric character possessed by the sCT framework in its 4-acetyl substituted version. In consideration of the large number of substances in which the 1,3,4-thiadiazoline heterocycle has been found as the active pharmacophore, the results discussed in this work may provide solid bases to allow a rational design of new chiral bioactive spiro-thiadiazolines characterized by well-defined stereochemical structures and single anancomeric geometries.

Full text of DOI:10.1021/acs.joc.5b01635

Article
pubs.acs.org/joc
The Anancomeric Character of the Pharmacophore 1,3,4-
Thiadiazoline Framework in Chiral Spiro-Cyclohexyl Derivatives:
Effects on Stereochemistry and Spiro-Junction Lability.
Thermodynamic Aspects
†
‡
†
§
†
,∥
Sergio Menta, Simone Carradori, Daniela Secci, Cristina Faggi, Luisa Mannina, Roberto Cirilli,*
,
†
and Marco Pierini*
†
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita
̀
di Roma, Piazzale Aldo Moro 5, 00185 Rome, Italy
Department of Pharmacy, “G. D’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
Dipartimento di Chimica, Universita degli studi di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy
Dipartimento del Farmaco, Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161 Rome, Italy
S Supporting Information
‡
§
∥
̀
̀
*
ABSTRACT: Three new and easily accessible chiral compounds, containing the
pharmacophore 1,3,4-thiadiazoline nucleus joined by a spiro center to a monoalkyl
(
methyl or t-butyl) substituted cyclohexyl fragment, have been synthesized and fully
characterized from the structural and stereochemical point of view. The formation of a
spiro-cyclohexyl-thiadiazoline system (sCT) offered the rare opportunity to generate at
room temperature both anancomeric structures, displaying alkyl groups bound to the
cyclohexyl ring in equatorial position, and other quite stable stereoisomers in which the
same alkyl moieties are, instead, inserted in axial position, even for the extreme case
represented by the really bulky t-butyl group. DFT calculations led to a clear rationalization
of such stereochemical behaviors, pointing out that in all cases they arise from the
unexpected strong anancomeric character possessed by the sCT framework in its 4-acetyl
substituted version. In consideration of the large number of substances in which the 1,3,4-
thiadiazoline heterocycle has been found as the active pharmacophore, the results discussed
in this work may provide solid bases to allow a rational design of new chiral bioactive spiro-
thiadiazolines characterized by well-defined stereochemical structures and single anancomeric geometries.
INTRODUCTION
and has also been the subject of several syntheses and
■
7
−9
methodological studies.
Many drugs containing the
As it is known, spiro structures are constituted by a couple of
rings connected through just one common sp hybridized atom,
3
thiadiazole nucleus are available on the market, such as
acetazolamide, methazolamide, and sulfamethazole. Keeping
in mind that the design of new substances based on privileged
scaffolds is one of the successful strategies in drug discovery,
the recourse to spiro-thiadiazoline structures could be a
promising “hybrid pharmacophore” approach to the develop-
ment of new pharmacological agents.
Starting from this premise, we designed and synthesized a
small series of chiral spiro compounds containing the 1,3,4-
thiadiazoline nucleus joined, by spiro center, to a cyclohexyl
fragment monoalkyl substituted: N-(4-acetyl-6- or 7-alkyl-1-
thia-3,4-diazaspiro[4.5]dec-2-en-2-yl)-acetamides obtained
starting from 2-methylcyclohexanone (compound 1), 2-t-
butylcyclohexanone (compound 2), and 3-methylcyclohexa-
none (compound 3, Scheme 1). This choice was based on the
consideration that:
called “spiro atom” (frequently a quaternary “spiro carbon
atom”). Due to the tetrahedral nature of the spiro atom, the
two rings are not coplanar but twisted almost perpendicularly
to each other. These particular arrangements, which are carriers
of strong steric constraints, make the construction of all-carbon
quaternary centers a formidable challenge for synthetic organic
chemists and may markedly characterize the biological activity
of synthetic and natural substances that include them in their
1
−6
structure.
Nevertheless, literature review reveals that the incorporation
of heterocyclic scaffolds into spiro structures attracts consid-
erable attention in synthetic and medicinal chemistry. Among
these, the 1,3,4-thiadiazole ring, a five-membered heterocycle,
in its original or reduced forms, has been found in molecules
endowed with a wide spectrum of pharmacological activities
e.g., antimicrobial, fungicidal, anticancer, analgesic, and anti-
inflammatory activity, etc.) probably by virtue of the NC−S
or its reduced) moiety. Accordingly, this peculiar structural
framework has been observed in a variety of natural products
(
(
Received: July 15, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01635
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Scheme 1. Series of Spiro Compounds Considered in the
Present Work, Each of Which Admitting the Existence of
Four Stereoisomers
largely disadvantaged because of the establishment of strongly
11
destabilizing 1−3 and 1−5 diaxial interactions. Similar effects,
of comparable extent, would be advisible and of wide interest if
associable to the structural properties of specific pharmaco-
phore frameworks. In the present article, we report about the
generation, separation, and characterization of the stereo-
chemistry and thermodynamic stability of both axial and
equatorial alkyl-substituted stereoisomers corresponding to the
general formulas of the spiro compounds 1−3 (Scheme 1). A
decisive contribution to the elucidation of the structural aspects
concerning the analyzed compounds has been obtained by
resorting to X-ray crystallography, as well as by carrying out
NMR measurements and a theoretical analysis founded on
density functional theory (DFT) calculations.
(
i) compounds 1−3 are easily accessible using cheap
reagents;
(
ii) in analogy with recent and relevant findings, the three-
dimensional structure of these chemotypes could be
correlated with stereospecificity to their potential bio-
RESULTS AND DISCUSSION
10
■
logical activity;
(
iii) the C-6 or C-7 substitution on the cyclohexyl fragment
offers the possibility to investigate the role played by
steric effects rising from the chosen alkyl substituents on
the configurational and conformational stability of the
structure.
Synthesis of the Substrates. The synthesis of the spiro
compounds 1−3 was carried out in two steps. The first
synthetic step involves the formation of the spirogenic
structure, the thiosemicarbazone of a monosubstituted cyclo-
hexanone, by reaction of the corresponding ketone with
thiosemicarbazide in ethanol, using acetic acid as the catalyst.
In the second step the cyclization is accomplished by treatment
of thiosemicarbazone with acetic anhydride at 90 °C for 1 h.
The heterocyclization reaction leads to the N-acetylation of the
With regard to this latter point, it is well-known as the presence
of a t-butyl substituent bound to a six-membered carbon ring
freezes thermodynamically the chair conformation of the
cyclohexyl structure. This is because the axial conformation is
Figure 1. Simultaneous HPLC enantio- and diastereoseparation of 1−3 obtained in conditions of kinetic control. Column: Chiralpak IC (250 mm ×
.6 mm i.d.). Eluent: (a) n-hexane−ethyl acetate−2-propanol 100:25:1 (v/v/v), (b) n-hexane−dichloromethane−2-propanol 10:90:0.5 (v/v/v), and
4
−1
(
c) n-hexane−ethyl acetate−2-propanol 100:10:1 (v/v/v). Detection: UV at 290 nm. Flow rate: 1.0 mL min . Temperature: 25 °C. Diastereomeric
ratios: (a) 2.1, (b) 20.6, (c) 7.0.
B
DOI: 10.1021/acs.joc.5b01635
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Figure 2. (a) Specific rotations of the stereoisomers of 1−3 in ethanol solution. (b) CD spectra of the stereoisomers of 1−3 in ethanol solution at 25
C.
°
thiosemicarbazone skeleton masked in the 1,3,4-thiadiazoline
nucleus of the spiro structure with yields ranging from 71 to
the species (i.e., their stereochemistry or relative stability). Each
symbol is constituted by a number, corresponding to the
analyzed compound (1, 2, or 3), followed by a letter (a, b, c, or
d) which denotes the stereoisomeric elution order.
9
2%, without any distinction about the kind of formed
stereoisomers.
Enantioselective and Diastereoselective HPLC. The
simultaneous separation of the enantiomers and diastereomers
of 1−3, obtained through reactions carried out under kinetic
control in order to increase the relative yield of the less stable
stereoisomers that are formed faster, was successfully achieved
by HPLC on a polysaccharide-based chiral stationary phase
under normal phase conditions. In all cases, at 25 °C the
chromatographic profile appeared without typical deformations
due to competitive on-column interconversion processes taking
place on the time scale of the HPLC elution, and the successful
separation into the four stereoisomers was clearly visible
The couple of peaks of equal area could be attributed to a
pair of enantiomers, while the peaks with different area could be
attributed to species in diastereomeric relationship. This
assignment was confirmed by chiroptical measurements (see
Figure 2 and next subsection). The values of the diastereomeric
ratios (dr) concerning the products formed in conditions of
kinetic control (which were provided by HPLC measurements)
turn out to be very different, being increased from 2.1 for the
compound 1 to 20.6 and 7.0 for the compounds 2 and 3,
respectively, with percentages of the minoritarian diastereomers
corresponding to 32.3, 4.6, and 12.5%. The percentages of the
same minoritarian diastereomers measured in conditions of
thermodynamic control were instead 0.8, 0.3, and 1.0%
(±0.1%), respectively (see Experimental Section).
(Figure 1). In order to distinguish in each chromatogram the
four resolved stereoisomers, at this early stage of the discussion
we find it convenient to represent them through short symbols,
devoid of any direct information regarding the characteristics of
C
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Structural Characterization. Structure and absolute
configuration of the stereoisomers 1d, 2b, 2c, and 3c, and
indirectly of their enantiomers 1c, 2d, 2a and 3d, was
unambiguously achieved by single crystal X-ray diffraction.
Unfortunately, our attempts to obtain crystals of 1a, 1b, 3a, and
highlighted the conformational axial/equatorial arrangement
that the alkyl substituents assume on the cyclohexyl fragment at
the solid state. According to this, it is observed that the methyl
or t-butyl group in the more stable stereoisomers of 2 and 3,
respectively, is arranged in an equatorial disposition of the chair
conformation of the cyclohexyl ring, regardless of the position
that it occupies (carbon C-6 or C-7) with respect to the spiro
center (carbon C-5, Cspiro). Hereafter, when for a same kind
of alkyl substitution 1, 2, or 3 it will be appropriate to
distinguish between the two possible couples of enantiomers,
these will be expressed through the shorter symbols M-x and L-
x, with the letters M and L indicating the more and less stable
couple of enantiomers, respectively, while x the species.
Coherently, the species 2a, 2c, 3c, and 3d, visible in the
chromatograms b and c of Figure 1 and quoted in the above
sentence, will correspond to the predominant pair of
enantiomers M-2 and M-3, respectively.
3
b of X-ray quality were unsuccessful. Therefore, the
stereochemistry of these four stereoisomers has had to be
established as follows:
(
i) by circular dichroism correlation, performed comparing
CD spectra registered for the couple of enantiomers 1a/
1b with those of the couple 2a/2c (Figure 2; about this,
it is important to note that, due to the different CIP
order of priority that the methyl group has with respect
to the t-butyl one, configuration 6R* in compound 1 is
structurally equivalent to configuration 6S* in compound
2);
(
ii) by chemical correlation for the couple of enantiomers
Differently from the conformational preferences assumed by
the above M isomers, in the minoritarian pair of enantiomers of
12
3a/3b (for details see Scheme S1).
1
and 2 (i.e., the species L-1 and L-2), the alkyl group assumes
On this basis, the resulting correspondence between absolute
configuration of the species and their HPLC elution order can
be summarized as follows:1a = (5R,6S)-1; 1b = (5S,6R)-1; 1c =
an unusual axial orientation, even in the case of the sterically
very demanding t-butyl group (compound 2b). The conforma-
tional axial/equatorial arrangement of 1−3 on the cyclohexyl
fragment, observed by X-ray in the solid state, was
experimentally confirmed also in solution (CDCl for M-1
and L-1, while CD OD for M-2, L-2, M-3, and L-3) by H
NMR analysis. The assignments were established by suitable
analysis of coupling constant values (J ) relevant to specific
protons (see Experimental Section and Supporting Information
for details).
(
=
5R,6R)-1; 1d = (5S,6S)-1; 2a = (5R,6R)-2; 2b = (5R,6S)-2; 2c
(5S,6S)-2; 2d = (5S,6R)-2; 3a = (5R,7S)-3; 3b = (5S,7R)-3;
3c = (5S,7S)-3; 3d = (5R,7R)-3.
3
1
As shown in the ORTEP projections reported in Figure 3,
3
their molecular conformations are typical of spiro structures
with the two rings almost perpendicular with one another. As a
further detail, the examination of the crystal structures has also
ab
13
Relative Stability of L and M Diastereomers and
Kinetic Aspects of Their Interconversion. The exper-
imental observation that in the course of synthesis of
compounds 1−3 the less stable diastereomers L-x are formed
faster than their more stable counterparts M-x, and that,
through a suitable choice of operative conditions, it is possible
and easy to switch from kinetic to thermodynamic control
(
allowing in this way the achievement of greater yields of either
L-x or M-x diastereomers), led us to deepen the knowledge
about both the relative stability existing between L-x and M-x
isomers and the kinetic aspects governing the related
isomerization processes. In order to obtain the goal we
analyzed the time-dependent decay of the diastereomeric
excess of single L-x stereoisomers isolated as virtually pure or
enriched species on a semipreparative scale. More in particular,
the spontaneous L-x → M-x interconversion, until achieving
equilibrium conditions, was monitored as a function of time at
5
5 °C by classical off-column kinetic determinations in both
chloroform (CHCl ) and acetic anhydride (AA, the solvent
3
used in the syntheses of 1−3), using stereoselective HPLC as
7b,14
monitoring tool.
Table 1.
The obtained results are collected in
As a first observation, inspection of the data reported in
Table 1 put in evidence that, with respect to the L-x isomers,
the greater stability possessed by the M-x species is never lesser
than 3 kcal mol− (compound 3 in AA), reaching for
1
−1
compound 2 the maximum difference of 6.6 kcal mol in
CHCl . In fact, these energy gaps lead, at achieved equilibrium,
3
the M-x structures to largely dominate their diastereomers,
from a minimum value of Boltzmann populations of 99.4% to a
maximum value virtually indistinguishable from 100%,
respectively. This means that under conditions of thermody-
namic control, the generation of M-x structures may be
Figure 3. ORTEPs of (5S,6S)-(−)-1, (5R,6S)-(+)-2, (5S,6S)-(+)-2,
and (5S,7S)-(−)-3. Ellipsoid contour percent probability: 50%.
D
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Table 1. Kinetic Results of the Thermal Diastereomerization of 1−3 Monitored by Stereoselective HPLC
a
kM→L (s−1
b
ΔG⧧
(kcal mol−1
ΔG⧧
(kcal mol−1
ΔG°L⇆M (kcal mol−1
c
no.
solvent
T (°C)
kL→M (s−1
)
6
)
)
)
)
t1/2 L→M
L→M
M→L
−8
−8
−9
−7
−7
−7
1
CHCl3
AA
55
55
55
55
55
55
8.22 × 10−
2.11 × 10
6.68 × 10−
1.23 × 10
1.68 × 10
2.67 × 10
1.57 × 10
2.80 × 10
2.58 × 10
26.90
27.79
25.54
25.72
25.51
26.12
31.14
30.94
32.14
29.48
29.11
29.16
−4.24
−3.15
−6.60
−3.76
−3.60
1 d
−
6
5
5
5
5
4 d
2
3
CHCl3
AA
174 min
248 min
163 min
533 min
−
5.06 × 10
CHCl3
AA
6.97 × 10−
2.72 × 10−
−3.04
c
a
b
Diastereomerization rate constants for the L → M process. Diastereomerization rate constants for the M → L process. t1/2 L→M: half-life time of
the L → M isomerization.
a
Scheme 2. Structures of Spiro-1,3,4-thiadiazoline-cyclohexyl Derivatives Used as Models
a
−1
Relative stability energies Eseq and Es , computed in chloroform, are reported in kcal mol .
ax
considered complete. Second, at the temperature of 55 °C, the
L → M isomerizations are all characterized by significantly high
activation energy barriers, even in the case of the couple of
enantiomers L-2 that show the t-butyl group in axial
disposition. This is stressed by the fact that, at room
temperature (and in the hypothesis of a negligible entropy
contribution), it is assessed a half-life time of about 7 days
calculations. Chloroform was the solvent considered in the
geometry-optimization procedure. For every compound and
each pair of relative configurations (i.e., the homochiral (5R*,(6
or 7)R*)-x and heterochiral (5R*,(6 or 7)S*)-x structures, with
x denoting the species 1−3), also taken into account were the
couples of conformational stereoisomers resulting by flip of the
cyclohexane ring.
(
while of about 1 day at the body temperature of 37 °C).
In this way it becomes possible to put in evidence the
Finally, from the data it can also be highlighted that, on increase
of solvent polarity, the L → M isomerization barriers also
increase, although of quite modest amounts.
conformational effects that would arise from the axial (S ) or
ax
equatorial (S ) disposition of the sulfur atom (i.e., the (5R*,(6
eq
or 7)R*)-x-S , (5R*,(6 or 7)R*)-x-S , (5R*,(6 or 7)S*)-x-S ,
ax
eq
ax
Generation of Anancomeric Conformations. Besides
the particular axial/equatorial arrangement that alkyl groups of
and (5R*,(6 or 7)S*)-x-S isomers). All the achieved values of
eq
absolute and relative energy stability have been collected in
Tables 2 (relative values) and S1 (absolute values), respectively.
From their first inspection, it is possible to note that for each
of the 1−3 compounds the relative energy stabilities
1
−3 assume on the cyclohexyl fragment, another key property
that emerges from inspection of the molecular structures of 1−
in their crystalline state is that the sulfur atom is always found
3
bound in axial to the cyclohexane ring. Therefore, also the
quoted stereochemical preferences observed into the crystals
must be related to peculiar steric interactions that the
substituted 1,3,4-thiadiazoline fragment establishes in answer
to its incorporation into the spiro-cyclohexyl system. In order
to shed light about such experimental evidence, the structures
of compounds 1−3, as well as that of their common spiro-
cyclohexyl-4-acetyl-2-acetamido-1,3,4-thiadiazoline framework
experimentally found between the M and L relevant stereo-
CHCl3
isomers in chloroform (i.e., the ΔG°
quantities obtained
M−L
⧧
CHCl3
⧧CHCl3
through the ΔG
− ΔG
differences) have been
finely reproduced by calculation. In fact, the experimental
M→L
L→M
CHCl3
M−L
CHCl3
M−L
−1
ΔG°
versus computed ΔE°
values in kcal mol are
4.24 against 3.95 for 1, 6.60 against 7.01 for 2, and 3.60 against
3.29 for 3 (data from Tables 1 and 2), and this points to a high
reliability of the level of theory used in all DFT calculations.
Moreover, in all cases, the thermodynamic preference of
geometries displaying the sulfur atom in axial position,
(
hereafter symbolized sCT , Scheme 2), that will be used as
0
a reference model, have been modeled by resorting to DFT
E
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Article
Table 2. Relative Energy Stabilities in Chloroform of
Compounds 1−3 and Model sCT0
conformationally “biased” or, in other words, fixed in just one
conformation, because of an energy gap from the possible
conformational stereoisomers not lower than 2.4 kcal
a
b
c
E (kcal mol−1
ORS
configuration
conformation
)
−1 11,15a
mol .
sCT0
Sax
Seq
Sax
Seq
Sax
0.00
5.25
0.00
9.09
3.95
5.78
0.00
13.29
7.01
7.25
0.00
7.34
3.29
Certainly, this has also a strong and direct reflex on the
conformational stability of its possible derivatives, as in fact
occurs in the case of compounds 1−3. More in particular,
1
M
M
L
(5R*,6S*)
(5R*,6S*)
(5R*,6R*)
(5R*,6R*)
(5R*,6R*)
(5R*,6R*)
(5R*,6S*)
(5R*,6S*)
(5R*,7R*)
(5R*,7R*)
(5R*,7S*)
(5R*,7S*)
calculations highlighted that the (5R*,6S*)-1-S , (5R*,6R*)-2-
ax
S , and (5R*,7R*)-3-S stereoisomers manifest themselves as
ax
ax
L
Seq
greatly more stable than their flipped counterparts with S and
eq
2
3
M
M
L
Sax
−1
axial alkyl groups (from 7.3 to 13.3 kcal mol , Table 2), and
Seq
therefore endowed with structures strictly anancomeric.
Importantly, such species display their alkyl groups always in
equatorial disposition, in agreement with the experimental
evidence coming from both X-ray and NMR measurements.
Sax
L
Seq
M
M
L
Sax
Seq
Sax
Seq
The highlighted dominant prevalence of x-S conformers could
ax
play a very important role if the species to which it is associated
is provided with biological activity (as, indeed, is the case of the
considered compounds), being well-known the general relation
existing between stereochemistry and bioactivity. Analogously,
their related diastereoisomers, always characterized by Sax
conformations but alkyl groups in axial disposition, display
again a greater stability with respect to their flipped conformers
L
5.10
a
b
ORS: order of relative stability between diastereomers. Relative
c
configuration of compounds. Axial or equatorial disposition of sulfur
atom on cyclohexane ring.
highlighted by X-ray analysis, has been correctly assessed by
theory. This evidence can be rationally justified by considering
the computed difference of stability found between the S and
(
with S and equatorial alkyl groups). Nevertheless, in this case
eq
eq
the calculated Boltzmann populations (BP) have been assessed
as less than 100% (96% in the case of both (5R*,6R*)-1-S and
S conformations of the sCT model (ΔEsCT -Sax‑eq), which
ax
0
0
−1
ax
amounts to 5.2 kcal mol . Such a significant energy gap, arising
from less destabilizing S···H and O···H steric interactions in the
sCT -S structure with respect to the flipped conformer sCT -
(
5R*,7S*)-3-S , while 60% in that of (5R*,6S*)-2-S ).
a
x
a
x
Noteworthy is the fact that, also for these species, the
stereochemistry assessed by calculations at the asymmetric
atoms 6 or 7 is just that observed by X-ray in the relevant
crystals of 1 and 2 and inferred in solution by NMR
0
ax
0
Seq (Figure 4), closely resembles the well-known effect
(
Supporting Information). Thus, even though in a not perfectly
additive way, the estimated conformational preferences found
−
1
in CH-tBu (i.e., ΔECH-tBu
= 5.5 kcal mol ) and sCT
0
ax‑eq
−1
(
i.e., ΔEsCT -S
= −5.2 kcal mol ) seem roughly to cancel
0
ax‑eq
each other within the isomer (5R*,6S*)-2-S , providing the
ax
rationale to explain the unusual axial orientation assumed by
the t-butyl group in this structure.
In consideration of the above interesting findings, we decided
to deepen the peculiar behavior of the spiro-1,3,4-thiadiazoline
fragment as a function of type of its chemical substitution on
the positions 2 and 4. The goal was achieved by extending the
DFT calculations to further three simplified models of sCT0,
Figure 4. Destabilizing S···H and O···H steric interactions inside the
structures of the sCT -S and sCT -S conformers.
that is to say, the species denoted as sCT , sCT , and sCT
1
2
3
0
ax
0
eq
reported in Scheme 2.
From the obtained results, collected in Table S1 as absolute
values and in Scheme 2 as relative data, it is possible to
highlight that, starting from the model sCT0:
produced by a t-butyl group (tBu) substituting a hydrogen
atom in a cyclohexane ring (CH). In this case, indeed,
according to literature data, the resulting axial and equatorial
conformational stereoisomers (i.e., the CH-tBu and CH-tBu
ax
eq
(i) the exclusion of the 2-acetamido moiety (sCT ) leads to
1
species, respectively) differ in energy (ΔECH-tBu ) by 4.7−
a little increase in the difference of energy stability
ax‑eq
11,15
1
5
.7 kcal mol− in favor of the equatorial species.
between the related Sax and S conformations, which
eq
In order to perform the above comparison in consistent
−1
amounts to 0.86 kcal mol in favor of the S-axial
operating conditions, we recomputed such a difference by
considering in the geometry optimization procedure of CH-
tBu and CH-tBu the chloroform as the solvent, obtaining
disposition;
(
ii) the contemporary loss of both the 2-acetamido and 4-
ax
eq
acetyl groups (sCT ) leads to a sharp drop in the
−1
2
5
.5 kcal mol as the new value of ΔECH-tBuax‑eq to be
compared with ΔEsCT -S (Table 2). Therefore, this result
difference of energy stability existing between the
0
ax‑eq
relevant Sax and Seq conformations, with the sCT -S
2
ax
confirms that, similarly to a t-butyl group, also the spiro-1,3,4-
thiadiazoline moiety, in its 4-acetyl and 2-acetamido substituted
version, can act on the cyclohexane ring as an effective “holding
framework”, leading to the generation of an “anancomeric”
structure. About this quite rarely used term, we consider useful
to remind that it may be employed to refer to a molecule
stereoisomer again more stable than the flipped
−1
equatorial one, but this time for only 0.67 kcal mol ;
iii) the loss of the 2-acetamido moiety and the substitution
of the 4-acetyl with a methyl group (sCT ) leads to a
(
3
significant reduction in the difference of energy stability
F
DOI: 10.1021/acs.joc.5b01635
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
between the relevant Seq and Sax conformations, which
M-x diastereomerization. For this purpose we have determined
the rate constant of the event in new solvents and temperatures
and elucidated, through a theoretical approach, the different
mechanisms governing the slow stage of the interconversion for
compounds L-1, L-2, and L-3, putting also in evidence the
effects played by a change of solvent. The obtained results will
be the subject of a new study, focused on mechanistic aspects.
−1
passes from 5.25 to only 2.46 kcal mol .
The whole of these results suggests therefore that specific
structural modifications can be rationally pursued in order to
modulate in a targeted way the conformational stability of
spiro-1,3,4-thiadiazoline-cyclohexyl derivatives. In particular,
starting from the essential spiro structure of sCT as the
2
reference, on increasing of the steric hindrance exercisable by a
group substituting the nitrogen atom in position 4, also the
difference of energy stability between the related Sax and Seq
cyclohexyl chair conformations progressively increases in favor
EXPERIMENTAL SECTION
■
Organic Synthesis. Chemicals, common solvents, and spectral
grade solvents were purchased and used without further purification.
Melting points (uncorrected) were determined automatically on an
of the S isomer. As a practical and impressive example of this
ax
1
13
FP62 apparatus. H and C spectra were recorded at 25 °C on a 600
effect, it may be considered the case of the couple of
MHz spectrometer using CDCl and CD OD as solvents. Chemical
3
3
(
5R*,6R*)-2-Sax enantiomers (i.e., the isomers M-2-Sax),
shifts are expressed as δ units (parts per millions) relative to the
solvent peak. Coupling constants J are valued in hertz (Hz). IR spectra
were registered on a FT-IR spectrometer. All reactions were
monitored by TLC on 0.2 mm thick silica gel plates (60 F254). Plates
were visualized by exposing them to ultraviolet (254 and 365 nm)
radiation. Silica gel 60 (70−230 mesh) was used for preparative
chromatography.
General procedure for the synthesis of 1-(cycloalkyliden)-
thiosemicarbazide derivatives: The appropriate ketone (3.4 mmol),
with catalytic amounts of acetic acid, was added to a stirring
suspension of thiosemicarbazide (0.30 g, 3.4 mmol) in 10 mL of
ethanol at 50 °C. After TLC completion of the reaction (12−24 h),
the suspension was filtered and the obtained solid washed with
petroleum ether, n-hexane, and diethyl ether. The crude product was
whose advantage in energy stability with respect to their
flipped counterparts (5R*,6R*)-2-Seq (i.e., the isomers M-2-
−1
S ) amounts to as much as 13.3 kcal mol !
eq
Thus, it appears possible, in principle, to design strictly
anancomeric thiadiazaspiro structures in which cyclohexyl
substituents endowed with steric hindrance even greater than
the t-butyl group may be thermodynamically frozen in axial
positions.
CONCLUSIONS
■
The synthesis of chiral spiro-cyclohexyl derivatives of type 1−3,
incorporating the pharmacophore 1,3,4-thiadiazoline frame-
work and made different from each other by the presence of an
alkyl group of different type or position on the cyclohexane
moiety, has been performed in good yields through an easily
accessible procedure. By the presence in each compound of two
asymmetric centers, the expected generation of four stereo-
isomers has been confirmed by enantio- and diastereoselective
HPLC resolution of the reaction mixture. A complete
assignment of the absolute configuration of all the separated
species has been accomplished. The couple of less stable
enantiomers, L-x, was found to be generated faster than their
diastereomers, so allowing their synthesis as enriched species in
the reaction mixture, by adopting conditions of kinetic control.
On the contrary, the other couple of more stable enantiomers,
M-x, could be quantitatively obtained under thermodynamic
control. The activation energy barrier that opposes the
spontaneous L-x → M-x diastereomerization has been
evaluated by classical off-column kinetic determinations in
both acetic anhydride and chloroform. DFT calculations
indicated that the greater stability of M-x geometries with
respect to those of L-x stereoisomers, as well as the capacity of
the L-x isomers to privilege the axial disposition of their alkyl
group, can be attributed to the anancomeric character
possessed by the common spiro-cyclohexyl-4-acetyl-2-acetami-
do-1,3,4-thiadiazoline framework. This suggests that, in the
future, specific structural modifications can be rationally
pursued in order to modulate in a targeted way the
conformational stability of spiro-1,3,4-thiadiazoline-cyclohexyl
derivatives by inserting a suitable substituent at the N-4
position. In consideration of the pharmacophore activity
connected to the 1,3,4-thiadiazoline framework, we believe
that all of the findings obtained in the present study may
provide solid bases to allow a rational design of new chiral
bioactive spirothiadiazolines characterized by well-defined
stereochemical structures and single anancomeric geometries.
As a further step, conceived in order to complete this study, we
have extended the kinetic investigation concerning the L-x →
purified by column chromatography (SiO , ethyl acetate/n-hexane,
2
3
:1).
General procedure for the conventional synthesis of N-(4-acetyl-6-/
7
-alkyl-1-thia-3,4-diazaspiro[4.5]dec-2-en-2-yl)acetamide (1−3): 1-(2-
Cycloalkyliden)thiosemicarbazide (1.5 mmol) was added to acetic
anhydride (7.5 mmol) at 90 °C. In order to perform kinetic control,
after 1 h the reaction mixture was poured into ice, extracted with
CHCl (3 × 50 mL), and desiccated over anhydrous sodium sulfate.
3
After evaporation under vacuum, the crude mixture was purified by
column chromatography (SiO , ethyl acetate/n-hexane 4:1). Com-
2
pound 1: 92% yield, 0.37 g. Compound 2: 71% yield, 0.33 g.
Compound 3: 87% yield, 0.35 g.
Information about the differential amounts of diastereomers
obtainable under thermodynamic control were achieved by dissolving
in acetic anhydride at 95 °C the diastereomeric mixture coming from
the reaction conducted under kinetic control, and monitoring over
time the conversion of the L-x stereoisomers in their related M-x
counterparts, until achieving conditions of equilibrium. The final
percentages of L-x and M-x species were provided by HPLC
measurements, with an associate error of 0.1%.
Chiral HPLC. HPLC enantioseparations and diastereoseparations
16
were performed by using the stainless-steel Chiralpak IC (250 mm ×
4
.6 mm i.d. and 250 mm × 10 mm i.d.) columns. All HPLC and
spectral grade solvents were used without further purification. The
analytical HPLC apparatus consisted of a pump equipped with a
Rheodyne injector, a 20 μL sample loop, a HPLC oven, and a UV/CD
detector. For semipreparative separations, a 500 μL sample loop was
used.
HRMS Experiments. The considered compounds were dissolved
−
6
in MeOH (∼10
M) and analyzed with an orbitrap mass
spectrometer set as follows: source, ESI (positive); capillary temp,
2
75 °C; spray voltage, 3.5 kV; capillary voltage 65 V; tube lens, 125 V.
Compound 1a: C H N O S requires 270.1271 (monoisotopic
12
20
3
2
+
mass), m/z found 270.1269 ([M + H] ), accuracy 0.7 ppm;
C H N O SNa requires 292.1090 (monoisotopic mass), m/z found
12
19
3
2
+
2
92.1085 ([M + Na] ), accuracy 1.7 ppm.
Compound 3a: C H N O S requires 270.1271 (monoisotopic
1
2
20
3
2
+
mass), m/z found 270.1269 ([M + H] ), accuracy 0.7 ppm;
C H N O SNa requires 292.1090 (monoisotopic mass), m/z found
12
19
3
2
+
292.1084 ([M + Na] ), accuracy 2.0 ppm.
G
DOI: 10.1021/acs.joc.5b01635
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Off-Column Studies. In off-column diastereomerization studies,
solutions of stereoisomers of 1−3 (concentration about 0.1 mg/mL)
were held at a fixed temperature in a closed vessel. The temperature
was monitored by a thermostat. Samples were withdrawn at fixed time
intervals and analyzed by HPLC on the Chiralpak IC (250 mm × 4.6
mm i.d.) column.
Polarimetry. Specific rotations were measured at 589 nm by a
polarimeter equipped with Na/Hg lamps. The volume of the cell was 1
mL, and the optical path was 10 cm. The system was set at a
temperature of 20 °C.
Circular Dichroism. The circular dichroism spectra were measured
by using a spectropolarimeter. The optical path and temperature were
set at 0.1 mm and 25 °C, respectively. The spectra are average
computed over three instrumental scans, and the intensities are
presented in terms of ellipticity values (mdeg).
M-2. H NMR (600 MHz, CD OD, Me Si): δ 1.012 (s, 9H, eq tBu-
3 4
6), 1.109 (dddd, J = 13.3 Hz, J = 13.3 Hz, J = 13.3 Hz, J = 3.1 Hz, 1H,
ax. CH -7), 1.293 (ddddd, J = 13.2 Hz, J = 13.2 Hz, J = 13.2 Hz, J = 3.6
Hz, J = 3.6 Hz, 1H, ax. CH -8), 1.551 (ddddd, J = 13.5 Hz, J = 13.5
Hz, J = 13.5 Hz, J = 3.9 Hz, J = 3.9 Hz, 1H, ax. CH -9), 1.740 (dm, J =
13.0 Hz, 1H, eq CH -8 or eq CH -9), 1.760 (dm, J = 13.0 Hz, 1H, eq
CH -8 or eq CH -9), 1.912 (dm, J = 13.0 Hz, 1H, eq CH -10), 2.008
(dm, J = 13.5 Hz, 1H, eq CH -7), 2.091 (s, 3H, CH ), 2.113 (s, 3H,
CH ), 2.898 (ddd, J = 13.4 Hz, J = 13.4 Hz, J = 4.1 Hz, 1H, ax. CH
0), 2.945 (dd, J = 12.4 Hz, J = 3.0 Hz, 1H, ax. CH-6). C NMR (150
MHz, CD OD): δ 22.7 (CH ), 25.2 (CH ), 25.2 (CH -9), 27.3 (CH -
2
2
2
2
2
2
2
2
2
3
-
2
3
1
3
1
3
3
3
2
2
8
5
(
), 29.4 (3 x CH ), 30.7 (CH -7), 35.7 (C(CH ) ), 41.9 (CH -10),
3 2 3 3 2
0.1 (CH-6), 88.9 (Cspiro), 145.3 (S−CN), 171.5 (CO), 172.1
CO). 1
L-2. H NMR (600 MHz, CD OD, Me Si): δ 1.052 (s, 9H, ax. tBu-
3
4
6
), 1.440 (m, 1H, eq CH -9), 1.513 (m, 1H, eq CH -8), 1.713 (m, 1H,
ax. CH -8), 1.780 (m, 1H, eq CH -7), 1.854 (m, 1H, ax. CH -9), 1.860
dd, J = 8.7 Hz, J = 3.7 Hz, 1H, eq CH-6), 2.036 (dm, J = 13.6 Hz, 1H,
eq CH -10), 2.087 (s, 3H, CH ), 2.155 (s, 3H, CH ), 2.220 (m, 1H,
ax. CH -7), 3.278 (ddd, J = 13.6 Hz, J = 13.0 Hz, J = 3.6 Hz, 1H, ax.
CH -10). From the H− C HSQC experiment (there are five missing
signals): C NMR (150 MHz, CD OD) δ 22.6 (CH ), 23.4 (CH -8),
Molecular Modeling Calculations. All calculations were
performed with the software package SPARTAN 10, v. 1.1.0.
Structures of ground states of spirothiadiazoline derivatives 1−3, as
well as those of models sCT −sCT , were modeled in two steps, first
2
2
2
2
2
(
2
3
3
0
3
2
performing a SCF optimization at the HF/3-21G level of theory, next
refining the obtained geometries through B3LYP/6-31G(d) calcu-
lations. In all cases, chloroform was the simulated medium, according
to the SM8 solvation model implemented in Spartan. Afterward, in
order to take into suitable account nonbonding interactions, all the
above generated ground state geometries were also submitted to single
point energy calculations performed at the higher level of theory M06-
1
13
2
13
3
3
2
2
1
3.6 (CH -9), 24.3 (CH -7), 25.3 (CH ), 30.6 (3 x CH ), 37.9 (CH -
2
2
3
3
2
0), 56.7 (CH-6).
1
M-3. H NMR (600 MHz, CD OD, Me Si): δ 0.960 (qd, J = 13.1
3
4
Hz, J = 3.9 Hz, 1H, ax. CH -8), 0.961 (d, J = 6.5 Hz, 3H, eq CH -7),
.490 (qt, J = 13.7 Hz, J = 3.5 Hz, 1H, ax. CH -9), 1.562 (m, 1H, ax.
CH-7), 1.684 (dm, J = 13.0 Hz, 1H, eq CH -8), 1.842 (dm, J = 13.9
Hz, 1H, eq CH
dm, J = 12.3 Hz, 1H, eq CH -6), 2.077 (s, 3H, CH ), 2.179 (s, 3H,
CH ), 2.640 (t, J = 12.4 Hz, 1H, ax. CH -6), 2.843 (td, 1H, ax. CH -
0). C NMR (150 MHz, CDCl ): δ 22.6 (CH -7), 22.7 (CH ), 24.6
2
3
1
2
2x/6-31+G(d), the M06-2x method being a meta-hybrid GGA DFT
2
functional known to have a very good response under dispersion
17
2
-9), 1.978 (dm, J = 13.0 Hz, 1H, eq CH -10), 2.000
2
forces.
(
2
3
NMR Spectroscopy. Samples M-1 and L-1 were dissolved in
3
2
2
CDCl (700 μL) whereas samples M-2, L-2, M-3, and L-3 in CD OD
13
3
3
1
(
4
(
3 3 3
(
700 μL). NMR spectra were recorded at 300 K on a spectrometer
CH ), 25.3 (CH -9), 33.0 (CH-7), 34.5 (CH -8), 36.4 (CH -10),
3 2 2 2
operating at 600.13 MHz and equipped with a multinuclear z-gradient
inverse probe head capable of producing gradients in the z direction
5.3 (CH -6), 85.8 (Cspiro), 145.5 (S−CN), 171.4 (CO), 171.9
2
−
1
1
1
with a strength of 55 G cm . 2D NMR experiments, namely, H− H
CO). 1
L-3. H NMR (600 MHz, CD OD, Me Si): δ 1.098 (d, J = 7.5 Hz,
1
13
3
4
COSY and H− C HSQC, have been acquired using a time domain
of 1024 data points in the F2 dimension and 512 data points in the F1
3
H, ax. CH -7), 1.420 (dm, J = 13.0 Hz, 1H, eq CH -8), 1.607 (m, 1H,
ax. CH -8), 1.680 (m, 2H, ax. and eq CH -9), 1.920 (dm, J = 13.9 Hz,
H, eq CH -6), 1.963 (dm, J = 13.2 Hz, 1H, eq CH -10), 2.077 (s, 3H,
3
2
2
2
dimension, and the recycle delay was 2 s. The HSQC experiments
1
2
2
1
were performed using a coupling constant J
of 150 Hz. The
C−H
CH ), 2.187 (s, 3H, CH ), 2.243 (m, 1H, eq CH-7), 2.772 (dm, J =
3
3
number of scans has been optimized for obtaining a good signal/noise
1
3.2 Hz, 1H, ax. CH -10), 3.395 (dd, J = 13.9 Hz, J = 5.9 Hz, 1H, ax.
2
CH -6). C NMR (150 MHz, CDCl ): δ 19.8 (CH -9), 20.4 (CH -
7), 22.7 (CH ), 25.0 (CH ), 29.5 (CH-7), 31.2 (CH -8), 37.0 (CH -
0), 41.7 (CH -6), 83.5 (Cspiro), 146.3 (S−CN), 171.5 (CO), 172.1
1
ratio. H NMR spectra were referenced with respect to the residual
13
2
3
2
3
proton signal of CDCl and CD OD at 7.26 and 3.31 ppm,
3
3
3 3 2 2
18
respectively.
1
2
1
M-1. H NMR (600 MHz, CDCl , Me Si): δ 0.937 (d, J = 6.5 Hz,
3
4
(CO).
3
3
1
H, eq CH -6), 1.072 (dddd, J = 13.2 Hz, J = 13.1 Hz, J = 13.1 Hz, J =
3
X-ray Diffraction Data. Cu Kα radiation (40 mA/−40 kV) was
used for cell parameter determination. The integrated intensities,
measured using the ω scan mode, were corrected for Lorentz and
polarization effects.
Direct methods of SIR2004 were used in solving the structures,
and they were refined using the full-matrix least-squares on F2
provided by SHELXL97.
Multiscan symmetry-related measurement was used as experimental
absorption correction type. The non-hydrogen atoms were refined
anisotropically whereas hydrogen atoms were refined as isotropic.
The X-ray CIF files for these structures have been deposited at the
Cambridge Crystallographic Data Center and allocated with the
deposition numbers CCDC 866489 for 1d, CCDC 866490 for 3c,
CCDC 1062909 for 2b, and CCDC 1062910 for 2c. Copies of the
data can be obtained, free of charge, from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ
U.K., via www.ccdc.cam.ac.uk/data_request/cif.
.4 Hz, 1H, ax. CH -7), 1.339 (ddddd, J = 13.1 Hz, J = 13.1 Hz, J =
2
3.1 Hz, J = 3.6 Hz, J = 3.6 Hz, 1H, ax. CH -8), 1.442 (ddddd, J = 13.3
2
1
9
Hz, J = 13.3 Hz, J = 13.3 Hz, J = 3.5 Hz, J = 3.5 Hz, 1H, ax. CH -9),
2
2
0
1
.628 (dm, J = 13.2 Hz, 1H, eq CH -8), 1.686 (dm, J = 13.2 Hz, 1H,
2
eq CH -7), 1.807 (dm, J = 13.2 Hz, 1H, eq CH -9), 2.125 (dm, J =
2
2
2
1
1
2
3
3.2 Hz, 1H, eq CH -10), 2.174 (s, 3H, CH ), 2.183 (s, 3H, CH ),
2
3
3
.930 (ddd, J = 13.2 Hz, J = 13.2 Hz, J = 4.0 Hz, 1H, ax. CH -10),
2
.007 (qdd, J = 6.5 Hz, J = 13.1 Hz, J = 3.2 Hz, 1H, ax. CH-6), 8.350
(
(
(
s, 1H, NH). 13C NMR (150 MHz, CDCl ): δ 16.7 (CH -6), 23.6
3 3
CH ), 24.6 (CH ), 24.8 (CH -9), 25.2 (CH -8), 32.9 (CH -7), 37.0
CH-6), 37.4 (CH -10), 91.4 (Cspiro), 143.2 (S−CN), 168.3 (CO),
3
3
2
2
2
2
169.7 (CO).
1
L-1. H NMR (600 MHz, CDCl , Me Si): δ 1.100 (d, J = 7.0 Hz,
3
4
3
H, ax. CH -6), 1.278 (ddddd, J = 13.5 Hz, J = 13.5 Hz, J = 13.5 Hz, J
3
=
3.8 Hz, J = 3.8 Hz, 1H, ax. CH -9), 1.480 (m, 1H, eq CH -8), 1.528
2
2
(
m, 1H, eq CH -7), 1.540 (m, 1H, ax. CH -8), 1.957 (dm, J = 13.7 Hz,
2
2
Details about crystal data for compounds 1d, 2b, 2c and 3c are
given in Supporting Information.
1
4
2
3
7
1
3
H, eq CH -9), 2.028 (dddd, J = 14.0 Hz, J = 14.0 Hz, J = 4.3 Hz, J =
2
.3 Hz, 1H, ax. CH -7), 2.135 (dm, J = 13.9 Hz, 1H, eq CH -10),
2
2
.185 (s, 3H, CH ), 2.202 (s, 3H, CH ), 2.300 (m, 1H, eq CH-6),
3
3
.550 (ddd, J = 13.5 Hz, J = 13.5 Hz, J = 4.1 Hz, 1H, ax. CH -10),
2
ASSOCIATED CONTENT
.970 (s, 1H, NH). 13C NMR (150 MHz, CDCl ): δ 16.0 (CH -6),
■
3
3
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01635.
9.8 (CH -8), 23.7 (CH ), 24.8 (CH ), 27.3 (CH -9), 29.7 (CH -7),
2
3
3
2
2
1.8 (CH -10), 41.8 (CH-6), 89.5 (Cspiro), 146.1 (S−CN), 167.9
2
(
CO), 170.8 (CO).
H
DOI: 10.1021/acs.joc.5b01635
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Experimental and characterization details (PDF)
X-ray crystallogrpahic data (CIF)
(15) (a) Anteunis, M.; Tavernier, D.; Borremans, F. Bull. Soc. Chim.
Belg. 1966, 75, 396. (b) Pihlaja, K. J. Chem. Soc., Perkin Trans. 2 1974,
8
1
90−896. (c) Booth, H.; Everett, J. R. J. Chem. Soc., Perkin Trans. 2
980, 255−259.
AUTHOR INFORMATION
(16) (a) Benincori, T.; Bonometti, V.; Cirilli, R.; Mussini, P. R.;
■
Corresponding Authors
̀
Marchesi, A.; Pierini, M.; Pilati, T.; Rizzo, S.; Sannicolo, F. Chem. - Eur.
J. 2013, 19, 165−181. (b) Gallinella, B.; Bucciarelli, L.; Zanitti, L.;
Ferretti, R.; Cirilli, R. J. Chromatogr. A 2014, 1339, 210−213.
*roberto.cirilli@iss.it
*marco.pierini@uniroma1.it
(c) Ferretti, R.; Gallinella, B.; La Torre, F.; Zanitti, L.; Turchetto, L.;
Author Contributions
Sergio Menta and Simone Carradori contributed equally to this
work.
Mosca, A.; Cirilli, R. J. Chromatogr. A 2009, 1216, 5385−5390.
d) Zhang, T.; Nguyen, D.; Franco, P.; Isobe, Y.; Michishita, T.;
Murakami, T. J. Pharm. Biomed. Anal. 2008, 46, 882−891.
17) (a) Tishchenko, O.; Truhlar, D. G. J. Phys. Chem. Lett. 2012, 3,
(
(
Notes
2834. (b) Hermans, I.; Jacobs, P.; Peeters, J. Phys. Chem. Chem. Phys.
2008, 10, 1125. (c) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008,
120, 215. (d) Bernini, R.; Crisante, F.; Gentili, P.; Menta, S.; Morana,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
F.; Pierini, M. RSC Adv. 2014, 4, 8183.
This work was conducted with financial support from the
Sapienza University Contract No. C26A143MYA (2014) and
MIUR (PRIN 2010-11, prot. 2010N3T9M4).
(18) Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and more basic NMR
experiments: a practical course; Wiley-VCH: Weinheim, Germany,
1998.
(
19) Walker, N.; Stuart, D. Acta Crystallogr., Sect. A: Found.
Crystallogr. 1983, 39, 158−166.
20) Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.;
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DOI: 10.1021/acs.joc.5b01635
J. Org. Chem. XXXX, XXX, XXX−XXX