Synthesis, Mechanism Elucidation and Biological Insights of Tellurium(IV)-Containing Heterocycles

Article abstract of DOI:10.1002/chem.202102287

Inspired by the synthetic and biological potential of organotellurium substances, a series of five- and six-membered ring organotelluranes containing a Te?O bond were synthesized and characterized. Theoretical calculations elucidated the mechanism for the oxidation-cyclization processes involved in the formation of the heterocycles, consistent with chlorine transfer to hydroxy telluride, followed by a cyclization step with simultaneous formation of the new Te?O bond and deprotonation of the OH group. Moreover, theoretical calculations also indicated anti-diastereoisomers to be major products for two chirality center–containing compounds. Antileishmanial assays against Leishmania amazonensis promastigotes disclosed 1,2λ⁴-oxatellurane LQ50 (IC₅₀=4.1±1.0; SI=12), 1,2λ⁴-oxatellurolane LQ04 (IC₅₀=7.0±1.3; SI=7) and 1,2λ⁴-benzoxatellurole LQ56 (IC₅₀=5.7±0.3; SI=6) as more powerful and more selective compounds than the reference, being up to four times more active. A stability study supported by ¹²⁵Te NMR analyses showed that these heterocycles do not suffer structural modifications in aqueous-organic media or at temperatures up to 65 °C.

Full text of DOI:10.1002/chem.202102287

Accepted Article
Accepted Article
Title: Synthesis, Mechanism Elucidation and Biological Insights of
Tellurium(IV)-containing Heterocycles
Authors: Leandro Piovan, João Pedro A. Souza, Pamela T. Bandeira,
Leociley R. A. Menezes, Mateus B. Bespalhok, Débora B.
Scariot, Francielle P. Garcia, Siddhartha O. K. Giese, David L.
Hughes, Celso V. Nakamura, Andersson Barison, Alfredo R.
M. Oliveira, and Renan B. Campos
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202102287
Link to VoR: https://doi.org/10.1002/chem.202102287
01/2020

10.1002/chem.202102287
Chemistry - A European Journal
RESEARCH ARTICLE
Synthesis, Mechanism Elucidation and Biological Insights of
Tellurium(IV)-Containing Heterocycles
João Pedro A. Souza,[a] Leociley R. A. Menezes,[a] Francielle P. Garcia,[b] Dꢀbora B. Scariot,[b] Pamela
T. Bandeira,[a] Mateus B. Bespalhok,[a] Siddhartha O. K. Giese,[a] David L. Hughes,[c] Celso V.
Nakamura,[b] Andersson Barison,[a] Alfredo R. M. Oliveira,[a] Renan B. Campos,*[d]and Leandro Piovan*[a]
[a]
J. P. A. Souza, Dr. P. T. Bandeira, Dr. L. R. A. Menezes, M. B. Bespalhok, Dr. S. O. K. Giese, Prof. Dr. A. Barison, Prof. Dr. A. R. M. Oliveira, Prof. Dr. L.
Piovan
Department of Chemistry, Universidade Federal do Paraná, Curitiba-PR, 81.931-480, Brazil
E-mail: lpiovan@ufpr.br
[b]
[c]
[d]
Dr. D. B. Scariot, Dr. F. P. Garcia, Prof. Dr C. V. Nakamura
Health Sciences Center, Universidade Estadual de Maringá, Maringá-PR, 87.020-900, Brazil
Dr. D. L. Hughes
School of Chemistry, University of East Anglia, Norwich NR4 7TJ, United Kingdom
Prof. Dr. R. B. Campos
Academic Department of Chemistry and Biology, Universidade Tecnológica Federal do Paraná, Curitiba-PR, 81.280-340, Brazil
E-mail: renan@utfpr.edu.br
Supporting information for this article is given via a link at the end of the document.
Abstract: Inspired by the synthetic and biological potential of
inflammatory,[7] antitumoral[8] and enzymatic inhibitors.[9]
Additionally, this element has been used for several applications
in organic and inorganic chemistry, like materials and medicinal
fields.[1,10]
As well established, tetra- and hexa-valent tellurium-containing
compounds (Te(IV) and Te(VI)) are exceptions to the Lewis octet
rule,[11] being classified as hypervalent compounds.[12] Such
hypervalent derivatives present great potential for biological
purposes.[13] For decades, numerous studies revealed that the
inorganic tellurane AS101 (Figure 1) is a potent inhibitor of the
cysteine proteases such as papain and cathepsin B.[9a,14] From
then on, several organic and inorganic hypervalent tellurium
organotellurium substances, we describe here the synthesis and
characterization of
a series of five- and six-membered ring
organotelluranes containing a Te–O bond. Theoretical calculations
elucidated the mechanism for the oxidation-cyclization processes
involved in the formation of the heterocycles, consistent with chlorine
transfer to hydroxy telluride, followed by cyclization step with
simultaneous formation of the new Te–O bond and the OH group
deprotonation. Moreover, theoretical calculations also indicated anti-
diastereoisomers as major products for two-chirality center-containing
compounds.
Antileishmanial
assays
against
Leishmania
amazonensis promastigotes disclosed 1,2λ4-oxatellurane LQ50 (IC50
= 4.1±1.0; SI = 12), 1,2λ4-oxatellurolane LQ04 (IC50 = 7.0±1.3; SI = 7)
and 1,2λ4-benzoxatellurole LQ56 (IC50 = 5.7±0.3; SI = 6) as more
powerful and more selective compounds, up to four times more active
than the reference. Stability study supported by 125Te NMR analyses
showed that these heterocycles do not suffer structural modifications
in aqueous-organic media and up to 65 °C.
compounds were reported as successful enzyme inhibitors,
9b-c, 15]
including cysteine,[6g,
and threonine proteases (20S
proteasome),[9h] and tyrosine phosphatases (PTP1B and
YopH),[9f] also indicated as promising antioxidants,[4d]
antimicrobial[6c,e, 16] and antitumor agents.[8j]
Another important example of a biologically active tellurium-
containing compound is the organotellurane RT-01 (Figure 1),
which presented in vivo antiprotozoal activity against Leishmania
amazonensis, leading to significant decrease of the parasitic load
compared to that of the reference drug.[17] Another
organotellurane, RF07 (Figure 1), was described as a powerful
leishmanicidal agent for Leishmania chagasi amastigotes with
selectivity index (SI = CC50/IC50) of 10, relating the specificity of
the activity in comparison to the cytotoxicity of the evaluated
compound.[18] This compound was previously described as a
cysteine protease cathepsin B inhibitor,[9b] and its antileishmanial
activity has been associated with inhibition of this enzyme in L.
chagasi protozoa. It is worth mentioning that the inorganic
tellurane AS101 (Figure 1) also presented antileishmanial activity,
Introduction
Tellurium is the only natural chalcogen with no apparent role in
vital biological processes. Tellurium toxicity for humans still
remains poorly understood, as its biological role is probably less
known than metals like osmium and ruthenium.[1] Some of the few
reports address the use of tellurium for the synthesis of amino
acids and proteins in fungi and bacteria.[2] Despite the presence
of tellurium in living organisms occurring only in exceptional cases,
synthetic tellurium-containing compounds have been applied in
biological systems[3] and reported as promising antioxidant
with IC50
=
26.9 μmol L-1 for Leishmania donovani
agents,[4]
immunomodulator,[5]
antimicrobial,[6]
anti-
promastigotes.[14f]
1
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10.1002/chem.202102287
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Figure 1. Chemical structures and antileishmanial activities of hypervalent tellurium compounds.
Hypervalent five- and six-membered Te–O bond-containing
heterocycles have already been described in the literature;[19]
however, their biological properties remain poorly explored. Then,
inspired by the potential of hypervalent tellurium compounds, in
the current work we discuss: i) the synthesis of a series of five-
(1,2λ4-oxatellurolanes and 1,2λ4-benzoxatelluroles) and six-
(1,2λ4-oxatelluranes) membered ring organotelluranes; ii)
calculations using Density Functional Theory (DFT), performed to
identify the most favorable mechanism and to rationalize the
diastereoselectivity observed for two-chirality center-containing
compounds; iii) the in vitro antileishmanial potential of all
hypervalent Te(IV)-containing compounds, evaluated against L.
amazonensis promastigotes; and iv) stability assays supported by
125Te NMR (thermal stability and chemical stability in aqueous-
organic media) for some representative hypervalent Te(IV)-
containing compounds.
tellurides 3g-h led to 1,2λ4-oxatellurolanes LQ51-53 in 30-79%
isolated yields (Scheme 2).
Hydrolysis of the acetal moiety of 3e led the hydroxy telluro ketone
3i (90% isolated yield), which was applied as an intermediate for
the hydroxy telluro oxime 3j (82% isolated yield). One-pot
sequential oxidation-cyclization sequential using NCS led to the
1,2λ4-oxatellurolanes LQ54 and LQ55 in 30 and 24% isolated
yields, respectively (Scheme 3).
2,5-Dihydro-1,2λ4-benzoxatelluroles LQ56 and LQ57 were
prepared in 30 and 24% isolated yield, respectively, employing
the same oxidation-cyclization approach with NBS or NCS from
benzyl hydroxy telluride 3k (Scheme 4).
All hypervalent Te-containing heterocycles (LQ02-04, LQ33-35
and LQ48-57) were purified by precipitation in H2O/Dimethyl
sulfoxide (10:1 v/v) followed by second precipitation in
hexane/CH2Cl2 (10:1 v/v), and were obtained as odorless white
solids with good solubility in organic solvents such as
dichloromethane, acetone, tetrahydrofuran, and dimethyl
sulfoxide. Eleven chlorinated and five brominated compounds
(thirteen unpublished) were obtained in 2−79% isolated yields in
the oxidation-cyclization step and overall yields ranging from
0.4% (LQ35) to 40% (LQ52). Structural characterizations were
Results and Discussion
Synthesis of Tellurium(IV)-Containing Heterocycles
The synthetic routes to access 1,2λ4-oxatellurolanes and 1,2λ4-
oxatelluranes were performed as shown in Scheme 1.
Bromobenzene (1a) or 4-substituted aryl bromides (1b-e) were
reacted with elemental magnesium, followed by the addition of
elemental tellurium and later air oxidation, leading to diaryl
ditellurides 2a-e in 27-65% isolated yields. The Te–Te bonds from
ditellurides 2a-e were cleaved employing sodium borohydride and
their respective tellurolates were captured by 3-chloropropan-1-ol
to produce hydroxy tellurides 3a-e or by 4-bromobutan-1-ol
leading to hydroxy telluride 3f. Finally, one-pot oxidation-
cyclization sequential reactions of 3a-f employing N-
chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) led to
corresponding 1,2λ4-oxatellurolanes (LQ02-04, 33-35 and 48) in
2-79% isolated yields and 1,2λ4-oxatelluranes (LQ49-50) in 5-
15% isolated yields (Scheme 1).
1
performed by melting point determination, H Nuclear Magnetic
Resonance spectroscopy (NMR), 13C NMR, 125Te NMR, Fourier-
transform infrared (FTIR) spectroscopy, and single-crystal X-ray
diffraction (if applicable).
Structural Characterization by NMR
Rotational restriction and a slightly bent conformation of the five-
membered rings in 1,2λ4-oxatellurolane forced the geminal
methylene hydrogens to assume pseudo-axial and pseudo-
equatorial positions. Furthermore, tetrasubstituted Te-atom is a
chirality center and the methylene hydrogens in the heterocycles
are diastereotopic. These structural features are easily observed
in three-dimensional projections (Figure 2a, b) and NMR data of
representative 1,2λ4-oxatellurolanes LQ02 (Figure 2c) and LQ03
(Figure 2d). Geminal methylene hydrogens presented distinct
signals that confirm the heterocyclization as can be seen in
correlation maps in Figure 2c and 2d. The multiplicity of
hydrogens at position 1 revealed the geminal coupling between
them (J = 10.0 Hz) and vicinal couplings with the hydrogens at
position 2 (J = 5.8, 4.0 and 3.4 Hz). The same pattern of
multiplicity was observed for hydrogens at position 3, with geminal
5-Methyl- (LQ51 and LQ52) and 5-phenyl-substituted 1,2λ4-
oxatellurolanes (LQ53) were prepared by a 1,4-addition of phenyl
tellurolate (from Te–Te bond cleavage of 2a with NaBH4) to but-
3-en-2-one or 1-phenylprop-2-en-1-one, followed by in situ
carbonyl reduction with NaBH4. In the sequence, NCS or NBS
mediated oxidation-cyclization sequential reactions of hydroxy
2
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Scheme 1. Synthesis of 1,2λ4-oxatellurolanes LQ02-04, 33-35 and 48 and 1,2λ4-oxatelluranes LQ49-50. Reagents and Conditions: i. 1. Mg0, I2, tetrahydrofuran, r.t.,
2 h; 2. Te0, 2 h; 3. O2, 15 min. ii. 3-chloropropan-1-ol or 4-bromobutan-1-ol, NaBH4, H2O/EtOH, 0 °C-r.t., 1 h. iii. NCS or NBS, CH2Cl2, 0 °C-r.t., 30 min.
Scheme 2. Synthesis of 1,2λ4-oxatellurolanes LQ51-53. Reagents and Conditions: i. 1. NaBH4, H2O/EtOH, 0 °C, 5 min. 2. α,β-unsaturated ketone, 0 °C-r.t., 1 h; 3.
NaBH4, 0 °C-r.t., 15 min. ii. NCS or NBS, CH2Cl2, 0°C-r.t., 30 min.
Scheme 3. 2-Methyl-1,3-dioxolan-2-yl group derivatization for the synthesis of 1,2λ4-oxatellurolanes LQ54 and LQ55. Reagents and Conditions: i. p-toluenesulfonic
acid (pTSA), acetone, reflux, 2 h. ii. (NH3OH)Cl, AcONa, MeOH, reflux, 2 h. iii. NCS, CH2Cl2, 0 °C-r.t., 30 min.
Scheme 4. Synthesis of 1,2λ4-benzoxatelluroles (LQ56 and LQ57). Reagents and Conditions: i. 1. BuLi, THF, -78 °C, 30 min; 2. (BuTe)2, r.t., 4 h. ii. NCS or NBS,
CH2Cl2, 0 °C-r.t., 30 min.
(J = 12.1 Hz) and vicinal couplings (J = 10.6, 8.2, 7.1 and 3.7 Hz).
Thereby, the hydrogens on position 2 showed a complex signal
composed by their geminal coupling and four more couplings with
close J values. The most deshielding hydrogens (at 2.14, 3.70
and 4.75 ppm) occupy pseudo-axial positions for this
conformation while the most shielding hydrogens (at 1.90, 3.47
and 3.68 ppm) occupy pseudo-equatorial positions. The chemical
shifts, multiplicity, and J values for LQ 02 are detailed in Figure
2e.
13C{1H} NMR spectra comparison of starting material (3a) and
product (LQ02) disclosed significant changes in chemical shifts,
mainly for the carbons directly attached to the tellurium atom.
Chemical shifts of aliphatic and aromatic carbon atoms (positions
3
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Figure 2. Three-dimensional structure of 1,2λ4-oxatellurolane LQ02 (a) and LQ03 (b; atom-color: Te-yellow, O-red, Cl-green, Br-dark red, C-gray, H-white.), 1H-13
HSQC correlation maps for LQ02 (c) and LQ03 (d) and chemical shift on 1H (blue), 13C (red) and 125Te (green) NMR analyses for LQ02 (e).
C
Figure 3. 125Te NMR spectrum (126.24 MHz, CDCl3, PhTeTePh (δ = 422)) of 1,2λ4-oxatellurolane LQ51.
3 and 4) changed from 5.1 and 109.4 ppm to 43.2 and 128.1 ppm,
respectively, after oxidation of hydroxy telluride 3a to LQ02 (See
Supporting Information). The most significant difference of
chemical shift after the oxidation step was observed in 125Te NMR
analyses, in which the chemical shift varied from 473 ppm (3a) to
1090 ppm (LQ02).
Formation of diastereoisomers for two-chirality center-containing
compounds was confirmed by the presence of two signals in 125Te
NMR spectra, as exemplified by LQ51 spectrum in Figure 3. The
difference in intensity between those signals demonstrated some
degree of diatereoselectivity during the cyclization step. Signals
at δ = 1101 and δ = 1105 are in accordance with chemical shifts
obtained for the other synthesized tellurium(IV)-containing
heterocycles and indicate that one of diastereoisomers (syn-
LQ51 or anti-LQ51) was preferentially formed.
LQ02 (Figure 4a) and LQ51 (Figure 4c) presented two
independent molecules, which are enantiomers, in their crystals,
and LQ49 (Figure 4b) and LQ56 (Figure 4d) are in
centrosymmetric space groups and these crystals therefore
contain both enantiomers too. Selected bons and crystallographic
data are listed in Tables 1 and 2. The structures revealed that all
the compounds adopted a seesaw-molecular geometry about the
20]
Te atom, typical for the hypervalent center of Te(IV).[19c,
Hypervalent O–Te–Cl bonding presented average 2.00 and 2.66
Å lengths for Te–O (Te1–O1 and Te2–O2, entries 1 and 2, Table
1) and Te–Cl (Te1–Cl1 and Te2–Cl2, entries 3 and 4) with an
average 170° angle (O1–Te1– Cl1 and O2–Te2–Cl2, entries 9
and 10). Te–C bonds at the equatorial positions had an average
2.13 Å length (entries 5-8) and an average 96° angle for C–Te–C
(entries 11 and 12). The chelating angles, between axial and
equatorial positions of type O–Te–C (O1–Te1–C10 and O2–Te2–
C20, entries 13 and 14, Table 1) presented an average of 98°
angle.
Single-crystal X-ray Crystallography
Single-crystal X-ray diffraction analysis for representative
compounds confirmed the cyclization products (Figure 4). Both
4
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Figure 4. ORTEP[21] representation of LQ02 (a), LQ49 (b), LQ51 (c) and LQ56 (d). Thermal ellipsoids are drawn at the 50% probability level.
Atom-color: Te-yellow, O-red, Cl-green, C- blue, H-white.
Table 1. Selected Bond Lengths (Å) and Angles (°) for organotelluranes LQ02, LQ49, LQ51, and LQ56.
Entry
Compound
LQ02[a]
LQ49
LQ51[a]
LQ56
Bond Lengths Lengths (Å)
1
2
3
4
5
6
7
8
Te1–O1
Te2–O2
Te1–Cl1
Te2–Cl2
Te1–C10
Te2–C20
Te1–C14
Te2–C24
2.011(4)
2.000(5)
2.642(2)
2.6811(14)
2.136(5)
2.144(7)
2.132(7)
2.130(7)
1.983(2)
1.995(4)
1.993(4)
2.653(2)
2.664(2)
2.129(5)
2.118(5)
2.134(5)
2.120(6)
2.009(3)
-
-
2.6752(9)
2.6353(11)
-
-
2.134(3)
2.140(4)
-
-
2.126(3)
-
2.111(4)
-
Angles (°)
9
O1–Te1–Cl1
O2–Te2–Cl2
C10–Te1–C14
C20–Te2–C24
O1–Te1–C10
O2–Te2–C20
170.16(14)
165.5(2)
94.8(3)
175.68(8)
168.55(11)
169.02(11)
96.2(2)
170.70(10)
10
11
12
13
14
-
-
96.12(13)
98.2(2)
95.5(3)
-
95.6(2)
-
84.5(2)
91.91(13)
-
83.6(2)
91.5(2)
-
83.5(2)
84.2(2)
[a] There are two independent molecules (enantiomers) in the crystal.
5
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Table 2. Crystal and structure refinement data for organotellurane LQ02, LQ49, LQ51, and LQ56.
LQ02
C9H11ClOTe
298.23
173(2)
LQ49
LQ51
C10H13ClOTe
312.25
302(2)
LQ56
C11H15ClOTe
326.28
Empirical formula
Molecular weight (g mol-1)
Temperature (K)
Crystal system
Space group
a (Å)
C10H13ClOTe
312.25
301(2)
200(2)
Orthorhombic
Pca21
Orthorhombic
Pbca
Orthorhombic
Pna21
Monoclinic
P21/c
8.6680(4)
9.7474(5)
23.1440(11)
90
10.4460(4)
9.0554(4)
23.4543(11)
90
13.3710(6)
16.9537(9)
10.0889(6)
90
8.4594(6)
16.8778(12)
8.7897(6)
108.582(2)
1189.54(15)
4
b (Å)
c (Å)
β (°)
V (ų)
1955.45(16)
8
2218.61(17)
8
2287.0(2)
8
Z
µ (mm-1)
26.126
74.979
136558
4020
2.882
2.796
21.535
θmax
27.498
170329
2543
27.500
150955
5227
74.957
Reflections collected
Independent reflections
Rint
70700
2447
0.084
0.051
0.046
0.076
Reflections with I > 2σI
R1 (I > 2σI)*
3909
2245
4742
2387
0.026
0.027
0.021
0.033
wR2 (I > 2σI)*
R1 all data[a]
0.066
0.063
0.048
0.093
0.026
0.033
0.027
0.034
wR2 all data[a]
Goodness-of-fit on F2
Largest diff. peak and hole (e Å-3)
0.067
0.065
0.050
0.093
1.057
1.154
1.066
1.087
1.28, -0.60
0.92, -0.81
0.52, -0.40
2.05, -0.81
[a] As defined by the SHELXL program.[22]
Mechanistic Studies
a 28.7 kcal mol-1 n(O)  σ*(Te–Cl) interaction, indicating a
chalcogen bonding of 2.39 Å[23]. Results also suggest a highly
structural resemblance between protonated intermediate (I) and
the final product LQ02. In fact, the O–H bond is responsible for
preventing the formation of LQ02, as revealed by comparing
Te···O and Te–Cl distances and bond lengths: Te–Cl bond
increases 0.26 Å from I to LQ02, whereas the Te···O distance
was shortened by 0.37 Å after deprotonation, which suggests the
formation of a new O–Te–Cl hypervalent bond.
Then we turned our attention to the cyclization step. After several
attempts, TSS (TSS2) was located. IRC calculations suggest a
complex intermediate (I’) in the reverse direction, formed by
coordination of oxygen atom of succinimide ion (NS-) to tellurium
atom of I (Figure 5 and 6). Since complex I is not conformationally
appropriate for the formation of I’, it is likely that that another NS-
anion could be involved in the formation of the latter (coming from
reaction occurring nearby), not necessarily the leaving group
formed in the oxidation step. After the release of NS-, the
To further investigate the oxidation-cyclization step for the
tellurium-containing heterocycles formation (Scheme 1, step iii), a
mechanistic study employing DFT calculations was performed for
LQ02 (see Experimental Section in Supporting Information for
computational details). First, the transition state structure (TSS)
involved in the oxidation step (TSS1) was located, consistent with
the chlorine atom transfer from NCS to the Te atom of hydroxy
telluride 3a forming a new Te–Cl bond with a low energy barrier
(4.9 kcal mol-1), as shown in Figure 5.
Intrinsic reaction coordinate (IRC) calculations indicated that the
Te–Cl bond is 69% formed at the TSS1 as observed in Figure 6.
Moreover, results suggest significant changing of the Cl–Te···O
angle along this step — ranging from 137° at the reactants to 165°
when intermediate is formed (Figure 6) — which was attributed to
the formation of strong Te···O interaction. Natural Bond Orbitals
(NBO) calculations confirmed this hypothesis, revealing electron
density donation from oxygen atom to tellurium atom resulting in
6
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Figure 5. Potential energy surface (PES) of oxidation-cyclization step of the tellurium-containing heterocycles formation obtained using M062X functional combined
with LANL2DZ (for Te atom) and 6-311++G(d,p) (for additional atoms). Atom-color: Te-yellow, O-red, Cl-green, N-blue, C-gray, H-white.
Figure 6. Optimized TSS1 and TSS2 IRC plot obtained with M062X combined with LANL2DZ (Te) and 6-311++G(d,p) basis sets.
makes it a great electrophile. Energy barrier of 8.3 kcal mol-1 to
reach TSS2 from I’ was observed. Calculations revealed a
concerted cyclization step involving the formation of the Te–O
bond in LQ02 and the proton transfer from hydroxyl group to the
nitrogen atom of NS-, with elimination of succinimide (NHS). The
complete mechanistic proposal is presented in Figure 7. IRC plot
presented in Figure 6 indicates that 48% of the Te–O bond was
formed at the TSS2 whereas 25% of the Te–O…NS- interaction
was broken, consistent with a highly asynchronous pathway. This
is also supported by the proton transfer of the O–H group to the
NS- anion, which is only 2% completed at the TSS2. Uniform Te–
Cl bond elongation along reaction pathway was also observed.
Figure 7. Proposed mechanism for the formation of LQ02.
The formation of the N–H bond is the last critical event of the
cyclization process, finally releasing the products. The oxidation
formation of I’ is likely to occur in a barrierless process, since a
chalcogen interaction (HO…Te) in I is replaced by a Te–O
covalent bond and an OH…N hydrogen bonding or, in other words,
a very energetically favorable formation of I’ should be expected.
Moreover, complex I features a positive tellurium center, which
process was found as the rate-determining step and the low
barrier of 4.9 kcal mol-1 is consistent with the reaction occurring at
0 °C.
Explaining the diastereoselectivity in LQ51 formation
7
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RESEARCH ARTICLE
Figure 8. PES of oxidation-cyclization step of the anti-LQ51 and syn-LQ51 formation obtained using M062X and single points using ωB97X-D (in parentheses)
functional combined with LANL2DZ (for Te atom) and 6-311++G(d,p) (for additional atoms). Atom-color: Te-yellow, O-red, Cl-green, N-blue, C-gray, H-white.
1,2λ4-oxatellurolane LQ51 is a two-chirality center-containing
compound, so a pair of diastereoisomers is also expected in its
preparation. Indeed, the two signals were observed in 125Te NMR
spectra of LQ51 at 1101 and 1105 ppm (Figure 3) indicating a
highly degree of diastereoselectivity. A 1:4 ratio between
diastereoisomers was determined using the relative areas of
some equivalent signs at 2.34 and 2.39, 3.50 and 3.61 and 8.16
and 8.21 ppm in the 1H NMR spectrum (600.13 MHz, CDCl3,
TMS) (see on Figures S88-91 in Supporting Information).
Supported by this experimentally observed selectivity and the
failure to assign NMR signals to diastereoisomer groups, a
mechanistic study employing DFT calculations were also carried
out to rationalize the diastereoselectivity and identify the
diastereoisomers preferably formed (syn-LQ51 or anti-LQ51,
Figure 3).
TSSs for the oxidation (TSS1) and the cyclization steps (TSS2)
were located for each diastereoisomer (syn-LQ51 or anti-LQ51)
as shown in Figure 8. Similar Potential energy surface (PES) and
TSSs were obtained for both diastereoisomers of LQ51 compared
to LQ02 (vide supra). For the oxidation step involved in the
formation of anti-LQ51, calculations revealed an energy barrier of
4.2 kcal mol-1, which is 2.0 kcal mol-1 lower that that observed for
the diastereoisomer syn-LQ51 (Figure 8). Such significant
difference in the rate determinant step of the reactions
corroborates the preferential formation of one of the
diastereoisomers, as indicated by NMR analyses. Single point
energy calculations using ωB97X-D[24] were also performed for
the stationary points involved in the rate determinant step and
similar results were observed. Thus, based on theoretical
calculations, anti-LQ51 corresponds to the major diastereoisomer
formed and observed experimentally in the 125Te NMR spectra at
1101 ppm, while the syn-LQ51 is the minor diastereoisomer with
signal at 1105 ppm.
Antiprotozoal
Heterocycles
Activity
of
Tellurium
(IV)-containing
Hypervalent Te-containing LQ02-04, LQ33-35, and LQ48-57
were submitted to in vitro assays against Leishmania
amazonensis promastigotes, and miltefosine was used as the
positive control (Table 3). Antileishmanial activities were
expressed as IC50 values - the inhibitory concentration able to
cause the death of 50% of the parasites in relation to the negative
control (non-treated infected cells) - and the cytotoxic of the
compounds were expressed as CC50 - the concentration able to
kill 50% of the cells (J774A1 macrophages) in relation to the
untreated cell control. The selectivity indexes (SI) were
determined as the ratio between the CC50 in macrophages and
the corresponding IC50 value in promastigotes, allowing to
determine how many times the assayed compound was more
selective against the protozoa than to the mammalian host
cell(macrophages).
1,4-Substituted 1,2λ4-oxatellurolanes showed higher activity and
selective (expressed by SI) in comparison to unsubstituted
analogs LQ02 (SI: 1, entry 1, Table 2) and LQ03 (inactive; entry
2, Table 2). In particular, R’ = OMe (LQ04, SI: 7, entry 3, Table 2)
and R’ = Cl (LQ33 and LQ34, SI: 5, entries 4 and 5, Table 2)
presented higher SI than miltefosine (SI: 3, entry 17, Table 2).
LQ35 (R’ = F) exhibited the same value of SI as miltefosine
(Figure 9). LQ48 and LQ51-55 were considered non-promising
compounds due to low SI values observed (< 2; entries 7-12,
Table 2).
8
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10.1002/chem.202102287
Chemistry - A European Journal
RESEARCH ARTICLE
Table 3. In vitro Activity toward L. amazonensis promastigotes, Cytotoxicity in macrophages, and Selectivity Indexes of LQ02-04, LQ33-35 and LQ48-57.[a]
[b]
[c]
Entry
Subst.
X
R
R’
IC50 ± SD (μmol L−1
)
CC50 ± SD (μmol L−1
)
SI[d]
1,2λ4-oxatellurolanes:
1
2
LQ02
LQ03
LQ04
LQ33
LQ34
LQ35
LQ48
LQ51
LQ52
LQ53
LQ54
LQ55
Cl
Br
Cl
Cl
Br
Cl
Cl
Cl
Br
Cl
Cl
Cl
H
H
H
34.7 ± 10.6
>100[e]
23.1 ± 2.8
7.8 ± 2.1
1
[f]
H
-
3
H
OMe
7.0 ± 1.3
13.0 ± 4.2
9.7 ± 0.3
7.7 ± 2.3
31.4 ± 7.4
35.0 ± 3.1
>100[e]
51.3 ± 12.4
64.0 ± 8.3
43.7 ± 2.5
23.3 ± 2.5
20.7 ± 7.4
34.0 ± 4.9
19.1 ± 2.1
13.9 ± 2.5
13.7 ± 3.7
58.0 ± 14.2
7
5
5
3
1
1
4
H
Cl
5
H
Cl
6
H
F
Ketal[g]
H
7
H
8
Me
Me
Ph
H
[f]
9
H
-
10
11
12
H
6.3 ± 0.3
32.8 ± 6.4
41.5 ± 7.0
2
0.4
1
Ac
H
Oxime[h]
1,2λ4-oxatelluranes:
13
14
LQ49
LQ50
Cl
Br
-
-
-
8.6 ± 2.5
4.1 ± 1.0
31.0 ± 7.8
49.0 ± 5.0
4
-
12
1,2λ4-benzoxatelluroles:
15
16
17
LQ56
LQ57
Cl
Br
-
-
-
-
5.7 ± 0.3
>100[e]
32.0 ± 6.2
16.0 ± 2.5
55.0 ± 1.9
6
[f]
-
-
-
Miltefosine
20.7 ± 0.2
3
[a] Data were expressed as the mean ± SD determined from three independent experiments. [b] IC50: the concentration that inhibit 50% of parasite growth in
relation to the untreated control. [c] CC50: cytotoxic concentration able to kill 50% of the macrophages in relation to the untreated control. [d] Selectivity index:
CC50/IC50. [e] Considered inactive. [f] Not applicable. [g] 2-Methyl-1,3-dioxolan-2-yl group. [h] (E)-1-(hydroxyimino)ethyl group.
The unique two 1,2λ4-oxatelluranes assayed here, LQ49 and
LQ50, exhibited higher SI than miltefosine (Figure 9). The SI for
LQ49 was 4 (entry 13, Table 2), while LQ50 was identified as the
most selective substance in our series with SI = 12 (entry 14,
Table 2). Among 1,2λ4-benzoxatelluroles, only the chlorinated
LQ56 was active (SI: 6, entry 15, Table 2) while its brominated
congener LQ57 was considered inactive, following the trend
observed for 1,2λ4-oxatellurolanes LQ02 and LQ03. LQ50
presented the highest SI in the antileishmanial assays (SI = 12,
entry 14, Table 2) and evidenced the great potential for Te-
containing six-membered heterocycles. The best results
observed for 1,2λ4-oxatellurolanes and 1,2λ4-benzoxatellurole
were highlights in LQ04 and LQ56, respectively. Besides,
chlorinated 1,2λ4-oxatellurolanes and 1,2λ4-benzoxatellurole
showed better performance than equivalent brominated Te-
containing heterocycles, except for 1,2λ4-oxatelluranes LQ49 and
LQ50. Despite the absence of a clear pattern for structure-activity
Figure 9. Selectivity indexes of assayed organotelluranes and miltefosine.
9
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10.1002/chem.202102287
Chemistry - A European Journal
RESEARCH ARTICLE
Figure 10. 125Te NMR (126.24 MHz, DMSO-d6, PhTeTePh (*, δ = 422)) on the stability assays for LQ02.
relationships, the three classes of hypervalent Te-containing
heterocycles studied in this work - 1,2λ4-oxatellurolanes (LQ04),
1,2λ4-oxatelluranes (LQ50) and 1,2λ4-benzoxatellurole (LQ56) -
showed potential as antileishmanial agents.
In summary, eleven chlorinated and five brominated compounds
– thirteen unpublished – hypervalent Te-containing heterocycles
(LQ02-04, LQ33-35, and LQ48-57) have been successfully
synthesized in 0.4% to 40% overall yields and LQ02, LQ49, LQ51,
and LQ56 structures were elucidated by NMR analysis and
single-crystal X-ray diffraction methods. Computational results
revealed that the oxidation-cyclization proceeds via two-step
mechanism: (1) the oxidation of the hydroxy telluride by NCS as
the rate determinant step with energy barrier of 4.9 kcal mol-1 and
(2) cyclization involving the formation of the new Te–O bond and
the O–H bond break in a concerted asynchronous fashion.
Additionally, the diastereoselectivity observed was rationalized
using theoretical calculations, allowing the identification of anti-
LQ51 as the major diastereoisomer formed.
Investigation
of
Hypervalent
Tellurium-containing
Heterocycles Stability.
In the literature, there is a debate about the stability of hypervalent
25]
tellurium compounds in organic-aqueous media.[9h,
So,
complement stability assays for some representative compounds
were also performed using 125Te NMR as analytical tool. Initially,
the thermal stability of LQ02 in dimethyl sulfoxide-d6 (DMSO-d6)
was investigated at temperatures ranging from 25 to 65 °C.[9h, 25a]
The results obtained by 125Te NMR are described in Figure 10, in
which no significant changes in chemical shifts were observed,
demonstrating the thermal stability of the studied organotellurane.
Additionally, 1H NMR analysis confirmed that the structure of
LQ02 remained intact. The same methodology was applied for
LQ51 to evaluate the possible cycle opening through variations
between the proportion of diastereoisomers. However,
satisfactorily no structural change was observed even after 5
hours in reflux in CDCl3 (see on Supporting Information, figure
S110).
In vitro activity assays against L. amazonensis promastigotes
showed that 1,2λ4-oxatellurane LQ50 (SI
=
12), 1,2λ4-
oxatellurolane LQ04 (SI = 7) and 1,2λ4-benzoxatellurole LQ56 (SI
= 6) were the most promising substances, with SI values higher
than that observed for miltefosine. Six-membered 1,2λ4-
oxatellurane presented better results than five-membered Te-
containing heterocycles (1,2λ4-oxatellurolane and 1,2λ4-
benzoxatellurole), suggesting this as a more promising class for
1
future investigations. 125Te and H NMR analysis showed LQ02
In the sequence, LQ02 was solubilized in DMSO-d6, followed by
distilled water addition (Figure 10).125Te NMR analyses presented
a single signal at δ = 1157, again suggesting no chemical
structure variation. Recovery and 1H NMR analysis of LQ02
confirmed no structural modifications in organic-aqueous media.
Since the tested organotelluranes did not suffer opening cycle and
and LQ51 as thermal stable (up to 65 °C) and in aqueous-organic
conditions. In conclusion, this work aims to contribute to the
search for bioactive organotellurium compounds and highlight the
biological potential of the hypervalent Te-containing heterocycles.
parallel undesired reactions up to 65 °C, including in organic-
Acknowledgements
b, d]
aqueous media, as observed for other telluranes,[24a,
in
association with the promising results of biological activity, 1,2λ4-
oxatellurolane, 1,2λ4-benzoxatellurole and especially 1,2λ4-
oxatellurane studied in this work present great potential in the
search for biologically active Te-containing compounds.
The authors thank the National Council for Scientific and
Technological Development (CNPq, Brazil), and the Coordination
for the Improvement of Higher Level Personnel (CAPES, Brazil)
for financial support and fellowships of J. P. A. Souza, P. T.
Bandeira, L. R. A. Menezes, M. B. Bespalhok, D. B. Scariot, F.P.
Garcia, D. L. Hughes and S. O. K. Giese.
Conclusion
Keywords: Hypervalent Tellurium compounds • Oxidation-
10
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10.1002/chem.202102287
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RESEARCH ARTICLE
Cyclization Mechanism • Leishmanicidal activity • 125Te NMR
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Entry for the Table of Contents
Promissory hypervalent Te(IV)-containing heterocycles were obtained with highlights for biological applications. Synthesis, most
favorable mechanism identification, in vitro antileishmanial potential against L. amazonensis and stability assays, supported by 125Te
NMR of a series of five- (1,2λ4-oxatellurolanes and 1,2λ4-benzoxatelluroles) and six- (1,2λ4-oxatelluranes) membered ring
organotelluranes, confirm products containing a Te–O bond.
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