Synthesis and antimycotic properties of hydroxy sulfides derived from exo- and endo-4-phenyl-3,5,8-trioxabicyclo[5.1.0]octanes

Article abstract of DOI:10.1016/j.mencom.2012.05.003

Both exo- and endo-isomers of 4-phenyl-3,5,8-trioxabicyclo[5.1.0]octane were reacted with thiophenol to afford individual diastereomers of hydroxy sulfides which were further processed in search for new antimycotic substances.

Full text of DOI:10.1016/j.mencom.2012.05.003

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 127–128
Synthesis and antimycotic properties of hydroxy sulfides derived
from exo- and endo-4-phenyl-3,5,8-trioxabicyclo[5.1.0]octanes
Roman S. Pavelyev,*a Sergey G. Gnevashev,a Rusalia M. Vafina,a Oleg I. Gnezdilov,b
Alexey B. Dobrynin,c Svetlana A. Lisovskaya,d Liliya E. Nikitinac and Evgenii N. Klimovitskiia
a A. M. Butlerov Chemical Institute, Kazan (Volga Region) Federal University, 420008 Kazan, Russian
Federation. Fax: +7 843 292 7278; e-mail: rpavelyev@gmail.com
b E. K. Zavoisky Physical-Technical Institute, Russian Academy of Sciences, 420008 Kazan, Russian Federation
c A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy
of Sciences, 420088 Kazan, Russian Federation
d Kazan Research Institute of Epidemiology and Microbiology, 420015 Kazan, Russian Federation
e Kazan State Medical University, 420012 Kazan, Russian Federation
DOI: 10.1016/j.mencom.2012.05.003
Both exo- and endo-isomers of 4-phenyl-3,5,8-trioxabicyclo[5.1.0]octane were reacted with thiophenol to afford individual diastereo-
mers of hydroxy sulfides which were further processed in search for new antimycotic substances.
b-Hydroxy sulfides are used in the synthesis of allylic alcohols,1
cyclic sulfides,2 thioketones,3 natural compounds and com-
pounds with biological activity.4,5 b-Hydroxy sulfones can be
transformed into lactones,6 2,5-disubstituted tetrahydrofurans7
and vinylsulfones.8 Moreover, compounds containing phenyl-
sulfonyl fragment are widely used in fine organic synthesis.9
In the continuation of our research,10 we report herein the
results on thiolysis of exo- and endo-isomers of 4-phenyl-
3,5,8-trioxabicyclo[5.1.0]octane with thiophenols, leading to
1,3-dioxepane b-hydroxy sulfides as a result of oxirane ring
opening. Isomerization of such hydroxy sulfides in the presence
of p-toluenesulfonic acid was also studied (Scheme 1).†
Starting 2-phenyl-1,3-dioxacyclohept-5-ene 1 was obtained
by acetalization of benzaldehyde with cis-but-2-ene-1,4-diol as
described.11 Epoxidation of compound 1 with oxone gave the
corresponding epoxides 2a and 2b.12 According to 1H NMR data
the ratio of these epoxy acetals is 2:1 in favour of the endo-
isomer 2b. Products 2a and 2b were separated by column chro-
matography on silica gel. Their neat reactions with thiophenol
in the presence of K2CO3 afford b-hydroxy sulfides 3a and 3b,
respectively, each of them being racemic individual diastereomer.
The retention of the 7-membered dioxepane cycle was confirmed
by 2D 1H-1H COSY NMR spectroscopy.
Hydroxy acetals 3a and 3b on keeping in chloroform in the
presence of p-toluenesulfonic acid, completely isomerise to the
6-membered acetal 3c as a result of intramolecular transacetaliza-
tion. Structure of acetal 3c was determined by means of 1D and
2D NMR spectroscopy, mass spectrometry and X-ray single
crystal diffraction of its derivative 5c (Figure 1).‡ To extend
diversity of new compounds, the corresponding acetates 5a–c
and sulfones 4a–c, 6a–c were prepared.
The 1,3-dioxepanes herein obtained demonstrate antimycotic
properties. To adequately study the influence of their structure
on the biological activity, we tried to separate these racemic
AcO
HO
O
AcO
PhS
O
O
i
Ph
Ph
Ph
OAc
80%
O
O
O
PhO2S
PhO2S
e
6a (rac)
5a (rac)
4a (rac)
O
a
e
PhS
Ph
i
iii 80%
O
O
79%
HO
O
5c (rac)
ii
i
iii
O
Ph
Ph
Ph
Ph
OAc
OH
93%
73%
88%
e
e
O
2a
+
O
PhS
O
O
3a (rac)
O
iv (3a + 3b)
a
a
i
e
e
PhS
Ph
PhO2S
Ph
Ph
85%
89%
O
O
O
O
HO
O
ii
OH
6c (rac)
3c (rac)
i
O
1
e
80%
79%
O
O
PhS
i
O
a
2b
3b (rac)
e
89%
PhO2S
Ph
iii 95%
O
O
4c
(rac)
AcO
O
HO
PhO2S
O
AcO
PhS
i
Ph
Ph
Ph
97%
O
PhO2S
O
O
6b (rac)
5b (rac)
4b (rac)
Scheme 1 Reagents and conditions: i, Oxone, acetone, NaHCO3, H2O; ii, PhSH, K2CO3, heat; iii, Ac2O, DMAP, Et3N, CH2Cl2; iv, TsOH, CHCl3.
For syntheses and characteristics of compounds 2–6, see Online Supplementary Materials.
†
© 2012 Mendeleev Communications. All rights reserved.
– 127 –

Mendeleev Commun., 2012, 22, 127–128
Table 1 Minimal inhibiting concentrations (MIC/mg cm–3) of synthesized
hydroxysulfides 3a–c.
Candida
albicans
(clinical strain)
Aspergillus
fumigatus
(typical strain)
Epidermophyton
floccosum
(clinical strain)
Com-
pound
3a (rac)
3b (rac)
3c (rac)
(+)-3b
~40
~10
>80
~5
~40
~10
>80
~5
~40
~10
~80
~5
(–)-3b
Fluconazole
~10
<0.5
~10
<0.5
~10
~0.6
Figure 1 Crystal structure of compound 5c.
compounds into enantiomers by lipase PS-catalyzed acylation
with vinyl acetate as the source of acetyl moiety (Scheme 2).†
Interestingly, under the same acylation conditions diastereo-
meric alcohols 3a and 3b differed in their behaviour. Alcohol 3b
was separated into enantiomers by two-stage synthesis (Scheme 2),
whereas its isomer 3a did not undergo enzymatic acylation. The
moduli of rotation angles of the obtained enantiomeric alcohols
3b and particularly their acetates 5b (see Scheme 2) were identical
what allowed judging of high enantioselectivity of this enzymatic
separation. Unfortunalely, the attempted use of chiral shift-reagent
to directly determine their er values was unsuccessful. The con-
figuration of chiral carbon atom at the hydroxy group was ascribed
on the basis of the literature data,13 since it is known that in the
presence of lipase PS only alcohols, having the hydroxy group
at the chiral carbon atom with R-configuration, are prone to
acylation. Hence, under conditions of trans-opening of epoxy
cycle by thiophenol the configurations of chiral carbon atoms in
enantiomers obtained correspond to those presented in Scheme 2.
We have theoretically evaluated biological activity of the com-
pounds synthesized by means of PASS Program.14–16 According
to the data obtained, compounds 3a–c most likely have high
antifungal activity. This type of activity of these substances, both
racemic and optically pure ones, have been investigated with the
use of clinical and typical strains of some fungi (Table 1).§
Table 1 demonstrates that the antimycotic activity of compound
3c is significantly lower compared to that of racemic isomers 3a
and 3b. Meanwhile, the MICs of stereoisomers 3a and 3b also
significantly differ. So, dioxepane 3b with cis-position of hydroxy
and phenyl groups in the cycle has four times higher activity than
its stereoisomer 3a with the same substituents in trans-position.
The dextrorotatory enantiomer, whose MIC is 5 mg cm–3 was
found to be more active as compared to levorotary enantiomer
with MIC of 10 mg cm–3 for all fungi investigated.
In conclusion, we have shown that compounds obtained may
be considered as prospective ones concerning their antifungal
activity: seven-membered isomers are more active than six-mem-
bered ones, the activity of cis-isomer of dioxepane series is signi-
ficantly higher than that of trans-isomer, and the dextrorotatory
enantiomer is more active as compared with levorotatory one.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.05.003.
HO
O
i
Ph
No acylation
O
PhS
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3a (rac)
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PhS
O
O
S
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R
i
S
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R
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Ph
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O
O
O
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AcO
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(+)-3b, 42%
(–)-5b, 40%
a2D4[CH2Cl2] = 0.7 aD24[CH2Cl2] = –24.2
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iii
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AcO
PhS
PhS
HO
O
O
S
S
R
S
R
R
Ph
Ph
O
O
(–)-3b
(+)-5b
aD24[CH2Cl2] = 24.2
aD24[CH2Cl2] = –0.7
[C] = 5.0
[C] = 5.0
Scheme 2 Reagents and conditions: i, lipase PS, vinyl acetate, THF, 40°C,
~90 days stirring; ii, Ac2O, DMAP, Et3N, CH2Cl2; iii, K2CO3, MeOH, room
temperature.
‡
Crystal data for 5c: colourless crystal, C19H20O4S (M = 344.42) mono-
15 A. Lagunin, A. Stepanchikova, D. Filimonov and V. Poroikov, Bio-
informatics, 2000, 16, 747.
clinic, space group C2/c, at 298(2) K: a = 30.710(4), b = 5.1147(6) and
c = 22.411(3) Å, b = 93.819(1)°, V = 3512.3(8) Å3, Z = 8, dcalc = 1.303 g cm–3
,
16 V. V. Poroikov, D. A. Filimonov, W.-D. Ihlenfeldt, T. A. Gloriozova,
A. A. Lagunin,Yu. V. Borodina, A. V. Stepanchikova and M. C. Nicklaus,
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m = 0.203 mm–1, Rint = 0.039, qmax = 27.0°, Bruker Smart Apex II CCD
diffractometer, 17922 reflections collected, 2585 observed reflections with
I > 2s(I), final R = 0.0593, wR2 = 0.1372, 3814 independent reflections
with F2 ³ 2s(I), S = 1.04.
Received: 5th December 2011; Com. 11/3848
CCDC 863301 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2012.
§
For determination of the fungal activity, see Online Supplementary
Materials.
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