Novel deoxy-selenylconduritols: chemoenzymatic synthesis and biological evaluation

Article abstract of DOI:10.1016/j.tetasy.2009.11.004

The first synthesis of two selenyldeoxycyclitols (4-bromo-2-phenylselenyl conduritol F and 6-phenylselenylconduritol F) is reported via a chemoenzymatic enantioselective route. The key step of the synthesis is the selenolysis of a vinyl epoxide. The new compounds were evaluated for their capacity to inhibit the growth of different microorganisms using a modification of the agar diffusion technique with thin layer chromatography plates as support.

Full text of DOI:10.1016/j.tetasy.2009.11.004

Tetrahedron: Asymmetry 20 (2009) 2673–2676
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel deoxy-selenylconduritols: chemoenzymatic synthesis
and biological evaluation
Ana Bellomo a, Ana Bertucci b, Hélio Stefani c,d, Álvaro Vázquez b, David Gonzalez a,
*
a Laboratorio de Síntesis Orgánica, Fac. de Química, Universidad de la República, UdelaR, Montevideo, Uruguay
b Laboratorio de Farmacognosia y Productos Naturales, Fac. de Química, Universidad de la República, UdelaR, Montevideo, Uruguay
c Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
d Departamento de Biofisica, Universidade Federal de São Paulo, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of two selenyldeoxycyclitols (4-bromo-2-phenylselenyl conduritol F and 6-phenylsel-
enylconduritol F) is reported via a chemoenzymatic enantioselective route. The key step of the synthesis
is the selenolysis of a vinyl epoxide. The new compounds were evaluated for their capacity to inhibit the
growth of different microorganisms using a modification of the agar diffusion technique with thin layer
chromatography plates as support.
Received 14 September 2009
Accepted 5 November 2009
Available online 4 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Conduritols are 5-cyclohexen-1,2,3,4-tetrols. In view of the
presence of four stereogenic centers, conduritols exist as ten ster-
eoisomers; four enantiomeric pairs (conduritols B, C, E, F) and
two meso-forms (conduritols A and D) (Fig. 1).1 Interest in con-
duritols and their derivatives has been expanded upon in recent
years since they have been found to possess antibiotic, antileuke-
mic and tumour-inhibitory properties, and glycosidase inhibitory
activity.2–4 In connection with the conduritols, deoxy-conduritols
and vinylic-substituted conduritols have also gained importance
over the last decade. A chemoenzymatic approach to several of
these compounds, which are available by the microbial oxidation
of aromatic compounds via whole-cell oxidation of aromatics via
toluene dioxygenase has extensively been explored by our
group5–10 and others.1,11–14 As a part of a programme for the syn-
thesis of deoxy-conduritols to be tested as glycosidase inhibitors
and antimicrobials, we herein report a practical route to enantio-
merically pure unnatural cyclitol derivatives containing a Se
group. In recent years chiral organoselenium compounds have
been prepared and some of them applied in asymmetric synthe-
sis. This subject constitutes a new trend in the field of organoel-
ement chemistry. In a search for practical ways of generating
selenium containing molecules bearing stereogenic centers, we
herein report a methodology for the preparation of previously un-
known deoxy-selenylconduritols 5 and 8 and their test results
against bacteria and fungi strains.
conduritol-A
conduritol-B
conduritol-C
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
conduritol-D
conduritol-E
conduritol-F
Figure 1. Structures of all conduritol isomers.
2. Results and discussion
Whole-cell fermentation of bromobenzene 1 with the mutant
strain Pseudomonas putida F39/D generated the chiral cis-cyclohex-
adienediol
2 with very high regio- and enantioselectivity
(Scheme 1). The homochiral cis-diol was protected as the corre-
sponding acetonide, which reacted with m-CPBA in methylene
chloride to furnish oxirane 3 with complete regio- and stereospe-
cifity.15 The resulting epoxide was subjected to a selenolysis reac-
tion following a procedure developed by Kim et al. for the
synthesis of muco-quercitol.16 Treating epoxide 3 with sodium
benzeneselenolate, generated in situ from diphenyldiselenide
(DPDS)17,18 and NaBH4, gave hydroxyselenide 4 in very good yield.
* Corresponding author. Tel.: +598 2 929 0106; fax: +598 2 924 1906.
E-mail address: davidg@fq.edu.uy (D. Gonzalez).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.004

2674
A. Bellomo et al. / Tetrahedron: Asymmetry 20 (2009) 2673–2676
Br
Br
Br
Br
Br
OH
OH
O
O
O
OH
OH
e
b, c
d
a
O
PhSe
PhSe
O
OH
OH
1
2
3
4
5
Scheme 1. Synthesis of 4-bromodeoxy-6-phenylselenylconduritol F 5. Reagents and conditions: (a) P. putida F39/D, mineral broth, arginine, 28 °C, 48 h, 2 g/L; (b) DMP, p-
TsOH, acetone, rt, 30 min, 98%; (c) m-CPBA, CH2Cl2, rt, overnight, 85%; (d) DPDS, NaBH4, DME, rt, 1 h, 89%; (e) Dowex resin-H+, MeOH–H2O, rt, 72 h, 70%.
The exclusive formation of 4 can be explained by considering that
the regiospecific opening of vinyl epoxides of type 3 is controlled
by stereoelectronic effects,19 via an SN2 process to give the anti
1,2-adducts, as we observed experimentally. Compound 4 was
treated with a cation-exchange resin in order to remove the aceto-
nide group. Subsequent resin filtration, concentration and purifica-
tion by flash chromatography rendered optically active
hydroxyselenide 5 as a white solid in 51% overall yield from
metabolite 1 (Scheme 1).
The inhibitory activities of compounds 4, 5, 7 and 8 were
screened for antimicrobial activity against several Gram-positive
and Gram-negative bacteria strains, fungi and yeast (Table 1). Anti-
microbial assays were performed using a modification of the agar
diffusion technique with thin layer chromatography plates as sup-
port.23,24 This technique, which is a hybrid of direct and contact
bioautography, relies on the transfer of active compounds by a dif-
fusion process from the stationary phase into an agar layer con-
taining the microorganism. When the plate is sprayed with a
tetrazolium salt a formazan is produced and inhibition zones are
observed against a purple background.25 The outcomes of this test
revealed that all compounds tested were active against Bacillus
To access a conduritol F analogue, we proceeded by performing
a radical dehalogenation reaction on compound 3 in order to ob-
tain epoxide 65 (Scheme 2). Treatment of oxirane 6 with DPDS/
NaBH4 gave hydroxyselenide 7. An attempt to prepare 7 by direct
dehalogenation of selenyl compound 4 with HBu3Sn and ABCC as
an initiator in anhydrous THF, led to the recovery of the starting
material. Acetonide 7 was deprotected to give 6-phenylselenylcon-
duritol F 8, the first reported Se-containing deoxy-conduritol.
Importantly, intermediate 7 was subjected to dihydroxylation
using catalytic RuCl3 and NaIO4 as co-oxidant so as to afford the
inositol oxidation level. Although this procedure had successfully
subtilis at 50 lg/mL concentration. Neither 6-phenylselenylcondur-
itol F nor its analogues 4, 5 and 7 exhibited activity against other
microorganisms.
In order to confirm that the phenylselenyl moiety was not so-
lely responsible for the activity observed, we synthesized isopropyl
phenyl selenide26,27 from DPDS and 2-bromopropane in excellent
yield. This compound showed no activity in the thin-layer bioauto-
graphic assay, which allowed us to use it as a negative control for
the process. Even though the method is qualitative, the results ob-
tained are useful to complement the biological activity observed
for some organoselenium compounds.28–32
been employed in our thiocyanodeoxy-L
-chiro-inositol synthesis,5
7 did not render the expected dihydroxylated compound as de-
duced from the 1H NMR data. In fact, analysis of the 1H and 1H
COSY spectra of this compound identified it as diol 920,21
(Scheme 2).
3. Conclusions
Diol 9 was presumably formed by a [2,3] sigmatropic rear-
rangement of allylic selenium compound 7 (Scheme 3).18 The
sigmatropic rearrangement via the allylic selenoxide intermedi-
ate I, involves an oxygen transfer from selenium to carbon and
after hydrolysis of the allylic selenenate (intermediate II), the
allylic alcohol 9 is obtained. Hoffmann proved that [2,3] sigma-
tropic rearrangements proceed predominantly via an endo transi-
In conclusion, we have simply and efficiently achieved the ster-
eoselective synthesis of the previously unknown deoxy-selenyl-
conduritols 5 and 8 by a chemoenzymatic strategy. All of the
synthesized molecules inhibited the growth of B. subtilis. Several
other conduritol analogues are currently being prepared in our lab-
oratory to be evaluated as antimicrobials. The complete account of
the synthesis and biological testing results for the whole library
will be reported in due course.
tion state.22 This observation led to
a
formal synthesis of
(ꢀ)-conduritol C.
Br
O
OH
OH
O
O
O
O
b
c
a
PhSe
PhSe
O
O
OH
OH
O
3
6
7
8
d
OH
O
O
OH
9
Scheme 2. Synthesis of deoxy-6-phenylselenylconduritol F 8 and formation of diol 9. Reagents and conditions: (a) Bu3SnH, ABCC, THF, reflux, 4 h, 70%; (b) DPDS, NaBH4, DME,
rt, 2 h, 72%; (c) Dowex resin-H+, MeOH–H2O, rt, 72 h, 77%; (d) RuCl3–NaIO4, AcOEt–CH3CN–H2O, 0 °C, 2 h, 30%.

A. Bellomo et al. / Tetrahedron: Asymmetry 20 (2009) 2673–2676
2675
Se Ph
H
OH
O
O
O
RuCl3-NaIO4
O
O
O
O
O
O
H2O
Ph
PhSe
Se
O
OH
OH
OH
OH
7
I
II
9
Scheme 3. [2,3] Sigmatropic rearrangement for the synthesis of 9.
312 (M+ꢀPh–CH3, 46), 154 (M+ꢀBr–PhSe–CH3, 55), 77 (Ph, 100);
1H NMR (CDCl3, 400 MHz) d: 7.59 (dd, 2H, J 1.6 Hz, J 7.5 Hz, Ph),
7.32 (m, 3H, Ph), 6.39 (d, 1H, J3,2 3.3 Hz, H-3), 4.63 (dd, 1H, J5,6
5.9 Hz, J5,2 1.2 Hz, H-5), 4.22 (dd, 1H, J6,1 7.2 Hz, J6,5 6.1 Hz, H-6),
3.92 (t, 1H, J1,2 7.2 Hz, J1,6 7.2 Hz, H-1), 3.58 (ddd, 1H, J2,1 7.2 Hz,
J2,3 3.3 Hz, J2,5 1.3 Hz, H-2), 2.59 (br s, 1H, OH), 1.47 (s, 3H, CH3),
1.40 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d: 135.1 (C Ph),
132.9 (C 3), 129.4 (C Ph), 128.5 (C Ph), 128.1 (C Ph–Se), 119.4 (C
4), 110.7 (C isopropylidene), 77.9 (C 6), 76.6 (C 5), 71.0 (C 1),
45.9 (C 2), 28.1 (CH3), 26.1 (CH3); HRMS: calcd for C15H17O3SeBr:
((M++2)+Na): 426.9416; found: 426.9436; calcd for (M++Na):
428.9403; found: 428.9423.
Table 1
Results obtained from the TLC bioautography test
Microorganisms
Compounds
4
5
7
8
Bacillus subtilis ATCC 6633
+
+
+
+
Staphylococcus aureus ATCC 6538p
Pseudomonas aeruginosa ATCC 15153
Escherichia coli ATCC 26
Aspergillus niger ATCC 9029
Candida albicans ATCC 10231
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4. Experimental
4.1. General
4.3. (1S,2S,5S,6S)-4-Bromo-6-(phenylselenyl)cyclohex-4-ene-
1,2,3-triol 5
A mixture of compound 4 (81.3 mg, 0.201 mmol), Dowex-50 (H+
form) resin (920 mg) and MeOH–H2O (3.0–0.2 mL) was stirred at
room temperature. After 72 h, the resin was filtered off, washed
with MeOH and the solvent was removed under reduced pressure.
The crude mixture was purified by flash chromatography (hexane/
ethyl acetate: 50:50 and then hexane/ethyl acetate: 30:70) to af-
All non-hydrolytic reactions were carried out under a nitrogen
atmosphere, with standard techniques for the exclusion of mois-
ture. All solvents were purified prior to use. The commercially
available reagents were purchased from Aldrich, Acros, Zur Syn-
these and Baker, and used without further purification. Optical
rotations were measured using a Kruss Optronic GmbH P8000
polarimeter with a 0.5 mL cell (concentration c given as g/
100 mL). Melting points were determined on a Fisher–Johns appa-
ratus and are uncorrected. Infrared spectra were recorded using a
Shimadzu FT-IR 8101A spectrometer and peaks are reported in re-
ciprocal cm along with relative signal intensities and characteris-
ford 5 as a white solid. Yield: 70%. Mp: (102–104) °C; ½a D20
¼ þ93
ꢂ
(c 0.2, MeOH); IR (KBr): 3500–3400 (OH, w), 739 (5H (Ph), s),
689 (C–Se, w); 1H NMR (MeOD, 400 MHz) d: 7.61 (dd, 2H, J
2.0 Hz, J 7.4 Hz, Ph), 7.30 (dd, 3H, J 2.0 Hz, J 5.0 Hz, Ph), 6.12 (d,
1H, J5,6 3.0 Hz, H-5), 4.19 (d, 1H, J3,2 4.1 Hz, H-3), 3.83 (dd, 1H,
J1,6 7.9 Hz, J1,2 9.6 Hz, H-1), 3.61 (dd, 1H, J6,1 7.7 Hz, J6,3 4.1 Hz, H-
6), 3.59 (m, 1H, H-2); 13C NMR (MeOD, 100 MHz) d: 136.2 (C Ph),
133.8 (C 5), 130.3 (C Ph), 130.0 (C Ph–Se), 129.2 (C Ph), 123.5 (C
4), 74.6 (C 2), 74.4 (C 3), 71.1 (C 1), 49.1 (C 6); HRMS: calcd for
C12H13O3SeBr: ((M++2)+Na): 388.9090; found: 388.9108; calcd for
(M++Na): 386.9103; found: 386.9126.
tics:
s (strong); m (medium); w (with). Nuclear magnetic
resonance spectra were recorded on a Bruker Avance DPX-400
instrument. Chemical shifts (d) are given in parts per million and
coupling constants (J) are reported in hertz. High-resolution mass
spectra were performed on a Bruker Daltonics spectrometer TOFQ
(ESI+ mode). Analytical TLC was performed on Silica Gel 60F-254
plates and visualized with UV light (254 nm) and/or anisalde-
hyde–H2SO4–AcOH as detecting agent. Flash column chromatogra-
phy was performed in silica gel (Kieselgel 60, EM reagents, 230–
400 mesh).
4.4. (1S,2S,5R,6S)-2-Phenylselenyl-5,6-isopropylidenedioxycy-
clohex-3-ene-1-ol 7
A solution of epoxide 6 (220.7 mg, 1.31 mmol) and DPDS
(688.2 mg, 2.20 mmol) in DME (25 mL) was treated with NaBH4
(221.5 mg, 5.85 mmol) at room temperature. The reaction mixture
was stirred for 2 h until consumption of the starting material mon-
itored by TLC. Water (10 mL) and EtOAc were added to the system
and the organic phase was treated with NH4Cl satd and NaCl satd It
was dried (anhyd Na2SO4), filtered and concentrated under re-
duced pressure to provide a crude mixture which was purified by
flash chromatography on silica (hexane/ethyl acetate: 70:30).
4.2. (1S,2S,5S,6S)-4-Bromo-2-phenylselenyl-5,6-isopropylidene-
dioxycyclohex-3-ene-1-ol 4
A mixture of a-oxirane 3 (358.1 mg, 1.45 mmol) was dissolved
in DME (12 mL) containing 2.47 equiv of DPDS (771.5 mg,
2.47 mmol). Next, NaBH4 (219.5 mg, 5.80 mmol) was added and
the reaction was stirred for 1 h at rt followed by the addition of
water (10 mL) and EtOAc. The organic layer was treated with
NH4Cl satd (1 ꢁ 10 mL) after which NaCl satd was added. The sys-
tem was dried (anhyd Na2SO4), filtered and concentrated under re-
duced pressure to provide a residue which was purified by flash
chromatography on silica, eluting with hexanes/ethyl acetate:
80:20 to afford the selenyl compound 4 as a white solid. Yield:
Compound
7 was obtained as a colourless oil. Yield: 72%.
½
a 2D1
ꢂ
¼ þ127 (c 1.1, CH2Cl2); IR (KBr): 3440 (OH, w), 1240, 1161
and 1060 (C–O–C–O–C, s), 741 (5H (Ph), s), 692 (C–Se, w); 1H
NMR (CDCl3, 400 MHz) d: 7.60 (dd, 2H, J 1.6 Hz, J 7.6 Hz, Ph),
7.28 (m, 3H, Ph), 6.05 (ddd, 1H, J3,2 2.2 Hz, J3,4 10.0 Hz, H-3), 5.75
(ddd, 1H, J4,3 10.0 Hz, J4,5 3.9 Hz, J4,2 2.2 Hz, H-4), 4.57 (br t, 1H,
J5,4 5.0 Hz, J5,6 5.0 Hz, H-5), 4.10 (dd, 1H, J6,1 8.1 Hz, J6,5 5.8 Hz, H-
6), 3.69 (t, 1H, J1,2 8.2 Hz, J1,6 8.2 Hz, H-1), 3.61 (ddd, 1H, J2,1
89%. Mp 107–109 °C; ½a D25
¼ þ168 (c 0.6, CH2Cl2); IR (KBr):
ꢂ
3500–3400 (OH, w), 1224, 1161 and 1072 (C–O–C–O–C, s), 740
(5H (Ph), s), 692 (C–Se, w); MS m/z: 314 ((M++2)ꢀPh–CH3, 51),

2676
A. Bellomo et al. / Tetrahedron: Asymmetry 20 (2009) 2673–2676
8.5 Hz, J2,3 2.2 Hz, J2,4 2.2 Hz, H-2), 3.06 (br s, 1H, OH), 1.43 (s, 3H,
CH3), 1.37 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d: 135.1 (C Ph),
132.9 (C 3), 129.0 (C Ph), 128.1 (C Ph), 125.5 (C Ph-Se), 123.9 (C 4),
109.8 (C isopropylidene), 77.8 (C 6), 71.9 (C 5 and C 1), 45.3 (C 2),
28.2 (CH3), 26.0 (CH3); HRMS: calcd for C15H18O3SeNa+: 349.0314;
found: 349.0315.
(@C–H, w), 1475 (CH3, s), 1383 and 1367 (–C(CH3)2, m), 737 (5H
(Ph), s), 692 (C–Se, w); 1H NMR (CDCl3, 400 MHz) d: 7.55 (m, 2H,
Ph), 7.25 (m, 3H, Ph), 3.43 (s, 1H, JH,CH3 6.8 Hz, CH), 1.40 (d, 6H,
JCH3,H 6.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz) d: 134.8 (C Ph),
129.4 (C Ph–Se), 128.6 (C Ph), 127.7 (C Ph), 33.8 (CH), 24.5 (CH3).
4.8. Biological assay
4.5. (1S,2R,3R,6S)-6-(Phenylselenyl)cyclohex-4-ene-1,2,3-triol 8
(phenylselenylconduritol F)
The antimicrobial activity of compounds synthesized against
Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus
(ATCC 6538p), B. subtilis (ATCC 6633), Listeria inocua (CCM-FQ
56), Escherichia coli (ATCC 26), Candida albicans (ATCC 10231) and
Aspergillus niger (ATCC 9029) was determined by variation of the
A mixture of compound 7 (22.8 mg, 0.07 mmol), Dowex-50 (H+
form) resin (300 mg) and MeOH–H2O (2.5–0.2 mL) was stirred at
room temperature for 72 h. After completion of the reaction, the
resin was filtered off, washed with MeOH and the solvent was re-
moved under reduced pressure. Purification by flash chromatogra-
phy (hexane/ethyl acetate: 50:50 and then hexane/ethyl acetate:
agar-overlay method23,24 using gentamicin (20
tin (50 U/mL) as positive controls.
lg/mL) and nysta-
30:70) rendered 8 as a white syrup. Yield: 77%. ½a D22
ꢂ
¼ þ71 (c
Acknowledgements
0.2, MeOH); IR (KBr): 3400–3300 (OH, w), 739 (5H (Ph), w), 689
(C–Se, w); 1H NMR (C3D6O, 400 MHz) d: 7.61 (m, 2H, Ph), 7.29
(m, 3H, Ph), 5.82 (dd, 1H, J5,6 2.5 Hz, J5,4 9.9 Hz, H-5), 5.66 (ddd,
1H, J4,3 4.8 Hz, J4,5 9.9 Hz, H-4), 4.30 (d, 1H, JOH,1 4.0 Hz, OH (H-
1)), 4.19 (q, 1H, J3,4 4.0 Hz, J3,2 4.0 Hz, J3,OH 4.0 Hz, H-3), 3.98 (s,
1H, J1,6 4.0 Hz, J1,2 4.0 Hz, J1,OH 4.0 Hz, H-1), 3.90 (d, 1H, JOH,2
5.3 Hz, OH (H-2)), 3.79 (d, 1H, JOH,3 4.7 Hz, OH (H-3)), 3.70 (m,
1H, H-6), 3.56 (q, 1H, J2,1 4.4 Hz, J2,3 4.4 Hz, J2,OH 4.4 Hz, H-2); 13C
NMR (C3D6O, 100 MHz) d: 134.0 (C Ph), 130.7 (C 5), 129.0 (C Ph–
Se and C Ph), 127.4 (C Ph), 127.3 (C 4), 73.0 (C 2), 71.3 (C 1), 66.0
(C 1), 47.12 (C 6).
The authors are grateful to PEDECIBA, ANII (FCE252), CNPq
(300.613/2007-5) and FAPESP (07/59404-2) for financial support
of this work. A.B. is grateful to ANII for a Doctoral Fellowship.
The authors acknowledge Dr. Alejandra Rodríguez and Ms. Natalia
Berta for recording HRMS spectra and Mr. Horacio Pezzaroglo for
recording NMR Spectra. MestreNova NMR software was used for
processing of all spectra.
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diol 920,21
A solution of compound 7 (38.3 mg, 0.118 mmol) in a mixture of
ethyl acetate (1.5 mL) and acetonitrile (1.5 mL) was cooled to 0 °C
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4.7. Isopropyl phenyl selenide26,27
A stirred solution of 2-bromopropane (131.0 mg, 1.06 mmol)
and DPDS (571.3 mg, 1.83 mmol) in DME (8.0 mL) was treated with
NaBH4 (284.2 mg, 7.51 mmol). After being left to stand at room
temperature for 12 h, water was added and the mixture was ex-
tracted using EtOAc. The organic phase was treated with NH4Cl
satd and NaCl satd, it was dried (anhyd Na2SO4) and filtered. Con-
centration of the solution rendered a crude oily product which was
purified over silica flash using hexane to provide 10 as a yellow li-
quid. Yield: quantitative. IR (neat): 2955 (C–H, m), 1948 and 1877
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