Synthesis and Antifungal Activity of β -Hydroxysulfides of 1,3-Dioxepane Series

Hindawi

Journal of Chemistry

Volume 2018, Article ID 3589342, 14 pages

https://doi.org/10.1155/2018/3589342

Research Article

Synthesis and Antifungal Activity of β-Hydroxysulfides of

1,3-Dioxepane Series

,

Roman S. Pavelyev ,¹Rusalia M. Vaﬁna,¹Konstantin V. Balakin ,^{1 2}Oleg I. Gnezdilov,³

Aleksey B. Dobrynin,⁴Olga A. Lodochnikova ,⁴Rashid Z. Musin,⁴Galina A. Chmutova,¹

Svetlana A. Lisovskaya ,⁵and Liliya E. Nikitina⁶

¹Kazan (Volga Region) Federal University, Kremlyovskaya 18, Kazan 420008, Russia

²I.M. Sechenov First Moscow State Medical University, Trubetskaya 8, Bldg 2, Moscow 119991, Russia

³Kazan E. K. Zavoisky Physical-Technical Institute of the Russian Academy of Sciences, Sibirsky Tract, 10/7, Kazan

420029, Russia

⁴A.E. Arbuzov Institute of Organic and Physical Chemistry; KazSC, Russian Academy of Sciences, Arbuzova 8, Kazan

420088, Russia

⁵Kazan Scientiﬁc and Research Institute of Epidemiology and Microbiology, Bolshaya Krasnaya 67, Kazan 420015, Russia

⁶Kazan State Medical University, Butlerova 49, Kazan 420012, Russia

Correspondence should be addressed to Roman S. Pavelyev; rpavelyev@gmail.com

Received 6 March 2018; Revised 11 July 2018; Accepted 25 July 2018; Published 10 October 2018

Academic Editor: Maria F. Carvalho

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

properly cited.

Synthesis of β-hydroxysulﬁdes of 1,3-dioxepane series and their further functionalization were performed. Chiral

β-hydroxysulﬁdes were separated into enantiomers using enzymatic acylation by lipase PS. Study of antifungal activity of the

obtained compounds showed that some enantiomerically pure 6-arylthio-1,3-dioxepan-5-ols represent promising anti-

fungal drug candidates.

mice with diabetes [10]. (e same group of researchers

reported several N-sulfonyl-tetrahydro[1, 3]dioxepino[5, 6]

azirines which also possessed hypoglycemic activity [11].

Optically active derivatives of 1,3-dioxepan-5-ol were de-

scribed as ﬂexible analogs of a known HIV-1 protease in-

hibitor (PI) darunavir [12]. (ey demonstrated excellent

potency against a variety of multi-PI-resistant clinical

strains, and the structure-activity studies indicated that the

ring size, stereochemistry, and position of oxygens were

important for the observed activity.

In attempt to combine the β-hydroxysulﬁde and 1,3-

dioxepane structural motifs, we previously synthesized

a series of 2-phenyl-6-arylthio-1,3-dioxepan-5-ols, which

possessed a moderate antifungal activity [13]. In order to

optimize structure-activity parameters of this interesting

structural chemotype, in this work we have prepared a series

of novel chiral β-hydroxysulﬁdes of 1,3-dioxepane series and

1. Introduction

β-Hydroxysulﬁdes are attractive tools in organic synthesis,

which are actively used in the synthesis of allylic alcohols,

cyclic sulﬁdes, thioketones, and physiologically active com-

pounds [1–5]. Products of their oxidation, β-hydroxysulfones,

are useful reagents for preparation of lactones [6], 2,5-

disubstituted tetrahydrofuranes [7], and vinyl sulfones

[8]. Compounds containing phenylsulfonyl fragment are

also widely used in organic synthesis [9].

Various 5- and 6-substituted 1,3-dioxepanes are rela-

tively scarce chemotype in medicinal chemistry due to

synthetic diﬃculties and stability issues under physiological

conditions. Nevertheless, in several reports, they were de-

scribed as promising physiologically active compounds.

(us, a series of 5-hydroxy-6-sulfonamido-1,3-dioxepanes

were reported as hypoglycemic agents which were active in

2

Journal of Chemistry

studied their antifungal activity against a panel of pathogenic

microscopic fungi. It should be noted that microscopic fungi

(micromycetes), causing mycoses, are signiﬁcantly diﬀerent

from other infectious agents. Fungi are eukaryotic and are

characterized by the presence of a rigid outer wall. Micro-

mycetes are classiﬁed according to morphological charac-

teristics, the degree of pathogenicity, and the ability to cause

diseases of various organs and systems. In this work, we

used four aggressive clinical isolates of Candida albicans,

Aspergillus fumigatus, Epidermophyton ﬂoccosum, and Mucor

pusillus species. Among mycelial pathogens of invasive

mycoses, Aspergillus spp. are the most widespread. Der-

matomycetes (Epidermophyton spp.) are one of the most

common causative agents of superﬁcial mycoses of skin,

hair, and nails. Zygomycetes (Mucor spp.) cause extremely

severe invasive mycoses with a very high mortality rate. And,

ﬁnally, the vast majority of cases of fungal lesions of mucous

membranes can be attributed to infections caused by yeast

fungi of Candida species.

on the standard target plate “AnchorChip” (Bruker Daltonik

GmbH, Germany) and left to dry.

For analyzing optically active substances, “ADP 440”

(B + S) polarimeter was used.

Quantum-chemical calculations were performed by DFT

method B3LYP/6-31G(d,p) using Gaussian-98 [14] program

with full geometry optimization without restrictions on

symmetry, and a matrix of second derivatives was cal-

culated for all stationary points. All discussed structures

have only positive frequencies. Scaling factors [15] were

not introduced.

Sompounds 2 [16], 11 [17], 12 [18], 13 [19], 14 [20], and

19 [28] were prepared according to previously described

methods with insigniﬁcant modiﬁcations.

2.2. Experimental Details

2.2.1. 3,5,8-Trioxabicyclo[5.1.0]octane (2). Oxone (169 mmol)

was slowly added by portions to a stirred solution

of 1,3-dioxacyclohept-5-en 1 (130.2 mmol) and NaHCO₃

(619 mmol) in 100 ml of acetone-water mixture (1 :1 v/v)

for 3 hours at 20^°C. (en, the reaction mixture was addi-

tionally stirred for 1 hour. (e product was extracted with

CH₂Cl₂(2 × 50 ml). Organic layers were combined and dried

over MgSO₄. (e solvent was evaporated under reduced

pressure, and the product was puriﬁed by column chro-

matography on silica gel (eluent petroleum ether-ethyl

acetate, 7 :1). Yield 75%, colorless crystals, m.p. 56^°C–57^°C.

2. Materials and Methods

2.1. General Information. Chromatographic puriﬁcation of

compounds was carried out using column chromatography

on Acros silica gel (60–200 mesh). Reaction progress and

purity of compounds were monitored by TLC on Sorbﬁl

PTLC-AF-A-UF plates.

Melting points of the products were determined using

a Stanford Research Systems M.P.A-100 OptiMelt apparatus.

¹H and ¹³C NMR spectra were recorded on a “Bruker

AVANCE 400” at operating frequency 400 and 100 MHz,

respectively, using TMS as an internal standard.

Gas chromatography/mass spectrometry experiments

were performed using DFS “(ermo Electron Corporation”

apparatus. (e following experimental conditions for mass

spectrometry measurements were used: method of ioni-

zation: electron ionization; electron energy: 70 eV; and ion

source temperature: 280^°C. For gas chromatography anal-

ysis, a capillary column DB-5MS (30 × 0.25) was used with

helium as the gas carrier. (e following experimental

conditions were applied: gas-carrier rate 1 ml/min; in-

jector temperature 250^°C; temperature gradient: 50 ^°C

(1 min)-6 grad/min-120^°C-20 grad/min-280^°C (15 min); and

sample volume 0.3 μl.

HPLC experiment was performed using the Chiralpak

AGP column (15.0 × 0.4 sm, 5 μm). A solution of methanol

and 0.01 M ammonium acetate buﬀer (1 : 99 v/v) was used as

the eluent. (e elution rate was 0.9 ml/min, and the product

was detected spectrophotometrically at 250 nm.

2.2.2. 6-(Phenylthio)-1,3-dioxepan-5-ol (3). (1) General

Procedure for Preparation of β-Hydroxysulﬁdes 3, 21–23

A

mixture of thiophenol (2.7 mmol), K₂CO₃

(0.15 mmol), and epoxide (2.6 mmol) was heated until the

appearance of the ﬁrst bubbles. (e heating source was

removed, and a short-time (<1 minute) spontaneous

boiling-up with a sharp increase of the temperature was

observed. (e reaction mixture was cooled, and the product

was puriﬁed by column chromatography (eluent petroleum

ether-ethyl acetate, 4 :1).

Yield 93%, colorless oil. ¹H NMR (CDCl₃), δ: 3.13 br. s

3

(1O, PO), 3.23–3.27 m (1O, O⁶, J(O⁶O⁵) � 5.5 Hz, J(O⁶

O⁷_A) � 6.5 Hz, ³J(O⁶O⁷_C) � 2.7 Hz), 3.69–3.75 m (1O, O⁵, ³J

(O⁵O⁴_A) � 6.0 Hz, J(O⁵O⁴_C) � 1.7 Hz), 3.75–3.79 m (1O,

3

O⁴_A, J(O⁴O⁴_C) � −12.0 Hz), 3.81–3.88 m (1O, O⁷_A, J

2

(O⁷O⁷_C)^A� −12.5 Hz), 4.04–4.12 m (2O, O⁷_C, O⁴_C), 4.74

and^A4.77 (AB, 2O, 2O², ²J(O²O²_C) � −4.5 Hz), 7.24–

A

7.48 m (5O, S₆O₅). ¹³C NMR (CDCl₃), δ: 54.63 (S⁶), 65.32

(S⁷), 66.39 (S⁴), 71.34 (S⁵), 94.07 (S²), 127.32 (C_Ar), 129.05

(C_Ar), 131.73 (C_Ar), 133.22 (C_Ar). MS (EI): m/z (%) � 226

(N⁺, 56).

MALDI-TOF experiments were performed using an

ULTRAFLEX III TOF/TOF mass spectrometer (Bruker

Daltonik GmbH, Germany). (e spectra of positive ions

were recorded in linear mode with ion acceleration up to

20 keV. (e energy of the laser beam was attenuated down to

70% of the full laser power. Analyte and p-nitroaniline

matrix compounds were dissolved in acetone (1% in case of

matrix and 0.1% in case of analyte) using glassware. (e

samples were prepared by a “dried-droplet” method: 0.3 µl

droplets of the solutions were deposited on the marked spots

2.2.3. 6-(Phenylsulfonyl)-1,3-dioxepan-5-ol (4). Oxone

(2.0 mmol) was added by portions for 1.5 hour to a stirred

solution of sulﬁdes (1.5 mmol) and NaHCO₃(7.3 mmol) in

20 ml of acetone-water mixture (1 :1, v/v). (e reaction

mixture was stirred for 1 hour, then CHCl₃(100 ml) was

added. (e aqueous layer was separated, saturated with

Journal of Chemistry

3

NaCl, and extracted with CHCl₃. Organic phases were

combined and dried over MgSO₄. (e product was puriﬁed

by column chromatography (eluent petroleum ether-ethyl

acetate, 2 :1).

2.2.6. 5-(Phenylsulfonyl)-4,7-dihydro-1,3-dioxepine (7).

K₂CO₃(9 mmol) was added to a solution of acetate 5

(3 mmol) in 20 ml of methanol. (e mixture was stirred for

1 hour, K₂CO₃was ﬁltered oﬀ, and then the solvent was

removed. (e product was puriﬁed by column chroma-

tography (eluent petroleum ether-ethyl acetate, 1 :1).

Yield 95%, colorless crystals, m.p. 86^°C–87^°C. ¹H NMR

(CDCl₃), δ: 4.41–4.45 br. m (2O, O⁴), 4.45–4.48 br. m (2O,

Yield 85%, colorless oil. ¹H NMR (CDCl₃), δ: 3.24 br. s

(1O, PO), 3.30–3.36 m (1O, O⁶, ³J(O⁶O⁵) � 6.75 Hz, ³J(O⁶

O⁷_C) � 3.65 Hz, ³J(O⁶O⁷_A) � 8.14 Hz), 3.73–3.80 m (1O,

O⁴

,

²J(O⁴O⁴_C) � −12.23 Hz, ³J(O⁴O⁵) � 7.1 Hz),

A

3.81–3.88 m ^A(1O, O⁷

,

²J(O⁷O⁷_C) � −12.8 Hz), 3.96–

O⁷), 4.82 s (2O, O²), 7.02 t (1O, O⁶, J(O⁶O⁷) � 3.3 Hz),

3

A

4.04 m (2O, O⁷_C, O⁴_A, J(O⁴_CO⁵) � 3.3 Hz), 4.26 dt (1O,

7.51–7.88 m (5O, S₆O₅). ¹³C NMR (CDCl₃), δ: 63.80 (S⁷),

65.95 (S⁴), 96.58 (S²), 128.01 (C_Ar), 129.54 (C_Ar), 133.81

(C_Ar), 139.20 (C_Ar), 141.35 (S⁶), 143.52 (S⁵). MALDI-MS:

241 [N + O]⁺.

3

O⁵, J(O⁵PO) � 3.0 Hz), 4.60 and 4.71 (AB, 2O, 2O²,

3

²J(O²O²_A) � −4.82 Hz), 7.57–7.94 m (5O, S₆O₅). ¹³C

NMR^C(CDCl₃), δ: 61.57 (S⁷), 67.91 (S⁵), 68.59 (S⁴), 69.96

(S⁶), 95.07 (S²), 128.72 (C_Ar), 129.57 (C_Ar), 134.51 (C_Ar),

137.41 (C_Ar). MALDI-MS: 259 [N + O]⁺, 281 [N + Na]⁺,

297 [M + K]⁺.

2.2.7. cis-2,3-Epoxybutane-1,4-diol (11). Compound 11

was obtained from compound 10 (1.76 g, 20 mmol) using

a procedure similar to that used for the synthesis of epoxide

2. Yield 85% (1.77 g), colorless crystals, m.p. 50–51^°C.

2.2.4. 6-(Phenylthio)-1,3-dioxepan-5-yl Acetate (5). Ac₂O

(7.5 mmol), Et₃N (7.5 mmol), and DMAP (0.05 mmol) were

successively added to a stirred solution of hydroxyl sulﬁde

(5 mmol) in 20 ml of CH₂Cl₂, and the reaction mixture was

stirred for 1 hour. (en, the solvent was evaporated under

reduced pressure, and the product was puriﬁed by column

chromatography (eluent petroleum ether-ethyl acetate, 7 :1).

Yield 96%, colorless oil. ¹H NMR (CDCl₃), δ: 2.02 s (3O,

2.2.8. 3-(Phenylthio)butane-1,2,4-triol (12). A mixture of

epoxide 11 (1.77 g, 17 mmol), thiophenol (1.91 ml,

18.7 mmol), and DABCO (0.019 g, 0.17 mmol) in 50 ml of

water was heated on an oil bath (90^°C) under stirring. (e

reaction was monitored by TLC. (e reaction mixture was

extracted with CH₂Cl₂(3 ×15 ml), and the organic layers

were combined and dried over MgSO₄. (e product was

puriﬁed by column chromatography (eluent acetone). Yield

82%, colorless crystals, m.p. 91–92^°C.

3

SO₃), 3.33 dt (1O, O⁶, J(O⁶O⁵) � 5.7 Hz, J(O⁶O⁷_A) �

6.35 Hz, J(O⁶O⁷_C) � 2.5 Hz), 3.78 dd (1O, O⁷_A, J(O⁷

3

2

A

O⁷_C) � −12.3 Hz), 3.82 dd (1O, O⁴_A, ²J(O⁴_AO⁴_C) � −12.6 Hz,

³J(O⁴_AO⁵) � 5.5 Hz), 3.99 dd (1O, O⁴_C, ³J(O⁴_CO⁵) � 2.4 Hz),

4.09 dd (1O, O⁷_C), 4.63 and 4.75 (AB, 2O, 2O², J(O²

2

A

O²) � −4.5 Hz), 4.91 m (1O, O⁵), 7.18–7.47 m (5O, S₆O₅).

B

2.2.9. (Z)-4-Hydroxybut-2-en-1-ylAcetate(13). A solution of

Ac₂O (5.1 g, 50 mmol) in 40 ml of CH₂Cl₂was slowly added

to a stirred solution of diol 10 (5.35 g, 60.72 mmol) and Et₃N

(5.06 g, 50.1 mmol) in 120 ml of CH₂Cl₂, and the reaction

mixture was stirred for an additional 1 hour. (en, the

reaction mixture was washed with saturated aqueous so-

lutions of NaHCO₃(50 ml) and NaCl (2 × 50 ml), and the

organic layer was dried over MgSO₄. (e product was

puriﬁed by column chromatography (eluent petroleum

ether-ethyl acetate, 4 :1). Yield 58%. (e spectral data for

the obtained compound completely correspond to those

reported in literature [19].

¹³C NMR (CDCl₃), δ: 20.53 (SO₃), 51.59 (S⁶), 64.94 (S⁷⁽⁴⁾),

65.01 (S⁴⁽⁷⁾), 73.30 (S⁵), 93.91 (S²), 127.01 (C_Ar), 128.69 (C_Ar),

131.46 (C_Ar), 133.07 (C_Ar), 169.42 (SP). MS (EI): m/z (%) �

268 (N⁺, 5).

2.2.5. 6-(Phenylsulfonyl)-1,3-dioxepan-5-yl Acetate (6).

Oxone (2.0 mmol) was added by portions for 1.5 hour to

a stirred solution of sulﬁdes (1.5 mmol) and NaHCO₃

(7.3 mmol) in 20 ml of acetone-water mixture (1 :1, v/v). (e

reaction mixture was stirred for 1 hour, and then CHCl₃

(20 ml) was added. (e aqueous layer was separated, satu-

rated with NaCl, and extracted with CHCl₃. Organic layers

were combined and dried over MgSO₄. (e product was

puriﬁed by column chromatography (eluent petroleum

ether-ethyl acetate, 7 :1).

2.2.10. (3-(Hydroxymethyl)oxirane-2-yl)methyl Acetate (14).

Compound 14 was obtained from compound 13 (1.41 g,

10.6 mmol) using a procedure similar to that used for the

synthesis of epoxide 2. Yield 70% (1.1 g), colorless oil. (e

spectral data for the obtained compound completely cor-

respond to those reported in literature [20].

Yield 80%, colorless crystals, m.p. 88^°C–89^°C. ¹H NMR

3

(CDCl₃), δ: 1.84 s (3O, SO₃), 3.48–3.53 m (1O, O⁶, J(O⁶

3

O⁵) � 5.6 Hz, J(O⁶O⁷_A) � 6.88 Hz, J(O⁶O⁷_C) � 3.03 Hz),

3.87–3.97 m (2O, O⁴_A, O⁴

,

C

²J(O⁴O⁴_C) � −13.06 Hz,

A

³J(O⁴O⁵) � 4.9 Hz, J(O⁴O⁵) � 2.75 Hz), 4.13 dd (1O,

3

O⁷_A, ^A²J(O⁷_AO⁷_C) � −12.96 Hz), 4.36 dd (1O, O⁷_C), 4.63 and

2.2.11. 3,4-Dihydroxy-2-(phenylthio)butyl Acetate (16) and

2,4-Dihydroxy-3-(phenylthio)butylAcetate(15). Compounds 15

and 16 were obtained from epoxide 14 (0.57 g, 3.85 mmol)

using a procedure similar to that used for the synthesis of

dioxepane 3. An inseparable mixture of isomers 15 and 16 in 1 :

1 ratio was obtained as clear oil. Yield 63% (0.63 g). Mass

spectrum (EI) m/z (%): 256 (N⁺, 83).

C

4.81 (AB, 2O, 2O², J(O²O²_C) � −5.16 Hz), 5.34 m (1O,

2

A

O⁵), 7.56–7.95 m (5O, S₆O₅). ¹³C NMR (CDCl₃), δ: 20.62

(SO₃), 61.83 (S⁷), 67.83 (S⁶), 67.94 (S⁴), 69.58 (S⁵), 95.90

(S²), 128.84 (C_Ar), 129.33 (C_Ar), 134.18 (C_Ar), 138.19 (C_Ar),

169.42 (SP). MALDI-MS: 301 [N + O]⁺, 323 [N + Na]⁺,

339 [M + K]⁺.

4

Journal of Chemistry

2.2.12. (5-(Phenylthio)-1,3-dioxan-4-yl)methanol (9). A

mixture of acetates 15 and 16 (3.0 g, 11.72 mmol), para-

formaldehyde (1.0 g), and calcined copper sulfate (1.0 g) in

CH₂Cl₂in the presence of catalytic amounts of p-toluene-

sulfonic acid was stirred at 20^°C for 48 hours. Copper sulfate

was removed by ﬁltration, and the solvent was removed

under vacuum. (e product was puriﬁed by column

chromatography (eluent petroleum ether-ethyl acetate, 5 :1).

Yield 24%, colorless crystals, m.p. 85^°C–86^°C. ¹H NMR

(CDCl₃), δ: 2.2 br. s (1O, PO), 3.06–3.09 m (1O, O⁵, ³J(O⁵

O⁴) � 2.3 Hz, ³J(O⁵O⁶_A) � 2.0 Hz, ³J(O⁵O⁶_C) � 1.8 Hz),

2.2.14. 5-Methoxy-6-(phenylthio)-1,3-dioxepane (18).

CH₃OH (30 ml) and double molar excess of NaOH were

added to dioxepane 3 (1.57 g, 6.42 mmol), and the reaction

mixture was heated on an oil bath under reﬂux for 10 hours.

(e solvent was evaporated, and the product was extracted

with diethyl ether (2 ×10 ml) from the residue. (e extract

was evaporated under vacuum, and the product was puriﬁed

by column chromatography (eluent petroleum ether-ethyl

acetate, 9 :1).

Yield 46% (0.7 g), colorless oil. ¹H NMR (CDCl₃), δ: 3.22

3

dt (1O, O⁶, J(O⁶O⁵) � 4.9 Hz, J(O⁶O⁷_A) � 5.2 Hz, J(O⁶

O⁷_C) � 2.2 Hz), 3.28–3.34 m (1O, O⁵, ³J(O⁵O⁴_A) � 5.9 Hz, ³J

(O⁵O⁴_C) � 2.5 Hz, ⁴J(O⁵O⁷_A) � −1.1 Hz), 3.34 s (3O, SO₃),

3.59

dd

(1O,

SO_A

O_CPO,

²J(SO_AO_CPO

SO_AO_CPO) � −11.7 Hz, ³J(SO_AO_CPO O⁴) � 4.7 Hz),

2

3.80–3.87 m

(2O,

O⁶

,

SO_AO_CPO,

²J(O⁶

3.75–3.87 m (1O, O⁴_A, O⁷_A, J(O⁴O⁴_C) � −12.3 Hz, J

A

O⁶_C) � −11.8 Hz, ⁴J(O⁶O²_C) � −1.0 Hz, ³J(SO_AO_CPO

(O⁷O⁷_C) � −12.6 Hz), 3.96 dd (1O, O⁷_C), 4.05 dd (1O,

O⁴) � 7.7 Hz), 3.93–3.9^A7 m (1O, O⁴), 3.99–4.04 m (1O,

O⁶_C), 4.64 and 5.03 (AB, 2O, 2O², ²J(O²_AO²_C) � −6.3 Hz),

7.07–7.35 m (5O, C₆H₅). ¹³C NMR (CDCl₃), δ: 47.27 (S⁵),

63.80 (SO₂PO), 70.86 (S⁶), 79.48 (S⁴), 94.18 (S²), 127.48

(C_Ar), 129.31 (C_Ar), 132.12 (C_Ar), 134.67 (C_Ar). MS (EI):

m/z (%) � 226 (N⁺, 93).

O⁴_C), 4.69 and 4.73 (AB, 2O, 2O², ²J(O²_AO²_C) � −4.45 Hz),

7.17–7.44 m (5O, S₆O₅).¹³C NMR (CDCl₃), δ: 52.41 (S⁶),

57.43 (SO₃), 64.63 (S⁷), 65.32 (S⁴), 81.37 (S⁵), 94.46 (S²),

127.24 (C_Ar), 129.15 (C_Ar), 131.67 (C_Ar), 134.35 (C_Ar). MS

(EI): m/z (%) � 240 (N⁺, 86).

A

2.2.15. 3,5-Dioxa-8-thiabicyclo[5.1.0]octane (19). A mixture

of epoxide 2 (1 g, 8.62 mmol), CS(NH₂)₂ (0.66 g, 8.62 mmol),

0.2 ml of concentrated H₂SO₄, and 2.5 ml of water was

stirred for 10 minutes at 20^°C. (en, the solution of 0.8 g of

K₂CO₃ in 4 ml of water was added dropwise to the reaction

mixture. (e product was extracted with benzene (3 × 5 ml),

and the extract was dried over MgSO₄. (e solvent was

removed on a rotary evaporator at 20^°C. Yield 68% (0.77 g),

colorless crystals. (e spectral data for the obtained com-

pound completely correspond to those reported in literature

[28].

2.2.13. 5-Chloro-6-(phenylthio)-1,3-dioxepane (17)

Method 1. Et₃N (0.6 ml, 4.3 mmol) and p-toluenesulfonyl

chloride (TsCl) (0.81 g, 4.25 mmol) were added to a solution

of dioxepane 3 (0.96 g, 4.25 mmol) in 20 ml of CH₂Cl₂. (e

reaction mixture was allowed to stay at 20^°C for 24 hours.

(en, the solvent was removed under vacuum, and the

product was puriﬁed by column chromatography (eluent

petroleum ether-ethyl acetate, 9 :1).

1

Yield 87% (0.9 g), colorless oil. H NMR (CDCl₃), δ:

3.23–3.29 m (1O, O⁶, ³J(O⁶O⁵) � 5.5 Hz, ³J(O⁶O⁷) �

6.3 Hz, ³J(O⁶O⁷_A) � 2.7 Hz, ⁴J(O⁶O⁴_A) � −1.0 Hz), 3.72^Bddd

2.2.16. 6-(Phenylthio)-1,3-dioxepan-5-thiol (20). A mixture

of thiophenol (0.45 g, 4.1 mmol), thiirane 19 (0.53 g,

4.02 mmol), and a catalytic amount of L₂SP₃was heated

until the appearance of ﬁrst bubbles. (e heating source was

removed, and a short-time (<1 minute) spontaneous

boiling-up with a sharp increase of the temperature was

observed. (e reaction mixture was cooled, and the product

was puriﬁed by column chromatography (eluent petroleum

ether-ethyl acetate, 9 :1).

2

3

(1O, O⁴_A, J(O⁴O⁴_C) � −12.5 Hz, J(O⁴O⁵) � 6.1 Hz),

A

3.75 ddd (1O, O⁷_A, J(O⁷O⁷_C) � −12.4 Hz), 3.83 dt (1O,

2

A

O⁵, J(O⁵O⁴_C) � 2.2 Hz), 4.08 dd (1O, O⁷_C), 4.11 dd (1O,

3

O⁴_C), 4.62 and 4.65 (AB, 2O, 2O², ²J(O²_AO²_C) � −4.4 Hz),

7.12–7.35 m (5O, S₆O₅). ¹³C NMR (CDCl₃), δ: 55.71 (S⁶),

60.67 (S⁷), 65.34 (S⁴), 66.89 (S⁵), 93.93 (S²), 127.76 (C_Ar),

129.28 (C_Ar), 132.16 (C_Ar), 133.01 (C_Ar). MS (EI): m/z (%) �

244 (N⁺, 83), 245 (N⁺, 12), 246 (N⁺, 38).

1

Yield 62% (0.6 g), colorless oil. H NMR (CDCl₃), δ:

2.02 d (1O, SH, ³J(SH H⁵) � 7.9 Hz), 2.77–2.86 m (1O, H⁵, ³J

(H⁵H⁶) � 6.4 Hz, ³J(H⁵H⁴_A) � 6.8 Hz, ³J(H⁵H⁴) � 2.8 Hz, ⁴J

(H⁵H⁷_A) � −0.7 Hz), 3.05 dt (1O, H⁶, ³J(H⁶H⁷_A^B) � 7.0 Hz, ³J

Method 2. Et₃N (1.33 ml, 9.5 mmol) and methylsulfonyl

chloride (MsCl) (1.15 g, 10 mmol) were added to a solution of

dioxepane 3 (2.12 g, 9.4 mmol) in 20 ml of CH₂Cl₂. (e re-

action mixture was allowed to stay at 20^°C for 24 hours. (en,

the solvent was removed under vacuum, and the product was

puriﬁed by column chromatography (eluent petroleum ether-

ethyl acetate, 9 :1). Yield 76% (1.75 g), colorless oil.

(H⁶H⁷_C) � 2.8 Hz, ⁴J(H⁶H⁴_A) � −0.7 Hz), 3.54 dd (1O, H⁴

,

A

²J(H⁴H⁴_C) � −12.1 Hz), 3.67 dd (1O, H⁷

,

²J(H⁷

H⁷_C)^A� −12.3 Hz), 3.94 dd (1O, H⁷_C), 3.99 dd (1O,^AH⁴_C), 4.5^A5

and 4.65 (AB, 2O, 2O², ²J(O²O²_C) � −4.3 Hz), 7.03–

A

7.31 m (5O, S₆O₅). ¹³C NMR (CDCl₃), δ: 43.31 (S⁵), 56.78

(S⁶), 66.39 (S⁷), 67.64 (S⁴), 93.80 (S²), 127.53 (C_Ar), 129.13

(C_Ar), 132.20 (C_Ar), 133.36 (C_Ar). MS (EI): m/z (%) � 242

(N⁺, 5).

Method 3. SOCl₂(0.31 g, 2.6 mmol) was added to a solution

of dioxepane 3 (0.3 g, 1.3 mmol) in 30 ml of CHCl₃. (e

mixture was allowed to stay at 20^°C for 24 hours. (en, the

solvent was removed by distillation under vacuum, and the

product was puriﬁed by column chromatography (eluent

petroleum ether-ethyl acetate, 9 :1). Yield 52% (0.17 g),

colorless oil.

2.2.17. 6-(Benzylthio)-1,3-dioxepan-5-ol (21). Compound 21

was obtained from epoxide 2 (1.12 g, 9.66 mmol) using

Journal of Chemistry

5

a procedure similar to that used for the synthesis of com-

4.04 dd (1O, O⁷_C), 4.13 dd (1O, O⁴_C), 4.76 and 4.77 (AB, 2O,

2O², ²J(O²O²_C) � −4.9 Hz), 7.13–7.44 m (4O, 2-CH₃S₆O₄).

¹³C NMR (^ACDCl₃), δ: 20.90 (CH₃), 54.13 (S⁶), 65.42 (S⁷), 66.50

(S⁴), 71.73 (S⁵), 94.38 (S²), 126.77 (C_Ar), 127.38 (C_Ar), 130.66

(C_Ar), 131.41 (C_Ar), 132.99 (C_Ar), 139.56 (C_Ar). MS (EI): m/z

(%) � 240 (N⁺, 39).

pound 3. NaOH was used instead of K₂CO₃.

1

Yield 71% (1.64 g), colorless oil. H NMR (CDCl₃), δ:

2.68–2.73 m (1O, O⁶, ³J(O⁶O⁵) � 6.0 Hz, ³J(O⁶O⁷_A) �

6.7 Hz, ³J(O⁶O⁷_C) � 3.0 Hz, ⁴J(H⁶O⁴_A) � −0.9 Hz), 2.78 br. s

3

(1O, PO), 3.62 dt (1O, O⁵, J(O⁵O⁴_A) � 6.2 Hz, J(O⁵

O⁴_C) � 2.1 Hz), 3.67 dd (1O, O⁷_A, ²J(O⁷_AO⁷_C) � −12.4 Hz),

3.70 ddd (1O, O⁴_A, J(O⁴O⁴_C) � −11.9 Hz), 3.78 s (2H,

2

A

CH₂S), 3.88 dd (1O, O⁷_C), 4.00 dd (1O, O⁴_C), 4.70 and 4.72

2.2.21. 6-(p-Tolylthio)-1,3-dioxepan-5-ol (25). Compound

25 was obtained from epoxide 2 (0.2 g, 1.72 mmol) using

a procedure similar to that used for the synthesis of com-

pound 24.

(AB, 2O, 2O², J(O²O²_C) � −4.5 Hz), 7.23–7.39 m (5O,

2

S₆O₅). ¹³C NMR (CD^ACl₃), δ: 35.83 (CH₂S), 51.71 (S⁶), 65.93

(S⁷), 66.77 (S⁴), 72.03 (S⁵), 94.25 (S²), 127.45 (C_Ar), 128.80

(C_Ar), 128.89 (C_Ar), 138.16 (C_Ar). MS (EI): m/z (%) � 240

(N⁺, 51).

1

Yield 88% (0.36 g), colorless crystals, m.p. 54–55^°C. H

NMR (CDCl₃), δ: 2.33 s (1O, CH₃), 2.80 br. s (1O, PO),

3.10–3.14 m (1O, O⁶, ³J(O⁶O⁵) � 6.0 Hz, ³J(O⁶O⁷_A) �

6.7 Hz, J(O⁶O⁷_C) � 2.9 Hz, J(H⁶O⁴_A) � −0.7 Hz), 3.66 dt

3

4

3

2.2.18. 6-Phenoxy-1,3-dioxepan-5-ol (22). Compound 22

was obtained from epoxide 2 (0.75 g, 6.47 mmol) using

(1O, O⁵, J(O⁵O⁴_A) � 6.2 Hz, J(O⁵O⁴_C) � 2.1 Hz), 3.73

ddd (1O, O⁴_A, ²J(O⁴_AO⁴_C) � −11.8 Hz), 3.79 dd (1O, O⁷

,

A

a procedure similar to that used for the synthesis of com-

pound 3.

²J(O⁷O⁷_C) � −12.4 Hz), 4.04 dd (1O, O⁷_C), 4.08 dd (1O,

O⁴_C),^A4.72 and 4.75 (AB, 2O, 2O², ²J(O²_AO²_C) � −4.5 Hz),

7.09–7.37 m (4O, 4-CH₃S₆O₄). ¹³C NMR (CDCl₃), δ: 21.19

(CH₃), 55.41 (S⁶), 65.74 (S⁷), 66.60 (S⁴), 71.51 (S⁵), 94.31

(S²), 129.28 (C_Ar), 130.07 (C_Ar), 132.98 (C_Ar), 138.07 (C_Ar).

MS (EI): m/z (%) � 240 (N⁺, 51).

Yield 81% (1.1 g), colorless oil. ¹H NMR (CDCl₃), δ: 3.30

br. d (1O, PO, ³J(PH H⁵) � 7.4 Hz), 3.77 ddd (1O, O⁷_A, ²J

(O⁷

O⁷_C) � −12.3 Hz, ³J(O⁶O⁷_A) � 5.0 Hz, ⁴J(H⁵

A

O⁷_A) � −0.8 Hz), 3.87–3.96 m (3O, O⁵, O⁴O⁴_C), 4.03 dd

A

(1O, O⁷_C, J(O⁶O⁷_C) � 1.8 Hz), 4.31–4.35 m (1O, O⁶), 4.77

3

and 4.80 (AB, 2O, 2O², ²J(O²_AO²_C) � −4.7 Hz), 6.94–7.32 m

(5O, S₆O₅). ¹³C NMR (CDCl₃), δ: 64.50 (S⁴), 65.53 (S⁷), 70.97

(S⁵), 78.94 (S⁶), 94.59 (S²), 115.96 (C_Ar), 121.61 (C_Ar), 129.68

(C_Ar), 157.07 (C_Ar). MS (EI): m/z (%) � 210 (N⁺, 71).

2.2.22. 6-((2-Chlorophenyl)thio)-1,3-dioxepan-5-ol (26).

Compound 26 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

Yield 68% (0.31 g), yellow oil. ¹H NMR (CDCl₃), δ: 3.08

3

2.2.19. 6-(Phenylamino)-1,3-dioxepan-5-ol (23). Compound

23 was obtained from epoxide 2 (0.36 g, 3.10 mmol) using

a procedure similar to that used for the synthesis of com-

pound 3. NaOH was used instead of K₂CO₃.

br. s (1O, PO), 3.28–3.32 m (1O, O⁶, J(O⁶O⁵) � 5.3 Hz,

³J(O⁶O⁷_A) � 5.7 Hz, ³J(O⁶O⁷_C) � 2.7 Hz, ⁴J(H⁶

3

O⁴_A) � −1.1 Hz), 3.68–3.74 br. m (1O, O⁵, J(O⁵O⁴_A) �

3

2

5.5 Hz, J(O⁵O⁴_C) � 1.7 Hz), 3.77 ddd (1O, O⁴_A, J(O⁴

Yield 29% (0.19 g), yellow oil. ¹H NMR (CDCl₃), δ: 2.80

br. s (1O, PO), 3.52–3.56 m (1O, O⁶), 3.74–3.91 m (4O, O⁵,

O⁴_A, O⁷_A, O⁷_C), 4.00 dd (1O, O⁴_C, ²J(O⁴_AO⁴_C) � −12.2 Hz,

O⁴_C) � −12.1 Hz), 3.91 ddd (1O, O⁷_A, ²J(O⁷_AO⁷_C) � −12.6 H^Az,

⁴J(O⁷_AH⁵) � −0.5 Hz), 4.07 dd (1O, O⁷_C), 4.13 dd (1O, O⁴),

4.75 and 4.76 (AB, 2O, 2O², J(O²O²_C) � −4.5 Hz), 7.1^C6–

2

A

⁴J(H⁶O⁴) � −1.5 Hz), 4.31 br. s (1O, NO), 4.78 and 4.80

7.48 m (4O, 2-ClS₆O₄). ¹³C NMR (CDCl₃), δ: 53.85 (S⁶), 65.23

B

2

(AB, 2O, O², J(O²O²_C) � −4.4 Hz), 6.64–7.23 m (5O,

(S⁷), 66.49 (S⁴), 71.57 (S⁵), 94.39 (S²), 127.46 (C_Ar), 128.51

(C_Ar), 130.28 (C_Ar), 132.50 (C_Ar), 132.97 (C_Ar), 136.23 (C_Ar).

MS (EI): m/z (%) � 260 (N⁺, 53), 262 (N⁺, 24).

A

S₆O₅). ¹³C NMR (CDCl₃), δ: 56.98 (S⁶), 64.41 (S⁷), 65.57

(S⁴), 69.98 (S⁵), 94.20 (S²), 113.04 (C_Ar), 117.73 (C_Ar),

129.63 (C_Ar), 146.12 (C_Ar). MS (EI): m/z (%) � 209 (N⁺, 61).

2.2.23. 6-((4-Chlorophenyl)thio)-1,3-dioxepan-5-ol (27).

Compound 27 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

2.2.20. 6-(o-Tolylthio)-1,3-dioxepan-5-ol (24). Epoxide 2

(0.2 g, 1.72 mmol) was added to a solution of o-toluenethiol

(0.257 g, 2.07 mmol) and NaOH (0.083 g, 2.07 mmol) in

30 ml of methanol, and the reaction mixture was stirred at

50^°C for 3 hours. (e solvent was evaporated, and the

product was extracted with diethyl ether (2 ×10 ml) from the

residue. (e extract was concentrated under vacuum, and

the product was puriﬁed by column chromatography (eluent

petroleum ether-ethyl acetate, 4 :1).

1

Yield 88% (0.4 g), colorless crystals, m.p. 67–68^°C. H

NMR(CDCl₃), δ: 2.79 dd (1O, PO, ³J(PHH⁵) � 6.8 Hz,

⁴J � −1.4 Hz), 3.02–3.06 m (1O, O⁶, ³J(O⁶O⁵) � 5.7 Hz, ³J(O⁶

3

O⁷_A) � 6.0 Hz, J(O⁶O⁷_C) � 2.7 Hz), 3.50–3.55 br. m (1O,

3

O⁵, J(O⁵O⁴_A) � 5.7 Hz, J(O⁵O⁴_C) � 1.8 Hz), 3.61 ddd

(1O, O⁴_A, J(O⁴O⁴_C) � −12.1 Hz, J(O⁴H⁶) � −0.8 Hz),

2

4

A

1

2

Yield 85% (0.35 g), yellow oil. H NMR (CDCl₃), δ:

3.69 dd (1O, O⁷_A, J(O⁷O⁷_C) � −12.6 Hz), 3.90 dd (1O,

A

2.43 s (1O, CH₃), 2.93 br. s (1O, PO), 3.21–3.25 m (1O,

O⁷_C), 3.93 dd (1O, O⁴_C), 4.59 and 4.61 (AB, 2O, 2O²,

²J(O²O²_C) � −4.5 Hz), 7.10–7.24 m (4O, 4-ClS₆O₄). ¹³C

NMR^A(CDCl₃), δ: 55.13 (S⁶), 65.35 (S⁷), 66.40 (S⁴), 71.49

(S⁵), 94.32 (S²), 129.46 (C_Ar), 32.01 (C_Ar), 133.27 (C_Ar),

133.79 (C_Ar). MS (EI): m/z (%) � 260 (N⁺, 61), 262 (N⁺, 28).

3

O⁶, J(O⁶O⁵) � 5.5 Hz, J(O⁶O⁷_A) � 5.8 Hz, J(O⁶O⁷_C) �

2.7 Hz, J(H⁶O⁴_A) � −0.9 Hz), 3.72 dt (1O, O⁵, J(O⁵O⁴_A) �

4

3

5.7 Hz, ³J(O⁵O⁴_C) � 1.6 Hz), 3.78 ddd (1O, O⁴

,

²J(O⁴

O⁴_C) � −11.9 Hz), 3.87 dd (1O, O⁷_A, ²J(O⁷_AO⁷_C) �^A−12.5 Hz^A),

6

Journal of Chemistry

1

2.2.24. 6-((2,4-Dichlorophenyl)thio)-1,3-dioxepan-5-ol (28).

Compound 28 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

Yield 78% (0.41 g), colorless oil. H NMR (CDCl₃), δ:

3.01 br. s (1H, PO), 3.29–3.33 m (1H, H⁶, ³J(H⁶H⁵) � 5.5 Hz,

³J(H⁶H⁷_A) � 5.7 Hz, ³J(H⁶H⁷_C) � 2.7 Hz, ⁴J(H⁶H⁴_A) � −1.2 Hz),

3.72 dt (1H, H⁵, J(H⁵H⁴_A) � 5.3 Hz, J(H⁵H⁴_C) � 1.5 Hz),

3

1

2

Yield 80% (0.40 g), colorless crystals, m.p. 70–71^°C. H

3.78 ddd (1H, H⁴_A, J(H⁴H⁴_C) � −12.1 Hz), 3.93 dd (1O,

A

NMR (CDCl₃), δ: 3.13 br. d (1O, PO, J(PHH⁵) � 5.6 Hz),

H⁷_A, J(H⁷H⁷_C) � −12.6 Hz), 4.14 dd (1O, H⁷_C), 4.14 dd

3

2

3.24–3.28 m (1O, O⁶, J(O⁶O⁷_A) � 5.4 Hz, J(O⁶O⁷_C) �

(1O, H⁴_C), ^A4.75 and 4.76 (AB, 2O, ²J(O²_AO²_C) � −4.6 Hz),

3

2.6 Hz), 3.67–3.72 br. m (1O, O⁵, ³J(O⁵O⁴_A) � 5.2 Hz, ³J(O⁵

7.07–7.60 m (4H, 2-BrS₆O₄). ¹³C NMR (CDCl₃), δ: 54.17

O⁴_C) � 1.7 Hz), 3.78 ddd (1O, O⁴_A, ²J(O⁴_AO⁴_C) � −12.2 Hz,

(S⁶), 65.21 (C⁷), 66.51 (C⁴), 71.51 (C⁵), 94.42 (C²), 126.70

(C_Ar), 128.12 (C_Ar), 128.50 (C_Ar), 132.03 (C_Ar), 133.59 (C_Ar),

135.14 (C_Ar). MALDI-MS: 328 [M + Na]⁺, 344 [M + K]⁺.

⁴J(O⁴

H⁶) � −1.1 Hz), 3.91 ddd (1O, O⁷

,

²J(O⁷

O⁷_C)^A� −12.6 Hz, ⁴J(O⁷_AH⁵) � −0.7 Hz), 4.06 dd^A(1O, O⁷_C),

4.12 dd (1O, O⁴_C), 4.76 s (2O, 2O²), 7.19–7.45 m (3O, 2,4-

Cl₂S₆O₃). ¹³C NMR (CDCl₃), δ: 54.11 (S⁶), 65.07 (S⁷), 66.34

(S⁴), 71.51 (S⁵), 94.40 (S²), 127.77 (C_Ar), 129.05 (C_Ar),

130.13 (C_Ar), 131.71 (C_Ar), 133.37 (C_Ar), 133.96 (C_Ar), 137.11

(C_Ar). MS (EI): m/z (%) � 294 (N⁺, 46), 296 (N⁺, 22).

A

2.2.28. 6-((3-Bromophenyl)thio)-1,3-dioxepan-5-ol (32).

Compound 32 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

Yield 89% (0.47 g), colorless oil. ¹H NMR (CDCl₃), δ: 2.96 br.

s (1H, PO), 3.22–3.26 m (1H, H⁶, J(H⁶H⁵) � 5.4 Hz, J(H⁶

3

2.2.25. 6-((2-Fluorophenyl)thio)-1,3-dioxepan-5-ol (29).

Compound 29 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

H⁷_A) � 5.8 Hz, J(H⁶H⁷_C) � 2.7 Hz), 3.69 dt (1H, H⁵, J(H⁵

3

H⁴_A) � 5.5 Hz, J(H⁵H⁴_C) � 1.5 Hz), 3.76 dd (1H, H⁴_A, J(H⁴_A

3

2

H⁴_C) � −12.0 Hz), 3.84 dd (1O, H⁷_A, J(H⁷_AH⁷_C) � −12.5 Hz),

2

4.04 dd (1O, H⁷_C), 4.06 dd (1O, H⁴_C), 4.73 and 4.74 (1O, ²J(O²

O²) � −4.6 Hz), 7.13–7.56 m (4O, 3-BrS₆O₄). ¹³C NM^AR

1

Yield 93% (0.39 g), colorless oil. H NMR (CDCl₃), δ:

C

3.07 br. s (1H, PO), 3.15–3.19 m (1H, H⁶, ³J(H⁶H⁵) � 5.4 Hz,

(CDCl₃), δ: 54.75 (S⁶), 65.22 (C⁷), 66.39 (C⁴), 71.50 (C⁵), 94.27

(C²), 122.98 (C_Ar), 129.86 (C_Ar), 130.44 (C_Ar), 130.53 (C_Ar), 133.86

(C_Ar), 136.13 (C_Ar). MALDI-MS: 328 [M + Na]⁺, 344 [M + K]⁺.

³J(H⁶H⁷_A) � 6.3 Hz, ³J(H⁶H⁷_C) � 2.8 Hz), 3.63–3.67 m (1H,

H⁵, ³J(H⁵H⁴_A) � 5.7 Hz, ³J(H⁵H⁴_C) � 1.8 Hz), 3.74 ddd (1H,

2

H⁴_A, J(H⁴H⁴_C) � −12.0 Hz), 3.83 dd (1O, H⁷_A), 4.04 dd

(1O, H⁷

,

^A²J(H⁷H⁷_C) � −12.5 Hz), 4.09 dd (1O, H⁴_C),

A

4.72 and 4.74 (AB, 2O, ²J(O²O²_C) � −4.4 Hz), 7.04–

7.51 m (4H, 2-FS₆O₄). ¹³C NM^AR (CDCl₃), δ: 54.61 (S⁶,

⁴J(FS⁶) � −1.2 Hz), 65.41 (C⁷), 66.44 (C⁴), 71.63 (C⁵), 94.20

(C²), 116.20 (C_Ar, ²J � −23.1 Hz), 120.02 (C_Ar, ²J � −18.0 Hz),

2.2.29. 6-((4-Bromophenyl)thio)-1,3-dioxepan-5-ol (33).

Compound 33 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

1

3

Yield 91% (0.48 g), colorless crystals, m.p. 58–59^°C. H

124.75 (C_Ar, J � 3.8 Hz), 130.38 (C_Ar, J � 8.1 Hz), 135.49

(C_Ar), 162.59 (C_Ar, ¹J � 246.0 Hz). MALDI-MS: 267 [M + Na]⁺,

283 [M + K]⁺.

NMR (CDCl₃) δ: 3.00 br. d (1H, PO, J(PH H⁵) � 3.5 Hz),

3

3.18–3.23 m (1H, H⁶, ³J(H⁶H⁵) � 5.5 Hz, ³J(H⁶H⁷_A) � 5.9 Hz,

³J(H⁶H⁷) � 2.7 Hz, J(H⁶H⁴) � −0.8 Hz), 3.72–3.77 br. m

4

C

A

(1H, H⁵, J(H⁵H⁴_A) � 5.7 Hz), 3.74–3.78 m (1H, H⁴_A, J(H⁴

H⁴) � −12.1 Hz), 3.83 dd (1O, H⁷_A, ²J(H⁷_AH⁷) � −12.5 Hz^A),

4.0^C5 t (1O, H⁷), 4.06 t (1O, H⁴), 4.73 and 4.^C75 (AB, 2O, ²J

(O²O²_C) �^C−4.6 Hz), 7.27–7.^C44 m (4O, 4-BrS₆O₄). ¹³C

NM^AR (CDCl₃), δ: 54.91 (S⁶), 65.28 (C⁷), 66.39 (C⁴), 71.46 (C⁵),

94.30 (C²), 121.66 (C_Ar), 132.36 (C_Ar), 132.74 (C_Ar), 133.30

(C_Ar). MALDI-MS: 328 [M + Na]⁺, 344 [M + K]⁺.

3

2

2.2.26. 6-((4-Fluorophenyl)thio)-1,3-dioxepan-5-ol (30).

Compound 30 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

Yield 89% (0.37 g), colorless crystals, m.p. 86–87^°C.

¹H NMR (CDCl₃), δ: 2.91 br. s (1H,PO), 3.08–3.12 m (1H,

3

H⁶, J(H⁶H⁵) � 5.9 Hz, J(H⁶H⁷_A) � 6.4 Hz, J(H⁶H⁷_C) �

2.8 Hz, ⁴J(H⁶H⁴_A) � −0.8 Hz), 3.63–3.68 br. m (1H, H⁵, ³J(H⁵

2.2.30. He Separation of Racemic 6-(Phenylthio)-1,3-

dioxepan-5-ol 3 to Enantiomers by Fermentative Acylation

with Use of Lipase PS. A mixture of vinyl acetate (2.3 ml,

25 mmol) and lipase PS (0.5 g) immobilized on a diatomite

was added to a solution of racemic 6-(phenylthio)-1,3-

dioxepan-5-ol 3 (2.83 g, 12.52 mmol) in 30 ml of toluene.

(e reaction mixture was stirred at 20^°C for 48 hours. (en,

lipase was ﬁltered oﬀ, the solvent was evaporated under

reduced pressure, and the product was separated by column

chromatography (eluent petroleum ether-ethyl acetate, 7 :1).

H⁴_A) � 6.0 Hz, ³J(H⁵H⁴_C) � 2.1 Hz), 3.74 ddd (1H, H⁴

,

A

²J(H⁴

H⁴_C) � −12.0 Hz), 3.80 dd (1O,H⁷

,

²J(H⁷

H⁷_C)^A� −12.5 Hz), 4.02dd (1O, H⁷_C), 4.07 dd (1O, H⁴_C), 4.7^A2

and 4.74 (AB, 2O, ²J(O²_AO²_C) � −4.4 Hz), 9.97–7.48 m (4H,

4-FS₆O₄). ¹³C NMR (CDCl₃), δ: 55.89 (S⁶), 65.47 (C⁷),

66.47 (C⁴), 71.44 (C⁵), 94.31 (C²), 116.46 (C_Ar, ²J � −21.9 Hz),

A

128.19 (C_Ar), 135.14 (C_Ar

,

³J � 8.2 Hz), 162.76 (C_Ar

,

¹J � 248.5 Hz). MALDI-MS: 267 [M + Na]⁺, 283 [M + K]⁺.

2.2.27. 6-((2-Bromophenyl)thio)-1,3-dioxepan-5-ol (31).

Compound 31 was obtained from epoxide 2 (0.2 g, 1.72 mmol)

using a procedure similar to that used for the synthesis of

compound 24.

2.2.31. (5S,6S)-6-(Phenylthio)-1,3-dioxepan-5-ol (3-SS).

Yield 45% (1.42 g), [α]²⁴_D� 1.7^°(c, 5; CH₂Cl₂), ee > 99%. (e

spectral data completely correspond to the racemic sample.

Journal of Chemistry

7

2.2.32. (5R,6R)-6-(Phenylthio)-1,3-dioxepan-5-yl Acetate (5-

2.2.38. (5R,6R)-6-((2-Bromophenyl)thio)-1,3-dioxepan-5-yl

RR). Yield 46% (1.55 g), [α]²⁴_D� −5.3^°(c, 5; CH₂Cl₂),

ee > 99%. (e spectral data completely correspond to the

racemic sample.

Acetate (35). (is compound was obtained from racemic

alcohol 31 (1 g, 3.28 mmol) using a procedure similar to that

used for the synthesis of compound 5-RR.

Yield 45% (0.51 g), colorless oil, [α]²⁴_D� −0.2^°(c, 5;

CH₂Cl₂), ee > 99%. ¹H NMR (CDCl₃), δ: 2.08 s (3O, SO₃),

3.43–3.48 m (1O, O⁶, ³J(O⁶O⁵) � 4.6 Hz, ³J(O⁶O⁷_A) � 5.3 Hz,

2.2.33. (5R,6R)-6-(Phenylthio)-1,3-dioxepan-5-ol (3-RR).

K₂CO₃(28 g, 9.3 mmol) was added to a solution of com-

pound 5-RR (0.83 g, 3.1 mmol) in 20 ml methanol. (e

mixture was stirred for 1 hour, then K₂CO₃was ﬁltered oﬀ,

and the solvent was removed under vacuum. (e product

was puriﬁed by column chromatography (eluent petroleum

ether–ethyl acetate, 1 :1). Yield 84% (0.59 g), [α]²⁴_D� −1.7^°

(c, 5; CH₂Cl₂), ee > 99%. (e spectral data completely cor-

respond to the racemic sample.

³J(O⁶O⁷_C) � 2.2 Hz, ⁴J(O⁶O⁴) � −1.2 Hz), 3.92 ddd (1O, O⁴,

A

²J(O⁴_AO⁴) � −12.8 Hz, ³J(O⁴O⁵) � 4.7 Hz), 3.96 ddd (1O,

B

O⁷_A, ²J(O⁷_AO⁷_C) � −12.3 Hz,^A⁴J(O⁷_AO⁵) � −0.8 Hz), 4.13 dd

(1O, O⁴_C, ³J(O⁴O⁵) � 2.0 Hz), 4.18 dd (1O, O⁷_C), 4.77 and

C

4.82 (AB, 2O, 2O², ²J(O²_AO²_C) � −4.4 Hz), 4.92 dt (1O, O⁵),

7.09–7.60 m (4O, 2−BrS₆O₄). ¹³S NMR (CDCl₃), δ: 21.13

(SO₃), 51.72 (S⁶), 64.87 (S⁷⁽⁴⁾), 65.47 (S⁴⁽⁷⁾), 73.65 (S⁵), 94.47

(S²), 126.64 (C_Ar), 128.05 (C_Ar), 128.55 (C_Ar), 132.40 (C_Ar),

133.49 (C_Ar), 134.97 (C_Ar), 170.10 (SP). MALDI-MS: 370

[M + Na]⁺, 386 [M + L]⁺.

2.2.34. (5S,6S)-6-((2-Fluorophenyl)thio)-1,3-dioxepan-5-ol

(29-SS). (is compound was obtained from racemic alco-

hol 29 (1.00 g, 4.09 mmol) using a procedure similar to that

used for the synthesis of compound 3-SS. Yield 45% (0.45 g),

colorless oil, [α]²⁴_D� 1.2^°(c, 5; CH₂Cl₂), ee > 99%. (e spectral

data completely correspond to the racemic sample.

2.2.39. (5R,6R)-6-((2-Bromophenyl)thio)-1,3-dioxepan-5-ol

(31-RR). (is compound was obtained from acetate 35

(0.5 g, 1.44 mmol) using a procedure similar to that used for

the synthesis of compound 3-RR. Yield 98% (0.43 g), col-

orless oil, [α]²⁴_D� −1.0^°(c, 5; CH₂Cl₂), ee > 99%. (e spectral

data completely correspond to the racemic sample.

2.2.35. (5R,6R)-6-((2-Fluorophenyl)thio)-1,3-dioxepan-5-yl

Acetate (34). (is compound was obtained from racemic

alcohol 29 (1.00 g, 4.09 mmol) using a procedure similar to

that used for the synthesis of compound 5-RR.

2.2.40. (5S,6S)-6-((3-Bromophenyl)thio)-1,3-dioxepan-5-ol

(32-SS). (is compound was obtained from racemic alco-

hol 32 (1.0 g, 3.28 mmol) using a procedure similar to that

used for the synthesis of compound 3-SS. Yield 40% (0.40 g),

colorless crystals, m.p. 69–70^°C, [α]²⁴_D� 1.2^°(c, 5; CH₂Cl₂),

ee > 99%. (e spectral data completely correspond to the

racemic sample. HPLC retention time 109.9 min (chiral

stationary phase).

Yield 46% (0.54 g), colorless crystals, m.p. 51–52^°C,

[α]²⁴_D� −0.4^°(c, 5; CH₂Cl₂), ee > 99%. ¹H NMR (CDCl₃),

3

δ: 2.05 s (3O, SO₃), 3.34–3.38 m (1O, O⁶, J(O⁶O⁵) �

5.5 Hz, ³J(O⁶O⁷_A) � 6.5 Hz, ³J(O⁶O⁷_C) � 2.1 Hz), 3.87 dd

(1O, O⁷_A, ²J(O⁷_AO⁷_C) � −12.3 Hz), 3.89 dd (1O, O⁴_A, ²J

(O⁴_AO⁴_C) � −12.7 Hz, ³J(O⁴_AO⁵) � 5.6 Hz), 4.08 dd (1O,

3

O⁴_C, J(O⁴O⁵) � 2.1 Hz), 4.15 ddd (1O, O⁷_C), 4.75 and

C

2.2.41. (5R,6R)-6-((3-Bromophenyl)thio)-1,3-dioxepan-5-yl

Acetate (36). (is compound was obtained from racemic

alcohol 32 (1.0 g, 3.28 mmol) using a procedure similar to

that used for the synthesis of compound 5-RR.

4.80 (AB, 2O, 2O², J(O²_AO²_C) � −4.4 Hz), 4.87 dt (1O,

2

O⁵), 7.08–7.54 m (4O, 2-FS₆O₄). ¹³S NMR (CDCl₃), δ:

21.15 (SO₃), 51.89 (S⁶), 65.23 (S⁷⁽⁴⁾), 65.34 (S⁴⁽⁷⁾), 73.82

(S⁵), 94.49 (S²), 116.18 (C_Ar, ²J � −23.1 Hz), 120.09 (C_Ar

,

Yield 40% (0.45 g), colorless oil, [α]²⁴_D� −0.1^°(c, 5;

²J � −17.8 Hz), 124.76 (C_Ar

,

³J � 3.7 Hz), 130.49 (C_Ar

CH₂Cl₂), ee > 99%. ¹H NMR (CDCl₃), δ: 2.09 s (3O, SO₃),

³J � 8.0 Hz), 135.60 (C_Ar), 162.69 (C_Ar

,

¹J � 246.4 Hz),

3

3.45 dt (1O, O⁶, J(O⁶O⁵) � 5.4 Hz, J(O⁶O⁷_A) � 6.2 Hz,

170.19 (SP). MALDI-MS: 309 [M + Na]⁺, 328 [M + L]⁺.

³J(O⁶O⁷_C) � 2.3 Hz), 3.84 dd (1O, O⁷

, )

²J(O⁷O⁷

3

A

C

� −12.3 Hz), 3.87 dd (1O, O⁴_A, J(O⁴O⁴_C) � −12.3 Hz, J

2

(O⁴O⁵) � 5.4 Hz), 4.03 dd (1O, O⁴_C,^A³J(O⁴O⁵) � 2.3 Hz),

A

C

2.2.36. (5R,6R)-6-((2-Fluorophenyl)thio)-1,3-dioxepan-5-ol

(29-RR). (is compound was obtained from acetate 34

(0.5 g, 1.75 mmol) using a procedure similar to that used for

the synthesis of compound 3-RR. Yield 93% (0.40 g), col-

orless oil, [α]²⁴_D� −1.2^°(c, 5; CH₂Cl₂), ee > 99%. (e spectral

data completely correspond to the racemic sample.

4.13 dd (1O, O⁷_C), 4.74 and 4.80 (AB, 2O, 2O², J(O²

2

A

O²_C) � −4.6 Hz), 4.92 dt (1O, O⁵), 7.15–7.63 m (4O,

3-BrS₆O₄). ¹³S NMR (CDCl₃), δ: 21.07 (SO₃), 52.06 (S⁶),

65.08 (S⁷⁽⁴⁾), 65.40 (S⁴⁽⁷⁾), 73.65 (S⁵), 94.38 (S²), 122.84

(C_Ar), 129.85 (C_Ar), 130.37 (C_Ar), 130.42 (C_Ar), 133.81

(C_Ar), 136.07 (C_Ar), 170.04 (SP). MALDI-MS: 370 [M

+ Na]⁺, 386 [M + L]⁺.

2.2.37. (5S,6S)-6-((2-Bromophenyl)thio)-1,3-dioxepan-5-ol

(31-SS). (is compound was obtained from racemic alco-

hol 31 (1.0 g, 3.28 mmol) using a procedure similar to that

used for the synthesis of compound 3-SS. Yield 41% (0.41 g),

2.2.42. (5R,6R)-6-((3-Bromophenyl)thio)-1,3-dioxepan-5-ol

(32-RR). (is compound was obtained from acetate 36

(0.5 g, 1.44 mmol) using a procedure similar to that used for

colorless oil, [α]²⁴_D� 1.0^°(c, 5; CH₂Cl₂), ee > 99%. (e spectral

the synthesis of compound 3-RR. Yield 98% (0.43 g), col-

data completely correspond to the racemic sample.

orless crystals, m.p. 69–70^°C, [α]²⁴_D� −1.2^°(c, 5; CH₂Cl₂),

8

Journal of Chemistry

ee > 99%. (e spectral data completely correspond to the

racemic sample. HPLC retention time 116.6 min (chiral

stationary phase).

2.4. Biological Studies

2.4.1. Antifungal Activity Studies. (e antifungal activity has

been tested against 4 clinical strains, C. albicans, A. fumi-

gatus, E. ﬂoccosum, and Mucor pusilos, that were obtained

from a collection of typical and clinical cultures of the

mycological laboratory of the Kazan Research Institute of

Epidemiology and Microbiology.

(e fungal activity was evaluated in vitro using a mini-

mum inhibitory concentration (MIC) test according to

NCCLS guidelines. (e tested substances were dissolved in

Sabouraud medium to obtain the solutions with concen-

trations two times higher than the ﬁnal ones. (en, 1 ml of

each solution and 1 ml of fungal spore suspension (con-

centration of 10⁶fungal spores per 1 ml) were added to the

test tube. (e ﬁnal concentrations of the tested compounds

were (mg/ml): 10; 5; 2.5; 1.2; 0.6; 0.3; 0.15; 0.07; 0.03; 0.015;

and 0.007. (e fungal spore solutions or vegetative cells were

obtained from a viable 48-hour old yeast-like fungal culture

and 6-day old mycelial fungi. (e test tubes were incubated

at 28^°C–30^°C for 9 days. (e culture growth was followed

with a photoelectric colorimeter at 530 nm using pure

medium as a blank control.

2.2.43. (5S,6S)-6-((4-Bromophenyl)thio)-1,3-dioxepan-5-ol

(33-SS). (is compound was obtained from racemic alco-

hol 33 (1.0 g, 3.28 mmol) using a procedure similar to that

used for the synthesis of compound 3-SS. Yield 39% (0.39 g),

colorless crystals, m.p. 68–69^°C, [α]²⁴_D� 1.0^°(c, 5; CH₂Cl₂),

ee > 99%. (e spectral data completely correspond to the

racemic sample.

2.2.44. (5R,6R)-6-((4-Bromophenyl)thio)-1,3-dioxepan-5-yl

Acetate (37). (is compound was obtained from racemic

alcohol 33 (1.0 g, 3.28 mmol) using a procedure similar to

that used for the synthesis of compound 5-RR. Yield 40%

(0.46 g), colorless oil, [α]²⁴_D� −0.9^°(c, 5; CH₂Cl₂), ee > 99%.

¹H NMR (CDCl₃), δ: 2.09 s (3O, SO₃), 3.32 dt (1O, O⁶,

³J(O⁶O⁵) � 5.4 Hz, ³J(O⁶O⁷_A) � 6.1 Hz, ³J(O⁶O⁷_C) �

2.4 Hz), 3.82 dd (1O, O⁷_A, ²J(O⁷_AO⁷_C) � −12.3 Hz), 3.86 dd

2

3

(1O, O⁴_A, J(O⁴O⁴_C) � −12.5 Hz, J(O⁴O⁵) � 5.3 Hz),

4.03 dd (1O, O⁴_C, ³J(O⁴_CO⁵) � 2.3 Hz), 4.1^A3 dd (1O, O⁷_C),

4.73 and 4.80 (AB, 2O, 2O², ²J(O²_AO²_C) � −4.6 Hz), 4.91 dt

(1O, O⁵), 7.32–7.44 m (4O, 4-BrS₆O₄). ¹³S NMR (CDCl₃),

δ: 21.13 (SO₃), 52.26 (S⁶), 65.23 (S⁷⁽⁴⁾), 65.45 (S⁴⁽⁷⁾), 73.66

(S⁵), 94.46 (S²), 121.75 (C_Ar), 132.27 (C_Ar), 132.68 (C_Ar),

133.48 (C_Ar), 170.11 (SP). MALDI-MS: 370 [M + Na]⁺, 386

[M + L]⁺.

A

2.4.2. Cytotoxicity Studies. Human skin ﬁbroblasts (HSFs)

were isolated from the skin explant according to the con-

ventional protocol [24]. HSFs cells were cultured in the

minimum essential medium Eagle (a-MEM) supplemented

with 10% fetal bovine serum, 2 mM L-glutamine, 100 µg/mL

streptomycin, and 100 U/mL penicillin under standard

conditions (37^°C, 5% CO₂atmosphere). Adhered cells were

collected from the culture ﬂask by detaching them with

trypsin-EDTA solution. Suspended cells were by centrifu-

gation at 200g in PBS. Cytotoxic concentrations (IC₅₀) of

compounds were determined with the use of MTT assay.

Cells were preseeded in a 96-well plate at the density of

1,000–2,000 cells per well and then incubated with aqueous

solutions of the tested compounds for 3 days under standard

conditions. Culture medium in the plate was then replaced

by the fresh one supplemented with 0.5 mg/mL MTT and

additionally kept for 4 h to allow for reduction of MTT into

colored product (formazan) by metabolically active cells.

Optical absorbance of produced formazan, proportional to

viable cell number, was registered on an Inﬁnite 200 PRO

analyzer at 550 nm.

2.2.45. (5R,6R)-6-((4-Bromophenyl)thio)-1,3-dioxepan-5-ol

(33-RR). (is compound was obtained from racemic ace-

tate 37 (0.5 g, 1.44 mmol) using a procedure similar to that

used for the synthesis of compound 3-RR. Yield 91%

(0.40 g), colorless crystals, m.p. 68–69^°C, [α]²⁴_D� −1.0^°(c, 5;

CH₂Cl₂), ee > 99%. (e spectral data completely correspond

to the racemic sample.

2.3. Crystal Structure Determinations

He X-ray diﬀraction data for the crystals of 6, 7, and 9 were

collected on a Smart Apex II automatic diﬀractometer using

graphite monochromated radiation MoK_α(λ 0.71073). (e

structures were solved by a direct method using the SHELXS

[21] program and reﬁned by full-matrix least-squares using

SHELXL2014 [21] program. All the nonhydrogen atoms

were reﬁned with anisotropic atomic displacement param-

eters. H(C) atoms were constrained as riding atoms, with the

3. Results and Discussion

In continuation of our research on reactions of 3,5,8-tri-

oxabicyclo[5.1.0]octanes with nucleophiles and antimycotic

properties of the obtained products [13], in this work we

have carried out the thiolysis reaction of epoxide 2 by

thiophenol followed by functionalization of the resulting

β-hydroxysulﬁde 3 (Scheme 1). (e functionalization was

performed by oxidation of the sulfur atom and/or acylation

of the hydroxyl group (compounds 4–6). Our attempts to

synthesize compound 4 from acetate 6 by removing the

acetate group with potassium carbonate led to formation of

˚

C–H set to 0.95 A. All calculations were performed using

WinGX [22] and APEX [23] programs. Crystallographic

data (excluding structure factors) for the structures 6, 7, and

9 reported in this paper have been deposited with the

Cambridge Crystallographic Data Centre as supplementary

publication, the corresponding CCDC numbers are given in

Table 1. (ese data can be obtained free of charge from (e

Cambridge Crystallographic Data Centre via http://www.

ccdc.cam.ac.uk/data_request/cif.

Journal of Chemistry

Table 1: Parameters of crystals of compounds 6, 7, and 9 and conditions of X-ray diﬀraction experiments.

9

Compound reference

6

7

9

Temperature (K)

Chemical formula

Formula mass

293 (2)

C₁₃H₁₆O₆S

300.32

293 (2)

C₁₁H₁₂O₄S

240.27

Monoclinic

12.770 (5)

7.578 (3)

11.525 (5)

90

293 (2)

C₁₁H₁₄O₃S

226.28

Monoclinic

17.337 (6)

4.8550 (16)

13.336 (4)

90

96.440 (3)

90

Crystal system

Triclinic

8.2534 (12)

9.2870 (14)

10.2792 (15)

110.116 (2)

97.389 (2)

105.359 (2)

692.09 (18)

P-1

˚

A (A)

˚

b (A)

˚

c (A)

α (^°)

β (^°)

c (^°)

100.639 (5)

90

3

˚

Unit cell volume (A )

Space group

No. of formula units per unit cell (Z)

No. of reﬂections measured

No. of independent reﬂections

R_int

1096.1 (8)

P21/c

1115.4 (6)

P21/c

2

4

3436

6931

8394

1883

1764

2414

0.109

0.030

0.031

Final R₁values (I > 2σ(I))

Final wR (F²) values (I > 2σ(I))

Final R₁values (all data)

Final wR (F²) values (all data)

CCDC numbers

0.0664

0.1807

0.0704

0.1858

1513085

0.0351

0.0902

0.0426

0.0949

1513086

0.0546

0.1462

0.0670

0.1568

1513087

OH

O

PhS

HO

PhS

O

a

75%

O

b

93%

e

+

O

OH

1

2

3

8

9

a

c 96%

85%

SO₂Ph

PhO₂S

OAc

PhS

OAc

PhO₂S

OH

O

d

a

O

80%

O

95%

O

7

6

5

4

a - oxone, (CH₃)₂CO, NaHCO₃, H₂O, r.t.; b - PhSH, K₂CO₃, t°C; c - (CH₃C(O))₂O, Et₃N, CH₂Cl₂, r.t.;

d - K₂CO₃, MeOH, 50°C; e - PhCH₃, TsOH, reflux, 10 h

Scheme 1: Synthesis of hydroxysulﬁde of 1,3-dioxepane series and its further functionalization.

compound 7. (is result suggested that the presence of the

electron-withdrawing PhSO₂fragment increased the acidity

of methine proton which led to its elimination even under

weak alkali treatment. Our further attempts to obtain the

corresponding 1,3-dioxolane 8 and 1,3-dioxane 9 with the

reduced cycle size via acidic isomerization of compound 3

were not successful.

initial 1,3-dioxepane 3 was the major component of the

reaction mixture in all cases. Similar results were described

in a previous paper [25]. (e condensation reaction of

butane-1,2,4-triol with paraformaldehyde under similar

conditions led to a mixture of ﬁve- and six-membered rings,

where six-membered ring structure was the product of both

kinetic and thermodynamic control [26, 27]. It was clear that

the presence of thiophenyl group in triol 12 signiﬁcantly

changed the ratio of the obtained isomers. In general, the

obtained results suggested that this method was unsuitable

for the synthesis of 8 and 9.

To evaluate the relative stability of the isomeric ﬁve-, six-,

and seven-membered formals, we calculated the free ener-

gies for their structures by DFT quantum-chemical

B3LYP/6-31G (d,p) method, which was previously vali-

dated for solution of the similar task for stereoisomers of

In order to obtain compounds 8 and 9, we then tried

alternative synthetic routes depicted in Scheme 2. (e in-

termediate 12 was obtained from diol 10 via its oxidation

with oxone followed by thiolysis of the resulting epoxide 11

with thiophenol in hot water in the presence of DABCO.

Further condensation of triol 12 with paraformaldehyde

resulted in an inseparable mixture of compounds 3, 8, and 9,

as well as the products of their reaction with para-

1

formaldehyde. H NMR spectral data demonstrated that

10

Journal of Chemistry

HO

PhS

O

HO

OH

SPh

c

a

85%

b

82%

HO+

OH

O

10

11

12

9

8

24%

not isolated

d 58%

c

HO

OH

SPh

OH

PhS

O

a

70%

e

+

63% (1:1)

OH

OAc

OH

OAc

OH

OAc

13

14

16

15

a - oxone, (CH₃)₂CO, NaHCO₃, H₂O, r.t.; b - PhSH, DABCO, H₂O, 90°C; c - (CH₂O)n, TsOH, CH₂Cl₂, r.t.;

d - (CH₃C(O))₂O, Et₃N, CH₂Cl₂, r.t.; e - PhSH, K₂CO₃, t°C

Scheme 2: Synthesis of hydroxysuldes of 1,3-dioxane and 1,3-dioxolane series.

oxirane 2 and related compounds [28, 29]. ese calcula-

tions aimed at determination of relative thermodynamic

stability of cyclic acetals of diꢀerent types–dioxepanes, di-

oxanes, and dioxolanes. It was found that dioxolane 8 and

dioxane 9 were less stable than dioxepane 3. e diꢀerences

in the relative values of free energies for the mentioned rings

(∆∆G₂₉₈for the most stable conformers: 0.00 kcal/mol–

dioxepan, 0.12 kcal/mol–dioxolane, and 0.69 kcal/mol–

dioxane) allowed us to evaluate the expected “thermody-

namic” ratio of products in the gas phase as 56:38:6. Ac-

counting of solvation eꢀects and possible involvement of

other conformers of each cyclic isomer, as well as calcula-

tions using a diꢀerent basis, could slightly change this ratio,

but the same trend was observed. us, the replacement of

proton on thiophenyl group in the third position of butane-

1,2,4-triol led to preferential formation of the seven-

membered cyclic product in the reaction of condensation

of this triol with paraformaldehyde. It can be concluded that

formation of the seven-membered ring is advantageous both

in terms of thermodynamic (calculated data) and kinetic

(experimental data for the condensation reaction) control.

Compound 9 was obtained using a series of reactions

depicted in Scheme 2. At the rst step, reaction of diol 10

with acetic anhydride (0.8 mol. equiv.) resulted in mono-

isolated by column chromatography on silica gel in 24%

yield as white crystals. Its structure was conrmed by X-ray

analysis (Figure 1). Dioxolane 8 could not be isolated in an

individual form due to presence of impurities with close

chromatographic mobility.

Our further synthetic eꢀort was focused on structural

modications of compound 3, including their enantio-

merically enriched forms (Scheme 3). Treatment of alcohol 3

with para-toluenesulfonyl chloride or methanesulfonyl

chloride in the presence of triethylamine (path a) resulted in

formation of chloride 17 in 87% and 76% yields, respectively.

e reaction with thionyl chloride (path b) was less suc-

cessful and led to the desired product in 52% yield. Methyl

ester 18 was prepared by reaction of chloride 17 in boiling

methanol in the presence of an excess of sodium hydroxide.

e treatment of epoxide 2 with thiourea under aqueous

acidic conditions led to episulde 19. e latter was treated

with thiophenol in the presence of potassium carbonate

without a solvent to obtain mercaptan 20 [28]. In addition,

reactions of epoxide 2 with various nucleophiles, including

benzylthiol, phenol, aniline, and halogen-substituted thio-

phenols, resulted in a series of congeneric alcohols 21–33.

Structures of all the synthesized compounds were con-

rmed by 1D and 2D NMR spectroscopy, mass spectros-

copy, and X-ray analysis. X-ray structures of compounds 6,

7, and 9 are shown in Figure 1.

At the next stage, several racemic compounds were

separated into enantiomers using enzymatic acylation by

lipase PS (Scheme 4) [18]. As a result of two-step synthesis,

we obtained optically active alcohols 3, 29, 31, 32, and 33,

which had equal but opposite values of the rotation angles.

Conguration of the chiral carbon atom at the hydroxyl

group was assigned using the stereospecicity prole of

reactions in the presence of lipase PS, in which only hy-

droxyl groups with R-conguration at the chiral center

were prone to acylation. It was observed that the enzymatic

reaction rate and optical purity of the resulting products

did not depend on the nature and position of the halogen

substituent in the aromatic rings of the studied thiophenyl

moieties.

1

acetylated derivative 13. According to H NMR spectral

data, the ratio of mono- and diacetylated products in un-

separated mixture was 3 :1. e analytical data for the ob-

tained monoacetate 13 completely corresponded to those

described in literature [19]. Compound 13 was then oxidized

by oxone to previously described epoxide 14 [20]. Treatment

of compound 14 with thiophenol in the presence of K₂CO₃

led to a mixture of regioisomers 15 and 16. e reaction was

strongly exothermic, with the temperature increase up to

150^°C that could explain the lack of the reaction selectivity.

e resulting mixture of acetates 15 and 16 was puried

from initial thiophenol and triol 12, formed in small

amounts, by column chromatography on silica gel.

e

resulting acetates 15 and 16, which could not be separated,

were treated with paraformaldehyde to obtain the corre-

sponding mixture of compounds 8 and 9. Dioxane 9 was

Journal of Chemistry

11

C(9)

O(8)

C(12)

O(7)

C(11)

C(10)

C(8)

O(2)

C(13)

C(8)

C(13)

O(4)

C(7)

C(3)

C(2)

S(1)

C(12)

C(11)

C(9)

O(2)

O(1)

C(5)

C(2)

C(7)

O(3)

C(14)

C(15)

C(10)

C(12)

O(6)

O(4)

C(9)

S(1)

C(4)

C(1)

C(2)

C(10)

C(8)

C(1)

C(11)

C(5)

C(1)

C(6)

O(6)

C(7)

C(3)

C(13)

S(1)

O(3)

O(1)

O(5)

6

7

9

Figure 1: e geometry of compounds 6, 7, and 9 according to X-ray structural analysis.

also conrmed by HPLC analysis on a chiral stationary

phase.

PhS

Cl

O

PhS

O

PhS

OH

c

At the nal stage of the work, the antimycotic activity of the

synthesized compounds against a panel of pathogenic mi-

croscopic fungi was tested. Specically, we used four aggressive

clinical isolates of fungi belonging to C. albicans, A. fumigatus,

E. ꢀoccosum, and M. pusillus species. e in vitro experiment

was carried out in liquid medium (Sabouraud glucose

broth) using 2-fold serial dilutions in biological test tubes.

Assessment of the culture growth was performed visually

by comparing the growth of microorganisms in the

presence of the studied test compounds and without them.

e rst lowest concentration of the tested sample (from

a series of serial dilutions), where fungi growth was not

visually detected, was considered as the minimum inhibitory

concentration (MIC). As the reference compounds, two

antimycotics with a broad spectrum of activity frequently

used in clinical practice, £uconazole and terbinane, were

used.

a or b

46%

87% (TsCl)

O

76% (MsCl)

52% (SOCl₂)

17

3

18

PhS

SH

O

S

d

e

68%

62%

O

19

2

20

e 29 - 83%

Nu

OH

a - TsCl or MsCl, CH₂Cl₂, Et₃N, r.t.;

b - SOCl₂, CH₂Cl₂, Et₃N, r.t.;

c - CH₃OH, NaOH, refux;

d - (NH₂)₂CS, H₂O, H₂SO₄, K₂CO₃, r.t.;

e - NuH, K₂CO₃, 70°C

O

21 - 33

e data presented in Table 2 indicate that several

compounds had an expressed antifungal activity with MICs

in the range of 15–60 μg/ml. us, the leading compound 32

in the form of a dextrorotatory SS-enantiomer inhibited the

growth of the studied fungi at the level of terbinane, one of

the most powerful systemic antimycotics. Fluconazole was

signicantly less active in this experimental series. To assess

potential therapeutic window, we have measured the

cytotoxic activity of the obtained compounds against the

NuH: BnSH (21), PhOH (22), PhNH₂(23), 2-CH₃PhSH (24),

4-CH₃PhSH (25), 2-ClPhSH (26), 4-ClPhSH (27),

2,4-Cl₂PhSH (28), 2-FPhSH (29), 4-FPhSH (30),

2-BrPhSH (31), 3-BrPhSH (32), 4-BrPhSH (33)

Scheme 3: Synthesis of new functional derivatives of 1,3-dioxepane

series.

normal cells, human adipose tissue broblasts.

e pre-

To conrm the enantiomeric purity of the obtained al-

cohols, NMR spectra were obtained in the presence of a shift

reagent, europium(III) tris[3-(hepta£uoropropylhydroxy-

methylene)-(+)-camphorate. Figure 2 shows fragments of

¹H NMR spectra of the studied samples in the region of

signals of hydrogen atoms at the acetal carbon atom. For

the optically active alcohols, there are no signals of the

second enantiomer, and these data suggest that the en-

antiomeric excess is close to 100%. It should also be noted

that a mismatch in the chemical shifts of the signals for

each enantiomer with respect to racemate is explained by

diꢀerent amounts of the sample compounds loaded into

sented experimental data (Table 2) indicate that the leading

compound 32-SS possesses a remarkable selectivity of action

against the studied fungal pathogens (selectivity index is

5–10) as compared to terbinane (selectivity index is 0.6–2

against the studied pathogens).

4. Conclusions

In conclusion, in this work, we have developed e¦cient

synthetic approaches to a series of novel 6-(arylthio)-1,3-

dioxepan-5-ols starting from 1,3-dioxacyclohept-5-ene

through its oxidation followed by thiolysis with various

thiophenols. Depending on the reaction conditions, this

process can theoretically lead to the corresponding isomeric

a vial and the shift reagent.

shape and intensity of signals.

is factor also aꢀects the

e high enantiomeric

purity (ee > 99%) of the leading compound 32-SS was

12

Journal of Chemistry

R¹

R³

HO

O

HO

S

O

S

O

R²

a

S

R

+

R²

S

O

R³

R¹

rac

R¹

O

(3) R¹= R²= R³= H

(5) R¹= R²= R³= H

(29) R¹= F, R²= R³= H

(31) R¹= Br, R²= R³= H

(32) R²= Br, R¹= R³= H

(33) R³= Br, R¹= R²= H

(29) R¹= F, R²= R³= H

(31) R¹= Br, R²= R³= H

(32) R²= Br, R¹= R³= H

(33) R³= Br, R¹= R²= H

(34) R¹= F, R²= R³= H

(35) R¹= Br, R²= R³= H

(36) R²= Br, R¹= R³= H

(37) R³= Br, R¹= R²= H

R¹

S

O

R²

R³

R²

R

b

HO

O

R³

O

(3) R¹= R²= R³= H

(5) R¹= R²= R³= H

(29) R¹= F, R²= R³= H

(31) R¹= Br, R²= R³= H

(32) R²= Br, R¹= R³= H

(33) R³= Br, R¹= R²= H

(34) R¹= F, R²= R³= H

(35) R¹= Br, R²= R³= H

(36) R²= Br, R¹= R³= H

(37) R³= Br, R¹= R²= H

a - Lypase PS, 30–40°C, PhCH₃, vinylacetate; b - MeOH, K₂CO₃, r.t.

Scheme 4: Separation of racemic hydroxysulﬁdes into enantiomers.

rac 3

10

[α]²⁴D [CH₂Cl₂]=+1.7°

[α]²⁴D [CH₂Cl₂]=–1.7°

4.70

4.60

4.50

4.40

δ. ppm

Figure 2: Fragments of 1H NMR spectra of racemic alcohol 3 and its enantiomers in the presence of a shift reagent.

Journal of Chemistry

Table 2: Minimum inhibitory concentrations (μg/ml) of the synthesized compounds against the studied fungal strains.

13

Candida

albicans

Aspergillus

fumigatus

Epidermophyton

ﬂoccosum

Mucor

pusilos

IC₅₀(µg/ml), human adipose tissue

Compound

ﬁbroblasts

3-SS

3-RR

3

120

250

500

250

500

120

250

171.6 5.8

81.9 2.2

n/a

21

>500

n/a

22

23

24

25

26

60

>500

120

>500

120

>500

120

>500

120

92.2 8.7

n/a

202.2 10.1

248.8 12.5

142.2 12.9

120

500

250

27

500

>500

250

135.5 16.4

28

>500

120

250

60

>500

120

250

60

>500

120

250

120

15

>500

120

250

120

30

n/a

30

29-SS

29-RR

29

364.5 23.6

500.6 16.1

390.1 20.1

166.6 12.8

141.4 14.5

143.3 10.2

156.0 5.2

178.3 11.5

160.0 4.1

99.8 2.9

76.4 4.8

80.9 1.7

>1500

31-SS

31-RR

31

32-SS

32-RR

32

33-SS

33-RR

33

Fluconazole

Terbinaﬁne

60

120

15

60

120

15

120

15

60

120

250

15

60

120

250

15

120

30

120

250

50

29.2 3.4

ﬁve-, six-, and seven-membered cyclic acetals: 1,3-dioxo-

lanes, 1,3-dioxanes, and 1,3-dioxepanes, respectively.

However, our experimental data supported by quantum-

chemical calculations using B3LYP/6-31G (d,p) method

demonstrated that cyclic formals of 1,3-dioxepane series

are the major products of this reaction. For such struc-

tures, the isomerization reaction is impossible due to

instability of the intermediate carbocation. We have

demonstrated that the corresponding 1,3-dioxolanes and

1,3-dioxanes can be obtained via alternative synthetic

route based on condensation of monoacetylated butanetriols

with paraformaldehyde.

Data Availability

All the necessary analytical and other data are presented in

the manuscript.

Conflicts of Interest

(e authors declare that there are no conﬂicts of interest

regarding the publication of this manuscript.

Acknowledgments

(is paper is dedicated to Professor Evgenii Naumovich

Klimovitskii, the scientist, who made a signiﬁcant contri-

bution to this direction of research, and the teacher, whose

memory will remain forever in our hearts. (is work was

supported by Programs of Competitive Growth of Kazan

(Volga region) Federal University and I.M. Sechenov First

Moscow State Medical University.

Several racemic compounds of 1,3-dioxepane series have

been separated into enantiomers using enzymatic acylation

by lipase PS. For the optically active alcohols, our experi-

mental data suggest that the developed approach leads to

enantiomerically pure compounds with the enantiomeric

excess close to 100%.

Biological screening experiments have demonstrated

that several compounds possess promising antifungal ac-

tivity. (us, the leading compound 32 with S-conﬁguration

of both stereocenters has expressed antifungal activity

against four highly aggressive clinical isolates of fungi

belonging to C. albicans, A. fumigatus, E. ﬂoccosum, and

M. pusillus species, which is comparable with that of

terbinaﬁne and higher than activity of ﬂuconazole. Of

note, the synthesized 1,3-dioxanes were inactive against

the studied fungal strains. (e obtained chemotype rep-

resents a promising starting point for the development of

viable antifungal drug candidates.

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Synthesis and Antifungal Activity of β -Hydroxysulfides of 1,3-Dioxepane Series

DOI: 10.1155/2018/3589342

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