Stereoselective Synthesis of Carane-Type Hydroxythiols and Disulfides Based on Them

Article abstract of DOI:10.1007/s10600-016-1605-8

Isomeric 10-sulfanylcaran-4-ols and 4-sulfanylcaran-3-ols were synthesized and used to prepare disulfides in high yields.

Full text of DOI:10.1007/s10600-016-1605-8

DOI 10.1007/s10600-016-1605-8
Chemistry of Natural Compounds, Vol. 52, No. 2, March, 2016
STEREOSELECTIVE SYNTHESIS OF CARANE-TYPE
HYDROXYTHIOLS AND DISULFIDES BASED ON THEM
1
1*
2
O. A. Banina, D. V. Sudarikov, P. A. Slepukhin,
1
1
L. L. Frolova, and A. V. Kuchin
Isomeric 10-sulfanylcaran-4-ols and 4-sulfanylcaran-3-ols were synthesized and used to prepare disulfides
in high yields.
Keywords: 3-carene, hydroxythiols, disulfides, XSA.
Monoterpene thiols and hydroxythiols are convenient starting materials for asymmetric synthesis of several biologically
active compounds [1]. In particular, this applies to amino derivatives that act as chiral inductors [2–4]. Disulfides, which are
used as ligands in various asymmetric transformations, are some of the oxidation products of thioalcohols [5–9]. Hydroxythiols
and disulfides based on them are also used as chiral inductors for preparing ꢀ,ꢁ-unsaturated sulfoxides and their derivatives
[10, 11] and ꢀ-branched diols [12, 13] and as structural units of biologically active compounds [14].
We reported earlier on the synthesis of pinane-type hydroxythiols [15]. 3-Carene (1) and its oxide were used earlier
to prepare thiols, sulfides, and disulfides of various structures [16]. Herein, results from a search for new chiral inductors such
as ꢁ- and ꢂ-hydroxythiols and disulfides based on O-containing 3-carene derivatives are presented (Scheme 1).
OH
OH
SAc
SH
f
e
7
8
10
SH
OH
SAc
SH
OH
3
O
O
OH
O
a
b
d
e
c
1*
7
+
5
9
1
2
3
4
5
6a
6b
8
OH
11
OH
HO
O
Br
SAc
SH
f
g
h
e
9
10
12
OAc
OAc
I
DATMP =
BAIB =
TEMPO =
N
N
AlEt
2
OH
a. m-CPBA, CHCl , 0ꢃÑ; b. n-BuLi, DATMP, C H , 0ꢃÑ; c. BAIB, TEMPO, CH Cl , room temp.; d. AcSH, Py, 0°Ñꢄ20°Ñ; e. LiAlH ,
3
6
6
2
2
4
Et O, –5ꢃÑ; f. AcSH, TMAF, 40ꢃC; g. NBS, CaCO , dioxane, room temp.; h. t-BuOK, t-BuOH, room temp. (all atoms in NMR spectra are
2
3
numbered as for 3-carene for convenience)
Scheme 1
1) Institute of Chemistry, Komi Scientific Center, Ural Branch, Russian Academy of Sciences, 48 Pervomaiskaya St.,
Syktyvkar, 167982 Republic of Komi, e-mail: sudarikov-dv@chemi.komisc.ru; 2) I. Ya. Postovsky Institute of Organic Synthesis,
Ural Branch, RussianAcademy of Sciences, 20 S. Kovalevskoi St., Ekaterinburg, 620041. Translated from Khimiya Prirodnykh
Soedinenii, No. 2, March–April, 2016, pp. 211–217. Original article submitted July 13, 2015.
©
240
0009-3130/16/5202-0240 2016 Springer Science+Business Media New York

10
3
O
1
8
9
10'
7
5'
3'
1'
O
5
8'
7'
9'
4a
Natural 3-carene (1) was used in the well-known method to produce trans-epoxide 2 [17] (Scheme 1), which is
known to isomerize non-selectively through the action of Al(i-PrO) in toluene. According to GC data, the mixture contained
3
trans-3(10)-caren-4-ol (3, 39%), p- and m-cymene (38%), cis-3(10)-caren-4-ol (12%), trans-2-caren-4-ol (5%), and m-mentha-
4,6-dien-8-ol (3%) [18]. In our hands, alcohol 3 was obtained under analogous conditions as the major product (51% according
to GC). Isomerization of trans-epoxide 2 and ꢀ-pinene trans-epoxide by potassium tert-butoxide (t-BuOK) was reported
[19]. We performed the reaction in anhydrous THF in the presence of t-BuOK and obtained 4-caren-3-ol as the main product
(63% according to GC); in DMSO, primarily m-mentha-4,6-dien-8-ol (85% according to GC). Target trans-3(10)-caren-4-ol
(3) was synthesized by the literature method [17] using diethylaluminum 2,2,6,6-tetramethylpiperidide (DATMP), which
isomerized epoxide 2 into the corresponding alcohol 3 in 97% yield. Subsequent oxidation of 3 used [bis(acetoxy)iodine]benzene
(BAIB)–TEMPO, which is highly selective and effective for oxidation of alcohols into carbonyl compounds [20]. We found
that oxidation of 3 by this system in CH Cl at room temperature for 6 h gave 95% conversion and formed ketone 4 with 70%
2
2
selectivity. However, this compound dimerized during column chromatography over silica gel. The mass spectrum of dimer
4a agreed with the reported structure [21]. Therefore, 10-acetylthiocaran-4-one (5) was synthesized in situ via the reaction
with thioacetic acid in the presence of Py at room temperature. Column chromatography isolated pure thioacetate 5. Its IR
–1
4
spectrum showed two absorption bands at 1690 and 1711 cm that were characteristic of cyclohexane C =O and thioacetate
11
13
10
11
4
S–C =O. The C NMR spectrum contained resonances for C H – (27.9 ppm), S–C =O (196.1), and C =O (214.4). The
NOESY spectrum had cross peaks H /H and H /H that confirmed the cis-configuration of 5. Reduction of 5 by LiAlH
2
8
10
3
1
3
2
4
(2 mol) in Et O formed a mixture of the two diastereomers 6a and 6b (2:1) that was separated into the pure compounds by
2
column chromatography. IR spectra of the resulting thioalcohols were compared with those of the starting thioacetate. Absorption
–1
bands for carbonyls disappeared. Bands in the range 3470–3480 cm appeared and were characteristic of an OH group. PMR
4
spectra of hydroxythiols 6a and 6b showed resonances for H –O at 3.4–4.2 ppm and triplets for SH at 1.31–1.35 ppm with
4
6
4
8
SSCC 8 Hz. The NOESY spectrum of major thiol 6a showed coupling of the H and H protons; of minor 6b, of H and H .
3
This confirmed their stereochemistries.
8
8
8
8
SH
OH
H
SH
10
NOE
NOE
NOE
NOE
10
10
3
1
3
3
1
1
3
1
H
OH
SH
4
4
6
6
6
6
H
4
H
H
H
H
4
H
OH
10
H
H
H
H
H
H
OH
SH
6a
6b
8
12
Other strategies for synthesizing various hydroxysulfides have employed thiolysis of epoxides by potassium thioacetate
in the presence of BF 4Et O [22], thioacetic acid with ꢁ-cyclodextrin [23], Na B O 410H O [24], ion-exchange resinsAmberlist-15
3
2
2
4
7
2
[25] and Amberlite IRA-400 [26], Et N [27], and 1,1ꢅ-bi-2-naphthol [28]. However, trans-epoxide 2 was not opened under
3
the aforementioned conditions. The reaction with thioacetic acid in H O formed 3ꢁ,4ꢀ-caranediol. Opening of epoxide 2 by
2
thioacetic acid in the presence of SiO , Al O , and B O without a solvent formed thioacetate 7, the yields of which were less
2
2
3
2 3
than 10–15%. The side products according to GC-MS were 3(10)-caren-4-ol, 4-isocaranone, 3-acetylthiocaran-4-ol, 4-carene
epoxide, and isopulegone. Thiolysis of 2 by HSAc in Py reduced the amount of side products and increased the yield of 7 by
25%. The best results were obtained by using 2 with acid in the presence of tetramethylammonium fluoride (TMAF). Thioacetate
7 was isolated pure in 48% yield by column chromatography. The IR spectrum contained characteristic absorption bands for
–1
8
10
4
6
4
OH at 3446 cm and for S–C=O at 1691. The NOESY spectrum of 7 showed cross peaks H /H , H /H , and H /OH. This
3
3
confirmed its stereochemistry. Removal of the thioacetate from 7 by LiAlH (1 equiv.) in Et O produced corresponding
4
2
–1
hydroxythiol 8 in 80% yield. The IR spectrum retained the OH absorption band at 3420 cm . The PMR spectrum showed an
SH doublet at 1.42 ppm with SSCC 7 Hz. The NOESY spectrum of 8 retained all characteristic couplings of 7 and confirmed
its configuration.
241

C9
C8
C2
S1
C16
C7
C20
C1
C18
C17
C12
C3
O1
C11
C15
C14
C10
C4
C19
C6
S2
C13
C5
O2
13
C19
C10
C1
C2
C18
O1
S1
C7
C17
C15
C14
C16
C6
O2
C11
C4
C5
C12
C20
C13
C3
C8
S2
C9
16
Fig. 1. X-ray molecular structures of 13 and 16.
cis-Epoxide 10, which was prepared from 3-carene through bromohydrin 9 by the literature method [29] (61% overall
yield from 3-carene), underwent an analogous thiolysis to give thioacetate 11 (48% yield). Its IR spectrum had characteristic
–1
–1
8
4
absorption bands for OH at 3460 cm and S–C=O at 1687 cm . The NOESY spectrum of 11 showed cross peaks H /H ,
3
10
1
4
H
/H , and H /OH. This confirmed its stereochemistry. Reduction of 11 by LiAlH (1 mol) in Et O produced corresponding
3
4 2
–1
hydroxythiol 12 in 76% yield. Its IR spectrum displayed an absorption band for SH at 2553 cm . The PMR spectrum had an
SH doublet (1.31 ppm) with SSCC 9 Hz. The NOESY spectrum of 12 retained all characteristic couplings of 11 and confirmed
its configuration.
Oxidative dimerization of hydroxythiols 6a, 6b, 8, and 12 by I produced the corresponding disulfides 13, 14, 15, and
2
16 (Scheme 2) in 78–99% yields. PMR spectra of the resulting disulfides lacked SH proton resonances of the starting thiols.
13
10
4
C NMR spectra showed that resonances of C in disulfides 13 and 14 and C in 15 and 16 were shifted to weak field by an
average of 15 ppm compared with the starting thiols. The structures of disulfides 13 and 16 were proved by X-ray crystal
structure analyses (XSA) (Fig. 1).
The XSA showed that 13 crystallized in a chiral monoclinic space group. The absolute configuration of the compound
could not be determined using anomalous scattering because the absolute Flack structure parameter was only slightly greater
than its uncertainty. A final conclusion was made by invoking information about the known absolute configurations of the
starting materials. The alcohol fragments were situated anticlinal relative to the S–S bond. The cyclohexane rings had the
half-chair conformation with the C atom bonded to the CH S group deviating from the plane. The CH S group was situated
2
2
in the pseudo-equatorial position; the OH, pseudo-axial. The molecules in the crystal formed infinite chains in which they
were bound to each other via intermolecular H-bonds between OH groups. Other specific intermolecular contacts in the
crystal were not observed.
8
6a
6b
12
a
OH
OH
HO
HO
S
S
S
S
S
S
S
S
OH
OH
HO
HO
13
14
15
16
à. I , EtOH, NaHCO , room temp.
2
3
Scheme 2
242

Compound 16, in contrast with 13, had anomalous scattering that enabled the absolute configuration to be found and
confirmed fully using information about the configurations of the starting reagents. Two crystallographically independent
molecules of 16 crystallized in a chiral orthorhombic space group. The molecules were geometrically similar to each other.
Their confirmations differed sharply from that of 13. The CSSC torsion angle for both molecules was close to 90°. The
cyclohexane fragments adopted the half-chair conformation with the C atom bound to the OH deviating from the plane. The
OH and CH S groups were pseudo-equatorial. An interesting feature of the crystal packing was a cyclic system of two
2
intramolecular and two intermolecular H-bonds involving four O atoms that combined the disulfide molecules into dimers.
The H-bonds in this system also explained the distinct conformational differences between the bicyclic systems of 13 and 16.
The molecules remained rather conformationally flexible despite the structurally rigid cyclopropane fragment in the
bicycle. This was related not only to rotation around the S–S bond but also conformational transitions of the cyclohexane ring.
This should be considered for simulating the interaction of the molecules with various substrates and for predicting the biological
activity of the compounds.
Thus, new isomeric 10-thiocaran-4-ols and 4-thiocaran-3-ols were synthesized. Opening of the 3-carene trans- and
cis-epoxides by thioacetic acid occurred most selectively in the presence of TMAF and formed a single stereoisomer. The
corresponding disulfides were prepared in high yields from the synthesized hydroxythiols.
EXPERIMENTAL
IR spectra were recorded in thin layers or KBr pellets on a Shimadzu IR Prestige 21 FT-IR spectrometer. Melting
13
points were determined on a Gallencamp-Sanyo apparatus. PMR and C NMR spectra were recorded in CDCl with solvent
3
resonances as standards on a Bruker Avance-300 spectrometer (operating frequencies 300.17 and 75.48 MHz, respectively).
13
1
1
1
1
Proton and C resonances were assigned fully using 2D homo- ( H– H COSY, H– H NOESY) and heteronuclear experiments
1
13
( H– C HSQC, HMBC). GC used a Shimadzu GC-2010AF chromatograph, HP1 column, flame-ionization detector, and He
carrier gas and a Focus GC chromatograph (Thermo Scientific) with an HP-5ms column and N carrier gas. GC-MS analysis
2
was performed on a Shimadzu GCMS-QP2010 Plus with an HP-5ms column, He carrier gas, and NIST database. MS analysis
used a Thermo Finnigan LCQ Fleet instrument (electrospray). Optical rotation angles were measured on a Kruss P3002RS
automated polarimeter (Germany). TLC was carried out on Sorbfil plates with detection by phosphomolybdic acid solution
(10%) in EtOH, vanillin solution (3%) in EtOH, and 5% aqueous KMnO . Column chromatography was performed over
4
20
silica gel (0.06–0.2 mm, Alfa Aesar). (+)-3-Carene (94% by GC), [ꢀ] +17.1° (neat), was used. TMAF was prepared by
D
dehydration of the commercial tetrahydrate using azeotropic distillation with benzene.
XSA of 13 and 16 was performed on an Xcalibur 3 automated four-circle diffractometer (Oxford Diffraction) with a
CCD using the standard procedure [Mo Kꢀ-radiation, graphite monochromator, 295(2) K, -scanning in 1° steps] [30].
Absorption corrections were not applied. The structures were solved and refined using the SHELXTL program suite [31].
The structures were solved by direct method and refined for non-hydrogen atoms by anisotropic full-matrix least-squares
2
method over F . H atoms of CH bonds were added at calculated positions and included in the refinement as a rider model with
dependent isotropic thermal parameters. Coordinates of OH H atoms were refined isotropically and independently.
Results of the XSA were deposited in the Cambridge Crystallographic Data Centre under numbers CCDC 1423125-
1423126 with full access and can be requested at www.ccdc.cam.ac.uk/data_request/cif.
23
(+)-(1S,3S,4R,6R)-3,4-Epoxy-3,7,7-trimethylbicyclo[4.1.0]heptane (2), [ꢀ] +12.0° (c 1.0, EtOH)
D
20
23
{lit. [ꢀ] +13.9° (neat)}, and (–)-(1R,3R,6S)-4-methylene-7,7-dimethylbicylco[4.1.0]heptan-3-ol (3), [ꢀ] –110.6° (c 0.9,
D
D
20
CHCl ) {lit. [ꢀ] –119.8° (c 2.5, CHCl )}, were synthesized by the published methods [17].
3
D
3
(–)-(1S,6R)-7,7-Dimethyl-4-methylenebicyclo[4.1.0]heptan-3-one (4). Alcohol 3 (0.41 g, 2.7 mmol) and TEMPO
(0.04 g, 0.3 mmol) in CH Cl (5 mL) at 0°C were treated with BAIB (1.0 g, 3.1 mmol) and stirred at room temperature with
2
2
TLC monitoring. Ketone 4 dimerized during isolation by column chromatography.
Compound 4a was characterized in the literature only by mass spectrometry [21]. Therefore, we characterized it
more fully.
3,5
(1S,3S,3ꢅS,5ꢅR,6R)-4ꢅ,4ꢅ,7,7-Tetramethyl-8ꢅ-oxaspiro[bicyclo[4.1.0]heptane-3,9ꢅ-tricyclo[5.4.0.0 ]undecan]-
26
1ꢅ(7ꢅ)-en-4-one (4a). Orange powder, mp 83°C, [ꢀ] +5.5° (c 0.3, CHCl ), R 0.44 (petroleum ether–Et O, 10:1). IR spectrum
D
3
f
2
–1
+
(KBr, ꢆ, cm ): 1716 (C=O), 1155 (C–O–C). Mass spectrum (ESI, 5 kV), m/z (I , %): 301 ([M + H] , 100), 283 (8), 149 (8).
H NMR spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.63 (1H, br.t, J = 8.4, H-1), 0.76–0.89 (2H, m, H-6, 1ꢅ), 0.83 (6H, s,
rel
1
3
243

CH -8, 8ꢅ), 1.02 (6H, s, CH -9, 9ꢅ), 1.25–1.65 (4H, m, H-6ꢅ, 10ꢅꢀ, 10ꢀ), 1.80–2.13 (4H, m, H-2ꢀ, 10ꢅꢁ, 5ꢀ, 10ꢁ), 2.24–2.36
3
3
13
(3H, m, H-2ꢁ, 5ꢅꢀ, 5ꢁ), 2.40 (1H, dd, J = 15.7, 9.7, H-2ꢅꢁ), 2.82 (1H, dd, J = 16.2, 9.0, H-5ꢅꢁ). C NMR spectrum (75 MHz,
CDCl , ꢇ, ppm): 13.1, 14.5 (C-8, 8ꢅ), 16.4 (C-7), 17.0 (C-1ꢅ), 17.7 (C-1), 19.1 (C-6), 19.6 (C-7ꢅ), 22.8, 22.9 (C-2, 10), 25.1
3
(C-5), 25.9 (C-6ꢅ), 26.7 (C-10ꢅ), 28.1 (C-9, 9ꢅ), 34.4 (C-2ꢅ), 35.9 (C-5ꢅ), 77.1 (C-3ꢅ), 103.8 (C-3), 143.5 (C-4), 215.4 (C-4ꢅ).
S-{(1S,3R,6R)-7,7-Dimethyl-4-oxobicyclo[4.1.0]heptan-3-yl}methyl ethanethioate (5) was synthesized in situ.
A flask with ketone 4 was treated with Py (two drops), cooled to 0°C, treated with HSAc (0.42 mL, 5.9 mmol), stirred at room
temperature for 3 h, and extracted with Et O. The extract was washed successively with saturated Na S O , NaHCO , and
2
2
2
3
3
NaCl solutions and dried over Na SO . The solvent was vacuum distilled. Column chromatography over silica gel [CHCl
2
4
3
23
and CHCl –Et O (50:1) eluents] isolated 0.29 g (48%) of a yellow oily liquid, [ꢀ] –72.5° (c 1.8, CHCl ); R 0.21 (petroleum
3
2
D
3
f
–1
1
ether–Et O, 5:1). IR spectrum (KBr, ꢆ, cm ): 1710 (C=O), 1689 (C=O). H NMR spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz):
2
3
0.83 (3H, s, CH -8), 0.97–1.11 (2H, m, H-6, 1), 1.03 (3H, s, CH -9), 1.31 (1H, td, J = 13.5, 5.1, H-2ꢀ), 2.31 (3H, s, CH -12),
3
3
3
13
2.36–2.60 (4H, m, H-5ꢀ, 2ꢁ, H-3, 5ꢁ), 2.85, 3.03 (2H, 2d, J = 13.5, 6.5, ÑH -10). C NMR spectrum (75 MHz, CDCl , ꢇ,
2
3
ppm): 14.9 (C-8), 19.6 (C-7), 20.0 (C-6), 22.8 (C-1), 27.0 (C-2), 27.8 (C-9), 27.9 (C-10), 30.5 (C-12), 37.2 (C-5), 47.6 (C-3),
196.1 (C-11), 214.4 (C-4).
Hydroxythiols (6a and 6b). A well-stirred suspension of LiAlH (0.27 g, 7.1 mmol) in dry Et O (20 mL) was cooled
4
2
to –5°C under Ar, treated dropwise with a solution of 10-acetylthiocaran-4-one (0.80 g, 3.6 mmol) in dry Et O (10 mL), and
2
stirred for 3 h with TLC monitoring. When the reaction was finished, the mixture was treated (carefully!) with HCl solution
(10%, 10 mL) and extracted with Et O. The combined organic phase was washed with saturated NaCl solution and dried over
2
Na SO . Column chromatography over silica gel [CHCl and CHCl –Et O (20:1) eluents] afforded hydroxythiols 6a (0.17 g,
2
4
3
3
2
22%) and 6b (0.41 g, 52%).
(1R,3S,4R,6S)-7,7-Dimethyl-4-(sulfanylmethyl)bicyclo[4.1.0]heptan-3-ol (6a). White powder, [ꢀ] +72.9° (c 1.8,
23
D
–1
1
CHCl ), R 0.54 (petroleum ether–EtOAc, 4:1). IR spectrum (KBr, ꢆ, cm ): 3473 (OH), 2557 (SH). H NMR spectrum
3
f
(300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.40 (1H, td, J = 9.2, 2.3, H-6), 0.79 (1H, td, J = 9.2, 6.6, H-1), 0.98–1.07 (1H, m, H-2ꢀ),
3
0.99 (3H, s, CH -9), 1.06 (3H, s, CH -8), 1.35–1.45 (1H, m, H-3), 1.35 (1H, t, J = 7.5, SH), 1.46 (1H, s, OH), 1.56 (1H, dt,
3
3
J = 16.0, 2.2, H-5ꢀ), 1.71 (1H, m, H-2ꢁ), 2.24 (1H, ddd, J = 16.2, 8.7, 7.7, H-5ꢁ), 2.45–2.61 (2H, m, ÑH -10), 4.11 (1H, d,
2
13
J = 7.5, H-4). C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.1 (C-8), 17.6 (C-7), 17.7 (C-6), 19.4 (C-2), 22.2 (C-1), 26.9
3
(C-10), 28.7 (C-5), 28.9 (C-9), 42.2 (C-3), 65.1 (C-4).
23
(1R,3R,4R,6S)-7,7-Dimethyl-4-(sulfanylmethyl)bicyclo[4.1.0]heptan-3-ol (6b). Colorless oily liquid, [ꢀ] –71.0°
D
–1
1
(c 1.0, CHCl ), R 0.23 (petroleum ether–EtOAc, 4:1). IR spectrum (KBr, ꢆ, cm ): 3379 (OH), 2559 (SH). H NMR spectrum
3
f
(300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.69–0.78 (2H, m, H-6, 1), 0.89–1.02 (1H, m, H-2ꢀ), 0.92 (3H, s, CH -8), 0.98 (3H, s,
3
3
CH -9), 1.31 (1H, t, J = 8.3, SH), 1.35–1.45 (1H, m, H-3), 1.59–1.70 (1H, m, H-5ꢀ), 1.71 (1H, s, OH), 2.01–2.19 (2H, m,
3
H-5ꢁ, 2ꢁ), 2.53 (1H, ddd, J = 13.2, 8.3, 7.0, ÑH -10ꢀ), 2.78 (1H, ddd, J = 13.2, 8.3, 3.8, ÑH -10ꢁ), 3.40 (1H, td, J = 9.0, 7.5,
2
2
13
H-4). C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.9 (C-8), 17.9 (C-7), 19.8 (C-9), 21.5 (C-1), 24.2 (C-2), 27.3 (C-10),
3
28.8 (C-6), 30.9 (C-5), 43.7 (C-3), 71.5 (C-4).
S-{(1R,3S,4S,6S)-4-Hydroxy-4,7,7-trimethylbicyclo[4.1.0]hept-3-yl}ethanethioate (7). A mixture of epoxide 2
(0.28 g, 1.9 mmol) and TMAF (35 mg, 0.4 mmol) was treated with HSAc (0.53 mL, 7.5 mmol) and stirred at 40°C until the
epoxide disappeared according to TLC. When the reaction was finished, the mixture was extracted with EtOAc. The extract
was washed with saturated NaHCO solution and dried over Na SO . The solvent was removed. Column chromatography
3
2
4
over silica gel [hexane and hexane–Et O (4:1) eluents] isolated the thioacetate (0.20 g, 48%), yellowish oily liquid,
2
23
–1
1
[ꢀ] +0.4° (c 0.5, CHCl ), R 0.71 (benzene–Et O, 3:1). IR spectrum (KBr, ꢆ, cm ): 3446 (OH), 1691 (C=O). H NMR
D
3
f
2
spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.75–0.88 (2H, m, H-1, 6), 0.96 (3H, s, CH -8), 1.01–1.13 (2H, m, H-2ꢀ, 5ꢀ),
3
3
1.03 (3H, s, CH -9), 1.14 (3H, s, CH -10), 1.99 (1H, dd, J = 15.4, 8.0, H-2ꢁ), 2.12 (1H, ddd, J = 14.2, 8.3, 5.5, H-5ꢁ), 2.35 (3H,
3
3
13
s, CH -12), 3.04 (1H, br.s, OH), 3.59 (1H, dd, J = 10.4, 5.5, H-4). C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.6 (C-8),
3
3
17.9 (C-1), 18.5 (C-7), 21.9 (C-6), 25.1 (C-5), 27.9 (C-10), 28.3 (C-9), 30.4 (C-12), 33.1 (C-2), 51.0 (C-4), 72.1 (C-3), 197.6
(C-11).
(1S,3S,4S,6R)-3,7,7-Trimethyl-4-sulfanylbicyclo[4.1.0]heptan-3-ol (8). A well-stirred suspension of LiAlH
4
(0.02 g, 0.6 mmol) in dry Et O (5 mL) was cooled to –5°C under Ar, treated dropwise with a solution of 7 (0.14 g, 0.6 mmol)
2
in dry Et O (5 mL), and stirred for 10 min. The course of the reaction was monitored by TLC. When the reaction was finished,
2
the mixture was treated (carefully!) with HCl solution (10%, 10 mL) and extracted with Et O. The combined organic phases
2
were washed with saturated NaCl solution and dried over Na SO to afford the compound (0.09 g, 80%), colorless oily liquid,
2
4
23
–1
[ꢀ] +47.4° (c 0.9, CHCl ), R 0.58 (petroleum ether–Et O, 1:2). IR spectrum (KBr, ꢆ, cm ): 3422 (OH), 2554 (SH).
D
3
f
2
244

1
H NMR spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.70–0.83 (2H, m, H-1, 6), 0.99 (3H, s, CH -8), 1.02 (3H, s, CH -9),
3
3
3
1.15 (1H, ddd, J = 15.2, 9.1, 5.9, H-5ꢀ), 1.24 (3H, s, CH -10), 1.39 (1H, dd, J = 15.5, 6.0, H-2ꢀ), 1.42 (1H, d, J = 7.2, SH), 1.99
3
13
(1H, dd, J = 15.5, 8.4, H-2ꢁ), 2.12 (1H, br.s, OH), 2.12 (1H, ddd, J = 15.2, 8.3, 6.6, H-5ꢁ), 3.03 (1H, dt, J = 8.3, 7.2, H-4).
C
NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.5 (C-8), 18.6 (C-1), 18.6 (C-7), 21.5 (C-6), 26.7 (C-10), 28.4 (C-9), 28.7 (C-5),
3
31.6 (C-2), 45.6 (C-4), 72.3 (C-3).
(–)-(1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol (9), [ꢀ] –55.0° (c 2.0, CCl ), and
(–)-(1S,3R,4S,6R)-3,4-epoxy-3,7,7-trimethylbicyclo[4.1.0]heptane (10), [ꢀ] –2.1° (c 1.0, CHCl ) {lit. [ꢀ] –5.0° (c 2.0,
23
D
4
23
20
D
3
D
EtOH) were synthesized by the literature methods [29].
S-{(1R,3R,4R,6S)-4-Hydroxy-4,7,7-trimethylbicyclo[4.1.0]hept-3-yl}ethanethioate (11). A mixture of epoxide
10 (0.43 g, 2.8 mmol) and TMAF (52 mg, 0.6 mmol) was treated with HSAc (0.9 mL, 12.6 mmol) and stirred at 40°C until the
oxirane disappeared according to TLC. When the reaction was finished, the mixture was extracted with EtOAc. The extract
was washed with saturated NaHCO solution and dried over Na SO . Column chromatography over silica gel [benzene and
3
2
4
23
benzene–Et O (5:1) eluents] isolated the thioacetate (0.31 g, 48%), yellowish oily liquid, [ꢀ] –30.6° (c 1.0, CHCl ), R 0.73
(benzene–Et O, 3:1). IR spectrum (KBr, ꢆ, cm ): 3458 (OH), 1687 (C=O). H NMR spectrum (300 MHz, CDCl , ꢇ, ppm,
2
D
3
f
–1
1
2
3
J/Hz): 0.59 (1H, t, J = 9.5, H-6), 0.81 (1H, td, J = 9.5, 5.0, H-1), 0.99 (3H, s, CH -8), 1.09 (3H, s, CH -9), 1.18 (3H, s,
3
3
CH -10), 1.36 (1H, dd, J = 14.3, 4.7, H-2ꢀ), 1.15 (1H, ddd, J = 14.9, 12.5, 8.0, H-5ꢀ), 2.08–2.17 (1H, m, H-2ꢁ, 5ꢁ), 2.16 (1H,
3
13
s, OH), 2.33 (3H, s, CH -12), 3.59 (1H, dd, J = 12.5, 7.3, H-4). C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.4 (C-8), 17.9
3
3
(C-7), 19.6 (C-6), 20.7 (C-1), 21.6 (C-10), 27.0 (C-5), 28.7 (C-9), 30.7 (C-12), 35.5 (C-2), 51.0 (C-4), 71.5 (C-3), 197.2
(C-11).
23
(1S,3R,4R,6R)-3,7,7-Trimethyl-4-sulfanylbicyclo[4.1.0]heptan-3-ol (12), yield 76%, white powder, [ꢀ] –61.9°
D
–1
1
(c 1.0, CHCl ), R 0.59 (petroleum ether–Et O, 1:1). IR spectrum (KBr, ꢆ, cm ): 3437 (OH), 2553 (SH). H NMR spectrum
3
f
2
(300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.58 (1H, t, J = 9.7, H-6), 0.81 (1H, td, J = 9.7, 5.0, H-1), 0.98 (3H, s, CH -8), 1.01 (3H, s,
3
3
CH -9), 1.18–1.29 (1H, m, H-2ꢀ), 1.22 (3H, s, CH -10), 1.31 (1H, d, J = 9.0, SH), 1.79 (1H, ddd, J = 14.9, 12.4, 8.0, H-5ꢀ), 2.11
3
3
(1H, dd, J = 14.1, 9.7, H-2ꢁ), 2.27 (1H, s, OH), 2.29 (1H, dd, J = 14.9, 7.0, H-5ꢁ), 2.65 (1H, ddd, J = 12.4, 9.0, 7.0, H-4).
13
C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.3 (C-8), 17.7 (C-7), 20.3 (C-6), 20.4 (C-1), 20.5 (C-10), 28.8 (C-9), 31.5
3
(C-5), 33.8 (C-2), 48.3 (C-4), 71.1 (C-3).
Disulfides (13, 14, 15, 16) (General Method). A solution of hydroxythiol (0.9 mmol) in EtOH (3 mL) was treated
with NaHCO (0.08 g, 1.0 mmol) and I (0.12 g, 0.5 mmol) in EtOH (5 mL), and stirred at room temperature. The course of
3
2
the reaction was monitored by TLC. When the reaction was finished, the EtOH was distilled off. The solid was dissolved in
H O (10 mL) and extracted with Et O (3 ꢈ 15 mL). The extract was washed with saturated KI (15 mL) and NaCl (3 ꢈ 15 mL)
2
2
solutions and dried over Na SO . The ether was distilled off.
2
4
(1R,1ꢅR,3S,3ꢅS,4R,4ꢅR,6S,6ꢅS)-4,4ꢅ-[Disulfandiylbis(methylene)]bis(7,7-dimethylbicyclo[4.1.0]heptan-3-ol) (13).
26
–1
Yield 93%, colorless crystals, mp 87°C, [ꢀ] +51.2° (c 1.5, CHCl ), R 0.76 (hexane–EtOAc, 4:1). IR spectrum (KBr, ꢆ, cm ):
D
3
f
+
3496 (OH). Mass spectrum (ESI, 5 kV), m/z (I , %): 371 ([M + H] , 19), 353 (100), 335 (17), 167 (24), 135 (23), 91 (9).
H NMR spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.42 (1H, td, J = 9.2, 2.1, H-6), 0.81 (1H, td, J = 9.2, 6.7, H-1), 0.99–1.08
rel
1
3
(1H, m, H-2ꢀ), 1.00 (3H, s, CH -8), 1.07 (3H, s, CH -9), 1.50 (1H, br.s, OH), 1.54–1.77 (3H, m, H-5ꢀ, 3, 2ꢁ), 2.27 (1H, ddd,
3
3
13
J = 16.2, 8.7, 7.8, H-5ꢁ), 2.71 (2H, m, CH -10), 4.06 (1H, d, J = 7.8, H-4). C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.2
3
3
(C-8), 17.6 (C-7), 17.7 (C-6), 19.2 (C-2), 22.1 (C-1), 28.4 (C-5), 28.8 (C-9), 38.6 (C-3), 41.4 (C-10), 65.0 (C-4). The crystals
°
°
°
° 3
were monoclinic, space group P2 , a = 6.5426 (6) A, b = 9.7711 (12) A, c = 16.010 (2) A, ꢁ = 99.779 (11)ꢃ, V = 1008.6 (2) A ,
1
–1
–3
Z = 2, F(000) = 404, ꢉ = 0.274 ìì , ꢊ = 1.220 g·cm . A total of 6731 reflections was collected at scan angles 3.16 < ꢋ < 28.35°.
Of these, 4036 were independent (R = 0.0365), including 2589 with I > 2ꢌ(I). The completeness was 99.4%; GooF = 1.005;
int
R = 0.0381; wR = 0.0835 [over reflections with I > 2ꢌ(I)], R = 0.0601, wR = 0.864 (over all reflections). The absolute
1
2
1
2
° –3
Flack structure parameter was –0.05(6). The maximum and minimum residual electron densities were 0.284/–0.183 e4A
.
(1R,1ꢅR,3R,3ꢅR,4R,4ꢅR,6S,6ꢅS)-4,4ꢅ-[Disulfandiylbis(methylene)]bis(7,7-dimethylbicyclo[4.1.0]heptan-3-ol) (14).
26
Yield 99%, yellowish oily liquid, mp 76°C, [ꢀ] –95.8° (c 1.9, CHCl ), R 0.71 (hexane–EtOAc, 2:1). IR spectrum (KBr, ꢆ,
D
3
f
–1
+
1
cm ): 3286 (OH). Mass spectrum (ESI, 5 kV), m/z (I , %): 371 ([M + H] , 100), 353 (72), 167 (13), 135 (17). H NMR
rel
spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.69–0.78 (2H, m, H-1, 6), 0.81–0.94 (1H, m, H-2ꢀ), 0.91 (3H, s, CH -8), 0.98
3
3
(3H, s, CH -9), 1.47–1.67 (2H, m, H-5ꢀ, 3), 1.99–2.20 (2H, m, H-2ꢁ, 5ꢁ), 2.35 (1H, br.s, OH), 2.61 (1H, dd, J = 13.3, 7.0,
3
13
CH -10ꢀ), 3.11 (1H, dd, J = 13.3, 3.7, CH -10ꢁ), 3.39 (1H, td, J = 9.3, 6.8, H-4). C NMR spectrum (75 MHz, CDCl , ꢇ,
3
3
3
ppm): 15.3 (C-8), 17.9 (C-7), 19.9 (C-6), 21.5 (C-1), 25.00 (C-2), 28.8 (C-9), 30.6 (C-5), 41.5 (C-3), 42.0 (C-10), 71.5 (C-4).
245

(1S,1ꢅS,3S,3ꢅS,4S,4ꢅS,6R,6ꢅR)-4,4ꢅ-Disulfandiylbis(3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol) (15). Yield 99%,
26
–1
yellowish oily liquid, [ꢀ] +64.0° (c 1.1, CHCl ), R 0.76 (hexane–EtOAc, 1:1). IR spectrum (KBr, ꢆ, cm ): 3417 (OH).
D
3
f
+
1
Mass spectrum (ESI, 5 kV), m/z (I , %): 371 ([M + H] , 20), 353 (100), 201 (23), 167 (33), 135 (19), 93 (20). H NMR
rel
spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.73 (1H, td, J = 8.5, 7.2, H-1), 0.82 (1H, td, J = 8.5, 6.7, H-6), 0.99 (3H, s,
3
CH -8), 1.03 (3H, s, CH -9), 1.19–1.32 (1H, m, H-2ꢀ, 5ꢀ), 1.29 (3H, s, CH -10), 2.29 (1H, dd, J = 15.6, 8.5, H-5ꢁ), 2.20 (1H,
3
3
3
13
s, OH), 2.35 (1H, ddd, J = 14.8, 8.4, 6.0, H-2ꢁ), 3.00 (1H, dd, J = 9.4, 6.0, H-4). C NMR spectrum (75 MHz, CDCl , ꢇ, ppm):
3
15.5 (C-8), 17.9 (C-6), 18.7 (C-7), 21.8 (C-1), 24.9 (C-2), 27.3 (C-10), 28.3 (C-9), 33.3 (C-5), 59.1 (C-4), 73.0 (C-3).
(1S,1ꢅS,3R,3ꢅR,4R,4ꢅR,6R,6ꢅR)-4,4ꢅ-Disulfandiylbis(3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol) (16). Yield 78%,
26
–1
colorless crystals, mp 109°C, [ꢀ] –128.5° (c 1.0, CHCl ), R 0.8 (hexane–EtOAc, 1:1). IR spectrum (KBr, ꢆ, cm ): 3267
D
3
f
+
1
(OH). Mass spectrum (ESI, 5 kV), m/z (I , %): 371 ([M + H] , 18), 353 (100), 201 (22), 167 (35), 135 (20), 93 (21). H NMR
rel
spectrum (300 MHz, CDCl , ꢇ, ppm, J/Hz): 0.62 (1H, dd, J = 9.5, 8.0, H-6), 0.62 (1H, td, J = 9.5, 4.9, H-1), 1.00 (3H, s,
3
CH -9), 1.02 (3H, s, CH -8), 1.20 (3H, s, CH -10), 1.29 (1H, dd, J = 14.4, 4.9, H-2ꢀ), 1.92 (1H, ddd, J = 14.9, 12.6, 8.0, H-5ꢀ),
3
3
3
2.05 (1H, dd, J = 14.4, 9.5, H-2ꢁ), 2.27 (1H, dd, J = 14.9, 7.3, H-5ꢁ), 2.53 (1H, s, OH), 1.79 (1H, dd, J = 12.6, 7.3, H-4).
13
C NMR spectrum (75 MHz, CDCl , ꢇ, ppm): 15.3 (C-8), 17.9 (C-7), 20.2 (C-6), 20.3 (C-1), 21.7 (C-10), 28.0 (C-5), 28.7
3
°
(C-9), 35.3 (C-2), 63.6 (C-4), 72.5 (C-3). The crystals were orthorhombic, space group P2 2 2 , a = 27.2030 (19) A,
b = 12.2545 (11) A, c = 13.0167 (11) A, V = 4339.2(6) A , Z = 8, F(000) = 1616, ꢉ = 0.254 ìì , ꢊ = 1.135 g·cm . A total
1 1 1
°
°
° 3
–1
–3
of 20,466 reflections was collected at scan angles 2.73 < ꢋ < 26.47°. Of these, 8950 were independent (R = 0.0604),
int
including 3385 with I > 2ꢌ(I). The completeness was 99.7%; GooF = 1.002; R = 0.0424; wR = 0.0605 [over reflections with
1
2
I > 2ꢌ(I)], R = 0.1430, wR = 0.0659 (over all reflections). The absolute Flack structure parameter was –0.13(5). The
1
2
° –3
maximum and minimum residual electron densities were 0.178/–0.163 e4A
.
ACKNOWLEDGMENT
The work was sponsored by the Russian Foundation for Basic Research (13-03-01312 a) and the Ural Branch, RAS
(15-21-3-16). We thank E. N. Zainullina and I. N. Alekseev, staff members of the Laboratory of Physicochemical Research,
Institute of Chemistry, Komi SC, UB, RAS, and S. P. Kuznetsov and E. U. Ipatova for recording the spectral data and
V. A. Belyi, S. A. Patov, and S. L. Smoleva for performing the GC and GC-MS studies.
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