TBD-catalyzed α-sulfenylation of cyclic ketones: Desymmetrization of 4-substituted cyclohexanones

Article abstract of DOI:10.1016/j.tet.2012.05.124

A low loading of triazabicyclo[4.4.0]dec-5-ene (TBD) catalyzes the α-sulfenylation reaction of ketones employing tetramethylthiuram disulfide (TMTDS) as electrophilic reagent. This methodology is mild, effective and straightforward, rendering the desired products in high yield. Prochiral 4-substituted cyclohexanones can be desymmetrized with remarkable diastereoselectivity following this protocol. The dithiocarbamoyl function was shown to be easily removed upon reduction, affording thiols (1-mercaptan-2-ols).

Full text of DOI:10.1016/j.tet.2012.05.124

Tetrahedron 68 (2012) 6438e6446
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
TBD-catalyzed
a
-sulfenylation of cyclic ketones: desymmetrization
of 4-substituted cyclohexanones
ꢀ
*
ꢀ
~
ꢀ
Belen Poladura, Angel Martínez-Castaneda, Humberto Rodríguez-Solla, Carmen Concellon ,
*
Vicente del Amo
ꢀ
ꢀ
ꢀ
Departamento de Química Organica e Inorganica, Universidad de Oviedo, C/Julian Clavería 8, 33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2012
Received in revised form 24 May 2012
Accepted 29 May 2012
Available online 4 June 2012
A low loading of triazabicyclo[4.4.0]dec-5-ene (TBD) catalyzes the a-sulfenylation reaction of ketones
employing tetramethylthiuram disulfide (TMTDS) as electrophilic reagent. This methodology is mild,
effective and straightforward, rendering the desired products in high yield. Prochiral 4-substituted cy-
clohexanones can be desymmetrized with remarkable diastereoselectivity following this protocol. The
dithiocarbamoyl function was shown to be easily removed upon reduction, affording thiols
(1-mercaptan-2-ols).
Keywords:
Organocatalysis
Guanidines
Ó 2012 Elsevier Ltd. All rights reserved.
Stereoselective reactions
1. Introduction
ketones employing triazabicyclo[4.4.0]dec-5-ene (TBD, 5, Fig. 1) as
organocatalyst, and TMTDS as electrophilic reagent.
Sulfur-containing organic structures, particularly carbonyl
compounds, constitute an important class of ligands, display
pharmacological properties, and are useful intermediates in syn-
thetic chemistry.1 The formation of CeS bonds
a to a carbonyl
function (ketones or aldehydes) is a challenging task. Of the
methods employed in their preparation organocatalytic protocols,
either chiral or non-chiral, are especially attractive.2 The advan-
tages are sound and convincing: processes that avoid the use of
metals and take place typically under mild and straightforward
conditions, some of them affording products with high enantio-
meric excess. The sulfur-based electrophilic reagents 1e3 have
been commonly used for such transformations (Fig. 1). Dis-
advantaging, only reagent 2 (Ar¼Ph) is commercially available.
Recently, Enders and co-workers have reported the use of tetra-
methylthiuram disulfide (TMTDS, 4, Fig. 1) in the first base-
promoted a-sulfenylation of aldehydes and ketones that employs
this electrophile.3 TMTDS, a very cheap available reagent,4 was
previously employed in the synthesis of aromatic and hetero-
aromatic thiols from functionalized Grignard5 or zinc reagents.6
Considering our interest in the development of organocatalytic
processes assisted by guanidines and guanidinium salts,7 in this
Fig. 1. Reagents 1e3, employed in organocatalyzed a-sulfenylation reactions of alde-
hydes and ketones. Structures of TMTDS (4) and TBD (5).
paper we present an efficient
a-sulfenylation reaction of cyclic
2. Results and discussion
Guanidines, being extensively used as organocatalysts, present
a rich chemistry.8 Recently we have reported a novel Al2O3/TBD-
catalyzed aldol/retro-aldol reaction that allows preparing dynamic
* Corresponding authors. Tel.: þ34 (0)985 10 3457; fax: þ34 (0)985 10 3075;
ꢀ
e-mail addresses: ccf@uniovi.es (C. Concellon), vdelamo@uniovi.es (V. del Amo).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.124

B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
6439
combinatorial libraries that exhibit complex system behaviour.9
Continuing with our research program we decided to investigate
the ability of this readily available guanidine base on the electro-
philic sulfenylation of ketones employing TMTDS, 4, as electrophilic
reagent. The reaction of TMTDS with a 10-fold excess of cyclohex-
anone, in the presence of 10 mol % TBD, 5, for 120 h, at 20 ꢀC, was
adopted as a model system. In a preliminary study we scrutinized
the role of different common organic solvents, and water, on the
course of this reaction (Table 1). No reaction took place with water,
non-polar organic solvents, acetonitrile or isopropanol (Table 1,
entries 1e5). Moderate conversion was observed in the case of
methanol and dimethylformamide (Table 1, entries 6 and 7),
whereas dimethyl sulfoxide (Table 1, entry 8), or the absence of
solvent (Table 1, entry 9), afforded a mixture of the corresponding
co-workers3 (A: TMTDS (1 equiv), ketone (10 equiv), pyrrolidine
(0.3 equiv), NEt3 (2 equiv) in CH3CN/CH2Cl2 (3:1, 0.5 M) at ꢁ20 ꢀC,
for 6 days; or alternatively B: TMTDS (1 equiv), ketone (10 equiv),
neat, 50 ꢀC). Following either of these protocols A or B, the corre-
sponding a-sulfenylated ketones were all isolated in inferior yield
compared to Table 2.
Considering the efficiency of our catalytic system we decided to
study the possibility of exploring the a-sulfenylation of prochiral 4-
substituted cyclohexanones. Although desymmetrization reactions
are usual in enzymatic transformations, there are few examples of
desymmetrizations using well-established chemical organic sys-
tems.12 Granting conditions in which products can be obtained with
high stereoselectivity, these reactions are a powerful method
for the stereocontrolled preparation of complex synthetic struc-
mono- and
a,
a
0-disulfenylated ketones, 6a and 7,10 respectively,
tures. Initially we explored the a-sulfenylation reaction of
with nearly full conversion, strongly favouring product 6a. Under
neat conditions, rising up the temperature to 30 ꢀC implied a con-
siderable diminution of reaction time11 with a negligible decrease in
the ratio 6a/7 (Table 1, entry 10). Moreover, at 30 ꢀC, the catalyst
loading could be conveniently reduced to 5 mol % (Table 1, entry 11).
4-methylcyclohexanone, a readilyavailable ketone liquid at the mild
temperature of our reaction (30 ꢀC). To our delight, without altering
our standard conditions the sulfenylated product 6e could be iso-
lated in high yield displaying a substantial syn-diastereoselectivity
(Table 3, entry 1). 4-Ethyl- and 4-propylcyclohexanone were simi-
Table 1
Screening of solvents and reaction conditions on the TBD-catalyzed a
-sulfenylation of cyclohexanonea
Entry
Solvent
6a/7
Conversionb (%)
1
2
3
4
5
6
7
8
H2O
d
0
0
0
0
0
43
63
>99
94
99
99
CH2Cl2
Toluene
CH3CN
i-PrOH
MeOH
DMF
DMSO
Neat
Neat
d
d
d
d
88:12
85:15
83:17
98:2
96:4
97:3
9c
10d
11e
Neat
a
General reaction conditions: cyclohexanone (4.0 mmol), TMTDS (0.4 mmol), TBD (0.04 mmol), stirred at 20 ꢀC, for 120 h, unless otherwise stated.
Conversion of TMTDS (limiting reagent) to sulfenylated ketones 6aþ7 as determined by 1H NMR spectroscopy on crude reaction mixtures.
No solvent was used in the reaction apart from the excess of cyclohexanone, acting as reagent and reaction medium.
Reaction carried out at 30 ꢀC for 24 h.
b
c
d
e
Reaction carried out at 30 ꢀC for 24 h, employing 5 mol % of TBD catalyst.
With optimum conditions at hand (Table 1, entry 11) we decided
to explore the scope and limitations of our electrophilic -sulfeny-
lation reaction on simple cyclic ketones. Cyclopentanone, tetrahy-
dropyranone and acetone were used as starting materials (Table 2).
larly desymmetrized, products 6f and 6g, respectively, being
obtained with comparable yield and syn-selectivity (Table 3, entries
2 and 3). Solid ketones can be also employed as substrates for this
desymmetrization reaction. In this later case solid mixtures con-
sisting of TBD, TMTDS, and a 10-fold excess of the corresponding
ketone were heated up at a temperature moderately above ketone’s
melting point. Following this procedure 4-tert-butyl- and 4-
a
All the corresponding
a-sulfenylated products were isolated in ex-
cellent yield.
a,a
0-Disulfenylated byproducts were only observed in
reaction mixtures where cyclohexanone, cyclopentanone oracetone
was employed, and could be easily removed by flash chromatogra-
phy. Unfortunately, linear ketones (symmetrical, non-symmetrical,
linear or branched) proved to be unsuccessful substrates for this
transformation. It is worth noting that analogous products 6aec
can be prepared according to the methodology of Enders and
phenylcyclohexanone afforded their corresponding a-sulfenylated
products, 6h and 6i, in high yield and excellent diastereoselectivity
(Table 3, entries 4 and 5). Other functionalized solid ketones were
also conveniently sulfenylated (Table 3, entries 6 and 7). In all cases
the diastereoisomeric ratio (dr) of products 6eei was determined by

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B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
Table 2
Scope of the a
-sulfenylation reaction of ketonesa
Entry
1
R
Product
Yieldb (%)
84
eCH2CH2CH2e
6a
6b
6c
2c
eCH2CH2e
93
94
3c
eCH2OCH2e
4
d
84
6d
a
General conditions: ketone (4.0 mmol), TMTDS (0.4 mmol), TBD (0.02 mmol), stirred at 30 ꢀC, for 24 h, unless otherwise stated.
Isolated yield of analytically pure products.
Reaction time: 72 h.
b
c
high-field 1H NMR spectroscopy (300 MHz) on crude reaction
8k in very high isolated yield (Table 5). Moreover, all products 8a,b,
8eei present remarkable dr favouring the 1,2-trans di-
astereoisomer with no exception. Worth considering are products
8eei in which the relative stereochemistry of three different ster-
eogenic centres has been fixed (Table 5, entries 3e7).
The stereochemical assignment of products 8eei was done by
analogy to the reduction of 2-carbamoylcyclohexanone 6a to its
corresponding alcohol 8a, discussed above. Nonetheless, 2D NMR
and NOE experiments on products 8eei revealed a large transoid
3JHeH coupling constant for H1eH2 protons (10e15 Hz), along with
a through-space relation between their H2 and H4 protons, which
satisfies the chair-like structure outlined in Fig. 3.
mixtures bydeconvoluting and comparing the integralvalues for the
resonance of the C2 proton for the syn- and anti-diastereoisomers.
The stereochemical assignment was made feasible by 2D NMR and
NOE experiments, where it was observed a strong spatial contact
between the H1 and H2 protons in products 6eei, which presumably
adopt the chair-like structure illustrated in Fig. 2, with both sub-
a
stituents occupying
position.
a thermodynamically-favoured equatorial
a-Sulfenylated cyclohexanone 6a was adopted as a model sub-
strate to study theconversion of thethiocarbamategroup intovarious
thio derivatives. Originally we pursued the deprotection of 6a to the
corresponding 2-thiol ketone. Knochel’s method (NaOH, or KOH, in
MeOH),5 applied to aromatic non-functionalized substrates, proved
to be fruitless on our model compound 6a. Changes in the nature of
the base or solvent were likewise ineffective. These unfavourable
results motivated us to consider the feasibility of reducing the ketone
moiety on 6a to the secondary alcohol 8a prior to the deprotection of
From the bases of the procedure for the stereoselective re-
duction of our
a-sulfenylated ketones shown in Table 5 we de-
veloped a one-pot protocol for the full deprotection of the family of
compounds 6. Initially, ketone 6i, available as a single pure di-
astereoisomer, was chosen as a paradigm. A solution of ketone 6i, in
dry THF, was treated with an equimolar amount of LiAlH4 (1 M in
Et2O) at ꢁ78 ꢀC, for 16 h before it was allowed to get room tem-
perature. Further addition of LiAlH4, and stirring for 5 h rendered
thiol 9i in excellent yield and total diastereoselectivity, after
quenching and purification by flash chromatography. The same
one-pot sequence was successfully applied on ketones 6eeh (Table
6). Remarkably, products 9feh were isolated in a diastereopure
form after purification. The thiol groups on compounds 9 could be
conveniently transformed into other functions according to pro-
cedures well documented in the literature.
the thiocarbamoyl function (Table 4). Accordingly, when a-sulfeny-
lated cyclohexanone 6a, dissolved in dry THF, was treated with an
equimolar amount of LiAlH4 (1 M, in dry Et2O) at ꢁ20 ꢀC for 16 h the
corresponding 1-hydroxy-2-thyocarbamoylcyclohexane 8a was
obtained with full conversion and a dr of 71:29, biasing the product
with a relative 1,2-trans disposition. Lowering the reaction temper-
ature delivered a notable increment of diastereoselection, being
particularly favourable at ꢁ78 ꢀC (Table 4, entries 2 and 3). Reacting
further product 8a, retaken in THF, with LiAlH4 at room temperature
gave rise, after purification, to trans-1-mercaptocyclohexan-2-ol (9a)
verifiedfromthe spectroscopic data presentintheliterature.13 Hence,
it confirmed the correct stereochemical assignment of 1-hydroxy-2-
thiocarbamoylcyclohexane 8a.
3. Conclusion
A collection of previously prepared
a
-sulfenylated ketones (6a,b,
Summarizing, we have developed a simple and efficient pro-
6eei, 6k) was subjected to analogous reaction conditions to afford
their homologous 1-hydroxy-2-carbamoyl derivatives 8a,b, 8eei,
tocol for the
a-sulfenylation of cyclic ketones. This procedure em-
ploys inexpensive tetramethylthiuram disulfide as sulfenylating

B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
6441
Table 3
Desymmetryzation of 4-substituted cyclohexanonesa
Entry
1d
R
X
Product
dr (syn/anti)b
Yieldc (%)
eCH3
CH
92:8
81
6e
6f
2
3
eCH2CH3
CH
CH
88:12
88:12
91
84
eCH2CH2CH3
6g
4e
eC(CH3)3
CH
CH
98:2
97
95
6h
5f
eC6H5
>99:1
6i
6j
6g
d
S
d
d
94
73
7f
eOCH2CH2Oe
C
6k
a
General conditions: ketone (4.0 mmol), TMTDS (0.4 mmol), TBD (0.02 mmol), stirred at 30 ꢀC, for 72 h, unless otherwise stated.
Diastereoisomeric ratio of products as determined by 1H NMR spectroscopy on crude reaction mixtures.
b
c
d
e
f
Isolated yield of analytically pure products.
Reaction time: 48 h.
Reaction temperature: 55 ꢀC.
Reaction temperature: 80 ꢀC.
Reaction temperature: 65 ꢀC.
g
group of the a-sulfenylated ketones can be conveniently unmasked,
upon reduction of the ketone function in a process that occurs with
good stereochemical control. Chiral guanidines, acting as catalysts
for the sulfenylation reaction, are currently being investigated in
our laboratory, and the results will be reported in due course.
4. Experimental section
Fig. 2. Stereochemical assignment of compounds 6eei.
4.1. General considerations
reagent and catalytic amounts of TBD, a readily available guanidine
base, under solvent-free conditions and at mild temperatures. This
methodology has been successfully implemented on different
prochiral 4-substituted cyclohexanones rendering the corre-
sponding 2-thiocarbamoyl-4-substituted derivatives with high
yield and relative syn-diastereoselectivity. The thiocarbamoyl
All commercially available reagents and solvents were used
without further purification unless otherwise stated. Flash chro-
matography of reaction products was carried out using Silica 60A,
particle size 230e400 micron (Merck). Analytical thin layer chro-
matography (TLC) was performed on DC-Alufolien Kieselgel 60F254
0.2 mm plates (Merck) and compounds were visualized by UV

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B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
Table 4
Screening of temperatures on the reduction of the ketone functional group on a
-sulfenylated derivative 6aa
Entry
Temperature (ꢀC)
Conversion (%)
dr (trans/cis)b
1
2
3
ꢁ20
ꢁ40
ꢁ78
99
99
99
71:29
85:15
92:8
a
General conditions: ketone 6a (0.3 mmol), LiAlH4 (1 M in dry Et2O, 0.3 mL, 0.3 mmol), dry THF (3 mL), stirred at the indicated temperature for 16 h.
Diastereoisomeric ratio (trans/cis) of 1-hydroxy-2-thiocarbamoyl product 8a as determined by 1H NMR spectroscopy on crude reaction mixtures.
b
Table 5
Reduction of ketones 6a,b, 6eei, 6ka
Fig. 3. Stereochemical assignment of compounds 8eei.
Entry
1
Ketone
Product
dr (trans/cis)b
92:8
Yieldc (%)
90
Table 6
One-pot protocol for the reduction of ketones 6eeia
6a
6b
8a
8b
2
3
93:7
97:3
91
93
Entry
1
Ketone
Product
dr (trans/cis)b
98:2b
Yieldc (%)
87
6e
6f
8e
8f
4
5
6
7
92:8
97:3
96:4
90
95
95
6e
6f
9 e
2
3
4
>99:1d
83
9 f
6g
6h
8g
8h
>99:1d
>99:1d
>99:1d
91
88
93
6g
6h
6i
9 g
9 h
9 i
96:4
96
87
6i
8i
5
8
>99:1
6k
8k
a
General conditions: ketone (0.3 mmol), LiAlH4 (1 M in dry Et2O, 0.3 mL,
0.3 mmol), dry THF (3 mL), stirred at ꢁ78 ꢀC for 16 h, then LiAlH4 (0.45 mmol),
ꢁ78 ꢀC to rt, 5 h.
a
General conditions: ketone (0.3 mmol), LiAlH4 (1 M in dry Et2O, 0.3 mL,
0.3 mmol), dry THF (3 mL), stirred at ꢁ78 ꢀC for 16 h.
b
b
Diastereoisomeric ratio (trans/cis) of pure products 9, referring to the relative
Diastereoisomeric ratio (trans/cis) of 1-hydroxy-2-thiocarbamoyl products, as
disposition of the CeOH and CeSH centres, as determined by 1H NMR spectroscopy.
determined by 1H NMR on pure products 8. Diastereoisomeric ratio refers to the
relative disposition of the CeOH and CeSR centres.
c
Isolated yield of analytically pure products.
Product isolated as a single diastereoisomer.
d
c
Isolated yield of analytically pure products.

B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
6443
fluorescence or 5% phosphomolybdic acid in methanol. 1H NMR and
13C NMR spectra were recorded on a Bruker AC-300, a Bruker DPX-
300 or a Bruker AMX-400 spectrometer, using deuterated solvents
and were referenced internally to the residual solvent peak
volatiles were evaporated under vacuum. Purification by flash
chromatography on silica gel yielded pure compounds 9.
4.6. Synthesis of 2-(dimethylaminothiocarbonylthio)
cyclohexanone (6a)3
(
dH¼7.26 ppm, dC¼77.36 ppm) signal.14 Coupling constants (J-
values) are given in hertz (Hz). The DEPT 135 technique was used to
assign methylene (CH2) signals. Chemical shifts are reported as
follows: value (description of absorption, coupling constant(s)
where applicable, number of protons). 2D NMR experiments (COSY,
HMBC, HMQC) and NOE experiments (NOESY) were used to de-
termine the stereochemistry of products. Mass spectrometry was
performed on an Agilent 5973N A spectrometer (MS) or a Finnigan-
Mat 95-S spectrometer (HRMS) employing in both cases the elec-
trospray ionization technique on positive mode (ESþ).
Prepared in 84% yield according to SP1. White solid. Purified by
flash chromatography (hexane/EtOAc, 5:1). 1H NMR (300 MHz,
CDCl3):
d
4.97 (dd, J¼6.0, 12.0 Hz, 1H), 3.53 (s, 3H), 3.41 (s, 3H),
2.59e2.49 (m, 3H), 2.19e2.09 (m, 1H), 1.99e1.64 (m, 4H); 13C NMR
(75 MHz, CDCl3):
d 206.2 (C), 195.3 (C), 62.5 (CH), 45.7 (CH3), 42.5
(CH2), 41.9 (CH3), 35.4 (CH2), 27.8 (CH2), 25.9 (CH2); MS (ESþ): m/z
(%)¼220 (7) [MþH]þ, 242 (100) [MþNa]þ; HRMS (ESþ): m/z calcd
for [MþH]þ [C9H16NOS2]þ 218.0591, found 218.0669.
4.2. Standard procedure for the
ketones (SP1)
a-sulfenylation of liquid
4.7. Synthesis of 2-(dimethylaminothiocarbonylthio)
cyclopentanone (6b)3
Triazabicyclo[4.4.0]dec-5-ene 5 (0.02 mmol, 3.0 mg) and tetra-
methylthiuram disulfide 4 (0.4 mmol, 96 mg) were weighed to-
gether inside a screw-capped test tube. Ketone (4.0 mmol) was
added to the mixture and the resulting suspension was stirred in-
side a water bath at 30 ꢀC. The reaction progress was followed up by
TLC before it was quenched with NH4Cl (aq satd), extracted with
DCM (2ꢂ15 mL) and washed again with NaHCO3 (aq satd 2ꢂ10 mL).
The combined organic liquors were dried (MgSO4). Solvents and
excess of ketone were eliminated under high vacuum. Crude re-
action products were purified by flash chromatography on silica gel.
Prepared in 93% yield according to SP1. Brown solid. Purified by
flash chromatography (hexane/EtOAc 10:1). 1H NMR (300 MHz,
CDCl3):
(m, 1H), 2.49e2.40 (m, 1H), 2.33e2.20 (m, 1H), 2.14e2.07 (m, 1H),
2.00e1.85 (m, 2H); 13C NMR (75 MHz, CDCl3):
213.8 (C), 195.2 (C),
d
4.73(t, J¼9.0 Hz, 1H), 3.50 (s, 3H), 3.35 (s, 3H), 2.70e2.58
d
57.8 (CH), 46.2 (CH3), 41.8 (CH3), 37.3 (CH2), 31.1 (CH2), 20.7 (CH2);
MS (ESþ): m/z (%)¼228 (100) [MþNa]þ; HRMS (ESþ): m/z calcd for
[MþH]þ [C8H14NOS2]þ 204.0439, found 204.0511.
4.8. Synthesis of 3-(dimethylaminothiocarbonylthio)
tetrahydro-4H-pyran-4-one (6c)3
4.3. Standard procedure for the
ketones (SP2)
a-sulfenylation of solid
Prepared in 94% yield according to SP1. Yellow solid. Purified by
flash chromatography (hexane/Et2O 2:1). 1H NMR (300 MHz,
Triazabicyclo[4.4.0]dec-5-ene 5 (0.02 mmol, 3.0 mg) and tetra-
methylthiuram disulfide 4 (0.4 mmol, 96 mg) were weighed to-
gether inside a screw-capped test tube. Solid ketone (4.0 mmol)
was added to the mixture and heated at the melting point tem-
perature of the corresponding ketone. The reaction progress was
followed up by TLC before it was quenched with NH4Cl (aq satd),
extracted with DCM (2ꢂ15 mL) and washed again with NaHCO3 (aq
satd 2ꢂ10 mL). The combined organic liquors were dried (MgSO4).
Solvents were eliminated under reduced pressure and crude re-
action products were purified by flash chromatography on silica gel.
CDCl3):
d
5.16 (dd, J¼10.6, 6.9 Hz, 1H), 4.45 (ddd, J¼11.9, 7.1, 0.9 Hz,
1H), 4.35e4.27 (m, 1H), 3.79 (td, J¼11.6, 2.9 Hz, 1H), 3.59 (t,
J¼10.7 Hz, 1H), 3.53 (s, 3H), 3.40 (s, 3H), 2.93e2.81 (m, 1H),
2.62e2.56 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 201.7 (C), 193.6 (C),
72.4 (CH2), 68.4 (CH2), 60.7 (CH), 46.0 (CH3), 43.5 (CH2), 41.9 (CH3);
MS (ESþ): m/z (%)¼218 (65), 220 (100), 222 (20); HRMS (ESþ): m/z
calcd for [MþH]þ [C8H14NO2S2]þ 220.0388, found 220.0468.
4.9. Synthesis of 1-(dimethylaminothiocarbonylthio)propan-
2-one (6d)
4.4. Standard procedure for the stereoselective ketone
reduction of
a-sulfenylated ketones 6 (SP 3)
Prepared in 84% yield according to SP1. Yellow solid. Purified by
flash chromatography (hexane/EtOAc 10:1). 1H NMR (300 MHz,
Either -sulfenylated ketones 6a,b, 6fek (0.30 mmol), dissolved
a
CDCl3):
(75 MHz, CDCl3):
d
4.21 (s, 2H), 3.54 (s, 3H), 3.43 (s, 3H), 2.36 (s, 3H); 13C NMR
in dry THF (3.0 mL) at ꢁ78 ꢀC, were treated with LiAlH4 (1 M in dry
Et2O, 0.30 mmol, 0.3 mL), and stirred for 16 h. The reaction was
quenched with EtOAc (1 mL) and filtered through a pad of Celite.
The organic liquors were washed with 1 M HCl (aq), extracted with
Et2O (2ꢂ15 mL), and dried over MgSO4. Solvents and volatiles were
evaporated under vacuum. Purification by flash chromatography on
silica gel yielded pure alcohols 8a,b, 8fek.
d
202.4 (C), 195.8 (C), 47.5 (CH2), 46.1 (CH3), 42.0
(CH3), 28.8 (CH3); MS (ESþ): m/z (%)¼176 (45) [MꢁH]þ, 178 (100)
[MþH]þ; HRMS (ESþ): m/z calcd for [C6H12NOS2]þ [MþH]þ
178.0282, found 178.0353.
4.10. Synthesis of (2S
*
,4S )-2-
*
(dimethylaminothiocarbonylthio)-4-methylcyclohexanone
(6e)
4.5. Standard procedure for the one-pot full reduction of
sulfenylated ketones 6 (SP 4)
a-
Prepared in 81% yield according to SP1. Yellow solid. Purified by
flash chromatography (hexane/EtOAc 10:1). 1H NMR (300 MHz,
Either a-sulfenylated ketone 6 (0.3 mmol), dissolved in dry THF
(3.0 mL) at ꢁ78 ꢀC, was treated with LiAlH4 (1 M in dry Et2O,
0.30 mmol, 0.3 mL), and stirred for 16 h. After this time the reaction
mixture was cooled to room temperature and powdered LiAlH4
(17 mg, 0.45 mmol) was added. After 5 h of stirring the reaction
mixture was quenched with EtOAc and filtered through a pad of
Celite. The organic liquors were washed with 1 M HCl (aq),
extracted with Et2O (2ꢂ15 mL), and dried over MgSO4. Solvents and
CDCl3):
d
(syn diastereoisomer) 5.01 (dd, J¼13.5, 5.8 Hz, 1H), 3.51 (s,
3H), 3.38 (s, 3H), 2.65e2.43 (m, 3H), 2.17e2.04 (m, 2H), 1.58e1.20
(m, 2H), 1.00 (d, J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d (syn
diastereoisomer) 206.4 (C), 195.5 (C), 61.8 (CH), 45.8 (CH3), 43.3
(CH2), 42.0 (CH3), 41.7 (CH2), 35.8 (CH2), 32.9 (CH), 21.3 (CH3); MS
(ESþ): m/z (%)¼232 (100) [MþH]þ; HRMS (ESþ): m/z calcd for
[MþH]þ [C10H18NOS2]þ 232.0752, found 232.0829.

6444
B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
4.11. Synthesis of (2S
*
,4S
*
)-2-
(s, 3H), 3.44e3.38 (m, 1H), 3.38 (s, 3H), 3.10e2.90 (m, 5H); 13C NMR
(dimethylaminothiocarbonylthio)-4-ethylcyclohexanone (6f)
(75 MHz, CDCl3): d 203.8 (br s, C), 194.1 (C), 63.9 (CH), 45.9 (CH3),
45.6 (CH2), 42.1 (CH3), 37.4 (CH2), 31.1 (CH2); MS (ESþ): m/z (%)¼236
(100) [MþH]þ, 242 (39) [MþNaꢁCH4]þ; HRMS (ESþ): m/z calcd for
[MþH]þ [C8H14NOS3]þ 236.0238, found 236.0237.
Prepared in 91% yield according to SP1. Yellow oil. Purified by
flash chromatography (hexane/EtOAc, 10:1). 1H NMR (300 MHz,
CDCl3):
d
(syn diastereoisomer) 5.02 (dd, J¼13.6, 5.7 Hz, 1H), 3.53 (s,
3H), 3.41 (s, 3H), 2.61e2.52 (m, 3H), 2.21e2.11 (m, 1H), 1.97e1.85
(m, 1H), 1.51e1.30 (m, 4H), 0.95 (t, J¼7.4 Hz, 3H). 13C NMR (75 MHz,
4.16. Synthesis of 2-(dimethylaminothiocarbonylthio)-4-(1,4-
dioxolano)-cyclohexanone (6k)
CDCl3):
d (syn diastereoisomer) 206.7 (C), 195.6 (C), 61.9 (CH), 45.8
(CH3), 42.0 (CH3), 41.7 (CH2), 41.1 (CH2), 39.4 (CH), 33.4 (CH2), 28.7
(CH2), 11.9 (CH3); MS (ESþ): m/z (%)¼246 (100) [MþH]þ; HRMS
(ESþ): m/z calcd for [MþH]þ [C11H20NOS2]þ 246.0908, found
246.0980.
Prepared in 73% yield according to SP2 (reaction temperature:
80 ꢀC). Yellow solid. Purified by flash chromatography (hexane/
Et2O, 2:1). 1H NMR (300 MHz, CDCl3):
4.16e4.03 (m, 2H), 3.99e3.94 (m, 2H), 3.47 (s, 3H), 3.36 (s, 3H),
d
5.18 (dd, J¼13.6, 6.0 Hz, 1H),
2.88e2.77 (m, 1H), 2.57e2.48 (m, 2H), 2.09e2.00 (m, 3H); 13C NMR
4.12. Synthesis of (2S
*
,4S
*
)-2-
(75 MHz, CDCl3): d 204.5 (C), 194.5 (C), 106.87 (C), 64.9 (CH2), 64.7
(dimethylaminothiocarbonylthio)-4-propylcyclohexanone
(6g)
(CH2), 58.1 (CH), 45.5 (CH3), 41.7 (CH3), 40.7 (CH2), 38.0 (CH2), 34.7
(CH2); MS (ESþ): m/z (%)¼276 (100) [MþH]þ; HRMS (ESþ): m/z
calcd for [MþH]þ [C11H18NO3 S2]þ 276.0650, found 276.0729.
Prepared in 84% yield according to SP1. Yellow oil. Purified by
flash chromatography (hexane/EtOAc, 10:1). 1H NMR (300 MHz,
4.17. Characterization of syn-2,6-[bis-
CDCl3):
d
(syn diastereoisomer) 5.02 (dd, J¼13.4, 5.7 Hz, 1H), 3.52 (s,
(dimethylaminothiocarbonylthio)]cyclohexanone (7)10
3H), 3.40 (s, 3H), 2.61e2.51 (m, 3H), 2.16e2.05 (m, 1H), 2.16e1.97
(m, 1H), 1.55e1.24 (m, 6H), 0.94e0.89 (m, 3H); 13C NMR (75 MHz,
Off-white solid. Purified by flash chromatography (hexane/
CDCl3):
d
(syn diastereoisomer) 206.5 (C), 195.5 (C), 61.9 (CH), 45.7
EtOAc, 5:1). 1H NMR (400 MHz, CDCl3):
d
5.28e5.05 (m, 2H), 3.54 (s,
6H), 3.42 (s, 6H), 2.80e2.59 (m, 2H), 2.23e1.94 (m, 2H), 1.95e1.72
(m, 2H); 13C NMR (75 MHz, CDCl3):
(CH3), 41.9 (CH3), 41.6 (CH2), 41.3 (CH2), 38.0 (CH2), 37.4 (CH), 33.7
(CH2), 20.5 (CH2), 14.4 (CH3); MS (ESþ): m/z (%)¼260 (100) [MþH]þ;
HRMS (ESþ): m/z calcd for [MþH]þ [C12H22NOS2]þ 260.1065, found
260.1141.
d
201.3 (C), 194.8 (2ꢂC), 62.6
(2ꢂCH), 45.4 (2ꢂCH3), 41.6 (2ꢂCH3), 35.8 (2ꢂCH2), 25.9 (CH2); MS
(ESþ): m/z (%)¼337 (100) [MþH]þ; HRMS (ESþ): m/z calcd for
[MþH]þ [C12H21N2OS4]þ 337.0537, found 337.0539.
4.13. Synthesis of (2S
*
,4S )-2-
*
(dimethylaminothiocarbonylthio)-4-(tert-butyl)-
4.18. Synthesis of (1S
*
,2S )-2-hydroxycyclohexyl
*
cyclohexanone (6h)
dimethylcarbamodithioate (8a)
Prepared in 97% yield according to SP2 (reaction temperature:
Prepared in 90% yield according to SP3. White solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
55 ꢀC). Yellow solid. Purified by flash chromatography (hexane/
Et2O, 3:1). 1H NMR (300 MHz, CDCl3):
d
(syn diastereoisomer) 5.00
CDCl3):
d
(trans diastereoisomer) 4.06 (ddd, J¼15.8, 10.4, 5.8 Hz,
(dd, J¼12.5, 5.1 Hz, 1H), 3.53 (s, 3H), 3.40 (s, 3H), 2.60e2.56 (m, 3H),
1H), 3.55 (s, 3H), 3.51 (ddd, J¼14.6, 10.3, 4.3 Hz, 1H), 3.40 (s, 3H),
2.18e2.14 (m, 1H), 1.85e1.76 (m, 1H), 1.64e1.56 (m, 2H), 0.92 (s,
2.40 (br s, 1H), 2.22e2.13 (m, 1H), 1.83e1.69 (m, 2H), 1.57e1.25 (m,
9H); 13C NMR (75 MHz, CDCl3):
d
(syn diastereoisomer) 206.7 (C),
5H); 13C NMR (75 MHz, CDCl3):
d (trans diastereoisomer) 198.0 (C),
195.5 (C), 62.3 (CH), 47.9 (CH), 45.7 (CH3), 41.9 (CH3), 41.7 (CH2),
36.7 (CH2), 32.8 (C), 28.6 (CH2), 27.5 (3ꢂCH3); MS (ESþ): m/z (%)¼
274 (100) [MþH]þ; HRMS (ESþ): m/z calcd for [MþH]þ
[C13H24NOS2]þ 274.1221, found 274.1290.
75.0 (CH), 52.2 (CH), 45.9 (CH3), 42.2 (CH3), 36.3 (CH2), 32.2 (CH2),
26.4 (CH2), 24.6 (CH2); MS (ESþ): m/z (%)¼220 (4) [MþH]þ, 242
(100) [MþNa]þ; HRMS (ESþ): m/z calcd for [MþNa]þ
[C9H17NONaS2]þ 242.0649, found 242.0650.
4.14. Synthesis of (2S
*
,4S
*
)-2-
4.19. Synthesis of (1S
*
,2S )-2-hydroxycyclopenthyl
*
(dimethylaminothiocarbonylthio)-4-phenylcyclohexanone
(6i)
dimethylcarbamodithioate (8b)
Prepared in 91% yield according to SP3. Off-white solid. Purified
by flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3): d (trans diastereoisomer) 4.29e4.23 (m, 1H), 3.97 (ddd,
Prepared in 95% yield according to SP2 (reaction temperature:
80 ꢀC). Orangish solid. Purified by flash chromatography (hexane/
Et2O, 3:1). 1H NMR (300 MHz, CDCl3):
d
(syn diastereoisomer)
J¼11.1, 8.0, 3.0 Hz, 1H), 3.54 (s, 3H), 3.36 (s, 3H), 2.35e2.25 (m, 1H),
7.37e7.20 (m, 5H), 5.21 (dd, J¼13.2, 5.7 Hz, 1H), 3.53 (s, 3H), 3.40 (s,
1.98e1.82 (m, 2H), 1.80e1.54 (m, 4H); 13C NMR (75 MHz, CDCl3):
3H), 3.32 (tt, J¼12.1, 3.5 Hz, 1H), 2.80e2.67 (m, 3H), 2.35e2.28 (m,
d
(trans diastereoisomer) 198.2 (C), 81.3 (CH), 57.5 (CH), 45.4 (CH3),
1H), 2.10e2.00 (m, 2H); 13C NMR (75 MHz, CDCl3):
d
(syn di-
42.2 (CH3), 34.0 (CH2), 30.0 (CH2), 24.1 (CH2); MS (ESþ): m/z (%)¼
228 (100); HRMS (ESþ): m/z calcd for [MþNa]þ [C8H15NONaS2]þ
228.0493, found 228.0487.
astereoisomer) 205.7 (C), 195.3 (C), 143.8 (C), 128.9 (2ꢂCH), 127.7
(CH), 127.0 (2ꢂCH), 62.1 (CH), 45.8 (CH3), 43.9 (CH), 42.4 (CH2), 42.0
(CH3), 41.9 (CH2), 34.7 (CH2); MS (ESþ): m/z (%)¼294 (100) [MþH]þ,
216 (5) [MꢁC6H5]þ; HRMS (ESþ): m/z calcd for [MþH]þ
[C15H20NOS2]þ 294.0908, found 294.0982.
4.20. Synthesis (1S
*
,2S
*
,5S )-2-hydroxy-5-methylcyclohexyl
*
dimethylcarbamodithioate (8e)
4.15. Synthesis of 3-(dimethylaminothiocarbonylthio)
tetrahydro-4H-thiopyran-4-one (6j)
Prepared in 93% yield according to SP3. White solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3):
d
(major diastereoisomer) 4.12 (ddd, J¼12.9, 10.6, 4.4 Hz,
Prepared in 94% yield according to SP2 (reaction temperature:
1H), 3.55 (s, 3H), 3.48 (ddd, J¼15.6, 10.8, 4.4 Hz, 1H), 3.40 (s, 3H),
2.21e2.08 (m, 2H), 1.99 (br s, 1H), 1.79e1.71 (m, 1H), 1.70e1.58 (m,
1H), 1.51 (ddd, J¼24.3, 13.3, 3.7 Hz, 1H), 1.24 (dd, J¼24.7, 12.8 Hz,
65 ꢀC). Brown solid. Purified by flash chromatography (hexane/Et2O
2:1). 1H NMR (400 MHz, CDCl3):
d
5.18 (dd, J¼11.4, 5.1 Hz, 1H), 3.50

B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
6445
1H), 1.03 (ddd, J¼25.5, 13.5, 3.4 Hz, 1H), 0.93 (d, J¼6.5 Hz, 3H); 13C
4.25. Synthesis of (1S
*
,6S )-6-hydroxy-3-oxocyclohexyl
*
NMR (75 MHz, CDCl3):
d (major diastereoisomer) 198.0 (C), 75.2
dimethylcarbamodithioate ethylene ketal (8k)
(CH), 58.0 (CH), 45.9 (CH3), 42.2 (CH3), 40.8 (CH2), 36.1 (CH2), 33.3
(CHþCH2), 22.0 (CH3); MS (ESþ): m/z (%)¼234 (10) [MþH]þ, 256
(100) [MþNa]þ; HRMS (ESþ): m/z calcd for [MþNa]þ [C10H19NO-
Prepared in 87% yield according to SP3. Reddish solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
NaS2
]
þ 256.0806, found 256.0811.
CDCl3):
d
(trans diastereoisomer) 4.34 (ddd, J¼12.4, 9.9, 4.3 Hz, 1H),
4.05e3.89(m, 4H),3.60(ddd, J¼14.3,10.0, 4.4 Hz,1H), 3.53 (s, 3H), 3.38
(s, 3H), 2.79 (br s,1H), 2.23 (ddd, J¼13.1, 4.0, 3.1 Hz,1H), 2.14e2.08 (m,
1H), 1.86e1.72 (m, 3H), 1.69e1.57 (m, 1H); 13C NMR (75 MHz, CDCl3):
4.21. Synthesis of (1S
*
,2S
*
,5S )-5-ethyl-2-hydroxycyclohexyl
*
dimethylcarbamodithioate (8f)
d
(trans diastereoisomer) 197.4 (C),108.1 (C), 73.7 (CH), 64.8 (CH2), 64.7
Prepared in 90% yield according to SP3. White solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
(CH2), 54.9 (CH), 45.8 (CH3), 42.1 (CH3), 39.1 (CH2), 33.0 (CH2), 32.1
(CH2); MS (ESþ): m/z (%)¼300 (100) [MþNa]þ; HRMS (ESþ): m/z calcd
for [MþNa]þ [C11H19NO3NaS2]þ 300.0704, found 300.0697.
CDCl3):
d
(major diastereoisomer) 4.11 (ddd, J¼12.8, 10.5, 4.0 Hz,
1H), 3.56 (s, 3H), 3.49 (ddd, J¼15.2, 10.8, 4.4 Hz, 1H), 3.40 (s, 3H),
2.23e2.14 (m, 2H), 1.95e1.72 (m, 2H), 1.56e1.36 (m, 2H), 1.31e1.15
(m, 3H),1.04e0.91 (m, 1H), 0.89 (t, J¼7.4 Hz, 3H); 13C NMR (75 MHz,
4.26. Synthesis of (1S
*
,2S
)-2-mercaptocyclohexanol (9a)13
*
CDCl3):
d
(major diastereoisomer) 197.8 (C), 75.3 (CH), 58.0 (CH),
Prepared in 94% yield according to SP4. Colourless oil. Purified
by flash chromatography (hexane/EtOAc, 3:1). 1H NMR (300 MHz,
45.8 (CH3), 42.1 (CH3), 39.8 (CH), 38.4 (CH2), 36.0 (CH2), 30.7 (CH2),
29.2 (CH2), 11.8 (CH3); MS (ESþ): m/z (%)¼248 (4) [MþH]þ, 270
(100) [MþNa]þ; HRMS (ESþ): m/z calcd for [MþNa]þ
[C11H21NONaS2]þ 270.0962, found 270.0968.
CDCl3):
d
(trans diastereoisomer) 3.20 (ddd, J¼14.0, 10.0, 4.3 Hz,
1H), 2.58e2.44 (m, 1H), 2.22e2.04 (m, 2H), 1.97 (br s, 1H), 1.85e1.65
(m, 2H), 1.42 (d, J¼9.2 Hz, 1H), 1.39e1.19 (m, 4H); 13C NMR (75 MHz,
CDCl3):
d (trans diastereoisomer) 77.0 (CH), 48.0 (CH), 36.8 (CH2),
4.22. Synthesis of (1S
*
,2S
*
,5S
*
)-2-hydroxy-5-propylcyclohexyl
34.3 (CH2), 26.9 (CH2), 25.0 (CH3).
dimethylcarbamodithioate (8g)
4.27. Synthesis of (1S
*
,2S
*
,4S )-2-mercapto-4-
*
Prepared in 95% yield according to SP3. White solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
methylcyclohexan-1-ol (9e)
CDCl3):
d
(major diastereoisomer) 4.11 (ddd, J¼13.0,10.5, 4.0 Hz,1H),
Prepared in 87% yield according to SP4. Colourless oil. Purified
by flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
3.55 (s, 3H), 3.53e3.44 (m, 1H), 3.39 (s, 3H), 2.22e2.12 (m, 2H),
1.88e1.41 (m, 5H),1.38e1.14 (m, 4H), 0.98 (ddd, J¼25.3, 13.4, 3.5 Hz,
CDCl3):
d
(major diastereoisomer) 3.18 (ddd, J¼14.7, 10.4, 4.4 Hz,
1H), 0.88 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
(major di-
1H), 2.59e2.51 (m, 1H), 2.30 (br s, 1H), 2.14e2.03 (m, 2H), 1.77e1.66
(m, 1H), 1.57e1.45 (m, 1H), 1.41 (d, J¼9.3 Hz, 1H), 1.38e1.28 (m, 1H),
1.14e0.99 (m, 2H), 0.90 (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz,
astereoisomer) 197.9 (C), 75.3 (CH), 58.1 (CH), 45.8 (CH3), 42.1 (CH3),
38.8 (CH2), 38.7 (CH2), 37.8 (CH), 36.0 (CH2), 31.1 (CH2), 20.3 (CH2),
14.4 (CH3); MS (ESþ): m/z (%)¼284 (100) [MþNa]þ; HRMS (ESþ): m/z
calcd for [MþNa]þ [C12H23NONaS2]þ 284.1119, found 284.1125.
CDCl3):
d (major diastereoisomer) 77.0 (CH), 47.6 (CH), 45.3 (CH2),
33.9 (CH2), 33.6 (CH), 33.5 (CH2), 21.9 (CH3).
4.23. Synthesis of (1S
*
,2S
*
,5S
*
)-5-tert-butyl-2-
4.28. Synthesis of (1S
*
,2S
*
,4S )-2-mercapto-4-
*
hydroxycyclohexyl dimethylcarbamodithioate (8h)
ethylcyclohexan-1-ol (9f)
Prepared in 95% yield according to SP3. Yellow solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
Prepared in 83% yield according to SP4. Colourless oil. Purified
by flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3):
d
(major diastereoisomer) 4.14e4.04 (m, 1H), 3.55 (s, 3H),
CDCl3):
d
3.18 (ddd, J¼14.7, 10.4, 4.4 Hz, 1H), 2.58e2.49 (m, 1H), 2.38
3.47 (ddd, J¼15.3, 10.8, 4.5 Hz, 1H), 3.40 (s, 3H), 2.29 (br s, 1H),
2.27e2.16 (m, 2H), 1.86e1.78 (m, 1H), 1.53e1.41 (m, 1H), 1.34e1.24
(m, 2H), 1.15e1.03 (m, 1H), 0.87 (s, 9H); 13C NMR (75 MHz, CDCl3):
(s, 1H), 2.19e2.14 (m, 1H), 2.11e2.05 (m, 1H), 1.82e1.76 (m, 1H), 1.43
(d, J¼9.2 Hz, 1H), 1.36e1.19 (m, 4H), 1.10e0.95 (m, 2H), 0.88 (d,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 77.2 (CH), 47.7 (CH),
d
(major diastereoisomer) 197.9 (C), 75.3 (CH), 58.7 (CH), 48.3 (CH),
43.0 (CH2), 40.2 (CH), 33.9 (CH2), 31.1 (CH2), 39.3 (CH2), 11.9 (CH3).
45.8 (CH3), 42.1 (CH3), 36.3 (CH2), 33.6 (CH2), 32.7 (C), 27.8 (3ꢂCH3),
25.5 (CH2); MS (ESþ): m/z (%)¼276 (15) [MþH]þ, 298 (100)
[MþNa]þ; HRMS (ESþ): m/z calcd for [MþNa]þ [C13H25NONaS2]þ
298.1275, found 298.1278.
4.29. Synthesis of (1S
*
,2S
*
,4S )-2-mercapto-4-
*
propylcyclohexan-1-ol (9g)
Prepared in 91% yield according to SP4. Colourless oil. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
4.24. Synthesis of (1S
*
,2S
*
,5S )-2-hydroxy-5-phenylcyclohexyl
*
dimethylcarbamodithioate (8i)
CDCl3):
d
3.17 (ddd, J¼14.7, 10.3, 4.3 Hz, 1H), 2.59e2.48 (m, 2H),
2.17e2.11 (m, 1H), 2.09e2.03 (m, 1H), 1.80e1.74 (m, 1H), 1.43 (d,
J¼9.1 Hz, 1H), 1.40e1.24 (m, 4H), 1.20e1.12 (m, 2H), 1.09e0.94 (m,
Prepared in 96% yield according to SP3. Yellow solid. Purified by
flash chromatography (hexane/EtOAc, 3:1). 1H NMR (400 MHz,
2H), 0.86 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 77.2 (CH),
CDCl3):
d
(major diastereoisomer) 7.33e7.27 (m, 2H), 7.23e7.17 (m,
47.7 (CH), 43.3 (CH2), 38.8 (CH2), 38.2 (CH), 33.9 (CH2), 31.5 (CH2),
20.4 (CH2), 14.6 (CH3).
3H), 4.29 (ddd, J¼12.8, 10.6, 3.9 Hz, 1H), 3.63 (ddd, J¼15.0, 10.6,
4.4 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H), 2.80 (tt, J¼12.0, 3.4 Hz, 1H),
2.39e2.28 (m, 1H), 2.02e1.94 (m, 1H), 1.76 (dd, J¼25.4, 12.7 Hz, 1H),
4.30. Synthesis of (1S
butylcyclohexan-1-ol (9h)
*
,2S
*
,4S )-2-mercapto-4-tert-
*
1.74e1.51 (m, 4H); 13C NMR (75 MHz, CDCl3):
d (major di-
astereoisomer) 197.5 (C), 145.2 (C), 128.7 (2ꢂCH), 126.9 (2ꢂCH),
126.6 (CH), 74.6 (CH), 58.1 (CH), 45.8 (CH3), 44.3 (CH), 42.1 (CH3),
39.8 (CH2), 36.2 (CH2), 32.1 (CH2); MS (ESþ) m/z (%)¼318 (100)
[MþNa]þ; HRMS (ESþ): m/z calcd for [MþNa]þ [C15H21NONaS2]þ
318.0962, found 318.0959.
Prepared in 88% yield according to SP4. Colourless oil. Purified
by flash chromatography (hexane/EtOAc, 3:1); 1H NMR (400 MHz,
CDCl3):
d
3.16 (ddd, J¼14.7, 10.3, 4.4 Hz,1H), 2.59e2.49 (m, 1H), 2.40
(br s, 1H), 2.23e2.08 (m, 2H), 1.85e1.73 (m, 1H), 1.46 (d, J¼9.2 Hz,

6446
B. Poladura et al. / Tetrahedron 68 (2012) 6438e6446
1H), 1.34e1.23 (m, 1H), 1.21e1.05 (m, 3H), 0.86 (s, 9H); 13C NMR
(100 MHz, CDCl3): 77.2 (CH), 48.8 (CH), 48.4 (CH), 38.1 (CH2), 34.2
(CH2), 32.7 (C), 27.9 (3ꢂCH3), 25.9 (CH2).
2. (a) Wang, W.; Li, H.; Wang, J.; Liao, L. Tetrahedron Lett. 2004, 45, 8229; (b)
Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794; (c) Sobhani, S.; Fielenbach, D.; Marigo, M.; Wabnitz, T. C.;
Jørgensen, K. A. Chem.dEur. J. 2005, 11, 5689; (d) Yadav, J. S.; Subba Reddy, B. V.;
Jain, R.; Baishya, G. Tetrahedron Lett. 2008, 49, 3015; (e) Zhao, G.-L.; Rios, R.;
d
ꢀ
Vesely, J.; Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2008, 47, 8468; (f) Fang,
4.31. Synthesis of (1S ,2S ,4S )-2-mercapto-4-
*
*
*
L.; Lin, A.; Hu, H.; Zhu, C. Chem.dEur. J. 2009, 15, 7039; (g) Dubey, R.; Polaske,
N. W.; Nichol, G. S.; Olenyuk, B. Tetrahedron Lett. 2009, 50, 4310; (h) Armstrong,
A.; Deacon, N.; Donald, C. Synlett 2011, 2347.
phenylcyclohexan-1-ol (9i)
3. Enders, D.; Rembiak, A.; Liebich, J. X. Synthesis 2011, 281.
Prepared in 93% yield according to SP4. Colourless oil. Purified by
flash chromatography (hexane/EtOAc, 3:1); 1H NMR (400 MHz,
4. The current commercial prize of TMTDS is 33.90 Euro per 500 g (Alfa-Aesar).
5. Krasovskiy, A.; Gavryushin, A.; Knochel, P. Synlett 2005, 2691.
6. Krasovskiy, A.; Gavryushin, A.; Knochel, P. Synlett 2006, 792.
CDCl3):
d
7.33e7.29 (m, 2H), 7.23e7.19 (m, 3H), 3.34 (td, J¼10.2, 4.4 Hz,
~
ꢀ
7. (a) Martínez-Castaneda, A.; Poladura, B.; Rodríguez-Solla, H.; Concellon, C.;
1H), 2.79e2.62 (m, 2H), 2.57 (br s, 1H), 2.39e2.30 (m, 1H), 2.27e2.16
~
del Amo, V. Org. Lett. 2011, 13, 3032; (b) Martínez-Castaneda, A.; Poladura,
(m,1H), 2.03e1.87(m,1H),1.73e1.55 (m, 3H), 1.51 (d, J¼9.2 Hz,1H); 13C
ꢀ
B.; Rodríguez-Solla, H.; Concellon, C.; del Amo, V. Chem.dEur. J. 2012, 18,
NMR (75 MHz, CDCl3):
d
145.3 (C), 128.8 (2ꢂCH), 127.0 (2ꢂCH), 126.7
5188.
8. For some recent reviews on the chemistry of guanidines, see: (a) Ishikawa, T.;
Kumamoto, T. Synlett 2006, 737; (b) Leow, D.; Tan, C.-H. Chem.-Asian J. 2009, 4,
488; (c) Coles, M. P. Chem. Commun. 2009, 3659; (d) Leow, D.; Tan, C.-H. Synlett
2010, 1589; (e) Ishikawa, T. Chem. Pharm. Bull. 2010, 58, 1555; (f) Fu, X.; Tan, C.-
H. Chem. Commun. 2011, 8210; (g) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem.
Soc. Rev. 2012, 41, 2109.
(CH), 76.7 (CH), 47.7 (CH), 44.8 (CH), 44.1 (CH2), 34.2 (CH2), 30.5 (CH2).
Acknowledgements
The authors thank Ministerio de Economía y Competitividad
(CTQ2010-14959) for financial support. B.P., C.C., and V.d.A. thank
MICINN for a predoctoral fellowship, a Juan de la Cierva contract,
~
ꢀ
9. Martínez-Castaneda, A.; Rodríguez-Solla, H.; Concellon, C.; del Amo, V. Org.
Biomol. Chem. 2012, 10, 1976.
10. Product 7 is formed in a diastereoisomerically pure form, with the dithio-
carbamoyl functions born on positions C2 and C6 in a relative syn-disposition
as depicted in the reaction scheme of Table 1. Full spectroscopy data for this
compound is provided in Experimental section.
ꢀ
and a Ramon y Cajal contract, respectively.
Supplementary data
11. The progress of the reaction was carefully followed by TLC.
12. Recent examples of organocatalyzed desymmetrization reactions: (a) Ram-
achary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1577; (b) Luo, S.; Zhang, L.; Mi, X.;
Qiao, Y.; Cheng, J.-P. J. Org. Chem. 2007, 72, 9350; (c) Ho, S.; Rho, H. S.; Lee, J. W.;
Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed. 2008, 47, 7872;
(d) Peschiulli, A.; Gun’ko, Y. K.; Connon, S. J. J. Org. Chem. 2008, 73, 2454; (e)
Peschiulli, A.; Quigley, C.; Tallon, S.; Gun’ko, Y. K.; Connon, S. J. J. Org. Chem.
A copy of the spectra of all the compounds described in this
manuscript. Supplementary data associated with this article can
be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.05.124.
ꢀ
2008, 73, 6409; (f) Companyo, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R.
Chem.dEur. J. 2009, 15, 6564.
References and notes
13. (a) Adams, H.; Bell, R.; Cheung, Y.-Y.; Jones, D. N.; Tomkinson, N. C. O. Tetra-
hedron: Asymmetry 1999, 10, 4129; (b) Li, Z.; Zhou, Z.; Li, K.; Wang, L.; Zhou, Q.;
Tang, C. Tetrahedron Lett. 2002, 43, 7609.
ꢀ
1. Solladie, G. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Win-
terfeld, E., Eds.; Pregamon: Oxford, 1991; Vol. 6, pp 133e170.
14. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 14.