Unsymmetrical α,ω-end-functionalized oligo(cyclohexylidenes): efficient synthesis and conformational analysis

Article abstract of DOI:10.1016/j.tet.2016.05.040

The title compounds were efficiently synthesized by decarboxylative dehydration of β-hydroxy acids. This iterative process allowed to obtain bis- and ter-cyclohexylidenes with good yield. The conformations of trans and cis isomers of an unsymmetrical α,ω-

Full text of DOI:10.1016/j.tet.2016.05.040

Tetrahedron 72 (2016) 4032e4038
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unsymmetrical
a,
u-end-functionalized oligo(cyclohexylidenes):
efficient synthesis and conformational analysis
Wa e€ l Zeinyeh a,b, Sylvie Radix , Raphael Terreux , Julie-Anne Chemelle ,
Nadia Walchshofer
a
a
,
€
c
c
*
a,
*
Univ Lyon, Universit ꢀe Lyon 1, EA 4446 Bioactive Molecules and Medicinal Chemistry (B2MC), ISPB-Facult ꢀe de Pharmacie, 8 avenue Rockefeller, F-69373
Lyon Cedex 08, France
b
Hospices Civils de Lyon, Laboratoire d’Hormonologie, Centre de Biologie Est, Groupement Hospitalier Est, Bron F-69677, France
Univ Lyon, Universit ꢀe Lyon 1, CNRS, LBTI UMR 5305, Laboratory of Tissue Biology and Therapeutic Engineering, IBCP, 7 Passage du Vercors, F-69367
c
Lyon Cedex 07, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The title compounds were efficiently synthesized by decarboxylative dehydration of b-hydroxy acids.
Received 4 February 2016
Received in revised form 12 May 2016
Accepted 13 May 2016
This iterative process allowed to obtain bis- and ter-cyclohexylidenes with good yield. The conformations
of trans and cis isomers of an unsymmetrical
a,
u-end-functionalized biscyclohexylidene were studied by
NMR and DFT methods.
Available online 14 May 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Oligo(cyclohexylidenes)
Decarboxylative dehydration
Syn/anti bicyclohexylidenes
DFT calculations
13
1
Ce H coupling constants
1
. Introduction
McMurry reaction,4 we report here an alternative synthetic ap-
proach involving a decarboxylative dihydration of -hydroxy acids.
This method allowed the iterative constructions of C]C bond by
using suitable coupling partners, and thus provides an efficient way
b
1
As part of our work about bioactive bivalent compounds, we
investigated oligo(cyclohexylidenes) as linker agents between two
bioactive moieties. Indeed, these structures are sufficiently chem-
ically inert, and they have a relatively well-defined length due to
the average increment of 4.1 A in relation with n (Fig. 1). Although
the carbonecarbon double bond formation in such compounds are
to prepare various unsymmetrical a,u-end-functionalized oligo(-
cyclohexylidenes) with different n. With two easily derivatized
end-functional groups, these compounds could be conveniently
linked to other bioactive fragments, to obtain eventually bivalent
hybrids.
ꢁ
2
3
often achieved through the Barton-Kellogg olefin synthesis or the
Furthermore, the conformation analysis of a typical bis(cyclo-
hexylidene) 1(1) is also described herein, which will help to better
understand the relationships between the property and the struc-
ture of these compounds.
2
2
. Results and discussion
.1. Synthesis
Fig. 1. Unsymmetrical a,u-end-functionalized oligo(cyclohexylidenes).
The overall process of oligo(cyclohexylidenes) 1(n) synthesis is
reported in Scheme 1. 4-(tert-butyldimethylsilanoxy) cyclo-
hexanecarboxylicacid3waseasilyobtained inquantitativeyieldfrom
the commercially available ethyl 4-hydroxycyclohexanecarboxylate 2
*
Corresponding authors. Tel.: þ33 (0)478777253 (S.R.); tel.: þ33 (0)478777006
(
N.W.); e-mail addresses: sylvie.radix@univ-lyon1.fr (S. Radix), nadia.walchshofer@
univ-lyon1.fr (N. Walchshofer).
http://dx.doi.org/10.1016/j.tet.2016.05.040
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

W. Zeinyeh et al. / Tetrahedron 72 (2016) 4032e4038
4033
ꢀ
ꢀ
ꢀ
Scheme 1. Reagents and Conditions: (a) (i) TBSCl, imidazole, DMF, rt (ii) LiOH, THF, MeOH, 60 C, quant. over 2 steps; (b) (i) LDA, THF, ꢁ40 C then 0 C (ii) 1,4-dioxa-spiro[4.5]
ꢀ
ꢀ
decan-8-one 4 or ketone 8, THF, ꢁ40 C then 50 C (iii) HCl, H
2 2 2 3 2
O, 53% for 5, 45% for 9; (c) Me NCH(OCH CMe ) , MeCN, rt then reflux, 90% for 6, 68% for 10; (d) TBAF, THF, reflux,
90%; (e) PDC, DCM, rt, 90%. Numbering system for NMR data.
5
used as a cis/trans mixture. Then, the coupling reaction between the
lithium dianion of 3 with the monoprotected cyclohexanedione 4
yielded
b-hydroxy acid 5 as a mixture of diastereoisomers. The next
decarboxylative dehydration in presence of N,N-dimethylformamide
2
,6
dineopentyl acetal (DMF-DNA), developed by Jenneskens et al., led
to the bicyclohexylidene 6 with an excellent 90% yield (48% overall
yield from alcohol 2). Deprotection of the silyl ether 6 by tetrabuty-
lammonium fluoride (TBAF) eventually gave the alcohol 7, which was
used as a valuable precursor for the synthesis of the a,u-end-func-
tionalized biscyclohexylidene 1(1) (Pathway A). Compound 7 also
allowed us to prepare longer oligo(cyclohexylidenes) 1(n) (Pathway
B). Asa result, pyridinium dichromate (PDC)oxidation of7 yieldedthe
bicyclohexylidene ketone 8, that could re-enter the coupling/olefi-
nation sequence to afford tercyclohexylidene 10 in three steps with
a good overall 28% yield (Pathway B). After deprotection of the hy-
droxyl group of 10, completion of the synthesis route should lead to
1(2) through pathway A or 1(n>2) through pathway B.
As described in Scheme 2, the synthesis of the bicyclohex-
ylidene 1(1) was performed from alcohol 7 in four steps. The
cyano group was readily introduced by displacement of a mesyl
7
group. In classical thermal conditions, this nucleophilic sub-
stitution was extremely slow and gave a mixture of compounds.
Hence the reaction was carried out under microwave irradiation
ꢀ
at 100 C for 10 min in presence of tetrabutylammonium cyanide
to produce nitrile 12 with a moderate yield. Increasing the re-
action temperatures or varying the reaction duration did not lead
to higher yield. Nitrile 12 was obtained in mixture with the
elimination product 13 and traces of the isocyanide 14. In In-
frared spectra, the isocyanide group was characterized by
ꢀ
Scheme 2. Reagents and conditions of Pathway A: (a) CH
3
SO
2
Cl, NEt
3
ꢀ
, THF, 0 C then
ꢀ
rt, quant.; (b) NBu
MeOCH PPh
for NMR data.
4
CN, THF, MW, 100 C. (c) HCl 5%, H
2
O, THF, 70 C, quant.; (d) (i)
O, 0 C, 85%; Numbering system
ꢀ
ꢀ
2
3
Cl, tBuOK, THF, 0 C then rt (ii) HCl 6N, H
2
ꢁ
1
a strong absorption band at 2140 cm while the cyanide func-
ꢁ
1
tion displayed a medium absorption band at 2234 cm . These
13
compounds were also identified by NMR. The C NMR spectrum
showed a typical signal at 154.7 ppm for the isocyano carbon
whereas the cyano carbon signal appeared at 122.1 ppm. More-
Hydrolysis of the acetal 12 under slightly acidic conditions led to
the ketone 15. The oxo group was subsequently converted into
a formyl group in a one-pot two-step Wittig/hydrolysis sequence.
First, the ketone 15 was allowed to react with chloride methox-
ymethyltriphenylphosphonium and potassium tert-butoxide to
over, the C1-proton signal in isonitrile (
nificantly deshielded compared with the corresponding signal in
nitrile (
¼2.77 ppm).
d
¼3.77 ppm) was sig-
d

4034
W. Zeinyeh et al. / Tetrahedron 72 (2016) 4032e4038
provide a methyl enol ether that was directly hydrolyzed to give the
aldehyde 1(1) as an equimolar mixture of cis/trans isomers with an
excellent 85% overall yield from the acetal 12. Pure analytical
samples of cis-1(1) and trans-1(1) were obtained after silica gel
flash column chromatography performed with a dichloromethane/
methanol gradient.
This confirmed that the trans and cis isomers adopted an anti- and
a syn-conformation, respectively.
3. Conclusion
Oligo(cyclohexylidenes) are length-defined structures which
have been particularly described for their self-assembly properties
to form ordered structures. We described here the synthesis of
original derivatives with two easily derivatized end-functional
groups. These compounds, which adopt a rigid conformation in
solution, could be conveniently linked to bioactive fragments.
Hence they would constitute very good candidates as linker agents
for the design of bivalent compounds.
2
.2. Structural analysis
At this point, we tried to determine the privileged conformation
for both the cis and trans isomers of the bicyclohexylidene 1(1) by
high-resolution X-ray diffraction analysis. However, whatever the
solvent system used to recrystallize these compounds, no suitable
crystals were grown for the X-ray diffraction study. A structural
analysis was therefore performed by NMR spectroscopy and Den-
sity Functional Theory (DFT) methods, based on anterior theoretical
2
studies that had predicted that oligo(cyclohexylidenes) possess
chairlike geometries.
First, both biscyclohexylidenes were fully characterized using
1
13
1
13
1
-
D NMR ( H and
decoupled edited HSQC (Heteronuclear Single Quantum Co-
herence) sequence in which positive CH correlations were distin-
guished from negative CH correlations.
C) and 2D { H; C} proton-coupled and
2
The interpretation was made easier by an unexpected weak
two-bond correlation between the aldehyde proton (9.66 or
0
9
.65 ppm) and carbon C-4 (49.9 or 50.0 ppm) visible in each
decoupled HSQC spectrum registered for isomers cis-1(1) and
trans-1(1) (Fig. 2). Moreover, according to the HSQC experiments,
each methylene carbon atom correlated with two inequivalent
6
a,8
proton resonances. Contrary to generally accepted standards,
this indicated that axial and equatorial protons were anisochro-
nous in solution at room temperature. These results suggest that
each cis-1(1) and trans-1(1) isomer adopted a frozen conformation
in solution on the NMR timescale at room temperature, with no
interconversion of cyclohexyl-type rings.
In addition, values for cyclohexane derivatives in their chair
conformation are typically Jae 2e6 Hz, Jee 2e5 Hz and Jaa 8e13 Hz.
1
As shown by their 1D H projections of decoupled edited HSQC
0
spectra, H-4 and H-4 protons of cis-1(1) and trans-1(1) bicyclo-
hexylidenes provided triplet of triplet resonance patterns due to
3
the vicinal coupling constants ( JHH) Jaa and Jae (Fig. 3).
This indicated that in both isomers, formyl and cyano sub-
stituents occupy a sterically favored equatorial position. So, trans
and cis isomers could adopt an anti- and a syn-conformation, re-
spectively (Fig. 4).
0
1
To confirm the axial position of both H-4 and H-4 protons, JC,H
1
13
coupling constants were extracted from 2D { H; C} proton-
coupled edited HSQC spectrum (Fig. 5). First, experimental values
of JC,H coupling constants of both isomers were found to be in good
1
agreement with the estimated values. Actually, the additivity rule
for estimating 13Ce H-coupling constants across one bond in ali-
1
9
1
phatic compounds applied to the axial
JC,H in cyclohexane
1
1
1
0
(
J
C,Hax¼122.4 Hz) led to J(C-4,Hax)¼133.4 Hz and J(C-4 ,Hax)¼
124.4 Hz.
1
To confirm these experimental results, JC,H coupling constants
0
in position 4 and 4 were calculated with good accuracy by DFT
methods for each inverted chair conformers of both trans-1(1) and
cis-1(1) isomers (Fig. 6). Hence, all compounds were constructed
1
0,11
and minimized with B3LYP
DFT calculations. NMR calculations
12e14
were computed on resulting structures by GIAO
methods with
C,H values of axial and
equatorial protons bonded to the same carbon atom were in
1
spin-spin coupling. First, the calculated
J
Fig. 2. 500 MHz { H;13C} decoupled edited HSQC sequence registered in CDCl3 at
298 K with high-resolution 1D proton spectra as top projection and high-resolution 1D
carbon spectra as left projection for each isomer of 1(1). For each isomer, arrow in-
dicates folded CHO peak in the indirect dimension and square box shows the two-bond
1
1
agreement with the normal Perlin effect: axial
than equatorial JC,H (Table 1).
Second, for each isomer, the calculated values of axial JC,H (Table
) were in good agreement with the experimental values (Fig. 5).
JC,H was smaller
1
15
1
0
1
correlation between the aldehyde proton and carbon C-4 .

W. Zeinyeh et al. / Tetrahedron 72 (2016) 4032e4038
4035
0
Fig. 3. Enlarged views of H-4 and H-4 signals for each isomer of compound 1(1) from
1
1
1
13
D F2 ( H) projections of 500 MHz { H; C} decoupled edited HSQC spectra.
Fig. 4. Proposed conformations for trans-1(1) and cis-1(1).
Fig. 5. 500 MHz { H;13C} coupled edited HSQC sequence registered in CDCl
1
3
at 298 K
with high-resolution 1D proton spectra as top projection and high-resolution 1D
carbon spectra as left projection for each isomer of 1(1).
4
4
4
. Experimental section
coupling constants J are reported in hertz (Hz). Carbon multiplicity
was determined by DEPT experiments. The following abbreviations
are used: s: singlet; bs: broad singlet; d: doublet; t: triplet; bt: broad
triplet; dd: doubled doublet; dt: doubled triplet; q: quartet; m:
multiplet; C: quaternary carbons. Chromatographic separations
were performed on silica gel columns by column chromatography
.1. Chemistry
.1.1. General procedures. All air- and moisture-sensitive reactions
were carried out under a nitrogen atmosphere. All commercially
available chemicals were used as received. Melting points were
determined with an Electrothermal 9200 capillary apparatus. The IR
spectra were recorded on a Perkin Elmer Spectrum Two IR Spec-
trometer. H spectra were recorded with Bruker DRX300, Bruker
DRX400 and Bruker DRX500 Fourier transform spectrometers, using
an internal deuterium lock, operating at 300 MHz, 400 MHz and
(Kieselgel 300e400 mesh). Preparative thin layer chromatography
plates were prepared using Kieselgel Silica Gel 60 F254 for thin-layer
chromatography. All reactions were monitored by TLC on GF254
plates that were visualized under a UV lamp (254 nm). Evaporation
of solvent was performed under vacuum with a rotating evaporator.
Low- and high-resolution mass spectra were performed on a Ther-
moFinnigan MAT 95 XL apparatus operating at 70 eV.
1
13
5
00 MHz, respectively. C NMR spectra were recorded with Bruker
DRX300, Bruker DRX400 and Bruker DRX500 Fourier transform
spectrometers, using an internal deuterium lock, operating at
7
reported in part per million (ppm) relative to residual protons of
CDCl
4
.1.2. 4-(tert-Butyldimethylsilanoxy)cyclohexane carboxylic acid
3). To a solution of ethyl 4-hydroxycyclohexanecarboxylate 2
(mixture of cis and trans) (2.5 g, 14.5 mmol) and imidazole (1.97 g,
5 MHz, 100 MHz and 125 MHz respectively. Chemical shifts are
(
1
13
3
(d
¼7.26 ppm for H NMR and
d
¼77.00 ppm for C NMR) and

4036
W. Zeinyeh et al. / Tetrahedron 72 (2016) 4032e4038
cooled in an ice bath then acidified to pH¼1 with 1M aqueous HCl.
After extraction with ethyl acetate, the organic phases were dried
over Na SO , filtered and concentrated. The residue was purified by
flash chromatography on silica gel (cyclohexane/ethyl acetate,
0:50) to give the title compound 3 as a mixture of cis/trans isomers
3.48 g,100% yield) as a colorless oil; (400 MHz, CDCl ) 10.84 (2H,
m, 2*COOH), 3.89 and 3.56 (2*1H, 2*bs, 2*H-4), 2.41e2.18 (2H, m,
2
4
5
(
d
H
3
2
0
2
*H-1), 2.10e1.83 (6H, m), 1.74e1.59 (4H, m), 1.58e1.23 (6H, m),
.88 and 0.87 (2*9H, 2*s, 2*(CH CSi), 0.05 and 0.03 (2*6H, 2*s,
*(CH Si); (100 MHz; CDCl ) 181.8 (2*COOH), 70.5 and 66.7
), 32.9 (2*CH ), 27.1
CSi), 18.3 and 18.2
3 3
)
3
)
2
d
C
3
(2*C-4), 42.0 and 41.9 (2*C-1), 34.8 (2*CH
(2*CH ), 23.4 (2*CH ), 26.1 and 26.0 (2*(CH
(2*(CH Si).
CSi), ꢁ4.5 and ꢁ4.7 (2*(CH
2
2
2
2
3 3
)
3
)
3
3 2
)
4
.1.3. 4-(tert-Butyldimethylsilanoxy)-1-(8-hydroxy-1,4-dioxaspiro
[4.5]dec-8-yl)cyclohexanecarboxylic acid (5). To a solution of diiso-
propylamine (1.63 mL, 11.6 mmol) in anhydrous THF (20 mL) at
ꢀ
ꢁ
40 C, nBuLi (1.8M in hexane, 6.45 mL, 11.6 mmol) was added. The
ꢀ
ꢀ
mixture was stirred at ꢁ40 C for 15 min, then at 0 C for additional
5 min. A solution of acid 3 (1.5 g, 5.8 mmol) in anhydrous THF
5 mL) was then added to this lithium diisopropylamide (LDA) so-
1
(
ꢀ
ꢀ
lution at ꢁ40 C. The mixture was stirred at ꢁ40 C for 15 min then
ꢀ
ꢀ
heated to 50 C for 2 h and, once again cooled to ꢁ40 C. A solution
of ketone 4 (0.907 g, 5.8 mmol) in anhydrous THF (3 mL) was then
ꢀ
added and the mixture was stirred at ꢁ40 C for 15 min, then
ꢀ
heated to 50 C for 1 h 30. The mixture was cooled in an ice bath
and water (30 mL) was added. After removal of organic solvents,
the aqueous layer was acidified to pH¼1 with 1M aqueous HCl and
extracted with dichloromethane. Combined organic extracts were
dried over Na SO , filtered and concentrated. The residue was pu-
2 4
rified by silica gel flash chromatography (dichloromethane/meth-
anol, 93:7) to give the title compound 5 as a mixture of two
diastereoisomers (1.27 g, 53% yield) as a white solid;
.00e3.87 (9H, m, 2*OCH CH O, H-4), 3.55 (1H, m, H-4), 2.27e1.20
16H, m), 2.09e1.38 (16H, m), 0.88 (2*9H, s, 2*(CH CSi), 0.07 and
.01 (2*6H, 2*s, 2*(CH Si); (100 MHz) 180.5 and 179.2
2*COOH), 108.64 and 108.57 (2*C-5 ), 74.0 and 73.5 (2*C(8 ), 72.1
H
d (400 MHz)
4
(
0
(
2
2
Fig. 6. Proposed interconversion equilibrium for each isomer.
3 3
)
3
)
2
d
C
Table 1
0
0
0
1
Calculated C-4,H- and C-4 ,H-coupling constants ( JCH/Hz) in each inverted con-
and 65.3 (2*C-4), 64.4 (OCH
2
), 64.3 (OCH
2
), 64.2 (OCH
), 31.2 (2*CH
), 27.5 (2*CH
2
), 63.8
), 30.4
), 22.3
CSi),
formers of bicyclohexylidenes trans-1(1) and cis-1(1)
(
(
OCH
2*CH
2
), 55.3 and 54.7 (2*C-1), 33.2 (2*CH
2
2
Isomers
Type
1JCH(calcd) (Hz)a
2
), 30.4 (2*CH
2
), 30.2 (2*CH
2
), 29.9 (2*CH
2
2
trans-1(1)
C-4, H-4ax
C-4 , H-4 ax
C-4, H-4eq
136.14
126.74
140.88
126.91
136.13
128.83
135.99
126.58
140.76
126.43
135.94
128.62
(2*CH
), 26.01 and 25.96 (2*(CH
3
)
3
CSi), 18.4 and 18.1 (2*(CH
)
2
3
3
0
0
þ
ꢁ
4.61 and ꢁ4.75 (2*(CH
3
)
2
Si); m/z (ESI) 437 (MNa , 100%), 375
A
þ
0
0
(42); HRMS (ESI): MNa , found: 437.2337. C21
H38NaO
6
Si requires
C-4 , H-4 ax
C-4, H-4ax
437.2335.
B
0
0
C-4 , H-4 eq
C-4, H-4ax
cis-1(1)
4
.1.4. 8-(4-(tert-Butyldimethylsilanoxy) cyclohexylidene)-1,4-
0
0
C-4 , H-4 ax
C-4, H-4eq
dioxaspiro[4.5]decane (6). To a suspension of acid 5 (0.55 g,
1.32 mmol) in anhydrous acetonitrile (20 mL), DMF-DNA (2.2 mL,
7.92 mmol) was added. The mixture was stirred at room temper-
ature for 1 h then refluxed overnight. After removal of the solvent,
the residue was purified by silica gel flash chromatography (cy-
C
0
0
C-4 , H-4 ax
C-4, H-4ax
D
0
0
C-4 , H-4 eq
a
GIAO calculations. Optimized with B3LYP/6-311þG(d,p).
clohexane/ethyl acetate, 95:5) to give the title compound 6 (0.42 g,
ꢀ
9
OCH
0% yield) as a white solid; Mp 72 C;
d
H
(400 MHz) 3.93 (4H, m,
0
2
CH
2
O), 3.82 (1H, m, H-4 ), 2.59e2.45 (2H, m), 2.41e2.18 (4H,
2
9 mmol) in anhydrous DMF (20 mL), tert-butyldimethylsilyl
chloride (2.63 g, 17.5 mmol) was added. After stirring overnight,
Et O (60 mL) and 1M aqueous HCl (60 mL) were added. After ex-
traction with Et O, the combined organic phases were washed with
M aqueous HCl and brine, dried over Na SO , filtered and con-
m), 2.03e1.83 (3H, m), 1.80e1.60 (5H, m), 1.51e1.32 (2H, m), 0.88
(9H, s, (CH
3
)
3
CSi), 0.05 (6H, s, (CH
3
)
2
Si);
d
C
(100 MHz) 129.7 (C]C),
CH O), 36.9
0
0
2
127.5 (C]C), 109.2 (C-5 ), 70.2 (C-4 ), 64.4 (OCH
2
2
2
(2*CH
18.3 ((CH
2
), 36.4 (2*CH
2
), 26.7 (2*CH
2
), 26.4 (2*CH
2
), 26.0 ((CH
3
)
3
CSi),
þ
1
2
4
3
)
3
CSi), ꢁ4.50 ((CH
3
)
2
Si); m/z (ESI) 353 (MH , 95%), 239
þ
centrated under reduced pressure to give a TBS-protected alcohol
as a colorless oil (4.14 g), which was used in the next step without
further purification. To a solution of the former alcohol (4.14 g,
(17), 221 (100); HRMS (ESI): MH , found: 353.2510. C20
requires 353.2512.
37 3
H O Si
1
4.5 mmol) in THF (20 mL) and methanol (12 mL), lithium hy-
4.1.5. 4-(1,4-Dioxaspiro[4.5]dec-8-ylidene) cyclohexanol (7). A so-
lution of bicyclohexylidene 6 (0.6 g, 1.7 mmol) and tetrabuty-
lammonium fluoride (1M in THF, 4.5 mL, 4.5 mmol) in anhydrous
THF (36 mL) was refluxed for 1 h 30. After removal of the solvent,
droxide (0.7 g, 29 mmol) was added. The mixture was then stirred
at 60 C for 3 h. After removal of the solvents, water and Et
added and the aqueous layer was extracted with diethyl ether,
ꢀ
2
O were

W. Zeinyeh et al. / Tetrahedron 72 (2016) 4032e4038
4037
dichloromethane was added. The organic phase was washed with
water then dried over Na SO , filtered and concentrated. The resi-
2 4
over Na SO , filtered and concentrated to give the mesylate 11
(0.415 g, 95% yield) as a white solid which was used in the next step
2
4
due was purified by silica gel flash chromatography (dichloro-
without further purification.
methane/methanol, 97:3) to give the title compound 7 (0.36 g, 90%
ꢀ
yield) as a white solid; Mp 120 C;
d
H
(400 MHz) 3.96 (4H, m,
4.1.9. Microwave-assisted cyanation. A solution of 11 (0.150 g,
0.47 mmol) and of tetrabutylammonium cyanide (0.752 g,
2.80 mmol) in anhydrous THF (15 mL) was heated under microwave
2 2
OCH CH O), 3.83 (1H, m, H-1), 2.63e2.56 (2H, m), 2.39e2.24 (4H,
m), 1.98e1.82 (4H, m), 1.69e1.58 (4H, m), 1.57 (1H, s, OH), 1.42e1.30
0
ꢀ
(
2H, m);
d
C
(100 MHz) 128.9 (C]C), 128.2 (C]C), 109.1 (C-5 ), 70.1
irradiation to 100 C for 10 min. After removal of the solvent, ethyl
(
2
C-1), 64.4 (OCH
2
CH
2
O), 36.5 (2*CH
2
), 36.4 (2*CH
2
), 26.7 (2*CH
2
),
acetate was added. The organic phase was washed with water,
þ
6.6 (2*CH
2
); m/z (EI) 238 (M , 40%), 220 (10), 176 (38), 86 (100);
dried Na
by silica gel flash chromatography (cyclohexane/ethyl acetate,
0:10) to give nitrile 12 (0.055 g, 47% yield) as a white solid, the
2 4
SO , filtered and concentrated. The residue was purified
þ
HRMS (EI): M , found: 238.1568. C14
H
22
O
3
requires 238.1569.
9
4
.1.6. 4-(1,4-Dioxaspiro[4.5]dec-8-ylidene) cyclohexanone (8). A so-
elimination product 13 (0.035 g, 33% yield) as a white solid and
isocyanide 14 (0.010 g, 8% yield) as a white solid.
lution of alcohol 7 (0.100 g, 0.42 mmol) and PDC (0.189 g,
0
2
.50 mmol) in anhydrous dichloromethane (10 mL) was stirred for
days. Then the mixture was filtered over Celite and the filtrate
4.1.9.1. 4-(1,4-Dioxaspiro[4.5]dec-8-ylidene)
cyclo-
ꢀ
was concentrated. The residue was purified by silica gel flash
chromatography (cyclohexane/ethyl acetate, 2:1) to give the title
compound 8 (0.090 g, 90% yield) as a white solid; Mp 100e102 C;
hexanecarbonitrile (12). Mp 126 C;
n
max (KBr) 2979, 2947, 2927,
ꢁ1
2886, 2871, 2848, 2234, 1439, 1282, 1121, 1099, 980 cm
(300 MHz) 3.96 (4H, m, OCH CH O), 2.77 (1H, tt, J 4.0 Hz, 8.0 Hz, H-
; d
H
ꢀ
2
2
d
H
(300 MHz) 3.94 (4H, br s, OCH
.39e2.31 (8H, m), 1.67e1.63 (4H, m);
2
CH
2
O), 2.57e2.53 (4H, m),
1), 2.54e2.45 (2H, m), 2.32e2.28 (4H, m), 2.19e2.10 (2H, m),
þ
2
d
C
(75 MHz) 212.6 (CO), 131.0
1.93e1.62 (8H, m); m/z (EI) 247 (M , 16%), 86 (100);
129.0 (C]C), 127.1 (C]C), 122.1 (CN), 109.2 (C-5 ), 64.4 (OCH
d
C
(75 MHz)
0
0
(C]C), 124.9 (C]C), 108.8 (C-5 ), 64.4 (OCH
2
CH
2
O), 40.7 (2*CH
2
),
2
-
þ
3
5.9 (2*CH
2
), 26.8 (2*CH
2
), 26.8 (2*CH
2
); m/z (EI) 236 (M , 27%), 86
CH
(2*CH
47.1572.
2
O), 35.9 (2*CH
2
), 30.6 (2*CH
2
), 28.3 (2*CH
2
), 28.1 (C-1), 26.5
requires
þ
þ
(
100); HRMS (EI): M , found: 236.1411. C14
H
20
O
3
requires 236.1412.
2
); HRMS (EI): M , found: 247.1559. C15
H
21NO
2
2
0
0
4
.1.7. 8-(4 -(tert-Butyldimethylsilanoxy)-1,1 -bicyclohexylidene-4-
ylidene)-1,4-dioxaspiro [4.5]decane (10). A solution of LDA (1.4M in
hexane, 0.625 mL, 0.87 mmol) was added to a solution of acid 3
4.1.9.2. 8-Cyclohex-3-enylidene-1,4-dioxaspiro
(13). d
H
[4.5]decane
(300 MHz) 5.76e5.62 (2H, m, CH]CH), 3.95 (4H, s,
2 2
OCH CH O), 2.81 (2H, m), 2.36e2.28 (6H, m), 2.08 (2H, m),
ꢀ
(
0.109 g, 0.42 mmol) in anhydrous THF (0.5 mL) at ꢁ40 C. The
ꢀ
ꢀ
mixture was stirred for 15 min at ꢁ40 C, then heated to 50 C for
1.67e1.62 (4H, m).
ꢀ
2
(
h, and once again cooled to ꢁ40 C. A solution of ketone 8
0.236 g, 0.87 mmol) in anhydrous THF (1 mL) was added and the
4.1.9.3. 4-(1,4-Dioxaspiro[4.5]dec-8-ylidene) cyclohexane-1-
ꢀ
ꢀ
mixture was stirred at ꢁ40 C for 15 min, then heated to 50 C for
isocyanide (14).
2140, 1438, 1229, 1121, 1072, 944 cm
OCH CH O), 3.77 (1H, m, H-1), 2.51e2.42 (2H, m), 2.33e2.29 (4H,
nmax (KBr) 2978, 2946, 2924, 2881, 2869, 2851,
ꢁ
1
2
h30. The mixture was cooled in an ice bath and water (2 mL) was
H
; d (300 MHz) 3.96 (4H, s,
added. After removal of organic solvents, the aqueous layer was
acidified to pH¼1 with 1M aqueous HCl and extracted with
dichloromethane. Combined organic extracts were washed with
2
2
m), 2.19e2.10 (2H, m), 1.91e1.62 (8H, m);
128.8 (C]C), 128.3 (C]C), 109.1 (C-5 ), 64.4 (OCH
d
C
(75 MHz) 154.7 (NC),
CH O), 51.5 (C-1),
), 26.7 (2*CH ).
0
2
2
brine, dried over Na
2
SO
4
, filtered and concentrated. The residue
37.6 (2*CH
2
), 36.4 (2*CH
2
), 27.2 (2*CH
2
2
was purified by silica gel flash chromatography (dichloromethane/
methanol, 98:2 then 90:10) to give the compound 9 as a mixture of
two diastereoisomers (0.095 g, 45% yield) as a white solid; m/z (ESI)
0
0
4.1.10. 4 -Oxo-1,1 -bicyclohexylidene-4-carbonitrile (15). To a solu-
tion of acetal 12 (0.093 g, 0.37 mmol) in THF (2 mL) 5% aqueous HCl
þ
þ
þ
ꢀ
1011 ([2MþNa] , 100%), 517 (MNa , 72); HRMS (ESI): MNa , found:
(2 mL) was added. The mixture was heated to 70 C for 1 h. After
removal of solvent, dichloromethane was added. Organic phase was
5
17.2930. C27 46NaO Si requires 517.2956.
H
6
To a suspension of bicyclohexylidene 9 (0.050 g, 0.10 mmol) in
anhydrous acetonitrile (1.5 mL), DMF-DNA (0.112 mL, 0.40 mmol)
was added. The mixture was stirred for 1 h at room temperature
then refluxed overnight. After removal of the solvent, the residue
was purified by silica gel flash chromatography (cyclohexane/ethyl
4
washed with water, dried over MgSO , filtered and concentrated
under reduced pressure to give ketone 15 (0.076 g, 100% yield) as
ꢀ
a white solid; Mp 66e68 C;
H
d (400 MHz) 2.80 (1H, m, H-4),
2.58e2.37 (10H, m), 2.22e2.14 (2H, m), 1.95e1.73 (4H, m);
(100 MHz) 212.2 (CO), 129.6 (C]C), 126.1 (C]C), 122.1 (CN), 40.4
d
C
acetate, 94:6) to give the title compound 10 (0.030 g, 68% yield) as
(2*CH
2
), 30.5 (2*CH
2
), 28.1 (C-4), 27.5 (2*CH
2
), 26.5 (2*CH
2
); m/z
ꢀ
þ
þ
a white solid; Mp 137e138 C;
d
H
(300 MHz) 3.91 (4H, br s,
(ESI) 204 (MH , 100%); HRMS (ESI): MH , found: 204.1380.
C H18NO requires 204.1388.
13
00
OCH
m), 1.93e1.79 (2H, m), 1.76e1.55 (6H, m), 1.44e1.26 (2H, m), 0.83
9H, s, (CH CSi), 0.00 (6H, s, (CH Si); (75 MHz) 129.7 (C]C),
28.9 (C]C), 128.6 (C]C), 127.5 (C]C), 109.3 (C-5), 70.4 (C-4 ),
4.4 (OCH CH O), 36.7 (2*CH ), 36.2 (2*CH ), 29.7 (2*CH ), 29.6
2*CH ), 26.6 (2*CH ), 26.3 (2*CH CSi), 18.3
(CH
2
CH
2
O), 3.76 (1H, m, H-4 ), 2.53e2.38 (2H, m), 2.31e2.07 (12H,
(
3
)
3
3
)
2
d
C
0
0
0
0
1
4.1.11. 4 -Formyl-1,1 -bicyclohexylidene-4-carbonitrile (1(1)). A sus-
pension of (methoxymethyl)triphenylphosphonium chloride
(0.710 g, 2.06 mmol) and t-BuOK (0.229 g, 2.06 mmol) in anhydrous
6
2
2
2
2
2
(
(
2
2
2
2
), 26.0 ((CH
3
)
3
þ
ꢀ
)
3
CSi), ꢁ4.5 ((CH
3
)
2
Si); m/z (ESI) 433 (MH , 17%), 301 (100),
THF (10 mL) was stirred at 0 C for 30 min. A solution of ketone 15
3
þ
39 (16); HRMS (ESI): MH , found: 433.3130. C26
H
45
O
3
Si requires
(0.210 g, 1.03 mmol) in anhydrous THF (3.5 mL) was added. The
mixture was stirred overnight at room temperature. Water (0.8 mL)
and 6M aqueous HCl (2.8 mL) were added and the mixture was
stirred for further one hour. After removal of solvent, dichloro-
methane was added. Organic phase was washed with water, dried
4
33.3138.
4.1.8. Mesylate (11). To an ice bath cooled solution of alcohol 7
(
0.330 g, 1.38 mmol) in anhydrous THF (11 mL), methanesulfonyl
chloride (0.118 mL, 1.52 mmol) and triethylamine (0.258 mL,
.80 mmol) were added. The mixture was allowed to warm to room
2 4
over Na SO , filtered and concentrated. The residue was purified by
1
silica gel flash chromatography (cyclohexane/ethyl acetate, 4:1) to
give aldehyde 1(1) as an equimolar mixture of cis/trans isomers
(0.188 g, 85% yield) as a white solid. Analytical sample of each
temperature within 1 h. After removal of the solvent, ethyl acetate
was added. The organic phase was washed with water then dried

4038
W. Zeinyeh et al. / Tetrahedron 72 (2016) 4032e4038
isomer was obtained using gradient-elution flash silica gel chro-
matography (cyclohexane/dichloromethane, 50:50 to 30:70).
calculations of the spin-spin coupling constant and mixed
methods set was selected.
16
4
.1.11.1. Isomer 1.
d
H
(400 MHz) 9.66 (1H, br s, CHO), 2.76 (1H, tt,
0
Acknowledgements
J 8.0 Hz, 4.2 Hz, H-4), 2.57 (2H, m, 2*H-2 ), 2.45 (2H, m, 2*H-2), 2.43
1H, tt, J 10.2 Hz, 4.3 Hz, H-4 ), 2.16 (2H, m, 2*H-2), 2.03e1.82 (6H,
0
(
We thank the R
eꢀ gion Rh o^ ne-Alpes for financial support. The
0
0
0
m, 2*H-3 , 2*H-2 , 2*H-3), 1.77 (2H, m, 2*H-3), 1.46 (2H, m, 2*H-3 );
(100 MHz) 204.3 (CHO), 129.9 (C]C), 127.2 (C]C), 122.3 (CN),
authors are grateful to Pr. Philippe Lawton (UCB Lyon 1) for a careful
reading of the manuscript.
d
C
0 0
9.9 (C-4 ), 30.9 (2*C-3), 28.4 (C-4), 28.1 (2*C-2 ), 27.4 (2*C-2, 2*C-
4
3
2
0
þ
þ
); m/z (CI) 218 (MH , 100%), 200 (84); HRMS (CI): MH , found:
18.1533. C14 20NO requires 218.1545.
H
References and notes
4
.1.11.2. Isomer 2.
d
H
(400 MHz) 9.65 (1H, d, J 1.2, CHO), 2.77
1. (a) Zeinyeh, W.; Mahiout, Z.; Radix, S.; Lomberget, T.; Dumoulin, A.; Barret, R.;
Grenot, C.; Rocheblave, L.; Matera, E.-L.; Dumontet, C.; Walchshofer, N. Steroids
0
(
1
4
2
8
(
3
(
C
1H, tt, J 8.2 Hz, 4.1 Hz, H-4), 2.61 (2H, m, 2*H-2 ), 2.50 (2H, ddd, J
2012, 77, 1177e1191; (b) Zeinyeh, W.; Alameh, G.; Radix, S.; Grenot, C.; Du-
4.0 Hz, 7.5 Hz, 3.8 Hz, 2*H-2 equatorial), 2.43 (1H, tt, J 10.4 Hz,
montet, C.; Walchshofer, N. Bioorg. Med. Chem. Lett. 2010, 20, 3165e3168.
2. Hoogesteger, F. J.; Hevenith, R. W. A.; Zwikker, J. W.; Jenneskens, L. W.; Kooij-
man, H.; Veldman, N.; Spek, A. L. J. Org. Chem. 1995, 60, 4375e4384.
3. (a) Barton, D. H. R.; Willis, B. J. J. Chem. Soc., Perkin Trans. 1 1972, 305e310; (b)
Buter, J.; Wassenaar, S.; Kellogg, R. M. J. Org. Chem. 1972, 37, 4045e4060; (c)
Plunkett, K. N.; Godula, K.; Nuckolls, C.; Tremblay, N.; Whalley, A. C.; Xiao, S.
Org. Lett. 2009, 11, 2225e2228.
0
.3 Hz, H-4 ), 2.14 (2H, ddd, J 13.9 Hz, 9.2 Hz, 3.8 Hz, 2*H-2 axial),
0
0
.01e1.84 (6H, m, 2*H-3 , 2*H-2 , 2*H-3), 1.75 (2H, ddd, J 12.8 Hz,
.5 Hz, 3.8 Hz, 2*H-3 axial),1.48 (2H, m, 2*H-3 );
CHO), 129.9 (C]C), 127.2 (C]C), 122.3 (CN), 50.0 (C-4 ), 30.9 (2*C-
), 28.4 (C-4), 28.2 (2*C-2 ), 27.43 (2*C-2, 2*C-3 ); m/z (CI) 218
MH , 100%), 200 (84); HRMS (CI): MH , found: 218.1533.
14
H20NO requires 218.1545.
0
d
C
(100 MHz) 204.3
0
0
0
þ
þ
4. (a) Mc Murry, J. E.; Fleming, M. P. J. Org. Chem. 1976, 41, 896e897; (b) Duan, X.-
F.; Zeng, J.; L u€ , J.-W.; Zhang, Z.-B. J. Org. Chem. 2006, 71, 9873e9876.
5
6
. Madar, D. J.; Djuric, S. W.; Michmerhuizen, M. J.; Kopecka, H. A.; Li, X.; Lon-
genecker, K. L.; Pei, Z.; Pireh, D.; Sham, H. L.; Stewart, K. D.; Szczepankiewicz, B.
G.; Wiedeman, P. E.; Yong, H. U.S. Patent 0 215 784, 2005.
. (a) Hoogesteger, F. J.; Grove, D. M.; Jenneskens, L. W.; de Bruin, T. J. M.; Jansen,
B. A. J. J. Chem. Soc., Perkin Trans. 2 1996, 2327e2334; (b) Abdulla, R. F.; Brink-
meyer, R. S. Tetrahedron 1979, 35, 1675e1735; (c) Hara, S.; Taguchi, H.; Yama-
moto, H.; Nozaki, H. Tetrahedron Lett. 1975, 19, 1545e1548.
4
.2. DFT calculations
For all calculations the quantum chemistry methods were ap-
plied. The Density Functional Theory (DFT) was chosen because it is
correlative and compatible with the size of the system. The
7. Churcher, I.; Beher, D.; Best, J. D.; Castro, J. L.; Clarke, E. E.; Gentry, A.; Harrison,
T.; Hitzel, L.; Kay, E.; Kerrad, S.; Lewis, H. D.; Morentin-Gutierrez, P.; Mortishire-
Smith, R.; Oakley, P. J.; Reilly, M.; Shaw, D. E.; Shearman, M. S.; Teall, M. R.;
Williams, S.; Wrigley, J. D. J. Bioorg. Med. Chem. Lett. 2006, 16, 280e284.
. (a) Hoogesteger, F. J.; van Walree, C. A.; Jenneskens, L. W.; Roest, M. R.; Ver-
hoeven, J. W.; Schuddeboom, W.; Piet, J. J.; Warman, J. M. Chem.dEur. J. 2000, 6,
2948e2959; (b) Marsman, A. W.; Havenith, R. W. A.; Bethke, S.; Jenneskens, L.
W.; Gleiter, R.; van Lenthe, J. H. Eur. J. Org. Chem. 2000, 2629e2641.
. (a) Pretsch, E.; Seibl, J.; Simon, W.; Clerc, T. In Tables of Spectral Data for
Structural Determination of Organic Compounds; Springer-Verlag: Berlin, New-
York, 1981; (b) Malinowski, E. R. J. Am. Chem. Soc. 1961, 83, 4479e4480.
10,11
B3LYP
algorithm was selected for all calculations with various
atomic basis sets. All calculations were computed with the Gauss-
ian 09 Rev D.01 running a single-Nehalem CPU workstation with
Linux Redhat 6.5 workstation as OS.
For optimization and energy calculation the atomic basis set of
-31G(d,p) was selected. The classic scheme for the energetic
minimization was used and for intermediate conformation the re-
dundant coordinate was used to constraint value of dihedral angle.
All results were expressed in kJ.mol . All optimized conformation
were energy computed with a single point procedure using the
same atomic basis set and the B3LYP method.
8
9
6
10. Becke, A. D. Phys. Rev. A 1988, 38, 3098e3100.
11. Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200e206.
ꢁ
1
1
1
2. Ditchfield, R. Mol. Phys. 1974, 27, 789e807.
3. Wolinski, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251e8260.
14. Cheeseman, J. R.; Trucks, G. W.; Keith, T. A.; Frisch, M. J. J. Chem. Phys. 1996, 104,
497e5509.
5. Perlin, A. S.; Casu, B. Tetrahedron Lett. 1969, 34, 2921e2924.
6. Deng, W.; Cheeseman, J. R.; Frisch, M. J. J. Chem. Theory Comput. 2006, 2,
1028e1037.
5
For NMR calculations, the 6-311þG(d,p) atomic basis set was
1
1
chosen instead of 6-31G(d,p) to increase precision of the results for
12e14
the spin-spin coupling constant. The GIAO
method with