Chemoenzymatic route to various spirocyclic compounds based on enantiomerically enriched tertiary allylic, homoallylic, and homopropargylic alcohols

Article abstract of DOI:10.1016/j.tetasy.2014.03.004

A ring closing metathesis (RCM) reaction of dienes and an intramolecular Pauson-Khand (PKR) reaction of enynes derived from tertiary allyl, homoallyl, and homopropargyl alcohol backbones to afford the corresponding spirocyclic dihydrofuran and dihydropyra

Full text of DOI:10.1016/j.tetasy.2014.03.004

Tetrahedron: Asymmetry 25 (2014) 658–666
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic route to various spirocyclic compounds based
on enantiomerically enriched tertiary allylic, homoallylic,
and homopropargylic alcohols
Cihangir Tanyeli a, Devrim Özdemirhan b,
⇑
a Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Department of Chemistry, Abant Izzet Baysal University, 14280 Bolu, Turkey
b
_
a r t i c l e i n f o
a b s t r a c t
Article history:
A ring closing metathesis (RCM) reaction of dienes and an intramolecular Pauson–Khand (PKR) reaction
of enynes derived from tertiary allyl, homoallyl, and homopropargyl alcohol backbones to afford the cor-
responding spirocyclic dihydrofuran and dihydropyrans and spirocyclic cyclopentenone pyrans, respec-
tively, are described. Cyclopent-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols
1a–c have been efficiently resolved via enzymatic resolution with high ee (up to 90%) with 44%, 40%,
and 43% chemical yields, respectively. Moreover, the cyclohex-2-ene anchored tertiary allyl, homoallyl,
and homopropargyl alcohols 3a–c have also been resolved in the same manner with high ee (up to
97%) and in 42%, 45%, and 49% chemical yields. Enantiomerically enriched dienes derived from tertiary
homoallyl alcohols yield the corresponding enantiomerically enriched spirocyclic dihydropyran deriva-
tives via RCM with 74% and 78% chemical yields and with 90% and 97% ee, respectively. Moreover, enan-
tiomerically enriched enynes derived from tertiary homoallyl alcohols afford the corresponding
enantiomerically enriched cyclopentenone pyrans with spirocyclic motifs via PKR with 80% and 81%
chemical yields, respectively, and as single diastereomers.
Received 13 February 2014
Accepted 5 March 2014
Available online 2 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
increased in the field of organic optoelectronic materials such as
light emitting diodes (LEDs) and organic solar cells.7
Spirocyclic compounds have attracted considerable attention
due to their occurrence as substructures of many naturally occur-
ring substances derived from plants, fungi, especially marine
organisms and are a rich source for drugs.1 The pharmaceutically
active substances containing a spiro framework make the synthesis
and chemical reactivity of spirocyclic scaffolds an important area
of investigation in organic chemistry.2
Several synthetic methodologies have been applied to obtain
heterocyclic, carbocyclic, and especially spirocyclic compounds,
the ring closing metathesis (RCM) reaction has become a major
tool for synthetic organic chemists for constructing spirocyclic
scaffolds. RCM has recently been improved upon by introducing
well defined molybdenum and ruthenium catalysts developed by
Shrock8 and Grubbs,9 respectively. The Pauson–Khand reaction
has also become a powerful method over the last decade for the
synthesis of cyclopentenone ring systems used as building blocks
to obtain natural cyclopentenoids,10 especially possessing spiro
junction cyclopenta[c]-pyran and furan units.
Enantiomerically enriched tertiary allylic, homoallylic, and
homopropargylic alcohols are valuable structural units from which
to obtain cyclic and spirocyclic ethers, such as spirocyclic buteno-
lides chlorotricolide and androlactones,11 ligands for HIV protease
inhibitors,12 and other natural product inhibitors such as phoslac-
tomycins and leustroducsins.
As an important subclass, spirocyclic ethers3 containing dihy-
dropyrans and dihydrofurans have a junction with cyclic alkanes,
alkenes, lactones, or heterocyclic compounds, occurring as
subunits of natural products such as clementin,4 clerocidin,5 and
theaspirone.6 Furthermore, large numbers of biologically active
natural and unnatural compounds based on O-, N-, and S-, contain-
ing five- and six-membered heterocycles are very prominent in the
field of pharmaceutical chemistry as building blocks for the con-
struction of polyfunctionalized forms and their application has also
Although, the enzyme catalyzed kinetic resolution of secondary
alcohols with various lipases and esterases has been described
with high activity and enantioselectivity,13 there are only a few
⇑
Corresponding author. Tel.: +90 374 254 1000; fax: +90 374 253 4642.
E-mail address: ozdemirhan_d@ibu.edu.tr (D. Özdemirhan).
http://dx.doi.org/10.1016/j.tetasy.2014.03.004
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
659
O
AcO
HO
HO
HO
AcO
HO
d
a
b
d
+
+
n
n
n
n
n
n
n
(+)-2b, (+)-4b
(-)-1b, (-)-3b
1a 3a
,
1a
(-)- , (+)-
3a
(+)-2a, (-)-4a
1b 3b
,
rac-
rac-
n:1,2
c
HO
HO
HO
HO
HO
n
1a
(-)-
3a
(+)-
AcO
(-)-1b
(-)-3b
rac-1c, 3c
AcO
AcO
AcO
d
(+)-2a
(-)-4a
2b
(+)-
4b
(+)-
HO
AcO
+
n
n
2c
(-)- , (+)-
4c
1c
(+)- , (-)-
3c
HO
HO
1c
(+)-
3c
(-)-
AcO
AcO
(-)-2c
(+)-4c
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide (1 M in THF), dry ether; (b) allylmagnesium bromide (1 M in THF), dry ether; (c) propargyl bromide, Zn–Cu,
dry THF; (d) CAL-A-CLEA, vinyl acetate, co-solvent.
examples of biocatalytic routes for the production of chiral tertiary
alcohols.14 We have already reported initial studies on the enzyme
catalyzed resolution of aromatic ring fused cyclic tertiary alcohols
rac-3a–c by the enzymes to produce the enantiomerically enriched
tert-allylic, homoallylic, and homopropargylic alcohols, respec-
tively, that could serve as noteworthy templates for the construc-
tion of the corresponding spirocyclic dihydrofuran and
dihydropyran type compounds. All of the enantiomeric resolution
reactions were performed using various lipases; that is CAL-A,
from
a-indanone and a
-tetralone.15 In continuation of this, we
herein report the results of the enzymatic resolution of racemic
allylic, homoallylic, and homopropargylic cyclopent-2-en-1-ols
1a–c and cyclohex-2-en-1-ols 3a–c (Scheme 1).
CAL-B, CRL, Amano PS-C II, and CAL-A-CLEA with
a sub-
strate:enzyme ratio (w/w) 1:0.5 at a screening temperature 25 °C
to 38 °C in various co-solvents such as THF, TBME and DIPE, and vi-
nyl acetate as the acyl donor. CAL-A-CLEA afforded the most prom-
ising results among the lipases screened in terms of reaction
duration and enantioselectivity. CAL-B and Amano PS-C-II showed
no activity toward the corresponding tertiary alcohols. These re-
sults could be attributed to the lack of a required ‘GGGX-motif’ lo-
cated in the active site of the enzymes, as proposed by Bornscheuer
et al.17,18 The best results are summarized in Table 1. Tertiary
allylic substrate rac-1a resolution (entry 1) gave (ꢀ)-1-vinylcyclo-
pent-2-enol (ꢀ)-1a and (+)-1-vinylcyclopent-2-nyl acetate (+)-2a
in 45% and 52% ee, respectively, in THF as the co-solvent at 26 °C
after 50 h of shaking. Additionally, rac-3a (entry 2) resulted in
(+)-1-vinylcyclohex-2-enol (+)-3a and (ꢀ)-1-vinylcyclohex-2-enyl
acetate (ꢀ)-3b in 55 and 58% ee, respectively, by using TBME as
the co-solvent at 30 °C after shaking for 75 h. The next attempt
was carried out with the tertiary homoallylic alcohols rac-1b and
rac-3b (entries 3 and 4). (ꢀ)-1-Allylcyclopent-2-enol (ꢀ)-1b (entry
3) was isolated with excellent ee (90%) and the corresponding ester
2. Results and discussion
The parent tertiary allylic rac-1a,3a and homoallylic alcohols
rac-1b,3b that were used as templates for the construction of
spirocyclic scaffolds, were synthesized by the addition of vinyl-
magnesium bromide and allylmagnesium bromide, respectively,
to commercially available 2-cyclopenten-1-one and 2-cyclohex-
en-1-one. Since the same procedure is not available in the case of
propargylation, homopropargylic alcohols rac-1c and rac-3c were
prepared by the addition of propargyl bromide (80% wt in toluene)
to the carbonyl group, using a Zn–Cu couple as described in our
previous work,16 as shown in Scheme 1.
2.1. Enzymatic resolution of racemic tert-allylic, homoallylic,
and homopropargylic alcohols
The fundamentally most important step is the enantiomeric
resolution of racemic tertiary alcohol substrates rac-1a–c and

660
C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
Table 1
The results of CAL-A-CLEA-catalyzed resolution of tert-allylic rac-1a, rac-3a, homoallylic rac-1b, rac-3b, and homopropargylic rac-1c, rac-3c alcohols
Entry
Substrate
Co-solvent
Temperature (°C)
Time (h)
ca (%)
eepb(%)
ees (%)
Ec
1
2
3
4
5
6
rac-1a
rac-3a
rac-1b
rac-3b
rac-1c
rac-3c
THF
TBME
THF
—
DIPE
—
26
30
30
33
31
38
50
75
65
70
70
96
46
49
51
40
42
26
52
58
85
97
84
72
45
55
90
65
60
25
5
6
42
21
20
7.5
a
b
c
c = ees/ees + eep.
Enantiomeric excesses were determined by HPLC analysis with Daicel Chiralcel OD-H and OJ-H columns.
E = ln [(1 ꢀ c)(1 ꢀ ees)]/ln [(1 ꢀ c)(1 + ees)].19
(+)-2b with 85% ee in the THF as co-solvent at 30 °C after 65 h of
shaking. Furthermore, the enzymatic resolution of compound rac-
3b (entry 4) afforded (ꢀ)-1-allylcyclohex-2-enol (ꢀ)-3b in 65% ee
and (+)-1-allylcyclohex-2-enyl acetate (+)-4b in 97% ee which is
the highest in the series at 33 °C without any co-solvent with shak-
ing for 75 h. Finally, the enzymatic resolution of the tertiary homo-
propargylic alcohols rac-1c and rac-3c (entries 5 and 6) was
examined. (+)-1-(Prop-2-ynyl)cyclopent-2-enol (+)-1c and (ꢀ)-1-
(prop-2-ynyl)cyclopent-2-enyl acetate (ꢀ)-2c were obtained with
60% ee and 84% ee, respectively, by using DIPE as the co-solvent
at 31 °C for 70 h of shaking. However, the transesterification reac-
tion of compound rac-3c (entry 6) afforded (ꢀ)-1-(prop-2-
ynyl)cyclohex-2-enol (ꢀ)-3c with the lowest ee value (25%) in
the series, whereas (+)-1-(prop-2-ynyl)cyclohex-2-enyl acetate
(+)-4c was isolated with 72% ee at 38 °C without any co-solvent
with shaking for 96 h.
The successful synthesis of spirocyclic dihydrofurans rac-7a and
rac-8a prompted us to investigate the construction of spirocyclic
dihydropyran systems using appropriate diene scaffolds via RCM
reactions. tert-Homoallylic alcohols (ꢀ)-1b and (+)-3b were chosen
as templates, due to their high ee values, 90% and 97% ee, respec-
tively. Initially, acetate derivative (+)-4b was transformed into the
corresponding alcohol (+)-3b with K2CO3 in MeOH. By applying the
aforementioned protocol, diene scaffolds (ꢀ)-9b and (+)-10b were
isolated in 79% and 85% chemical yields, respectively. A subsequent
RCM reaction afforded enantiomerically enriched spirocyclic dihy-
dropyrans (+)-11b and (ꢀ)-12b with 74% and 78% chemical yields
and with 90% and 97% ee, respectively (Scheme 3).
HO
O
O
a
a
b
b
2.2. RCM reactions
(+)-11b
The acyclic unsaturated motifs on the tert-allylic, homoallylic,
and homopropargylic alcohol series 1a–c and 3a–c, together with
the alcohol unit for the subsequent second acyclic unsaturated
moiety could make them valuable candidates in terms of spirocy-
clic target formation. We chose ring closing metathesis (RCM) and
intramolecular Pauson–Khand reactions (PKR) as methods to build
up spirocyclic molecules.
1b
9b
(-)-
(-)-
HO
O
O
Initially, the applicability of RCM was tested on allylic rac-1a
and rac-3a serving as the background reactions. The second acyclic
unsaturated unit was tailored by O-allylation, using allyl bromide
with KH and tetrabutylammonium iodide (TBAI) in THF (Scheme 2).
The diene scaffolds rac-5a and rac-6a were subsequently subjected
to RCM with a Grubbs’ first generation catalyst in DCM to afford
spirocyclic dihydrofurans rac-7a and rac-8a in 72% and 75% chem-
ical yields, respectively (Scheme 2).
(+)-10b
(+)-3b
12b
(-)-
Scheme 3. Reagents and conditions: (a) KH, allyl bromide, THF, TBAI; (b) Grubbs’
1st generation catalyst (5 mol %), DCM.
Among the alcohols studied, only homoallylic alcohol derivative
1-allylcyclohex-2-enol 3b has been synthesized in an asymmetric
manner and has already been claimed to have an (R)-configuration
without any specific rotation value.20 Therefore, we were unable to
make a specific rotation comparison to determine the absolute
configuration of (+)-3b. Although many attempts have been made
to determine the absolute configuration of all allylic, homoallylic,
and homopropargylic alcohol derivatives by anchoring chiral units
such as; (1S)-(+)-10-camphorsulfonyl chloride and (S)-(+)-man-
delic acid, we were unable to obtain any suitable crystalline struc-
ture for X-ray analysis.
HO
O
O
a
b
rac-5a
-7a
rac
-1a
rac
2.3. Intramolecular PKR
HO
O
We also planned to investigate the applicability of intramolec-
ular PKR to build up cyclopentenone-furan and pyran fused ring
systems with spirocyclic motifs on tert-allylic 1a, 3a, homoallylic
1b, 3b, and homopropargylic 1c, 3c templates. Initial efforts were
made to ensure the availability of intramolecular PKR by con-
structing enynes tethered to cyclopentene and cyclohexene rings
via O-propargylation of tert-allylic alcohols rac-1a and rac-3a
O
a
b
8a
rac-
3a
rac-
rac-6a
Scheme 2. Reagents and conditions: (a) KH, allyl bromide, THF, TBAI; (b) Grubbs’
1st generation catalyst (5 mol %), DCM.

C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
661
O
using TMS-propargyl bromide, or via O-allylation of tert-homo-
propargylic alcohols, rac-1c and rac-3c using allyl bromide with
KH and tetrabutylammonium iodide (TBAI) in THF (Scheme 4).
Cyclopentene and cyclohexene tethered enynes rac-13a, rac-14a,
rac-17c, and rac-18c were isolated in 80%, 82%, 80%, and 84%
yields, respectively. Subsequently, all enynes were subjected to
intramolecular PKR. In this protocol, cobalt alkyne complexes were
prepared using enyne/dicobalt octacarbonyl in a molar ratio of
1.0:1.7 in DCM and then N-methyl-morpholine N-oxide monohy-
drate was added as a promoter. All of the reactions were moni-
tored by thin layer chromatography (TLC). Enynes leading to
pyran fused cyclopentenone frameworks afforded single diaste-
reomers rac-19c and rac-20c (82% and 85% chemical yields,
respectively), whereas enynes leading to furan fused cyclopente-
none derivatives rac-13a and rac-14a resulted in diastereomeric
mixtures of rac-15a and rac-16a with 1.33:1 and 1.57:1 ratios,
as established by 1H NMR spectroscopy in 77% and 79% yields,
respectively (Scheme 4). The lack of diastereoselectivity in furan
fused cyclopentenone derivatives was presumably due to the
smaller conformational effect of the furan rings on the diastere-
oselectivity when compared with the more favored chair confor-
mation of pyran rings as indicated in our previous study.21
O
HO
O
a
b
(+)-21a
(-)-23a
(-)-1b
O
HO
O
O
a
b
(+)-3b
22a
(-)-
(-)-24a
Scheme 5. Reagents: (a) KH, allyl bromide, TBAI, THF; (b) Co2CO8, NMO, DCM.
3. Conclusion
Herein we have demonstrated the first enzyme-catalyzed reso-
lution of tertiary allylic rac-1a,3a, homoallylic rac-1b,3b, and
homopropargylic alcohols rac-1c,3c. According to the results ob-
tained, CAL-A-CLEA was found to be the best biocatalyst, and affor-
ded (ꢀ)-1-allylcyclopent-2-enol (ꢀ)-1b in 90% and the
corresponding ester (+)-2b in 85% ee together with (ꢀ)-1-allylcy-
clohex-2-enol (ꢀ)-3b in 65% ee and the corresponding ester with
97% ee. The applicability of RCM has also been tested on diene sys-
tems anchored to tert-allylic alcohol backbones to obtain spirocy-
clic dihydrofuran compounds. Subsequent application with
enantiomerically enriched dienes tethered to tert-homoallylic tem-
plate afforded enantiomerically enriched spirocyclic dihydropyran
compounds (+)-11b and (ꢀ)-12b, respectively in good chemical
yields. We have also applied intramolecular PKR to enyne systems
constructed on tert-allylic and tert-homopropargylic templates by
anchoring propargyl and allyl units, respectively. The cyclopente-
none furans with spirocyclic motifs 15–16a were isolated as dia-
stereomeric mixtures, whereas pyrans 19–20c were isolated as
single diastereomers due to more favored chair conformation of
the pyran ring. By using this testing background, enantiomerically
enriched homoallylic templates (ꢀ)-1b and (+)-3b were used to
obtain the corresponding enynes (+)-21a and (ꢀ)-22a, respectively.
Subsequent intramolecular PKR afforded enantiomerically en-
riched cyclopentenone pyrans (ꢀ)-23a and (ꢀ)-24a, respectively,
with spirocyclic motifs as single diastereomers in good chemical
yield and with excellent diastereoselectivity.
O
HO
O
O
b
a
a
-1a
rac
rac-13a
rac-15a
O
HO
O
O
b
rac-3a
rac-14a
rac-16a
O
HO
O
O
b
a
-17c
rac
-1c
rac
rac-19c
O
HO
4. Experimental
4.1. General
O
O
a
b
-18c
rac
rac-3c
rac-20c
All experiments were carried out in pre-dried glassware (1 h,
150 °C) under an inert atmosphere of argon. The following reaction
solvents were distilled from the indicated drying agents: dichloro-
methane (P2O5), and tetrahydrofuran (sodium, benzophenone). 1H
NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker
Spectrospin Avance DPX-400 spectrometer. 1H (400 MHz) and 13C
NMR were recorded in CDCl3 and the chemical shifts are expressed
in ppm relative to CDCl3 (d 7.26 and 77.0 for 1H and 13C NMR,
respectively) as the internal standard. Standard COSY, HETCOR,
and DEPT experiments were performed to establish NMR assign-
ments. Infrared spectra were recorded on a Thermo Nicolet IS10
ATR-FT-IR spectrophotometer. HRMS spectra were detected on an
Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS at the
Scheme 4. Reagents and conditions: (a) KH, propargyl bromide, TBAI, THF; (b)
Co2CO8, NMO, DCM.
In the light of this, enantiomerically enriched tert-homoallylic
alcohols (ꢀ)-1b and (+)-3b were subjected to propargylation to
construct the corresponding enynes (+)-21a and (ꢀ)-22a, which
were isolated in 82% and 84% chemical yields, respectively
(Scheme 5). Subsequent intramolecular PKR afforded enantiomeri-
cally enriched pyran fused cyclopentenone derivatives (ꢀ)-23a and
(ꢀ)-24a in 80% and 81% chemical yields, respectively, as single
diastereomers.

662
C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
National Nanotechnology Research Center of Bilkent University
(UNAM). Optical rotations were measured employing a Rudolph
research analytical, autopol III automatic polarimeter.
4.2.4. rac-1-Allylcyclohex-2-enol 3b
Light yellow oil (0.50 g, 89% yield). IR mmax (neat cmꢀ1): 3461,
1163, 940, 710. 1H NMR (CDCl3, 400 MHz): d 5.88–5.93 (m, 1H),
5.87–5.97 (m, 1H), 5.62 (d, J = 10.0 Hz, 1H), 5.09–5.14 (m, 2H),
2.35 (d, J = 7.1 Hz, 2H) 2.01–2.08 (m, 1H), 1.89–1.96 (m, 1H), 1.86
(br s, 1H, (O-H), 1.57–1.77 (m, 3H), 1.27–1.23 (m, 1H). 13C NMR
(CDCl3, 100.6 MHz): d 133.7, 132.4, 129.9, 118.4, 69.1, 46.7, 35.4,
25.2, 18.9. HRMS (ESI-TOF) for C9H15O [M+H]+, calcd 139.1123,
found 139.1127.
Flash column chromatography was performed by using
thick-walled glass columns with a flash grade (Merc Silica Gel
60). Reactions were monitored by thin layer chromotography using
precoated silica gel plates (Merc Silica Gel PF-254), visualized by
UV-light and polymolybden phosphoric acid in ethanol as appropri-
ate. All extracts were dried over anhydrous magnesium sulfate and
solutions were concentrated under vacuum by using a rotary evap-
orator. All of the racemic tertiary alcohols 1a,22 1b,23 1c,24,27,28 3a,25
3b,20 and 3c,26–28 were prepared by reported procedures.
4.3. Synthesis of homopropargyl alcohols rac-1c,3c
Initially, the Zn–Cu couple preparation required an oxygen free
environment. Zinc dust (9.54 g, 74 mmol) was suspended in dis-
tilled water (10 mL), after which acidic cupric chloride solution
(0.15 M in 5% hydrochloric acid, 22 mL) was added with vigorous
magnetic stirring. When the evolution of the gas ceased, the sus-
pension was filtered and the black solid was washed with water
until the wash gave a negative test with 6% silver nitrate solution.27
To a stirred mixture of corresponding ketone rac-1c (6.08 g) and
rac-3c (7.11 g) (74 mmol) and freshly prepared Zn–Cu couple
(10.32 g, 80 mmol) in THF (30 mL), propargyl bromide (11.90 g,
80 mmol, 80 wt% in toluene) was added dropwise at 0 °C. Next,
the mixture was heated at reflux for 5 h with monitoring by TLC.
The resulting mixture was hydrolyzed with 1 M HCl (7 mL) and ex-
tracted with diethylether (3 ꢁ 30 mL), dried over MgSO4, and evap-
orated in vacuo. The crude product was purified by flash column
chromatography using a mixture of ethylacetate and hexane in
suitable ratios.
4.2. Synthesis of allylic rac-1a,3a and homoallylic alcohols rac-
1b,3b
To a stirred solution of Mg turnings (15 mmol) and iodine (two
pieces) in dry diethyl ether (15 mL) at room temperature equipped
with a reflux condenser was added dropwise a mixture of allylbr-
omide (11 mmol) in anhydrous diethyl ether (7 mL). The mixture
was allowed to reflux for 25 min. In the synthesis of allylic alco-
hols, vinyl magnesiumbromide 1.0 M in THF (11 mmol) was added
dropwise to dry diethylether without refluxing at the end of addi-
tion. Next, the mixture was cooled down to 0 °C followed by the
addition of the corresponding ketone (cyclopent-2-enone or cyclo-
hex-2-enone) (10 mmol) in dry diethylether (5 mL), which was
added dropwise. The resultant mixture was then stirred for 4 h.
The reaction mixture was hydrolyzed with saturated ammonium
chloride solution (20 mL) and then with HCl (3 mL). The resultant
mixture was then extracted with diethyl ether (3 ꢁ 30 mL). The
combined organic phase was washed with brine (20 mL) and dried
over MgSO4 and evaporated in vacuo. The crude products were
purified by flash column chromatography with a mixture of ethyl-
acetate and hexane in suitable ratios.
4.3.1. rac-1-(Prop-2-ynyl)cyclopent-2-enol 1c
Yellow oil (0.50 g, 89% yield). IR mmax (neat cmꢀ1): 3558, 3300,
2119, 949, 754. 1H NMR (CDCl3, 400 MHz): d 5.85 (td, J = 2.4 and
5.6 Hz, 1H) 5.67 (td, J = 2.0 and 5.4 Hz, 1H), 2.54 (br s, (O-H), 1H),
2.41–2.54 (m, 1H), 2.45 (d, J = 2.8 Hz, 2H), 2.23–2.32 (m, 1H),
2.01–2.08 (m, 1H), 1.94 (t, J = 2.4 Hz, 1H), 1.82–1.88 (m, 1H). 13C
NMR (CDCl3, 100.6 MHz): d 135.0, 134.6, 84.5, 80.9, 70.2, 37.3.
31.3, 31.1. HRMS (ESI-TOF) for C8H10O [M]+, calcd 122.0732, found
122.0740.
4.2.1. rac-1-Vinylcyclopent-2-enol 1a
Light yellow oil (0.45 g, 87% yield). IR mmax (neat, cmꢀ1): 3459,
2932, 933, 871. 1H NMR (CDCl3, 400 MHz): d 5.95, (dd, J = 10. 4
and 17. 2 Hz, 1H), 5.89 (td, J = 2.4 and 5.6 Hz, 1H), 5.57 (td, J = 2.0
and 5.4 Hz, 1H), 5.13 (dd, J = 1.2 and 17.2 Hz, 1H), 4.95 (dd,
J = 1.2 and 10.4 Hz, 1H), 2.43–2.50 (m, 1H), 2.24–2.32 (m, 1H)
1.99–2.07 (m, 1H), 1.86–1.91 (m, 1H), 1.76 (br s, 1H, (O-H)). 13C
NMR (CDCl3, 100.6 MHz): d 141.8, 134.5, 133.3, 110.5, 84.6, 37.9,
29.9. HRMS (ESI-TOF) for C7H11O [M+H]+, calcd 111.0810, found
111.0815.
4.3.2. rac-1-(Prop-2-ynyl)cyclohex-2-enol 3c
Colorless oil (0.30 g, 85% yield). IR m
max (neat cmꢀ1): 3465, 3405,
2115, 957, 747. 1H NMR (CDCl3, 400 MHz): d 5.77–5.82 (m, 1H),
5.64 (d, J = 10.0 Hz, 1H), 2.37 (d, J = 2.4 Hz, 2H), 2.02 (br s, (O-H),
1H), 2.00–2.04 (m, 2H), 1.99 (t, J = 2.4 Hz, 1H) 1.87–1.95 (m, 1H),
1.57–1.78 (m, 2H), 1.55–1.63 (m, 1H). 13C NMR (CDCl3,
100.6 MHz): d 129.9, 129.8, 95.1, 79.4, 70.1, 67.4, 34.2, 31.6, 24.1,
18.0. HRMS (ESI-TOF) for C9H12O [M]+, calcd 136.0888, found
136.0892.
4.2.2. rac-1-Vinylcyclohex-2-enol 3a
Colorless oil (0.45 g, 88% yield). IR m
max (neat cmꢀ1): 3365, 2937,
925, 817. 1H NMR (CDCl3, 400 MHz): d 5.85 (dd, J = 17.2 and
10.4 Hz, 1H), 5.76–5.80 (m, 1H), 5.46 (d, J = 10.0 Hz, 1H), 5.13 (d,
J = 17.2 Hz, 1H), 5.00 (d, J = 10.8 Hz, 1H), 2.01–2.11 (m, 2H), 1.70–
1.87 (m, 2H), 1.41–1.66 (m, 3H). 13C NMR (CDCl3, 100.6 MHz): d
144.2, 131.2, 130.0, 112.9, 70.9, 36.4, 25.0, 19.0. HRMS (ESI-TOF)
for C8H13O [M+H]+, calcd 125.0966, found 125.0969.
4.4. General procedure for the enzymatic resolution of rac-1a–c
and rac-3a–c
To 100 mg of substrates rac-1a–c and rac-3a–c and 1 mL of vinyl
acetate, was added 50 mg of the enzyme shaken at a suitable tem-
perature (26–38 °C). The reaction was followed by TLC. When it
came to the end, the mixture was filtered, and the residue was con-
centrated in vacuo, which was followed by flash-column chroma-
tography to purify the crude mixture using ethylacetate/hexane
as the eluent.
4.2.3. rac-1-Allylcyclopent-2-enol 1b
Pale yellow oil (0.45 g, 92% yield). IR mmax (neat, cmꢀ1): 3310,
1172, 918, 702. 1H NMR (CDCl3, 400 MHz): d 5.79–5.83 (m, 1H),
5.72–5.77 (m, 1H) 5.62 (td, J = 2.0 and 5.6 Hz, 1H), 5.08 (d,
J = 5.2 Hz, 1H), 5.04 (s, 1H), 2.38–2.47 (m, 1H), 2.33 (d, J = 7.6 Hz,
2H), 2.17–2.26 (m, 1H), 1.86 (ddq, J1 = 4.0, J2 = 13.5 and
J3 = 83.0 Hz, 2H), 1.70 (br s, (O-H), 1H). 13C NMR (CDCl3,
100.6 MHz): d 135.1, 133.0, 132.5, 117.3, 84.0, 44.3, 36.3, 30.0.
4.4.1. (ꢀ)-1-Vinylcyclopent-2-enol (ꢀ)-1a
Light yellow oil (44 mg, 44% yield). ½a D26
¼ ꢀ7:5 (c 0.70, CHCl3),
ꢂ
45% ee. The enantiomeric excess of the product was determined by
HPLC analysis (Daicel Chiralcel OD-H, k = 215 nm, n-hexane/2-pro-
panol 98:2, 0.5 mL/min), t1 = 19.3 min (minor) and t2 = 20.6 min
(major).
HRMS (ESI-TOF) for C8H13
125.0971.
O
[M+H]+, calcd 125.0966, found

C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
663
4.4.2. (+)-1-Vinylcyclopent-2-enyl acetate (+)-2a
111.2, 66.6, 28.3, 21.5, 19.1, 16.7; HPLC conditions: (Daicel Chiral-
cel OJ-H, k = 220 nm, n-hexane/2-propanol 98:2, 0.5 mL/min),
t1 = 12.6 min (minor) and t2 = 13.5 min (major). HRMS (ESI-TOF)
for C10H15O2 [M+H]+, calcd 167.1072, found 167.1064.
Yellow oil (35 mg, 25% yield). ½a D26
¼ þ7:1 (c 1.0, CHCl3), 52% ee.
ꢂ
IR mmax (neat, cmꢀ1): 1718, 947, 875. 1H NMR (CDCl3, 400 MHz): d
6.49 (dd, J = 10.4 and 17.2 Hz, 1H), 5.67 (d, J = 1.6 Hz, 1H), 5.61 (dd,
J = 2.4 and 6.8 Hz, 1H), 5.17 (d, J = 16.8 Hz, 1H), 5.13 (d, J = 9.6 Hz,
1H), 2.49–2.59 (m, 1H), 2.25–2.34 (m, 2H), 1.94 (s, 3H), 1.78–
1.87 (m, 2H). 13C NMR (CDCl3, 100.6 MHz): d 170.3, 147.8, 132.8,
127.9, 117.2, 80.1, 29.9, 29.1, 21.1; HPLC conditions: (Daicel Chiral-
cel OD-H, k = 230 nm, n-hexane/2-propanol 98:2, 0.5 mL/min),
t1 = 15.5 min (major) and t2 = 16.6 min (minor). HRMS (ESI-TOF)
for C9H13O2 [M+H]+, calcd 153.0915, found 153.0905.
4.4.9. (ꢀ)-1-Allylcyclohex-2-enol (ꢀ)-3b
Light yellow oil (45 mg, 45% yield). ½a D26
¼ ꢀ8:65 (c 1.0, CHCl3),
ꢂ
65% ee. The enantiomeric excess of the product was determined by
HPLC analysis (Daicel Chiralcel OD-H, k = 210 nm, n-hexane/2-pro-
panol 98:2, 0.5 mL/min) t1 = 14.0 min (major) and t2 = 15.9 min
(minor).
4.4.3. (ꢀ)-1-Allylcyclopent-2-enol (ꢀ)-1b
4.4.10. (+)-1-Allylcyclohex-2-enyl acetate (+)-4b
Pale yellow oil (40 mg, 40% yield). ½a D26
ꢂ
¼ ꢀ4:7 (c 1.10, CHCl3),
Dark-yellow oil (30 mg, 23% yield). ½a D26
¼ þ8:2 (c 1.0, CHCl3),
ꢂ
90% ee. The enantiomeric excess of the product was determined
by HPLC analysis (Daicel Chiralcel OD-H, k = 215 nm, n-hexane/2-
propanol 100:0, 1.0 mL/min), t1 = 11.5 min (major) and
t2 = 15.9 min (minor).
97% ee. IR mmax (neat cmꢀ1): 1725, 990, 720. 1H NMR (CDCl3,
400 MHz): d 5.65–5.75 (m, 1H), 5.41–5.42 (m, 1H), 5.17–5.18 (m,
1H), 4.98–5.00 (m, 2H), 2.64 (d, J = 7.0 Hz, 2H), 1.91 (s, 3H), 1,83-
1,90 (m, 2H), 1.54–1.66 (m, 2H), 1.66–1.76 (m, 2H). 13C NMR
(CDCl3, 100.6 MHz): d 169.4 141.5, 134.2, 119.2, 115.1, 67.4, 40.6,
26.9, 26.8, 20.0, 17.7. HPLC conditions: (Daicel Chiralcel OD-H,
k = 210 nm, n-hexane/2-propanol, 98:2, 0.5 mL/min t1 = 7.7 min
(minor) and t2 = 7.8 min (major). HRMS (ESI-TOF) for C11H17O2
[M+H]+, calcd 181.1229, found 181.1220.
4.4.4. (+)-1-Allylcyclopent-2-enyl acetate (+)-2b
Yellow oil (40 mg, 40% yield). ½a D26
¼ þ5:7 (c 1.20, CHCl3), 85%
ꢂ
ee. IR mmax (neat, cmꢀ1): 1722, 998, 725. 1H NMR (CDCl3,
400 MHz): d 5.73–5.83 (m, 1H), 5.59 (d, J = 7.2 Hz, 1H), 5.03 (d,
J = 1.6 Hz, 1H), 5.02 (dd, J = 1.6 and 11.6 Hz, 1H), 4.99 (dd, J = 1.2
and 3.2 Hz, 1H) 2.75–2.87 (m, 2H), 2.36–2.40 (m, 1H), 2.23–2.29
(m, 1H), 2.11–2.20 (m, 1H), 1.96 (s, 3H), 1.75–1.81 (m, 1H). 13C
NMR (CDCl3, 100.6 MHz): d 171.0, 150.7, 135.0, 123.3, 116.5,
80.9, 35.8, 33.5, 30.4, 21.3. HPLC conditions: (Daicel Chiralcel OD-
4.4.11. (ꢀ)-1-(Prop-2-ynyl)cyclohex-2-enol (ꢀ)-3c
Colorless oil (49 mg, 49% yield). ½a D26
¼ ꢀ5:7 (c 1.0, CHCl3), 25%
ꢂ
ee. The enantiomeric excess of the product was determined by
HPLC analysis (Daicel Chiralcel OD-H, k = 215 nm, n-hexane/2-pro-
panol, 98:2, 0.5 mL/min t1 = 13.1 min (major) and t2 = 15.1 min
(minor).
H,
k = 215 nm,
n-hexane/2-propanol
98:2,
0.5 mL/min),
t1 = 11.5 min (minor) and t2 = 13.7 min (major). HRMS (ESI-TOF)
for C10H15O2 [M+H]+, calcd 167.1072, found 167.1052.
4.4.12. (+)-1-(Prop-2-ynyl)cyclohex-2-enyl acetate (+)-4c
4.4.5. (+)-1-(Prop-2-ynyl)cyclopent-2-enol (+)-1c
Dark-yellow oil (18 mg, 14% yield). ½a D26
¼ þ9:6 (c 0.5, CHCl3),
ꢂ
Yellow oil (43 mg, 43% yield). ½a D26
ꢂ
¼ þ3:9 (c 1.40, CHCl3), 60%
72% ee. IR mmax (neat cmꢀ1): 2112, 2225, 1718, 1522, 975, 750.
1H NMR (CDCl3, 400 MHz): d 6.02 (d, J = 10.4 Hz, 1H), 5.85 (td,
J = 3.6 and 10.4 Hz, 1H), 2.95 (dd, J = 2.4 and 16.8 Hz, 1H), 2.68
(dd, 2.8 and 16.8 Hz, 1H), 2.25 (d, J = 6.0 Hz, 1H), 2.10–2.16 (m,
1H), 1.99–2.06 (m, 1H), 1.94 (s, 3H), 1.89 (t, J = 2.8 Hz, 1H), 1.61–
1.74 (m, 3H). 13C NMR (CDCl3, 100.6 MHz): d 170.1, 132.2, 128.3,
79.2, 78.1, 70.4, 32.9, 28.5, 24.9, 18.3. HPLC conditions: (Daicel Chi-
ralcel OD-H, k = 215 nm, n-hexane/2-propanol, 98:2, 0.5 mL/min
t1 = 11.3 min (minor) and t2 = 12.8 min (major). HRMS (ESI-TOF)
for C11H14O2 [M]+, calcd 178.0994, found 178.0989.
ee. The enantiomeric excess of the product was determined by
HPLC analysis (Daicel Chiralcel OD-H, k = 215 nm, n-hexane/2-pro-
panol 98:2, 0.5 mL/min), t1 = 24.9 min (minor) and t2 = 27.6 min
(major).
4.4.6. (ꢀ)-1-(Prop-2ynyl)cyclopent-2-enyl acetate (ꢀ)-2c
Yellow oil (32 mg, 24% yield). ½a D26
¼ ꢀ6:6 (c 0.50, CHCl3), 84%
ꢂ
ee. IR mmax (neat cmꢀ1): 2110, 2220, 1729, 1520, 1120. 1H NMR
(CDCl3, 400 MHz): d 5.69 (d, J = 1.6 Hz, 1H), 5.59 (dd, J = 1.6 and
5.6 Hz, 1H), 2.96 (d, J = 0.8 Hz, 2H), 2.39–2.51 (m, 1H), 2.21–2.37
(m, 2H), 2.01 (t, J = 2.8 Hz, 1H), 1.96 (s, 3H), 1.79–1.86 (m, 1H).
13C NMR (CDCl3, 100.6 MHz): d 169.4, 144.8, 123.8, 78.9, 77.8,
68.9, 31.8 29.3, 19.9, 19.8. HPLC conditions: (Daicel Chiralcel
OJ-H, k = 215 nm, n-hexane/2-propanol 98:2, 0.5 mL/min),
t1 = 19.8 min (major) and t2 = 21.6 min (minor). HRMS (ESI-TOF)
for C10H12O2 [M]+, calcd 164.0837, found 164.0827.
4.5. General procedure for the O-allylation and O-propargylation
To a solution of rac-1a,3a or (ꢀ)-1b, (+)-3b or rac-1c,3c
(1.2 mmol) in dry THF (20 mL) was added KH (3.26 g, 24.4 mmol,
30 wt % dispersion in mineral oil) under argon. The solution was
stirred until H2 gas removal was complete (approximately
50 min). Next, allyl bromide or propargyl bromide (13.4 mmol) in
THF (3 mL) was added dropwise followed by tetrabutylammonium
iodide (1.2 mmol). The mixture was stirred for an additional 2 h
and hydrolyzed by cautious addition of water (20 mL). The aque-
ous layer was extracted with ether (3 ꢁ 20 mL). The combined or-
ganic phase was dried over MgSO4 and evaporated in vacuo. The
crude product mixtures were purified by flash column chromatog-
raphy using ethyl acetate/ hexane as the eluent.
4.4.7. (+)-1-Vinylcyclohex-2-enol (+)-3a
Colorless oil (42 mg, 42% yield). ½a D26
¼ þ5:9 (c 1.0, CHCl3), 55%
ꢂ
ee. The enantiomeric excess of the product was determined by
HPLC analysis (Daicel Chiralcel OJ-H, k = 215 nm, n-hexane/2-pro-
panol 98:2, 0.5 mL/min), t1 = 13.8 min (major) and t2 = 16.4 min
(minor).
4.4.8. (ꢀ)-1-Vinylcyclohex-2-enyl acetate (ꢀ)-4a
Yellow oil (37 mg, 27% yield). ½a D26
ꢂ
¼ ꢀ5:2 (c 0.70, CHCl3), 58%
4.5.1. 3-(Allyloxy)-3-vinylcyclopent-1-ene 5a
ee. IR mmax (neat cmꢀ1): 1722, 975, 724. 1H NMR (CDCl3,
Dark-yellow oil (0.46 g, 82% yield). IR mmax (neat, cmꢀ1): 1078,
1021 915, 852. 1H NMR (CDCl3, 400 MHz): d 5.97 (td, J = 2.0 and
8.0 Hz, 1H), 5.94 (dd, J = 4.4 and 11.2 Hz, 1H), 5.80–5.91 (m, 1H),
5.67 (td, J = 2.0 and 5.8 Hz, 1H), 5.19 (qd, J = 1.6 and 17.1 Hz, 2H)
5.08 (dd, J = 1.2 and 17.2 Hz, 1H), 5.02 (dd, J = 1.6 and 10.8 Hz,
1H), 3.77–3.86 (m, 2H), 2.35–2.51 (m, 1H) 2.17–2.33 (m, 1H),
400 MHz):
d 6.26 (dd, J = 10.8 and 17.6 Hz, 1H), 5.64 (d,
J = 3.6 Hz, 1H), 5.28 (d, J = 2.8 Hz, 1H), 5.16 (d, J = 17.6 Hz, 1H),
5.00 (d, J = 5.6 Hz, 1H), 2.26–2.34 (m, 1H), 2.14–2.20 (m, 1H),
1.98–2.11 (m, 1H), 1.98 (s, 3H), 1.78–1.85 (m, 1H), 1.59–1.77 (m,
2H). 13C NMR (CDCl3, 100.6 MHz): d 168.2, 138.2, 136.9, 124.3,

664
C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
1.97 (dq, J = 5.2 and 13.6 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz): d
141.8, 135.9, 135.8, 132.4, 115.9, 113.2, 91.1, 64.6, 35.3, 31.3.
HRMS (ESI-TOF) for C10H14ONa [M+Na]+, calcd 173.0942, found
173.0950.
1H), 2.09–2.18 (m, 1H), 2.16 (t, J = 2.4 Hz, 1H) 1.96 (ddd, J = 4.8,
8.4 and 13.8 Hz, 1H), 1.81 (ddd, J = 4.4, 8.8 and 13.8 Hz, 1H). 13C
NMR (CDCl3, 100.6 MHz): d 141.3, 137.0, 131.9, 114.3, 92.2, 81.7,
73.5, 51.9, 35.8, 31.6. HRMS (ESI-TOF) for C10H12O [M]+, calcd
148.0888, found 148.0880.
4.5.2. (ꢀ)-3-Allyl-3-(allyloxy)cyclopent-1-ene (ꢀ)-9b
Yellow oil (0.43 g, 79% yield). ½a D26
ꢂ
¼ ꢀ5:3 (c 1.0, CHCl3). IR mmax
4.5.8. (+)-3-Allyl-3-(prop-2-ynyloxyl)cyclopent-1-ene (+)-21a
(neat, cmꢀ1): 1095, 1027, 944, 895. 1H NMR (CDCl3, 400 MHz): d
5.90, (dd, J = 2.4 and 5.6 Hz, 1H), 5.75–5.91 (m, 2H), 5.54 (ddd,
J = 2.4, 4.8 and 8.0 Hz, 1H), 5.17 (qd, J = 2.0 and 17.2, 1H), 4.93–
5.03 (m, 3H), 3.70–3.79 (m, 2H), 2.30–2.39 (m, 1H), 2.36 (d,
J = 7.2 Hz, 2H), 2.18–2.25 (m, 1H), 1.77–1.89 (m, 2H). 13C NMR
(CDCl3, 100.6 MHz): d 136.1, 134.9, 134.5, 133.8, 117.1, 115.3,
90.7, 63.7, 44.4, 31.9, 31.8. HRMS (ESI-TOF) for C11H17O [M+H]+,
calcd 165.1279, found 165.1283.
Dark-yellow oil (0.48 g, 82% yield). ½a D26
¼ þ2:9 (c 1.6, CHCl3). IR
ꢂ
mmax (neat, cmꢀ1): 3315, 2124, 1070, 1012, 915, 742. 1H NMR
(CDCl3, 400 MHz): d 5.84 (td, J = 2.0 and 5.9 Hz, 1H), 5.57–5.67
(m, 1H), 5.44 (td, J = 2.0 and 5.6 Hz, 1H) 4.87–4.89 (m, 1H), 4.85
(t, J = 1.6 Hz, 1H), 3.73–3.82 (m, 2H), 2.21–2.29 (m, 1H), 2.25 (d,
J = 7.2 Hz, 2H), 2.06–2.15 (m, 1H), 2.13 (t, J = 2.4 Hz, 1H), 1.78–
1.85 (m, 1H), 1.67–1.75 (m, 1H). 13C NMR (CDCl3, 100.6 MHz): d
136.1, 134.1, 133.1, 117.4, 91.8, 81.7, 72.9, 51.0, 44.4, 31.8, 31.8.
HRMS (ESI-TOF) for C11H14O [M]+, calcd 162.1045, found 162.1038.
4.5.3. 3-(Allyloxy)-3-(prop-2-ynyl)cyclopent-1-ene 17c
Yellow oil (0.49 g, 80% yield). IR mmax (neat, cmꢀ1): 3305, 2251,
1089, 1062, 908, 759. 1H NMR (CDCl3, 400 MHz): d 5.99 (td, J = 2.4
and 8.0 Hz, 1H), 5.80–5.88 (m, 1H) 5.59 (td, J = 2.0 and 5.6 Hz, 1H)
5.20 (qd, J = 1.6 and 17.1 Hz, 1H), 5.04 (qd, J = 1.6 and 10.5 Hz, 1H),
3.75–3.83 (m, 2H), 2.52 (d, J = 2.8, 2H), 2.26–2.43 (m, 2H), 1.88–
2.03 (m, 2H) 1.88 (t, J = 2.4 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz):
d 135.2, 134.8, 131.7, 117.7, 89.2, 80.1, 68.3, 63.2, 31.2, 31.1,
29.0. HRMS (ESI-TOF) for C11H14O [M]+, calcd 162.1045, found
162.1036.
4.5.9. 3-(Prop-2-ynyloxy)-3-vinylcyclohex-1-ene 14a
Dark-reddish oil (0.48 g, 82% yield). IR mmax (neat, cmꢀ1): 3345,
2118, 1082, 1022, 969, 857, 724. 1H NMR (CDCl3, 400 MHz): d 5.81,
(td, J = 3.6 and 10.0 Hz, 1H), 5.66 (dd, J = 10.4 and 17.2 Hz, 1H), 5.48
(td, J = 2.0 and 10.4 Hz, 1H), 4.92–5.12 (m, 2H), 3.86–3.89 (m, 2H),
2.16 (t, J = 2.4 Hz, 1H), 1.85–1.92 (m, 1H), 1.77–1.83 (m, 1H), 1.69–
1.76 (m, 1H), 1.57–1.63 (m, 1H) 1.35–1.47 (m, 2H). 13C NMR
(CDCl3, 100.6 MHz): d 141.0, 131.6, 126.5, 118.1, 80.6, 76.0, 72.3,
50.1, 32.4, 24.4, 17.9. HRMS (ESI-TOF) for C11H14O [M]+, calcd
162.1045, found 162.1038.
4.5.4. 3-(Allyloxy)-3-vinylcyclohex-1-ene 6a
Yellow oil (0.51 g, 85% yield). IR mmax (neat, cmꢀ1): 1098, 1017,
910, 895. 1H NMR (CDCl3, 400 MHz): d 5.74–5.90 (m,3H), 5.59 (d,
J = 10.0 Hz, 1H), 5.20 (qd, J = 1.6 and 3.6 Hz, 1H) 5.04–5.17 (m,
2H), 5.02 (qd, J = 2.0 and 5.4 Hz, 1H), 3.83–3.86 (m, 2H), 1.86–
2.04 (m, 2H), 1.74–1.86 (m, 1H), 1.66–1.74 (m, 1H), 1.45–1.59
(m, 2H). 13C NMR (CDCl3, 100.6 MHz): d 143.7, 136.1, 131.6,
128.4, 115.7, 115.2, 76.6, 63.8, 33.3, 25.3, 18.9. HRMS (ESI-TOF)
for C11H16ONa [M+Na]+, calcd 187.1099, found 187.1105.
4.5.10. (ꢀ)-3-Allyl-3-(prop-2-ynyloxy)cyclohex-1-ene (ꢀ)-22a
Dark-yellow oil (0.54, 84% yield). ½a D26
¼ ꢀ3:9 (c 0.65, CHCl3). IR
ꢂ
mmax (neat, cmꢀ1): 3215, 2199, 1062, 1037, 947, 745. 1H NMR
(CDCl3, 400 MHz): d 5.90 (td, J = 3.6 and 10.0 Hz, 1H), 5.73–5.83
(m, 1H), 5.52 (td, J = 2.0 and 10.0 Hz, 1H), 4.95–5.01 (m, 2H) 4.02
(d, J =2.8 Hz, 2H), 2.27–2.34 (m, 1H), 2.26 (t, J = 2.4 Hz, 1H), 2.22–
2.34 (m, 1H), 1.86–2.01 (m, 1H), 1.76–1.82 (m, 2H) 1.66–1.71 (m,
1H), 1.46–1.58 (m, 2H). 13C NMR (CDCl3, 100.6 MHz): d 133.4,
131.2, 128.3, 116.0, 80.3, 74.1, 71.4, 49.4, 42.9, 30.5, 23.6, 17.7.
HRMS (ESI-TOF) for C12H16O [M]+, calcd 176.1202, found 176.1197.
4.5.5. (+)-3-Allyl-3-(allyloxy)cyclohex-1-ene (+)-10b
Yellow oil (0.55 g, 85% yield). ½a D26
¼ þ2:7 (c 1.0, CHCl3). IR mmax
ꢂ
(neat, cmꢀ1): 1078, 1022, 980, 897, 769. 1H NMR (CDCl3, 400 MHz):
d 5.51–5.87 (m, 3H), 5.21 (td, J = 2.0 and 10.0 Hz, 1H), 5.19 (qd,
J = 2.0 and 17.0 Hz, 1H), 5.03–5.04 (m, 1H) 5.00–5.02 (m, 1H),
4.96–4.98 (m, 1H), 3.87 (td, J = 1.0 and 5.0 Hz, 2H), 2.22–2.33 (m,
2H), 1.82–2.00 (m, 1H) 1.64–2.79 (m, 2H), 1.45–1.56 (m, 3H). 13C
NMR (CDCl3, 100.6 MHz): d 135.2, 133.2, 130.5, 129.6, 116.1,
114.3, 73.4, 62.3, 43.0, 30.8, 24.0, 18.3. HRMS (ESI-TOF) for
4.6. General procedure for ring closing metathesis
The O-allyl diene skeletons (1.5 mmol) rac-5a,6a or (ꢀ)-9b,
(+)-10b were dissolved in DCM (15 mL) after which Grubbs’ first
generation catalyst (5 mol %) was added to the solution. The
reaction was monitored by TLC. After the reaction was completed,
the crude product was concentrated in vacuo and purified by flash
column chromatography using ethylacetate/hexane as the eluent.
C
12H19O [M+H]+, calcd 179.1436, found 179.1438.
4.5.6. 3-(Allyloxy)-3-(prop-2-ynyl)cyclohex-1-ene 18c
Colorless oil (0.33 g, 84% yield). IR mmax (neat, cmꢀ1): 3314,
2156, 1080, 1009, 949, 772. 1H NMR (CDCl3, 400 MHz): d 5.91
(td, J = 3.6 and 10.0 Hz, 1H), 5.78–5.88 (m, 1H), 5.63 (d,
J = 10.0 Hz, 1H), 5.21 (dd, J = 2.0 and 17.2 Hz, 1H), 5.03 (dd, J = 1.6
and 10.4 Hz, 1H) 3.90 (dd, J = 1.6 and 5.2 Hz, 2H) 2.40 (d,
J = 2.8 Hz, 2H), 1.93–1.98 (m, 2H), 1.90 (t, J = 2.8 Hz, 1H), 1.82–
1.87 (m, 1H) 1.66–1.73 (m, 2H), 1.41–1.50 (m, 1H). 13C NMR
(CDCl3, 100.6 MHz): d 134.9, 131.5, 128.5, 114.6, 79.7, 72.7, 69.2,
62.9, 31.1, 29.1, 24.1, 18.4. HRMS (ESI-TOF) for C12H16O [M]+, calcd
176.1202, found 176.1195.
4.6.1. 1-Oxaspiro[4,4]nona-3,6-diene 7a
Colorless oil (0.30 g, 72% yield). IR mmax (neat, cmꢀ1): 1223,
1062, 910, 827. 1H NMR (CDCl3, 400 MHz): d 5.86 (td, J = 5.4 and
2.4 Hz, 1H), 5.79 (td, J = 1.2 and 6.0 Hz, 1H), 5.62 (td, J = 2.4 and
6.0 Hz, 1H), 5.52–5.55 (m, 1H), 4.54 (s, 2H), 2.42–2.50 (m, 1H),
2.21–2.29 (m, 1H), 1.87–2.00 (m, 3H), 1.75–1.86 (m, 1H). 13C
NMR (CDCl3, 100.6 MHz): d 134.3, 133.8, 132.2, 125.8, 76.7, 74.0,
36.0, 31.2. HRMS (ESI-TOF) for C8H11O [M+H]+, calcd 123.0810,
found 123.0798.
4.6.2. 1-Oxaspiro[4,5]deca-3,6-diene 8a
Reddish oil (0.32 g, 75% yield). IR m
max (neat, cmꢀ1): 1215, 1052,
4.5.7. 3-(Prop-2-ynyloxy)-3-vinylcyclopent-1-ene, 13a
974, 815. 1H NMR (CDCl3, 400 MHz): d 5.79 (dd, J = 1.6 and 6.0 Hz,
1H), 5.75–5.77 (m, 1H), 5.64 (td, J = 2.4 Hz and 6.0 Hz, 1H), 5.48 (d,
J = 10.0 Hz, 1H), 4.57 (q, J = 12.0 Hz, 2H), 1.96–2.03 (m, 1H), 1.83–
1.92 (m, 1H), 1.66–1.79 (m, 2H), 1.56–1.65 (m, 2H). 13C NMR
(CDCl3, 100.6 MHz): d 132.6, 129.1, 129.0 125.0, 85.8, 72.9, 33.7,
Reddish-brown oil (0.48 g, 80% yield). IR mmax (neat, cmꢀ1):
3227, 2251, 1065, 1020, 909, 733. 1H NMR (CDCl3, 400 MHz): d
5.90 (td, J = 2.4 and 5.6 Hz, 1H), 5.81 (dd, J = 10.4 and 17.6 Hz,
1H) 5.58 (td, J = 2.0 and 5.6 Hz, 1H), 5.00 (d, J = 1.2 Hz, 1H) 4.94
(dd, J = 1.2 and 10.4 Hz, 1H), 3.83 (t, J = 2.4 Hz, 2H), 2.29–2.37 (m,

C. Tanyeli, D. Özdemirhan / Tetrahedron: Asymmetry 25 (2014) 658–666
665
23.8, 19.0. HRMS (ESI-TOF) for C9H13O [M+H]+, calcd 137.0966,
found 137.0962.
5.86 (s, 1H), 5.84–5.86 (m, 1H), 3.97–4.01 (m, 2H), 3.21 (t,
J = 11.2 Hz, 1H), 2.87–2.93 (m, 1H), 2.70 (dd, J = 13.6 and 17.2 Hz,
2H), 2.48–2.54 (m, 1H), 2.41 (dd, J = 6.4 and 18.4 Hz, 1H), 2.24–
2.32 (m, 1H), 2.07–2.13 (m, 1H), 1.84–1.92 (m, 1H). 13C NMR
(CDCl3, 100.6 MHz): d 206.1, 177.9, 136.0, 128.9, 126.8, 87.4,
67.5, 40.5, 40.0, 37.5, 36.2, 29.7. HRMS (ESI-TOF) for C12H15O2
[M+H]+, calcd 191.1072, found 191.1068.
4.6.3. (+)-6-Oxaspiro[4,5]deca-1,8-diene (+)-11b
Colorless oil (0.29 g, 74% yield). ½a D26
¼ þ4:1 (c 2.20, CHCl3). IR
ꢂ
mmax (neat, cmꢀ1): 1219, 1055, 984, 821. 1H NMR (CDCl3,
400 MHz): d 5.88 (td, J = 2.4 and 8.0 Hz, 1H), 5.76–5.79 (m, 1H),
5.61–5.67 (m, 1H), 5.52–5.57 (m, 1H), 4.58 (s, 2H), 2.41–2.50 (m,
1H), 2.15–2.29 (m, 1H), 2.08–2.15 (m, 1H), 1.99–2.06 (m, 1H),
1.91–1.98 (m, 1H), 1.70–1.77 (m, 1H). 13C NMR (CDCl3,
100.6 MHz): d 133.9, 133.2, 126.0, 123.7, 84.7, 62.1, 35.7, 34.2.
30.9. HRMS (ESI-TOF) for C9H12O [M]+, calcd 136.0888, found
136.0879.
4.7.4. 70,7a0-Dihydro-10H-spiro[cyclohex[2]ene-1,30-cyclopenta-
[c]pyran]-60(40H)-one 20c
Colorless oil (0.33 g, 85% yield). IR mmax (neat, cmꢀ1): 1724,
1058, 972. 1H NMR (CDCl3, 400 MHz): d 5.89 (s, 1H), 5.83 (td,
J = 3.6 and 10.0 Hz, 1H) 5.52 (d, J = 10.0 Hz, 1H), 4.02 (dd, J = 6.2
and 10.8 Hz, 2H), 3.31 (t, J = 10.8 Hz, 1H), 2.85–2.90 (m, 1H), 2.71
(d, J = 13.6 Hz, 1H), 2.43 (d, J = 8.4 Hz, 1H), 2.38 (dd, J = 6.4 and
12.4 Hz, 1H), 1.89–2.07 (m, 2H) 1.84 (dd, J = 2.0 and 18.4 Hz, 1H)
1.55–1.69 (m, 2H), 1.40–1.49 (m, 1H). 13C NMR (CDCl3,
100.6 MHz): d 206.0, 177.2, 131.0, 129.9, 127.9, 72.8, 65.7, 40.1,
39.6, 36.3, 27.8, 24.0, 17.8. HRMS (ESI-TOF) for C13H17O2 [M+H]+,
calcd 205.1229, found 205.1220.
4.6.4. (ꢀ)-1-Oxaspiro[5,5]undeca-3,7-diene (ꢀ)-12b
Dark brown oil (0.36, 78% yield). ½a D26
¼ ꢀ1:9 (c 1.0, CHCl3). IR
ꢂ
mmax (neat, cmꢀ1): 1210, 1030, 917. 1H NMR (CDCl3, 400 MHz): d
5.78–5.82 (m, 1H), 5.65–5.70 (m, 3H), 4.05–4.18 (m, 2H), 1.97–
2.07 (m, 2H), 1.87–1.95 (m, 2H) 1.70–1.77 (m, 2H), 1.48–1.56 (m,
2H). 13C NMR (100 MHz, CDCl3): d 129.9, 128.9, 124.9, 121.7,
67.6, 60.1, 34.3, 32.6, 34.6, 17.6. HRMS (ESI-TOF) for C10H14
O
[M]+, calcd 150.1045, found 150.1038.
4.7.5. (ꢀ)-4a0,50-Dihydro-10H-spiro[cyclopent[2]ene-1,30-cyclo-
penta[c]pyran]-60(40H)-one (ꢀ)-23a
4.7. General procedure for the Pauson–Khand reaction
Yellow oil (0.45 g, 80% yield). ½a D26
¼ ꢀ1:7 (c 0.5, CHCl3). IR mmax
ꢂ
(neat, cmꢀ1): 1717, 1095, 924. 1H NMR (CDCl3, 400 MHz): d 5.85 (s,
1H), 5.18 (d, 1H), 5.12 (d, J = 0.2 Hz, 1H), 4.36 (d, J = 14.0 Hz, 2H),
2.99–3.02 (m, 1H), 2.77 (q, J = 6.8 Hz, 1H), 2.55 (d, J = 6.4 Hz, 1H),
2.43–2.49 (m, 1H), 2.11–2.18 (m, 1H), 1.92–2.01 (m, 1H), 1.76–
1.84 (m, 1H), 1.72–1.78 (m, 1H), 1.60–1.71 (m, 1H). 13C NMR
(CDCl3, 100.6 MHz): d. 207.7, 178.0, 135.0, 133.1, 119.9, 88.0,
62.4, 51.7, 42.8, 39.6, 31.4, 24.3. HRMS (ESI-TOF) for C12H15O2
[M+H]+, calcd 191.1072, found 191.1065.
To a solution of rac-13a,14a, and rac-17c,18c or (+)-21a,
(ꢀ)-22a (1.13 mmol) in DCM (15 m L) was added Co2(CO)8
(0.683 g, 2 mmol) and stirred for 2 h with TLC monitoring. Next,
NMO (1.32 g, 11.3 mmol) was added and stirred for 24 h. The crude
products were purified by flash column chromatography using
EtOAc/hexane as the eluent.
4.7.1. 60,6a0-Dihydrospiro[cyclopent[2]ene-1,10cyclopenta[c]-
furan]-50(30H)-one 15a
4.7.6. (ꢀ)-4a0,50-Dihydro-10H-spiro[cyclohex[2]ene-1,30-cyclo-
penta[c]pyran]-60(40H)-one (ꢀ)-24a
Yellow oil (0.44 g, 77% yield). IR mmax (neat, cmꢀ1): 1732, 1097,
949. Diastereomeric ratio was determined as 1.33:1 from 1H NMR.
1H NMR (CDCl3, 400 MHz): d 6.00–6.01 (m, 1H), 5.99 (s, 2H), 5.96
(d, J = 1.2 Hz, 1H), 5.64–5.65 (m, 1H), 5.40–5.41 (m, 1H), 4.65 (dd,
J = 8.0 and 16.0 Hz, 2H), 4.47 (dd, J = 4.8 and 16.0 Hz, 2H), 3.28 (s,
2H), 2.45–2.54 (m, 2H), 2.43 (dd, J = 6.4 and 18.4 Hz, 2H), 2.17–
2.32 (m, 3H), 2.03–2.11 (m, 1H), 1.92–1.99 (m, 2H), 1.53–1.69
(m, 2H). 13C NMR (CDCl3, 100.6 MHz): d 207.5, 206.0, 182.9,
180.1, 136.1, 135.1, 129.2, 129.1, 126.6, 126.5, 93.7, 93.0, 63.1,
62.8, 50.5, 50.4, 36.6, 35.4, 32.3, 31.2, 29.8, 29.2. HRMS (ESI-TOF)
for C11H13O2 [M+H]+, calcd 177.0915, found 177.0926.
Yellow oil (0.51 g, 81% yield). ½a D26
¼ ꢀ1:6 (c 0.25, CHCl3). IR
ꢂ
mmax (neat, cmꢀ1): 1729, 1074, 947. 1H NMR (CDCl3, 400 MHz): d
5.80–5.90 (m, 1H), 5.10 (dd, J = 1.2 and 10.0 Hz, 1H), 5.04 (d,
J = 2 Hz, 1H), 4.56 (tq, J = 1.6 and 16.0 Hz, 2H), 3.00–3.02 (m, 1H),
2.70 (q, J = 7.6 Hz, 1H) 2.41 (ddd, J = 6.4, 14.0 and 42.2 Hz, 2H)
1.80–1.87 (m, 1H), 1.61–1.66 (m, 1H), 1.42–1.48 (m, 1H), 1.19–
1.29 (m, 4H). 13C NMR (CDCl3, 100.6 MHz): d 210.3 181.2, 131.8,
119.8, 116.8, 79.4, 63.0, 49.2, 44.9, 41.9, 31.2, 23.8, 18.9. HRMS
(ESI-TOF) for C13H17O2 [M+H]+, calcd 205.1229, found 205.1222.
Acknowledgements
4.7.2. 60,6a0-Dihydrospiro[cyclohex[2]ene-1,10-cyclopenta[c]-
furan]-50(30H)-one 16a
We are grateful to the Turkish Scientific and Technical Research
Council for a Grant (No. 110T169).
Yellow oil (0.44 g, 79% yield). IR mmax (neat, cmꢀ1): 1725, 1062,
987. Diastereomeric ratio was determined as 1.57:1 from 1H NMR.
1H NMR (CDCl3, 400 MHz): d 5.95–6.00 (m, 1H), 5.98 (s, 2H), 5.86–
5.91 (m, 1H), 5.56 (d, J = 9.6 Hz, 1H). 5.24 (dd, J = 1.2 and 10.0 Hz,
1H) 4.65 (dd, J = 7.2 and 16.4 Hz, 2H), 4.49 (dd, 16.0 and 33.2 Hz,
2H), 3.04 (s, 1H), 3.15 (s, 1H) 2.45 (dd, J = 6.4 and 18.0 Hz, 2H)
2.13 (dd, J = 2.0 and 17.6 Hz, 1H), 1.98–2.07 (m, 3H), 1.85–1.95
(m, 3H), 1.66–1.82 (m, 3H), 1.52–1.60 (m, 2H), 1.38–1.52 (m,
1H), 1.38–1.51 (m, 1H). 13C NMR (CDCl3, 100.6 MHz): d 208.5,
208.4, 184.2, 184.7, 133.3, 132.1, 128.5, 128.4, 123.5, 123.2, 79.9,
78.4, 63.4, 63.0, 53.9, 53.4, 37.5, 36.5, 33.8, 33.7, 24.2, 24.0, 19.0,
17.7. HRMS (ESI-TOF) for C12H15O2 [M+H]+, calcd 191.1072, found
191.1074.
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