Stereoselective synthesis of optically active dihydrofurans and dihydropyrans via a ring closing metathesis reaction

Article abstract of DOI:10.1016/j.tetasy.2011.07.003

A ring closing metathesis reaction of dienes and a ring closing enyne metathesis reaction derived from allyl, homoallyl and homopropargyl alcohol backbones are described. 2-Heteroaryl substituted allyl, homoallyl and homopropargyl alcohols have been easily and efficiently resolved through enzymatic resolution with high ee (93-99%) and known stereochemistry. Enantiomerically enriched dienes derived from allyl and homoallyl alcohols afforded the corresponding enantiomerically enriched dihydrofuran and dihydropyran derivatives, respectively, with chemical yields which varied between 72% and 88%. On the other hand, enantiomerically enriched enynes derived from homoallyl and homopropargyl alcohols gave the corresponding optically active dihydropyrans with conjugated diene units with chemical yields between 70% and 80%. A subsequent Diels-Alder reaction of the dihydropyran derivatives with a diene unit with tetracyanoethylene resulted in the formation of a diastereomeric dihydroisochromene ring system as the sole product.

Full text of DOI:10.1016/j.tetasy.2011.07.003

Tetrahedron: Asymmetry 22 (2011) 1161–1168
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of optically active dihydrofurans and dihydropyrans
via a ring closing metathesis reaction
⇑
Merve Çayir, Sema Demirci, Serdar Sezer, Cihangir Tanyeli
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
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 reaction of dienes and a ring closing enyne metathesis reaction derived from
allyl, homoallyl and homopropargyl alcohol backbones are described. 2-Heteroaryl substituted allyl,
homoallyl and homopropargyl alcohols have been easily and efficiently resolved through enzymatic res-
olution with high ee (93–99%) and known stereochemistry. Enantiomerically enriched dienes derived
from allyl and homoallyl alcohols afforded the corresponding enantiomerically enriched dihydrofuran
and dihydropyran derivatives, respectively, with chemical yields which varied between 72% and 88%.
On the other hand, enantiomerically enriched enynes derived from homoallyl and homopropargyl alco-
hols gave the corresponding optically active dihydropyrans with conjugated diene units with chemical
yields between 70% and 80%. A subsequent Diels–Alder reaction of the dihydropyran derivatives with
a diene unit with tetracyanoethylene resulted in the formation of a diastereomeric dihydroisochromene
ring system as the sole product.
Received 16 May 2011
Accepted 5 July 2011
Available online 4 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
dihydrofuran and dihydropyrans is the ring-closing metathesis11
reaction where intra- and intermolecular reactions of alkenes gen-
The stereoselective synthesis of substituted tetrahydrofuran
and pyran derivatives has been widely investigated due to the
number of natural products and other biologically active mole-
cules, which have various biological activities including antimicro-
bial, antitumor, antimalarial, antihelmic, and antiprotozoal such as
C-nucleosides,1 macrolides,2 polyether antibiotics,3 annonaceous
acetogenins,4 lignons,5 polyether ionophores,6 brevetoxins7 and
some macrolide antibiotics,8 that contain these structural motifs.9
In order to modify and improve biological properties, there have
been many reports9 in the literature on the use of substituted tet-
rahydropyran and furan modified complex natural or synthetic
molecules since the modification of the substituents on these het-
erocycles has a potential impact on drug design and development.
Therefore, the development of a concise and efficient strategy to
generate skeletal diversity has gained much attention over the last
two decades involved in drug discovery especially in a diversity-
oriented synthesis approach.10
erate target cycles in the presence of a metathesis catalyst, for
example, first12 and second13 generation of Grubbs’ ruthenium-
based catalyst (Fig. 1).
Mes
N
N
Mes
Ph
PCy3
Ru
Ph
Cl
Cl
Cl
Cl
Ru
PCy3
Second generation
PCy3
First generation
Figure 1. First and second generation Grubbs’ catalysts.
Chiral allylic, homoallylic, and homopropargylic alcohols are
important precursors14 for generating chiral diene and enyne sys-
tems. To date, a number of reports have been published on the
enantioselective synthesis of these secondary alcohols. Although
different strategies such as asymmetric organometallic additions
to aldehydes have been reported,15 biocatalytic approaches have
emerged as a powerful and alternative tool for the development
of enantioselective processes over the last few decades.16 Our
group has reported initial studies on the enzyme-catalyzed resolu-
tion of racemic furyl and thienylcarbinols with high enantiomeric
Herein, we describe the chemoenzymatic synthesis of optically
active heteroaryl substituted dihydrofuran and pyrans, which can
be directly converted to the analogous tetrahydrofuran and pyrans
starting from common precursors. Although various strategies
have been published for the stereoselective synthesis of these het-
erocyclic systems, the most practical method for the synthesis of
⇑
Corresponding author. Tel.: +90 312 210 3222; fax: +90 312 210 3200.
E-mail address: tanyeli@metu.edu.tr (C. Tanyeli).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.003

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M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
purity and yields.17 Moreover, our current studies have extended
the scope of enzyme variety on heteroaryl carbinols.18
2. Results and discussion
The resulting heteroaryl substituted chiral dienes and enynes
underwent ring closing metathesis and ring closing enyne
metathesis reactions, respectively, to afford target dihydrofurans
or pyrans. Generally, enyne metathesis requires special reaction
conditions19 such as an ethylene atmosphere to obtain the target
The target parent allylic alcohols rac-2a–b and homoallylic
alcohols rac-3a–c were synthesized by the addition of vinylmagne-
sium bromide and allylmagnesium bromide, respectively, to the
commercially available 2-heterocarbaldehydes. Homopropargylic
alcohols rac-4a–b were synthesized by the addition of propargyl
bromide to the carbonyl group using a Zn–Cu couple as described
in our previous work17b,18a in a racemic manner as depicted in
Scheme 1.
The key step is the enantiomeric resolution of the racemic sub-
strates rac-2a–b, rac-3a–c and rac-4a–b by enzymes to construct
the enantiomerically enriched allylic, homoallylic and homoprop-
argylic alcohol skeletons, respectively. All of the enantiomeric res-
olution reactions were performed using various lipases with a 1:1
substrate/enzyme ratio and vinyl acetate as the acyl donor and
THF as the solvent at 24 °C according to the procedure in our pre-
vious work.17b,18a,b All of the best results are summarized in
Table 1.
product with
a high yield depending on the substituents.
However, in our case, simple and mild reaction conditions led
to the predicted structures. We have also investigated the role
of a stereogenic center located on the pyran ring, on a newly cre-
ated stereogenic center as a result of Diels–Alder cyclization.
There are a few studies in the literature related to this concept.20
In our previous works, we have explained the conformational
effect of pyran and furan units on Pauson-Khand cycliza-
tion.18a,b,21 For this purpose, chiral diene systems were subjected
to Diels–Alder reactions and dihydroisochromene analogues were
obtained with high diastereoselectivity. These results showed
that these enynes have a potential for stereocontrolled access to
enantiomerically pure heterocyclic compounds. Herein we report
a simple route to synthesize chiral heteroarylsubstituted dihydro-
furan and pyrans and dihydroisochromene analogues with high
diastereoselectivities.
The diene systems were synthesized from enantiomerically en-
riched allylic (S)-2a–b and homoallylic alcohol (S)-3a–c backbones
by O-allylation using allyl bromide together with NaH and tetrabu-
tylammonium iodide (TBAI) in THF. In order to synthesize the
O
d
R
R
R
R
R
R
c
a
d
+
R
H
+
OH
rac-2a-b
OH
(S)-2a-b
OAc
1
OH
OAc
OH
rac-4a-b
(S)-4a-b
(R)-7a-b
(R)-5a-b
b
R
O
S
O
S
OH
rac-3a-c
OH
OH
OH
OH
(S)-(-)-2b
(S)-(+)-4a
(S)-(+)-2a
(S)-(+)-4b
d
O
S
O
O
S
O
R
R
O
O
O
O
+
(R)-5b
(R)-5a
(R)-(+)-7a
(R)-(+)-7b
OH
OAc
O
O
(S)-3a-c
(R)-6a-c
Decomposed on silica
R=
,
,
S
O
N
O
S
N
a
b
c
OH
OH
OH
(S)-(-)-3a
(S)-(-)-3b
(S)-(-)-3c
O
S
N
O
O
O
O
O
O
(R)-(+)-6a
(R)-(+)-6b
(R)-(+)-6c
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) lipase, vinyl acetate, THF.

M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
1163
Table 1
Enzymatic kinetic resolution of allylic, homoallylic and homopropargylic alcohols rac-2a–b, rac-3a–c and rac-4a–b
a
a
Entry
Substrate
Enzyme
Time (h)
Estersd eep (%)
Alcoholsd ees (%)
cb (%)
Ec
1
2
3
4
5
6
7
rac-2a
rac-2b
rac-3a
rac-3b
rac-3c
rac-4a
rac-4b
PS-C IIe
70 min
65 min
4 h
20 h
30 h
—
—
99 (S)
97 (S)
99 (S)
99 (S)
98 (S)
93 (S)
99 (S)
60
56
51
71
51
51
52
—
—
211
11
154
60
116
CAL-Be
PS-C Amona IIf
PS-C Amona IIf
PS-C Amona IIf
PS-C Amona IIf
PS-C Amona IIf
96 (R)
40 (R)
95 (R)
90 (R)
92 (R)
1.5 h
2.5 h
a
b
c
d
e
f
Determined by HPLC analysis employing Diacel Chiralcel OD-H and OJ-H columns.
c = ees/(ees + eep).
E = ln [(1 ꢀ c)(1 ꢀ ees)]/ln [(1 ꢀ c)(1 + ees)].22
The absolute configurations were found to be (S) for the alcohols and (R) for the esters according to the specific rotations reported in literature.
The reactions were carried out at 26 °C.
The reactions were carried out at 24 °C.
enantiomerically enriched 2-heteroaryl substituted 2,5-dihydrofu-
ran (S)-10a–b and 3,6-dihydro-2H-pyran (S)-11a–c derivatives,
dienes (S)-8a–b and (S)-9a–c were subjected to common condi-
tions for ring closing metathesis (Scheme 2).23 In this protocol, ring
closing metathesis reactions were carried out by using 5 mol % of
Grubbs’ 1st generation catalyst in DCM. The reactions were moni-
tored by thin layer chromatography (TLC). The HPLC analyses of
the products (S)-10a–b and (S)-11a–c with a chiral stationary
phase (Chiralcel OJ-H column) proved that the ring closing metath-
esis reactions proceeded without racemization.
The configuration of (+)-16b was also determined by differential
NOE experiments. We observed significant NOE enhancement be-
tween the methine proton attached to the stereogenic carbon of
the pyran ring at 5.44 ppm and the methine proton at the newly
created stereogenic carbon center at 3.45 ppm; we hence decided
that the methine protons were in a cis-relationship (Fig. 2). Thus,
the absolute configurations of (+)-16a (cis-1,3) and (+)-16b (cis-
1,3) were determined as (3S,4aR).
3. Conclusion
In order to explore the availability of these enantiomerically en-
riched homoallylic (S)-(ꢀ)-3a–b and homopropargylic alcohol (S)-
(+)-4a–b in ring closing metathesis, we turned our attention to the
application of the ring closing enyne metathesis. This strategy of-
fers a flexible diversity approach in that two distinct scaffolds
can be obtained in a straightforward manner, depending on the
homoallyl or homopropargyl derivative chosen as the starting
material (Scheme 3). Indeed the transformation of homoallylic
and homopropargylic alcohol backbones to the corresponding eny-
ne scaffolds and subsequent cyclization via ring closing enyne
metathesis would allow the formation of 3,6-dihydro-2H-pyran
derivatives with a conjugated diene unit, a direct precursor of a
Diels–Alder adduct. For the synthesis of enantiomerically enriched
isomeric enyne scaffolds, the homoallylic (S)-(ꢀ)-3a–b and homo-
propargylic alcohols (S)-(+)-4a–b were subjected to O-propargyla-
tion and O-allylation using propargyl bromide and allyl bromide
with NaH and TBAI in THF to afford the corresponding enynes
(S)-(ꢀ)-12a–b and (S)-(ꢀ)-13a–b, respectively. Over the course of
the enyne construction reactions, the configurations at the
stereogenic centers were all preserved. Using our optimized ring
closing enyne metathesis conditions, the desired regioisomeric
3,6-dihydro-2H-pyran derivatives with conjugated diene unit
(S)-(ꢀ)-14a–b and (S)-(ꢀ)-15a–b were isolated in good yields of
70–82%.23
With the 3,6-dihydro-2H-pyran derivatives having a conjugated
diene unit (S)-(ꢀ)-14a–b in hand, we next investigated the synthe-
sis of 4,4a-dihydro-1H-isochromene derivatives via Diels–Alder
reaction in a diastereoselective manner. The use of tetracyanoeth-
ylene as a dienophile in dry toluene at 65 °C allowed the transfor-
mation of (S)-(ꢀ)-14a–b to the corresponding bicycloadducts
(+)-16a–b in 72% and 63%, respectively (Scheme 4). In both cases,
single diastereomers of bicycloadducts (+)-16a–b were obtained
as established by NMR spectroscopy.23
The relative configuration of (+)-16a was determined by differ-
ential NOE experiments. The characteristic methine proton at-
tached to the stereogenic carbon of the pyran ring at 5.20 ppm
and the methine proton of cyclohexene-pyran-fused carbon at
3.60 ppm showed significant NOE enhancements, which indicate
the cis-relationship between the protons of the stereogenic center.
New enantiomerically enriched 2-furyl, thiophenyl and pyridi-
nyl substituted dienes anchored to allyl and homoallyl alcohol
backbones have been synthesized. Their ring closing metathesis
reactions using Grubbs’ first generation catalyst afforded enantio-
merically enriched dihydrofuran and dihydropyran derivatives
with the known absolute configurations, since over the course of
O-allylation and ring closing metathesis reactions, the configura-
tions at the stereogenic centers of allyl and homoallyl alcohol
backbones were all preserved. We have also synthesized enantio-
merically enriched 2-heteroaryl substituted enynes tethered to
homoallyl and homopropargyl alcohol backbones, which were sub-
jected to ring closing enyne metathesis. The resulting enantiomeri-
cally enriched dihydropyran rings have conjugated diene units,
which are valuable candidates in Diels–Alder reactions to construct
bicyclic ring systems. Two derivatives were subjected to a Diels–
Alder reaction with tetracyanoethylene. In both cases, single dia-
stereomers of the dihydroisochromene products were obtained
as established by NMR spectroscopy. Their absolute configurations
were determined by differential NOE experiments.
4. Experimental
4.1. General
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:
dichloromethane (P2O5), tetrahydrofuran (sodium, benzophenone).
1H NMR and 13C NMR spectra were recorded in CDCl3 on Bruker
Spectrospin Avance DPX-400 spectrometer. 1H (400 MHz) and 13C
NMR were recorded in CDCl3 and the chemical shift was 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. The mass spectra were recorded
on Thermo Scientific DSQ II Single Quadrupole GC/MS. HRMS data

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M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
c
a
a
O
O
O
OH
O
O
(S)-(-)-10a
(S)-(+)-2a
(S)-(-)-8a
c
S
S
S
OH
O
O
(S)-(-)-2b
(S)-(-)-8b
(S)-(+)-10b
c
a
O
O
O
O
OH
O
(S)-(-)-3a
(S)-(-)-9a
(S)-(-)-11a
c
a
S
S
S
O
OH
O
(S)-(-)-11b
(S)-(-)-3b
(S)-(-)-9b
a
b, c
N
N
N
O
O
OH
(S)-(-)-3c
(S)-(-)-11c
(S)-(-)-9c
Scheme 2. Reagents and conditions: (a) allyl bromide, NaH, TBAI, THF; (b) HCl (g), CH2Cl2; (c) Grubbs’ 1st generation catalyst (5 mol %), CH2Cl2.
a
c
c
O
O
O
O
O
OH
(S)-(-)-3a
(S)-(-)-12a
(S)-(-)-14a
a
S
S
S
O
OH
O
(S)-(-)-14b
(S)-(-)-3b
(S)-(-)-12b
b
b
c
c
O
O
O
O
O
OH
(S)-(+)-4a
(S)-(-)-13a
(S)-(-)-15a
S
S
S
O
OH
O
(S)-(-)-15b
(S)-(+)-4b
(S)-(-)-13b
Scheme 3. Reagents and conditions: (a) propargyl bromide, NaH, TBAI, THF; (b) allyl bromide, NaH, TBAI, THF; (c) Grubbs’ 1st generation catalyst (5 mol %), CH2Cl2.

M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
1165
NC
CN
NC
NC
CN
CN
H
O
H
CN
CN
a
+
O
S
O
1
3
O
(S)-(-)-14a
(+)-16a (cis-1,3)
NC
CN
NC
NC
CN
CN
H
O
H
CN
CN
a
+
S
1
3
O
(S)-(-)-14b
(+)-16b (cis-1,3)
Scheme 4. Reagents and conditions: (a) 65 °C, toluene.
4.2.1. (S)-(+)-1-(Furan-2-yl)prop-2-en-1-ol (S)-(+)-2a
NOE
A yellow oil; ½a 2D8
¼ þ1:1 (c 2.24, CHCl3) for 99% ee. The enan-
ꢁ
NOE
tiomeric purity of the product was determined by HPLC analysis
NC
(Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate = 1 mL minꢀ1
,
CN
NC
CN
Ha
Hb
Ha
CN
CN
Hb
CN
CN
k = 230 nm), tR = 18.26 min [(S)-isomer], tR = 19.75 min [(R)-iso-
mer] in comparison with a racemic sample.
O
S
O
O
4.2.2. (S)-(ꢀ)-1-(Thiophen-2-yl)prop-2-en-1-ol (S)-(ꢀ)-2b
A yellow oil; ½a 2D8
¼ ꢀ2:7 (c 1, CHCl3) for 97% ee. The enantio-
ꢁ
(+)-16a (cis-1,3)
(+)-16b (cis-1,3)
meric purity of the product was determined by HPLC analysis
(Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate = 1 mL minꢀ1
,
Figure 2. NOE correlations observed between the Ha and Hb protons of (+)-16a
(cis-1,3) and (+)-16b (cis-1,3).
k = 230 nm), tR = 20.93 min [(S)-isomer], tR = 27.14 min [(R)-iso-
mer] in comparison with a racemic sample.
were obtained via LC–MS analysis performed with APCI-Q-TOF II
(Waters, Milford, MA, USA) at the Mass Spectrometry Facility
Center for Functional Genomics University at Albany and with a
Waters Synapt mass spectrometer at the central laboratory of
Middle East Technical University. Optical rotations were measured
employing a Rudolph research analytical, autopol III automatic
polarimeter. Melting points were obtained on a Thomas Hoover
capillary melting point apparatus and are uncorrected.
4.2.3. (S)-(ꢀ)-1-(Furan-2-yl)but-3-en-1-ol (S)-(ꢀ)-3a
A yellow oil; ½a 2D9
¼ ꢀ40:0 (c 5.0, CH2Cl2) for 99% ee. The enan-
ꢁ
tiomeric purity of the product was determined by HPLC analysis
(Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate = 1 mL minꢀ1
,
k = 230 nm), tR = 11.20 min [(R)-isomer], tR = 12.64 min [(S)-iso-
mer] in comparison with a racemic sample.
Flash column chromatography was performed by using
thick-walled glass columns with a flash grade (Merck Silica Gel
60). Reactions were monitored by thin layer chromatography using
precoated silica gel plates (Merck 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
evaporator.
4.2.4. (S)-(ꢀ)-1-(Thiophen-2-yl)but-3-en-1-ol (S)-(ꢀ)-3b
A yellow oil; ½a 2D7
¼ ꢀ17:1 (c 1.2, CH2Cl2) for 99% ee. The enan-
ꢁ
tiomeric purity of the product was determined by HPLC analysis
(Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate = 1 mL minꢀ1
,
k = 230 nm), tR = 12.98 min [(S)-isomer], tR = 15.01 min [(R)-iso-
mer] in comparison with a racemic sample.
4.2.5. (S)-(ꢀ)-1-(Pyridin-2-yl)but-3-en-1-ol (S)-(ꢀ)-3c
All of the racemic secondary alcohols 2a,17a 2b,17b 3a,18a 3b,17b
3c,17b 4a,18a and 4b,17b were prepared by reported procedures.
The absolute configurations were found to be (S) for alcohols (S)-
(+)-2a,17a (S)-(ꢀ)-2b,17b (S)-(ꢀ)-3a,18a,23 (S)-(ꢀ)-3b,17b (S)-(ꢀ)-
3c,24 (S)-(+)-4a,18a,25 and (S)-(+)-4b,17b according to the specific
rotations reported in the literature.
A yellow oil; ½a 2D9
¼ ꢀ42:9 (c 0.86, CH2Cl2) for 98% ee. The enan-
ꢁ
tiomeric purity of the product was determined by HPLC analysis
(Daicel Chiralcel OJ-H, hexane/i-PrOH 99:1, flow rate =
0.3 mL minꢀ1, k = 254 nm), tR = 58.75 min [(S)-isomer], tR = 63.74
min [(R)-isomer] in comparison with a racemic sample.
4.2.6. (S)-(+)-(Furan-2-yl)but-3-yn-1-ol (S)-(+)-4a
4.2. General procedure for enzymatic resolution
A yellow oil; ½a 2D9
¼ þ6:7 (c 3.1, MeOH) for 93% ee. The enantio-
ꢁ
meric purity of the product was determined by HPLC analysis
To a solution of the rac-2a–b, rac-3a–c and rac-4a–b (3 mmol)
in anhydrous THF (3 mL) and vinyl acetate (2.7 mL) in a 25 mL
round bottom flask, was added lipase (1 equiv w/w). The reaction
mixture was stirred at constant temperature26 and monitored by
TLC and recorded by HPLC. At the desired conversion, the reaction
mixture was filtered off, the solid was washed with Et2O, and the
solvent was evaporated under vacuum to give a residue which
was purified by column chromatography on silica gel. Experiments
were repeated at least twice.
(Daicel Chiralcel OD-H, hexane/i-PrOH 96:4, flow rate =
1 mL minꢀ1
, k = 230 nm), tR = 16.84 min [(S)-isomer], tR = 23.15
min [(R)-isomer] in comparison with a racemic sample.
4.2.7. (S)-(+)-1-(Thiophen-2-yl)but-3-yn-1-ol (S)-(+)-4b
A yellow oil; ½a 2D8
¼ þ26:5 (c 1, EtOH) for 99% ee. The enantio-
ꢁ
meric purity of the product was determined by HPLC analysis
(Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate = 1 mL minꢀ1
,

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M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
k = 230 nm), tR = 35.56 min [(R)-isomer], tR = 41.75 min [(S)-iso-
mer], in comparison with a racemic sample.
803 cmꢀ1. MS (EI) m/z (rel. intensity) 138 (M+ꢀ56(+OCH2CH@CH2),
base).
4.3. General procedure for O-allylation and O-propargylation
4.3.5. (S)-(ꢀ)-2-(1-(Allyloxy)but-3-enyl)pyridine (S)-(ꢀ)-9c
Colorless oil (0.25 g, 95% yield), ½a D29
ꢁ
¼ ꢀ69:8 (c 1.00, EtOH). 1
H
To a solution of (S)-(+)-2a and (S)-(ꢀ)-2b or (S)-(ꢀ)-3a, (S)-(ꢀ)-
3b and (S)-(ꢀ)-3c or (S)-(+)-4a and (S)-(+)-4b (1.4 mmol) in dry
THF (15 mL) was added NaH (0.62 g, 60% dispersion in oil,
1.54 mmol) under argon. The solution was heated at reflux until
H2 gas removal was complete (nearly 45 min). Next, allylbromide
or propargylbromide (1.54 mmol) was added dropwise followed
by tetrabutylammonium iodide (0.5 mmol). The mixture was re-
fluxed for another 2 h and hydrolyzed by the cautious addition of
water (15 mL). The aqueous layer was extracted with ether
(3 ꢂ 20 mL). The combined organic phase was dried over MgSO4
and evaporated in vacuo. The crude product mixtures were sepa-
rated by flash column chromatography using ethylacetate/hexane
solvent as eluent (1:6) for compounds (S)-(ꢀ)-8a, (S)-(ꢀ)-8b, (S)-
(ꢀ)-9a, (S)-(ꢀ)-9b, (S)-(ꢀ)-12b, (S)-(ꢀ)-13b, a 2:1 system for (S)-
(ꢀ)-9c, and a 1:9 system for (S)-(ꢀ)-12a, (S)-(ꢀ)-13a.
NMR: d 8.45 (dm, J = 4.8 Hz, 1H), 7.57 (td, J = 7.6 and 1.6 Hz, 1H),
7.32 (d, J = 7.8 Hz, 1H), 7.06 (br t, J = 6.1 Hz, 1H), 5.68–5.85 (m,
2H), 5.16 (dd, J = 17.3 and 1.6 Hz, 1H), 5.05 (dd, J = 10.4 and
1.2 Hz, 1H), 4.92 (m, 1H), 4.91 (br d, J = 17.1 Hz, 1H), 4.41 (t,
J = 6.3 Hz, 1H), 3.80 (dd, AB system diastereotopic CHaHb,
JAB = 12.8 and 5.1 Hz, 1H), 3.89 (dd, AB system diastereotopic
CHaHb, JAB = 12.8 and 5.1 Hz, 1H), 2.47 (br t, J = 6.6 Hz, 2H). 13C
NMR: d 161.8, 148.8, 136.3, 134.5, 134.2, 122.1, 120.3, 117.0,
116.6, 81.9, 70.0, 40.9. IR (neat): 3077, 2927, 2858, 2361, 1590,
1081,
918 cmꢀ1
.
MS
(EI)
m/z
(rel.
intensity)
148
(M+ꢀ41(+CH2CH@CH2), base).
4.3.6. (S)-2-(1-(Prop-2-ynyloxy)but-3-enyl)furan (S)-(ꢀ)-12a
Yellow oil (0.20 g, 83% yield). ½a D25
¼ ꢀ78:5 (c 2.7, CH2Cl2) for
ꢁ
99% ee.18a
4.3.1. (S)-(ꢀ)-2-(1-(Allyloxy)allyl)furan (S)-(ꢀ)-8a
4.3.7. (S)-2-(1-(Prop-2-ynyloxy)but-3-enyl)thiophene (S)-(ꢀ)-
Colorless oil (0.21 g, 93% yield). ½a D26
ꢁ
¼ ꢀ23:35 (c 1, CHCl3). 1H
12b
NMR: d 7.32 (dd, J = 1.8 and 0.8 Hz, 1H), 6.25 (dd, J = 3.2 and
1.8 Hz, 1H), 6.19 (d, J = 3.2 Hz, 1H), 5.95 (ddd, J = 10.5, 6.6 and
3.7 Hz, 1H), 5.83 (ddd, J = 16.0, 10.5 and 5.6 Hz, 1H), 5.29 (dt,
J = 17.2 and 1.4 Hz, 1H), 5.24–5.23 (m, 1H), 5.20 (br d, J = 6.4 Hz,
1H), 5.11 (br d, J = 10.4 Hz, 1H), 4.78 (d, J = 6.6 Hz, 1H), 3.93 (br
d, J = 5.6 Hz, 2H). 13C NMR: d 153.6, 142.4, 135.4, 134.6, 117.6,
117.1, 110.1, 107.8, 75.0, 69.2. IR (neat): 2924, 2361, 2342, 1301,
Yellow oil (0.24 g, 89% yield). ½a D29
¼ ꢀ135:9 (c 1, CH2Cl2) for
ꢁ
99% ee.18b
4.3.8. (S)-2-(1-(Allyloxy)but-3-ynyl)furan (S)-(ꢀ)-13a
Yellow oil (0.20 g, 80 % yield). ½a D29
¼ ꢀ103:4 (c 1.0, CH2Cl2) for
ꢁ
93% ee.18a
1278, 1122, 808 cmꢀ1
.
MS (EI) m/z (rel. intensity) 108
4.3.9. (S)-2-(1-(Allyloxy)but-3-ynyl)tiophene (S)-(ꢀ)-13b
(M+ꢀ56(+OCH2CH@CH2), base).
Yellow oil (0.23 g, 85% yield). ½a D29
¼ ꢀ35:3 (c 1.0, CH2Cl2) for
ꢁ
99% ee.18b
4.3.2. (S)-(ꢀ)-2-(1-(Allyloxy)allyl)thiophene (S)-(ꢀ)-8b
Colorless oil (0.24 g, 95% yield). ½a D22
ꢁ
¼ ꢀ12:1 (c 0.5, CHCl3). 1H
4.4. General procedure for ring closing metathesis
NMR: d 7.17 (t, J = 3.2 Hz, 1H), 6.80 (m, 2H), 5.79–5.98 (m, 2H),
5.22 (dm, J = 16.8 Hz, 1H), 5.21 (m, 2H), 5.10 (ddm, J = 10.4 and
1.5 Hz, 1H), 4.96 (d, J = 6.7 Hz, 1H), 3.90–4.00 (m, 2H). 13C NMR:
d 144.4, 137.7, 134.2, 126.1, 124.9, 124.4, 116.6, 116.5, 76.2, 68.7.
IR (neat): 2923, 2854, 1042, 801 cmꢀ1. MS (EI) m/z (rel. intensity)
124 (M+ꢀ56(+OCH2CH@CH2), base).
O-Allyl anchored substrate (S)-(ꢀ)-8a–b and (S)-(ꢀ)-9a–b
(1.0 mmol) were dissolved in DCM (10 mL) and Grubbs’ first gener-
ation catalyst (5 mol %) was added to the solution. The reaction
was monitored by TLC. The crude product was concentrated and
purified by short column chromatography [Celite, EtOAc/hexane
1:15 for (S)-(ꢀ)-10a, (S)-(+)-10b, (S)-(ꢀ)-11a–b, 1:2 for (S)-(ꢀ)-
11c].
4.3.3. (S)-(ꢀ)-2-(1-(Allyloxy)but-3-enyl)furan (S)-(ꢀ)-9a
Colorless oil (0.22 g, 90% yield), ½a D32
ꢁ
¼ ꢀ35:4 (c 0.5, CHCl3).1H
NMR: d 7.29 (dd, J = 1.8 and 0.7 Hz, 1H), 6.23 (dd, J = 3.2 and
1.8 Hz, 1H), 6.16 (d, J = 3.24 Hz, 1H), 5.62–5.82 (m, 2H), 5.13–5.18
(br d, J = 17.2 Hz, 1H), 5.05–5.08 (dm, J = 8.8 Hz, 1H), 4.96–5.02
(br d, J = 17.1 Hz, 1H), 4.92–4.95 (dm, J = 10.7 Hz, 1H), 4.28 (t,
J = 7.1 Hz, 1H), 3.86–3.91 (ddm, AB system diastereotopic CHaHb,
JAB = 12.8 and 5.2 Hz, 1H), 3.72–3.78 (ddm, AB system diastereo-
topic CHaHb, JAB = 12.8 and 5.1 Hz, 1H), 2.55–2.62 (m, 1H), 2.46–
2.53 (m, 1H). 13C NMR: d 154.2, 142.1, 134.7, 134.1, 117.2, 116.6,
109.9, 107.9, 73.8, 69.4, 39.7. IR (neat): 2920, 2359, 1063,
803 cmꢀ1. MS (EI) m/z (rel. intensity) 122 (M+ꢀ56(+OCH2CH@CH2),
base).
4.4.1. (S)-(ꢀ)-2-(2,5-Dihydrofuran-2-yl)furan (S)-(ꢀ)-10a
Colorless oil (0.12 g, 85% yield). ½a D27
¼ ꢀ42:1 (c 1, CHCl3) for 99%
ꢁ
ee. The enantiomeric purity of the product was determined by HPLC
analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate =
1 mL minꢀ1, k = 230 nm), tR = 8.72 min [(S)-isomer], tR = 9.48 min
[(R)-isomer] in comparison with the racemic sample. 1H NMR: d
7.30–7.33 (br s, 1H), 6.23–6.27 (m, 1H), 6.18 (d, J = 3.0 Hz, 1H),
6.02 (d, J = 6.1 Hz, 1H), 5.78–5.84 (m, 1H), 5.70–5.75 (m, 1H), 4.72
(d, AB system diastereotopic CHaHb, JAB = 12.7 Hz, 1H), 4.62 (dd, AB
system diastereotopic CHaHb, JAB = 12.7 and 5.6 Hz, 1H). 13C NMR:
d 154.1, 142.6, 128.6, 126.4, 110.2, 107.3, 80.5, 75.2. IR(neat):
2945, 2930, 1420, 1190, 987, 801 cmꢀ1. HRMS, Calcd [M+H]+
137.0602, Measured [M+H]+ 137.0603.
4.3.4. (S)-(ꢀ)-2-(1-(Allyloxy)but-3-enyl)thiophene (S)-(ꢀ)-9b
Colorless oil (0.25 g, 92% yield). ½a D19
¼ ꢀ55:0 (c 1.00, CH2Cl2).
ꢁ
1H NMR: d 7.18–7.20 (m, 1H), 7.85–7.90 (m, 2H), 5.65–5.88 (m,
2H), 5.15–5.22 (dm, J = 17.3 Hz, 1H), 5.07–5.12 (br d, J = 10.5 Hz,
1H), 4.99–5.04 (dm, J = 17.3 Hz, 1H), 4.94–4.99 (dm, J = 10.3 Hz,
1H), 4.53 (t, J = 17.3 Hz, 1H), 3.93 (ddm, AB system diastereotopic
CHaHb, JAB = 12.8 and 5.1 Hz, 1H), 3.80 (ddm, AB system diastereo-
topic CHaHb, JAB = 12.8 and 5.1 Hz, 1H), 2.58–2.68 (m, 1H), 2.40–
2.50 (m, 1H). 13C NMR: d 145.8, 134.7, 134.3, 126.3, 125.2, 125.0,
117.3, 117.1, 76.5, 69.4, 42.8. IR (neat): 2924, 2856, 2361, 1063,
4.4.2. (S)-(+)-2-(Thiophene-2-yl)-2,5-dihydrofuran (S)-(+)-10b
Colorless oil (0.13 g, 82% yield). ½a D28
¼ þ12:1 (c 1.00, CH2Cl2) for
ꢁ
97% ee. The enantiomeric purity of the product was determined by
HPLC analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow
rate = 1 mL minꢀ1
, k = 230 nm), tR = 9.35 min [(S)-isomer], tR =
15.11 min [(R)-isomer] in comparison with the racemic sample.
1H NMR: d 7.18–7.19 (m, 1H), 6.88–6.92 (m, 2 H), 6.00–6.03 (m,
1 H), 5.95–5.98 (m, 1H), 5.85–5.88 (m, 1 H), 4.73–4.78 (br d,

M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
1167
J = 12.8 Hz, 1H), 4.61–4.66 (dm, J = 12.8 Hz, 1H). 13C NMR: d 146.3,
and stirred at room temperature until all of the starting com-
pounds were consumed. Purification was carried out with short
column chromatography (EtOAc/hexane: 1:15 for all products).
130.0, 128.0, 127.0, 125.7, 124.9, 83.2, 75.4. IR(neat): 2959, 2928,
2858, 1415, 1262, 1043, 798 cmꢀ1
.
HRMS, Calcd [M+H]+
153.0374, Measured [M+H]+ 153.0375.
4.5.1. (S)-2-(Furan-2-yl)-5-vinyl-3,6-dihydro-2H-pyran (S)-(ꢀ)-
4.4.3. (S)-(ꢀ)-2-(Furan-2-yl)-3,6-dihydro-2H-pyran (S)-(ꢀ)-11a
14a
Colorless oil (0.13 g, 88% yield). ½a D25
ꢁ
¼ ꢀ77:2 (c 1.00, CH2Cl2) for
Pale yellow oil (0.13 g, 76% yield). ½a D27
¼ ꢀ50:1 (c 1.0, CH2Cl2)
ꢁ
99% ee. The enantiomeric purity of the product was determined by
for 99% ee. The enantiomeric purity of the product was determined
HPLC analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow
by HPLC analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow
rate = 1 mL minꢀ1
,
k = 230 nm), tR = 8.41 min [(R)-isomer], tR =
rate = 1 mL minꢀ1
, k = 230 nm), tR = 7.56 min [(R)-isomer], tR =
10.73 min [(S)-isomer] in comparison with the racemic sample.
1H NMR: d 7.25–7.26 (br s, 1H), 6.20–6.25 (m, 1H), 6.15–6.25 (m,
1H), 5.76–5.82 (m, 1H), 5.66 (br d, J = 10.2 Hz, 1H), 4.53 (dd,
J = 9.7 and 3.6 Hz, 1H), 4.17 (dm, diastereotopic CHaHb,
J = 16.5 Hz, 2H), 2.15–2.51 (m, 2H). 13C NMR: d 154.5, 141.9,
126.3, 123.6, 110.1, 106.6, 68.7, 65.5, 28.7. IR(neat): 2951, 2867,
1390, 1056, 893 cmꢀ1. HRMS, Calcd [M+H]+ 151.0759, Measured
[M+H]+ 151.0750.
8.53 min [(S)-isomer] in comparison with a racemic sample. 1H
NMR: d 7.31 (dd, J = 2.0 and 0.8 Hz, 1H), 6,25 (dd, J = 3.2 and
1.6 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 6.19 (dd, J = 17.9 and 11.2 Hz,
1H), 5.81 (br d, J = 2.4 Hz, 1H), 4.88 (d, J = 11.0 Hz, 1H), 4.86 (d,
J = 17.9 Hz, 1H), 4.53 (dd, J = 10.0 and 4.0 Hz, 1H) 4.37 (br s, 2H),
2.60 (ddd, J = 17.4, 9.8 and 2.4 Hz, 1H), 2.33–2.27 (m, 1H). 13C
NMR: d 152.0, 140.1, 133.5, 132.8, 122.6, 109.1, 107.9, 104.7,
66.7, 63.0, 26.8. IR(neat): 3054, 2986, 1265, 737, 704 cmꢀ1. HRMS,
Calcd [M+H]+ 177.0916, Measured [M+H]+ 177.0905.
4.4.4. (S)-(ꢀ)-2-(Thiophene-2-yl)-3,6-dihydro-2H-pyran (S)-(ꢀ)-
11b
4.5.2. (S)-2-(Thiophen-2-yl)-5-vinyl-3,6-dihydro-2H-pyran (S)-
(ꢀ)-14b
Colorless oil (0.14 g, 86% yield). ½a D26
¼ ꢀ17:8 (c 1.00, EtOH) for
ꢁ
99% ee. The enantiomeric purity of the product was determined by
Yellowish oil (0.15 g, 80% yield). ½a D25
¼ ꢀ107:1 (c 1.0, CH2Cl2)
ꢁ
HPLC analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow
for 99% ee. The enantiomeric purity of the product was determined
rate=1 mL minꢀ1
,
k = 230 nm), tR = 9.27 min [(S)-isomer], tR =
by HPLC analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow
11.38 min [(R)-isomer] in comparison with the racemic sample.
1H NMR: d 7.19 (dd, J = 5.0 and 1.3 Hz, 1H), 6.92–6.94 (br d,
J = 3.6 Hz, 1H), 6.80–6.91 (br d, J = 11.5 Hz, 1H), 5.84 (ddd, J = 5.4,
3.8 and 2.3 Hz, 1H), 5.72 (dt, J = 10.3 and 1.3 Hz, 1H), 4.27–4.35
(dm, AB system diastereotopic CHaHb, JAB = 17.3 Hz, 1H), 4.21–
4.26 (br d, AB system diastereotopic CHaHb, JAB = 17.3 Hz, 1H),
4.15 (dd, J = 9.7 and 3.7 Hz, 1H), 2.40–2.49 (br d, AB system diaste-
reotopic CHaHb, JAB = 16.5 Hz, 1H), 2.26–2.36 (br d, AB system dia-
stereotopic CHaHb, JAB = 16.5 Hz, 1H). 13C NMR: d 146.5, 126.5,
126.4 (overlapped), 124.8, 123.8, 71.5, 66.8, 32.7. IR(neat): 2956,
2927, 2857, 2361, 2341, 1653, 1261, 1070, cmꢀ1. HRMS, Calcd
[M+H]+ 167.0531, Measured [M+H]+ 167.0332.
rate = 1 mL minꢀ1
, k = 230 nm), tR = 8.12 min [(S)-isomer], tR =
11.34 min [(R)-isomer] in comparison with a racemic sample. 1H
NMR: d 7.18 (dd, J = 4.8 and 1.2 Hz, 1H), 6.91 (d, J = 3.2 Hz, 1H),
6.90 (dd, J = 4.8 and 3.6 Hz, 1H), 6.21 (dd, J = 17.9 and 11.2 Hz,
1H), 5.82 (br d, J = 2.0 Hz, 1H), 4.90 (d, J = 11.0 Hz, 1H), 4.88 (d,
J = 17.9 Hz, 1H), 4.72 (dd, J = 9.6 and 3.6 Hz, 1H), 4.46 (d,
J = 15.6 Hz, 1H), 4.40 (dd, J = 15.6 and 2.0 Hz, 1H), 2.57–2.49 (m,
1H), 2.43 (dm, J = 17.8 Hz, 1H). 13C NMR: d 144.1, 134.6, 134.0,
125.4, 123.9, 123.7, 122.8, 110.3, 70.5, 64.5, 31.9. IR(neat): 3054,
2879, 1264, 702 cmꢀ1. HRMS, Calcd [M+H]+ 193.0609, Measured
[M+H]+ 193.0726.
4.5.3. (S)-2-(Furan-2-yl)-4-vinyl-3,6-dihydro-2H-pyran (S)-(ꢀ)-
4.4.5. (S)-(ꢀ)-2-(3,6-Dihydro-2H-pyran-2-yl)pyridine (S)-(ꢀ)-11c
Before the ring closing metathesis, in order to avoid complexa-
tion of the Grubbs’ catalyst with the free electrons of the pyridine
ring system, it was transformed into the corresponding HCl salt by
passing HCl gas through the DCM solution of (S)-(ꢀ)-9c. At the end
of the ring closing metathesis reaction, the product was isolated in
the free form. The reaction was monitored by TLC. Colorless oil
15a
Yellow oil (0.12 g, 70 % yield) ½a D29
¼ ꢀ17:9 (c 1.0, CH2Cl2) for
ꢁ
93% ee. The enantiomeric purity of the product was determined
by HPLC analysis (Daicel Chiralcel OD-H, hexane/i-PrOH 96:4, flow
rate = 1 mL minꢀ1
, k = 230 nm), tR = 9.54 min [(S)-isomer], tR =
15.41 min [(R)-isomer] in comparison with a racemic sample. 1H
NMR: d 7.33 (dd, J = 1.6 and 0.8 Hz, 1H), 6.32 (dd, J = 17.6 and
10.8 Hz, 1H), 6.27 (dd, J = 3.2 and 1.6 Hz, 1H), 6.25 (d, J = 3.2 Hz,
1H), 5.69 (m, 1H), 5.11 (d, J = 17.6 Hz, 1H), 4.96 (d, J = 10.8 Hz,
1H), 4.59 (dd, J = 9.6 and 3.6 Hz, 1H), 4.34 (dd, J = 17.6 and
2.4 Hz, 1H), 4.26 (dm, J = 17.6 Hz, 1H), 2.59–2.50 (m, 1H), 2.39
(dm, J = 16.5 Hz, 1H). 13C NMR: d 153.2, 141.2, 136.8, 132.1,
125.1, 110.6, 109.1, 105.9, 67.8, 64.6, 26.6. IR(neat): 3048, 2956,
1275, 741, 707 cmꢀ1. HRMS, Calcd [M+H]+ 177.0916, Measured
[M+H]+ 177.0912.
(0.12 g, 72% yield). ½a D26
¼ ꢀ18:8 (c 1.00, EtOH) for 98% ee. The
ꢁ
enantiomeric purity of the product was determined by HPLC
analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow rate =
1 mL minꢀ1
,
k = 254 nm), tR = 15.02 min [(S)-isomer], tR =
19.17 min [(R)-isomer] in comparison with a racemic sample. 1H
NMR: d 8.46 (d, J = 10.3 and 3.5 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H),
7.41 (d, J = 8.1 Hz, 1H), 7.10 (dd, J = 7.5 and 5.1 Hz, 1H), 5.82–5.90
(m, 1H), 5.73 (dt, J = 10.3 and 1.2 Hz, 1H), 4.60 (dd, J = 10.3 and
3.5 Hz, 1H), 4.25–4.55 (m, 2H), 2.36–2.46 (br d, AB system diaste-
reotopic CHaHb, JAB = 17.3 Hz, 1H), 2.20–2.32 (br d, AB system dia-
stereotopic CHaHb, JAB = 17.3 Hz, 1H). 13C NMR: d 162.0, 149.0,
136.8, 126.5, 124.7, 122.5, 120.3, 76.5, 66.7, 31.7. IR(neat): 3077,
2927, 2858, 2360, 2341, 1589, 1430, 1096, 993, 866 cmꢀ1. HRMS,
Calcd [M]+ 162.0919, Measured [M]+ 162.0918.
4.5.4. (S)-2-(Thiophen-2-yl)-4-vinyl-3,6-dihydro-2H-pyran (S)-
(ꢀ)-15b
Yellow oil (0.15 g, 78% yield). ½a D25
¼ ꢀ5:8 (c 1.0, CH2Cl2) for 99%
ꢁ
ee. The enantiomeric purity of the product was determined by
HPLC analysis (Daicel Chiralcel OJ-H, hexane/i-PrOH 96:4, flow
rate = 1 mL minꢀ1
, k = 230 nm), tR = 8.25 min [(R)-isomer], tR =
4.5. General procedure of the ring closing enyne metathesis
reaction
14.47 min [(S)-isomer] in comparison with a racemic sample. 1H
NMR: d 7.20 (dd, J = 5.2 and 1.2 Hz, 1H), 6.95 (dt, J = 3.2 and
1.2 Hz, 1H), 6.91 (dd, J = 5.2 and 3.2 Hz, 1H), 6.32 (dd, J = 17.6
and 10.8 Hz, 1H), 5.71–5.70 (m, 1H), 5.10 (d, J = 17.2 Hz, 1H),
4.96 (d, Jcis = 10.8 Hz, 1H), 4.78 (dd, J = 9.2 and 4.0 Hz, 1H), 4.37–
4.34 (m, 2H), 2.53–2.41 (m, 2H). 13C NMR: d 144.3, 136.7, 132.3,
To a solution of enyne system (S)-(ꢀ)-12a–b and (S)-(ꢀ)-13a–b
(1.0 mmol) in CH2Cl2 (8 mL), Grubbs’ first generation catalyst [5%
for (S)-(ꢀ)-12a–b and (S)-(ꢀ)-13a, 8% for (S)-(ꢀ)-13b] was added

1168
M. Çayir et al. / Tetrahedron: Asymmetry 22 (2011) 1161–1168
2. Kang, E. J.; Lee, E. Chem. Rev. 2005, 105, 4348.
125.4, 125.2, 123.7, 122.8, 110.6, 70.4, 65.0, 30.7. IR(neat): 3057,
2882, 1271, 701 cmꢀ1. HRMS, Calcd [M+H]+ 193.0609, Measured
[M+H]+ 193.0684.
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Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374; (c) Aissa, C.; Riveiros, R.;
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Olah, G. A. J. Org. Chem. 1987, 52, 4314; (b) Wolfe, J. P.; Hay, M. B. Tetrahedron
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51.
4.6. General procedure for the Diels–Alder reaction
To a solution of diene (S)-(ꢀ)-14a and (S)-(ꢀ)-14b (1.0 mmol) in
dry toluene (8 mL), tetracyanoethylene (1.2 equiv) was added and
the reaction was stirred at 65 °C under an argon atmosphere until
all of the diene was consumed. For purification column chromatog-
raphy was used (EtOAc/hexane: 1:3 for each product).
4.6.1. (3S,4aR)-3-(Furan-2-yl)-4,4a-dihydro-1H-isochromene-
5,5,6,6(3H,7H)-tetracarbonitrile (3S,4aR)-(+)-16a
White crystals (0.22 g, 72% yield). Mp: 113–114 °C.
½
a 2D7
ꢁ
¼ þ98:1 (c 1.0, CH2Cl2). 1H-NMR: d 7.43 (d, J = 1.6 Hz, 1H),
6.39 (dd, J = 3.2 and 1.6 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.58–5.62
(m, 1H), 5.20 (d, J = 6.0 Hz, 1H), 4.06 (d, J = 14.4 Hz, 1H), 4.00 (d,
J = 13.6 Hz, 1H), 3.60 (d, J = 12.0 Hz, 1H), 3.16 (dd, J = 18.4 and
2.8 Hz, 1H), 3.06–3.00 (m, 1H), 2.63 (dd, J = 13.2 and 5.2 Hz, 1H),
2.33 (dt, J = 12.8 and 6.0 Hz, 1H). 13C NMR: d 150.1, 142.2, 131.2,
113.3, 109.8, 109.6, 109.4, 109.0, 108.8, 107.6, 66.7, 63.4, 43.4,
43.1, 36.9, 31.2, 28.5. IR(neat): 2932, 2255, 1291,761 cmꢀ1. HRMS
(ESI negative), Calcd [MꢀH]ꢀ 303.0882, Measured [MꢀH]ꢀ
303.0889.
11. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol.
2,.
12. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
13. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
14. (a) Son, S. U.; Yoon, Y. A.; Choi, D. S.; Park, J. K.; Kim, B. M.; Chung, Y. K. Org.
Lett. 2001, 3, 1065; (b) Son, S. U.; Paik, S.-J.; Lee, S. I.; Chung, Y. K. J. Chem.
Soc., Perkin Trans. 1 2000, 141; (c) Hong, S. H.; Kim, J. W.; Choi, D. S.; Chung,
Y. K.; Lee, S.-G. J. Chem. Soc., Chem. Commun. 1999, 2099; (d) Son, S. U.; Choi,
D. S.; Chung, Y. K. Org. Lett. 2000, 2, 2097; (e) Lee, S. I.; Son, S. U.; Choi, M.
R.; Chung, Y. K.; Lee, S.-G. Tetrahedron Lett. 2003, 44, 4705; (f) Son, S. U.;
Park, K. H.; Lee, S. J.; Kim, B. M.; Chung, Y. K. Synlett 2003, 1101; (g) Muto,
R.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4143; (h) Tamao, K.; Kobayashi,
T.; Ito, Y. Synlett 1992, 539.
15. Handbook of Asymmetric Heterogeneous Catalysis; Ding, K., Uozumi, Y., Eds.;
Wiley-VCH: Weinheim, 2008.
16. Hydrolases in Organic Synthesis; Kazlauskas, R. J.; Bornscheuer, U. T., Eds., 2nd
ed.; Wiley-VCH: Weinheim, 2006.
17. (a) Tanyeli, C.; Demir, A. S.; Arkın, H.; Akhmedov, I. M. Enantiomer 1997, 2,
433; (b) Tanyeli, C.; Akhmedov, I. M.; Özdemirhan, D. Enantiomer 2001,
259.
18. (a) Sezer, S.; Ozdemirhan, D.; Sahin, E.; Tanyeli, C. Tetrahedron: Asymmetry
2006, 17, 2981; (b) Sezer, S.; Sßahin, E.; Tanyeli, C. Tetrahedron: Asymmetry 2010,
21, 476.
4.6.2. (3S,4aR)-3-(Thiophen-2-yl)-4,4a-dihydro-1H-
isochromene-5,5,6,6(3H,7H)-tetracarbonitrile (3S,4aR)-(+)-16b
White crystals (0.20 g, 63% yield). Mp: 151–153 °C.
½
a 2D7
ꢁ
¼ þ85:2 (c 1.0, CH2Cl2). 1H NMR: d 7.32 (d, J = 5.2 Hz, 1H),
7.01 (dd, J = 5.2 and 3.6 Hz, 1H), 6.95–6.93 (m, 1H), 5.60 (dd,
J = 5.2 and 2.0 Hz, 1H), 5.44 (d, J = 5.6 Hz, 1H), 4.24 (d, J = 14.0 Hz,
1H), 4.03 (d, J = 14.0 Hz, 1H), 3.45 (d, J = 12.4 Hz, 1H), 3.18–3.11
(m, 1H), 3.05–2.98 (m, 1H), 2.75 (ddd, J = 13.2, 4.8 and 1.2 Hz,
1H), 2.43 (td, J = 12.8 and 5.6 Hz, 1H). 13C NMR: d 140.1, 131.2,
126.6, 125.7, 124.6, 113.1, 109.6, 109.4, 108.9, 107.6, 69.1, 62.7,
43.0, 36.8, 36.5, 31.1, 30.0. IR(neat): 3062, 2323, 1257, 727 cmꢀ1
.
HRMS (ESI negative), Calcd [MꢀH]ꢀ 319.0654, Measured [MꢀH]ꢀ
319.0659.
19. Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082.
20. (a) Schreiber, S. L.; Burke, M. D. Angew. Chem. 2004, 43, 46; (b) Bergman, Y. E.;
Mulder, R.; Perlmutter, P. J. Org. Chem. 2009, 74, 2589.
Acknowledgment
21. Sezer, S.; Gümrükçü, Y.; Sßahin, E.; Tanyeli, C. Tetrahedron: Asymmetry 2008, 19,
2705.
We are grateful to the Turkish Scientific and Technical Research
Council for a grant (No. TBAG-108T072).
22. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294.
23. Final compounds were identified and characterized by 1H NMR, 13C NMR,
COSY, HMBC, HMQC, and MS, HRMS, and/or elemental analysis. The new
stereogenic center on the products (S)-(+)-16a–b can be discerned by
differential NOE experiments relative to homoallylic alcohols.
24. Sing, S.; Kumar, S.; Chimni, S. Tetrahedron: Asymmetry 2002, 13, 2679.
25. Soderquist, A.; Lai, C. Org. Lett. 2005, 7, 799.
References
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26. Enzyme catalyzed reactions were performed in a water bath shaker at different
temperatures shown in Table 1.