Stereoselective synthesis of optically active cyclopenta[c]pyridines and tetrahydropyridines

Article abstract of DOI:10.1016/j.tetasy.2012.04.016

The intramolecular Pauson-Khand and ring closing metathesis (RCM) reactions of nitrogen containing chiral enynes and dienes are described. The enyne and diene systems comprised of N-propargylated and N-allylated units are constructed on chiral homoallylic

Full text of DOI:10.1016/j.tetasy.2012.04.016

Tetrahedron: Asymmetry 23 (2012) 662–669
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of optically active cyclopenta[c]pyridines
and tetrahydropyridines
⇑
_
Serdar Sezer, Yasemin Gümrükçü, Irem Bakırcı, M. Yag˘ız Ünver, Cihangir Tanyeli
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular Pauson–Khand and ring closing metathesis (RCM) reactions of nitrogen containing
chiral enynes and dienes are described. The enyne and diene systems comprised of N-propargylated
and N-allylated units are constructed on chiral homoallylic or homopropargylic alcohol backbones,
respectively, via SN2 and/or modified Mitsunobu reactions. The racemic homoallylic and homopropargy-
lic alcohol derivatives were successfully resolved in high ee (93–99%) by applying chemoenzymatic
methods using various lipases such as PS-C II, Lipozyme, and CAL-B. Each enantiomerically enriched eny-
ne afforded the most conformationally stable diastereomeric cyclopenta[c]pyridine ring system as the
sole product, whereas enantiomerically enriched dienes gave tetrahydropyridine derivatives as a result
of intramolecular Pauson–Khand and RCM reactions, respectively.
Received 26 March 2012
Accepted 25 April 2012
Available online 8 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
H
The Pauson–Khand reaction (PKR)1 is a powerful tool for the
construction of cyclopentenones2 from an alkyne–cobalt complex
with alkenes via [2+2+1] cyclizations. Due to its potential applica-
bility in the synthesis of many natural products,3 both intermolec-
ular and intramolecular versions have attracted much interest.4
Although the stereoselectivity of the intramolecular PKR is known,
especially in the studies of Magnus et al.,5 little attention has been
directed toward the PKR of chiral enyne systems. In our previous
studies, we described the effect of conformational control on the
remote stereochemistry in the intramolecular PKR of chiral enyne
systems affording chiral cyclopenta-pyran or cyclopenta-furan
fused ring systems with excellent diastereoselectivity.6 Enyne sys-
tems possessing nitrogen atoms are good candidates for PK cycliza-
tion. Especially, heterocycles containing substituted piperidine
rings are of particular interest in synthetic organic chemistry be-
cause they are potent pharmacophores and substructures of many
alkaloids.7 For instance, kinabalurine B8 and tecomanine9 are a
class of monoterpene alkaloids with varied physiological activity
with a piperidine fused cyclopentanone or cyclopentenone back-
bone, respectively, and have been stereoselectively synthesized
via intramolecular PKR as the key step (Fig. 1).10 The control of
the configuration of the newly created stereogenic center located
on the ring junction between the piperidine and cyclopentenone
is the main issue with regard to the cyclization in PKR. It can be as-
sumed that the piperidine unit possesses a chair-like transition
O
O
MeN
MeN
H
H
kinabalurine B
tecomanine
Figure 1. Monoterpene alkaloids.
state in the intramolecular PKR. The ring junction stereochemistry
could be affected by the substituents on the enyne systems when
the chair-like six-membered piperidine ring is formed. Therefore,
we turned our attention to the synthesis of cyclopenta[c]pyridine
fused ring systems and investigated the conformational effect of
2-heteroaryl substituted piperidine ring on the diastereoselectivity
in the intramolecular PKR.
Chiral homoallylic and homopropargylic alcohols are good pre-
cursors for preparing chiral diene and enyne systems with a nitro-
gen functionality, respectively.11 Recently, we have demonstrated
the utility of biocatalysts in the resolution of racemic a-heterocy-
clic carbinols,6,12 potentially useful scaffolds for anchoring allyl
and propargyl substituted amines. With regard to the generation
of chiral dienes and enynes, the nucleophilic addition of amines
or tosylamides to secondary chiral homoallylic or homopropargylic
alcohols could generate target RCM and PKR precursors via SN2
and/or modified Mitsunobu reactions.
As part of our ongoing efforts to study the effect of conforma-
tional control on remote stereochemistry in the intramolecular
PKR, we recently described the excellent conformational control
⇑
Corresponding author.
E-mail address: tanyeli@metu.edu.tr (C. Tanyeli).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.016

S. Sezer et al. / Tetrahedron: Asymmetry 23 (2012) 662–669
663
properties of pyran and furan rings.6 These results prompted us to
synthesize diastereomerically enriched heteroaryl substituted
cyclopenta[c]pyridine units. To the best of our knowledge,
Pauson–Khand reactions starting from optically active heteroaryl
substituted enyne systems with a nitrogen atom have not been
described. Herein we report a simple route to synthesize chiral het-
eroaryl substituted cyclopenta[c]pyridine fused ring systems with
high diastereoselectivity. Moreover, we have also demonstrated
the concise synthesis of chiral tetrahydropyridine units via RCM.
due to coordination of the transition metal complex Co2(CO)8 to
the nitrogen.13 In order to overcome this problem, (R)-(+)-7 was
protected with tosyl group. Consequently, the N-tosyl protected
enyne tethered system (R)-(+)-8 afforded the target cyclo-
penta[c]pyridine (+)-9 as the sole diastereomeric product (as deter-
mined by 1H and 13C NMR) in 80% chemical yield. This observation
supports our previous results6a–c regarding the conformational
control concept. The relative configuration of (+)-9 was determined
by differential NOE experiments. The characteristic methine proton
attached to the stereogenic center [with the known (R) absolute
configuration] of the piperidine ring resonated at 5.26 ppm while
the newly created stereogenic center methine proton on the cyclo-
penta[c]piperidine scaffold resonated at 2.97–3.00 ppm as a multi-
plet and showed significant NOE enhancements, which indicated a
cis-relationship between the stereogenic center protons. Thus, the
absolute configuration of (+)-9 (cis-1,3) was determined as
(3R,4aS).
Parallel to the synthesis of (3R,4aS)-(+)-9, a similar pathway
was followed for the synthesis of (+)-13 to explore the scope and
limitations (Scheme 3). The homopropargyl alcohol (S)-(ꢀ)-3c
was mesylated in quantitative yield and the resulting product
(S)-10 underwent a substitution reaction with allylamine followed
by N-tosylation to give chiral enyne (R)-(+)-12. The intramolecular
Pauson–Khand reaction afforded cyclopenta[c]pyridine (+)-13 as a
single diastereomer in 82% yield. In the NOE experiment, we did
not observe NOE enhancement between the methine proton at-
tached to the stereogenic carbon of the piperidine ring and the
methine proton of the newly created stereogenic carbon center.
Therefore, the absolute stereochemistry could not be determined.
The synthesis of 2-furyl substituted chiral fused cyclo-
penta[c]pyridine derivative was performed with 2-furyl substi-
tuted homoallyl alcohol (S)-(ꢀ)-2a by following the conditions
found in pyridinyl substituted systems. In the first step, we at-
tempted to mesylate (S)-(ꢀ)-2a with MsCl in the presence of
2. Results and discussion
The target parent homoallylic alcohols rac-2a–c were synthe-
sized by the addition of allylmagnesium bromide to the commer-
cially available 2-heterocarbaldehydes, whereas homopropargylic
alcohols rac-3a–b were synthesized by the addition of propargyl
bromide using Zn-Cu couple as described in our previous work6a,-
c,12a
(Scheme 1). Homopropargyl alcohol rac-3c was synthesized
by an HgCl2 catalyzed Grignard reaction.6c
The fundamental crucial step is the enantiomeric resolution of
the racemic substrates rac-2a–c and rac-3a–c by hydrolase type
enzymes. All of the enantiomeric resolution reactions were per-
formed by using various immobilized lipases with a 1:1 sub-
strate/enzyme ratio (w/w), and with vinyl acetate as an acyl
donor and THF as a solvent at 24 °C according to the literature.6a,c
The best results are summarized in Table 1.
In our synthetic strategy, the second step involves the construc-
tion of dienes and enynes with a nitrogen atom in a stereospecific
manner. For this purpose, pyridine substituted homoallyl alcohol
(S)-(ꢀ)-2c was quantitatively transformed into O-mesyl derivative
(S)-(ꢀ)-6 which was subsequently subjected to an SN2 type reac-
tion with propargyl amine to afford the enyne tethered system
(R)-(+)-7 in 67% yield (Scheme 2). Direct PK application of (R)-
(+)-7 did not afford any cyclization product. This was presumably
O
O
S
R=
N
,
,
S
O
N
OH
2a
OH
OH
2c
(S)-(-)-
(S)-(-)-2b
(S)-(-)-
a
b
c
a
R
d
R
R
S
N
+
O
O
O
OH
rac-2a-c
OH
(S)-2a-c
OAc
O
O
(R)-4a-c
O
4a
(R)-(+)-
(R)-(+)-4b
4c
(R)-(+)-
O
R
H
1a-c
O
S
N
R
R
R
d
OH
OH
+
OH
OH
3a-c
OH
3a-c
OAc
(S)-(+)-3a
3b
(S)-(+)-
3c
(S)-(-)-
b or c
rac-
5a-c
(R)-
(S)-
O
S
N
O
O
O
O
O
O
(R)-(+)-5a
5b
(R)-(+)-
5c
(R)-(+)-
Scheme 1. Reagents: (a) allyl bromide, Mg, I2, dry ether; (b) propargyl bromide, Zn–Cu, dry THF for 3a–b; (c) propargyl bromide, HgCl2, Mg, I2, dry ether for 3c; (d) lipase,
vinyl acetate, THF.

664
S. Sezer et al. / Tetrahedron: Asymmetry 23 (2012) 662–669
Table 1
Enzymatic kinetic resolution of homoallylic and homopropargylic alcohols rac-2a–c and rac-3a–c
a
a
Entry
Substrate
Enzyme
Time (h)
Estersd eep (%)
Alcoholsd ees (%)
cb (%)
Ec
1
2
3
4
5
6
rac-2a
rac-2b
rac-2c
rac-3a
rac-3b
rac-3c
PS-C Amona IIe
PS-C Amona IIe
PS-C Amona IIe
PS-C Amona IIe
PS-C Amona IIe
PS-C Amona IIe
4
20
30
1.5
2.5
25
96 (R)
40 (R)
95 (R)
90 (R)
92 (R)
92 (R)
99 (S)
99 (S)
98 (S)
93 (S)
99 (S)
95 (S)
51
71
51
51
52
51
211
11
154
60
116
82
a
b
c
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)].19
d
e
The absolute configurations were found to be (S) for alcohols and (R) for esters according to the specific rotations reported in the literature.
The reactions were carried out at 24 °C.
H2N
MsCl, Et3N, DCM
N
N
N
quantitative
K2CO3, r.t.
67%
OH
HN
OMs
(S)-6
2c
(S)-(-)-
7
(R)-(+)-
TsCl, Et3N
DCM
47%
NOE
H
N
H
Co2(CO)8
N
N
O
N
NMO, r.t.
80%
Ts
Ts
(3R,4aS)-(+)-9
(R)-(+)-8
Scheme 2. Synthetic strategy towards compound (3R,4aS)-(+)-9.
H2N
MsCl, Et3N
N
N
N
DCM
K2CO3, r.t.
OH
3c
OMs
HN
quantitative
65%
(S)-(-)-
(S)-10
(R)-(+)-11
TsCl, Et3N
DCM
53%
H
Co2(CO)8
N
N
O
NMO, r.t.
82 %
N
N
Ts
Ts
H
12
(R)-(+)-
13
(3R)-(+)-
Scheme 3. Synthetic strategy towards compound (3R)-(+)-13.
Et3N in DCM at room temperature. However, we were unable to
obtain the 1-(furan-2-yl)but-3-en-1-yl methanesulfonate product
in an acceptable yield. Next, NaOH and pyridine were used sepa-
rately instead of Et3N. However, the desired compound was again
obtained in low yields. The tosylation reaction was then applied in-
stead of mesylation. However, the yields were again found to be
low. Consequently, we changed the synthetic strategy and planned
to apply the modified Mitsunobu reaction.14 Firstly, the propargyl
amine was protected with tosyl chloride15 in H2O in 92% yield
and then subjected to Mitsunobu reaction with furyl substituted
homoallylic alcohol (S)-(ꢀ)-2a in the presence of PPh3 and DEAD
in dry THF. The resultant enyne tethered compound (R)-(+)-14

S. Sezer et al. / Tetrahedron: Asymmetry 23 (2012) 662–669
665
NOE
H
H
Co2(CO)8, NMO
PPh3, DEAD
O
O
O
O
N
TsHN
62%
DCM
58%
OH
N
Ts
Ts
2a
(S)-(-)-
14
15
(3R,4aS)-(+)-
(R)-(+)-
NOE
H
H
Co2(CO)8, NMO
PPh3, DEAD
S
S
S
O
DCM
64%
TsHN
65%
N
N
OH
Ts
Ts
(3R,4aS)-(+)-17
(S)-(-)-2b
(R)-(+)-16
Scheme 4. Synthetic strategy towards compounds 15 and 17.
PPh3, DIAD
5% cat.*
O
O
O
PCy3
Ts
N
DCM, RT
88%
N
Ph
OH
N
Cl
Cl
Ts
Ts
Ru
H
62%
(S)-(-)-2a
(R)-(+)-18
(R)-(+)-19
PCy3
catalyst*
PPh3, DIAD
5% cat.*
DCM, RT
85%
Grubbs' 1st
generation
S
S
S
N
OH
Ts
N
N
Ts
Ts
H
60%
(S)-(-)-2b
(R)-(+)-20
(R)-(+)-21
Scheme 5. Synthetic strategy towards compounds (+)-19 and 21.
was isolated in 62% yield (Scheme 4), which was then subjected to
PKR to afford compound (+)-15 in 58% yield as a single diastereo-
mer. Similarly, the configuration of compound (+)-15 was deter-
mined as (3R,4aS) by differential NOE experiments. Depending
upon the results found in the synthesis of (3R,4aS)-(+)-15, the tar-
get compound thiophene substituted fused cyclopenta[c]pyridine
(+)-17 was synthesized by using the same procedure. Starting with
enantiomerically enriched thiophene substituted homoallyl alco-
hol (S)-(ꢀ)-2b, compound (3R,4aS)-(+)-17 was obtained in 64%
chemical yield as the sole diastereomer via an intramolecular
Pauson–Khand reaction (Scheme 4). In the case of heteroaryl
substituted homopropargylic alcohols, their mesylated or tosylated
derivatives were not obtained in good yields. Similar to homoal-
lylic alcohols, the homopropargylic alcohols were subjected to
Mitsunobu conditions to obtain the target enyne systems. How-
ever, these conditions did not give the desired products in accept-
able yields.
The Mitsunobu approach for anchoring an amine unit to the
main scaffold prompted us to synthesize piperidine skeletons,
which are important intermediates for many azasugars,16 using a
short route. For this purpose, a similar methodology to that de-
scribed above was applied and chiral diene systems were obtained
in 55% and 58% yields, respectively. At this point, different reaction
conditions were also investigated in an attempt to improve on the
moderate yields. In this manner, different temperatures were
screened, however, the yields were not changed. Another reagent
diisopropyl azodicarboxylate17 (DIAD) was used instead of diethyl
azodicarboxylate (DEAD) but again there was no drastic change.
After the optimum conditions were found, the diene systems
underwent a ruthenium mediated ring closing metathesis (RCM)
reaction and the target piperidine skeletons (R)-(+)-19 and 21 were
obtained in high yields (Scheme 5).
3. Conclusion
In conclusion, four 2-heteroaryl substituted chiral fused cyclo-
penta[c]pyridine derivatives were synthesized successfully. Their
intramolecular PKRs showed high conformational control on the
new stereocenter formed in the cyclopentenone-pyridine ring sys-
tem. Moreover, new enantiomerically enriched 2-furyl and 2-thio-
phenyl substituted dienes containing an amine functionality have
been synthesized. Their RCM reactions using Grubbs’ first genera-
tion catalyst afforded enantiomerically enriched tetrahydropiperi-
dine derivatives with known absolute configurations. Further
applications, especially of the conformational control concept and
target aza sugar synthesis, are now under investigation.
4. Experimental
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-

666
S. Sezer et al. / Tetrahedron: Asymmetry 23 (2012) 662–669
methane (P2O5), tetrahydrofuran (sodium, benzophenone). 1H
NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker
Spectrospin Avance DPX-400 spectrometer 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 assignments. Infrared spectra were recorded on a Thermo
Nicolet IS10 ATR-FT-IR spectrophotometer. The mass spectra were
recorded on a Thermo Scientific DSQ II Single Quadrupole GC/MS.
HRMS data were obtained via LC–MS analysis performed with
APCI-Q-TOF II (Waters, Milford, MA, USA) at the Mass Spectrome-
try Facility Center for Functional Genomics University at Albany
and with a Waters Synapt mass spectrometer at the central labora-
tory 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.
Flash column chromatography was performed by using thick-
walled glass columns with a flash grade (Merc Silica Gel 60). Reac-
tions were monitored by thin layer chromatography using pre-
coated silica gel plates (Merc Silica Gel PF-254), visualized by
UV-light and phosphomolybdic acid in ethanol. All extracts were
dried over anhydrous magnesium sulfate and solutions were con-
centrated under vacuum by using a rotary evaporator. All of the
racemic secondary alcohols rac-2a, 2b, 2c, 3a, 3b, and 3c were pre-
pared by our reported procedures6a,c,18 and references cited there-
in. The absolute configurations were found to be (S) for alcohols
(S)-(ꢀ)-2a, (S)-(ꢀ)-2b, (S)-(ꢀ)-2c, (S)-(+)-3a, (S)-(+)-3b, and (S)-
(ꢀ)-3c according to the specific rotations as reported in the
literature.6a,c,18
4.1.4. (S)-(ꢀ)-(Furan-2-yl)but-3-yn-1-ol (S)-(+)-3a
This compound was obtained as a yellow oil; ½a D29
¼ þ6:7 (c 3.1,
ꢁ
MeOH) 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 = 16.84 min
[(S)-isomer], tR = 23.15 min [(R)-isomer] in comparison with the
racemic sample.
4.1.5. (S)-(ꢀ)-1-(Thiophen-2-yl)but-3-yn-1-ol (S)-(+)-3b
This compound was obtained as a yellow oil; ½a D28
¼ þ26:5 (c 1,
ꢁ
EtOH) 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 = 35.56 min
[(R)-isomer], tR = 41.75 min [(S)-isomer] in comparison with the
racemic sample.
4.1.6. (S)-(ꢀ)-1-(Pyridin-2-yl)but-3-yn-1-ol (S)-(ꢀ)-3c
This compound was obtained as a yellow oil; ½a D28
¼ ꢀ6:7 (c 1,
ꢁ
CH2Cl2) for 95% ee. The enantiomeric purity of the product was
determined by HPLC analysis (Daicel Chiralcel OJ–H, n-hexane/i-
PrOH 99:1, flow rate = 0.3 mL minꢀ1, k = 254 nm), tR = 90.56 min
[(R)-isomer], tR = 97.90 min [(S)-isomer] in comparison with the
racemic sample.
4.2. General procedure for the mesylation of homoallyl and
homopropargyl alcohols
The mesyl chloride (4 mmol) solution in DCM was added drop-
wise at 0 °C to a mixture of Et3N (3 mmol) and the corresponding
2-substituted homoallyl and homopropargyl alcohol (1 mmol) in
DCM (5 mL). The reaction was stopped after 15 min. by TLC moni-
toring and the reaction mixture was extracted with water
(3 ꢂ 10 mL). The remaining organic phase was dried over anhy-
drous MgSO4 and evaporated in vacuo. Since the mesylated com-
pound decomposed easily, it was used in the synthesis without
further purification.
4.1. General procedure for enzymatic resolution
To a solution of the rac-2a–c and rac-3a–c (3 mmol) in anhy-
drous THF (3 mL) and vinyl acetate (2.7 mL) in a 25 mL round bot-
tomed flask, was added lipase (1 equiv w/w). The reaction mixture
was stirred at constant temperature and monitored by TLC and re-
corded on 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 puri-
fied by column chromatography on silica gel. Experiments were re-
peated at least twice.
4.3. General procedure for N-allylation and N-propargylation
To a suspension of K2CO3 (1.2 mmol) in allylamine (8 mmol)
and propargylamine (8 mmol) was slowly added homopropargyl
and homoallyl mesylate, respectively, via syringe addition over a
period of 30 min. The solvent free reaction mixture was then stir-
red at room temperature for 24 h. Next, the K2CO3 was filtered and
washed with DCM. The filtrate was concentrated in vacuo and
purified by flash column chromatography with a 5% methanol–
chloroform mixture.
4.1.1. (S)-(ꢀ)-1-(Furan-2-yl)but-3-en-1-ol (S)-(ꢀ)-2a
This compound was obtained as a yellow oil; ½a D29
¼ ꢀ40:0(c
ꢁ
5.0, CH2Cl2) for 99% ee. The enantiomeric purity of the product
was determined by HPLC analysis (Daicel Chiralcel OJ–H, n-hex-
ane/i-PrOH 96:4, flow rate = 1 mL minꢀ1, k = 230 nm), tR = 11.2 min
[(S)-isomer], tR = 10.5 min [(R)-isomer] in comparison with the
racemic sample.
4.3.1. (R)-(+)-N-(Prop-2-yn-1-yl)-1-(pyridin-2-yl)but-3-en-1-
amine (R)-(+)-7
This compound was obtained as a yellow oil (67% yield).
4.1.2. (S)-(ꢀ)-1-(Thiophen-2-yl)but-3-en-1-ol (S)-(ꢀ)-2b
½
a 3D1
ꢁ
¼ þ79:2 (c 1.0, EtOH). 1H NMR: d 8.48 (d, J = 4.0 Hz, 1H),
This compound was obtained as a yellow oil; ½a D29
ꢁ
¼ ꢀ17:1 (c
7.55 (td, J = 7.8 and 1.7 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.07 (ddd,
J = 7.4, 4.8 and 1.1 Hz, 1H), 5.61–5.72 (m, 1H), 4.96–5.03 (m, 2H),
3.94 (dd, J = 7.9 and 5.6 Hz, 1H), 3.30 (dd, AB system, JAB = 16.9
and 2.4 Hz, 1H), 3.06 (dd, AB system, JAB = 16.9 and 2.4 Hz, 1H),
2.29–2.50 (m, 2H), 2.09 (t, J = 2.4 Hz, 1H), 2.03 (brs, 1H). 13C
NMR: d 162.4, 149.6, 136.4, 135.0, 122.2, 122.0, 118.0, 82.1, 71.6,
61.9, 41.5, 36.3. IR (neat): 2919, 1588, 1473, 1434, 1112, 995,
1.2, CH2Cl2) for 99% ee. The enantiomeric purity of the product
was determined by HPLC analysis (Daicel Chiralcel OJ–H, n-hex-
ane/i-PrOH
96:4,
flow
rate = 1 mL minꢀ1
,
k = 230 nm),
tR = 12.09 min [(S)-isomer], tR = 13.76 min [(R)-isomer] in compar-
ison with the racemic sample.
4.1.3. (S)-(ꢀ)-1-(Pyridin-2-yl)but-3-en-1-ol (S)-(ꢀ)-2c
919, 749 cmꢀ1
.
This compound was obtained as a yellow oil; ½a D25
¼ ꢀ42:9 (c
ꢁ
0.86, CH2Cl2) for 98% ee. The enantiomeric 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 = 63.74 min
[(S)-isomer], tR = 58.75 min [(R)-isomer] in comparison with the
racemic sample.
4.3.2. (R)-(+)-N-Allyl-1-(pyridin-2-yl)but-3-yn-1-amine (R)-(+)-
11
This compound was obtained as a yellow oil (65% yield).
½
a 2D4
ꢁ
¼ þ25:9 (c 1.0, CHCl3). 1H NMR: d 8.49–8.50 (m,1H), 7.56–
7.59 (m, 1H), 7.28 (dd, J = 7.7 and 0.8 Hz, 1H), 7.08–7.11 (m, 1H),

S. Sezer et al. / Tetrahedron: Asymmetry 23 (2012) 662–669
667
5.75–5.85 (m, 1H), 4.99–5.10 (m, 2H), 3.86 (t, J = 6.6 Hz, 1H), 3.00–
3.12 (m, 2H), 2.51–2.63 (m, 2H), 2.06 (brs, 1H), 1.86 (m, 1H). 13C
NMR: d 160.1, 148.0, 135.1, 134.7, 120.8, 120.7, 114.6, 79.8, 68.9,
60.2, 48.6, 24.8. IR (neat): 2964, 1591, 1259, 1099, 1018, 801,
(dddd, J = 17.1, 13.8, 10.1 and 6.9 Hz, 1H), 5.00–5.03 (m, 2H), 4.95
(m, 1H), 3.98 (dd, AB system JAB = 18.5 and 2.4 Hz, 1H), 3.72 (dd, AB
system JAB = 18.5 and 2.4 Hz, 1H), 2.57–2.77 (m, 2H), 2.35 (s, 3H),
1.93 (t, J = 2.4 Hz, 1H). 13C NMR: d 150.3, 142.0, 141.1, 136.6, 132.7,
128.1, 126.7, 116.9, 109.1, 108.2, 78.1, 70.7, 54.0, 34.7, 31.9, 20.4. IR
744 cmꢀ1
.
(neat): 2922, 1337, 1259, 1162, 1089, 817, 730, 699, 663 cmꢀ1
.
4.4. General procedure for the tosylation of N-tethered enyne
derivatives
4.5.2. (R)-(+)-4-Methyl-N-(prop-2-yn-1-yl)-N-(1-(thiophen-2-
yl)but-3-en-1-yl) benzenesulfonamide (R)-(+)-16
To a solution of N-tethered enyne compound (1 mmol) in DCM
(20 mL) was added TsCl (1.5 mmol) and Et3N (2 mmol) at 0 °C. The
mixture was allowed to stir at room temperature for 30 min. The
reaction was ended by TLC monitoring. Next, 20 mL of water was
added and extracted with DCM, dried over anhydrous MgSO4,
and evaporated in vacuo. Purification was carried out by flash col-
umn chromatography with a 1:3 ratio of ethyl acetate/hexane.
This compound was obtained as a yellow oil (65% yield).
½
a 3D1
ꢁ
¼ þ9:9 (c 1.0, CHCl3). 1H NMR: d 7.66–7.72 (m, 2H), 7.18–
7.21 (m, 2H), 7.12 (dd, J = 5.0 and 1.0 Hz, 1H), 6.87–6.88 (m, 1H),
6.81–6.84 (m, 1H), 5.50–5.71 (m, 1H), 5.18 (t, J = 7.6 Hz, 1H), 4.99
(dd, J = 17.1 and 1.5 Hz, 1H), 4.89 (dd, J = 10.1 and 1.35 Hz, 1H),
4.10 (dd, AB system JAB = 18.6 and 2.4 Hz, 1H), 3.62 (dd, AB system
JAB = 18.6 and 2.4 Hz, 1H), 2.63–2.81 (m, 2H), 2.36 (s, 3H), 2.02 (t,
J = 2.4 Hz, 1H). 13C NMR: d 142.1, 140.5, 136.9, 133.1, 128.3,
126.6, 125.7, 125.5, 124.7, 116.8, 78.6, 71.3, 55.9, 36.9, 31.5, 20.5.
4.4.1. (R)-(+)-4-Methyl-N-(prop-2-yn-1-yl)-N-(1-(pyridin-2-yl)
but-3-en-1-yl)benzenesulfonamide (R)-(+)-8
IR (neat): 2925, 1337, 1165, 1089, 704, 662 cmꢀ1
.
This compound was obtained as a yellow oil (47% yield).
½
a 3D1
ꢁ
¼ þ83:7 (c 1.0, CH2Cl2). 1H NMR: d 8.41 (d, J = 4.0, 1H),
4.5.3. (R)-(+)-N-Allyl-N-(1-(furan-2-yl)but-3-en-1-yl)-4-methyl-
benzenesulfonamide (R)-(+)-18
7.70–7.72 (m, 2H), 7.51 (td, J = 7.6 and 1.8 Hz, 1H), 7.16–7.21 (m,
3H), 7.09 (ddd, J = 7.4, 4.8 and 1.0 Hz, 1H), 5.45 (dddd, J = 17.1,
13.9, 10.1 and 6.9 Hz, 1H), 4.93 (dd, J = 8.7 and 6.6 Hz, 1H), 4.87
(dd, J = 17.1 and 1.6 Hz, 1H), 4.76 (dt, J = 10.1 and 0.8 Hz, 1H),
4.19 (dd, AB system, JAB = 18.5 and 2.4 Hz, 1H), 4.11(dd, AB system
JAB = 18.5 and 2.4 Hz, 1H), 2.91–2.99 (m, 1H), 2.45–2.52 (m, 1H),
2.34 (s, 3H), 1.94 (t, J = 2.4 Hz, 1H). 13C NMR: d 155.6, 146.5,
140.9, 135.6, 134.4, 132.4, 127.0, 125.6, 121.9, 120.6, 115.3, 77.7,
69.9, 59.4, 33.0, 30.7, 19.3. IR (neat): 2922, 1588, 1332, 1159,
1094, 812, 660 cmꢀ1. HRMS, Calcd [M+H]+ 341.1324, Measured
[M+H]+ 341.1319.
This compound was obtained as a yellow oil (62% yield).
½
a 3D1
ꢁ
¼ þ4:5(c 1.0, CH2Cl2). 1H NMR (CDCl3): d 7.61 (d, J = 8.2 Hz,
2H), 7.16–7.20 (m, 3H), 6.11–6.19 (m, 1H), 6.00 (d, J = 3.3 Hz,
1H), 5.60–5.72 (m, 2H), 4.88–5.07 (m, 5H), 3.70 (ddt, AB system
JAB = 1.5, 5.3 and 16.3 Hz, 1H), 3.47 (dd, AB system JAB = 7.2 and
16.3 Hz, 1H), 2.53–2.70 (m, 2H), 2.36 (s, 3H). 13C NMR: d 152.4,
142.5, 140.8, 136.0, 134.3, 131.4, 128.4, 126.7, 117.8, 115.8,
109.1, 106.8, 54.0, 46.2, 35.4, 20.5. IR (neat): 2965, 2923, 2358,
1456, 1153, 1088, 956, 810, 661 cmꢀ1
.
4.5.4. (R)-(+)-N-Allyl-4-methyl-N-(1-(thiophen-2-yl)but-3-en-1-
yl)benzenesulfonamide (R)-(+)-20
4.4.2. (R)-(+)-N-Allyl-4-methyl-N-(1-(pyridin-2-yl)but-3-yn-1-
yl)benzenesulfonamide (R)-(+)-12
This compound was obtained as a yellow oil (60% yield).
This compound was obtained as a yellow oil (53% yield).
½
a 3D1
ꢁ
¼ þ11:6 (c 1.0, CH2Cl2). 1H NMR (CDCl3):
d 7.61 (d,
½
a 2D5
ꢁ
¼ þ41:4 (c 1.0, CHCl3). 1H NMR: d 8.37 (d, J = 4.0 Hz, 1H),
J = 8.3 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.07 (dd, J = 1.1 and 5.1 Hz,
1H), 6.78–6.80 (m, 1H), 6.75 (dm, J = 3.5 Hz, 1H), 5.35–5.70 (m,
2H), 5.20 (t, J = 7.7 Hz, 1H), 4.90–5.03 (m, 4H), 3.77 (ddt, AB system
JAB = 1.5, 5.3 and 16.3 Hz, 1H,), 3.48 (dd, AB system JAB = 7.4 and
16.3 Hz, 1H), 2.57–2.74 (m, 2H), 2.34 (s, 3H). 13C NMR: d 141.9,
141.1, 137.2, 134.7, 133.2, 128.4, 126.4, 125.6, 125.4, 124.4,
116.9, 116.1, 55.6, 45.8, 37.7, 20.4. IR (neat): 2965, 2925, 1380,
7.62–7.65 (m, 2H), 7.51 (td, J = 7.6 and 1.7 Hz, 1H), 7.27 (d,
J = 7.8 Hz, 1H), 7.13–7.15 (m, 2H), 7.05–7.08 (m, 1H), 5.41–5.51
(m, 1H), 5.21 (t, J = 7.6 Hz, 1H), 4.91 (dd, J = 17.1 and 1.3 Hz, 1H),
4.79 (dd, J = 10.1 and 1.2 Hz, 1H), 3.73–3.84 (m, 2H), 3.08 (ddd,
AB system JAB = 16.7, 8.1 and 2.6 Hz, 1H), 2.59 (ddd, AB system
JAB = 16.7, 7.1 and 2.6 Hz, 1H), 2.31 (s, 3H), 1.64 (t, J = 2.6 Hz, 1H).
13C NMR: d 155.4, 146.8, 141.2, 136.5, 134.7, 133.4, 127.6, 125.9,
122.2, 121.1, 115.3, 79.2, 68.9, 58.9, 45.1, 19.7, 19.5. IR (neat):
2925, 1573, 1332, 1159, 1091, 738, 663 cmꢀ1. HRMS, Calcd
[M+H]+ 341.1324, Measured [M+H]+ 341.1318.
1157, 1123, 960, 812 cmꢀ1
.
4.6. General procedure for the intramolecular Pauson–Khand
reaction
4.5. General procedure for the Mitsunobu reaction
To a solution of enyne tethered compound (1 mmol) in DCM
(20 mL) was added Co2(CO)8 (1.7 mmol) and stirred for 30 min at
room temperature. Then, NMO (9 mmol) was added to the mixture
and stirred overnight. The reaction mixture concentrated under re-
duced pressure and purified by flash column chromatography
using ethyl acetate/hexane as eluent, in a 3:1 ratio for compounds
(+)-9 and (+)-13, or a 1:1 ratio for compounds (+)-15 and (+)-17.
AT first, PPh3 (1.4 mmol) in freshly distilled THF (3.6 mL) was
cooled to 0 °C and N-tosylated propargyl amine (0.7 mmol) was
added by stirring for 10 min. Next, the reaction was treated with
DIAD for (R)-18 and (R)-20 or DEAD for (R)-14 and (R)-16
(1.3 mmol) and stirred for 10 min. The reaction mixture was then
added dropwise to a solution of homoallyl alcohol (1 mmol). The
resultant mixture was stirred at 0 °C until the reaction was ended
by TLC monitoring. The reaction mixture was concentrated under
reduced pressure and purified by flash column chromatography
with ethyl acetate/hexane mixture in 1:6 ratio.
4.6.1. (3R,4aS)-(+)-3-(Pyridin-2-yl)-2-tosyl-3,4,4a,5-tetrahydro-
1H-cyclopenta[c]pyridin-6(2H)-one (3R,4aS)-(+)-9
This compound was obtained as a white foam. Mp: 90–92 °C
(80% yield). ½a 2D5
ꢁ
¼ þ55:40 (c 1.0, CHCl3). 1H NMR: d 8.36 (d,
J = 4.4 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.53–7.55 (m, 3H), 7.09–
7.16 (m, 3H), 5.79 (s, 1H), 5.26 (d, J = 4.4 Hz, 1H), 4.77 (d, AB system
JAB = 15.4 Hz, 1H), 3.97 (d, AB system JAB = 15.4 Hz, 1H), 2.97–3.00
(m, 1H), 2.77 (dd, AB system JAB = 12.7 and 4.5 Hz, 1H), 2.42 (dd,
AB system JAB = 18.8 and 6.4 Hz, 1H), 2.33 (s, 3H), 1.70 (dd, AB sys-
tem JAB = 18.8 and 2.2 Hz, 1H), 1.22 (dt, AB system JAB = 12.7 and
4.5.1. (R)-(+)-N-(1-(Furan-2-yl)but-3-en-1-yl)-4-methyl-N-(prop-
2-yn-1-yl)benzene sulfonamide (R)-(+)-14
This compound was obtained as a yellow oil (62% yield).
½
a 3D5
ꢁ
¼ þ10:1 (c 1.0, CHCl3). 1H NMR: d 7.69–7.71 (d, J = 8.3 Hz, 2H),
7.16–7.19 (m, 3H), 6.16–6.17 (m, 1H), 6.06 (d, J = 3.2 Hz, 1H), 5.63

668
S. Sezer et al. / Tetrahedron: Asymmetry 23 (2012) 662–669
5.4 Hz, 1H). 13C NMR: d 205.7, 172.1, 156.8, 147.7, 142.5, 136.0,
135.9, 128.5, 126.9, 126.1, 121.3, 121.2, 55.6, 42.8, 40.5, 33.9,
32.9, 20.4. IR (neat): 2921, 1710, 1631, 1590, 1348, 1161, 1092,
690, 561 cmꢀ1. HRMS, Calcd [M+H]+ 369.1273, Measured [M+H]+
369.1271.
JAB = 17.4 Hz, 1H), 2.52 (dm, J = 17.5 Hz, 1H), 2.33–2.39 (m, 1H),
2.33 (s, 3H). 13C NMR: d 151.5, 141.8, 140.4, 136.0, 128.2, 126.3,
122.2, 122.0, 109.1, 106.1, 47.0, 40.2, 27.2, 20.4. IR (neat): 2921,
2841, 2358, 1443, 1356, 1259, 1165, 804, 668 cmꢀ1. HRMS, Calcd
[M+Na]+ 326.0811, Measured [M+Na]+ 326.0818.
4.6.2. (3R)-(+)-3-(Pyridin-2-yl)-2-tosyl-3,4,7,7a-tetrahydro-1H-
cyclopenta[c]pyridin-6(2H)-one (3R)-(+)-13
4.7.2. (R)-(+)-2-Thiophen-2-yl)-1-tosyl-1,2,3,6-tetrahydropyridine
(R)-(+)-21
This compound was obtained as a viscous liquid (82% yield).
This is a viscous liquid (85% yield). ½a D31
¼ þ4:1 (c 1.0, CH2Cl2).
ꢁ
½
a 2D5
ꢁ
¼ þ124:0 (c 1.0, CHCl3). 1H NMR: d 8.36 (d, J = 4.1 Hz, 1H),
1H NMR (CDCl3): d 7.55 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H),
7.04 (dd, J = 1.2 and 5.1 Hz, 1H), 6.83 (dt, J = 1.0 and 3.5 Hz, 1H),
6.78 (dd, J = 5.1 and 3.5 Hz, 1H), 5.69–5.73 (m, 1H), 5.57 (dm,
J = 10.3 Hz, 1H), 5.49 (d, J = 6.5 Hz, 1H), 4.03 (dm, AB system
JAB = 17.3 Hz, 1H), 3.47 (dm, AB system JAB = 17.5 Hz, 1H), 2.53
(dm, J = 17.6 Hz, 1H), 2.27–2.35 (m, 4H). 13C NMR: d 141.9, 141.7,
136.2, 128.3, 126.1, 125.2, 124.8, 123.8, 122.5, 122.3, 48.6, 39.8,
28.8, 20.4. IR (neat): 2925, 2849, 2360, 1777, 1677, 1450, 1371,
7.70–7.72 (m, 2H), 7.54 (td, J = 7.7 and 1.7 Hz, 1H), 7.22–7.26 (m,
3H), 7.05 (dd, J = 7.4 and 4.9 Hz, 1H), 5.80 (s, 1H), 5.50 (d,
J = 7.0 Hz, 1H), 4.15 (dd, J = 11.7 and 4.3 Hz, 1H), 3.72 (d, AB system
JAB = 13.4 Hz, 1H), 2.62–2.74 (m, 2H), 2.54 (dd, AB system JAB = 13.4
and 7.1 Hz, 1H), 2.37 (s, 3H), 2.31 (dd, AB system JAB = 18.6 and
6.2 Hz, 1H), 1.68 (d, AB system JAB = 18.6 Hz, 1H). 13C NMR: d
206.6, 176.9, 157.4, 149.3, 143.9, 138.2, 137.0, 130.4, 130.2,
127.4, 122.6, 121.9, 57.5, 48.1, 39.7, 38.6, 32.0, 21.8. IR (neat):
2924, 1707, 1628, 1263, 1157, 1094, 947, 802, 563 cmꢀ1. HRMS,
Calcd [M+H]+ 369.1273, Measured [M+H]+ 369.1269.
1154, 717 cmꢀ1
.
HRMS, Calcd [M+Na]+ 342.0598, Measured
[M+Na]+ 342.0593.
Acknowledgment
4.6.3. (3R,4aS)-(+)-3-(Furan-2-yl)-2-tosyl-3,4,4a,5-tetrahydro-1H-
cyclopenta[c]pyridin-6(2H)-one (3R,4aS)-(+)-15
We are grateful to the Turkish Scientific and Technical Research
Council for a Grant (No. TBAG-108T072).
This compound was obtained as a white foam. Mp: 92–95 °C
(58% yield). ½a 3D2
ꢁ
¼ þ13:5 (c 1.0, CHCl3). 1H NMR: d 7.52–7.54 (m,
2H), 7.15–7.19 (m, 3H), 6.23–6.24 (m, 1H), 6.15 (d, J = 3.2 Hz,
1H), 5.86 (s, 1H), 5.31 (d, J = 4.3 Hz, 1H), 4.68 (d, AB system
JAB = 14.9 Hz, 1H), 3.87 (d, AB system JAB = 14.9 Hz, 1H), 2.90–2.93
(m, 1H), 2.48 (dd, AB system JAB = 18.7 and 6.5 Hz, 1H), 2.41
(ddd, AB system JAB = 13.0, 5.5 and 1.8 Hz, 1H), 2.34 (s, 3H), 1.82
(dd, AB system JAB = 18.7 and 2.6 Hz, 1H), 1.49 (dt, AB system
JAB = 13.0 and 5.2 Hz, 1H). 13C NMR: d 205.3, 171.13, 150.6, 142.5,
141.1, 135.6, 128.5, 127.3, 126.2, 109.5, 107.2, 49.8, 42.4, 40.3,
34.6, 34.4, 20.4. IR (neat): 2925, 1709, 1631, 1347, 1161, 1017,
1092, 699, 549 cmꢀ1. HRMS, Calcd [M+H]+ 358.1113, Measured
[M+H]+ 358.1116.
References
1. (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc., Chem.
Commun. 1971, 36; (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., Perkin Trans 1 1973, 977; (c) Pauson, P. L.; Khand, I.
U. Ann. N.Y. Acad. Sci. 1977, 295, 2.
2. (a) Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436; (b) Exon, C.;
Magnus, P. J. Am. Chem. Soc. 1983, 105, 2477; (c) Sugihara, T.; Yamada, M.;
Yamaguchi, M.; Nishizawa, M. Synlett 1999, 771; (d) Sugihara, T.; Yamada, M.;
Ban, H.; Yamaguchi, M.; Kaneko, C. Angew. Chem., Int. Ed. 1997, 36, 2801; (e)
Pérez-Serrano, L.; Casarrubios, L.; Domínguez, G.; Pérez-Castells J. Org. Lett.
1999, 1, 1187;; (f) Blanco-Urgoiti, J.; Casarrubios, L.; Domínguez, G.; Pérez-
Castells, J. Tetrahedron Lett. 2002, 43, 5763; (g) Krafft, M. E.; Boñaga, L. V. R.;
Hirosawa, C. J. Org. Chem. 2002, 67, 1233.
3. (a) Castro, J.; Sorensen, H.; Riera, A.; Moyano, A.; Pericas, M. A.; Greene, A. E. J.
Am. Chem. Soc. 1990, 112, 9388; (b) Takano, S.; Inomata, K.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1992, 169; (c) Rowley, E. G.; Schore, N. E. J. Org.
Chem. 1992, 57, 6853; (d) Hegedus, L. S. Transition Metals in the Synthesis of
Complex Organic Molecules; University Science Books, 1994. pp 243–247; (e)
Pallerla, M. K.; Fox, J. M. Org. Lett. 2007, 26, 5625; (f) Jamison, T. F.; Shambayati,
S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353; (g) Honda, T.;
Kaneda, K. J. Org. Chem. 2007, 72, 6541; (h) Min, S. J.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2007, 46, 2199; (i) Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org.
Chem. 2007, 72, 10147.
4. Reviews (a) Ingate, S. T.; Contelles, M. Org. Prep. Proced. Int. 1998, 30, 121; (b)
Geis, O.; Schmalz, H. G. Angew. Chem., Int. Ed. 1998, 37, 911; (c) Chung, Y. K.
Coord. Chem. Rev. 1999, 188, 297; (d) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc.,
Perkin Trans. 1 2000, 1657; (e) Brummond, K. M.; Kent, J. L. Tetrahedron 2000,
56, 3263; (f) Gibson, S. E.; Stevanazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800;
(g) Blanco-Urgoiti, J.; A-norbe, L.; Perez-Serrano, L.; Dominguez, G.; Perez-
Castells, J. Chem. Soc. Rev. 2004, 33, 32; (h) Bonaga, L. V. R.; Krafft, M. E.
Tetrahedron 2004, 60, 9795; (i) Laschat, S.; Becheanu, A.; Bell, T.; Baro, A. Synlett
2005, 2547; (j) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022;
(k) Park, K. H.; Chung, Y. K. Synlett 2005, 545; (l) Shibata, T. Adv. Synth. Catal.
2006, 348, 2328.
4.6.4. (3R,4aS)-(+)-3-(Thiophen-2-yl)-2-tosyl-3,4,4a,5-tetrahydro-
1H-cyclopenta[c] pyridin-6(2H)-one (3R,4aS)-(+)-17
This compound was obtained as a viscous liquid (64% yield).
½
a 3D2
ꢁ
¼ þ10:6 (c 1.0, CHCl3). 1H NMR: d 7.59–7.61 (m, 2H), 7.16–
7.20 (m, 3H), 6.89–6.90 (m, 2H), 5.82 (s, 1H), 5.47 (d, J = 4.4 Hz,
1H), 4.74 (d, AB system JAB = 15.7 Hz, 1H), 3.94 (d, AB system
JAB = 15.7 Hz, 1H), 2.96–2.99 (m, 1H), 2.38–2.48 (m, 2H), 2.35 (s,
3H), 1.78 (dd, J = 18.7 and 2.5 Hz, 1H), 1.47 (td, J = 13.2 and
5.2 Hz, 1H). 13C NMR: d 206.2, 172.0, 143.8, 141.8, 137.0, 129.7,
128.2, 127.3, 127.1, 125.6, 125.5, 52.9, 42.8, 41.3, 36.5, 34.9, 21.5.
IR (neat): 2926, 1703, 1629, 1344, 1160, 1092, 928, 732,
554 cmꢀ1. HRMS, Calcd [M+Na]+ 396.0704, Measured [M+Na]+
396.0701.
4.7. General procedure for the ring closing metathesis
5. (a) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851; (b) Magnus, P.;
Exon, C.; Albaugh-Robertson, P. Tetrahedron 1985, 41, 5861; (c) Magnus, P.;
Principe, L. M.; Slater, M. J. J. Org. Chem. 1987, 52, 1483.
6. (a) Sezer, S.; Özdemirhan, D.; Sßahin, E.; Tanyeli, C. Tetrahedron: Asymmetry
2006, 17, 2981; (b) Sezer, S.; Gümrükçü, Y.; Sßahin, E.; Tanyeli, C. Tetrahedron:
Asymmetry 2008, 19, 2705; (c) Sezer, S.; Sßahin, E.; Tanyeli, C. Tetrahedron:
Asymmetry 2010, 21, 476.
7. (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679; (b) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953; (c) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701.
8. Kam, T. S.; Yoganathan, K.; Wei, C. J. Nat. Prod. 1997, 60, 673.
9. (a) Jones, G.; Fales, H. M.; Wildman, W. C. Tetrahedron Lett. 1963, 4, 397; (b)
Dickinson, E. M.; Jones, G. Tetrahedron 1969, 25, 1523; (c) Hammouda, Y.; Amer,
M. S. J. Pharm. Sci 1966, 55, 1452; (d) Lozoya-Meckes, M.; Mellado-Campos, V. J.
Ethnopharmacol. 1985, 14, 1.
O-Allyl anchored substrate (R)-(+)-18 or (R)-(+)-20 (1.0 mmol)
was dissolved in DCM (5 mL) and Grubbs’ first generation 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 (ethyl acetate/hexane 1:4).
4.7.1. (R)-(+)-2-(Furan-2-yl)-1-tosyl-1,2,3,6-tetrahydropyridine
(R)-(+)-19
This is a viscous liquid (88% yield). ½a D31
¼ þ5:0 (c 1.0, CH2Cl2).
ꢁ
1H NMR: d 7.58 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 7.10 (d,
J = 1.3 Hz, 1H), 6.12 (dd, J = 1.9 and 3.2 Hz, 1H), 5.98 (d, J = 3.3 Hz,
1H), 5.66–5.71 (m, 1H), 5.53–5.56 (m, 1H), 5.30 (d, J = 6.6 Hz,
1H), 4.01 (dm, AB system JAB = 17.4 Hz, 1H), 3.36 (dm, AB system
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