Combined organo- and gold-catalyzed enantioselective synthesis of bicyclic enones

Article abstract of DOI:10.1016/j.tetasy.2010.05.044

By combining organocatalysis with gold catalysis highly enantioenriched bicyclic enones are available via an operationally simple one-pot procedure. Iminium-ion activation by cinchona alkaloid-derived primary amine catalysts induces the Michael addition of propargylated malononitriles and cyanoacetates to α,β-unsaturated ketones. The resulting intermediates undergo an exo-dig cyclization, forming a new C-C bond followed by double-bond isomerization to give highly functionalized bicyclic enones in good yields and high enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2010.05.044

Tetrahedron: Asymmetry 21 (2010) 1624–1629
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Combined organo- and gold-catalyzed enantioselective synthesis of bicyclic
enones
*
Theo Zweifel, Dirk Hollmann, Birgit Prüger, Martin Nielsen, Karl Anker Jørgensen
Center for Catalysis, Aarhus University, Department of Chemistry, DK-8000, Aarhus C, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
By combining organocatalysis with gold catalysis highly enantioenriched bicyclic enones are available via
an operationally simple one-pot procedure. Iminium-ion activation by cinchona alkaloid-derived primary
amine catalysts induces the Michael addition of propargylated malononitriles and cyanoacetates to a,b-
unsaturated ketones. The resulting intermediates undergo an exo-dig cyclization, forming a new C–C
bond followed by double-bond isomerization to give highly functionalized bicyclic enones in good yields
and high enantioselectivities.
Received 10 March 2010
Accepted 25 May 2010
Available online 28 June 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
works have led to the development of asymmetric versions of
these processes.9
Chemists remain intrigued by the ability of biological systems
to transform simple compounds into a myriad of complex mole-
cules. Cascade and tandem methods represent a possible way to
mimic the efficiency of Nature, minimizing the number of required
synthetic steps, and thus improving atom economy and lowering
solvent use.1 Asymmetric organocatalytic processes have become
a powerful tool in the one-pot formation of multiple bonds and ste-
reocenters without isolation of intermediates.2 For example, the
use of amine organocatalysts in iminium-ion/enamine activation
sequences allows the efficient, consecutive introduction of nucleo-
philes and electrophiles.3 To date these organocatalytic, asymmet-
ric cascade reactions often rely on only one catalyst. However, the
combination of two catalysts provides the opportunity of dual-
activation of the substrates, and thus a more general approach.4
Soft transition metals such as gold and copper are capable of
Herein, we present the reaction of a,b-unsaturated ketones 1
with alkyne-tethered nucleophiles 2 to give, via intermediates 3,
bicyclic enones 4 in a highly enantioselective tandem reaction
(Scheme 1).
O
O
EWG
EWG
+
1. Organocatalysis
2. Gold catalysis
( )m
R
R
R
R
m( )
( )n
( )n
EWG
EWG
4
1
2
n = 0,1,2
m = 1,2
Iminium-ion
activation
Isomerisation
activating p-bonds under mild conditions using low catalyst load-
O
O
ings. Numerous cascade reactions utilizing this relatively recently
developed chemistry have appeared.5 Specifically, these Lewis
acids have been shown to be good catalysts for the synthesis of
complex carbocycles.6 Moreover, the combination of transition-
metal catalysis with organocatalysis has received increasing atten-
tion and proven to be an important strategy for the development of
many unprecedented transformations.7
Au
Gold catalysis
( )m
EWG
R
R
R
( )m
( )n
( )n
R
EWG
EWG EWG
3
Scheme 1. Combination of enantioselective organo- and gold-catalysis.
Kirsch et al. were able to combine gold- and amino-catalysis in
a carbocyclization of aldehydes with alkynes.6f Recently, Dixon
et al. combined amino- and copper-catalysis in a one-pot cascade
2. Results and discussion
The formation of bicyclic enones is based on the following reac-
tion sequence: First, the iminium-ion activation of a,b-unsaturated
ketones 1 induces the Michael addition of propargylated nucleo-
philes 2. Then, the resulting intermediate 3 undergoes an exo-dig
cyclization, forming the second C–C bond followed by double-bond
isomerization to give bicyclic enones 4.
reaction of propargylated malonates with a,b-unsaturated ketones
and aldehydes forming racemic cyclopentene products.8 These
* Corresponding author. Tel.: +45 89423910; fax: +45 86196199.
E-mail address: kaj@chem.au.dk (K.A. Jørgensen).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.044

T. Zweifel et al. / Tetrahedron: Asymmetry 21 (2010) 1624–1629
1625
Initial screening with an alkyne-tethered malonate (EWG =
CO2Me) and 1,3-diketone (EWG = COMe) led to no satisfactory con-
version in the addition step.9a However, switching to the more
reactive and less sterically hindered propargylated malononitrile
2a proved to be successful and allowed us to study the Michael
addition reaction. Different organocatalysts were tested and the re-
sults are listed in Table 1.10
Non-polar solvents, such as CH2Cl2, toluene, or Et2O, were found
to be best suited for the reaction and could be used without affect-
ing the yields or enantioselectivities of the reaction. Lowering the
temperature to 4 °C increased the enantioselectivity only margin-
ally; however, the reaction rate was reduced considerably. Finally,
utilizing the quasienantiomeric combination of 5e and 6c under
the optimal conditions gave the opposite enantiomer of the prod-
uct with nearly identical results (entry 11). The absolute configura-
tion of the product 3a was assigned to be (S) by single-crystal
analysis (Fig. 1).11 The stereochemistry of the product formed indi-
cates that the nucleophile attacks from the Si-face of the iminium-
ion intermediate.
Table 1
Screening of organocatalysts for the Michael addition of propargylated malononitrile
2a to cyclohexenone 1a
O
O
NC
CN
5 6
,
+
NC CN
1a
2a
3a
H
N
Ph
Ph
N
N
N
N
N
N
CO2H
CO2H
N
H
N
H
N
H
Bn
Bn
H
5a
5b
5c
N
N
H2N
H2N
Figure 1. Ortep plot at 30% ellipsoid probability of 3a.
MeO
OH
MeO
Having found the optimal conditions for the first step of the cas-
cade reaction, the second step was investigated. Several transition
metals such as Cu, Ag, Au, Pt, and Pd are known to activate alkynes
toward nucleophilic attack.5,6 A variety of transition metal salts and
additives were tested in the 5-exo-dig cyclization reaction of 3a to
4a and some representative results are presented in Table 2. It
was found that gold complexes showed promising reactivities (en-
tries 4–11), and thus the Lewis-acid catalyst [bis(trifluoromethane-
sulfonyl)imidate](PPh3)Au(I) (2:1) toluene adduct (Au(NTf2)PPh3)
N
N
5e
5d
OH
OH
OH
CO2H
CO2H
OH
6b
Acidc
CO2H
CO2H
HO2C
HO2C
OH
6a
6c
6d
eee (%)
Entry
Organocatalyst
Solvent
Yield 3ad (%)
1
2
3
4
5
6
7
8
9
5aa
5ba
5ca
5da
5da
5da
5da
5da
5da
5db
5eb
—
—
—
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
0
58
65
84
91
86
68
80
—
Table 2
20
33
66
76
0
53
6
88
92
92
Screening of different Lewis-acid catalysts for the cyclization
TFAc
TFAc
—
O
O
Metal
catalyst
6ac
6bc
6cc
6dc
6cc
CN
NC CN
NC
97
90
10
11
3a
4a
(92% ee)
Et2O
95 (ent-3a)
Entry Metal catalyst
Additive
Yieldd
(%)
eee
(%)
Conditions: 0.3 mmol 1a and 0.2 mmol 2a, rt, 18 h.
a
20 mol %.
5 mol %.
Two equivalents relative to catalyst.
Isolated yield.
a
1
2
3
4
Pd(OAc)2
Pd(PPh3)4
—
—
—
—
—
—
—
89
(100)
—
85
(100)
—
—
—
—
90
b
a
c
Cu(MeCN)4OTfa
Au(NTf2)(PPh3)a
d
e
Determined by chiral HPLC.
5
6
Au(NTf2)(PPh3)b
Au(NTf2)(PPh3)b
PPh3
—
0
1 equiv Pyrrolidine
Table 1 shows that cinchona alkaloid-derived primary amine
catalysts 5d,e gave the best results, both in terms of yield and
the enantioselectivity of 3a. Furthermore, the acid additive has a
very important influence on the enantioselectivity of the reaction.
Protonation of the imine by the acid additive gives an iminium-ion,
which is tightly ion-paired with the respective anion, responsible
for the observed effect. Ion-pairing in iminium-ions has been pro-
posed by previous calculations.10p If catalyst 5d is used without
additive the reaction still proceeds with good yield, but only race-
mic adduct 3a is formed (entry 6). The best results, up to 92% ee,
were obtained with mandelic acid 6c/d (entries 9 and 10). The
reaction proceeded efficiently at a catalyst loading of 5 mol % (en-
tries 10 and, 11). Lower catalyst loadings (2.5 mol % and 1 mol %)
gave also good results, but required prolonged reaction times.
7
8
9
Au(NTf2)(PPh3)b
Au(NTf2)(PPh3)b
Au(NTf2)(PPh3)b
5 mol % 5d
—
5 mol % 5d, 10 mol % 6d
5 mol % 5d, 10 mol % 6d
10 mol % pTSA
5 mol % 5d, 10 mol % 6d
20 mol % pTSA
22 (35) 89
45 (74) 91
10
11
Au(NTf2)(PPh3)b
56
(100)
70
91
91
Au(NTf2)(PPh3)b,c 5 mol % 5d, 10 mol % 6d
20 mol % pTSA
(100)
Conditions: 0.1 mmol 3a, 0.4 mL CH2Cl2, 45 °C.
a
20 mol %.
5 mol %.
b
c
0.4 mL Et2O was used instead of CH2Cl2.
Isolated yield, conversion given in parenthesis.
Determined by HPLC on a chiral stationary phase.
d
e

1626
T. Zweifel et al. / Tetrahedron: Asymmetry 21 (2010) 1624–1629
was chosen for this work. Application of this complex allowed us to
perform the cyclization reaction with full retention of the stereo-
center, which was obtained in the first step. Pyrrolidine was also
found to accelerate the reaction as observed in previous work8
but led to racemization of the product obtained (entry 6). In con-
trast to this, it was found that organocatalysts 5d/e impede the
reaction (entries 7 and 8). By 31P NMR spectroscopy, coordination
of the organocatalyst to the gold cation was observed. To overcome
this problem 20 mol % para-toluenesulfonic acid (pTSA) was added
to block the organocatalyst and keep the gold catalyst sufficiently
active (entries 9–11). Diethylether was found to be a good solvent
for the carbocyclization reaction and 70% yield from isolated inter-
mediate 3a was obtained in the presence of the organocatalyst 5d
(entry 11). With this information in hand, a two-step protocol for
the cascade reaction was elaborated. First, organocatalyst 5d/6d
or 5e/6c activates enone 1a for the attack of nucleophile 2a to give
3a or ent-3a, respectively. After full conversion, pTSA and gold salt
were added and the mixture was heated to 45 °C to cause the car-
bocyclization to give 4a or ent-4a, respectively, in a one-pot reac-
tion. Lowering the amount of cyclohexenone 1a from 2 equiv to
1.5 equiv was important in order to minimize side product forma-
tion and thus increase the yield of 4a to 70% in one-pot (see
Scheme 2).
Furthermore, we investigated the scope of the cascade reaction
for different cycloalkenones 1 with propargylated malononitriles
2a,d and cyanoacetates 2b,c (Scheme 2). For cyclohexenone 1a
reacting with propargylated malononitrile 2a, bicyclic enone 4a
was obtained in 70% yield and 91% ee. Compound 1a reacted with
the propargylated cyanoacetates 2b,c to give optically active prod-
ucts 4b and 4c as a 2:1 diastereomeric mixture with high enanti-
oselectivity (up to 97% ee). The addition of homo-propargylated
malononitrile 2d proceeded smoothly. However, to effect the
6-exo-dig cyclization, intermediate 3d had to be isolated and re-
acted separately in order to obtain an acceptable yield of 4d
(42%) with 91% ee. 5,5-Dimethyl cyclohexenone 1e reacted cleanly
with the chosen reaction conditions giving 4e in a moderate yield
(59%) and with 89% ee. The 5-ethyl substituted cyclohexenones 1f
and 1g were prepared in enantioenriched form (90% ee) with a
known absolute configuration.12 As anticipated, a matched/mis-
matched situation was found. Whereas 1f gave a 1:5 diastereose-
lectivity in the addition to 2a with catalyst 5d/6d, 1g gave a 1:1
mixture of diastereoisomers. Using the pseudo-enantiomeric cata-
lyst 5e/6c with 1g and 2a, comparable results were obtained (dr
5:1). The relative configurations 4f/g were assigned assuming re-
agent control by the organocatalyst.
Isolated compound 3h from cyclopentenone 1h was success-
fully cyclized using a combination of Au(IPr)Cl/AgOTf (IPr = N,N0-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as the catalyst.13
Unfortunately, the cyclization of addition product 3i, derived from
cycloheptenone 1i and 2a, was not observed under all conditions
tested.
5d/6d
or
O
O
O
EWG
EWG
5e/6c
[Au]
+
( )m
R
R
R
R
R
( )m
m( )
( )n
( )n
( )n
EWG
R
EWG
EWG EWG
Additionally, we were able to reduce product 4a with NaBH4 in
CH2Cl2/MeOH (Scheme 3). Alcohol 7 was obtained in a highly dia-
stereoselective manner (dr >99:1) and with an excellent yield
(92%). The relative stereochemistry of 7 (4R,7aR) was assigned by
an NOE experiment and is in agreement with the stereochemical
expectation.
3
4
1
2
n = 0,1,2
m = 1,2
O
O
O
NC
R
2a
R = CN
Et
2b R = CO2Me
R =CO2iPr
2c
1a
1e
1f
O
OH
O
NC CN
O
NaBH4,
O
CH2Cl2/MeOH (4:1)
0 °C
CN
CN
NC
NC
Et
O
1g
1h
1i
2d
4a
7
92%
dr >99:1
O
O
Scheme 3. Reduction of 4a with NaBH4.
CN
NC
O
NC
O
NC
4a
3. Conclusion
O
O
4b
4c
We have shown a tandem reaction sequence, combining the
iminium-ion activation of cyclic ,b-unsaturated ketones with
gold-catalyzed carbocyclization of the generated addition prod-
ucts. Highly enantioenriched bicyclic enones 4 have been formed.
Despite limitations in the scope, the reaction can be useful in the
construction of highly functionalized, versatile molecules.
70% (91% ee)a
67% (dr 2:1 dr, 96/97% ee) 88% (dr 2:1, 95:97% ee)
a
O
O
O
Et
CN
CN
NC
4e
NC
4f
NC CN
4d
42% (91ee)b
59% (89% ee)
68% (dr 5:1, 95:76% ee)
4. Experimental
O
O
O
4.1. General methods
The NMR spectra were acquired on a Varian AS 400 spectrome-
ter, running at 400 MHz and 100 MHz for 1H and 13C, respectively.
Chemical shifts (d) are reported in ppm relative to CDCl3 1H NMR:
7.26 ppm; 13C NMR (77.0 ppm). The following abbreviations are
used to indicate the multiplicity in 1H NMR spectra: s, singlet; d,
doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s,
broad signal. Mass spectra were recorded on a micromass LCT
Et
CN
NC
CN
CN
NC
NC
4g
65% (dr 5:1, 93:78% ee)c
4h
3i
81% (23% ee)d
95% (95% ee)
a
b
Scheme 2. Scope and limitations of the cascade reaction. Both 4a and ent-4a,
two-pot procedure, 5e/6c was used as organocatalyst,
Au(Cl)(IPr)/AgOTf was used as metal catalyst.
c
d
two-pot procedure;

T. Zweifel et al. / Tetrahedron: Asymmetry 21 (2010) 1624–1629
1627
spectrometer using electrospray ionization (ESI) techniques. Opti-
cal rotations were measured on a Perkin–Elmer 241 polarimeter.
The enantiomeric excess (ee) of the products was determined by
chiral stationary-phase HPLC (Daicel Chiralpak AD column) or GC
(Agilent Cyclosil B). Analytical grade solvents and commercially
available reagents, including gold catalysts [bis(trifluoromethane-
sulfonyl)imidate](PPh3)Au(I) (2:1) toluene adduct and chloro[1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene]Au(I), were pur-
chased from Aldrich and used without further purification. Nucle-
ophiles 2a–d14a and ketones 1e–g12,14b were synthesized according
to the literature procedures.
(m, 1H), 2.74 (dd, J = 16.5, 2.6 Hz, 1H), 2.80 (dd, J = 16.5, 2.6 Hz,
1H), 3.89 (s, 3H); 13C NMR (CDCl3): d = 24.0, 25.3, 27.5, 40.7, 43.0
(CH3, OMe), 42.5, 53.8 (CH), 53.9 (Cq), 73.6 (CH, alkyne), 76.1 (Cq,
alkyne), 116.5 (Cq, CN), 167.3 (Cq, COO), 207.6 (Cq, C@O); minor
diastereoisomer: 1H NMR (CDCl3): d = 1.60–1.75 (m, 2H), 1.78–
1.83 (m, 1H), 2.11–2.17 (m, 1H), 2.23 (t, J = 2.7 Hz, 1H), 2.27–2.41
(m, 3H), 2.42–2.48 (m, 2H), 2.53–2.58 (m, 1H), 2.79 (dd, J = 16.7,
2.7 Hz, 1H), 2.86 (dd, J = 16.7, 2.7 Hz, 1H), 3.85 (s, 3H); 13C NMR
(CDCl3): d = 23.9, 25.5, 26.2, 40.5, 43.2 (CH3, OMe), 43.5, 53.9
(CH), 53.9 (Cq), 73.6 (CH, alkyne), 76.2 (Cq, alkyne), 116.7 (Cq,
CN), 167.1 (Cq, COO), 207.5 (Cq, C@O); HRMS: calcd for
C13H15NNaO3 [M+Na]: 256.0950; found: 256.0948.
4.2. General procedures
4.2.3.4. (S)-Methyl-1-cyano-3-methyl-4-oxo-2,4,5,6,7,7a-hexa-
hydro-1H-indene-1-carboxylate 4b. Colorless oil; Rf = 0.49 and
4.2.1. Addition
Nucleophile 2 (0.2 mmol) and the salt of 5d and 2 equiv 6d
(3.1 mg, 5 mol %) were dissolved in Et2O (0.8 mL). Ketone 1
(0.3 mmol) was added and the resulting mixture stirred at room
temperature for 16 h. Adduct 3 was isolated by FC with a gradient
of 10–30% Et2O in pentane.
0.48 (major/minor diastereoisomer, Et2O/pentane 2:1);
½ ꢁ
a 2D5
¼ þ7:7 (c 0.5, CH2Cl2), 96% ee major diastereoisomer, 97% ee minor
diastereoisomer, dr = 1:2; HPLC: tR = 25.3/34.6 and 27.8/36.0 min.
(major/minor diastereoisomer, AD, 97:3 hexane/isopropanol, flow:
1 mL/min); major diastereoisomer: 1H NMR (CDCl3): d = 1.20–1.27
(m, 1H), 1.70–1.89 (m, 2H), 2.09–2.17 (m, 2H), 2.14 (s, 3H), 2.18–
2.33 (m, 1H), 2.45–2.53 (m, 1H), 2.88–2.92 (m, 1H), 3.24–3.29 (m,
1H), 3.35–3.40 (m, 1H), 3.87 (s, 3H); 13C NMR (CDCl3): d = 14.9,
21.7, 26.5, 29.3 (Cq), 39.5, 46.7, 52.3, 52.9, 117.2 (Cq, CN), 130.1 (Cq,
C@C), 147.7 (Cq, C@C), 167.5 (Cq, COO), 197.0 (Cq, C@O); minor dia-
stereoisomer: 1H NMR (CDCl3): d = 1.20–1.27 (m, 1H), 1.70–1.89 (m,
2H), 2.09–2.17(m, 2H), 2.14 (s, 3H), 2.18–2.33 (m, 1H), 2.45–2.53(m,
1H), 3.02–3.14 (m, 2H), 3.61–3.66 (m, 1H), 3.83 (s, 3H); 13C NMR
(CDCl3): d = 14.6, 21.8, 25.9, 28.7 (Cq), 39.3, 46.3, 52.0, 56.0, 119.0
(Cq, CN), 129.5 (Cq, C@C), 149.1 (Cq, C@C), 166.7 (Cq, COO), 196.8
(Cq, C@O); HRMS: calcd for C13H15NNaO3 [M+Na]: 256.0950; found:
256.0948.
4.2.2. Carbocyclization
Adduct
3
(0.2 mmol), pTSAꢀH2O (3.8 mg, 20 mol %), and
Au(NTf2)(PPh3)(C7H8)0.5 (4 mg, 5 mol %) were dissolved in Et2O
(0.8 mL). The mixture was warmed to 45 °C for 16 h in a tightly
closed screw-capped vial and the cyclopentene product 4 was iso-
lated by FC with a gradient of 10–30% Et2O in pentane.
4.2.3. Combination
Nucleophile 2 (0.2 mmol) and the pre-formed salt of 5d and
2 equiv 6d (3.1 mg, 5 mol %) were dissolved in Et2O (0.8 mL). Ke-
tone 1 (0.3 mmol) was added and the resulting mixture was stirred
at room temperature for 16 h. pTSAꢀH2O (3.8 mg, 20 mol %) and
[Au(NTf2)(PPh3)] (C7H8)0.5 (4 mg, 5 mol %) were added and the
mixture was warmed to 45 °C for 16 h. Product 4 was isolated by
FC with a gradient of 10–30% Et2O in pentane.
4.2.3.5. (S)-Isopropyl 2-cyano-2-(3-oxocyclohexyl)pent-4-yno-
ate 3c. Colorless oil; Rf = 0.34 and 0.32 (major/minor diastereoiso-
mer, Et2O/pentane 2:1); dr = 1:2; major diastereoisomer: 1H NMR
(CDCl3): d = 1.34 (d, J = 6.3 Hz, 3H), 1.35 (d, J = 1.3 Hz, 3H), 1.60–
1.76 (m, 2H), 1.80–1.85 (m, 1H), 2.12–2.17 (m, 1H), 2.20 (t,
J = 2.7 Hz, 1H), 2.27–2.39 (m, 3H), 2.41–2.48 (m, 1H), 2.53–2.56
(m, 1H), 2.72 (dd, J = 16.7, 2.7 Hz, 1H), 2.78 (dd, J = 16.7, 2.7 Hz,
1H), 5.17 (sept, J = 6.3 Hz, 1H); 13C NMR (CDCl3): d = 21.8 (CH3),
24.3, 25.5, 27.6, 41.0, 42.8, 43.3 (CH, OCH), 54.1 (Cq), 72.0 (CH),
73.8 (CH, alkyne), 76.5 (Cq, alkyne), 116.9 (Cq, CN), 166.3 (Cq,
COO), 208.0 (Cq, C@O); minor diastereoisomer: 1H NMR (CDCl3):
d = 1.34 (d, J = 6.3 Hz, 3H), 1.35 (d, J = 1.3 Hz, 3H), 1.60–1.76 (m,
2H), 1.80–1.85 (m, 1H), 2.12–2.17 (m, 1H), 2.20 (t, J = 2.7 Hz, 1H),
2.27–2.39 (m, 3H), 2.41–2.48 (m, 1H), 2.53–2.56 (m, 1H), 2.76
(dd, J = 16.5, 2.6 Hz, 1H), 2.85 (dd, J = 16.5, 2.6 Hz, 1H), 5.17 (sept,
J = 6.3 Hz, 1H); 13C NMR (CDCl3): d = 21.8 (CH3), 24.2, 25.8, 26.4,
40.8, 43.4 (CH, OCH), 43.8, 53.9 (Cq), 72.1 (CH), 73.7 (CH, alkyne),
76.6 (Cq, alkyne), 117.1 (Cq, CN), 166.5 (Cq, COO), 207.9 (Cq,
C@O); HRMS: calcd for C15H19NNaO3 [M+Na]: 284.1263; found:
284.1263.
4.2.3.1. (S)-2-(3-Oxocyclohexyl)-2-(prop-2-ynyl)malononitrile
3a. Colorless solid; mp: 78 °C; Rf = 0.26 (Et2O/pentane = 2:1);
½
a 2D5
ꢁ
¼ ꢂ17:1 (c 1, CH2Cl2); 92% ee; GC: tR = 48.5 and 48.8 min
(1 min at 70 °C heated to 160 °C at 10 °C/min, hold 30 min, then
heated to 180 °C at 10 °C/min., hold 10 min.; flow: 1 mL/min); 1H
NMR (CDCl3): d = 1.67–1.80 (m, 2H), 2.24–2.40 (m, 4H), 2.47–
2.57 (m, 2H), 2.65–2.71 (m, 1H), 2.92 (dd, J = 17.0, 2.7 Hz, 1H),
3.00 (dd, J = 17.0, 2.7 Hz, 1H); 13C NMR (CDCl3): d = 23.8, 26.4,
27.1, 40.6, 41.7 (Cq), 42.7, 42.7, 73.9 (Cq, alkyne), 76.1 (CH, alkyne),
113.3 (Cq, CN), 113.7 (Cq, CN), 206.4 (Cq, C@O); HRMS: calcd for
C12H12N2NaO [M+Na]: 223.0847; found: 223.0842.
4.2.3.2. (R)-3-Methyl-4-oxo-5,6,7,7a-tetrahydro-1H-indene-1,1
(2H,4H)-dicarbonitrile 4a. Colorless oil; Rf = 0.34 (Et2O/pentane
2:1), ½a 2D5
ꢁ
¼ ꢂ7:6 (c 0.44, CH2Cl2), 90% ee; ent-4a: ½a D25
¼ þ7:2 (c
ꢁ
0.56, CH2Cl2), 90% ee; HPLC: tR = 13.1 min, 16.8 min (AD, 90:10
hexane/isopropanol, flow: 1 mL/min); 1H NMR (CDCl3): d = 1.74–
1.91 (m, 2H), 2.18 (s, 3H), 2.19–2.22 (m, 1H), 2.27–2.36 (m, 2H),
2.52–2.59 (m, 1H), 3.01–3.14 (m, 1H), 3.21–3.26 (m, 1H), 3.46–
3.50 (m, 1H); 13C NMR (CDCl3): d = 15.9, 22.2, 26.9, 38.3 (Cq),
40.4, 48.7, 54.9, 114.4 (Cq, CN), 115.0 (Cq, CN), 130.9 (Cq, C@C),
148.4 (Cq, C@C), 196.9 (Cq, C@O); HRMS: calcd for C12H12N2NaO
[M+Na]: 223.0847; found: 223.0842.
4.2.3.6. (S)-Isopropyl 1-cyano-3-methyl-4-oxo-2,4,5,6,7,7a-hexa-
hydro-1H-indene-1-carboxylate 4c. Colorless oil; Rf = 0.64 and
0.59 (major/minor diastereoisomer, Et2O/pentane 2:1);
½ ꢁ
a 2D5
¼ þ14:0 (c 0.5, CH2Cl2), 95% ee major diastereoisomer, 97% ee min-
or diastereoisomer, dr = 1:2; HPLC: tR = 13.9/17.0 and 23.2/
25.7 min (major/minor diastereoisomer, AD, 97:3 hexane/isopro-
panol, flow: 1 mL/min). major diastereoisomer: 1H NMR (CDCl3):
d = 1.32 (d, J = 6.2 Hz, 3H), 1.33 (d, J = 6.2 Hz, 3H), 1.72–1.90 (m,
2H), 2.08–2.14 (m, 2H), 2.14 (s, 3H), 2.24–2.34 (m, 1H), 2.47–
2.53 (m, 1H), 2.86–2.91 (m, 1H), 3.23–3.28 (m, 1H), 3.32–3.38
(m, 1H), 5.11 (sept, J = 6.2 Hz, 1H); 13C NMR (CDCl3): d = 15.9
(CH3), 21.5 (CH3), 21.6 (CH3), 22.7, 27.5, 40.5, 47.5, 53.2 (CH),
4.2.3.3. (S)-Methyl 2-cyano-2-(3-oxocyclohexyl)pent-4-ynoate
3b. Colorless oil; Rf = 0.29 (both diastereoisomers, Et2O/pentane
2:1); dr = 1:2; major diastereoisomer: 1H NMR (CDCl3): d = 1.60–
1.75 (m, 2H), 1.78–1.83 (m, 1H), 2.11–2.17 (m, 1H), 2.22 (t,
J = 2.6 Hz, 1H), 2.27–2.41 (m, 3H), 2.42–2.48 (m, 2H), 2.53–2.58

1628
T. Zweifel et al. / Tetrahedron: Asymmetry 21 (2010) 1624–1629
53.4 (Cq), 71.3 (Cq), 118.4 (Cq, CN), 131.1 (Cq, C@C), 148.8 (Cq, C@C),
167.3 (Cq, COO), 198.1 (Cq, C@O); minor diastereoisomer: 1H NMR
(CDCl3): d = 1.29–1.36 (m, 1H), 1.33 (d, J = 6.2 Hz, 6H), 1.66–1.79
(m, 1H), 2.09–2.25 (m, 3H), 2.13 (s, 3H), 2.45–2.51 (m, 1H), 3.01–
3.14 (m, 2H), 3.60–3.66 (m, 1H), 5.09 (sept, J = 6.2 Hz, 1H); 13C
NMR (CDCl3): d = 15.9 (CH3), 21.9 (CH3), 22.0 (CH3), 23.2, 27.0,
40.6, 47.7, 48.7, 57.2 (CH), 71.6 (Cq), 120.4 (Cq, CN), 130.9 (Cq,
C@C), 150.5 (Cq, C@C), 166.8 (Cq, COO), 198.2 (Cq, C@O); HRMS:
calcd for C15H19NNaO3 [M+Na]: 284.1263; found: 284.1262.
26.5, 29.6, 29.9, 33.5, 38.0 41.8, 42.2, 46.8, 73.9 (Cq, alkyne), 76.2
(CH, alkyne), 113.3 (Cq, CN), 113.8 (Cq, CN), 206.4 (Cq, C@O); HRMS:
calcd for C14H16N2NaO [M+Na] calcd: 251.1160; found: 251.1158.
4.2.3.12. (6R,7aR)-6-Ethyl-3-methyl-4-oxo-2,4,5,6,7,7a-hexahy-
dro-1H-indene-1,1-dicarbonitrile 4f and (6S,7aS)-6-ethyl-3-
methyl-4-oxo-2,4,5,6,7,7a-hexahydro-1H-indene-1,1-dicarboni-
trile 4g. The addition was performed at 45 °C. Colorless oil;
Rf = 0.41 (Et2O/pentane 2:1), 4f: ½a D25
¼ þ5:1 (c 0.55, CH2Cl2), 94%
ꢁ
ee major diastereoisomer, 76% ee minor diastereoisomer,
4.2.3.7. (S)-2-(But-3-ynyl)-2-(3-oxocyclohexyl)malononitrile
3d. Colorless oil; Rf = 0.22 (Et2O/pentane 2:1); 1H NMR (CDCl3):
d = 1.55–1.75 (m, 2H), 2.06 (t, J = 2.6 Hz, 1H), 2.10–2.35 (m, 7H),
2.37–2.47 (m, 1H), 2.55 (td, J = 7.88, 2.57 Hz, 2H), 2.62–2.68 (m,
1H); 13C NMR (CDCl3): d = 15.8, 23.8, 27.4, 33.9, 40.7, 42.3 (Cq),
43.1, 44.1, 71.5 (CH, alkyne), 80.0 (Cq, alkyne), 113.6 (Cq, CN),
114.0 (Cq, CN), 206.5 (Cq, C@O); HRMS: calcd for C13H14N2NaO
[M+Na]: 237.1004; found: 237.1007.
dr = 1:5; 4g: ½a 2D5
¼ ꢂ4:1 (c 0.32, CH2Cl2), 93% ee major diastereo-
ꢁ
isomer, 77% ee minor diastereoisomer, dr = 1:5; HPLC: tR = 15.2/
23.3 and 14.5/17.7 min (major/minor diastereoisomer, AD, 97:3
hexane/isopropanol, flow: 1 mL/min); major diastereoisomer: 1H
NMR (CDCl3): d = 0.92 (t, J = 7.3 Hz, 3H), 1.50 (q, J = 12.5 Hz, 2H),
1.72–1.82 (m, 1H), 1.92 (d, J = 12.8 Hz, 1H), 1.97 (d, J = 12.5 Hz,
1H), 2.11 (br s, 3H), 2.21–2.29 (m, 1H), 2.54 (ddd, J = 17.3, 3.9,
2.2 Hz, 1H), 3.07 (d, J = 17.6 Hz, 1H), 3.19 (d, J = 17.6 Hz, 1H),
3.38–3.47 (m, 1H); 13C NMR (CDCl3): d = 11.4 (CH3), 29.2, 29.9
(CH3), 33.1, 36.7, 38.6 (Cq), 47.2, 49.2, 54.8, 114.7 (Cq, CN), 115.3
(Cq, CN), 130.9 (Cq, C@C), 148.4 (Cq, C@C), 196.9 (Cq, C@O); HRMS:
calcd for C14H16N2NaO [M+Na] calcd: 251.1160; found: 251.1156.
4.2.3.8. (R)-4-Methyl-5-oxo-2,3,6,7,8,8a-hexahydronaphthalene
-1,1(5H)-dicarbonitrile 4d. From 3d. Colorless oil; Rf = 0.23 (Et2O/
pentane 2:1); ½a D25
¼ ꢂ29:0 (c 0.5, CH2Cl2), 91% ee; HPLC: tR = 11.6
ꢁ
and 13.4 min (AD, 90:10 hexane/isopropanol, flow: 1 mL/min); 1H
NMR (CDCl3): d = 1.70–1.76 (m, 1H), 1.80 (dd, J = 12.1, 2.6 Hz, 1H),
1.86 (dd, J = 12.1, 3.0 Hz, 1H), 1.92 (d, J = 1.83 Hz, 3H), 2.09 (dd,
J = 11.9, 5.3 Hz, 1H), 2.10–2.16 (m, 1H), 2.27–2.57 (m, 5H), 2.79–
2.86 (m, 1H); 13C NMR (CDCl3): d = 22.2 (CH3), 22.3, 28.7, 29.9,
30.6, 37.3 (Cq), 42.2, 45.6, 113.7 (Cq, CN), 116.1 (Cq, CN), 128.7
(Cq, C@C), 145.1 (Cq, C@C), 200.5 (Cq, C@O); HRMS: calcd for
4.2.3.13. ((S)-2-(3-Oxocyclopentyl)-2-(prop-2-ynyl)malononitri-
le 3h. Colorless solid; mp: 95 °C; Rf = 0.20 (Et2O/pentane 2:1); 1H
NMR (CDCl3): d = 1.98 (qd, J = 11.7, 8.7 Hz, 1H), 2.22–2.39 (m,
2H), 2.43 (t, J = 2.7 Hz, 1H), 2.42–2.50 (m, 1H), 2.53–2.64 (m, 2H),
2.91–3.04 (m, 1H), 2.94 (dd, J = 16.9, 2.7 Hz, 1H), 3.01 (dd,
J = 16.9, 2.7 Hz, 1H); 13C NMR (CDCl3): d = 25.6, 27.3, 38.0, 40.3,
40.7 (Cq), 41.9, 73.8 (Cq, alkyne), 75.8 (CH, alkyne), 113.1 (Cq,
CN), 113.2 (Cq, CN), 212.1 (Cq, C@O); HRMS: calcd for C11H10N2NaO
[M+Na]: 209.0691; found: 209.0689.
C13H14N2NaO [M+Na] calcd: 237.1004; found: 237.1004.
4.2.3.9. (S)-2-(3,3-Dimethyl-5-oxocyclohexyl)-2-(prop-2-ynyl)
malononitrile 3e. The addition was performed at 45 °C. Colorless
solid; mp: 85 °C; Rf = 0.43 (Et2O/pentane 2:1), 1H NMR (CDCl3):
d = 0.94 (s, 3H), 1.18 (s, 3H), 1.71 (t, J = 12.8 Hz, 1H), 1.88–1.94
(m, 1H), 2.21 (dt, J = 13.0, 1.8 Hz, 1H), 2.27 (t, J = 13.9 Hz, 2H),
2.41 (t, J = 2.8 Hz, 1H), 2.61–2.74 (m, 2H), 2.94 (dd, J = 17.1,
2.8 Hz, 1H), 3.01 (dd, J = 17.0, 2.8 Hz, 1H); 13C NMR (CDCl3):
d = 25.7 (CH3), 26.5 (CH3), 31.9, 34.5 (Cq), 39.3, 40.1, 41.7, (Cq),
41.8, 53.9, 73.8 (Cq, alkenyl), 76.1 (CH, alkenyl), 113.4 (Cq, CN),
113.6 (Cq, CN), 206.5 (Cq, C@O); HRMS: calcd for C14H16N2NaO
[M+Na]: 251.1160; found: 251.1165.
4.2.3.14. (R)-3-Methyl-4-oxo-4,5,6,6a-tetrahydropentalene-1,1
(2H)-dicarbonitrile 4h. Cyclization was done using isolated 3h
with [Au(Cl)(IPr)] (5 mol %) and AgOTf (10 mol %). Colorless oil;
Rf = 0.25 (Et2O/pentane 2:1); ½a D25
¼ ꢂ11:3 (c 0.5, CH2Cl2), 23% ee;
ꢁ
HPLC: tR = 15.0 min, 16.7 min (AD, 90:10 hexane/isopropanol, flow:
1 mL/min); 1H NMR (CDCl3): d = 2.00–2.11 (m, 1H), 2.06 (s, 3H),
2.34–2.41 (m, 1H), 2.55–2.72 (m, 2H), 3.32–3.36 (m, 1H), 3.58–
3.64 (m, 1H), 3.86–3.92 (m, 1H); 13C NMR (CDCl3): d = 14.9, 25.0,
29.9 (Cq), 44.1, 54.9, 56.9, 114.3 (Cq, CN), 115.1 (Cq, CN), 136.8
(Cq, C@C), 144.7 (Cq, C@C), 198.6 (Cq, C@O); HRMS: calcd for
4.2.3.10. (R)-3,6,6-Trimethyl-4-oxo-5,6,7,7a-tetrahydro-1H-ind-
ene-1,1(2H,4H)-dicarbonitrile 4e. The addition was performed at
C11H10N2NaO [M+Na]: 209.0691; found: 209.0690.
45 °C. Colorless oil; Rf = 0.44 (Et2O/pentane 2:1); ½a D25
ꢁ
¼ ꢂ11:0 (c
4.2.3.15. (S)-2-(3-Oxocycloheptyl)-2-(prop-2-ynyl)malononitrile
3i. Colorless oil; Rf = 0.32 (Et2O/pentane 2:1); 1H NMR (CDCl3):
d = 1.43–1.72 (m, 3H), 1.98–2.06 (m, 1H), 2.11–2.18 (m, 1H),
2.22–2.26 (m, 1H), 2.42 (t, J = 2.7 Hz, 1H), 2.43–2.55 (m, 2H),
2.58–2.64 (m, 1H), 2.68–2.72 (m, 2H), 2.96 (dd, J = 17.1, 2.7 Hz,
1H), 3.02 (dd, J = 17.1, 2.7 Hz, 1H); 13C NMR (CDCl3): d = 23.8,
26.4, 27.7, 32.3, 40.9, 41.9 (Cq), 43.4, 44.6, 73.8 (Cq, alkyne), 75.8
(CH, alkyne), 113.4 (Cq, CN), 113.7 (Cq, CN), 208.9 (Cq, C@O); HRMS:
calcd for C13H14N2NaO [M+Na]: 237.1004; found: 237.1005.
0.39, CH2Cl2), 89% ee; HPLC: tR = 6.6 and 8.5 min (AD, 90:10 hex-
ane/isopropanol, flow: 1 mL/min); 1H NMR (CDCl3): d = 0.95 (s,
3H), 1.10 (s, 3H), 1.78 (t, J = 12.7 Hz, 1H), 1.96 (ddd, J = 12.7, 5.6,
2.2 Hz, 1H), 2.08–2.11 (m, 3H), 2.15 (d, J = 16.5 Hz, 1H), 2.25 (dd,
J = 16.5, 2.2 Hz, 1H), 3.08 (d, J = 17.2 Hz, 1H), 3.15–3.23 (m, 1H),
3.48–3.57 (m, 1H); 13C NMR (CDCl3): d = 26.1 (CH3), 29.9, 31.5
(CH3), 33.9, 39.1 (Cq), 39.6 (CH3), 49.2, 52.3 (Cq), 54.5, 114.7 (Cq,
CN), 115.2 (Cq, CN), 130.3 (Cq, C@C), 148.3 (Cq, C@C), 197.1 (Cq,
C@O); HRMS: calcd for C14H17N2O [M+H+]: 229.1341; found:
229.1342.
4.2.3.16. (4R,7aR)-4-Hydroxy-3-methyl-5,6,7,7a-tetrahydro-1H-
indene-1,1(2H,4H)-dicarbonitrile 7. To a solution of 4a (80 mg,
0.4 mmol) in CH2Cl2/MeOH (4:1; 1 mL) NaBH4 (45 mg, 1.2 mmol)
was added at 0 °C and the mixture was stirred for 40 min. Usual
workup and FC (CH2Cl2) provided 7 in 92% yield as a colorless oil
4.2.3.11. 2-((1S,3R)-3-Ethyl-5-oxocyclohexyl)-2-(prop-2-ynyl)-
malononitrile 3f and 2-((1S,3S)-3-ethyl-5-oxocyclohexyl)-2-
(prop-2-ynyl)malononitrile 3g. The addition was performed at
45 °C. Colorless oil; Rf = 0.40 (Et2O/pentane 2:1), dr = 1:5; major
diastereoisomer: 1H NMR (CDCl3): d = 0.90 (t, J = 7.5 Hz, 3H),
1.35–1.50 (m, 3H), 1.60–1.73 (m, 2H), 1.98 (t, J = 13.6 Hz, 1H),
2.19 (m, 1H), 2.27 (d, J = 13.6 Hz, 1H), 2.32–2.36 (m, 1H), 2.45–
2.52 (m, 1H), 2.56–2.63 (m, 1H), 2.86 (dd, J = 17.2, 2.6 Hz, 1H),
2.96 (dd, J = 17.2, 2.6 Hz, 1H); 13C NMR (CDCl3): d = 11.2 (CH3),
and single diastereoisomer (dr >99:1); ½a D25
¼ þ9:1 (c 2.0, CH2Cl2);
ꢁ
1H NMR (CDCl3): d = 1.23–1.50 (m, 3H), 1.94 (s, 3H), 1.96–2.09 (m,
4H), 3.02–3.11 (m, 3H), 4.28 (br s, 1H); 13C NMR (CDCl3): d = 14.0,
22.9, 29.4, 35.9 (Cq), 36.0, 49.6, 55.9, 71.2, 115.0 (Cq, CN), 116.8 (Cq,
CN), 127.2 (Cq, C@C), 134.4 (Cq, C@C); HRMS: calcd for
C
12H14N2NaO [M+Na+]: 225.1004; found: 225.0994.

T. Zweifel et al. / Tetrahedron: Asymmetry 21 (2010) 1624–1629
1629
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Acknowledgments
This research was funded by a grant from the Carlsberg Founda-
tion and OChemSchool. T.Z. thanks the Swiss National Science
Foundation for a post-doctoral fellowship. We are grateful to Dr.
Jacob Overgaard for X-ray crystallographic analysis of 3a.
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