One-pot organocatalytic domino michael/α-alkylation reactions: Direct catalytic enantioselective cyclopropanation and cyclopentanation reactions

Article abstract of DOI:10.1002/chem.200800442

The development of one-pot organocatalytic domino Michael/α- alkylation reactions between bromomalonates or bromoacetoacetate esters and α,β-unsaturated aldehydes is presented. The chiral-amine-catalyzed reactions with bromomalonates as substrates give access to the corresponding 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99% ee. The catalytic domino Michael/α- alkylation reactions between 4-bromo-acetoacetate and enals provide a route for the synthesis of functionalized cyclopentanones in good to high yields with 93-99 % ee. The products from the organocatalytic reactions were also reduced with high diastereoselectivity to the corresponding cyclopropanols and cy-clopentanols, respectively. Moreover, one-pot combinations of amine and heterocyclic carbene catalysis (AHCC) enabled the highly enantioselective synthesis of β-malonate esters (91-97% ee) from the reaction between bromomalonates and enals. The tandem catalysis included the catalytic domino reaction followed by catalytic in situ chemoselective ring-opening of the 2-formylcyclopropane intermediates.

Full text of DOI:10.1002/chem.200800442

FULL PAPER
DOI: 10.1002/chem.200800442
One-Pot Organocatalytic Domino Michael/a-Alkylation Reactions: Direct
Catalytic Enantioselective Cyclopropanation and Cyclopentanation
Reactions
Ismail Ibrahem,[a, b] Gui-Ling Zhao,[a, b] Ramon Rios,[a] Jan Vesely,[a, b] Henrik SundØn,[a]
Pawel Dziedzic,[a, b] and Armando Córdova*[a, b]
Abstract: The development of one-pot
organocatalytic domino Michael/a-al-
kylation reactions between bromomal-
onates or bromoacetoacetate esters
and a,b-unsaturated aldehydes is pre-
sented. The chiral-amine-catalyzed re-
actions with bromomalonates as sub-
strates give access to the corresponding
2-formylcyclopropane derivatives in
high yields with excellent diastereose-
lectivity and up to 99% ee. The catalyt-
ic domino Michael/a-alkylation reac-
tions between 4-bromo-acetoacetate
and enals provide a route for the syn-
thesis of functionalized cyclopenta-
nones in good to high yields with 93–
99% ee. The products from the organo-
catalytic reactions were also reduced
with high diastereoselectivity to the
corresponding cyclopropanols and cy-
clopentanols, respectively. Moreover,
one-pot combinations of amine and
heterocyclic carbene catalysis (AHCC)
enabled the highly enantioselective
synthesis of b-malonate esters (91–
97% ee) from the reaction between
bromomalonates and enals. The
tandem catalysis included the catalytic
domino reaction followed by catalytic
in situ chemoselective ring-opening of
the 2-formylcyclopropane intermedi-
ates.
Keywords: Unsaturated aldehydes ·
asymmetric catalysis
tanes cyclopropanes
reactions · organocatalysis
·
cyclopen-
· domino
·
Introduction
been made in the development of asymmetric domino and
tandem reactions by using chiral precursors for stereocon-
trol. However, it is more challenging to develop catalytic
asymmetric domino reactions. Therefore, there are still only
a limited number of catalytic enantioselective domino reac-
tions. In this context, the development of organocatalytic
enantio- and diastereoselective one-pot domino reactions is
a rapidly growing research area.[4–5]
The cyclopropane motif has long been an exciting target
for organic chemists and is an important molecular architec-
ture in a large number of naturally occurring and medicinal-
ly relevant substances (>4000 isolated; 100 biological
active).[6] Moreover, cyclopropyl derivatives are attractive as
intermediates in complex molecule synthesis,[7] synthetic
building blocks,[8] and as templates for the construction of
conformationally restricted amino acids and peptides.[9] In
addition, the strained cyclopropane derivatives can undergo
a variety of ring-opening reactions leading to the synthesis
of a variety of complex molecules.[10] Thus, it is not surpris-
ing that an intense research effort has been focused on find-
ing new catalytic methods for the preparation of cyclopro-
pane derivatives. High levels of asymmetric induction have
been achieved in metal-catalyzed intermolecular cyclopropa-
Carbon–carbon bond-forming reactions are of immense im-
portance in organic synthesis. Domino, tandem, or cascade
reactions, which involve the formation of multiple C C
bonds and stereocenters in one pot, are a rapidly growing
research field within the synthesis of small molecules with
complex molecular scaffolds.[1] The undeniable benefits of
domino reactions include “green chemistry” factors such as
atom economy,[2] reduction of synthetic steps, and minimiza-
tion of solvents and waste.[3] Thus, significant efforts have
À
[a] Dr. I. Ibrahem, Dr. G.-L. Zhao, Dr. R. Rios, Dr. J. Vesely,
Dr. H. SundØn, P. Dziedzic, Prof. Dr. A. Córdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
[b] Dr. I. Ibrahem, Dr. G.-L. Zhao, Dr. J. Vesely, P. Dziedzic,
Prof. Dr. A. Córdova
Berzelii Center EXSELENTon Porous Materials
Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
Chem. Eur. J. 2008, 14, 7867 – 7879
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7867

nations of electron-rich olefins involving Simmons–Smith
and metal-carbenoid
methodologies.[11] Aggarwal,[12]
Results and Discussion
Gaunt,[13] and MacMillan[14] and their co-workers have pio-
neered the development of enantioselective cyclopropana-
tions of a,b-unsaturated ketones, amides, esters, nitriles, sul-
fones, and aldehydes by using either preformed or in situ
generated ylides.[12–14] Connon and co-workers have also re-
ported the employment of Cinchona alkaloid derivatives as
catalysts for the asymmetric cyclopropanation of nitroal-
kenes.[15] Inspired by these investigations and our previous
experience in organocatalytic cascade catalysis,[16] we envi-
sioned a simple asymmetric entry to 2-formyl cyclopropanes
by chiral-amine-mediated domino reactions between halo-
malonates or 2-halo-b-ketoesters and a,b-unsaturated alde-
hydes (Scheme 1).
Catalyst screen for the cyclopropanation reaction: In initial
experiments, we screened chiral amines 4–11 (20 mol%) for
the reaction between cinnamic aldehyde 1a (0.3 mmol) and
bromomalonate 2a (0.25 mmol) with NEt3 (0.25 mmol) as a
proton sponge in CHCl3 (1 mL) (Table 1). To our delight,
[a]
Table 1. Catalyst screen.
Entry
Catalyst
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
14
14
14
14
24
3
80
62
55
72
Traces
91
87
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
nd[e]
30
9
71
À63
nd[e]
96
Scheme 1. Asymmetric synthesis of 2-formyl cyclopropanes.
Moreover, based on the importance of the cyclopenta-
none molecular architecture in natural products (e.g. prosta-
glandins),[17,18] we became intrigued as to whether we could
expand the scope of chiral-amine-catalyzed domino Mi-
chael/intramolecular a-alkylation reactions to the assembly
of highly substituted cyclopentanones in an asymmetric fash-
ion (Scheme 2).[19–20]Notably, during our initial studies Ley
14
14
99
traces
nd[e]
[a] Experimental conditions: A mixture of 2a (0.25 mmol), aldehyde 1a
(0.3 mmol), NEt3 (0.25 mmol) and catalyst (20 mol%) in 1.0 mL CHCl3
was stirred at the temperature and conditions displayed in the Table.
[b] Yield of isolated product. [c] Determined by NMR analyses of the
crude reaction mixture. [d] Determined by chiral-phase HPLC analysis.
[e] Not determined.
(S)-proline catalyzed the asymmetric formation of the corre-
sponding 2-formylcyclopropane 3a with excellent diastereo-
selectivity (>25:1 d.r. (trans/cis)) but low enantioselectivity
(30% ee). Decreasing the bulk of the chiral pyrrolidine to
an alcohol moiety as in catalyst 5 did not affect the diaste-
reoselectivity but decreased the enantioselectivity of the
transformation (Table 1, entry 2). Increasing the bulk of the
chiral moiety to pyrrolidine as in catalyst 6 gave the corre-
sponding cyclopropane 3a in moderate yield with excellent
diastereoselectivity (>25:1 d.r.) and good enantioselectivity
(71% ee) (Table 1, entry 3).
The use of 2-carboxylic acid dihydroindole 7, which has
been successfully employed in the cyclopropanation of enals
with dimethylphenylacyl sulfonium ylide, allowed the forma-
tion of ent-3a in 72% yield with >25:1 d.r. and 63% ee
(Table 1, entry 4). Furthermore, the bulky prolinol 8 cata-
lyzed the cyclopropanation reaction with very low conver-
sion (Table 1, entry 5). Notably, chiral amines 9[25] and 10
were the most efficient catalysts under our reaction condi-
tions and catalyzed the formation of 3a with excellent dia-
Scheme 2. Organocatalytic synthesis of highly substituted cyclopenta-
nones.
and co-workers disclosed an elegant organocatalytic nitrocy-
clopropanation of cyclohexanone.[21] Our group has recently
reported the organocatalytic asymmetric domino Michael/a-
alkylation between bromomalonates and enals.[22] We also
employed this catalytic strategy for the synthesis of cyclo-
pentanones by using enals as substrates.[23] Wang and co-
workers later reported very elegant similar results.[24]
Herein, we describe our findings, including the scope, the
combination with heterocyclic carbene catalysis, synthetic
applications, and mechanisms of chiral-amine-catalyzed
domino-asymmetric conjugate addition/a-alkylation reac-
tions.
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Chem. Eur. J. 2008, 14, 7867 – 7879

Organocatalytic Cyclopropanation and Cyclopentanation Reactions
FULL PAPER
[a]
Table 2. Solvent screen.
range under our reaction conditions to the achiral enal 12a
in DMF, CH2Cl2, CH3CN, Et2O, and EtOH. The ratio of 3a/
12a ranged from 1:1 to >25:1. The highest yield and ee of
3a were obtained in CHCl3 where 12a was not detected
(Table 2, entry 1). The enantioselectivity of the reaction
slightly decreased in DMF, CH3CN, and EtOH (Table 2, en-
tries 3, 6, and 8). In diethyl ether, 3a was isolated with ex-
cellent enantiomeric excess (99% ee) but significant
amounts of 12a (3a/12a=1:1) were also formed (Table 2,
entry 7). We also screened the influence of the base additive
on the chiral-amine-9-catalyzed reactions in CHCl3
(Table 3).
Entry
Solvent
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
3a/12a[c]
1
2
3
4
5
6
7
8
CHCl3
MeOH
DMF
Toluene
CH2Cl2
CH3CN
Et2O
3
3
24
3
6
6
91
23
24
76
50
50
45
55
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
96
89
87
92
97
91
99
88
>25:1
>25:1
2:1
>25:1
2:1
3:1
1:1
2:1
14
14
EtOH
Excellent diastereoselectivity (>25:1) and high enantiose-
lectivity (89–98% ee) were achieved for all bases investigat-
ed and the side product 12a was formed in low amounts (0–
13%). The reactions with organic amine-base additives were
efficient and gave the corresponding formylcyclopropyl de-
rivative 3a in high yield. Of the organic bases investigated,
the addition of NEt3 gave the best results with respect to the
efficiency of the reaction (Table 3, entry 1). However, the
inorganic base additives KOH and K2CO3 slightly decreased
the enantioselectivity (Table 3, entries 3 and 4). The catalyt-
ic cyclopropanation reaction between the aliphatic enal 1b
and 2a was also investigated (Table 4).
[a] Experimental conditions: A mixture of 2a (0.25 mmol), aldehyde 1a
(0.3 mmol), NEt3 (0.25 mmol) and catalyst 9 (20 mol%) in 1.0 mL solvent
was stirred at the temperature and conditions displayed in the Table.
[b] Yield of isolated product. [c] Determined by NMR analyses of the
crude reaction mixture. [d] Determined by chiral-phase HPLC analyses.
Table 3. The direct asymmetric a-aminomethylation of aldehydes 2 cata-
lyzed by chiral diphenyl prolinol 9.[a]
Interestingly, in this case cyclopropane 3b, Michael
adduct 13b, and epoxide 14b were formed depending upon
the solvent. The aliphatic rearrangement product 12b was
not detected. For example, the reaction in CHCl3 without
the addition of NEt3 gave the corresponding cyclopropane
derivative 3b in 20% (99% ee) conversion together with
Michael adduct 13b in 20% conversion after 3 h (Table 4,
entry 1). Prolonging the reaction time did not increase the
conversion of enal 1b (Table 4, entry 2). The addition of
NEt3 as a proton sponge significantly improved the efficien-
cy and diastereoselectivity of the reaction (15:1 d.r.) while
the excellent enantioselectivity (99% ee) of the transforma-
tion was maintained. Hence, the in situ formation of HBr in
the a-alkylation step inhibits the product formation. Per-
forming the reaction in methanol without addition of NEt3
Entry Base
t [h] Yield [%][b] d.r.[c]
ee [%][d] 3a/12a[c]
1
2
3
4
5
6
NEt3
NaOAc
KOH
3
14
14
14
91
68
59
44
48
68
>25:1 96
>25:1
9:1
>25:1 98
>25:1 90
>25:1 89
>25:1 93
>25:1 96
7:1
K2CO3
>25:1
>25:1
14:1
DABCO[e] 14
DBU[f]
14
[a] Experimental conditions: A mixture of 2a (0.25 mmol), aldehyde 1a
(0.3 mmol), base (1 equiv) and catalyst 9 (20 mol%) in 1.0 mL CHCl3
was stirred at the temperature and conditions displayed in the Table.
[b] Isolated yield. [c] Determined by NMR analyses of the crude reaction
mixture. [d] Determined by chiral-phase HPLC analyses. [e] DABCO=
1,4-diazabicyclo
ene.
N
G
stereo- (>25:1) and enantiose-
lectivity (96 and 99% ee, re-
spectively; Table 1, entries 6
and 7).
Table 4. The asymmetric cyclopropanation of enal1b catalyzed by the chiral diphenyl prolinol 9.[a]
Solvent and base screen: We
next decided to perform a sol-
vent screen by using chiral
Entry Solvent Additive t [h] Conv. [%][b] 3b [%][c] d.r.[b]
ee [%][d] 13b [%][c] 14b [%][c]
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
MeOH
MeOH
None
None
NEt3
NEt3
None
None
3
16
1
3
3
16
3
16
41
41
50
95
40
65
20
20
20
20
50
95
0
5
20
20
5:1
5:1
15:1
15:1
–
99
99
99
99
–
20
20
<1
<1
0
<1
<1
0
amine
9
as the catalyst
(Table 2).
The chiral amine 9 was able
to catalyze the formation of 3a
with excellent diastereoselectiv-
ity (>25:1) and high enantiose-
lectivity (87–99% ee) in all sol-
vents investigated. We also
found that the optically active
cyclopropane 3a could rear-
0
40
60
0
nd[e] nd[e]
>25:1
>25:1
0
0
CH3CN None
CH3CN None
99
99
0
0
[a] Experimental conditions: A mixture of 2a (0.25 mmol), aldehyde 1b (0.3 mmol) and catalyst 9 (20 mol%)
in 1.0 mL solvent was stirred at the temperature and conditions displayed in the Table. [b] Determined by
NMR analyses of the crude reaction mixture. [c] Percent formed product as determined by NMR analyses.
[d] Determined by chiral-phase GC analyses. [e] Not determined (nd).
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7869

A. Córdova et al.
[a]
Table 5. Scope of the organocatalytic asymmetric cyclopropanation reaction.
Entry
R
Catalyst
Product
Time [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
Ph
10
9
14
3
87
83
80
>25:1
>25:1
15:1
99
Ph
94[e]
99
n-Pr
9
3
4
5
9
9
3
5
74
88
25:1
9:1
94
94
Me
6
7
8
10
9
14
14
14
81
50
83
>25:1
>25:1
>25:1
98
CO2Et
93[f]
9
96[g]
9
10
9
3g
14
3
80
76
>25:1
93
99
10
14:1
11
12
9
9
4
60
72
>25:1
>25:1
96
90
14
13
14
9
9
4
3
79
61
>25:1
>25:1
94
98
[a] Experimental conditions: A mixture of 2 (0.25 mmol), aldehyde 1 (0.30 mmol), triethylamine (0.25 mmol) and catalyst 9 or 10 (10 or 20 mol%) in
CHCl3 (1.0 mL) was stirred at room temperature. The crude product 3 was purified by column chromatography. [b] Isolated yield of pure product 3 after
silica-gel column chromatography. [c] Determined by NMR analysis. [d] Determined by chiral-phase HPLC or GC analyses. [e] 10 mol% catalyst. [f] Re-
action performed at À208C. [g] Reaction performed at 48C.
completely switched the chemoselectivity of the transforma-
tion and the corresponding Darzens epoxidation compound
14b was exclusively furnished.
Substrate scope: Based on the results from the catalyst-, sol-
vent-, and base-screens, we decided to investigate the scope
of the reaction by using chiral amines 9 or 10 as the cata-
lysts, NEt3 as the base and CHCl3 as the solvent (Table 5).
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Chem. Eur. J. 2008, 14, 7867 – 7879

Organocatalytic Cyclopropanation and Cyclopentanation Reactions
FULL PAPER
The reactions had a broad substrate scope and catalyst 9
was the most efficient. The corresponding products 3a–3l
were isolated in good to high yields with up to >25:1 d.r.
and 90–99% ee. Moreover, the substrates did not rearrange
to compounds 12 under these reaction conditions. a,b-Unsa-
turated aldehydes with an aryl substituent were isolated in
high yields with excellent diastereomeric ratios (>25:1) and
high ee values (90–99%). Enals with aliphatic substituents
were rapidly converted to their corresponding 2-formyl cy-
clopropane derivatives and formed with high diastereoselec-
tivity (9:1–25:1 d.r.) and 94–99% ee (Table 5, entries 3–5).
Notably, the reaction was regiospecific when 2,4-hexadienal
was used as the substrate (Table 5, entry 10). In this case,
the E/Z ratio of the starting dienal 1h was 3:1, while the
diastereomeric ratio of the corresponding trans product 3h
was 14:1. The reaction also gave similar results when the
catalyst loading was decreased to 10 mol% (Table 5,
entry 2). We also investigated the effect of the ester moiety
of the 2-halomalonates 2 (Table 6).
Scheme 3. Chiral amine-9-catalyzed domino reaction between 2e and
enal 1a.
bromonitromethane and enals 1. For example, chiral amine
9 catalyzed the domino reaction between cinnamic aldehyde
1a and bromonitromethane and the corresponding 2-formyl-
cyclopropane derivative was isolated in 67% yield with 1:1
d.r. and 95% ee.[26] The 2-formyl cyclopropanes 3 from the
catalytic reaction are valuable chiral precursors to 3–5 bicy-
clic frameworks with a quarternary carbon stereocenter. Ac-
cordingly, cyclopropane 3a was treated with NaBH3CN in
THF, to afford the corresponding alcohol 15a, which upon
intramolecular cyclization gave the corresponding lactone
16a by treatment with p-TsOH in CHCl3 (Scheme 4).
Table 6. Enantioselective cyclopropanation with different halomalonates
2 catalyzed by the chiral diphenyl prolinol 9.[a]
Entry
R1
X
Prod.
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
Et
Br
Br
Br
Cl
3a
3
14
14
14
91
42
78
73
>25:1
>25:1
>25:1
>25:1
96
99
96
97
Bn
Me
Et
3ab
3ac
3a
[a] Experimental conditions: A mixture of 2 (0.25 mmol), aldehyde 1a
(0.30 mmol), triethylamine (0.25 mmol) and catalyst (20 mol%) in
9
CHCl3 (1.0 mL) was stirred at room temperature. The crude product 3
was purified by column chromatography. [b] Isolated yield of pure prod-
uct 3 after silica-gel column chromatography. [c] Determined by NMR
analysis. [d] Determined by chiral-phase HPLC analyses.
Scheme 4. Two-step asymmetric synthesis of chiral lactone 16.
We found that the efficiency of the reaction decreased
with increased size of the ester groups of halomalonates 2a–
2d. However, the enantioselectivity increased. For example,
the reaction between enal 1a and dibenzyl bromomalonate
ester 2b gave the corresponding cyclopropane derivative
3ab in 42% yield and 99% ee (Table 6, entry 2). Moreover,
changing the halogen substituent from bromo to chloro did
not affect the reaction. We also investigated the enantiose-
lective organocatalytic cyclopropanation reaction between
2-bromoketoesters and enals. For example, the reaction be-
tween enal 1a and ethyl-2-bromo-3-oxobutanoate 2e was
highly diastereo- and enantioselective (>25:1 d.r., 94% ee)
and gave the corresponding cyclopropane products 3m and
3m’ in a 3:1 ratio (Scheme 3).
Notably, we also investigated whether bromomalonates 2
could be used as electrophiles in intermolecular a-alkylation
reactions of aldehydes by using chiral amine 9 as the catalyst
(Scheme 5). However, only the a-brominated aldehyde
product was formed.
Scheme 5. Synthesis of a-bromoaldehydes.
The relative configuration of cyclopropane 3m was estab-
lished by NOE experiments. Hence, NOEs were measured
between Ha and Hc, and Hb and Hd, respectively. The pro-
tected diarylprolinol catalysts could also catalyze highly
enantioselective nitrocyclopropanation reactions between
The mechanism of the chiral-amine-catalyzed cyclopropa-
nation is depicted in Scheme 6. Accordingly, efficient shield-
ing of the Si-face (Re when R=Aryl) of the chiral iminium
intermediate I by the bulky aryl groups of chiral pyrrroli-
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7871

A. Córdova et al.
II, which is formed either from the cyclopropanation reac-
tion (Scheme 7) or by in situ condensation between the
chiral-amine catalyst and the cyclopropyl derivative 3, un-
dergoes base promoted enamine formation followed by sub-
sequent ring-opening. Hydrolysis of iminium intermediate
III liberates the chiral-amine catalysts and gives the enal 12.
The mechanism was further supported by the ability of
chiral amine 9 to catalytically rearrange cyclopropyl deriva-
tive 3a to enal 12a in the presence of NEt3 in CH2Cl2.[24]
Performing the reaction without catalyst did not give the
corresponding enal 12a.
One-pot combination of catalytic domino Michael/a-alkyla-
tion reactions and heterocyclic carbene catalysis: Selective
ring-openings of cyclopropane derivatives are important in
organic synthesis.[10] In this context, Bode has recently
shown that 2-cyclopropyl aldehydes can be converted into
the corresponding acyclic esters under mild conditions.[27] In-
trigued by this and the benefits of developing asymmetric
one-pot multicomponent reactions, we decided to investi-
gate the possibility of combining amine and heterocyclic car-
bene catalysis (AHCC) for the direct conversions of enals 1
to valuable b-malonate esters (Scheme 8).[28]
Scheme 6. Catalytic tandem asymmetric cyclopropanation/esterification
of enals.
dines 9 and 10 leads to stereoselective Re-facial nucleophilic
conjugate addition by the 2-bromo substituted malonates
and b-ketoesters 2 (Scheme 6). Next, the generated chiral
enamine intermediate performs an intramolecular 3-exo-tet
nucleophilic attack to form the cyclopropane ring. The intra-
molecular ring-closure pushes the equilibrium forward and
makes this step irreversible. This is the same type of mecha-
nism that is present in the organocatalytic asymmetric epox-
idation of enals[5h,k] and asymmetric aziridination of
enals.[16d] Hydrolysis of iminium intermediate II releases the
catalyst and gives the corresponding 2-formyl cyclopropane
3. In the case of (S)-2-carboxylic acid dihydroindole 7 catal-
ysis, the bromomalonate 2 approached the opposite face of
the iminium intermediate to give cyclopropanes ent-3.
Scheme 8. Catalytic tandem asymmetric cyclopropanation/esterification
of enals.
The proposed mechanism for the formation of side-prod-
uct 12 is depicted in Scheme 7. Thus, iminium intermediate
To achieve this, we envisioned that enal 1 first would
react according to our organocatalytic cyclopropanation re-
action with bromomalonate 2a to form the corresponding 2-
À
formylcyclopropane 3. Next, organocatalytic in situ C C
bond-cleavage/ring-opening followed by concomitant oxida-
tion of the aldehyde and subsequent esterification would
give the corresponding optically active b-malonate ester 18.
In Table 7, the results from our combined AHCC experi-
ments are shown.
The organocatalytic one-pot tandem reactions gave the
corresponding b-malonate esters 18 in good to high yields
with 94–97% ee. For example, b-malonate ester 18b was iso-
lated in 74% overall yield with 94% ee (Table 7, entry 3).
The enantioselectivity achieved in the catalytic cyclopropa-
nation step was not affected by the ring-opening step. More-
over, the alcohol used in the ring-opening step can be readi-
ly changed and b-malonate esters are valuable chiral syn-
Scheme 7. Catalytic formation of side-product 12.
7872
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7867 – 7879

Organocatalytic Cyclopropanation and Cyclopentanation Reactions
FULL PAPER
Table 7. Catalytic tandem asymmetric cyclopropanation/esterification of
enals.
tate 2 as substrates (Scheme 2). This was not straightfor-
ward, since Jørgensen and co-workers recently showed that
the reaction between 4-choloro-acetoacetate and enals 1
only gave the corresponding Michael adduct.[30] Neverthe-
less, in an initial experiment, we performed the reaction be-
tween heptenal 1j and 4-bromo-acetoacetate 2 f under our
optimized cyclopropanation conditions (Scheme 10). To our
dismay, the reaction did not give the desired cyclopentane
product 19a.
Entry
R
R1
Product
Yield [%][a]
ee [%][b]
However, a catalyst and solvent screen for the organoca-
talytic reaction between heptenal 1j and 4-bromo-acetoace-
tate 2 f was performed (Table 8).
Several chiral amines were screened and it was found that
(S)-proline catalyzed the formation of ent-19a in high yield
with moderate enantioselectivity (55% ee) when AcONa
was used as the proton sponge (Table 8, entry 1). Out of the
four possible diastereoisomers only two (19a and 19a’) were
1
2
3
4
5
Ph
Ph
Ph
Et
18a
18b
18b
18c
18d
69
56
97
Me
Me
Me
Me
97
74[c]
74[d]
74[e]
94[c]
95
4-NO2C6H4
2-Naph
96
[a] Isolated yield of the pure product 18 after silica-gel chromatography.
[b] Determined by chiral-phase HPLC analyses. [c] 30 mol% 17. [d] Re-
action first run for 1.5 h at room temperature followed by addition of 17.
[e] Reaction first run for 6 h at 48C followed by addition of 17. DIPEA=
Diisopropylethyl amine.
thons for further transforma-
tions. Comparison with the lit-
erature revealed that the abso-
lute configuration of compound
18b at C3 was R ([a]2D5 =À33.2
(c=1.0, CHCl3), Lit. ((R)-18b,
[a]2D5 =À29 (c=1.0, CHCl3)[29]).
Hence, the reactions with cata-
lysts (S)-9 and (S)-10 give
access to (2R,3R)-2-formyl-cy-
clopropanes 3.
The mechanism of the one-
pot conversion of enals 1 to b-
malonate esters 18 by tandem
AHCC catalysis starts with the
diastereo- and enantioselective
domino-iminium/enamine-acti-
vation mechanism (Scheme 9).
Next, the base-generated heter-
ocyclic carbene catalyst catalyz-
À
es the C C bond-cleavage/ring-
opening, which is followed by
concomitant oxidation of the al-
dehyde and subsequent esterifi-
cation.
Amine-catalyzed domino Mi-
chael/a-alkylation reactions be-
tween enals and 4-bromo-ace-
toacetate: As described below,
we became intrigued as to
whether highly substituted cy-
clopentanones could be assem-
bled in an asymmetric fashion
by our organocatalytic domino
Michael/intramolecular a-alky-
lation reaction strategy by using
enals 1 and 4-bromo-acetoace- Scheme 9. One-pot combination of AHCC catalysis.
Chem. Eur. J. 2008, 14, 7867 – 7879
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7873

A. Córdova et al.
tioselectivity of the domino reaction could be further im-
proved if the reaction temperature was decreased. For ex-
ample, running the reaction at 48C with K2CO3 as the
proton sponge allowed for the isolation of 19e in 72% yield
with 10:1 d.r. and 99% ee (Table 8, entry 15). With these re-
sults in hand we decided to investigate the catalytic domino
reaction between 4-bromo-b-ketoester 2 f and different
enals 1 with (S)-chiral amine 9 as the organocatalyst and
K2CO3 as the inorganic base (Table 9).
Scheme 10. Attempted synthesis of cyclopentanone 19a.
Table 8. Catalytic domino reactions between enal 1j and bromoacetoace-
tate 2 f.[a]
Table 9. Direct organocatalytic asymmetric domino reactions between 4-
bromo b-ketoester 2 f and enals 1.[a]
Entry
R
Prod.
T [8C]
t [h]
Yield[b]
72
d.r.[c]
10:1
98
10:1
ee[d]
99
1
2
3
n-Bu
n-Bu
n-Pr
19a
19a
19b
4
RT14
4
14
88
14
8:1
83
>99
4
19c
RT3
58
12:1
99
5
6
Et
Me
19d
19e
4
4
14
14
70
76
9:1
6:1
98
93
Entry
Catalyst
Solvent
Base
Yield [%][b]
d.r.[c]
ee[d]
1
2
3
4
5
6
7
8
4
6
7
20
8
9
10
9
9
9
9
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
toluene
THF
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
NEt3
74
0
0
0
0
67
0
0
88
55
77
62
55
80
72
8:1
–
–
–
–
8:1
–
–
8:1
8:1
8:1
8:1
8:1
8:1
10:1
À53
–
–
–
–
97
–
–
98
96
91
96
96
88
99
[a] Experimental conditions: a,b-Unsaturated aldehyde 1 (0.30 mmol),
K2CO3 (0.25 mmol) and ethyl 4-bromo-3-oxobutanoate 2 f (0.25 mmol)
were added to
(1.0 mL). The reaction was vigorously stirred for the time shown in the
Table at 48C or room temperature. Next, the crude product was purified
by silica-gel column chromatography (pentane/EtOAc-mixtures) to give
the corresponding cyclopentanones 19. [b] Isolated yield of pure com-
pound 19. [c] The ratio of 19:19’ as determined by 1H NMR analysis.
[d] Determined by chiral-phase GC analysis.
a stirred solution of catalyst (20 mol%) in solvent
9
K2CO3
KOH
10
11
12
13
14
15
AcONa
AcONa
AcONa
AcONa
AcONa
9
9
The organocatalytic domino process allowed for the for-
mation of chiral cyclopentanones 19a–e possessing three
new stereocenters in good to high yields with 6:1–12:1 d.r.
and 93–>99% ee from simple starting materials. For exam-
ple, cyclopentanone 19c was isolated in 58% yield with
12:1 d.r. and 99% ee (Table 9, entry 4). In this case, the best
results were achieved at room temperature. Highly diaste-
reoselective reduction of chiral cyclopentanones 19 with
NaBH3CN gave access to the corresponding diols 20 con-
taining four stereocenters without affecting the enantiomeric
excess. For example, diol 20d was isolated in 63% yield as
the predominant diastereomer with 98% ee (Scheme 11).
9
MeOH
CHCl3
9[e]
[a] Experimental conditions: To a stirred solution of catalyst (20 mol%)
in solvent (1.0 mL) was added a,b-unsaturated aldehyde 1j (0.30 mmol),
base (0.25 mmol) and ethyl 4-bromo-3-oxobutanoate 2 f (0.25 mmol). The
reaction was vigorously stirred for 14 h at room temperature. The crude
product was purified by silica-gel column chromatography (pentane/
EtOAc mixtures) to give cyclopentanone 19a. [b] Isolated yield of pure
compound 19a. [c] The ratio of 19a/19a’ as determined by 1H NMR.
[d] Determined by chiral-phase GC analysis. [e] Reaction run at 48C.
formed in a ratio of 8:1. To our delight, chiral amine 9 cata-
lyzed the formation of cyclopentanone 19a with three con-
tiguous stereocenters with high diastereo- (8:1 d.r.) and
enantioselectivity (97% ee, Table 8, entry 6). Hence, one
predominant enantiomer was formed under these reaction
conditions. In contrast to the cyclopropanation reactions, the
use of an inorganic base additive was essential for product
formation. The chiral amine 9 catalyzed highly stereoselec-
tive assembly of cyclopentane 19a in an asymmetric fashion
in several solvents. Notably, cyclopentanone 19a was isolat-
ed in 88% yield with 8:1 d.r. and 98% ee when K2CO3 was
used as the base (Table 8, entry 9). The diastereo- and enan-
Scheme 11. Synthesis of cyclopentanediol 20d.
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Chem. Eur. J. 2008, 14, 7867 – 7879

Organocatalytic Cyclopropanation and Cyclopentanation Reactions
FULL PAPER
Thus, highly functionalized cyclopentanes containing pri-
mary and secondary alcohol groups can be synthesized by
the organocatalytic domino reaction.
The relative stereochemistry of the alcohol 20d was estab-
lished by NOE experiments and from the coupling constants
of the ring protons. The experiments revealed that all the
substituents of 20d were trans.
Conclusion
We report the scope, applications, and mechanism of orga-
nocatalytic asymmetric domino Michael/a-alkylation reac-
tions between a,b-unsaturated aldehydes and bromomalo-
nates or bromoacetoacetate esters. The protected chiral dia-
rylprolinol-catalyzed reactions were highly diasetereo- and
enantioselective and provide direct routes to functionalized
The proposed mechanism for
the organocatalytic domino Mi-
cyclopropanes and cyclopentanes with 90–99% ee. T he
chael/a-alkylation reaction be-
tween enals 1 and 4-bromo-ace-
toacetate 2 f is similar to that of
the cyclopropanation reaction
(Scheme 12). Thus, efficient
shielding of the Si-face of the
chiral-amine-catalyzed domino reactions were also com-
bined in a one-pot tandem process with heterocyclic carbene
catalysis for the conversion of enals to valuable optically
active products such as b-malonate esters (94–97% ee).
Thus, amine and heterocyclic carbene catalysis (AHCC) can
be combined. Further, expansion of organocatalytic asym-
metric domino Michael/a-alkylation reactions such as nitro-
cyclopropanations and application in functional carbocycle
synthesis are ongoing.
Experimental Section
General procedures: Chemicals and solvents were either purchased
puriss p. A. from commercial suppliers or purified by standard tech-
niques. Catalysts 9 and 10 were synthesized according to literature proce-
dures.[5h,k,25] For thin-layer chromatography (TLC), silica-gel plates
Merck 60 F254 were used and compounds were visualized by irradiation
with UV light and/or by treatment with a solution of phosphomolybdic
acid (25 g), Ce(SO4)2·H2O (10 g), conc. H2SO4 (60 mL), and H2O
G
(940 mL) followed by heating or by treatment with a solution of p-anisal-
dehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol
(900 mL) followed by heating. Flash chromatography was performed
with silica-gel Merck 60 (particle size 0.040–0.063 mm), 1H and 13C NMR
spectra were recorded on a Varian AS 400 spectrometer. Chemical shifts
are given in d relative to tetramethylsilane (TMS), the coupling constants
J are given in Hz. The spectra were recorded in CDCl3 as solvent at
room temperature, TMS served as internal standard (d=0 ppm) for
1H NMR spectroscopy, and CDCl3 was used as internal standard (d=
77.0 ppm) for 13C NMR spectroscopy. HPLC was carried out with a
Waters 2690 Millennium instrument with a photodiode array detector.
Optical rotations were recorded on a Perkin–Elemer 241 Polarimeter
(l=589 nm, 1 dm cell). HRMS were recorded on a Bruker MicrOTOF
spectrometer.
Scheme 12. The proposed mechanism for the chiral-amine-catalyzed
enantioselective domino Michael/a-alkylation reaction between enals 1
and 2 f.
Typical experimental procedure for the organocatalytic cyclopropanation
reactions: a,b-Unsaturated aldehyde 1 (0.3 mmol, 1.2 equiv), triethyla-
mine (0.25 mmol, 1.0 equiv), and diethyl bromomalonate 2a (0.25 mmol,
1.0 equiv) were added to a stirred solution of catalyst (20 mol%) in
CHCl3 (1.0 mL). The reaction was vigorously stirred for the time de-
scribed in the Tables. Next, the crude product was purified by silica-gel
chromatography (pentane (toluene)/EtOAc-mixtures) to give the corre-
sponding cyclopropane derivatives 3.
Cyclopropane 3a: Colorless oil; [a]2D5 =À20.8 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.45 (d, J=4.4 Hz, 1H), 7.35–7.20 (m,
5H), 4.35–4.25 (m, 2H), 3.92 (qd, J=7.2 Hz, J’=2.0 Hz, 2H), 3.82 (d, J=
7.2 Hz, 1H), 3.37 (dd, J=7.2 Hz, J’=4.4 Hz, 1H), 1.30 (t, J=7.2 Hz,
3H), 0.93 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
196.1, 166.0, 164.6, 132.2, 128.5, 128.4, 128.0, 62.5, 62.0, 44.7, 38.1, 35.3,
14.0, 13.7 ppm; IR (KBr): n˜ =2983, 2938, 2872, 1732, 1448, 1369, 1295,
1288, 1247 1217, 1182, 1145, 1028 cmÀ1; HRMS (ESI): m/z: calcd for
C16H18O5Na: 313.1046 [M+Na+]; found: 313.1049; HPLC (ODH column,
n-hexane/iPrOH 95:5, l=210 nm, 0.5 mLminÀ1): tR (major enantiomer)=
19.0, tR (minor enantiomer)=25.6 min.
chiral iminium intermediate I by the bulky aryl groups of
chiral pyrrrolidine 9 leads to stereoselective Re-facial nucle-
ophilic conjugate addition by the 4-bromoacetoacetate 2 f.
Next, the in situ generated chiral enamine undergoes an in-
tramolecular 5-exo-tet cyclization from the same face as the
incoming 2 f, followed by hydrolysis of the resulting iminium
intermediate II to give the cyclopentanone product 19. In
the case of (S)-proline 5 catalysis, the b-ketoester approach-
ed the opposite face of the iminium intermediate to give cy-
clopentanones ent-19.
Cyclopropane 3b: Colorless oil; [a]2D5 =À43.4 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.23 (d, J=5.2 Hz, 1H), 4.32–4.14 (m,
Chem. Eur. J. 2008, 14, 7867 – 7879
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7875

A. Córdova et al.
4H), 2.65 (dd, J=7.2 Hz, J’=5–2 Hz, 1H), 2.49 (m, 1H), 1.52–1.40 (m,
4H), 1.30–1.20 (m, 6H), 0.92 ppm (t, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): 196.7, 166.5, 166.0, 62.1, 62.1, 42.9, 40.3, 32.0, 28.5,
21.8, 14.1, 13.9, 13.5 ppm; IR (KBr): n˜ =2964, 2936, 2874, 1731, 1466,
1447, 1369, 1295, 1223, 1201, 1146 cmÀ1; HRMS (ESI): m/z: calcd for
C13H20O5 +Na+: 279.1203 [M+Na]+; found: 279.1195; GC (chrompak
CP-Chirasil-Dex CB-column; Temperature program: 5 min,708C//28C
minÀ1//1108C, 10 min//108C minÀ1//200,10 min): tR (major enantiomer)=
40.3, tR (minor enantiomer)=40.4 min.
Cyclopropane 3c: Colorless oil; [a]2D5 =À12.8 (c=1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=9.18 (d, J=4.8 Hz, 1H), 7.40–7.10 (m, 5H), 4.35–
4.10 (m, 4H), 2.71 (td, J=7.8 Hz, J’=2.1 Hz, 2H), 2.61 (dd, J=7.2 Hz,
J’=5.1 Hz, 1H), 2.48 (m, 1H), 1.96–1.82 (m, 1H), 1.82–1.68 (m, 1H),
1.30–1.22 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): 196.5, 166.3, 166.0,
140.4, 128.5, 128.5, 126.3, 62.2, 62.2, 42.8, 40.2, 34.8, 31.7, 28.5, 14.1,
14.0 ppm; IR (KBr): n˜ =2983, 1733, 1466, 1288, 1217, 697 cmÀ1; HRMS
(ESI): m/z: calcd for C18H22O5 +Na+: 341.1359 [M+Na]+; found:
341.1371; the enantiomeric excess was determined after in situ reduction
with NaBH4 of the aldehyde to the corresponding alcohol: HPLC (OD-
H column, n-hexane/iPrOH 90:10, l=250 nm, 0.5 mLminÀ1): tR (major
enantiomer)=16.9, tR (minor enantiomer)=19.6 min.
3H), 1.30–1.23 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=196.0,
166.0, 166.5, 132.2, 122.5, 62.2, 62.2, 43.4, 39.9, 34.3, 18.0, 14.0, 13.9 ppm;
IR (KBr): n˜ =2983, 2856, 1731, 1465, 1369, 1294, 1280, 1224, 1199,
1019 cmÀ1
;
HRMS (ESI): m/z: calcd for C13H18O5 +Na+: 277.1046
[M+Na]+, found 277.1057; GC (chrompak CP-Chirasil-Dex CB-column.
Temperature program: 5 min,708C//28C minÀ1//1108C, 10 min//108C
minÀ1//200,10 min): tR (major enantiomer)=15.2, tR (minor enantio-
mer)=15.4 min.
1
Cyclopropane 3i: Colorless oil; [a]2D5 =À31.6 (c=0.6 in CHCl3); H NMR
(400 MHz, CDCl3): d=9.46 (d, J=4.7 Hz, 1H), 8.27 (d, J=8.4 Hz, 2H),
7.17 (d, J=8.4 Hz, 2H), 4.20–4.35 (m, 2H), 3.89–4.02 (m, 2H), 3.76 (d,
J=7.4 Hz, 1H), 3.33 (dd, J=4.7, 7.6 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H),
0.99 ppm (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d= 195.7,
165.8, 164.4, 134.0, 130.8, 129.9, 128.6, 62.5, 62.2, 44.7, 38.1, 34.5, 14.0,
13.8 ppm; HRMS (ESI) m/z: calcd for C16H17ClO5 +Na+: 347.0657
[M+Na+]; found 347.0656; the enantiomeric excess was determined after
in situ reduction with NaBH4 of the aldehyde to the corresponding alco-
hol: HPLC (AD column, n-hexane/iPrOH 95:5, l=254 nm, 1 mLminÀ1):
tR (major enantiomer)=24.6, tR (minor enantiomer)=29.3 min.
1
Cyclopropane 3j: Colorless oil. [a]D =À32.9 (c=1.0 in CHCl3); H NMR
(400 MHz, CDCl3): d=9.43 (d, J=4.7 Hz, 1H), 7.15 (d, J=8.9 Hz, 2H),
6.81 (d, J=8.8 Hz, 2H), 4.34–4.21 (m, 2H), 4.00–3.90 (m, 2H), 3.85 (d,
J=1.0 Hz 1H), 3.77 (s, 3H), 3.31 (d,d, J=3.8–7.5 Hz, 1H), 1.30 (t, J=
7.1–14.3 Hz, 3H), 0.98 ppm (t, J=7.1–14.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=196.5, 166.4, 165.0, 159.6, 129.9, 124.3, 114.1, 62.6, 62.2, 55.5,
38.7, 35.1, 14.2, 14.0 ppm; IR (KBr): n˜ =2982, 2938, 2873, 1732, 1465,
1445, 1369, 1287, 1254, 1245, 1218, 1177, 1145, 1030 cmÀ1; HRMS (ESI)
Cyclopropane 3d: Colorless oil; [a]2D5 =À62.2 (c=1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d= 9.21 (d, J=5.3 Hz, 1H) 4.11–4.28 (m, 4H), 2.59
(dd, J= 7.4, 5.2 Hz, 1H), 2.52 (m, 1H), 1.24 (q, J=7.3, 15.1 Hz, 6H),
1.20 ppm (d, J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d= 196.8,
166.5, 165.8, 62.2, 62.1, 43.2, 41.1, 26.6, 14.1, 14.0, 11.8 ppm; HRMS
(ESI): m/z: calcd for C11H16O5 +Na+: 251.0890 [M+Na]+; found:
251.0895; GC (chrompak CP-Chirasil-Dex CB-column; temperature pro-
gram: 5 min,708C//28CminÀ1//1108C, 10 min//108CminÀ1//200,10 min.): tR
(major enantiomer)=36.7, tR (minor enantiomer)=38.2 min.
m/z: calcd for [C17H20O6+Na]+: 343.1152[M+Na]+; found: 343.1165;
A
HPLC (ODH column, n-hexane/iPrOH 97:3, 0.5 mLminÀ1): tR (major en-
antiomer)=37.2, tR (minor enantiomer)=46.9 min.
Cyclopropane 3e: Colorless oil; [a]2D5 =À58.2 (c=1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d= 9.54 (d, J=4.1 Hz, 1H) , 8.17 (d, J=8.6 Hz, 2H),
7.44 (d, J=8.62 Hz, 2H) , 4.23–4.38 (m, 2H), 3.91–4.05 (m, 2H), 3.85 (d,
J=7.6 Hz,1H), 3.44 (dd, J=7.6,4.1 Hz, 1H) , 1.31 (t, J=7.0 Hz, 3H),
1.01 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d= 195.0,
165.3, 165.3, 147.6, 139.8, 129.6, 123.6, 62.8, 62.5, 45.0, 38.0, 34.6, 14.0,
13.8 ppm; HRMS m/z calcd for C16H17NO7 +Na+: 358.0897 [M+Na]+;
found: 358.0897; the enantiomeric excess was determined after in situ re-
duction with NaBH4 of the aldehyde to the corresponding alcohol;
HPLC (AD column, n-hexane/iPrOH 90:10, l=250 nm, 1 mLminÀ1): tR
(major enantiomer)=22.2, tR (minor enantiomer)=30.7 min.
Cyclopropane 3 f: Colorless oil; 1H NMR (400 MHz, CDCl3): d=9.40 (d,
J=4.6 Hz, 1H), 4.33–4.14 (m, 6H), 3.27 (d, J=6.7 Hz, 1H), 3.12 (dd, J=
4.5, 6.9 Hz, 1H), 1.27 ppm (m, 9H); 13C NMR (100 MHz, CDCl3): d=
194.3, 166.9, 165.0, 164.0, 63.0, 62.5, 62.1, 43.1, 38.3, 32.2, 14.0, 13.9
13.9 ppm; HRMS m/z: calcd for C13H18O7 +Na+: 309.0945 [M+Na]+;
found: 309.0954; [a]2D5 =À42.2 (c=1 in CHCl3). The enantiomeric excess
was determined after in situ reduction with NaBH4 of the aldehyde to
the corresponding alcohol. GC (chrompak CP-Chirasil-Dex CB-column,
temperature program: 1308C isocratic): tR (minor enantiomer)=14.3, tR
(major enantiomer)=14.5 min.
Cyclopropane 3g: Pale yellow oil; [a]2D5 =À55.7 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.52 (d, J=4.8 Hz, 1H), 7.82–7.75 (m,
3H), 7.69 (s, 1H), 7.50–7.30 (m, 3H) 4.40–4.20 (m, 2H), 3.98 (d, J=
7.6 Hz, 1H), 3.90–3.80 (m, 2H), 3.51 (dd, J=7.6 Hz, J’=4.8 Hz, 1H),
1.32 (t, J=7.6 Hz, 3H), 0.86 ppm (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=196.1, 166.0, 164.6, 132.9, 132.8, 129.6, 128.2,
127.7, 127.6, 127.5, 126.4, 126.3, 126.3, 62.5, 62.0, 44.8, 38.3, 35.5, 14.0,
13.7 ppm; IR (KBr): n˜ = 3054, 2982, 2929, 2850, 1731, 1715, 1369, 1287,
1213, 1020, cmÀ1; HRMS (ESI): m/z: calcd for C20H20O5 +Na+: 363.1203
[M+Na]+; found: 363.1215; HPLC (ODH column, n-hexane/iPrOH=
90:10, l=250 nm, 1 mLminÀ1): tR (major enantiomer)=10.7, tR (minor
enantiomer)=29.6 min.
Cyclopropane 3h: Colorless oil; [a]2D5 =À31.4 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.30 (d, J=4.8 Hz, 1H), 5.86 (ddq, J=
14.4 Hz, J’=6.8 Hz, J’’=0.8 Hz, 1H), 5.15 (ddq, J=14.4 Hz, J’=7.6 Hz,
J’’=1.6 Hz, 1H), 4.30–4.10 (m, 4H), 3.09 (dd, J=7.2 Hz, J’=7.2 Hz, 1H),
2.89 (dd, J=7.2 Hz, J’=4.8 Hz, 1H), 1.68 (dd, J=6.8 Hz, J’=1.6 Hz,
Cyclopropane 3k: Colorless oil; [a]D =À28.1 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.47 (d, J=4.5 Hz, 1H), 7.30–7.22 (m,
4H), 4.34–4.23 (m, 2H), 4.01–3.94 (m, 2H), 3.77 (d, J=7.56 Hz 1H), 3.35
(d,d, J=4.3–7.4 Hz, 1H), 1.30 (t, J=7.2–14.2 Hz, 3H), 0.99 ppm (t, J=
7.1–14.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=195.8, 166.0, 164.7,
134.6, 134.5, 130.0, 129.1, 128.5, 127.0, 62.8, 62.4, 38.2, 35.0, 14.2,
14.0 ppm; IR (KBr): n˜ =2984, 2939, 2873, 1732, 1466, 1445, 1369, 1291,
1278, 1245, 1218, 1186, 1145, 1021 cmÀ1; HRMS (ESI): m/z: calcd for
C16H17ClO5 +Na+: 347.0657 [M+Na]+, found: 347.0673; the enantiomeric
excess was determined after in situ reduction of the aldehyde to the cor-
responding alcohol with NaBH4: HPLC (AD column, n-hexane/iPrOH
97:3, 1.0 mLminÀ1): tR (major enantiomer)=37.7, tR (minor enantio-
mer)=66.8 min.
Cyclopropane 3l: Colorless oil; 1H NMR (400 MHz, CDCl3): d=9.46 (d,
J=4.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 4.35–
4.21 (m, 2H), 4.03–3.90 (m, 2H), 3.74 (d, J=7.6 Hz 1H), 3.33 (dd, J=
4.5,7.5 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H), 0.99 ppm (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=195.9, 166.0, 165.0, 131.8, 131.6, 130.5,
122.3, 62.8, 62.4, 38.2, 35.0, 14.2, 14.0 ppm; IR (KBr): n˜ =2982, 2937,
2873, 1735, 1466, 1445, 1369, 1288, 1278, 1245, 1218, 1181, 1145,
1011 cmÀ1; [a]D =À31.0 (c=1.0 in CHCl3); HRMS (ESI): m/z: calcd for
C16H17BrO5+Na+: 391.0152 [M+Na]+; found: 391.0145; The enantiomer-
ic excess was determined after in situ reduction of the aldehyde to the
corresponding alcohol with NaBH4: HPLC (ODH column, n-hexane/
iPrOH 97:3, 1.0 mLminÀ1): tR (major enantiomer)=41.5, tR (minor enan-
tiomer)=43.8 min.
Cyclopropane 3ab: Colorless oil; [a]D =À56.5 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.40 (d, J=4.6 Hz, 1H), 7.36–7.19 (m,
13H), 6.98–6.94 (m, 2H), 5.23 (q, J=12.4–38.1 Hz, 2H), 4.84 (q, J=12.1–
26.7 Hz, 2H), 3.86 (d, J=7.6 Hz, 1H), 3.41 ppm (dd, J=4.6–7.7 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=196.1, 166.1, 165.0, 135.1, 134.8, 132.2,
129.6, 129.3, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 68.4, 68.1, 38.6,
36.0 ppm; IR (KBr): n˜ =2955, 2924, 2850, 1728, 1498, 1455, 1378, 1286,
1278, 1215, 1217, 1179, 1142, 1029 cmÀ1; HRMS (ESI): m/z: calcd for
C26H22O5+Na+: 437.1359 [M+Na]+; found 437.1351; HPLC (ODH
column, n-hexane/iPrOH 97:3, 1.0 mLminÀ1): tR (major enantiomer)=
37.8, tR (minor enantiomer)=53.1 min.
7876
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7867 – 7879

Organocatalytic Cyclopropanation and Cyclopentanation Reactions
FULL PAPER
Cyclopropane 3ac: Colorless oil; [a]D =À51.1 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.49 (d, J=4.5 Hz, 1H), 7.30–7.22 (m,
5H), 3.83–3.82 (m, 1H), 3.81 (s, 3H), 3.46 (s, 3H), 3.39 ppm (dd, J=7.5,
4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=196.2, 166.7, 165.3, 132.4,
128.7, 128.6, 128.3, 53.6, 53.1, 38.5, 36.0 ppm; IR (KBr): n˜ =2956, 2936,
2849, 1731, 1499, 1437, 1392, 1291, 1278, 1251, 1217, 1195, 1144,
or MeOH (3.0 equiv). The reaction mixture was vigorously stirred at RT
for 3 h. To this mixture was added DIPEA (40 mol%) and thiazolium
precatalyst 17 (20 mol%). The resulting solution was warmed to 308C
and stirred for 15 h. Next, the reaction mixture was treated with sat. aq.
NH4Cl (1 mL) and extracted with EtOAc (2”5 mL). The combined or-
ganic extracts were washed with brine, dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (hexane/EtOAc 6:1) to afford the corresponding esters 18a and
18b, respectively.
1028 cmÀ1
;
HRMS (ESI): m/z: calcd for C14H14O5+Na+: 285.0733
[M+Na]+; found 285.0743; HPLC (ODH column, n-hexane/iPrOH 97:3,
0.5 mLminÀ1): tR (major enantiomer)=39.0, tR (minor enantiomer)=
54.8 min.
(R)-1,1-diethyl 3-ethyl 2-phenylpropane-1,1,3-tricarboxylate 18a:[32]
Cyclopropane 3m: Colorless oil; [a]2D5 =À66.8 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=9.50 (d, J=4.8 Hz, 1H), 7.35–715 (m, 5H), 4.38–
4.26 (m, 2H), 3.89 (d, J=7.6 Hz, 1H), 3.49 (dd, J=4.8, 7.6 Hz, 1H), 1.98
(s, 3H), 1.33 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): 196.4,
196.0, 167.1, 131.3, 128.6, 128.2, 128.2, 62.6, 51.6, 37.2, 36.8, 29.2,
1
[a]2D5 =À8.4 (c=0.5 in CHCl3); H NMR (CDCl3, 400 MHz): d=7.26–7.21
(m, 5H), 4.21 (q, J=7.2 Hz, 2H), 3.90–4.00 (m, 5H), 3.72 (d, J=10.4 Hz,
1H), 2.84 (dd, J=15.6, 5.2 Hz, 1H), 2.72 (dd ,J=15.6, 10.0 Hz, 1H), 1.26
(t, J=7.2 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H), 0.98 ppm (t, J=7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d=171.3, 168.2, 167.7, 140.0, 128.5, 128.4,
14.0 ppm; IR (KBr): n˜ =2983, 2855, 1708, 1358, 1279, 1176, 698 cmÀ1
HRMS m/z: calcd for C15H16O4 +Na+: 283.0941 [M+Na]+); found
;
127.4, 61.8, 61.5, 60.6, 57.5, 41.7, 38.9, 14.19, 14.15, 13.9 ppm; HRMS(ESI)
A
m/z: calcd for C18H24O6+Na+: 359.1465 [M+Na]+; found 359.1476;
(
ACHTREUNG
HPLC (Chiralpak AD column, hexane/2-propanol 95:5, 0.5 mLminÀ1
,
283.0950; HPLC (ODH column, n-hexane/iPrOH 90:10, l=240 nm,
1 mLminÀ1): tR (major enantiomer)=10.8, tR (minor enantiomer)=
17.3 min.
210 nm): tR (major)=24.714, tR (minor)=38.629 min.
(R)-1,1-diethyl 3-methyl 2-phenylpropane-1,1,3-tricarboxylate 18b:[29]
1
[a]2D5 =À 33.2 (c=1 in CHCl3); H NMR (CDCl3, 300 MHz): d=7.29–7.19
Synthesis of alcohol 15a: Concentrated AcOH (0.18 mL) and NaCNBH3
(0.225 mmol, 1.5 equiv) were added to a solution of cyclopropane 3a
(0.15 mmol, 1 equiv) in THF (1 mL)at 08C. The reaction mixture was
warmed up to RTovernight. Next, brine (1 mL) was added and pH was
adjusted to 7 with saturated NaHCO3 solution. The aqueous layer was
extracted with Et2O (3”10 mL) and the combined organic layers were
dried over MgSO4. After evaporation of the solvents under vacuum the
crude product was purified by column chromatography to afford the cor-
responding alcohol 15a.
Alcohol 15a: Colorless oil; [a]2D5 =À91.3 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.30–7.10 (m, 5H), 4.35–4.25 (m, 2H), 4.02 (dd,
J=12.0, 5.6 Hz, 1H), 3.91–3.82 (m, 2H), 3.62 (dd, J=12.0, 8.4 Hz, 1H),
3.17 (d, J=8.0 Hz, 1H), 2.87–2.80 (m, 1H), 1.31 (t, 7.2 Hz, 3H), 0.89 ppm
(t, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=168.3, 166.8, 134.3,
128.8, 128.3, 127.5, 62.2, 61.5, 61.0, 42.2, 35.0, 32.3, 14.2, 13.8 ppm; IR
(KBr): n˜ =3430, 2981, 2933, 1723, 1370, 1298, 1029 cmÀ1; HRMS (ESI):
m/z: calcd for C16H20O5 +Na+: 315.1203 [M+Na]+; found: 315.1203;.
(m, 5H), 4.20 (q, J=7.2 Hz, 2H), 3.92 (q, J=7.2 Hz, 2H), 3.92–3.87 (m,
1H), 3.74 (d, J=7.2 Hz, 1H), 3.52 (s, 3H), 2.86 (dd, J=4.5, 15.6 Hz, 1H),
2.74 (dd ,J=6.9, 15.6 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H), 0.98 ppm (t, J=
7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=171.7, 168.1, 167.6, 140.0,
128.5, 128.2, 127.4, 61.8, 61.5, 57.4, 51.7, 41.6, 38.7, 14.2, 13.8 ppm;
HRMS
(ESI): m/z: calcd for C17H22O6+Na+: 345.1309 [M+Na]+; found:
R
345.1306; HPLC (Chiralpak ODH column, hexane/2-propanol 97:3,
1.0 mL/min, 210 nm): tR (minor enantiomer)=15.513, tR (major enantio-
mer)=18.297 min.
One-pot reaction procedure for the synthesis of tri-carboxylate ester 18c:
To a stirred solution of (S)-9 (16 mg, 20 mol%) in CHCl3 (1 mL), was
added trans-4-nitro-cinnamic aldehyde (0.3 mmol), BrCH(CO2Et)2 2a
T
(0.25 mmol), NEt3 (0.25 mmol) and MeOH (30 mL, 3.0 equiv). The reac-
tion was vigorously stirred at room temperature for 1.5 h. To this mixture
was added diisopropylethylamine (40 mol%) and thiazolium precatalyst
17 (20 mol%). The resulting solution was warmed to 308C and stirred for
15 h. Next the reaction mixture was treated with sat. aq. NH4Cl (1 mL)
and extracted with EtOAc (2”5 mL). The combined organic extracts
were washed with brine, dried over Na2SO4 and concentrated under re-
duced pressure. The residue was purified by flash chromatography
(hexane/EtOAc 6:1) to afford the corresponding ester 18c.
Synthesis of lactone 16a: p-Toluenesulfonic acid (0.01 mmol, 0.1 equiv)
was added to a solution of compound 15a (0.1 mmol, 1 equiv) in CHCl3
(10 mL). The reaction was stirred overnight at 458C. Next, the reaction
mixture was treated with sat. aq. NaHCO3 and extracted with CHCl3 (2”
5 mL). The combined organic extracts were washed with brine, dried
over Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc mixtures) to afford the
cyclic compound 16a.
(R)-1,1-Diethyl 3-methyl 2-(4-nitrophenyl)propane-1,1,3-tricarboxylate
18c: [a]2D5 =À20.4 (c=1 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=8.15
(d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 4.22 (dq, J=1.2, 7.2 Hz, 2H),
4.07–4.03 (m, 1H), 3.97 (dq, J=2.4, 7.2 Hz, 2H), 3.76 (d, J=10.0 Hz,
1H), 3.54 (s, 3H), 2.91 (dd, J=4.8, 16.4 Hz, 1H), 2.78 (dd ,J=10.0,
16.4 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H), 1.04 ppm (t, J=7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d=171.1, 167.6, 167.2, 147.9, 147.3, 129.4,
123.8, 62.2, 61.9, 56.7, 52.0, 41.1, 38.1, 14.2, 14.0 ppm; HRMS (ESI): m/z:
calcd for C17H21O8N+Na+: 390.1159 [M+Na]+; found 390.1150; HPLC
Compound 16a: Colorless oil; [a]2D5 =À21.7 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.35–7.20 (m, 5H), 4.51 (dd, J=9.2, 4.8 Hz, 1H),
4.37 (d, J=9.2 Hz, 1H), 4.04–3.88 (m, 2H), 3.31 (t, J=5.2 Hz, 1H), 2.91
(d, J=5.6 Hz, 1H), 0.91 ppm (t, 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=170.2, 163.6, 131.9, 128.8, 128.5, 67.4, 61.9, 37.9, 37.5, 27.5,
13.9 ppm; IR (KBr): n˜2980, 2918, 1779, 1726, 1374, 1351, 1058 cmÀ1
;
HRMS m/z: calcd for C14H14O4 +Na+: 269.0784 [M+Na]+; found:
(Chiralpak ODH column, n-hexane/2-propanol 90:10, 0.5 mLminÀ1
,
269.0796.
210 nm): tR (major enantiomer)=26.499, tR (minor enantiomer)=
32.644 min.
Synthesis of thiazolium catalyst 17: Benzyl chloride (1.27 g, 10 mmol,
1.0 equiv) was added dropwise over 10 min To 2,3-dimethylthiazole
(1.074 mL, 10 mmol, 1.0 equiv) in CH3CN (5 mL). The solution was
heated to reflux for 24 h. Following cooling to room temperature and
gentle scraping with a spatula, a white precipitate formed, which was col-
lected by filtration and washed with cold CH3CN. Vacuum drying gave 17
(2.13 g, 72%) as a white solid.
17:[31] 1H NMR (CDCl3, 300 MHz): d=12.1 (s, 1H), 7.38–7.34 (m, 5H),
6.15 (s, 2H), 2.47 (s, 3H), 2.38 ppm (s, 3H); 13C NMR (CDCl3, 75 MHz):
d=158.4, 141.9, 133.2, 132.2, 129.6, 129.5, 128.4, 57.5 ppm.
One-pot reaction procedure for the synthesis of tri-carboxylate esters
18d:
To a stirred solution of (S)-11 (16 mg, 20 mol%) in CHCl3 (1 mL) at 48C,
was added aldehyde 1h (0.3 mmol), BrCH(CO2Et)2 2a (0.25 mmol),
N
NEt3 (0.25 mmol) and MeOH (30 mL, 3.0 equiv). The reaction was vigo-
rously stirred at 48C for 6 h. To this mixture was added DIPEA
(40 mol%) and thiazolium precatalyst 17 (20 mol%). The resulting solu-
tion was warmed to 308C and stirred for 15 h. Next the reaction mixture
was treated with sat. aq. NH4Cl (1 mL) and extracted with EtOAc (2”
5 mL). The combined organic extracts were washed with brine, dried
over Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc=6:1) to afford the
corresponding ester 18d.
One-pot reaction procedure for the synthesis of tri-carboxylate esters
18a and 18b from enal 1a: To a stirred solution of (S)-9 (16 mg,
20 mol%) in CHCl3 (1 mL), was added trans-cinnamic aldehyde 1a
(0.3 mmol), BrCH(CO2Et)2 2a (0.25 mmol), NEt3 (0.25 mmol) and EtOH
A
Chem. Eur. J. 2008, 14, 7867 – 7879
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7877

A. Córdova et al.
(R)-1,1-diethyl 3-methyl 2-(naphthalen-2-yl)propane-1,1,3-tricarboxylate
18d: [a]2D5 =À17.3 (c=1 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=
7.79–7.76 (m, 3H), 7.70 (d, J=1.2 Hz, 1H), 7.46–7.43 (m, 2H), 7.39 (dd,
J=1.2, 8.8 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.11 (ddd, J=4.8, 10.0,
10.0 Hz, 1H), 3.92–3.85 (m, 3H), 3.50 (s, 3H), 2.95 (dd, J=4.8, 15.6 Hz,
1H), 2.87 (dd ,J=10.0, 15.6 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H), 0.92 ppm (t,
J=7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d=171.7, 168.1, 167.6,
137.6, 133.4, 132.8, 128.3, 128.0, 127.7, 127.2, 126.22, 126.16, 125.9, 61.9,
61.5, 57.4, 51.7, 41.6, 38.6, 14.2, 13.8 ppm; HRMS (ESI): m/z: C21H24O6 +
Na+ requires 395.1465 [M+Na]+; found: 395.1459; HPLC (Chiralpak
IR (KBr): n˜ =3584, 2967, 2922, 2882, 1724, 1463, 1372, 1259, 1147,
1030 cmÀ1
;
HRMS
(ESI): m/z: calcd for C10H14O4 +Na+: 221.0784
A
[M+Na]+; found: 221.0789; GC(IVADEX-1 chiral column (25 m,
0.25 mm, 0.15 mm), temperature program: 1058C 45 min, 1058C//0.58C
minÀ1//1108C, 1108C//808C minÀ1//2008C 5 min): tR (major enantiomer)=
43.8, tR (minor enantiomer)=45.3 min.
Diasteroselective synthesis of cyclopentanediol 20d: Acetic acid (225 mL)
and NaBH3CN (29 mg, 0.45 mmol) were added to a stirred solution of cy-
clopentanone 19d (42 mg, 0.20 mmol) in THF (1.0 mL), at 08C. The reac-
tion was stirred at this temperature for 1 h and then at RTovernight. The
crude product was purified by silica-gel chromatography (pentane/EtOAc
mixtures) to give the corresponding cyclopentanol 20d (27 mg, 63%
yield).
AD column, n-hexane/2-propanol=80:20, 0.5 mLminÀ1
, 210 nm): tR
(major enantiomer)=18.178, tR (minor enantiomer)=28.392 min.
Typical experimental procedure for the organocatalytic domino reactions
with 4-bromoacetoacetate 2 f: a,b-Unsaturated aldehyde 1 (0.30 mmol,
1.2 equiv), K2CO3 (0.25 mmol, 1.0 equiv) and ethyl 4-bromo-3-oxobuta-
noate 2 f (0.25 mmol, 1.0 equiv) were added to a stirred solution of cata-
lyst 9 (0.05 mmol, 20 mol%) in CHCl3 (1.0 mL). The reaction was vigo-
rously stirred for the time and the temperature listed in Table 2. Next,
the crude product was purified by silica-gel chromatography (pentane/
EtOAc mixtures) to give the corresponding cyclopentanone 19.
Cyclopentanol 20d: Colourless oil; [a]D =À9.7 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=4.37 (dd, J=7.6 Hz, 13.6 Hz, 1H;
CHOH), 4.17 (q, J=7.2 Hz, 2H; COOCH2CH3), 3.64 (dd, J=4.4 Hz,
10.4 Hz, 1H; CH2OH), 3.51 (dd, J=7.6 Hz, 10.4 Hz, 1H; CH2OH), 2.43
(dd, J=7.6 Hz, 8.8 Hz, 1H; CHCOOCH2CH3), 2.10–2.01 (m, 1H;
CHCH2CH3), 1.99–1.78 (m, 3H; CH2, CHCH2OH), 1.64–1.52 (m, 2H;
CH2CH3), 1.27 (t, J=7.2 Hz, 3H; CH2CH3), 0.92 ppm (t, J=7.2 Hz, 3H;
COOCH2CH3); 13C NMR (100 MHz, CDCl3): d=175.0, 75.6, 66.2, 60.9,
58.7, 44.9, 44.0, 37.1, 27.8, 14.4, 11.8 ppm. IR (KBr): n˜ =3353, 2960, 2932,
2877, 1727, 1463, 1378, 1261, 1162, 1095, 1037, 914 cmÀ1; HRMS (ESI):
m/z: calcd for C11H20O4 +Na+: 239.1254 [M+Na]+; found: 239.1262.
Cyclopentanone 19a: Colorless oil; [a]D =À65.5 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.73 (d, J=2.8 Hz, 1H), 4.21 (q, J=
7.2 Hz, 2H), 3.05–2.45 (m, 4H), 1.76–1.60 (m, 2H), 1.60–1.43 (m, 2H),
1.40–1.20 (m, 6H), 0.88 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=207.7, 200.1, 168.6, 61.8, 61.2, 52.3, 41.6, 38.6, 34.0, 29.5, 22.6,
14.1, 13.8 ppm; HRMS (ESI): m/z: calcd for C13H20O4 + Na+: 263.1254
[M+Na]+; found 263.1253; GC (chrompak CP- Chirasil-Dex CB-column,
temperature program: 5 min,708C//28C minÀ1//1108C, 10 min//108C
minÀ1//200,10 min): tR (major enantiomer)=11.3, tR (minor enantio-
mer)=11.6 min.
Acknowledgements
We gratefully acknowledge the Swedish National Research Council,
Wenner-Gren, Lars Hierta, Magnus Bergvall and Carl-Trygger Founda-
tions for financial support. The Berzelii Center EXSELENT is financially
supported by VR and the Swedish Governmental Agency for Innovation
Systems (VINNOVA).
Cyclopentanone 19b: Colorless oil; [a]D =À78.4 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.73 (d, J=2.8 Hz, 1H), 4.25–4.18 (m,
2H), 3.05–2.40 (m, 4H), 1.70–1.25 (m, 8H), 1.00–0.90 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d=207.6, 200.1, 168.6, 61.8, 61.2, 52.3, 41.4,
38.6, 35.5, 20.6, 14.1, 14.0 ppm; IR (KBr): n˜ =2964, 2936, 2874, 1731,
1466, 1447, 1369, 1295, 1223, 1201, 1146 cmÀ1; HRMS (ESI): m/z: calcd.
for C12H18O4 +Na+ 249.1097 [M+Na]+; found 249.1100; GC (chrompak
CP- Chirasil-Dex CB-column, temperature program: 1308C 10 min,
1308C//38C minÀ1//1608C, 1608C 2 min, 1308C//808C minÀ1//2008C
minÀ1//5 min): tR (major enantiomer)=12.8, tR (minor enantiomer)=
13.2 min.
[1] For reviews on this concept, see: a) L. F. Tietze, G. Brasche, K. Ger-
icke, Domino Reactions in Organic Synthesis, Wiley-VCH, Wein-
heim 2006, p. 672; b) L. F. Tietze, Chem. Rev. 1996, 96, 115; c) K. C.
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Cyclopentanone 19c: Colorless oil; [a]D =À34.2 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.71 (d, J=2.8 Hz, 1H), 7.30–7.10 (m,
5H), 4.22 (q, J=7.2 Hz, 2H), 3.10–2.55 (m, 4H), 2.08–1.98 (m, 1H),
1.92–1.80 (m, 1H), 1.30–1.20 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=207.2, 199.8, 168.4, 140.6, 128.6, 128.5, 128.1, 126.3, 61.9, 61.1, 52.4,
41.1, 38.5, 36.1, 33.5, 14.1 ppm; IR (KBr): n˜ =2962, 2937, 2877, 1751,
1730, 1459, 1443, 1374, 1301, 1265, 1194, 1106, 1054, 1027 cmÀ1; HRMS
(ESI): m/z: calcd for C13H20O4 +Na+: 263.1254 [M+Na]+; found
263.1253; HPLC(ODH column, n-hexane: iPrOH=95:5, l=305 nm),
0.5 mLminÀ1): tR (major enantiomer)=26.3, tR (minor enantiomer)=
35.6 min.
Cyclopentanone 19d: Colorless oil; [a]D =+103.8 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.74 (d, J=2.4 Hz, 1H), 4.21 (q, J=
7.2 Hz, 2H), 3.02–2.66 (m, 4H), 2.60–2.53 (m, 1H), 1.78–1.69 (m, 1H),
1.64–1.54 (m, 1H), 1.32–1.26 (m, 3H), 0.96 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=207.7, 200.2, 168.7, 62.0, 60.9, 52.0, 43.2,
38.8, 27.1, 14.3 ppm, 11.8 ppm; IR (KBr): n˜ =2968, 2937, 2880, 1755,
1728, 1464, 1447, 1372, 1262, 1174, 1096, 1030, 854 cmÀ1; HRMS (ESI):
m/z: calcd for C11H16O4 +Na+ 235.0941 [M+Na]+; found 235.0939; GC
(chrompak CP- Chirasil-Dex CB-column, temperature program: 1208C
10 min, 1208C//38C minÀ1//1608C//808C minÀ1//2008C minÀ1//5 min.): tR
(major enantiomer)=8.8 min, tR (minor enantiomer)=9.2 min.
Cyclopentanone 19e: Colorless oil. [a]2D5= +53.4 (c=0.5 in CHCl3);
1H NMR (400 MHz, CDCl3): d=9.75 (d, J=2.4 Hz, 1H), 4.23 (q, J=
7.2 Hz, 2H), 2.96 (dd, J=0.8, 7.2 Hz, 1H), 2.85–2.84 (m, 1H), 2.73–2.61
(m, 3H), 1.30 (s, 3H), 1.30 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=207.1. 199.9, 168.0, 62.8, 62.0, 53.7, 38.9, 37.0, 18.5, 14.3 ppm;
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Received: March 11, 2008
Published online: July 11, 2008
Chem. Eur. J. 2008, 14, 7867 – 7879
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7879