A general organocatalytic enantioselective malonate addition to α,β-unsaturated enones

Article abstract of DOI:10.1002/chem.200800673

A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to α,β-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic e

Full text of DOI:10.1002/chem.200800673

FULL PAPER
DOI: 10.1002/chem.200800673
A General Organocatalytic Enantioselective Malonate Addition to
a,b-Unsaturated Enones
Veit Wascholowski, Kristian Rahbek Knudsen, Claire E. T. Mitchell, and
Steven V. Ley*[a]
Abstract: Ageneral enantioselective
organocatalytic conjugate addition pro-
cedure of a variety of malonates to
a,b-unsaturated enone systems is pre-
sented. The reaction is efficiently cata-
lysed by the pyrrolidinyl tetrazole cata-
lyst 1. Cyclic, acyclic and aromatic
enones can be used and the reaction
with ethyl malonates 3b provides the
Michael addition products in high
yields with good to excellent enantiose-
lectivities. Since only 1.5 equivalents of
malonate are used as a reagent, the re-
action is readily scaled and practical to
operate. Furthermore, the malonate ad-
dition products can be easily mono de-
carboxylated without loss in enantio-
meric excess by enzymatic or sodium
hydroxide mediated methods.
Keywords: asymmetric catalysis
chirality enantioselectivity
Michael addition · organocatalysis
·
·
·
Introduction
and readily available, non-toxic and inert toward moisture
and oxygen.[4c]
Catalytic asymmetric conjugate additions play a prominent
Proline rubidium salts have been used for the 1,4-addition
of malonates to a,b-unsaturated enones,[5] but the first
highly enantioselective truly organocatalytic reaction was
developed in the presence of an imidazoline catalyst.[6]
Other organocatalysts,[7] for example, thioureas,[8] chinchona
alkaloids,[9] diaryl-2-pyrrolidine-methanols[10] or chiral ionic
liquids[11] have also been introduced to catalyse this impor-
À
role in carbon carbon bond-forming reactions in modern
synthetic chemistry and natural product assembly especially
during the synthesis of polyketides.[1] The 1,4-addition has in
recent years been the subject of numerous advances aimed
at the discovery of efficient chiral catalysts. As a result,
many methods have been developed for the stereoselective
1,4-addition,[2] and malonates most notably have been
proved to be easily accessible nucleophilic donors,[3] as the
two electron-withdrawing esters enable enolate formation
under mild conditions.
À
tant carbon carbon forming reaction. Unfortunately, these
methods often have drawbacks such as tedious procedures,
reaction times up to weeks in some cases and the enantiose-
lectivities can be variable depending on the nature of the
a,b-unsaturated enones and malonates employed. Further-
more, the malonates were often employed in excess or as
the reaction solvent and since these malonates are not vola-
tile, their removal is problematic.
Since the start of this decade, great progress has been
made in the field of asymmetric organocatalysis.[4] The in-
creasing interest is mainly due to the possibility of easy and
environmentally acceptable access to important chiral build-
ing blocks for life science and agriculture applications. Fur-
thermore, organocatalysts can be used in a range of reac-
tions with a multitude of advantages over metal-mediated
reactions: for example, they are usually robust, inexpensive
Since the introduction of the pyrrolidinyl tetrazole deriva-
tive 1 in enantioselective organocatalysed reactions by our-
selves,[12] Yamamoto[13] and Arvidsson,[14] its use is now
widely accepted.
In recent studies in this area, we described an enantiose-
lective conjugate addition of different malonates to mainly
aromatic enones in the presence of piperidine (4) and the
pyrrolidinyl tetrazole catalyst 1, after an extensive screening
of different organocatalysts (Scheme 1).[12j]
Here, we report the evolution of these studies and the re-
sulting development of a more general and practical enan-
tioselective organocatalytic conjugate addition of malonates
[a] Dr. V. Wascholowski, Dr. K. R. Knudsen, Dr. C. E. T. Mitchell, Prof.
Dr. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (+44)1223-336442
E-mail: svl1000@cam.ac.uk
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Table 2. Optimisation of the malonate addition: solvent screen.[12j]
Scheme 1. Enantioselective organocatalytic malonate addition to differ-
ent enones 2.
Entry
Malonate
Solvent
Product
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
3a
3a
3b
3b
3c
3c
3c
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CH3CN
7a
7a
7b
7b
7c
7c
7c
85
87
89
69
63
87
80
83
85
92
93
82
81
70
to a,b-unsaturated enones with excellent yields and enantio-
selectivities, where cyclic, acyclic and aromatic enones are
also be applied.
[a] Conditions: 2-cyclohexenone 6 (0.5 mmol), malonate 3 (0.75 mmol), 4
(0.5 mmol), (S)-1 (15 mol%), solvent (2 mL), 3 d, RT. [b] Determined by
1H NMR. [c] Determined by chiral GC.
Results and Discussion
We have shown that the tetrazole derivative 1 is an im-
proved catalyst for the conjugate addition of nitroalkanes to
both cyclic and acyclic enones,[12g] using the meso base 2,5-
dimethylpiperazine 8 as an additive under conditions adapt-
ed from those previously developed by Hanessian and Pham
for the addition of nitroalkanes to cyclic enones catalysed
by proline.[15]
Using these reaction conditions, we were able to obtain
the benzyl malonate-addition product 7c in 65% conversion
and 77% ee (Table 1, entry 4). Due to the fact that malo-
nates (diethyl malonate pKa 13) are less acidic than nitroal-
kanes (MeNO2 pKa 10), the use of stronger bases was next
investigated. Indeed, piperidine (4) increased the enantiose-
lection of the reaction of 2-cyclohexenone 6 with methyl,
ethyl and benzyl malonates (Table 1).[12j]
entry 7) led to a decrease in both yield and enantioselectivi-
ty.
To obtain the best result in the conjugate malonate addi-
tion methyl, ethyl and benzyl malonates 3a–c were added to
2-cyclohexenone 6 and to trans 4-phenyl-3-butene-2-one 9 as
a less reactive Michael acceptor (Table 3). In contrast to
other publications, under these optimised conditions with
the use of the pyrrolidinyl tetrazole catalyst 1 ethyl malo-
nate 3b gave the best results in enantioselection and was
chosen for use in the next investigations. It is interesting to
note that usually benzyl malonate 3c has been selected as
the malonate of choice in these Michael addition to a,b-un-
saturated enones[6] and a,b-unsaturated aromatic alde-
On closer examination of the reaction solvent chloroform
proved to be the optimal solvent in terms of both yield and
enantioselection (Table 2, entries 2, 4 and 6). The use of
non-chlorinated solvents, for example, acetonitrile (Table 2,
hydes.[10a] Indeed, only one other publication uses ethyl mal-
onates in the conjugate addition to various chalcones cata-
lysed by an amine thiourea.[8a]
Table 1. Optimisation of the malonate addition: base screen.[12j]
Table 3. Malonate addition to cyclic and aromatic enones.
Entry
Malonate
Base[b]
Product
Conversion [%][c]
ee [%][d]
Entry
Malonate
Enone
Product [%]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
3a
3b
3b
3c
3c
3c
4
8
4
8
4
7a
7b
7b
7c
7c
7c
85
65
89
65
63
49
83
79
92
77
82
81
1
2
3
4
5
6
3a
3a
3b
3b
3c
3c
6
9
6
9
6
9
7a
10a
7b
10b
7c
87
89
94
89
86
85
83
86
93
87
81
83
Et2NH
10c
[a] Conditions: 2-cyclohexenone 6 (0.5 mmol), malonate 3 (0.75 mmol),
base (0.5 mmol), (S)-pyrrolidinyl tetrazole 1 (15 mol%), CH2Cl2 (2 mL),
3 d, RT. [b] Piperidine (4); meso-2,5-dimethylpiperazine (8). [c] Deter-
[a] Conditions: Enone 6 or 9 (0.5 mmol), malonate 3 (0.75 mmol), 4
(0.5 mmol), (S)-1 (15 mol%), CHCl3 (2 mL), 3 d, RT. [b] Isolated yield.
[c] Determined by chiral HPLC or GC.
1
mined by H NMR. [d] Determined by chiral GC.
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Organocatalytic Enantioselective Addition
FULL PAPER
Table 5. The 1,4-addition of ethyl malonate to linear a,b-unsaturated
The absolute configuration of the compounds was con-
firmed by a comparison of the sign of optical rotation with
literature values,[8a,16] and the compounds proved to be (R)-
configured in the case of cyclic enones and (S)-configured in
the case of linear and aromatic enones. Thus, the pyrrolidin-
yl tetrazole catalyst 1 gave products with the same sense of
stereoinduction as observed in the addition to
nitroalkanes.[12g]
enones.[a]
Entry
Product
Yield [%][b]
ee [%][c]
1
86
87
The enantioselective organocatalytic conjugate addition
was first applied to cyclic enones (Table 4). It was pleasing
to find that as well as the known compound 7b, the seven-
membered congener (Table 4, entry 2) was also formed in a
similarly high yield (91%) and enantioselectivity (93%). In
fact, only the five-membered 2-cyclopentenone (Table 4,
entry 3) gave a moderate enantioselectivity (30%), but re-
tained the high yield (88%).
2
3
82
82
64
77
Table 4. 1,4-Addition of ethyl malonate to cyclic a,b-unsaturated
enones.[a]
Entry
Product
Yield [%][b]
ee [%][c]
[a] Conditions: a,b-unsaturated enone (0.5 mmol), diethyl malonate 3b
(0.75 mmol), piperidine (0.5 mmol), (S)-pyrrolidinyl tetrazole
4
1
(15 mol%), CHCl3 (2 mL), 3 d, RT. [b] Isolated yield. [c] Determined by
chiral HPLC or GC.
1
94
93
(Cl, Br, CF3, Table 6, entries 2–6) and electron-donating
(OH, OR, Table 6, entries 7–11) substituents can be intro-
duced on the aromatic ring without loss in yield or enantio-
selection. Furthermore, the position of the substituent on
the aromatic ring, for example, bromine seems to have no
influence, apart from the ortho-position (Table 6, entry 5). It
is thought that in this case an unfavourable interaction with
the methyl carbonyl function takes place, but regardless, the
Michael addition product 19 was isolated in a similar high
2
3
91
88
89
30
yield (81%) with
(60%).
a slightly reduced enantioselectivity
In the case of the para-hydroxy substituted aromatic
enone (Table 6, entry 8) the reaction was run with two
equivalents of base 4 required to increase yield and enantio-
selectivity, since the pKa of the phenol proton is comparable
to that of the malonate.[12j] This afforded the product 22 in a
moderate yield (68%) and enantioselectivity (51%). After
protection of the para-hydroxy substituent as a benzyl ether
the product 23 was obtained again with the use of one
equivalent of 4 in very good yield (82%) and enantioselec-
tivity (85%) (Table 6, entry 9). Afterwards, the protective
group may be removed under standard hydrogenation con-
ditions without affecting the ethyl esters. The only exception
to the generally high enantioselectivities with aromatic
enones was the Michael addition to a chalcone, where the
a-methyl group is replaced with an a-phenyl group. Here
the product 26 was only obtained in a moderate enantiose-
lectivity (44% ee) (Table 6, entry 12) and it is thought that
an unfavourable interaction with the other aromatic ring
takes place. Furthermore, the reaction was quite slow and
further trials to optimise this reaction have so far been un-
successful. However, the product 26 was obtained in a very
[a] Conditions: enone (0.5 mmol), diethyl malonate 3b (0.75 mmol), 4
(0.5 mmol), (S)-1 (15 mol%), CHCl3 (2 mL), 3 d, RT. [b] Isolated yield.
[c] Determined by chiral HPLC or GC.
The ethyl malonates 3b were next applied in the addition
to linear (E)-enones (Table 5). Again, it was most encourag-
ing to see that they did indeed react with generally compa-
rable high yields and enantioselectivities as the 2-cyclohexe-
none system 6. 3-Nonen-2-one (Table 5, entry 1) worked just
as well as the truncated linear enone 3-penten-2-one
(Table 5, entry 2) with very good yields and enantioselectivi-
ties. Furthermore, the branched example 15 (Table 5,
entry 3) also worked well and was obtained in good yields
(82%), retaining the good enantioselectivity (77%).
To further explore the scope of the reaction, a series of ar-
omatic (E)-a,b-unsaturated enones were used as substrates
in the 1,4-addition of ethyl malonate 3b (Table 6). It was
pleasing to find that these also worked very well and the
Michael adducts were all formed in high yields and general-
ly excellent enantioselectivities. Both electron-withdrawing
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S. V. Ley et al.
Table 6. 1,4-Addition of ethyl malonate to aromatic a,b-unsaturated enones.[a]
[b]
[b]
Entry
Product
Yield [%]
ee [%][c]
Entry
10
Product
Yield [%]
88
ee [%][c]
1
89
87
84
84
44
2
3
94
88
83
85
11
12
87
86[e]
4
5
6
87
81
82
86
60
79
13
14
15
81
84
91
88
85
84
7
8
9
93
68[d]
82
88
51
85
16
17
18
83
89
88
79
88
85
[a] Conditions: a,b-unsaturated enone (0.5 mmol), diethyl malonate 3b (0.75 mmol), 4 (0.5 mmol), (S)-1 (15 mol%), CHCl3 (2 mL), 3 d, RT. [b] Isolated
yield. [c] Determined by chiral HPLC or GC. [d] Two equivalents of piperidine was used. [e] 5 d reaction time.
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Organocatalytic Enantioselective Addition
FULL PAPER
Table 7. Krapcho decarboxylation of 7a, and 7b.
high yield (86%) without formation of by-products and it
was only the enantiomeric excess that was moderate. Conse-
quently, it was pleasing to find that both heteroaromatic
enones and biaryl compounds were also good substrates for
this malonate addition, retaining the very high yield and
enantioselection formed in the more standard aromatic ex-
amples (Table 6, entries 13–18). It should be noted that no
by-products were observed in any of these reactions with
cyclic, acyclic and aromatic enones.
Entry
R
Conditions
Yield
ee
[%][a] [%][b]
As the general nature of the reaction protocol has been
proven, obtaining the products in good to excellent yields
and enantioselectivities, the Michael adducts 5 could be fur-
ther decarboxylated to give the corresponding optically
active d-ketoesters 33 (Scheme 2). Usually, for this reaction
benzyl esters are used, which are first deprotected via hy-
drogenolysis to yield the free acids, then mono-decarboxy-
lated and finally re-esterified. Although this reaction can be
performed in a one-pot decarboxylation–transesterification
procedure, the reaction protocol is tedious and the yields
are poor.[6]
1
2
Et DMSO, 2 equiv H2O, 3 h, 1758C
Et 2 equiv LiBr, 1 equiv H2O, 0.2 equiv
Bu4NBr, 3 h, 1758C[18]
0[c]
53
–
47
3
4
5
6
Et 2 equiv LiBr, 2 equiv H2O, 0.2 equiv
84[e]
46
76
44
–
Bu4NBr, microwave[d]
Et 2 equiv LiBr, 2 equiv H2O, 0.1 equiv
Bu4NBr, 5 h, 1758C[18]
Me 2 equiv LiBr, 2 equiv H2O, 0.1 equiv
0[f]
16
Bu4NBr, 5 h, 1758C[18]
Me 4 equiv (CH3)4NOAc, 6 equiv H2O, 1008C,
5 h[17a]
10
7
8
9
10
Me 1 equiv LiI, 6 equiv H2O, 1708C, 1 h[20]
Et 1 equiv LiCl, 1 equiv H2O, 3 h, 1708C[21]
Et 1 equiv NaCl, 1 equiv H2O, 3 h, 1758C[22]
Et 1 equiv NaCl, 0.1 equiv H2O, 3 h, 1758C[22]
34
42
79
37
73
86
33[g]
36[g]
[a] Isolated yield. [b] Determined by chiral HPLC or GC. [c] Full recov-
ery of starting material. [d] Lit.:[18] 30 W for 10 min. [e] Many by-products
are formed. [f] Decomposition of starting material. [g] Mixture of prod-
uct/starting material 1:1.
the yield decreased dramatically (Table 8, entry 3). Further-
more, the buffer used for the enzymatic reaction must be
carefully chosen, with PLE in a Tris/HCl buffer[26] (pH 7.4)
the product was obtained in a yield of 90–96% whereas a
potassium phosphate buffer[27] (pH 7.0) decreased the yield
slightly (Table 8, entry 4). By heating to 1608C, the mono
acids 35a,b decarboxylate to the corresponding mono ester
34a,b without a loss in enantiomeric excess (Table 8).
Scheme 2. Decarboxylation of Michael addition product 5 to the d-ke-
toesters 33.
The Krapcho reaction[17] is another well-known one-pot
decarboxylation procedure which yields the corresponding
monoester 33 directly and was investigated using the cyclic
six-membered Michael addition products 7a and 7b. Avari-
ety of methods were employed, where the kind of salt and
the equivalents of water were changed (Table 7). Further-
more, a microwave procedure[18] was investigated (Table 7,
entry 3). However, unexpectedly, in all cases, there was a
loss in enantiomeric excess with both methyl and ethyl die-
sters, which could have been due to the use of inorganic
salts, because during a simple heating with water no reaction
takes place and all starting material could be recovered
(Table 7, entry 1). It is postulated that this loss of enantio-
meric excess arises from a retro-Michael addition reaction
and indeed with 1,5-dicarbonyl compounds a facile retro-Mi-
chael addition[19] can take place instead of formation of the
expected products 34a,b.
Therefore, a mono-hydrolysis decarboxylation strategy
was investigated as an alternative way to obtain the mono-
ester 33 directly (Scheme 2). Indeed, the six-membered
mono-acids 35a,b could be produced from the correspond-
ing starting material 7a,b by sodium hydroxide-mediated
hydrolysis[23] or alternatively by the use of the enzyme por-
cine liver esterase[24] (PLE) (Table 8). The use of an alterna-
tive enzyme mixture, for example, liver acetone powder[25]
gave the product without a loss in enantiomeric excess, but
Table 8. Decarboxylation of cyclic malonate adducts 7a,b.
Entry
R
Conditions[a]
Yield[b]
ee[c]
1
2
3
4
5
6
Me
Et
Et
Et
Et
A92
A92
B[d]
B[e]
B
86
92
64
87
90
96
92
93
93
85
Me
B
[a] Conditions A: diester (0.5 mmol), THF/H2O (12 mL, 1:11), NaOH
(0.25m; 0.6 mmol for Me, 3.5 mmol for Et), RT; then DMSO (2 mL),
H2O (drops), 1608C, 1–3 h. Conditions B: diester (0.5 mmol), Tris/HCl
buffer (2 mL, 0.375m, pH 7.5), DMSO (25% v/v), pig liver esterase (1–
2 mg), 258C, pH 7.5; then DMSO (2 mL), H2O (10 mL), 1608C, 1–3 h.
[b] Isolated yield. [c] Determined by chiral GC. [d]Liver acetone powder
(Sigma) was used instead of PLE. [e] 50 mm potassium phosphate buffer
was used instead of the Tris/HCl buffer.
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S. V. Ley et al.
Table 9. Decarboxylation of aromatic malonate adducts 10a,b.
of petroleum. Anhydrous chloroform was bought from Sigma-Aldrich.
Enones were bought or synthesised according to reference.[28] All other
reagents and solvents were used as supplied
General procedure for the conjugate addition of malonate to a,b-unsatu-
rated aldehydes: To a stirred suspension of the enone starting material
(0.5 mmol) and pyrrolidinyl tetrazole 1 (15 mol%) in CHCl3 (2 mL) was
added diethylmalonate (0.75 mmol) and piperidine (0.5 mmol) at RT for
3 d. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed
one time with saturated ammonium chloride solution (10 mL). The aque-
ous phase was then extracted three times with CH2Cl2 (10 mL). The com-
bined organic phase was dried (MgSO4), concentrated in vacuo, and the
residue was purified by flash chromatography.
Entry
R
Conditions[a]
Yield[b]
ee[c]
1
2
3
4
Me
Et
Me
Et
A94
A99
B
84
89
97
97
General procedure for the enzyme-mediated decarboxylation of the mal-
onate aducts: The diester (0.5 mmol) was dissolved in tris(hydroxymeth-
yl)aminomethane (2 mL, Tris/HCl, 0.375m, pH 7.5) buffered batches con-
taining DMSO (25% v/v). To this solution pig liver esterase (1–2 mg)
was added. The reaction temperature was kept at 258C and the reaction
pH value was carefully monitored (pH 7 to 8) until the consumption of
the starting diester was detected (TLC control). Then the reaction mix-
ture was acidified with 1n HCl at 08C, saturated with NaCl, extracted
three times with ethyl acetate (10 mL), and dried with magnesium sul-
phate. The solvent was evaporated and the residue solved in DMSO
(2 mL) and water (10 mL). The reaction mixture was heated to 1608C for
1 to 3 h. After cooling to ambient temperature, the solution was diluted
with water (10 mL) and extracted three times with diethyl ether. The
combined organic phase was dried (MgSO4), concentrated in vacuo, and
the residue was purified by flash chromatography.
84
90
B
[a] Conditions A: diester (0.5 mmol), THF/H2O (12 mL, 1:11), NaOH
(0.25m; 0.6 mmol for R=Me, 3.5 mmol for R=Et), RT; then DMSO
(2 mL), H2O (10 mL), 1608C, 1–3 h. Conditions B: diester (0.5 mmol),
Tris/HCl buffer (2 mL, 0.375m, pH 7.5), DMSO (25% v/v), pig liver es-
terase (1–2 mg), 258C, pH 7.5; then DMSO (2 mL), H2O (drops), 1608C,
1–3 h. [b] Isolated yield. [c] Determined by chiral HPLC.
Correspondingly, it was pleasing to find that the aromatic
Michael addition products 10a,b could also be successfully
mono-decarboxylated under the developed conditions by
both sodium hydroxide or enzymatic methods without loss
in enantiomeric excess (Table 9).
General procedure for the NaOH-mediated decarboxylation of the malo-
nate adducts: The diester (0.5 mmol) was dissolved in THF/H2O (12 mL,
1:11) and cooled to 08C. To this solution 0.25n NaOH (0.6 mmol for Me
and 3.5 mmol for Et esters) was added in small portions with stirring
until the consumption of the starting diester was detected (TLC control).
Then the reaction mixture was acidified with 1n HCl at 08C, saturated
with NaCl, extracted three times with ethyl acetate (10 mL), and dried
with magnesium sulphate. The solvent was evaporated and the residue
solved in DMSO (2 mL) and water (10 mL). The reaction mixture was
heated to 1608C for 1 to 3 h. After cooling to ambient temperature, the
solution was diluted with water (10 mL) and extracted three times with
diethyl ether. The combined organic phase was dried (MgSO4), concen-
trated in vacuo, and the residue was purified by flash chromatography.
Conclusion
In summary, a general enantioselective organocatalytic con-
jugate addition procedure of a variety of malonates to a,b-
unsaturated enone sytems has been developed. The reaction
is efficiently catalysed by the pyrrolidinyl tetrazole catalyst
1. Cyclic, acyclic and aromatic enones can be used and the
reaction with ethyl malonates 3b provides the Michael addi-
tion products in high yields with good to excellent enantio-
selectivities. Because only 1.5 equivalents of malonate are
used as a reagent, the reaction is readily scaled and practical
to operate. Furthermore, the malonate addition products
can be easily mono decarboxylated without loss in enantio-
meric excess by enzymatic or sodium hydroxide mediated
methods.
Dimethyl 2-((R)-3-oxocyclohexyl)malonate (7a): The title compound was
obtained according to the general procedure. White solid; Yield: 87%;
Rf =0.14 (PE/Et2O 2:1); m.p. 358C; [a]2D0 = +2.4 (c=1 in chloroform);
1H NMR (400 MHz, CDCl3): d=1.39–1.49 (m, 1H, CH2a), 1.56–1.68 (m,
1H, CH2b), 1.86–1.90 (m, 1H, CH2c), 1.98–2.05 (m, 1H, CH2d), 2.16–2.24
(m, 2H, CH2), 2.32–2.38 (m, 2H, CH2), 2.42–2.51 (m, 1H, CHCH2),
3.29 ppm (d, 3J
U
G
d=24.88, 29.13 (2”CH2), 38.47 (CH), 41.33, 45.42 (2”CH2), 52.95 (2”
COOCH3), 56.94 (CH(COOMe)2), 168.54, 168.63 (2”CO, ester),
U
209.88 ppm (CO); HRMS-ESI: m/z: calcd for C11H16O5Na: 251.0895;
found: 251.0898 [M+Na]+; the ee was determined by GC analysis by
using a Chirasil DEx-CB column (83% ee).
Experimental Section
Diethyl 2-((R)-3-oxocyclohexyl)malonate (7b): The title compound was
obtained according to the general procedure. Colourless oil; Yield: 94%;
Rf =0.27 (PE/Et2O 2:1); [a]2D0 = +3.3 (c=1 in chloroform); 1H NMR
(400 MHz, CDCl3): d=1.18–1.22 (m, 6H, 2”COOCH2CH3), 1.45–1.73
(m, 2H, CH2), 1.93–2.10 (m, 2H, CH2), 2.21–2.30 (m, 2H, CH2), 2.63–
General: Flash column chromatography was carried out using Merck
Kieselgel (230–400 mesh). 1H NMR were recorded on a Bruker DRX-
400 and Bruker DRX-600 spectrometer. The residual protic solvent
CHCl3 (dH =7.26 ppm) in CDCl3 was used as an internal standard.
13C NMR spectra were recorded on the same spectrometer at 100 and
150 MHz, using central resonance of CDCl3 (dC =77.0 ppm). Accurate
mass data were obtained on Micromass Q-TOF by electrospray ionisa-
tion (ESI). Optical rotations were measured on a Perkin Elmer 343 po-
larimeter at 258C; concentrations (c) are reported in g per 100 mL. Melt-
ing points were measured on a Reichert hot stage apparatus, and are un-
corrected. The enantiomeric excess (ee) of the products was determined
by chiral stationary phase GC or SFC.
2.57 (m, 3H, CH2, CHCH2), 3.28 (d, 3J
(COOEt)2), 4.17–4.23 ppm (m, 4H, 2”COOCH2CH3); 13C NMR
(100 MHz, CDCl3): d=14.01, 14.03 (2”COOCH2CH3), 24.49, 28.71 (2”
CH2), 37.97 (CH), 40.95, 45.02 (2”CH2), 56.81 (CH(COOEt)2), 61.47 (2”
(H,H)=8.1 Hz, 1H, CH-
AHCTREUNG
AHCTREUNG
COOCH2CH3), 167.73, 167.82 (2”CO, ester), 209.60 ppm (CO); HRMS-
ESI: m/z: calcd for C13H20O5Na: 279.1208; found: 279.1208 [M+Na]+;
the ee was determined by GC analysis by using a Chirasil DEx-CB
column (93% ee).
Materials: All reactions were carried out under an atmosphere of argon.
Petroleum ether (PE) used refers to the 40–608C boiling point fraction
Dibenzyl 2-((R)-3-oxocyclohexyl)malonate (7c): The title compound was
obtained according to the general procedure. White solid; Yield: 86%;
6160
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6155 – 6165

Organocatalytic Enantioselective Addition
FULL PAPER
Rf =0.22 (PE/Et2O 2:1); m.p. 468C; [a]2D0 = À1.1 (c=1 in chloroform);
1H NMR (400 MHz, CDCl3): d=1.41–1.51 (m, 1H, CH2a), 1.56–1.68 (m,
1H, CH2b), 1.84–1.92 (m, 1H, CH2c), 1.97–2.04 (m, 1H, CH2d), 2.15–2.27
(m, 2H, CH2), 2.34–2.38 (m, 1H, CH2e), 2.42–2.47 (m, 1H, CH2e), 2.51–
Diethyl 2-((R)-3-oxocyclopentyl)malonate (12): The title compound was
obtained according to the general procedure. Colourless oil; Yield: 88%;
Rf =0.19 (PE/Et2O 2:1); [a]D20 = +22.2 (c=0.9 in chloroform); 1H NMR
(400 MHz, CDCl3): d=1.24–1.30 (m, 6H, 2”COOCH2CH3), 1.52–1.76
(m, 1H, CH2a), 1.98–2.05 (m, 1H, CH2b), 2.14–2.36 (m, 3H, CH2, CH2c),
2.61 (m, 1H, CHCH2), 3.42 (d, 3J
A
N
2.47–2.53 (m, 1H, CH2d), 2.81–2.88 (m, 1H, CHCH2), 3.32 (d, 3J
9.0 Hz, 1H, CH(COOEt)2), 4.17–4.25 ppm (m, 4H, 2”COOCH2CH3);
13C NMR (100 MHz, CDCl3): d=14.45, 14.48 (2”COOCH2CH3), 27.88
(CH2), 36.71 (CH), 38.56, 43.28 (2”CH2), 56.94 (CH(COOEt)2), 61.96,
A
5.14 (s, 2H, CH2Ph), 5.15 (s, 2H, CH2Ph), 7.26–7.34 ppm (m, 10H,
CHarom.); 13C NMR (100 MHz, CDCl3): d=24.48, 28.64 (2”CH2), 38.10
AHCTREUNG
(CH), 40.94, 45.04 (2”CH2), 56.75 (CH(COOMe)2), 67.22, 67.25 (2”
U
AHCTREUNG
CH2Ph), 128.25, 128.45, 128.47, 128.59 (10”CHarom.), 167.46, 167.52 (2”
CO, ester), 209.26 ppm (CO); HRMS-ESI: m/z: calcd for C23H24O5Na:
403.1521; found: 403.1511 [M+Na]+; the ee was determined by GC anal-
ysis by using a Chirasil DEx-CB column (81% ee).
61.99 (2”COOCH2CH3), 168.43, 168.52 (2”CO, ester), 217.42 ppm
(CO); HRMS-ESI: m/z: calcd for C12H18O5Na: 265.1052; found: 265.1042
[M+Na]+; the ee was determined by GC analysis by using a Chirasil
DEx-CB column (30% ee).
Dimethyl 2-((S)-3-oxo-1-phenylbutyl)malonate (10a): The title com-
pound was obtained according to the general procedure. White solid;
Yield: 89%; Rf =0.17 (PE/Et2O 2:1); m.p. 428C; [a]2D0 = +11.4 (c=1 in
chloroform); 1H NMR (400 MHz, CDCl3): d=1.99 (s, 3H, COCH3),
2.86–2.98 (m, 2H, CHCH2), 3.46 (s, 3H, COOCH3), 3.69–3.72 (m, 4H,
COOCH3, CHCOOCH3), 3.92–3.98 (m, 1H, CHCH2), 7.14–7.26 ppm (m,
5H, CHarom.); 13C NMR (100 MHz, CDCl3): d=30.28 (COCH3), 40.39
(CHCH2), 47.10 (CH2), 52.36, 52.63 (2”COOCH3), 57.10 (CH-
Diethyl 2-((S)-2-oxononan-4-yl)malonate (13): The title compound was
obtained according to the general procedure. Colourless oil; Yield: 86%;
Rf =0.56 (PE/Et2O 2:1); [a]2D0 = +8.5 (c=1 in chloroform); 1H NMR
(400 MHz, CDCl3): d=0.84 (t, 3J
ACHTREUNG
AHCTREUNG
AHCTREUNG
(100 MHz, CDCl3): d=14.32, 14.43 (2”COOCH2CH3), 14.44 (wCH3),
22.83, 26.96 (CH2), 30.61 (CH3), 32.07, 32.55 (2”CH2), 33.93 (CH), 45.68
A
168.97 (2”CO, ester), 206.41 ppm (CO); HRMS-ESI: m/z: calcd for
C15H18O5Na: 301.1052; found: 301.1049 [M+Na]+; the ee was determined
by SFC analysis by using a Chiralpak AD-H column (10% iPrOH); flow
rate=1.0 mLminÀ1; tmajor =8.3, tminor =7.4 min (89% ee).
(CH2), 54.43 (CH(COOEt)2), 61.51, 61.61 (2”COOCH2CH3), 169.08,
G
169.34 (2”CO, ester), 207.82 ppm (CO); HRMS-ESI: m/z: calcd for
C16H28O5Na: 323.1834; found: 323.1834 [M+Na]+; the ee was determined
by GC analysis by using a Chirasil DEx-CB column (87% ee).
Diethyl 2-((S)-3-oxo-1-phenylbutyl)malonate (10b): The title compound
was obtained according to the general procedure. White solid; Yield:
89%; Rf =0.30 (PE/Et2O 2:1); m.p. 388C; [a]2D0 =+15.8 (c=1.1 in
Diethyl 2-((S)-2-oxopentan-4-yl)malonate (14): The title compound was
obtained according to the general procedure. Colourless oil; Yield: 82%;
Rf =0.41 (PE/Et2O 2:1); [a]D20 = +9.0 (c=0.75 in chloroform); 1H NMR
chloroform); 1H NMR (400 MHz, CDCl3): d=0.98 (d, 3J
ACHTREUNG
(400 MHz, CDCl3): d=1.01 (t, 3J
3J
(m, 1H, CHCH2), 2.65–2.86 (m, 2H, CH2CO), 3.33 (d, 3J
1H, CH
(COOEt)2), 4.14–4.20 ppm (m, 4H, 2”COOCH2CH3); 13C NMR
(100 MHz, CDCl3): d=14.03, 14.04 (2”COOCH2CH3), 17.68 (wCH3),
28.88 (CH3), 30.22 (CH), 47.59 (CH2), 56.22 (CH(COOEt)2), 61.20 (2”
ACHTREUNG
3H, COOCH2CH3), 1.22 (d, 3J
ACHTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG
1H, CH(COOEt)2), 3.81–4.03 (m, 3H, COOCH2CH3, CHCH2), 4.13–4.18
A
AHCTREUNG
(m, 2H, COOCH2CH3), 7.14–7.26 ppm (m, 5H, CHarom.); 13C NMR
(100 MHz, CDCl3): d=14.14, 14.41 (2”COOCH2CH3), 30.70 (COCH3),
AHCTREUNG
40.86 (CHCH2), 47.82 (CH2), 57.81 (CH(COOEt)2), 61.72, 62.05 (2”
E
COOCH2CH3), 168.51, 168.55 ppm (2”CO, ester), 207.08 (CO); HRMS-
ESI: m/z: calcd for C12H21O5: 245.1389; found: 245.1391 [M+H]+; the ee
was determined by GC analysis by using a Chirasil DEx-CB column
(64% ee).
COOCH2CH3), 127.61, 128.54, 128.87 (5”CHarom.), 140.79 (Cq), 168.053,
168.60 (2”CO, ester), 206.51 ppm (CO); HRMS-ESI: m/z: calcd for
C17H22O5Na: 329.1365; found: 329.1354 [M+Na]+; the ee was determined
by SFC analysis by using a Chiralpak AD-H column (10% iPrOH); flow
rate=1.0 mLminÀ1; tmajor =9.9, tminor =7.5 min (87% ee).
Diethyl 2-((R)-2-methyl-5-oxohexan-3-yl)malonate (15): The title com-
pound was obtained according to the general procedure. Colourless oil;
Yield: 82%; Rf =0.41 (PE/Et2O 2:1); m.p. 208C; [a]2D0 = +14.1 (c=1.1 in
Dibenzyl 2-((S)-3-oxo-1-phenylbutyl)malonate (10c): The title compound
was obtained according to the general procedure. White solid; Yield:
85%; Rf =0.37 (PE/Et2O 2:1); m.p. 598C; [a]2D0 = +5.1 (c=1 in chloro-
chloroform); 1H NMR (400 MHz, CDCl3): d=0.81 (d, 3J
ACHTREUNG
3H, CH3), 0.89 (d, 3J
ACHTREUNG
1
3
form); H NMR (400 MHz, CDCl3): d=1.96 (s, 3H, COCH3), 2.91 (d, J-
(H,H)=6.9 Hz, 2H, CHCH2), 3.87 (d, 3J
(H,H)=9.9 Hz, 1H, CHCOO),
A
ACHTREUNG
AHCTREUNG
4.02–4.08 (m, 1H, CHCH2), 4.91 (s, 2H, CH2Ph), 5.12–5.17 (m, 2H,
CH2Ph), 7.07–7.09 (m, 2H, CHarom.), 7.18–7.37 ppm (m, 13H, CHarom.);
13C NMR (100 MHz, CDCl3): d=30.20 (COCH3), 40.51 (CHCH2), 47.12
AHCTREUNG
(100 MHz, CDCl3): d=14.36, 14.37 (2”COOCH2CH3), 19.21, 20.95
(CH3), 30.23 (CH), 30.59 (CH3), 39.29 (CH), 43.07 (CH2), 54.05 (CH-
(COOEt)2), 61.58, 61.73 (2”COOCH2CH3), 169.29, 169.59 (2”CO,
(CH2), 57.37 (CH(COOMe)2), 67.10, 67.29 (2”CH2Ph), 127.26, 128.14,
N
G
128.17, 128.25, 128.29, 128.42, 128.46, 128.57, 128.59 (15”CHarom.), 135.11,
135.24, 140.37 (3”Cq), 167.39, 167.87 (2”CO, ester), 205.79 ppm (CO);
HRMS-ESI: m/z: calcd for C27H27O5: 431.1858; found: 431.1855
[M+Na]+; the ee was determined by HPLC analysis by using a Chiralpak
ester), 207.6 ppm (CO); HRMS-ESI: m/z: calcd for C14H24O5Na:
295.1521; found: 295.1517 [M+Na]+; the ee was determined by GC anal-
ysis by using a Chirasil DEx-CB column (77% ee).
Diethyl 2-((S)-1-(4-chlorophenyl)-3-oxobutyl)malonate (16): The title
compound was obtained according to the general procedure. Pale-yellow
solid; Yield: 94%; Rf =0.28 (PE/Et2O 2:1); m.p. 398C; [a]2D0 =+13.9 (c=
1.2 in chloroform); 1H NMR (400 MHz, CDCl3): d=0.90–1.03 (m, 3H,
COOCH2CH3), 1.19–1.23 (m, 3H, COOCH2CH3), 1.99 (s, 3H, COCH3),
AD-H column (hexane/iPrOH 90:10); flow rate=1.0 mLminÀ1; tmajor
37.1, tminor =25.8 min (83% ee).
=
Diethyl 2-((R)-3-oxocycloheptyl)malonate (11): The title compound was
obtained according to the general procedure. Colourless oil; Yield: 91%;
Rf =0.20 (PE/Et2O 2:1); [a]D20 = +23.4 (c=0.1 in chloroform); 1H NMR
(400 MHz, CDCl3): d=1.25–1.28 (m, 6H, 2”COOCH2CH3), 1.36–1.62
(m, 3H, CH2, CH2a), 1.84–1.97 (m, 3H, CH2, CH2b), 2.45–2.60 (m, 5H,
2.82–2.95 (m, 2H, CHCH2), 3.63 (d, 3J
(H,H)=10.0 Hz, 1H, CH-
A
A
2H, COOCH2CH3), 7.15–7.21 ppm (m, 4H, CHarom.); 13C NMR
(100 MHz, CDCl3): d=13.76, 13.98 (2”COOCH2CH3), 30.28 (COCH3),
2”CH2, CH), 3.29 (d, 3J
U
G
39.64 (CHCH2), 47.14 (CH2), 57.05 (CH(COOEt)2), 61.42, 61.71 (2”
E
COOCH2CH3), 128.56, 129.60 (4”CHarom.), 132.88 (CqCl), 139.05 (Cq),
167.45, 167.95 ppm (2”CO, ester), 205.67 (CO); HRMS-ESI: m/z: calcd
for C17H21Cl1O5Na: 363.0975; found: 363.0972 [M+Na]+; the ee was de-
termined by SFC analysis by using a Chiralpak AD-H column (10%
iPrOH); flow rate=1.0 mLminÀ1; tmajor =14.1, tminor =9.6 min (83% ee).
47.68 (2”CH2), 57.88 (CH(COOEt)2), 61.95 (2”COOCH2CH3), 168.56,
R
168.63 (2”CO, ester), 213.10 ppm (CO); HRMS-ESI: m/z: calcd for
C14H23O5: 271.1545; found: 271.1551 [M+H]+; the ee was determined by
GC analysis by using a Chirasil DEx-CB column (89% ee).
Chem. Eur. J. 2008, 14, 6155 – 6165
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6161

S. V. Ley et al.
Diethyl 2-((S)-1-(4-bromophenyl)-3-oxobutyl)malonate (17): The title
compound was obtained according to the general procedure. White solid;
Yield: 88%; Rf =0.27 (PE/Et2O 2:1); m.p. 428C; [a]2D0 =+12.3 (c=1.1 in
chloroform); 1H NMR (400 MHz, CDCl3): d=0.99–1.05 (m, 3H,
COOCH2CH3), 1.19–1.25 (m, 3H, COOCH2CH3), 2.08 (s, 3H, COCH3),
93%; Rf =0.11 (PE/Et2O 2:1); [a]2D0 =+14.0 (c=1.1 in chloroform);
1H NMR (400 MHz, CDCl3): d=1.00 (t, 3J
ACHTREUNG
COOCH2CH3), 1.22 (t, 3J
ACHTREUNG
A
ACHTREUNG
2.80–2.97 (m, 2H, CHCH2), 3.63 (d, 3J
(COOEt)2), 3.86–3.99 (m, 3H, COOCH2CH3, CHCH2), 4.10–4.20 (m,
A
ACHTREUNG
H
ACHTREUNG
2H, COOCH2CH3), 7.08–7.14 (m, 2H, CHarom.), 7.33–7.40 ppm (m, 2H,
CHarom.); 13C NMR (100 MHz, CDCl3): d=13.76, 14.28 (2”
COOCH2CH3), 30.26 (COCH3), 39.70 (CHCH2), 47.07 (CH2), 56.98 (CH-
AHCTREUNG
61.67, 61.98 (2”COOCH2CH3), 128.36, 128.53 (4”CHarom.), 137.11,
137.68 (2”Cq), 168.07, 168.64 (2”CO, ester), 206.61 ppm (CO); HRMS-
ESI: m/z: calcd for C18H24O5Na: 343.1521; found: 343.1514 [M+Na]+;
the ee was determined by SFC analysis by using a Chiralpak AD-H
A
(4”CHarom.), 139.63 (Cq), 167.43, 167.92 (2”CO, ester), 205.56 ppm
(CO); HRMS-ESI: m/z: calcd for C17H22Br1O5: 385.0651; found:
385.0648 [M+H]+; the ee was determined by SFC analysis by using a
column (10% iPrOH); flow rate=1.0 mLminÀ1
8.2 min (88% ee).
; tmajor =10.9, tminor =
Chiralpak AD-H column (10% iPrOH); flow rate=1.0 mLminÀ1; tmajor
17.4, tminor =11.9 min (85% ee).
=
Diethyl 2-((S)-1-(4-hydroxyphenyl)-3-oxobutyl)malonate (22): The title
compound was obtained according to the general procedure. White solid;
Yield: 68%; Rf =0.50 (PE/Et2O 1:3); m.p. 498C; [a]2D0 =+13.0 (c=0.6 in
Diethyl 2-((S)-1-(3-bromophenyl)-3-oxobutyl)malonate (18): The title
compound was obtained according to the general procedure. Colourless
oil; Yield: 87%; Rf =0.54 (PE/Et2O 2:1); [a]2D0 =+12.0 (c=0.5 in chloro-
chloroform); 1H NMR (400 MHz, CDCl3): d=1.02 (t, 3J
ACHTREUNG
form); 1H NMR (400 MHz, CDCl3): d=1.00 (t, 3J
N
3H, COOCH2CH3), 1.24 (t, 3J
ACHTREUNG
COOCH2CH3), 1.19 (t, 3J
A
ACHTREUNG
A
ACHTREUNG
CH
C
ACHTREUNG
ACHTREUNG
39.84 (CHCH2), 46.93 (CH2), 56.95 (CH
A
ACHTREUNG
COOCH2CH3), 122.32 (CqBr), 127.01, 129.96, 130.24, 131.20 (4”CHarom.),
143.05 (Cq), 167.36, 167.85 (2”CO, ester), 205.35 ppm (CO); HRMS-ESI:
m/z: calcd for C17H22Br1O5: 385.0651; found: 385.0648 [M+H]+; the ee
was determined by SFC analysis by using a Chiralpak AD-H column
COOCH2CH3), 115.88, 129.57 (4”CHarom.), 131.48, 155.75 (2”Cq),
168.41, 168.70 (2”CO, ester), 208.38 ppm (CO); HRMS-ESI: m/z: calcd
for C17H23O6Na: 323.1495; found: 323.1494 [M+H]+; the ee was deter-
mined by SFC analysis by using a Chiralpak AD-H column (10%
iPrOH); flow rate=1.0 mLminÀ1; tmajor =45.0, tminor =28.3 min (51% ee).
(10% iPrOH); flow rate=1.0 mLminÀ1
(86% ee).
; tmajor =11.4, tminor =9.6 min
Diethyl 2-((S)-1-(4-(benzyloxy)phenyl)-3-oxobutyl)malonate (23): The
title compound was obtained according to the general procedure. Colour-
less oil; Yield: 82%; Rf =0.37 (PE/Et2O 2:1); [a]2D0 =+11.6 (c=0.5 in
Diethyl 2-((S)-1-(2-bromophenyl)-3-oxobutyl)malonate (19): The title
compound was obtained according to the general procedure. Colourless
oil; Yield: 81%; Rf =0.46 (PE/Et2O 2:1); [a]2D0 =+1.6 (c=0.5 in chloro-
chloroform); 1H NMR (400 MHz, CDCl3): d=1.01 (t, 3J
ACHTREUNG
form); 1H NMR (400 MHz, CDCl3): d=1.08 (t, 3J
A
3H, COOCH2CH3), 1.24 (t, 3J
ACHTREUNG
COOCH2CH3), 1.19 (t, 3J
A
ACHTREUNG
3
3
ACHTREUNG
3H, COCH3), 3.04 (d, J
A
(H,H)=
ACHTREUNG
8.3 Hz, 1H, CH
A
(m, 2H, COOCH2CH3), 4.99 (s, 2H, CH2OBn), 6.81–6.88 (m, 2H,
CHarom.), 7.09–7.17 (m, 2H, CHarom.), 7.26–7.40 ppm (m, 5H, CHarom.);
13C NMR (100 MHz, CDCl3): d=14.21, 14.42 (2”COOCH2CH3), 30.66
(m, 2H, COOCH2CH3), 4.40–4.46 (m, 1H, CHCH2), 7.02–7.06 (m, 1H,
CHarom.), 7.19–7.26 (m, 2H, CHarom.), 7.51–7.53 ppm (m, 1H, CHarom.);
13C NMR (100 MHz, CDCl3): d=13.78, 13.93 (2”COOCH2CH3), 30.01
(COCH3), 40.24 (CHCH2), 47.97 (CH2), 58.00 (CH(COOEt)2), 61.65,
A
(COCH3), 39.15 (CHCH2), 45.59 (CH2), 55.18 (CH
A
61.95 (2”COOCH2CH3), 70.34 (CH2OBn), 115.20, 127.85, 128.31, 128.93,
129.64 (9”CHarom.), 133.10, 137.42, 158.26 (3”Cq), 168.09, 168.61 (2”CO,
ester), 206.52 ppm (CO); HRMS-ESI: m/z: calcd for C24H28O6Na:
435.1784; found: 435.1788 [M+Na]+; the ee was determined by SFC anal-
ysis by using a Chiralpak AD-H column (10% iPrOH); flow rate=
1.0 mLminÀ1; tmajor =62.4, tminor =35.1 min (85% ee).
61.51 (2”COOCH2CH3), 124.76 (CqBr), 127.46, 128.56, 133.41 (4”
CHarom.), 139.54 (Cq), 167.64, 168.01 (2”CO, ester), 205.86 ppm (CO);
HRMS-ESI: m/z: calcd for C17H22Br1O5: 385.0651; found: 385.0638
[M+H]+; the ee was determined by SFC analysis by using a Chiralpak
AD-H column (10% iPrOH); flow rate=1.0 mLminÀ1
tminor =9.9 min (60% ee).
Diethyl 2-((S)-1-(4-methoxyphenyl)-3-oxobutyl)malonate (24): The title
compound was obtained according to the general procedure. Colourless
oil; Yield: 88%; Rf =0.21 (PE/Et2O 2:1); [a]2D0 =+ 16.4 (c=1.1 in
Diethyl 2-((S)-1-(4-(trifluoromethyl)phenyl)-3-oxobutyl)malonate (20):
The title compound was obtained according to the general procedure.
White solid; Yield: 82%; Rf =0.37 (PE/Et2O 2:1); m.p. 498C; [a]D20
chloroform); 1H NMR (400 MHz, CDCl3): d=0.98 (t, 3J
ACHTREUNG
+12.2 (c=1 in chloroform); 1H NMR (400 MHz, CDCl3): d=0.98 (t,
3J(H,H)=7.2 Hz, 3H, COOCH2CH3), 1.21 (t, 3J
(H,H)=7.2 Hz, 3H,
COOCH2CH3), 2.01 (s, 3H, COCH3), 2.88–3.01 (m, 2H, CHCH2), 3.68
(d, 3J
(H,H)=9.5 Hz, 1H, CH(COOEt)2), 3.90–3.95 (m, 2H,
COOCH2CH3), 3.98–4.04 (m, 1H, CHCH2), 4.10–4.22 (m, 1H,
COOCH2CH3), 7.50 (d, 3J
(H,H)=8.0 Hz, 2H, CHarom.), 7.36 ppm (d,
3J(H,H)=8.4 Hz, 2H, CHarom.); 13C NMR (100 MHz, CDCl3): d=13.64,
13.93 (2”COOCH2CH3), 30.21 (COCH3), 39.90 (CHCH2), 46.91 (CH2),
56.80 (CH(COOEt)2), 61.47, 61.78 (2”COOCH2CH3), 122.64 (Cq),
3H, COOCH2CH3), 1.20 (t, 3J
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
A
N
COOCH2CH3, CHCH2), 4.11–4.17 (m, 2H, COOCH2CH3), 6.73–6.77 (m,
2H, CHarom.), 7.09–7.13 ppm (m, 2H, CHarom.); 13C NMR (100 MHz,
CDCl3): d=13.75, 13.97 (2”COOCH2CH3), 30.22 (COCH3), 39.77
AHCTREUNG
A
(CHCH2), 47.54 (CH2), 55.09 (OCH3), 57.57 (CH(COOEt)2), 61.20, 61.51
R
(2”COOCH2CH3), 113.77, 129.14 (4”CHarom.), 132.27, 158.56 (2”Cq),
167.63, 168.18 (2”CO, ester), 206.15 ppm (CO); HRMS-ESI: m/z: calcd
for C18H24O6Na: 359.1417; found: 359.1463 [M+Na]+; the ee was deter-
mined by SFC analysis by using a Chiralpak AD-H column (10%
iPrOH); flow rate=1.0 mLminÀ1; tmajor =15.7, tminor =10.2 min (84% ee).
ACHTREUNG
125.34, 128.67 (4”CHarom.), 129.49 (CF3), 144.81 (Cq), 167.38, 167.86 (2”
CO, ester), 205.39 ppm (CO); HRMS-ESI: m/z: calcd for C18H21F3O5Na:
397.1239; found: 397.1236 [M+Na]+; the ee was determined by SFC anal-
ysis by using a Chiralpak AD-H column (10% iPrOH); flow rate=
1.0 mLminÀ1; tmajor =6.5, tminor =5.2 min (79% ee).
Diethyl 2-((S)-1-(3,4-dimethoxyphenyl)-3-oxobutyl)malonate (25): The
title compound was obtained according to the general procedure. Pale-
yellow oil; Yield: 87%; Rf =0.46 (PE/Et2O 1:3); [a]2D0 =+ 8.7 (c=1.2 in
Diethyl 2-((S)-3-oxo-1-p-tolylbutyl)malonate (21): The title compound
was obtained according to the general procedure. Colourless oil; Yield:
chloroform); 1H NMR (400 MHz, CDCl3): d=0.96 (t, 3J
(H,H)=7.1 Hz,
A
6162
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6155 – 6165

Organocatalytic Enantioselective Addition
FULL PAPER
3H, COOCH2CH3), 1.17 (t, 3J
(s, 3H, COCH3), 2.77–2.86 (m, 2H, CHCH2), 3.60 (d, 3J
1H, CH(COOEt)2), 3.74 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.80–3.90
(m, 3H, COOCH2CH3, CHCH2), 4.03–4.16 (m, 2H, COOCH2CH3), 6.66–
6.70 ppm (m, 3H, CHarom.); 13C NMR (100 MHz, CDCl3): d=13.78, 13.95
(2”COOCH2CH3), 30.28 (COCH3), 40.09 (CHCH2), 47.47 (CH2), 55.69,
N
4.17–4.30 (m, 3H, COOCH2CH3, CHCH2), 6.29 (s, 1H, CH=), 7.05–7.08
(m, 1H, CHarom.), 7.16–7.20 (m, 1H, CHarom.), 7.29–7.31 (m, 1H, CHarom.),
7.51–7.53 ppm (m, 1H, CHarom.); 13C NMR (100 MHz, CDCl3): d=13.76,
14.03 (2”COOCH2CH3), 29.70 (COCH3), 30.44 (CHCH2), 31.25 (NCH3),
AHCTREUNG
ACHTREUNG
47.79 (CH2), 57.23 (CH(COOEt)2), 61.50, 61.76 (2”COOCH2CH3), 98.35
A
(CH=), 109.38, 119.31, 120.02, 121,12 (4”CHarom.), 127.67, 136.98, 141.10
(3”Cq), 167.57, 167.96 (2”CO, ester), 205.64 ppm (CO); HRMS-ESI:
m/z: calcd for C20H25N1O5Na: 382.1630; found: 382.1645 [M+Na]+; the
ee was determined by SFC analysis by using a Chiralpak AD-H column
55.76 (2”OCH3), 57.45 (CH(COOEt)2), 61.22, 61.53 (2”COOCH2CH3),
N
110.92, 111.55, 119.92 (3”CHarom.), 132.86, 147.90, 148.56 (3”Cq), 167.61,
168.13 (2”CO, ester), 206.17 (CO); HRMS-ESI: m/z: calcd for
C19H26O7Na: 389.1576; found: 389.1572 [M+Na]+; the ee was determined
by SFC analysis by using a Chiralpak AD-H column (10% iPrOH); flow
rate=1.0 mLminÀ1; tmajor =14.3, tminor =10.1 min (84% ee).
(10% iPrOH); flow rate=1.0 mLminÀ1
(84% ee).
; tmajor =14.3, tminor =13.4 min
Diethyl 2-((S)-3-oxo-1-(quinolin-3-yl)butyl)malonate (30): The title com-
pound was obtained according to the general procedure. Colourless oil;
Yield: 83%; Rf =0.46 (PE/Et2O 2:1); [a]2D0 =+25.0 (c=0.25 in chloro-
Diethyl 2-((S)-3-oxo-1,3-diphenylpropyl)malonate (26): The title com-
pound was obtained according to the general procedure (reaction time 5
days). White solid; Yield: 86%; Rf =0.42 (PE/Et2O 2:1); m.p. 548C; [a]D20
=+ 10.0 (c=0.25 in chloroform); 1H NMR (400 MHz, CDCl3): d=1.00
form); 1H NMR (400 MHz, CDCl3): d=0.92 (t, 3J
ACHTREUNG
COOCH2CH3), 1.19 (t, 3J
ACHTREUNG
(t, 3J
COOCH2CH3), 3.42–3.57 (m, 2H, CHCH2), 3.82 (d, 3J
1H, CH(COOEt)2), 3.92–3.97 (m, 2H, COOCH2CH3), 4.13–4.25 (m, 3H,
A
N
ACHTREUNG
E
ACHTREUNG
N
COOCH2CH3, CHCH2), 7.44–7.48 (m, 1H, CHarom.), 7.59–7.63 (m, 1H,
CHarom.), 7.70–7.72 (m, 1H, CHarom.), 7.99–8.01 (m, 2H, CHarom.), 8.82–
8.84 ppm (m, 1H, CHarom.); 13C NMR (100 MHz, CDCl3): d=13.68, 13.94
(2”COOCH2CH3), 30.19 (COCH3), 37.76 (CHCH2), 46.83 (CH2), 56.69
COOCH2CH3, CHCH2), 7.14–7.18 (m, 1H, CHarom.), 7.21–7.27 (m, 4H,
CHarom.), 7.39–7.43 (m, 2H, CHarom.), 7.50–7.54 (m, 1H, CHarom.), 7.88–
7.91 ppm (m, 1H, CHarom.); 13C NMR (100 MHz, CDCl3): d=14.17, 14.43
(2”COOCH2CH3), 41.21 (CHCH2), 43.04 (CH2), 57.99 (CH
G
(CH(COOEt)2), 61.49, 61.76 (2”COOCH2CH3), 126.72, 127.64, 129.11,
N
61.77, 62.08 (2”COOCH2CH3), 127.55, 128.50, 128.64, 128.80, 128.96,
133.45 (10”CHarom.), 137.18, 140.84 (2”Cq), 168.16, 168.77 (2”CO,
ester), 197.95 ppm (CO); HRMS-ESI: m/z: calcd for C22H24O5Na:
391.1521; found: 391.1519 [M+Na]+; the ee was determined by SFC anal-
ysis by using a Chiralpak AD-H column (10% iPrOH); flow rate=
1.0 mLminÀ1; tmajor =45.1, tminor =31.0 min (44% ee).
129.26 (4”CHarom.), 133.59 (Cq), 134.84 (CHarom.), 147.31, 147.32 (2”Cq),
151.22 (CHarom.), 167.35, 167.83 (2”CO, ester), 205.14 ppm (CO);
HRMS-ESI: m/z: calcd for C20H24O5N1: 358.1654; found: 358.1653
[M+H]+; the ee was determined by SFC analysis by using a Chiralpak
AD-H column (40% iPrOH); flow rate=1.0 mLminÀ1
tminor =5.0 min (79% ee).
; tmajor =6.4,
Diethyl 2-((S)-3-oxo-1-(thiophen-2-yl)butyl)malonate (27): The title com-
pound was obtained according to the general procedure. Colourless oil;
Diethyl 2-((S)-1-(naphthalen-3-yl)-3-oxobutyl)malonate (31): The title
compound was obtained according to the general procedure. White solid;
Yield: 89%; Rf =0.31 (PE/Et2O 2:1); m.p. 468C; [a]2D0 =+15.3 (c=1 in
Yield: 81%; Rf =0.29 (PE/Et2O 2:1); [a]D20
=
+14.3 (c=1 in chloro-
(H,H)=7.1 Hz, 3H,
(H,H)=7.0 Hz, 3H, COOCH2CH3), 2.04 (s,
form); 1H NMR (400 MHz, CDCl3): d=1.08 (t, 3J
G
chloroform); 1H NMR (400 MHz, CDCl3): d=0.93 (t, 3J
ACHTREUNG
COOCH2CH3), 1.20 (t, 3J
A
3H, COOCH2CH3), 1.24 (t, 3J
ACHTREUNG
3
3
ACHTREUNG
3H, COCH3), 2.97 (d, J
A
(H,H)=
ACHTREUNG
9.5 Hz, 1H, CH
G
G
ACHTREUNG
(m, 2H, COOCH2CH3), 4.23–4.29 (m, 1H, CHCH2), 6.82–6.86 (m, 2H,
CHarom.), 7.09–7.11 ppm (m, 1H, CHarom.); 13C NMR (100 MHz, CDCl3):
d=13.82, 13.97 (2”COOCH2CH3), 30.27 (COCH3), 35.61 (CHCH2),
4.13–4.23 (m, 3H, COOCH2CH3, CHCH2), 7.38–7.45 (m, 3H, CHarom.),
7.70–7.71 (m, 1H, CHarom.), 7.75–7.77 ppm (m, 3H, CHarom.); 13C NMR
(100 MHz, CDCl3): d=13.69, 14.00 (2”COOCH2CH3), 30.28 (COCH3),
47.90 (CH2), 57.03 (CH
G
40.54 (CHCH2), 47.37 (CH2), 57.40 (CH(COOEt)2), 61.29, 61.62 (2”
N
124.18, 125.72, 126.56 (3”CHarom.), 143.51 (Cq), 167.51, 167.84 (2”CO,
ester), 205.66 ppm (CO); HRMS-ESI: m/z: calcd for C15H20S1O5Na:
335.0929; found: 335.0924 [M+Na]+; the ee was determined by SFC anal-
ysis by using a Chiralpak AD-H column (10% iPrOH); flow rate=
1.0 mLminÀ1; tmajor =9.2, tminor =7.8 min (88% ee).
COOCH2CH3), 125.79, 126.06, 126.16, 127.08, 127.55, 127.79, 128.18 (7”
CHarom.), 132.59, 133.29, 138.05 (3”Cq), 167.62, 168.19 (2”CO, ester),
205.89 ppm (CO); HRMS-ESI: m/z: calcd for C21H25O5: 357.1702; found:
357.1700 [M+H]+; the ee was determined by SFC analysis by using a
Chiralpak AD-H column (10% iPrOH); flow rate=1.0 mLminÀ1; tmajor
27.1, tminor =19.7 min (88% ee).
=
Diethyl 2-((S)-1-(furan-2-yl)-3-oxobutyl)malonate (28): The title com-
pound was obtained according to the general procedure. Pale-yellow oil;
Yield: 84%; Rf =0.29 (PE/Et2O 2:1); [a]2D0 =+10.1 (c=1 in chloroform);
Diethyl 2-((S)-1-(4-phenyl-phenyl)-3-oxobutyl)malonate (32): The title
compound was obtained according to the general procedure. White solid;
Yield: 88%; Rf =0.36 (PE/Et2O 2:1); m.p. 648C; [a]2D0 =+ 14.3 (c=1 in
1H NMR (400 MHz, CDCl3): d=1.13 (t, 3J
ACHTREUNG
COOCH2CH3), 1.20 (t, 3J
A
chloroform); 1H NMR (400 MHz, CDCl3): d=1.01 (t, 3J
ACHTREUNG
C
3H, COOCH2CH3), 1.25 (t, 3J
ACHTREUNG
A
ACHTREUNG
2H, COOCH2CH3), 6.05–6.07 (m, 1H, CHarom.), 6.20–6.22 (m, 1H,
CHarom.), 7.22–7.26 ppm (m, 1H, CHarom.); 13C NMR (100 MHz, CDCl3):
d=14.30, 14.37 (2”COOCH2CH3), 30.45 (COCH3), 34.25 (CHCH2),
ACHTREUNG
(m, 2H, COOCH2CH3), 7.28–7.33 (m, 3H, CHarom.), 7.38–7.41 (m, 2H,
CHarom.), 7.48–7.57 ppm (m, 4H, CHarom.); 13C NMR (100 MHz, CDCl3):
d=13.75, 14.01 (2”COOCH2CH3), 30.27 (COCH3), 40.12 (CHCH2),
44.89 (CH2), 55.35 (CH(COOEt)2), 61.91, 61.95 (2”COOCH2CH3),
G
107.31, 110.64, 141.97 (3”CHarom.), 153.85 (Cq), 168.08, 168.24 (2”CO,
ester), 206.17 ppm (CO); HRMS-ESI: m/z: calcd for C15H20O6Na:
319.1158; found: 319.1156 [M+Na]+; the ee was determined by SFC anal-
ysis by using a Chiralpak AD-H column (10% iPrOH); flow rate=
1.0 mLminÀ1; tmajor =6.0, tminor =5.6 min (85% ee).
47.35 (CH2), 57.36 (CH(COOEt)2), 61.32, 61.62 (2”COOCH2CH3),
A
126.93, 127.09, 127.24, 128.61, 128.73 (9”CHarom.), 139.61, 139.97, 140.64
(3”Cq), 167.67, 168.17 (2”CO, ester), 205.94 ppm (CO); HRMS-ESI:
m/z: calcd for C23H26O5Na: 405.1678; found: 405.1666 [M+Na]+; the ee
was determined by SFC analysis by using a Chiralpak AD-H column
(10% iPrOH); flow rate=1.0 mLminÀ1
(85% ee).
; tmajor =46.9, tminor =25.9 min
Diethyl 2-((S)-1-(1-methyl-1H-indol-2-yl)-3-oxobutyl)malonate (29): The
title compound was obtained according to the general procedure. Yellow
oil; Yield: 91%; Rf =0.44 (PE/Et2O 2:1); [a]2D0 = À4.0 (c=1.1 in chloro-
Methyl 2-((R)-3-oxocyclohexyl)acetate (34a): The title compound was
obtained according to the general procedure. Pale-yellow oil; Yield:
92%; Rf =0.27 (PE/Et2O 2:1); [a]2D0 =+4.3 (c=1 in chloroform);
1H NMR (400 MHz, CDCl3): d=1.36–1.43 (m, 1H, CH2a), 1.59–1.71 (m,
1H, CH2b), 1.86–1.93 (m, 1H, CH2c), 1.97–2.10 (m, 2H, CH2), 2.17–2.43
form); 1H NMR (400 MHz, CDCl3): d=1.08 (t, 3J
(H,H)=7.1 Hz, 3H,
G
COOCH2CH3), 1.28 (t, 3J
3H, COCH3), 2.97–3.01 (m, 2H, CHCH2), 3.79 (d, 3J
CH(COOEt)2), 3.88 (s, 3H, NCH3), 3.92–4.05 (m, 2H, COOCH2CH3),
ACHTREUNG
AHCTREUNG
ACHTREUNG
Chem. Eur. J. 2008, 14, 6155 – 6165
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6163

S. V. Ley et al.
(m, 6H, CH2d, 2”CH2, CH), 3.63 ppm (s, 3H, COOCH3); 13C NMR
(100 MHz, CDCl3): d=25.15, 31.25 (2”CH2), 35.91 (CH), 41.07, 41.42,
47.79 (3”CH2), 51.97 (COOCH3), 172.52 (CO, ester), 210.62 ppm (CO);
HRMS-ESI: m/z: calcd for C9H14O3Na: 193.0841; found: 193.0846
[M+Na]+; the ee was determined by GC analysis by using a Chirasil
DEx-CB column (86% ee).
Tetrahedron Lett. 2005, 46, 5377–5381; e) Y. Xu, K. Ohori, T. Ohshi-
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E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 11204–11205; g) M. S.
Taylor, D. N. Zalatan, A. N. Lerchner, E. N. Jacobsen, J. Am. Chem.
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Feringa, G. Roelfes, Angew. Chem. 2007, 119, 9468–9471; Angew.
Chem. Int. Ed. 2007, 46, 9308–9311; b) F.-X. Chen, C. Shao, Q.
Wang, P. Gong, D.-Y. Zhang, B.-Z. Zhang, R. Wang, Tetrahedron
Lett. 2007, 48, 8456; c) J.-M. Xu, F. Zhang, Q. Wu, Q.-Y. Zhang, X.-
F. Lin, J. Mol. Catal. B 2007, 49, 50–54; d) J. Lubkoll, H. Wennem-
ers, Angew. Chem. 2007, 119, 6965–6968; Angew. Chem. Int. Ed.
2007, 46, 6841–6844; e) M. L. Kantam, K. V. S. Ranganath, K. Ma-
hendar, L. Chakrapani, B. M. Choudary, Tetrahedron Lett. 2007, 48,
7646–7649; f) S. Krishnan, B. M. Stoltz, Tetrahedron Lett. 2007, 48,
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72, 5905–5907; h) G.-L. Zhai, A. Cordova, Tetrahedron Lett. 2007,
48, 5976–5980; i) S. Takizawa, M. L. Patil, Tetrahedron 2007, 63,
6512–6528; j) C. Camarero, I. Gonzalez-Temprano, E. Lete, N. So-
tomayor, Synlett 2007, 1101–1105; k) S. G. Davies, P. M. Roberts,
A. D. Smith, Org. Biomol. Chem. 2007, 5, 1405–1415; l) J. Matsuo,
H. Kawai, H. Ishibashi, Tetrahedron Lett. 2007, 48, 3155–3158;
m) R. Rasappan, M. Hager, A. Gissibl, O. Reiser, Org. Lett. 2006, 8,
6099–6102; n) N. Sasamoto, C. Dubs, Y. Hamashima, M. Sodeoka,
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Carlson, Eur. J. Org. Chem. 2006, 2005–2013.
[4] a) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248–5286;
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Johansson, A. McNally, N. T. Vo, Drug Discovery Today 2007, 12,
8–27; c) Asymmetric Organocatalysis (Eds.: A. Berkessel, H.
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[5] a) M. Yamaguchi, T. Shiraishi, M. Hirama, Angew. Chem. 1993, 105,
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Ethyl 2-((R)-3-oxocyclohexyl)acetate (34b): The title compound was ob-
tained according to the general procedure. Pale-yellow oil; Yield: 90%;
Rf =0.31 (PE/Et2O 2:1); [a]2D0 =+ 8.0 (c=1 in chloroform); 1H NMR
(400 MHz, CDCl3): d=1.23 (t, 3J
(H,H)=7.1 Hz, 3H, COOCH2CH3),
R
1.36–1.44 (m, 1H, CH2a), 1.62–1.72 (m, 1H, CH2b), 1.88–1.96 (m, 1H,
CH2c), 1.99–2.10 (m, 2H, CH2), 2.19–2.45 (m, 6H, CH2d, 2”CH2, CH),
4.11 ppm (q, 3J(H,H)=7.1 Hz, 2H, COOCH2CH3); 13C NMR (100 MHz,
N
CDCl3): d=14.19 (COOCH2CH3), 24.76, 30.86 (2”CH2), 35.55 (CH),
40.96, 41.05, 47.42 (3”CH2), 60.42 (COOCH2CH3), 171.69 (CO, ester),
210.29 ppm (CO); HRMS-ESI: m/z: calcd for C10H17O3: 185.1178; found:
185.1183 [M+H]+; the ee was determined by GC analysis by using a
Chirasil DEx-CB column (93% ee).
Methyl 5-oxo-(3S)-phenylhexanoate (37a): The title compound was ob-
tained according to the general procedure. Pale-yellow solid; Yield:
97%; Rf =0.31 (PE/Et2O 2:1); m.p. 398C; [a]2D0 =À4.6 (c=1 in chloro-
form); 1H NMR (400 MHz, CDCl3): d=2.03 (s, 3H, COCH3), 2.56–2.70
(m, 2H, CH2), 2.75–2.87 (m, 2H, CH2), 3.56 (s, 3H, COOCH3), 3.63–3.70
(m, 1H, CHCH2), 7.16–7.20 (m, 3H, CHarom.), 7.25–7.29 ppm (m, 2H,
CHarom.); 13C NMR (100 MHz, CDCl3): d=30.74 (COCH3), 37.68
(CHCH2), 40.98, 49.74 (2”CH2), 51.91 (COOCH3), 127.24, 127.61, 129.03
(5”CHarom.), 143.48 (Cq), 172.56 (CO, ester), 207.09 ppm (CO); HRMS-
ESI: m/z: calcd for C13H16O3Na: 243.0997; found: 243.1009 [M+Na]+;
the ee was determined by SFC analysis by using a Chiralpak AD-H
column (7% iPrOH); flow rate=1.0 mLminÀ1
12.4 min (84% ee).
; tmajor =11.4, tminor =
Ethyl 5-oxo-(3S)-phenylhexanoate (37b): The title compound was ob-
tained according to the general procedure. Pale-yellow oil; Yield: 99%;
Rf =0.35 (PE/Et2O 2:1); [a]2D0 =À6.6 (c=1 in chloroform); 1H NMR
3
(400 MHz, CDCl3): d=1.13 (t, J
A
(s, 3H, COCH3), 2.55–2.68 (m, 2H, CH2), 2.75–2.86 (m, 2H, CH2), 3.62–
3.70 (m, 1H, CHCH2), 4.02 (d, 3J
AHCTREUNG
7.16–7.21 (m, 3H, CHarom.), 7.25–7.29 ppm (m, 5H, CHarom.); 13C NMR
(100 MHz, CDCl3): d=14.45 (COOCH2CH3), 30.74 (COCH3), 37.76
(CHCH2), 41.22, 49.81, 60.73 (3”CH2), 127.18, 127.66, 128.96 (5”
CHarom.), 143.45 (Cq), 172.08 (CO, ester), 207.09 ppm (CO); HRMS-ESI:
m/z: calcd for C14H18O3Na: 257.1154; found: 257.1152 [M+Na]+; the ee
was determined by SFC analysis by using a Chiralpak AD-H column
(7% iPrOH); flow rate=1.0 mLminÀ1; tmajor =7.7, tminor =7.1 min (90%
ee).
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Received: April 9, 2008
Published online: June 2, 2008
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