PAPER
1509
Catalytic Direct Asymmetric Michael Reactions: Addition of Unmodified
Ketone and Aldehyde Donors to Alkylidene Malonates and Nitro Olefins
Cat lyticDirectAsym etricMichaelReactions M. Betancort, Kandasamy Sakthivel, Rajeswari Thayumanavan, Fujie Tanaka, Carlos F. Barbas III*
Juan
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, USA
Fax +1(858)7842583; E-mail: carlos@scripps.edu
Received 20 April 2004
We would like to dedicate this paper to Prof. T. Mukaiyama on the occasion of his 77th birthday
Abstract: The Michael additions of a number of ketones and aldehydes to alkylidene malonates and nitro olefins were studied. The
reactions employ small organic molecules as catalyst under mild reaction conditions and do not require preactivation of the carbonyl
donors. These reactions afforded a variety of highly functionalized
products in good yields with moderate to good enantioselectivity.
Key words: asymmetric catalysis, Michael additions, organocatalysis, ketones, enamines
The development of new methodologies in asymmetric
synthesis is of tremendous importance given the increasing demand for optically active compounds.1 Though remarkable advances have been made in the development of
asymmetric catalysts containing metals, relatively few
asymmetric transformations have been reported that employ small organic molecules as catalysts. As the field of
enantioselective catalysis has evolved during the last few
years, highly reliable methods that predictably generate
products with known stereochemistry have been developed and demand has increased for environmentally
benign and highly efficient catalytic processes. Enantioselective organocatalysis in which the reaction is mediated by a catalytic amount of a chiral organic molecule is
emerging as a powerful tool within this context.2 This approach is very attractive given the many advantages it provides ranging from operational simplicity and ease of
handling to the use of inexpensive, nontoxic, and readilyavailable catalysts.
Asymmetric carbon–carbon bond forming reactions are
among the most challenging endeavors in organic synthesis. The Michael reaction is generally regarded as one of
the most efficient and effective transformations, and studies concerning this reaction have played an important role
in the development of modern synthetic organic chemistry.3 Over many years, the scope of this reaction has been
extended in both reactant structure and catalyst efficiency.
Much progress has been made in the development of
asymmetric variants of this reaction, providing for the
preparation of Michael adducts with high enantiomeric
purity.4 Typically, carbon nucleophiles that contain an active methylene center such as malonic acid esters, b-keto
esters, or nitroalkanes have been studied in the Michael
reaction.5 Carbonyl compounds, and ketones in particular,
have generally been used as donors only following their
pre-activation by conversion into a more reactive species
such as enol or enamine equivalents.6,7 In these cases, additional synthetic step(s), stoichiometric amounts of base,
additional reagents, or chiral ligands are required. A potentially advantageous strategy in terms of atom economy
would involve direct additions of unmodified carbonyl
compounds to Michael-type acceptors.8
Research in our laboratories has recently focused on the
concept of catalysis mediated by amino acids and
amines.9–21 These studies led to the development of
amine-catalyzed direct asymmetric aldol and Mannich reactions, Robinson annulations, Diels–Alder cycloadditions, and a variety of asymmetric multicomponent or
assembly reactions. The common feature of these reactions is the use of unmodified nucleophilic donors that,
upon activation by intermediate enamine formation, add
stereoselectively to the corresponding acceptor electrophiles under very mild conditions. Herein, we disclose a
full account of our efforts in broadening the applicability
of this approach to the catalytic direct asymmetric Michael reaction of unmodified ketone and aldehyde donors
to alkylidene malonates and nitro olefins.22
Chiral amines have been used in the catalytic asymmetric
Michael addition, serving either to activate the Michael
acceptor via formation of an iminium species (I,
Scheme 1)5c,d or as bases where a complex formed between the amine and the enolate react with the acceptor
(II, Scheme 1).23 We have explored a third mechanism
that involves transient activation of carbonyl donors
through formation of an enamine intermediate (III,
Scheme 1).
+
O
+
*
HNR2
*
: NR
2
R2
R1
_
Nu
I
SYNTHESIS 2004, No. 9, pp 1509–1521xx. 204
Advanced online publication: 26.05.2004
DOI: 10.1055/s-2004-822392; Art ID: C0404SS
© Georg Thieme Verlag Stuttgart · New York
_
NR*2
Scheme 1
tions
R1
EWG
II
R1
EWG
III
Possible mechanisms for amine-catalyzed Michael reac-
1510
Table 1
O
Catalyst Screening
EtO2C
CO2Et
20 mol% cat
+
Ph
Entry
PAPER
J. M. Betancort et al.
EtO2C
O
CO2Et
Ph
THF, 4 days
Catalyst (%)
1
Yield (%)a
ee (%)b
No reaction
–
No reaction
–
<5
–
<5
–
25
50
47
59
61
59
80
61
From this study, diamine 8 emerged as a superior catalyst,
both in terms of yield and enantioselectivity, to (S)-1-(2pyrrolidinylmethyl)pyrrolidine (6). Reactions with L-proline and its analogs provided only trace amounts of the
Michael adducts. The most efficient catalysts in terms of
both yield and enantioselectivity were the diamine catalysts. Key features of these catalysts are the presence of a
secondary amine required for enamine formation and a
tertiary amine that provides a diversity point and may also
be involved in the reaction. Substitution on the pyrrolidine
ring improved the enantioselectivity but caused a decrease
in yield.
61
Similar diamine catalysts have been introduced recently
by Alexakis et al. These catalysts are also 1,2-diamines
possessing a pyrrolidine ring and an additional tertiary
amine.26
COOH
N
H
2
S
N
H
3
COOH
NHPh
N
H
4
N
NH2
5
OMe
N
H
6
N
N
H
7
N
N
H
8
N
N
H
9
59
N
N
H
10
61
60
51
66
70
64
N
N
H
11
O
N
N
H
12
N
H
C10H21
N
C10H21
13
40
76
a
Isolated yield after column chromatography.
Determined by chiral-phase HPLC analysis using a Chiralcel AD
column.
b
Synthesis 2004, No. 9, 1509–1521
Our previous studies had identified L-proline as a catalyst
for direct asymmetric aldol reactions, Mannich reactions,
and Robinson annulations (Michael–Aldol).9–11 On the
basis of these successful precedents, we decided to employ Michael acceptors as electrophilic counterparts to the
enamines. As a model transformation we studied the proline-catalyzed Michael addition of acetone to diethyl benzalmalonate in DMSO. The Michael adduct was isolated,
albeit in racemic form, together with (E)PhCHCHCOCH3 as a byproduct. Similar results were obtained with other amino acids, but when (S)-1-(2-pyrrolidinylmethyl)pyrrolidine (6) was used as a catalyst, the
addition product was formed exclusively in 41% yield and
47% enantiomeric excess (ee). Screening of diverse solvents allowed us to further improve both yield and enantioselectivity; THF provided superior results (47% yield
with 59% ee). In order to achieve higher enantioselectivity, a set of chiral amines was synthesized and screened
(Table 1).24,25
© Thieme Stuttgart · New York
With optimal catalyst and solvent conditions established,
we studied other factors that might affect selectivities. To
study the influence of the ester moiety of the Michael acceptors, a number of benzylidene malonates were synthesized. The substrates were reacted with acetone and the
corresponding addition products were isolated (Table 2).
Again, catalyst 8 was superior to diamine 6. The reactions
were also conducted at lower temperature with the aim of
improving selectivities. Although reduced temperature
enhanced enantioselectivies, it also dramatically reduced
yields.
A variety of alkylidene malonates were then evaluated as
substrates for reaction with acetone (Table 3). Aromatic
substituents provided good enantioselectivies (entries 1 to
10). The degree of substitution and consequently the steric
bulk at the ortho position of the aryl ring played an important role in the outcome of the reaction. For example, the
2-trifluoromethyl derivative gave excellent enantioselectivity and good yield (entries 9–10). The 2-furyl substitution gave a higher yield of the addition product than other
catalysts, but lower selectivity (entries 11–12). Alkyl substrates gave the corresponding Michael adducts in low
PAPER
Table 2
tion
Effect of Ester Substituent on the Michael Addition Reac-
Entry
R
Catalyst
Yield (%)a
ee (%)b
1
Me
8
88
57
6
55
56
8
80
61
6
47
59
8
42
62
6
22
61
8
85
51
2
3
Et
4
5
i-Pr
6
7
Bn
a
Isolated yield after column chromatography.
Determined by chiral-phase HPLC analysis using a Chiralcel AD
column.
b
Table 3
tion
Effect of the Malonate b-Substituent on the Michael Reac-
yields and with low enantioselectivities (entries 13–18).27
These aliphatic substrates turned out to be unstable under
the reaction conditions and significant amounts of the malonate and the corresponding aldehyde were formed (presumably via a retro-Knovenagel reaction).
We next examined a series of ketone donors as nucleophilic counterparts in the reaction. While aliphatic ketones
were poor substrates, cyclic ketones were successfully
used as nucleophiles (Table 4). The structure of the catalyst has a subtle influence upon the yield and stereochemical outcome of the reaction. When diamine 6 was used as
a catalyst (entry 1), cyclopentanone reacted with diethyl
benzalmalonate to provide two readily separable diastereomers, syn and anti in 55 and 6% yield with 53 and 55%
ee, respectively; use of catalyst 8 brought a decrease in
both yield and enantioselectivity (entry 2). When cyclohexanone was used as a substrate, catalyst 8 provided superior yields and ee values in shorter reaction times (77%
ee and 32% yield after 7 days) as compared to 6 (entries 3
and 4).
Table 4 Influence of the Catalyst Choice on the Outcome of
Michael Reactions of Cyclic Ketones
O
EtO2C
CO2Et
+
( )n
Entry
1
R
R1
Catalyst
Yield (%)a ee (%)b
Ph
Et
8
80
61
6
47
59
8
45
71
6
31
64
8
87
58
6
60
55
8
36
72
6
17
70
8
62
73
6
46
70
8
95
2
6
84
33
8
41
20
6
16
24
8
64
17
6
27
14
8
53
19
6
16
17
2
3
1-Naphthyl
Et
4
5
2-Napthhyl
Et
6
7
2-tolyl
Et
8
9
2-CF3Ph
Et
10
11
2-furyl
Et
12
13
n-Pentyl
Bn
14
15
Cyclohexyl
Bn
16
17
18
a
i-Pr
Bn
Isolated yield after column chromatography.
Determined by chiral-phase HPLC analysis using a Chiralcel AD
column.
b
1511
Catalytic Direct Asymmetric Michael Reactions
O
Ph
20 mol% cat
THF
Ph
CO2Et
( )n
CO2Et
Entry
n
Catalyst Yield (%)a drb (syn: eec (syn) Time
anti)
1
1
6
61
9:1
53
4 days
2
1
8
28
7:1
39
4 days
3
2
6
24
25:1
65
14 days
4
2
8
32
19:1
77
7 days
a
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis using a Chiralcel AD
column.
b
The potential of this methodology can be further extended
as these diamines can also catalyze the Knovenagel reaction used to synthesize alkylidene malonates. This synthetic multistep procedure involves the synthesis of two
carbon–carbon bonds catalyzed by a single multi-acting
entity. Using the procedure described above, a multicomponent reaction that directly converts an aldehyde into the
final Michael adduct via amine catalysis of both steps can
be carried out in one pot. In this case, DMSO was the solvent of choice (Scheme 2). Though the yields and enantioselectivities obtained were modest, these results
certainly point to the high potential and usefulness of this
multicomponent reaction sequence.28 The Michael adducts arising from the addition of ketones to alkylidene
malonates undergo facile monodecarbomethoxylation under Krapcho conditions to afford synthetically useful
chiral 3-substituted-5-keto esters.29
Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
1512
PAPER
J. M. Betancort et al.
O
EtO2C
O
CH2(CO2Et)2
20 mol% cat 6
H
DMSO/acetone
R
R
R=H
52% yield, 49% ee
R = CF3
62% yield, 70% ee
Scheme 2
previously. These studies were performed on the reaction
of cyclohexanone with trans-b-nitro styrene (Table 5). LProline and analogs lacking the tertiary amine were the
least effective catalysts. The superior levels of reaction efficiency observed with diamine 12 (entry 8) prompted us
to select this catalyst for further exploration. It is worth
noting that the modular nature of these catalytic molecules
allows easy modification of their structures to fine-tune
their reactivity for a particular application.
CO2Et
One-pot Knovenagel–Michael addition
Following our success in carrying out direct catalytic
asymmetric Michael additions of unmodified ketones to
alkylidene malonates through formation of an enamine intermediate, we decided to explore the more reactive nitro
olefins as electrophiles.30 The Michael adducts obtained
are versatile synthons. Further transformations involving
the newly formed nitro ketone functionality such as reduction or hydrogenation will allow access to other synthetically valuable building blocks.31
When acetone was reacted with trans-b-nitro styrene in
DMSO at room temperature employing L-proline as catalyst, the corresponding Michael adduct was isolated in
80% yield, but in almost racemic form.9c The reaction of
cyclopentanone employing the same catalyst in THF provided improved results since the addition product was isolated in 88% yield as a 5:1 syn–anti mixture in 29 and 52%
ee, respectively. This reaction constituted the first example of a proline-catalyzed asymmetric Michael addition to
a nitro styrene electrophile.22a In view of the improvements in ee observed when diamine catalysts were employed in the addition of unmodified ketones to alkylidene
malonates, these catalysts were evaluated in this reaction.
When diamine 6 was employed as a catalyst for the addition of acetone, the product was formed in 81% yield and
35% ee after 3 days (Scheme 3). The reaction of cyclopentanone with trans-b-nitro styrene catalyzed by 6 also
proceeded smoothly at room temperature to furnish the
Michael adducts in 78% yield, with a diastereomeric ratio
of 4:1 in favor of the syn isomer and 78% ee (Scheme 3).
We next initiated the search for a suitable chiral catalyst
for the addition of unmodified ketones to nitro olefins by
screening the collection of diamines we had synthesized
O
+
Ph
NO2
Cat. 6
20 mol %
O
Ph
NO2
THF
81% yield, 35% ee
O
+
Ph
NO2
Cat.
20 mol %
O
Ph
NO2
THF
Scheme 3
L-proline
88% yield, 29% ee
Diamine 6
78% yield, 78% ee
Addition of ketones to nitro olefin electrophiles
Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
Table 5
Olefins
Catalyst Screening for the Addition of Ketones to Nitro
O
+
Ph
NO2
Cat.
20 mol %
O
Ph
NO2
THF, 22h
Entry
Catalyst
Yield (%)a
1
1
7
2
5
3
drb (syn–anti)
eec (syn)
98:2
56
<2
–
–
6
21
98:2
73
4
7
89
>98:2
84
5
8
93
>98:2
89
6
10
90
>98:2
86
7
11
81
98:2
78
8
12
92
98:2
90
9
13
95
94:6
67
a
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis using a Chiralcel AS
column.
b
In an effort to study the scope and generality of this transformation, the reactions of a variety of ketones and nitro
olefins catalyzed by 12 were analyzed (Table 6). We speculated that the high enantioselectivities we had observed
for the reaction of ketones with alkylidene malonates
bearing ortho substituents on the aromatic ring could also
be obtained in this case. Gratifyingly, the reaction of acetone with the o-trifluoromethyl derivative provided the
Michael adduct in 72% ee (entry 2) versus 56% ee for
trans-b-nitrostyrene (entry 1). Within this series, 3-pentanone and acetophenone derived ketones were less reactive, providing Michael adducts in modest yield (entries 4
and 5). 2-Butanone is of particular interest since this nonsymmetrical ketone could form two regioisomeric addition products, one of which gives rise to possible syn-anti
isomers. The main product results from the nucleophilic
attack of the less hindered methyl group of the ketone in a
3:1 ratio (entry 3). Cyclic ketones were good substrates
for the reaction, with cyclopentanone and cyclohexanone
providing for the best results (entries 7 and 8); however,
the reaction with the higher homologue cycloheptanone
(entry 9) was sluggish (32% yield after 5 days). Hydroxy-
PAPER
1513
Catalytic Direct Asymmetric Michael Reactions
acetone (entry 10) could also be employed as donor and
yielded 3-hydroxy-5-nitro-4-phenylpentan-2-one as a
69:31 mixture of isomers in favor of the syn stereochemistry. The trans-b-methyl-b-nitrostyrene (entry 11) is an
interesting acceptor, since one of the two stereocenters
created in the Michael reaction is located a to the nitro
group; the reaction with acetone as donor gave excellent
yield for the addition product, but had poor syn–anti selectivity (62:38).
Table 6
The reaction possesses notable water tolerability. When
cyclohexanone was reacted with either p-methoxy-transb-nitro styrene or the o-trifluoromethyl derivative in up to
10% of water, the addition products were isolated with excellent stereoselectivities, and moderate to good yields
and enantioselectivities after three days at room temperature (Scheme 4).
O
Cat. 12
20 mol %
O
+
NO2
R
NO2
+ 4-OMe-Ph
Addition of Ketones to Nitro Olefins
THF/H2O
(90:10)
4 °C
R
O
Cat. 6
20 mol %
NO2
O
Ar
NO2
84% yield
dr > 98:2, 70% ee
THF, r.t., t
O
Entry Ketone
1
O
2
O
3
O
eec
Time Yield drb
(%)a syn–anti syn
Nitro olefin
Ph
17 h
61
–
56
26 h
54
–
72
NO2
2d
90
88:12
68
NO2
5d
27
92:8
67
NO2
5d
21
–
72
NO2
5d
<2
–
–
NO2
3d
46
86:14
74
NO2
22 h
92
98:2
90
NO2
5d
32
88:12
53
NO2
NO2
CF3
4
Ph
O
5
Ph
O
Ph
Ph
6
O
Ph
Ph
7
8
9
O
Ph
O
Ph
O
Ph
+
O
Ph
NO2
17 h
81
69:31
2-CF3-Ph
Cat. 6
20 mol %
THF/H2O
(90:10)
4 °C
Scheme 4
O
Ar
NO2
60% yield
dr > 98:2, 88% ee
Water tolerability of the reaction
On the basis of the findings described, the methodology
was extended to other carbonyl compounds that could
form enamine intermediates. Due to the difficulty in controlling reactions of enolates or enols of aldehydes, there
were no examples of catalytic asymmetric conjugate additions of naked aldehydes at the time we published our first
studies in this area.22b,32 The reaction of isovaleraldehyde
with diethyl benzalmalonate was explored as a model
transformation (Scheme 5). Initial experiments were performed using (S)-1-(2-pyrrolidinylmethyl)pyrrolidine (6)
as a catalyst. Under these conditions, no product formation was detected. However, when the more reactive
trans-b-nitrostyrene acceptor was employed, the reaction
proceeded smoothly to furnish the Michael adducts in
80% yield, with a dr of 80:20 in favor of the syn stereochemistry and 75% ee. The syn selectivity of this reaction
is in accord with our studies concerning ketone donors described above.
To search for more optimal catalysts for the reaction of
isovaleraldehyde with trans-b-nitrostyrene, we screened a
number of structurally related amines (Table 7). We
found that (S)-2-(morpholinomethyl)pyrrolidine (11) (enOHC
10
NO2
EtOOC
+
COOEt
Ph
–
Cat. 6
20 mol %
EtOOC
COOEt
OHC
Ph
THF
No reaction
OH
11
O
Ph
NO2
2d
97
62:38
70
OHC
+
Ph
NO2
Cat. 6
20 mol %
Ph
OHC
NO2
THF, 22h
a
Isolated yield after column chromatography.
b
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis.
80% yield, 75% ee
Scheme 5
Asymmetric conjugate additions of naked aldehydes
Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
1514
PAPER
J. M. Betancort et al.
try 6) was the most effective catalyst of the group in terms
of stereochemical control, providing a high level of diastereoselection and good enantioselection. In contrast to
results obtained with diamine catalysts, reactions with Lproline provided only trace amounts of the Michael adducts (entry 1).
Table 7
Olefins
Table 9
Effect of Catalyst Loading on Reaction Efficiency
OHC
+
Cat. 11
n mol %
NO2
Ph
C4H9
10 equiv
Ph
OHC
NO2
C4H9
THF, r.t., t
Time (d) Yield (%)a drb (syn–anti) eec (syn)
Entry
n mol%
1
20
1
87
85: 15
69
2
10
4
88
75: 25
72
3
5
10
92
69: 31
68
Catalyst Screening for the Addition of Aldehydes to Nitro
OHC
+
Ph
NO2
Ph
Cat.
20 mol %
OHC
NO2
THF, r.t., 3 d
Entry
Catalyst
Yield (%)
a
a
b
dr (syn–anti) ee (syn)
1
1
<5
93:7
25
2
6
80
80:20
75
3
7
89
83:17
73
4
8
80
82:18
64
5
10
70
82:18
70
6
11
78
92:8
72
7
12
88
80:20
47
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis.
b
c
diastereoselectivity of the reaction was sensitive to the
longer reaction times required to obtain high conversions.
a
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis.
b
Additional studies of this reaction catalyzed by (S)-2(morpholinomethyl)pyrrolidine (11) indicated a temperature profile of ascending selectivity with descending temperature (Table 8). Upon cooling the reaction, the addition
product was obtained with higher diastereo- and enantioselectivity but lower yield. While the reaction at room
temperature provided the addition product in 78% yield,
the reaction at –24°C provided only traces of the Michael
adduct.
The effect of catalyst loading on reaction efficiency was
evaluated (Table 9). While 20% of 11 was routinely employed, catalyst loadings as low as 5 mol% (entry 3) provided useful levels of enantioselectivity though the
The equivalents of aldehyde required for optimal results
in this Michael addition were also studied. In the case of
the more reactive unsubstituted substrates such as hexanal, the reaction proceeded smoothly when the amount of
aldehyde was reduced to 2 equiv and the Michael adduct
was obtained in 85% yield, though a decrease in dr and ee
associated with longer reaction times was noted
(Table 10). When the same study was carried out with a
branched aldehyde, isovaleraldehyde, the reaction rate decreased drastically. In order to achieve high yields in a
short period of time, 10 equiv of aldehyde were routinely
used.
Table 10
Effect of Aldehyde Equivalents on Reaction Efficiency
OHC
+
Cat. 11
n mol %
NO2
Ph
C4H9
10 equiv
Ph
OHC
NO2
C4H9
THF, r.t., t
Entry
n mol%
Time (d) Yield (%)a drb (syn–anti) eec (syn)
1
10
1
87
85:15
69
2
5
3
92
78:22
63
3
2
5
85
75:25
55
a
Table 8
Effect of Temperature on the Selectivity of the Reaction
OHC
+
Ph
NO2
Ph
OHC
NO2
THF, T, 3 d
10 equiv
Entry
Cat. 11
20 mol %
Temp (°C)
Yield (%)a
drb (syn–anti) eec (syn)
1
24
78
92:8
72
2
4
20
97:3
78
3
–24
6
98:2
86
a
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis.
b
Synthesis 2004, No. 9, 1509–1521
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis.
b
© Thieme Stuttgart · New York
With catalyst 11 in hand and optimum conditions established, we examined a series of aldehydes and nitro olefins in order to establish the scope of the reaction
(Table 11). Higher enantioselectivity was achieved with
increasing substituent bulk on the aldehyde donor in the
order Me < Et < Bu < i-Pr (entries 1–4). On the basis of
our previous results, we anticipated that ortho-substitution on the aromatic ring would affect both diastereoselectivity and enantioselectivity. Gratifyingly, excellent dr
(up to 98:2) and good ee were obtained when 1-napthyl
and o-trifluoromethyl derivatives were employed, albeit
PAPER
Catalytic Direct Asymmetric Michael Reactions
with a slight decrease in yield (entries 6 and 8). Alkyl nitro
olefins also provided Michael adducts but in low yield
(entry 10). Based on these results, it is clear that steric factors play an important role in the outcome of the reaction.
While isovaleraldehyde was a suitable aldehyde for the reaction, the more sterically hindered 3,3-dimethylbutyraldehyde was ineffective (entry 5). Introduction of an
isopropyl substituent on the nitro olefin precluded any reaction (entry 11).
Table 11
Addition of Aldehydes to Nitro Olefins
CHO +
R
NO2
R1
Entry Aldehyde
2
OHC
CHO
CHO
R1
NO2
R
THF, r.t.
10 equiv
1
R1
Cat. 11
20 mol %
eec
Time Yield drb
(%)a syn–anti syn
Ph
3h
85
90:10
56d
Ph
27 h
94
86:14
65
The employment of unmodified aldehydes as donors in
the asymmetric Michael reaction provides an easy and
convenient way of synthesizing novel optically active 2,3disubstituted g-formyl nitro compounds in one step. These
useful synthons can be further converted into a wide array
of interesting building blocks such as 1,4-amino alcohols
or amino acids in a straightforward manner. The application of this approach to the synthesis of pyrrolidines particularly attracted our attention. Substituted chiral, nonracemic pyrrolidines are common structural motifs found
in many natural and unnatural products that possess interesting and important biological activities, and a great deal
of effort has been devoted toward the development of
asymmetric methods for their synthesis.33,34 To demonstrate the effectiveness of the present reaction, optically
active g-formyl nitro compounds were hydrogenated with
Pd(OH)2. The reductive amination proceeded smoothly to
afford the desired pyrrolidines that were isolated as their
N-tosyl derivatives in good overall yields (Scheme 6).
CHO
NO2
27 h
87
85:15
69
78
92:8
72
Scheme 6
pounds
Though further studies are needed to firmly elucidate the
mechanism of these Michael additions, the reaction very
likely proceeds via an enamine mechanism.35 The high
syn selectivity we observe is in accord with results obtained in conjugate additions of preformed enamines to
both alkylidene malonates and nitro olefins.36 In the case
of the addition of ketones to alkylidene malonates, we can
rationalize the observed stereochemistries through a favored transition state where the alkylidene malonate approaches the enamine from the less hindered re face. In
the case of additions to nitro olefins, the syn selectivity
may be explained by an acyclic synclinal model, in which
there are favorable electrostatic interactions between the
partially positive nitrogen of the enamine and the partially
negative nitro group in the transition state (Figure 1).37
For the addition of aldehydes, approach of the nitro olefin
from the less hindered si face of the enamine would produce the observed stereochemistry. This conformation
would place the tertiary-amine-containing arm of the catalyst syn to the aldehydic hydrogen because this is sterically less congested. In the case of ketones, however,
discrimination by the catalyst arm between the two groups
of the enamine intermediate is challenging, because of the
similarity of their environments. Nevertheless, the smaller
and flat olefinic sp2 carbon would be preferred to the bulkier free-rotating tetrahedral sp3 carbon. The observed stereochemistries of the products in this case could be
explained by approach of the nitro olefin from the less
hindered re face of the enamine.
R = Me
R = iPr
C4H10
CHO
Ph
3d
5
CHO
Ph
3 dg –
–
–
6
CHO
3d
67
96:4
75e
7
CHO
3d
96
89:11
69
8
CHO
3d
77
98:2
78
2d
82
86:14
71
3d
42
89:11
NDf
–
–
CF3
CHO
S
10
CHO
11
CHO
a
C3H7
3 dg –
Isolated yield after column chromatography.
Determined by 1H NMR analysis of unpurified products.
c
Determined by chiral-phase HPLC analysis.
d
Determined after conversion to the corresponding pyrrolidine.
e
Determined after conversion to the corresponding primary alcohol.
f
Not determined.
g
No reaction.
b
N
Ts
2. TsCl
R
Ph
1. H2, Pd(OH)2
Ph
4
9
R
Ph
OHC
3
1515
79% yield
82% yield
Hydrogenation of optically active g-formyl nitro com-
Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
1516
PAPER
J. M. Betancort et al.
13
C NMR (125 MHz, CDCl3): d = 62.6, 56.4, 55.8, 45.7, 29.5, 28.2,
27.1, 24.8.
Ketone-malonate:
N
HRMS: m/z calcd for C11H23N2 [M + H]+: 183.1856; found:
183.1853.
R2N
CO2R
RO2C
2¢S-1-Pyrrolidin-2¢-ylmethylazocane (1.9)
[a]D25 +13.40 (c 3.6, CHCl3).
Ph
1
H NMR (500 MHz, CDCl3): d = 3.20 (dddd, J = 6.8, 6.8, 6.8, 6.8
Hz, 1 H), 2.98 (ddd, J = 9.6, 6.6, 6.6 Hz, 1 H), 2.87 (ddd, J = 9.6,
7.0, 7.0 Hz, 1 H), 2.61–2.56 (m, 2 H), 2.54–2.49 (m, 2 H), 2.38 (dd,
J = 12.1, 5.3 Hz, 1 H), 2.34 (dd, J = 12.1, 8.5 Hz, 1 H), 2.31 (br s,
1H), 1.90–1.82 (m, 1 H), 1.74 (dddd, J = 7.2, 7.2, 7.2, 7.2 Hz, 2 H),
1.67–1.62 (m, 2 H), 1.60–1.53 (m, 8 H), 1.37–1.31 (m, 1 H).
Aldehyde-nitro olefin:
N NO
2
R2N H
Ph
Ketone-nitro olefin:
NO2
Ph
Figure 1
Potential transition states
In summary, we have developed and studied organocatalytic asymmetric Michael additions of ketones and aldehyde donors to both alkylidene malonates and nitro
olefins using pyrrolidine based diamine catalysts, easily
prepared from L-proline. The Michael additions proceed
in moderate to good enantioselectivies under operationally simple reaction conditions. The optically active adducts
are readily modified through additional synthetic manipulations to provide access to valuable synthons.
Chemicals and solvents were either purchased puriss p.A. from
commercial suppliers or purified by standard techniques. For TLC,
silica gel plates (Merck 60 F254) were used. Liquid chromatographic purifications were performed by flash column chromatography
using glass columns packed with silica gel (Merck 60, particle size
0.040–0.063 mm). 1H and 13C NMR spectra were recorded either on
a Bruker AMX300 or an Avance 500. HPLC was carried out using
a Hitachi organizer consisting of a D-2500 Chromato-Integrator, an
L-4000 UV-Detector, and a l-6200 Intelligent Pump. Optical rotations were recorded on a Perkin–Elmer 241 Polarimeter (l = 589
nm, 1 dm cell). HRMS were recorded on an IonSpec FTMS mass
spectrometer with a DHB matrix. Gas chromatography, mass spectrometry (GCMS) experiments were performed on a Hewlett Packard 5890 gas chromatograph and a 5971A mass selective detector.
Electrospray ionization (ESI) mass spectrometry experiments were
performed on an API 100 Perkin–Elmer SCIEX single quadrupole
mass spectrometer.
2¢S-1-Pyrrolidin-2¢-ylmethylazepane (1.8)
Diamine catalysts were synthesized according to literature procedures.24
[a]D25 +13.61 (c 2.8, CHCl3).
1
H NMR (500 MHz, CDCl3): d = 3.27–3.22 (m, 1 H), 3.12 (br s, 1
H), 3.00 (ddd, J = 10.3, 6.6, 6.6 Hz, 1 H), 2.89 (ddd, J = 10.3, 7.0,
7.0 Hz, 1 H), 2.73–2.68 (m, 2 H), 2.65–2.59 (m, 2 H), 2.49 (dd,
J = 12.5, 4.8 Hz, 1 H), 2.38 (dd, J = 12.5, 8.8 Hz, 1 H), 1.91–1.84
(m, 1 H), 1.75 (dddd, J = 7.2, 7.2, 7.2, 7.2 Hz, 2 H), 1.65–1.54 (m,
8 H), 1.38–1.31 (m, 1 H).
Synthesis 2004, No. 9, 1509–1521
C NMR (125 MHz, CDCl3): d = 64.9, 56.7, 54.8, 45.7, 29.3, 28.1,
27.6, 26.2, 24.8.
HRMS: m/z calcd for C12H25N2 [M + H]+: 197.2012; found:
197.2012.
N
R2N
13
© Thieme Stuttgart · New York
2S-Bis(decyl)pyrrolidin-2-ylmethylamine (1.12)
[a]D25 +17.33 (c 1.6, CHCl3).
1
H NMR (500 MHz, CDCl3): d = 3.20 (dddd, J = 6.4, 6.4, 6.4, 6.4
Hz, 1 H), 2.98–2.93 (m, 1 H), 2.88–2.82 (m, 1 H), 2.47–2.41 (m, 2
H), 2.38–2.28 (m, 4 H), 1.88–1.82 (m, 1 H), 1.74 (dddd, J = 7.2, 7.2,
7.2, 7.2 Hz, 2 H), 1.43–1.36 (m, 3 H), 1.31–1.21 (m, 30 H), 0.88 (dd,
J = 7.0, 7.0 Hz, 3 H).
13
C NMR (125 MHz, CDCl3): d = 59.6, 56.4, 54.6, 45.6, 31.9, 29.7,
29.6, 29.4, 29.3, 27.5, 27.2, 24.7, 22.7, 14.1.
HRMS: m/z calcd for C25H53N2 [M + H]+: 381.4203; found:
381.4206.
2¢S-1-(4¢-tert-Butoxypyrrolidin-2¢-ylmethyl)pyrrolidine (1.13)
[a]D25 +3.60 (c 1.4, CHCl3).
1
H NMR (500 MHz, CDCl3): d = 4.18–4.13 (m, 1 H), 3.45 (dddd,
J = 7.7, 7.7, 7.7, 5.5 Hz, 1 H), 3.19 (dd, J = 11.0, 5.9 Hz, 1 H), 2.96
(br s, 1 H), 2.75 (dd, J = 11.0, 4.8 Hz, 1 H), 2.60–2.50 (m, 5 H), 2.39
(dd, J = 12.1, 5.5 Hz, 1 H), 1.84–1.75 (m, 5 H), 1.61 (ddd, J = 13.2,
7.7, 7.7 Hz, 1 H), 1.17 (s, 9 H).
13
C NMR (125 MHz, CDCl3): d = 73.3, 71.5, 61.9, 56.2, 54.6, 54.5,
39.7, 28.4, 23.4.
HRMS: m/z calcd for C13H27N2O [M + Na]+: 227.2118; found:
227.2118.
Addition of Ketones to Alkylidene Malonates; General Procedure
To a solution of diethyl benzalmalonate in a mixture of THF (2 mL)
and acetone (0.5 mL) was added (S)-1-(2-pyrrolidinylmethyl)pyrrolidine (8.5 mL, 20% mol). The reaction was stirred at r.t. for 4 d.
Then, the solution was diluted with CH2Cl2 (5 mL) and treated with
aq HCl (0.1 M; 4 mL) with vigorous stirring. The layers were separated, and the aq phase was extracted thoroughly with CH2Cl2
(3 × 2 mL). The combined organic phases were dried (MgSO4),
concentrated and purified by flash column chromatography (silica
gel) affording the Michael adduct.
Yield: 47% (36 mg, 0.12 mmol).
One-Pot Knovenagel-Michael Addition; General Procedure
To a solution of diethyl malonate (40 mg, 0.25 mmol) in DMSO (2
mL) was added benzaldehyde (25.5 mL, 0.25 mmol), followed by
(S)-1-(2-pyrrolidinylmethyl)pyrrolidine (8.5 mL, 20% mol). After 5
h (complete consumption of the aldehyde by TLC), acetone (0.5
mL) was added. The reaction was stirred for 4 d. The work-up was
identical to that already described for the Michael reaction, and the
addition product was isolated.
PAPER
Yield: 52% yield (40 mg, 0.13 mmol).
2-(3-Oxo-1-phenylbutyl)malonic Acid Dimethyl Ester (2.1)
[a]D25 +6.97 (c 2.5, CHCl3, 56% ee) {Lit. [a]D25 –13.2 (c 1.5, CHCl3,
95% ee for the R enantiomer)};38 tR (minor) 19.59 min, tR
(major) 21.59 min (Chiralcel AD; l 254 nm; 1% i-PrOH–hexanes,
1 mL/min).
2-(3-Oxo-1-phenylbutyl)malonic Acid Diethyl Ester (2.3)
[a]D25 +10.17 (c 1.7, CHCl3, 60% ee); tR (minor) 6.62 min, tR
(major) 9.04 min (Chiralcel AD; l 254 nm; 10% i-PrOH–hexanes,
1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.28–7.23 (m, 4 H), 7.21–7.18 (m,
1 H), 4.21–4.17 (m, 2 H), 3.99–3.93 (m, 1 H), 3.94 (ddd, J = 7.2,
7.2, 7.2 Hz, 2 H), 3.69 (d, J = 9.9 Hz, 1 H), 2.96 (dd, J = 16.5, 4.9
Hz, 1 H), 2.90 (dd, J = 16.5, 8.8 Hz, 1 H), 2.02 (s, 3 H), 1.25 (dd,
J = 7.2, 7.2 Hz, 3 H), 1.01 (dd, J = 7.2, 7.2 Hz, 3 H).
13
C NMR (125 MHz, CDCl3): d = 206.1, 168.2, 167.6, 140.4, 128.4,
128.1, 127.2, 61.6, 61.3, 57.4, 47.4, 40.4, 30.3, 14.0, 13.7.
HRMS: m/z calcd for C17H22O5Na [M + Na]+: 329.1359; found:
329.1359.
2-(3-Oxo-1-phenylbutyl)malonic Acid Diisopropyl Ester (2.5)
[a]D25 +12.64 (c 0.9, CHCl3, 61% ee) {Lit. [a]D25 +11 (c 1.0, CHCl3,
53% ee for the S enantiomer)};39 tR (minor) 10.67 min, tR
(major) 15.52 min (Chiralcel AD; l 254 nm; 4% i-PrOH–hexanes,
1 mL/min).
2-(3-Oxo-1-phenylbutyl)malonic Acid Dibenzyl Ester (2.7)
[a]D25 +3.25 (c 2.0, CHCl3, 50% ee); tR (minor) 10.80 min, tR
(major) 13.87 min (Chiralcel AD; l 254 nm; 15% i-PrOH–hexanes, 1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.43–7.41 (m, 3 H), 7.39–7.25 (m,
5 H), 7.23–7.18 (m, 5 H), 7.06–7.04 (m, 2 H), 5.15 (d, J = 12.3 Hz,
1 H), 5.11 (d, J = 12.3 Hz, 1 H), 4.89 (s, 2 H), 4.02–3.98 (m, 1 H),
3.82 (d, J = 9.6 Hz, 1 H), 2.88–2.87 (m, 2 H), 1.95 (s, 3 H).
13
C NMR (125 MHz, CDCl3): d = 205.9, 167.8, 167.4, 140.2, 135.1,
135.0, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 127.7, 67.3, 67.1,
57.3, 47.1, 40.4, 30.2.
HRMS: m/z calcd for C27H26O5Na [M + Na]+: 453.1672; found:
453.1684.
2-(1-Naphthalen-1-yl-3-oxobutyl)malonic Acid Diethyl Ester
(3.3)
[a]D25 –3.49 (c 1.5, CHCl3, 64% ee); tR (minor) 17.56 min, tR
(major) 24.98 min (Chiralcel AD; l 254 nm; 4% i-PrOH–hexanes,
1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 8.30 (d, J = 8.4 Hz, 1 H), 7.82 (d,
J = 8.1 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.59–7.55 (m, 1 H),
7.49–7.46 (m, 1 H), 7.41–7.36 (m, 2 H), 4.94 (br s, 1 H), 4.19–4.13
(m, 2 H), 3.93 (m, 1 H), 3.87–3.83 (m, 2 H), 3.18 (dd, J = 17.3, 5.5
Hz, 1 H), 3.12 (dd, J = 17.3, 7.9 Hz, 1 H), 2.02 (s, 3 H), 1.22 (dd,
J = 7.2, 7.2 Hz, 3 H), 0.87 (dd, J = 7.0, 7.0 Hz, 3 H).
Catalytic Direct Asymmetric Michael Reactions
1517
1
H NMR (500 MHz, CDCl3): d = 7.77–7.76 (m, 3 H), 7.69 (d,
J = 1.5 Hz, 1 H), 7.44–7.38 (m, 3 H), 4.22–4.13 (m, 3 H), 3.92–3.87
(m, 2 H), 3.81 (d, J = 9.9 Hz, 1 H), 3.03 (d, J = 7.0 Hz, 2 H), 2.02
(s, 3 H), 1.25 (dd, J = 7.2, 7.2 Hz, 3 H), 0.93 (dd, J = 7.2, 7.2 Hz, 3
H).
13
C NMR (125 MHz, CDCl3): d = 206.0, 168.2, 167.6, 137.9, 133.2,
132.5, 128.1, 127.7, 127.5, 127.0, 126.1, 126.0, 125.7, 61.6, 61.3,
57.3, 47.3, 40.4, 30.3, 14.0, 13.6.
HRMS: m/z calcd for C21H24O5Na [M + Na]+: 379.1516; found:
379.1510.
2-(3-Oxo-1-o-tolylbutyl)malonic Acid Diethyl Ester (3.7)
[a]D25 +3.02 (c 0.6, CHCl3, 68% ee); tR (minor) 7.39 min, tR
(major) 11.63 min (Chiralcel AD; l 254 nm; 8% i-PrOH–hexanes,
1.0 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.13–7.07 (m, 4 H), 4.25 (ddd,
J = 9.9, 8.1, 5.9 Hz, 1 H), 4.21–4.17 (m, 2 H), 3.95–3.90 (m, 2 H),
3.68 (d, J = 10.3 Hz, 1 H), 2.94–2.92 (m, 2 H), 2.47 (s, 3 H), 1.99
(s, 3 H), 1.26 (dd, J = 7.2, 7.2 Hz, 3 H), 0.98 (dd, J = 7.2, 7.2 Hz, 3
H).
13
C NMR (125 MHz, CDCl3): d = 206.1, 168.4, 167.8, 139.1, 136.9,
130.7, 126.8, 126.0, 61.6, 61.3, 57.1, 47.7, 35.2, 30.5, 19.8, 14.0,
13.7.
HRMS: m/z calcd for C18H24O5Na [M + Na]+: 343.1516; found:
343.1503.
2-[3-Oxo-1-(2-trifluoromethylphenyl)butyl]malonic Acid Diethyl Ester (3.9)
[a]D25 –1.40 (c 1.8, CHCl3, 70% ee); tR (minor) 7.68 min, tR
(major) 14.19 min (Chiralcel AD; l 254 nm; 10% i-PrOH–hexanes,
0.8 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.66 (d, J = 7.7 Hz, 1 H), 7.50–
7.45 (m, 2 H), 7.35–7.32 (m, 1 H), 4.40–4.36 (m, 1 H), 4.19–4.12
(m, 2 H), 4.04 (ddd, J = 7.1, 7.1, 7.1 Hz, 2 H), 3.95 (d, J = 7.7 Hz,
1 H), 3.10–3.00 (m, 2 H), 2.08 (s, 3 H), 1.22 (dd, J = 7.2, 7.2 Hz, 3
H), 1.09 (dd, J = 7.0, 7.0 Hz, 3 H).
13
C NMR (125 MHz, CDCl3): d = 206.0, 168.2, 167.6, 140.0, 131.9,
128.3, 127.1, 126.5, 125.4, 123.2, 61.6, 61.5, 55.9, 46.7, 35.5, 30.0,
13.9, 13.7.
HRMS: m/z calcd for C18H21F3O5Na [M + Na]+: 397.1233; found:
397.1236.
2-(1-Furan-2-yl-3-oxobutyl)malonic Acid Diethyl Ester (3.11)
tR 27.23 and 30.27 min (Chiralcel AD; l 280 nm; 1% i-PrOH–hexanes, 0.8 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.29–7.28 (m, 1 H), 6.25–6.24 (m,
1 H), 6.10–6.09 (m, 1 H), 4.18 (ddd, J = 7.1, 7.1, 7.1 Hz, 2 H), 4.13–
4.07 (m, 3 H), 3.77 (d, J = 8.1 Hz, 1 H), 3.00 (dd, J = 17.1, 9.0 Hz,
1 H), 2.92 (dd, J = 17.1, 4.8 Hz, 1 H), 2.11 (s, 3 H), 1.24 (dd, J = 7.2,
7.2 Hz, 3 H), 1.17 (dd, J = 7.0, 7.0 Hz, 3 H).
13
C NMR (125 MHz, CDCl3): d = 205.8, 167.8, 167.7, 153.4, 141.6,
110.2, 106.9, 61.6, 61.5, 55.0, 44.5, 33.9, 30.1, 14.0, 13.9.
13
C NMR (125 MHz, CDCl3): d = 206.2, 168.4, 167.8, 137.2, 134.0,
131.4, 128.8, 127.7, 126.3, 125.7, 125.1, 123.3, 61.6, 61.3, 56.9,
47.1, 30.2, 14.0, 13.5.
HRMS: m/z calcd for C15H20O6Na [M + Na]+: 319.1152; found:
319.1152.
HRMS: m/z calcd for C21H24O5Na [M + Na]+: 379.1516; found:
379.1509.
2-[1-(2-Oxopropyl)hexyl]malonic Acid Dibenzyl Ester (3.13)
[a]D25 +1.15 (c 1.3, CHCl3, 20% ee); tR (minor) 28.87 min, tR
(major) 31.66 min (Chiralcel AD; l 254 nm; 1% i-PrOH–hexanes,
0.8 mL/min).
2-(1-Naphthalen-2-yl-3-oxobutyl)malonic Acid Diethyl Ester
(3.5)
[a]D25 +8.44 (c 4.9, CHCl3, 55% ee); tR (minor) 14.60 min, tR
(major) 20.50 min (Chiralcel AD; l 254 nm; 8% i-PrOH–hexanes,
1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.34–7.29 (m, 10 H), 5.17–5.09
(m, 4 H), 3.66 (d, J = 5.5 Hz, 1 H), 2.71–2.63 (m, 2 H), 2.46 (dd,
J = 17.6, 6.6 Hz, 1 H), 2.03 (s, 3 H), 1.34–1.14 (m, 8 H), 0.83 (dd,
J = 7.2, 7.2 Hz, 3 H).
Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
1518
PAPER
J. M. Betancort et al.
13
C NMR (125 MHz, CDCl3): d = 207.4, 168.7, 168.4, 135.3, 135.2,
128.5, 128.4, 128.3, 128.2, 67.0, 66.9, 53.9, 45.1, 33.7, 32.1, 31.6,
30.2, 26.6, 22.4, 14.0.
13
HRMS: m/z calcd for C26H32O5Na [M + Na]+: 447.2142; found:
447.2158.
HRMS: m/z calcd for C19H24O5Na [M + Na]+: 355.1516; found:
355.1521.
2-(1-Cyclohexyl-3-oxobutyl)malonic Acid Dibenzyl Ester (3.15)
[a]D25 +2.30 (c 1.7, CHCl3, 14% ee); tR (minor) 12.04 min, tR
(major) 13.82 min (Chiralcel AD; l 254 nm; 3% i-PrOH–hexanes,
1.0 mL/min).
2-[(2-Oxocyclohexyl)phenylmethyl]malonic Acid Diethyl Ester
(4.3)
[a]D25 –35.75 (c 0.9, CHCl3, 71% ee) {Lit. [a]D25 –43.5 (c 2.0,
CHCl3, 95% ee for the 1¢S, 1¢¢S diastereomer)};40 tR (minor) 22.31
min, tR (major) 28.10 min (Chiralcel AD; l 254 nm; 2% i-PrOH–
hexanes, 1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.33–7.28 (m, 10 H), 5.12 (d,
J = 12.2 Hz, 1 H), 5.11 (s, 2 H), 5.09 (d, J = 12.2 Hz, 1 H), 3.68 (d,
J = 6.3 Hz, 1 H), 2.73–2.68 (m, 1 H), 2.65 (dd, J = 18.2, 5.5 Hz, 1
H), 2.53 (dd, J = 18.2, 5.5 Hz, 1 H), 2.01 (s, 3 H), 1.67–1.56 (m, 3
H), 1.50–1.47 (m, 1 H), 1.27–1.21 (m, 2 H), 1.08–1.02 (m, 3 H),
0.94–0.82 (m, 2 H).
13
C NMR (125 MHz, CDCl3): d = 207.2, 169.1, 168.6, 135.3, 135.2,
128.5, 128.4, 128.3, 128.2, 67.1, 67.0, 53.0, 43.4, 40.3, 38.4, 30.8,
29.8, 29.5, 26.3, 26.2.
HRMS: m/z calcd for C27H32O5Na [M + Na]+: 459.2142; found:
459.2126.
2-(1-Isopropyl-3-oxobutyl)malonic Acid Dibenzyl Ester (3.17)
[a]D25 +2.28 (c 1.1, CHCl3, 17% ee); tR (minor) 13.11 min, tR
(major) 14.62 min (Chiralcel AD; l 254 nm; 2% i-PrOH–hexanes,
0.8 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.34–7.27 (m, 10 H), 5.11 (s, 2 H),
5.10 (s, 2 H), 3.63 (d, J = 6.3 Hz, 1 H), 2.75–2.72 (m, 1 H), 2.66 (dd,
J = 18.0, 5.5 Hz, 1 H), 2.48 (dd, J = 18.0, 5.5 Hz, 1 H), 2.07 (s, 3 H),
1.72–1.65 (m, 1 H), 0.87 (d, J = 6.6 Hz, 3 H), 0.79 (d, J = 6.6 Hz, 3
H).
13
C NMR (125 MHz, CDCl3): d = 207.2, 168.9, 168.6, 135.2, 128.5,
128.3, 128.2, 67.2, 67.0, 53.5, 42.8, 39.0, 30.2, 29.8, 20.5, 18.9.
+
HRMS: m/z calcd for C24H28O5Na [M + Na] : 419.1829; found:
419.1821.
2-[(2-Oxocyclopentyl)phenylmethyl]malonic Acid Diethyl Ester
(4.1-anti)
[a]D25 +77.06 (c 0.5, CHCl3, 55% ee); tR (major) 6.51 min, tR
(minor) 12.11 min (Chiralcel AD; l 254 nm; 2% i-PrOH–hexanes,
1.0 mL/min).
C NMR (125 MHz, CDCl3): d = 218.5, 168.4, 167.6, 138.3, 129.3,
128.1, 127.1, 61.7, 61.2, 55.2, 52.0, 44.2, 38.6, 26.1, 20.4, 14.0,
13.6.
Addition of Ketones and Aldehydes to Nitro Olefins; General
Procedure
To a solution of the nitro olefin (0.25 mmol) in THF (2.2 mL) was
added the aldehyde (2.5 mmol) and (S)-2-(morpholinomethyl)pyrrolidine (8.5 mg, 20% mol). The reaction was stirred at r.t. for the
appropriate time. The solution was then diluted with CH2Cl2 (5 mL)
and treated with aq HCl (0.1 M; 4 mL) with vigorous stirring. The
layers were separated and the aq phase was extracted thoroughly
with CH2Cl2 (3 × 2 mL). The combined organic phases were dried
(MgSO4), concentrated and purified by flash column chromatography (silica gel; mixture of CH2Cl2, hexanes and toluene).
5-Nitro-4-phenylpentan-2-one (7.1)
[a]D25 –0.51 (c 0.8, CHCl3, 56% ee) {lit. [a]D25 –1.33 (c 2.0, C6H6,
10% ee)};41 tR (minor) 15.76 min, tR (major) 18.88 min (Chiralcel
AS; l 254 nm; 15% i-PrOH–hexanes, 1.1 mL/min).
5-Nitro-4-(2-trifluoromethylphenyl)pentan-2-one (7.2)
[a]D25 –11.30 (c 1, CHCl3, 73% ee); tR (minor) 31.23 min, tR
(major) 34.51 min (Chiralcel OD-H; l 254 nm; 1% i-PrOH–hexanes, 1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.71 (d, J = 7.1 Hz, 1 H), 7.54 (dd,
J = 7.1, 7.1 Hz, 1 H), 7.40 (dd, J = 7.1, 7.1 Hz, 1 H), 7.36 (d, J = 7.1
Hz, 1 H), 4.75–4.73 (m, 2 H), 4.42 (m, 1 H), 3.01 (dd, J = 18.0, 8.6
Hz, 1 H), 2.91 (dd, J = 18.0, 5.2 Hz, 1 H), 2.16 (s, 3 H).
13
C NMR (125 MHz, CDCl3): d = 205.0, 137.6, 132.4, 128.7, 128.4,
127.9, 127.5, 126.8, 125.2, 123.0, 78.2, 46.1, 34.3, 30.0.
Anal. Calcd for C12H12F3NO3: C, 52.37; H, 4.39; N, 5.09. Found: C,
52.28; H, 4.20; N, 5.04.
1
H NMR (500 MHz, CDCl3): d = 7.26–7.17 (m, 5 H), 4.76 (d,
J = 12.1 Hz, 1 H), 4.24–4.19 (m, 2 H), 3.87–3.81 (m, 2 H), 3.66 (dd,
J = 12.1, 4.0 Hz, 1 H), 2.66–2.61 (m, 1 H), 2.21–2.15 (m, 1 H),
2.13–2.08 (m, 1 H), 1.87–1.79 (m, 1 H), 1.71–1.60 (m, 3 H), 1.29
(dd, J = 7.2, 7.2 Hz, 3 H), 0.88 (dd, J = 7.2, 7.2 Hz, 3 H).
3-Methyl-5-nitro-4-phenylpentan-2-one (7.3)
[a]D25 –9.64 (c 0.3, CHCl3, 68% ee); tR (minor) 19.80 min, tR
(major) 25.40 min (Chiralcel AD; l = 254 nm; 1% i-PrOH–hexanes, 1 mL/min). 1H NMR and 13C NMR were consistent with those
reported in the literature.42
13
C NMR (125 MHz, CDCl3): d = 220.4, 168.8, 168.2, 138.9, 129.3,
128.3, 127.2, 61.6, 61.1, 53.8, 50.5, 45.7, 39.9, 27.4, 20.6, 14.0,
13.6.
HRMS: m/z calcd for C19H24O5Na [M + Na]+: 355.1516; found:
355.1514.
2-[(2-Oxocyclopentyl)phenylmethyl]malonic Acid Diethyl Ester
(4.1-syn)
[a]D25 –42.60 (c 1.9, CHCl3, 54% ee); tR (minor) 10.02 min, tR
(major) 11.80 min (Chiralcel AD; l 254 nm; 2% i-PrOH–hexanes,
1.0 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.26–7.17 (m, 5 H), 4.24–4.18 (m,
2 H), 4.06 (d, J = 11.4 Hz, 1 H), 4.00 (dd, J = 11.2, 5.3 Hz, 1 H),
3.91–3.84 (m, 2 H), 2.52–2.47 (m, 1 H), 2.20–2.15 (m, 1 H), 2.07–
2.01 (m, 1 H), 1.89–1.77 (m, 2 H), 1.71–1.59 (m, 2 H), 1.27 (dd,
J = 7.2, 7.2 Hz, 3 H), 0.92 (dd, J = 7.2, 7.2 Hz, 3 H).
Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
4-Methyl-6-nitro-5-phenyl-hexan-3-one (7.4)
tR 8.35 and 9.98 min (Chiralcel AD; l 254 nm; 1% i-PrOH–hexanes, 0.8 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.35–7.31 (m, 2 H), 7.29–7.26 (m,
1 H), 7.17–7.15 (m, 2 H), 4.67 (dd, J = 12.3, 9.7 Hz, 1 H), 4.60 (dd,
J = 12.3, 4.8 Hz, 1 H), 3.70 (ddd, J = 9.7, 9.7, 4.8 Hz, 1 H), 2.99
(dddd, J = 9.7, 7.4, 7.4, 7.4 Hz, 1 H), 2.61 (dddd, J = 18.1, 7.4, 7.4,
7.4 Hz, 1 H), 2.41 (dddd, J = 18.1, 7.4, 7.4, 7.4 Hz, 1 H), 1.07 (dd,
J = 7.4, 7.4 Hz, 3 H), 0.97 (d, J = 7.4 Hz, 3 H).
13
C NMR (125 MHz, CDCl3): d = 213.5, 137.6, 129.0, 127.9, 78.3,
48.3, 46.0, 35.4, 16.3, 7.6.
HRMS: m/z calcd for C13H17NO3Na [M + Na]+: 258.1101; found:
258.1106.
PAPER
Catalytic Direct Asymmetric Michael Reactions
2-(2-Nitro-1-phenylethyl)cyclopentanone (7.7)
Anti isomer: tR (major) 10.52 min, tR (minor) 12.03 min; syn isomer:
tR (minor) 13.42 min, tR (major) 18.80 min (Chiralcel AD; l = 254
nm; 1% i-PrOH–hexanes, 1 mL/min).
1519
2.90 (dd, J = 17.4, 7.7 Hz, 1 H), 2.12 (s, 3 H), 1.48 (d, J = 6.6 Hz, 3
H).
13
C NMR (125 MHz, CDCl3): d = 205.6, 137.8, 128.7, 128.1, 127.9,
85.8, 44.7, 44.5, 30.6, 16.7.
13
C NMR (125 MHz, CDCl3): (major) d = 218.4, 137.7, 128.8,
127.9, 127.8, 78.2, 50.4, 44.1, 38.6, 28.2, 20.2; (minor) d = 219.0,
137.6, 128.9, 128.4, 127.9, 77.1, 51.4, 43.9, 39.2, 26.9, 20.5.
+
HRMS: m/z calcd for C13H15NO3Na [M + Na] : 256.0944; found:
256.0945.
2-(2-Nitro-1-phenylethyl)cyclohexanone (7.8)
[a]D25 –24.03 (c 1.6, CHCl3, 90% ee) {Lit. [a]D25 –27.2 (c 1.0,
CHCl3, 96% ee for the 2S, 1¢R diastereomer)};43 tR (minor) 9.06
min, tR (major) 11.78 min (Chiralcel AS; l 254 nm; 5% i-PrOH–
hexanes, 1.0 mL/min).
1
H NMR and 13C NMR were consistent with those reported in the
literature.43
2-(2-Nitro-1-phenylethyl)cycloheptanone (7.9)
tr = 13.86 and 18.87 min (Chiralcel AD; l 254 nm; 2% i-PrOH–
hexanes, 1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.35–7.32 (m, 2 H), 7.29–7.27 (m,
1 H), 7.18–7.17 (m, 2 H), 4.67 (dd, J = 12.5, 8.5 Hz, 1 H), 4.63 (dd,
J = 12.5, 5.2 Hz, 1 H), 3.68 (ddd, J = 10.3, 8.5, 5.2 Hz, 1 H), 3.01
(ddd, J = 10.3, 10.3, 3.3 Hz, 1 H), 2.59–2.49 (m, 2 H), 1.94–1.86
(m, 2 H), 1.79–1.74 (m, 1 H), 1.70–1.63 (m, 1 H), 1.61–1.57 (m, 1
H), 1.57 (s, 3 H), 1.27–1.14 (m, 3 H).
13
C NMR (125 MHz, CDCl3): d = 214.7, 137.7, 129.0, 128.1, 127.9,
78.7, 53.7, 45.5, 43.4, 29.9, 28.6, 28.5, 23.9.
3-Hydroxy-5-nitro-4-phenyl-pentan-2-one (7.10)
1
H NMR (500 MHz, CDCl3): (major) d = 7.40–7.21 (m, 5 H), 5.03
(dd, J = 13.6, 8.1 Hz, 1 H), 4.73 (dd, J = 13.6, 7.0 Hz, 1 H), 4.54–
4.52 (m, 1 H), 4.05–4.01 (m, 1 H), 3.72 (d, J = 4.8 Hz, 1 H), 2.19 (s,
3 H); (minor) d = 7.40–7.21 (m, 5 H), 4.82 (dd, J = 13.6, 6.4 Hz, 1
H), 4.65 (dd, J = 13.6, 8.5 Hz, 1 H), 4.40 (dd, J = 5.3, 5.3 Hz, 1 H),
3.85–3.81 (m, 1 H), 3.71 (d, J = 5.2 Hz, 1 H), 2.07 (s, 3 H).
13
C NMR (125 MHz, CDCl3): (major) d = 206.1, 133.7, 129.0,
128.7, 128.4, 76.9, 45.7, 25.5; (minor) d = 207.8, 137.1, 129.3,
128.5, 128.0, 78.7, 76.0, 46.9, 26.5.
HRMS: m/z calcd for C11H13NO4Na [M + Na]+: 246.0737; found:
246.0738.
5-Nitro-4-phenyl-hexan-2-one (7.11-major)
[a]D25 –10.34 (c 0.9, CHCl3, 70% ee); tR (major) 32.24 min, tR
(minor) 37.84 min (Chiralcel AS; l 254 nm; 1% i-PrOH–hexanes,
1.1 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.35–7.31 (m, 2 H), 7.28–7.25 (m,
1 H), 7.20–7.19 (m, 2 H), 4.76 (m, 1 H), 3.71 (ddd, J = 9.6, 9.6, 4.3
Hz, 1 H), 2.97 (dd, J = 17.2, 9.6 Hz, 1 H), 2.74 (dd, J = 17.2, 4.3 Hz,
1 H), 2.01 (s, 3 H), 1.32 (d, J = 7.0 Hz, 3 H).
13
C NMR (125 MHz, CDCl3): d = 204.9, 138.2, 129.0, 128.2, 127.8,
87.1, 46.2, 45.3, 30.4, 17.8.
HRMS: m/z calcd for C12H15NO3Na [M + Na]+: 244.0944; found:
244.0949.
5-Nitro-4-phenylhexan-2-one (7.11-minor)
[a]D25 –1.54 (c 0.7, CHCl3, 69% ee); tR (minor) 24.83 min, tR
(major) 27.58 min (Chiralcel AS; l = 254 nm; 1% i-PrOH–hexanes, 1.0 mL/min).
1
H NMR (500 MHz, CDCl3): d = 7.32–7.25 (m, 3 H), 7.15–7.13 (m,
2 H), 4.88 (m, 1 H), 3.73 (m, 1 H), 3.05 (dd, J = 17.4, 6.6 Hz, 1 H),
Acknowledgment
This work was supported by the NIH (CA27489) and The Skaggs
Institute for Chemical Biology.
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© Thieme Stuttgart · New York
1520
(11)
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(17)
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Synthesis 2004, No. 9, 1509–1521
© Thieme Stuttgart · New York
PAPER
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(35) When (S)-1-(2-pyrrolidinylmethyl)pyrrolidine and 2,4pentanedione are mixed in equimolar amounts in DMSO,
enamine formation is detected through UV spectroscopy.
Furthermore, while pyrrolidine itself promotes the Michael
reaction, the N-methyl derivative, which lacks the secondary
amine is ineffective as catalyst. Alexakis et al. have also
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PAPER
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Synthesis 2004, No. 9, 1509–1521
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