β-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis

Article abstract of DOI:10.1038/nchem.1710

The activation of the α-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert β-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the β-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester β-carbons as nucleophiles (β-carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic β-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester α-carbons, we expect this catalytic activation mode for saturated ester β-carbons to open a valuable new arena for new and useful reactions and synthetic strategies.

Full text of DOI:10.1038/nchem.1710

ARTICLES
PUBLISHED ONLINE: 21 JULY 2013 | DOI: 10.1038/NCHEM.1710
b-Carbon activation of saturated carboxylic esters
through N-heterocyclic carbene organocatalysis
Zhenqian Fu, Jianfeng Xu, Tingshun Zhu, Wendy Wen Yi Leong and Yonggui Robin Chi
*
The activation of the a-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as
nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical
synthesis could be greatly expanded if the typically inert b-carbons of saturated esters could be used as nucleophiles.
However, despite the rather significant fundamental and practical values, direct use of the b-carbons of saturated carbonyl
compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester b-carbons as
nucleophiles (b-carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic
b-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich
chemistry of ester a-carbons, we expect this catalytic activation mode for saturated ester b-carbons to open a valuable
new arena for new and useful reactions and synthetic strategies.
arbonyl compounds such as esters, ketones and aldehydes are addition of NHC catalyst to ester substrate I yields an NHC-
essential building blocks for the synthesis of fine chemicals, bounded ester intermediate II. The reactive ester intermediate (II)
C
pharmaceuticals and materials, and, not surprisingly, manipu- bearing acidic a-CHs can undergo a deprotonation to form an
lation of carbonyl groups is routinely involved in their preparation. enolate intermediate (III) containing a nucleophilic a-carbon.
Functionalization of the a-carbons of carbonyl compounds The feasibility of similar enolate chemistry (I to III) in relation to
(Fig. 1a), such as esters, is a basic activation mode that prepares the the reactivity of ester a-carbons has recently been demonstrated
a-carbons as nucleophiles for a wide range of applications. Among by our laboratory23. In the present study, we hypothesized that,
the many high-impact transformations based on a-carbons of carbo- because of the electron-withdrawing ability of the triazolium
nyl compounds are the aldol reactions1–5 and Mannich reactions6–8
.
moiety and the conjugated nature of the triazolium-bounded
To obtain b-carbon functionalization of carbonyl compounds, the
corresponding a,b-unsaturated substrates are typically used. In this
case, the b-carbons in a,b-unsaturated compounds such as
a,b-unsaturated aldehydes can behave as electrophiles via lowest
unoccupied molecular orbital (LUMO) activation (for example,
iminium organocatalysis)9 or as nucleophiles via polarity inversion
Table1 | Reaction of ester (b-carbon) with enone.
Ph
O
OAr
Ph
O
O
O
Ph
20 mol% NHC
200 mol% DBU
(R)
α
(R)
Ph
+
+
β
β
CH3CN (0.4 M)
4Å MS, RT, 24 h
3a
Ph
(0.4 mmol)
(Ar = 4-NO2-C6H4)
4a
(for example, N-heterocyclic carbene (NHC) organocatalysis)10–13
.
Ph
(0.2 mmol)
Ph
Ph Ph
α-Activation
product
1a
2a
β-Activation
product
Alternatively, oxidative approaches have also been developed to
turn saturated carbonyl compounds (such as esters and aldehydes)
into the corresponding a,b-unsaturated carbonyl derivatives as
intermediates14–16. However, strategies for directly activating the
b-carbons of simple saturated carbonyl compounds (such as
esters) as nucleophiles remain elusive17,18. Perhaps the most relevant
method is directing group-assisted metal insertion and C–H bond
activation involving ester b-carbons, using palladium-based tran-
sition-metal catalysts19–21. Recently, during the resubmission of our
manuscript, MacMillan and co-workers reported photoredox one-
electron oxidation of enamine to the b-carbon radical for direct
functionalization of saturated aldehydes and ketones (Fig. 1a)22.
Here, we describe organocatalytic activation of saturated car-
boxylic esters for the direct generation of nucleophilic ester
b-carbons (Fig. 1a). The reactivities of the ester b-carbon nucleo-
philes were demonstrated in enantioselective reactions with electro-
philes such as enones, trifluoroketones and hydrazones to afford
cyclopentenes, g-lactones and g-lactams, respectively.
(undesired)
BF4–
BF4–
Mes
N
BF4–
Ph
N
N
Cl–
+
+ Ar
N
N
+
+
N
Ph
N
N
N
N
Mes
N
R = Ph, F
R
i-Pr, G
R
R = i-Pr, D
t-Bu, E
Ar = Ph, B
Mes, C
A
t-Bu, H
Entry
NHC
3a:4a
3a Yield
3a d.r.
3a e.r.
1
2
3
4
5
6
7
8*
9*
A
B
C
D
E
n.d.
.20:1
5:1
.20:1
.20:1
8:1
.20:1
.20:1
>20:1
,5
80
75
69
27
54
70
74
66
n.d.
14:1
7:1
11:1
8:1
16:1
12:1
14:1
7:1
–
–
–
87:13
95:5
87:13
91:9
91:9
96:4
F
G
G
H
The ratio of 3a to 4a, and the d.r. of 3a, were estimated by 1H NMR analysis. The e.r. of 3a (major
diastereomer) was determined by chiral-phase high-performance liquid chromatography analysis,
and the absolute configuration of 3a was determined from the X-ray structure of 3y (Table 2).
The structure of a-activation product 4a was confirmed by 1H NMR analysis. Yields of 3a were
isolated yields after SiO2 chromatography purification. *150 mol% DBU was used. MS, molecular
sieve; Mes, 1,3,5-trimethylbenzene; i-Pr, isopropyl; t-Bu, tert-butyl; n.d., not determined.
Results and discussion
Our postulated catalytic cycle for the b-activation of an ester to react
with enone as a model electrophile is illustrated in Fig. 1b. The
Nanyang Technological University, Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Singapore 637371, Singapore.
e-mail: robinchi@ntu.edu.sg
*
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
1

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1710
ARTICLES
a
Activation of saturated carbonyl compound carbonyl carbon, α- and β-sp3 carbons
Table2 | Examples of ester and enone substrates.
O
Ketone/
aldehyde
N
O
Amine
cat.
O
BF4–
+
O
O
NHC
cat.
R2
R2
O
Ester
O
OAr
N
R'
NHC+
R'
20 mol% H
150 mol% DBU
OR'
R'
R'
N
Ph
1e
R
R1
N
+
β
R
β
R
R
R
R
C=O & α-CH
("Known"
chemistry)
R
CH3CN (0.4 M)
4A MS, RT, 24 h
β-sp3 CH
(elusive)
R
1
R1
3
2
H
β-Carbon radical
Nucleophilic β-carbon
(0.4 mmol)
(0.2 mmol)
(ref. 22)
β-Activation
product
(this work)
(Ar = 4-NO2-C6H4)
Examples of esters (1), with 2a as the model electrophile:
b Our postulated catalytic ester β-activation (& reaction with enone electrophile)
Ph
Ph
Ph
R = CH3
DBU-H /
ArO
DBU
(base)
X = F, 3d; 60% yield
3b; 60% yield
8:1 d.r., 97:3 e.r.
Ph
Ph
N
Ph
8:1 d.r., 96:4 e.r.
N
N
O
R
N
X = Cl, 3e; 67% yield
N
Ph
O
R = OCH3
3c; 53% yield
9:1 d.r., 95:5 e.r.
7:1 d.r., 95:5 e.r.
N
α-CH
Deprotonation
N
3a; 66% yield
7:1 d.r., 95:5 e.r.
X = Br, 3f; 68% yield
H
N
O
R
III
R
X
7:1 d.r., 95:5 e.r.
ArOH
N
H
OAr
O
R
R
Ph
Ph
Transfer
Ph
Ph
Ph
II
β-CH
Deprotonation
Ester
Ph
β
I
Ph
Ph
N
Ph
CH3
3j*; 40% yield
17:1 d.r., 94:6 e.r.
N
HO
N
Ester
β-carbon activation
O
Ph
N
N
CH3
H
H
N
3i*; 27% yield
20:1 d.r., 91:9 e.r.
3g*; 39% yield
6:1 d.r., 95:5 e.r.
3h*; 51% yield
5:1 d.r., 91:9 e.r.
3k; 8% yield
e.r. not determined
R
IV
(NHC)
Ph
O
Ph
R
Examples of enones (2), with 1a as the model ester:
O
Ph
Michael
addition
Ph
VIII
Ph
O
Ph
R = CH3, 3l; 50% yield
13:1 d.r., 95:5 e.r.
X = p-NO2, 3o; 53% yield
Lactone
X
(electrophile)
R
8:1 d.r., 95:5 e.r.
formation
Ph
Ph
X = m-NO2, 3p; 81% yield
R = Cl, 3m; 75% yield
6:1 d.r., 95:5 e.r.
N
Ph
Ph
Ph
CO2
N
O
HO
R
N
N
7:1 d.r., 96:4 e.r.
VII
(refs 25-27)
N
O
R = Br, 3n; 76% yield
7:1 d.r., 96:4 e.r.
X = o-NO2, 3q; 61% yield
N
Ph
Ph
8:1 d.r., 96:4 e.r.
Ph
O
Y
N
R
V
Ph
O
N
Y = CH3, 3t; 47% yield
O
R
Ph
N
7:1 d.r., 95:5 e.r.
Aldol
addition
O
β
H
Y = Cl, 3u; 70% yield
R
Transfer
IX
Ph
Ph
7:1 d.r., 95:5 e.r.
S
VI
Ph
Ph
Y = Br, 3v; 76% yield
Ph
7:1 d.r., 96:4 e.r.
Ph
Figure 1 | Organocatalytic b-sp3-CH activation of saturated ester.
a, Carbonyl compounds can be selectively activated to react at the carbonyl
carbon a- or b-positions. b, Addition of NHC to ester I gives NHC-bounded
ester intermediate II, which undergoes successive deprotonations under
basic conditions to generate intermediate IV. Intermediate IV reacts with
enone to give cyclopentene IX via Michael addition, aldol addition, lactone
formation and decarboxylation. NHC, N-heterocyclic carbene; DBU,
1,8-diazabicyclo[5.4.0]undec-7-ene.
3r; 68% yield
5:1 d.r., 94:6 e.r.
3s; 58% yield
12:1 d.r., 94:6 e.r.
Z
(R)
Z = Cl, 3w; 69% yield
Cl
7:1 d.r., 95:5 e.r.
Z
(R)
Z = Br, 3x; 60% yield
Ph
3y; 50% yield
10:1 d.r., 97:3 e.r.
(for X-ray structure)
6:1 d.r., 95:5 e.r.
H3CO
Conditions as in Table 1, entry 9. Yields (after SiO2 chromatography purification) were based on
enone 2. *Reactions run with 3.0 equiv. ester and 200 mol% DBU for 48 h. The d.r. was
estimated via 1H NMR analysis and e.r. was determined via chiral-phase HPLC analysis
(see Supplementary Information). Supplementary crystallographic data for 3y can be found in
CCDC 900975.
enolate intermediate III, the formal ester b-CH protons (of III)
could become acidic (Fig. 1b). Deprotonation of the b-CHs of
enolate III could afford intermediate IV with b-carbon as a nucleo-
philic centre. The overall hypothesized pathway (from ester sub-
strate I to intermediate IV with a nucleophilic b-carbon) may be
considered as an analogous process, but inverse, to that found in 1a underwent hydrolysis with an elongated reaction time. The struc-
the NHC-mediated activation of a,b-unsaturated aldehydes12,13,24,25
.
ture of 3a was later confirmed after accumulating enough material
The b-carbon of intermediate IV might undergo nucleophilic from several batches of larger-scale reactions. This proof-of-prin-
additions to electrophiles. Shown in Fig. 1b is the addition of the ciple result clearly suggests that activation of the b-carbon of a satu-
ester b-carbon to chalcone to eventually form a cyclopentene rated ester as nucleophile using NHC organocatalysts is feasible. We
product (IV to VII), via a cascade process similar to that in then found that the use of achiral triazolium B as an NHC pre-ca-
NHC-catalysed reactions of a,b-unsaturated aldehydes26–28, invol- talyst could lead to desired product 3a in good yield and diastereo-
ving
a
Michael reaction, an aldol reaction, lactonization meric ratio (d.r.), as well as the formation of trace a-activation
adduct d-lactone 4a (entry 2). Switching to a sterically more bulky
and decarboxylation.
Experimentally, we set out to achieve a b-carbon activation (I to catalyst C (N-1,3,5-trimethylbenzene (N-Mes), instead of N-Ph in
IV, Fig. 1b) using 1a as a model ester substrate and enone 2a as a B) resulted in more side product 4a (entry 3). Because the 4-nitro-
model electrophile. The key results of extensive studies, with phenol released from the ester substrate in this reaction is weakly
careful analysis of the reaction mixtures, are summarized in acidic, the use of a stoichiometric amount of base (for example,
Table 1. With imidazolium A as the NHC pre-catalyst, 1,8-diazabi- 200 mol% DBU) was necessary to achieve the two key deprotona-
cyclo[5.4.0]undec-7-ene (DBU) as the base and CH3CN as the tion steps (Fig. 1b, II to III and III to IV).
solvent, we observed a tiny amount of b-activation product 3a fol-
lowing H NMR spectroscopy and mass spectral analysis (Table 1, substituent (D–H) derived from a-amino acids for enantioselective
entry 1). Under this condition (entry 1), most of ester substrate reactions (entries 4–9). The use of L-valine-derived catalyst D led to
We next examined chiral triazolium NHC catalysts with an N-Ph
1
2
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1710
ARTICLES
Table 3 | Reactions of ester b-carbon with trifluoroketone or hydrazone as electrophiles.
Trifluoroketone as electrophile:
Hydrazone as electrophile:
O
O
OAr
O
O
ArOCHN
O
O
Ar
O
OAr
20 mol% H
150 mol% DBU
O
ArOCHN
H
20 mol% H
150 mol% DBU
F3C
Ar
N
N
+
+
Ar
CF3
β
F3C
EtO2C
+
β
CO2Et
R
Toluene (0.2 M)
4A MS, 0 oC, 48 h
R
Ar = Ph, 4a
(0.2 mmol)
EtOAc (0.2 M)
4A MS, RT, 48 h
R
R = Ph, 1a
(0.4 mmol)
R
R
6
5a
(R = Ar = Ph)
54% yield, 1.3:1 d.r., 91:9/94:6 e.r.
5a'
1a
(0.1 mmol)
7
(0.2 mmol)
PhOCHN
EtO2C
(tBuOH as solvent: 73% yield, 3:1 d.r., 72:28/75:25 e.r.)
O
N
X =
H, 7a, 74% yield, 6:1 d.r., 97:3 e.r.
F, 7b, 72% yield, 6:1 d.r., 97:3 e.r.
Cl, 7c, 70% yield, 5:1 d.r., 97:3 e.r.
Br, 7d, 74% yield, 5:1 d.r., 97:3 e.r.
CH3, 7e, 76% yield, 5:1 d.r., 97:3 e.r.
OCH3, 7f, 73% yield, 7:1 d.r., 97:3 e.r.
H3C
Cl
O
Br
S
O
O
O
O
O
O
O
F3C
F3C
F3C
F3C
Ph
Ph
Ph
Ph
X
PhOCHN
O
5b (+5b')
60% yield,
1.4:1 d.r.,
5d(+5d')
59% yield,
1.4:1 d.r.,
5c (+5c')
5e (+5e')
80% yield,
1.6:1 d.r.,
PhOCHN
EtO2C
N
O
61% yield,
1.6:1 d.r.,
94:6/94:6 e.r.
PhOCHN
O
N
EtO2C
N
93:7/95:5 e.r.
93:7/94:6 e.r.
90:10/91:9 e.r.
EtO2C
O
O
O
O
O
Ph
F3C
O
Ph
F3C
Ph
O
O
O
O
Ph
OCH3
7i, 72% yield
5:1 d.r., 96:4 e.r.
F3C
7h, 68% yield
4:1 d.r., 95:5 e.r.
7g, 55% yield
4:1 d.r., 97:3 e.r.
F3C
O
ArOCHN
O
CH3
N
Br
F
Ar = different aryl groups; 6 additional examples
comparable yield, d.r., and e.r.
EtO2C
5i(+5i')
30% yield,
1.9:1 d.r.,
5f(+5f')
29% yield,
1.5:1 d.r.,
5h(+5h')
62% yield,
1.6:1 d.r.,
5g(+5g')
52% yield,
4.5:1 d.r.,
(7j-o; see Supplementary information)
Ph
84:16/84:16 e.r.
92:8/95:5 e.r.
94:6/96:4 e.r.
95:5/92:8 e.r.
(7c and 7i can be converted to commercial drugs, see Fig. 2)
Yields (two diastereomers combined) are isolated yields after SiO2 column chromatography. The d.r. was estimated via 1H NMR analysis, and the e.r. was determined via chiral-phase HPLC analysis (see
Supplementary Information). Supplementary crystallographic data for 7j can be found in CCDC 910100. t-Bu, tert-butyl; EtOAc, ethyl acetate.
an effective reaction (69% yield) with encouraging d.r. (11:1) and tert-butanol as the solvent, the corresponding g-lactone product
enantiomeric ratio (e.r.) (87:13) (entry 4). Use of the more bulky 5a was obtained in 73% isolated yield with moderate d.r. (3:1)
catalyst E prepared from L-tert-leucine gave a better e.r. (95:5), but and e.r. Using toluene as the solvent led to better values of e.r.
a significantly reduced yield (entry 5). Phenylalanine-derived triazo- (91:9 and 94:6) for both diastereomers, albeit with a slight decrease
lium F performed similarly to catalyst D (entries 6 and 4, respect- in yield and d.r. Variations with both trifluoroketone and ester sub-
ively), affording 3a with 54% yield, 16:1 d.r. and 87:13 e.r. strates were well tolerated, affording the b-activation products in
Replacing the phenyl group from phenylalanine in F with an isopro- moderate to good yields under current conditions (Table 3, left).
pyl substituent (that is, to obtain L-leucine-derived catalyst G) gave a
better yield (70%) and e.r. (91:9) (entry 7). The use of 150 mol%
DBU was then found to perform better, leading to a slightly
higher yield of 3a and a smaller amount of ester hydrolysis
(compare entries 7 and 8). Finally, by using catalyst H, derived
from L-neopentylglycine with a bulky tert-butyl substituent, the b-
ester activation product 3a could be obtained in good yield, accep-
table d.r. and 96:4 e.r. (entry 9).
The generality of this ester b-activation strategy with respect to
different ester substrates was then examined by using catalyst H.
As outlined in Table 2, the efficiencies and selectivities of this
reaction were relatively insensitive to changes to the (hetero)aryl
substituents when various 3-(hetero)aryl-propanoic esters were
used (3a–h). When the b-aryl unit in the propanoic esters was
replaced by simple alkyl substituents, b-activation cyclopentene
adducts (3i, 3j) were obtained in lower yields (with good d.r.
and e.r.). The relatively low yields for 3i and 3j were a result of com-
peting ester hydrolysis and the formation of ester a-activation
d-lactone side products. Additional studies for b-alkyl ester sub-
strates are in progress. The scope of the chalcone substrates was
also investigated (Table 2). Variations of the (hetero)aryl substitu-
ents on either the carbonyl or alkene b-carbon side of the enones
were all tolerated, giving the corresponding cyclopentene products
in acceptable yields, good d.r. and excellent e.r. (3l–3y).
a
PhOCHN
EtO2C
O
O
N
HN
Ref. S10
(see Supplementary
Information)
EtO2C
SmI2, EtOH
N2, 1.5 h
CO2H
H2N
2 steps
Cl
7c
Cl
8c
72% Isolated yield
Cl
9c
(S)-Baclofen
(5:1 d.r., 97:3 e.r.)
(single major diastereomer)
96:4 e.r.
b
PhOCHN
O
Boc
O
O
N
N
HN
Ref. S11
(see Supplementary
Information)
i SmI2, EtOH
ii LiBH4,THF
EtO2C
HOH2C
See SI
2 steps
O
O
O
OCH3
OCH3
OCH3
9i
(S)-Rolipram
7i
(5:1 d.r., 96:4 e.r.)
8i
47% overall yield
(single major diastereomer)
96:4 e.r.
Figure 2 | Synthetic transformation to bioactive molecules. a, Preparation
The applicability of the b-ester activation strategy was further of drug (S)-Baclofen (9c) from lactam 7c. b, Lactam 7i could be converted
demonstrated by using trifluoroketone (for example, 4a)13 or to (S)-Rolipram (9i), which is a potent inhibitor for the treatment of central
hydrazone (for example, 6a)29 as the electrophile (Table 3). With nervous disorders.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
3
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1710
ARTICLES
Breslow intermediate. In contrast, our ester ‘homoenolate’ is
obtained through b-carbon deprotonation of an ‘enolate intermedi-
ate’ (Fig. 1b). The ester ‘homoenolate’ intermediate with a formal
nucleophilic b-carbon may be stabilized in a different form.
Additional mechanistic studies are in progress. On the application
side, our ester b-activation strategy can provide solutions (for
example, the trans-selective formation of 3a or 7a with better e.r.)
that are not readily available with enal reactions.
Table 4 | Comparison of enal and ester reactions.
Carbon #2
(enone carbon)
O
OAr
O
H
Ph
O
Ph
Conditions
β
β
(R)
(R)
or
+
Ph
Ph
Ph
Ph
2a
(0.2 mmol)
3a
Enal 10a
Ester 1a
(0.4 mmol)
Ph
Carbon #1
(0.4 mmol)
(ester/enal β-carbon)
In short, we have undertaken the challenging task of developing
an organocatalytic activation of the otherwise inert b-sp3 carbon of
saturated esters as nucleophiles. Given the broad utility of the ester
a-carbons as nucleophiles, this long-awaited realization of nucleo-
philic b-carbons should significantly expand the use of esters for
new reaction development. Furthermore, the direct use of ester
b-carbons may offer previously unavailable insights into the
design of concise synthetic strategies for complex molecules36.
Further studies from both mechanistic and application perspectives
are being pursued in our laboratory.
Reaction 3a
Carbon #1 Carbon #2
Ester (1a) 66% yield, 7:1 d.r. 96:4 e.r.
(trans-3a) 81:19 e.r. (cis-3a)
Enal (10a) 51% yield, 1.8:1 d.r. 57:43 e.r.
(trans-3a) 88:12 e.r. (cis-3a)
87:13 (R/S) 94:6 (R/S)
44:56 (R/S) 66:34 (R/S)
Cyclopentane 3a is obtained by reaction of either ester 1a or enal 10a, but different (or even
opposite) enantioselectivities are obtained. Similar trends hold for other NHC catalysts, substrates
and conditions (see Supplementary Information).
Our examination also showed that hydrazone (for example, 6a) as
the electrophile29 could react with the b-carbons of esters, affording
g-lactams (for example, 7a) with good yield and e.r. (Table 3, right).
For the two types of reactions illustrated in Table 3, formation of the
corresponding ester a-activation product (b-lactone and b-lactam,
respectively) was negligible. The major side reactions were ester sub-
strate hydrolysis and NHC catalyst deactivation23. The success with
trifluoroketone and hydrazone electrophiles provides strong evi-
dence that, with further studies, the ester b-activation strategy can
be made general for a diverse set of substrates.
The catalytic reaction products obtained here are bioactive mol-
ecules or important building blocks that can be readily converted
into useful molecules such as pharmaceuticals. For example, the
chiral cyclopentenes are precursors for optically enriched epoxides,
1,2-diols and amino alcohols30–32. g-Butyrolactone is key unit in
many natural products33. Here, we have demonstrated that the
hydrozone reaction g-lactam products could be effectively con-
verted to pharmaceutical Baclofen (9c) (used to treat spasticity34)
and potent phosphodiesterase inhibitor Rolipram (9i)35 (Fig. 2).
Received 24 April 2013; accepted 14 June 2013;
published online 21 July 2013
References
1. Wurtz, Ad. Ueber einen Aldehyd-Alkohol. J. Prakt. Chem. 5, 457–464 (1872).
2. Mukaiyama, T., Narasaka, K. & Banno, B. New aldol type reaction. Chem. Lett.
1011–1014 (1973).
3. Evans, D. A., Bartroli, J. & Shih, S. L. Enantioselective aldol condensations. 2.
Erythro-selective chiral aldol condensations via boron enolates. J. Am. Chem.
Soc. 103, 2127–2129 (1981).
4. List, B., Lerner, R. A. & Barbas III, C. F. Proline-catalyzed direct asymmetric
aldol reactions. J. Am. Chem. Soc. 122, 2395–2396 (2000).
5. Northrup, A. B. & MacMillan, D. W. C. The first direct and enantioselective
cross-aldol reactions of aldehydes. J. Am. Chem. Soc. 124, 6798–6799 (2002).
6. Mannich, C. & Kro¨sche, W. Ueber ein kondensationsprodukt aus formaldehyd,
ammoniak und antipyrin. Arch. Pharm. Pharm. Med. Chem. 250, 647–667 (1912).
7. List, B. The direct catalytic asymmetric three-component Mannich reaction.
J. Am. Chem. Soc. 122, 9336–9337 (2000).
´
8. Cordova, A., Watanabe, S., Tanaka, F., Notz, W. & Barbas, C. F. III A highly
enantioselective route to either enantiomer of both a- and b-amino acid
derivatives. J. Am. Chem. Soc. 124, 1866–1867 (2002).
9. Ahrendt, K. A., Borths, C. J. & MacMillan, D. W. C. New strategies for organic
synthesis: the first highly enantioselective organocatalytic Diels–Alder reaction.
J. Am. Chem. Soc. 122, 4243–4244 (2000).
Comparison between enal and ester reactions
Because a,b-unsaturated aldehydes (enals)26–28 can be activated by
NHC catalysts to also generate similar intermediates with nucleo-
philic b-carbons (IV, as shown in Fig. 1b), we compared the reac-
tion outcomes from the enal approach and our ester activation
strategy. It should be clarified that, for the three types of trans-selec-
tive products (for example, 3f and 7a) obtained here, our ester acti-
vation approach gave significantly better enantioselectivities than
the reported approaches using enal substrates. For example,
Bode’s enal reactions27 for the highly enantioselective formation
of cis-cyclopentenes gave trans-3f with a moderate 77:23 e.r.,
whereas our ester approach gave trans-3f with an excellent
95:5 e.r. Another important point is that the ester and enal acti-
vations require different optimal NHC catalysts. For example, cata-
lysts (for example, H) found effective in our ester reactions do not
work well for the corresponding enal substrates. Remarkably, we
found that with identical chiral NHC catalysts, the reactions with
enals and esters as substrates gave very different and even opposite
enantioselectivities (Table 4; Supplementary Tables S3–S5). For
example, for carbon #1 of product 3a, the ester reaction favoured
the R-configuration (87:13 R/S), whereas the enal reaction favoured
the S-configuration (44:56 R/S). We have ruled out the effect of
solvents or additives on the reaction enantioselectivities (see
Supplementary Information). These results suggest that the
‘similar’ homoenolate intermediates obtained using the enal and
our ester approaches showed different reactivities and selectivities.
More specifically, the enal homoenolate intermediate comes from
the addition of NHC to the aldehyde group of enal to form a
10. Breslow, R. On the mechanism of thiamine action. IV.1 Evidence from studies on
model systems. J. Am. Chem. Soc. 80, 3719–3726 (1958).
11. Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic
carbenes. Chem. Rev. 207, 5606–5655 (2007).
12. Sohn, S. S., Rosen, E. L. & Bode, J. W. N-heterocyclic carbene-catalyzed
generation of homoenolates: g-butyrolactones by direct annulations of enals and
aldehydes. J. Am. Chem. Soc. 126, 14370–14371 (2004).
13. Glorius, F. & Burstein, C. Conjugate umpolung of a,b-unsaturated aldehydes for
the synthesis of g-butyrolactones. Angew. Chem. Int. Ed. 43, 6205–6208 (2004).
14. Zhang, S. L. et al., Organocatalytic enantioselective b-functionalization of
aldehydes by oxidation of enamines and their application in cascade reactions.
Nature Commun. 2, 211–217 (2011).
15. Ueno, S., Shimizu, R. & Kuwano, R. Nickel-catalyzed formation of a carbon–
nitrogen bond at the b position of saturated ketone. Angew. Chem. Int. Ed. 48,
4543–4545 (2009).
16. Renaudat A. et al. Palladium-catalyzed b arylation of carboxylic esters. Angew.
Chem. Int. Ed. 49, 7261–7265 (2010).
17. Nickon, A., James, L. & Lambert, S. J. Homoenolate anions. J. Am. Chem. Soc.
84, 4604–4605 (1962).
18. Nakamura, E. & Kuwajima, I. Metal homoenolate chemistry. Isolation and reactions
of titanium homoenolates of esters. J. Am. Chem. Soc. 105, 651–652 (1983).
19. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of
sp3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127,
13154–13155 (2005).
20. Giri, R. et al. Palladium-catalyzed methylation and arylation of sp2 and sp3 C–H
bonds in simple carboxylic acids. J. Am. Chem. Soc. 129, 3510–3511 (2007).
21. Ano, Y., Tobisu, M. & Chatani, N. Palladium-catalyzed direct ethynylation of
C(sp3)–H bonds in aliphatic carboxylic acid derivatives. J. Am. Chem. Soc. 133,
12984 (2011).
22. Pirnot, M. T., Rankic, D. A., Martin, D. B. C. & MacMillan, D. W. C. Photoredox
activation for the direct b-arylation of ketones and aldehydes. Science 339,
1593–1596 (2013).
4
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1710
ARTICLES
23. Hao, L. et al. Enantioselective activation of stable carboxylic esters as enolate
equivalents via N-heterocyclic carbene catalysts. Org. Lett. 14,
2154–2157 (2012).
24. Chan, A. & Scheidt, K. A. Conversion of a,b-unsaturated aldehydes into
saturated esters: an umpolung reaction catalyzed by nucleophilic carbenes. Org.
Lett. 7, 905–908 (2005).
25. Vora, H. U. & Rovis, T. N-Heterocyclic carbene catalyzed asymmetric hydration:
direct synthesis of a-protio and a-deuterio a-chloro and a-fluoro carboxylic
acids. J. Am. Chem. Soc. 132, 2860–2861 (2010).
26. Nair, V., Vellalath, S., Poonoth, M. & Suresh, E. N-Heterocyclic carbene-
catalyzed reaction of chalcones and enals via homoenolate: an efficient synthesis
of 1,3,4-trisubstituted cyclopentenes. J. Am. Chem. Soc. 128, 8736–8737 (2006).
27. Chiang, P., Kaeobamrung, J. & Bode, J. W. Enantioselective, cyclopentene-
forming annulations via NHC-catalyzed benzoin-oxy-Cope reactions. J. Am.
Chem. Soc. 129, 3520–3521 (2007).
34. Jane, D. E. et al. Diastereoselective synthesis of all four isomers of 3-(4-
chlorophenyl)glutamic acid: identification of the isomers responsible for the
potentiation of L-homocysteic acid-evoked depolarizations in neonatal rat
motoneurons. J. Med. Chem. 39, 4738–4743 (1996).
35. Butler, C., Campbell, S. & Comm, A. T. O. Evidence of the effects of intrathecal
baclofen for spastic and dystonic cerebral palsy. Dev. Med. Child Neurol. 42,
634–645 (2000).
36. Gutekunst, W. R., Gianatassio, R. & Baran, P. S. Sequential Csp3–H arylation and
olefination: total synthesis of the proposed structure of pipercyclobutanamide A.
Angew. Chem. Int. Ed. 51, 7507–7510 (2012).
Acknowledgements
The authors acknowledge support from the Singapore National Research Foundation
(NRF), the Singapore Economic Development Board (EDB), GlaxoSmithKline (GSK) and
Nanyang Technological University (NTU). The authors thank R. Ganguly and Y. Li (NTU)
for assistance with X-ray structure analysis, and Z. Jin, L. Hao, X. Chen and J. Mo (NTU) for
help with catalyst and substrate preparation.
28. Cardinal-David, B., Raup, D. E. A. & Scheidt, K. A. Cooperative N-heterocyclic
carbene/Lewis acid catalysis for highly stereoselective annulation reactions with
homoenolates. J. Am. Chem. Soc. 132, 5345–5347 (2010).
Author contributions
29. Raup, D. E. A., Cardinal-David, B., Holte, D. & Scheidt, K. A. Cooperative
catalysis by carbenes and Lewis acids in a highly stereoselective route to g-
lactams. Nature Chem. 2, 766–771 (2010).
30. Pezet, F., Ait-Haddou, H., Daran, J. C., Sasaki, I. & Balavoine, G. G. A.,
Ruthenium bis(bipyridine) sulfoxide complexes: new catalysts for alkene
epoxidation. Chem. Commun. 510–511 (2002).
Z.F. conducted most of the experiments. J.X. and W.W.Y.L. conducted some experiments
on the hydrazone reactions. T.Z. contributed to the synthetic transformation of catalytic
reaction products. Y.R.C. conceptualized and directed the project, and drafted the
manuscript with assistance from all co-authors. All authors contributed to discussions.
Additional information
Supplementary information and chemical compounds are available in the online version of
the paper. Reprints and permissions information is available online at www.nature.com/
reprints. Correspondence and requests for materials should be addressed to Y.R.C.
31. Rosatella, A. A. & Afonso, C. A. M. Bronsted acid-catalyzed dihydroxylation of
olefins in aqueous medium. Adv. Synth. Catal. 353, 2920–2926 (2011).
32. Kozhushkov, S. I., Yufit, D. S. & de Meijere, A. Convenient and inexpensive
synthesis of (1R,2R)-trans-1-amino-6-nitroindan-2-ol. Adv. Synth. Catal. 347,
255–265 (2005).
33. Hoffmann, H. M. R. & Rabe, J. Synthesis and biological-activity of a-methylene- Competing financial interests
g-butyrolactones. Angew. Chem. Int. Ed. 24, 94–110 (1985).
The authors declare no competing financial interests.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
5
© 2013 Macmillan Publishers Limited. All rights reserved.