Enantioselective Michael addition of α-substituted cyanoacetates to vinyl ketones catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1002/chem.200600796

A highly enantioselective Michael addition of α-substituted cyanoacetates to vinyl ketones was accomplished in the presence of simple bifunctional thiourea/tertiary amine organocatalysts. A number of α-aryl or alkyl cyanoacetates have been successfully ap

Full text of DOI:10.1002/chem.200600796

FULL PAPER
DOI: 10.1002/chem.200600796
Enantioselective Michael Addition of a-Substituted Cyanoacetates to Vinyl
Ketones Catalyzed by Bifunctional Organocatalysts
[a]
Tian-YuLiu,
Rui Li,[b] Qian Chai,[a] Jun Long,[a] Bang-Jing Li,[b] Yong Wu,[a]
Li-Sheng Ding,[b] and Ying-Chun Chen*[a]
Abstract: A highly enantioselective Mi-
chael addition of a-substituted cyano-
acetates to vinyl ketones was accom-
plished in the presence of simple bi-
functional thiourea/tertiary amine or-
ganocatalysts. A number of a-aryl or
alkyl cyanoacetates have been success-
fully applied to give multifunctional
compounds with an all-carbon-substi-
tuted quaternary stereocenter in excel-
to variously structured b2,2-amino acid
esters. Moreover, an interesting reac-
tion model involving multiple hydro-
gen-bonding interactions amongst the
thiourea/tertiary amine catalyst and the
reactants has been proposed based on
the absolute configuration of the
adduct and computational studies.
lent enantioselectivities (82–97% ee)
and yields (61–99%). The optical pure
adducts could be smoothly converted
Keywords: amino acids · asymmet-
ric organocatalysis · cyanoacetate ·
Michael addition · thiourea
Introduction
There is a high demand for enantiopure b-amino acids in
both academia and industry owing to their unique pharma-
cological properties, their occurrence in natural products,
and as potential precursors for b-lactams.[1] Furthermore,
the corresponding b-peptides can form much more stable
secondary structures (turns, sheets, and helices) in solution
than their a-peptidic natural counterparts.[2] Therefore the
development of efficient protocols for the enantioselective
synthesis of b-amino acids has been the subject of ever-
growing interest over the past years. Different from their a-
amino acid correlates, b-amino acids have a more complicat-
ed structural designation because the amino group is shifted
away from the carboxyl group by one carbon in the skeleton
(Figure 1). Although a number of methods have been suc-
Figure 1. Designation of b-amino acids.
cessfully developed for the synthesis of b3-amino acids[3] or
b2-amino acids,[4] the stereoselective preparation of b3,3-
amino acids, b2,3,3-amino acids, or b2,2-amino acids still re-
mains a major challenge for synthetic chemists,[1c,d] especially
in catalytic strategies, as an all-carbon-substituted quaterna-
ry stereocenter has to be generated.[5] It could be envisioned
that b2,2-amino acids might be easily accessible from the cor-
responding chiral a,a-disubstituted cyanoacetates,[6] which
could be prepared through the direct asymmetric Michael
addition of a-substituted cyanoacetates to activated vinyl
compounds (Scheme 1).
[a] T.-Y. Liu, Q. Chai, J. Long, Prof. Dr. Y. Wu, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug-Targeting of Education Ministry and
Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu 610041 (China)
Fax : (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] R. Li, Dr. B.-J. Li, Prof. Dr. L.-S. Ding
Chengdu Institute of Biology, Chinese Academy of Sciences
Chengdu 610041 (China)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author and contains com-
putational studies, NMR, HRMS, and HPLC spectra for all products.
Scheme 1. Retrosynthesis of b2,2-amino acids. EWG=electron withdraw-
ing group.
Chem. Eur. J. 2007, 13, 319 – 327
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
319

The a-cyano ester stereocenter is readily epimerizable,
and therefore the use of a-substituted cyanoacetate deriva-
tives offers the possibility of generating a configurationally
stable quaternary stereocenter under kinetic control. The
formation of such nucleophilic species is easy by in situ de-
protonation of a-acidic hydrocarbons, and direct carbon–
carbon bond-forming reactions, such as Michael additions,
to construct a quaternary carbon center, may be conducted
in an operationally simple and atom economical way. How-
ever, in comparison with their b-dicarbonyl analogues,[7] the
application of a-substituted cyanoacetates in catalytic asym-
metric Michael additions is far from satisfying, probably
owing to their incapability of two-point binding with cata-
lysts. In 1992, Ito and co-workers reported the conjugate re-
action of a-methyl cyanoacetate and vinyl ketones catalyzed
by rhodium-TRAP (TRAP=2,2’’-bis[1-(diphenylphosphi-
no)ethyl]-1,1’’-biferrocene) complex in less than 90% ee,
while other substituted cyanoacetates have not been
tested.[8] Various palladium or platinum complexes have also
been tested in the asymmetric Michael addition of a-methyl
cyanoacetates and vinyl ketones, but low to moderate ee
was achieved.[9] Recently, Jacobsen presented the highly
enantioselective Michael addition of a-substituted cyanoace-
tates to a,b-unsaturated imides or ketones in the presence
of a Salen-Al complex.[10] On the other hand, the natural
cinchona alkaloids have been applied in the asymmetric cat-
alysis of ethyl a-phenyl cyanoacetate and methyl vinyl
ketone (MVK) three decades ago,[11] but good ee has only
been achieved very recently in the addition reactions of a-
substituted cyanoacetates catalyzed by some modified cin-
chona alkaloids.[12] Therefore, the development of efficient
enantioselective catalytic systems for a-substituted cyanoa-
cetates is highly desirable. Recently, we have shown that bi-
functional thiourea/tertiary amine compounds[13,14] derived
from simple chiral diamines are highly enantioselective or-
ganocatalysts for the Michael addition of a-substituted cya-
noacetates to vinyl sulfones, and chiral b2,2-amino acid esters
could be smoothly prepared from the addition products.[15]
Nevertheless, in an effort to develop more applicable asym-
metric transformations of cyanoacetates, we found that the
Michael acceptors were not limited to vinyl sulfones. Here
we would like to report the highly enantioselective Michael
addition of a-substituted cyanoacetates to vinyl ketones pro-
moted by simple bifunctional
been successfully applied in a range of asymmetric 1,2- or
1,4-addition reactions,[13] were screened in the Michael addi-
tion of ethyl a-phenyl cyanoacetate 2a and methyl vinyl
ketone 3a (MVK) in toluene at room temperature. Some
4 Š molecular sieves were used to remove a trace amount
of water in the reaction. As summarized in Table 1, all cata-
Table 1. Catalysts screening studies of the Michael addition of a-phenyl
cyanoacetate 2a to methyl vinyl ketone 3a.[a]
Entry
Cat. 1
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
1a
1b
1c
1d
1e
1a
1a
1d
1a
20
20
20
20
20
20
À40
À40
À60
4
4
4
4
4
96
54
95
97
80
75
95
93
95
73
56
60
62
60
40
86
75
91
5
6[d]
7
4
48
48
96
8
9
[a] Reaction conditions: 2a (0.1 mmol), 3a (0.2mmol), and catalyst
1
(0.01 mmol) were stirred in toluene (1 mL). After the stated time, the
product was purified by FC. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] Dichloromethane as the solvent.
lysts exhibited high catalytic activity and the Michael addi-
tion product 4a was cleanly isolated (Table 1, entries 1–5).
The highest enantioselectivity (73% ee) was observed in the
reaction catalyzed by 1a, derived from (R,R)-1,2-diaminocy-
clohexane (entry 1). As previously reported,[15] the enantio-
selectivity was also dramatically decreased in dichlorome-
thane (entry 6). Subsequently, we conducted the Michael re-
action at lower temperature to improve the enantioselectivi-
ty. We were pleased to find that a high ee (86% ee) was ob-
tained when using 1a as the catalyst at À408C (entry 7).
Lower ee was observed in the presence of quinine derivative
1d under the same conditions (entry 8). Moreover, the reac-
tion could be smoothly conducted at À608C catalyzed by 1a
(10 mol%), and an excellent ee (91% ee) was achieved in
95% yield after 96 h (entry 9).
thiourea/tertiary amine organo-
catalysts,[16] giving a more effi-
cient protocol for structurally
variable acyclic and cyclic b2,2-
amino acid esters.
Results and Discussion
Catalysts screening: Bifunction-
al thiourea/tertiary amine cata-
lysts 1a–e (10 mol%) with vari-
ous chiral scaffolds, which have
320
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 319 – 327

Michael Addition
FULL PAPER
Michael addition of a-aryl cyanoacetates to vinyl ketones:
With the optimized reaction conditions in hand, the scope
and limitation of the bifunctional organocatalyst 1a promot-
ed asymmetric Michael reactions were explored. A series of
a-aryl substituted ethyl cyanoacetates 2 were reacted with
vinyl ketones 3 in the presence of 10 mol% of 1a at À608C.
As summarized in Table 2, excellent enantioselectivities
presence of 1a (10 mol%), we delightfully found that the
Michael reaction could be considerably accelerated by em-
ploying the more reactive phenyl vinyl ketone 3b as the Mi-
chael acceptor. As summarized in Table 3, the addition
Table 3. Asymmetric Michael addition of a-alkyl cyanoacetates 2 to aryl
vinyl ketone 3.[a]
Table 2. Asymmetric Michael addition of a-aryl cyanoacetates 2 to vinyl
ketones 3.[a]
Entry
1
R
3
T
[8C]
t
Product
4
Yield
[%][b]
ee
[h]
[%][c]
methyl (2k)
3b
2
0
4s5
81
76
7292
90
66
67
61
91
98
73
91
96 4s[d]
Entry Ar
3
Product 4 Yield [%][b] ee [%][c]
2methyl (
2k)
3b À60
3b À60
3b À60
3
4
5
6
7
8
9
n-butyl (2l)
benzyl (2m)
96 4t
96 4u
120 4v
96 4w
96 4x
96 4y
96 4z
1
2
3
4
5
6
7
8
Ph (2a)
3a 4a
3a 4b
3a 4c
3a 4d
3a 4e
3a 4 f
3a 4g
95
87
86
94
95
95
95
88
93
94
93
90
95
97
99
97
97
99
91
87
86
92
95
85
90
95
82
86
85
97
89
91
92
91
97
93
92
93
85
85
96
97
p-Cl-Ph (2b)
p-Br-Ph (2c)
p-F-Ph (2d)
o-F-Ph (2e)
m-CF3-Ph (2 f)
p-CH3O-Ph (2g)
3,4-(CH3O)2-Ph (2h) 3a 4h
2-thienyl (2i)
Ph (2a)
p-Br-Ph (2c)
o-F-Ph (2e)
p-CH3O-Ph (2g)
1-naphthyl (2j)
o-F-Ph (2e)
o-F-Ph (2e)
o-F-Ph (2e)
Ph (2a)
isopropyl (2n) 3b À20
methyl (2k)
methyl (2k)
methyl (2k)
benzyl (2m)
3c À60
3d À60
3e À60
3e À60
[a] Reaction conditions: 2 (0.1 mmol), 3 (0.2mmol), and catalyst 1a
(0.01 mmol) were stirred in toluene (1 mL). [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis. [d] Absolute configuration was deter-
mined by comparison with reported optical rotation, see reference [8].
Other adducts were assigned accordingly.
9
3a 4i
3b 4j
3b 4k
3b 4l[d]
3b 4m
3b 4n
3c 4o
3d 4p
3e 4q
3e 4r
10
11
12[e]
13
14[e]
15
16
17
18
product 4s was obtained in 81% yield with 73% ee at room
temperature after 5 h (Table 3, entry 1). Gratifyingly, the
Michael reaction of a-methyl cyanoacetate 2k and phenyl
vinyl ketone 3b could smoothly proceed at lower tempera-
ture. An excellent ee (91% ee) was achieved with good yield
(76%) at À608C for 96 h (entry 2). a-n-Butyl and benzyl
substrates 2l and 2m were also successfully applied under
the same conditions and excellent results were obtained (en-
tries 3 and 4). Substrate 2n with a branched alkyl group
showed slightly lower reactivity, but a high ee (91% ee) was
still obtained at À208C (entry 5). In addition, aryl vinyl ke-
tones with electron-withdrawing or -donating substituents
gave good results in the reactions with a-methyl cyanoace-
tate 2k (entries 6 and 7). Notably, 2-thienyl vinyl ketone 3e
exhibited higher reactivity, and excellent ee and yields were
gained (entries 8 and 9).
[a] Reaction conditions: 2 (0.1 mmol), 3 (0.2mmol), and catalyst 1a
(0.01 mmol) were stirred in toluene (1 mL) at À608C for 96 h. [b] Isolat-
ed yield. [c] Determined by chiral HPLC analysis. [d] The absolute con-
figuration was determined to be S, and other Michael addition products
were assigned accordingly. [e] After 120 h.
(85–95% ee) with high yields (86–95%) were obtained in
the reactions of MVK 3a and a-aryl cyanoacetates 2b–f
with various electron-withdrawing substituents at para,
meta, or ortho positions (Table 2, entries 2–6). Notably, aryl
substrates 2g and 2h with electron-donating substituents
also exhibited high reactivity and excellent ee was achieved
(entries 7 and 8). For thienyl derivative 2i, a lower ee
(82% ee) was given under the same conditions (entry 9). On
the other hand, a variety of aryl vinyl ketones 3b–d and 2-
thienyl vinyl ketone 3e could be also successfully applied in
the Michael reactions with variously substituted a-aryl cya-
noacetates (entries 10–18), and generally excellent ee and
yields were achieved under the optimized conditions, even
for the bulky 1-naphthyl substrate 2j (entry 14).
Synthesis of b2,2-amino acids from the adducts: Scheme 2il-
lustrates the synthetic versatility of the multifunctional Mi-
chael addition products in this methodology. The ketone
group of compound 4d was protected as a glycol ketal, and
then the cyano group was easily converted to the protected
amino group in the presence of (Boc)2O through Raney-Ni-
catalyzed hydrogenation,[15] to give functionalized b2,2-amino
ester 5. The ketone group might allow further transforma-
tions, and thus variously structured b2,2-amino acids might
be accessible. On the other hand, 3-piperidinecarboxylate
derivatives 6 and 7 could be easily prepared in a pot from
the addition products 4a and 4l, respectively. Only one dia-
Michael addition of a-alkyl cyanoacetates to aryl vinyl ke-
tones: Subsequently we investigated the Michael reactions
of a-alkyl cyanoacetates and vinyl ketones. Although very
poor reactivity was observed in the reaction of a-methyl cy-
anoacetate 2k and MVK 3a at ambient temperature in the
Chem. Eur. J. 2007, 13, 319 – 327
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
321

Y.-C. Chen et al.
tween the OH group of the
enolate and the (CH3)2N group,
there is a weak hydrogen-bond-
ing interaction between the
OEt group of the enolate and a
NH of the thiourea moiety,
which is thought to be essential
to keep the enolate in a more
rigid conformation and afford
better enantiocontrol in this re-
action. Therefore, the nucleo-
phile 2e and the electrophile
3b are simultaneously activated
by bifunctional organocatalyst
1a through multiple hydrogen-
bonding interactions, and the
desired S enantiomer is pro-
Scheme 2. Synthesis of various b2,2-amino acid esters.
duced through Re-face attack
stereomer was detected for both cyclic products. The chiral
3-benzyl 3-piperidinecarboxylate is an important intermedi-
ate in the synthesis of potent growth hormone secretago-
gues,[17] thus the current methodology supplies a facile syn-
thetic route to variously structured 3-piperidinecarboxylic
analogues. Moreover, to determine the absolute configura-
tion of the piperidine derivative, the Boc group of com-
pound 7 was converted to a tosyl functionality. Fortunately,
single crystals suitable for X-ray crystallographic analysis
were obtained from enantiopure 8. The absolute configura-
tion of 8 was determined to be (C1R, C4S), so the absolute
configuration of the a-quaternary carbon center of Michael
addition product 4l was S (Figure 2).
of the Z-enolate of 2e (Figure 3a). In contrast, the Si-face
attack of the E enolate of 2e would be highly disfavored be-
cause of the steric interaction between the bulky aryl group
and phenyl vinyl ketone 3b. In addition, the relative space
from the a-carbon of the enolate and the b-vinyl carbon of
3b in calculated mode (Figure 3b) is also remoter than that
Figure 2. X-ray structure of compound 8.
Stereochemical course of the asymmetric induction: Based
on the absolute configuration of 4l, the possible reaction in-
termediates in the Michael addition of 2e to 3b were inves-
tigated. With the help of PM3 (semi-empirical method) cal-
culations,[18] it is found that, apart from the H-bonding be-
Figure 3. Possible active intermediates in the Michael reaction catalyzed
by 1a.
322
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 319 – 327

Michael Addition
FULL PAPER
t
(major)=12.63 min); 1H NMR (300 MHz, CDCl3): d=7.47 (d, J=
A
in mode (Figure 3a) (5.49 Š versus 4.31 Š), probably be-
cause of steric reasons.
8.9 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H), 4.28–4.20 (m, 2H), 2.66–2.57 (m,
2H), 2.53–2.34 (m, 2H), 2.14 (s, 3H), 1.24 ppm (t, J=7.2Hz, 3H);
13C NMR (75 MHz, CDCl3): d=205.6, 166.8, 135.3, 132.4, 129.4, 127.5,
117.7, 63.6, 52.6, 39.2, 31.6, 30.0, 13.8 ppm; IR (film): n˜ =2247, 1745,
1718 cmÀ1
; ESI-HRMS: m/z: calcd for C15H16ClNO3 +Na: 316.0711;
Conclusion
found: 316.0713.
(S)-Ethyl 2-(4’-bromophenyl)-2-cyano-5-oxohexanoate (4c): Colorless
oil; Yield: 86%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]2D0 =+5.4 (c=
0.21 in CHCl3); 86% ee (determined by HPLC analysis: Daicel chiralcel
We have presented a highly enantioselective Michael addi-
tion of a-substituted cyanoacetates to vinyl ketones syner-
A
AS, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t
ACHTREUNG
amine organocatalysts. The reaction scope is substantial and
a number of a-aryl or alkyl cyanoacetates could be success-
fully applied to give multifunctional compounds with an all-
carbon-substituted quaternary stereocenter with excellent
enantioselectivities (82–97% ee). Moreover, the biologically
important b2,2-amino acid esters with various structures
could be efficiently prepared from the optical pure adducts.
In addition, based on the absolute configuration of the con-
jugate adduct and computational studies, an interesting reac-
tion model involving multiple hydrogen-bonding interac-
tions amongst the thiourea/tertiary amine catalyst and the
reactants has been proposed. Currently work is actively
under way to expand this organocatalytic system to other
valuable transformations.
t
ACHTREUNG
8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 4.28–4.19 (m, 2H), 2.66–2.57 (m,
2H), 2.53–2.36 (m, 2H), 2.14 (s, 3H), 1.24 ppm (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=205.6, 166.7, 132.9, 132.4, 127.8, 123.4,
117.6, 63.6, 52.7, 39.2, 31.5, 30.0, 13.8 ppm; IR (film): n˜ =2246, 1745,
1718 cmÀ1
; ESI-HRMS: m/z: calcd for C15H16BrNO3 +Na: 360.0206;
found: 360.0209.
(S)-Ethyl 2-(4’-fluorophenyl)-2-cyano-5-oxohexanoate (4d): Colorless oil;
Yield: 94%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]2D0 =+9.0 (c=0.42
in CHCl3); 92% ee (determined by HPLC analysis: Daicel chiralcel AS,
hexane/iPrOH 90:10, 1.0 mLminÀ1, l=220 nm, t
(minor)=11.40 min, t-
1
A
7.19–7.08 (m, 2H), 4.29–4.20 (m, 2H), 2.67–2.58 (m, 2H), 2.54–2.35 (m,
2H), 2.15 (s, 3H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=205.7, 167.0, 162.8 (d, 1J(C,F)=247.9 Hz), 129.6, 128.0 (d, 3J-
A
A
G
29.9, 13.7 ppm; IR (film): n˜ =1742, 1717 cmÀ1; ESI-HRMS: m/z: calcd for
C15H16FNO3 +Na: 300.1006; found 300.0999.
(S)-Ethyl 2-(2’-fluorophenyl)-2-cyano-5-oxohexanoate (4e): Colorless oil;
Yield: 95%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]2D0 =+0.9 (c=0.33
in CHCl3); 95% ee (determined by HPLC analysis: Daicel chiralcel AD,
Experimental Section
hexane/iPrOH 90:10, 1.0 mLminÀ1
,
l=220 nm,
t(major)=8.58 min, t-
A
AHCTREUNG
General: TLC was performed on glass-backed silica plates. Column chro-
1H), 7.44–7.37 (m, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.15–7.08 (m, 1H),
4.33–4.25 (m, 2H), 2.74–2.59 (m, 2H), 2.57–2.49 (m, 2H), 2.15 (s, 3H),
1.27 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=205.7,
matography was performed by using silica gel (200–300 mesh) with ethyl
1
acetate/petroleum ether as eluent. H and 13C NMR spectra were record-
ed on Bruker 300 or 400 MHz spectrometers. Chemical shifts were re-
ported in ppm downfield from TMS with the solvent resonance as the in-
ternal standard. ESI-HRMS spectra were recorded on BioTOF instru-
ment of Bruker Daltonics. Enantiomeric excess was determined by
HPLC analysis on Chiralpak AS, AD, OD or OJ columns. Bifunctional
thiourea/tertiary amine catalysts 1a–f were prepared as previously report-
ed.[13] a-Substituted cyanoacetates 2[19] and aryl vinyl ketones 3b–e[20]
were prepared according to literature procedures.
166.3, 160.0 (d, 1J
124.7 (d, 3J(C,F)=3.0 Hz), 122.4 (d, 2J
2J
(C,F)=21.3 Hz), 63.5, 49.5, 39.1, 30.0, 29.4, 13.7 ppm; IR (film): n˜ =
A
ACHTREUNG
A
ACHTREUNG
R
2245, 1749, 1717 cmÀ1; ESI-HRMS: m/z: calcd for C15H16FNO3 +Na:
300.1006; found: 300.0997.
(S)-Ethyl 2-cyano-5-oxo-2-(3’-(trifluoromethyl)phenyl)hexanoate (4 f):
Colorless oil; Yield: 95%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]D20
=
+6.6 (c=0.38 in CHCl3); 85% ee (determined by HPLC analysis: Daicel
chiralcel OD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=220 nm, t
(minor)=
7.12min,
(major)=8.29 min); 1H NMR (300 MHz, CDCl3): d=7.79 (s,
General procedures for asymmetric Michael addition: Catalyst 1a
(4.2mg, 0.01 mmol, 10 mol%), a-substituted cyanoacetate 2 (0.1 mmol),
and 4 Š MS (20 mg) were stirred in dry toluene (0.5 mL) and cooled to
the desired temperature under argon. Then vinyl ketone 3 (0.2mmol) in
dry toluene (0.5 mL) was added. After the stated reaction time, the prod-
uct was purified by flash chromatography (FC) on silica gel (Previously
saturated with cold petroleum ether; in general slightly lower enantiose-
lectivity was obtained when FC was conducted at room temperature,
probably due to the rapid reaction of the unchanged starting materials in
column) to give the addition product 4.
ACHTREUNG
t
ACHTREUNG
1H), 7.76 (d, J=7.8, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz,
1H), 4.31–4.24 (m, 2H), 2.72–2.64 (m, 2H), 2.57–2.35 (m, 2H), 2.16 (s,
3H), 1.26 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=205.5,
166.5, 135.1, 131.7 (q, 2J
3J(C,F)=3.3 Hz), 123.5 (q, 1J
ACHTREUNG
N
G
ACHTREUNG
3.5 Hz), 117.4, 63.8, 53.0, 39.2, 31.8, 29.9, 13.7 ppm; IR (film): n˜ =2248,
1746, 1718 cmÀ1; ESI-HRMS: m/z: calcd for C16H16F3NO3 +Na: 350.0974;
found: 350.0980.
(S)-Ethyl 2-cyano-5-oxo-2-phenylhexanoate (4a): Colorless oil; Yield:
95%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]2D0 =+4.9 (c=0.25 in
CHCl3); 91% ee (determined by HPLC analysis: Daicel chiralcel AS,
(S)-Ethyl 2-cyano-2-(4’-methoxyphenyl)-5-oxohexanoate (4g): Colorless
oil; Yield: 95%; Rf =0.15 (petroleum ether/EtOAc 10:1); [a]2D0 =+7.2
(c=0.44 in CHCl3); 90% ee (determined by HPLC analysis: Daicel chir-
hexane/iPrOH 90:10, 1.0 mLminÀ1
,
l=254 nm,
t
A
alcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1
12.45 min, t
,
l=220 nm,
t
A
t
ACHTREUNG
AHCTREUNG
2H), 7.45–7.37 (m, 3H), 4.31–4.18 (m, 2H), 2.71–2.60 (m, 2H), 2.54–2.43
(m, 2H), 2.14 (s, 3H), 1.25 ppm (t, J=6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=205.9, 167.1, 133.8, 129.2, 129.0, 126.0, 118.0, 63.4, 53.0, 39.3,
31.6, 30.0, 13.8 ppm; IR (film): n˜ =2246, 1742, 1717 cmÀ1; ESI-HRMS:
m/z: calcd for C15H17NO3 +Na: 282.1101; found: 282.1103.
(d, J=8.9 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 4.27–4.18 (m, 2H), 3.81 (s,
3H), 2.65–2.44 (m, 4H), 2.14 (s, 3H), 1.24 ppm (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=205.9, 167.3, 159.9, 127.2, 125.6, 118.2,
114.4, 63.2, 55.3, 52.3, 39.2, 31.5, 29.9, 13.7 ppm; IR (film): n˜ =2246, 1741,
1717 cmÀ1; ESI-HRMS: m/z: calcd for C16H19NO4 +Na: 312.1206; found:
312.1209.
(S)-Ethyl 2-(4’-chlorophenyl)-2-cyano-5-oxohexanoate (4b): Colorless
oil; Yield: 87%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]2D0 =+4.5 (c=
0.44 in CHCl3); 87% ee (determined by HPLC analysis: Daicel chiralcel
(S)-Ethyl 2-cyano-2-(3’,4’-dimethoxyphenyl)-5-oxohexanoate (4h): Color-
less oil; Yield: 88%; Rf =0.15 (petroleum ether/EtOAc 7:1); [a]2D0 =+5.8
AS, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t
(minor)=10.51 min,
A
Chem. Eur. J. 2007, 13, 319 – 327
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
323

Y.-C. Chen et al.
(c=0.36 in CHCl3); 95% ee (determined by HPLC analysis: Daicel chir-
alcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1
l=220 nm, (minor)=
14.82min,
(major)=15.66 min); 1H NMR (300 MHz, CDCl3): d=7.09
(dd, J=2.3, 8.4 Hz, 1H), 6.98 (d, J=2.2 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H),
4.29–4.19 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.70–2.35 (m, 4H), 2.14 (s,
3H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=205.9,
167.2, 149.4, 149.2, 125.8, 118.5, 118.1, 111.1, 108.7, 63.2, 55.9, 55.8, 52.5,
39.2, 31.4, 29.9, 13.7 ppm; IR (film): n˜ =2246, 1743, 1720 cmÀ1; ESI-
HRMS: m/z: calcd for C17H21NO5 +Na: 342.1312; found: 342.1322.
(S)-Ethyl 2-cyano-2-(naphthalen-1-yl)-5-oxo-5-phenylpentanoate (4n):
,
t
G
Colorless oil; Yield: 97%; Rf =0.1 (petroleum ether/EtOAc 55:1); [a]D20
=
À25.8 (c=0.52in CHCl 3); 91% ee (determined by HPLC analysis:
Daicel chiralcel AS, hexane/iPrOH 90:10, 1.0 mLminÀ1
l=220 nm,
(major)=12.37 min, t
(minor)=14.83 min); 1H NMR (300 MHz, CDCl3):
t
ACHTREUNG
,
t
A
ACHTREUNG
d=8.13 (d, J=8.4 Hz, 1H), 7.96–7.91 (m, 4H), 7.82(d, J=7.4 Hz, 1H),
7.58–7.46 (m, 6H), 4.24 (q, J=7.1 Hz, 2H), 3.35–3.25 (m, 2H), 3.09–3.03
(m, 2H), 1.15 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
197.5, 168.4, 136.2, 134.4, 133.4, 130.4, 130.0, 129.8, 129.5, 128.7, 128.0,
127.2, 126.2, 125.5, 125.1, 122.9, 118.6, 63.5, 52.5, 34.6, 30.3, 13.8 ppm; IR
(film): n˜ =1738, 1676 cmÀ1; ESI-HRMS: m/z: calcd for C24H21NO3 +Na:
394.1414; found: 394.1422.
(S)-Ethyl 2-cyano-5-oxo-2-(thien-2-yl)hexanoate (4i): Colorless oil;
Yield: 93%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]2D0 =À13.1 (c=
0.21 in CHCl3); 82% ee (determined by HPLC analysis: Daicel chiralcel
OJ, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=220 nm, t
ACHTREUNG
(S)-Ethyl
5-(4’-bromophenyl)-2-cyano-2-(2’-fluorophenyl)-5-oxopenta-
noate (4o): Colorless oil; Yield: 99%; Rf =0.1 (petroleum ether/EtOAc
45:1); [a]2D0 =+19.4 (c=0.83 in CHCl3); 92% ee (determined by HPLC
analysis: Daicel chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=
t
ACHTREUNG
5.2Hz, 1H), 7.25 (dd, J=1.3, 3.7 Hz, 1H), 7.0 (dd, J=3.7, 18.6 Hz, 1H),
4.32–424 (m, 2H), 2.67–2.48 (m, 4H), 2.16 (s, 3H), 1.30 ppm (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=205.5, 166.5, 136.5, 127.1,
126.9, 117.4, 63.7, 50.1, 39.2, 33.1, 30.0, 13.8 ppm; IR (film): n˜ =2247,
1742, 1717 cmÀ1; ESI-HRMS: m/z: calcd for C13H15NO3S+Na: 288.0665;
found: 288.0658.
254 nm, t
N
N
CDCl3): d=7.81 (d, J=8.7 Hz, 2H), 7.65–7.59 (m, 3H), 7.48–7.40 (m,
1H), 7.27 (td, J=1.3, 7.6 Hz, 1H), 7.19–7.12(m, 1H), 4.38–4.31 (m, 2H),
3.35–3.24 (m, 1H), 3.14–3.03 (m, 1H), 2.92–2.82 (m, 1H), 2.79–2.69 (m,
1H). 1.30 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=196.4,
(S)-Ethyl 2-cyano-5-oxo-2,5-diphenylpentanoate (4j): Colorless oil;
Yield: 94%; Rf =0.1 (petroleum ether/EtOAc 35:1); [a]2D0 =+21.4 (c=
0.58 in CHCl3); 86% ee (determined by HPLC analysis: Daicel chiralcel
166.3, 159.7 (d, 1J
ACHTREUNG
3J
2J
A
ACHTREUNG
A
ACHTREUNG
OD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=220 nm, t
ACHTREUNG
30.0, 13.7 ppm; IR (film): n˜ =2240, 1738, 1680 cmÀ1; ESI-HRMS: m/z:
calcd for C20H17BrFNO3 +Na: 440.0268; found: 440.0272.
t
ACHTREUNG
7.60–7.54 (m, 3H), 7.47–7.39 (m, 5H), 4.32–4.20 (m, 2H), 3.29–3.17 (m,
1H), 3.09–2.98 (m, 1H), 2.87–2.77 (m, 1H), 2.70–2.60 (m, 1H), 1.26 ppm
(t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=197.5, 167.2, 136.2,
133.9, 133.4, 129.3, 129.1, 128.6, 128.0, 126.0, 118.2, 63.4, 53.3, 34.5, 32.2,
13.8 ppm; IR (film): n˜ =2245, 1743, 1683 cmÀ1; ESI-HRMS: m/z: calcd
for C20H19NO3 +Na: 344.1257; found: 344.1255.
(S)-Ethyl 2-cyano-2-(2’-fluorophenyl)-5-(4’-methoxyphenyl)-5-oxopenta-
noate (4p): Colorless oil; Yield: 97%; Rf =0.1 (petroleum ether/EtOAc
20:1); [a]2D0 =+17.1 (c=0.67 in CHCl3); 91% ee (determined by HPLC
analysis: Daicel chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=
254 nm, t
N
N
CDCl3): d=7.94 (d, J=8.9 Hz, 2H), 7.62 (td, J=1.6, 7.8 Hz, 1H), 7.45–
7.40 (m, 1H), 7.30–7.24 (m, 1H), 7.19–7.12 (m, 1H), 6.95 (d, J=8.9 Hz,
2H), 4.38–4.30 (m, 2H), 3.89 (s, 3H), 3.33–3.22 (m, 1H), 3.13–3.02 (m,
1H), 2.92–2.70 (m, 2H), 1.31 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
(S)-Ethyl 2-(4’-bromophenyl)-2-cyano-5-oxo-5-phenylpentanoate (4k):
Colorless oil; Yield: 93%; Rf =0.1 (petroleum ether/EtOAc 45:1); [a]D20
=
+21.1 (c=0.44 in CHCl3); 85% ee (determined by HPLC analysis:
Daicel chiralcel OD, hexane/iPrOH 90:10, 1.0 mLminÀ1
l=254 nm,
(minor)=9.56 min, t
(major)=11.87 min); 1H NMR (300 MHz, CDCl3):
CDCl3): d=195.9, 166.5, 163.7, 159.8 (d, 1J
(C,F)=248.0 Hz), 131.1 (d, 3J-
(C,F)=3.1 Hz), 122.6 (d,
(C,F)=21.4 Hz), 113.8, 63.5, 55.4,
,
(C,F)=8.5 Hz), 130.3, 129.4, 128.4, 124.8 (d, 3J
ACHTREUNG
t
A
ACHTREUNG
d=7.93–7.90 (m, 2H), 7.60–7.52 (m, 3H), 7.50–7.43 (m, 4H), 4.29–4.22
(m, 2H), 3.27–3.16 (m, 1H), 3.08–2.97 (m, 1H), 2.86–2.76 (m, 1H), 2.67–
2.57 (m, 1H), 1.26 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=197.3, 166.8, 136.1, 133.4, 133.0, 132.4, 128.6, 128.0, 127.8, 123.5, 117.7,
63.6, 52.9, 34.4, 32.1, 13.8 ppm; IR (film): n˜ =1742, 1685 cmÀ1; ESI-
HRMS: m/z: calcd for C20H18BrNO3 +Na: 422.0362; found: 422.0364.
A
ACHTREUNG
49.7, 34.0, 30.2, 13.8 ppm; IR (film): n˜ =2287, 1739, 1672 cmÀ1; ESI-
HRMS: m/z: calcd for C21H20FNO4 +Na: 392.1269; found: 392.1275.
(S)-Ethyl 2-cyano-2-(2’-fluorophenyl)-5-oxo-5-(thiophen-2-yl)pentanoate
(4q): Colorless oil; Yield: 97%; Rf =0.1 (petroleum ether/EtOAc 20:1);
[a]2D0 =+10.3 (c=0.55 in CHCl3); 97% ee (determined by HPLC analysis:
Daicel chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1
,
l=254 nm,
(S)-Ethyl 2-cyano-2-(2’-fluorophenyl)-5-oxo-5-phenylpentanoate (4l):
Colorless oil; Yield: 90%; Rf =0.1 (petroleum ether/EtOAc 45:1); [a]D20
=
t
A
ACHTREUNG
+16.0 (c=0.30 in CHCl3); 97% ee (determined by HPLC analysis:
Daicel chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1
l=254 nm,
(major)=13.23 min, t
(minor)=15.13 min); 1H NMR (300 MHz, CDCl3):
d=7.94–7.91 (m, 2H), 7.63–7.54 (m, 2H), 7.48–7.38 (m, 3H), 7.27–7.22
(m, 1H), 7.16–7.10 (m, 1H), 4.35–4.28 (m, 2H), 3.36–3.25 (m, 1H), 3.15–
3.04 (m, 1H), 2.90–2.70 (m, 2H), 1.28 ppm (t, J=7.1 Hz, 3H); 13C NMR
d=7.74 (dd, J=1.1, 3.8 Hz, 1H), 7.68 (dd, J=1.1, 5.0 Hz, 1H), 7.62(td,
J=1.7, 7.8 Hz, 1H), 7.48–7.40 (m, 1H), 7.26 (td, J=1.3, 7.7 Hz, 1H),
7.19–7.12 (m, 1H), 4.38–4.31 (m, 2H), 3.32–3.21 (m, 1H), 3.11–3.01 (m,
,
t
G
ACHTREUNG
1H), 2.92–2.70 (m, 2H), 1.31 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
1
CDCl3): d=190.2, 166.3, 159.8 (d, J
ACHTREUNG
131.1 (d, 3J
(d, 2J
C
ACHTREUNG
(75 MHz, CDCl3): d=197.4, 166.4, 160.0 (d, 1J
133.4, 131.1 (d, 3J
3.2 Hz), 122.5 (d, 2J
ACHTREUNG
A
A
G
(C,F)=12.3 Hz), 117.3, 116.6 (d, 2J
ACHTREUNG
63.5, 49.7, 34.4, 30.1, 13.8 ppm; IR (film): n˜ =1744, 1684 cmÀ1; ESI-
HRMS: m/z: calcd for C20H18FNO3 +Na: 362.1163; found: 362.1180.
(S)-Ethyl 2-cyano-5-oxo-2-phenyl-5-(thiophen-2-yl)pentanoate (4r): Col-
orless oil; Yield: 99%; Rf =0.1 (petroleum ether/EtOAc=20:1); [a]D20
=
+20.6 (c=0.57 in CHCl3); 93% ee (determined by HPLC analysis:
(S)-Ethyl 2-cyano-2-(4’-methoxyphenyl)-5-oxo-5-phenylpentanoate (4m):
Daicel chiralcel OD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t-
Colorless oil; Yield: 95%; Rf =0.1 (petroleum ether/EtOAc 20:1); [a]D20
=
A
G
+17.9 (c=0.38 in CHCl3); 89% ee (determined by HPLC analysis:
Daicel chiralcel OD, hexane/iPrOH 90:10, 1.0 mLminÀ1
l=254 nm,
(minor)=10.71 min, t
(major)=11.75 min); 1H NMR (300 MHz, CDCl3):
d=7.93–7.90 (m, 2H), 7.59–7.42 (m, 5H), 6.96–6.91 (m, 2H), 4.28–4.22
(m, 2H), 3.82 (s, 3H), 3.26–3.15 (m, 1H), 3.08–2.97 (m, 1H), 2.84–2.74
(m, 1H), 2.69–2.59 (m, 1H), 1.26 ppm (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=197.6, 167.4, 160.0, 136.3, 133.4, 129.1, 128.6, 128.0,
127.4, 125.7, 118.4, 114.6, 63.3, 55.3, 52.6, 34.5, 32.1, 13.8 ppm; IR (film):
n˜ =2246, 1742, 1686 cmÀ1; ESI-HRMS: m/z: calcd for C21H21NO4 +Na:
374.1363; found: 374.1360.
d=7.72(dd, J=1.1, 3.8 Hz, 1H), 7.67 (dd, J=1.1, 5.0 Hz, 1H), 7.63–7.59
(m, 2H), 7.49–7.41 (m, 3H), 7.16–7.13 (m, 1H), 4.32–4.26 (m, 2H), 3.24–
3.13 (m, 1H), 3.05–2.94 (m, 1H), 2.89–2.79 (m, 1H), 2.73–2.63 (m, 1H),
1.28 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=190.4,
167.1, 143.5, 134.0, 133.8, 132.2, 129.3, 129.1, 128.1, 126.0, 118.1, 63.4,
53.3, 35.1, 32.4, 13.8 ppm; IR (film): n˜ =2249, 1738, 1651 cmÀ1; ESI-
HRMS: m/z: calcd for C18H17NO3S+Na: 350.0821; found: 350.0807.
,
t
G
ACHTREUNG
(R)-Ethyl 2-cyano-2-methyl-5-oxo-5-phenylpentanoate (4s): Colorless
oil; Yield: 76%; Rf =0.1 (petroleum ether/EtOAc 30:1); [a]2D0 =+10.7
324
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 319 – 327

Michael Addition
FULL PAPER
(c=0.34 in CHCl3); 91% ee (determined by HPLC analysis: Daicel chir-
(R)-Ethyl 2-cyano-2-methyl-5-oxo-5-(thiophen-2-yl)pentanoate (4y): Col-
alcel OJ, hexane/iPrOH 90:10, 1.0 mLminÀ1
,
l=220 nm,
t
C
orless oil; Yield: 91%; Rf =0.1 (petroleum ether/EtOAc 25:1); [a]D20
=
+5.0 (c=0.48 in CHCl3); 96% ee (determined by HPLC analysis: Daicel
chiralcel OJ, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t
(major)=
25.01 min, t
(minor)=27.52 min); 1H NMR (300 MHz, CDCl3): d=7.79
20.25 min, t
ACHTREUNG
ACHTREUNG
7.96 (m, 2H), 7.59 (t, J=7.2Hz, 1H), 7.48 (t, J=7.2 Hz, 2H), 4.32–4.24
(m, 2H), 3.29–3.11 (m, 2H), 2.49–2.41 (m, 1H), 2.28–2.21 (m, 1H), 1.68
(s, 3H), 1.33 ppm (t, J=7.2Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
197.4, 168.9, 136.2, 133.5, 128.7, 128.0, 119.7, 63.0, 43.3, 34.4, 32.1, 23.7,
14.0 ppm; IR (film): n˜ =2244, 1738, 1684 cmÀ1; ESI-HRMS: m/z: calcd
for C15H17NO3 +Na: 282.1101; found: 282.1103.
AHCTREUNG
(dd, J=1.1, 3.8 Hz, 1H), 7.70 (dd, J=1.1, 4.9 Hz, 1H), 7.19–7.16 (m,
1H), 4.34–4.27 (m, 2H), 3.26–3.06 (m, 2H), 2.52–2.42 (m, 1H), 2.31–2.21
(m, 1H), 1.70 (s, 3H), 1.35 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=190.3, 168.8, 143.4, 134.1, 132.2, 128.2, 119.6, 63.0, 43.3, 35.0,
32.2, 23.6, 13.9 ppm; IR (film): n˜ =2244, 1737, 1672 cmÀ1; ESI-HRMS: m/
z: calcd for C13H15NO3S+Na: 288.0665; found: 288.0663.
(R)-Ethyl 2-cyano-2-(3-oxo-3-phenylpropyl)hexanoate (4t): Colorless oil;
Yield 72%; Rf =0.1 (petroleum ether/EtOAc 55:1); [a]2D0 =+3.1 (c=0.26
in CHCl3); 92% ee (determined by HPLC analysis: Daicel chiralcel AS,
(S)-Ethyl 2-benzyl-2-cyano-5-oxo-5-(thiophen-2-yl)pentanoate (4z): Col-
orless oil; Yield 98%; Rf =0.1 (petroleum ether/EtOAc 25:1); [a]D20
=
hexane/iPrOH 90:10, 1.0 mLminÀ1
, l=220 nm, t (major)=6.78 min,
1
+16.3 (c=0.63 in CHCl3); 97% ee (determined by HPLC analysis:
t (minor)=7.47 min); H NMR (300 MHz, CDCl3): d=7.96 (d, J=7.2Hz,
2H), 7.59 (t, J=7.1 Hz, 1H), 7.48 (t, J=7.2Hz, 2H), 4.29 (q, J=7.1 Hz,
2H), 3.33–3.22 (m, 1H), 3.11–3.00 (m, 1H), 2.46–2.36 (m, 1H), 2.30–2.20
(m, 1H), 2.05–1.95 (m, 1H), 1.90–1.80 (m, 1H), 1.41–1.25 (m, 7H),
0.93 ppm (t, J=7.2Hz, 3H); 13C NMR (75 MHz, CDCl3): d=197.5,
168.7, 136.2, 133.4, 128.7, 128.0, 119.1, 62.8, 49.1, 37.3, 34.4, 31.3, 27.5,
22.4, 14.1, 13.7 ppm; IR (film): n˜ =2244, 1740, 1688 cmÀ1; ESI-HRMS: m/
z: calcd for C18H23NO3 +Na: 324.1570; found: 324.1564.
Daicel chiralcel OD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t-
A
N
d=7.77 (dd, J=1.1, 3.8 Hz, 1H), 7.69 (dd, J=1.1, 5.0 Hz, 1H), 7.40–7.32
(m, 5H), 7.18–7.15 (m, 1H), 4.20 (q, J=7.2Hz, 2H), 3.33–3.14 (m, 3H),
3.10–2.99 (m, 1H), 2.61–2.51 (m, 1H), 2.37–2.27 (m, 1H), 1.21 ppm (t,
J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=190.1, 168.0, 143.4,
134.1, 133.8, 132.2, 129.9, 128.6, 128.2, 127.9, 118.5, 62.9, 50.7, 43.2, 35.0,
31.3, 13.8 ppm; IR (film): n˜ =2248, 1735, 1671 cmÀ1; ESI-HRMS: m/z:
calcd for C19H19NO3S+Na: 364.0978; found: 364.0974.
(S)-Ethyl 2-benzyl-2-cyano-5-oxo-5-phenylpentanoate (4u): Colorless oil;
Yield: 90%; Rf =0.1 (petroleum ether/EtOAc 35:1); [a]2D0 =+18.0 (c=
0.50 in CHCl3); 92% ee (determined by HPLC analysis: Daicel chiralcel
Synthesis of optically active b2,2-amino acid esters 5, 6, and 7
AS, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=220 nm, t
ACHTREUNG
Compound 5: Ethylene glycol (59.8 mg, 0.96 mmol) was added to a solu-
tion of 4d (134.0 mg, 0.48 mmol, 92% ee) and pTsOH (18.3 mg,
0.096 mmol) in benzene (10 mL). The mixture was heated to reflux for
6 h. After concentration, the residue was subjected to flash chromatogra-
phy (elution gradient: petroleum ether/EtOAc 25:1) to give the ketal in-
termediate. (Boc)2O (116.0 mg, 0.53 mmol) and Raney-Ni (28.5 mg) were
added to a solution of above compound in ethanol (3.0 mL). The mixture
was stirred under H2 (50 psi) at room temperature for 12h. Then the mix-
ture was filtered through celite, washed with EtOAc (20 mL) and the re-
sulting filtrate was concentrated in vacuum. The residue was subjected to
t
ACHTREUNG
2H), 7.61–7.56 (m, 1H), 7.50–7.45 (m, 1H), 7.36–7.30 (m, 5H), 4.17 (q,
J=7.1 Hz, 2H), 3.35–3.24 (m, 2H), 3.17–3.01 (m, 2H), 2.58–2.48 (m,
1H), 2.36–2.26 (m, 1H), 1.17 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=197.3, 168.1, 136.2, 133.8, 133.5, 129.9, 128.7, 128.6, 128.0,
118.7, 62.9, 50.7, 43.3, 34.4, 31.3, 13.9 ppm; IR (film): n˜ =2245, 1740,
1687 cmÀ1; ESI-HRMS: m/z: calcd for C21H21NO3 +Na: 358.1414; found:
358.1401.
(S)-Ethyl 2-cyano-2-isopropyl-5-oxo-5-phenylpentanoate (4v): Colorless
oil; Yield: 66%; Rf =0.1 (petroleum ether/EtOAc 45:1); [a]2D0 =+15.8
(c=0.32in CHCl 3); 93% ee (determined by HPLC analysis: Daicel chir-
flash chromatography to give the Boc-protected
b 5
2,2-amino ester
(168.8 mg, 83% yield for two steps). Rf =0.15 (petroleum ether/EtOAc
10:1); [a]2D0 =+21.7 (c=0.78 in CHCl3); 92% ee (determined by HPLC
analysis: Daicel chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=
alcel AS, hexane/iPrOH 90:10, 1.0 mLminÀ1
6.90 min, t
,
l=254 nm,
t(major)=
A
ACHTREUNG
254 nm, t
N
N
7.93 (m, 2H), 7.61–7.56 (m, 1H), 7.50–7.45 (m, 2H), 4.30 (q, J=7.1 Hz,
2H), 3.27–3.22 (m, 1H), 2.99–2.92 (m, 1H), 2.35–2.24 (m, 3H), 1.34 (t,
J=7.1 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.08 ppm (d, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=197.6, 168.8, 136.2, 133.4, 128.7, 128.0,
118.0, 62.7, 54.9, 35.2, 34.7, 29.1, 19.0, 17.7, 14.1 ppm; IR (film): n˜ =2242,
1739, 1688 cmÀ1; ESI-HRMS: m/z: calcd for C17H21NO3 +Na: 310.1414;
found: 310.1411.
CDCl3): d=7.25–7.22 (m. 2H), 7.06–7.00 (m, 2H), 4.78 (t, J=5.6 Hz,
1H), 4.25–4.17 (m, 2H), 3.97–3.89 (m, 4H), 3.78–3.73 (m, 1H), 3.61–3.56
(m, 1H), 2.13–2.07 (m, 2H), 1.71–1.65 (m, 1H), 1.57–1.51 (m, 1H), 1.37
(s, 9H), 1.32(s, 3H), 1.25 ppm (t, J=7.2Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=174.5, 161.7 (d, 1J
(C,F)=7.7 Hz), 115.2(d, 2J
45.4, 33.4, 25.7, 28.2, 23.7, 14.0 ppm; IR (KBr): n˜ =3460, 3388, 1722 cmÀ1
ACHTREUNG
A
ACHTREUNG
;
(R)-Ethyl 5-(4’-bromophenyl)-2-cyano-2-methyl-5-oxopentanoate (4w):
ESI-HRMS: m/z: calcd for C22H32FNO6 +Na: 448.2106; found: 448.2105.
Colorless oil; Yield: 67%; Rf =0.1 (petroleum ether/EtOAc 50:1); [a]D20
=
Compound 6: Compound 6 was prepared by a similar hydrogenation pro-
cedure to the above (31.6 mg, 91% yield); Rf =0.10 (petroleum ether/
EtOAc 50:1); [a]2D0 =+78.4 (c=0.56 in CHCl3); 91% ee (determined by
+2.8 (c=0.35 in CHCl3); 85% ee (determined by HPLC analysis: Daicel
chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t
(minor)=
9.29 min, t
(major)=9.91 min); 1H NMR (300 MHz, CDCl3): d=7.87–7.83
AHCTREUNG
HPLC analysis: Daicel chiralcel AD, hexane/iPrOH 95:5, 1.0 mLminÀ1
,
ACHTREUNG
l=254 nm,
t
A
t
N
1H NMR
(m, 2H), 7.67–7.62 (m, 2H), 4.34–4.27 (m, 2H), 3.28–3.07 (m, 2H), 2.51–
2.41 (m, 1H), 2.30–2.20 (m, 1H), 1.70 (s, 3H), 1.35 ppm (t, J=7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=196.4, 168.8, 135.0, 132.0, 129.5,
128.7, 119.6, 63.0, 43.2, 34.4, 31.9, 23.7, 14.0 ppm; IR (film): n˜ =2251,
(400 MHz, CDCl3): d=7.48 (d, J=7.6 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H),
7.22 (t, J=7.2Hz, 1H), 4.89 (d, J=14.0 Hz, 1H), 4.30–4.20 (m, 1H),
4.09–3.97 (m, 2H), 3.17 (d, J=14.4 Hz, 1H), 2.49–2.43 (m, 1H), 2.14 (td,
J=5.6, 14.2Hz, 1H), 1.59–1.46 (m, 10H), 1.34–1.30 (m, 1H), 1.18–
1.11 ppm (m, 6H); 13C NMR (75 MHz, CDCl3): d=174.1, 154.6, 138.2,
128.3, 127.4, 126.8, 79.7, 60.9, 49.5, 45.2, 42.2, 28.4, 27.1, 25.2, 15.6,
13.9 ppm; IR (KBr): n˜ =1729, 1691 cmÀ1; ESI-HRMS: m/z: calcd for
C20H29NO4 +Na: 370.1989; found: 370.2004.
1726, 1690 cmÀ1
;
ESI-HRMS: m/z: calcd for C15H16BrNO3 +Na:
360.0206; found: 360.0196.
(R)-Ethyl 2-cyano-5-(4’-methoxyphenyl)-2-methyl-5-oxopentanoate (4x):
Colorless oil; Yield 61%; Rf =0.1 (petroleum ether/EtOAc 25:1); [a]D20
=
+3.3 (c=0.29 in CHCl3); 85% ee (determined by HPLC analysis: Daicel
chiralcel AD, hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, t
(minor)=
13.52min,
(major)=14.34 min); 1H NMR (300 MHz, CDCl3): d=7.97
AHCTREUNG
Compound 7: Compound 7 was prepared by a similar hydrogenation pro-
cedure to above (103.0 mg, 93% yield); Rf =0.15 (petroleum ether/
EtOAc 50:1); [a]2D0 =+87.7 (c=0.31 in CHCl3); 96% ee (determined by
t
ACHTREUNG
(d, J=6.9 Hz, 2H), 6.97 (d, J=7.0 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.90
(s, 3H), 3.27–3.05 (m, 2H), 2.50–2.40 (m, 1H), 2.30–2.20 (m, 1H), 1.70 (s,
3H), 1.35 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=195.9,
168.9, 163.7, 130.3, 129.3, 119.7, 113.8, 62.9, 55.5, 43.3, 34.0, 32.3, 23.6,
13.9 cmÀ1; IR (film): n˜ =2245, 1732, 1683 cmÀ1; ESI-HRMS: m/z: calcd
for C16H19NO4 +Na: 312.1206; found: 312.1197.
HPLC analysis: Daicel chiralcel AS, hexane/iPrOH 90:10, 1.0 mLminÀ1
,
l=254 nm,
t
A
t
N
1H NMR
(300 MHz, CDCl3): d=7.59 (t, J=8.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.30–
7.21 (m, 4H), 7.17–7.12 (m, 1H), 7.06–6.99 (m, 1H), 5.31 (brs, 1H), 4.80
(d, J=13.7 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.30 (d, J=14.2Hz, 1H),
Chem. Eur. J. 2007, 13, 319 – 327
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
325

Y.-C. Chen et al.
2.24–2.17 (m, 3H), 1.96 (brs, 1H), 1.38 (s, 9H), 1.09 ppm (t, J=7.1 Hz,
J. Am. Chem. Soc. 2004, 126, 9918–9919; e) L. Qiu, F. Y. Kwong, J.
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ces therein.
1
3H); 13C NMR (75 MHz, CDCl3): d=173.9, 161.1 (d, J
155.3, 139.9, 129.5 (d, 3J
(C,F)=3.9 Hz), 128.9, 128.7, 128.4, 126.8, 126.1,
123.9, 115.8 (d, 2J
A
AHCTREUNG
A
24.3, 13.9 ppm; IR (KBr): n˜ =1733, 1691 cmÀ1; ESI-HRMS: m/z: calcd
for C25H30FNO4 +Na: 450.2051; found: 450.2039.
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X-ray crystallographic determination of 8: Trifluoroacetic acid (2.0 mL)
was added to a solution of 7 (75.0 mg, 0.18 mmol, 96% ee) in CH2Cl2
(5.0 mL). The mixture was stirred at room temperature for 30 min, and
then the mixture was concentrated in vacuum. The residue was purified
by flash chromatography (elution gradient: petroleum ether/EtOAc 10:1)
to give the b2,2-amino ester intermediate. p-Toluenesulfonyl chloride
(35.1 mg, 0.18 mmol) in CH2Cl2 (5.0 mL) was dropped into a solution of
the above compound and NEt3 (48.7 mL, 0.35 mmol) in CH2Cl2 (5.0 mL)
at 08C. After 12h, the solution was concentrated in vacuum. The residue
was purified by flash chromatography to give compound 8 (74.0 mg, 87%
yield for two steps). Rf =0.10 (petroleum ether/EtOAc 15:1); [a]D20
=
+22.4 (c=0.37 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.57 (t, J=
8.0 Hz, 1H), 7.30–7.15 (m, 8H), 7.11 (t, J=7.6 Hz, 1H), 7.01–6.92(m,
3H), 5.09 (t, J=4.5 Hz, 1H), 4.51 (d, J=13.9 Hz, 1H), 4.13–4.04 (m,
2H), 3.83 (d, J=13.9 Hz, 1H), 2.34 (s, 3H), 2.23–2.09 (m, 4H), 1.11 ppm
(t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.6, 161.0 (d,
1J
129.0, 128.9, 128.4, 127.7, 127.5, 127.2, 127.0, 124.1, 115.9 (d, 2J
22.7 Hz), 61.3, 56.1, 47.4, 47.1, 26.7, 25.9, 21.4, 13.8 ppm; IR (KBr): n˜ =
1729 cmÀ1
ESI-HRMS: m/z: calcd for C27H28FNO4S+Na: 504.1615;
A
ACHTREUNG
AHCTREUNG
;
found: 504.1609. Single crystals of enantiopure 8 suitable for X-ray analy-
sis were obtained by recrystallization from acetone/hexane at room tem-
perature. Crystal data for 8: C27H28FNO4S (481.56), orthorhombic, space
group P212121, a=9.667(4), b=12.493(5), c=20.354(8) Š, U=
2458.1(17) Š3, Z=4, specimen 0.52”0.40”0.38 mm3, T=299(2) K, SIE-
MENS P4 diffractometer, absorption coefficient 0.173 mmÀ1, reflections
collected: 5437, independent reflections: 4570 [Rint =0.0267], refinement
by full-matrix least-squares on F2, data/restraints/parameters 4570/0/309,
goodness-of-fit on F2 =0.852, final
R indices [I>2s(I)] R1=0.0446,
wR2=0.0630, R indices (all data) R1=0.0869, wR2=0.0691, largest diff.
peak and hole 0.187 and À0.168 eŠÀ3. CCDC-617621 contains the sup-
plementary crystallographic data for this paper. These data can be ob-
tained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
This work was financially supported by the National Natural Science
Foundation of China (20502018), Ministry of Education of China
(NCET-05–0781) and Sichuan University. We are grateful for the help of
Prof. K-B. Yu on the X-ray analysis of compound 8.
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Received: June 7, 2006
Published online: October 13, 2006
Chem. Eur. J. 2007, 13, 319 – 327
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