Asymmetric chemoenzymatic synthesis of N-acetyl-α-amino esters based on lipase-catalyzed kinetic resolutions through interesterification reactions

Article abstract of DOI:10.1016/j.tet.2014.02.012

Several phenylalanine analogs have been synthesized through a four-step route starting from easily available ethyl acetamidocyanoacetate. In a first reaction, and making use of phase transfer catalysts, this compound reacted with several alkyl halides, being benzyltributylammonium chloride identified as the best one for the production of a series of quaternary amino acids in moderate to excellent yields (52-95%). Then, the corresponding N-acetyl-phenylalanine methyl and allyl ester derivatives were obtained through acidic hydrolysis, esterification, and N-acetylation. Rhizomucor miehei lipase was found as a versatile enzyme for the resolution of these amino esters, finding the best results through interesterification reactions with butyl butyrate in acetonitrile. A great influence in the stereoselectivity was found depending on the chemical structure of the compound, achieving for the non- or para-substituted in the phenyl ring excellent stereoselectivities, being moderate for the meta-nitro derivative, while the ortho-nitro amino ester did not react.

Full text of DOI:10.1016/j.tet.2014.02.012

Tetrahedron 70 (2014) 2264e2271
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric chemoenzymatic synthesis of N-acetyl-
a-amino esters
based on lipase-catalyzed kinetic resolutions through
interesterification reactions
,
Marcos Reinaldo da Silva a, Marcos Carlos de Mattos a
*
,
a
a
~
Maria da Conceic¸ ao Ferreira de Oliveira , Telma Leda Gomes de Lemos ,
Nagila Maria Pontes Silva Ricardo , Gonzalo de Gonzalo , Ivan Lavandera ,
a
b
b
ꢀ
ꢀ
b
b,
*
ꢀ
Vicente Gotor-Fernandez , Vicente Gotor
a
^
^
ꢀ
ꢀ
Departamento de Química Organica e Inorganica, Universidade Federal do Ceara, 60451-970 Fortaleza, Ceara, Brazil
Departamento de Química Organica e Inorganica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, c/Julian Clavería 8,
b
ꢀ
ꢀ
ꢀ
33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Several phenylalanine analogs have been synthesized through a four-step route starting from easily
available ethyl acetamidocyanoacetate. In a first reaction, and making use of phase transfer catalysts, this
compound reacted with several alkyl halides, being benzyltributylammonium chloride identified as the
best one for the production of a series of quaternary amino acids in moderate to excellent yields
(52e95%). Then, the corresponding N-acetyl-phenylalanine methyl and allyl ester derivatives were ob-
tained through acidic hydrolysis, esterification, and N-acetylation. Rhizomucor miehei lipase was found as
a versatile enzyme for the resolution of these amino esters, finding the best results through inter-
esterification reactions with butyl butyrate in acetonitrile. A great influence in the stereoselectivity was
found depending on the chemical structure of the compound, achieving for the non- or para-substituted
in the phenyl ring excellent stereoselectivities, being moderate for the meta-nitro derivative, while the
ortho-nitro amino ester did not react.
Received 16 November 2013
Received in revised form 19 November 2013
Accepted 5 February 2014
Available online 11 February 2014
Keywords:
Amino acids
Asymmetric synthesis
Interesterification
Kinetic resolution
Lipases
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
relevance in the area of medicinal chemistry, as for instance, en-
zyme inhibitors.3
a
-Amino acids are essential to life as building blocks of pep-
In the last years, many efforts have been focused on the in-
troduction of unnatural amino acids in peptidic chains to afford
peptidomimetics designed to improve their binding potency to
a desired biological target, their chemical and/or biological stability,
and their pharmacokinetic properties compared to the natural
compounds, providing useful information for the elucidation of
different enzymatic mechanisms.4
Biocatalytic and chemoenzymatic methods have been de-
scribed for the production of unnatural or non-proteinogenic
amino acids through many routes,5 receiving hydrolase-catalyzed
reactions great attention due to their easy manipulation and
commercial availability.6 Particularly, lipases (EC 3.1.1.3) have
largely demonstrated their applicability with synthetic purposes,
being the most employed enzymes in industrial processes in the
last three decades. This fact is mainly based on their wide avail-
ability in nature and their broad substrate acceptance. Signifi-
cantly this class of hydrolases acts with high levels of selectivity in
the transformation of achiral but also racemic, prochiral or meso-
tides, proteins, hormones, and as a source of low-molecular
weight nitrogenated substances with enormous biological impor-
tance, such as glutathione, taurine, nitric oxide, polyamines, etc.
The applicability of amino acids is also well documented as ag-
rochemicals, antibacterial agents, fungicides, neuroactive com-
pounds, food supplements, enzyme inhibitors, and pharmaceutical
materials.1 They are involved in the synthesis of a great number of
organic substances as a source of chiral raw materials, as synthetic
targets, and as reagents and/or catalysts in asymmetric synthesis.2
For all these reasons, the development of synthetic strategies for
the preparation of amino acids has been object of intense in-
vestigation.1 Particularly, optically active phenylalanine analogs
are interesting compounds because of their synthetic possibilities
as chiral building blocks of more complex structures with
* Corresponding authors. E-mail address: VGS@fq.uniovi.es (V. Gotor).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.012

M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
2265
Table 2
compounds, their usefulness being extensively demonstrated
through hydrolytic or synthetic processes in both aqueous and
organic media.7
Alkylation of (ꢀ)-1 with 2 equiv of alkyl halides (4aeh) and BTBAC (10 mol %) as PTC
in toluene and potassium carbonate (1 equiv) for 5 h at 70 ꢁ
C
Candida antarctica lipase B (CAL-B) is probably the most ver-
satile catalyst,8 although others, such as Pseudomonas cepacia
lipase (PSL or PCL) or Rhizomucor miehei lipase (RML)9 have also
shown excellent activities in a series of synthetic transformations,
such as aminolysis, esterification, and transesterification
reactions. Although less employed, the interconversion between
two reacting esters (interesterification), is another process that
can be successfully used operating with lipases.10 Herein, we wish
to report our latest results in the field of asymmetric synthesis
Entry
R1X
Isolated yield 3aeh (%)a
1
2
3
4
5
6
7
8
Benzyl bromide (4a)
95
52
78
80
93
94
92
89
4-Methoxybenzyl chloride (4b)
4-Methybenzyl bromide (4c)
4-Chlorobenzyl bromide (4d)
4-Nitrobenzyl bromide (4e)
3-Nitrobenzyl bromide (4f)
2-Nitrobenzyl bromide (4g)
2-(Bromomethyl)naphthalene (4h)
of amino acids. For that reason,
a family of amino esters
was chemically prepared to later explore their kinetic resolution
(KR), RML being found as the most versatile enzyme for
interesterification reactions.
a
Isolated yield after flash chromatography.
2. Results and discussion
These conditions were then extended to other alkyl halides,
selecting the bromide halides when they were commercially
available. The results are summarized in Table 2, observing
a lower reactivity for the 4-methoxybenzyl chloride (4b) in
comparison with bromide salts 4a,ceh, all the amino esters being
obtained with good to very high yields after 5 h. In addition,
para-substituted derivatives with methyl (3c) or chloro sub-
stitution (3d) were achieved in 78e80% yield (entries 3 and 4).
Compounds bearing a nitro functionality led to excellent results
independently of the substituent position (3eeg, entries 5e7),
while the most hindered napthyl derivative 3h was isolated in
89% yield (entry 8).
The corresponding amino acid derivatives 3aeh were then
subjected to a chemical sequence based on their acidic hydroly-
sis,12 subsequent esterification reaction using different alcohols
(i.e., methanol, butanol or allyl alcohol), and final N-acetylation
protection (Scheme 1), leading to racemic compounds 9aeh,
10aeh, and 11aeh in a straightforward manner. In general
moderate to good yields were obtained for the global three-step
process, the poorer results being found with the allylic
derivatives.
Next, the enzymatic kinetic resolution of methyl N-acetylated
amino ester 9a was studied. It must be mentioned that previous
reports have appeared in the literature leading to the preparation of
optically active N-acylated phenylalanine derivatives by means of
highly selective hydrolytic processes,13 while transesterification
reactions led to the desired compounds with high selectivity but
modest conversions.14 For this reason, we decided to explore an
alternative, such as the interesterification reaction.10 Thus, butyl
butyrate was selected as both resolving agent and solvent. A set of
hydrolases including C. antarctica lipase type A (CAL-A), C. antarc-
tica lipase type B (CAL-B), Candida rugosa lipase (CRL), porcine
pancreas lipase (PPL), Pseudomonas cepacia lipase (PSL-IM), R.
miehei lipase (RML), lipase AK from Pseudomonas fluorescens (AK)
and Thermomyces lanuginosus lipase (TLL) were tested in this re-
action at 30 and 60 ꢁC. Only RML was able to produce the butyl ester
in 53% conversion and 80% ee after 8.2 h at 60 ꢁC (Table 3, entry 1),
while no reaction was observed with the other lipases after 24 h.
Then, the reaction was analyzed studying the influence of the
temperature and the enzyme loading in the lipase catalysis.
A slightly better enantiopreference was observed when the re-
action was carried out in milder conditions (30 ꢁC, entry 2),
attaining 50% conversion after 48 h. In order to improve the re-
action rate, enzyme loading was doubled leading to a similar con-
version value at 24 h (entry 3).
Due to the relevance of phenylalanine analogs, a series of N-
acetylated O-esterified derivatives was synthesized through
a four-step methodology. Starting from a common precursor,
racemic ethyl acetamidocyanoacetate (1), firstly the alkylation at
its
a-position was carried out using the desired alkyl halide in
order to afford the corresponding quaternary esters. These in-
termediates will be hydrolyzed, esterified, and acetylated in the
subsequent steps, giving access to the target compounds. With
that purpose and considering that phase transfer catalysis is
a highly demanded strategy for the synthesis of amino acids
through alkylation reactions,11 this approach was applied to the
transformation of commercially available 1 with 2 equiv of
benzyl chloride (2), thus producing the N-acetyl amino ester
(ꢀ)-3a in the presence of potassium carbonate at 70 ꢁC. A panel
of phase transfer catalysts (PTCs) was employed, such as ben-
zyltriethylammonium bromide (BTAB), tetrabutylammonium
hydrogen sulfate (TBAH), dodecyltrimethylammonium chloride
(DTMAC), cetyltrimethylammonium bromide (CTMAB), benzyl-
tributylammonium
bromide
(BTBAB)
or
benzyl-
tributylammonium chloride (BTBAC), Aliquat or 18-crown-6,
obtaining in all cases moderate to good yields of (ꢀ)-3a as the
unique product when 10 mol % of the PTC was used (Table 1). The
best results were achieved using the chloride salt BTBAC, so at
this point benzyl bromide (4a) was used in order to improve the
conversion of the process. Satisfyingly, the reaction with 4a led to
a further improvement in the isolated yield of 3a in comparison
with the reaction with 2 as alkylating agent (from 75 to 95%
isolated yield, see entry 1 in Table 2).
Table 1
Alkylation of (ꢀ)-1 with 2 (2 equiv) and a phase transfer catalyst (10 mol %) in
toluene and potassium carbonate (1 equiv) for 5 h at 70 ꢁ
C
Entry
PTC
Isolated yield 3a (%)a
1
2
3
4
5
6
7
8
BTAB
TBAH
DTMAC
CTMAB
BTBAB
BTBAC
Aliquat
18-Crown-6
62
59
65
64
63
75
66
66
Looking at these results, we turned our attention to the sol-
vent effect in the RML-catalyzed reaction. By this,
a
Isolated yield after flash chromatography.

2266
M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
Scheme 1. Chemical synthesis of racemic N-acetylated amino esters (ꢀ)-9e11.
Table 3
interesterification was carried out with 10 equiv of butyl butyrate,
but no changes were observed in the conversion. At this point, we
decided to explore new insights in these processes, combining the
use of different organic solvents with a lower temperature (4 ꢁC),
trying in this way to obtain better stereoselectivities (entries 9e12).
This goal was reached, and a remarkable conversion value of 48%
was attained with MTBE (entry 11), while a better selectivity was
observed for toluene (entry 12), although it decreased at longer
reaction times.
Interesterification reaction of (ꢀ)-9a (120 mM) using butyl butyrate and RML
Entry
Enzyme:9aa
T (ꢁC)
t (h)
ees (%)b
eep (%)b
c (%)c
Ed
1
2
3
1:1
1:1
2:1
60
30
30
8.2
48
24
89
86
90
80
85
87
53
50
51
27
34
44
Once that the potential of the interesterification reaction was
demonstrated in the resolution of the N-acetylated phenylalanine
methyl ester, we decided to study the effect of the ester moiety
making use of the allyl ester 11a as starting material. Due to the
fact that the best selectivity achieved for 9a and PrCO2Bu was
achieved employing MeCN as organic solvent, we decided to
compare the effect of the substrate under these conditions (en-
tries 1 and 2, Table 5). As can be observed, a very high stereo-
selectivity towards the formation of the butyl ester (S)-10a and
the allyl derivative (R)-11a was reached after 72 h of reaction. This
trend was shared in all cases, the reactivity of the allyl amino
esters 11 being much higher than the ones from the correspond-
ing methylated derivatives 9. There was just one exception for the
hindered ortho-nitrobenzyl compounds (9g and 11g), which did
not shown appreciable activity (entries 13 and 14). Allyl para-
a
Ratio of RML:amino ester 9a in weight/weight.
b
c
Enantiomeric excess of substrate and product determined by HPLC.
Conversion value: c¼ees/(eesþeep).
d
Enantioselectivity value: E¼ln[1ꢂc(1þeep)]/ln[1ꢂc(1ꢂeep)].
tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, toluene,
acetonitrile, n-hexane, and diethyl ether were tested using
5 equiv of butyl butyrate (Table 4). The results were compared
with the reaction carried out with PrCO2Bu as solvent (entry 1).
Aliquots were regularly taken at intervals between 1 and 72 h,
and the most representative results are shown. Reactions carried
out at 30 ꢁC in THF, n-hexane, and diethyl ether almost led to 50%
conversion after 24 h with moderate enantioselectivity (E <50,
entries 2e4), while in 1,4-dioxane the RML activity was lower
with a similar selectivity (entry 5).
Table 5
Interesterificaton reaction of (ꢀ)-9aeh and 11aeh (120 mM) using butyl butyrate
and RML (ratio 2:1 in weight respect to the amino ester) in MeCN at 30 ꢁC and
250 rpm
Table 4
Interesterification reaction of (ꢀ)-9a using butyl butyrate in different organic
solventsa
Entry
Solvent
T (ꢁC)
t (h)
ees (%)b
eep (%)b
c (%)c
Ed
1
2
3
4
5
6
7
8
PrCO2Bu
THF
n-Hexane
Et2O
Dioxane
MTBE
Toluene
MeCN
30
30
30
30
30
30
30
30
4
24
24
24
24
72
8
90
17
75
83
44
79
79
16
41
31
83
96
87
95
83
88
94
88
93
>99
89
96
51
50
47
49
32
47
47
14
32
24
48
34
44
50
25
39
50
38
38
>200
35
63
Entry
Substrate
t (h)
ees (%)a
eep (%)a
c (%)b
Ec
1
2
3
4
5
6
7
8
9a
11a
9b
11b
9c
11c
9d
11d
9e
11e
9f
11f
9g
11g
9h
24
72
24
57
240
72
240
64
120
30
144
72
240
24
16
90
44
90
75
91
78
89
86
90
48
81
<3
<3
27
81
>99
98
14
48
31
48
43
48
44
47
47
48
37
48
<3
<3
23
49
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
18
8
24
24
24
24
24
>99
>99
>99
>99
>99
>99
98
>99
84
87
9
n-Hexane
Et2O
MTBE
10
11
12
4
4
4
92
49
64
89
Toluene
a
Reaction conditions: 5 equiv of butyl butyrate and RML (ratio 2:1 of enzyme:9a),
120 mM substrate concentration at 250 rpm.
9
b
Enantiomeric excess of substrate and product determined by HPLC.
10
11
12
13
14
15
16
c
Conversion value: c¼ees/(eesþeep).
d
Enantioselectivity value: E¼ln[1ꢂc(1þeep)]/ln[1ꢂc(1-eep)].
35
<3
<3
92
78
n.dd
n.dd
120
120
31
19
Biotransformations in MTBE and toluene (entries 6 and 7)
showed the fastest reaction rates, attaining 47% conversion after
only 8 h. Finally, an excellent selectivity was observed when the
reaction was performed in acetonitrile, unfortunately the conver-
sion value was not synthetically useful. For that reason,
11h
a
Enantiomeric excess of substrate and product determined by HPLC.
Conversion value: c¼ees/(eesþeep).
b
c
Enantioselectivity value: E¼ln[1ꢂc(1þeep)]/ln[1ꢂc(1ꢂeep)].
n.d.: not determined.
d

M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
2267
substituted derivatives with methoxy (b), methyl (c), chloro (d) or
nitro (e) functionalities produced the butyl esters in enantiopure
form and gratifyingly with conversions close to 50% (47e48%,
entries 4, 6, 8, and 10). For the 3-nitrobenzyl ester (11f) and the 2-
naphthylmethyl ester (11h) a significant lost of stereoselectivity
was observed, but still better activities were achieved than for the
methyl counterparts.
a BrukerMicroTofQ spectrometer. Measurement of the optical ro-
tation was done in a PerkineElmer 241 polarimeter. High perfor-
mance liquid chromatography (HPLC) analyses were carried out in
a Hewlett Packard 1100 chromatograph with a UV detector
at 210 nm using a Chiralpak AS column (25 cmꢃ4.6 mm I.D.),
Chiralpak IC (25 cmꢃ4.0 mm I.D.) and Chiralcel OB-H column
(25 cmꢃ4.6 mm I.D.).
3. Conclusions
4.2. General procedure for the alkylation of racemic ethyl
The selective synthesis on non-proteinogenic amino acid de-
rivatives has been the focus of many efforts by organic chemists
during the last years due to the novel properties attained when
introduced in proteins and peptides. In this sense, while both en-
antiomers of phenylalanine could be obtained through hydrolase-
catalyzed resolutions via transesterification or hydrolysis proc-
esses,13a,b,14 the synthesis of other phenylalanine analogs has been
scarcely studied.13c,d Herein we show a methodology applicable for
a series of phenylalanine derivatives making use of an interester-
ification reaction as a versatile approach to obtain them in an
enantioenriched form.
Twenty-four N-acetyl amino esters have been chemically pre-
pared from easily accessible ethyl acetamidocyanoacetate (1) fol-
lowing a phase transfer catalytic C-alkylation, acidic hydrolysis and
later esterification and acetylation sequence. Several phase transfer
catalysts were tested in the reaction between 1 and alkyl halides,
finding the best results with benzyltributylammonium chloride
(BTBAC). The obtained methyl amino esters were then subjected to
enzymatic kinetic resolution using a set of lipases as biocatalysts. R.
miehei lipase was found as a versatile enzyme for the asymmetric
synthesis of the corresponding N-acetyl protected amino esters.
The best results were found when carrying out interesterification
reactions with butyl butyrate in acetonitrile as solvent at 30 ꢁC.
A great influence in the activity and stereoselectivity has been
observed depending on the chemical structure of the amino ester.
Allyl esters reacted faster than the corresponding methyl esters,
achieving, with the exception of the ortho-nitro amino ester, ex-
cellent stereoselectivities for the non- or para-substituted analogs
in the phenyl ring, while moderate ones for the meta-nitro or
a bulky naphthalene derivative.
acetamidocyanoacetate (1) with alkyl halides 4aeh
A suspension of (ꢀ)-1 (511 mg, 3 mmol), BTBAC (31 mg, 0.1 mol),
the corresponding alkyl halides (2 or 4aeh, 6 mmol), and potas-
sium carbonate (415 mg, 3 mmol) were heated in toluene (5 mL) for
5 h at 70 ꢁC under magnetic stirring. The reaction mixture was
cooled to room temperature and diluted with CHCl3 (20 mL), then
the solution was washed with water (3ꢃ40 mL). The organic phase
was dried with Na2SO4, filtered and the solvent evaporated under
reduced pressure, obtaining a crude product that was purified by
flash chromatography on silica gel (30e100% EtOAc/hexane). The
amino esters 3aeh were obtained as solids in 52e95% isolated yield
(see Table 2).
4.2.1. Spectroscopical data of ethyl 2-acetylamino-2-cyano-3-
phenylpropanoate (3a). Solid. Rf (50% EtOAc/hexane): 0.38. Mp:
121e122 ꢁC. IR (NaCl): v 3277, 1753, 1668, 1527, and 1220 cmꢂ1. 1H
NMR (300.13 MHz, CDCl3)
d
(ppm): 1.23 (t, 3H, J¼14.3 Hz), 2.07 (s,
3H), 3.38 (d, 1H, J¼13.4 Hz), 3.52 (d, 1H, J¼13.4 Hz), 4.16e4.30 (m,
2H), 6.87 (s, 1H), 7.23 (s, 1H), and 7.26e7.37 (m, 5H). 13C NMR
(75.5 MHz, CDCl3)
d (ppm): 13.8 (CH3), 22.6 (CH3), 41.6 (CH2), 57.9
(C), 63.7 (CH2), 116.4 (C), 128.6 (CH), 128.9 (2CH), 130.1 (2CH), 131.7
(C), 165.8 (C), and 170.1 (C). HRMS [ESIþ, m/z] calcd for
C
14H16N2O3[Naþ] 283.1059, found 283.1054.
4.2.2. Spectroscopical data of ethyl 2-acetylamino-2-cyano-3-(4-
methoxyphenyl)propanoate (3b). Solid. Rf (50% EtOAc/hexane):
0.16. Mp: 181e184 ꢁC. IR (NaCl): v 3250, 1697, 1633, 1512, and
1248 cmꢂ1 1H NMR (300.13 MHz, Py-d5)
. d (ppm): 1.20 (t, 3H,
J¼7.0 Hz), 2.23 (s, 3H), 3.76e3.89 (m, 5H), 4.32e4.40 (m, 2H), 7.13
(dd, 2H, J¼11.4 and 3.0 Hz) and 7.62 (dd, 2H, J¼11.2 and 2.4 Hz). 13
C
4. Experimental section
NMR (75.5 MHz, Py-d5) d (ppm): 14.6 (CH3), 22.8 (CH3), 42.2 (CH2),
55.9 (C), 60.8 (CH3), 63.7 (CH2), 115.1 (2CH), 119.0 (C), 125.5 (C),
132.7 (2CH), 160.8 (C), 168.0 (C) and 171.6 (C). HRMS [ESIþ, m/z]
calcd for C15H18N2O4[Naþ] 313.1164, found 313.1161.
4.1. General considerations
Chemical reagents were purchased from different commercial
sources and used without further purification. Solvents were dis-
tilled over an adequate desiccant under nitrogen. C. antarctica li-
pase type B (CAL-B, Novozyme 435, 7300 PLU/g) was a gift from
Novozymes. P. cepacia lipase currently known as Burkhlolderia
cepacia lipase (PSL-IM, 1638 U/g solid) and P. fluorescens lipase (AK,
22,100 U/g) were acquired from SigmaeAldrich. C. antarctica lipase
A (CAL-A, 2.6 U/mg solid) was purchased from Codexis. Pancreas
porcine lipase (PPL, 46 U/mg solid), C. rugosa lipase (CRL, 1.41 U/g)
and Candida cylindracea lipase (CCL, 1.41 U/mg solid) were obtained
from Sigma. R. miehei lipase (RML, 150 IUN/g) and T. lanuginosus
lipase (TLL, 250 IUN/g) were purchased from Novozymes.
4.2.3. Spectroscopical data of ethyl 2-acetylamino-3-(4-
methylphenyl)-2-cyanopropanoate (3c). Solid. Rf (50% EtOAc/hex-
ane): 0.3. Mp: 149.5e150.1 ꢁC. IR (NaCl) v 3404, 3250, 1730, 1697,
1512, and 1248 cmꢂ1. 1H NMR (300.13 MHz, MeOD)
d (ppm): 1.10 (t,
3H, J¼6.0 Hz), 2.05 (s, 3H), 2.34 (s, 3H), 4.06e4.12 (q, 2H, J¼6.0 Hz),
4.27e4.34 (m, 1H), and 7.18 (s, 4H). 13C NMR (75 MHz, MeOH)
d
(ppm): 14.1 (CH3), 21.2 (CH3), 21.9 (CH3), 42.5 (CH2), 60.5 (CH2),
64.1 (C), 118.1 (C), 130.2 (2CH), 130.3 (C), 131.3 (2CH), 139.4 (C), 167.6
(C), and 173.2 (C). HRMS [ESIþ, m/z] calcd for C15H18N2O3[Naþ]
297.1215, found 297.1209.
Flash chromatography was performed using silica gel 60
(230e240 mesh). Melting points were taken on samples in open
capillary tubes and are uncorrected. IR spectra were recorded on
a PerkineElmer 1720-X F7 using NaCl plates or KBr pellets in. 1H,
13C NMR, and DEPT were obtained using AV-300 (1H, 300.13 MHz
and 13C, 75.5 MHz) and AV-400 (1H, 400.13 MHz and 13C,
4.2.4. Spectroscopical data of ethyl 2-acetylamino-3-(4-
chlorophenyl)-2-cyanopropanoate (3d). Solid. Rf (50% EtOAc/hex-
ane): 0.28. Mp: 151e152 ꢁC. IR (NaCl) v 3250, 1730, 1697, 1512, 1248,
and 1032 cmꢂ1. 1H NMR (300.13 MHz, MeOD)
d (ppm): 1.13 (t, 3H,
J¼7.1 Hz), 2.05 (s, 3H), 3.27 (d, 1H, J¼13.4 Hz), 3.40 (d, 1H,
J¼13.3 Hz), 4.09e4.15 (q, 2H, J¼7.1 Hz), 7.30 (d, 2H, J¼8.7 Hz), and
100.6 MHz) spectrometers. The chemical shifts are given in delta (
d)
7.38 (d, 2H, J¼8.7 Hz). 13C NMR (75.5 MHz, MeOD)
d (ppm): 14.1
values and the coupling constants (J) in Hertz (Hz). High resolution
(CH3), 21.8 (CH3), 41.9 (CH2), 60.2 (C), 64.2 (CH2), 117.8 (C), 129.8
(2CH), 132.3 (C), 133.0 (2CH), 135.5 (C), 167.4 (C), and 173.2 (C).
mass spectra (HRMS) experiments were carried out by ESIþ using

2268
M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
HRMS [ESIþ, m/z] calcd for C14H15N2O3Cl[Naþ] 317.0669, found
317.0666.
temperature for 4 h, and then diluted with CH2Cl2 (30 mL) and
washed with a 10% CuSO4 aqueous solution (3ꢃ30 mL). The re-
action mixture was concentrated under reduced pressure and the
reaction crude products were purified by flash chromatography on
silica gel. The corresponding esters were obtained as follows: 9aeh
(52e80% isolated yield), 10aeh (52e88% isolated yield) and 11aeh
(43e63% isolated yield), see Scheme 1 and Supplementary data for
further details.
4.2.5. Spectroscopical data of ethyl 2-acetylamino-2-cyano-3-(4-
nitrophenyl)propanoate (3e). Solid. Rf (60% EtOAc/hexane): 0.31.
Mp: 141e143 ꢁC. IR (NaCl) v 3244, 3034, 1743, 1656, 1528, and
1211 cmꢂ1 1H NMR (300.13 MHz, Py-d5)
. d (ppm): 1.07 (t, 3H,
J¼7.2 Hz), 2.11 (s, 3H), 3.81 (d, 1H, J¼13.3 Hz), 3.92 (d, 1H,
J¼13.1 Hz), 4.24 (q, 2H, J¼7.2 Hz), 7.70 (d, 2H, J¼8.8 Hz), and 8.23 (d,
2H, J¼8.8 Hz). 13C NMR (75.5 MHz, Py-d5)
d
(ppm): 14.3 (CH3), 22.6
4.4. General procedure for the lipase-catalyzed inter-
esterification of 11aeh
(CH3), 41.7 (CH2), 59.9 (C), 63.9 (CH2), 118.2 (C), 124.4 (2CH), 132.5
(2CH), 141.1 (C), 148.7 (C), 167.3 (C), and 171.6 (C). HRMS [ESIþ, m/z]
calcd for C14H15N3O5[Naþ] 328.0909, found 328.0909.
To a suspension of the corresponding allylated amino ester
11aeh (20 mg, 0.09 mmol) and RML (40 mg) in dry MeCN
4.2.6. Spectroscopical data of ethyl 2-acetylamino-2-cyano-3-(3-
nitrophenyl)propanoate (3f). Solid. Rf (EtOAc/hexane:MeOH
4:5:1): 0.33. Mp: 120e123 ꢁC. IR (NaCl) v 3244, 3043, 1759, 1656,
(0.75 mL), butyl butyrate (75 mL, 0.45 mmol) was added under ni-
trogen atmosphere. The resulting suspension was shaken at 30 ꢁC
and 250 rpm in an orbital shaker, following the time course of the
reactions by HPLC analysis (see further details in the
Supplementary data). After the adequate time, the reaction was
stopped, and the enzyme filtered off and washed with CH2Cl2
(15 mL). The solvent was evaporated under reduced pressure and
the reaction crude purified by flash chromatography on silica gel
(10e70% EtOAc/hexane), yielding (S)-11aeh and (R)-10aeh, and
their enantiomeric excess (see Table 5) were determined by HPLC.
1530, and 1204 cmꢂ1. 1H NMR (300.13 MHz, Py-d5)
d (ppm): 1.04 (t,
3H, J¼7.2 Hz), 2.07 (s, 3H), 3.78e3.93 (m, 2H), 4.18e4.25 (q, 2H,
J¼7.2 Hz), 7.52 (apparent t, 1H, J¼7.9 Hz), 7.90 (d, 1H, J¼7.6 Hz), 8.19
(dd,1H, J¼8.3 and 1.5 Hz), and 8.44 (s, 1H). 13C NMR (75 MHz, Py-d5)
d
(ppm): 14.1 (CH3), 22.3 (CH3), 41.3 (CH2), 59.9 (C), 63.7 (CH2), 117.9
(C),125.9 (CH),130.3 (CH),135.5 (CH),137.4 (CH),148.8 (C),167.1 (C),
and 171.4 (C). HRMS [ESIþ, m/z] calcd for C14H15N3O5[Naþ]
328.0909, found 328.0915.
4.4.1. Spectroscopical data of methyl 2-acetylamino-3-
4.2.7. Spectroscopical data of ethyl 2-acetylamino-2-cyano-3-(2-
nitrophenyl)propanoate (3g). Solid. Rf (60% EtOAc/hexane): 0.31.
Mp: 140e143 ꢁC. IR (NaCl) v 3241, 3045, 1755, 1659, 1529, and
phenylpropanoate (9a). Solid. Rf (50% EtOAc/hexane): 0.15. Mp:
88e90 ꢁC. IR (NaCl): v 3280, 1744, 1656, 1544, and 1217 cmꢂ1 1H
.
NMR (500 MHz, CDCl3)
d
(ppm): 1.93 (s, 3H), 3.03 (dd, 1H, J¼5.9 and
1202 cmꢂ1
.
1H NMR (300.13 MHz, Py-d5)
d
(ppm): 1.05 (t, 3H,
5.8 Hz), 3.10 (dd, 1H, J¼5.9 and 5.8 Hz), 3.68 (s, 3H), 4.84 (ddd, 1H,
J¼6.9, 6.8 and 6.0 Hz), 6.19 (br d, 1H, J¼7.3 Hz), 7.07 (m, 2H), and
J¼7.3 Hz), 2.07 (s, 3H), 4.18e4.23 (m, 3H), 4.42 (d,1H, J¼8.4 Hz), 7.44
(dd, 1H, J¼4.9, 0.9 Hz), 7.57 (apparent t, 1H, J¼3.7 Hz), 7.74 (d, 1H,
J¼4.6 Hz), and 8.07 (d, 1H, J¼4.8 Hz). 13C NMR (75.5 MHz, Py-d5)
7.20e7.27 (m, 3H). 13C NMR (75.5 MHz, CDCl3)
d (ppm): 23.1 (CH3),
37.9 (CH2), 52.4 (CH), 53.3 (CH3), 127.2 (CH), 128.6 (2CH), 129.3
d
(ppm): 14.6 (CH3), 23.0 (CH3), 38.4 (CH2), 60.1 (C), 64.4 (CH2),
(2CH), 136.0 (C), 169.9 (C) and 172.3 (C). HRMS [ESIþ, m/z] calcd for
118.4 (C), 124.7 (CH), 126.7 (CH), 128.9 (CH), 130.8 (CH), 134.4 (C),
C
12H15NO3[Naþ] 244.095, found 244.0989. [
a
]
20 ꢂ83.5 (c 1.0, CHCl3)
D
20
135.2 (C), 167.6 (C), and 171.8 (C). HRMS [ESIþ, m/z] calcd for
for 82% ee of the (R)-enantiomer. Lit [
a
]
D
ꢂ96.3 (c 1.0, CHCl3) for
C
14H15N3O5[Naþ] 328.0909, found 328.1001.
90% ee of the (R)-enantiomer.15 Lit [
ee of the (R)-enantiomer.16
a]
20 ꢂ99.3 (c 1.0, CHCl3) for 94%
D
4.2.8. Spectroscopical data of ethyl 2-acetylamino-2-cyano-3-
(naphthalen-2-yl)propanoate (3h). Solid. Rf (50% EtOAc/hexane):
0.21. Mp: 170e172 ꢁC. IR (NaCl) v 3293, 1752, 1666, 1528, and
4.4.2. Spectroscopical data of butyl 2-acetylamino-3-
phenylpropanoate (10a). Oil. Rf (50% EtOAc/hexane): 0.38. IR
1224 cmꢂ1
.
1H NMR (500 MHz, CDCl3)
d
(ppm): 1.25 (t, 3H,
(NaCl) v 3282, 2960, 1740, 1659, 1549, and 1211 cmꢂ1 1H NMR
.
J¼7.3 Hz), 2.04 (s, 3H), 3.51 (d, 1H, J¼8.2 Hz), 3.77 (d, 1H, J¼8.1 Hz),
4.22e4.33 (q, 2H, J¼7.3 Hz), 6.43 (s, 1H), and 7.27e7.35 (m, 1H), 7.51
(m, 2H), 7.69 (s, 1H), 7.82 (m, 3H). 13C NMR (125 MHz, CDCl3)
(500 MHz, CDCl3)
d
(ppm): 0.90 (t, 3H, J¼14.8 Hz), 1.28e1.35 (m,
2H), 1.54e1.60 (m, 2H), 1.97 (s, 3H), 3.06e3.14 (m, 2H), 4.04e4.13
(m, 2H), 4.85 (m, 1H), 6.02 (br d, 1H, J¼7.0 Hz), 7.09 (m, 2H), and
d
(ppm): 13.9 (CH3), 22.7 (CH3), 41.6 (CH2), 57.5 (C), 64.0 (CH2), 116.3
7.21e7.28 (m, 3H). 13C NMR (125 MHz, CDCl3)
d (ppm): 13.8 (CH3),
(C), 126.6e133.3 (10CAr), 165.9 (C), and 169.7 (C). HRMS [ESIþ, m/z]
19.2 (CH2), 23.3 (CH3), 30.6 (CH2), 38.2 (CH2), 53.4 (CH), 65.6 (CH2),
127.2 (CH), 128.7 (2CH), 129.5 (2CH), 136.1 (C), 169.8 (C), and 172.0
calcd for C18H18N2O3[Naþ] 333.1215, found 333.1214.
(C). HRMS [ESIþ, m/z] calcd for C15H21NO3[Naþ] 286.1419, found
20
4.3. General procedure for the hydrolysis of amino esters
3aeh and subsequent esterification and N-acetylation
reactions
286.1383. [
a]
þ7.5 (c 1.0, CHCl3) for 98% ee (S).
D
4. 4. 3. Spectroscopical data of allyl 2-acetylamino-3-
phenylpropanoate (11a). Oil. Rf (50% EtOAc/hexane): 0.28. IR
(NaCl) v 3283, 1743, 1659, 1539, and 1230 cmꢂ1. 1H NMR (500 MHz,
A suspension of amino ester 3aeh (0.3 M) in an aqueous 20% HCl
solution (20 mL), was refluxed for 30 h, obtaining the amino acid
salts 5aeh as white solids, which were washed with Et2O (30 mL).
Then a solution of 5aeh (0.03 M) in the corresponding alcohol
(methanol, butanol or allyl alcohol, 30 mL) was prepared and
a catalytic amount of a concentrated HCl solution (0.03 mL) was
added. The solution was stirred at reflux for 1 h, and after that time
the solvent was evaporated under reduced pressure, and the crude
product was washed with Et2O (30 mL). The resulting solid without
further purification was subjected to N-acetylation reaction, by
dissolving it in CH2Cl2 (5 mL, 0.25 M), and then acetic anhydride
(2.3 mL, 24.3 mmol), pyridine (1.0 mL, 12 mmol) and DMAP
(30.5 mg, 0.25 mmol) were added. The reaction was stirred at room
CDCl3)
d
(ppm): 2.01 (s, 3H), 3.16 (m, 2H), 4.63 (d, 2H, J¼6.0 Hz),
4.93 (d, 1H, J¼7.5 Hz), 5.31 (m, 2H), 5.88 (m, 1H), 5.97 (br d, 1H,
J¼6.5 Hz), 7.12 (m, 2H), and 7.27e7.32 (m, 3H). 13C NMR (125 MHz,
CDCl3)
d (ppm): 23.3 (CH3), 38.0 (CH2), 53.3 (CH), 66.3 (CH2), 119.3
(CH2), 127.3 (CH), 128.7 (2CH), 129.5 (2CH), 131.5 (CH), 135.9 (C),
169.8 (C), and 171.5 (C). HRMS [ESIþ, m/z] calcd for C14H17NO3[Naþ]
270.1106, found 270.1101. [
a
]
20 ꢂ58.2 (c 1.0, CHCl3) for 90% ee (R).
D
4.4.4. Spectroscopical data of methyl 2-acetylamino-3-(4-
methoxyphenyl)propanoate (9b). Solid. Rf (50% EtOAc/hexane):
0.16. Mp: 106e107 ꢁC. IR (NaCl): v 3280, 1748, 1640, 1511, and
1223 cmꢂ1 1H NMR (300.13 MHz, CDCl3)
. d (ppm): 2.00 (s, 3H),

M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
2269
3.01e3.14 (m, 2H), 3.74 (s, 3H), 3.80 (s, 3H), 4.85 (dd, 1H, J¼7.2 and
5.7 Hz), 5.92 (br d, 1H, J¼7.2 Hz), 6.83 (d, 2H, J¼8.6 Hz) and 7.02 (d,
5.30 (m, 2H), 5.89 (m, 1H), 6.02 (br d, 1H, J¼7.5 Hz), 6.99 (d, 2H,
J¼7.9 Hz), and 7.09 (d, 2H, J¼7.9 Hz). 13C NMR (75 MHz, CDCl3)
2H, J¼8.6 Hz). 13C NMR (75.5 MHz, CDCl3)
d
(ppm): 23.0 (CH3), 37.1
d (ppm): 21.2 (CH3), 23.3 (CH3), 37.6 (CH2), 53.4 (CH), 66.2 (CH2),
(CH2), 52.2 (CH), 53.1 (CH3), 55.2 (CH3), 114.1 (2CH), 127.8 (C), 130.2
119.3 (CH2), 129.4 (2CH), 129.5 (2CH), 131.6 (CH), 132.8 (C), 136.9
(2CH), 158.7 (C), 169.8 (C), and 172.0 (C). HRMS [ESIþ, m/z] calcd for
(C), 170.0 (C), and 171.7 (C). HRMS [ESIþ, m/z] calcd for
20
C
13H17NO4[Naþ] 274.1055, found 274.1052. [
a]
20 ꢂ45.2 (c 1.0, CHCl3)
C
15H19NO3[Naþ] 284.1263, found 284.1220. [
a
]
ꢂ53.9 (c 0.7,
D
D
20
for 44% ee of the (R)-enantiomer. Lit [
a
]
þ82.3 (c 1.0, CHCl3) for
CHCl3) for 91% ee (R).
D
20
84.5% ee of the (S)-enantiomer.15 Lit [
>99% ee of the (S)-enantiomer.17
a]
þ102.5 (c 1.0, CHCl3) for
D
4.4.10. Spectroscopical data of methyl 2-acetylamino-3-(4-
chlorophenyl)propanoate (9d). Oil. Rf (50% EtOAc/hexane): 0.49. IR
4.4.5. Spectroscopical data butyl 2-acetylamino-3-(4-
methoxyphenyl)propanoate (10b). Oil. Rf (50% EtOAc/hexane):
0.23. IR (NaCl): v 3276, 1752, 1648, 1527, and 1221 cmꢂ1. 1H NMR
(NaCl) v 3267, 1748, 1691, 1503, 1201, and 1049 cmꢂ1 1H NMR
.
(300.13 MHz, CDCl3)
d
(ppm): 1.99 (s, 3H), 3.09 (dd, 1H, J¼14.0 and
5.8 Hz), 3.13 (dd, 1H, J¼14.0 and 6.0 Hz), 3.73 (s, 3H), 4.87 (ddd, 1H,
J¼7.4, 6.0 and 5.8 Hz), 6.05 (br d, 1H, J¼7.4 Hz), 7.03 (d, 2H,
J¼8.4 Hz), and 7.26 (d, 2H, J¼8.5 Hz). 13C NMR (75 MHz, CDCl3)
(300.13 MHz, CDCl3)
d
(ppm): 0.92 (t, 3H, J¼7.3 Hz), 1.28e1.40 (m,
2H), 1.55e1.64 (m, 2H), 1.98 (s, 3H), 2.99e3.17 (m, 2H), 3.78 (s, 3H),
3.99e4.12 (m, 2H), 6.0 (br d, 1H, J¼7.4 Hz), 6.82 (d, 2H, J¼8.4 Hz),
d
(ppm): 23.3 (CH3), 37.5 (CH2), 52.6 (CH3), 53.3 (CH), 128.9 (2CH),
7.02 (d, 2H, J¼8.5 Hz). 13C NMR (75.5 MHz, CDCl3)
d
(ppm): 13.8
130.8 (2CH), 133.3 (C), 134.6 (C), 169.9 (C), and 172.1 (C). HRMS
(CH3), 19.2 (CH2), 23.3 (CH3), 30.7 (CH2), 37.3 (CH2), 53.5 (CH), 55.4
(CH3), 65.5 (CH2), 114.1 (2CH), 128.0 (C), 130.4 (2CH), 158.9 (C),
[ESIþ, m/z] calcd for C12H14NO3Cl[Naþ] 278.0560, found 278.0559.
[a
]
20 ꢂ101.9 (c 1.0, CHCl3) for 78% ee (R).
D
169.8 (C), and 172.1 (C). HRMS [ESIþ, m/z] calcd for
20
C
16H23NO4[Naþ] 316.1525, found 316.1523. [
a
]
þ53.7 (c 0.8,
4.4.11. Spectroscopical data of butyl 2-acetylamino-3-(4-
D
CHCl3) for >99% ee (S).
chlorophenyl)propanoate (10d). Oil. Rf (50% EtOAc/hexane): 0.35.
IR (NaCl) v 3259, 1750, 1683, 1512, and 1021 cmꢂ1 1H NMR
.
4.4.6. Spectroscopical data of allyl 2-acetylamino-3-(4-
methoxyphenyl)propanoate (11b). Oil. Rf (50% EtOAc/hexane):
0.18. IR (NaCl): v 3280, 1759, 1642, 1521, and 1232 cmꢂ1. 1H NMR
(300.13 MHz, CDCl3)
d
(ppm): 0.92 (t, 3H, J¼7.1 Hz), 1.26e1.38 (m,
2H), 1.53e1.63 (m, 2H), 1.99 (s, 3H), 3.02e3.15 (m, 2H), 4.03e4.17
(m, 2H), 4.82e4.88 (m, 1H), 6.13 (br d, 1H, J¼7.5 Hz), 7.04 (d, 2H,
J¼7.9 Hz), and 7.25 (d, 2H, J¼8.4 Hz). 13C NMR (75 MHz, CDCl3)
(300.13 MHz, CDCl3)
d
(ppm): 1.98 (s, 3H), 3.07 (dd, 2H, J¼6.8 and
3.5 Hz), 3.78 (s, 3H), 4.61 (d, 2H, J¼5.5 Hz), 4.86 (d, 1H, J¼7.7 Hz),
5.25e5.34 (m, 2H), 5.88 (m, 1H), 5.99 (s, 1H), 6.81 (d, 2H,
J¼8.5 Hz), and 7.01 (d, 2H, J¼8.5 Hz). 13C NMR (75.5 MHz, CDCl3)
d (ppm): 13.8 (CH3), 19.2 (CH2), 23.3 (CH3), 30.6 (CH2), 37.6 (CH2),
53.3 (CH), 65.8 (CH2), 128.9 (2CH), 130.8 (2CH), 133.2 (C), 134.7 (C),
170.0 (C), and 171.9 (C). HRMS [ESIþ, m/z] calcd for C15H20NO3Cl
d
(ppm): 23.3 (CH3), 37.2 (CH2), 53.5 (CH), 55.4 (CH3), 66.2 (CH2),
[Naþ] 320.1029, found 320.0994. [
a]
20 þ77.6 (c 0.5, CHCl3) for >99%
D
114.2 (2CH), 119.3 (CH2), 127.9 (CH), 130.5 (2CH), 131.6 (2CH),
ee (S).
158.9 (C), 169.9 (C), and 171.6 (C). HRMS [ESIþ, m/z] calcd for
20
C
15H19NO4[Naþ] 300.1212, found 320.1210. [
a
]
ꢂ39.1 (c 0.6,
4.4.12. Spectroscopical data of allyl 2-acetylamino-3-(4-
chlorophenyl)propanoate (11d). Solid. Rf (50% EtOAc/hexane):
0.42. Mp: 140e141.2 ꢁC. IR (NaCl) v 1754, 1699, 1523, 1225, and
D
CHCl3) for 90% ee (R).
4.4.7. Spectroscopical data of methyl 2-acetylamino-3-(4-
methylphenyl)propanoate (9c). Solid. Rf (50% EtOAc/hexane): 0.28.
Mp: 123e123.6 ꢁC. IR (NaCl): v 3273, 1747, 1662, 1521, and
1046 cmꢂ1 1H NMR (300.13 MHz, CDCl3)
. d (ppm): 2.00 (s, 3H),
3.04e3.18 (m, 2H), 4.62 (d, 2H, J¼5.9 Hz), 4.89 (m, 1H),
5.26e5.36 (m, 2H), 5.81e5.89 (m, 1H), 6.26 (br d, 1H, J¼7.6 Hz),
7.06 (d, 2H, J¼8.3 Hz), and 7.26 (d, 2H, J¼8.5 Hz). 13C NMR
1207 cmꢂ1. 1H NMR (300.13 MHz, CDCl3)
d (ppm): 1.96 (s, 3H), 2.30
(s, 3H), 2.99e3.13 (m, 2H), 3.71 (s, 3H), 4.81e4.88 (m, 1H), 6.07 (br
d, 1H, J¼7.4 Hz), 6.97 (d, 2H, J¼7.8 Hz), and 7.08 (d, 2H, J¼7.7 Hz).
(75 MHz, CDCl3) d (ppm): 23.0 (CH3), 37.3 (CH2), 53.2 (CH), 66.2
(CH2), 119.3 (CH2), 128.7 (2CH), 130.7 (2CH), 131.3 (CH), 133.0
13C NMR (75 MHz, CDCl3)
d
(ppm): 21.1 (CH3), 23.1 (CH3), 37.4
(C), 134.5 (C), 169.9 (C), and 171.2 (C). HRMS [ESIþ, m/z] calcd for
20
(CH2), 52.3 (CH), 53.2 (CH3), 129.1 (2CH), 129.3 (2CH), 132.7 (C),
C
14H16NO3Cl[Naþ] 304.0716, found 304.0710. [
a
]
ꢂ24.9 (c 0.7,
D
136.7 (C), 169.7 (C), and 172.2 (C). HRMS [ESIþ, m/z] calcd for
CHCl3) for 89% ee (R).
20
C
13H17NO3[Naþ] 258.1106, found 258.1059. [
a
]
ꢂ43.8 (c 1.0,
D
CH2Cl2) for 75% ee (R).
4.4.13. Spectroscopical data of methyl 2-acetylamino-3-(4-
nitrophenyl)propanoate (9e). Solid. Rf (EtOAc): 0.45. Mp:
112e113 ꢁC. IR (NaCl): v 3278, 1743, 1654, 1352, 1219, and
4.4.8. Spectroscopical data of butyl 2-acetylamino-3-(4-
methylphenyl)propanoate (10c). Solid. Rf (50% EtOAc/hexane):
0.37. Mp: 62.7e63.0 ꢁC. IR (NaCl) v 3270, 1756, 1642, 1559, and
736 cmꢂ1. 1H NMR (300.13 MHz, CDCl3)
d (ppm): 2.02 (s, 3H), 3.19
(dd, 1H, J¼13.9 and 5.7 Hz), 3.32 (dd, 1H, J¼13.7 and 6.1 Hz), 3.76
(s, 3H), 4.94 (ddd, 1H, J¼7.4, 7.3, and 5.8 Hz), 6.03 (br d, 1H,
J¼6.8 Hz), 7.30 (d, 2H, J¼8.7 Hz), and 8.17 (d, 2H, J¼8.6 Hz). 13C
1211 cmꢂ1 1H NMR (300.13 MHz, CDCl3)
. d (ppm): 0.94 (t, 3H,
J¼7.3 Hz), 1.27e1.42 (m, 2H), 1.56e1.66 (m, 2H), 2.00 (s, 3H),
3.01e3.13 (m, 2H), 3.79 (s, 3H), 4.09e4.15 (m, 2H), 4.81e4.87 (m,
1H), 5.92 (br d, 1H, J¼7.9 Hz), 6.83 (dd, 2H, J¼6.8 and 2.0 Hz), and
NMR (75.5 MHz, CDCl3)
d (ppm): 25.1 (CH3), 39.9 (CH2), 54.6
(CH3), 54.9 (CH), 125.7 (2CH), 132.2 (2CH), 145.8 (C), 149.2 (C),
7.02 (dd, 2H, J¼6.7 and 2.0 Hz). 13C NMR (75 MHz, CDCl3)
d
(ppm):
171.7 (C), and 173.5 (C). HRMS [ESIþ, m/z] calcd for
20
13.8 (CH3), 19.2 (CH2), 23.3 (CH3), 30.7 (CH2), 37.3 (CH2), 53.5 (CH),
55.4 (CH3), 65.5 (CH2), 114.1 (2CH), 128.0 (C), 130.5 (2CH), 158.9 (C),
169.7 (C), and 172.0 (C). HRMS [ESIþ, m/z] calcd for C16H23NO3[Naþ]
C
12H14N2O5[Naþ] 289.0800, found 289.0801. [
a
]
ꢂ83.6 (c 0.7,
D
CHCl3) for 86% ee (R).
300.1576, found 300.1553. [
a]
20 þ45.4 (c 1.0, CHCl3) for >99% ee (S).
4.4.14. Spectroscopical data of butyl 2-acetylamino-3-(4-
nitrophenyl)propanoate (10e). Solid. Rf (EtOAc/Hexane/MeOH
4:5:1): 0.5. Mp: 102.9e103.4 ꢁC. IR (NaCl) v 3271, 3060, 1759, 1670,
D
4.4.9. Spectroscopical data of allyl 2-acetylamino-3-(4-
methylphenyl)propanoate (11c). Oil. Rf (75% EtOAc/hexane): 0.48.
1536, and 1209 cmꢂ1. 1H NMR (300.13 MHz, CDCl3)
d (ppm): 0.93 (t,
IR (NaCl) v 3259, 1749, 1640, 1211, and 891 cmꢂ1
.
1H NMR
3H, J¼7.2 Hz), 1.27e1.39 (m, 2H), 1.55e1.65 (m, 2H), 2.03 (s, 3H),
3.16e3.33 (m, 2H), 4.06e4.21 (m, 2H), 4.95 (m, 1H), 6.07 (br d, 1H,
J¼7.2 Hz), 7.31 (d, 2H, J¼8.7 Hz), and 8.17 (d, 2H, J¼8.7 Hz). 13C NMR
(300.13 MHz, CDCl3)
d (ppm): 1.99 (s, 3H), 2.31 (s, 3H), 3.09 (m,
2H), 4.61 (d, 2H, J¼5.7 Hz), 4.88 (ddd, 1H, J¼7.5, 6.7, and 5.8 Hz),

2270
M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
(75.5 MHz, CDCl3)
d
(ppm): 15.6 (CH3), 21.0 (CH2), 25.1 (CH3), 32.5
150.3 (C), 170.3 (C), and 172.1 (C). HRMS [ESIþ, m/z] calcd for
C
(CH2), 40.0 (CH2), 54.9 (CH), 67.8 (CH2), 125.6 (2CH), 132.2 (2CH),
12H14N2O5[Naþ] 289.0800, found 289.0767.
145.9 (C), 149.2 (C), 171.7 (C), and 173.2 (C). HRMS [ESIþ, m/z] calcd
20
for C15H20N2O5[Naþ] 331.1270, found 331.1295. [
a
]
þ93.1 (c 1.0,
4.4.20. Spectroscopical data of butyl 2-acetylamino-3-(2-
nitrophenyl)propanoate (10g). Solid. Rf (50% EtOAc/hexane): 0.34.
Mp: 94e96 ꢁC. IR (NaCl) v 3263, 3059, 1752, 1657, 1522, and
D
CHCl3) for 98% ee (S).
4.4.15. Spectroscopical data of allyl 2-acetylamino-3-(4-nitrophenyl)
1203 cmꢂ1 1H NMR (300.13 MHz, CDCl3)
. d (ppm): 0.90 (t, 3H,
propanoate (11e). Solid. Rf (EtOAc/Hexane:MeOH 4:5:1): 0.78. Mp:
J¼7.4 Hz), 1.23e1.34 (m, 2H), 1.51e1.58 (m, 2H), 1.92 (s, 3H), 3.31
(dd, 1H, J¼13.6 and 8.1 Hz), 3.49 (dd, 1H, J¼13.8 and 6.1 Hz),
4.01e4.16 (m, 2H), 4.91 (apparent dt, 1H, J¼8.1 and 6.1 Hz), 6.32 (br
d, 1H, J¼7.6 Hz), 7.41 (m, 2H), 7.55 (dd, 1H, J¼7.7 and 1.3 Hz), and
92e94 ꢁC. IR (NaCl): v 3280, 1761, 1650, 1529, and 1355 cmꢂ1 1H
.
NMR (300.13 MHz, CDCl3)
d
(ppm): 2.01 (s, 3H), 3.19 (dd, 1H, J¼13.7
and 5.7 Hz), 3.31 (dd, 1H, J¼13.8 and 6.3 Hz), 4.62 (d, 2H, J¼5.8 Hz),
4.94 (m, 1H), 5.27e5.35 (m, 2H), 5.80e5.93 (m, 1H), 6.04 (br d, 1H,
J¼7.2 Hz), 7.30 (d, 2H, J¼8.5 Hz), and 8.14 (d, 2H, J¼8.5 Hz). 13C NMR
7.92 (d, 1H, J¼8.4 Hz). 13C NMR (75.5 MHz, CDCl3)
d (ppm): 14.0
(CH3), 19.4 (CH2), 23.3 (CH3), 30.8 (CH2), 35.2 (CH2), 53.4 (CH), 66.1
(CH2), 125.2 (CH), 128.6 (CH), 132.0 (C), 133.1 (CH), 133.4 (CH), 149.8
(C), 170.2 (C), and 171.8 (C). HRMS [ESIþ, m/z] calcd for
(75.5 MHz, CDCl3)
d (ppm): 23.3 (CH3), 38.0 (CH2), 53.1 (CH), 66.6
(CH2), 119.9 (CH2), 123.9 (2CH), 130.4 (2CH), 131.2 (2CH), 144.0 (C),
147.4 (C), 169.9 (C), and 171.0 (C). HRMS [ESIþ, m/z] calcd for
C
15H20N2O5[Naþ] 331.1270, found 331.1269.
20
C
14H16N2O5[Naþ] 315.0957, found 315.0955. [
a
]
ꢂ37.0 (c 0.7,
D
CHCl3) for 90% ee (R).
4.4.21. Spectroscopical data of allyl 2-acetylamino-3-(2-nitrophenyl)
propanoate (11g). Oil. Rf (50% EtOAc/hexane): 0.71. IR (NaCl): v
3250,1749,1660,1556, and 1341 cmꢂ1. 1H NMR (300.13 MHz, CDCl3)
4.4.16. Spectroscopical data of methyl 2-acetylamino-3-(3-
nitrophenyl)propanoate (9f). Oil. Rf (50% EtOAc/hexane): 0.47. IR
d
(ppm): 1.95 (s, 3H), 3.35 (dd, 1H, J¼13.6 and 8.1 Hz), 3.55 (dd, 1H,
(NaCl): v 3280, 1744, 1658, 1530, and 1352 cmꢂ1
.
1H NMR
J¼13.8 and 6.1 Hz), 4.55e4.68 (m, 2H), 4.91 (apparent dt, 1H, J¼8.1
and 6.1 Hz), 5.24e5.32 (m, 2H), 5.79e5.93 (m, 1H), 6.23 (br d, 1H,
J¼7.9 Hz), 7.42 (m, 2H), 7.55 (m, 1H), and 7.92 (dd, 1H, J¼8.4 and
(300.13 MHz, CDCl3)
d
(ppm): 2.00 (s, 3H), 3.17 (dd, 1H, J¼13.7 and
5.8 Hz), 3.31 (dd, 1H, J¼13.9 and 5.7 Hz), 3.76 (s, 3H), 4.92 (m, 1H),
6.23 (br d, 1H, J¼6.8 Hz), 7.48 (d, 2H, J¼5.2 Hz), 7.98 (s, 1H), and 8.11
1.7 Hz). 13C NMR (75.5 MHz, CDCl3)
d (ppm): 22.9 (CH3), 37.2 (CH2),
(m, 1H). 13C NMR (75.5 MHz, CDCl3)
d
(ppm): 25.0 (CH3), 39.6 (CH2),
53.3 (CH), 68.0 (CH2), 116.6 (CH2), 125.2 (CH),128.6 (CH), 129.4 (CH),
132.0 (C), 133.1 (CH), 133.4 (CH), 150.4 (C), 166.3 (C), and 170.1 (C).
HRMS [ESIþ, m/z] calcd for C14H16N2O5[Naþ] 315.0957, found
315.0949.
54.6 (CH3), 55.0 (CH), 124.2 (CH), 126.2 (CH), 131.5 (CH), 137.4 (CH),
140.2 (C), 150.2 (C), 171.9 (C), and 173.6 (C). HRMS [ESIþ, m/z] calcd
20
for C12H14N2O5[Naþ] 289.0800, found 289.0803. [
CH2Cl2) for 60% ee (R).
a]
ꢂ90.6 (c 1.0,
D
4.4.22. Spectroscopical data of methyl 2-acetylamino-3-(naphthalen-
2-yl)propanoate (9h). Solid. Rf (50% EtOAc/hexane): 0.35.
Mp¼93e95 ꢁC. IR (NaCl) v 3277, 3056, 1745, 1655, 1544, and
4.4.17. Spectroscopical data of butyl 2-acetylamino-3-(3-
nitrophenyl)propanoate (10f). Solid. Rf (50% EtOAc/hexane): 0.38.
Mp: 103e105 ꢁC. IR (NaCl) v 3280, 3071, 1740, 1659, 1531, and
1219 cmꢂ1. 1H NMR (300.13 MHz, CDCl3)
d (ppm): 1.95 (s, 3H), 3.22
1211 cmꢂ1
.
1H NMR (300.13 MHz, CDCl3)
d
(ppm): 0.88 (t, 3H,
(dd, 1H, J¼20.2 and 6.3 Hz), 3.30 (dd, 1H, J¼19.9 and 6.0 Hz), 3.71 (s,
3H), 4.97 (apparent dt, 1H, J¼6.9 and 6.0 Hz), 6.37 (br d, 1H,
J¼7.7 Hz), 7.24 (dd, 1H, J¼8.0 and 1.6 Hz), 7.42e7.49 (m, 2H), 7.58 (s,
J¼7.6 Hz), 1.23e1.35 (m, 2H), 1.52e1.61 (m, 2H), 1.96 (s, 3H), 3.13
(dd, 1H, J¼13.9 and 6.1 Hz), 3.26 (dd, 1H, J¼13.7 and 6.0 Hz), 4.09 (t,
2H, J¼6.6 Hz), 4.83e4.89 (m,1H), 6.47 (br d,1H, J¼7.2 Hz), 7.41e7.49
(m, 2H), 7.97 (s, 1H), and 8.06 (d, 1H, J¼7.4 Hz). 13C NMR (75.5 MHz,
1H), and 7.77 (d, 3H, J¼3.4 Hz). 13C NMR (75.5 MHz, CDCl3)
d (ppm):
23.3 (CH3), 38.3 (CH2), 52.7 (CH3), 53.7 (CH), 126.2e133.9 (10CAr),
CDCl3)
d
(ppm): 15.6 (CH3), 21.0 (CH2), 24.9 (CH3), 32.4 (CH2), 39.6
170.4 (C), and 172.6 (C). HRMS [ESIþ, m/z] calcd for C16H17NO3[Naþ]
20
(CH2), 55.1 (CH), 67.7 (CH2), 124.1 (CH), 126.2 (CH), 131.4 (CH), 137.5
294.1106, found 294.1068. [
a
]
D
ꢂ28.2 (c 1.0, CHCl3) for 27% ee of
(CH), 140.4 (C), 150.2 (C), 172.0 (C), and 173.3 (C). HRMS [ESIþ, m/z]
the (R)-enantiomer. Lit [
a]
20 þ91.5 (c 1.0, CHCl3) for 86% ee for the
D
calcd for C15H20N2O5[Naþ] 331.1270, found 331.1267. [
0.9, CHCl3) for 87% ee (S).
a]
20 þ51.9 (c
(S)-enantiomer.15 Lit [
(R)-enantiomer.18
a
]
20 ꢂ104.7 (c 0.99, CHCl3) for>99% ee for the
D
D
4.4.18. Spectroscopical data of allyl 2-acetylamino-3-(3-nitrophenyl)
propanoate (11f). Oil. Rf (60% EtOAc/hexane): 0.34. IR (NaCl): v
3277, 1743, 1659, 1531, and 1352 cmꢂ1. 1H NMR (300.13 MHz, CDCl3)
4.4.23. Spectroscopical data of butyl 2-acetylamino-3-(naphthalen-
2-yl)propanoate (10h). Solid. Rf (50% EtOAc/hexane): 0.43. Mp:
148e150 ꢁC. IR (NaCl) v 3280, 3056, 1739, 1659, 1545, and
d
(ppm): 1.99 (s, 3H), 3.17 (dd, 1H, J¼13.9 and 6.0 Hz), 3.30 (dd, 1H,
1202 cmꢂ1 1H NMR (300.13 MHz, CDCl3)
. d (ppm): 0.86 (t, 3H,
J¼13.9 and 5.9 Hz), 4.62 (m, 2H), 4.92 (m, 1H), 5.25e5.34 (m, 2H),
5.87 (m, 1H), 6.33 (br d, 1H, J¼7.4 Hz), 7.43e7.51 (m, 2H), 7.98 (d, 1H,
J¼7.2 Hz), 1.21e1.31 (m, 2H), 1.50e1.59 (m, 2H), 1.97 (s, 3H),
3.21e3.33 (m, 2H) 4.10 (t, 2H, J¼6.6 Hz), 4.97 (apparent dt, 1H, J¼7.1
and 6.0 Hz), 6.23 (br d, 1H, J¼7.7 Hz), 7.26 (dd, 1H, J¼8.3 and 1.9 Hz),
7.46 (m, 2H), 7.57 (s, 1H), and 7.73e7.86 (m, 3H). 13C NMR
J¼2.0 Hz), and 8.08 (m, 1H). 13C NMR (75.5 MHz, CDCl3)
d (ppm):
23.3 (CH3), 37.9 (CH2), 53.4 (CH), 68.7 (CH2), 120.0 (CH2), 122.5 (CH),
124.6 (CH), 129.7 (CH), 131.3 (CH), 135.9 (CH), 138.5 (C), 148.5 (C),
170.2 (C), and 171.2 (C). HRMS [ESIþ, m/z] calcd for C14H16N2O5[Naþ]
(75.5 MHz, CDCl3)
d (ppm): 13.6 (CH3), 19.0 (CH2), 23.1 (CH3), 30.5
(CH2), 38.2 (CH2), 53.3 (CH), 65.4 (CH2), 125.3e133.6 (10CAr), 169.8
315.0957, found 315.0954. [
a
]
20 ꢂ67.9 (c 0.8, CHCl3) for 81% ee (R).
(C), and 171.9 (C). HRMS [ESIþ, m/z] calcd for C19H23NO3[Naþ]
D
336.1576, found 336.1544. [
a
]
20 þ90.2 (c 0.5, CHCl3) for 92% ee (S).
D
4.4.19. Spectroscopical data of methyl 2-acetylamino-3-(2-
nitrophenyl)propanoate (9g). Oil. Rf (60% EtOAc/hexane): 0.23. IR
4.4.24. Spectroscopical data of allyl 2-acetylamino-3-(naphthalen-2-
(NaCl):
v
3278, 1740, 1659, 1541, and 1339 cmꢂ1
.
1H NMR
yl)propanoate (11h). Oil. Rf (50% EtOAc/hexane): 0.42. IR (NaCl): v
(300.13 MHz, CDCl3)
d
(ppm): 1.94 (s, 3H), 3.33 (dd, 1H, J¼13.9 and
1739, 1699, 1510, and 1374 cmꢂ1 1H NMR (300.13 MHz, CDCl3)
.
8.0 Hz), 3.52 (dd, 1H, J¼13.9 and 6.0 Hz), 3.72 (s, 3H), 4.92 (dt, 1H,
J¼7.9 and 5.8 Hz), 6.32 (br d, 1H, J¼7.7 Hz), 7.39e7.45 (m, 2H), 7.57
d
(ppm): 1.99 (s, 3H), 3.24e3.37 (m, 2H), 4.63 (d, 2H, J¼6.0 Hz), 5.01
(apparent dt, 1H, J¼13.0 and 5.8 Hz), 5.22e5.34 (m, 2H), 5.80e5.93
(m, 1H), 6.09 (br d, 1H, J¼7.5 Hz), 7.26 (dd, 1H, J¼9.0 and 1.6 Hz),
7.48 (m, 2H), 7.58 (s, 1H), and 7.74e7.82 (m, 3H). 13C NMR (75 MHz,
(dt, 1H, J¼7.8 and 1.4 Hz), and 7.92 (dd, 1H, J¼7.9 and 1.4 Hz). 13
C
NMR (75.5 MHz, CDCl3)
d (ppm): 23.3 (CH3), 35.0 (CH2), 53.0 (CH),
53.3 (CH3), 125.3 (CH), 128.6 (CH), 131.9 (C), 133.1 (CH), 133.5 (CH),
CDCl3) d (ppm): 23.3 (CH3), 38.2 (CH2), 53.5 (CH), 66.4 (CH2), 119.5

M.R. da Silva et al. / Tetrahedron 70 (2014) 2264e2271
2271
J. Am. Chem. Soc. 1995, 117, 3808e3819; (d) Paradisi, M. P.; Torrini, I.; Zecchini,
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HRMS [ESIþ, m/z] calcd for C18H19NO3[Naþ] 320.1263, found
320.1260. [
a
]
20 ꢂ74.6 (c 0.5, CHCl3) for 81% ee (R).
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€
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Acknowledgements
The authors thank to the Brazilian and Spanish agencies CAPES-
DGU (Process: 149/07), CNPq, FUNCAP, PRONEX, and Spanish
Ministerio de Ciencia e Innovacion (MICINN, Project CTQ 2011-
24237) for fellowships and financial support. I.L. also thanks
MICINN for personal funding (Ramon y Cajal Program).
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Supplementary data
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data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.02.012.
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