Asymmetric addition of a nitrogen nucleophile to an enoate in the presence of a chiral phase-transfer catalyst: A novel approach toward enantiomerically enriched protected β-amino acids

Article abstract of DOI:10.1002/hc.21004

A proof of concept for the asymmetric organocatalytic aza-Michael addition reaction of nitrogen nucleophiles with simple and readily available alkyl enoates as acceptor molecules in the presence of a chiral phase-transfer catalyst has been demonstrated. T

Full text of DOI:10.1002/hc.21004

Heteroatom Chemistry
Volume 23, Number 2, 2012
Asymmetric Addition of a Nitrogen
Nucleophile to an Enoate in the Presence of a
Chiral Phase-Transfer Catalyst: A Novel
Approach toward Enantiomerically Enriched
Protected β-Amino Acids
Markus Weiß,1 Sonja Borchert,1 Emmanuelle Re´mond,2
Sylvain Juge´,2 and Harald Gro¨ger1,3
1Department of Chemistry and Pharmacy, University of Erlangen–Nu¨ rnberg, Henkestr. 42,
91054 Erlangen, Germany
2Institut de Chimie Mole´culaire de l’Universite´ de Bourgogne, UMR CNRS 5260, 9 avenue Alain
Savary, BP 47870, 21078 Dijon Cedex, France
3Faculty of Chemistry, Bielefeld University, Universita¨tsstr. 25, 33615 Bielefeld, Germany
Received 19 September 2011; revised 21 December 2011
thereof [1,2]. This is in particular due to an increas-
ABSTRACT: A proof of concept for the asymmetric
ing tendency to apply such molecules as key inter-
organocatalytic aza-Michael addition reaction of ni-
mediates in the synthesis of pharmaceuticals. A rep-
trogen nucleophiles with simple and readily available
resentative standard technology for their prepara-
alkyl enoates as acceptor molecules in the presence of a
tion is based on chiral pool derivatization through
chiral phase-transfer catalyst has been demonstrated.
chain elongation of readily available α-amino acids
The desired enantiomerically enriched β-amino acid
[1]. However, this approach requires the use of sto-
derivatives were obtained in up to 86% yield and
ichiometric amount of a chiral substrate (L- or D-
ꢀ
C
with enantioselectivities of up to 37% ee.
2012 Wi-
amino acid). In addition, this route appears attrac-
tive only when the corresponding required α-amino
acids are readily available and economically attrac-
tive. Highly efficient alternatives for the enantios-
elective synthesis of β-amino acids are, for exam-
ple, the use of catalytic methods such as enzymatic
resolution (e.g., of racemic β-amino esters) [1–3],
enzymatic transamination of prochiral β-keto acid
derivatives [4], and chemocatalytic hydrogenation of
suitable prochiral enamines [5]. A key feature of the
latter two approaches is the use of prochiral start-
ing materials with the perspective to obtain (theo-
retically) a quantitative yield of the desired product.
Consequently, there has been an ongoing search for
further (catalytic) alternatives, which are based on
ley Periodicals, Inc. Heteroatom Chem 23:202–209, 2012;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.21004
INTRODUCTION
In recent years, there has been a strong interest
in synthetic methodologies for the asymmetric syn-
thesis of β-amino acids and protected derivatives
Correspondence to: Harald Gro¨ger; e-mail: harald.groeger@uni-
bielefeld.de.
c
ꢀ
2012 Wiley Periodicals, Inc.
202

Asymmetric Addition of a Nitrogen Nucleophile to an Enoate in the Presence of a Chiral Phase-Transfer Catalyst 203
ance of aqueous media as a convenient technical
Phase-
solvent [11]. Interestingly, an intramolecular aza-
Michael addition with an enoate bearing an in-
dol substituent in the presence of a cinchona al-
Base,
Simple
kaloid PTC-type catalyst was recently reported by
the Bandini and Umani-Ronchi group [12]. Thus,
phase-transfer catalysis might also represent a suit-
able tool to realize an intermolecular asymmetric
addition of a prochiral nitrogen nucleophile toward
an α,β-unsaturated enoate (acid or simple alkyl es-
ter thereof). An intermolecular enantioselective aza-
Michael reaction with thiophenyl substituted cyclic
α,β-unsaturated ketones as acceptors proceeding
with cinchona-based PTCs (20–50 mol%) has been
reported as the initial step in a ring closure reac-
tion under formation of 2-(phenylsulfanyl)aziridines
(with 17%–75% ee) [13]. In the following, we re-
port our preliminary results toward an asymmetric
synthesis of protected β-amino acids via the PTC-
catalyzed intermolecular aza-Michael addition with
alkyl enoates.
As a model substrate, ethyl 4,4,4-trifluoro-
crotonate (1) was chosen as well as an N-protected
carbamate 2 as a nitrogen nucleophile. The concept
of this PTC-catalyzed target reaction is shown in
Scheme 2. The carbamate 2 has been chosen because
of its successful use—in combination with tetrabutyl
ammonium bromide as a catalyst—as a nucleophile
in nonenantioselective additions to a wide range of
electron-deficient alkenes [14].
SCHEME 1
Michael addition.
Concept of an asymmetric catalytic aza-
the use of prochiral substrates in asymmetric cat-
alytic syntheses. The aza-Michael addition, which is
conceptually shown in Scheme 1, represents such an
interesting approach because α,β-unsaturated car-
boxylic esters, which are required as Michael accep-
tors, are often readily available.
However, the development of suitable catalysts
for this type of reaction turned out to be chal-
lenging [6–10]. Several elegant and efficient aza-
Michael addition processes have been successfully
established when using acyloxazolidinones [7], α,β-
unsaturated N-acylpyrroles [8], and α,β-unsaturated
pyrazole crotonates [9] as enoate derivatives or
enals [10] as enoate precursors. The synthetic strate-
gies are based on, for example, activation of the
α,β-unsaturated carbonyl component with a tran-
sition metal catalyst (via Lewis acid catalysis)
[6a,b,d,f,7,8], thiourea-type organocatalyst (via H-
bonding) [9], and pyrrolidine-derived organocatalyst
(via iminium catalysis) [6c,e,h,10a–d]. Notably, how-
ever, to the best of our knowledge, the use of simple
enoate (alkyl) esters as attractive substrates in such
intermolecular asymmetric aza-Michael additions
has not been reported so far. We envisioned that
chiral phase-transfer catalysts (PTCs) might serve
as an alternative chemocatalyst for such an inter-
molecular aza-Michael addition with alkyl enoates
as a result of their successful applications in asym-
metric aldol and Michael additions of carbon nu-
cleophiles and alkylation reactions [11]. Advantages
of PTCs are their ready availability and the toler-
In our search for suitable chiral PTCs for the
desired enantioselective aza-Michael addition of ni-
trogen nucleophile 2 to the activated C C dou-
ble bond of the enoate 1 as a model substrate,
we focused on chiral ammonium–based as well as
phosphonium-based PTCs of types 4 and 5, respec-
tively. An overview about the PTC-type catalysts ap-
plied in our study is given in Scheme 3.
The reaction temperature has been set to −20◦C
because of the suppression of the undesired non-
catalyzed aza-Michael addition as a side reaction,
Chiral
Base,
SCHEME 2 Concept of the desired asymmetric aza-Michael addition using a PTC catalyst (PG = protecting group).
Heteroatom Chemistry DOI 10.1002/hc

204 Weiß et al.
Applied chiral ammonium-type PTC catalysts 4
Applied chiral phosphonium-type PTC catalyst 5
SCHEME 3 Overview about chiral PTC catalysts applied in the aza-Michael addition reaction.
which occurs to a minor extent at this temperature
when using toluene as a solvent. This “background
reaction” (in the absence of any PTC-type catalyst,
but in the presence of NaOH as a base component)
was found to give the product 3a with 13% yield after
23 h of stirring at −20◦C (Table 1, entry 1). A further
decrease in the reaction temperature did not appear
to be a valuable option because comparison experi-
ments revealed that under these reaction conditions,
the aqueous phase is present in a liquid form only
when temperatures are not below ca. −20◦C.
alyst (–)-N-dodecyl-N-methylephedrinium bromide,
4a, was used as a PTC-type catalyst. When using
a catalyst amount of 30 mol% of 4a, the desired
product 3a has been obtained in 57% yield, but
enantioselectivity was low with only 9% ee (entry
2). Because cinchona alkaloid-based PTC-type cat-
alysts have been widely used with great success in
asymmetric catalysis [11], we studied the potential
of the alkaloid derivative 4b as a PTC-type catalyst
for the desired aza-Michael addition. Surprisingly,
however, the reaction proceeds in a nonenantiose-
lective fashion, thus furnishing the product 3a as a
racemate in 57% yield (entry 3).
In the initial experiments with chiral PTC-type
catalysts, the cheap and commercially available cat-
Heteroatom Chemistry DOI 10.1002/hc

Asymmetric Addition of a Nitrogen Nucleophile to an Enoate in the Presence of a Chiral Phase-Transfer Catalyst 205
TABLE 1 Aza-Michael Additions with Chiral Ammonium and Phosphonium PTC catalysts
Phase-
Toluene,
Entry
N Donor 2
Catalyst 4
Catalyst Amount (%)
Product 3
PG
Yield (%)
ee (%)
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2b
2b
–
4a
4ba
4c
4d
4c
5
–
3a
3a
3a
3a
3a
3b
3b
Boc
Boc
Boc
Boc
Boc
Cbz
Cbz
13b
57
57
81
84
86
47
–
9
0
22
2
17
0
30
15
30
36
30
30
PG, protecting group; Boc, tert-butyloxycarbonyl; Cbz, benzyloxycarbonyl.
aSubstrate 1 was added slowly by dosage of a solution of 1 with a speed of 50 μL/h within 10 h.
bConversion related to the formation of product 2a; determined via 1H NMR.
The commercially available chiral ammonium
salt 4c represents a PTC-type catalyst, which is
not based on an alkaloid starting material. This
type of catalyst (4c), which has been developed
by the Maruoka group, turned out to be an ex-
cellent PTC-type catalyst for many applications
in asymmetric catalysis [11]. We were pleased to
also find that the aza-Michael addition of nucle-
ophile 2a to Michael acceptor 1 proceeds enan-
tioselectively, leading to the desired β-amino acid
derivative 3a in 81% yield and with 22% ee (entry
4). Notably, using a more simplified ammonium-
type catalyst 4d, which also has been developed
by the Maruoka group and which earlier turned
out to be highly efficient in asymmetric alkyla-
tion [11b], enantioselectivity significantly decreased
to 2% ee, although yield remained high with
84% (entry 5). This indicates that the rigid chi-
ral framework in the organocatalyst 4c is required
for a significant asymmetric induction. Because
of the encouraging result with the organocatalyst
4c and 2a as a nucleophile, an analogous reac-
tion has been carried out with 2b as an alter-
native N-protected carbamate. When applying this
nitrogen nucleophile 2b, the reaction gave prod-
uct 3b with an increased yield of 86%, but with
a somewhat reduced enantioselectivity of 17% ee
(entry 6).
been used as a PTC-type catalyst in the aza-Michael
addition of enoate 1 with N-Cbz-protected carba-
mate, 2b. When applying 5 with a catalyst loading
of 30 mol%, the desired aza-Michael addition pro-
ceeds under formation of product 3b with a satis-
factory yield of 47%. However, the reaction did not
proceed in an enantioselective fashion under these
conditions (Table 1, entry 7).
Because catalyst 4c turned out to be most suit-
able among the tested catalysts in the aza-Michael
addition reaction of 1 with 2 (when using this cata-
lyst in combination with 2a as a nitrogen donor; see
Table 1, entry 4), we further studied the impact of
the base on this transformation. We were pleased
to find an increase in the enantioselectivity of this
asymmetric aza-Michael addition when using KOH
as a base (as a 50% aqueous solution), leading to
the desired β-amino acid derivative 3a in an enan-
tiomeric excess of 37% ee, while maintaining a high
yield of 81% (Scheme 4).
In conclusion, a proof of concept for the asym-
metric aza-Michael addition reaction with a sim-
ple and readily available alkyl enoate as a substrate
in the presence of a chiral PTC, leading to enan-
tiomerically enriched β-amino acid derivates of type
3 has been demonstrated. Asymmetric induction,
however, remained limited so far with enantioselec-
tivities of up to 37% ee. Currently, research work
toward the improvement of particularly the enan-
tioselectivities of this asymmetric process with the
PTC-type catalysts is in progress.
A further alternative in the catalyst screening of
the tetraaryl phosphonium salt 5, which has very re-
cently been synthesized by the Juge´ group [15], has
Heteroatom Chemistry DOI 10.1002/hc

206 Weiß et al.
Phase-transfer catalyst
4c (25 mol%)
−
SCHEME 4 Asymmetric aza-Michael addition with an aqueous KOH solution (50%) as a base component.
EXPERIMENTAL
neutral alumina oxide). Thin-layer chromatogra-
phy (TLC) was performed on silica gel TLC cards
Materials and Methods
R
ꢀ
(Alugramm
SIL G, layer thickness 0.20 mm;
The chemicals purchased from commercial sources
were used without further purification unless other-
wise stated. All solvents were freshly distilled (via ro-
tary evaporation) before usage. 1H NMR (13C NMR)
spectra were recorded at room temperature on a
Bruker Avance 300 or JEOL JNM GX 400 spec-
trometer operating at 300 or 400 MHz. Chemical
shifts (δ) are reported in parts per million relative
to tetramethylsilane (δ 0.00). NMR raw data were
processed with the program MestreC 4.9.9.9. Mass
spectra (matrix-assisted laser desorption/ionization–
time-of-flight) were recorded on a Shimadzu Biotech
Axima Confidence spectrometer. Mass spectra (EI)
were recorded on a Micromass Zabspec spectrom-
eter with electron ionization. Elemental analyses
were carried out by means of an EA 1119 CHNS,
CE instrument, and IR spectra were recorded on
a Thermo Scientific Nicolet IR-100 FT-IR spec-
trometer. The absorption is given in wavelength
ν˜ (cm−1). High-performance liquid chromatogra-
phy (HPLC) spectra were recorded at room tem-
perature on a Jasco HPLC system (PU-1587 In-
telligent Prep. Pump, LC-Net II and ADC device)
or Shimadzu HPLC system (RID-10A refractome-
ter, CDM-10A device, SPD-M10A pump, SIL-10A
device, LC-10AT device). As the chiral stationary
phase, the Daicel column IA or IB was used. Prepara-
tive (flash) column chromatography was performed
on Merck Silica gel 60 (230–400 mesh) as a sta-
tionary phase or neutral aluminum oxide (Baker
Fluka) with a fluorescence indicator or neutral
aluminum oxide (Polyram ALOX N; Carl Roth)
with a fluorescence indicator (lamp wavelength
254nm/366 nm).
Synthesis of Racemic Ethyl 3-[(benzyloxy)-
(tert-butoxycarbonyl)amino]-4,4,4-
trifluorobutanoate, rac-3a (as a Reference
Compound for Analytical Purpose)
In a reaction tube, tetra-n-butyl ammonium chloride
(34.1 mg, 0.15 mmol) was suspended in toluene
(5.0 mL) and stirred for 15 min. Then, tert-butyl
benzyloxycarbamate, 2a (223.2 mg, 1.0 mmol),
an aqueous solution of NaOH (12.5 M, 48.0 μL,
0.6 mmol), and (E)-ethyl 4,4,4-trifluorobut-2-enoate,
1 (75.0 μL, 0.5 mmol) were added successively and
the resulting mixture was stirred at room tempera-
ture for 21 h. The reaction mixture was dried over
MgSO4 and extracted three times with ethyl acetate.
The crude, predried reaction mixture was purified
by column chromatography [d = 1.9 cm, h = 20 cm,
SiO2, petroleum ether/ethyl acetate, 96:4 (v/v), 0.2%
diethylamine, R = 0.30] to yield the desired product
f
as a colorless oil. Yield: 80 mg (41%). Retention
time (chiral HPLC): 5.35 min, 5.64 min, (IB, hex-
ane/isopropanol, 99:1, 0.1% DEA, flow 1.0 mL/min,
258 nm); alternative method: 13.2 min, 14.6 min
(IA, hexane/isopropanol, 99:1, flow 0.5 mL/min, 220
1
nm). H NMR (400 MHz, CDCl3): δ (ppm) = 1.20
Heteroatom Chemistry DOI 10.1002/hc

Asymmetric Addition of a Nitrogen Nucleophile to an Enoate in the Presence of a Chiral Phase-Transfer Catalyst 207
3
Calcd for C21H21F3NO5: C: 59.29, H: 5.21, N: 3.29;
found: C: 59.06, H: 5.37, N: 3.31.
(t, J = 7.1 Hz, 3H, H-C1), 1.51 (s, 9H, H-C9), 2.66
(dd, J = 16.7 Hz,3 J = 4.2 Hz, 1H, H-C4), 2.97 (dd,
2
2 J = 16.7 Hz, 3 J = 10.2 Hz, 1H, H-C4), 4.12 (q, 3 J =
2.6 Hz, 2H, H-C2), 4.86 (m, 2H, H-C10), 5.08 (m,
1H, H-C5), 7.32–7.36 (m, 5H, H-C12-H-C16). 13C
NMR (100 MHz, CDCl3): δ (ppm) = 14.0 (C1), 28.1
(C9), 29.9 (C4), 57.0 (JC F = 30.3 MHz, C5), 61.2 (C2),
78.2 (C10), 83.0 (C8), 123.1 (C6), 125.9 (C14), 128.4,
128.6, 128.7, 129.3 (C12, C13, C15, C16), 134.9 (C11),
156.0 (C7), 169.0 (C3). 19F NMR (282 MHz, CDCl3):
−72.98. MS (EI): m/z = 392 (26%) (M+•), 336 (68%)
(M+•-C(CH3)3), 291 (100%) (M+•-Boc). IR ν˜(cm−1):
2979 (CHarom.), 2942 (CHaliph.), 1718 (C O), 1477
(C C), 1156, 1127 (C C, δ CHaliph.), 742, 695
General Procedure for the Non-PTC-Catalyzed
Synthesis of Ethyl rac-3-[(benzyloxy)-(tert-
butoxycarbonyl)amino]-4,4,4-
trifluorobutanoate, rac-3a (According to
Table 1, Entry 1; “Background Reaction”)
In a reaction tube, N,O-protected hydroxylamine 2a
(corresponding to 2.0 eq.; entry 1: 1.0 mmol), an
aqueous solution of NaOH (12.5 M, corresponding
to 1.2 eq.; entry 1: 0.6 mmol), and α,β-unsaturated
enoate 1 (corresponding to 1.0 eq.; entry 1:
0.5 mmol) were added successively to 5.0 mL
toluene. After stirring, the resulting mixture at −20◦C
MgSO4 was added to the reaction mixture. Four hun-
dred microliters of the reaction mixture were in-
serted into an NMR tube, and 250 μL CDCl3 were
added. Subsequently, the conversion of the reaction
was determined by means of 1H NMR spectroscopy.
(δ-CHarom.).
Elemental
Analysis:
Calcd
for
C18H24F3NO5: C: 55.24, H: 6.18, N: 3.58; found:
C: 55.08, H: 6.36, N: 3.71,
Synthesis of Racemic Ethyl 3-[(benzyloxy)-
(benzyloxycarbonyl)amino]-4,4,4-
trifluorobutanoate, rac-3b (as a Reference
Compound for Analytical Purpose)
In a reaction tube, butyltriphenylphosphonium bro-
mide (30 mg, 0.075 mmol) was suspended in toluene
(2.5 mL) and stirred for 15 min. Then, benzyl benzy-
loxycarbamate, 2b (128.6 mg, 0.5 mmol) (223.2 mg,
1.0 mmol), an aqueous solution of NaOH (12.5 M,
24.0 μL, 0.3 mmol), and (E)-ethyl 4,4,4-trifluorobut-
2-enoate, 1 (37.5 μL, 0.25 mmol) were added succes-
sively and the resulting mixture was stirred at room
temperature for 23 h. The crude reaction mixture
was directly purified by column chromatography
(d = 1.4 cm, h = 20 cm, SiO2, petroleum ether/ethyl
General Procedure for the PTC-Catalyzed
Synthesis of Ethyl 3-[(benzyloxy)-(tert-
butoxycarbonyl)amino]-4,4,4-
trifluorobutanoate, 3a, Using NaOH as a Base
(According to Table 1, Entries 2–5)
In a reaction tube, a chiral PTC 4 (corresponding
to 0.1–0.3 eq.; entry 2: 4a, 113 μmol, entry 3: 4b,
19 μmol, entry 4: 4c, 20 μmol, entry 5: 4d, 24 μmol)
was suspended in toluene (entry 2: 3.75 mL, entry
3: 1.25 mL, entry 4: 0.60 mL, entry 5: 0.67 mL)
and stirred for 15 min. Then, N,O-protected hy-
droxylamine 2a (corresponding to 2.0 eq.; entry 2:
750 μmol, entry 3: 250 μmol, entry 4: 132 μmol, entry
5: 132 μmol), an aqueous solution of NaOH (12.5 M,
corresponding to 1.2 eq.; entry 2: 450 μmol, entry 3:
150 μmol, entry 4: 78 μmol, entry 5: 79 μmol), and
α,β-unsaturated enoate 1 (corresponding to 1.0 eq.;
entry 2: 375 μmol, entry 3: 125 μmol, entry 4:
66 μmol, entry 5: 67 μmol) were added successively.
In the experiment described in Table 1, entry 3, 1
was added slowly as a 0.25 M solution (500 μL) with
a rate of 50 μL/h within 10 h. After stirring the result-
ing mixture at −20◦C for 23 h, the combined organic
layer was dried over MgSO4 and subsequent purifi-
cation by column chromatography (d = 1.3–1.9 cm,
h = 20 cm, SiO2, petroleum ether/ethyl acetate, 96:4
acetate, 96:4 (v/v), 0.2% diethylamine, R = 0.30)
f
to yield the desired product as a colorless oil.
Yield: 64 mg (60%). Retention time (chiral HPLC):
8.70 min, 10.65 min, (IB, hexane/isopropanol, 99:1,
1
0.1% diethylamine, flow 1.0 mL/min, 254 nm). H
NMR (400 MHz, CDCl3): δ (ppm) = 1.16 (t, 3 J =
7.1 Hz, 3H, H-C1), 2.69 (dd, 2 J = 16.8 Hz,3 J =
3.9 Hz, 1H, H-C4), 3.01 (dd, 2 J = 16.8 Hz,3 J =
10.4 Hz, 1H, H-C4), 4.12 (q, 3 J = 7.15 Hz, 2H,
H-C2), 4.86 (m, 2H, H-C15), 5.18 (m, 1H, H-C5),
5.26 (m, 2H, H-C8), 7.30–7.40 (m, 10H, H-C10-H-
C14, H-C17-H-C21). 13C NMR (100 MHz, CDCl3): δ
(ppm) = 14.0 (C1), 29.9 (C4), 57.0 (JCF = 40.4 MHz,
C5), 61.3 (C2), 68.8 (C15), 78.5 (C8), 122.9 (C6),
125.7, 127.2, 128.2, 128.4, 128.6, 128.7, 128.9, 129.3,
(C10 C14, C17 C21), 134.5 (C9), 135.3 (C16), 157.1
(C3), 168.8 (C7). 19F NMR (282 MHz, CDCl3): δ
(ppm) = −73.17. MS (EI): m/z = 181 (50%) (M+•-
BnO, CO2Bn, +Na+). IR ν˜(cm−1): 2921 (CHarom.),
1738 (C O), 1455, 1366 (C C), 1253, 1177 (C C,
δ-CHaliph.), 751, 696 (δ-CHarom.). Elemental Analysis:
(v/v), 0.2% diethylamine, R = 0.30) yielded the prod-
f
uct as a colorless oil. The spectroscopic data are in
accordance with the data of the corresponding race-
mate rac-3a.
Heteroatom Chemistry DOI 10.1002/hc

208 Weiß et al.
within the scholarship program “Nachhaltige Bio-
prozesse” (“Sustainable Bioprocesses”), which is
gratefully acknowledged.
General Procedure for the PTC-Catalyzed
Synthesis of Ethyl 3-[(benzyloxy)-
(benzyloxycarbonyl)amino]-4,4,4-
trifluorobutanoate, 3b, Using NaOH as a Base
(According to Table 1, Entries 6 and 7)
In a reaction tube, a chiral PTC 4 or 5 (corre-
sponding to 0.1–0.3 eq.; entry 6: 4c, 20 μmol, en-
try 7: 5, 37.5 μmol) was suspended in toluene (en-
try 6: 0.6 mL, entry 7: 1.25 mL) and stirred for
15 min. Then, N,O-protected hydroxylamine 2b (cor-
responding to 2.0 eq.; entry 6: 132 μmol, entry 7:
250 μmol), an aqueous solution of NaOH (12.5 M,
corresponding to 1.2 eq.; entry 6: 78 μmol, entry
7: 150 μmol), and α,β-unsaturated enoate 1 (cor-
responding to 1.0 eq.; entry 6: 66 μmol, entry 7:
125 μmol) were added successively, and the resulting
mixture was stirred at −20◦C for 23 h. The combined
organic layer was dried over MgSO4, and subsequent
purification by column chromatography (d = 1.4 cm,
h = 20 cm, SiO2, petroleum ether/ethyl acetate, 96:4
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uct as a colorless oil. The spectroscopic data are in
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General Procedure for the PTC-Catalyzed
Synthesis of Ethyl 3-[(benzyloxy)-(tert-
butoxycarbonyl)amino]-4,4,4-
trifluorobutanoate, 3a, Using KOH as a Base
(According to Scheme 4)
In a reaction tube, a chiral PTC 4c (correspond-
ing to 0.25 eq.; 16 μmol) was suspended in
toluene (0.67 mL) and stirred for 15 min. Then,
N,O-protected hydroxylamine 2a (corresponding to
2.0 eq.; 132 μmol), an aqueous solution of KOH
(50%, corresponding to 1.2 eq.; 0.08 mmol), and
α,β-unsaturated enoate 1 (corresponding to 1.0 eq.;
67 μmol) were added successively. After stirring the
resulting mixture at −20◦C for 23 h, the solvent com-
ponents were removed in vacuo and the resulting
crude product was subsequently purified by column
chromatography (d = 1.4 cm, h = 20 cm, SiO2, cyclo-
hexane/ethyl acetate, 96:4 (v/v), 0.2% diethylamine,
R = 0.14) yielded the product as a colorless oil. The
f
spectroscopic data are in accordance with the data
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ACKNOWLEDGMENTS
This work has been generously supported by a grant
for M.W. from the Deutsche Bundesstiftung Umwelt
Heteroatom Chemistry DOI 10.1002/hc

Asymmetric Addition of a Nitrogen Nucleophile to an Enoate in the Presence of a Chiral Phase-Transfer Catalyst 209
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Heteroatom Chemistry DOI 10.1002/hc