Selective synthesis of unnatural α-, β- and γ-amino esters

Article abstract of DOI:10.1002/ejoc.200700345

Reductive animation of keto esters 1 with α-methylbenzylamine (α-MBA) in the presence of hydrogen and Raney-Ni allows direct access to diastereomeric amino esters 2 in good to high de (72-94 %). For the α-keto ester 1d and the β-keto esters 1a, 1b and 1c

Full text of DOI:10.1002/ejoc.200700345

FULL PAPER
DOI: 10.1002/ejoc.200700345
Selective Synthesis of Unnatural α-, β- and γ-Amino Esters
Thomas C. Nugent*[a] and Abhijit K. Ghosh[a]
Keywords: Asymmetric reductive amination / Amino esters / Heterogeneous hydrogenation
Reductive amination of keto esters 1 with α-methylbenzyl-
amine (α-MBA) in the presence of hydrogen and Raney-Ni
allows direct access to diastereomeric amino esters 2 in good
to high de (72–94%). For the α-keto ester 1d and the β-keto
esters 1a, 1b and 1c the reaction is optimally performed in
the presence of AcOH, while the γ-keto ester 1h requires
Ti(OiPr)4. The reductive amination product of 1d is an ad-
vanced homophenylalanine building block for Angiotensin
Converting Enzyme (ACE) inhibitor drugs. The reductive
amination product of 1h is converted in two additional steps
to a protected chiral 2-methylpyrrolidine 4h, which is an ad-
vanced amine intermediate for pharmaceutical drugs, e.g.
ABT-239. The strategy presented here obviates the need for
preforming enamine or imine intermediates for amino ester
synthesis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
acids. Among them the Arndt–Eistert homologations of α-
amino acids,[3a] the 1,4-addition of homochiral lithium
amides to α-,β-unsaturated esters,[6] and the highly dia-
stereoselective addition of enolates to tert-butylsulfinyl-
imines stand out as very useful.[7] Additionally, access to
amino acids through enzymatic pathways are in use by in-
dustry and actively pursued by academic researchers.[8]
The industrial preoccupation with generating stereocen-
ters by catalytic enantioselective hydrogenation is well justi-
fied based on the afforded atom economy,[9] and this meth-
odology has been extensively examined for the synthesis of
both α-[10] and β-[11]amino acids as championed by Burke,
Zhang, and Boaz. In this regard, very high enantio-
selectivity has been obtained when reducing N-acetyl-pro-
tected dehydro-α- or -β-amino acid derivatives in the pres-
ence of Ru or Rh homogeneous chiral hydrogenation cata-
lysts;[12] but the precursor syntheses are lengthy and the chi-
ral ligands must be optimized on a case-by-case basis. Hsiao
et al. have begun to seriously address the Achilles heel of
lengthy N-acetyl-dehydroamino acid synthesis by showing
that non-acetylated dehydro-β-amino acid derivatives are
excellent substrates for β-amino acid synthesis.[11b] Further
modifications have since come forth.[13]
Chiral auxiliary approaches utilizing inexpensive chiral
amine sources for amino acid synthesis are not common,
only a few examples are reported in the literature and then
mainly for β-amino acid formation. To this end, (R)-α-
MBA has been used in several stepwise processes employing
preformed enamines, that were subsequently reduced with
NaHB(OAc)3 to form acyclic or cyclic β-amino esters in
moderate diastereoselectivity and yield,[14] in another exam-
ple a cyclic β-amino acid was generated in low overall yield
(29%) but high de (99%) after enrichment.[15] The reduction
of (S)-phenylglycine dehydro-β-amino esters or dehydro-β-
Introduction
Natural and unnatural amino acids are indispensable for
pharmaceutical drug development and receptor research,
the latter being exemplified by the unprecedented access to
new protein targets through advances in proteomics re-
search. Novel α- and β-amino acids are particularly useful
for designing peptides with controlled conformation and
thus targeted function, e.g. enhanced enzymatic stability.[1]
Furthermore, the incorporation of unnatural amino acids
into pharmaceutical drug products is well established. For
example (S)-homophenylalanine is a key building block for
no less than 10 unique drugs that are classified as ACE
inhibitors, of which Lisinopril is a multibillion-dollar (per
year) example.[2]
Because of the wide application potential of α- and β-
amino acids, innumerable methodologies for their synthesis,
and the corresponding ester derivatives, have been de-
scribed.[3] Regarding α-amino acids, a noteworthy example
is the reductive amination of α-keto acids using cationic
Rh(deguphos) catalysts in exceptional overall yield and
ee.[4] Another example is the preparation of homophenylal-
anine derivatives starting from acetophenone and diethyl
oxalate.[2b] Unnatural α-amino acids have also been pre-
pared in enantiopure form utilizing palladium-catalyzed
Suzuki cross-coupling reactions.[5] Versatile methodologies
are also available for the asymmetric synthesis of β-amino
[a] Department of Chemistry, School of Engineering and Science,
Jacobs University Bremen (formerly International University
Bremen),
Campus Ring 1, 28759 Bremen, Germany
Fax: +49-421-200-3229
E-mail: t.nugent@jacobs-university.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 3863–3869
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3863

T. C. Nugent, A. K. Ghosh
FULL PAPER
aminoamides with PtO2 has been reported on and proceeds Table 1. Reductive amination of keto ester (1a); Lewis and
Brønsted acid screening.[a]
in very good ee, but in low overall yield from the starting
β-keto esters.[16] Herein, we report on the reductive amin-
Entry Brønsted or Lewis acid Equiv.
de
Product
(GC area%)
(GC area%)
ation of keto esters 1 with (R)- or (S)-α-MBA to generate
amino esters 2 using heterogeneous hydrogenation catalysts
(optimally Raney-Ni) with a Brønsted acid (optimally
AcOH) for α- and β-keto esters, and with a Lewis acid [op-
timally Ti(OiPr)4] for a γ-keto ester.
1
2
3
4
5
6
7
8
BF3·THF
L-mandelic acid
L-tartaric acid
HCl
1.0
2.0
0.2
0.05
0.05
1.25
2.0
1.0
1.0
–
84
78
88
88
88
81
90
90
91
57
26
41
12
49
53
67
74
76
88
16
H2SO4
Ti(OiPr)4
AcOH
AcOH
AcOH
Results and Discussion
9[b]
10
no acid
We have recently demonstrated that unfunctionalized
ketones are optimally reductively aminated in the presence
of Ti(OiPr)4. Depending on the ketone substrate category,
Raney-Ni, Pt-C, or Pd-C hydrogenation catalysts are re-
quired and provide good to excellent yield and diastereo-
selectivity for the amine products.[17] This prompted us to
investigate the reductive amination of keto esters, and we
[a] 1a (2.50 mmol), α-MBA (1.50 equiv.), EtOH (3.0 mL), Raney-
Ni (100 wt.-%), H2 (20 bar), 65 °C, the remainder of the product
profile was mainly the hydroxy ester by-product. Concentrated HCl
(12 ) and H2SO4 (18 ) were diluted in EtOH to the appropriate
molarity. [b] MgSO4 (1.1 equiv.) added (vacuum-dried at 22 °C).
Before settling on Raney-Ni as optimal (yield and de) for
chose to begin our studies with β-keto ester 1a (tert-butyl all keto ester substrates, we probed for a link between the
acetylacetonate). The reaction was performed in EtOH heterogeneous hydrogenation catalyst used and the steric
using a combination of Ti(OiPr)4, Raney-Ni, and α-MBA and/or electronic properties of various substrates. For this
(1.5 equiv.) in the presence of hydrogen (8.3 bar) at 22 °C, purpose, β-keto ester 1a (Scheme 1) and α-keto ester 1d
but these conditions failed to produce the desired product. (Scheme 2) were examined with several heterogeneous hy-
When the hydrogen pressure was increased to 20 bar and drogenation catalysts. In the event, a temperature of 65 °C
the temperature increased to 65 °C, β-amino ester 2a was was required for β-keto ester 1a, while 22 °C was sufficient
observed in 67 area% (GC) and in 81% de after 19 h of for the α-keto ester 1d. Regardless, PtO2 (Table 2, Entry 3
reaction (Scheme 1). This level of diastereoselectivity was and 5) and Pd-C (Entry 6) provided low diastereoselectivity
encouraging but the low GC yield prompted us to screen a (51–62%) regardless of the starting substrate. For β-keto
variety of alternative acids (Table 1). Of the Brønsted acids ester 1a, Pd-C (Table 2, Entry 1) failed to produce the de-
examined, AcOH provided the best reaction profile (dia- sired product, and only the intermediate enamine was
stereoselectivity and yield). Examination of further achiral noted. The effect of double stereo-differentiation was very
and chiral carboxylic acids, e.g. -mandelic acid (Entry 2) briefly examined by investigating the use of Pt/Al2O3 with
and -tartaric acid (Entry 3), in addition to stronger min- adsorbed cinchonidine, but no influence on the diastereo-
eral acids, e.g. HCl (Entry 4), H2SO4 (Entry 5), confirmed selectivity of the product was noted (Table 2, Entry 2). Rh
the superiority (Table 1, Entry 9) of AcOH (1.00 equiv.). and Ru catalysts, supported on carbon, were also examined;
Other researchers have previously shown that acetic acid, under the mild conditions of 22 °C and 8.3 bar of H2,
trifluoroacetic acetic acid, and formic acid can be useful for Ͻ65% de was observed and unreacted starting material was
the synthesis of enamines from β-keto esters.[18]
always noted. Under more forcing conditions (Ͼ20 bar of
We were able to further optimize our initial AcOH result H2, 65 °C) an intolerable amount of what is presumed to
(90% de and 76% GC yield) for 1a (Table 1, Entry 8) by be the benzene ring hydrogenated product was noted. These
adding MgSO4 (1.10 equiv.) (Table 1, Entry 9). The MgSO4 studies confirmed Raney-Ni as the catalyst of choice for
likely only facilitates faster in situ enamine, dehydro-β- good yield and high diastereoselectivity (Table 2, Entries 4
amino ester, formation by sequestration of the eliminated and 7), and was used in 100 wt.-% loading which is not
H2O. A solvent screen (tetrahydrofuran, dichloromethane, uncommon for reductive amination.[19] It should be noted
tert-butyl methyl ether, hexane, toluene) carried out under that the Raney-Ni catalyst loading had no influence on the
these optimal conditions (AcOH/MgSO4, 65 °C, 20 bar hy- diastereoselectivity of the observed products.
drogen) corroborated EtOH as the appropriate choice re-
The scope and versatility of the reductive amination
garding reaction rate (19 h), isolated yield (70%), and de method, from the perspective of yield and diastereoselec-
(91%). Binary solvent mixtures with EtOH proved fruitless. tivity, was then examined by screening various keto esters
Scheme 1. Reductive amination of β-keto ester 1a.
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Selective Synthesis of Unnatural α-, β- and γ-Amino Esters
FULL PAPER
Scheme 2. Reductive amination of ethyl 2-oxo-4-phenylbutanoate (1d).
Table 2. Reductive amination of keto esters 1a and 1d; hetero-
geneous hydrogenation catalyst screening.
Table 3. A comparative reactivity study of α-, β- and γ- keto esters.
Entry Heterogeneous catalyst
Loading
Amino esters
de
(GC area%)
1[a]
2[a]
3[a]
4[a]
5[b]
6[b]
7[b]
Pd/C
Pt/Al2O3 (cinchonidine)
PtO2
0.25 mol-%
1 mol-%
2 mol-%
100 wt.-%
2 mol-%
0.25 mol-%
100 wt.-%
2a
2a
2a
2a
2d
2d
2d
only enamine
60
62
91
51
60
94
Raney-Ni
PtO2
Pd/C
Raney-Ni
[a] 1a (2.50 mmol), α-MBA (1.50 equiv.), AcOH (1.0 equiv.), EtOH
(3.0 mL), indicated hydrogenation catalyst, H2 (20 bar), 65 °C. [b]
1d (2.50 mmol), α-MBA (1.50 equiv.), AcOH (3.0 equiv.), EtOH
(4.0 mL), indicated hydrogenation catalyst, H2 (30 bar), room tem-
perature.
(Table 3). α-Keto ester 1d, (Table 3, Entry 1), was chosen
because reductive amination, followed by hydrogenolysis of
the auxiliary, allows access to homophenylalanine esters,
which are vital building blocks for many ACE inhibitor
drugs.[2] Although 1d provided 2d in high de (94%), a low
isolated yield (55%) was observed, and could be accounted
for by keto amide by-product formation and to a smaller
extent from α-hydroxy ester by-product formation. The for-
mation of these by-products could be controlled to some
extent by using a large excess of AcOH (3.00 equiv.). Re-
placement of AcOH by Ti(OiPr)4 in the aprotic solvents
tetrahydrofuran, dichloromethane, tert-butyl methyl ether,
hexane, or toluene, resulted in appreciable transesterifica-
tion, resulting in the desired product 2d (ethyl ester) and
the corresponding isopropyl ester of 2d.[20] Prior to our in-
vestigation, the α-keto ester ethyl pyruvate (not shown) was
reductively aminated with α-MBA and Pd-C/H2, resulting
in 9% de for the β-amino ester product.[21]
Regarding β-keto esters, as the steric bulk of the ester
moiety was increased a clear trend of higher diastereoselec-
tivity for the β-amino ester product was noted, thus tert-
butyl acetoacetate (1a) provided 91% de, while ethyl aceto-
acetate (1b) 84% de, and methyl acetoacetate (1c) 72% de
(Table 3, Entries 2–4). Regarding the level of induced dia-
stereoselectivity for 1b, Palmieri et al.[14] have previously re-
duced the (R)-α-MBA enamine of 1b with NaHB(OAc)3,
[a] Keto ester (2.50 mmol), α-MBA (1.50 equiv.), AcOH
(3.00 equiv.), EtOH (4.0 mL), Raney-Ni (100 wt.-%), H2 (30 bar),
room temperature. [b] Keto ester (2.50 mmol), α-MBA
(1.50 equiv.), AcOH (1.00 equiv.), EtOH (3.0 mL), Raney-Ni
(100 wt.-%), H2 (20 bar), 65 °C. [c] Keto ester (2.50 mmol), α-MBA
(1.50 equiv.), Ti(OiPr)4 (1.50 equiv.), EtOH (5.0 mL), Raney-Ni
(100 wt.-%), H2 (30 bar), 22 °C. [d] Solvent: MeOH; T = 55 °C. [e]
Diastereoselectivity verified by 1H NMR and GC (area%) of 4h.
[f] GC (area%). [g] This represents the overall yield of 4h from 1h,
see Scheme 3.
achieving 58% de for 2b. We verified this earlier reported clic β-keto ester 1f (Table 3, Entry 6) allowed high dia-
two-step approach,[22] and note that our Raney-Ni re- stereoselectivity (92%) for the cis product but with marginal
ductive amination method does not require preformation of product formation noted (25 area%, GC) after 24 h. Substi-
the enamine and provides superior de for 2b (Table 3, En- tution in the form of a tBu group at the ketone carbonyl
try 3, 84% de). This successful outcome prompted us to ex- moiety (Table 3, Entry 7) generated none of the desired
amine β-keto esters with different substitution patterns. In- product, but did allow enamine formation. These results
vestigation of β-keto ester 1e, with methyl substitution at clearly show that dehydro-β-amino esters with tetrasubsti-
the acidic C-2 atom (Table 3, Entry 5), unexpectedly pro- tuted alkenes are not tolerated by this methodology, nor are
hibited in situ enamine formation from occurring, while cy- sterically demanding substituents (tBu of 1g) on the ketone
Eur. J. Org. Chem. 2007, 3863–3869
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3865

T. C. Nugent, A. K. Ghosh
FULL PAPER
Scheme 3. Conversion of γ-keto ester 1h to the protected 2-methylpyrrolidine 4h.
moiety tolerated. The assignment of stereochemistry has more acidic carboxylic acids, trifluoroacetic acid and ben-
been made by direct comparison with the previously pub- zoic acid, produced the largest quantities of the γ-hydroxy
lished amino ester structures 2.[14,15]
ester by-product (Ͼ20%). The use of substoichiometric
In an attempt to broaden the substrate breadth, we next quantities (5 mol-%) of a strong Brønsted acid (HCl or
chose to examine a γ-keto ester, levulinic ester (1h). The H2SO4) or more equiv. of α-MBA for the reductive amin-
carbonyl group in a γ-keto ester is too remote from the ester ation of 1h did not solve the problems associated with the
moiety to promote tautomerization of the initially formed use of a Brønsted acid. Instead, the mild Lewis acid
imine. Because of this, the carbonyl moiety would be ex- Ti(OiPr)4 optimally facilitates the reductive amination, but
pected to react like a non-functionalized ketone substrate, it unlike α-keto ester 1d, no transesterification was noted.
was therefore not surprising that our previously established
method for ketone reductive amination using Ti(OiPr)4 and
Raney-Ni was optimal.[17] With acetic acid, an undesirable
mixture of the product (2h), the corresponding ring-closed
lactam (3h), and larger quantities of the hydroxy ester were
noted. Ti(OiPr)4 reductive amination of γ-keto ester 1h was
optimally performed in EtOH at a hydrogen pressure of
30 bar (22 °C); these conditions allowed full consumption
of 1h within 18 h with smooth formation of 2h in 74% de.
Interestingly, the optimal conditions for 2-octanone, which
is structurally similar although not further functionalized,
were the following: tetrahydrofuran, Raney-Ni/H2 (8 bar),
and α-MBA (1.1 equiv.) at 22 °C, providing 72% de.[17] In
other polar (dichloromethane or EtOAc) or non-polar (hex-
ane or toluene) aprotic solvents, 2-octanone provided sim-
ilar results, but these aprotic solvents significantly slowed
down the rate of reaction for γ-keto ester 1h.
Conclusions
The reductive amination of α-, β- and γ-keto esters with
the chiral ammonia equivalent (R)- or (S)-α-methylbenzyl-
amine has been demonstrated, allowing the time-consuming
and sometimes tedious task of enamine or ketimine synthe-
sis to be avoided. The presented strategy allows the one-
step synthesis of unnatural methylbenzylamine-protected α-
or -β-amino esters in high de (91–94%) and can thus be
considered as an alternative to using N-acetyl-protected de-
hydro-α- or -β-amino acid derivatives for amino acid syn-
thesis. The latter method requires four reaction steps from
a ketone to produce an amino acid; by comparison, our
methodology would require two steps to arrive at α-, -β, or
γ-amino esters. Although substrate limitations clearly exist
for the presented methodology, the pharmaceutically im-
portant keto esters 1d and 1h, underwent smooth reductive
amination. The method is of future potential use because it
is stepwise efficient and provides a low-cost entry into either
enantiomeric series of α-, β- or γ-amino esters.
The difficulty of separating the product diastereomers of
2h, (S,S)-2h and (R,S)-2h, and the importance of 2-methyl-
pyrrolidine, an advanced intermediate for the synthesis of
histamine H3 receptor antagonist ABT-239 used in the
treatment of Alzheimer disease,[23] encouraged us to further
convert it into the substituted pyrrolidine 4h. The synthesis
(Scheme 3) relies on commercially available starting materi-
als and inexpensive reagents to provide the methylbenzyl
protected pyrrolidine.[24] Thus, crude reaction product 2h
was heated with pivalic acid (1.50 equiv.) to produce the γ-
lactam 3h. In turn, crude product 3h was then reduced with
BH3·THF to obtain 4h in 51% overall yield from 1h in 74%
de (GC area%). Attempts to replace Ti(OiPr)4 with pivalic
acid, acetic acid, trifluoroacetic acid, or benzoic acid for a
one-pot reductive amination/lactamization of 1h to 3h re-
sulted in significantly larger quantities of the hydroxy ester
by-product in addition to the desired lactam 3h under vari-
Experimental Section
General: NMR spectra were recorded with a JEOL ECX 400 spec-
trometer, operating at 400 MHz (1H) and 100 MHz (13C), respec-
tively. Chemical shifts (δ) are reported in parts per million (ppm)
downfield from TMS (δ = 0 ppm) or relative to CHCl3 (δ =
7.26 ppm) for 1H NMR spectroscopy. For 13C NMR, chemical
shifts were reported in the scale relative to CHCl3 (δ =77.0 ppm)
as an internal reference. Multiplicities are abbreviated as: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br., broad. The coup-
ling constants are given in Hertz (Hz). FTIR spectra were obtained
with a Nicolet Avatar 370 spectrometer. Mass spectra were re-
ous conditions of time, temperature, and H2 pressure. The corded with a Finnigan MAT 95 (EI) instrument with an ionization
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Selective Synthesis of Unnatural α-, β- and γ-Amino Esters
FULL PAPER
potential of 70 eV. Elemental analysis was performed at the Analy-
tische Laboratorien, Lindlar, Germany, with an Elementar Vario
EL III instrument. For the amine products 2, reaction progress and
diastereomeric ratio measurements were measured with a Shim-
adzu GC-2010 instrument on an Rtx-5 amine column (Restec,
30 mϫ0.25 mm); Tinj = 300 °C and Tdet = 300 °C were always con-
stant; program A: 50Ǟ160 °C at 20 °C/min then Ǟ280 °C at 20 °C/
(S,S)-2a (Major Isomer): Rf
=
0.42 (hexane/EtOAc/NH4OH,
72:24:4). 1H NMR (CDCl3, 400 MHz): δ = 7.20–7.32 (m, 5 H),
3.88 (q, J = 6.4 Hz, 1 H), 2.94 (sext, J = 6.2 Hz, 1 H), 2.34 (dd, J
= 5.6, J = 14.4 Hz, 1 H), 2.28 (dd, J = 6.4, J = 14.4 Hz, 1 H), 1.51
(br. s, 1 H), 1.45 (s, 9 H), 1.32 (d, J = 6.4 Hz, 3 H), 1.04 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.7, 146.2,
128.4, 126.8, 126.6, 80.3, 55.2, 48.1, 42.1, 28.2, 24.6, 21.4 ppm.
min, 1 min at 280 °C; program B: 50Ǟ215 °C at 20 °C/min then HRMS (70 eV): calcd. for C16H25NO2 [M+] 263.1885; found
263.1889. LRMS (EI): m/z (%) = 263 (2), 248 (68), 206 (42), 192
Ǟ280 °C at 20 °C/min, 1 min at 280 °C; program C: 50Ǟ150 °C at
5 °C/min and then at 150 °C for 40 min. Column chromatography
was performed using silica gel 60 (0.040–0.063 mm). Thin-layer
chromatography (TLC) was performed using precoated plates of
silica gel 60 F254 and visualized under ultraviolet irradiation
(254 nm) or by potassium permanganate staining [2 g of KMnO4,
13.3 g of K2CO3, 3.3 mL of 5% (w/w) NaOH, 200 mL of H2O].
All reagents were obtained from Sigma–Aldrich and used without
further purification unless stated. 99.999% grade Ti(OiPr)4 was
purchased from Sigma–Aldrich (catalog number 377996) and
AcOH was purchased from Fluka (catalog number 45740, Ͼ 99%).
(S)-α-Methylbenzylamine was purchased from Aldrich (catalog
number 115568, 98% pure and 97.5% ee). The Raney nickel (in
water) was purchased from Fluka (catalog number 83440). Pd/C
[Յ 50% water, 5 wt.-% loading (dry basis)] was purchased from
Aldrich (catalog number 276707). PtO2 was purchased from Ald-
rich (catalog number 206032). MgSO4 was purchased from Aldrich
(catalog number 246972) and dried under high vacuum at 22 °C
for 4 h before use. All reactions were performed under argon and
under anhydrous conditions.
(94), 148 (52), 132 (20), 120 (64), 105 (100). IR (KBr): ν = 3320,
˜
1726, 1157 cm–1.
(R,S)-2a (Minor Isomer): Rf = 0.35 (hexane/EtOAc/NH4OH,
72:24:4). 1H NMR (CDCl3, 400 MHz): δ = 7.20–7.32 (m, 5 H),
3.91 (q, J = 6.8 Hz, 1 H), 2.87 (sext, J = 6.4 Hz, 1 H), 2.29 (dd, J
= 7.6, J = 14.8 Hz, 1 H), 2.21 (dd, J = 5.2, J = 14.8 Hz, 1 H), 1.43
(s, 9 H), 1.34 (d, J = 6.4 Hz, 3 H), 1.05 (d, J = 6 Hz, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 171.8, 145.4, 128.4, 126.8, 126.6,
80.4, 54.7, 47.2, 43.5, 28.1, 25.1, 19.8 ppm.
(S)-Ethyl 4-Phenyl-2-{[(S)-1-phenylethyl]amino}butanoate [(S,S)-
2d]: Reaction details: 2.50 mmol scale of ethyl 2-oxo-4-phenylbut-
anoate (516 mg, 0.48 mL, 1.00 equiv.); solvent: EtOH (5.0 mL,
0.5 ); prestirred at room temperature for 1 h; hydrogen pressure
30 bar; AcOH (7.50 mmol, 0.43 mL, 3.00 equiv.); Raney-Ni
(500 mg, 100 wt.-%); room temperature. Reaction time: 20 h; 94%
de. The mixture of diastereomers was isolated as a colorless liquid
using flash chromatography (hexane/EtOAc/NH4OH, 79:20:1),
then converted to the hydrochloride salt (semi-solid) by ethereal
HCl (478 mg, 55% yield). The diastereomers were separated after
further flash chromatography (hexane/EtOAc/NH4OH, 94:5:1) of
the free base. GC (program B): retention time: 23.9 [major (S,S)
isomer]; 25.8 min [minor (R,S) isomer].
General Procedure for the Reductive Amination of α- and β-Keto
Esters: Keto ester (1.00 equiv., 2.50 mmol), AcOH (1.00–
3.00 equiv.,
0.14–0.43 mL),
and
(S)-α-methylbenzylamine
(1.50 equiv., 3.75 mmol, 0.48 mL) in EtOH (3.0–5.0 mL) were com-
bined. This mixture was prestirred for 1 h and then hydrogenated
at 20–30 bar in the presence of Raney-Ni (100 wt.-% based on the
limiting reagent, the keto ester) [prewashed with EtOH (3ϫ)] at
22 °C. The reactions were monitored by GC. At complete conver-
sion, the reaction mixture was treated with a saturated aqueous
solution of Na2CO3 (15 mL) and stirred for 10 min. The solution
was then filtered through Celite and the Celite washed with EtOH
(3ϫ20 mL). The filtrate was concentrated in a rotary evaporator
(TՅ35 °C) to remove most of the EtOH and the remaining aque-
ous solution, then extracted with CH2Cl2 (3ϫ30 mL). The com-
bined extracts were then treated with aqueous saturated NaCl
(20 mL), dried with Na2SO4, filtered, and concentrated (rotary
evaporator, TՅ25 °C). The diastereomeric excess of the crude
product was then assessed by GC using either program A or B.
The yield of the diastereomers was recorded after flash chromatog-
raphy and drying to constant weight under high vacuum of their
hydrochloride salts.
(S,S)-2d (Major Isomer): Rf
= 0.52 (hexane/EtOAc/NH4OH,
76:20:4). 1H NMR (CDCl3, 400 MHz): δ = 7.07–7.34 (m, 10 H),
4.17 (q, J = 7.2 Hz, 2 H), 3.70 (q, J = 6.4 Hz, 1 H), 3.03 (dd, J =
5.2, J = 8 Hz, 1 H), 2.75–2.82 (m, 1 H), 2.50–2.57 (m, 1 H), 1.76–
1.9 (m, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 175.9, 145.1, 141.7, 128.4,
128.3, 127.1, 125.8, 60.6, 58.8, 56.8, 35.8, 32.2, 25.4, 14.4 ppm.
HRMS (70 eV): calcd. for C20H25NO2 [M+] 311.1885; found
311.1886. LRMS (EI): m/z (%) = 311 (4), 238 (100), 134 (44), 105
(79). IR (KBr): ν = 3330, 1730, 1179 cm–1.
˜
(R,S)-2d (Minor Isomer): Rf = 0.47 (hexane/EtOAc/NH4OH,
76:20:4). 1H NMR (CDCl3, 400 MHz): δ = 7.18–7.31 (m, 10 H),
3.98–4.11 (m, 2 H), 3.74 (q, J = 6.6 Hz, 1 H), 3.30 (t, J = 6.6 Hz,
1 H), 2.71 (t, J = 8 Hz, 2 H), 1.83–2.01 (m, 3 H), 1.33 (d, J =
6.4 Hz, 3 H), 1.21 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 171.8, 145.4, 128.4, 126.8, 126.6, 80.4, 54.7, 47.2,
43.6, 28.1, 25.1, 19.8 ppm.
(S)-2-Methyl-1-[(S)-1-phenylethyl]pyrrolidine [(S,S)-4h]: Ethyl 4-
oxopentanoate (1h, 360 mg, 0.35 mL, 2.50 mmol, 1.00 equiv.),
Ti(OiPr)4 (3.75 mmol, 1.10 mL, 1.50 equiv.), and (S)-α-MBA
(3.75 mmol, 0.48 mL, 1.50 equiv.) in EtOH (5.0 mL) were com-
bined. This mixture was prestirred for 30 min and then hydroge-
nated at 30 bar (H2) in the presence of Raney-Ni (360 mg, 100 wt.-
%) [prewashed with EtOH (3ϫ)] at 22 °C. The reaction was moni-
tored by GC. At complete conversion, after 18 h, the reaction mix-
ture was treated with a saturated aqueous solution of Na2CO3
(15 mL) and stirred for 1 h. The solution was then filtered through
Celite and the Celite washed with EtOH (3ϫ20 mL). The filtrate
was concentrated in a rotary evaporator (TՅ35 °C) to remove
most of the EtOH and the remaining aqueous solution then ex-
tracted with CH2Cl2 (3ϫ30 mL). The combined extracts were then
(S)-tert-Butyl 3-{[(S)-1-Phenylethyl]amino}butanoate [(S,S)-2a]: Re-
action details: 2.50 mmol scale of tert-butyl acetylacetonate
(395 mg, 0.41 mL, 1.00 equiv.); AcOH (2.50 mmol, 0.14 mL,
1.00 equiv.); solvent: EtOH (3.0 mL, 0.83 ); MgSO4 (331 mg,
1.10 equiv.); prestirred at room temperature for 1 h; hydrogen pres-
sure 20 bar; Raney-Ni (400 mg, 100 wt.-%); 65 °C. Reaction time:
16 h; 91% de. The mixture of diastereomers was isolated as a color-
less liquid using flash chromatography (hexane/EtOAc/NH4OH,
79:20:1) then converted to a free-flowing white solid by ethereal
HCl (525 mg, 70% yield). The diastereomers were separated after
further flash chromatography (hexane/EtOAc/NH4OH, 94:5:1) of
the free base. GC (program A): retention time: 23.9 [major (S,S)
isomer]; 22.9 min [minor (R,S) isomer].
Eur. J. Org. Chem. 2007, 3863–3869
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3867

T. C. Nugent, A. K. Ghosh
FULL PAPER
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filtered and concentrated (rotary evaporator, TՅ25 °C). To this
crude mixture pivalic acid (383 mg, 1.50 equiv.) was added in EtOH
(5.0 mL) and the mixture stirred at 60 °C. After 6 h, the reaction
mixture was worked up as above, and the crude product 3h was
then treated with BH3·THF (2 mL, 1.0 ) in THF (5.0 mL) at 0 °C
for 15 min and then heated at reflux for 1 h. The refluxing solution
was cooled to room temperature, and aqueous hydrochloric acid
(10 mL, 1.0 ) was added. After removal of the THF, the neutral
organic compounds were removed by washing the aqueous layer
with Et2O (2ϫ20 mL). The aqueous layer was basified with NaOH
(20 mL, 1.0 ) to pH = 10–12. This was then further extracted with
Et2O (3ϫ20 mL), the diethyl ether layer washed with saturated
aqueous NaCl, dried with Na2SO4, and filtered to obtain the crude
diastereomeric mixture which can be isolated as a colorless liquid
using flash chromatography (hexane/EtOAc/NH4OH, 59:40:1).
Ethereal HCl was then added to the pure diastereomers and the
mixture concentrated (rotary evaporator) to obtain a hydrochloride
salt of (S)-2-methyl-1-[(S)-1-phenylethyl]pyrrolidine which is semi-
solid (288 mg, 51% overall yield from the keto ester 1h, 74% de).
The major diastereomer can be separately obtained by further flash
chromatography (hexane/EtOAc/NH4OH, 86:12:6). GC (program
C): retention time: 24.3 [major (S,S) isomer]; 23.7 min [minor (R,S)
isomer].
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(S,S)-4h (Major Isomer): Rf
= 0.40 (hexane/EtOAc/NH4OH,
59:40:1). 1H NMR (CDCl3, 400 MHz): δ = 7.20–7.38 (m, 5 H),
3.67 (q, J = 6.8 Hz, 1 H), 2.95–2.88 (m, 1 H), 2.79–2.74 (m, 1 H),
2.45 (q, J = 8 Hz, 1 H), 1.96–1.85 (m, 1 H), 1.80–1.60 (m, 2 H),
1.45–1.35 (m, 1 H), 1.36 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 128.1, 127.7, 126.7,
60.5, 56.3, 50.0, 32.9, 22.3, 19.4, 18.4 ppm. LRMS (EI): m/z (%) =
[11]
189 (11), 174 (100), 112 (8), 105 (50), 70 (56). IR (KBr): ν = 3083,
˜
3061, 3027, 2963, 2795, 1452, 1209, 1150 cm–1.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra and GC chromatography (de) data
are supplied for compounds 2a, 2d and 4h.
Acknowledgments
The authors are grateful for financial support from Jacobs Univer-
sity Bremen. This work has been performed within the graduate
program of Nanomolecular Science.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3863–3869

Selective Synthesis of Unnatural α-, β- and γ-Amino Esters
FULL PAPER
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Received: April 18, 2007
Published Online: June 18, 2007
Eur. J. Org. Chem. 2007, 3863–3869
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3869