Synthesis of chiral β2-amino acids by asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2012.08.010

The synthesis of chiral β²-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α- aminomethylacrylates used as substrates were prepared by a Baylis-Hillman react

Full text of DOI:10.1016/j.tetasy.2012.08.010

Tetrahedron: Asymmetry 23 (2012) 1301–1319
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of chiral b2-amino acids by asymmetric hydrogenation
Susan Lühr a, Jens Holz a, , Odalys Zayas a, Volkmar Wendisch b, Armin Börner a,c,
⇑
⇑
a Leibniz-Institut für Katalyse an der Universität Rostock e.V., A.-Einstein-Str. 29a, 18059 Rostock, Germany
b ChiroBlock GmbH, Andresenstrasse 1a, 06766 Wolfen, Germany
c Institut für Chemie der Universität Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
The synthesis of chiral b2-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochi-
ral b-aryl- or b-hetaryl- -N-benzyl/N-acetyl/N-Boc substituted -aminomethylacrylates used as sub-
strates were prepared by a Baylis–Hillman reaction, followed by acylation and amination. For the
asymmetric hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing commer-
cially available phosphorus ligands were tested. Conversions and enantioselectivities were dependent
Article history:
Received 26 July 2012
Accepted 17 August 2012
Available online 25 September 2012
a
a
on the reaction conditions and varied strongly between the substrates used. A chiral N-a-phenylethyl
group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect
could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some
cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After
optimization of the hydrogenation conditions (chiral catalyst, H2-pressure, temperature, solvent), full
conversions and products with up to 99% ee were achieved.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
to enzymatic degradation.3 This property can be a decisive advan-
tage in the effect of peptide-based drugs in comparison to their
b-Amino acids are present in several natural products, however
they are much less abundant than their -analogs. In general, b-
natural analogs.
a
Several protocols for the synthesis of b2-amino acids have been
described.2 The rhodium catalyzed asymmetric hydrogenation of
the corresponding unsaturated prochiral precursors assisted by
chiral phosphorus ligands is of particular interest due to its high
efficiency and atom economy, which is especially attractive for
preparation on an industrial scale. However, in contrast to the syn-
amino acids can be classified by the position of the alkyl or aryl
substituent in b2-, b3-, and b2,3-amino acids.
CO2H
NH2
R
CO2H
NH2
R
CO2H
H2N
CO2H
thesis of b3-amino acids by asymmetric hydrogenation, this pro-
4
R
R
R'
cedure has only rarely been applied to the preparation of the title
NH2
5,6
compounds.
This is surprising since thousands of chiral phos-
α-
β2-
amino acids
β3-
β2,3
-
phorus ligands have been tested for other asymmetric hydrogena-
tions.7 Several of them are commercially available and the
elucidation of their potential for the production of chiral b2-amino
acids seems to be a promising task.
One of the first examples with regards to asymmetric hydroge-
nation was published by Jackson et al. in 2001, who reduced pro-
chiral phthalimido nitriles and esters, respectively, with an Rh-
BINAP catalyst to afford chiral b2-amino acid derivatives with
enantioselectivities of up to 84%.8 The same research group also re-
In recent years, the synthesis of enantiopure b-amino acids has
received increasing attention. They have found application in phar-
maceutical research and are important chiral building blocks for
the construction of the corresponding b-polypeptides.1,2 The poly-
mers show an interesting folding mechanism and can be resistant
ported on the Rh-catalyzed hydrogenation of
a-substituted b-
amidoacrylates with Burk’s bisphospholane ligands DuPHOS or
BPE with up to 67% ee.9 In 2006, Zheng et al. achieved up to 99%
ee via the asymmetric hydrogenation of b-phthalimide acrylates
with a Rh catalyst bearing a monodentate sugar based phosphite
ligand.10 The authors emphasized that bidentate ligands were not
effective. Additional substitution on the olefin seriously affected
the stereoselectivity and the rate of the reaction. In general, only
⇑
Corresponding authors.
E-mail addresses: jens.holz@catalysis.de (J. Holz), armin.boerner@catalysis.de
(A. Börner).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.010

1302
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
the E-configured isomers were investigated. Two years later, it was
shown that with a bidentate coordinating ligand (BoPhoz), excel-
lent enantioselectivities could be achieved in CH2Cl2 as the sol-
vent.11 Toluene or isopropanol diminished the yields and ee-
values. These results provide evidence that the catalytic transfor-
mation is very sensitive to the reaction conditions applied and to
the structure of the prochiral substrate. In order to speed up the
time for the identification of the most efficient catalyst, Minnaard
and Feringa suggested the application of high throughput experi-
mentation for the asymmetric hydrogenation of prochiral b-aryl-
CO2R
CO2R
*
Ar
Ar
[Rh(ligand)(COD)]BF4
H2, solvent
NH
Pg
NH
Pg
E or Z
Ar = Ph, 2-thiophenyl, 2-furanyl, 4-acetoxymethyl-2-furanyl
R = H, Me, tBu, (R)-α-phenylethyl
Pg = Bn, Boc, (R)- or (S)-α-phenylethyl
a
-acetamidomethylacrylic acids.12 The best results were noted by
Scheme 1. Stereoselective hydrogenation of b-aryl- or b-hetaryl-a-N-protected a-
aminomethylacrylates.
a combination of chiral monophosphoroamidites with achiral
monophosphines (up to 91% ee). It is noteworthy that the employ-
ment of a corresponding methyl ester as the substrate led only to
very poor conversion and low stereoselectivity. In an alternative
approach Chan and Qiu investigated the asymmetric hydrogena-
Herein we report on the synthesis of the relevant prochiral sub-
strates and on the results of the asymmetric hydrogenation and its
dependency on the nature of the aryl/hetaryl, ester and N-protect-
ing groups as well as on the reaction conditions. In order to take
advantage of the double asymmetric induction in selected cases,
chiral ester or N-protecting groups were also incorporated into
the substrate. In general, all substrates were produced via a Bay-
lis–Hillman reaction followed by acylation and amination. As li-
gands for the asymmetric hydrogenation, the following trivalent
phosphorus ligands were used (Fig. 1).
tion of some b-alkyl and b-aryl substituted
a-aminomethylacry-
lates.13 In order to gain benefit from the basicity of the
secondary NH-group, instead of using the commonly applied N-
acetyl group, N-benzyloxy was chosen as the protective group. Un-
der these conditions, in addition to excellent enantioselectivities,
full conversions were observed at substrate/catalyst ratios up to
10,000/1. Similarly, as found frequently with related b3-dehydroa-
mino acid precursors,14,15 E-configured substrates gave higher
enantioselectivites than their Z-counterparts. The most efficient
chiral ligands were Et-DuPhos and TangPhos. Quite recently, Pig-
nataro, Piarulli and Gennari et al. published their results on the
hydrogenation of methyl 2-(acetamidomethyl)-3-phenylacrylate
using a supramolecular Rh catalyst assembled on the basis of a
PhthalaPhos ligand and obtained enantioselectivities of up to
99%.16
2. Results and discussion
2.1. Synthesis of prochiral substrates
For the generation of the acrylate derivatives, which would be
used as starting materials for the synthesis of the substrates for
the hydrogenation, we used the Baylis–Hillman reaction where
aromatic aldehydes were reacted with acrylic acid esters 1 to give
compounds 2a–f (Scheme 2).17 After acetylation of the hydroxyl
group with acetyl chloride, products 3a–f were treated with ben-
Interestingly, there are no systematic studies on the stereose-
lective hydrogenation of b-aryl- or b-hetaryl-a-N-benzyl substi-
tuted -aminomethylacrylates (Scheme 1). Chiral products would
a
be interesting as chiral building blocks.
R
R
P
Me
o-An
F
F
P
P
P
Ph
P
F
F
Cy2P
Me
R
R
R
R
Me
Me
PPh2
Fe
P
Ph
P
P
o-An
R
R
Me
(S,S)-R-DuPhos
(S,S)-R-BPE
catASium® MQF(R)
(S)-(R)-JosiPhos
(R,R)-DIPAMP
with R = Me, Et, iPr, Ph (R,R)
Et
Me
N
H
Et
PAr
PAr
P
PPh2
Ph2P
Fe
P
H
tBu
P
Fe
P
Me
tBu
Et
Et
(R)-Me-BoPhozTM
(S)-BINAP
with Ar = Ph, 3,5-xylyl
(S,S)-Et-FerroTANE ®
(S,S,R,R)-Tangphos
CH3
O
Ph
Ph
Me
O
O
O
O
P
O
O
Me
Me
Ph
Bn
Bn
P
NMe2
N
P NMe2
N
O
O
Cy2PO
Ph
Ph
CH3
(S,S)-cy2PThrePHOX
L2
L3
L1
Figure 1. Chiral phosphorus ligands used in the asymmetric hydrogenations described herein.

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1303
zylamine13a,18 to yield N-benzylaminomethyl acrylates 4a–f. The
2.2. Asymmetric hydrogenations
corresponding chiral derivatives 5a–e were prepared by reaction
with (R)- or (S)-1-phenylethylamine. As expected the sterically less
hindered E-isomer dominated in the crude mixture of products. In
some cases, the pure E-isomers could be isolated after purification
by column chromatography. With (R)-5a even the corresponding
Z-isomer could be obtained as a pure compound.
2.2.1. N-Benzyl protected substrates
We started the catalytic screening with the asymmetric hydro-
genation of acrylates 4a–f and 5a–e (Scheme 3).
First E-4a was used as the substrate (Table 1). Several commer-
cially available chiral rhodium complexes derived from the ligands
described in Figure 1 were tested at an initial H2-pressure of 6 MPa
at 40 °C over a period of 20 h in methanol as the solvent (entries 1–
8).
Under these conditions, full conversion was observed. It
should be noted that in entries 3, 5 and 7, some side products
were formed in yields of 4–14%. Obviously, migration of the dou-
ble bound in 4a led to the formation of enamide 12 (Scheme 3).22
This olefin might also serve as a substrate for the hydrogenation
to give 10a, however we noted that in general, such acyl amides
cannot be hydrogenated under the conditions applied.23 In addi-
tion the characteristic signals of methyl 2-methyl-3-phenylpro-
panoate 13 were visible in the NMR spectrum; this compound
is probably formed by the elimination of benzylamine from chiral
product 10a and subsequent hydrogenation of the intermediary
acrylate.
For the preparation of the N-Boc protected prochiral com-
pounds 8, the Baylis–Hillman adducts 2 were first treated with
hydrobromic acid in the presence of sulfuric acid to give bromo
compounds 6a,c.9,10 However, under these conditions the synthesis
of 6d was unsuccessful. In this case, the bromination could be suc-
cessfully carried out by using phosphorus tribromide as the re-
agent.19 With compound 2e, the OAc-group at the furan was also
replaced by bromine; therefore this compound could not be de-
rived in this way. Subsequent treatment of 6a,c,d with NaN3 gave
organic azides 7a,c,d in yields of 51–94%.20 In the next step, the
azido group was reduced to an amino group by triphenylphos-
phine. N-Protection with Boc-anhydride could be carried out in
the same step and afforded 8a,c,d in 48–92% yield.21 Finally,
methyl esters 8 were hydrolyzed with an aqueous NaOH solution
to give the corresponding carboxylic acids 9a,c,d in 34–75% yield.18
O
+
R1
H
CO2R2
1
DABCO,
BnNH2
CO2R2
NHBn
R1
dioxane/H2O
AcCl, py,
CH2Cl2
OAc
OH
4a-f
CO2R2
CO2R2
THF
R1
R1
Me
3
CO2R2
NH
2
H2N
Ph
R1
*
for R2 = Me
R1
(R) or (S)
*
R2
HBr/
Me
Ph
H2SO4
or
a
b
c
Ph
Ph
2-Thiophenyl
Me
tBu
Me
Me
5a-e
PBr3
d 2-Furyl
e
f
4-Acetoxymethyl-2-furyl Me
Ph
(R)-α-Phenylethyl
NaN3,
acetone/H2O
CO2Me
NHBoc
1.) PPh3, THF/H2O
2.) Boc2O, CH2Cl2
R1
CO2Me
N3
CO2Me
R1
R1
Br
6a,c,d
8a,c,d
7a,c,d
NaOH,
EtOH
CO2H
R1
NHBoc
9a,c,d
Scheme 2. Synthetic routes to prochiral substrates 4a–f, 5a–e, 8a,c,d, and 9a,c,d, used for the asymmetric hydrogenation.

1304
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
CO2R2
CO2R2
NH
R1
R1
for 10a
chiral Rh-cat.
H2 (1-80 bar)
*
-BnNH2
NH
*
CO2Me
*
R3
Ph
R3
Ph
Ph
R3 = H
R3 = H
4a-f,
5a-e,
10a-f,
11a-e,
3
3
R = Me
R = Me
for 4a
chiral Rh-cat.,
H2 (1-80 bar)
cat., H2
CO2Me
X
CO2Me
Ph
Ph
+
CH3
13
NHBn
12
Scheme 3. Stereoselective hydrogenation of N-benzylated substrates 4a–f and 5a–e.
Table 1
Initial screening of the asymmetric hydrogenation of E-4aa
CO2Me
CO2Me
NH
*
[Rh(Ligand)(COD)]BF4
H2 (6 MPa), 40 °C, 20 h
NH
10a
4a
Entry
Ligand
Solvent
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
(S,S)-Me-BPE
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
CH2Cl2
MeOH
MeOH
iPrOH
>99
>99
>99d
>99
>99d
>99d
>99
>99
20
45 (R)
26 (S)
27 (S)
19 (R)
17 (S)
24 (S)
69 (S)
72 (R)
53 (R)
61 (R)
23 (S)
84 (R)
67 (R)
catASiumÒMQF(R)
(S)-(R)-Josiphos
(R,R)-DIPAMP
(S)-BINAP
(S,S)-Et-FerroTANEÒ
(S,S,R,R)-Tangphos
(S,S)-Me-DuPhos
(S,S)-Me-DuPhos
(S,S)-Me-DuPhos
(S,S)-iPr-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
20
>99
>99
>99
a
b
c
The reactions were performed with 0.33 mmol of substrate at 40 °C under 6 MPa of H2-pressure in 4 mL of MeOH for 20 h, S:C = 100:1.
Conversions were determined by 1H NMR.
ee-values were determined by HPLC analysis.
d
By-products were analyzed by NMR (4–14%; see Section 4).
Amongst all of the precatalysts tested, [Rh((S,S)-Me-DuPhos)
pressure from
(entries 1–7).
8 to 0.1 MPa, the enantioselectivity increases
(COD)]BF4 and [Rh(S,S,R,R)-Tangphos)(COD)]BF4 gave superior ee-
values (entries 7 and 8). The application of aprotic solvents such
as THF and CH2Cl2 only led to poor conversions and lowered the
enantioselectivities (entries 9 and 10). Interestingly, using the
bulkier iPr-DuPhos as the ligand caused a serious decrease in the
enantioselectivity (entry 11). The highest enantioselectivity of
84% was obtained by application of Rh-Et-DuPhos in methanol as
the solvent (entry 12). Replacement of methanol with 2-propanol
diminished the ee-value (entry 13).
At ambient pressure, 93% ee was obtained (entry 7). The use of
an E/Z-mixture of 84/16 or up-scaling of the amount of the sub-
strate to 1 g only led to a slight decrease in the enantioselectivity
(entries 8 and 9). Under the optimized reaction conditions found
for E-4a, the hydrogenation of the corresponding tert-butyl ester
E-4b was carried out. At an initial pressure of 0.1 MPa, the reaction
with the pure E-isomer proceeded with full conversion and affor-
ded the product with 95% ee (entry 10). Obviously the tert-butyl
ester group does not significantly affect the enantioselectivity (en-
try 10 vs 7). As expected at an elevated pressure of 4 MPa with an
E/Z-mixture of 4b (84/16), a significant decrease in the ee-values
In the next set of trials, the effect of the initial H2 pressure was
investigated (Table 2). As substrates two esters were tested. Our
results give clear evidence that with a decrease of the initial H2

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1305
Table 2
Screening of the Rh-catalyzed asymmetric hydrogenation of 4a,b with (S,S)-Et-Duphos as ligand by variation of the initial H2-pressure and the ester groupa
CO2R
NH
CO2R
NH
*
[Rh((S,S)-Et-DuPhos)(COD)]BF4
H2, MeOH, 25 °C
10a,b
4a,b
Entry
R
pH2 (MPa)
t (h)
eeb (%)
1
2
3
4
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
tBu
tBu
tBu
8
6
4
2
20
20
20
20
20
20
6
2
2
5
20
20
80 (R)
83 (R)
84 (R)
87 (R)
88 (R)
90 (R)
93 (R)
90 (R)
88 (R)
95 (—)
26 (—)
52 (—)
1
6
0.5
0.1
0.1
0.1
0.1
4
7
8c
9c,d
10
11e
12e,f
4
a
The reactions were performed with 0.33 mmol of substrate at 25 °C in 4 mL of MeOH. All reactions proceeded with complete conversion.
ee-values were determined by HPLC analysis. Debenzylation of the product from entry 7 yielded a free amino acid ester with a positive sign for the specific rotation, which
b
corresponded to the described (R)-enantiomer in the literature.13b
c
E/Z = 90/10.
Scale-up to 1 g of substrate.
E/Z = 84/16.
Rh-(S,S)-Me-BPE was used.
d
e
f
was observed both with Rh-(S,S)-Et-DuPHOS as well as with Rh-
(S,S)-Me-BPE (entries 11 and 12). In all cases, (ꢀ)-rotating products
were obtained, which should correspond to the (R)-enantiomer as
found for the methyl ester 10a.
With these results in mind, two rhodium catalysts bearing the
bisphospholane ligands (S,S)-Et-DuPhos and (S,S)-Me-BPE were
screened for asymmetric hydrogenation of the 2-thiophenyl-
substituted substrate 4c (Table 3). In strong contrast to the behav-
ior of 4a, in no case was full conversion achieved, even at a pres-
sure of 8 MPa (entry 5). This is probably because the sulfur-atom
in the heteroaromatic cycle affects the reaction by an undesired
interaction between the metal and the substrate.24 As shown, the
enantioselectivity decreased when increasing the H2-pressure.
The best conversion was achieved with the Rh-Me-BPE catalyst,
Table 3
Rh-catalyzed asymmetric hydrogenation of 4c (E/Z = 95/5) with bisphospholane ligandsa
CO2Me
CO2Me
S
S
NH
NH
[Rh(Bisphospholane)(COD)]BF4
H2, MeOH, 25 °C, 20 h
4c
10c
Entry
Ligand
pH2 (MPa)
Conv.b (%)
eec (%)
1
2
3
4
5
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Me-BPE
2
5
8
4
8
65
82
85
89
94
76 (—)
73 (—)
72 (—)
81 (—)
80 (—)
(S,S)-Me-BPE
a
b
c
The reactions were performed with 0.25 mmol of substrate at 25 °C in 4 mL of MeOH for 20 h, S:C = 100:1.
The conversions were determined by 1H NMR.
ee-values were determined by HPLC.

1306
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
Table 4
Rh-catalyzed asymmetric hydrogenation of E-4d with bisphospholane ligandsa
CO2Me
NH
CO2Me
[Rh(Bisphospholane)(COD)]BF4
O
O
NH
H2, 25 °C, solvent, 20 h
4d
10d
Entry
Ligand
Solvent
pH2 (MPa)
t (h)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Me-BPE
(S,S)-Me-BPE
(S,S)-Me-BPE
(S,S)-Me-BPE
(S,S)-Et-BPE
iPrOH
THF
1
1
1
4
8
0.1
1
4
8
20
20
20
20
20
5
20
20
20
20
20
20
20
7
7
40 (—)
76 (—)
62 (—)
65 (—)
66 (—)
90 (—)
82 (—)
69 (—)
69 (—)
82 (—)
81 (—)
7 (—)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
41
0.1
1
1
(S,S)-Et-BPE
(R,R)-iPr-BPE
(R,R)-Ph-BPE
1
13 (—)
a
b
c
The reactions were performed with 0.25 mmol of substrate at 25 °C in 4 mL of MeOH for 20 h, S:C = 100:1.
The conversions were determined by 1H NMR.
ee-values were determined by HPLC.
which induced ca. 80% ee in the product under these conditions
(entries 4 and 5).
was noted (entries 7–9). Interestingly at a pressure of 0.1 MPa,
the reaction was complete within 5 h (entry 6). Moreover, the
highest enantioselectivity of 90% was noted under these condi-
tions. Increasing of the bulk of the alkyl groups (Et, iPr) at the
2,5-position of the phospholane ligand or incorporating phenyl
groups led to inferior results (entries 9–13).
Substrate 4e bears an acetoxymethyl substituent at the 5-posi-
tion of the furan. Obviously, this feature has a negative influence
on the catalytic hydrogenation (Table 5).
With substrate 4d, the same tendencies were noted when
[Rh((S,S)-Et-DuPhos)(COD)]BF4 was used as the precatalyst
(Table 4). A poor reaction rate was observed in iPrOH and THF
(entries 1 and 2). In general, a superior catalytic performance
was observed in methanol as the solvent (entries 3–13). At a pres-
sure range of 1–8 MPa, only a marginal effect on the ee-values was
observed (entries 3–5). With Rh-(S,S)-Me-BPE, the same tendency
Table 5
Rh-catalyzed asymmetric hydrogenation of E-4e by variation of the solvent, H2-initial pressure, and bisphospholane liganda
CO2Me
CO2Me
NH
O
O
[Rh(Bisphospholane)(COD)]BF4
H2, 25 °C, solvent, 20 h
NH
AcO
AcO
4e
10e
Entry
Bisphospholane
Solvent
pH2 (MPa)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(S,S)-Me-BPE
MeOH
MeOH
MeOH
MeOH
iPrOH
THF
THF
MeOH
MeOH
0.1
1
4
5
1
1
6
0.1
4
0
>99
>99
>99
<5
<5
<5
0
>99
—
66
65
56
39
70
63
—
(S,S)-Me-BPE
65
a
b
c
The reactions were performed with 0.25 mmol of substrate at 25 °C in 4 mL of MeOH for 20 h, S:C = 100:1.
The conversions were determined by 1H NMR.
ee-values were determined by HPLC. No mapping of the sign of the specific rotation was possible.

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1307
Table 6
Diastereoselective hydrogenation of the chiral ester (R)-4fa
O
CH3
O
CH3
Ph
*
O
Ph
O
[Rh(Ligand)(COD)]BF4
H2, 25 °C, solvent
NH
NH
(R)-4f
10f
(R)-
Entry
Ligand
Solvent
PH2 (MPa)
t (h)
Conv.b (%)
deb (%)
1c
2d
3c
4c
5
6
7
8
DPPB
DPPB
MeOH
THF
MeOH
MeOH
THF
CH2Cl2
acetone
AcOEt
5
5
5
5
4
4
4
4
15
10
15
15
20
20
20
20
78
46
81
84
8
10
20
6
14
16
64
73
n.d.
n.d.
n.d.
n.d.
(R,R)-Me-BPE
(S,S)-Me-BPE
S,S)-Et-DuPhos
(S,S)-Et-DuPhos
S,S)-Et-DuPhos
((S,S)-Et-DuPhos
a
b
c
The reactions were performed with 0.25 mmol of substrate (E-isomer) at 25 °C in 4 mL of solvent.
Conversions and de-values were determined by 1H NMR and HPLC.
Transesterification occurred.
S/C = 50/1.
d
Thus at an initial pressure of 0.1 MPa, no reaction took place
In methanol at an initial pressure of 5 MPa (entry 1) the olefin
was not reduced at the same reaction rate as non-chiral esters
4a,b. After 15 h only 78% of conversion was observed. Moreover,
the reaction was accompanied by partial transesterification that
afforded the chiral methyl ester 10a. In THF, the reaction was addi-
tionally decelerated although a higher concentration of the precat-
alyst was used (entry 2). Under both conditions, the chiral product
was obtained with 14% and 16% ee, respectively. This indicates that
the stereoface-discriminating effect of the chiral ester group in the
substrate is only marginal. A similar tendency was found when chi-
ral catalysts were employed. Thus, when under identic conditions,
but using chiral ligands with the opposite configuration, only small
differences in the diastereoselectivities were observed (entries 3
and 4). The HPLC analysis clearly showed that the product formed
had the opposite configuration at the newly formed stereogenic
center. These results are in agreement with the observation de-
(entry 1), which is in strong contrast to the hydrogenation of the
non-substituted furan substrate 4d. Only by increasing the pres-
sure were full conversions achieved. In general, moderate
enantioselectivities were obtained (entries 2–4). For this transfor-
mation, methanol was the solvent of choice. Changing to either
iPrOH or THF led to poor conversions (entries 5–7). Similar
behavior was observed when applying the conformationally more
flexible ligand (S,S)-Me-BPE (entries 8 and 9).
The incorporation of chiral groups into the substrate may con-
tribute to the improvement of the stereoselectivity by taking ben-
efit from the double asymmetric induction caused by the chiral
substrate and the chiral catalyst.25 In order to confirm this
assumed correlation, the chiral ester 4f was treated with a Rh cat-
alyst bearing the achiral ligand DPPB (1,4-bis(diphenylphos-
phino)butane) (Table 6).
Rh(L)(COD)]BF4
Rh(L)(COD)]BF4
H2
H2
CO2Me
CO2Me
S
(R(S),R) (S(R),R)
(S(R),S) (R(S),S)
S
NH
Ph
NH
Ph
Me
Me
(S)-5c
5c
(R)-
Rh(L)(COD)]BF4
Rh(L)(COD)]BF4
H2
H2
Figure 2. HPLC-spectra for the analysis of hydrogenation products of 5c using ligands L [above: achiral L = DPPB; bottom: chiral L = (S,S)-Me-BPE].

1308
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
Table 7
Diastereoselective hydrogenation of chiral amides (R)- or (S)-10a–ea
CO2R
*
CO2R
Ar
Ar
[Rh(Ligand)(COD)]BF4
H2 (4 MPa), MeOH, 20 h
NH
*
NH
*
H3C
H3C
(R)- or (S)-5a-e
17a-e
d
Entry
Substrate (E/Z)
Conf.
DPPBb de (conv.)d
(S,S)-Et-DuPhos de (conv.)d
D
dec
(S,S)-Me-BPE de (conv.)
D
dec
1
2
3
4
5
6
7
8
9
5a (87/13)
5a (87/13)
5b (100/0)
5b (100/0)
5c (84/16)
5c (84/16)
5d (100/0)
5d (100/0)
5e (100/0)
5e (100/0)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
55 (100)
58 (100)
44 (95)
43 (95)
50 (100)
50 (100)
30 (100)
30 (100)
6 (92)
56 (82)e
86 (93)e
24 (59)
41 (72)
63 (24)
83 (52)
60 (50)
86 (42)
59 (39)
79 (26)
7 (100)e
56 (100)e
16 (54)
57 (51)
72 (81)
89 (86)
60 (100)
69 (51)
65 (56)
55 (24)
+30
+17
+20
+26
+20
+49
+31
+27
+9
10
6 (93)
ꢀ10
a
b
c
The reactions were performed with 0.25 mmol of substrate (S/C = 100/1) at 25 °C, 4 MPa of H2-pressure, 4 mL of MeOH, 20 h.
S/C = 50/1; 5 MPa, 15 h, in methanol.
Corresponds to the difference de(S)ꢀde(R)
.
d
e
de-values and conversions were determined by NMR and HPLC.
The new stereogenic center has an (R)-configuration.
scribed above (Table 2); that the replacement of the methyl with a
tert-butyl ester group does not affect the hydrogenation. Variation
of the solvent (THF, CH2Cl2, acetone, and ethyl acetate) lowered the
conversion and therefore diastereoselectivities could not be deter-
mined accurately (entries 5–8).
In an analogous manner, we conducted asymmetric hydrogena-
tions with the chiral substrates 5a–e where the chiral auxiliary was
linked to the nitrogen atom. For the substrates, E/Z-mixtures or
pure isomers were used (Fig. 2 and Table 7).
The hydrogenation of the enantiomers of 5b, which are avail-
able as pure E-configured compounds, was first investigated using
the achiral Rh-complex with DPPB as the ligand (Table 7, entries 3
and 4). At 5 MPa initial pressure, the reaction proceeded in a quan-
titative manner. As illustrated in Figure 1 and as expected, the
same degree of diastereoselectivity was obtained. The observed
high value of more than 40% de indicates the large steering effect
of the chiral auxiliary. Obviously, a chiral amide group should have
a much more pronounced effect on the stereoface recognition than
a chiral ester group. The hydrogenation of the other pure chiral
substrates 5d (entries 7 and 8) and 5e (entries 9 and 10) as well
as that of E/Z-mixtures of 5a (entries 1 and 2) and 5c (entries 5
and 6) followed the same tendency.
In the next step for the hydrogenation of pure isomers (R)-5b
and (S)-5b, chiral Rh-complexes with (S,S)-Et-DuPhos or (S,S)-Me-
BPE as ligands were used (entries 3 and 4). From the results a clear
matched and unmatched pairing effect, respectively, between the
chirality of catalyst and the chiral substrate can be deduced. Thus,
the diastereoselectivity achieved with (S,S)-Me-BPE takes benefit
from the (S)-configured auxiliary in the substrate: ‘matched pair’
(Fig. 1, Table 7, entry 3). In contrast, the (R)-configuration in the
ences of de-values. Thus, with (S,S)-Et-DuPhos and the enantio-
meric substrates of 5a, the effect is less pronounced in
comparison to the use of (S,S)-Me-BPE as the ligand (entries 1
and 2). With the latter, an improvement in the de-value of 49%
could be realized. The other chiral substrates 5b–e displayed the
same tendencies (entries 3–10). With the exception of the sub-
strate-ligand pair (R)-5e and (S,S)-Me-BPE (entry 10), in all other
cases, the (S)-substrates induced higher selectivities than their
(R)-counterparts. This indicates that the (S)-configured amine aux-
iliary matches better the (S,S)-configuration of the chiral bisphos-
pholane ligands in the rhodium catalysts.
Since we saw for 4a a dependency of the ee-value on the initial
H2-pressure was found (see Table 2), we also reduced 5a under dif-
ferent pressures (Table 8, entries 1–3).
The hydrogenation of the isomeric mixture (E/Z = 87/13) at
0.5 MPa led to an improvement in the diastereoselectivity to 87%
de (52% de at 4 MPa, entry 1 in Table 7). When the isomerically
pure E-isomer of (R)-5a was used, an enhancement of the stereose-
lectivity (matched pair) to 98% de was obtained (entry 3). When
(S,S)-Et-DuPhos was used, only a slight change in the de value
was obtained (entry 2) showing that at very low H2-pressure, the
unmatching effect described above between the substrate and
the ligand is suspended (entry 2). In order to compare the differ-
ences in reactivity and selectivity between E- and Z-isomer we car-
ried out the hydrogenation of pure Z-(R)-5a under the same
reaction conditions optimized for E-(R)-4a (entry 4). Following this
protocol, the reaction rate and enantioselectivity greatly de-
creased; after 24 h we observed only 24% yield and the product
was formed in 42% de.
For the determination of the absolute chirality at the newly
formed stereogenic center, 11a (from entry 3 in Table 8) was re-
duced with a heterogeneous Pd-catalyst to remove the chiral N-1-
phenylethyl group (Scheme 4). The formed amino acid ester 14a
displayed a negative sign for the specific rotation. Taking the posi-
N-a-ethylphenyl moiety lowered the diastereoselectivity: ‘un-
matched pair’ (entry 4).
The degree of diastereoselective discrimination is dependent on
the ligand and the substrate as indicated in Table 7 by the differ-

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1309
COOMe
COOMe
COOMe
Pd(OH)2/C
H2
HCl/MeOH
for (S) -14a
NH
Ph
NH2 * HCl
NH2
R
11a
(S,R)-
(R = Me)
(S)-14a
(R)-14a
(S)-15a
(R,R)-11a (R = Me)
(R)-10a (R = H)
Scheme 4. Cleavage of the N-benzyl group of 10a and 11a and formation of a hydrochloride salt.
tive value published for the (R)-enantiomer into consideration, it
can be concluded that we have (S)-14a in hand.13b This means that
in entry 3 of Table 8 the predominantly formed diastereomer of 11a
has an (S,R)-configuration. Recrystallization of the corresponding
hydrochloride (S)-15a gave the ester of the chiral b2-amino acid
with almost perfect enantioselectivity (>99% ee). Debenzylation of
product 11a obtained from the hydrogenation of (R)-5a with Rh-
(S,S)-Et-DuPhos (from entry 2 in Table 8) and the N-benzyl
derivative 10a (from entry 7 in Table 2) gave a product with an
(R)-configuration of the newly formed stereogenic center.
Table 8
Diastereoselective hydrogenation of the chiral amide (R)-5a varying the H2-pressurea
CO2Me
*
CO2Me
NH
[Rh(Et-DuPhos)(COD)]BF4
H2, 25 °C, MeOH
NH
H3C
H3C
11a
(R)-5a
Entry
Ligand
E/Z
pH2 (MPa)
t (h)
Conv.b (%)
dec (%)
1
2
3
4
(S,S)-Et-DuPhos
(S,S)-Et-DuPhos
(R,R)-Et-DuPhos
(R,R)-Et-DuPhos
87/13
E-
E-
0.5
0.1
0.1
0.1
20
2.5
2
>99
>99
>99
24
87 (R,R)
96 (R,R)
98 (S,R)
42 (S,R)
Z-
24
a
b
c
The reactions were performed with 0.25 mmol of substrate at 25 °C in 4 mL of MeOH, S:C = 100:1.
The conversions were determined by 1H NMR.
de-values were determined by 1H NMR and HPLC.
Table 9
Initial screening of the asymmetric hydrogenation of E-8aa
CO2Me
NHBoc
CO2Me
NHBoc
precatalyst
*
H2 (4 MPa), MeOH, 20 h
16a
E-8a
Precatalyst
Entry
Conv.b (%)
eec (%)
1
2
3
[Rh((S,S)-Et-DuPhos)(COD)]BF4
[Rh(catASiumÒMQF(R))(COD)]BF4
[Rh((S)-(R)-Josiphos)(COD)]BF4
[Rh((S)-3,5-xylyl-BINAP)(COD)]BF4
[Rh((R)-Me-Bophoz)(COD)]BF4
[Rh(S,S,R,R)-Tangphos)(COD)]BF4
Rh((S,S)-Me-BPE)(COD)]BF4
0
0
10
45
100
0
45
83
0
—
—
0
5(S)
0
4d
5d
6
—
7d
8d,e
9
8(S)
33(R)
—
[Rh((R,R)-DIPAMP)(COD)]BF4
[Ru((R)-BINAP)Cl2]
10d
[Ir((S,S)-cy2PThrePHOX)(COD)]BArF
13
8(S)
4
a
b
c
The reactions were performed with 0.25 mmol of substrate at 25 °C, 4 MPa of H2-pressure, 4 mL of MeOH, 20 h, S:C = 100:1.
The conversions were determined by 1H NMR.
ee-values were determined by HPLC.
Side products were observed by NMR.
Reaction was performed at 5 MPa bar of H2-pressure.
d
e

1310
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
2.2.2. N-Boc protected derivatives
amounts of side products was observed by NMR spectroscopy (en-
tries 4, 5, 7, 8 and 10). Obviously, isomerization of the double bond
To the best of our knowledge, N-Boc protected aminomethylac-
rylates have never been used as substrates for asymmetric hydro-
genations with the aim of obtaining chiral b2-amino acids. The N-
Boc group is considered to be a very versatile protective group,
especially valuable for subsequent peptide synthesis. Interestingly,
in strong contrast to the use of N-benzyl derivatives 4 and 5 in the
application of the Rh-Et-DuPhos catalyst on the hydrogenation of
the N-Boc derivative 8a, even after 20 h no hydrogen consumption
was observed under 4 MPa of H2-pressure (Table 9, entry 1). For
this reason we have also included other chiral Rh-complexes; a
Ru- and an Ir-catalyst (Table 9, entries 2–11). However, only a
few catalysts showed some hydrogenation activity. The best con-
version was achieved with Rh-Me-BoPhoz but no enantioselectivi-
ty was induced (entry 5). In addition, the formation of significant
takes place and a mixture of E/Z-methyl
a-benzyl-3-(tert-butoxy-
carbonylamino)acrylate is formed, which is quite inert under these
conditions (vide supra).
Due to its superior performance, we chose Rh-DIPAMP as the
catalyst to test the hydrogenation in various solvents (Table 10, en-
tries 1–6). The best results were obtained in iPrOH at an initial H2-
pressure of 5 MPa, where the desired b2-amino acid derivative 16a
was exclusively formed without the formation of any side products
and 50% ee. A further increase of the pressure to 8 MPa led to an
enhancement of the enantioselectivity to 70% (entry 8). Beyond
this pressure the enantioselectivity slightly decreased (entry 9).
Increasing the temperature did not improve this result (entries 4
and 8 vs 10 and 11).
Table 10
Rh(DIPAMP)-catalyzed asymmetric hydrogenation of the N-Boc-protected substrate E-8aa
CO2Me
CO2Me
*
[Rh((R,R)-DIPAMP)(COD)]BF4
H2, 20 h
NHBoc
NHBoc
16a
8a
Entry
Solvent
pH2 (MPa)
T (°C)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
MeOH
CH2Cl2
THF
5
5
5
5
5
5
1
8
10
5
25
25
25
25
25
25
25
25
25
40
40
83d
24
33 (R)
70 (R)
63 (R)
50 (R)
n.d.
44 (R)
42 (R)
70 (R)
63 (R)
27 (R)
55 (R)
55d
100
5
iPrOH
Toluene
CF3CH2OH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
27
71
100
100
100
100
10
11
8
a
b
c
The reactions were performed with 0.25 mmol of substrate; 4 mL of solvent; 20 h, S:C = 100:1.
The conversions were determined by 1H NMR.
ee-values were determined by HPLC.
d
Side products were observed by NMR (see Section 4).
Table 11
Rh-catalyzed asymmetric hydrogenation of the N-Boc-protected substrate E-9a with monodentate ligandsa
CO2H
CO2H
*
[Rh(COD)2]BF4 + L* + PR3
NHBoc
H2, 20 h
NHBoc
E-9a
17a
Entry
L⁄, PR3
Solvent
pH2 (MPa)
T (°C)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
L1, PPh3
L1, PPh3
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
MeOH
MeOH
MeOH
MeOH
MeOH
5
40
40
40
40
30
30
30
30
30
30
100
100
100
74
100
79
100
100
100
100
71 (S)
74 (S)
77 (S)
46 (S)
82 (S)
49 (S)
6 (R)
79 (S)
81 (S)
28 (S)
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
L1, P(1-naphthyl)3
L2, P(1-naphthyl)3
L1, P(1-naphthyl)3
L2, P(1-naphthyl)3
L3, P(1-naphthyl)3
L1, PPh3
L1, P(o-Tolyl)3
L1, BuPAd2
10
MeOH
a
b
c
The reactions were performed with 0.2 mmol of 9a, 2
The conversions were determined by 1H NMR.
ee-values were determined by HPLC.
lmol of [Rh(COD)2]BF4, 4
lmol of ligand L, and 2 lmol PR3; in 4 mL of solvent for 20 h, S:C = 100:1.

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1311
Table 12
Rh-catalyzed asymmetric hydrogenation of N-Boc-protected substrates 8c,d and 9c,d (E-isomer)a
CO2R2
CO2R2
NHBoc
*
catalyst
Y
Y
H2
NHBoc
R = Me
2
2
8c,d
9c,d R2 = H
16c,d
R = Me
17c,d R2 = H
Entry
Precatalyst
Substrate
Solvent
pH2 (MPa)
T (°C)
Conv.b (%)
eec (%)
1
2
3
4
5
6
[Rh((R,R)-DIPAMP)(COD)]BF4
[Rh((R,R)-DIPAMP)(COD)]BF4
[Rh(COD)2]BF4, L1, P(1-naphthyl)3
[Rh(COD)2]BF4, L1, P(1-naphthyl)3
[Rh(COD)2]BF4, L1, P(1-naphthyl)3
[Rh(COD)2]BF4, L1, P(1-naphthyl)3
8c
8d
8c
8d
9c
9d
iPrOH
iPrOH
MeOH
MeOH
MeOH
MeOH
8
8
2.5
2.5
2.5
2.5
25
25
30
30
30
30
50
53
43
9
10
81
5
0
4
0
44
71
a
b
c
The reactions were performed with 0.25 mmol of substrate in 4 mL of solvent for 20 h, S:C = 100:1.
Conversions were determined by 1H NMR.
ee-values were determined by HPLC.
In order to find a more selective catalytic system, we turned our
the aim of producing the corresponding b2-amino acids in high
enantioselectivity. The reaction is strongly dependent on the struc-
ture of the substrate and the reaction conditions. Commercially
available Rh-catalysts based on chiral diphosphine ligands, such
as DuPhos or BPE, allow the hydrogenation to take place in quan-
titative yields and with up to 99% ee. Substrates with N-benzyl
groups give higher enantioselectivites than the corresponding N-
Boc protected compounds. The enantioselectivity can be advanta-
attention to the approach used by Minaard and Feringa, who re-
duced the free acids of their N-acetyl protected substrates instead
of the corresponding esters with monodentate Rh-catalysts.12
For this reason methyl ester 8a was saponified with sodium
hydroxide in ethanol to give the carboxylic acid 9a.19 In turn this
substrate was hydrogenated with catalysts formed by mixing
[Rh(COD)2]BF4 with achiral monodentate phosphines and chiral
phosphoroamidites. Under these conditions, similar results were
obtained to those with N-acetylated substrates (Table 11).
We next studied the combination of chiral amidite L1 (see
Fig. 1) and PPh3 as ligands in a mixture of iPrOH-H2O as solvent
at 5 and 2.5 MPa, respectively (entries 1 and 2). At 40 °C quanti-
tative conversion was achieved. Moderate enantioselectivities
were obtained almost independent of the H2-pressure. A slight
enhancement of the enantioselectivity to 77% was observed
when using P(1-naphthyl)3 as an achiral ligand (entry 3). There-
fore, this phosphine was combined with chiral ligands L2 and L3,
respectively. Next, we used methanol as the solvent. Under these
conditions the reaction could be conducted at a lower tempera-
ture (30 °C) and an enantioselectivity of up to 82% was observed
(entry 5). In general, when achiral triarylphosphines such as PPh3
or P(o-Tolyl)3 were applied in combination with chiral phosp-
horoamidites, the enantioselectivity and conversion remained
almost constant, whereas when a bulky ligand BuPAd2 was used,
the enantioselectivity was markedly decreased to 28% (entries
8–10).
geously supported by linkage of a chiral
a-phenylethyl group to
the amino group, where a positive double stereodifferentiation in
combination with the chiral catalyst could be achieved. In contrast,
the use of a chiral ester group has almost no effect on the stereose-
lectivity of the reaction. In cases where chiral catalysts bearing
bidentate diphosphine ligands were unsuccessful, the applications
of mixtures consisting of achiral monodentate phosphines and
chiral monodentate phosphoroamidites were revealed to be
advantageous.
4. Experimental
4.1. General
Solvents were dried and freshly distilled under argon before
use. All reactions were performed under an argon atmosphere.
Thin layer chromatography was carried out on precoated TLC
plates (silica gel 60 F254). Flash chromatography was conducted
with the CombiFlash Rf system from Teledyne ISCO (NF column;
silica gel; particle size 0.035–0.070 mm). Melting points were
estimated with the SMP3 from Stuart. NMR spectra were recorded
on a Bruker ARX 300 spectrometer at the following frequencies:
300.13 MHz (1H) and 75.47 MHz (13C). Chemical shifts of 1H and
13C NMR spectra are reported in ppm downfield from TMS as
internal standard. Signals are quoted as s (singlet), d (doublet),
br (broad), and m (multiplet). Optical rotations were determined
using an Anton Paar MCP200 polarimeter. The elemental
analyses were measured with TrueSpec CHNS from Leco and
Titralab 870 from Radiometer Analytical SAS. HRMS were recorded
on an ESI-TOF-MS 6210 Agilent mass spectrometer. GC analyses
were performed using Agilent System 6890. HPLC analyses
were conducted on an Agilent 1200 Series instrument with a
DA-detector.
In order to test the hydrogenation of the heteroaromatic deriv-
atives of esters 8c,d, we applied the Rh-DiPAMP catalyst at an ele-
vated pressure of 8 MPa (Table 12, entries 1 and 2). However, the
conversions were only poor and almost no enantioselectivity was
induced.
The application of the optimal reaction conditions derived from
Table 11 did not improve the results. Only when the corresponding
acids 9c,d were submitted to the hydrogenation, were moderate
conversion and enantioselectivity observed (entry 6).
3. Conclusion
The asymmetric hydrogenation of prochiral b-aryl- or b-het-
aryl-substituted
a-aminomethylacrylates was investigated with

1312
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
4.2. Synthesis of alkyl 2-[hydroxy(aryl)methyl]acrylates 2
1H, OH), 1.51 (d, J = 6.4 Hz, 1H, CH3). Minor diastereomer: 1H
NMR (CDCl3) d = 7.48–7.20 (m, 10H, Ar-H), 6.41 (m, 1H, CH2@),
5.90 (m, 1H, CH2@), 5.88 (br d, J = 6.6 H, 1H, CH–O), 5.55 (m, 1H,
CH–OH), 3.16 (d, J = 5.8 Hz, 1H, OH), 1.47 (d, J = 6.6 Hz, 1H, CH3).
By 13C NMR it was not possible to differentiate between signals
of both diastereomers, 13C NMR (CDCl3) d = 165.6, 165.5, 142.4,
142.4, 141.5, 141.4, 141.4, 141.3, 128.6, 128.6, 128.5, 128.5,
128.0, 128.0, 127.9, 127.9, 126.9, 126.7, 126.3, 126.0, 126.0,
125.9, 73.4, 73.2, 73.2, 73.2, 22.2, 22.2. Anal. Calcd For C18H18O3:
C, 76.57; H, 6.43. Found: C, 76.17; H, 6.17.
4.2.1. (R)-1-Phenylethyl acrylate 1
26
ˇ
According to the procedure of Kadlcíková et al. acryloyl chlo-
ride (134 mmol, 12.1 g) was added dropwise to a stirred solution of
(R)-(+)-1-phenylethanol (67 mmol, 8.18 g), 4-DMAP (0.05 mmol,
6 mg), and Et3N (147 mmol, 14.9 g) in CH2Cl2 (50 mL) under an ar-
gon atmosphere at 0 °C. The mixture was stirred at room temper-
ature for 3 h and then poured into water. After separation, the
organic layer was washed with brine (2 ꢁ 50 mL) and the aqueous
layer was extracted with CH2Cl2 (50 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure to yield pure (R)-1-phenylethyl
4.3. Alkyl 2-[acetoxy(aryl)methyl]acrylates 3 (general
procedure)
acrylate 1. ½a 2D0
ꢂ
¼ þ91:0 (c 1.0, CHCl3). 1H NMR (CDCl3) d = 7.48–
7.29 (m, 5H, Ar-H), 6.45 (dd, J = 17.3, 1.5 Hz, 1H, CH2@), 6.19 (dd,
J = 17.3, 10.3 Hz, 1H, CH2@), 6.09 (q, J = 6.6 Hz, 2H, CH), 5.86 (dd,
J = 10.4, 1.5 Hz, 1H, CH@), 1.62 (d, J = 6.6 Hz, 3H, CH3). 13C NMR
(CDCl3) d = 165.3, 141.5, 130.6, 128.6, 128.4, 127.8, 126.0, 72.4,
22.1.
Acetylchloride (23 mmol, 1.81 g) was added dropwise to a mix-
ture of alkyl 2-[hydroxy(aryl)methyl]acrylates 2 (20 mmol) and
pyridine (23 mmol, 1.82 g) in dry CH2Cl2 (10 mL) at 0–5 °C. The
resulting solution was warmed to room temperature within 1 h.
After stirring overnight, the mixture was diluted with CH2Cl2
(70 mL), treated with 2 M HCl (100 mL), and washed with H2O
(100 mL). After drying over anhydrous Na2SO4, the mixture was fil-
tered and the organic layer was concentrated under reduced pres-
sure. In most cases, the crude product 3 was used in the next step
without further purification.
4.2.2. General procedure for the formation of the Baylis–
Hillman adducts 2a–f
Following the general procedure of Hu et al.,17 the aldehyde
(30 mmol), acrylate (90 mmol), and DABCO (30 mmol, 3.36 g) were
dissolved in 300 mL of 1,4-dioxane/water (1:1 v/v) and the mixture
was stirred at room temperature overnight. After completion of the
reaction, MTBE (500 mL) and H2O (250 mL) were added to the mix-
ture. After phase separation, the organic layer was washed with
brine (2 ꢁ 100 mL), dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. When required, the crude prod-
uct was purified by column chromatography to yield the desired
products 2a–f. The NMR spectra of 2a,27 2b,28 2c,29 and 2d28 corre-
sponded to the published data.
4.3.1. Methyl 2-[acetoxy(phenyl)methyl]acrylate 3a
Yield: 92%, orange oil obtained as pure compound without fur-
ther purification. NMR spectra were in agreement with published
data.30
4.3.2. tert-Butyl 2-[acetoxy(phenyl)methyl]acrylate 3b
Yield: 98%, colorless oil obtained as pure compound without
further purification. 1H NMR (CDCl3) d = 7.32–7.17 (m, 5H, Ar-H),
6.56 (m, 1H, CH), 6.24 (m, 1H, CH2@), 5.64 (m, 1H, CH2@), 2.00
(s, 3H, COCH3), 1.29 (s, 9H, CH3). 13C NMR (CDCl3) d = 169.4,
164.2, 141.2, 138.1, 128.4, 127.9, 124.7, 81.4, 73.4, 27.9, 21.1.
4.2.2.1. Methyl2-[hydroxy(phenyl)methyl]acrylate2a.
Yield: 61%;
colorless oil isolated by flash chromatography (eluent: n-heptane/ethyl
acetate = 3:1).
4.3.3. Methyl 2-[acetoxy(thiophen-2-yl)methyl]acrylate 3c
Yield: 95%, yellow oil isolated by flash chromatography (n-hep-
tane/ethyl acetate = 2:1). 1H NMR (CDCl3) d = 7.29 (dd, J = 5.1 Hz,
1.3 Hz, 1H, Ar-H), 7.09 (m, 1H, Ar-H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H,
Ar-H), 6.95 (m, 1H, CH), 6.44 (m, 1H, CH2@), 6.02 (m, 1H, CH2@),
3.74 (s, 3H, OCH3), 2.11 (s, 3H, CH3). 13C NMR (CDCl3) d = 169.2,
165.0, 140.7, 139.2, 127.1, 126.7, 126.2, 125.6, 68.1, 52.0, 20.9.
4.2.2.2. -Butyl 2-[hydroxy(phenyl)methyl]acrylate 2b.
colorless oil isolated by flash chromatography (n-heptane/ethyl
acetate = 19:1).
Yield: 47%,
4.2.2.3. Methyl 2-[hydroxy(2-thiophenyl)methyl]acrylate 2c.
73%, yellow oil isolated by flash chromatography (cyclohexane/ethyl ace-
tate = 19:1–9:1).
Yield:
4.3.4. Methyl 2-[acetoxy(furan-2-yl)methyl]acrylate 3d
Yield: 94%, orange oil isolated by flash chromatography (cyclo-
hexane/ethyl acetate = 9:1–4:1). 1H NMR (CDCl3) d = 7.35 (m, 1H,
Ar-H), 6.72 (m, 1H, CH2@), 6.43 (m, 1H, CH2@), 6.29 (m, 2H, CH,
Ar-H), 5.97 (m, 1H, CH2@), 3.70 (s, 3H, OCH3), 2.07 (s, 3H, CH3).
13C NMR (CDCl3) d = 169.2, 164.9, 150.3, 143.1, 136.9, 126.6,
110.4, 109.7, 66.0, 52.0, 20.8.
4.2.2.4. Methyl 2-[hydroxy(2-furanyl)methyl]acrylate 2d.
82%, orange oil obtained as pure compound without further
purification.
Yield:
4.2.2.5.
Methyl
2-[hydroxy(5-(acetoxymethyl)-2-furanyl)
methyl]acrylate 2e.
Yield: 76%, orange oil obtained as pure com-
pound without further purification. 1H NMR (CDCl3) d = 6.36 (m,
1H, CH2@), 6.29 (d, J = 3.2 Hz, 1H, Ar-H), 6.16 (d, J = 3.2 Hz, 1H,
Ar-H), 5.95 (m, 1H, CH2@), 5.54 (br d, J = 6.2 H, 1H, CH), 4.95 (s,
2H, OCH2), 3.72 (s, 3H, OCH3), 3.48 (br d, J = 6.2 H, 1H, OH), 2.02
(s, 3H, CH3). 13C NMR (CDCl3) d = 170.6, 166.3, 155.0, 149.1,
139.2, 126.9, 111.4, 108.0, 66.8, 58.0, 52.0, 20.7. Anal. Calcd for
4.3.5. Methyl 2-[(5-(acetoxymethyl)furan-2-yl)methyl]acrylate
3e
Yield: 93%, yellow powder obtained as pure compound without
further purification. mp 88–89 °C. 1H NMR (CDCl3) d = 6.69 (m, 1H,
CH2@), 6.45 (m, 1H, CH), 6.32 (d, 1H, J = 3.2 Hz, Ar-H), 6.26 (d, 1H,
J = 3.2 Hz, Ar-H), 5.97 (m, 1H, CH2@), 4.98 (s, 2H, OCH2), 3.72 (s, 3H,
OCH3), 2.10 (s, 3H, CH3), 2.05 (s, 3H, CH3). 13C NMR (CDCl3)
d = 170.5, 169.3, 165.0, 151.0, 150.2, 136.7, 127.0, 111.4, 110.7,
66.1, 58.0, 52.2, 20.9, 20.8.
C12H14O6: C, 56.69; H, 5.55. Found: C, 56.87; H, 5.73.
4.2.2.6. (R)-1-Phenylethyl 2-[hydroxy(phenyl)methyl]acrylate
2f. Yield: 41%, colorless oil isolated by flash chromatography
(cyclohexane/ethyl acetate = 9:1–4:1). 54:46 mixture of both dia-
stereomers: Major diastereomer: 1H NMR (CDCl3) d = 7.40–7.16
(m, 10H, Ar-H), 6.42 (m, 1H, CH2@), 5.89 (br d, J = 6.4 H, 1H, CH–
O), 5.84 (m, 1H, CH2@), 5.56 (m, 1H, CH–OH), 3.03 (d, J = 5.4 Hz,
4.3.6. (R)-1-Phenylethyl 2-[acetoxy(phenyl)methyl]acrylate 3f
Yield: 72%, white solid isolated by flash chromatography (cyclo-
hexane/ethyl acetate = 9:1), mp 63–65 °C, ½a D23
¼ þ14:9 (c 1.0,
ꢂ

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1313
CHCl3). 54:46 mixture of diastereomers: Major diastereomer: 1H
NMR (CDCl3) d = 7.39–7.20 (m, 8H, Ar-H), 7.10–7.05 (m, 2H, Ar-H),
6.70 (m, 1H, CH), 6.44 (m, 1H, CH2@), 5.85 (q, J = 6.6 Hz, 1H, CH),
5.84 (m, 1H, CH2@), 2.08 (s, 3H, CH3), 1.49 (d, J = 6.6 Hz, 3H, CH3).
Minor diastereomer: 1H NMR (CDCl3) d = 7.39–7.20 (m, 8H, Ar-H),
7.10–7.05 (m, 2H, Ar-H), 6.70 (m, 1H, CH), 6.43 (m, 1H, CH@), 5.89
(q, J = 6.6 Hz, 1H, CH), 5.79 (m, 1H, CH2@), 2.02 (s, 3H, COCH3),
1.42 (d, J = 6.6 Hz, 3H, CH3). By 13C NMR spectroscopy it was not pos-
sible to differentiate between signals of both diastereomers, 13C
NMR (CDCl3) d = 169.4, 169.3, 164.2, 164.1, 141.2, 141.1, 139.9,
139.7, 137.8, 137.7, 128.5, 128.4, 128.4, 128.3, 127.9, 127.7, 127.7,
126.3, 126.0, 126.0, 125.8 73.2, 73.2, 73.1, 73.1, 22.2, 21.9, 21.1, 21.0.
136.2, 134.4, 133.6, 128.3, 128.1, 127.9, 127.6, 126.9, 81.2, 53.1,
52.5, 27.7. Anal. Calcd for C21H25NO2: C, 77.99; H, 7.79; N, 4.33.
Found: C, 77.94; H, 7.70; N, 4.15.
4.4.3. Methyl (E/Z)-2-[(benzylamino)methyl]-3-(thiophen-2-yl)
acrylate 4c
Yield: 91% (mixture of E/Z isomers = 86/14). The E-isomer was
obtained by flash chromatography (cyclohexane/ethyl ace-
tate = 4:1). E-Isomer: yellow oil, 1H NMR (CDCl3) d = 7.91 (s, 1H,
CH@), 7.43 (m, 1H, Ar-H), 7.38–7.20 (m, 6H, Ar-H), 7.03 (dd,
J = 5.1 Hz, 3.6 Hz, 1H, Ar-H), 3.87 (s, 2H, CH2N), 3.83 (s, 2H, CH2N),
3.79 (s, 3H, OCH3), 1.80 (br s, 1H, NH). 13C NMR (CDCl3) d = 168.2,
139.9, 137.4, 134.0, 132.8, 129.9, 128.2, 128.1, 127.3, 126.9, 126.7,
53.5, 51.9, 45.4. Anal. Calcd for C16H17NO2S: C, 66.87; H, 5.96; N,
4.54; S, 11.16. Found: C, 66.60; H, 5.99; N, 4.54; S, 11.12.
4.4. Alkyl 2-[(benzylamino)methyl]-3-(2-aryl)acrylate 4 and
alkyl 2-[(1-phenylethylamino)methyl]-3-(2-aryl)acrylate 5
(general procedure)
4.4.4. Methyl (E/Z)-2-[(benzylamino)methyl]-3-(2-furan-2-yl)
acrylate 4d18
Method A: A mixture of 2-acetoxy(phenyl)methylacrylate 3a
(10 mmol, 2.34 g) and benzylamine (20 mmol, 6.83 g) or (R)- or
(S)-1-phenylethylamine (20 mmol, 7.11 g) in dry THF (20 mL)
was stirred at room temperature under an argon atmosphere over-
night. The reaction mixture was concentrated under reduced pres-
sure and the residue was redissolved in ethyl acetate (100 mL). The
organic phase was washed with a saturated solution of NaHCO3
(20 mL), followed by H2O (20 mL), and dried over anhydrous
Na2SO4. After filtration and evaporation of the solvent the products
4a, (R)-5a and (S)-5a were purified by flash chromatography to
yield the products as E/Z-mixtures.
Yield: 63% (mixture of E/Z isomers = 88/12). The E-isomer was
isolated by flash chromatography (cyclohexane/ethyl ace-
tate = 4:1–1:1). E-Isomer: orange oil; 1H NMR (CDCl3) d = 7.50 (s,
1H, CH@), 7.42 (d, J = 1.7 Hz, 1H, Ar-H), 7.36–7.20 (m, 5H, Ar-H),
6.60 (d, J = 3.4 Hz, 1H, Ar-H), 6.44 (dd, J = 3.4 Hz, 1.8 Hz, 1H, Ar-
H), 3.91 (s, 2H, CH2N), 3.83 (s, 2H, CH2N), 3.80 (s, 3H, OCH3), 1.98
(br s, 1H, NH). 13C NMR (CDCl3) d = 168.5, 150.9, 144.7, 140.3,
128.2, 128.2, 127.6, 126.8, 126.6, 116.6, 112.0, 53.0, 52.0, 45.0.
Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.45; H, 6.27; N, 4.83.
Method B: Following the procedure of Foucaud et al.18 a solution
of acrylates 3b–f (10 mmol) and the relevant benzylamine
(20 mmol) in dry THF (20 mL) was stirred at reflux for 2 h. The
reaction mixture was concentrated under reduced pressure and
the residue was redissolved in diethyl ether (50 mL), washed with
H2O (20 mL), and dried over anhydrous Na2SO4. The organic layer
was concentrated under reduced pressure to provide the products
4b–f and 5b–e as E/Z-mixtures. The products were purified by col-
umn chromatography.
4.4.5. Methyl (E/Z)-2-[(benzylamino)methyl]-3-[(5-(acetoxymeth-
yl)furan-2-yl)]acrylate 4e
Yield: 49% (mixture of E/Z isomers = 88/12). The isomers were
separated by column chromatography (cyclohexane/ethyl ace-
tate = 2:1). E-Isomer: brown oil; 1H NMR (CDCl3) d = 7.46 (s, 1H,
CH@), 7.36–7.19 (m, 5H, Ar-H), 6.55 (d, J = 3.4 Hz, 1H, Ar-H), 6.44
(d, J = 3.4 Hz, 1H, Ar-H), 4.96 (s, 2H, OCH2), 3.90 (s, 2H, CH2N),
3.82 (s, 2H, CH2N), 3.80 (s, 3H, OCH3), 2.04 (s, 3H, COCH3), 2.03
(br s, 1H, NH). 13C NMR (CDCl3) d = 170.3, 168.3, 151.7, 151.2,
140.3, 128.2, 128.1, 127.3, 127.3, 126.8, 117.2, 112.6, 57.8, 53.0,
52.0, 45.1, 20.7. Z-Isomer: 1H NMR (CDCl3) d = 7.36–7.19 (m, 5H,
Ar-H), 6.80 (d, J = 3.4 Hz, 1H, Ar-H), 6.61 (s, 1H, CH@), 6.43 (d,
J = 3.4 Hz, 1H, Ar-H), 5.02 (s, 2H, OCH2), 3.83 (s, 3H, OCH3), 3.80
(s, 2H, CH2N), 3.56 (s, 2H, CH2N), 2.08 (s, 3H, COCH3), 1.78 (br s,
1H, NH). 13C NMR (CDCl3) d = 170.4, 168.4, 150.7, 149.9, 140.0,
128.9, 128.3, 128.1, 126.9, 122.9, 113.9, 112.6, 57.9, 52.4, 52.4,
51.7, 20.8. Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08.
Found: C, 66.30; H, 6.02; N, 3.64.
4.4.1. Methyl (E/Z)-2-[(benzylamino)methyl]-3-(phenyl)acrylate
4a18
Yield: 91% (mixture of E/Z-isomers = 85/15). The isomers were
separated by flash chromatography (n-heptane/ethyl ace-
tate = 4:1). E-Isomer: pale yellow oil. 1H NMR (CDCl3) d = 7.82 (s,
1H, CH@), 7.46–7.38 (m, 2H, Ar-H), 7.35–7.19 (m, 8H, Ar-H), 3.82
(s, 3H, OCH3), 3.82 (s, 2H, CH2N), 3.60 (s, 2H, CH2N), 2.25 (br s,
1H, NH). 13C NMR (CDCl3) d = 168.5, 142.1, 139.8, 134.9, 130.3,
129.6, 128.8, 128.4, 128.3, 127.0, 53.6, 52.0, 45.3. Z-Isomer: pale
yellow oil. 1H NMR (CDCl3) d = 7.38–7.24 (m, 10H, Ar-H), 6.81 (s,
1H, CH@), 3.85 (s, 2H, CH2N), 3.68 (s, 3H, CH3), 3.61 (d, 2H, J=
1.3 Hz, CH2N), 2.01 (br s, 1H, NH). 13C NMR (CDCl3) d = 169.5,
139.8, 135.5, 134.8, 132.3, 128.3, 128.2, 128.1, 128.1, 128.0,
126.9, 52.8, 52.3, 51.6. Anal. Calcd for C18H19NO2: C, 76.84; H,
6.81; N, 4.98. Found: C, 76.56; H, 6.72; N, 4.67.
4.4.6. (R)-1-Phenylethyl (E/Z)-2-[(benzylamino)methyl]-3-(ph-
enyl)acrylate 4f
Yield: 97% (mixture of E/Z isomers = 73/27). The isomers were
separated by column chromatography (cyclohexane/ethyl ace-
tate = 19:1–4:1). E-Isomer: ½a D23
¼ ꢀ47:0 (c 1.0, CHCl3), yellow pale
ꢂ
oil. 1H NMR (CDCl3) d = 7.85 (s, 1H, CH@), 7.46–7.18 (m, 15H, Ar-H),
6.02 (q, J = 6.6 Hz, 1H, CH), 3.78 (s, 2H, CH2N), 3.59 (s, 2H, CH2N),
1.93 (br s, 1H, NH), 1.61 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3)
d = 167.3, 141.9, 141.7, 140.0, 135.0, 130.9, 129.6, 128.8, 128.5,
128.4, 128.3, 127.9, 126.9, 126.0, 72.9, 53.7, 45.5, 22.3. Z-Isomer:
4.4.2. tert-Butyl (E/Z)-2-[(benzylamino)methyl]-3-(phenyl)acr-
ylate 4b
Yield: 91% (mixture of E/Z isomers = 80/20). Purification by flash
chromatography (n-heptane/ethyl acetate = 19/1–4:1); E-Isomer:
white powder; mp 72–74 °C, 1H NMR (CDCl3) d = 7.70 (s, 1H,
CH@), 7.43 (m, 2H, Ar-H), 7.34–7.20 (m, 8H, Ar-H), 3.79 (s, 2H,
CH2N), 3.54 (s, 2H, CH2N), 2.00 (br s, 1H, NH), 1.53 (s, 9H, CH3).
13C NMR (CDCl3) d = 167.3, 140.8, 140.2, 135.3, 132.2, 129.5,
128.5, 128.4, 128.3, 128.3, 126.9, 80.9, 53.8, 45.6, 28.2. Z-Isomer:
pale yellow oil, 1H NMR (CDCl3) d = 7.37–7.18 (m, 10H, Ar-H),
6.73 (s, 1H, CH@), 3.82 (s, 2H, CH2N), 3.56 (s, 2H, CH2N), 1.67 (br
s, 1H, NH), 1.34 (s, 9H, CH3). 13C NMR (CDCl3) d = 168.2, 140.2,
½
a 2D3
ꢂ
¼ þ52:0 (c 1.0, CHCl3). 1H NMR (CDCl3) d = 7.36–7.12 (m,
15H, Ar-H), 6.81 (s, 1H, CH@), 5.94 (q, J = 6.6 Hz, 1H, CH), 3.80 (s,
2H, CH2N), 3.60 (s, 2H, CH2N), 1.64 (br s, 1H, NH), 1.41 (d,
J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 168.2, 141.0, 140.0,
135.7, 134.9, 133.0, 128.3, 128.1, 128.0, 127.8, 127.7, 126.9,
126.2, 72.9, 53.1, 52.5, 21.7. Anal. Calcd for C25H25NO2: C, 80.83;
H, 6.78; N, 3.77. Found: C, 80.51; H, 6.67; N, 3.62. HRMS (ESI

1314
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
371.18853) m/z: [M+Na]+ Calcd for C25H25NNaO2 394.17775.
Found: 394.17877.
1H, HB-CH2N), 1.80 (br s, 1H, NH), 1.39 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (CDCl3) d = 168.5, 145.2, 137.6, 133.8, 132.7, 129.7,
128.3, 127.4, 127.3, 126.9, 58.4, 52.0, 44.5, 24.2. Z-Isomer: 1H
NMR (CDCl3) d = 7.43–7.18 (m, 7H, Ar-H), 6.99 (dd, J = 5.1 Hz,
3.6 Hz, 1H, Ar-H), 6.91 (s, 1H, CH@), 3.84 (q, J = 6.6 Hz, 1H, CH),
3.82 (s, 3H, OCH3), 3.51 (dd, J = 14.2 Hz, 1.0 Hz, 1H, HA-CH2N),
3.30 (dd, J = 14.2 Hz, 0.9 Hz, 1H, HB-CH2N), 1.80 (br s, 1H, NH),
1.34 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 168.0, 145.3,
137.7, 133.3, 131.5, 128.4, 127.3, 126.9, 126.7, 126.5, 126.0, 56.6,
51.6, 51.4, 24.6. Anal. Calcd for C17H19NO2S: C, 67.75; H, 6.35; N,
4.65; S, 10.64. Found: C, 67.60; H, 6.67; N, 4.39; S, 10.52.
4.4.7. Methyl (E/Z)-3-phenyl-2-{[(R)-1-phenylethylamino]methyl}
acrylate (R)-5a
Yield: 69% (mixture of E/Z isomers = 84/16). The isomers were
separated by flash chromatography (cyclohexane/ethyl ace-
tate = 4:1). E-Isomer: ½a D21
þ 110:0 (c 1.0, CH2Cl2), pale yellow oil.
ꢂ
1H NMR (CDCl3) d = 7.75 (s, 1H, CH@), 7.39–7.19 (m, 10H, Ar-H),
3.82 (s, 3H, OCH3), 3.77 (q, J = 6.6 Hz, 1H, CH), 3.46 (d, J = 11.9 Hz,
1H, HA-CH2N), 3.41 (d, J = 11.9 Hz, 1H, HB-CH2N), 1.88 (br s, 1H,
NH), 1.37 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 168.7,
145.2, 141.8, 134.9, 130.5, 129.5, 128.8, 128.3, 128.3, 126.9, 58.6,
4.4.12. Methyl (E/Z)-2-{[(S)-1-phenylethylamino]methyl}-3-
(thiophen-2-yl)acrylate (S)-5c
Yield: 96% (mixture of E/Z isomers = 83/17), orange oil. Separa-
tion of the isomers by flash column chromatography (cyclohexane/
ethyl acetate = 4:1, E/Z = 84:16) was not possible. NMR-spectra of
both isomers correspond to the spectra of (R)-5c. Anal. Calcd for
52.0, 44.4, 24.2. Z-Isomer: ½a D20
ꢂ
= +54.0 (c 1.0, CH2Cl2), pale yellow
oil. 1H NMR (CDCl3) d = 7.36–7.17 (m, 10H, Ar-H), 6.66 (s, 1H, CH@),
3.85 (q, J = 6.6 Hz, 1H, CH), 3.62 (s, 3H, OCH3), 3.49 (dd, J1 = 14.1,
1.4, 1H, HA-CH2N), 3.33 (dd, 1H, J = 14.1 Hz, 1.1 Hz, HB-CH2N),
1.77 (br s, 1H, NH), 1.33 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3)
d = 169.4, 145.1, 135.4, 134.5, 132.5, 128.3, 128.1, 128.0, 127.9,
126.8, 126.5, 56.5, 51.4, 51.3, 24.3. Anal. Calcd for C19H21NO2: C,
77.26; H, 7.17; N, 4.74. Found: C, 77.35; H, 7.19; N, 4.55.
C17H19NO2S: C, 67.75; H, 6.35; N, 4.65; S, 10.64. Found: C, 68.33;
H, 6.63; N, 4.46; S, 10.52.
4.4.13. Methyl (E/Z)-3-(furan-2-yl)-2-{[(R)-1-phenylethylamino]
methyl}acrylate (R)-5d
4.4.8. Methyl (E/Z)-3-phenyl-2-{[(S)-1-phenylethylamino]methyl}
acrylate (S)-5a
Yield: 84% (mixture of E/Z isomers = 88/12). The isomers were
separated by flash chromatography (cyclohexane/ethyl ace-
Yield: 95% (mixture of E/Z isomers = 83/17). The isomers were
separated by flash chromatography (cyclohexane/ethyl ace-
tate = 4:1). E-Isomer: ½a D23
ꢂ
¼ þ35:6 (c 1.0, CH2Cl2), brown oil. 1H
tate = 4:1). E-Isomer: ½a D21
ꢂ
¼ ꢀ111:0 (c 1.0, CH2Cl2), pale yellow
NMR (CDCl3) d = 7.44 (s, 1H, CH@), 7.38–7.21 (m, 6H, Ar-H), 6.51
(d, J = 3.5 Hz, 1H, Ar-H), 6.40 (dd, J1 = 3.4 Hz, 1.8 Hz, 1H, Ar-H),
3.84 (q, J = 6.5 Hz, 1H, CH), 3.79 (s, 3H,OCH3), 3.75 (d, J = 12.5 Hz,
1H, HA-CH2N), 3.71 (d, J = 12.5 Hz, 1H, HB-CH2N), 1.95 (br s, 1H,
NH), 1.37 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 168.5,
150.8, 145.5, 144.6, 128.1, 127.4, 126.8, 126.7, 126.7, 116.4,
111.9, 57.7, 51.9, 43.8, 24.5. Z-Isomer: 1H NMR (CDCl3) d = 7.40
(m, 1H, Ar-H), 7.34–7.20 (m, 5H, Ar-H), 6.86 (d, J = 3.5 Hz, 1H, Ar-
H), 6.55 (s, 1H, CH@), 6.41 (dd, J = 3.4 Hz, 1.8 Hz, 1H, Ar-H), 3.84
(q, J = 6.6 Hz, 1H, CH), 3.80 (s, 3H, OCH3), 3.48 (dd, J = 14.4 Hz,
1.4 Hz, 1H, HA-CH2N), 3.29 (dd, J = 14.4 Hz, 1.1 Hz, 1H, HB-CH2N),
1.67 (br s, 1H, NH), 1.34 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3)
d = 168.4, 150.3, 145.2, 143.2, 128.4, 127.8, 126.9, 126.6, 123.4,
113.2, 111.8, 56.5, 51.6, 50.9, 24.4. Anal. Calcd for C17H19NO3: C,
71.56; H, 6.71; N, 4.91. Found: C, 71.21; H, 6.62; N, 4.62.
oil. Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found:
C, 77.29; H, 7.20; N, 4.63. NMR-spectra of both isomers correspond
to the spectra of (R)-5a.
4.4.9. tert-Butyl (E/Z)-3-phenyl-2-{[(R)-1-phenylethylamino]
methyl}acrylate (R)-5b
Yield: 47% (mixture of E/Z isomers = 73/27). The pure E-isomer
could be obtained by flash chromatography (n-heptane/ethyl ace-
tate = 19/1). E-Isomer: ½a D20
¼ þ98:0 (c 1.0, CH2Cl2), pale yellow
ꢂ
oil. 1H NMR (CDCl3) d = 7.78 (s, 1H, CH@), 7.38–7.18 (m, 10H, Ar-
H), 3.77 (q, J = 6.6 Hz, 1H, CH), 3.40 (AB-spectra, 2H, CH2), 2.01 (br
s, 1H, NH), 1.54 (s, 9H, CH3), 1.38 (d, J = 6.6 Hz, 3H, CH3). 13C NMR
(CDCl3) d = 167.3, 145.2, 140.6, 135.1, 132.1, 129.4, 128.4, 128.2,
128.1, 126.9, 126.8, 80.8, 58.5, 44.6, 28.1, 24.1. Z-Isomer: 1H NMR
(CDCl3) d = 7.38–7.20 (m, 10H, Ar-H), 6.62 (s, 1H, CH@), 3.88 (q,
J = 6.6 Hz, 1H, CH), 3.50 (dd, J = 14.1 Hz, 1.4 Hz, 1H, HA-CH2N), 3.31
(dd, J = 14.1 Hz, 1.0 Hz, 1H, HB-CH2N), 1.85 (br s, 1H, NH), 1.36 (s,
9H, CH3), 1.36 (d, J = 6.5 Hz, 3H, CH3). 13C NMR (CDCl3) d = 168.2,
145.3, 136.2, 134.6, 133.4, 128.4, 128.3, 127.9, 127.6, 126.8, 126.7,
81.2, 56.6, 51.6, 27.7, 24.4. Anal. Calcd for C22H27NO2: C, 78.30; H,
8.06; N, 4.15. Found: C, 78.18; H, 8.00; N, 3.96.
4.4.14. Methyl (E/Z)-3-(furan-2-yl)-2-{[(S)-1-phenylethylamino]
methyl}acrylate (S)-5d
Yield: 82% (mixture of E/Z isomers = 88/12). The isomers were
separated by flash column chromatography (cyclohexane/ethyl
acetate = 4:1). E-Isomer: ½a D23
¼ ꢀ39:6 (c 1.0, CH2Cl2), brown oil.
ꢂ
NMR-spectra of both isomers correspond to the spectra of (R)-5d.
Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C,
71.61; H, 6.60; N, 4.76.
4.4.10. tert-Butyl (E/Z)-3-phenyl-2-{[(S)-1-phenylethylamino]
methyl}acrylate (S)-5b
Yield: 47% (mixture of E/Z isomers = 73/27). The pure E-isomer
could be obtained by flash chromatography (n-heptane/ethyl ace-
4.4.15. Methyl (E/Z)-3-(5-acetoxymethylfuran-2-yl)-2-{[(R)-1-
phenylethylamino]methyl}acrylate (R)-5e
tate = 19/1). E-Isomer: ½a D20
ꢂ
¼ ꢀ99:5 (c 1.0, CH2Cl2), pale yellow
Yield: 75% (mixture of E/Z isomers = 84/16). The pure E-isomer
was obtained by flash chromatography (cyclohexane/ethyl ace-
oil. NMR-spectra of both isomers correspond to the spectra of
(R)-5b. Anal. Calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found:
C, 78.39; H, 8.10; N, 3.92.
tate = 4:1–2:1). E-Isomer: ½a D20
¼ ꢀ10:5 (c 1.0, CH2Cl2), brown oil.
ꢂ
1H NMR (CDCl3) d = 7.41 (s, 1H, CH@), 7.35–7.18 (m, 5H, Ar-H),
6.46 (d, J = 3.5 Hz, 1H, Ar-H), 6.40 (d, J = 3.5 Hz, 1H, Ar-H), 4.94 (d,
J = 13.3 Hz, 1H, HA-CH2O), 4.85 (d, J = 13.4 Hz, 1H, HB-CH2O), 3.83
(q, J = 6.7 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 3.76 (d, J = 12.6 Hz, 1H,
HA-CH2N), 3.69 (d, J = 12.6 Hz, 1H, HB-CH2N), 2.06 (s, 3H, COCH3),
2.00 (br s, 1H, NH), 1.36 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3)
d = 170.3, 168.3, 151.5, 151.1, 145.4, 128.2, 127.4, 127.1, 126.8,
126.7, 117.0, 112.5, 57.8, 57.7, 52.0, 44.0, 24.4, 20.7. Z-Isomer: 1H
NMR (CDCl3) d = 7.35–7.19 (m, 5H, Ar-H), 6.78 (d, J = 3.4 Hz, 1H,
Ar-H), 6.52 (s, 1H, CH@), 6.42 (d, J = 3.4 Hz, 1H, Ar-H), 5.02, (s, 2H,
4.4.11. Methyl (E/Z)-2-{[(R)-1-phenylethylamino]methyl}-3-
(thiophen-2-yl)acrylate (R)-5c
Yield: 86% (mixture of E/Z isomers = 83/17), orange oil. Separa-
tion of the isomers by flash chromatography (cyclohexane/ethyl
acetate = 4:1, E/Z = 84:16) was not possible. E-Isomer: 1H NMR
(CDCl3) d = 7.90 (s, 1H, CH@), 7.43–7.18 (m, 7H, Ar-H), 7.00 (dd,
J = 5.1 Hz, 3.6 Hz, 1H, Ar-H), 3.86 (q, J = 6.6 Hz, 1H, CH), 3.78 (s,
3H, OCH3), 3.66 (d, J = 12.4 Hz, 1H, HA-CH2N), 3.62 (d, J = 12.4 Hz,

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1315
OCH2), 3.83 (m, 1H, CH), 3.80 (s, 3H, OCH3), 3.45 (dd, J = 14.6 Hz,
1.3 Hz, 1H, HA-CH2N), 3.30 (dd, J = 14.6 Hz, 1.0 Hz, 1H, HB-CH2N),
2.07 (s, 3H, COCH3), 1.64 (br s, 1H, NH), 1.34 (d, 3H, J = 6.6 Hz,
CH3). 13C NMR (CDCl3) d = 170.5, 168.5, 150.8, 149.9, 145.2, 129.1,
128.4, 127.0, 126.7, 122.7, 113.8, 112.7, 58.0, 56.6, 51.7, 50.8,
24.4, 20.8. Anal. Calcd for C20H23NO5: C, 67.21; H, 6.49; N, 3.92.
Found: C, 67.23; H, 6.60; N, 3.69.
tion mixture was then stirred at room temperature for 30 min. The
mixture was diluted with CH2Cl2, washed with H2O (20 mL) and
brine (20 mL), dried over anhydrous Na2SO4, and filtered. The sol-
vent was evaporated under reduced pressure to afford azido com-
pounds 7, which were purified if required.
4.6.1. Methyl (E)-2-(azidomethyl)-3-phenylacrylate 7a18
Yield: 94%, pale yellow oil obtained without further purifica-
tion. 1H NMR (CDCl3) d = 7.96 (s, 1H, CH@), 7.45–7.36 (m, 5H, Ar-
H), 4.18 (s, 2H, CH2), 3.88 (s, 3H, OCH3). 13C NMR (CDCl3)
d = 167.5, 144.6, 134.0, 129.6, 129.5, 128.8, 126.5, 52.4, 46.9. Anal.
Calcd for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34. Found: C, 60.73;
H, 5.13; N, 19.62.
4.4.16. Methyl (E/Z)-3-(5-acetoxymethylfuran-2-yl)-2-{[(R)-1-
phenylethylamino]methyl}acrylate (S)-5e
Yield: 80%, (mixture of E/Z isomers = 85/15). The pure E-isomer
was obtained by flash chromatography (cyclohexane/ethyl ace-
tate = 4:1–2:1). E-Isomer: ½a D20
¼ þ12:8 (c 1.0, CH2Cl2), NMR-spec-
ꢂ
tra of both isomers correspond to the spectra of (R)-5e. Anal.
Calcd for C20H23NO5: C, 67.21; H, 6.49; N, 3.92. Found: C, 67.09;
H, 6.49; N, 3.70.
4.6.2. Methyl (E)-2-(azidomethyl)-3-(2-thiophenyl)acrylate 7c18
Yield: 95%, colorless oil isolated by flash chromatography
(cyclohexane/ethyl acetate = 4:1). 1H NMR (CDCl3) d = 8.02 (s, 1H,
CH@), 7.55 (m, 1H, Ar-H), 7.36 (m, 1H, Ar-H), 7.11 (dd, J = 5.1 Hz,
3.8 Hz, 1H, Ar-H), 4.38 (s, 2H, CH2), 3.84 (s, 3H, OCH3). 13C NMR
(CDCl3) d = 167.4, 136.7, 136.4, 133.7, 131.1, 127.9, 122.2, 52.4,
46.7. Anal. Calcd for C9H9N3O2S: C, 48.42; H, 4.06; N, 18.82; S,
14.36. Found: C, 48.57; H, 4.19; N, 18.47; S, 14.14.
4.5. Procedures for the Synthesis of Methyl (Z)-2-bromomethyl-
3-arylacrylates 6
Method for 6a,c: Applying the slightly modified procedure of Hu
and Zheng et al.11 aq HBr (10 g, 48%) and concentrated H2SO4
(0.5 mL) were added to methyl 2-hydroxy(aryl)acrylate
2
(10 mmol). The reaction mixture was stirred at room temperature
overnight, and then extracted with CH2Cl2 (2 ꢁ 50 mL). The com-
bined organic layers were washed with brine (20 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure to afford the product 6 which was used in the next step with-
out further purification.
4.6.3. Methyl (E)-2-(azidomethyl)-3-(2- furanyl)acrylate 7d18
Yield: 51%, pale yellow oil isolated by flash column chromatog-
raphy (n-heptane/ethyl acetate = 9:1). 1H NMR (CDCl3) d = 7.58 (s,
1H, CH@), 7.57 (m, 1H, Ar-H), 6.73 (d, J= 3.4 Hz, 1H, Ar-H), 6.50
(dd, J = 3.5 Hz, 1.8 Hz, 1H, Ar-H), 4.46 (s, 2H, CH2), 3.81 (s, 3H,
OCH3). 13C NMR (CDCl3) d = 167.4, 150.1, 145.7, 129.3, 121.5,
118.3, 112.4, 52.3, 46.7. Anal. Calcd for C9H9N3O9: C, 52.17; H,
4.38; N, 20.28. Found: C, 52.41; H, 4.59; N, 20.02.
Method for 6d: In accordance to the procedure of Yu et al.,31
a
solution of PBr3 (10 mmol, 2.68 g) in CH2Cl2 (20 mL) was added
dropwise to a stirred solution of 2d (10 mmol, 1.82 g) in CH2Cl2
(10 mL) at 0 °C. The reaction mixture was stirred at this tempera-
ture for 2 h, and then poured into ice-water and extracted with
CH2Cl2 (2 ꢁ 50 mL). The combined organic layers were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure to afford product 6d, which was
used in the next step without further purification.
4.7. Methyl 2-[(tert-butoxycarbonylamino)methyl]-3-arylacr -
ylates 8 (general procedure)
To a stirred solution of allylic azide 7 (8 mmol) in dry THF
(20 mL) were added PPh3 (8.4 mmol, 2.20 g) and H2O (0.2 mL).
The reaction mixture was stirred overnight at room temperature
after which di-tert-butyl dicarbonate (8 mmol, 1.75 g) was added
and the stirring was continued for a further 2 h. The reaction mix-
ture was concentrated under reduced pressure to afford 8, which
was purified by flash chromatography on silica gel.
4.5.1. Methyl (Z)-2-bromomethyl-3-phenylacrylate 6a
Yield: 92%, yellow oil. NMR spectra are in agreement with pub-
lished data.32
4.5.2. Methyl (Z)-2-(bromomethyl)-3-(thiophen-2-yl)acrylate
6c33
4.7.1. Methyl (E)-2-[(tert-butoxycarbonylamino)methyl]-3-phe-
nylacrylate 8a
Yield: 98%, colorless crystals, mp 51–53 °C. 1H NMR (CDCl3)
d = 8.02 (s, 1H, CH@), 7.54 (m, 1H, Ar-H), 7.36 (m, 1H, Ar-H), 7.10
(dd, J = 5.1 Hz, 3.8 Hz, 1H, Ar-H), 4.38 (s, 2H, CH2), 3.83 (s, 3H,
OCH3). 13C NMR (CDCl3) d = 167.4, 136.6, 136.4, 133.6, 131.1,
127.9, 122.2, 52.3, 46.6. Anal. Calcd for C9H9BrO2S: C, 41.39; H,
3.47; Br, 30.60; S, 12.28. Found: C, 41.22; H, 3.39; Br, 30.40; S, 12.39.
Yield: 73%, white powder isolated by column chromatography
on silica gel (n-heptane/ethyl acetate = 9:1–2:1), mp 70–71 °C. 1H
NMR (CDCl3) d = 7.77 (s, 1H, CH@), 7.52–7.30 (m, 5H, Ar-H), 5.07
(br s, 1H, NH), 4.21 (d, J = 5.9 Hz, 1H, CH2), 3.83 (s, 3H, OCH3),
1.43 (s, 9H, CH3). 13C NMR (CDCl3) d = 168.2, 155.4, 142.1, 134.3,
129.7, 129.2, 128.7, 128.5, 79.3, 52.2, 37.6, 28.3. HRMS (ESI
291.14706) m/z: [M+Na]+ calcd for C16H21NNaO4 314.13628.
Found: 314.13703.
4.5.3. Methyl (Z)-2-(bromomethyl)-3-(furan-2-yl)acrylate 6d33
Yield: 98%, yellow oil. 1H NMR (CDCl3) d = 7.63 (m, 1H, Ar-H),
7.46 (s, 1H, CH@), 6.80 (d, J = 3.4 Hz, 1H, Ar-H), 6.52 (dd,
J = 3.5 Hz, 1.8 Hz, m, Ar-H), 4.68 (s, 2H, CH2), 3.82 (s, 3H, OCH3).
13C NMR (CDCl3) d = 166.6, 150.2, 146.1, 128.2, 124.0, 118.6,
112.6, 52.3, 26.6. Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70; Br,
32.60. Found: C, 44.21; H, 3.72; Br, 32.47.
4.7.2. Methyl (E)-2-[(tert-butoxycarbonylamino)methyl]-3-
(thiophen-2-yl)acrylate 8c
Yield: 48%, white powder isolated by flash chromatography
(cyclohexane/ethyl acetate = 9:1), mp 83–84 °C. 1H NMR (CDCl3)
d = 7.84 (s, 1H, CH@), 7.51 (m, 1H, Ar-H), 7.44 (m, 1H, Ar-H), 7.09
(m, 1H, Ar-H), 5.11 (br s, 1H, NH), 4.37 (d, J = 5.3 Hz, 2H, CH2),
3.81 (s, 3H, OCH3) 1.44 (s, 9H, CH3). 13C NMR (CDCl3) d = 167.7,
155.4, 136.8, 133.8, 132.8, 130.2, 127.6, 124.4, 79.0, 51.9, 37.5,
28.1. Anal. Calcd for C14H9NO4S: C, 56.55; H, 6.44; N, 4.71; S,
10.78. Found: C, 57.01; H, 6.30; N, 5.00; S, 10.64. HRMS (ESI
297.10348) m/z: [M+Na]+ calcd for C14H19NNaO4S 320.09270.
Found: 320.09286.
4.6. Methyl (E)-2-azidomethyl-3-arylacrylates 7 (general
procedure)
Following the procedure of Sá et al.34 NaN3 (8.0 mmol, 52 mg)
was added to a stirred solution of methyl 2-bromomethyl-3-aryl-
acrylates 6 (4.0 mmol) in a mixture of acetone/H2O (3/1). The reac-

1316
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
4.7.3. Methyl (E)-2-[(tert-butoxycarbonylamino)methyl]-3-
(furan-2-yl)acrylate 8d
were transferred into a glass vial, which was placed into a stainless
steel autoclave. The solvent (4 mL) was then added under an argon
atmosphere. The autoclave was purged three times with argon
followed by three cycles with hydrogen. The desired reaction
conditions, such as H2-pressure, temperature, and time were deter-
mined in an automatic program as indicated in Tables 1–8. At the
end of the reactions, the reaction mixtures were concentrated un-
der reduced pressure. The enantiomeric excess was determinated
by HPLC or GC. The signs of the specific rotations of the enantio-
mers were detected by using a chiral detector. For the preparation
of racemic mixtures as samples for quantitative and qualitative
analyses of the hydrogenation products, the N-benzyl derivatives
were reduced with [Rh(DPPB)(COD)]BF4. The N-Boc-derivatives
8a,c were reduced with Pd/C. For the hydrogenation of 8b
[Rh(DPPB)(COD)]BF4 was also employed.
Yield: 92%, orange-red oil isolated by flash chromatography (n-
hexane/ethyl acetate = 4:1). 1H NMR (CDCl3) d = 7.55 (s, 1H, Ar-H),
7.38 (s, 1H, CH@), 6.84 (br s, 1H, Ar-H), 6.48 (dd, J = 3.0 Hz, 2.0 Hz,
1H, Ar-H), 5.03 (br s, 1H, NH), 4.41 (d, J = 6.0 Hz, 2H, CH2), 3.79 (s,
3H, OCH3), 1.40 (s, 9H, CH3). 13C NMR (CDCl3) d = 168.1, 155.6,
150.4, 145.2, 127.8, 124.5, 117.0, 112.4, 79.2, 52.2, 37.6, 28.4.
HRMS (ESI 281.12632) m/z: [M+Na]+ calcd for C14H19NNaO5
304.11554. Found: 304.11541.
4.8. 2-[(tert-Butoxycarbonylamino)methyl]-3-aryl-acrylic acid 9
(general procedure)
Methyl ester 8 (3.4 mmol) and 2 M NaOH (2 mL) in absolute
ethanol (8 mL) were stirred for 3 h. The reaction mixture was di-
luted with H2O and the ethanol was distilled off. The aqueous solu-
tion was acidified by the addition of 10% aqueous KHSO4 and
extracted with diethyl ether (2 ꢁ 50 mL). The organic layer was
washed with water (20 mL) and brine (20 mL) and dried over
anhydrous Na2SO4. The mixture was filtered and the solvent was
evaporated under reduced pressure to give 9.
4.9.1. Methyl 2-benzyl-3-(benzylamino)propanoate 10
½
a 2D2
ꢂ
¼ ꢀ12:2 (c 1.0; CHCl3) for 93% ee; 1H NMR (CDCl3)
d = 7.42–7.20 (m, 10H, Ar-H), 3.86 (d, J = 13.4 Hz, 1H, HA-CH2N),
3.80 (d, J = 13.4 Hz, 1H, HB-CH2N), 3.71 (s, 3H, OCH3), 3.10–2.77
(m, 5H, PhCH2CHCH2N), 1.88 (br s, 1H, NH). 13C NMR (CDCl3)
d = 175.1, 139.9, 138.9, 128.7, 128.3, 128.2, 127.9, 126.8, 126.3,
53.5, 51.5, 49.9, 47.7, 36.1. HPLC: Chiralcel OJ-H (150 ꢁ 4.6), flow
rate = 1.25 mL minꢀ1, UV 220 nm, n-hexane/2-PrOH = 97/3, tR =
13.8 min (S)-enantiomer and tR = 14.9 min (R)-enantiomer. Ob-
served by-product methyl 2-methyl-3-phenylpropanoate 13: 1H
NMR (CDCl3) d = 1.23 (d, J = 6.7 Hz, 3H, CH3), 3.71 (s, 3H, OCH3)
other signals are overlapping with those of 10a. 13C NMR (CDCl3)
d = 176.4, 139.2, 128.8, 128.4, 126.2, 51.5, 41.3, 39.6, 16.7. The
13C NMR spectrum is in accordance with the published data.36
4.8.1. (E)-2-[(tert-Butoxycarbonylamino)methyl]-3-phenylacrylic
acid 9a21
Yield: 73%, white crystals, mp 128–129 °C. (ca. 1:1 mixture of
rotamers);35 1H NMR (CDCl3) d = 10.80 (br s, 1H, OH), 7.90 (br s,
0.5H, CH@rotamer), 7.80 (br s, 0.5H, CH@rotamer), 7.63–7.29 (m, 5H,
Ar-H), 6.86 (br s, 0.5H, NHrotamer), 5.18 (br s, 0.5H, NHrotamer),
4.25 (d, J = 5.9 Hz, 2H, CH2), 1.45 (s, 4.5H, CH3rotamer), 1.24 (s,
4.5H, CH3rotamer). 13C NMR (CDCl3) d = 172.7 (rotamer), 171.0 (rot-
amer), 157.6 (rotamer), 155.6 (rotamer), 144.1 (rotamer), 141.0
(rotamer), 134.8 (rotamer), 134.1 (rotamer), 129.8 (rotamer),
129.4 (rotamer), 128.9, 128.7, 128.6, 127.9, 80.9 (rotamer), 79.6
(rotamer), 38.0 (rotamer), 37.4 (rotamer), 28.4 (rotamer), 28.1 (rot-
amer). HRMS (ESI 277.13141) m/z: [M+Na]+ calcd for C15H19NNaO4
300.12063. Found: 300.12142.
4.9.2. tert-Butyl 2-benzyl-3-(benzylamino)propanoate 10b
½
a 2D2
ꢂ
¼ ꢀ6:4 (c 1.0, CHCl3) for 95% ee; 1H NMR (CDCl3) d = 7.39–
7.21 (m, 10H, Ar-H), 3.85 (d, J = 13.4 Hz, 1H, HA-CH2N), 3.79 (d,
J = 13.4 Hz, 1H, HB-CH2N), 3.02–2.72 (m, 5H, PhCH2CHCH2N), 1.55
(br s, 1H, NH), 1.42 (s, 9H, CH3). 13C NMR (CDCl3) d = 174.0,
140.3, 139.2, 128.9, 128.3, 128.2, 128.0, 126.8, 126.2, 80.4, 53.7,
50.6, 48.5, 36.4, 28.0. HPLC: Chiralpak AD-H (150 ꢁ 4.6), flow
rate = 1.25 mL minꢀ1, UV 220 nm, n-hexane/2-PrOH = 99/1, tR =
10.2 min (+)-isomer and tR = 10.8 min (ꢀ)-isomer.37
4.8.2. (E)-2-[(tert-Butoxycarbonylamino)methyl]-3-(thiophen-
2-yl)acrylic acid 9c
Yield: 75%, white powder, mp 145–146 °C. (ca. 60:40 mixture of
rotamers) 1H NMR (CDCl3) d = 9.50 (br s, 1H, OH), 7.95 (br s, 0.6H,
CH@rotamer), 7.90 (br s, 0.4H, CH@rotamer), 7.55 (m, 0.4H, Ar-Hrot-
amer), 7.53 (m, 0.6H, Ar-Hrotamer), 7.49 (m, 0.6H, Ar-Hrotamer), 7.34
(m, 0.4H, Ar-Hrotamer), 7.11 (m, 1H, Ar-H), 6.38 (br s, 0.4H, NHrot-
amer), 5.10 (br s, 0.6H, NHrotamer), 4.38 (d, J = 5.7 Hz, 2H, CH2), 1.40
(s, 9H, CH3). 13C NMR (CDCl3) d = 172.7, 156.1, 137.0, 136.0,
134.0, 131.3, 128.0, 124.0, 79.8, 37.5, 28.4. HRMS (ESI 283.08783)
m/z: [M+Na]+ calcd for C13H17NNaO4S 306.07705. Found:
306.07760.
4.9.3. Methyl 3-benzylamino-2-(thiophen-2-ylmethyl)
propanoate 10c
1H NMR (CDCl3) d = 7.36–7.20 (m, 5H, Ar-H), 7.11 (dd, J = 5.2 Hz,
1.2 Hz, 1H, Ar-H), 6.89 (dd, J = 5.2 Hz, 3.5 Hz, 1H, Ar-H), 6.77 (m,
1H, Ar-H), 3.78 (d, J = 13.4 Hz, 1H, HA-CH2N), 3.74 (d, J = 13.4 Hz,
1H, HB-CH2N), 3.67 (s, 3H, OCH3), 3.20 (dd, J = 15.0 Hz, 6.5 Hz,
HA-CH2Ar), 3.08 (dd, J = 15.0 Hz, 5.8 Hz, HB-CH2Ar), 2.91–2.75 (m,
3H, CHCH2N), 1.61 (br s, 1H, NH). 13C NMR (CDCl3) d = 174.7,
141.2, 140.1, 128.3, 127.9, 126.9, 126.7, 125.5, 123.8, 53.6, 51.6,
49.8, 48.0, 30.0. HPLC: Chiralpak IA (150 ꢁ 4.6), flow rate = 1.25 -
mL minꢀ1, UV 220 nm, n-hexane/EtOH = 99/1, tR = 6.4 min (+)-iso-
mer and tR = 6.9 min (ꢀ)-isomer.37
4.8.3. (E)-2-[(tert-Butoxycarbonylamino)methyl]-3-(furan-2-
yl)acrylic acid 9d
Yield: 34%, thick brownish syrup, 1H NMR (CDCl3/CD3OD)
d = 7.53 (br s, 1H, CH@), 7.41 (m, 1H, Ar-H), 6.75 (m, 1H, Ar-H),
6.44 (dd, J = 3.4 Hz, 1.8 Hz, 1H, Ar-H), 4.34 (s, 2H, CH2), 1.35 (s,
9H, CH3). 13C NMR (CDCl3/CD3OD) d = 170.0, 156.1, 150.4, 145.3,
128.2, 124.4, 117.2, 112.2, 79.6, 37.2, 28.2. HRMS (ESI 267.11067)
m/z: [M+Na]+ calcd for C13H17NNaO5 290.09989. Found: 290.09939.
4.9.4. Methyl 3-benzylamino-2-(furan-2-ylmethyl)propanoate
10d
½
a 2D3
ꢂ
¼ ꢀ10:0 (c 1.0, CHCl3) for 90% ee, 1H NMR (CDCl3) d = 7.35–
7.20 (m, 6H, Ar-H), 6.44 (dd, J = 3.2 Hz, 1.9 Hz, 1H, Ar-H), 6.01 (m,
1H, Ar-H), 3.80 (d, J = 13.4 Hz, 1H, HA-CH2N), 3.75 (d, J = 13.4 Hz,
1H, HB-CH2N), 3.68 (s, 3H, OCH3), 3.04–2.72 (m, 5H,
ArCH2CHCH2N), 1.53 (br s, 1H, NH). 13C NMR (CDCl3) d = 174.7,
152.8, 141.3, 140.1, 128.3, 127.9, 126.8, 110.1, 106.3, 53.5, 51.7,
49.9, 45.0, 28.4. HPLC: Chiralpak IA (150 ꢁ 4.6), flow rate = 1.25 -
mL minꢀ1, UV 220 nm, n-hexane/ EtOH = 99/1, tR = 6.1 min (+)-iso-
mer and tR = 6.5 min (ꢀ)-isomer.37
4.9. General procedure for hydrogenation
The substrate (0.33 mmol) and 3.3
Rh-precatalyst (or a mixture of [Rh(COD)2]BF4 (3.3
phosphoramidite (6.6 mol) and achiral phosphine (3.3
l
mol of the corresponding
mol), mono-
mol))
l
l
l

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1317
4.9.5. Methyl 3-benzylamino-2-[5-(acetoxymethyl)furan-2-yl-
methyl]propanoate 10e
126.1, 80.3, 58.1, 49.1, 48.6, 36.3, 27.9, 24.2. A total peak-separa-
tion of both diastereomers with the HPLC-method was not possi-
ble. The determination of the diastereomeric excess and
conversion was realized by NMR.
1H NMR (CDCl3) d = 7.34–7.17 (m, 5H, Ar-H), 6.26 (d, J = 3.1 Hz,
1H, Ar-H), 5.96 (d, J = 3.2 Hz, 1H, Ar-H), 4.96 (s, 2H, OCH2), 3.79 (d,
J = 13.4 Hz, 1H, HA-CH2N), 3.73 (d, J = 13.4 Hz, 1H, HB-CH2N), 3.67
(s, 3H, OCH3), 3.03–2.81 (m, 5H, ArCH2CHCH2N), 2.37 (br s, 1H,
NH), 2.05 (s, 3H, COCH3). 13C NMR (CDCl3) d = 174.6, 170.6, 153.7,
148.2, 139.8, 128.3, 128.0, 126.9, 111.4, 107.5, 58.1, 53.5, 51.7,
49.7, 44.4, 28.4, 20.8. HPLC: Chiralcel OD-H (150 ꢁ 4.6), flow
4.9.10. tert-Butyl 2-benzyl-3-[(S)-1-phenylethylamino]
propanoate (S)-11b
NMR-spectra of both isomers correspond to the spectra of (R)-
11b. HPLC: Chiralcel OJ-H (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1
,
rate = 1.25 mL minꢀ1
,
UV 220 nm, n-hexane/2-PrOH = 97/3,
UV 220 nm, n-hexane/EtOH = 99/1, tR = 3.2 min diastereomer B
and tR = 3.8 min diastereomer A.
tR = 9.6 min major isomer and tR = 11.1 min minor isomer. The spe-
cific rotation sign of the isomers could not be clearly estimated by
the chiral detector due to their low optical power.
4.9.11. Methyl 3-[(R)-1-phenylethylamino]-2-(thiophen-2-yl-
methyl)propanoate (R)-11c
4.9.6. (R)-1-Phenylethyl 2-benzyl-3-(benzylamino)propanoate
10f
Diastereomer A: 1H NMR (CDCl3) d = 7.33–7.17 (m, 5H, Ar-H),
7.08 (dd, J = 5.1 Hz, 1.3 Hz, 1H, Ar-H), 6.85 (dd, J = 5.2 Hz, 3.4 Hz,
1H, Ar-H), 6.70 (m, 1H, Ar-H), 3.71 (q, J = 6.6 Hz, 1H, CH), 3.65 (s,
3H, OCH3), 3.20–2.55 (m, 5H, ArCH2CHCH2N), 1.47 (br s, 1H, NH),
1.30 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 174.6, 145.3,
141.3, 128.3, 126.8, 126.7, 126.5, 125.4, 123.7, 57.9, 51.6, 48.4,
48.2, 30.0, 24.5. Diastereomer B: 1H NMR (CDCl3) d = 7.33–7.17
(m, 5H, Ar-H), 7.08 (dd, J = 5.1 Hz, 1.3 Hz, 1H, Ar-H), 6.86 (dd,
J = 5.2 Hz, 3.4 Hz, 1H, Ar-H), 6.73 (m, 1H, Ar-H), 3.70 (q,
J = 6.6 Hz, 1H, CH), 3.63 (s, 3H, OCH3), 3.20–2.55 (m, 5H,
ArCH2CHCH2N), 1.47 (br s, 1H, NH), 1.30 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (CDCl3) d = 174.7, 145.5, 141.3, 128.3, 126.8, 126.7,
126.5, 125.4, 123.7, 58.1, 51.6, 48.3, 48.2, 29.9, 24.3. HPLC: Knauer
Eurocel 01 (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1, UV 220 nm, n-
Diastereomer A: 1H NMR (CDCl3) d = 7.38–7.06 (m, 15H, Ar-H),
5.87 (q, J = 6.6 Hz, 1H, CHO), 3.75 (d, J = 13.3 Hz, 1H, HA-CH2N),
3.70 (d, J = 13.3 Hz, 1H, HB-CH2N), 3.00–2.70 (m, 5H,
PhCH2CHCH2N), 1.51 (br s, 1H, NH), 1.49 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (CDCl3) d = 173.9, 141.4, 140.2, 138.8, 128.8, 128.5–
128.3, 128.0, 127.6, 126.8, 126.3, 126.0, 72.3, 53.7, 50.3, 47.9,
36.1, 22.0. Diastereomer B: 1H NMR (CDCl3) d = 7.38–7.06 (m,
15H, Ar-H) 5.83 (q, J = 6.6 Hz, 1H, CHO), 3.71(d, J = 13.2 Hz, 1H,
HA-CH2N), 3.65 (d, J = 13.2 Hz, 1H, HB-CH2N), 3.00–2.70 (m, 5H,
PhCH2CHCH2N), 1.51 (br s, 1H, NH), 1.36 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (CDCl3) d = 174.0, 141.5, 140.1, 139.0, 128.9, 128.5–
128.3, 128.0, 127.7, 126.8, 126.3, 126.1, 72.2, 53.6, 50.5, 47.9,
36.3, 21.8. HPLC: Chiralcel OD-H (150 ꢁ 4.6), flow rate = 1.25 -
mL minꢀ1, UV 220 nm, n-hexane/EtOH = 99/1, tR = 6.7 min diaste-
reomer A and tR = 7.8 min diastereomer B.
hexane/2-PrOH = 99/1, tR = 10.8 min diastereomer
tR = 12.3 min diastereomer B.
A
and
4.9.12. Methyl 3-[(S)-1-phenylethylamino]-2-(thiophen-2-yl-
methyl)propanoate (S)-11c
NMR-spectra of both isomers correspond to the spectra of (R)-
11c. Knauer Eurocel 01 (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1, UV
220 nm, n-hexane/2-PrOH = 99/1, tR = 8.1 min diastereomer B and
tR = 9.4 min diastereomer A.
4.9.7. Methyl 2-benzyl-3-[(R)-1-phenylethylamino]propanoate
(R)-11a
(S,R)-Diastereomer of 11a: 96% de, ½a D22
¼ þ34:0 (c 1.13, CHCl3);
ꢂ
1H NMR (CDCl3) d = 7.31–7.03 (m, 10H, Ar-H), 3.67 (q, J = 6.6 Hz,
1H, CH), 3.59 (s, 3H, OCH3), 2.94–2.51 (m, 5H, PhCH2CHCH2N),
1.51 (br s, 1H, NH), 1.27 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3)
d = 175.1, 145.4, 139.0, 128.7, 128.3, 126.8, 126.5, 126.3, 57.9,
51.5, 48.6, 48.0, 36.2, 24.6. Diastereomer B: 1H NMR (CDCl3)
d = 7.31–7.03 (m, 10H, Ar-H), 3.67 (q, J = 6.6 Hz, 1H, CH), 3.57 (s,
3H, OCH3), 2.94–2.51 (m, 5H, PhCH2CHCH2N), 1.51 (br s, 1H, NH),
1.27 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 175.2, 145.6,
139.0, 128.7, 128.3, 126.8, 126.5, 126.3, 58.1, 51.4, 48.6, 48.0,
36.1, 24.2. HPLC: Chiralcel OD (250 ꢁ 4.6), flow rate = 1.25 -
4.9.13. Methyl 3-(furan-2-yl)-2-{[(R)-1-phenylethylamino]
methyl}propanoate (R)-11d
Diastereomer A: 1H NMR (CDCl3) d = 7.33–7.17 (m, 6H, Ar-
H),6.22 (m, 1H, Ar-H), 5.96 (m, 1H, Ar-H), 3.70 (q, J = 6.6 Hz, 1H,
CH), 3.64 (s, 3H, OCH3), 3.00–2.52 (m, 5H, ArCH2CHCH2N), 1.47
(br s, 1H, NH), 1.29 (d, J = 6.6 Hz, 3H, CH3). 113C NMR (CDCl3)
d = 174.8, 152.9, 145.5, 141.3, 128.3, 127.3, 126.8, 126.5, 110.1,
106.3, 58.1, 51.7, 48.4, 45.2, 28.3, 24.4. Diastereomer B: 1H NMR
(CDCl3) d = 7.33–7.17 (m, 6H, Ar-H), 6.21 (m, 1H, Ar-H), 5.92 (m,
1H, Ar-H), 3.71 (q, J = 6.6 Hz, 1H, CHCH3), 3.66 (s, 3H, OCH3),
3.00–2.52 (m, 5H, ArCH2CHCH2N), 1.47 (br s, 1H, NH), 1.29 (d,
J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 174.8, 152.9, 145.4,
141.3, 128.3, 126.8, 126.5, 110.1, 106.3, 57.9, 51.7, 48.4, 45.1,
28.4, 24.6. HPLC: Knauer Eurocel 01 (150 ꢁ 4.6), flow rate = 1.25 -
mL minꢀ1
,
UV 220 nm, n-hexane/2-PrOH = 99/1, tR = 9.4 min
(R,R)-diastereomer and tR = 10.9 min (S,R)-diastereomer.
4.9.8. Methyl 2-benzyl-3-[(S)-1-phenylethylamino]propanoate
(S)-11a
NMR-spectra of both isomers correspond to the spectra of (R)-
11a. HPLC: Chiralpak IA (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1
,
UV 220 nm, n-hexane/2-PrOH = 99/1, tR = 4.0 min (S,S)-diastereo-
mer and tR = 4.4 min (R,S)-diastereomer.
mL minꢀ1
,
UV 220 nm, n-hexane/2-PrOH = 99/1, tR = 7.9 min
diastereomer A and tR = 8.8 min diastereomer B.
4.9.9. tert-Butyl 2-benzyl-3-[(R)-1-phenylethylamino]
propanoate (R)-11b
4.9.14. Methyl 3-(furan-2-yl)-2-{[(S)-1-phenylethylamino]methyl}
propanoate (S)-11d
Diastereomer A: 1H NMR (CDCl3) d = 7.45–7.17 (m, 10H, Ar-H),
3.82 (q, J = 6.6 Hz, 1H, CH), 3.00–2.62 (m, 5H, PhCH2CHCH2N),
1.73 (br s, 1H, NH), 1.46 (s, 9H, CH3), 1.40 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (CDCl3) d = 174.0, 145.4, 139.3, 128.9, 128.3, 128.1,
126.8, 126.5, 126.1, 80.3, 57.8, 49.0, 48.5, 36.6, 28.0, 24.5. Diaste-
reomer B: 1H NMR (CDCl3) d = 7.45–7.17 (m, 10H, Ar-H), 3.81 (q,
J = 6.6 Hz, 1H, CH), 3.00–2.62 (m, 5H, PhCH2CHCH2N), 1.73 (br s,
1H, NH), 1.44 (s, 9H, CH3), 1.40 (d, J = 6.6 Hz, 3H, CH3). 13C NMR
(CDCl3) d = 174.1, 145.7, 139.3, 128.9, 128.3, 128.1, 126.8, 126.5,
NMR-spectra of both isomers correspond to the spectra of (R)-
11d. HPLC: Chiralcel OJ-H (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1
,
UV 220 nm, n-hexane/EtOH = 99/1, tR = 10.4 min diastereomer A
and tR = 12.2 min diastereomer B.
4.9.15. Methyl 3-(5-(acetoxymethyl)furan-2-yl)-2-{[(R)-1-phenyl
ethylamino]methyl}propanoate (R)-11e
Diastereomer A: 1H NMR (CDCl3) d = 7.33–7.18 (m, 5H, Ar-H),
6.24 (d, J = 3.3 Hz, 1H, Ar-H), 5.90 d, J = 3.2 Hz, 1H, Ar-H), 4.95 (s,

1318
S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
2H, OCH2), 3.72 (q, J = 6.6 Hz, 1H, CH), 3.67 (s, 3H, OCH3), 3.01–2.53
(m, 5H, ArCH2CHCH2N), 2.06 (s, 3H, COCH3), 1.47 (br s, 1H, NH),
1.30 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d = 174.6, 170.5,
153.9, 148.0, 145.3, 128.3, 126.8, 126.5, 111.4, 107.3, 58.2, 57.9,
51.6, 48.3, 44.9, 28.4, 24.5, 20.8. Diastereomer B: 1H NMR (CDCl3)
d = 7.33–7.18 (m, 5H, Ar-H), 6.25 (d, J = 3.2 Hz, 1H, Ar-H), 5.93 d,
J = 3.2 Hz, 1H, Ar-H), 4.95 (s, 2H, OCH2), 3.71 (q, J = 6.6 Hz, 1H,
CH), 3.64 (s, 3H, OCH3), 3.01–2.53 (m, 5H, ArCH2CHCH2N), 2.06
(s, 3H, COCH3), 1.47 (br s, 1H, NH), 1.30 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (CDCl3) d = 174.6, 170.5, 154.0, 148.0, 145.5, 128.3,
126.8, 126.5, 111.4, 107.3, 58.2, 57.9, 51.6, 48.3, 45.1, 28.3, 24.3,
was treated with 2.5 equiv of triethylamine and 1.5 equiv Boc2O
to give in situ derivative 16a. HPLC analysis: >99% ee.
4.9.19. Methyl 2-benzyl-3-(tert-butoxycarbonylamino)propan-
oate 16a
1H NMR (CDCl3) d = 7.36–7.16 (m, 5H, Ar-H), 5.00 (br s, 1H, NH),
3.66 (s, 3H, OCH3), 3.47–2.47 (m, 5H, PhCH2CHCH2N), 1.46 (s, 9H,
CH3). 13C NMR (CDCl3) d = 174.6, 155.7, 138.2, 128.7, 128.4,
126.5, 79.2, 51.7, 47.2, 41.4, 35.8, 28.2. HPLC: Chiralpak AD-H
(150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1
, UV 220 nm, n-hexane/
EtOH = 98/2, tR = 6.7 min (S)-enantiomer and tR = 7.3 min (R)-
20.8. HPLC: Chiralcel OD-H (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1
,
enantiomer.
UV 220 nm, n-hexane/2-PrOH = 98/2, tR = 7.0 min diastereomer A
and tR = 8.0 min diastereomer B.
4.9.20. Methyl 3-tert-butoxycarbonylamino-2-(2-thiophenyl-
methyl)propanoate 16c
4.9.16. Methyl 3-(5-(acetoxymethyl)furan-2-yl)-2-{[(S)-1-phenyl
ethylamino]methyl}propanoate (S)-11e
1H NMR (CDCl3) d = 7.08 (m, 1H, Ar-H), 6.87 (m, 1H, Ar-H), 6.78
(m, 1H, Ar-H), 4.93 (br s, 1H, NH), 3.67 (s, 3H, OCH3), 3.43–2.85 (m,
5H, ArCH2CHCH2N), 1.40 (s, 9H, CH3). 13C NMR (CDCl3) d = 174.2,
155.7, 140.3, 127.0, 126.0, 124.1, 79.5, 52.0, 47.5, 41.3, 29.8, 28.4.
HPLC: Chiralpak AD-H (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1, UV
220 nm, n-hexane/EtOH = 98/2, tR = 9.6 min major isomer and
tR = 11.1 min minor isomer.37 The specific rotation sign of the iso-
mers could not be clearly estimated by the chiral detector due to
their low optical power.
NMR-spectra of both isomers correspond to the spectra of (R)-
11e. HPLC: Chiralpak IA (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1
,
UV 220 nm, n-hexane/EtOH = 99/1, tR = 7.9 min diastereomer B
and tR = 13.7 min diastereomer A.
4.9.17. General procedure for the debenzylation reaction for
determination of the absolute configuration of methyl 2-
amino-3-benzylpropanoate 14a
A solution of the corresponding benzylated amine 10a or 11a
(2.35 mmol) and 10–20% Pd(OH)2 on charcoal (350 mg) in dry eth-
anol (10 mL) was hydrogenated with stirring (ambient pressure of
hydrogen, 25 °C) until no further consumption of hydrogen was
observed. The reaction mixture was filtered to remove the catalyst
and concentrated under reduced pressure. The crude product was
treated with a saturated solution of NaHCO3 (10 mL) and extracted
with CH2Cl2 (3 ꢁ 10 mL). The organic layer was dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure
to afford product 14a as a pale yellow oil. 1H NMR (CDCl3)
d = 7.32–7.11 (m, 5H, Ar-H), 3.64 (s, 3H, OCH3), 3.01–2.70 (m, 5H,
PhCH2CHCH2N), 1.30 (br s, 2H, NH2). 13C NMR (CDCl3) d = 175.1,
138.9, 128.8, 128.5, 126.4, 51.6, 50.8, 43.4, 35.9. For the HPLC anal-
ysis a sample of the amino derivative 14a in a glass vial was treated
each with 1.5 equiv of Boc2O and triethylamine, to form in situ the
N-Boc derivative 16a. The mixture was used directly for the HPLC
analysis.
4.9.21. Methyl 3-tert-butoxycarbonylamino-2-(2-furanylmethyl)
propanoate 16d
1H NMR (CDCl3) d = 7.28 (m, 1H, Ar-H), 6.25 (m, 1H, Ar-H), 6.05
(m, 1H, Ar-H), 5.00 (br s, 1H, NH), 3.68 (s, 3H, OCH3), 3.42–2.72 (m,
5H, ArCH2CHCH2N), 1.43 (s, 9H, CH3). 13C NMR (CDCl3) d = 174.1,
155.7, 152.0, 141.5, 110.2, 106.7, 79.1, 51.8, 44.7, 41.3, 28.2, 27.9.
HPLC: Chiralcel OJ-H (150 ꢁ 4.6), flow rate = 1.25 mL minꢀ1, UV
220 nm, n-hexane/2-PrOH = 99/1, tR = 11.1 min major isomer and
tR = 12.9 min minor isomer.37 The specific rotation sign of the iso-
mers could not be clearly estimated by the chiral detector due to
their low optical power.
4.9.22. (E)-2-[(tert-butoxycarbonylamino)methyl]-3-phenyl
propanioc acid 17a
(ca. 1:1 mixture of rotamers) 1H NMR (CDCl3) d = 8.02 (s, 1H,
OH), 7.33–7.25 (m, 2H, Ar-H), 7.24–7.16 (m, 3H, Ar-H), 6.51 (br s,
0.5H, NHrotamer), 5.02 (br s, 0.5H, NHrotamer), 3.45–2.63 (m, 5H,
PhCH2CHCH2N), 1.43 (s, 4.5H, CH3rotamer), 1.38 (s, 4.5H, CH3rotamer).
13C NMR (CDCl3) d = 178.8 (rotamer), 177.9 (rotamer), 157.9 (rot-
amer), 155.9 (rotamer), 138.2 (rotamer), 138.1 (rotamer), 128.9
(rotamer), 128.7 (rotamer), 128.5, 126.6, 81.1 (rotamer), 79.6 (rot-
amer), 47.5 (rotamer), 47.1 (rotamer), 42.0 (rotamer), 41.3 (rot-
amer), 35.8 (rotamer), 35.6 (rotamer), 28.3 (rotamer), 28.2
(rotamer). For HPLC-analysis the acid 17a was esterified to its
methylester 16a by dropwise addition of an ether solution of
2.0 M TMSCHN2 until the solution retained the yellow color.
Compound 14a from product 11a (98% de; entry 3 in Table 8):
77% yield; ½a 2D3
¼ ꢀ21:5 (c 1.0, CHCl3) corresponds to the (S)-enan-
ꢂ
tiomer; HPLC analysis of N-Boc-derivative 16a: 97% ee (S).
Compound 14a from product 11a (96% de; entry 2 in Table 8):
88% yield; ½a 2D2
¼ þ19:9 (c 1.07, CHCl3) corresponds to the (R)-
ꢂ
enantiomer; HPLC analysis of N-Boc-derivative 16a: 96% ee (R).
Compound 14a from product 10a (93% ee; entry 7 in Table 2):
85% yield; ½a 2D1
¼ þ19:3 (c 1.0, CHCl3) corresponds to the (R)-enan-
ꢂ
tiomer; HPLC analysis of N-Boc-derivative 16a: 93% ee (R).
4.9.18. Methyl (S)-2-amino-3-benzylpropanoate hydrochloride
15a
4.9.23. (E)-2-[(tert-Butoxycarbonylamino)methyl]-3-(thiophen-
2-yl)propanioc acid 17c
At first, (S)-14a (0.34 g, 1.75 mmol) was dissolved with stirring
in a methanolic solution of HCl (0.65 mL, 3 M, ca. 1.1 equiv). The
addition of diethyl ether (3 mL) gave a white solid precipitate. After
cooling in a refrigerator for one hour, the solid was filtered under
an inert atmosphere, washed once with ether, and recrystallized
in 2-propanol to yield the desired product 15a in 70% yield, white
Due to the low conversion during the hydrogenation compound
17c could not be obtained in a sufficiently pure form for NMR
analysis. For the HPLC analysis the acid 17c was esterified to give
methylester 16c by dropwise addition of an ether solution of 2.0
M TMSCHN2 until the solution retained the yellow color.
powder, mp 181–182 °C. ½a D24
ꢂ
¼ ꢀ11:6 (c 1.00, methanol); 1H NMR
4.9.24. (E)-2-[(tert-Butoxycarbonylamino)methyl]-3-(furan-2-yl)
propanioc acid 17d
(CD3OD) d = 7.40–7.16 (m, 5H, Ar-H), 3.70 (s, 3H, OCH3), 3.23–2.84
(m, 5H, PhCH2CHCH2N). 13C NMR (CD3OD) d = 174.2, 138.6, 130.0,
129.8, 128.1, 52.8, 46.1, 41.0, 36.9. HRMS (ESI 194.11810) m/z:
[MꢀCl]+ calcd for C11H16NO2 194.11756. Found: 194.11745. For
the determination of enantiomeric purity a sample in a glass vial
1H NMR (CDCl3) d = 8.06 (br s, 1H, OH), 7.26 (m, 1H, Ar-H), 6.25
(m, 1H, Ar-H), 6.04 (m, 1H, Ar-H), 3.40–2.67 (m, 5H,
ArCH2CHCH2N), 1.38 (s, 9H, CH3). 13C NMR (CDCl3) d = 178.5 (rot-
amer), 177.5 (rotamer), 157.8 (rotamer), 156.0 (rotamer), 152.0,

S. Lühr et al. / Tetrahedron: Asymmetry 23 (2012) 1301–1319
1319
11. Deng, J.; Hu, X.-P.; Huang, J.-D.; Yu, S.-B.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. J.
Org. Chem. 2008, 73, 2015–2017.
141.5, 110.3, 106.9(rotamer), 106.7 (rotamer), 81.2 (rotamer), 79.7
(rotamer), 45.0 (rotamer), 44.7 (rotamer), 42.2 (rotamer), 41.1 (rot-
amer), 28.3 (rotamer), 27.9 (rotamer). For the HPLC-analysis the
acid 17d was esterified to its methylester 16d by dropwise addi-
tion of an ether solution of 2.0 M TMSCHN2 until the solution re-
tained the yellow color.
12. Hoen, R.; Tiemersma-Wegman, T.; Procuranti, B.; Lefort, L.; de Vries, J. G.;
Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2007, 5, 267–275.
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Acknowledgments
We acknowledge the highly skilled technical assistance by Mrs.
G. Wenzel and Mrs. H. Borgwaldt. For the analysis of the hydroge-
nation products by HPLC we thank Dr. C. Fischer, Mrs. S. Schareina
and Mrs. S. Buchholz. We appreciate financial support by AiF.
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