Enantioselective synthesis of β2-amino acids using rhodium-catalyzed hydrogenation

Article abstract of DOI:10.1039/b615131k

A series of protected β²-dehydroamino acids has been prepared in three steps from commercially available starting materials in good yields. These were used as substrates in rhodium-catalyzed asymmetric hydrogenation applying a mixed ligand syst

Full text of DOI:10.1039/b615131k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective synthesis of b2-amino acids using rhodium-catalyzed
hydrogenation
Rob Hoen,a Theodora Tiemersma-Wegman,a Barbara Procuranti,b Laurent Lefort,b Johannes G. de Vries,a,b
Adriaan J. Minnaard*a and Ben L. Feringa*a
Received 18th October 2006, Accepted 20th November 2006
First published as an Advance Article on the web 8th December 2006
DOI: 10.1039/b615131k
A series of protected b2-dehydroamino acids has been prepared in three steps from commercially
available starting materials in good yields. These were used as substrates in rhodium-catalyzed
asymmetric hydrogenation applying a mixed ligand system of monodentate phosphoramidites and
phosphines. Optimization of the catalyst structure was achieved by high throughput experimentation.
High enantioselectivities were obtained (up to 91%) with full conversion for a number of b-amino acids.
stereoselective alkylation of b-homoglycine derivatives,11 addition
of chiral enolates to acyliminium salts,12 Curtius rearrangement of
Introduction
enantiomerically pure succinates,13 resolution of racemic b2-amino
acids14 and enantioselective organocatalytic aminomethylation of
aldehydes.15 Limited effort has been devoted to the synthesis of
b2-amino acids by transition metal catalysis. Examples are Pd-
catalyzed allylic substitution,16 Rh-catalyzed CH activation,17 Cu-
catalyzed conjugate addition18 and Rh-catalyzed hydrogenation.19
In contrast to the asymmetric hydrogenation of b3-
dehydroamino acid esters,20 the asymmetric hydrogenation of the
corresponding b2-amino acid precursors is still less developed.
Robinson and co-workers19 have reported the asymmetric hy-
drogenation of b2-amino acid precursors. Phthalimido nitriles
were hydrogenated, which form b2-amino acids after simultaneous
hydrolysis of the phthalimido and the nitrile functional groups.
Promising enantioselectivities (78%) were obtained with Rh–
DuPHOS or Rh–BPE complexes. The substrates, however, are
prepared by Ni-catalyzed addition of the toxic hydrogen cyanide
to alkynes. The same group recently described an alternative
preparation of b2-amino acids in three steps with modest ee’s
(67%).19c
Very recently, Zheng and co-workers reported a short synthesis
of b2-amino acids via rhodium-catalyzed asymmetric hydrogena-
tion of b2-dehydroamino acids using monodentate phosphites
as ligands.21 Excellent enantioselectivities were obtained with
precursors containing 1,1-disubstituted olefinic bonds. For the
trisubstituted analogues good ee’s were accompanied by incom-
plete conversions even after 12 h at 85 atm of hydrogen pressure.
This paper prompted us to report our results on the synthesis of
b2-amino acids via asymmetric rhodium-catalyzed hydrogenation
reactions employing a mixed ligand system consisting of chiral
monodentate phosphoramidites and achiral phosphines.
Since the seminal reports on the use of monodentate ligands
in the highly enantioselective rhodium-catalyzed asymmetric
hydrogenation by the groups of Pringle,1a Feringa, De Vries,
Minnaard1b and Reetz,1c the number of studies on the use of
monodentate ligands increased spectacularly.2 Furthermore, the
fact that two monodentate ligands coordinate to the metal-
centre in the catalytically active species, was exploited by Reetz
and coworkers3 and our own group4 to show that mixtures of
monodentate ligands can be used in the hydrogenation to enhance
selectivities and reactivity.5
In recent years, we have focused on the development of new cat-
alytic systems for asymmetric hydrogenations,6 and considerable
effort has been directed towards the exploration of new substrate
classes.7
b-Peptides have attracted considerable interest in the last
decade.8 Interesting features of these molecules are that they can
fold in a predictable way to form secondary structures in solution,
they show resistance to cleavage by peptidases and other metabolic
transformations and mimic a-peptides in protein–protein and
peptide–protein interactions. The building blocks for b-peptides
are b-amino acids which can be subdivided in three categories, i.e.
b2-, b3- and b2,3-amino acids (Fig. 1).
Fig. 1 b-Amino acids.
A wide variety of methods are available to prepare enan-
tiomerically pure b-amino acids.9 The synthesis of b3-amino
acids has received most attention although a number of studies
have focused on b2-amino acids. Approaches taken include10
Results and discussion
The synthesis of the substrates was executed on a multi-gram scale,
in three steps starting from benzaldehydes 1–8 and methyl acrylate
9 (Scheme 1).
The synthesis starts with a Baylis–Hillman reaction that is
well documented22 and proceeds smoothly with good yields (77–
87%) for substrates 1 and 5–8. The methyl-substituted products
aStratingh Institute, University of Groningen, Nijenborgh 4, 9747 AG,
Groningen, The Netherlands. E-mail: a.j.minnaard@rug.nl, b.l.feringa@
rug.nl
bDSM Research, Advanced Synthesis, Catalysis and Development, PO Box
18, 6160 MD, Geleen, The Netherlands
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 267–275 | 267
©

View Article Online
Table 1 Screening of L1–L4 on the hydrogenation of 18 in i-PrOH and
a,b,c
CH2Cl2
Entry
Solvent
Ligand
Conversion
Eed,e
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
i-PrOH
i-PrOH
i-PrOH
i-PrOH
L1
L2
L3
L4
L1
L2
L3
L4
0
0
0
—
—
—
—
46
ND
—
10
0
20
< 10
0
15
Scheme 1 Synthesis of substrates 26–33.
a Reaction conditions: 0.2 mmol of substrate in 4 ml of solvent with
0.002 mmol of Rh(COD)2BF4, 0.004 mmol of phosphoramidite. b 16 h
at rt and 25 bar H2. c Conditions are reported in ref. 1b, 20a and 24. d Ee’s
were determined by chiral RP-HPLC, see Experimental section. e Absolute
configuration of product is unknown.
11–13 were obtained in low yield, due to incomplete conversions,
even after 10 d reaction time. The second step, recently reported
by Basavaiah et al.,23 is a Ritter-type reaction. This reaction
proceeded in good yields with exclusive formation of the E-isomer.
Subsequently, the dehydroamino acids 26–33 could be obtained in
high yield after straightforward hydrolysis of 18–25.
Table 2 Influence of PPh3 on the hydrogenation of 26a,b
Initially, we attempted the asymmetric hydrogenation of sub-
strate 18, applying the conditions developed previously24 for the
hydrogenation of b3-dehydroamino acids using phosphoramidite
ligands L1–L4 (Table 1). Surprisingly, when these reactions were
performed with Rh–Lx in CH2Cl2 and 25 bar of hydrogen pressure
no conversion was seen at 25 ◦C. Reactions performed with
Rh–Lx in i-PrOH gave in some cases low conversions, but the
enantioselectivities obtained were poor. Ee determination was
carried out by RP-HPLC using an acetonitrile–NaH2PO4 buffer
(see Experimental section).25
Recently, we described the successful rhodium-catalyzed asym-
metric hydrogenation of a,b-unsaturated carboxylic acids.4b In
this study, the combination of an achiral phosphine and a chiral
phosphoramidite increased the rate of the reaction and enantiose-
lectivity dramatically. The presence of a carboxylic acid instead of
the corresponding methyl ester appeared to be important. Since
the structure of 26 bears some relationship to the substrates used
in our previous study, hydrogenations were studied under similar
conditions (Table 2).
Entry
Ligand
Conversion
Eec,d
1
2
3
4
5
6
L3
L3 + PPh3
L5
L5 + PPh3
L6
L6 + PPh3
100
100
100
100
100
100
0
66
0
75
0
83
a Reaction conditions: 0.2 mmol of substrate in 4 ml of an i-PrOH–
H2O (4 : 1) mixture with 0.002 mmol of Rh(COD)2BF4, 0.004 mmol of
phosphoramidites and possibly 0.002 mmol of PPh3. b 16 h at 60 ◦C and
25 bar H2. c Ee’s were determined by chiral RP-HPLC after conversion
of product to the corresponding methyl ester (for details see experimental
section). d Absolute configuration of product is unknown.
Employing a Rh–Lx catalyst, increasing the temperature to
◦
60 C, adding 20% water4b and using carboxylic acid 26 led
to full conversion, although a racemic mixture was obtained
(Table 2). Addition of an equivalent of triphenylphosphine increased
the ee dramatically, however. The largest increase was observed
in combination with L6. The homo-combination of L6 induced
no selectivity, whereas the hetero-combination of L6 with PPh3
led to an ee of 83% (entries 5 and 6). As observed previously,
phosphoramidites substituted with two methyl groups at the 3 and
3ꢀ positions of the BINOL moiety, led to higher enantioselectivities
than the unsubstituted BINOL based phosphoramidites (entries
2 and 6).
One of the major advantages of monodentate phosphoramidite
ligands is their straightforward synthesis, which makes structural
variation easy. This has been exploited by the development of an
automated method for the parallel solution phase synthesis of
monodentate phosphoramidite ligands and their corresponding
catalyst libraries.26 This approach allows the screening of a large
number of structurally diverse phosphoramidites over a short
period of time. We have used this method to optimize the catalyst
in terms of conversion and enantioselectivity.
268 | Org. Biomol. Chem., 2007, 5, 267–275
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Fig. 2 Hydrogenation results with first library.
A first library of 48 monodentate ligands, based on 4 phospho-
rochloridites and 12 different amines and alcohols, was used in
the hydrogenation of substrate 26 at 25 bar of H2 and 40 ◦C using
one equivalent of PPh3 as the co-ligand (Scheme 2). The results
are depicted in Fig. 2.
Scheme 3 Setup of second library of phosphoramidites and phosphites.
obtained, with some exceptions, mostly phosphoramidites based
on fully aliphatic amines and phosphites. With most ligands,
enantioselectivities of >80% were obtained using PPh3 (P1) as
an achiral co-ligand. The use of other phosphines did not show
any improvements. Although modest to good ee’s were obtained
with P5, the conversions were incomplete in all cases. Contrarily
use of P6 resulted in good to excellent conversions, but the
enantioselectivities remained low.
The results of the library screenings showed that L6 (a com-
bination of PCl-3 and A4) in combination with PPh3 (P1) or
P(o-tolyl)3 (P4) led to the best results in terms of conversion and
enantioselectivity (full conversion and 90% ee).
Scheme 2 Setup of first library of phosphoramidites and phosphites.
Ligands based on a 3,3ꢀ-dimethyl BINOL (PCl-3) induced in
most cases full conversion and modest to good ee’s. By contrast,
ligands based on BINOL (PCl-1), 8H BINOL (PCl-2) and 4,4ꢀ-
dibromo BINOL (PCl-4) led to relatively low active catalysts
with, in general, decreased ee’s. The enantioselectivities induced by
ligands based on primary amines A5–A8 and alcohols A10–A12
were poor. The best results were obtained with ligands based on
combinations of PCl-3 with secondary amines A1, A2 and A4 (full
conversion and 89% ee).
Following on from these results, a second library with 16
different phosphoramidites based on 3,3ꢀ-dimethyl BINOL and 16
different secondary amines was designed. Each phosphoramidite
was combined with 6 different achiral phosphines (Scheme 3) to
afford in total 96 Rh-catalysts.
The results of the screening of the hydrogenation of substrate
26 of the second library are depicted in Fig. 3. In general, most
of the ligands performed well. Good to full conversions were
It has been observed previously that small alterations in the
phosphine structure can have large effects on the selectivity and
conversion in the hydrogenation reactions. Table 3 represents
the results obtained from a screening of structural different
phosphines on the hydrogenation of substrate 26 under optimized
conditions, i.e. Rh(COD)2BF4, L6 and PR3 (2 : 1 ratio of L6 :
PR3), MeOH, 30 ◦C, 25 bar H2. Although the variation in
enantioselectivity is not as large as for the hydrogenation of
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 267–275 | 269
©

View Article Online
Fig. 3 Hydrogenation results with first library.
Table 3 Screening of phosphinesa,b
Table 4 Expanding the scope of substratesa,b
Entry
R
Eec,d,e
Phosphinesc,d,e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph (P1)
o-Tolyl (P4)
m-Tolyl (P7)
p-Tolyl (P8)
Xylyl (P9)
Mesityl (P10)
m-ClPh (P11)
p-ClPh (P12)
p-FPh (P13)
1,2,3,4,5-FPh (P14)
1-Naphthyl (P15)
p-MeOPh (P2)
Cyclohexyl (P6)
tert-Butyl (P16)
89
91
89
85
85
33 (53)
89
88
87
0 (12)
91
66 (88)
62 (86)
0 (29)
Entry Substrate
P1 P4
P7
P8 P15
77 —(< 5)
1
2
3
4
27
28
29
33
82
83
78
85
90
86
89
82
84
81
84
85
78
91
91
56 (86)
80 (65) 79 (90)
a Reaction conditions: 0.2 mmol of substrate in 4 ml of MeOH with
0.002 mmol of Rh(COD)2BF4, 0.004 mmol of phosphoramidites and
0.002 mmol of PR3. b 16 h at 25 bar H2 and 30 ◦C. c Ee’s were determined by
chiral RP-HPLC after conversion of the products to their corresponding
methyl ester (for details see Experimental section). d Conversion is depicted
in brackets in cases where full conversion is not reached. e Absolute
configuration of products is unknown.
a Reaction conditions: 0.2 mmol of substrate in 4 ml of MeOH with
0.002 mmol of Rh(COD)2BF4, 0.004 mmol of phosphoramidite and
0.002 mmol of PR3; b 16 h, 25 bar H2 and 30 ◦C; c Ee’s were determined by
chiral RP-HPLC after conversion of product to the corresponding methyl
ester (for details see experimental section). d Conversion is depicted in
brackets in case no full conversion is reached; e Absolute configuration of
product is unknown.
consists of L6 and an ortho-substituted phenylphosphine e.g. P4
and P15.
To broaden the substrate scope, the hydrogenation of a series
of substituted b2-phenyl alanine precursors was performed. L6
was used as ligand in combination with phosphines P1, P4, P7,
P8 and P15. The results are depicted in Table 4. The highest
enantioselectivities in the hydrogenation of substrates 27–29 were
obtained using ortho-substituted phosphines P4 and P15 (up to
91% ee). While for substrates 28 and 29 the best results were
obtained with phosphine P15, substrate 27 with an o-methyl
group, was not converted using this phosphine as co-ligand,
probably due to steric hindrance. The enantioselectivity obtained
with chloro-substituted substrate 33 was in general lower than
for those obtained with the methyl substituted derivatives. In
addition to the lower ee, a drop in reaction rate was observed,
which can be seen from the incomplete conversions obtained
with phosphines P4, P7 and P15. Whereas in the hydrogenation
a,b-unsaturated carboxylic acids,4b substantial effects were also
observed in this case.
Substitution of the phenyl at the ortho position in the tri-
arylphosphine increased the ee slightly (compare entries 1, 2 and
11). Substitution on other positions had no effect. Introduction
of electron withdrawing groups had no influence on the enan-
tioselectivity (entries 7–9). On the other hand, introduction of an
electron donating methoxy group decreased the ee and the rate of
the reaction (entry 12). Sterically crowded phosphines induced low
reactivity and low selectivity (entries 6 and 14). Furthermore, alkyl
phosphines led to poorer results than aryl phosphines (entries 1,
13 and 14). This screening showed that an optimal ligand system
270 | Org. Biomol. Chem., 2007, 5, 267–275
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
of 27–29 use of the ortho-substituted phosphines gave the best
results, with 33 the less hindered phosphine P1 induced the highest
ee (85%).†
General method for Baylis–Hillman preparation of 11–17
A mixture of 100 mmol of aldehyde, 150 mmol of methyl acrylate
and 10 mmol of DABCO in 50 ml of MeOH was stirred at
RT until the reaction was complete (monitored by TLC). The
mixture was diluted with 150 ml of Et2O. The organic layer was
washed with water (2 × 150 ml), brine (150 ml), dried on Na2SO4,
filtered and concentrated. Products 11–17 were purified by column
chromatography. (SiO2; heptane : EtOAc 5 : 1) Products 11–17
were used as obtained.
Conclusions
b2-Amino acids have been prepared in high enantiomeric excess
employing rhodium-catayzed hydrogenation using a mix-ligand
approach comprising chiral and achiral ligands. The substrates are
synthesized in a 3-step procedure with reasonable yields (up to 50%
over 3 steps), starting from commercially available aryl aldehydes
and methyl acrylate (9). Optimization of the catalytic system was
performed using library screening. The results obtained in the
hydrogenations are the best so far for this class of substrate, and
comparable to the results reported by Zheng and co-workers,21
with an ee up to 91% obtained for several compounds at full
conversion.
2-(Hydroxy-o-tolyl-methyl)-acrylic acid methyl ester (11).
1
4.65 g (22.6 mmol; 23%) of a colorless oil. H-NMR (400 MHz,
CDCl3) d = 7.73–7.35 (m, 1H), 7.18–7.10 (m, 3H), 6.27 (s, 1H),
5.76 (s, 1H), 5.57 (s, 1H), 3.71 (s, 3H), 2.85 (bs, 1H), 2.28 (s, 3H);
13C-NMR (101.0 MHz, CDCl3) d = 167.1 (s), 141.2 (s), 138.7 (s),
135.6 (s), 130.4 (d), 127.4 (d), 126.2 (d), 126.2 (t), 126.1 (d), 69.2
(d), 52.0 (q), 19.1 (q); HRMS calcd for C12H14O3 206.094 found
206.095.
Experimental
2-(Hydroxy-m-tolyl-methyl)-acrylic acid methyl ester (12).
3.17 g (15.4 mmol; 31%) of a colorless oil.28 1H-NMR (400 MHz,
CDCl3) d = 7.21–7.09 (m, 3H), 7.04 (d, J = 7.3 Hz, 1H), 6.29 (d,
J = 1.1 Hz, 1H), 5.81 (d, J = 1.1 Hz, 1H), 5.46 (s, 1H), 3.65 (s,
3H), 3.21 (bs, 1H), 2.30 (s, 3H); 13C-NMR (101.0 MHz, CDCl3)
d = 166.6 (s), 141.9 (s), 141.1 (s), 137.9 (s), 128.4 (d), 128.2 (d),
127.2 (d), 125.8 (t), 123.6 (d), 72.9 (d), 51.8 (q), 21.3 (q); HRMS
calcd for C12H14O3 206.094 found 206.095.
General remarks
1H-NMR, 13C-NMR and 31P-NMR spectra were recorded on
a Varian Gemini-200, Varian VXR-300 or a Varian Mercuri
Plus. Chemical shifts are reported in d units (ppm) relative to
the residual deuterated solvent signals of CHCl3 (1H-NMR: d
7.26; 13C-NMR: d 77.0); DMSO (1H-NMR: d 2.49; 13C-NMR:
d 39.5) or relative to an external standard for 31P (H3PO4 at d
0.0). The splitting patterns are designated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), b (broad). Optical rotations were
measured with a Schmidt + Haensch Polartronic MH8. Column
chromatography was performed using silica gel (Aldrich 60, 230–
400 mesh). Mass spectra (HRMS) were recorded on an AEI
MS-902. Phosphoramidites L1–L6 were commercially available
or made by literature procedures.24 (S)-3,3ꢀ-Dimethylbinol and
phosphoramidite L5 were donated by DSM. Phosphines P1–P13
were purchased from Aldrich or Strem Chemicals.
2-(Hydroxy-p-tolyl-methyl)-acrylic acid methyl ester (13)27.
3.64 g (17.7 mmol; 35%) of a colorless oil.28 1H-NMR (400 MHz,
CDCl3) d = 7.21 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.7 Hz, 2H), 6.28
(d, J = 0.9 Hz, 2H), 5.82 (d, J = 0.9 Hz, 2H), 5.47 (s, 1H), 3.66 (s,
3H), 3.03 (bs, 1H), 2.29 (s, 3H); 13C-NMR (101.0 MHz, CDCl3)
d = 166.7 (s), 142.0 (s), 138.3 (s), 137.4 (s), 129.0 (d), 126.5 (d),
125.7 (t), 72.9 (d), 51.8 (q), 21.0 (q); HRMS calcd for C12H14O3
206.094 found 206.094.
2-[(2-Bromo-phenyl)-hydroxy-methyl]-acrylic acid methyl ester
(14)27. 23.6 g (87 mmol; 87%) of a colorless oil. 1H-NMR
(400 MHz, CDCl3) d = 7.44–7.40 (m, 2H), 7.21 (dd, J = 7.7 Hz,
7.0 Hz, 1H), 7.04 (dt, J = 7.7 Hz, 1.5 Hz, 1H), 6.23 (s, 1H), 5.84
(d, J = 4.4 Hz, 1H), 5.51 (s, 1H), 3.80 (d, J = 4.4 Hz, 1H), 3.62
(s, 3H); 13C-NMR (101.0 MHz, CDCl3) d = 166.5 (s), 140.6 (s),
139.4 (s), 132.4 (d), 129.0 (d), 128.1 (d), 127.3 (d), 126.7 (t), 122.9
(s), 70.8 (d), 51.8 (q); HRMS calcd for C11H11BrO3 270.979 found
270.981.
2-(Hydroxy-phenyl-methyl)-acrylic acid methyl ester (10)27. To
4.06 ml (40 mmol) of benzaldehyde (1) and 10 ml of a 33% (w/v)
aqueous solution of Me3N in 40 ml of MeOH was added 120 mmol
of methyl acrylate. The solution was stirred for 48 h and 400 ml
of CHCl3 and 100 ml H2O were added. The layers were separated
and the aqueous layer was extracted twice with 100 ml CHCl3. The
organic layers were dried on Na2SO4, filtered and concentrated.
The product was purified by column chromatography (SiO2;
heptane : EtOAc 5 : 1) to yield 5.9 g (30.7 mmol; 77%) of a
colorless oil. 1H-NMR (400 MHz, CDCl3) d = 7.30–7.21 (m, 5H),
6.26 (d, J = 6.0 Hz, 1H), 5.83 (s, 1H), 5.48 (d, J = 6.0 Hz, 1H),
3.62 (s, 1H), 3.60 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d =
166.3 (s), 141.9 (s), 141.2 (s), 128.1 (d), 127.4 (d), 126.4 (d), 125.4
(t), 72.4 (d), 51.6 (q); HRMS calcd. for C11H11O3 191.071 found
191.070.
2-[(3-Bromo-phenyl)-hydroxy-methyl]-acrylic acid methyl ester
(15)27. 9.62 g (35.5 mmol; 86%) of a colorless oil.29 1H-NMR
(400 MHz, CDCl3) d = 7.44 (d, J = 1.5, 1H), 7.32 (dd, J = 7.7 Hz,
1.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.12 (dt, J = 7.7 Hz, 1.8 Hz,
1H), 6.27 (s, 1H), 5.80 (s, 1H), 5.40 (d, J = 4.4 Hz, 1H), 3.63 (s,
3H), 3.50 (bs, 1H); 13C-NMR (101.0 MHz, CDCl3) d = 166.3 (s),
143.6 (s), 141.2 (s), 130.7 (d), 129.8 (d), 129.5 (d), 126.4 (t), 125.1
(d), 122.3 (s), 72.2 (d), 51.9 (q); HRMS calcd. for C11H11BrO3
271.987 found 271.987.
† Attempts to hydrogenate the bromo-substituted substrates 30–32 met
with failure. In all cases incomplete conversion was obtained. In addition
to the desired hydrogenation product, the formation of the dehalogenated
product 35 was observed, in combination with other unidentified side-
products.
2-[(4-Bromo-phenyl)-hydroxy-methyl]-acrylic acid methyl ester
(16). 23.1 g (85 mmol; 85%) of a colorless oil. 1H-NMR
(400 MHz, CDCl3) d = 7.38 (d, J = 8.4 Hz, 2H), 7.16 (d, J =
8.4 Hz, 2H), 6.26 (s, 1H), 5.78 (s, 1H), 5.41 (s, 1H), 3.63 (s, 1H),
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 267–275 | 271
©

View Article Online
3.39 (bs, 1H); 13C-NMR (101.0 MHz, CDCl3) d = 166.4 (s), 141.5
(s), 140.3 (s), 131.3 (d), 128.3 (d), 126.1 (t), 121.6 (s), 72.3 (d), 51.9
(q); HRMS calcd. for C11H11BrO3 271.987 found 271.987.
J = 7.7 Hz, 1H), 6.22 (bs, 1H), 4.16 (d, J = 5.5 Hz, 2H), 3.83
(s, 3H), 1.91 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d = 169.3
(s), 167.6 (s), 141.2 (d), 134.6 (s), 132.5 (d), 130.6 (d), 130.3 (d),
129.5 (s), 127.5 (d), 123.8 (s), 52.3 (q), 36.7 (t), 23.2 (q); HRMS
calcd. for C13H14BrNO3 313.014 found 313.013; Anal. Calc. for
C13H14BrNO3: C, 50.16%; H, 4.54%; N, 4.50%, found: C, 50.25%;
H, 4.52%; N, 4.45%.
2-[(4-Chloro-phenyl)-hydroxy-methyl]-acrylic acid methyl ester
(17)27. 19.5 g (86 mmol; 86%) of a colorless oil. 1H-NMR
(400 MHz, CDCl3) d = 7.24 (s, 4H), 6.27 (s, 1H), 5.78 (s, 1H),
5.44 (s, 1H), 3.65 (s, 1H), 3.21 (bs, 1H); 13C-NMR (101.0 MHz,
CDCl3) d = 166.5 (s), 141.5 (s), 139.7 (s), 133.4 (s), 128.4 (d), 127.9
(d), 126.2 (t), 72.4 (d), 51.9 (q); HRMS calcd. for C11H11ClO3
226.040 found 226.041.
(E)-2-(Acetylamino-methyl)-3-(3-bromo-phenyl)-acrylic
acid
methyl ester (23). 1H-NMR (400 MHz, CDCl3) d = 7.58 (s,
2H); 7.39 (dd, J = 7.3 Hz, 7.0 Hz, 2H), 7.18 (t, J = 8.1 Hz, 1H),
6.22 (bs, 1H), 4.19 (d, J = 5.9 Hz, 2H), 3.74 (s, 3H), 1.87 (s, 3H);
13C-NMR (101.0 MHz, CDCl3) d = 169.6 (s), 167.8 (s), 140.4 (d),
136.1 (s), 132.3 (d), 132.0 (d), 130.1 (d), 129.2 (s), 127.9 (d), 122.6
(s), 52.2 (q), 36.6 (t), 23.1 (q); HRMS calcd. for C13H14BrNO3
313.014 found 313.014; Anal. Calc. for C13H14BrNO3: C, 50.16%;
H, 4.54%; N, 4.50%, found: C, 50.30%; H, 4.53%; N, 4.48%.
General procedure for the synthesis of 18–25
A solution of 80 mmol of Baylis–Hillman adduct in 350 ml of
◦
CH3CN was heated to 60 C. To this mixture was added◦215 ml
of CH3SO3H. The resulting solution was warmed to 110 C and
stirred for 6 h. After cooling, the mixture was poured into 150 ml
of H2O. The solution was neutralized with K2CO3(s) (pH paper).
The resulting solution was extracted with Et2O (2 × 400 ml).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated. To the remaining yellow solid
was added 100 ml of Et2O. The pure product precipitated as a
white solid and was collected (58–65% yield).
(E)-2-(Acetylamino-methyl)-3-(4-bromo-phenyl)-acrylic
acid
methyl ester (24). 1H-NMR (400 MHz, CDCl3) d = 7.64 (s, 1H),
7.48 (d, J = 8.4, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.30 (bs, 1H),
4.23 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H), 1.92 (s, 3H); 13C-NMR
(101.0 MHz, CDCl3) d = 169.6 (s), 167.8 (s), 140.8 (d), 132.8 (s),
131.7 (d), 131.0 (d), 128.4 (s), 123.5 (s), 52.1 (q), 36.5 (t), 23.1 (q);
HRMS calcd. for C13H14BrNO3 313.014 found 313.013; Anal.
Calc. for C13H14BrNO3: C, 50.16%; H, 4.54%; N, 4.50%, found:
C, 50.15%; H, 4.51%; N, 4.48%.
(E)-2-(Acetylamino-methyl)-3-phenyl-acrylic acid methyl ester
(18)23. 1H-NMR (400 MHz, CDCl3) d = 7.78 (s, 1H), 7.50 (d, J =
7.3 Hz, 2H), 7.42–7.34 (m, 3H), 6.18 (bs, 1H), 4.32 (d, J = 5.9 Hz,
2H), 3.83 (s, 3H), 1.96 (s, 3H); 13C-NMR (101.0 MHz, CDCl3)
d = 169.6 (s), 168.2 (s), 142.4 (d), 134.0 (s), 129.5 (d), 129.2 (d),
128.6 (d), 127.7 (s), 52.1 (q), 36.7 (t), 23.2 (q); HRMS calcd. for
C13H15NO3 233.105 found 233.106; Anal. Calc. for C13H15NO3:
C, 66.92%; H, 6.49%; N, 6.01%, found: C, 66.65%; H, 6.44%; N,
5.98%.
(E)-2-(Acetylamino-methyl)-3-(4-chloro-phenyl)-acrylic
acid
methyl ester (25). 1H-NMR (400 MHz, CDCl3) d = 7.72 (s, 1H),
7.51 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 6.12 (bs, 1H),
4.31 (d, J = 5.9 Hz, 2H), 3.85 (s, 3H), 1.99 (s, 3H); 13C-NMR
(101.0 MHz, CDCl3) d = 169.6 (s), 168.0 (s), 140.9 (d), 135.3 (s),
132.5 (s), 130.9 (d), 128.9 (d), 128.3 (s), 52.2 (q), 36.6 (t), 23.2
(q); HRMS calcd. for C13H14ClNO3 267.066 found 267.066; Anal.
Calc. for C13H14ClNO3: C, 58.41%; H, 5.28%; N, 5.24%, found:
C, 58.45%; H, 5.22%; N, 5.21%.
(E)-2-(Acetylamino-methyl)-3-o-tolyl-acrylic acid methyl ester
(19). 1H-NMR (400 MHz, CDCl3) d = 7.82 (s, 1H), 7.29–7.14
(m, 4H), 6.05 (bs, 1H), 4.14 (d, J = 5.5 Hz, 2H), 3.81 (s, 3H), 2.23
(s, 3H), 1.89 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d = 169.3 (s),
168.1 (s), 141.9 (d), 136.7 (s), 133.5 (s), 130.1 (d), 129.1 (d), 128.8
(d), 128.6 (s), 126.0 (d), 52.2 (q), 36.8 (t), 23.3 (q), 19.9 (q); HRMS
calcd. for C14H17NO3 247.121 found 247.122.
General procedure for the synthesis of 26–33
The ester (25.8 mmol) and LiOH (250 mmol) in 160 ml of a 1 :
1 mixture of H2O and MeOH were stirred overnight at RT. The
mixture was diluted with 100 ml of H2O, washed with CH2Cl2 and
acidified with 2 M HCl (aq) to pH = 1. The white precipitate was
collected and dried in vacuo. The products were obtained as white
solids in >85% yield.
(E)-2-(Acetylamino-methyl)-3-m-tolyl-acrylic acid methyl ester
(20). 1H-NMR (400 MHz, CDCl3) d = 7.71 (s, 1H), 7.21 (m,
3H), 7.12 (d, J = 5.1 Hz, 1H), 6.01 (bs, 1H), 4.28 (d, J = 5.5 Hz,
2H), 3.78 (s, 3H), 2.32 (s, 3H), 1.92 (s, 3H); 13C-NMR (101.0 MHz,
CDCl3) d = 169.5 (s), 168.3 (s), 142.7 (d), 138.3 (s), 134.0 (s), 130.3
(d), 130.1 (d), 128.6 (d), 127.5 (s), 126.6 (d), 52.2 (q), 36.8 (t), 23.3
(q), 21.3 (q); HRMS calcd. for C14H17NO3 247.121 found 247.122.
(E)-2-(Acetylamino-methyl)-3-phenyl-acrylic acid (26). 1H-
NMR (400 MHz, CDCl3) d = 12.68 (bs, 1H), 7.98 (bs, 1H), 7.72
(s, 1H), 7.48–7.38 (m, 5H), 4.01 (d, J = 4.2 Hz, 2H), 1.82 (s, 3H);
13C-NMR (101.0 MHz, CDCl3) d = 169.1 (s), 168.3 (s), 141.0 (d),
134.5 (s), 129.5 (d), 129.2 (s), 129.1 (d), 128.6 (d), 36.3 (t), 22.3 (q);
HRMS calcd. for C12H13NO3 219.090 found 219.089; Anal. Calc.
for C12H13NO3: C, 65.74%; H, 5.98%; N, 6.39%, found: C, 65.35%;
H, 5.95%; N, 6.40%.
(E)-2-(Acetylamino-methyl)-3-p-tolyl-acrylic acid methyl ester
(21)23. 1H-NMR (400 MHz, CDCl3) d = 7.74 (s, 1H), 7.37 (d,
J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 6.27 (bs, 1H), 4.31 (d,
J = 5.5 Hz, 2H), 3.80 (s, 3H), 2.33 (s, 3H), 1.95 (s, 3H); 13C-NMR
(101.0 MHz, CDCl3) d = 169.7 (s), 168.3 (s), 142.6 (d), 139.6 (s),
131.1 (s), 129.6 (d), 129.3 (d), 126.6 (s), 52.1 (q), 36.7 (t), 23.1 (q),
21.3 (q); HRMS calcd. for C14H17NO3 247.121 found 247.121.
(E)-2-(Acetylamino-methyl)-3-o-tolyl-acrylic acid (27). 1H-
NMR (400 MHz, CDCl3) d = 7.90 (bs, 1H), 7.76 (s, 1H), 7.29–7.20
(m, 4H), 3.85 (d, J = 4.4 Hz, 2H), 2.23 (s, 3H), 1.78 (s, 3H); 13C-
NMR (101.0 MHz, CDCl3) d = 168.8 (s), 168.1 (s), 140.1 (d), 136.6
(s), 134.0 (s), 130.1 (s), 129.9 (d), 128.7 (d), 128.5 (d), 125.7 (d),
(E)-2-(Acetylamino-methyl)-3-(2-bromo-phenyl)-acrylic
acid
methyl ester (22). 1H-NMR (400 MHz, CDCl3) d = 7.78 (s,
1H), 7.59 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.7 Hz, 1H), 7.19 (t,
272 | Org. Biomol. Chem., 2007, 5, 267–275
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
36.4 (t), 22.4 (q), 19.6 (q); HRMS calcd. for C13H15NO3 233.105
found 233.106.
General procedure for the synthesis of solution phase
phosphoramidite ligand libraries26a
(E)-2-(Acetylamino-methyl)-3-m-tolyl-acrylic acid (28). 1H-
NMR (400 MHz, CDCl3) d = 7.97 (bs, 1H), 7.68 (s, 1H), 7.33–7.26
(m, 3H), 7.20 (d, J = 6.2 Hz, 1H), 4.01 (d, J = 4.0 Hz, 2H), 2.30
(s, 3H), 1.83 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d = 169.0 (s),
168.5 (s), 141.2 (d), 137.8 (s), 134.4 (s), 130.2 (d), 129.8 (d), 129.0
(s), 128.5 (d), 126.6 (d), 36.3 (t), 22.4 (q), 21.0 (q); HRMS calcd.
for C13H15NO3 233.105 found 233.106; Anal. Calc. for C13H15NO3:
C, 66.92%; H, 6.49%; N, 6.01%, found: C, 67.00%; H, 6.56%; N,
5.84%.
Stock solutions were prepared by dissolving the proper amounts
of every reagent necessary for the library synthesis in anhydrous
toluene (all by weight). For the phosphorochloridites a concen-
tration of 0.150 M was used, for the amines 0.158 M, and for
the triethylamine 0.538 M. Using the liquid handling robot in a
glovebox 0.333 ml (1.00 eq.) of each of the phosphorochloridites
was transferred into one of the 3 corresponding 32 wells of the
Whatman PKP filter plate. The triethylamine solution, 0.100 ml
(1.00 eq.) was added to each of the 96 wells. Next 0.333 ml (1.05 eq.)
of each of the amines was added to one of the 3 corresponding 32
wells of one of the 3 plates. The microplate was placed on an orbital
shaker and vortexed for 2 h at room temperature. The microplate
was then placed onto the vacuum manifold and filtration was
performed upon application of vacuum. The filtrates, i.e. the
solutions of different phosphoramidites in dry toluene (0.766 ml;
0.065 M) were collected and stored into a 96-well polypropylene
microplate.
(E)-2-(Acetylamino-methyl)-3-p-tolyl-acrylic acid (29). 1H-
NMR (400 MHz, CDCl3) d = 7.96 (bs, 1H), 7.68 (s, 1H), 7.38
(d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 4.01 (d, J = 4.4 Hz,
2H), 2.32 (s, 3H), 1.82 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d =
169.1 (s), 168.5 (s), 141.2 (d), 138.9 (s), 131.6 (s), 129.6 (d), 129.3
(d), 128.3 (s), 126.0 (d), 36.4 (t), 22.4 (q), 20.9 (q); HRMS calcd.
for C13H15NO3 233.105 found 233.106; Anal. Calc. for C13H15NO3:
C, 66.92%; H, 6.49%; N, 6.01%, found: C, 66.75%; H, 6.49%; N,
5.84%.
General procedure for the screening of solution phase
phosphoramidite ligand libraries in rhodium-catalyzed
hydrogenation of 2626a
(E)-2-(Acetylamino-methyl)-3-(2-bromo-phenyl)-acrylic
acid
(30). 1H-NMR (400 MHz, CDCl3) d = 7.95 (bs, 1H), 7.70 (d,
J = 8.1 Hz, 1H), 7.65 (s, 1H), 7.53 (d, J = 5.9 Hz, 1H), 7.43 (dd,
J = 7.7 Hz, 7.3 Hz, 1H), 7.32 (dd, J = 7.7 Hz, 7.3 Hz, 1H), 3.87
(d, J = 4.0 Hz, 2H), 1.78 (s, 3H); 13C-NMR (101.0 MHz, CDCl3)
d = 169.0 (s), 167.8 (s), 139.4 (d), 134.7 (s), 132.6 (d), 131.3 (s),
130.7 (d), 130.6 (d), 127.8 (d), 123.6 (s), 36.2 (t), 22.4 (q); HRMS
calcd. for C12H12BrNO3 297.000 found 296.999; Anal. Calc. for
C12H12BrNO3: C, 48.34%; H, 4.06%; N, 4.70%, found: C, 48.40%;
H, 4.03%; N, 4.67%.
Using the liquid handling robot 0.100 ml (2.0 eq.) of the
ligand solution was transferred from the microplate into 96
vials, equipped with stirring bars. Then 0.1 ml (1.0 eq.) of a
0.0329 M PPh3 stock solution in DCM, 0.25 ml (0.1 eq.) of a
0.0131 M Rh(COD)2BF4 stock solution in DCM and 2.25 ml
of a 0.073 M (50 eq.) substrate stock solution in MeOH was
added. The mixtures were capped under inert atmosphere and
transferred to a parallel hydrogenation reactor. The vials were
purged with nitrogen and then with hydrogen (25 bar) and heated
to 40 ◦C. The reaction mixtures were left stirring for 16 h. Samples
of the mixtures were analyzed by chiral HPLC to determine the
conversion and the ee (see Table 5).
(E)-2-(Acetylamino-methyl)-3-(3-bromo-phenyl)-acrylic
acid
(31). 1H-NMR (400 MHz, CDCl3) d = 7.99 (bs, 1H), 7.72 (s,
2H); 7.65 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 7.7 Hz,
1H), 7.38 (t, J = 7.7 Hz, 1H), 3.97 (d, J = 4.4 Hz, 2H), 1.81
(s, 3H); 13C-NMR (101.0 MHz, CDCl3) d = 169.1 (s), 168.1 (s),
139.2 (d), 137.0 (s), 131.9 (d), 131.6 (d), 130.9 (s), 130.6 (d), 128.4
(d), 121.9 (s), 36.2 (t), 22.4 (q); HRMS calcd. for C12H12BrNO3
297.000 found 296.998; Anal. Calc. for C12H12BrNO3: C, 48.34%;
H, 4.06%; N, 4.70%, found: C, 48.35%; H, 4.00%; N, 4.65%.
Table 5 Ee determination of 35–39a,b
Retention timesc
Entry Product Enantiomer 1 Enantiomer 2 Starting material
1
2
3
4
5
35
36
37
38
39
19.5
26.8
31.5
35.4
52.7
21.7
31.5
35.1
40.3
59.3
33.0
39.9
64.1
75.5
96.6
(E)-2-(Acetylamino-methyl)-3-(4-bromo-phenyl)-acrylic
acid
(32). 1H-NMR (400 MHz, CDCl3) d = 8.00 (bs, 1H), 7.64 (s,
1H), 7.61 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 3.97 (d,
J = 4.0 Hz, 2H), 1.81 (s, 3H); 13C-NMR (101.0 MHz, CDCl3)
d = 169.2 (s), 168.2 (s), 139.7 (d), 133.8 (s), 131.6 (d) (4×), 130.1
(s), 122.5 (s), 36.2 (t), 22.4 (q); HRMS calcd. for C12H12BrNO3
297.000 found 296.999.
a Products were analyzed as their corresponding Me-esters. b All products
were analyzed by the same method: RP-HPLC, AD-RH Chiralpak;
acetonitrile–NaH2PO4 buffer (pH 2.7) 20 : 80 (flow 0.5 ml min−1).
c Retention times in min.
(E)-2-(Acetylamino-methyl)-3-(4-chloro-phenyl)-acrylic
acid
(33). 1H-NMR (400 MHz, DMSO-d6) d = 8.00 (bs, 1H), 7.67 (s,
1H), 7.52 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 3.98 (d,
J = 4.4 Hz, 2H), 1.81 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d =
169.1 (s), 168.2 (s), 139.6 (d), 133.7 (s), 133.4 (s), 131.3 (d), 131.0
(s), 128.6 (d), 36.2 (t), 22.4 (q); HRMS calcd. for C12H12ClNO3
253.051 found 253.050; Anal. Calc. for C12H12ClNO3: C, 56.82%;
H, 4.77%; N, 5.52%, found: C, 56.50%; H, 4.74%; N, 5.50%.
General procedure for hydrogenation reactions in EndeavorTM30
In a glass tube, 0.81 mg (2 lmol) of Rh(COD)2BF4, 4 lmol of
ligand, 0.2 lmol of phosphine, 0.2 mmol of the substrate and
4 ml of solvent, was added. The small glass tube was placed in
a semi-automated autoclave with eight reactors (EndeavorTM
30
)
that was purged 4 times with nitrogen and once with hydrogen
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 267–275 | 273
©

View Article Online
and heated if necessary. Then, the autoclave was pressurized with
hydrogen. The reaction was stirred for 16 h. A sample of the
resulting mixture was converted into the corresponding methyl
ester by 2 M solution of trimethylsilyl diazomethane in ether until
the yellow color persisted. MeOH was added to the sample in those
cases where the reaction was performed in another solvent than
MeOH. This sample was filtered over a silica plug and subjected
to conversion (1H NMR) and ee determination (HPLC).
2 (a) M. van den Berg, B. L. Feringa and A. J. Minnaard, in Handbook
of Homogeneous Hydrogenation, ed. J. G. de Vries and C. J. Elsevier,
Wiley-VCH, Weinheim, Germany, 2006, ch. 28; (b) J. G. de Vries, in
Handbook of Chiral Chemicals, ed. D. J. Ager, CRC Press,Boca Raton,
2nd edn, 2005, pp. 269–286; (c) H. Guo, K. Ding and L. Dai, Chin. Sci.
Bull., 2004, 49, 2003; (d) T. Jerphagnon, J.-L. Renaud and C. Bruneau,
Tetrahedron: Asymmetry, 2004, 15, 2101.
3 (a) M. T. Reetz, T. Sell, A. Meiswinkel and G. Mehler, Angew. Chem.,
Int. Ed., 2003, 42, 790; (b) M. T. Reetz and G. Mehler, Tetrahedron Lett.,
2003, 44, 4593; (c) M. T. Reetz, Chim. Oggi, 2003, 21, 5; (d) M. T. Reetz,
G. Mehler and A. Meiswinkel, Tetrahedron: Asymmetry, 2004, 15, 2165;
(e) M. T. Reetz and X. Li, Tetrahedron, 2004, 60, 9709; (f) M. T. Reetz
and X. Li, Angew. Chem., Int. Ed., 2005, 44, 2959; (g) M. T. Reetz, Y. Fu
and A. Meiswinkel, Angew. Chem., Int. Ed., 2006, 45, 1412; (h) M. T.
Reetz and M. Surowie, Heterocycles, 2006, 67, 567.
2-(Acetylamino-methyl)-3-phenyl-propionic acid (35). 1H-
NMR (400 MHz, CDCl3) d = 9.12 (bs, 1H), 7.25–7.07 (m, 5H),
6.56 (s, 1H), 3.58–3.42 (m, 1H), 3.32–3.22 (m, 1H), 2.98–2.84
(m, 2H), 2.77–2.67 (m, 1H), 1.85 (s, 3H); 13C-NMR (101.0 MHz,
CDCl3) d = 177.4 (s), 171.7 (s), 138.0 (s), 128.8 (d), 128.5 (d),
126.6 (d), 46.5 (d), 40.4 (t), 35.7 (t), 22.7 (q); HRMS calcd. for
C12H15NO3 221.105 found 221.106.
4 (a) D. Pen˜a, A. J. Minnaard, J. A. F. Boogers, A. H. M. de Vries, J. G.
de Vries and B. L. Feringa, Org. Biomol. Chem., 2003, 1, 1087; (b) R.
Hoen, J. A. F. Boogers, H. Bernsmann, A. J. Minnaard, A. Meetsma,
T. D. Tiemersma-Wegman, A. H. M. de Vries, J. G. de Vries and B. L.
Feringa, Angew. Chem., Int. Ed., 2005, 44, 4209.
5 For a highlight see: J. Hartwig, Nature, 2005, 437, 487.
2-(Acetylamino-methyl)-3-o-tolyl-propionic acid (36). 1H-
NMR (400 MHz, CDCl3) d = 9.21 (bs, 1H), 7.15–7.08 (m, 4H),
6.38 (bs, 1H), 3.51–3.38 (m, 2H), 3.06–3.01 (m, 1H), 2.93–2.88
(m, 1H), 2.77–2.72 (m, 1H), 2.31 (s, 3H), 1.92 (s, 3H); 13C-NMR
(101.0 MHz, CDCl3) d = 178.1 (s), 171.5 (s), 136.3 (s), 136.2 (s),
130.5 (d), 129.4 (d), 126.8 (d), 126.1 (d), 45.4 (d), 40.7 (t), 33.1
(t), 22.9 (q), 19.4 (q); HRMS calcd. for C13H15NO3 235.121 found
235.122.
6 For recent examples see: (a) R. Hoen, S. Leleu, P. N. M. Botman,
V. A. M. Appelman, B. L. Feringa, H. Hiemstra, A. J. Minnaard and
J. H. van Maarseveen, Org. Biomol. Chem., 2006, 4, 613; (b) C. Simons,
U. Hanefeld, I. W. C. E. Arends, A. J. Minnaard, T. Maschmeyer and
R. A. Sheldon, Chem. Commun., 2004, 2830.
7 (a) L. Panella, B. L. Feringa, J. G. de Vries and A. J. Minnaard, Org.
Lett., 2005, 7, 4177; (b) L. Panella, A. M. Aleixandre, G. J. Kruidhof,
J. Robertus, B. L. Feringa, J. G. de Vries and A. J. Minnaard, J. Org.
Chem., 2006, 71, 2026.
8 (a) Pseudo-peptides in drug discovery, ed. P. E. Nielsen, Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim, 2004; (b) D. Seebach, T.
2-(Acetylamino-methyl)-3-m-tolyl-propionic acid (37). 1H-
NMR (400 MHz, CDCl3) d = 9.19 (bs, 1H), 7.16 (t, J = 7.4 Hz,
1H), 7.03–6.97 (m, 3H), 6.33 (bs, 1H), 3.54–3.49 (m, 1H), 3.36–
3.32 (m, 1H), 3.01–2.90 (m, 2H), 2.78–2.73 (m, 1H), 2.30 (s, 3H),
1.92 (s, 3H); 13C-NMR (101.0 MHz, CDCl3) d = 177.9 (s), 171.4
(s), 138.1 (s), 137.9 (s), 129.6 (d), 128.4 (d), 127.4 (d), 125.8 (d),
46.6 (d), 40.5 (t), 35.7 (t), 22.9 (q), 21.3 (q); HRMS calcd. for
C13H15NO3 235.121 found 235.122.
ˇ
Kimmerlin, R. Sebesta, M. A. Campo and A. K. Beck, Tetrahedron,
2004, 60, 7455; (c) R. P. Cheng, S. H. Gellman and W. F. DeGrado,
J. Am. Chem. Soc., 2001, 101, 3219.
9 (a) Enantioselective synthesis of b-amino acids, ed. E. Juaristi and
V. Soloshonok, Wiley, Hoboken, 2nd edn, 2005; (b) M. Liu and M. P.
Sibi, Tetrahedron, 2002, 58, 7991.
10 For a detailed review see:G. Lelais and D. Seebach, Biopolymers, 2004,
76, 206.
11 (a) D. Seebach, A. R. Boog and W. B. Schweizer, Eur. J. Org. Chem.,
1999, 335;(b) M. Akssira, M. Boumzebra, H. Kasmi, M. L. Roumestant
and P. Viallefont, Amino Acids, 1994, 7, 79.
12 A. A. D’Souza, M. Motevalli, A. J. Robinson and P. B. Wyatt, J. Chem.
Soc., Perkin Trans. 1, 1995, 1.
2-(Acetylamino-methyl)-3-p-tolyl-propionic acid (38). 1H-
NMR (400 MHz, CDCl3) d = 9.12 (bs, 1H), 7.07 (s, 4H), 6.32
(bs, 1H), 3.53–3.48 (m, 1H), 3.36–3.30 (m, 1H), 3.00–2.89 (m,
2H), 2.79–2.72 (m, 1H), 2.30 (s, 3H), 1.92 (s, 3H); 13C-NMR
(101.0 MHz, CDCl3) d = 178.0 (s), 171.4 (s), 136.2 (s), 134.8 (s),
129.2 (d), 128.7 (d), 46.7 (d), 40.4 (t), 35.3 (t), 22.9 (q), 21.0 (q);
HRMS calcd. for C13H15NO3 235.121 found 235.122.
13 J. J. Talley (Monsanto Company), Method of preparation chiral b-amino
acids, Patent EP 0396526, 1990.
14 (a) K. Balenovic and N. Bregnant, Tetrahedron, 1959, 5, 44; (b) K.
Kakimoto and M. D. Armstrong, J. Biol. Chem., 1961, 236, 3283; (c) E.
Testa, G. Cignarella, G. Pifferi, S. Fu¨resz, M. T. Timbal, P. Schiatti and
G. Maffi, Farmaco, Ed. Sci., 1964, 11, 895; (d) H. Yuki, Y. Okamoto
and Y. J. Kobayashi, J. Polym. Sci., Polym. Chem. Ed., 1979, 17, 3867;
(e) S. Abele, P. Seiler and D. Seebach, Helv. Chim. Acta, 1999, 82, 1559.
15 Y. Chi and S. H. Gellman, J. Am. Chem. Soc., 2006, 128, 6804.
16 (a) J. F. Bower and J. M. J. Williams, Synlett, 1996, 685; (b) J. F. Bower,
R. Jumnah, A. C. Williams and J. M. J. Williams, J. Chem. Soc., Perkin
Trans. 1, 1997, 1411.
2-(Acetylamino-methyl)-3-(4-chloro-phenyl)-propionic acid (39).
1H-NMR (400 MHz, CDCl3) d = 9.22 (bs, 1H), 7.23 (d, J = 8.4 Hz,
2H), 7.12 (d, J = 8.4 Hz, 2H), 6.43 (bs, 1H), 3.52–3.47 (m, 1H),
3.37–3.30 (m, 1H), 2.99–2.88 (m, 2H), 2.78–2.74 (m, 1H), 1.93 (s,
3H); 13C-NMR (101.0 MHz, CDCl3) d = 177.4 (s), 171.6 (s), 136.5
(s), 132.5 (s), 130.2 (d), 128.7 (d), 46.6 (d), 40.5 (t), 35.0 (t), 22.9
(q); HRMS calcd. for C12H12ClNO3 255.066 found 255.066.
17 H. M. L. Davies and C. Venkataramani, Angew. Chem., Int. Ed., 2002,
41, 2197.
18 (a) A. Duursma, A. J. Minnaard and B. L. Feringa, J. Am. Chem.
Soc., 2003, 125, 3700; (b) U. Eilitz, F. Lessmann, O. Seidelmann and
V. Wendisch, Tetrahedron: Asymmetry, 2003, 14, 189; (c) U. Eilitz, F.
Lessmann, O. Seidelmann and V. Wendisch, Tetrahedron: Asymmetry,
2003, 14, 3095; (d) A. Rimkus and N. Sewald, Org. Lett., 2003,
5, 79.
19 (a) A. J. Robinson, C. Y. Lim, L. He, P. Ma and H.-Y. Li, J. Org. Chem.,
2001, 66, 4141; (b) D. Saylik, E. M. Campi, A. C. Donohue, W. R.
Jackson and A. J. Robinson, Tetrahedron: Asymmetry, 2001, 12, 657;
(c) J. Elaridi, A. Thaqi, A. Prosser, W. R. Jackson and A. J. Robinson,
Tetrahedron: Asymmetry, 2005, 16, 1309.
20 (a) D. Pen˜a, A. J. Minnaard, J. G. de Vries and B. L. Feringa, J. Am.
Chem. Soc., 2002, 124, 14552; (b) Y. Fu, X.-X. Guo, S.-F. Zhu, A.-G.
Hu, J.-H. Xie and Q.-L. Zhou, J. Org. Chem., 2004, 69, 4648.
21 H. Huang, H. Liu, J. Deng, M. Qui and Z. Zheng, Org. Lett., 2006, 8,
3359.
Acknowledgements
The authors thank the NRSC-Catalysis for financial support.
References
1 (a) C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J. Hyett, A.
Martorell, A. G. Orpen and P. G. Pringle, Chem. Commun., 2000, 961;
(b) M. van den Berg, A. J. Minnaard, E. P. Schudde, J. van Esch,
A. H. M. de Vries, J. G. de Vries and B. L. Feringa, J. Am. Chem. Soc.,
2000, 122, 11539; (c) M. T. Reetz and G. Mehler, Angew. Chem., Int.
Ed., 2000, 39, 3889.
274 | Org. Biomol. Chem., 2007, 5, 267–275
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
22 D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103,
811.
23 D. Basavaiah and T. Satyanarayana, Chem. Commun., 2004, 32.
24 H. Bernsmann, M. van den Berg, R. Hoen, A. J. Minnaard, G. Mehler,
M. T. Reetz, J. G. de Vries and B. L. Feringa, J. Org. Chem., 2005, 70,
943.
25 Initial attempts to determine the ee by chiral GC or normal phase
HPLC were not successful, since separations of substrate/product or
enantiomers were not obtained.
de Vries, L. Lefort, J. A. F. Boogers, J. G. de Vries and D. J. Ager, Chim.
Oggi, 2005, 23, 18; (c) A. Duursma, L. Lefort, J. A. F. Boogers, A. H. M.
de Vries, J. G. de Vries, A. J. Minnaard and B. L. Feringa, Org. Biomol.
Chem., 2004, 2, 1682; (d) J. G. de Vries and L. Lefort, Chem.–Eur. J.,
2006, 12, 4722.
27 F. Coelho, W. P. Almeida, D. Veronese, C. R. Mateus, E. C. S. Lopes,
R. C. Rossi, G. P. C. Silveira and C. H. Pavam, Tetrahedron, 2002, 58,
7437.
28 Reaction was performed on 50 mmol scale.
26 (a) L. Lefort, J. A. F. Boogers, A. H. M. de Vries and J. G. de Vries, Org.
29 Reaction was performed on 41 mmol scale.
30 http://www.biotage.com.
Lett., 2004, 6, 1733; (b) ”Supplement to chiral technologies” A. H. M.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 267–275 | 275
©