Large scale enantiomeric synthesis, purification, and characterization of ω-unsaturated amino acids via a Gly-Ni(II)-BPB-complex

Article abstract of DOI:10.1016/j.tet.2004.06.087

The enantiomeric syntheses of ω-unsaturated amino acids and β-substituted ω-unsaturated amino acids were accomplished by using Gly-Ni-2[N-(N′-benzylprolyl)amino]benzophenone (BPB) as a chiral auxiliary. The synthesis provides excellent yields and high diastereoselectivities. The product crystallization followed by isomer epimerization strategy makes the reaction practical and useful for large-scale preparations. Dialkylation of the Ni(II)-complex, which was designed for mechanistic considerations, revealed that high diastereoselectivity is obtained due to the thermodynamic conformational stability of the Ni(II)-complex. The assignment of absolute configuration was accomplished by NMR, which is supported by corresponding X-ray structure and optical rotation data. Both enantiomerically pure amino acids can be synthesized in this alkylation-hydrolysis two-step strategy in multi gram scales.

Full text of DOI:10.1016/j.tet.2004.06.087

Tetrahedron 60 (2004) 8233–8243
Large scale enantiomeric synthesis, purification,
and characterization of v-unsaturated amino acids
via a Gly-Ni(II)-BPB-complex
Xuyuan Gu, John M. Ndungu, Wei Qiu,† Jinfa Ying, Michael D. Carducci, Hank Wooden
*
and Victor J. Hruby
Department of Chemistry, The University of Arizona, Tucson, AZ 85721, USA
Received 16 March 2004; revised 3 June 2004; accepted 16 June 2004
Available online 28 July 2004
Abstract—The enantiomeric syntheses of v-unsaturated amino acids and b-substituted v-unsaturated amino acids were accomplished by
using Gly-Ni-2[N-(N0-benzylprolyl)amino]benzophenone (BPB) as a chiral auxiliary. The synthesis provides excellent yields and high
diastereoselectivities. The product crystallization followed by isomer epimerization strategy makes the reaction practical and useful for
large-scale preparations. Dialkylation of the Ni(II)-complex, which was designed for mechanistic considerations, revealed that high
diastereoselectivity is obtained due to the thermodynamic conformational stability of the Ni(II)-complex. The assignment of absolute
configuration was accomplished by NMR, which is supported by corresponding X-ray structure and optical rotation data. Both
enantiomerically pure amino acids can be synthesized in this alkylation–hydrolysis two-step strategy in multi gram scales.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
boron neutron capture therapy.8 The masked diol, obtained
by osmylation of the double bond, is a useful equivalent of
an a-amino acid aldehyde.9
Proteinogenic amino acids have been extensively applied to
the area of synthetic organic chemistry.1 However,
opportunities for the use of these naturally occurring
amino acids for synthetic purposes are hampered by the
limited number of functional groups on the side chains. In
addition, replacing natural amino acids with nonproteino-
genic counterparts often is applied to peptides and proteins
in order to change their secondary structure and function-
alities in order to enhance binding to specific receptors,2
or to obtain more potent inhibition of target enzymes.3
v-Unsaturated amino acids are of value in terms of their
biological importance and their utility as asymmetric
synthetic building blocks.4 The double bond is a masked
functional group, and is stable to most acidic and basic
reaction conditions. As a precursor, it can be easily
transferred to v-hydroxyl, v-halogen, v-epoxy, v-amino,
aldehyde, and carboxyl amino acids.5 They also have been
used in cyclization of peptides through ring closing
metathesis.6 They act as precursors of boron containing
biomolecules,7 which are interesting for application in
In the course of our ongoing peptide and nonpeptidomimetic
research, a practical large-scale synthesis of enantio-
merically pure v-unsaturated amino acids 1 and 2 (Fig. 1)
has become required in several of our research projects. For
example, both the enantiomerically pure forms of allylgly-
cine were used as precursors in the synthesis of [3.3.0]-
BTD[2,3] (bicyclic b-turn dipeptide) Leu-enkephalin ana-
logues.10 The two enantiomers of homoallylglycine have
been used in the development of a novel strategy for [6,5]-
bicyclic b-turn dipeptides.11 Homoallylglycine and bis-
homoallylglycine, both in enantiomerically pure forms,
currently are being used for the synthesis of [4.3.0]- and
[5.3.0]-BTD[2,3]-Leu-enkephalin analogues. v-Unsaturated
Keywords: Ni(II)-complex chiral auxiliary; Alkylation; Diastereo-
selectivity; Epimerization; Amino acids.
*
Corresponding author. Tel.: þ1-520-621-6332; fax: þ1-520-621-8407;
e-mail address: hruby@u.arizona.edu
Current address: Tularik Inc. 1120 Veterans Blvd. South San Francisco,
CA, 94080, USA.
†
Figure 1. Structures of the v-unsaturated amino acids and the (S)-Ni(II)-
complex auxiliary.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.087

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X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
amino acids with b-substituents provide further constraints
and functionality at b-positions.12 b-Phenyl-d, e-unsatu-
rated amino acid 2 was the first example we synthesized
using a Ni(II)-complex, and it was used in the synthesis of
functionalized thiazolizidinone [4.3.0]-bicyclic b-turn
mimetics.13 For all of these projects and other potential
applications, enantiomerically pure v-unsaturated amino
acids are needed in multi-gram quantities.
Some v-unsaturated amino acids have been isolated from
mushrooms. For example, (S)-allylglycine was isolated
from Amanita, while (S)-homoallylglycine was found in
Amanita gymnopus.14 S- and R-allylglycine are commer-
cially available (Acros, Pittsburgh, PA, USA) and the
enzymatic separation of S-allylglycine from its racemate is
well described.15 v-Unsaturated amino acid analogue
synthesis from Sharpless asymmetric epoxidation also has
been reported.16 However, it is more direct and less
expensive to synthesize them by using a Ni(II)-complex in
a two-step strategy,0 because the essential part of auxiliary,
(S)-BPB {2-[N-(N -benzylprolyl)amino]benzophenone},
can be reused in the synthesis of the Gly-Ni(II)-BPB-
complex. This chiral auxiliary has been widely used in
amino acid synthesis since it was developed by Belokon
et al. in 1985.17 Many different types of amino acids have
been synthesized using different reactions, such as alkyl-
ation,18 Michael addition,19 and the aldol reactions.20
Although these synthetic methodologies can introduce
different side chain groups, the introduction of an
v-terminal double bond using a Ni(II)-complex was only
reported by Collet et al. with low yields and limited
preparative applications.7,21 Application of Ni(II)-com-
plexes for the synthesis of unsaturated amino acids as
synthetic building blocks for constrained amino acids, and
dipeptides is, however, limited by undeveloped methods
especially for large-scale synthesis. We report herein a full
account of the preparation of these amino acids on multi-
gram scales. The mechanistic considerations involved in the
alkylation, characterization of the stereochemical outcome,
and the diastereoselectivities of the Ni(II)-complex products
also were investigated and are discussed.
Scheme 1. The alkylation of the Ni(II)-complex.
better results and also provided a homogenous reaction
(Scheme 1). The enolate generation, which was indicated by
formation of a green color occurred within 2 min, and the
reaction was completed in 3 min at room temperature. No
difference was observed when ground KOH was used
instead of ground NaOH.
The alkylation in DMF was optimized using different
temperatures (Table 1). It was found that the reaction was
prolonged at lower temperatures, and gave poorer dia-
stereoselectivities, while elevated temperatures gave incon-
clusive results, and the Ni(II)-complex was partially
decomposed. The best diastereoselectivity was obtained at
ambient temperature with a reaction time of less than 5 min.
Based on these reaction results and considering an
exothermic reaction in a large scale synthesis, we scaled
up the alkylation at ambient temperature in a water bath in
5 min, and the reaction was very efficient (Table 1).
5-Bromo-1-pentene 4c was used in the Ni(II)-complex
alkylation under the same reaction conditions with high
diastereoselectivity (Table 1). When allyl bromide was used
as an electrophile, an unidentified byproduct was generated,
and lowing the reaction temperature to 0 8C did not result in
any improvement. However, when the allylic chloride 4a
was used at room temperature, the reaction was very clean
and gave a diastereoselectivity of 87:13. In order to avoid
dialkylation, all the above electrophilic halides 4a,c were
2. Results and discussion
2.1. Monoalkylation of Ni(II)-complex
The Ni(II)-complex was synthesized in three steps on a
50–100 g scale based on a reported method.22 The
alkylation of 4-bromo-1-butene 4b on Ni(II)-complex has
been reported in low yield,7,21 which may be attributed to
the limited solubility of Ni(II)-complex (,40 mg/mL) and
sodium hydroxide in acetonitrile. The alkylation reaction
was optimized by first modifying the solvent, and then
temperature conditions were investigated. We found that
although the Ni(II)-complex was soluble in methanol, the
alkylation was slow and TLC showed only a 25%
conversion in 16 h. The reaction can be accelerated by
using excess NaOMe as base instead of sodium hydroxide.
However, the reaction was not completed in 24 h and the
Ni(II)-complex suffered significant decomposition during
the prolonged reaction time under argon atmosphere. THF
was not an efficient solvent either, but DMF gave much
Table 1. The alkylation conditions and results in DMF
Electrophile Reaction temp. Reaction time Isomer ratioa Yield
( 8C)
(min)
(%)b
1
2
3
4
5
6
7
8
4b
4b
4b
4b
4b
4b
4a
4c
230
0
35
10
5
10
20
5
92:8
91:9
95:5c
95:5
95:5
95
95
98
96
96
20
20
20
50
20
20
Inconclusive ,80
5
5
87:13c
93:7c
96
98
a
b
c
1
The diastereomeric ratio (2S/2R) was determined by H NMR.
Combined yield of two diastereomers.
The diastereomeric ratios were obtained in the reactions on a 20 g scale.
All the other results were obtained in ,1 g scale.

X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
8235
used in slightly less than 1 equiv. For the 20 g scale
reactions, no secondary alkylation was observed under these
reaction conditions, and no elimination of halogen was
detected.
The crude product mixture was dissolved in benzene and
washed with brine four times to remove DMF. We also tried
using toluene but the Ni(II)-alkylation product has limited
solubility in it. While DCM and chloroform are good
solvents, washing with brine was not efficient with these
solvents. Fractional recrystallization was used to isolate the
products, because the minor products often overlap on TLC
(hexane/acetone¼1:1), and thus it was not always easy to
purify these diastereomers with flash liquid chromatograph.
The enantiomeric purity of the major isomer 5a and 5b was
improved by fractional recrystallization from a mixture of
DCM and ether. A fast flash chromatograph was usually
employed for the mother liquor after the first crystallization
to separate the remaining diastereomeric mixture from
impurities which came from the starting material of the
Ni(II)-complex and from decomposition in the reaction. The
reddish eluent was used for further recrystallization, and
finally the minor enriched mixture was subjected to the
same alkylation reaction conditions for 5 min. Epimeriza-
tion transferred the minor product to the major one with the
same diastereomeric ratio (Scheme 1). In this way, over
90–95% yield of alkylation products can be collected with
.98% de. The S(2R) allyl alkylation product 6a in mother
liquor was further purified on an analytical silica gel HPLC
column (IBM Silica 2872053, hexane/2-propanol¼98:2,
UV detector at 232 nm) for characterization. Attempts
to characterize the minor product S(2R) of homoallyl
alkylation 6b using the same HPLC column failed due
to poor resolution. In the case of 5-bromo-1-pentenyl
bromide alkylation, both the major 5c and minor 6c
products crystallize out in DCM/ether solution at the
same time but as different crystals. The mother liquor,
however, became a pure solution of major product 5c.
The crystal mixture was subjected to three fractional
crystallizations until the mixture became enriched with the
S(2R)-product.
Figure 2. The proton NMR spectra of the downfield protons Ha and Hb of
unalkylated and various alkylated complexes. (i) Ni(II)-complex 3; (ii)
S(2S)-monoalkylated product; (iii) S(2R)-monoalkylated product; (iv)
dialkylated product.
2.2. Dialkylation and face selectivity
Previous studies have attempted to understand the origin of
the high diastereoselectivity in alkylation reactions of the
Gly-Ni(II)-BPB-complex.18,19 Although the kinetic con-
trolled reaction has been studied for dialkylation,23 the
difficulty in understanding the absolute configuration of
the a, a-dimethyl product makes the results unclear. Since
the exact model to mimic the kinetic vs thermodynamic
selectivity in monoalkylation is not available due to fast
epimerization, we designed the following dialkylation
reactions (Scheme 2) by using different aliphatic electro-
philes so that the kinetic ratio for reaction in dialkylation
could be trapped. The reactions were accomplished in
DMF and 10 equiv. of NaOH at ambient temperature. The
dialkylation reaction times and their diastereoselectivities
are listed in Table 2. For comparison, the monoalkylation of
4-bromo-1-butene 4b and MeI also is listed.
The configuration of the major product generated from the
si-face of the glycine enolate was assigned as S(2S).18,19 The
diastereomeric ratio was determined from the relative
intensity of the peaks in the region of 8.0–8.5 ppm (Fig. 2)
in the 1H NMR of the crude product. The two most
downfield proton peaks are doublets of the ortho protons Ha
and Hb in a ratio of 1:2 in the Ni(II)-complex and its
products, as indicated by the following results observed in
DQF-COSY and 1D NOE experiments. The spin systems in
aromatic ring B and C, identified in the DQF-COSY
spectrum, were differentiated by the NOE correlation
between the Hb protons and both a and d protons in proline.
The spin system in ring A is unique. The resonance from
the Ha and Hd protons were unambiguously assigned using
the NOE’s between Hd and the protons in ring C, and
between Ha and the protons in ring B. All the S(2S) products
5 have their Ha and Hb protons at about 8.0–8.2 ppm (Fig. 2,
item ii). However, in the S(2R) products 6 proton spectra,
the Ha proton resonance shifts downfield (,8.5 ppm), while
an upfield shift occurs for the Hb (,8.0 ppm) (Fig. 2, item
iii).
In our first attempt at dialkylation, the purified homoallyl
Gly-Ni-(S)-BPB 5b was used in a reaction with MeI
(Scheme 2). The reaction cannot be monitored because the
product 9 shared the same Rf value as the starting material
5b on TLC (acetone/hexane¼1:1, Rf¼0.45). The reaction
was optimized for completion in 3 h by adding another

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X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
diastereoselectivity in alkylation actually may be generated
by epimerization. The epimerization reaction proved to be
very fast in transferring the minor enriched mixture to the
major product. It explains why the room temperature
reaction actually can provide better diastereoselectivity.
We also found that the diastereoselectivity in asymmetric
dialkylation increased if a large electrophile (1-bromo-4-
butene compare to methyl iodide) was used in the second
alkylation.
It should be pointed out that the newly generated chiral
configuration in dialkylation products cannot be determined
based on the most downfield proton peaks in NMR spectra.
Both products gave Ha and Hb close to 8.2 ppm (see Fig. 2,
item iv), Interestingly, we were able to determine the weak
NOE interactions between the protons on the side chains
and N p-benzyl ring in both 8 and 9. These unexpected
results indicated that the N p-benzyl ring stays on the Ni(II)-
complex plane. This assumption was confirmed by the
X-ray structure of 8 (Fig. 3), which is consistent with NMR
NOE results. The a-configurations of 8 and 9 were assigned
as in Scheme 2, relating them to the known absolute
configuration of proline.
Scheme 2. Dialkylation of the Ni(II)-complex and their diastereo-
selectivity.
Table 2. Alkylation and their diastereoselectivities
Starting
material
Electro-
phile
Reaction
time
Diastereo-
meric ratioa
Yield
Ni(II)-3
5b
Ni(II)-3
5d
4b
MeI
MeI
4b
5 min
3 h
5 min
1.5 h
2R/2S
8/9
2R/2S
8/9
5:95
45:55
24:76
32:68
98
65
80
50
a
The diastereomeric ratio was determined by 1H NMR.
Figure 3. X-ray structure of the dialkylation product 8.
3 equiv. of MeI after the 1.5 h reaction. However, the
diastereoselectivity was only 45:55; almost no si-face
preference. We also synthesized the methyl Gly-Ni-(S)-
BPB 5d from the Ni(II)-complex as starting material
(Scheme 2). This gave a 24:76 diastereomeric mixture.
This mixture also can be obtained by using racemic alanine
in generation of the Ni(II)-complex. However, an attempt to
isolate the pure diastereomeric products by fractional
crystallization failed. The mixture then was used for
alkylation with 4-bromo-1-butene, and the reaction was
completed in about 1.5 h. Although this reaction was faster
than the first one, it was not as clean. The diastereomeric
ratio was 32:68. Both of these kinetic control selectivities
are much lower than the thermodynamic control mono-
alkylation results we observed in Table 1.
It is interesting to note that the chemical shifts of the most
downfield protons Ha and Hb of the dialkylation products are
similar by comparison to the starting material 3 and other
S(2S) monoalkylation products 4a–c. By examining all of
the crystal structures,19d,24 we found that the NMR results
are consistent with the X-ray structure conformation. For
the S(2R) products, the N p-benzyl ring moves outside of
Ni(II)-complex plane which results in no NOE interactions
between the proton Ha and Hb in the Ni(II)-complex
products. As a result, both the chemical shifts of Ha
(8.5 ppm) and Hb (,8.0 ppm) became ‘normal’. When the
N p-benzyl ring covers the top of Ni(II)-complex plane, the
Ha was shielded and shifts upfield, while Hb was deshielded
and shifts downfield. It is not completely clear why, in
dialkylation products, the N p-benzyl ring can stay on top of
the Ni(II)-complex plane and both products 8 and 9 show Ha
and Hb proton close to 8.1 ppm. However, it is noteworthy
that all S(2R) products gave negative data for their optical
rotations while the others are always positive. Presumably
From the above results, we conclude that the kinetic si-face
selectivity for monoalkylation is very limited. For the small
electrophile, the si-face selectivity is not that obviously
favored over the re-face reaction. We suggest that the high

X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
Table 3. The secondary bromide in alkylation
8237
these results also are related and consistent with different
conformations of the Ni(II)-complex in these isomers.
Entry
12 (equiv.)
S.M.
13aa
13ba
13ca
From the above analysis, we assume that the face selectivity
in Ni(II)-complex is not caused simply by the steric
hindrance of the N p-benzyl ring25 because it can move
outside of the Ni(II)-complex plane. There is no evidence
for the a-H existing in a pseudo-axial or pseudo-equatorial
position19a, because in the transition state, the Gly-Ni(II)-5-
membered ring can be very close to planar. However, the
difference in the thermodynamic stability of the two
alkylated products, due to their different conformations,
gives high diastereoselectivity. Efforts to increase the
selectivity by increasing the steric hindrance of the N p-
substituted benzyl ring25 is not necessary in monoalkyl-
ation, because the minor product can be converted to the
major one by epimerization. Asymmetric synthesis of a,
a-dialkylated amino acids26 using different nucleophiles
also is not a practical method, due to the low diastereo-
selectivity and low isolated yield.
1
2
3
4
5
6
1
2
2.5
2.8
3
7
0
0
0
0
0
21
15
15
10
11
9
10
6
4
4
3
62
76
81
86
86
85
4
6
a
The diastereomeric ratios were determined by 1H NMR.
High diastereoselectivity of S(2S,3S)/S(2R,3R) is generated
from si-face selectivity. Again, it is lower than the results in
Table 1, even though the electrophile is much bulkier due to
the b-substitution. The major product S(2S,3S) is a kinetic
product, while the S(2S,3R) minor product may have been
produced from epimerization of the S(2R,3R) product. The
high selectivity for S(2S,3S)/S(2S,3R) at position 3 is
difficult to understand. A model in previous work18a
suggested that one of the electrophilic enantiomers is
matched in the reaction transition state. This explains why
high diastereoselectivity was obtained when using 3 equiv.
of bromide. As a matter of fact, we recovered the remaining
bromide from the column, presumably an (R)-enriched form
if the reaction is a typical SN2 reaction. This enriched
compound has an optical rotation of [a]2D4¼þ8.98 (c¼2.4,
CHCl3). However, when we used this enantiomerically
enriched bromide (2 or 3 equiv.) in an alkylation with the
(R)-Ni(II)-complex, presumably a matched case, the
reaction did not provide any obvious diastereomeric
improvement. It should be pointed out that although
about 1.5 equiv. of bromide can be recovered and reused
in the alkylation, its optical activity drops (racemized)
dramatically during storage.
2.3. Alkylation with racemic secondary bromide
When a secondary bromide is used in the alkylation
reaction, four possible isomers of the b-substituted
alkylation products can be generated.18b The secondary
bromide 1-bromo-3-butenyl-benzene 12 was synthesized in
two steps from commercially available starting materials in
moderate yield (Scheme 3).27 Both the alcohol and bromide
were purified by liquid chromatograph. Alkylation of the
secondary bromide 12, generated a mixture of three
diastereomers (Scheme 3). This reaction was examined
using different amounts of bromide at ambient temperature
and the results are summarized in Table 3. The results
showed that the diastereomeric ratio increased as the
amount of bromide increased to 2.8 equiv. Although the
diastereoselectivity was increased as the temperature
decreased,13 the selectivity dropped when the reaction was
scaled up due to the exothermic nature of the reaction. In
practice, 3.0 equiv. of racemic bromide was used so that the
reaction gives high diastereoselectivity.
A fast flash column chromatograph was used to recover the
bromide and to purify the product mixture before fractional
crystallization. In the process, a 1:1 mixture of S(2S,3S) and
S(2R,3R) crystals and an S(2S,3S) enriched mother liquor
was obtained. A crystal carefully prepared for single X-ray
crystallography, was found to be a diastereomeric co-crystal
of S(2S, 3S) and S(2R, 3R).24 Interaction between the
racemic side chain groups could be the major packing force
in initial crystalline formation, which can explain why a
diastereomeric co-crystal forms. This 1:1 co-crystal mixture
can be further isolated by flash liquid chromatograph. The
S(2S,3R) 13b minor product (,3%), which has a similar Rf
value as the S(2S,3S) product, always coexisted in the
mother liquor [Rf¼0.62 for S(2S,3S) and 0.59 for S(2R,3R)
in a 1:1 mixture of hexane and acetone]. The purity of the
major product in the mother liquor was further improved by
crystallization.
The unique NMR spectra of these monoalkylation products
can be used to assign their configurations at position 2. Both
the major S(2S,3S) and minor S(2S,3R) products have the
typical Ha and Hb signal near 8.2 ppm (Fig. 2). The minor
product S(2R,3R) has its Ha proton at 8.6 ppm, while the Hb
is even further upfield, overlapping with the other aromatic
protons. The 3S configuration in the major product S(2S,3S)
was further confirmed by NOE studies of the [6,5]-bicyclic
b-turn dipeptide13 and by the X-ray structure of the
co-crystal.24 The minor product S(2R,3R) was crystallized
Scheme 3. The synthesis of a secondary bromide and its alkylation.

8238
X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
indicated the completeness of hydrolysis. After evaporation,
the above products mixture was diluted in aqueous solution,
and (S)-BPB 14 was extracted with CHCl3, recovering 96%.
This byproduct can be used in the regeneration of Ni(II)-
complex 3 without further purification. The mixture of
amino acid and Ni2þ salt in aqueous phase was then
concentrated and loaded on an Hþ form ion exchange resin
column. It is very important to wash the column with
deionized water to pH¼7 before washing with the
concentrated aqueous ammonia and water (4:1) mixture.
For 15c and d, a mixture of ammonia, water and ethanol
(4:1:2) is needed for fast collection of the amino acid. The
Ni2þ salt remained on the column which was regenerated
with 1 N HCl solution. The amino acids were collected after
evaporation of the ammonia aqueous solution and the
residue was redissolved in small amounts of water and dried
by lyophilization. All the amino acids can be collected in
this way in over 95% yield.
Scheme 4. Epimerization of the S(2R,3R) to the S(2S,3R) product.
and its single X-ray structure was obtained.24 It was found
that the crystalline form had two conformers that showed
the N p-benzyl ring was outside of the Ni(II)-complex plane,
which is consistent with the NMR result. The stereoisomer
relationship of the S(2R,3R) and S(2S,3R) compounds can
be confirmed by epimerization (Scheme 4). The assigned
S(2R,3R) 13a minor product was subjected to the same
reaction conditions of alkylation, but at ambient tempera-
ture and at different reaction times, with the results
shown in Table 4. The reaction gave a mixture of
S(2R,3R):S(2S,3R)¼16:84 at equilibrium after 20 h reac-
tion. However, decomposition occurred frequently with
more than half of the material destroyed in about 2 h, and
over 70% of the starting material was decomposed in the
20 h reaction. The major product S(2S,3R) was isolated
from the S(2R,3R) isomer by liquid chromatograph. This
epimerization provides a unique way to obtain this pure
minor product for characterization.
(R)-Amino acids are important in peptidomimetics at
position 2 of Leu-enkephalin analogues28 and at position 7
in a-MSH analogues.29 Thus R-allylglycine, R-homoallyl-
glycine, and R-bishomoallylglycine derivatives have been
synthesized in 3 g scales from the (R)-Ni(II)-complex,
which was synthesized from (R)-proline in comparable
yields (Scheme 6). (R)-2-Amino-hept-6-enyl carboxylic
acid was synthesized on a 1 g scale by using bromide 12
as an electrophile.
Table 4. The epimerization of Ni(II)-alkylation product
Entry
Reaction time (min)
Starting materiala
Producta S(2S, 3R)
1
2
3
4
5
20
40
120
360
20 h
82
43
23
19
16
18
57
77
81
84
a
1
The percentages were determined by H NMR.
2.4. Hydrolysis of the Ni(II)-complex
Amino acids 15a–d were generated by decomposition of
the Ni(II)-complex products with 3 N HCl in methanol (1:1)
(Scheme 5). A mixture of methanol and DCM (approx. 2:1)
was used to increase the solubility of the Ni(II)-alkylated
product. Hydrolysis of b-phenyl-homoallylglycine 13c was
very slow and the disappearance of the reddish color
Scheme 6. Synthesis of the (R)-Ni(II)-complex and the R-amino acids.
During purification of (R)-4-pentenyl-glycine-Ni(II)-BPB-
complex, a purple minor product, R(2S), crystallized out
before the red major product, R(2R). Both the R(2R) and
R(2S) products were characterized using samples collected
by hand picking individual crystals. It is interesting to note
that visually the R(2S) minor product is a notably darker
color, and apparently a different crystal form compared
with its S(2R) enantiomer, which was synthesized from the
(S)-Ni(II)-complex. However, in attempts to obtain better
purity crystals in small scales for X-ray analysis, we found
that the R(2S) and S(2R) compounds grew as identical red-
orange plate-like crystals. Because of the visual differences,
we were curious to see if a racemic crystal could be grown.
When equal quantities of R(2S) and S(2R) were mixed in
DCM and ether, red-orange plates were again obtained.
X-ray diffraction determined that these crystals are identical
to the pure individual enantiomers and thus indicates that
Scheme 5. Hydrolysis of the alkylated Ni(II)-complex.

X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
8239
spontaneous self-resolution has occurred. The X-ray
diffraction results of these molecules will be reported
elsewhere.
pure by 1H NMR spectroscopy. Unless otherwise stated, all
reactions were run under an atmosphere of argon.
4.1.1. 1-Bromo-3-butenyl-benzene (12). In a 500-mL
flame-dried flask, 1 M allyl magnesium bromide in diethyl
ether (100 mL, 100 mmol) was diluted with 140 mL of
anhydrous ether. The solution was cooled down to 0 8C
before benzaldehyde (10.1 mL, 100 mmol) was added
slowly. It was kept at 0 8C for 1 h before being quenched
by slowly adding 60 mL of 10% H2SO4. The organic phase
was then separated and washed with NaHCO3 and brine, and
dried over anhydrous MgSO4. The solution was concen-
trated in vacuo and the crude material was purified by flash
liquid chromatograph. A colorless liquid product (11) was
obtained (14.1 g, 95% yield).
3. Conclusions
The Ni(II)-complex derived from a glycine Schiff base with
2-[N-(N0-benzylprolyl)amino]benzophenone was found to
be an ideal equivalent of nucleophilic glycine in reactions
with various alkyl halides affording an efficient, generalized
and practically useful method for the large scale preparation
of enantiomerically pure v-unsaturated amino acids. High
diastereoselectivities and high yields were achieved by
homogenous reaction and epimerization. The fractional
crystallization employed in this method has been a reliable
way to prepare diastereomerically pure Ni(II)-complex
products on about a 20 g scale, which after hydrolysis
affords multi-gram amounts of enantiomerically pure amino
acids. This synthetic strategy and the crystallization
purification methods are not limited to the synthesis of
v-unsaturated amino acids but to all the possible electro-
philes that can be used in Ni(II)-complex alkylation. It
should be indicated that the above simple but efficient
method could not be used for the synthesis of vinylglycine
analogues and b-substituted allylglycine analogues. A novel
methodology to synthesize these v-unsaturated amino
acids by using the Ni(II)-complex as a chiral auxiliary are
presently under investigation.
The above alcohol 11 (14.1 g, 95 mmol) was dissolved in
250 mL anhydrous ether in a 500-mL flame-dried flask. The
solution was cooled down to 0 8C and then PBr3 (4.75 mL,
150 mmol) was added. The reaction was kept at 0 8C until
completed in 45 min. It was quenched by saturated NH4Cl
aqueous solution (150 mL). The organic phase was then
separated and washed with NaHCO3 and brine, and dried
over MgSO4. The product solution was then concentrated in
vacuo, and the residue was purified on a silica gel column
using hexane. A slight yellowish liquid (12.8 g, 65% yield)
1
was obtained. Rf¼0.33 (hexane); H (500 MHz, CDCl3), d
2.95–3.05 (2H, m), 4.96 (1H, t, J¼7.5 Hz), 5.09–5.15 (2H,
m), 5.70–5.77 (1H, m), 7.26–7.41 (5H, m); 13C (125 MHz,
CDCl3), d 44.2, 54.0, 118.1, 127.3, 128.4, 128.7, 134.7,
141.6; HRMS (FAB) calcd for (C10H11)þ 131.0861, found
131.0857.
4. Experimental
4.1. General
4.2. General procedure for alkylation of Ni(II)-complex
Ni(II)-complex 3 (1 equiv.) and ground NaOH (10 equiv.)
were added to a flask which was purged two times with
argon. Anhydrous DMF (4 mL/mmol) was added by syringe
and the mixture was allowed to react for 5 min at room
temperature before bromide 4a, 4b, 4c (0.98 equiv. each) or
12 (3.0 equiv.) was added in one portion, respectively. The
reaction was then kept at room temperature for another
5 min (for bromide 12, 1-bromo-but-3-enyl-benzene,
3 equiv., 230 8C, 45 min reaction). The solution was
decanted into an aqueous solution (40 mL/mmol) contain-
ing 5% of HOAc. The suspension was dissolved in benzene
(20 mL/mmol) and the emulsion was diminished by
filtration through celite. The benzene solution was washed
with brine (4£40 mL/mmol) and dried over anhydrous
MgSO4 and concentrated in vacuo. The residue was first
purified by fractional recrystallization in DCM/ether
solution. The mother liquor was purified by flash liquid
chromatograph before they were further purified by
fractional recrystallization. The alkylation with electro-
philes 4a, 4b, 4c were performed in 20 g scales, while the
alkylation with electrophile 12 was performed in 10 g scale.
1H and 13C NMR spectra were recorded on a Bruker DRX-
500 MHz NMR spectrometer equipped with a Nalorac
triple-resonance 3-axis gradient 5-mm probe. The chemical
shifts were reported in d, parts per million (ppm), relative to
TMS (d¼0.00 ppm) as an internal standard. For amino acids
1
in D2O, H chemical shifts were referenced to the HOD
peak at 4.76 ppm, and 13C chemical shifts were indirectly
referenced to CDCl3 at 7.26 ppm. In DMSO, the spectra
1
were referenced to solvent peaks at 2.49 ppm for H and
39.5 ppm for 13C. Coupling constants, J, were reported in
Hertz (Hz) and refer to apparent peak multiplicities and not
true coupling constants. The DQF-COSY30a,b and 1D
transient selective NOE30c,d (350 ms mixing time) spectra
were acquired. Mass spectrometric analyses were conducted
by the Mass Spectrometry Facility at the Department of
Chemistry of the University of Arizona on a Jeol HX-110A.
Optical rotations were measured on a JASCO P1010
polarimeter. All the reagents and solvents, unless otherwise
stated, are commercially available and were used as
received. Flash column chromatograph was performed
with 230–400 mesh size silica gel which was purchased
from Aldrich Chemical Co. Thin-layer chromatograph
4.2.1. (S)-Allylglycine-Ni-(S)-BPB (5a). Yield 83.5%, Mp:
203–205 8C; [a]D24¼þ24408 (c 0.012, CHCl3); 1H
(500 MHz, CDCl3), d 2.07–2.16 (2H, m), 2.41–2.57 (3H,
m), 2.82 (1H, bs), 3.48 (1H, dd, J¼6.0, 10.5 Hz), 3.49–3.64
(3H, m), 4.05 (1H, dd, J¼4.0, 6.0 Hz), 4.46 (1H, d, J¼
12.5 Hz), 5.21 (1H, d, J¼17.0 Hz), 5.42 (1H, d, J¼10.0 Hz),
(TLC) was performed with Merck silica gel 60 F254
.
Melting points (Mp) are uncorrected and were obtained in
open capillaries. The compounds were characterized by Mp,
1
[a]D, H, 13C NMR and high resolution mass spectrometry
(HRMS). All new compounds were determined to be .95%

8240
X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
6.44–6.49 (1H, m), 6.65–6.70 (2H, m), 6.98 (1H, d,
J¼7.0 Hz), 7.17 (1H, t, J¼7.0 Hz), 7.22 (1H, t, J¼7.0 Hz),
7.29 (1H, bs), 7.37 (2H, t, J¼7.5 Hz), 7.49–7.55 (3H, m),
8.07 (2H, d, J¼7.0 Hz), 8.20 (1H, d, J¼8.5 Hz); 13C
(125 MHz, CDCl3), d 23.3, 30.7, 38.4, 56.8, 63.1, 70.3 (two
carbons), 119.7, 120.6, 123.6, 126.4, 127.0, 127.7, 128.79,
128.83, 128.9, 129.7, 131.5, 132.1, 133.1, 133.2, 133.9,
142.4, 170.8, 178.8, 180.3; HRMS (FAB) MHþ calcd for
C30H30N3NiO3 538.1641, found 538.1638.
128.82, 128.85, 128.87, 129.6, 131.5, 132.1, 133.15, 133.17,
136.8, 137.7, 142.2, 170.3, 179.3, 180.3; HRMS (FAB)
MHþ calcd for C32H34N3NiO3 566.1954, found 566.1954.
4.2.7. (S)-Pent-4-enyl-glycine-Ni-(S)-BPB (5c). Yield
85%, 1H and 13C (CDCl3) spectra are identical to
(S)-pent-4-enyl-glycine-Ni-(S)-BPB (5c).
4.2.8. (R)-Pent-4-enyl-glycine-Ni-(S)-BPB (6c). Yield 9%,
1
[a]2D4¼211808 (c 0.040, CHCl3); H (500 MHz, CDCl3), d
4.2.2. (R)-Allylglycine-Ni-(R)-BPB. Yield 85%, 1H and
13C (CDCl3) spectra are identical to (S)-allylglycine-Ni-(S)-
BPB (5a).
1.50–1.52 (2H, m), 1.84–1.91 (4H, m), 1.98–1.20 (1H, m),
2.12–2.18 (1H, m), 2.22–2.24 (1H, m), 2.52–2.58 (1H, m),
2.64–2.69 (1H, m), 3.59 (1H, d, J¼13.0 Hz), 3.67 (1H, d,
J¼6.0 Hz), 3.79 (1H, d, J¼6.5 Hz), 4.21 (1H, t, J¼5.0 Hz),
4.48 (1H, d, J¼13.0 Hz), 4.93–4.97 (2H, m), 5.63–5.69
(1H, m), 6.72 (1H, t, J¼7.5 Hz), 6.76 (1H, d, J¼8.0 Hz),
7.00 (1H, d, J¼6.5 Hz), 7.19 (1H, bs), 7.26 (1H, bs), 7.45–
7.50 (6H, m), 7.99 (2H, d, J¼7.0 Hz), 8.50 (1H, d, J¼
9.0 Hz); 13C (125 MHz, CDCl3), d 23.3, 24.6, 30.5, 33.2,
35.4, 58.6, 61.5, 69.1, 70.4, 115.1, 120.7, 123.7, 125.9,
126.9, 127.9, 128.6, 129.0, 129.1, 129.6, 131.6, 132.4,
133.5, 133.7, 134.1, 137.9, 142.8, 170.8, 179.7, 182.3;
HRMS (FAB) MHþ calcd for C32H34N3NiO3 566.1954,
found 566.1954.
4.2.3. (R)-Allylglycine-Ni-(S)-BPB (6a). Yield 12.5%,
1
[a]2D4¼211908 (c 0.049, CHCl3); H (500 MHz, CDCl3), d
1.87 (1H, bs), 2.06–2.10 (1H, m), 2.21–2.24 (1H, m),
2.50–2.64 (3H, m), 3.63 (1H, dd, J¼4.0, 10.0 Hz), 3.73
(1H, d, J¼13.0 Hz), 3.93 (1H, dd, J¼3.5, 7.5 Hz), 4.10–
4.14 (1H, m), 4.63 (1H, d, J¼13.0 Hz), 5.03 (1H, d, J¼
17.0 Hz), 5.23 (1H, d, J¼9.5 Hz), 6.04–6.10 (1H, m), 6.72
(1H, t, J¼7.5 Hz), 6.79 (1H, d, J¼7.5 Hz), 7.06 (1H, d,
J¼4.0 Hz), 7.20 (1H, bs), 7.28 (1H, m), 7.44–7.51 (6H, m),
7.93 (2H, d, J¼7.0 Hz), 8.5 (1H, d, J¼8.5 Hz); 13C
(125 MHz, CDCl3), d 23.4, 30.7, 39.3, 58.0, 61.6, 68.9,
70.5, 119.0, 120.7, 123.7, 125.8, 126.9, 128.1, 128.6, 129.0,
129.1, 129.3, 129.7, 131.7, 132.3, 132.5, 133.1, 133.7,
134.2, 142.9, 171.4, 179.1, 182.3; HRMS (FAB) MHþ calcd
for C30H30N3NiO3 538.1641, found 538.1644.
4.2.9. (2S,3S)-(1-Phenyl)-3-butenyl-glycine-Ni(II)-(S)-
BPB (13c). Yield 82%, Mp: 135–137 8C; [a]2D4¼þ21838
(c 0.033, CHCl3); 1H (500 MHz, CDCl3), d 1.37–1.45 (1H,
m), 1.68–1.76 (1H, m), 1.95 (1H, dt, J¼7.0, 11.0 Hz),
2.12–2.23 (2H, m), 2.79 (1H, dt, J¼6.0, 11.5 Hz), 3.24 (1H,
t, J¼8.5 Hz), 3.38 (1H, d, J¼12.5 Hz), 4.21 (1H, d,
J¼12.5 Hz), 4.28 (1H, d, J¼3.0 Hz), 4.63 (1H, dd, J¼3.0,
9.0 Hz), 4.75–4.86 (1H, m), 4.82 (1H, d, J¼3.0 Hz), 6.64–
6.69 (2H, m), 7.08 (1H, t, J¼7.5 Hz), 7.13 (2H, t, J¼
13.5 Hz), 7.27 (2H, t, J¼7.5 Hz), 7.31 (1H, d, J¼7.0 Hz),
7.38 (2H, d, J¼7.0 Hz), 7.45–7.60 (6H, m), 8.00 (2H, d,
J¼7.5 Hz), 8.25 (1H, d, J¼9.0 Hz); 13C (125 MHz, CDCl3),
d 23.0, 30.7, 36.3, 50.2, 57.4, 63.6, 70.4, 73.2, 117.3, 120.4,
123.1, 126.1, 127.6, 127.7, 128.2, 128.65, 128.71, 128.91,
128.93, 129.3, 129.7, 129.9, 131.5, 132.3, 133.3, 133.5,
134.4, 135.0, 139.9, 143.0, 170.9, 177.4, 180.4; HRMS
(FAB) MHþ calcd for C37H35N3NiO3 628.2110, found
628.2122.
4.2.4. (S)-But-3-enyl-glycine-Ni-(S)-BPB (5b). Yield 93%,
Mp: 207–209 8C (lit.,21 210 8C); [a]2D4¼þ44718 (c 0.014,
CHCl3); 1H (500 MHz, CDCl3), d 1.73 (1H, bs), 2.07–2.12
(1H, m), 2.17–2.21 (1H, m), 2.28–2.31 (1H, m), 2.53–2.58
(1H, m), 2.78 (1H, bs), 3.48–3.57 (2H, m), 3.61 (2H, d,
J¼12.5 Hz), 3.93 (1H, d, J¼6.0 Hz), 4.47 (1H, d, J¼
12.5 Hz), 4.89 (1H, d, J¼10.5 Hz), 4.99 (1H, d, J¼17.0 Hz),
5.54–5.59 (1H, m), 6.65–6.71 (2H, m), 6.95 (1H, d,
J¼7.5 Hz), 7.16 (1H, t, J¼7.0 Hz), 7.22 (1H, t, J¼7.0 Hz),
7.29 (1H, bs), 7.38 (2H, t, J¼7.5 Hz), 7.48–7.49 (1H, m),
7.51–7.54 (2H, m), 8.08 (2H, d, J¼7.5 Hz), 8.15 (1H, d,
J¼8.5 Hz); 13C (125 MHz, CDCl3), d 23.7, 29.4, 30.7, 35.0,
57.0, 63.1, 69.9, 70.2, 115.7, 120.7, 123.7, 126.5, 127.3,
127.5, 128.8, 128.89, 128.91, 128.93, 129.7, 131.5, 132.1,
133.2, 136.6, 142.2, 170.4, 179.1, 180.4; HRMS (FAB)
MHþ calcd for C31H32N3NiO3 552.1797, found 552.1807.
4.2.10. (2R,3R)-(1-Phenyl)-3-butenyl-glycine-Ni(II)-(R)-
BPB. Yield 83%, 1H and 13C (CDCl3) spectra are identical
to
(13c).
(2S,3S)-(1-phenyl)-3-butenyl-glycine-Ni(II)-(S)-BPB
1
4.2.5. (R)-But-3-enyl-glycine-Ni-(R)-BPB. Yield 91%, H
and 13C (CDCl3) spectra are identical to (S)-allylglycine-Ni-
(S)-BPB (5b).
4.2.11. (2R,3R)-(1-Phenyl)-3-butenyl-glycine-Ni(II)-(S)-
BPB (13a). Yield 10%, Mp: 187–189 8C; [a]2D4¼220308
(c 0.024, CHCl3); 1H (500 MHz, CDCl3), d 1.14–1.18 (1H,
m), 1.31–1.35 (1H, m), 1.80–1.84 (1H, m), 2.04–2.10 (1H,
m), 2.38–2.42 (1H, m), 2.48–2.56 (2H, m), 2.81 (1H, bs),
3.32–3.34 (1H, m), 3.37 (2H, AB, J¼14.0, 35.5 Hz), 3.79
(1H, m), 4.29 (1H, d, J¼2.5 Hz), 4.63–4.65 (1H, m), 4.85–
4.95 (1H, m), 4.88 (1H, d, J¼3.5 Hz), 6.76 (1H, t, J¼
7.5 Hz), 6.82 (1H, d, J¼7.5 Hz), 7.13 (1H, d, J¼6.0 Hz),
7.17 (1H, d, J¼5.0 Hz), 7.28–7.34 (5H, m), 7.50 (1H, t,
J¼7.0 Hz), 7.53–7.60 (7H, m), 8.44 (1H, d, J¼8.5 Hz); 13C
(125 MHz, CDCl3), d 23.7, 31.4, 35.5, 50.9, 55.0, 59.2,
68.6, 73.5, 117.4, 120.7, 123.5, 126.4, 127.6, 127.9, 128.2,
128.66, 128.71, 128.90, 128.93, 129.3, 129.8, 130.5, 131.8,
4.2.6. (S)-Pent-4-enyl-glycine-Ni-(S)-BPB (5c). Yield
86%, Mp: 191–192 8C (lit.,21 192 8C); [a]D24¼þ25608 (c
1
0.033, CHCl3); H (500 MHz, CDCl3), d 1.65–1.67 (2H,
m), 1.91–2.07 (4H, m), 2.14–2.23 (2H, m), 2.50–2.55 (1H,
m), 2.76 (1H, bs), 3.47 (1H, dd, J¼6.0, 10.0 Hz), 3.52–3.60
(3H, m), 3.91 (1H, d, J¼5.0 Hz), 4.44 (1H, d, J¼12.5 Hz),
4.95–5.00 (2H, m), 5.70–5.75 (1H, m), 6.62–6.67 (2H, m),
6.92 (1H, d, J¼6.5 Hz), 7.14 (1H, t, J¼7.0 Hz), 7.19 (1H, t,
J¼7.0 Hz), 7.27 (1H, bs), 7.34 (2H, t, J¼7.0 Hz), 7.45–7.50
(3H, m), 8.05 (2H, d, J¼7.0 Hz), 8.13 (1H, d, J¼8.0 Hz);
13C (125 MHz, CDCl3), d 23.6, 24.6, 30.7, 33.2, 34.8, 56.9,
63.0, 70.2, 70.3, 115.2, 120.7, 123.6, 126.5, 127.1, 127.6,

X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
8241
131.9, 132.6, 133.8, 134.3, 134.9, 141.1, 143.2, 170.7,
176.9, 181.8; HRMS (FAB) MHþ calcd for C37H35N3NiO3
628.2110, found 628.2119.
residue was purified by recrystallization in DCM/ether
solution and product 5d (1.22 g, 80% yield) was obtained as
a diastereomeric mixture.
4.2.12. (2S,3R)-(1-Phenyl)-3-butenyl-glycine-Ni(II)-(S)-
BPB (13b). The above purified (2R, 3R)-product (170 mg,
0.271 mmol) and ground NaOH (120 mg, 3.0 mmol) were
added to a 10-mL flask. The flask was purged with argon
two times and anhydrous DMF (2 mL) was added by
syringe. The mixture was kept at room temperature for 20 h
before it was quenched by an aqueous acidic solution
(20 mL, 5% HOAc). The product mixture was treated as in
the general procedure for Ni(II)-complex alkylation, and
the product was isolated by flash chromatograph.
The above methyl-Ni(II) product 5d (256 mg, 0.5 mmol)
and ground NaOH (40 mg, 5.0 mmol) were added to a flask
which was purged two times with argon. Anhydrous DMF
(2 mL) was added by syringe and the mixture was allowed
to react for 5 min at room temperature before 1-bromo-4-
butene (102 mL, 1.0 mmol) was added. The reaction was
then kept at room temperature for 90 min before it was
decanted into an aqueous solution (40 mL) containing 5% of
HOAc. The suspension was dissolved in benzene (40 mL)
and the emulsion was diminished by filtration through
celite. The benzene solution was washed with brine
(4£40 mL), dried over anhydrous MgSO4, and concentrated
in vacuo. The residue was purified by flash liquid
chromatograph, and product 8 (45 mg) and product 9
(96 mg) were obtained (50% total yield).
1
[a]2D4¼þ15658 (c 0.061, CHCl3); H (500 MHz, CDCl3), d
2.10–2.21 (1H, m), 2.61–2.67 (1H, m), 2.81–2.87 (1H, m),
2.90–2.95 (1H, m), 3.46–3.53 (3H, m), 3.57 (1H, d,
J¼12.5 Hz), 3.83–3.92 (1H, m), 4.10 (1H, d, J¼6.0 Hz),
4.45 (1H, d, J¼12.0 Hz), 4.94 (1H, dd, J¼1.0, 10.0 Hz),
5.09 (1H, dd, J¼1.0, 17.0 Hz), 5.54–5.61 (1H, m), 6.17
(1H, d, J¼8.0 Hz), 6.53 (1H, dd, J¼1.5, 8.5 Hz), 6.63 (1H, t,
J¼7.5 Hz), 6.72 (2H, d, J¼7.0 Hz), 7.06–7.24 (7H, m),
7.30 (2H, t, J¼7.5 Hz), 7.43–7.46 (2H, m), 8.05 (2H, d,
J¼7.0 Hz), 8.21 (1H, d, J¼8.5 Hz); 13C (125 MHz, CDCl3),
d 23.4, 30.9, 34.8, 52.1, 56.9, 63.0, 70.7, 75.7, 117.1, 120.6,
123.1, 126.5, 127.0, 127.5, 128.3, 128.6, 128.71, 128.79,
128.81, 128.84, 128.88, 129.5, 131.5, 132.4, 133.1, 133.6,
134.7, 135.7, 138.2, 142.6, 170.7, 177.0, 180.1; HRMS
(FAB) MHþ calcd for C37H35N3NiO3 628.2110, found
628.2114.
4.3.1. (2R)-2-Buten-30-yl-2-methyl-glycine-Ni(II)-(S)-
1
BPB (8). [a]2D4¼þ14518 (c 0.032, CHCl3); H (500 MHz,
CDCl3), d 1.26 (3H, s), 1.73 (1H, dt, J¼4.0, 13.0 Hz), 1.83
(1H, dt, J¼4.5, 13.0 Hz), 2.03–2.08 (2H, m), 2.46–2.51
(1H, m), 2.67–2.71 (2H, m), 2.98–3.03 (1H, m), 3.24–3.27
(1H, m), 3.44 (1H, dd, J¼5.5, 10.5 Hz), 3.65 (1H, d, J¼
10.0 Hz), 3.69 (1H, d, J¼13.0 Hz), 4.48 (1H, d, J¼12.5 Hz),
5.03 (1H, d, J¼10.0 Hz), 5.11 (1H, d, J¼17.0 Hz), 5.78–
5.84 (1H, m), 6.61–6.66 (2H, m), 6.99 (1H, d, J¼7.5 Hz),
7.13 (1H, t, J¼6.5 Hz), 7.29–7.32 (2H, m), 7.37–7.46 (3H,
m), 7.46–7.47 (2H, m), 8.01 (1H, d, J¼8.5 Hz), 8.08 (1H, d,
J¼7.5 Hz); 13C (125 MHz, CDCl3), d 23.2, 29.4, 29.8, 30.6,
39.2, 57.0, 63.3, 69.9, 77.6, 115.4, 120.7, 123.9, 126.9,
127.2, 127.9, 128.5, 128.8, 128.9, 129.3, 130.1, 131.5,
131.6, 133.3, 136.4, 136.8, 141.4, 172.5, 180.4, 182.1;
HRMS (FAB) MHþ calcd for C32H34N3NiO3 566.1954,
found 566.1968.
4.3. Dialkylation of Ni(II)-complex
Eq. 1. Monoalkylated Ni(II)-product 5b (277 mg,
0.5 mmol) and ground NaOH (40 mg, 5.0 mmol) were
added to a flask which was purged two times with argon.
Anhydrous DMF (2 mL) was added by syringe and the
mixture was allowed to react for 5 min at room temperature
before methyl iodide (94 mL, 1.5 mmol) was added. The
reaction was then kept at room temperature for 90 min
before a second addition of methyl iodide (94 mL,
1.5 mmol). After another 90 min reaction, the solution
was decanted into an aqueous solution (40 mL) containing
5% of HOAc. The suspension was dissolved in benzene
(40 mL) and the emulsion was diminished by filtration
through celite. The benzene solution was washed with brine
(4£40 mL), dried over anhydrous MgSO4, and concentrated
in vacuo. The residue was purified by flash liquid
chromatograph, and product 8 (83 mg) and product 9
(100 mg) were obtained (65% total yield).
4.3.2. (2S)-2-Buten-30-yl-2-methyl-glycine-Ni(II)-(S)-
1
BPB (9). [a]2D4¼þ9608 (c 0.031, CHCl3); H (500 MHz,
CDCl3), d 1.46–1.50 (1H, m), 1.52 (3H, s), 1.75–1.79 (1H,
m), 2.04–2.13 (4H, m), 2.46–2.51 (1H, m), 2.60–2.65 (1H,
m), 3.33–3.39 (1H, m), 3.45 (1H, dd, J¼5.5, 11.0 Hz), 3.64
(1H, d, J¼12.5 Hz), 3.72 (1H, dd, J¼6.0, 10.0 Hz), 4.39
(1H, d, J¼12.5 Hz), 5.00 (1H, d, J¼10.0 Hz), 5.04 (1H, dd,
J¼1.0, 17.0 Hz), 5.70–5.75 (1H, m), 6.61–6.67 (2H, m),
7.03 (1H, d, J¼7.5 Hz), 7.12 (1H, dt, J¼1.5, 7.5 Hz), 7.26–
7.31 (2H, m), 7.36–7.49 (5H, m), 7.96 (1H, d, J¼8.5 Hz),
8.14 (1H, d, J¼7.5 Hz); 13C (125 MHz, CDCl3), d 23.7,
27.8, 28.9, 30.6, 38.9, 57.6, 63.7, 70.4, 77.6, 115.1, 120.7,
124.1, 127.1, 127.7, 128.2, 128.3, 128.7, 128.9, 129.0,
129.4, 131.39, 131.43, 133.1, 133.9, 136.1, 136.8, 141.3,
172.4, 180.5, 182.6; HRMS (FAB) MHþ calcd for
C32H34N3NiO3 566.1954, found 566.1958.
Eq. 2. Ni(II)-complex 3 (1.5 g, 3.0 mmol) and ground
NaOH (1.2 g, 30 mmol) were added to a flask which was
purged two times with argon. Anhydrous DMF (12 mL) was
added by syringe and the mixture was allowed to react for
5 min before it was cooled to 0 8C. Methyl iodide (184 mL,
2.9 mmol) was added in one portion and the reaction was
kept for another 5 min at 0 8C before quenching with an
aqueous solution (120 mL) containing 5% of HOAc. The
suspension was dissolved in benzene (120 mL) and the
emulsion was diminished by filtration through celite. The
benzene solution was washed with brine (4£80 mL), dried
over anhydrous MgSO4, and concentrated in vacuo. The
4.4. General procedure for hydrolysis of alkylation
product of Ni(II)-complex
The Ni(II)-alkylated product (5a,b,c and 13c) (1 equiv.) was
dissolved in a methanol and DCM mixture (2:1, 3 mL/
mmol) and added dropwise into a mixture of HCl (3 N,
2 mL/mmol) and methanol (2 mL/mmol) solution at 60 8C.
The solution turned green (for the b-phenyl-substituted

8242
X. Gu et al. / Tetrahedron 60 (2004) 8233–8243
product 13c, 6 N HCl at 60 8C for 1 h). The methanol–water
solution was evaporated and the residue was re-dissolved in
water (3£5 mL/mmol) and evaporated to remove the HCl.
NH4OH (5 mL/mmol), and then water (5 mL/mmol) was
added and the mixture was concentrated in vacuo to dryness.
The residue was then dissolved in water (5 mL/mmol) and
CHCl3 (5 mL/mmol). The organic phase was separated and
the water phase was washed with CHCl3 (2£5 mL/mmol).
The combined organic phase was washed with brine and
dried over MgSO4, and then concentrated in vacuo. (S)-BPB
(about 96%) was recovered. The aqueous phase was
evaporated to 10 mL and loaded on an ion-exchange
column (DOWEX 50Wx2-100 resin) which was pre-washed
with water to neutral pH. The column was eluted by water to
pH¼7 and then washed with ammonium hydroxide/water
(4:1) until all the amino acid was washed out (for 5c and
13c, a mixture of ammonium hydroxide/water/ethanol
(4:1:2) was used). The column can be regenerated by 1 N
HCl. The aqueous solution collected from the column was
concentrated and the colorless amino acid was collected
after lyophilization.
J¼10.0 Hz), 5.06 (1H, d, J¼17.0 Hz), 5.61–5.68 (1H, m),
7.26 (2H, d, J¼7.0 Hz), 7.32 (1H, t, J¼7.0 Hz), 7.37 (2H, t,
J¼7.0 Hz); 13C (125 MHz, D2O), d 34.2, 45.7, 57.8, 117.6,
128.2, 128.6, 129.1, 135.3, 136.8, 171.1; HRMS (FAB)
MHþ calcd for C12H15NO2 206.1181, found 206.1184.
4.4.8. (2R, 3R)-2-Amino-3-phenyl-hexenoic acid (18c).
Yield 95%, 1H and 13C (D2O) spectra are identical to
(2S,3S)-2-amino-3-phenyl-hexenoic acid (15c).
Crystallographic data (excluding structure factors) for the
structure 8 in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplementary
publication number CCDC 231756. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
This research was supported by grants from the US Public
Health Service DA 13449, DA 06284, and DK 17420. The
DRX 500 MHz spectrometer was obtained by a grant from
the NSF (9729350). This work was supported in part by a
fellowship to J.Y. from Merck Research Laboratories.
4.4.1. (S)-2-Allylglycine (15a). Yield 96%, Mp: .275 8C
1
(decomp.) (lit.,7 208 8C); [a]D24¼þ21.18 (c 1.53, H2O); H
(500 MHz, DMSO), d 2.46–2.57 (2H, m), 3.69 (1H, t,
J¼5.5 Hz), 5.13–5.18 (2H, m), 5.62–5.70 (1H, m); 13C
(125 MHz, DMSO), d 35.2, 54.3, 120.8, 131.7, 174.4;
HRMS (FAB) MHþ calcd for C5H10NO2 116.0712, found
116.0717.
References and notes
1
4.4.2. (R)-2-Allylglycine (18a). Yield 90%, H and 13C
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(500 MHz, DMSO), d 1.83–1.87 (2H, m), 2.02–2.07 (1H,
m), 2.14–2.19 (1H, m), 3.80 (1H, t, J¼6.0 Hz), 4.96 (1H, d,
J¼10.5 Hz), 5.03 (1H, d, J¼17.5 Hz), 5.71–5.77 (1H, m);
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þ8.48); H (500 MHz, D2O), d 1.37–1.42 (2H, m), 1.73–
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1.80 (2H, m), 2.00–2.04 (2H, q, J¼7.0 Hz), 3.64 (1H, t,
J¼5.5 Hz), 4.93 (1H, d, J¼10.0 Hz), 4.98 (1H, d,
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23.9, 30.2, 32.9, 55.1, 115.4, 139.0, 175.3; HRMS (FAB)
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1H (500 MHz, D2O), d 2.61–2.74 (2H, m), 3.34 (1H, dt,
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