Improved synthesis of proline-derived Ni(II) complexes of glycine: Versatile chiral equivalents of nucleophilic glycine for general asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1021/jo0301494

A synthetically practical and operationally convenient method for preparing (S)-2-[N-(N′-benzylprolyl)-amino]benzophenone (BPBP) and hitherto unknown (S)-2-[N-(N′-benzylprolyl)amino]-4-methylbenzophenone (4-Me-BPBP), (S)-2-[N-(N′-benzylprolyl)amino]-5-nitrobenzophenone (5-NO₂-BPBP), and their corresponding Ni(II) complexes with glycine [GlyNi(II)BPBP], a widely used chiral equivalent of nucleophilic glycine, and new analogues [GlyNi(II)-4-Me-BPBP] and [GlyNi(II)-5-NO₂-BPBP] is described. The key step of the method is the synthetically efficient amid bond formation between the corresponding o-aminobenzophenones, featuring significant steric shielding and low nucleophilicity of the amino functionality as well as sterically constrained (S)-N-benzylproline (BP).

Full text of DOI:10.1021/jo0301494

turally complex and sterically constrained derivatives.4,6
Among the vast variety of chiral equivalents of glycine
developed to date,1-4,6 the Ni(II) complex of glycine Schiff
base with (S)-2-[N-(N′-benzylprolyl)amino]benzophenone
[(BPBP)-1a ] and GlyNi(II)BPBP-2a (Scheme 1), intro-
duced by Bolokon’ et al.,7 has several unique features.
The Ni(II) complex 2a is the only chiral equivalent of
glycine to offer a stereochemically reliable and efficient
(>95% de) homologation via alkyl halide alkylation, aldol,
and Michael addition reactions under operationally con-
venient conditions, i.e., without recourse to inert atmo-
sphere, rigorously dried and degassed solvents, and low
temperature. Furthermore, the glycine equivalent 2a
features attractive physicochemical characteristics such
as high crystallinity and solubility in certain organic
solvents leading to a convenient purification of the
homologation products and high volume yields. Practical
synthesis of various R-amino acids using the glycine
equivalent 2a , including fluorine-, phosphorus-, and
sulfur-containing analogues as well as isotopically labeled
derivatives, is well-documented by Belokon’s group,8 our
group,9 and other groups.10
Im p r oved Syn th esis of P r olin e-Der ived
Ni(II) Com p lexes of Glycin e: Ver sa tile
Ch ir a l Equ iva len ts of Nu cleop h ilic Glycin e
for Gen er a l Asym m etr ic Syn th esis of
r-Am in o Acid s
Hisanori Ueki, Trevor K. Ellis, Collin H. Martin,
Tomas U. Boettiger, Shawna B. Bolene, and
Vadim A. Soloshonok*
Department of Chemistry and Biochemistry,
University of Oklahoma, Norman, Oklahoma 73019
vadim@ou.edu
Received April 28, 2003
Abstr a ct: A synthetically practical and operationally con-
venient method for preparing (S)-2-[N-(N′-benzylprolyl)-
amino]benzophenone (BPBP) and hitherto unknown (S)-2-
[N-(N′-benzylprolyl)amino]-4-methylbenzophenone (4-Me-
BPBP), (S)-2-[N-(N′-benzylprolyl)amino]-5-nitrobenzophenone
(5-NO2-BPBP), and their corresponding Ni(II) complexes
with glycine [GlyNi(II)BPBP], a widely used chiral equiva-
lent of nucleophilic glycine, and new analogues [GlyNi(II)-
4-Me-BPBP] and [GlyNi(II)-5- NO2-BPBP] is described. The
key step of the method is the synthetically efficient amid
bond formation between the corresponding o-aminoben-
zophenones, featuring significant steric shielding and low
nucleophilicity of the amino functionality as well as sterically
constrained (S)-N-benzylproline (BP).
Unfortunately, practitioners in academic and indus-
trial research laboratories have been discouraged from
forming a wider synthetic appreciation and application
of the chiral glycine equivalent 2a for preparing various
tailor-made R-amino acids8-10 due to the unreasonably
high commercial price11 and inefficient literature proce-
dures12 for its preparation. In this paper, we report a full
and detailed account of the synthesis of complex 2a as
well as its hitherto unknown derivatives 2b,c, recently
developed by our laboratories. The method presented
here involves application of inexpensive reagents and
operationally convenient conditions, therefore allowing
the synthetically efficient and large-scale preparation of
ligands 1a -c and complexes 2a -c.
Asymmetric synthesis of R-amino acids1,2 via homolo-
gation of chiral equivalents of electrophilic1-3 or nucleo-
philic1,2,4 glycine is methodologically the most straight-
forward, practical and so far the most reliable5 approach
for preparing various amino acids, in particular, struc-
* To whom correspondence should be addressed. Phone: (405)-325-
8279. Fax: (405)-325-6111..
(3) For most recent leading papers on asymmetric synthesis of
R-amino acids via alkylation of electrophilic glycine equivalents, see:
(a) O’Donnell, M. J .; Cooper, J . T.; Mader, M. M. J . Am. Chem. Soc.
2003, 125, 2370-2371. (b) O’Donnell, M. J .; Drew, M. D.; Cooper, J .
T.; Delgado, F.; Zhou, C. J . Am. Chem. Soc. 2002, 124, 9348-9349. (c)
Bull, S. D.; Davies, S. G.; Garner, C. A.; O’Shea, M. D.; Savory, E. D.;
Snow, E. J . J . Chem. Soc., Perkin Trans. 1, 2002, 2442-2448 and
references on the previous works cited in these papers.
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glycine, see: (a) Williams, R. M. In Synthesis of Optically Active
R-Amino Acids; Baldwin, J . E., Ed.; Organic Chemistry Series; Per-
gamon Press: Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994, 50,
1539-1650. (c) Cativiela, C.; Diaz-De-Villegas, M. D. Tetrahedron:
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10.1021/jo0301494 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/06/2003
7104
J . Org. Chem. 2003, 68, 7104-7107

SCHEME 1
reagents, such as KOH, for preparation of N-benzylpro-
line 4 (BP) (Scheme 1), and SOCl2 for the activation of 4,
to react with o-aminobenzophenone 5a . While this pro-
cedure, in our hands, generated the target compounds
4, 1a , and finally 2a , many of its features made it
ultimately unattractive for large-scale preparation, for
example, the problems associated with the control of pH,
merely using indicating paper, for preparing BP-4. In
addition, further transformation to the ligand 1a , em-
ploying excess SOCl2, led to variable and generally low
chemical yields. Moreover, formation of numerous byprod-
ucts on the stage of amidation of o-aminobenzophenone
5a and incomplete transformation to ligand 1a neces-
sitated laborious purification of 1a prior to its use for
preparing complex 2a . Furthermore, the published pro-
cedure employs an almost 50% excess of BP-4 on the
amidation stage rendering the method economically
unattractive, especially for preparing the target com-
pounds starting from rather expensive (R)-Pro-3. The
above listed problems, associated with the control of pH,
in the synthesis of BP-4, as well as the amidation stage,
had to be resolved.
We have achieved an improved synthesis of BP-4, as
depicted in Scheme 1. Application of the commercially
available and cheap NaOMe as a base and MeOH as
solvent in the reaction of Pro-3 with benzyl chloride was
found to lead to clean and efficient mono-benzylation of
3 affording BP-4 with a reproducible >85% chemical
yield. Since the commercial NaOMe, in contrast to KOH,
does not contain unknown amounts of water or carbon-
ates, the calculated amount of concentrated HCl was
reliably used in order to quench the reaction mixture.
According to the optical rotation and 1H NMR data of
the crude product, thus prepared (S)-BP-4 was found to
be >95% pure and therefore was used without further
purification for preparing ligand 1a .
With an improved route to BP-4 in hand, we were in
position to turn our attention to its condensation with
o-aminobenzophenones 5a -c. Amidation of carboxylic
acids in general, especially the formation of a peptide
bond, has been an area of intense research and is well
documented.13,14 On the other hand, examples of the
synthesis of amides using sterically hindered acids and
The published route for preparation of complex 2a ,
starting from enantiomerically pure (S)- or (R)-proline
(Pro) (3), reported by Bolokon’ et al.,12 employed cheap
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(11) Commercial source for the ligand 1a and complex 2a is ACROS
Organics, offering compounds 1a and 2a for unreasonable price of
$58.90, $150.80 per gram, respectively. Using our procedure, described
in this paper, complex (S)-2a could be prepared at less than $10 per
gram.
J . Org. Chem, Vol. 68, No. 18, 2003 7105

TABLE 1. Am id a tion of (S)-N-Ben zylp r olin e 4 w ith
o-Am in oben zop h en on es 5a -c via th e In ter m ed ia te Mixed
An h yd r id e F or m a tion a
particular the large-scale preparations. Therefore, we
directed our efforts to find a cheap but effective additive
to be used in the place of DMAP. N-Methylimidazole
(MeIm), which is substantially cheaper than DMAP, was
shown to play a similar catalytic role to DMAP in
acylations on nitrogen.15 To our satisfaction, the reaction
conducted using MeIm (1 equiv) along with TEA (2 equiv)
gave results comparable with those of the DMAP-assisted
reaction (entry 5 vs 3). Taking into account that the best
conversion of the starting amine 5a was achieved when
we used DMAP as a catalyst and a base (entry 4), we
conducted the analogous reaction using 3 equiv of MeIm.
The result obtained was slightly lower compared with
that of DMAP-assisted reaction (entry 6 vs 4). However,
it was in the range of a synthetically useful outcome. In
a successive series of experiments, gradually decreasing
the amount of MeIm, we found that at least 2.2 equiv of
MeIm were necessary to reliably reproduce >90% con-
version of amine 5a to ligand 1a (entry 7). Finally, we
conducted a series of experiments using various ana-
logues of TsCl to improve the chemical and/or economical
outcome of this key amidation step. As a result, we found
that the application of methansulfonyl chloride (MsCl)
in place of TsCl allowed for a noticeable improvement of
the method. Thus, the use of MsCl, which is cheaper and
easier to handle compared to TsCl, afforded a syntheti-
cally useful conversion of amine 5a to the target ligand
1a which was isolated in 93.5% yield (entry 8). Under
the same reaction conditions the methyl-containing ben-
zophenone 5b was used to prepare a new ligand 1b,
which was isolated in a chemical yield similar to 1a
(entry 9). In contrast, the application of the nitro-
containing derivative 5c resulted in a noticeably lower
conversion (entry 10), apparently due to the strong
electron-withdrawing effect of the nitro group in direct
conjugation with the amino function. Nevertheless the
ligand 1c was isolated in a synthetically useful chemical
yield.
yieldc
conditions
amine
entry 5a ,b
ratiob
(%)
acid-Cl 5a ,b/1a ,b 1a ,b
base (equiv)
TEA (2.0)
TEA (2.0)/DMAP (0.2) TsCl
TEA (2.0)/DMAP (1.0) TsCl
DMAP (3.0)
TEA (2.0)/MeIm (1.0)
MeIm (3.0)
MeIm (2.2)
MeIm (2.2)
MeIm (2.2)
MeIm (2.2)
1
2
3
4
5
6
7
8
9
a
a
a
a
a
a
a
a
b
c
TsCl
65/35
41/59
8/92
<5/95
11/89
8/92
ND
ND
88.5
93.0
ND
90.0
90.5
93.5
94.0
77.0
TsCl
TsCl
TsCl
TsCl
MsCl
MsCl
MsCl
8/92
<5/95
<5/95
20/80
10
a
All reactions were run in commercial-grade dichloromethane;
b
(4/5a -c ) 1.1/1). Determined by NMR (300 MHz) analysis of
the crude reaction mixtures. c Isolated yield of pure products based
on 5.
sterically hindered or low-nucleophilic amines are quite
rare in the literature.14 In particular, synthesis of the
target ligand 1a , derived from sterically constrained BP-4
and o-aminobenzophenones 5a -c, possessing both un-
desirable features of steric hindrance and low nucleo-
philicity of the amino group, cannot be performed with
synthetically useful yields by straightforward application
of the literature methods.14 Of the literature methods,
activation of the carboxylic function by in situ formation
of the corresponding mixed carboxylic-sulfonic or -car-
bonic anhydrides14d-g was shown to be the most effective
for reactions with sterically hindered or low-nucleophilic
amines. However, the first amidation attempt of BP-4
with benzophenone 5a in a solution of dichloromethane,
using p-tolylsufonyl chloride (TsCl), to generate the
corresponding mixed anhydride, and triethylamine (TEA),
as a base, gave a rather disappointing result. The reac-
tion proceeded sluggishly giving rise to a mixture of the
target 1a and starting amine 5a in ratio of 65/35 (Table
1, entry 1). To improve the conversion of 5a to 1a , we
decided to use 4-(N,N-dimethylamino)pyridine (DMAP)
as a catalyst, since it has a known powerful effect on
many reactions including acylations on nitrogen.15 Using
a catalytic amount of DMAP along with TEA, we obtained
a noticeable increase in the conversion of starting 5a
(entry 2). After several attempts, we found that the use
of a stoichiometric amount of DMAP resulted in a dra-
matic improvement of the ratio affording the target 1a
in a synthetically useful yield (Table 1, entry 3). Further
attempts to improve the ratio by running the reaction at
higher temperature (dichloroethane was used as a sol-
vent) resulted in a decreased conversion, suggesting that
the corresponding mixed anhydride might be unstable
at high temperature. On the other hand, application of
DMAP as a base, instead of TEA, as well as an additive
allowed us to further increase the conversion of 5a and
isolated yield of the target ligand 1a (entry 4).
The purification of ligands 1a -c from the residual
amounts of 5a -c and some byproducts merits additional
comments. According to the Bolokon’ procedure,12 the
ligand 1a can be purified by crystallization of the crude
product from ethanol. While this procedure generated
relatively pure samples of 1a , we found this crystalliza-
tion protocol rather unpractical, as the recovery of the
ligand 1a , in a series of experiments was generally below
75%. Considering some other options to isolate the target
ligand 1a in the highest possible chemical yield, we ruled
out the use of expensive silica gel column chromatogra-
phy because it is inappropriate for the large scale
preparations. After several attempts, using differences
in physicochemical properties of 1a and 5a , we found that
precipitation of the target 1a , as the hydrochloric salt
from a solution of the reaction mixture in acetone offers
a simple, efficient and operatively convenient procedure.
The corresponding Ni(II) complexes 2a -c were pre-
pared from ligands 1a -c under previously reported
conditions.12
We assumed that, though successful, the application
of a stoichiometric amount of relatively expensive DMAP
would render the method economically unattractive, in
In the 1H NMR spectra of complexes 2a -c, the protons
of the glycine methylene moiety were found to be sensi-
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7106 J . Org. Chem., Vol. 68, No. 18, 2003

tive to the effect of the substituent. Thus, the chemical
shift of the protons of the glycine methylene group in 2c
were found to be shifted downfield (3.79 ppm) and in 1b
shifted upfield (3.70 ppm), as compared with that of the
unsubstituted complex 2a (3.73 ppm). These data sug-
gested that the glycine methylene moiety in 2c is more,
and in 2b is less CH acidic as compared with the complex
2a . This observation provides ground for the rational
design of this type of complexes with controlled reactivity
of the glycine methylene group.
method is formation of the mixed anhydrides derived
from N-benzylproline and methanesulfonyl chloride.
Ack n ow led gm en t. The work was supported by the
start-up fund provided by the Department of Chemistry
and Biochemistry, University of Oklahoma, and by the
Undergraduate Research Opportunities Program, Hon-
ors College, University of Oklahoma.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal procedures and H and 13C spectra for obtained compounds.
In summary, an efficient, large-scale method for pre-
paring BP and hitherto unknown ligands 4-Me-BPBP,
5-NO2-BPBP, and their corresponding Ni(II) complexes
with glycine has been developed. The key step of the
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0301494
J . Org. Chem, Vol. 68, No. 18, 2003 7107