New generation of nucleophilic glycine equivalents

Article abstract of DOI:10.1016/j.tetlet.2004.12.050

A new generation of nucleophilic glycine equivalents, designed to contain a functional framework, that allows control over the physical properties as well as the reactivity, is described. The reactivity of these nucleophilic glycine equivalents have been compared to previously described examples with the application of various transformations such as alkyl halide alkylations, Michael additions, and aldol condensations.

Full text of DOI:10.1016/j.tetlet.2004.12.050

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 941–944
New generation of nucleophilic glycine equivalents
Trevor K. Ellis, Hisanori Ueki and Vadim A. Soloshonok*
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
Received 20 October 2004; revised 9 December 2004; accepted 10 December 2004
Available online 25 December 2004
Abstract—A new generation of nucleophilic glycine equivalents, designed to contain a functional framework, that allows control
over the physical properties as well as the reactivity, is described. The reactivity of these nucleophilic glycine equivalents have been
compared to previously described examples with the application of various transformations such as alkyl halide alkylations, Michael
additions, and aldol condensations.
Ó 2004 Elsevier Ltd. All rights reserved.
Among the most practical and generalized approaches
for preparing amino acids is the homologation of nucleo-
philic glycine equivalents (NGEs). Analysis of the
relevant literature, dealing with the asymmetric homolo-
gation approach, revealed two general approaches. The
first involves the design of properly protected NGEs
that incorporate an element of chirality into their frame-
work. This approach has enjoyed a great deal of
creativity producing dozens of various chiral NGEs.
The second approach revolves around the alkylation
of the tert-butyl glycinate benzophenone Schiff base 1
have been made to improve on the structure of Schiff
3
base 1 until recently. Recently, we have synthesized
picolinic acid/o-aminoacetophenone derived glycine
Schiff base 2a (Fig. 1) and demonstrated its potential
as a NGE for asymmetric, organic base-catalyzed
4
Michael addition reactions. On the other hand the
o-aminobenzophenone derivative 2b, described by
5
BelokonÕ et al, has proven to be an excellent NGE for
the practical large-scale preparation of sym-a,a-dialkyl
5
,6
amino acids.
Although Schiff bases 2a,b possess
advantages over 1, such as stability and predictable
formation of the (E)-enolates, their synthetic value is
greatly limited by poor solubility in most organic
solvents.
(
a catalytic amount of chiral quaternary ammonium
Fig. 1) under phase transfers conditions (PTC) using
1
salt. Most of the work in this area has concentrated
on the development of new catalysts, which recently
culminated with the discovery of N-spiro C -symmetric
2
quaternary ammonium salts. By contrast, fewer studies
We report herein a new generation of NGEs 3a–c
(Scheme 1), which can be easily prepared on the kilo-
gram scale from ligands 4a–c, glycine and a source of
Ni(II). Ligands 4a–c in turn, are easily available in high
chemical yields starting from the acid bromide 5, a dialk-
ylamine and either o-aminobenzophenone or o-
2
7
aminoacetophenone.
The major concern with this design was the potential
problem with chemoselectivity, as one may envision that
both of the glycine moieties in 3a–c may be alkylated,
especially under the harshly basic conditions necessary
to perform bis-alkylations (Scheme 1). However, it was
exciting to find that in the presence of sodium t-butoxide
in DMF, alkyl halides such as benzyl, cinnamyl, and
allyl bromides alkylated the methylene moiety of the
glycine Schiff base exclusively. These reactions pro-
ceeded to completion, at room temperature, to afford
the corresponding a,a-disubstituted a-amino acid
Figure 1.
Keywords: Glycine equivalents; Asymmetric synthesis; Amino acids;
Homologation.
*
Corresponding author. Tel.: +1 405 325 8279; fax: +1 405 325
111; e-mail: vadim@ou.edu
6
0
040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.050

942
T. K. Ellis et al. / Tetrahedron Letters 46 (2005) 941–944
containing products 7a–c; 8a; 9a in high yields, >92%
from 3a to 3c (Table 1). The products 7a–c; 8a; 9a were
found to be extremely clean, eliminating any need for
purification before their disassembly.
With the chemoselectivity issue no longer a concern, it
seemed as if a side-by-side comparison of the NGEs 1,
2
ations were performed in 30% aqueous NaOH/CH Cl
a,b, and 3a–c was in order. Therefore, PTC benzyl-
2
2
with N-(n-Pr) Br as the catalyst (Table 2). It was found
4
that compound 3b was more reactive than 2b, however
less reactive than 1. Although, 2b and 3b gave rise to
the corresponding products 11b, 12b in virtually quanti-
tative yield, Schiff base 1 underwent partial hydrolysis,
significantly lowering the yield of 10.
The most interesting results were obtained from of the
PTC homologation of complex 3a with benzyl bromide
and various chiral quaternary ammonium salts. Initial
attempts to benzylate complex 3a with the use of cincho-
nidine derived catalysts (15 mol %) proved dishearten-
ing as they resulted in racemic products. However,
Scheme 1. Reagents and conditions: (i) 3 N HCl, 60 °C; (ii) o-
0
aminobenzophenone, K
2
CO , acetonitrile, rt; (iii) NHR , K
3
2
CO
3
,
2
0
acetonitrile, 60 °C; (iv) KOH, MeOH, 60 °C; (a) R = Bu; (b)
8
0
0
R ¼ piperidyl; (c) R = Bn.
2
Table 1.
0
a
Conversion 3/7
b
Yield (%)
Entry
R
R
Time (min)
Product
1
2
3
Bn (3c)
Piperidyl (3b)
Bu (3a)
3a)
Bn
Bn
15
15
15
15
15
7c
7b
7a
8a
9a
>99
>99
>99
>99
>99
90
91
93
92
88
Bn
Allyl
Cinnamyl
4
5
Bu (
Bu (3a)
a
Determined by NMR analysis of the crude reaction mixtures.
Isolated yield of the crude product.
b
Table 2.
a
Ratio reac/prod
b
Yield (%) 10, 11b, 12b
Entry
Sub.
Solvent
Base
Time (h)
Product
c
1
3b
2b
1
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
NaOH aq
NaOH aq
NaOH aq
1
12b
11b
10
<1/>99
<1/>99
<1/>99
>99
>99
86
2
1.5
0.5
3
a
Determined by NMR analysis of the crude reaction mixtures.
Isolated yield of the crude product.
For reactions with chiral PTCs the solvent was toluene and the base as well as the temperature were varied.
b
c

T. K. Ellis et al. / Tetrahedron Letters 46 (2005) 941–944
943
Table 3.
a
Conversion reac/prod
b
Yield (%) 13, 14b, 15b, 16b
Entry
Sub.
R
Time
Product
de
1
2
3
3b
3b
2b
3b
1
Ph
4min
20 min
50 min
15b
16b
14b
15b
13
<1/>99
<1/>99
<1/>99
<5/>95
>70
>99
90
>98
>98
>98
>90
n-Pr
Ph
>99
>95
>70
c
4
c
Ph
Ph
18.5 h
18.5 h
d
5
—
a
Determined by NMR analysis of the crude reaction mixtures.
Isolated yield of the crude product.
b
c
Reaction conducted in CH
2
Cl
2
in the presence of DBU (1.15 equiv).
d
Three products obtained in a ratio of 72:12:10.
reactions catalyzed by the N-spiro C -symmetric quater-
2
9
nary ammonium salt (1 mol %), provided the corre-
sponding amino acid derivative in high optical purity
in a biphasic system of toluene and crushed potassium
hydroxide, at 0 °C. Although the 92% ee obtained from
the reaction is impressive, it was interesting to note that
the true stereochemical outcome of the catalyzed reac-
tion is being concealed by the presence of a noncatalytic
pathway that provides 8% yield of racemic products.
Therefore suggesting, virtually complete control of the
stereochemical outcome may be realized by eliminating
Scheme 2.
1
0
the noncatalytic pathway.
In order to expand the comparison of reactivities,
Michael additions between the three Schiff base derived
glycine equivalents and 3-substituted acryloyloxazoli-
din-2-one derivatives were evaluated (Table 3). Again
compound 3b reacted at a much higher rate than 2b, how-
ever both provided the appropriate products in nearly
quantitative yield and virtually complete diastereoselec-
proper choice of the corresponding o-aminobenzophe-
none or o-aminoacetophenone and dialkylamine. More-
over, the structural flexibility included in this design
allows for the connection between the stoicheometric
and catalytic approaches to the asymmetric synthesis
of amino acids, as the application of various C -sym-
2
metrical dialkylamines can provide for an internal
source of chirality. With respect to efficiency, com-
1
1
tivity. In contrast, the Michael addition of Schiff base
failed to advance to completion and provided at least
1
3
1
pounds 3a–c are very inexpensive, and can be stored
at room temperature in an open atmosphere while
retaining high chemical reactivity. The homologation
of NGEs 3a–c can be conducted under homogeneous
or PTC conditions via alkyl halide alkylations,
Michael and aldol addition reactions affording the
corresponding products in high chemical yields and
enantio- or diastereoselectivity. These products can also
be easily isolated and disassembled to release the target
amino acids along with quantitative recovery and reuse
of the ligands 4a–c.
three of the four possible diastereomers in a 7.2:1.2:1.0
ratio.
Finally to emphasize the truly versatile nature of the
compounds 3b, an aldol reaction was conducted, under
conditions not compatible with either of the other Schiff
bases 1 or 2a,b, due to low solubility 2a,b or instability
of 1 (Scheme 2). However, allowing 3b and an aldehyde,
such as benzaldehyde, to react in the presence of sodium
methoxide, in methanol provided the corresponding
1
2
(
2S*,3R*) b-hydroxy-a-amino acid in 98% de.
In summary, a new generation of nucleophilic glycine
equivalents has been introduced With several points of
flexibility incorporated into this design, considerable
control over the reactivity and physical properties, solu-
bility in particular, of these NGEs can be realized by the
Acknowledgements
The work was supported by the start-up fund provided
by the Department of Chemistry and Biochemistry, Uni-
versity of Oklahoma.

944
T. K. Ellis et al. / Tetrahedron Letters 46 (2005) 941–944
6. (a) Ellis, T. K.; Martin, C. H.; Tsai, G. M.; Ueki, H.;
Supplementary data
Soloshonok, V. A. J. Org. Chem. 2003, 68, 6208; (b) Ellis,
T. K.; Hochla, V. M.; Soloshonok, V. A. J. Org. Chem.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2
003, 68, 4973.
7
. The Supplementary data is available online with the paper
in ScienceDirect. The Supplementary data includes spec-
tral characterization data for all new compounds as well as
representative experimental procedures and catalyst
structures.
8. N-(9-Anthracenylmethyl)-cinchonidinium chloride, and
O-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide
were used.
2
004.12.050.
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the relative configuration of the products are assigned
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. While compound 1 features excellent solubility in most of
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4
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5
13. Compounds 3a–j may be synthesized from $0.65 to $0.80
per gram, depending on the price of the dialkylamine
employed.