Toward design of a practical methodology for stereocontrolled synthesis of χ-constrained pyroglutamic acids and related compounds. Virtually complete control of simple diastereoselectivity in the Michael addition reactions of glycine Ni(II) complexes with N-(enoyl)oxazolidinones

Article abstract of DOI:10.1016/S0040-4039(99)02018-3

A Ni(II) complex of the Schiff base of glycine with o-[N-α- picolylamino]benzophenone or -acetophenone as a nucleophilic glycine equivalent, and N-trans-enoyloxazolidinones, as a derivative of an α,β- unsaturated carboxylic acid, were found to be the substrates of choice in the corresponding Michael addition reactions. The reactions proceed at room temperature in the presence of catalytic amounts of DBU to afford quantitatively a virtually diastereocomplete formation of the corresponding addition products with (2R*,3R*) or (2R*,3S*) relative configuration, depending on the nature of the starting N-enoyloxazolidinones, Acidic decomposition of the products followed by treatment of the reaction mixture with NH₄OH gives rise to the corresponding diastereomerically pure 3- substituted pyroglutamic acids.

Full text of DOI:10.1016/S0040-4039(99)02018-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 135–139
Toward design of a practical methodology for stereocontrolled
synthesis of χ-constrained pyroglutamic acids and related
compounds. Virtually complete control of simple
diastereoselectivity in the Michael addition reactions of glycine
Ni(II) complexes with N-(enoyl)oxazolidinones
Vadim A. Soloshonok,∗ Chaozhong Cai and Victor J. Hruby ∗
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 22 October 1999; accepted 25 October 1999
Abstract
A Ni(II) complex of the Schiff base of glycine with o-[N-α-picolylamino]benzophenone or -acetophenone
as a nucleophilic glycine equivalent, and N-trans-enoyloxazolidinones, as a derivative of an α,β-unsaturated
carboxylic acid, were found to be the substrates of choice in the corresponding Michael addition reactions. The
reactions proceed at room temperature in the presence of catalytic amounts of DBU to afford quantitatively a
virtually diastereocomplete formation of the corresponding addition products with (2R*,3R*) or (2R*,3S*) relative
configuration, depending on the nature of the starting N-enoyloxazolidinones. Acidic decomposition of the products
followed by treatment of the reaction mixture with NH4OH gives rise to the corresponding diastereomerically pure
3-substituted pyroglutamic acids. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: amino acids; amino acid derivatives; asymmetric synthesis; addition reactions; nickel; mechanism.
Sterically constrained, tailor-made amino acids are of paramount importance in the de novo design
of peptides with a pre-supposed pattern of biological and biophysical properties, and ultimately for the
development of a new generation of highly selective and potent peptide-based drugs.1 Systematic studies
into the chemical–physical basis for peptide-mediated biological information transfer, as a function
of the topographical properties and three-dimensional structures of peptide molecules, critically need
readily available and structurally varied amino acid analogues in optically pure form and on multi-gram
scales. Our current efforts in this field are focusing on the stereocontrolled synthesis of χ-constrained
pyroglutamic acids which, apart from their own promising applications to peptide design, are key
compounds for a whole family of corresponding glutamic acids, glutamines and prolines, all of which
∗
Corresponding authors. E-mail: vadym@u.arizona.edu (V. A. Soloshonok), caic@u.arizona.edu (C. Cai),
hruby@u.arizona.edu (V. J. Hruby)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02018-3
tetl 15946

136
are extremely important structural units for rational modification of the conformational and topographical
features of peptide and peptidomimetic molecules.2
Michael addition reactions between a nucleophilic glycine equivalent and an α,β-unsaturated
carboxylic acid derivative have been shown to be a generalized approach to 3-substituted
glutamic/pyroglutamic acids.3 Although some of the diastereoselective Michael addition reactions
reported in the literature excel in chemical yields and a degree of induced stereocontrol, their synthetic
value is often compromised by incomplete diastereoselectivity, lack of generality, and problematic
applicability for large-scale synthesis. Thus, we set ourselves a goal to develop a new protocol for
Michael addition reactions which would be experimentally simple (room temperature reactions with
no air/moisture sensitive reagents) and allowing for generalized access to the target amino acids with
complete chemical yield and stereochemical control. In this Communication we report that the reactions
between a Ni(II) complex of the Schiff bases of glycine 1a,b, as a nucleophilic glycine equivalent,
and N-trans-enoyloxazolidinones 2, as derivatives of α,β-unsaturated carboxylic acids, meet the above
requirements, and provide the basis for a highly practical approach to the target amino acids 7 (Scheme
1).
Scheme 1.
The origin of diastereoselectivity in Michael addition reactions, as a case of coupling of two unsym-
metrically substituted trigonal centers, has been extensively studied.2,3 Analysis of the literature data2–4
reveals that the geometric and conformational homogeneity of an enolate derived from a glycine
equivalent and an α,β-unsaturated carboxylic acid derivative, respectively, would have a major impact
on the stereochemical outcome of the reaction. Thus, the best diastereoselectivity achieved so far in
these type of Michael addition reactions has been reported by Seebach et al. who employed 2,6-di-t-
butyl-4-methoxyphenyl esters as ‘sterically protected but electronically effective’ Michael acceptors.3d
Unfortunately, the difficulties associated with the preparation of these derivatives and deprotection of the
carboxylic function via Ce(IV) oxidation limits the synthetic value of the 2,6-di-t-butyl-4-methoxyphenyl
esters, in particular, for large-scale preparations. Considering other α,β-unsaturated carboxylic acid
derivative as candidates for an ideal Michael acceptor our attention was directed to the readily available
and inexpensive N-trans-enoyloxazolidinones 2 (Scheme 1), which are thought to exist exclusively in
the s-trans conformation by virtue of unfavorable electrostatic repulsive interactions between the two
carbonyl groups.5 As to the choice of a nucleophilic glycine equivalent, our major concern was its ability

137
to form geometrically homogeneous enolates on its own, without external chelating agents. The latter
requirement could be met by a cyclic structure of a glycine equivalent. Among the literature data on
various glycine derivatives we took note of the recent publication by Belokon et al. on a Ni(II)-complex of
the Schiff base of alanine with o-[N-α-picolylamino]benzaldehyde.6 Following also our own experience
in the chemistry of Ni(II)-complexes of amino acids,3 we designed and synthesized Ni(II)-complexes of
Schiff bases of glycine with o-[N-α-picolylamino]benzophenone and -acetophenone 1a,b (Scheme 1).
Our first examination of the reaction between the complex 1a and N-(trans-cinnamoyl)oxazolidinone 2a
gave unexpectedly excellent results. The reaction, catalyzed by 15 mol% DBU, was completed at rt in 50
min affording the diastereomerically pure product 6a in quantitative chemical yield (Table 1, entry 1). The
stereochemical outcome of the reaction was found to be kinetically controlled, as a resubmission of pure
product 6a to the original reaction conditions did not give starting compounds 1a and 2a in detectable
amounts (1H NMR, 500 MHz). Compound 6a was isolated simply by pouring the reaction mixture
into water followed by a filtration of the crystalline material. Without any purification, complex 6a was
decomposed to give the (2R*,3S*)-configured pyroglutamic acid 7a along with quantitative recovery of
ligand 3.7 Inspired by this outcome, we studied the addition reactions between Ni(II)-complexes 1a,b
and N-cinnamoyl derivatives of 3-oxazolidin-2-one 2a, pyrrolidin-2-one 4 and succinimide 5, to find the
best combination of nucleophile/electrophile, and to get some insight into the origins of stereogenesis
in these reactions (Table 1). Thus, under the same conditions, reaction of oxazolidinone 2a with the
acetophenone derived complex 1b occurred at a substantially higher reaction rate (entry 2) furnishing
the corresponding (2R*,3S*)-diastereomer as the sole product in quantitative chemical yield. On the
other hand, reaction of the pyrrolidin-2-one derived electrophile 4 with complex 1b had a decreased
rate of reaction, but afforded the product 8 with the same excellent stereochemical outcome (entry 3).
Surprisingly, the reaction between complexes 1a,b and the succinimide derivative 5 did not take place
at all, even under forcing conditions (entry 4). These results suggested that both complexes 1a and
1b provide virtually complete diastereoselectivity in the reactions with N-cinnamoyl derivative 2a. In
terms of reactivity, 1b should be superior to 1a, which could be rationalized by assuming that 1b has
a less sterically shielded glycine moiety. However, the observed reactivity in the reactions of complex
1b with 3-oxazolidin-2-one 2a, pyrrolidin-2-one 4 and succinimide 5 is quite intriguing, because the
electrophilicity of the C,C double bond of these compounds increases in the same order.
Table 1
The additions of oxazolidinones 2a, 4, 5 with Ni(II)-complexes 1a,ba
Having selected complex 1b and the oxazolidinones 2 as the best glycine and α,β-unsaturated

138
carboxylic acid derivatives, respectively, we studied the generality of this reaction. We investigated
additions between 1b and a series of N-(enoyl)-3-oxazolidin-2-one derivatives 2 (Scheme 2, Table 2)
bearing in the β-position a phenyl ring with electron withdrawing (CF3, 2b) and electron donating groups
(OMe, 2c), and with bulky β-2d and α-naphthyl 2e, and electron rich (N-Mts-β-indolyl, 2f) and electron
deficient (C6F5, 2g) aromatic rings, as well as alkyl substituents Me 2h and n-Pr 2i. To our satisfaction, all
reactions, occurred under the same conditions at rt, and gave rise to only one diastereomer in quantitative
yield regardless of the steric or electronic nature of the substituent of the starting oxazolidinone 2b–i.
However, the nature of the substituent had a substantial effect on the reaction rate. Thus, the addition
of the trifluoromethyl-containing 2b (Table 2, entry 1) and pentafluorophenyl derivatives 2g (entry 6)
with complex 1b occurred almost instantly, while the reactions of compounds 2c and 2f, bearing electron
donating substituents, were markedly slower (entries 2 and 5). Increase in the steric bulk of the subsituent
also decreased the reaction rates, which was observed in both the aromatic (entries 3 and 4) and aliphatic
series (entries 7 and 8).
Table 2
The additions of 2b–i with 1ba
Scheme 2.
In conclusion, we have found a unique combination of nucleophilic glycine and α,β-unsaturated
carboxylic acid derivatives allowing the corresponding Michael addition reactions to proceed at room
temperatures in the presence of a catalytic amount of organic non-chelating base with virtually complete

139
diastereoselectivity and quantitative chemical yield. Moreover, the reactions showed extraordinary gen-
erality, suggesting an intriguing transition state for the stereoselective step, which is currently under
investigation. Taking into account that both the Ni(II)-complexes 1 and the N-(enoyl)-3-oxazolidin-2-
ones 2 can easily be prepared in chiral versions, or a chiral base could be used in the place of DBU, the
discovered process provides a realistic basis for a truly practical entry into a large family of β-substituted
and stereochemically defined amino acids of synthetic and biomedicinal importance.
Acknowledgements
The work was supported by grants from U.S. Public Health Service Grant and the National Institute of
Drug Abuse DA 06284, DA 04248 and DK 17420. The views expressed are those of the authors and not
necessarily of the USPHS.
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7. To a stirred suspension of complex 1b (1.64 g, 4.64 mmole) and oxazolidinone 2a (1.01 g, 4.64 mmole) in DMF (18 mL),
DBU (0.107 g, 0.696 mmole) was added at ambient temperature. The progress of the reaction was monitored by TLC and
upon completion the reaction mixture was poured into water (200 mL). The resultant crystalline product was filtered and
washed thoroughly with water. The product 6b (2.63 g, 4.6 mmole) was dried in the air, dissolved in methanol (60 mL) and
added to a 1/1 mixture (120 mL) of 3 N HCl and water at 70°C. After the decomposition of the complex was completed
(disappearance of the orange color) the mixture was evaporated and treated with conc. ammonia and extracted with CHCl3
to give ligand 3b (1.07 g, 96% yield). The aqueous phase was evaporated and the solid residue was washed with acetone to
remove 2-oxazolidinone (0.4 g, 99% yield). The resultant product was dissolved in water and loaded on Dowex ion-exchange
resin column, which was washed with H2O:EtOH (2:1). The acidic fraction which emerged from the column was collected
and evaporated to afford (2R*,3S*)-3-phenylpyroglutamic acid 7a (0.85 g, 90% yield). The product was recrystallized from
THF/hexanes to give the analytically pure sample of 7a.