Asymmetric Michael addition reactions of chiral Ni(II)-complex of glycine with (N-trans-enoyl)oxazolidines: Improved reactivity and stereochemical outcome

Article abstract of DOI:10.1016/S0957-4166(99)00483-8

Application of the (N-trans-enoyl)oxazolidines as Michael acceptors in the kinetically controlled additions with a Ni(II)-complex of the chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone 1 was shown to be synthetically advantageous over the alkyl enoylates, allowing for remarkable improvement in reactivity and, in most cases, diastereoselectivity of the reactions. While the stereochemical outcome of the Michael additions of the aliphatic (N-trans-enoyl)oxazolidines with complex 1 depended on the steric bulk of the alkyl group on the starting oxazolidines, the diastereoselectivity of the aromatic (N-trans-enoyl)oxazolidines reactions was found to be controlled by the electronic properties of the aryl ring. In particular, the additions of complex 1 with (N-cinnamoyl)oxazolidines, bearing electron-withdrawing substituents on the phenyl ring, afforded the (2S,3R)-configured products with synthetically useful selectivity and in quantitative chemical yield, thus allowing an efficient access to sterically constrained β-substituted pyroglutamic acids and related compounds. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00483-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4265–4269
Asymmetric Michael addition reactions of chiral Ni(II)-complex
of glycine with (N-trans-enoyl)oxazolidines: improved reactivity
and stereochemical outcome
Vadim A. Soloshonok,∗ Chaozhong Cai and Victor J. Hruby ∗
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 21 September 1999; accepted 25 October 1999
Abstract
Application of the (N-trans-enoyl)oxazolidines as Michael acceptors in the kinetically controlled additions
with a Ni(II)-complex of the chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone
1 was shown to be synthetically advantageous over the alkyl enoylates, allowing for remarkable improvement in
reactivity and, in most cases, diastereoselectivity of the reactions. While the stereochemical outcome of the Michael
additions of the aliphatic (N-trans-enoyl)oxazolidines with complex 1 depended on the steric bulk of the alkyl group
on the starting oxazolidines, the diastereoselectivity of the aromatic (N-trans-enoyl)oxazolidines reactions was
found to be controlled by the electronic properties of the aryl ring. In particular, the additions of complex 1 with
(N-cinnamoyl)oxazolidines, bearing electron-withdrawing substituents on the phenyl ring, afforded the (2S,3R)-
configured products with synthetically useful selectivity and in quantitative chemical yield, thus allowing an
efficient access to sterically constrained β-substituted pyroglutamic acids and related compounds. © 1999 Elsevier
Science Ltd. All rights reserved.
Recently, we reported asymmetric Michael addition reactions between a Ni(II)-complex of the chi-
ral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone 1 and a series of the
β-trifluoromethyl substituted alkyl acrylates to afford the corresponding sterically constrained and
trifluoromethyl-containing pyroglutamic acids in enantiomerically pure form.1 The unique physicochem-
ical properties of complex 1 and products of its homologation, as well as the simplicity of the experimen-
tal procedure,2 makes the method synthetically attractive, in particular, for large scale preparations of the
target amino acids. Since pyroglutamic acids can be conventionally transformed to a whole variety of
amino acids such as prolines,3 glutamines, and glutamic acids,4 we were interested in generalizing this
methodology to afford the corresponding β-alkyl and β-aryl substituted derivatives, which are extraor-
dinary useful compounds in the de novo design of peptides with rationally modified three-dimensional
structure and biological functions.5 However, our attempts to involve β-alkyl- or β-arylacrylic esters in
∗
Corresponding authors. E-mail: hruby@mail.arizona.edu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00483-8
tetasy 3119

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the reaction with complex 1 encountered unexpected problems of low reactivity and poor stereochemical
outcome. Apparently, the successful results of the additions between 1 and trifluoromethyl containing
acrylates are due to the enhanced electrophilicity and steric demands of these derivatives provided
by the trifluoromethyl group.6 To overcome the problems associated with β-alkyl- and β-arylacrylic
esters we searched for other derivatives which would feature higher electrophilicity (issue of reactivity)
and s-trans conformational homogeneity (issue of diastereoselectivity). Recently we have found that
readily available and inexpensive (N-trans-enoyl)oxazolidines 2 have the required characteristics of the
Michael acceptor allowing the corresponding additions with achiral Ni(II)-complexes of Schiff bases of
glycine with o-[N-α-picolylamino]benzophenone and -acetophenone to proceed with virtually complete
diastereoselectivity.7 In this communication we report the asymmetric version of the reaction, applying
Ni(II)-complex 1 as a chiral equivalent of nucleophilic glycine in the additions with various oxazolidines
2 to demonstrate the generality and synthetic efficacy of the method.
Previously we have shown that the Michael addition reaction between complex 1 and ethyl crotonate,
conducted in DMF in the presence of DBU (50 mol%) for 1 h gave rise to a mixture of (2R,3R)-,
(2S,3S)- and (2S,3R)-diastereomers in a ratio of 19.0:76.2:4.8, respectively, and in 78% chemical yield.
In contrast, N-crotonyloxazolidine 2a (Scheme 1) was found to react with complex 1 in the presence of
catalytic amounts of DBU with a substantially higher reaction rate, affording quantitatively a mixture
of (2S,3S)-3a and (2R,3R)-configured products 4a in a ratio of 71:29, respectively (Scheme 1, Table 1,
entry 1). Due to the quantitative chemical yield, this outcome is synthetically superior over the previously
reported procedure,8 as the diastereomerically pure major product (2S,3S)-3a could be isolated in 67%
yield simply by crystallizing the resulting mixture from benzene/hexanes. Increasing the steric bulk
of the alkyl group on the starting oxazolidine resulted in a reduced reaction rate of the addition of
complex 1 with (N-hexenoyl)oxazolidine 2b. However, the major product (2S,3S)-3b was obtained with
slightly higher selectivity (entry 2). Having previously failed to conduct the Michael addition between
complex 1 and alkyl 4-methylpentanoylate,9 we were interested in the reaction of 1 with [N-(3-iso-
propylacryloyl)]oxazolidine 2c to provide access to 3-iso-propyl substituted pyroglutamic acid and its
Table 1
The reactions of 1 with 2a–ja

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4267
derivatives, a particularly important sterically constraining unit in peptide design. To our satisfaction,
sterically bulky oxazolidine 2c readily reacted with complex 1 to give quantitatively a mixture of (2S,3S)-
3c and (2R,3R)-diastereomers 4c with a synthetically meaningful excess of the major product (entry 3).
Considering the stereochemical outcome of these reactions one might conclude that oxazolidines 2a–c
feature much higher reactivities than the corresponding alkyl esters and provide better diastereoselectivity
in the addition reaction with complex 1. The absolute configuration of the diastereomeric products10
suggests virtually complete diastereo-face selectivity on the part of oxazolidines 2a–c, while the complex
1 (2S)/(2R)-face selectivity is relatively poor.3
Scheme 1.
With these results in hand, we next studied a series of the reactions between complex 1 and oxa-
zolidines 2d–j which bear aromatic substituents on the C,C double bond. Interestingly, the addition of
phenyl-containing oxazolidine 2d with 1 occurred with the same rate and quantitative yield as the reaction
of methyl derivative 2a, but with higher diastereoselectivity (entry 4). The main product (2S,3R)-3d10,11
was isolated in 76% chemical yield simply by crystallizing the resultant mixture of diastereomers. The
reaction of the more sterically bulky naphthyl-containing oxazolidine 2e proceeded at a slightly lower rate
but with better diastereoselectivity (entry 5). To investigate electronic effects of substituents on the phenyl
ring of the starting oxazolidines on the stereochemical outcome of the reactions, we conducted additions
of complex 1 with oxazolidines 2f and 2g, bearing methoxy and trifluoromethyl groups, respectively.
The reaction of 2f proceeded at a relatively slow rate, as the electron-donating methoxy group decreased
the electrophilicity of the C,C double bond, but with a slightly higher stereoselectivity as compared with
the results of the addition of the unsubstituted phenyl-containing derivative 2d (entry 6). In contrast,
the addition of trifluoromethyl oxazolidine 2g occurred almost instantly and with unexpectedly high
diastereoselectivity (80% de, entry 7). Drawing inspiration from these results, we conducted the addition
between complex 1 and pentafluorophenyl derivative 2h. The exothermic reaction afforded the major
product (2S,3R)-3h with 92% ee. To examine the origin and generality of the unexpectedly high stereo-
selectivity observed in these additions, and bearing in mind the unique stereocontrolling ability of fluorine
atoms,7 we investigated the reactions of the oxazolidines bearing electron-withdrawing substituents other

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than fluorine. To our satisfaction, the exothermic and quantitative additions of complex 1 with the 4-
nitro 2i and 3,4-dichloro derivatives 2j featured high diastereoselectivity (entries 9 and 10) suggesting
that the electron-deficiency of the phenyl ring and not the presence of fluorine atoms is the cause of
the observed results. Thus, considering the stereochemical outcome of the reactions in the aromatic
series, one can conclude that, as was observed in the aliphatic series, (N-β-arylacryloyl)oxazolidines 2d–j
featured perfect face-selectivity giving rise to a mixture of (2S,3R)- and (2R,3S)-configured diastereomers
as a result of incomplete (2S)/(2R)-face control of the corresponding enolate derived from complex 1.3
However, in contrast to the aliphatic series, the stereoselectivity of the reaction of aromatic oxazolidines
2d–j was found to be a function of the substituent on the phenyl ring in 2d–j. Such a pronounced
effect of electronic properties of the aromatic ring on the stereochemical outcome of the asymmetric
reactions is quite rare and difficult to rationalize at the present stage, in particular, considering that
these DBU-catalyzed additions might proceed via unchelated, non-cyclic transition states. However, one
might assume that electrostatic repulsive or attractive interactions of the electron-deficient phenyl ring of
2g–j with, respectively, partially positively (Ni cation) or negatively (enolate oxygen, π-stacking effects)
charged sites of complex 1 could account for the observed stereochemical outcome. Molecular modelling
and calculations of possible transition states, as well as additional series of the reactions, are currently in
progress to further evaluate these observations.
The diastereomerically pure addition products 3a–j were readily decomposed to afford the target enan-
tiomerically pure pyroglutamic acids 4a–j, along with the recovered chiral ligand (S)-5 and oxazoline.12
The former was conventionally transformed to the starting chiral Ni(II)-complex (S)-1.
In conclusion, application of (N-trans-enoyl)oxazolidines 2 as Michael acceptors in kinetically con-
trolled additions with Ni(II)-complex 1 allowed for remarkable improvement in reactivity and, in most
cases, diastereoselectivity of the reactions. While in the aliphatic series the stereochemical outcome
was found to be a function of the steric bulk of the alkyl group on the starting oxazolidines 2, in the
aromatic series electronic properties of substituents on the phenyl ring of 2 were shown to control the
diastereomeric ratio of the products, suggesting quite intriguing transition states involved. Synthetically
attractive characteristics of the method, such as (i) room temperature reactions, (ii) quantitative chemical
yields and (iii) simple work-up and isolation of the target products, should render it a useful alternative
to literature methods, in particular for preparing the corresponding aromatic amino acid analogues with
electron-withdrawing substituents.
Acknowledgements
The work was supported by the grants from US 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 the USPHS.
References
1. (a) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V.; Mischenko, N. Tetrahedron 1999, 55, 12031. (b) Soloshonok,
V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V. Tetrahedron 1999, 55, 12045.
2. For reviews on reactivity, properties and applications of complex (S)-1 in the asymmetric synthesis of α-amino acids, see:
(a) Belokon, Yu. N. Janssen Chimica Acta 1992, 10, 2, 4. (b) Belokon, Yu. N. Pure Appl. Chem. 1992, 64, 1917. (c)
Kukhar’, V. P.; Resnati, G.; Soloshonok, V. A. In Fluorine-Containing Amino Acids. Synthesis and Properties; Kukhar’,
V. P.; Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester, 1994; Chapter 5. (d) Soloshonok, V. A. In Biomedical
Frontiers of Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; ACS Books, American Chemical Society:

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4269
Washington, D. C., 1996; Chapter 2. (e) Soloshonok, V. A. In Enantiocontrolled Synthesis of Fluoro-Organic Compounds:
Stereochemical Challenges and Biomedicinal Targets; Soloshonok, V. A., Ed.; Wiley & Sons: Chichester, 1999.
3. Kanemasa, S.; Tatsukawa, A.; Wada, E. J. Org. Chem. 1991, 56, 2875.
4. Schöllkopf, U.; Pettig, D.; Busse, U. Synthesis 1986, 737.
5. For reviews, see: (a) Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug Discovery, 5th ed.; Wolff, M. E., Ed.;
John Wiley & Sons: New York, 1995; Vol. 1, pp. 803–861. (b) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699. (c)
Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (d) Hruby, V. J.; Al-Obeidi, F.; Kazmierski, W. Biochem.
J. 1990, 268, 249. (e) Hruby, V. J. Med. Res. Rev. 1989, 9, 343.
6. Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets;
Soloshonok, V. A., Ed.; Wiley & Sons: Chichester, 1999.
7. Soloshonok, V. A.; Cai, C.; Hruby, V. J. Tetrahedron Lett. 1999, 41, 135.
8. In the reaction of complex 1 with ethyl crotonate, the main (2S,3S)-diastereomer was isolated in 53% yield by crystallizing
the resultant mixture of three diastereomeric products; see Ref. 2a.
9. Soloshonok, V. A.; Cai, C.; Hruby, V. J., unpublished data.
10. The absolute configuration of the products was unambiguously assigned on the basis of chiroptical and spectral properties
of the corresponding Ni(II)-complexes as well as by comparison of chiroptical and spectral data of the isolated pyroglutamic
acids with the literature data; see Ref. 2 and literature cited therein.
11. The (2S,3R)-configuration, a consequence of the Cahn–Ingold–Prelog priority, is stereochemically equivalent to the (2S,3S)-
configuration in the aliphatic series: Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966, 5, 385.
12. A general procedure is illustrated by the synthesis of (2S,3R)-3-phenylpyroglutamic acid. To a stirred suspension of complex
1 (1.50 g, 3.0 mmol) and oxazolidinone 2d (0.65 g, 3.0 mmol) in DMF (8.0 mL), DBU (0.061 g, 0.4 mmol) was added at
ambient temperature. The progress of the reaction was monitored by TLC and upon completion the reaction mixture was
poured into water (100 mL). The resultant crystalline product was filtered and washed thoroughly with water, dried in the
air and recrystallized from benzene/hexanes to afford 1.64 g (76%) of diastereomerically pure 3d. The product 3d (1.64 g,
2.3 mmol) was dissolved in methanol (20 mL) and added to a 1:1 mixture (40 mL) of 3N HCl and water at 70oC. After the
decomposition of the complex was completed (disappearance of the orange color) the mixture was evaporated and treated
with concd ammonia and extracted with CHCl3 to give ligand 5 (0.88 g, >99% yield). The aqueous phase was evaporated
and the solid residue was washed with acetone to remove 2-oxazolidinone (0.18 g, 90% yield). The resultant product was
dissolved in water and loaded on a 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 6d
(0.40 g, 85% yield). The product was recrystallized from THF/hexanes to give an analytically pure sample of 6d.