Rational Design of Highly Diastereoselective, Organic Base-Catalyzed, Room-Temperature Michael Addition Reactions

Article abstract of DOI:10.1021/jo0008791

Via the rational design of a single-preferred transition state, stabilized by electron donor - acceptor-type attractive interactions, structural and geometric requirements for the corresponding starting compounds have been determined. The Ni(II) complex of the Schiff base of glycine with o-[N-α-picolylamino]acetophenone, as a nucleophilic glycine equivalent, and N-(trans-enoyl)oxazolidin-2-ones, as derivatives of an α,β-unsaturated carboxylic acid, were found to be the substrates of choice featuring geometric/conformational homogeneity and high reactivity. The corresponding Michael addition reactions were found to proceed at room temperature in the presence of catalytic amounts of DBU to afford quantitatively the addition products with virtually complete diastereoselectivity. Acidic decomposition of the products followed by treatment of the reaction mixture with NH₄OH gave rise to the diastereomerically pure 3-substituted pyroglutamic acids.

Full text of DOI:10.1021/jo0008791

6688
J . Org. Chem. 2000, 65, 6688-6696
Ra tion a l Design of High ly Dia ster eoselective, Or ga n ic
Ba se-Ca ta lyzed , Room -Tem p er a tu r e Mich a el Ad d ition Rea ction s1
Vadim A. Soloshonok,* Chaozhong Cai, and Victor J . Hruby*
Department of Chemistry, University of Arizona, Tucson, Arizona 85721
Luc Van Meervelt
K. U. Leuven - Department of Chemistry, Celestijnenlaan 200F, B-3001 Heverlee-Leuven, Belgium
Takashi Yamazaki
Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, J apan
hruby@mail.arizona.edu
Received J une 8, 2000
Via the rational design of a single-preferred transition state, stabilized by electron donor-acceptor-
type attractive interactions, structural and geometric requirements for the corresponding starting
compounds have been determined. The Ni(II) complex of the Schiff base of glycine with o-[N-R-
picolylamino]acetophenone, as a nucleophilic glycine equivalent, and N-(trans-enoyl)oxazolidin-2-
ones, as derivatives of an R,â-unsaturated carboxylic acid, were found to be the substrates of choice
featuring geometric/conformational homogeneity and high reactivity. The corresponding Michael
addition reactions were found to proceed at room temperature in the presence of catalytic amounts
of DBU to afford quantitatively the addition products with virtually complete diastereoselectivity.
Acidic decomposition of the products followed by treatment of the reaction mixture with NH4OH
gave rise to the diastereomerically pure 3-substituted pyroglutamic acids.
In tr od u ction
search.6 Following the introduction by our group of the
local constraint paradigm for understanding peptide
structure-activity relationship and in de novo peptide
design,7 we have needed a series of novel, stereochemi-
cally defined and ø-constrained8 derivatives of glutamic/
pyroglutamic acids to implement some of our current
projects in the understanding of the chemical-physical
basis of peptide-mediated biological information transfer.9
NGUCA reactions have been extensively studied by
many research groups, and a plethora of original ap-
proaches have been developed to control both simple and
face diastereoselectivities of the additions.3,10 Though
some of these methods excel in chemical yields and a
degree of stereocontrol, their synthetic value is often
compromised by incomplete stereoselectivity, lack of
generality, and most importantly, problematic applicabil-
ity for large-scale preparations. Therefore, we set for
The Michael addition reaction is one of the most
synthetically powerful and versatile ways to form a C,C
bond.2 Of particular interest for us are the reactions
between nucleophilic glycine equivalents and R,â-unsat-
urated carboxylic acid derivatives (NGUCA reactions),
the most methodologically concise and generalized ap-
proach to the family of five-carbon-atom amino acids such
as glutamic and pyroglutamic acids, glutamines, prolines,
ornithines, and arginines.3-5 All of these amino acids play
a critical pharmacophore role in numerous natural pep-
tides and therefore are a focus of current peptide re-
* To whom correspondence should be addressed. (V.A.S.) Fax: (520)
621-4964. vadym@u.arizona.edu. (V.J .H.) Fax: (520) 621-8407.
(1) Stereochemically Defined C-Substituted Glutamic Acids and
Their Derivatives. 7. For previous papers, see: (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. (c) Soloshonok, V. A.; Cai, C.; Hruby, V.
J . Tetrahedron: Asymmetry 1999, 10, 4265. (d) Soloshonok, V. A.; Cai,
C.; Hruby, V. J . Tetrahedron Lett. 2000, 41, 135. (e) Soloshonok, V.
A.; Cai, C.; Hruby, V. J . Angew. Chem., Int. Ed. Engl. 2000, 39, 2172.
(f) Soloshonok, V. A.; Cai, C.; Hruby, V. J . Organic Lett. 2000, 2, 747.
(2) (a) Oare, D. A.; Heathcock, C. H. In Topics in Stereochemistry;
Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1990; Vol. 19, pp
227-407. (b) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock,
C. H. J . Org. Chem. 1990, 55, 132.
(3) For reviews on asymmetric synthesis of R-amino acids in general
and the target amino acids in particular, see: (a) Duthaler, R. O.
Tetrahedron 1994, 50, 1539. (b) Williams, R. M. Synthesis of Optically
Active R-Amino Acids; Pergamon Press: Oxford, 1989.
(4) For papers, see: (a) Kanemasa, S.; Tatsukawa, A.; Wada, E. J .
Org. Chem. 1991, 56, 2875. (b) Scho¨llkopf, U.; Pettig, D.; Busse, U.;
Egert, E.; Dyrbusch, M. Synthesis 1986, 737.
(6) (a) Hruby, V. J .; Sharma, S. D.; Collins, N.; Matsunaga, T. O.;
Russell, K. C. In Synthetic Peptides: A User’s Guide; Grant, G. A., Ed.;
W. H. Freeman and Co., New York, 1992; pp 259-345. (b) Hruby, V.
J .; Qian, X. In Methods in Molecular Biology, Vol. 35, Peptide Synthesis
and Purification Protocols; Pennington, M. W., Dunn, B. M., Eds.;
Humana Press: Clifton, NJ , 1994; pp 201-240.
(7) (a) Meraldi, J .-P.; Yamamoto, D.; Hruby, V. J .; Brewster, A. I.
R. In Peptides: Chemistry, Structure and Biology; Walter, R., Meien-
hofer, J ., Eds.; Ann Arbor Science Publishers: Ann Arbor, MI, 1975;
pp 803-814. (b) Meraldi, J .-P.; Hruby, V. J .; Brewster, A. I. R. Proc.
Nat. Acad. Sci. U.S.A. 1977, 74, 1373. (c) Hruby, V. J . In Perspectives
in Peptide Chemistry; Eberle, A., Geiger, R., Wieland, T., Eds.; S.
Karger: Basel, Switzerland, 1981; pp 207-220. (d) Hruby, V. J . Life
Sci. 1982, 31, 189.
(8) For recent reviews on ø-constrained amino acids, see: (a) Hruby,
V. J .; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Biopolymers
(Peptide Sci.) 1997, 43, 219. (b) Gibson, S. E.; Guillo, N.; Tozer, M. J .
Tetrahedron 1999, 55, 585.
(9) Fan, W.; Boston, B. A.; Kesterson, R. A.; Hruby, V. J .; Cone, R.
D. Nature 1997, 385, 165 and references therein.
(5) For recent review on various synthetic transformations of
pyroglutamic acid and its derivatives, see: Na´jera, C.; Yus, M.
Tetrahedron: Asymmetry 1999, 10, 2245.
10.1021/jo0008791 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Rational Design of Michael Addition Reactions
J . Org. Chem., Vol. 65, No. 20, 2000 6689
ourselves a goal to develop a new protocol for Michael
addition reactions which would be experimentally simple
and allow for generalized access to the target amino acids
with nearquantitative chemical yields and complete
stereochemical control. In this paper, we describe in full12
the basic, paramount steps toward this goal, the design
of a starting nucleophilic glycine equivalent and R,â-
unsaturated carboxylic acid derivatives which allow the
corresponding addition reactions to proceed with virtually
complete simple diastereoselectivity (>98% de) at room
temperature in the presence of nonchelating organic
bases.
might be regarded as a critical factor in determining the
diastereoselectivity of the reactions and, therefore, should
be a central issue in design.
Considering the NGUCA reactions as a case of coupling
of two unsymmetrically substituted trigonal centers, one
can expect up to 18 TSs to be involved in determining
the stereochemical outcome of the reaction. Such a large
number of theoretically possible TSs is a result of the
fact that both starting nucleophilic glycine equivalent,
in its enolate form, and Michael acceptor can react in two
geometric (cis vs trans) forms and in two conformations
(s-cis vs s-trans), respectively. If we can control geometric
homogeneity of the glycine enolate and conformational
homogeneity of the Michael acceptor, then the number
of possible TSs will be substantially reduced to only 6.
Further reduction of the possible TSs, to only one out of
six, is a much more formidable task. This problem might
be solved by the right choice of substitution pattern on
the starting nucleophilic glycine equivalent, and Michael
acceptor, that will give preference to a single TS as a
result of steric or electron donor-acceptor type attractive
interactions. Apart from stereochemical considerations,
our design of organic base-catalyzed, room-temperature
reactions involves also the issue of reactivity, C-H
acidity of the glycine methylene moiety and electrophi-
licity of the Michael acceptor C,C double bond. Thus, both
starting nucleophilic glycine equivalent and Michael
acceptor should possess high reactivity to be able to react
in the presence of relatively weak organic bases. With
this set of requirements for starting compounds, we
started our design using available literature data and
molecular modeling/calculations.
Design of th e Nu cleop h ilic Glycin e Equ iva len t.
A number of potential candidates for a nucleophilic
glycine equivalent of choice was substantially narrowed
by the requirements for geometric homogeneity and high
C-H acidity. The latter could be provided by the presence
of a strong electron-withdrawing Schiff base function, and
the former by a cyclic structure of the glycine equivalent.
Taking advantage of Professor Belokon’s studies,10h,o,13,14
as well as our extensive experience in the chemistry of
Ni(II) complexes of R-amino acids,1a,b,15,16 we designed and
synthesized a new Ni(II) complex of glycine Schiff base
derived from 2-aminoacetophenone 2 (Scheme 1). Prepa-
ration of complex 2 is very simple and can be easily
performed on a multigram (50 g and more) scale. The
glycine complex 2 is reasonably soluble in polar organic
Resu lts a n d Discu ssion
Analysis of the relevant literature reveals that, in all
previously studied NGUCA reactions, application of
lithium reagents as bases (n-BuLi) or additives (LiCl) was
of critical importance to obtain synthetically useful
stereochemical outcomes.3,10 The well-defined mechanism
of these addition reactions postulates the formation of
highly organized transition states (TSs) in which the
lithium cation plays a paramount role, chelating the
glycine enolate oxygen and nitrogen, as well as the
oxygen of the Michael acceptor carbonyl group. Organic
bases, for instance, triethylamine (TEA) or 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU), are ineffective for playing
the role of chelating agent. Therefore, not surprisingly,
organic base-catalyzed and highly diastereoselective
NGUCA reactions have not been reported so far.3,10
Obviously, application of organic bases in NGUCA reac-
tions would necessitate the development of a new and
nontraditional way to provide the formation of highly
organized TSs. Besides the role of chelated TSs, the
importance of stereochemical discriminations between
substituents on the starting nucleophilic glycine equiva-
lent and on the R,â-unsaturated carboxylic acid deriva-
tives was also well defined.3,10 Surprisingly, a geometric/
conformational homogeneity of the starting compounds,
as one more important factor that can contribute to the
origin of simple diastereoselectivity in the NGUCA
reactions, has not received much attention in the litera-
ture.3,10 Analysis of the stereochemical outcomes of
reported NGUCA reactions suggests that the geometric/
conformational properties of the starting compounds
(10) (a) Ezquerra, J .; Pedregal, C.; Merino, I.; Flo´rez, J .; Barluenga,
J .; Garc´ıa-Granda, S.; Llorca, M.-A. J . Org. Chem. 1999, 64, 6554. (b)
Seebach, D.; Hoffman, M. Eur. J . Org. Chem. 1998, 1337. (c) Shibuya,
A.; Kurishita, M.; Ago, C.; Taguchi, T. Tetrahedron 1996, 52, 271.11
(d) Antolini, L.; Forni, A.; Moretti, I.; Prati, F.; Laurent, E.; Gestmann,
D. Tetrahedron: Asymmetry 1996, 7, 3309. (e) Gestmann, D.; Laurent,
A. J .; Laurent, E. G. J . Fluor. Chem. 1996, 80, 27. (f) Hartzoulakis,
B.; Gani, D. J . Chem. Soc., Perkin Trans. 1 1994, 2525. (g) Suzuki, K.;
Seebach, D. Liebigs Ann. Chem. 1992, 51. (h) Belokon’, Y. N.; Bulychev,
A. G.; Pavlov, V. A.; Fedorova, E. B.; Tsyryapkin, V. A.; Bakhmutov,
V. I.; Belikov, V. M. J . Chem. Soc., Perkin Trans. 1 1988, 2075. (i) El
Achqar, A.; Boumzebra, M.; Roumestant, M.-L.; Viallefont, P. Tetra-
hedron 1988, 44, 5319. (j) Pettig, D.; Scho¨llkopf, U. Synthesis 1988,
173. (k) Scho¨llkopf, U.; Pettig, D.; Schulze, E.; Klinge, M.; Egert, E.;
Benecke, B.; Noltemeyer, M. Angew. Chem., Int. Ed. Engl. 1988, 27,
1194. (l) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277. (m) Hartwig,
W.; Born, L. J . Org. Chem. 1987, 52, 4352. (n) Minowa, N.; Hirayama,
M.; Fukatsu, S. Bull. Chem. Soc. J pn. 1987, 60, 1761. (o) Belokon’, Y.
N.; Bulychev, A. G.; Ryzhov, M. G.; Vitt, S. V.; Batsanov, A. S.;
Struchkov, Y. T.; Bakhmutov, V. I.; Belikov, V. M. J . Chem. Soc., Perkin
Trans. 1 1986, 1865.
(13) For reviews, see: (a) Belokon’, Y. N. J anssen Chim. Acta 1992,
10(2), 4. (b) Belokon’, Y. N. Pure Appl. Chem. 1992, 64, 1917.
(14) Belokon’, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov,
N. S.; Chesnokov, A. A.; Larionov, O. V.; Parma´r, V. S.; Kumar, R.;
Kagan, H. B. Tetrahedron: Asymmetry 1998, 9, 851.
(15) For reviews, see: (a) Kukhar’, V. P.; Resnati, G.; Soloshonok,
V. A. In Fluorine-Containing Amino Acids. Synthesis and Properties;
Kukhar’, V. P., Soloshonok, V. A., Eds.; J ohn Wiley and Sons Ltd.:
Chichester, 1994; Chapter 5. (b) Soloshonok, V. A. In Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J .
T., Eds.; ACS Books, American Chemical Society: Washington, D.C.,
1996; Chapter 2. (c) Soloshonok, V. A. In Enantiocontrolled Synthesis
of Fluoro-Organic Compounds: Stereochemical Challenges and Bio-
medicinal Targets; Soloshonok, V. A., Ed.; Wiley: Chichester, 1999;
Chapter 7.
(16) For successive papers, see: (a) Soloshonok, V. A.; Avilov, D.
V.; Kukhar’, V. P.; Tararov, V. I.; Savel’eva, T. F.; Churkina, T. D.;
Ikonnikov, N. S.; Kochetkov, K. A.; Orlova, S. A.; Pysarevsky, A. P.;
Struchkov, Y. T.; Raevsky, N. I.; Belokon’, Y. N. Tetrahedron: Asym-
metry 1995, 6, 1741. (b) Soloshonok, V. A.; Avilov, D. V.; Kukhar’, V.
P. Tetrahedron: Asymmetry 1996, 7, 1547. (c) Soloshonok, V. A.; Avilov,
D. V.; Kukhar’, V. P. Tetrahedron 1996, 52, 12433. (d) Qiu, W.;
Soloshonok, V. A.; Cai, C.; Tang, X.; Hruby, V. J ., Tetrahedron 2000,
56, 2577.
(11) Correction of the absolute configuration of products reported
in the paper was made latter: Shibuya, A.; Sato, A.; Taguchi, T. Bioorg.
Med. Chem. Lett. 1998, 8, 1979.
(12) For short communications on some aspects of the results
presented in this paper, see ref 1d.

6690 J . Org. Chem., Vol. 65, No. 20, 2000
Soloshonok et al.
F igu r e 1. Design of the Michael acceptor.
Sch em e 1
F igu r e 2. X-ray structures of compounds 3b, 4b, and 5b.
Sch em e 2a
solvents, diamagnetic, and can be stored in crystalline
form in the air for at least one year without any signs of
partial decomposition. At room temperature and in the
presence of TEA (slow) and DBU (fast), the methylene
protons of complex 2 underwent complete deutero-
exchange, suggesting that the corresponding enolate
could be easily generated under mild conditions using
these organic bases. Due to the cyclic structure of complex
2, the corresponding enolate can be generated only in cis-
form and thus, complex 2 perfectly meets the require-
ments for high reactivity and enolate geometric homo-
geneity.
Design of th e Mich a el Accep tor . Apart from the
required characteristics for high reactivity and geometric
homogeneity, the structure of complex 2 possesses one
more unique feature, the positively charged Ni(II) atom,
a potential center to coordinate a negatively charged
species. As discussed above, electron donor-acceptor-type
attractive interactions, which provide a way to give
thermodynamic preference for a single TS, could be
realized involving the Ni atom in complex 2.17 To this
end, we considered all possible TSs representing the
interaction between complex 2 and various hypothetical
Michael acceptors in their s-cis or s-trans conformations.
As a result, we came up with a potential structure for
the corresponding Michael acceptors shown in Figure 1.
In our model, the carbonyl group of the Michael acceptor
is located in close proximity to the enolate oxygen. That
would allow the reactions to occur with a thermodynami-
cally advantageous minimum charge separation.10b,g Next,
the group X1 should be oxygen or nitrogen to afford, upon
hydrolysis, the corresponding glutamic/pyroglutamic acid.
Finally, the group X, located under or above the Ni(II)
ion, should contain an atom, for instance O or N, capable
of electron donor-acceptor type attractive interactions
a
Key: (i) Me3CCOCl; (ii) SOCl2; (iii) n-BuLi. R ) Me (a), Ph
(b), n-Pr (c), i-Pr (d), â-naphthyl (e), R-naphthyl (f), 4-CF3-C6H4
(g), 4-MeO-C6H4 (h), N-Mts-â-indolyl (i), C6F5 (j).
with the nickel. Using this pattern of structural features
for the ideal Michael acceptor, and bearing in mind the
requirement for high electrophilicity of the C,C double
bond and conformational homogeneity, we considered
numerous derivatives of R,â-unsaturated carboxylic acid
derivatives. Finally, we identified a group of cyclic imides
3-5 shown in Scheme 2, as potential candidates for the
ideal Michael acceptor. Our reasoning leading to com-
pounds 3-5, in particular 3 and 4,19 turned out to be very
successful, and we were surprised to find out that these
derivatives of R,â-unsaturated carboxylic acids have
never been used as Michael acceptors in reactions with
nucleophilic glycine equivalents.3,10 Compounds 3-5 were
readily prepared according to standard procedures, as
depicted in Scheme 2. Single-crystal X-ray analyses of
compounds 3b, 4b, and 5b (Figure 2), revealed an
important fact that all three imides exist exclusively in
the s-cis conformation. However, while molecules of 3b
and 4b are virtually flat, the succinimide derivative 5b
is twisted at the acyclic amide bond [torsion angle C2-
N1-C8-C10 of 40.1(4)°]. The angle between the best
planes through the five- and six-membered rings is 1.2-
(2)° (3b), 7.6(1)° (4b) and 60.2(2)° (5b). On the other hand,
the five-membered rings in 3b and 4b have an envelope
structure, while in 5b this ring is planar [maximum
(18) Soloshonok, V. A.; Kukhar’, V. P.; Galushko, S. V.; Svistunova,
N. Y.; Avilov, D. V.; Kuz’mina, N. A.; Raevsky, N. I.; Struchkov, Y. T.;
Pysarevsky, A. P.; Belokon’, Y. N. J . Chem. Soc., Perkin Trans. 1 1993,
3143.
(19) Apart from the perfect conformational/electronic properties of
these compounds (see text), the ready availability of their chiral
versions renders cyclic imides 3 and 4 particularly promising Michael
acceptors.
(17) Electron donor-acceptor type attractive interactions between
the nickel (II) ion and fluorine atoms, were shown to be a critical factor
controlling virtually complete diastereoselectivity in the aldol addition
reaction between trifluoroacetone and Ni(II) complex of the Schiff bases
of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone (see ref
18).

Rational Design of Michael Addition Reactions
J . Org. Chem., Vol. 65, No. 20, 2000 6691
A and D, with the enolate oxygen and the carbonyl of
Michael acceptor in close proximity to each other, are
routinely used to account for the stereochemical outcome
of the addition reactions between nucleophilic glycine
equivalents and R,â-unsaturated carboxylic esters.1a,b,10
In this case, the diastereoselectivity of the additions was
shown to be a result of nonbonding stereochemical
discriminations between the substituents on both start-
ing compounds. Thus, if the stereochemical outcome of
the addition reactions under study were governed exclu-
sively by steric interactions, two diastereomeric products
would be obtained in a ratio of roughly 1:2. This outcome
stands in a good agreement with the 70:30 ratio of the
corresponding (2S,3R)/(2S,3S)-diastereomers obtained in
the DBU-catalyzed addition reactions between Ni(II)-
complex of the Schiff bases of glycine with (S)-o-[N-(N-
benzylprolyl)amino]benzophenone and the esters of cin-
namic acid.23 In contrast, according to our design, the
preference for a single TS would not only be steric in
origin, but also electron donor-acceptor type attractive
interactions between, for example, the oxazolidin-2-one
carbonyl group of 4b and the Ni(II) atom of complex 2,
situated in close proximity to each other in TS A (Figure
3). If the designed interactions do take place, then TS A
would be substantially thermodynamically favored rela-
tive to TS D, and the addition reactions might proceed
with high diastereoselectivity. Interestingly, the calcula-
tions also suggested that for the reaction of complex 2
with succinimide derivative 5, TS A cannot be formed
due to the nonflat geometry of the latter. In contrast, the
flat geometry of pyrrolidin-2-one derivatives 3, similar
to oxazolidin-2-one-containing 4, allows minimization of
steric interactions in both TS A and TS D.
Mich a el Ad d ition Rea ction s betw een Glycin e
Com p lex 2 a n d r,â-Un sa tu r a ted Ca r boxylic Acid
Der iva tives 3-5. The choice of the solvent, as a medium
for the addition reactions, turned out to be limited to
aprotic solvents only. We found that when alcohols (for
instance methanol) were used as a reaction medium, the
oxazolidin-2-one derivative 4 easily underwent nucleo-
philic substitution of the oxazolidin-2-one moiety by the
corresponding alkoxy group, generated in the presence
of the base (for instance DBU). Chloroform, the best
solvent for Ni(II)-complexes of type 2, was found to be
unsuitable, as the addition reactions did not proceed in
this solvent, neither in the presence of TEA or DBU.
Finally, N,N-dimethylformamide (DMF) was found to be
a solvent of choice.
F igu r e 3. Possible TSs in the addition between 2 and 4b.
deviation of 0.029(2) Å for atom N1]. Conformational s-cis
homogeneity of compounds 3b, 4b and 5b is a result of
nonbonding steric repulsive interactions between the
â-hydrogen of the C,C double bond and the carbonyl
oxygen of the pyrrolidin-2-one (3), oxazolidin-2-one (4)
or succinimide (5) ring, and electrostatic repulsive inter-
actions between the oxygens of the carbonyl groups in
3b, 4b, and 5b.20 In addition to the conformational
homogeneity of the R,â-unsaturated carboxylic moiety in
compounds 3-5, the electrophilicity of the C,C double
bond in 3-5 is substantially enhanced, as compared with
the corresponding esters. According to the pKa data (in
DMSO),21 the pyrrolidin-2-one (pKa ) 24.1), oxazolidin-
2-one (20.5), and succinimide (14.7) rings are substan-
tially stronger electron-withdrawing substituents, as
compared with alkoxy groups (MeOH, 27.9) and their
enhancing effect on electrophilicity of the C,C double
bond is comparable with that of a phenoxy group (18.0).22
Thus, the Michael acceptors 3-5, comparing with the
cyclic imide moiety, meet the necessary requirements for
conformational homogeneity and high reactivity of the
C,C double bond.
Mech a n istic Con sid er a tion s. Since both starting
compounds, glycine complex 2, and Michael acceptors
3-5, are geometrically/conformationally homogeneous,
six theoretically possible TSs could be involved in deter-
mining the stereochemical outcome of the corresponding
addition reactions. Figure 3 shows the model TSs A-F
constructed for the reaction of glycine complex 2 with the
cinnamoyl derived oxazolidin-2-one 4b. According to the
molecular mechanics calculations of these TSs, account-
ing only for steric but not electrostatic interactions (see
the Experimental Section), TS A (0.000 kcal/mol, popula-
tion 54.8%), in the series of the TSs with approach
geometry like, and TS D (0.348 kcal/mol, 30.4%), in the
series of TSs with approach geometry unlike, might be
substantially favored over the rest of the TSs. TSs of type
First we tried the reaction between complex 2 and
N-(trans-crotonyl)pyrrolidin-2-one 3. The addition did not
occur in the presence of TEA at room temperature in
DMF. Attempts to conduct the reaction at higher tem-
perature (50 °C) resulted in partial decomposition of the
starting compounds. In sharp contrast, DBU, even when
used in catalytic amounts (15 mol %), was effective in
catalyzing the reaction at room temperature (18-23 °C)
which proceeded smoothly to completion in 2.5 h afford-
ing a single diastereomer 6 (Scheme 3) in quantitative
chemical yield (Table 1, entry 1). Being satisfied and
excited with the desired virtually complete diastereo-
selectivity and excellent chemical yield obtained in this
reaction, we studied the additions of complex 2 with the
two other designed Michael acceptors 4 and 5. The
reaction of 2 with N-(trans-crotonyl)oxazolidin-2-one
(20) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238.
(21) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) A pKa
table is available on the WWW-Home-Page of Professor David A.
Evans’ group: http://daeiris.harvard.edu//DavidEvans.html.
(22) Evans, D. A.; Anderson, J . C.; Taylor, M. K. Tetrahedron Lett.
1993, 34, 5563.
(23) Soloshonok, V. A.; Cai, C.; Hruby, V. J ., unpublished data.

6692 J . Org. Chem., Vol. 65, No. 20, 2000
Soloshonok et al.
Sch em e 3a
Sch em e 4
stage might be based on, as revealed by X-ray analysis
(Figure 2), the nonplanar geometry of derivatives 5a ,b.
This phenomenon might be general in nature,24 raising
an interesting issue of topographically controlled reactiv-
ity.
Resubmission of pure products 6a ,b and 7a ,b to the
original reaction conditions did not give the starting
compounds in detectable amounts (1H NMR, 500 MHz).
These results suggested that the reactions are rather
irreversible and thus, the stereochemical outcome of the
successful reactions between complex 2 and derivatives
3a ,b, 4a ,b is most likely kinetically controlled. Taking
advantage of the fact that the data for the diastereo-
merically pure â-methyl- and â-phenyl-substituted py-
roglutamic acids are available from the literature, we
decided to decompose products 6a ,b and 7a ,b to afford
the corresponding pyroglutamic acids and thus, to de-
termine the relative configuration of the products. To this
end we performed preparative (3-5 g) synthesis of 6a ,b
and 7a ,b which were isolated simply by pouring the
reaction mixtures into water followed by a filtration of
the crystalline materials. Without any purification, com-
plexes 6a ,b and 7a ,b were decomposed to give pyro-
glutamic acids 8a ,b along with quantitative recovery of
ligand 1 and the corresponding pyrrolidin-2-one or ox-
azolidin-2-one (see the Experimental Section) (Scheme
4). Comparison of the spectral characteristics, in par-
ticular the R-H/â-H coupling constants, of the obtained
acids 8a,b with the literature values revealed a (2R*,3R*)-
configuration for 8a and (2R*,3S*) for 8b.25 These data
indicate that all successful additions between glycine
complex 2 and Michael acceptors 3a ,b and 4a ,b might
proceed exclusively through TS A (Figure 3), suggesting
a complete success of our design.
With these excellent results in hand we next studied
the generality of the method. Since the oxazolinin-2-one
derived Michael acceptors 4a ,b were found to be superior,
in terms of reactivity, over the pyrrolidin-2-one deriva-
tives 3a ,b (Table 1, entry 2 vs 1, 4 vs 3), we synthesized
a series of the corresponding N-(enoyl)oxazolidin-2-one
derivatives 4c-j (Scheme 2). To investigate the steric and
electronic effects of the substituents on the stereochem-
ical outcome of the addition reactions, we studied the
reactions of glycine complex 2 with Michael acceptors
bearing in the â-position various groups differing in steric
bulk and electronic nature as well. Thus, in the aliphatic
series, besides the methyl-substituted derivative 4a , we
studied also the reactions of Michael acceptors with n-Pr
a
Key: (i) DMF, DBU (15 mol %), rt (18-23 °). R ) Me (a), Ph
(b), n-Pr (c), i-Pr (d), â-naphthyl (e), R-naphthyl (f), 4-CF3-C6H4
(g), 4-MeOC6H4 (h), N-Mts-â-indolyl (i), C6F5 (j).
Ta ble 1. Ad d ition Rea ction s of Ni(II) Com p lexes 2 w ith
Mich a el Accep tor s 3a ,b a n d 4a ,ba
products 6, 7a ,b
entry 3a ,b/4a ,b
time
yield,b % de,c %
config-ond
1
2
3
4
3a
4a
3b
4b
2.5 h
98
99
99
99
>98
>98
>98
>98
(2R*,3R*)-6a
(2R*,3R*)-7a
(2R*,3S*)-6b
(2R*,3S*)-7b
10 min
35 min
20 min
a
All reactions were run in DMF in the presence of 15 mol % of
b
DBU at ambient temperature. Ratio 2/3,4 1/1.05-1.1. Isolated
yield of crude product. c Determined by NMR (500 MHz) analysis
d
of the crude reaction mixtures. Relative configuration of the
products was determined by comparison of the spectral charac-
teristics of the corresponding pyroglutamic acids 8, isolated from
complexes 6 and 7, with the literature data; see also the text.
derivative 4a , conducted under same conditions, occurred
at a surprisingly high rate being completed in just 10
min. NMR analysis of the crude product revealed that
only diastereomeric product 7a was obtained in quantita-
tive chemical yield (entry 2). In sharp contrast, the
addition between complex 2 and succinimide derivative
5 did not proceed at all, even under forcing reaction
conditions (1 mole DBU, 50 °C).
Next, we investigated a series of the reactions between
glycine complex 2 and cinnamic acid derived Michael
acceptors 3b, 4b, and 5b, conducted under the same
conditions (Scheme 3). Addition of complex 2 with pyr-
rolidin-2-one 3b occurred at a substantially higher rate,
as compared with the crotonyl derivative 3a (entry 3 vs
1), giving rise quantitatively to a single diastereomer 6b.
In contrast, the reaction between complex 2 and oxazo-
lidin-2-one 4b proceeded slower, as compared with the
methyl containing derivative 4a (entry 4 vs 2), but faster
than addition of 2 with 3b (entry 4 vs 3). Similar to the
failed addition between complex 2 and 5a , the reaction
of 2 with cinnamic acid derived 5b also did not occur
under the standard or forced conditions.
(24) Taking into account that the particular planar geometry of the
Ni(II) complex 2 could be a reason for the failure of the additions with
5a ,b, we studied the reactions of the acyclic and more flexible
N-(diphenylmethylene)glycine ethyl ester with 5a ,b (DMF, rt, DBU).
The results were the same; no trace of the addition products was found.
As one can assume, the planar geometry, like for instance in the case
of 3 and 4, is the critical topographic requirement for TS of type A or
B (Figure 4) to be formed.
(25) The (2R*,3S*) relative stereochemistry for the aromatic (R )
Ph) derivatives is a consequence of the Cahn-Ingold-Prelog priority
(see ref 26) and is stereochemically equivalent to the (2R*,3R*)
configuration in the aliphatic (R ) Me) series of compounds.
Taking into account that in a series of Michael accep-
tors 3-5, the succinimide derivatives 5a ,b should be
regarded as the most electrophilic, the negative outcome
of their reactions with complex 2 was quite unexpected.
The only plausible rationale that can be provided at this

Rational Design of Michael Addition Reactions
J . Org. Chem., Vol. 65, No. 20, 2000 6693
Ta ble 2. Ad d ition Rea ction s of Ni(II) Com p lexes 2 w ith
to be pronounced like the steric effects. Thus, the reac-
tions of the derivatives containing the electron-withdraw-
ing trifluoromethyl group on the phenyl 4g and the
electron-deficient pentafluorophenyl ring 4j occurred
almost instantly (Table 2, entries 5, 8), affording the
single diastereomeric products 7g,j in quantitative chemi-
cal yield. In contrast, the additions of less electrophilic
derivatives bearing the electron-donating methoxy group
on the phenyl 4h and the electron-rich â-indolyl group
4i proceeded at substantially slower rates (Table 2,
entries 6, 7).
N-(E-En oyl)oxa zolid in -2-on es 4c-ja
products 7c-j
entry
4c-j
time
yield,b %
de,c %
config-ond
1
2
3
4
5
6
7
8
c
d
e
f
g
h
i
2.5 h
22 h
25 min
1.5 h
5 min
2 h
94
e
95
96
>96
92
>96
e
(2R*,3R*)
(2R*,3S*)
(2R*,3S*)
(2R*,3S*)
(2R*,3S*)
(2R*,3S*)
(2R*,3S*)
(2R*,3S*)
>98
>96
>98
>96
>96
>98
2.5 h
2 min
92
>96
j
In conclusion, via the rational design described in this
paper, we have found a unique combination of nucleo-
philic glycine and R,â-unsaturated carboxylic acid deriva-
tives allowing us to develop for the first time Michael
addition reactions proceeding with virtually complete
diastereoselectivity and excellent chemical yield at room
temperatures in the presence of a catalytic amounts of
organic nonchelating base. Since both the Ni(II)-com-
plexes 2 and the N-(enoyl)oxazolidin-2-ones 4 can be
prepared easily in chiral versions, or a chiral base can
could be used in the place of DBU, the discovered process
provides a realistic basis for a highly practical and
general entry into a large family of â-substituted and
stereochemically defined amino acids of synthetic and
biomedical importance. Future work to realize this
process in an asymmetric sense is currently in progress
and will be reported in due course.
a
All reactions were run in DMF in the presence of 15 mol % of
b
DBU at ambient temperature. Ratio 2/4 1/1.05-1.1. Isolated
yield of crude product. c Determined by NMR (500 MHz) analysis
d
of the crude reaction mixtures. Relative configuration of the
products was determined by comparison of the spectral charac-
teristics of the corresponding pyroglutamic acids 8, isolated from
complexes 6a ,b and 7a ,b, with the literature data; The relative
configuration of products 7c-j was assigned by analogy; see also
the text. e Less then 36% conversion of the starting materials.
Formation of only one diastereomeric product was observed,
however.
4c and i-Pr 4d groups. In the aromatic series we chose
the derivatives containing bulky â-4e and R-naphthyl
groups 4f, a phenyl ring with electron withdrawing (CF3,
4g) and electron donating groups (MeO, 4h ), electron rich
(N-Mts-â-indolyl, 4i) and electron deficient (C6F5, 4j)
aromatic rings as well.
All reactions, conducted under the same conditions
(DMF, 15 mol % of DBU, r.t.), gave rise to only one
diastereomer27 in excellent yields regardless of the steric
or electronic nature of the substituent of the starting
oxazolidin-2-one 4c-j (Scheme 3, Table 2). However, the
nature of the substituent had a substantial effect on the
reaction rate. Thus, the addition of the n-Pr derivative
4c occurred at a noticeably slower rate (Table 2, entry
1) as compared with the reaction of the methyl containing
derivative (Table 1, entry 2). However, the resultant
product was obtained in diastereomerically pure form and
with excellent chemical yield. The addition of more
sterically bulky i-Pr derivative 4d exposed some limita-
tions of the method. Thus after 22 h of the reaction
between complex 2 and oxazolidin-2-one 4d , we observed
less than 36% conversion of the starting materials (Table
2, entry 2). Attempts to run the reaction at higher
temperature or in the presence of the equimolar amount
of DBU resulted in increasing decomposition of the
starting compounds. Apparently the present method
could not be extended to substrates containing tertiary
alkyl R groups. In the aromatic series the â-naphthyl
derivative 4e reacted with complex 2 at a rate compa-
rable with that of the phenyl containing Michael acceptor
4b (Table 2, entry 3 vs Table 1, entry 4), while the
R-naphthyl 4f addition was remarkably slower (Table 2,
entry 4). These data suggest that synthesis of o-phenyl
substituted derivatives by this method could have some
limitations, while preparation of compounds containing
m-mono- or m,p-disubstituted phenyl rings would meet
no synthetic problems. Effects of the electronic properties
of the substituents on the reaction rate also were found
Exp er im en ta l Section
Gen er a l Meth od s. 1H, 13C, and 19F NMR (299.94 MHz),
recorded using TMS, CDCl3 and CCl3F as internal standards,
and High Resolution Mass Spectra (HRMS) were performed
on facilities available at the Department of Chemistry, Uni-
versity of Arizona. Melting points (mp) are uncorrected and
were obtained in open capillaries. All reagents and solvents,
unless otherwise stated, are commercially available and were
used as received. All new compounds were characterized by
1H, 13C, 19F NMR and HRMS.
X-r a y Diffr a ction Stu d ies. Crystals of compounds 3b, 4b,
and 5b were grown from acetone. All data were collected at
16 °C on a diffractometer available at K. U. Leuven -
Department of Chemistry, with graphite-monochromated Mo
KR radiation (λ ) 0.710 73 Å) in the ω-scan mode (2θmax
)
50°). The data were corrected for Lorentz and polarization
effects. The lattice parameters were calculated by least-squares
refinements of 35 (3b), 25 (4b), and 30 (5b) reflections. The
structures were solved by direct methods and refined by full-
matrix least-squares techniques on F2 (SHELXTL-PC)28 to an
R1 value of 0.0528 (wR2 ) 0.1646) for 3b, 0.0509 (wR2
)
0.1195) for 4b and of 0.0418 (wR2 ) 0.0983) for 5b. These final
R1 values are based on the reflections with F > 4σ(F), wR2
values on all data. The non-hydrogen atoms were refined
anisotropically. The hydrogen atoms were placed at calculated
positions with fixed isotropic temperature factors (1.2 times
Ueq of the carrying atom), except for 5b where the C-H
distances were also free to refine. The figures were drawn with
PLATON.29
Crystal data for 3b: C13H13NO2, Mr ) 215.24, orthorhombic,
space group Pbca (No. 61), lattice parameters: a ) 11.733(2)
Å, b ) 8.113(2) Å, c ) 24.004(5) Å, Z ) 8, V ) 2284.9(8) Å3, Dc
) 1.251 g/cm3, µ(Mo KR) ) 0.085 mm-1, F(000) ) 912,
transparent blocks, crystal size: 0.2 × 0.2 × 0.35 mm, 2651
reflections collected, 2002 unique reflections, R(int) ) 0.031,
1211 observed reflections (F > 4σ(F)).
(26) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed. Engl.
1966, 5, 385.
(27) Analysis of the crude reaction mixture (NMR) showed that the
content of the major diastereomer 7c-j was at least 97%, while the
second diastereomer and/or byproducts was/were formed in an amount
not greater than 3%.
(28) Sheldrick, G. M. (1998) SHELXTL-Plus. Program for the
Solution and Refinement of Crystal Structures. Bruker Analytical
X-ray Systems, Madison, WI.
(29) Spek, A. L. Acta Crystallogr. 1990, A46, C-34.

6694 J . Org. Chem., Vol. 65, No. 20, 2000
Soloshonok et al.
Crystal data for 4b: C12H11NO3, Mr ) 217.22, monoclinic,
space group P21/c (No. 14), lattice parameters: a ) 9.450(2)
Å, b ) 6.568(1) Å, c ) 17.012(3) Å, â ) 97.42(1)°, Z ) 4, V )
1047.1(3) Å3, Dc ) 1.378 g/cm3, µ(Mo KR) ) 0.100 mm-1, F(000)
) 456, transparent blocks, crystal size: 0.2 × 0.3 × 0.35 mm,
2608 reflections collected, 1843 unique reflections, R(int) )
0.037, 1069 observed reflections (F > 4σ(F)).
Crystal data for 5b: C13H11NO3, Mr ) 229.23, orthorhombic,
space group P212121 (No. 19), lattice parameters: a ) 5.948-
(2) Å, b ) 7.722(3) Å, c ) 24.858(4) Å, Z ) 4, V ) 1141.7(6) Å3,
Dc ) 1.334 g/cm3, µ(Mo KR) ) 0.096 mm-1, F(000) ) 480,
transparent plates, crystal size: 0.15 × 0.3 × 0.4 mm, 1722
reflections collected, 1539 unique reflections, R(int) ) 0.032,
1149 observed reflections (F > 4σ(F)).
(1.1 equiv) in dried THF (5 mL/1 mmol of acid) were added
triethylamine (1.2 equiv) and pivaloyl chloride (1.1 equiv) at
-78 °C under Ar atmosphere. The resulting mixture was
stirred at -78 °C for 15 min, at 0 °C for 1 h, and recooled at
-78 °C. To the above solution was added a precooled lithiated
oxazolidin-2-one or pyrrolidin-2-one or succinimide suspension
solution prepared by adding n-butyllithium (1 equiv) into a
solution of oxazolidin-2-one or pyrrolidin-2-one or succinimide
(1 equiv) in dried THF (5 mL/1 mmol of oxazolidinone) at -78
°C. The resulting reaction was stirred at -78 °C for 2 h and
room temperature overnight. The reaction was quenched by
adding saturated NH4Cl solution and the solvent was removed
by rotary evaporation. The residue was extracted with EtOAc,
washed with dilute NaHCO3 and brine, and dried over
anhydrous MgSO4. After filtration and evaporation, the crude
product was purified by column chromatography (silica gel) if
it was a liquid or recrystallization from EtOAc otherwise.
Meth od B. Into a boiling mixture of acid (1 equiv) in CH2-
Cl2 (1 mL/1 mmol of acid) was added dropwise a solution of
SOCl2 (2 equiv) in CH2Cl2. The reaction mixture was refluxed
for 2 h (until a clear solution formed). The solvent and
remaining SOCl2 was removed by reduced pressure distilla-
tion. After cooling to room temperature, the resulting carbonyl
chloride was dissolved in dried THF (1 mL/mmole of acid) and
transferred a precooled lithiated oxazolidin-2-one or pyrrolidin-
2-one or succinimide suspension solution, which was prepared
in advance by adding n-butyllithium (1 equiv) into a solution
of oxazolidin-2-one or pyrrolidin-2-one or succinimide (1 equiv)
in dried THF (5 mL/mmole of oxazolidinone) at -78 °C. The
resulting reaction was stirred at -78 °C for 2 h and room-
temperature overnight. The reaction was quenched by adding
saturated aqueous NH4Cl solution and the solvent was re-
moved by rotary evaporation. The residue was extracted with
EtOAc, washed with dilute NaHCO3 and brine, and dried over
anhydrous MgSO4. After filtration and evaporation, the crude
product was purified by column chromatography (silica gel) if
it was a liquid or recrystallization from EtOAc and hexanes
otherwise.
Full crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre, and can be obtained
on request from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, U.K.
Molecu la r Mech a n ics Ca lcu la tion s. The TS models,
using the already optimized 4b and complex 2 and Me3N, were
constructed by (1) fixing the distance between the reaction
centers CdC [enolate derived from 2 (d)]‚‚‚CdC [Michael
acceptor (a)] at 2.20 Å, (2) initially setting the angles of CdC
(d)‚‚‚CdC (a) and CdC (d)‚‚‚CdC (a) both at 90 degrees, (3)
changing the dihedral angle CdC (d)‚‚‚CdC (a) to 0, 120, or
240°. This method when considering the two faces matching
(like and unlike) eventually furnished six independent con-
formers. After optimization, the population percentage was
obtained from the Boltzmann distribution equation at 25 °C
considering their energy differences. Molecular mechanics
calculations were performed by the Mechanics software imple-
mented in the CAChe WorkSystem version 4.1.1.
o-[N-(r-P icolyl)a m in o]a cetop h en on e (P AAP ) 1. Into a
solution of 2-aminoacetophone (4.1 g, 30 mmol) and picolinic
acid (3.7 g, 30 mmol) in dry CH2Cl2 (60 mL) was added
triethylamine (8.4 mL, 60 mmol) with stirring, followed by
benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexaflu-
orophosphate (BOP) (14.6 g, 33 mmol). The reaction mixture
was stirred at room temperature overnight. After completion,
the reaction was quenched by adding 1 N HCl (30 mL) and
stirred for another 30 min. The organic phase was separated,
washed with H2O, saturated NaHCO3 solution, and brine and
dried over anhydrous MgSO4 overnight. Removal of solvents
gave a crude product (6.7 g, 95%) as an off-white solid, which
was used in the next reaction without further purification. An
analytic sample was purified by silica gel chromatography
(EtOAc-hexanes: 4/6, v/v) for characterization: mp 112.0-
N-(tr a n s-Cr oton yl)p yr r olid in -2-on e 3a (method B): yield
91%; oil; 1H NMR (CDCl3) δ 1.95 (3H, dd, J ) 1.2 Hz, 6.4 Hz),
1.99-2.09 (2H, m), 2.62, 3.86 (4H, AB, J ) 8.1 Hz), 7.07-7.29
(2H, m); 13C NMR (CDCl3) δ 17.2, 18.4, 33.9, 45.7, 123.6, 145.8,
166.1, 175.5.
N-(tr a n s-Cin n a m oyl)p yr r olid in -2-on e 3b (method B):
1
yield 80%; mp 101.0-102.0 °C; H NMR (CDCl3) δ 2.08 (2H,
tt, J ) 6.8 Hz, 7.2 Hz), 2.66 (2H, t, J ) 6.8 Hz), 3.93 (2H, t, J
) 7.2 Hz), 7.38-7.41 (3H, m), 7.61-7.64 (2H, m), 7.84, 7.95
(2H, AB, J ) 15.9 Hz); 13C NMR (CDCl3) δ 17.2, 34.0, 45.9,
119.0, 128.5, 128.8, 130.3, 134.9, 145.5, 166.3, 175.7.
1
112.5 °C; H NMR (CDCl3) δ 2.73 (3H, s), 7.16-7.21 (1H, m),
7.47-7.51 (1H, m), 7.60-7.66 (1H, m), 7.90 (1H, dt, J ) 1.7
Hz, 8.7 Hz), 7.97 (1H, dd, J ) 1.5 Hz, 7.8 Hz), 8.29 (1H, d, J
) 8.1 Hz), 8.80-8.82 (1H, m), 9.03 (1H, dd, J ) 1.0 Hz, 8.5
Hz); 13C NMR (CDCl3) δ 28.6, 121.1, 122.7, 123.1, 126.4, 131.7,
134.9, 137.3, 140.2, 148.7, 150.4, 163.9, 202.2.
N-(tr a n s-Cr oton yl)oxazolidin -2-on e 4a (method A): yield
1
65%; mp 42.0-43.0 °C; H NMR (CDCl3) δ 1.97 (3H, dd, J )
0.7 Hz, 5.4 Hz), 4.07, 4.43 (4H, AB, J ) 8.1 Hz), 7.12-7.29
(2H, m); 13C NMR (CDCl3) δ 18.5, 42.6, 62.0, 121.4, 146.8,
153.5, 165.1.
Ni(II) Com p lex of Glycin e Sch iff Ba se w ith o-[N-(r-
P icolyl)a m in o]a cetop h en on e (P AAP ) 2. Into a suspension
of o-[N-(R-picolyl)amino]acetophenone (PAAP) (4.8 g, 20 mmol),
glycine (7.5 g, 100 mmol), and NiCl2 × 6H2O (9.5 g, 40 mmol)
in methanol (100 mL) was added a suspension of NaOH (5.6
g, 40 mmol) in methanol (40 mL) at 60 °C. After being stirred
at 60 °C for 4 h and at room temperature overnight, the
reaction mixture was poured into a solution of ice-water (100
mL) and glacial acetic acid (10 mL) and stirred for a 10 min.
The solid was filtered off, washed with hexanes, and dried in
vacuo to afford the desired product (6.5 g, 95%): mp >290.0
°C; 1H NMR (CDCl3) δ 2.43 (3H, s), 4.20 (2H, s), 6.99-7.04
(1H, m), 7.32-7.43 (2H, m), 7.62-7.65 (1H, m), 7.81-7.83 (1H,
m), 7.93-7.98 (1H, m), 8.18-8.20 (1H, m), 8.70 (1H, d, J )
8.4 Hz); 13C NMR (CDCl3) δ 19.1, 60.6, 121.9, 124.0, 124.5,
126.4, 126.9, 130.1, 132.7, 140.5, 142.1, 147.1, 153.3, 169.9,
170.6, 177.1; HRMS(FAB) [M + H]+ calcd for C16H14N3NiO3
354.0389, found 354.0386.
N-(tr a n s-Cin n a m oyl)oxa zolid in -2-on e 4b (method A):
1
yield 66%; mp 151.0-151.5 °C; H NMR (CDCl3) δ 4.15, 4.47
(4H, AB, J ) 8.0 Hz), 7.40-7.42 (3H, m), 7.62-7.65 (2H, m),
7.87, 7.93 (2H, AB, J ) 15.9 Hz); 13C NMR (CDCl3) δ 42.8,
62.1, 116.5, 128.7, 128.9, 130.7, 134.5, 146.3, 153.6, 165.4.
N-(tr a n s-2′-Hexen oyl)oxa zolid in -2-on e 4c (method A):
yield 53%; oil; 1H NMR (CDCl3) δ 0.95 (3H, t, J ) 7.3 Hz),
1.50 (2H, tq, J ) 7.3 Hz), 2.23-2.30 (2H, m), 4.07, 4.43 (4H,
AB, J ) 8.1 Hz), 7.12-7.27 (2H, m); 13C NMR (CDCl3) δ 13.7,
21.3, 34.6, 42.7, 62.0, 120.0, 151.6, 153.5, 165.3.
N-(4′-Met h yl-tr a n s-2′-p en t en oyl)oxa zolid in -2-on e 4d
1
(method A): yield 67%; oil; H NMR (CDCl3) δ 1.10 (6H, d, J
) 6.8 Hz), 2.48-2.63 (1H, m), 4.07, 4.43 (4H, AB, J ) 8.0 Hz),
7.09-7.29 (2H, m); 13C NMR (CDCl3) δ 21.2, 31.4, 42.7, 62.0,
117.3, 153.5, 157.7, 165.6.
N -[3′-(2′′-Na p h t h yl)-t r a n s-p r op e n oyl]oxa zolid in -2-
1
on e 4e (method B): yield 86%; mp 212.5-213.5 °C; H NMR
Gen er a l P r oced u r e for P r ep a r a tion of th e N-(En oyl)-
p yr r olid in -2-on es 3a ,b, N-(En oyl)oxa zolid in -2-on es 4a -
j, a n d N-(En oyl)su ccin im id es 5a ,b. Meth od A. Into a cooled
solution of the corresponding R,â-unsaturated carboxylic acid
(CDCl3) δ 4.17, 4.48 (4H, AB, J ) 8.0 Hz), 7.51-7.54 (2H, m),
7.77-7.90 (4H, m), 8.02-8.04 (3H, m); 13C NMR (CDCl3) δ
42.9, 62.1, 116.6, 124.0, 126.3, 126.7, 127.4, 127.8, 128.7, 130.7,
132.0, 133.2, 134.4, 146.4, 153.7, 165.4.

Rational Design of Michael Addition Reactions
J . Org. Chem., Vol. 65, No. 20, 2000 6695
N -[3′-(1′′-Na p h t h yl)-t r a n s-p r op e n oyl]oxa zolid in -2-
on e 4f (method B): yield 78%; mp 156.0-157.0 °C; H NMR
(CDCl3) δ 4.19, 4.49 (4H, AB, J ) 8.0 Hz), 7.49-7.62 (3H, m),
7.88-7.94 (3H, m), 8.01, 8.73 (2H, AB, J ) 15.9 Hz), 8.25 (1H,
d, J ) 8.1 Hz); 13C NMR (CDCl3) δ 42.9, 62.1, 118.9, 123.3,
125.5, 125.7, 126.2, 126.9, 128.8, 131.0, 131.6, 133.7, 143.0,
153.6, 165.4.
Ni(II) com p lex of t h e Sch iff ba se of P AAP w it h
(2S*,3R*)-3-p h en yl-5-p yr r olid in on ylglu ta m ic a cid 6b: mp
266.0-266.5 °C; 1H NMR (CDCl3) δ 2.04-2.11 (2H, m), 2.58-
2.65 (2H, m), 2.88 (3H, s), 3.43 (1H, part of ABX, J ) 2.7 Hz,
19.3 Hz), 3.74-3.95 (3H, m), 4.40 (1H, part of ABX, J ) 11.2
Hz, 19.3 Hz), 4.72 (1H, d, J ) 4.1 Hz), 6.70-6.75 (1H, m),
7.00-7.36 (5H, m), 7.47-7.54 (3H, m), 7.69-7.75 (2H, m),
7.83-7.89 (1H, m), 8.55 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3)
δ 17.2, 18.3, 33.5, 38.0, 45.2, 45.4, 74.4, 121.7, 123.3, 123.8,
126.0, 127.3, 127.5, 128.0, 130.2, 130.5, 132.5, 139.2, 139.5,
141.9, 146.6, 153.3, 168.6, 168.9, 173.4, 175.1, 176.7; HRMS-
(FAB) [M + H]+ calcd for C29H27N4NiO5 569.1335, found
569.1357.
1
N-(tr a n s-4′-Tr iflu or om et h ylcin n a m oyl)oxa zolid in -2-
1
on e 4g (method B): yield 82%; mp 182.5-183.5 °C; H NMR
(CDCl3) δ 4.16, 4.49 (4H, AB, J ) 8.0 Hz), 7.65, 7.72 (4H, AB,
J ) 8.4 Hz), 7.85, 7.98 (2H, AB, J ) 15.6 Hz); 19F NMR (CDCl3)
δ -64.0 (3F, s); 13C NMR (CDCl3) δ 42.8, 62.2, 119.0, 123.5 (q,
J ) 274.0 Hz), 125.8 (q, J ) 4.0 Hz), 128.7, 131.5, (q, J ) 32.2
Hz), 137.8, 144.2, 153.6, 164.9; HRMS(FAB) [M + H]+ calcd
for C13H11F3NO3 286.0691, found 286.0692.
Ni(II) com p lex of t h e Sch iff ba se of P AAP w it h
(2S*,3S*)-3-m et h yl-5-(2′-oxa zolid in on yl)glu t a m ic a cid
1
7a : mp 194.0-195.0 °C; H NMR (CDCl3) δ 2.12 (3H, d, J )
N-(tr a n s-4′-Met h oxycin n a m oyl)oxa zolid in -2-on e 4h
(method B): yield 86%; mp 151.5-152.0 °C; 1H NMR (CDCl3)
δ 3.85 (3H, s), 4.13, 4.45 (4H, AB, J ) 8.0 Hz), 6.91, 7.58 (4H,
AB, J ) 8.8 Hz), 7.77, 7.85 (2H, AB, J ) 15.9 Hz); 13C NMR
(CDCl3) δ 42.8, 55.4, 62.0, 114.0, 114.3, 127.3, 130.4, 146.1,
6.8 Hz), 2.48-2.60 (1H, m), 2.78 (3H, s), 2.98, 3.75 (2H, ABX,
J ) 3.9 Hz, 10.3 Hz, 18.8 Hz), 3.99-4.07 (2H, m), 4.40-4.45
(2H, m), 4.62 (1H, d, J ) 3.9 Hz), 7.00-7.06 (1H, m), 7.35-
7.45 (2H, m), 7.74-8.01 (3H, m), 8.19 (1H, d, J ) 4.6 Hz), 8.82
(1H, d, J ) 7.6 Hz); 13C NMR (CDCl3) δ 16.8, 18.9, 33.6, 38.5,
42.4, 62.0, 72.8, 121.8, 123.8, 123.9, 126.8, 130.4, 132.7, 140.4,
142.0, 146.9, 153.2, 153.3, 169.6, 170.5, 172.6, 177.5; HRMS-
(FAB) [M + H]+ calcd for C23H23N4NiO6 509.0971, found
509.0974.
153.6, 161.7, 165.6; HRMS(FAB) [M + H]+ calcd for C13H14
NO4 248.0923, found 248.0919.
-
N-[3′-[3′′(1′′-Mesitylen esu lfon yl)in d olyl]]-tr a n s-p r op e-
n oyl]oxa zolid in -2-on e 4i (method B): yield 73%; mp 250.0-
1
251.0 °C; H NMR (CDCl3) δ 2.30 (3H, s), 2.54 (6H, s), 4.17,
Ni(II) com p lex of t h e Sch iff ba se of P AAP w it h
(2S*,3R*)-3-p h en yl-5-(2′-oxa zolid in on yl)glu ta m ic a cid 7b:
mp 261.5-262.0 °C; 1H NMR (CDCl3) δ 2.85 (3H, s), 3.47 (1H,
part of ABX, J ) 2.9 Hz, 19.0 Hz), 3.76 (1H, td, J ) 3.7 Hz,
11.2 Hz), 4.00-4.11 (2H, m), 4.37-4.49 (3H, m), 4.74 (1H, d,
J ) 4.6 Hz), 6.72-6.77 (1H, m), 7.00-7.38 (5H, m), 7.46-7.56
(3H, m), 7.70-7.90 (3H, m), 8.56 (1H, d, J ) 8.5 Hz); 13C NMR
(CDCl3) δ 18.2, 36.5, 42.4, 45.0, 62.1, 74.3, 121.7, 123.3, 123.9,
126.1, 127.3, 127.7, 128.1, 130.2, 130.5, 132.6, 138.7, 139.6,
142.0, 146.6, 153.2, 153.3, 168.6, 169.0, 172.6, 176.7; HRMS-
(FAB) [M + H]+ calcd for C28H25N4NiO6 571.1128, found
571.1114.
4.48 (4H, AB, J ) 8.0 Hz), 6.97 (2H, S), 7.25-7.36 (3H, m),
7.96-8.00 (2H, m), 7.99, 8.07 (2H, AB, J ) 15.9 Hz); 13C NMR
(CDCl3) δ 21.1, 22.7, 42.8, 62.1, 112.6, 115.8, 116.4, 121.3,
124.0, 125.2, 127.4, 130.6, 132.1, 132.6, 135.5, 137.6, 140.3,
144.6, 153.8, 165.5. HRMS(FAB) [M + H]+ calcd for C23H23
-
N2O5S 439.1328, found 439.1326.
N-(tr a n s-2′,3′,4′,5′,6′-P en ta flu or ocin n a m oyl)oxa zolid in -
2-on e 4j (method B): yield 87%; mp 145.5-146.0 °C; 1H NMR
(CDCl3) δ 4.15, 4.50 (4H, AB, J ) 8.0 Hz), 7.78, 8.15 (2H, AB,
J ) 15.9 Hz); 19F NMR (CDCl3) δ -162.6 (2F, m), -151.7 (1F,
m), -139.9 (2F, m); 13C NMR (CDCl3) δ 42.7, 62.2, 124.5 (m),
129.1, 136.1 (m), 139.5 (m), 144.1 (m), 147.4 (m), 153.3, 164.6;
HRMS(FAB) [M + H]+ calcd for C12H7F5NO3 308.0346, found
308.0345.
Ni(II) com p lex of t h e Sch iff ba se of P AAP w it h
(2S*,3S*)-3-n -p r op yl-5-(2′-oxa zolid in on yl)glu ta m ic a cid
1
7c: mp 189.0-190.0 °C; H NMR (CDCl3) δ 0.94 (3H, t, J )
N-(tr a n s-Cr oton yl)su ccin im id e 5a (method B): yield
7.2 Hz), 1.25-1.45 (1H, m), 1.58-1.72 (1H, m), 1.84-1.79 (1H,
m), 2.35-2.43 (1H, m), 2.80 (3H, s), 3.11 (1H, part of ABX, J
) 2.7 Hz, 19.3 Hz), 3.65-3.77 (2H, m), 3.95-4.09 (2H, m),
4.39-4.44 (2H, m), 4.61 (1H, d, J ) 4.2 Hz), 7.01-7.06 (1H,
m), 7.36-7.45 (2H, m), 7.76-8.01 (3H, m), 8.19 (1H, d, J )
4.9 Hz), 8.84 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 14.0,
19.1, 20.7, 31.9, 35.1, 38.3, 42.4, 62.0, 72.2, 121.8, 123.9, 126.8,
126.9, 130.4, 132.7, 140.4, 142.0, 147.0, 153.2, 153.3, 169.6,
170.7, 173.3, 177.9; HRMS(FAB) [M + H]+ calcd for C25H27N4-
NiO6 537.1284, found 537.1299.
1
86%; mp 108.0-109.0 °C; H NMR (CDCl3) δ 2.00 (3H, dd, J
) 1.7 Hz, 7.1 Hz), 2.82 (4H, s), 6.42 (1H, qd, J ) 1.7 Hz, 15.4
Hz), 7.25 (1H, qd, J ) 7.1 Hz, 15.4 Hz); 13C NMR (CDCl3) δ
18.7, 28.6, 124.6, 150.1, 163.9, 174.5.
N-(tr a n s-Cin n a m oyl)su ccin im id e 5b (method B): yield
84%; mp 119.0-120.0 °C; 1H NMR (CDCl3) δ 2.87 (4H, s), 7.03,
7.92 (2H, AB, J ) 15.6 Hz), 7.38-7.46 (3H, m), 7.59-7.63 (2H,
m); 13C NMR (CDCl3) δ 28.7, 119.2, 128.9, 129.0, 131.5, 133.9,
148.7, 164.2, 174.5.
Gen er a l P r oced u r e for th e Rea ction s of Glycin e Ni-
(II) com p lex 2 w ith N-En oylp yr r olid in -2-on es 3a ,b or
-oxa zolid in -2-on es 4a -j. To a suspension of Ni(II) complex
2 (0.177 g, 0.500 mmol) in DMF (3.0 mL) was added N-enoylpyr-
rolidin-2-ones 3a , 3b or -oxazolidin-2-ones 4a -j (0.525 mmol).
After stirring the mixture for 10 min at ambient temperature,
DBU (0.01 mL, 0.07 mmol) was added. The reaction was
monitored by TLC. After completion, the reaction mixture was
poured into H2O (60 mL). The resultant crystalline product
was filtered and washed thoroughly with H2O and dried in
vacuo. An analytical sample was purified by chromatography
on silica gel with CHCl3 and acetone (1:1, v/v) as eluent. Yields
and stereochemical outcomes of the reactions are given in
Tables 1 and 2.
Ni(II) com p lex of t h e Sch iff ba se of P AAP w it h
(2S*,3R*)-3-isop r op yl-5-(2′-oxa zolid in on yl)glu ta m ic a cid
7d : mp 186.0-187.0 °C; H NMR (CDCl3) δ 1.07 (3H, d, J )
1
6.8 Hz), 1.20 (3H, d, J ) 6.8 Hz), 2.64-2.68 (1H, m), 2.89 (3H,
s), 2.93, 3.68 (2H, ABX, J ) 1.5 Hz, 11.5 Hz, 19.3 Hz), 3.90-
3.41 (6H, m), 4.50 (1H, d, J ) 6.1 Hz), 7.03 (1H, t, J ) 7.2
Hz), 7.35-7.45 (2H, m), 7.75-8.01 (3H, m), 8.16 (1H, d, J )
5.4 Hz), 8.85 (1H, d, J ) 8.1 Hz); 13C NMR (CDCl3) δ 16.9,
19.0, 23.7, 26.9, 30.4, 42.5, 44.3, 62.0, 71.5, 121.9, 123.7, 124.0,
126.7, 126.9, 130.6, 132.8, 140.4, 142.0, 146.8, 153.3, 153.4,
169.7, 170.4, 173.5, 178.6; HRMS(FAB) [M + H]+ calcd for
C
25H27N4NiO6 537.1284, found 537.1293.
Ni(II) com p lex of t h e Sch iff ba se of P AAP w it h
(2S*,3R*)-3-(2′-n a p h t h yl)-5-(2′-oxa zolid in on yl)glu t a m ic
a cid 7e: mp 287.0-288.0 °C; 1H NMR (CDCl3) δ 2.92 (3H, s),
3.59 (1H, part of ABX, J ) 3.0 Hz, 18.9 Hz), 3.97 (1H, td, J )
3.6 Hz, 11.2 Hz), 4.02-4.14 (2H, m), 4.44-4.59 (3H, m), 4.77
(1H, d, J ) 4.1 Hz), 6.79-6.83 (1H, m), 7.01-7.14 (1H, m),
7.16-7.38 (7H, m), 7.44-7.50 (1H, m), 7.56-7.76 (3H, m), 8.07
(1H, s), 8.55 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 18.2,
36.6, 42.5, 45.2, 62.2, 74.7, 121.7, 122.8, 123.9, 125.4, 125.6,
126.1, 127.4, 127.8, 128.3, 130.1, 132.7, 133.1, 136.5, 139.1,
142.2, 145.6, 152.1, 153.2, 167.1, 167.0, 172.6, 176.7; HRMS-
(FAB) [M + H]+ calcd for C32H27N4NiO6 621.1284, found
621.1284.
Ni(II) com p lex of t h e Sch iff ca se of P AAP w it h
(2S*,3S*)-3-m eth yl-5-p yr r olid in on ylglu ta m ic a cid 6a : mp
232.0-233.0 °C; 1H NMR (CDCl3) δ 2.01-2.14 (5H, m), 2.50-
2.62 (3H, m), 2.80 (3H, s), 2.95, 3.73 (2H, ABX, J ) 3.7 Hz,
10.3 Hz, 19.0 Hz), 3.78-3.84 (2H, m), 4.62 (1H, d, J ) 4.2 Hz),
7.00-7.05 (1H, m), 7.35-7.44 (2H, m), 7.74-8.00 (3H, m), 8.19
(1H, d, J ) 5.4 Hz), 8.82 (1H, d, J ) 8.7 Hz); 13C NMR (CDCl3)
δ 16.9, 17.1, 18.9, 33.5, 33.6, 40.0, 45.3, 72.9, 121.8, 123.8,
123.9, 126.8, 130.4, 132.6, 140.3, 141.9, 146.9, 153.3, 169.5,
170.4, 173.4, 175.2, 177.6; HRMS(FAB) [M + H]+ calcd for
C
24H25N4NiO5 507.1178, found 507.1171.

6696 J . Org. Chem., Vol. 65, No. 20, 2000
Soloshonok et al.
7.45 (2H, m), 7.69-8.04 (4H, m), 8.60 (1H, d, J ) 8.5 Hz); 19
NMR (CDCl3) δ -162.6 (1F, m), -161.8 (1F, m), -155.0 (1F,
m), -140.1 (1F, m), -133.8 (1F, m); 13C NMR (CDCl3) δ 18.2,
34.6, 35.2, 42.4, 62.3, 71.9, 122.0, 123.8, 124.0, 127.0, 130.2,
133.1, 140.6, 142.0, 146.5, 152.9, 153.1, 168.3, 171.1, 171.8,
176.0, the resonance of C6F5 carbons was obscured due to their
low intensities; HRMS(FAB) [M + H]+ calcd for C28H20F5N4-
NiO6 661.0656, found 661.0671.
Decom p osition of Com p lex 6a ,b or 7a ,b a n d Isola tion
of (2S*,3S*)-3-Meth ylp yr oglu ta m ic Acid 8a or (2S*,3R*)-
3-P h en ylp yr oglu ta m ic Acid 8b. A solution of complex 6a ,b
or 7a ,b (15.4 mmol) in MeOH (60 mL) was slowly added with
stirring to a mixture of aqueous 3 N HCl and MeOH (120 mL,
ratio 1/1) at 70 °C. Upon disappearance of the red color of the
starting complex, the reaction mixture was evaporated in
vacuo to dryness. Water (80 mL) was added, and the resultant
mixture was treated with excess of NH4OH and extracted with
CHCl3. The CHCl3 extracts were dried over MgSO4 and
evaporated in vacuo to afford free PAAP (3.63 g, 98%). The
aqueous phase was evaporated and the solid residue was
washed with acetone to remove pyrrolidin-2-one (1.18 g, 90%
yield) or oxazolidin-2-one (1.21 g, 90% yield). The resultant
product was dissolved in water and loaded on a Dowex 50 ×
2 100 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 the corresponding
pyroglutamic acids. The products were recrystallized from
THF/hexanes to give analytically pure samples.
Ni(II) com p lex of t h e Sch iff b a se of P AAP w it h
F
(2S*,3R*)-3-(1′-n a p h t h yl)-5-(2′-oxa zolid in on yl)glu t a m ic
1
a cid 7f: mp 190.0-191.0 °C; H NMR (CDCl3) δ 2.91 (3H, s),
3.68 (1H, part of ABX, J ) 2.9 Hz, 19.0 Hz), 4.02-4.12 (2H,
m), 4.43-4.49 (2H, m), 4.63 (1H, part of ABX, J ) 10.5 Hz,
19.0 Hz), 4.85 (1H, d, J ) 4.4 Hz), 4.94 (1H, td, J ) 3.7 Hz,
10.5 Hz), 6.94-7.06 (2H, m), 7.18-7.30 (6H, m), 7.45-7.88
(6H, m), 8.41 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 18.3,
36.9, 37.3, 42.5, 62.1, 75.3, 121.7, 122.2, 123.1, 123.3, 125.3,
125.9, 126.1, 126.3, 126.8, 127.0, 127.9, 128.8, 130.0, 132.5,
133.5, 133.6, 135.5, 139.5, 142.0, 146.3, 153.0, 153.2, 167.6,
169.3, 172.7, 176.9; HRMS(FAB) [M + H]+ calcd for C32H27N4-
NiO6 621.1284, found 621.1275.
Ni(II) com p lex of t h e Sch iff b a se of P AAP w it h
(2S*,3R*)-3-(4′-t r iflu or om et h yl)p h en yl-5-(2′-oxa zolid i-
n on yl)glu ta m ic a cid 7g: mp 261.0-262.0 °C; 1H NMR
(CDCl3) δ 2.88 (3H, s), 3.45 (1H, part of ABX, J ) 3.2 Hz, 19.0
Hz), 3.80 (1H, td, J ) 3.7 Hz, 11.2 Hz), 3.98-4.13 (2H, m),
4.37-4.50 (3H, m), 4.74 (1H, d, J ) 4.2 Hz), 7.01-7.06 (1H,
m), 7.22-7.27 (1H, m), 7.32-7.38 (1H, m), 7.44-7.54 (3H, m),
7.62-7.77 (4H, m), 7.84-7.90 (1H, m), 8.62 (1H, d, J ) 8.8
Hz); 19F NMR (CDCl3) δ -63.4 (3F, s); 13C NMR (CDCl3) δ 18.4,
36.3, 42.4, 44.9, 62.2, 73.9, 121.7, 123.7, 123.8, 125.0, 126.3,
126.9, 130.0, 130.3, 130.5, 131.0, 132.8, 140.2, 142.0, 142.9,
146.0, 152.6, 153.2, 168.7, 170.0, 172.0, 176.3; HRMS(FAB)
[M + H]+ calcd for C29H24F3N4NiO6 639.1001, found 639.0998.
Ni(II) com p lex of t h e Sch iff b a se of P AAP w it h
(2S*,3R*)-3-(4′-m et h oxyl)p h en yl-5-(2′-oxa zolid in on yl)-
glu ta m ic a cid 7h : mp 269.0-269.5 °C; 1H NMR (CDCl3) δ
2.84 (3H, m), 3.42 (1H, part of ABX, J ) 3.2 Hz, 19.0 Hz),
3.49 (3H, s), 3.73 (1H, td, J ) 3.8 Hz, 11.2 Hz), 3.97-4.12 (2H,
m), 4.37 (1H, part of ABX, J ) 11.2 Hz, 19.0 Hz), 4 42-4.48
(2H, m), 4.71 (1H, d, J ) 4.4 Hz), 6.64 (2H, part of AB, J )
8.8 Hz), 7.00-7.06 (1H, m), 7.27-7.39 (4H, m), 7.57-7.91 (4H,
m), 8.53 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 18.2, 36.7,
42.4, 44.4, 54.6, 62.1, 74.4, 113.2, 121.7, 123.0, 123.8, 126.0,
127.4, 130.2, 130.7, 131.6, 132.5, 139.6, 141.9, 146.6, 153.1,
153.2, 159.1, 168.7, 172.6, 176.6; HRMS(FAB) [M + H]+ calcd
for C29H27N4NiO7 601.1233, found 601.1248.
Ni(II) com p lex of t h e Sch iff b a se of P AAP w it h
(2S*,3R*)-3-(N-m esitylen esu lfon yl-3′-in d olyl)-5-(2′-oxa zo-
lid in on yl)glu ta m ic a cid 7i: mp 188.0-189.0 °C; 1H NMR
(CDCl3) δ 2.24 (3H, s), 2.46 (6H, s), 2.90 (3H, s), 3.49 (1H, part
of ABX, J ) 3.9 Hz, 18.6 Hz), 3.99-4.17 (3H, m), 4.38-4.47
(3H, m), 4.75 (1H, d, J ) 3.9 Hz), 6.88 (2H, s), 6.94-7.03 (4H,
m), 7.19-7.37 (3H, m), 7.48-7.55 (2H, m), 7.73-7.82 (3H, m),
8.66 (1H, d, J ) 7.8 Hz); 13C NMR (CDCl3) δ 18.4, 20.9, 22.6,
30.9, 36.4, 37.0, 42.4, 62.2, 74.5, 112.0, 118.2, 120.5, 121.4,
122.7, 123.4, 123.9, 124.7, 126.3, 126.6, 127.1, 130.1, 130.5,
132.3, 132.6, 132.8, 134.5, 139.3, 140.0, 142.3, 143.9, 145.9,
152.3, 153.2, 168.7, 169.4, 172.0, 177.0; HRMS(FAB) [M + H]+
calcd for C38H36N5NiO8S 792.1638, found 792.1664.
(2S*,3S*)-3-Met h ylp yr oglu t a m ic a cid (8a ): yield 88%;
1
mp 108.0-109.0 °C; H NMR (CD3OD) δ 1.28 (3H, d, J ) 6.6
Hz), 1.99 (1H, part of ABX, J ) 9.6 Hz, 19.8 Hz), 2.50-2.59
(2H, m), 3.82 (1H, d, J ) 4.8 Hz); 13C NMR (CD3OD) δ 20.1,
34.8, 38.4, 63.1, 174.0, 178.3; HRMS(FAB) [M + H]+ calcd for
C6H10NO3 144.0661, found 144.0660.
(2S*,3R*)-3-P h en ylp yr oglu ta m ic a cid (8b): yield 85%;
1
mp 166.5-167.0 °C; H NMR (CD3COCD3) δ 2.35, 2.76 (2H,
ABX, J ) 6.3 Hz, 9.3 Hz, 16.8 Hz), 2.88 (1H, br s), 3.72 (1H,
m), 4.26 (1H, d, J ) 4.9 Hz), 7.21-7.43 (5H, m); 13C NMR (CD3-
COCD3) δ 38.7, 44.9, 63.1, 127.8, 127.9, 129.6, 143.9, 173.5,
176.4; HRMS(FAB) [M + H]+ calcd for C11H12NO3 206.0817,
found 206.0809.
Ack n ow led gm en t. The work was supported by the
grants from U.S. Public Health Service Grant and the
National Institute of Drug Abuse DA 06284, DA 04248,
DA 123941, and DK 17420. The views expressed are
those of the authors and not necessarily of the USPHS.
L.V.M. is a Research Director of the Fund for Scientific
Research (Flanders).
Su p p or tin g In for m a tion Ava ila ble: Complete set of
Ni(II) com p lex of t h e Sch iff b a se of P AAP w it h
(2S *,3R *)-3-p e n t a flu or op h e n yl-5-(2′-oxa zolid in on yl)-
glu ta m ic a cid 7j: mp 224.0-225.0 °C; 1H NMR (CDCl3) δ 2.82
(3H, s), 3.51 (1H, d, J ) 16.4 Hz), 4.01-4.13 (2H, m), 4.36-
4.49 (4H, m), 4.69-4.71 (1H, m), 7.01-7.06 (1H, m), 7.32-
1
X-ray data for compounds 3b, 4b, and 5b. Copies of H NMR
spectra of compounds 6a ,b, 7a -j, and 8a ,b. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0008791