â-Substituted Pyroglutamic Acids and Prolines
SCHEME 1
ated carboxylic acid derivatives, which provide the most
straightforward and general approach to â-substituted
glutamic and pyroglutamic acids, glutamines, and pro-
lines, have been extensively studied over the past 15
years.1,2o,4 Analysis of the relevant literature1-4 reveals
that thus far only one strategy to control the stereochem-
ical outcome in these reactions has been explored. In this
approach, addition reactions of various chiral glycine
equivalents with R,â-unsaturated carboxylic acid deriva-
tives were studied and, in some cases, reasonably high
levels of asymmetric induction at both R- and â-positions
of the resultant glutamic acid derivatives were obtained.
Surprisingly, the alternative strategy, application of
chiral derivatives of R,â-unsaturated carboxylic acids
in reactions with achiral glycine equivalents, remains
virtually unexplored so far.4a In this paper we report in
full1g that enantiomerically pure N-(E-enoyl)-4-phenyl-
1,3-oxazolidin-2-ones serve as ideal chiral Michael ac-
ceptors to afford virtually complete control of simple and
face diastereoselectivity in the corresponding addition
reactions with achiral Ni(II)-complexes of glycine Schiff
bases. The high chemical and optical yields achieved
under the operationally convenient conditions,5 combined
with the quantitative recovery of both the chiral auxiliary
and the glycine Schiff base precursor, render this new
strategy truly practical and synthetically superior over
previously reported approaches.2,4
the asymmetric version of this reaction by employing a
Ni(II)-complex of the chiral Schiff base of glycine with
(S)-o-[N-(N-benzylprolyl)amino]benzophenone 4 (Scheme
1), though successful, did not give the desired result.1d,j
Specifically, the problem we met was generally poor
si/re face stereocontrol of the complex (S)-4 derived
enolate, while the face selectivity of the Michael acceptors
2 was perfect giving rise only to the corresponding
diastereomeric products resulting from the transition
states (TSs)1d,j with the approach geometry like.6 There-
fore, we decided to explore an alternative approach, the
additions of the achiral Ni(II)-complex of glycine with
chiral 4-substituted N-(E-enoyl)oxazolidin-2-ones.
Ach ir a l Equ iva len ts of Nu cleop h ilic Glycin e. Pi-
colinic acid derived Ni(II)-complex 1a has emerged as a
new type of highly efficient achiral nucleophilic glycine
equivalent.1e,h,7-9 Its synthetically superior qualities
over the conventional esters of benzophenone-derived
glycine Schiff base have been convincingly demonstrated,
including the chemical stability and predictable forma-
tion of the corresponding (Z)-geometrically homogeneous
enolates,1e,h a feature of paramount importance for highly
diastereoselective/enantioselective homologation of the
glycine moiety in 1a . Thus, we recently reported the first
practical synthesis of symmetrically R,R-dialkyl-substi-
tuted amino acids,7 including 2-aminoindane-2-carboxylic
acid,8 using complex 1a as a stable, yet highly reactive
glycine equivalent. Recently, Belokon’s group has de-
scribed successful catalytic asymmetric alkylation of the
glycine equivalent 1a under phase-transfer conditions.9
As reported by us, the Ni(II)-complex 1a , as well as its
various analogues, can be readily prepared on a >100 g
scale (Scheme 2) under operationally convenient condi-
tions and with inexpensive reagents.10
Resu lts a n d Discu ssion
Recently we have discovered that the inexpensive and
readily available N-(E-enoyl)-1,3-oxazolidin-2-ones 2
(Scheme 1), featuring conformational homogeneity and
enhanced electrophilicity of the C,C double bond, serve
as ideal Michael acceptors in the corresponding addition
reactions with an achiral equivalent of nucleophilic
glycine 1a .1e,g The synthetically advantageous character-
istics of these reactions over the literature methods4 are
that they occur at operationally convenient conditions,5
such as, room temperature in the presence of nonchelating
organic bases, and with virtually complete simple dias-
tereoselectivity (>98% de). Our first attempt to realize
(4) For some representative papers, see: (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) Antolini, L.; Forni, A.; Moretti, I.; Prati, F.
Tetrahedron: Asymmetry 1996, 7, 3309. (d) Gestmann, D.; Laurent,
A. J .; Laurent, E. G. J . Fluorine Chem. 1996, 80, 27. (e) Hartzoulakis,
B.; Gani, D. J . Chem. Soc., Perkin Trans. 1 1994, 2525. (f) Suzuki, K.;
Seebach, D. Liebigs Ann. Chem. 1992, 51. (g) 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. (h) El
Achqar, A.; Boumzebra, M.; Roumestant, M.-L.; Viallefont, P. Tetra-
hedron 1988, 44, 5319. (i) Pettig, D.; Scho¨llkopf, U. Synthesis 1988,
173. (j) Scho¨llkopf, U.; Pettig, D.; Schulze, D.; Klinge, M.; Egert, E.;
Benecke, B.; Noltemeyer, M. Angew. Chem., Int. Ed. Engl. 1988, 27,
1194. (k) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277. (l) Hartwig,
W.; Born, L. J . Org. Chem. 1987, 52, 4352. (m) Minowa, N.; Hirayama,
M.; Fukatsu, S. Bull. Chem. Soc. J pn. 1987, 60, 1761. (n) 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. (o) Scho¨llkopf, U.; Pettig, D.; Busse, U. Synthesis
1986, 737.
Ch ir a l Mich a el Accep tor s. Chiral, 4-substituted
oxazolidin-2-ones are readily available and well-studied
chiral auxiliaries. As shown by the pioneering work of
Evans et al., the 4-substituted oxazolidin-2-one moiety
has a remarkable stereocontrolling power in alkylation,11a
acylation,11b aldol condensation,11c and Diels-Alder
(6) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982, 21,
654.
(7) (a) Ellis, T. K.; Martin, C. H.; Ueki, H.; Soloshonok, V. A.
Tetrahedron Lett. 2003, 4, 1063-1066. (b) Ellis, T. K.; Martin, C. H.;
Tsai, G. M.; Ueki, H.; Soloshonok, V. A. J . Org. Chem. 2003, 68, 6208-
6214.
(8) Ellis, T. K.; Hochla, V. M.; Soloshonok, V. A. J . Org. Chem. 2003,
68, 4973-4976.
(5) A conception of the “Atom Economy” introduced by Professor
Barry M. Trost has found quick and unanimous understanding,
support, and appreciation in the chemistry community as a philosophi-
cal guideline for the development of organic synthesis in the 21st
century. On the other hand, in the current literature one can notice
another trend developing as a paradigm for the synthetic methodology
of the future, which is simplicity of experimental conditions, or as we
prefer to call it, operationally convenient reaction conditions.
(9) Belokon, Yu. N.; Bespalova, N. B.; Churkina, T. D.; Cisarova, I.;
Ezernitskaya, M. G.; Harutyunyan, S. R.; Hrdina, R.; Kagan, H. B.;
Kocovsky, P.; Kochetkov, K. A.; Larionov, O. V.; Lyssenko, K. A.; North,
M.; Polasek, M.; Peregudov, A. S.; Prisyazhnyuk, V. V.; Vyskocil, S. J .
Am. Chem. Soc. 2003, 125, 12860-12871.
(10) Ellis, T. K.; Martin, C. H.; Ueki, H.; Soloshonok, V. A. Eur. J .
Org. Chem. 2003, 1954-1957.
J . Org. Chem, Vol. 69, No. 15, 2004 4985