New Modular Nucleophilic Glycine EquiValents
SCHEME 1
that need to be addressed with respect to this synthetic approach,
it seems that most involve the insufficient design of the glycine
equivalents themselves. The majority of the commercially
available glycine equivalents may be characterized as having
unacceptable properties such as chemical instability, poor
industrial scalability, or poor economic feasibility.
Results and Discussion
Therefore, to overcome these shortcomings, our laboratory
has recently developed a new series of modified glycine
equivalents based on a modular skeleton9 that has provided
superior chemical reactivity, stability, solubility, and cost
efficiency, even compared to their Ni(II)-containing counterparts
previously introduced by our laboratory10 and others.11 The
modular design concept of the glycine equivalents has opened
(1) The rapidly growing list of amino acids isolated from various natural
sources makes the terms unnatural, unusual, noncoded, or nonproteinogenic
amino acids, which are most frequently used in the literature, dependent
on the success of specific scientific achievements. For instance, amino acids
containing the most xenobiotic element fluorine have been shown to be
synthesized by microorganisms. Moreover, recent spectacular developments
in the generation of bacteria with an expanded genetic code make all above-
mentioned definitions rather obsolete. Therefore, the time-independent term
tailor-made, meaning rationally designed/synthesized amino acids with
presupposed physical, chemical, 3D-structural, and biological features, in
the absence of a better definition, seems to be a more appropriate use as a
common name for such amino acids. (a) Kukhar’, V. P.; Soloshonok, V.
A., Eds.; Fluorine-Containing Amino Acids. Synthesis and Properties; John
Wiley and Sons Ltd.: Chichester, 1994. (b) Mehl, R. A.; Anderson, J. C.;
Santoro, S. W.; Wang, L.; Martin, A. B.; King, D. S.; Horn, D. M.; Schultz,
P. G. J. Am. Chem. Soc. 2003, 125, 935.
various avenues of opportunity for a whole host of reaction
conditions, given the advantage of virtually complete substrate
adaptability.
There are several modules that must be combined to assemble
the desired Ni(II) complexes; however, a simple, general, and
reliable synthetic route has been devised for this purpose
(Scheme 1). The first step is the coupling to the proper
“phenone” module with the corresponding “acid” module to
form the intermediate “acetamide” module. This is accomplished
by the slow addition of a 2-aminophenone 1/acetonitrile solution
to slurry of bromoacetyl bromide 2, potassium carbonate, and
acetonitrile. This procedure is usually accomplished with yields
greater than 90% and nearly ideal chemical purity. Next, the
ligand 6a-f or 7a-f will be produced from the substitution of
the bromine atom from the acetamide module intermediate 3
or 4 with virtually any secondary amine 5a-f. This reaction is
also accomplished in an acetonitrile solution with potassium
carbonate, to liberate the hydrobromic salt of the amine
produced; however, the application of heat is generally utilized
to accelerate the reaction rate. It should also be noted that the
previous two reactions may be conducted via a one-pot reaction;
however, we have found it more convenient to store large
amounts of the acetamide intermediates 3 or 4 for their eventual
conversion to their corresponding ligands 6a-f or 7a-f as
needed. The final reaction of the glycine equivalent synthesis
is the Schiff base formation, between the ligand 6a-f or 7a-f
and glycine 8, coupled with the simultaneous Ni(II) complex-
ation accomplished in methanol with heat to accelerate the
reaction. Potassium hydroxide is utilized to catalyze the imine
formation as well as to neutralize the corresponding acid formed
from the reaction.
(2) (a) Najera, C. Synlett 2002, 1388. (b) Park, K. H.; Kurth, M. J.
Tetrahedron 2002, 58, 8629.
(3) (a) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; KeBeler, M.;
Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788. (b) Wang,
L.; Brock, A.; Herberich, B.; Schultz, P. G. Science 2001, 292, 498. (c)
Gallos, J. K.; Sarli, V. C.; Massen, Z. S.; Varvogli, A. C.; Papadoyanni, C.
Z.; Papasyrou, S. D.; Argyropoulos, N. G. Tetrahedron 2005, 61, 565. (d)
Wang, M.-X.; Lin, S.-J.; Liu, J.; Zheng, Q.-Y. AdV. Synth. Catal. 2004,
346, 439.
(4) (a) Zhang, X.; Ni, W.; Van der Donk, W. A. J. Org. Chem. 2005,
70, 6685. (b) O’Donnell, M. J.; Alsina, J.; Scott, W. L. Tetrahedron Lett.
2003, 44, 8403.
(5) (a) Karle, I. L.; Kaul, R.; Rao, R. B.; Raghothama, S.; Balaram, P.
J. Am. Chem. Soc. 1997, 119, 12048. (b) Marshall, B. R.; Hodgkin, E. E.;
Langs, D. A.; Smith, G. D.; Zabrocki, J.; Leplawy, M. T. Proc. Natl. Acad.
Sci. U.S.A. 1990, 31, 129. (c) Toniolo, C.; Crisma, M.; Bonora, G. M.;
Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Santini, A. Biopolymers
1991, 31, 129. (d) Huston, S. E.; Marshall, G. R. Biopolymers 1994, 34,
75. (e) Aleman, C. Biopolymers 1994, 34, 841. (f) Yokum T. S.; Gauthier,
T. J.; Hammer, R. P.; McLaughlin, M. L. J. Am. Chem. Soc. 1997, 119,
1167. (g) Rossi, P.; Felluga, F.; Tecilla, P.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Scrimin, P. J. Am. Chem. Soc. 1999, 121, 6948.
(6) (a) Peptide Secondary Structure Mimetics. Tetrahedron Symposia-
in-Print; Kahn, M., Ed.; Tetrahedron 1993, 49, No. 50 and references therein.
(b) Machetti, F.; Cordero, F. M.; De Sarlo, F.; Papini, A. M.; Alcaro, M.
C.; Brandi, A. Eur. J. Org. Chem. 2004, 2928. (c) Giannis, A.; Kolter, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(7) Special Issue. Protein Design. Degrado, W. F., Guest Ed. Chem. ReV.
2001, 101.
Now that the ease and cost efficiency for the synthesis of
the new generation of glycine equivalents has been established,
the versatility, chemical stability, and chemical reactivity need
to be evaluated. Therefore, it was determined that these glycine
equivalents 9a-f or 10a-f should first be subjected to extreme
conditions to confirm the stability of the complex as well as to
ensure that the methylene moiety, introduced into the ligand
6a-f or 7a-f via the addition of bromoacetyl bromide 2, is
nonenolizable and therefore would not interfere with the overall
atom economy of the process or the recyclable nature of the
ligand 6a-f or 7a-f. Therefore, to evaluate these possibilities
(8) Special Issue. Asymmetric Synthesis of Novel Sterically Constrained
Amino Acids. Tetrahedron Symposia-in-Print #88; Hruby, V. J., Soloshonok,
V. A., Guest Eds. Tetrahedron 2001, 57, No. 30 and references therein.
(9) Ellis, T. K.; Ueki, H.; Soloshonok, V. A. Tetrahedron Lett. 2005,
46, 941.
(10) (a) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Org. Lett. 2000, 2,
747. (b) Ueki, H.; Ellis, T. K.; Martin, C. H.; Soloshonok, V. A. Eur. J.
Org. Chem. 2003, 10, 1954.
(11) Belokon, Y. 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.; Prisyazhnyulk, V. V.; Vyskocil, S. J.
Am. Chem. Soc. 2003, 125, 12860.
J. Org. Chem, Vol. 71, No. 22, 2006 8573