Aizpurua et al.
JOCArticle
that the 1,4-dihydropyridine ring adopts a flat boat confor-
mation in the enzymatic process, facilitating the stereospecific
transfer of the pseudoaxial C4-H hydride placed in a syn
disposition with respect to the carboxamide CdO. This “Hsyn
transfer rule” is generally accepted to be at the origin of the
facial discrimination and subsequent enantioselectivity in the
nonenzymatic reduction of alkyl benzoylformates with
NADH/Mg2+ systems.12
Unfortunately, most of the structures 3-(I) to 3-(VI) used
to describe enzyme-free ternary entities from chelated chiral
NADH models are approximative drafts rather than actual
molecular modeling structures. As a matter of fact, no
accurate ab initio computational study has been reported
yet detailing the structures and relative stabilities of the
Mg2+-centered ternary complexes and the transition states
that account for the experimental enantioselectivities attai-
ned in NADH model-based nonenzymatic reductions.13
Considerable efforts have also been devoted to provide
spectroscopic evidence for the structural elucidation of the
intermediates involved in the enzyme-free enantioselective
reduction of R-keto esters with chiral NADH models. For
example, the complexation between metal ions and several
NADH models to form the rather stable binary complexes 2
has been extensively investigated with use of NMR, UV, IR,
and fluorescence techniques2b,8,14 and the structural features
of some of them have been established in detail. In contrast,
the very few examples in the literature so far dealing with the
direct detection of ternary entities 315 concern only achiral
NADH mimetics.
FIGURE 2. The “β-Lactam Scaffold-Assisted Design” (β-LSAD)
approach to NADH models: formal insertion in the native peptide
of a carbon atom (CR-H þ H-N f CR-CH2-N) provides
pseudopeptides 5 rigidified around the ψ (≈ 120°) torsion angle.
Definition of dihedral angles: R, (C2-C3-C4-N5); φ, (C4-N5-
C6-C7); and ψ, (N5-C6-C7-N8).
We present herein a detailed computational model to
explain the enantioselective reduction of methyl benzoylfor-
mate with peptide-containing NADH mimetics under none-
nzymatic conditions. The proposed model is based on the
combination of two structural features: first, the chelation of
NADH peptides with Mg2þ cation to form a seven-mem-
bered ring (Figure 2), and second, the application of the
Freidinger’s lactam peptidomimetic16 approach to promote
the covalent rigidification of the amide linkage in NADH
peptide ligands. In particular, using specially designed chiral
β-lactam NADH models that favor stereodifferentiation
with respect to the corresponding open peptides, we have
conducted a combined experimental and DFT computa-
tional study that has allowed us to establish for the first time
the quantification of the relative stabilities and structural
characteristics of the chelated ternary complexes peptide-
NADH/Mg2þ/PhCOCO2Me and the transition states there-
of. Furthermore, incorporation of diastereotopic silyl tags in
these β-lactam NADH models has permitted the detection of
a NADH/Mg2þ/PhCOCO2Me ternary complex with NMR
spectroscopy techniques.
(12) Vasse, J. L.; Levacher, V.; Bourguignon, J.; Dupas, G. Tetrahedron:
Asymmetry 2002, 13, 227–232.
(13) For a semiempirical (MNDO-PM3) study of the Mg2þ-mediated
reduction of methyl benzoylformate with achiral dihydronicotinamide, see:
(a) Toyooka, Y.; Matsuzawa, T.; Eguchi, T.; Kakinuma, K. Tetrahedron
1995, 51, 6459–6474. For theoretical studies on conformational features of
NADH analogues, see: (b) Donkersloot, M. C. A.; Buck, H. M. J. Am.
Chem. Soc. 1981, 103, 6554–6558. (c) Brewster, M. E.; Pop, E.; Huang, M.-J.;
Bodor, N. Heterocycles 1994, 37, 1373–1415. (d) Okamura, M.; Mikata, Y.;
Yamazaki, N.; Tsutsumi, A.; Ohno, A. Bull. Chem. Soc. Jpn. 1993, 66, 1197–
1203. (e) Obika, S.; Nishiyama, T.; Tatematsu, S.; Miyashita, K.; Imanishi,
T. Tetrahedron 1997, 53, 3073–3082. (f) De Luca, G.; Marino, T.; Mineva, T.;
Russo, N.; Toscano, M. J. Mol. Struct. (THEOCHEM) 2000, 501-502, 215–
220. (g) Zhong, H.; Bowen, J. P. J. Mod. Graph. Model. 2005, 24, 1–9.
(14) (a) Hughes, M.; Prince, R. H. J. Inorg. Nucl. Chem. 1978, 40, 703–
712. (b) De Kok, P. M. T.; Donkersloot, M. C. A.; van Lier, P. M.;
Meulendijks, G. H. W. M.; Bastiaansen, L. A. M.; van Hooff, H. J. G.;
Kanters, J. A.; Buck, H. M. Tetrahedron 1986, 42, 941–959. (c) Zehani, S.;
Lin, J.; Gelbard, G. Tetrahedron 1989, 45, 733–740. (d) Tamagaki, S.;
Simojo, Y.; Mimura, T.; Tagaki, W. Bull. Chem. Soc. Jpn. 1989, 62, 1593–
1600. (e) Wu, Y. D.; Houk, K. N. J. Org. Chem. 1993, 58, 2043–2045. (f)
Results and Discussion
NADH Model Design. Among the diverse families of
NADH models, nicotinamide peptides 417 (Figure 2) are
known to represent the closest imitation of the enzyme/
coenzyme complex and were expected to provide valuable
information concerning the NADH/substrate/coenzyme in-
teraction. From a structural viewpoint, they are also expe-
cted to arrange around the Mg2þ cation in a doubly coordi-
nated fashion within a seven-membered chelation pseudo-
plane. However, NADH peptides 4 could still enjoy
considerable conformational freedom because of the rotations
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Bedat, J.; Ple, N.; Dupas, G.; Bourguignon, J.; Queguiner, G. Tetrahedron:
Asymmetry 1995, 6, 923–932. (g) Leroy, C.; Levacher, V.; Dupas, G.;
ꢀ
Queguiner, G.; Bourguignon, J. Tetrahedron: Asymmetry 1997, 8, 3309–
3318. (h) Vitry, C.; Bedat, J.; Prigent, Y.; Levacher, V.; Dupas, G.; Salliot, I.;
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Queguiner, G.; Bourguignon, J. Tetrahedron 2001, 57, 9101–9108.
(15) (a) Fukuzumi, S.; Nishizawa, N.; Tanaka, T. Chem. Lett. 1983, 1755–
1758. (b) Ohno, A.; Yamamoto, H.; Oka, S. Bull. Chem. Soc. Jpn. 1981,
3489–3491.
(16) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brookas, J. R.;
Saperstein, R. Science 1980, 210, 656–658. (b) Freidinger, R. M. J. Med.
Chem. 2003, 46, 5553–5566.
(17) For extended NADH peptide models, see: (a) Endo, T.; Hayashi, Y.;
Okawara, M. Chem. Lett. 1977, 391–394. (b) Endo, T.; Kawasaki, H.;
Okawara, M. Tetrahedron. Lett. 1979, 23–26. (c) Saito, R.; Naruse, S.;
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