J. M. Rodriguez, A. D. Hamilton / Tetrahedron Letters 47 (2006) 7443–7446
7445
Figure 4. Tautomers of 5: (A) ketoamino, (B) iminoenol, and (C)
oxoimino.
H-bonded proton around 13 ppm suggested the
presence of the ketoamino or iminoenol tautomer of
Figure 6. Stereoview of an X-ray crystal structure of 3a.
1
the Z-enaminone. Extensive H and 17O NMR studies
on intramolecularly hydrogen bonded Z-enaminone
compounds have shown that the ketoamino tautomer
is preferred even when the alternative iminoenol form
would benefit from additional resonance stabilization
as in the case of 3 (Fig. 4B).19,24
(d = 13.00 ppm, Dd = 0.002 ppm) and DMSO (d =
13.14 ppm, Dd = 0.009 ppm) when the concentration of
the sample was varied between 0.005 and 0.5 M. This
suggests that the enaminones are intra- rather than
intermolecularly hydrogen bonded even in polar
solvents like DMSO. The temperature dependence
coefficients of 3b were determined from VT-NMR in
both CDCl3 (Dd/DT = 1.5 ppb Kꢁ1) and DMSO (Dd/
DT = 2.0 ppb Kꢁ1). These results fall within the range
of intramolecular hydrogen bonded amide –NHꢀ ꢀ ꢀO@C
1H NMR NOE-difference experiments were performed
on a model enaminone 3b (where R1, R2 = Me,
R3 = H) in order to confirm the regioselective formation
of the enaminones due to the possibility of forming
regioisomers in going from 7 to derivatives of 3 in
Scheme 1 (Fig. 5). Regioisomer 8 would, like 3b, have
a characteristic vinylic and H-bonded resonance at
around 5 and 13 ppm, respectively. However, saturation
of the vinylic methyl protons in 3b showed enhancement
of the vinyl proton and ortho-aromatic protons. This is
in agreement with the enaminone structure of 3b instead
of 8, where only the vinyl proton would have been en-
hanced. This was further confirmed with an X-ray crys-
tal analysis of 3a which crystallized as the ketoamino
tautomer with an intramolecular hydrogen bond be-
tween the –NH and the carbonyl oxygen atom having
interactions found for small peptides in DMSO
(<3.0 ppb Kꢁ1
)
also suggesting that the enaminone
17
proton is intra-molecularly hydrogen bonded.
In summary, a new scaffold based on an intramolecu-
larly hydrogen bonded enaminone core was designed
to mimic the i, i + 4, and i + 7 residues of an a-helix.
Further derivatization of the R-groups in 3, will allow
us to target important a-helix mediated protein–protein
interactions.
˚
an interatomic –Hꢀ ꢀ ꢀO distance of 1.82 A (–Nꢀ ꢀ ꢀO dis-
Acknowledgement
˚
tance of 2.62 A) and an –N–Hꢀ ꢀ ꢀO angle of 140.5°.
The structure also showed that the resulting six-mem-
bered hydrogen bonded enaminone group has a planar
We thank the National Institutes of Health (GM69850)
for financial support of this work.
˚
deviation of 0.02 A, making the vinylogous amide func-
tionality a suitable aromatic ring analogue (Fig. 6).
Supplementary data
Additional 1H NMR studies of enaminone 3b were done
in order to probe the existence of an intramolecular
hydrogen bond. Enaminone 3b showed very little
change in the amine –NH resonance in both CDCl3
Supplementary data, including X-ray crystallographic
data, experimental procedures, characterizations, and
spectra of all compounds associated with this article
References and notes
1. Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.;
Moore, J. S. Chem. Rev. 2001, 101, 3893–4011.
2. Moorlag, C.; Sih, B. C.; Stott, T. L.; Wolf, M. O. J.
Mater. Chem. 2005, 15, 2433–2436.
3. Ernst, J. T.; Becerril, J.; Park, H. S.; Yin, H.; Hamilton, A.
D. Angew. Chem., Int. Ed. 2003, 42, 535–539.
4. Kritzer, J. A.; Stephens, O. M.; Guarracino, D. A.;
Reznik, S. K.; Schepartz, A. Bioorg. Med. Chem. 2005, 13,
11–16.
Figure 5. NOEs observed for 3b, and regioisomer 8.