Chiral Helicity Induced by Hydrogen Bonding and Chirality of Podand Histidyl Moieties

Article abstract of DOI:10.1021/ol0100327

figure presented The single-crystal X-ray structure determination of N,N′-bis{(S)-(+)-1-methoxycarbonyl-2-(4-imidazolyl)ethyl}-2,6- pyridinedicarboxamide (L-BHisPA) and the D-isomer (D-BHisPA) derived from the corresponding chiral histidine revealed a left- and right-handed helical conformation, respectively, through intramolecular hydrogen bonding and chirality of the podand histidyl moieties. Furthermore, each helical molecule is connected by continuous intermolecular hydrogen bonds to afford a left- or right-handed helical assembly, respectively, in the crystal packing.

Full text of DOI:10.1021/ol0100327

ORGANIC
LETTERS
2
001
Vol. 3, No. 10
459-1461
Chiral Helicity Induced by Hydrogen
Bonding and Chirality of Podand
Histidyl Moieties
1
Toshiyuki Moriuchi, Masahito Nishiyama, Kazuhiro Yoshida, Takuji Ishikawa, and
Toshikazu Hirao*
Department of Applied Chemistry, Faculty of Engineering,Osaka UniVersity,
Yamada-oka, Suita, Osaka 565-0871, Japan
hirao@ap.chem.eng.osaka-u.ac.jp
Received February 22, 2001
ABSTRACT
The single-crystal X-ray structure determination of N,N′-bis{(S)-(+)-1-methoxycarbonyl-2-(4-imidazolyl)ethyl}-2,6-pyridinedicarboxamide (L-
BHisPA) and the D-isomer (D-BHisPA) derived from the corresponding chiral histidine revealed a left- and right-handed helical conformation,
respectively, through intramolecular hydrogen bonding and chirality of the podand histidyl moieties. Furthermore, each helical molecule is
connected by continuous intermolecular hydrogen bonds to afford a left- or right-handed helical assembly, respectively, in the crystal packing.
2
The utilization of self-assembling properties of amino acids
is considered to be a convenient approach to a highly ordered
system. The secondary structures such as R-helices, â-sheets,
and â-turns, which play an important role in protein folding,
are driven by hydrophobic interaction and hydrogen bonding
crystal packing. On the other hand, the 2,6-pyridinedicar-
boxamide scaffold has also been exploited for a building
3
block to create helices. Introduction of chiral amino acids
(
2) (a) Nomoto, A.; Moriuchi, T.; Yamazaki, S.; Ogawa, A.; Hirao, T.
1
of amino acids. The highly ordered structures of these
Chem. Commun. 1998, 1963. (b) Moriuchi, T.; Nomoto, A.; Yoshida, K.;
Hirao, T. J. Organomet. Chem. 1999, 589, 50. (c) Moriuchi, T.; Nomoto,
A.; Yoshida, K.; Ogawa, A.; Hirao, T. J. Am. Chem. Soc. 2001, 123, 68.
(d) Moriuchi, T.; Nomoto, A.; Yoshida, K.; Hirao, T. Organometallics 2001,
secondary structures are created in protein to fulfill the unique
1
functions as observed in enzymes, receptors, etc. We have
2
0, 1008.
(
already demonstrated that the introduction of dipeptide chains
into the ferrocene scaffold permits chirality organization
through the intramolecular interchain hydrogen bonding, in
which a helical molecular arrangement is achieved in the
3) (a) Geib, S. J.; Vicent, C.; Fan, E.; Hamilton, A. D. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 119. (b) Hamuro, Y.; Geib, S. J.; Hamilton, A. D.
Angew. Chem., Int. Ed. Engl. 1994, 33, 446. (c) Kawamoto, T.; Prakash,
O.; Ostrander, R.; Rheingold, A. L.; Borovik, A. S. Inorg. Chem. 1995,
3
4, 4294. (d) Kawamoto, T.; Hammes, B. S.; Haggerty, B.; Yap, G. P. A.;
Rheingold, A. L.; Borovik, A. S. J. Am. Chem. Soc. 1996, 118, 285. (e)
Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118,
7529. (f) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1997,
119, 10587. (g) Kawamoto, T.; Hammes, B. S.; Ostrander, R.; Rheingold,
A. L.; Borovik, A. S. Inorg. Chem. 1998, 37, 3424. (h) Yu, Q.; Baroni, T.
E.; Liable-Sands, L.; Rheingold, A. L.; Borovik, A. S. Tetrahedron Lett.
1998, 39, 6831.
(
1) (a) Schulz, G. E.; Schirmer, R. H. Principles of Protein Structure;
Springer: New York, 1979. (b) Creighton, T. E. Proteins: Structures and
Molecular Properties, 2nd ed.; Freeman: New York, 1993. (c) Kyte, J.
Structure in Protein Chemistry; Garland: New York, 1995. (d) Branden,
C.; Tooze, J. Introduction to Protein Structure, 2nd ed.; Garland: New
York, 1998.
1
0.1021/ol0100327 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/19/2001

Figure 1. (a) Molecular structures of L-BHisPA and (b) D-BHisPA.
into this scaffold can be designed to afford a chiral molecular
arrangement. Histidine has the advantage of forming an
lecular conformation, the crystal structure of D-BHisPA
derived from D-histidine methyl ester was investigated. It
should be noted that a right-handed helical conformation was
formed in the crystal structure of D-BHisPA.7 Similar
intramolecular hydrogen bondings between NH (amide) and
N (pyridine) (NH‚‚‚N, 2.291 Å) were observed in this helical
structure (Figure 1b). The molecular structures of L-BHisPA
and D-BHisPA are in a good mirror-image relationship,
4
ordered structure on the basis of the chiral center and an
additional hydrogen bonding site of the imidazolyl group.
From these points of view, we herein report that the chiral
helicity of N,N′-bis{1-methoxycarbonyl-2-(4-imidazolyl)-
ethyl}-2,6-pyridinedicarboxamide induces a self-assembled
helix in the crystal packing, which provides a key procedure
to construct highly ordered structures by using amino acids.
N,N′-Bis{(S)-(+)-1-methoxycarbonyl-2-(4-imidazolyl)-
ethyl}-2,6-pyridinedicarboxamide (L-BHisPA) was synthe-
sized from 2,6-pyridinedicarboxylic acid dichloride and
8
indicating conformational enantiomers. The propensity to
form the chiral helicity appears to be controlled by the
configuration of the histidyl R-carbon atoms.
5
L-histidine methyl ester. The single-crystal X-ray structure
determination of L-BHisPA confirmed a left-handed helical
conformation through chirality of the histidyl moieties and
intramolecular hydrogen bonding between NH (amide) and
N (pyridine) (NH‚‚‚N, 2.230 Å) to give five-membered
6
hydrogen-bonded rings as depicted in Figure 1a. To
elucidate the capability of the 2,6-pyridinedicarboxamide
bearing podand histidyl moieties to induce the chiral mo-
(4) (a) Yu, Q.; Baroni, T. E.; Liable-Sands, L.; Yap, G. P. A.; Rheingold,
A. L.; Borovik, A. S. Chem. Commun. 1999, 1467. (b) Karle, I. L.;
Ranganathan, D.; Kurur, S. J. Am. Chem. Soc. 1999, 121, 7156.
(
5) The selected data are as follows. L-BHisPA: mp 198-199 °C
-1 1
(
uncorrected); IR (KBr) 3394, 3126, 1743, 1666 cm ; H NMR (300 MHz,
CD3OD) δ 8.23 (d, 2H, J ) 7.5 Hz), 8.12 (t, 1H, J ) 7.5 Hz), 7.57 (s, 2H),
6
4
.93 (s, 2H), 4.93 (dd, 2H, J ) 8.7, 5.1 Hz), 3.76 (s, 6H), 3.36-3.19 (m,
+
H); EI-MS m/z 469 (M ). Anal. Calcd for C21H23N7O6‚H2O: C, 51.74;
H, 5.17; N, 20.11. Found: C, 51.57; H, 5.01; N, 20.16. D-BHisPA: mp
-
1 1
1
98-199 °C (uncorrected); IR (KBr) 3394, 3126, 1743, 1666 cm ; H
NMR (300 MHz, CD3OD) δ 8.23 (d, 2H, J ) 7.5 Hz), 8.12 (t, 1H, J ) 7.5
Hz), 7.57 (s, 2H), 6.93 (s, 2H), 4.93 (dd, 2H, J ) 8.7, 5.1 Hz), 3.76 (s,
+
6
H), 3.36-3.19 (m, 4H); EI-MS m/z 469 (M ). Anal. Calcd for C21H23N7O6‚
H2O: C, 51.74; H, 5.17; N, 20.11. Found: C, 51.51; H, 4.78; N, 19.83.
Another interesting feature is that each molecule of
L-BHisPA is connected by continuous intermolecular hy-
drogen bonds to give a left-handed helix (M-form) as shown
L-HisPA: mp 174-175 °C (uncorrected); IR (KBr) 3348, 3116, 1728, 1658
-
1 1
cm ; H NMR (300 MHz, CD3OD) δ 8.62 (ddd, 1H, J ) 5.4, 1.8, 0.9
Hz), 8.05 (ddd, 1H, J ) 7.5, 1.5, 0.9 Hz), 7.94 (td, 1H, J ) 7.5, 1.8 Hz),
7
1
.63 (s, 1H), 7.54 (ddd, 1H, J ) 7.5, 5.4, 1.5 Hz), 6.89 (s, 1H), 4.91 (dd,
H, J ) 7.2, 5.4 Hz), 3.74 (s, 3H), 3.25-3.21 (m, 2H); EI-MS m/z 274
+
(M ). Anal. Calcd for C13H14N4O3: C, 56.93; H, 5.14; N, 20.43. Found:
(td, 1H, J ) 7.5, 1.8 Hz), 7.63 (s, 1H), 7.54 (ddd, 1H, J ) 7.5, 5.4, 1.5
Hz), 6.89 (s, 1H), 4.91 (dd, 1H, J ) 7.2, 5.4 Hz), 3.74 (s, 3H), 3.25-3.21
C, 56.56; H, 5.21; N, 20.26. D-HisPA: mp 174-175 °C (uncorrected); IR
-
1
1
+
(
(
KBr) 3348, 3116, 1728, 1658 cm ; H NMR (300 MHz, CD3OD) δ 8.62
ddd, 1H, J ) 5.4, 1.8, 0.9 Hz), 8.05 (ddd, 1H, J ) 7.5, 1.5, 0.9 Hz), 7.94
(m, 2H); EI-MS m/z 274 (M ). Anal. Calcd for C13H14N4O3: C, 56.93; H,
5.14; N, 20.43. Found: C, 56.89; H, 5.06; N, 20.38.
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Org. Lett., Vol. 3, No. 10, 2001

Figure 2. (a) A portion of a layer containing the helical assembly of crystal packing of L-BHisPA and (b) D-BHisPA (methyl ester moieties
are omitted for clarity). Each helical molecule is connected by continuous intermolecular hydrogen bonds to induce chiral helicity.
in Figure 2a. Noteworthy is that an opposite helically ordered
molecular assembly, a right-handed helix (P-form), was
formed in the crystal packing of D-BHisPA (Figure 2b). On
the contrary, such chiral helicity was not observed in the
pyridinecarboxamide derivatives bearing one histidyl pendant
difference between BHisPA and HisPA existed in the torsion
angle φ defined as C(4)-N(2)-C(5A)-C(6) (L-BHisPA,
1
-131.7°; D-BHisPA, 131.9°; L-HisPA, -102.7°; D-HisPA,
102.2°). The helical arrangement requires rotation of the
pendant chains, resulting in the above-mentioned torsion
angles. The podand histidyl moieties of the pyridinedicar-
boxamide scaffold are likely to play an important role in
creating the helical arrangement.
In conclusion, the intramolecular hydrogen bondings and
chirality of the podand histidyl pendant groups on the 2,6-
pyridinedicarboxamide scaffold allow induction of the chiral
helicity, creating the left- or right-handed helical assembly
by the connection of each helical molecule through continu-
ous intermolecular hydrogen bonds in the crystal packing.
Studies on the application of chiral helicity to molecular
recognition and asymmetric reaction are now in progress.
group, {(S)-(+)-1-methoxycarbonyl-2-(4-imidazolyl)ethyl}-
9
2-pyridinecarboxamide (L-HisPA) and D-isomer (D-HisPA).
A hydrogen-bonded network was only formed in the crystal
packing, wherein each molecule is connected to four
neighboring molecules by intermolecular hydrogen bonds
(Figures S2-S7, Supporting Information). The structural
(
6) Crystal data for L-BHisPA: C21H23N7O6‚H2O, fw ) 487.47, ortho-
rhombic, space group C2221 (No. 20), a ) 12.317(1) Å, b ) 9.1373(9) Å,
3
-3
c ) 22.507(2) Å, V ) 2533.1(4) Å , Z ) 4, Dcalcd ) 1.278 g cm , R )
.089, Rw ) 0.211.
7) Crystal data for D-BHisPA: C21H23N7O6‚H2O, fw ) 487.47, ortho-
rhombic, space group C2221 (No. 20), a ) 9.105(1) Å, b ) 12.297(1) Å,
0
(
3
-3
c ) 22.403(3) Å, V ) 2508.4(5) Å , Z ) 4, Dcalcd ) 1.291 g cm , R )
.074, Rw ) 0.183.
8) The mirror image of the CD signals between L-BHisPA and
Acknowledgment. Thanks are due to the Analytical
Center, Faculty of Engineering, Osaka University, for the
use of the NMR and MS instruments.
0
(
D-BHisPA was obtained (Figures S1, Supporting Information), suggesting
that a chiral molecular conformation based on an ordered structure through
intramolecular hydrogen bondings and chirality of the histidyl moieties is
present even in solution.
Supporting Information Available: Tables of X-ray
crystallographic data for L-BHisPA, D-BHisPA, L-HisPA, and
D-HisPA. ORTEP figures and crystal packings for L-HisPA
and D-HisPA. This material is available free of charge via
the Internet at http://pubs.acs.org.
(
9) Crystal data for L-HisPA: C13H14N4O3, fw ) 274.28, orthorhombic,
space group P212121 (No. 19), a ) 9.650(2) Å, b ) 16.262(2) Å, c )
3
-3
8
.872(2) Å, V ) 1392.2(3) Å , Z ) 4, Dcalcd ) 1.308 g cm , R ) 0.091,
Rw ) 0.136. D-HisPA: C13H14N4O3, fw ) 274.28, orthorhombic, space
group P212121 (No. 19), a ) 9.6490(6) Å, b ) 16.3212(9) Å, c )
3
-3
8
.8998(6) Å, V ) 1401.6(1) Å , Z ) 4, Dcalcd ) 1.300 g cm , R ) 0.038,
Rw ) 0.128.
OL0100327
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