Effect of an internal anthranilamide turn unit on the structure and conformational stability of helically biased intramolecularly hydrogen-bonded dendrons

Full text of DOI:10.1021/ja0042229

J. Am. Chem. Soc. 2001, 123, 2689-2690
Effect of an Internal Anthranilamide Turn Unit on
2689
the Structure and Conformational Stability of
Helically Biased Intramolecularly Hydrogen-Bonded
Dendrons
Baohua Huang and Jon R. Parquette*
Department of Chemistry
The Ohio State UniVersity
Columbus, Ohio 43210
Figure 1. Notional depiction of intramolecularly H-bonded dendrons
with internal and peripheral helicity (G ) generation).
ReceiVed December 11, 2000
The synthesis of nonnatural molecules that adopt a specific,
compact conformation in solution has been the subject of intense
recent interest.1 Developing dendrimers that fold into stable,
ordered conformations remains an elusive goal due to the
conformational flexibility of most commonly studied systems.2-4
Previous work in our group demonstrated that dendrons (with
chiral termini, Figure 1, Type I), rigidified through intramolecular
hydrogen-bonding interactions, adopt a specific, chiral helical
secondary structure at higher generations. However, this secondary
structure was only present at the dendron periphery and was
extremely sensitive to solvent quality and temperature.5 In this
communication, the stability of helical secondary structure is
dramatically enhanced by linking each generational shell through
an anthranilamide turn unit (Type II). This modification induces
the dendrons to fold into a tightly packed conformation that
expresses helical order at each generational shell.6
In the folded conformational state, the extremely tight packing
of the protein interior is an important determinant of protein
stability.7 Consequently, improvements in packing efficiency
usually impart increased stability to the protein.8 Type I dendrons
develop a bias for an M-type helicity, relating a pair of
anthranilamide termini at the second and third generations;
however, at 60 °C in CH3CN, this chiral secondary structure is
destroyed for I-G2Cl and partially destroyed for I-G3Cl.5b We
propose that intraterminal group packing interactions engender
cooperativity in the conformational equilibria of the peripheral
subunits causing small energetic differences between conforma-
tional states to be magnified, leading to a more stable folded state.
Figure 2. Stereo depiction of lowest energy conformer of II-G2Cl (2a)
by MM2.11
These cooperative effects increasingly favor a single helical sense
as the number of terminal groups increase at higher generations.9
We reasoned that the stability of the dendron secondary
structure would increase if internal helical equilibria were
sympathetically correlated with the peripheral helicity. Therefore,
to increase packing efficiency and to extend the peripheral helicity
to the internal regions of the dendrons, an anthranilamide turn
unit was used to link each generational shell of the dendrons.
The stable six-membered ring hydrogen bond that forms between
adjacent amides linked through this subunit and the s-trans-
preference of secondary amides induces a turn in the dendron
that folds the outer dendritic shells above and below the plane of
the branch point (Figure 1, Type II). Monte Carlo conformational
analysis at the second generation supports this potential folding
model (Figure 2).
A 2-aminobenzamide connector was incorporated at each
generational shell as depicted in Scheme 1. Circular dichroic
spectra of G1-Cl, I-G2Cl, II-G2Cl (2a), and II-G3Cl (3) in
acetonitrile are compared in Figure 3.10 The transition that occurs
in all the CD spectra in the region of 300-340 nm is exclusively
due to a π f π* transition of the anthranilamide chromophore
centered at 316 nm that is polarized along the axis containing
C3 and C6 (Figure 4).12 This transition corresponds to a simple
Cotton effect (CE) at the first generation, indicating that the
equilibria interconverting two diastereomeric helical conforma-
tions (M and P helices) relating a pair of anthranilamide termini
is unbiased (Figure 4). However, this transition becomes an
exciton couplet (negative chirality) for I-G2Cl and II-G2Cl (2a),
indicating a preference for the M helical conformation of the
anthranilamide chromophores. Whereas for I-G2Cl this couplet
is destroyed upon heating to 60 °C, the couplet remains
unchanged up to 60 °C in CH3CN in the spectra of II-G2Cl (2a),
and only slight changes are reVealed at 110 °C in bis(2-
butoxyethyl)ether (Figure 3). In contrast to the extreme solvent
dependence of I-G2Cl,5b the spectra of II-G2Cl (2a) were
insensitive to solvent (see Supporting Information). Furthermore,
(1) For some reviews, see: (a) Barron, A. E.; Zuckermann, R. N. Curr.
Opin. Chem. Biol. 1999, 3, 681. (b) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173.
(2) For recent studies relevant to the conformational behavior of dendrimers,
see: (a) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999, 99,
1665. (b) Wooley, K. L.; Klug, C. A.; Tasaki, K.; Schaefer, J. J. Am. Chem.
Soc. 1997, 119, 53 and references therein.
(3) For some reviews of chiral dendrimers, see: (a) Peerlings, H. W. I.;
Meijer, E. W. Chem. Eur. J. 1997, 3, 1563. (b) Seebach, D.; Rheiner, P. B.;
Greiveldinger, G.; Butz, T.; Sellner, H. Top. Curr. Chem. 1998, 197, 125. (c)
Thomas, C. W.; Tor, Y. Chirality 1998, 10, 53.
(4) Seebach has observed solvent-dependent variations in chiroptical data,
see: Murer, P.; Seebach, D. HelV. Chim. Acta 1998, 81, 603.
(5) Huang, B.; Parquette, J. R. Org. Lett. 2000, 2, 239. (b) Recker, J.;
Tomcik, D.; Parquette, J. R. J. Am. Chem. Soc. 2000, 122, 10298.
(6) For oligoanthranilamides related to these dendrons that fold into linear
sheet and helical conformations, see: (a) Hamuro, Y.; Geib, S. J.; Hamilton,
A. D. J. Am. Chem. Soc. 1997, 119, 10587. (b) Hamuro, Y.; Geib, S. J.;
Hamilton, A. D. J. Am. Chem. Soc. 1996, 118, 7529.
(7) Creighton, T. E. Proteins: Structures and Molecular Properties; 2nd
ed. W. H. Freeman: New York, 1993. (b) Jaenicke, R. J. Biotechnol. 2000,
79, 193. (c) Jaenicke, R.; Bohm, G. Curr. Opin. Struct. Biol. 1998, 8, 738.
(d) Levitt, M.; Gerstein, M.; Huang, E.; Subbiah, S.; Tsai, J. Annu. ReV.
Biochem. 1997, 66, 549.
(8) Mutter, M.; Tuchscherer, G. Cell. Mol. Life Sci. 1997, 53, 851. (b)
Ramachandran, S.; Udgaonkar, J. B. Biochemistry 1996, 35, 8776.
(9) For examples of cooperativity in helical polymers, see: (a) Green, M.
M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science
1995, 268, 1860. (b) Langeveld-Voss, B. M. W.; Waterval, R. J. M.; Janssen,
R. A. J.; Meijer, E. W. Macromolecules 1999, 32, 227. (c) Palmans, A. R.
A.; Vekemans, J. A. J. M.; Havinga, E. E.; Meijer, E. W. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2648.
(10) All CD spectra were normalized with respect to concentration and
the number of chiral terminal groups.
(11) Generated by employing a Monte Carlo conformational search using
the MM2* force field as implemented in Macromodel 6.0.
(12) For a TDDFT study of the electronic transitions of the anthranilamide
chromophore, see ref 5b.
10.1021/ja0042229 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/27/2001

2690 J. Am. Chem. Soc., Vol. 123, No. 11, 2001
Scheme 1. Dendron Synthesisa
Communications to the Editor
Figure 5. NOESY spectrum (600 MHz, THF-d8, 27 °C) of II-G3Cl (3).
F ) focal (1st) shell; I ) internal (2nd) shell; P ) peripheral (3rd) shell.
The conformation of 2a and 3 were investigated further by
1
2D (NOESY) H NMR to ascertain if close contacts consistent
with the folded conformations shown in Figures 1 and 2 were
present. Five cross-peaks between protons of the peripheral and
the first (for 2a) or second (for 3) shell anthranilamides are readily
apparent for both 2a (500 MHz, C6D6, 50 °C, Supporting
Information) and 3 (Figure 5).13 The presence of these nOe
enhancements provides strong evidence for the folded structure
depicted in Figure 2 because protons associated with the first shell
(for 2a) or second shell (for 3) and the peripheral anthranilamide
groups within a single dendritic branch would be too distant for
nOe enhancements to be possible (Figure 2).14 However, the
folded conformation places each anthranilamide in close proximity
with an anthranilamide present one shell lower in an adjacent
branch of the dendron (Figure 2). The fact that these enhancements
can be observed at 50 °C for 2a provides further evidence of the
unusually high thermal stability of this conformation. Further, a
weak cross-peak (0.8%) between protons of the first (focal) and
the second (internal) shells (Fâ,IR) is evident for 3, confirming
the presence of a similar helical fold of the anthranilamides at
the focal shell.15 At 50 °C in THF-d8 this cross-peak is not evident;
however, four cross-peaks between the internal/peripheral an-
thranilamides are present in the spectrum (see Supporting
Information). The temperature dependence of this cross-peak
(Fâ,IR) suggests that the helical conformation relating the anthra-
nilamides at the focal shell is less compact than at the internal
shell.
a (a) 2-NO2C6H4COCl, pyr., (b) H2, Pd-C, EtOAc-CH3OH, (c)
4-chloropyridine-2,6-dicarbonyl chloride, pyr., (d) NaN3, DMF, 50 °C.
Figure 3. CD Spectra in CH3CN of Type I and II dendrons (left) and
temperature-dependence of exciton couplet of 2a (right).
In conclusion, we have described dendrons that exhibit a helical
secondary structure that occurs over three generational levels. The
preliminary evidence described in this paper suggests that
molecular packing plays an important role in stabilizing secondary
structure in dendrimeric systems.
Figure 4. Helical interconversion of anthranilamide chromophores.
Acknowledgment. This work was supported by the National Science
Foundation CAREER program (CHE-98-75458).
the increased intensity of this transition indicates that the
conformational equilibrium of the focal anthranilamides is
similarly biased toward an M-type helicity and, therefore,
constructively contributes to the couplet. The exciton couplet at
316 nm for II-G3Cl (3) in acetonitrile at 25 °C (Figure 3) is similar
in magnitude to that observed for II-G2Cl (2a) and also shows
little solvent or temperature dependence (see Supporting Informa-
tion). This observation indicates that the second and third shells
fold into a helical conformation that is biased toward an M-type
helicity by the terminal groups as observed for II-G2Cl (2a).
Accordingly, we can conclude that the first (focal) shell anthra-
nilamide groups of 3 are not contributing significantly to the
couplet due to greater conformational freedom that reduces the
effect of the chiral terminal groups on the helical bias of this
shell.
Supporting Information Available: H-H COSY, NOESY, and
selective TOCSY NMR spectra and solvent- and temperature-dependent
CD spectra for 2a and 3; full experimental procedures and analytical
detail for dendrons 1b-3 (PDF). This material is free of charge via the
Internet at http://pubs.acs.org.
JA0042229
(13) Proton assignments for 2a and 3 based on H-H COSY and selective
TOCSY NMR experiments (see Supporting Information).
(14) This structural information is based on crystal structures of closely
related structures. See ref 5a and references therein.
(15) See Supporting Information for vertical and horizontal cross-sections
of the unsymmetrized NOESY spectrum for this cross-peak.