Minimalist end groups for control of absolute helicity in salen- and salophen-based metallofoldamers

Article abstract of DOI:10.1021/ol101583v

(S)-1-Methylindan end groups are effective controllers of absolute helicity in Ni-salen- and Ni-salophen-based foldamers derived from (R,R)-trans-1,2- cyclohexanediamine and 1,2-phenylenediamine, respectively. Evidence for the helicity of the described complexes was provided through X-ray crystallography and study of chiroptical properties in solution. The chiral end groups control the absolute sense of helicity for the salen complexes, even in a case where the helical bias of the end group is mismatched relative to that of the internal diamine.

Full text of DOI:10.1021/ol101583v

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4002-4005
Minimalist End Groups for Control of
Absolute Helicity in Salen- and
Salophen-Based Metallofoldamers
Zhenzhen Dong, James N. Plampin III, Glenn P. A. Yap, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, UniVersity of
Delaware, Newark, Delaware 19716
jmfox@udel.edu
Received July 8, 2010
ABSTRACT
(S)-1-Methylindan end groups are effective controllers of absolute helicity in Ni-salen- and Ni-salophen-based foldamers derived from (R,R)-
trans-1,2-cyclohexanediamine and 1,2-phenylenediamine, respectively. Evidence for the helicity of the described complexes was provided
through X-ray crystallography and study of chiroptical properties in solution. The chiral end groups control the absolute sense of helicity for
the salen complexes, even in a case where the helical bias of the end group is mismatched relative to that of the internal diamine.
The design of foldamerssunnatural molecules that fold into
distinct secondary structuresshas been inspired by natural
strategies for creating three-dimensional structure in mac-
romolecules.1 As the unnatural analogues of metallopeptides,
single-stranded metallofoldamers2,3 present intriguing pos-
sibilities for the study of asymmetric catalysts. In particular,
the ability to control the three-dimensional structure of
metallofoldamers presents a unique tool for understanding
the role of secondary structure in enantioselective catalysis.
Our group has been engaged in the use of metallofoldam-
ers as tools for probing the role of helicity in asymmetric
induction by metal-salen catalysts.4 Previously, we described
the properties of a number of large metallofoldamers such
as 1 and 2 (Figure 1), and we determined that stereocenters
at the periphery of the foldamers can control the absolute
sense of helicity.4c In 2, the end group overwhelms the chiral
(2) (a) Maayan, G. Eur. J. Org. Chem. 2009, 33, 5699. (b) Becerril, J.;
Rodriguez, J. M.; Saraogi, I.; Hamilton, A. D. In Foldamers: Structure,
Properties and Applications; Hecht, S., Huc, I., Eds.; Wiley-VCH:
Weinheim, Germany, 2007; p 193. (c) Prince, R. B.; Okada, T.; Moore,
J. S. Angew. Chem., Int. Ed. 1999, 38, 233. (d) Mizutani, T.; Yagi, S.;
Morinaga, T.; Nomura, T.; Takagishi, T.; Kitagawa, S.; Ogoshi, H. J. Am.
Chem. Soc. 1999, 121, 754. (e) Constable, E. C. Tetrahedron 1992, 48,
10013. (f) Constable, E. C.; Drew, M. G. B.; Forsyth, G.; Ward, M. D.
J. Chem. Soc., Chem. Commun. 1988, 1450. (g) Ho, P. K.-K.; Cheung,
K.-K.; Peng, S.-M.; Che, C.-M. J. Chem. Soc., Dalton Trans. 1996, 1411.
(h) Kim, H.-J.; Zin, W.-C.; Lee, M. J. Am. Chem. Soc. 2004, 126, 7009. (i)
Maayan, G.; Ward, M. D.; Kirshenbaum, K. Chem. Commun. 2009, 56. (j)
Zhong, Z.; Zhao, Y. Org. Lett. 2007, 9, 2891. (k) Zhao, Y.; Zhong, Z.
J. Am. Chem. Soc. 2006, 128, 9988. (l) Kawamoto, T.; Hammes, B. S.;
Haggerty, B.; Yap, G. P. A.; Rheingold, A. L.; Borovik, A. S. J. Am. Chem.
Soc. 1996, 118, 285.
(1) (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893. (b) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173. (c) Juwarker, H.; Suk, J.-m.; Jeong, K.-S. Chem. Soc. ReV. 2009,
38, 363. (d) Cubberley, M. S.; Iverson, B. L. Curr. Opin. Chem. Biol. 2001,
5, 650. (e) Foldamers: Structure, Properties and Applications; Hecht, S.,
Huc, I., Eds.; Wiley-VCH: Weinheim, Germany, 2007. (f) Goodman, C. M.;
Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252.
10.1021/ol101583v  2010 American Chemical Society
Published on Web 08/26/2010

of a new class of foldamers with structure 3, in which small
chiral end groups are able to control the absolute sense of
helicity. Asymmetry is derived from chiral 1-methylindan
groups at the periphery of the foldamer (Figure 2a), and
Figure 1. Chiral end groups control the sense of helicity in
metallofoldamers. Diastereomeric complexes 1 and 2 fold as (M)-
helical diastereomers. In 2, the directing ability of the end group
completely overwhelms the influence of the chiral diamine, which
ordinarily directs for a (P)-helix. As for 1, the (M)-helicity of 2
results in significant chiroptical properties.
Figure 2. Design of metallofoldamers with minimalist end groups.
diamine, which ordinarily directs for the opposite helical
diastereomer.
In foldamers 1 and 2, the metal center is embedded within
the helix. To design foldamers that can be used in catalysis,
it will be necessary to utilize analogues in which the metal
center is not blocked by the ends of the helices. Accordingly,
we envisioned salen and salophen foldamers with “mini-
malist” end groups, which retain virtue of peripheral control
over helicity5 without precluding the possibility of axial
coordination. Herein, we describe the synthesis and properties
control over absolute helicity is predicted, as shown in Figure
2b. It is speculated that conformer 4 will be disfavored as a
result of a steric interaction, which causes deviation from
planarity and consequently disrupts π-stacking interactions
with the underlying ring.
The goal of this study was to demonstrate the ability of
the chiral end groups to enforce absolute helicity in metal-
lofoldamers of structure 3. Because the chiroptical signatures
of folding are well understood for Ni-salen foldamers and
Ni-salophen foldamers, we focused initial studies on Ni
complexes of 3.4 We demonstrate that these complexes adopt
helical structures in solution and the crystalline state. The
absolute sense of helicity is dominated by stereocenters at
the periphery for all of these metallofoldamers, including
those in which the end group chirality is mismatched relative
to the diamine chirality.
(3) For metallofoldmamers based on the 1,2-bis(salicylideneaminooxy)-
ethane framework, see: (a) Akine, S.; Morita, Y.; Utsuno, F.; Nabeshima,
T. Inorg. Chem. 2009, 48, 10670. (b) Akine, S.; Taniguchi, T.; Nabeshima,
T. Inorg. Chem. 2008, 47, 3255. (c) Akine, S.; Matsumoto, T.;
Nabeshima, T. Chem. Commun. 2008, 4604. (d) Akine, S.; Taniguchi, T.;
Nabeshima, T. J. Am. Chem. Soc. 2006, 128, 15765. (e) Akine, S.;
Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2006, 47, 8419. (f) Akine,
S.; Taniguchi, T.; Matsumoto, T.; Nabeshima, T. Chem. Commun. 2006,
4961. (g) Akine, S.; Taniguchi, T.; Saiki, T.; Nabeshima, T. J. Am. Chem.
Soc. 2005, 127, 540. (h) Akine, S.; Taniguchi, T.; Nabeshima, T. Angew.
Chem., Int. Ed. 2002, 41, 4670. For an example of a metal-free, chiral salen-
based macrocycle, see: Brooker, S.; Dunbar, G.; Weyhermuller, T.
Supramol. Chem. 2001, 13, 601.
Foldamers 3 were synthesized from salicylaldehyde 10,
which was prepared as outlined in Scheme 1. The known
(4) (a) Zhang, F.; Bai, S.; Yap, G. P. A.; Tarwade, V.; Fox, J. M. J. Am.
Chem. Soc. 2005, 127, 10590. (b) Dong, Z.; Karpowicz, R. J., Jr.; Bai, S.;
Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 14242. (c) Dong,
Z.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 11850.
(5) Lead examples of abiotic foldamers where absolute helicity is
controlled by stereocenters at the termini: (a) Moore, J. S. Acc. Chem. Res.
1997, 30, 402. (b) Mamula, O.; von Zelewsky, A. Coord. Chem. ReV. 2003,
242, 87. (c) Baum, G.; Constable, E. C.; Fenske, D.; Housecroft, C. E.;
Kulke, T.; Neuburger, M.; Zehnder, M. J. Chem. Soc., Dalton Trans. 2000,
945. (d) Yagi, S.; Morinaga, T.; Nomura, T.; Takagishi, T.; Mizutani, T.;
Kitagawa, S.; Ogoshi, H. J. Org. Chem. 2001, 66, 3848. (e) Hofacker, A. L.;
Parquette, J. R. Proc. R. Soc. London, Ser. A. 2010, 466, 1469. (f) Hu,
H.-Y.; Xue, W.; Hu, Z.-Q.; Xiang, J.-F.; Chen, C.-F.; He, S.-G. J. Org.
Chem. 2009, 74, 4949. (g) Naidu, V. R.; Kim, M. C.; Suk, J.-m.; Kim,
H.-J.; Lee, M.; Sim, E.; Jeong, K.-S. Org. Lett. 2008, 10, 5373. (h) Akazome,
M.; Ishii, Y.; Nireki, T.; Ogura, K. Tetrahedron Lett. 2008, 49, 4430. (i)
Petitjean, A.; Cuccia, L. A.; Schmutz, M.; Lehn, J.-M. J. Org. Chem. 2008,
73, 2481. (j) Clayden, J.; Lemie`gre, L.; Morris, G. A.; Pickworth, M.; Snape,
T. J.; Jones, L. H. J. Am. Chem. Soc. 2008, 130, 15193. (k) Hu, H.; Xiang,
J.-F.; Yang, Y.; Chen, C.-F. Org. Lett. 2008, 10, 1275. (l) Li, C.; Wang,
G.; Yi, H.; Jiang, X.; Li, Z.; Wang, R. Org. Lett. 2007, 9, 1797. (m)
Maurizot, V.; Dolain, C.; Huc, I. Eur. J. Org. Chem. 2005, 1293. (n) Dolain,
C.; Jiang, H.; Leger, J.-M.; Guonneau, P.; Huc, I. J. Am. Chem. Soc. 2005,
127, 12943.
Scheme 1. Salicylaldehyde Synthesis
Org. Lett., Vol. 12, No. 18, 2010
4003

compound 5 was readily prepared from commercially avail-
able 4-aminoindan.6
Grignard addition followed by dehydration of compound
5 provided compound 6. Hydrogenation of 6 at 30 psi
provided compound 7, and subsequent deacetylation gave
8. Coupling to benzofuran-8-carbonyl chloride4,7 gave ra-
cemic 9 in excellent yield. Compound 9 was separated on
semipreparative scale using chiral chromatography (Chiral
Technologies, AD column): the slower eluting enantiomer
was determined to have the S-configuration. Ozonolysis of
(S)-9 and (R)-9 generated the enantiomerically pure salicyl-
aldehydes (S)-10 and (R)-10, respectively.
Combination of (S)-10 with 1,2-phenylenediamine and
Ni(OAc)2 produced 3a, which crystallized and was analyzed
by X-ray diffraction. A helical structure was observed with
the terminal methyl group pointing to the outside of the helix.
Upon refinement of Flack parameters based on anomalous
dispersion, it was possible to assign (P)-helicity to the
structure (Figure 3). In solution studies, it was observed that
Figure 4. CD spectrum of 3a.
in solution. However, it cannot be ruled out that another
conformer is not present in small amounts, as complex 3a
may have a barrier to helical inversion that is rapid on the
NMR time scale even at -100 °C. Nonetheless, the large
magnitude of the chiroptical properties implies that the (P)-
helix is the thermodynamically dominant conformation for
3a in solution.
Combination of (R)-9 with (R,R)-trans-cyclohexane-1,2-
diamine and Ni(OAc)2 gave the “matched” complex 3b upon
reaction with Ni(OAc)2 (Scheme 2). In 3b, the diamine and
Scheme 2
.
Synthesis of Matched Complex 3b and Mismatched
Complex 3c
Figure 3
side view.
. (a) Salophen 3a. X-ray structure: (b) top view and (c)
the magnitudes of the specific rotation ([R]25 +1500) and
D
the CD spectrum are both large (Figure 4). The significant
chiroptical properties of complex 3a suggests that there is a
dominant (P)-helix in the solution.
Compound 3a was also analyzed in solution by variable-
1
temperature H NMR (see Supporting Information). In our
prior work on Ni-salen and salophen foldamers, the inter-
conversion between two helical conformers was observed
in VT-NMR experiments with coalescence observed at -10
the end group both bias for (M)-helicity. The structure of
3b was determined by crystallography (Figure 5) and found
to be (M)-helical and structurally analogous to 3a. The
combination of (R)-9 with (R,R)-trans-cyclohexane-1,2-
diamine and Ni(OAc)2 gave the mismatched complex 3c, in
which the chiral diamine biases for an (M)-helix, but the
end group biases for a (P)-helix. The magnitude of the
chiroptical properties of 3b and 3c are similar to those
observed previously in 1 and 2, which were shown to be
dominated by a single helical diastereomer in solution.
to -25 °C.4b,c In contrast, the H NMR spectrum of 3a in
1
CD2Cl2 does not broaden upon cooling to -100 °C. This
may be consistent with a single helical diastereomer for 3a
(6) Nguyen, P.; Corpuz, E.; Heidelbaugh, T. M.; Chow, K.; Garst, M. E.
J. Org. Chem. 2003, 68, 10195.
(7) (a) Stanetty, P.; Pu¨rstinger, G. J. Chem. Res. (M) 1991, 78. (b)
Stanetty, P.; Koller, H.; Pu¨rstinger, G. Monatsh. Chem. 1990, 121, 883. (c)
Toyota, M.; Itoh, K.; Sekizaki, H.; Tanizawa, K. Bioorg. Chem. 1996, 24,
150
.
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Org. Lett., Vol. 12, No. 18, 2010

Figure 5. X-ray crystal structure of 3b. The unit cell contained
two very similar, but symmetry unique molecules.
Consistent with end group control over the absolute sense
of helicity, the chiroptical properties of 3b and 3c are
comparable in magnitude but opposite in sign. Thus, the
Figure 6. CD spectra and specific rotations for 3b and 3c.
specific rotation of 3b is [R]25 -1100, whereas the
D
specific rotation of 3c is [R]25 +970. The CD spectrum
D
(Figure 6) of the matched complex 3b is dominated by
strongly negative dichroisms, as expected for a chiral
structure with (M)-helicity. For 3c, the sign of the
dichroisms is reversed, indicating (P)-helicity.
is predominantly (P)-helical. Overall, these observations are
consistent with helical structures for 3b and 3c in which the
sense of absolute helicity is dominated by the end group and
not the chiral diamine.
In Ni-salen complexes, the long wavelength dichroisms
above 400 nm are attributed to MLCT bands,4,8 and the
intensity of these dichroisms is an indicator of helicity.
As the secondary structures of compounds 1 and 2
(Scheme 1) are established to be highly helical, the CD
spectra4b,c of these compounds serve as convenient bench-
marks for comparison. Complex 3b was compared to 1, as
both have end groups and diamines with matched chirality
(Figure 6). For 3b, the dichroisms at 416 nm (∆ε -35) and
442 nm (∆ε -34) are similar in intensity to the dichroisms
at 421 (∆ε -40) and 446 nm (∆ε -28) in 1, indicating that
3b is predominantly (M)-helical. We also compared the long
wavelength dichroisms of 3c and 2, as both of these
complexes have end groups with mismatched chirality. For
3c, the dichroisms at 416 nm (∆ε 22) and 435 nm (∆ε 28)
are similar in intensity to the dichroisms at 423 (∆ε -26)
and 443 nm (∆ε -28) in 2. This comparison implies that 3c
In conclusion, a new class of metallofoldamers has been
described in which small end groups control the sense of
helical folding, even in a case where the helical bias of the
end group is mismatched relative to that of the internal
diamine. Applications of these and related complexes in
asymmetric catalysis are the focus of current study.
Acknowledgment. For financial support of this work, we
thank the NSF (CHE-0547865). NMR spectra were obtained
with instrumentation supported by NSF CRIF:MU Grant
CHE 0840401.
Supporting Information Available: Full experimental
details, 1H and 13C NMR spectra, and X-ray data for
compounds 3a and 3b. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) (a) Dai, Y.; Katz, T. J. J. Org. Chem. 1997, 62, 1274. (b) Bosnich,
B. J. Am. Chem. Soc. 1968, 90, 627.
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