β-homoalanyl PNAs: Synthesis and indication of higher ordered structures

Article abstract of DOI:10.1002/(SICI)1521-3773(19980216)37:3<302::AID-ANIE302>3.0.CO;2-4

Self-pairing complexes with extraordinarily high stability are formed by β-PNAs with four to six units of the nucleo-β-amino acid 1. The key step in the synthesis is a Mitsunobu reaction between a β-homoserine and a purine derivative.

Full text of DOI:10.1002/(SICI)1521-3773(19980216)37:3<302::AID-ANIE302>3.0.CO;2-4

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CB21EZ, UK (Fax: int. code ‡ (44)1223336-033; e-mail: depos-
it@ccdc.cam.ac.uk).
Experimental Section
[13] A. L. Barra, D. Gatteschi, R. Sessoli, Phys. Rev. B, in press.
[14] P. Polito, A. Rettori, F. Hartmann-Boutron, J. Villain, Phys. Rev. Lett.
1995, 75, 537; A. Garg in Quantum Tunneling of MagnetizationÐ
QTMꢀ94 (Eds.: L. Gunther, B. Barbara); Kluwer, Dordrecht, 1995,
pp. 273 ± 287. A. Garg, Phys. Rev. B 1995, 51, 15161.
Samples of complex 1 were synthesized as previously described.[15]
[Mn12(m3-O)12(m-RCOO)16(H2O)4], R ˆ C6H4-2-Cl, C6H4-2-Br: A slurry of
[Mn12(m3-O)12(m-MeCOO)16(H2O)4] (0.50 g, 0.25 mmol) in CH2Cl2 (50 mL)
was treated with an excess of the corresponding carboxylic acid RCOOH
(8.0 mmol). The mixture was stirred overnight in a closed flask and filtered
to remove any undissolved solid. Hexanes were added to the filtrate until
precipitation of a dark brown solid was observed. The resulting solid was
collected by filtration and the above treatment was repeated. The resulting
filtrate was layered with hexanes (100 ± 150 mL) and stored at room
temperature for several days. Since the acid was highly soluble in diethyl
ether but the Mn12 complex was only partially soluble in this solvent, a
diethyl ether/hexane(s) mixture (1:4) was used to wash the resulting solid,
which was finally dried in air. Recrystallization from CH2Cl2/hexane(s)
gave crystals of complex 2 suitable for X-ray structure analysis. Complex 2:
Elemental analysis calcd for [Mn12O12(O2CC6H4-2-Cl)16(H2O)4] ´ 4H2O,
C112H80O52Cl16Mn12: C 38.58, H 2.30, Cl 16.30; found: C 38.4, H 2.4, Cl
16.2%. FT-IR (KBr): nÄ ˆ 1589, 1560, 1544, 1519, 1473, 1412, 1164, 1054,
750, 725, 702, 651, 614, 552, 522 cm 1. Complex 3: Elemental analysis calcd
[15] T. Lis, Acta Crystallogr. Sect. B 1980, 36, 2042.
b-Homoalanyl PNAs: Synthesis and Indication
of Higher Ordered Structures**
Ulf Diederichsen* and Harald W. Schmitt
Peptide nucleic acids (PNAs) are oligomers possessing a
polyamide backbone in which the nucleobases of DNA/RNA
function as recognition units. The interaction of PNAs with
DNA double strands or RNA have increased in importance
because of their potential use in antigene or antisense
therapy.[1] In contrast, helical[2] or linear PNA ± PNA self-
pairing complexes[3] are uncharged models that are appro-
priate for investigating interactions between nucleobases or
between nucleobases and amino acids[4] and for examining
intercalation.[5] The linearity of two complementary strands is
an important structural feature of our previous investigations
on a-alanyl and a-homoalanyl PNAs. It is based on the 3.6-Š
distance between two consecutive amino acid side chains in
the b-sheet conformation, which is similar to the stacking
distance of base pairs in DNA. Here we describe the synthesis
of Boc-b-homoalanyladenine (1) and its oligomerization to b-
PNAs. UV and CD spectra suggest that the hexamer and
pentamer are self-organized in higher ordered structures,
which can be rationalized from model studies as being
structurally inevitable.
for [Mn12O12(O2CC6H4-2-Br)16(H2O)4] ´ 3H2O, C112H78O51Br46Mn12
32.17, H 1.88, Br 30.64; found: C 32.1, H 1.9, Br 30.7%. FT-IR (KBr):
:
C
nÄ ˆ 1585, 1543, 1518, 1470, 1411, 1161, 1045, 1028, 747, 695, 644, 614, 552,
1
518 cm
.
Received: August 11, 1997 [Z10800IE]
German version: Angew. Chem. 1998, 110, 315 ± 318
Keywords: magnetic properties ´ manganese ´ single-mole-
cule magnets ´ tunneling
[1] B. Schwarzschild, Physics Today 1997, January 17; E. M. Chudnovsky,
Science 1996, 274, 938.
[2] H. J. Eppley, H.-L. Tsai, N. De Vries, K. Folting, G. Christou, D. N.
Hendrickson, J. Am. Chem. Soc. 1995, 117, 301.
[3] R. Sessoli, D. Gatteschi, A. Caneschi, M. A. Novak, Nature 1993, 365,
141; D. Gatteschi, A. Caneschi, L. Pardi, R. Sessoli, Science 1994, 265,
1054.
[4] M. A. Novak, R. Sessoli in Quantum Tunneling of MagnetizationÐ
QTMꢀ94 (Eds: L. Gunther, B. Barbara), Kluwer, Dordrecht, 1995,
pp. 189 ± 207.
[5] R. Sessoli, H.-L. Tsai, A. R. Schake, S. Wang, J. B. Vincent, K. Folting,
D. Gatteschi, G. Christou, D. N. Hendrickson, J. Am. Chem. Soc. 1993,
115, 1804.
[6] A. L. Burion, N. V. Prokof'ev, P. C. E. Stamp, Phys. Rev. Lett. 1996, 76,
3040.
Although there are many methods to synthesize b-amino
acids[6], nucleo-b-amino acids have not been described to date.
The following difficulties have to be considered in linking the
nucleobase to the g position of the side chain (Scheme 1):
1) Nucleobases are poorly soluble in most organic solvents.
2) The desired nucleophilic attack by the N9 nitrogen atom of
[7] F. Lionti, L. Thomas, R. Ballou, B. Barbara, A. Sulpice, R. Sessoli, D.
Matteschi, J. Appl. Phys. 1997, 81, 4608.
[8] D. P. Di Vincenzo, Physica B 1994, 197, 109; D. Loss, D. P. Di Vin-
cenzo, G. Grinstein, D. D. Awschalom, J. F. Smyth, ibid. 1993, 189,
189.
NH2
7
N
regioisomers by
N7/N9 nucleophilic attack
intramolecular
aziridin formation
N
[9] J. R. Friedman, M. P. Sarachik, J. Tejada, R. Ziolo, Phys. Rev. Lett.
1996, 76, 3830.
[10] L. Thomas, F. Lionti, R. Ballou, D. Gatteschi, R. Sessoli, B. Barbara,
Nature 1996, 383, 145.
NH2
N
9
X
N
γ
O
O
N
N
Boc
Boc
N
+
β
OH
N
H
OH
N
α
N
[11] J. Tejada, R. F. Ziolo, X. X. Zhang, Chem. Mater. 1996, 8, 1784.
[12] Crystal data for [Mn12O12(O2CC6H4-o-Cl)16(H2O)4] ´ (CH2Cl2) ´
5(H2O) (complex 2): C113H82Cl18Mn12O56, noncentrosymmetric space
group Pnn2, Tˆ 1758C, a ˆ 18.033(3), b ˆ 22.752(4), c ˆ
17.319(3) Š, Vˆ 7105.62, Z ˆ 2, 6.08 ꢀ 2q ꢀ 458. There were 4197
unique reflections with 3702 unique reflections with F > 2.33s(F);
R(F) ˆ 0.0880; Rw(F) ˆ 0.0872. Several of the 2-chlorobenzoate li-
gands exhibited disorder in the position of the chlorine atom. The
CH2Cl2 and five H2O solvate molecules were present at about 50%
occupancy. Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tion no. CCDC-100605. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
H
H
1
Scheme 1. Side reactions in the synthesis of nucleo-b-amino acid 1.
[*] Dr. U. Diederichsen, H. W. Schmitt
Institut für Organische Chemie und Biochemie der
Technischen Universität München
Lichtenbergstrasse 4, D-85747 Garching (Germany)
Fax: Int. code ‡ (49)892891-3210
E-mail: ud@linda.org.chemie.tu-muenchen.de
[**] This work was supported by the Hermann-Schlosser-Stiftung (Ph.D.
fellowship for H.W.S.) and the Deutsche Forschungsgemeinschaft
(Di 542 2-1). We are grateful to Professor H. Kessler, Garching,
for generous support.
302
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the purine competes with that by the N7 nitrogen atom and
with intramolecular azridine formation. 3) In situ generation
of the leaving group at the g position of the amino acid
appears significant. 4) Arndt ± Eistert homologization of ar-
omatic a-amino acids is expected to proceed with racemiza-
tion.[6d]
The desired coupling to provide a purine attached through
the N9 nitrogen atom to the g position of the b-homoalanine
was performed with the Mitsunobu reaction[7] (Scheme 2).
of a double strand can be recognized in UV melting curves by
the sigmoidal increase in absorption upon raising the temper-
ature. The extraordinary high stability of H-(b-HalA)6-Lys-
NH2 was surprising; it was not possible to detect a melting
point up to 958C (Figure 1). Furthermore, the unusual high
hyperchromicity (Arel. > 40%) is striking. We also observed
this effect with alternating G/C sequences in the alanyl PNA
series for the formation of higher ordered structures.[13] The
shorter oligomers H-(b-HalA)5-Lys-NH2 and H-(b-HalA)4-
Lys-NH2 were synthesized to obtain UV melting curves within
a measurable temperature range. Indeed, the pentamer melts
at Tm ˆ 728C (Arel. > 60%), and the tetramer at Tm ˆ 268C
(Arel. ˆ 16%). The remarkable difference in stability and
hyperchromicity of the two species (Figure 1) indicates that
the structural organizations are not identical. The CD spectra
of pentamer H-(b-HalA)5-Lys-NH2 measured at different
temperatures confirm the UV melting curve. The nucleobases
display a strong Cotton effect when conformationally re-
stricted in a double strand, which begins to diminish at 408C
when the number of flexible single strands increases. The high
stabilities of adenine b-PNA oligomers is only partly the result
of depairing of double strands, because the formation of
higher ordered structures is indicated for the pentamer and
hexamer. b-Homoalanyl PNA has a particular potential for
Cl
N
N
Cl
OH
PPh3, DEAD,
N
THF, RT
N
N
N
O
N
O
+
Boc
27 - 40 %
N
Boc
N
H
OBzl
N
H
OBzl
H
2
4
3
N
NH
N
2
3
N
N
N
N
.
PdO H2O, H2, 10 %
NaN3, 2-methoxy-
ethanol, 60 °C
AcOH, MeOH, RT
N
N
N
O
O
64 %
73 %
Boc
Boc
N
OH
OBzl
N
H
H
50
40
30
20
10
25
20
5
1
H-(b-HalA)4-LysNH2
H-(b-HalA)6-LysNH2
Scheme 2. Synthesis of nucleo-b-amino acid 1: The key step is the
attachment of amino acid with under Mitsunobu conditions
(DEAD ˆ diethyl azodicarboxylate).
2
3
15
Tm > 90 oC, 3 µM
Arel./%
Tm = 26 oC, 5 µM
Arel./%10
5
At room temperature the b-homoserine derivative 2[8] was
added to 6-chloropurine (3) together with the Mitsunobu
reagents. The direct use of adenine was not successful; the 6-
chloropurine nucleo amino acid 4 could be converted into the
azidopurine derivative 5, which then was reduced and
deprotected to yield 1.[9] The presence of the N9 regioisomer
was proven by HMQC and HMBC NMR experiments.[10]
Nucleo amino acid 1 was oligomerized by solid-phase peptide
synthesis (SPPS) on a 4-methylbenzhydrylamine (MBHA) ±
polystyrene support loaded with r-lysine(Z)-OH (Z ˆ ben-
zyloxycarbonyl; lysine was introduced at the C terminus for
solubility reasons). The coupling was activated by O-(7-
azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate (HATU) and proceeded with at least 95% yield.
After the oligomers were purified with HPLC (RP-C18), they
were characterized with electrospray ionization mass spec-
20
40
60
80
20
40
60
T / oC
80
100
T / oC
2
0
70
50
30
10
H-(b-HalA)5-LysNH2
H-(b-HalA)5-LysNH2
60 o
50 o
40 o
30 o
20 o
10 o
C
C
C
C
C
C
Arel./%
Tm = 72 oC, 4 µM
∆e
0
oC
8
20
40
60
80
100
210
320
T / oC
l / nm
Figure 1. UV melting curves of b-PNA oligomers H-(b-HalA)n-Lys-NH2
(n ˆ 4 ± 6) and CD spectra of H-(b-HalA)5-Lys-NH2 (0.1m NaCl, 0.01m
Na2HPO4/H3PO4, pH 7).
1
trometry (ESI-MS) and H NMR spectroscopy.
forming higher associations, as shown by a single-strand
model (Figure 2): A homochiral b-homoalanyl PNA strand
with an extended conformation provides a uniform orienta-
tion of all the side chains, and all adenine bases are aligned in
the same way. This leads to pairing planes based on all
Watson ± Crick and Hoogsteen sites, respectively.
Adenine ± adenine self-pairing can be achieved in three
pairing modes: the symmetrical reverse Watson ± Crick and
reverse Hoogsteen modes as well as the Hoogsteen mode
(Scheme 3). A chain of H-(b-HalA)n-Lys-NH2 oligomers
based on adenine self-pairing with simultaneous participation
Although adenine ± adenine pairing is not observed in
DNA because of the helix topology, it is well established for
oligomer pairing complexes[11] with a linear backbone. High
stability of hexamer double strands based on A ± A base pairs
is known for the homo-DNA series (which contain 2',3'-
dideoxyglucopyranosyl sugar moieties, Tm ˆ 478C)[12] as well
as for a-alanyl PNA (Tm ˆ 318C).[3] We investigated the
pairing of b-homoalanyl PNAs by examining hexamer H-(b-
HalA)6-Lys-NH2
alanine, Lys-NH2 ˆ (R)-lysine amide). Cooperative depairing
(b-HalA ˆ g-(adenin-9-yl)-b-(S)-homo-
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the salts were removed by filtration, the product was purified by flash
chromatography with silica gel (110 g) and hexanes:ethyl acetate (3:1);
yield: 512 mg (73%); m.p. 76 ± 788C, [a]2D5 ˆ 40 (c ˆ 1 in CHCl3); RF ˆ 0.30
(hexanes:ethyl acetate 1:3); 1H NMR (250 MHz, [D6]DMSO): d ˆ 1.15 ±
1.23 (m, 9H, tBu), 2.54 ± 2.86 (m, 2H a-CH2), 4.28 ± 4.42 (m, 2H, g-CH2),
4.44 ± 4.68 (m, 1H, b-CH), 5.09 (s, 2H, CH2 Ph), 7.00 (d, 1H, 3J(H,H) ˆ
8 Hz, NH), 7.33 (m, 5H, Ph), 8.48 (s, 1H, H8), 10.13 (s, 1H, H2); 13C NMR
(62 MHz, [D6]DMSO): d ˆ 27.8, 36.4, 47.5, 47.6, 65.7, 78.0, 119.5, 127.8, 127.9,
‡
128.3, 135.4, 135.9, 142.7, 144.8, 145.4, 154.7, 170.1; MS: m/z: 904.8 (M2H) ,
‡
453.2 (MH) ; elemental analysis calcd for C21H24N8O4: C 55.75, H 5.35, N
24.76; found: C 55.60, H 5.52, N 24.53.
1: A solution of 5 (457 mg, 1.02 mmol) in methanol:acetic acid (9:1,
110 mL) was treated with palladium oxide hydrate (220 mg, 1.80 mmol)
under argon and saturated with hydrogen. After 105 min the catalyst and the
partially precipitated nucleo amino acid were separated by centrifugation,
and the solid phase was extracted several times with ethyl acetate:acetic
acid (9:1). Subsequent flash chromatography (ethyl acetate:methanol:wa-
ter:acetic acid 40:7:3:1). Yield: 218 mg (64%). M.p. 2868C (decomp);
[a]2D5 ˆ 41 (c ˆ 1 in DMSO); RF ˆ 0.36 (ethyl acetate:methanol:water:acetic
acid 10:1:1:0.5, NaCl saturated); 1H NMR (500 MHz, [D6]DMSO): d ˆ
0.95 ± 1.03 (m, 1.5H, tBu), 1.15 ± 1.30 (m, 7.5H, tBu), 2.36 ± 2.52 (m, 2H, a-
CH2), 4.05 ± 4.20 (m, 2H, g-CH2), 4.21 ± 4.30 (m, 1H, b-CH), 6.42 (m, 0.2H,
NH), 6.90 (d, 0.8H, J ˆ 7.1 Hz, NH), 7.13 (s, 2H, NH2), 7.92 (s, 1H, H8), 8.12
(s, 1H, H2); 13C NMR (125 MHz, [D6]DMSO): d ˆ 27.6 (tBu), 37.1 (Ca),
45.8 (Cb), 47.3 (Cg), 77.5 (tBu), 118.3 (C5), 140.6 (C8), 149.5 (C4), 152.0
(C2), 154.5 (CO of Boc), 156.0 (C6), 171.7 (COOH); the 13C NMR signals
were assigned with HMBC and HMQC experiments; MS: m/z: 337.1
Figure 2. Model of a homochiral b-homoalanyl PNA single strand: In the
extended backbone conformation, all nucleobases are uniformly aligned.
This creates a pairing plane at the Watson ± Crick and the Hoogsteen site.
Scheme 3. Possible adenine ± adenine pairing modes.
‡
(MH) ; UV (H2O): lmax ˆ 263 nm (14000).
1
H-(b-HalA)4-Lys-NH2: H NMR (500 MHz, D2O): d ˆ 1.29 ± 1.35 (m, 2H,
Lys), 1.50 ± 1.71 (m, 4H, Lys), 2.00 (m, 1H, Ha), 2.12 (m, 1H, Ha), 2.18 ±
2.38 (m, 4H, Ha), 2.42 (m, 1H, Ha), 2.65 (m, 1H, Ha), 2.85 (m, 2H, He-
Lys), 3.22 ± 3.50 (m, 4H, Hb, Hg), 3.55 (m, 1H, Hb, Hg), 3.63 ± 3.84 (m, 3H,
Hb, Hg), 3.98 (m, 1H, Hb, Hg), 4.11 (m, 1H, Ha-Lys), 4.25 ± 4.35 (m, 2H,
Hb, Hg), 4.42 (m, 1H, Hb, Hg), 7.79 (s, 1H, H2, H8), 7.84 (s, 1H, H2, H8),
7.90 (s, 1H, H2, H8), 7.91 (s, 1H, H2, H8), 7.97 (s, 1H, H2, H8), 7.98 (s, 1H,
of the Watson ± Crick and Hoogsteen site is possibly respon-
sible for the strong aggregation indicated by the melting
curves.
We introduced nucleo amino acid 1 as a new building block
for the synthesis of b-PNA oligomers. b-PNA is a special case
of b-peptides.[14] Nevertheless, differences in structure are
expected because the aggregates of b-PNA are defined by the
b-peptide backbone and base-pair stabilization. The uniform
alignment of all nucleobases in the extended conformation
could be causal for the exceptional self-pairing of adenine
oligomers in higher ordered structures. We are presently
investigating the pairing possibilities and selectivities of the
other canonical nucleobases as well as the influence of
heterochiral base pairs.
H2, H8), 8.00 (s, 1H, H2, H8), 8.02 (s, 1H, H2, H8); MS: m/z: 1018.3
‡
(MH) , 511.0 (MH2)2‡
.
1
H-(b-HalA)5-Lys-NH2: H NMR (500 MHz, D2O): d ˆ 1.21 ± 1.40 (m, 2H,
Lys), 1.50 ± 1.75 (m, 4H, Lys), 2.15 ± 2.40 (m, 7H, Ha), 2.42 ± 2.55 (m, 2H,
Ha), 2.68 (m, 1H, Ha), 2.87 (m, 2H, He-Lys), 3.70 ± 4.50 (m, 16H, Hb, Hg,
‡
Ha-Lys), 7.95 ± 8.20 (m, 10H, H2, H8); MS: m/z: 1236.4 (MH) , 619.0
(MH2)2‡
.
1
H-(b-HalA)6-Lys-NH2: H NMR (500 MHz, D2O): d ˆ 1.25 ± 1.38 (m, 2H,
Lys), 1.50 ± 1.72 (m, 4H, Lys), 2.11 ± 2.40 (m, 9H, Ha), 2.41 ± 2.56 (m, 2H,
Ha), 2.68 (m, 1H, Ha), 2.87 (m, 2H, He-Lys), 3.58 (m, 1H, Hb, Hg), 3.61 ±
3.75 (m, 2H, Hb, Hg), 3.77 ± 3.98 (m, 8H, Hb, Hg), 4.06 (m, 1H, Ha-Lys),
4.10 ± 4.20 (m, 2H, Hb, Hg), 4.24 ± 4.36 (m, 3H, Hb, Hg), 4.38 ± 4.49 (m, 2H,
Hb, Hg), 7.77 (s, 1H, H2, H8), 7.82 (s, 1H, H2, H8), 7.90 (m, 2H, H2, H8),
7.94 (s, 1H, H2, H8), 7.96 (s, 1H, H2, H8), 7.97 (s, 2H, H2, H8), 8.03 (s, 1H,
Experimental Section
H2, H8), 8.04 (s, 1H, H2, H8), 8.07 (s, 1H, H2, H8), 8.08 (s, 1H, H2, H8);
4: DEAD (1.69 g, 14.55 mmol) was added at room temperature under
argon to PPh3 (3.82 g, 14.55 mmol) in THF (18 mL) within 10 min. 6-
Chloropurine (3, 1.45 g, 9.70 mmol) was added, and the suspension heated
to 408C until a clear yellow solution was obtained. A solution of 2 (3.00 g,
9.70 mmol) in THF (10 mL) was added dropwise within 10 min at room
temperature. After the reaction mixture was stirred for 2 d, it was heated
for 4 h at 608C. The product was purified by consecutive flash chromatog-
raphy with hexanes:ethyl acetate (1:3), hexanes:ethyl acetate (1:1), and
hexanes:acetone (7:3); yield: 1.15 g (27%). Further experiments improved
the yield up to 40%. M.p. 131 ± 1328C; a2D5 ˆ 31 (c ˆ 5 in CHCl3); RF ˆ 0.27
(hexanes:acetone 7:3); 1H NMR (250 MHz, CDCl3): d ˆ 1.21 ± 1.45 (m, 9H,
tBu), 2.70 (d, 2H, 3J(H,H) ˆ 6 Hz, a-CH2), 4.33 ± 4.43 (m, 1H, b-CH),
4.43 ± 4.55 (m, 2H, g-CH2), 5.14 (s, 2H, CH2 Ph), 5.30 (m, 1H, NH), 7.35
(m, 5H, Ph), 8.04 (s, 1H, H8), 8.68 (s, 1H, H2); 13C NMR (62 MHz, CDCl3):
d ˆ 28.0, 36.0, 46.5, 47.6, 66.8, 80.1, 128.3, 128.5, 128.6, 131.3, 135.0, 145.7,
‡
MS: m/z: 1455.4 (MH) , 727.9 (MH2)2‡
.
Received: June 26, 1997
Revised version: August 7, 1997 [Z10603IE]
German version: Angew. Chem. 1998, 110, 312 ± 315
Keywords: amino acids ´ Mitsunobu reaction ´ nucleic acids
´ peptide nucleic acids ´ supramolecular chemistsry
[1] a) M. Egholm, O. Buchardt, L. Christensen, C. Behrens, S. M. Freier,
Â
D. A. Driver, R. H. Berg, S. K. Kim, B. Norden, P. E. Nielsen, Nature
1993, 365, 566; b) B. Hyrup, P. E. Nielsen, Bioorg. Med. Chem. 1996, 4,
5.
‡
150.9, 151.8, 152.0, 154.8, 170.4; MS: m/z: 446.3 (MH) ; elemental analysis
Â
[2] P. Wittung, P. E. Nielsen, O. Buchardt, M. Egholm, B. Norden, Nature
calcd for C21H24N5O4Cl: C 56.57, H 5.42, N 15.71; found: C 56.60, H 5.36, N
15.71.
1994, 368, 561.
[3] a) U. Diederichsen, Angew. Chem. 1996, 108, 458; Angew. Chem. Int.
Ed. Engl. 1996, 35, 445; b) U. Diederichsen, H. W. Schmitt,
Tetrahedron Lett. 1996, 37, 475.
5: A solution of 4 (690 mg, 1.547 mmol) and sodium azide (1.10 g,
16.92 mmol) in 2-methoxyethanol (8 mL) was heated for 5 h at 608C. The
solvent was evaporated, and the residue suspended in ethyl acetate. After
[4] U. Diederichsen, D. Weicherding, unpublished results.
304
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such as data storage.[2±8] Redox switches require a) compo-
nents whose structures and physical properties can be turned
on or off electrochemically,[3, 6±8] and b) sufficiently different
optical spectra that allow the individual states to be ad-
dressed.[2, 4] Here we describe a method for generating a redox
switch through redox control of the ligand conformation. This
approach resulted in a novel molecular switch with reprodu-
cible redox-dependent optical properties; the switch should
be easily adaptable to solid-state technology.
[5] U. Diederichsen, Bioorg. Med. Chem. Lett. 1997, 7, 1743.
[6] a) E. Juaristi, D. Quintana, J. Escalante, Aldrichim. Acta 1994, 27, 3;
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Nucleosides Nucleotides 1994, 13, 491.
Our molecular redox switch is based on a) complexes in
which a single metal center can exist in two different oxidation
states, and b) chiral ligands having easily distinguishable
optical properties. Copper(iii) complexes are particularly
suitable since they show fast ligand exchange, which poten-
tiates fast signal interchange. The ligand (S)-N,N-bis[(2-
quinolyl)methyl]-1-(2-quinolyl)ethylamine, (S)-a-MeTQA,
was selected for this study because of the steric hindrance
and strong chromophoric properties presented by the 2-
quinolyl groups and the expected optimal chromophoric
orientation provided by the propellerlike geometry of the
complexes. Reduction of the sterically hindered CuII complex
was anticipated to result in a change in the orientation of the
2-quinolyl arms with respect to the central axis (Scheme 1).
Since the exciton-coupled circular dichroism (ECCD) signal
generated from these complexes is critically dependent upon
the distance and dihedral angle between the planar chromo-
phores,[9] the magnitude of the ECCD spectrum was expected
to vary with the oxidation state of the copper ion.
The preparation of the ligand (S)-a-MeTQA began with
the asymmetric synthesis of (S)-2-(1-aminoethyl)quinoline
from the 2-aminomethylquinoline imine of (‡)-pinanone.[10]
A single recrystallization of the l-(‡)-tartrate salt of the
chiral primary amine yielded the desired product with 99.7%
ee in 19% overall yield. Alkylation of the enantiomerically
pure amine with 2-bromomethylquinoline provided (S)-a-
MeTQA in 81% yield. Copper complexes 1 and 2 were
prepared by mixing homogeneous solutions of the ligand and
the appropriate salt.[11, 12] The UV/Vis spectrum of 2 shows a
[8] Homoserine derivative 2 was obtained in 95% yield by reduction of
the C-terminal carbonyl group of Boc-Asp(Bzl)OH in analogy to G.
Kokotos, Synthesis 1990, 299.
[9] a) Z. Kazimierczuk, H. B. Cottam, G. R. Revankar, R. K. Robins, J.
Am. Chem. Soc. 1994, 106, 6379; b) F. R. Benson, T. W. Hartzel, E. A.
Otten, ibid. 1954, 76, 1858.
[10] H. Kessler, S. Seip in Two-Dimensional NMR Spectroscopy (Eds.:
W. R. Croasmun, R. M. K. Carlson), 2nd ed., VCH, Weinheim, 1994,
p. 619.
[11] a) W. Saenger, Principles of Nucleic Acid Structure, Springer, New
York, 1983; b) I. Berger, C. Kang, A. Fredian, R. Ratliff, R. Moyzis, A.
Rich, Nat. Struct. Biol. 1995, 2, 416; c) K. J. Baejens, H. L. De Bondt,
A. Pardi, S. R. Holbrook, Proc. Natl. Acad. Sci. USA 1996, 93, 12851.
[12] J. Hunziker, H.-J. Roth, M. Böhringer, A. Giger, U. Diederichsen, M.
Göbel, R. Krishnan, B. Jaun, C. Leumann, A. Eschenmoser, Helv.
Chim. Acta 1993, 76, 259.
[13] U. Diederichsen, Angew. Chem. 1997, 109, 1966; Angew. Chem. Int.
Ed. Engl. 1997, 36, 1886.
[14] The preferred conformation of a b-peptide hexamer in pyridine is the
31 helix. For b-peptides, compare with a) D. Seebach, M. Overhand,
F. N. M. Kühnle, B. Martinoni, L. Oberer, U. Hommel, H. Widmer,
Helv. Chim. Acta 1996, 79, 913; b) D. Seebach, P. E. Ciceri, M.
Overhand, B. Jaun, D. Rigo, L. Oberer, U. Hommel, R. Amstutz, H.
Widmer, ibid. 1996, 79, 2043; c) D. H. Appella, L. A. Christianson,
I. L. Karle, D. R. Powell, S. H. Gellman, J. Am. Chem. Soc. 1996, 118,
13071; d) D. H. Appella, L. A. Christianson, D. A. Klein, D. R.
Powell, X. Huang, J. J. Barchi, Jr., S. H. Gellman, Nature 1997, 387,
381. The conformation of b-PNA should not be helical because of the
base-pair distances of 5 Š and the maximum of two bases on top of
each other, which leads to a substantial loss of stacking interactions.
[CuI{(S)-a-MeTQA}](PF6)
1
Redox-Switched Exciton-Coupled Circular
Dichroism: A Novel Strategy for Binary
Molecular Switching**
[CuII{(S)-a-MeTQA}](ClO4)(PF6)
2
d ± d transition at 691 nm (e ˆ 202), which is consistent with a
coordination geometry for the CuII ion that is closer to a
square pyramid than the desired trigonal bipyramid.[11, 13]
However, addition of one equivalent of NH4NCS (to yield
4) resulted in two d ± d bands (719 nm, e ˆ 202; 867 nm, e ˆ
296); this indicates trigonal-bipyramidal geometry.[13] The
color change of 4 from turquoise to green-yellow is due to a
ligand-to-metal charge transfer (LMCT) at 420 nm (e ˆ
445).[14] Cyclic voltammograms of the copper complexes in
acetonitrile or dimethylformamide were well-behaved and
displayed single quasi-reversible one-electron redox waves
(ipa/ipc ꢁ 1).[15]
Steffen Zahn and James W. Canary*
A recent and exciting prospect in the area of information
technology lies in the development of molecular switches that
operate with efficiency, reversibility, and resistance to fa-
tigue.[1] The development of electrochemical switches has
recently attracted much attention due to possible applications
[*] Prof. J. W. Canary, S. Zahn
Department of Chemistry
New York University
New York, NY 10003 (USA)
Fax: Int. code ‡ (1)212260-7905
E-mail: james.canary@nyu.edu
The CD spectra of 1 (A ˆ 174) and 2 (A ˆ 455) displayed
bisignate curves with remarkably large amplitudes (that is,
large positive and negative Cotton effects).[16] The split CD
[**] We thank the National Institutes of Health (GM 49170) for financial
support of this work.
Angew. Chem. Int. Ed. 1998, 37, No. 3
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