Induction of diastereoselectivity in fe(II) Tris(amino acid-bipyridine) complexes

Article abstract of DOI:10.1021/jo001261u

A group of iron(II) tris-bipyridine complexes bearing L-amino acids (L-Lys, L-Phe, L-Ser, L-Val) was prepared to investigate the predetermination of chirality of metal complexes by the chiral amino acid subunits. Noncovalent interactions and solvent polarity seemed to be important factors in inducing diastereoselectivity of the metal complexes. These phenomena were explained by ¹H NMR and CD spectroscopic studies and molecular mechanics calculations.

Full text of DOI:10.1021/jo001261u

5
008
J . Org. Chem. 2001, 66, 5008-5011
In d u ction of Dia ster eoselectivity in F e(II) Tr is(a m in o
a cid -bip yr id in e) Com p lexes
Dae-Ro Ahn, Tae Woo Kim, and J ong-In Hong*,†
School of Chemistry and Molecular Engineering, College of Natural Sciences, Seoul National University,
Seoul, 151-747, Korea
jihong@plaza.snu.ac.kr
Received August 18, 2000
A group of iron(II) tris-bipyridine complexes bearing L-amino acids (L-Lys, L-Phe, L-Ser, L-Val) was
prepared to investigate the predetermination of chirality of metal complexes by the chiral amino
acid subunits. Noncovalent interactions and solvent polarity seemed to be important factors in
1
inducing diastereoselectivity of the metal complexes. These phenomena were explained by H NMR
and CD spectroscopic studies and molecular mechanics calculations.
In tr od u ction
Despite the wide potential application of octahedral
and the solvation effect.10 This paper reports the synthe-
sis and Fe(II) complexing behavior of a series of 2,2′-
bipyridines substituted with L-amino acid derivatives
metal complexes with bipyridine-derived chiral ligands,1
predetermination of chirality at the metal centers has
only recently become a subject of systematic investiga-
tion.2 Mononuclear metal complexes containing more
than one bipyridine ligand in cis configuration have two
forms of helical chirality (∆ and Λ configuration). Pre-
determination of chirality in octahedral metal complexes
can be reached only through diastereoselective processes.
Optically pure complexes can be obtained by incorporat-
(
L-Lys, L-Phe, L-Ser, and L-Val). Circular dichroism (CD)
spectroscopy was used to identify the major compound
of the diastereomeric mixture in each complex and the
1
diastereomeric excess was determined by the H NMR
spectroscopy. In addition, the roles of the amino acid side
chains and solvents in the diastereomeric complex forma-
tion are discussed.
3
Resu lts a n d Discu ssion
ing chiral centers into the ligating chains. Relatively less
successful chiral predetermination with chiral bidentate
bipyridyl ligands has been achieved,4 whereas many
metal complexes showing diastereomeric excess with
Syn th eses of Liga n d s a n d Com p lexes. The synthe-
ses of ligands (3, 4, 5, and 6) and metal complexes (7, 8,
9
, and 10) are outlined in Scheme 1. 1 and 2 were
2
various multidentate ligands (even diastereomerically
11
prepared according to a reported procedure. Ligands (3,
, 5, and 6) were synthesized by adding DIEA (diisopro-
pure compounds showing a complete chiral induction)5
have been reported.
4
pylethylamine) and acid-protected L-amino acid deriva-
tives to a solution of 2 in methylene chloride. Fe(II)
complexes were prepared by mixing iron(II) chloride
tetrahydrate and each ligand (3, 4, 5, and 6) in 5%
methylene chloride/methanol solution as previously
We are interested in generating enantiomerically pure
helical tris(bipyridine)-type complexes by diastereoselec-
tive complexation with three chiral bidentate bipyridyl
ligands, in which chirality comes from L-amino acids
attached on the 5 and 5′ positions of 2,2′-bipyridine-5,5′-
dicarboxylic acid.4 This approach exploits nonbonded
interactions between peripheral chiral appendages on
bidentate chelate units.7 The factors influencing the
chirality induction in the formation of these chiral tris-
10b
described.
a,6
Deter m in a tion of Dia ster eom er ic Excess (d e). The
1
H NMR spectra of the Fe(II) tris(amino acid-bipyridine)
were used to determine the relative ratio between the
5
b,6,12
major and minor isomers using peak intensities,
but
(
bipyridine)-type complexes are noncovalent interactions
they cannot be used to deduce absolute structural infor-
mation. Each of the Fe(II) tris(amino acid-bipyridine)
was examined by CD spectroscopy to determine the
absolute configuration of the major coordination isomer
8
9
such as hydrogen bonds and van der Waals interactions
†
Phone: +82-2-880-6682. Fax: +82-2-889-1568.
(1) (a) Lehn, J .-M. Supramolecular Chemistry: Concepts and Per-
spectives; VCH: Weinheim, 1995. (b) Zelewsky, A. V. Coordination
Compounds in Supramolecular Chemistry; Wiley: Chichester, 1996.
13
in solution. Since the sign of the CD bands in the 300-
(
c) J uris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.;
von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85-277.
2) Knof, U.; von Zelewsky, A. Angew. Chem., Int. Ed. 1999, 38, 302-
22.
(8) Shanzer, A.; Libman, J .; Lifson, S.; Felder, C. E. J . Am. Chem.
Soc. 1986, 108, 7609-7619.
(
3
1
1
(9) Okawa, H.; Tokunaga, H.; Katsuki, T.; Koikawa, M.; Kida, S.
Inorg. Chem. 1988, 27, 4373.
(3) Shanzer, A.; Libman, J .; Lifson, S. Pure Appl. Chem. 1992, 64,
421-1435.
(10) (a) Biscarini, P.; Kuroda, R. Inorg. Chem. Acta 1988, 154, 209.
(b) Breault, G. A.; Hunter, C. A.; Mayers, P. C. J . Am. Chem. Soc. 1998,
120, 3402-3410.
(11) Newkome, G. R.; Gross, J .; Patri, A. K. J . Org. Chem. 1997,
62, 3013-3014.
(12) (a) Kersting, B.; Telford, J . R.; Meyer, M.; Raymond, K. N. J .
Am. Chem. Soc. 1996, 118, 5712-5721. (b) Regnouf-de-Vains, J .-B.;
Lamartine, R.; Fenet, B. Helv. Chim. Acta 1998, 81, 661-669.
(13) Milder, S. J .; Gold, J . S.; Kliger, D. S. J . Am. Chem. Soc. 1986,
108, 8295-8296.
(4) (a) Lieberman, M.; Sasaki, T. J . Am. Chem. Soc. 1991, 113,
470-1471. (b) Weizman, H.; Libman, J .; Shanzer, A. J . Am. Chem.
Soc. 1998, 120, 2188-2189.
(5) (a) Hayoz, P.; von Zelewsky, A.; Stoeckli-Evans, H. J . Am. Chem.
Soc. 1993, 115, 5111-5114. (b) Karpishin, T. B.; Stack, T. D. P.;
Raymond, K. N. J . Am. Chem. Soc. 1993, 115, 6115-6125.
(6) Lieberman, M.; Tabet, M.; Sasaki, T. J . Am. Chem. Soc. 1994,
1
16, 5035-5044.
(7) Okawa, H. Coord. Chem. Rev. 1988, 92, 1.
1
0.1021/jo001261u CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/04/2001

Diastereoselectivity in Fe(II) Tris-bipyridine Complexes
J . Org. Chem., Vol. 66, No. 15, 2001 5009
Sch em e 1
F igu r e 1. Time-dependent isomerization of the Fe(II) com-
plexes in acetone-d at 300 K. The minus sign means that ∆
6
isomer is the major isomer.
Ta ble 1. Deter m in a tion of Con figu r a tion s a n d d e’s by
1
CD a n d H NMR
CD (sign and configuration)a
NMR (de, %)b
F igu r e 2. Circular dichroism spectra of 10 in methanol and
acetone at 300 K.
acetone
methanol
acetone
methanol
c
7
8
9
0
-(∆)
0
-80
0
71
-1
-48
32
0
-(∆)
+(Λ)
+(Λ)
+(Λ)
-(∆)
1
-47
24
a
The major isomers were identified by the CD sign in the 300-
1
3
b
3
40 nm range.
The de’s were determined by comparing the
peak intensities of the 6-Py-H proton or chiral methine proton in
1
c
the H NMR spectrum; de ) % of Λ isomer - % of ∆ isomer. The
minus (-) sign indicates that the configuration of the major isomer
is ∆.
3
40 nm range is known to be due to chirality at the metal
center, the absolute configurations of the major isomers
of the Fe(II) complexes in solution can be deduced by
comparison of their CD spectra with the reported CD
in that region.4
,6,13
The results
data of Fe(II)(bipyridine)
are summarized in Table 1.
3
F igu r e 3. Circular dichroism spectra of 7 and 10 in acetone
at 300 K.
All Fe(II) complexes were equilibrated between the
major and minor isomers in each solvent by storage for
removed the CD bands of Fe(II)(peptide-bipyridine)
3
5
days before CD and NMR measurements were per-
between 300 and 350 nm, which indicated that the folded
protein structure rather than the mere proximity of
L-amino acids appended on bipyridine should be respon-
formed. It emerged that about 2 days were required to
reach equilibrium for each solvent (Figure 1). The major
4
a
isomers were identified in each solvent by the CD sign
sible for the chirality induction at the metal center.
in the 300-340 nm range4
,6,13
(Figures 2 and 3), and the
However, our results suggest that noncovalent intra- and/
or interligand interactions between L-amino acid units
should result in the induction of a de in each complex.
As shown in Table 1, not only the intra- and/or
interligand interactions but also solvation effects should
play important roles in the determination of de’s and
major isomers. Compounds 7 and 9, which contain
hydrogen bond donors and acceptors in the side chains
of the amino acid units, showed a higher de in acetone
than in methanol which precludes the formation of
hydrogen bonds. Since hydrogen bonds between L-amino
acid moieties are dependent on the polarity of a solvent,
relative abundance of the diastereomeric coordination
isomers in each solvent was determined by comparing
the peak intensities of the 6-Py-H proton or chiral
1
methine proton in the H NMR spectrum (Figure 4); the
results are also summarized in Table 1.
The CD signals also appear in the metal-to-ligand
charge-transfer region of the Fe(II) complexes (Figure 3),
showing positive bands at around 583 nm. This implies
that the Fe(II) tris(amino acid-bipyridine) complexes are
formed. Sasaki and co-workers showed that a strong
denaturant (6 M guanidine hydrochloride) completely

5
010 J . Org. Chem., Vol. 66, No. 15, 2001
Ahn et al.
tion of Fe(II) trischelate complexes by amino acid groups
is effective.
We have investigated the structural origin of the
induced diastereoselectivity of 9 by molecular modeling
studies. The X-ray crystal structure of Fe(II) tris-bi-
pyridine was retrieved from the Cambridge Crystal-
lographic Database and used as a starting point for
molecular mechanics calculations.14 Six L-Ser methyl
esters were attached on the 5 and 5′ positions of bipyri-
dine ligands through amide bonds (see 9 of Scheme 1).
Conformational searches on ∆ and Λ complexes of 9 were
carried out using the MacroModel15 implementation of
the Amber force field and constraining the Fe(II) tris-
bipyridine core to the X-ray structure geometry. The
energy difference of the two diastereomers seems to
originate from the different numbers of H-bonds and van
der Waals repulsive interactions between intra- and/or
interligand amino acid side chains. Figure 5 showed that
the lowest energy conformation of the Λ isomer (-925.3
kJ /mol) has 6 intraligand hydrogen bonds and that of the
F igu r e 4. 1H NMR spectrum of 9 in acetone-d
at 300 K.
6
solvents should play an important role in the predeter-
mination of chirality at the metal center. Difficulty in
forming hydrogen bonds due to the nonpolar side chains
of L-amino acid units of 8 and 10 presumably resulted in
lower de’s compared to 7 and 9. van der Waals interac-
tions between the nonpolar side chains of L-amino acid
units of 8 and 10 may be responsible for the different
extent of induction of de’s in 8 and 10. However, there
exist possible explanations for the influence of hydrogen
bonds on the predetermination of chirality of 7 and 9. A
cosolvent system (acetone/methanol, v/v, 1:1) was used
to investigate the role of the solvent and the participation
of hydrogen bonds in the chirality induction. 7 and 9 in
that solvent system exhibited values of de between those
for acetone and methanol. (7, -45%; 9, 47%). This result
shows that hydrogen bonds dependent on the solvent
polarity play an important role in inducing de. Therefore,
we believe that the hydrogen bonding interaction and/or
van der Waal interactions and the solvation effect should
play a cooperative role in the determination of de.
Consequently, this result indicates that the chiral induc-
∆
isomer (-849.1 kJ /mol) has 4 intraligand hydrogen
bonds and 1 interligand hydrogen bond. The diastereo-
selectivity of 9 probably does not arise from favorable
hydrogen bonding interactions within the Λ isomer
formed to a greater extent but rather through destabi-
lization of the ∆ isomer formed to a lesser extent. Though
the structures shown in Figure 5 may not be the optimal
conformations, they show representative conformations
populated to a significant extent.
Con clu sion . We have prepared a group of Fe(II) tris-
bipyridine complexes bearing L-amino acids (L-Lys, L-Phe,
L-Ser, L-Val) to investigate the induction of diastereo-
selectivity of metal complexes by the chiral amino acid
subunits. Noncovalent interactions such as hydrogen
bonding, steric interactions, and the solvation effect
seemed to be important factors in determining the
diastereoselectivity of the metal complexes. These phe-
F igu r e 5. The lowest-energy conformations of Λ-9 (left) and ∆-9 (right). Hydrogens except NH and OH have been omitted for
clarity.

Diastereoselectivity in Fe(II) Tris-bipyridine Complexes
J . Org. Chem., Vol. 66, No. 15, 2001 5011
1
nomena were explained by H NMR and CD spectroscopic
5,5′-Di-L-P h e-2,2′-bip yr id in e (4) a n d Ir on (II)tr is(5,5′-d i-
L-P h e-2,2′-bip yr id yl) Dich lor id e (8). Purification by column
studies and molecular mechanics calculations.
chromatography (CH
of 4 as a white solid: 1H NMR (300 MHz, CDCl
dd, J ) 24.6 Hz, J ) 14.1 Hz, PhCH ), 3.74 (6H, s, COCH
.05 (2H, dd, J ) 13 Hz, J ) 5.6 Hz, -NCHCO -), 6.64 (2H,
3
OH/CH
2
Cl
2
1:20) afforded 130 mg (56%)
) δ 3.23 (4H,
),
3
Exp er im en ta l Section
1
2
2
3
5
1
2
2
All reagents were used as received without further purifica-
tion. All solvents were purified by known standard procedures.
was prepared according to a literature procedure. NMR
d, J ) 7.5 Hz, -NHCO-), 7,19 (10H, m, PhH), 8.10 (2H, d, J
) 8.1 Hz, 3-pyH), 8.46 (2H, d, J ) 8.4 Hz,4-pyH), 8.94 (2H, s,
1
1
1
6-pyH); 13C NMR (75 MHz, CDCl
) δ 38.12, 53.0, 54.0, 121.5,
1
13
3
spectra were recorded at 300 MHz ( H) and 75 MHz ( C) using
a Bruker AMX-300 spectrometer. Chemical shift values are
reported in ppm using known chemical shift values of residual
nondeuterated solvent peaks as a reference. CD spectra were
collected on a J ASCO J -720 spectropolarimeter. Elemental
analyses were performed by the Inter-University center for
Natural Science Research Facilities at Seoul National Uni-
versity.
Gen er a l P r oced u r e for th e Liga n d Syn th eses. Thionyl
chloride (10 mL) was added to 100 mg (0.41 mmol) of 5,5′-
dicarboxy-2,2′-bipyridyl with stirring and was refluxed for 3
h. After cooling the reaction mixture, excess thionyl chloride
was removed in vacuo to give the diacid chloride which was
used without further purification. To a solution of the above
diacid chloride and DIEA (1 mL) in methylene chloride was
added C-protected L-amino acid methyl ester hydrochloride (1.6
mmol), and the mixture was stirred at room temperature for
1
1
27.8, 129.2, 129.7, 130.0, 136.1, 136.3, 148.3, 157.7, 165.5,
72.3. Anal. Calcd for C32 : C, 67.83; H, 5.34; N, 9.89.
30 4 6
H N O
Found: C, 66.66; H, 5.34; N, 9.91.
8
was prepared by the general procedure: UV/vis (CH Cl )
2 2
-
1
-1
+
λ
max (ꢀ, M cm ) ) 308 (91253), 562 nm (5646); MS (ES )
-
+
- 2+
m/z 1791.1 ([M - Cl ] , 7%), 878.0 ([M - 2Cl ] , 100%). Anal.
Calcd for C96 18FeCl C, 63.13; H, 4.97; N, 9.20.
Found: C, 63.31; H, 5.01; N, 9.05.
,5′-Di-L-Ser -2,2′-bip yr id in e (5) a n d Ir on (II)tr is(5,5′-d i-
L-Ser -2,2′-bip yr id yl) Dich lor id e (9). Purification by column
chromatography (CH OH/CH Cl 1:10) and recrystallization
) afforded 136 mg (74%) of 5 as a white solid: H NMR
300 MHz, DMSO-d ) δ 3.67 (6H, s, CO CH ), 3.83 (4H, d, J )
.4 Hz, CH OH), 4.59 (2H, dd, J ) 15.5 Hz, J ) 5.4 Hz,
NCHCO -), 5.13 (2H, t, J ) 6.0 Hz, OH), 8.42 (2H, d, J )
.3 Hz, 3-pyH), 8.55 (2H, d, J ) 8.4 Hz, 4-pyH) 9.01 (2H, d, J
7.5 Hz, NHCO-), 9.17 (2H, s, 6-pyH); 13C NMR (75 MHz,
DMSO-d ) δ 171.7, 165.7, 157.4, 149.6, 137.5, 130.5, 121.5,
1.7, 56.5, 52.8; MS (FAB ) m/z 447 [M + H] . Anal. Calcd for
: C, 53.81; H, 4.97; N, 12.55. Found: C, 54.08; H,
.01; N, 12.54.
was prepared by the general procedure: UV/vis (CH
H
90
N
12
O
2
:
5
3
2
2
1
2 2
(CH Cl
(
6
2
3
5
2
1
2
-
8
2
)
1
8 h. The reaction mixture was washed with a saturated
aqueous NaHCO solution and with brine. Solvent removal
6
3
+
+
6
followed by trituration with diethyl ether afforded the desired
product as an amorphous solid. The white solid was further
purified by column chromatography or recrystallization.
Gen er a l P r oced u r e for th e Ir on (II) Com p lex Syn th e-
ses. A third equivalent of iron(II) chloride tetrahydrate was
mixed with each ligand in 5% CH Cl /methanol. The solvent
2 2
was removed to give the corresponding iron(II) complex in
quantitative yield.
20 22 4 8
C H N O
5
9
2 2
Cl )
-
1
-1
+
λ
max (ꢀ, M cm ) ) 308 (31908), 569 nm (2639); MS (ES )
m/z 1430.5 ([M - Cl ] , 1%), 697.5 ([M - 2Cl ] , 100%). Anal.
-
+
- 2+
Calcd for C60
Found: C, 47.42; H, 4.81; N, 11.04.
,5′-Di-L-Va l-2,2′-bip yr id in e (6) a n d Ir on (II)tr is(5,5′-d i-
L-Va l-2,2′-bip yr id yl) Dich lor id e (10). Purification by column
chromatography (CH OH/CH Cl 1:20) afforded 136 mg (71%)
of 6 as a white solid: 1H NMR (300 MHz, CDCl
) δ 1.03 (12H,
m, (CH C), 2.32 (2H, dd, J ) 6.9 Hz, Me CH),
.81 (6H, s, CO CH ), 4.82 (2H, dd, J ) 8.4 Hz, J ) 4.8 Hz,
NCHCO-), 6.70 (2H, d, J ) 8.1 Hz, -NHCO-), 8.25 (2H, d,
H
66Cl
2
FeN12
O
24‚3H
2
O: C, 47.41; H, 4.77; N, 11.06.
5
5
,5′-Di-L-Lys-2,2′-bip yr id in e (3) a n d Ir on (II)tr is(5,5′-d i-
L-Lys-2,2′-bip yr id yl) Dich lor id e (7). Purification by column
chromatography (CH OH/CH Cl 1:20 to 1:10) and recrystal-
lization (CH OH/CH Cl /Et O 20:1:5) afforded 80 mg (25%) of
as a white solid: H NMR (300 MHz, DMSO-d ) δ 1.42 (8H,
m, -CH CH -), 1.83 (4H, m, -EtCH CHN-), 2.99 (4H, m,
EtCH CHN-), 3.66 (6H, s, CO CH ), 4.44 (2H, t, J ) 14.6
Hz, -CHN-), 4.98 (4H, s, PhCH ), 7.34 (10H, m, PhH), 8.42
2H, d, J ) 10.5 Hz, 3-pyH), 8.54 (2H, d, J ) 8.1 Hz, 4-pyH),
3
2
2
3
2
2
3
3
2
2
2
3
)
2
1
) 11.7 Hz, J
2
2
1
3
6
3
-
2
3
1
2
2
2
2
-
2
2
3
J ) 7.5 Hz, 3-pyH), 8.59 (2H, d, J ) 8.4 Hz, 4-pyH), 9.12 (2H,
2
s, 6-pyH); 13C NMR (75 MHz, CDCl
8.1, 121.4, 130.2, 136.3, 148.4, 157.6, 165.9, 172.8. Anal. Calcd
for C24 : C, 61.26; H, 6.43; N, 11.91. Found: C, 61.35;
H, 6.50; N, 12.00.
2
0 was prepared by the general procedure: UV/vis (CH -
3
) δ 18.5, 19.4, 31.9, 52.8,
(
5
9
3
1
.16 (2H, s, 6-pyH); 13C NMR (75 MHz, DMSO-d
1.0, 52.8, 53.5, 53.6, 65.9, 128.5, 129.2, 130.5, 137.5, 138.1,
48 6 10
49.6, 156.9, 157.3, 165.7, 173.4. Anal. Calcd for C42H N O :
6
) δ 23.8, 29.8,
30 4 6
H N O
1
C, 63.30; H, 6.07; N, 10.55. Found: C, 63.26; H, 5.81; N, 10.52.
-
1
-1
+
Cl
m/z 1502.6 ([M - Cl ] ; 10%), 733.7 ([M - 2Cl ] ; 80%). Anal.
Calcd for C72 C, 56.22; H, 5.90, N, 10.93.
2
) λmax (ꢀ, M cm ) ) 311 (62544), 565 nm (8738); MS (ES )
7
was prepared by the general procedure: UV/vis (CH Cl )
2
2
+
-
+
- 2+
-
1
-1
λ
max (ꢀ, M cm ) ) 307 (49438), 562 nm (4594); MS (ES )
H
2 18
90Cl FeN12O :
-
2+
m/z 1222.9 ([M - 2Cl ] , 100%). Anal. Calcd for C126
H
6
144
-
F
12
-
Found: C, 55.91; H, 6.01; N, 10.79.
-
FeN18
O
30
P
2
(counter anion Cl was replaced with PF
): C,
5
5.30; H, 5.30; N, 9.21. Found: C, 54.96; H, 5.42; N, 8.92.
Ack n ow led gm en t. Financial support from CMDS
(
KOSEF) is gratefully acknowledged. T.W.K. thanks the
(
14) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J . Chem. Inf.
Comput. Sci. 1996, 36, 746-749.
15) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Ministry of Education for the BK 21 postdoctral
fellowship.
(
Lipton, M.; Caufield. C.; Chang, G.; Hendrikson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440-467.
J O001261U