Helical chirality induction in zinc bilindiones by amino acid esters and amines

Article abstract of DOI:10.1021/jo980819j

Complexation of α-amino acid esters, β-amino ethers, and amines with a series of zinc 1,19-bilindione derivatives was studied, particularly focusing on the helical chirality induction in the bilindione framework triggered by the binding of chiral guests. Comparative studies of binding and helical chirality induction indicated that binding and chiral induction were markedly affected by polar substituents present in both zinc bilindiones and guests. 2-Hydroxyethyl groups at the 2,18-positions of zinc bilindione largely assisted the binding of amines and amino acid esters but not the chiral induction. 19O-Alkylation of the zinc bilindiones had inhibitory effects on the binding but enhanced efficiency of helical chirality induction. The enantiomeric excess of 19O-alkyl zinc bilindione complexed with L-Trp-OMe in CD₂Cl₂ was 73% at 223 K. A COOR group and an aromatic group in the guest promoted helical chirality induction of 19O-alkylated zinc bilindiones. The patterns of ¹H NMR complexation-induced shifts of zinc bilindiones and guests and a molecular modeling study of the complexes showed that electrostatic repulsion between the COOR group of amino acid esters and the lactam ring of zinc bilindiones, and stacking of the side chain groups of amino acid esters on the C ring of zinc bilindione made a significant contribution to efficient helical chirality induction.

Full text of DOI:10.1021/jo980819j

J . Org. Chem. 1998, 63, 8769-8784
8769
Helica l Ch ir a lity In d u ction in Zin c Bilin d ion es by Am in o Acid
Ester s a n d Am in es
Tadashi Mizutani,*,1 Shigeyuki Yagi,2 Atsushi Honmaru,1 Shinji Murakami,2
Masaru Furusyo,3 Toru Takagishi,2 and Hisanobu Ogoshi*,1,4
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501 J apan, Department of Applied Materials Science,
Osaka Prefecture University, Gakuen-cho, Sakai, Osaka 599-8531 J apan, CAE Research Center,
Sumitomo Electric, Ltd., Hikari-dai 1-7, Seika-cho, Souraku-gun, Kyoto 619-0237 J apan, and
Fukui National College of Technology, Geshi, Sabae, Fukui 916-0064 J apan
Received April 30, 1998
Complexation of R-amino acid esters, â-amino ethers, and amines with a series of zinc 1,19-bilindione
derivatives was studied, particularly focusing on the helical chirality induction in the bilindione
framework triggered by the binding of chiral guests. Comparative studies of binding and helical
chirality induction indicated that binding and chiral induction were markedly affected by polar
substituents present in both zinc bilindiones and guests. 2-Hydroxyethyl groups at the 2,18-
positions of zinc bilindione largely assisted the binding of amines and amino acid esters but not
the chiral induction. 19O-Alkylation of the zinc bilindiones had inhibitory effects on the binding
but enhanced efficiency of helical chirality induction. The enantiomeric excess of 19O-alkyl zinc
bilindione complexed with L-Trp-OMe in CD2Cl2 was 73% at 223 K. A COOR group and an aromatic
group in the guest promoted helical chirality induction of 19O-alkylated zinc bilindiones. The
1
patterns of H NMR complexation-induced shifts of zinc bilindiones and guests and a molecular
modeling study of the complexes showed that electrostatic repulsion between the COOR group of
amino acid esters and the lactam ring of zinc bilindiones, and stacking of the side chain groups of
amino acid esters on the C ring of zinc bilindione made a significant contribution to efficient helical
chirality induction.
Conformational changes induced by molecular recogni-
tion are closely related to the functions of many biological
processes as seen in allosteric enzymes, for example. To
elucidate the nature of interactions inducing conforma-
tional changes in a model system, a flexible host with
well-defined conformations5 is required. The zinc com-
plexes of 1,19-bilindione derivatives (ZnBD) have two
degenerate helical conformations with right-handed he-
licity (P-form) and left-handed helicity (M-form),6 which
are rapidly interconverting in a solution.7 By addition
of a chiral guest, the conformation of ZnBD can be driven
to preferred chirality.8-11 Helical chirality induction has
two important implications. First, helical structures are
seen in proteins and DNAs as a structural motif, and
their helical sense is ultimately determined by the
chirality of constituent monomers. Therefore, the favor-
able combination of point chirality of a monomer and
helical chirality of the resultant polymer should be
important for stability of such highly organized biomol-
ecules.12,13 Second, understanding of the mechanism of
helical chirality induction would lead to the utilization
of helical molecules as an auxiliary group for asymmetric
synthesis14 or as a chirality probe.15 The helical chirality
induction by a chiral guest having only one chiral carbon
attracts interest, since such a system can be a simplest
model for helical structure formation from simpler chiral-
ity.
For the classification of chirality, point chirality is only
one of chemical structural feature, while helical chirality
is functional in the sense that it will determine the
motional direction, for instance. Understanding the
mechanism of point chirality-helical chirality intercon-
version is thus important from the view of the structure-
function relationship. We report here that chiral R-amino
(1) Kyoto University.
(2) Osaka Prefecture University.
(3) Sumitomo Electric, Ltd.
(4) Fukui National College of Technology.
(5) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1992, 31, 1124-
1134.
(6) (a) Bonfiglio, J . V.; Bonnett, R.; Hursthouse, M. B.; Malik, K.
M. J . Chem. Soc., Chem. Commun. 1977, 83-84. (b) Balch, A. L.;
Mazzanti, M.; Noll, B. C.; Olmstead, N. M. J . Am. Chem. Soc. 1994,
116, 9114.
(7) Lehner, H.; Riemer, W.; Schaffner, K. Liebigs Ann. Chem. 1979,
1798.
(8) (a) Lightner, D. A.; Gawronski, J . K.; Wijekoon, W. M. D. J . Am.
Chem. Soc. 1987, 109, 6354. (b) Krois, D. Tetrahedron 1993, 49, 8855-
8864.
(11) For chirally bridged biliverdins, see: (a) Krois, D.; Lehner, H.
J . Chem. Soc., Perkin Trans. 2 1989, 2085-2090. (b) Krois, D.; Lehner,
H. J . Chem. Soc., Perkin Trans. 1 1989, 2179-2185. (c) Krois, D.;
Lehner, H. J . Chem. Soc., Perkin Trans. 2 1993, 1351-1360. (d) Krois,
D.; Lehner, H. J . Chem. Soc., Perkin Trans. 2. 1993, 1837-1840.
(12) Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook,
R.; Lifson, S. Science 1995, 268, 1860.
(9) For chiral induction in biliverdin by complexation with proteins,
see: (a) Huber, R.; Schneider, M.; Mayr, I.; Muller, R.; Deutzmann,
R.; Suter, F.; Zuber, H.; Falk, H.; Kayser, H. J . Mol. Biol. 1987, 198,
499-513. (b) Marko, H.; Mueller, N.; Falk, H. Monatsh. Chem. 1989,
120, 163. (c) Trull, F. R.; Ibars, O.; Lightner, D. A. Arch. Biochem.
Biophys. 1992, 298, 710-14. (d) Wagner, U. G.; Muller, N.; Schmitzberg-
er, W.; Falk, H.; Kratky, C. J . Mol. Biol. 1995, 247, 326-337.
(10) For biliverdin bearing chiral peptides via a covalent bond, see:
(a) Krois, D.; Lehner, H. J . Chem. Soc., Perkin Trans. 2 1987, 219-
225. (b) Krois, D.; Lehner, H. J . Chem. Soc., Perkin Trans. 2 1987,
1523-1526. (c) Krois, D.; Lehner, H. J . Chem. Soc., Perkin Trans 2
1990, 1745-1755.
(13) For review of supramolecular chemistry of helical molecules,
see: Piguet, C.; Bernardinelli, G.; Hopfgartner, G. Chem. Rev. 1997,
97, 2005-2062.
(14) Reetz, M. T.; Beuttenmu¨ller, E. W.; Goddard, R. Tetrahedron
Lett. 1997, 38, 3211-3214.
(15) Yashima, E.; Matsushima, T.; Okamoto, Y. J . Am. Chem. Soc.
1997, 119, 6345-6359.
10.1021/jo980819j CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/01/1998

8770 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
Sch em e 1
acid esters, â-amino ethers, and amines induced helical
chirality in a series of ZnBDs upon complexation.16
Forces that effectively induce chirality were elucidated
on the basis of systematic investigations on the complex-
ation equilibria by use of variable-temperature NMR,
circular dichroism (CD), and UV-vis spectroscopies and
molecular modeling studies.
15c, and 15e, were similarly prepared. To convert
bilindione 15 to 19O-alkyl bilindione 17, reactions de-
veloped by Fuhrhop18 were employed. Thus, bilindione
15 was reacted with acetic anhydride to afford the
oxoniaporphyrin 16, which was readily cleaved by a
nucleophilic attack of alkoxide ions and metalated to yield
the zinc complexes of 19O-alkylated bilindiones 4-8. For
the preparation of 5 and 6, 1 equiv of a methoxide ion
afforded 6 and excess methoxide afforded 5. ZnBDs 1-8
Resu lts a n d Discu ssion
1
were characterized by H NMR, IR, UV-vis, and high-
Zinc bilindiones 1-8 were prepared according to the
Lightner’s route (Schemes 1 and 2).17 Dipyrrole 14 was
resolution mass spectroscopies and elemental analyses.
Bin d in g of r-Am in o Acid Ester s, â-Am in o Eth er s,
a n d Am in es by a Ser ies of Zin c Bilin d ion es. UV-
vis spectral changes of ZnBDs in CH2Cl2 and CHCl3 at
288 K upon addition of R-amino acid esters, â-amino
alcohol methyl ethers, and amines exhibited saturation
behaviors, indicating that these amines were complexed
with ZnBDs. As representative examples, UV-vis spec-
tral changes of 2 in CH2Cl2 upon addition of L-Trp-OMe
and of 4 in CH2Cl2 upon addition of L-Leu-OMe are shown
in Figure 1. The binding constants were determined by
least-squares analysis of the absorbance changes at 346
and 402 nm for 1-3 (1.25 × 10-5-4.51 × 10-5 M) and at
702 and 770 nm for 4-8 (2.97 × 10-5-4.50 × 10-5 M) as
a function of guest concentrations 0-0.85 mM for 1-3
and 0-171 mM for 4-8 and are summarized in Table 1.
The spectral changes showed isosbestic points (at 378,
458, and 678 nm for 1, 370 and 446 nm for 2, 322, 378,
and 460 nm for 3, and 320-322 and 796-816 nm for
4-8) and fitting of the changes to the calculated curve
based on 1:1 complexation was satisfactory.
prepared from trialkylpyrrole 11. Coupling of 14b
yielded O-acetylated compound 15b, which was acid-
hydrolyzed to give bilindione 15c. Other bilindiones, 15a ,
(18) (a) Fuhrhop, J .-H.; Salek, A.; Subramanian, J .; Mengersen, C.;
Besecke, S. Liebigs Ann. Chem. 1975, 1131-1147. (b) Fuhrhop, J .-H.;
Kruger, P.; Sheldrick, W. S. Liebigs Ann. Chem. 1977, 339. The
oxoniaporphyrin was then cleaved to yield a 19-methoxy-1-bilinone
derivative: (c) Fuhrhop, J .-H.; Kruger, P. Liebigs Ann. Chem. 1977,
360.
(16) For preliminary account of this work, see: Mizutani, T.; Yagi,
S.; Honmaru, A.; Ogoshi, H. J . Am. Chem. Soc. 1996, 118, 5318-5319.
(17) (a) Shrout, D. P.; Lightner, D. A. Synthesis 1990, 1062. (b)
Shrout, D. P.; Puzicha, G.; Lightner, D. A. Synthesis 1992, 328.

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8771
Sch em e 2
F igu r e 1. UV-vis spectral changes of (a) a solution of 2 (2.26
× 10-5 M) in CH2Cl2 upon addition of L-Trp-OMe (0, 3.12 ×
10-6, 6.22 × 10-6, 1.38 × 10-5, 1.83 × 10-5, 2.99 × 10-5, 5.95
× 10-5, 1.18 × 10-4, and 1.61 × 10-4 M) at 288 K and (b) a
solution of 4 (3.79 × 10-5 M) in CH2Cl2 upon addition of L-Leu-
OMe (0, 8.16 × 10-4, 2.42 × 10-3, 4.78 × 10-3, 7.81 × 10-3
1.55 × 10-2, 3.08 × 10-2, and 8.20 × 10-2 M) at 288 K.
,
zinc bilindiones 1-3 were less stable than 4-8 in CH2-
Cl2 and CHCl3 solutions: 1-3 with a 19-OH group were
gradually demetalated in a few hours and the demeta-
lation was suppressed by the addition of amino acid
esters or amines. No demetalation was observed for 19O-
alkylated ZnBDs 4-8 within a few days in the solution.
The binding constants for amines and amino acid
esters showed a considerable diversity depending on the
combinations of substituents at the 2,18-positions (R1)
and the 19O-position (R2). The effects of the substituents
can be summarized as follows. (1) The 2-hydroxyethyl
groups at the 2,18-positions strongly enhanced the bind-
ing affinity of ZnBDs, and the binding constants of guests
by 2 were increased by a factor of 10 as compared to the
corresponding binding constants of 1. (2) Protection of
the hydroxy groups by acetyl groups reduced the binding
constants to the magnitude comparable to those of parent
For a comparative study, eight zinc bilindiones (1-8)
were used as hosts. ZnBDs 1-3 have a lactim OH group,
while 4-7 and 8 have a methyl group and an isopropyl
group on the lactim oxygen, respectively. The substitu-
ents on the A- and D-rings are also varied: 1, 4, and 8
have 2,18-dimethyl, 2 and 5 have 2,18-bis(2-hydroxy-
ethyl), and 3 and 6 have 2,18-bis(2-acetoxyethyl) groups.
Guests used were methyl, dimethyl, benzyl, or naphth-
ylmethyl esters of R-amino acids, several chiral amines
18-22, and â-amino alcohol methyl ethers 23-24.19 The
(19) Guests used and their abbreviations: glycine methyl ester (Gly-
OMe), alanine methyl ester (Ala-OMe), valine methyl ester (Val-OMe),
leucine methyl ester (Leu-OMe), leucine benzyl ester (Leu-OBz), leucine
1-naphthylmethyl ester (Leu-ONp), isoleucine methyl ester (Ile-OMe),
methionine methyl ester (Met-OMe), aspartic acid dimethyl ester (Asp-
(OMe)2), glutamic acid dimethyl ester (Glu-(OMe)2), phenylalanine
methyl ester (Phe-OMe), tryptophan methyl ester (Trp-OMe), phe-
nylglycine methyl ester (PhGly-OMe), and proline methyl ester (Pro-
OMe).

8772 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
Ta ble 1. Bin d in g Con sta n ts (K288, M-1) for a Ser ies of Zin c Bilin d ion e Der iva tives (1-8) of Va r iou s Am in o Acid Ester s
a n d Am in es in CH2Cl2 a t 288 Ka ,b
guest
1
2
3
4
5
6
7
8
L-Ala-OMe
L-Val-OMe
L-Leu-OMe
L-Ile-OMe
L-Met-OMe
L-Asp-(OMe)2
L-Glu-(OMe)2
L-Phe-OMe
L-Trp-OMe
D-PhGly-OMe
(R)-18
3480
3410
4780
4560
1770
34400
29700
45500
45500
18600
16700
11600
29000
89700d
14300
190000
368000
>106
4170
3740
4750
3960
1760
2850
636
4490
13700
4150
13760
37700
331700
f
90
55
106
91
66
53
230
177
271
248
161
145
111
231
631
200
546
882
1980
f
194
119
210
200
143
128
88
108
191
153
415
631
1330
f
99
67
111
109
80
70
53
117
g
78
79
41
98
64
49
44
33
72
64
1640
890
20
96
3690
7010c
1940
115
76
205
296
600
454
55
13700e
21600
277000
79700
209
324
661
f
133
171
457
f
(R)-19
(R)-20
(S)-21
f
a
For abbreviations, see footnote 19. Standard deviations for the curve fitting were typically 2% and less than 5%, except for the 1-20,
2-20, 3-20, 2-18, and 2-19 complexes. K288 (2-Gly-OMe) ) 38 000 M-1, K288 (1-Pro-OMe) ) 26 400 M-1, K288 (1-(R)-22) ) 1970
b
M-1, K288 (1-(S)-23) ) 49 400 M-1, K288 (1-(S)-24) ) 130 000 M-1, K288 (4-Pro-OMe) ) 45 M-1, K288 (4-(R)-22) ) 4.4 M-1, K288 (4-
(S)-23) ) 300 M-1, K288 (4-(S)-24) ) 370 M-1
.
c K288 (1-D-Trp-OMe) ) 6550 M-1
.
K288 (2-D-Trp-OMe) ) 89 500 M-1 e K288 (1-(S)-18)
.
d
) 13 600 M-1
.
f Not determined. During titration, demetalation occurred.
g
1. (3) The 19O-methyl group also suppressed the bind-
ing, with the binding constants of 4 decreased by a factor
of ca. 50 as compared to 1. The binding affinity enhanced
by the 2-hydroxyethyl groups was seen for all of the
guests irrespective of the existence of a hydrogen-bonding
site in the guest. One can explain the high binding
affinity of 2 by assuming that the 2-hydroxyethyl group
forms intramolecular hydrogen bonding to the lactam
carbonyl, decreasing the electron density of zinc, and
activating the zinc as a Lewis acid. The inhibitory effects
of the 19O-alkyl group on the binding appear to originate
from (1) increased electron density on zinc due to the
electron-donating alkyl group and (2) loss of polar
interactions, possibly hydrogen bonding, between the
lactim OH group and the amino group of guest (vide
infra, Figure 8).
The amines 18-21 were more tightly bound to 1-8
than the amino acid esters. The same trend was seen
for the binding by zinc porphyrin derivatives.20 This
trend can be ascribed to the higher basicity of the amino
group of amines than that of R-amino acid esters.
Secondary amines such as 22 and Pro-OMe were bound
weakly to 4, while Pro-OMe was tightly bound to zinc
porphyrin.20 This weak affinity for secondary amines
may reflect more crowded geometry around zinc in zinc
bilindione compared to zinc porphyrin.
UV-vis titration experiments showed that addition of
amino alcohols such as leucinol to 4 caused demetalation,
and the binding affinity toward amino alcohols could not
be determined. Instead, binding of amino alcohol methyl
ethers was studied. Phenylalaninol methyl ether (23)
and leucinol methyl ether (24) showed large binding
constants comparable to those of amines.
F igu r e 2. CD spectra of the 4-Leu-OMe complex in CH2Cl2.
(a) L-Leu-OMe at 288 K, (b) D-Leu-OMe at 288 K, and (c) L-Leu-
OMe at 223 K. [4] ) 3.79 × 10-5 M, [D/L-Leu-OMe] ) 8.20 ×
10-2 M at 288 K, 2.77 × 10-2 M at 223 K.
K are shown in Figure 2. The positive Cotton effect at
the higher energy band and the negative one at the lower
energy band revealed that L-Leu-OMe induced M-helicity
in the framework of 4.21 The values of differential
dichroic absorption (∆ꢀ288, ∆ꢀ223) of the higher energy
band for ZnBD-amino acid ester (or amine) complexes in
CH2Cl2 at 288 and 223 K are listed in Tables 2 and 3,
respectively, where the observed differential dichroic
absorption was corrected for the concentrations of the
complexes. In all cases, Cotton effects with an opposite
sign were observed at the lower energy band as typically
shown in Figure 2.
Typical titration curves of UV-vis and CD spectra for
formation of the 2-L-Phe-OMe complexes are shown in
Figure 3. The induced Cotton effects developed concur-
rently as the UV-vis spectral changes, showing that the
complexation with L-Phe-OMe directly induced the helical
chirality in the zinc bilindione. The binding constants
of ZnBD 2 determined by UV-vis (Kvis) and those
Cir cu la r Dich r oism Stu d ies on Helica l Ch ir a lity
In d u ction . ZnBDs 1-8 exist as racemates in a solution
and exhibit no Cotton effects. Addition of chiral R-amino
acid methyl esters, â-amino ethers, and amines to solu-
tions of 1-8 in CH2Cl2 or CHCl3 induced Cotton effects
in the zinc bilindione bands. The induced Cotton effects
were characteristic of a helical structure of the chromo-
phore.11d,21 As a representative example, the CD spectra
of a solution of 4 and Leu-OMe in CH2Cl2 at 288 and 223
(21) (a) Bulke, M. J .; Pratt, D. C.; Moscowitz, A. Biochemistry 1972,
11, 1, 4025-4031. (b) Blauer, G.; Wagniere, G. J . Am. Chem. Soc. 1975,
97, 1949-1954. (c) Wagniere, G.; Blauer, G. J . Am. Chem. Soc. 1976,
98, 7806-7810. (d) Scheer, H.; Formanek, H.; Schneider, S. Photochem.
Photobiol. 1982, 36, 259-272.
(20) Mizutani, T.; Ema, T.; Yoshida, T.; Kuroda, Y.; Ogoshi, H. Inorg.
Chem. 1993, 32, 2072.

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8773
Ta ble 2. Differ en tia l Dich r oic Absor p tion (∆E288/M-1 cm -1) in th e High er En er gy Ba n d of Com p lexes betw een 1-8 a n d
Va r iou s Ch ir a l Am in o Acid Ester s a n d Am in es in CH2Cl2 a t 288 Ka
guest
1
2
3
4
5
6
7
8
L-Ala-OMe
L-Val-OMe
L-Leu-OMe
L-Ile-OMe
L-Met-OMe
L-Asp-(OMe)2
L-Glu-(OMe)2
L-Phe-OMe
L-Trp-OMe
D-PhGly-OMe
(R)-18
<1.5
19.8
16.0
22.9
13.0
2.3
<1
15.4
13.2
21.4
12.2
5.0
1.7
32.2
32.5
37.3
46.8
31.4
46.1
30.2
36.7
46.6
-38.8
0
22.8
18.3
31.3
33.4
25.7
32.6
18.3
30.3
16.8
-28.7
<2.7
24.1
3.3
29.4
26.2
36.3
40.0
32.1
42.2
25.5
37.1
26.2
-33.2
-2.7
25.3
4.1
35.0
28.1
39.0
45.3
35.1
49.1
29.7
37.8
e
-38.7
-3.9
24.5
5.4
29.1
28.6
36.9
45.5
30.7
42.4
23.7
33.8
40.4
-35.3
0
18.4
14.4
18.9
12.2
3.7
-3.1
21.2
16.3
-17.2
12.1
12.8
5.0
3.3
2.9
18.3
14.9b
-19.0
13.4d
16.3
6.2
21.8
14.6c
-20.2
14.4
16.1
16.1
f
(R)-19
(R)-20
(S)-21
28.3
7.9
6.1
34.9
8.1
f
0
f
f
f
f
a
∆ꢀ288 (1-L-Pro-OMe) ) -6.1, ∆ꢀ288 (1-(R)-22) ) 3.8, ∆ꢀ288 (1-(S)-23) ) 4.8, ∆ꢀ288 (1-(S)-24) ) -4.5, ∆ꢀ288 (4-L-Pro-OMe) ) -6.5,
∆ꢀ288 (4-(R)-22) ) -6.1, ∆ꢀ288 (4-(S)-23) ) 9.0, ∆ꢀ288 (4-(S)-24) ) -3.9. ∆ꢀ (1-D-Trp-OMe) ) -14.5. c ∆ꢀ (2-D-Trp-OMe) ) -15.2.d ∆ꢀ
b
(1-(S)-18) ) -13.8. e Not determined because the stoichiometry of the complex other than 1:1 also contribute to the ICD. f Not determined.
Ta ble 3. Th e Differ en tia l Dich r oic Absor p tion (∆E/M-1
cm -1),a th e Bin d in g Con sta n ts for Ea ch Dia ster eom er
(K223, K223′/M-1),b a n d Dia ster eom er ic Excess (d e) for th e
Com p lexes betw een Hosts 4 a n d 8 a n d Va r iou s Ch ir a l
Am in o Acid Ester s a n d Am in es in Dich lor om eth a n e a t
223 K
host
guest
∆ꢀ223
K223
K223′
de (%)c
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
8
8
8
8
8
8
L-Ala-OMe
L-Val-OMe
L-Leu-OMe
L-Leu-OBz
L-Leu-ONpb
L-Ile-OMe
L-Trp-OMe
L-Phe-OMe
L-Asp-(OMe)2
L-Glu-(OMe)2
D-PhGly-OMe
(S)-23
(S)-24
(R)-18
(R)-19
(R)-20
L-Leu-OMe
L-Trp-OMe
L-Phe-OMe
(R)-18
(R)-19
(R)-20
52.9
47.3
51.4
d
5050
2450
4750
6720
4960
5170
e
6350
9260
4010
2590
52400
41500
7750
11900
32700
4150
e
2790
1060
1980
2960
2310
1780
e
2150
2150
1290
980
45100
42300
6480
6680
29700
1980
e
1470
6420
7410
20700
42
42
37
41
41
46
73
57
70
51
42
13
9
14
30
6
36
70
46
10
31
2
d
60.9
87.7
60.9
83.8
60.5
-60.7
15.3
-14.7
-12.5
37.7
5.1
47.8
78.1
55.8
-14.3
42.6
3.8
F igu r e 3. UV-vis titration and CD titration curves. To a
solution of 2 in CH2Cl2 was added L-Phe-OMe at 288 K. Peaks
at 390 nm in the UV-vis spectra and at 368 nm in the CD
spectra were monitored as a function of [L-Phe-OMe]. [2] )
2.49 × 10-5 M for UV-vis and 1.98 × 10-5 M for CD.
4120
7490
13200
23300
esters, Asp-(OMe)2, and Ile-OMe. The large value of ∆ꢀ
for Asp-(OMe)2 was unexpected: 4 can distinguish two
similar groups attached to the chiral carbon, COOMe and
CH2COOMe.
a
The values of ∆ꢀ at 399-405 nm for 4 and 398-408 nm for 8
are reported. [4 or 8] ) 3.2 × 10-5-4.5 × 10-5 M, [guest] ) 23-
Table 2 shows that there are interesting differences
in helical chirality induction between 1 and 4. Ala-OMe
induced almost no Cotton effects in 1, while it induced
distinct Cotton effects in 4 as efficiently as Val-OMe and
Leu-OMe. Asp-(OMe)2 and Glu-(OMe)2 induced strong
Cotton effects in 4, while they induced small Cotton
effects in 1. Thus, the 19O-alkyl groups affected not only
the overall binding affinity but also the interactions
inducing helical chirality. An important structural dif-
ference between 1 and 4 is that the polarity of the D ring
is reversed: the terminal D ring of 1 has a positively
charged hydrogen, while that of 4 a negatively charged
oxygen. For efficient helical chirality induction in 4, a
repulsive interaction between the negatively charged
terminal D or A ring of ZnBDs and the COOR group of
the guest appears to be important.
b
33 mM. Binding constants K′ and K′′ are defined in Scheme 3.
The binding constants were determined by the 1H NMR titration
at 223 K. c Determined by the 1H NMR signal integration in
CD2Cl2 at 223 K. [4 or 8] ) 2.2 mM, [guest] ) 14-62 mM. Under
these conditions more than 98% of 4 was complexed with the guest.
Not determined. e Not determined owing to the anomalous
d
dependence of chemical shift displacements on Trp-OMe concen-
trations.
determined by CD spectroscopy (KCD) in CH2Cl2 at 288
K were the following: L-Val-OMe, Kvis ) 29 700 ( 1200,
KCD ) 28 700 ( 2900 M-1; L-Phe-OMe, Kvis ) 29 000 (
1100, KCD ) 36 600 ( 6300 M-1; L-Trp-OMe, Kvis ) 89
700 ( 5100, KCD ) 68 300 ( 3900 M-1
. Considering
relatively large standard deviations for KCD, the agree-
ment between Kvis and KCD was satisfactory.
As described later in this paper, the values of ∆ꢀ
directly reflected the enantiomeric excess of ZnBDs
complexed with guest. Comparison of ∆ꢀ values in Table
2 indicates that helical chirality induction behaviors were
similar among 1-3 and among 4-8. Helical chirality
was induced in 4 efficiently by aromatic amino acid
NMR St u d ies of t h e Com p lexa t ion a n d Ch ir a l
1
In d u ction . The H NMR signals of 4 were assigned by
NOESY experiments. The cross-peaks were observed
between the protons as shown in Figure 4, which

8774 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
1
F igu r e 4. NOESY correlations in the H NMR of 4 in CD2Cl2
at 298 K.
Sch em e 3
F igu r e 5. 500 MHz 1H NMR spectra of solutions of 2.46 ×
10-3 M of host 4 in the presence of varying concentrations of
L-Leu-OMe in CD2Cl2 at 223 K. The concentrations of Leu-
OMe were (a) 0, (b) 9.03 × 10-4, (c) 3.56 × 10-3, and (d) 2.51
× 10-2 M.
established that 4 assumed a helical conformation along
with complete assignments of these signals.22
Addition of 4 to a solution of 19 in dry CDCl3 at 296 K
caused the complexation-induced shift (CIS) of the NH2
protons of 19 from 1.50 to 3.00 ppm with some signal
broadening, where 46% of 4 was complexed with 19. This
result clearly indicates that the amino group of 19 was
coordinated to the zinc of 4.
OMe-M-4 complex on the basis of the sign of Cotton
effects of the complex. From the integration of each of
1
the 19-MeO signals in the H NMR spectra taken at 223
K, the diastereomeric excesses (de) were determined for
the 4-chiral guest complexes. Similarly, on the basis of
the integration of 10-H and 15-H signals, the de was
determined for 8-chiral guest complexes. The values of
de are listed in Table 3.
The binding constants of chiral guest to M-4 and P-4
(K223, K′223) were determined by the 1H NMR titration
experiments at 223 K, where the complexation-induced
shifts of each of the 19-methoxy signals were monitored
as a function of guest concentrations (Table 3). For 8,
the complexation-induced shifts of 10-H and 15-H were
monitored. By using the binding constants, diastereo-
meric excesses were calculated according to the equation,
de ) (K223 - K′223)/(K223 + K′223) × 100 (%), which were
mostly in good agreement with those determined by the
integration of the 19-MeO signal.23
In Figure 6 are plotted the values of ∆ꢀ223 at 400 nm
for the 4-guest complexes determined by CD spectro-
scopy against the diastereomeric excesses determined by
1H NMR signal integration at 223 K. A good linear
correlation indicates that the induced Cotton effects
originated from the distribution over the two enantio-
meric helical conformations and any direct electromag-
netic coupling between the guest chromophore and the
bilindione chromophore makes a negligibly small contri-
bution to the induced CD. Thus, the magnitude of Cotton
The equilibria shown in Scheme 3 should be considered
to explain 1H NMR spectral behaviors of a solution of
4-guest complexes. Only averaged signals between
complexed 4 and free 4 were observed in the temperature
range of 223-288 K, indicating that complex formation
and dissociation were fast on the NMR time scale over
this temperature range. Thus, at room temperature, only
one set of signals appeared. When the solution was
cooled, however, these signals decoalesced into two sets
of signals and two sets of well-resolved signals appeared
at 223 K, showing that the helix inversion between
guest-P-4 and guest-M-4 became slow on the NMR time
scale at low temperatures. Addition of excess guest
caused the coalescence of the signals, indicating that the
helix inversion was catalyzed by guest. The details of
kinetic aspects will be reported elsewhere.
Because two diastereomers gave resolved signals at low
1
temperature, H NMR at 223 K afforded valuable infor-
mation on diastereomeric excess of the complexes. Typi-
1
cal H NMR spectra of solutions of 4 and L-Leu-OMe in
CD2Cl2 at 223 K are shown in Figure 5. Upon addition
of a small amount of L-Leu-OMe, the 5-H, 10-H, 15-H
and MeO signals of 4 split into two with almost the same
intensity. When more L-Leu-OMe was added, these
signals were shifted and one set of the signals became
dominant, which was in this case assigned to the L-Leu-
(23) Diastereomer excess determined by signal integration and that
by the binding constants agreed within 15% except for the 4-Ala-OMe,
4-18, 4-20, 8-18, and 8-20 complexes.
(22) Sturrock, E. D.; Bull, J . R.; Kirsch, R. E.; Pandey, R. K.; Senge,
M. O.; Smith, K. M. J . Chem. Soc., Chem. Commun. 1993, 872-874.

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8775
F igu r e 6. Plot of |∆ꢀ| at the higher energy band maxima in
the CD spectra against diastereomeric excesses (de) deter-
mined by NMR peak integration. Both the CD and the NMR
spectra were recorded at 223 K in CH2Cl2 and CD2Cl2,
respectively. [4] ) 3.5 × 10-5-4.2 × 10-5 M, [guest] ) 0.025-
0.049 M for the CD studies. For NMR conditions, see footnote
c to Table 3.
effects is a good measure of diastereomeric excesses and
the efficiency of helical chirality induction. A similar plot
for the 8-guest complexes also gave a good linear
correlation with almost the identical slope.24 Therefore,
4 and 8 showed quite similar behavior both in the helical
chirality induction and induced CD.
F igu r e 7. Complexation-induced shifts of 5-H, 10-H, 15-H,
and MeO signals of 4 in the H NMR spectra in CD2Cl2 at 223
1
K upon addition of various guests, (R)-18-20, L-Ala-OMe,
L-Val-OMe, L-Leu-OMe, L-Leu-OBz, L-Leu-ONp, L-Ile-OMe,
L-Asp-(OMe)2, L-Glu-(OMe)2, L-Phe-OMe, and L-Trp-OMe. Open
squares, circles, and triangles represent the major M-isomer,
while filled squares, circles, and triangles the minor P-isomer.
Complexation-induced shifts of 4 upon addition of
various guests are summarized in Figure 7. The upfield
shifts of the 10-H proton of the major diastereomer
induced by Phe-OMe and Trp-OMe revealed that the
aromatic moiety of the guest was stacked with the B or
C ring in the major diastereomer. Perturbation in the
5-H proton by the aromatic guests was small. The
resonances of the indole 2-H and N-H of Trp-OMe were
also shifted upfield upon complexation (vide infra),
consistent with the stacking of the indole ring on bilin-
dione. When complexed with 19, the resonance of 5-H
of 4 in the major diastereomer was shifted upfield, while
that of 15-H of the minor one shifted upfield, indicating
that the naphthyl group took different positions in the
two diastereomers. In the 1H NMR spectra of the 4-Leu-
ONp complex and the 4-Leu-OBz complex, there was no
particular difference in the pattern of the complexation-
induced shifts of 5-, 10-, and 15-H and 19-OMe protons
when compared to that of the 4-Leu-OMe complex.
These results for Leu-OR (R ) Me, benzyl, and 1-naph-
thylmethyl) strongly suggest that the COOR group is not
in van der Waals contact with the bilindione framework
and is away from it.
F igu r e 8. Two isomers of the [1,19-bilindionato]zinc-NH3
complex optimized by ab initio MO calculations at the HF/6-
311G level.
As shown in Figure 8, there are two possible isomers
of ZnBD-NH2R complexes, one with the NH2 group
coordinated from the A ring side (isomer I), the other
from the D ring side (isomer II). A similar behavior
between 4 and 8 in the binding affinity and helical
chirality induction (Tables 1-3) implies that isomer I is
favorable. The ab initio calculations of the [19-methoxy-
(21H,24H)-1-bilinonato(2-)-N21,N22,N23,N24]zinc(II)-
NH3 complex were performed at the 3-21G, 6-311G, and
B3LYP levels. On the basis of the 3-21G-optimized
geometry, isomer I was more stable than isomer II by
1.8 kcal/mol. Similar results were obtained by using a
larger basis set: on the basis of the 6-311G-optimized
geometry, isomer I was more stable than isomer II by
1.2 kcal/mol (6-311G) or by 1.9 kcal/mol (B3LYP). In
Figure 8, the 6-311G-optimized structures are shown.
The (N-)H to O distances were 2.154 Å (isomer I) and
2.260 Å (isomer II), and the N-H-O bond angles were
1
Comparison of the H NMR spectra of 4-guest com-
plexes ([4] ) [guest] ) 22 mM) in CD2Cl2 at 223 K with
those of free guest indicated that the H-2 proton of indole
of Trp-OMe and the ortho protons of phenyl of Phe-OMe
were shifted upfield by 0.61 and 0.5 ppm, respectively.
For Leu-OMe, no characteristic shift was observed.
These chemical shift displacements suggest that the
aromatic rings in the side chain of Trp-OMe and Phe-
OMe are stacked with the bilindione.
(24) The slope of the plot for 4 was 121.8 and that for 8 was 118.5.

8776 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
For Asp-(OMe)2, ∆H° ) -1.50 ( 0.04 kcal/mol, ∆S° )
-3.74 ( 0.16 cal/mol/K, for Phe-OMe, ∆H° ) -0.98 (
0.02 kcal/mol, ∆S° ) -2.30 ( 0.07 cal/mol/K, and for Leu-
OMe, ∆H° ) -0.57 ( 0.02 kcal/mol, ∆S° ) -0.78 ( 0.09
cal/mol/K. Thus, the negative sign of ∆H° indicated that
the helical chirality induction was enthalpically driven
and the enthalpic contribution was largest for the 4-Asp-
(OMe)2 complex. As the origin of these negative enthalpy
changes, attractive forces between the aromatic group in
the side chain of guests and the bilindione B and C rings
are expected to contribute helical chirality induction,
when one considers the complexation-induced upfield
shift of the 10-H proton of the 4-Trp-OMe complex and
the 4-Phe-OMe complex of the major diastereomers in
the 1H NMR spectra. For Asp-(OMe)2, dipole-dipole
interaction between the ester group in the side chain and
the bilindione framework could play a major role. In the
case of Leu-OMe, an entropic contribution to helical
chirality induction was larger than the others. Chiral
induction in Ile-OMe showed a similar temperature
dependence. It showed large ∆ꢀ at 288 K (46.8 cm-1M-1),
while ∆ꢀ at 223 K was moderate (60.9 cm-1M-1). There-
fore, for aliphatic amino acid esters, entropic forces
contributed to helical chirality induction, resulting in
comparatively higher helical chirality induction at higher
temperature compared to aromatic amino acid esters.
F igu r e 9. Plot of ln K′′ against T-1 for the 4-L-Asp-(OMe)2
complex, the 4-L-Phe-OMe complex, and the 4-L-Leu-OMe
complex. K′′ is the equilibrium constant between the two
diastereomers, the L-guest-M-4 and L-guest-P-4 complexes
(Scheme 3).
144.5° (isomer I) and 142.9° (isomer II), showing strong
hydrogen-bonding between the NH3 ligand and the
bilindione oxygen. We suggest that isomer I is favorable
because a CdO group is a better hydrogen bond acceptor
than a MeO group.
Mech a n ism of Helica l Ch ir a lity In d u ction . As
discussed above, an aromatic group in the side chain of
amino acid esters caused an upfield shift of 10-H of 4,
while an aromatic group (Ar) in the ester group (COOCH2-
Ar) scarcely influenced the CIS patterns (Figure 7),
suggesting that the side chain is above the B and C rings
and the ester group is away from the bilindione frame-
work.
The 1H NMR spectral features of the complexes be-
tween 1-3 and chiral guests differed from those between
4-8 and chiral guests in two respects. (1) Complex
formation and complex dissociation were slow on the
NMR time scale even at 288 K, and thus the signals from
the free host and the complexed host appeared sepa-
rately. (2) Tautomeric isomerization of the lactim OH
proton also affected the dynamics of the 1H NMR spectra,
complicating analysis of the diastereomer distribution
based on the variable-temperature NMR. Therefore, the
diastereomeric excess of the complexes between 1-3 and
chiral guest could not be determined by 1H NMR studies.
Tem p er a tu r e Dep en d en ce of th e Bin d in g a n d
Ch ir a l In d u ction . The binding constants of amino acid
esters and amines by ZnBDs 4 and 8 in CH2Cl2 at 223 K
were larger than those at 288 K by a factor of 25-56.
Therefore, the binding was enthalpically driven, and the
estimated values of ∆H° were -6.3 to -7.9 kcal/mol. This
is close to the value of ∆H° for complex formation between
Leu-OMe and [2,3,7,8,12,13,17,18-octaethyl-5,10-bis(1-
naphthyl)porphyrinato]zinc(II) in CHCl3, which was re-
ported to be -8.3 kcal/mol.25
The ∆ꢀ values of the 4-guest complexes at 223 K were
larger in magnitude than those at 288 K except for 20,
indicating that the helical chirality induction was also
enthalpically driven. In Figure 9 is shown the plot of ln
K′′ against T-1 for the complexes between 4 and L-Asp-
(OMe)2, L-Phe-OMe, and L-Leu-OMe, where K′′ repre-
sents the equilibrium constant between the two diaster-
eomers (see Scheme 3). The values of K′′ were obtained
from the ∆ꢀ values at each temperature, taking advan-
tage of the linear relationship between ∆ꢀ223 and diaster-
eomeric excesses shown in Figure 6 and assuming the
same relationship is valid at higher temperatures. From
this plot, the enthalpy changes and entropy changes on
going from L-guest-P-4 to L-guest-M-4 were obtained.
In Figure 10 is shown one of the possible structures of
L-Ala-OMe-M-[19-methoxy-(21H,24H)-1-bilinonato(2-)-
N21,N22,N23,N24]zinc(II) complex optimized by semiem-
pirical molecular orbital calculations at the PM3 level.
The zinc complex of 19-methoxybilinone was used here
as a model compound of 4. This structure was obtained
as the most stable one when 36 conformations were
calculated at the PM3 level in which the amino group is
coordinated to zinc and the substituents on the chiral
carbon of L-Ala-OMe were rotated along the N-CR bond
by 10°, and other coordinates were optimized. The side
chain group of amino acid ester (the methyl group in the
case of Ala-OMe) is on the C ring, R-H on the B ring, the
COOMe group nearly perpendicular to the bilindione
framework, and the NH2 group of Ala-OMe hydrogen
bonded to the lactam carbonyl oxygen. This binding
mode is consistent with the following features of chiral
induction.
(1) R-Amino acid esters induced helical chirality more
effectively than amines and amino alcohol methyl ethers,
indicating that the COOR group of R-amino acid esters
plays a crucial role in the helical chirality induction. The
helical sense induced by amino acid esters was consistent,
that is, all L-amino acid esters induced M-helicity except
for the 1-L-Pro-OMe complex, the 4-L-Pro-OMe complex,
and the 3-L-Glu-(OMe)2 complex at 288 K. On the other
hand, the helical sense induced by amines and amino
ethers was not consistent. For instance, (R)-19 induced
M-helicity, (R)-18 induced almost no helical chirality, and
(R)-22 induced P-helicity in 4 at 288 K (Table 2).
Therefore, the point chirality of the R-carbon of amino
(25) Mizutani, T.; Murakami, T.; Kurahashi, T.; Ogoshi, H. J . Org.
Chem. 1996, 61, 539.

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8777
F igu r e 11. A simple model for interactions between two chiral
molecules and three possible interaction modes.
Ta ble 4. In ter a ction En er gies betw een Recogn ition
Gr ou p s of Tw o Ch ir a l Molecu les
A (COOR)
B (side chain group)
C (R-H)
P (remote site)
Q (C ring)
R (B ring)
a11
a21
a31
a12
a22
a32
a13
a23
a33
(4) Different patterns of helical chirality induction
between 1 and 4 (Table 2) indicate that the polarity of
the terminal rings of the bilindiones, possibly a repulsive
force between the lactam ring of ZnBD and the ester
group of guest, is one of the important factors for the
chiral induction.
A Sim p le Mod el for Ch ir a lity-Ch ir a lity In ter a c-
tion . If a variety of chirality can be quantitatively
expressed in terms of a single measure, it would be useful
for understanding chiral recognition.27 One simple model
is to consider a chiral molecule consisting of three
elementary interacting groups, A, B, and C. Another
chiral molecule has P, Q, and R. There are three possible
binding modes between the two chiral molecules as
shown in Figure 11. If the interaction energies for each
pair of elementary parts are defined as in Table 4, then
total energy E can be given by eqs 1-3
E ) (e1 exp(-e1/kT) + e2 exp(-e2/kT) +
e3 exp(-e3/kT))/Z (1)
Z ) exp(-e1/kT) + exp(-e2/kT) + exp(-e3/kT) (2)
e1 ) a11 + a22 + a33, e2 ) a12 + a23 + a31, e3 ) a31
+
a21 + a32 (3)
where e1 is the energy for conformer 1, e2 for conformer
2, e3 for conformer 3, k Boltzman’s constant, and T the
absolute temperature. We simplify the model further by
assuming that the conformation involving A-P pairing
is much more stable than the others, then eq 1 can be
reduced to eq 4.
F igu r e 10. A possible structure for the M-[19-methoxy-(21H,
24H)-1-bilinonato(2-)-N,21N,22N,23N24]zinc(II) complex-L-Ala-
OMe complex, consistent with the 1H NMR studies and helical
chirality induction patterns. The geometry was optimized at
the PM3 level.
E ) e1
(4)
acid esters directly determined the helical sense, while
that is not the case for amines and amino ethers.26
(2) An aromatic group and a carbomethoxy group in
the side chain of the guest made a significant contribution
to the chiral induction, as seen in higher diastereomeric
excesses for the complexes between 4 and Trp-OMe, Phe-
OMe, Asp-(OMe)2, and 19.
(3) The binding constants of Leu-ONp and Leu-OBz
by 4 at 223 K were similar to those of Leu-OMe.
Diastereomeric excesses at 223 K were 41% for both of
the aromatic esters, being similar to that of the methyl
ester (37%). Compared with the high de of Trp-OMe and
Phe-OMe, one can see that the aromatic group in the side
chain helps induce helical chirality, while the aromatic
group in the ester group had only minor effects on binding
and chiral induction.
Similarly the energy E′ for the complex between
molecule ABC and enantiomeric molecule PQR, i.e., the
corresponding diastereomer, is
E′ )e1′ ) a11 + a32 + a23
The difference in energy between the diastereomers is
∆E ) e1 - e1′ ) a22 + a33 - a23 - a32 (6)
Therefore, the primary interaction energy term, a11
(5)
,
is canceled and the energy difference between the dia-
stereomers (∆E) is determined by the difference in the
second and the third interaction pairs.
We apply the above model to the bilindione chiral
induction in a slightly modified way. We assume that
the COOR group, the side chain group, and R-H consti-
(26) Unusual behavior in helicity induction by Pro-OMe is readily
understood if the coordination geometry around zinc should be much
different for the secondary amine.
(27) (a) Gilat, G. J . Phys. A: Math. Gen. 1989, 22, L545-L550. (b)
Alvira, E. Amino Acids (Vienna) 1992, 2, 97-102. (c) Caravella, J . A.;
Richards, W. G. Eur. J . Med. Chem. 1995, 30, 727-728.

8778 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
Ma ter ia ls a n d Solven ts. Zinc bilindione 1 was prepared
by the similar procedure of Falk.30 (Oxoniaporphyrinato)zinc-
(II) chlorides 16a -c were prepared following the method of
Fuhrhop.18b Preparation of 19-alkoxy-22H-bilin-1-ones 17a -e
was carried out by the method of Fuhrhop,18c which was
somewhat modified by us. Amino acid esters for the spectro-
scopic measurements were obtained by neutralization of
commercially available hydrochlorides followed by distillation
just prior to use: L-Ala-OMe‚HCl, L-Phe-OMe‚HCl, L-Asp-
(OMe)2‚HCl, L-Glu-(OMe)2‚HCl, and D-Trp-OMe‚HCl were
purchased from Sigma Chemical Company, L-Val-OMe‚HCl,
L-Leu-OMe‚HCl, Gly-OMe‚HCl, and L-Trp-OMe‚HCl were from
Nacalai Tesque Chemical Company, L-Ile-OMe‚HCl was from
Peptide Institute, Inc., L-Met-OMe‚HCl was from Kokusan
Chemical Works, and D-PhGly-OMe‚HCl was from Wako Pure
Chemicals Industries. Compounds (R)-18 and (S)-18 were
purchased from Nacalai Tesque, Inc., and used without
purification. Compound (R)-19 was purchased from Tokyo
Chemical Industries and used after distillation. Compounds
(R)-20, (S)-21, and (R)-22 were purchased from Aldrich
Chemical Co., Inc., and used without purification. All solvents
for the UV-vis, CD, and NMR measurements were of spec-
troscopic grade.
Zin c(II) Com p lex of 15a (1). This compound was reported
by Falk et al. and prepared by their procedure (mp > 350 °C).30
For 1: 1H NMR (500 MHz, CDCl3) δ 0.93 (t, J ) 7.6 Hz, 3H),
1.11-1.18 (m, 12H), 1.61 (s, 3H), 1.89 (s, 3H), 2.06 (s, 3H),
2.23-2.29 (m, 2H), 2.36 (q, J ) 7.6 Hz, 2H), 2.49-2.60 (m,
4H), 5.60 (s, 1H), 5.82 (s, 1H), 6.64 (s, 1H); UV-vis (CH2Cl2,
15 °C) ꢀ366 ) 32 200, ꢀ674 ) 15 300 M-1 cm-1; FAB MS m/z 560
([M+]); HR FAB MS calcd for [C31H36N4O264Zn]+ 560.2130,
found 560.2146.
Zn (II) Com p lex of 15c (2). Compound 15c (84.0 mg, 0.150
mmol) was dispersed in a saturated ethanolic solution of zinc
acetate (45 mL), followed by stirring at reflux for 0.5 h. As
the temperature raised, the reaction mixture became a dark
green homogeneous solution. After cooling, water (45 mL) was
added, and precipitates were collected by filtration, which were
dried in vacuo over silica gel. Recrystallization from ethanol
afforded 2 as a dark green powder (58.0 mg, 0.0932 mmol,
62%): mp 248-250 °C (dec); 1H NMR (500 MHz, DMSO-d6) δ
1.08 (t, J ) 7.9 Hz, 6H), 1.14 (t, J ) 7.9 Hz, 6H), 2.01 (s, 6H),
2.39 (t, J ) 7.3 Hz, 4H), 2.52-2.59 (m, 8H), 3.46 (m, 4H), 4.75
(br s, 2H, D2O exchangeable), 5.97 (s, 2H), 6.75 (s, 1H), 9.68
(s, 1H, D2O exchangeable); IR (KBr) 3397, 2965, 2931, 2870,
1686, 1576, 1206 cm-1; UV-vis (CH2Cl2, 15 °C) ꢀ358 ) 39 700,
ꢀ726 ) 13 600 M-1 cm-1; FAB MS m/z 621 ([M + H]+); HR FAB
MS calcd for [C33H40N4O464Zn]+ 620.2341, found 620.2322.
Anal. Calcd for C33H40N4O4Zn‚2.2 H2O: C, 59.90; H, 6.76; N,
8.47. Found: C, 59.93; H, 7.28; N, 8.06.
tute three elementary groups of guest (A, B, and C). For
ZnBD, based on the structure shown in Figure 10, we
assume that P, Q, and R are a remote site from the
bilindione framework, the B ring, and the C ring,
respectively. Comparison of the helical chirality induc-
tion for a series of guest molecules indicated that the
COOR group plays an important role. We thus regard
the COOR group as group A. Then on the basis of the
foregoing argument, group A preferentially occupies the
remote site of 4, namely site P. In the L-amino acid
ester-M-4 combination, the side chain group interacts
with the C ring, and R-H with the B ring, while vice versa
in the L-amino acid ester-P-4 combination. ∆E can then
be given by the difference between B-Q/C-R pairing
energy and B-R/C-Q pairing energy. According to this
model, the helical chirality induction originates from an
unfavorable interaction between the side chain group of
amino acid ester and the B ring in the “wrong” diaste-
reomer complex and a favorable interaction between the
side chain group and the C ring in the “correct” complex.
Con clu sion s. Point chirality of amino acid esters
induced helical chirality in zinc bilindiones. Coordination
of the NH2 group of guest to Zn forced the substituents
on the chiral carbon of amino acid esters to contact the
helical surface of zinc bilindione. Comparative studies
of the helical chirality induction in 19O-alkyl zinc bilin-
dione 4 showed that the contribution of the substituents
around point chirality to chiral induction decreased in
the order COOR > side chain > R-H. By assigning the
preferable sites for these substituents on zinc bilindione,
we presented a model for point chirality-helical chirality
intercoversion. Electrostatic repulsion between the COOR
group and the bilindione lactam rings, i.e., complemen-
tarity of polarity, and an attractive stacking interaction
between the aromatic group or the carbomethoxy group
in the side chain of guest and the bilindione pyrrole rings
were key forces for efficient chiral induction.
Exp er im en ta l Section
Gen er a l. 1H NMR spectra (500 and 270 MHz) were
recorded in CDCl3, DMSO-d6 and CD2Cl2, using TMS (0 ppm),
DMSO (2.50 ppm), and CHDCl2 (5.32 ppm) as internal
standards, respectively. The NOESY spectrum was obtained
for 4 at a concentration of 10 mM at 25 °C, where a pulse delay
of 2.2 s and mixing time of 500 ms were employed. UV-vis
absorption and circular dichroism spectra were recorded on
the spectrometer equipped with a thermostated cell compart-
ment. A cryostat (Oxford, DN1704) was used for CD spectral
measurements at low temperatures. For the preparation of
sample solutions for variable-temperature spectroscopic mea-
surements, dichloromethane solutions of zinc bilindiones and/
or guests were prepared in a volumetric flask at 15 °C, and
the concentrations at low temperatures were calculated on the
basis of the thermal expansion coefficient of dichloromethane
(0.001 391 K-1).28 FAB mass spectra were obtained using
3-nitrobenzyl alcohol as a matrix. The optical rotation of
1-naphthylmethyl L-leucinate was recorded using a polarim-
eter with a sodium lamp (D-line, 589 nm) as a light source.
Grid conformational search was performed using Sybyl 6.1,
Tripos Inc. The ab initio MO calculations were performed by
using the Gaussian 94 program package.29 Full geometry
optimization was performed at the Hartree-Fock (HF) level
using the 3-21G and 6-311G basis set with the Fopt keyword.
The single-point calculations were also carried out at the MP2
level with density functional theory method (B3LYP) using the
6-311G basis set.
Zn (II) Com p lex of 15b (3). Compound 15b (321 mg, 0.499
mmol) was dissolved in a small amount of CH2Cl2 (ca. 5 mL),
and to the solution was added a saturated ethanolic solution
of zinc acetate (75 mL), followed by stirring at reflux for 0.5
h. After cooling, water (75 mL) was added and green solids
were collected by filtration. The solid was dispersed in ethanol
(50 mL), and the suspension was refluxed for 15 min. After
cooling, the solid was collected by filtration, washed with a
small amount of ether and then dried in vacuo to yield 3 as a
dark green powder (337 mg, 0.477 mmol, 95%): mp 272-274
°C (dec); 1H NMR (500 MHz, DMSO-d6) δ 1.08-1.16 (m, 12H),
1.98 (s, 6H), 2.02 (s, 6H), 2.52-2.62 (m, 6H), 4.09 (m, 4H), 6.03
(s, 2H), 6.77 (s, 1H), 9.68 (br s, 1H, D2O exchangeable) (six
other protons seem to be masked by residual solvent protons
and H2O); IR (KBr) 3440, 2965, 2931, 2871, 1738, 1687, 1576,
(29) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian
94, Revision D.4; Gaussian, Inc.: Pittsburgh, PA, 1996.
(28) Riddick, J . A.; Bunger, W. B.; Sakano, T. K. Organic Solvents;
Wiley and Sons: New York, 1986.
(30) Falk, H.; Schlederer, T. Liebigs Ann. Chem. 1979, 1560-1570.

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8779
1245, 1204 cm-1; UV-vis (CH2Cl2, 15 °C) ꢀ360 ) 36 900, ꢀ706
)
202-204 °C (dec); 1H NMR (500 MHz, CDCl3) δ 0.86-0.89 (m,
6H), 1.11 (t, J ) 7.6 Hz, 3H), 1.12-1.15 (m, 6H), 1.17 (t, J )
7.6 Hz, 3H), 1.36-1.49 (m, 4H), 2.00 (s, 3H), 2.05 (s, 3H), 2.09
(t, J ) 7.6 Hz, 2H), 2.17 (t, J ) 7.6 Hz, 2H), 2.39 (q, J ) 7.6
Hz, 2H), 2.43-2.56 (m, 6H), 4.20 (s, 3H), 5.48 (s, 1H), 6.47 (s,
1H), 6.48 (s, 1H); IR (KBr) 2959, 2926, 2867, 1658, 1575, 1204
cm-1; UV-vis (CH2Cl2, 15 °C) ꢀ402 ) 35 000, ꢀ786 ) 17 200 M-1
cm-1; FAB MS m/z 630 ([M+]); HR FAB MS calcd for
[C36H46N4O264Zn]+ 630.2912, found 630.2928. Anal. Calcd for
12 800 M-1 cm-1; FAB MS m/z 705 ([M + H]+); HR FAB MS
calcd for [C37H45N4O664Zn]+ 705.2631, found 705.2646. Anal.
Calcd for C37H44N4O6Zn‚2H2O: C, 59.88; H, 6.52; N, 7.55.
Found: C, 60.20; H, 6.11; N, 7.21.
Zn (II) Com p lex of 17a (4). A mixture of 17a (115.0 mg,
0.224 mmol) and MeOH saturated with zinc acetate (45 mL)
was heated at reflux for 30 min. After cooling, the reaction
mixture was condensed to ca. 10 mL by evaporation, and CH2-
Cl2 (80 mL) was added. Precipitates of insoluble zinc acetate
were removed by filtration, which were washed with a small
amount of CH2Cl2 (ca. 10 mL). The washing was combined
to the filtrate, washed with water (100 mL × 2), and saturated
(sat.) brine (100 mL), and dried over anhydrous Na2SO4. The
solvent was removed by evaporation, and the resultant solid
was recrystallized from CH2Cl2-hexane to yield 4 as a dark
green powder (113 mg, 0.196 mmol, 88%): mp 260-262 °C
(dec); 1H NMR (500 MHz, CD2Cl2) δ 1.118 (t, J ) 7.6 Hz, 3H,
CH3CH2), 1.122 (t, J ) 7.6 Hz, 3H, CH3CH2), 1.14 (t, J ) 7.6
Hz, 3H, 8-CH3CH2), 1.17 (t, J ) 7.6 Hz, 3H, 17-CH3CH2), 1.72
(s, 3H, 18-Me), 1.75 (s, 3H, 2-Me), 2.01 (s, 3H, 7-Me), 2.07 (s,
3H, 13-Me), 2.40 (q, J ) 7.6 Hz, 3-CH3CH2), 2.48-2.59 (m,
6H, 8,12,17-CH3CH2), 4.16 (s, 3H, MeO), 5.53 (s, 1H, 5-H), 6.52
(s, 1H, 10-H), 6.53 (s, 1H, 15-H); IR (KBr) 2965, 2931, 2870,
1663, 1570, 1207 cm-1; UV-vis (CH2Cl2, 15 °C) ꢀ402 ) 33 600,
ꢀ780 ) 17 000 M-1 cm-1; FAB MS m/z 574 ([M+]); HR FAB MS
calcd for [C32H38N4O264Zn]+ 574.2286, found 574.2297. Anal.
Calcd for C32H38N4O2Zn: C, 66.72; H, 6.65; N, 9.73. Found:
C, 66.98; H, 6.81; N, 9.56.
C
36H46N4O2Zn: C, 68.40; H, 7.33; N, 8.86. Found: C, 68.09;
H, 7.39; N, 8.67.
Zn (II) Com p lex of 17d (8). This compound was prepared
by a procedure similar to that employed for 4 using 17d (115.0
mg, 0.224 mmol) dissolved in a small amount of CH2Cl2 and
2-propanol saturated with zinc acetate (75 mL). The reaction
mixture was treated by the analogous procedure to that used
for 4, and the crude product was recrystallized from CH2Cl2-
hexane to yield 8 as a dark green crystal (130 mg, 0.215 mmol,
85%): mp 222-224 °C (dec); 1H NMR (500 MHz, CDCl3) δ
1.10-1.17 (m, 12H), 1.20 (d, J ) 5.9 Hz, 3H), 1.34 (d, J ) 5.9
Hz, 3H), 1.71 (s, 3H), 1.76 (s, 3H), 2.02 (s, 3H), 2.07 (s, 3H),
2.38 (q, J ) 7.8 Hz, 2H), 2.40-2.56 (m, 6H), 5.46 (spt, J ) 5.9
Hz, 1H), 5.54 (s, 1H), 6.49 (s, 1H), 6.50 (s, 1H); IR (KBr) 2965,
2930, 2870, 1663, 1574, 1207 cm-1; UV-vis (CH2Cl2, 15 °C)
ꢀ401 ) 34 700, ꢀ778 ) 17 200 M-1 cm-1; FAB MS m/z 602 ([M+]);
HR FAB MS calcd for [C34H42N4O264Zn]+ 602.2599, found
602.2573. Anal. Calcd for C34H42N4O2Zn: C, 67.60; H, 7.01;
N, 9.27. Found: C, 67.30; H, 7.11; N, 8.85.
Meth yl (4-Acetyl-2-m eth oxyca r bon yl-5-m eth yl-1H-p yr -
r ol-3-yl)a ceta te (9b). To a mixture of 1,3-acetonedicarboxylic
acid (92.0 g, 0.528 mol) and concentrated HCl (2.0 mL) was
added dropwise amyl nitrite (67.9 g, 0.580 mol) over 3 h below
5 °C. After 12 h of stirring at room temperature, acetic acid
(550 mL), acetylacetone (58.0 g, 0.580 mol), and sodium acetate
(52.5 g, 0.640 mol) were added to the mixture, followed by zinc
powder (104 g, 1.59 mol) in portions with vigorous stirring.
The reaction was exothermic, and the temperature in the flask
was kept between 70 and 90 °C during the addition of zinc.
The mixture was then heated at 100 °C for 3 h. The hot
mixture was poured into ice-water, and the resultant suspen-
sion was allowed to stand for a few hours. The zinc dusts were
removed by decantation, and the suspension was extracted
with CH2Cl2 (300 mL × 3). The organic layer was washed with
water (500 mL × 2) and sat. brine (500 mL), followed by drying
over anhydrous MgSO4. After removal of the solvent, the
residue was recrystallized from CHCl3-hexane to yield 9b as
a pale yellow solid (66.8 g, 0.264 mol, 50%): mp 138-140 °C;
1H NMR (270 MHz, CDCl3) δ 2.42 (s, 3H), 2.54 (s, 3H), 3.73
(s, 3H), 3.85 (s, 3H), 4.20 (s, 2H), 9.25 (br s, 1H); IR (KBr)
3286, 2956, 1734, 1673, 1646 cm-1; EI MS (relative intensity)
m/z 253 (M+, 39), 221 (100), 193 (59), 162 (81). Anal. Calcd
for C12H15NO5: C, 56.91; H, 5.97; N, 5.53. Found: C, 56.66;
H, 6.03; N, 5.32.
Zn (II) Com p lex of 17c (5). To a solution of 17c (88.0 mg,
0.154 mmol) in CH2Cl2 (1 mL) was added MeOH saturated
with zinc acetate (35 mL), and the mixture was stirred under
reflux for 1 h. After cooling, CH2Cl2 (40 mL) was added and
washed with water (40 mL × 2) and sat. brine (40 mL). After
drying over anhydrous Na2SO4, recrystallization of the residue
from CH2Cl2-hexane afforded a dark green powder of 5 (72.0
1
mg, 0.113 mmol, 73%): mp 194-196 °C (dec); H NMR (500
MHz, CDCl3) δ 1.09-1.13 (m, 9H), 1.22 (t, J ) 7.6 Hz, 3H),
1.95 (s, 3H), 2.00 (s, 3H), 2.26-2.31 (m, 1H), 2.34 (q, J ) 7.6
Hz, 2H), 2.39-2.54 (m, 9H), 3.57-3.62 (m, 1H), 3.64-3.73 (m,
3H), 3.84 (br s, 1H, D2O exchangeable), 4.04 (br s, 1H, D2O
exchangeable), 4.40 (s, 3H), 5.47 (s, 1H), 6.39 (s, 1H), 6.40 (s,
1H); IR (KBr) 3462, 2962, 2931, 2870, 1605, 1572, 1531, 1201
cm-1; UV-vis (CH2Cl2, 15 °C) ꢀ404 ) 36 500, ꢀ801 ) 14 400 M-1
cm-1; FAB MS m/z 634 ([M+]); HR FAB MS calcd for
[C34H42N4O464Zn]+ 634.2498, found 634.2471. Anal. Calcd for
C
34H42N4O4Zn‚1.5H2O: C, 61.58; H, 6.84; N, 8.45. Found: C,
61.56; H, 6.55; N, 8.20.
Zn (II) Com p lex of 17b (6). A mixture of 17b (127 mg,
0.193 mmol) and MeOH saturated with zinc acetate (35 mL)
was heated at reflux for 1 h. After cooling, CH2Cl2 (60 mL)
was added and washed with water (60 mL × 3) and sat. brine
(60 mL). Drying over anhydrous Na2SO4 followed by recrys-
tallization of the residue from CH2Cl2-hexane afforded a dark
green powder of 6 (78.0 mg, 0.108 mmol, 56%): mp 203-204.5
°C (dec); 1H NMR (500 MHz, CDCl3) δ 1.11 (t, J ) 7.6 Hz,
3H), 1.13 (t, J ) 7.6 Hz, 3H), 1.15 (t, J ) 7.6 Hz, 3H), 1.20 (t,
J ) 7.6 Hz, 3H), 1.98 (s, 3H), 2.006 (s, 3H), 2.012 (s, 3H), 2.04
(s, 3H), 2.40 (q, J ) 7.6 Hz, 2H), 2.46-2.59 (m, 10H), 3.99-
4.05 (m, 2H), 4.09-4.12 (2H, m), 4.26 (s, 3H), 5.49 (s, 1H), 6.44
(s, 1H), 6.49 (s, 1H); IR (KBr) 2964, 2930, 2873, 1740, 1655,
1572, 1244, 1206 cm-1; UV-vis (CH2Cl2, 15 °C) ꢀ408 ) 35 100,
ꢀ794 ) 15 300 M-1 cm-1; FAB MS m/z 718 (M+); HR FAB MS
calcd for [C38H46N4O664Zn]+ 718.2709, found 718.2740. Anal.
Calcd for C38H46N4O6Zn: C, 63.37; H, 6.44; N, 7.78. Found:
C, 62.99; H, 6.49; N, 7.87.
Zn (II) Com p lex of 17e (7). A mixture of 17e (80.0 mg,
0.141 mmol) was dissolved in CH2Cl2 (1 mL). To the solution
was added MeOH saturated with zinc acetate (25 mL), and
the mixture was stirred under reflux for 1 h. After cooling,
the solvent was removed by evaporation. To the residue was
added CH2Cl2 (40 mL) and washed with water (40 mL × 2)
and sat. brine (40 mL). After drying over anhydrous Na2SO4,
recrystallization from of the residue CH2Cl2-hexane afforded
a dark green powder of 7 (65.6 mg, 0.104 mmol, 74%): mp
E t h yl 4-Acet yl-5-m et h yl-3-p r op yl-1H -p yr r ole-2-ca r b -
oxyla te (9c). To a solution of ethyl 3-oxohexanoate (25.2 g,
0.159 mol) in acetic acid (75 mL) was added dropwise below 5
°C a solution of sodium nitrite (13.2 g, 0.191 mol) in H2O (25
mL). The mixture was stirred overnight at room temperature,
followed by adding acetylacetone (17.5 g, 0.175 mol) and
sodium acetate (17.0 g, 0.207 mol) and then heating at 60 °C.
Zinc powder (22.9 g, 0.350 mol) was added portionwise so as
to keep the temperature at 90 °C. After completion of addition
of zinc, the mixture was heated with vigorous stirring at 100
°C for 2.5 h. The hot mixture was poured into 500 g of ice,
and the solids that precipitated were extracted with CH2Cl2
(200 mL × 3). The organic phase was washed with water (300
mL × 2) and sat. brine (300 mL) and dried over anhydrous
MgSO4. Evaporation afforded the solid residue, which was
recrystallized from hexanes-ethyl acetate to yield 9c as an
1
ivory crystal (23.1 g, 0.0975 mol, 61%): mp 107-109 °C; H
NMR (270 MHz, CDCl3) δ 0.98 (t, J ) 7.3 Hz, 3H), 1.38 (t, J
) 7.3 Hz, 3H), 1.57 (sextet, J ) 7.3 Hz, 2H), 2.46 (s, 3H), 2.53
(s, 3H), 3.03 (t, J ) 7.3 Hz, 2H), 4.34 (q, J ) 7.3 Hz, 2H), 9.39
(br s, 1H); IR (KBr) 3178, 3111, 3054, 2983, 2957, 2870, 1689,
1629, 1284 cm-1; EI MS (rel intensity) m/z 237 (M+, 39), 222

8780 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
(39), 208 (25), 190 (30), 176 (100). Anal. Calcd for C13H19
NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.61; H, 8.19; N,
5.67.
-
mixture was heated at reflux for 3.5 h. After cooling, the
mixture was condensed to ca. 30 mL and acidified to pH 3 with
concentrated HCl. The pale pink solid was precipitated, which
was separated by filtration. The filtrate was separated into
two phases, from which the organic layer was taken up with
ether (50 mL × 2). The solids were dried over P2O5 in vacuo
and then dissolved in ethanolamine (100 mL) followed by
reflux for 30 min. After cooling, the solution was poured into
water (500 mL) and extracted with ether several times until
the organic phase became colorless. The ether layer was
combined with the former ether extract, washed with H2O (250
mL × 2) and sat. brine (250 mL), and dried over anhydrous
MgSO4. After removal of the solvent, the residue was distilled
at the reduced pressure to afford 11c as a colorless oil (7.05 g,
0.0466 mol, 59%): bp 91-93 °C at 1 mmHg; 1H NMR (270
MHz, CDCl3) δ 0.98 (t, J ) 7.3 Hz, 3H), 1.08 (t, J ) 7.3 Hz,
3H), 1.58 (sextet, J ) 7.3 Hz, 2H), 2.17 (s, 3H), 2.35-2.43 (m,
4H), 6.37 (d, J ) 2.4 Hz, 2H), 7.49 (br s, 1H); IR (CCl4) 3487,
2961, 2928, 2869 cm-1; EI MS (rel intensity) m/z 151 (M+, 43),
136 (28), 122 (100); HR EI MS calcd for [C10H17N]+ 151.1361,
found 151.1365.
Met h yl 4-E t h yl-3-(2-h yd r oxyet h yl)-5-m et h yl-1H-p yr -
r ole-2-ca r boxyla te (10b). A mixture of 9b (29.7 g, 0.117 mol)
and NaBH4 (17.5 g, 0.463 mol) in THF (360 mL) was cooled to
0 °C and then BF3‚Et2O (101 g, 0.712 mol) was added dropwise
over 2 h so as to maintain the reaction mixture at 0 °C. After
4 h of stirring, water (50 mL) and 1 M HCl (20 mL) were added
while cooled in an ice bath, followed by neutralization with
sat. NaHCO3. The THF was removed by evaporation, and the
aqueous mixture was extracted with CH2Cl2 (350 mL × 3).
The organic layer was washed with water (500 mL × 2) and
sat. brine (500 mL), followed by drying over anhydrous
MgSO4. Evaporation followed by drying in vacuo afforded 10b
as an ivory solid (20.6 g, 0.0975 mol, 84%). The product was
1
pure on the basis of the H NMR spectra, and it was used in
the following reaction without further purification: mp 110-
112 °C; 1H NMR (270 MHz, CDCl3) δ 1.06 (t, J ) 7.3 Hz, 3H),
2.21 (s, 3H), 2.40 (q, J ) 7.3 Hz, 2H), 3.01 (t, J ) 6.7 Hz, 2H),
3.78 (t, J ) 6.7 Hz, 2H), 3.81 (s, 3H), 8.96 (br s, 1H); IR (KBr)
3331, 2961, 2928, 2869, 1680, 1271 cm-1; EI MS (rel intensity)
2-(4-Eth yl-2,5-d ih yd r o-5-m eth yl-2-oxo-1H-p yr r ol-3-yl)-
eth a n ol (12b). To a solution of 11b (6.61 g, 0.0431 mol) in a
solvent mixture of MeOH and water (3:1, v/v, 55 mL) was
added dropwise 30% H2O2 (5.36 g, 0.0437 mol) at 50 °C. The
mixture was stirred for 2.5 h at the same temperature and
then heated at reflux for 1.5 h. After cooling, a solution of
K2CO3 (2.35 g, 0.0170 mol) in 25 mL of water was added, and
the resultant mixture was stirred overnight. The mixture was
condensed to ca. 15 mL by evaporation and neutralized with
concentrated HCl, followed by extraction with CH2Cl2 (100 mL
× 3). The organic layer was dried over anhydrous MgSO4. The
solvent was removed by evaporation, and the residue was
purified by silica gel column chromatography (20:1 CH2Cl2-
MeOH, v/v, as eluent). Crystallization was induced by scratch-
ing the product obtained as an oil on the flask to yield 12b
(3.91 g, 0.0231 mol, 54%) as an ivory solid: mp 90-92 °C; 1H
NMR (270 MHz, CDCl3) δ 1.09 (t, J ) 7.3 Hz, 3H), 1.29 (d, J
) 6.7 Hz, 3H), 2.17-2.30 (m, 1H, CH3CHH), 2.40-2.51 (m,
1H, CH3CHH), 2.54 (t, J ) 5.5 Hz, 2H), 3.73 (q, J ) 5.5 Hz,
2H), 4.15 (q, J ) 6.7 Hz, 1H), 4.35 (t, J ) 5.5 Hz, 1H), 7.33 (br
m/z 211 (M+, 67), 180 (100), 148 (59). Anal. Calcd for C11H17
-
NO3: C, 62.53; H, 8.11; N, 6.63. Found: C, 62.14; H, 8.31; N,
6.50.
E t h yl 4-E t h yl-5-m et h yl-3-p r op yl-1H -p yr r ole-2-ca r b -
oxyla te (10c). A mixture of 9c (22.1 g, 0.0931 mol) and
NaBH4 (8.88 g, 0.235 mol) in THF (200 mL) was cooled below
0 °C. To the mixture was added dropwise BF3‚Et2O (46.2 g,
0.325 mol) so that the temperature of the solution could be
kept at 0 °C. After the addition of BF3‚Et2O was completed,
the mixture was stirred for 1 h at room temperature. Water
(50 mL) and concentrated HCl (20 mL) were carefully added
while cooled in an ice bath with stirring, and then the mixture
was neutralized with sat. NaHCO3, followed by removal of the
THF by evaporation. The residual water layer was extracted
with CH2Cl2 (200 mL × 2). The organic phase was washed
with water (200 mL × 2) and sat. brine (200 mL) and dried
over anhydrous MgSO4. The solvent was removed and the
residue was dried in vacuo to afford 10c (18.6 g, 0.0834 mol,
90%), which was used in the next step without further
purification: mp 98-99 °C; 1H NMR (270 MHz, CDCl3) δ 0.96
(t, J ) 7.3 Hz, 3H), 1.06 (t, J ) 7.3 Hz, 3H), 1.34 (t, J ) 7.3
Hz, 3H), 1.54 (sextet, J ) 7.3 Hz, 2H), 2.21 (s, 3H), 2.38 (q, J
) 7.3 Hz, 2H), 2.66 (t, J ) 7.3 Hz, 2H), 4.28 (q, J ) 7.3 Hz,
2H), 8.70 (br s, 1H); IR (KBr) 3304, 2960, 2927, 2866, 1672,
1272 cm-1; EI MS (rel intensity) m/z 223 (M+, 85), 208 (23),
s, 1H); IR (KBr) 3397, 3359, 3249, 2972, 2935, 2874, 1681 cm-1
;
EI MS (rel intensity) m/z 169 (M+, 18), 151 (55), 139 (100).
Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28.
Found: C, 63.50; H, 9.17; N, 8.07.
2,5-Dih yd r o-4-et h yl-5-m et h yl-2-oxo-3-p r op yl-1H -p yr -
r ole (12c). To a solution of 11c (6.56 g, 0.0434 mol) in a
solvent mixture of MeOH and water (3:1, v/v, 50 mL) was
added dropwise 30% H2O2 (6.56 g, 0.0579 mol) at 55 °C. The
mixture was stirred for 2 h at the same temperature and then
heated at reflux for 2 h. After cooling, K2CO3 (2.99 g, 0.0216
mol) in 20 mL of water was added, followed by stirring
overnight at room temperature. The mixture was neutralized
with 1 M HCl, and the MeOH was removed by evaporation.
The residual solution was extracted with CH2Cl2 (50 mL ×
3), and the organic layer was washed with water (50 mL × 2)
and sat. brine (50 mL), followed by drying over anhydrous
MgSO4. The solvent was removed, and the residue was
purified by distillation at reduced pressure to afford 12c (5.68
194 (93), 176 (22), 162 (55), 148 (100). Anal. Calcd for C13H21
NO2: C, 69.92; H, 9.48; N, 6.27. Found: C, 70.07; H, 9.74; N,
6.12.
-
2-(3-Eth yl-2-m eth yl-1H-p yr r ol-4-yl)eth a n ol (11b).
A
solution of 10b (10.6 g, 0.0502 mol) and NaOH (6.02 g, 0.151
mol) in 3:1 (v/v) EtOH/H2O (120 mL) was heated at reflux for
3 h. After cooling to room temperature, the solution was
condensed to ca. 30 mL by evaporation. Acidification to pH 3
with concentrated HCl in an ice-water bath afforded pale pink
precipitates, which were collected by filtration and then dried
in vacuo. The solid was dissolved in ethanolamine (100 mL)
and heated at reflux for 2.5 h. After cooling, the solution was
poured to water (500 mL) followed by extraction with CH2Cl2
(150 mL × 3). The organic layer was washed with water (300
mL × 2) and sat. brine (300 mL) and dried over anhydrous
MgSO4. The solvent was removed by evaporation to yield 11b
(6.61 g, 0.0431 mol, 86%) as a dark red oil. The product was
quite unstable, so it was used in the following reaction without
purification: 1H NMR (500 MHz, CDCl3) δ 1.08 (t, J ) 7.6
Hz, 3H), 2.18 (s, 3H), 2.40 (q, J ) 7.6 Hz, 2H), 2.70 (t, J ) 6.7
Hz, 2H), 3.74 (t, J ) 6.7 Hz, 2H), 6.47 (d, J ) 2.1 Hz, 1H),
7.68 (br s, 1H) (the OH proton was not observed); IR (KBr)
3367, 2960, 2924, 2871 cm-1; EI MS (rel intensity) m/z 153
(M+, 45), 122 (100); HR EI MS calcd for [C9H15NO]+ 153.1153,
found 153.1158.
1
g, 0.0340 mol, 78%): bp 91-93 °C at 1 mmHg; H NMR (270
MHz, CDCl3) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.09 (t, J ) 7.3 Hz,
3H), 1.26 (d, J ) 6.7 Hz, 3H), 1.51 (sextet, J ) 7.3 Hz, 3H),
2.14-2.29 (m, 3H, CH3CHH), 2.42-2.56 (m, 1H, CH3CHH),
4.07 (q, J ) 6.7 Hz, 1H), 6.79 (br s, 1H); IR (CCl4) 3213, 2969,
2935, 2873, 1689 cm-1; EI MS (rel intensity) m/z 167 (M+, 66),
152 (32), 138 (100); HR EI MS calcd for [C10H17NO]+ 167.1310,
found 167.1304.
2-(5-Br om om et h ylen e-4-et h yl-2,5-d ih yd r o-2-oxo-1H -
p yr r ol-3-yl)eth yl Aceta te (13b). To a stirred solution of 12b
(18.6 g, 0.110 mol) in ethyl acetate (200 mL) was added
dropwise Br2 (35.6 g, 0.222 mol) at 55 °C. The mixture was
stirred at reflux for 15 min. After cooling, the solution was
washed with sat. NaHCO3 (150 mL × 3), water (150 mL), and
sat. brine (150 mL). During washing the solution, heavy
precipitate formed, which was removed by filtration. The
3-Eth yl-2-m eth yl-4-p r op yl-1H-p yr r ole (11c). To a solu-
tion of 10c (17.5 g, 0.0784 mol) in ethanol (85 mL) was added
a solution of NaOH (10.2 g, 0.255 mol) in water (30 mL). The

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8781
organic layer was dried over anhydrous MgSO4, reduced to
50 mL by evaporation, and then cooled to -20 °C. The light
brown solid was precipitated, which was filtered to yield 13b
(13.1 g, 0.0455 mol). The filtrate was evaporated to dryness,
followed by purification of the residue by silica gel chroma-
tography (5:1 benzene-acetone, v/v, as eluent) to afford
another crop of 13b (5.97 g, 0.0207 mol): total yield 60%; mp
113.7-114.2 °C; 1H NMR (270 MHz, CDCl3) δ 1.18 (t, J ) 7.9
Hz, 3H), 2.03 (s, 3H), 2.45 (q, J ) 7.9 Hz, 2H), 2.65 (t, J ) 6.7
Hz, 2H), 4.22 (t, J ) 6.7 Hz, 2H), 5.98 (s, 1H), 7.37 (br s, 1H);
IR (KBr) 3161, 3102, 2969, 2934, 2875, 1740, 1705, 1641, 1241
cm-1; EI MS (rel intensity) m/z 289 (5, M+ + 2), 287(5, M+),
246 (19), 244 (19), 229 (99), 227 (100), 202 (8), 200 (8). Anal.
Calcd for C11H14NO3Br: C, 45.85; H, 4.90; N, 4.86. Found:
C, 45.47; H, 4.85; N, 4.59.
2,18-Bis(2-a cetoxyeth yl)-7,13-d im eth yl-3,8,12,17-tetr a -
eth yl-1,19,21,24-tetr a h yd r o-1,19-bilin d ion e (15b). To a
refluxed solution of p-chloranil (3.07 g, 12.5 mmol) in CH2Cl2
(300 mL) was added dropwise a solution of 14b (1.65 g, 5.00
mmol) in CH2Cl2 (200 mL) over an hour, followed by addition
of formic acid (30 mL). The mixture was stirred under reflux
for 30 h and then condensed to ca. 300 mL, followed by stirring
for additional 12 h. After cooling, the mixture was allowed to
stand overnight at -20 °C to afford brownish green precipi-
tates which were removed by filtration. The bluish green
filtrate was neutralized with sat. Na2CO3, followed by extrac-
tion with CHCl3 (200 mL × 3). The organic phase was
combined, washed with water (300 mL × 2) and sat. brine
(300 mL), and dried over anhydrous MgSO4. The solvent was
removed by evaporation to afford a dark blue residue, which
was purified by silica gel column chromatography (40:1
CHCl3-MeOH, v/v, as eluent). Recrystallization from CHCl3-
MeOH afforded a dark blue crystal of 15b (1.15 g, 1.79 mmol,
5-Br om om eth ylen e-4-eth yl-2,5-dih yd r o-2-oxo-3-p r opyl-
1H-p yr r ole (13c). To a stirred solution of 12c (5.35 g, 0.0320
mol) in ethyl acetate (45 mL) was added Br2 (3.3 mL, 0.064
mol) at 55 °C over 1 h. After the completion of the addition,
the mixture was heated at reflux for 15 min. After cooling,
the solution was washed with sat. NaHCO3 (100 mL × 3),
water (100 mL), and sat. brine (100 mL), and then was dried
over MgSO4. The solvent was evaporated to afford precipi-
tates, which were separated by filtration and washed with a
small amount of cold ether. The filtrate and washings were
combined and evaporated. To the residue was added a small
amount of hexane, followed by standing overnight at -20 °C
to afford precipitates. This procedure was repeated until
further precipitations were not obtained. All the precipitates
were combined and dried in vacuo to yield 13c (5.96 g, 0.0244
mol, 76%), which was used in the next step without further
purification: mp 89-91 °C; 1H NMR (270 MHz, CDCl3) δ 0.94
(t, J ) 7.3 Hz, 3H), 1.16 (t, J ) 7.3 Hz, 3H), 1.54 (sextet, J )
7.3 Hz, 2H), 2.27 (t, J ) 7.3 Hz, 2H), 2.42 (q, J ) 7.3 Hz, 2H),
5.91 (s, 1H), 7.24 (br s, 1H); IR (KBr) 3166, 3104, 2958, 2935,
2872, 1704, 1691, 1641 cm-1; EI MS (rel intensity) m/z 245
(99, M+ + 2), 243(100, M+), 230 (36), 228 (39), 216 (65), 214
1
72%): mp 214-216 °C; H NMR (500 MHz, CDCl3) δ 1.16 (t,
J ) 7.9 Hz, 6H), 1.25 (t, J ) 7.9 Hz, 6H), 2.03 (s, 6H), 2.06 (s,
6H), 2.54 (q, J ) 7.9 Hz, 4H), 2.57 (q, J ) 7.9 Hz, 4H), 2.61 (t,
J ) 7.3 Hz, 4H), 4.16 (t, J ) 7.3 Hz, 4H), 5.92 (s, 2H), 6.61 (s,
1H); IR (KBr) 3450, 2967, 2932, 2871, 1736, 1689, 1591, 1244
cm-1; EI MS (rel intensity) m/z 642 (M+, 100), 582 (27), 522
(6); HR FAB MS calcd for [C37H46N4O6]+ 642.3417, found
642.3444. Anal. Calcd for C37H46N4O6: C, 69.14; H, 7.21; N,
8.72. Found: C, 68.78; H, 7.28; N, 8.38.
3,8,12,17-Tet r a et h yl-1,19,21,24-t et r a h yd r o-2,18-b is(2-
h ydr oxyeth yl)-7,13-dim eth yl-1,19-bilin dion e (15c). A mix-
ture of 15b (336 mg, 0.523 mmol), 5% HCl (15 mL) and acetone
(15 mL) was boiled for 2.5 h. After cooling, 1.6 M NaOH (ca.
20 mL) was added to the reaction mixture, and the solution
was acidified with acetic acid to pH 4, followed by neutraliza-
tion with sat. NaHCO3. Extraction with CHCl3 (50 mL × 3)
was carried out, and the organic phase was washed with sat.
NaHCO3 (50 mL), water (50 mL), and sat. brine (50 mL), and
dried over anhydrous MgSO4. After evaporation of the CHCl3,
the residue was purified by silica gel column chromatography
(20:1 CHCl3-MeOH, v/v, as eluent) to yield 15c (222 mg, 0.397
mmol, 76%): mp 239-241 °C (dec); 1H NMR (500 MHz, CDCl3)
δ 1.15 (t, J ) 7.3 Hz, 6H), 1.23 (t, J ) 7.9 Hz, 6H), 2.02 (s,
6H), 2.48-2.57 (m, 12H), 3.74 (t, J ) 5.5 Hz, 4H), 5.86 (s, 2H),
6.54 (s, 1H) (NH and OH protons were not observed because
of rapid proton exchanges); IR (KBr) 3397, 3368, 3248, 2963,
2929, 2870, 1688, 1588, 1214 cm-1; HR FAB MS calcd for
[C33H42N4O4]+ 558.3206, found 558.3231. Anal. Calcd for
(64), 164 (73), 136 (89), 135 (76); HR EI MS calcd for [C10H14
-
NOBr]+ 243.0259, found 243.0268.
2-[3,8-Dieth yl-7,9-dim eth yl-1-oxo-1,10-dih ydr odipyr r in -
2-yl]eth yl Aceta te (14b). A mixture of 4-ethyl-3,5-dimethyl-
1H-pyrrole-2-carboxylic acid (2.61 g, 15.6 mmol) and 13b (2.07
g, 7.18 mmol) in MeOH (15 mL) was heated at reflux for 1 h.
After cooling, the yellow precipitates were collected by filtra-
tion and dissolved in a small amount of CH2Cl2. Addition of
MeOH with stirring afforded a yellow solid, and the suspension
was cooled to -20 °C. The solid was filtered and dried in vacuo
to yield 14b (1.42 g, 4.31 mmol, 60%) which was used in the
next step without further purification: mp 184-185 °C (dec);
1H NMR (500 MHz, CDCl3) δ 1.08 (t, J ) 7.9 Hz, 3H), 1.23 (t,
J ) 7.9 Hz, 3H), 2.02 (3H, s), 2.14 (3H, s), 2.37 (3H, s), 2.41
(q, J ) 7.9 Hz, 2H), 2.60 (q, J ) 7.9 Hz, 2H), 2.74 (t, J ) 6.9
Hz, 2H), 4.20 (t, J ) 6.9 Hz, 2H), 6.21 (s, 1H), 10.3 (br s, 1H),
11.3 (br s, 1H); IR (KBr) 3342, 2966, 2932, 2872, 1742, 1673,
1637, 1239 cm-1; EI MS (rel intensity) m/z 330 (M+, 100), 270
(88). Anal. Calcd for C19H26N2O3: C, 69.06; H, 7.93; N, 8.48.
Found: C, 68.68; H, 8.10; N, 8.32.
C
33H42N4O4 + CH3OH: C, 69.13; H, 7.21; N, 8.72. Found: C,
68.78; H, 7.28; N, 8.38.
3,8,12,17-T e t r a e t h y l-7,13-d im e t h y l-2,18-d ip r o p y l-
1,19,21,24-tetr a h yd r o-1,19-bilin d ion e (15d ). To a refluxed
solution of p-chloranil (2.46 g, 10.0 mmol) in CH2Cl2 (250 mL)
was added dropwise a solution of 14c (1.15 g, 4.00 mmol) in
CH2Cl2 (300 mL) over an hour, and then formic acid (25 mL)
was added at a time. The color of the solution was initially
dark yellow and changed to dark bluish green as the reaction
proceeded. The mixture was heated at reflux for 24 h and
condensed to 150 mL by distillation, followed by reflux for
additional 12 h. Cooling to -20 °C followed by standing
overnight afforded heavy precipitates, which were filtered off.
The filtrate was neutralized with sat. Na2CO3. The organic
phase was separated, washed with 1 M NaOH (300 mL × 3),
water (500 mL × 3), and sat. brine (500 mL × 3), and dried
over MgSO4. Evaporation of the organic solution followed by
recrystallization from CH2Cl2-MeOH yielded 15d as a dark
blue crystal (614 mg, 1.11 mmol, 55%): mp 238-240 °C (dec);
1H NMR (500 MHz, CDCl3) δ 0.94 (t, J ) 7.3 Hz, 6H), 1.17 (t,
J ) 7.3 Hz, 6H), 1.23 (t, J ) 7.3 Hz, 6H), 1.51 (sextet, J ) 7.3
Hz, 6H), 2.07 (s, 6H), 2.23 (t, J ) 7.3 Hz, 4H), 2.48-2.63 (m,
8H), 5.91 (s, 2H), 6.64 (s, 1H) (NH protons were not observed
because of rapid proton exchanges); IR (KBr) 2963, 2929, 2868,
3,8-Die t h yl-7,9-d im e t h yl-1-oxo-2-p r op yl-1,10-d ih y-
d r od ip yr r in (14c). A mixture of 3-ethyl-2,4-dimethyl-1H-
pyrrole (1.49 g, 0.0121 mol) and 13c (2.44 g, 0.0100 mol) in
MeOH (20 mL) was heated at reflux under Ar for 2 h. After
cooling, the mixture was allowed to stand overnight at -20
°C to afford yellow precipitates, which were separated by
filtration. Washing the precipitates with CH2Cl2-MeOH (1:
1, v/v, 75 mL) afforded 14c (1.68 g, 5.85 mmol, 59%), which
was used in the next step without further purification: mp
1
211-213 °C (dec); H NMR (500 MHz, CDCl3) δ 0.94 (t, J )
7.3 Hz, 3H), 1.08 (t, J ) 7.3 Hz, 3H), 1.20 (t, J ) 7.3 Hz, 3H),
1.56 (sextet, J ) 7.3 Hz, 2H), 2.14 (3H, s), 2.35 (t, J ) 7.3 Hz,
2H), 2.40 (3H, s), 2.41-2.44 (m, 2H), 2.56 (q, J ) 7.3 Hz, 2H),
6.14 (s, 1H), 10.3 (br s, 1H), 11.3 (br s, 1H); IR (KBr) 3351,
2961, 2929, 2869, 1669, 1635, 1245 cm-1; EI MS (rel intensity)
m/z 286 (M+, 100), 257 (73), 241 (44), 212 (21). Anal. Calcd
for C18H26N2O: C, 75.48; H, 9.15; N, 9.78. Found: C, 75.06;
H, 9.46; N, 9.65.
1698, 1680, 1591, 1214 cm-1; HR FAB MS calcd for [C35H46
N4O2]+ 554.3621, found 554.3644. Anal. Calcd for
35H46N4O2: C, 75.78; H, 8.36; N, 10.10. Found: C, 75.62; H,
8.59; N, 10.13.
-
C

8782 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
(2,8,13,17-Tetr aeth yl-3,7,12,18-tetr am eth yl-5-oxon iapor -
p h yr in a to)zin c(II) Ch lor id e (16a ). A mixture of 15a (1.20
g, 2.41 mmol), acetic anhydride (45 mL), ethanol saturated
with zinc acetate (45 mL), and CHCl3 (250 mL) was boiled for
0.5 h in an oil bath with a temperature of 80 °C. After cooling,
the solvent was removed by evaporation, and CH2Cl2 (250 mL)
was added to the residue, followed by washing with water (150
mL × 3), 10% NH4Cl (150 mL × 3), and sat. brine (200 mL).
After the extracts were dried over anhydrous MgSO4, a dark
blue solid was obtained by evaporating the solvent. Purifica-
tion by silica gel column chromatography (20:1 CH2Cl2-MeOH,
v/v, as eluent) followed by recrystallization from CH2Cl2-
hexane yielded a dark blue crystal of 16a (1.14 g, 1.96 mmol,
residue by silica gel column chromatography (75:1 CH2Cl2-
MeOH, v/v, as eluent) followed by recrystallization from
CHCl3-hexane yielded 17a as a dark blue solid (181 mg, 0.354
mmol, 82%): mp 229-231 °C (dec), (lit.31 mp 233-235 °C); 1H
NMR (500 MHz, CDCl3) δ 1.13-1.18 (m, 9H), 1.19 (t, J ) 7.9
Hz, 3H), 1.73 (s, 3H), 1.84 (s, 3H), 2.02 (s, 3H), 2.11 (s, 3H),
2.47 (q, J ) 7.9 Hz, 4H), 2.54 (q, J ) 7.9 Hz, 2H), 2.57 (q, J )
7.9 Hz, 2H), 3.97 (s, 3H), 5.76 (s, 1H), 6.29 (s, 1H), 6.61 (s,
1H), 10.2 (br s, 1H), 12.9 (br s, 1H); IR (KBr) 3445, 2961, 2925,
2865, 1701, 1627, 1588, 1212 cm-1; EI MS (rel intensity) m/z
512 (M+, 100), 497 (74), 483 (30). Anal. Calcd for
C32H40N4O2: C, 74.97; H, 7.86; N, 10.93. Found: C, 74.57; H,
8.00; N, 10.88.
1
81%): mp > 250 °C (dec); H NMR (500 MHz, CDCl3) δ 1.61
3,7-Bis(2-a cetoxyeth yl)-3,8,12,17-tetr a eth yl-1,21-d ih y-
d r o-19-m eth oxy-7,13-d im eth yl-22H-bilin -1-on e (17b). A
mixture of 16b (204 mg, 0.282 mmol) and sodium methoxide
(17.9 mg, 0.331 mmol) in dry MeOH (17 mL) was stirred at
room temperature for 4 h. Dichloromethane (60 mL) was
added, and the mixture was washed with water (60 mL) and
then vigorously shaken with phthalate buffer (pH ) 4.01, 60
mL × 3). The organic layer was washed with sat. brine (60
mL) and dried over anhydrous Na2SO4, followed by removal
of the solvent. Purification of the residue by silica gel column
chromatography (100:1 CH2Cl2-MeOH, v/v, as eluent) followed
by recrystallization from CH2Cl2-hexane yielded a dark blue
crystal of 17b (132 mg, 0.201 mmol, 71%): mp 146-148 °C
(t, J ) 7.9 Hz, 6H), 1.64 (t, J ) 7.9 Hz, 6H), 3.00 (s, 6H), 3.06
(s, 6H), 3.48-3.58 (m, 8H), 9.19 (s, 2H), 9.27 (s, 2H); IR (KBr)
2968, 2929, 2870, 1546, 1210 cm-1; FAB MS m/z 543 ([M -
Cl]+); HR FAB MS calcd for [C31H35N4O64Zn]+ 543.2102, found
543.2080. Anal. Calcd for C31H35N4OZnCl: C, 64.14; H, 6.08;
N, 9.65. Found: C, 64.31; H, 6.11; N, 9.76.
[3,7-Bis(2-a cet oxyet h yl)-2,8,13,17-t et r a et h yl-12,18-d i-
m eth yl-5-oxon ia p or p h yr in a to]zin c(II) Ch lor id e (16b). A
mixture of 15b (324 mg, 0.504 mmol), acetic anhydride (10
mL), ethanol saturated with zinc acetate (10 mL), and CHCl3
(50 mL) was boiled for 0.5 h in an oil bath with a temperature
of 80 °C. After cooling, the solvent was removed by evapora-
tion, and to the resultant mixture was added CH2Cl2 (75 mL).
The mixture was washed with water (50 mL × 3), 10% NH4Cl
(60 mL × 3), and sat. brine (50 mL), and then dried over
anhydrous MgSO4, followed by removal of the solvent. Puri-
fication of the residue by silica gel column chromatography
(40:1 CH2Cl2-MeOH, v/v, as eluent) followed by recrystalli-
zation from CH2Cl2-hexane yielded a dark blue crystal of 16b
(0.248 mg, 0.343 mmol, 68%): mp 216-219 °C (dec); 1H NMR
(500 MHz, CDCl3) δ 1.62 (t, J ) 7.9 Hz, 6H), 1.71 (t, J ) 7.9
Hz, 6H), 2.03 (s, 6H), 3.07 (s, 6H), 3.49-3.64 (m, 8H), 3.75-
3.81 (m, 2H), 3.83-3.89 (m, 2H), 4.71-4.76 (m, 2H), 4.78-
4.83 (m, 2H), 9.27 (s, 2H), 9.30 (s, 1H); IR (KBr) 2967, 2932,
2873, 1740, 1546, 1243 cm-1; FAB MS m/z 687 ([M - Cl]+);
HR FAB MS calcd for [C37H43N4O564Zn]+ 687.2525, found
687.2530. Anal. Calcd for C37H43N4O5ZnCl: C, 61.33; H, 5.98;
N, 7.73. Found: C, 61.26; H, 6.07; N, 7.75.
(2,8,13,17-Tetr aeth yl-12,18-dim eth yl-3,7-dipr opyl-5-oxo-
n ia p or p h yr in a to)zin c(II) Ch lor id e (16c). A mixture of 15d
(277 mg, 0.499 mmol), acetic anhydride (10 mL), ethanol
saturated with zinc acetate (10 mL), and CHCl3 (50 mL) was
boiled for 2 days in an oil bath with a temperature of 90 °C.
After cooling, the solvent was removed by evaporation, and to
the resultant mixture was added CH2Cl2 (75 mL). The mixture
was washed with water (50 mL × 3), 10% NH4Cl (60 mL × 3),
and sat. brine (50 mL), and then dried over anhydrous MgSO4,
followed by removal of the solvent. Purification of the residue
by silica gel column chromatography (40:1 CH2Cl2-MeOH, v/v,
as eluent) followed by recrystallization from CH2Cl2-hexane
yielded a dark blue crystal of 16c (134 mg, 0.210 mmol, 42%):
mp 238-241 °C (dec); 1H NMR (500 MHz, CDCl3) δ 1.24 (t, J
) 7.3 Hz, 6H), 1.61 (t, J ) 7.6 Hz, 6H), 1.67 (t, J ) 7.6 Hz,
6H), 2.15 (sextet, J ) 7.3 Hz, 4H), 3.06 (s, 6H), 3.33-3.39 (m,
2H), 3.41-3.47 (m, 2H), 3.48-3.60 (m, 8H), 9.21 (s, 2H), 9.27
(s, 1H); IR (KBr) 2962, 2931, 2869, 1549, 1204 cm-1; FAB MS
m/z 599 ([M - Cl]+); HR FAB MS calcd for [C35H43N4O64Zn]+
599.2728, found 599.2701. Anal. Calcd for C35H43N4OClZn:
C, 66.04; H, 6.81; N, 8.80. Found: C, 66.41; H, 6.96; N, 8.79.
3,8,12,17-Tetr aeth yl-1,21-dih ydr o-19-m eth oxy-2,7,13,18-
tetr a m eth yl-22H-bilin -1-on e (17a ). A mixture of 16a (250
mg, 0.431 mmol) and sodium methoxide (73 mg, 1.35 mmol)
in dry MeOH (55 mL) was stirred at room temperature for
1.5 h. To the reaction mixture was added 10% NH4Cl (100
mL), followed by extractive work up with CHCl3 (55 mL × 2).
The organic layer was washed with 10% NH4Cl (100 mL × 2)
and vigorously shaken with phthalate buffer (pH ) 4.01, 100
mL × 2). The dark green solution then turned blue. The
solution was washed with water (100 mL) and sat. brine (100
mL). After the extracts were dried over anhydrous Na2SO4,
the solvent was removed by evaporation. Purification of the
1
(dec); H NMR (500 MHz, CDCl3) δ 1.13-1.16 (m, 6H), 1.20
(t, J ) 7.9 Hz, 3H) 1.22 (t, J ) 7.6 Hz, 3H), 2.01 (s, 3H), 2.020
(s, 3H), 2.022 (s, 3H), 2.10 (s, 3H), 2.47-2.59 (m, 10H), 2.63
(t, J ) 7.0 Hz, 2H), 4.02 (s, 3H), 4.06 (t, J ) 7.0 Hz, 2H), 4.14
(t, J ) 7.0 Hz, 2H), 5.78 (s, 1H), 6.31 (s, 1H), 6.59 (s, 1H),
10.42 (br s, 1H), 13.04 (br s, 1H); IR (KBr) 3444, 2967, 2933,
2871, 1739, 1697, 1590, 1242, 1213 cm-1; FAB MS m/z 657 (M
+ H+); HR FAB MS calcd for [C38H48N4O6]+ 656.3574, found
656.3553. Anal. Calcd for C38H48N4O6: C, 69.49; H, 7.37; N,
8.53. Found: C, 69.29; H, 7.57; N, 8.06.
3,8,12,17-Tet r a et h yl-1,21-d ih yd r o-3,7-b is(2-h yd r oxy-
eth yl)-19-m eth oxy-7,13-d im eth yl-22H-bilin -1-on e (17c). A
mixture of 16b (126 mg, 0.218 mmol) and sodium methoxide
(126 mg, 2.33 mmol) in dry MeOH (13 mL) was stirred at room
temperature for 4 h. Dichloromethane (50 mL) was added,
and the mixture was washed with water (50 mL) and then
vigorously shaken with phthalate buffer (pH ) 4.01, 50 mL ×
3). The solution was washed with sat. brine (50 mL) and dried
over anhydrous Na2SO4, followed by removal of the solvent.
Purification of the residue by silica gel column chromatography
(30:1 CH2Cl2-MeOH, v/v, as eluent) followed by recrystalli-
zation from CH2Cl2-hexane yielded a dark blue crystal of 17c
1
(96.0 mg, 0.168 mmol, 77%): mp 171-173 °C (dec); H NMR
(500 MHz, CDCl3) δ 1.12-1.15 (m, 6H), 1.19 (t, J ) 7.3 Hz,
3H), 1.22 (t, J ) 7.3 Hz, 3H), 2.00 (s, 3H), 2.08 (s, 3H), 2.40-
2.57 (m, 12H), 3.16 (br s, 1H, D2O exchangeable), 3.65 (br s,
1H, D2O exchangeable), 3.67-3.69 (m, 4H), 4.15 (s, 3H), 5.77
(s, 1H), 6.26 (s, 1H), 6.55 (s, 1H), 10.88 (br s, 1H), 13.43 (br s,
1H); IR (KBr) 3343, 2965, 2931, 2872, 1680, 1587, 1218 cm-1
;
FAB MS m/z 572 (M + H+); HR FAB MS calcd for [C34H44N4O4]+
572.3363, found 572.3375. Anal. Calcd for C34H44N4O4: C,
71.30; H, 7.74; N, 9.78. Found: C, 70.91; H, 7.89; N, 9.68.
3,8,12,17-Tetr aeth yl-1,21-dih ydr o-2,7,13,18-tetr am eth yl-
19-(2-p r op oxy)-22H-bilin -1-on e (17d ). This compound was
prepared by a procedure similar to 17b using 16a (174 mg,
0.300 mmol) and sodium 2-propoxide (3 mL, 0.3 M in 2-pro-
panol) and 2-propanol (30 mL). After the reaction was
completed, the mixture was treated with 10% NH4Cl (40 mL),
followed by extractive work up with CHCl3 (40 mL × 3). The
organic layer was washed with 10% NH4Cl (40 mL × 3) and
vigorously shaken with phthalate buffer (pH ) 4.01, 40 mL ×
3). The solution was washed with water (50 mL × 2) and sat.
brine (50 mL). After drying the extracts were dried anhydrous
Na2SO4, the solvent was removed by evaporation. Purification
of the resultant mixture by silica gel column chromatography
(31) Falk, H.; Grubmeyer, K.; Thirring, K. Z. Naturforsh. 1978, 33b,
924-931.

Helical Chirality Induction in Zn Bilindiones
J . Org. Chem., Vol. 63, No. 24, 1998 8783
(100:1 CH2Cl2-MeOH, v/v, as eluent) followed by recrystalli-
zation from CHCl3-hexane yielded 17d as a dark blue crystal
tributylamine (53.7 mg, 0.290 mmol) in 1 mL of dry CH2Cl2
was stirred at reflux under argon for 1.5 h. Purification by
silica gel thin-layer chromatography (hexane-ethyl acetate 1:1
(v/v) as eluent) yielded the amide of (+)-benzylmethylphenyl-
silylacetic acid with (S)-23 (36.9 mg, 0.0884 mmol, 76%): 1H
NMR (270 MHz, CDCl3) δ 0.31 (s, 3H), 1.94 (d, J ) 12.8 Hz,
1H), 2.00 (d, J ) 12.8 Hz, 1H), 2.43 (d, J ) 14.0 Hz, 1H), 2.50
(d, J ) 14.0 Hz, 1H), 2.59-2.72 (m, 2H), 3.06 (dd, J ) 9.5, 3.7
Hz, 1H), 3.16 (dd, J ) 9.5, 3.7 Hz, 1H), 3.25 (s, 3H), 4.10-
4.23 (m, 1H), 5.32 (d, J ) 8.6 Hz, 1H), 6.99 (dd, J ) 7.6, 1.8
Hz, 2H), 7.04-7.42 (m, 11H), 7.46 (dd, J ) 7.6, 1.8 Hz, 2H);
FAB MS m/z 418 ([M + H]+).
1
(133 mg, 0.245 mmol, 82%): mp 199-201 °C (dec); H NMR
(500 MHz, CDCl3) δ 1.13-1.19 (m, 18H), 1.74 (s, 3H), 1.84 (s,
3H), 2.04 (s, 3H), 2.12 (s, 3H), 2.44-2.50 (m, 4H), 2.52-2.61
(m, 4H), 5.31 (spt, J ) 6.1 Hz, 1H), 5.81 (s, 1H), 6.28 (s, 1H),
6.64 (s, 1H), 10.17 (br s, 1H), 12.65 (br s, 1H); IR (KBr) 3461,
2961, 2930, 2867, 1701, 1582, 1209 cm-1; FAB MS m/z 540
([M+]); HR FAB MS calcd for [C34H44N4O2]+ 540.3464, found
540.3483. Anal. Calcd for C34H44N4O2: C, 75.52; H, 8.20; N,
10.40. Found: C, 75.82; H, 8.18; N, 10.27.
3,8,12,17-Tetr a eth yl-1,21-d ih yd r o-19-m eth oxy-7,13-d i-
m eth yl-2,18-d ip r op yl-22H-bilin -1-on e (17e). A mixture of
16c (127 mg, 0.200 mmol) and sodium methoxide (33.0 mg,
0.61 mmol) in dry MeOH (20 mL) was stirred at room
temperature for 1 h. To the reaction mixture was added CHCl3
(30 mL), followed by washing with 10% NH4Cl (30 mL). The
organic layer was vigorously shaken with phthalate buffer (pH
) 4.01, 30 mL × 3), and the dark green solution then turned
blue. The organic layer was washed with water (30 mL) and
sat. brine (30 mL). After drying the extracts over anhydrous
Na2SO4, the solvent was removed by evaporation. Purification
of the residue by silica gel column chromatography (75:1 CH2-
Cl2-MeOH, v/v, as eluent) followed by recrystallization from
CH2Cl2-hexane yielded 17e as a dark blue crystal (85.2 mg,
0.150 mmol, 75%): mp 215-217 °C (dec); 1H NMR (270 MHz,
CDCl3) δ 0.86-0.94 (m, 6H), 1.11-1.26 (m, 12H), 1.36-1.54
(m, 4H), 2.01 (s, 3H), 2.10 (s, 3H), 2.12-2.17 (m, 2H), 2.24 (t,
J ) 7.3 Hz, 2H), 2.43-2.61 (m, 8H), 3.99 (s, 3H), 5.75 (s, 1H),
6.28 (s, 1H), 6.60 (s, 1H), 10.3 (br s, 1H), 12.9 (br s, 1H); IR
(KBr) 2961, 2930, 2868, 1701, 1582, 1209 cm-1; FAB MS m/z
568 ([M+]); HR FAB MS calcd for [C36H48N4O2]+ 568.3777,
found 568.3758. Anal. Calcd for C36H48N4O2: C, 76.02; H,
8.51; N, 9.85. Found: C, 75.97; H, 8.65; N, 9.63.
The 1H NMR spectrum of the amide showed that the
enantiomeric excess of the amine is higher than 90%; the
SiCH3 signal in the 1H NMR spectrum was observed only at
0.31 ppm, while that of the amide derived from (+)-benzyl-
methylphenylsilylacetic acid and racemic 2-amino-1-methoxy-
3-phenylpropane was observed at 0.31 and 0.33 ppm.
(S)-2-Am in o-1-m et h oxy-4-m et h ylp en t a n e (Leu cin ol
Meth yl Eth er , 24). The synthesis of (S)-24 was carried out
similarly. Potassium hydride (3.93 g, 0.0343 mol, 35 wt % oil
dispersion) was placed in a flask and washed with hexane
several times. THF (45 mL) was added, and to the suspension
was then added dropwise (S)-2-amino-1-hydroxy-4-methylpen-
tane (4.02 g, 0.0343 mol) dissolved in THF (30 mL). The
mixture was stirred overnight at room temperature and then
cooled to 0 °C. Iodomethane (4.87 g, 0.0343 mol) in THF (45
mL) was added dropwise over 30 min. After 30 min of stirring,
the mixture was poured into ice (15 g), followed by addition of
30 mL of water. The THF was removed by evaporation, and
the aqueous mixture was extracted with hexane (30 mL × 3).
The organic phase was dried over anhydrous MgSO4, and the
solvent was then removed on a rotary evaporator. Distillation
at the reduced pressure yielded pure (S)-24 as a colorless oil
(1.21 g, 0.00922 mol, 27%): bp 63.5-64.5 °C at 25 mmHg; 1H
NMR (500 MHz, CDCl3) δ 0.90 (d, J ) 6.7 Hz, 3H), 0.93 (d, J
) 6.7 Hz, 3H), 1.16-1.20 (m, 2H), 1.43 (br s, 2H), 1.69-1.78
(m, 1H), 3.00-3.05 (m, 1H), 3.11 (dd, J ) 8.9, 7.9 Hz, 1H),
3.33 (dd, J ) 8.9, 3.7 Hz, 1H), 3.36 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 22.0, 23.4, 24.6, 43.3, 48.6, 58.9, 78.8.
(+)-Ben zylm eth ylp h en ylsilyla ceta m id e Der ived fr om
(S)-2-Am in o-1-m eth oxy-4-m eth ylp en ta n e. A mixture of
(S)-24 (14.2 mg, 0.108 mmol), (+)-benzylmethylphenylsilylace-
tic acid (29.2 mg, 0.108 mmol), 2-chloro-1-methylpyridinium
iodide (33.1 mg, 0.130 mmol), and tributylamine (50.0 mg,
0.270 mmol) in 1 mL of dry CH2Cl2 was stirred at reflux under
argon for 1.5 h. Purification by silica gel thin-layer chroma-
tography (hexane-ethyl acetate 1:1 (v/v) as eluent) yielded the
amide of (+)-benzylmethylphenylsilylacetic acid with (S)-24
(36.0 mg, 0.0938 mmol, 87%): 1H NMR (270 MHz, CDCl3) δ
0.37 (s, 3H), 1.16 (t, J ) 7.3 Hz, 1H), 1.96 (d, J ) 12.8 Hz,
1H), 2.01 (d, J ) 12.8 Hz, 1H), 2.43 (d, J ) 14.0 Hz, 1H), 2.50
(d, J ) 14.0 Hz, 1H), 3.17 (dd, J ) 9.5, 3.7 Hz, 1H), 3.22 (dd,
J ) 9.5, 3.7 Hz, 1H), 3.25 (s, 3H), 4.09-3.97 (m, 1H), 5.05 (d,
J ) 8.6 Hz, 1H), 6.99 (dd, J ) 7.6, 1.8 Hz, 2H), 7.14-7.04 (m,
1H), 7.26-7.15 (m, 2H), 7.42-7.31 (m, 3H), 7.47 (dd, J ) 7.6,
1.8 Hz, 2H); FAB MS m/z 384 ([M + H]+).
1-Na p h th ylm eth yl N-ter t-Bu toxyca r bon yl-L-leu cin a te.
To a stirred mixture of N-Boc-leucine monohydrate (997 mg,
4.00 mmol), 1-naphthylmethanol (633 mg, 4.00 mmol), and
4-(N,N-dimethylamino)pyridine (54 mg, 0.44 mmol) in dry CH2-
Cl2 (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride (843 mg, 4.40 mmol) at 0 °C. The
mixture was stirred at the same temperature and then stirred
overnight at ambient temperature. The solvent was removed
by evaporation, and the residue was dissolved in ethyl acetate
(150 mL). The solution was washed with sat. Na2CO3 (30 mL
× 2), water (30 mL × 2), and saturated brine (30 mL) and
dried over anhydrous MgSO4. Purification by silica gel column
chromatography afforded N-tert-butoxycarbonyl-L-leucine 1-
naphthylmethyl ester as a syrup (977 mg, 2.63 mmol, 66%):
1H NMR (500 MHz, CDCl3) δ 0.85 (d, J ) 6.1 Hz, 3H), 0.86 (d,
J ) 6.1 Hz, 3H), 1.40-1.71 (m, 12H), 4.34-4.39 (m, 1H), 4.91
(d, J ) 8.6 Hz, 1H), 5.59 (d, J ) 12.5 Hz, 1H), 5.65 (d, J )
12.5 Hz, 1H), 7.45 (t, J ) 7.9 Hz, 1H), 7.49-7.57 (m, 3H), 7.85
P r ep a r a tion of Am in o Alcoh ol Meth yl Eth er s. Prepa-
ration of amino alcohol methyl ethers followed the literature
procedure.32 The optical purity of each compound was checked
by 1H NMR of their (+)-benzylmethylphenylsilylacetyl-
amide derivatives.33 For example, the SiCH3 signals of the
amide derived from racemic 24 appeared at 0.35 and 0.37 ppm.
1
There was no peak at 0.35 ppm in the H NMR spectra of (S)-
24 prepared here, showing that its enantiomeric excess is
higher than 90%. A similar result was obtained for 23.
(S)-2-Am in o-1-m et h oxy-3-p h en ylp r op a n e (P h en yla -
la n in ol Meth yl Eth er , 23). Potassium hydride (2.95 g,
0.0257 mol, 35 wt % oil dispersion) was placed in a flask and
washed with hexane several times. THF (50 mL) was added,
and to the suspension was added dropwise (S)-2-amino-1-
hydroxy-3-phenylpropane (4.09 g, 0.027 mol) dissolved in THF
(50 mL). The mixture was stirred overnight at room temper-
ature and then cooled to 0 °C. Iodomethane (3.57 g, 0.0252
mol) in THF (10 mL) was added dropwise over 30 min. After
1 h of stirring, the mixture was poured into ice (10 g), followed
by addition of 100 mL of water. The THF was removed by
evaporation, and the aqueous mixture was extracted with
hexane (50 mL × 3). The organic phase was dried over
anhydrous MgSO4, and the solvent was then removed on a
rotary evaporator. Distillation at the reduced pressure (4
mmHg) yielded pure (S)-23 as a colorless oil (2.45 g, 0.0148
mol, 55%): bp 100-102 °C at 4 mmHg (lit.32 95-100 °C at 15
mmHg); 1H NMR (500 MHz, CDCl3) δ 1.43 (br s, 2H), 2.55
(dd, J ) 13.4, 7.9 Hz, 1H), 2.78 (dd, J ) 13.4, 4.9 Hz, 1H),
3.21-3.24 (m, 2H), 3.35-3.39 (m, 4H), 7.20-7.23 (m, 3H),
7.29-7.32 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 40.8, 52.3,
58.9, 77.4, 126.3, 128.4, 129.2, 138.8.
(+)-Ben zylm eth ylp h en ylsilyla ceta m id e Der ived fr om
(S)-2-Am in o-1-m eth oxy-3-p h en ylp r op a n e. Conversion to
the amide was carried out according to the procedure of
Nohira.33 A mixture of (S)-23 (19.2 mg, 0.116 mmol), (+)-
benzylmethylphenylsilylacetic acid (31.5 mg, 0.116 mmol),
2-chloro-1-methylpyridinium iodide (34.5 mg, 0.135 mmol), and
(32) Welch, J . T.; Seper, K. W. J . Org. Chem. 1988, 53, 2991-2999.
(33) Terunuma, D.; Kato, M.; Kamei, M.; Uchida, H.; Ueno, S.;
Nohira, H. Bull. Chem. Soc. J pn. 1986, 59, 3581-3587.

8784 J . Org. Chem., Vol. 63, No. 24, 1998
Mizutani et al.
(d, 1H, J ) 7.9 Hz), 7.88 (d, 1H, J ) 8.6 Hz), 7.99 (d, 1H, J )
8.6 Hz); 13C NMR (125 MHz, CDCl3) δ 21.8, 22.7, 24.7, 28.3,
41.6, 52.3, 65.2, 79.8, 123.5, 125.2, 125.9, 126.6, 127.5, 128.7,
129.4, 130.7, 131.5, 133.7, 155.35, 173.3; IR (CCl4) 3441, 2960,
2932, 2873, 1743, 1721 cm-1; FAB MS m/z 372 ([M + H]+).
P-host‚guest complex, respectively, and [H]0 and [G]0 are the
total concentrations of the host and the guest, respectively.
Since the helix inversion of ZnBD is slow and the complex
formation and dissociation are fast on the NMR time scale at
lower temperatures, the following equations gave the observed
chemical shifts, δobs and δobs′, for M species and P species,
respectively:
1-Na p h th ylm eth yl L-leu cin a te (L-Leu -ONp ). To 20 mL
of trifluoroacetic acid (TFA) was added 1-naphthylmethyl
N-tert-butoxycarbonyl-L-leucinate (1.62 g, 4.36 mmol), and the
mixture was stirred for 30 min at room temperature. After
removal of the TFA at the reduced pressure by water aspirator,
the residue was dissolved in CH2Cl2 (25 mL), followed by
washing with saturated NaHCO3 (25 mL×3), water (25 mL),
and sat. brine (25 mL). The solution was dried over anhydrous
MgSO4, and the solvent was removed by evaporation. Puri-
fication by silica gel column chromatography using CH2Cl2 as
eluant afforded 1-naphthylmethyl L-leucinate as an oil (415
mg, 1.53 mmol, 35%): 1H NMR (500 MHz, CDCl3) δ 0.86 (d, J
) 6.7 Hz, 3H), 0.88 (d, J ) 6.7 Hz, 3H), 1.42 (ddd, J ) 13.6,
8.2, and 6.1 Hz, 1H), 1.56 (ddd, J ) 13.6, 8.2, and 5.8 Hz, 1H),
1.57 (br s, 2H), 1.67-1.78 (m, 1H), 3.51 (dd, J ) 8.2, 5.8 Hz,
1H), 5.59 (d, J ) 12.5 Hz, 1H), 5.62 (d, J ) 12.5 Hz, 1H), 7.44-
7.47 (m, 1H), 7.51-7.57 (m, 3H), 7.86 (d, J ) 8.2 Hz, 1H), 7.88
(dd, J ) 8.2, 1.5 Hz, 1H), 8.00 (d, J ) 8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 21.8, 22.9, 24.7, 44.0, 53.0, 64.9, 123.5,
125.2, 126.0, 126.5, 127.6, 128.7, 129.4, 131.2, 131.6, 133.7,
176.5; IR (CCl4) 3443, 2959, 2932, 2872, 1736 cm-1; FAB MS
δobs ) {[M-G]/([M] + [M-G])}‚δM-G + {[M]/([M] +
[M-G])}‚δM (6)
δobs′ ) {[P-G]/([P] + [P-G])}‚δP-G + {[P]/([P] +
[P-G])}‚δP (7)
where the δM, δP, δM-G, and δP-G are the chemical shifts of the
protons of M-host, P-host, the M-host‚guest complex, and the
P-host‚guest complex, respectively. In the present case, δM
and δP are the same, and δM-G and δP-G are obtained by
extrapolation of the titration curves.
If [H]0 and [G]0 are given, [M], [P], [M-G], and [P-G] are
derived from eqs 1-5 as functions of K223 and K223′. Therefore,
δ
obs and δobs′ are also represented as functions of K223 and K223′.
The 1H NMR measurements in the presence of varying
concentrations of the guest afford the titration curves of the
chemical shift changes, which are fitted to the theoretical eqs
6 and 7 by optimizing K223 and K223′. The numerical calcula-
tions were carried out with computer assistance based on a
damping Gauss-Newton method, finally, to give K223 and K223′.
m/z 272 ([M + H]+); [R]23 +4.9° (c 0.53, CH2Cl2).
D
An a lysis of Bin d in g Con sta n ts by 1H NMR Sp ectr o-
scop y. The binding constants of 4-8 with amino acid esters
and amines, K223 and K223′, were obtained by least-squares
curve fitting of 1H NMR complexation-induced shifts to the
theoretical equations. In the present case, the following
equations are taken into consideration:
Ack n ow led gm en t. This work was supported by a
Grant-in Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, J apan. We
appreciate Professor Toshikazu Takata’s kind coopera-
tion in the measurements of optical rotation. We thank
T. Kobatake for help in mass spectroscopic studies. We
also thank Professor Hiroyuki Nakazumi for his kind
help in IR studies.
K223 ) [M-G]/[M]‚[G]
(1)
(2)
(3)
(4)
(5)
K
223′ ) [P-G]/[P]‚[G]
[P] ) [M]
Su p p or tin g In for m a tion Ava ila ble: 1H-1H NOESY
1
spectrum of compound 4, and H NMR spectrum of compound
[H]0 ) [M] + [P] + [M-G] + [P-G]
[G]0 ) [G] + [M-G] + [P-G]
13c (2 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
where [M], [P], [G], [M-G], and [P-G] are the concentrations
of M-host, P-host, guest, the M-host‚guest complex, and the
J O980819J