Zinc porphyrin tweezer in host-guest complexation: Determination of absolute configurations of primary monoamines by circular dichroism

Article abstract of DOI:10.1002/(SICI)1521-3765(20000117)6:2<216::AID-CHEM216>3.0.CO;2-1

A nonempirical exciton chirality circular dichroic (CD) method for determining the absolute configurations of primary monoamines with amino group directly linked to the stereogenic center is described. Conventional exciton chirality CD method cannot be applied to these compounds since they lack the two sites for attaching the interacting chromophores. This was solved by covalently linking the monoamine to a trifunctional bidentate carrier moiety 1. Treatment of the carrier/monoamine conjugate with the porphyrin tweezer 4 consisting of two pentanediol-linked zinc porphyrins gives rise to 1:1 host-guest macrocyclic complexes that exhibit exciton- coupled CD spectra. The sign of the CD couplet can then be correlated with the absolute configuration of the monoamine as follows: a clockwise arrangement of the L, M, and S (large, medium, small) groups in the Newman projection of the monoamine with the amino group in the rear gives rise to a positive CD couplet, and vice versa; the assignments of L, M, S groups are based on conformational energies (A values). This method is applicable to cyclic and acyclic aliphatic amines, aromatic amines, amino esters, amides, and cyclic amino alcohols, and can be performed at the several microgram level.

Full text of DOI:10.1002/(SICI)1521-3765(20000117)6:2<216::AID-CHEM216>3.0.CO;2-1

FULL PAPER
Zinc Porphyrin Tweezer in Host ± Guest Complexation: Determination of
Absolute Configurations of Primary Monoamines by Circular Dichroism
Xuefei Huang,[a] Babak Borhan,[b] Barry H. Rickman,[a] Koji Nakanishi,*[a] and
Nina Berova*[a]
Abstract: A nonempirical exciton chir-
ality circular dichroic (CD) method for
determining the absolute configurations
of primary monoamines with amino
group directly linked to the stereogenic
center is described. Conventional exci-
ton chirality CD method cannot be
applied to these compounds since they
lack the two sites for attaching the
interacting chromophores. This was
solved by covalently linking the mono-
amine to a trifunctional bidentate car-
rier moiety 1. Treatment of the carrier/
monoamine conjugate with the porphyr-
in tweezer 4 consisting of two pentane-
diol-linked zinc porphyrins gives rise to
1:1 host ± guest macrocyclic complexes
that exhibit exciton-coupled CD spectra.
The sign of the CD couplet can then be
correlated with the absolute configura-
tion of the monoamine as follows: a
clockwise arrangement of the L, M, and
S (large, medium, small) groups in the
Newman projection of the monoamine
with the amino group in the rear gives
rise to a positive CD couplet, and vice
versa; the assignments of L, M, S groups
are based on conformational energies
(A values). This method is applicable to
cyclic and acyclic aliphatic amines, aro-
matic amines, amino esters, amides, and
cyclic amino alcohols, and can be per-
formed at the several microgram level.
Keywords: amines ´ circular dichro-
ism ´ configuration determination ´
host ± guest chemistry
phyrin tweezer
´ zinc por-
herein allows one to extend the exciton-coupled CD method
to primary monoamines linked directly to a chiral center
(Scheme 1). Derivatization of amine 2 with carrier 1 yields the
carrier/monoamine conjugate 3; binding of the conjugate 3
with porphyrin tweezer 4[12] produces a 1:1 chiral macrocyclic
host ± guest complex 5 that exhibits exciton-coupled CD
spectra reflecting the absolute configuration of monoamine 2.
The stereochemistry of primary monoamines has been
investigated by benzene chirality rules (aromatic
amines),[13, 14] and CD induced by 1-indan-carboxylic acid,[15]
benzoylbenzoic acid,[16±18] or polyacetylene carboxylic acid
helices.[19, 20] These methods normally generate weak CD
signals (CD amplitudes <10, in many cases <1), and require
milligram quantities of sample.
Recently, we reported that the zinc porphyrin tweezer 4 can
be used to determine the absolute configuration of diamines
at the low microgram level.[12] Porphyrin tweezer 4 is capable
of binding various acyclic chiral a,w-diamines through zinc
nitrogen coordination to form 1:1 macrocyclic host ± guest
complexes 6 (Figure 1). In the sterically more favored
conformation of the complex, the small group at the stereo-
genic center of the guest molecule would be sandwiched
between the two porphyrins, while the large group points
outside; this orientation leads to a chiral twist between the
two porphyrin effective transition moments[21] and a CD
couplet with the sign determined by the chirality of the guest.
The method can be extended to other compounds with two
Introduction
The exciton chirality circular dichroic (CD) method, a
nonempirical approach for absolute stereochemical determi-
nations[1, 2] has been applied to a wide variety of compounds,
such as polyols,[3] carbohydrates,[4±6] quinuclidines,[7, 8] hydroxy
acids,[9±11] and others.[2] This method is based on the through-
space exciton coupling between two or more chirally oriented
chromophores which are usually introduced through deriva-
tizations of functional groups present in the substrate. There-
fore, unless a chromophore already exists in the molecule, the
presence of at least two functional groups which can be
transformed into chromophores is the prerequisite for apply-
ing this chiroptical method, that is, two attachment sites for
chromophore(s) are necessary. This prerequisite, however, is
not satisfied in some molecules to be studied, such as
monoamines in which the amino function is the sole site for
derivatization. However, the carrier molecule 1 described
[a] Prof. K. Nakanishi, Dr. N. Berova, X. Huang, Dr. B. H. Rickman
Department of Chemistry, Columbia University
New York, NY, 10027 (USA)
Fax : (‡ 1)212-932-8273
E-mail: ndb1@columbia.edu
[b] Dr. B. Borhan
Present address: Department of Chemistry
Michigan State University
East Lansing, MI, 48824 (USA)
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Chem. Eur. J. 2000, 6, No. 2

216±224
R2
R1
N
R1
Zn
R2
H
H
NHR
H
O
HN
R1
N
Zn
Zn
a)
H
R2
NH2
Zn
O
N
O
NH2
O
Exciton-
coupled
CD
N
COOH
2
O
O
O O
Porphyrin tweezer 4
1 a R=Boc
1 R=H
b) deprotection
3
O
O
NH2
5
Scheme 1. Complex formation between carrier 1/monoamine conjugate and porphyrin tweezer 4.
Results and Discussion
The testing of several candidate
compounds such as pyrazine
carboxylic acid and 1,4-diami-
no- 2-benzoic acid showed that
pyridine-4-aminomethyl-2-car-
boxylic acid 1 having the fol-
lowing attributes was suited to
perform the role of the carrier
molecule: i) presence of the
carboxyl group to derivatize
primary amines; ii) presence
of the two nitrogen groups to
bind to the tweezer; iii) pres-
ence of the pyridine nitrogen in
the vicinity of the chiral center
in the carrier/monoamine con-
jugate and a relatively rigid
structure to reflect the chirality
of the amine in the tweezer
complex.
Figure 1. CD and UV/Vis spectra of the 1:1 macrocyclic complex 6 formed in n-hexane between porphyrin
tweezer 4 host (dashed line shows the direction of the porphyrin effective transition moment m) and a chiral
diamine guest l-lysine methyl ester. CD amplitude denotes the difference between CD extrema (Cotton effects)
in De; either a positive or negative sign is assigned to it depending on whether the Cotton effect at longer
wavelength is positive or negative (- - - - noncomplexed tweezer 4, ÐÐ 1:1 complex 6).
Carrier 1 was synthesized in
high yield from commercially
available compounds as shown
in Scheme 2.[22] Boc protection
of 4-aminomethylpyridine fol-
lowed by 3-chloroperoxybenzoic acid (mCPBA) oxidation
gave pyridine oxide 7, which upon treatment with trimethyl-
silyl cyanide (TMSCN) and dimethylcarbamyl chloride gave
pyridine-4-N-Boc-aminomethyl-2-nitrile (8);[23] this was then
hydrolyzed to yield 1a in the gram scale, overall 50% yield for
sites of attachment such as amino acids and amino alcohols by
converting them into diamines via simple derivatizations with
ethylene diamine and glycine, respectively.[12] This sensitive
method requires less than 10 mg of both the host and the guest,
and unlike the traditional exciton-coupled CD approach, the
chromophores, that is zinc por-
phyrins, can be recycled as they
NHBoc
are not covalently attached to
the compounds of interest.
Bidentate carriers exempli-
fied by 1 were developed in
order to extend this tweezer
method to primary mono-
amines with the amino group
linked directly to stereogenic
centers (Scheme 1). The angu-
lar arrangement of the two
porphyrin rings in complex
5 gives rise to an exciton-cou-
pled CD that reflects the abso-
lute configuration of mono-
amine 2.
NH2
NHBoc
NHBoc
c
a, b
d
8
7
1a
N
N
N
CN
N
COOH
O—
H2N
NHBoc
R2
H
R1
e,f
3
H2N
1a
O
N
N
COOH
H
HN
R2
R1
Scheme 2. Synthesis of the carrier 1a and the carrier/monoamine conjugate 3. a) (Boc)2O, THF, TEA, room
temperature, overnight (96%); b) mCPBA, CH2Cl2, room temperature, 12 h (82%); c) dimethylcarbamyl
chloride, TMSCN, CH2Cl2, room temperature, 48 h (65%); d) NaOH, EtOH(aq), reflux, 24 h (quant.); e) BOP,
DIPEA, THF, room temperature, 4h; f) 10% TFA/CH2Cl2, room temperature, 2 h (70 ± 95%).
Chem. Eur. J. 2000, 6, No. 2
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217

K. Nakanishi, N. Berova et al.
FULL PAPER
the four steps. The coupling of 1a with monoamines using
benzotriaoyl-1-yloxytris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP)[24] as the coupling reagent under mild
conditions followed by removal of the Boc group generated
the carrier/monoamine conjugate in high yield. Although the
coupling reaction was usually performed at the milligram
scale, it was found that the conjugate could also be readily
prepared with about 5 mg of the monoamine followed by
HPLC purification to provide material sufficient for CD
measurements (see Experimental Section).
Mixing of conjugate 10, formed by carrier 1 and (S)-
cyclohexylethylamine, with porphyrin tweezer 4 gave rise to a
positive exciton CD couplet in a nonpolar solvent such as
methylcyclohexane (MCH) as shown in Figure 2a.[25] Forty
equivalents of the conjugate 3 was found out to be the
optimum amount of the guest since this yielded maximum CD
amplitudes (Figure 2b). CD spectra measured in other
solvents, for example, hexane, benzene, toluene, methylene
chloride, chloroform, and acetonitrile, disclosed that the CD
amplitudes in hexane were similar to those in MCH, while
they were much weaker or almost negligible in other solvents.
The following CD measurements were performed in MCH.
A standard Job plot revealed a 1:1 stoichiometry for the
binding between porphyrin tweezer 4 and the bidentate
conjugate guest at low guest concentration (less than
20 equiv).[26] Formation of the 1:1 macrocyclic complex
between porphyrin tweezer 4 and the bidentate conjugate
guest is supported by changes in UV/Vis and CD spectra with
different amounts of the guest (Figure 2). With increasing
amounts of the guest such as conjugate 10 (0 to 200 equiv), the
UV/Vis maxima is shifted from 416 nm (Figure 2b, 0 equiv
curve) to 424 nm (saturated host, Figure 2b, 200 equiv curve)
with the presence of an isosbestic point indicating a single-
step transformation. The absorption maximum of the complex
formed between a monoamine and porphyrin tweezer 4 is at
428 nm; in contrast that of the complex between the conjugate
such as 10 and tweezer 4 is at 424 nm (complex 11 in
Figure 2d). This apparent blue shift seen in the latter is most
Figure 2. UV/Vis and CD spectra of porphyrin tweezer 4/conjugate 10 complex with different concentrations of 10 in methylcyclohexane (MCH). (The
tweezer concentration is kept constant at 1 mm in all cases). a) UV/Vis and CD spectra of 4/10 complex with 40 equiv of 10. b) Change in UV/Vis spectrum
with different equivalents of 10. c) Change in CD amplitude with different equivalents of 10. d) Schematic representation of the equilibria between porphyrin
tweezer 4, complex 11 (1:1 macrocyclic host ± guest complex), and complex 12 (flexible 1:2 host ± guest complexes).
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Zinc Porphyrin Tweezer for Determining Absolute Configurations
216±224
likely due to exciton coupling between the two nearby
porphyrins held rigidly in a close to parallel orientation.[27±30]
This clearly indicates the transition of the noncomplexed
tweezer 4 to the 1:1 host ± guest macrocyclic complex 11
(Figure 2b, 2d).[30±32] It is only after the guest concentration
exceeds 200 equiv that UV/Vis maxima of the complex is
shifted to longer wavelengths beyond 424 nm (Figure 2b,
400 equiv to 1600 equiv curves). This red shift of the maxima
beyond 424 nm with no isosbestic point points an increase in
the population of the flexible 1:2 host ± guest complexes 12.
The changes in the host ± guest complex structures accom-
panying the addition of conjugate 10 to porphyrin tweezer 4 is
also corroborated by changes in their CD spectra. As shown in
Figure 2c, the CD amplitudes of the host ± guest complex
increase as the guest concentration increases from 2 to
10 equiv and reaches a maximum at 40 equiv, indicating
formation of the 1:1 complex 11. The CD amplitudes, while
varying little between 10 to 200 equivalents of guest concen-
tration, decrease above 200 equivalents (Figure 2c) suggesting
an increase in the population of 1:2 complex 12 devoid of
exciton coupling.[33±36] Forty equivalents of the guest was used
as the optimal amount for the following CD investigations.
The principle by which the conjugate/porphyrin tweezer 5
complex yields an exciton-coupled CD spectrum with a
specific sign is based on the steric differentiation of the three
substituent groups at the chiral center by the two zinc
porphyrins. Nonempirical assignments can be made if the
spatial orientation of the two porphyrins could be predicted.
moiety in the Cambridge Structural Database have the
ˆ
Npyr C C O projection angle close to 1808 (Figure 4a). The
preferred conformation around bond II is s-trans as shown in
numerous cases[41±43] and in our calculations (Figure 3). The
This is attainable only if rotations around Cpyr
CCˆO (bond I),
CCˆO NH (bond II), and HN Cchiral (bond III) bonds of the
conjugates are restricted (Figure 3). Molecular modeling of
the conjugate[37] has yielded useful insights towards under-
standing the preferred conformations of these bonds. The
conjugation favors a coplanar orientation of the carbonyl
group to the pyridine ring. Moreover, possibly due to electro-
static repulsion, the anti carbonyl oxygen/pyridine nitrogen
ˆ
Figure 4. a) Projection angle (Npyr C C O) distribution in crystal struc-
tures of compounds containing pyridine-2-carboxamide in Cambridge
ˆ
Structural Database. b) Projection angle (O C C H) distribution in
crystal structures of compounds containing secondary amide in Cambridge
Structural Database.
methine hydrogen at the chiral center prefers to be syn to the
carbonyl by about 9 kJmol in CHCl3. Search of the Cam-
1
1
disposition is almost exclusively preferred by ꢀ30 kJmol
(Figure 3).[38±40] This is supported by the finding that all crystal
structures of compounds bearing the pyridine-2-carboxamide
bridge Structural Database for secondary amides also indi-
cates that this syn conformation is more favorable, that is, the
projection angles between the
carbonyl and the methine hy-
drogen are normally small
(Figure 4b). Thus it is clear
that conformer I (Figure 3) is
the most favored for the con-
jugate.
Due to the aforementioned
conformational rigidity of the
conjugate (Figure 3), it was as-
sumed that a conformation sim-
ilar to I was preferred for the
conjugate in the host ± guest
complex as well. The correla-
tion between sign of the exci-
ton-coupled CD and the abso-
lute stereochemistry of 10 can
then be deduced as follows. The
three substituents at the chiral
center are assigned S (small), M
Figure 3. Four major types of conformers of conjugate 10 in CHCl3 from Monte Carlo conformational searches
using Amber* force field (MacroModel 6.0). (Most of hydrogen atoms are omitted for the sake of clarity.)
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K. Nakanishi, N. Berova et al.
FULL PAPER
(medium), and L (large) accord-
ing to their sizes, with hydrogen
as S, methyl as M, and cyclohexyl
ring as L. When the L, M, and S
groups constitute a clockwise
arrangement with the amino
group in the rear as in the New-
man projection for (S)-cyclohex-
ylethylamine (Figure 5 and com-
pound 10 in Table 1), the zinc
porphyrin complexing with the
pyridine nitrogen would prefer
an approach from the side of the
M group rather than the L group
due to the unfavorable steric
interactions with the L group.
This leads to a clockwise twist
between the two porphyrins, that
is, a positive exciton-coupled CD
spectrum, De ‡ 135 (432 nm)/
108 (424 nm), amplitude ‡243
Figure 5. Conformations and CD spectrum of the complex formed by porphyrin tweezer 4 host and conjugate
10 guest in MCH.
(Figure 5).
stereochemistry of the amines can be correlated with the sign
of the exciton CD couplet. Namely, when the L, M, and S
For other primary monoamines conjugated with carrier 1
(compound 13 to 18), as shown in Table 1, the absolute
Table 1. CD amplitudes of carrier 1/monoamine conjugates and porphyrin tweezer 4 complex in MCH. All spectra were taken at room temperature with
40 equiv of the guest.
Schematic
representation
Predicted
sign
Schematic
representation
Predicted
sign
CD
amplitude
CD
amplitude
Parent amine
∆ε
Parent amine
∆ε
L
L
L
L
432 nm +135
H
432 nm +33
423 nm -31
S
S
S
S
H
M
M
+243
positive
positive
positive
+64
S
S
S
S
positive 424 nm -108
10[a]
13[a]
NH2
NH2
M
NH2
M
M
M
L
NH2
L
432 nm +78
423 nm -78
H
H
H
M
432 nm -123
negative
S
+156
L
-220
-249
S
15[a]
423 nm +97
NH2
NH2
14
NH2
M
L
NH2
L
L
M
M
L
435 nm +25
425 nm -13
433 nm -143
negative
S
M
+38
H
S
423 nm +106
NH2
M
M
NH2
17
OMe
16[a]
L
L
NH2
NH2
O
M
L
431 nm -114
422 nm +84
S
-198
L
negative
431 nm +111
positive 423 nm -86
S
S
H
M
+197
+286
S
H
NH2
19
L
NH2
18
M
NH2
NH2
O
L
L
O
M
M
431 nm +160
422 nm -126
S
433 nm -122
422 nm +107
S
S
H
M
S
L
negative
negative
H
H
positive
-229
-66
S
S
COOMe
NH2
NH2
M
M
21
NH2
L
NH2
20
H
N
M
M
O
OMe
NH2
M
L
432 nm -39
423 nm +27
H
432 nm -191
negative
L
S
-364
-108
S
S
S
423 nm +173
NH2
23
L
L
NH2
22
NH2
AcO
L
NH2
L
432 nm +136
423 nm -110
S
α / β =3 /1
M
M
+246
M
432 nm -56
negative
S
positive
S
O
L
AcO
AcO
423 nm +52
NH2
OAc
M
25
NH2
NH2
L
L
HO
HO
24
M
M
OCH3
S
NH2
OH
438 nm -5
431 nm +16
421 nm +3
L
L
negative
S
S
C13H27
H3C
HO
431 nm +66
positive
O
M
+126
NH2
421 nm -60
L
H2N
NH2
27
26
M
[a] The enantiomer exhibited mirror image CD.
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Zinc Porphyrin Tweezer for Determining Absolute Configurations
216±224
groups are arranged in a clockwise fashion with the amino
group in the rear in Newman projections, positive exciton-
coupled CD spectra are observed, and vice versa. Even the
small steric difference between methyl and ethyl groups
(compound 13) can be distinguished by porphyrin tweezer 4
which yields a positive exciton-coupled CD spectrum. The
amplitudes of exciton-coupled CD spectra increase as the size
of the L group increases from ethyl (13) to isopropyl (14) or
from phenyl (15) to naphthyl (16). The smaller amplitudes of
compound 17 compared to compound 15 is probably due to
the fact that the phenyl L group is fused into a five-membered
ring, therefore leading to a flatter molecule and less steric
differentiation.
Conclusion
A protocol utilizing zinc porphyrin tweezer 4 to determine the
absolute stereochemistry of primary monoamines has been
established. This method requires only microgram amounts of
sample and can be applied to cyclic and acyclic aliphatic
amines, aromatic amines, amino esters, amides, and cyclic
amino alcohols. The stereochemistry of the monoamine can
be readily determined from the sign of the exciton-coupled
CD spectrum: a positive CD couplet corresponds to a
clockwise arrangement of the L, M, and S groups in the
Newman projection of the amine with amino group in the
rear, while a negative couplet corresponds to a counterclock-
wise arrangement. Assignments of the M, L groups are based
on their conformational energies (A values). Further studies
on structures of carriers for secondary amines and alcohols
are underway.
With substituent groups other than aliphatic groups and
aromatic groups, the assignment of L and M groups becomes
difficult. However, considerations based on conformational
energies[44] expressed in A values[45, 46] turned out to be very
useful to avoid ambiguities. For example, in the case of
alanine derivative 19 the methyl carboxylate (A value ˆ 5.0 ±
1
5.4 kJmol ) should be considered as M and the methyl group
Experimental Section
1
(A value ˆ 7.28 kJmol ) as L since the methyl A value is
larger than that of the methyl carboxylate. This leads to a
counterclockwise arrangement of the L, M, and S groups in
19, and thus a negative exciton-coupled CD spectrum, De ˆ
114 (431 nm)/ ‡ 84 (422 nm), amplitude 198. The stereo-
chemistry of valine derivative 20, lactone 21, and lactam 22
can be determined similarly by assigning the ester or amide
groups as M. The CD amplitude of the Val derivative 20 is
larger than that of Ala derivative 19 because the isopropyl
Materials and general procedures: Anhydrous CH2Cl2 was dried over CaH2
and distilled. Other solvents used for CD measurements were either
Optima or HPLC grade. Unless otherwise noted, materials were obtained
from commercial suppliers and were used without further purification. All
reactions were performed in dried glassware under argon. Column
chromatography was performed by using ICN silica gel (32 ± 63 mesh).
1H NMR spectra were obtained on Bruker DMX 300, 400 or 500 and are
reported in parts per million (ppm) relative to the solvent resonances (d),
with coupling constants (J) in Hertz (Hz). Low-resolution and high-
resolution FAB mass spectra were measured on a JEOL JMS-DX303 HF
mass spectrometer using a glycerol matrix and Xe ionizing gas. ESI mass
spectra were measured on a JEOL LC mate mass spectrometer. UV/Vis
spectra were recorded on a Perkin-Elmer Lambda 40 spectrophotometer,
and reported as lmax [nm]. CD spectra were recorded on a JASCO J-720
spectropolarimeter, and reported as l [nm] (Demax [Lmol 1 cm 1]).
1
group (A value ˆ 9.25 kJmol ) is larger than the methyl
1
group (A value ˆ 7.28 kJmol ). Although the absolute ster-
eochemistry of the amino acids can be determined as
previously described,[12] the present method is preferred for
amino esters (e.g. 19 ± 21) and amino amides (e.g. 22), since it
does not require hydrolysis to generate the free acid which
could be accompanied by epimerization. (S)-1-Methoxy
2-propylamine derivative 23 yielded a CD spectrum with the
predicted sign despite the small difference in conformational
General procedures for preparation of carrier 1/monoamine conjugate: To
a solution of carrier 1a (1 equiv) in THF (3 mL), BOP (1.2 equiv),
diisopropylethylamine (DIPEA) (5 equiv), and the primary monoamine
(0.95 equiv) were added. The solution was stirred overnight at room
temperature. All the solvents were evaporated by a rotary evaporator and
the remaining solid was dissolved in CH2Cl2 (10 mL). The solution was
washed twice with aqueous NaHCO3 (10 mL), and the organic layer was
separated and dried with Na2SO4. The mixture was then separated by silica
gel flash chromatography to yield the Boc-protected carrier/amine
conjugate. The Boc group was removed by treatment with 10% trifluoro-
acetic acid (TFA) in CH2Cl2 (5 mL) at room temperature for two hours.
Evaporation of all the solvents yielded the analytically pure carrier/amine
conjugate.
1
energies of M and L groups (A value ˆ 7.20 kJmol for
1
CH2OMe vs. 7.28 kJmol for Me). Tetraacetyl glucosamine
derivative 24 with multiple chiral centers also gave the
predicted CD sign.
To further test the scope of the present method, chiral
primary amines bearing free hydroxy groups were investigat-
ed. With molecules having hydroxy groups attached to a cyclic
skeleton such as steroidal amine 25 and acosamine 26, the
absolute configuration at the amino center can be determined
in a similar manner, namely, clockwise arrangement of L, M,
and S groups gives positive exciton-coupled CD; presence of
free hydroxy groups does not interfere with the determina-
tions because they are locked in a cyclic system. In contrast,
flexible acyclic monoamines containing hydroxy groups, such
as L-threo-sphingosine derivative 27, yielded complex CD
spectra, presumably due to multiple conformations of the
host ± guest complexes. The current method is therefore not
applicable to acyclic amino alcohols. However, the absolute
configuration of such acyclic amino alcohols can be deter-
mined using other exciton-coupled CD approaches[12, 47] since
they possess two sites of attachment.
Procedures for CD measurements: For a typical experiment, to prepare the
amine solution, Na2CO3 (30 mg) was added to the solution of carrier 1a/
(S)-cyclohexylethylamine conjugate 10 (1 mg) in MeOH (0.2 mL). The
solution was dried under a stream of argon and then on a high-vacuum
pump (0.2 Torr) for 20 min. Anhydrous CH2Cl2 (1 mL) was added to yield a
solution of 10 (2mm). An aliquot of the amine solution (20 mL) was added
to porphyrin solution (1mm) in MCH prepared by addition of porphyrin
tweezer 4 solution (0.1mm) in anhydrous CH2Cl2 (10 mL) to MCH (1 mL)
(this corresponds to about 1.6 mg of porphyrin tweezer 4 and 18 mg of
conjugate 10). The porphyrin/amine solution was shaken, then UV/Vis and
CD spectra were recorded and corrected by background subtraction at
258C. The CD spectra were measured in millidegrees and normalized into
De/l [nm] units.
Procedures for obtaining the Job plot: Solutions of carrier 1a/(S)-cyclo-
hexylethylamine conjugate 10 (0.50mm) in anhydrous CH2Cl2 (1 mL) and
porphyrin tweezer 4 (0.1mm) in anhydrous CH2Cl2 (1 mL) were prepared
similarly as described above. Aliquots of the two solutions were mixed in
Chem. Eur. J. 2000, 6, No. 2
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221

K. Nakanishi, N. Berova et al.
FULL PAPER
MCH (1 mL) to obtain twenty different solutions with the ratio (c) of the
host/(host ‡ guest) concentrations ranging from 0.00 to 0.95 with 0.05
increments. The total concentration of the host and guest is kept constant at
3 mm in all solutions. The UV/Vis absorbance of these solutions at 417 nm
was plotted against c. Linear extrapolation of the absorbance measured
near c ˆ 0 and c ˆ 1 resulted in two straight lines that intersected at the
stoichiometric equivalence point where c ˆ 0.52. This indicates that the
stoichiometric ratio of the host and guest in the complex is 1:1.
For CD measurements, the amine solution was prepared by dissolving the
conjugate (16 mg) in MeOH (50 mL) with Na2CO3 (1 mg). The solvent was
dried by a stream of argon and then on a high-vacuum pump (0.2 Torr) for
20 min. CH2Cl2 (40 mL) was added to the residue followed by a solution of
the porphyrin tweezer 4 (1mm) in MCH (1 mL). CD spectra of the
porphyrin/amine solution were then recorded according to the general
procedures with amplitudes within 10% of the values obtained by using the
conjugate from milligram-scale synthesis.
4-[(tert-Butoxycarbonylamino)methyl]pyridine oxide (7): To a solution of
4-aminomethylpyridine (3.24 g, 30 mmol) in THF (20 mL) was added di-
tert-butyl dicarbonate (6.48 g, 30 mmol) and triethylamine (1 mL). A lot of
white precipitate was formed. After the mixture had been stirred at room
temperature overnight, it was filtered and the light brown filtrate was
concentrated to yield an oil-like liquid. Upon standing in air, it crystallized
to yield 4-[(tert-butoxycarbonylamino)methyl]pyridine (6.0 g, 96%). To a
solution of 4-[(tert-butoxycarbonylamino)methyl]pyridine (6.0 g, 29 mmol)
in CH2Cl2 (50 mL), mCPBA (9.0 g, 30 mmol) was added. The solution was
stirred at room temperature for 12 h and then washed with 0.5n aqueous
NaOH solution (10 mL). The aqueous layer was extracted with CH2Cl2
(10 Â 20 mL) until no product was left in the aqueous phase. The organic
layers were combined and purified by flash chromatography (9:1 CH2Cl2/
MeOH) to yield 7 (5.3 g, 82%). 1H NMR (300 MHz, CD3OD): d ˆ 1.44 (s,
9H; C(CH3)3), 4.27 (d, J ˆ 5.7, 2H; CH2), 7.44 (d, J ˆ 6.6 Hz 2H), 8.27 (d,
J ˆ 6.7 Hz, 2H).
Carrier 3/(S)-2-butylamine conjugate 13: (S)-2-Butylamine (4 mg,
55 mmol) was treated with carrier 1a, and then with TFA to yield the
conjugate 13 (18 mg, 75%) according to the general procedures for
conjugate synthesis. 1H NMR (CD3OD, 300 MHz): d ˆ 0.94 (t, J ˆ 7.40 Hz,
3H; CH3), 1.24 (d, J ˆ 6.63 Hz, 3H; CH3), 1.52 ± 1.65 (m, 2H, CH2CH3),
3.95 ± 4.09 (m, 1H; NHCHCH3), 4.27 (s, 2H; CH2NH2TFA), 7.58 (d, J ˆ
4.96 Hz, 1H), 8.16 (s, 1H), 8.69 (d, J ˆ 4.94 Hz, 1H).
Carrier 3/(R)-3-methyl 2-butylamine conjugate 14: (R)-3-Methyl 2-butyl-
amine (4 mg, 46 mmol) was treated with carrier 1a and then with TFA to
yield the conjugate 14 (15 mg, 74%) according to the general procedures
for conjugate synthesis. 1H NMR (CD3OD, 300 MHz): d ˆ 0.94 (t, J ˆ
3.46 Hz, 3H; CH3), 0.95 (d, J ˆ 3.48 Hz, 3H; CH3), 1.24 (d, J ˆ 6.75 Hz,
3H; CH3), 1.78 ± 1.92 (m, 1H; CH(CH3)2), 3.86 ± 4.02 (m, 1H; NHCH), 4.27
(s, 2H; CH2NH2TFA), 7.65 (d, J ˆ 4.96 Hz, 1H), 8.16 (s, 1H), 8.69 (d, J ˆ
‡
4.95 Hz, 1H); MS (ESI): m/z: [M‡H] 222.2.
Carrier 3/(S)-methylbenzylamine conjugate 15: (S)-Methylbenzylamine
(4 mg, 33 mmol) was treated with carrier 1a and then with TFA to yield the
conjugate 15 (12 mg, 70%) according to the general procedures for
conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 1.59 (d, J ˆ 7.00 Hz,
3H; CH3), 4.25 (s, 2H; CH2NH2TFA), 5.22 (q, J ˆ 7.05 Hz, 1H; NHCH),
7.20 ± 7.27, 7.29 ± 7.36, 7.38 ± 7.42 (m, 5H; C6H5), 7.59 (d, J ˆ 4.96 Hz, 1H),
8.13 (s, 1H), 8.60 (d, J ˆ 4.96 Hz, 1H).
2-Cyano-4-[(tert-butoxycarbonylamino)methyl]pyridine (8): To a solution
of 7 (2.0 g, 8.7 mmol) in CH2Cl2 (30 mL) under Ar was added TMSCN
(1.44 mL, 11.3 mmol). After the mixture had been stirred for 5 min,
dimethylcarbamyl chloride (0.94 mL, 9.5 mmol) was added. The solution
was further stirred at room temperature for 48 h and washed with saturated
aqueous NaHCO3 solution (20 mL). The organic layer was dried with
Na2SO4 and purified by flash chromatography (20:1 CH2Cl2/MeOH) to
yield 8 (1.1 g, 53%). 1H NMR (300 MHz, CDCl3): d ˆ 1.47 (s, 9H;
C(CH3)3), 4.38 (d, J ˆ 6.2 Hz, 2H; CH2), 5.32 ± 5.42 (br. s, 1H; NH), 7.44
(dd, J ˆ 0.7, 5.1 Hz; 1H), 7.63 (d, J ˆ 0.7 Hz; 1H), 8.65 (d, J ˆ 5.1 Hz; 1H);
Carrier 3/(R)-1-naphthylethylamine conjugate 16: (R)-1-Naphthylethyl-
amine (16 mg, 94 mmol) was treated with carrier 1a and then with TFA to
yield the conjugate 16 (38 mg, 75%) according to the general procedures
for conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 1.73 (d, J ˆ
6.90 Hz, 3H; CH3), 4.24 (s, 2H; CH2NH2TFA), 6.06 (q, J ˆ 6.90 Hz, 1H;
NHCH), 7.42 ± 7.52 (m, 4H; CH), 7.55 ± 7.60 (m, 1H; CH), 7.62 (d, J ˆ
7.16 Hz, 1H; CH), 7.78 (d, J ˆ 8.20 Hz, 1H; CH), 7.84 ± 7.88 (m, 1H; CH),
8.12 ± 8.19 (m, 2H; 2CH), 8.67 (d, J ˆ 4.98 Hz, 1H); MS (ESI): m/z:
‡
MS (EI): m/z: [M‡H] 234.
4-[(tert-Butoxycarbonylamino)methyl]pyridine-2-carboxylic acid (1a): To
a solution of 8 (1.1 g, 4.6 mmol) in EtOH (20 mL) was added 1n aqueous
NaOH solution (5 mL). The solution was refluxed for 24 h and washed with
CH2Cl2 (30 mL). The aqueous layer was acidified to about pH 6 and all the
solvent was evaporated. The solid was then suspended in MeOH (20 mL)
and filtered. The solvent of the filtrate was removed to yield 1a (1.2 g,
100%). 1H NMR (300 MHz, CD3OD): d ˆ 1.45 (s, 9H; C(CH3)3), 4.30 (s,
2H; CH2), 5.32 ± 5.42 (br. s, 1H; NH), 7.31 (d, J ˆ 5.0 Hz, 1H), 7.92 (s, 1H),
8.47 (d, J ˆ 4.9 Hz, 1H); 13C NMR (75 MHz, CD3OD): d ˆ 28.73, 43.97,
80.42, 123.37, 124.40, 149.54, 152.10, 155.13, 158.39, 172.00; m.p. > 2208C
‡
[M‡H] 306.2.
Carrier 3/(S)-1-aminoindane conjugate 17: (S)-1-Aminoindane (21 mg,
160 mmol) was treated with carrier 1a and then with TFA to yield the
conjugate 17 (70 mg, 82%) according to the general procedures for
conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 1.95 ± 2.08 (m, 1H;
CH), 2.53 ± 2.62 (m, 1H; CH), 2.88 ± 2.95 (m, 1H; CH), 3.02 ± 3.12 (m, 1H;
CH), 4.28 (s, 2H; CH2NH2TFA), 5.55 ± 5.62 (m, 1H; NHCHCOO), 7.14 ±
7.28 (m, 4H; CH), 7.60 (d, J ˆ 4.90 Hz, 1H), 8.17 (s, 1H), 8.65 (d, J ˆ
‡
(decomp); MS (EI): m/z: [M‡H] 253; HR-FABMS of C12H16O4N2K: m/z:
‡
[M‡K] calcd 291.0747, found 291.0739.
‡
4.91 Hz, 1H); MS (ESI): m/z: [M‡H] 268.2; HR-FABMS of C16H17ON3K:
Carrier 3/(S)-cyclohexylethylamine conjugate 10: (S)-Cyclohexylethyl-
amine (2.6 mg, 20 mmol) was treated with carrier 1a and then with TFA
to yield the conjugate 10 (8.6 mg, 89%) according to the general
procedures for conjugate synthesis. 1H NMR (CD3OD, 300 MHz): d ˆ
1.23 (d, J ˆ 6.19 Hz, 3H; CH3), 0.88 ± 1.38, 1.42 ± 1.58, 1.62 ± 1.89 (m, 11H,
C6H11), 3.88 ± 3.98 (m, 1H, NHCHCH3), 4.26 (s, 2H, CH2NH2TFA), 7.58 (d,
J ˆ 4.96 Hz, 1H), 8.15 (s, 1H), 8.69 (d, J ˆ 4.98 Hz, 1H); MS (ESI): m/z:
‡
m/z: [M‡K] calcd. 306.1009, found 306.1004.
Carrier 3/(R)-bornylamine conjugate 18: (R)-Bornylamine (15 mg,
94 mmol) was treated with carrier 1a and then with TFA to yield the
conjugate 18 (45 mg, 88%) according to the general procedures for
1
conjugate synthesis. H NMR (CD3OD, 400 MHz): d ˆ 0.85 (s, 3H; CH3),
0.94 (s, 3H; CH3), 1.03 (s, 3H; CH3), 1.05 ± 1.14 (m, 1H; CH), 1.32 ± 1.44 (m,
2H; 2CH), 1.63 ± 1.74 (m, 2H; 2CH), 1.78 ± 1.88 (m, 1H; CH), 2.34 ± 2.44
(m, 1H; CH), 4.27 (s, 2H; CH2NH2TFA), 4.38 ± 4.47 (m, 1H; CHNH),
7.65 (d, J ˆ 4.70 Hz, 1H), 8.18 (s, 1H), 8.73 (d, J ˆ 4.75 Hz, 1H); MS (ESI):
‡
‡
[M‡H] 262.2; HR-FABMS of C15H24ON3: m/z: [M‡1] calcd. 262.1919,
found 262.1925.
Procedures for the microgram-scale preparation of conjugate 10 and CD
measurements: To a solution of carrier 1a (10 mg, 40 mmol) in THF (1 mL)
were added BOP (19mg, 44 equiv) and DIPEA (50 mL). The solution was
stirred at room temperature for 10 min. An aliquot of this solution (5 mL)
was added to a solution of (S)-cyclohexylethylamine (4.6 mg, 36 nmol) in
THF (10 mL) in a 0.3 mLWheaton V-Vial with a Spinvane magnetic stirring
bar (both available from Aldrich). After the mixture had been stirred at
room temperature overnight, all solvents were evaporated and the residue
was treated with 10% TFA in CH2Cl2 (20 mL) for two hours. The conjugate
(16 mg, 92% obtained from UV absorbance at 268 nm) was purified by
reverse-phase HPLC (solvent system: 67% H2O, 33% CH3CN, 0.1% TFA;
analytical C18 column; flow rate 1.3 mLmin 1; retention time: 4.2 min;
monitored at 220 nm).
‡
m/z: [M‡H] 288.2.
Carrier 3/(S)-alanine methyl ester conjugate 19: (S)-Alanine methyl ester
hydrochloride (13 mg, 93 mmol) was treated with carrier 1a and then with
TFA to yield the conjugate 19 (33 mg, 73%) according to the general
procedures for conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 1.52
(d, J ˆ 7.24 Hz, 3H; CH3), 3.75 (s, 3H; CO2CH3), 4.27 (s, 2H;
CH2NH2TFA), 4.68 (q, J ˆ 7.29 Hz, 1H; CHCH3), 7.62 (d, J ˆ 4.89 Hz,
‡
1H), 8.16 (s, 1H), 8.72 (d, J ˆ 4.96 Hz, 1H); MS (ESI): m/z: [M‡H] 238.1;
‡
HR-FABMS of C11H16O3N3: m/z: [M‡1] calcd. 238.1192, found
238.1186.
Carrier 3/(R)-valine methyl ester conjugate 20: (R)-Valine methyl ester
trifluoroacetate (23 mg, 94 mmol) was treated with carrier 1a and then with
222
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0947-6539/00/0602-0222 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 2

Zinc Porphyrin Tweezer for Determining Absolute Configurations
216±224
TFA to yield the conjugate 20 (36 mg, 70%) according to the general
procedures for conjugate synthesis. 1H NMR (CD3OD, 300 MHz): d ˆ 0.99
(s, 3H; CH3), 1.01 (s, 3H; CH3), 2.20 ± 2.38 (m, 1H; CH(CH3)2), 3.76 (s, 3H;
CO2CH3), 4.28 (s, 2H; CH2NH2TFA), 4.53 ± 4.62 (m, 1H; CHCH(CH3)2),
7.65 (dd, J ˆ 1.72, 4.99 Hz, 1H), 8.18 (d, J ˆ 1.72 Hz, 1H), 8.73 (d, J ˆ
4.96 Hz, 1H).
Acknowledgment
The studies were supported by NIH grant GM 34509.
[1] N. Harada, K. Nakanishi, Circular Dichroic Spectroscopy - Exciton
Coupling in Organic Stereochemistry, University Science Books, Mill
Valley, 1983, p. 350.
[2] K. Nakanishi, N. Berova in Circular Dichroism, Principles and
Applications, (Eds.: K. Nakanishi, N. Berova, R. W. Woody), VCH
Publishers, New York, 1994, pp. 361 ± 398.
[3] D. Rele, N. Zhao, K. Nakanishi, N. Berova, Tetrahedron 1996, 52,
2759 ± 2776.
[4] M. Ojika, H. V. Meyers, M. Chang, K. Nakanishi, J. Am. Chem. Soc.
1989, 111, 8944 ± 8946.
Carrier 3/(S)-a-amino-g-butyrolactone conjugate 21: (S)-a-Amino-g-bu-
tyrolactone hydrobromide (18 mg, 96 mmol) was treated with carrier 1a and
then with TFA to yield the conjugate 21 (38 mg, 86%) according to the
general procedures for conjugate synthesis. 1H NMR (CD3OD, 400 MHz):
d ˆ 2.42 ± 2.53 (m, 1H; CHCH2), 2.58 ± 2.65 (m, 1H; CHCH2), 4.27 (s, 2H;
CH2NH2TFA), 4.32 ± 4.38 (m, 1H; CHOCO), 4.45 ± 4.53 (m, 1H;
CHOCO), 4.85 (dd, J ˆ 9.31, 11.01 Hz, 1H; NHCHCOO), 7.62 (d, J ˆ
4.90 Hz, 1H), 8.16 (s, 1H), 8.71 (d, J ˆ 4.94 Hz, 1H); MS (ESI): m/z:
‡
[M‡H] 236.1.
Carrier 3/l-a-amino-e-caprolactam conjugate 22: l-a-Amino-e-caprolac-
tam (13 mg, 94 mmol) was treated with carrier 1a and then with TFA to
yield the conjugate 22 (36 mg, 75%) according to the general procedures
for conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 1.34 ± 1.45 (m,
1H; CH), 1.55 ± 1.65 (m, 1H; CH), 1.82 ± 1.94 (m, 2H; 2CH), 1.96 ± 2.13 (m,
2H; 2CH), 3.25 ± 3.40 (d, J ˆ 9.80 Hz, 1H; NHCHCO), 4.27 (s, 2H;
CH2NH2TFA), 7.65 (d, J ˆ 4.85 Hz, 1H), 8.18 (s, 1H), 8.69 (d, J ˆ 4.86 Hz,
[5] W. T. Wiesler, N. Berova, M. Ojika, H. V. Meyers, M. Chang, P. Zhou,
L. C. Lo, M. Niwa, R. Takeda, K. Nakanishi, Helv. Chim. Acta. 1990,
73, 509 ± 551.
[6] M. Chang, H. V. Meyers, K. Nakanishi, M. Ojika, J. H. Park, M. H.
Park, R. Takeda, J. T. Vazquez, W. T. Wiesler, Pure Appl. Chem. 1989,
61, 1193 ± 1200.
[7] N. Zhao, K. Narendra, K. Neuenschwander, K. Nakanishi, N. Berova,
J. Am. Chem. Soc. 1995, 117, 7844 ± 7845.
[8] N. Zhao, N. Berova, K. Nakanishi, M. Rohmer, P. Mougenot, U. J.
Jurgens, Tetrahedron 1996, 52, 2777 ± 2788.
‡
1H); MS (ESI): m/z: [M‡H] 263.2; HR-FABMS of C13H19O2N4: m/z:
‡
[M‡1] calcd. 263.1508, found 263.1508.
Carrier 3/(S)-1-methoxy 2-propylamine conjugate 23: (S)-1-Methoxy
2-propylamine (4.5 mg, 51 mmol) was treated with carrier 1a and then
with TFA to yield the conjugate 23 (16 mg, 72%) according to the general
procedures for conjugate synthesis. 1H NMR (CD3OD, 300 MHz): d ˆ 1.27
(d, J ˆ 6.78 Hz, 3H; CH3), 3.38 (s, 3H; OCH3), 3.42 ± 3.53 (m, 2H;
CH2OCH3), 4.27 (s, 2H; CH2NH2TFA), 4.24 ± 4.35 (m, 1H; NHCH), 7.58
(d, J ˆ 4.93 Hz, 1H), 8.17 (s, 1H), 8.69 (d, J ˆ 4.93 Hz, 1H).
[9] B. H. Rickman, S. Matile, K. Nakanishi, N. Berova, Tetrahedron 1998,
54, 5041 ± 5064.
[10] O. Gimple, P. Schreier, H.-U. Humpf, Tetrahedron: Asymmetry 1997, 8,
11 ± 14.
[11] O. Gimple, P. Schreier, H.-U. Humpf, J. Org. Chem. 1998, 63, 322 ±
325.
[12] X. Huang, B. H. Rickman, B. Borhan, N. Berova, K. Nakanishi, J. Am.
Chem. Soc. 1998, 120, 6185 ± 6186.
[13] H. E. Smith, J. R. Neergaard, J. Am. Chem. Soc. 1997, 119, 116 ± 124.
[14] H. E. Smith in Circular Dichroism. Principles and Applications, (Eds.:
K. Nakanishi, N. Berova, R. W. Woody), VCH Publishers, New York,
1994, pp. 413 ± 442.
[15] S. Takenaka, M. Koden, J. Chem. Soc. Chem. Commun. 1978, 830.
[16] S. Takenaka, M. Ako, T. Kotani, A. Matsubara, N. Tokura, J. Chem.
Soc. Perkin Trans. 2 1978, 95 ± 99.
[17] S. Takenaka, K. Kondo, N. Todura, J. Chem. Soc. Perkin Trans. 2 1975,
1520 ± 1524.
[18] S. Takenaka, Y. Miyauchi, N. Tokura, Tetrahedron Lett. 1976, 42,
3811 ± 3814.
Carrier 3/tetraacetyl d-glucosamine conjugate 24: Tetraacetyl d-glucos-
amine hydrochloride (10 mg, 21 mmol) was treated with carrier 1a and then
with TFA to yield the conjugate 24 (12 mg, 71%) according to the general
procedures for conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 1.91,
2.05, 2.09, 2.19 (4s, 12H; 4CH3), 4.05 ± 4.12 (m, 1H; CH), 4.17 ± 4.25 (m,
1H; CH), 4.27 (s, 2H; CH2NH2TFA), 4.53 ± 4.62 (m, 1H; CH), 5.18 ± 5.28
(m, 1H; CH), 5.42 ± 5.55 (m, 1H; CH), 6.04 (d, J ˆ 8.77 Hz, 0.25H, b
anomeric proton), 6.22 (d, J ˆ 3.63 Hz, 0.75H, a anomeric proton), 7.62 (d,
J ˆ 4.95 Hz, 1H), 8.14 (s, 1H), 8.69 (d, J ˆ 4.90 Hz, 1H); MS (ESI): m/z:
‡
‡
[M‡H] 482.2; HR-FABMS of C21H27O10N3K: m/z: [M‡K] calcd.
520.1334, found 520.1340.
Carrier 3/5-androsten-17b-amino-3b-ol conjugate 25: 5-Androsten-17b-
amino-3b-ol (15 mg, 52 mmol) was treated with carrier 1a and then with
TFA to yield the conjugate 25 (32 mg, 95%) according to the general
procedures for conjugate synthesis. 1H NMR (CD3OD, 400 MHz): d ˆ 0.82,
1.02 (2s, 6H; 2CH3), 1.08 ± 1.88, 1.92 ± 2.05, 2.11 ± 2.30 (m, 20H), 3.48 ± 3.58
(m, 1H; CHOH), 4.02 ± 4.12 (m, 1H; CHNH), 4.28 (s, 2H; CH2NH2TFA),
5.38 (d, J ˆ 5.15 Hz, 1H; CH), 7.38 (d, J ˆ 4.95 Hz, 1H), 8.09 (s, 1H), 8.52
(d, J ˆ 4.90 Hz, 1H).
[19] E. Yashima, T. Matsushima, Y. Okamoto, J. Am. Chem. Soc. 1995, 117,
11596 ± 11597.
[20] E. Yashima, T. Matsushima, Y. Okamoto, J. Am. Chem. Soc. 1997, 119,
6345 ± 6359.
[21] S. Matile, N. Berova, K. Nakanishi, J. Fleischhauer, R. Woody, J. Am.
Chem. Soc. 1996, 118, 5198 ± 5206.
[22] 4-N-Boc-aminomethyl 2-carboxylic acid (1a) and porphyrin tweezer 4
will be made commercially available by TCI America.
[23] W. K. Fife, J. Org. Chem. 1983, 48, 1375 ± 1377.
[24] J.-A. Fehrentz, B. Castro, Synthesis 1983, 676 ± 678.
[25] Mirror image CD spectrum was obtained when the enantiomer of 10
was measured with porphyrin tweezer 4.
[26] C. R. Cantor, P. R. Schimmel in Biophysical Chemistry, Vol. 3, W. H.
Freeman and Company, San Francisco, 1980, pp. 1135 ± 1138.
[27] M. Kasha, Radiat. Res. 1963, 20, 1059 ± 1071.
[28] M. Kasha, H. R. Rawls, M. A. El-Bayoumi, Pure Appl. Chem. 1965,
11, 371 ± 392.
[29] C. A. Hunter, J. K. M. Sanders, A. J. Stone, J. Chem. Phys. 1989, 133,
395 ± 404.
[30] X. Huang, B. Borhan, N. Berova, K. Nakanishi, J. Ind. Chem. Soc.
1998, 75, 725 ± 728.
[31] With monoamines such as (S)-cyclohexylethylamine, formation of the
1:1 host ± guest macrocyclic complex is not possible. No isosbestic
point was observed during addition of the monoamine to porphyrin
tweezer 4, while the UV/Vis maxima of the monoamine/porphyrin
tweezer 4 complex shifted continuously from 416 nm (empty host) to
428 nm (saturated host).
Carrier 3/methyl l-acosamine conjugate 26: Methyl l-acosaminide hydro-
chloride (9 mg, 45 mmol) was treated with carrier 1a and then with TFA to
yield the conjugate 26 (20 mg, 93%) according to the general procedures
for conjugate synthesis. 1H NMR (CD3OD, 500 MHz): d ˆ 1.28 (d, J ˆ
4.85 Hz, 3H; CH3), 1.82 ± 1.88 (m, 1H; CH), 2.06 ± 2.14 (m, 1H; CH),
3.18 ± 3.25 (m, 1H; CH), 3.35 (s, 3H; OCH3), 3.66 ± 3.74 (m, 1H; CH), 4.25
(s, 2H; CH2NH2TFA), 4.31 ± 4.38 (m, 1H; CH), 4.71 (d, J ˆ 2.95 Hz, 1H;
OCHOCH3), 7.58 (d, J ˆ 4.95 Hz, 1H), 8.14 (s, 1H), 8.69 (d, J ˆ 5.01 Hz,
‡
1H); MS (ESI): m/z: [M‡H] 296.2.
Carrier 3/l-threo-sphingosine conjugate 27: l-threo-Sphingosine (2 mg,
6.7 mmol) was treated with carrier 1a and then with TFA to yield the
conjugate 27 (3.7 mg, 83%) according to the general procedures for
conjugate synthesis. 1H NMR (CD3OD, 500 MHz): d ˆ 0.89 (t, J ˆ 6.86 Hz,
3H; CH3), 1.19 ± 1.40 (m, 22H), 1.95 ± 2.05 (m, 2H; CH), 3.65 ± 3.72, 3.74 ±
3.80 (m, 2H, CH2OH), 4.02 ± 4.12 (m, 1H; NHCHCH2OH), 4.25 (s, 2H;
CH2NH2TFA), 4.38 ± 4.42 (m, 1H; NHCHCHOH), 5.48 ± 5.52 (m, 1H;
CHCHCH2), 5.70 ± 5.79 (m, 1H; CHCHCH2), 7.58 (d, J ˆ 4.95 Hz, 1H),
8.14 (s, 1H), 8.68 (d, J ˆ 4.96 Hz, 1H).
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K. Nakanishi, N. Berova et al.
FULL PAPER
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Received: May 26, 1999 [F1811]
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