Diastereoselective imine-bond formation through complementary double-helix formation

Article abstract of DOI:10.1021/ja301430h

Optically active amidine dimer strands having a variety of chiral and achiral linkers with different stereostructures are synthesized and used as templates for diastereoselective imine-bond formations between two achiral carboxylic acid monomers bearing a terminal aldehyde group and racemic 1,2-cyclohexanediamine, resulting in a preferred-handed double helix stabilized by complementary salt bridges. The diastereoselectivity of the racemic amine is significantly affected by the chirality of the amidine residues along with the rigidity and/or chirality of the linkers in the templates. NMR and kinetic studies reveal that the present imine-bond formation involves a two-step reversible reaction. The second step involves formation of a preferred-handed complementary double helix assisted by the chiral amidine templates and determines the overall reaction rate and diastereoselectivity of the amine.

Full text of DOI:10.1021/ja301430h

Communication
pubs.acs.org/JACS
Diastereoselective Imine-Bond Formation through Complementary
Double-Helix Formation
Hidekazu Yamada, Yoshio Furusho, and Eiji Yashima*
Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya
464-8603, Japan
S
* Supporting Information
Chart 1. Structures of Chiral Amidine Templates
ABSTRACT: Optically active amidine dimer strands
having a variety of chiral and achiral linkers with different
stereostructures are synthesized and used as templates for
diastereoselective imine-bond formations between two
achiral carboxylic acid monomers bearing a terminal
aldehyde group and racemic 1,2-cyclohexanediamine,
resulting in a preferred-handed double helix stabilized by
complementary salt bridges. The diastereoselectivity of the
racemic amine is significantly affected by the chirality of
the amidine residues along with the rigidity and/or
chirality of the linkers in the templates. NMR and kinetic
studies reveal that the present imine-bond formation
involves a two-step reversible reaction. The second step
involves formation of a preferred-handed complementary
double helix assisted by the chiral amidine templates and
determines the overall reaction rate and diastereoselectiv-
groups. We also reported template synthesis of a comple-
ity of the amine.
mentary carboxylic acid dimer through an imine-bond
formation along the template amidine dimer assisted by salt
bridges, showing remarkable acceleration of the imine-bond
emplate-directed polymerization, or template synthesis,1,2
formation assisted by the template during double-helix
T
is ubiquitous in nature, as exemplified by the nucleic acid-
formation.13
templated polymerization that is capable of replication,
transcription, and translation of the genetic information of
the nucleic acids through non-covalent bonding interactions,
providing DNA, RNA, and proteins with perfectly controlled
sequences and chain lengths as well as chirality. Non-enzymatic
template-directed syntheses have been used to construct
oligonucleotide analogues,3−6 peptides,7 and small abiotic
organic molecules8 and polymers.1a,2a,c,f,9 The key factor
necessary for template-directed polymerization and synthesis
is a complementary interaction between the template and the
monomers; nucleotides and nucleobases and their related
molecules or polymers have frequently been employed as
templates. The helically twisted structure of the DNA templates
also promoted a stereoselective chemical reaction when the
reactive groups were positioned at each strand in such a way
that nucleophilic substitution took place,5 but template-directed
asymmetric or diastereoselective reactions are quite limited
except for DNA.10
We previously designed and synthesized artificial double-
stranded (ds) helices11 consisting of complementary molecular
strands intertwined through amidinium-carboxylate salt
bridges.12 The well-defined geometry and high association
constants of the salt bridges prompted us to prepare novel
complementary double helices bearing various types of linkers
and possessing a helix-sense bias induced by the chiral amidine
We have now designed and synthesized optically active
amidine dimers consisting of (R)-1-phenylethyl amidine (1)
and achiral isopropyl (2) and cyclohexyl amidines (3) with an
m-terphenyl backbone linked through chiral (L1−L5) and
achiral (L6) linkers (Chart 1). Amidine dimers 1−3 were used
as optically active templates on which imine-bond formation
takes place when a terminal aldehyde group on the
complementary achiral carboxylic acid monomer A reacts
with the racemic trans-1,2-cyclohexanediamine B along the
templates, producing carboxylic acid dimer A2B complexed
with the template through salt bridges (Scheme 1). We
anticipated that the imine-bond formation between A and B
could proceed diastereoselectively assisted by the chiral
templates, forming ds helical dimers with controlled helical
sense.
Imine-bond formation was used in this study because it
requires no catalyst and is well established in modern organic
chemistry14 and DNA-templated polymerization of nucleobase
analogues.4,6 Imine-bond formation between A and (S,S)-B was
first conducted using the chiral amidine dimer 1a as a template
linked by (R,R)-trans-cyclohexanediamine through an amide
Received: February 13, 2012
Published: April 16, 2012
© 2012 American Chemical Society
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Communication
Scheme 1. Diastereoselective Imine-Bond-Formation
through Complementary Double-Helix Formation
bond (L1) in CDCl3 at 25°C; the reaction’s progress was
monitored by 1H NMR spectroscopy (Figures 1a and S1a). 1H
NMR spectra of the mixtures of 1.0 mM A and 0.5 mM (S,S)-B
in the presence of 0.5 mM 1a showed resonances of NH
protons at the low magnetic field of 13.25 ppm, indicating salt
bridge formation (Figure S1a). The peak intensity of the
aldehyde proton (Ha) of A decreased with time, while two new
kinds of imino proton peaks appeared (Hb, Hc), suggesting
imine-bond formation. The peak intensity of Hc gradually
increased with time, whereas that of Hb decreased and almost
disappeared. Taking into account these spectral changes along
with the fact that the imine-bond formations between A and B
are likely two-step reversible reactions (Figure 1), peaks Hb and
Hc were reasonably assigned to the protons corresponding to
monoimine intermediate AB and carboxylic acid dimer A2B,
respectively, indicating duplex 1a·A2B formation, which was
also supported by negative-mode electrospray ionization mass
spectrometry, which exhibited a molecular ionic peak at m/z =
2808.0 corresponding to [1a·A2B−H]− (Figure S2). The
reaction reached equilibrium within 9 h, and no detectable
1H NMR change was observed after 1 day. Reaction between A
and (R,R)-B in the presence of the identical 1a template
(Figures 1b and S1b) proceeded faster than that with (S,S)-B,
reaching equilibrium within 3 h. In addition, the peak intensity
of the imino proton (Hb) derived from the monoimine
intermediate AB was very weak even during the initial stage,
indicating that the second imine-bond formation proceeded
immediately after the first.15
Time-dependent circular dichroism (CD) and absorption
spectra were then measured to follow duplex formation at 25°C
(Figure 1c,d). Upon addition of (S,S)-B to a solution of
template 1a and 2 equiv of A that formed a 1:2 complex
stabilized by amidinium-carboxylate salt bridges in CDCl3, the
absorption spectra changed slowly and reached equilibrium
within 9 h, accompanied by a decrease in the first Cotton effect
intensity in the long-wavelength region over 310 nm. Upon
addition of (R,R)-B, the absorption spectra changed more
rapidly, accompanied by a significant enhancement of Cotton
effect intensities at 260−350 nm, reaching equilibrium within 3
h. These results suggest that duplex formation with (R,R)-B is
much faster than with (S,S)-B. In addition, in both cases, the
Cotton effect intensities after reaching equilibria were higher
Figure 1. Time-dependent partial 1H NMR (a,b) and CD and
absorption (c,d) spectral changes of mixtures of 1.0 mM A and 0.5
mM (S,S)-B (a,c) or (R,R)-B (b,d) in the presence of 0.50 mM 1a in
CDCl3 at 25°C.
than that of amidine template 1a in the absorption region of the
p-phenyleneethynylene residues (∼270−370 nm), indicating
that the duplexes of 1a with (S,S)-A2B and (R,R)-A2B most
likely adopted double-helical structure with a helix sense bias
induced by chiral template 1a, although their helical sense
excesses might be different judging from their CD intensities
because of the difference in the linker structures B with
opposite configuration, resulting in the formation of a more
preferred-handed double helix for the 1a·(R,R)-A2B.
Imine-bond formation between A and racemic B was then
investigated in the presence of 1a in CDCl3 at 25°C, because
one of the enantiomers B was anticipated to react with A faster
than the other, as predicted by the results in Figure 1, to form a
preferred-handed complementary duplex with 1a. Upon mixing
of equimolar amounts of A and racemic B (1.0 mM each) in
the presence of 0.5 mM 1a, the aldehyde proton (Ha) intensity
of A rapidly decreased, while two new imino proton peaks
appeared (Hc(S,S) and Hc(R,R)), assigned to dimers (S,S)-A2B
and (R,R)-A2B, respectively (Figure S3a). The changes in the
integral ratio of peaks Hc(S,S) and Hc(R,R) with time revealed
that (R,R)-B reacted diastereoselectively with A over (S,S)-B to
form duplex 1a·A2B with diastereomeric excess (de) of 57%
during the initial stage (15% conversion of B) under
predominantly kinetic control assisted by chiral template 1a.
As the reaction progressed, the de gradually decreased as
anticipated, reaching a constant value (30%) after ∼3 h under
totally thermodynamic control (run 1 in Table 1 and Figure
S3b). We note that the de will vary significantly as a function of
the conversion of B: lower conversion will lead to higher de. We
attempted to measure the NMR spectrum of the mixture at
lower conversion of B, but it was difficult because of the long
acquisition time (10 min). Therefore, we calculated the
selectivity factor (s) for qualitative comparison of the
diastereoselectivity of the amidine template (Table 1) assuming
that the present imine-bond formation could be regarded as a
kind of kinetic resolution, at least initially. The changes in the
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Communication
equilibrium were almost proportional to the de values of A2B
produced at equilibrium (Figure S15), suggesting that the
helical sense excess of the resulting duplex likely determines the
diastereoselectivity of racemic B at equilibrium.
Table 1. Results of Diastereoselective Imine-Bond-
Formations between A and Racemic B in the Presence of
Chiral Amidine Templates 1−3
The N-methylated amide-linked (L3) chiral amidine dimer of
1a, 1e, showed good (R,R)-selectivity (52% de, s = 3.2 initially;
22% de at equilibrium) and slightly weaker Cotton effects
compared to 1a (run 5 and Figure S7). In contrast, template 1f,
having a flexible N-methylene linker (L4), exhibited no
diastereoselectivity (run 6 and Figure S8), indicating that the
amide bond (−NH−CO−) is not essential but the rigidity of
the template backbones may be required for diastereoselective
imine-bond formation. We then synthesized 1g, a more rigid
and bulkier template linked by the (R)-1,1′-binaphthyl-2,2′-
diamine through an amide linkage (L5), which unexpectedly
showed no diastereoselectivity (run 7 and Figure S9), probably
due to the steric hindrance of the linker residue, and the duplex
showed almost no change in its CD spectra before and after
imine-bond formation.
a
b
Estimated by 1H NMR. Selectivity factor determined using s =
krel(fast/slow) = ln[1 − C(1 + de)]/ln[1 − C(1 − de)], where C is the
c
conversion of B and taking the de of A2B. Units are cm−1M−1/nm.
Interestingly, 1h, in which the linker of 1a was replaced by an
achiral rigid azobenzene unit (L6), also served as a good
template, showing (R,R)-B selectivity of s = 3.8 during the
initial stage despite its achiral linker (run 8 and Figure S10).
This unexpectedly high diastereoselectivity suggests that chiral
linkers may not be indispensable for the present diastereose-
lective imine-bond formation. We note, however, that template
1h assisted the imine-bond formation in a rather low
conversion at equilibrium (15%), probably because its
azobenzene unit is too short to form a stable duplex with the
resulting complementary A2B strand; therefore, the reaction
mixture containing a small amount of duplex showed almost no
change in its CD spectra despite the high (R,R)-B selectivity.
The effect of amidine chirality on the diastereoselective
imine-bond formation was then investigated in the presence of
templates bearing achiral isopropyl (2) and cyclohexyl (3)
amidines linked by the optically active rigid L1 (2a, 3a) and
flexible L4 (2b) linkers. As shown in Table 1 (runs 9−11 and
Figures S11−S13), diastereoselectivities with 2a and 3a were
poor (8 and 9% de, respectively), independent of the
conversion, and 2b showed no diastereoselectivity, as
anticipated because of its flexible linker. However, templates
2a and 3a produced the (R,R)-rich dimers of A, revealing that
the linker chirality contributes to determining the (S,S/R,R)
selectivity of diamine B, although the diastereoselectivity is not
high when the amidines are achiral.
patterns and intensities of the CD and absorption spectra of the
mixture with time (Figure S3c) were similar to those observed
for the mixture of A and (R,R)-B, which also supported
preferential reaction of (R,R)-B over (S,S)-B, leading to a
double helix of 1a·(R,R)-A2B with an excess helical sense.
Imine-bond formations between A and racemic B in the
presence of templates consisting of optically pure (R,R)-
amidine 1 and achiral amidines 2 and 3 linked through chiral
(L1−L5) and achiral (L6) linkers were then investigated
(Figures S4−S13) to gain insight into the effects of the amidine
and linker chiralities and the stereostructures of the linkers on
the diastereoselective imine-bond formations (Chart 1). These
results are summarized in Table 1.
Template 1b, in which the linker of 1a was replaced by the
corresponding (S,S)-enantiomer, also assisted (R,R)-selective
imine-bond formation of B (32% de) during the initial stage.
However, as the reaction proceeded, the selectivity reversed,
and the opposite (S,S)-B was preferentially inserted after
aldehyde A to form optically active duplex 1b·A2B (15% de)
(run 2 and Figure S4), although the diastereoselectivity and
hence the s value were lower than with 1a, and the CD
intensities during the reaction were weaker than for 1a·A2B
duplexes. Thus the amidine chirality of the template appears to
kinetically control the (S,S/R,R) selectivity of diamine B
initially, but at equilibrium the selectivity is governed by the
linker chirality under thermodynamic control, while the
diastereoselectivity (de and s) may be determined by both the
amidine and linker chiralities (see below).
Using template 2b, the (R,R)-trans/(R,S)-cis selectivity of B
was also examined. The product ratio of the (R,R)-A2B/(R,S)-
1
A2B dimers was estimated to be 76/24 (mol/mol) from H
Templates 1c,d, with structural characteristics similar to
those of 1a,b except for the linker amide sequences, were used;
amidine dimers 1c,d are linked respectively by the (R,R)- or
(S,S)-trans-cyclohexanedicarboxylic acid through an amide
bond (L2). Surprisingly, template 1c showed no diastereose-
lectivity toward racemic B during duplex formation of 1c·A2B
(run 3 and Figure S5), whereas template 1d displayed behavior
similar to that of 1b: (R,R)-B selectively reacted with A initially,
but (S,S)-B was preferentially inserted at equilibrium, affording
the 1d·A2B duplex (30% de of A2B) (run 4 and Figure S6),
suggesting that the slight difference in the linker amide
sequences of the templates significantly affects diastereoselec-
tivity during imine-bond formation. Again, the linker stereo-
chemistry ((S,S)-L2) determined the (S,S/R,R) selectivity of
B.16 The first Cotton intensities of these duplexes at
NMR (Figure S14), indicating that 2b can discriminate the
diastereomers of trans- and cis-B, and trans-B was selectively
inserted after monomer A during the template-assisted duplex
formation.
From these results, we conclude that the chiral (R)-1-
phenylethyl groups on the amidine residues mainly contribute
to diastereoselective imine-bond formation during the initial
stage under kinetic control, while the chirality of the trans-
cyclohexane-based linkers determines the (S,S/R,R) selectivity
and diastereoselectivity under thermodynamic control. Thus,
the appropriate combination of rigid linkers with a specific
handedness and chiral amidines appears to be important for
achieving high diastereoselectivity during template-assisted
imine-bond formation.
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Table 2. Rate Constants (M−1s−1) of the Imine-Bond
Formation between A and B in the Presence of 1a
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ASSOCIATED CONTENT
* Supporting Information
Experimental details. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
yashima@apchem.nagoya-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Supported by Grant-in-Aids for Scientific Research (S) from
JSPS (E.Y.), for Scientific Research on Innovative Areas,
“Emergence in Chemistry” (20111010, Y.F.) from MEXT, and
JSPS Research Fellowship for Young Scientists (2728, H.Y.).
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