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Nonplanar Macrocycle Consisting of Four Pyridine and Phenol Units Connected with Acetylene Bonds Displaying Preferential Binding to Maltoside over Monosaccharides Yuki Ohishi, Naoto Yamamoto, Hajime Abe, and Masahiko Inouye J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00062 • Publication Date (Web): 30 Apr 2018 Downloaded from http://pubs.acs.org on May 1, 2018
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The Journal of Organic Chemistry
Nonplanar Macrocycle Consisting of Four Pyridine and Phenol Units Connected with Acetylene Bonds Displaying Preferential Binding to Maltoside over Monosaccharides Yuki Ohishi, Naoto Yamamoto, Hajime Abe*, Masahiko Inouye* Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan,
[email protected] Abstract A nonplanar macrocycle consisting of four pyridine‒acetylene‒phenol units was developed as a host for saccharide guest molecules. The macrocycle was found to strongly associate with a lipophilic maltose derivative, with an association constant of 107 M−1, over monosaccharide derivatives, for which much smaller association constants were determined, ranging from 103 M−1 to 104 M−1. The macrocycle was found to adopt a boat-like conformation, encapsulating
β-D-maltoside in a twisted manner through approximately seven intermolecular hydrogen bonds.
Macrocycles with acetylene bonds are appealing compounds, whose straightforward scaffolds display their interior and exterior functional groups in a predictable arrangement.1 Thus, these well-defined structures have also attracted more attention in host‒guest chemistry because their
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interaction sites can be preorganized into the holes within their cavity.2-6 When such host molecules recognize guest molecules fitted in the holes, entropic disadvantage accompanying complexation decreases because large conformational changes of hosts is not needed. Apart from its biological importance, saccharide recognition is a challenging topic in the field of artificial host‒guest chemistry, due to the three-dimensional complexity of saccharide structures, and difficulties in differentiating between closely-related saccharide families.2-5 During the course of our continuous studies on saccharide recognition, we have reported planar macrocyclic hosts such as 1, consisting of three pyridine–acetylene–phenol units (Figure 1A).2a Macrocycle 1 strongly recognizes monosaccharides in a multipoint push-pull hydrogen-bonding fashion, in which the pyridine and phenol rings work as hydrogen-bonding acceptor and donor, respectively (Figure 1B).7 The inwardly preorganized hydrogen-bonding motifs proved to be a superior scaffold for saccharide recognition taking advantage of the rigid hexagonal architecture of 1. Furthermore, the hexagonal shaped hole was a reasonable size for monosaccharide recognition, so that 1 showed selectivity for monosaccharides in comparison with its acyclic analogs.7b Adapting the pyridine–acetylene–phenol motif for the recognition of larger saccharides, we newly designed 2, possessing four pyridine–acetylene–phenol units (Figure 1C).9 Krishnan and Zhao have theoretically investigated the geometric and electronic structures of a macrocycle consisting of eight phenylene‒ethynylene units, and the macrocycle was proposed to adopt boatand/or chair-shaped conformation.10 Therefore, host 2 was also expected to form three-dimensional complexes with saccharides. Indeed, Macro Model-based Monte Carlo simulations proposed that 2 adopts a boat-like structure, encapsulating β -D-maltose through seven intermolecular hydrogen bonds in a twisted manner (Figure 1D).
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The Journal of Organic Chemistry
A
R1O
B
Ar
N R 1O
HO
Ar
1
OH
OR1
N
N H
Pr-i HO
Ar =
N
Ar
O
HO
R
Pr-i Pr-i
R1 O
R1 = C8 H17 -n
Ar
R1O
C
R2
D
N HO
R2
OR 1 N
OH 2 R1
= C 8H 17-n R2 = C 5H 11-n
N R 1O
HO R2
OH N
R2
OR 1
Figure 1. A) Planar macrocyclic host 1 with three pyridine–acetylene–phenol units. B) Push-pull hydrogen-bonding between a pyridine–acetylene–phenol molecule and an alcohol guest. C) Nonplanar macrocyclic host 2 with four pyridine–acetylene–phenol units. D) A model of a complex of macrocycle 2 with β-D-maltose proposed from Monte Carlo simulations. The model is an analog of 2, with side alkyl chains shortened to methyl groups. Conditions: OPLS2005, under CHCl3.
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Scheme 1 shows the synthetic procedure for macrocycle 2. The trimer building block 3 and 2,6-diiodo-4-(octyloxy)pyridine 4 were prepared according to literature methods.2a,11 A Sonogashira reaction using 3 and an excess amount of 4 yielded the pentamer precursor 5. Precursors 3 and 5 were reacted together under dilute conditions to give MOM-protected macrocycle 6 in an acceptable yield. Finally, the MOM groups of 6 were removed using trifluoroacetic acid (TFA) to produce target host 2.
OR 1 R1 = C 8H 17 -n R2 = C 5H 11 -n N
R2
R 1O
R2
OMOM
R2
N R 3O
MOMO
2
OR 1
R
3
N
OR 3 OR 1 excess I
N 4
Pd(PPh 3) 4, CuI, K2CO3
Pd(PPh3) 4, CuI, K 2CO3 , i-Pr 2NH, THF
I
i-Pr2 NH, THF 16%
71%
R3 O
N
R 1O
R2
R2
OR 3 N
R1 O
OR 1
OMOM N I
2 N 5
I
R2 TFA, t-BuOH, CH 2Cl2 43%
OR1 6:
R3
= MOM
2 : R3 = H
Scheme 1. Preparation of macrocyclic host 2.
The self-aggregation of 2 was investigated by 1H NMR measurements in CDCl3 (Figure S1). The aromatic proton signals of 2 had very simple pattern at lower concentrations ([2]
