Compounds Combining a Macrocyclic Building Block and Flexible Side-Arms as Carbohydrate Receptors: Syntheses and Structure-Binding Activity Relationship Studies

European Journal of Organic Chemistry

Accepted Article

Title: Compounds combining a macrocyclic building block and flexible

side-arms as carbohydrate receptors: syntheses and structure-

binding activity relationship studies

Authors: Felix Amrhein and Monika Mazik

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

to this Accepted Article as a result of editing. Readers should obtain

the VoR from the journal website shown below when it is published

to ensure accuracy of information. The authors are responsible for the

content of this Accepted Article.

To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100758

Link to VoR: https://doi.org/10.1002/ejoc.202100758

01/2020

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Compounds combining a macrocyclic building block and flexible side-arms as

carbohydrate receptors: syntheses and structure-binding activity relationship

studies

Felix Amrhein and Monika Mazik^*[a]

Dedicated to the memory of Prof. Dr. Klaus Hafner

Dr. Felix Amrhein, Prof. Dr. Monika Mazik

^[a]Institut für Organische Chemie, Technische Universität Bergakademie Freiberg, Leipziger Strasse 29,

09599 Freiberg, Germany; Tel.: 03731392389; Fax: 03731393170

e-mail: monika.mazik@chemie.tu-freiberg.de; https://tu-freiberg.de/fakultaet2/orgch

Abstract: A series of new representatives of compounds combining a macrocyclic building

block and flexible side-arms were prepared and their ability to act as carbohydrate receptors

evaluated. The target compounds were obtained via multi-step syntheses, which included the

preparation of numerous precursors as well as the isolation of a large number of by-products.

The structure-binding activity relationship studies comprise in particular the variation of the

side-arms in order to demonstrate the importance of the presence of a hydrogen bond donor in

these units for the effective complexation of carbohydrates. Based on the findings of our

previous studies, the variation of the bridge units is limited to benzene- and pyrrole-based

moieties, whereby the use of the last-mentioned bridge type was expected to produce more

effective systems. This assumption was confirmed by ¹H NMR titrations and isothermal titration

calorimetry.

________________________________________________________________________________________

1 Introduction

In the course of our studies on the molecular recognition of carbohydrates by artificial receptors

operating through noncovalent interactions, we have developed a whole range of receptor

molecules, including both acyclic compounds^[1-4]and macrocyclic ones with flexible side-arms.^5-

⁷First representatives of the macrocyclic systems (compounds 1-11; see Figure 1 and Supporting

Information) have been reported by us in 2013^[5]and 2015.^[6]This was followed by a further

10.1002/ejoc.202100758

European Journal of Organic Chemistry

structural optimization including the replacement of the heterocyclic units in the two side-arms

by hydroxy groups (compounds 12-14).^[7]Receptors 12-14 impressively demonstrated that even

a structurally very simple recognition unit, such as the hydroxymethyl group, enables effective

complexation of the carbohydrate substrate. The incorporation of the hydroxy groups into the

receptor structure was inspired by the participation of the side chains of serine and threonine in

the natural recognition^[8]of carbohydrates, as shown in Figure 2. The OH group is available to

act both as a hydrogen bond donor and as an acceptor and can thus participate in the formation

of cooperative hydrogen bonds. These studies repeatedly showed that mimicking the natural

binding motifs represents a valuable strategy for the development of effective carbohydrate

receptors.

Figure 1. Structures of the macrocyclic compounds 1−14 with two flexible side-arms acting as

recognition units, reported by us previously. ^[5-7]

2

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Figure 2. Examples of hydrogen bonds and CH··· interactions in the complex of influenza

hemagglutinin with N-acetylneuraminic acid (left)^[8a]and galectin-1 with N-acetyllactosamine

(right).^[8b]

Furthermore, it should be emphasized that the design of the compounds consisting of a

macrocyclic building block and flexible side-arms was inspired by the results of our

crystallographic studies, including the analysis of the binding motifs in a 2:1 receptor-sugar

complex (see Figure 3a), reported by us some time ago^[9](for recent reports on crystalline

complexes formed between acyclic receptors and -/-D-glucosides, see ref.^[10a,b]).

Figure 3. (a) Crystal structure of a 2:1 receptor-carbohydrate complex^[9]that served as a source

of inspiration for the (b) design of carbohydrate receptors combining both a macrocyclic

building block and flexible side-arms (Y = bridge units, CH₂X = side-arms).^[5-7]

Due to the combination of a macrocyclic backbone with flexible side-arms, this type of

compounds exhibits particularly interesting binding properties toward carbohydrates and is able

to form predictable 1:1 receptor-sugar complexes, especially with all-equatorial substituted

3

10.1002/ejoc.202100758

European Journal of Organic Chemistry

sugars, such as -glucopyranoside.^[5-7]The carbohydrate is sandwiched between two benzene

rings and participates in the formation of both hydrogen bonding and CH··· interactions with

the receptor molecule.

In this work we describe further structural modifications of this type of compounds, particularly

involving the variation of the side-arms, as shown in Figure 4 (selection criteria for the

corresponding subunits are given below).

Figure 4. Building blocks [side-arms (X) and bridge units (Y)] used for the construction of the

target compounds considered in this work (replacement of the two CH₂OH side-arms by CH₂OR

or CH₂NHR units); the OH group’s ability^[8k,8l]to participate in cooperative hydrogen bonds is

also illustrated in this figure.

It should be mentioned that artificial carbohydrate receptors represent valuable model systems to

study the basic principles of molecular recognition of carbohydrates^[11-13]and are also regarded

as a potential basis for the development of new therapeutics.^[14]

2 Results and discussion

2.1

Structures of the target compounds (selection criteria)

To demonstrate the importance of the presence of a hydrogen bond donor in the side-arms for

the effective complexation of carbohydrates, structural variations were carried out in which the

CH₂OH groups (acting as side-arms in compounds 12 and 13) were replaced by CH₂OR units

(Figure 4). The significance of the hydrogen bond donor should further to be visualised by

4

10.1002/ejoc.202100758

European Journal of Organic Chemistry

comparing the complexation properties of the compounds bearing CH₂OR groups with those of

the analogues compounds having CH₂NHR units as side-arms, which were expected to be more

powerful carbohydrate receptors. In this context, the residue R should not contain any donor site

for the formation of classical hydrogen bonds and should be relatively easy to incorporate into

the receptor structure. In addition, a sterically demanding residue R should confirm the thesis

that, despite the steric hindrance emanating from this residue, the neighbouring hydrogen bond

donor site (e.g. NH in CH₂NHR) can exert a favourable influence on the complexation

properties of the target compounds. This was done by applying the tert-butyloxycarbonyl moiety

(Boc group) as a bulky group, which is synthetically easy to incorporate. Furthermore,

unsubstituted and methoxy-substituted (o-, m- and p-substituted) phenyl groups were taken into

account as residue R for incorporation into the CH₂NHR and CH₂OR side-arms.

Based on the findings of our previous studies, the variation of the bridge units only includes the

use of the benzene- and pyrrole-based moieties, whereby the use of the last-mentioned bridge

type was expected to produce more effective systems. The combination of the building blocks,

which are given in Figure 4, provided the structures of the target compounds 15-24 shown in

Figures 5 and 6.

Figure 5. Structures of the macrocyclic compounds 15-18 with CH₂OBoc and CH₂NHBoc units

as side-arms.

5

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Figure 6. Structures of the macrocyclic compounds 19–24 with two flexible side-arms bearing

unsubstituted and methoxy-substituted phenyl groups.

2.2 Syntheses of the target compounds 15-18.

The syntheses of the macrocyclic compounds 15-18 were performed on the basis of the reaction

of the bis(aminomethyl)benzene derivatives 25 and 26a, bearing

a

tert-

butoxycarbonyloxymethyl and tert-butoxycarbonylaminomethyl moiety as a side-arm,

respectively, with the corresponding bisaldehyde, such as isophthalaldehyde and 1H-pyrrole-2,5-

dicarboxaldehyde (see Scheme 1). The macrocyclization reactions were carried out in dry

ethanol in the presence of a catalytic amount of acetic acid at 45-50 °C and provided the

compounds 15-I to 18-I, having four imine functionalities, with 70 to 93 % yield (see Scheme

1). The best yield was achieved in the case of the benzene-bridged derivative 15-I (see Scheme

1). Crystallization of 18-I from methanol provided crystals suitable for X-ray analysis.^[15]The

6

10.1002/ejoc.202100758

European Journal of Organic Chemistry

compound was found to crystallize as a methanol solvate of the space group P2₁/c with the

asymmetric part of the unit cell containing one half of the macrocyle and one solvent molecule

(1:2 host-guest complex).

Scheme 1. Syntheses of compounds 15–18. Reaction conditions: (a) dry EtOH, catalytic amount

of acetic acid; 93 % of 15-I, 80 % of 16-I, 70 % of 17-I, 81 % of 18-I; (b) 1. NaBH₄,

MeOH/CH₂Cl₂, 2. CHCl₃/H₂O; 89 % of 15, 100 % of 16, 97 % of 17, 98 % of 18.

The imines 15-I to 18-I were reduced to the target compounds 15–18 using sodium borohydride.

While the reduction of 16-I was successful in pure methanol, the addition of dry

dichloromethane was necessary in the case of 15-I. This was subsequently established as the

standard procedure. After the final hydrolysis and extraction, the target compounds were

obtained in 89-100 % yield. The yield of the macrocyclisation over two stages was between 68

% (17) and 83 % (15).

The syntheses of the precursors 25 and 26a, used for the macrocyclization reactions, started with

1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene (27), which was treated with potassium

phthalimide in water-containing DMSO to obtain the compounds 28^[7]and 29, as shown in

7

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Scheme 2. Depending on the water content of the solvent, different products can be obtained. In

an anhydrous environment, in addition to the compound 29, mainly the aldehyde 32 (see Scheme

3) is formed by Kornblum oxidation.^[16]When the water content is between 2.5 % and 15 %,

compound 28, containing one hydroxymethyl and two phthalimidomethyl groups, is formed in

39-43 % yield. At high water contents, the bis(hydroxymethyl)benzene derivative 33 (see

Scheme 3) is also obtained in an appreciable amount (~ 10 %).

Scheme 2. Syntheses of compounds 25–26a. Reaction conditions: (a) DMSO/H₂O, 43 % of 28,

40 % of 29^[7]; (b) di-tert-butyl dicarbonate, zinc acetate dihydrate, CH₂Cl₂, 51 % of 30; (c, d)

hydrazine hydrate, toluene/EtOH, 86 % of 25, 97 % of 31; (e) di-tert-butyl dicarbonate, CHCl₃,

41 % of 26a.

8

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Scheme 3. Products of the reaction of 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene (27) with

potassium phthalimide, formed in dependence of the water content of DMSO [in the case of (c),

compound 32 was isolated in traces).

The conversion of compounds 28 and 29 to the corresponding amino derivatives 25 and 26a was

performed in two different ways. The derivative 28 was converted by the procedure described

for benzyl alcohol by Bartoli et al.,^[17]which includes the use of di-tert-butyl dicarbonate in

dichloromethane under Lewis acid catalysis of zinc acetate (see Scheme 2). The obtained Boc-

protected derivative 30 was further converted into 25 by the treatment with hydrazine hydrate in

a mixture of toluene and ethanol (86 % yield).

The synthesis of 26a, which is also shown in Scheme 2, includes the conversion of compound

29 into 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene (31) by treatment with hydrazine hydrate

(97 % yield) and the subsequent reaction of 31 with di-tert-butyl dicarbonate in chloroform. The

latter reaction is based on the findings of Anslyn et al.^[18]and was optimized to obtain the best

yield of the product containing only one Boc-protected amino group. To increase the yield of

26a, the amount of di-tert-butyl dicarbonate was reduced from 1.10 (21 % yield)^[18a]and 0.78

(18 % yield)^[18b]equivalents to 0.60 equivalents. Furthermore, the concentration of the di-tert-

butyl dicarbonate solution was decreased, and the addition time of this solution was increased

from 2^[18a]to 9 hours. Especially the lowering of the concentration of the di-tert-butyl

dicarbonate solution from 0.26 mol/L to 0.09 mol/L is likely to play an important role in

9

10.1002/ejoc.202100758

European Journal of Organic Chemistry

suppressing the multiple substitutions. Through this reaction optimization the yield of compound

26a was almost doubled from 21 %^[18a]to 41 %.

2.3 Syntheses of the macrocyclic compounds 19-24.

The target macrocycles 19-24, consisting of two side-arms each bearing a phenyl group, were

prepared through the reduction of the macrocyclic precursors 19-I to 24-I possessing four imine

functionalities. The syntheses of the last mentioned compounds are based on the

macrocyclization reactions of the educts 34-38, containing two aminomethyl groups, with

isophthalaldehyde and 1H-pyrrole-2,5-dicarbaldehyde (see Scheme 4).

Scheme 4. Syntheses of compounds 19–21. Reaction conditions: (a) dry EtOH, catalytic amount

of acetic acid, 56 % of 19-I, 58 % of 20-I, 84 % of 21-I, 73 % of 22-I, 66 % of 23-I, 70 % of 24-

I; (b) 1. NaBH₄, MeOH/CH₂Cl₂, 2. CHCl₃/H₂O, 100 % of 19, 93 % of 20, 100 % of 21, 94 % of

22, 97 % of 23, 100 % of 24.

10

10.1002/ejoc.202100758

European Journal of Organic Chemistry

The reactions were carried out in dry ethanol in the presence of catalytic amounts of acetic acid

and depend on the same factors as observed in the case of the macrocycles 15-18 with Boc-

containing side-arms. The phenylene-bridged imines 21-I to 24-I were obtained in acceptable to

very good yields of 66-84 %, whereas the yields of the pyrrole-bridged imines 19-I and 20-I

were lower with 56 % and 58 %, respectively. The reduction of 19-I to 24-I with sodium

borohydride in a methanol/dichloromethane mixture provided the target molecules 19-24 in 93

% to 100 % yield.

The starting point of the synthesis routes to the above mentioned compounds 34–38 was again

1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene (27) (see Schemes 5 and 7). Two strategies were

applied, which are described below.

The first strategy involves the monosubstitution of 27 with a phenoxy group, followed by the

conversion

of

the

prepared

compounds

39a-42a

into

the

corresponding

bis(phthalimidomethyl)benzene derivative 43a-46a (see Scheme 5), and finally their

hydrazinolysis to the corresponding amino derivatives 34 and 36-38.

The second strategy first provides compound 48 through the reaction of 27 with potassium

phthalimide (see Scheme 7), followed by the incorporation of a phenoxy or phenylamino group

to produce compounds 43a-46a and 49, the hydrazinolysis of which is the basis for the

preparation of the desired compounds 34-38.

In the case of the first strategy shown in Scheme 5, the phenol derivative dissolved in

acetonitrile was deprotonated by potassium carbonate and then reacted with 27 (the progress of

the reactions was monitored by thin layer chromatography). After the chromatographic

separation of the di- (39b-42b) and trisubstituted derivatives (39c-41c), the desired

monosubstituted compounds 39a-42a were obtained with 40-52 % yield. Optimization of the

reaction conditions for the formation of the monosubstituted derivatives was performed in detail

for compound 39a and is described in Supporting Information. The knowledge gained from this

was transferred to the syntheses of 40a-42a.

11

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Scheme 5. Syntheses of compounds 39a-42a and 43a–46a. Reaction conditions: (a) K₂CO₃,

acetonitrile/THF, 40 % of 39a, 8 % of 39b, 42 % of 40a, 11 % of 40b, 50 % of 41a, 22 % of

41b, 52 % of 42a, 30 % of 42b; (b) DMSO, 47 % of 43a, 57 % of 44a, 59 % of 45a, 32 % of

46a (experimental data for the by-products 39b-46b and 43c-46c are given in Experimental

Section).

The aforementioned reaction of 39a-42a with potassium phthalimide provided the derivatives

43a–46a with yields in the range of only 32 to 59 %. This is due to the Kornblum oxidation that

occurs during this process, which causes the formation of the by-products 43b-46b containing an

aldehyde group (see Scheme 5). These have an almost identical retention behaviour as the

compounds 43a–46a and are difficult to separate by column chromatography. The problematic

separation and the resulting mixed fractions lead to further reduction of the yields of the desired

products. To develop a method for a better isolation of the target compound 43a–46a, water-

containing DMSO (0.5 –1.0 % water) was used as an alternative (see Scheme 6). This procedure

also results in yield losses, but the formation of by-products containing a hydroxymethyl group

12

10.1002/ejoc.202100758

European Journal of Organic Chemistry

instead of an aldehyde functionality (compounds 43c-46c) enables easier chromatographic

separation of the raw mixture, due to the much lower retention factor of these compounds. All

by-products (compounds 43b-46b and 43c-46c) were isolated and are described in Experimental

Section.

Scheme 6. Synthesis of bis(phthalimidomethyl)benzene derivatives 43a–46a on the basis of the

reactions of 39a-42a with potassium phthalimide in DMSO and water-containing DMSO

(influence of the presence of water on the product formation).

To further improve the yields of the derivatives 43a–46a, containing two phthalimidomethyl

moieties, an alternative synthetic route was developed (above-named as the second strategy, see

Scheme 7), which includes the preparation of the precursor 48 having a good linkage possibility

due to the presence of the bromomethyl functionality. This synthetic route also makes the

compound 49 accessible, which is the basis for the synthesis of the bis(aminomethyl)-substituted

derivative 35 and therefore of the target macrocycle 20 (see Scheme 4).

13

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Scheme 7. Syntheses of compounds 34 – 38. Reaction conditions: (a) 1,4-dioxane/DMF, 19 %

of 47, 49 % of 48, 15 % of 29, (b) K₂CO₃, acetonitrile/toluene, 65 % of 43a, 67 % of 44a, 63 %

of 45a, 65 % of 46a, 87 % of 49; (c) hydrazine hydrate, toluene/EtOH, 87 % of 34, 83 % of 35,

90 % of 36, 89 % of 37, 87 % of 38.

The syntheses started again with 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene (27), which was

reacted with two equivalents of potassium phthalimide in a 1,4-dioxane/DMF mixture. The

desired disubstituted derivative 48 was separated from the mono- and trisubstituted

triethylbenzenes (47 and 29, respectively) by column chromatography. Compounds 43a-46a and

49 were then readily accessible by reacting the precursor 48 with the corresponding phenol

derivative or aniline in acetonitrile/toluene in the presence of potassium carbonate. The

compounds 43a-46a were synthesized with 63 - 67 % yield and the compound 49 was obtained

in a very good yield of 87 %. It should be noted, that the directly reaction of 27 with aniline

would lead to an inseparable mixture of compounds with various substitution patterns, whereas

the use of the reactant 48 only yields the desired product 49. In summary, the second strategy

14

10.1002/ejoc.202100758

European Journal of Organic Chemistry

(Scheme 7) is to be preferred, since only two instead of 14 by-products are synthesized on the

preparation of compounds 43a-46a. Furthermore, the chromatographic separation in both stages

(starting from 27) is easy to realize.

Compound 49 could also be obtained under the reaction conditions described by Sing et al,.^[19]

which involve the heating of urea and choline chloride under an argon atmosphere to form a

deep eutectic solvent, which serves as reaction matrix for the two reactants. After extraction and

column chromatography, the product was obtained with a yield of 65 %. Due to the more

difficult handling, the aforementioned "classical" synthesis is recommended.

The prepared bis(phthalimidomethyl)-substituted triethylbenzenes 44a- 46a and 49 could finally

be converted into the corresponding amino derivatives 34-38 in very good yields of 83 % – 90 %

via reaction with hydrazine hydrate.

2.4 Binding properties of compounds 15–24.

The ability of the macrocyclic compounds 15-24 to act as carbohydrate receptors was evaluated

on the basis of ¹H NMR titrations and isothermal titration calorimetry (ITC).

Taking into account the findings of our previous studies, which have shown the particular

suitability of this type of compounds for complexing all-equatorial substituted sugars, octyl -D-

glucopyranoside (Glc) was selected as a test substrate for the binding studies.

2.4.1 ¹H NMR spectroscopic titrations.

The ¹H NMR titrations were performed either at a constant concentration of the receptor or at a

constant concentration of the substrate ("inverse" titrations). The titration data were evaluated on

the basis of WinEQNMR,^[20]HypNMR^[21]and SupraFit programs,^[22]and the complex

stoichiometry was analyzed by using the mole ratio method^[23](for examples, see Supporting

Information); the determined association constants are summarized in Table 1.

The formation of complexes showing slow exchange on the NMR time scale and the coexistence

of fast and slow exchanging complexes prevented the use of the NMR method for the

determination of the binding constants in some cases; the binding properties were then only

analyzed on the basis of the isothermal titration calorimetry.

15

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Table 1. Association constants^a,bfor the complexation of octyl -D-glucoside (Glc) with

compounds 15-24.

Compound

Aromat in the bridge unit Y /

Side-arm X

K₁₁[M^-1]

Method

benzene / CH₂OBoc

benzene / CH₂NHBoc

360

4810

NMR

ITC^e

NMR

ITC^e

ITC^f

15

16

4990

pyrrole / CH₂OBoc

pyrrole / CH₂NHBoc

pyrrole / CH₂OH

3400

17

18^c

13^c

79000

195000

19^d

20

21

22

23

24

pyrrole / CH₂OPh

12000

36000

550

ITC^e

pyrrole / CH₂NHPh

NMR, ITC^e

benzene / CH₂OPh

NMR

benzene / CH₂O(o-OCH₃)C₆H₄

benzene / CH₂O(m-OCH₃)C₆H₄

benzene / CH₂O(p-OCH₃)C₆H₄

640

NMR

590

NMR

540

NMR

^aIn CDCl₃, 20°C or 22°C (NMR), 25°C (ITC); ^bErrors are ≤ 8 %; ^cSlow exchanging complex; Fast and

d

slow exchanging complex; ^eFor further details, see Table 2; ^fRef.^[7]

The results of the binding studies of compounds 15-24 towards octyl -D-glucoside (Glc) are

summarized in points (a) - (e).

(a) As expected, compounds with flexible side-arms bearing a hydrogen bond donor group were

found to be more powerful receptors than the analogs lacking such donor groups. This is clearly

visible by comparing the binding properties of compounds 15 and 17, containing two CH₂OBoc

moieties, with those of the analogs 16 and 18, having CH₂NHBoc groups as side-arms.

Depending on the type of the bridging unit Y (benzene- or pyrrole-based bridge), the value of the

complexation constant increased by a factor of 14 (15 to 16) and 23 (17 to 18), due to the

presence of the amino functionality in the side-arms (see Table 1 and Figures 7 and 9). The same

tendency, but less pronounced, is shown by comparing the binding constants determined for

compounds 19 and 20, containing CH₂OPh and CH₂NHPh groups as side-arms, respectively. In

this case, the incorporation of the amino functionality leads to an increase in the binding strength

by a factor of 3 (see Table 1 and Figures 8 and 9).

16

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Figure 7. Partial ¹H NMR spectra (500 MHz, CDCl₃, 295 K) of compound 15 (a), 16 (b), 17 (c)

and 18 (d) after the addition of octyl -D-glucoside (Glc). (a) 0.00-6.26 equiv of Glc, [15] =

1.00 mM; (b) 0.00-6.07 equiv of Glc, [16] = 1.01 mM; (c) 0.00-6.00 equiv of Glc, [17] =

1.00 mM; (d) 0.00-2.54 equiv of Glc, [18] = 1.00 mM. Shown are the chemical shifts of the

CH₂NHCH₂signals of 15-18, the CH₂NHBoc signals (NH marked by triangles) of 16/18 and the

pyrrole NH signals of 17/18 (marked by triangles in the case of 18).

17

10.1002/ejoc.202100758

European Journal of Organic Chemistry

1

Figure 8. Partial H NMR spectra (500 MHz, CDCl₃, 293 K) of compound 19 (a) and 20 (b)

after the addition of octyl -D-glucoside (Glc). (a) 0.00-4.50 equiv of Glc, [19] = 1.00 mM;

(b) 0.00-4.01 equiv of Glc, [20] = 1.00 mM. Shown are the chemical shifts of the pyrrole NH

(marked by triangles and/or rhombs) and CH₂NHCH₂signals of 19 and 20 as well as the

CH₂NHPh signals of 20 (CH₂marked by triangles, NH marked by rhombs).

Figure 9. (Left) Bar graph illustrating the higher binding affinity of compounds containing

CH₂NHR groups as side-arms (compounds 16, 18 and 20) in comparison to their analogues with

CH₂OR groups (15, 17 and 19) towards octyl -D-glucoside (Glc) (increase of the binding

constants K₁₁given as a factor). (Right) Energy-minimized structure of the 1:1 complex of

compound 18 and octyl -D-glucopyranoside (18•Glc; the glucoside ring is located in the

18

10.1002/ejoc.202100758

European Journal of Organic Chemistry

cavity of the receptor molecule). MacroModel V.9.8, OPLS_2001 force field, MCMM, 50000

steps; Color code: receptor N, blue; receptor C, grey; receptor O, red; sugar molecule, orange.

(b) The binding properties of the pyrrole-bridged compound 18, bearing two CH₂NHBoc

groups, support the thesis that even in the presence of a sterically demanding residue, the

adjacent hydrogen bond donor can significantly contribute to effective complexation (K₁₁

=

-1

79000 M versus 3400 M for the analogue 17 lacking the donor site; see Figure 7). Compound

16 with benzene-based bridges and two side-arms containing the NH functionality also shows

-1

this in direct comparison to the donor-free analogue 15 (K₁₁= 4900 M versus 360 M ), as

shown in Figure 7. This confirms that the presence of hydrogen bond donating groups in the

side-arms is of great importance for the development of effective receptors belonging to the

class of compounds, which consist of a macrocyclic building block and two flexible side-arms.

(c) The present study confirmed our previous findings regarding the influence of the type of

bridge unit on the binding properties and showed that the incorporation of pyrrole-containing

bridges leads to more effective receptors than in the case of the use of benzene-based bridge

units (for examples of other macrocyclic carbohydrate receptors bearing pyrrole-based bridges,

see ref.^[24]).

A significantly improved binding affinity could be observed between compounds 15 and 17

(factor 9) and 16 and 18 (factor 16). The 22-fold increase in binding strength between 21 and 19

is similar to that observed previously for the analogues 12 and 13, bearing hydroxymethyl

groups as side-arms (about 24-fold weaker binding of Glc by 12 in comparison to 13).

In general, it can be stated that the pyrrole-based bridging units lead to a significantly more

effective carbohydrate recognition, as illustrated also by bar graph in Figure S109. However, if

the units, which function as side-arms, are not capable of effective interactions with the

substrate, pyrrole-bridged derivatives also represent weak systems. Thus, the nature of the side-

arms has a strong influence on the binding properties of the potential receptor (see Figure S108).

(d) The combination of phenoxymethyl units, acting as side-arms, with benzene-based bridges

provides compounds displaying very weak binding affinity towards -glucopyranoside

(compounds 21-24). As mentioned above, the presence of a hydrogen bond donating

functionality in the side-arms (as in 20) and/or the use of pyrrole-based bridge units (as in 20 and

19) causes a significant increase in the binding affinity. In the case of compounds 19-24 the

19

10.1002/ejoc.202100758

European Journal of Organic Chemistry

receptor efficiency decreases in the sequence: pyrrole / CH₂NHPh (20) > pyrrole / CH₂OPh (19)

>> benzene /CH₂OPh (21) (specified is: aromatic ring in the bridge unit / side-arm).

Energy-minimalized structure of the complex 21•βGlc in comparison with the structures of the

more stable complexes 19•βGlc and 20•βGlc are shown in Figure S110 in Supporting

Information.

Pyrrole-bridged compound 19, containing CH₂OPh units as side-arms, is about 19- to 22-fold

more effective than the phenylene-bridged analogues 21-24 (without and with methoxy

substituent in the phenyl ring of the CH₂OPh units). Beside the unfavourable structural

properties of the side-arms, the formation of intramolecular interactions seems to be further

responsible for the weak binding properties of compounds 21-24, as indicated by molecular

modeling calculations (for example, see Figure 10) and determined by ROESY experiments (for

examples, see Figures S111 and S112).

Figure 10. (Left) Energy-minimized structure of compound 23 indicating the formation of

intramolecular interactions. MacroModel V.9.8, OPLS_2001 force field, MCMM, 50000 steps;

Color code: receptor N, blue; receptor C, grey; receptor O, red. (Right) Schematic illustration of

the intramolecular interactions.

(e) According to the design principle, which is illustrated in Figure 3, the receptor molecules

form 1:1 complexes with the tested carbohydrate. As in the case of the previously investigated

compounds of this type (see Figure 1), the complexation-induced chemical shifts observed

during the titrations performed with compounds 15-20 show that the receptor-sugar complexes

are stabilized by both hydrogen bonds (see Figures 7, 8 and 11) and CH···^interactions. The

involvement of the sugar CH’s in CH··· interactions with the central benzene rings of the

receptor is for example indicated by the upfield shift of the CH peaks observed during the

titrations of Glc with the corresponding receptor molecule (for an example, see Figure S105).

20

10.1002/ejoc.202100758

European Journal of Organic Chemistry

The most effective receptor 18, equipped with pyrrole-based bridging units and CH₂NHBoc

groups as side-arms, shows a slow exchange on the NMR time scale when using the octyl β-D-

glucopyranoside as substrate (see Figures 7d and 11), which can be explained by a special

positioning of the carbohydrate in the receptor cavity, as illustrated by the schematic

representation of the receptor-sugar complex in Figure 11 (for excerpts from the ROESY

spectrum of 18•βGlc in CDCl₃, see Figure S113 in the Supporting Information). While slow

exchange can be observed for compound 18, the analogue 17, bearing two CH₂OBoc groups as

side-arms, forms complexes that show fast exchange on the NMR time scale (see Figure 11).

Furthermore, fast and slow exchanging complexes also coexist, as in the case of compound 19

(see Figure 8a; for excerpts from the ROESY spectrum of 19•βGlc. see Figure S114).

Figure 11. Partial ¹H NMR spectra (500 MHz, CDCl₃, 295 K) of compounds 17 and 18 after the

addition of octyl -D-glucoside (Glc). [17] = 1.00 mM, 0.00-6.00 equiv of Glc; [18] = 1.00

mM, 0.00-2.54 equiv of Glc. Shown are the chemical shifts of the pyrrole NH (marked by

triangles in the case of 18) and the schematic illustration of the receptor-sugar complexes

showing different positioning of the -D-glucopyranoside in the receptor cavity.

It is also worth noting that a different positioning of the -D-glucopyranoside in the receptor

cavity was observed in two crystalline complexes, which were recognized in a crystal structure

of an acyclic receptor.^[10a]In each of the two 1:1 receptor-sugar complexes the hydroxy groups

of the sugar interact in a different way with the binding site of the receptor molecule belonging

to the class of compounds consisting of a 1,3,5-trisubstituded 2,4,6-triethylbenzene scaffold.

21

10.1002/ejoc.202100758

European Journal of Organic Chemistry

2.4.2 Microcalorimetric titrations.

The microcalorimetric titrations were carried out by adding increasing amounts of the sugar to a

solution of the corresponding receptor (compounds 16 and 18-20; see Table 2 and Figure 12).

The binding constants were determined from three independent microcalorimetric titrations and

in all cases the best fit of the titration data was obtained with the 1:1 receptor-sugar binding

model (data were evaluated on the basis of NanoAnalyze and SupraFit programms).

Table 2. Results of microcalorimetric titrations of compounds 16 and 18-20 with octyl -D-

glucopyranoside.^a-c

Compound

lg K₁₁

(K₁₁[M^-1])

G

H

TS

[kJ/mol]

-42.9

S

[J/mol K]

-144

[kJ/mol]

-21.1 ± 0.6

[kJ/mol]

-64.0 ± 4.6

3.70 ± 0.05

16

(4990 ± 570)

4.90 ± 0.03

-27.9 ± 0.5

-23.3 ± 0.5

-26.0 ± 0.1

-75.9 ± 2.3

-43.0 ± 1.5

-65.9 ± 0.3

-48.0

-19.7

-39.9

-161

-66

18

19

20

(79000 ± 5500)

4.08 ± 0.05

(12000 ± 1380)

4.55 ± 0.01

-134

(36000 ± 800)

a

In dry CDCl₃at 25 °C.^bUsed concentrations: [16] = 0.5 mM, [Glc] = 16.8 mM; [18] = 0.5 mM,

c

[Glc] = 7.2 mM; [19] = 0.5 mM, [Glc] = 10.8 mM; [20] = 0.4 mM, [Glc] = 5.7 mM. The errors

listed are the standard deviations for a minimum of three replicated ITC titrations.

22

10.1002/ejoc.202100758

European Journal of Organic Chemistry

Figure 12. ITC thermogram (left) and titration curve-fitting (right) for the titration of 18 with

Glc in dry CDCl₃(the heat of dilution has been subtracted). Titration mode: addition of -

glucoside (c_syringe= 7.23 mM) into  (c_cell= 0.52 mM) at 298 K in 35 steps.

The experiments showed that the enthalpic driving force of all the investigated binding

processes is partially compensated by negative entropy (S); the enthalpy (H) is more negative

than the free energy of binding (G) (as reported also for protein-carbohydrate complexes^[26]).

As already indicated by the results of the NMR titrations, compound 18 was found to be a much

more effective receptor for Glc.

Consideration of the results of all binding experiments (NMR and microcalorimetric titrations)

revealed that by replacing the CH₂OBoc by CH₂NHBoc units a gain in binding free energy

between -6 kJ/mol and -8 kJ/mol is observed. By changing the flexible side-arms from CH₂OPh

to CH₂NHPh units this energetic gain was about -3 kJ/mol. The incorporation of pyrrole- instead

of benzene-based bridges increases the binding free energy by about 6-7 kJ/mol.

At this point it should also be mentioned that a comprehensive discussion of the experimental

binding energies in supramolecular complexes, including receptor-sugar complexes, can be

found in an excellent review of F. Biedermann and H.-J. Schneider^[27](see also ref.^[28]).

3 Conclusion

To perform further structure-activity relationship studies with compounds consisting of a

macrocyclic building block and flexible side-arms, new representatives of this class of

compounds were prepared (compounds 15-24) and their binding properties toward a selected

sugar evaluated. The target compounds were obtained via multi-step syntheses, which included

the preparation of numerous precursors as well as the isolation of a large number of by-products.

The reduction of the macrocyclic precursors 15-I to 24-I possessing imine functionalites was not

performed in situ, but all of them were isolated in good to excellent yields of 70 –93 %. Beside

the 21 acyclic precursors (compounds 25, 26a, 28-31, 34-38, 39a-46a and 48), 19 by-products

were isolated and characterized (compounds 26b, 26c, 32, 33, 39b-46b, 39c, 41c, 43c-46c and

47).

1

Extensive H NMR and microcalorimetric titrations showed that under the experimental

conditions used, the macrocyclic compounds with a hydrogen bond donor site in each of the

flexible side-arms have a higher efficiency in carbohydrate complexation than the corresponding

analogues lacking such donor site. Even in the presence of a sterically demanding residue, the

23

10.1002/ejoc.202100758

European Journal of Organic Chemistry

adjacent hydrogen bond donor can contribute to effective complexation of the carbohydrate

substrate. By using of pyrrole-containing bridges more powerful receptors have been generated

than in the case of the use of benzene-based bridges; however, if the units acting as side-arms do

not possess the capability for effective interactions with the substrate, pyrrole-bridged

derivatives also represent weak systems. The present study confirmed the results of our previous

investigations and showed again that the structural properties of both the side-arms (units X) and

bridge units (Y) strongly influence the binding strength. It should be however noted that the

side-arms are essential for strong complexation.

It should also be emphasized that within the compounds 12-24 the structurally very simple

recognition unit, such as the hydroxymethyl group, enables the most effective complexation if

acting as a side-arm, as revealed by the comparison of the properties of the previously

investigated compounds 12-14 with those of 15-24 (see Figure 13).

Figure 13. Comparison of the binding strength of compounds 12, 13 and 15- 24 towards octyl

-1

-D-glucopyranoside (K₁₁values [M ]).

The new representatives once again show the importance of the design strategy of artificial

receptors that we reported some years ago,^[9]which comprises the adaptation of the binding

mode found in the crystal structure of a 2:1 receptor-carbohydrate complex, in which the all-

equatorial substituted substrate is sandwiched between the aromatic units of two identical

receptor molecules. This finding formed the basis for the development of the macrocyclic

receptor system by linking two triethylbenzene-based building blocks via bridging units.

In summary, compounds that display a combination of a macrocyclic backbone and flexible side

arms are valuable objects for conducting systematic studies on the molecular recognition of

carbohydrates. Our previous^[5-7]and current extensive studies on structure-binding activity

24

10.1002/ejoc.202100758

European Journal of Organic Chemistry

relationships using macrocyclic compounds possessing two flexible side-arms provide a large

number of findings that make a valuable contribution to the understanding of molecular

recognition processes and provide new impulses for further development in this field of

research.

4 Experimental Section

Analytical TLC was carried out on silica gel 60 F₂₅₄plates; column chromatography was carried

out on silica gel. Isophthalaldehyde is commercially available and 1H-pyrrole-2,5-

dicarboxaldehyde was synthesized according to the procedure reported by Sudhakar et al.^[29]The

precursors 26a,^[18a,b]27^[30]and 31^[30]are literature-known compounds. The NMR and mass

spectra as well as the melting point of compound 26a match the data published by Anslyn et al.

[7a,b]

Reaction optimization for compound 39a (by-products: 39b and 39c^[31]) is given in Supporting

Information and the experimental data for the by-products 32, 33, 39b-46b, 41c and 43c-46c are

given below. The NMR and mass spectra as well as the melting point of the by-product 26b

match the data published by Anslyn et al.^[18a,b]The NMR data of compounds 26c and 39c match

the data reported by Davis et al.^[18d]and by Kim et al.,^[31]respectively.

Binding studies (¹H NMR and microcalorimetric titrations) were carried out according to the

procedures described by us previously (see for example ref.’s ^[5-7]). Octyl -D-glycoside is

commercially available.

General procedure for the synthesis of the macrocyclic compounds 15-I–24-I and 15–24.

To a solution of the triethylbenzene derivative 25, 26a or 34-38 in dry ethanol the corresponding

aldehyde (isophthalaldehyde or 1H-pyrrole-2,5-dicarboxaldehyde) and one drop of acetic acid

were added and the resulting mixture was stirred (for details, see below). The formed

macrocyclic compound was separated by centrifugation, washed with small amounts of ethanol

and dried under vacuum. All imines except 19-I and 20-I were obtained as white solids; 19-I

was obtained as white-yellow and 20-I as yellow solid.

The corresponding imine was suspended in dry methanol (in the case of 16-I) or a mixture of

methanol and dichloromethane. To this suspension sodium borohydride (10 equiv.) was slowly

added and the mixture was stirred at room temperature (for details, see below). Then the solvent

was removed under vacuum, the residue was suspended in a mixture of water/chloroform [10

mL, 9:1 (v/v)] and the suspension stirred again for another 12 h. The mixture was extracted with

25

10.1002/ejoc.202100758

European Journal of Organic Chemistry

chloroform and the combined organic phases were washed with water and dried over magnesium

sulfate. The solvent was evaporated and the residue dried under vacuum. All products except 19

and 20 were obtained as white solids; 19 was obtained as pale yellow and 20 as yellow solid.

Compound 15-I was prepared from 25 (108 mg, 0.33 mmol) and isophthalaldehyde (44 mg,

0.33 mmol) in ethanol (4 mL); the reaction mixture was stirred at 45 °C for 4 h. Yield 93 % (128

1

mg, 0.14 mmol); m.p. 205 – 207 °C; H NMR (500 MHz, CDCl₃): δ = 1.19 (m, 18H), 1.49 (s,

18H), 2.40 (s, 4H), 2.61 (s, 8H), 5.01 (s, 8H), 5.20 (s, 4H), 7.48 (t, J = 10 Hz, 2H), 7.49 (br s,

13

2H), 7.92 (s, 4H), 8.02 (d, J = 7.6 Hz, 4H) ppm; C NMR (125 MHz, CDCl₃): δ = 15.7, 16.0,

23.2, 23.5, 27.8, 55.4, 63.4, 82.2, 128.7, 128.9, 129.8, 130.5, 131.8, 136.7, 144.8, 145.3, 153.6,

159.0 ppm; HRMS (ESI): m/z calcd for C₅₆H₇₂N₄O₆+H⁺: 897.55246 [M+H]⁺, found: 897.55360.

C₅₆H₇₂N₄O₆+ H⁺: 897.55246 [M+H]⁺, found: 897.55360.

Compound 15 was prepared from 15-I (114 mg, 0.13 mmol) and sodium borohydride (50 mg,

1.32 mmol) in methanol/dichloromethane [5 mL, 4:1 (v/v)]; the mixture was stirred at room

1

temperature for 4 h. Yield 89 % (102 mg, 0.11 mmol); m.p. 155 °C; H NMR (500 MHz,

CDCl₃): δ = 1.09 (t, J = 7.4 Hz, 6H), 1.22 (t, J = 7.5 Hz, 12H), 1.48 (s, 18H), 2.68 (q, J = 7.4 Hz,

4H), 2.82 (q, J = 7.5 Hz, 8H), 3.73 (s, 8H), 3.89 (s, 8H), 5.19 (s, 4H), 7.15 – 7.19 (m, 4H), 7.24

– 7.27 (m, 2H), 7.53 (s, 2H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ = 16.7, 22.6, 22.8, 27.8, 47.3,

54.9, 63.4, 81.9, 127.0, 127.1, 128.0, 129.0, 134.4, 140.5, 143.4, 144.4, 153.8 ppm; HRMS

(ESI): m/z calcd for C₅₆H₈₀N₄O₆+H⁺: 905.61506 [M+H]⁺, found: 905.61486.

Compound 16-I was prepared from 26a (245 mg, 0.70 mmol) and isophthalaldehyde (94 mg,

0.70 mmol) in ethanol (2 mL); the mixture was stirred at 50 °C for 8.25 h. Yield 80 % (252 mg,

0.28 mmol); m.p. 225 °C (decomp.); ¹H NMR (500 MHz, CDCl₃): δ = 1.18 (t, J = 7.4 Hz, 6H),

1.20 (t, J = 7.5 Hz, 12H), 1.43 (s, 18H), 2.51 (s, 4H), 2.60 (d, J = 7.4 Hz, 8H), 4.35 (d, J = 4.4

Hz, 4H), 4.47 (s, 2H), 4.97 (s, 8H), 7.49 (t, J = 7.8 Hz, 2H), 7.72 (s, 2H), 7.92 (d, J = 7.8 Hz,

4H), 8.07 (s, 4H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ = 15.6, 16.1, 23.1, 23.3, 28.4, 38.9, 56.1,

79.4, 128.7, 128.9, 129.6, 132.2, 132.3, 136.6, 143.7, 144.2, 155.4, 159.7 ppm; HRMS (ESI):

m/z calcd for C₅₆H₇₄N₆O₄+H⁺: 895.58443 [M+H]⁺, found: 895.58453.

Compound 16 was prepared from 16-I (220 mg, 0.24 mmol) and sodium borohydride (205 mg,

5.42 mmol) in methanol (10 mL); the mixture was stirred at room temperature for 3.5 h. Yield

100 % (221 mg, 0.24 mmol); m.p. 150 °C; ¹H NMR (500 MHz, CDCl₃): δ = 1.10 (t, J = 7.5 Hz,

6H), 1.23 (t, J = 7.5 Hz, 12H), 1.43 (s, 18H), 2.68 (q, J = 7.5 Hz, 4H), 2.76 (q, J = 7.5 Hz, 8H),

3.72 (s, 8H), 3.90 (s, 8H), 4.32 (d, J = 4 Hz, 4H), 4.37 (t, J = 4 Hz, 2H), 7.17 – 7.19 (m, 4H),

13

7.25 – 7.28 (m, 2H), 7.54 (s, 2H) ppm; C NMR (125 MHz, CDCl₃): δ = 16.85, 16.88, 22.6,

26

10.1002/ejoc.202100758

European Journal of Organic Chemistry

22.9, 28.5, 38.9, 47.4, 55.0, 79.3, 126.9, 127.2, 128.1, 131.7, 134.6, 140.5, 142.5, 143.2, 155.6

ppm; HRMS (ESI): m/z calcd for C₅₆H₈₂N₆O₄+H⁺: 903.64703 [M+H]⁺, found: 903.64661.

Compound 17-I was prepared from 25 (270 mg, 0.77 mmol) and 1H-pyrrole-2,5-

dicarboxaldehyde (95 mg, 0.77 mmol) in ethanol (8 mL); the mixture was stirred at 50 °C for

1

1.5 h. Yield 70 % (237 mg, 0.27 mmol); m.p. 180 °C (decomp. 190 °C); H NMR (500 MHz,

CDCl₃): δ = 1.14 (t, J = 7.5 Hz, 12H), 1.19 (t, J = 7.5 Hz, 6H), 1.44 (s, 18H), 2.64 (q, J = 7.5 Hz,

8H), 3.03 (q, J = 7.5 Hz, 4H), 4.75 (br. s, 8H), 5.14 (s, 4H), 6.52 (s, 4H), 8.17 (s, 4H) ppm; ¹³C

NMR (125 MHz, CDCl₃): δ = 15.0, 16.1, 22.5, 22.6, 27.7, 57.6, 63.1, 81.9, 113.9, 129.2, 132.9,

133.0, 143.8, 145.2, 151.2, 153.7 ppm; HRMS (ESI): m/z calcd for C₅₂H₇₀N₆O₆+H⁺: 875.54296

[M+H]⁺, found: 875.54276.

Compound 17 was prepared from 17-I (208 mg, 0.24 mmol) and sodium borohydride (90 mg,

2.38 mmol) in methanol/dichloromethane [10 mL, 1:1 (v/v)]; the mixture was stirred at room

temperature for 16 h. Yield 97 % (204 mg, 0.23 mmol); m.p. 152 – 155 °C; ¹H NMR (500 MHz,

CDCl₃): δ = 1.14 (t, J = 7.5 Hz, 6H), 1.20 (t, J = 7.5 Hz, 12H), 1.47 (s, 18H), 2.72 (q, J = 7.5 Hz,

8H), 2.96 (q, J = 7.5 Hz, 4H), 3.70 (s, 8H), 3.89 (s, 8H), 5.16 (s, 4H), 5.93 (d, J = 2.6 Hz, 4H),

8.94 (s, 2H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ = 16.1, 16.8, 22.2, 22.9, 27.8, 47.1, 47.6,

63.2, 82.0, 105.2, 128.9, 129.8, 134.3, 143.0, 145.1, 153.7 ppm; HRMS (ESI): m/z calcd for

C₅₂H₇₈N₆O₆+H⁺: 883.60556 [M+H]⁺, found: 883.60690.

Compound 18-I was prepared from 26a (172 mg, 0.50 mmol) and 1H-pyrrole-2,5-

dicarboxaldehyde (61 mg, 0.50 mmol) in ethanol (6 mL); the mixture was stirred at 45 °C for 5

1

h. Yield 81 % (173 mg, 0.20 mmol); m.p. 260 °C (decomp.); H NMR (500 MHz, CDCl₃): δ =

1.17 (t, J = 7.5 Hz, 6H), 1.21 (t, J = 7.5 Hz, 12H), 1.38 (s, 18H), 2.57 (q, J = 7.5 Hz, 8H), 3.05 –

3.08 (m, 4H), 4.26 (d, J = 4.2 Hz, 4H), 4.36 (s, 2H), 4.72 (br. s, 8H), 6.51 (s, 4H), 8.22 (s, 4H)

13

ppm; C NMR (125 MHz, CDCl₃): δ = 15.0, 16.2, 22.43, 22.45, 28.3, 38.7, 57.9, 79.2, 114.1,

131.5, 132.8, 133.4, 142.7, 144.1, 151.1, 155.5 ppm; HRMS (ESI): m/z calcd for

C₅₂H₇₂N₈O₄+H⁺: 873.57493 [M+H]⁺, found: 873.57663.

Compound 18 was prepared from 18-I (168 mg, 0.19 mmol) and sodium borohydride (84 mg,

2.22 mmol) in methanol/dichloromethane [6 mL, 2:1 (v/v)]; the mixture was stirred at room

1

temperature for 4.5 h. Yield 98 % (166 mg, 0.19 mmol); m.p. 165 °C (decomp. 175 °C); H

NMR (500 MHz, CDCl₃): δ = 1.15 (t, J = 7.5 Hz, 6H), 1.21 (t, J = 7.4 Hz, 12H), 1.42 (s, 18H),

2.66 (q, J = 7.4 Hz, 8H), 2.90 (q, J = 7.5 Hz, 4H), 3.71 (s, 8H), 3.88 (s, 8H), 4.29 (d, J = 4.4 Hz,

4H), 4.35 (s, 2H), 5.94 (d, J = 2.6 Hz, 4H), 9.01 (br. s, 2H) ppm; ¹³C NMR (125 MHz, CDCl₃):

27

10.1002/ejoc.202100758

European Journal of Organic Chemistry

δ = 16.1, 16.9, 22.1, 22.8, 28.4, 38.8, 47.2, 47.6, 79.3, 105.3, 129.7, 131.6, 134.5, 142.0, 143.7,

155.4 ppm; HRMS (ESI): m/z calcd for C₅₂H₈₀N₈O₄+H⁺: 881.63753 [M+H]⁺, found: 881.63562.

Compound 19-I was prepared from 34 (109 mg, 0.33 mmol) and 1H-pyrrole-2,5-

dicarboxaldehyde (41 mg, 0.34 mmol) in ethanol (7 mL); the mixture was stirred at 55 °C for

2.5 h. Yield 56 % (76 mg, 0.09 mmol); m.p. 260 °C (decomp.); ¹H NMR (500 MHz, CDCl₃): δ

= 1.18 (t, J = 7.5 Hz, 12H), 1.26 (t, J = 7.5 Hz, 6H), 2.68 (q, J = 7.5 Hz, 8H), 3.11 (q, J = 7.5

Hz, 4H), 4.79 (s, 8H), 5.00 (s, 4H), 6.50 (s, 4H), 6.95 – 6.99 (m, 2H), 7.00 – 7.02 (m, 4H), 7.29

13

– 7.33 (m, 4H), 8.24 (s, 4H), 9.59 (s, 2H) ppm; C NMR (125 MHz, CDCl₃): δ = 15.1, 16.3,

22.6, 22.7, 58.0, 64.1, 113.7, 114.6, 120.8, 129.6, 130.5, 132.9, 133.6, 143.6, 145.1, 151.0, 159.1

ppm; HRMS (ESI): m/z calcd for C₅₄H₆₂N₆O₂+H⁺: 827.50070 [M+H]⁺, found: 827.50112.

Compound 19 was prepared from 19-I (75 mg, 0.09 mmol) and sodium borohydride (34 mg,

0.90 mmol) in methanol/dichloromethane [8 mL, 1:1 (v/v)]; the mixture was stirred at room

1

temperature for 3.5 h. Yield 100 % (78 mg, 0.09 mmol); m.p. 130 °C; H NMR (500 MHz,

CDCl₃): δ = 1.19 – 1.25 (m, 18H), 2.74 (q, J = 7.5 Hz, 8H), 3.03 (q, J = 7.5 Hz, 4H), 3.75 (s,

8H), 3.93 (s, 8H), 5.00 (s, 4H), 5.95 (d, J = 2.6 Hz, 4H), 6.98 – 7.00 (m, 2H), 7.01 – 7.03 (m,

4H), 7.32 – 7.35 (m, 4H), 8.89 (s, 2H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ = 16.2, 17.0, 22.3,

23.0, 47.4, 47.8, 64.2, 105.2, 114.6, 120.9, 129.6, 129.9, 130.4, 134.7, 143.0, 145.0, 159.1 ppm;

HRMS (ESI): m/z calcd for C₅₄H₇₀N₆O₂+H⁺: 835.56330 [M+H]⁺, found: 835.56346.

Compound 20-I was prepared from 35 (153 mg, 0.47 mmol) and 1H-pyrrole-2,5-

dicarboxaldehyde (58 mg, 0.47 mmol) in ethanol (7 mL); the mixture was stirred at 60 °C for 5

1

h. Yield 58 % (110 mg, 0.13 mmol); m.p. 265 °C (decomp.); H NMR (500 MHz, CDCl₃): δ =

1.21 (t, J = 7.5 Hz, 12H), 1.28 (t, J = 7.5 Hz, 6H), 2.63 (d, J = 5.9 Hz, 8H), 3.11 (q, J = 7.5 Hz,

4H), 3.56 (s, 2 H), 4.16 (d, J = 2.2 Hz, 4H), 4.77 (br. s, 8H), 6.50 (s, 4H), 6.62 (d, J = 7.8 Hz,

13

4H), 6.71 (t, J = 7.3 Hz, 2H), 7.19 (t, J = 7.9 Hz, 4H), 8.27 (s, 4H), 9.54 (br. s, 2H) ppm; C

NMR (125 MHz, CDCl₃): δ = 15.1, 16.5, 22.4, 22.6, 42.0, 58.2, 112.24, 114.1, 117.0, 129.3,

132.6, 132.9, 133.6, 143.0, 143.9, 148.3, 151.1 ppm; HRMS (ESI): m/z calcd for C₅₄H₆₄N₈+H⁺:

825.53267 [M+H]⁺, found: 825.53297.

Compound 20 was prepared from 20-I (99 mg, 0.12 mmol) and sodium borohydride (45 mg,

1.20 mmol) in methanol/dichloromethane [8 mL, 1:1 (v/v)]; the mixture was stirred at room

temperature for 16.5 h. Yield 93 % (93 mg, 0.11 mmol); m.p. 184 °C (decomp.); ¹H NMR (500

MHz, CDCl₃): δ = 1.21 – 1.26 (m, 18H), 2.71 (q, J = 7.4 Hz, 8H), 2.98 (q, J = 7.5 Hz, 4H), 3.46

(t, J = 4.3 Hz, 2H), 3.75 (s, 8H), 3.92 (s, 8H), 4.17 (d, J = 4.1 Hz, 4H), 5.95 (d, J = 2.6 Hz, 4H),

6.64 – 6.66 (m, 4H), 6.73 – 6.76 (m, 2H), 7.22 – 7.25 (m, 4H), 8.89 (s, 2H) ppm; ¹³C NMR (125

28

10.1002/ejoc.202100758

European Journal of Organic Chemistry

MHz, CDCl₃): δ = 16.3, 17.2, 22.2, 23.0, 42.1, 47.4, 47.9, 105.4, 112.4, 117.3, 129.4, 129.9,

132.6, 134.7, 142.3, 143.8, 148.3 ppm; HRMS (ESI): m/z calcd for C₅₄H₇₂N₈+H⁺: 833.59527

[M+H]⁺, found: 833.59576.

Compound 21-I was prepared from 34 (101 mg, 0.31 mmol) and isophthalaldehyde (42 mg,

0.31 mmol) in ethanol (6 mL); the mixture was stirred at 50 °C for 1.5 h. Yield 84 % (111 mg,

1

0.13 mmol); m.p. 230 °C (decomp.). H NMR (500 MHz, CDCl₃): δ = 1.19 – 1.23 (m, 18H),

2.45 (s, 4H), 2.68 (s, 8H), 5.03 (s, 8H), 5.08 (s, 4H), 6.97 – 7.00 (m, 2H), 7.01 – 7.04 (m, 4H),

7.31 – 7.34 (m, 4H), 7.48 (t, J = 7.7 Hz, 2H), 7.59 (br. s, 2H), 7.95 – 7.97 (m, 4H), 8.00 (s, 4H)

13

ppm; C NMR (125 MHz, CDCl₃): δ = 15.7, 16.1, 23.2, 23.4, 55.8, 64.5, 114.8, 121.0, 128.9,

129.0, 129.5, 129.8, 131.2, 132.0, 136.7, 144.6, 144.9, 158.8, 159.4 ppm; HRMS (ESI): m/z

calcd for C₅₈H₆₄N₄O₂+H⁺: 849.51020 [M+H]⁺, found: 849.51058.

Compound 21 was prepared from 21-I (98 mg, 0.12 mmol) and sodium borohydride (44 mg,

1.15 mmol) in methanol/dichloromethane [6 mL, 1:1 (v/v)]; the mixture was stirred at room

1

temperature for 4 h. Yield 100 % (0.99 mg, 0.12 mmol); m.p. 207 – 210 °C; H NMR (500

MHz, CDCl₃): δ = 1.14 (t, J = 7.5 Hz, 6H), 1.24 (t, J = 7.5 Hz, 12H), 2.74 (q, J = 7.5 Hz, 4H),

2.82 (q, J = 7.5 Hz, 8H), 3.77 (s, 8H), 3.91 (s, 8H), 5.01 (s, 4H), 6.97 – 7.00 (m, 2H), 7.01 –

7.03 (m, 4H), 7.17 – 7.19 (m, 4H), 7.24 – 7.27 (m, 2H), 7.31 – 7.34 (m, 4H), 7.57 (s, 2H) ppm;

¹³C NMR (125 MHz, CDCl₃): δ = 16.7, 16.8, 22.6, 22.8, 47.4, 55.0, 64.3, 114.6, 120.7, 127.00,

127.05, 128.0, 129.5, 130.3, 134.5, 140.6, 143.3, 144.2, 159.1 ppm; HRMS (ESI): m/z calcd for

C₅₈H₇₂N₄O₂+H⁺: 857.57280 [M+H]⁺, found: 857.57275.

Compound 22-I was prepared from 36 (181 mg, 0.51 mmol) and isophthalaldehyde (68 mg,

0.51 mmol) in ethanol (7 mL); the mixture was stirred at 45 °C for 3 h. Yield 73 % (169 mg,

0.19 mmol); m.p. 200 – 202 °C; ¹H NMR (500 MHz, CDCl₃): δ = 1.18 (t, J = 7.6 Hz, 6H), 1.22

(t, J = 7.5 Hz, 12H), 2.37 (s, 4H), 2.71 (s, 8H), 3.77 (s, 6H), 5.05 (s, 8H), 5.08 (s, 4 H), 6.88 –

6.97 (m, 6H), 7.05 – 7.06 (m, 2H), 7.43 (s, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.90 (s, 4H), 8.02 (d, J

13

= 7.5 Hz, 4H) ppm; C NMR (125 MHz, CDCl₃): δ = 15.8, 16.1, 23.2, 23.4, 55.4, 55.7, 66.5,

112.1, 115.8, 120.8, 122.2, 128.4, 129.0, 131.3, 131.6, 136.7, 144.8, 145.0, 148.4, 150.6, 158.9

ppm; HRMS (ESI): m/z calcd for C₆₀H₆₈N₄O₄+H⁺: 909.53133 [M+H]⁺, found: 909.53230.

Compound 22 was prepared from 22-I (65 mg, 0.07 mmol) and sodium borohydride (27 mg,

0.71 mmol) in methanol/dichloromethane [6 mL, 1:1 (v/v)]; the mixture was stirred at room

1

temperature for 14 h. Yield 94 % (61 mg, 0.07 mmol); m.p. 125 °C; H NMR (500 MHz,

CDCl₃): δ = 1.12 (t, J = 7.5 Hz, 6H), 1.25 (t, J = 7.5 Hz, 12H), 2.74 (q, J = 7.4 Hz, 4H), 2.86 (q,

J = 7.5 Hz, 8H), 3.76 (s, 8H), 3.79 (s, 6H), 3.91 (s, 8H), 5.03 (s, 4H), 6.90 – 6.93 (m, 2H), 6.93 –

29

Article Doi

Compounds Combining a Macrocyclic Building Block and Flexible Side-Arms as Carbohydrate Receptors: Syntheses and Structure-Binding Activity Relationship Studies

DOI: 10.1002/ejoc.202100758

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.202100758

Full text of DOI:10.1002/ejoc.202100758

Products guided by the article

R&D Labs maybe for 828931-45-9

Relevant to this article

Hot Product