university of groningen exploitation of macrocyclic

University of Groningen

Exploitation of macrocyclic chemical space by multicomponent reaction (MCR) and theirapplications in medicinal chemistryAbdelraheem, Eman Mahmoud Mohamed

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Chapter 3

Ugi Multicomponent Reaction Based

Synthesis of Medium-Sized Rings

Eman M. M. Abdelraheem, Rudrakshula Madhavachary, Arianna Rossetti, Katarzyna

Kurpiewska, Justyna Kalinowska-Tłuścik, Shabnam Shaabani and Alexander Dömling

Published in: Org. Lett., 2017, 19, 6176−6179

Chapter 3

96

Abstract

An Ugi multicomponent reaction based two-step strategy was applied to generate medi-

um-sized rings. In the first linear expansion phase, a series of diamines reacted with cyclic

anhydrides to produce different lengths of terminal synthetic amino acids as the starting

material for the second phase. The Ugi-4-center 3-component reaction was utilized to con-

struct complex medium-sized rings (8-11) by the addition of isocyanides and oxo compo-

nents. This method features mild conditions and a broad substrate scope.

Introduction

Medium-sized rings are molecules which contain between 8 and 11 ring atoms.1,2 Sur-

prisingly, they are highly underrepresented in screening libraries and in general in the syn-

thetic organic chemistry world. Examples of bioactive medium-sized cycles, however, exist

and include taxol (8-membered), griseoviridin (9-membered),3 crotalanian alkaloids (10-

membered) and diplodialide natural products (11-membered).4 As opposed to small rings or

macrocycles, medium-sized rings are a challenging class of synthetic targets.5 While small

rings can often be closed based on favorable enthalpy, macrocyclic ring closure needs a

favorable entropic component.

Medium cycles, however, often show an unfavorable entropy and enthalpy component,

including Pitzer ring strains and transannular interactions, for their ring closure and thus are

highly demanding synthetic targets.6 Different synthetic methodologies have been applied

for the ring closure of medium-sized cycles, including ring-closing metathesis (RCM),

macro-lactonization, metal mediated C-C coupling reactions, and ring expansion.7 Howev-

er, these methods mostly suffer from low yields and limited substrate scope. Therefore, the

discovery of general methodologies for the fast and efficient construction of various medi-

um rings in good yields and with useful levels of diversity is of considerable importance.

Our design toward the synthesis of complex medium ring structures is based on two

simple but diverse reactions steps. Moreover, it is based on commercially available starting

materials. The first step involves a ring opening reaction of cyclic carboxylic acid anhy-

drides with unprotected diamines to afford -amino acids. In the next step, -amino

acids are used in an Ugi reaction with oxo components and isocyanides to close-medium

rings of 8-11 membered size (Figure 1). This method closely follows our recently described

strategy to create a manifold of artificial macrocycles by a short sequence involving an

initial linear diversification, followed by an exponential diversification step of macrocy-

clization using an Ugi and Passerini multicomponent reaction (MCR).8,9

Figure 1. Described Macrocyclization Strategy.

Ugi Multicomponent Reaction Based Synthesis of Medium-Sized Rings

97

We initially started our study by the synthesis of -amino -carboxylic acid by reacting

symmetrical and unsymmetrical cyclic anhydride with diamines followed by an Ugi reac-

tion. We reacted a total of nine cyclic anhydrides with five diamines providing 11 amino

acids of different linker length (Scheme 1).

* all starting materials are commercially available.

Scheme 1. Starting materials for the synthesis of -amino -carboxylic acids.

For the synthesis of medium-sized ring compounds, we focused on the small diamines,

such as ethylene diamine, propane diamine, butane diamine and pentane diamine deriva-

tives (Scheme 1). The ring opening reaction of cyclic anhydrides was carried out by slowly

dropping anhydride to the unprotected alkyl diamine solution in THF as an aprotic polar

solvent. This reaction proceeded under diluted conditions (0.1 M), on a 10 mmol scale, at

room temperature, and the product -amino -carboxylic acid was isolated in good yields

(59-80%).

Next, the macrocyclic ring closure was performed by Ugi MCR under optimized condi-

tions using 1 equiv. of oxo component and isocyanide (Scheme 1). We extensively

screened different conditions by varying temperature, solvent and time. By using methanol

as a solvent at 0.01 M concentrations of reactants and after 48 h at room temperature, a

range of medium-sized rings were obtained in optimal yields. To investigate substrate

scope and limitations, we synthesized 23 examples, as shown in Scheme 2. Several com-

mercially available aliphatic, aromatic, and heteroaromatic aldehyde and ketone building

blocks reacted as oxo-components in the Ugi reaction to afford the medium-sized cycles in

acceptable good to excellent yields (21–65%) after purification by column chromatography.

Variously functionalized isocyanides, such as aliphatic, aromatic, and benzylic, including

indole-derived isocyanides, reacted well to give the desired products.

Chapter 3

98

Scheme 2. Ugi-4CR synthesis of medium-sized rings and the product structures with

isolated yields.a,b

In the light of our efforts to find an effective method of synthesizing medium-sized

rings in a one-pot reaction, including amino acid synthesis and also in situ isocyanide syn-

thesis, we used some unpurified synthetic amino acids in the ring closure step by simply

removing the THF solvent from the anhydride ring opening reaction and reacting the crude


99

amino acid with the oxo and isocyanide components in methanol. With this one-pot

procedure, we were able to produce medium-sized rings (for examples, 6a, 6b, 6h, 6k, and

6u) in 27 to 65% yields. In a similar way, we also simplified and extensively studied the in

situ isocyanide formation and ring closure reactions in one pot. Thus, we used our recently

described in situ isocyanide synthesis protocol from formamides to produce the complex

IMCR products in one pot, without tedious synthesis and isolation of the foul-smelling and

toxic isocyanides.10 Triphosgene (0.4 equiv.) with Et3N (2.4 equiv.) in dichloromethane

(DCM) (0.5 M) proved to be the best dehydrating system for the isocyanide formation. N-

Benzylformamide was treated with 2.4 equiv of Et3N and 0.4 equiv of triphosgene in DCM

(0.5 M) as solvent at 0 C. After 15 min, the crude mixture was passed through a small bed

of silica gel into a round-bottom flask, which already contained amino acid 3i and 2-

azidobenzaldehyde, as shown in Scheme 3. The reaction mixture was stirred for another 48

h, and the 11-membered medium-sized ring product (6p) was obtained in 31% yield after

column purification. These in situ methods will increase the value of MCR chemistry, even

though the in situ isocyanide process gives a lower yield compared to the procedure involv-

ing isolation and purification of the isocyanide and amino acid (6p, 40% yield, Scheme 3).

Scheme 3. One-pot in situ isocyanide synthesis followed by Ugi-MCR.

A determinant of passive membrane permeation is the potential of macro- and medium-

sized cycles to form intramolecular hydrogen bonds which improve their chameleonic be-

havior by switching between conformations in aqueous solution and while passing through

lipid cell membranes by exposing polar atoms and hydrophobic residues, respectively.11

Chapter 3

100

Thus, we were interested in oxidizing the sulfur medium-sized cycle 6q to the sulfoxide

and the sulfone, respectively. The chemistry to the sulfoxide and sulfones was accom-

plished by m-chloroperbenzoic acid (mCPBA) in DCM (Scheme 4). The compound 6q was

reacted with 1.0 and 4.0 equiv of mCPBA in DCM for 4 h to afford sulfoxide 7qa and sul-

fone 7qb in excellent yields (70 and 90%, respectively). Our future plan is to investigate

how this sulfoxide and sulfone can participate in the formation of amide–sulfoxide and

amide–sulfone intramolecular hydrogen bonds and thus determine the 3D conformations.

Scheme 4. Selective oxidative modifications on refractory sulfur contained medium cycles.

Diastereomer formation was also investigated by reacting 3j, chlorobenzaldehyde, and

benzyl isocyanide. Not surprisingly, a moderate dr of 7:3 was observed by 1H NMR of the

crude reaction mixture (Scheme 5).

Scheme 5. Example of reaction diastereoselectivity.

In order to confirm the product structure and to gain insight into the ring conformation

and intra-vs intermolecular hydrogen bonding, we crystallized compound 6i and determined

its solid-state structure by X-ray crystallography (Figure 2). Interestingly, in the 6i struc-

ture, the exocyclic isocyanide derived amide group is bending back over the macrocycle to

form an intramolecular hydrogen bonding with the medium-sized cycle amide group.

Moreover, the medium cycle secondary amide undergoes a hydrogen bonding with the

same amide group of a neighboring medium cycle. This kind of intramolecular hydrogen

bonding in related medium or macrocyclic systems has been determined to facilitate pas-


101

sive membrane diffusion, an important determinant of cellular activity and oral bioavaila-

bility.12,13

Figure 2. Representative MCR-derived 10-membered ring- 6i in the solid state featuring

intramolecular and intermolecular hydrogen bonding contacts.

Physicochemical properties are of uttermost importance for the usefulness of com-

pounds as chemical probes or development candidates. What is the profile of our medium-

sized cycles? To answer this question, we constructed a random virtual 1000 medium ring

library. Then, we calculated the properties of the library, including molecular weight, lipo-

philicity, number of hydrogen bond donors and acceptors, number of rotatable bonds, polar

surface area and moment of inertia. Interestingly, an analysis of the library shows 30%

obey the Lipinski rule of five (RO5). Even more stringent central nervous system multipa-

rameter optimization (CNS MPO) desirability can be reached for a percentage of the com-

pound.14 The cLogP versus MW distribution is favorably drug-like with an average MW

and cLogP of 538 and 3.3, respectively (Figure 3). Moreover, punctual analysis of 3D

modeled representatives and X-ray structures underline the nonflat shapes of the medium-

sized rings.

Chapter 3

102

Figure 3. Some calculated physicochemical properties of the chemical space of medium-

sized rings. A: cLogP over MW scatter plot, B: oral CNS scoring radar plot. C:

compound distribution based on oral CNS scoring.14

Virtual library synthesis:

The virtual library of medium-sized cycles was created using ChemAxon’s REACTOR

software (http://www.chemaxon. com). 167 amino acids, 272 oxo compounds, and 645

isocyanides were used as reactants. Therefore, the theoretical chemical space of this virtual

library is 167 × 272 × 645 = 29298480 (stereoisomers are not included). To investigate

such large chemical space, the program Rand Reactor was used to provide smaller random

sublibrary (N=1000) as smiles file.21 The smiles file was then uploaded into Instant JChem

for calculating molecular weight and LogP. This data was exported as an excel file in order

to draw MW vs cLogP plot.21 For, oral CNS radar plot, the smiles file was then uploaded

into StarDrop for calculating molecular weight, logP, TPSA, log D, number of H bond

donor and acceptor. This data was scored based on oral CNS Scoring Profile already im-

plemented in the Scoring Profiles of StarDrop. The data were visualized in radar plot in

which the colors are formatted according to the scoring function. Yellow and red color

stand for high and low scores, respectively.


103

In conclusion, we introduced a very mild, straightforward two-step, rapid, and highly

diverse medium-sized cycle (8-11 membered) synthesis pathway via MCRs. The strategy

using an Ugi reaction in the cyclization is particularly appealing for several reasons. First, it

offers outstanding diversity. Second, it potentially provides various medicinally and phar-

maceutically important products containing an amide bond that can serve as conformation-

ally constrained peptidomimetics. Finally, this strategy will allow a unique route for the

synthesis of medium-sized cyclic nonpeptidic molecules. We are currently synthesizing and

screening extensive medium-ring libraries and will report on their biological activity in due

course.

General Experimental Procedures:

General procedure and analytical data for synthesis of -amino carboxylic acids:

Diamine 1 (10.0 mmol) was dissolved in THF (60 mL), then a solution of anhydride 2

(10.0 mmol) in THF (40 mL) was added dropwise during 60 mins. The reaction mixture

was further stirred for 1h. Solvents were removed under vacuum. The crude mixture was

purified by flash column chromatography using CH2Cl2:MeOH (1:9) to afford the product

3.

5-((2-Aminoethyl)amino)-3,3-dimethyl-5-oxopentanoic acid 3a:

The product was obtained as a colorless oil (71%, 1.43 g); 1H NMR

(500 MHz, D2O) δ 3.50 (t, J = 6.1 Hz, 2H), 3.15 (t, J = 6.1 Hz, 2H),

2.29 (s, 2H), 2.17 (s, 2H), 1.05 (s, 6H); 13C NMR (126 MHz, D2O) δ

181.0, 176.0, 49.7, 47.5, 39.1, 36.6, 32.7, 27.5, 27.5.

4-((3-Amino-2,2-dimethylpropyl)amino)-4-oxobutanoic acid 3b:

The product was obtained as a white solid (77%, 1.55 g); 1H NMR

(500 MHz, D2O) δ 3.02 (s, 2H), 2.67 (s, 2H), 2.44-2.33 (m, 4H), 0.90

(s, 6H); 13C NMR (126 MHz, D2O) δ 180.9, 177.0, 46.0, 45.7, 34.3,

32.8, 31.9, 22.4.

2-((2-((2-Aminoethyl)amino)-2-oxoethyl)thio)acetic acid 3c:


(500 MHz, D2O) δ 3.52 (t, J = 5.8 Hz, 2H), 3.40-3.28 (m, 5H), 3.25

(s, 2H), 3.16 (t, J = 5.8 Hz, 2H); 13C NMR (126 MHz, D2O) δ 176.7,

173.1, 39.1, 37.1, 36.7, 35.8.

5-((3-Aaminopropyl)amino)-3,3-dimethyl-5-oxopentanoic acid 3d:


(500 MHz, D2O) δ 3.17 (t, J = 7.1 Hz, 2H), 2.90 (t, J = 7.9 Hz,

2H), 2.14 (s, 2H), 2.05 (s, 2H), 1.82-1.70 (m, 2H), 0.93 (s, 6H); 13C

NMR (126 MHz, D2O) δ 181.1, 175.2, 49.9, 47.7, 37.1, 35.9, 32.7, 27.4, 27.3, 26.7.

4-((4-Aminobutyl)amino)-4-oxobutanoic acid 3e:

The product was obtained as a white solid (82%, 1.54 g). 1H NMR

(500 MHz, D2O) δ 3.12 (t, J = 6.6 Hz, 2H), 2.90 (d, J = 7.3 Hz,

2H), 2.41-2.31 (m, 4H), 1.62-1.52 (m, 2H), 1.52-1.42 (m, 2H); 13C

Chapter 3

104

NMR (126 MHz, D2O) δ 180.5, 175.8, 39.1, 38.4, 32.7, 32.2, 25.4, 24.0.

2-(2-((3-Aminopropyl)amino)-2-oxoethoxy)acetic acid 3f:


(500 MHz, MeOD-d4) δ 4.09 (s, 2H), 4.05 (s, 2H), 3.36 (t, J = 6.6

Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 1.93-1.82 (m, 2H); 13C NMR

(126 MHz, MeOD-d4) δ 172.5, 170.2, 68.4, 67.6, 35.3, 33.6, 25.7.

2-((4-Aminobutyl)carbamoyl)benzoic acid 3g:


(500 MHz, D2O) δ 7.54-7.49 (m, 1H), 7.44-7.35 (m, 2H), 7.33-7.28

(m, 1H), 3.25 (t, J = 6.5 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 1.69-1.59

(m, 2H), 1.59-1.50 (m, 2H); 13C NMR (126 MHz, D2O) δ 175.0,

172.8, 136.3, 134.7, 130.2, 129.7, 128.1, 127.1, 39.1, 38.9, 25.3, 24.1.

2-(1-(2-((4-Aminobutyl)amino)-2-oxoethyl)cyclohexyl)acetic acid 3h:


(500 MHz, D2O) δ 3.12 (t, J = 6.7 Hz, 2H), 2.90 (d, J = 7.1 Hz,

2H), 2.24 (s, 2H), 2.16 (s, 2H), 1.63-1.55 (m, 2H), 1.53-1.45 (m,

2H), 1.41-1.34 (m, 4H), 1.34-1.24 (m, 6H); 13C NMR (126 MHz,

D2O) δ 181.3, 175.0, 45.9, 44.2, 39.0, 38.3, 35.9, 35.8, 25.5, 24.3, 21.2.

2-(2-((4-Aminobutyl)amino)-2-oxoethoxy)acetic acid 3i:

The product was obtained as a white solid (69%, 1.40 g); 1H

NMR (500 MHz, D2O) δ 3.97 (s, 2H), 3.91 (s, 2H), 3.19 (t, J =

6.6 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 1.63-1.55 (m, 2H), 1.55-

1.48 (m, 2H); 13C NMR (126 MHz, D2O) δ 177.1, 172.4, 70.2, 69.6, 39.0, 38.1, 25.3, 24.1.

4-((2-((2-Aminoethyl)thio)ethyl)amino)-4-oxobutanoic acid 3j:


NMR (500 MHz, D2O) δ 3.28 (t, J = 6.6 Hz, 2H), 3.08 (t, J = 6.7

Hz, 2H), 2.74 (t, J = 6.7 Hz, 2H), 2.59 (t, J = 6.6 Hz, 2H), 2.34 (s,

4H); 13C NMR (126 MHz, D2O) δ 180.8, 176.0, 38.5, 38.3, 32.8, 32.2, 30.2, 28.1.

5-((4-Aminobutyl)amino)-3-methyl-5-oxopentanoic acid 3k:


NMR (500 MHz, D2O) δ 3.12 (t, J = 6.7 Hz, 2H), 2.91 (d, J = 7.1

Hz, 2H), 2.22-2.08 (m, 3H), 2.03-1.91 (m, 2H), 1.63-1.54 (m,

2H), 1.54-1.44 (m, 2H), 0.84 (d, J = 5.9 Hz, 3H); 13C NMR (126 MHz, D2O) δ 181.4,

175.6, 44.4, 43.0, 39.0, 38.5, 29.0, 25.4, 24.2, 18.8.

5-((4-Aminobutyl)amino)-3,3-dimethyl-5-oxopentanoic acid 3l:


NMR (500 MHz, D2O) δ 3.12 (t, J = 6.7 Hz, 2H), 2.89 (d, J = 7.5

Hz, 2H), 2.14 (s, 2H), 2.07 (s, 2H), 1.65-1.53 (m, 2H), 1.55-1.42


105

(m, 2H), 0.95 (s, 6H); 13C NMR (126 MHz, D2O) δ 180.8, 174.8, 49.6, 47.7, 39.0, 38.4,

32.7, 27.4, 25.5, 24.3.

2-((2-((4-Aminobutyl)amino)-2-oxoethyl)thio)acetic acid 3m:

The product was obtained as a yellow oil (60%, 1.32 g); 1H NMR

(500 MHz, D2O) δ 3.20 (s, 2H), 3.19-3.16 (m, 2H), 3.15 (s, 2H),

2.94-2.89 (m, 2H), 1.63-1.49 (m, 4H); 13C NMR (126 MHz,

D2O) δ 177.0, 172.2, 39.1, 38.9, 37.1, 35.7, 25.4, 24.3.

General procedure and analytical data for the macrocyclization reactions:

Aldehyde (1.0 mmol) and the -amino carboxylic acid (1.0 mmol) were dissolved in

methanol (10.0 ml). The solution stirred at room temperature for 30 min. Then isocyanide

(1.0 mmol) was added to the reaction mixture and the reaction mixture was diluted with

methanol to 0.01M and stirred further at room temperature for 48 h. After completion of the

reaction, the solvent was removed under reduced pressure and the residue was purified

using flash chromatography (DCM: MeOH 9:1).

General procedure for one-pot macrocyclization (compounds 6a, 6b, 6h, 6k, and 6m):

To the stirred solution of diamine 1 (1.0 mmol, 1.0 equiv.) in THF (6 mL) was added

solution of anhydride 2 (1.0 mmol in 4mL THF) dropwise at 25 oC for 30 mins with drop-

ping funnel. As soon as finished the addition of anhydride the reaction mixture was stirred

for another 30 mins. Then after THF was removed under vacuum and refilled with metha-

nol (0.01 M) followed by addition of aldehyde/ketone and isocyanide at 25 oC stirred for 48

h. The reaction mixture was evaporated on rotavapor. The crude mixture obtained was

purified by flash column chromatography using CH2Cl2: MeOH 9:1 to afford the medium

cycles 6.

Ugi reaction procedure through in situ generated isocyanides (compound 6p):

To a stirred solution of benzylformamide (1.2 mmol) in dichloromethane (1 mL), tri-

ethylamine (2.5 equiv.) was added at 0 °C. After 10 min, triphosgene (0.4 equiv.) in di-

chloromethane (1 mL) was added dropwise over a 10 min period. The reaction mixture was

stirred at 0 °C for an additional 10 min until the formamide was completely consumed

(TLC checked). In another round bottom flask, the aldehyde (1.0 mmol) and amino acid

(1.0 mmol) were stirred for 30 min. the crude mixture of the isocyanide was passed through

the small bed of silica gel into the round bottom flask which already contained amino acid

and the aldehyde. The solution was stirred for 24-48 h. The solvent was evaporated and

reaction mixture purified by flash chromatography on silica gel eluted with (DCM: MeOH

9:1).

N-(tert-Butyl)-2-(5,8-dioxo-1,4-diazocan-1-yl)-2-(4-formylphenyl)acetamide 6a:


(500 MHz, CDCl3) δ 11.11 (s, 1H), 8.98 (d, J = 7.8 Hz, 2H), 8.63 (d, J

= 7.8 Hz, 2H), 8.35 (s, 1H), 7.36 (s, 1H), 7.25 (s, 1H), 4.99-4.77 (m,

1H), 4.71-4.55 (m, 1H), 4.50- 4.32 (m, 1H), 4.12-3.86 (m, 3H), 3.84-

3.65 (m, 2H), 2.45 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 191.6,

Chapter 3

106

174.9, 173.2, 168.0, 142.3, 136.2, 130.2, 129.6, 60.6, 52.0, 45.4, 41.8, 31.9, 31.1, 28.5;

HRMS calculated for C19H26N3O4: 360.1918; found [M+H]+: 360.192.

N-(2-(1H-Indol-3-yl)ethyl)-2-(5,8-dioxo-1,4-diazocan-1-yl)-4-methylpentanamide 6b:

The product was obtained as a white solid (61%, 0.242 g). 1H NMR (500

MHz, DMSO-d6) δ 10.82 (s, 1H), 7.99 (t, J = 5.7 Hz, 1H), 7.55 (d, J =

7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 6.3 Hz, 1H), 7.13 (s,

1H), 7.07 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 4.97 (t, J = 7.4 Hz,

1H), 3.58- 3.44 (m, 2H), 3.38-3.30 (m, 4H), 3.22-3.10 (m, 1H), 2.82 (t, J

= 7.5 Hz, 2H), 2.75-2.66 (m, 1H), 2.63-2.56 (m, 1H), 2.46- 2.36 (m, 1H),

1.69-1.57 (m, 1H), 1.47-1.30 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.85 (d, J

= 6.4 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 174.3, 173.0, 170.6, 136.7, 127.7, 123.1,

123.1, 121.3, 118.7, 118.6, 112.2, 111.8, 54.8, 44.5, 41.7, 38.2, 32.2, 31.8, 25.4, 24.8, 23.2,

22.9; HRMS calculated for C22H31N4O3: 399.2391; found [M+H]+: 399.2387.

N-Benzyl-2-(3,3-dimethyl-6,9-dioxo-1,5-diazonan-1-yl)acetamide 6c:


(500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 6.83-6.62 (m, 1H), 4.54 (dd, J

= 14.8, 6.0 Hz, 1H), 4.42-4.37 (m, 1H), 4.17-4.01 (m, 1H), 3.89- 3.73

(m, 1H), 3.31 (d, J = 15.5 Hz, 1H), 3.07-2.94 (m, 1H), 2.93-2.77 (m,

1H), 2.64 (dd, J = 14.0, 2.1 Hz, 1H), 2.16-2.05 (m, 2H), 1.86-1.78 (m,

1H), 1.77-1.69 (m, 1H), 1.33 (s, 3H), 1.27 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 176.1,

174.0, 170.3, 137.8, 128.7, 127.8, 127.6, 77.3, 77.0, 76.8, 53.4, 50.0, 47.9, 43.7, 40.0, 38.0,

37.4, 32.6, 30.1; HRMS calculated for C18H26N3O3: 332.1969; found [M+H]+: 332.1966.

N-Benzyl-2-(3,3-dimethyl-6,9-dioxo-1,5-diazonan-1-yl)-2-ethylbutanamide 6d:


(500 MHz, CDCl3) δ 7.43-7.39 (m, 2H), 7.37-7.31 (m, 2H), 7.30-7.27

(m, 1H), 7.25- 7.20 (m, 1H), 5.97 (t, J = 5.7 Hz, 1H), 4.62 (dd, J =

14.8, 5.8 Hz, 1H), 4.38 (dd, J = 14.7, 5.4 Hz, 1H), 4.00-3.91 (m, 1H),

3.90-3.81 (m, 1H), 3.31 (dd, J = 15.8, 4.8 Hz, 1H), 2.97-2.86 (m, 1H), 2.61 (d, J = 14.3 Hz,

1H), 2.52-2.43 (m, 1H), 2.15-2.05 (m, 2H), 1.93-1.78 (m, 3H), 1.64-1.60 (m, 1H), 1.39 (s,

3H), 1.24 (s, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz,

CDCl3) δ 176.2, 175.9, 174.2, 138.2, 128.7, 128.1, 127.5, 69.3, 47.9, 44.1, 44.0, 41.2, 39.9,

38.1, 32.2, 30.3, 25.1, 21.0, 9.0, 7.9; HRMS calculated for C22H34N3O3: 388.2595; found

[M+H]+: 388.2595.

N-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(3,3-dimethyl-6,9-dioxo-1,5-diazonan-1-yl)-4-

methyl-pentanamide 6e:


(500 MHz, CDCl3) δ 8.64 (t, J = 5.6 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H),

6.99-6.80 (m, 1H), 6.60 (s, 1H), 4.88-4.69 (m, 1H), 4.48-4.25 (m,

1H), 3.72-3.54 (m, 1H), 3.16-2.99 (m, 1H), 2.78-2.58 (m, 4H), 2.57-

2.45 (m, 1H), 2.32 (s, 3H), 2.26-2.05 (m, 2H), 1.81-1.61 (m, 1H),

1.59-1.37 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.77 (s, 3H), 0.67-0.52 (m, 1H);


107

13C NMR (126 MHz, CDCl3) δ 176.0, 175.2, 172.3, 159.63 (d, J =248.5 Hz), 135.1, 132.4,

130.45 (d, J =9.0 Hz), 123.76 (d, J =17.5 Hz), 113.71 (d, J =22.6 Hz), 70.6, 60.3, 48.8,

39.4, 38.3, 35.4, 32.0, 29.9, 25.3, 24.2, 23.5, 23.0, 22.2, 20.2; HRMS calculated for

C23H34ClFN3O3: 454.2267; found [M+H]+: 454.2266.

2-(3,8-Dioxo-1,4,7-thiadiazonan-4-yl)-3,3-dimethoxy-N-phenethylpropanamide 6f:


(500 MHz, CDCl3) δ 7.82 (s, 1H), 7.35-7.29 (m, 2H), 7.26-7.19 (m,

3H), 7.14 (s, 1H), 5.09 (d, J = 7.8 Hz, 1H), 4.03-3.90 (m, 1H), 3.84-

3.74 (m, 1H), 3.64-3.57 (m, 2H), 3.51 (d, J = 11.8 Hz, 1H), 3.45-

3.38 (m, 3H), 3.37 (s, 3H), 3.34 (d, J = 7.1 Hz, 1H), 3.14 (s, 3H),

3.12-3.07 (m, 1H), 2.88-2.80 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 172.1, 172.1, 167.4,

138.7, 128.9, 128.6, 126.6, 101.8, 65.5, 57.1, 53.1, 50.7, 40.4, 36.4, 35.4, 35.2, 30.0;

HRMS calculated for C19H28N3O5S: 410.3214; found [M+H]+: 410.3214.

N-Benzyl-1-(7,7-dimethyl-5,9-dioxo-1,4-diazonan-1-yl)cyclopentanecarboxamide 6g:


(500 MHz, CDCl3) δ 7.38-7.32 (m, 3H), 7.30-7.22 (m, 2H), 6.43 (t, J =

5.9 Hz, 1H), 4.58 (dd, J = 15.0, 6.2 Hz, 1H), 4.35 (dd, J = 15.0, 5.4 Hz,

1H), 3.94-3.76 (m, 2H), 3.21 (dd, J = 15.7, 4.3 Hz, 1H), 2.88 (ddt, J =

13.4, 12.0, 4.1 Hz, 1H), 2.59 (d, J = 14.4 Hz, 1H), 2.47-2.38 (m, 1H),

2.12-2.07 (m, 1H), 2.04 (s, 2H), 1.96-1.85 (m, 2H), 1.85-1.79 (m, 1H), 1.75 (d, J = 14.4 Hz,

1H), 1.72-1.65 (m, 3H), 1.35 (s, 3H), 1.21 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 176.2,

176.0, 174.4, 138.3, 128.7, 127.7, 127.5, 73.4, 47.8, 44.3, 44.0, 41.2, 38.9, 38.1, 36.8, 35.5,

32.4, 30.3, 24.1, 23.7; HRMS calculated for C22H32N3O3: 386.4023; found [M+H]+:

386.4024.

N-(2-Cyanoethyl)-2-(4,4-dimethyl-1,7-dioxo-4,5,6,7-tetrahydro-1H-benzo[g][1,5]

diazonin-2(3H)-yl)acetamide 6h:

The product was obtained as brown solid (38%, 0.129 g). 1H NMR

(500 MHz, CDCl3) δ 8.00 (s, 1H), 7.68 (t, J = 5.6 Hz, 1H), 7.60-7.51

(m, 3H), 7.45-7.37 (m, 1H), 4.30 (d, J = 16.5 Hz, 1H), 4.13 (d, J =

16.5 Hz, 1H), 3.51-3.39 (m, 2H), 3.34-3.24 (m, 1H), 3.01 (dd, J =

14.8, 10.0 Hz, 1H), 2.94- 2.83 (m, 2H), 2.51-2.36 (m, 2H), 1.16 (s,

3H), 0.66 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 173.1, 171.9, 168.6, 134.6, 133.2, 130.0,

126.6, 125.4, 118.8, 61.2, 54.5, 35.7, 35.4, 26.0, 22.0, 17.5; HRMS calculated for

C18H23N4O3: 343.1765; found [M+H]+: 343.1764.

N-Benzyl-2-(8,8-dimethyl-6,10-dioxo-1,5-diazecan-1-yl)-4-methylpentanamide 6i:


(500 MHz, MeOD-d4) δ 7.44-7.25 (m, 5H), 4.64 (d, J = 15.3 Hz,

1H), 4.57-4.43 (m, 1H), 4.37 (d, J = 15.3 Hz, 1H), 4.09-3.86 (m,

2H), 3.38-3.29 (m, 2H), 3.19-3.06 (m, 1H), 2.80-2.66 (m, 1H), 2.42-

2.25 (m, 1H), 2.20-2.13 (m, 1H), 1.98-1.82 (m, 2H), 1.71-1.57 (m, 2H), 1.39 (s, 3H), 1.22

(s, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.99 (d, J =7.8 Hz, 3H); 13C NMR (126 MHz, MeOD-d4)

Chapter 3

108

δ 172.2, 171.4, 170.9, 137.2, 126.4, 125.4, 124.9, 58.2, 48.7, 44.8, 41.6, 38.0, 37.7, 35.5,

33.4, 28.7, 27.8, 23.3, 22.0, 21.3, 19.7; HRMS calculated for C23H36N3O3: 402.2751; found

[M+H]+: 402.275.

N-(Tert-butyl)-2-(6-chloro-1H-indol-3-yl)-2-(2,5-dioxo-1,6-diazecan-1-yl)acetamide 6j:


(500 MHz, CDCl3) δ 9.01 (s, 1H), 7.89-7.77 (m, 1H), 7.64-7.38 (m,

3H), 7.23-7.07 (m, 1H), 5.89 (s, 1H), 4.93 (s, 1H), 4.01-3.82 (m, 1H),

3.56-3.39 (m, 1H), 3.39-3.22 (m, 1H), 3.06-2.93 (m, 1H), 2.90-2.75 (m,

1H), 2.66-2.28 (m, 3H), 1.98-1.83 (m, 4H), 1.29 (s, 9H); 13C NMR (126

MHz, CDCl3) δ 172.9, 172.6, 168.9, 136.0, 128.7, 126.1, 125.8, 121.2,

118.8, 111.8, 110.3, 56.4, 51.5, 48.4, 40.2, 36.1, 31.5, 28.5, 26.3, 25.2; HRMS calculated

for C22H30N4O3Cl: 433.2001; found [M+H]+: 433.2002.

N-Benzyl-1-(3,3-dimethyl-6,10-dioxo-1,5-diazecan-1-yl)cyclopentanecarboxamide 6k:

The product was obtained as yellow solid (34%, 0.135 g). 1H NMR

(500 MHz, CDCl3) δ 9.06-8.68 (m, 1H), 7.36-7.33 (m, 3H), 7.31 (d,

J = 4.5 Hz, 2H), 4.70-4.52 (m, 2H), 4.46 (dd, J = 14.8, 5.7 Hz, 1H),

3.62 (dd, J = 13.0 Hz, 6.1 Hz, 1H), 3.05-2.86 (m, 1H), 2.82-2.68 (m,

1H), 2.65 (d, J = 12.8 Hz, 1H), 2.61-2.49 (m, 2H), 2.43-2.35 (m, 2H), 2.26-2.16 (m, 1H),

2.05-1.99 (m, 1H), 1.96-1.80 (m, 4H), 1.72-1.58 (m, 3H), 1.31 (s, 2H), 0.90 (d, J = 8.7 Hz,

3H), 0.78 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 177.5, 176.8, 175.4, 138.3, 128.6, 127.9,

127.4, 73.7, 52.2, 50.3, 44.4, 40.8, 38.3, 35.7, 35.2, 33.4, 28.3, 25.6, 24.3, 22.4, 20.2;


N-Benzyl-2-(3,9-dioxo-1,4,8-oxadiazecan-4-yl)-4-methylpentanamide 6l:


(500 MHz, CDCl3) δ 7.43 (s, 1H), 7.40-7.36 (m, 1H), 7.36-7.33 (m,

3H), 7.30-7.27 (m, 2H), 5.41-5.27 (m, 1H), 4.71-4.39 (m, 4H), 4.30-

4.07 (m, 2H), 3.97-3.58 (m, 3H), 3.44 (s, 1H), 2.15 (s, 1H), 2.06-1.94

(m, 1H), 1.60-1.51 (m, 1H), 1.33-1.25 (m, 1H), 0.97 (d, J = 4.5 Hz, 3H), 0.96 (d, J = 4.6

Hz, 3H), 0.93-0.87 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 170.7, 170.6, 170.2, 138.4,

128.6, 128.0, 127.3, 73.6, 72.6, 57.4, 45.0, 43.5, 41.0, 36.6, 26.2, 25.0, 22.8, 22.5; HRMS

calculated for C20H30N3O4: 376.3645; found [M+H]+: 376.3646.

2-(2,5-Dioxo-1,6-diazecan-1-yl)-2-(3-methoxyphenyl)-N-(2,4,4-trimethylpentan-2-

yl)acetamide 6m:


(500 MHz, CDCl3) δ 7.62-7.50 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.07-

7.03 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.92 (dd, J = 8.2, 2.5 Hz, 1H),

5.54 (s, 1H), 4.51 (s, 1H), 4.02-3.90 (m, 1H), 3.82 (s, 3H), 3.66-3.51

(m, 1H), 3.31-3.17 (m, 1H), 3.05- 2.87 (m, 2H), 2.62-2.46 (m, 3H),

2.01-1.77 (m, 6H), 1.45 (s, 3H), 1.39 (s, 3H), 0.84 (s, 9H); 13C NMR (126 MHz, CDCl3) δ

173.4, 172.6, 168.1, 160.2, 136.6, 130.3, 121.9, 115.3, 114.3, 65.2, 55.6, 55.3, 53.6, 47.6,


109

40.0, 36.0, 31.6, 31.5, 31.4, 28.4, 27.7, 26.1, 25.0; HRMS calculated for C25H40N3O4:

446.3013; found [M+H]+: 446.3004.

2-(1,8-Dioxo-3,4,5,6,7,8-hexahydrobenzo[c][1,6]diazecin-2(1H)-yl)-N-(4-

methoxybenzyl)-3,3-dimethylbutanamide 6n:


MHz, CDCl3) δ 7.83-7.77 (m, 2H), 7.71-7.65 (m, 2H), 7.29 (t, J = 5.9

Hz, 1H), 7.19-7.14 (m, 2H), 6.80-6.74 (m, 2H), 4.44-4.27 (m, 2H), 3.72

(s, 3H), 3.66-3.48 (m, 2H), 2.72 (s, 1H), 2.57-2.40 (m, 2H), 1.66-1.55

(m, 2H), 1.50-1.38 (m, 2H), 0.95 (s, 9H); 13C NMR (126 MHz, CDCl3) δ

172.8, 168.3, 158.8, 133.9, 132.1, 130.9, 129.2, 123.1, 113.9, 72.7, 55.2,

48.6, 42.4, 37.6, 33.7, 27.2, 27.2, 26.2; HRMS calculated for

C26H34N3O4: 452.2544; found [M+H]+: 452.2541.

2-(5-Bromo-2-methoxyphenyl)-N-(tert-butyl)-2-(8,15-dioxo-9,14-diazaspiro[5.10] hex-

adecan-9-yl)acetamide 6o:


(500 MHz, CDCl3) δ 8.44 (s, 1H), 7.45 (dd, J = 8.7, 2.5 Hz, 1H), 7.32-

7.29 (m, 1H), 6.83 (d, J = 8.7 Hz, 1H), 5.29 (s, 1H), 4.99 (s, 1H), 4.04-

3.92 (m, 1H), 3.86 (s, 3H), 3.71-3.54 (m, 1H), 2.97-2.68 (m, 2H), 2.53-

2.29 (m, 2H), 2.26-2.11 (m, 2H), 1.92-1.71 (m, 6H), 1.70-1.57 (m, 2H),

1.56-1.42 (m, 6H), 1.29 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 173.7, 171.4, 168.8, 156.8,

132.8, 131.3, 124.9, 113.9, 112.4, 60.4, 55.7, 51.5, 49.0, 43.4, 39.8, 38.2, 38.1, 37.2, 28.3,

27.8, 27.2, 26.3, 21.9, 21.9; HRMS calculated for C27H41N3O4Br: 550.2275; found [M+H]+:

550.2276.

2-(2-Azidophenyl)-N-benzyl-2-(3,10-dioxo-1-oxa-4,9-diazacycloundecan-4-

yl)acetamide 6p:


(500 MHz, CDCl3) δ 8.29 (d, J = 8.5 Hz, 1H), 7.44-7.38 (m, 1H),

7.27-7.21 (m, 3H), 7.17-7.09 (m, 5H), 6.23 (t, J = 5.8 Hz, 1H), 5.98

(s, 1H), 4.68 (d, J =14.4 Hz, 1H), 4.33 (d, J = 15.7 Hz, 1H), 3.82-

3.71 (m, 2H), 3.69-3.56 (m, 4H), 2.95 (d, J = 14.2 Hz, 1H), 2.89 –

2.80 (m, 2H), 2.68-2.55 (m, 1H), 2.01-1.90 (m, 1H), 1.86-1.78 (m, 2H), 1.75-1.67 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 172.8, 169.6, 169.1, 138.8, 138.3, 130.4, 129.2, 128.6,

128.6, 126.6, 126.2, 125.2, 118.6, 74.8, 74.4, 61.6, 46.2, 41.1, 40.1, 35.1, 26.4, 26.1;


2-(5,8-Dioxo-1-thia-4,9-diazacycloundecan-4-yl)-3,3-dimethyl-N-(4-methylbenzyl)

butanamide 6q:

The product was obtained as a white solid (55%, 0.230 g). 1H

NMR (500 MHz, CDCl3) δ 7.66 (s, 1H), 7.29 (d, J = 7.2 Hz, 2H),

7.15 (d, J = 7.8 Hz, 2H), 6.46 (d, J = 10.4 Hz, 1H), 4.68 (dd, J =

14.6, 6.6 Hz, 1H), 4.20 (s, 1H), 4.16 (dd, J = 14.7, 4.1 Hz, 1H),

4.00-3.92 (m, 1H), 3.82-.67 (m, 2H), 3.43-3.32 (m, 1H), 3.10-2.91 (m, 3H), 2.78-2.61 (m,

Chapter 3

110

2H), 2.54-2.40 (m, 1H), 2.34 (s, 3H), 2.32-2.18 (m, 2H), 1.05 (s, 9H); 13C NMR (126 MHz,

CDCl3) δ 173.9, 172.5, 168.7, 136.7, 135.2, 129.1, 128.1, 68.7, 44.8, 44.0, 41.2, 37.7, 36.1,

34.6, 33.9, 30.1, 27.2, 21.1; HRMS calculated for C22H34N3O3S: 420.2315; found [M+H]+:

420.2315.

N-(2,2-Diethoxyethyl)-2-(3,10-dioxo-1-oxa-4,9-diazacycloundecan-4-yl)-4-phenyl-

butan amide 6r:


(500 MHz, CDCl3) δ 7.47-7.37 (m, 1H), 7.35-7.28 (m, 2H), 7.27-

7.17 (m, 2H), 7.15-7.12 (m, 1H), 6.70 (t, J = 5.6 Hz, 1H), 4.57 (t, J

= 4.5 Hz, 1H), 4.32-4.25 (m, 1H), 4.01 (d, J = 14.4 Hz, 1H), 3.89-

3.82 (m, 1H), 3.80 (d, J = 15.4 Hz, 1H), 3.76-3.63 (m, 2H), 3.59-

3.42 (m, 6H), 3.04-.86 (m, 2H), 2.69-2.59 (m, 1H), 2.59-2.49 (m,

1H), 2.34-2.24 (m, 1H), 2.12-2.05 (m, 1H), 2.04-1.94 (m, 1H), 1.93-1.82 (m, 1H), 1.71-

1.59 (m, 1H), 1.53-1.37 (m, 1H), 1.21 (t, J =7.0 Hz, 3H), 1.20 (t, J =7.0 Hz, 3H); 13C NMR

(126 MHz, CDCl3) δ 172.1, 169.8, 168.7, 139.6, 128.9, 128.2, 126.7, 100.1, 74.9, 74.0,


C24H37N3O6Na: 486.2575; found [M+Na]+: 486.2573.

N-(4-Chlorobenzyl)-2-(9-methyl-7,11-dioxo-1,6-diazacycloundecan-1-yl)acetamide 6s:


NMR (500 MHz, CDCl3) δ 8.40-7.90 (m, 1H), 7.34-7.30 (m, 2H),

7.30-7.27 (m, 2H), 6.81 (t, J = 5.9 Hz, 1H), 4.50-.44 (m, 2H),

4.44-4.26 (m, 1H), 4.20-3.67 (m, 2H), 3.67-3.11 (m, 3H), 2.60-

2.44 (m, 2H), 2.32-2.17 (m, 2H), 2.00 (dd, J = 12.6, 4.8 Hz, 1H), 1.93 -1.66 (m, 4H), 1.27

(d, J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 173.5, 171.6, 170.3, 136.4, 133.4,


C19H27N3O3Cl: 380.1735; found [M+H]+: 380.1737.

N-(2-(1H-Indol-3-yl)ethyl)-2-(4-chlorophenyl)-2-(9,9-dimethyl-7,11-dioxo-1,6-diaza-

cycloundecan-1-yl)acetamide 6t:


MHz, MeOD-d4) δ 7.55 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H),

7.32-7.18 (m, 4H), 7.16- 7.10 (m, 1H), 7.07 (s, 1H), 7.03 (t, J = 7.5 Hz,

1H), 5.52 (s, 1H), 3.69-3.46 (m, 3H), 3.06-2.91 (m, 3H), 1.89-1.62 (m,

4H), 1.49-1.10 (m, 6H); 13C NMR (126 MHz, MeOD-d4) δ 171.4, 170.9,

169.3, 135.2, 132.8, 131.8, 129.8, 127.1, 125.8, 120.9, 119.4, 116.7,

116.4, 109.9, 109.4, 63.5, 43.9, 38.9, 38.7, 38.1, 32.9, 28.3, 27.6, 26.1,

25.4, 22.6; HRMS calculated for C29H36N4O3Cl: 523.247; found

[M+H]+:523.247.


111

2-(7-Dodecyl-5,8-dioxo-1-thia-4,9-diazacycloundecan-4-yl)-N-phenethylacetamide 6u:


NMR (500 MHz, CDCl3) δ 7.39-7.31 (m, 2H), 7.31-7.19 (m, 3H),

6.89-6.60 (m, 1H), 4.70-4.37 (m, 1H), 4.06-3.80 (m, 1H), 3.68-

3.48 (m, 2H), 3.47-3.30 (m, 1H), 3.22-3.06 (m, 1H), 3.06-2.81 (m,

4H), 2.81-2.54 (m, 4H), 2.49-2.35 (m, 1H), 1.82-1.64 (m, 1H),

1.55-1.18 (m, 21H), 0.92 (t, J = 6.9 Hz, 3H); 13C NMR (126 MHz, CDCl3, rotamers were

observed) δ 176.4, 174.8, 173.6, 172.0, 168.4, 168.3, 138.8, 138.7, 128.7, 128.7, 128.7,

128.6, 128.5, 126.5, 53.5, 48.9, 48.3, 46.3, 42.1, 40.9, 40.8, 40.7, 40.6, 39.2, 36.7, 35.7,

35.6, 35.5, 34.3, 33.6, 33.3, 32.9, 32.3, 31.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.5, 29.5, 29.3,

27.7, 27.3, 22.7, 14.1; HRMS calculated for C30H50N3O3S: 532.3567; found [M+H]+:

532.3568.

N-(tert-Butyl)-2-(3,10-dioxo-1-thia-4,9-diazacycloundecan-4-yl)-2-(4-nitrophenyl)

acetamide 6v:


(500 MHz, CDCl3) δ 8.25-8.22 (m, 2H), 8.22-8.19 (m, 1H), 7.64 (d, J =

8.8 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.06-6.97 (m, 1H), 5.45 (s, 1H),

4.88 (s, 1H), 4.09-3.98 (m, 1H), 3.80 (d, J = 15.0 Hz, 2H), 3.60-3.44 (m,

2H), 3.29-3.06 (m, 5H), 3.00 (d, J = 12.6 Hz, 2H), 1.89-1.75 (m, 5H),

1.46 (s, 5H), 1.31 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 172.1, 169.2,

168.7, 168.3, 168.0, 166.2, 148.1, 147.6, 144.0, 142.2, 131.8, 130.5, 128.1, 124.3, 124.1,

66.4, 65.6, 52.6, 52.3, 49.2, 46.4, 46.1, 41.2, 40.8, 40.1, 37.2, 36.7, 36.0, 34.9, 32.0, 28.6,

28.4, 28.3, 27.6, 27.2, 27.0, 26.9; HRMS calculated for C20H29N4O5S: 437.1853; found

[M+H]+: 437.1852.

N-(4-Methoxy-2-nitrophenyl)-2-(9-methyl-7,11-dioxo-1,6-diazacycloundecan-1-

yl)acetamide 6w:


NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 8.60 (d, J = 9.3 Hz, 1H),

7.82 (s, 1H), 7.69 (d, J = 3.1 Hz, 1H), 7.26 (dd, J = 9.3, 3.0 Hz,

1H), 3.88 (s, 3H), 3.79-3.61 (m, 1H), 3.56-3.18 (m, 2H), 2.65-2.54

(m, 1H), 2.51-2.38 (m, 1H), 2.38-2.26 (m, 2H), 2.12-2.01 (m, 1H), 1.97- 1.63 (m, 5H), 1.30

(d, J = 7.0 Hz, 3H), 1.09 (t, J = 6.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 173.5, 171.7,

168.9, 155.4, 137.5, 127.5, 124.2, 123.3, 108.7, 55.9, 52.8, 51.7, 40.6, 39.7, 36.2, 29.3,

28.8, 27.4, 21.0; HRMS calculated for C19H27N4O6: 407.1925; found [M+H]+: 407.1924.

General procedure and analytical data for the synthesis of sulfoxide macrocycle:

Macrocycle 6q (1.0 mmol) was dissolved in 1 ml DCM, and meta-chloroperoxybenzoic

acid (1 eq.) was added. The solution stirred at room temperature for 4 hr. After completion

of the reaction, the solvent was removed under reduced pressure and the residue was puri-

fied using flash chromatography (DCM: MeOH (9:1)).

Chapter 3

112

General procedure and analytical data for the synthesis of sulfones macrocycle:

Macrocycle 6q (1.0 mmol) was dissolved in 1 ml DCM, and meta-chloroperoxybenzoic

acid (4 eq.) was added. The solution stirred at room temperature for 4 hr. After completion

of the reaction, the solvent was removed under reduced pressure and the residue was puri-

fied using flash chromatography (DCM: MeOH (9:1)).

3,3-Dimethyl-N-(4-methylbenzyl)-2-(1-oxido-5,8-dioxo-1-thia-4,9-diazacycloundecan-

4-yl)butanamide 7a:


NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 6.4, 4.5 Hz, 1H), 7.32

(d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.16-7.11 (m,

1H), 4.68 (dd, J = 14.6, 6.4 Hz, 1H), 4.49 (dd, J = 13.8, 12.1,

1.4 Hz, 1H), 4.26 (dd, J = 14.6, 4.4 Hz, 1H), 4.10-4.02 (m, 1H),

4.01-3.90 (m, 1H), 3.83-3.73 (m, 1H), 3.29-3.18 (m, 2H), 3.17-

3.08 (m, 1H), 2.82- 2.73 (m, 1H), 2.73-2.66 (m, 1H), 2.66-2.56 (m, 1H), 2.45-2.36 (m, 2H),

2.35 (s, 3H), 2.27-2.14 (m, 1H), 1.04 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 174.6, 172.1,

168.2, 137.1, 134.6, 129.3, 128.3, 68.6, 55.8, 51.1, 43.8, 41.0, 37.9, 35.9, 32.4, 29.8, 27.2,

21.2; HRMS calculated for C22H34N3O4S: 436.2265; found [M+H]+: 436.2262.

2-(1,1-Dioxido-5,8-dioxo-1-thia-4,9-diazacycloundecan-4-yl)-3,3-dimethyl-N-(4-

methylbenzyl)butanamide 7b:


NMR (500 MHz, CDCl3) δ 8.00 (t, J = 1.9 Hz, 1H), 7.51 (t, J =

5.9 Hz, 1H), 7.39 (dd, J = 6.0, 4.5 Hz, 1H), 7.31-7.27 (m, 2H),

7.27-7.23 (m, 1H), 7.12 (d, J = 7.7 Hz, 2H), 4.79 (dd, J = 14.8,

10.2 Hz, 1H), 4.62 (dd, J = 14.5, 6.3 Hz, 1H), 4.26 (dd, J =

14.6, 4.7 Hz, 1H), 4.01-3.86 (m, 2H), 3.80-3.67 (m, 1H), 3.42-

3.21 (m, 3H), 3.12 -3.02 (m, 1H), 2.67 (d, J = 5.0 Hz, 1H), 2.51-2.41 (m, 2H), 2.31 (s, 3H),

1.05 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 175.9, 173.5, 167.4, 134.3, 133.3, 129.3,

128.4, 68.8, 53.5, 51.8, 43.5, 40.4, 38.4, 35.5, 35.2, 30.5, 27.6, 21.1; HRMS calculated for

C22H34N3O5S: 452.2214; found [M+H]+: 452.2214 .

Crystal structure determination:

X-ray diffraction data for single crystals of compound 6i was collected using SuperNo-

va (Rigaku-Oxford Diffraction) four-circle diffractometer with a mirror monochromator

and a microfocus MoKα radiation source (λ = 0.7107 Å) for 6i. Additionally, the diffrac-

tometer was equipped with a CryoJet HT cryostat system (Oxford Instruments) allowing

low-temperature experiments. Single crystals were mounted on Micro MountsTM. Intensi-

ties were collected at 120-130 K. The obtained data sets were processed with CrysAlisPro

software.15 The phase problem was solved by direct methods using SHELXS16 or

SUPERFLIP.17 Parameters of obtained models were refined by full-matrix least-squares on

F2 using SHELXL-2014/6.16 Calculations were performed using WinGX integrated system

(ver. 2013.2).18 Figures were prepared with Mercury 3.5 software.19


113

All non-hydrogen atoms in the crystal structures of 6i were refined anisotropically to

ensure the convergence of the refinement process. All hydrogen atoms attached to carbon

atoms were positioned with the idealized geometry and refined using the riding model with

the isotropic displacement parameter Uiso[H] = 1.2 (or 1.5) Ueq[C]. The position of hydro-

gen atoms linked to the N atoms was found on the difference Fourier map and refined with

no restrains on the isotropic displacement parameter. Crystal data and structure refinement

results for compounds 6i are shown in Table S1. Molecular geometry of compound 6i ob-

served in the crystal structures are shown in Figure 4.

Crystallographic data for structure presented in this paper have been deposited with the

Cambridge Crystallographic Data Centre as supplementary publication nos.

CCDC 1507158 (6i), Copies of the data can be obtained, free of charge, on application to

CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:

[email protected]).

Figure 4. Molecular geometry observed in the crystal structures of compound 6i, showing

the atom labeling scheme.

Table 1. Crystal data and structure refinement results for compounds 6i.

6i

Empirical moiety formula C23 H35 N3 O3

Formula weight [g/mol] 401.54

Temperature [K] 119.7 (6)

Wavelength [Å] 0.7107

Crystal system Triclinic

Space group P-1

Unite cell dimensions

a = 8.0603(4) Å

b = 9.4623(5) Å

c = 15.4776(8) Å

α=90.795(4)°

mailto:[email protected]

Chapter 3

114

=97.819(4)°

=112.566(5)°

Volume [Å3] 1077.13(10)

Z 2

Dcalc [Mg/m3] 1.238

μ [mm-1] 0.082

F(000) 436

Crystal size [mm3] 0.4 x 0.4 x 0.4

Θ range 3.03° to 28.56°

Index ranges -10 ≤ h ≤ 10, -12 ≤ k ≤ 12,

-19 ≤ l ≤ 20

Refl. collected 15230

Independent reflections 5492 [R(int) = 0.0356]

Completeness [%] to Θ 99.8 (Θ 26.31°)

Absorption correction Multi-scan

Max. and min. transmission 0.825 and 1.000

Refinement method Full-matrix least-squares on F2

Data/ restraints/parameters 5492 / 0 / 275

GooF on F2 1.018

Final R indices [I>2sigma(I)] R1= 0.0489, wR2= 0.1051

R indices (all data) R1= 0.0685, wR2= 0.1183

Δρmax, Δρmin [e·Å-3] 0.31 and -0.30

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