Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation

Volume 12 Number 23 21 June 2014 Pages 3757–4032

Organic &

Biomolecular

Chemistry

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ISSN 1477-0520

PAPER

Faiz Ahmed Khan, Roy Anindya et al.

Syntheses of a library of molecules on the marine natural product

ianthelliformisamines platform and their biological evaluation

Organic &

Biomolecular Chemistry

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Syntheses of a library of molecules on the marine

natural product ianthelliformisamines platform

and their biological evaluation†

Cite this: Org. Biomol. Chem., 2014,

12, 3847

Faiz Ahmed Khan,*^aSaeed Ahmad,^aNaveena Kodipelli,^bGururaj Shivange^band

Roy Anindya*^b

Ianthelliformisamines A–C are a novel class of bromotyrosine-derived antibacterial agents isolated

recently from the marine sponge Suberea ianthelliformis. We have synthesized ianthelliformisamines A–C

straightforwardly by the condensation of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic acid and the

corresponding Boc-protected polyamine followed by Boc-deprotection with TFA. Further, using this

reaction protocol, a library of their analogues (39 analogues) has been synthesized by employing

3-phenylacrylic acid derivatives and Boc-protected polyamine chains through various combinations of

these two fragments diﬀering in phenyl ring substitution, double bond geometry or chain length of the

central spacer of the polyamine chain (shown in red color). All the synthesized compounds (ianthelliformi-

samines A–C and their analogues) were screened for antibacterial activity against both Gram-negative

(Escherichia coli) and Gram-positive (Staphylococcus aureus) strains. All synthetic analogues of ianthelli-

formisamine A showed bacterial growth inhibition against both strains (Escherichia coli and Staphylococ-

cus aureus), having MIC values in the range of 117.8–0.10 μM, while none of the synthetic analogues of

ianthelliformisamine C as well as the parent compound showed any detectable antibacterial activity. Inter-

estingly, some of the synthetic analogues of ianthelliformisamines A and B exerted a bactericidal eﬀect

against both E. coli and S. aureus strains, decreasing viable bacterial count by 99% at concentrations as

low as 2 × MIC.

Received 20th December 2013,

Accepted 24th February 2014

DOI: 10.1039/c3ob42537a

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ranging from prokaryotic to eukaryotic cells and are con-

sidered as cell growth factors.^3,4In bacteria, they regulate key

Introduction

The emergence of antibiotic resistant bacterial pathogens is a cellular processes like DNA replication, transcription, and

major public health concern worldwide and it has highlighted translation and influence the optimal cell growth and viability

the need for the development of new antibiotics. Unfortu- by protecting from various toxic conditions, e.g., radiation,

nately, there have been only a few new classes of clinically acidic pH, and oxidative stress.^5–11Polyamine analogues, in

important antibiotics discovered in recent years, emphasizing contrast, completely lack any physiological function but, being

the need to develop antibiotics possessing new scaﬀolds with structurally similar to natural polyamines, act as decoys and

novel modes of action.¹Natural and artificial polyamines oﬀer compete with natural polyamines, and aﬀect major cellular

a promising new group of antibacterial compounds and have processes. Not surprisingly, polyamine analogues were develo-

been shown to increase the susceptibility of bacteria to several ped as potential antibiotics in treating several parasitic

antibiotics.²Natural polyamines, like spermine and spermi- diseases.^12–18

dine, are found in significant amounts in all organisms

Natural medicinal ingredients have been used by mankind

for thousands of years for the treatment of various diseases

and ailments, and also in the current paradigm, isolated

natural products have proven a rich source of potent biological

activities in all therapeutic areas.^19–21In the past few decades,

natural products have remarkably influenced the area of drugs

development. According to a report, in the last 30 years during

the period 1981–2010, approximately half of the drugs

approved by the US Food and Drug Administration (FDA) or by

similar organizations are actually either natural products or

^aDepartment of Chemistry, Indian Institute of Technology Hyderabad, Ordnance

Factory Estate, Yeddumailaram-502205, India. E-mail: faiz@iith.ac.in;

Tel: (+91) 40 2301 6084

^bDepartment of Biotechnology, Indian Institute of Technology Hyderabad, Ordnance

Factory Estate, Yeddumailaram-502205, India. E-mail: anindya@iith.ac.in;

Tel: (+91) 40 2301 6083

†Electronic supplementary information (ESI) available: Copies of ¹H NMR and

¹³C NMR spectra for products and biological evaluation test results. See DOI:

10.1039/c3ob42537a

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their derivatives or molecules designed and synthesized on

The isolated natural products ianthelliformisamines A–C

natural products platforms.²²In the search for therapeutic (1–3) exhibited antibacterial activity, and out of them, ianthelli-

agents against drug-resistant microbes with novel modes of formisamine A (1) was found most active against the Gram-

actions, natural products can be considered as pre-validated negative bacterium Pseudomonas aeruginosa with a MIC value

leads and one can reckon on nature’s ability to make biologi- of 35 μM.²⁶The profound potent antibacterial activities of

cally relevant chemical entities.²³Even though many well- ianthelliformisamines A–C prompted us to design and syn-

established techniques are available for the isolation and thesize a library of molecules on these platforms in order to

characterization of natural products, acquisition of new explore more potent leads than the original natural products.

natural products is still a very tedious and laborious task in We envisaged that bisecting the title molecules into two parts,

terms of diﬃculties associated with isolation, poor yield and viz., a 3-phenylacrylic acid derivative and a polyamine chain,

structure elucidation.²⁴In this aspect, synthesis of a library would provide a convenient handle to create a library through

of molecules on the biologically potent natural products various combinations of the two parts diﬀering in phenyl ring

template is one of the worthwhile approaches for finding lead substitution, double bond geometry or chain length of the

compounds.²⁵

central spacer of the polyamine chain (shown in red color). For

Recently, Quinn and co-workers isolated bromotyrosine- this purpose, we have used substituted aromatic aldehydes

derived alkaloids, ianthelliformisamines A–C (1–3, Fig. 1), 9a–d and Boc-protected polyamines (12a–c, 13a–c and 14a–c).

from the marine sponge Suberea ianthelliformis.²⁶Based on Interestingly, the choice of phenyl ring substituents in alde-

extensive NMR experiments, the structures of ianthelliformis- hydes 9a–d is inspired by the presence of these moieties

amines were assigned as a polyamine chain (spermine or sper- in marine natural products like amathamides,²⁸wilsoni-

midine) condensed with (E)-3-(3,5-dibromo-4-methoxyphenyl)- amines,^28cconvolutamines,²⁹and amathaspiramides.³⁰

acrylic acid, forming amide linkage.²⁶Previously isolated Herein, we report a synthesis of natural products ianthellifor-

natural products spermatinamine,^27apseudoceramines A–C^27bmisamines A–C and a library built on their platform. All the

and tokaradine C^27calso possess the same skeleton and are synthetic analogues of ianthelliformisamines were screened

represented in Fig. 1 (4–8).

for antibacterial activity. Our results revealed a set of synthetic

Fig. 1 Structures of naturally occurring bromotyrosine-derived alkaloids possessing polyamine chains.

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ianthelliformisamine-mimicking analogues exhibiting enhanced chromatographically separable cis and trans products in a ratio

antibacterial activity.

of 1 : 3, respectively. Further, α,β-unsaturated ethyl esters 10a–f

were hydrolyzed by lithium hydroxide monohydrate

(LiOH·H₂O)–THF–water³⁵to get α,β-unsaturated carboxylic

acids 11a–f (Scheme 1).

Results and discussion

Boc-protected spermines 12b and 13b were synthesized

from 1,4-diaminobutane according to the literature protocol³⁶

(Scheme 2). Other Boc-protected spermine analogues (12a, c

and 13a, c) were also synthesized by using the same literature

protocol from the corresponding diamines (Scheme 2).³⁶In

the reaction sequence, the corresponding diamines (n = 1, 2

and 4) on treatment with acrylonitrile (2.0 equiv.) gave the bis

Michael adduct. Further, central amines were protected with

the Boc-group and then nitrile groups were reduced by

RANEY-Ni® to get Boc-protected amines 12a–c.^36aTriBoc-tetra-

amines 13a–c were synthesized from amines 12a–c via a three

step one-pot protocol.³⁶In the reaction sequence, first, amines

12a–c were predominantly mono-trifluoroacetylated by treat-

ment of ethyl trifluoroacetate at −78 °C and then the remain-

ing amine group was protected with Boc by using Boc₂O.

Further, in situ deprotection of the trifluoroacetate group with

K₂CO₃under reflux conditions gave triBoc-tertaamines

13a–c.³⁶Boc-protected spermidine 14b and its analogues 14a,c

were synthesized from the corresponding diamines via selec-

tive mono-Michael addition to acrylonitrile and then Boc-

protection of primary and secondary amines^37afollowed by

reduction of the nitrile group with LiAlH₄.^37b

Chemistry

Ianthelliformisamines A–C (1–3) contain an (E)-3-(3,5-

dibromo-4-methoxyphenyl)acrylic acid moiety which is con-

nected with the polyamine chain spermine or spermidine via

amide functionality. We commenced the preparation of (E)-3-

(3,5-dibromo-4-methoxyphenyl)acrylic acid from 3,5-dibromo-

4-methoxybenzaldehyde 9a which was obtained from 4-hydroxy-

benzaldehyde by using the literature protocol via bromination

with Br₂/AcOH/NH₄OAc^31afollowed by methylation of the

hydroxyl group with MeI.^31bTo access a library of analogues,

2,4,6-tribromo-3-methoxybenzaldehyde 9b and 2,4-dibromo-5-

methoxybenzaldehyde 9d were prepared from 3-hydroxybenzal-

dehyde by treating it with Br₂/H₂O³²and Br₂/CHCl₃,³²respecti-

vely, followed by methylation of the hydroxyl group with MeI.³²

2,3,4-Tribromo-5-methoxybenzaldehyde 9c is accessible from

Grob-type fragmentation–aromatization reaction of 1,4,5,6-

tetrabromo-7,7-dimethoxybicyclo[2.2.1]-hept-5-en-2-one

fol-

lowed by further functional group transformations.³³The alde-

hydes 9a–d were converted into α,β-unsaturated ethyl esters

10a–f by Wittig reaction of ethoxycarbonylmethylenetriphenyl-

phosphorane in THF (Scheme 1).³⁴We found that aldehydes

9a and 9b gave exclusively trans products in excellent

yields, while other aldehydes 9c and 9d gave a mixture of

Coupling of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic

acid 11a and (N¹,N⁴,N⁹-tri-tert-butoxycarbonyl)-1,12-diamino-

Scheme 1 Syntheses of 3-phenylacrylic acid derivatives.

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Scheme 2 Syntheses of Boc-protected spermine, spermidine and their analogues.

4,9-diazadodecane 13b by using EDC·HCl as a coupling as a coupling reagent³⁸followed by deprotection of the Boc-

reagent³⁸gave the corresponding amide, which after Boc- group with trifluoroacetic acid³⁸yielded compound 2 as a TFA

38

deprotection with trifluoroacetic acid (TFA) in CH₂Cl₂

at salt with 74% yield in 2 steps (Scheme 3). Synthetic compound

0 °C yielded compound 1 as a TFA salt with 68% yield in 2 2 has all spectroscopic data in accordance with the literature

steps (Scheme 3). Synthetic 1 was confirmed as ianthelliformis- reported values of ianthelliformisamine B. Coupling of (E)-3-

amine A (1) by ¹H NMR, ¹³C NMR and high-resolution mass (3,5-dibromo-4-methoxyphenyl)acrylic acid 11a and N¹,N⁴-di-

spectrometry.

(tert-butyloxycarbonyl)-N¹,N⁴-di(3-aminopropyl)-1,4-butanedi-

Coupling of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic amine 12b gave the corresponding amide, which after Boc-

acid 11a and Boc-protected spermidine 14b by using EDC·HCl deprotection with trifluoroacetic acid yielded compound 3 as a

Scheme 3 Synthesis of ianthelliformisamine A (1), ianthelliformisamine B (2) and ianthelliformisamine C (3).

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TFA salt (Scheme 3). Synthetic 3 was confirmed to be identical Antibacterial activity

to ianthelliformisamine C (3) by NMR (¹H and ¹³C NMR) and

high-resolution mass spectrometry. Further,

a library of Synthetic analogues of ianthelliformisamines A–C were evalu-

ianthelliformisamines A–C analogues 15–53 (a total of 39 ana- ated for their in vitro antibacterial activity against representa-

logues, Tables 1–3) were synthesized by employing various tive Gram-positive (Staphylococcus aureus) and Gram-negative

α,β-unsaturated carboxylic acids having diﬀerently substituted (Escherichia coli) strains using standard techniques. Minimum

phenyl ring 11a–f and Boc-protected polyamines (spermine, inhibitory concentration (MIC) was defined as the lowest con-

spermidine and their analogues) (12a–c, 13a–c, 14a–c) using centration that inhibited bacterial growth and started the zone

the same reaction procedure as for ianthelliformisamines A–C. of inhibition as compared to the control, and MICs of the

Table 1 Antibacterial activities of ianthelliformisamine A (1) and its synthetic analogues

Inhibition zone

diameter against the

microorganism^b

MIC (μM)

E. coli

Compd.

Structure

Yield^a(%)

68

E. coli

S. aureus

1

++

11.04

15

16

17

18

70

73

89

74

++

11.04

1.1

11.04

1.6

+++

+

+++

+

1.2

0.12

107.8

19

20

68

71

+++

1.1

1.2

1.1

1.2

21

22

72

82

+++

++

+

0.12

11.2

117.8

11.2

++

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Table 1 (Contd.)

Inhibition zone

diameter against the

microorganism^b

MIC (μM)

Compd.

Structure

Yield^a(%)

80^c

E. coli

S. aureus

E. coli

S. aureus

23

++

10.3

24

25

73

+++

1.03

0.11

0.10

0.11

68^d

26

66

+++

+

0.11

112

^aAll reactions were performed at 0.1 or 0.2 mmol scale. Yield in 2 steps. ^bEﬀectivity was classified into three zones based on the diameter of

zone of inhibition; +++: most eﬀective; ++: moderately eﬀective; +: slightly eﬀective. ^cHas a mixture of E and Z isomers (5 : 1). ^dHas a mixture of E

and Z isomers (9 : 1).

Table 2 Antibacterial activities of ianthelliformisamine B (2) and its synthetic analogues

Inhibition zone

diameter against the

microorganism^b

MIC (μM)

E. coli

Compd.

Structure

Yield^a(%)

74

E. coli

S. aureus

2

++

+

14.5

144.7

27

28

29

30

85

78

84

+

129.8

14.5

129.8

144.7

+

++

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Table 2 (Contd.)

Inhibition zone

diameter against the

microorganism^b

MIC (μM)

Compd.

Structure

Yield^a(%)

75

E. coli

S. aureus

E. coli

S. aureus

31

+++

+

1.47

144.7

32

33

34

35

88

90

94

83^c

+++

++

+++

+

1.47

13.2

0.15

1.47

132.2

0.15

++

+

+++

36

37

83^d

82

+++

—

0.15

1.46

1476

1464

38

39

66

63

+

125.3

1.3

125.3

1.3

+++

40

41

74

77

—

NA

+

773.5

42

79

+++

+

1.39

139

^aAll reactions were performed at 0.1 or 0.2 mmol scale. Yield in 2 steps. ^bEﬀectivity was classified into three zones based on the diameter of

zone of inhibition; +++: most eﬀective; ++: moderately eﬀective; +: slightly eﬀective; —: not eﬀective. NA: no activity. ^cHas a mixture of E and Z

isomers (18 : 1). ^dHas a mixture of Z and E isomers (15 : 1).

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Table 3 Antibacterial activities of ianthelliformisamine C (3) and its synthetic analogues

Inhibition zone

diameter against the

microorganism^b

MIC (μM)

E. coli

NA

Compd.

Structure

Yield^a(%)

75

E. coli

S. aureus

3

—

NA

43

44

85

73

—

NA

45

46

47

89

88

83

—

NA

48

49

50

77

81

84

—

NA

51

81

—

NA

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Table 3 (Contd.)

Inhibition zone

diameter against the

microorganism^b

MIC (μM)

Compd.

Structure

Yield^a(%)

87

E. coli

S. aureus

E. coli

S. aureus

52

—

NA

53

88

—

NA

^aAll reactions were performed at 0.1 or 0.2 mmol scale. Yield in 2 steps. ^bEﬀectivity was classified into zones based on the diameter of zone of

inhibition; —: not eﬀective; NA: no activity.

synthesized compounds are reported in Tables 1–3 and ESI 10-fold in E. coli and 100-fold in S. aureus (compd. 32,

Fig. A.† These compounds did not belong to the PAINS (pan Table 2), while on increasing the terminal carbon chain of

assay interference compounds) category.³⁹

spermidine from four to six, antibacterial activity increased

The results indicate that in comparison with the natural 10-fold in E. coli and decreased 10-fold in S. aureus (compd.

product ianthelliformisamine A (1), when the phenyl ring is 37, Table 2). Among the synthetic analogues of ianthelliformi-

substituted with 2,3,4-tribromo-5-methoxy (compd. 15, samine B (2), compounds 32, 35 and 39 (MIC values 1.47, 0.15

Table 1), there was no change in antibacterial activity, while and 1.3 μM, respectively, against both E. coli and S. aureus)

when the phenyl ring is substituted with 2,4,6-tribromo-5- were found to be far better than the parent compound, ianthel-

methoxy (compd. 16, Table 1), antibacterial activity increased liformisamine B (2) (MIC values 14.5 and 144.7 μM against

up to 10-fold in both strains. After decreasing the middle E. coli and S. aureus, respectively) (Table 2). In this series the

carbon chain of spermine from four to three (represented in most eﬃcient synthetic analogue is 35 (MIC values 0.15 μM in

red color) antibacterial activity increased up to 10-fold in E. both strains). In the series of synthetic analogues of ianthelli-

coli and up to 100-fold in S. aureus (compd. 17, Table 1), while formisamines A and B, our finding was that substituted

by increasing the middle carbon chain of spermine from four phenyl rings as well as polyamines are both equally respon-

to six there was no eﬀect on antibacterial activity (compd. 22, sible for antibacterial activity. Unfortunately, the series of

Table 1). In conclusion, cis analogues are more or equally ianthelliformisamine C analogues (compd. 43–53) as well as

active in E. coli, but less active in S. aureus in comparison with parent compound 3 did not show any significant antibacterial

their trans counterparts (compd. 20, 21 and 25, 26, Table 1). activity against both E. coli and S. aureus (Table 3), and there

Among the synthetic analogues of ianthelliformisamine A, was no eﬀect of substituted phenyl rings, size of polyamine

antibacterial activities of compounds 16, 17, 19, 20 and 24 chains and double bond geometry.

were found highly potent against both Gram-positive and

To further investigate the antibiotic activity, we conducted

Gram-negative bacteria with MIC value less than 2 μM. In par- time-kill assays where cultures of E. coli and S. aureus were

ticular, compound 25 (MIC value 0.11 μM, against both E. coli exposed to the test compounds and at subsequent times

and S. aureus) was found to be the most potent antibacterial samples were recovered, diluted and plated for counting to

agent in this series and has 100-fold less MIC value than the diﬀerentiate between bacteriostatic and bactericidal eﬀects.

parent compound ianthelliformisamine A (1) (MIC value Interestingly, among the ianthelliformisamine A (1) analogues,

11.04 μM, against both E. coli and S. aureus) (Table 1).

compounds 15, 18, 20, 23, and among the ianthelliformisamine

In the series of ianthelliformisamine B (2) analogues, on B (2) analogues, compounds 33, 34, 38 exerted a bactericidal

changing the substituents on the phenyl ring, antibacterial eﬀect against E. coli and S. aureus reducing viable bacterial cfu

activity slightly changed in E. coli, but there was no change of by 99% within 4 h at concentrations as low as 2 × MIC (ESI

antibacterial activity in S. aureus (compd. 27–31, Table 2). In Fig. B†). Ianthelliformisamine A (1) analogues, compounds 22,

comparison with ianthelliformisamine B (2), on decreasing 24, 25, and ianthelliformisamine B (2) analogues, compounds

the terminal carbon chain of spermidine from four to three 27, 28, 41, showed bactericidal activity against Gram-negative

(represented in red color), antibacterial activity increased up to E. coli but partial activity to Gram-positive S. aureus.

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1

139–141 °C; H NMR (500 MHz, CDCl₃) δ 7.65 (s, 2H), 7.48 (d,

1H, J = 15.9 Hz), 6.34 (d, 1H, J = 16.2 Hz), 4.25 (q, 2H, J =

Conclusion

In conclusion, we have synthesized natural products ianthelli- 7.2 Hz), 3.90 (s, 3H), 1.32 (t, 3H, J = 7.2 Hz); ¹³C NMR

formisamines A–C by condensation of (E)-3-(3,5-dibromo-4- (125 MHz, CDCl₃) δ 166.3, 155.5, 141.0, 133.2, 132.0, 120.2,

methoxyphenyl)acrylic acid and Boc-protected polyamine 118.8, 60.9, 14.3; IR (KBr) 3065, 2977, 1719, 1638, 1476, 1175,

(spermine or spermidine) followed by Boc-deprotection with 991, 855 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₃Br₂O₃(M + H),

TFA. Further, a variety of synthetic analogues (39 analogues) of 362.9231; found, 362.9238.

ianthelliformisamines A–C, varying in substitution on the

(E)-Ethyl 3-(2,4,6-tribromo-3-methoxyphenyl)acrylate (10b).

phenyl ring, size of the polyamine chain and double bond geo- The product was obtained as a white solid (2.27 g, 96%); Mp

metry, were prepared by using 3-phenylacrylic acid derivatives 83–85 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.56 (d,

and Boc-protected polyamines (spermine, spermidine and 1H, J = 16.3 Hz), 6.35 (d, 1H, J = 16.3 Hz), 4.30 (q, 2H, J =

their analogues). All the synthesized compounds (ianthelli- 7.1 Hz), 3.88 (s, 3H), 1.36 (t, 3H, J = 7.1 Hz); ¹³C NMR

formisamines A–C and their 39 synthetic analogues) were (100 MHz, CDCl₃) δ 165.7, 154.2, 141.7, 136.6, 136.0, 127.4,

screened for antibacterial activity. In the series of analogues of 120.3, 118.3, 118.1, 61.0, 60.6, 14.3; IR (neat) 3068, 2934, 1719,

ianthelliformisamines A and B, the change in the substitution 1644, 1449, 1268, 1171, 938, 744 cm⁻¹; HRMS (APCI) calcd for

of the phenyl ring as well as the change in the size of poly- C₁₂H₁₂Br₃O₃(M + H), 440.8337; found, 440.8333.

amine chains are both equally responsible for antibacterial

activity. Our results revealed that synthetic analogues of and

(Z)-Ethyl 3-(2,3,4-tribromo-5-methoxyphenyl)acrylate (10c)

(E)-ethyl 3-(2,3,4-tribromo-5-methoxyphenyl)acrylate

ianthelliformisamines A and B are more potent against both (10d). After column purification Z-product 10c was obtained

Gram-negative and Gram-positive bacteria than the parent natural as a white puﬀy solid (0.58 g, 24%) and E-product 10d was

products.

obtained as a white crystalline solid (1.74 g, 73%). Data for

Z-product 10c: Mp 132–134 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.05 (s, 1H), 7.01 (d, 1H, J = 12.2 Hz), 6.06 (d, 1H, J =

12.2 Hz), 4.11 (q, 2H, J = 7.1 Hz), 3.87 (s, 3H), 1.20 (t, 3H, J =

7.1 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 155.5, 142.8,

137.0, 129.0, 122.2, 116.7, 116.2, 112.5, 60.6, 56.9, 14.1; IR

(neat) 2979, 1716, 1530, 1364, 1203, 1063, 864 cm⁻¹; HRMS

Experimental section

General methods

All reactions were performed in oven dried apparatus and

under an argon atmosphere. Commercial grade solvents were

distilled before use. Melting points were obtained in open

capillary tubes and are uncorrected. ¹H NMR spectra were

recorded at 400 MHz or 500 MHz and proton decoupled ¹³C

NMR spectra were recorded at 100 MHz or 125 MHz. Infrared

spectra were recorded as KBr pellets or as thin films. High-

resolution mass spectra (HRMS) were recorded using electron

spray ionization (ESI) or atmospheric pressure chemical ioniza-

tion (APCI) mode. The purity of all compounds (1–3 and

15–53), tested for biological activity, was determined by high-

pressure liquid chromatography (HPLC) and it was found

>95% pure. The HPLC method utilized for purity: Waters

HPLC with C18 column (5.0 μm, 4.6 × 250 mm²); flow rate =

0.1 mL min⁻¹; solvent 0.1% TFA–MeOH; pressure 135–140 psi;

wavelength 254 nm.

(ESI) calcd for

C₁₂H₁₂Br₃O₃(M + H), 440.8337; found,

440.8350. Data for E-product 10d: Mp 162–164 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.98 (d, 1H, J = 15.8 Hz), 6.99 (s, 1H), 6.31

(d, 1H, J = 15.8 Hz), 4.27 (q, 2H, J = 7.1 Hz), 3.91 (s, 3H), 1.33

(t, 3H, J = 7.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 156.2,

144.0, 136.1, 130.4, 122.5, 119.0, 118.1, 108.6, 61.0, 56.9, 14.3;

IR (neat) 2981, 1714, 1634, 1410, 1187, 1069, 965, 837 cm⁻¹

;

HRMS (ESI) calcd for C₁₂H₁₂Br₃O₃(M + H), 440.8337; found,

440.8331.

(Z)-Ethyl 3-(2,4-dibromo-5-methoxyphenyl)acrylate (10e) and

(E)-ethyl 3-(2,4-dibromo-5-methoxyphenyl)acrylate (10f). After

column purification Z-product 10e was obtained as a white

solid (1.29 g, 24%) and E-product 10f was obtained as a white

puﬀy solid (4.02 g, 74%). Data for Z-product 10e: Mp 83–85 °C;

¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.21 (s, 1H), 6.99 (d,

1H, J = 12.3 Hz), 6.08 (d, 1H, J = 12.3 Hz), 4.13 (q, 2H, J =

7.1 Hz), 3.88 (s, 3H), 1.21 (t, 3H, J = 7.2 Hz); ¹³C NMR

(100 MHz, CDCl₃) δ 165.4, 154.7, 141.5, 135.7, 135.4, 122.2,

General experimental procedure for the preparation of 10a–f

by Wittig reaction

To a cooled (0 °C) solution of ethoxycarbonylmethylenetri- 114.2, 114.0, 112.7, 60.5, 56.5, 14.1; IR (neat) 2981, 2849, 1713,

phenylphosphorane (Ph₃PCHCO₂Et, 1.1 mmol, 1.1 equiv.) in 1469, 1369, 1189, 1039, 874 cm⁻¹; HRMS (ESI) calcd for

THF (4 mL) was added an appropriate aromatic aldehyde C₁₂H₁₃Br₂O₃(M + H), 362.9231; found, 362.9210. Data for

(1.0 mmol, 1.0 equiv.) and then it was allowed to warm to E-product 10f: Mp 141–143 °C; ¹H NMR (400 MHz, CDCl₃) δ

room temperature with stirring. After complete consumption 7.93 (d, 1H, J = 15.8 Hz), 7.77 (s, 1H), 7.06 (s, 1H), 6.39 (d, 1H,

of the starting material (monitored by TLC), all volatiles were J = 16.0 Hz), 4.29 (q, 2H, J = 7.1 Hz), 3.92 (s, 3H), 1.35 (t, 3H,

removed under reduced pressure, and the residue was purified J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 166.1, 155.5, 142.3,

by silica gel column chromatography (3–8% EtOAc–hexane) to 136.9, 134.4, 121.4, 116.0, 114.6, 109.9, 60.9, 56.5, 14.3; IR

get the Wittig products 10a–f.

(neat) 2979, 2899, 1706, 1369, 1233, 1041, 871 cm⁻¹; HRMS

(E)-Ethyl 3-(3,5-dibromo-4-methoxyphenyl)acrylate (10a). (APCI) calcd for C₁₂H₁₃Br₂O₃(M + H), 362.9231; found,

The product was obtained as a white solid (1.84 g, 99%); Mp 362.9243.

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Paper

General experimental procedure for alkaline hydrolysis of

ethylesters 10a–f. Preparation of compounds 11a–f

1058, 872, 664 cm⁻¹; HRMS (ESI) calcd for C₁₀H₉Br₂O₃

(M + H), 334.8918; found, 334.8911.

(E)-3-(2,4-Dibromo-5-methoxyphenyl)acrylic acid (11f). The

To a cooled (0 °C) solution of an appropriate α,β-unsaturated product 11f was obtained as a white solid (2.43 g, 96%); Mp

ethyl ester (1.0 mmol, 1.0 equiv.) in THF–H₂O (5 mL : 1 mL) 215–218 °C (decomposed); ¹H NMR (400 MHz, DMSO-d₆)

was added lithium hydroxide monohydrate (LiOH·H₂O, δ 12.73 (br s, 1H), 7.91 (s, 1H), 7.73 (d, 1H, J = 15.7 Hz), 7.51 (s,

1.5 mmol, 1.5 equiv.) and then it was allowed to warm to room 1H), 6.78 (d, 1H, J = 15.7 Hz), 3.93 (s, 3H); ¹³C NMR (100 MHz,

temperature with stirring. After complete consumption of the DMSO-d₆) δ 167.1, 155.2, 140.6, 135.9, 133.9, 123.3, 115.1,

starting material (monitored by TLC), all volatiles were 113.7, 111.2, 56.8; IR (neat) 2848, 1690, 1625, 1469, 1369, 1210,

removed under reduced pressure, and the residue was diluted 1054, 973, 699 cm⁻¹; HRMS (ESI) calcd for C₁₀H₉Br₂O₃(M +

with water (1 mL) and made acidic up to pH 2–3 with 10% H), 334.8918; found, 334.8910.

HCl. The aqueous layer was extracted with EtOAc (4 × 5 mL).

The combined organic layers were washed with brine, dried

over Na₂SO₄and concentrated to get the carboxylic acid 11a–f.

General procedure for the synthesis of Boc-protected

tetraamines 12a–c

(E)-3-(3,5-Dibromo-4-methoxyphenyl)acrylic acid (11a). The To a cooled (0 °C) solution of diamine (11.8 mmol, 1.0 equiv.)

product 11a was obtained as a white puﬀy solid (5.0 g, 98%); in anhydrous MeOH (5 mL) was added a solution of acrylo-

Mp 202–205 °C (decomposed); ¹H NMR (400 MHz, DMSO-d₆) δ nitrile (1.25 g, 23.6 mmol, 2.0 equiv.) in anhydrous MeOH

12.52 (br s, 1H), 8.04 (s, 2H), 7.50 (d, 1H, J = 16.1 Hz), 6.62 (d, (25 mL) dropwise over a period of 30 min. The resulting reac-

1H, J = 15.6 Hz), 3.81 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ tion solution was allowed to warm to room temperature and

167.2, 154.4, 140.4, 133.6, 132.3, 121.4, 118.0, 60.5; IR (neat) stirred for 22–24 h at room temperature. All volatiles were

2803, 1695, 1631, 1422, 1214, 975, 850, 745 cm⁻¹; HRMS (ESI) removed under reduced pressure and the residue was purified

calcd for C₁₀H₉Br₂O₃(M + H), 334.8918; found, 334.8917.

by silica gel column chromatography (10–40% MeOH–CHCl₃)

(E)-3-(2,4,6-Tribromo-3-methoxyphenyl)acrylic acid (11b). to get both side Michael addition products.

The product 11b was obtained as a white solid (2.66 g, 97%);

To a cooled (0 °C) solution of the above obtained product

Mp 200–203 °C (decomposed); ¹H NMR (400 MHz, DMSO-d₆) δ (11.8 mmol, 1.0 equiv.) in anhydrous MeOH (50 mL) was

12.90 (br s, 1H), 8.09 (s, 1H), 7.41 (d, 1H, J = 16.2 Hz), 6.26 (d, added Et₃N (2.61 g, 25.8 mmol, 2.2 equiv.) and then a solution

1H, J = 16.3 Hz), 3.81 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ of Boc₂O (5.38 g, 24.7 mmol, 2.1 equiv.) in anhydrous MeOH

166.3, 153.6, 141.2, 136.6, 135.6, 128.1, 119.8, 117.85, 117.80, (55 mL) was added dropwise. The resulting reaction solution

60.3; IR (neat) 2977, 2845, 1691, 1417, 1288, 1037, 873, was allowed to warm to room temperature and stirred for 24 h

741 cm⁻¹; HRMS (ESI) calcd for C₁₀H₈Br₃O₃(M + H), 412.8024; at room temperature. All volatiles were removed under reduced

found, 412.8018.

pressure and the residue was purified by silica gel column

(Z)-3-(2,3,4-Tribromo-5-methoxyphenyl)acrylic acid (11c). chromatography (30–60% EtOAc–hexane or 2% MeOH–

The product 11c was obtained as a white solid (0.34 g, 96%); CH₂Cl₂) to get the Boc-protected compound.

Mp 250–253 °C (decomposed); ¹H NMR (400 MHz, DMSO-d₆) δ

To a solution of the above obtained Boc-protected com-

12.50 (br s, 1H), 7.18 (s, 1H), 7.04 (d, 1H, J = 11.7 Hz), 6.12 (d, pound in a mixture of dioxane–water 4 : 1 (250 mL) were added

1H, J = 12.2 Hz), 3.83 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ RANEY® nickel (7.5 g, 50% aqueous suspension), Pd/C

166.2, 155.2, 141.0, 138.2, 127.8, 124.0, 115.5, 114.5, 112.9, (250 mg) and lithium hydroxide monohydrate (940 mg,

57.0; IR (neat) 3051, 2963, 1701, 1632, 1469, 1376, 1235, 1071, 22.4 mmol). The resulting solution was stirred at room temp-

855 cm⁻¹; HRMS (ESI) calcd for C₁₀H₈Br₃O₃(M + H), 412.8024; erature under a hydrogen atmosphere for 2–10 h (monitored

found, 412.8032.

by TLC). The reaction solution was filtered and washed with

(E)-3-(2,3,4-Tribromo-5-methoxyphenyl)acrylic acid (11d). MeOH (2 × 50 mL). The filtrate was concentrated under

The product 11d was obtained as a white solid (1.53 g, 98%); reduced pressure and the residue was taken in CH₂Cl₂(60 mL)

1

Mp 250–255 °C (decomposed); H NMR (400 MHz, DMSO-d₆) and water (60 mL). The organic layer was separated and

δ 12.75 (br s, 1H), 7.80 (d, 1H, J = 15.8 Hz), 7.48 (s, 1H), 6.72 aqueous layer again extracted with CH₂Cl₂(3 × 50 mL). The

(d, 1H, J = 15.8 Hz), 3.95 (s, 3H); ¹³C NMR (100 MHz, DMSO- combined organic layers were washed with brine, dried over

d₆) δ 166.9, 156.1, 142.3, 135.7, 129.1, 124.4, 117.9, 117.0, Na₂SO₄and concentrated. The residue was pure enough to

110.1, 57.3; IR (neat) 2807, 1680, 1626, 1455, 1362, 1228, 1065, proceed further or it can be purified by silica gel column

940, 727 cm⁻¹; HRMS (ESI) calcd for C₁₀H₈Br₃O₃(M + H), chromatography (2–10% Et₃N–MeOH) to get the product.

412.8024; found, 412.8010.

General procedure for the synthesis of Boc-protected

tetraamines 13a–c

(Z)-3-(2,4-Dibromo-5-methoxyphenyl)acrylic acid (11e). The

product 11e was obtained as a white solid (0.82 g, 92%); Mp

227–230 °C (decomposed); ¹H NMR (400 MHz, DMSO-d₆) δ To a cooled (−78 °C) solution of appropriate amines 12a–c

12.63 (br s, 1H), 7.84 (s, 1H), 7.23 (s, 1H), 6.95 (d, 1H, J = 12.2 (1.0 mmol, 1.0 equiv.) in anhydrous MeOH (16 mL) was added

Hz), 6.14 (d, 1H, J = 12.2 Hz), 3.81 (s, 3H); ¹³C NMR (100 MHz, CF₃CO₂Et (1.0 mmol, 1.0 equiv.) dropwise over a period of

DMSO-d₆) δ 166.4, 154.2, 139.6, 136.2, 134.8, 123.9, 114.3, 10 min and stirred for 30 min at the same temperature. The

112.9, 111.3, 56.4; IR (neat) 2919, 2849, 1695, 1432, 1366, 1248, reaction solution was slowly allowed to warm to 0 °C. Then a

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solution of Boc₂O (1.5 mmol, 1.5 equiv.) in MeOH (4 mL) was with brine, dried over Na₂SO₄and concentrated. The residue

added dropwise at 0 °C. The resulting reaction solution was was purified by silica gel column chromatography

allowed to warm to room temperature and stirred for 10–15 h. (3 : 96 : 1–10 : 89 : 1 MeOH–CH₂Cl₂–25% aqueous NH₃) to get

Then K₂CO₃(5.0 mmol, 5.0 equiv.) and water (1.2 mL) were the amine product (4.8 g, 54%).

added, and then the reaction solution was refluxed for 2–3 h.

{6-[(3-Amino-propyl)-tert-butoxycarbonyl-amino]-hexyl}-

After that, all volatiles were removed under reduced pressure carbamic acid tert-butyl ester 14c. The product 14c was

1

and the residue was taken in water (10 mL) and extracted with obtained as a colorless viscous liquid (3.16 g, 56%); H NMR

CHCl₃(4 × 8 mL). The combined organic layers were washed (400 MHz, CDCl₃) δ 4.58 (br s, 1H), 3.26–3.06 (m, 6H), 2.94 (br

with brine, dried over Na₂SO₄and concentrated to get the Boc- s, 2H), 2.71 (br s, 2H), 1.69 (br s, 2H), 1.51–1.43 (m, 4H), 1.41

protected tetraamines 13a–c.

(s, 9H), 1.40 (s, 9H), 1.33–1.19 (m, 4H); ¹³C NMR (100 MHz,

(N¹,N⁴,N¹¹-Tri-tert-butyloxycarbonyl)-1,14-diamino-4,11-di- CDCl₃) δ 156.2, 156.0, 155.5, 79.6, 79.3, 79.0, 77.3, 47.0, 46.6,

azatetradecane 13c. The product 13c was obtained as a color- 44.4, 43.6, 41.7, 40.4, 39.3, 38.4, 32.3, 30.3, 30.0, 28.43, 28.41,

less viscous liquid (1.14 g, 57%); ¹H NMR (400 MHz, CDCl₃) 28.0, 26.5; IR (neat) 3350, 2974, 2930, 2861, 1678, 1365, 1248,

δ 5.30 and 4.75 (br s, 1H), 3.23–3.08 (m, 10H), 2.72–2.68 1162, 871, 734 cm⁻¹; HRMS (APCI) calcd for C₁₉H₄₀N₃O₄(M +

(m, 2H), 2.38 (br s, 2H), 1.72–1.58 (m, 4H), 1.52–1.42 (m, 31H), H), 374.3019; found, 374.3019.

1.28–1.23 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 156.1, 155.5,

79.4, 78.9, 77.3, 50.4, 46.9, 44.1, 43.6, 39.4, 38.7, 37.4, 32.4,

General procedure for amide synthesis

30.9, 28.4, 28.3, 28.2, 26.6; IR (neat) 3356, 2975, 2931, 1678, To a cooled (0 °C) solution of an appropriate α,β-unsaturated

1417, 1249, 1156, 733 cm⁻¹; HRMS (ESI) calcd for C₂₇H₅₅N₄O₆carboxylic acid (0.42 mmol) in anhydrous CH₂Cl₂(1.5 mL)

(M + H), 531.4122; found, 531.4123.

were added EDC·HCl (85 mg, 0.44 mmol) and HOBT (62 mg,

0.46 mmol). The resulting solution was stirred at 0 °C for

10 min, and then a solution of amine (0.2 mmol) in anhydrous

CH₂Cl₂(1.5 mL) was added at 0 °C. The reaction solution was

General procedure for the synthesis of Boc-protected triamines

14a–c

To a cooled (0 °C) solution of an appropriate diamine allowed to warm to room temperature and stirred at room

(34.9 mmol, 1.1 equiv.) in anhydrous MeOH (25 mL) was temperature until complete consumption of the starting material

added acrylonitrile (1.69 g, 31.8 mmol, 1.0 equiv.) dropwise (monitored by TLC). CH₂Cl₂(20 mL) was added and washed

over a period of 2 h. The resulting reaction solution was with saturated aqueous NaHCO₃solution (3 mL), water (3 mL),

allowed to warm to room temperature and stirred for 22–24 h and brine (5 mL), dried over Na₂SO₄and concentrated. The

at room temperature. All volatiles were removed under reduced residue was purified by silica gel column chromatography

pressure and the residue was co-evaporated with anhydrous (30–80% EtOAc–hexane) to get the coupled product.

toluene (3 × 25 mL).

Boc deprotection of the coupled product

In the case of 1,3-diaminopropane, all volatiles were

removed under reduced pressure and the residue was purified To a cooled (0 °C) solution of the coupled product (obtained

by silica gel column chromatography (10–50% MeOH–CHCl₃) above) in anhydrous CH₂Cl₂(10 mL) was added TFA (1 mL).

to get both side Michael addition products (618 mg, 36%) and The resulting solution was allowed to warm to room tempera-

(10 : 90 : 1–40 : 60 : 1 MeOH–CHCl₃–25% aqueous NH₃) to get ture until complete consumption of the starting material (∼1–3 h,

one side Michael addition product (1.36 g, 57%).

monitored by TLC). All volatiles were removed under reduced

To a cooled (0 °C) solution of the above obtained one side pressure till dryness and then it was co-evaporated with

Michael addition product (1.0 equiv.) in anhydrous CH₂Cl₂CH₂Cl₂(3 × 15 mL) to get the white amorphous solid or the

(50 mL) was added Boc₂O (13.0 g, 24.7 mmol, 2.1 equiv.) in residue was purified by silica gel column chromatography

portions. The resulting solution was stirred for 10 min and (MeOH–CH₂Cl₂–TFA, 30 : 70 : 1–60 : 40 : 1).

then ice was removed. i-Pr₂NEt (11.0 mL, 25.8 mmol,

Ianthelliformisamine A (1) tris-TFA salt

2.2 equiv.) was added dropwise over 1 h and then the reaction

mixture was stirred for 24 h at room temperature. All volatiles The product 1 was obtained as a white solid (118.2 mg, 68% in

1

were removed under reduced pressure and the residue was pur- two steps); Mp 206–209 °C (decomposed); H NMR (400 MHz,

ified by silica gel column chromatography (30–60% EtOAc– DMSO-d₆) δ 8.89 (br s, 2H), 8.74 (br s, 2H), 8.36 (t, 1H, J =

hexane) to get the Boc-protected compound.

5.7 Hz), 8.02 (br s, 3H), 7.88 (s, 2H), 7.35 (d, 1H, J = 15.8 Hz),

To a cooled (0 °C) suspension of LiAlH₄(3.5 g, 93.0 mmol, 6.68 (d, 1H, J = 15.8 Hz), 3.81 (s, 3H), 3.25 (q, 2H, J = 6.3 Hz),

3.6 equiv.) in anhydrous Et₂O (400 mL) was added a solution 2.98–2.92 (m, 10H), 1.90 (quintet, 2H, J = 7.6 Hz), 1.80

of the above obtained Boc-protected compound (8.8 g, (quintet, 2H, J = 7.1 Hz), 1.69–1.57 (m, 4H); ¹³C NMR

25.8 mmol, 1.0 equiv.) in anhydrous Et₂O (115 mL) dropwise (100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.3, 134.3, 131.5, 124.2,

via cannula. The resulting reaction solution was allowed to 118.0, 60.5, 46.1, 46.0, 44.6, 43.8, 36.1, 35.9, 25.9, 23.7, 22.6,

warm to room temperature and stirred for 7–16 h at room 22.6; IR (neat) 3051, 2928, 2854, 1664, 1472, 1192, 1131, 978,

temperature. The reaction was quenched by the dropwise 720 cm⁻¹; HRMS (APCI) calcd for C₂₀H₃₃Br₂N₄O₂(M + H −

addition of NaOH (1.0 N aq. solution, 50 mL) at 0 °C, and then 3TFA), 519.0970; found, 519.0955. HPLC purity 97.3%, RT =

it was filtered through a celite pad. The filtrate was washed 15.100 min.

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Ianthelliformisamine B (2) bis-TFA salt

17. The product 17 was obtained as a white solid (301.4 mg,

89% in two steps); Mp 214–217 °C (decomposed); ¹H NMR

(400 MHz, DMSO-d₆) δ 9.01 (br s, 2H), 8.87 (br s, 2H), 8.38 (t,

1H, J = 5.7 Hz), 8.04 (br s, 3H), 7.88 (s, 2H), 7.35 (d, 1H, J =

15.8 Hz), 6.68 (d, 1H, J = 15.8 Hz), 3.81 (s, 3H), 3.28–3.23 (m,

2H), 2.99–2.90 (m, 10H), 1.97–1.89 (m, 4H); 1.82–1.78 (m, 2H);

¹³C NMR (100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.3, 134.3,

131.5, 124.2, 118.0, 60.5, 44.8, 44.0, 43.9, 36.1, 35.9, 27.9, 25.9,

23.8, 22.4; IR (neat) 3071, 2862, 1665, 1616, 1421, 1196, 1127,

987, 720 cm⁻¹; HRMS (ESI) calcd for C₁₉H₃₁Br₂N₄O₂(M + H −

3TFA), 505.0814; found, 505.0812. HPLC purity 100%, RT =

16.045 min.

The product 2 was obtained as a colorless oil (114 mg, 74% in

two steps); ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (br s, 2H), 8.36

(t, 1H, J = 5.8 Hz), 7.91 (br s, 3H), 7.89 (s, 2H), 7.36 (d, 1H, J =

15.8 Hz), 6.69 (d, 1H, J = 15.8 Hz), 3.82 (s, 3H), 3.25 (q, 2H, J =

6.4 Hz), 2.93 (m, 4H), 2.85–2.80 (m, 2H), 1.84–1.77 (m, 2H),

1.62–1.60 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.8,

153.9, 135.4, 134.3, 131.5, 124.1, 118.0, 60.5, 46.0, 44.6, 38.2,

35.9, 25.9, 24.1, 22.5; IR (neat) 3390, 3068, 1671, 1425, 1182,

1135, 979, 723 cm⁻¹; HRMS (ESI) calcd for C₁₇H₂₆Br₂N₃O₂

(M + H − 2TFA), 462.0392; found, 462.0381. HPLC purity

100%, RT = 14.948 min.

(E)-N-(3-(3-(3-Aminopropylamino)propylamino)propyl)-3-(2,3,

4-tribromo-5-methoxyphenyl)acrylamide tris trifluoroacetate

18. The product 18 was obtained as a white solid (136.5 mg,

Ianthelliformisamine C (3) bis-TFA salt

The product 3 was obtained as a colorless oil (199.3 mg, 75% 74% in two steps); Mp 210–214 °C (decomposed); ¹H NMR

1

in two steps); H NMR (400 MHz, DMSO-d₆) δ 8.78 (br s, 4H), (400 MHz, DMSO-d₆) δ 8.97 (br s, 2H), 8.83 (br s, 2H), 8.62 (t,

8.40 (t, 2H, J = 5.8 Hz), 7.89 (s, 4H), 7.35 (d, 2H, J = 15.8 Hz), 1H, J = 5.7 Hz), 8.01 (br s, 3H), 7.68 (d, 1H, J = 15.6 Hz), 7.36

6.69 (d, 2H, J = 15.8 Hz), 3.81 (s, 6H), 3.25 (q, 4H, J = 6.4 Hz), (s, 1H), 6.80 (d, 1H, J = 15.5 Hz), 3.94 (s, 3H), 3.30–3.25 (m,

2.94 (m, 8H), 1.84–1.77 (m, 4H), 1.65 (m, 4H); ¹³C NMR 2H), 2.99–2.88 (m, 10H), 1.97–1.88 (m, 4H); 1.83–1.80 (m, 2H);

(100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.3, 134.3, 131.5, 124.2, ¹³C NMR (100 MHz, DMSO-d₆) δ 164.5, 156.0, 137.6, 136.6,

118.0, 60.5, 46.0, 44.6, 35.9, 25.9, 22.6; IR (neat) 3372, 3041, 129.1, 127.2, 117.7, 116.2, 109.5, 57.0, 44.8, 44.0, 43.9, 36.1,

2830, 1667, 1439, 1179, 1127, 977, 722 cm⁻¹; HRMS (APCI) 36.0, 25.9, 23.8, 22.4; IR (neat) 3074, 2942, 2869, 1667, 1422,

calcd for C₃₀H₃₉Br₄N₄O₄(M + H − 2TFA), 834.9705; found, 1367, 1197, 1161, 1132, 835, 721 cm⁻¹; HRMS (APCI) calcd for

834.9711. HPLC purity 100%, RT = 15.375 min.

C₁₉H₃₀Br₃N₄O₂(M + H − 3TFA), 582.9919; found, 582.9893.

(E)-N-(3-(4-(3-Aminopropylamino)butylamino)propyl)-3-(2,3,4- HPLC purity 98.1%, RT = 15.204 min.

tribromo-5-methoxyphenyl)acrylamide tris trifluoroacetate

(E)-N-(3-(3-(3-Aminopropylamino)propylamino)propyl)-3-(2,4,6-

15. The product 15 was obtained as a white solid (131.4 mg, tribromo-3-methoxyphenyl)acrylamide

tris

trifluoroacetate

70% in two steps); Mp 214–218 °C (decomposed); ¹H NMR 19. The product 19 was obtained as a white solid (126.5 mg,

(400 MHz, DMSO-d₆) δ 8.90 (br s, 2H), 8.75 (br s, 2H), 8.64 (t, 68% in two steps); Mp 228–231 °C (decomposed); ¹H NMR

1H, J = 5.4 Hz), 8.03 (br s, 3H), 7.68 (d, 1H, J = 15.6 Hz), 7.37 (400 MHz, DMSO-d₆) δ 8.98 (br s, 2H), 8.85 (br s, 2H), 8.60 (t,

(s, 1H), 6.82 (d, 1H, J = 15.6 Hz), 3.94 (s, 3H), 3.27 (q, 2H, J = 1H, J = 5.6 Hz), 8.11 (s, 1H), 8.02 (br s, 3H), 7.29 (d, 1H, J =

6.2 Hz), 2.93 (m, 10H), 1.90 (quintet, 2H, J = 7.6 Hz), 1.80 16.0 Hz), 6.45 (d, 1H, J = 16.0 Hz), 3.81 (s, 3H), 3.27 (q, 2H, J =

(quintet, 2H, J = 7.1 Hz), 1.64 (m, 4H); ¹³C NMR (100 MHz, 6.4 Hz), 3.00–2.89 (m, 10H), 2.00–1.87 (m, 4H); 1.86–1.79 (m,

DMSO-d₆) δ 164.5, 156.0, 137.6, 136.6, 129.1, 127.2, 117.7, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.9, 153.6, 137.2,

116.2, 109.5, 57.0, 46.1, 46.0, 44.7, 43.8, 36.1, 36.0, 25.9, 23.7, 136.5, 135.6, 130.3, 119.8, 117.9, 117.4, 60.3, 44.8, 44.0, 43.9,

22.6, 22.6; IR (neat) 3044, 2873, 1671, 1414, 1196, 1139, 837, 36.1, 25.9, 23.8, 22.4; IR (neat) 3071, 2942, 2877, 1665, 1418,

721 cm⁻¹; HRMS (APCI) calcd for C₂₀H₃₂Br₃N₄O₂(M + H − 1195, 1163, 835, 721 cm⁻¹

3TFA), 597.0075; found, 597.0060. HPLC purity 99.6%, RT = C₁₉H₃₀Br₃N₄O₂(M + H − 3TFA), 582.9919; found, 582.9902.

;

HRMS (ESI) calcd for

14.833 min.

HPLC purity 97.0%, RT = 15.426 min.

(E)-N-(3-(4-(3-Aminopropylamino)butylamino)propyl)-3-(2,4,6-

(E)-N-(3-(3-(3-Aminopropylamino)propylamino)propyl)-3-(2,4-

tribromo-3-methoxyphenyl)acrylamide tris trifluoroacetate dibromo-5-methoxyphenyl)acrylamide tris trifluoroacetate

16. The product 16 was obtained as a white solid (137.3 mg, 20. The product 20 was obtained as a white solid (119.8 mg,

73% in two steps); Mp 218–221 °C (decomposed); ¹H NMR 71% in two steps); Mp 219–223 °C (decomposed); ¹H NMR

(400 MHz, DMSO-d₆) δ 8.58 (t, 1H, J = 5.7 Hz), 8.45 (br s, 6H), (400 MHz, DMSO-d₆) δ 8.97 (br s, 2H), 8.83 (br s, 2H), 8.59 (t,

8.10 (s, 1H), 7.28 (d, 1H, J = 16.0 Hz), 6.44 (d, 1H, J = 15.9 Hz), 1H, J = 5.7 Hz), 8.02 (br s, 3H), 7.92 (s, 1H), 7.60 (d, 1H, J =

3.81 (s, 3H), 3.29–3.26 (m, 2H), 2.98–2.87 (m, 10H), 1.90 15.6 Hz), 7.37 (s, 1H), 6.85 (d, 1H, J = 15.6 Hz), 3.92 (s, 3H),

(quintet, 2H, J = 7.6 Hz), 1.80 (quintet, 2H, J = 7.1 Hz), 1.64 (m, 3.27 (q, 2H, J = 6.4 Hz), 3.00–2.87 (m, 10H), 1.98–1.89 (m, 4H);

4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.9, 153.6, 137.2, 1.84–1.80 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.7,

136.5, 135.6, 130.3, 119.8, 117.8, 117.4, 60.3, 46.0, 46.0, 44.7, 155.2, 136.0, 135.9, 134.8, 126.1, 114.8, 112.8, 110.5, 56.5, 44.8,

43.8, 36.1, 25.8, 23.8, 22.6, 22.5; IR (neat) 3067, 2850, 1670, 44.0, 43.9, 36.1, 36.0, 27.9, 25.9, 23.8, 22.4; IR (neat) 3068,

1418, 1197, 1131, 835, 721 cm⁻¹; HRMS (ESI) calcd for 2876, 1666, 1465, 1195, 1128, 835, 720 cm⁻¹; HRMS (ESI) calcd

C₂₀H₃₂Br₃N₄O₂(M + H − 3TFA), 597.0075; found, 597.0053. for C₁₉H₃₁Br₂N₄O₂(M + H − 3TFA), 505.0814; found, 505.0813.

HPLC purity 99.5%, RT = 14.788 min.

HPLC purity 99.9%, RT = 15.222 min.

(E)-N-(3-(3-(3-Aminopropylamino)propylamino)propyl)-3-

(Z)-N-(3-(3-(3-Aminopropylamino)propylamino)propyl)-3-

(3,5-dibromo-4-methoxyphenyl)acrylamide tris trifluoroacetate (2,4-dibromo-5-methoxyphenyl)acrylamide tris trifluoroacetate

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21. The product 21 was obtained as a white solid (122.1 mg, 1055, 836, 721 cm⁻¹; HRMS (ESI) calcd for C₂₂H₃₆Br₃N₄O₂(M

72% in two steps); Mp 220–223 °C (decomposed); ¹H NMR + H − 3TFA), 625.0388; found, 625.0360. HPLC purity 99.6%,

(400 MHz, DMSO-d₆) δ 8.81 (br s, 4H), 8.42 (t, 1H, J = 5.6 Hz), RT = 14.389 min.

8.03 (br s, 3H), 7.81 (s, 1H), 7.36 (s, 1H), 6.74 (d, 1H, J =

N-(3-(6-(3-Aminopropylamino)hexylamino)propyl)-3-(2,4-

12.2 Hz), 6.20 (d, 1H, J = 12.2 Hz), 3.79 (s, 3H), 3.14 (q, 2H, J = dibromo-5-methoxyphenyl)acrylamide tris trifluoroacetate 25.

6.4 Hz), 3.00–2.94 (m, 6H), 2.88 (t, 4H, J = 7.3 Hz), 1.95–1.89 The product 25 was obtained along with the Z-isomer (E : Z

(m, 4H); 1.76–1.72 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) ratio 9 : 1) as a white solid (120.3 mg, 68% in two steps); Mp

δ 164.9, 154.0, 136.3, 135.4, 134.7, 126.4, 114.5, 113.4, 110.9, 184–187 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (br s, 2H),

56.3, 44.8, 44.0, 43.9, 36.1, 35.7, 25.8, 23.8, 22.4; IR (neat) 8.68 (br s, 2H), 8.61 and 8.45 (each t, 1H, J = 5.6 Hz), 8.04 (br s,

3078, 2851, 1669, 1422, 1197, 1164, 835, 721 cm⁻¹; HRMS (ESI) 3H), 7.92 and 7.81 (each s, 1H), 7.60 and 6.75 (each d, 1H, J =

calcd for C₁₉H₃₁Br₂N₄O₂(M + H − 3TFA), 505.0814; found, 15.6 Hz and 12.2 Hz), 7.38 and 7.34 (each s, 1H), 6.87 and 6.20

505.0814. HPLC purity 99.8%, RT = 15.262 min.

(each d, 1H, J = 15.6 Hz and 12. 2 Hz), 3.93 and 3.79 (each s,

(E)-N-(3-(6-(3-Aminopropylamino)hexylamino)propyl)-3-(3,5- 3H), 3.27 and 3.14 (each q, 2H, J = 5.9 Hz), 2.98–2.89 (m, 10H),

dibromo-4-methoxyphenyl)acrylamide tris trifluoroacetate 1.90 (quintet, 2H, J = 7.6 Hz); 1.81 and 1.73 (each m, 2H), 1.58

22. The product 22 was obtained as a white solid (292.4 mg, (m, 4H), 1.32 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 165.0,

82% in two steps); Mp 157–160 °C; ¹H NMR (400 MHz, DMSO- 164.7, 155.2, 154.1, 136.0, 135.9, 134.8, 126.1, 114.8, 112.8,

d₆) δ 8.81 (br s, 2H), 8.65 (br s, 2H), 8.36 (t, 1H, J = 5.7 Hz), 110.6, 56.5, 56.4, 46.6, 44.7, 43.8, 36.1, 36.0, 25.9, 25.5, 25.3,

8.05 (br s, 3H), 7.88 (s, 2H), 7.35 (d, 1H, J = 15.8 Hz), 6.68 (d, 25.2, 23.7; IR (neat) 3064, 2937, 2866, 1667, 1467, 1193, 1056,

1H, J = 15.8 Hz), 3.81 (s, 3H), 3.27–3.22 (m, 2H), 2.98–2.88 (m, 835, 720 cm⁻¹; HRMS (ESI) calcd for C₂₂H₃₇Br₂N₄O₂(M + H −

10H), 1.94–1.88 (m, 2H); 1.81–1.77 (m, 2H), 1.57 (m, 4H), 1.31 3TFA), 547.1283; found, 547.1248. HPLC purity 100%, RT =

(m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.3, 15.148 min.

134.3, 131.5, 124.2, 118.0, 60.5, 46.6, 44.7, 43.8, 36.1, 35.9,

(Z)-N-(3-(6-(3-Aminopropylamino)hexylamino)propyl)-3-(2,4-

25.9, 25.4, 25.3, 25.2, 23.7; IR (neat) 3048, 2935, 2866, 1687, dibromo-5-methoxyphenyl)acrylamide tris trifluoroacetate 26.

1420, 1195, 1138, 834, 720 cm⁻¹; HRMS (APCI) calcd for The product 26 was obtained as a white solid (117.2 mg, 66%

1

C₂₂H₃₇Br₂N₄O₂(M + H − 3TFA), 547.1283; found, 547.1272. in two steps); Mp 157–160 °C; H NMR (400 MHz, DMSO-d₆) δ

HPLC purity 99.3%, RT = 15.051 min.

8.88 (br s, 2H), 8.68 (br s, 2H), 8.47 (t, 1H, J = 5.6 Hz), 8.07 (br

N-(3-(6-(3-Aminopropylamino)hexylamino)propyl)-3-(2,3,4-tri- s, 3H), 7.82 (s, 1H), 7.35 (s, 1H), 6.75 (d, 1H, J = 12.2 Hz), 6.21

bromo-5-methoxyphenyl)acrylamide tris trifluoroacetate 23. (d, 1H, J = 12.3 Hz), 3.80 (s, 3H), 3.14 (q, 2H, J = 6.4 Hz),

The product 23 was obtained along with the Z-isomer (E : Z 2.99–2.87 (m, 10H), 1.96–1.88 (m, 2H); 1.77–1.70 (m, 2H),

ratio 5 : 1) as a white solid (155 mg, 80% in two steps); Mp 1.58–1.55 (m, 4H), 1.30 (m, 4H); ¹³C NMR (100 MHz, DMSO-

197–200 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (br s, 2H), d₆) δ 165.0, 154.1, 136.5, 135.6, 134.7, 126.4, 114.5, 113.4,

8.60 and 8.45 (m and t, respectively, 3H, J = 5.4 Hz for t), 7.99 110.8, 56.4, 46.6, 44.6, 43.8, 36.1, 35.6, 25.8, 25.5, 25.3, 25.2,

(br s, 3H), 7.68 and 6.82 (each d, 1H, J = 15.7 Hz and 11.9 Hz), 23.7; IR (neat) 3065, 2937, 2867, 1667, 1471, 1194, 1056, 835,

7.37 and 7.19 (each s, 1H), 6.80 and 6.18 (each d, 1H, J = 15.6 720 cm⁻¹; HRMS (ESI) calcd for C₂₂H₃₇Br₂N₄O₂(M + H −

Hz and 11.7 Hz), 3.94 and 3.81 (each s, 3H), 3.27 and 3.13 3TFA), 547.1283; found, 547.1281. HPLC purity 100%, RT =

(each q, 2H, J = 6.4 Hz), 2.97–2.86 (m, 10H), 1.90 (quintet, 2H, 15.037 min.

J = 7.6 Hz); 1.81 and 1.71 (each quintet, 2H, J = 7.1 Hz and

(E)-N-(3-(4-Aminobutylamino)propyl)-3-(2,3,4-tribromo-

7.0 Hz); 1.57 (m, 4H), 1.31 (m, 4H); ¹³C NMR (100 MHz, 5-methoxyphenyl)acrylamide bis trifluoroacetate 27. The

DMSO-d₆) δ 164.7, 164.5, 156.0, 155.1, 138.7, 137.6, 137.4, product 27 was obtained as a white sticky solid (106.8 mg, 85%

1

136.6, 129.1, 127.6, 127.2, 126.1, 117.7, 116.2, 109.6, 57.0, 56.9, in two steps); H NMR (400 MHz, DMSO-d₆) δ 8.72 (br s, 2H),

46.6, 44.7, 43.8, 36.1, 36.0, 25.9, 25.5, 25.3, 25.2, 23.7; IR (neat) 8.64 (t, 1H, J = 5.9 Hz), 7.94 (br s, 3H), 7.68 (d, 1H, J = 15.6 Hz),

3325, 3062, 2935, 2843, 1658, 1458, 1190, 1137, 837, 707 cm⁻¹

;

7.37 (s, 1H), 6.82 (d, 1H, J = 15.6 Hz), 3.94 (s, 3H), 3.29–3.24

HRMS (ESI) calcd for C₂₂H₃₆Br₃N₄O₂(M + H − 3TFA), (m, 2H), 2.93 (m, 4H), 2.84–2.79 (m, 2H), 1.85–1.77 (m, 2H),

625.0388; found, 625.0360. HPLC purity 99.3%, RT

=

1.61 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.5, 156.0,

15.033 min.

137.6, 136.6, 129.1, 127.2, 117.7, 116.2, 109.5, 57.0, 46.0, 44.6,

(E)-N-(3-(6-(3-Aminopropylamino)hexylamino)propyl)-3-(2,4,6- 38.1, 36.0, 25.9, 24.1, 22.5; IR (neat) 3395, 1661, 1048, 993,

tribromo-3-methoxyphenyl)acrylamide tris trifluoroacetate 24. 762 cm⁻¹; HRMS (ESI) calcd for C₁₇H₂₅Br₃N₃O₂(M + H −

The product 24 was obtained as a white solid (140.8 mg, 73% 2TFA), 539.9497; found, 539.9493. HPLC purity 100%, RT =

1

in two steps); Mp 190–194 °C; H NMR (400 MHz, DMSO-d₆) 14.856 min.

δ 8.59 (t, 1H, J = 5.6 Hz), 8.52 (br s, 7H), 8.11 (s, 1H), 7.28 (d,

(Z)-N-(3-(4-Aminobutylamino)propyl)-3-(2,3,4-tribromo-

1H, J = 16.0 Hz), 6.45 (d, 1H, J = 16.0 Hz), 3.81 (s, 3H), 3.26 (q, 5-methoxyphenyl)acrylamide bis trifluoroacetate 28. The

2H, J = 6.4 Hz), 3.01–2.86 (m, 10H), 1.95–1.87 (m, 2H); product 28 was obtained as a white solid (60.1 mg, 78% in two

1.86–1.80 (m, 2H), 1.58 (m, 4H), 1.32 (m, 4H); ¹³C NMR steps); Mp 138–140 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.70

(100 MHz, DMSO-d₆) δ 163.9, 153.6, 137.3, 136.5, 135.6, 130.4, (br s, 2H), 8.46 (t, 1H, J = 5.6 Hz), 7.95 (br s, 3H), 7.20 (s, 1H),

119.8, 117.9, 117.4, 60.3, 46.6, 46.6, 44.7, 43.8, 36.1, 25.8, 25.5, 6.81 (d, 1H, J = 12.2 Hz), 6.18 (d, 1H, J = 12.2 Hz), 3.81 (s, 3H),

25.3, 25.2, 23.7; IR (neat) 3260, 2940, 2849, 1672, 1471, 1198, 3.14–3.09 (m, 2H), 2.87–2.79 (m, 6H), 1.75–1.68 (m, 2H),

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1.59–1.57 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.6, 23.8; IR (neat) 3037, 2930, 1666, 1264, 1166, 1132, 975,

155.0, 138.6, 137.2, 127.6, 126.2, 115.9, 114.1, 113.0, 56.9, 46.1, 721 cm⁻¹; HRMS (APCI) calcd for C₁₆H₂₄Br₂N₃O₂(M + H −

44.6, 38.2, 35.7, 25.9, 24.1, 22.5; IR (neat) 3289, 3027, 2841, 2TFA), 448.0235; found, 448.0237. HPLC purity 100%, RT =

1670, 1558, 1186, 1129, 841, 722 cm⁻¹; HRMS (APCI) calcd for 14.913 min.

C₁₇H₂₅Br₃N₃O₂(M + H − 2TFA), 539.9497; found, 539.9500.

HPLC purity 100%, RT = 15.230 min.

(E)-N-(3-(3-Aminopropylamino)propyl)-3-(2,3,4-tribromo-5-

methoxyphenyl)acrylamide bis trifluoroacetate 33. The

(E)-N-(3-(4-Aminobutylamino)propyl)-3-(2,4,6-tribromo-3- product 33 was obtained as a white solid (135.5 mg, 90% in

methoxyphenyl)acrylamide bis trifluoroacetate 29. The two steps); Mp 170–173 °C; ¹H NMR (400 MHz, DMSO-d₆) δ

product 29 was obtained as a white solid (134.3 mg, 78% in 8.76 (br s, 2H), 8.61 (t, 1H, J = 5.6 Hz), 7.98 (br s, 3H), 7.68 (d,

two steps); Mp 182–185 °C; ¹H NMR (400 MHz, DMSO-d₆) 1H, J = 15.6 Hz), 7.36 (s, 1H), 6.80 (d, 1H, J = 15.6 Hz), 3.94 (s,

δ 8.75 (br s, 2H), 8.61 (t, 1H, J = 5.7 Hz), 8.10 (s, 1H), 7.96 (br s, 3H), 3.27 (q, 2H, J = 6.4 Hz), 3.00–2.87 (m, 6H), 1.94–1.86 (m,

3H), 7.28 (d, 1H, J = 15.9 Hz), 6.44 (d, 1H, J = 16.0 Hz), 3.80 (s, 2H), 1.83–1.78 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.5,

3H), 3.26 (q, 2H, J = 6.4 Hz), 2.93 (m, 4H), 2.82–2.81 (m, 2H), 156.0, 137.6, 136.6, 129.1, 127.2, 117.7, 116.2, 109.5, 57.0, 44.8,

1.85–1.78 (m, 2H), 1.61 (m, 4H); ¹³C NMR (100 MHz, DMSO- 43.9, 36.1, 36.0, 25.9, 23.8; IR (neat) 3038, 2848, 1670, 1568,

d₆) δ 163.9, 153.6, 137.3, 136.5, 135.6, 130.3, 119.8, 117.9, 1368, 1139, 969, 723 cm⁻¹

117.4, 60.3, 46.0, 44.6, 38.1, 36.1, 25.8, 24.1, 22.5; IR (neat) C₁₆H₂₃Br₃N₃O₂(M + H − 2TFA), 525.9340; found, 525.9339.

3419, 3235, 3066, 2879, 1662, 1352, 1174, 1044, 949, 718 cm⁻¹

HPLC purity 97.3%, RT = 15.100 min. HPLC purity 100%, RT =

HRMS (ESI) calcd for C₁₇H₂₅Br₃N₃O₂(M + H − 2TFA), 14.825 min.

; HRMS (APCI) calcd for

;

539.9497; found, 539.9487. HPLC purity 99.5%, RT

=

(E)-N-(3-(3-Aminopropylamino)propyl)-3-(2,4,6-tribromo-3-

15.376 min.

methoxyphenyl)acrylamide bis trifluoroacetate 34. The

(E)-N-(3-(4-Aminobutylamino)propyl)-3-(2,4-dibromo-5-meth- product 34 was obtained as a white solid (284.9 mg, 94% in

1

oxyphenyl)acrylamide bis trifluoroacetate 30. The product 30 two steps); Mp 208–210 °C (decomposed); H NMR (400 MHz,

was obtained as a white sticky solid (129.5 mg, 84% in two DMSO-d₆) δ 8.77 (br s, 2H), 8.59 (t, 1H, J = 5.6 Hz), 8.10 (s, 1H),

1

steps); H NMR (400 MHz, DMSO-d₆) δ 8.75 (br s, 2H), 8.62 (t, 7.99 (br s, 3H), 7.28 (d, 1H, J = 16.1 Hz), 6.44 (d, 1H, J =

1H, J = 5.7 Hz), 7.96 (br s, 3H), 7.91 (s, 1H), 7.60 (d, 1H, J = 16.1 Hz), 3.81 (s, 3H), 3.29–3.24 (m, 2H), 3.00–2.89 (m, 6H),

15.6 Hz), 7.38 (s, 1H), 6.88 (d, 1H, J = 15.6 Hz), 3.92 (s, 3H), 1.93–1.86 (m, 2H), 1.85–1.79 (m, 2H); ¹³C NMR (100 MHz,

3.27 (q, 2H, J = 6.3 Hz), 2.94 (m, 4H), 2.85–2.80 (m, 2H), DMSO-d₆) δ 163.9, 153.6, 137.2, 136.5, 135.6, 130.3, 119.8,

1.86–1.79 (m, 2H), 1.66–1.59 (m, 4H); ¹³C NMR (100 MHz, 117.9, 117.4, 60.3, 44.8, 43.9, 36.1, 36.1, 25.9, 23.8; IR (neat)

DMSO-d₆) δ 164.7, 155.2, 136.0, 135.9, 134.8, 126.1, 114.8, 3062, 2932, 1671, 1351, 1173, 1131, 968, 720 cm⁻¹; HRMS

112.8, 110.6, 56.5, 46.0, 44.7, 38.1, 36.0, 25.9, 24.1, 22.5; IR (APCI) calcd for C₁₆H₂₃Br₃N₃O₂(M + H − 2TFA), 525.9340;

(neat) 3276, 3029, 2850, 1673, 1468, 1179, 1129, 1056, 970, found, 525.9341. HPLC purity 99.6%, RT = 15.124 min.

723 cm⁻¹; HRMS (ESI) calcd for C₁₇H₂₆Br₂N₃O₂(M + H −

2TFA), 462.0392; found, 462.0381. HPLC purity 99.9%, RT = oxyphenyl)acrylamide bis trifluoroacetate 35. The product 35

14.924 min. was obtained along with the Z-isomer (E : Z ratio 18 : 1) as a

(E)-N-(3-(3-Aminopropylamino)propyl)-3-(2,4-dibromo-5-meth-

1

(Z)-N-(3-(4-Aminobutylamino)propyl)-3-(2,4-dibromo-5-meth- white solid (112.5 mg, 83% in two steps); Mp 174–177 °C; H

oxyphenyl)acrylamide bis trifluoroacetate 31. The product 31 NMR (400 MHz, DMSO-d₆) δ 8.76 (br s, 2H), 8.58 and 8.42

was obtained as a white solid (103.6 mg, 75% in two steps); (each t, 1H, J = 5.6 Hz), 7.99 (br s, 3H), 7.91 and 7.81 (each s,

Mp 114–117 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (br s, 1H), 7.59 and 6.74 (each d, 1H, J = 15.6 Hz and 12.2 Hz), 7.37

2H), 8.44 (t, 1H, J = 5.6 Hz), 7.95 (br s, 3H), 7.81 (s, 1H), 7.35 and 7.36 (each s, 1H), 6.85 and 6.20 (each d, 1H, J = 15.6 Hz

(s, 1H), 6.74 (d, 1H, J = 12.2 Hz), 6.20 (d, 1H, J = 12.2 Hz), 3.79 and 12.2 Hz), 3.92 and 3.79 (each s, 3H), 3.27 and 3.14 (each q,

(s, 3H), 3.16–3.11 (m, 2H), 2.87–2.80 (m, 6H), 1.77–1.70 (m, 2H, J = 6.4 Hz), 3.00–2.89 (m, 6H), 1.94–1.87 (m, 2H), 1.85–1.78

2H), 1.60–1.58 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.9, (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.7, 155.2, 136.0,

154.0, 136.4, 135.4, 134.7, 126.4, 114.5, 113.4, 110.9, 56.4, 46.0, 135.9, 134.8, 126.1, 114.8, 112.8, 110.6, 56.5, 44.8, 43.9, 36.1,

44.6, 38.1, 35.7, 25.8, 24.1, 22.5; IR (neat) 3399, 3064, 1672, 36.0, 25.9, 23.8; IR (neat) 3278, 3066, 2850, 1671, 1464, 1131,

1196, 1130, 838, 720 cm⁻¹

;

HRMS (ESI) calcd for 970, 722 cm⁻¹; HRMS (ESI) calcd for C₁₆H₂₄Br₂N₃O₂(M + H −

C₁₇H₂₆Br₂N₃O₂(M + H − 2TFA), 462.0392; found, 462.0366. 2TFA), 448.0235; found, 448.0218. HPLC purity 99.8%, RT =

HPLC purity 99.1%, RT = 15.198 min.

15.510 min.

(E)-N-(3-(3-Aminopropylamino)propyl)-3-(3,5-dibromo-4-meth-

(Z)-N-(3-(3-Aminopropylamino)propyl)-3-(2,4-dibromo-5-meth-

oxyphenyl)acrylamide bis trifluoroacetate 32. The product 32 oxyphenyl)acrylamide bis trifluoroacetate 36. The product 36

was obtained as a white solid (239 mg, 88% in two steps); Mp was obtained along with the E-isomer (Z : E ratio 15 : 1) as a

1

119–121 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (br s, 2H), white solid (111.6 mg, 83% in two steps); Mp 154–157 °C; H

8.38 (t, 1H, J = 5.6 Hz), 8.03 (br s, 3H), 7.88 (s, 2H), 7.35 (d, 1H, NMR (400 MHz, DMSO-d₆) δ 8.80 (br s, 2H), 8.44 and 8.61

J = 15.6 Hz), 6.68 (d, 1H, J = 15.6 Hz), 3.81 (s, 3H), 3.25 (q, 2H, (each t, 1H, J = 5.6 Hz), 8.03 (br s, 3H), 7.81 and 7.91 (each s,

J = 6.4 Hz), 3.00–2.91 (m, 6H), 1.94–1.86 (m, 2H), 1.83–1.76 (m, 1H), 7.36 and 7.37 (each s, 1H), 6.74 and 7.59 (each d, 1H, J =

2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.4, 12.2 Hz and 15.6 Hz), 6.20 and 6.86 (each d, 1H, J = 12.3 Hz

134.3, 131.5, 124.1, 118.0, 60.5, 44.8, 43.9, 36.1, 35.9, 25.9, and 15.7 Hz), 3.79 and 3.92 (each s, 3H), 3.14 and 3.27 (each q,

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2H, J = 6.4 Hz), 2.95–2.87 (m, 6H), 1.92–1.85 (m, 2H), 1.77–1.70 DMSO-d₆) δ 163.9, 153.7, 137.3, 136.5, 135.6, 130.4, 119.9,

(m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.9, 154.1, 136.3, 117.9, 117.4, 60.3, 46.6, 44.7, 38.6, 36.2, 26.8, 25.8, 25.5, 25.3,

135.4, 134.7, 126.4, 114.6, 113.4, 110.9, 56.4, 44.8, 43.9, 36.1, 25.3; IR (neat) 3397, 3078, 1673, 1444, 1202, 1133, 843,

35.7, 25.8, 23.8; IR (neat) 3264, 3065, 2848, 1671, 1467, 1169, 724 cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₉Br₃N₃O₂(M + H −

1056, 722 cm⁻¹; HRMS (ESI) calcd for C₁₆H₂₄Br₂N₃O₂(M + H − 2TFA), 567.9810; found, 567.9815. HPLC purity 99.7%, RT =

2TFA), 448.0235; found, 448.0220. HPLC purity 100%, RT = 14.937 min.

15.841 min.

(E)-N-(3-(6-Aminohexylamino)propyl)-3-(2,4-dibromo-5-meth-

(E)-N-(3-(6-Aminohexylamino)propyl)-3-(3,5-dibromo-4-meth- oxyphenyl)acrylamide bis trifluoroacetate 41. The product 41

oxyphenyl)acrylamide bis trifluoroacetate 37. The product 37 was obtained as a white solid (165.5 mg, 77% in two steps);

was obtained as a colorless oil (118.3 mg, 82% in two steps); Mp 128–130 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.58

¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (br s, 2H), 8.38 (t, 1H, J = (t merged with br s, 3H, J = 5.9 Hz), 7.91 (s, 1H), 7.84 (br s,

5.8 Hz), 7.89 (s, 5H, br s merged with s of aromatic H), 7.35 (d, 3H), 7.59 (d, 1H, J = 15.6 Hz), 7.36 (s, 1H), 6.84 (d, 1H, J =

1H, J = 15.7 Hz), 6.70 (d, 1H, J = 15.7 Hz), 3.82 (s, 3H), 3.26 (q, 15.6 Hz), 3.92 (s, 3H), 3.27 (q, 2H, J = 6.2 Hz), 2.92–2.90 (m,

2H, J = 6.4 Hz), 2.93–2.86 (m, 4H), 2.81–2.75 (m, 2H), 1.82–1.79 4H), 2.80–2.75 (m, 2H), 1.84–1.77 (m, 2H), 1.56–1.53 (m, 4H),

(m, 2H), 1.57–1.52 (m, 4H), 1.33–1.31 (m, 4H); ¹³C NMR 1.31 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.7, 155.2,

(100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.3, 134.3, 131.5, 124.2, 136.0, 135.9, 134.8, 126.1, 114.8, 112.8, 110.5, 56.5, 46.6, 44.7,

118.0, 60.5, 46.6, 44.7, 38.6, 35.9, 26.7, 25.9, 25.4, 25.3; IR 38.6, 36.0, 26.8, 25.9, 25.4, 25.3; IR (neat) 3255, 2939, 2852,

(neat) 2948, 2867, 1668, 1472, 1131, 977, 722 cm⁻¹; HRMS 1667, 1462, 1129, 1056, 836, 721 cm⁻¹; HRMS (ESI) calcd for

(ESI) calcd for C₁₉H₃₀Br₂N₃O₂(M + H − 2TFA), 490.0705; C₁₉H₃₀Br₂N₃O₂(M + H − 2TFA), 490.0705; found, 490.0703.

found, 490.0697. HPLC purity 100%, RT = 15.130 min.

HPLC purity 99.9%, RT = 15.030 min.

(E)-N-(3-(6-Aminohexylamino)propyl)-3-(2,3,4-tribromo-5-meth-

(Z)-N-(3-(6-Aminohexylamino)propyl)-3-(2,4-dibromo-5-meth-

oxyphenyl)acrylamide bis trifluoroacetate 38. The product 38 oxyphenyl)acrylamide bis trifluoroacetate 42. The product 42

was obtained as a white solid (105 mg, 66% in two steps); Mp was obtained as a white sticky solid (113.8 mg, 79% in two

1

98–100 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (t, 3H, J = steps); H NMR (400 MHz, DMSO-d₆) δ 8.64 (br s, 2H), 8.46 (t,

5.4 Hz), 7.85 (br s, 3H), 7.68 (d, 1H, J = 15.6 Hz), 7.37 (s, 1H), 1H, J = 5.6 Hz), 7.90 (br s, 3H), 7.81 (s, 1H), 7.34 (s, 1H), 6.75

6.80 (d, 1H, J = 15.7 Hz), 3.94 (s, 3H), 3.27 (q, 2H, J = 6.4 Hz), (d, 1H, J = 12.2 Hz), 6.20 (d, 1H, J = 12.2 Hz), 3.79 (s, 3H), 3.14

2.93–2.86 (m, 4H), 2.80–2.75 (m, 2H), 1.83–1.78 (m, 2H), (q, 2H, J = 6.4 Hz), 2.84–2.75 (m, 6H), 1.73 (quintet, 2H, J = 7.1

1.57–1.51 (m, 4H), 1.31 (m, 4H); ¹³C NMR (100 MHz, DMSO- Hz), 1.55–1.52 (m, 4H), 1.30–1.29 (m, 4H); ¹³C NMR (100 MHz,

d₆) δ 164.5, 156.1, 137.6, 136.6, 129.1, 127.2, 117.7, 116.2, DMSO-d₆) δ 165.0, 154.1, 136.5, 135.6, 134.7, 126.4, 114.5,

109.6, 57.0, 46.7, 44.7, 38.6, 36.1, 26.8, 25.9, 25.4, 25.3; IR 113.4, 110.8, 56.4, 46.6, 44.6, 38.6, 35.6, 26.8, 25.8, 25.4, 25.3,

(neat) 3335, 3057, 2965, 2860, 1691, 1542, 1361, 1182, 1128, 25.3; IR (neat) 3283, 2946, 2845, 1677, 1465, 1126, 1054, 840,

974, 799 cm⁻¹; HRMS (APCI) calcd for C₁₉H₂₉Br₃N₃O₂(M + H 722 cm⁻¹; HRMS (ESI) calcd for C₁₉H₃₀Br₂N₃O₂(M + H −

− 2TFA), 567.9810; found, 567.9824. HPLC purity 100%, RT = 2TFA), 490.0705; found, 490.0705. HPLC purity 100%, RT =

15.376 min.

15.115 min.

(Z)-N-(3-(6-Aminohexylamino)propyl)-3-(2,3,4-tribromo-5-meth-

(2E,2′E)-N,N′-(3,3′-(Butane-1,4-diylbis(azanediyl))bis(propane-

oxyphenyl)acrylamide bis trifluoroacetate 39. The product 39 3,1-diyl))bis(3-(2,3,4-tribromo-5-methoxyphenyl)acrylamide) bis

was obtained as a white sticky solid (50.2 mg, 63% in two trifluoroacetate 43. The product 43 was obtained as a white

1

steps); H NMR (400 MHz, DMSO-d₆) δ 8.67 (br s, 2H), 8.50 (t, sticky solid (103.6 mg, 85% in two steps); H NMR (400 MHz,

1H, J = 5.4 Hz), 7.92 (br s, 3H), 7.19 (s, 1H), 6.81 (d, 1H, J = DMSO-d₆) δ 8.76 (br s, 4H), 8.64 (t, 2H, J = 5.6 Hz), 7.68 (d, 2H,

11.7 Hz), 6.19 (d, 1H, J = 11.7 Hz), 3.81 (s, 3H), 3.12 (q, 2H, J = J = 15.7 Hz), 7.37 (s, 2H), 6.82 (d, 2H, J = 15.2 Hz), 3.94 (s, 6H),

6.4 Hz), 2.83–2.76 (m, 6H), 1.72 (quintet, 2H, J = 7.0 Hz), 1.52 3.28–3.26 (m, 4H), 2.94 (m, 8H), 1.83–1.80 (m, 4H), 1.64 (m,

(m, 4H), 1.29–1.28 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.5, 156.0, 137.6,

δ 164.7, 155.1, 138.7, 137.4, 127.6, 126.2, 115.8, 114.0, 113.0, 136.6, 129.1, 127.2, 117.7, 116.2, 109.5, 57.0, 46.0, 44.7, 36.0,

56.9, 47.0, 44.6, 38.6, 35.6, 26.8, 25.9, 25.4, 25.3, 25.3; IR (neat) 25.9, 22.6; IR (neat) 3403, 3068, 2848, 1667, 1413, 1193, 1129,

3416, 3055, 2942, 2866, 1670, 1435, 1194, 1131, 839, 721 cm⁻¹

;

835, 718 cm⁻¹; HRMS (ESI) calcd for C₃₀H₃₇Br₆N₄O₄(M + H −

HRMS (ESI) calcd for C₁₉H₂₉Br₃N₃O₂(M + H − 2TFA), 2TFA), 990.7915; found, 990.7904. HPLC purity 100%, RT =

567.9810; found, 567.9810. HPLC purity 99.7%, RT

15.214 min.

=

15.119 min.

(2Z,2′Z)-N,N′-(3,3′-(Butane-1,4-diylbis(azanediyl))bis(propane-

(E)-N-(3-(6-Aminohexylamino)propyl)-3-(2,4,6-tribromo-3-meth- 3,1-diyl))bis(3-(2,3,4-tribromo-5-methoxyphenyl)acrylamide) bis

oxyphenyl)acrylamide bis trifluoroacetate 40. The product 40 trifluoroacetate 44. The product 44 was obtained as a white

was obtained as a white sticky solid (117.8 mg, 74% in two solid (89.3 mg, 73% in two steps); Mp 160–162 °C; ¹H NMR

1

steps); H NMR (400 MHz, DMSO-d₆) δ 8.87 (br s, 2H), 8.67 (t, (400 MHz, DMSO-d₆) δ 8.79 (br s, 4H), 8.48 (t, 2H, J = 5.6 Hz),

1H, J = 5.6 Hz), 8.09 (s, 1H), 7.98 (br s, 3H), 7.27 (d, 1H, J = 7.19 (s, 2H), 6.80 (d, 2H, J = 12.2 Hz), 6.18 (d, 2H, J = 12.2 Hz),

16.1 Hz), 6.45 (d, 1H, J = 16.1 Hz), 3.80 (s, 3H), 3.26 (q, 2H, J = 3.80 (s, 6H), 3.12 (q, 4H, J = 6.4 Hz), 2.86 (m, 8H), 1.72

6.4 Hz), 2.91–2.89 (m, 4H), 2.79–2.74 (m, 2H), 1.86–1.79 (m, (quintet, 4H, J = 7.0 Hz), 1.59 (m, 4H); ¹³C NMR (100 MHz,

2H), 1.59–1.54 (m, 4H), 1.31 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.6, 155.1, 138.7, 137.3, 127.6, 126.2, 115.9,

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114.1, 113.1, 56.9, 46.1, 44.6, 35.7, 25.9, 22.6; IR (neat) 3264, calcd for C₂₉H₃₅Br₆N₄O₄(M + H − 2TFA), 976.7759; found,

3078, 2839, 1670, 1532, 1129, 1066, 842, 723 cm⁻¹; HRMS 976.7781. HPLC purity 99.0%, RT = 15.191 min.

(APCI) calcd for C₃₀H₃₇Br₆N₄O₄(M + H − 2TFA), 990.7915;

(2E,2′E)-N,N′-(3,3′-(Propane-1,3-diylbis(azanediyl))bis(propane-

found, 990.7933. HPLC purity 99.5%, RT = 15.137 min.

3,1-diyl))bis(3-(2,4,6-tribromo-3-methoxyphenyl)acrylamide) bis

(2E,2′E)-N,N′-(3,3′-(Butane-1,4-diylbis(azanediyl))bis(propane- trifluoroacetate 49. The product 49 was obtained as a white

3,1-diyl))bis(3-(2,4,6-tribromo-3-methoxyphenyl)acrylamide) bis solid (195.4 mg, 81% in two steps); Mp 222–224 °C (decom-

trifluoroacetate 45. The product 45 was obtained as a white posed); ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (br s, 4H), 8.60 (t,

solid (135.6 mg, 89% in two steps); Mp 190–193 °C (decom- 2H, J = 5.4 Hz), 8.09 (s, 2H), 7.28 (d, 2H, J = 16.1 Hz), 6.44 (d,

posed); ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (br s, 4H), 8.60 (t, 2H, J = 16.1 Hz), 3.80 (s, 6H), 3.27 (q, 4H, J = 6.4 Hz), 3.01–2.95

2H, J = 5.6 Hz), 8.09 (s, 2H), 7.28 (d, 2H, J = 16.1 Hz), 6.44 (d, (m, 8H), 1.99–1.92 (m, 2H), 1.82 (quintet, 4H, J = 7.1 Hz); ¹³C

2H, J = 15.7 Hz), 3.81 (s, 6H), 3.26 (q, 4H, J = 6.4 Hz), 2.94 (m, NMR (100 MHz, DMSO-d₆) δ 163.9, 153.6, 137.2, 136.5, 135.6,

8H), 1.82 (quintet, 4H, J = 7.1 Hz), 1.64 (m, 4H); ¹³C NMR 130.3, 119.8, 117.9, 117.4, 60.3, 44.8, 43.9, 36.1, 25.9, 22.5; IR

(100 MHz, DMSO-d₆) δ 163.9, 153.6, 137.2, 136.5, 135.6, 130.3, (neat) 3253, 3072, 2869, 1665, 1558, 1196, 1135, 1043, 832,

119.8, 117.9, 117.4, 60.3, 46.0, 44.7, 36.1, 25.8, 22.6; IR (neat) 718 cm⁻¹; HRMS (APCI) calcd for C₂₉H₃₅Br₆N₄O₄(M + H −

3397, 3235, 3065, 1673, 1415, 1194, 1133, 965, 720 cm⁻¹

HRMS (ESI) calcd for C₃₀H₃₇Br₆N₄O₄(M + H − 2TFA), 15.174 min.

;

2TFA), 976.7759; found, 976.7747. HPLC purity 100%, RT =

990.7915; found, 990.7908. HPLC purity 100%, RT

=

(2E,2′E)-N,N′-(3,3′-(Hexane-1,6-diylbis(azanediyl))bis(propane-

14.804 min.

3,1-diyl))bis(3-(3,5-dibromo-4-methoxyphenyl)acrylamide) bis

(2E,2′E)-N,N′-(3,3′-(Butane-1,4-diylbis(azanediyl))bis(propane- trifluoroacetate 50. The product 50 was obtained as a white

3,1-diyl))bis(3-(2,4-dibromo-5-methoxyphenyl)acrylamide) bis solid (184.3 mg, 84% in two steps); Mp 56–58 °C; ¹H NMR

trifluoroacetate 46. The product 46 was obtained as a white (400 MHz, DMSO-d₆) δ 8.64 (br s, 4H), 8.36 (t, 2H, J = 5.6 Hz),

1

sticky solid (116.7 mg, 88% in two steps); H NMR (400 MHz, 7.88 (s, 4H), 7.35 (d, 2H, J = 15.7 Hz), 6.68 (d, 2H, J = 16.1 Hz),

DMSO-d₆) δ 8.80 (br s, 4H), 8.64 (t, 2H, J = 5.7 Hz), 7.90 (s, 2H), 3.81 (s, 6H), 3.25 (q, 4H, J = 6.4 Hz), 2.92–2.89 (m, 8H), 1.79

7.59 (d, 2H, J = 15.6 Hz), 7.37 (s, 2H), 6.89 (d, 2H, J = 15.6 Hz), (quintet, 4H, J = 7.1 Hz), 1.57 (m, 4H), 1.31 (m, 4H); ¹³C NMR

3.92 (s, 6H), 3.27 (q, 4H, J = 6.3 Hz), 2.95 (m, 8H), 1.86–1.79 (100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.4, 134.3, 131.6, 124.2,

(m, 4H), 1.66 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.7, 118.0, 115.2, 60.5, 46.6, 44.7, 36.0, 26.0, 25.4, 25.3; IR (neat)

155.2, 136.0, 135.8, 134.8, 126.2, 114.8, 112.8, 110.6, 56.5, 46.0, 3290, 2944, 2864, 1660, 1471, 1200, 1177, 1133, 982, 721 cm⁻¹

;

44.7, 36.0, 25.9, 22.6; IR (neat) 3395, 1678, 1444, 1202, 1137, HRMS (APCI) calcd for C₃₂H₄₃Br₄N₄O₄(M + H − 2TFA),

846, 725 cm⁻¹; HRMS (ESI) calcd for C₃₀H₃₉Br₄N₄O₄(M + H − 863.0018; found, 863.0023. HPLC purity 100%, RT

=

2TFA), 834.9705; found, 834.9703. HPLC purity 98.6%, RT = 14.871 min.

15.775 min.

(2E,2′E)-N,N′-(3,3′-(Hexane-1,6-diylbis(azanediyl))bis(propane-

(2E,2′E)-N,N′-(3,3′-(Propane-1,3-diylbis(azanediyl))bis(propane- 3,1-diyl))bis(3-(2,3,4-tribromo-5-methoxyphenyl)acrylamide) bis

3,1-diyl))bis(3-(3,5-dibromo-4-methoxyphenyl)acrylamide) bis tri- trifluoroacetate 51. The product 51 was obtained as a white

1

fluoroacetate 47. The product 47 was obtained as a white solid solid (101.3 mg, 81% in two steps); Mp 122–124 °C; H NMR

(174.1 mg, 83% in two steps); Mp 208–210 °C (decomposed); (400 MHz, DMSO-d₆) δ 8.62 (m, 6H), 7.67 (d, 2H, J = 15.7 Hz),

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (br s, 4H), 8.35 (t, 2H, J = 7.36 (s, 2H), 6.80 (d, 2H, J = 15.2 Hz), 3.94 (s, 6H), 3.27 (m,

5.6 Hz), 7.87 (s, 4H), 7.35 (d, 2H, J = 15.7 Hz), 6.67 (d, 2H, J = 4H), 2.92–2.90 (m, 8H), 1.81 (quintet, 4H, J = 7.1 Hz), 1.57 (m,

15.7 Hz), 3.81 (s, 6H), 3.26 (q, 4H, J = 6.4 Hz), 3.00–2.94 (m, 4H), 1.31 (m, 4H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.5,

8H), 1.95 (quintet, 2H, J = 7.3 Hz), 1.80 (quintet, 4H, J = 156.0, 137.7, 136.6, 129.1, 127.2, 117.7, 116.2, 109.5, 57.0, 46.6,

7.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.8, 153.9, 135.4, 44.7, 36.1, 25.9, 25.4, 25.3; IR (neat) 3326, 3062, 2842, 1657,

134.3, 131.5, 124.1, 118.0, 60.5, 44.8, 43.9, 35.9, 26.0, 22.4; IR 1361, 1188, 975, 707 cm⁻¹

(neat) 3082, 2865, 1664, 1472, 1196, 1132, 979, 743 cm⁻¹

C₃₂H₄₁Br₆N₄O₄(M + H − 2TFA), 1018.8228; found, 1018.8222.

HRMS (APCI) calcd for C₂₉H₃₇Br₄N₄O₄(M + H − 2TFA), HPLC purity 100%, RT = 14.803 min.

;

HRMS (ESI) calcd for

;

820.9548; found, 820.9547. HPLC purity 100%, RT

=

(2Z,2′Z)-N,N′-(3,3′-(Hexane-1,6-diylbis(azanediyl))bis(propane-

14.648 min.

3,1-diyl))bis(3-(2,3,4-tribromo-5-methoxyphenyl)acrylamide) bis

(2E,2′E)-N,N′-(3,3′-(Propane-1,3-diylbis(azanediyl))bis(propane- trifluoroacetate 52. The product 52 was obtained as a white

1

3,1-diyl))bis(3-(2,3,4-tribromo-5-methoxyphenyl)acrylamide) bis solid (108.7 mg, 87% in two steps); Mp 138–141 °C; H NMR

trifluoroacetate 48. The product 48 was obtained as a white (400 MHz, DMSO-d₆) δ 8.65 (br s, 4H), 8.49 (t, 2H, J = 5.9 Hz),

solid (94 mg, 77% in two steps); Mp 216–218 °C (decomposed); 7.19 (s, 2H), 6.81 (d, 2H, J = 12.2 Hz), 6.19 (d, 2H, J = 12.2 Hz),

¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (br s, 4H), 8.59 (t, 2H, J = 3.81 (s, 6H), 3.12 (q, 4H, J = 6.4 Hz), 2.84–2.81 (m, 8H), 1.72

5.6 Hz), 7.68 (d, 2H, J = 15.2 Hz), 7.35 (s, 2H), 6.77 (d, 2H, J = (quintet, 4H, J = 7.0 Hz), 1.52 (m, 4H), 1.26 (m, 4H); ¹³C NMR

15.7 Hz), 3.94 (s, 6H), 3.28 (q, 4H, J = 6.4 Hz), 3.00–2.95 (m, (100 MHz, DMSO-d₆) δ 164.7, 155.1, 138.7, 137.4, 127.6, 126.1,

8H), 1.98–1.93 (m, 2H), 1.85–1.79 (m, 4H); ¹³C NMR (100 MHz, 115.8, 114.0, 113.0, 56.9, 46.7, 44.6, 35.6, 25.9, 25.5, 25.3; IR

DMSO-d₆) δ 164.5, 156.0, 137.7, 136.6, 129.1, 127.1, 117.7, (neat) 3270, 3072, 2838, 1672, 1358, 1134, 839, 722 cm⁻¹; HRMS

116.2, 109.5, 57.0, 44.8, 43.9, 36.0, 26.0, 22.5; IR (neat) 3278, (APCI) calcd for C₃₂H₄₁Br₆N₄O₄(M + H − 2TFA), 1018.8228;

3077, 2862, 1665, 1367, 1197, 1134, 970, 719 cm⁻¹; HRMS (ESI) found, 1018.8204. HPLC purity 99.9%, RT = 15.304 min.

Org. Biomol. Chem., 2014, 12, 3847–3865 | 3863

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Organic & Biomolecular Chemistry

(2E,2′E)-N,N′-(3,3′-(Hexane-1,6-diylbis(azanediyl))bis(propane-

3,1-diyl))bis(3-(2,4,6-tribromo-3-methoxyphenyl)acrylamide) bis

Notes and references

trifluoroacetate 53. The product 53 was obtained as a white

solid (220.4 mg, 88% in two steps); Mp 186–188 °C; H NMR

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Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation

DOI: 10.1039/c3ob42537a

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