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  1  

Synthesis and pharmacological characterization of new tetrahydrofuran based compounds as conformationally

constrained histamine receptor ligands

Julian Bodensteiner,

a

Paul Baumeister,

b

Roland Geyer,

b

Armin Buschauer

b

* and Oliver Reiser

a

*

a

Institute of Organic Chemistry, Universität Regensburg, Regensburg, Germany

b

Institute of Pharmacy, Universität Regensburg, Regensburg, Germany

Supporting Information

Table of Content

1. NMR Spectra S2

2. HPLC purity data S34

(2)

  2  

1. NMR Spectra

1-(((1S,3R,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methyl)-2-cyano-3- methylguanidine (6a)

1

H-NMR (300 MHz, MeOD)

13

C-NMR (75 MHz, MeOD)

(3)

  3  

1-(((1S,3S,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methyl)-2-cyano-3- methylguanidine (6b)

1

H-NMR (600 MHz, MeOD)

13

C-NMR (150 MHz, MeOD)

(4)

  4  

2-cyano-1-methyl-3-(((1S,3R,5S,6R)-3-(oxazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6- yl)methyl) guanidine (7a)

1

H-NMR (400 MHz, CDCl

3

)

13

C-NMR (100 MHz, CDCl

3

)

(5)

  5  

((1S,3R,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine (8a)

1

H-NMR (300 MHz, MeOD)

13

C-NMR (75 MHz, MeOD)

(6)

  6  

((1S,3R,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine • 2TFA (8a•2TFA)

1

H-NMR (600 MHz, MeOD)

13

C-NMR (150 MHz, MeOD)

(7)

  7  

((1S,3S,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine • 2TFA 8b•2TFA)

1

H-NMR (600 MHz, MeOD)

13

C-NMR (150 MHz, MeOD)

(8)

  8  

((1S,3R,5S,6R)-3-(oxazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine (9a)

1

H-NMR (400 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(9)

  9  

(1S,3R,5S,6S)-ethyl 3-(hydroxymethyl)-2-oxabicyclo[3.1.0]hexane-6-carboxylate (14)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(10)

10    

(1S,3R,5S,6S)-ethyl 3-formyl-2-oxabicyclo[3.1.0]hexane-6-carboxylate (15)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(11)

11    

(1S,3R,5S,6S)-ethyl 3-(4-tosyl-4,5-dihydrooxazol-5-yl)-2-oxabicyclo[3.1.0]hexane-6- carboxylate (16)

1

H-NMR (400 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(12)

12    

(1S,3R,5S,6S)-ethyl 3-((tert-butyldimethylsilyloxy)methyl)-2-oxabicyclo[3.1.0]hexane-6- carboxylate (18)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (100 MHz, CDCl

3

)

(13)

13    

((1S,3R,5S,6R)-3-((tert-butyldimethylsilyloxy)methyl)-2-oxabicyclo[3.1.0]hexan-6-yl)- methanol (19)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(14)

14    

(((1S,3R,5S,6R)-6-(benzyloxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)methoxy)(tert-butyl)- dimethylsilane (20)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(15)

15    

(1S,3R,5S,6R)-6-(benzyloxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)methanol (21)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(16)

16    

(1S,3R,5S,6R)-6-(benzyloxymethyl)-2-oxabicyclo[3.1.0]hexane-3-carbaldehyde (22)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (100 MHz, CDCl

3

)

(17)

17    

5-((1S,3R,5S,6R)-6-(benzyloxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)-4-tosyl-4,5- dihydrooxazole (23)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(18)

18    

5-((1S,5S,6R)-6-(benzyloxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)-1H-imidazole (24ab)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(19)

19    

ethyl 5-((1S,5S,6R)-6-(benzyloxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)-1H-imidazole-1- carboxylate (25ab)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(20)

20    

ethyl 5-((1S,3R,5S,6R)-6-(hydroxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)-1H-imidazole- 1-carboxylate (26a)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(21)

21    

ethyl 5-((1S,3S,5S,6R)-6-(hydroxymethyl)-2-oxabicyclo[3.1.0]hexan-3-yl)-1H-imidazole- 1-carboxylate (26b)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(22)

22    

ethyl 5-((1S,3R,5S,6R)-6-((1,3-dioxoisoindolin-2-yl)methyl)-2-oxabicyclo[3.1.0]hexan-3- yl)-1H-imidazole-1-carboxylate (27a)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(23)

23    

ethyl 5-((1S,3S,5S,6R)-6-((1,3-dioxoisoindolin-2-yl)methyl)-2-oxabicyclo[3.1.0]hexan-3- yl)-1H-imidazole-1-carboxylate (27b)

1

H-NMR (400 MHz, CDCl

3

)

13

C-NMR (100 MHz, CDCl

3

)

(24)

24    

ethyl 5-((2R,4S,5R)-5-(1,3-dioxoisoindolin-2-yl)-4-vinyltetrahydrofuran-2-yl)-1H- imidazole-1-carboxylate (28a)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(25)

25    

ethyl 5-((2R,4S,5S)-5-(1,3-dioxoisoindolin-2-yl)-4-vinyltetrahydrofuran-2-yl)-1H- imidazole-1-carboxylate (28b)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(26)

26    

2-(((1S,3R,5S,6R)-3-((tert-butyldimethylsilyloxy)methyl)-2-oxabicyclo[3.1.0]hexan-6- yl)methyl)isoindoline-1,3-dione (30)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(27)

27    

2-((2R,3S,5R)-5-((tert-butyldimethylsilyloxy)methyl)-3-vinyltetrahydrofuran-2-yl)- isoindoline-1,3-dione (31a)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(28)

28    

2-((2S,3S,5R)-5-((tert-butyldimethylsilyloxy)methyl)-3-vinyltetrahydrofuran-2-yl)- isoindoline-1,3-dione (31b)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(29)

29    

(R)-tert-butyldimethyl((4-vinyl-2,3-dihydrofuran-2-yl)methoxy)silane (32)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(30)

30    

(1S,3R,5S,6S)-methyl 3-(oxazol-5-yl)-2-oxabicyclo[3.1.0]hexane-6-carboxylate (33)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(31)

31    

((1S,3R,5S,6R)-3-(oxazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanol (34)

1

H-NMR (400 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(32)

32    

2-(((1S,3R,5S,6R)-3-(oxazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methyl)isoindoline-1,3- dione (35)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(33)

33    

methyl N'-cyano-N-(((1S,3R,5S,6R)-3-(oxazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6- yl)methyl)carbamimidothioate (36)

1

H-NMR (300 MHz, CDCl

3

)

13

C-NMR (75 MHz, CDCl

3

)

(34)

34    

2. HPLC purity data

Table 1. HPLC purity data of the synthesized target compounds.

[a]

no. t

R

(min) k’ purity (%) no. t

R

(min) k’ purity (%) 6a

[b]

4.20 8.34 0.80

2.58 > 99 6c

[b]

4.20 8.35 0.80

2.58 > 99 6b

[b]

4.22 8.26 0.81

2.55 > 99 6d

[b]

4.22 8.29 0.81

2.56 > 99 7a

[b]

4.27 11.38 0.83

3.88 > 99 7b

[b]

4.16

11.33

0.79

3.86 95

8a 3.30 0.42 98 8c 3.31 0.42 94

8b 3.29 0.41 > 99 8d 3.30 0.42 > 99

9a 4.34 0.86 93 9b 4.23 0.82 91

[a] Eurosphere-­‐100 C18, 250 × 4.0 mm, 5 µm; Knauer, Berlin, Germany; t0 = 2.33 min; gradient mode: MeCN (0.1%

TFA)/water (0.1% TFA): 0 min: 10/90, 20 min: 90/10, 30 min: 90/10; [b] two tR values due two partial protonation of the cyanoguanidines.

Abbildung

Table 1. HPLC purity data of the synthesized target compounds. [a]

Referenzen

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