Synthesis of tetrahydronaphthalene lignan esters by intramolecular cyclization of ethyl p-azidophenyl-2-phenylalkanoates and evaluation of the growth inhibition of human tumor cell lines

Article abstract of DOI:10.1021/jm101182s

Figure Presented. Intramolecular cyclization via nitrenium ion of 2-phenylpentanoic/2-phenylbutanoic acid esters with a terminal p-azidophenyl group gives direct access to tetrahydronaphthalene lignan esters. The p-azidophenyl-substituted butanoate led to

Full text of DOI:10.1021/jm101182s

Supporting Information
Synthesis of tetrahydronaphthalene esters by intramolecular cyclization of
ethyl p-azidophenyl-2-phenylalkanoates and evaluation of the inhibition of
human tumor cells proliferation
Orlando Pinto,1 João Sardinha,1 Pedro D. Vaz,1 Fátima Piedade,1 Maria J. Calhorda,1 Rudolph
Abramovitch,2 Nair Nazareth,3 Madalena Pinto,3 Maria S. J. Nascimento,3 Amélia P. Rauter1*
1Universidade de Lisboa, Faculdade de Ciências, Centro de Química e Bioquímica/Departamento de
Química e Bioquímica, Ed. C8, Piso 5, 1749-016 Lisboa, Portugal
2Department of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
3Centro de Estudos de Química Medicinal da Universidade do Porto(CEQUIMED-UP), Departamento de
Ciências Químicas, Laboratório de QuímicaOrgânica e Farmacêutica, Faculdade de Farmácia,
Universidade do Porto, RuaAníbal Cunha 164, 4050-047 Porto, Portugal
*Corresponding author. E-mail:aprauter@fc.ul.pt
Universidade de Lisboa, Faculdade de Ciências, Centro de Química e Bioquímica/Departamento
de Química e Bioquímica, Ed. C8, Piso 5, 1749-016 Lisboa, Portugal. Telephone: +351 21
7500952. Fax: + 351 21 7500088.
S1

Table of Contents
Figure S1.1H NMR spectrum of ethyl 5-(3-nitrophenyl)-2-phenylpentanoate (16)................................................... S3
Figure S2.13C NMR spectrum of ethyl 5-(3-nitrophenyl)-2-phenylpentanoate (16).................................................. S4
Figure S3.1H NMR spectrum of ethyl 5-(4-nitrophenyl)-2-phenylpentanoate (17)................................................... S4
Figure S4.13C NMR spectrum of ethyl 5-(4-nitrophenyl)-2-phenylpentanoate (17).................................................. S5
Figure S5.1H NMR spectrum of ethyl 4-(3-nitrophenyl)-2-phenylbutanoate (18)..................................................... S5
Figure S6.13C NMR spectrum of ethyl 4-(3-nitrophenyl)-2-phenylbutanoate (18). .................................................. S6
Figure S7.1H NMR spectrum of ethyl 4-(4-nitrophenyl)-2-phenylbutanoate (19)..................................................... S6
Figure S8.13C NMR spectrum of ethyl 4-(4-nitrophenyl)-2-phenylbutanoate (19). .................................................. S7
Figure S9.1H NMR spectrum of ethyl 5-(3-aminophenyl)-2-phenylpentanoate (20). ............................................... S7
Figure S10.13C NMR spectrum of ethyl 5-(3-aminophenyl)-2-phenylpentanoate (20). ............................................ S8
Figure S11.1H NMR spectrum of ethyl 5-(4-aminophenyl)-2-phenylpentanoate (21). ............................................. S8
Figure S12.13C NMR spectrum of ethyl 5-(4-aminophenyl)-2-phenylpentanoate (21). ............................................ S9
Figure S13.1H NMR spectrum of ethyl 4-(3-aminophenyl)-2-phenylbutanoate (22).............................................. S10
Figure S14.13C NMR spectrum of ethyl 4-(3-aminophenyl)-2-phenylbutanoate (22)............................................. S10
Figure S15.1H NMR spectrum of ethyl 4-(4-aminophenyl)-2-phenylbutanoate (23).............................................. S10
Figure S16.13C NMR spectrum of ethyl 4-(4-aminophenyl)-2-phenylbutanoate (23)............................................. S11
Figure S17.1H NMR spectrum of ethyl 5-(3-azidophenyl)-2-phenylpentanoate (24).............................................. S11
Figure S18.13C NMR spectrum of ethyl 5-(3-azidophenyl)-2-phenylpentanoate (24)............................................. S12
Figure S19.1H NMR spectrum of ethyl 5-(4-azidophenyl)-2-phenylpentanoate (25).............................................. S12
Figure S20.13C NMR spectrum of ethyl 5-(4-azidophenyl)-2-phenylpentanoate (25)............................................. S13
Figure S21.1H NMR spectrum of ethyl 4-(3-azidophenyl)-2-phenylbutanoate (26). .............................................. S13
Figure S22.13C NMR spectrum of ethyl 4-(3-azidophenyl)-2-phenylbutanoate (26). ............................................. S14
Figure S23.1H NMR spectrum of ethyl 4-(4-azidophenyl)-2-phenylbutanoate (27). .............................................. S14
Figure S24.13C NMR spectrum of ethyl 4-(4-azidophenyl)-2-phenylbutanoate (27). ............................................. S15
Figure S25.1H NMR spectrum of ethyl 5-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylpentanoate (28).
.................................................................................................................................................................................. S15
Figure S26.13C NMR spectrum of ethyl 5-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylpentanoate
(28). .......................................................................................................................................................................... S16
Figure S27.1H NMR spectrum of ethyl 4-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylbutanoate (29).
.................................................................................................................................................................................. S16
Figure S28.13C NMR spectrum of ethyl 4-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylbutanoate (29).
.................................................................................................................................................................................. S17
Figure S29.1H NMR spectrum of ethyl 4-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (30)..... S17
Figure S30.13C NMR spectrum of ethyl 4-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (30).... S18
Figure S31.1H NMR spectrum of ethyl 4-oxo-3',4'-dihydro-2'H-spiro(cyclohexa[2,5]diene-1,1'-naphthalene)-4'-
carboxylate (31)........................................................................................................................................................ S18
Figure S32.13C NMR spectrum of ethyl 4-oxo-3',4'-dihydro-2'H-spiro(cyclohexa[2,5]diene-1,1'-naphthalene)-4'-
carboxylate (31)........................................................................................................................................................ S19
Table S1. Crystal data and Structure Refinement for Compounds 30 and 31……………………………………...S20
S2

Figure S1. 1H NMR spectrum of ethyl 5-(3-nitrophenyl)-2-phenylpentanoate (16).
S3

Figure S2.13C NMR spectrum of ethyl 5-(3-nitrophenyl)-2-phenylpentanoate (16).
Figure S3. 1H NMR spectrum ofethyl 5-(4-nitrophenyl)-2-phenylpentanoate(17).
S4

Figure S4. 13C NMR spectrum of ethyl 5-(4-nitrophenyl)-2-phenylpentanoate(17).
Figure S5. 1H NMR spectrum of ethyl 4-(3-nitrophenyl)-2-phenylbutanoate (18).
S5

Figure S6. 13C NMR spectrum of ethyl 4-(3-nitrophenyl)-2-phenylbutanoate (18).
Figure S7. 1H NMR spectrum of ethyl 4-(4-nitrophenyl)-2-phenylbutanoate (19).
S6

Figure S8. 13C NMR spectrum of ethyl 4-(4-nitrophenyl)-2-phenylbutanoate (19).
Figure S9. 1H NMR spectrum of ethyl 5-(3-aminophenyl)-2-phenylpentanoate (20).
S7

Figure S10. 13C NMR spectrum of ethyl 5-(3-aminophenyl)-2-phenylpentanoate (20).
Figure S11. 1H NMR spectrum of ethyl 5-(4-aminophenyl)-2-phenylpentanoate (21).
S8

Figure S12. 13C NMR spectrum of ethyl 5-(4-aminophenyl)-2-phenylpentanoate (21).
S9

Figure S13. 1H NMR spectrum of ethyl 4-(3-aminophenyl)-2-phenylbutanoate (22).
Figure S14. 13C NMR spectrum of ethyl 4-(3-aminophenyl)-2-phenylbutanoate (22).
Figure S15. 1H NMR spectrum of ethyl 4-(4-aminophenyl)-2-phenylbutanoate (23).
S10

Figure S16. 13C NMR spectrum of ethyl 4-(4-aminophenyl)-2-phenylbutanoate (23).
Figure S17. 1H NMR spectrum of ethyl 5-(3-azidophenyl)-2-phenylpentanoate (24).
S11

Figure S18. 13C NMR spectrum of ethyl 5-(3-azidophenyl)-2-phenylpentanoate (24).
Figure S19. 1H NMR spectrum of ethyl 5-(4-azidophenyl)-2-phenylpentanoate (25).
S12

Figure S20. 13C NMR spectrum of ethyl 5-(4-azidophenyl)-2-phenylpentanoate (25).
Figure S21. 1H NMR spectrum of ethyl 4-(3-azidophenyl)-2-phenylbutanoate (26).
S13

Figure S22. 13C NMR spectrum of ethyl 4-(3-azidophenyl)-2-phenylbutanoate (26).
Figure S23. 1H NMR spectrum of ethyl 4-(4-azidophenyl)-2-phenylbutanoate (27).
S14

Figure S24. 13C NMR spectrum of ethyl 4-(4-azidophenyl)-2-phenylbutanoate (27).
Figure S25. 1H NMR spectrum of ethyl 5-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylpentanoate (28).
S15

Figure S26. 13C NMR spectrumof ethyl 5-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylpentanoate (28).
Figure S27. 1H NMR spectrum of ethyl 4-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylbutanoate (29).
S16

Figure S28. 13C NMR spectrum of ethyl 4-[5-amino-2-(trifluoromethylsulfonyloxy)phenyl]-2-phenylbutanoate (29).
Figure S29. 1H NMR spectrum of ethyl 4-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (30).
S17

Figure S30. 13C NMR spectrum of ethyl 4-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate (30).
Figure S31. 1H NMR spectrum of ethyl 4-oxo-3',4'-dihydro-2'H-spiro(cyclohexa[2,5]diene-1,1'-naphthalene)-4'-
carboxylate (31).
S18

Figure S32. 13C NMR spectrum of ethyl 4-oxo-3',4'-dihydro-2'H-spiro(cyclohexa[2,5]diene-1,1'-naphthalene)-4'-
carboxylate (31).
Table S1. Crystal data and Structure Refinement for Compounds 30 and 31.
Compound 30
C19 H21 N O2
295.37
Compound 31
C18 H18 O3
282.32
Empirical formula
Formula weight
T/K
293(2)
293(2)
Wavelength/
Ǻ
1.54439
1.54439
Crystal size/mm
Color of crystal
Crystal system
Space group
a/Å
0.14 x 0.09 x 0.08
0.13 x 0.09 x 0.06
colourless
Monoclinic
P21/n
colourless
Monoclinic
P21
11.077(2)
5.958(3)
12.778(2)
103.792(10)
12.472(3)
9.898(2)
b/Å
c/Å
12.538(4)
104.47(2)
β
/deg
S19

V/Å3
818.9(5)
2
1498.7(7)
4
Z
ρcalcd/g cm-3
1.198
1.251
µ
/mm-1
0.611
0.678
F(000)
316
600
θ
limits/deg
3.56 - 66.77.
4.48 to 67.27
−1≤ h ≤ 13
−1 ≤ k ≤ 7
−15 ≤ l ≤ 15
−14 ≤ h ≤ 14
−11 ≤ k ≤ 0
−14 ≤ l ≤ 14
Limiting indices
Reflections
collected/unique
2218 / 1909 [R(int) = 0.0382]
5301 / 2659 [R(int) = 0.1232]
Completeness to
θ
100% (
θ
= 66.77)
99.9% (θ = 67.27)
Refinement method
Data / restraints /
parameters
Full-matrix least-squares on F2
Full-matrix least-squares on F2
1909 / 3 / 265
2659 / 1 / 234
GOF on F2
1.082
1.015
Final R indices
[I>2σ(I)]
R1 = 0.0602
R1 = 0.0717
R indices (all data)
Absolute structure
parameter
R1 = 0.0648
R1 = 0.1409
0.6(11)
-
Extinction coefficient
0.025(3)
-
Largest diff. peak and
hole/e.Å-3
0.321 and -0.226
0.400 and -0.329
S20