T. Lindel et al.
FULL PAPER
(br. s, 1 H, NOH), 7.43 (t, 3J = 7.8 Hz, 1 H, 5-H), 7.36 (d, 3J =
7.7 Hz, 1 H, 6-H), 7.13 (s, 1 H, 2-H), 7.10 (d, J = 7.8 Hz, 1 H, 4-
C
Ar3), 132.3 (1 C, CAr1), 130.9 (1 C, CAr4), 129.7 (1 C, CAr2), 129.0
3
(1 C, CAr5), 127.1 (1 C, CAr6), 123.3 (q, J = 279 Hz, 1 C, CF3),
H), 3.85 (s, 2 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ 58.5 (q, J = 34.1 Hz, 1 C, CCF3), 52.9 (1 C, OCH3), 30.3 (1 C,
= 165.0 (1 C, COOH), 149.4 (1 C, CNOH), 138.1 (1 C, C1), 130.6 CH2) ppm. 19F NMR (376 MHz, CDCl3): δ = –73.6 ppm. MS (EI):
(1 C, C6), 129.5 (1 C, C5), 127.6 (1 C, C3), 126.2 (1 C, C2), 124.2 m/z (%) = 309.0 (23), 247.0 (45), 232.0 (100), 207.0 (49), 164.0 (30),
(1 C, C4), 121.8 (q, 1JC,F = 275 Hz, 1 C, CF3), 29.7 (1 C, CH2), 27.9 59.0 (43). HRMS (ESI): calcd. for: C24H22Cl2F6N2NaO6 [2M +
(q, 2JC,F = 40 Hz, 1 C, CNN) ppm. 19F NMR (376 MHz, CDCl3): δ Na+] 641.06513; found 641.06540.
= –64.51 (s, 3 F, CF ) ppm. IR (ATR): ν = 3208 (w), 3063 (w, br),
˜
3
Methyl 2-(Hydroxyimino)-3-[3-(3,3,3-trifluoroprop-1-en-2-yl)phen-
yl]propanoate (24): H NMR (400 MHz, CDCl3): δ = 9.10 (s, 1 H,
1696 (m), 1608 (w), 1471 (m), 1432 (m), 1345 (m), 1242 (m), 1183
(m), 1141 (vs), 1066 (w), 1026 (m), 1005 (m), 888 (m), 782 (m), 732
(m), 698 (s), 655 (m), 576 cm–1. UV/Vis (MeOH): λmax (logε) = 357
(2.47), 203 (4.31) nm. MS (ESI): m/z (%) = 1187 (6) [4M + K]+,
884 (27) [3M + Na]+, 597 (17) [2M + Na]+, 310 (100) [M + Na]+.
HRMS (ESI): calcd. for C11H8F3NaO3 [M + Na]+ 310.04100;
found 310.04092.
1
OH), 7.62 (s, 1 H, 2Ar-H), 7.50–7.49 (m, 1 H, 6Ar-H), 7.41–7.38
(m, 1 H, 4Ar-H), 7.37–7.34 (m, 1 H, 5Ar-H), 4.43 (d, J = 12.5 Hz,
1 H, H2CCCF3), 4.19 (d, J = 12.5 Hz, 1 H, H2CCCF3), 4.03 (s, 2
H, CH2), 3.84 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 163.6 (1 C, COOCH3), 150.9 (1 C, CN), 136.0 (1 C, CAr3),
132.1 (1 C, CAr1), 130.6 (1 C, CAr4),129.4 (1 C, CAr2), 128.7 (1 C,
C
Ar5), 126.7 (1 C, CAr6), 123.6 (q, J = 283.8 Hz, 1 C, CF3), 72.7
Photopsammaplin (8): To a solution of acid 19 (0.18 g, 0.65 mmol,
1.00 equiv.) in DMF (10 mL) was added NHS (0.11 g, 0.98 mmol,
1.50 equiv.). After 5 min, DCC (0.20 g, 0.98 mmol, 1.50 equiv.) was
added and the mixture was stirred for 3 h. After complete con-
sumption of acid 19 (TLC; silica RP-18; H2O/MeOH, 1:1), a solu-
tion of cystamine dihydrochloride (20; 0.07 g, 0.31 mmol,
0.48 equiv.) and NEt3 (0.18 mL, 1.38 mmol, 2.00 equiv.) in DMF
(1 mL) was added and the mixture was stirred for 4 d at room temp.
The solvent was evaporated and the product was isolated by col-
umn chromatography on silica RP-18 (MeOH/H2O, 4:1) followed
by purification by HPLC on silica RP-18 (MeOH/H2O, 55:45 to
MeOH) to afford E,E-amide 8 (0.06 g, 0.08 mmol, 25%) as a pale-
yellow oil. TLC: Rf = 0.35 (silica RP-18; MeOH/H2O, 4:1). 1H
NMR (400 MHz, [D6]DMSO): δ = 11.98 (s, 2 H, 2ϫ NOH), 8.12
(q, J = 28.9 Hz, 1 C, CCF3), 52.9 (1 C, OCH3), 47.0 (1 C,
H2CCCF3), 30.5 (1 C, CH2) ppm. 19F NMR (376 MHz, CDCl3): δ
= –73.9 ppm. IR (ATR): ν = 3278 (w, br), 1726 (m), 1442 (m), 1305
˜
(m), 1251 (m), 1198 (s), 1168 (s), 1123 (m), 1004 (m), 947 (m), 780
(m), 760 (m), 711 (s), 658 (m) cm–1. UV/Vis (CHCl3): λmax (logε)
= 233 (2.97), 239 (3.27). MS (EI): m/z (%) = 287.1 (17), 271.1 (37),
211.1 (80), 210.1 (100), 185.1 (83), 142.1 (44), 115.0 (73) nm.
HRMS (EI): calcd. for C13H12F3NO3 [M+] 287.07638; found
287.07673.
Methyl 3-[3-(1-Acetoxy-2,2,2-trifluoroethyl)phenyl]-2-(hydroxy-
imino)propanoate (25): 1H NMR (400 MHz, CDCl3): δ = 8.83 (s, 1
H, OH), 7.42 (s, 1 H, 2Ar-H), 7.38–37 (m, 1 H, 5Ar-H), 7.33–7.32
(m, 2 H, 4Ar-H, 6Ar-H), 6.11 (q, J = 6.9 Hz, 1 H, CHCF3), 4.01
3
3
(s, 2 H, CH2), 3.84 (s, 3 H, OCH3), 2.20 (s, 3 H, OCCH3) ppm. 13
C
(t, J = 5.9 Hz, 2 H, 2ϫ NH), 7.40 (t, J = 7.7 Hz, 2 H, 2ϫ 5-H),
7.36 (d, 3J = 7.7 Hz, 2 H, 2ϫ 6-H), 7.11 (s, 2 H, 2ϫ 2-H), 7.09 (d,
NMR (100 MHz, CDCl3): δ = 168.8 (1 C, OCCH3), 163.2 (1 C,
COOCH3), 151.1 (1 C, CN), 136.1 (1 C, CAr3), 131.4 (1 C, CAr1),
130.7 (1 C, CAr5), 129.0 (1 C, CAr2), 128.9 (1 C, CAr4), 126.4 (1 C,
CAr6), 123.0 (q, J = 281 Hz, 1 C, CF3), 71.7 (q, J = 33.2 Hz, 1 C,
CCF3 ), 52.9 (1 C, OCH3 ), 30.4 (1 C, CH2 ), 20.7 (1 C,
OCCH3) ppm. 19F NMR (376 MHz, CDCl3): δ = –76.4 ppm.
HRMS (ESI): calcd. for C14H14F3NNaO5 [M + Na+] 356.07163;
found 356.07168.
3
3J = 7.7 Hz, 2 H, 2ϫ 4-H), 3.84 (s, 4 H, 2ϫ CH2), 3.41 (dd, J =
2
3
6.4, J = 13.3 Hz, 4 H, 2ϫ NCH2), 2.81 (t, J = 6.9 Hz, 4 H, 2ϫ
SCH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 163.0 (2 C,
2ϫ CO), 151.0 (2 C, 2ϫ CNOH), 138.2 (2 C, 2ϫ C1), 130.7 (2 C,
2ϫ C6), 129.3 (2 C, 2ϫ C5), 127.5 (2 C, 2ϫ C3), 126.4 (2 C, 2ϫ
1
C2), 124.1 (2 C, 2ϫ C4), 121.8 (q, JCF = 275 Hz, 2 C, 2ϫ CF3),
38.1 (2 C, 2ϫ NCH2), 36.8 (2 C, 2ϫ SCH2), 28.8 (2 C, 2ϫ CH2),
2
27.9 (q, JC,F = 40 Hz, 2 C, 2ϫ CNN) ppm. 19F NMR (376 MHz,
Methyl 2-(Hydroxyimino)-3-[3-(2,2,2-trifluoro-1-methoxyethyl)-
phenyl]propanoate (26): H NMR (400 MHz, CDCl3): δ = 8.95 (s,
CDCl ): δ = –64.12 (s, 3 F, CF ) ppm. IR (ATR): ν = 3221 (w, br),
˜
3
3
1
1658 (m), 1628 (m), 1527 (m), 1243 (m), 1194 (m), 1149 (vs), 1015
(m), 973 (m), 783 (m), 730 (m), 697 (m), 654 (m), 561 (m) cm–1.
UV/Vis (MeOH): λmax (log ε) = 355 (2.71), 203 (4.66) nm. MS
(ESI): m/z (%) = 1403 (19) [2M + Na]+, 713 (100) [M + Na]+.
HRMS (ESI): calcd. for C26H24F8N8NaO3S2 [M + Na]+ 713.11583;
found 713.11616.
1 H, OH), 7.38–7.36 (m, 2 H, 4Ar-H, 2Ar-H), 7.35–7.32 (m, 1 H,
5Ar-H), 7.30–7.28 (m, 1 H, 6Ar-H), 4.48 (q, J = 6.6 Hz, 1 H,
CHCF3), 4.02 (s, 2 H, CH2), 3.84 (s, 3 H, COOCH3), 3.41 (s, 3
H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.8 (1 C,
COOCH3), 151.3 (1 C, CN), 136.1 (1 C, CAr3), 132.7 (1 C, CAr1),
130.3 (1 C, CAr4), 129.1 (1 C, CAr2), 128.8 (1 C, CAr5), 126.5 (1 C,
CAr6), 123.7 (q, J = 282.0 Hz, 1 C, CF3); 81.2 (q, J = 31.1 Hz, 1
C, CCF3), 58.2 (1 C, OCH3), 52.9 (1 C, COOCH3), 30.4 (1 C,
CH2) ppm. 19F NMR (376 MHz, CDCl3): δ = –77.0 ppm. HRMS
(ESI): calcd. for C13H14F3NNaO4 [M + Na+] 328.07671; found
328.07682.
Irradiation Experiments: Diazirine 18 (55 mg, 180 μmol, 1.0 equiv.)
was dissolved in anhydrous CH2Cl2 (16 mL) and a solution of
MeOH (1.0 equiv.) and AcOH (1.0 equiv.) in CH2Cl2 (1.0 mL) was
added. The solution was irradiated for 2 h at 350 nm (λmax
,
Rayonet apparatus), then the solvent was removed under reduced
pressure and the products were separated by RP-HPLC. In a sec-
ond experiment, diazirine 18 (100 mg, 332 μmol) was dissolved in
anhydrous CH2Cl2 (33 mL) and irradiated for 2 h at 350 nm. The
solvent was removed under reduced pressure and the products were
separated by RP-HPLC.
Biological Tests
MTT Assays with Mouse Cell Line L-929: An MTT [3-(4,5-dimeth-
ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Sigma] assay was
used to measure the influence of compounds on the propagation
and viability of L-929 mouse fibroblasts (DSMZ ACC2) in 96-well
plates. Cells are able to reduce MTT to a violet formazan product.
The resulting purple color gives a measure of the metabolic activity
in each well. Cells were kept in Dulbecco’s Modified Eagle’s (DME)
Methyl 3-[3-(1-Chloro-2,2,2-trifluoroethyl)phenyl]-2-(hydroxy-
imino)propanoate (23): 1H NMR (400 MHz, CDCl3): δ = 9.28 (s, 1
H, OH), 7.45 (s, 1 H, 2Ar-H), 7.40–7.37 (m, 2 H, 6Ar-H, 4Ar-H),
7.35–7.34 (m, 1 H, 5Ar-H), 5.08 (q, J = 6.8 Hz, 1 H, CHCF3), 4.01 medium supplemented with 10% Fetal Bovine Serum (FBS). Serial
(s, 2 H, CH2), 3.85 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.6 (1 C, COOCH3), 150.7 (1 C, CN), 136.3 (1 C,
dilutions of the test compounds (60 μL) were added to aliquots
(120 μL) of a cell suspension (50.000 cells/mL) in each well. Blank
2126
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2120–2127