Diastereomeric Ketoprofen−Quencher Conjugates
A R T I C L E S
1H NMR (300 MHz, CDCl3): δ 7.76 (d, J ) 7.8 Hz, 2H), 7.52-7.39
(m, 3H), 7.30 (s, 1H), 7.14-7.03 (m, 4H), 6.98 (t, J ) 7.5 Hz, 1H),
6.92 (d, J ) 7.5 Hz, 2H), 6.76-6.69 (m, 2H), 5.35 (d, J ) 14.7 Hz,
1H), 4.88 (dd, J ) 10.6 Hz, 5.3 Hz, 1H), 4.76 (d, J ) 10.6 Hz, 1H),
4.01 (d, J ) 14.7 Hz, 1H), 3.69 (q, J ) 7.0 Hz, 1H), 3.07-2.96 (m,
1H), 2.40 (br s, 1H), 1.56 (d, J ) 7.0 Hz, 3H), 1.16 (d, J ) 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 173.7, 166.7, 142.8, 141.5, 139.2,
138.4, 129.0, 128.9, 128.6, 128.3, 128.1, 127.4, 126.6, 126.3, 126.0,
124.8, 83.4, 63.5, 62.1, 46.5, 41.4, 23.3, 16.9. HRMS (EI): calcd for
C27H27NO4, 429.1940; found, 429.1930.
Isolation of Photoproducts 7bA-7bD. The irradiation mixture
obtained from 4b was dissolved in acetonitrile and injected into a
semipreparative HPLC system (Waters Spherisorb ODS2, reversed
phase C18, 5 µm, length 25 cm, diameter 2.0 cm) using acetonitrile/
water (50/50 v/v) as isocratic eluent. The system was operated at a
flow rate of 10 mL min-1. Photoproducts 7bA-7bD were isolated and
characterized as pure compounds. An additional mixed fraction
including compounds 8A-8D was also obtained (cf. isolation of
photoproducts 8A-8D).
2-Hydroxy-9-methyl-5,8-dioxo-2-phenyl-3-[(2R)-phenylethyl]-
(2S,3S,9S)-7-oxa-4-azabicyclo[8.3.1]tetradeca-1(14),10,12-triene (7bA).
1H NMR (300 MHz, CDCl3): δ 7.87-7.70 (m, 4H), 7.63 (d, J ) 8.0
Hz, 1H), 7.52-7.38 (m, 5H), 7.18-7.07 (m, 3H), 6.87-6.70 (m, 1H),
4.95 (d, J ) 10.0 Hz, 1H), 4.63 (d, J ) 13.2 Hz, 1H), 4.62 (m, 1H),
4.42 (d, J ) 13.2 Hz, 1H), 3.95 (q, J ) 7.2 Hz, 1H), 3.23-3.12 (m,
1H), 1.46 (d, J ) 7.2 Hz, 3H), 1.24 (d, J ) 7.2 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 174.5, 165.9, 143.3, 142.0, 138.0, 130.3, 128.8, 128.3,
128.2, 128.1, 128.0, 127.6, 126.6, 125.3, 124.9, 83.0, 64.5, 62.6, 46.6,
41.5, 23.5, 14.9. HRMS (EI): calcd for C27H27NO4, 429.1940; found,
429.1942.
and an n-hexane/ethanol mixture (97/3 v/v) as eluent, operated under
isocratic conditions at a flow rate of 4 mL min-1. Compounds 8B and
8C were obtained as pure products, while 8A and 8D were collected
together in one fraction, which was finally resolved by a subsequent
preparative chromatography (column Kromasil 100, reversed phase C18,
5 µm, length 25 cm, diameter 1.0 cm; eluent methanol/water 60/40
v/v; flow rate 4 mL min-1).
2-Hydroxy-3,10-dimethyl-6,9-dioxo-2,3-diphenyl-(2S,3S,10S)-8-
oxa-5-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene (8A). 1H NMR
(300 MHz, CDCl3): δ 7.80 (d, J ) 8.3 Hz, 1H), 7.62-7.53 (m, 3H),
7.43-7.29 (m, 4H), 7.23-7.10 (m, 4H), 7.04-6.97 (m, 2H), 6.41 (br.
s, 1H), 5.30 (d, J ) 15.3 Hz, 1H), 4.51 (dd, J ) 15.1 Hz, 4.1 Hz, 1H),
4.15 (d, J ) 15.3 Hz, 1H), 3.82 (q, J ) 7.2 Hz, 1H), 3.32 (dd, J )
15.1 Hz, 3.7 Hz, 1H), 1.40 (d, J ) 7.2 Hz, 3H), 1.32 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 173.2, 167.9, 143.9, 143.7, 141.4, 140.2,
129.0, 128.4, 128.2, 128.0, 127.9, 127.8, 127.6, 127.4, 127.3, 126.1,
80.7, 62.7, 51.0, 48.8, 45.2, 22.5, 18.0. HRMS (EI): calcd for C27H27-
NO4, 429.1940; found, 429.1966.
2-Hydroxy-3,10-dimethyl-6,9-dioxo-2,3-diphenyl-(2R,3R,10S)-8-
oxa-5-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene (8B). 1H NMR
(300 MHz, CDCl3): δ 7.75 (s, 1H), 7.45 (d, J ) 8.0 Hz, 2H), 7.41-
7.15 (m, 7H), 7.14-7.01 (m, 2H), 6.90 (d, J ) 8.0 Hz, 2H), 6.43 (br.
s, 1H), 4.66 (d, J ) 15.2 Hz, 1H), 4.52 (d, J ) 15.2 Hz, 1H), 4.02
(dd, J ) 14.5 Hz, 4.0 Hz, 1H), 3.85 (q, J ) 7.0 Hz, 1H), 3.62 (dd, J
) 14.5 Hz, 6.0 Hz, 1H), 1.57 (d, J ) 7.0 Hz, 3H), 1.34 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 172.8, 167.7, 143.9, 142.2, 139.2, 129.8,
128.2, 127.9, 127.4, 127.4, 127.3, 125.6, 116.7, 81.1, 62.7, 51.2, 48.4,
45.4, 23.0, 15.0. HRMS (EI): calcd for C27H27NO4, 429.1940; found,
429.1937.
2-Hydroxy-3,10-dimethyl-6,9-dioxo-2,3-diphenyl-(2R,3S,10S)-8-
oxa-5-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene (8C). 1H NMR
(300 MHz, CDCl3): δ 7.92 (s, 1H), 7.46-7.34 (m, 2H), 7.33-7.24
(m, 3H), 7.24-7.12 (m, 8H), 5.46 (m, 1H), 4.63 (d, J ) 15.1 Hz, 1H),
4.54 (d, J ) 15.1 Hz, 1H), 4.07 (q, J ) 7.2 Hz, 1H), 3.95 (dd, J )
14.0 Hz, 3.0 Hz, 1H), 3.62 (dd, J ) 14.0 Hz, 8.0 Hz, 1H), 2.78 (s,
1H), 1.66 (d, J ) 7.2 Hz, 3H), 1.54 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 172.9, 167.5, 145.2, 144.4, 144.0, 138.6, 129.6, 128.3, 128.1,
127.9, 127.5, 127.4, 127.2, 127.1, 127.0, 125.6, 81.2, 62.7, 51.2, 46.7,
45.9, 21.5, 15.3. HRMS (EI): calcd for C27H27NO4, 429.1940; found,
429.1881.
2-Hydroxy-9-methyl-5,8-dioxo-2-phenyl-3-[(2R)-phenylethyl]-
(2R,3R,9S)-7-oxa-4-azabicyclo[8.3.1]tetradeca-1(14),10,12-triene (7bB).
1H NMR (300 MHz, CDCl3): δ 7.65-7.52 (m, 4H), 7.49-7.42 (m,
1H), 7.40 (s, 1H), 7.35-7.29 (m, 3H), 7.08 (d, J ) 4.7 Hz, 2H), 6.89-
6.78 (m, 3H), 6.00 (d, J ) 10.2 Hz, 1H), 5.05 (d, J ) 11.3 Hz, 1H),
4.45 (dd, J ) 10.2 Hz, 2.5 Hz, 1H), 4.34 (d, J ) 11.3 Hz, 1H), 3.78
(q, J ) 7.0 Hz, 1H), 3.52-3.42 (m, 1H), 1.55 (d, J ) 7.0 Hz, 3H),
1.26 (d, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 175.0, 165.8,
142.5, 142.3, 142.1, 139.5, 129.5, 128.7, 128.5, 128.0, 127.9, 127.8,
127.4, 126.8, 126.1, 124.5, 81.5, 66.4, 60.7, 47.6, 39.3, 20.2, 16.4.
HRMS (EI): calcd for C27H27NO4, 429.1940; found, 429.1941.
2-Hydroxy-9-methyl-5,8-dioxo-2-phenyl-3-[(2R)-phenylethyl]-
(2R,3S,9S)-7-oxa-4-azabicyclo[8.3.1]tetradeca-1(14),10,12-triene (7bC).
1H NMR (300 MHz, CDCl3): δ 7.52-7.17 (m, 12H), 7.07 (d, J ) 8.3
Hz, 2H), 5.50 (d, J ) 15.0 Hz, 1H), 5.36 (d, J ) 10.6 Hz, 1H), 5.02
(dd, J ) 10.6 Hz, 3.2 Hz, 1H), 4.30 (d, J ) 15.0 Hz, 1H), 3.87 (q, J
) 7.0 Hz, 1H), 3.00-2.90 (m, 1H), 2.24 (br. s, 1H), 1.64 (d, J ) 7.0
Hz, 3H), 0.54 (d, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
173.7, 167.0, 147.1, 141.5, 139.6, 139.3, 131.6, 128.9, 128.8, 128.5,
128.4, 128.2, 127.1, 126.8, 126.6, 125.5, 84.5, 63.7, 61.5, 46.7, 40.2,
20.1, 16.9. HRMS (EI): calcd for C27H27NO4, 429.1940; found,
429.1949.
2-Hydroxy-3,10-dimethyl-6,9-dioxo-2,3-diphenyl-(2S,3R,10S)-8-
oxa-5-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene (8D). 1H NMR
(300 MHz, CDCl3): δ 7.86 (s, 1H), 7.80 (d, J ) 8.0 Hz, 1H), 7.37 (t,
J ) 7.8 Hz, 1H), 7.25-7.06 (m, 7H), 7.01-6.93 (m, 4H), 5.12 (d, J )
15.3 Hz, 1H), 4.93 (m, 1H), 3.96 (d, J ) 15.3 Hz, 1H), 3.91 (dd, J )
10.5, 13.8 Hz, 1H), 3.82 (q, J ) 7.0 Hz, 1H), 3.60 (dd, J ) 13.8 Hz,
3.3 Hz, 1H), 1.70 (d, J ) 7.0 Hz, 3H), 1.57 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 173.4, 167.5, 144.2, 143.8, 142.5, 139.0, 130.3, 128.9,
128.0, 127.6, 127.4, 127.3, 127.2, 127.1, 126.7, 80.1, 62.6, 52.5, 45.8,
44.3, 20.4, 17.3. HRMS (EI): calcd for C27H27NO4, 429.1940; found,
429.1890.
Single-Crystal X-ray Data. Suitable crystals were obtained by slow
evaporation of the respective organic solvent at room temperature.
Crystal data were collected on a NONIUS KappaCCD2000 diffracto-
meter using OSMIC-graded monochromatic multilayer Cu KR radiation.
The structure was solved by direct methods and refined using SHELX97
(Sheldrick, G. M., University of Go¨ttingen). Non-hydrogen atoms were
found by successive full matrix least-squares refinement on F2.
Hydrogen atoms were placed at idealized positions and refined with a
riding model. Crystallographic information for compounds 6aB, 6aD,
6bC-6bD, 7aA, 7bA-7bC, and 8B-8D are given in Tables 3 and 4.
2-Hydroxy-9-methyl-5,8-dioxo-2-phenyl-3-[(2R)-phenylethyl]-
(2S,3R,9S)-7-oxa-4-azabicyclo[8.3.1]tetradeca-1(14),10,12-triene (7bD).
1H NMR (300 MHz, CDCl3): δ 7.57-7.30 (m, 6H), 7.24-7.04 (m,
8H), 6.07 (d, J ) 10.5 Hz, 1H), 5.03 (d, J ) 13.3 Hz, 1H), 4.77 (dd,
J ) 10.5 Hz, 4.2 Hz, 1H), 4.24 (d, J ) 13.3 Hz, 1H), 3.90 (q, J ) 7.2
Hz, 1H), 3.09 (m, 1H), 1.56 (d, J ) 7.2 Hz, 3H), 1.19 (d, J ) 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 173.6, 165.4, 146.9, 142.8, 142.1,
137.2, 130.1, 128.4, 128.4, 128.3, 127.7, 127.2, 126.9, 126.1, 125.2,
124.5, 83.1, 65.2, 59.7, 45.9, 40.1, 19.2, 13.1. HRMS (EI): calcd for
C27H27NO4, 429.1940; found, 429.1922.
Isolation of Photoproducts 8A-8D. The mixed fraction containing
photoproducts 8A-8D (which could not be resolved with a reversed
phase HPLC column) was separated by HPLC with a semipreparative
chiral column (Dancel Chiracel OD, length 25 cm, diameter 1.0 cm)
Acknowledgment. We acknowledge the financial support by
the Spanish Ministry of Education and Science, Madrid (Grant
No. CTQ 2004-03811, doctoral fellowship for S.A. and Ramo´n
9
J. AM. CHEM. SOC. VOL. 129, NO. 23, 2007 7419