ESI-MS: (signal), 2.45C2.25 (m, 2H), 2.05C1.75 (m, 3H), 1.53C1.37 (m, 1H), 1.02C0.93 (m, 3H); ESI-MS: (transmission), 2.08C1.93 (m, 2H), 1.90C1.75 (m, 1H), 1.60C1.35 (m, 1H), 1.04C0.91 (m, 3H); 13C NMR (101 MHz, DMSO-signal), 2.09C1.96 (m, 2H), 1.92C1.76 (m, 1H), 1.60C1.36 (m, 1H), 1.02C0.90 (m, 3H); 13C NMR (101 MHz, DMSO-signal), 2.41C2.23 (m, 2H), 2.12C1.77 (m, 3H), 1.62C1.37 (m, 1H), 1.01C0.86 (m, 3H); 13C NMR (101 MHz, DMSO-= 8.4 Hz, 2H), 7.64C7.52 (m, 1H), 7.39 (d, = 8.3 Hz, 2H), 7.22C7.05 (m, 1H), 4.44C4.19 (m, 2H), 4.15C3.92 (m, 2H), 3.84C3.74 (m, 0.45H), 3.67C3.57 (m, 0.55H), 3.16C3.06 (m, 0.45H), 3.05C2.92 (m, 0.55H), 2.87C2.75 (m, Latrunculin A 0.55H), 2.70C2.55 (m, 0.45H), 2.32 (s, 3H), 2.07C1.90 (m, 1H), 1.90C1.68 (m, 2H), 1.68C1.35 (m, 1H); ESI-MS: (m/z) 544.8 [M + Na]+, 520.7 [M ? H]?; HPLC method A: tr = 8.439 min. The purified material from the first step (91.0 mg, 0.17 mmol) was reacted with KtBuO (136.7 mg, 1.22 mmol) in dry THF (10 mL) according to general process D (reaction time 2 h). and biological activities of compounds 2, 18C24, and 45C50. percentage of 399 were recognized in the LC-MS analysis and likely result from monooxygenation of the parent compound. However, no elimination of the piperidine nitrogen substituent was seen, which helps our initial hypothesis concerning stability of the amide relationship. Open in a separate window Number 3 Microsomal degradation and formation of recognized metabolites of (a) = 310 K, NosCHoover method; = 1.01325 bar, MartynaCTobiasCKlein method) with the default Desmond settings as described previously [5]. Before the actual production run, the default Desmond relaxation protocol was applied for both systems. For the conformation assessment of different enantiomers of 2 (in Number 2f), = 0). NMR spectra of compounds with acyl substituents within the piperidine nitrogen regularly showed mixtures of amide relationship rotamers resulting in Latrunculin A complex reports. The percentage of rotamers TLR3 was estimated from the respective integrals in the 1H-NMR spectra. Thin coating chromatography (TLC) was performed on silica gel coated aluminum linens (Merck TLC Silica gel F254, Merck, Darmstadt, Germany or Macherey-Nagel Alugram Sil G/UV254, Macherey-Nagel, Dren, Germany), recognized under UV light (254 nm). 3.2.2. General Methods(1) General Process AThe appropriate intermediate (3a,b and 3dCl) was suspended in dry tetrahydrofurane (THF). NaH was added, and the combination was stirred at space heat (rt) and under N2 atmosphere for 15C30 min. = 7.9 Hz, 2H), 7.68 (s, 1H), 7.35 (d, = 7.5 Hz, 1H), 7.25 (d, = 8.9 Hz, 2H, overlap with CHCl3 signal), 6.44C4.91 (m, 1H), 4.55C4.31 (m, 1H), 4.23C3.66 (m, 2H), 3.54C2.97 (m, 2H), 2.46C2.01 (m, 4H), 1.97C1.79 (m, 1H), 1.75C1.30 (m, 11H); ESI-MS: (= 8.4 Hz, 2H), 7.62 (br s, 1H), 7.49 (dd, = 8.1, 1.3 Hz, 1H), 7.25 (d, 2H, overlap with CHCl3 signal), 6.14C5.03 (m, 1H), 4.45C4.32 (m, 1H), 4.20C3.72 (m, 2H), 3.47C2.98 (m, 2H), 2.42C2.02 (m, 4H), 1.92C1.78 (m, 1H), 1.75C1.32 (m, 11H); ESI-MS: (= 7.7 Hz, 1H), 7.43C7.35 (m, 1H), 7.25 (t, = 7.4 Hz, 1H), 4.30C3.72 (m, 3H), Latrunculin A 3.20C3.04 (m, 4H), 2.79C2.60 (m, 1H), 2.09C1.71 (m, 3H), 1.51C0.99 (m, 10H); HPLC method B: tr = 8.335 min. = 10.2, 2.4 Hz, 1H), 8.10 (d, = 8.4 Hz, 2H), 7.65 (s, 1H), 7.26 (d, = 8.2 Hz, 2H, overlap with CHCl3 transmission), 7.17 (td, = 8.7, 2.4 Hz, 1H), 4.49C3.89 (m, 3H), 3.13 (s, 3H), 3.11C3.02 (m, 1H), 2.76C2.65 (m, 1H), 1.99C1.70 (m, 3H), 1.67C1.29 (m, 10H); ESI-MS: (= 8.9, 2.3 Hz, 1H), 7.05 (td, = 9.1, 2.4 Hz, 1H), 4.59C3.98 (m, 3H), 3.27 (s, 3H), 3.12C3.02 (m, 1H), 2.77C2.60 (m, 1H), 2.08C1.77 (m, 3H), 1.69C1.54 (m, 1H), 1.43 (s, 9H); ESI-MS: (= 8.6, 1.8 Hz, 1H), 4.52C4.01 (m, 3H), 3.27 (s, 3H), 3.13C3.01 (m, 1H), 2.77C2.62 (m, 1H), 2.09C1.77 (m, 3H), 1.72C1.56 (m, 1H), 1.43 (s, 9H); ESI-MS: (= 1.4 Hz, 1H), 8.62 (s, 1H), 8.09 (d, = 8.4 Hz, 2H), 7.74 (dd, = 8.4, 1.4 Hz, 1H), 7.41 (d, = 7.9 Hz, 1H), 7.27 (d, = 8.1 Hz, 2H; overlap with CHCl3 transmission), 4.47C3.90 (m, 3H), 3.11 (s, 3H), 3.08C2.98 (m, 1H), 2.77C2.60 (m, 1H), 2.37 (s, 3H), 2.01C1.71 (m, 3H), 1.64C1.29 (m, 10H); 13C NMR (50 MHz, CDCl3) 160.5, 157.0, 154.8, 154.4, 145.8, 136.4, 135.4, 133.2, 129.8, 128.2, 124.0, 123.1, 121.3, 101.2, 91.3, 80.0, 55.6 (br), 46.7, 44.1 (br), 33.7 (br), 28.5, 28.1, 24.8, 21.8; ESI-MS: (= 1.1 Hz, 1H), 7.61 (dd, = 8.5, 1.4 Hz, 1H), 7.53 (d, = 8.5 Hz, 1H), 4.55C4.04 (m,.
Categories:DHCR