Synthesis and chemistry of dynemicin A models - Journal of the

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J . Am. Chem. SOC.1991, 113, 3106-3114

3106

rotary evaporation of solvent was subjected to HPLC with 15% ethyl acetate in hexanes as eluting solvent. Data for spatol benzyl ether (+)-54 (3.6 mg, 62.2%) thus obtained: [ c Y ] ~ + ~ D8' (C 0.12, CHCI,); 'H NMR (CDCI,) 6 7.22 (2 H, d, J = 8.2 Hz), 6.83 (2 H, d, J = 8.2 Hz), 5.09 ( I H, s), 5.02 ( I H,s), 4.48 ( 1 H , d , J = 11.8 Hz),4.29 ( 1 H , d , J = 11.8Hz),3.77(3H,s),3.43(1 H,d,J=4.4Hz),3.38(1 H , d , J = 3 Hz), 2.93 ( I H, m), 2.87 ( I H, dd, J = 7.8, 4.4 Hz), 2.52 (1 H, d, J = 7.8 Hz), 2.11-1.61 (10 H), 1.41 (3 H, s), 1.30 (3 H, s), 1.01 (3 H, s), 0.89 (3 H, d, J = 6.4 Hz). (+)-Spat01 (3). To a magnetically stirred solution of spatol benzyl ether (+)-54 (3.6 mg, 0.0081 mmol) in methylene chloride (1.5 mL) and water (84 pL) was added DDQ (6.0 mg) at 0 OC, and stirring was continued at the same temperature. After 1 h, TLC analysis showed no unreacted starting material. Solvents were rotary evaporated, and the residue was passed through a short column of silica gel with 30% ethyl acetate in hexanes as eluant. The residue obtained after rotary evaporation was purified by HPLC with 24% ethyl acetate in hexanes as eluant +44.2O (c 0.66, CHCI,) (reto deliver ( + ) - 3 (2.1 mg, 81%): ported2 [(Y]D +45.6' (C 1.56, CHCI3)): 'H NMR (400 MHz, CDCI,) 6 5.13 ( I H, dd, J = 3.0, 1.5 Hz), 5.03 ( 1 H, s), 3.74 ( 1 H, d, J = 4.4 Hz),3.44(1 H , d , J = 3 . 8 H z ) , 3 . 0 3 ( 1 H , d d d , J = 1 4 . 5 , 5 . 5 , 5 . 5 H z ) , 2.87 ( I H, dd, J = 7.9, 4.3 Hz), 2.49 ( I H, d, J = 7.9 Hz), 2.28 (1 H, ddd,J=13.2,13.2,4.3H~),2.12-2.05(2H),1.97(1 H,t,J=6.8Hz), 1.89-1.80 (2 H), 1.78-1.65 (2 H), 1.47-1.18 (3 H), 1.41 (3 H, s), 1.29 (3 H, s), 0.99 (3 H, s), 0.91 (3 H, d, J = 6.7 Hz); "C NMR (100.607 MHz, CDCI,, for APT spectra a (+) indicates 0 or 2 attached protons and a (-) indicates 1 or 3 attached protons) 6 141.5 (+), 11 1.0 (+), 79.96 (-), 58.42 (+), 58.12 (+), 57.06 (-), 55.14 (-), 47.21 (+), 43.79 (-), 43.40 (-), 43.25 (-), 37.82 (-), 36.87 (+), 36.56 (-), 35.18 (+), 27.87 (+), 24.23 (-), 19.26 (-), 14.47 (-), 12.97 (-).

Acknowledgment. This research was assisted financially by

G r a n t C A 3 1595 from t h e National Cancer Institute of t h e National Institutes of Health. W e thank M. Jirousek, B. Banik, K. Murthy, a n d A. Valeriu for technical assistance and Professor Fenical for copies of NMR spectra and for a n authentic sample of natural spatol. Registry No. ( & ) - l , 89196-20-3; 2, 132199-63-4; 3, 76520-52-0; 5, 930-30-3; (f)-6, 89165-79-7; (1)-7, 89165-80-0; (+)-7, 127182-28-9; (1)-8, 89177-59-3; 9, 132101-35-0; (+)-11, 127182-29-0; (+)-12, 132101-36-1; (+)-13, 132199-64-5; (+)-14, 132199-65-6; 19, 13210137-2; 19 alcohol, 26639-84-9; (&)-20, 132199-66-7; 21, 132101-38-3; (*)-22, 13210 1-39-4; (&)-23, 132 101-40-7; (f)-24e, 132 101-41-8; (1)-24t, 132199-69-0; (f)-25e, 132101-42-9; (f)-25t, 132199-70-3; (&)-26e, 132 IO 1-43-0; (&)-26t, 132199-7 1-4; (1)-27, 132101-44-1; (1)-28, 132 101-45-2; (f)-29, 132 101-46-3; (f)-truns,erythro-31, 13210 1-47-4; (*)-cis,erythro-31, 132 199-72-5; (&)-32, 132101-48-5; (&)-33, 13210 1-49-6; (*)-34, 132101-50-9; (&)-35, 132101-51-0; (1)-36, 132101-52-1; (1)-37e, 132101-53-2; (&)-37t, 132101-65-6; (&)-38e, 132101-54-3; (1)-38t, 132199-73-6; 39, 132 101-55-4; 40t, 132199-75-8; 4Oe, 132101-56-5; 41t, 132199-74-7; 41e, 132101-57-6; 42, 132101-58-7; 42 (tosylate precursor), 132101-66-7; (+)-43, 132101-59-8; (-)-44, 132101-60-1; (-)-45, 132101-61-2; (+)-46, 127156-24-5; (-)-47a, 132199-67-8; (-)-47b, 127135-70-0; (-)-48a, 127135-76-6; (-)-49b, 127135-7 1- 1 ; threo-50a, 132199-68-9; threo-50b, 127 182-31-4; erythro50b, 127 135-72-2; threo-50b TES ether, 127182-32-5; eryrhro-50b TES ether, 127135-73-3; 51, 132101-62-3; (-)-52, 127135-75-5; (-)-53, 127304-32-9; (+)-54, 127182-33-6; HC=C(CH,),OH, 115-19-5; H C G C(CH3)20TES, 17963-41-6; (f)-HCGC(CH,)20THP, 132101-64-5; HC300 OC (from ether); R, = 0.80 (30% ether in petroleum ether); IR (CDCI,) umaX2870,2080,2040,1510 cm-I; 'H NMR (500 MHz, CDCI,) b 7.50 (d, J = 7.4 Hz, I H, aromatic), 7.04 (t, J = 7.4 Hz, I H, aromatic), 6.73 (t, J = 7.4 Hz, 1 H, aromatic), 6.40 (d, J = 7.4 Hz, 1 H, aromatic), 6.31 (d, J = 12.3 Hz, 1 H, olefinic), 6.19 (d, J = 12.3 Hz, 1 H, olefinic), 4.97 (s, 1 H, CHN), 4.30 and 4.20 (2 s, 2 H, CHCCo, NH), 2.60-1.50 (m, 6 H, CHI); MS (FAB+) m / e (re1 intens) 978 (M Cs, 19), 950 (20), 894 (25), 838 (28), 810 (25), 705 (39), 677 (78), 633 (80), 593 (74), 523 (100); HRMS for C31HIS013NCo4C~ (M + Cs), calcd 977.6926, found 977.6966. Compound 32. Carbamate 22 (42 mg,0.1 1 mmol) in T H F (3 mL) was treated at 0 "C with LiAIH, (0.25 mL of a 1.O M solution in ether, 0.25 mmol). After the solution was stirred for 30 min, the reaction was quenched with saturated ammonium chloride solution (1 mL) and the solution diluted with ether (15 mL), washed with water (2 X IO mL) and brine (IO mL), and dried (Na2S04). The solvent was removed in vacuo, and the residue was dissolved in ethanol and stirred 5 h. The ethanol was removed in vacuo and the residue purified by flash chromatography (silica, 30% ether in petroleum ether) to give 32 (1 1 mg,28%): colorless gum;R, = 0.45 (50% ether in petroleum ether); IR (CDCI,) Y,, 3400, 3350, 2920, 2840, 1500 cm-I; ' H N M R (500 MHz, CDCI,) b 7.40 (br s, 1 H, NH), 7.30 ( d , J = 7.1 Hz, 1 H, aromatic), 7.20 ( d , J = 7.7 Hz, 1 H, aromatic), 7.17 (t, J = 6.5 Hz, 1 H, aromatic), 7.12 (t, J = 7.1 Hz, 1 H, aromatic), 7.03 (t, J = 7.7 Hz, 2 H, aromatic), 6.97 (t, J = 7.7 Hz, 1 H, aromatic), 6.93 (d, J = 7.7 Hz, 1 H, aromatic), 6.82 (t, J = 7.1 Hz, 1 H, aromatic), 6.77 (d, J = 8.3 Hz, 2 H, aromatic), 6.72 (t, J = 7.1 Hz, 1 H, aromatic), 6.45 (d, J = 7.7 Hz, 1 H, aromatic), 4.42 (br s, 1 H, CHN), 3.60 (br s, 1 H, OH), 3.52 (s, 1 H, benzylic), 2.61 (t, J = 11.1 Hz, 1 H, CH,), 2.29 (dt, J = 3.3, 10.2 Hz, 1 H, CHI), 1.69 (dd, J = 3.3. 10.2 Hz,1 H, CHI), 1.50 (dd, J = 8.3, 10.2 Hz, 1 H, CH2), 1.38 (d, J = 10.2 Hz, I H, CHI), 0.88 (m, 1 H, CH,); 13C NMR (125 MHz, CDCI,) 6 158.1, 147.8, 140.7, 138.2, 137.9, 128.4, 128.2, 128.1, 127.9, 127.6, 126.9, 126.4, 120.5, 120.3, 119.6, 116.8, 80.3, 70.4, 64.5, 56.2, 32.3, 27.9, 18.7; MS m/e (re1 intens) 276 (M+ - OPh, 59), 258 (loo), 218 (21), 204 (25), 162 (14), 141 (10); HRMS for C I 9 H l 8 N O( M + OPh), calcd 276.1388, found 276.1379. DNA-Cleavage Assay of Compound 30. The ethereal solution of 30 produced as above by the LiAIH4 reduction of 22 (39 mg, 0.10 mmol) was evaporated in vacuo to dryness and dissolved in T H F (4 mL) to give a 25 mM solution of 30, assuming complete conversion of 22. Analysis of compound 30 induced damage to supercoiled, covalently closed, circular (form I) 9 x 1 7 4 DNA was performed by incubation at varying concentrations of 30 (100-5000 pM) in buffered aqueous solution at 37 OC for 12 h, followed by agarose gel electrophoresis to separate the various DNA products-namely, nicked relaxed circular DNA (form 11) and linearized DNA (form 111). DNA bands were visualized with use of ethidium bromide binding and UV illumination.

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Acknowledgment. We t h a n k Dr. R a j C h a d h a , University of California, San Diego, for t h e X-ray crystallographic analyses and Drs. Dee H. H u a n g and G a r y Siuzdak, Research Institute of Scripps Clinic, for their NMR and mass spectroscopic assistance, respectively. DNA-cleavage experiments were performed by Peter Maligres (these laboratories). This work was financially supported by the National Institutes of Health a n d t h e Research Institute of Scripps Clinic.