Epothilone A and B - Novel 16-membered macrolides with cytotoxic activity: Isolation, crystal structure, and conformation in solution
Epothilone A and B - Novel 16-membered macrolides with cytotoxic activity: Isolation, crystal structure, and conformation in solution
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DOI：
10.1002/anie.199615671
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发表时间：
1996-07-26
期刊：
影响因子：
--
通讯作者：
Reichenbach, H
中科院分区：
文献类型：
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作者：
Hofle, GH;Bedorf, N;Reichenbach, H
表1化合物la和b. la: Colorles晶体从乙酸乙酯/甲苯的物理和光谱数据；mp95“C；在20" C的水中溶解度：0.7 gL-'；色谱：R = 0.75(硅胶Si60；二氯甲烷/甲醇，香兰素/硫酸检测，加热至120“C时呈蓝灰色)：高效液相色谱：R，= 3.5 min(核sil 100。C-18.5 p， 125 x 4 mm柱，溶剂甲醇水65/35,1 mlmin-'， 254 nm检测):UV (MeOH): 1。…(E) = 211(17800), 249海里(12500),(一):“= -47.1 (c = 1.0甲醇):红外(KBr):我= 3476。2974、2938、2882。1738. 1692厘米-”:I3C NMR (150 MHz, [DJDMSO): 6 = 170.3 (CI), 38.4 (c - 2), 71.2(颈),53.1 (c - 4), 217.1 (c - 5), 45.4(其他)。75.9(即),35.4 (8),29.6 (C-9), 23.6 (C-10), 27.2 (C-11)。56.6(技术)。54.4 (c13)。32.1(碳14)。76.3 (C-15)。137.3 (C-16)。119.1 (c - 17)。152.1 (C-18)。117.7 (C-19)。164.2 (C-20)。18.8 (c - 21)。20.8 (C-22)。22.6 (c-23), 16.7 (c-24), 18.4 （c-25）。14.2 (C-27)[a], EI-MS (70 eV): mi；（%）： 493.2485 (22)[C,， H,， NO, S: 493.24981]。421(20)。306(70), 166（50）。165(84)。164 (100) 1b：无色结晶形式乙酸乙酯；mp 93-94“C，色谱：R，= 0.75; HPLC: R,= 4.1 min（条件见1a）；UV (MeOH): i，…(E) = 211(18600), 249海里(14100);[a];“= -35.0 (c = 0.7甲醇);IR (KBr): i.= 3487, 2966, 2935, 2880。1738、1690厘米-”;“C核磁共振（150 MHz）。[DJDMSO]: 6= 170 1 (Cl), 38.2 （C-2）。70.5 (c-3), 53.2 （c-4）。217.4 (c - 5)。44.9(其他)。75.5(即)。35.6 (c-8), 29.6 （c-9）。23.0 (C-lo), 32.1 (c - 1l), 61.0 （C-12）。61.5 (c13)。33.0(碳14)。76.6 (c-15), 137.2 (c-16), 119.2 （c-17）。152.1 (C-18)。117.7 (C-19)。164.3 (C-20)。18.9 (c - 21)。19.7 (c-22), 22.5 （c-23）。16.4 (C-24)。18.4 (C-25)。22.1 (c-26), 14.1 ('2-27)；EI-MS (70eV): m/i (%): 507.2568 （15）C,， H,， NO, S: 507.25761。421(20)。306(70)。166(50)。165 (84), 164 (100)[a]为了便于比较，la中C-16上的甲基也被命名为C-27。与埃波霉素的结构一致。这被lb的x射线结构分析证实，[']也给出了8个立体中心的绝对构型（图1）。[lo]从二氯甲烷中获得的晶体（空间群P2，）在单元胞中包含两个lb分子和一个无序的二氯甲烷分子。分子间氢键存在于3-OH和环氧氧原子之间，以及7-OH和C-5羰基之间。大环的碳主链大部分是平坦的，与C-6 （-0.96 A）和C-3 （0.85 A）的最佳拟合平面偏差最大。甲基C-22、C-25和C-26采用近似轴向位置，与噻唑环的侧链为赤道位置；避免了1,3 -二轴相互作用。只有环氧化物的顺式结构才会产生分子无法避免的张力。通过环质子的邻域耦合常数得到溶液中构象的信息，并将其与表2.1121中晶体结构的预期值进行比较。由于预期值与实测值一致，可以得出la和
Table 1 Physical and spectroscopic data for compounds la and Ib. la: Colorles crystals from ethyl acetate/toluene; mp 95" C; solubility in water at 20" C: 0.7 gL-'; chromatography: R,= 0.75 (silica gel Si60. dichloromethane/methanol, detection with vanillin/sulfuric acid, blue-gray coloration on heating to 120" C): HPLC: R,= 3.5 min (Nucleosil 100. C-18.5 p, 125 x 4 mm column, solvent methanoliwater 65/35, 1 mlmin-', detection at 254 nm): UV (MeOH): 1.,,,(E)= 211 (17800), 249 nm (12500),[a]:'=-47.1 (c= 1.0 in methanol): IR (KBr): i.= 3476. 2974, 2938, 2882. 1738. 1692 cm-': I3C NMR (150 MHz,[DJDMSO): 6= 170.3 (CI), 38.4 (C-2), 71.2 (C-3), 53.1 (C-4), 217.1 (C-5), 45.4 (C-6). 75.9 (C-7), 35.4 (C-8), 29.6 (C-9), 23.6 (C-10), 27.2 (C-11). 56.6 (C-12). 54.4 (C-13). 32.1 (C-14). 76.3 (C-15). 137.3 (C-16). 119.1 (C-17). 152.1 (C-18). 117.7 (C-19). 164.2 (C-20). 18.8 (C-21). 20.8 (C-22). 22.6 (C-23), 16.7 (C-24), 18.4 (C-25). 14.2 (C-27)[a], EI-MS (70 eV): mi;(%): 493.2485 (22)[Calcd for C,, H,, NO, S: 493.24981. 421 (20). 306 (70), 166 (50). 165 (84). 164 (100) 1 b: colorless crystals form ethyl acetate; mp 93-94" C, chromatography: R,= 0 75: HPLC: R,= 4.1 min (conditions see 1 a); UV (MeOH): i,..(E)= 211 (18600), 249 nm (14100);[a];'=-35.0 (c= 0.7 in methanol); IR (KBr): i.= 3487, 2966, 2935, 2880. 1738, 1690cm-';" C NMR (150 MHz.[DJDMSO): 6= 170 1 (Cl), 38.2 (C-2). 70.5 (C-3), 53.2 (C-4). 217.4 (C-5). 44.9 (C-6). 75.5 (C-7). 35.6 (C-8), 29.6 (C-9). 23.0 (C-lo), 32.1 (C-1 l), 61.0 (C-12). 61.5 (C-13). 33.0 (C-14). 76.6 (C-15), 137.2 (C-16), 119.2 (C-17). 152.1 (C-18). 117.7 (C-19). 164.3 (C-20). 18.9 (C-21). 19.7 (C-22), 22.5 (C-23). 16.4 (C-24). 18.4 (C-25). 22.1 (C-26), 14.1 ('2-27); EI-MS (70eV): m/i (%): 507.2568 (15)[calcd. for C,, H,, NO, S: 507.25761. 421 (20). 306 (70). 166 (50). 165 (84), 164 (100)[a] To aid comparison, the methyl group on C-16 in la is also designated C-27. in agreement with the epothilone structures. This was confirmed by an X-ray structural analysis of lb,['] which also gave the absolute configuration of the eight stereogenic centers (Fig. 1).[lo] The crystals obtained from dichloromethane (spatial group P2,) contain two molecules of lb and a disordered molecule of dichloromethane in the unit cell. Intermolecular hydrogen bonds are present between 3-OH and the epoxide oxygen atom, and between 7-OH and the C-5 carbonyl group. The carbon backbone of the macrocycle is largely flat, with maximum deviation from the best-fit plane for C-6 (-0.96 A) and C-3 (0.85 A). The methyl groups C-22, C-25, and C-26 adopt an approximately axial position and the side chain with the thiazole ring an equatorial position; 1, 3-diaxial interactions are avoided. Only the cis configuration of the epoxide ["] pro-duces strain that the molecule cannot avoid. Information about the conformation in solution was obtained from the vicinal coupling constants of the ring protons, which are compared to the values expected for the crystal structure in Table 2.1121 Since the expected and measured values are consistent, it can be concluded that the conformation of la and