(1'R,2'S)-bicyclomycin C(2'),C(3') acetonide | 158849-69-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (1'R,2'S)-bicyclomycin C(2'),C(3') acetonide
• CAS: 158849-69-5
• 化学式: C₁₅H₂₂N₂O₇
• 分子量: 342.349
• InChiKey: ZYBSLKGBERYUPB-UVCAVOOOSA-N

物化性质

• 沸点：
  651.3±55.0 °C(predicted)
• 密度：
  1.42±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  24.0
• 可旋转键数：
  2.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  126.35
• 氢给体数：
  4.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (1'R,2'S)-bicyclomycin C(2'),C(3') acetonide 在 硫酸 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以35%的产率得到(1'R,2'S)-bicyclomycin
  参考文献：
  名称：

  Chemical, biochemical, and biological studies on select C1 triol modified bicyclomycins

  摘要：

  To determine the importance of the C(1) triol group to bicyclomycin (1)-mediated transformations we prepared the bicyclomycin diastereomers 6 (C(1')-R, C(2')-S) and 7 (C(1')-S, C(2')-R), in which the stereochemical configuration at C(1') and C(2') in the triol group in 1 (C(1')-S, C(2')-S) was reversed, and the C(1') ketone analogue 8 (C(2')-S), in which the stereogenic center at C(1') in 1 was removed. Synthesis of 6 and 8 proceeded from C(1') ketobicyclomycin C(2'), C(3') acetonide (10). Reduction (NaBH4, CeCl3) of 10 produced a diastereomeric mixture, that, after separation and removal of the acetonide protecting group, gave 6. Correspondingly, deprotection of 10 gave 8. Bicyclomycin analogue 7 was prepared by dissolving the known bicyclomycin C(2'), C(3') epoxide (13) in dilute methanolic sulfuric acid; this process produced the novel [O(9)-C(2')]cyclized bicyclomycin (14). Compound 14 formed with inversion of the C(2') center. Subsequent aqueous acid hydrolysis yielded 7. Data documenting the proposed reaction pathways and structures for compounds 6-8 are presented. The stability of bicyclomycin analogues 6-8 and 1 in deuterium oxide (pD 5.6-5.8, 7.4, 9.2-9.4) and in DMF-d(7) solutions were examined. Compounds 7 and 8 were stable under these conditions (room temperature, 14 days), whereas bicyclomycin underwent noticeable change only in basic deuterium oxide. Correspondingly, 6 was rapidly converted (t(1/2) < 30 h) to a new set of products in both acidic and basic deuterium oxide as well as in DMF-d(7). The facility of these conversions have been attributed in part to the role of the C(1) triol substituent in the ring opening of the C(6) hemiketal group in 6. All three bicyclomycin analogues reacted with ethanethiol at the C(5)-C(5a) exomethylene unit at rates comparable to 1 in buffered (''pH'' 8.0-8.5) THF-H2O (3:1) mixtures. The products generated from 6 and 7 were similar to those previously determined for 1, except for the configuration of the C(1') and C(2') substituents, whereas 8 yielded the novel piperidine adduct 33. The ethanethiol-8 reaction proceeded easily in spite of earlier projections that the C(1') hydroxyl group in bicyclomycin was required for exomethylene modification. Similarly the corresponding C(2'), C(3') acetonide of 8, 10, readily underwent reaction with ethanethiol. Significantly, compounds 6 and 7 only partially (25-35%) inhibited rho-dependent hydrolysis of ATP at the concentration levels observed to block ATPase activity by 1, and no inhibition of ATP hydrolysis was detected for 8. Our previous studies established that the primary site of bicyclomycin action in Escherichia coli is the cellular protein transcription termination factor rho. Similarly, none of the three compounds exhibited antibiotic activity at a concentration of 1200 mu g/mL, using a filter disc assay. These cumulative results suggested that key interactions existed between the C(1) triol group in bicyclomycin and the antibiotic binding site in rho, which are necessary for drug utilization and function.

  DOI：

  10.1021/ja00101a001
• 作为产物：
  描述：

  二环霉素 在 sodium tetrahydroborate 、 cerium(III) chloride 、 对甲苯磺酸 、 二甲基亚砜 、 三乙胺 、 三氟乙酸酐 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.5h， 生成 (1'R,2'S)-bicyclomycin C(2'),C(3') acetonide
  参考文献：
  名称：

  Chemical, biochemical, and biological studies on select C1 triol modified bicyclomycins

  摘要：

  To determine the importance of the C(1) triol group to bicyclomycin (1)-mediated transformations we prepared the bicyclomycin diastereomers 6 (C(1')-R, C(2')-S) and 7 (C(1')-S, C(2')-R), in which the stereochemical configuration at C(1') and C(2') in the triol group in 1 (C(1')-S, C(2')-S) was reversed, and the C(1') ketone analogue 8 (C(2')-S), in which the stereogenic center at C(1') in 1 was removed. Synthesis of 6 and 8 proceeded from C(1') ketobicyclomycin C(2'), C(3') acetonide (10). Reduction (NaBH4, CeCl3) of 10 produced a diastereomeric mixture, that, after separation and removal of the acetonide protecting group, gave 6. Correspondingly, deprotection of 10 gave 8. Bicyclomycin analogue 7 was prepared by dissolving the known bicyclomycin C(2'), C(3') epoxide (13) in dilute methanolic sulfuric acid; this process produced the novel [O(9)-C(2')]cyclized bicyclomycin (14). Compound 14 formed with inversion of the C(2') center. Subsequent aqueous acid hydrolysis yielded 7. Data documenting the proposed reaction pathways and structures for compounds 6-8 are presented. The stability of bicyclomycin analogues 6-8 and 1 in deuterium oxide (pD 5.6-5.8, 7.4, 9.2-9.4) and in DMF-d(7) solutions were examined. Compounds 7 and 8 were stable under these conditions (room temperature, 14 days), whereas bicyclomycin underwent noticeable change only in basic deuterium oxide. Correspondingly, 6 was rapidly converted (t(1/2) < 30 h) to a new set of products in both acidic and basic deuterium oxide as well as in DMF-d(7). The facility of these conversions have been attributed in part to the role of the C(1) triol substituent in the ring opening of the C(6) hemiketal group in 6. All three bicyclomycin analogues reacted with ethanethiol at the C(5)-C(5a) exomethylene unit at rates comparable to 1 in buffered (''pH'' 8.0-8.5) THF-H2O (3:1) mixtures. The products generated from 6 and 7 were similar to those previously determined for 1, except for the configuration of the C(1') and C(2') substituents, whereas 8 yielded the novel piperidine adduct 33. The ethanethiol-8 reaction proceeded easily in spite of earlier projections that the C(1') hydroxyl group in bicyclomycin was required for exomethylene modification. Similarly the corresponding C(2'), C(3') acetonide of 8, 10, readily underwent reaction with ethanethiol. Significantly, compounds 6 and 7 only partially (25-35%) inhibited rho-dependent hydrolysis of ATP at the concentration levels observed to block ATPase activity by 1, and no inhibition of ATP hydrolysis was detected for 8. Our previous studies established that the primary site of bicyclomycin action in Escherichia coli is the cellular protein transcription termination factor rho. Similarly, none of the three compounds exhibited antibiotic activity at a concentration of 1200 mu g/mL, using a filter disc assay. These cumulative results suggested that key interactions existed between the C(1) triol group in bicyclomycin and the antibiotic binding site in rho, which are necessary for drug utilization and function.

  DOI：

  10.1021/ja00101a001

文献信息

• The role of the C-1 triol group in bicyclomycin
  作者：Zhuming Zhang、Harold Kohn

  DOI：10.1039/c39940001343

  日期：——

  Comparison of the chemical, biochemical, and biological activities of the antibiotic, bicyclomycin, with three C-1 triol modified derivatives demonstrated that all four compounds intercepted thiols but only bicyclomycin effectively inhibited the transcription termination factor rho and possessed significant antimicrobial activity, indicating that the stereochemical and chemical structure of the C-1 triol group played a key role in the drug recognition process.

  对抗生素双环霉素和三种 C-1 三醇修饰衍生物的化学、生化和生物活性进行比较后发现，这四种化合物都能拦截硫醇，但只有双环霉素能有效抑制转录终止因子 rho，并具有显著的抗菌活性，这表明 C-1 三醇基团的立体化学和化学结构在药物识别过程中起到了关键作用。
• Role of the [4.2.2] Bicyclic Unit in Bicyclomycin:  Synthesis, Structure, Chemical, Biochemical, and Biological Properties
  作者：Alejandro Santillán,、Hyeung-geun Park、Xiangdong Zhang、Oh-Seuk Lee、William R. Widger、Harold Kohn

  DOI：10.1021/jo961003q

  日期：1996.1.1

  modifications conducted within the [4.2.2] bicyclic unit led to a loss of rho-dependent ATPase (I(50) > 400 &mgr;M) and to transcription termination (I(50) > 100 &mgr;M) inhibitory activities, as well as a loss of antimicrobial activity (MIC > 32 mg/mL). Only N(10)-methylbicyclomycin (2) displayed moderate inhibitory activities in these assays. These findings indicated that the [4.2.2] bicyclic unit played

  合成了十二种双环霉素衍生物，以确定双环霉素（1）中[4.2.2]双环单元的修饰对药物功能的影响。很少有双环霉素衍生物被描述，其中[4.2.2]环系统已被修饰。评估的化合物分为两类：两种N-甲基修饰的双环霉素（2，3）和十种C（6）取代的双环霉素（4-13）。在C（6）位置引入的取代基包括烷氧基，硫代烷氧基，噻吩氧基，苯胺基和氢。开发了一种程序来合成选择的C（6）-取代的双环霉素。首先将双环霉素转化为双环霉素C（2'），C（3'）-丙酮化物（16），然后用甲磺酰氯处理，原位生成相应的甲磺酸C（6）17。用适当的亲核试剂处理17，然后除去C（2'），C（3'）-丙酮化物基团，得到所需的C（6）-取代的双环霉素。检查了C（6）O-甲基双环霉素（4）的化学性质。用过量的EtSH处理4的THF-H（2）O混合物，将其保持在“ pH” 8.0-9.0时，未检测到反应，而在更碱性的“ pH”值4下，则进
• Role of the C(5)−C(5a) Exomethylene Group in Bicyclomycin:  Synthesis, Structure, and Biochemical and Biological Properties
  作者：Hyeung-geun Park、Zhuming Zhang、Xiangdong Zhang、William R. Widger、Harold Kohn

  DOI：10.1021/jo961004i

  日期：1996.1.1

  Thirty-two C(5)-C(5a) exomethylene-modified bicyclomycin derivatives were prepared to determine the effect of structural modification of this unit on bicyclomycin (1) function. The compounds were grouped into three categories: the C(5)-unsaturated bicyclomycins, the C(5a)-substituted C(5)-C(5a)-dihydrobicyclomycin derivatives, and the C(5)-modified norbicyclomycins. An efficient three-step procedure was developed to synthesize C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins. Bicyclomycin was converted to bicyclomycin C(2'),C(3')-acetonide (36) and then treated with a nucleophile in 50% aqueous methanol (''pH'' 10.5) to give the C(5a)-substituted C(5),C(5a)-dihydrobicyclomycin C(2'),C(3')-acetonide. Removal of the acetonide group (trifluoroacetic acid in 50% aqueous methanol) in the final step provided the desired bicyclomycin derivative. All the compounds were evaluated using the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay. Most of the compounds were also tested in the transcription termination assay. We observed that many of the C(5)-unsaturated bicyclomycins effectively inhibited ATP hydrolysis at 400 mu M and inhibited the production of rho-dependent transcripts at 100 mu M. The biochemical activities of C(5a)-bicyclomycincarboxylic acid (5), methyl C(5a)-bicyclomycincarboxylate (6), ethyl C(5a)-bicyclomycincarboxylate (7), and bicyclomycin C(5)-norketone O-methyloxime (11) were all similar to 1. Compounds 6, 7, and 11 exhibited diminished antibiotic activity compared to 1, and 5 displayed no detectable activity. Several C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins showed significant inhibition of rho-dependent ATPase and transcription termination activities. The inhibitory properties of C(5),C(5a)-dihydrobicyclomycin C(5a)-methyl sulfide (18), C(5),C(5a)-dihydrobicyclomycin C(5a)-phenyl sulfide (23), and C(5)-C(5a)-dihydrobicyclomycin-5,5a-diol (31) approached those of 1. Compounds 18, 23, and 31 did not exhibit antibiotic activity. Two of the four C(5)-modified norbicyclomycin adducts showed moderate inhibitory activities in the ATPase assay, and none showed significant antibiotic activity. Our findings showed that the C(5)-C(5a) exomethylene unit retention in 1 was not essential for inhibition of in vitro rho activity. The structure-activity relationship data indicated that bicyclomycins that contained a small unsaturated C(5) unit or C(5),C(5a)-dihydrobicyclomycins that possessed a small, nonpolar C(5a) substituent effectively inhibited rho function in in vitro biochemical assays. We concluded that the C(5)-C(5a) unit in 1 was not a critical structural element necessary for drug binding to rho and that irreversible, inactivating units placed at this site would permit the bicyclomycin derivative to bind efficiently to rho.