Synthesis of (9R)-9-dihydro-6,9-anhydroerythromycin A
Synthesis of (9R)-9-dihydro-6,9-anhydroerythromycin A
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(9R)-9-二氢-6,9-脱水红霉素A的合成
DOI：
10.1021/jo00063a056
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发表时间：
1993
影响因子：
3.6
通讯作者：
R. Henry
中科院分区：
文献类型：
--
作者：
L. L. Klein;L. Freiberg;P. Kurath;R. Henry
抗生素红霉素A的主要缺点之一是其酸不稳定性导致的不良药代动力学特征。在低pH条件下，会形成相对无活性的6，9-烯醇醚1和6，9-9，12螺缩酮2 * 1（方案I），并且已经进行了许多尝试，通过修饰C-9羰基中心或封闭C-6羟基来避免这种降解过程。2.本文报道了9（R）-二氢-6，9-脱水红霉素A（4）和其它6，9-连接的类似物的合成，它们与红霉素A相比具有更高的酸稳定性。目标是6，9-醚结构，因为建模研究预测内酯和侧糖的结构完整性的保守性。我们的第一种方法涉及红霉素A烯醇醚的催化氢化，并且最初按照Kurath 3还原红霉素B的烯醇醚进行。在类似的条件下（TFA、乙酸、50 psi H2），红霉素A烯醇醚产生复杂的产物混合物，在冗长的分离之后，以低收率得到作为主要产物的6，9-醚3a。通过对以标准方式制备的2/-0-对溴苯甲酸酯衍生物的X射线晶体学分析4，化合物3a显示具有9（fi）构型和非天然的8（S）立体化学（图1）。该立体化学结果表明试剂从a面顺式加成。通过修改还原条件，我们可以以最佳50%的产率生产3a。由于化合物3a在C-8位具有非天然的和通常活性较低的构型，因此尝试了其他制备天然8（f）环系统的方法。9（R），9（S）-红霉素基胺的重氮化，6 C-9半缩酮中间体的脱氧，7烯醇醚的硼氢化反应均未能得到
One of the major disadvantages of the antibiotic erythromycin A is the poor pharmacokinetic profile caused by its acid instability. Underlow pH conditions, the formation of the relatively inactive 6, 9-enol ether 1 and6, 9-9, 12 spiroketal 2 occurs* 1 (Scheme I), and many attempts at avoiding this degradative process through modification of the C-9 carbonyl center or blocking of the C-6 hydroxyl have been pursued. 2 In this paper we report our synthesis of 9 (fi)-dihydro-6, 9-anhydroerythromycin A (4) and other 6, 9-linked analogs which should have increased acid stability as compared to erythromycin A. The 6, 9-ether structure was targeted since modeling studies predicted conservation of the structural integrity of the lactone and pendant sugars. Our first approach involved the catalytic hydrogenation of erythromycin A enol ether and was initially carried out as per the reduction by Kurath3 of the enol ether of erythronolide B. Under similar conditions (TFA, acetic acid, 50 psi of H2), erythromycin A enol ether led to a complex mixture of products which, following a tedious isolation, afforded 6, 9-ether 3a as the major product in low yield. Compound 3a was shown to have the 9 (fi) configuration and the unnatural 8 (S) stereochemistryby X-ray crystallographic analysis4 of the 2/-0-p-bromobenzoatederivative prepared in stan-dard fashion (Figure 1). This stereochemical result indicates a cis addition of the reagent from the a face. By modifying the conditions5 for the reduction, we could produce 3a in an optimal 50% yield. Since compound 3a had the unnatural and normally less active configuration at C-8, other approaches toward the preparation of the natural8 (fi) ring system were attempted. Diazotization of 9 (fi), 9 (S)-erythromycyl-amines, 6 deoxygenation of C-9 hemiketal intermediates, 7 and hydroboration of the enol ether all failed to produce