Total synthesis of caprazol, a core structure of the caprazamycin antituberculosis antibiotics
Total synthesis of caprazol, a core structure of the caprazamycin antituberculosis antibiotics
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DOI：
10.1002/anie.200462439
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Matsuda, A
中科院分区：
文献类型：
--
作者：
Hirano, S;Ichikawa, S;Matsuda, A
结核病 (TB) 是一种主要影响呼吸系统的疾病，每年有 200 万人死于该病。随着耐药菌株的不断出现，开发具有新作用机制的新型抗结核药物至关重要。卡普拉霉素（CPZ；1，方案 1）[1] 是从放线菌菌株链霉菌的培养液中分离出来的。 MK730-62F2于2003年在体外对药物敏感和多重耐药的结核分枝杆菌菌株表现出优异的抗分枝杆菌活性，并且在小鼠中没有表现出明显的毒性。 Caprazol（2，方案2）是一种脱酰化CPZ，其立体化学结构（5'S、6'S、2'''S、3'''S）最近通过X射线晶体分析[2]被揭示，由尿苷、氨基核糖和特征性二氮杂酮组成。脂霉素 (LPS) 是一种相关的核苷抗生素，也具有与 CPZ 类似的抗菌活性。 [3] LPS 通过抑制 Mra Y（肽聚糖生物合成的关键酶）来阻止细菌细胞壁成分之一肽聚糖的形成。 [4]有人认为，由于 CPZ 具有复杂的结构和生物学相似性，因此它们可能遵循与 LPS 相同的作用模式。因此，它们已成为有趣的、具有挑战性的合成目标。 [5]我们在此报告了卡拉唑（2）的首次合成。该合成带来的主要困难之一是在构建尿苷二氮杂酮部分后引入2中发现的5-氨基核糖部分，因为二氮杂酮结构中包含的叔胺抑制了路易斯酸促进的常见核糖基化，[6]并且5'-羟基被认为是 处于高度空间阻碍的位置。[7]此外，含有β-杂取代的羧基部分的化合物2对碱性条件敏感。[3c]虽然存在通过使用受2-O-酰基保护的糖基供体参与邻基参与构建β-糖苷的通用方法，然后通常在碱性条件下脱保护，但我们计划引入用酸不稳定的氨基核糖保护 在合成的早期阶段保护基团。这样做，我们希望通过呋喃核苷α面上安装的基团的空间位阻来控制β-选择性引入。 [8]用 IBX [9] 氧化 2', 3'-O-异亚丙基神经苷 (3)，然后用 Ph3P= CHCO2Me 进行二碳延伸，并用 BOM 保护尿嘧啶部分 3 位的 NH 基团，经过三个步骤得到 4（反式/顺式 = 37:1）（方案 3）。使用 (DHQD) 2AQN 作为手性配体对 4 进行 Sharpless 氨基羟基化 [10]，得到 5 [11]，5’S、6’S/5’R、6’R 比例为 86:14。在不存在手性配体的情况下，非对映选择性逆转，得到 5，比例为 40:60，但产率有所下降。当异亚丙基保护的核糖基氟6a[12]在~308℃下用BF3·Et2O[13]活化时，得到相应的核苷，收率79%，异头位置的立体选择性为27:73(α/β)。使用 AgOTf 和 Cp2HfCl2[14](OTf= tri-
Tuberculosis (TB) is a disease, primarily of the respiratory system, from which two million people die each year. With resistant strains continuing to emerge, the development of new anti-TB agents with new mechanisms of action is of critical importance. The caprazamycins (CPZs; 1, Scheme 1),[1] which were isolated from a culture broth of the Actinomycete strain Streptomyces sp. MK730-62F2 in2003, have shown excellent antimycobacterial activity in vitro against drug-susceptible and multidrug-resistant Mycobacterium tuberculosis strains and exhibit no significant toxicity in mice. Caprazol (2, Scheme 2), the deacylated CPZ whose stereochemical structure (5’S, 6’S, 2’’’S, 3’’’S) was recently revealed through X-ray crystal analysis,[2] consists of a uridine, an aminoribose, and a characteristic diazepanone. Liposidomycins (LPSs), which are related nucleoside antibiotics, are also known to exhibit antibacterial activity similar to that of CPZs.[3] LPSs prevent the formation of one of the components of bacterial cell walls, peptidoglycan, by inhibiting Mra Y, a key enzyme for peptidoglycan biosynthesis.[4] It has been suggested that CPZs might follow the same mode of action as LPSs because of their complex structural and biological similarities. Consequently, they have become intriguing, challenging synthetic targets.[5] We report herein the first synthesis of caprazol (2).One of the major difficulties posed by the synthesis is the introduction of the 5-aminoribose moiety found in 2 after construction of the uridyldiazepanone moiety, because the tertiary amines contained in the diazepanone structure inhibit the usual ribosylation promoted by Lewis acid,[6] and the 5’-hydroxy group is presumed to be in a highly sterically hindered position.[7] Furthermore, compound 2, which contains a β-heterosubstituted carboxyl moiety, would be sensitive to basic conditions.[3c] Although a general method exists for the construction of β-glycosides through neighboringgroup participation by using a glycosyl donor protected with a 2-O-acyl group, which is then usually deprotected under basic conditions, we planned to introduce the aminoribose protected with an acid-labile protecting group at an early stage of the synthesis. In so doing, we hoped to control the β-selective introduction by steric hindrance of a group installed on the α face of the ribofuranoside.[8] Oxidation of 2’, 3’-O-isopropylideneuridine (3) with IBX [9] followed by a two-carbon elongation with Ph3P= CHCO2Me and BOM protection of the NH group at position 3 of the uracil moiety provided 4 (trans/cis= 37: 1) over three steps (Scheme3). Sharpless aminohydroxylation [10] of 4 with (DHQD) 2AQN as a chiral ligand afforded 5 [11] with a 5’S, 6’S/5’R, 6’R ratio of 86: 14. In the absence of the chiral ligand, the diastereoselectivity was reversed to give 5 in a ratio of 40: 60 with a decrease in yield. When the ribosyl fluoride 6a [12] protected with an isopropylidene group was activated with BF3· Et2O [13] at À308C, the corresponding ribosides were obtained in 79% yield and the stereoselectivity at the anomeric position was 27: 73 (α/β). The use of AgOTf and Cp2HfCl2[14](OTf= tri-