Practical Synthesis Routes Towards Antitumor Antibiotic Duocarmycin SA

抗肿瘤抗生素 Duocarmycin SA 的实用合成路线

• 批准号: 07672305
• 负责人: MURATAKE Hideaki
• 金额: $ 1.47万
• 依托单位: Research Foundation Itsuu Laboratory
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672305/
• 关键词: Duocarmycin SA; antitumor antibiotic; pyrrolo [3,2-f]quinoline; the first route; the second route; the third route; analog synthesis; 三種全合成ルート; 光学分割; Pd触媒反応; Lーリンゴ酸; キラルプール法; 高度官能基化インドール; 絶対構造; チオフェン類縁体

Duocarmycin SA (1) is the most potent and most stable member among the antitumor antibiotics, including CC-1065 and Duocarmycin A,which bear cyclopropa [c] pyrrolo [3,2-e] indole pharmacophore.Our recent studies on the synthesis of this antibiotic clminated in achievement of three distinctive synthesis routes which are applicable to the preparation of synthetic analogs of 1.The initial rote realized the first enantio-selective synthesis of (+) -1. Pyrrolo [3,2-f] quinolinol derivative (2) , prepared from methyl 5-acetyl-4-bromopyrrole-2-carboxylate (3) in the steps, was readily optically resolved by use of Chiralcel OD HPLC column to (S)-2 and (R)-2. The former was led to (+) -1, and the latter unnatural isomer, was inverted to (S)-2 under the Mitsunobu reaction conditions. An enatio-convergent synthesis of (+) -1 was thus established.The second rote wa most featred by methyl 4- (methoxycarbonyloxy) pyrrolo [3,2-f] quinoline-2-carboxylate (4). The pyrrole derivative 3 was copled with 2-fluoro-3- (trimethylstannyl) pyridine under the Stille reaction conditions, and the resulting pyridylpyrrole derivative was cyclized to 4 in five steps involving a palladim-catalyzed arylation reaction of the acetyl group. It was then readily transformed to ( (]SY.+-。[) ) -2. The overall yield was much improved by this rote, and it was applied to the preparation of DSA furan and thiophene analogs.The third route is the first asymmetirc synthesis without an optical resolution among the syntheses of the duocarmycin class of antibiotics. A highly functionalized optica active indole derivative was prepared from L-malic acid adoptiong our indole formation reaction. The following C-ring formation gave the enatiomerically pure (S) -2, completing the third route. The absolute structure of (+) -1 was unequivocally established by this study.A further elaboration is now in progress.

Duocarmycin SA(1)是包括CC-1065和Duocarmycin A在内的具有环丙[c]吡咯[3,2-e]吲哚药效团的抗肿瘤抗生素中最有效、最稳定的成员。我们最近对这种抗生素的合成研究最终获得了三条不同的合成路线，适用于1的合成类似物的制备。最初的机器实现了(+)-1的首次对映体选择性合成。由5-乙酰-4-溴吡咯-2-羧酸甲酯(3)合成的吡咯[3,2-f]喹啉酚衍生物(2)，利用Chiralcel OD高效液相色谱柱容易光学分解为(S)-2和(R)-2。前者在Mitsunobu反应条件下被转化为(+)-1，后者的非自然异构体被转化为(S)-2。这样就建立了(+)-1的生成收敛合成。第二种结构主要是甲基4-（甲氧基羰基）吡咯[3,2-f]喹啉-2-羧酸盐(4)。在Stille反应条件下，吡咯衍生物3与2-氟-3-（三甲基锡基）吡啶偶联，得到的吡咯衍生物在钯催化的乙酰基芳化反应中经过5步环化得到4。然后，它很容易转化为(()SY.+-。[)] 2。该方法可用于呋喃和噻吩类似物的制备。第三种途径是多霉素类抗生素合成中第一个无光学分辨的不对称合成途径。以l -苹果酸为原料，采用吲哚生成反应制备了高功能化的光学活性吲哚衍生物。接下来的c环形成得到了纯的(S) -2，完成了第三条路线。本研究明确了(+)-1的绝对结构。进一步的阐述目前正在进行中。

项目成果

Hideaki Muratake, Itsuko Abe, Mitsutaka Natsume: "Total Synthesis of an Antitumor Antibiotic, ( (]SY.+-。[) ) -Duocarmycin SA" Tetrahedron Letters. Vol. 35, No 16. 2573-2576 (1994)

Hideaki Muratake、Itsuko Abe、Mitsutaka Natsume：“抗肿瘤抗生素的全合成，((]SY.+-.[))-Duocarmycin SA”Tetrahedron Letters，第 35 卷，第 16 期。2573-2576 (1994)

H. Muratake: "Total Synthesis of Natural(+)-Duocarmycin SA." Chem. Pharm. Bull.43. 1064-1066 (1995)

H. Muratake：“天然 ( )-Duocarmycin SA 的全合成。”

Hideaki Miyaki Tongawa, , Mitsutaka Natsume: "Alternative Synthesis of Duocarmycin SA Using a Tricyclic Heteroaromatic Intermediate Prepared by Palladim-Catalyzed Coupling Reactions" Chemical & Pharmaceutical Bulletin. Vol. 44, No 8. 1631-1633 (1996)

Hideaki Miyaki Tongawa、Mitsutaka Natsume：“使用 Palladim 催化偶联反应制备的三环杂芳族中间体替代合成 Duocarmycin SA”

H. Muratake: "Total Synthesis of an Antitumor Antibiotic, (±)-Duocarmycin SA." Tetrahedron Letters. 35. 2573-2576 (1994)

H. Muratake：“抗肿瘤抗生素的全合成，(±)-Duocarmycin SA。”35. 2573-2576 (1994)

H.Muratake: "Total Synthesis of Natural (+)-Duocarmycin SA." Chem.Pharm.Bull.43. 1064-1066 (1995)

H.Muratake：“天然 ( )-Duocarmycin SA 的全合成。”