Synthetic Studies on Anthracysline Antibiotics

蒽环类抗生素的合成研究

• 批准号: 60470147
• 负责人: TAMURA Yasumitsu
• 金额: $ 3.26万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1985
• 资助国家: 日本
• 起止时间: 1985 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-60470147/
• 关键词: Anticancer antibiotics; anthracyclenes; 4-demethoxydaunomycin; daunomycin; 4-demethoxy-11- deoxydaunomycin; 11-deoxydaunomysin; ダウノサミン; 4-デメトキシダウノマイシン;ダウノマイシン; 4-デメトキシ-11-デオキシダウノマイシン; 11-デオキシダウノマイシン;制癌抗生物質

The anthracycline antibiotics, 4-demethoxydaunomycin (1), daunomycin (2), and 11-deoxydaunomycin (3), are clinically signigicant drugs for the treatment of a broad spectrum of human cancers. In the course of investigations in our labolatory concerning the synthesis of anthra- cyclines, three successful results have been obtained in this project. In the first place, facile and versatile methods suitable for a large scale preparation of the aglycones of 1-3 were established. Three different routes using cycloaddition reaction of 4-acetoxy-homophthalic anhydride to chloroquinone acetal, nucleophilic addition reaction of ethynylcerium reagent to the C-9 ketone of 6-hydroxy(or 6,11-dihydroxy)-4-methoxy(or 4-demethoxy)-7,8-dihydro-naphthacene-5,9(10H),12-trione, and cycloaddition reaction of 6-ethyny1-6-hydroxy-5,6,7,8-tetrahydrohomophthalic anhydride to naphthoquinone-type compounds, have been developed. Secondly, asymmetric synthesis of ortically pure daunomycinone, the aglycone of 2, has been achivevd. That is, highly diastereoselective alkylation reaction to the chiral -keto acetal derived from (-)-(2S,3S)-1,4-dimethoxy-2,3-butane- diol was applied for the construction of chiral AB-ring system. Then, a new chiral AB-synthon, (-)-2-bromo-6-ethyny1-6-hybroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone, was preapred and used for the synthesis of optically pure (-)-7-deoxydaunomycinone, the late stage precursor for daunomycinone. Thirdly, syntheses of antracyclines were achieved. Thus, natural anthracyclines were prepared in optically active form by glycosidation reactions of racemic aglycones with the suitably protected 1-0-acy1 sugar derived from L-daunosamine in the presence of teimethylsilyltriflate. Other anthra- cyclines were synthesized by glycosidation reactions of racemic glycones with 1-chlorosugars, derived from neutral sugars, using mercuric oxide as a catalyst.

蒽环类抗生素，4-去甲氧基道诺霉素(1)、道诺霉素(2)和11-脱氧道诺霉素(3)，是临床上治疗多种人类癌症的重要药物。在本实验室对炭疽环素类化合物的合成进行研究的过程中，取得了三个成功的结果。首先，建立了适合于1-3苷元大规模制备的简便、通用的方法。利用4-乙酰氧基-同邻苯二酸酐的环加成反应，乙基铈试剂对6-羟基（或6,11-二羟基）-4-甲氧基（或4-去甲氧基）-7,8-二氢萘-5,9(10H)，12-三酮的C-9酮的亲核加成反应，以及6-乙基- 1-6-羟基-5,6,7,8-四氢同邻苯二酸酐的环加成反应，建立了3种不同的反应路线。其次，采用不对称方法合成了异纯的2的苷元道诺霉素酮。即对(-)-(2S,3S)-1,4-二甲氧基-2,3-丁烷-二醇衍生的手性-酮缩醛进行高度非对映选择性烷基化反应，构建手性ab环体系。然后，合成了一种新的手性ab -合成体(-)-2-溴-6-乙炔-1 -6-羟基-5,6,7,8-四氢-1,4-萘醌，并用于合成光纯的(-)-7-脱氧道诺霉素酮，这是道诺霉素酮的后期前体。第三，完成了蒽环类药物的合成。因此，天然蒽环类药物是通过外消旋苷元与适当保护的1-0-酰基1糖在四甲基硅酸三氟化酯存在下的糖苷化反应，以光学活性形式制备的。其他的炭疽环类化合物是在氧化汞催化下，由中性糖衍生的外消旋糖醛酸与1-氯糖糖化反应合成的。

项目成果

田村恭光: J.Org.Chem.(1987)

田村康光：有机化学杂志（1987）

田村恭光: Chem. Pharm. Bull. ,. 35. 1405-1412 (1987)

田村康光：化学。 35。1405-1412（1987）

Yasumitsu,Tamura Hirokazu,Annoura Hirofumi,Yamamoto Hiroshi,Kondo Yasuyuki kita Hiromichi Fujioka: "Asymmetric Synthesis of Anthracyclinones using Chiral Acetal: Synthesis of a new Chiral AB-Syuthon, (-)-2-Bromo-6-ethyny1-6-hydrixy-5,6,7,8- tetrahydro-1,4

Yasumitsu、Tamura Hirokazu、Annoura Hirofumi、Yamamoto Hiroshi、Kondo Yasuyuki kita Hiromichi Fujioka：“使用手性乙缩醛不对称合成蒽环酮：合成新的手性 AB-Syuthon，(-)-2-Bromo-6-ethyny1-6-Hydrixy

田村恭光: Tetrahedron Letters. 28. 5709-5712 (1987)

田村康光：《四面体信件》28。5709-5712 (1987)

Yasumitsu,Tamura Mananbu,Sasho Shuji,Akai Hisakazu,Kishimoto, Jun-ichi,Sekinachi Yasuyuki,Kita: An Efficient,Regiospecific Synthesis of 4-demethoxydaunomysinone and Daunomycinone Chem. Pharm, Bull. 35. 1405-1412 (1987)

Yasumitsu，Tamura Mananbu，Sasho Shuji，Akai Hisakazu，Kishimoto，Jun-ichi，Sekinachi Yasuyuki，Kita：4-去甲氧基道诺霉素酮和道诺霉素酮化学的高效、区域特异性合成。