ASYMMETRIC-SYNTHESIS OF THE AB RING SEGMENTS OF DAUNOMYCIN AND 4-DEMETHOXYDAUNOMYCIN
ASYMMETRIC-SYNTHESIS OF THE AB RING SEGMENTS OF DAUNOMYCIN AND 4-DEMETHOXYDAUNOMYCIN
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DOI：
10.1021/jo00084a042
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发表时间：
1994-03-11
影响因子：
3.6
通讯作者：
CHEN, BC
中科院分区：
文献类型：
--
作者：
DAVIS, FA;CLARK, C;CHEN, BC
β -酮酯14烯酸钾与（樟脑磺酰基）-恶氮吡啶(-)-7c[四氢-9,9-二甲基-8,8-二甲基- 4h -4a，7-甲氧基恶氮基[3,2-i][2,1]-苯并异噻唑3,3-二氧化]的不对称羟基化反应得到α -羟基β -酮酯(R)-(+)-15。由于分子内螯合作用，这种烯酸酯可能以一种几何形式存在，这是高ee的原因。用三乙基硅烷还原15中的酮，并将酯基转化为甲基酮，可以高效合成AB环构建基(R)-(-)-2-乙酰-5,8-二甲氧基-1,2,3,4-四氢-2-萘酚（3b），这是抗肿瘤药物4-去甲氧基道诺霉素不对称合成的关键中间体（1c）。用BBr3选择性地去保护3b中的8-甲氧基得到3a，这在临床上有用的抗肿瘤药物阿霉素的对映选择性合成中很重要（1b）。试图通过不对称羟基化5,8-二甲氧基-1,2,3,4-四氢-2-萘酸甲酯(9)的烯醇酸酯或16的8-苯氧基衍生物来更直接地制备3a和3b，导致低ee's，这是由于E/Z烯醇酸混合物的形成和羟基化过渡态中空间堵塞的增加。
Asymmetric hydroxylation of the potassium enolate of beta-keto ester 14, with (camphorsulfonyl)-oxaziridine (-)-7c [tetrahydro-9,9-dimethyl-8,8-dimethorry-4H-4a,7-methanooxazirino[3,2-i][2,1]-benzisothiazole 3,3-dioxide] affords alpha-hydroxy beta-keto ester (R)-(+)-15 in >95% ee. The high ee's are attributed to the fact that this enolate probably exists in one geometric form as a consequence of intramolecular chelation. Reduction of the ketone in 15 with triethylsilane and conversion of the ester group into the methyl ketone results in a highly efficient synthesis of the AB ring building block (R)-(-)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-napthol (3b), a key intermediate in the asymmetric synthesis of the antitumor agent 4-demethoxydaunomycin (1c). Selective deprotection of the 8-methoxy group in 3b with BBr3 gives 3a, important in the enantioselective synthesis of the clinically useful antitumor agent adriamycin (1b). Attempts to prepare 3a and 3b more directly by asymmetric hydroxylation of the enolates of methyl 5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoate (9) or the 8-benzyloxy derivative of 16 resulted in low ee's, attributable to the formation of E/Z enolate mixtures and increased steric congestion in the transition state for hydroxylation.