STEREOCONTROLLED TOTAL SYNTHESIS OF (+/-)-TIRANDAMYCIN-A
STEREOCONTROLLED TOTAL SYNTHESIS OF (+/-)-TIRANDAMYCIN-A
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DOI：
10.1021/ja00278a032
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发表时间：
1986-09-03
影响因子：
15
通讯作者：
BARTLETT, PA
中科院分区：
文献类型：
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作者：
NEUKOM, C;RICHARDSON, DP;BARTLETT, PA
提出了一种与以前报道的路线或方法根本不同的标题化合物的全合成。通过二乙基丙烯丙烯诱导环氧化物置换和碘内顿化/环氧化的顺序制备了关键的立体化学中间体乙基内酯16。这个序列中的一个重要步骤是保护.alpha。-羟基酸作为其六氟丙酮（15）。以丙酮酮18为模型底物，建立了二烯基四羧酸侧链的引入方法。以丙酸甲酯为原料，用铜酸乙烯酯21加成二烯二烯酯22，通过丙二胺硅酯25的酰化和环化引入四羧酸单元。通过向内酯32中加入锂酮31，完成了双环酮的精化。这种材料的直接环化是不可行的，因此研究了一个涉及逐步闭合环的序列。氧化yrylide的分子内环加成。43)挫败了引入双键后生成烯酮酮9的一种方法；用晶体学方法对环加合物43的结构进行了表征。烯酮9最终是由还原中间体通过醇45进行环化，然后是醇的氧化和脱氢，并通过晶体学验证了结构。从中间体45开始，在模型系统中开发的方法被应用于引入二烯酯侧链（.fwdarw）。48)，烯酮功能（.fwdarw）。49)，四羧酸部分(.fwdarw。53)。(+ -)。如前所述，-地兰达霉素A是由三氟乙酸催化的N-（2,4-二甲氧基苄基）基的裂解产生的。
A total synthesis of the title compound which is fundamentally different from previously reported routes or approaches is presented. The key stereochemical intermediate, acetylenic lactone 16, is prepared in a sequence involving diethyl-propynylalane-induced epoxide displacement and iodolactonization/epoxidation. An important step in this sequence is the protection of an .alpha.-hydroxy acid as its hexafluoroacetonide (15). Methodology for introduction of the dienoyl tetramic acid side chain was developed with the ketal acetonide 18 as a model substrate. The dienoic ester 22 was prepared via addition of vinyl cuprate 21 to methyl propiolate, and the tetramic acid unit was introduced via acylation of silyl malonamidate 25 followed by cyclization. Elaboration of the bicyclic ketal was accomplished via addition of lithio ketal 31 to lactone 32. Direct cyclization of this material was not feasible, and a sequence involving stepwise ring closure was investigated. Intramolecular cycloaddition of an oxidopyrylium ylide (41 .fwdarw. 43) foiled one approach to generate enone ketal 9 after introduction of the double bond; the structure of the cycloadduct 43 was elucidated by crystallography. Enone 9 was eventually produced by cyclization of a reduced intermediate, via alcohol 45, followed by oxidation and dehydrogenation of the alcohol, and the structure was verified by crystallography. From intermediate 45, the methodology developed in the model systems was applied to the introduction of the dienoic ester side chain (.fwdarw. 48), the enone functionally (.fwdarw. 49), and the tetramic acid moiety (.fwdarw. 53). (.+-.)-Tirandamycin A was produced from trifluoroacetic acid catalyzed cleavage of the N-(2,4-dimethoxybenzyl) group, as reported previously.