Stereoselective preparation of (E)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its C7 epimer.
Stereoselective preparation of (E)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its C7 epimer.
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DOI：
10.1002/chem.201201600
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发表时间：
2012-08
期刊：
影响因子：
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通讯作者：
T. Hampel;T. Neubauer;T. Van Leeuwen;T. Bach
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文献类型：
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作者：
T. Hampel;T. Neubauer;T. Van Leeuwen;T. Bach
标题化合物以27个线性步骤的最长序列合成，总收率为2.9%和3.9%。在合成过程中，从D-甘露醇制备了代表碳片段C1-C7（东部片段）和C9-C21（西部片段）的两种醛，其中每一种都在各自的仲甲基醚基团（C6、C12）处掺入了关键的立体中心来自手性池材料。采用α-氯乙基氯化镁作为两碳结构单元实现了两种醛的组装。α-氯乙基对甲苯基亚砜经亚砜-镁交换反应生成类卡宾试剂，并与Eastern片段（C1-C7）的高灵敏醛顺利加成。氧化后，生成α-氯乙基酮，其在SmI（2）促进下与另一个醛片段进行干净且高产率的还原加成。脱水在四个步骤中以72%的总产率递送C8和C9之间的关键双键。该方法被证明是普遍适用于几种醛的外消旋自由转化为相应的α-氯乙基酮（11例，64-95%）和偶合协议（5例，66-90%）。格尔德霉素氢醌合成的进一步过程包括在C7处的非对映选择性还原和在C20处的氨基的实施。由于两个异丙基保护基的脱保护不能以显着的产率实现，18，21-二异丙基-格尔德霉素氢醌的结构通过其从天然产物的独立合成来证明。
The title compounds were synthesized in a longest sequence of 27 linear steps and with an overall yield of 2.9 and 3.9%. In the course of the synthesis, two aldehydes representing carbon fragments C1-C7 (Eastern fragment) and C9-C21 (Western fragment) were prepared from D-mannitol, each of which incorporated a key stereogenic center at the respective secondary methyl ether group (C6, C12) from the chiral pool material. The assembly of the two aldehydes was achieved employing α-chloroethyl magnesium chloride as a two-carbon building block. The carbenoid reagent was generated from α-chloroethyl para-tolylsulfoxide by sulfoxide-magnesium exchange and it added smoothly to the highly sensitive aldehyde of the Eastern fragment (C1-C7). Upon oxidation, an α-chloroethyl ketone was generated, which underwent a clean and high-yielding reductive SmI(2) -promoted addition to the other aldehyde fragment. Dehydration delivered the key double bond between C8 and C9 in an overall yield of 72% over four steps. The method was shown to be generally applicable to the racemization-free conversion of several aldehydes into the respective α-chloroethyl ketone (11 examples, 64-95%) and to the coupling protocol (5 examples, 66-90%). The further course of the geldanamycin hydroquinone synthesis included a diastereoselective reduction at C7 and the implementation of the amino group at C20. Since deprotection of the two isopropyl protecting groups could not be achieved in significant yields, the structure of 18,21-diisopropyl-geldanamycin hydroquinone was proven by its independent synthesis from the natural product.