Synthesis of rimocidinolide methyl ester, the aglycone of (+)-rimocidin.
Synthesis of rimocidinolide methyl ester, the aglycone of (+)-rimocidin.
复制标题
利莫西丁内酯甲酯（( )-利莫西丁的苷元）的合成。
DOI：
10.1002/anie.200453697
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Rychnovsky,ScottD
中科院分区：
文献类型：
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作者：
Packard,GarrickK;Hu,Yueqing;Vescovi,Andrea;Rychnovsky,ScottD
氰醇丙酮化物在我们的实验室中已被广泛用作顺式-1，3-二醇的取代基[14]，并且该策略已被应用于例如罗沙替星[15]和皮肤抑制素的合成。[16]然而，rimocidin的结构不包含任何顺式-1，3-二醇片段。在我们制备rimocidin的方法中，氰醇丙酮化物将用作β-羟基酮的取代基，而不是顺式-1，3-二醇丙酮化物。因此，氰醇将恢复其早期的应用作为酰基阴离子等价物，[17]并且该策略与广泛使用的二噻烷断开相当。[18]在方案1中给出了rimocidinesteryl甲酯（2）的逆合成分析。大环内酯环将由两个片段制备，不饱和醛3和复合膦酸酯4。在3和4之间会形成两个键：酯键和烯烃。酯和烯烃可以以任何顺序形成，但一般来说，Horner-Emmons环化路线有更好的先例，将首先进行研究。膦酸酯4将由受保护的多元醇5制备。我们计划通过氰醇丙酮偶联组装多元醇5。多元醇链中最复杂的链段是C12-C17链段10，它是半缩醛环的前体。其基于对映选择性羟醛缩合反应的合成概述于方案2中。7和醛6之间的Evans羟醛缩合反应[19]得到了被去共轭巴豆酸酯污染的预期产物。羟醛加合物在转化成其Weinreb酰胺8后最方便地分离。[20]用烯丙基溴化镁处理，随后用Evans三乙酰氧基硼氢化物进行反选择性还原[21]，生成作为单一非对映异构体的二醇9。丙酮化合物的形成没有进行到完全，回收的起始材料被再循环以提高材料产量。TIPS基团的裂解和用PPh 3和I2引入碘取代基完成了10的合成，七步总产率为44%。制备了两种氰醇丙酮化物16和20用于合成。16的合成在方案3中给出，并且也使用Evans羟醛偶联。[19]11和醛12之间的羟醛缩合导致预期的加合物。生产二醇13的最佳工艺包括水解除去助剂和用LAH还原酸。加合物的直接还原产生复杂的混合物。研究了几种用于选择性苄基化的方法，
Cyanohydrin acetonides have been used extensively in our laboratories as synthons for syn-1, 3-diols,[14] and this strategy has been applied, for example, to syntheses of roxaticin [15] and dermostatin.[16] The structure of rimocidin, however, does not contain any syn-1, 3-diol segments. In our approach to rimocidin, cyanohydrin acetonides would be used as synthons for β-hydroxyketones rather than for syn-1, 3-diol acetonides. Thus the cyanohydrin would revert to its earlier application as an acyl anion equivalent,[17] and the strategy is comparable to the widely used dithiane disconnection.[18] A retrosynthetic analysis of rimocidinolide methyl ester (2) is presented in Scheme 1. The macrolide ring would be prepared from two segments, an unsaturated aldehyde 3 and the complex phosphonate 4. Two bonds would be formed between 3 and 4: an ester linkage and an alkene. The ester and alkene could be formed in either order, but in general the Horner–Emmons cyclization route has better precedent and would be investigated first. The phosphonate 4 would be prepared from protected polyol 5. We planned to assemble the polyol 5 through cyanohydrin acetonide couplings. The most complex segment of the polyol chain is the C12–C17 segment 10, the precursor to the hemiacetal ring. Its synthesis, based on an enantioselective aldol reaction, is outlined in Scheme 2. An Evans aldol reaction [19] between 7 and aldehyde 6 gave the expected product contaminated with the deconjugated crotonate. The aldol adduct was most conveniently isolated after conversion into its Weinreb amide 8.[20] Treatment with allyl magnesium bromide and subsequent anti-selective reduction with the Evans triacetoxyborohydride [21] generated diol 9 as a single diastereomer. Acetonide formation did not proceed to completion, and the recovered starting material was recycled to improve material throughput. Cleavage of the TIPS group and introduction of the iodide substituent with PPh3 and I2 completed the synthesis of 10 [22] in an overall yield of 44% in seven steps. Two cyanohydrin acetonides, 16 and 20, were prepared for the synthesis. The synthesis of 16 is presented in Scheme 3 and also uses an Evans aldol coupling.[19] Aldol coupling between 11 and aldehyde 12 led to the expected adduct. The optimal procedure for producing diol 13 involved hydrolytic removal of the auxiliary and reduction of the acid with LAH. Direct reduction of the adduct led to complex mixtures. Several approaches were investigated for the selective benzylation of