Intermolecular oxidative enolate heterocoupling
Intermolecular oxidative enolate heterocoupling
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DOI：
10.1002/anie.200603024
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
DeMartino, Michael P.
中科院分区：
文献类型：
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作者：
Baran, Phil S.;DeMartino, Michael P.
烯醇化物的氧化二聚化自1935年以来就已为人所知[1]，并在20世纪70年代由Saegusa，Mislow和其他人进一步研究（方案1a）。[2]形式上，这种转化通过利用它们的固有氧化态来实现两个相同的sp3杂化碳原子的直接结合，而没有底物预官能化。使用两种不同类型的偶联配偶体的类似过程尚未探索。[2d在2004年，我们提出了一种通过烯醇化物杂偶联将含NH的杂环直接偶联到各种羰基化合物的方法（方案1b）。[3，4]后来证明，两种不同类型的羰基物质可以在分子内（酯-酰胺）偶联。[5]在本文中，在分子间环境中探索了这种方法，并将其应用于医学相关化合物[6]和抗癌天然产物（α）-bursehernin（1）的对映选择性合成。考虑到可能发生的潜在背景反应，两个烯醇化物的分子间杂偶联是特别具有挑战性的化学转化。这些反应包括但不限于各单体的α-羟基化、单体或新形成的C12 C键的脱氢、分子间交叉和均-Dieckmann/羟醛缩合以及任一偶联配偶体的氧化均二聚化。事实上，如果分子间的交叉和同偶联过程仅由统计学控制，则两种烯醇化物物质的等摩尔混合物的异偶联将以最大50%的转化率发生。已经报道了两种不同酮的交叉偶联，但需要大量过量的一种配偶体（3-3.5当量，沿着另外的碱和氧化剂）。[2d原则上，如果烯醇化物各自的氧化电位和/或同二聚化的相对速率存在足够的差异，使得可以使用等摩尔比的起始材料，则烯醇化物的分子间杂偶联可以是合成上实用的。如表1所示，酰亚胺与酮（条目1-8）、酯（条目9 -11）和内酯（条目12）的交叉偶联现在是可能的。还发现内酰胺如羟吲哚适于交叉偶联（条目13-17）。在几乎所有情况下，使用等摩尔比的羰基物质，并且获得了合成有用的产率（大于50%的统计限度），即使在克规模上进行时（条目3和11，表1）。在所有情况下，剩余的材料主要是回收的单体，尽管在条目9-17中产生了少量的酰亚胺/羟吲哚同二聚体。值得注意的是，在条目9 -12（表1）中，产生了具有类似于N-酰基恶唑烷酮的非对映选择性烷基化的Evans模型的立体化学的产物，[7]而在条目1-8中，获得的加合物在该碳中心是差向异构的。这一经验性的观察结果目前还没有被完全理解，这一发现的机制基础正在调查中。尽管在大多数情况下非对映选择性是适度的，但是当形成这样的C13 C键时，该方法提供了明显的战略益处，因此提供了难以通过使用当前方法直接获得的分子。此外，产物可以服从于热力学平衡，如在天然产物合成的以下应用中。（S）-Bursehernin（1）是天然存在的一大类生物活性g-丁内酯木脂素的成员。[8]对1的研究表明，两种二氢肉桂酸衍生物的氧化偶联将是构建这些木脂素内酯的直观和有利的途径（方案2a）。实际上，对称的二苄基木脂素...
Oxidative dimerization of enolates has been known since 1935 [1] and was studied further by Saegusa, Mislow, and others in the 1970s (Scheme1a).[2] Formally, this transformation accomplishes the direct union of two identical sp3-hybridized carbon atoms with no substrate prefunctionalization by exploiting their innate oxidation state. The analogous process using two different types of coupling partners has remained unexplored.[2d, e] In 2004, we presented a method for the direct coupling of NH-containing heterocycles to various carbonyl compounds through enolate heterocoupling (Scheme 1b).[3, 4] It was later shown that two different types of carbonyl species can be coupled in an intramolecular sense (ester-amide).[5]Herein, this approach is explored in an intermolecular setting with application to the enantioselective synthesis of medicinally relevant compounds [6] and the anticancer natural product (À)-bursehernin (1). The intermolecular heterocoupling of two enolates is a particularly challenging chemical transformation given the potential background reactions that can occur. These include, but are not limited to, α-hydroxylation of each monomer, dehydrogenation of either the monomers or the newly forged CÀC bond, intermolecular cross-and homo-Dieckmann/aldol condensations, and oxidative homodimerization of either coupling partner. In fact, if the intermolecular cross-and homocoupling processes alone were governed by only statistics, the heterocoupling of an equimolar mixture of two enolate species would take place with a maximum of 50% conversion. Cross-coupling of two different ketones has been reported, but required a large excess of one partner (3–3.5 equiv, along with additional base and oxidant).[2d, e] In principle, intermolecular heterocoupling of enolates could be synthetically pragmatic if sufficient differences existed in their respective oxidation potentials and/or relative rates of homodimerization, such that equimolar ratios of the starting materials can be used. As depicted in Table1, the crosscouplings of imides with ketones (entries 1–8), esters (entries9–11), and lactones (entry12) are now possible. Lactams such as oxindoles were also found to be amenable to cross-coupling (entries 13–17). In nearly all cases, equimolar ratios of the carbonyl species are employed and synthetically useful yields (greater than the 50% statistical limit) were obtained, even when performed on a gram scale (entries 3 and 11, Table 1). In all cases, the remaining material was largely recovered monomer, although minor amounts of imide/oxindole homodimer were produced in entries 9–17. Notably, in entries9–12 (Table1), products with stereochemistry analogous to those of Evans model for the diastereoselective alkylation of N-acyl oxazolidinones were produced,[7] whereas in entries 1–8, the adducts obtained were epimeric at this carbon center. This empirical observation is not fully understood at this time, and the mechanistic basis for this finding is under investigation. Although the diastereoselectivity is modest in most cases, this method offers a clear strategic benefit when forging such CÀC bonds and thus provides molecules that would be difficult to access directly through use of current methods. Moreover, products may be amenable to thermodynamic equilibration, as in the following application to natural product synthesis.(À)-Bursehernin (1) is a member of a large class of naturally occurring bioactive g-butyrolactone lignans.[8] Inspection of 1 reveals that oxidative coupling of two dihydrocinnamic acid derivatives would be an intuitive and expedient route to construct these lignan lactones (Scheme2a). Indeed, symmetric dibenzyl lignan …