A modular, efficient, and stereoselective synthesis of substituted piperidin-4-ols.
A modular, efficient, and stereoselective synthesis of substituted piperidin-4-ols.
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DOI：
10.1002/anie.201004712
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发表时间：
2010-11-22
影响因子：
16.6
通讯作者：
Zhang, Liming
中科院分区：
文献类型：
--
作者：
Cui, Li;Li, Chaoqun;Zhang, Liming
哌啶是药物化学中研究的各种生物碱和多种化合物中的关键结构基元。虽然已经开发了许多方法来构建它们，但仍然需要新的方法，特别是那些高效率、良好的模块化和良好的立体选择性的方法。最近对金催化的研究[1]提供了几种新的合成哌啶的方法。例如，我们早些时候报道过，可以通过两步、[4+2]的方式合成哌啶-4-酮；[2a]然而，产品仅限于那些具有难以去除的脂肪基的环氮取代或区域选择性较低的苄基。为了解决这一缺陷并开发一种普遍有效和模块化的N-未取代哌啶类化合物的合成，我们设想，如方案1所示，N-高丙叉酰胺2的金催化环化反应将提供环酰亚胺3，它可以被化学选择性地还原为α-氨基醚A。我们预计A将经过自发的费里尔重排提供哌啶-4-酮B，后者可能进一步原位还原为相应的醇(即4)。这种设计的几个方面值得注意：1)序列是高度模块化和灵活的；它是由容易获得的亚胺、炔丙基格氏和羧酸或其衍生物组成的整体{[2+3]+1}环；2)对映体合成很容易实现，因为手性亚胺很容易得到手性胺1；[4]3)它构成了尚未实现的氮杂-佩塔西-费里尔重排的替代品。[5，6]这是一个令人惊讶的空白，因为佩塔西-费里尔重排[7]已经在复杂的天然产物的全合成中获得了很大的成功。[8]4)哌啶氮是自由的，可以很容易地衍生化；5)金催化不是关键的转化，而是用来提供后续过程所需的中间体。这种金催化和其他截然不同的转化在一锅法中的顺序组合为开发高效的多种合成方法提供了新的机会。
Piperidine is a key structural motif in various alkaloids and a variety of compounds studied in medicinal chemistry. Though many methods have been developed for their construction, there is still a need for noval approaches, especially those with high efficiency, good modularity and excellent stereoselectivity.Recent intense research in gold catalysis [1] has provided several novel methods of piperidine synthesis.[2, 3] For example, we reported earlier that piperidin-4-ones could be prepared in a two-step,[4+ 2] manner;[2a] however, the products are limited to those with ring nitrogen substituted with hard-to-remove aliphatic groups or benzyl groups suffering from low regioselectivities. To address this deficiency and develop a generally effective and modular synthesis of N-unsubstituted piperidines, we envisioned, as shown in Scheme 1, that a goldcatalyzed cyclization of N-homopropargyl amide 2 would offer cyclic imidate 3, which could be chemoselectively reduced to afford α-amino ether A. We anticipated that A would undergo spontaneous Ferrier rearrangement to furnish piperidin-4-one B, which might be further reduced in situ to the corresponding alcohol (ie 4). Several aspects of this design are noteworthy: 1) the sequence is highly modular and flexible; it is an overall {[2+ 3]+ 1} annulation from readily available imines, propargyl Grignard, and carboxylic acids or their derivatives; 2) enantiomeric synthesis is readily achievable as chiral amine 1 would be easily prepared from chiral sulfinyl imines;[4] 3) it constitutes an alternative to an aza-Petasis-Ferrier rearrangement, which has not been realized.[5, 6] This is a surprising void as the Petasis-Ferrier rearrangement [7] has been applied with much success in total synthesis of complex natural products.[8] 4) the piperidine nitrogen is free and could be readily derivatized; 5) the gold catalysis is not the key transformation but instead employed to deliver requisite intermediates for subsequent processes. This sequential combination of gold catalysis and other distinctively different transformations in a one-pot process offer new opportunities to develop versatile synthetic methods with high efficiency.
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影响因子：
--
作者：
Chalard, P;Remuson, R;Gramain, JC
通讯作者：
Gramain, JC
影响因子：
2.8
作者：
Hashmi, A. Stephen K.;Rudolph, Matthias;Frey, Wolfgang
通讯作者：
Frey, Wolfgang
影响因子：
15
作者：
Smith, Amos B., III;Bosanac, Todd;Basu, Kallol
通讯作者：
Basu, Kallol
DOI：
10.1039/c001314e
发表时间：
2010-05-21
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Cui L;Ye L;Zhang L
通讯作者：
Zhang L
影响因子：
9.6
作者：
Cui Li;Zhang LiMing
通讯作者：
Zhang LiMing