Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules.
Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules.
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DOI：
10.1021/ar5004658
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发表时间：
2015-03-17
影响因子：
18.3
通讯作者：
Stoltz BM
中科院分区：
文献类型：
--
作者：
Liu Y;Han SJ;Liu WB;Stoltz BM
对疗效更好、副作用更小的药物的需求不断促使科学家探索广阔的化学空间。传统上，药物化学家把注意力集中在非手性或所谓的“扁平”分子上。最近，人们的注意力转向了具有立体中心的分子，因为它们的三维结构代表了化学空间的更大一部分，并且与扁平芳香化合物相比具有许多优越的性质。特别是四元立体中心，极大地增加了分子的三维性和新颖性。然而，在构建四元立体中心方面的合成挑战在很大程度上阻碍了它们在药物发现中的实施。在简单分子支架中，缺乏有效和广泛的对映选择性形成四元立体中心的方法，这促使我们研究新的化学和开发创新的工具和解决方案。在这篇文章中，我们描述了三种构造季立体中心的方法：3-卤代吲哚的亲核取代，硼酸与环烯酮的共轭加成，烯醇酸的烯丙基烷基化。在第一种方法中，丙二酸酯亲核试剂在铜(II)-双恶唑啉催化剂的催化下攻击亲电的3-卤代啉。通过这种方法可以得到多种含苯基四元立体中心的氧吲哚。然而，它只适用于专门的3,3-二取代氧吲哚体系。为了在更普遍的情况下获得苯基四元立体中心，我们将注意力转向了碳亲核试剂对α，β-不饱和羰基受体的对映选择性共轭加成。我们发现，在钯吡啶肟唑啉催化配合物的存在下，芳基硼酸在β-取代环烯酮上平稳地加成，使酮具有高收率和对映选择性的β-苯基季立体中心。该反应与广泛的芳基硼酸、β取代基和环尺寸兼容。除了苯基四元立体中心外，一个更具挑战性的基序是不与芳香基团相邻的四元立体中心。这种中心在化学空间中代表了更一般的结构，但更难以通过不对称催化形成。为了应对这一更大的挑战，并受到更大回报的激励，我们大约在十年前进入了钯催化的前手性烯醇酯亲核试剂的不对称烯丙基烷基化领域。在Tsuji解决了不对称酮的位置选择性问题的基础上，我们发现膦酰萘唑啉配体有效地使该反应具有对映选择性。从那时起，广泛的研究表明，该反应具有广泛的范围，并接受一系列底物类别，每种底物在合成应用中都有其独特的优势。以优异的收率和对映选择性获得了一系列具有α-季位立体中心的羰基化合物，并探索了更多的可能性。作为钯催化的替代品，我们还研究了铱催化的不对称烯丙基烷基化反应，该反应在一次转化中产生邻近的季和叔立体中心。总的来说，这些方法提供了获得具有单季立体中心的小分子构建块的途径，可以应用于各种分子支架，并且可以耐受广泛的官能团。我们设想在这个帐户中报告的化学将在药物发现和设计中越来越有用。
The ever-present demand for drugs with better efficacy and fewer side effects continually motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have focused much attention on achiral or so-called “flat” molecules. More recently, attention has shifted toward molecules with stereogenic centers since their three-dimensional structures represent a much larger fraction of the chemical space and have a number of superior properties compared with flat aromatic compounds. Quaternary stereocenters, in particular, add greatly to the three-dimensionality and novelty of the molecule. Nevertheless, synthetic challenges in building quaternary stereocenters have largely prevented their implementation in drug discovery. The lack of effective and broadly general methods for enantioselective formation of quaternary stereocenters in simple molecular scaffolds has prompted us to investigate new chemistry and develop innovative tools and solutions. In this Account, we describe three approaches to constructing quaternary stereocenters: nucleophilic substitution of 3-haloindoles, conjugate addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach, malonic ester nucleophiles attack electrophilic 3-halooxindoles, mediated by a copper(II)-bisoxazoline catalyst. A variety of oxindoles containing a benzylic quaternary stereocenter can be accessed through this method. However, it is only applicable to the specialized 3,3-disubstituted oxindole system. To access benzylic quaternary stereocenters in a more general context, we turned our attention to the enantioselective conjugate addition of carbon nucleophiles to α,β-unsaturated carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline complex, arylboronic acids add smoothly to β-substituted cyclic enones to furnish ketones with a β-benzylic quaternary stereocenter in high yields and enantioselectivities. The reaction is compatible with a wide range of arylboronic acids, β-substituents, and ring sizes. Aside from benzylic quaternary stereocenters, a more challenging motif is a quaternary stereocenter not adjacent to an aromatic group. Such centers represent more general structures in chemical space, but are more difficult to form by asymmetric catalysis. To address this greater challenge, and motivated by the greater reward, we entered the field of palladium-catalyzed asymmetric allylic alkylation of prochiral enolate nucleophiles about a decade ago. On the basis of Tsuji’s work, which solved the issue of positional selectivity for unsymmetrical ketones, we discovered that the phosphinooxazoline ligand effectively rendered this reaction enantioselective. Extensive investigations since then have revealed that the reaction exhibits broad scope and accepts a range of substrate classes, each with its unique advantage in synthetic applications. A diverse array of carbonyl compounds bearing α-quaternary stereocenters are obtained in excellent yields and enantioselectivities, and more possibilities have yet to be explored. As an alternative to palladium catalysis, we also studied iridium-catalyzed asymmetric allylic alkylations that generate vicinal quaternary and tertiary stereocenters in a single transformation. Overall, these methods provide access to small molecule building blocks with a single quaternary stereocenter, can be applied to various molecular scaffolds, and tolerate a wide range of functional groups. We envision that the chemistry reported in this Account will be increasingly useful in drug discovery and design.
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影响因子：
21.8
作者：
通讯作者：
--
影响因子：
15
作者：
Edmondson, S;Danishefsky, SJ;Rosen, N
通讯作者：
Rosen, N
影响因子：
4.9
作者：
Helmchen, Guenter;Dahnz, Axel;Weihofen, Robert
通讯作者：
Weihofen, Robert
DOI：
10.1021/jo502534g
发表时间：
2015-01-02
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Han SJ;Vogt F;May JA;Krishnan S;Gatti M;Virgil SC;Stoltz BM
通讯作者：
Stoltz BM
3,3-二取代羟吲哚的催化不对称合成：重氮杂吲哚加入该领域
影响因子：
1.8
作者：
Cao, Zhong-Yan;Wang, Yu-Hui;Zhou, Jian
通讯作者：
Zhou, Jian