Alternate Self-Regeneration of Stereocenters: Enantioselective Generation of a C2-Symmetric Chiral Nitroxide and Its Reduction to the Corresponding, Highly Sterically Hindered Amine
Alternate Self-Regeneration of Stereocenters: Enantioselective Generation of a C2-Symmetric Chiral Nitroxide and Its Reduction to the Corresponding, Highly Sterically Hindered Amine
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立体中心的交替自我再生：C2对称手性氮氧化物的对映选择性生成及其还原为相应的高空间位阻胺
DOI：
10.1021/jo971812p
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发表时间：
1997
影响因子：
3.6
通讯作者：
J. Pierre
中科院分区：
文献类型：
--
作者：
J. Einhorn;C. Einhorn;F. Ratajczak;I. Gautier;J. Pierre
氮氧自由基在有机稳定自由基中继续发挥核心作用。它们一直被广泛用作自旋标记1和自旋捕获实验2，但最近出现了许多其他有前途的应用：它们现在被研究为有机磁性材料制备的自旋源，3作为高选择性氧化剂的前体，4或作为控制“活性”自由基聚合过程的封端剂。5手性氮氧自由基近年来由于其作为对映选择性氧化催化剂、顺磁性手性液晶的开发或与前手性自由基的立体选择性偶联反应的潜在应用而引起了人们的特别兴趣。6此外，手性氮氧化物可以通过非常简单和温和的化学过程还原转化为相应的、潜在有价值的手性胺。2a在这种情况下，C2-对称手性氮氧自由基似乎是有价值的合成目标，由于C2手性助剂在不对称合成中的重要性。7到目前为止，虽然已经描述了几种C2-对称氮氧自由基的外消旋形式，但光学活性C2氮氧自由基的实例仍然很少。Müllen 8 f和Sogah 5c制备了外消旋反式-2，5-二甲基-2，5-二苯基吡咯烷-1-氧基自由基3。Müllen通过手性HPLC以半克规模分离其对映异构体。然而，立体中心的绝对构型仍然未知。我们在此描述了从容易获得的光学活性反式-2，5-二甲基吡咯烷（1b）开始的氮氧自由基3的对映选择性方法（方案1）。合成的原理非常简单：C2-对称的光学活性吡咯烷1b，带有两个等价的立体中心，首先被氧化成光学活性硝酮2。以下合成利用最初由Keana 8a-d开发并且也由Mullen 8 f使用的方法，并且通过两个连续的硝酮亲核加成-氧化序列进行。这种方法被认为是允许一个有效的控制新创建的立体中心的相对立体化学，亲核试剂被引入到中间硝酮的最易接近的面，即，在反式关系相对于庞大的取代基。当应用于光学活性硝酮2时，对新产生的立体中心进行绝对控制，产生光学活性的C2-对称氮氧自由基3。从C2-对称吡咯烷1开始，整个过程可以在概念上与Seebach的立体中心自再生（SRS）的一般原理相关。9在我们的例子中，每个立构中心交替地起着“手性记忆”的作用，第二个立构中心在氧化成硝酮的过程中被破坏。因此，剩余的立构中心能够确保对该硝酮的后续亲核加成的绝对立体化学控制。已知用于合成光学活性反式-2，5-二甲基吡咯烷的改进方法。10 Masamune报道的最方便的方法之一，11从光学纯的（2S，5S）-2，5-己二醇开始，12现在（1）（a）Keana，JFW Chem.Rev.1978，78，37-64。（B）Bossmann，SH; Ghatlia，ND; Ottaviani，MF; Turro，C.; Dürr，H.; Turro，NJ Synthesis 1996，1313-1319. (c)Ulrich，G; Turek，P.; Ziessel，R.; De Cian，A.; Fischer，J. Chem. Commun. 1996，2461-2462。（2）（a）奥里奇，《硝酮、硝膦酸盐和氮氧化物》中的HG; Patai，S.，拉波波特，Z.，编辑; John Wiley & Sons，Inc.：纽约，1989年;第313-399页。最近的一个例子，见：（B）Sankuratri，N.; Janzen，E. G.地; West，MS; Poyer，JL J.Org.Chem.1997，62，1176-1178和其中的参考文献。
Nitroxides continue to play a central role among organic stable free radicals. They have been, and are still, extensively used as spin labels1 and in spin trapping experiments, 2 but many other promising applications have emerged more recently: they are now studied as spin sources for the elaboration of organic magnetic materials, 3 as precursors of highly selective oxidants, 4 or as capping agents for the control of “living” free-radical polymerization processes. 5 Chiral nitroxides have attracted a special interest in very recent years due to their potential applications as enantioselective oxidation catalysts, for the development of paramagnetic chiral liquid crystals, or in stereoselective coupling reactions with prochiral radicals. 6 Moreover, chiral nitroxides can be reductively transformed into the corresponding, potentially valuable, chiral amines by very simple and mild chemical processes. 2a In this context, C2-symmetric chiral nitroxides appear to be valuable synthetic targets, owing to the well-recognized importance of C2 chiral auxiliaries in asymmetric synthesis. 7 Up to now, although several C2-symmetric nitroxide have been described in their racemic form, 5c, 8a-e examples of optically active C2 nitroxides remain scarce. Müllen8f and Sogah5c prepared racemic trans-2, 5-dimethyl-2, 5-diphenylpyrrolidin-1-oxy radical 3. Müllen separated its enantiomers on a half gram scale by chiral HPLC. However, the absolute configurations of the stereocenters remained unknown. We describe herein an enantioselective approach to nitroxide 3, starting from readily available optically active trans-2, 5-dimethylpyrrolidine (1b)(Scheme 1). The principle of the synthesis is very simple: C2-symmetric optically active pyrrolidine 1b, bearing two equivalent stereogenic centers, was first oxidized into optically active nitrone 2. The following synthesis utilized the methodology originally developed by Keana8a-d and also used by Mullen8f and proceeded via two successive nitrone nucleophilic addition-oxidation sequences. This method was known as allowing an efficient control of the relative stereochemistry of the newly created stereocenters, the nucleophiles being introduced on the most accessible faces of the intermediate nitrones, ie, in the trans relationship with respect to the bulkiest substituent. When applied to optically active nitrone 2, an absolute control of the newly created stereocenters was performed, generating optically active, C2-symmetric nitroxide 3. Starting from C2-symmetric pyrrolidine 1, the whole process can be conceptually related to Seebach’s general principle of self-regeneration of stereocenters (SRS). 9 In our case, each stereocenter alternatively plays the role of “chiral memory”, the second one being destroyed during oxidation into a nitrone. The remaining stereocenter is, therefore, able to ensure the absolute stereochemical control of the subsequent nucleophilic addition to this nitrone. Improved methods are known for the synthesis of optically active trans-2, 5-dimethylpyrrolidine. 10 One of the most convenient methods, reported by Masamune, 11 starts from optically pure (2S, 5S)-2, 5-hexanediol, 12 now (1)(a) Keana, JFW Chem. Rev. 1978, 78, 37-64. For recent examples see:(b) Bossmann, SH; Ghatlia, ND; Ottaviani, MF; Turro, C.; Dü rr, H.; Turro, NJ Synthesis 1996, 1313-1319.(c) Ulrich, G; Turek, P.; Ziessel, R.; De Cian, A.; Fischer, J. Chem. Commun. 1996, 2461-2462.(2)(a) Aurich, HG in Nitrones, Nitronates and Nitroxides; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons, Inc.: New York, 1989; pp 313-399. For a recent example, see:(b) Sankuratri, N.; Janzen, E. G.; West, MS; Poyer, JL J. Org. Chem. 1997, 62, 1176-1178 and references therein.