Toward and Around Nitrogen-Containing Molecules: Synthesis, Asymmetric Induction and Mechanistic Studies.

含氮分子及其周围：合成、不对称诱导和机理研究。

• 批准号: RGPIN-2014-05281
• 负责人: Lebel, Hélène
• 金额: $ 3.93万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567067
• 关键词: Toward; Around; Nitrogen; Containing; Molecules

The global scientific objective of this project is to study the synthesis, biological, and physical properties of various nitrogen-containing molecules. The creation of C–N bonds is still an important challenge in synthetic organic chemistry, especially to produce chiral amines as one stereoisomer. Nitrogen-containing molecules are an important class of compounds to study, as they are ubiquitous components of biologically active molecules; “greater than 75% of drugs and drug candidates incorporate amine functionality.” (Liu, Cogan, Ellman, J. Am. Chem. Soc. 1997, 119, 9913). Furthermore, many novel organic materials that display interesting properties also incorporate nitrogen atoms. My group has been interested at using metal nitrene species to create C–N bonds. Novel metal nitrene precursors, namely N-tosyl- and N-mesyl-oxycarbamates have been developed for the synthesis of oxazolidinones, aziridines, benzylic, allylic, and propargylic amines, as well as sulfilimines. In many cases, stereoselective reactions were achieved to produce the desired chiral nitrogen-containing molecules with high level of diastereoselectivity. There are many aspects of this chemistry that remain unexplored, and this proposal will address these unsolved areas. Intramolecular C–H amination reactions from sulfonyoxycarbamates using rhodium dimer catalysts produced oxazolidinones in good to high yields. However, despite many efforts by us, and others, no general asymmetric version of this reaction has been reported. Furthermore, rhodium is among the most expensive metals. We have recently determined that iron complexes could also catalyze this reaction and we plan to develop novel ligands to induce stereoselectivities. We have recently developed a novel stereoselective method to synthesize chiral sulfimines. Few stereoselective methods have been reported to synthesize sulfilimines, and none furnish aliphatic derivatives in high yield and stereoselectivity. Importantly, the recent discovery of sulfilimine crosslinks in collagen IV networks has shed light on the importance of this class of chemical compounds and highlights the need to develop new synthetic methods around this moiety. We were encouraged to discover that our amination reagents performed well with not only aromatic thioethers, but also with aliphatic thioethers. Both yield and dr were significantly enhanced in the presence of catalytic amount of DMAP and BisDMAPCH2Cl2. An X-ray crystal structure of the Rh2[(S)-nttl]4•(DMAP)2 has been obtained. Mechanistic studies (cyclic voltammetry) suggested the involvement (participation) of a Rh(II)–Rh(III) complex as catalytically active species. We plan to study the reactivity of sulfilimines and sulfoximines and develop new chiral ligands based on these motifs. Finally, continuous flow synthesis will be explored as a technique to achieve chemical reactivity otherwise unattainable through traditional batch methods for both metal nitrene reactions and transition metal-catalyzed olefination reactions with diazo reagents. In summary, the proposed research program aims at making significant discoveries in the area of metal nitrene chemistry to perform C–H and thioether aminations. We plan to focus on first row transition metal complexes and to explore novel chiral ligands. Indeed we envision exploiting the rich chemistry of chiral sulfur nitrogen compounds and exploring these as novel chiral ligands. Finally we plan to make fundamentally new discoveries by taking advantages of the Continuous flow synthesis technology

该项目的全球科学目标是研究各种含氮分子的合成、生物和物理特性。C-N键的形成仍然是有机合成中的一个重要挑战，特别是在制备手性胺作为一种立体异构体方面。含氮分子是一类重要的研究化合物，因为它们是生物活性分子的普遍存在的组分;“超过75%的药物和候选药物含有胺官能团。(Liu供稿：Cogan，Ellman，J. Am. 1997，119，9913）。此外，许多显示出有趣性质的新型有机材料也包含氮原子。我的团队一直对使用金属氮烯物种来创建C-N键感兴趣。新的金属氮烯前体，即N-甲苯磺酰基-和N-甲磺酰基-氧代氨基甲酸酯已被开发用于合成恶唑烷酮，氮杂环丙烷，苄基，烯丙基和炔丙基胺，以及磺酰亚胺。在许多情况下，实现立体选择性反应以产生具有高水平的非对映选择性的所需手性含氮分子。这种化学有许多方面尚未探索，本提案将解决这些未解决的领域。使用铑二聚体催化剂从磺酰氧基氨基甲酸酯进行分子内C-H胺化反应，以良好至高产率产生恶唑烷酮。然而，尽管我们和其他人做了许多努力，但还没有报道这种反应的一般不对称版本。此外，铑是最昂贵的金属之一。我们最近已经确定，铁配合物也可以催化这一反应，我们计划开发新的配体诱导立体选择性。我们最近开发了一种新颖的立体选择性方法来合成手性硫胺。很少有立体选择性的方法被报道用于合成硫亚胺，并且没有一种以高产率和立体选择性提供脂肪族衍生物。重要的是，最近在胶原蛋白IV网络中发现的硫亚胺交联揭示了这类化合物的重要性，并强调了围绕这一部分开发新合成方法的必要性。令人鼓舞的是，我们发现我们的胺化试剂不仅与芳香族硫醚，而且与脂肪族硫醚表现良好。在催化量的DMAP和BisDMAPCH2Cl2的存在下，产率和dr均显着提高。获得了Rh_2 [（S）-nttl]_4·（DMAP）_2的X射线晶体结构。机理研究（循环伏安法）表明Rh（II）-Rh（III）络合物作为催化活性物质参与（参与）。我们计划研究硫亚胺和亚砜亚胺的反应活性，并基于这些基序开发新的手性配体。最后，连续流合成将探索作为一种技术，以实现化学反应性，否则无法通过传统的间歇方法，金属氮烯反应和过渡金属催化的烯烃化反应与重氮试剂。总之，拟议的研究计划旨在在金属氮烯化学领域取得重大发现，以进行C-H和硫醚胺化。我们计划集中在第一行过渡金属配合物和探索新的手性配体。事实上，我们设想利用丰富的化学手性硫氮化合物和探索这些作为新的手性配体。最后，我们计划通过利用连续流合成技术来进行根本性的新发现