Development and Understanding of Synthetic Methodologies Using an Experimental-Computational Strategy

这项研究计划的目标是开发对环境影响小的高效合成方法。特别是，我们希望在立体选择性合成化学领域取得重大贡献。随着获得具有高选择性的一个或多个立体中心的化合物的需求日益增长，这是一个非常感兴趣的领域。完成这一壮举是大胆的，因为反应性和选择性必须同时优化。主要的挑战是理解立体诱导过程，以便获得高的立体选择性。我们的方法依赖于实验和计算研究之间的强烈互动，以最有效的方式获得这种类型的信息。分子模拟特别适合于理解这些过程。通过实现计算研究和实验研究之间的协同，我们将能够迅速获得机械性的见解，以加快研究进程。 在实验层面，该计划的重点是开发具有广泛适用性的有用的合成方法。因此，该计划分为两个不同的研究项目：1.基于高价碘化学的合成方法的开发；2.新配体的开发及其在有机金属催化中的应用。最终，这些工具将为合成复杂分子设计出更好的策略。它将促进学术界和工业界化学家的工作。在应用方面，这些方法将用于合成新的生物活性化合物(如抗生素、杀虫剂、抗癌剂)或功能材料。 我们的第一个研究主题是发展立体选择性碘(III)介导的过程。高价碘试剂由于是多价亲电体和温和的氧化剂而备受关注。它们是有毒过渡金属的一种很好的替代品，通常用于进行类似的转化。我们将在过去四年中在该领域获得的专业知识和机械洞察力的基础上，进入更高的影响力研究。这将通过在两个方面探索新的合成转化来实现：a)研究用于合成手性α-官能化羰基化合物的烯醇类似物；b)研究碘(III)化学中的新试剂和底物。为了促进这一发展，我们将同时进行计算研究，以更好地了解这些试剂和底物的反应途径。 我们的第二个研究主题将集中在基于N-亚氨基咪唑叶立德基序的配体和催化剂的合成和研究。发散的反合成断链和模块化是这些配体前体的关键特征。这种多样性是至关重要的，因为它将使配体前体文库的快速合成成为可能。这将极大地促进金属络合物反应性的微调。我们目前的工作集中在开发合成方法来获得这些化合物。我们现在将转向在催化方面的应用。我们将首先完成这些配体的两个新家族的开发，以巩固创建文库的潜力。同时，我们将评估非手性配合物在关键的氧化合成转化中作为催化剂的作用，并开发简单的合成路线来获得这些配体的手性版本。最终，我们将继续开发手性配体来创建用于立体选择性氧化合成转化的手性催化剂。这类广泛的配体的开发将极大地促进现有催化合成方法的扩展。

The goal of this research program is oriented toward the development of efficient synthetic methodologies with low environmental impact. In particular, we want to achieve significant contributions in the field of stereoselective synthetic chemistry. This is a domain of great interest with the growing need to obtain compounds bearing one or multiple stereogenic centers with high selectivities. Accomplishing this feat is audacious since both reactivity and selectivity must be optimized concurrently. The main challenge is to comprehend the stereoinduction process in order to attain high stereoselectivities. Our approach relies on a strong interaction between experimental and computational studies to acquire this type of information in the most efficient manner. Molecular modeling is particularly well suited to understand these processes. By achieving a synergy between computational and experimental studies, we will be able to rapidly obtain mechanistic insights to accelerate the research process. At the experimental level, the program focuses on the development of useful synthetic methods with broad applicability. Consequently, this program is divided in two distinct research projects: 1. Development of synthetic methods based on hypervalent iodine chemistry; 2. Development of new ligands and applications in organometallic catalysis. Ultimately, these tools will serve to devise better strategies for the synthesis of complex molecules. It will facilitate the work of chemists in both academia and industry. In terms of applications, these methods will be used for example for the synthesis of new bioactive compounds (e.g. antibiotics, insecticides, anti-cancer agents) or functional materials. Our first research theme targets the development of stereoselective iodine(III)-mediated processes. Hypervalent iodine reagents are of interest as they are polyvalent electrophiles and mild oxidants. They are a great alternative to toxic transition metals often used to perform similar transformations. We will construct upon the expertise and mechanistic insights that we gained in the last 4 years in this field, to move into higher impact research. This will be accomplished by exploring new synthetic transformations on two fronts: a) Study of enol analogs for the synthesis of chiral alpha-functionalized carbonyl compounds; b) Study of new reagents and substrates in iodine(III)-chemistry. To facilitate this development, we will undertake computational studies in parallel to better understand the reaction pathways of such reagents and substrates. Our second research theme will focus on the synthesis and investigation of ligands as well as catalysts based on these ligands built from the N-iminoimidazolium ylide motif. The divergent retrosynthetic disconnections and modularity are the key features of these ligand precursors. This diversity is crucial as it will enable the rapid synthesis of libraries of ligand precursors. It will greatly facilitate the fine tuning of the metal complexes reactivity. Our current work focuses on the development of synthetic methods to access these compounds. We will now move toward applications in catalysis. We will first finalize the development of two new families of these ligands to consolidate the potential of library creation. Concurrently, we will evaluate the achiral complexes as catalysts in key oxidative synthetic transformations and develop simple synthetic routes to access chiral versions of these ligands. Ultimately, we will move forward to exploit the chiral ligands for the creation of chiral catalysts used in stereoselective oxidative synthetic transformations. The development of this broad class of ligands will contribute greatly to the expansion of available catalytic synthetic methods.