Iodine-Based Electrophilic Chiral Reagents – Design and Applications in Asymmetric Synthesis – IODINNOV
New chiral iodine-based reagents for metal-free asymmetric synthesis.
Chiral hypervalent iodine-based reagents, a “green” alternative to metal-based oxidants, for the synthesis of compounds with pharmacological potential.
Chiral hypervalent iodine-based reagents, a “green” alternative to metal-based oxidants, for the synthesis of compounds with pharmacological potential.
The chemistry of hypervalent iodine organic compounds, also referred to as iodanes, has experienced an impressive development since the early 1990s. Several reagents are now commercially available or readily accessible in a few synthesis steps. Used in routine by chemists as agents for oxidation reactions, they allow to perform selective chemical transformations in synthesis of complex molecules, such as some active principles found in drugs. The environmental impact of iodanes is benign, as opposed to that of the toxic heavy metal-based reagents (e.g., lead, thallium or mercury). Several areas of iodane chemistry continue to fuel research efforts worldwide. The development of new chiral iodanes is among the most competing ones. These reagents would make it possible to control the stereochemistry of some oxygenative reactions and would find applications in the chemical synthesis of natural products with pharmacological potential.
Our development of new and effective chiral iodanes is based not only on experimental organic chemistry to synthesize iodinated precursors to be converted into hypervalent iodine(III) and/or iodine(V)-based compounds, but also on theoretical chemistry to try to rationalize the iodanes formation (IIII versus IV) according to the nature of the iodinated precursor. These two approaches are complementary in our efforts aimed at identifying the best structural modifications to be done on our chiral iodo-compounds to increase their efficiency as inductors of asymmetry. Theoretical calculations also allow to gather crucial information on the reaction intermediates bearing a hypervalent iodine center, and to better understand the mechanisms underlying these reagent-controlled asymmetric chemical transformations. These investigations will benefit to chemists involved in hypervalent iodine chemistry worldwide.
Two new families of chiral iodanes are now accessible. The oxidation step was found selective as far as the hypervalent species are concerned (IIII or IV) and DFT calculations were performed to better understand the reactivity of the iodine centers. These reagents were successfully applied in asymmetric oxygenative reactions for the synthesis of natural products, such as bis(thymol) (94% selectivity), bacchopetiolone (first total synthesis) and scyphostatine. Two new collaborations (Dr. Berthiol, Univ. Grenoble; Pr. Aizpurua, Univ. Basque Country, San-Sebastian, Spain) were established.
The knowledge acquired throughout the realization of the Iodinnov project should make it possible to consider other methodological developments for these iodanes, not only in other asymmetrical oxygenative reactions (e.g., a-oxytosylation of ketones, oxidation of sulfides into sulfoxydes) but also, in a more challenging way, in the introduction of carbon-based ligands on the iodine centers of the biarylic and of Salen-type structures for the stereocontrolled creation of quaternary carbon centers.
Two students, R. Coffinier (ANR) and C. Bosset (CNRS/Conseil Régional Aquitaine) carried out their thesis at the University of Bordeaux and obtained end 2013 the degree of Doctor in Organic chemistry. They are currently post-doctoral researchers in Pr. Cossy group (ESPCI-Paris Tech). A first publication was published in 2014 in Angewandte Chemie, a high impact international scientific journal, and this work was presented in international conferences. Two other publications are in preparation.
The prime objective of this project is the development of new electrophilic iodine-based chiral reagents capable of promoting asymmetric induction in oxygenative dearomatization of phenols into cyclohexadienone derivatives. Indeed, examples of chiral organoiodine reagents capable of controlling efficiently the stereoselectivity of chemical transformations are very scarce. The best results reported so far concern the oxidation of methyl t-butyl sulfide (56% ee) using a (+)-menthylated variant of the ?3-iodane Koser reagent and that of methyl p-tolyl sulfide (29% ee) using a chiral lambda5-iodane NIPA reagent developed by Zhdankin, the a-oxytosylation of propiophenone (40% ee) and the dioxytosylation of styrene (65% ee) using a chiral Koser-type reagent developed by Wirth, and the a-arylation of ketones (37% ee) using a binaphthylic lambda3-iodane reagent proposed by Ochiai. More recent examples are the intramolecular dearomatizing spirolactonization of a series of naphthol derivatives (78-86% ee) using a chiral bis-lambda3-iodane spirobiindane-based reagent developed by Kita, the phenol dearomatization/[4+2] cyclodimerization sequence of 2-alkylphenols (63% ee) using the lambda5-iodane oxazoline-type reagent described by Birman, and our own chiral carboxylated binaphthylic iodoarene developed in the Quideau group. A recent preliminary study led us to identify the use of our chiral iodoarene and meta-chloroperbenzoic acid (m-CPBA) as a co-oxidant, as a very promising system that enables enantioselectivities up to 50% ee in asymmetric (intermolecular) hydroxylative dearomatization of 2-methylnaphthol. Besides, using this chiral iodobinaphthyle as a reacting organocatalyst with m-CPBA in excess enables subsequent regio- and diastereo-selective epoxidation of the dearomatized naphthol.
This proposal is thus aimed at studying in-depth this promising hypervalent iodine-mediated transformation in order to improve, on one hand, its stereoselectivity and, on the other hand, its efficiency as an organocatalytic process. Design and synthesis of new chiral iodoarenes, as well as screening of co-oxidants, are the main aspects that require further investigation. These developments will rely on both organic (partner 1) and computational (partner 2) chemistries that are expected to be complementary in our common efforts to identify the best structural modifications to perform on chiral iodoarenes as efficient inductors of asymmetry. DFT calculations should also allow us to gather crucial information on hypervalent iodine-containing reaction intermediates and hence to better understand the mechanisms underlying this reagent-controlled asymmetric reaction.
Project coordination
Laurent POUYSEGU (UNIVERSITE BORDEAUX I)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
ISM (CNRS-UMR 5255) UNIVERSITE BORDEAUX I
IPREM (CNRS-UMR 5254) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION AQUITAINE LIMOUSIN
Help of the ANR 339,999 euros
Beginning and duration of the scientific project:
- 36 Months
