Iodine(III)-mediated synthesis of chiral α-substituted ketones: recent advances and mechanistic insights

Abstract

The development of iodine(III)-mediated synthetic transformations has received growing interest, in particular to mediate enantioselective processes. In this class, the α-tosyloxylation of ketone derivatives using iodine(III) is a particularly powerful one, as it yields α-tosyloxy ketones – versatile chiral precursors that enable rapid access to numerous α-chiral ketones through nucleophilic displacement. Despite years of research from numerous groups, the enantioselectivities for this transformation have remained modest. Using quantum chemical calculations, we have uncovered a possible rational for the lack of selectivity. With these computational insights, we have developed an alternative experimental strategy and achieved unprecedented levels of selectivities. Applying this newfound knowledge, we have recently developed a new method to access α-halo ketones from non-ketonic precursors.

Iodine(III)-Mediated Oxidative Hydrolysis of Haloalkenes: Investigation of the Effect of Iodine(III) Reagents

“…5 Our group has been involved in the development of iodine(III)-mediated methods to access functionalized ketone derivatives. 6 This has been an active area of research in hypervalent iodine chemistry, 7 because of the widespread presence and usefulness of α-functionalized ketones. Our approach has focused on the introduction of a leaving group α to the carbonyl, because we considered these products to be versatile synthetic precursors.…”

Iodine(III)-Mediated Contraction of 3,4-Dihydropyranones: Access to Polysubstituted γ-Butyrolactones

“…In particular, numerous efforts have been invested in developing stereoselective methodologies . Our group has been involved in the development of iodine­(III)-mediated processes to access chiral nonracemic α-functionalized carbonyl compounds . These products are of particular interest because of their ubiquity in nature and potential in synthesis.…”

“…The desired products were obtained, albeit in lower yields. Almost no elimination product was observed in the crude products, in contrast to the results observed with acyclic enol esters …”

“…It was possible to obtain an extremely fast reaction (∼5 min) by using a stoichiometric quantity of TsOH·H 2 O, with a slight decrease in diastereoselectivity. We currently hypothesize that the role of TsOH·H 2 O is to increase the effective concentration of the reactive iodine­(III) species . We obtained increased selectivities in less polar solvents (Table , entries 4 and 5).…”

Chiral Hypervalent Organoiodine-Catalyzed Enantioselective Oxidative Spirolactonization of Naphthol Derivatives

“…The enantioselective oxidative dearomatization of arenols and their analogues is a useful method for the synthesis of several important medicinally and biologically active compounds . On the other hand, the development of asymmetric redox catalysis based on hypervalent iodine chemistry is currently one of the most progressive research areas in asymmetric organocatalysis. , Kita and colleagues succeeded in the first enantioselective oxidative dearomatization of 1-naphthol derivatives with chiral a μ-oxo-bridged-hypervalent iodine­(III), which has a conformationally rigid 1,1-spiroindanone backbone . In contrast to Kita’s conformationally rigid catalysts, we demonstrated the rational design of conformationally flexible hypervalent organoiodines­(III) as chiral catalysts based on secondary nonbonding interactions (i.e., intramolecular hydrogen-bonding interactions between the acidic amido protons and the iodine­(III) ligands) for the same reaction (Scheme ).…”