A Family of Chiral Ferrocenyl Diols: Modular Synthesis, Solid‐State Characterization, and Application in Asymmetric Organocatalysis

Abstract

Readily available chiral diol scaffolds are useful as sources of chirality for asymmetric synthesis, however, few such scaffolds are readily available in enantiopure form. Reported herein is a cheap and modular synthesis of a novel family of chiral ferrocenyl diols in excellent yields with excellent enantio- and diastereoselectivity (>99 % ee and 99 % de). These diols possess not only planar and central chirality, but also axial chirality around the central iron atom. Characterization of these diols by X-ray crystallography revealed intra- and intermolecular hydrogen-bond networks depending on substitution at the carbinol positions. The potential of these diols as catalysts was subsequently demonstrated in an asymmetric hetero-Diels-Alder reaction which provided cycloadducts in up to 84 % yield with ee values ranging from -92 to +72 %.

Enantioselective Synthesis of Planar Chiral Ferrocifens that Show Chiral Discrimination in Antiproliferative Activity on Breast Cancer Cells

“…The palladium-catalysed CÀ H activation functionalisation/cyclisation procedure, shown in Scheme 3, allowed for the preparation of both enantiomers of the planar chiral ketone, 11, in quantitative yield with > 99 % ee by simply selecting the required hand of BINAP. This synthesis is based on work from the groups of You and Gu for the preparation of the enantioenriched ketones (R)-11 and (S)-11; You noted that these conditions result in a reduction of ee when the scale was increased to 1 g. [38,39] Minor modifications to their methodology enabled the scale up of the reaction to 6 g (19 mmol) while simultaneously increasing the ee from 97 % (as reported by You) to 99 %; in line with the procedure previously described by us, [37] there is, no need for the use of column chromatography.…”

“…[28] However, they were prepared only in a racemic fashion, whereas it is, of course, of particular interest to be able to prepare and test separately each enantiomer of a novel biologically active compound. Chiral ferrocifens of type 7 were selected as ideal targets since methodology to access the related ferrocenyl ketone enantioselectively has previously been employed in our laboratory, [37] based on methodology developed by Gu and You, [38,39] thus enabling an efficient route to the first reported enantiopure chiral ferrocifens.…”

Controlling the Reactivity of Ferrocenyl Carbocations: Routes to Enantiomerically Pure Chlorophosphites and Solid‐State Characterization of a Benzopentalene Dimer

“…General Methods: Unless otherwise noted, all commercial reagents were used as received without further purification. Chiral diols 4 , 7 – 10 , 15 and 23 were prepared as previously reported . Standard Schlenk techniques were employed for moisture sensitive reactions.…”

“…Our recent report on the syntheses of novel ferrocenyl diols of type 1 in enantiopure form prompted us to explore the potential of these diols as precursors for phosphorus‐containing ligands and catalysts (Scheme ). We note, however, that such a procedure requires the inhibition, or at least minimization, of a competitive reaction, i.e., dehydroxylation to form a ferrocenyl‐stabilized α‐carbocation .…”

Ferrocene as a Privileged Framework for Chiral Organocatalysts

“…Chirald iols such as BINOLs and TADDOLs are good examples for hydrogen-bonding catalysis. [45] Guiry [46] and colleagues constructed ag roup of chiral diols Fc-OC-50 based on ferrocene framework from easily available startingm aterials ortho-bromobenzoic acid and ferrocenei n four steps (Scheme 19). These diols possessed not only planar and central chirality,b ut also axial chiralitya roundt he central iron atom.…”