Steroids bearing C12 oxidations are widespread in nature yet only one preparative chemical method addresses this challenge in a low-yielding and not fully understood fashion: Schönecker's Cu-mediated oxidation. This work shines new light onto this powerful C–H oxidation method through mechanistic investigation, optimization, and wider application. Culminating in a scalable, rapid, high-yielding, and operationally simple protocol, this procedure is applied to the first synthesis of several parent polyoxypregnane natural products, representing a gateway to over 100 family members.

The use of copper in directed C−H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O2 promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu2O2 intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCuII(OOR) intermediate undergoes homolytic O−O cleavage to generate reactive RO• species, which are responsible for key C−H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.

Direct catalytic transposition of allylic alcohols is a powerful approach to the synthesis of complex hydroxylated organic compounds.1 Several transition metal catalysts have been developed for this purpose, including vanadium,2 molybdenum,2 and rhenium reagents. 3 Among these, rhenium(VII) oxide and triphenylsilyl perrhenate have been found to be superior in terms of reactivity and chemoselectivity, displaying high activity at low temperatures with no competitive oxidation observed with some of the other catalysts. One drawback of the reversible process (eq 1) is a general lack of regioselectivity; 4 stereoselectivity in the transposition of primary allylic alcohols is also low.(1)In this communication, we describe a practical method that allows for control of the regioand stereoselectivity in the rhenium-catalyzed transposition of allylic alcohols, expanding the scope of the reaction for the stereoselective synthesis of complex molecules. 5 In our initial experiments, rearrangement of substrate 1 in the presence of Re 2 O 7 (2.5 mol %) occurred with low regio-and stereoselectivity as expected, delivering 2 with 60% conversion as a 3:2 mixture of diastereomers (Scheme 1). We hypothesized that the reaction medium must be slightly acidic due to formation of a catalytic amount of perrhenic acid (pK a = 1.25) 6 upon interaction of rhenium(VII) oxide with the substrate and/or adventitious water. 7 In the presence of a catalytic acid the rearranged product can in principle be trapped as an acetal or ketal, and then the 1,3-syn diastereomer should be favored on thermodynamic grounds. Remarkably, upon exposure of 1 to benzaldehyde dimethyl acetal and Re 2 O 7 (2.5 mol %), essentially a single product was formed in 94% yield after 20 h at room temperature. Thus, the rhenium catalyst performs a dual catalytic function as a transition metal catalyst for the hydroxyl group transposition and as an acid catalyst for acetal formation.Screening of the reaction parameters demonstrated that although a number of solvents can be used (toluene, Et 2 O, THF, CH 2 Cl 2 ), 8 dichloromethane provides the best results in terms © XXXX American Chemical Society *zakarian@chem.ucsb.edu . Supporting Information Available: Experimental procedures, copies of 1 H and 13 C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. of reaction rate. Typically, reactions are characterized by a rapid formation of a diastereomeric mixture of rearranged diol acetals (within ~20 min at room temperature) followed by slow equilibration of the acetals to the 1,3-syn product (3). NIH Public AccessThe influence of reaction time with alternative rhenium catalysts is summarized in Table 1. With all three catalysts studied, methyltrioxorhenium (MTO), Ph 3 SiOReO 3 , and Re 2 O 7 , the rearrangement/acetalization was complete within 3 h at room temperature. As expected, MTO is the least reactive catalyst. 2c,9 Notably, with all of the three rhenium catalysts the initial acetal formation was followed by equilibration to 3....

A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N-acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner.

A direct α-fluorination of N-acyloxazolidinones based on the unique reactivity of group IVa metal enolates has been developed. The reaction is an experimentally simple, low-cost, quick, and energy-efficient alternative for asymmetric α-fluorination of N-acyloxazolidinones. Preliminary studies have shown compatibility with alkyl, alkenyl, and alkynyl, aromatic, and several heteroaromatic substituents. High diastereoselectivities have been achieved with most substrates tested, and the reaction is typically complete within 1 h at ambient temperature.