Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different types of nucleophiles: phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electron-rich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same is true of the acid derivatives. The racemic conditions served as a platform for the development of an enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule out a "Wacker-type" mechanism involving anti oxypalladation and suggest that the reaction proceeds by syn oxypalladation for both mono-and bidentate ligands. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation.

Catalytic asymmetric oxidation-chemistry involving heteroatom transfer from a reagent to a substrate is perhaps unparalleled in synthetic utility for the construction of enantioenriched materials.[1] Conversely, there is a significant deficiency of asymmetric two-electron oxidations that do not involve heteroatom transfer. Some potentially valuable reactions of this type include the oxidation of secondary alcohols and oxidative heterocyclizations (Scheme 1). The design of efficient processes of this nature requires an abundant, inexpensive, and effective stoichiometric oxidant, and a solvent that is amenable to asymmetric catalysis. To begin to address this general synthetic problem, we recently developed a Pd-catalyzed oxidative kinetic resolution of secondary alcohols in toluene that uses molecular oxygen as the terminal oxidant (Scheme 1). [2,3] Herein we demonstrate the utility of this simple system (Pd catalyst, ligand, PhCH 3 , O 2 ) for the construction of a range of heterocycles by catalytic oxidative cyclization. We also demonstrate for the first time that aerobic cyclizations of this type are amenable to asymmetric catalysis, and thereby establish a critical proof of concept for the further development of catalytic asymmetric oxidative cyclizations that use molecular oxygen as the sole stoichiometric oxidant.Palladium-catalyzed bond-forming constructions have become indispensable in organic chemistry.[4] A favorable property of palladium is that it can serve as both a nucleophile (i.e., Pd 0 ) and an electrophile (i.e., Pd II ), which produces many opportunities for catalysis. Although both modes are prevalent, electrophilic oxidative catalysis by Pd II has garnered less attention in the asymmetric arena. Adding to the disparity is the fact that until recently, cocatalysts (e.g., copper salts) or organic oxidants (e.g., benzoquinone) were necessary for the reoxidation of Pd 0 to Pd II , thus creating a nearly intractable situation for asymmetric catalysis. For example, the use of the traditional copper/O 2 reoxidation system introduces a secondary catalytic cycle, while the benzoquinone system requires the removal of stoichiometric quantities of organic compounds at the end of the reaction. In contrast, reactions that proceed under direct dioxygen coupled catalysis produce H 2 O as the sole byproduct. Despite the difficulties of the traditional systems, seminal works by Hosokawa and Murahashi, [5] Hayashi, [6] Sasai, [7] and Bäckvall [8] have established the potential for enantioselective Pd II -catalyzed oxidative cyclizations and dialkoxylations. [9] To the best of our knowledge, however, there were no examples of direct dioxygen-coupled enantioselective Pd II

Rapid resolution: A new catalyst system for the oxidative kinetic resolution of secondary alcohols leads to dramatic rate increases. This system allows the use of a diamine to provide access to either enantiomer of a range of alcohols with good selectivity factors (see scheme). This method has been applied to the formal total synthesis of (−)‐amurensinine.

A model for asymmetric induction in palladium-catalyzed aerobic oxidative kinetic resolution is described. The model is based on coordination complexes and general reactivity trends of the parent (sp)PdCl2 catalyst. The first example of a nonracemic chiral palladium alkoxide complex is presented, and exhibits the subtle steric influences of the C 1 symmetric ligand sparteine.

Catalytic asymmetric oxidation-chemistry involving heteroatom transfer from a reagent to a substrate is perhaps unparalleled in synthetic utility for the construction of enantioenriched materials.[1] Conversely, there is a significant deficiency of asymmetric two-electron oxidations that do not involve heteroatom transfer. Some potentially valuable reactions of this type include the oxidation of secondary alcohols and oxidative heterocyclizations (Scheme 1). The design of efficient processes of this nature requires an abundant, inexpensive, and effective stoichiometric oxidant, and a solvent that is amenable to asymmetric catalysis. To begin to address this general synthetic problem, we recently developed a Pd-catalyzed oxidative kinetic resolution of secondary alcohols in toluene that uses molecular oxygen as the terminal oxidant (Scheme 1). [2,3] Herein we demonstrate the utility of this simple system (Pd catalyst, ligand, PhCH 3 , O 2 ) for the construction of a range of heterocycles by catalytic oxidative cyclization. We also demonstrate for the first time that aerobic cyclizations of this type are amenable to asymmetric catalysis, and thereby establish a critical proof of concept for the further development of catalytic asymmetric oxidative cyclizations that use molecular oxygen as the sole stoichiometric oxidant.Palladium-catalyzed bond-forming constructions have become indispensable in organic chemistry.[4] A favorable property of palladium is that it can serve as both a nucleophile (i.e., Pd 0 ) and an electrophile (i.e., Pd II ), which produces many opportunities for catalysis. Although both modes are prevalent, electrophilic oxidative catalysis by Pd II has garnered less attention in the asymmetric arena. Adding to the disparity is the fact that until recently, cocatalysts (e.g., copper salts) or organic oxidants (e.g., benzoquinone) were necessary for the reoxidation of Pd 0 to Pd II , thus creating a nearly intractable situation for asymmetric catalysis. For example, the use of the traditional copper/O 2 reoxidation system introduces a secondary catalytic cycle, while the benzoquinone system requires the removal of stoichiometric quantities of organic compounds at the end of the reaction. In contrast, reactions that proceed under direct dioxygen coupled catalysis produce H 2 O as the sole byproduct. Despite the difficulties of the traditional systems, seminal works by Hosokawa and Murahashi, [5] Hayashi, [6] Sasai, [7] and Bäckvall [8] have established the potential for enantioselective Pd II -catalyzed oxidative cyclizations and dialkoxylations. [9] To the best of our knowledge, however, there were no examples of direct dioxygen-coupled enantioselective Pd II