Palladium-catalyzed cross-coupling of alcohols with olefins by positional tuning of a counteranion.

Transition metal-catalyzed cross-couplings have great potential to furnish complex ethers; however, challenges in the C(sp)-O functionalization step have precluded general methods. Here, we describe computationally guided transition metal-ligand design that positions a hydrogen-bond acceptor anion at the reactive site to promote functionalization. A general cross-coupling of primary, secondary, and tertiary aliphatic alcohols with terminal olefins to furnish >130 ethers is achieved.

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic -heterocycles.

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative.

Allylic C-H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis.

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines-a common motif in pharmaceuticals-remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal-catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage.

Late-Stage Intermolecular Allylic C-H Amination.

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [Mn(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination.

Late-stage oxidative C(sp)-H methylation.

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules. However, existing methylation methods show limited scope and have not been demonstrated in complex settings. Here we report a regioselective and chemoselective oxidative C(sp)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products.

Chemoselective Tertiary C-H Hydroxylation for Late-Stage Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis.

Aromatic and heterocyclic functionality are ubiquitous in pharmaceuticals. Herein, we disclose a new Mn(PDP)catalyst system using chloroacetic acid additive capable of chemoselectively oxidizing remote tertiary C( )-H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.

Synthesis of anti-1,3 Amino Alcohol Motifs via Pd(II)/SOX Catalysis with the Capacity for Stereodivergence.

We report the development of a Pd(II)/(±)-MeO-SOX/2,5-dimethylbenzoquinone system that enables unprecedented access to anti-1,3 amino alcohol motifs in good yields (33 substrates, avg. 66% isolated yield, >20:1 dr) and high selectivities (avg. 10:1 dr).

Chemoselective methylene oxidation in aromatic molecules.

Despite significant progress in the development of site-selective aliphatic C-H oxidations over the past decade, the ability to oxidize strong methylene C-H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late-stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Here, we report a simple manganese small-molecule catalyst Mn(CF-PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive.

Aliphatic C-H Oxidations for Late-Stage Functionalization.

The atomistic change of C( sp)-H to C( sp)-O can have a profound impact on the physical and biological properties of small molecules. Traditionally, chemical synthesis has relied on pre-existing functionality to install new functionality, and directed approaches to C-H oxidation are an extension of this logic. The impact of developing undirected C-H oxidation reactions with controlled site-selectivity is that scientists gain the ability to diversify complex structures at sites remote from existing functionality, without having to carry out individual de novo syntheses.

Asymmetric Allylic C-H Alkylation via Palladium(II)/ cis-ArSOX Catalysis.

We report the development of Pd(II)/ cis-aryl sulfoxide-oxazoline ( cis-ArSOX) catalysts for asymmetric C-H alkylation of terminal olefins with a variety of synthetically versatile nucleophiles. The modular, tunable, and oxidatively stable ArSOX scaffold is key to the unprecedented broad scope and high enantioselectivity (37 examples, avg. > 90% ee).

Manganese-catalysed benzylic C(sp)-H amination for late-stage functionalization.

Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity.

C-H to C-N Cross-Coupling of Sulfonamides with Olefins.

Cross-coupling of nitrogen with hydrocarbons under fragment coupling conditions stands to significantly impact chemical synthesis. Herein, we disclose a C(sp)-N fragment coupling reaction between terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/SOX (sulfoxide-oxazoline) catalyzed intermolecular allylic C-H amination. A range of (56) allylic amines are furnished in good yields (avg.

Remote, Late-Stage Oxidation of Aliphatic C-H Bonds in Amide-Containing Molecules.

Amide-containing molecules are ubiquitous in natural products, pharmaceuticals, and materials science. Due to their intermediate electron-richness, they are not amenable to any of the previously developed N-protection strategies known to enable remote aliphatic C-H oxidations. Using information gleaned from a systematic study of the main features that makes remote oxidations of amides in peptide settings possible, we developed an imidate salt protecting strategy that employs methyl trifluoromethanesulfonate as a reversible alkylating agent.

Catalytic C(sp)-H Alkylation via an Iron Carbene Intermediate.

The catalytic transformation of a C(sp)-H bond to a C(sp)-C bond via an iron carbene intermediate represents a long-standing challenge. Despite the success of enzymatic and small molecule iron catalysts mediating challenging C(sp)-H oxidations and aminations via high-valent iron oxos and nitrenes, C(sp)-H alkylations via isoelectronic iron carbene intermediates have thus far been unsuccessful. Iron carbenes have been inert, or shown to favor olefin cyclopropanation and heteroatom-hydrogen insertion.

Oxidative diversification of amino acids and peptides by small-molecule iron catalysis.

Secondary metabolites synthesized by non-ribosomal peptide synthetases display diverse and complex topologies and possess a range of biological activities. Much of this diversity derives from a synthetic strategy that entails pre- and post-assembly oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis.

Enantioselective Allylic C-H Oxidation of Terminal Olefins to Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis.

The enantioselective synthesis of isochroman motifs has been accomplished by palladium(II)-catalyzed allylic C-H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The allylic C-H oxidation reaction proceeds with the broadest scope and highest levels of asymmetric induction reported to date (avg.

Aerobic Linear Allylic C-H Amination: Overcoming Benzoquinone Inhibition.

An efficient aerobic linear allylic C-H amination reaction is reported under palladium(II)/bis-sulfoxide/Brønsted base catalysis. The reaction operates under preparative, operationally simple conditions (1 equiv of olefin, 1 atm O2 or air) with reduced Pd(II)/bis-sulfoxide catalyst loadings while providing higher turnovers and product yields than systems employing stoichiometric benzoquinone (BQ) as the terminal oxidant. Pd(II)/BQ π-acidic interactions have been invoked in various catalytic processes and are often considered beneficial in promoting reductive functionalizations.

Remote Oxidation of Aliphatic C-H Bonds in Nitrogen-Containing Molecules.

Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Brønsted acid (HBF4) or an azaphilic Lewis acid (BF3) to enable remote, non-directed C(sp(3))-H oxidations of tertiary, secondary, and primary amine- and pyridine-containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.

A C-H oxidation approach for streamlining synthesis of chiral polyoxygenated motifs.

Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation state manipulations. Herein a strategy for synthesizing a readily diversifiable class of chiral building blocks, allylic alcohols, through sequential asymmetric C-H activation/resolution is evaluated against the state-of-the-art. The C-H oxidation routes' capacity to strategically introduce oxygen into a sequence and thereby minimize non-productive manipulations is demonstrated to effect significant decreases in overall step-count and increases in yield and synthetic flexibility.

N-Boc amines to oxazolidinones via Pd(II)/bis-sulfoxide/Brønsted acid co-catalyzed allylic C-H oxidation.

A Pd(II)/bis-sulfoxide/Brønsted acid catalyzed allylic C-H oxidation reaction for the synthesis of oxazolidinones from simple N-Boc amines is reported. A range of oxazolidinones are furnished in good yields (avg 63%) and excellent diastereoselectivities (avg 15:1) to furnish products regioisomeric from those previously obtained using allylic C-H amination reactions. Mechanistic studies suggest the role of the phosphoric acid is to furnish a Pd(II)bis-sulfoxide phosphate catalyst that promotes allylic C-H cleavage and π-allylPd functionalization with a weak, aprotic oxygen nucleophile and to assist in catalyst regeneration.

Terminal olefins to chromans, isochromans, and pyrans via allylic C-H oxidation.

The synthesis of chroman, isochroman, and pyran motifs has been accomplished via a combination of Pd(II)/bis-sulfoxide C-H activation and Lewis acid co-catalysis. A wide range of alcohols are found to be competent nucleophiles for the transformation under uniform conditions (catalyst, solvent, temperature). Mechanistic studies suggest that the reaction proceeds via initial C-H activation followed by a novel inner-sphere functionalization pathway.

General allylic C-H alkylation with tertiary nucleophiles.

A general method for intermolecular allylic C-H alkylation of terminal olefins with tertiary nucleophiles has been accomplished employing palladium(II)/bis(sulfoxide) catalysis. Allylic C-H alkylation furnishes products in good yields (avg. 64%) with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z).

Catalyst-controlled aliphatic C-H oxidations with a predictive model for site-selectivity.

Selective aliphatic C-H bond oxidations may have a profound impact on synthesis because these bonds exist across all classes of organic molecules. Central to this goal are catalysts with broad substrate scope (small-molecule-like) that predictably enhance or overturn the substrate's inherent reactivity preference for oxidation (enzyme-like). We report a simple small-molecule, non-heme iron catalyst that achieves predictable catalyst-controlled site-selectivity in preparative yields over a range of topologically diverse substrates.

Catalyst-controlled C-O versus C-N allylic functionalization of terminal olefins.

The divergent synthesis of syn-1,2-aminoalcohol or syn-1,2-diamine precursors from a common terminal olefin has been accomplished using a combination of palladium(II) catalysis with Lewis acid cocatalysis. Palladium(II)/bis-sulfoxide catalysis with a silver triflate cocatalyst leads for the first time to anti-2-aminooxazolines (C-O) in good to excellent yields. Simple removal of the bis-sulfoxide ligand from this reaction results in a complete switch in reactivity to afford anti-imidazolidinone products (C-N) in good yields and excellent diastereoselectivities.

Oxidative Heck vinylation for the synthesis of complex dienes and polyenes.

We introduce an oxidative Heck reaction for selective complex diene and polyene formation. The reaction proceeds via oxidative Pd(II)/sulfoxide catalysis that retards palladium-hydride isomerizations which previously limited the Heck manifold's capacity for furnishing stereodefined conjugated dienes. Limiting quantities of nonactivated terminal olefins (1 equiv) and slight excesses of vinyl boronic esters (1.