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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. Herein we report a simple manganese small molecule catalyst Mn(CF3–PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic, and biaryl moieties. Late stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C–H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated., Graphical Abstract

The atomistic change of C(sp(3))—H to C(sp(3))—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. This perspective offers a historical view of why as recently as 2007, it was thought that the differences between aliphatic C—H bonds of the same bond type (for example, 2° aliphatic) were not large enough to distinguish them preparatively with small molecule catalysis in the absence of directing groups or molecular recognition elements. We give an account of the discovery of Fe(PDP)-catalyzed non-directed aliphatic C—H hydroxylations and how the electronic, steric, and stereoelectronic rules for predicting site-selectivity that emerged have affected a shift in how the chemical community views the reactivity among these bonds. The discovery that site-selectivity could be altered by tuning the catalyst [i.e. Fe(CF(3)-PDP)] with no changes to the substrate or reaction now gives scientists the ability to exert control on the site of oxidation on a range of functionally and topologically diverse compounds. Collectively, these findings have made possible the emerging area of late-stage C—H functionalizations for streamlining synthesis and derivatizing complex molecules.

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. In the presence of a Bronsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities.

Cross-coupling of nitrogen with hydrocarbons under fragment coupling conditions stands to significantly impact chemical synthesis. Herein, we disclose a C(sp3)–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. 75%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). Mechanistic studies reveal that the SOX ligand framework is effective at promoting functionalization by supporting cationic π-allyl Pd.

The catalytic transformation of a C(sp3)–H bond to a C(sp3)–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(sp3)–H oxidations and aminations via high-valent iron oxos and nitrenes, C(sp3)–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. Herein we report an iron phthalocyanine-catalyzed alkylation of allylic and benzylic C(sp3)–H bonds. Mechanistic investigations support that an electrophilic iron carbene mediates homolytic C–H cleavage and rebounds from the resulting organoiron intermediate to form the C–C bond; both steps are tunable via catalyst modifications. These studies suggest that for iron carbenes, distinct from other late metal carbenes, C–H cleavage is partially rate-determining and must be promoted to effect reactivity.

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 molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.

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(sp(3))—H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10–15% higher isolated yields on these substrates and is uniquely effective for remote C(sp(3))—H hydroxylations in substrates housing basic nitrogen heterocycles. The demonstrated ability to perform Mn(PDP)/chloroacetic acid C(sp(3))—H oxidations in pharmaceutically relevant complex molecules on multi-gram scales will facilitate drug discovery processes via late-stage functionalization.

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). Switching ligands to (±)-CF(3)-SOX using a less bulky quinone oxidant, the kinetic syn-1,3 amino alcohol motif can be accessed in comparable yields and selectivities. Advantages of the stereodivergent nature of this reaction are seen in the synthesis of anti- and syn-1,3-amino alcohol vitamin D3 analogue intermediates in half the steps and higher overall yield to previous routes. Additionally, all eight possible stereoisomers of a chiral diamino alcohol core are generated from two amino acids. Mechanistic studies reveal that the anti-isomer is furnished through concurrent Pd(II)(SOX) catalyzed C—H amination and Pd(0)(SOX)-catalyzed isomerization cycles.

Secondary metabolites synthesized by nonribosomal peptide synthetases (NRPSs) display diverse and complex topologies and possess an impressive range of biological activities1,2 Much of this diversity derives from a synthetic strategy that entails the oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds pre-3 and post-assembly2. 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.4 However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized outside of nature.5 In this manuscript, we report that two small-molecule iron catalysts are capable of facilitating the targeted C—H oxidative modification of amino acids and peptides with preservation of α-center chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins, and amines in both monomer and peptide settings. The value of this C—H oxidation strategy is demonstrated in its capacity for generating diversity: four 'chiral pool' amino acids are transformed to twenty-one chiral unnatural amino acids (UAAs) representing seven distinct functional group arrays; late-stage C—H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different UAAs. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C—H oxidation to one containing a linear UAA.

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. 92 % ee, 13 examples with greater than 90 % ee).

We report the development of 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). Pd(II)/cis-ArSOX is unique in its ability to effect high reactivity and catalyst-controlled diastereoselectivity on the alkylation of aliphatic olefins. We anticipate that this new chiral ligand class will find use in other transition metal catalyzed processes that operate under oxidative conditions.

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 (MeOTf) as a reversible alkylating agent. The imidate salt strategy enables, for the first time, remote, non-directed, site-selective C(sp3)—H oxidation with Fe(PDP) and Fe(CF3PDP) catalysis in the presence of a broad scope of tertiary amides, anilide, 2-pyridone, and carbamate functionality. Secondary and primary amides can be masked as N-Ns amides to undergo remote oxidation. This novel imidate strategy facilitates late-stage oxidations in a broader scope of medicinally important molecules and may find use in other C—H oxidations and metal-mediated reactions that do not tolerate amide functionality.

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. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities.

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.

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. Consistent with this, the reaction shows reactivity trends orthogonal to those of traditional Pd(0)-catalyzed allylic substitutions.

A panel of seventeen experts from academia, industry, and government laboratories share their thoughts on a variety of matters of importance to the readership of Organometallics. These include directions for the field and recent breakthroughs (illustrated with selected examples), the interface with green chemistry, the quest for reproducible experimental procedures, data and research integrity, laboratory safety, the preparation of coworkers for non-academic careers, and needs regarding instrumentation, infrastructure, shared facilities, and computational methods. A lively give and take is evident in the edited transcript, which continues a biennial tradition initiated in 2011.

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). For the first time, the olefin scope encompasses unactivated aliphatic olefins as well as activated aromatic/heteroaromatic olefins and 1,4-dienes. The ease of appending allyl moieties onto complex scaffolds is leveraged to enable this mild and selective allylic C−H alkylation to rapidly diversify phenolic natural products. The tertiary nucleophile scope is broad and includes latent functionality for further elaboration (e.g., aliphatic alcohols, α,β-unsaturated esters). The opportunities to effect synthetic streamlining with such general C−H reactivity are illustrated in an allylic C−H alkylation/Diels−Alder reaction cascade: a reactive diene is generated via intermolecular allylic C−H alkylation and approximated to a dienophile contained within the tertiary nucleophile to furnish a common tricyclic core found in the class I galbulimima alkaloids.

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. A catalyst reactivity model quantitatively correlates the innate physical properties of the substrate to the site-selectivities observed as a function of the catalyst.

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. 92 % ee, 13 examples with greater than 90 % ee).

Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Bronsted acid (HBF4) or an azaphilic Lewis acid (BF3) to enable remote, non-directed C(sp3)–H oxidations of tertiary, secondary, and primary amine- and pyridine-containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.

The first general strategy for a directing effect on metal (oxo)-promoted C-H hydroxylations is described. Carboxylic acid moieties on the substrate overcome unfavorable electronic, steric, and stereoelectronic biases in C-H hydroxylations catalyzed by the non-heme iron complex Fe(PDP). In a demonstration of the power of this directing effect, C-H oxidation is diverted away from an electronically favored C-1 H abstraction/rearrangement pathway in the paclitaxel framework to enable installation of C-2 oxidation in the naturally occurring oxidation state and stereoconfiguration.

Tandem reaction sequences that selectively convert multiple C-H bonds of abundant hydrocarbon feedstocks to functionalized materials enable rapid buildup of molecular complexity in an economical way. A tandem C-H amination/vinylic C-H arylation reaction sequence is described under Pd(II)/sulfoxide-catalysis that furnishes a wide range of α- and β-homophenylalanine precursors from commodity α-olefins and readily available aryl boronic acids. General routes to enantiopure amino acid esters and densely functionalized homophenylalanine derivatives are demonstrated.

The erythromycins, discovered and isolated in the early 1950s, are the best-known members of the clinically important macrolide class of antibiotics. The 14-membered macrolactone core imbedded in these natural products has inspired new synthetic methods for the construction of large ring lactones, beginning with the landmark synthesis of erythronolide B by the Corey group in 1978. During these studies, a single acetonide protecting group was utilized at the C-3/C-5 position. Similarly, this protecting group was used by the Masamune group years later for the synthesis of 6-deoxyerythronolide B (6-dEB). While no rationale was given for the use of this acetonide at the time, its function was revealed during the historic synthesis of erythromycin A in 1981 by Woodward et al. In three consecutive reports, the Woodward group extensively explored the conformational requirements for efficient acylation-based macrolactonization of erythromycin A seco acid derivatives. In particular, cyclic protecting groups were placed at various positions to serve as biasing elements, that is, artificial structural features intended to aid macrocyclic ring closure through substrate preorganization. The results from this study led the Woodward group to conclude that “certain structural features such as ... cyclic protecting groups at C-3/C-5 and C-9/C-11 are required for efficient lactonization” and that “these structural requirements probably arise from conformation requirements for lactonization.” This conclusion—that preorganization is required for efficient cyclization—has become a wellaccepted doctrine that has influenced the planning of all ensuing erythromycin syntheses (see below). We now report for the first time that conformational restraining elements are in fact not required for attaining efficient lactonization of the erythromycin core structure, 6-deoxyerythronolide B (6dEB). Moreover, we demonstrate that the removal of biasing elements allows for more stereochemical flexibility in the cyclization of 6-dEB, thus enabling access to stereochemical analogues that are not readily accessible with the biasing elements in place. Overall these findings require revision of the 30-year-old dogma that preorganization is mandatory for achieving macrocyclization of the erythromycins. Inspired by the Woodward report, synthetic endeavors by the research groups of Stork, Nakata, Yonemitsu, Danishefsky, Kochetkov, Hoffmann, Evans, Woerpel, Nelson, and us have reduced the conformational space available to the seco acid backbones of the erythronolide series (that is, 6-dEB, erythronolide B, and erythronolide A) through the use of sixmembered-ring protecting groups on C-3/C-5 and C-9/C-11 (Scheme 1). In addition to scaffolds with cyclic protecting

Carboxylate-ligated, non-haem iron enzymes demonstrate the capacity for catalysing such remarkable processes as hydroxylations, chlorinations and desaturations of inert, aliphatic C-H bonds. A key to functional diversity is the enzymes' ability to divert fleeting radicals towards different types of functionalization using active site and/or substrate modifications. We report that a non-haem iron hydroxylase catalyst [Fe(PDP)] can also be diverted to catalytic, mixed hydroxylase/desaturase activity with aliphatic C-H bonds. Using a taxane-based radical trap that rearranges under Fe(PDP) oxidation to furnish a nortaxane skeleton, we provide the first direct evidence for a substrate radical using this class of stereoretentive hydroxylation catalysts. Hydroxylation and desaturation proceed by means of a short-lived radical that diverges in a substrate-dependent manner in the presence of carboxylic acids. The novel biomimetic reactivity displayed by this small molecule catalyst is harnessed to diversify natural product derivatives as well as interrogate their biosynthetic pathways.

This report describes the use of Pd(II)/bis-sulfoxide 1 catalyzed intra- and intermolecular allylic C-H amination reactions to rapidly diversify structures containing a sensitive β-lactam core similar to that found in the monobactam antibiotic Aztreonam. Pharmacologically interesting oxazolidinone, oxazinanone, and linear amine motifs are rapidly installed with predictable and high selectivities under conditions that use limiting amounts of substrate. Additionally, we demonstrate for the first time that intramolecular C-H amination processes may be accelerated using catalytic amounts of a Lewis acid co-catalyst [Cr(III)(salen)Cl 2].

A highly selective and general Pd/sulfoxide-catalyzed allylic C-H amination reaction en route to syn-1,3-amino alcohol motifs is reported. Key to achieving this reactivity under mild conditions is the use of electron-deficient N-nosyl carbamate nucleophiles that are thought to promote functionalization by furnishing higher concentrations of anionic species in situ. The reaction is shown to be orthogonal to classical C-C bond-forming/-reduction sequences as well as nitrene-based C-H amination methods.

This report describes a slow addition protocol for the Fe(PDP)-catalyzed aliphatic C–H oxidation reaction. Under this protocol, the reaction can be productively driven to higher conversions without decreasing site-selectivity or chemoselectivity. The operational advantages of this procedure are highlighted in the oxidation of two complex natural product derivatives. Hydroxylated products can be obtained in high isolated yields without the need for recycling recovered starting materials.

C–H oxidation reactions have the potential to significantly streamline synthetic processes. However, to be useful for the synthesis of complex molecules, these reactions must proceed with high levels of chemo-, regio-, and stereoselectivity, Chiral bisoxazoline/copper-catalyzed systems have shown promising levels of asymmetric induction in the enantioselective allylic C–H esterification of symmetrical, cyclic olefins. Application of these systems to complex substrates is limited by a lack of chemo- and regioselectivity as well as the need to use a large excess of reactant (4 to 10 equiv).[1] A direct allylic C–H oxidation route would significantly increase the efficiency of producing chiral allylic esters; their syntheses generally require lengthy sequences of functional-group manipulations from preoxidized materials.[2,3]

An efficient aerobic linear allylic C—H amination reaction (LAA) is reported under Pd(II)/bis-sulfoxide/Brønsted base catalysis. The reaction operates under preparative, operationally simple conditions (1 equiv. 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. Palladium(II)/benzoquinone π-acidic interactions have been invoked in various catalytic processes and are often considered beneficial in promoting reductive functionalizations. When such electrophilic activation for functionalization is not needed, however, benzoquinone at high concentrations may compete with crucial ligand (bis-sulfoxide) binding and inhibit catalysis. Kinetic studies reveal an inverse relationship between the reaction rate and the concentration of BQ, suggesting that benzoquinone is acting as a ligand for Pd(II) which results in an inhibitory effect on catalysis.

Realizing the extraordinary potential of unactivated sp 3 C–H bond oxidation in organic synthesis requires the discovery of catalysts that are both highly reactive and predictably selective. We report an iron (Fe)–based small molecule catalyst that uses hydrogen peroxide (H 2 O 2 ) to oxidize a broad range of substrates. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C–H bonds, without the need for directing groups. Additionally, carboxylate directing groups may be used to furnish five-membered ring lactone products. We demonstrate that these three modes of selectivity enable the predictable oxidation of complex natural products and their derivatives at specific C–H bonds with preparatively useful yields. This type of general and predictable reactivity stands to enable aliphatic C–H oxidation as a method for streamlining complex molecule synthesis.

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(sp3)—H oxidations of tertiary (3°), secondary (2°), and primary (1°) amine- and pyridine- containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.

C-H bond oxidation reactions underscore the existing paradigm wherein high reactivity and high selectivity are inversely correlated. The development of catalysts capable of oxidizing strong aliphatic C(sp(3))-H bonds while displaying chemoselectivity (that is, tolerance of more oxidizable functionality) remains an unsolved problem. Here, we describe a catalyst, manganese tert-butylphthalocyanine [Mn((t)BuPc)], that is an outlier to the reactivity-selectivity paradigm. It is unique in its capacity to functionalize all types of C(sp(3))-H bond intramolecularly, while displaying excellent chemoselectivity in the presence of π functionality. Mechanistic studies indicate that [Mn((t)BuPc)] transfers bound nitrenes to C(sp(3))-H bonds via a pathway that lies between concerted C-H insertion, observed with reactive noble metals such as rhodium, and stepwise radical C-H abstraction/rebound, as observed with chemoselective base metals such as iron. Rather than achieving a blending of effects, [Mn((t)BuPc)] aminates even 1° aliphatic and propargylic C-H bonds, demonstrating reactivity and selectivity unusual for previously known catalysts.

[Reaction: see text] A hydrocarbon oxidation approach has been applied to the construction of several linear (E)-allylic alcohols that have served as intermediates in the synthesis of natural products and natural product-like molecules. In the original syntheses, these intermediates were constructed using a standard Wittig-type olefination approach. We report here that routes to these same intermediates designed around a hydrocarbon oxidation approach are more efficient both in the total number of functional group manipulations (FGMs) and overall steps, as well as in the overall yield.

Aliphatic C–H bonds are among the least reactive in organic chemistry, yet enzymes have evolved that not only oxidize them, but can discriminate between individual tertiary (3°) and secondary (2°) C–H bonds in complex molecules. Chemists considered reactivity differences between these inert bonds too minor for a small-molecule catalyst to discriminate ( 1 ); bio-inspired catalysts with intricate binding pockets were thought to be the only viable solution ( 2 ). This view pervaded because the reported examples of selective aliphatic C–H oxidations [halogenations ( 3 ), alkylations ( 4 ), aminations ( 5 ), hydroxylations ( 6 ), and dehydrogenations ( 7 )] were not sufficiently high in yield or predictable in site selectivity to be useful in synthesis, except in some special cases such as steroids (see below). In the past several years, however, aliphatic C–H oxidations and simple rules for predicting their selectivities have been emerging prominently in synthetic planning. Powerful small-molecule catalysts have been invented that furnish high enough yields (>50%) to be preparatively useful and can predictably discriminate between aliphatic C–H bonds even within complex molecules that have many possible sites of oxidation.

A broad spectrum of starting alcohols can be used for the synthesis of the desired oxygen heterocycles which bear a vinyl function at the ortho-position (detailed reaction mechanism).

The process leads to formation of oxazolidine structures in moderate yields and good to excellent diastereoselectivity.

A general method for intermolecular allylic C—H alkylation of terminal olefins with tertiary nucleophiles is developed employing palladium(II)/bis(sulfoxide) catalysis.

Four new conformationally restricted hybrid analogues of the hormone 1 alpha-25-dihydroxyvitamin D(3) (1,25D3) have been synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketones (-)-15 and (-)-17 with racemic 1-hydroxymethyl A-ring phosphine oxide (+/-)-18. Parent hybrid analogue 6, which combines the calcemia-inactivating 1 beta-hydroxymethyl A-ring modification with the antiproliferation- activating 20-epi-22-oxa-25-hydroxydiethyl C,D-ring side chain modification, is comparable in potency to 1,25D3 at the low nM level in inhibiting proliferation in a wide assortment of malignant cell lines in vitro with extremely low calcemic activity in vivo. Surprisingly, both conformationally restricted analogues of 6 (8b and 9b), which incorporate rigidifying units at their 25-hydroxyl side chain termini, retained the desirable antiproliferative, transcriptional, and calcemic activities of the parent compound.

A novel heterobimetallic Pd(II)sulfoxide/(salen)Cr(III)Cl-catalyzed intermolecular linear allylic C−H amination (LAA) is reported. This reaction directly converts densely functionalized α-olefin substrates (1 equiv) to linear (E)-allylic carbamates with good yields and outstanding regio- and stereoselectivities (>20:1). Chiral bis-homoallylic and homoallylic oxygen, nitrogen, and carbon substituted α-olefins undergo allylic C−H amination with good yields, excellent selectivities, and no erosion in enantiomeric purity. Streamlined routes to (E)-allylic carbamates that can be further elaborated to medicinally and biologically relevant allylic amines are also demonstrated. Valuable 15N-labeled allylic amines may be generated directly from allyl moieties at late stages of synthetic routes by using the readily available 15N-(methoxycarbonyl)-p-toluenesulfonamide nucleophile. Evidence is provided that this reaction proceeds via a heterobimetallic mechanism where Pd/sulfoxide mediates allylic C−H cleavage to for...

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. A catalyst reactivity model quantitatively correlates the innate physical properties of the substrate to the site-selectivities observed as a function of the catalyst.

Depending on the reaction conditions and especially the reaction time, the substrates can be converted to either aminooxazolines or imidazolidinones (with the respective other being a side-product in small amounts).

Different substituted dienes are obtained by using this Heck vinylation and also the long polyene chain (XII) can be synthesized in a highly stereoselective manner.

Using PhI(O-Ac)2 as a co-catalyst is proved to be the key for performing the title reaction under mild conditions (35°C, absence of any Broensted acids).

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.

We introduce an oxidative Heck reaction for selective complex diene and polyene formation. The reaction proceeds via oxidative Pd(II)/sulfoxide catalysis that retards palladiumhydride isomerizations which previously limited the Heck manifold’s capacity for furnishing stereodefined conjugated dienes. Limiting quantities of non-activated terminal olefins (1 equiv.) and slight excesses of vinyl boronic esters (1.5 equiv.) that feature diverse functionality can be used to furnish complex dienes and polyenes in good yields and excellent selectivities (generally E:Z = >20:1; internal:terminal = >20:1). Because this reaction only requires prior activation of a single vinylic carbon, improvements in efficiency are observed for synthetic sequences relative to ones featuring reactions that require activation of both coupling partners.

1 alpha-hydroxymethyl-25-hydroxyvitamin D3 and 1 beta-hydroxymethyl -3 alpha,25-hydroxyvitamin D3, two analogs with modifications restricted to the A ring, bind poorly to vitamin D receptor (VDR). The effective doses required for 50% of maximal binding activity (ED50) are 7 x 10(-7) M for the former and 8 x 10(-8) M for the latter, and the ED50 for their growth-inhibitory activities is greater than 10(-6) M. Unexpectedly, a hybrid analog with 20-epi configuration at its side chain and a 1 beta-hydroxymethyl group but not a 1 alpha-hydroxymethyl group inhibits malignant cell growth with an ED50 of 7 x 10(-9) M. To determine if the restored biological activity of the hybrid analog is associated with better binding to VDR, we performed competitive binding assays in vitro with calf thymus VDR and in vivo with recombinant human VDR. We found that the 20 epi side chain reduced the affinity of the 1 beta- and the 1 alpha-hydroxymethyl hybrid analogs for VDR in vitro and in vivo fourfold to tenfold. To determine whether the 1 beta-hydroxymethyl analogs induced a VDR-mediated transcription, we tested the induction of reporter gene expression through the osteocalcin vitamin D response element (VDRE) in ROS 17/2.8 cells and the induction of binding activity of VDR to VDRE in COS-1 cells. We found that the ED50 for transcriptional activity of 1 beta-hydroxymethyl-3 alpha,25-hydroxyvitamin D3 was greater than 10(-6) M, but its 1 alpha diastereomer had barely detectable transcriptional activity. The 20-epi side chain preferentially increased the transcriptional activity of the 1 beta-hydroxymethyl hybrid analog to an ED50 of 10(-8) M, but the 1 alpha-hydroxymethyl hybrid analog remained inactive. To confirm that this transcriptional activity was dependent on the VDR, we repeated the assay in VDR-negative CV-1 cells and compared ligand-dependent expression of the VDRE/growth hormone reporter in the presence of either wild-type or transcriptionally inactive mutant VDR expression vectors. Transcription was induced by the 1 beta-hydroxymethyl compounds only in the presence of wild-type VDR. Thus, we conclude that it is possible, by adding a 20 epi side chain, to restore growth-inhibitory and VDR-mediated transcriptional activities without increasing binding to the VDR of A ring-modified analogs.

Among the frontier challenges facing synthetic chemistry in the 21st century are the interconnected goals of increasing control of chemical reactivity and synthesizing complex molecules with higher levels of efficiency. Catalytic C–H bond functionalization reactions are increasingly being discovered that meet the criterion for useful reactivity (i.e. preparative, predictably selective, and general). Consequently, such reactions are enabling chemists to exploit strategies for complex molecule synthesis and derivatization previously accessible only in nature. This preface highlights some of the achievements and important challenges that remain in the area of C–H bond functionalization.�

Tandem reaction sequences that selectively convert multiple C–H bonds of abundant hydrocarbon feedstocks to functionalized materials enable rapid buildup of molecular complexity in an economical way. A tandem C–H amination/vinylic C–H arylation reaction sequence is described under Pd(II)/sulfoxide-catalysis that furnishes a wide range of α- and β-homophenylalanine precursors from commodity α-olefins and readily available aryl boronic acids. General routes to enantiopure amino acid esters and densely functionalized homophenylalanine derivatives are demonstrated.

A highly selective C–H amination reaction under iron catalysis has been developed. This novel system, which employs an inexpensive, nontoxic [FeIIIPc] catalyst (typically used as an industrial ink additive), displays a strong preference for allylic C–H amination over aziridination and all other C–H bond types (i.e., allylic > benzylic > ethereal > 3° > 2° ≫ 1°). Moreover, in polyolefinic substrates, the site selectivity can be controlled by the electronic and steric character of the allylic C–H bond. Although this reaction is shown to proceed via a stepwise mechanism, the stereoretentive nature of C–H amination for 3° aliphatic C–H bonds suggests a very rapid radical rebound step.