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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 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.

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

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.

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.

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...

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.

Traditionally, C–H oxidation reactions install oxidized functionality onto a preformed molecular skeleton, resulting in a local molecular change. The use of C–H activation chemistry to construct complex molecular scaffolds is a new area with tremendous potential in synthesis. We report a Pd(II)/bis-sulfoxide-catalyzed dehydrogenative Diels–Alder reaction that converts simple terminal olefins into complex cycloadducts in a single operation.

Conventionally, C–H oxidation reactions are used to install functional groups. The use of C–H oxidation to transform simple starting materials into highly versatile intermediates, which enable rapid access to a range of complex target structures, is a new area with tremendous potential in synthesis. Herein we report a Pd(II)/sulfoxide-catalyzed allylic C–H oxidation to form anti-1,4-dioxan-2-ones from homoallylic oxygenates. These versatile building blocks are rapidly elaborated to differentiated syn-1,2-diols, stereodefined amino-polyols, and syn-pyrans, structures ubiquitous in medicinally important complex molecules found in Nature. We also demonstrate that a C–H oxidation approach to the synthesis of these motifs is orthogonal and complementary to other state-of-the-art methods.

A highly general, predictably selective C-H oxidation method for the direct, catalytic synthesis of complex allylic esters is introduced. This Pd(II)/sulfoxide-catalyzed method allows a wide range of complex aryl and alkyl carboxylic acids to couple directly with terminal olefins to furnish (E)-allylic esters in synthetically useful yields and selectivities (16 examples, E/Zor= 10:1) and without the use of stoichiometric coupling reagents or unstable intermediates. Strategic advantages of constructing allylic esters via C-H oxidation vs C-C bond-forming methods are evaluated and discussed in four "case studies".

Secondary Selectivity Organic molecules consist principally of rings and chains of methylene (secondary) CH 2 groups, intermittently adorned with oxygen or nitrogen centers and more heavily substituted carbons at the junctions. Synthetic transformations would be most efficient if the C–H bonds in any particular methylene group along the framework could be targeted for selective modification. However, for the most part, these carbon centers prove remarkably hard to differentiate for reactive purposes. Chen and White (p. 566 ) now show that an iron catalyst can direct peroxide to oxidize specific secondary C–H bonds preferentially, and with reasonable efficiency, in a range of complex molecules. The observed selectivities follow predictable trends correlated with the electronic and steric environment of the target site.

Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C–H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C–H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C–H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C–O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C–H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core. A synthesis of 6-deoxyerythronolide B is reported that uses a late-stage C–H oxidative macrocyclization reaction to forge the key macrocyclic core found in the erythromycins. By installing oxygen at a late-stage, this strategy improves synthetic efficiency by minimizing the ‘oxygen load’, and provides stereochemical versatility at the site of oxidation.

A Bronsted base activation mode for oxidative, Pd(II)/sulfoxide-catalyzed, intermolecular C-H allylic amination is reported. N,N-diisopropylethylamine was found to promote amination of unactivated terminal olefins, forming the corresponding linear allylic amine products with high levels of stereo-, regio-, and chemoselectivity. The predictable and high selectivity of this C-H oxidation method enables late-stage incorporation of nitrogen into advanced synthetic intermediates and natural products.

A novel Pd/sulfoxide catalyzed diastereoselective allylic C−H amination reaction of chiral homoallylic N-tosyl carbamates is reported. Densely oxygenated α-olefin substrates with multiple stereogenic centers undergo allylic C−H amination in excellent yields and with diastereoselectivities that are controlled by the stereocenter that bears the N-tosyl carbamate. Streamlined routes to stereochemically defined anti-oxazolidinones that can be further elaborated to medicinally and biologically relevant 1,2-amino alcohols are also demonstrated. Evidence is provided that this reaction proceeds via a Pd/sulfoxide-mediated allylic C−H cleavage to form a π-allylPd intermediate followed by Pd(II) counterion-assisted deprotonation of the nitrogen nucleophile to effect functionalization.

A novel Pd/sulfoxide catalyzed diastereoselective allylic C−H amination reaction of chiral homoallylic N-tosyl carbamates is reported. Densely oxygenated α-olefin substrates with multiple stereogenic centers undergo allylic C−H amination in excellent yields and with diastereoselectivities that are controlled by the stereocenter that bears the N-tosyl carbamate. Streamlined routes to stereochemically defined anti-oxazolidinones that can be further elaborated to medicinally and biologically relevant 1,2-amino alcohols are also demonstrated. Evidence is provided that this reaction proceeds via a Pd/sulfoxide-mediated allylic C−H cleavage to form a π-allylPd intermediate followed by Pd(II) counterion-assisted deprotonation of the nitrogen nucleophile to effect functionalization.

Direct oxidation of C–H bonds has the potential to emerge as a powerful approach for introducing oxygen and nitrogen functionality in the synthesis of complex molecules.[1] Functional-group manipulations (FGMs) that are required for carrying oxygenated functionalities throughout a synthetic route may be avoided by installing them directly into the hydrocarbon framework.[2] For a hydrocarbon oxidation strategy to reach its full potential, C–H-oxidation reactions with high levels of chemo-, regio- and stereoselectivity must be identified and developed. We recently described a DMSO-promoted, Pd(OAc)2-catalyzed allylic oxidation reaction that furnishes E allylic acetates from α-olefins with high regio- and stereoselectivity, and with outstanding tolerance of functional groups.[3] Herein, we describe advances in this methodology for the oxidation of C–H bonds which enabled the development of a new hydrocarbon oxidation strategy for the rapid assembly of polyol frameworks. This strategy has been validated in an enantioselective, de novo synthesis of differentially protected L-galactose from a commercial, achiral starting material in which all new oxygen functionality has been installed through oxidation reactions of C–H and C=C bonds. A short hydrocarbon oxidation strategy for the synthesis of chiral polyols is presented in Scheme 1. Key to the efficiency of this strategy is the rapid access to chiral (E)-2-butene-1,4-diols such as 2, which may be directly elaborated to polyol structures through asymmetric dihydroxylation (AD). Compounds like 2 are particularly attractive building blocks because of their dense functionalization, dissonant relationship between the oxygen atoms,[4] and the ease with which they can be further elaborated through the established oxidation chemistry of olefins. Compounds similar to 2 have been routinely employed as intermediates to install a diverse range of structures in the synthesis of natural products; for example, five- and six-membered mono- and polycyclic ethers,[5] epoxy alcohols,[6] and, most extensively, contiguous polyol structures.[7] Notably, compounds analogous to 2 have been used as intermediates in several stereodivergent syntheses of the hexoses, an important class of polyols (Scheme 2).[8a,9] State-of-the-art syntheses of 2 based on Wittig-type olefinations[10] or cross-metathesis reactions[11] suffer from lengthy sequences, in part because of the difficulty in accessing enantioenriched α-hydroxyaldehyde and α-hydroxy olefin starting materials. Alternatively, 2 may be synthesized directly from protected chiral homoallylic alcohols such as 3 through the DMSO/PdII-promoted allylic oxidation by using the strategy presented in Scheme 1. [2,3a] Homoallylic alcohols 3 are readily accessible from the asymmetric allylation of aldehydes[12,13] or the regioselective vinylation of chiral epoxides (Scheme 1).[14] Scheme 1 A hydrocarbon oxidation strategy for the streamlined construction of polyols. Scheme 2 Chiral (E)-2-butene-1,4-diols as key intermediates in stereodivergent hexose syntheses. 4-Methoxybenzoate derivatives of chiral (E)-2-butene-1,4-diols 2 are unique among allylic alcohol derivatives in their ability to undergo AD with excellent reagent-controlled diastereoselectivity and minimal acyl transfer.[8] We recently demonstrated that the DMSO/PdII-promoted linear allylic oxidation of protected chiral homoallylic alcohols with acetic acid furnishes the acetate derivatives of 2 with excellent regio-and stereoselectivities and with no erosion of optical purity.[2] To avoid FGMs, we set out to identify conditions for allylic oxidation of α-olefins using p-anisic acid (5) to directly generate 4-methoxybenzoate derivatives of 2 from α-olefins (Scheme 1). As shown in Table 1, preliminary studies with α-olefin 4 suggested that acid 5 may be a competent nucleophile in the DMSO/PdII-promoted linear allylic oxidation reaction to form the hexose precursor 6, if the challenges associated with high acid loadings and low yields were resolved (15 equiv of 5, 23% yield, Table 1, entry 1). We were encouraged by the observation that significant amounts of the α-olefin starting material remained at the end of the reaction, thus suggesting that the acid-labile acetonide functionality was tolerant of these conditions. The addition of DIPEA, a noncoordinating base additive, effected a significant increase in yield (45%, Table 1, entry 2). Although the exact role of the base is currently unclear, we hypothesize that it increases concentrations of the benzoate anion. The yield was also increased on switching oxidants from benzoquinone (BQ) to phenyl-benzoquinone (PhBQ, 55%, Table 1, entry 3). Finally, on increasing the reaction concentration to 2.0M, we achieved further increases in yields, and were able to use fewer equivalents of carboxylic acid (2.0M, 3 equiv 5, 75% yield, Table 1, entry 6). Table 1 Investigation into the linear allylic oxidation reaction to form the hexose precursor 6. The linear allylic oxidation reaction is exceptionally stereo- and regioselective, with the major product formed being the linear E isomer (linear/branched >300:1, E/Z = 30→36:1, entries 6 and 7, Table 1). The reaction is also preparatively convenient, with all reactions carried out in an air atmosphere with no precautions taken to exclude moisture or O2. Significantly, with these newly developed conditions, the catalyst loading may be decreased to 5 mol% with only a minor decrease in yield (63%, Table 1, entry 8). Moreover, useful yields are obtained from fragment couplings with 1.5 equivalents of carboxylic acid at 3.0M concentrations of α-olefin (50%, Table 1, entry 9). The only by-product we observed in the reaction using Pd(OAc)2 as the PdII source was allylic acetate, which can be eliminated by using [Pd(CH3CN)4](BF4)2 (Table 1, entry 7). We set out to test the efficiency of this overall strategy for polyol construction in the context of a short, de novo synthesis of the differentially protected L-galactose (−)-11 (Scheme 3). Bulk chemical (Z)-2-butene-1,4-diol (7) was epoxidized with m-chloroperbenzoic acid (mCPBA) to give the meso-epoxide 8 in 74% yield. The meso-epoxide 8 was then desymmetrized by using the enantioselective Payne rearrangement with oligomeric (R,R)-[(salen)CoIII]OTf catalyst (salen =N,N′-bis(salicylidene)ethylenediamine, Tf =trifluoromethanesulfonyl) and subsequently ketalized in situ to give the chiral epoxyketal (S,S)-9.[15,16] Regioselective opening at the terminal position of the epoxyketal with vinylcuprate and subsequent protection of the intermediate alcohol gave the benzyl ether protected homoallylic alcohol (−)-4 in 54% overall yield (3 steps, 99% ee).[14,15b] Linear allylic C–H oxidation of (−)-4 using 10 mol% [Pd(CH3CN)4](BF4)2 in DMSO under the optimized conditions (2M, PhBQ, 50 mol% DIPEA) with 3 equivalents of p-anisic acid 5 furnished the 4-methoxybenzoate-derived (E)-2-butene-1,4-diol (+)-6 in 71% yield (along with 13% recovered (−)-4) as essentially one isomer (linear/branched =>300:1; E/Z =36:1) and with no erosion of enantiopurity.[17] Alternatively, on using 10 mol% Pd(OAc)2 in DMSO under the same conditions, (+)-6 was obtained in 75% yield with around 10% of the allylic acetate product that was arduous to separate by silica gel chromatography. Asymmetric dihydroxylation of (+)-6 proceeded smoothly to give the polyoxygenated (−)-10 in 96% yield and greater than 20:1 d.r. (1H NMR).[18] Protection of the diol (−)-10 as the silyl ether, followed by removal of the p-methoxybenzoate ester with DIBAL, Swern oxidation of the resulting primary alcohol, and removal of the isopropyl-idene ketal group with Zn(NO3)·6H2O[19] gave the differentially protected L-galactose (−)-11 in 74% yield (over 4 steps).[20] The enantioselective, de novo synthesis of (−)-11 thus proceeded in a total of 10 linear steps with 20% overall yield from the commercially available 7. Scheme 3 Total synthesis of differentially protected L-galactose (−)-11 (see the Supporting Information for full experimental details). a) mCPBA, CH2Cl2, 0 °C→RT (74%); b) oligomeric (R,R)-[(salen)CoIII]-OTf (0.05 mol%), CH3CN; then 2-methoxypropene, ... Several stereodivergent, de novo syntheses of the hexoses from 7 have employed chiral (E)-2-butene-1,4-diols analogous to 6 as intermediates. The C–H-oxidation route to 6 (5 steps, 28% overall yield) compares favorably, in number of steps and overall yield, with the Wittig olefination routes previously reported (for example: 11 steps, 18% overall yield,[9] and 9 steps, 16% overall yield[8a]). The strategy developed herein, along with these previous syntheses, provides access to hexose stereoisomers that are complementary to those obtained through aldol-based approaches.[21] In summary, we have reported a mild and efficient hydrocarbon oxidation strategy for the preparation of chiral polyols, a process validated by an efficient, enantioselective synthesis of the differentially protected L-galactose (−)-11. The synthesis used a highly regio- and stereoselective linear allylic C–H-oxidation reaction that generated 4-methoxybenzoate derivatives of chiral (E)-2-butene-1,4-diols directly from readily available chiral homoallylic alcohols and carboxylic acids. We anticipate that the simple and mild nature of this transformation (that is 2→3, Scheme 1) will render it useful for the synthesis of polyoxygenated motifs in complex molecules.

We are reporting a mild, chemo-, and highly regioselective Pd(II)-catalyzed allylic oxidation of alpha-olefins to furnish branched allylic esters that proceeds via a novel serial ligand catalysis mechanism in which two different ligands (i.e., vinyl sulfoxide 2 and BQ) interact sequentially with the metal to promote distinct steps of the catalytic cycle (i.e., C-H cleavage and pi-allyl functionalization, respectively).

Sulfoxide ligation to Pd(II) salts is shown to selectively promote C-H oxidation versus Wacker oxidation chemistry and to control the regioselectivity in the C-H oxidation products. A catalytic method for the direct C-H oxidation of monosubstituted olefins to linear (E)-allylic acetates in high regio- and stereoselectivities and preparatively useful yields is described. The method using benzoquinone as the stoichiometric oxidant and 10 mol % of Pd(OAc)2 or Pd(O2CCF3)2 as the catalyst in a DMSO/AcOH (1:1) solution was found to be compatible with a wide range of functionality (e.g., amides, carbamates, esters, and ethers, see Table 2). Addition of DMSO was found to be critical for promoting the C-H oxidation pathway, with AcOH alone or in combination with a diverse range of dielectric media, leading to mixtures favoring Wacker-type oxidation products (Tables 1, S3). To explore the role of DMSO as a ligand, the bis-sulfoxide Pd(OAc)2 complex 1 was formed and found to be an effective C-H oxidation catalyst in the absence of DMSO (eqs 2, 3). Moreover, catalyst 1 effects a reversal of regioselectivity, favoring the formation of branched allylic acetates.

A Pd(II)/sulfoxide-catalyzed sequential allylic C-H oxidation/vinylic C-H arylation of alpha-olefins to furnish E-arylated allylic esters in high regio- and E:Z selectivities (20:1) is reported. The broad scope of this method with respect to the alpha-olefin, carboxylic acid, and aryl boronic acid enables the rapid assembly of densely functionalized fragments for complex molecule synthesis from cheap, abundant hydrocarbon starting materials. The Pd(II)/sulfoxide-catalyzed vinylic C-H arylation of electronically unbiased olefins with aryl boronic acids proceeds under oxidative, acidic conditions and mild temperatures (room temperature to 45 degrees C).

A novel Pd/sulfoxide-catalyzed macrolactonization reaction of linear omega-alkenoic acids is reported that proceeds via serial ligand-catalyzed allylic C-H oxidation. The scope of this macrolactonization appears to be very broad. Aryl, alkyl, and (Z)-alpha,beta-unsaturated acids are all competent nucleophiles for this reaction, with the latter undergoing macrolactonization with no olefin isomerization. High functional group compatibility is observed that includes biologically and medicinally relevant functionality such as ortho-substituted salicylate esters, bis(indoyl)maleimides, and peptides. Evidence is provided to support the hypothesis that macrolactonization proceeds via inner-sphere functionalization from a templated pi-allylPd carboxylate intermediate.