M. Christina White

Combined Effects on Selectivity in Fe-Catalyzed Methylene Oxidation

Secondary Selectivity Organic molecules consist principally of rings and chains of methylene (secondary) CH2 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. An iron catalyst shows selectivity for the oxidation of secondary C–H bonds in organic molecules. Methylene C–H bonds are among the most difficult chemical bonds to selectively functionalize because of their abundance in organic structures and inertness to most chemical reagents. Their selective oxidations in biosynthetic pathways underscore the power of such reactions for streamlining the synthesis of molecules with complex oxygenation patterns. We report that an iron catalyst can achieve methylene C–H bond oxidations in diverse natural-product settings with predictable and high chemo-, site-, and even diastereoselectivities. Electronic, steric, and stereoelectronic factors, which individually promote selectivity with this catalyst, are demonstrated to be powerful control elements when operating in combination in complex molecules. This small-molecule catalyst displays site selectivities complementary to those attained through enzymatic catalysis.

Adding Aliphatic C–H Bond Oxidations to Synthesis

Oxidations of aliphatic C–H bonds, known since the 1800s, have only recently been considered for use in organic synthesis. 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.

Catalytic Intermolecular Linear Allylic C-H Amination via Heterobimetallic Catalysis

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...

Iron-Catalyzed Intramolecular Allylic C–H Amination

A highly selective C-H amination reaction under iron catalysis has been developed. This novel system, which employs an inexpensive, nontoxic [Fe(III)Pc] 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.

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 substrates 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.

A chiral Lewis acid strategy for enantioselective allylic C-H oxidation.

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]

Total synthesis and study of 6-deoxyerythronolide B by late-stage C–H oxidation

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.

Catalytic Intermolecular Allylic C—H Alkylation

The first electrophilic Pd(II)-catalyzed allylic C H alkylation is reported, providing a novel method for formation of sp3-sp3 C C bonds directly from C H bonds. A wide range of aromatic and heteroaromatic linear (E)-alpha-nitro-arylpentenoates are obtained as single olefin isomers in excellent yields directly from terminal olefin substrates and methyl nitroacetate. The use of DMSO as a pi-acidic ligand was found to be crucial for promoting functionalization of the pi-allylPd intermediate. Products from this reaction are valuable synthetic intermediates and are readily transformed to amino esters via selective reduction and optically enriched alpha,alpha-disubstituted amino acid precursors via asymmetric conjugate addition.

Allylic C—H Amination for the Preparation of syn-1,3-Amino Alcohol Motifs

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.

A general and highly selective chelate-controlled intermolecular oxidative Heck reaction.

A novel chelate-controlled intermolecular oxidative Heck reaction is reported that proceeds with a wide range of nonresonance stabilized alpha-olefin substrates and organoboron reagents to afford internal olefin products in good yields and outstanding regio- and E: Z stereoselectivities. Pd-H isomerization, common in many Heck reactions, is not observed under these mild, oxidative conditions. This is evidenced by outstanding E: Z selectivities (>20:1 in all cases examined), no erosion in optical purity for proximal stereogenic centers, and a tolerance for unprotected alcohols. Remarkably, a single metal/ligand combination, Pd/bis-sulfoxide complex 1, catalyzes this reaction over a broad range of coupling partners. Given the high selectivities and broad scope, we anticipate this intermolecular Heck reaction will find heightened use in complex molecule synthesis.