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ABSTRACT: The tricalysiolides are a recently isolated class of diterpene natural products featuring the carbon backbone of the well-known coffee extract, cafestol. Herein we validate the use of our non-heme iron complex, Fe(PDP), as an oxidative tailoring enzyme mimic to test the proposal that this class of natural products derives from cafestol via cytochrome P-450-mediated furan oxidation. Thereafter, as predicted by computational analysis, C-H oxidation derivatization studies provided a novel 2° alcohol product as a single diastereomer.
Synlett 12/2012; 23(19):2768-2772. · 2.71 Impact Factor
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ABSTRACT: 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.
Journal of the American Chemical Society 05/2012; 134(23):9721-6. · 9.91 Impact Factor
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ABSTRACT: 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.
Organic Letters 02/2012; 14(6):1386-9. · 5.86 Impact Factor
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ABSTRACT: 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.
Journal of the American Chemical Society 08/2011; 133(32):12584-9. · 9.91 Impact Factor
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ABSTRACT: 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.
Journal of the American Chemical Society 08/2011; 133(38):14892-5. · 9.91 Impact Factor
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Angewandte Chemie International Edition 06/2011; 50(30):6824-7. · 13.45 Impact Factor
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ABSTRACT: 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.
Nature Chemistry 03/2011; 3(3):216-22. · 20.52 Impact Factor
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Angewandte Chemie International Edition 02/2011; 50(9):2094-7. · 13.45 Impact Factor
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ABSTRACT: 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/Z >or= 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".
Journal of the American Chemical Society 08/2010; 132(32):11323-8. · 9.91 Impact Factor
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ABSTRACT: 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].
Tetrahedron 06/2010; 66(26):4816-4826. · 3.03 Impact Factor
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ABSTRACT: 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.
Science 01/2010; 327(5965):566-71. · 31.20 Impact Factor
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ABSTRACT: 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.
Nature Chemistry 10/2009; 1(7):547-51. · 20.52 Impact Factor
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ABSTRACT: 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.
Journal of the American Chemical Society 08/2009; 131(33):11707-11. · 9.91 Impact Factor
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ABSTRACT: A Brønsted 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.
Journal of the American Chemical Society 08/2009; 131(33):11701-6. · 9.91 Impact Factor
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Angewandte Chemie International Edition 08/2008; 47(34):6448-51. · 13.45 Impact Factor
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ABSTRACT: 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.
Journal of the American Chemical Society 08/2008; 130(34):11270-1. · 9.91 Impact Factor
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Journal of the American Chemical Society 04/2008; 130(11):3316-8. · 9.91 Impact Factor
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ABSTRACT: Realizing the extraordinary potential of unactivated sp3 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 (H2O2) 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.
Science 12/2007; 318(5851):783-7. · 31.20 Impact Factor
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Journal of the American Chemical Society 07/2007; 129(23):7274-6. · 9.91 Impact Factor
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Angewandte Chemie International Edition 01/2007; 45(48):8217-20. · 13.45 Impact Factor
