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M. Christina White
Department of Chemistry
University of Illinois
470 Roger Adams Laboratory
600 South Mathews Ave.
Urbana, IL 61801
"Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization"
Joeseph R. Clark, Kaibo Feng, Anasheh Sookezian and M. Christina White
Nat. Chem., 2018, DOI: 10.1038/s41557-018-0020-0
Introduction of nitrogen into existing bioactive molecules has the potential to drastically change the bioactivity of that molecule. An easily accessible manganese catalyst opens a new path for such drug diversification. The manganese catalyst selectively aminates benzylic C–H bonds while tolerating other reactive sites and functional groups. Previously reported noble metal catalysts can carry out this type of amination, but are expensive and aminate C–H bonds unselectively to produce inseparable mixtures. Known methods do not tolerate tertiary amines, prevalent in drugs, resulting in no reactivity or functionalization on or α to nitrogen. Meanwhile, inexpensive base metals are either too weak for preparative amination or epimerize stereocenters.
In this manuscript, we report a manganese(III) perchlorophthalocyanine catalyst that selects one benzylic C–H bond over all others in amination, including more hindered or electron-poor secondary benzylic sites and tertiary sites. Substrates containing basic nitrogen can be effectively protected with a Brønsted (HBF4) or Lewis acid (BF3), to give remotely aminated products. We carried out late-stage amination on a series of drugs and drug-like molecules, including citalopram, analogs of estrone and dextromethorphan, and biflavanoids, many of which cannot be accessed by other amination methods due to the presence of basic nitrogen. We show the sulfamate protecting group can be readily taken off to generate the free amine. The catalyst can be synthesized in one step and University has licensed it to MilliporeSigma, which is making it commercially available.
"C–H to C–N Cross-Coupling of Sulfonamides with Olefins"
Rulin Ma and M. Christina White
J. Am. Chem. Soc., 2018, 140, 3202, DOI: 10.1021/jacs.7b13492
The ubiquity of C(sp3)—N bonds in natural products and pharmaceuticals, suggests that development of cross-coupling reactions of nitrogen functionality with hydrocarbons under fragment coupling conditions (1 equivalent) will significantly impact chemical synthesis. Whereas significant progress has been made in cross-couplings of amines with aryl halides to form C(sp2)—N bonds, the development of analogous C(sp3)—N coupling reactions remains an elusive goal. Herein, we demonstrate a C(sp3)—N fragment coupling reaction between abundant terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/sulfoxide (SOX) 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). For the first time, a variety of singly activated aromatic and aliphatic nitrogen nucleophiles, including ones with stereochemical elements, can be used in fragment coupling stoichiometries for intermolecular C-H amination reactions.
Kinetic isotope effect studies reveal a mechanism proceeding via C—H cleavage to furnish a π-allylPd intermediate followed by functionalization and Pd(0) reoxidation. Nucleophile competition studies and stoichiometric π-allyl Pd functionalization studies strongly supports that a unique feature of the SOX ligand platform is the ability to chelate and stabilize cationic π-allyl Pd intermediates electrophilically activated towards functionalization. This is analogous to the role of phosphine ligands in Pd(0) catalysis and suggests that the SOX framework may provide an oxidatively stable ligand platform for C—H oxidation that controls functionalization.Publication 47. SI.
"Remote, Late-Stage Oxidation of Aliphatic C–H Bonds in Amide-Containing Molecules"
Takeshi Nanjo‡, Emilio C. de Lucca Jr.‡ and M. Christina White
J. Am. Chem. Soc. , 2017, 139, 14586, DOI: 10.1021/jacs.7b07665
Nitrogen-containing functionalities append notable physical and bioactivity properties to organic molecules. Among them, amides are considered a privileged scaffold in medicinal chemistry, natural products, and materials science. Despite the ability to use amides as directing groups for C—H functionalizations proceeding via organometallic intermediates, there is no general means for effecting non-directed, remote aliphatic C—H hydroxylation of simple amide-containing molecules. The intermediate electron-richness of simple amide-containing molecules renders them not electron-deficient enough to enable remote oxidations without protection and not sufficiently electron-rich to be amenable to the N-protection strategies previously developed in our group (i.e. irreversible binding with acids, see publication 41). 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 to convert the amide to cationic imidate salt. 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 functionalities. This novel imidate strategy facilitates late-stage oxidations on 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.Publication 46. SI.
"Catalytic C(sp3)−H Alkylation via an Iron Carbene Intermediate"
Jennifer R. Griffin, Chloe I. Wendell, Jacob A. Garwin, and M. Christina White
J. Am. Chem. Soc., 2017, 139, 13264, DOI: 10.1021/jacs.7b07602
Iron is one of the most abundant elements, totaling one-third of the Earth’s mass. Although iron enzymes and small molecule catalysts have been shown to catalyze difficult aliphatic C(sp3)—H oxidations and aminations via high valent iron oxos and iron nitrenes pathways, catalytic C(sp3)—H alkylations via isolelectronic iron carbene intermediates have been elusive. This is particularly curious given that nearly all of iron’s closest neighbors in the periodic table (i.e. copper, cobalt, silver, palladium, rhodium, and ruthenium) all form metallocarbenes capable of C—H alkylation. Why not iron? We hypothesized that unlike many of iron’s neighbors (e.g. rhodium and copper) whose energetically hard step in the reaction is forming the metallocarbene, for iron the hard step is performing the C—H alkylation after forming the metallocarbene relatively easily. We found that the combination of an electron deficient iron phthalocyanine catalyst with an electron poor carbene precursor, a diazosulfonate ester, enabled the first catalytic C—H alkylation. The method currently enables catalytic alkylation of allylic, benzylic, and ethereal C(sp3)—H bonds. We additionally demonstrate this strategy can be applied late-stage in a complex molecule setting to alkylate at the benzylic site of tocopherol. Mechanistic investigations support that the reaction proceeds via an electrophilic iron carbene that mediates homolytic C—H cleavage followed by rebound from an organoiron intermediate that mediates new C—C bond. KIE studies reveal that the rate determining step of this iron catalyzed process is partially C—H cleavage, which contrasts what has been observed with copper- and rhodium-catalyzed C—H alkylations. Importantly, these mechanistic studies suggest that the reactivity and selectivity of the iron carbene intermediate can be readily tuned via the catalyst ligand framework.Publication 45. SI.
"Oxidative diversification of amino acids and peptides by small-molecule iron catalysis"
Thomas J. Osberger†, Donald C. Rogness†, Jeffery T. Kohrt, Antonia F. Stepan and M. Christina White
Nature, 2016, 537, 214, DOI: 10.1038/nature18941
Small-peptide therapeutics are becoming increasingly important for human health, as evidenced by recently approved peptidic drugs like Daklinza (BMS) and Ledipasvir (Gilead) for the treatment of hepatitis C. Current methods for making structural varients of these types molecules to test for new or improved biological activities require a de novo synthesis to change one of their amino acid building blocks.
In contrast, iron-based oxidation enzymes in NRPS biosynthetic pathways frequently effect site-selective C-H oxidation reactions on individual amino acid residues in peptides to generate new structures containing unnatural amino acids (UAAs). While this strategy for incorporating UAAs has been attractive to chemists for some time, iron enzymes are very difficult to work with in the laboratory and lack generality (often it is a one enzyme per substrate scenario). The small-molecule approaches developed so far have been limited in their utility because of difficulty in reagent preparation, potential loss of stereochemistry in the amino acid, and the inability to react selectively with a single amino acid in complex peptide settings. We have found that our small-molecule iron catalysts Fe(PDP) and Fe(CF3PDP) are capable of site-selective C-H oxidation reactions at specific amino acid sites in peptides, with preservation of -center stereochemistry, enabling the rapid oxidative diversification of amino acids and complex peptides. By applying the small-molecule iron catalyzed C-H oxidation reactions to proline and proline-containing peptides, we found that 5-hydroxyproline is selectively formed despite the conventionally more labile C-H bonds at the C2 position (oxidation at C2 scrambles stereochemistry). Proline is also selectively oxidized over other amino acids, such as leucine or alanine. Performing C—H oxidations followed by arylations, olefinations, reductions, reductive aminations, and further oxidations, we were able to efficiently convert proline into a variety of optically enriched UAAs containing aromatic rings, olefins, alcohols, amines and carboxylic acids. Additionally, Fe(PDP) and Fe(CF3PDP) C-H oxidations of leucine and valine-containing peptides yielded hydroxyl containing UAAs, which could be transformed into fluorinated UAAs. To highlight the power of these oxidation reactions to diversify peptides, we transformed a single proline-containing tripeptide into eight different UAA-containing tripeptides. Traditional chemical routes to make all eight peptides would require eight de novo syntheses, including seperate syntheses of the unnatural amino acid building blocks. We also demonstrated the ability of the iron catalysts to oxidize proline residues at any position in a peptide. This culminated in the selective oxidative transformation of a proline residue in a pentapeptide macrocycle into a linear ornithine derivative, inducing a major change in the peptide structure. In addition to diversifying peptides, these C—H oxidation reactions are also able to significantly expand the chiral pool of amino acid building blocks available. Specifically, we demonstrate that four chiral pool amino acids are efficiently transformed into 21 UAAs. Importantly, the valuable stereochemistry of amino acids was preserved over the synthetic sequences, creating stereochemically enriched UAAs from widely available starting materials (for example, proline is a bulk commodity chemical).
"Base-Metal Catalysis: Embrace the Wild Side."
M. Christina White
Adv. Synth. Catal., 2016, 358, 2364, DOI: 10.1002/adsc.201600766
Publication 43. SI.
"Enantioselective Allylic C–H Oxidation of Terminal Olefins to Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis"
Stephen E. Ammann†, Wei Liu†, and M. Christina White
Angew. Chem. Int. Ed., 2016, 55, 9571, DOI: 10.1002/anie.201603576
Reported is a novel chiral aryl sulfoxide-oxazoline (ArSOX)/Pd(II) catalyst that enables asymmetric allylic C—H oxidation with the broadest scope and highest enantioselectivities to date (avg. 92% ee, 13 examples ≥90% ee). Pd/ArSOX catalysis furnishes enantioenriched isochromans from terminal olefins under robust conditions tolerant of air and moisture. Stereochemically-defined substitution on the isochroman at the 3- and 4- positions is well-tolerated with asymmetric catalysis affording either enhanced diastereoselectivities (e.g. 1.5:1 to >20:1) or a slight turnover (e.g. 1.5:1 to 1:2.8). The streamlining potential of the asymmetric C–H oxidation is demonstrated in the total synthesis of (S)-PNU-109291, a pharmaceutical compound that functions as a selective 5HT1D agonist. Preliminary mechanistic studies indicate that the reaction proceeds via allylic C–H cleavage with subsequent functionalization of the π-allylpalladium intermediate likely to be the enantiodetermining step.
A Pd(II)/sulfoxide-catalyzed linear allylic C—H amination reaction is reported which employs molecular oxygen as the stoichiometric oxidant. This aerobic linear allylic amination (LAA) shows broad scope for terminal olefin substrates (1 equiv.) and utilizes 2.5-5 mol% of Pd(II)/sulfoxide catalyst under mild conditions of temperature (45oC) and O2 pressure (1 atm). The use of O2 as the stoichiometric oxidant in a Co-mediated redox-relay catalytic cycle results in a marked increase in reaction efficiency providing higher catalyst turnover numbers with higher or comparable yields of aminated product to the previous systems using BQ as the terminal oxidant. Experiments aimed at understanding this effect have revealed an inhibitory effect of BQ at high concentrations on both overall reaction yields and the rate of product formation. Kinetic experiments have demonstrated that an increase in concentration of benzoquinone leads to a progressive decrease in reaction rate. At elevated concentrations, BQ may bind to Pd(II) in a manner that competes with coordination of the bis-sulfoxide ligand, required for C—H cleavage and productive reactivity.
Late stage C—H oxidation using preparative, site-selective catalysis is a powerful strategy for diversification to furnish novel oxidized compounds with altered physical and biological properties. However, a major limitation of this strategy has been the inability to evaluate remote aliphatic C—H oxidations in compounds containing nitrogen, a functionality ubiquitous in biologically active compounds.
Nitrogen is ubiquitous in pharmacologically important compounds. Late-stage introduction of nitrogen directly into C—H bonds is highly desirable, however broad application of current C—H amination methods has been thwarted by the “reactivity-selectivity” paradigm typical of high valent metal-catalyzed C—H oxidation chemistry (e.g. metallonitrene, metalloxo), wherein reactivity and selectivity are inversely correlated. For example, precious metal rhodium catalysts are effective for the amination of strong aliphatic C—H bonds, but do not tolerate reactive π-functionality (i.e. olefins). Previous work by our group (see Publication 25) and others showed that Earth-abundant iron catalysts are highly selective for allylic C—H amination in the presence of reactive π-functionality, but are poorly reactive for strong aliphatic C—H bonds. Here we report a manganese phthalocyanine catalyst, [Mn(tBuPc)]·SbF6, that defies the “reactivity-selectivity” paradigm. [Mn(tBuPc)] is unique in its capacity to functionalize all types of C(sp3)—H bonds intramolecularly, including very strong 1° aliphatic, while also maintaining high selectivity for C—H amination in the presence of π-functionality, e.g. olefins and alkynes, a combination of reactivity and selectivity unprecedented for previous catalysts. Our mechanistic studies reveal a reaction pathway for manganese that lies between the concerted C—H insertion pathway of rhodium and the stepwise C—H abstraction/rebound pathway of iron. Unexpectedly, rather than blending these effects, [Mn(tBuPc)] is an outlier. It promotes C—H amination with higher reactivity than rhodium while maintaining the high chemoselectivity observed with iron catalysis. The reactivity and synthetic utility of this unusually general intramolecular C—H amination method is showcased in the late stage C–H amination of a range of alcohol-containing complex molecules (7 total), including the site-selective amination of 1° aliphatic C—H bonds in a derivative of betulinic acid, a readily available natural product with promising antitumor activity but limited bioavailability.This manganese catalyst is synthesized in one step from commercial materials (and will be available from Aldrich this Fall: Product number 799688) and uses a non-toxic metal that is ten million times more abundant than its precious metal rhodium predecessor. The discovery of an Earth-abundant metal catalyst capable of aminating all types of C—H bonds, including those challenging to access with precious metals (i.e. allylic, propargylic, and 1˚ aliphatic), underscores the potential for the continued development of inexpensive, underexplored base metal catalysts for important synthetic reactions that will be both environmentally friendly and sustainable.
Publication 39. SI. 2.
"Terminal Olefins to Chromans, Isochromans, and Pyrans via Allylic C–H Oxidation."
Stephen E. Ammann , Grant T. Rice , and M. Christina White
J. Am. Chem. Soc., 2014, 136, 10834, DOI: 10.1021/ja503322e
Reported is a general method for intramolecular allylic C—H oxidation of terminal olefins to access six-membered cyclic ethers via palladium(II)/bis-sulfoxide/Lewis acid co-catalysis. The high chemoselectivity of this method is underscored by the ability to oxidize an allylic C—H bond in the presence a broad range of alcohols (phenols, benzylic alcohols, aliphatic alcohols). Chroman, isochroman, and pyran motifs are furnished under uniform (solvent, catalyst, temperature) and operationally simple reaction conditions (open to air and moisture). Experimental investigations suggest a mechanism where initial Pd/sulfoxide-mediated C–H cleavage is followed by a Pd-assisted deprotonation / inner-sphere reductive elimination pathway. Consistent with this mechanism, orthogonal reactivity and electronic trends are observed between this reaction and traditional Pd(0)-catalyzed allylic substitutions that proceed via outer-sphere functionalization pathways.
We report the synthesis of oxazolidinones directly from N-Boc amines via Pd(II)/Bis-sulfoxide/Brønsted acid co-catalyzed allylic C-H oxidation. This method allows for the efficient construction of a range of oxazolidinone rings with good yields (avg. 63%) and excellent diastereoselectivities (avg. >14:1 dr). The products generated via this method are regioisomeric to those furnished via our previously reported allylic C-H amination system (see publication 7 below). Investigation of the role of the Brønsted acid (dibutyl phosphate) cocatalyst suggests that it plays multiple roles in the catalytic cycle that include: generation of a Pd(II)/Bis-sulfoxide phosphate species competent in C-H cleavage, generation of an electrophilic π-allylPd species that enables functionalization with the aprotic Boc group, promotion of quinone-mediated Pd(0)→ Pd(II) catalyst regeneration.
A general method for intermolecular allylic C—H alkylation of terminal olefins with tertiary nucleophiles is disclosed. Palladium(II)/bis-sulfoxide catalysis affords alkylation products in good yield (avg. 64%) with excellent chemo-, regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z). Notably, both activated (aromatic, heteroaromatic, 1,4-dienes) and unactivated aliphatic olefins are successfully alkylated for the first time under the same general and mild reaction conditions. Facile diversification of phenolic natural products is demonstrated by combining known allylation reactions with allylic C—H alkylation. The tertiary nucleophile scope is broad and tolerant of latent functionality that may be further elaborated. The generality of this method in both reaction partners enables its use to streamline synthesis via expedient generation of molecular complexity. Underscoring this is a tandem allylic C—H alkylation/Diels-Alder reaction cascade used to rapidly furnish the common tricyclic core found in the class I galbulimima alkaloids: a reactive diene is generated via intermolecular allylic C—H alkylation and subsequently engages in cycloaddition with a dienophile in the tertiary nucleophile.
The ubiquity of C—H bonds in organic molecules makes them ideal targets for complex molecule diversification as well as late-stage synthetic streamlining. These advantages are contrasted by the challenge of targeting one C—H bond among many with predictable selectivity. Central to harnessing C—H oxidations is development of 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 the design and application of a simple small molecule catalyst [Fe(CF3-PDP)] that provides catalyst-controlled site-selectivity over a broad range of topologically and functionally diverse molecules. In contrast to previous catalyst designs that mimicked the encapsulation strategy of enzyme active sites, our trajectory restriction approach created sufficient catalyst-substrate interactions needed to control site selectivity, while maintaining the flexibility required for broad substrate scope. To provide a practical tool for understanding and predicting the reactivity of both substrate-controlled Fe(PDP) and catalyst-controlled Fe(CF3-PDP), a structure-based catalyst reactivity model is disclosed that quantitatively correlates the innate physical properties of the substrate to the site-selectivities observed as a function of the catalyst.
Publication 34. SI. 2.
"Catalyst-Controlled C−O versus C−N Allylic Functionalization of Terminal Olefins."
Iulia I. Strambeanu and M. Christina White
J. Am. Chem. Soc., 2013, 135, 12032, DOI: 10.1021/ja405394v
Selectively transforming one C−H bond in a common starting material into diverse products is a powerful strategy for streamlining and diversifying synthetic sequences. In this regard, homoallylic N-nosyl ureas were investigated as they could give rise to functionally diverse products (O or N heterocycles). The divergent synthesis of syn-1,2-aminoalcohol or syn-1,2-diamine precursors from a common terminal olefin has been accomplished using a combination of Pd(II) catalysis with Lewis acid co-catalysis. Pd(II)/bis-sulfoxide with a silver triflate co-catalyst leads for the first time to anti-2-aminooxazolines (C—O) in good to excellent yields. Simply removing the bis-sulfoxide ligand results in a complete switch in reactivity to afford anti-imidazolidinones (C—N). Mechanistic studies support that the divergent reactivity from the common ambident nucleophile is catalyst dependent and arises from a switch in mechanism from allylic C—H cleavage/ functionalization with Pd(II)/bis-sulfoxide to olefin isomerization/ oxidative amination with simple Pd(II) salts.Click here for photo of Iulia.
Publication 33. SI. 2.
"Oxidative Heck Vinylation for the Synthesis of Complex Dienes and Polyenes."
J. H. Delcamp, P. E. Gormisky, and M. C. White
J. Am. Chem. Soc., 2013, 135, 8460, DOI: 10.1021/ja402891m
We introduce an oxidative Heck reaction for selective complex diene and polyene formation. The reaction proceeds via oxidative Pd(II)/sulfoxide catalysis that retards palladium-hydride isomerizations which previously limited the Heck manifold's capacity for furnishing stereodefined conjugated dienes. Limiting quantities of 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). For example, we are able to form the (E,E,E,Z)-tetraene DHR derivative shown above with excellent selectivities; this example represents the longest polyene synthesized highly stereoselectively via the Heck vinylation. 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.
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. Such motifs are particularly challenging to construct asymmetrically when the oxygen atom is remote from other functionality, rendering stereochemical relay approaches not viable. 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.
Development of a mild (35 C, no Bronsted acids) tandem Wacker oxidation-dehydrogenation of terminal olefins was accomplished using palladium(II) and hypervalent iodine co-catalysis. The reaction affords linear aryl and alkyl a,B-unsaturated ketones directly from readily available terminal olefins in good yields (average 75% per step) with excellent functional group tolerance and chemo- and stereoselectivities. The hypervalent iodine co-catalyst was found to be critical for dehydrogenation but was not effective as a stoichiometric oxidant.
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 ex- ploit strategies for complex molecule synthesis and derivatization previously accessible only in nature. This perspective highlights some of the achievements and important challenges that remain in the area of C-H bond functionalization.
The tricalysiolides are a recently isolated class of di- terpene 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. Whereas tricalysiolide B was isolated from the tree tricalysia dubia in milligram quantities, it can be easily generated in multigram quantities from coffee grinds using Fe(PDP)-mediated oxidation.
Despite long-standing interest in the use of high valent metal oxo's for C-H hydroxylation, no general approach has been reported due to the predominant use of porphyrin-ligated catalysts unable to bind both oxidant and substrate simultaneously at proximal coordination sites. Herein we report the 1st general strategy for a directing effect on metal oxo-promoted C-H hydroxylation using a non-heme iron catalyst, Fe(PDP), with cis-open coordination sites. Carboxylic acid moieties on the substrate are shown to direct the sites of oxidation and overcome unfavorable electronic, steric, and stereoelectronic effects.
Oxidations of aliphatic C-H bonds (unactivated, isolated, alkyl sp3 C-H bonds) have appeared in the literature sporadically since the late 1800s. However, synthetic chemists considered these transformations to be too unselective and/or inefficient for routine utilization in synthesis. This view has changed dramatically during the past several years. Specifically, it is now widely accepted that predictable selectivity and preparative utility for aliphatic C-H oxidations is possible with small molecule catalysts. This perspective explains how we arrived at this point.
We demonstrate a sequential C-H amination/vinylic C-H arylation reaction proceeding via Pd(II)/sulfoxide catalysis that transforms commodity a-olefins into a- and b-homophenylalanine precursors. This work demonstrates the power of sequential, selective C-H functionalization methods to incorporate functional group handles rapidly onto simple and inexpensive hydrocarbon feedstocks, thereby enabling their use as starting materials for medicinally important compounds.
We report herein the first example of a general and synthetically useful iron-catalyzed C-H amination reaction. This reaction proceeds via an iron nitrenoid intermediate and displays reactivity trends that are orthogonal to or more preferential than traditional second row metal-catalyzed nitrene-based aminations. [Fe(III)Pc]-catalyzed C-H aminations have an extraordinarily high preference for aminating the allylic C-H bond rather than aziridinating the olefin itself (generally >20:1). Additionally, allylic C-H bonds are strongly preferred to react with this catalyst over all other bond types, closely paralleling C-H bond dissociation energies (allylic > benzylic > ethereal > 3° > 2° >> 1°). Excitingly, in substrates that have multiple olefins, the [Fe(III)Pc]-catalyst demonstrates the ability to effectively discriminate between allylic C-H bonds based on their electronic and steric properties. Although this reaction is shown to proceed via a stepwise mechanism (radical C-H abstraction/rebound), the stereoretentive nature of C-H amination for 3° aliphatic C-H bonds suggests a very rapid radical rebound step.
Notably, iron phthalocyanine [Fe(III)Pc] is an inexpensive and non-toxic complex that is already being used industrially as a pigment/additive for printing inks and as a vulcanizing agent (cross-linking catalyst) in rubber manufacturing. Click here for photo of Shauna and MCW.
In this communication, we report the first dehydrogenative Diels-Alder reaction. Using a palladium(II)/benzylbis-sulfoxide catalyst, simple terminal olefin starting materials are transformed into reactive diene intermediates as a mixture of E/Z isomers via sequential allylic C-H cleavage/homoallylic b-hydride elimination. In the presence of a reactive dienophile, the palladium catalyst also promotes a diene isomerization event to enrich the E-diene isomer, followed by a classic Diels-Alder cycloaddition to generate the complex cyclohexenyl products. This chemistry has been used to forge a variety of different molecular scaffolds that are important in natural product synthesis and medicinal chemistry (i.e. hydroisoindolines, cis-decalins, hydroisoquinolines, and isoindoloquinolines) in fewer steps and higher yields than traditional Diels-Alder routes that require independent synthesis of the E-dienes.
Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.
Publication 23. SI. 2.
"Synthetic Versatility in C-H Oxidation: A Rapid Approach to Differentiated Diols and Pyrans from Simple Olefins"
P. E. Gormisky and M. C. White
Journal of the American Chemical Society, 2011, 133, 12584 DOI: 10.1021/ja206013j
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.
Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.
Publication 22. SI.
"Allylic C-H Alkylation of Unactivated α-Olefins: Serial Ligand Catalysis Resumed"
A. J. Young and M. C. White
Angewandte Chemie International Edition, 2011, 50, 6824 DOI: 10.1002/anie.201101654
Reactions that proceed via serial ligand catalysis mechanisms require a delicate interplay of several kinetically labile ligands. We report an investigation of the disruption of this balance and its ramifications in the case of allylic C-H alkylation. Overly competitive ligands, like the DMSO required for functionalization, were found to disrupt formation of the Pd/bis-sulfoxide catalyst required for C-H cleavage and inhibit the catalytic cycle. Insights derived from this study were applied to identify an alternate bis-sulfoxide ligand that could better compete with DMSO for binding to Pd. This has led to the development of the first intermolecular allylic C-H alkylation of unactivated α-olefins.
Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.
Publication 21. SI.
"On the Macrocyclization of the Erythromycin Core: Preorganization is Not Required."
E.M. Stang and M.C. White
Angewandte Chemie International Edition, 2011, 50, 2094 DOI: 10.1002/anie.201007309
In this report, we demonstrate that preorganization is not a requirement for the efficient cyclization of the erythromycin core, as has always been assumed. We attempted a traditional acylation-based macrolactonization with unbiased hydroxy acids and CH oxidative macrolactonization with an unbiased hydroxy acid to give the erythromycin core sturcture. Despite decades of erythromycin syntheses, this is the first reported case where precursors to any member of the erythromycins have been successfully cyclized without the use of biasing elements to aid 14-membered macrolide formation. This finding has enabled CH oxidative cyclization or Yamaguchi macrocyclization to form stereochemically modified erythromycin structures that were previously inaccessible by using the traditional biasing element approach.
Publication 20. SI.
"Diverting non-haem iron catalysed aliphatic CH hydroxylations towards desaturations."
M.A. Bigi, S.A. Reed and M.C. White
Nature Chemistry, 2011 DOI: 10.1038/nchem.967
We report the first example of mixed hydroxylase/desaturase activity with a small molecule catalyst for unactivated, aliphatic C-H bonds outside the realm of enzymatic catalysis. The intriguing question is what causes the switch in Fe(PDP) from pure hydroxylase (Science 2007, 2010) to mixed hydroxylase/desaturase activity reported here (Nature Chemistry, 2011) in the presence of remote carboxylic acid moieties on the substrate. One hypothesis is that it is the orientation of the iron oxidant [LnFe(OH)] relative to a key carbon centered radical intermediate on the substrate. In fact, in nature's oxidation enzymes, this radical intermediate is the gatekeeper from which all kinds of fascinating reactivities can be obtained: i.e. hydroxylations, chlorinations, desaturations, rearrangements. Carboxylic acids, known to bind to Fe(PDP) and direct the site of substrate oxidation, may play a role in altering oxidant/substrate radical orientation. Because Fe(PDP) is stereoretentive (i.e. it doesn't scramble stereocenters during oxidation) the validity of this radical intermediate was up for debate. Prior to this work, many thought that this iron catalyst operated via direct, concerted C-H insertion (like the organic oxidant TFDO). If a concerted rather than a radical mechanism was operating, this, and other biomimetic reaction pathways, would not be accessible with Fe(PDP). To address this issue, a novel taxane-based radical trap that rearranges to nortaxane was used to provide the first direct evidence for a substrate radical intermediate. Interestingly, numerous biologically active nortaxanes have been isolated; however, there biogenic origins are controversial. This result suggests that radical-induced rearrangement of the taxane skeleton to nortaxane may be happening in nature during the oxidase phase of Taxol biosynthesis. Oxidation of Taxol in nature is performed by iron hydroxylation enzymes (p-450s) that also operate through a mechanism similar to the one proposed for Fe(PDP). The prospect of using Fe(PDP) to explore unusual reactivities (e.g. mixed hydroxylase/desaturase) and interrogate natural product biosynthesis pathways (e.g. origin of nortaxanes) performed by oxidation enzymes that operate by similar mechanisms is exciting.Click here for photo of Marinus, Sean and MCW. Second pic.
Publication 19. SI. 2.
"Synthesis of Complex Allylic Esters via C-H Oxidation vs C-C Bond Formation."
N.A. Vermeulen, J.H. Delcamp and M.C.White
JACS, 2010, 132, 11323 DOI: 10.1021/ja104826g
A highly general and selective C-H oxidation method for the synthesis of complex allylic esters is described. This Pd(II)/sulfoxide-catalyzed method allows for a wide range of complex aryl and alkyl carboxylic acids to be coupled directly with terminal olefins to yield (E)-allylic esters in synthetically useful yields and selectivities without the use of stoichiometric coupling reagents or unstable intermediates.Click here for photo of Nicolaas and MCWProblem:
Publication 18. SI.
"Diversification of a β-lactam pharmacophore via allylic C-H amination: accelerating effect of Lewis acid co-catalyst."
X. Qi, G. T. Rice, M. S. Lall, M. S. Plummer, M. C. White
Tetrahedron, 2010, 66, 4816 DOI: doi:10.1016/j.tet.2010.04.064
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].
Publication 17. SI.
"Combined Effects on Selectivity in Fe-Catalyzed Methylene Oxidation."
M.S. Chen and M.C. White
Science, 2010, 327, 566 DOI: 10.1126/science.1183602
Introductory organic chemistry students are taught that organic molecules are largely composed of hydrocarbon skeletons, i.e. carbons linked together by single bonds with hydrogens attached (methylene units). When more electronegative elements are attached to carbon, they are comparably more reactive and therefore referred to as functional groups. These are the groups that control the physical and chemical properties of molecules in addition to regulating what portions of the molecule will be chemically reactive. For chemical reactivity at functional groups, students are taught two simple lessons: 1. Reactions occur at the less sterically hindered functional group in molecules, 2. Electrophilic reagents prefer to pair with the most electron-rich functional group, 3. Stereoelectronic factors (orientation of molecular orbitals in space) can drive selectivity. In contrast, the C-H bonds of methylene units are considered unreactive due to high bond dissociation energies (BDE) and the fact that they are relatively non-polar and non-acidic. Therefore, students are also taught to ignore the hydrocarbon skeleton in their synthetic planning. We now show that the same simple rules that govern reactivity of traditional organic "functional groups" can also direct site-selectivity in high energy oxidations of inert methylene (secondary) C-H bonds. Building on previous results with tertiary C-H bond oxidations (Science 2007, 327, 566, Publication 8.), we now show that the bulky, electrophilic iron catalyst, Fe(PDP), is able to achieve useful levels of discriminate oxidation between inert methylene (secondary) C-H bonds based on subtle differences in their steric, electronic, and stereoelectronic environments. These rules are revealed through 29 individual examples of methylene oxidations that all proceed under synthetically useful conditions (1 equivalent of substrate) with an average of 50% isolated yield of mono-oxidized product. While each of these factors works independently in simple compounds, the most dramatic effects are seen in complex natural products where all the effects are working in combination.
Publication 16. SI.
"Total synthesis and study of 6-deoxyerythronolide B by late-stage C-H oxidation."
E.M. Stang and M.C. White
Nature Chemistry, 2009, 1, 547 DOI: 10.1038/NCHEM.351
A novel strategy for the 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. Starting from a linear alkenoic acid intermediate lacking oxygen at C13, a Pd(II) catalyzed C-H oxidation reaction generated the 14-memebred macrocycle with the natural configuration at C13 in >40:1 diastereoselectivity. Controlling the functionalization mechanism allowed for the alternative C13 diastereomer to be synthesized for the first time. By installing oxygen at a late-stage, this strategy improves synthetic efficiency by minimizing the "oxygen load" over lengthy linear sequences. Moreover, this work provides a new way to think about constructing macrolide natural products. Click here for photo of Erik and MCW
Publication 15. SI.
"A Catalytic, Bronsted Base Strategy for Intermolecular Allylic C-H Amination."
S.A. Reed; A.R. Mazzotti; and M.C. White
JACS, 2009 DOI: 10.1021/ja903939k
In this article, a Bronsted base activation mode for oxidative, Pd(II)/sulfoxide-catalyzed, intermolecular C-H allylic amination is described. A catalytic amount of N,N-diisopropylethylamine was found to efficiently promote the linear allylic amination reaction with high levels of stereo-, regio-, and chemoselectivity. This departure from Lewis acid activation allows unprecedented functional group tolerance for a C-H amination method. For example, powerful synthetic building blocks and natural product derivatives containing reactive Lewis basic functionality such as epoxides, aldehydes, esters, nitriles, phenols, and even alcohols can be aminated without the use of protecting groups. Useful transformations of N-tosylcarbamate products as well as evidence to support this novel activation mode are discussed. Click here for photo of Sean, Anthony and MCW
Publication 14. SI.
"Allylic C-H Amination for Preparation of syn-1,3-Amino Alcohol Motifs."
G.T. Rice and M.C. White
JACS, 2009 DOI: 10.1021/ja9054959
We report a palladium/sulfoxide catalyzed allylic C-H amination to furnish syn-oxazinanone heterocycles en route to syn-1,3-amino alcohols. Key to the high reactivity observed under mild conditions (45°C, 24h) is the use of an electron deficient N-nosyl carbamate nitrogen nucleophile that enables high concentrations of the active anionic species to be reached using endogenous catalytic acetate base. The scope for this C-H amination reaction is very broad and orthogonal to both classical C-C bond forming/reduction sequences and metal nitrene-based C-H amination methods for furnishing this motif. The streamlining potential of this method is highlighted in the concise and high yielding total synthesis of (+)-allosedridine. Using this approach, significantly shorter reaction times (72h to 24h) could also be achieved for our previously reported allylic C-H amination reaction to furnish syn-1,2-amino alcohols. Click here for photo of Grant and MCW
"The Fe(PDP)-catalyzed aliphatic C-H oxidation: a slow addition protocol."
N.A. Vermeulen; M.S. Chen; and M.C. White
Tetrahedron, 2009 DOI: 10.1016/j.tet.2008.11.082
A slow addition protocol for the Fe(PDP)-catalyzed aliphatic C-H oxidation reaction is described. Under this protocol, the reaction can be productively driven to higher conversions without the need for recycling.
"Catalytic Intermolecular Allylic C-H Alkylation."
A.J. Young and M.C. White
JACS, 2008 DOI: 10.1021/ja806867p
We report the first electrophilic Pd(II)-catalyzed allylic C-H alkylation. This method enables the direct conversion of allylic C-H bonds to C-C bonds. Using Pd(II)/bis-sulfoxide catalysts, α-olefin substrates can be alkylated with a series of weak carbon nucleophiles such as methyl nitroacetate, benzoylnitromethane, and (phenylsulfonyl)nitromethane. For example, allylated aromatic substrates and methyl nitroacetate yield a wide range of aromatic and heteroaromatic linear (E)-α-nitro-arylpentenoates as single olefin isomers in excellent yields. The π-acceptor ligand DMSO was found to play a crucial role in promoting functionalization of the π-allylPd intermediate. Products are readily transformed to amino esters via selective reduction and enantiomerically enriched α,α-disubstituted amino acid precursors via asymmetric conjugate addition. Click here for photo of Andrew and MCW
"A General and Highly Selective Chelate-Controlled Intermolecular Oxidative Heck Reaction."
J.H. Delcamp; A.P. Brucks; and M.C. White
JACS, 2008 DOI: 10.1021/ja804120r
In this communication, we report a novel intermolecular Heck reaction that significantly expands the scope of the olefin in this classic cross-coupling method. A general Pd/bis-sulfoxide complex 1 catalyzes a chelate-controlled, oxidative Heck reaction with a wide range of non-stabilized -olefins and organoboron reagents in good yields and outstanding regio- and E:Z selectivities. Pd-H isomerization, a side-process deleterious to selectivities in many Heck reactions, is not observed under these mild, oxidative conditions. This is evidenced by a tolerance of unprotected alcohols, no erosion of optical purity for proximal stereogenic centers, and outstanding E:Z selectivities (>20:1 in all cases examined). We anticipate that this advance will bring the intermolecular Heck reaction a step closer to realizing its tremendous potential in streamlining complex molecule synthesis. Click here for photo of Jared, Alex and MCW
"A Chiral Lewis Acid Strategy for Enantioselective Allylic C-H Oxidation."
D.J. Covell and M.C. White.
ACIEE, 2008 DOI: 10.1002/anie.200802106
Conventionally, enantioselective transition metal catalyzed processes use chiral metal ligands. A Lewis acid strategy for effecting asymmetric induction in oxidative systems not amenable to such chiral ligands is disclosed and its mechanism investigated. Addition of chiral Cr(III)(salen) catalyst to the Pd(II)/sulfoxide catalyzed branched allylic C-H oxidation achieves the highest levels of enantioselectivity for C-H oxidation of terminal olefins to date. When paired with enzymatic resolution, this method rapidly generates chiral building blocks in high yields. Click here for photo of MCW and Dustin
"Catalytic Intermolecular Linear Allylic C-H Amination via Heterobimetallic Catalysis."
S.A. Reed and M.C. White.
JACS, 2008, 130, 3316.
Utilizing a heterobimetallic Pd/Cr(salen)Cl catalyst system, a wide variety of alpha olefins can be transformed directly into the corresponding allylic carbamates with good yields (50-72%), and excellent selectivity for E linear product (>20:1). This represents the first direct, general, intermolecular allylic C-H amination reaction for small molecule synthesis. To demonstrate its outstanding streamlining potential, the reaction was employed in a synthesis of an analogue of the antibiotic deoxynegamycin that proceeded in ca. half the number of steps from commercial starting materials and twice the overall yield when compared to a route employing oxygenated intermediates. It is noteworthy that 15N can now be installed directly into complex molecules using this method, as illustrated by its incorporation into an aminosugar precursor. Click here for photo of MCW and Sean
"A Predictably Selective Aliphatic C-H Oxidation Reaction for Complex Molecule Synthesis."
M.S. Chen and M.C. White.
Science, 2007, 318, 783.
We report an iron-based small molecule catalyst that uses hydrogen peroxide to oxidize a broad range of substrates. Predictable selectivity is achieved solely based on 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 5-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 to streamline the process of complex molecule synthesis. Click here for photo of MCW and Mark Alt Photo
"syn-1,2-Amino Alcohols via Diastereoselective Allylic C-H Amination."
K.J. Fraunhoffer and M.C. White.
JACS 2007, 129, 7274-7276.
This communication describes the first general, stereoselective allylic C-H amination reaction for synthesis. The key to solving this problem in chemical reactivity was the discovery that a bis-sulfoxide/Pd(II) catalyst can divert aminopalladation pathways to allylic C-H cleavage. The acetate counterion associated with Pd(II) is demonstrated to activate the weak nitrogen nucleophile towards intramolecular attack of the pi-allylPd. The ability to skip the oxygen required in conventional allylic amine forming reactions is shown to result in a significant streamlining effect on their synthesis. Click here for photo of MCW and Ken
"Sequential Hydrocarbon Functionalization: Allylic C−H Oxidation/Vinylic C−H Arylation".
J.H. Delcamp and M.C. White.
JACS 2006, 128, 15076-15077.
This communication describes a method that rapidly converts inexpensive and abundant hydrocarbon, carboxylic acid and boronic acid starting materials to densely functionalized fragments for complex molecule synthesis. The Pd(II)/bis-sulfoxide complex catalyzes vinylic C-H arylation of electronically unbiased allylic ester intermediates with a wide range of aryl boronic acids under acidic, oxidative conditions and mild temperatures (rt to 45°C). Click here for photo Alt Photo
"Polyol Synthesis through Hydrocarbon Oxidation: De Novo Synthesis of L-Galactose".
D.J. Covell; N.A. Vermeulen; N.A. Labenz; and M.C. White.
ACIEE 2006, 45, 8217-8220.
This communication describes a strategy for rapidly building chiral polyol structures starting with readily accessible chiral building blocks (1 & 2). Key to the effciency of this strategy is the ability to convert chiral homoallylic ethers (3) directly to 4-methoxybenzoate allylic esters (4). These compounds undergo reagent controlled asymmetric dihydroxylations (AD) with high diastereoselectivities and no acyl transfer. We describe conditions that allow p-anisic acid to act as a nucleophile for the linear allylic oxidation reaction to directly generate (4) with good yields (70%) and outstanding selectivities (E:Z = 97:3). Click here for photo Alt Photo
"Macrolactonization via Hydrocarbon Oxidation".
K.F. Fraunhoffer; N. Prabagaran; L.E. Sirois; and M.C. White.
JACS 2006, 128, 9032-9033.
Click here for photo of the macrolactonization group. Alt Photo
"Serial Ligand Catalysis: A Highly Selective Allylic C-H Oxidation".
M.S. Chen; N. Prabagaran; N.A. Labenz; and M.C. White.
JACS 2005, 127, 6970-6971.
In this communication, we show that replacing DMSO with a catalytic amount of polydentate sulfoxide ligand results in an unexpected reversal in regioselectivities favoring the branched allylic ester product. Together, the branched and linear allylic C-H oxidation reactions are rare examples of highly selective, intermolecular C-H oxidation processes. By studying the mechanism of the branched allylic C-H oxidation reaction, we demonstrate for the first time the concept of serial ligand catalysis: two (or more) different ligands binding reversibly to one metal to promote different product forming steps in a catalytic cycle. Click here for photo of serial ligand catalysis group.
"Hydrocarbon Oxidation vs C-C Bond-Forming Approaches for Efficient Synthesis of Oxygenated Molecules".
K. J. Fraunhoffer; D. A. Bachovchin; and M.C. White.
Org. Lett. 2005, 7, 223-226.
The discovery of regio-, chemo- and stereoselective C-H oxidation reactions stands to significantly impact the ways in which small molecules are constructed. Specifically, such reactions enable oxygenated functionality to be installed late in a synthetic sequence, thereby eliminating functional group manipulations (FGMs) required to carry it throughout a synthesis. In this communication, we test this strategy for streamlining synthesis for the first time. Click here for photo.
" A Sulfoxide-Promoted, Catalytic Method for the Regioselective Synthesis of Allylic Acetates from Monosubstituted Olefins via C-H Oxidation".
M.S. Chen; M.C. White
J. Am. Chem. Soc. 2004, 126, 1346-1347.
In this communication we disclose that addition of sulfoxide to Pd(OAc)2/benzoquinone (BQ)/AcOH diverts oxidation away from the olefin to the allylic C-H bond resulting in the first allylic C-H oxidation system for alpha-olefins. This reaction has very broad scope (R = esters, amides, ketals, silyl and benzyl ethers, etc.) and proceeds with high regio- and stereoselectivities to furnish linear E-allylic esters in preparatively useful yields. Click here for photo.