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.


Publication 32. SI.
"A C-H Oxidation Approach for Streamlining Synthesis of Chiral Polyoxygenated Motifs."
D. J. Covell and M. C. White
Tetrahedron: Symposium In Print Special Issue for Paul Wender, 2013, In Print

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.


Publication 31. SI. 2.
"Terminal Olefins to Linear a,B-Unsaturated Ketones: Pd(II)/Hypervalent Iodine Co-catalyzed Wacker Oxidation-Dehydrogenation"
M. A. Bigi and M. C. White
J. Am. Chem. Soc. 2013, 135, ASAP, DOI: 10.1021/ja402651q|

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.


Publication 30.
"C-H Bond Functionalization and Synthesis in the 21st Century: A Brief History and Prospectus."
M. C. White
SYNLETT (Special Cluster on C-H Oxidation), 2012, 23, 2746, DOI: 10.1055/s-0032-1317701

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.


Publication 29.
"Cafestol to Tricalysiolide B and Oxidized Analogues: Biosynthetic and Derivitization Studies Using Non-heme Iron Catalyst Fe(PDP)"
M. A. Bigi, P. Liu, L. Zou, K. N. Houk, and M. C. White
SYNLETT (Special Cluster on C-H Oxidation), 2012, 23, 2768, DOI: 10.1055/s-0032-1317708

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.


Publication 28. SI. 2.
"Directed Metal (Oxo) Aliphatic C-H Hydroxylations: Overriding Substrate Bias"
M. A. Bigi, S. A. Reed, and M. C. White
JACS, 2012, 134, 9721, DOI: 10.1021/ja301685r

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.


Publication 27.
"Adding Aliphatic C-H Bond Oxidations to Synthesis."
M. C. White
Science, 2012, 335, 807, DOI: 10.1126/science.1207661

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.


Publication 26. SI. 2.
"Sequential Allylic C-H Amination/Vinylic C-H Arylation: A Strategy for Unnatural Amino Acid Synthesis from a-Olefins."
C. Jiang, D. J. Covell, A. F. Stepan, M S. Plummer, and M. C. White
Organic Letters, 2012, 14, 1386, DOI: 10.1021/ol300063t

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.


Publication 25. SI. 2.
"Iron-catalysed Intramolecular Allylic C-H Amination"
S. M. Paradine and M. C. White
Journal of the American Chemical Society, 2012, 134, DOI: 10.1021/ja211600g

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.


Publication 24. SI. 2.
"Molecular Complexity via C-H Activation: A Dehydrogenative Diels-Alder Reaction"
E. M. Stang and M. C. White
Journal of the American Chemical Society, 2011, 133, 14892 DOI: 10.1021/ja2059704

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.

Problem:

Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.

Click here to see synthetic route using standard olefination chemistry.

Click here to see synthetic route using C-H activation chemistry.

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.

Problem:

Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.

Click here to see synthetic route using standard olefination chemistry.

Click here to see synthetic route using C-H activation chemistry.

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.

Problem:

Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.

Click here to see synthetic route using standard olefination chemistry.

Click here to see synthetic route using C-H activation chemistry.

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 C—H 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.

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.

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 MCW

Propose a synthesis of this molecule using standard chemical transformations and the C-H activation chemistry shown in this work.

Click here to see synthetic route using standard olefination chemistry.

Click here to see synthetic route using C-H activation chemistry.

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].

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.

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

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

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

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.

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