M. Christina White

Research

Introduction

Functionalized hydrocarbons represent the vast majority of molecules having highly valuable and diverse molecular and physical properties (e.g. small molecules modulating protein function, poly(lactic acid) polymers serving as biodegradable packing materials). A fundamental challenge that faces organic synthesis in the twenty-first century is significantly increasing the efficiency with which carbon frameworks can be constructed and functionalized. The primary focus of our research group is the discovery of highly selective, catalytic C-H functionalization methods that can be applied to synthesis. Using these reactions to develop strategies for streamlining the synthesis of molecules with valuable properties is our ultimate goal.

Research Areas.

• Discovery of catalytic C-H oxidation/ functionalization reactions for synthesis.
  
  
• Development of new synthetic strategies based on these reactions for streamlining small molecule synthesis (e.g. macrolides, carbohydrates).
  
  
• Mechanistic study of such systems in order to elucidate new fundamental principles of catalyst design and chemical reactivity.
  

Sulfoxide-Promoted Palladium(II)- Catalysts for Highly Selective Allylic C-H Oxidations.^1,3

We have recently discovered a new class of sulfoxidebased palladium C-H oxidation catalysts that provide access to either (E)-allylic acetates or branched allylic acetates from a wide variety of α-olefin substrates. Under identical conditions lacking sulfoxide, α-olefin substrates predominantly undergo a different reaction pathway, i.e. olefin oxidation to give mixtures of vinyl acetate products. The distinctive feature of our C-H oxidation systems is that they require no heteroatom directing functional group on the substrate to achieve high reactivity and regioselectivity and are extraordinarily functional group tolerant. On the basis of these initial highly promising results, we plan to pursue mechanistic studies of these systems directed towards optimizing yields, E/Z selectivities and catalyst, loadings.

Streamlining Synthesis via C-H oxidation.²

Oxygenated hydrocarbons represent many of the therapeutically important small molecules found in Nature. As evidenced by biosynthetic pathways, methods enabling direct oxidative functionalization of C-H bonds should advance the goal of streamlining the syntheses of oxygenated targets. The extraordinarily high selectivities observed for our allylic oxidation systems have enabled us to begin to test their potential for improving the efficiency of oxygenated small molecule synthesis. Specifically, we selected from published syntheses of natural products or natural product-like compounds a collection of (E)-allylic alcohol intermediates that were prepared using standard CC bond forming methods (Wittig type olefination/reduction). We evaluated the efficiency of hydrocarbon oxidation routes against those of the published C-C bond forming routes. In all cases evaluated thus far, we have found improved efficiencies (fewer steps, fewer functional group manipulations, higher overall yields) for routes to (E)- allylic alcohol intermediates that are designed around a hydrocarbon oxidation approach vs. the current standard C-C bond forming approach. We plan to continue to evaluate this synthetic approach in the context of accessing functionally dense targets of medicinal value such as macrolides, polyols and aminopolyols.

Serial Ligand Catalysis.³

These initial reactivity findings suggested that a change in the sulfoxide ligand environment on the Pd catalyst was responsible for the observed reversal of regioselectivities between the two allylic oxidation systems. Preliminary mechanistic studies indicate that this is in fact not the case. Investigation of the vinyl sulfoxide/Pd(II)/BQ system (branched allylic acetates) revealed that a palladium-vinyl sulfoxide species promotes the initial C-H cleavage step whereas a Pd-benzoquinone (BQ) complex alone promotes and controls the regioselectivity of the functionalization step. This is the first reported case of two different ligands (vinyl sulfoxide and BQ) working with one metal to promote, different, steps within a catalytic cycle.

We believe that this phenomenon of serial ligand catalysis may prove general. Serial ligand catalysis as a strategy may provide uniquely mild solutions towards effecting catalytic reactions requiring multiple product forming steps that impose different electronic and/or steric demands on the metal catalyst. Further studies are targeted toward determining the role of vinyl sulfoxide in promoting allylic C-H cleavage, exploring nitrogen and carbon nucleophiles as functionalization reagents, and developing asymmetric versions of this reaction. Moreover, the generality of serial ligand catalysis for effecting other challenging transition-metal mediated transformations will be explored.

Future mechanistic studies are focused on elucidating the mechanism of allylic oxidation for the DMSO/Pd(II)/BQ system which yields linear E allylic acetate products. Based on these results, it is reasonable to think that mechanistic studies of these highly selective allylic oxidation systems will continue to provide valuable new principles of catalyst design and chemical reactivity.

Publications

Reed, S.A.; White, M.C. "Catalytic Intermolecular Linear Allylic C-H Amination via Heterobimetallic Catalysis." J. Am. Chem. Soc., 2008, 130, 3316.

Chen, M.S.; White, M.C. "A Predictably Selective Aliphatic C-H Oxidation Reaction for Complex Molecule Synthesis." Science, 2007, 318, 783.

Fraunhoffer, K.J.; White, M.C. "syn-1,2-Amino Alcohols via Diastereoselective Allylic C-H Amination." J. Am. Chem. Soc. 2007, 129, 7274.

Delcamp, J.H.; White, M.C. "Sequential Hydrocarbon Functionalization: Allylic C-H Oxidation/Vinylic C-H Arylation." J. Am. Chem. Soc. 2006, 128, 15076.

Covell, D.J.; Vermeulen, N.A.; Labenz, N.A.; White, M.C. "Polyol Synthesis via Hydrocarbon Oxidation: De Novo Synthesis of L-Galactose." Angew. Chem., Int. Ed. Engl. 2006, 45, 8217.

Fraunhoffer, K.J.; Prabagaran, N.; Sirios, L.E.; White, M.C. "Macrolactonization via Hydrocarbon Oxidation." J. Am. Chem. Soc. 2006, 128, 9032.

Chen, M.S.; Prabagaran, N.; Labenz, N.; White, M.C. "Serial Ligand Catalysis: A Highly Selective Allylic C-H Oxidation." J. Am. Chem. Soc. 2005, 127, 6970-6971.

Fraunhoffer, K. J.; Bachovchin, D.A.; White, M.C. "Hydrocarbon Oxidation vs. C-C Bond Forming Approaches for Efficient Syntheses of Oxygenated Molecules." Org. Lett. 2005, 7, 223-226.

Awards

• AstraZeneca Excellence in Chemistry Award, 2008
• Camille Dreyfus Teacher Scholar Award, 2008
• Amgen Young Investigator Award, 2008
• Boehringer Ingelheim Pharmaceuticals New Investigator Award, 2008
• Bristol-Myers Squibb "Unrestricted Grant in Synthetic Organic Chemistry", 2008-2009.
• Pfizer Award for Creativity in Organic Chemistry, 2008-2009
• Eli Lilly Grantee Award, 2007-2009
• Alfred P. Sloan Research Fellow, 2008-2010
• Fellow, UIUC Center for Advanced Study, 2006
• NSF CAREER Award, 2006-2010
• Camille and Henry Dreyfus New Faculty Award, 2002-2007
• National Institutes of Health Postdoctoral Fellowship, 1999-2002
• American Chemical Society Predoctoral Fellowship, 1997-1998

Highlights

Publication Highlights

"Science Concentrate Highlight" in Chemical & Engineering News: "Revised Amination Skips Olefin Tether." Chem. Eng. News, 2008, 86 (11), 42.

"A Predictably Selective Aliphatic C-H Oxidation Reaction for Complex Molecule Synthesis" by Chen, M.S.; White, M.C. was highlighted in the following publications:

• Nature : "Green Cleaver." Nature 2007, 450 (8), 139.
• Chemistry & Industry: Patrick Walter "Green Catalyst Could Clean Up in Drug Production." Chemistry & Industry 2007, 21, 7.
• Science: R.H. Crabtree, "No Protection Required." Science, 2007, 318, 756.
• "News of the Week" highlight in Chemical & Engineering News: Jyllian Kemsley, "Catalyst Oxidizes Selectively." Chem. Eng. News, 2007, 85 (45), 8.
• Chemistry World: Richard Van Noorden, "Step Change for Organic Synthesis.", Chemistry World, 2007.
• Technology Review: Kevin Bullis, "Drugs That Are Easier on the Environment." Technology Review, 2007.

"syn-1,2-Amino Alcohols via Diastereoselective Allylic C-H Amination." by Fraunhoffer, K.J. and White, M.C. was recently highlighted in the following publications:

• "News of the Week" highlight in Chemical & Engineering News: Stu Borman "Amination Advance: New Reaction is first to catalytically convert allylic C-H to C-N." Chem. Eng. News, 2007, 85 (23), 7.
• This article is the most-accessed web article in J. Am. Chem. Soc. in April-June 2007. Click here to see the list

"Sequential Hydrocarbon Functionalization: Allylic C-H Oxidation/Vinylic C-H Arylation," by Delcamp, J.H. and White, M.C. was featured in an oxidation methods review in Annu. Rep. Prog. Chem., Sect. B, 2007, 103, 35-46.

"Serial Ligand Catalysis: A Highly Selective Allylic C-H Oxidation" by Chen, M.S.; Prabagaran, N.; Labenz, N. and White, M.C. received commentary in Science and Technology Concentrate in Chem. & Eng. News 2005, 83, 31.

"Hydrocarbon Oxidation vs. C-C Bond Forming Approaches for Efficient Syntheses of Oxygenated Molecules" by Fraunhoffer, K. J.; Bachovchin, D.A. and White, M.C. was reviewed and recognized in the following publications:

• This article was selected by the Organic Letters Editorial Board as one of the 9 best Organic Letters articles in 2004.
• For an excellent review highlighting this synthetic strategy see: Hoffmann, R.H. "Protecting-Group-Free Synthesis." Synthesis 2006, 3531.

Other Highlights

Dr. White and Sean A. Reed's work in developing the first catalytic intermolecular allylic C-H amination reaction has been reviewed in C&E News. Read the C&E News article here.