Despite great progress in organic reaction development, there remains a great need for new organic reactions for the stereo- and enantioselective synthesis of functionally rich molecules under operationally and environmentally friendly reaction conditions.

See the highlight of our novel catalytic reaction in Angew. Chemie!

Our interests in this area include:

(1) Catalytic Generation of Activated Carboxylates

We have recently developed a method for the truly catalytic generation of activated carboxylates. Widely available, non-toxic organic heterocycles promote the intramolecular redox reaction of alpha-heteroatomic aldehydes. This leads to catalytic generation of a catalyst-bound activated carboxylates, which reacts with nucleophiles to afford esters, thioesters, or amides.
 

  • J. Am. Chem. Soc. 2004, 126, 8126–8127. Link

We are currently exploiting the broad substrate scope of these reaction to develop catalytic, asymmetric routes to a variety of highly prized molecules including alpha-chiral esters, beta-amino acids, anti-aldol adducts, and chiral ketones. We have also developed a new, highly active organocatalyst for the redox esterification of enals.

 

  • Org. Lett. 2005, 7, 3873–3876. Link

(2) New Catalytic, Asymmetric Carbon-Carbon Bond Forming Reactions

With insights gained from our development of catalytically generated activated carboxylates, we are have developed the first truly catalytic method for the generation and reaction of homoenolates from readily availalbe starting materials. These reaction proceed under mild, convenient reaction conditions and do not require stoichiometric reagents. The transient homoenolates react with a variety of electrophiles, or can be protonated to give activated carboxylates. We have applied this methodology to the direct annulation of enals and aldehydes, leading to the stereoselective synthesis of gamma-butyrolactones and gamma-lactams. Currently, we are developing catalytic homoenolate approaches to other hetero- and carbocyclic structures, exploring catalytic, asymmetric methods, and applying these reactions to the total synthesis of biologically active pharmacueticals and natural products.

 

  • J. Am. Chem. Soc. 2004, 126, 14370–14371. Link

 

  • Org. Lett. 2005, 7, 3131–3134. Link

We are exploiting unique organic reactions to develop small organic molecules (mw 200 - 1500) with the ability to rapidly change their chemical and physical properties without chemical reagents. Using synthetic organic chemistry and reaction development, along with inspiration from natural products and physical organic chemistry, we are synthesizing molecular entities that can morph themselves into 10^5 different constitutional isomers, thus modulating their chemical and physical properties. The ability of these molecules to dramatically adjust their shape and chemistry will be exploited throughout the spectrum of contemporary chemical and biological problem.

 

  • J. Am. Chem. Soc. 2006, 128, 14738–14739. Link

 

The discovery of novel chemoselective reactions for selectively joining two unprotected fragments under mild, physiologically compatible reaction conditions has enabled remarkable progress in the synthesis and study of biological molecules including proteins and carbohydrates. We are contributing to this area through the development of unprecedented organic reactions leading directly to amide bond formation. Recently, we developed the first general method for chemoselective amide bond formation by direct decarboxylative condensations of alpha-ketoacids and N-alkylhydroxylamines.

 

  • Angew. Chem. Int. End. 2006, 45, 1248-1252. Link

The wide-spread availability of the starting materials, minimal byproducts, and ability to utilize these reactions under aqueous conditions and in the presence of biologically relevant functional group will enable these methodologies to significantly impact progress in the synthesis of proteins, glycoproteins, biomaterials, and biologically active natural products.

We have extended this remarkable reaction to the iterative synthesis of beta-oligopeptides in water by using a unique set of isoxazolidine substrates. Each coupling leads to the formation of an easily hydrolyzed alpha-keto ester primed for chain extension with another equivalent of isoxazolidine.

 

  • J. Am. Chem. Soc. 2006, 128, 1452-1453. Link

 

Natural products and other biologically active synthetic targets are chosen for their relavance to either ongoing methodology accomplishments within our group or for intriguing structural or physiological properties. Selected targets and potential targets are shown below. Structural features highlighted in blue are directly accessible via methodologies under development in our group.