Dennis G. Hall
Modern organic synthesis stands as a powerful discipline, defining our ability to create and transform new molecules with tailored properties and functions. To advance, organic synthesis relies on the development of new reaction methods that efficiently enable the construction of compounds with precise structural characteristics. The research interests in my laboratory are focused on the development of new reactions and strategies to access functional molecules with potential uses in biology and medicine. As exemplified with the projects described below, we are interested in addressing a wide variety of fundamental and practical problems. To this end, our main approach is to explore applications of organoboron compounds using both rational design and combinatorial strategies.
The design of unnatural biopolymers offers an alternative to the peptide backbone with the goal of creating and improving desirable biological properties. For example, our laboratory has developed methods to assemble large encoded libraries (pools of molecules) of bead-supported oligoamines by split-pool synthesis, a powerful combinatorial strategy to rapidly access thousands of distinct compounds in a minimal number of operations (Figure 1). Polyamines, a class of cationic endogenic biopolymer, play vital roles in several cellular events. Using our synthetic libraries and the concept of multivalent ion-pairing, we target the selective binding of polyanionic biomolecules. Boronic acids are also employed as components of artificial biopolymers for their unique ability to form esters with sugars in water. This key feature is exploited in the design of combinatorial libraries of oligoboronate receptors with the objective of discovering potent and selective ligands for cell-surface oligosaccharides of medicinal relevance.
Figure 1. A bead-supported combinatorial library of 2744 tetra-amines made from randomization of 14 aminoacid building blocks at three positions (R1-R3).
Solid-phase organic synthesis is an invaluable tool in combinatorial chemistry. My group is also involved in developing new resins, linkers, reactions and strategies applicable to the elaboration of small molecule libraries with potential in drug discovery and catalysis. One such example is the development and commercialization of N,N-diethanolaminomethyl polystyrene (DEAM-PS), a useful solid support for the immobilization, solid-phase transformations, and resin-to-resin transfer reactions of boronic acids.
The development of efficient methods for stereocontrolled synthesis is crucial to allow access to new types of organic compounds with biological interest. Recently we have invented a multicomponent reaction to construct polysubstituted piperidine derivatives in one operation from simple reactants. This stereoselective [4+2]/allylboration tandem reaction can be used both in diversity-oriented synthesis (Fig. 2a) and in target-oriented synthesis of natural products (Fig. 2b). More recently, our laboratory has reported the first examples of metal-catalyzed allylborations, providing general access to γ-lactones with a stereodefined quaternary carbon center (Fig. 2c). Ongoing work is directed at understanding the nature of metal-promoted activation and at optimizing a catalytic enantioselective process.
Figure 2. (a) a-Hydroxyalkyl piperidines via a one-pot three-component reaction. (b) The alkaloid methyl palustramate. (c) Stereospecific Lewis acid-catalyzed allylboration of aldehydes.
Students involved in these research projects are exposed to a multidisciplinary environment that provides opportunity to develop expertise in a wide range of contemporary concepts and techniques of organic synthesis and combinatorial chemistry.
F. Peng, D.G. Hall; Simple, Stable, and Versatile Double-Allylation Reagents for the Stereoselective Preparation of Skeletally Diverse Compounds; J. Am. Chem. Soc. 2007, 129, 3070-3071.
D.G. Hall; Lewis and Bronsted Acid Catalyzed Allylboration of Carbonyl compounds: From Discovery to Mechanism and Applications; Synlett 2007, 1644-1655.
M. Dowlut, D.G. Hall; An Improved Class of Sugar-Binding Boronic Acids, Soluble and Capable of Complexing Glycosides in Neutral Water; J. Am. Chem. Soc. 2006, 128, 4226-4227.
V. Rauniyar, D.G. Hall; Catalytic Enantioselective and Catalyst-Controlled Diastereofacial-Selective Additions of Allyl- and Crotylboronates to Aldehydes Using Chiral Brønsted Acids; Angew. Chem. Int. Ed. 2006, 45, 2426-2428.
X. Gao, D.G. Hall; Catalytic Asymmetric Synthesis of a Potent Thiomarinol Antibiotic; J. Am. Chem. Soc. 2005, 127, 1628-1629.
B.B. Touré, D.G. Hall; Three-Component Sequential Aza[4+2] Cycloaddition/Allylboration/Retro-Sulfinyl-Ene Reaction: A New Stereocontrolled Entry to Palustrine Alkaloids and Other 2,6-Disubstituted Piperidines; Angew. Chem. Int. Ed. 2004, 43, 2001-2004.
J.W.J. Kennedy, D.G. Hall; Dramatic Rate Enhancement with Preservation of Stereospecificity in the First Metal-Catalyzed Allylborations; J. Am. Chem. Soc. 2002, 124, 11586-11587.
M. Gravel, K.A. Thompson, M. Zak, C. Bérubé, D.G. Hall; Universal Solid-Phase Approach to the Immobilization, Derivatization, and Resin-to-Resin Transfer Reactions of Boronic Acids; J. Org. Chem. 2002, 67, 3-15. [Cover Page Graphics].