A semi-synthetic organism that stores and retrieves increased genetic information
Since the last common ancestor of all life on earth, the biological diversity has been encoded in a four letter, two base pair genetic alphabet. Expansion of the genetic alphabet to include a fifth and sixth letter than for a third, unnatural base pair not only has immediate utility for a number of applications, such as site-specific oligonucleotide labeling, but also serves as the foundation for an organism with an expanded genetic code. Toward this goal, we have examined a large number of different unnatural nucleotides bearing mainly hydrophobic nucleobase analogs that pair based on packing and hydrophobic interactions rather than H-bonding. Optimization based on extensive structure-activity relationship studies and two screens resulted in the identification of a class of unnatural base pairs that are well recognized by DNA and RNA polymerases. More recently, we have engineered E. coli to import the requisite unnatural triphosphates and shown that DNA containing the unnatural base pair is efficiently replicated, transcribed, and translated within the cell, resulting in the first semi-synthetic organism that stores and retreives increased information.
Enantioselective formation of remote tertiery and quaternary chiral centers
A long-standing challenge to synthetic organic chemists is the ability to forge stereocenters in substructures that do not contain pre-installed functional groups. In this regard, we have recently developed a catalytic and enantioselective intermolecular Heck-type reaction of multi-substituted alkenyl alcohols allowing for the installation of various groups (aryl and alkenyl) that are remote from the alcohol. The reported methods allow direct access to β-, γ-, δ-, or ζ aryl carbonyl functionalized compounds, as the unsaturation of the alkene is relayed to the alcohol resulting in the formation of a carbonyl. This is accomplished through a series of migratory insertion/β-hydride elmination events, which allows the Pd-center to chain walk to the prefunctionalized site in the molecule. In this lecture, the design, development, scope, and mechanistic analysis will be discussed of this reaction as well as new findings guided by the mechansitic insight garnered in our studies.
F. Dean Toste
Organic reactions inspired by the organometallic chemistry of gold
The past decade has witnessed remarkable development in the use of cationic gold(I) complexes as homogenous catalysts for the transformation of carbon-carbon π-bonds. Several years ago, we demonstrated that the reactivity of these complexes could be controlled by modification of the counter anion to these cationic transition metal complexes. This discovery provided a general platform for inducing enantioselectivity in reaction not only using cationic transition metal complexes, but also with reactive cationic reagents and intermediates. As an extension of this concept, we have been exploring the use of supramolecular assemblies as chiral anion for catalysis or as the anionic component in reactions catalyzed by cationic transition metal complexes. Finally, recent studies aimed at harnessing the reactivity of gold(III) will be introduced. This will include mechanistic studies on the reductive elimination for gold(III) and utility in carbon-carbon formation.
Utilization of the inherent stereochemical and functional diversities of natural products to produce unique biomedical materials
A primary interest in the Wooley laboratory is the production of functional polymers from renewable sources that are capable of reverting to those natural products once their purpose has been served. The inherent stereochemical and functional diversities of natural products provide opportunities to expand the scopes and complexities of polymer materials, by utilizing fundamental synthetic organic chemistry approaches. This presentation will highlight synthetic strategies for the development of polymers, block polymers and crosslinked network materials, which can be produced by relatively simple approaches from complex polyhydroxyl natural products and can be made to exhibit a range of properties. It is expected that the physical, mechanical, supramolecular assembly and stability properties will be tuned by the chemical compositions and structures, controlled by the advancement of synthetic methodologies by which to prepare such materials. Polycarbonates and polyphosphoesters that can be produced rapidly as well-defined block polymers and then undergo multiple chemical transformations and direct assembly in water into functional nanomaterials are serving as platforms for several directions toward their development as biomedical devices for the treatment of lung infections and osteosarcoma lung metastases. If time allows, recent developments toward the preparation of functional polypeptides and their assemblies will also be described.
Stereocontrol in photochemical reactions
Photochemistry is intriguing as a synthetic tool because the absorption of light by an organic molecule results in the formation of exceptionally energetic reactive intermediates that can react in ways that are inaccessible to ground-state molecules. However, this high reactivity is also a challenge for stereoselective synthesis: control over the stereochemistry of photochemical reactions, particularly using enantioselective catalysts, has been a long-standing challenging synthetic problem with few general solutions. We recently developed a method for highly enantioselective [2+2] photocycloaddition reactions using a combination of chiral Lewis acid and transition metal photocatalysis. This dual catalyst approach offers a robust strategy to control the reactivity of a wide range of reactive intermediates that can easily be generated using photoredox catalysis.