I. Photolabile Protecting Group Development and Applications
Protecting groups are indispensable tools in organic chemistry. Among various protecting groups, photolabile protecting groups (PPGs) have very valuable and unique features. Typically, they can be removed under mild conditions by light without using any chemical reagents. They are also capable of releasing substrates in a spatially and temporally controlled manner. These advantages are appealing to both basic and applied sciences. We are interested in developing structurally simple and mechanistically novel PPGs for protection of carbonyl and hydroxyl groups. A series of new PPGs has been recently developed in our lab.
Carbonyl PPGs: These PPGs are divided into three subgroups based on their UV absorption profiles. The PPGs from different subgroups can be removed sequentially with different UV irradiation wavelengths. New methods of PPG installation have also been developed. For the first time, a PPG can be installed and removed efficiently without using any other chemical reagents. We envision the new PPGs are potentially useful in many applications owing to their advantageous chemical features.
Applications under exploration: The novel PPGs provide unique opportunities for a wide spectrum of applications in different fields. While we continue to develop more PPGs, we also explore new applications, not only for caging biochemically/biomedically relevant molecules but also for synthetic applications and for developing novel photoresponsive smart polymers and surfaces. We’ve established active collaborations with scientists of complementary expertise in pursuing various new applications.
Hydroxyl PPGs: We have recently demonstrated that the traditional acid-sensitive hydroxyl protecting group, the trityl (Tr) group, can be converted to a robust photolabile hydroxyl protecting group, i.e. DMATr group, by introducing a meta dimethylamino group to one of the three phenyl rings. It is relatively insensitive toward acid treatments and can also be installed and removed efficiently without using any other chemical reagents.
II. Development of Step Economy-Oriented Carbohydrate Synthesis
We have been pursuing step economy-oriented carbohydrate synthesis in solution phase for rapid access to oligosaccharides of biochemical and biomedical significance. An efficient synthesis demands (1) efficient and effective glycosylation methods with minimal anomeric position manipulation of glycosyl donors and (2) tactically planned protecting group strategy to minimize selective protecting/deprotecting steps. A successful solution-phase synthetic approach, in combination with the solid-, polymer-, or ionic liquid-supported strategy, will significantly improve the overall efficiency of carbohydrate synthesis.
Along this direction, we have recently demonstrated a simple and mild glycosylation reaction employing only allyl glycosides as building blocks. Thus, a prop-1-enyl glycosyl donor readily derived from an allyl glycoside can undergo a highly effective glycosylation reaction with an allyl glycosyl acceptor upon activation with NIS or NIS/TfOH at room temperature.
Advantages of this approach:
1. As prop-1-enyl glycosyl donors are directly isomerized from allyl glycosides, time-consuming anomeric group replacement and intermediate purification are avoided.
2. The isomerization of the anomeric allyl group to the corresponding prop-1-enyl is typically of high efficiency with a variety of facile methods available in literature.
3. Allyl glycosides have widespread use in carbohydrate synthesis. The anomeric allyl group is typically installed onto unprotected free monosaccharides at the very first step of building block preparation via a Fischer glycosylation process, greatly simplifying building block preparation.
4. With much simplified building block preparation, versatile isomerization methods, and simple reaction conditions, this approach should significantly advance the latent-active strategy for iterative oligosaccharide synthesis. This strategy features no requirement for any building block reactivity tuning as necessary for the armed/disarmed approach employing thio and n-pentenyl donors in iterative syntheses.
III. Discovery of New Fluoroquinolone Drugs to Overcome Resistance
Fluoroquinolones are antibacterial agents that are widely used for many bacterial infections. They kill bacteria by disrupting the normal functions of gyrase/ topoisomerase IV, resulting in permanent damage to genomic integrity and eventually cell death. For diseases such as multidrug-resistant tuberculosis, fluoroqinolones are considered to be agents of last resort. However, fluoroquinolone use is threatened by an increasing prevalence of resistance, now seen with almost every bacterial species treated. Even highly susceptible species are exhibiting quinolone resistance. Moreover, engineered drug-resistant strains of bioterrorism agents have been created in the laboratory setting. Therefore, development of potent new drugs to overcome resistance is highly desirable. In collaboration with biochemists, we design, synthesize and assess new fluoroquinolone drugs.