 |
|
|
|
|
|
 |
|
 |
|
|
|
|
| |
The goal of the Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) is to expand the diversity of small-molecule libraries by creating general, useful protocols for stereocontrolled synthesis. The overall approach involves creation of novel chemical libraries that uniquely probe three-dimensional space by employing stereochemical and positional variation within the molecular framework as diversity elements in library design. Design of stereocontrolled chemical libraries at the CMLD-BU is guided by three core strategies : |
|
|
|
|
|
|
|
| |
Project 1: Stereoselective Synthesis of Polypropionate Derived Libraries
Novel polyketide-like libraries are being assembled which bear natural product-like structures, yet contain diversification elements for additional chemical modification (Figure 1). This project involves synthesis of linear polyketide structures and macrocycles such as those shown below, the latter displaying structural motifs reminiscent of potent antibiotic macrolides, but with novel structural features and stereochemistries.
|
|
|
|
 |
| |
Figure 1. Representative
polyketide-derived molecules |
|
|
|
|
|
| |
Project 2: Novel Scaffolds Containing Positional and Stereochemical Diversity
A second core strategy involves synthesis and elaboration of novel scaffolds containing positional and stereochemical diversity. Such projects are distinguished by synthesis of novel molecular and atomic frameworks for derivatization, with at least one diversity element defined as a stereochemical element directing the attached functionality into different regions of chemical space. Heterocycles are well known in the pharmaceutical industry and display key drug-like features. This project also involves the synthesis of a number of new heterocyclic scaffolds that have not been previously pursued in combinatorial chemistry (Figure 2). Two of these scaffolds, pipecolic acids and 1,2,3,4-tetrahydronaphthyridines, are novel nitrogen heterocycles. Each scaffold also presents stereochemical diversity with a minimum of three diversification points on each scaffold which are being utilized to develop several libraries.
|
|
|
| |
 |
| |
Figure 2. Representative scaffold
architectures
|
|
|
|
|
|
| |
Project 3: Convergent, Synthesis of Complex Molecules through Domain Shuffling
A third core strategy involves convergent synthesis of complex molecules through domain shuffling. Convergent synthesis strategies are conventionally used in complex molecule synthesis and involve independent synthesis and coupling of fragments (Figure 3). In this project, homo- and heterodimerization of fragments prepared in both polyketide and scaffold projects will be achieved to create novel and highly complex natural product-like molecules. Domain Shuffling by combination of different substructures will be used to further explore three-dimensional chemical space and create target structures with expanded diversity and complexity. |
|
|
| |
 |
| |
Figure 3. Convergent Synthesis |
|
| |
|
|
|
|
|
| |
|
|
