Jonathan R. Thielman

Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.

Diversity-oriented synthesis (DOS)is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors, derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.

New structural classes of antibiotics are rare, structurally-novel broad-spectrum antibiotics exceptionally so. The recently discovered baulamycins constitute a remarkable example of these highly-prized compounds and, as such, have attracted considerable attention in the form of both synthetic efforts and biological studies. For the first time, we report a gram-scale preparation of the common carbon framework of the baulamycin family, as well as the total synthesis of its most potent member, baulamycin A. Our approach employs highly-stereoselective, catalyst-controlled asymmetric conjugate additions to thioesters to set key stereocenters, as well as the first reported use of “dry ozonolysis” to reveal a masked carboxylic acid in the total synthesis of a natural product.