Contents of the Course
The course focuses on the most useful aspects of synthetic heterocyclic chemistry. Well-regarded, preparatively useful, real-world techniques are showcased. See sample pages below.
The vast and diverse field of heterocyclic chemistry is central to preparing pharmaceutical and agricultural compounds, yet it is a field that many synthetic chemists are not specifically trained in. This course provides an approachable, useable, and memorable form that can be used to plan the synthesis of new chemical entities of relevance to the pharmaceutical and agricultural fields.
An extensive and up-to-date set of notes on state-of-the art synthetic heterocyclic chemistry will be provided that includes carefully chosen literature citations. At over 500 pages, the notes serve as a valuable resource during the course and a comprehensive reference source afterwards.
In addition to the main course, an optional company-specific module can be added. Thus, participants will learn broadly useful skills in heterocyclic chemistry as well as more focused chemistry relevant to an ongoing project. Please contact Will about this option.
Many of the examples used in the course are take from the literature of drug synthesis. This assures relevance to the drug endeavor and provides validation that the synthetic methods are workable in real-world settings. To enhance learning, specific case studies (e.g., protein kinase inhibitors) appear throughout the course. While examples from the drug literature are highly relevant, the course also covers basic heterocycle construction techniques that will prove useful for the synthesis of novel drug-like molecules that are new chemical entities.
Traditional monographs and textbooks on heterocyclic chemistry are typically organized by the type of heterocycle, e.g., “six-membered rings with one nitrogen atom.” While this is a logical and useful approach that is to some extent used here, the course covers an equally powerful and complementary approach, i.e., retrosynthetic analysis. Rather than relying solely on a literature resource for the synthesis of a target molecule, retrosynthetic analysis allows the chemist to work backwards from the target molecule to viable starting materials. Further, the retrosynthetic analysis approach leads to a substantial simplification of this field, since it provides a logical way to organize this body of knowledge.
1. Introduction – Importance of heterocycles to the drug endeavor
2. Developing a working toolbox for heterocyclic chemistry
• Literature, nomenclature
• Structure and reactivity of heterocycles
• Reactions of heteroaromatics (reactions at ring atoms, reduction, etc.)
3. General synthetic strategies & retrosynthetic analysis
4. Synthesis of aromatic heterocycles
• Five-membered ring heteroaromatics, including multiheteroatomic and benzo-fused systems
• Six-membered ring heteroaromatics, including multiheteroatomic and benzo-fused systems
• More complex structures with multiple rings and multiple heteroatoms (e.g., purines, aza- and deazapurines, azaindoles, multicyclic compounds with bridgehead nitrogen, etc.)
5. Synthesis of nonaromatic heterocycles
Saturated heterocycles are becoming increasingly important in drug discovery as chemists attempt to craft the physical properties of drug candidates, seeking desirable lipophilicity, molecular weight, and complexity. In recent years, transition metal reactions have increased the availability of flat aromatic molecules, generating the need for a balance between the number of sp2 and sp3 centers. In addition, chirality can increase molecular complexity without increasing molecular weight and may also lead to less promiscuous drugs. Thus, saturated heterocycles are featured prominently in the current course, comprising nearly half of the material. Rather than organizing the material by the type of saturated heterocycle, it is organized into retrosynthetically-derived categories based on the key bond constructions, for example:
• Making the C-X bond
• Making the C-C bond adjacent to a heteroatom
• Making C-C bonds further from a heteroatom
• Formation of saturated heterocyclic C-C and C=C bonds using transition metals
• The use of cycloaddition reactions to make saturated heterocycles