Rapid synthesis of pomalidomide-conjugates for the development of protein degrader libraries

• Published in: Chemical science (Cambridge) 2021-04, Vol.12 (12), p.4519-4525
• Main Authors: Brownsey, Duncan K, Rowley, Ben C, Gorobets, Evgueni, Gelfand, Benjamin S, Derksen, Darren J
• Format: Article
• Language: English
• Subjects: Amines; Chemistry; Conjugates; Crystallography; Dimers; Libraries; Proteins; Synthesis
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d0sc05442a

Current methods for the preparation of heterobifunctional pomalidomide-conjugates rely on methods that are often low yielding and produce intractable byproducts. Herein we describe our strategy for the reliable and succinct preparation of pomalidomide-linkers which is essential to the formation of these conjugates. We present the preparation of 18 pomalidomide-linkers in high yield compared to current literature methods. Our findings show that secondary amines consistently afford greater yields than their primary counterparts, a trend that we were able to exploit in the synthesis of several new pomalidomide homo-dimers in enhanced yields compared to similar literature syntheses. This trend was further utilised to develop the first one-pot synthesis of JQ1-pomalidomide conjugates in yields up to 62%, providing a method that is suited to rapid preparation of conjugate libraries as is frequently required for the development of new protein degraders. Current methods for the preparation of heterobifunctional pomalidomide-conjugates rely on methods that are often low yielding and produce intractable byproducts. Herein we describe our strategy for the succinct preparation of pomalidomide-linkers.