Dearomative intermolecular [2+2] photocycloaddition for construction of C(sp3)-rich heterospirocycles on-DNA

DNA-encoded library (DEL) screens have significantly impacted new lead compound identification efforts within drug discovery. An advantage of DELs compared to traditional screening methods is that an exponentially broader chemical space can be effectively screened using only nmol quantities of billions of DNA-tagged, drug-like molecules. The synthesis of DELs containing diverse, sp(3)-rich spirocycles, an important class of molecules in drug discovery, has not been previously reported. Herein, we demonstrate the synthesis of complex and novel spirocyclic cores via an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition of olefins with heterocycles, including indoles, azaindoles, benzofurans, and coumarins. The DNA-tagged exo-methylenecyclobutane substrates were prepared from easily accessible alkyl iodides and styrene derivatives. Broad reactivity with many other DNA-conjugated alkene substrates was observed, including unactivated and activated alkenes, and the process is tolerant of various heterocycles. The cycloaddition was successfully scaled from 10 to 100 nmol without diminished yield, indicative of this reaction's suitability for DNA-encoded library production. Evaluation of DNA compatibility with the developed reaction in a mock-library format showed that the DNA barcode was maintained with high fidelity, with 99% amplifiable DNA from quantitative polymerase chain reaction (PCR) and next generation sequencing (NGS).

Automated summary

DNA-encoded library (DEL) screens have revolutionized the identification of lead compounds in drug discovery by enabling the screening of a vast chemical space using small quantities of DNA-tagged molecules. In this study, we successfully synthesized complex and novel spirocyclic cores using an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition. The reaction was scalable and compatible with DNA encoding, making it suitable for DEL production.