Abstract
Background: Azaspirocycles are important frameworks in biologically active natural products and are an emerging pharmacophore in drug design. We prepared ten novel zwitterionic azaspirocyclic hydantoins along with their ring-opened and nitro-group reduced analogues.
Methods: Zwitterionic azaspirocyclic hydantoins were synthesized in high yield from 2,4- dinitrobenzoic acid and a range of carbodiimides in dichloromethane as solvent. These novel molecules were purified by reverse-phase medium pressure (flash) chromatography and fully characterized. Some molecules were evaluated in the NIH NCI-60 anti-cancer screen.
Results: Intense red zwitterionic azaspirocyclic hydantoins were fashioned from an electron-deficient benzoic acid, 2,4-dinitrobenzoic acid, in a dearomatizing intramolecular ipso-spiroannulation using 1,3- disubstituted carbodiimides. Our proposed reaction mechanism invokes a rearrangement to an N-acylurea intermediate that spontaneously ipso-spirocyclizes under our reaction conditions in a 100% atom efficient manner. A broad survey of available carbodiimides revealed that only molecules with sterically undemanding N-alkyl groups on this N-acylurea precursor were able to form the most stable products. A diagnostic analytical pattern was observed in tandem MS in ESI- mode that revealed an unusual degradation by way of R-NCO neutral fragment loss. Catalytic hydrogenation gave quantitative conversion to the ring-opened 2,4-diaminoaromatic N-acylurea. Stable structures were tested for anticancer activity, yet without success.
Conclusion: We have presented an efficient and atom-economical synthetic approach to zwitterionic azaspirocyclic hydantoins using the in situ intramolecular dearomatization of electrophilic N-acylureas.
Keywords: Azaspirocycle, carbodiimide, dearomatization, SNAr mechanism, spirocyclic, zwitterion.
Graphical Abstract
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