Synthesis Of Water-soluble Sulfonic Acid-DBCO

Dibenzocyclooctyne(DBCO)is a cyclooctyne molecule with the best lipid solubility and reactivity among various cyclooctyne molecules used in the strain-promoted azide-alkyne cycload-dition(SPAAC)reaction.It has been widely used in innovative drug development,life science and material science research.However,due to the presence of two benzene rings in the DBCO molecule,the whole molecule is very hydrophobic.Although the water solubility of the whole molecule can be increased by connecting PEG and side chains with sulfonic acid groups,the hydrophobicity of the dibenzocyclooctyne part directly involved in the reaction cannot be changed.The hydrophobicity of the dibenzocyclooctyne part results in binding to non-specific proteins in some application scenarios,reducing the bioavailability.Therefore,the development of DBCO molecules with simple synthesis process and water-soluble has very broad application prospects.Based on this,this thesis intends to synthesize water-soluble DBCO molecules substituted with quaternary ammonium salt or sulfonate on the aromatic ring of DBCO,and the following research results are mainly obtained.(1)Dibenzocyclooctene and dibenzodibromocyclooctane,which are the intermediates in the synthesis of DBCO,were used as raw materials to introduce sulfonic acid groups through direct sulfonation,after multiple substrates and multiple sulfonation reaction conditions were tried,they were unsuccessful.The reason may be that the activity of the aromatic ring is not enough.In view of the fact that the more active sulfonating reagent fuming sulfuric acid is regulated,we can only try to introduce an activating group on the aromatic ring to achieve sulfonation by improving the electrophilic substitution reaction activity of the aromatic ring.(2)Using 3-methoxybenzoic acid and 3-methoxyaniline as raw materials,a 4-step reaction was carried out to synthesize dibenzocyclooctenone 90 with two methoxy groups substituted on the aromatic ring.After the compound 90 was demethylated and converted into the corresponding trifluorosulfonate,we tried to introduce diethylamine using a metal-catalyzed method,and then converted it into a quaternary ammonium salt.Multiple amination reaction conditions were tried,none of them were successful.(3)Using 3-dimethylaminoaniline and 3-dimethylaminobenzoic acid as raw materials,a 4-step reaction was used to synthesize dibenzocyclooctenone with two dimethylamino groups substituted on the aromatic ring.Under the irradiation of ultraviolet light,carbon monoxide was removed,and dibenzocyclooctyne 112 with two dimethylamino groups substituted on the aromatic ring was obtained,but the yield of the product was too low had no practical value.(4)Using diphenylcyclooctenone 97 and 121 substituted with two methoxy groups on the aromatic ring as raw materials,the monosulfonated products 114 and 122 were obtained under the condition of chlorosulfonic acid and dichloromethane and the yield was 80%and 75%.Subsequently,carbon monoxide was removed under the irradiation ultraviolet lamps,and further hydrolyzed to obtain sulfonic acid-DBCO-COOH 117 and sulfonic acid-DBCO-amine 124.These two sulfonic acids modified DBCO molecules have very good water solubility.In addition,experiments show that the reaction rate,stability and bio-orthogonality of this type of molecule are similar to DBCO,which has a very broad application prospect.