Synthesis Of Spiroisoxazolines From Anisaldehyde And Its Derivatives

Spiroisoxazolines,which share a spiro framework by an isoxazoline and another ring moiety,show rich biological activities,such as antibacterial,antitumor,hypoglycemic and reverting antibiotic resistance.Not surprisingly,the spiroisoxazoline structure has become the essential skeleton of many potential drugs and functional materials.Additionally,various natural products containing a spiroisoxazoline core structure have also been found in marine sponges and the flowers and husks of Xanthoceras sorbifolia Bunge.Nevertheless,low efficiencies usually take place during natral products extraction from plants and conventional mtheods of spiroisoxazoline synthesis still suffer limitations.Hence,new methods to access spiroisoxazolines and related natural products from simple raw materials are highly desirable.Anisaldehyde,known as an abundant plant extract and cheap chemical material,could be converted to raw materials for the synthesis of spiroisoxazolines,including napthalene-containing dihydrochalcones and benzene-containing oximes,due to its aldehyde and methoxy groups.This thesis is mainly focused on the synthesis of spiroisoxazolines from anisaldehyde and its derivates,and consisted of five parts.?1?A series of starting materials for spiroisoxazolines were prepared from anisaldehyde and its derivatives,including napthalene-containing dihydrochalcones via Aldol reaction and double-bond reduction with ketones,and benzene-containing oximes by oximation of corresponding chalcones.?2?A new approach to afford sulfur-containing dihydrochalcones via[3,3]-sigmatropic rearrangement or intramolecular nucleophilic addition has been studied.This efficient method successfully expands the range of raw materials for spiroisoxazolines and features broad scope,good functional group tolerance and high yields up to 93%,which is able to overcome the limitations of conventional methods such as long steps,low yields and difficulties in accessing sulfur-containing products.The reaction intermediate could be captured to support our proposed reaction mechanism.?3?A new method for the synthesis of spiroisoxazolines from naphthalene-containing dihydrochalcones has been studied.This reaction started with a transformation of dihydrochalcone to keto-oxime,followed by a catalytic dearomatization to afford the desire product with a yield up to 99%,in the presence of 1.2 equivalent NaNO₂ and 3.6 equivalent conc.HCl under air.Substrates with drug or natural product skeletons can also react smoothly under this condition,giving the desired spiroisoxazolines in 98-99%yields.Additionally,the reaction intermediate detecting and radical trapping experiment were conducted for mechanism study.Comparing to conventional methods,this approach offers several advantages:1)air was used as a sustainable oxidant.2)NaNO₂ plays dual roles,a hydroxylamine source and a catalyst,in this cascade.Regardless of the oximation,0.2 equivalent NaNO₂ is sufficient for the catalystic dearomatization in the presence of HCl and air.3)metal-free and no need of sophisticated synthesis of raw materials.4)one-pot oximation/catalysic dearomatization to access spiroisoxazolines,which features broad scope,good functional group tolerance and high yields.?4?A new method for the synthesis of spiroisoxazolines from oximes has been studied.Products were accessed with high yields up to 91%via a catalytic dearomatization with NaNO₂,and TEMPO as the catalysts,in the presence of 1 equivalent conc.HCl and 0.1 MPa O₂.Substrates derived from natural products such as tyrosine,vanillylacetone,safrole and loureirin A were able to react smoothly in this condition.Key intermediates of?+?-epi-calafianin were also synthesized.Additionally,control experiments were conducted for the mechanism study.Comparing to conventional methods,this approach offers several advantages:1)oxygen as the sustainable oxidant.2)0.2 equivalent NaNO₂ and 0.25 equivalent TEMPO are sufficient for the oxidative dearomatization in the presence of 1 equivalent HCl and 0.1 MPa O₂.3)for the first time,raw materials are extended to phenylalkyl ether oximes,phenylalkyl thioether oximes and thiol oximes,not only limit to phenylic oximes like the reported methods.?5?A preliminary study of spiroisoxazoline synthesis in water has been undertaken.New amphiphiles were prepared first and their micellar catalysis activities were tested by comparing with other commercially available surfactants with the oxidation of tertiary alcohols in water as the model reaction.Dynamic light scattering and cryo-TEM were conducted for the mechanism study of micellar catalysis.These new rosin-based surfactants were then introduced to the spiroisoxazoline synthesis in water and the transformation of oximes to spiroisoxazolines was successfully achieved.