Total Synthesis Of(R)-(-)-antofine And(R)-(-)-tylophorine And Study On The Schmidt Reaction Of Alkyl Azides With Acyl Silanes

In the thesis,the Schmidt rearrangement was explored as the research point,and two phenanthroindolizidine alkaloids,(R)-(-)-antofine and(R)-(-)-tylophorine,were efficiently prepared.Further more,the intermolecular Schmidt reaction of acyl silanes and alkyl azides was reported for the first time.The dissertation includes the following three parts:1.a brief summary of the synthetic strategy of antofine and tylophorine;2.our synthetic study on the(R)-(-)-antofine and(R)-(-)-tylophorine;3.research on the intermolecular Schmidt reaction of alkyl azides with acyl silanes.In the first chapter,the isolation and physiological activities of antofine and tylophorine were concisely reviewed.According to the ring-closure orders during the skeleton construction,the synthetic strategies were classified as the ABC-DE,ABC-ED,ABC-DE and ABDE-C strategies,and the syntheses of the two alkaloids after 2012 was briefly recalled.Among the preparation of chiral antofine and tylophorine,generally the chiral starting materials or the chiral suxiliaries were employed for construction of the only stereo-center in the alkaloids,and the chiral catalysis strategy was relatively rare.Therefore,it is necessary to seek a more efficient chiral catalytic strategy for syntheses of these alkaloids under more mild reaction conditionsIn the second chapter,the synthetic study toward(R)-(-)-antofine and(R)-(-)-tylophorine using an asymmetric hydrogenation of the allyl alcohol and an intramolecular Schmidt reaction of alkyl azides with the aldehydes as the key steps was described.The synthesis of(R)-(-)-antofine is outlined as following:Homer-Wadsworth-Emmons olefination of a substituted phosphonate ester with a known phenanthrene aldehyde well produced a conjugated ester.The ester was reduced to an allyl alcohol,then it was subjected for the asymmetric hydrogenation reaction,producing the chiral alcohol with 81%ee.Further recrystallization of the hydrogenated alcohol enhanced the ee value to 99%.Azidation and oxidation of the enantio-pure alcohol to an ?-azido aldehyde were easily addressed.Treatment of the ?-azido aldehyde under the improved conditions produced the desired formamide with 87%yield,where the Schmidt reaction proceeded with better control of alkyl migaration.Finally,deformylation of the formamide followed by Pictet-Spengler cyclization reaction gave the R-(-)-antofine.The overall yield for synthesis of antofine from the phenanthrene aldehyde is 19%for 7 steps.The R-(-)-tylophorine was also prepared using a similar strategy,and the overall yield was 14%.The important features of the strategy included the following three aspects:1.construction of the stereo-center using asymmetric catalysis strategy;2.construction of the E-ring with the Schmidt reaction;3.cyclization of D ring by the Pictet-Spengler reaction.In the third chapter,the Schmidt reaction of alkyl azides with acyl silanes was extensively explored.The reaction might proceeded through the inatial attack of the azide to the carbonyl group,producing an amino diazonium salt intermediate.Then elimination of nitrogen gas and 1,2-migration of the silyl group to nitrogen atom might be reasonable.Finally,desilylation would deliever the amide as the product.During the rearrangement process,the shift of alkyl group was absolutely inhibited.Another possible reaction process was that desilylation of acyl silane to the corresponding aldehyde could be prefered,then Schmidt reaction of the resulting aldehyde with alkyl azides would also produce the final amide.Several control experiments showed that the aldehydes could not be efficiently produced under the acidic conditions and the Schmidt reaction of aldehyde with alkyl azides was also not reliable,which ruled out the latter process.Here,nine acyl silanes and five alkyl azides were prepared,and 23 reactions were carried out.The 74-99%yields of amides was observed.From this research,the electrophiles for the Schmidt reaction were extended from the aldehydes,ketones and carboxylic acids to the acyl silanes.Compared with the intermolecular Schmidt reaction of aldehydes or ketones,the intermolecular reaction of acyl silanes and alkyl azides produces the amide with very high yield.