Studies Towards Asymmetric Total Synthesis Of Aconitine

Aconitine is the first diterpenoid alkaloid discovered from nature.It was isolated from Aconitum napellus L in 1833,and characterized in 1959.As the star molecule in C19-diterpenoid alkaloids,aconitine features the congested hexacyclic framework,nine oxygen-containing functional groups and fourteen consecutive chiral centers including four quaternary carbons,which is one of the most complex diterpenoid alkaloids.In this thesis,the first synthesis of fully oxygenated A/E fragment of aconitine has been achieved,and the highly oxygenated C/D ring system of aconitine has been constructed via an enyne cycloisomerization.Also,the further research on the synthesis of aconitine based on these ring systems has been discussed,which has laid an important foundation for the total synthesis of aconitine and other highly oxygenated C19-diterpenoid alkaloids.Firstly,we attempted to construct the A ring of aconitine from the known chiral building block 193.However,it was difficult to achieve the introduction of the oxygen-containing substitution at C3 and the one-carbon elongation of C4 at the same time.In the revised approach,an asymmetric synthesis of aconitine’s A/E fragment 332 b was achieved by using(-)-carvone as starting material after 27 steps of transformations with 1.64% overall yield.Key features of the synthesis include an intramolecular [3+2] cycloaddtion to establish the chiral quaternary carbon C4 and oxygen-containing substitution at C18,an intramolecular Mannich reaction to synthesize A/E ring system as well as a successful one-carbon elongation of C5 based on Corey-Chaykovsky epoxidation.In the second part,the chiral quaternary carbon C13 was constructed by twice Grignard addtions at C13,after which a ring-close metathesis was employed to build C ring of aconitine.Then,after several functional-group transformations,aconitine’s C fragment 349 was synthesized from the known chiral butyraldehyde 367 in 11 steps with 7.2% overall yield.Moreover,a ruthenium-catalyzed enyne cycloisomerization was employed to build C/D fragment of aconitine after the reaction of alkyne 349 with isobutyraldehyde.Lastly,two parts of aconitine were connected by alkyne-aldehyde addition between C fragment 349 and A/E fragment 332 a.Moreover,aconitine’s A/C/D/E tetracyclic skeleton 392 was synthesized by the pivotal enyne cycloisomerization reaction.