Total Synthesis And Biological Study Of Jungermanenone Type Tertracyclic Diterpenoids

Diterpenoids are attention-grabbed natural products with complex,bridged,and polycyclic structure which display various biological properties including anticancer,anti-inflammatory and antiviral.However,solely rely on isolation of natural products cannot provide sufficient quantity for biology studies,not to mention using the isolated natural prodcuts for drug development.Therefore,it requires an alternative pathway to access natural products in a reliable manner,one classical solution is total synthesis by which construct these secondary metabolites from commercially available materials.This thesis will describe an asymmetric total synthesis of(+)-jungermatrobrunin A and(-)-jungermannenone C.The highlight of the total synthesis of(-)-jungermannenone C involves a SOMO catalyzed polyene reaction to construct contiguous chiral centers and an methylene cyclopentenone.Moreover,a late-stage radical induced dienyne cyclization was developed to form the [3.2.1]bicyclic skeleton,which is the backbone in ent-kaurane diterpenoids.In short,(-)-jungermannenone C was synthesized in 13 steps,and(+)-jungermannenone C was also achieved using similar protocol.We found that(+)-jungermannenone C is more toxic than natural(-)-jungermannenone C.We discovered that jungermannenone C interacts with cysteine residue on peroxidase Prx I and Prx II,which induces intracellular ROS accumulation and differentiation of AML cells.Combination of jungermannenone C with ATRA can overcome ATRA resistance in some cancer cell lines.It demonstrates(+)-jungermannenone C can be used as a drug candidate of differentiation therapy.Jungermatrobrunin A containing the first peroxide bridge in jungermannenone diterpenoids,shows anti-fungal activity.Our total synthesis of jungermatrobrunin A began with an asymmetric Michael addition,followed by intramolecular Pd-catalysedα-arylation to achieve the cis-A/B bicycle.The trans-A/B bicycle with four contiguous chiral centers were built in one step from cis-A/B bicycle,takeing adavantage of the property of carbonyl group.This methodology was later applied in the preparation of[3.2.1]bicyclic system afforded(-)-1α,6α-diacetoxy jungermannenone C in 12 steps.Interestingly,starting from(-)-1α,6α-diacetoxyjungermannenone C,(+)-12β-hydroxy-1α,6α-diacetoxy-ent-kaura-9(11),16-dien-15-one was synthesized through a UV light induced bicyclo[3.2.1]octene ring rearrangement,while(+)-jungermatrobrunin A was obtained under visible light via Schenck ene reaction.Both(+)-12β-hydroxy-1α,6α-diacetoxy-ent-kaura-9(11),16-dien-15-one and(+)-jungermatrobrunin A were afforded from(-)-1α,6α-diacetoxy jungermannenone C under sunlight,strongly suggesting the plausible biosynthetic pathway for the two complex natural products.