Syntheses And Structure Modification Of Type B PPAPs From Garcinia Plants

OBJECTIVEStarting from the cheap and readily available chemical compounds,a new efficient and practical synthetic strategy was developed to construct biocyclo[3.n.1]alkanones.This versatile method was also applied in the synthesis of type B PPAPs which affored the natural products in 8-10 steps very rapidly and efficiently.The biological inverstigation of the natural products and synthetic comounds resulted in a set of structure-activity relationships,which would facilitate the further struture simplification and lead compounds screening.METHODSThe biocyclo[3.n.1]alkanones were constructed via a cascade intramolecular Dieckmann cyclization between the methyl ketone and the diesters which has never been explored so far.The synthesis of diesters is designed in both racemic and asymmetric pathways.Li HMDS or Me₂Al SEt promoted cascade Dieckmann cyclization and Sm Cl₃-catalyzed C-acylation reactions were used to construct the core biocyclo[3.n.1]alkanes and introduce the steric aryl acyl group.The total synthesis of oblongifolin A,oblongifolin D,guttiferone I,garcimultiflorones H,garcimultiflorones I,epi-clusianone,regio-guttiferone I,epi-guttiferone O and regio-garcimultiflorones I were completed in 8-10steps.The synthesized natural products,analogues and other biocyclo[3.n.1]alkanones prepared were tested for their inhibitory activity against threehuman cells in vitro.Taxol was used as a positive control.The three cell lines were He La（cervical cancer cell line）,SGC7901（gastric cancer cell line）,and HCT116（colon cancer cell line）.RESULTSA series of type B PPAPs（oblongifolin A,oblongifolin D,guttiferone I,garcimultiflorones H,garcimultiflorones I,epi-clusianone）as well as their analogues（regio-garcimultiflorone I,regio-guttiferone I and epi-guttiferone O）with different substituents at C1-C3,C5 and C7 are inverstigated.The core biocyclo[3.n.1]alkanones are assembled efficiently via a newly developed cascade Dieckmann cyclization promoted by the in-situ generated Me₂Al SEt.The syntheses have typically demonstrated the general synthetic utility in the PPAPs with substituent diversity at C1-C3,C5 and C7,particularly with the sterically hindered geranyl group.A late-stage C-acylation with bulky aryl group is also developed under Lewis acid conditions.At the same time,the asymmetric synthesis of（3R）-3-12a,（3R）-3-12b,（3R）-3-12b’were also completed for the formal synthesis of such natural products.Moreover,biological investigation against the cancer cell lines are also conducted with a set of structure-activity relationships identified.The activity study indicated that the natural products oblongifolin D,guttiferone I,garcimultiflorone H,garcimultiflorone I,epi-clusianone and regio-garcimultiflorone I showed good inhibitory activity,while other simple biocyclo[3.n.1]alkanones without substituents at C7-C8showed no activity against the three cell lines.CONCLUSIONWe have accomplished the short total synthesis of six natural PPAPs and three unnatural PPAPs in 8-10 steps.The synthesis features a novel Li HMDS or Me₂Al SEt promoted cascade Dieckmann cyclization to construct the core biocyclo[3.n.1]alkanones and Sm Cl₃catalyzed C-acylation reactions to introduce the steric aryl acyl group.The generality of Li HMDS-promoted cascade Dieckmann condensation in making biocyclo[3.n.1]alkanones and the analogues of PPAPs has also been demonstrated.The Dieckmann cyclization in the total synthesis goes through an unprecedented 8-membered intermediate followed by a second transannular Dieckmann condensation to construct the biocyclo[3.n.1]alkanones smoothly.The mechanism for this novel cyclization is also preliminarily studied.Taking advantages of the modular introduction of side chains and efficient construction of biocyclo[3.n.1]alkanones,these strategies are generally applicable in the total synthesis of type B PPAPs and their analogues.The total synthesis can be run in large scales with a couple of PPAPs achieved divergently in one sequence from the same starting materials.Moreover,biological evaluation of the synthesized compounds against the cancer cell lines led to the identification of simplified potent antitumor agents and derived a set of structure-activity relationships（SARs）that could facilitate further optimization studies.