Total Synthesis Of Cephalotaxus Norditerpenoids: Cephanolides A And B

There are nine species of Cephalotaxus,and seven species widely distribute in the southern provinces of China.The Cephalotaxus norditerpenoids possess potent anti-tumor,anti-inflammatory and anti-fungal activities.The challenging architectures and potential biological activities of this family of natural products have attracted attention from chemists.Cephanolides A-B were C₁₈Cephalotaxus norditerpenoid,which were isolated by Yue and coworkers from Cephalotaxus sinensis.Structurally,they all feature a complex cage-like skeleton,a multi-substituted aromatic A ring,and cyclohexane C ring containing six contiguous stereogenic centers.This thesis focused on the synthetic studies of Cephalotaxus norditerpenoids.Our synthesis mainly devoted to the stereoselective construction of the challenging cis-hexahydrofluorenone and cage-like skeleton.A convergent synthetic route was successfully developed to accomplish the first asymmetric total synthesis of cephanolide A and B.For the construction of the core A-B-C ring,1)A substrate-controlled Michael addition,2)a Pd-catalyzed decarboxylative allylic alkylation,and 3)a Lewis acid mediated aldol reaction were employed as the key steps to build C ring containing four contiguous stereogenic centers.A palladium-catalyzed Suzuki–Miyaura cross-coupling reaction was used to connect A and C rings.We then developed a one-pot of Prins cyclization and oxidation to close B ring.A remote hydroxy-directed reduction strategy was applied for the selective reduction of C1=C10 tetrasubstituted olefin.Based on our preparation of the core A-B-C ring,1)The cage-like architecture was assembled by lactonization to form F ring from the known tricyclic A-B-C ring.A cation-mediated cascade cyclization,involving etherification and Friedel–Crafts cyclization,was utilized to build D-E ring.The first asymmetric total synthesis of cephanolide A was achieved from the known chiral pool compound in 15 steps on a hundred milligrams scale.2)Regarding to cephanolide B,the synthesis started from the known tricyclic A-B-C ring.Redox manipulations were realized at C-3 and C-20 via single electron reduction and Barton–Mc Combie deoxygenation,respectively.The formation of D-E ring relied on the similar transformations,including cation-mediated Friedel–Crafts cyclization and lactonization.The first asymmetric total synthesis of cephanolide B was achieved from the known chiral pool compound in 21 steps.