Studies On The Total Synthesis Of Opium Alkaloid Codeine

Morphine, an alkaloid isolated from the opium poppy with a serious addictive side effect, has been widely used as an analgesic and anesthetic drug. It has been a fascinating synthetic target of organic chemists. The structure of morphine, first proposed in 1925, is quite unique among alkaloids; it has a strained pentacyclic core (morphine skeleton) with five contiguous chiral centers including a benzylic quaternary carbon. The asymmetric construction of the benzylic quaternary carbon center as well as the special structure of morphine is the major challenge in the synthesis of morphine alkaloids. Since Gates published the first total synthesis of morphine, the synthesis of morphinans has attracted the attention of many genernation of synthetic chemists. To date, there are more than 30 reported routes for the total synthesis or formal synthesis of codeine, morphine and its analogues. During the synthetic studies of morphine, many useful new reactions and innovative synthetic methodologies have been developed, however, a truly practical synthesis of the title alkaloid still remains a distant dream. The developments of novel and effective synthetic method of morphine and its related compounds are still an important task in modern synthetic organic chemistry. In this thesis, a cascade cyclization to construct the dihydrofuran ring and an intramolecular palladium catalyzed C-H olefination method to install the morphinan ring B have been described. Based on this methodology, a protecting group free total synthesis of codeine was completed.Three chapters are included in the thesis. In the first chapter, the structure of morphine, its biosynthesis, and some important total syntheses of morphine and related alkaloids are summarized.In chaper 2, we discuss the new approaches towards the total synthesis of codeine. Starting from arylboronic acid 226 and iodocyclohexenone 225, a Suzuki coupling provided phenol 227. The key all carbon quaternary centers required for the synthesis of opium alkaloids were constructed by an intramolecular alkylation of ketone 246a. Lactone ring opening and dihydrofuran ring closing sequential reaction of epoxide 278 afforded 290a. A palladium catalyzed C-H olefination of 299 to connect the C10-C11 bond followed by functional group transformation leaded to intermediate 303 (Guillou’s intermediate). Based on this methodology, a protecting group free approach was established for the synthesis of codeine.In chaper 3, experiment procedure, physical and spectrum data for compounds described in chapter 2 are recorded.