Total Synthesis Of (R)-Apomorphine, (R)-Aporphine And Their Derivatives Via Recycling Resolution

(R)-Apomorphine, (R)-Aporphine and their derivatives are important alkaloids with interesting biological activity. They mediate human physiology by interaction with kinds of body receptors such as DA receptors, 5-Ht receptors and adrenergic receptors. The preparation and biological activity of them were well studied in the past century. More and more attentions have been focused on (R)-Apomorphine as a medicine for Parkinson's Disease since 1951. In April 2004, apomorphine injection was approved as the first and only therapy in the US for the acute'off'episodes associated with advanced Parkinson's disease. Until now, most of these alkaloids were prepared by rearrangement from natural compounds which can not satisfy the requirement from scientific study and clinical evaluation. Therefore, a general method for synthesis of these optical active compounds is necessary and important.In this dissertation, two synthetic routes were investigated for preparation of (R)-Apomorphine, (R)-Aporphine and their derivatives. One is a route developed from Nemeyer's method which was used to prepare racemic Apomorphine and Aporphine. Through optimization, our lab apply this method to synthesis their (R)-isomers and (R)-derivatives. Beginning with isoquinoline, this route includes Reissert reaction, Reissert alkylation and elimination, formation of ammonium salt and reduction of isoquinoline ring, then hydrogenation and Pschorr cyclization. After resolution, the target chiral compounds were obtained. The other is a new route characterized with lewis acid catalyzed Pictet-Spengler reaction. This reaction developed from our lab was used to synthesize tetrahydroisoquinoline compounds without activation group. With catalytic amounts of lewis acid, the reaction of sulfonamide with phenylacealdehyde was successfully employed to the formation of Aporphines'B ring. After the following hydrogenation, Pschorr reaction and hydrolysis, noraporphine and dimethoxy norapomorphine were gained easily. Other (R)-alkaloid was derived from these two intermediates by recycling resolution and alkylation. This strategy, alternation of N-alkyl group at the end of synthetic route, avoided much work on the investigation of various N-alkyl group involved reactions and resolutions. The application of recycling resolution to total synthesis of (R)-Apomorphine, (R)-Aporphine and their derivatives was also studied. At first, the resolution of compounds was investigated by parallel screening. (+)-DBTA show good discrimination for two isomers of these compounds, especially for methylic and allylic noraporphines and dimethoxy norapomorphines. Combined with base catalyzed racemization discovered in our lab, resolution was developed into recycling resolution which allows the transformation of racemate into its (R)-isomer in a theoretical yield of 100%. By this method, allylic compounds was converted into their (R)-isomers and then transformed into other title compounds via Pd/C catalyzed removal of allylic group and alkylation.