Studies toward the total synthesis of (+/-)-Plicamine Alkaloid: synthesis of intermediate dihydroisoquinoline N-alkylated.

Author(s)

Elizandra Cristiane da Silva Lopes

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2006-07-28

Examining board members

Fernando Antonio Santos Coelho; Timothy John Brocksom; Luiz Fernando da Silva Junior; Raquel Marques Braga; Lucia Helena Brito Baptistella

• Advisor: Fernando Antonio Santos Coelho

Abstract

The alkaloids isolated from plants of the Amaryllidaceae family are well known since the ancient times and are used in folk medicine for the treatment of several diseases. Due to the great structural complexity exhibited by these alkaloids, they could show a great diversity of biological effects. Among them we can cite the following: antiviral, anticholinergic, antineoplasic, antiinflammatory, analgesic, citotoxic, anti malarial and central nervous system activating. (+)-Plicamine (10), an alkaloid belonging to this botanic family, has been isolated fram plants of the specie Galanthus plicatus subsp. byzantinus by Hesse et aI. in 1999. This compound exhibits a relatively complex 2-benzopyran[3,4-c]-hydroindolane system in its structure (Figure 1). Ley et al. have described the first asymmetric total synthesis of (+)-Plicamine (10), in 2002, employing a strategy based on the utilization of solid-phase supported reagents only. This work has as a main purpose to establish a new approach for the racemic total synthesis of the (±)-Plicamine (10), based on the exploration of the synthetic potentiality of BaylisHillman adducts, which could be considered as a simples and cheap starting material. Besides, these adducts are easy to obtain and show a highly synthetic versatility. The results obtained in the development of this work, which culminated with the stereoselective synthesis of the isoquinolinic fragment of our target, are depicted in Scheme 1. The N-alkylated dihydroisoquinolinic (±)-164, a key intermediate for the preparation of (±)-Plicamine (10), was prepared from the Baylis-Hillman adduct 90. Then, the alIylic alcohol fragment of adduct 90 was treated with silicon reagents to afford the corresponding silylated ethers, which are used as substrate for the reaction with DIBAL-H. The resulting alcohol was protected to furnish the silylated alIylic diol, which in turn was used as substrate for the hydroboration reaction to provide the intermediate (±)-101. Depending on the borane used the diastereoselectivity of this step can be very good. A sequence of oxidations gave the carboxylic acid (±)-107, which was transformed into the (±)-126, via a Curtius rearrangement. The N-alkylation reaction of (±)-126 provided (±)-161, which was acylated and treated with t-BuLi to afford the (±)-164, by an intramolecular cyclization reaction mediated by a halogen-metal exchange, in 12 steps and an overalI yield of 6%. Based on our synthetic retrosynthetic analysis, the intermediate (±)-164 bears in its structure alI the functional groups, which could permit us to accomplish the total synthesis of (±)-Plicamine, in its racemic form (Scheme 1). (AU)