Total synthesis of 2,6‐dimethylergolin‐8α‐amines

Abstract

AbstractA stereoselective total synthesis of the racemic form of the 2,6‐dimethylergolin‐8ã‐amine derivative III, previously obtained semi‐synthetically from lysergic acid, is described. Starting from the commercially available tricyclic lactam 1, the 9,10‐didehydroergoline skeleton containing an angular Me group in position 3 (see 18) is built up in several steps applying a Woodward D‐ring annelation sequence. The introduction of the 8‐amino group is achieved with complete diastereoselectivity to give exclusively the 8ã‐derivative 22. Subsequently, a Wagner‐Meerwein‐type migration of the angular Me group yields the 2‐methylated 9,10‐didehydroergoline derivative 31. The feasibility of this key transformation was tested on the two model systems 4 and 7 prior to the evaluation of the total synthesis. A stereoselective Birch reduction to the trans‐fused ergoline, and deacetylation/acylation conclude the total synthesis of the racemic target compound 34.In addition, the resolution of an early intermediate (see 3) by chromatography on a chiral stationary phase is presented which demonstrates that the described total synthesis could also be used for the preparation of the biologically active (5R,8S,10R)‐enantiomer III.