1374817-75-0Relevant academic research and scientific papers
General route for the preparation of diverse 17-membered macrocycles based on RCM and examination of the E/Z selectivity
Heckrodt, Thilo J.,Singh, Rajinder
, p. 2854 - 2865 (2012/07/16)
(Chemical Equation Presented) A convergent, general synthetic route to 17-membered macrocycles was developed to support biological evaluation and structure-activity relationship (SAR) studies during phenotypic screening for immunology targets. A series of amide coupling reactions led to a ring-closing metathesis (RCM) precursor that was cyclized using Grubbs' catalysts. It was found that the reaction formed the macrocyclic products in a 3:1 ratio of E/Z isomers. Moreover, it was shown that a number of similarly substituted RCM precursors undergo cyclization to produce the geometric E/Z isomers in roughly the same 3:1 ratio. The remarkable independence of the E/Z outcome from the substitution pattern of the RCM precursor makes this synthetic approach generally applicable. Separation of the E/Z isomers was achieved by preparative high-performance liquid chromatography and allowed biological profiling of the geometric isomers. Reactive groups in the macrocycle were utilized for late-stage modifications in the fashion of diversity-orientated synthesis (DOS), yielding analogs for SAR studies. Copyright Rigel Pharmaceuticals, Inc.
