(E)-,(Z)-Parallel Preparative Methods for Stereodefined β,β-Diaryl- and α,β-Diaryl-α,β-unsaturated Esters: Application to the Stereocomplementary Concise Synthesis of Zimelidine

Parallel and practical methods for the preparation of both (E)‐ and (Z)‐β‐aryl1‐β‐aryl2‐α,β‐unsaturated esters 1 and (E)‐ and (Z)‐α‐aryl1‐β‐aryl2‐α,β‐unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N‐methylimidazole (NMI)‐mediated enol tosylations (14 examples, 70–99 % yield), as well as stereoretentive Suzuki–Miyaura cross‐couplings (36 examples, 64–99 % yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)‐ and (Z)‐pure products 1 and 2 by utilizing sequential enol tosylations and cross‐coupling reactions. An expeditious and parallel synthesis of (E)‐ and (Z)‐zimelidine (3), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods. Working together: Parallel synthetic methods for (E)‐ and (Z)‐β‐Ar1‐β‐Ar2‐α,β‐unsaturated esters 1 and (E)‐ and (Z)‐α‐Ar1‐β‐Ar2‐α,β‐unsaturated esters 2 (see scheme), involving accessible stereocomplementary N‐methylimidazole (NMI)‐mediated enol tosylations and stereoretentive Suzuki–Miyaura cross‐couplings, are presented. Application to an expeditious parallel synthesis of the selective serotonin reuptake inhibitor (E)‐,(Z)‐zimelidine is presented.