Synthesis of AE and BE Ring Analogues of the Alkaloid Methyllycaconitine

Abstract

The synthesis of AE and BE analogues of the alkaloid methyllycaconitine is reported. The analogues contain two key pharmacophores: a 2‐(2‐methylmaleimido)benzoate ester and a homocholine motif formed from a tertiary N‐(3‐phenylpropyl)amine incorporated into either a 3‐azabicyclo[3.3.1]nonane (AE) or octahydroquinoline (BE) ring system. An additional aromatic group is introduced into the AE bicyclic system using a Horner–Wadsworth–Emmons reaction. The BE analogues are synthesised by a one‐pot cyclisation using ethyl α‐(bromomethyl)acrylate, a primary amine and cyclohexanone leading to an efficient assembly of an octahydroquinoline ring system that mimics the BE‐rings of methyllycaconitine. In both the AE and BE analogues, the key 2‐(2‐methylsuccinimido)benzoate ester pharmacophore is introduced by esterification of the alcohol precursors with 2‐(2‐methylmaleimido)benzoic acid (10) under Steglich conditions followed by hydrogenation over palladium on charcoal.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Stereoselective Synthesis of 4-Substituted 4-Hydroxypiperidines via Epoxidation-Ring Opening of 4-Methylenepiperidines

“…To explore the selectivity of the epoxidation further, we attempted the reaction on keto alkene 33, where Baeyer-Villiger oxidation is a competing process, as well as styrenes 18 34 and 35 (Scheme 6). In all cases the reaction was rapid and, again, completely selective, giving syn-epoxides 36-38 in 87-95% yields.…”

Bicyclic β-amino acids

“…The first examples of this transformation were known since late 1950s; 223 typical conditions included three-component reaction of the corresponding β-ketoester 460, primary amine and formaldehyde (Scheme 115). 224,225 Alternative procedure for the preparation of bicyclic adducts 461 involved MeSiCl 3 -promoted reactions of 460 and bis-aminol ethers 462 and led to higher yields of the products. 226,227 Scheme 115.…”

A new end group structure of poly(ethylene glycol) for hydrolysis‐resistant biomaterials

“…Synthesis of Ethyl 2-(Bromomethyl) Acrylate (EBrMA) 20 EBrMA is commercially available; but in this study, we synthesized it in-house following the protocol in literature. EHMA (7.8 g, 60 mmol) was dissolved in 60 mL diethyl ether, and PBr 3 (2.0 mL, 21 mmol) was slowly added while the vessel was cooled with an ice bath.…”