The Synthesis of Certain Derivatives and Analogues of (−)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase

Abstract

Syntheses of certain di- and mono-oxygenated derivatives (e.g., 2 and 3, respectively) and analogues (e.g., 4, a D-ring monoseco-analogue of 2) of both the (-)- and (+)-enantiomeric forms of the alkaloid galanthamine [(-)-1] are reported. All have been assessed for their capacities to inhibit acetylcholine esterase but, in contrast to the predictions from docking studies, none bind strongly to this enzyme.

The Exploitation of Enzymatically‐Derived cis‐1,2‐Dihydrocatechols and Related Compounds in the Synthesis of Biologically Active Natural Products

“…Given the capacity it provides to construct quaternary carbon centers in a predictable manner, the Eschenmoser‐Claisen rearrangement reaction has also played a pivotal role in our development of total syntheses of the clinically‐deployed anti‐Alzheimer's drug galanthamine ( 187 ) and various analogues from starting materials such as 1 (X=Br) . When used in conjunction with the Suzuki‐Miyaura cross‐coupling, intramolecular S N ′ and Pictet‐Spengler reactions, the Eschenmoser‐Claisen rearrangement has also allowed us to establish a total synthesis of (+)‐amabiline ( 188 ), the enantiomer of a crinine alkaloid …”

Recent advancements in the use of Bobbitt's salt and 4-acetamidoTEMPO

“…Buckler, Banwell, and co-workers prepared a number of derivatives for further biological evaluation, and four of the analogues ( 195 , 196 , 197 , 198 ) all stem from primary alcohol 194 . 122 Through oxidation with 1 in wet MeCN solvent, 194 is converted to carboxylic acid 195 , allowing for advancement to 196 , 197 , and hydroxylated galanthamine analogue 198 (Scheme 55).…”

“…Scheme 55 Synthesis of galanthamine derivatives195, 196, 197, 198 from advanced alcohol intermediate 194 122. …”

A Review on Recent Syntheses of Amaryllidaceae Alkaloids and Isocarbostyrils (Time period mid-2016 to 2017)

“…ii) The synthesis of derivatives and analogues of (-)-and (+)galanthamine, by Banwell and co-workers: Banwell and coworkers developed an effective and neat protocol for the synthesis of analogues of (-)-and (+)-galanthamine 133 in order to evaluate their acetylcholine esterase inhibition potential [29]. The group's synthesis commenced by the coupling between vinyl bromide 134 and boronic ester 135 with PdCl 2 catalyst to afford the arylated cyclohexene 136 (68%).…”