Total Synthesis of (±)‐Scopolamine: Challenges of the Tropane Ring

Abstract

Scopolamine was synthesized using 6,7-dehydrotropine as a key intermediate. Rhodium-catalyzed [4 + 3] cycloaddition chemistry and a modified Robinson-Schöpf reaction

Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis

“…Przewalkia tangutica is a rare medicinal solanaceous plant found in the Tibetan Plateau of China in which the roots, seeds and entire vegetative tissues are utilized [14]. P. tangutica contains several biologically active TAs including anisodamine (2), scopolamine (3) and atropine (the racemic mixture of hyoscyamine (4). The TAs present in P. tangutica are associated with many biological activities including analgesic, spasm modulation, pesticidal, and anti-inflammatory effects [14].…”

“…Synthesizing TAs chemically in the lab has also been difficult and costly because of their stereochemical nature. Nocquet et al attempted a total synthesis approach to produce the compound scopolamine (3), however their low yield of 16% does not make this method economically feasible [2]. A major problem for the commercial production of scopolamine (3) in hairy root cultures is achieving industrial level yields [132].…”

“…In particular alkaloids, pharmacologically active cyclic nitrogen containing metabolites derived from amino acids, are known for their pharmacological effects and frequently serve as the starting point for drug development [2]. Some of the oldest domesticated medicinal plants have been those that produce alkaloids.…”

“…Despite their similarities, TAs and GAs show different distribution patterns across the plant kingdom. The N-methyl-8-azabicyclo[3.2.1]-octane core structure of TAs is found in over 200 alkaloids [2,5,6] (Figure 1). In contrast, N-methyl-9-azabicyclo [3.3.1]-nonane, the core scaffold of GAs, appears in considerably fewer alkaloid metabolites ( Figure 1).…”

Palladium-Catalyzed α-Arylation of Dimethyl Malonate and Ethyl Cyanoacetate with o-Alkoxybromobenzenes for the Synthesis of Phenylacetic Acid, Esters and Phenylacetonitriles

“…2 They can also be used as intermediates for the synthesis of 3-hydroxy-2-phenylpropanoic acid derivatives, through the reduction of one carboxylate group, to obtain tropic acid derivatives such as the tropane alkaloid scopolamine, an antiemetic drug. 3 The decarboxylation reaction of α-aryl dicarbonyl compounds leads to α-phenylacetic acids, which are found for example in the structure of ibuprofen (antiinflammatory activity), 4 in UPF523 (active in the CNS), 5 and in JSTX-3 (a neurotoxin found in spider venom). 6 They have also been used in the total synthesis of isoflavonoids such as cajanol and daidzein.…”