Asymmetric Transformation of Either Enantiomer of Narwedine via Total Spontaneous Resolution Process, a Concise Solution to the Synthesis of (-)-Galanthamine

Total Synthesis of (−)‐Galanthamine by Remote Asymmetric Induction

“…[2] Its limited supply and the high costs associated with isolating this compound from natural sources [3] are two compelling reasons for the need for an efficient synthesis. (À)-Galanthamine (1) has usually been prepared industrially through the crystallization-induced asymmetric transformation [3,4] of the intermediate (AE )-narwedine (2). [5] As the latter compound is highly allergenic, chemists must be extremely careful when working with it, which underscores the necessity for safer and more efficient methods for the synthesis of (À)-1.…”

Biomimetic Synthesis of (.+-.)-Galanthamine and Asymmetric Synthesis of (-)-Galanthamine Using Remote Asymmetric Induction

“…30,60) Moreover, the synthetic intermediate 3 was found recently to exist as a racemic conglomerate, i.e., a yield of more than 70% of an enantiomerically pure form of 3 could be obtained from a supersaturated solution of (Ϯ)-narwedine (3) in ethanol and triethylamine, by seeding not only optically pure crystals of 3 but also foreign substances such as (ϩ)-and (Ϫ)-galanthamine (1). 61) Thus, conversion of 24 to 3 was also examined to find an alternative effective synthetic route of optically pure (Ϫ)-1. The carbonyl group of 24 was protected with ethylene glycol to give acetal 25, which was reduced with lithium aluminum hydride, followed by deprotection of the acetal group with acid to achieve an overall good yield (76%) of (Ϯ)-3.…”

Asymmetric Synthesis of Bioactive Hydrodibenzofuran Alkaloids: (−)‐Lycoramine, (−)‐Galanthamine, and (+)‐Lunarine

“…In regard to these three natural alkaloids, there are several synthetic routes for the asymmetric synthesis of galanthamine and lycoramine, [3][4][5][6][7] but no reports on the chiral synthesis of lunarine. [8] Over the past five decades since the first pioneering studies on the synthesis of (À)-galanthamine and (À)-lycoramine by Barton and Kirby in 1962, [4a] the stereoselective installation of such key quaternary stereogenic centers in the asymmetric total synthesis of these compounds has been strategically approached in the following two ways: 1) the indirect approach, which accesses such stereogenic centers from the prochiral quaternary carbon atom through the enantioselective desymmetrization [4] of racemic substrates by retro-oxa-Michael addition/oxa-Michael addition/spontaneous resolution or through the diastereoselective desymmetrization [5] of chiral substrates by intramolecular oxa-Michael addition, and 2) the direct approach for the formation of a C À C bond centered on the chiral quaternary carbon atom through diastereoselective intramolecular Heck reactions [6] and diastereoselective [3,3]-sigmatropic rearrangements, [7] with stoichiometric amounts of chiral precursors. To our knowledge, however, no direct C À C bond-forming, catalytic, enantioselective approach to the key quaternary stereogenic centers in galanthamine, lycoramine, and lunarine ( Figure 1) has been reported.…”

“…To our knowledge, however, no direct C À C bond-forming, catalytic, enantioselective approach to the key quaternary stereogenic centers in galanthamine, lycoramine, and lunarine ( Figure 1) has been reported. [3][4][5][6][7][8] To address this topic, a strategic diversity-oriented retrosynthetic analysis is shown in Scheme 1; the key feature of this analysis is a new catalytic asymmetric intermolecular Michael addition of a-cyanoketones with acrylates for the stereocontrolled construction of highly functionalized building blocks 3, which contain the key sterically congested aryl-substituted quaternary carbon atom. [9][10][11] Notably, the catalytic enantioselective assembly of all-carbon quaternary stereocenters by a Michael addition has still not yet been fully explored in natural product total synthesis.…”

“…[19] Because of their biological significance and unique tetracyclic structure, several elegant asymmetric routes have been described. [3][4][5][6][7] In this context, our enantioselective synthesis is shown in Scheme 5. (S)-3 ab, obtained above, underwent an intramolecular ketone-ester condensation in the presence of sodium tert-butoxide to give the 1,3-diketone I. Acid-catalyzed regioselective methyl etherification, followed by the in situ deprotection of the phenolic MOM ether, afforded the labile phenolic enol ether II, which was then sequentially subjected to a Luche reduction, acidic hydrolysis, and an in situ intramolecular oxa-Michael addition, to give the tricyclic intermediate 5 a with the key cishydrodibenzofuran skeleton in 40 % yield over 4 steps.…”