Divergent Entry to Gelsedine-Type Alkaloids: Total Syntheses of (−)-Gelsedilam, (−)-Gelsenicine, (−)-Gelsedine, and (−)-Gelsemoxonine

Abstract

The gelsedine-type alkaloids possess a common oxabicyclo[3.2.2]nonane core and spiro- N-methoxyindolinone moiety along with a diversely functionalized heterocycle embedded in the compact framework. Herein we disclose a divergent entry to gelsedine-type alkaloids that hinges on rapid assembly of the common core by the orchestrated application of an asymmetric Michael addition, a tandem oxidation/aldol cyclization, and a pinacol rearrangement and generation of the structural diversity via a late-stage heterocyclization. The power of this strategy has been demonstrated through very short total syntheses of four gelsedine-type alkaloids: gelsedilam, gelsenicine, gelsedine, and gelsemoxonine.

Evolution of Strategies in Protecting‐Group‐Free Synthesis of Natural Products: A Recent Update

“…The collective and divergent PGF‐synthesis of (–)‐gelsedilam ( 143 ), (–)‐gelsenicine ( 146 ), (–)‐gelsedine ( 147 ), and (–)‐gelsemoxonine ( 148 ) was completed in 24 % (7 steps), 8.4 % (7 steps), 7.2 % (8 steps) and 11 % (9 steps) overall yields, respectively from known compounds 136 and 137 . The synthesis is highly efficient in step‐economy and overall yields in comparison to earlier reports, like Hiemstra's [ 56b ] synthesis (1999) of gelsedine (21 steps, 0.09 % overall yield), Carreira's [ 56c ] (2015) synthesis of gelsemoxonine (21 steps, 0.8 % overall yield), Ferreira's [ 56d ] synthesis (2016) of gelsenicine (13 steps and 4.2 % overall yield), Zhoa's [ 56e ] synthesis (2016) of gelsedilam (18 steps and 1.5 % overall yield) and the Fukuyama's [ 56f ] synthesis (2016) of gelsedilam (24 steps, 2 % overall yield), gelsenicine (24 steps, 2.5 % overall yield) and gelsedine (25 steps and 2.3 % overall yield).…”

“…Several structurally interesting alkaloids were isolated from the Gelsemium plants and shown to possess analgesic, antitumor, and anti‐inflammatory activities. [ 54,55 ] Ma and co‐workers [ 56a ] cleverly developed a divergent PGF approach to the gelsedine‐type alkaloids ( 143 , 146–148 ) possessing an oxabicyclo[3.2.2]nonane and a spiro‐ N ‐methoxyindolinone moiety by using the chiral auxiliary approach (Scheme 16). The (–)‐menthol‐derived enone 136 was subjected to Michael addition with indole compound 137 to deliver adduct 138 as diastereomeric (1:1) mixture.…”

Meeting Proceedings from ICBS 2018—Toward Translational Impact

“…Dawei Ma (Chinese Academy of Sciences) focused on the challenging total synthesis of bioactive alkaloids. To begin, he illustrated this approach for gelsedine-type alkaloids . By making key intermediates from two building blocks with convergent synthesis, the route to total synthesis could be significantly reduced.…”

“…To begin, he illustrated this approach for gelsedine-type alkaloids. 79 By making key intermediates from two building blocks with convergent synthesis, the route to total synthesis could be significantly reduced. In the second part of the talk, Ma presented additional examples of advances in alkaloid chemistry, including the retrosynthesis of the diterpenoids azitine and navirine C in less than 20 steps 80 and kopsia alkaloids.…”

Total Synthesis of (−)-14-Hydroxygelsenicine and Six Biogenetically Related Gelsemium Alkaloids

“…In 2016, Ferreira and Zhao, respectively, reported the total syntheses of (±)-gelsenicine and (±)-gelsedilam. The recent total syntheses of four gelsedine-type alkaloids, (−)-gelsedilam, (−)-gelsenicine, (−)-gelsedine, and (−)-gelsemoxonine, by Ma and co-workers were quite efficient . They developed an elegant strategy that involved an asymmetric Michael addition, a tandem oxidation/aldol cyclization, and a pinacol rearrangement to construct an oxabicyclo[3.2.2]­nonane core and a spiro- N a -methoxyoxindole moiety.…”