Protecting-Group-Free Formal Synthesis of Aspidospermidine: Ring-Opening Cyclization of Spirocyclopropane with Amine Followed by Regioselective Alkylations

Abstract

A concise formal synthesis of (±)-aspidospermidine via Stork's intermediate, which could be used as a divergent synthesis of Aspidosperma alkaloids, was achieved by employing a ring-opening cyclization of spirocyclopropane with amine followed by a regioselective intramolecular/intermolecular alkylation sequence. Stork's intermediate was synthesized in only six steps from a simple starting material, 1,3-cyclohexanedione, and was converted into (±)-aspidospermidine. To the best of our knowledge, this synthesis of Stork's intermediate involves the least number of steps to date. Furthermore, no protecting groups were used during this synthesis.

Synthetic Approaches to Tricyclic Aminoketones in the Total Synthesis of Aspidosperma and Kopsia Alkaloids

“…Tricyclic vinylogous amides are also received close attention from organic researchers because they can be converted into both cis ‐ or trans ‐CDE rings tricyclic aminoketones 1 under different conditions [24–28] . This synthetic strategy provides a powerful help for the determination of the configuration of 1 .…”

“…Therefore, this review will summarize the synthetic approaches to the tricyclic aminoketones 1 since 1963, including highlight the construction of the C‐/D‐/E‐ring with the all‐carbon quaternary stereogenic center, and subsequent give a brief introduction to complete the synthesis of aspidosperma and kopsia alkaloids. In addition, this review will discuss the formation of tricyclic aminoketones 1 based on their precursors, including tricyclic lactams, [10–23] tricyclic vinylogous amides, [24–28] tricyclic enones, [29–31] tricyclic ethers, [32] tricyclic ketals, [33] tricyclic esters, [34] and non‐tricyclic precursors [35–38] …”

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

“…Aspidospermidine ( 380 ) belonging to the Aspidosperma alkaloid family consist of a [6.5.6.6.5]‐pentacyclic ring system. Nambu and co‐workers [ 133a ] reported the formal synthesis involving ring‐opening cyclization of spirocyclopropane with amine followed by the intermolecular/intramolecular regioselective alkylations (Scheme 45). The synthesis started from the conversion of 1,3‐cyclohexanedione 374 into spirocyclopropane 375 by their own method.…”

“…[ 135 ] The cyclopropane ring opening and intra‐ and intermolecular alkylations could easily set the tricyclic core with correctly placed keto group for Fischer‐indole synthesis completing the PGF‐synthesis of aspidospermidine ( 380 ) in 8 steps and 6.5 % overall yield. A recent synthesis of (+)‐aspidospermidine by Song [ 133b ] in 2019 involving benzyl protections required 11 steps for completion with 9 % overall yield. The earlier 2000 syntheses, first by Aubé [ 135a ] required 16 steps with 4.6 % overall yield, while the racemic synthesis by Heathcock [ 133c ] required 13 steps and had 5.7 % overall yield.…”

“…A recent synthesis of (+)‐aspidospermidine by Song [ 133b ] in 2019 involving benzyl protections required 11 steps for completion with 9 % overall yield. The earlier 2000 syntheses, first by Aubé [ 135a ] required 16 steps with 4.6 % overall yield, while the racemic synthesis by Heathcock [ 133c ] required 13 steps and had 5.7 % overall yield.…”