New Synthetic Routes to (+)-Uleine and (−)-Tubifolidine: General Approach to 2-Azabicyclo[3.3.1]nonane Indole Alkaloids

Abstract

Novel asymmetric synthetic routes to (+)-uleine and (−)-tubifolidine are reported herein. The regioselective formation of enol triflates from 2-azabicyclo[3.3.1]­nonane ketones followed by indolizations of the resultant ene-hydrazides allowed the efficient construction of key indole intermediates, facilitating the total synthesis of the target natural alkaloids.

Novel Pathway for the Synthesis of 20-Deethyltubifolidine

“…With a success route to the pentacyclic structure established, we endeavored to complete the Strychnos core structure. The imine (5) was treated with zinc dust in methanol in the presence of acetic acid as a supplement, presenting exceptional proceeds of amide (6), and by using a one-pot, two-step reductant method compound 6 was succeeded. Finally, compound 6 was reduced with LiALH4 in refluxing THF-furnished 20-Deethyltubifolidine [21,36,38,40,47].…”

“…The mixture was cooled and diluted with EtOAc (50 mL) and then filtrated by means of a sintered funnel. The organic residue was dried, treated in concentration process in vacuo, and the remainder was subjected to purification by using silica gel chromatography (EtOAc) to give 662 mg of amide (6)…”

“…The compound of biological features and charming molecular structures have made chemists' attempts concentrate on the improvement of process for synthesizing such compounds. Accordingly, there have been numerous strategies for the construction of these compounds [5][6][7][8]. Even so, uncharted synthetic closings to this frame could very little ensure a precious origin for these kinds of the framework.…”

Synthesis of N‐Aryl‐ and N‐Alkenylhydrazides through C(sp2)−N Bond Construction

“…Subsequent transformation gave the desired natural products. Most recently, they discovered regioselective generation of desired enol triflates 225 rather than 226 from 224 by careful tuning the base strength and solvent mixture [97c] . Further conversion of 225 or 229 furnished the 2‐azabicyclo[3.3.1]nonane indole alkaloids (+)‐uleine or (−)‐tubifolidine.…”

Enantioselective Total Synthesis of (+)‐Nordasycarpidone, (+)‐Dasycarpidone, and (+)‐Uleine

“…Total syntheses of uleine type alkaloids have attracted synthetic chemists for many years and different approaches to the tetracyclic skeleton 1 have been developed. They can be classified into the following five strategies based on how the bridged ring system was generated: 1 ) C b −C c bond formation by Mannich reaction [6–10] 2 ) C c −N d bond formation by aza‐ Michael addition; [11,12] 3 ) C e −C f bond formation through radical addition; [13] 4 ) C a −C f bond formation by Friedel–Crafts acylation; [14–15] 5 ) C b −C g bond formation by Fischer indole synthesis [16–18] and 6 ) one pot formation of both the C a −N h and C c −N d bonds [19] …”