Total Synthesis of (−)‐Alstofolinine A through a Furan Oxidation/Rearrangement and Indole Nucleophilic Cyclization Cascade

Abstract

Areaction cascade of aza-Achmatowicz rearrangement followed by indole nucleophilic cyclization was developed to generate the common indole-fused azabicyclo-[3.3.1]nonane core of the macroline family alkaloids.T he key to the success of the strategy relies on the careful manipulation of protecting groups and judicious selection of chemoselective furan oxidation conditions.The synthetic utility was further demonstrated on the asymmetric total synthesis of (À)-alstofolinine A.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids

“…This would increase the potential for late‐stage structural diversifications [9] . To access the azabicyclo[3.3.1]nonane motif, seminal and effective methods such as Dieckmann cyclization, [5] olefin metathesis, [6a,b] indolyl Friedel–Crafts reaction, [6c,d] and [5+2]‐cycloaddition/ring enlargement, [6e,f] have been developed. We envisioned that a tandem amine oxidation and cyclopropanol ring‐opening cyclization of substrate 5 a would allow rapid assemble of the azabicyclo[3.3.1]nonane skeleton and introduction of a versatile ketone group [10] .…”

Multicomponent Cascade Reaction of 3-Formylchromones: Highly Selective Synthesis of Functionalized 9-Azabicyclo[3.3.1]nonane Derivatives

“…A s a privileged N-heterocyclic unit, 9-azabicyclo[3.3.1]nonane (ABCN) derivatives are ubiquitously found in natural products, such as (−)-cocaine, 1,2 (−)-suaveoline, 3 (−)-alstofolinine A, 4 algemonine, 5 (+)-euphococcinine, 6 and (−)-adaline 7 (Figure 1). The pharmacological activity of (−)-cocaine is believed to be due to inhibition of dopamine uptake at dopamine transporters (DAT).…”

“…1−11 Consequently, various routes have been constructed for the preparation of ABCNs. 1−11 These strategies include the Cu-catalyzed oxidative cyclization of tetrahydro-isoquinolin-3-yl)cyclo-propan-1-ol, 3 the furan oxidation and rearrangement or indole nucleophilic cyclization, 4 the 1,5-Michael-like reaction of TpMo(CO) 2 (5-oxo-η 3 -pyranyl), the intramolecular Mannich cyclization of cyclic N-sulfinyl-β-amino ketone ketals, 6 and others. 7−11 Although these methods have been crucial for synthesis of these compounds, they have some disadvantages, such as using a metal catalyst and utilizing prefunctionalized substrates obtained by tedious multistep reactions, and using an intramolecular reaction rather than an intermolecular reaction (especially the intramolecular reaction that limits the structural diversity of the target compounds).…”

“…As a privileged N -heterocyclic unit, 9-azabicyclo[3.3.1]­nonane (ABCN) derivatives are ubiquitously found in natural products, such as (−)-cocaine, , (−)-suaveoline, (−)-alstofolinine A, algemonine, (+)-euphococcinine, and (−)-adaline (Figure ). The pharmacological activity of (−)-cocaine is believed to be due to inhibition of dopamine uptake at dopamine transporters (DAT). , The ABCN skeleton is widely used in the synthesis of synthetic drugs with excellent and important biological activities, such as granisetron, a highly selective 5-HT3 receptor antagonist widely used as anesthetic or vasoconstrictor agents; compound A, a σ2 receptor used as anticancer agents; and compound B, a hedgehog-signaling inhibitor.…”

“…The pharmacological activity of (−)-cocaine is believed to be due to inhibition of dopamine uptake at dopamine transporters (DAT). , The ABCN skeleton is widely used in the synthesis of synthetic drugs with excellent and important biological activities, such as granisetron, a highly selective 5-HT3 receptor antagonist widely used as anesthetic or vasoconstrictor agents; compound A, a σ2 receptor used as anticancer agents; and compound B, a hedgehog-signaling inhibitor. The synthetic protocols for synthesis of ABCNs have been extensively investigated due to their interesting medicinal properties. − Consequently, various routes have been constructed for the preparation of ABCNs. − These strategies include the Cu-catalyzed oxidative cyclization of tetrahydro-isoquinolin-3-yl)­cyclo-propan-1-ol, the furan oxidation and rearrangement or indole nucleophilic cyclization, the 1,5-Michael-like reaction of TpMo­(CO) 2 (5-oxo-η 3 -pyranyl), the intramolecular Mannich cyclization of cyclic N-sulfinyl-β-amino ketone ketals, and others. − …”