Development of the Vinylogous Pictet–Spengler Cyclization and Total Synthesis of (±)‐Lundurine A

Abstract

A novel vinylogous Pictet-Spengler cyclization has been developed for the generation of indole-annulated medium-sized rings. The method enables the synthesis of tetrahydroazocinoindoles with a fully substituted carbon center, a prevalent structural motif in many biologically active alkaloids. The strategy has been applied to the total synthesis of (±)-lundurine A.

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…Interestingly, a Pictet–Spengler reaction is critical in the biosynthesis of indole alkaloids, which is presented in Section 3.1 (Scheme ). The Pictet–Spengler reaction has found numerous applications in natural product synthesis, including many biomimetic‐inspired routes, and drug development . The synthesis of Cialis ( 57 ), a clinical agent used to treat erectile dysfunction, involves a key stereoselective Pictet–Spengler reaction (Scheme B) …”

“…Indole heterocycles are known to engage in Pictet-Spengler reactions [6,8,21,[44][45][46] (Scheme 4B)u tilizing tryptamine derivatives (e.g., 49,54). In this reaction, at ryptamine undergoes an initial condensation reactionw ith an aldehyde/ketone to give an imine intermediate (51), which undergoes as ubsequente lectrophilica romatic substitution atC -2 of the indolen ucleus to afford tryptoline-containing compounds (53).…”

“…The Pictet-Spengler reaction has found numerousa pplications in natural product synthesis, including many biomimetic-inspired routes, and drug development. [8,21,[44][45][46] The synthesis of Cialis (57), ac linical agentu sed to treat erectile dysfunction, involves ak ey stereoselective Pictet-Spengler reaction(Scheme 4B). [8]…”

Microwave-Assisted aza-Friedel–Crafts Arylation of N-Acyliminium Ions: Expedient Access to 4-Aryl 3,4-Dihydroquinazolinones

“…In particular, in situ-generated N -acyliminium ions have been widely exploited in the synthesis of bioactive nitrogen-containing heterocycles, especially in the preparation of alkaloid natural products. 1,2,6,7 Accordingly, the development of rapid, convenient, and high-yielding protocols for the selective intra- or intermolecular nucleophilic addition to cyclic N -acyliminium ions remains a field of considerable interest. 8−11 The C4-substituted quinazolinone framework is known to exhibit a wide range of biological properties.…”

Unexpected PF6 Anion Metathesis during the Bischler–Napieralski Reaction: Synthesis of 3,4-Dihydroisoquinoline Hexafluorophosphates and Their Tetrahydroisoquinoline Related Alkaloids

“…Phosphoryl chloride (POCl 3 ) has been traditionally used as a dehydrating agent in the synthesis of nitriles from amides, 1 but when N-phenethylacylamides are employed as the substrate, the formed nitrilium intermediate can easily undergo an intramolecular cyclization to afford 3,4-dihydroisoquinolines in what is well known as a Bischler-Napieralski reaction (BNR). 2 Despite its harsh reaction conditions, the BNR is still preferred over other methodologies, such as the intramolecular cyclization of N-(2-acetylphenethyl)acetamides promoted by HCl, 3 the Pictet-Spengler, 4 and Pomeranz-Fritsch reaction, 5 for the construction of the isoquinoline ring system, since it is not a stereospecific reaction it does not require chiral catalysts, it is more versatile, and allows the synthesis of functionalized isoquinoline compounds, including numerous relevant alkaloids like protoberberines 1, benzylisoquinolines 2, phenanthridones 3, pyrrolo[2,1a]isoquinolines 4, aporphines 5, and β-carbolines 6 ( Figure 1). 6,7…”