The Pictet-Spengler Reaction Updates Its Habits

Abstract

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

The scaffold-forming steps of plant alkaloid biosynthesis

“…In this reaction, the intermolecular condensation of an amine and aldehyde forms an iminium, which is then quenched through intramolecular electrophilic aromatic substitution. 166,167 The tethered nucleophilic aromatic system bypasses the requirement for accumulation of a distinct nucleophile. Mechanistic and biocatalytic aspects of Pictet-Spenglerases have been reviewed recently.…”

A unique high-diversity natural product collection as a reservoir of new therapeutic leads

“…109 Accordingly, the synthesis of alkaloids has become possible via a P-S reaction, which has been widely studied for its application in the preparation of tetrahydro-β-carbolines (THBCs) and THIQ. [110][111][112][113] In the last few decades, a metathesis-based process has also been kept under consideration as a potential tool for accessing the pyrrolizidine and quinolizidine cores, typical of alkaloids. 114,115 Within the in house library outlined in this review, alkaloids represent around 20% of all natural compounds, including the different subclasses mentioned above, and are found in more than 10 plant families, including the Apocynaceae, Loganiaceae, Berberidaceae, Papaveraceae, and Rubiaceae.…”

Naturally-Occurring Alkaloids of Plant Origin as Potential Antimicrobials against Antibiotic-Resistant Infections

“…One of the most direct, efficient, and variable synthetic methods for the construction of privileged pharmacophores (i.e., tetrahydro-isoquinolines, tetrahydro-β-carbolines and polyheterocyclic frameworks) and for the creation of natural compounds libraries in medicinal chemistry proved to be the Pictet-Spengler reaction [ 57 , 58 ]. This reaction, in combination with chiral catalysts, has been reported in the total synthesis of complex alkaloids [ 59 ]. Another synthetic approach widely employed for the construction of sophisticated macromolecules architecture, such as alkaloids, is the olefin metathesis reaction, which is one of the most powerful tools for the formation of challenge polycyclic frameworks and bridged nitrogen heterocycles [ 60 , 61 , 62 ].…”