Modular Synthesis of Dipyrroloquinolines: A Combined Synthetic and Mechanistic Study

Abstract

A straightforward synthesis of [1,2-a][3',2'-c]dipyrroloquinolines has been developed generating up to eight new σ-bonds and five new stereogenic centers in a simple and modular one-pot operation. Generally good to excellent yields and moderate to good stereoselectivities in favor of the all-cis stereoisomer were observed. A detailed investigation combining synthetic studies, analytical measurements, and theoretical calculations has been conducted to elucidate the reaction mechanism using ESI- and liquid-beam IR-laser desorption mass spectrometry as well as DFT calculations. Key steps of this sequential transformation include a Lewis acid-catalyzed vinylogous Mukaiyama-Mannich reaction of bis(silyl) dienediolate 1 and a Brønsted acid-promoted Mannich-Pictet-Spengler reaction cascade reaction to complete the synthesis of the dipyrroloquinoline core of the target compounds.

How and Why to Investigate Multicomponent Reactions Mechanisms? A Critical Review

“…Studies of MCRs presenting "plausible mechanisms" based solely on "logical" organic transformations but lacking experimental (or theoretical) support are out of the scope of this tutorial review. Schneider and co-workers [94] have developed a MCR that gives efficient access to [ Gutierrez and co-workers also described a three component reaction to synthesize indeno[1,2-b]-pyrazolo[4,3-e]pyridine (IPP) derivatives catalyzed by a simple imidazolium-based ionic liquid (Scheme 17) and evaluated its mechanism by ESI-MS(/MS). [95] The 1,3-dicarbonyl reagent was proposed to be activated by the noncovalent intermolecular C 2 À HÀ O=C interaction between the imidazolium-based catalyst and the 1,3-dicarbonyl reagent, thus favoring the Knoevenagel condensation with the aldehyde.…”

“…Schneider and co‐workers [94] have developed a MCR that gives efficient access to [1,2‐ a ][3’,2’‐ c ]dipyrroloquinoline (DPQ) derivatives in an one‐pot transformation (Scheme 16). The developed conditions form, in the same one‐pot reaction, up to eight new σ‐bonds, as well as five new stereogenic centers.…”

Catalytic Approaches to Multicomponent Reactions: A Critical Review and Perspectives on the Roles of Catalysis

“…Catalysis is therefore indispensable for MCRs performed at more amenable temperature conditions. Some elegant examples of MCRs have been performed at nearly room temperature (≈25 °C), and the presence of a catalyst proved to be essential to the success of the transformation at lower temperatures [ 120 , 121 , 122 , 123 , 124 , 125 , 126 ]. It is important to bear in mind that many reagents are less stable and less reactive than those typically used in model reactions characteristically described during the initial evaluation of an MCR.…”

Toward the synthesis of incargranine B and seneciobipyrrolidine. Synthesis of octahydro‐dipyrroloquinoline skeleton via dipolar cycloaddition/amination sequence

“…Many other approaches to the synthesis of the core structure have been reported in the literature, but essentially they are based on the oxidative transformations of N‐phenylpyrrolidines or the cyclative processes of N‐phenylhomopropargyl amines [7–19]. Of other methods, perhaps, notable are those based on intramolecular dipolar cycloaddition reactions of azomethine ylides which have been explored in the synthesis of martinelline [20–31].…”