Synthesis of 2,2‐Disubstituted Spirocyclic Pyrrolidines by Intramolecular Dieckmann Condensation

Abstract

Novel spirocyclic pyrrolidines were synthesized in three steps from cyclic α‐amino acids with a 3‐ to 7‐membered cycle. The key transformation was the Dieckmann condensation reaction. The described approach opens a door to various novel spirocyclic building blocks for drug design.

Strategies and methodologies for the construction of spiro-γ-lactams: an update

“…270) from cyclic -amino acid substrates has been reported (Scheme 69). 100 Amide 269 was obtained by acylation of amino ester 267 with methyl malonyl choride (268) and was used without purification in the spirocyclization step. Spirocyclic dione 270 was obtained in high yield by an initial Dieckmann condensation of amide 269, carried out in methanol in the presence of sodium methoxide, followed by hydrolysis and decarboxylation.…”

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…However, the lack of stereocontrol during the key cycloaddition step is the main weakness of this strategy. Recently Mykhailiuk reported a unified spirolactam synthesis from α‐aminoesters, relying on Dieckmann condensation (Scheme 1b) [40] . Gaunt reported a visible‐light‐mediated synthesis of aza‐sprirocycles using photocatalytic single electron transfer (SET) reduction of iminium intermediate‐radical cyclization sequence [41] .…”

“…Recently Mykhailiuk reported a unified spirolactam synthesis from α-aminoesters, relying on Dieckmann condensation (Scheme 1b). [40] Gaunt reported a visible-light-mediated synthesis of aza-sprirocycles using photocatalytic single electron transfer (SET) reduction of iminium intermediate-radical cycliza-tion sequence. [41] Bode employed catalytic hydrogen atom transfer reduction of electron-rich olefins with a generation of C-centered radicals in the presence of imines for the intramolecular radical cyclization with the formation of spirocyclic morpholines.…”

Asymmetric Dieckmann Condensation towards Spirocyclic Oxindoles Catalyzed by Amino Acid‐Derived Phosphonium Salts

“…In the presence of strong bases such as NaH, NaOMe, and t-BuOK, Dieckmann condensation is an exceptionally effective process for generating 1,3dicarbonyl compounds. [5] Due to the harsh conditions, only one report on catalytic and asymmetric Dieckmann condensation has been published. [6] Recently, our lab has concentrated on the design, synthesis, and applications of chiral ion pairing catalysts generated from natural amino acids in a wide range of asymmetric processes.…”