Chemodivergent Preparation of Various Heterocycles via Phase‐Transfer Catalysis: Enantioselective Synthesis of Functionalized Piperidines

Abstract

In this work, a new chemodivergent domino approach for the preparation of various saturated heterocycles, based on phase‐transfer catalysis (PTC), is presented. The versatile nature of doubly electrophilic substrates, showing both a Michael acceptor and a ketone, tethered by a heteroatom, enables three different domino reaction pathways. The nucleophile dictates the chemoselectivity of the reaction. Sulfa‐Michael/aldol, cyanide addition/oxa‐Michael and Michael/H‐shift/aldol processes, along with the variation of the tethering heteroatom, results in the formation of six different classes of saturated heterocycles. DFT calculations account for the observed chemo‐ and diastereoselectivity of the two most productive processes. Moreover, an extensive investigation on the sulfa‐Michael/aldol pathway was carried out, ultimately leading to the development of a new enantioselective domino approach to multi‐substituted piperidines based on PTC.

Catalytic role of the enol ether intermediate in the intramolecular Stetter reaction: a computational perspective

“…[43][44][45] As shown in Scheme 5(a), the alkoxide generated in situ from a ketone reacts with an a,b-unsaturated ester to give a Michael adduct. 46 A phosphonate was also reported to act as a nucleophilic to trigger an intramolecular cyclization (Scheme 5(b)). 47 Furthermore, an enol ether compound was reported to undergo retro oxa-Michael reaction under NHC-based catalytic conditions (Scheme 5(c)).…”

Divergent Reactivity of D-A Cyclopropanes under PTC Conditions, Ring-Opening vs. Decyanation Reaction

“…However, to the best of our knowledge, the reactivity of D-A cyclopropanes has never been studied under phase-transfer catalysis (PTC) [32][33][34][35]. Having maturated a broad expertise in the use of PTC in recent years [36][37][38][39][40][41][42][43], and inspired by the versatility of DA-cyclopropanes, we decided to study their reactivity with nucleophiles under PTC conditions.…”

Cobalt-Catalyzed Chemoselective Transfer Hydrogenative Cyclization Cascade of Enone-Tethered Aldehydes

“…To this end, chemoselective variation toward multifunctional substrates is generally a prerequisite to form precursors of the sequence. For instance, the intramolecular cyclization of enone-tethered electrophiles, such as aldehyde, ketone, enone, and nitro functionalities, provides a good setup for a Michael–Aldol coupling cascade reaction with nucleophiles to construct cyclic alcohol motifs. − However, such a Michael-addition-initiated cascade may be replaced by a nucleophilic attack on the more reactive electrophiles to alter the reaction sequence. , Despite a wealth of research on both cascades toward intramolecular enone-tethered aldehydes, transition-metal-catalyzed reductive cyclization remains less developed. Experimental investigations into the approach of chemoselective reductive cyclization and exploration of the different reactivities between two modes with the same catalyst would advance the potential of such strategies in depth.…”