Using Heteroaryl-lithium Reagents as Hydroxycarbonyl Anion Equivalents in Conjugate Addition Reactions with (S,S)-(+)-Pseudoephedrine as Chiral Auxiliary; Enantioselective Synthesis of 3-Substituted Pyrrolidines

Abstract

We have developed an efficient protocol for carrying out the stereocontrolled formal conjugate addition of hydroxycarbonyl anion equivalents to α,β-unsaturated carboxylic acid derivatives using (S,S)-(+)-pseudoephedrine as chiral auxiliary, making use of the synthetic equivalence between the heteroaryl moieties and the carboxylate group. This protocol has been applied as key step in the enantioselective synthesis of 3-substituted pyrrolidines in which, after removing the chiral auxiliary, the heteroaryl moiety is converted into a carboxylate group followed by reduction and double nucleophilic displacement. Alternatively, the access to the same type of heterocyclic scaffold but with opposite absolute configuration has also been accomplished by making use of the regio- and diastereoselective conjugate addition of organolithium reagents to α,β,γ,δ-unsaturated amides derived from the same chiral auxiliary followed by chiral auxiliary removal, ozonolysis, and reductive amination/intramolecular nucleophilic displacement sequence.

Direct Synthesis of Chiral 3‐Arylsuccinimides by Rhodium‐Catalyzed Enantioselective Conjugate Addition of Arylboronic Acids to Maleimides

“…While a slightly lower selectivity was observed for 2‐methyl‐, 4‐methyl‐, and 4‐fluoro‐phenylboronic acids, the enantioselectivity was improved when conducting the reactions in the presence of 5 mol % of the Rh I / L2 catalyst (entries 2, 3, and 6). Variously substituted arylboronic acids underwent the addition reaction to N ‐(4‐ m ethoxylbenzyl)maleimide ( 1 g ) in a highly enantiocontrolled manner (89–97 % ee ) to generate the corresponding N ‐PMB15‐protected 3‐arylsuccinimides in excellent yields (90–99 %, entries 8–14). Maleimide 1 h , harboring an N ‐phenylethyl substituent, was also compatible in the transformation with variously substituted arylboronic acids, producing the desired products in chemical yields ranging from 90 to 99 % and in 90 to 98 % ee (entries 15–21).…”

Recent Functionalizations of Primary Sulfonamides

“…intermolecular ring closure can lead to the formation of various heterocycles (Scheme 14). [64][65][66]…”

Intramolecular Addition of Heteroaryllithium Compounds onto Activated Alkenes: Access to Heterofused Indolizines and Pyrroloazepines

“…Therefore, we decided to extend this protocol to electron‐rich (thiophene) and electron‐deficient heteroaryl halides (e.g., pyridines and quinolines), which would involve heteroaryllithium compounds generated by halogen/lithium exchange. Heteroaryllithium compounds are very versatile intermediates that have been used in different types of organic transformations, such as copper‐catalyzed α‐selective allylic alkylations, palladium‐catalyzed cross‐coupling reactions, conjugate additions, coupling of boronic acids, or Parham‐type cycliacylations . These examples illustrate the utility of heteroaryllithium compounds in heterocycle synthesis and also demonstrate the possibility of introducing the lithium atom regioselectively at different positions of the ring systems.…”