Double Regioselective Asymmetric C‐Allylation of Isoxazolinones: Iridium‐Catalyzed N‐Allylation Followed by an Aza‐Cope Rearrangement

Abstract

Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionalization of isoxazolinones is often plagued by regioselectivity issues due to the competition of various nucleophilic centers within the heterocycles. We report the first regio- and enantioselective C-allylations of isoxazolinones. These occur with high regioselectivity in favor of the linear allylation products, although Ir phosphoramidite catalysts were used, which commonly results in branched isomers. Our studies suggest that this outcome is the result of a reaction cascade via an initial regio- and enantioselective N-allylation to provide a branched allyl intermediate, followed by a spontaneous [3,3]-rearrangement resulting in chirality transfer.

Isoxazol-5-ones as Strategic Building Blocks in Organic Synthesis

“…The second approach was based on a synergistic combination of Pd and Ir catalysts, in order to perform an N-allylation step employing allyl carbonates 57, followed by aza-Cope rearrangement to produce the corresponding 4allylisoxazol-5-ones 58. 50 The use of Pd(OAc) 2 as co-catalyst is justified by the authors as being responsible for facilitating the enolization of isoxazol-5-one 1, and has been identified as having a positive influence on the enantioselectivity of this transformation 51 Also in this context, a reaction sequence involving an asymmetric thiourea-catalyzed Michael addition of isoxazol-5-ones to nitroalkenes, followed by 4-fluorination of the isoxazol-5-one intermediate has been described by Ma and co-workers. 52,53…”

Organocatalytic Enantioselective 1,6‐aza‐Michael Addition of Isoxazolin‐5‐ones to p‐Quinone Methides

“…The same group reported later a regioselective asymmetric C ‐allylation of isoxazolinones via a iridium‐catalyzed N ‐allylation followed by a spontaneous aza ‐Cope rearrangement. In this study, N ‐allylated products were obtained when allyl carbonates substituted with alkyl chains were used . Finally, an organocatalytic asymmetric four‐component [5+1+1+1] cycloaddition via a cascade process that involves a double alkylation at C4 in isoxazolinones has been developed by Du and Chen, recently …”

Aminodecalone Scaffolds – Enantioselective Synthesis, Indole and Quinoline Annulation

“…The synthesis of optically active compounds with quaternary stereocenters remains one of the most challenging tasks in synthetic organic chemistry . Several approaches towards this problem were successful in the recent years, either with the use of chiral auxiliaries, chiral metal catalysts or with enantioselective organocatalysis . Since quite a time we are interested in piperidine derivatives as scaffolds for lead discovery in medicinal chemistry .…”