NHC-Promoted Asymmetric β-Lactone Formation from Arylalkylketenes and Electron-Deficient Benzaldehydes or Pyridinecarboxaldehydes

Abstract

A chiral NHC catalyzes the asymmetric formal [2 + 2] cycloaddition of alkylarylketenes with both electron-deficient benzaldehydes and 2- and 4-pyridinecarboxaldehydes to generate stereodefined β-lactones. In the benzaldehyde series, optimal product diastereo- and enantiocontrol is observed using 2-nitrobenzaldehyde (up to 93:7 dr (syn:anti) and 93% ee). Substituted 2- and 4-pyridinecarboxaldehydes are also tolerated in this process, generating the corresponding β-lactones in good yield and enantioselectivity, although the diastereocontrol in these processes is highly dependent upon the aldehyde substitution. These processes are readily scalable, allowing multigram quantities of the β-lactone products to be prepared. Derivatization of these products, either through ring opening into the corresponding stereodefined β-hydroxy and β-amino acid derivatives without loss of stereochemical integrity or via cross-coupling, is demonstrated.

Recent Advances in the Organocatalytic Enantioselective Synthesis of Functionalized β‐Lactones

“…In 2013, Smith and co-workersr eported an enantioselective [2+ +2] annulation reactionb etween aryl alkyl ketenes and electron-deficient aldehydes 11 for the synthesis of b-lactones 12 (Scheme 8). [23] Notably,t his reactionw as limited to 2-nitrobenzaldehyde and pyridine carboxaldehydes,a nd simple benzaldehyde failed to undergo this reaction. The NHC pre-catalyst that was used by the Ye group (A)w as found to be the best cata-Scheme3.NHC-catalyzed [2+ +2] cycloaddition reaction between ketenes and 2-oxoaldehydes.…”

“…In 2013, Smith and co‐workers reported an enantioselective [2+2] annulation reaction between aryl alkyl ketenes and electron‐deficient aldehydes 11 for the synthesis of β‐lactones 12 (Scheme ) . Notably, this reaction was limited to 2‐nitrobenzaldehyde and pyridine carboxaldehydes, and simple benzaldehyde failed to undergo this reaction.…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…reported reactions of aromatic aldehydes and ketenes to construct β‐lactones via [2+2] cycloaddition. Moderate to very good results can be attained by deployment of NHC catalyst 186 (Scheme ) 209…”

“…Moderate to very good results can be attained by deployment of NHC catalyst 186 (Scheme 96). [209] Just recently Xu et al reported a method for the synthesis of cyclobutanes. 2-Vinyl pyrroles and cinnamaldehyde derivatives are applied in these diarylprolinolsilyl ether 87 catalyzed transformations.…”

Palladium‐Catalyzed Cascade Annulation To Construct Functionalized β‐ and γ‐Lactones in Ionic Liquids

“…Recently, Smith and co-workers discovered an elegant method for the stereoselective synthesis of stereodefined b-lactones based on a [2+2] cycloaddition of alkylarylketenes with electron-deficient benzaldehydes or pyridinecarboxaldehydes. [15] However, complex substrates and harsh reaction conditions are required in these reactions. Very recently, we reported an intermolecular carboxylative annulation cascade to construct saturated functionalized g-lactones in ionic liquids (ILs) through palladium-catalyzed, one-pot, four-step cascade methods.…”