Development of a Modified System to Provide Improved Diastereocontrol in the Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenamides

Abstract

Chiral γ-lactones are prevalent organic architectures found in a large array of natural products. In this work, we disclose the development of a modified catalytic system utilizing a commercially available Cu-phosphite catalyst for the diastereoselective reductive coupling of chiral allenamides and ketones to afford chiral γ-lactone precursors in 80:20 to 99:1 dr.

Development of regiodivergent asymmetric reductive coupling reactions of allenamides to access heteroatom-rich organic compounds

“…43 The substrate scope in this process was shown to be quite broad, and an average stereocontrol of 83 : 17 dr could be obtained for the 21 examples investigated. A more detailed investigation 47 into factors controlling diastereoselectivity then led to the identification of an alternative system employing chiral allenamide 21b with a readily available commercial aryl phosphite ligand to provide improved stereocontrol across the same 21 examples (93 : 7 avg. dr).…”

“…In general, excellent diasteroselectivities were obtained in these processes, but the identity of the major diastereomer of 51 was not determined. Enantioselective Cu-catalysed reductive coupling of allenamides and carbonyl-based electrophiles: 1,2-aminoalcohol synthesis While the initial studies confirmed the ability to access alternate heteroatom substitution patterns from the same allenamide starting material through catalyst modulation, 43,44,47 stereocontrol was achieved by the chirality of the allenamide. It is reasonable to consider that an appropriately tuned chiral Cu-catalyst could enable the same type of transformations through enantioselective catalysis while utilizing an achiral allenamide.…”

“…1). [43][44][45][46][47][48][49][50] As a result, we have primarily focused on accessing coupling products at C1 and C3 of the hypothetical starting material 10 (e.g. 11 and 13, respectively) since these products are typically more challenging to access due to the dissonant charge affinity [9][10][11] produced by the relationship of the two electron-withdrawing heteroatom substituents.…”

“…However, all these past precedented processes are typically branched-selective and access to the linear products are rare. 43,47,69 Furthermore, much of the work in this area has investigated the use of unsaturated hydrocarbon coupling partners bearing only carbon-substituents and the application and use of N-substituted reagents (e.g. 16) has been less well developed prior to our work.…”

Evans’ Chiral Auxiliary‐Based Asymmetric Synthetic Methodology and Its Modern Extensions

“…(PhO) 2 PNMe 2 could provide the highest reaction yield with excellent linear selectivity and good diastereoselectivity, while umpolung reagent SIMes⋅HCl was used for the branched amino alcohols. Furthermore, in 2022, the author investigated the effect of ligands and different chiral oxazolidinone‐derived allenamides on the reaction, additional linear selective examples were given to prove that the protocol was useful for the synthesis of important chiral γ‐lactones (e. g. ( S )‐(−)‐boivinianin A 90 ) with high recovery of the auxiliary (Scheme 23c) [73c] …”