Aminoalcohol Synthesis through Nonprecious Metal Catalysis: Enantioselective Cu-Catalyzed Reductive Coupling of Aldehydes and Allenamides

Abstract

Herein, we report the development of a Cu-catalyzed aminoallylation of aldehyde electrophiles through reductive coupling by circumventing the problematic competitive reduction of the aldehyde electrophile by a CuH catalyst. This leads to a highly diastereo-and enantioselective process for the synthesis of chiral 1,2-aminoalcohols containing secondary alcohol substitution. Cleavage of the N substituents on the reaction products was performed, allowing access to the other diastereomer of the aminoalcohol, which was investigated in the context of a synthesis of eligulstat.

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

“…Utilizing this approach, a CuH-catalysed enantioselective reductive coupling of aldehydes and a N-Boc derived acyclic allenamide (71) was developed to provide access to chiral 1,2-amionalcohols bearing a secondary alcohol motif (72, Scheme 12). 50 Again, the anti-diastereomer of product was the major diastereomer formed when using the acyclic allenamide 71. The yields and enantioselectivities of this process ranged from good to excellent and both aromatic and aliphatic aldehydes could be used.…”

“…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.…”

“…Furthermore, we chose to study Cu-catalysed reductive coupling processes due to the improved sustainability and safety of Cu relative to the competitive Type 1 reductive coupling catalysts derived from the precious metals Ru, Rh, or Ir due to the high availability, low cost, and reduced toxicity of Cu compared with these other precious metal pre-catalysts. 50 Gratifyingly, a systematic study of monodentate phosphorous based ligands in the coupling of 21a with ketone electrophiles demonstrated that high linear selectivity could be obtained to provide homoaldol products 22 in excellent yield and stereocontrol when using phosphoramidite ligand (PhO) 2 PNMe 2 . 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.…”

Copper-Catalyzed Diastereo-, Enantio-, and (Z)-Selective Aminoallylation of Ketones through Reductive Couplings of Azatrienes for the Synthesis of Allylic 1,2-Amino Tertiary Alcohols

“… Inspired by that disclosure, we have developed a ( Z )-selective aminoallylation of ketones through reductive coupling of 2-azatrienes, a new class of enamine umpols reported by our laboratory . Reactions are highly stereoselective and take place with both aryl/alkyl and dialkyl ketones, significantly expanding the chemical space available within enantioenriched 1,2-amino tertiary alcohols that may be readily accessed through C–C bond formation. , Functionalizations of the products, including those that take advantage of the amino alcohol’s nearby ( Z )-alkene, highlight the synthetic utility of this method.…”