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

Abstract

Organic compounds of biological importance often contain multiple stereogenic C-heteroatom functional groups (e.g. amines, alcohols, and ethers). As a result, synthetic methods to access such compounds in a reliable and...

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

“…Transformations of this ketone class were largely unsuccessful in our prior Cu-catalyzed azadiene reductive couplings, with only acetone participating after extensive reaction reoptimization over the aryl/alkyl ketone conditions . Work from the Sieber laboratory has also illustrated the challenge imposed by aminoallylations of dialkyl ketones . We were thus pleased to find that addition of acetone and cyclohexanone proceeded smoothly under identical conditions to acetophenone coupling, affording amido alcohols 3p and 3q in 98.5:1.5 and 95.5:4.5 er, respectively; the reactions occur with complete ( Z )-selectivity for the olefin.…”

“…Finally, treatment of amido alcohol 3a with thionyl chloride allows for cyclization to form oxazoline 11 with stereochemical inversion at the carbinol (70% yield), ,, providing a pathway to access ( Z )-allylic syn -amino alcohols. In total, the transformations in Scheme are illustrative of the potential the ( Z )-allylic amino alcohol products hold for the preparation of complex fragments for downstream synthesis.…”

“…Aminoallylation, an important class of carbonyl allylations, has gained recent attention as a means to prepare 1,2-amino alcohols enantioselectively (Scheme ). Both the Krische and Sieber groups have utilized N -substituted allenes as an umpolung approach toward β-amino alcohols, the latter illustrating syn - or anti -selective processes in couplings with aryl/alkyl ketones through CuH catalysis; , however, these methods lead to products containing terminal olefins.…”

“… 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.…”