US scientists have used a retrosynthetic approach to uncover a method for synthesising β-amino amides with improved stereocontrol in what the research group are calling ‘the first enantioselective double umpolung reaction’ to β-amino amides.
β-amino amide structures are motifs found in many complex natural products, differing from their more common α-amino amide counterparts by an extra carbon between the amino and amide groups. This extra C–C bond endows the structure with better proteolytic stability, in comparison to α-amino amides, and has led to their use in many important therapeutic molecules. However, forming certain configurations of β-amino amides in a stereocontrolled manner is often difficult.
Jeffrey Johnston and Mahesh Vishe of Vanderbilt University wanted to find a better strategy for making these structures. Starting with β-amino amide products, they took a retrosynthetic approach, disconnecting the key bonds within the molecules. From this, they could evaluate the possible different synthetic routes to the molecule by examining the different theoretical starting structures, known as synthons.
In a typical synthetic strategy, the synthons will have a negative charge on the more electronegative atoms (ie the nitrogen or oxygen); however, it is also possible to disconnect a bond in the opposite way to give synthons of the opposite polarity. This approach is termed umpolung, from the German word for reversal. By disconnecting not one but two bonds in this manner – a double umpolung strategy – the researchers developed a new synthetic method with improved stereocontrol.
The overall synthesis has three steps. First, using a conformationally restricted catalyst, nitroalkanes undergo an enantioselective Michael addition to give β-nitro nitroalkanes. These are then stereospecifically converted to the corresponding β-oximino-amides; the nitroalkane groups converting to amides whilst the β-nitro group reduces to a β-oximino group. The final step reduces the β-oximino to give the anti-β2,3-amino amide products.