Asymmetric Ruthenium‐Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives

Abstract

The asymmetric hydroalkylation of racemic allylic alcohols has been developed for the synthesis of chiral amino acid derivatives with two remote chiral centers by borrowing hydrogen catalysis. The stereoselectivities are controlled by a single chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and an interesting diastereoselectivity amplification process of the product. The method could be used for the synthesis of several types of biologically important molecules, including stereodivergent synthesis of chiral pyrrolidine derivatives.

Transforming Racemic Compounds into Two New Enantioenriched Chiral Products via Intermediate Kinetic Resolution

“…Recently, we developed a catalytic system for the asymmetric hydroalkylation 7 of racemic allylic alcohols, which affords chiral amino acid derivatives with two remote chiral centers via borrowing hydrogen catalysis. 8 The stereoselectivities of the transformation are controlled by a chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and a diastereoselectivity amplification process of the product [eq 1]. However, the substrate scope for the catalytic system was limited to allylic alcohols with a terminal olefin group.…”

“…Our initial thoughts were to use a chiral dehydrogenation/hydrogenation catalyst to control the enantioselectivity of the alcohol group and a chiral phase transfer catalyst 9 (PTC) to control the stereoselectivity of the Michael addition step. It was found that the reaction of the model substrates 1a and 2a in the presence of a chiral PTC (PTC-1 or PTC-2) and a chiral Ru catalyst (3a) could afford the desired product 5a with excellent diastereo-and enantioselectivities in yields close to 50% (Table 1, entries 1 and 2, 2a was used in excess based on our previous work 8,10 ). Interestingly, a ketone product 4a was also formed in 25% (with PTC-1) and 41% (with PTC-2) yields, respectively, with >20:1 diastereoselectivities and good enantioselectivities.…”

“…15 It is worth noting that a DKR process is not involved in the reaction, which departs from our previous work. 8 The reason could be that the increased steric hindrance of 4a and 4a′ makes it difficult to deprotonate the relative acidic hydrogen atom on the carbon adjacent to the ester group.…”