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 of racemic allylic alcohols, which affords chiral amino acid derivatives with two remote chiral centers via borrowing hydrogen catalysis . 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 ].…”

“…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 (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 , entries 1 and 2, 2a was used in excess based on our previous work , ). 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.…”

“…Based on our previous work on the enantioselective transformation of allylic alcohols , and the above time course of the reaction, the transformation may proceed via a dehydrogenation/Michael addition/reduction process. Our previous studies showed that catalyst 3a could dehydrogenate alcohols to initiate hydrogen transfer processes. ,,, The dehydrogenation of allylic alcohol 2a would produce chalcone as an intermediate. With this in mind, the reaction of 1a with chalcone under the standard reaction conditions in the absence of 2a was carried out.…”

Enantioconvergent transformations of secondary alcohols through borrowing hydrogen catalysis

“…In 2022, Wang and co-workers reported another elegant example of converting racemic secondary allylic alcohols 21-1 and glycine-derived Schiff base 21-2 to chiral amino esters 21-3 with two 1,4-stereocenters in high enantio- and diastereoselectivity (Scheme 21). 34 The amino acid products could find applications for the synthesis of various bioactive molecules or chiral ligands. Mechanistically, this transformation involved dehydrogenation of 21-1 to yield the achiral α,β-unsaturated ketone intermediate, which underwent Michael addition with the carbon-based nucleophile 21-2 to generate the key ketone intermediate 21-I with a stereogenic center at the α-amino ester unit.…”

Applications of Vanadium, Niobium, and Tantalum Complexes in Organic and Inorganic Synthesis

“…Transition metals are very important catalysts in organic synthesis, so it is of great value to find suitable options. In the past decade, metal catalysis technology has been widely developed and has achieved great success. − Due to the unique advantages of transition metals in organic catalytic reactions, metal catalysis has been developed vigorously in recent years. Metal-catalyzed organic reactions have attracted the attention of many organic chemists, because the results of transformative reaction processes continuously produce chemicals used in daily life, especially cheap metals like nickel, − copper, , iron, , and cobalt. , Therefore, it is important to use abundant and relatively biocompatible metals, such as vanadium.…”