Enantioselective synthesis of α-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution.
An enantioselective method for the synthesis of α-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important α-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.
Thalén
Lisa K
LK
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
Sumic
Anna
A
Bogár
Krisztián
K
Norinder
Jakob
J
Persson
Andreas K Å
AK
Bäckvall
Jan-E
JE
D000171:Acrolein / Q000031:analogs & derivatives* / Q000737:chemistry; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D005656:Fungal Proteins; D007700:Kinetics; D008049:Lipase / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D020005:Propanols / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
D002264:Carboxylic Acids; D005656:Fungal Proteins; D009942:Organometallic Compounds; D020005:Propanols; C006463:allyl alcohol; D000171:Acrolein; D008049:Lipase; C431349:lipase B, Candida antarctica; D010447:Peptide Hydrolases; C012843:cinnamaldehyde