Highly enantioselective catalytic asymmetric synthesis of a (R)-sibutramin precursor.
The first highly enantioselective, catalytic asymmetric synthesis of di-des-methylsibutramine 3 is described. Dienamide 10, prepared by acetic acid anhydride quenching of the condensation product of nitrile 4 with a methallyl magnesium chloride, proved to be an excellent substrate for ruthenium-catalyzed asymmetric hydrogenation with atropisomeric diphosphine ligands. Hydrogenation with a ruthenium/(R)- MeOBiPheP catalyst at S/C = 500, gave the chiral amide (R)-9 in 98.5% ee in almost quantitative yield. After acidic amide hydrolysis the desired amine (R)-3 was obtained without erosion of enantioselectivity. It is anticipated that the overall process will be amenable to large-scale production.
BASF SE GCI/P-M 311 D-67056 Ludwigshafen am Rhein, Germany. ulrich.berens@basf.com
Ulrich
U
Berens
Andreas
A
Hafner
Oliver
O
Dosenbach
Tanja
T
Tritschler
Franz
F
Schwarzenbach
Hans-Jörg
HJ
Kirner
Christophe
C
Malan
Oanh
O
Mai-Huynh
D001067:Appetite Depressants / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry; D006865:Hydrogenation; D015394:Molecular Structure; D013237:Stereoisomerism
D001067:Appetite Depressants; D003503:Cyclobutanes; C058254:sibutramine