Synthesis of a 9-Fluorenone Derived β-Amino Alcohol Ligand Depicting High Catalytic Activity and Pronounced Non-linear Stereochemical Effects

The Jacobsen epoxidation of 9-alkylidenefluorenes 4a (ethylidene), 4b (benzylidene) and 4c (1-naphtylmethylene) with standard (R,R)-manganese salen catalyst has been studied. Both conversion and enantioselectivity depend on the steric bulk of the olefin substituent, best results being recorded with 4b (96% yield, 99% ee). The stereochemical course of the epoxidation of 4a is highly dependent on temperature and solvent, the ee of the resulting epoxide (S)-5a varying from 22% (-18°C, CH₂Cl₂) to 49% (55°C, MTBE). The lithium perchlorate induced ring-opening of 5a with piperidine in MeCN affords a mixture of regioisomeric amino alcohols 3a/2a arising from the amine attack at the more substituted and less substituted carbons, respectively. The 3a/2a ratio can be modulated by the LiClO₄ concentration and the reaction temperature, and varies from 44 : 56 to 91 : 9. An independent, completely regio-controlled synthesis of 3a has been developed involving ring-opening by the more substituted carbon of epoxide 5a with diisopropoxytitanium diazide, reduction of azidoalcohol 10a (H₂, Pd/C) and cycloalkylation (1,5-dibromopentane, K₂CO₃) of the amine alcohol 11a. The amino alcohol 3a exhibits a positive nonlinear stereochemical effect in its action as a ligand for the enantioselective addition of Et₂Zn to benzaldehyde. The use of regiochemically pure 3a of > 99% ee has been studied in the addition of Et₂Zn to a representative family of aldehydes [19 examples, 93.6% mean ee]. The use of the directly available 9 : 1 mixture of 3a and 2a derived from 46-47% ee 5a as a ligand system for the enantioselective addition of Et₂Zn to aldehydes [8 examples, 93.1% mean ee] is also reported.

addition reactions - epoxidations - amino alcohols - asymmetric catalysis - ligands