Synthesis of a 9-fluorenone derived beta-amino alcohol ligand depicting high catalytic activity and pronounced non-linear stereochemical effects

The Jacobsen epoxidation of 9-alkylidenefluorenes 4a (ethylidene), 4b (benz ylidene) and 4c (1-naphtylmethylene) with standard (R,R)-manganese salen ca talyst has been studied. Both conversion and enantioselectivity depend on t he 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 epo xide (S)-5a varying from 22% (-18 degrees C, CH2Cl2) to 49% (55 degrees C, MTBE). The lithium perchlorate induced ring-opening of 5a with piperidine i n MeCN affords a mixture of regioisomeric amino alcohols 3a/2a arising from the amine attack at the more substituted and less substituted carbons, res pectively. 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, c ompletely regiocontrolled synthesis of 3a has been developed involving ring -opening by the more substituted carbon of epoxide 5a with diisopropoxytita nium diazide, reduction of azidoalcohol 10a (H-2, Pd/C) and cycloalkylation (1,5-dibromopentane, K2CO3) of the amino alcohol 11a. The amino alcohol 3a exhibits a positive nonlinear stereochemical effect in its action as a lig and for the enantioselective addition of Et2Zn to benzaldehyde. The use of regiochemically pure 3a of >99% ee has been studied in the addition of Et2Z n 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 ald ehydes [8 examples, 93.1% mean ee] is also reported.