Efficient asymmetric alkylation reactions have been a longsought goal in organic synthesis. The recent literature1 reports elegant three-step sequences to achieve high enantiomeric excesses (ee's); however, these procedures are complex and require the use of stoichiometric quantities of chiral auxiliaries. Chiral phasetransfer-mediated alkylations offer a potentially simple, one-step solution to this problem. The first reports2 of such using cyclic i8-keto esters as substrates and ephedrinium halides as catalysts claimed ee's of only 15%. These results have subsequently been disputed.3
The phase-transfer methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone by MeCl in 50% NaOH/toluene using substituted N-benzylcinchoninium halides has provided the methylated indanone 2 in ee's up to 94%. The effects of solvent, alkylating agent, temperature, and catalyst were investigated: nonpolar solvents gave higher ee's than polar solvents; MeCl gave a higher ee than did MeBr and Mel; and temperature had little effect on the reaction. A Hammett plot of log ee/ee0 vs. a for the N-benzylcinchoninium halide catalysts gave a reaction constant p of 0.21 with an ee range of 60% to 94%, demonstrating that substituents with increasing electronwithdrawing power improve catalyst selectivity. A kinetic and mechanistic study of the reaction has revealed several unusual features. In 50% NaOH/toluene these include the following: (1) the indanone 1 is deprotonated at the interface to form the sodium enolate as a separate solid phase; (2) the substituted IV-benzylcinchoninium catalysts are extracted into the organic layer as dimers; and (3) the kinetic order in MeCl is 0.7 and in catalyst is 0.55. In 30% NaOH/toluene the following obtain: (1) no solid enolate is formed; (2) an order in catalyst of 0.5 was found for the chiral methylation pathway, while an order of 1.0 was found for the racemic methylation pathway.
Described herein is an efficient asymmetric synthesis of the potent antiarrhthymia agent The route is convergent and is highlighted by two stereoselective reactions. A rutheniumcatalyzed, enantioselective hydrogenation of an enamide was developed for the preparation of the key amine intermediate. Oxazaborolidine-mediated ketone reduction was utilized to establish the alcohol stereochemistry. Optimization of this chemistry led to an IPA modified reduction method which provides enhanced stereoselectivity.
An improved and efficient bromination of 3,5-bis(trifluoromethyl)benzene was developed. A safe and reliable preparation of the potentially explosive 3,5-bis(trifluoromethyl)phenyl Grignard and 3-trifluoromethylphenyl Grignard reagents, from the precursor bromides, is described. Reaction System Screening Tool (RSST) and Differential Thermal Analysis (DTA) studies suggest these trifluoromethylphenyl Grignard reagents can detonate on loss of solvent contact or upon moderate heating. When prepared and handled according to the methods described herein, these Grignard reagents can be safely prepared and carried on to advanced intermediates.
An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported.The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific intramolecular alkylation of the ester enolate by the phosphate of the alcohol, resulting in the desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers that set the chirality of the molecule were both induced from cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol to the carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleachcatalyzed oxidation by sodium chlorite (NaClO 2 ) or chromium oxide catalyzed oxidation by periodic acid. The overall process has been run successfully to make multikilograms of the drug in high purity.
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