Lithium aluminum hydride reduction kinetics

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

Based on the accompanying kinetic data and an observation that lithium cation is essential in the lithium aluminum hydride reduction,5 Ashby and Boone proposed that the reduction would occur via a six-membered transition state in which the lithium cation is involved4 (Scheme 4.II). Because the aluminum in the boat transition state TS-boat is proximal to the carbonyl oxygen, the boat transition state might be of lower energy than the chairlike transition state TS-chair. Furthermore, the boatlike transition state would be a favored states as it results in direct formation of the lithium alkoxyaluminum hydride intermediate. 

The propensity for intramolecular transannular bonding could be controlled during lithium aluminum hydride reduction, the symmetric lactol 560 being obtained from 543 in good yield, 431 The indicated structure was not the product of kinetic control rather, equilibration of the hydroxyl groups was noted to occur during workup and recrystallization. When dissolved in thionyl chloride, 560 was quantitatively converted to bis-chloro ether 561 (Scheme 82). On treatment with... 

Ashby, E. C., Boone, J. R., Mechanism of Lithium Aluminum Hydride Reduction of Ketones. Kinetics of Reduction of Mesityl Phenyl Ketone, J. Am. Chem. Soc. 1976, 98, 5524 5531. 

The second synthesis of lasubine II (6) by Narasaka et al. utilizes stereoselective reduction of a /3-hydroxy ketone O-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-/3-amino alcohol (Scheme 5) 17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehyde was converted to 46 in 64% yield via alkylation with 2-bromo-l,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with O-benzylhydroxylamine hy-... 

Kinetic resolution was first observed in the partial reduction of racemic methoxysilanes by chiral reducing complexes of lithium aluminum hydride (66) (eq. [24].)... 

With less hindered hydride donors, particularly sodium borohydride and lithium aluminum hydride, cyclohexanones give predominantly the equatorial alcohol. There has been less agreement about the factors that lead to this result. The equatorial alcohols are, of course, the more stable of the two isomers. The stereochemistry of hydride reduction is determined by kinetic control, but it was argued that the relative stability of the equatorial alcohol might be reflected in the transition state and be the dominant factor when no major steric problems intervened. The term product development control was introduced to indicate this explanation of the reaction stereochemistry. A number of objections were raised to this idea, primarily on the basis of the Hammond principle. The common hydride reductions are exothermic reactions with low activation energies. The transition state should resemble starting ketone and reflect little of the structural features that are present in the product, so that it is difficult to see why product stability should determine the product composition. 

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