Selective Reductions. 45. Asymmetric Reduction of Prochiral Ketones by Iso-2-methyl, Iso-2-ethyl-, and apopinocampheyl>-tert-butylchloroboranes. Evidence for a Major Influence of the Steric Requirements of the 2-Substituent on the Efficiency of Asymmetric Redu.

Article abstract of DOI:10.1021/jo00280a013

The asymmetric reduction of prochiral aliphatic ketones with chiral organylboranes has not yet given desirable results although considerable success has been achieved for the reduction of prochiral aralkyl and related ketones.We have now developed more efficient chiral reducing agents for aliphatic ketones following a strategy based on a tentative hypothesis that the steric requirements of the substituent at the 2-position of apopinene may be a major factor in achieving successful asymmetric reduction.The adduct of nopol benzyl ether and tert-butylchloroborane was prepared and characterized.This compound reduces prochiral ketones to the product alcohols in very high enantiomeric excess.For example, 3-methyl-2-butanone is reduced, in THF, 0.5 M, at room temperature, to the R alcohol in 89percent ee.Cyclohexyl methyl ketone is reduced to the alcohol in 96percent ee.Cyclohexyl ethyl ketone, cyclohexyl n-propyl ketone, and cyclopentyl methyl ketone are all reduced to the corresponding R alcohols in 85percent, 83percent, and 81percent ee, respectively. 2-Cyclohexen-1-one is reduced to (S)-2-cyclohexen-1-ol in 88percent ee.Finally, 2-octanone is converted to (R)-2-octanol in 40percent ee.Unfortunately, these reductions are very slow, requiring 2 to 14 days, or more.The slowness of the reaction is attributed to the coordination of the ether oxygen to the boron atom.The higher optical yields achieved over those realized previously with the related isopinocampheyl-tert-butylchloroborane are attributed to the greater steric requirement of the (benzyloxy)ethyl group as compared to the methyl group of the α-pinene unit.On this basis, the corresponding derivative, (iso-2-ethylapopinocampheyl)-tert-butylchloroborane was synthesized in the hope that the rates would be higher, because of the absence of a coordinating ether linkage, while the optical yields would be comparable, because of the larger steric requirements of the 2-ethyl substituent.Indeed, the rates are considerably faster and the enantiomeric excesses achieved are almost comparable. 3-Methyl-2-butanone is reduced, in THF, 0.5 M, at room temperature, in 16 h to an alcohol of 84percent ee.Cyclohexyl methyl ketone, cyclohexyl ethyl ketone, cyclohexyl n-propyl ketone, and cyclopentyl methyl ketone are all reduced to the corresponding R alcohols in 90percent, 73percent, 73percent, and 72percent ee, respectively. 2-Octanone is reduced to (R)-2-octanol in 33percent ee.For comparison, the reductions of the same ketones with Ipc-t-BuBCl at room temperature and Ipc2BCl at -25 deg C were carried out. ^dIpc-t-BuBCl reduces (25 deg C) 3-methyl-2-butanone, cyclohexyl methyl ketone, cyclohexyl ethyl ketone, cyclohexyl n-propyl ketone, and cyclopentyl methyl ketone to the corresponding S alcohols in 37percent, 48percent, 53percent, 50percent, and 26percent ee, respectively, whereas ^dIpc2BCl reduces (-25 deg C) the same ketones to the corresponding S alcohols in 32percent, 26percent, 23percent, 38percent, and 45percent ee, respectively.This study supports the conclusion that the chiral outcome in reduction with reagents derived from pinanyl derivatives is influenced by the steric requirements of the group at position 2 of ap.