Chiral hydride reagents

In an attempt to prepare alkylamines by asymmetric reduction of imines with chiral hydride reagents, diphenylphosphinyl imines (38), prepared by reaction of ketoximes (39) with chlorodiphenylphosphine [(Cg 115)2 PCI], were reduced in the presence of a variety of chiral aluminum and boron hydride reagents43. Among the most promising reagents was BINAHL-H44 (40), a chiral hydride compound prepared by the modification of lithium... 

Reviews on chiral hydride reagents M. Nishizawa and R. Noyori, Reduction of C=X to CHXH by Chirally Modified Hydride Reagents, in B. M. Trost and I. Fleming, eds., Comprehensive Organic Synthesis, Vol. 8, Chap. 1, p. 159, Per-gamon Press, Oxford, 1991 V. K. Singh, Synthesis, 605 (1992). 

In this context, a chiral hydride reagent, BINAL-H, prepared by modification of lithium aluminum hydride with equimolar amounts of optically pure binaphthol and a simple alcohol, is extremely useful (9b, 18a, 35) Scheme 15 shows the utility of the three-component coupling synthesis. The < > side-chain unit and the hydroxycyclopentenone can be prepared with very high enantioselectivity by reduction of the corresponding enone precursors (35-38). 

Preparative Methods a IM THF solution of BH3 (3.0 mmol) was added to a THF solution of (—)-norephedrine (1.5 mmol) at —30°C and the resulting mixture was warmed to 20 °C the thus-formed chiral hydride reagent was used in situ for enan-tioselective reductions. 

Enantioselective Reductions. This chiral hydride reagent reduces aromatic ketones to the corresponding alcohols with high enantioselectivity (eq 1). ... 

Table 1 Optical Yields for Asymmetric Reduction of Typical C=X Compounds with Selected Chiral Hydride Reagents... 

Asymmetric reduction of prochiral a,p-unsaturated ketones with chiral hydride reagents derived from LiAlH4 and (5)-4-anilino- and (S)-4-(2,6-xylidino)-3-methylamino-l-butanol gives (S)- and ( )-allylic alcohols, respectively, in high chemical and optical yields (Scheme 44).2° ... 

The asymmetric reduction of prochiral ketones employing chiral hydride reagents has been the subject of extensive work, and a number of methods have been reported. 

In general, the chiral hydride reagent is generated in situ by reaction of a suitable metal hydride with chiral ligands such as alkaloids , sugar derivatives , amino alcohol chiral oxazolines tartaric acid derivatives chiral amines and chiral diols... 

Relatively high optical yields were achieved in the asymmetric reduction of acetophenone by these chiral hydride reagents however, the optimum enantiomeric excess (e.e.) achievable was 83% at that time. Two effective methods have been reported since then Thus, we initiated a study on the exploration of a new and efficient chiral ligand suitable for the asymmetric reduction of prochiral ketones, and found that a chiral hydride reagent formed in situ from LiAlHj and the chiral diamine (S)-2-(anilinomethyI)pyrrolidine la) is efficient for the reduction of acetophenone, affording (S)-l-phenylethanol in 92% e.e. . Examination of the effect of the N-substituent in the diamine la-m) on the enantioselectivity in the asymmetric reduction of acetophenone, revealed that when a phenyl or 2,6-xylyl substituent was employed, 1-phenylethanol was obtained in 95% e.e. (Table 1)... 

Other results obtained by the asymmetric reduction of various ketones, in ether, using the chiral hydride reagent prepared from LiAlH and la or lb are summarized in Table 2 . ... 

Conventional chiral hydride reagents are not very effective at forming these intermediates in the synthesis of adrenergic drugs, because active hydrogens are present on the starting ketones and the latter is unstable under basic conditions. 

Asymmetric syntheses based on chiral diamines. Optically active secondary alcohols are obtained by reduction of prochiral ketones with the chiral hydride reagent 1 prepared from lithium aluminium hydride and ( )-2-(N-substituted aminomethyl)-... 

Asymmetric reduction of prochiral ketones, A chiral hydride reagent formed by treating the chiral diamine 1 with LiAlH was postulated to assume a cis-fused five-membered bicyclic ring structure Highly enantiomerically pure alcohols were obtained when the reaction was carried out in ether at low temperature (-100 C) by employing diamines 1 having 2,6-xylyl or phenyl substituents on nitrogen, ... 

Now we analyze what happens when optically pure chiral hydride reagent is used. 

Full details have been published of the reduction of aryl alkyl ketones with a chiral hydride reagent prepared from the diamine (23), available from (5)-proline, and L1A1H4 (Scheme 10). Enantiomeric excesses of (S)-carbinols in the range 50—92% are reported. The related chiral pyrrolidine ligand (24) has been... 

BINAL-H (Noyori) Noyori has devised a chiral hydride reagent and its enantiomer by the modification of lithium aluminum hydride with equimolar amounts of either... 

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