Chiral hydride

Das aus (-)-Menthol hergestellte chirale Hydrid liefert in erster Linie mit zweizahnigen Substraten [fi-Amino- ketone, En-(2)-in-(4)-ole (s.S. 74)] gute optische Ausbeuten1. Als chirale vie. Diole werden Zucker-2,1 und Terpen-Derivate wie cis- und rrans-Pinandiol-(2,3)4 verwendet. Von den Zucker-Derivaten hat sich der Kom-plex mit 3-0-Benzyl-l,2-0-cyclohexyliden-a-D-glucofuranose am besten bewahrt2,5 (Vorschrift S. 74). 

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... 

A chiral hydride complex, tentatively assumed to be 86, prepared by partially reacting LAH with (- )-N-methylephedrine (1 equivalent) and /V-ethylaniline (2 equivalents) was found to reduce 2-acetyl-5,8-dimethoxy-3,4-dihydronaphtha-lene (87) quantitatively to the (- )-carbinol (88) with 92% e.e. (94,95). Carbinol 88, which was obtained optically pure by recrystallization, could be converted to (/ )-(-)-2-acetyl-5,8-dimethoxy-l,2,3,4-tetrahydro-2-naphthol (89). The lat-... 

Brinkmeyer and Kapoor (101) reported that the chiral hydride complex formed from LAH and (+ )-90 (Darvon alcohol) gave high enantiomeric ratios of chiral propargylic carbinols in the reduction of acetylenic ketones (Table 10, entries... 

The first report in this regard described a method for direct formation of the desired optically active (S)-alcohol 32a, via enantioselective reduction with a chiral amine complex of lithium aluminum hydride (Scheme 14.9). Therefore, the necessary chiral hydride complex 38 was preformed in toluene at low temperature from chiral amino alcohol 37. The resulting hydride solution was then immediately combined with ketone 31 to afford the desired (S)-alcohol 32a in excellent yield and enantiomeric excess. In addition to providing a more efficient route to the desired drug molecule, this work also led to the establishment of the absolute configuration of duloxetine (3) as S). 

The polarized carbon-nitrogen double bond can also be reduced enantiospecifically using chiral hydrides (7lJCS(C)2560). Although only modest asymmetric inductions were observed, this method holds promise for the synthesis of chiral piperidines (equation 54). 

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). 

Figure 13. Reductions of alkynones with some chiral hydrides.

The use of a chiral hydride complex has been central to the asymmetric reduction of ketones such as acetophenone (58). A number of excellent chiral metal hydride complexes have been introduced by many researchers, including Noyori (59,60), Meyers (61), Mukaiyama (62,63), Terashima (64,65), and others (58). It is apparent that there is a close similarity in structure between acetophenone and the proposed intermediate in enamide photocyclization, therefore suggesting the possibility of undergoing photocyclization in an asymmetric manner. 

After a metal hydride complex was prepared from LAH and quinine (1 1), irradiation of a mixture of the resulting solution containing the above chiral hydride agent and the enamide (133) led to the formation of two optically active lactams 158 [6%, [a]D —63° (c = 0.48, CHC13)] and 155 [ 13%, [a]D — 102° (c = 0.44, CHC13)] with 37% optical purity. Reduction of the lactam 155 with LAH furnished (—)-xylopinine (20) in 48% chemical yield. 

Asymmetric reduction of cyclic ketones. Prochiral cyclic ketones arc reduced to (R)-alcohols in 75-96% ee by a chiral hydride obtained by refluxing a mixture of lithium aluminum hydride, (— )-N-methylephedrine (I equiv.), and 2-ethylaminopyridine (2 cquiv.) in ether for 3 hours. Reduction of prochiral acychc ketones with this hydride also results in (R)-alcohols, but only in moderate yield. 

The enantioselective synthesis of optically active secondary amines via asymmetric reduction of prochiral ketimines was studied by screening various chiral hydrides. In this case, K-glucoride gave only disappointing results and was inferior to other reagents. Better results were obtained in the asymmetric reduction of prochiral Af-diphenylphosphinylimines to chiral N-(diphenylphosphinyl)amines (eq 1), which can then be readily converted into optically active primary amines. For this reaction the stereochemical course depends dramatically on the relative bulkiness of the groups R and R. The reaction conditions for reduction of C=N double bonds are the same as used for ketones, but the high reactivity of diphenylphosphinylimines dramatically reduces the reaction time. 

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 . ... 

Asymmetric reductions. These reactions have rapidly developed since the First Edition. In addition to chiral hydrides, other strategies for asymmetric reduction include the use of reagents such as chiral chloroboranes or hydrogenation in the presence of catalysts bearing chiral ligands [S3]. 

This complex chiral hydride 12 reduces acetylenic ketones such as 13 with reasonable selectivity.1 The other enantiomer of 14 comes from reduction of 13 with the enantiomeric reagent derived from NOVRAD. Note that the absolute sense of the induction in the reduction of 13 is the same with 12 and with the Alpine borane from (+)-a-pinene, below. 

Scheme 47 shows a case 2 example for double stereodifferentiation, the problem being to reduce enone 47-1 preferentially to alcohol 47-2 or 47-3 [110]. The substrate control (DIBAH or L-selectride) is essentially zero, so that the chiral hydride donor must do the job. It can be seen that BINAL-H [ 111 ] is ineffective whereas diborane plus the CBS catalyst [112] shows a very pronounced reagent control so that either one of 47-2 and 47-3 may be generated selectively for the formation of 47-3 the reagent control is much higher than for 47-2, which is surprising in view of the low substrate control of the process. 

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. 

Table 6. Asymmetric Reduction of Prostereogenic Diphenylphosphinyl Imines with Chiral Hydride Reagents46...

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, ... 

Dihydropyridines (39) for use as chiral hydride-ion-transfer agents have been prepared from the chiral 3-pyridyloxazoline (38) (Scheme 27) chemical yields are good, as are the enantiomeric excesses (e.e.)/ ... 

---