Asymmetric reduction chiral boranes

Boranes have opened the door to asymmetric reduction of carbonyl compounds. The first attempt at modifying borane with a chiral ligand was reported by Fiaud and Kagan,75 who used amphetamine borane and desoxyephedrine borane to reduce acetophenone. The ee of the 1-phenyl ethanol obtained was quite low (<5%). A more successful borane-derived reagent, oxazaborolidine, was introduced by Hirao et al.76 in 1981 and was further improved by Itsuno and Corey.77 Today, this system can provide high stereoselectivity in the asymmetric reduction of carbonyl compounds, including alkyl ketones. 

Scheme 7-26. Asymmetric synthesis of the chiral co-side chain via chiral borane reduction.

The synthesis of chiral liquid-crystalline allenes was reported by Tschierske and co-workers (Scheme 4.10) [14]. An asymmetric reduction of 41 with Alpine borane was a key step to an enantioenriched allene 44. After removal of the silyl group, the allenic alcohol was etherified by the Mitsunobu method to give 45, the first liquid-crystalline allene derivatives. 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

High stereoselectivities (94-100 %) are attained in the reduction of aromatic ketones by use of a new chiral borane complex with (S)-2-amino-3-methyl-l,l-diphenylbutan-l-ol,(S-68) readily prepared in two steps from (S)-valine, in an experimentally convenient procedure961. (S)-Valine methyl ester hydrochloride was converted with excess of phenylmagnesium bromide into (S-68). The same treatment of (R)-valine gave (R-68). In a typical asymmetric reduction the reagent, prepared from (S-68) and borane, and the ketone (69) in tetrahydrofuran were kept at 30 °C for some hours. The corresponding alcohols were obtained in high optical purity. (S-68) could be recovered to more than 80% without racemization 96). 

Asymmetric reduction of a,f -acetylenic ketones. This borane can be used to reduce 1-deulerio aldehydes to chiral (S)-l-deulerio primary alcohols in 90% optical yields. It also reduces a,/ -acctylcnic ketones to (R)-propargylic alcohols with enantiomeric purity of 73-100%. The ee value is increased by an increase in the size of the group attached to the carbonyl group. The value is also higher in reductions of terminal ynones. Alcohols of the opposite configuration can be obtained with the reagent prepared from (— )-a-pinene. 

The steric bulk of the silyl groups in acylsilanes influences their asymmetric reduction to give chiral secondary alcohols by borane complexed with )-2-amino-3-... 

An asymmetric synthesis of 3,4,5-trisubstituted-tetrahydro-l-benzazepines has been reported based on a type a ring construction process mediated by triethylaluminium with a chiral amino ester followed by lactam reduction with borane <2006OL2667>. Dynamic thermodynamic resolution in a lithiation-substitution sequence was integral to the preparation of the amino ester. An acid-catalyzed ring construction approach to the asymmetric synthesis of 4,5,6-trisubstituted- and 3,4,5,6-tetrasubstituted azepanes based on chiral acyclic precursors has also been described <2006JA2178>. 

A catalytic asymmetric in situ reduction of N-H imines has been achieved in a sequence in which trifluoroacetophenones, ArCOCF3, are first converted to silylimines [using LiN(SiMe3)2], and then on to give trifluoromethylated amine salts, Ar-C(CF3)-NH2.HC1, in good to excellent yield and ee.5s The intermediate N-H imines can be isolated via methanolysis of the N-Si bond, while the enantioselective reduction can be carried out using a chiral borane auxiliary. 

While chiral catalysts containing N-P=0 moieties have been increasingly studied in borane-mediated asymmetric reduction of ketones, a study of a range of such species (e.g. 81) indicates that the configuration at phosphorus plays little or no role in determining enantioselectivity, and indeed the stereochemistry at the phosphorus centre may be scrambled under the reaction conditions.304... 

The asymmetric reduction of ketones by borane catalyzed by oxazaborolidines has been widely studied since the beginning of the 1980s. Despite the use of borane complexes, which are hazardous chemicals, this reaction is an excellent tool to introduce the chirality in a synthesis and has demonstrated its usefulness in industrial preparation of chiral pharmaceutical intermediates. As a result of its performance, versatility, predictability, and scale up features, this method is particularly suitable for the rapid preparation of quantities of complex chiral molecules for clinical trials. 

A chiral lanthanoid complex, which was prepared similarly to La-(/ )-17,7 23 is an effective catalyst for asymmetric reduction of ketones.102 With 10 mol % of the catalyst, borane reduction of ketones proceeds very smoothly to give alcohols in up to 62% ee (Figure 48). 

The use of chiral oxazaborolidines as catalysts for the enantioselective addition of alkynylboranes to aldehydes took place in a manner analogous to the asymmetric reduction of ketones with boranes mediated by proline-derived oxazaborolidines (Equation (127)).587 Addition of alkynylboranes to A-aziridinylimines provided a convenient method to prepare allenes from carbonyl compounds (Equation (128)).5... 

The CBS reduction has also proven to be an efficient method for asymmetric reduction of a,ft-unsaturated enones14 and ynones15 (Scheme 4.31). The asymmetric reduction of alkynyl ketones affords propargylic alcohols 30 with high levels of enantioselectivity and in moderate to good yields. Optimized reaction conditions for the reduction are the use of THF at — 30° C, 2 equivalents of chiral oxazaborolidine 28b, and 5 equivalents of borane methyl sulfide complex. 

Reduction of C=0 and C=N Bonds. Asymmetric reductions of prochiral ketones (19) to the corresponding chiral alcohols (20) using (S)-proline-modified borohydride reagents as the reductant have been published. The borane reductions of ketones (19) employing (S)-proline as chiral mediator proceeds with enantiomeric... 

The (S)-prolinate-borane complex (5)-(22) reduces ketones to the corresponding alcohols with optical yields up to 50%. The asymmetric reduction of cyclic imines (24) with chiral sodium triacyloxyborohydride (S)-(23) was utilized to prepare optically active alkaloids (25) with optical yields up to 86% (eq 9). ... 

Asymmetric Reduction with Chirally Modified Boranes and Alanes 170... 

Asymmetric Reduction with Chirally Modifled Boranes and Alanes... 

Asymmetric reduction of or y-functionalized alkyl aryl ketones provides a wide variety of chiral amino alcohols. Commercial -chloropropiophenone is reduced with borane-tetrahydrofuran adduct catalyzed by oxazaborolidine 45 to provide the chlorohydrin in over 99 % yield with 94 % ee. The resulting alcohol is a key intermediate for synthesis of the R form of fluoxetine (Prozac ), a serotonin-uptake inhibitor [53]. Using hydrogenation processes the functionalized amino ketones are converted directly into the respective products [8, 43e],... 

Hirao, A., Itsuno, S., Nakahama, S., Yamazaki, N. Asymmetric reduction of aromatic ketones with chiral alkoxyamine-borane complexes. J. Chem. Soc., Chem. Commun. 1981, 315-317. 

Chiral borane catalyst 47g, prepared from N-losyl-(a.S, /j R)-/i-melhyltryptophari and (p-chlorophenyl)dibromoborane, is fairly effective in asymmetric aldol-type reaction of 1,3-dioxolanes bearing an aryl or vinyl group at fhe 2-position (Scheme 10.45) [125]. The ring-cleavage products can be converted into free aldols without epimerization by iodination and subsequent reduction. The chiral borane-promoted reaction wifh 48 is very valuable for asymmetric desymmetrization of symmetric 1,3-dioxolanes and 1,3-dioxanes leading to mono protected 1,2- and 1,3-diols, respectively [126]. 

Another method of asymmetric reduction of unsymmetrical dialkylketones is to use chiral borane 3.87 [IT2, NNl, S3, S4] (Figure 3.28). As shown by Masamune and co-workers, asymmetric induction occurs by coordination of the carbonyl group of the ketone to mesylate 3.88, which is present in catalytic amounts. This is followed by hydride transfer in such a fashion that steric interactions are minimized (Figure 3.28). However, the chiral reducing agent has to be used in stoichiometric amounts. 

Asymmetric reduction of ketoxime O-alkylethers to chiral primary amines can be carried out with a high enantiomeric excess by borane or better by NaBH4-ZrCl4 in THF in the presence of a chiral amino alcohol [IS2, WM2, ZHl]. 

Valinol 27 and phenylalaninol 29 are used to make the Evans chiral auxiliaries used in asymmetric aldol reactions (chapter 27) and Evans prefers reduction with borane itself as its complex with Me2S. The phenylalanine based auxiliary 30 is generally preferred as the compounds are more likely to be crystalline and can easily be made11 on a 150 g scale. 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

Asymmetric reductions of saturated and unsaturated carbonyl compounds are performed either with alkoxyaluminum hydrides or alkoxyboron hydrides bearing chiral substituents, with chiral boranes, or with achiral boranes in the presence of stoichiometric or catalytic amounts of oxazaborolidines [602, 604, 611] (see Chapter 2). The most efficient chiral alkoxyaluminum hydrides [87, 566] are generated in situ from solutions ofLiAfflU by addition of (17 ,23)-A -methylepkedrine... 

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