Chiral borohydride reagents

E. Amination of Alkenes with Chiral Borohydride Reagents. 117... 

The reduction of an unsymmetrical ketone creates a new stereo center. Because of the importance of hydroxy groups both in synthesis and in relation to the properties of molecules, including biological activity, there has been a great deal of effort directed toward enantioselective reduction of ketones. One approach is to use chiral borohydride reagents.92 Boranes derived from chiral alkenes can be converted to borohydrides, and there has been much study of the enantioselectivity of these reagents. Several of the reagents are commercially available. 

A suspension of sodium borohydride is essentially inert to chiral amino alcohols and is unable to reduce ketoxime O-alkyl ethers. On the other hand, when combined with a Lewis acid (e.g., ZrCb), sodium borohydride reacts with chiral amino alcohols with evolution of hydrogen to form a chiral borohydride reagent. This chirally modified borohydride has the ability to reduce the C —N double bond of ketone O-alkyl ethers to give chiral primary amines in 78-95% yield with 43-90% ee34. 

Full details have been published on the reduction of imines to optically active amines with chiral borohydride reagents. The homogeneous hydrogenation of azo-, imino-, and nitro-groups to amine derivatives is reported a rhodium salt-sodium borohydride system is used. 

Organocatalytic asymmetric carbonyl reductions have been achieved with boranes in the presence of oxazaborolidine and phosphorus-based catalysts (Section 11.1), with borohydride reagents in the presence of phase-transfer catalysts (Section 11.2), and with hydrosilanes in the presence of chiral nucleophilic activators (Section 11.3). 

More effective is the chiral borohydride analogue developed by Corey, Bakshi, and Shibita. It is based upon a stable boron heterocycle made from an amino alcohol derived from proline, and is known as the CBS reagent after its developers. 

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... 

Among the chiral borohydrides, ate complexes generated from a-pinene, such as Alpine-hydride 3.64 and related reagents, reduce 2-octanone or acetylcyclohexane... 

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). 

Stereoselective reduction of ketones to alcohols by means of borohydride reagents (Li s-Bu3BH) or f-BuCIBR for formation of chiral alcohols. 

The earliest use of a borohydride reagent for the enantioselective preparation of a chiral amine by amination of the corresponding alkene employed diisopinocampheylborane (50) prepared from (- -)-a-pmene . Thus c -2-butene [(Z)-51] was treated with 50 in diglyme to form an organoborane intermediate which, on treatment with hydroxylamine-0-sulphonic acid (52) in diglyme, gave (R)-2-aminobutane [(/f)-53], which after correction for the low enantiomeric excess of the (-l-)-a-pinene (68%) used to form 50, had an ee of 76%, but in rather low chemical yield (13%). ... 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

Reduction of 19-nortestosterone (23) with sodium borohydride leads to a mixture of isomers consisting largely of the 3p-alcohol (24) the lack of stereospecificity can be traced back to the relative remoteness of that 3-position from chiral centers which could direct the incoming reagent. Acylation of diol 24 with acetic anhydride in the presence of... 

Transfer hydrogenation is a mild and efficient means of reducing aldehydes, and can be advantageous over other reagents such as sodium borohydride. Clearly, the product is a primary alcohol and therefore not chiral, but a chiral center might be alpha to the aldehyde, in which case a resolution can be effected. Indeed, under the appropriate conditions the chiral center can be race-mized and a dynamic kinetic resolution effected [57]. 

A review describing the major advances in the field of asymmetric reduction of achiral ketones using borohydrides, exemplified by oxazaborolidines and /9-chlorodiisopino- camphenylborane, has appeared. Use of sodium borohydride in combination with chiral Lewis acids has been discussed.298 The usefulness of sodium triacetoxyboro-hydride in the reductive amination of aldehydes and ketones has been reviewed. The wide scope of the reagent, its diverse and numerous applications, and high tolerance for many functional groups have been discussed.299 The preparation, properties, and synthetic application of lithium aminoborohydrides (LABs) have been reviewed. 

---