Chiral borohydrides

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. 

The boron atom dominates the reactivity of the boracyclic compounds because of its inherent Lewis acidity. Consequently, there have been very few reports on the reactivity of substituents attached to the ring carbon atoms in the five-membered boronated cyclic systems. Singaram and co-workers developed a novel catalyst 31 based on dicarboxylic acid derivative of 1,3,2-dioxaborolane for the asymmetric reduction of prochiral ketones 32. This catalyst reduces a wide variety of ketones enantioselectively in the presence of a co-reductant such as LiBH4. The mechanism involves the coordination of ketone 32 with the chiral boronate 31 and the conjugation of borohydride with carboxylic acid to furnish the chiral borohydride complex 34. Subsequent transfer of hydride from the least hindered face of the ketone yields the corresponding alcohol 35 in high ee (Scheme 3) <20060PD949>. 

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. 

According to these, for purely aliphatic ketones the highest enantioselectivities are achieved for methyl ketones with a second, branched-chained alkyl substituent (84-94% ee). The value of 75 % ee obtained with the straight-chain hexan-2-one is, to the best of our knowledge, in any case better than anything achieved to date with nonenzymatic systems and homogeneous catalysis. Higher selectivities have been reported for reductions with stoichiometric amounts of chiral borohydrides (e.g. 80 % ee for the reduction of octan-2-one) [20]. 

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). 

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. 

Chiral borohydrides. Transfer of [LiH] to chiral organoboranes leads to the chiral reducing agents. 

By resolution of the benzyltetrahydroisoquinoline or preferably asymmetric reduction with a chiral borohydride of the precursor the chiral members of the series should be accessible bearing in mind the the efficient transformations already acomplished (ref. 167). In the light of potential shortages (ref. 186) and avoidance of dependence upon the sole natural commercial sourse, this synthetic strategy represents a practical approach to the medical opiates. 

One of the more widely used solutions to this challenge is the chiral borohydride analogue invented by Itsuno in Japan and developed by Corey, Bakshi, and Shibata. It is based on a stable boron heterocycie made from an amino alcohol derived from proline (see the box below for the synthesis), and is known as the CBS catalyst after its developers. The active reducing agent is generated when the heterocycie forms a complex with borane. Only catalytic amounts (usually about 10%) of the boron heterocycie are needed because borane is sufficiently reactive to reduce ketones only when complexed with the nitrogen atom. The rest of the borane just waits until a molecule of catalyst becomes free. 

K-Glucoride is inefficient for the reduction of prochiral unhindered aliphatic ketones. Hence, Cho and Chun [1] have synthesized various chiral borohydrides using monosaccharide units potassium 9-0-(l,2 5,6-di-0-isopropylidene-a-D-allofuranosyl)- 9-boratabicyclo[3.3.1]nonane from l,2 5,6-di-0-isopropylidene-a-D-allofuranose (DIPAF) a C-3 epimer of DIPGF potassium 9-0-(l,2 5,6-di-0-cyclohexylidene-a-D-glucofuranosyl)-9-boratabicyclo [3.3.1] nonane utilizing... 

The chiral borohydride formed from l,2 5,6-di-0-cyclohexylidene-a-D-glucofuranoside, 9-BBN, and potassium hydride gives good chiral induction in reactions with ketones reduction of acetophenone led to (/f)-methyl phenyl carbinol in 77% e.e.92 Aminoalcohols derived from D-glucose can catalyse enantioselective Michael additions of arylthiols to cyclohexenone. 3... 

Asymmetric Reductions. In a review of asymmetric syntheses via chiral organoborane intermediates. Brown has surveyed ketone-to-alcohol reductions with chiral trialkylboranes, chiral borohydrides, and mono- or di-isopinocam-pheylborane. ... 

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. 

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