Alpine borane, enantioselective reductions

Enantioselective reduction is not possible for aldehydes, since the products are primary alcohols in which the reduced carbon is not chiral, but deuterated aldehydes RCDO give a chiral product, and these have been reduced enantioselectively with B-(3-pinanyl)-9-borabicyclo[3.3.1]nonane (Alpine-Borane) with almost complete optical purity. ... 

The enantioselective reduction of 3-butyn-2-one (7) is achieved in 82 % ee by use of the Eapine-Borane 22.9 Application of the commercial available Alpine Borane leads to a lower enantio-selectivity (77 % ee). The mechanism of this reduction is explained in Chapter 13. 

Figure 3.21 shows reaction equations and the energy relationships of the hydrobo-ration of enantiomerically pure a-pinene with 9-BBN. The reagent approaches only the side of the C=C double bond that lies opposite the isopropylidene bridge. The addition is thus completely diastereoselective. Moreover, the trialkylborane obtained is a pure enantiomer. It is used as Alpine-Borane for the enantioselective reduction of carbonyl compounds (Section 8.4). 

Alpine-Borane,prepared by hydroborationofa-pinenewith9-borabicyclo[3.3. Ijnonane (9-BBN), reduces aldehydes, a-keto esters and acetylenic ketones with excellent enantioselectivity. The reduction proceeds via a cyclic process similar to the MPV reaction. 

Midland Alpine borane reduction Enantioselective reduction of ketones using Alpine borane. 288... 

To circumvent the problem of competitive dehydroboration with ketones, the Alpine-borane reductions can be conducted in neat (excess) reagent [57] or at high pressure (6000 atm, [58]). Experiments done in neat reagent take several days to go to completion, and afford enantioselectivities of 70-98% [57. At pressures of 6000 atmospheres, the reactions are faster and dehydroboration is completely suppressed. Ketones are reduced with slightly higher enantioselectivities (75-100% es) under these conditions [58]. 

The Midland reduction is the enantioselective reduction of a ketone (It to an optically active alcohol (2) using the commercially available reagent alpine borane (3). ... 

Asymmetric reduction of ketones. Both Alpine-Borane and B>chlorodiisopino-campheylborane (IpcaBCl) have one main defect for asymmetric reduction of prochiral ketones they show little enantioselectivity in reduction of dialkyl ketones in which the alkyl groups are similar in size. This problem is now solved by reductions with Eap2BCI (1). Thus acetylcyclohexane is reduced by 1 in 97% ee and isopropyl methyl ketone is reduced in 95% ee (65% yield). 

Reduction of acetylenic ketones, RC=CCR Alpine-Borane can effect this reduction in high enantioselectivity, but this borane is very sensitive to steric effects. Thus it fails to reduce a carbonyl group adjacent to a t-butyl group. In contrast, asymmetric reduction of alkyl aryl ketones with 1 is increased by a hindered alkyl group. The same effect obtains in reduction of actylenic ketones (2). Thus as the steric bulk of R increases, the enantioselectivity also increases. 

The use of elevated pressures (2,000-6,000 atm.) accelerates asym. reduction of prochiral ketones with B-3-pinanyl-9-borabicyclo[3.3.1]nonane while suppressing competing dehydroboration-reduction which erodes enantioselectivity at atm. pressure. E Neat Alpine-Borane at 0° treated with 3-acetylpyridine via a syringe under Nj, stirred for 20 min at room temp., the mixture [in a capped syringe] placed in a high-pressure cell, pressurized to 6,000 atm. for 1.5 days, and worked up by the standard oxidative procedure - (S)-methyl(3-pyridyl)carbinol. Y 67% (100% e.e. ... 

Hydroxy-esters. - Once again, most contributions to this area involve the synthesis of chiral hydroxy-esters. Almost complete enantioselectivity is achieved in the reduction of a-keto-esters to a-hydroxy-esters using Alpine-Borane (B-(3-pinanyl)-9-BBN) derived from either (+)- or (-)-a-pinene when the reactions are carried out at relatively high concentrations (>2M). Many other types of prochiral ketones are also reduced with excellent asymmetric inductions although 3-keto-esters may not be particularly suitable substrates as ethyl acetoacetate is reduced to ethyl 3-hydroxybutanoate with an enantiomeric excess of only... 

Consequently, a chiral site reinforces or diminish enantioselectivity as well as influence the rate of asymmetric reduction of a-chiral alkynyl ketones with Alpine-Borane. This type of influence of an asymmetric induction has not been observed in the reduction of p-chiral alkynyl ketones [14,20]. 

Figure 14.10 Explanation for eroded enantioselectivity in the reduction of ketones with Alpine-Borane. ...

Another approach in the search for useful chiral reducing agents has been the derivatization of borane and boron hydrides [110, 111, 114]. Some of the most successful chiral reagents based on boron are those derived from the hydroboration of a-pinene, which is conveniently available in both enantiomeric forms (Scheme 2.22). Midland reported that the hydroboration product of a-pinene with 9-BBN, a reagent that subsequently came to be known as Alpine-Borane (179), is superb in the enantioselective reduction of aiyl alkynyl ketones [124]. He showcased the use of Alpine-Borane in the context of an enantioselective synthesis of Prelog-Djerassi lactone 181... 

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