Ketones, reaction with Alpine borane

Similar to the reduction of aldehydes, reduction of ketones with Alpine-Borane also involves two competing reaction pathways, a bimolecular -hydride elimination process (cyclic mechanism) affording optically active product [6], and a dehydroboration-reduction sequence yielding racemic product [2] (Scheme 26.1). 

Ketone Reagent equiv Reaction time (days) Percentage ee Percentage ee with Alpine-Borane... 

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. 

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]. 

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... 

The reaction is extended [3] to the reduction of a-ketoesters, another class of ketones, possessing powerful electron-withdrawing ester group. The reduction of a-ketoesters with 40% excess of neat Alpine-Borane proceeds rapidly at 25 °C (Eq. 26.4 Table 26.9) [3,4b]. 

Midland and coworkers [Ic] have reported that reduction of alkynyl ketones affords excellent chemical and optical yields that approached 100% in many cases. In general, under Midland s reaction condition, for example, 4-phenyl-3-butyn-2-one takes 48 h for complete reduction at 25 °C with 100% excess of Alpine-Borane. On the other hand Brown has reported [3] the reduction of ketones in 8-12 h, using a 40% excess of the neat reagent (Scheme 26.2 Table 26.12), and products show a substantially higher optical rotation as compared to reported by Midland [Ic]. 

Using neat (S)-Alpine-Borane the reaction is 67% complete in 92 h, and 22-(S)- is obtained in a 7 1 ratio. It is thus apparent that for (R)-Alpine-Borane the double asymmetric inductions are working together, whereas in (S)-Alpine-Bo-rane they are working in opposite direction. A similar change in selectivities is observed in the asymmetric reduction of these acetylenic ketones using (+)-and (-)-A-methylephedrine/LAH [18]. The faster rate of reduction with (R)-... 

The reagent Eapine-Borane, prepared (Eq. 26.15) from (-)-2-ethylapopinene by hydroboration with 9-BBN have been studied for its reaction with representative ketones and is found to react at faster rate than NB-Enantrane, but at slightly slower rate than Alpine-Borane (Table 26.15) [1]. 

As can be seen from the diagram, the reaction probably proceeds by P-hydride transfer via a boat-shaped transition state in which the less bulky substituent buttresses the methyl group of the pinene, accounting for the high selectivities seen with ketones containing the slender ethynyl group. Note that the pinene is regenerated and can be reconverted to Alpine borane as shown. In this way (+)-a-pinene can be seen merely as an asymmetric carrier for the hydride of 9-BBN. 

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