Oxazaborolidines optimization

Table 11.5 Optimization of enantioselectivity as a function of borane source and temperature using aminoindanol oxazaborolidine.

The chiral reduction of phenacyl chloride (2) was run using either the methyl- or methoxy- oxazaborolidine (3) as the catalyst. After optimization of the reaction... 

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. 

R) -1 on a preparative scale. Variation of several reaction parameters such as catalyst loading, solvent, temperature, and addition order, have led to the development of an optimized procedure for this reduction. To achieve a selectivity of >90% ee, the reaction requires the use of 10 mol% of the oxazaborolidine catalyst, which is easily prepared in two steps from natural proline4 or in one step from commercially available... 

When enantiomeric excess versus temperature is plotted, all reductions show the same shape of curve. At a low temperature, lower enantiomeric excesses are obtained. When the temperature is increased, the enantiomeric excess reaches a maximum value that depends on the reducing agent and the structure of the amino alcohol, of the catalyst itself (methyl, butyl, and phenyl oxazaborolidines do not give the same result), and the substrate. As the temperature increases further, the enantiomeric excess decreases once again. This general behavior was experienced in the reduction of /j-chloro-chloroacetophenone (5), where the range of optimal reaction temperature is broad and very practical. Indeed, a very high enantiomeric excess could be obtained at 20°C (Scheme 3). 

In many stereoselective reactions, the effect of temperature on the selectivity is as expected, with better results being obtained at lower temperature. A lower tempertaure is often required to increase the selectivitty. From the practical point of view, one of the most attractive feature of this enantioselective reduction is that excellent enantioselectivity is obtained at a relatively high temperature such as room temperature. In some cases, the selectivity of the oxazaborolidine catalyzed borane reduction increases with increasing temperature until an optimal range is reached (30-50 °C) where the selectivity then begins to decrease [76]. Interpretation of this phenomena is not so easy. The amount of catalyst dimer that exists in a temperature-dependent equiUbrium with the monomeric form, might have an effect on the selectivity. 

Proline-derived oxazaborolidines 45 have shown to be effective pre-catalysts with triflic acid as an activator to generate cationic Lewis acids.18,15 The optimal proportions of 45 and triflic acid was found to be 1.2 1. Protonation of 45 produced a 1.5 1 mixture of 46 and 47 as determined by low temperature H NMR. Their interconversion at low temperature (-80 °C) is slow on the NMR timescale. However, this interconversion increases as the temperature rises and at 0 °C this becomes rapid (Tc). Phenyl or o-tolyl were determined to be the best substituents for the R group in 45. For the Ar group of 45, phenyl and 3,5-dimethylphenyl were determined to be optimal. 

An optimized procedure (in situ) for the oxazaborolidine-catalyzed reduction is disclosed. Several papers describe the access to propargylic alcohols,and it is interesting to note that strong remote steric effects are transmitted across the triple bond. ... 

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