Enantioselective Reduction of Prochiral Ketones using Spiroborate Esters as Catalysts.

The asymmetric synthesis of secondary enantiopure alcohols from prochiral ketones is a key step in the preparation of a variety of pharmaceutical products.1,2 To accomplish this transformation with high enantioselectivity, new methods, such as, asymmetric transfer hydrogenation,3 metal catalyzed hydrogenations,4 enzymatic reactions5 and novel metal hydride reagents,6–9 are continuously being developed as valuable synthetic tools. Chiral boron reagents, in particular oxazaborolidines7 derived from nonracemic 1,2-aminoalcohols, are well known catalysts for the synthesis of highly enantiopure secondary alcohols. Other oxazaborolidine-like compounds have been applied for the borane reduction of prochiral ketones with good to excellent enantioselectivities.8,9 Borates and boronates have been established previously as effective chirality transfer reagents.10 Borates accessed from nonracemic 1,1′-bi-2-naphtyldiol and complexed to anilines reduce acetophenone with up to 64% ee.11 Spiroborate esters prepared from nonracemic 1,1′-bi-2-naphtylborate esters and enantiopure 1,2-aminoalcohols (or 2-aminoacids) have been found to catalytically reduce prochiral aromatic and aliphatic ketones with modest to high enantioselectivities.8b,c We recently reported the synthesis of a new class of crystalline, air- and moisture stable spiroborate esters that were examined for the reduction of acetophenone as a model substrate to obtain nonracemic 1-phenylethanol.12 Catalysts 1–3 (Scheme 1) proved to be the most valuable due to their outstanding enantioselectivity, facile synthesis, purity and convenience of handling. We present here the X-ray crystal structure of catalyst 1, a correlation study of the catalytic load of 1 with the enantio-purity of the alcohol, and the asymmetric borane reduction of representative ketones using 1–3 as catalyst. Scheme 1 The spiroborate esters 1 and 2 are readily prepared from commercially available diphenyl valinol and diphenylprolinol, respectively, according to the reported procedure.13 The 1,1,2-triphenyl ethanolamine was synthesized by established methods.14 The white crystalline spiroborate complex 1 was found to be particularly stable after being exposed to moist air for 24 h at 25 °C, as evidenced by its unchanged 11B, 1H and 13C NMR spectra. The X-ray diffraction analysis of 1 presented in Fig. 1 shows clearly the structure of the amino spiroborate complex.15 The observed B1-N1 bond distance at 1.665 (2) is comparable to the bonds of similar boron nitrogen coordinated complexes.16 Fig. 1 Crystal structure of spiroborate 1. To establish the optimal catalytic load required to achieve high enantioselectivity, the reduction of acetophenone was studied using different molar equivalents of catalyst 1 with 0.7 molar equivalents of BH3-DMS complex in THF at room temperature. As indicated in Fig. 2, 10 mol % of catalyst 1 afforded (R)-1-phenylethanol with 99% ee. Moreover, higher enantioselectivities (98% ee) were achieved with as low as 0.5 molar % of catalytic load, and even with 0.1 molar % of catalyst 1, the enantiomeric excess was high (89%). Fig. 2 Asymmetric reduction of acetophenone in the presence of catalyst 1. Spiroborates 2 and 3 were also investigated for the reduction of acetophenone obtaining (R)-1-phenylethanol with excellent chemical yield and 98% and 96% ee, respectively. In addition, catalyst 2 showed excellent enantioselectivity even with 5 molar % loading (98% ee). The reduction of representative arylakyl and aliphatic ketones were also investigated and the results are shown in Table 1.17 In general, the optical active alcohols were obtained in excellent chemical yields and outstanding enantio-purity for ketones with bulky group differentiation. Table 1 Electronic and steric effects on asymmetric reduction of aromatic and aliphatic ketones using spiroborates It was of interest to study the effect of electronic and steric factors in the reduction of halogenated acetophenones. Moreover, their enantiopure alcohols are very important intermediaries in organic synthesis. Several halogenated ketone were reduced with borane-DMS in the presence of 10 mol % of catalyst 1 providing their corresponding alcohols with high enantiopurity (94–99% ee), except for the highly reactive 2,2,2,-trifluoroacetophenone (82% ee, entry 5), as illustrated in Table 2. Table 2 Reduction of representative halogenated aromatic ketones with spiroborate with 0.1 equiv of catalyst 1 In conclusion, a facile and efficient method for the reduction of aralky-, aliphatic- and halogenated aromatic ketones in the presence of up to 0.5 mol % catalysts 1 with outstanding enantioselectivities has been established. Catalyst 1 offer an excellent alternative for asymmetric reduction of ketones similar in enantioselectivity to those reported for the B-methyl oxazaborolidine (CBS reagent).7