Practical Enantioselective Reduction of Ketones Using Oxazaborolidine Catalysts Generated In Situ from Chiral Lactam Alcohols

Abstract

Oxazaborolidine catalyst (CBS catalyst) has been extensively used for catalytic borane reduction with a predictable absolute stereochemistry and high enantioselectivity. However, the use of isolated CBS catalyst sometimes has the drawback of low reproducibility due to the aging of the CBS catalyst during storage. Therefore, we investigated a more reliable and practical method for the reduction of a variety of ketones including challenging substrates, primary aliphatic ketones, α,β-enones, and trifluoromethyl ketones. This review surveys the developments in borane reduction using oxazaborolidine catalysts generated in situ from chiral lactam alcohols and borane.

Keywords: asymmetric synthesis; borane; enantioselective; lactam alcohol; reduction.

Figure 1

Various chiral catalysts and precatalysts.

Scheme 1

Generation of oxazaborolidine 1a in situ from 1 and borane.

Scheme 2

Generation of oxazaborolidine 1a in situ from 2 and borane.

Figure 2

¹¹B NMR shifts.

Scheme 3

Asymmetric reduction of ketones using chiral lactam alcohol 2. All reactions were carried out with 10 mol% of 2 and 1.0 equiv of BH₃ in THF at room temperature.

Figure 3

Various chiral catalysts and precatalysts.

Scheme 4

Asymmetric reduction ^a of benzylacetone using chiral lactam alcohol 2. ^a All reactions were carried out with 10 mol% of 2 and 1.2 equiv of BH₃ and ROH in THF at room temperature. ^b pK_a 9.99. ^c pK_a 10.10. ^d pK_a 9.17. ^e pK_a 9.21. ^f pK_a 8.68.

Scheme 5

Effect of temperature on enantioselectivity for the reduction of benzylacetone using 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH₃ and p-iodophenol in THF at room temperature.

Scheme 6

Asymmetric reduction of aliphatic ketones using the chiral lactam alcohol 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH₃ and p-iodophenol in THF at −20 °C.

Scheme 7

Chiral catalysts for the borane reduction of benzalacetone.

Scheme 8

Mechanism of the CBS reduction of ketones, proposed by Core et al.

Figure 4

Proposed transition state model.

Scheme 9

Asymmetric reduction of α,β-enones using 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH₃ and p-iodophenol in THF at −40 °C.

Scheme 10

Various chiral catalysts for the borane reduction of 2,2,2-trifluoroacetophenone.

Figure 5

Proposed transition state models.

Scheme 11

Asymmetric reduction of various trifluoromethyl ketones using 2. All reactions were carried out with 10 mol% of 2, 160 mol% of BF₃ and 0.8 equiv of BH₃ in CHCl₃ at room temperature. ^a Temperature, 40 °C.