Asymmetric transformation of ketone

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor.26 Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17).26b However, reaction time (96 h) was unsatisfactory.

Asymmetric reductive acetylation process was also applicable to acetox-yaryl ketones.27 For example, m-acetoxyacetophenone 10 was transformed to

RiOR2

R1XR2 R I

Ru OH

Lipase

AcOR

R1 R2

Scheme 6: Asymmetric reductive acetylation of ketones.

Table 17

Asymmetric reductive acetylation of ketones

calb 1

R

R'

ee (%)

Yield (%)

Ph

Me

96

81

4-MeO-Ph

Me

99

85

4-Cl-Ph

Me

97

72

1-Indanyl

99

89

a-Tetralyl

99

87

C-C6H11

Me

90

87

CH3(CH2 )4CH2

Me

91

87

PhCH2CH2

Me

72

83

(R)-1-(3-hydroxyphenyl)ethyl acetate 11 under 1 atm H2 in 95% yield. The overall reaction seems to involve simple reduction and acyl migration reaction. In fact, however, it is the result of nine catalytic steps: two steps for ruthenium-catalyzed reductions, two steps for ruthenium-catalyzed racemization, two steps for ruthenium-catalyzed deacylations, and three steps for lipase-catalyzed acyla-tions (Scheme 7). This process was applicable to a wide range of acyloxyphenyl ketones (Table 18).

Lipase Ac-lipase

Ac-lipase Lipase Lipase Ac-lipase

Lipase Ac-lipase

Ac-lipase Lipase 11

Scheme 7: Multistep acyl transfer of m-acetoxyacetophenone. 3.2. Asymmetric transformation of enol ester

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (R)-1-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee.26a Molecular hydrogen (1 atm) was almost equally effective for the transformation.2613 A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (R)-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates.

Table 18

Asymmetric transformations of acyloxyphenyl ketones

O calb OCOR

RCOO H2 HO

Substrate

Product

RCOO

RCOO

RCOO

OCOR

OCOR

OCOR

OCOR

Me Pr

Me Pr

98 98

93 96

RCOO

RCOO

RCOO

OCOR

OCOR

Me Pr

89 98

88 88

OCOR

OCOR

Me Pr

96 98

92 89

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