DKR of secondary alcohols

The KR of secondary alcohols by some hydrolytic enzymes has been well known. The combinations of these hydrolytic enzymes with racemization catalysts have been explored as the catalysts for the efficient DKR of the secondary alcohols. Up to now, lipase and subtilisin have been employed, respectively, as the R- and S-selective resolution enzymes in combination with metal catalysts (Scheme 2).

R1 R2 R1 R2

Metal

R1^R2 R1"^R2

Scheme 1: DKR by enzyme-metal combination.

OH Lipase OCOR

OH Subtilisin OCOR

R1 R2 RCO2R' R1^R2

Scheme 2: DKR of secondary alcohol.

2.1.1. (R)-selective DKR of secondary alcohols

The use of metal catalysts with the hydrolytic enzymes in the DKR of simple secondary alcohols was investigated by several groups including our, Williams, and Backvall groups. In 1996, Williams et al. reported for the first time the use of a metal catalyst in the DKR of secondary alcohols.7 The DKR was performed on 1-phenylethanol with the combination of a lipase and a rhodium complex to result in the product albeit in low enantiomeric excess (80% ee). Later, Backvall et al. reported a significant improvement of the enantiomeric output by using a diruthenium complex 1 along with an immobilized and thermally stable lipase (Candida antarctica lipase B (CALB); trade name Novozym-435).10 A notable modification in this method was the use of p-chlorophenyl acetate (PCPA), which was found to be more compatible with the racemization catalyst than popular acyl donors such as vinyl and isopropenyl acetate. Thus, the DKR of 1-phenylethanol by this procedure resulted in optically pure (R)-a-phenylethyl acetate in high yield (Table 1).10b However, the procedure has some drawbacks. First, it requires

Table 1

DKR of 1-phenylethanol with diruthenium complex 1 OH

Ph calb 1

Acyl donor acetophenone f-BuOH, 70°C

Acyl donor acetophenone f-BuOH, 70°C

Acyl donor

ee (%)

Yield (%)

^OAc

>99

50

^OAc

>99

72

Cl —<\^y>—OAc

>99

100

an elevated temperature (70°C) for the activation of the diruthenium catalyst. The high temperature is unacceptable for thermally less-stable enzymes. Second, a stoichiometric amount of acetophenone should be added as hydrogen mediator for inducing racemization and thus achieving high conversion yield. The absence of acetophenone usually costs 10-15% lowering in yield. Third, unreacted PCPA is often difficult to remove from the acylated products during work-up. To overcome these limitations, more efficient racemization catalyst should be developed, which is highly active at room temperature, compatible with readily available acyl donors such as vinyl and isopropenyl acetate, and does not require a hydrogen mediator for racemization.

Later, in a modification to the above system, we reported the use of an indenylruthenium complex 2 as a racemization catalyst for the DKR of secondary alcohols, which does not require ketones but a weak base like triethylamine and molecular oxygen to be activated.11 The DKR with 2 in combination with immobilized Pseudomonas cepacia lipase (PCL, trade name, Lipase PS-C®) was carried out at a lower temperature (60°C) and provided good yields and high optical purities (Table 2). This paved the way for the omission of ketones as

Table 2

DKR of secondary alcohols with indenyl ruthenium complex 2

OH PCL OAc

OH PCL OAc

R

R'

ee (%)

Yield (%)

Ph

Me

96

86

4-MeO-Ph

Me

99

82

4-Br-Ph

Me

99

98

1-Indanyl

82

88

PhCH2

Me

97

DKR of secondary alcohols with cymene-ruthenium catalyst 3

OH pcl OAc

R PCPA, Et3N R

Ph 94 95

4-MeO-Ph 99 93

PhCH2 >99 85

hydrogen mediators for the racemization. However, we wanted that ideally the reaction should be carried out at ambient temperature. Towards that goal, soon after, we discovered a remarkable cymene-ruthenium catalyst 3 and its hydride form 4 as effective catalyst systems for a facile DKR of secondary alcohols at 40°C (Table 3). A noticeable feature of this catalyst system was that allylic alcohols12 also underwent facile DKR at room temperature to provide high yields of corresponding chiral acetates with excellent optical purities (Table 4). Additionally, even in ionic liquids such as [EMIm]BF4 and [BMIm]PF6 ([EMIm] = 1-ethyl-3-methylimidazolium, [BMIm] = 1-butyl-3-methylimidazolium),13 the

Table 4

DKR of allylic alcohols with cymene-ruthenium catalyst 4 OH

pcl 4

R

ee (%)

Yield (%)

Ph

>99

84

4-Cl-Ph

99

91

4-MeO-Ph

99

85

2-Furyl

99

92

C-C6H11

95

90

(CH3)3C

>99

DKR of alcohols with cymene-ruthenium catalyst 3 in [BMIm]PF6

OH pcl OAc

R R CH3CO2CH2CF3, Et3N R R

OH pcl OAc

R R CH3CO2CH2CF3, Et3N R R

R

R'

ee (%)

Yield (%)

Ph

Me

99

85

PhCHCH2

Me

99

85

3-Me-Ph

Me

98

87

4-Me-Ph

Me

99

87

4-MeO-Ph

Me

99

85

4-Cl-Ph

Me

99

87

4-Br-Ph

Me

99

92

1-Indanyl

99

85

4-[CH3CH(OH)]Ph

Me

99 (de 99%)

87

3-[CH3 CH(OH)]Ph

Me

99 (de 97%)

86

same efficacious DKR was retained for benzylic alcohols at room temperature. It was observed that the Ru-catalyzed racemization occurred more rapidly in ionic liquids compared to organic solvents. The added advantage of the use of ionic liquids has been the reusability of both the catalyst and the enzyme by a simple extraction of the products by ether (Table 5).14

OC-Ru

In an effort directed at developing a racemization catalyst which works uniformly for all the substrates at room temperature, we designed and synthesized a novel aminocyclopentadienyl ruthenium chloride complex 5.9 The DKR of aromatic as well as aliphatic alcohols could be conducted at room temperature. In case of aromatic alcohols, the substituent effects were found insignificant in the DKR; however, aromatic alcohols have comparatively faster conversion rates than their aliphatic counterparts. This is the first ever report of a catalyst

Table 6

DKR of alcohols with aminocyclopentadienyl ruthenium complex

OH calb OAc

Isopropenyl acetate fBuOK, Na2CO3

toluene, 25°C

R

R'

Catalyst

ee (%)

Yield (%)

Ph

Me

5

>99

95

6

>99

92

4-Cl-Ph

Me

5

>99

94

6

>99

91

4-MeO-Ph

Me

5

>99

90

6

>99

94

1-Indanyl

5

95

89

4-NO2-Ph

Me

6

>99

97

4-CN-Ph

Me

6

>99

95

C-C6H11

Me

5

>99

86c

6

>99

98

CH3(CH2)4CH2

Me

5

91

89c

PhCH=CH

Me

5

98

93

(Ph)3COCH2

Me

5

99

97

Ph

CH=CH2

5

81

62

C-C6H11

CH=CH2

5

>99

90

system that works efficiently at room temperature for the successful DKR of secondary alcohols. The resulting acylated products were obtained in high yields and high enantiomeric excess (Table 6). An additional feature is the use of isopropenyl acetate, which is readily available, more active than PCPA, and easily separable from the DKR mixtures.15 Although the mechanism of catalytic racem-ization is not yet clear, according to our interpretation, it can be deduced that the amino group in 5 seems to play a crucial role in the racemization, though Backvall suggests a different pathway16 for a similar yet modified complex 6 that has no amino functionality. At the same time, Sheldon et al. reported a new catalyst system of [TosN(CH2)2NH2]RuCl(p-cymene) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) for the DKR of alcohols17 but resulted in the conversion of 1-phenylethanol to its corresponding acetate with only 76% yield.

The DKR of functionalized alcohols such as diols, hydroxy esters, hydroxy aldehydes, azido alcohols and hydroxy nitriles was also taken up as the synthetic utility of the products is very high; besides such a study will bring out the effect of multifunctional substrates under these reaction conditions to broaden the scope of DKR. Initially, the DKR of diols was achieved with diruthenium catalyst 1

and CALB in the presence of PCPA to give the corresponding diacetates of (R, R)-configuration from the mixture of dl- and meso-isomers (Table 7).18 The DKRs of rigid benzylic diols with 1 gave better results in terms of diastereose-lectivity compared to those of more flexible aliphatic diols, reflecting that lipase displays higher stereoselectivity towards benzylic diols than aliphatic diols.

The DKRs of a-, P-, 7- and 8-hydroxy esters were also accomplished with PCL and 1 at 60-70°C.19 In the DKRs, the enantioselectivities were good in most cases though the yields were moderate. The use of H2 was necessary in the DKR of 7- and 8-hydroxy esters to suppress the formation of ketones (Tables 8-10).

The DKRs of small functionalized alcohols such as 2-hydroxybutanoic acid, 2-hydroxypropanal, and 1,2-propanediol were carried out after the protection of the terminal groups with a bulky group (Tables 11 and 12) since the bulky protecting groups enhanced the enantioselectivity of the enzyme in the DKR.20 In the DKR of hydroxy acids, t-butyl group was found to be the best for carboxyl group protection. The trityl group was a proper choice for the protection of primary alcohols in diols such as 1,2-propanediol, 1,2-butanediol, and 1,3-butanediol.20 1,2-Benzenedimethanol was used for protecting the formyl groups of a- and P-hydroxy aldehydes.20 High enantiomeric excesses (95% and higher) were obtained in the DKRs of the protected diols and hydroxy aldehydes. 2,6-Dimethyl-4-heptanol was used as a hydrogen source to suppress the formation of oxidized side products.

Table 7

DKR of diols with ruthenium complex

Table 7

DKR of diols with ruthenium complex

OH OH

A A

calb [Ru]

OAc OAc

OAc

OAc

Acyl donor

z^X -

toluene

(r, r)

meso

X

[Ru]

eea (%)

(R, R)/meso

Yield (%)

CH2CH2

i

>99

86/14

63

CH2

i

>99

38/62

90

CH2CH2CH2

i

>97

90/10

63

CH=CH

i

>99

74/26

43

1,3-Ph

i s

>99 >99

98/2 99/1

76 95

1,4-Ph

i

>99

98/2

77

s

>99

98/2

94

6

>99

99/1

90

2,5-Pyr

i

>99

100/0

78

CH2N(n-Bu)CH2

i

>96

89/11

DKR of a-hydroxy esters OH

R ^CO2Me pcl 1

PCPA cyclohexane, 60°C

OAc R """"CO2Me

Table 8

DKR of a-hydroxy esters OH

R ^CO2Me

PCPA cyclohexane, 60°C

OAc R """"CO2Me

R

ee (%)

Yield (%)

Ph

94

80

4-MeO-Ph

94

76

4-Br-Ph

98

69

c-C6Hii

98

80

PhCH2CH2

30

62

CH3CH2CH2CH2

80

60

Table 9

DKR of ^-hydroxy esters

OH

pcl 1

OAc

r >\/CO2Me

R

PCPA (CH3)3COCH3 60°C, 6 days

R

ee (%)

Yield (%)

Ph

95

76

4-MeO-Ph

99

74

C-C6H11

70

82

PhCH2

96

80

Table 10

DKR of 7- and 8-hydroxy esters

OH

pcl

OAc

f-BuO2C

1

n R

n 'R

PCPA, toluene

n R

Equiv. of PCPA Temp (°C)

eep (%) Yield (%)

2 Me

3.9

60

94 70

3 Me

3

70

98 89

3 Et

3

70

DKR of hydroxy acids, diols and hydroxy aldehydes

O OH PCL O OAc

RO PCPA RO

toluene, 70°C

Ph 86 88

4-MeO-Ph 93 91

Table 12

DKR of protected diols and hydroxy aldehydes by lipase-ruthenium combination OH pcl OAc

2,6-dimethyl-4-heptanol toluene, 70°C

96 91

The DKRs of (3-azido alcohols19d and ^-hydroxy nitriles21a were also accomplished by employing 1 and CALB with PCPA as the acyl donor. The DKRs of P-azido alcohols were performed at 60°C while those of ^-hydroxy nitriles required higher temperature (100°C) primarily to enhance the racemization rate. The optical purities of products were satisfactory in all cases. In the case of P-hydroxy nitriles, dehydrogenation lowered the yield.

2.1.2. (S)-Selective DKR of secondary alcohols

The lipase-catalyzed DKRs provide only (R)-products; to obtain (S)-products, we needed a complementary (S)-stereoselective enzyme. A survey of (S)-selective enzymes compatible to use in DKR at room temperature revealed that subtilisin is a worthy candidate, but its commercial form was not applicable to DKR due to its low enzyme activity and instability. However, we succeeded in enhancing its activity by treating it with a surfactant before use. At room temperature DKR with subtilisin and ruthenium catalyst 5, trifluoroethyl butanoate was employed as an acylating agent and the (S)-products were obtained in good yields and high optical purities (Table 13).22

The (S)-selective DKR of alcohols with subtilisin was also possible in ionic liquid at room temperature (Table 14).14 In this case, the cymene-ruthenium complex 3 was used as the racemization catalyst. In general, the optical purities of (S)-esters were lower than those of (R)-esters described in Table 5.

2.1.3. DKR of secondary alcohols by air-stable metal catalyst

All the Ru-based racemization catalysts described earlier are air-sensitive and thus difficult to reuse. We found that a modified Ru complex 7 was air-stable and recyclable, in particular, in a polymer-supported form 8. The racemization of secondary alcohols with 7 took place equally well under both oxygen and argon atmospheres. The subsequent DKRs of several alcohols using 7 or 8 under aerobic

Table 13

DKR of secondary alcohols by subtilisin-ruthenium bicatalysisa

OH Subtilisin OCOPr

R PrCO2CH2CF.

'2CH2CT3

'2CH2CT3

R

ee (%)

Yielda (%)

Ph

92

95

4-Cl-Ph

99

92 (90)

4-MeO-Ph

94

93 (91)

C-C6H11

98

80 (74)

PhCH2

92

77 (76)

PhCH2CH2

98

80 (78)

CH3(CH2)4CH2

98

77 (67)

PhCH=CH

95

90 (90)

a Isolated yields in parentheses.

a Isolated yields in parentheses.

Table 14

DKR by subtilisin-ruthenium bicatalysis in [BMIm]PF6

OH Subtilisin-CLEC OCOPr _3_^ J^

R

R'

ee (%)

Yield (%)

PhCH2

Me

97

89

PhCH2CH2

Me

97

90

3-Me-Ph

Me

85

90

4-Me-Ph

Me

85

90

4-MeO-Ph

Me

99

80

4-Cl-Ph

Me

87

92

4-Br-Ph

Me

82

91

1-Indanyl

86

84

4-[CH3CH(OH)]Ph

Me

86

78

(de 52%)

3-[CH3 CH(OH)]Ph

Me

96

83

(de 63%)

conditions at room temperature provided excellent yields with high optical purities (Table 15).

2.1.4. DKR of esters

The hydrolytic DKR of allyl esters has been studied as a DKR of esters. The first DKR was accomplished through Pd-catalyzed racemization and enzymatic hydrolysis of allylic acetates in a buffer solution.6 However, the DKR under these conditions was limited to cyclohexenyl acetates to give symmetrical palladium-allyl intermediates. Among them, 2-phenyl-2-cyclohexenyl acetate 9 was the only substrate to have been resolved with good results (81% yield, 96% ee).

Ps. fluorescence lipase PdCl2(MeCN)2

Phosphate buffer 37-40°C, 19d

Table 15

DKR of secondary alcohols with air-stable ruthenium catalysts

Isopropenyl acetate, K3PO4 toluene, 25°C

R

R'

Catalyst

ee (%)

Yield (%)

Ph

Me

7

>99

98

8

>99

98

4-MeO-Ph

Me

7

>99

98

8

>99

98

4-Cl-Ph

Me

7

>99

98

8

>99

98

4-MeO-Ph

Me

7

>99

92

1-Indanyl

7

88

91

1-Naphthyl

Me

7

>99

98

8

>99

98

2-Naphthyl

Me

7

>99

98

8

>99

98

C-C6H11

Me

7

>99

98

8

>99

95

CH3 (CH2)4CH2

Me

7

>99

98

8

>99

95

We improved the DKR of allylic acetates significantly by replacing the enzymatic hydrolytic reaction with enzymatic transesterification reaction and employing Pd(0) as the racemizing catalyst in organic solvent (Scheme 3).23 Here, Pd-catalyzed racemization is usually accompanied by reductive elimination giving 1,3-dienes as byproducts. The side reaction was effectively suppressed by the addition of a chelating ligand 1,1'-bis(diphenylphosphino)ferrocene (dppf). The

ROH ri^^R2

Scheme 3: DKR of allylic acetates.

DKR reactions were performed with lipase and Pd(PPh3)4 in the presence of dppf and 2-propanol in THF. 2-Propanol was used as an acyl acceptor. Various acyclic allylic acetates were transformed to their corresponding allylic alcohols at room temperature in good yields and excellent optical purities (Table 16).

Was this article helpful?

0 0

Post a comment