Pchiral hydroxy phosphoryl compounds

The first P-chiral hydroxy phosphoryl compounds that were enzymatically resolved into enantiomers were o-hydroxyaryl phosphines and their oxides 75. The resolution was achieved via enzyme-assisted hydrolysis of their O-acetyl derivatives 74, the most effective enzymes being CE and lipase from C. rugosa (CRL) (Equation 35). The highest enantioselectivity was observed in the case of naphthyl derivatives (Equation 36), having a P=O moiety.88

rac-74A 74A 75A

rac-74A 74A 75A

X

Enzyme

ee of 74B (%) (abs. conf.)

ee of 75B (%) (abs. conf.)

E

O

CE

61 (S)

89 (R)

32

O

CRL

69 (S)

95 (R)

81

Lone pair

CE

44 (R)

43 (S)

3.8

Lone pair

CRL

11 (R)

15 (S)

1.5

Hydroxymethylphosphine oxides, hydroxymethylphosphinates and hydrox-ymethylphosphonates 76, the primary alcohols with a phosphorus stereogenic centre, have been a subject of our intense investigations for several years. This was due to the fact that some of them proved to exhibit herbicidal activity (as part of larger molecules), which was strongly dependent on their absolute configuration.89 Thus, the resolution of hydroxymethylphosphinates and -phosphonates was achieved using lipase-promoted acylation or hydrolysis of the corresponding O-acyl derivatives (Equation 37) in various solvents: organic solvents (i-Pr2O, CH2Cl2, t-BuOMe),90 ionic liquids (IL)91 eg. BMIM PF6 and supercritical carbon dioxide (scCO2).92 A similar resolution of hydroxymethylphosphine oxides was carried out by Shioji et al.93 in an excess of the acylating agent. Selected results are presented in Table 8.

BMIMPF8

PFf<

Inspection of Table 8 clearly shows that the highest enantioselectivity was observed in the case of phosphine oxides when the acylation was performed with a more bulky acyl donor, serving also as solvent (entries 16, 17 and 19).93 The ionic liquid91 enhanced stereoselectivity in comparison with organic solvents89 90 only for the substrates which contained larger organic substituents (entry 9 versus entry 8).91 In turn, supercritical carbon dioxide proved to be the worst solvent among those investigated. The main reason seems to be a relatively high polarity of the substrates for which scCO2 with its low polarity is not a suitable reaction medium.92 An exceptional reversal of the sense of enantioselectivity for the sole example, when CAL-B was used in the acylation of t-butyl(hydroxymethyl)phenylphosphine oxide (entry 17 versus entries 15 and 16), must be at present left without explanation.93 Kinetic resolution of diastereomerically pure racemic 1-hydroxyalkylphosphinates having two stereogenic centres 78 proceeded in a highly enantioselective manner to give both the unreacted substrates and the acetylated products 79 with ees exceeding 98% (Equation 38).94

However, when each diastereomerically pure 1-acetoxy-H-phosphinate 80 was subjected to enzymatic hydrolysis, only one of them, namely (R* , Sp)-80, underwent the desired reaction, the other one, (R* , Rp )-80, being totally unreactive

Table 8

Kinetic resolution of racemic hydroxymethylphosphoryl compounds rac-76

Entry

R1

R2

R3

Method

Solvent

Lipase

Alcohol 76

Acetate 77

E

Ref.

Yield

ee (%) (abs.

Yield

ee (%) (abs.

(%)

conf.)

(%)

conf.)

1

Ph

MeO

Me

A

i-Pr2O

PFL

44

80 (R)

39

89 (S)

45

90

2

Ph

MeO

Me

A

CH2Cl2

PS

42

92 (r)

44

86 (s)

40

90

3

Ph

MeO

Me

A

IL

AK

34

89 (r)

38

89 (s)

51

91

4

Ph

MeO

Me

A

scCO2

CAL-B

81

4 (R)

5

7 (S)

1.5

92

5

Ph

EtO

Me

A

i-Pr2O

PFL

42

54 (R)

53

47 (S)

5

90

6

Ph

EtO

Me

A

IL

AK

36

79 (R)

37

83 (s)

26

91

7

Ph

EtO

Me

A

scCO2

CAL-B

6

88 (R)

82

6 (S)

3

92

8

Ph

i-PrO

Me

A

i-Pr2O

PFL

37

80 (R)

46

21(S)

5

90

9

Ph

i-PrO

Me

A

IL

AK

36

95 (R)

48

80 (S)

32

91

10

Ph

i-PrO

Me

A

scCO2

CAL-B

52

28 (R)

46

27(S)

3

92

11

i-PrO

MeO

Me

B

CH2Cl2/buffer

PFL

55

16

45

34

n.r.

90

12

Et

i-PrO

Me

A

i-Pr2O

PFL

39

86

58

64

12

89

13

Et

i-PrO

Me

A

IL

AK

32

95

55

50

12

91

14

Et

i-PrO

Me

A

scCO2

CAL-B

0

-

100

-

-

92

15

Ph

i-Bu

Me

A

IL

AK

33

43 (S)

42

53 (R)

5

91

16

Ph

i-Bu

n-Pr

A

PrC(O)Ovinyl

AK

30

>98 (S)

55

68 (r)

27

93

17

i-Bu

Ph

Me

A

MeC(O)Opropenyl

CAL-B

40

>98 (r)

n.r.

n.r.

21

93

18

Ph

Me

n-Pr

A

PrC(O)Ovinyl

AK

40

>98 (s)

55

86(R)

65

93

19

Ph

c-C6Hn

n-Pr

A

PrC(O)Ovinyl

AK

45

90(S)

45

94 (R)

95

93

20

Ph

Me

Me

A

MeC(O)Ovinyl

PS

60

51

30

88

23

93

IL, ionic liquid - BMIM PF6; for lipase see Tables 3 and 4.

Jj n

VJ k

IL, ionic liquid - BMIM PF6; for lipase see Tables 3 and 4.

O OAc EtOi.rJ_L.tR

O OH

Scheme 7

On the basis of this result, a method was developed which allowed to stereoselectively obtain one diastereomer of the product with a high enantiomeric excess, but in a maximum yield of 25%, starting from a diastereomeric mixture of the substrate (Equation 39).95

R Starting 80 d.r. (R,SP)-81 Recovered 80

Yield (%) ee (%) Yield (%) Diastereomeric ratio

p-Tol

1.3:1

14

>99

39

2.0:1

Ph

1.5:1

17

>99

45

2.8:1

PhCH2

1.3:1

14

74

76

1.4:1

Finally, prochiral bis(hydroxymethyl)phenylphosphine oxide 82 was desym-metrisized using either a lipase-catalysed acetylation (Method A) or hydrolysis of the corresponding diacetyl derivative 83 (Method B), to give the chiral monoacetate 84. Application of the two reverse procedures made it possible to obtain both enantiomerically enriched forms of 84 (Equation 40).87

Lipase Solvent Method Monoacetate 84

Md

Yield (%)

ee (%)

Abs. conf.

PFL

CHCl3

A

+3.9

50

79

(R)

PFL

i-Pr2O/buffer

B

-3.4

50

68

(S)

PS

THF

A

+ 1.8

57

37

(R)

PFL

BMIM PF6

A

+0.6

35

14

(R)

PFL

BMIM PF6/buffer

B

-3.3

28

65

(S)

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