Cchiral hydroxy phosphorus derivatives

C-chiral hydroxy phosphorus derivatives, which have been described so far in the literature, are secondary alcohols. Thus, the syntheses of non-racemic compounds of this type comprise two main approaches (cf. C-chiral hydroxyalkyl sulfones, Section 2.2): asymmetric reduction of the corresponding keto derivatives and resolution of racemic hydroxyalkanephosphorus substrates.

Thus, 2-oxoalkanephosphonates 40 were successfully reduced using baker's yeast to give the corresponding 2-hydroxyalkanephosphonates 41 in reasonable yields and with ees of ca. 97% (Equation 22).52a The same concerns 3-oxoalkanephosphonates52b (for a review see Ref. 52c). Interestingly, 1-oxoalkanephosphonates could not be used as substrates in this reaction due to their instability in aqueous media.52a However, this obstacle was removed by applying lyophilized cells of baker's yeast or various types of fungi, immobilized on Celite in anhydrous media. The corresponding 1-hydroxyalkanephosphonates were obtained in yields up to 85% and with ees up to 99%.52d

This methodology was also applied to the enantioselective reduction of 3-halo-2-oxopropanephosphonates 40 (R = CH2Cl, CH2Br) to give the corresponding 3-halo-2-hydroxypropanephosphonates in good yield and with ees up to 81%.5354 The 3-chloro derivative was then used in the synthesis of 2,3-epoxyphosphonates and phosphorus analogues of (R)-GABOB53 and of phos-phocarnitine (vide infra).54 A series of 2-oxoalkanephosphonates were also screened for reduction with the fungi Geotrichum candidum and only diethyl

2-oxopropanephosphonate 40 (R = Me) proved to undergo the desired reaction to give (+)-(R)-diethyl 2-hydroxypropanephosphonate 41 (R = Me) in 78% yield and with ee = 98%.55

However, the most common and important method of synthesis of chiral non-racemic hydroxy phosphoryl compounds has been the resolution of racemic substrates via a hydrolytic enzyme-promoted acylation of the hydroxy group or hydrolysis of the O-acyl derivatives, both carried out under kinetic resolution conditions. The first attempts date from the early 1990s56'57 and have since been followed by a number of papers describing the use of a variety of enzymes and various types of organophosphorus substrates, differing both by the substituents at phosphorus and by the kind of hydroxy (acetoxy)-containing side chain.

Thus, these methodologies were used to resolve 1-hydroxyalkanephospho-nates 41 by either their enzyme-mediated acylation (Method A) or hydrolysis of the corresponding acyloxy derivatives 42 (Method B) (Equation 23). Selected examples are collected in Table 3.

In a similar way, non-racemic 2-hydroxyalkanephosphonates (phosphine oxides) 43 and their O-acyl derivatives were obtained (Equation 24, Table 4).

O Enzyme

R3C(Q)Ovinyl

OH A

rac-43

The results presented in Tables 3 and 4 deserve some comments. First, a variety of enzymes, including whole-cell preparations, proved suitable for the resolution of different hydroxyalkanephosphorus compounds, giving both unreacted substrates and the products of the enzymatic transformation in good yields and, in some cases, even with full stereoselectivity. Application of both methodologies, acylation of hydroxy substrates rac-41 and rac-43 or the reverse (hydrolysis of the acylated substrates rac-42 and rac-44), enables one to obtain each desired enantiomer of the product. This turned out to be particularly important in those cases when a chemical transformation OH ^ OAc or reverse was difficult to perform. As an example, our work is shown in Scheme 3. In this case, chemical hydrolysis of the acetyl derivative 46 proved difficult due to some side reactions and therefore an enzymatic hydrolysis, using the same enzyme as that in the acylation reaction, was applied. Not only did this provide access to the desired hydroxy derivative 45 but it also allowed to improve its enantiomeric excess. In this way,

Table 3

Kinetic resolution of l-hydroxy(acetoxy)alkanephosphonates

Entry R1 R2 R3 Method Enzyme

1

BnO

Et

Me

A

PFL

2

MeO

Ph

Me

B

F-AP

3

¡-PrO

Ph

Me

B

F-AP

4

¡-PrO

Ph

Me

B

AP-6

5

MeO

£-MeCH=CH

Me

B

F-AP

6

¡-PrO

Et

Me

B

AP-6

7

¡-PrO

w-Pr

Me

B

AP-6

8

¡-PrO

w-C5Hn

Me

B

AP-6

9

¡-PrO

w-CvHi5

CH2C1

B

AP-6

10

EtO

w-C5Hn

Me

B

AP-6

11

¡-PrO

o-Tol

CH2C1

B

AP-6

12

¡-PrO

2-Naphth

Me

B

AP-6

13

¡-PrO

2-Furyl

Me

B

F-AP

14

¡-PrO

3-Pyridyl

Me

B

AP-6

15

¡-PrO

Et

CH2C1

B

SP-254

16

¡-PrO

¡-Bu

ch2ci

B

P-2

17

EtO

w-Pr

w-Pr

B

WCPC

Hydroxy compound 41

Acyloxy compound 42

Hydroxy compound 41

Acyloxy compound 42

Yield

conf.)

Yield (%)

conf.)

41

-51

>99

(+)

n.r.

58

31

-46

>99 (5)

35a

+41.2*

90a (R)

>100

59

37

-28.2

>99 (5)

46a

+22. la

86a (R)

>100

59

46

-25.1

95 (S)

29a

+24.6a

91a (/?)

138

59

39

-9.8

89 (S)

45

+ 16.5

(«)

35

59

37

+ 12.5

77 (S)

47a

-17

51 (i?)

n.r.

60

39

+ 16.2

83 (S)

45a

-22.6

68 (R)

n.r.

60

43

+15.5

87 (S)

36a

-21.8

80 (/?)

n.r.

60

51

+11.9

73 (S)

43a

-22.7

84 (/?)

n.r.

60

38

+ 14.0

69 (5)

49a

-14.8

48 (/?)

n.r.

60

38

-28.2

55 (5)

50a

+15.2

46 (R)

n.r.

61

38

-30.4

90 (S)

38

+44.7

78 (/?)

n.r.

61

34

-15.8

93 (5)

26

+48.1

67 («)

n.r.

61

40

-30.2

77 (S)

34

+26.2

66 (/?)

n.r.

61

34

16.2

95 (5)

43

-38

n.r.

n.r.

62

44

-22.5

76

41

+38.5

99

n.r.

62

29

+15

75

26

-27

n.r.

n.r.

63

18

EtO

Ph

n-Pr

B

WCPFL

20

-29

80

50

+20

n.r.

n.r.

63

19

EtO

Me

Me

A

CAL-B

43

-5.5

>95 (R)

44

+26.5

>95 (S)

>100

64

20

i-PrO

Me

Me

A

CAL-B

42

-6.1

>95 (r)

43

+20.1

>95 (s)

>100

64

21

MeO

Et

Me

A

CAL-B

50

-4.3

51 (R)

31

+44.2

>95 (s)

50

64

22

EtO

Et

Me

A

CAL-B

47

-4.9

80 (R)

41

+41.3

>95 (s)

95

64

23

EtO

ch2=ch

Me

A

CAL-B

41

-12.7

>95(R)

40

+23.8

>95 (s)

>100

64

24

i-PrO

ch2=ch

Me

A

CAL-B

43

-14.4

>95 (R)

44

+26.5

>95 (s)

>100

64

25

EtO

Me

Meb

A

CAL-B

n.r

n.r (-)

99 (R)

50

n.r.(+)

>99 (s)

>500

65

26

EtO

Et

Meb

A

CAL-B

n.r.

n.r.(-)

90 (R)

45

n.r.(+)

98 (S)

300

65

27

EtO

ch2=ch

Meb

A

PS-C

n.r.

n.r.(-)

60 (R)

40

n.r.(+)

84 (s)

21

65

28

EtO

Ph

Meb

A

PS-C

n.r.

n.r.

3

2

n.r.

>95

n.r.

65

29

EtO

3- PhOC6H4(CH2 )3

Mec

A

GCL

62

n.r.(-)

n.r. (R)

34

+7.5

95

n.r.

66

Enzymes: PFL, lipase from Pseudomonas fluorescens; F-AP, lipase from Rhizopus orizae; AP-6, lipase from Aspergillus niger; SP-254, lipase from Aspergillus oryzae; P-2, Chirazyme®; WCPC, whole cell cultures of Penicillium citrinum; WCPFL, whole cell cultures of Pseudomona fluorescens; CAL-B, lipase from Candida antarctica B; PS-C, lipase from Pseudomonas cepacia; GCL, lipase from Geotrichum candidum. n.r.: not reported. a Alcohol obtained by chemical hydrolysis of the corresponding enzymatically resolved acyloxy derivative. b p-Chlorophenyl acetate used as the acetylating agent. c Isopropenyl acetate used as the acetylating agent.

Table 4

Kinetic resolution of 2-hydroxy(acetoxy)alkanephosphonates or phosphine oxides

Entry

R1

R2

R3

Method

Enzyme

Hydroxy compound 43

Acyloxy compound 44

E

Ref.

Yield

MD

ee (%)

Yield

Md

ee (%)

(%)

(abs. conf.)

(%)

(abs. conf.)

1

Ph

Me

Me

A

RGL

n.r.

-7.2

88

n.r.

n.r.

69

16

57

2

Ph

Et

Me

A

RGL

n.r.

+9.8

47

n.r.

n.r.

76

12

57

3

Ph

MeOCH2

Me

A

RGL

n.r.

+8.5

80

n.r.

n.r.

77

18

57

4

EtO

Me 2

Me

A

AK

44

+6.7

90 (R)

47

+7. 2

93 (S)

95

55

5

EtO

Me

Me

A

PS

45

+6.4

87 (r)

46

+7. 1

89 (s)

50

55

6

MeO

n-Bu

Me

A

AK

30

-11.6a

92 (r)

61

+59

49 (s)

8

55

7

EtO

2-Pyridyl

Me

A

LPL

46

-18.8

62

45

+32

72

11

55

8

EtO

ClCH2

Me

A

AH-S

40

+7.0

89 (R)

45

-1. 3

88 (S)

n.r.

54

9

MeO

Me

Me

A

CAL-B

39

+13.6

>95 (S)b

40

+5.7

>95 (R)b

>100

64

10

EtO

Me

Me

A

CAL-B

40

+15.2

>95 (s)b

39

+9.7

>95 (R)b

>100

64

11

EtO

Et

Me

A

CAL-B

43

+13.1

85 (S)b

35

+8.2

>95 (R)b

>100

64

12

EtO

Me

Mec

A

CAL-B

n.r.

n.r. (+)

98

49

n.r. (+)

99

>500

65

13

MeO

Me

Mec

A

CAL-B

n.r.

n.r. (+)

90

47

n.r. (+)

>99

>500

65

14

MeO

Et

Mec

A

CAL-B

n.r.

n.r. (+)

13

12

n.r. (+)

>99

>225

65

15

EtO

Ph

n-Pr

B

CRL

41

n.r.

>95

42

n.r.

>95

>100

68

16

EtO

2-CF3C6H4

n-Pr

B

CRL

44

n.r.

>95

42

n.r.

>95

>100

68

17

EtO

2-Furyl

n-Pr

B

CRL

45

n.r.

88.7

40

n.r.

93.8

93

68

n.r.: not reported. Enzymes: RGL: rabbit gastric lipase; AK: lipase from Pseudomonas fluorescens (AMANO); PS: lipase from Pseudomonas cepacia (AMANO); LPL: lipoprotein lipase from Pseudomonas aeruginosa; CAL-B: lipase from Candida antarctica B; AH-S: lipase AH-S (AMANO). a Specific rotation of the corresponding acetate.

b Absolute configurations were ascribed on the basis of an empirical model by analogy to 1-hydroxyalkanephosphonates. They are opposite to those obtained from the NMR spectra of the Mosher's esters of 2-hydroxyalkanephosphonates (entries 4-6) and whose absolute configuration is known.52a'67 c p-Chlorophenyl acetate was used as the acetylating agent.

Jj c n VJ k both enantiopure alcohols 45 were obtained and then transformed into (R)- and (S)-phosphocarnitine 47 (Scheme 3).54

Scheme 3

Interestingly, for the transformation of both the racemic 1-hydroxyalkanephosphonates 41 and 2-hydroxyalkanephosphonates 43 into almost enantiopure acetyl derivatives 42 and 44, respectively, a dynamic kinetic resolution procedure was applied. Pamies and Backvall65 used the enzymatic kinetic resolution in combination with a ruthenium-catalysed alcohol racemization and obtained the appropriate O-acetyl derivatives in high yields and with almost full stereoselectivity (Equation 25, Table 5). It should be mentioned that lowering qi_I 0 Lipase, AcOCgH^-p-CI Q^g Q

Table 5

Dynamic kinetic resolution of hydroxyalkanephosphonates

R1 R2 n Enzyme Acetate

of the yields of 2-acetoxyphosphonates was due to the formation of byproducts, 2-ketophosphonates, arising from the oxidation of the substrates by the catalyst; to prevent this side reaction, a source of hydrogen was sometimes added to the reaction mixture.

There are several other examples of C-chiral hydroxy phosphorus compounds which were obtained in enantiomerically enriched forms using enzymatic methodology. Thus, ds-1-diethylphosphonomethyl-2-hydroxycyclohexane 48 was resolved into enantiomers by enzymatic acetylation: the highest enantioselectivity was achieved using lipase PS in THF or lipase AK without solvent and vinyl acetate as the acetylating agent (Equation 26).69

Lipase Solvent 48 49 E

PS THF 60 62 35 97 62

AK none 41 >99 35 93 152

Prochiral 2-(w-phosphono)alkyl-1,3-propanediols 50 were enantioselec-tively acetylated to give the corresponding O-acetyl derivatives 51 in very high yields and with high ees (Equation 27).70

Lipase/solvent

Product 51

PS/THF

PS/i-Pr2O

PS/THF

PS/THF

PS/i-Pr2O

None None ch2

98 92 85 98 98

98 98 93 98 98

Two types of racemic 3-hydroxy phosphonates, in which the phosphono and hydroxy moieties are separated by double bond, were successfully resolved using a common enzyme-catalysed acetylation. Both acyclic 52 (Equation 28)71 and cyclic 54 (Equation 29)72 derivatives underwent easy acetylation under the kinetic resolution conditions to give the products in high yield and with almost full stereoselectivity.

Lipozyme 99 96 >200

PPL 22 99 130

Lipase

n

54

55

E

Yield (%)

ee (%)

Yield (%)

ee (%)

AK

2

48

98

50

>99

>200

PS

1

41

<99

48

84

57

AK

3

48

>99

50

>99

>200

PS

3

56

70

42

97

130

Finally, 2-keto-4-hydroxyalkanephosphonates 56 were resolved either by CAL-B-promoted acetylation or by lipase from Candida rugosa (CRL)-mediated hydrolysis of the corresponding O-butyrates 57 (Scheme 4).73

Scheme 4

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