Biocatalysis and Blotransformalion, Vol. 19, pp. 163 - 180 Reprints available directly from the publisher Photocopying permitted by license only

0 2001 OPA (Overseas Publishers Associa[ion) N V Published by license under

the Harwood Academic Pubhhers imprint, part of The Gordon and Breach Publishing Group.

METHODOLOGIES FOR THE STEREOSELECTIVE SYNTHESIS OF ADRENERGIC P-BLOCKERS: AN OVERVIEW

c. CAMPO, E. F. LLAMA, J. L. BERMUDEZ and J. V. SINISTERRA*

Dpto. Quimica Organica y Farmaceutica, Facultad de Farmacia, UCM, 28040-Madrid, Spain

(Received 28 July 2000; Injinal form 12 October 2000)

The importance of the adrenergic ,!?-blockers with structure of (5') l-aryloxy-3-amino-2- propanol in the treatment of different diseases has led the development of a variety of stereoselective synthetic methodologies for this stereoisomer. In this review we present several methodologies to obtain this compound using (i) chiral substrates, (ii) chiral catalysts (organometallic or enzymes) and (iii) preparative chiral chromatography, showing the advan- tages and disadvantages of each methodology.

Keywords: Adrenergic P-blockers; Chiral substrates; Chiral organometallic complexes; Enzymes; Whole cells; Lipases; Chiral stationary phase chromatography

1. INTRODUCTION

The treatment of hypertension has advanced significantly in the last decade with the marketing of drugs that produce a long-lasting diminution of blood pressure, without side-effects. Several drug leaders have been described as therapeutic for this disease. Probably, the best-studied therapeutic group has been the adrenergic P-blockers (ABBs) that are useful in the treatment of angina pectoris and in high blood pressure pathology. The importance of these drugs is related to their high efficiency and low collateral effects. Thus,

*Corresponding author.

163

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164 C . C A M P 0 rt al.

OH

1

SCHEME 1

ABBs are widely prescribed, and together with 1,4-benzodiazepines and 3-lactam antibiotics, are one of the most widely sold drugs in developed countries.

The general structure of ABBs is of l-aryloxy-3-amino-2-propanols 1 (Richards et al., 1975; Main, 1982; Kaiser et al., 1977).

Propranolol 2 (Ar = I-naphthyl, X = 0-CH2, R = i-Pr) is the prototype of this kind of drug.

Considering the fundamental structure 1, for arylethanolamines ( X = direct link) and aryloxypropanolamines (X = OCH,), two functions which are essential for .3-blockade, namely the 3-aminoethanol chain and the aromatic ring can be identified. Experience with the arylethanolamine series had shown that optimum 3-antagonist activity resided with branched alkylamine substituents. the best of which are isopropyl and t-butyl. This characteristic was also found true for the aryloxypropanolamines and in all the early work on 3-blockers the isopropyl- or t-butyl-amino substituents were retained. The insertion of additional groups between the amine and carbinol group. removal or alkylation of the hydroxyl group or acylation of the amine led to a substantial or total loss of ,$blocking activity (Crowther, 1990).

Propranolol is a lipophilic compound with known CNS side effects resulting from transfer across the blood brain barrier. It was felt that these effects could be reduced by making these compounds more hydrophilic such as 3.

The next development came when a -CH2- group was introduced between the ainide function and aromatic ring. The first compound prepared, Atenolol 4, is considerably more hydrophilic than Propranolol 2. Its cardioselectivity is related to the interaction of the drug with a relatively hydrophilic J1-receptor rather than with a more lipophilic p2-

receptor (Crowther and Smith, 1968; Barret et uf., 1972). The &I-adrenergic receptors are chiral as we can deduce from their

interaction with adrenaline (Ganellin and Roberts, 1994). This takes place through the antiperiplanal conformation and only with the R-isomer

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SYNTHESIS OF ADRENERGIC &BLOCKERS 165

SCHEME 2

(R)-ADRENALM (S)PROPRANOLOL

OH k OH . . - . - . - . . . - . . . . . . . . . . . . . . .

RECEPTOR RECEPTOR

FIGURE 1 Interaction of adrenergic receptor and (R) Adrenalin or (8 Propranolol

due to an H-bonding stereospecific interaction (Fig. 1). S-Adrenaline cannot interact with the receptor because the OH group does not have the proper geometric configuration to interact with the active site by H-bonding. In the case of the adrenergic P-blockers the interaction with the receptor takes place by means of the (9-stereoisomer as we show above, because only this stereoisomer imitates the adrenaline-receptor interaction.

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166 C. CAMP0 ef al.

2. ENANTIOSELECTIVE SYNTHESIS OF ADRENERGIC fl-BLOCKERS (ABBs)

The therapeutic activity of ABBs is related to the S-enantiomer. Many synthetic methodologies have been described to obtain this enantiomer with high stereoselectivity, especially after the F.D.A. (Food and Drug Administration) recommended that Pharmaceutical Industries develop only the enantiomer of the new drug that has the pharmacological activity.

The most general synthetic methodology of ABBs is related to an epoxide structure, as starting product. This chiral epoxide may be obtained in three different ways:

(i) from natural products, which have the adequate stereochemistry, (ii) from an ally1 alcohol by Sharpless epoxidation, (iii) from an epichlorhydrin.

The generation or the resolution of the stereogenic center in the synthesis of ABBs may be carried out by using three different synthetic methods:

(1) Using chiral synthons. (2) Using chiral catalysts

2.a. Chemical chiral catalysts 2.b. Enzymes.

In the present review, we will discuss these different methodologies showing the advantages and the disadvantages of each synthetic procedure.

2.1. Chiral Synthons

Sugars and L-aminoacids are available and cheap substrates which are used as chiral starting materials in many organic syntheses. In this way, D- mannitol was used to obtain (R) or (S) epichlorhydrin (Baldwin et al., 1978) that let us synthesise both enantiomers of ABBs (Scheme 4). The process takes place by oxidative cleavage of the C3-C4 bond followed by reduction with NaBH4 to give two moles of the S-acetonide of glycerol.

Another alternative is the oxidative cleavage of the bis-acetonide of D- mannitol to ( R ) 2,3-O-isopropylidenglyceraldehyde (Tsuda et al., 1981) (Scheme 5).

This compound may be transformed into the aryloxyglycidol 5 (Scheme 5), that can easily be transformed into the S-adrenergic ,&blocker as described in Scheme 6 (steps f and g).

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SYNTHESIS OF ADRENERGIC 0-BLOCKERS I67

DManitol BE-acetonide

(pacetonide (R)3-tOS90Xy I ,Z-propanediol

I v

(S)Epichlorhydrine (R)-Olycidol

(R)-E$ichbrhydrine (S)mesylylgJycidol

i. 1) Pb(OAc)d, 2 ) NaBHI. ii. 1) TsC1, py. 2) Hf. iii. P(C,jHs)s, CC4, DMF. iv. Ethyleneglycol, Na. v. CH30H, NaOH. vi. MsCl, NEt3, toluene. vii. HCI. viii.

Ethyleneglycol, Na.

SCHEME 3

(S)Epichlorhydrin (R)ABB

(R)Epichlorhydrin (S)ABB

SCHEME 4

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I68 C. CAMP0 et ul

HO1 t-OH

t:>c

OBz I ,O-OH

Ar

5

(R) 2.3-0-isopropyl~denglyceraldehyde

SCHEME 5

a) hlsCl(l.1 eq.). pyridine. -10" C. 1 h. b) BLCI. (1.2 eq.). RT. 3 h. c) a-naphthol. KO1- Ru. DMSO. R.T.. 17 h:.d) cthylenegl>col. MeOH. HCI. 65" C. e) I-NaIOJ (4,O eq.).

diosane. R.1.. I 7 h: 3- NaI3H4 (3.0 eq). dioxane. R.T.. 1 h. f) pTsC1. pyridine, DMPA. R.T.. 7 d. g) MeOH. isopropylamine. 65" C. J h .

SCHEME 6

Sorbitol dibenzylacetal has also been used as the starting material by Veloo and Koomenn (1993) to obtain the drugs by an analogous synthetic pathway (Scheme 6).

Unfortunately three carbon atoms are lost for each propranolol molecule, 2: obtained.

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SYNTHESIS OF ADRENERGIC P-BLOCKERS 169

L-Serine (Lok et al., 1976) has also been used as a starting material for the preparation of (9-glycidol, substituting the NH2 of the L-aminoacid by OH by reaction with NaNOz in acid medium to get (9-glycidol (Streiwieser, 1957) (Scheme 7).

The (s) glycidol can easily be transformed into aryloxyglycidol and then in (9-adrenergic P-blocker (Scheme 9). However, these synthetic procedures are only justified by the low price of the starting material because many synthetic steps are necessary to get to the (9-adrenergic P-blockers.

2.2. Chiral Catalysts

The development of chiral catalysts in the last decade has been spectacular, especially in the scope of (i) organometallic catalysis, (ii) imprinting of solid catalysts and (iii) in the application of enzymes or whole cells to organic synthesis. We will deal with the applications of chiral catalysts to the ABBs synthesis in this section.

2.2.1. Chemical Chiral Catalysts

The enantioselective Sharpless epoxidation (Klunder et al., 1986) has been successfully used in the synthesis of the glycidol intermediate in ABB synthesis. Both enantiomers of glycidol may be obtained with a 90% e.e. by epoxidations of ally1 alcohol using the (+)(R, R)-diethyltartrate (natural) or ( - ) (S , 9-diethyltartrate (unnatural) as chiral catalysts and an organic peroxide as oxene donor (Scheme 8).

The glycidol or the gycidyltosylate may be transformed in the (s)- adrenergic P-blockers but from different stereoisomers (Scheme 9).

In the first reaction (Scheme 9) (R)-glycidol is opened “in situ” by a regioselective reaction at C-3 with sodium 1-naphthoxide giving the aryloxyglycerol that can be converted in (9-propranolol. In the other

v

(S)-glycidol

i. 1) NaN02IHCI. 2) (CH&C(OCH&. 3) LiAlh. ii. 1) PPh3/CC14 2) HOAc. 3 ) NaOMe.

SCHEME 7

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SCHEME 8

(2~)-Propranolol

SCHEME 9

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SYNTHESIS OF ADRENERGIC O-BLOCKERS 171

process (9-glycidol may be converted to tosylglycidol that reacts at C- 1 with naphthol. This difference is explained because glycidol and glycidyltosylate have two electrophilic reactive carbons that can be interconverted by Payne rearrangement (Payne, 1962) under basic condi- tions (Scheme 10).

Due to the symmetry of the molecule, the absolute configuration of glycidol remains unaltered. Because of this, the nucleophilic opening of glycidol takes place at C-1. In glycidyltosylate, there is a competition between the nucleophilic substitution in the tosylated carbon C-1 and the ring opening in C-3. In the later case, the intramolecular removal of the tosyl group gives a product with the opposite configuration to the one obtained in the other process. Nevertheless, this process is highly regio and stereo- selective because the ($'-tosylate gives a product with %%($) and 7%(R). Therefore, nucleophilic substitution at C-1 is the main process. The reduction in enantioselectivity is not a problem. The homochiral ABB may be obtained with high optical purity (990/,) by fractional recrystalliza- tion. Both processes are general and can be used to obtain the ($) or (R) ,O- blockers, although in Scheme 9 we have only presented these two syntheses to obtain the active ($' isomer. These methodologies are general and allow us to obtain a great number of ABBs with high e.e. (90-95%), and predictable configuration of the stereocenter. The only problem is that the chiral catalyst is not regenerated in the process increasing the production cost and making scale up difficult.

Another highly stereoselective epoxide opening by nucleophilic attack at C-3 may be performed using a titanium alkoxide as chiral catalyst. This compound produces a very rigid complex with only one route to stereoselective nucleophilic ring opening at C-3 (Scheme 1 1).

SCHEME 10

SCHEME 11

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172 C. C A M P 0 et al.

The asymmetric carbonyl reduction of aminoketones, 7, (ABBs pre- cursors) has been carried out using Rhodium complexes (Sakurava et al., 1995). However, the chiral catalysts are very expensive.

2.2.2. Enzymatic Catalysts

Enzymes and whole cells have been used in the preparation of chiral ABBs or of chiral synthons used in their preparation. Two different kinds of enzyme have been used: (i) monoxygenases and (ii) lipases (Takeshita et al., 1992).

2.2.2.1. Epuxide Syntheses Catalysed by Monoxygenases Epoxidations of C=C bonds may be carried out with high stereoselectivity and with low structural requirements using whole cells of hydrocarbon utilizing bactera. Using whole cells of Nucardia curalfina (R = alkyl) (Furuhashi et al., 1989), Rho~lococcus eqiti (R’ = CH2CH20CH3) (Johnstone et al., 1987), or Psezidumunas oleovorans (R’ = CHzC02CH3) (Johnstone et ul., 1987) ally1 ethers may be stereoselectively epoxidized to (S)-glycidyl ethers (Scheme 13).

SCHEME 13

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SYNTHESIS OF ADRENERGIC &BLOCKERS 173

The chiral epoxides produced may be regioselectively reduced using LiAlH4 to give chiral, 1 -aryloxy-1 ,Zpropanodiols (Furuhashi et al., 1989), or regioselectively opened with N-alkylamines to give the ABB-structures.

2.2.2.2. Resolution of Racemates Using Lipases Lipases are widely used in the resolution of secondary alcohol racemates, due to the high enantioselectivity and stability of these kind of extracellular enzymes in organic solvents (Schmid and Verger, 1998). These enzymes have been used in the resolution of several ABB-synthons (Kamal et al., 1992; Mohapatra and Hsu, 1994) (Scheme 14).

In this way, the enantioselective resolution of racemic glycidylbutyrate using pancreatic porcine lipase (PPL) (Aragozzini et al., 1989) was achieved with excellent enantioselectivity. This procedure gives the synthon with the adequate stereochemistry to obtain the (9-adrenergic @-blocker.

Nevertheless, the most useful methodology is the resolution of halocompounds (Scheme 15). Pederson et al. (1990) have carried out the PPL-catalysed resolution of the racemic acetate to give the (a-0- benzylglycidol after one chemical step.

Takano et al., obtained (R)-epichlorhydrin with e.e. > 99% in the resolution of the primary racemic alcohol with the stereogenic center in

PPL 0 - + 0 60% yield

H2O

45% (92% e.e.R)

SCHEME 14

O A C

I

PPL - CI-OCH2Ph C l x O C H 2 P h 60 YO yield I NaOH

SCHEME 15

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174 C. C A M P 0 er (I! .

Ca (Scheme 16) using lipase from Pseudomoim sp. The unreacted (S)- isomer is easily transformed in the (R)-epichlorhydrin (Takano et ai., 1989).

This epichlorhydrin can be transformed in the adrenergic P-blocker according to Scheme 4.

An alternative to this methodology has been developed in our laboratory using lipase B from Cundida antarcticu (Scheme 17). Both strategies- hydrolysis of secondary acetate or acylation of secondary alcohol were tested by 11s (Bermlidez et al., 1996).

Several halohydrins (8a - d) and their acetates (7a - d), both precursors of ABBs. were tested to determine the generality of the methodology (practolol, metoprolol, acebutol, propranolol). In addition, several nucleo- philes were tested (water, methanol, n-butanol). Some results are shown in Table I .

SCHEME 16

7a-d 5 a-d 6 a-d

8a-d 6 a-d 5 a-d

SCHEME 17

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TA

BL

E 1

Pr

epar

atio

n of

chi

ral p

recu

rsor

s of

AB

B u

sing

C. a

ntar

ctic

a lip

ase

B. R

eact

ion

carr

ied

out w

ith l

Om

l of t

-BuO

Me,

5m

g of

na

tive

lioas

e

Rea

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n M

ain

Mai

n co

nditi

ons

Tim

e Yi

eld

isom

er

isom

er

Com

p T

a ("

C)

0"

(h)

("/I

ees

of S

USt

ee

P of

prod

E(

23)

7a

25

(5) H

20

144

41

95(7

a)

-R

95(8

a)

+S

10

3 37

(5

) H2O

48

50

95

(7 a

) -R

95

(8 a

) +

S

145

25

(10)

H20

16

8 31

67

(7 a

) -R

95

(8 a

) +

S

68

25

(5)

MeO

H

168

39

77(7

a)

-R

95(8

a)

+S

72

25

(20)

H20

16

8 13

20

(7 a

) -R

95

(8 a

) +

S

20

25

(5) B

uOH

6

39

59(7

a)

-R

71(8

a)

+S

9

7b

25

(5) H20

168

40

79(7

b)

-R

95(8

b)

+S

15

7c

25

(5

) H2O

14

4 37

70

(7 c

) -R

95(8

c)

+S

50

7d

25

(5

) H2O

16

8 39

77

(7 d

) -R

95

(8 d

) +

S

12

8a

25

(3) V

A

72

26

28(8

a)

-R

88(7

a)

+S

21

5 18

(8 b

) -R

95

(7 b

) +

S

34

8b

25

(3) V

A

168

sc

25

(3)

VA

I4

4 5

20(8

c)

-R

95(7

c)

+S

34

8d

25

(3

) V

A

168

10

18(8

d)

-R

95(7

d)

fS

43

34

96

3 27

(8 a

) -R

95

(7 a

) +

S

31

(3) V

A

~~~~

~

aMol

ar ra

tio n

ucle

ophi

le/7

or

VA

j8

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176 C. CAMP0 et ul.

The best yields and enantioselectivities (e.e.) were obtained using 5 eq. H 2 0 per equivalent of 7a. An increase in the reaction temperature from 25°C to 37°C reduced the reaction time without reducing e.e. An increase in the molar ratio H20/7a reduced the yield. MeOH and n-BuOH were less interesting than H 2 0 because a lower e.e. was achieved.

The acylation reactions were performed with vinyl acetate (VA) as acyl donor. Lipase B of Cundida antarctica gave the (R)-acetate precursor of (3- ABB acetate with good e.e. as the main ester. An alternative has been reported by Matsuo and Ohno (1985). These authors reported that (9-1- acetoxy-2-aryloxy-propanonitrile and the (R)-alcohol might be obtained easily by enantioselective and chemoselective hydrolysis from racemic ester using a lipase from Pseudonionas sp. as biocatalyst. The S-acetate may be converted in the (9-ABBs in two steps. Ohta et al. (Ohta et al., 1986) have reported the same racemic resolution but using crude extracts from a Bacillus sp. (Scheme 18).

The combination of preparative chiral HPLC and the enantioselective hydrolysis of 1 -aryloxy-3-chloro-2-propyl esters as been used to screen, lipases from Aspergillus o r p a e , Aspergillus niger, Aspergillus sojae, Candida lipolyticu, Cnndidu sp., Cliromobacterium viscosum, Humicola laruginosa, Geotrichum candidum, Mucor miehei, Penicillium roquejortii, Rhizopus delamur, Pseudonionm fluoresceiis, Pseudomonas sp., porcine pancreatic lipcrsr (PPL), as well as cltolesterol esterase and porcine liver esterase (PLE) (Ader and Schneider. 1992a, 1992b, 1992~). The best results were obtained with PLE and lipase from Pseudomonas sp.

The hydrolysis reactions are, generally, faster compared with the other reactions (transesterification, esterification or interesterification). The latter reactions are thermodynamically more favourable in hydrophobic organic solvents with limited quantities of water, where the enzyme has reduced flexibility. Another common limitation on the lipase-catalysed hydrolysis reaction is that the oily ABB precursor substrates are insoluble in water. Emulsification of the substrate with a surfactant results in difficult downstream processing, poor yield and difficulties in scale up.

SCHEME 18

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SYNTHESIS OF ADRENERGIC BBLOCKERS 177

Complete solubilization of the substrate in water, by addition of polar organic solvents, reduces the catalytic activity of lipase because these enzymes need an oil/water interface to be active (Mohapatra and HSU, 1997). Chemical modification of external amino acids of the lipase by means of amphipathic substrates has been reported to overcome this problem and is useful for obtaining good yield and e.e. (Mohapatra and Hsu, 1994) using THF or acetone (33% v/v) as cosolvent.

2.2.3. Use of Chiral stationary Phases (CSPs)

An alternative to the resolution of racemates by lipases is to use chiral Stationary Phases (CSPs). In Scheme 19 we show the host-guest matrix and the propranolol precursor used (Campo et al., 1996).

The propranolol precursor was initially transformed to I. The naphthal- ene ring in the guest molecule I1 allows us to follow the separation by fluorescence or UV-absorption, continuously.

The CSP matrix (11) was packed into a MPLC column and the product eluted with hexane/Zpropanol (95/5% v/v). The elution of ( R 9 - I renders firstly (R)-I and then the (9-isomer that is more retained than (R)-I because the complex formed with I1 is more stable, as was proved by MM calculus (Campo et al., 1996).

2 I

y COW- C -CWH

COOH

I O2N

SCHEME 19

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178 C. CAMP0 et (11

This method gave an 85% yield of pure enantiomers but it is complicated to generalise because one CSP and one guest must be prepared for each adrenergic R-blocker.

3. CONCLUSION

The different general methodologies to prepare chiral ABBs are described in Scheme 20. From the discussion presented in this paper, chiral synthesis may be scaled up from any compound (Scheme 20). Therefore selection of the best synthetic pathway must be determined by scale up factors and not on chemical criteria.

Natural Products Sharpless Epoxidation

I

10

AroTcl 8

OH \ . ' O T H / ,PH

OH

1

SCHEME 20

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SYNTHESIS OF ADRENERGIC 8-BLOCKERS 179

Thus, the separation of racemic ABBs using a Chiral Stationary Phase is very efficient but the separation of the racemic mixture is carried out at the end of the process (Scheme 20). This is not very attractive from the point of view of scale up.

The use of natural products, or the Sharpless epoxidation may be attractive because the chiral synthons (9 or 10) are generated at the beginning of the synthesis. However many steps (natural products pathway) or the regeneration of an expensive chiral catalyst (Sharpless epoxidation) are necessary. So each alternative must be carefully considered for each adrenergic P-blocker drug.

The resolution of (R,S) 9 or (R S) 10, by lipase-catalysed reactions are interesting procedures for scale up. The chiral synthons may be obtained with high e.e. and yields near 50%, by selecting the lipase and reaction conditions. Additionally, the low substrate specificity of lipases makes the process general for different ABBs. Medium engineering and stabilisation of the lipases through immobilisation must be the key to scaling up this process, which should be considered as the most interesting route to obtain these chiral drugs.

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