Tetrahedron Vol. 49. No. 37. PP. 84334440.1993 0040-4020/93 $6.00+.00 Rited in Great Britain Pergamon Press Lid

Chemoenzymatic Synthesis of Pure Enantiomeric 2-Aryl Propionic Acids.

Mariano Garcia, Carmen del Campo, Emilio F. Llama, Josh M. Shnchez-Montero, Jose V. Sinisterra*

Department of Organic and F’hannxeutical Chemistry, Faculty of Pharmacy,Unive.rs&i Complutense, 28040 Madrid, Spain

(Received in UK 11 March 1993; accepted 16 Jury 1993)

Abstract-A new chemoenzymatic procedure to obtain pure enantiomeric 2-arylpropionic acids is described. The one pot svntbesis of W-2-arvkxooionic acids is carried out bv addition of dichlorocarbcn c to the C=O bond of arvlmethviketones and cydrogenoly% of &ad&ion product. The tacemid mixture is resolved by enantiospecific hydrolysis bf the kcemic ethyl esters using native lipase from Cat&& rugosa . The good yields. the accessibility of the starting ary~ethylketones and the stereospecificity of the enzymatic hydrolysis make the process interesting in order to obtain the same non stemidal antiinflammatory drugs such as Ibuprofen or Napmxen.

2-Arylpropionic acids and derivates are very interesting in the therapeutic1 and agricultural2 fields. A great number of these compounds have a chiml center and one of the enantiomers is biologically active, e.g. Naproxen, as antiinflammatory.3 Many synthetic methodologies have been described for the synthesis of these acids with enantiomeric excess, generally as patents:4 chemical resolution of racemates of the acid, using chiral amines? chemical resolution of diastereomeric mixtures;6 reaction of chiral alcohols with ketones;7 Friedel-Crafts alkylation using lactic derivates;g asymmetric carboalkoxylation of arylalkenes;g asymmetric carbonylation of benzyl halides,lO stereoespecific rearrangement of camphosulfonyloxypropanes;11 asymmetric hydrogenation of unsaturated carboxylic acids;12 alkylation of chiral enolates of imides, l3 etc.

One alternative to these complex methodologies, is the synthesis of the racemic acid and the stereoespecific resolution using lipases. 14 Two different methods can be used: i) enantioespecific esterificationl5 or transesterificacion of the racemic acid, 15 ii) enantioespecific hydrolysis of the racemic ester. l6

In the present paper, we show the combination of the addition of dichlorocarbene to arylmethylketones and hydrogenolysis of the reaction product in a one pot process, give (f)-2- arylpropionic acids with good yields. The combination of this one pot process with the enzymatic hydrolysis of (*)-ester using lipase from Catrdida rugosa as catalyst, give (+)-2-arylpropionic acid with good total yield.

The generation of dihalocarbenes by phase transfer catalysis WC), in the presence of alkenes has been described as a good methodology to obtain dihalocyclopropanes.17,1* Nevertheless, the addition of dihalocarbenes to C=X bonds has not been extensively studied.19 We have observed that this process yields 2-hydroxy-2-arylpropionic acids with good yield. These 2-hydroxyacids can be reduced to the (i)- 2-arylpropionic acids by treatment with sodium cyanoborohydride / zinc iodide or by catalytic

hydrogenation with Pd/C using hydrogen, or an hydrogen donor such as HCOOH.

8433

8434 M. GARCIA er al.

The addition of dicholorocarbene to C=O bond is carried out in a phase medium (n-hexane) using potassium tert-butoxide as a base.This is the best methodology because isolation of the 2-hydroxy-2- arylpropionic acids is not necessary (Scheme 1).

Scheme 1

NaOH&O

I-

Ar

2) Method A: H2 / W-C Method B: HCOOH / Pd-C

This one pot methodology is general and can be applied to arylmethylketones to obtain (i)-Zaryl- propionic acids with good yields in short times. The results obtained are shown in Table 1:

Table 1

entry Ar yields (9%)

Method A Method B

C6H5 55 60

p-Me WG 40 45

p-iso-C3H7C& 40 45

p-iso-QHgC& 40 40

p-Me0Cd-Q 45 50

P-CGiH4 35 45

6-methoxy-2-naphtyl 40 45

a-thienyl 35 45

Method A: Hp / Pd-C; Method B: HCOOH I Pd-C

Synthesis of enantiomeric 2-aryl propionic acids 8435

We can observe that the origin of the hydrogen is not important as can be expected from a process that takes place on the palladium stuface. Similar conclusions have been reported by others workers.20 The greater the steric hindrance, the lower the yield. In this way, benzophenone and ketones a,a-

sustituted such as: phenyl-2.2~dimethylpropan-l-one and 2.2.4.4-tetramethylpentan-3-one, give very poor results probably due to the steric hiidrance for the addition of dichlorocarbene to C=O bond and in the adsorption of the 2-hydroxypropionic acid obtained on the Pd surface.

Our one pot methodology represents an improvement in this process as we show in Table 2 for the synthesis of (f)-6-methoxy-2-naphtyl propionic acid, we can observe that the reaction time is disminished, the obtained yield is similar or greater than that described in the literature, and our initial

products are very cheap.

Table 2

Method total yield (96) time (days) Ref

a) Methylation of arylacetic esters b) Condensation of ketones with ethyl cyanacetate

c) Condensation of ketones with

methoxymethylene triphenyl phosphorane d) Regioselective alkylation of halomethylthiopropionates e) Wildgerodt-Kindler reaction f) One pot reacction

12 5 21 20 8 22

25 2 23 46 5 24 29 7 3 50 1

The racemic mixture of acids was ester&d with ethanol25 and then hydrolysed in the presence of Cundidu rugosa lipase according to the described stereoespecifici@f of the enzyme versus the (S)- este@ (Scheme 2).

Scheme 2

-3

+

CH3 EtOH

Ar COOH 5 Ar

+

COOCH2CH3

H H

( RS )

COOH

+

CH3 Ar

(R) (S)

8436 M. GARCIA et al.

The hydrolysis time course obtained with the reference compound W-ethyl 2-phenylpropionate and with (&)-ethyl Ibuprofen, (*)-ethyl-6-methoxy-2-naphtyl propionate and (f)-ethyl-2(3benzoylphenyl)- propionate(Ketoprofen) are shown in Figure 1.

5 ._ t!

60

$ s 0 40

0

0 50 100 150

time(houn)

l:Ethyl-2(3-benzoilpheny1)propionat.e 2:Ethyl-p-isobuthyl-2-phenylptopionate 3:EthyL6-methoxy-2-naphtylpropionate &Ethyl-2-phenylpropionate

Figure 1

-+I 42 +3 *4

The enantiospecificity of the enzymatic reaction was determined after column chromatography (Si@,

CH2C12) separation of the acid from the reaction medium. Then, the diastereomeric salt of two equivalents of acid and one equivalent of the (lR,2R)-(+)-1,2diphenylethylendiamine is obtained in benzene.26 The different chemical shift values observed in methyl and methynic groups of the acids allowed us to analyse by NMR the different proportion of R and/or S isomer. In all cases the reaction of enzymatic hydrolysis was enantioespeciiic.

The yields described in the Figure 1 are referred to as the percentage of (S) acid obtained. The lower

yields obtained with the ethyl ester of 2-aryl-propionic acid and the ethyl ester of (f)-2(3benzoylphenyl)- propionic acid must be related to the instability of the emulsion oil-water. Due to the fact that lipases are enzymes that work at the interface of the microemulsion. 27 It is well known, that the enzymatic activity

of the lipase in the interface oil-water may be controlled according to the lipidic properties of the

substrate, which can be described by Hansh parameter A. This parameter has been calculated from the

literature 28 using 2-phenylpropionic ethyl ester as reference compounds. The obtained results are shown in Table 3.

Synthesis of enantiomeric 2-aryl propionic acids 8431

entry

Table 3 I Conversion(%) t=120 h.

Ethyl-2phenylpropionate 0 33.56 Ethyl-p-isobuthyl-2-phenylpmpionate 2.83 71.66 Ethyl-6-methoxy-2-naphylpropionate 4.13 93.00 Ethyl-2-(3benzoylphenyl)propionate 0.83 38.40

We can observe how the lower K value, the lower the observed microemulsion stabily and the lower the yield obtained at 120 h. In this way, the use of (f)-ethyl-6-methoxy-2naftylpropanoate(with a high rt

value 4.3) allows the obtention of higher yields, while the use of (*) 2-phenylpropionic and (f)2(3- benzoylphenyl)-propionic ethyl esters(with very different steric volumes), but with similar A values(i both cases rt* 1) gave similar yields at 120 h.

Therefore the combination of the one pot chemical synthesis of 2-aryl propionic acids by means of the addition of dichlorocarbene to the methylarylketones with the enzymatic resolution of racemates give

us an excellent procedure to prepare non steroidal an&flammatory drugs.

EXPERIMENTAL tH-NMR spectra were taken with a Varian VXR-300 NMR spectrometer using CDC13 with TMS as

an internal standard. IR spectra were obtained with a Buck Scientific 500 spectrophotometer. The reaction products were quantitatively analyzed by mvemed phase HPLC using a Tracer analytical C8 (10 nm) column, a LDC analytical pump and a LDC analytical 3100 W detector. Elution was carried out by acetonitrile / water ( 50/50 ), at a flow rate of 1 ml/mm during 20 mm, and was monitored at 258 or 254 run. Commercial Merck silica gel was used for column chromatography.

Typical general procedure. The starting ketones were obtained from Aldrich Chem, or they were

prepared according to the methods previously described in the literature.29 To a stirred mixture of 5 mmoles of ketone and potassium tert-butoxide (5 mmoles) in dry n-hexane

(10 ml), cooled in an ice bath at 00 C, was added dropwise dry chloroform (5 mmoles); the reaction mixture was stirred for 30 min at room temperature. Then the reduction step was carried out by either of the methods described below.

Merhod A (Using Hz, Pd/C). To the above solution perchloric acid (0.5 ml) and 10% Pd/C (50 mg) were added. The reaction was hydrogenated at room temperature until hydrogen uptake stopped. The catalyst was removed by filtration. The organic layer was diluted with water and extracted with Et30. The ethereal phase was dried and evaporated to yield the crude acid. The product was chromatographied on

SiO;! using dichloromerhane / n-hexane 9: 1, v/v as eluent. Methodi? (Using HC02H). To the above solution, 85% formic acid (5ml.O.13 moles) were added.

The reaction was stirred with 10% Pd/C (50 mg) at room temperature for 6 hours. The catalyst was then filtered off and the filtrate was diluted with water. The product was worked up as above to give a 50% yield.

8438 M. GARCU et al.

(RS)-2-Phenyl propionic acid 1. Elemental analysis; Found: C, 71.79; H, 6.62. Calc for

C9H1002: C. 71.98; H. 6.71%. IH-NMR (CDC13.6): 10.9 (s, H-I), 7.3-6.8 (m, 4H), 3.55 (q. lH), 1.35 (d, 3H), IR (vmax cm-t): 3680-2740, 1717 (strong).

(R,S)-2-(4’-Merhylphenyl) propionic acid 2. Elemental analysis; Found: C. 73.06; H. 7.50. Calc

for C1oH1202: C, 73.15; H. 7.37%. IH-NMR (CDC13.6): 10.9 (s, lH), 7.3-6.8 (m, 4H). 3.5 (q, lH),

2.15 (s, 3H). 1.30 (d, 3H), IR (vmax cm-l): 3600-2780, 1700 (strong).

(R&2-(4 ‘Ysopropylphenyl) propionic acid 3. Elemental analysis; Found: C, 74.77; H, 8.46.

(XC for Ci2Hl6%: C, 74.97; H, 8.39%. IH-NMR (CDC13,6): 9.55 (s, H-I), 8.25-6.45 (m, 4H), 3.60

(q. 1H). 2.80 (m. lH), 1.50 (d, 3H), 1.25 (d, 6H) IR (vmax cm-t): 3580-2800, 1710 (strong).

(R,S)-2-(4 ‘-Isobutyiphenyf) propionic acid 4. Elemental analysis; Found: C, 75.58; H, 8.96. Calc

for C13H1802: C. 75.69; I-I, 8.79%. IH-NMR (CDC13, 6): 10.55 (s, lH), 8.4-6.7 (m, 4I-l). 3.60 (q,

lH), 2.40 (d. 2H), 1.80 (m, lH), 1.4 (6 3H). 0.8 (6H).IR (vmax cm-t): 3400-2400, 1730 (strong).

fR,S)-2-(4 ‘-Methoxyphenyl) propionic acid 5. Elemental analysis; Found: C, 66.75; H. 6.82. Calc

for CloHi203: C, 66.65; H, 6.71%. ‘H-NMR (CD@, 6): 10.05 (s. lH), 7.5-6.4 (m, 4I-I). 3.65 (q,

lH), 3.30 (s, 3H), 1.60 (d, 3H). IR (vmax cm-l): 3600-2800, 1710 (strong).

fR,S)-2-f4 ‘-Chlorophenyl) propionic acid 6. Elemental analysis; Found: C. 58.43; H, 5.06. Calc

for C9H&Cl : C, 58.55; H, 4.91%. IH-NMR (CDC13,6): 10.0 (s, Hi), 8.55-7.0 (m, 4H), 3.77 (q.

lH), 1.55 (d, 3H) IR (v- cm-l): 3600-2420. 1700 (strong).

(R,S)-2-(6’-Methoxy-2 ‘-naphtyl) propionic acid 7. Elemental analysis: Found: C, 73.10; H. 6.29. Calc for C14H1403 C. 73.03; H, 6.13%. 1H-NMR (CDC13,6): 11.0 (s, lH), 7.85-6.95 (m. 6H). 3.90

(s. 3H), 3.70 (q. lH). 1.55 (d, 3H). IR (vmax cm-l): 3220-2720. 1730 (strong).

(R,S)-Wcr-Thienyl) propionic acid 8. Elemental analysis; Found: C. 53.89; H, 5.22. Calc for

C7H&S : C, 53.83; H, 5.16%. IH-NMR (CDC13, 6): 10.4 (s, lH), 8.0-6.3 (m, 4H), 4.10 (q, lH),

1.65 (d, 3H). IR (vmax cm-l): 3600-2400, 1720 (strong).

1. 2.

3.

4.

REFERENCES

Shen. T.Y. Angew. Chem. Int. Ed. Engl. 1972, 11, 460.

Art, D.; Jautelat, M.; Lautzch, R. Angew. Chem. IN. Ed. Engl 1981,20, 703.

Harrison, LT.; Lewis, B.; Nelson, P.; Rooks, W.; Fried, J.H.; Roszkowski, A.; Tomolonis, A.

J. Med. Chem. 1970, 13,203.

(a) Hayashi, T.; Konishi, M ; Fukushima, M.; Kanehira, K ; Hioki, T.; Kumada, M. J. Org. Chem. 1983,48.2195. (b) Franck, A.; Ruechartdt, C. Chem. Left. 1984, 1431.(c) Hiyama, T.;

Wakasa, N. Tetrahedron Lett. 1985, 3259. (d) Rieu, J.P.; Boucherle, A.; Cousse, II.; Mouzin,

G. Tetrahedron 198642.4095. (e) Hiyama, T.; Saito, K.; Wakasa, N.; Inoue, M. Chem. Letr. 1986, 1471. (f) Gu, Q.-M.; Chen. C.-S.; Sih, C.J. Tetrahedron Left. 1986, 27, 1763. (g) Parrinello, G.; Stille, J.K. J. Am. Chem. Sot. 1987. 109.7122. (h) Piccolo, 0.; Spreafico, F.;

Visentin, 0.; Valoti, E. J. Org. Chem. 1987,52, 10. (i) C.; Castaldi. C.; Cavicchiloli, S.;

Giordano, C.; Uggeri, F. J. Org. Chem. 1987, 52, 3018. (j) Giordano, C.; Castaldi,

GXavicchiloli, S.; Villa, M. Tetrahedron 1989,45.4243. (k) Takano. S.; Yanase, M.;

Ogasawara, K. Heterocycfes 1989, 29, 1849. (1) Ahmar, M.; Girard, C.; Bloch, R. Terruhedron

Synthesis of enantiomeric 2-aryl propionic acids 8439

5.

6.

7.

8. 9. 10.

11.

12. 13.

14.

15.

16.

17.

18. 19.

20.

21. Nelson, P.H. U.S. 3681432, 1972. C.A. 77, 1263173.

Lert. 1989, 30, 7053. (m) Wu, S.-H.; Gu. S.-W.; Sih, C.J. J. Am. Chem. Sot. 1990, 112, 1190. (n) Hiyama, T.; Wakasa, N.; Ueda, T.; Kusumoto, T. Bull. Chem. Sot. Jpn. 1!290,63,

640. (0) Guanti, G.; Narisano. E.; Podgrski. S.; Thea, S.; Andew, W.Tefrahedron 1990.46,

7081.(p) Baird, J.M.; Kern, J.R.; Lee, G.R.J. Org. Chem. 1991, 56, 1928. (q) Sonawane. H.R.; Bellur, N.S.; Ahuja. J.R.; Kulkami, D.G. Tetrahedron Asymetry 1992.3, 163. Newman, P. Optical Resolution Procedures for Chemical Compoun&, Optical Resolution Information Center: New York. vol. II, 198 1.

(a) Nicholson. J.S.; Tantum. J.G. Ger. Ofin. DE. 2809794 1979, Chem. Abstr.1979.90, 2261Oj.(b) Shijata, S.; Noguchi, M.; Matsushita, H.; Kaneko, H.; Saturi, M.; Yohikawa, S. Bull. Chem. Sot. Jpn. 1982,55,3546. (c) Frack, A.; Ruechardt, C. Chem. Len. 1984, 1431. (d) Ruechardt, C.; Gaermer, H.; Sudz, U. Angew. Chem. fnr. Ed. Bngl. 1984,23, 162.

(a) Jaehme, I.; Ruechardt, C. Angew. Chem. Inr. Ed. Engl. 1981.20, 885. (b) Saltz, U.; Ruechardt, C. Tetrahedron Left. 1982.4017. Pk~olo. 0.; Spreafico. F.; Visentin, G.; Valoti, E. J. Org. Chem. 1985, 50, 1985. Cometti, G.; Chiusoli, G.P. J. Orgatwmetal. Chem. 1982, ~31.236. Arzoumanian, H.; Buono, G.; Petrignani, J.F.; Choukrad, M. III OMCOS I-45 105.1985, Kyoto.

Tsuchihashi, G.; Mitamura, S; Kitajima, K.; Kobayashi, K. Tetrahedron L.&t. 1982.5427. Ohta, T.; Takaya, H.; Kitamura, M.; Nagoi, N.; Noyori. R.; J. Org. Chem. 1987.52.3174. Fadel, A. Syn. Lett. 1992, 48.

(a) Kirchner, G.; Scollar, M.P.; Klibanov, A.M. J. Am. Chem. Sot. 1985, 107, 7072. (b) Chen, C.S.; Sih, C.J. Angew. Chem. Int. Ed. Engl. 1989. 28,695. (c) Battistel, E.; Bianch, D.; Cesti, P.; Pina, C. Biorechnol. Bioeng. 1991, 38, 659.

(a) Chen, C.-S.; Wu, S.-H.; Girdaukas, G.; Sih, C.J. J. Am. Chem. Sot. 1987, 109, 2812. (b). Bjorkling, F.; God&&en, S.E., Kirk, 0. J. Chem. Sot. Chem. Commun. 1989, 934.(c) Bodn& J.; Gubicza, L.; Szab6 L.-P. J. Mol.Car. 1990. 61, 353. (d) Klibanov, A.M.;

Act. Chem. Res. 1990, 23, 114.(e) Carta, G.; Gainer, J.L.; Benton, A.H.; Biotechnol. Bioeng. 1991, 37, 1004. (f) Engel, K.-H.; Bohnen, M.; Dobe. M. Enzyme Microb. Technol. 1991, 13. 655. (g) Holmberg, E.; Huh, K. Biocatalysis 1992, 5,289. (h) Reslow, M., Adlercreutz, P.; Mattianson, B. Biocatalysis 1992, 6,307. (a) Holmberg, E.; Dahlen, E.; Norin. T.; Huh, K. Biocatalysis 1991.4, 305. (b) Bevinakatti,

H.S.; Bane@, A.A.; Newadkar, R.V., Mukesh, D. Biocatafysis 1991.5, 99. (c) Gu, Q.-M.; Sih, J.C. Biocatafysis 1992, 6, 115. (d) Chiou, A.-J., Wu, S.-H., Wang, K.-T. Biotechnology Letters 1992, 14, 461. (e) Ader, U.; Schneider, M. Tetrahedron Asymefry 1992,3, 201. (f) ibid. 205. (g) ibid. 521. (h) Naemura, K.; Furutani, A. J. Chem. Research. 1992, 174. Makosza, M.; Wawrzyniewicz, Tetrahedron Lett. 1%9,4659. Demlow, E.V Angew. Chem. Inr. Ed. Engl. 1977, 17,493. (a) Dockx, J. Synthesis 1973, 441. (b) Merz, A. ibid. 1976,724. (c) Kuhl, P; Mtlhlstadt, M; Graefe, J. ibid. 1976, 825. (d) Makoska, M. Usp. Khim. 1977, 46, 2174. (e) Jefferies, I. Diss. Abstr. Int. B. 1988, 49, 112. (a) Aramendia, M.A.; Borau, V.; Jimenez, C.; Marinas, J.M. Perez, C. Acra Cient. Venezolana 1982.33. 126. (b) Aramendia, M.A; Borau, V.; Gomez, M.C.; Jimenez. C. Marinas, J.M. AppBed Cafal. 1983,8, 177. (c) Aramendia M.A.; Borau, V. Jimenez, C. Marinas, J.M. Gazzetta Chim. Ital. 1984, 114,451.

8440 M. GARCIA et al.

22.

23. 24.

25.

26.

27

28.

29.

Kigazawa, K.; Hiiragi. M.; Ishimura, H.; Haga, S.; Shirayama. K. J.P. 78.07.655. 1978. C.A. 88, 1698266. Nelson, P.H. U.S. 3562336, 1971, C.A. 74. 1413874. Arai. A., Oharu, Y.. Izumi, T. Takakuwa, J. Tetrahedron Lett. 19g3.24, 1531. Achivia, K.; Yamache, S.Y. Chem. Pharm. Bull. 1966, 14.53. Fulwood, R.; Parker, D. Tetrahedron Asymetry 1992,3,25.

a) Benzonana, G.; Desnuelle, P. Biochem. Biophys. Acta 1967, 144,703. b) Entressangles, B.; Desnuelle, P. Biochem. Biophys. Acta 1968, 159.285. c) Broekman, H.L.; Law, V.H.; KCzdy, F. J. Biol. Chem. 1973, 248. 4965. Hansch. C and Leo, A. Sustituent constants for Correlation analysis in Chemistry and Biology-

J.Wiley and Sons-New York.1979.

(a) Gore, P.H.; Chem. Rev. 1955, 55, 229. (b) Arsenijevic. L.; Horeau, A.; Jacques, J. Org.

Syn. 1973, 55, 5.