Argade, Narshinha P

Desai, Shrivallabh B

Ganesh, Krishna N

NOPR

Indian Journal of ChemistryVol. 37B, September 1998, pp. 918 - 920Highly efficient chemo- andenantioselective enzymatic resolution of(±)-methyl O-acetylmandelatesShrivallabh B Desai, Krishna N Ganesh* &Narshinha P Argade*Division of Organic Chemistry (Synthesis), National ChemicalLaboratory, Pune 411 008, IndiaReceived 24 February 1998; accepted 15 April 1998Chemo- and enantioselective enzymatic hydrolysis of (±)-methyl O-acetylmandelates using AmanoPS has beendescribed with very high yields and optical purity of theproducts.The utility of enantiopure enzymatic mandelic acidderivatives has been well-proved in practice. Thesecompounds are generally prepared by conventionalresolution', asymmetric synthesist, microbial3 . .4-6Thconversions and enzymatic preparations eenzyme catalyzed transesterification of (±)-methylmandelate and its acetyl derivatives 1 is knowrr' inthe literature with 25-61 % conversions and 82-99% ee of one of the isomers while the opticalpurities obtained6 during the enzymatic hydrolysisof methyl mandelates were low to moderate (15 to85% ee). Our recent success" with enzymaticresolution of chiral intermediates of (+)-diltiazemusing AmanoPS encouraged us to target theenzymatic reaction on 1 to obtain higherselectivities, and we herein report a highly efficientenzymatic hydrolysis of 1 (Scheme I).The (±)-methyl mandelate on treatment withAC20fPy for 24 hr at rt furnished (±)-methyl 0-acetylmandelate 1a in 98% yield. The AmanoPScatalyzed biphasic enzymatic hydrolysis" of 1a inbenzene plus pet. ether and 5 roM sodiumphosphate buffer of pH 7.0 at rt yielded a mixtureof (S)-methyl mandelate 2a and (R)-methylO-acetylmandelate 3a in a quantitative yield,demonstrating -100% chemoselectivity (-OAchydrolysed rather than -COOMe). The mixture of2a and 3a on separation by silica gel columnchromatography gave pure 2a and 3a in 47 and50% yields respectively. The optical purity of 2awas determined by specific rotation and 'H NMRNoter\c AmanoPS(e)soMifiU&Jffer •A C02Ms(B-1~ Ar ~ phenyl, Q Ar ~ p- Anisyl.2 3 R~COCH3K2C03~ MeOH4 R= HScheme Iof its MTPA derivative" (98-99% ee), revealingvery high enantioselectivity in the enzymatichydrolysis of 1a. The optical purity of theunhydrolysed 3a was measured by specificrotation". Compound 3a was deacylated in thepresence of a catalytic amount of K2C03 inmethanol at rt in 1 hr to obtain 4a in 95-96% yield.The optical purity of 4a was determined byspecific rotation and 'H NMR of its MTPA-derivative (90-92% ee). Similarly, the enzymatichydrolysis of 1b was performed to obtain 2b and4b (via 3b) and the results obtained aresummarized in Table 1. It is seen that the presenceof p-methoxy group on the aromatic ring does notaffect9a the high chemo- and enantioselectivity ofthe enzyme AmanoPS.In summary we have demonstrated a enzymaticresolution of (±)-methyl O-acetylmandelate usingAmanoPS with high yields and optical purities.Experimental SectionGeneral. Stereochemical assignments are based. I . f h kn d 6c,'Oon optica rotation 0 t e own compoun s .Optical rotations were measured on a JASCO DIP-181 polarimeter. Melting points are uncorrected.Column chromatographic separations were carriedout on ACME silica gel (100-200 mesh). (+)-MTPA was used for 'H NMR estimation of % ee.The enzyme AmanoPS (1420U) was obtained fromAmano pharmaceuticals [1 Unit corresponding tomicromoles of butyric acid (estimation by GC)liberated from glyceryl tributyrate per min. per mgof enzyme powder].(±)-Methyl O-acetylmandelate 1a. To asolution of methyl mandelate (2.0 g) in pyridine(10 mL) was added acetic anhydride (5 ml.), andthe reaction mixture kept in the dark for 24 hr at rt.NOTES 919Table I-Biphasic AmanoPS catalyzed hydrolysis of methyl O-acetylmandelates 1Solvent system Period (S)-methy1mandelate 2 (R)-methyl O-acetylmandelate 3(1:2) (hr) Yield [a]D25 % ee Yield [a]D25 % ee(%) (%)la Ct;H6:Pet. ether 144 47 +144O(d) 98-99 50 -1460(e) 90-92la C6H6: iso-octane 168 46 +144O(d) 98-99 50 -1450(e) 90-92Ib C6H6:Pet. ether 144 42 +1390(0 96-97 55 -I 240(e) 72-74Ib C6H6:lso-octane 168 44 +1400(0 97-98 54 -I 350(e) 78-80(c) AmanoPS-1420U, Amano Pharmaceuticals, Japan, (d) Optical rotation in methanol (c=1.0)10. (e) Optical rotation in benzene(C=1.9)5d.(f) Optical rotation in ethanol (c=I)9a.CompdLater it was concentrated in vacuo. The oilyresidue was dissolved in ether (75 mL) and theorganic layer washed with water, aqueousbicarbonate, brine and dried over Na2S04.Concentration in vacuo followed by columnchromatographic purification gave pure la as athick oil in 98% yield; IR (neat): 1740, 1725 cm':IH NMR (CDCh, 200 MHz): 8 2.20 (s, 3H,), 3.78fs, 3H), 5.95 (s, IH), 7.25-7.50 (m, 5H); I3C NMR(CDCh, 50 MHz): 820.3,52.2, 74.3, 127.6, 128.7,129.1, 133.8, 169.1, 170.0. Similarly, Ib was alsoobtained as a thick oil; IR (neat): 1740, 1725 cm':IH NMR (CDCh, 200 MHz): 82.18 (s, 3H), 3.85(s, 3H), 3.76, (s, 3H), 5.87 (s, IH), 6.95 (d, J=1OHz, 2H), 7.40 (d, J=1O Hz, 2H).AmanoPS catalyzed hydrolysis of (±)-methylO-acetylmandelate la. A solution of la (208 mg,1 mmole) in benzene-pet. etherlbenzene-isooctane(1 :2) mixture (20 mL) was added to a suspensionof AmanoPS lipase (250 mg) in 5mM aqueoussodium phosphate buffer of pH 7.0 (7 mL). Thereaction mixture was stirred at 25°C for 1441168 hrand filtered through Celite and extracted with ethylacetate (15 mLx3). The combined organic layerwas washed with water, aqueous bicarbonate,brine, dried over Na2S04 and concentrated undervacuo to give an oily residue, which was subjectedto column chromatography. Elution with ethylacetate-pet. ether (15:85) gave 3a as a thick oil, 78mg (47% yield) and 2a, 104 mg (50% yield), m.p.56-58°C. Similarly Ib on AmanoPS catalyzedhydrolysis furnished 3b as a thick oil (44% yield)and 2b (54% yield), m.p. 63-6SoC.(R)-Methyl mandelate 4a.To a solution of 3a(100 mg) in dry methanol (3 mL) was addedanhyd. K2C03 (2-3 mg) and the reaction mixturestirred at rt for I hr. Thereafter, it was filteredthrough Celite and washed with methanol. Thecombined methanol solution on concentration invacuo gave a thick oil which was dissolved in ethylacetate (15 mL) and dried over Na2S04. Removalof ethyl acetate in vacuo followed by silica gelcolumn chromatographic purification gave 4a,76 mg (95% yield), m.p. 56-58°C. Similarly 4bwas obtained from 3b (95-96% yield), m.p. 63-65°C.MTPA-esters 2a and 4a of (±)-methylmandelate. To a solution of methyl mandelate (17mg, 0.1 mmole) in pyridine (0.4 mL) was addedO.SM solution of (5)-(+)-MTPA-CI in EDC (0.4mL) at O°C and the reaction mixture further stirredfor 4 hr at rt. Usual aqueous work-up followed byether extraction (10 mLx2) , aqueous bicarbonatewash, brine wash, Na2S04 drying andconcentration in vacuo furnished correspondingMTPA derivative as thick oil.MTPA-ester of (±)-methyl mandelate: IHNMR (CDCh, 200 MHz): 8 3.58 (bs, 3H), 3.72(bs, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 6.10 (s, IH),6.13 (s, IH), 7.30-7.70 (m, 20H).. IMTPA-ester of (S)-methyl mandelate 2a: HNMR (CDCI3, 200 MHz): 8 6.10 (s, R-isomer),6.30 (s, S-isomer). The integral ratios of theseprotons indicated 98-99% ee of 2a.MTPA-ester of (R)-methyl mandelate 4a: IHNMR (CDCI3, 200 MHz): 8 6.10 (s, R-isomer),6.30 (s, S-isomer). The integral ratios of theseprotons indicated 90-92% ee of 4a.MTPA-esters of (±)-methyl a-hydroxy-a-(4-methoxyphen-yl)acetate 2b and 4b were preparedsimilarly.MTPA-ester of (±)-methyl p-methoxy-mandelate. IH NMR (CDCh, 200 MHz): 83.55 (s,920 INDIAN J CHEM, SEC.B, SEPTEMBER 19983H), 3.68 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H), 3.78(s, 3H), 3.80 (s, 3H), 6.06 (s, IH), 6.08 (s, IH),6.80-7.80 (m, 18H).MTPA-ester of methyl (S)-a-hydroxy-(4-methoxyphenyl)acetate 2b: IH NMR (CDCh, 200MHz): ~ 6.06 (s, R-isomer), 6.08 (s, S-isomer). Theintegral ratios of these protons indicated 97-98%ee of2b.MTPA-ester of methyl (R)-a-hydroxy-a-(4-methoxyphenyl)acetate 4b: IH NMR (CDCh, 200MHz): ~ 6.06 (s, R-isomer), 6.08 (s, S-isomer). Theintegral ratios of these protons indicated 78-80 %ee of 4b.AcknowledgementWe thank Amano Pharmaceuticals Co., Japanfor a generous gift of Amanof'S. One of theauthors (S B D) thanks CSIR, New Delhi for theaward of fellowship.References and Notes1 Kirk-Othrner, Encyclopedia of chemical technology, Vol.18, 4th Edn, 1976, p. 519.2 Masai M & Shiori T, Synlett, 1996,49.3 Takahashi E, Nakamichi K, Furui M & Mori T, J FennenBioeng, 79, 1995,439.4 Bradshaw C W, Humel W & Wong C H, J Org Chem, 57,1992,1532.5 (a) Vantinnen E& Kanerva L T, Tetrahedron Asymm, 6,1995,1779.(b) Miyazawa T, Kurita S, Ueji S, Yamada T & Kuwata S,J C S Perkin Trans J, 1992,2253.(c) Hsu S H, Wu S S, Wang Y F & Wong C H,Tetrahedron Lett, 31, 1990, 6403.(d) Bevinkatti H S, Banerji A A & Newadkar R V, J OrgChem, 54,1989,2453.6 (a) Lalonde J J, Govardhan C, Khalaf N, Martinez A G,Visari K & Margolin L, JAm Chem Soc, 117,1995,6845.(b) Fuganti C, Rosell C L, Servi S, Tagilani A & TerreniM, Tetrahedron Asymm, 3,1992,383.(c) Chnevert R & Letoureneau M, Can J Chem, 68, 1990,314.7 Desai S B, Argade N P & Ganesh K N, J Org Chern, 61,1996,6730.8 For enzymatic hydrolysis of 1 with pig liver acetonepowder (PLAP) and microbial hydrolysis with Bacillussubtilis var Niger see ref. 9.9 (a)Basavaiah D & Krishna, P R, Tetrahedron, 51, 1995,2403.(b) Ziffer H, Kawai·K, Kasai M, Imuta M & Froussios C, JOrg Chem, 54,1983,3017.(c) Mori K & Akao H, Tetrahedron, 36,1980,91.\0 Aldrich, Catalog handbook of fine chemicals, 1996-1997,p. 1002.11 (a) Dale J A, Dull D L & Mosher H S, J Org Chem, 34,1969,2543.(b) Dale J A & Mosher H S, JAm Chem Soc, 95, 1973,512.

Highly efficient chemo- and enantioselective enzymatic resolution of (±)-methyl O-acetylmandelates

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Highly efficient chemo- and enantioselective enzymatic resolution of (±)-methyl O-acetylmandelates

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