Chiral reduction of 2-oxosuccinic acid esters with fermenting bakers' yeast gave (S)-(-)- malic acid esters in 34-54% isolated yield with 85-100% ee

Ono, Shin-ichiro

Tsuboi, Sadao

Utaka, Masanori

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Asymmetric Synthesis of Optically Active Malic Acid

Okayama University Scientific Achievement Repository

Journal of the Faculty of Environmental Science and Technology, Okayama UniversityVol. 1 , No.1, pp.205-210, March 1996Asymmetric Synthesis of Optically Active Malic Acid tSadao TSUBOI,* Shin-ichiro ONO,** and Ma.'ianori UTAKA***(Received November 17 , 1995)AbstractChiral reduction of 2-oxosuccinic acid esters with fermenting bakers' yeast gave (S)-(-)-malic acid esters in 34-54% isolated yield with 85-100% ee.Key words: optically active, malic acid, bakers' yeast, asymmetric reduction, a-ketoester.1. INTRODUCTIONOptically active malic acid has been efficiently employed as a chiral building block for asymmetricsynthesis of optically active natural products,l-4) Although optically active malic acid is commerciallyavailable, there are few reports on its asymmetric syntheses.5,6) In this paper, we report higWy asymmetricsynthesis of optically active malic acid esters with fermenting bakers' yeast.2. MATERIALS AND MEfHODSChemicalsEthyl 2-oxosuccinate (la) was obtained from sodium salt of diethyl oxalacetate purchased from KantoChemical Co. LTD, as shown below. Sodium salt of diethyl oxalacetate was dissolved in water, acidified with10% HCl, and then the organic materials were extracted with ethyl acetate. The combined extracts were washedwith water, dried over MgS04, and concentrated to give la. Other 2-oxosuccinates were prepared by modifyingthe known method,7)I-methyl 4-butyl 2-oxosuccinate (1 b)To a solution of diisopropylamine [1.88 g (2.6 mI), 25.9 mmol] in tetrahydrofuran (THF) (17 mI) wasadded 12.4 mI (18.6 mmol) of 15% butyllithium in hexane at -20°C. After 20 min, butyl acetate [2.0 g (2.3mI), 17.2 mmol] was added at -78°C. The mixture was stirred for 10 min and subsequently a solution ofdimethyl oxalate (2.07 g, 19.2 mmol) in TIIF (7 mI) was added dropwise. After being stirred for 30 min at -78°C and for 1 h at room temperature, the mixture was poured into ice \vater and acidified with 10% HCI. Theorganic materials were extracted with ethyl acetate, washed with water, and dried over MgS04' Concentrationt Dedicated to the memory of our late Professor Akira Takeda. * Department of EnvironmentalChemistry and Materials, Okayama University, Okayama 700, Japan. **Present address: The Green Cross Co.Ltd., Osaka, *** Department of Applied Chemistry, FacuIty of Engineering, Okayama University.205206J. Fac. Environ. Sci. and Tech., Okayama Univ. 1 (1) 1996of the solvent left 3.18 g of an oil, which was chromatographed on Si02 (hexane-ethyl acetate = 20: 1-1: 1) togive 1.82 g (52.3%) of 1b: Colorless oil, IR: 3000, 1740, 1660, 1280, 1118, 795 cm-I. IH NMR (60 MHz,CCI4, coupling constants in Hz) 6=1.00 (t, J = 7, C02(CH2BCH3), 1.18-1.80 (m, C02CH2(CH2)2CH3),3.85 (s, C02CH3), 4.21 (t, J = 7, C02CH2), 5.91 (s, CH2CO). Other 2-oxosuccinates were prepared by thesame method.I-Methyl4-tert-butyl 2-oxosuccinate (1 c): Colourless oil, 53% Yield, IR: 3000,1740,1655,1260,1150,835 em-I. IH N.MR (60 MHz, CCI4) 0=1.50 (s, qCH3)3), 3.56 (s, CH2CO), 3.78 (s, C02CH3), 5.78(s, CH=C-OI-I), 11.56 (broad s, 01-1).I-Methyl4-benzyl 2-oxosuccinate (1 d): Colourless oil, 36% Yield, IR: 1740, 1660, 1100, 780 cm-1; IH NMR (60 MHz, CCI4) 0=3.69 (s), 3.75 (s), 5.12 (s), 5.90 (s), 7.19 (s), 11.43 (broad s).l-IsopropyI4-ethyl 2-oxosuccinate (l e): Colorless oil, 70% yield, IR: 1730, 1660, 1100,780 em-IH NMR (60 MHz, CC14, coupling constants in Hz) 0=1.31 (t, J = 7),1.32 (d, J = 7), 3.66 (s), 4.23 (q, J= 7), 5.06 (m, J = 7), 5.85 (s).MicroorganismsIndustrial bakers' yeast was purchased from Oriental Yeast Co. LTD., and it was stored in a refrigerator at 40c. The bakers' yeast was used within 10 days.Fermentation procedure, and Isolation and Purification of ProductsFermentation was carried out in a thermostat bath at 32±2 0c. All glasswares were sterilized by boilingwater before use.For example, the preparation of (S)-(-)-diethyl malate (2a) is shown below. To a mixture of glucose (42g), KH2P04 (0.6 g), NH4H2P04 (0.6 g), MgS04 (0.16 g), CaC03 (1.6 g), and boiling water (600 ml) wasadded industrial bakers' yeast (12 g, Oriental Yeast Co.) and the mixture was stirred for 20 min at 33°C. Tothe fermenting mixture was added Ia (4.32 g, 23.0 mmol) and the resulting mixture was stirred at 33°C. Theamount of glucose was checked by a test paper for sugar diabetes. When the amount of glucose was less than0.1 %, glucos was added. So, glucose (42 g) was added after 7 and 19 h. Mter 23 h the organic materials wereextracted with ethyl acetate. The crude product (3.55 g) was chromatographed on Si02 (hexane-ethyl acetate =10: 1) to afford 2.00 g (43%) of 2a: Thin Layer Chromatography (hexane- ethyl acetate = 1: 1), Rf 0.47.3. IDENTIRCATION OF PRODUCTSAnalytical spectra were obtained with the following instruments: IR spectra, a JASCO Model A-102; IH1';'MR spectra (60 MHz), a JEOL JNM-PMX60S1 apparatus; IH NMR spectra (100 MHz) and BC NMRspectra (25 rv1Hz), a JEOL Th'M-l"j( 100 apparatus. Optical rotations were measured on a JASCO DIP-4spectrometer. Enantiomeric excess was determined by IH NMR (100 MHz) spectrum in the presence ofEu(hfc)3·S. TSUBOI et al. / ASYMMETRIC SYNTHESIS OF OPTICALLY ACTIVE MALIC ACID(S)-(-)-Diethyl Malate (2a): Colorless oil, IR and IH NMR data were identical with those of anauthentic sample. When IH NMR (100 MHz) spectrum was measured in the presence of Eu(hfc)3 (0.5 molarratio), only one enantiomer was observed.(S)-( -)-l-Methyl 4-tert-butyl 2-Hydroxysuccinate (2c): Colorless oil, IR: 3400, 1735, 1150,840 em-I, IH NMR (60 MHz, CCI4, coupling constants in Hz): 0=1.50 (s), 2.65 (d, J = 8),3.60 (s), 3.80 (s),4.30 (t, J = 8).(S)-(-)-l-Methyl 4-Benzyl 2-Hydroxysuccinate (2d): Colorless oil, IR: 3500, 1740, 1170, 750em-I, IH NMR (60 MHz, CC4, coupling constants in Hz): 0 = 2.71 (d, J = 6), 3.61 (s), 3.83 (broad s), 4.36(t, J = 6), 5.01 (s), 7.17 (s).(S)-( -)-l-Isopropyl 4-Ethyl 2-Hydroxysuccinate (2 e): Colorless oil, IR: 3400, 1740, 1180, 1040em-I, IH NMR (60 MHz, CC4, coupling constants in Hz): 0 = 1.23 (t, J = 7), 1.24 (d, J = 6), 2.63 (d, J =6),3.32 (broad s), 4.08 (q, J = 7), 4.27 (t, J = 6).4. RESULTSEnantioselective reductions of a-keto esters with fermenting bakers' yeast giving optically active a-hydroxy esters are well known.7,8,9) However, the treatment of 2-oxosuccinates 1 with fermenting bakers'yeast is not reported. Recently we found that diethyl 2-oxosuccinate (1 a) is reduced with bakers' yeast to affordalmost optically pure (S)-(-)-dietbyl malate (2a). Since the absolute configuration and the optical purity of thereduced207EI02C"!C02Et1aBakers' Yeast------.(S)-(-)-Diethyl Malate (2a)products depends strongly upon the nature of the ester moiety,1O,11) some 2-oxosuccinic acid esters 1 wereprepared and reduced with fermenting bakers' yeast. These results are summarized in Table 1. Optical purity ofdiethyl malate (2a) obtained by the present reaction was shown to be 97-100% ee by comparison of the opticalrotation with that of the authentic sample. 12,13) "The optical purities of other esters such as 2 b (R = n-(A,H9,R' = CH3), 2c (R = t-(4H9, R' = CH3), and 2d (R = CH2C6H5, R' = C1I3) decreased than that of 2a asshown in Table 1.All of the reactions afforded (S)-malates in moderate yields regardless of the ester moiety.Absolute Configuration of the Malates 2The absolute configuration of the optically active malates 2 was determined as (S) after conversion of 2 tothe 1,2-acetonide (5) of (S)-(+)-I,2,4-butanetriol by comparing the sign of optical rotation with that of anauthentic sample. Reduction of (S)-(-)-I-methyI4-terl-butyl 2-hydroxysuccinate (2 c) with NaBH4 in methanol~00Table 1. Asymmetric Reduction of 2-0xosuccinates 1 to 2-Hydroxysuccinates 2a withRO c/')(C02R'2 .HO ·-:'H2Baker' s YeastBaker's YeastR02C~C02R'o ------.:=..~1FermentingChern. Yieldb Optical YieldNo. R R'% %ee[ 0:] 0(c, solvent)AbsoluteConfiguration.,....'"'1"'"tTl"<§'pif]p.a C2HS C2HS 43 97-100c [0:]023 -9.94° (neat) Sb n-C4H9 CH3 S2 9Sd [ 0:] 017 +1.72° (2.67, CHCl 3) Sc t-C4H9 CH3 47 100e [0:]033 +4.30° (3.07, CHCl3 ) Sd CH2C6HS CH3 S4 9Sd [0:]026 +0.78°(S.6S, CHCl3) Se C2HS CH(CH3 )2 34 8Sf [0:]022 -11.2S0(3.20, CHCl3 ) S"'"c.....,ro'"'Fo:>;""''<"'s"'c:::":;:'......<0~a Compounds 2 except 2a are new. Satisfactory spectral and analytical data were obtained.b Isolated yield. c Calculated by comparison with the known data: [0:]0 -10.3° 0.1 (neat)[0:]02S -9.3° (neat) (see ref. 13). d Pure by 1H NMR analysis in the presence ofEu(hfc)3. e By comparing the optical rotation after the conversion to dimethyl malate.f By comparing the optical rotation after the conversion to malic acid.S. TSUBOI et a1. / ASYMMETRIC SYNTHESIS OF OPTICALLY ACTIVE MALIC ACIDat 25°C gave telt-butyl (S)-3,4-dihydroxybutanoate (3c) in 78% yield. Acetonidation of diol 3c was carriedout by stirring the solution of 3c in acetone in the presence of catalytic amount of p-toluenesulfonic acid for11 h, giving tert- butyl (S)-3,4-0-isopropylidene-3,4-dihydroxybutanoate (4c). 'The subsequent reduction of theacetonide 4c with LiAU4 in dry ether at -45 °C afforded (S)-(+)-1,2-isopropylidenebutane-l,2,4-triol (5):[a]o20+2.68° (c 0.82, EtOH)[lit.) [a]o20.5_3.7° (c 3.6, EtOIl) for (R)-(-)-5]. Its conversion was alsoconducted by the acetonidation of (S)-butane-l,2,4-triol (6) obtained by the direct reduction of 2 with LiAlI4.Spectral data of 5 were identical with those of the literature3 )The present method provides optically pure (S)-(-)-diethyl malate in a moderate yield by experimentallysimple procedures.2092c-----~MeOH,25°C3c5. REFERENCES AND NOTES4cether, -45°CHHO~o 0~..",5(1) M. A. Abdallah, and 1. N. Shah, An Approach to the Synthesis of (3R)- and (3S)-2,3-Epoxysqualene, J.Chern. Soc. Perkin 1,888 (1975).(2) O. B. Collum, 1. H. McDonald III, and W. C. Still, Synthesis of the Polyether Antibiotic Monensin. 2.Preparation oflntermediates, J. Am. Chern. Soc., 102,2118 (1980).(3) K. Mori, T. Takigawa, and T. Matsuo, Synthesis of Optically Active Forms of Ipsdienol and Ipsenol,Tetrahedron, 35,. 933 (1979).(4) Y. Ohfune, M. Tomita, and K. Nomoto, Total Synthesis of 2'-Deoxymugineic Acid, the !vletal ChelatorExcreted from Wheat Root, J. Am. Chern. Soc., 103,2409 (1981).(5) H. F. Fisher, C. Frieden, 1. S. M. McKee, and R. A. Alberty, Concerning the Stereospecificity of the210 1. Fac. Environ. Sci. and Tech., Okayama Univ. 1 (1) 1996Fumarase Reaction and the Demonstration of a New Intermediate, J. Am. Chem. Soc., 77,4436 (1955).(6) E. HlmgerbuWer, D. Seebach, and D. Wasmuth, Doppelt and dreifach funktionalisierte, enantiomerenreineC4-Synthesebausteine aus ~-Hydroxybuttersaure, Apfelsaure und Weinsaure, Helv. Chirn. Acta, 64, 1467(1981).(7)(a) H. Akita, A. Furuichi, H. Koshiji, K. Horikoshi, and T. Oishi, The Use of Microorganisms in OrganicSynthesis. I. Microbiological Asymmetric Reduction of 2-Methyl-3-oxobutyrates, Chern. Pharrn. Bull.,31,4376 (1983).(b) H. Akita, A. Furuichi, H. Koshiji, K. Horikoshi, and T. Oishi, The Use of Microorganisms in OrganicSynthesis. II. Mirobiological Asymmetric Reduction of 2-Methyl-3-oxosuccinates, Chern. Pharm. Bull.,31,4384(1983).(8) D. D. Ridley, and M. Stralow, The Stereospecific Asymmetric Reduction of Functionalized Ketones, J.Chern. Soc. Chern. Cornrnun.,400 (1975).(9) S. Tsuboi, E. Nishiyama, M. Utaka, and A. Takeda, A Facile Synthesis of (R)-(-)-HexahydromandelicAcid with Fermenting Bakers' Yeast, Tetrahedron Letters, 27, 1915 (1986).(10) B. Zhou, A. S. Gopalan, F. V. Middlesworth, W.-R. Shieh, and C. .T. Sih, Stereochemical Control ofYeast Reductions. 1. Asymmetric Synthesis of L-Carnitine, 1. Am. Chern. Soc., lOS, 5925 (1983).(11) W.-R. Shieh, A. S. Gopalan, and C. .T. Sih, Stereochemical Control of Yeast Reductions. 5.Characterization of the Oxidoreductases Involved in the Reduction of b-Keto Esters, 1. Am. Chern. Soc.,107,2993 (1985).(12) B. Seuring, and D. Seebach, Synthese von vier chiralen, elektrophilen C3- and C4-Synthesebausteinen ausHydroxycarbonsauren, Helv. Chirn. Acta, 60,1175 (1977).(13) D. Seebach, E. HungerbuWer, R. Naef, P. Schnurrenberger, B. Weidmarm, and M. Zuger, Titanate-Mediated Transesterifications with Functionalized Substrates, Synthesis, 138 (1982).

Asymmetric Synthesis of Optically Active Malic Acid

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