Krupadanam, G L David

Ramadas, S

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Indian Journal of ChemistryVol. 36B, December 1997, pp.1119 - 1122Baker's yeast catalysed enantioselective reduction of chroman-4-onesS Ramadas & G L David Krupadanam*Department of Chemistry, Osmania University,Hyderabad 500 007, IndiaReceived 30 April 1997; accepted (revised) 2 September 1997Substituted chroman-4-ones la-lOa on catalytic reduction with Baker's Yeast give (S)-chroman-4-ols Ic-I Ic with high enantioselectivity. The absolute configuration has been determined by specificrotation and CD spectra.The enantioselective reduction of carbonylcompounds using bio-catalysts such as isolatedpure enzymes or whole cells such as yeasts,bacteria and fungi continue to attract the attentionof synthetic organic chemists 1.2. Whole cell yeastcatalysed reactions are particularly attractive inthis respect as yeast is readily and cheaplyavailable bio-catalyst and the use of whole cellsobviates the need for the addition of expensive co-factors. It is now known that, in general, theBaker's yeast catalysed enantioselective reductionof carbonyl compounds proceed in accordancewith the Prelog's rule', Earlier, (S)-chorman-4-01le was obtained by the lipase catalysed kineticresolution of racemic chroman-a-ol Ib".Substituted chroman-4-ones, a class of oxygenheterocyclics, are common among natural productsand are extensively used as syntheticintermediates'. Earlier Holl et al.6 studied theMortierella isabellina catalysed reduction ofchroman-4-one la and thiochroman-4-one and theproducts are (S)-chroman-4-ol le and (S)-thiochroman-4-ol in 84% ee and 88% eerespectively. There are no reports in the literatureregarding the enantioselective reduction ofchroman-4-ones using Baker's yeast. We reportherein the bio-reduction of several substitutedchroman-4-ones la-lOa using Baker's yeast(Scheme I).In a typical experiment, chroman-4-ones la-lOa(0.3 mol) dissolved in ethanol (5 mL) was slowlyadded during 24 hr to a citrate buffer 0.05 M (300ml) containing Baker's yeast beads immobilised incalcium alginate" and stirred at RT for 48-168 hr,':*>" -~i-~;-:u-:~-:b-:~-:a_f:-:_. ,:!~Q"R4 0 pH= 4,5-5·0 R4 H OH48-168 hrs.(10-110) (Ie-lie)I a,b,c = RI ,R2,R3,R4,R5=H2 a,b,c = RI ,R2,R4,R5=Hj R3=CI3 a,b,c = RI ,R2,R4 ,R5=H; R3=CH34 a,b,c = RI, R2,R3 ,R5::,Hj R4=CH35 a,b,c = R2,R3,R4,R5=Hj RI =CH36 a,b,c = RI ,R3,R4 ,R5=Hj R2=OCH37 a,b,c = R3,R4,R5=Hj RI=CH3,R2.=OCH38 a,b,c = RI, R2,R4,R5=HjR3=Br9a,b,c =RI,R3,R4,R5=HjR2=CI10 a,b,c = RI ,R3,R4 ,R5=H j R2=CH20-@II a,b,c = RI,R2,R4=H;R3=CI;R5=~Scheme Imaintaining. pH of the reaction mixture at 4.5-5.0by the addition of ammonia. The reduction wasmonitored by TLC by comparison with authenticracemic chroman-4-ols lb-lOb. When there is nofurther increase in the product concentration, thesupernatant solution was decanted, extracted withethyl acetate and column chromatographed onsilica gel. The yields of le-IOe was 30-40% (TableI). Racemic Ib-lOb needed to moriitor the bio-1120 INDIAN J CHEM. SEC. B, DECEMBER 1997Table I--Characterization data of (S)-chroman-4-ols I c-I OeCompel Reaction %of %ofee Specific CD 9xlO-ltime Chemical (from chiral rotation data (deg.cm'.d. mol:')(hr) yield HPLC) (in CHCll)Ie 48 30 88.4 -40.00 (-)228 nm (-) 220x10-l(c,O.5%) (-)280 nm (-) 48x10-l2e 96 40 73.3 -30.30 (-)232 nm (-) 293x10-l(c,0.33%) (-)240 nm (-) 79xlO-l3e 72 34 44.2 -2.70 (-)230 nm (-) 21 Ox1o-(c,2%) (-)285 nm (-) 59xlO-l4e 168 37 32.5 -28:04 (-)234 nm (-) 200x io-(c,0.97%) (-)270 nm (-) 25x 10-l5e 72 36 10.3 -2.00 (-)233 nm (-) 234x 10-l(c,0.5%) (-)279 nm (-) 52x10-l6e 96 30 74.1 -8.80 (-)229nm (-) 249xlO-l(c,0.05%) (-)262 nm (-) 27x10-l7e 48 30 25.0 -8.46 (-)243 nm (-) 246x IO-l(c,0.26%) (-)274 nm (-) 33x IO-lge 48 30 53.1 -25.00 (-)233 nm (-) 236x IO-l(c,I%) (-)275 nm (-) 47x IO-lIOe 168 35 65.8 -9.00 (-)236 nm (-) 220x 10-l(c,I%) (-) 203 nm (-) 39x IO-lreduction were obtained by the NaBH4 reductionof la-lOa using reported methods.The absolute configuration of the Baker's yeastreduction products Je-Hle as S is determined fromspecific rotation and CD spectra. Earlier Maja etal.' reported the CD spectral data for I e. It showednegative cotton effect with bands at 228 and 280nm. Ic-Hlc showed negative CD spectral bandssimilar to the reported for Ic (Table I). The % eeof the (S)-chroman-4-0Is is determined by chiralHPLC. Table I gives the % chemical yields, % ee,specific rotation and CD spectral data of Baker'syeast reduction products. Good enantioselectivitywas observed for unsubstituted chroman-4-one laand 6- and 7-substituted chroman-4-ones 2a, 6a,8a. The bio-reduction of prochiral chroman-4-onesproceed in accordance with Prelog's rule, with thehydride delivered to the re-face. This study showsthat Baker's yeast reduction of chroman-4-onesla-lOa offers a new route to optically active (S)-chroman-t-ols I c-I Oe.Experimental SectionBaker's yeast, Eagle brand, India was used.Specific rotations were recorded on JASCO J-20polarimeter. and CD spectra on JASCO J-20spectropolarimeter. Chiral HPLC was done onShimadzu LC 6A with Chiracel OD column(2S0xS mm), using n-hexane: isopropanol (98:2).IH (200 MHz) and l3C N!vfR (50.3) MHz) wererecorded on Varian Gemini 200 NMRspectrometer.The chiral HPLC of (±) racemic chroman-4-olsIb-IOb as well as the Baker's yeast reductionproducts le-IOe was recorded on Chiracel O.D.column (2Sx0.46 cm, Diacel, Japan) underfollowing conditions: flow 0.5 mLimin using 2%isopropanol in n-hexane as the eluent. Theretention times (min) were (±) lb 23.4 and 26.9,(±) 2b 13.0 and 14.1, (±) 3b 18.0 and 20.3, (±) 4b10.6 and 13.5, (±) 5b, 13.5 and 16.9, (f) 6b 22.0and 27.6, (±) 7b 16.3 and 18.4, (±) 8b 13.2 and16.1, (±) 9b 13.0 and 14.5, (±) lOb 17.2 and 18.3;(±) llb 17.7 and 20.2; (-) Ic 23.6 and 27.0, (-) 2e13.1 and 14.7, (-) 3e 18 and 20.4, (-)4e 10.7 and13.9, (-) 5e 13.9 and 17.1, (-)6e 22.1 and 27.6, (-)7c 16.4 and 18.7, (-) 8c 13.8 and 15.2, (-) 9c 13.1and 14.6, (-) IOe 17.4 and 18.4; (-) lle 17.9 and20.6.Chroman-4-ones la-lOa are already known",Ib-IOb were obtained by NaBH4 reduction ofchroman-4-ones La-Hla". (±) Chroman-s-ols (Ib,2b, 3b, 6b, 8b, 9b, lOb) are already known".Baker's yeast beads immobilised in calciumalginate are prepared as per reported method':".General procedure for the Baker's yeastmediated synthesis of (S)-ehroman-4-o1s. Baker'sRAMADAS et al.: ENANTIOSELECTIVE REDUCTION OF CHROMAN4-ONES 1121yeast (lOg) immobilised in calcium alginate togive beads, was kept in 20% glucose solution for48 hr The beads were filtered, washed with waterand transferred to a flask containing 0.05 M citratebuffer (300 mL) with pH 4.5-5.0. Chroman-4-onesla-lOa (0.3 mol) dissolved in ethanol (5 ml) wereadded slowly during 24 hr The reaction mixturewas gently stirred at RT for 48-168 hr The pH ofthe reaction mixture was maintained by addition of3 N NH3. The progress of the reaction wasmonitored by TLC by comparison with racemicchroman-4-ols. When there is no further increasein the concentration of the product, the supernatantsolution decanted and extracted with ethyl acetate(200 ml), dried and chromatographed on silica gel.Chroman-4-ols Ic-Iflc were obtained in 30-40%yield.lb: IR: 3375 em"; IH NMR (CDC13): & 4.15 (m,2H, OCHz), 1.95 (m, 2H, CHz), 4.60 (t, J = 2 Hz,1H, H-4), 3.0 (bs, 1H, OH), 6.82 (m, 2H, H-5, 8),7.20 (m, 2H, H-6); l3C NMR (CDC13): s 62.0 (C-2), 37.1 (C-3), 63.0 (C-4), 124.4 (C-4a), 130.0 (C-5), 121.0 (C-6) 130.0 (C-7), 117.0 (C-8), 135.0 (C-8a). MS: (m/z) 150 (100), 121 (75), 105 (20), 77(25) and 51 (20).2b: IR: 3352 em"; IH NMR (CDC13): s 4.18(m, 2H, OCHz), 2.00 (m, 2H, CHz), 4.65 (bs, IH,H-4), 1.90 (bs, 1H, OH), 7.20 (d, J = 2 Hz, 1H, H-5), 7.08 (dd, J = 10 Hz, 2 Hz, 1H, H-7), 6.70 (d, J= 10 Hz, 1H, H-8); l3C NMR (CDC13): & 62.1 (C-2),)0.3 (C-3), 63.0 (C-4), 125.7 (C-4a), 130.0 (c~5), 125.2 (C-6), 129.2 (C-7), 118.5 (C-8), 153.3(C-8a). MS: (m/z) 184 (90), 165 (20), 156 (70),107 (20), 103 (20), 75 (20), 63 (25) and 39 (20).3b: IR: 3348 ern"; IH NMR (CDC13): s 4.15 (m,2H, OCHz), "1.98 (m, 2H, CHz), 4.60 (t, J=2Hz, IH,H-4), 2.40 (bs, 1H, OH), 7.02 (d, J=2Hi, IH, H-5),6.95 (dd, J=10 Hz, 2 Hz, IH, B-7) 6.60 (d, J=10Hz, IH, H-8), 2.26 (bs, 3H, CH3); l3C NMR(CDC13): & 62.0 (C-2), 31.0 (C-3), 63.0 (C-4),124.0 (C-4a), 130.2 (C-5), 130.0 (C-6), 130.0 (C-7), 117.0 (C-8), 152,3 (C-8a), 20.1 (CH3)' MS:(m/z) 164 (100), 149 (70), 135 (.80), 121 (25), 107(30), 91 (20), 77 (30) and 51 (20).4b: IR: 3334 cm'; IH NMR (CDC13): s 4.24 (m,2H, OCHz), 2.10 (m, 2H, CHz,), 4.70 (bs,lH, H-4),1.65 (bs, iu, OR), 6.74 (dd, J = 10 Hz, 2Hz, lH,H-6), 6.74 (dd, J=10 Hz, 2 Hz, 1H, H-7), 7.00 (m,IH, H-8) 2.20 (m, 3H, CH3); BC NMR (CDC13): s62.0 (C-2), 31.0 (C-3), 63.2 (C-4), 123.8 (C-4a),126.3 (C-5), 127.3 (C-6), 131.0 (C-7), 120.0 (C-8)153.0 (C-8a), 16.0 (CH3)'5b: R: 3299 cm'; IH NMR (CDC13): s 4.20 (m,2H, OCHz), 2.02 (m, 2H, CHz), 4.70 (bs,lH, H-4),1.72 (bs, 1H, OH), 7.21 (m, 1H, H- 5) 6.64 (m, 1H,H-6) 6.64 (m, 1H, H-7), 2.28(s, 3H, CH3); l3CNMR (CDC13): & 61.6 (C-2), 30.9 (C-3), 62.9 (C-4), 123.8 (C-4a), 129.1 (C-5), 129.9 (C-6), 130.1(C-7), 116.7 (C-8) 152.2 (C-8a), 20.4 (CH3)'6a: IR: 3336 ern"; IH NMR (CDC13): s 4.28 (m,2H, OCHz), 2.05 (m, 2H, CHz,), 4.75 (bs,lH, H-4),1.95 (bs, 1H, OH), 7.20 (d, J=10 Hz, 1H, H-5),6.52 (dd, J=lO Hz, 2 Hz, 1H, H-6), 6.38 (d, J=2Hz, 1H, H-8), 3.80 (s, 3H, OCH3); 13C NMR(CDC13): & 61.7 (C-2), 30.8 (C-3), 62.0 (C-4),130.8 (C-4a), 131.0 (C-5), 116.8 (C-6), 130.9 (C-7), 101.1 (C-8) 155.5 (C-8a), 55.1.(OCH3)'7b: IR: 3375 ern"; IH NMR (CDC13): s 4.38 (m,2H, OCHz), 2.10 (m, 2H, CHz), 4.80 (bs,lH, H-4),1.75 (d, J=6 Hz, 1H, OH~ 7.15 (d, J=10 Hz, 1H,H-5), 6.55 (d, J=10 Hz, 1H, H-6), 3.90 (s, 3H,OCH3)' 2.15 (s, 3H, CH3); 13 C NMR (CDC13): s61.9 (C-2), 30.9 (C-3), 63.4 (C-4), 117.3 (C-4a),127.0 (C-5), 103.1 (C-6), 153.1 (C-7), 113.7 (C-8)158.3 (C-8a), 55.7 (OCH3), 8.0 (CH3)'8b: IR: 3389 cm'; IH NMR (CDC13): s 4.25 (m,2H, OCH2), 2.05 (m, 2H, CH2,), 4.75 (m,lH, H-4),1.75 (bs, 1H, OH), 7.44 (d, J=2 Hz, 1H, H-5), 7.28(dd, J=10 Hz, 2 Hz, lH, H-7), 6.72 (d, J=10 Hz,m, H-8). 13C NMR (CDC13): s 62.0 (C-2), 30.3(C-3), ·62.7 (C-4), 126.2 (C-4a), 132.4 (C-5), 112.3(C-6), 132.1 (C-7), 119.0 (C-8) 153.8 (C-8a). MS:(m/z) 228 (100),211 (25),200 (75), 149 (75), 131(20), 107 (40), 103 (15),91 (15) and 63 (30).9b: IR: 3297 ern"; IH NMR (CDC13): & 4.18 (m,2H, OCH2), 2_00 (m, 2H, CH2), 4.68 (bs, 1H, H-4),1.68 (bs, 1H, OH), 7.12 (d, J=10 Hz, 1H, H-5),6.80 (m, 1H, H-6), 6.80 (m, IH, H-8); l3C NMR(CDC13): 8 62.0 (C-2), 30.8 (C-3), 62.9 (C-4),122.2 (C-4a), 130.5 (C-5), 121.0 (C-6), 130.1 (C-7),_96.3 (C-8) 154.1 (C-8a). MS: (m/z) 184 (95),165 (35),155 (100),149 (95), 131 (10), 103 (5), 91(10),75 (20);'63 (15) and 51 (20).lOb: IR: 3364 cm'; IH NMR (CDC13): 8 4.18(m, 2H, OCH2), 2.00 (m, 2H, CH2,), 4.63 (bs, 1H,H-4),1.52 (bs, 1R, OR), 7.10 (d, J=10 Hz, 1H, H-5),6.47 (dd, J=10 Hz, 2 Hz, IH, H-6), 6.32 (d, 1=2Hz, IH, H-8), 4.95 (s, 2H, OCH2) , 7.30 (m, 5H,1122 INDIAN J CHEM, SEC. B, DECEMBER 1997Ph);13C NMR (CDCl3): s 61.7 (C':2), 30.8 (C-3),61.7 (C-4), 117.1 (C-4a), 128.4 (C-5), 108.3 (C-6),159.7, (C-7) l02.3 (C-8) 155.5 (C-8a). 69.7(OCH2), 127.2, 128.4, 136.8 130.5 (Ph).llb: IR: 3274 cm'; IHNMR (CDCl3): 04.85 (s,2H, OCH2), 5.15 (d, J=8 Hz, 1H, H-4), 1.90 (bs,lH, OH), 7.10-7.50 (m, 1H, H-5), 7.10-7.50 (m,lH, H-5), 7.10-7.5Q (m, 1H, H-1), 6.74 (d, J=9 Hz,1H, H-8), 6.90 (lH, =CH), 7.10-7.50 (m, 5H, Ph).AcknowledgementWe thank Heterodrugs (P) Ltd, Hyderabad,India for a research fellowship to SR.ReferencesI Servi S, Synthesis, 1990, 1.2 Roberts S M, Wiggins K, Casy K & Phythian S,Preparative Bio-transformations of whole cell andisolated enzymes in organic synthesis (John Wiley, NewYork), 1993.3 Prelog V, Pure Appl Chem, 9, 1964,119.4 Majeric M, Gelo-pujic M, Sunjic V, Levai A, Sebok P &Timar T, Tetrahedron Asymmetry, 6,1995,937.5 Ellis G P, Chromenes, chromanones and Chromones(John Wiley, New York), 1977.6 Holland H L, Manoharan S T & Schweizer F, TetrahedronAsymmetry, 2, 1991,335.7 Utaka M, Konishi S, Okubo T, Tsuboi S &- Takeda A,Tetrahedron Lett, 28,1987, 1447.8 (i) Thakar G P, Janaki N & Subba Rao B C, Indian JChem, 3,1965,74.(ii) Canalini G, Degani I, Fochi R, Spunta G, Ann Chim(Rome), 57, 1967, 1045.(iii) Steven M F, Lai, Orchison J A, Whiting D A,Tetrahedron, 45, 1989,5895.(iv) Breytenbach J C, Rail G J H, J Chem Soc Perkin I,1980,1804.9 (i) Loudon J D & Razdan R K, J Chem Soc, 1954,4299.(ii) Chakravarti D & Dutta J, J Indian Chem Soc, 16, 1939,639.(iii) Bennett P, Donnelly J A, Meaney D C & Boyle P 0, JChem Soc Perkin 1,1972, 1554.10 Bhalerao U T, Chandraprakash Y, Lukebabu R &Fadnavis N W, Synthetic Commun, 29,1993,1201.

Baker's yeast catalysed enantioselective reduction of chroman-4-ones

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Baker's yeast catalysed enantioselective reduction of chroman-4-ones

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