Enantioselective synthesis of [alpha]-hydroxy ketones via benzaldehyde lyase-catalyzed c-c bond formation reaction

Enantioselective Synthesis of a-Hydroxy Ketones via Benzaldehyde Lyase-Catalyzed CÀC Bond Formation Reaction Ayhan S. Demir,a,* ÷zge SÀesÀenoglu,a Elif Eren,a Birsu Hosrik,a Martina Pohl,b,dElena Janzen,b Doris Kolter,c Ralf Feldmann,c Pascal D¸nkelmann,c Michael M¸llerc,* Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey,Fax: ( ‡ 90)-312-2101280, e-mail: [email protected] Institut f¸r Enzymtechnologie der Heinrich-Heine Universit‰t D¸sseldorf im Forschungszentrum J¸lich, 52426 J¸lich, Germany Institut f¸r Biotechnologie 2, Forschungszentrum J¸lich GmbH, 52425 J¸lich, Germany,Fax: ( ‡ 49)-2461-613870, e-mail: [email protected] Present address: MPB Cologne GmbH, Neurather Ring 1, 51063 Kˆln, Germany ReceivedMay 21, 2001; ReceivedrevisedNovember 19, 2001; AcceptedNovember 23, 2001 Abstract: (R)-Benzoins and(R)-2-hydroxypropiophenone diphosphate-dependent enzyme was examined with respect derivatives are formed on a preparative scale by benzalde- to a broadapplicability of this benzoin condensation-type hyde lyase (BAL)-catalyzed CÀC bondformation from reaction in stereoselective synthesis.
aromatic aldehydes and acetaldehyde in aqueous buffer/DMSO solution with remarkable ease in high chemical yield Keywords: benzoin condensation; biocatalyst; carboligation; andhigh optical purity. The substrate range of this thiamin hydroxy ketones; thiamin diphosphate.
The benzoin reaction,[1] one of the oldest CÀC bond-forming Benzaldehyde lyase (BAL, EC 4.1.2.38) from Pseudomonas reactions in organic chemistry, has been developed for classical fluorescens Biovar I was first reportedby Gonza¬les and organic synthesis using non-chiral catalysts[2] andfor asym- Vicunƒa.[13] They showedthat this strain can grow on benzoin metric synthesis using chiral thiazolium andtriazolium salts as as a sole carbon andenergy source due to the ability of BAL to catalyst.[3] Numerous other chemical methods for the enantio- catalyze the cleavage of the acyloin linkage of benzoin yielding selective synthesis of 2-hydroxy ketones, which are not based on benzaldehyde. The enzyme used in this study was expressed CÀC bondformation, have been evolved.[4] As an alternative to andpurifiedfrom a recombinant Escherichia coli strain. For chemical methods, enantiomerically pure 2-hydroxy ketones easier purification a hexahistidine tag was cloned to the C- are preparedenzymatically[5] by reduction of the correspond- ing a-diketone with baker×s yeast[6] or an enzymatic kinetic We investigatedthe potential of BAL for catalyzing CÀC resolution of the racemate of either 2-peroxo,[7] 2-hydroxy[8] or bondformation. As shown in Scheme 1, performing the 2-acetoxy ketones.[9] In addition to these methods enzymatic carboligation reaction with BAL by using benzaldehyde as a acyloin condensation furnishing a-hydroxy ketone function- sole substrate in potassium phosphate buffer [(50 mmol LÀ1, ality in one step has recently gainedincreasing attention.[10] In our ongoing studies, we established that aromatic aldehydes (0.15 mmol LÀ1)] at 218 C andmonitoring of the reaction by can be convertedinto acyloins by a benzoyl formate decarboxy- HPLC using a chiral stationary phase column with authentic lase (BFD)-catalyzedreaction. The reaction affords (R)-benzoins samples as reference showedthe formation of (R)-benzoin and(S)-2-hydroxypropiophenone [(S)-2-HPP] derivatives with an ee > 99%, however only in low to moderate yield. The with high enantiomeric excess andin goodchemical yields.
low solubility of the aromatic substrate in aqueous buffer However, only meta- and para-substitutedbenzaldehydes could solution can be regarded as a fundamental problem. With other be usedas substrates.[11] In a preliminary communication we ThDP-dependent enzymes, e.g., benzoyl formate decarboxy- reported the ability of benzaldehyde lyase (BAL), another thi- lase (BFD) from Ps. putida, we observed that addition of amin diphosphate (ThDP)-dependent enzyme, for the enan- cyclodextrin or DMSO as cosolvent facilitates the formation of tioselective formation of (R)- and(S)-benzoins and(R)-2-HPP acyloins in high yieldstarting from hydrophobic substrates.[11c] derivatives via CÀC bondcleavage andCÀC bondforma-tion.[12] In this paper we focus on the synthetic potential of BALwith regardto the ability to catalyze CÀC bondformation on a preparative scale for the synthesis of enantiopure 2-hydroxy ketones. Another aim of this work was to give a broadsurvey of the substrate andproduct range of the BAL-catalyzedCÀC structural importance of substituents of the substrate alde- 2 (ee 91% to >99%)
hydes with regard to enzyme activity and enantiomeric excess.
¹ VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1615-4150/02/34401096 ± 103 $ 17.50-.50/0 Enantioselective Synthesis of a-Hydroxy Ketones Accordingly, addition of DMSO (20%, v/v) to the aqueous drawing properties, and heteroaromatic aldehydes. In contrast medium containing BAL resulted in the formation of (R)- to BFD, BAL accepts aromatic aldehydes substituted at the benzoin starting from benzaldehyde. This conversion worked ortho-position as well, e.g., compounds 1b ± e. Only a few almost quantitatively and(R)-benzoin was obtainedin opti- aromatic aldehydes such as pyridine-3- and -4-carbaldehyde, 4- cally pure form (ee > 99%). During the reaction most of the hydroxybenzaldehyde and pyrrole-2-carbaldehyde as well as benzoin precipitates from the reaction mixture. A small sterically demanding aldehydes like vanillin, isovanillin and amount of benzaldehyde was present at the end of the reaction 3,4-dimethoxybenzaldehyde gave either very low yield or no The reaction was carriedout on a semipreparative scale with In some cases, e.g., for the halogenatedcompound different aromatic and heteroaromatic aldehydes and the observedthe formation of trace amounts of the corresponding corresponding (R)-benzoins 2a ± s were obtainedin high yield benzils, a known side reaction which is probably due to andmostly in enantiomerically pure form (Table 1). The enantiomeric excess of the products was determined by HPLC To further demonstrate the usefulness of BAL-catalyzed on a chiral stationary phase column comparedto racemic reactions on a preparative scale the synthesis of (R)-3,3'- products, which were synthesized using classical chemical dimethoxybenzoin (2i) was performedin a repetitive batch benzoin synthesis methodology.[14] The absolute configuration mode. Starting from 2 Â 1.62 g (24 mmol) 3-methoxybenzal- of the benzoins 2a, b, i, k ± o, r, s was assignedto be R according dehyde and 60 U BAL, after 6 hours at room temperature the to a correlation of the optical rotation value of benzoins with enantiopure product 2i was isolatedin 93% yield.
data from the literature and to HPLC data of commercially The BAL-catalyzedtransformation of benzaldehyde in the available enantiomers of benzoins. The absolute configuration presence of acetaldehyde afforded (R)-benzoin (2a) and(R)-2- of 2c ± h, j, p, q was assignedassuming a uniform reaction HPP 3a in enantiomerically pure form. We observedthat the mechanism. As can be seen from Table 1, BAL is able to benzaldehyde/acetaldehyde ratio is very important for the activate and dimerize a broad range of aromatic aldehydes, product distribution, since excess acetaldehyde resulted in high substitutedwith electron-releasing as well as electron-with- yieldformation of (R)-2-HPP, whereas a 1 : 1 ratio of benzal-dehyde/acetaldehyde gave an almost equimolar mixture of(R)-benzoin and(R)-2-HPP.
As expectedfrom the above-mentionedresults, a wide range Table 1. BAL-catalyzed carboligation of aromatic aldehydes to the of aromatic aldehydes substituted at ortho-, meta-, and para- position and heteroaromatic aldehydes were accepted as donor substrates for the formation of (R)-2-HPP analogues 3a ± p (Table 2). In general ortho-substituted aromatic aldehydes afforded HPPs 3 in lower yields than the meta-, and para- substituted aldehydes. 2-Chlorobenzaldehyde and 2-methyl- benzaldehyde gave no 2-HPP formation. The preference ofBAL for aromatic substrates is underlined by the observation that 2,2'-disubstituted benzoins were formed with remarkable ease, e.g., compound 2e, whereas the corresponding 2-HPP prolongedreaction time. Interestingly, even sterically demand- ing aromatic aldehydes were accepted as donor substrates in the presence of acetaldehyde (3m ± o, Table 2). Enantiomeric excess of 2-HPP derivatives 3 was determined by chiral phase HPLC analysis using racemic compounds 3c, o[16] or (S)- acyloins 3a, d ± l preparedby BFD-catalyzedreaction[11a, c] as references. The absolute configuration of the acyloins 3a, b, d, e, g, h, j ± l, p was assignedto be R according to the correlation of the optical rotation of acyloins with data from the literature Enantiomeric excess of benzoins 2 was determined by chiral phaseHPLC analysis ( Chiralpak AD column, UV detection at 254 nm, eluent: n-hexane/2-propanol ˆ 90 : 10, flow 0.80 mL minÀ1, 20 8C ) usingracemic compounds as references.
3 (ee 93% to >99%)
Eluent: n-hexane/2-propanol ˆ 98:2, flow 0.90 mL minÀ1, 20 8C.
BAL-mediated carboligation of aromatic aldehydes Eluent: n-hexane/2-propanol ˆ 75:25, flow 0.95 mL minÀ1, 20 8C.
and acetaldehyde to the corresponding (R)-2-hydroxypropiophe- Eluent: n-hexane/2-propanol ˆ 10:90, flow 0.95 mL minÀ1, 20 8C.
Table 2. BAL-catalyzed carboligation of aromatic aldehydes and acetal- the viewpoint of the organic-preparative chemist, it is impor- dehyde to the corresponding ( R )-2-hydroxypropiophenone derivatives 3.
tant to mention that a crude cell extract of the recombinant E.
coli strain overexpressing the BAL gene[21] is sufficient for catalysis hence purification of the enzyme is not necessary. As shown for the synthesis of 3k, it is important to remove the major fraction of protein by ultrafiltration (cut-off 10 kDa) inorder to facilitate product isolation. In doing so, the desired(R)-2-HPP 3k was isolatedin 65% yieldon a 3-gram scale. As described for the benzoins, oxidation of acyloins to diketones was observed in some cases as a side reaction during work-up or even in aqueous buffer after prolongedreaction time.
The results presentedare in accordwith mechanistic investigations of other ThDP-dependent enzymes.[11a,22] Since structural information about BAL is still lacking, a structure- iscussion of the observedstereocontrol is not yet possible. Nevertheless, the carboligation must be a conse- quence of a selective attack of an enamine intermediate to an acceptor aldehyde yielding (R)-benzoins and(R)-2-HPP analogues in optically pure form. We expect that our inves- tigations concerning the substrate andproduct range of this valuable biocatalyst will be helpful for elucidation of the Enantiomeric excess of 2-HPP derivatives 3 was determined by chiralphase HPLC analysis ( Chiralcel OB column, UV detection at 254 nm,eluent:isohexane/2-propanol ˆ 95 : 5, flow 0.75 mL minÀ1, 20 8C ) using racemic compounds or ( S )-acyloins (preparedby BFD-catalyzedreaction) as references.[11] In conclusion, the methoddescribedhere presents a conven- Chiralpak AD, eluent: isohexane/2-propanol ˆ 90 : 10, flow 0.80 mL ient one-enzyme-catalyzed, highly selective synthesis of (R)- Chiralcel OB column, eluent: isohexane/2-propanol ˆ 98 : 2, flow benzoins and(R)-2-HPP analogues. The reaction works in organic-aqueous medium, overcomes the solubility problem Chiralcel OB column, eluent: isohexane/2-propanol ˆ 90 : 10, flow with organic substrates, andopens the way for large-scale preparation. The products are obtained in high yield starting Chiralpak AD column, eluent: isohexane/2-propanol ˆ 95 : 5, flow from simple, easily available aromatic aldehydes and acetal- dehyde via carboligation reactions. In this way, BAL representsa valuable alternative to BFD concerning the formation of (R)-benzoins.[11b] Since these two enzymes are enantiocomplimen-tary with regardto 2-HPP formation, most members of this configuration of 3c, f, i, m ± o was assignedassuming a uniform class of substances, except for ortho-substituted(S)-2-HPP derivatives, can be synthesized in either enantiomeric form Recently, several chiral 2-HPP derivatives became of interest as starting material for the stereoselective synthesesof biologically active substances, especially for pharmaceuti-cals possessing antifungal properties. The 2-HPP derivatives,(R)-1-(3-chlorophenyl)-2-hydroxypropan-1-one ( material for Bupropion,[17] (R)-1-(2,4-difluorophenyl)-2-hy-droxypropan-1-one (3k), starting material for Ro 09-3355[18] andSM 8668/Sch 39304,[19] and(R)-1-(3,5-difluorophenyl)-2- Enzymatic syntheses were performedin stand hydroxypropan-1-one (3l), potential starting material for 1555U88,[20] were synthesizedon a preparative scale. From (2.5 mmol LÀ1) andThDP (0.15 mmol LÀ1). NMR spectra were recordedon a Bruker DPX 400 or on a Bruker AMX 300. Chemical shifts d arereportedin ppm relative to CHCl3 (1H: d ˆ 7.27) and CDCl3 (13C: d ˆ 77.0) orDMSO (1H: d ˆ 2.49) andDMSO-d6 (13C: d ˆ 39.7) as internal standard.
Column chromatography was conducted on silica gel 60 (40 ± 63 mm). TLC was carriedout on aluminium sheets precoatedwith silica gel 60F254(Merck), andthe spots were visualizedwith UV light (l ˆ 254 nm).
Enantiomeric excesses were determined by HPLC analysis using a Thermo Quest (TSP) GC-LC-MS equippedwith an appropriate optically active column, as described in the footnotes of the corresponding Tables. GC-massspectra were determined on a phenomenex Zebron ZB-5 capillary column (5% phenylmethylsiloxane, 30 m, 250 mm; TGC (injector) ˆ 2508 C, TMS (ion source) ˆ 2008 C, time program (oven): T Enantioselective Synthesis of a-Hydroxy Ketones (R)-1,2-Bis(2-bromophenyl)-2-hydroxyethan-1-one (2d) 3008 C, MS: EI, 70 eV). Optical rotations were measuredwith a Bellingham & Stanley P20 polarimeter or a Perkin-Elmer Semisolid; yield: 90% (> 99% ee); [a]20 241 polarimeter. Mps were measuredon a capillary tube apparatus andare uncorrected. HRMS (EI) and microanalyses were carried out at the t (S) ˆ 23.1 min; Rt (R) ˆ 26.4 min; 1H NMR (400 MHz, Analytical Department, Chemische Institute der Universit‰t Bonn.
3/CCl4): d ˆ 6.97 ± 7.93 (m, 8H), 6.22 (d, J ˆ 4.9 Hz, 1H), 4.22 (d, J ˆ 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 201.6, 138.1, 134.7,133.7, 133.5, 132.4, 130.5, 129.7, 128.2, 127.9, 127.2, 124.6, 123.6, 77.6.
(R)-2-Hydroxy-1,2-bis(2-methoxyphenyl)ethan-1-one (2e) Hexahistidine-tagged BAL was obtained from recombinant E. coli SG13009cells following a procedure described previously.[11a] One unit (U) of activity Colorless solid; yield: 87% (> 99% ee); mp 998 C [Lit.[25], mp 98 ± 998 C for is defined as the amount of enzyme which catalyzes the cleavage of 1 mmol D : À 125.0 (c 0.9, CHCl3); HPLC (Chiralpak AD, n- benzoin (1.5 mM) into benzaldehyde in potassium phosphate buffer hexane/2-propanol ˆ 98:2, flow 0.90 mL minÀ1, 20 8C): Rt (R) ˆ 31.2 min.; Rt (0.15 mmol LÀ1) and15% PEG 400 (v/v)] in 1 min at 308 C.
5.92 (d, J ˆ 5.1 Hz, 1H), 4.29 (d, J ˆ 5.1 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H); 13CNMR (100 MHz, CDCl3/CCl4): d ˆ 201.6, 158.4, 157.6, 134.0, 131.1, 130.3,129.8, 128.2, 125.8, 120.9, 120.8, 111.4, 111.2, 76.1, 55.5, 55.4.
Representative Example for the Synthesis of (R)-Benzoins:(R)-2-Hydroxy-1,2-diphenylethan-1-one (2a) (R)-1,2-Bis(3-fluorophenyl)-2-hydroxyethan-1-one (2f) Benzaldehyde (318 mg, 3 mmol) was dissolved in a mixture of dimethyl Colorless solid; yield: 80% (97% ee); mp 70 ± 718 C [Lit.[24], mp 73 ± 768 C for sulfoxide (20 mL) and potassium phosphate buffer [80 mL, 50 mM, pH 7.0, D : À 38.2 (c 2.5, CHCl3); HPLC (Chiralpak AD): Rt containing MgSO4 (2.5 mM) and ThDP (0.15 mM)]. After addition of BAL (R) ˆ 18.9 min; Rt (S) ˆ 23.9 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ (20 U) the reaction mixture was allowedto standat 258 C for 48 h before a 7.67 ± 7.71 (m, 2H), 7.40 ± 7.62 (m, 4H), 6.96 ± 7.32 (m, 2H), 5.77 (d, J ˆ further 20 U of BAL were added. After 62 h no more benzaldehyde was 4.8 Hz, 1H), 4.45 (d, J ˆ 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): detected (GC-MS). The reaction mixture was extracted with dichloro- d ˆ 197.2, 163.0 (d, J ˆ 247 Hz), 162.7 (d, J ˆ 248 Hz), 140.9 (d, J ˆ 7 Hz), methane (250 mL) andthe organic layer washedwith water (25 mL) and 135.5 (d, J ˆ 7 Hz), 130.7 (d, J ˆ 8 Hz), 130.4 (d, J ˆ 7 Hz), 124.8 (d, J ˆ riedover Na2SO4. Evaporation of the solvent and 3 Hz), 123.4 (d, J ˆ 3 Hz), 121.1 (d, J ˆ 21 Hz), 115.9 (d, J ˆ 23 Hz), 115.8 (d, purification of the crude product by crystallization afforded (R)-2-hydroxy- J ˆ 21 Hz), 114.7 (d, J ˆ 21 Hz), 75.7.
1,2-diphenylethan-1-one as a colorless solid; yield: 305 mg (96%, > 99% ee);mp 133 ± 1348 C [Lit.[23], mp 132 ± 1338 C for (R)-enantiomer]; [a]22 D : À 118.3 (c 2.5, CH3COCH3) for > 99% ee]; HPLC: (Chiralpak AD) Rt (R) ˆ 27.1 min; Rt (S) ˆ 34.5 min; 1H NMR(400 MHz, CDCl (R)-1,2-Bis(3-chlorophenyl)-2-hydroxyethan-1-one (2g) 3/CCl4): d ˆ 7.92 (d, J ˆ 7.9 Hz, 2H), 7.29 ± 7.52 (m, 8H), 5.97 (d, J ˆ 6.1 Hz, 1H), 4.58 (d, J ˆ 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 198.9, 139.6, 134.1, 134.0, 129.5, 129.4, 128.9, 128.8, 128.2, 76.5.
Colorless solid; yield: 94% (> 99% ee); mp 76 ± 788 C [Lit.[30], mp 768 C forracemic compound]; [a]20 D : À 31.0 (c 1.2, CHCl3); HPLC (Chiralpak AD): Rt (R) ˆ 20.2 min; Rt (S) ˆ 26.2 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ7.09 ± 7.82 (m, 8H), 5.76 (d, J ˆ 5.7 Hz, 1H), 4.32 (d, J ˆ 5.7 Hz, 1H); 13CNMR (100 MHz, CDCl3/CCl4): d ˆ 197.5, 140.8, 135.7, 135.6, 135.3, 134.4, (R)-1,2-Bis(2-fluorophenyl)-2-hydroxyethan-1-one (2b) 130.7, 130.4, 129.5, 129.4, 128.3, 127.5, 126.1, 75.9.
Colorless solid; yield: 68% (96% ee); mp 61 ± 628 C [Lit.[24], mp 60 ± 628 C forracemic compound]; [a]20 D : À 264.1 (c 0.5, CH3OH) [Lit.[11b], [a]20 0.5, CH3OH) for > 99% ee]; HPLC (Chiralpak AD): Rt (S) ˆ 17.8 min; Rt (R)-1,2-Bis(3-bromophenyl)-2-hydroxyethan-1-one (2h) (R) ˆ 20.2 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.80 ± 7.91 (m, 1H),7.55 ± 7.67 (m, 1H), 6.98 ± 7.30 (m, 6H), 5.91 (d, J ˆ 5.6 Hz, 1H), 4.33 (d, J ˆ Colorless solid; yield: 94% (> 99% ee); mp 75 ± 778 C [Lit.[26], mp 758 C for 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 198.6, 164.2 (d, J ˆ 253 Hz), 163.5 (d, J ˆ 251 Hz), 134.7 (d, J ˆ 13 Hz), 134.1 (d, J ˆ 12 Hz), D : À 38.0 (c 2.0, CHCl3); HPLC (Chiralpak AD): Rt 130.6, 131.2, 129.2, 128.9, 124.4, 123.6, 116.2 (d, J ˆ 24 Hz), 115.4 (d, J ˆ t (S) ˆ 28.0 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.31 ± 8.30 (m, 8H), 6.01 (d, J ˆ 5.5 Hz, 1H), 4.72 (d, J ˆ 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.4, 141.1, 137.2, 137.1, 132.9, 132.6,132.2, 131.1, 130.9, 130.8, 127.8, 126.6, 123.6, 75.9.
(R)-1,2-Bis(2-chlorophenyl)-2-hydroxyethan-1-one (2c) (R)-2-Hydroxy-1,2-bis(3-hydroxyphenyl)ethan-1-one (2j) Colorless solid; yield: 80% (97% ee); mp 57 ± 618 C [Lit.[30], mp 648 C forracemic compound]; [a]20 D : À 46.0 (c 1.0, CHCl3); HPLC (Chiralpak AD): Rt Colorless solid; yield: 84% (ee not determined); mp 1508 C [Lit.[27], mp. 173 ± (S) ˆ 21.7 min; Rt (R) ˆ 24.1 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.19 ± 7.47 (m, 8H), 6.32 (d, J ˆ 5.8 Hz, 1H), 4.35 (d, J ˆ 5.8 Hz, 1H); (300 MHz, DMSO-d6): d ˆ 9.91 (s, 1H), 9.41 (s, 1H), 7.42 (d, J ˆ 7.9 Hz, 1H), 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 200.8, 136.2, 135.4, 134.2, 133.0, 7.30 (s, 1H), 7.24 (t, J ˆ 7.9 Hz, 1H), 7.09 (t, J ˆ 7.7 Hz, 1H), 6.95 (d, J ˆ 132.8, 132.3, 131.2, 130.2, 129.6, 129.3, 127.8, 126.7, 75.6; HRMS: m/z calcd.
8.0 Hz, 1H), 6.79 (t, J ˆ 7.7 Hz, 2H), 6.63 (d, J ˆ 8.0 Hz, 1H), 5.87 (s, 2H); 13C for C14H10O2Cl2 [M‡ À Cl]: 245.0375, found: 245.0372; anal. calcd. for C14H10 NMR (75.5 MHz, DMSO-d6): d ˆ 199.1, 157.44, 157.41, 141.2, 136.1, 129.7, O2Cl2: C, 59.81; H, 3.59%; found: C, 60.07; H, 3.79%.
129.5, 120.3, 119.8, 118.0, 115.1, 114.7, 114.0, 75.7.
(R)-1,2-Bis(4-fluorophenyl)-2-hydroxyethan-1-one (2k) (dd, J ˆ 12, 257 Hz), 162.9 (dd, J ˆ 12, 250 Hz), 161.9 (dd, J ˆ 12, 257 Hz),160.9 (dd, J ˆ 12, 251 Hz), 132.9 (dd, J ˆ 4, 11 Hz), 130.7 (dd, J ˆ 5, 10 Hz),121.5 (dd, J ˆ 3, 14 Hz), 118.8 (dd, J ˆ 4, 13 Hz), 112.5 (dd, J ˆ 3, 21 Hz), Colorless solid; yield: 89% (> 99% ee); mp 81 ± 828 C [Lit.[24], mp 80 ± 828 C 111.6 (dd, J ˆ 4, 21 Hz), 105.2 (dd, J ˆ 26 Hz), 104.7 (dd, J ˆ 25 Hz), 72.9 (d, D : À 95.2 (c 1.1, CH3OH) [Lit.[3c], [a]r:t: 1.0, CH3OH) for 44% ee]; HPLC (Chiralpak AD): Rt (S) ˆ 22.5 min; Rt(R) ˆ 26.5 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.84 (m, 2H), 7.25 (m,2H), 7.12 (m, 2H), 7.09 (m, 2H), 5.86 (d, J ˆ 5.4 Hz, 1H), 4.12 (d, J ˆ 5.4 Hz,1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.2, 166.7 (d, J ˆ 246 Hz),165.7 (d, J ˆ 232 Hz), 135.1, 134.9, 132.1 (d, J ˆ 9.6 Hz), 130.2 (d, J ˆ 9.4 Hz), (R)-2-Hydroxy-1,2-di(2-naphthalenyl)ethan-1-one (2q) 116.8 (d, J ˆ 22 Hz), 116.1 (d, J ˆ 20 Hz), 75.4.
Colorless solid; yield: 98% (> 99% ee); mp 1278 C [Lit.[31], mp 125 ± 1268 Cfor racemic compound]; [a]20 D : 21.0 (c 1.1, CHCl3); HPLC (Chiralpak AD, n- (R)-1,2-Bis(4-chlorophenyl)-2-hydroxyethan-1-one (2l) hexane/2-propanol ˆ 10:90, flow 0.95 mL minÀ1, 20 8C): Rt (R) ˆ 18.5 min; Rt(S) ˆ 30.0 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 6.71 ± 7.76 (m, 14H),5.92 (d, J ˆ 6.1 Hz, 1H), 4.86 (d, J ˆ 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl Colorless solid; yield: 95% (> 99% ee); mp 898 C [Lit.[28,30], mp 87 ± 888 C for 4): d ˆ 198.9, 137.3, 136.5, 134.5, 134.4, 132.9, 131.5, 129.7, 129.2, 128.9, D : À 29.0 (c 0.1, CH3OH) [Lit.[3c], [a]r:t: 128.3, 127.9, 127.2, 126.4, 124.7, 122.9, 76.7.
3OH) for 29% ee; Lit.[3b], [a]D: 32.0, (CH3OH) for 76% ee (S)]; HPLC (Chiralpak AD): Rt (R) ˆ 26.7 min; Rt (S) ˆ 31.5 min; 1H NMR (400 MHz,CDCl3/CCl4): d ˆ 7.75 (d, J ˆ 8.5 Hz, 2H), 7.31 (d, J ˆ 8.5 Hz, 2H), 7.22 (d,J ˆ 8.5 Hz, 2H), 7.15 (d, J ˆ 8.5 Hz, 2H), 5.75 (d, J ˆ 5.2 Hz, 1H), 4.32 (d, J ˆ5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.5, 141.1, 137.7, (R)-1,2-Di(2-furanyl)-2-hydroxyethan-1-one (2r) 135.2, 132.0, 130.8, 129.8, 129.5, 129.4, 75.8.
Brown solid; yield: 88% (92% ee); mp 1368 C [Lit.[2c], mp 135 ± 1368 C forracemic compound]; [a]20 D : À 21.6 (c 0.1, CH3OH) [Lit.[32], [a]20 (R)-1,2-Bis-(4-bromophenyl)-2-hydroxyethan-1-one (2m) 0.01, CH3OH) for 94% ee]; HPLC (Chiralpak AD): Rt (S) ˆ 22.8 min; Rt(R) ˆ 28.6 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.90 ± 7.91 (m, 1H), Colorless solid; yield: 83% (> 99% ee); mp 85 ± 878 C [Lit.[29], mp 95 ± 988 C 7.51 ± 7.52 (m, 1H), 7.44 (d, J ˆ 3.6 Hz, 1H), 6.60 (dd, J ˆ 1.5, 3.6 Hz, 1H), 6.32 ± 6.36 (m, 2H), 5.84 (d, J ˆ 5.6 Hz, 1H), 3.98 (d, J ˆ 5.6 Hz, 1H); 13C D : À 13.0 (c 0.5, CH3OH) [Lit.[3c], [a]r:t: NMR (100 MHz, DMSO-d6): d ˆ 185.2, 152.6, 149.9, 148.5, 143.3, 120.6, D : À 12.0, (c 0.5, CH3OH) for > 99% ee]; t (R) ˆ 32.4 min; Rt (S) ˆ 36.5 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.65 (d, J ˆ 8.5 Hz, 2H), 7.49 (d, J ˆ 8.5 Hz,2H), 7.38 (d, J ˆ 8.5 Hz, 2H), 7.10 (d, J ˆ 8.5 Hz, 2H), 5.72 (d, J ˆ 6.1 Hz,1H), 4.29 (d, J ˆ 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.6,138.1, 132.7, 132.5, 132.0, 130.6, 129.8, 129.7, 123.4, 75.8.
(R)-1,2-Di(2-thienyl)-2-hydroxyethan-1-one (2s) Colorless solid; yield: 73% (91% ee); mp 1078 C [Lit.[33], mp 108 ± 1098 C for (R)-2-Hydroxy-1,2-bis(4-methoxyphenyl)ethan-1-one (2n) D : À 392.0 (c 0.1, CHCl3) [Lit.[32], [a]20 0.1, CHCl3) for 95% ee]; HPLC (Chiralpak AD): Rt (R) ˆ 35.0 min; Rt (S) ˆ Colorless solid; yield: 95% (> 99% ee); mp 1128 C [Lit.[2c], mp 109 ± 1108 C 40.6 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.10 ± 7.40 (m, 4H), 6.41 ± 6.60 (m, 2H), 5.81 (d, J ˆ 5.8 Hz, 1H), 4.14 (d, J ˆ 5.8 Hz, 1H); 13C NMR D : À 90.4 (c 1.0, CH3OH) [Lit.[3c], [a]r:t: (100 MHz, CDCl3/CCl4): d ˆ 196.2, 148.1, 143.5, 124.7, 119.6, 119.2, 113.1, 3OH) for 86% ee]; HPLC (Chiralpak AD, n-hexane/2-propanol ˆ 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.85 (d, J ˆ 8.6 Hz, 2H), 7.24 (d, J ˆ8.6 Hz, 2H), 7.16 (d, J ˆ 8.6 Hz, 2H), 6.82 (d, J ˆ 8.6 Hz, 2H), 5.84 (d, J ˆ5.7 Hz, 1H), 4.46 (d, J ˆ 5.7 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H); 13C NMR(100 MHz, CDCl3/CCl4): d ˆ 197.3, 164.2, 159.9, 132.4, 131.9, 129.4, 126.8, Synthesis of (R)-2-Hydroxy-1,2-bis(3-methoxyphenyl)ethan- To a suspension of 3-methoxybenzaldehyde (1.62 g, 12 mmol) in dimethyl (R)-2-Hydroxy-1,2-bis(4-methylphenyl)ethan-1-one (2o) sulfoxide (40 mL) and potassium phosphate buffer [160 mL, 50 mM, pH 7.0,containing MgCl2 (2.5 mM) andThDP (0.15 mM)] BAL (0.3 U/mL) was Colorless solid; yield: 94% (> 99% ee); mp 908 C [Lit.[30], mp 898 C for added and the reaction-mixture stirred at 218 C. After a reaction-time of 3 h the product, which accumulates as a yellow oil, was separated by D : À 150.0 (c 0.7, CH3OH) [Lit.[3c], [a]r:t: centrifugation and 3-methoxybenzaldehyde (1.62 g, 12 mmol) was added 3OH) for 82% ee; Lit.[3b], [a]D: 107.0, (CH3OH) for 82.5% ee (S)]; to the buffer solution. The reaction-mixture was stirred for an additional 3 h t (R) ˆ 30.2 min; Rt (S) ˆ 36.0 min; 1H NMR at 218 C before extraction with dichloromethane (3 x 50 mL) was carried out.
3/CCl4): d ˆ 7.83 (d, J ˆ 8.1 Hz, 2H), 7.18 ± 7.22 (m, 4H), 7.16 (d, J ˆ 8.1 Hz, 2H), 5.88 (d, J ˆ 5.8 Hz, 1H), 4.52 (d, J ˆ 5.8 Hz, 1H), 2.36 After drying the collected organic phase over Na2SO4, removal of the solvent (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl under reduced pressure gave the crude product. Crystallization at 138.3, 136.9, 131.5, 130.0, 129.7, 129.6, 128.1, 76.1, 22.1, 21.6.
À 188C from isohexane/ethyl acetate afforded the pure product as a whitesolid; yield: 3.03 g (93%, > 99% ee); mp 558 C [Lit.[34], mp 558 C for racemiccompound]; [a]20 D : À 156.0 (c 1.0, CH3OH) [Lit.[3c], [a]r:t: OH) for 66% ee]; HPLC (Chiralpak AD, n-hexane/2-propanol ˆ 90:10, flow (R)-1,2-Bis(2,4-difluorophenyl)-2-hydroxyethan-1-one (2p) 0.90 mL minÀ1, 20 8C): Rt (R) ˆ 41.0 min; Rt (S) ˆ 54.1 min; 1H NMR(300 MHz, CDCl3): d ˆ 7.46 ± 7.51 (m, 2H), 7.22 ± 7.34 (m, 2H), 7.07 (d, Semisolid; yield: 87% (> 99% ee); [a]20 J ˆ 8.4 Hz, 1H), 6.94 (d, J ˆ 6.9 Hz, 1H), 6.86 (t, J ˆ 2.4 Hz, 1H), 6.82 (d, J ˆ (Chiralpak AD): Rt (R) ˆ 17.3 min; Rt (S) ˆ 18.3 min; 1H NMR (400 MHz, 8.4 Hz, 1H), 5.90 (d, J ˆ 6.1 Hz, 1H), 4.54 (d, J ˆ 6.1 Hz, 1H), 3.81(s, 3H), 3.77 CDCl3/CCl4): d ˆ 7.82 ± 7.97 (m, 2H), 6.86 ± 7.10 (m, 4H), 5.87 (s, 1H), 4.18 (s, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 198.9, 160.3, 159.9, 140.6, 134.9, (br.s, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 195.2 (d, J ˆ 5 Hz), 166.3 130.4, 129.9, 122.0, 120.7, 120.3, 114.3, 113.5, 113.3, 76.4, 55.6, 55.4.
Enantioselective Synthesis of a-Hydroxy Ketones Representative Example for the Synthesis of (R)-2-Hydroxy- (R)-1-(3-Bromophenyl)-2-hydroxypropan-1-one (3f) 1-phenylpropan-1-one Derivatives: (R)-2-Hydroxy-1-phenylpropan-1-one [(R)-2-HPP] (3a) OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): Rt (S) ˆ23.0 min; R Benzaldehyde (212 mg, 2 mmol) was dissolved in a mixture of dimethyl t (R) ˆ 33.7 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 8.04 ± 8.05 (m, 1H), 7.82 ± 7.84 (m, 1H), 7.73 ± 7.75 (m, 1H), 7.36 ± 7.40 (m, 1H), 5.09 sulfoxide (20 mL) and potassium phosphate buffer [80 mL, 50 mM, pH 7.0, (q, J ˆ 6.9 Hz, 1H), 3.78 (br.s, 1H), 1.41 (d, J ˆ 6.9 Hz, 3H); 13C NMR (100 containing MgSO4 (2.5 mM) andThDP (0.15 mM)]. To this solution 88 mg (2 mmol) acetaldehyde was added. After addition of BAL (20 U) the 3/CCl4): d ˆ 200.3, 141.3, 136.7, 132.0, 130.4, 126.4, 123.4, 69.8, reaction mixture was allowedto standat 258 C. After 24 h 20 U of BAL and176 mg (4 mmol) of acetaldehyde were added. This was repeated every 24 h.
After 96 h the conversion was determined as 97% (GC-MS). Work-upaccording to the former procedure afforded (R)-2-HPP as a viscous oil; yield:285 mg (94%, > 99% ee); [a]22 (R)-2-Hydroxy-1-(3-methoxyphenyl)propan-1-one (3g) D : À 80.9 (c 2.0, CHCl3) for > 95% ee (S)]; HPLC (Chiralpak AD, isohexane/2-propanol ˆ 90:10, flow 0.80 mL minÀ1, Viscous oil; yield: 80% (> 99% ee); [a]20 D : 67.8 (c 1.0, CHCl3) [Lit.[11c], [a]20 20 8C): Rt (S) ˆ 12.1 min; Rt (R) ˆ 14.3 min; 1H NMR (400 MHz, CDCl3/ À65.2 (c 1.1, CHCl3) for 96% ee (S)]; HPLC (Chiralcel OB, isohexane/2- CCl4): d ˆ 7.90 (dd, J ˆ 1.4, 8.2 Hz, 2H), 7.40 ± 7.60 (m, 3H), 5.13 (q, J ˆ propanol ˆ 90:10, flow 0.75 mL minÀ1, 20 8C): Rt (S) ˆ 12.9 min; Rt (R) ˆ 6.0 Hz, 1H), 3.80 (br.s, 1H), 1.41 (d, J ˆ 6.0 Hz, 3H); 13C NMR (100 MHz, 14.4 min; 1H NMR (300 MHz, CDCl3): d ˆ 7.15 ± 7.47 (m, 4H), 5.14 (q, J ˆ CDCl3/CCl4): d ˆ 202.7, 134.4, 134.0, 128.9, 128.7, 69.2, 22.0.
6.8 Hz, 1H), 3.89 (s, 3H), 3.78 (d, J ˆ 6.8 Hz, 1H), 1.45 (d, J ˆ 6.8 Hz, 3H); 13CNMR (100 MHz, CDCl3/CCl4): d ˆ 201.9, 160.2, 135.2, 130.1, 121.9, 121.6,113.4, 69.5, 55.5, 22.5.
(R)-1-(2-Fluorophenyl)-2-hydroxypropan-1-one (3b) (R)-1-(4-Chlorophenyl)-2-hydroxypropan-1-one (3h) (Chiralpak AD, isohexane/2-propanol ˆ 90:10, flow 0.80 mL minÀ1, 20 8C):Rt (S) ˆ 9.7 min; Rt (R) ˆ 11.1 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ7.81 ± 7.90 (m, 1H), 7.56 ± 7.67 (m, 1H), 7.12 ± 7.31 (m, 2H), 4.96 (q, J ˆ Viscous oil; yield: 88% (> 99% ee); [a]20 6.8 Hz, 1H), 3.72 (br.s, 1H), 1.29 (d, J ˆ 6.8 Hz, 3H); 13C NMR (100 MHz, 15.2 (c 1.0 ± 2.0, CHCl3) for 83% ee]; HPLC (Chiralcel OB, isohexane/2- propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): R 3/CCl4): d ˆ 198.2, 163.8 (d, J ˆ 251 Hz), 134.5 (d, J ˆ 12 Hz), 131.3, 129.9, 124.5, 115.9 (d, J ˆ 23 Hz), 72.2, 21.1.
28.9 min.; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.83 (d, J ˆ 8.3 Hz, 2H),7.48 (d, J ˆ 8.3 Hz, 2H), 4.98 (q, J ˆ 6.7 Hz, 1H), 3.59 (br.s, 1H), 1.42 (d, J ˆ6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 199.5, 134.6, 132.5,130.9, 129.1, 69.5, 22.1.
(R)-2-Hydroxy-1-(2-methoxyphenyl)propan-1-one (3c) Viscous oil; yield: 63% (> 99% ee); [a]20 (Chiralcel OB, isohexane/2-propanol ˆ 98:2, flow 0.75 mL minÀ1, 20 8C): Rt (R)-1-(4-Bromophenyl)-2-hydroxypropan-1-one (3i) (S) ˆ 34.9 min; Rt (R) ˆ 42.7 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ7.70 ± 7.78 (m, 1H), 7.39 ± 7.51 (m, 1H), 6.91 ± 7.01 (m, 2H), 5.05 (q, J ˆ6.8 Hz, 1H), 3.89 (s, 3H), 3.68 (br.s, 1H),1.42 (d, J ˆ 6.8 Hz, 3H); 13C NMR Viscous oil; yield: 86% (> 99% ee); [a]20 (Chiralcel OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): Rt 3/CCl4): d ˆ 203.7, 158.2, 134.5, 131.3, 125.1, 121.1, 111.3, 72.9, 55.2, 20.7; HR-MS: m/z: calcd. for C (S) ˆ 19.2 min; Rt (R) ˆ 27.6 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.73 (d, J ˆ 8.5 Hz, 2H), 7.58 (d, J ˆ 8.5 Hz, 2H), 4.96 (q, J ˆ 7.0 Hz, 1H), 3.57 (br.s, 1H), 1.40 (d, J ˆ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ200.4, 137.1, 133.0, 131.4, 129.4, 71.4, 22.4.
(R)-1-(3-Fluorophenyl)-2-hydroxypropan-1-one (3d) (R)-2-Hydroxy-1-(4-methoxyphenyl)propan-1-one (3j) isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): Rt (S) ˆ 16.5 min; Viscous oil; yield: 64% (> 99% ee); [a]20 Rt (R) ˆ 25.8 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.71 ± 7.76 (m, 1H), 32.8 (c 1.4, CH3OH) for 99% ee; Lit.[36], [a]20 7.59 ± 7.66 (m, 1H), 7.41 ± 7.50 (m, 1H), 7.22 ± 7.31 (m, 1H), 4.92 (q, J ˆ 6.8 Hz, : À 41.1 (c 1.12, CH3OH) for 92% ee (S)]; HPLC 1H), 3.71 (br.s, 1H), 1.41 (d, J ˆ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3/ (Chiralcel OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): Rt CCl4): d ˆ 198.8, 164.1 (d, J ˆ 246 Hz), 134.2 (d, J ˆ 7 Hz), 130.2 (d, J ˆ 7 Hz), (S) ˆ 26.9 min; Rt (R) ˆ 36.4 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 124.3 (d, J ˆ 3 Hz), 114.1 (d, J ˆ 23 Hz), 113.8 (d, J ˆ 22 Hz), 71.8, 21.4.
7.92 (d, J ˆ 8.6 Hz, 2H), 6.97 (d, J ˆ 8.6 Hz, 2H), 5.11 (q, J ˆ 7.0 Hz, 1H), 3.89(s, 3H), 3.52 (br.s, 1H), 1.44 (d, J ˆ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 200.6, 164.1, 130.9, 125.9, 114.0, 68.8, 55.5, 22.6.
(R)-1-(3-Chlorophenyl)-2-hydroxypropan-1-one (3e) Viscous oil; yield: 94% (> 99% ee); [a]20 (Chiralcel OB, isohexane/2-propanol ˆ 98:2, flow 0.75 mL minÀ1, 20 8C): R (R)-1-(3,5-Difluorophenyl)-2-hydroxypropan-1-one (3l) (S) ˆ 28.5 min; Rt (R) ˆ 48.2 min; 1H NMR (300 MHz, CDCl3): d ˆ 7.91 (s,1H), 7.69 (d, J ˆ 8.0 Hz, 1H), 7.56 (d, J ˆ 8.0 Hz, 1H), 7.43 (dd, J ˆ 8.0 Hz, Viscous oil; yield: 67% (> 99% ee); [a]20 1H), 5.12 (q, J ˆ 7.0 Hz, 1H), 3.70 (br. s, 1H), 1.41 (d, J ˆ 7.0 Hz, 3H); (Chiralcel OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): Rt 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 200.9, 135.7, 133.8, 130.6, 130.3, 129.1, (S) ˆ 12.7 min; Rt (R) ˆ 16.7 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 126.9, 69.7, 22.2; HR-MS m/z calcd. for C9H9O2Cl [M‡]: 184.0291, found: 7.78 ± 8.18 (m, 1H), 6.70 ± 7.31 (m, 2H), 4.99 (q, J ˆ 6.6 Hz, 1H), 3.36 (br.s, 184.0272; anal. calcd. for C9H9O2Cl: C, 58.55; H, 4.91%; found: C, 58.23; H, 1H), 1.42 (d, J ˆ 6.6 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.3, 163.5 (d, J ˆ 252 Hz), 136.5, 112.0 (d, J ˆ 17 Hz), 109.6 (t, J ˆ 25 Hz), 70.1, 22.3.
(R)-2-Hydroxy-1(3-hydroxy-4-methoxyphenyl)propan-1-one 10.9 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.91 ± 8.05 (m, 1H), 6.83 ± 7.10 (m, 2H), 5.02 (q, J ˆ 6.5 Hz, 1H), 3.76 (br. s, 1H), 1.42 (d, J ˆ 6.5 Hz, 3H);13C NMR (75.5 MHz, CDCl3): d ˆ 199.5, 166.4 (d, J ˆ 259 Hz), 162.2 (d, J ˆ259 Hz), 133.2, 118.7, 113.0 (d, J ˆ 21 Hz), 105.1 (dd, J ˆ 27 Hz), 72.7, 20.8; Colorless oil; yield: 80%; (ee not determined); [a]20 HR-MS: m/z calcd. for C9H8O2F2 [M‡]: 186.0493, found: 186.0520.
NMR (300 MHz, CDCl3): dˆ 7.52 (s, 1H), 7.47 (d, J ˆ 8.1 Hz, 1H), 6.92 (d,J ˆ 8.1 Hz, 1H), 5.82 (br.s, 1H), 5.11 (q, J ˆ 7.1 Hz, 1H), 3.97 (s, 3H), 3.80(br.s, 1H), 1.44 (d, Jˆ 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.6,153.5, 146.6, 131.5, 124.8, 114.8, 113.2, 71.9, 56.3, 23.8; HR-MS: m/z: calcd. for C10H12O4 [M‡]: 196.0735; found: 196.0735.
Financial support by the Deutsche Forschungsgemeinschaft in the scope ofSFB 380 is gratefully acknowledged. We thank Alexander von Humboldt (R)-2-Hydroxy-1(4-hydroxy-3-methoxyphenyl)propan-1-one Foundation, DAAD, Turkish Scientific and Technical Research Council(TUBITAK) and Turkish State Planning Organisation (for GC-LC-MS). E.
J. is recipient of a Konrad Adenauer Stiftung fellowship. The authors thankProf. R. Vicunƒa for providing the BAL gene.
Colorless oil; yield: 90%; (ee not determined); [a]20 NMR (300 MHz, CDCl3): d ˆ 7.58 (s, 1H), 7.42 (d, J ˆ 8.4 Hz, 1H), 6.96 (d,J ˆ 8.4 Hz, 1H), 6.35 (br.s, 1H), 5.10 (q, J ˆ 7.0 Hz, 1H), 3.93 (br. s, 4H), 1.44(d, J ˆ 7.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl 126.5, 124.7, 114.8, 111.1, 69.5, 56.8, 23.6; HR-MS: m/z: calcd. for C10H12O4[M‡]: 196.0736; found: 196.0741; anal. calcd. for C10H12O4: C, 61.22, H, [1] a) F. Wˆhler, J. Liebig, Ann. Pharm. 1832, 3, 249 ± 282; b) H.
Staudinger, Ber. Dtsch. Chem. Ges. 1913, 46, 3535 ± 3538.
[2] a) T. Ukai, R. Tanaka, S. Dokawa, J. Pharm. Soc. Jpn. 1943, 63, 296 ± 300; b) R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719 ± 3726; c) H.
(R)-2-Hydroxy-1(3,4,5-trimethoxyphenyl)propan-1-one (3o) Stetter, Y. R‰msch, H. Kuhlmann, Synthesis 1976, 733 ± 735; d) J.
Castells, F. Lo¬pez-Calahorra, L. Domingo, J. Org. Chem. 1988, 53,4433 ± 4436; e) T. Matsumoto, M. Ohishi, S. Inoue, J. Org. Chem.
Colorless oil; yield: 92% (> 99% ee); [a]20 (Chiralpak AD, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 20 8C): Rt [3] a) J. C. Sheehan, T. Hara, J. Org. Chem. 1974, 39, 1196 ± 1199; b) R. L.
(S) ˆ 28.5 min; Rt (R) ˆ 36.4 min; 1H NMR (300 MHz, CDCl3): dˆ 7.11 (s, Knight, F. J. Leeper, J. Chem. Soc. Perkin Trans. 1 1998, 1891 ± 1893; 2H), 5.07 (q, J ˆ 7.1 Hz, 1H), 3.81 (s, 9H), 3.72 (br. s, 1H), 1.45 (d, J ˆ 7.1 Hz, c) D. Enders, K. Breuer, J. H. Teles, Helv. Chim. Acta 1996, 79, 1217 ± 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.5, 153.5, 143.5, 128.9, 106.4, 69.4, 1221; d) D. Enders, K. Breuer in Comprehensive Asymmetric 56.6, 56.4, 23.6; HR-MS: m/z: calcd. for C12H16O5 [M‡]: 240.0992; found: Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), 240.0995; anal. calcd. for C12H16O5: C, 59.99, H, 6.71%; found: C, 59.84, H, Springer, Berlin, 1999, pp. 1093-1102.
[4] For some recent examples see: a) W. Adam, M. M¸ller, F. Prechtl, J.
Org. Chem. 1994, 59, 2358 ± 2364; b) W. Adam, R. T. Fell, V. R.
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