| 100% |
With urea hydrogen peroxide adduct;Ia-2-2; In acetone; at 20℃; for 19h;Conversion of starting material; |
An oxidization of <strong>[52784-31-3]3-phenyl cyclobutanone</strong> is carried out by the same manner as in Example 1 except that the complex represented by the formula (Ia-2-2) is used as a catalyst with a solvent, a reaction temperature and a reaction time shown in Table 2. The results are shown in Table 2 |
| 100% |
With urea hydrogen peroxide adduct;Ia-2-2; at 20℃; for 2h;Conversion of starting material; |
The same procedure as in Example 3 is repeated except that silver hexafluoroantimonate [AgSbF6] (3.4 mg, 10 mol) is used instead of silver tetrafluoroborate [AgBF4] (1.9 mg, 10 mol) to synthesize a complex represented by the following formula (Ia-2-2). The reaction is also carried out under the same conditions as in Example 1 except that the reaction time is 2 hours and the product is analyzed by the same manner as in Example 1. The results are shown in Table 1. |
| 100% |
With urea hydrogen peroxide adduct;iib; at 20℃; for 18h;Conversion of starting material; |
The same procedure as in Example 3 is repeated except that a compound represented by the formula (II) in which R2 is t-butyl group (2.1 mg, 5.5 mol) is used as a ligand instead of the compound represented by the formula (I) in which R1 is isopropyl group (2.3 mg, 5.5. mol) to synthesize a complex represented by the following formula (IIb). Also, the reaction is carried out under the same conditions as in Example 1 except that the complex of the formula (IIb) is used as a catalyst and the reaction time is 18 hours, and the product is analyzed by the same manner as in Example 1. The results are shown in Table 1.Moreover, a synthetic example of a Pd complex having substantially the same ligand as the complexes of the formulae (IIa) and (IIb) in spite of having a different counter anion is described in J. Sprinz, M. Kiefer, G. Helmchen, M. Reggelin, G. Huttner, O. Walter and L. Zscinal, Tetrahedron Letters, 1994, 35, 1523-1526. |
| 98% |
With urea hydrogen peroxide adduct;Ia-2-2; In DMF (N,N-dimethyl-formamide); at 20℃; for 23h;Conversion of starting material; |
An oxidization of <strong>[52784-31-3]3-phenyl cyclobutanone</strong> is carried out by the same manner as in Example 1 except that the complex represented by the formula (Ia-2-2) is used as a catalyst with a solvent, a reaction temperature and a reaction time shown in Table 2. The results are shown in Table 2 |
| 95% |
With urea hydrogen peroxide adduct;Ia-2-2; In 1,4-dioxane; at 20℃; for 19h;Conversion of starting material; |
An oxidization of <strong>[52784-31-3]3-phenyl cyclobutanone</strong> is carried out by the same manner as in Example 1 except that the complex represented by the formula (Ia-2-2) is used as a catalyst with a solvent, a reaction temperature and a reaction time shown in Table 2. The results are shown in Table 2 |
| 94% |
With urea hydrogen peroxide adduct;Ia-2-2; In diethyl ether; at 20℃; for 18h;Conversion of starting material; |
An oxidization of <strong>[52784-31-3]3-phenyl cyclobutanone</strong> is carried out by the same manner as in Example 1 except that the complex represented by the formula (Ia-2-2) is used as a catalyst with a solvent, a reaction temperature and a reaction time shown in Table 2. The results are shown in Table 2 |
| 94% |
With urea hydrogen peroxide adduct;IIa; at 20℃; for 17h;Conversion of starting material; |
The same procedure as in Example 3 is repeated except that a compound represented by the formula (II) in which R2 is phenyl group (1.9 mg, 5.5 mol) is used as a ligand instead of the compound represented by the formula (I) in which R1 is isopropyl group (2.3 mg, 5.5 mol) to synthesize a complex represented by the following formula (IIa). Also, the reaction is carried out under the same conditions as in Example 1 except that the complex of the formula (IIa) is used as a catalyst and the reaction time is 17 hours, and the product is analyzed by the same manner as in Example 1. The results are shown in Table 1. |
| 93 - 100% |
With urea hydrogen peroxide adduct;Ia-2-2; In 1,2-dimethoxyethane; at -40 - 20℃; for 0.5 - 46h;Combinatorial reaction / High throughput screening (HTS);Conversion of starting material; |
An oxidization of <strong>[52784-31-3]3-phenyl cyclobutanone</strong> is carried out by the same manner as in Example 1 except that the complex represented by the formula (Ia-2-2) is used as a catalyst with a solvent, a reaction temperature and a reaction time shown in Table 2. The results are shown in Table 2 |
| 91 - 100% |
With urea hydrogen peroxide adduct;Ia-2-2; In tetrahydrofuran; at -80 - 20℃; for 18 - 214h;Combinatorial reaction / High throughput screening (HTS);Conversion of starting material; |
An oxidization of <strong>[52784-31-3]3-phenyl cyclobutanone</strong> is carried out by the same manner as in Example 1 except that the complex represented by the formula (Ia-2-2) is used as a catalyst with a solvent, a reaction temperature and a reaction time shown in Table 2. The results are shown in Table 2 |
| 88% |
With dihydrogen peroxide;Ia-2-1; In water; at 20℃; for 20h;Conversion of starting material; |
The same procedure as in Example 1 is repeated except that the complex of the formula (Ia-2-1) is used as a catalyst, and an aqueous solution of 30% hydrogen peroxide (15 L, content of hydrogen peroxide: 0.13 mmol) is used as an oxidizer, and the reaction time is 20 hours. The results are shown in Table 1. |
| 87% |
With urea hydrogen peroxide adduct;Ia-2-1; at 20℃; for 20h;Conversion of starting material; |
To a solution of bis(benzonitrile)palladium(II) chloride (1.9 mg, 5.0 mol) in 1,2-dichloroethane (0.4 mL) is added a compound represented by the formula (I) in which R1 is isopropyl group (2.3 mg, 5.5 mol) under a nitrogen atmosphere and stirred at room temperature for 1 hour. The resulting mixture is added to another flask previously containing silver tetrafluoroborate [AgBF4] (1.9 mg, 10 mol) under a nitrogen atmosphere, and further stirred at room temperature for 1 hour to synthesize a complex represented by the following formula (Ia-2-1) as a complex solution likewise Example 1 To the resulting complex solution is added <strong>[52784-31-3]3-phenylcyclobutanone</strong> (15.2 mg, 0.1 mmol). Then, the resulting solution is added with urea-hydrogen peroxide adduct (UHP) (12.2 mg, 0.13 mmol) and further stirred at room temperature for 20 hours. The resulting mixture is analyzed by the same manner as in Example 1. The results are shown in Table 1. |
| 84% |
With dihydrogen peroxide;Ia-1; In water; at 20℃; for 24h;Conversion of starting material; |
The same procedure as in Example 1 is repeated except that an aqueous solution of 30% hydrogen peroxide (15 L, content of hydrogen peroxide: 0.13 mmol) is used instead of the urea-hydrogen peroxide adduct (UHP) (12.2 mg, 0.13 mmol). The results are shown in Table 1. |
| 80% |
With dihydrogen peroxide; urea;C72H54N2O4Zr; In chlorobenzene; at 25℃; for 24h;Product distribution / selectivity; |
The same procedure as in Example 1 is repeated except that chlorobenzene (PhCd, 1.0 ml) is used instead of the dichloromethane (CH2Cl2, 1.0 ml) to obtain results as shown in Table 3. |
| 79% |
With urea hydrogen peroxide adduct;Ia-1; at 20℃; for 24h;Conversion of starting material; |
To a solution of 1,5-cyclooctadiene platinum dichloride [(COD)PtCl2] (2.2 mg, 5.0 mol) in 1,2-dichloroethane (0.4 mL) is added a compound represented by the formula (I) in which R1 is isopropyl group (2.3 mg, 5.5 mol) under a nitrogen atmosphere and stirred at room temperature for 1 hour. The resulting mixture is added to another flask previously containing silver tetrafluoroborate [AgBF4] (1.9 mg, 10 mol) under a nitrogen atmosphere, which is further stirred at room temperature for 1 hour, and filtered through a pad of Celite to give a complex solution. The resulting complex is represented by the following formula (Ia-1). To the resulting complex solution is added <strong>[52784-31-3]3-phenylcyclobutanone</strong> (15.2 mg, 0.1 mmol). Then, to the resulting solution is added urea-hydrogen peroxide adduct (UHP) (12.2 mg, 0.13 mmol) and further stirred at room temperature for 24 hours. After the completion of the stirring, the resulting mixture is concentrated on a rotary evaporator and is chromatographed on a silica gel using a mixed solution of hexane/ethyl acetate (= 9/1) to obtain beta-(R)-phenyl-gamma-butyrolactone (13.3 mg, yield: 79%). As the enantiomeric excess of this product is determined by a high performance liquid chromatography (HPLC) using a DAICEL CHIRALPAK AD-H column and hexane/isopropanol(= 95/5), it is 7 %ee. Moreover, the absolute configuration of the product is determined by comparison of the elution time with the authentic sample (See Uchida T., Katsuki T., Ito K., Akashi S., Ishii A. and Kuroda T., Helv. Chim. Acta., 2002, 85, 3078). The results are shown in Table 1. |
| 68 - 78% |
With dihydrogen peroxide; urea;C72H54N2O4Zr; In dichloromethane; at 0 - 40℃; for 24h;Product distribution / selectivity; |
EXAMPLE 1 [0085] <strong>[52784-31-3]3-phenylcyclobutanone</strong> (14.6 mg, 0.1 mmol) is dissolved into dichloromethane (CH2Cl2, 1.0 ml) at room temperature (25 C.). To this solution are successively added the complex of the formula (XVII) (5.5 mg, 5.0 mumol) and urea-hydrogen peroxide adduct (UHP, 12 mg, content of hydrogen peroxide: 0.12 mmol) and the resulting mixture is stirred at room temperature for 24 hours. [0086] The mixture is concentrated in a rotary evaporator and chromatographed on silica gel using a mixed solution of hexane and ethyl acetate (=6.5/1) as an elute to obtain beta-phenyl-gamma-butyrolactone (10.9 mg, yield: 68%). [0087] As the enantiomeric excess of this product is determined by a high-speed liquid chromatography (HPLC) analysis using a Daicel Chiralpak AD-H and an elute of hexane/isopropanol (=49/1), the product is mainly composed of R-isomer and its enantiomeric excess is 87% ee as shown in Table 1.EXAMPLE 6 [0103] The same procedure as in Example 1 is repeated except that the reaction is carried out at 0 C. instead of the room temperature (25 C.) to obtain results as shown in Table 4. EXAMPLE 7 [0104] The same procedure as in Example 1 is repeated except that the reaction is carried out at 40 C. instead of the room temperature (25 C.) to obtain results as shown in Table 4. [TABLE-US-00004] TABLE 4 Enantiomeric Temperature ( C.) Yield (%) excess (% ee) Example 1 25 68 87 Example 6 0 58 81 Example 7 40 78 81 [0105] The reaction formula corresponding to Examples 6 and 7 of Table 4 is shown as follows: [CHEMMOL-00038] [0106] As seen from Table 4, the reaction rate rises as the temperature rises within a range of 0 to 40 C., but the enantioselectivity lowers even at a higher temperature or a lower temperature and hence the reaction temperature is preferable to be room temperature. |
| 52% |
With urea hydrogen peroxide adduct;Ib; at 20℃; for 45h;Conversion of starting material; |
The same procedure as in Example 3 is repeated except that a compound represented by the formula (I) in which R1 is 1-methyl-1-(t-butyldimethylsiloxy) ethyl group (3.0 mg, 5.5 mol) is used as a ligand instead of the compound represented by the formula (I) in which R1 is isopropyl group (2.3 mg, 5.5 mol) to synthesize a complex represented by the following formula (Ib). Also, the reaction is carried out under the same conditions as in Example 1 except that the complex of the formula (Ib) is used as a catalyst and the reaction time is 45 hours, and the product is analyzed by the same manner as in Example 1. The results are shown in Table 1. |
| 44% |
With urea hydrogen peroxide adduct;IVb; at 20℃; for 70h;Conversion of starting material; |
The same procedure as in Example 3 is repeated except that a compound represented by the formula (IV) in which every R4 is t-butyl group (1.6 mg, 5.5 mol) is used as a ligand instead of the compound represented by the formula (I) in which R1 is isopropyl group (2.3 mg, 5.5 mol) to synthesize a complex represented by the following formula (IVb). Also, the reaction is carried out under the same conditions as in Example 1 except that the complex of the formula (IVb) is used as a catalyst and the reaction time is 70 hours, and the product is analyzed by the same manner as in Example 1. The results are shown in Table 1.Moreover, an example of using a Pd complex having the same ligand as the above complex in spite of having a different counter anion for another reaction is described in K. Ito, R. Kashiwagi, K. Iwasaki and T. Katsuki, Synlett, 1999, 1563-1566. |
|
With D-glucose; cycloalkanone monooxygenase from Cylindrocarpon radicicola ATCC 11011; beta?cyclodextrin; In N,N-dimethyl-formamide; at 25℃; for 20h;pH 8;Enzymatic reaction; |
General procedure: Biotransformations were carried out at 25 C in Tris-HCl buffer (50 mM, pH 8.0) using resting cells of E. coli BL21 (DE3) expressing STMO at a final OD600 nm of 15 in 24-well deep well plates covered with a breathable AeraSeal sealing film (Excel Scientific, Victorville, USA). The reaction mixtures of a total volume of 2.5 ml contained 5 mM <strong>[52784-31-3]3-phenylcyclobutanone</strong>, 10 mM beta-cyclodextrine, 100 mM glucose, and 2% (v/v) of dimethylformamide. Samples were taken after 0, 3, and 20 h, extracted with ethyl acetate and analyzed by GC-MS. |
| > 99%Chromat. |
With alpha-D-glucopyranose; glucose dehydrogenase (GDH-105); Baeyere-Villiger monooxygenase P1-D08; oxygen; NADPH; In methanol; aq. phosphate buffer; at 30℃; for 24h;pH 9;Enzymatic reaction; |
General procedure: In a typical experiment carried out in 1.5 mL tubes (total volume of 500 muL), the substrate 1a-j, m-v (10 mM) was dissolved in methanol (5 muL, 1% v/v) and KPi buffer (100 mM, pH 9.0, 482 muL), containing glucose (20 mM), glucose dehydrogenase (GDH-105, 10 U, from stock solution of 1.275 U/muL), NADPH (0.2 mM, from a 20 mM stock solution) and the corresponding Baeyere-Villiger monooxygenase (2 mg). The mixture was shaken at 250 rpm at 30 C for 24 h. The reaction was stopped by extracting with diethyl ether (2x400 muL) and centrifugedat 13,000 rpm in order to separate both phases and pellet the suspended protein. The organic phases were combined, dried over anhydrous sodium sulfate and analyzed by GC in order to determine the conversion values. Then, the solvent in GC samples was evaporated with a continuous flow of nitrogen, the residue redissolved in a mixture of hexane:ethanol 90:10 and the new sample filtered and analyzed by HPLC, leading to the measurement of the enantiomeric excess of the lactones. Control experiments in the absence of enzyme were performed for all substrates, not observing any reaction product after similar periods of time (Tables S1-S19). |
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