CN114478558A

CN114478558A - Enantiomer-pure tetrahydrofuran spiro-oxoindole derivative and preparation method and application thereof

Info

Publication number: CN114478558A
Application number: CN202210080758.5A
Authority: CN
Inventors: 华远照; 邢胜南; 杨小超; 贾世坤; 王敏灿
Original assignee: Zhengzhou University
Current assignee: Zhengzhou University
Priority date: 2022-01-24
Filing date: 2022-01-24
Publication date: 2022-05-13

Abstract

The invention belongs to the field of organic synthesis, and relates to an enantiomer pure tetrahydrofuran spiro-oxoindole derivative, a preparation method and application thereof, wherein a 1-p-toluenesulfonyl indoline-2, 3-diol compound (I) and beta, gamma-unsaturated-alpha-ketoamide (II) are dissolved in an organic solvent, react for 72 hours under the catalysis of a binuclear zinc catalyst (C1-C3), then 0.5mL of trifluoroacetic acid is added for reaction for 1 hour, a saturated sodium bicarbonate solution is used for treatment and generation, and the enantiomer pure tetrahydrofuran spiro-oxoindole derivative (III) is obtained through separation and purification, so that the whole process is completed. The invention utilizes the catalyst to firstly realize the polarity reversal of the reaction activity of the 1-p-toluenesulfonyl indoline-2, 3-diol to prepare the enantiomer pure tetrahydrofuran spiro-oxoindole derivative under the mild condition, and simultaneously provides the application of the tetrahydrofuran spiro-oxoindole derivative with a novel structure in organic synthesis.

Description

Enantiomer-pure tetrahydrofuran spiro-oxoindole derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to an enantiomer pure tetrahydrofuran spiro-oxoindole derivative, and a preparation method and application thereof.

Background

The pyrrolidine spiro oxindole structure is widely present in a plurality of natural products with biological activity, and the biological activity and the substituent groups on the ringAnd chiral configuration, and the chiral spiro tetrahydropyrrole oxindole compound also contains the structure in active ingredients of a plurality of chiral drugs, and is an important intermediate in organic synthesis. Therefore, the construction of the chiral spiro tetrahydropyrrole oxindole structure becomes a hotspot for the research of chemists. In addition, N-hetero hemiacetals are often used as electrophiles (imine cation precursors or chain aminoaldehyde substitutes) in organic synthesis to react with nucleophiles to form cyclic amine derivatives, which are important intermediates in organic synthesis. However, the alpha-carbon (sp attached to the nitrogen atom) of N-hetero hemiacetals has not been found to date³Hybridized carbon atoms) as nucleophilic sites.

Disclosure of Invention

The invention aims to provide an enantiomer pure tetrahydrofuran spiro-oxoindole derivative, a preparation method and application thereof, which utilize alpha-carbon (sp connected with nitrogen atom) of 1-p-toluenesulfonyl indoline-2, 3-diol compound (N-hetero hemiacetal)³Hybridized carbon atom) as a nucleophilic site, and utilizes the reaction activity of polarity reversal to prepare the enantiomer pure tetrahydrofuran spiro-oxoindole derivative, and has the advantages of mild reaction conditions and simple preparation method.

In order to achieve the purpose, the invention adopts the technical scheme that:

an enantiomerically pure tetrahydrofuran spirooxindole derivative having the formula:

wherein R is¹Is H, F, Cl, Br, CH₃、OCH₃，R²Is CH₃、CH₂CH₃、Bn，R³Is H, 4-CH₃O、4-CH₃、4-F、4-Cl、4-Br、2-CH₃One of O, Ar³Is C₆H₅、4-CH₃O-C₆H₄、4-CH₃-C₆H₄、4-F-C₆H₄、4-Cl-C₆H₄、4-Br-C₆H₄、4-NO₂-C₆H₄、3-Br-C₆H₄、3-CH₃-C₆H₄、3,4-(CH₃)₂-C₆H₃One kind of (1).

A process for the preparation of enantiomerically pure tetrahydrofuran spirooxindole derivatives comprising the steps of: dissolving a compound I1-p-toluenesulfonyl indoline-2, 3-diol compound and a compound IIbeta, gamma-unsaturated-alpha-ketoamide in an organic solvent, reacting for 72 hours under the catalysis of a binuclear zinc catalyst C1-C3, adding 0.5mL of trifluoroacetic acid, reacting for 1 hour, treating a resultant with a saturated sodium bicarbonate solution, and separating and purifying to obtain a compound III tetrahydrofuran spiro-oxoindole derivative, wherein the compound I1-p-toluenesulfonyl indoline-2, 3-diol compound is used as a nucleophilic reagent for reaction, and alpha-carbon atoms (sp connected with nitrogen atoms) in the compound are reacted³Hybridized carbon atom) is a nucleophilic site in the reaction, and the chemical reaction process is as follows:

further, the structural general formula of the compound I1-p-toluenesulfonyl indoline-2, 3-diol compound is

Wherein R is¹Is H, F, Cl, Br, CH₃、OCH₃One of (1); the structural general formula of the compound IIbeta, gamma-unsaturated-alpha-ketoamide is as follows:

wherein R is²Is CH₃One of Et and Bn, R³Is H, 4-CH₃O、4-CH₃、4-F、4-Cl、4-Br、2-CH₃One of O, Ar³Is C₆H₅、4-CH₃O-C₆H₄、4-CH₃-C₆H₄、4-F-C₆H₄、4-Cl-C₆H₄、4-Br-C₆H₄、4-NO₂-C₆H₄、3-Br-C₆H₄、3-CH₃-C₆H₄、3,4-(CH₃)₂-C₆H₃One of (1); the structural general formula of the binuclear zinc catalyst C1-C3 is as follows:

wherein Ar is¹、Ar²Are respectively C₆H₅、4-Cl-C₆H₄、4-CF₃-C₆H₄、4-CH₃-C₆H₄One kind of (1).

Further, the organic solvent is one of tetrahydrofuran, toluene, acetonitrile, dichloromethane and chloroform, the reaction temperature is 25 ℃, and the molar ratio of the compound I, the compound II and the binuclear zinc catalyst C1-C3 is 1:1: 0.05-0.2.

The application of enantiomer pure tetrahydrofuran spiro-oxoindole derivative as intermediate in organic synthesis is to synthesize one of the products III-aa (wherein R is¹＝H,R²＝CH₃,R³＝H,Ar³＝C₆H₅And) as an intermediate for organic synthesis, the reaction thereof in organic synthesis is as follows:

the conditions of the reaction formula a are: reacting NH₂OH HCl, NaOAc and III-aa to CH₃Heating and refluxing in OH; the conditions of the reaction formula b are: in NaBH₄And CH₃Reacting under the action of OH; the conditions of reaction c are: at H₂SO₄、H₂O, DCM under the condition of formula d: at NH₄OAc、CuCl₂·2H₂O、TBHP、CH₃Reacting under the action of OH; the conditions of reaction e are: in acetylacetone, HCl, H₂Reacting under the action of O.

The invention has the advantages that: the application firstly utilizes a 1-p-toluenesulfonyl indoline-2, 3-diol compound (N-heterohemiacetal) as a nucleophilic reagent, and utilizes the reaction activity of polarity inversion to prepare the enantiomerically pure tetrahydrofuran spiro-oxoindole derivative, the method is simple, the reaction condition is mild, the enantiomerically pure tetrahydrofuran spiro-oxoindole derivative is obtained through tandem reaction under the catalysis of 10 mol% (0.1 times) of binuclear zinc catalyst, the prepared derivative has a Dr value of more than 20/1, and the ee value can reach as high as 99%.

Drawings

FIG. 1 shows the preparation of the product of example 1 of the present invention¹H NMR chart and¹³c NMR chart.

FIG. 2 shows a product prepared in example 21 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 3 shows a product prepared in example 22 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 4 shows a product prepared in example 22 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 5 shows a product prepared in example 24 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 6 shows a product prepared in example 25 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 7 shows a product prepared in example 26 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 8 shows a product prepared in example 27 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 9 shows a product prepared in example 28 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 10 shows a product prepared in example 29 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 11 shows a product prepared in example 33 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 12 shows a product prepared in example 34 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 13 shows a product prepared by the method of application example 1 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 14 shows a product prepared by the method of application example 2 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 15 shows a product produced by application example 3 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 16 shows a product produced by application example 4 of the present invention¹HNMR map and¹³c NMR chart.

FIG. 17 shows a product produced by application example 5 of the present invention¹HNMR map and¹³c NMR chart.

Detailed Description

The invention is further illustrated by the following specific examples.

Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.

The general reaction involved in the following examples is:

example 1

The preparation method of the enantiomer pure tetrahydrofuran spiro-oxoindole derivative III comprises the following steps: to a dry Schlenk reaction tube was added anhydrous tetrahydrofuran (2.0mL), a binuclear zinc catalyst C1a (i.e., a

a＝b＝1，Ar¹＝Ar²＝C₆H₅0.02mmol), controlling the temperature at 25 ℃, adding the compound I-a (namely, under the protection of nitrogen gas)

R¹H, 0.2mmol), compound ii-a (i.e., compound ii-a

R²＝CH₃，R³＝H，Ar³Ph, 0.2mmol), reaction at 25 ℃ until TLC monitored its reaction complete. Then the solvent is removed by rotary evaporation, and the mixture is added at 0 DEG C2mL of dichloromethane and 0.5mL of trifluoroacetic acid were stirred at room temperature for 1 hour. After the reaction was complete, 5mL of saturated NaHCO was added₃Solution quenching reaction, CH₂Cl₂3X 10mL of the extract was extracted, and the organic phase was purified with anhydrous Na₂SO₄Drying, removing solvent by rotary evaporation, purifying the crude product by column chromatography, developing with petroleum ether/ethyl acetate 2/1 to obtain pure product (III-aa) with yield of 45% and dr>20/1, 31% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 37.97min, secondary peak retention time 26.14 min).¹H NMR(400MHz,CDCl₃)δ11.25(s,1H),7.82–7.75(m,1H),7.60(d,J＝8.3Hz,2H),7.50(d,J＝8.3Hz,1H),7.39(d,J＝8.7Hz,3H),7.30–7.23(m,4H),7.19(s,1H),7.08(t,J＝7.3Hz,1H),7.00(d,J＝8.1Hz,2H),6.85–6.80(m,1H),6.76(d,J＝7.8Hz,1H),5.59(d,J＝9.7Hz,1H),4.27–4.15(m,1H),3.15(s,3H),2.87–2.76(m,1H),2.59(dd,J＝12.9,8.5Hz,1H),2.21(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.3,176.9,143.9,143.3,140.8,137.9,136.3,135.4,133.1,130.2,129.9,129.6,128.9,128.3,127.5,127.2,124.2,123.6,122.6,120.9,118.4,108.6,86.4,83.9,47.0,43.8,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₉N₂O₅S⁺]:553.1792,found:553.1782.IR:～(cm^-1)＝3675,2922,1712,1554,1494,1260,1162,1091,806,749,564.

Example 2

The specific process was the same as in example 1, except that the catalyst was changed to C1b (a ═ b ═ 1, Ar)¹＝Ar²＝4-CH₃-C₆H₄) III-aa yield 32% (dr)>20/1)，28％ee。

Example 3

The specific process was the same as in example 1, except that the catalyst was changed to C1C (a ═ b ═ 1, Ar)¹＝Ar²＝4-CF₃-C₆H₄) III-aa yield 37% (dr)>20/1)，56％ee。

Example 4

The specific process was the same as in example 1, except that the catalyst was changed to C2a (a ═ b ═ 2, Ar)¹＝Ar²＝C₆H₅) III-aa yield 45% (dr)>20/1)，94％ee。

Example 5

The specific process was the same as in example 1, except that the catalyst was changed to C2b (a ═ b ═ 2, Ar)¹＝Ar²＝4-CH₃-C₆H₄) III-aa yield 40% (dr)>20/1)，84％ee。

Example 6

The specific process was the same as in example 1, except that the catalyst was changed to C2C (a ═ b ═ 2, Ar)¹＝Ar²＝4-CF₃-C₆H₄) III-aa yield 42% (dr)>20/1)，92％ee。

Example 7

The specific process was the same as in example 1, except that the catalyst was changed to C2d (a ═ b ═ 2, Ar)¹＝Ar²＝4-Cl-C₆H₄) III-aa yield 41% (dr)>20/1)，88％ee。

Example 8

The specific procedure was the same as in example 1, except that the catalyst was changed to C3a (a: 2, b: 1, Ar)¹＝Ar²Ph), III-aa yield 41% (dr)>20/1)，58％ee。

Example 9

The specific procedure was the same as in example 1, except that the catalyst was changed to C3b (a: 2, b: 1, Ar)¹＝Ar²＝4-CH₃-C₆H₄) III-aa yield 33% (dr)>20/1)，40％ee。

Example 10

The specific procedure was the same as in example 1, except that the catalyst was changed to C3C (a: 2, b: 1, Ar)¹＝4-CF₃-C₆H₄，Ar²Ph), III-aa yield 49% (dr)>20/1)，86％ee。

Example 11

The specific procedure was the same as in example 1, except that the catalyst was changed to C3d (a: 2, b: 1, Ar)¹＝C₆H₄，Ar²＝4-CF₃-C₆H₄) III-aa yield 34% (dr)>20/1)，60％ee。

Example 12

The specific procedure was the same as in example 1, except that the catalyst was changed to C3e (a: 2, b: 1, Ar)¹＝4-CF₃-C₆H₄，Ar²＝C₆H₄) III-aa yield 34% (dr)>20/1)，62％ee。

Example 13

The specific procedure was the same as in example 1, except that the catalyst was changed to C3f (a: 2, b: 1, Ar)¹＝Ph，Ar²＝4-CF₃-C₆H₄) III-aa yield 41% (dr)>20/1)，84％ee。

Example 14

The specific procedure was the same as in example 1, except that the catalyst was changed to C3g (a: 2, b: 1, Ar)¹＝4-CF₃-C₆H₄，Ar²＝4-CF₃-C₆H₄) III-aa yield 35% (dr)>20/1)，62％ee。

Example 15

The procedure is as in example 4, except that the solvent is replaced by toluene and the III-aa yield is 58% (dr >20/1) and 92% ee.

Example 16

The procedure is as in example 4, except that the solvent is replaced by acetonitrile, and the III-aa yield is 53% (dr >20/1) and 95% ee.

Example 17

The procedure is as in example 4, except that the solvent is replaced by dichloromethane, and the III-aa yield is 65% (dr >20/1) and 97% ee.

Example 18

The procedure is as in example 4, except that the solvent is replaced by chloroform, and the III-aa yield is 71% (dr >20/1) and 95% ee.

Example 19

The procedure is as in example 17, except that the catalyst is used in an amount of 0.01mmol, and the III-aa yield is 47% (dr >20/1), 97% ee.

Example 20

The procedure is as in example 17, except that the catalyst is used in an amount of 0.02mmol, the III-aa yield is 66% (dr >20/1), and 97% ee.

Example 21

The procedure is as in example 17, except that the compound I-a is replaced by I-b (R)¹Yield of iii-ba 46% (dr ═ F), iii-ba>20/1), 92% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 4/1, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 25.30min, secondary peak retention time 15.30 min).¹H NMR(400MHz,CDCl₃)δ10.84(s,1H),7.58–7.49(m,3H),7.45(dd,J＝9.2,2.9Hz,1H),7.37(t,J＝7.4Hz,3H),7.28(d,J＝7.2Hz,2H),7.21(t,J＝7.2Hz,2H),7.08(d,J＝7.5Hz,1H),7.01(dd,J＝9.3,2.6Hz,1H),6.94(d,J＝8.2Hz,2H),6.77(d,J＝7.8Hz,1H),5.45(d,J＝9.6Hz,1H),4.14(dd,J＝20.4,9.3Hz,1H),3.15(s,3H),2.80(d,J＝12.7Hz,1H),2.59(dd,J＝13.0,8.7Hz,1H),2.19(s,3H).¹³C NMR(101MHz,CDCl₃)δ197.6,176.7,158.8,156.4,144.1,143.4,137.8,136.8,135.9,130.3,129.6,129.0,128.3,127.7,127.2,124.0,123.6,122.6(d,J＝22.6Hz),122.4(d,J＝6.2Hz),121.1(d,J＝7.4Hz),118.9(d,J＝23.9Hz),108.7,86.8,84.0,47.1,43.7,26.4,21.5.¹⁹FNMR(376MHz,CDCl₃)δ-117.86.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈FN₂O₅S⁺]:571.1697,found:5711698.IR:～(cm^-1)＝3672,2920,1722,1615,1493,1160,1065,900,676,547.

Example 22

The procedure is as in example 17, except that the compound I-a is replaced by I-c (R)¹Cl), iii-ca yield 59% (dr)>20/1), 83% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 28.15min, minor peak retention time 15.92 min).¹H NMR(400MHz,CDCl₃)δ11.09(s,1H),7.71(d,J＝2.4Hz,1H),7.64(d,J＝8.3Hz,2H),7.57(d,J＝9.0Hz,1H),7.45(dd,J＝13.9,7.3Hz,3H),7.39–7.32(m,3H),7.32–7.26(m,2H),7.16(t,J＝7.5Hz,1H),7.09(d,J＝8.1Hz,2H),6.85(d,J＝7.8Hz,1H),5.59(d,J＝9.7Hz,1H),4.28–4.06(m,1H),3.23(s,3H),3.00–2.81(m,1H),2.67(dd,J＝12.9,8.6Hz,1H),2.29(s,3H).¹³C NMR(101MHz,CDCl₃)δ197.9,176.6,144.2,143.4,139.2,137.6,136.0,135.2,132.3,130.2,129.7,129.0,128.2,128.1,127.8,127.2,124.1,123.6,122.1,120.1,108.7,86.6,84.0,47.6,43.8,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈ClN₂O₅S⁺]:587.1402,found:587.1400.IR:～(cm^-1)＝3675,2921,1717,1615,1471,1375,1164,1065,750,545.

Example 23

The procedure is as in example 17, except that the compound I-a is replaced by I-d (R)¹Br), III-da yield 56% (dr)>20/1), 89% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 30.94min, secondary peak retention time 17.41 min).¹H NMR(400MHz,CDCl₃)δ11.13(s,1H),7.81(d,J＝2.2Hz,1H),7.65(d,J＝8.3Hz,2H),7.53–7.46(m,2H),7.46–7.40(m,3H),7.40–7.32(m,3H),7.31–7.28(m,1H),7.20–7.15(m,1H),7.10(d,J＝8.1Hz,2H),6.85(d,J＝7.8Hz,1H),5.60(d,J＝9.7Hz,1H),4.22–4.10(m,1H),3.24(s,3H),2.95–2.84(m,1H),2.67(dd,J＝12.9,8.5Hz,1H),2.30(s,3H).¹³C NMR(101MHz,CDCl₃)δ197.9,176.6,144.3,143.4,139.6,138.1,137.5,136.0,135.2,130.2,129.8,129.1,128.2,127.8,127.2,124.1,123.6,122.3,120.2,115.3,108.7,86.6,84.0,47.8,43.9,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈BrN₂O₅S⁺]:630.0897,found:630.0895.IR:～(cm^-1)＝3675.5,2922.6,1720.9,1615.2,1471.6,1375.5,1161.7,1089.1,751.8,546.1.

Example 24

The procedure is as in example 17, except that the compound I-a is replaced by I-e (R)¹＝CH₃) III-ea yield 48% (dr)>20/1), 89% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 15.45min, minor peak retention time 9.80 min).¹H NMR(400MHz,CDCl₃)δ11.12(s,1H),7.64(d,J＝8.3Hz,2H),7.52(d,J＝8.4Hz,2H),7.45–7.38(m,3H),7.38–7.28(m,3H),7.28–7.24(m,1H),7.21–7.13(m,2H),7.07(s,2H),6.84(d,J＝7.8Hz,1H),5.68(d,J＝9.7Hz,1H),4.22–4.01(m,1H),3.23(s,3H),2.90(dd,J＝12.7,11.8Hz,1H),2.65(dd,J＝12.8,8.4Hz,1H),2.27(s,3H),2.08(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.6,176.8,143.8,143.3,138.2,138.0,136.4,136.2,132.8,132.4,130.1,130.0,129.6,128.9,128.2,127.6,127.2,124.2,123.6,121.2,118.9,108.6,86.4,84.0,47.8,44.0,26.4,21.5,20.5.HRMS(ESI):[M+H]+calcd for[C₃₃H₃₁N₂O₅S⁺]:567.1948,found:567.1950.IR:～(cm^-1)＝3675,2988,1721,1614,1493,1375,1163,1066,751,524.

Example 25

The procedure is as in example 17, except that the compound I-a is replaced by I-f (R)¹＝OCH₃) Yield of III-fa 51% (dr)>20/1), 91% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 4/1, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 37.78min, secondary peak retention time 20.71 min).¹H NMR(400MHz,CDCl₃)δ10.73(s,1H),7.58(dd,J＝8.6,6.5Hz,3H),7.49(d,J＝6.9Hz,1H),7.42(d,J＝7.1Hz,2H),7.37–7.29(m,3H),7.30–7.25(m,1H),7.21(d,J＝2.9Hz,1H),7.17(t,J＝7.5Hz,1H),6.99(d,J＝8.1Hz,2H),6.94(dd,J＝9.1,2.9Hz,1H),6.84(d,J＝7.8Hz,1H),5.61(d,J＝9.6Hz,1H),4.18–4.08(m,1H),3.58(s,3H),3.22(s,3H),2.86(dd,J＝12.8,11.5Hz,1H),2.65(dd,J＝12.9,8.6Hz,1H),2.25(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.2,176.9,155.0,143.8,143.4,138.0,136.2,133.7,130.2,129.9,129.5,129.0,128.3,127.6,127.2,124.2,123.6,122.8,122.1,121.5,116.2,108.6,86.6,83.9,55.5,47.5,43.9,26.4,21.5.HPLC(IF,i-PrOH/n-hexane＝30/70,flow rate＝1.0mL/min,λ＝254nm)t_R＝37.78min(major),t_R＝20.71min(minor).HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₆S⁺]:583.1897,found:583.1896.IR:～(cm^-1)＝3675,2971,1719,1614,1494,1342,1161,1089,751,540.

Example 26

The procedure is as in example 17, except that the compound II-a is replaced by II-b (R)²＝Et，R³＝H，Ar³＝C₆H₅) Yield of III-ab 55% (dr)>20/1), 91% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 2.0mL/min, wavelength 254nm, major peak retention time 14.07min, minor peak retention time 10.06 min).¹H NMR(400MHz,CDCl₃)δ11.36(s,1H),7.86(dd,J＝8.1,1.2Hz,1H),7.71(d,J＝8.3Hz,2H),7.62(dd,J＝8.4,0.6Hz,1H),7.53(dd,J＝7.4,0.6Hz,1H),7.50–7.45(m,2H),7.40–7.33(m,4H),7.29(d,J＝8.2Hz,1H),7.21–7.15(m,1H),7.11(d,J＝8.1Hz,2H),6.96–6.85(m,2H),5.71(d,J＝9.7Hz,1H),4.34–4.24(m,1H),3.80(q,J＝7.2Hz,2H),2.99–2.85(m,1H),2.69(dd,J＝12.8,8.5Hz,1H),2.31(s,3H),1.32(t,J＝7.2Hz,3H).¹³C NMR(101MHz,CDCl₃)δ＝198.5,176.5,144.0,142.4,140.8,137.9,136.3,135.4,133.0,130.2,130.1,129.7,128.9,128.3,127.5,127.3,124.4,123.4,122.6,120.9,118.4,108.8,86.4,84.0,47.2,43.8,35.0,21.5,12.6.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₅S⁺]:567.1968,found:567.1951.IR:～(cm^-1)＝3665,2929,1714,1631,1490,1372,1159,911,727,545.

Example 27

The procedure is as in example 17, except that the compound II-a is replaced by II-c (R)²＝PhCH₂，R³＝H，Ar³＝C₆H₅) III-ac yield 53% (dr)>20/1), 90% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 14.21min, minor peak retention time 11.86 min).¹H NMR(400MHz,CDCl₃)δ11.25(s,1H),7.76(d,J＝8.0Hz,1H),7.60(d,J＝8.2Hz,2H),7.51(d,J＝8.4Hz,1H),7.41(dd,J＝15.4,7.3Hz,3H),7.28–7.16(m,9H),7.13(dd,J＝7.7,1.2Hz,1H),7.03(dd,J＝15.8,7.8Hz,3H),6.84–6.78(m,1H),6.63(d,J＝7.8Hz,1H),5.65(d,J＝9.7Hz,1H),4.84(dd,J＝40.0,15.7Hz,2H),4.19(dd,J＝20.4,9.2Hz,1H),2.94–2.83(m,1H),2.65(dd,J＝12.8,8.6Hz,1H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ＝198.4,177.2,144.0,142.4,140.8,137.9,136.4,135.4,135.3,133.0,130.1,129.9,129.7,129.0,128.9,128.3,127.8,127.6,127.3,127.2,124.3,123.7,122.5,120.9,118.3,109.6,86.5,84.0,47.3,44.0,43.9,34.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₈H₃₃N₂O₅S⁺]:629.2105,found:629.2105.IR:～(cm^-1)＝2920,1717,1603,1491,1340,1159,1089,909,812,696,545.

Example 28

The procedure is as in example 17, except that the compound II-a is replaced by II-d (R)²＝CH₃，R³＝4-F，Ar³＝C₆H₅) Yield of III-ad 49% (dr)>20/1), 91% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 15.85min, minor peak retention time 14.99 min).¹H NMR(400MHz,CDCl₃)δ11.19(s,1H),7.74(dd,J＝8.0,0.9Hz,1H),7.60(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,1H),7.36(d,J＝7.3Hz,2H),7.32–7.22(m,3H),7.19(d,J＝7.3Hz,1H),7.15(dd,J＝7.5,2.5Hz,1H),7.02(d,J＝8.1Hz,2H),7.00–6.92(m,1H),6.81(dd,J＝11.4,4.0Hz,1H),6.68(dd,J＝8.5,4.0Hz,1H),5.58(d,J＝9.7Hz,1H),4.20–4.06(m,1H),3.13(s,3H),2.88–2.73(m,1H),2.57(dd,J＝13.0,8.5Hz,1H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.1,176.6,160.9,158.5,144.0,140.9,139.2,137.6,136.4,135.5,133.0,131.4(d,J＝7.6Hz),129.6,129.0,128.3,127.6,127.3,122.6,120.9,118.5,116.3(d,J＝23.5Hz),(d,J＝25.0Hz),109.3(d,J＝8.0Hz),86.5,83.9,47.0,43.8,26.6,21.5.¹⁹F NMR(376MHz,CDCl₃)δ-118.84.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈FN₂O₅S⁺]:571.1697,found:571.1694.IR:～(cm^-1)＝3699,2921,1713,1551,1494,1343,1160,1090,902,698,565.

Example 29

The procedure is as in example 17, except that the compound II-a is replaced by II-e (R)²＝CH₃，R³＝4-Cl，Ar³＝C₆H₅) III-ae yield 50% (dr)>20/1), 90% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 24.57min, minor peak retention time 20.12 min).¹H NMR(400MHz,CDCl₃)δ11.20(s,1H),7.73(dd,J＝8.1,1.1Hz,1H),7.61(d,J＝8.3Hz,2H),7.54(d,J＝8.0Hz,1H),7.40–7.33(m,3H),7.31–7.22(m,4H),7.20(d,J＝7.3Hz,1H),7.03(d,J＝8.1Hz,2H),6.86–6.77(m,1H),6.69(d,J＝8.3Hz,1H),5.59(d,J＝9.7Hz,1H),4.18–4.08(m,1H),3.14(s,3H),2.86–2.73(m,1H),2.58(dd,J＝13.0,8.6Hz,1H),2.21(s,3H).¹³C NMR(101MHz,CDCl₃)δ＝197.9,176.5,144.0,141.9,140.9,137.5,136.3,135.5,132.9,131.5,130.0,129.6,129.0,128.3,127.6,127.3,124.7,122.6,120.9,118.5,109.6,86.6,83.7,47.0,43.8,26.5,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈ClN₂O₅S⁺]:587.1402,found:567.1949.IR:～(cm^-1)＝2924,1721,1552,1491,1260,1159,1089,811,734,564.

Example 30

The procedure is as in example 17, except that the compound II-a is replaced by II-f (R)²＝CH₃，R³＝4-Br，Ar³＝C₆H₅) Yield of III-af 42% (dr)>20/1), 93% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 2.0mL/min, wavelength 254nm, main peak retention time 22.63min, secondary peak retention time 12.21 min).¹H NMR(400MHz,CDCl₃)δ11.20(s,1H),7.72(dd,J＝8.1,1.3Hz,1H),7.60(d,J＝8.3Hz,2H),7.52(dd,J＝8.4,0.8Hz,1H),7.48(d,J＝1.9Hz,1H),7.40–7.33(m,3H),7.28–7.22(m,3H),7.19–7.15(m,1H),7.02(d,J＝8.1Hz,2H),6.85–6.76(m,1H),6.65(s,1H),5.58(d,J＝9.7Hz,1H),4.16–4.07(m,J＝11.3,9.1Hz,1H),3.12(s,3H),2.78(dd,J＝13.0,11.6Hz,1H),2.57(dd,J＝13.0,8.6Hz,1H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ197.9,176.4,144.0,142.4,140.8,137.5,136.3,135.5,133.0,132.9,131.8,129.7,129.0,128.3,127.6,127.4,127.3,122.6,120.9,118.5,116.2,110.2,86.6,83.6,47.0,43.826.5,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈BrN₂O₅S⁺]:631.0897,found:631.0897.IR:～(cm^-1)＝3675,2924,1714,1573,1492,1166,1089,836,699,565.

Example 31

The procedure is as in example 17, except that the compound II-a is replaced by II-g (R)²＝CH₃，R³＝4-OMe，Ar³＝C₆H₅) Yield of III-ag 53% (dr)>20/1), 90% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 40.09min, secondary peak retention time 26.00 min).¹H NMR(400MHz,CDCl₃)δ11.31(s,1H),7.85(dd,J＝8.1,1.3Hz,1H),7.67(d,J＝8.3Hz,2H),7.58(dd,J＝8.4,0.7Hz,1H),7.51–7.42(m,2H),7.34(t,J＝7.4Hz,3H),7.28(d,J＝5.3Hz,1H),7.09(t,J＝5.2Hz,3H),6.93–6.88(m,1H),6.86(dd,J＝8.5,2.5Hz,1H),6.74(d,J＝8.5Hz,1H),5.67(d,J＝9.6Hz,1H),4.31–4.21(m,1H),3.86(s,3H),3.21(s,3H),2.88(dd,J＝12.8,11.7Hz,1H),2.65(dd,J＝12.9,8.6Hz,1H),2.28(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.3,176.6,156.7,143.9,140.8,137.9,136.6,136.3,135.4,133.1,131.1,129.6,128.9,128.3,127.5,127.2,122.6,121.0,118.4,114.3,111.5,109.1,86.5,84.2,56.0,46.9,43.9,26.5,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₆S⁺]:583.1897,found:583.1896.IR:～(cm^-1)＝3679,2726,1722,1615,1494,1159,1065,907,676,545.

Example 32

The procedure is as in example 17, except that the compound II-a is replaced by II-h (R)²＝CH₃，R³＝4-Me，Ar³＝C₆H₅) III-ah yield 53% (dr)>20/1), 96% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 3/2, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 13.02min, minor peak retention time 12.00 min).¹H NMR(400MHz,CDCl₃)δ11.23(s,1H),11.23(s,1H),7.78(dd,J＝8.1,1.3Hz,1H),7.78(dd,J＝8.1,1.3Hz,1H),7.59(d,J＝8.3Hz,2H),7.59(d,J＝8.3Hz,2H),7.51(dd,J＝8.4,0.8Hz,1H),7.51(dd,J＝8.4,0.8Hz,1H),7.42–7.35(m,2H),7.42–7.34(m,2H),7.30–7.23(m,3H),7.33–7.17(m,5H),7.20(d,J＝5.2Hz,1H),7.01(t,J＝5.4Hz,3H),7.01(t,J＝5.4Hz,3H),6.85–6.80(m,1H),6.87–6.74(m,2H),6.78(dd,J＝8.5,2.5Hz,1H),6.66(d,J＝8.5Hz,1H),6.66(d,J＝8.5Hz,1H),5.59(d,J＝9.6Hz,1H),4.23–4.23(m,1H),3.78(s,3H),3.13(s,3H),2.80(dd,J＝12.8,11.7Hz,1H),2.58(dd,J＝12.9,8.6Hz,1H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.2,176.6,156.7,143.9,140.8,137.9,136.6,136.3,135.4,133.1,131.0,129.6,128.9,128.3,127.5,127.2,122.6,121.0,118.4,114.3,111.5,109.1,86.5,84.2,56.0,46.9,43.9,26.5,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₅S⁺]:567.1948,found:567.1946.IR:～(cm^-1)＝3669,2924,1719,1601,1493,1158,1035,821,661,546.

Example 33

The procedure is as in example 17, except that the compound II-a is replaced by II-i (R)²＝CH₃，R³＝2-OMe，Ar³＝C₆H₅) III-ai yield 54% (dr)>20/1), 92% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 35.10min, secondary peak retention time 21.04 min).¹H NMR(400MHz,CDCl₃)δ11.23(s,1H),7.78(dd,J＝8.1,1.3Hz,1H),7.58(d,J＝8.3Hz,2H),7.49(dd,J＝8.4,0.7Hz,1H),7.41–7.34(m,2H),7.29–7.22(m,3H),7.16(d,J＝1.1Hz,1H),7.03–6.97(m,4H),6.85–6.79(m,2H),5.58(d,J＝9.7Hz,1H),4.22–4.10(m,1H),3.76(s,3H),3.41(s,3H),2.77(dd,J＝12.8,11.6Hz,1H),2.56(dd,J＝12.9,8.7Hz,1H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.3,177.3,145.6,143.9,140.8,138.0,136.3,135.4,133.1,131.5,131.0,129.6,128.9,128.4,127.5,127.2,124.3,122.6,121.0,118.4,116.6,114.0,86.5,83.9,56.1,47.0,44.0,29.8,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₆S⁺]:583.1897,found:583.1896.IR:～(cm^-1)＝2924,1712,1601,1493,1339,1250,1159,1089,911,564.

Example 34

The procedure is as in example 17, except that the compound II-a is replaced by II-j (R)²＝CH₃，R³＝H，Ar³＝4-F-C₆H₄) Yield of III-aj 57% (dr)>20/1), 89% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 41.43min, secondary peak retention time 25.43 min).¹H NMR(400MHz,CDCl₃)δ11.32(s,1H),7.90(dd,J＝8.1,1.2Hz,1H),7.71(d,J＝8.3Hz,2H),7.61(dd,J＝8.3,0.6Hz,1H),7.51–7.44(m,3H),7.40–7.32(m,2H),7.20–7.15(m,1H),7.13(d,J＝8.1Hz,2H),7.04(t,J＝8.6Hz,2H),6.98–6.92(m,1H),6.86(d,J＝7.8Hz,1H),5.66(d,J＝9.6Hz,1H),4.29(dd,J＝20.4,9.2Hz,1H),3.25(s,3H),2.84(dd,J＝12.8,11.4Hz,1H),2.69(dd,J＝12.9,8.8Hz,1H),2.31(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.0,176.8,163.1,160.9,144.1,143.3,140.8,136.3,135.5,133.7(d,J＝3.2Hz),130.3,130.0,129.91(d,J＝8.0Hz),127.2,124.1,123.6,122.6,120.8,118.3,115.8(d,J＝21.3Hz),108.7,86.4,83.8,46.1,43.6,26.4,21.5.¹⁹FNMR(376MHz,CDCl₃)δ＝-114.90.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈FN₂O₅S⁺]:571.1697,found:571.1695.IR:～(cm^-1)＝3672,2987,1718,1494,1379,1160,1090,922,751,564.

Example 35

The procedure is as in example 17, except that the compound II-a is replaced by II-k (R)²＝CH₃，R³＝H，Ar³＝4-Cl-C₆H₄) III-ak yield 55% (dr)>20/1), 91% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 16.99min, secondary peak retention time 11.84 min).¹H NMR(400MHz,CDCl₃)δ11.28(s,1H),7.92(dd,J＝8.1,1.3Hz,1H),7.69(d,J＝8.3Hz,2H),7.62(dd,J＝8.4,0.8Hz,1H),7.50–7.43(m,3H),7.43–7.35(m,2H),7.36–7.32(m,2H),7.20–7.14(m,1H),7.11(d,J＝8.0Hz,2H),7.00–6.93(m,1H),6.86(d,J＝7.8Hz,1H),5.65(d,J＝9.6Hz,1H),4.36–4.24(m,1H),3.25(s,3H),2.83(dd,J＝12.9,11.3Hz,1H),2.69(dd,J＝13.0,8.8Hz,1H),2.32(s,3H).¹³C NMR(101MHz,CDCl₃)δ197.6,176.6,144.0,143.4,140.8,136.6,136.3,135.6,133.3,133.2,130.3,129.8,129.7,129.6,129.0,127.2,124.1,123.6,122.6,120.9,118.5,108.7,86.4,83.8,46.1,43.5,26.4,21.4.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈ClN₂O₅S⁺]:587.1402,found:587.1389.IR:～(cm^-1)＝2923,1717,1614,1492,1159,1089,812,750,660,564.

Example 36

The procedure is as in example 17, except that the compound II-a is replaced by II-l (R)²＝CH₃，R³＝H，Ar³＝4-Br-C₆H₄) III-al yield 52% (dr)>20/1), 99% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 2.0mL/min, wavelength 254nm, main peak retention time 17.62min, secondary peak retention time 12.50 min).¹H NMR(400MHz,CDCl₃)δ11.29(s,1H),7.93(dd,J＝8.1,1.3Hz,1H),7.69(d,J＝8.3Hz,2H),7.62(dd,J＝8.4,0.7Hz,1H),7.51–7.45(m,3H),7.43–7.35(m,4H),7.18(dd,J＝7.5,0.5Hz,1H),7.11(d,J＝8.1Hz,2H),7.00–6.94(m,1H),6.86(d,J＝7.8Hz,1H),5.64(d,J＝9.6Hz,1H),4.34–4.24(m,1H),3.25(s,3H),2.83(dd,J＝12.9,11.3Hz,1H),2.70(dd,J＝13.0,8.8Hz,1H),2.32(s,3H).¹³C NMR(101MHz,CDCl₃)δ197.9,176.9,144.0,143.4,140.8,136.3,135.6,133.2,132.0,130.3,130.1,129.7,129.5,127.2,124.1,123.6,122.7,121.4,118.5,108.7,86.4,83.9,46.2,43.4,26.5,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈BrN₂O₅S⁺]:631.0897,found:631.0893.IR:～(cm^-1)＝3672,2962,1716,1614,1491,1159,1089,811,750,564.

Example 37

The procedure is as in example 17, except that the compound II-a is replaced by II-m (R)²＝CH₃，R³＝H，Ar³＝4-OMe-C₆H₄) III-am yield 60% (dr)>20/1), 93% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 31.69min, minor peak retention time 22.56 min).¹H NMR(400MHz,CDCl₃)δ11.25(s,1H),7.77(dd,J＝8.1,1.3Hz,1H),7.59(d,J＝8.3Hz,2H),7.50(dd,J＝8.4,0.7Hz,1H),7.40(dd,J＝7.4,0.6Hz,1H),7.32–7.23(m,4H),7.10–7.03(m,1H),7.01(d,J＝8.1Hz,2H),6.85–6.73(m,4H),5.53(d,J＝9.7Hz,1H),4.21–4.09(m,1H),3.71(s,3H),3.14(s,3H),2.83–2.70(m,1H),2.55(dd,J＝12.8,8.5Hz,1H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.5,176.9,159.0,143.9,143.3,140.8,136.3,135.4,133.1,130.1,130.0,129.6,129.3,127.2,124.1,123.6,122.6,121.0,118.3,114.3,108.6,86.4,83.9,55.3,46.3,43.8,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₆S⁺]:583.1897,found:583.1898.IR:～(cm^-1)＝3678,2928,1720,1613,1493,1159,1089,911,727,563.

Example 38

The procedure is as in example 17, except that the compound II-a is replaced by II-n (R)²＝CH₃，R³＝H，Ar³＝4-Me-C₆H₄) Yield of III-an 53% (dr)>20/1), 91% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 2.0mL/min, wavelength 254nm, major peak retention time 16.73min, minor peak retention time 13.11 min).¹H NMR(400MHz,CDCl₃)δ11.24(s,1H),7.79(dd,J＝8.1,1.3Hz,1H),7.58(d,J＝8.3Hz,2H),7.50(dd,J＝8.4,0.7Hz,1H),7.40(dd,J＝7.4,0.6Hz,1H),7.29–7.23(m,4H),7.07(dt,J＝7.5,1.5Hz,3H),6.99(d,J＝8.0Hz,2H),6.86–6.79(m,1H),6.74(d,J＝7.8Hz,1H),5.55(d,J＝9.7Hz,1H),4.22–4.13(m,1H),3.14(s,3H),2.87–2.72(m,1H),2.55(dd,J＝12.8,8.4Hz,1H),2.25(s,3H),2.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.4,176.9,143.9,143.3,140.8,137.2,136.3,135.4,134.8,133.1,130.1,130.0,129.6,129.6,128.2,127.2,124.1,123.6,122.6,121.0,118.4,108.6,86.4,83.9,60.2,46.6,43.9,26.4,21.5,21.1.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₅S⁺]:567.1948,found:567.1946.IR:～(cm^-1)＝3675,2922,1719,1613,1493,1338,1160,1089,751,563.

Example 39

The specific method is the same as example 17, but the method is different from the methodConversion of compound II-a to II-o (R)²＝CH₃，R³＝H，Ar³＝3-Br-C₆H₄) III-ao yield 61% (dr)>20/1), 91% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 2.0mL/min, wavelength 254nm, major peak retention time 15.92min, minor peak retention time 9.96 min).¹H NMR(400MHz,CDCl₃)δ11.28(s,1H),7.94(dd,J＝8.1,1.2Hz,1H),7.70(d,J＝8.3Hz,2H),7.66–7.59(m,2H),7.46(dd,J＝7.2,4.2Hz,2H),7.44–7.34(m,3H),7.24(t,J＝7.8Hz,1H),7.16(t,J＝7.5Hz,1H),7.12(d,J＝8.1Hz,2H),7.00–6.93(m,1H),6.86(d,J＝7.8Hz,1H),5.66(d,J＝9.6Hz,1H),4.33–4.23(m,1H),3.25(s,3H),2.84(dd,J＝12.8,11.5Hz,1H),2.68(dd,J＝12.9,8.7Hz,1H),2.30(s,3H).¹³C NMR(101MHz,CDCl₃)δ＝197.8,176.7,144.0,143.4,140.9,140.6,136.3,135.6,133.2,131.3,130.7,130.5,130.3,129.7,129.6,127.2,127.2,124.1,123.6,122.9,122.7,120.8,118.5,108.7,86.4,83.8,46.2,43.5,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₂₈BrN₂O₅S⁺]:631.0897,found:631.0894.IR:～(cm^-1)＝3672,2924,1718,1614,1492,1450,1159,1089,727,564.

Example 40

The procedure is as in example 17, except that the compound II-a is replaced by II-p (R)²＝CH₃，R³＝H，Ar³＝3-Me-C₆H₄) Yield of III-ap 60% (dr)>20/1), 96% ee (HPLC assay, Chiralpak IC, mobile phase n-hexane/i-PrOH 3/2, flow rate 2.0mL/min, wavelength 254nm, main peak retention time 31.71min, sub-peak retention time 18.88 min).¹H NMR(400MHz,CDCl₃)δ11.24(s,1H),7.79(d,J＝7.9Hz,1H),7.59(d,J＝8.1Hz,2H),7.49(d,J＝8.3Hz,1H),7.40(d,J＝7.3Hz,1H),7.26(t,J＝7.4Hz,2H),7.17(dd,J＝13.0,9.2Hz,3H),7.07(t,J＝7.5Hz,1H),6.99(d,J＝7.9Hz,3H),6.82(t,J＝7.6Hz,1H),6.74(d,J＝7.7Hz,1H),5.57(d,J＝9.6Hz,1H),4.17(dd,J＝20.3,9.3Hz,1H),3.14(s,3H),2.80(t,J＝12.3Hz,1H),2.55(dd,J＝12.7,8.4Hz,1H),2.26(s,3H),2.19(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.4,176.9,143.9,143.3,140.8,138.6,137.8,136.3,135.4,133.1,130.1,130.0,129.6,129.0,128.8,128.3,127.2,125.4,124.1,123.6,122.6,121.0,118.3,108.6,86.4,84.0,46.9,43.9,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₃H₃₁N₂O₅S⁺]:567.1948,found:567.1949.IR:～(cm^-1)＝3669,2921,1721,1614,1492,1374,1159,1089,911,564.

EXAMPLE 41

The procedure is as in example 17, except that the compound II-a is replaced by II-q (R)²＝CH₃，R³＝H，Ar³＝3,4-Me₂-C₆H₄) Yield of III-aq 47% (dr)>20/1), 99% ee (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 28.06min, secondary peak retention time 25.28 min).¹H NMR(400MHz,CDCl₃)δ11.36(s,1H),7.93(dd,J＝8.1,1.2Hz,1H),7.70(d,J＝8.3Hz,2H),7.61(d,J＝8.4Hz,1H),7.51(d,J＝6.8Hz,1H),7.43–7.33(m,2H),7.24(s,2H),7.19(dd,J＝11.0,4.0Hz,1H),7.14(d,J＝7.6Hz,1H),7.09(d,J＝8.1Hz,2H),6.99–6.91(m,1H),6.86(d,J＝7.8Hz,1H),5.65(d,J＝9.7Hz,1H),4.33–4.23(m,1H),3.25(s,3H),2.91(t,J＝12.3Hz,1H),2.64(dd,J＝12.8,8.3Hz,1H),2.33–2.25(m,9H).¹³C NMR(101MHz,CDCl₃)δ198.4,176.9,176.9,143.9,143.3,140.8,137.2,136.3,135.9,135.3,135.1,133.2,130.2,130.1,129.6,129.5,127.3,125.7,124.1,123.6,122.6,121.0,118.3,108.6,86.4,83.9,46.5,44.0,26.4,21.5,19.9,19.4.HRMS(ESI):[M+H]⁺calcd for[C₃₄H₃₃N₂O₅S⁺]:581.2105,found:581.2105.IR:～(cm^-1)＝3662,2922,1722,1614,1493,1338,1159,1090,912,563.

Application example 1

Hydroxylamine hydrochloride (71mg, 1.0mmol), sodium acetate (100mg, 1.2mmol) and tetrahydrofuran spiroxoindole compound III-aa (55mg, 0.1mmol) were added to 5mL of methanol, and the reaction was refluxed for 10 hours to complete the reaction. Adding 3mL water to quench the reaction, extracting with dichloromethane three times (5 mL each time), drying the organic phase with anhydrous sodium sulfate, and separating by column chromatography to obtain pure compound (IV) with high yield87%, 92% ee. (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 46.92min, minor peak retention time 42.42 min).¹H NMR(400MHz,CDCl₃)δ7.50(s,3H),7.38–7.12(m,8H),7.03(d,J＝7.9Hz,3H),6.94(s,1H),6.85(d,J＝7.5Hz,1H),6.75(d,J＝7.8Hz,1H),6.58(s,1H),5.36(d,J＝10.5Hz,1H),3.52(dd,J＝19.1,10.6Hz,1H),3.12(s,3H),2.74–2.52(m,1H),2.38(dd,J＝12.8,8.2Hz,1H),2.22(s,3H).¹³C NMR(101MHz,CDCl₃)δ153.60,153.50,143.33,143.09,137.10,135.06,130.13,130.07,129.93,129.49,129.06,128.20,127.64,127.39,123.73,123.42,108.65,87.98,83.18,48.46,45.16,26.48,21.53.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₃₀N₃O₅S⁺]:568.1901,found:568.1900.IR:～(cm^-1)＝3239,1703,1493,1157,1089,935,749,659,563,544.

Application example 2

Tetrahydrofuran spirooxindole compound III-aa (55mg, 0.1mmol) was added to 5mL of methanol, and sodium borohydride (15mg, 0.4mmol) was added in portions at 0 ℃ and then stirred at room temperature for 0.5 hour to complete the reaction. The reaction was quenched by addition of 3mL of saturated ammonium chloride solution, extracted three times with 5mL of dichloromethane, the organic phase was dried over anhydrous sodium sulfate and column chromatographed to give pure compound (V) in 90% yield and 92% ee. (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 18.31min, minor peak retention time 41.36 min).¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.44(d,J＝8.3Hz,2H),7.31–7.23(m,3H),7.18(t,J＝7.3Hz,3H),7.10(t,J＝7.3Hz,1H),7.08–7.01(m,3H),7.01–6.95(m,2H),6.91(dd,J＝10.7,4.2Hz,2H),6.75(d,J＝7.8Hz,1H),4.83(dd,J＝10.1,4.5Hz,1H),4.77(d,J＝4.4Hz,1H),3.38(dd,J＝19.4,10.5Hz,1H),3.09(s,3H),2.63–2.49(m,1H),2.42(dd,J＝13.1,8.8Hz,1H),2.25(s,3H).¹³C NMR(101MHz,CDCl₃)δ177.1,143.4,143.4,139.0,137.1,136.1,130.1,129.8,129.7,129.5,128.9,128.8,128.6,128.0,127.2,124.5,123.6,123.5,122.8,108.6,89.8,82.6,74.5,48.3,45.8,26.3,21.6.HRMS(ESI):[M+H]⁺calcd for[C₃₂H₃₁N₂O₅S⁺]:555.1948,found:555.1945.IR:～(cm^-1)＝3209,2926,1688,1615,1334,1157,1090,747,672,564.

Application example 3

Tetrahydrofuran spirooxindole compound III-aa (55mg, 0.1mmol) was added to 2mL of dichloromethane, and two drops of concentrated sulfuric acid were added dropwise at 0 ℃ and then stirred at room temperature for 0.5 hour to terminate the reaction. The reaction was quenched by addition of 3mL saturated sodium bicarbonate solution, extracted three times with 5mL of dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and column chromatography gave pure compound (VI) in 80% yield and 95% ee. (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 19.56min, minor peak retention time 17.48 min).¹H NMR(400MHz,CDCl₃)δ7.70(dd,J＝8.2,1.3Hz,1H),7.45(dd,J＝12.0,4.6Hz,3H),7.29–7.20(m,3H),7.18–7.12(m,1H),7.13–7.06(m,1H),7.06–6.99(m,1H),6.73(d,J＝7.8Hz,1H),6.55–6.40(m,2H),6.36–6.05(m,1H),5.69(d,J＝9.7Hz,1H),4.37–4.25(m,1H),3.15(s,3H),2.92–2.76(m,1H),2.58(dd,J＝12.8,8.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ196.0,177.2,151.2,143.3,138.6,134.9,132.6,130.5,129.9,128.8,128.3,127.2,124.3,123.4,117.1,116.8,116.0,108.4,86.2,83.8,46.8,44.0,26.4.HRMS(ESI):[M+H]⁺calcd for[C₂₅H₂₃N₂O₃ ⁺]:399.1703,found:399.1700.IR:～(cm^-1)＝3447,3331,2949,1713,1614,1493,1224,1024,746,537.

Application example 4

Compound VI (40mg, 0.1mmol) was added to 2mL of methanol and CuCl was added thereto at room temperature₂·2H₂O(3.4mg，0.02mmol)、NH₄OAc (15.4mg, 0.2mmol) and TBHP (t-butyl peroxide, 41uL, 0.3mmol), then warmed to 60 ℃ and stirred for 4 hours. The reaction was quenched by addition of 3mL of saturated sodium bicarbonate solution, extracted three times with 5mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and column chromatographed to give pure compound (VII) in 80% yield and 93% ee. (HPLC assay, Chiralpak IA, mobile phase n-hexane/i-PrOH. RTM. 19/1, flow rate 1.0mL/min, wavelength 254nm, main peak retention time 22.88min, secondary peak retention time 29.10 min).¹H NMR(400MHz,CDCl₃)δ9.39(s,1H),8.22(d,J＝8.1Hz,1H),7.98(d,J＝8.4Hz,1H),7.84–7.77(m,1H),7.62(dd,J＝7.4,0.7Hz,1H),7.53(dd,J＝11.4,4.2Hz,3H),7.33–7.26(m,3H),7.22–7.17(m,1H),7.13–7.07(m,1H),6.81(d,J＝7.8Hz,1H),6.35(d,J＝9.8Hz,1H),4.92–4.80(m,1H),3.25(s,3H),3.05(dd,J＝12.8,11.7Hz,1H),2.81(dd,J＝12.8,8.5Hz,1H).¹³C NMR(101MHz,CDCl₃)δ177.6,165.0,154.6,150.5,143.4,138.4,133.8,130.4,130.0,128.7,128.7,128.4,127.9,127.2,125.2,124.6,124.4,123.5,108.4,84.3,83.6,47.8,44.2,26.4.HRMS(ESI):[M+H]⁺calcd for[C₂₂H₂₂N₃O₂ ⁺]:408.1707,found:408.1704.IR:～(cm^-1)＝2926,1716,1561,1462,1065,1014,745,690,534,462.

Application example 5

Compound VI (40mg, 0.1mmol) was added to 2mL of water, and acetylacetone (12mg, 0.12mmol) and FeCl were added at room temperature₃·6H₂O (2.7mg, 0.01mmol) and two drops of concentrated hydrochloric acid, and then heated to 60 ℃ and stirred for 4 hours to complete the reaction. The reaction was quenched by addition of 3mL of saturated sodium bicarbonate solution, extracted three times with 5mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and column chromatographed to give pure compound (VIII) in 82% yield and 93% ee. (HPLC assay, Chiralpak IF, mobile phase n-hexane/i-PrOH 7/3, flow rate 1.0mL/min, wavelength 254nm, major peak retention time 18.07min, minor peak retention time 12.48 min).¹H NMR(400MHz,CDCl₃)δ7.90(dd,J＝7.3,5.3Hz,2H),7.53–7.45(m,1H),7.44–7.35(m,3H),7.26–7.14(m,4H),7.08(d,J＝8.2Hz,1H),6.97(t,J＝7.5Hz,1H),6.87(d,J＝7.7Hz,1H),6.51(d,J＝9.9Hz,1H),3.93(dd,J＝19.0,10.1Hz,1H),3.25(s,3H),2.94(dd,J＝13.6,10.7Hz,1H),2.84(dd,J＝13.6,8.5Hz,1H),2.67(s,3H),2.37(s,3H).¹³C NMR(101MHz,CDCl₃)δ198.3,176.9,148.1,146.9,144.0,143.3,140.8,136.4,135.4,133.1,131.6,130.2,129.8,129.7,127.3,124.1,123.6,122.6,121.7,120.9,118.3,108.6,108.5,108.4,101.2,86.2,83.8,46.7,43.8,26.4,21.5.HRMS(ESI):[M+H]⁺calcd for[C₃₀H₂₆N₂O₃ ⁺]:463.2016,found:463.2017.IR:～(cm^-1)＝2922,1700,1601,1461,1364,1087,749,523,451.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims

1. An enantiomerically pure tetrahydrofuran spiro-oxindole derivative characterized by: the structural formula is as follows:

wherein R is¹Is H, F, Cl, Br, CH₃、OCH₃，R²Is CH₃、CH₂CH₃、Bn，R³Is H, 4-CH₃O、4-CH₃、4-F、4-Cl、4-Br、2-CH₃One of O, Ar³Is C₆H₅、4-CH₃O-C₆H₄、4-CH₃-C₆H₄、4-F-C₆H₄、4-Cl-C₆H₄、4-Br-C₆H₄、4-NO₂-C₆H₄、3-Br-C₆H₄、3-CH₃-C₆H₄、3,4-(CH₃)₂-C₆H₃To (3) is provided.

2. A process for the preparation of enantiomerically pure tetrahydrofuran spirooxindole derivatives according to claim 1 comprising the steps of: dissolving a compound I1-p-toluenesulfonyl indoline-2, 3-diol compound and a compound IIbeta, gamma-unsaturated-alpha-ketoamide in an organic solvent, reacting for 72 hours under the catalysis of a binuclear zinc catalyst C1-C3, adding 0.5mL of trifluoroacetic acid, reacting for 1 hour, treating a resultant with a saturated sodium bicarbonate solution, and separating and purifying to obtain a compound III tetrahydrofuran spiro-oxoindole derivative, wherein the chemical reaction process is as follows:

3. a process for the preparation of enantiomerically pure tetrahydrofuran spirooxindole derivatives according to claim 2, wherein: the structural general formula of the compound I1-p-toluenesulfonyl indoline-2, 3-diol compound is

wherein Ar is¹、Ar²Are respectively C₆H₅、4-Cl-C₆H₄、4-CF₃-C₆H₄、4-CH₃-C₆H₄To (3) is provided.

4. A process for the preparation of enantiomerically pure tetrahydrofuran spirooxindole derivatives according to claim 3 wherein: the organic solvent is one of tetrahydrofuran, toluene, acetonitrile, dichloromethane and chloroform, the reaction temperature is 25 ℃, and the molar ratio of the compound I, the compound II and the binuclear zinc catalyst C1-C3 is 1:1: 0.05-0.2.

5. Use of enantiomerically pure tetrahydrofuran spirooxindole derivatives according to claim 1 as intermediates in organic synthesis, using III-aa of the prepared product as an intermediate in organic synthesis, R of III-aa¹Is H, R²Is CH₃,R³Is H, Ar³Is C₆H₅The reaction in organic synthesis is as follows: