CN108129367B

CN108129367B - Construction method for constructing chiral sulfinyl imine alpha-site chiral quaternary carbon, product and application thereof

Info

Publication number: CN108129367B
Application number: CN201810111787.7A
Authority: CN
Inventors: 杨诚; 杨光; 周红刚; 孙涛; 覃双林; 刘双伟; 卢骋
Original assignee: Nankai University
Current assignee: Nankai University
Priority date: 2018-02-05
Filing date: 2018-02-05
Publication date: 2020-10-02
Anticipated expiration: 2038-02-05
Also published as: CN108129367A

Abstract

The invention provides an alkylation method for constructing chiral sulfinyl imine alpha position chiral four-level carbon, a product and an application thereof, wherein the alkylation method has the advantages of cheap reaction raw materials, mild reaction conditions, simple reaction steps, easy operation, high regioselectivity and high stereoselectivity, and a chiral sulfinyl imine derivative with the chiral four-level carbon at the alpha position, which is difficult to obtain by the previous method, is obtained with higher yield, so that the method is suitable for industrial production; moreover, the chiral sulfinyl imine with the chiral quaternary carbon at the alpha position has better effect of inhibiting organ fibrosis, has important theoretical value and practical significance for national economy, social development, human health and the like, and has good application prospect.

Description

Construction method for constructing chiral sulfinyl imine alpha-site chiral quaternary carbon, product and application thereof

Technical Field

The invention belongs to the field of organic synthesis, and relates to an alkylation method of chiral sulfinyl imine alpha-site chiral quaternary carbon, and a chiral sulfinyl imine product with the chiral quaternary carbon in the alpha site, which is prepared by the synthesis method.

Background

Alpha-functionalization of carbonyl compounds can build a large number of building blocks for natural products and drug molecules. The alpha-position asymmetric functionalization of carbonyl compounds by means of chiral auxiliary chiral sulfinamide is a novel method which is easy to separate and has large-scale production potential. However, the alkylation method of chiral sulfimide reported at present is generally harsh in conditions, and often generates multiple substitution and elimination of byproducts.

In addition, the construction of chiral quaternary carbon is also a big problem in the current synthesis world. The prior art also provides a synthesis method of some quaternary carbons, for example, chinese patent CN107188874A provides a method for constructing chiral quaternary carbons by Michael addition reaction, in which B-unsaturated ketene site raw material is used, and chirality is controlled by chiral catalyst to perform Michael addition reaction, so as to successfully obtain target products with chiral quaternary carbon centers, but the chiral catalyst required by the method is difficult to synthesize or expensive; for another example, CN104744394B discloses a Ni-catalyzed asymmetric reaction to construct a class of compounds with trifluoromethyl chiral quaternary carbon center, but this method also requires the use of expensive chiral ligands, and metal catalysis is generally sensitive to air and moisture in air, which is not favorable for scale-up production. Therefore, the development of an efficient chiral quaternary carbon construction method with mild conditions, simple reaction steps, easy operation, high regioselectivity and high stereoselectivity is one of the current research focuses of researchers in the field.

Disclosure of Invention

In order to overcome the defects and shortcomings in the prior art, the invention aims to provide a simple, high-regioselectivity and stereoselectivity construction method of an alpha-site quaternary carbon chiral center of imine and ketone compounds by utilizing the synergistic effect of chiral auxiliary tert-butyl sulfinamide and an electron-withdrawing guiding group. The synthetic route is as follows:

and, the method comprises the steps of:

(1) using a carbonyl compound A1 as an initial raw material, and condensing with chiral sulfinamide to prepare an intermediate A2;

(2) the intermediate A2 reacts with a guide group donor such as allyl chloroformate and the like to prepare an intermediate A3;

(3) and (3) performing alkylation reaction on the intermediate A3 to obtain the chiral sulfinyl imine A with the alpha position having chiral four-stage carbon.

According to the above synthesis method, the general structural formula of the compound which can be prepared comprises a cyclic structural general formula I:

and, the structural general formula I has the following characteristics:

(I1) the directing group DG may be a variety of electron withdrawing groups: including ester groups, ketone groups, amide groups, cyano groups, nitro groups, and the like;

(I2) the electrophilic substituent R may be; alkylaryl, alkylalkenyl, alkylalkynyl, alkyl F, CF₃Br, Cl and Michael acceptors;

(I3) the B ring can be C4-C30 carbocycle, C4-C30 carbon heterocycle containing nitrogen, sulfur, oxygen, phosphorus and the like;

(I4) the tert-butyl group (t-Bu) in the compound may be 2,4, 6-trimethylphenyl (Mes), methylphenyl (Tol), phenyl (Ph), isopropyl (i-pr) and the like, and the sulfinyl group may have the configuration of R, S.

According to the above synthesis method, the general structural formula of the compound which can be prepared comprises a cyclic structural formula II:

and, the general structural formula II has the following characteristics:

(II1) the guide group DG can be a variety of electron withdrawing groups: including ester groups, ketone groups, amide groups, cyano groups, nitro groups, and the like;

(II2) substituent R may be; alkylaryl, alkylalkenyl, alkylalkynyl, alkyl;

(II3) R1 and R2 are each independently selected from: h, chain alkyl of C1-C30, cyclopropyl of C3-C30, alkenyl of C2-C30, cycloalkenyl of C3-C30, alkynyl of C2-C30, alkoxy of C1-C30, aryl alkoxy of C7-C30, aryl of C6-C30, heterocyclic aryl of C4-C30.

The tert-butyl group (t-Bu) in the compound (II4) may be 2,4, 6-trimethylphenyl (Mes), methylphenyl (Tol), phenyl (Ph), isopropyl (i-pr) or the like, and the sulfinyl group may have the configuration R, S.

Preferably, in formula I, II:

(1) the directing group DG may preferably be: allyloxycarbonyl, benzyloxycarbonyl, isopropyloxycarbonyl, methoxycarbonyl;

(2) the substituent R may preferably be benzyl, substituted benzyl, allyl, substituted allyl, propargyl, substituted propargyl and saturated alkane;

preferably, the compound synthesis method comprises the following steps:

(1) dissolving the compound A1 in tetrahydrofuran, sequentially adding R-tert-butyl sulfinamide and titanium tetraisopropoxide for reaction, and performing aftertreatment to obtain an intermediate A2;

(2) dissolving the intermediate A2 in tetrahydrofuran, cooling to-78 ℃, adding alkali B1 for reaction, adding allyl chloroformate and other guiding group donors, stirring for reaction at-78 ℃, and performing aftertreatment to obtain an intermediate A3;

(3) dissolving the intermediate A3 in tetrahydrofuran, cooling to 0 ℃, adding alkali B2 for reaction, adding an electrophilic reagent (R-X) for reaction, and carrying out post-treatment to obtain the target product A.

Preferably, in the above synthesis method, the step (1) is:

dissolving a compound A1 in tetrahydrofuran, sequentially adding R-tert-butyl sulfinamide and titanium tetraisopropoxide at room temperature, heating to 40-70 ℃, reacting for 6-12 hours, and performing aftertreatment to obtain an intermediate A2;

preferably, in the above synthesis method, the step (2) is:

dissolving the intermediate A2 in tetrahydrofuran, cooling to-78 ℃ under a low-temperature reactor, adding alkali B1 for reaction for 1 hour, slowly dropwise adding a guide group donor such as allyl chloroformate and the like, stirring and reacting for 2-5 hours at-78 ℃, and performing aftertreatment to obtain an intermediate A3;

preferably, the base B1 may preferably be NaHMDS, KHMDS, LiHMDS;

preferably, in the above synthesis method, step (3) is:

dissolving the intermediate A3 in tetrahydrofuran, cooling to 0 ℃, adding alkali B2 to react for 15 minutes, stirring at 0 ℃ to react for 15-60 minutes, adding electrophilic reagents (R-X), reacting for 5-60 minutes, moving to 20-60 ℃ to react for 8-24 hours, and carrying out post-treatment to obtain a target product A;

preferably, the base B2 may preferably be NaHMDS, KHMDS, LiHMDS.

In addition, in the above synthesis method, the "post-treatments" described in each of the reaction steps (1) to (4) are all suitable post-treatments made by those skilled in the art according to the reaction conditions of the step, and these post-treatments are intended to remove impurities and solvents and to ensure that a pure product is obtained to some extent.

Optionally, the post-processing in step (1) refers to: after the reaction is finished, adding water into the reaction liquid for quenching, filtering to remove the precipitate, washing the precipitate with ethyl acetate, drying the obtained organic phase with anhydrous sodium sulfate, filtering, concentrating, and separating by fast column chromatography to obtain an intermediate A2.

Optionally, the post-processing in step (2) refers to: after the reaction is finished, adding a saturated ammonium chloride solution into the reaction solution for quenching, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating, and separating by using fast column chromatography to obtain an intermediate A3.

Optionally, the post-processing in step (3) refers to: after the reaction is finished, adding a saturated ammonium chloride solution into the reaction solution for quenching, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating, and separating by using fast column chromatography to obtain a target product A.

The invention also provides an application of the compound A in preparing a medicament for inhibiting organ fibrosis.

A pharmaceutical composition comprising a therapeutically effective amount of said compound a, together with pharmaceutically acceptable excipients;

preferably, the pharmaceutical composition is a medicament in dosage forms of tablets, capsules, aerosols, dispersible tablets, oral liquids, suppositories, dropping pills, large infusion solutions, small needles, freeze-dried powder injections, ointments or liniments and the like, and comprises various sustained-release and controlled-release dosage forms or nano preparations which are conventionally prepared by adopting the accepted common sense of pharmacy.

The alkylation method provided by the invention has the advantages of cheap reaction raw materials, mild reaction conditions, simple reaction steps, easiness in operation, high regioselectivity and high stereoselectivity, can obtain a chiral sulfinimide derivative with alpha-position chiral quaternary carbon, which is difficult to obtain by the previous method, in a higher yield, and is suitable for industrial production; moreover, the chiral sulfinyl imine with the chiral quaternary carbon at the alpha position has better effect of inhibiting organ fibrosis, has important theoretical value and practical significance for national economy, social development, human health and the like, and has good application prospect.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:

FIG. 1 shows nuclear magnetic data (NMR spectra of Compounds) of example 20 of the present invention;

FIG. 2 shows the nuclear magnetic data of example 21 of the present invention.

Detailed Description

Unless otherwise defined, terms used herein have meanings that are conventionally understood by those skilled in the art, and some terms used herein are defined as follows in order to facilitate understanding of the present invention.

As used in the specification and in the claims, the singular form of "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, the term "cell" includes a plurality of cells, including mixtures thereof.

All numerical designations such as pH, temperature, time, concentration, including ranges, are approximations. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term "about". It is also to be understood that, although not always explicitly recited, the reagents described herein are merely exemplary and equivalents thereof are known in the art.

In a first aspect of the present invention, a synthetic method of a chiral sulfinimide derivative having a chiral quaternary carbon at an α -position is provided, wherein the synthetic route is as follows:

and, the synthesis method comprises the steps of:

(1) dissolving the compound A1 in tetrahydrofuran, and adding R-tert-butyl sulfinamide and titanium tetraisopropoxide in sequence for reaction. Post-treatment to obtain an intermediate A2;

(2) dissolving the intermediate A2 in tetrahydrofuran, cooling to-78 ℃, adding NaHMDS or KHMDS for reaction, adding allyl chloroformate and other guiding group donors, stirring for reaction at-78 ℃, and performing post-treatment to obtain an intermediate A3;

(3) dissolving the intermediate A3 in tetrahydrofuran, cooling to 0 ℃, adding NaHMDS or KHMDS for reaction, adding an electrophilic reagent (R-X) for reaction, and performing aftertreatment to obtain a target product A4.

In a second aspect of the present invention, there is provided a chiral sulfinimide derivative having a chiral quaternary carbon at the α -position, wherein the chiral sulfinimide derivative having a chiral quaternary carbon at the α -position is the target product a obtained by the synthesis method according to the first aspect of the present invention.

Example 1: synthesis of key intermediate 1

The method comprises the following operation steps: under the protection of argon, the sulphoimine (30mmol) is added into a round-bottom flask, tetrahydrofuran (150mL) is added for dissolution, and the mixture is cooled to-78 ℃ under a low-temperature reactor. NaHMDS (30mL,2M in THF) was added dropwise and allyl chloroformate (60mmol) was added dropwise after 1 hour of reaction. The reaction was continued at-78 ℃ for 3 hours. After TLC monitoring reaction is complete, saturated NH is used₄The Cl (100mL) solution was quenched and extracted three times with ethyl acetate (3X 100 mL). The organic phase was collected over anhydrous sodium sulfate (Na)₂SO₄) Drying, filtering and spin-drying with a rotary evaporator. The crude product is separated by column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain the target product 1.

8.5g, yield 95%, pale yellow oil α]_D ²³＝-24.67(c 1.0,CHCl₃).IR(KBr)ν_max:2962,2864,1659,1602,1260,1229,1097,1039,1031,1001,801cm^-1.¹H NMR(400MHz,CDCl₃)10.91(s,1H),6.00–5.87(m,1H),5.25(dd,J＝33.6,13.7Hz,2H),4.60(s,2H),2.77(m,2H),2.49(m,2H),1.83–1.58(m,4H),1.46(m,2H),1.31(s,9H).¹³C NMR(100MHz,CDCl₃)169.9,161.6,132.7,117.6,105.7,64.8,56.8,31.8,30.5,26.9,26.1,24.9,22.8.HRMS(ESI)calculated for C₁₅H₂₅NNaO₃S⁺[M+Na]⁺:322.1447,found 322.1443.

Example 2: synthesis of Key intermediate 2 (preparation method as for Key intermediate 1)

7.6g, 93% yield, pale yellow oil [ α ]]_D ²³＝-54.69(c 0.5,CHCl₃).IR(KBr)ν_max:2949,2863,1653,1600,1230,1229,1088,1055,803cm^-1.¹H NMR(400MHz,CDCl₃)9.17(s,1H),6.15–5.62(m,1H),5.23(ddd,J＝13.8,11.5,1.2Hz,2H),4.60(m,2H),2.87(dd,J＝16.4,8.3Hz,1H),2.66(dd,J＝16.7,8.6Hz,1H),2.60–2.46(m,2H),1.95–1.84(m,2H),1.27(s,9H).¹³C NMR(100MHz,CDCl₃)167.4,158.2,132.6,117.8,103.6,64.3,56.8,32.6,29.2,22.4,20.6.HRMS(ESI)calculated for C₁₃H₂₁NNaO₃S⁺[M+Na]⁺:294.1134,found294.1131.

Example 3: synthesis of Key intermediate 3 (preparation method as for Key intermediate 1)

8.0g, 93% yield, pale yellow oil [ α ]]_D ²⁰＝-28.41(c 0.5,CHCl₃).IR(KBr)ν_max:2959,2865,1662,1598,1259,1231,1088,1055,1021,804cm^-1.¹H NMR(400MHz,CDCl₃)10.72(s,1H),5.94(ddd,J＝22.6,10.6,5.4Hz,1H),5.27(ddd,J＝13.8,11.8,1.4Hz,2H),4.66–4.57(m,2H),2.72(dt,J＝11.1,6.2Hz,1H),2.48(dt,J＝17.9,6.2Hz,1H),2.34(dt,J＝11.2,5.4Hz,2H),1.82–1.61(m,4H),1.32(s,9H).¹³C NMR(100MHz,CDCl₃)170.0,154.0,132.6,117.7,100.9,64.7,56.6,27.3,24.0,22.8,22.3,22.0.HRMS(ESI)calculated forC₁₄H₂₃NNaO₃S⁺[M+Na]⁺:308.1291,found 308.1290.

Example 4: synthesis of Key intermediate 4 (preparation method as for Key intermediate 1)

8.6g, 92% yield, light yellow oil [ α ]]_D ²⁷＝-11.62(c 1.0,CHCl3).IR(KBr)ν_max:2963,2870,1659,1589,1453,1230,1097,1054,1019,803cm^-1.¹H NMR(400MHz,CDCl₃)10.91(s,1H),5.88(ddd,J＝16.8,10.5,5.3Hz,1H),5.24(dd,J＝17.2,1.4Hz,1H),5.14(dd,J＝10.5,1.3Hz,1H),4.76–4.44(m,2H),2.88–2.67(m,2H),2.49–2.30(m,2H),1.79(m,1H),1.61–1.39(m,7H),1.26(s,9H).¹³C NMR(100MHz,CDCl₃)170.0,157.8,132.7,117.4,103.0,64.6,56.8,30.4,29.3,28.3,26.8,26.3,25.9,22.8.HRMS(ESI)calculated forC₁₆H₂₇NNaO₃S⁺[M+Na]⁺:336.1604,found 336.1602.

Example 5: synthesis of Compound 5

The method comprises the following operation steps: under argon protection, compound 1(0.10g,0.33mmol) was added to a round bottom flask and addedTetrahydrofuran (1mL) was cooled to 0 ℃ on an ice bath and NaHMDS (0.25mL,2M in THF) was added dropwise. After 15 minutes of reaction benzyl bromide (BnBr) was added dropwise. The reaction was allowed to stand overnight at room temperature and saturated NH was used after TLC to monitor completion of the reaction₄The Cl (10mL) solution was quenched and extracted three times with ethyl acetate (3X 10 mL). The combined organic phases were washed with anhydrous sodium sulfate (Na)₂SO₄) Drying, filtering, rotary drying with rotary evaporator, and separating the crude product by column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain colorless oily product 5(105mg, yield: 82%) [ α ]]_D ²⁰＝-140.54(c 2.0,CHCl₃).IR(KBr)ν_max:2931,2862,1733,1618,1453,1192,1080,933,739,703cm^-1.1`¹H NMR(400MHz,CDCl₃)7.24(ddd,J＝9.1,6.5,2.6Hz,3H),7.12–7.06(m,2H),5.90(ddt,J＝16.4,10.5,5.9Hz,1H),5.29(ddd,J＝13.8,11.5,1.2Hz,2H),4.64(dd,J＝13.1,5.8Hz,1H),4.56(dd,J＝13.1,5.9Hz,1H),3.38(d,J＝13.7Hz,1H),3.01–2.90(m,2H),2.60(ddd,J＝12.6,10.0,3.0Hz,1H),2.00(dd,J＝14.0,8.8Hz,1H),1.78(m,4H),1.62(m,1H),1.53–1.44(m,2H),1.30(s,9H).¹³C NMR(100MHz,CDCl₃)185.2,172.6,137.1,131.8,130.6,128.3,126.9,119.1,66.1,63.0,58.2,42.2,32.9,32.0,29.9,26.3,23.7,23.0.HRMS(ESI)calculated for C₂₂H₃₁NNaO₃S⁺[M+Na]⁺:412.1917,found 412.1915.

Example 6: synthesis of Compound 6

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophilic reagent 4-nitrobenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 3: 1) to afford product 6(132mg, yield: 92%) as a pale yellow oil [ α% ]]_D ²⁰＝-100.65(c 2.0,CHCl₃).IR(KBr)ν_max:2959,2930,2860,1734,1622,1605,1521,1456,1346,1261,1174,1080,994,856,802,741,701cm^-1.¹H NMR(400MHz,CDCl₃)8.12(d,J＝7.6Hz,2H),7.28(d,J＝7.7Hz,2H),5.89(dq,J＝11.0,5.8Hz,1H),5.31(dd,J＝21.7,13.8Hz,2H),4.65(dd,J＝12.4,4.4Hz,1H),4.57(dd,J＝12.4,5.3Hz,1H),3.47(d,J＝13.6Hz,1H),3.09(dd,J＝20.2,12.2Hz,2H),2.62(t,J＝11.0Hz,1H),2.09–2.00(m,1H),1.85–1.65(m,5H),1.51(dd,J＝22.1,12.1Hz,2H),1.29(s,9H).¹³C NMR(100MHz,CDCl₃)184.1,172.0,147.0,145.3,131.5,131.4,123.4,119.6,66.4,62.9,58.4,41.7,32.6,32.4,29.8,26.3,23.7,22.9.HRMS(ESI)calculated forC₂₂H₃₀N₂NaO₅S⁺[M+Na]⁺:457.1768,found 457.1767.

Example 7: synthesis of Compound 7

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophile 4-trifluoromethylbenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to afford product 7(139mg, yield: 92%) as a pale yellow oil [ α% ] [ α ]]_D ²⁰＝-97.23(c 1.0,CHCl₃).IR(KBr)ν_max:2958,2933,2860,1731,1620,1601,1519,1454,1350,1260,1180,1083,993,853,801,744,701cm^-1.¹H NMR(400MHz,CDCl₃)7.50(d,J＝7.0Hz,2H),7.21(d,J＝7.1Hz,2H),5.94–5.82(m,1H),5.29(dd,J＝23.0,13.7Hz,2H),4.64(dd,J＝13.0Hz,1H),4.55(dd,J＝13.1Hz,1H),3.42(d,J＝13.5Hz,1H),3.02(t,J＝11.8Hz,2H),2.61(t,J＝10.9Hz,1H),2.01(d,J＝11.6Hz,1H),1.74(m,5H),1.50(d,J＝11.5Hz,2H),1.29(s,9H).¹³C NMR(100MHz,CDCl₃)184.5,172.2,141.5,131.5,130.9,125.2,125.2,119.4,66.3,62.9,58.3,41.8,32.7,32.2,29.9,26.3,23.7,22.9.HRMS(ESI)calculated for C₂₃H₃₀F₃NNaO₃S⁺[M+Na]⁺:480.1791,found 480.1788.

Example 8: synthesis of Compound 8

The procedure was carried out using compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophilic reagent 3-methylbenzyl bromide the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 5: 1) to give the product 8(118mg, yield: 89%) as a colorless oil [ α ]]_D ²⁰＝-102.82(c 1.0,CHCl₃).IR(KBr)ν_max:2928,2861,1735,1620,1456,1389,1261,1231,1195,1175,1146,1081,1037,992,933,796,703cm^-1.¹H NMR(400MHz,CDCl₃)7.14(t,J＝7.2Hz,1H),7.02(d,J＝7.4Hz,1H),6.88(d,J＝9.1Hz,2H),5.96–5.84(m,1H),5.29(dd,J＝29.4,13.8Hz,2H),4.60(qd,J＝13.1,5.7Hz,2H),3.34(d,J＝13.6Hz,1H),2.94(dd,J＝23.2,12.7Hz,2H),2.58(t,J＝11.1Hz,1H),2.30(s,3H),2.01(dd,J＝22.7,9.0Hz,1H),1.87–1.70(m,4H),1.62(m,1H),1.54–1.45(m,2H),1.30(s,9H).¹³C NMR(100MHz,CDCl₃)185.3,172.6,137.8,137.0,131.8,131.4,128.2,127.6,127.6,119.1,66.1,63.0,58.2,42.1,32.9,31.9,29.9,26.3,23.7,23.0,21.5.HRMS(ESI)calculated for C₂₃H₃₃NNaO₃S⁺[M+Na]⁺:426.2073,found 426.2070.

Example 9: synthesis of Compound 9

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophilic reagent 3-chlorobenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 5: 1) to give product 9(126mg, yield: 90%) as a colorless oil [ α ]]_D ²⁰＝-104.62(c 1.0,CHCl₃).IR(KBr)ν_max:2959,2930,2862,1735,1621,1597,1572,1475,1456,1261,1231,1197,1173,1146,1081,1023,994,876,703,686cm^-1.¹H NMR(400MHz,CDCl₃)7.18(d,J＝4.9Hz,2H),7.09(s,1H),6.96(d,J＝6.0Hz,1H),5.89(dq,J＝10.3,6.0Hz,1H),5.30(dd,J＝25.7,13.8Hz,2H),4.59(qd,J＝12.9,5.8Hz,2H),3.35(d,J＝13.7Hz,1H),3.10–3.02(m,1H),2.90(d,J＝13.8Hz,1H),2.57(t,J＝11.1Hz,1H),2.06–1.97(m,1H),1.85–1.70(m,4H),1.63–1.43(m,3H),1.29(s,9H).¹³C NMR(100MHz,CDCl₃)184.6,172.2,139.3,134.1,131.6,130.7,129.5,128.8,127.1,119.6,66.3,63.0,58.3,41.6,32.7,32.0,29.9,26.3,23.6,23.0.HRMS(ESI)calculated for C₂₂H₃₀ClNNaO₃S⁺[M+Na]⁺:446.1527,found 446.1523.

Example 10: synthesis of Compound 10

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophilic allyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 5: 1) to give product 10(101mg, yield: 90%) as a colorless oil [ α ]]_D ²⁰＝-182.74(c 1.0,CHCl₃).IR(KBr)ν_max:2928,2859,1735,1620,1456,1361,1261,1198,1081,1020,919,802cm^-1.¹H NMR(400MHz,CDCl₃)5.87(ddt,J＝16.3,10.5,5.8Hz,1H),5.79–5.68(m,1H),5.26(ddd,J＝13.8,11.6,1.3Hz,2H),5.10–5.02(m,2H),4.61(dd,J＝13.2,5.8Hz,1H),4.54(dd,J＝13.2,5.8Hz,1H),3.17–3.09(m,1H),2.75(dd,J＝13.9,6.7Hz,1H),2.62(ddd,J＝12.7,9.6,3.3Hz,1H),2.38(dd,J＝13.9,7.9Hz,1H),2.13(dd,J＝13.3,9.2Hz,1H),1.85–1.70(m,4H),1.62–1.41(m,3H),1.26(s,9H).¹³C NMR(100MHz,CDCl₃)185.1,172.8,134.0,131.9,118.9,118.8,65.9,61.8,58.1,41.2,33.1,32.9,30.1,26.5,24.1,22.9.HRMS(ESI)calculated for C₁₈H₂₉NNaO₃S⁺[M+Na]⁺:362.1760,found362.1758.

Example 11: synthesis of Compound 11

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophilic reagent 3-bromo-2-methylpropene and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give product 11(111mg, yield: 95%) as a colorless oil [ α ]]_D ²³＝-67.69(c 0.5,CHCl₃).IR(KBr)ν_max:2936,2862,1733,1621,1459,1360,1259,1203,1083,1021,918,801cm^-1.¹H NMR(400MHz,CDCl₃)5.87(dq,J＝10.7,5.9Hz,1H),5.26(dd,J＝33.6,13.8Hz,2H),4.85(s,1H),4.68(s,1H),4.61(dd,J＝13.1,5.8Hz,1H),4.52(dd,J＝13.1,5.9Hz,1H),3.24–3.12(m,1H),2.85(d,J＝14.0Hz,1H),2.60–2.50(m,1H),2.38(d,J＝14.0Hz,1H),2.16(dd,J＝14.8,9.3Hz,1H),1.87–1.71(m,4H),1.63(s,3H),1.61–1.49(m,2H),1.40(m,1H),1.26(s,9H).¹³C NMR(100MHz,CDCl₃)184.8,173.0,141.9,131.7,119.1,115.9,66.1,61.4,58.2,43.8,32.2,31.7,30.0,26.5,23.7,23.0.HRMS(ESI)calculated for C₁₉H₃₁NNaO₃S⁺[M+Na]⁺:376.1917,found 376.1916.

Example 12: synthesis of Compound 12

Using compound 5 procedure, starting material 1(0.10g,0.33mmol) was reacted with electrophile 1-bromo-3-methyl-2-butene and the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give product 12(111mg, yield: 92%) as a colorless oil [ α% ] [ α ]]_D ²⁷＝-69.25(c 1.0,CHCl₃).IR(KBr)ν_max:2937,2866,1730,1618,1462,1359,1257,1201,1079,1019,921,801cm^-1.¹H NMR(400MHz,CDCl₃)5.85(ddd,J＝16.0,10.7,5.5Hz,1H),5.29(d,J＝17.2Hz,1H),5.21(d,J＝10.4Hz,1H),5.04(s,1H),4.56(ddd,J＝33.0,13.1,5.4Hz,2H),3.20–3.05(m,1H),2.73–2.54(m,2H),2.35(dd,J＝14.0,8.2Hz,1H),2.15–2.06(m,1H),1.73(d,J＝12.3Hz,5H),1.63(m,7H),1.42(d,J＝9.0Hz,1H),1.26(s,9H).¹³C NMR(100MHz,CDCl₃)185.3,173.0,135.1,131.9,119.4,118.8,65.9,62.2,58.1,35.0,32.8,30.2,26.5,26.2,24.1,22.9,22.5,18.1.HRMS(ESI)calculated forC₂₀H₃₃NNaO₃S⁺[M+Na]⁺390.2073, found 390.2077 example 13: synthesis of Compound 13

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with the electrophile bromopropyne and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give product 13(106mg, yield: 95%) as a colorless oil [ α ]]_D ²⁰＝-198.40(c 1.0,CHCl₃).IR(KBr)ν_max:2928,2859,1737,1621,1455,1362,1260,1191,1151,1082,936,802,688,641cm^-1.¹H NMR(400MHz,CDCl₃)5.86(dq,J＝11.0,5.8Hz,1H),5.26(dd,J＝36.2,13.8Hz,2H),4.66–4.60(dd,J＝13.3,5.8Hz,1H),4.58-4.55(dd,J＝13.3,5.8Hz,1H),3.41–3.30(m,1H),2.98(d,J＝16.8Hz,1H),2.57–2.46(m,2H),2.29(dd,J＝14.8,9.8Hz,1H),2.12(dd,J＝14.7,9.6Hz,1H),2.00(s,1H),1.80(m,2H),1.66–1.53(m,2H),1.44–1.29(m,2H),1.25(s,9H).¹³C NMR(100MHz,CDCl₃)183.5,171.6,131.6,118.9,80.7,71.3,66.3,61.3,58.3,32.3,32.3,30.1,26.3,26.1,23.8,22.9.HRMS(ESI)calculated for C₁₈H₂₇NNaO₃S⁺[M+Na]⁺:360.1604,found 360.1601.

Example 14: synthesis of Compound 14

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with electrophilic reagent 1-bromo-2-butyne and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give 14(110mg, yield: 95%) as a colorless oily product [ α ]]_D ²⁰＝-142.84(c 2.0,CHCl₃).IR(KBr)ν_max:2926,2860,1737,1621,1455,1361,1260,1192,1178,1082,994,932,802cm^-1.¹H NMR(400MHz,CDCl₃)5.86(dq,J＝10.7,5.7Hz,1H),5.25(dd,J＝39.1,13.8Hz,2H),4.59(m,2H),3.29(dd,J＝11.2,5.0Hz,1H),2.90(d,J＝16.6Hz,1H),2.55–2.37(m,2H),2.23(dd,J＝14.9,9.6Hz,1H),2.08(dd,J＝14.8,9.7Hz,1H),1.82–1.72(m,6H),1.63–1.49(m,2H),1.41–1.31(m,1H),1.24(s,9H).¹³C NMR(100MHz,CDCl₃)183.9,171.9,131.8,118.6,78.6,75.2,66.1,61.6,58.2,32.5,32.4,30.1,26.8,26.1,23.8,22.8,3.6.HRMS(ESI)calculated for C₁₉H₂₉NNaO₃S⁺[M+Na]⁺:374.1760,found374.1759.

Example 15: synthesis of Compound 15

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with iodobutane, an electrophilic reagent, at 50 ℃ and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give the product 15(105mg, yield: 90%) as a colourless oil [ α ]]_D ²⁰＝-287.27(c 0.5,CHCl₃).IR(KBr)ν_max:2962,2937,2860,1732,1649,1607,1456,1263,1200,1091,1019,801cm^-1.¹H NMR(400MHz,CDCl₃)5.88(ddd,J＝16.3,10.9,5.8Hz,1H),5.37–5.18(m,2H),4.61(dd,J＝13.3,5.7Hz,1H),4.55(dd,J＝13.3,5.8Hz,1H),3.05–2.93(m,1H),2.72(ddd,J＝12.3,9.2,3.0Hz,1H),2.20(dd,J＝14.1,8.9Hz,1H),1.97–1.79(m,2H),1.78–1.59(m,5H),1.49(dd,J＝22.4,14.5Hz,2H),1.33–1.19(m,13H),0.88(t,J＝7.0Hz,3H).¹³C NMR(100MHz,CDCl₃)186.1,173.4,132.0,118.7,65.7,62.0,57.9,36.9,33.9,33.1,30.2,26.9,24.6,23.4,22.9,14.1.HRMS(ESI)calculated for C₁₉H₃₃NNaO₃S⁺[M+Na]⁺:378.2073,found378.2076.

Example 16: synthesis of Compound 16

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with the electrophile isopentane iodide at 50 ℃ and the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give product 16(110mg, yield: 90%) as a colorless oil [ α ]]_D ²⁶＝-55.64(c 2.0,CHCl₃).IR(KBr)ν_max:2960,2931,2862,1733,1638,1603,1455,1269,1203,1100,1022,802cm^-1.¹H NMR(400MHz,CDCl₃)5.88(qd,J＝10.9,5.7Hz,1H),5.26(dd,J＝33.3,13.8Hz,2H),4.65–4.53(m,2H),2.98(t,J＝10.3Hz,1H),2.72(t,J＝10.6Hz,1H),2.19(dd,J＝14.2,8.8Hz,1H),1.95(t,J＝12.7Hz,1H),1.84(s,1H),1.72(m,3H),1.60(m,2H),1.54–1.42(m,3H),1.25(s,9H),1.22–1.15(m,1H),1.09–1.00(m,1H),0.86(d,J＝6.5Hz,6H).¹³C NMR(100MHz,CDCl₃)186.1,173.3,132.0,118.7,65.7,62.0,57.9,35.0,33.7,33.6,33.1,30.2,28.8,27.0,24.5,22.9,22.7.HRMS(ESI)calculatedfor C₂₀H₃₅NNaO₃S⁺[M+Na]⁺:392.2230,found 392.2229.

Example 17: synthesis of Compound 17

Using the procedure of Compound 5, starting material 1(0.10g,0.33mmol) was reacted with iodobutane, an electrophilic reagent, at 50 deg.C, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to afford product 17(115mg, yield: 92%) as a pale yellow oil [ α ]]_D ²³＝-260.69(c 1.0,CHCl₃).IR(KBr)ν_max:2930,2863,1733,1619,1456,1361,1254,1225,1166,1079,984,936cm^-1.¹H NMR(400MHz,CDCl₃)5.88(dq,J＝10.7,5.6Hz,1H),5.27(dd,J＝30.0,13.8Hz,2H),4.62(dd,J＝13.1,5.6Hz,1H),4.54(dd,J＝13.2,5.7Hz,1H),3.52(s,1.5H),3.15(s,0.5H),2.97(t,J＝10.0Hz,1H),2.76(t,J＝10.0Hz,1H),2.20(dd,J＝14.1,9.2Hz,1H),2.05(t,J＝11.4Hz,1H),1.74(ddd,J＝26.9,18.7,7.2Hz,8H),1.54(dd,J＝14.1,7.3Hz,2H),1.25(s,9H).¹³C NMR(100MHz,CDCl₃)185.6,173.0,131.8,119.0,65.9,61.4,58.0,45.4,38.1,34.6,34.1,33.1,30.2,28.8,28.1,27.1,24.6,22.9.HRMS(ESI)calculated for C₁₈H₃₀ClNNaO₃S⁺[M+Na]⁺:398.1527,found398.1523.

Example 18: synthesis of Compound 18

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophilic reagent benzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 18(100mg, yield: 75%) as a colorless oil [ α ]]_D ²³＝-102.43(c 1.0,CHCl₃).IR(KBr)ν_max:3062,3029,1733,1640,1495,1474,1390,1263,1219,1146,1084,931,795,770,703cm^-1.¹H NMR(400MHz,CDCl₃)7.26–7.18(m,3H),7.17–7.11(m,2H),5.89(ddt,J＝17.1,10.4,5.9Hz,1H),5.28(ddq,J＝24.0,10.4,1.3Hz,2H),4.58(ddt,J＝5.9,4.6,1.3Hz,2H),3.32(d,J＝13.7Hz,1H),3.16–3.04(m,2H),2.52(ddd,J＝14.9,9.4,7.9Hz,1H),2.26(dt,J＝12.7,6.4Hz,1H),1.89–1.74(m,2H),1.56–1.47(m,1H),1.29(s,9H).¹³C NMR(100MHz,CDCl₃)188.5,172.1,137.2,131.8,130.4,128.4,126.9,119.1,66.3,62.8,58.4,40.9,33.4,31.9,22.9,22.7.HRMS(ESI)calculated forC₂₀H₂₇NNaO₃S⁺[M+Na]⁺:384.1604,found384.1603.

Example 19: synthesis of Compound 19

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophile 4-nitrobenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 6: 1) to afford product 19(123mg, yield: 82%) as a pale yellow oil [ α ]]_D ²²＝-59.22(c 0.5,CHCl₃).IR(KBr)2960,2925,1732,1642,1604,1521,1347,1262,1052,858,660ν_max:cm^-1.¹H NMR(400MHz,CDCl₃)8.17–8.10(m,2H),7.35(d,J＝8.7Hz,2H),5.87(ddt,J＝16.3,10.4,6.0Hz,1H),5.29(ddq,J＝16.6,10.4,1.3Hz,2H),4.58(ddt,J＝6.1,3.6,1.3Hz,2H),3.45(d,J＝13.7Hz,1H),3.23–3.03(m,2H),2.60(dt,J＝19.8,8.1Hz,1H),2.36–2.23(m,1H),1.98–1.83(m,1H),1.77–1.64(m,2H),1.28(s,9H).¹³C NMR(100MHz,CDCl₃)187.3,171.5,147.1,145.2,131.5,131.3,123.6,119.6,66.6,62.6,58.6,40.6,33.1,32.2,22.8,22.7.HRMS(ESI)calculated for C₂₀H₂₆N₂NaO₅S⁺[M+Na]⁺:429.1455,found429.1453.

Example 20: synthesis of Compound 20

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophile 4-trifluoromethylbenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 20(143mg, yield: 90%) as a colorless oil [ α ]]_D ²³＝-80.43(c 1.0,CHCl₃).IR(KBr)2961,2928,1733,1618,1583,1456,1418,1326,1164,1123,1068,993ν_max:cm^-1.¹H NMR(400MHz,CDCl₃)7.52(d,J＝8.2Hz,2H),7.28(d,J＝9.2Hz,2H),5.87(ddt,J＝16.6,10.6,5.9Hz,1H),5.38–5.20(m,2H),4.58(dd,J＝5.5,4.6Hz,2H),3.39(d,J＝13.7Hz,1H),3.21–3.03(m,2H),2.57(dt,J＝19.6,7.8Hz,1H),2.27(dt,J＝17.4,5.6Hz,1H),1.89(m,1H),1.78–1.69(m,1H),1.63(ddd,J＝15.1,10.4,6.2Hz,1H),1.28(s,9H).¹³C NMR(100MHz,CDCl₃)187.7,171.8,141.4,131.6,130.8,125.4,125.4,125.3,125.3,125.2,119.4,66.4,62.7,58.5,40.6,33.2,32.1,22.8,22.7.HRMS(ESI)calculated for C₂₁H₂₆F₃NNaO₃S⁺[M+Na]⁺:452.1478,found 452.1477.

Example 21: synthesis of Compound 21

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophilic reagent 2-bromomethylnaphthalene and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give the product 21(114mg, yield: 75%) as a pale yellow oil [ α% ]]_D ²³＝-61.21(c 1.0,CHCl₃).IR(KBr)2959,2925,1732,1640,1508,1455,1389,1256,1220,1146,1083,1016,931,821,773,650,584,477ν_max:cm^-1.¹H NMR(400MHz,CDCl₃)7.82–7.72(m,3H),7.62(s,1H),7.49–7.41(m,2H),7.28(dd,J＝8.4,1.6Hz,1H),5.89(ddt,J＝16.3,10.4,5.9Hz,1H),5.36–5.21(m,2H),4.59(dd,J＝5.9,1.2Hz,2H),3.49(d,J＝13.7Hz,1H),3.29(d,J＝13.7Hz,1H),3.11(ddd,J＝19.5,8.0,5.4Hz,1H),2.52(ddd,J＝19.5,11.8,6.1Hz,1H),2.28(dd,J＝11.3,5.4Hz,1H),1.89–1.77(m,2H),1.59–1.51(m,1H),1.31(d,J＝1.9Hz,9H).NMR(400MHz,)188.5,172.1,134.8,133.4,132.4,131.8,129.2,128.6,127.9,127.8,127.7,126.2,125.8,119.2,66.3,63.0,58.4,41.0,33.4,32.0,22.9,22.8.HRMS(ESI)calculated for C₂₄H₂₉NNaO₃S⁺[M+Na]⁺:434.1760,found434.1763.

Example 22: synthesis of Compound 22

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophilic reagent 3-methylbenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 22(111mg, yield: 80%) as a colorless oil [ α ]]_D ²³＝-94.93(c 0.3,CHCl₃).IR(KBr)ν_max:1960,2925,2856,1731,1606,1456,1262,1086,1019,800cm^-1.¹H NMR(400MHz,CDCl₃)7.14(t,J＝7.5Hz,1H),7.02(d,J＝7.5Hz,1H),6.98–6.90(m,2H),5.89(ddd,J＝16.5,11.1,5.8Hz,1H),5.28(dd,J＝28.0,13.8Hz,2H),4.57(d,J＝5.7Hz,2H),3.28(d,J＝13.6Hz,1H),3.14–3.03(m,2H),2.51(dt,J＝19.4,7.8Hz,1H),2.30(s,3H),2.25(dd,J＝12.3,6.7Hz,1H),1.89–1.74(m,2H),1.57–1.51(m,1H),1.29(s,9H).¹³C NMR(100MHz,CDCl₃)188.6,172.2,137.9,137.1,131.8,131.3,128.3,127.7,127.4,119.1,66.3,62.9,58.3,40.9,33.4,31.9,22.9,22.7,21.6.HRMS(ESI)calculated for C₂₁H₂₉NNaO₃S⁺[M+Na]⁺:398.1760,found 398.1757.

Example 23: synthesis of Compound 23

Using compound 5 procedure, starting material 2(0.10g,0.37mmol) was reacted with electrophilic reagent 3-chlorobenzyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to afford product 23(117mg, yield: 80%) as a pale yellow oil [ α% ]]_D ²³＝-104.25(c 0.5,CHCl₃).IR(KBr)ν_max:2959,2926,2867,1733,1641,1475,1455,1362,1260,1214,1164,1147,1083,996,932,788,705,684cm^-1.¹H NMR(400MHz,CDCl₃)7.22–7.14(m,3H),7.03(d,J＝6.2Hz,1H),5.93–5.82(m,1H),5.29(dd,J＝23.9,13.8Hz,2H),4.57(d,J＝5.9Hz,2H),3.31(d,J＝13.7Hz,1H),3.10(ddd,J＝24.7,16.6,11.1Hz,2H),2.55(dt,J＝19.4,7.8Hz,1H),2.28(dt,J＝12.6,6.2Hz,1H),1.94–1.83(m,1H),1.78–1.69(m,1H),1.32–1.20(m,10H).¹³C NMR(100MHz,CDCl₃)187.9,171.8,139.3,134.2,131.6,130.6,129.6,128.6,127.2,119.4,66.4,62.7,58.4,40.5,33.3,32.1,22.8,22.7.HRMS(ESI)calculated for C₂₀H₂₆ClNNaO₃S⁺[M+Na]⁺:418.1214,found 418.1210.

Example 24: synthesis of Compound 24

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophilic allyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 24(78mg, yield: 68%) as a colorless oil [ α mg, yield: 68%)]_D ²³＝-130.32(c 1.0,CHCl₃).IR(KBr)ν_max:2960,2936,1733,1641,1453,1366,1263,1201,1139,1067,1009,853,801cm^-1.¹H NMR(400MHz,CDCl₃)5.86(ddt,J＝17.1,10.4,5.8Hz,1H),5.78–5.66(m,1H),5.34–5.18(m,2H),5.12–5.03(m,2H),4.55(ddt,J＝5.8,2.5,1.4Hz,2H),3.20–3.02(m,1H),2.79–2.61(m,2H),2.40(dd,J＝13.9,7.5Hz,1H),2.33–2.23(m,1H),2.02–1.90(m,1H),1.89–1.77(m,2H),1.22(s,9H).¹³C NMR(100MHz,CDCl₃)188.6,172.1,133.7,131.8,119.0,118.9,77.5,77.2,76.8,66.1,61.4,58.2,39.7,33.3,32.1,22.7,22.7.HRMS(ESI)calculated for C₁₆H₂₅NNaO₃S⁺[M+Na]⁺:334.1447,found 334.1449.

Example 25: synthesis of Compound 25

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with electrophile 3-bromo-2-methylpropene and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give 25(108mg, yield: 90%) as a colorless oily product [ α ]]_D ²⁰＝-148.68(c 1.0,CHCl₃).IR(KBr)ν_max:2962,2925,1731,1640,1474,1376,1261,1195,1148,1085,1019,931,863,801cm^-1.¹H NMR(400MHz,CDCl₃)5.88(ddt,J＝16.3,10.5,5.9Hz,1H),5.27(ddd,J＝13.8,11.5,1.2Hz,2H),4.82(s,1H),4.70(s,1H),4.55(d,J＝5.9Hz,2H),3.12(ddd,J＝19.5,8.7,5.7Hz,1H),2.89(d,J＝14.3Hz,1H),2.66(dt,J＝19.5,7.7Hz,1H),2.44–2.32(m,2H),1.98–1.73(m,3H),1.65(s,3H),1.23(s,9H).¹³C NMR(101MHz,CDCl₃)188.5,171.9,141.9,131.8,119.0,115.2,66.2,61.3,58.2,43.3,32.9,31.9,23.7,22.8,22.7.HRMS(ESI)calculated for C₁₇H₂₇NNaO₃S⁺[M+Na]⁺:348.1604,found348.1601.

Example 26: synthesis of Compound 26

Using compound 5 procedure, starting material 2(0.10g,0.37mmol) was reacted with electrophile 1-bromo-3-methyl-2-butene and the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 26(107mg, yield: 85%) as a colorless oil [ α ]]_D ²³＝-134.43(c 1.0,CHCl₃).IR(KBr)ν_max:2963,2937,1733,1644,1484,1379,1271,1197,1153,1091,1019,937,866,802cm^-1.¹H NMR(400MHz,CDCl₃)5.88(ddd,J＝22.6,10.9,5.7Hz,1H),5.27(dd,J＝31.1,13.8Hz,2H),5.06(t,J＝7.3Hz,1H),4.56(t,J＝5.3Hz,2H),3.11(ddd,J＝19.4,8.7,6.2Hz,1H),2.68(dt,J＝18.5,7.3Hz,2H),2.41(dd,J＝14.4,7.5Hz,1H),2.33–2.23(m,1H),1.95(dd,J＝14.2,6.9Hz,1H),1.85(dd,J＝14.3,6.5Hz,1H),1.79(s,1H),1.69(s,3H),1.61(s,3H),1.24(s,9H).¹³C NMR(101MHz,CDCl₃)188.9,172.5,135.3,131.9,119.3,118.8,66.1,62.0,58.2,33.9,33.4,32.2,26.1,22.9,22.8,18.2.HRMS(ESI)calculated for C₁₈H₂₉NNaO₃S⁺[M+Na]⁺:362.1760,found 362.1761.

Example 27: synthesis of Compound 27

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with the electrophile 3-bromopropyne and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 27(103mg, yield: 90%) as a colorless oil [ α ]]_D ²⁰＝-121.17(c 1.0,CHCl₃).IR(KBr)ν_max:2963,2927,1735,1642,1456,1363,1261,1225,1151,1085,1019,801cm^-1.¹H NMR(400MHz,CDCl₃)5.95–5.84(m,1H),5.38–5.21(m,2H),4.60(td,J＝5.8,1.2Hz,2H),3.29–3.13(m,1H),2.85(dt,J＝5.2,2.6Hz,1H),2.78–2.63(m,2H),2.43–2.31(m,1H),2.17–1.96(m,4H),1.25(s,9H).¹³C NMR(100MHz,CDCl₃)187.9,171.5,131.6,119.1,80.5,70.6,66.3,60.4,58.2,33.5,32.6,25.2,23.1,22.7.HRMS(ESI)calculated for C₁₆H₂₃NNaO₃S⁺[M+Na]⁺:332.1291,found 332.1289.

Example 28: synthesis of Compound 28

Using Compound 5 procedure, starting material 2(0.10g,0.37mmol) was reacted with electrophile 1Crude product was separated by column chromatography (petroleum ether: ethyl acetate 8: 1) to give product 28(102mg, yield: 85%) as colorless oily product [ α ]]_D ²⁰＝-99.34(c 1.0,CHCl₃).IR(KBr)ν_max:2962,2922,1735,1642,1362,1261,1224,1087,1020,801cm^-1.¹H NMR(400MHz,CDCl₃)5.87(ddd,J＝17.0,11.0,5.8Hz,1H),5.26(dd,J＝32.6,13.8Hz,2H),4.57(t,J＝5.6Hz,2H),3.16(dt,J＝13.8,6.6Hz,1H),2.79–2.60(m,3H),2.31(dt,J＝12.1,6.1Hz,1H),2.13–1.94(m,3H),1.73(s,3H),1.22(s,9H).¹³C NMR(100MHz,CDCl₃)188.4,171.8,131.7,118.9,77.9,75.1,66.2,60.8,58.2,33.7,32.7,25.6,23.1,22.7,3.6.HRMS(ESI)calculated for C₁₇H₂₅NNaO₃S⁺[M+Na]⁺:346.1447,found346.1449.

Example 29: synthesis of Compound 29

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with the electrophile iodomethane at 50 ℃ and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give the product 29(90mg, yield: 85%) as a colourless oil [ α ]]_D ²⁷＝-74.6(c 1.0,CHCl₃).IR(KBr)ν_max:2962,2927,2857,1731,1641,1455,1267,1089,801cm^-1.¹H NMR(400MHz,CDCl₃)5.88(ddd,J＝22.7,10.8,5.7Hz,1H),5.33–5.21(m,2H),4.57(ddd,J＝33.8,13.1,5.7Hz,2H),3.12–3.00(m,1H),2.91–2.78(m,1H),2.41–2.30(m,1H),2.04–1.82(m,2H),1.70(dt,J＝13.2,6.7Hz,1H),1.38(s,3H),1.23(s,9H).¹³C NMR(151MHz,CDCl₃)190.0,173.5,131.9,118.8,66.0,58.3,57.7,36.2,33.3,29.8,22.7,21.7.HRMS(ESI)calculated for C₁₄H₂₃NNaO₃S⁺[M+Na]⁺:308.1291,found 308.1290.

Example 30: synthesis of Compound 30

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with iodobutane, an electrophilic reagent, at 50 ℃ and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give the product 30(109mg, yield: 90%) as a colourless oil [ α ]]_D ²³＝-48.49(c 0.25,CHCl₃).IR(KBr)ν_max:2962,2927,2858,1732,1641,1457,1261,1090,1021,801cm^-1.¹H NMR(400MHz,CDCl₃)5.87(ddd,J＝22.8,11.0,5.8Hz,1H),5.26(dd,J＝31.4,13.8Hz,2H),4.56(m,2H),3.13(ddd,J＝19.5,8.5,5.9Hz,1H),2.65(dt,J＝19.4,7.9Hz,1H),2.36(dt,J＝12.7,6.2Hz,1H),2.16–1.78(m,4H),1.76–1.68(m,1H),1.58(dd,J＝13.2,4.2Hz,1H),1.34–1.26(m,2H),1.24(d,J＝5.5Hz,9H),0.96(dd,J＝14.6,7.1Hz,1H),0.88(t,J＝6.9Hz,3H).¹³C NMR(100MHz,CDCl₃)189.0,172.4,131.9,118.8,66.0,62.0,58.2,35.3,33.2,32.6,27.3,23.9,23.3,22.8,14.1.HRMS(ESI)calculatedfor C₁₇H₂₉NNaO₃S⁺[M+Na]⁺:350.1760,found 350.1757.

Example 31: synthesis of Compound 31

Using the procedure of Compound 5, starting material 2(0.10g,0.37mmol) was reacted with the electrophile 1-bromoisopentane at 50 deg.C and the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 31(116mg, yield: 92%) as a colorless oil [ α ]]_D ²³＝-78.36(c 0.4,CHCl₃).IR(KBr)ν_max:2958,2926,2866,1732,1640,1461,1364,1261,1150,1087,1022,803cm-¹.¹H NMR(400MHz,CDCl₃)5.88(ddd,J＝22.8,11.0,5.8Hz,1H),5.35–5.20(m,2H),4.56(d,J＝5.7Hz,2H),3.15(ddd,J＝19.5,8.8,5.7Hz,1H),2.65(dt,J＝19.4,8.0Hz,1H),2.39–2.31(m,1H),2.05–1.83(m,3H),1.73–1.61(m,2H),1.53–1.40(m,2H),1.24(s,9H),1.13–1.03(m,1H),0.88(dd,J＝6.5,4.9Hz,6H).¹³C NMR(100MHz,CDCl₃)189.0,172.4,131.9,118.8,66.0,62.0,58.2,34.1,33.4,33.2,32.6,29.9,28.6,22.8,22.7,22.6.HRMS(ESI)calculated for C₁₈H₃₁NNaO₃S⁺[M+Na]⁺:364.1917,found 364.1913.

Example 32: synthesis of Compound 32

Using compound 5 procedure, starting material 2(0.10g,0.37mmol) was reacted with electrophile 1-bromo-3-chloropropane at 50 ℃ and the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 32(118mg, yield: 92%) as a pale yellow oil [ α% ] []_D ²³＝-74.78(c 0.7,CHCl₃).IR(KBr)ν_max:2962,2926,2859,1732,1650,1455,1281,1088,1019,801cm-¹.1H NMR(400MHz,CDCl₃)5.88(ddd,J＝22.8,11.0,5.8Hz,1H),5.28(dd,J＝28.1,13.8Hz,2H),4.57(d,J＝5.7Hz,2H),3.64–3.35(m,2H),3.20–3.12(m,1H),2.70(dt,J＝19.5,7.9Hz,1H),2.36(dt,J＝11.2,6.0Hz,1H),2.17–2.04(m,1H),2.02–1.84(m,3H),1.82–1.68(m,3H),1.24(s,9H).¹³C NMR(100MHz,CDCl₃)188.2,172.0,131.6,119.0,66.0,61.2,58.2,45.1,32.9,32.9,32.8,28.3,22.6.HRMS(ESI)calculated forC₁₆H₂₆ClNNaO₃S⁺[M+Na]⁺:370.1214,found 370.1217.

Example 33: synthesis of Compound 33

Using the procedure of Compound 5, starting material 3(0.10g,0.35mmol) was reacted with the electrophile, benzyl bromide, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 33(98mg, yield: 75%) as a colorless oil [ α ]]_D ²⁰＝-190.84(c 0.5,CHCl₃).IR(KBr)ν_max:2928,2865,1739,1630,1453,1390,1260,1181,1079,804,742,702cm-¹.1H NMR(400MHz,CDCl₃)7.23(dd,J＝8.4,5.9Hz,3H),7.05(dd,J＝7.6,1.6Hz,2H),5.92–5.82(m,1H),5.29(ddd,J＝13.8,11.5,1.3Hz,2H),4.58(dd,J＝6.0,1.1Hz,2H),3.80–3.71(m,1H),3.36(d,J＝13.8Hz,1H),2.93(d,J＝13.8Hz,1H),2.37–2.30(m,1H),2.19(ddd,J＝14.2,12.4,5.1Hz,1H),1.91–1.83(m,1H),1.71–1.62(m,2H),1.55–1.40(m,2H),1.32(s,9H).¹³C NMR(100MHz,CDCl₃)183.6,171.4,136.8,131.6,130.4,128.2,126.9,119.5,66.0,60.2,58.3,42.2,35.5,32.4,27.4,22.9,22.3.HRMS(ESI)calculated for C₂₁H₂₉NNaO₃S⁺[M+Na]⁺:398.1760,found 398.1757.

Example 34: synthesis of Compound 34

Using the procedure of Compound 5, starting material 3(0.10g,0.35mmol) was reacted with electrophilic allyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give product 34(91mg, yield: 80%) as a colorless oil [ α ]]_D ²⁰＝-186.03(c 0.4,CHCl₃).IR(KBr)ν_max:2961,2929,2865,1737,1630,1416,1261,1207,1083,1021,918,802cm^-1.¹H NMR(400MHz,CDCl₃)5.92–5.83(m,1H),5.75(ddd,J＝23.1,15.5,7.4Hz,1H),5.28(dd,J＝34.0,13.8Hz,2H),5.10–5.01(m,2H),4.60(d,J＝5.9Hz,2H),3.62–3.52(m,1H),2.67(dd,J＝14.0,7.0Hz,1H),2.49–2.31(m,3H),1.86(dd,J＝11.8,5.2Hz,1H),1.72–1.62(m,2H),1.57–1.40(m,2H),1.27(s,9H).¹³C NMR(101MHz,CDCl₃)183.9,172.1,133.6,131.8,119.2,118.6,66.0,59.2,57.9,40.5,35.7,32.3,27.3,22.8,22.3.HRMS(ESI)calculated for C₁₇H₂₇NNaO₃S⁺[M+Na]⁺:348.1604,found 348.1600.

Example 35: synthesis of Compound 35

Using Compound 5 procedure, starting material 35(0.10g,0.35 mm) at 50 deg.Col) with electrophilic reagent iodomethane the crude product was separated by column chromatography (petroleum ether: ethyl acetate: 10: 1) to give 7c (68mg, yield: 65%) as a colourless oil [ α ]]_D ²⁷＝-57.388(c 0.2,CHCl₃).IR(KBr)ν_max:2962,2949,1736,1630,1423,1261,1209,1183,1031,802cm^-1.¹H NMR(400MHz,CDCl₃)5.94–5.83(m,1H),5.28(dd,J＝32.6,14.1Hz,2H),4.61(d,J＝5.6Hz,2H),3.57(d,J＝14.6Hz,1H),2.61–2.29(m,2H),1.88(s,1H),1.74–1.59(m,2H),1.53–1.41(m,2H),1.35(s,3H),1.26(s,9H).¹³C NMR(100MHz,CDCl₃)184.4,173.7,131.8,119.0,66.0,58.0,55.7,38.5,31.8,27.3,23.4,22.8,22.6.HRMS(ESI)calculated for C₁₅H₂₅NNaO₃S⁺[M+Na]⁺:322.1447,found 322.1444.

Example 36: synthesis of Compound 36

Using the procedure of Compound 5, starting material 4(0.10g,0.32mmol) was reacted with the electrophile, benzyl bromide, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 9: 1) to give product 36(116mg, yield: 90%) as a colorless oil [ α ]]_D ²⁰＝-315.66(c 0.5,CHCl₃).IR(KBr)ν_max:2959,2926,2857,1738,1619,1465,1454,1361,1261,1173,1089,1078,1017,801,701,678cm^-1.¹H NMR(400MHz,CDCl₃)7.23(dd,J＝10.0,7.1Hz,3H),7.07–7.03(m,2H),5.87(ddt,J＝16.6,10.4,6.0Hz,1H),5.35–5.24(m,2H),4.61(dd,J＝12.9,5.9Hz,1H),4.54(dd,J＝12.9,6.1Hz,1H),3.46–3.34(m,2H),2.99(d,J＝14.1Hz,1H),2.29–2.07(m,3H),1.84–1.77(m,2H),1.73(m,2H),1.55(m,1H),1.47–1.40(m,1H),1.35(s,9H),1.26(m,2H).¹³C NMR(101MHz,CDCl₃)184.7,172.0,137.6,131.6,130.0,128.4,126.9,119.5,66.2,63.1,58.7,38.2,30.7,29.8,27.1,26.0,25.3,25.2,24.2,23.2.HRMS(ESI)calculated for C₂₃H₃₃NNaO₃S⁺[M+Na]⁺:426.2073,found 426.2077.

Example 37: synthesis of Compound 37

Using the procedure of Compound 5, starting material 4(0.10g,0.32mmol) was reacted with electrophilic allyl bromide and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 9: 1) to give product 37(102mg, yield: 90%) as a colorless oil [ α ]]_D ²⁰＝-335.32(c 1.0,CHCl₃).IR(KBr)ν_max:2927,2861,1734,1616,1460,1361,1191,1081,991,919,798,753,639cm^-1.¹H NMR(400MHz,CDCl₃)5.90–5.79(m,1H),5.73–5.62(m,1H),5.26(dd,J＝29.9,13.8Hz,2H),5.13–5.05(m,2H),4.56(d,J＝5.5Hz,2H),3.39(dt,J＝12.7,4.4Hz,1H),2.86(dd,J＝14.4,6.2Hz,1H),2.46–2.33(m,2H),2.25(td,J＝12.4,3.4Hz,1H),2.07–1.93(m,2H),1.86–1.67(m,3H),1.59–1.52(m,1H),1.43(m,2H),1.31(s,9H),1.14–1.07(m,1H).¹³C NMR(100MHz,CDCl₃)185.1,172.1,134.2,131.7,119.2,118.5,66.2,61.5,58.5,36.9,30.4,27.3,26.8,25.3,24.9,23.1,23.1.HRMS(ESI)calculatedfor C₁₉H₃₁NNaO₃S⁺[M+Na]⁺:376.1917,found376.1913.

Example 38: synthesis of Compound 38

Using the procedure of Compound 5, starting material 4(0.10g,0.32mmol) was reacted with iodobutane, an electrophilic reagent, at 50 ℃ and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate: 9: 1) to give product 38(106mg, yield: 90%) as a colorless oil [ α ]]_D ²⁶＝-102.49(c 0.4,CHCl₃).IR(KBr)ν_max:2960,2927,2859,1734,1649,1617,1466,1261,1190,1081,1021,802cm^-1.¹H NMR(400MHz,CDCl₃)5.84(ddt,J＝16.3,10.4,5.9Hz,1H),5.25(ddd,J＝13.8,11.5,1.3Hz,2H),4.55(d,J＝5.9Hz,2H),3.44–3.28(m,1H),2.36(ddd,J＝15.5,11.0,4.7Hz,1H),2.25(td,J＝12.4,3.5Hz,1H),2.12–1.94(m,3H),1.86–1.61(m,4H),1.53–1.46(m,2H),1.36(dd,J＝18.2,10.0Hz,2H),1.32–1.27(m,9H),1.24(dd,J＝11.7,4.9Hz,2H),1.13–1.00(m,2H),0.89(t,J＝7.2Hz,3H).¹³C NMR(101MHz,CDCl₃)185.7,172.8,131.8,119.0,65.9,61.4,58.5,32.1,30.4,27.4,27.0,26.9,25.3,24.9,23.4,23.3,23.1,14.1.HRMS(ESI)calculated forC₂₀H₃₅NNaO₃S⁺[M+Na]⁺:392.2230,found 392.2227.

TGF-beta 1 cytokines are thought to be key profibrotic factors, and therefore a cell screening system has been established for the TGF-beta 1/Smad3 signaling pathway. The system uses a CAGA-NIH3T3 stable transfer cell line which is added with a promoter sequence CAGA conservatively combined with a Smad3 transcription factor at the downstream of TGF-beta 1 on the basis of a Luciferase reporter gene, and the cell line has hypersensitivity to the stimulation of TGF-beta 1. When TGF-beta 1 stimulates CAGA-NIH3T3 cells, Smad transcription factor can be induced to be activated into a nuclear binding promoter sequence CAGA, so that luciferase can be induced to be transcribed and translated from a luciferase gene sequence behind the CAGA box, luciferase can oxidize luciferin and emit bioluminescence in the process, the expression condition of the luciferase can be known according to the strength of the luciferase, and the expression amount of the luciferase is in direct proportion to the action intensity of the transcription factor Smad. The system can detect whether the compound has an inhibition effect on a TGF-beta Smad signaling pathway.

For a better understanding of the present invention, experiments are performed below with compounds 1-38, illustrating the potential utility of these compounds in the pharmaceutical field. It must be noted that the pharmacological examples of the invention are intended to illustrate the invention and not to limit it. The simple modification of the present invention according to the essence of the present invention falls within the scope of the present invention.

Experimental procedure

Luciferase reporter gene detection

CACG-NIH3T3 cells were first collected at the logarithmic growth phase at 0.5 × 10⁵100. mu.L of each/ml cell suspension was plated in a 96-well plate and cultured overnight. Removing blood serum when cell grows to about 70%, culturing for 24 hr, adding each compound into experimental group, and detecting by adding drugsThe blank control group and the non-medicated TGF- β 1 stimulated group were cultured in an incubator for 18h, then lysed and the change in fluorescence was detected with substrate.

Test results

As shown in table 1.

TABLE 1

The specific embodiments of the present invention have been described in detail above, but they are merely exemplary, and the present invention is not limited to the specific embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, it is intended that all equivalent alterations and modifications be included within the scope of the invention, without departing from the spirit and scope of the invention.

Claims

1. An alkylation method for constructing chiral four-stage carbon at alpha position of chiral sulfinyl imine is characterized in that the synthetic route is as follows:

and, the method comprises the steps of:

(1) taking a compound A1 as an initial raw material, and condensing with chiral sulfinamide to prepare an intermediate A2;

(2) reacting the intermediate A2 with a donor of a guide group DG to prepare an intermediate A3;

(3) the intermediate A3 is subjected to alkylation reaction to prepare chiral sulfinyl imine A with chiral quaternary carbon at alpha position;

according to the synthesis method, the structural general formula of the prepared compound A is I:

and, the structural general formula I has the following characteristics:

(I1) the guide group DG is an allyloxycarbonyl group;

(I2) the electrophilic substituent R is; benzyl, allyl, propargyl, F, CF3, Br, and Cl;

(I3) R1R2 is a B ring, the B ring is a C4-C30 carbocycle;

(I4) t-Bu in the compound is tert-butyl.

2. The method of claim 1, wherein:

in the step (1), dissolving a compound A1 in tetrahydrofuran, and sequentially adding R-tert-butylsulfinamide and titanium tetraisopropoxide to react to obtain an intermediate A2;

dissolving the intermediate A2 in tetrahydrofuran in the step (2), cooling to-78 ℃, adding alkali B1 for reaction, adding a donor of a guide group DG, and stirring at-78 ℃ for reaction to prepare an intermediate A3;

and (3) dissolving the intermediate A3 in tetrahydrofuran, cooling to 0 ℃, adding alkali B2 for reaction, and then adding an electrophilic reagent, namely R-X for reaction to obtain a target product A, wherein X is bromine or iodine.

3. The method of claim 2, wherein: in the step (1), the compound A1 is dissolved in tetrahydrofuran, R-tert-butylsulfinamide and titanium tetraisopropoxide are sequentially added at room temperature, and the mixture is heated to 40-70 ℃ to react for 6-12 hours, so that an intermediate A2 is prepared.

4. The method of claim 2, wherein: dissolving the intermediate A2 in tetrahydrofuran in the step (2), cooling to-78 ℃ under a low-temperature reactor, adding alkali B1 for reacting for 1 hour, slowly dropwise adding a donor of a guide group DG, and stirring and reacting for 2-5 hours at-78 ℃ to prepare an intermediate A3.

5. The method of claim 4, wherein: the alkali B1 is NaHMDS, KHMDS or LiHMDS.

6. The method of claim 2, wherein: dissolving the intermediate A3 in tetrahydrofuran, cooling to 0 ℃, adding alkali B2 to react for 15 minutes, stirring at 0 ℃ to react for 15-60 minutes, adding an electrophilic reagent R-X to react for 5-60 minutes, and moving to 20-60 ℃ to react for 8-24 hours to obtain the target product A.

7. The method of claim 6, wherein: the alkali B2 is NaHMDS, KHMDS or LiHMDS.

8. The method of claim 2, wherein: the post-treatment in step (1) means: after the reaction is finished, adding water into the reaction liquid for quenching, filtering to remove the precipitate, washing the precipitate with ethyl acetate, drying the obtained organic phase with anhydrous sodium sulfate, filtering, concentrating, and separating by fast column chromatography to obtain an intermediate A2.

9. The method of claim 2, wherein: the post-treatment in step (2) means: after the reaction is finished, adding a saturated ammonium chloride solution into the reaction solution for quenching, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating, and separating by using fast column chromatography to obtain an intermediate A3.

10. The method of claim 2, wherein: the post-treatment in step (3) means: after the reaction is finished, adding a saturated ammonium chloride solution into the reaction solution for quenching, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating, and separating by using fast column chromatography to obtain a target product A.

11. A chiral sulfinyl imine compound with chiral four-stage carbon at alpha position is characterized in that the structural general formula of the compound is I,

wherein the general structural formula I is characterized in that:

(I1) the guide group DG is an allyloxycarbonyl group;

(I2) electrophilic substituent R is benzyl, allyl, propargyl, F, CF3, Br, Cl;

(I3) the ring B is a C4-C30 carbocycle;

(I4) t-Bu in the compound is tert-butyl.

12. A chiral sulfinimide compound having a chiral quaternary carbon at position α, wherein the compound has the formula shown in nos. 5-38:

。

13. use of a compound according to any one of claims 11 to 12 in the manufacture of a medicament for inhibiting organ fibrosis.

14. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of a compound of claim 11 or 12, and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition of claim 14, wherein: the pharmaceutical composition is tablet, capsule, aerosol, oral liquid, suppository, drop pill, infusion solution, small needle, lyophilized powder for injection, ointment or liniment.