WO2024017221A1 - SYNTHESIS METHOD FOR α-AZIDO KETONE CONTAINING TERTIARY STEREOCENTER - Google Patents

SYNTHESIS METHOD FOR α-AZIDO KETONE CONTAINING TERTIARY STEREOCENTER Download PDF

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WO2024017221A1
WO2024017221A1 PCT/CN2023/107817 CN2023107817W WO2024017221A1 WO 2024017221 A1 WO2024017221 A1 WO 2024017221A1 CN 2023107817 W CN2023107817 W CN 2023107817W WO 2024017221 A1 WO2024017221 A1 WO 2024017221A1
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tert
butoxycarbonyl
azido
nmr
product
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郭文岗
周英
乐鑫
江枫
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常州大学
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07B2200/13—Crystalline forms, e.g. polymorphs
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the chiral product obtained by the present invention can be used as a useful organic synthesis building block for the preparation of biologically active molecules, heterocycles and chiral ligands, and specifically relates to the synthesis of an ⁇ -azido ketone containing a tertiary chiral center. method.
  • Organic azides are high value-added synthetic building blocks with a wide range of applications in chemical biology, materials science, and medicinal chemistry. Therefore, the synthesis and application of organic azide compounds have aroused great research interest among chemists in the past few decades.
  • the ⁇ -carbonyl azides synthesized by chiral catalytic methods reported in the literature all have quaternary carbon chiral centers, and the asymmetric catalytic synthesis methods of ⁇ -azido ketones containing tertiary chiral centers are still limited. There are no relevant literature reports.
  • the purpose of this application is to provide a synthetic method for ⁇ -azido ketones containing tertiary stereocenters.
  • Y Ph, Me, F, Br, Cl, any substituent.
  • the synthesis method includes: under the action of a catalyst (such as SQ3), the sulfonium oxide ylide derivative reacts with the azide reagent HN3 produced in situ to generate the ⁇ -azido ketone, and the sulfonium oxide ylide derivative ( ⁇ -).
  • a catalyst such as SQ3
  • the sulfonium oxide ylide derivative reacts with the azide reagent HN3 produced in situ to generate the ⁇ -azido ketone
  • the sulfonium oxide ylide derivative ⁇ -
  • the structural formula of sulfonium carbonyl oxide (sulfonium carbonyl oxide) is
  • the present invention adopts the in-situ reaction between TMSN 3 and benzoic acid to produce the azide reagent HN 3 , and other methods that can produce HN 3 in situ are applied to the reaction with sulfonium ylide to synthesize chiral ⁇ -carbonyl azide compounds, which all belong to the content of the present invention. logical expansion.
  • the proton source for the in situ generated azide reagent HN 3 can be benzoic acid, N ⁇ Boc ⁇ L ⁇ Proline, N ⁇ Boc ⁇ D ⁇ Proline, N ⁇ Boc ⁇ L ⁇ Leucine, N ⁇ Boc ⁇ D ⁇ Leucine, N-Boc-L-tert-Leucine, N-Boc-D-tert-Leucine, N-Boc-L-Valine, N-Boc-D-Valine, H 2 O, MeOH, HFIP, AcOH, (p Any one of -OH)C 6 H 4 CO 2 H and (p-Cl)C 6 H 4 CO 2 H.
  • the sulfonium oxide ylide derivative of the present invention is protonated by HN 3 produced in situ to form an unstable sulfonium ion intermediate 1', and other stable sulfonium ions and azide reagents are used to synthesize chiral ⁇ -carbonyl azide
  • the compounds all belong to the logical expansion of the content of the present invention.
  • the structural formula of the sulfonium ion intermediate 1' is:
  • the catalyst SQ3 used is the preferred catalyst of the present invention, and its structure is:
  • it also includes the following steps: cooling the system added with sulfonium oxide ylide derivatives, proton source, squarylamide catalyst and CHCl 3 to -15 ⁇ 0°C (-15 ⁇ 0°C can obtain a yield range of 50-95 %, ee range 80-95%); continue stirring at the same temperature, add TMSN 3 , and then continue stirring at the same temperature until the reaction is completed.
  • the molar ratio of the proton source to the sulfonium oxide ylide derivative is 1 to 2:1, and the molar ratio of TMSN 3 to the sulfonium oxide ylide derivative is 1 to 4: 1.
  • the reaction temperature is -15°C
  • the molar ratio of the proton source to the sulfonium oxide ylide derivative is 1.1:1; the molar ratio of TMSN 3 to the sulfonium oxide ylide derivative is 2:1.
  • a specific preferred preparation method using the proton source as benzoic acid includes the following steps: sulfonium oxide ylide derivative 1 represented by the following formula, TMSN 3 and benzoic acid are used as raw materials, and squarylamide is used as a catalyst to synthesize a third-order stereoscopic structure
  • sulfonium oxide ylide derivative 1 represented by the following formula
  • TMSN 3 and benzoic acid are used as raw materials
  • squarylamide is used as a catalyst to synthesize a third-order stereoscopic structure
  • the reaction formula is as follows:
  • the dosage of sulfonium oxide ylide derivative is 0.2mmol; the dosage of benzoic acid is 0.22mmol; the dosage of squarylamide catalyst derivative is 20mol% of sulfonium oxide ylide; the dosage of TMSN 3 is 0.4mmol; the dosage of CHCl 3 is about 1mL .
  • the chiral product obtained by the present invention also has certain application value in the synthesis of ligands and bioactive compounds.
  • the product was a light yellow oil (120h, 39.4mg, 83% yield, 90%ee).
  • the product was a white solid (120 h, 60.2 mg, 96% yield, 85% ee).
  • the product was a white solid (120 h, 59.4 mg, 88% yield, 90% ee).
  • the product was colorless oil (120h, 48.8mg, 92% yield, 85%ee).
  • the product was a colorless oil (168h, 40.2mg, 74% yield, 92%ee).
  • the product was colorless oil (168h, 35.4mg, 56% yield, 91%ee).
  • the product was colorless oil (168h, 31.6mg, 50% yield, 84%ee).
  • the product was colorless oil (168 h, 36.1 mg, 67% yield, 96% ee).
  • the product was colorless oil (168h, 53.1mg, 87% yield, 96%ee).
  • the product was a colorless oil (168 h, 52.7 mg, 79% yield, 91% ee).
  • the product was colorless oil (120h, 43.7mg, 76% yield, 77%ee).
  • the product was colorless oil (168h, 23.5mg, 46% yield, 67%ee).
  • Chiral aminoalcohols are an important class of pharmaceutical intermediates and an important chiral ligand widely used in chiral synthetic chemistry (Chem. Rev. 1996, 96, 835-875; J. Med. Chem. 2005, 48,4220-4223).
  • the present invention uses the following application examples to illustrate:
  • the chiral azide compound obtained by the present invention can be converted into the corresponding chiral triazole heterocyclic compound through a copper-catalyzed click reaction. It is worth noting that studies have proven that ⁇ -carbonyltriazole compounds containing tertiary chiral centers have certain anti-tumor activity (Eur.J.Med.Chem.2010,45,5044-5050; ARKIVOC 2012,279-296 ), but due to the constraints of related asymmetric catalytic synthesis methods, there have been no chiral synthesis reports of ⁇ -carbonyltriazole compounds containing tertiary chiral centers so far, so people cannot further explore the structure of the chiral centers. The relationship between type and drug activity. Based on this, the present invention demonstrates that the obtained chiral azide compounds can be converted into related chiral triazole heterocyclic compounds:
  • Example 1 Effect of other types of catalysts on the reaction results of the present invention—chiral phosphoric acid a Determined by crude 1 H NMR anaylsis using CH 2 Br 2 as an internal standard.All the reactions described above provided clean conversion. b Determined by Chiral HPLC analysis.
  • Example 2 The influence of other types of catalysts on the reaction results of the present invention - other hydrogen bonding catalysts a Determined by crude 1 H NMR anaylsis using CH 2 Br 2 as an internal standard. b Determined by Chiral HPLC analysis. c The reaction gave a messy mixture, likely due to the incompatibility of the reaction with the basic cinchona alkaloid functionality.
  • the SQ3 catalyst used in the present invention is effective in the target reaction. It has significant advantages in stereoselectivity control; at the same time, because the reaction conditions of the present invention are relatively mild, the optical purity of the product will not be affected by racemization (the product is sensitive to acids and bases due to the electron-withdrawing properties of the carbonyl group and the azide group) And easy to racemize).
  • Example 3 Effect of chiral proton source on the reaction results of the present invention - amino acids as chiral protons a Determined by crude 1 H NMR analysis using CH 2 Br 2 as an internal standard. b Determined by chiral HPLC analysis. c ent ⁇ SQ3was used as the catalyst.
  • Example 4 The influence of other achiral proton sources on the reaction results of the present invention - alcohols and carboxylic acids as proton sources Reaction scale: 1a (0.1mmol), TMSN 3 (0.2mmol), proton source (0.11mmol), SQ3 (0.01mmol), solvent (0.5 mL),24h.Yield was determined by 1 H NMR spectra of the crude mixture using CH 2 Br 2 as an internal standard.Ee was determined by HPLC on a chiral stationary phase.

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Abstract

A synthesis method for an α-azido ketone containing a tertiary chiral center, the synthesis method comprising: under the action of a squaramide catalyst, reacting a sulfoxonium ylide derivative with an azidation reagent HN3 generated in situ from TMSN3 and a proton source, so as to generate the α-azido ketone. The reaction conditions are mild, and no metal is needed; and the method has good yield and enantiomeric selectivity.

Description

含三级立体中心的α-叠氮酮的合成方法Synthesis method of α-azido ketone containing tertiary stereocenter 技术领域Technical field
本发明所获得的手性产物能够作为有用的有机合成砌块，用于制备生物活性分子、杂环和手性配体，具体涉及一种含三级手性中心的α-叠氮酮的合成方法。The chiral product obtained by the present invention can be used as a useful organic synthesis building block for the preparation of biologically active molecules, heterocycles and chiral ligands, and specifically relates to the synthesis of an α-azido ketone containing a tertiary chiral center. method.
背景技术Background technique
有机叠氮化物是一种高附加值的合成砌块，在化学生物学、材料科学和药物化学等领域有着广泛的应用。因此，在过去几十年里，有机叠氮化合物的合成及应用引起了化学工作者极大的研究兴趣。然而目前为止，文献中报道的通过手性催化方法合成的α-羰基叠氮化合物均具有季碳手性中心，含三级手性中心的α-叠氮酮的不对称催化合成方法目前为止仍未有相关的文献报道。这种局限性来源于三级手性中心在羰基及叠氮基团的吸电子诱导效应存在下极易通过烯醇互变异构而消旋化，因此含该类手性中心的α-叠氮酮对酸、碱手性催化剂皆很敏感，进一步造成了其通过不对称催化合成的难度。Organic azides are high value-added synthetic building blocks with a wide range of applications in chemical biology, materials science, and medicinal chemistry. Therefore, the synthesis and application of organic azide compounds have aroused great research interest among chemists in the past few decades. However, so far, the α-carbonyl azides synthesized by chiral catalytic methods reported in the literature all have quaternary carbon chiral centers, and the asymmetric catalytic synthesis methods of α-azido ketones containing tertiary chiral centers are still limited. There are no relevant literature reports. This limitation comes from the fact that the tertiary chiral center is easily racemized through enol tautomerization in the presence of the electron-withdrawing induction effect of the carbonyl and azide groups. Therefore, α-azide containing this type of chiral center Azones are very sensitive to both acidic and basic chiral catalysts, further making their synthesis through asymmetric catalysis difficult.
虽然Corey课题组在2019年报道了碱性条件下利用手性相转移催化方法合成含三级手性中心的α-叠氮酮(J.Am.Chem.Soc.2019,141,20058–20061)，但其是通过手性中间体的水解而间接获得的。受限于上述提到的稳定性因素，直接通过催化不对称合成方法来获得该类手性化合物目前仍未有相关的文献报道。Although Corey's research group reported in 2019 the use of chiral phase transfer catalysis method to synthesize α-azido ketones containing tertiary chiral centers under alkaline conditions (J.Am.Chem.Soc.2019,141,20058–20061) , but it is obtained indirectly through the hydrolysis of chiral intermediates. Limited by the stability factors mentioned above, there are still no relevant literature reports on directly obtaining such chiral compounds through catalytic asymmetric synthesis.
发明内容Contents of the invention
本申请的目的在于提供一种含三级立体中心α-叠氮酮的合成方法。The purpose of this application is to provide a synthetic method for α-azido ketones containing tertiary stereocenters.
含三级立体中心的α-叠氮酮的结构式如下：
The structural formula of α-azido ketone containing tertiary stereocenter is as follows:
其中Ar1＝where Ar 1 =
中的任意一种； any of;
X＝Me、OMe、F、中的任意一种取代基；X＝Me、OMe、F、 any substituent in;
Ar2＝中的任意一种；Ar 2 = any of;
Y＝Ph、Me、F、Br、Cl、中的任意一种取代基。Y＝Ph, Me, F, Br, Cl, any substituent.
合成方法包括：在催化剂(例如SQ3)的作用下，氧化锍叶立德衍生物与通过原位产生的叠氮化试剂HN3反应生成所述的α-叠氮酮，氧化锍叶立德衍生物(α-羰基氧化锍叶立德)的结构式为 The synthesis method includes: under the action of a catalyst (such as SQ3), the sulfonium oxide ylide derivative reacts with the azide reagent HN3 produced in situ to generate the α-azido ketone, and the sulfonium oxide ylide derivative (α- The structural formula of sulfonium carbonyl oxide (sulfonium carbonyl oxide) is
本发明采用TMSN3与苯甲酸原位反应来产生叠氮化试剂HN3，其他可原位产生HN3的方法应用于与锍叶立德反应来合成手性α-羰基叠氮化合物均属于本发明内容的逻辑拓展。例如，原位产生的叠氮化试剂HN3的质子源可以为苯甲酸、N‐Boc‐L‐Proline、N‐Boc‐D‐Proline、N‐Boc‐L‐Leucine、N‐Boc‐D‐Leucine、N‐Boc‐L‐tert‐Leucine、N‐Boc‐D‐tert‐Leucine、N‐Boc‐L‐Valine、N‐Boc‐D‐Valine、H2O、MeOH、HFIP、AcOH、(p‐OH)C6H4CO2H、(p‐Cl)C6H4CO2H中的任意一种。The present invention adopts the in-situ reaction between TMSN 3 and benzoic acid to produce the azide reagent HN 3 , and other methods that can produce HN 3 in situ are applied to the reaction with sulfonium ylide to synthesize chiral α-carbonyl azide compounds, which all belong to the content of the present invention. logical expansion. For example, the proton source for the in situ generated azide reagent HN 3 can be benzoic acid, N‐Boc‐L‐Proline, N‐Boc‐D‐Proline, N‐Boc‐L‐Leucine, N‐Boc‐D‐ Leucine, N-Boc-L-tert-Leucine, N-Boc-D-tert-Leucine, N-Boc-L-Valine, N-Boc-D-Valine, H 2 O, MeOH, HFIP, AcOH, (p Any one of -OH)C 6 H 4 CO 2 H and (p-Cl)C 6 H 4 CO 2 H.
本发明的氧化锍叶立德衍生物被原位产生的HN3质子化而形成不稳定的锍鎓离子中间体1'，应用其他稳定的锍鎓离子与叠氮试剂来合成手性α-羰基叠氮化合物均属于本发明内容的逻辑拓展，锍鎓离子中间体1'的结构式为：
The sulfonium oxide ylide derivative of the present invention is protonated by HN 3 produced in situ to form an unstable sulfonium ion intermediate 1', and other stable sulfonium ions and azide reagents are used to synthesize chiral α-carbonyl azide The compounds all belong to the logical expansion of the content of the present invention. The structural formula of the sulfonium ion intermediate 1' is:
所用催化剂SQ3为本发明的较优催化剂，结构为：
The catalyst SQ3 used is the preferred catalyst of the present invention, and its structure is:
其中Ar＝1-pyrenyl，包括其相应的对应异构体。针对于最优催化剂的结构修饰所获得的任意变种催化剂并应用于氧化锍叶立德衍生物的不对称叠氮化来合成手性叠氮化合物均属于本发明内容的逻辑拓展。Where Ar=1-pyrenyl, including its corresponding enantiomers. Any variant catalyst obtained by structural modification of the optimal catalyst and applied to the asymmetric azation of sulfonium oxide ylide derivatives to synthesize chiral azide compounds is a logical extension of the present invention.
进一步的，还包括如下步骤：将添加有氧化锍叶立德衍生物、质子源、方酸酰胺催化剂和CHCl3的体系冷却至-15～0℃(-15～0℃可以获得收率范围50-95％，ee范围80-95％)；在相同温度下持续搅拌，并加入TMSN3，然后继续在相同的温度下搅拌至反应结束。Further, it also includes the following steps: cooling the system added with sulfonium oxide ylide derivatives, proton source, squarylamide catalyst and CHCl 3 to -15~0°C (-15~0°C can obtain a yield range of 50-95 %, ee range 80-95%); continue stirring at the same temperature, add TMSN 3 , and then continue stirring at the same temperature until the reaction is completed.
从收率和选择性及经济性的角度，进一步优选的，质子源与氧化锍叶立德衍生物的摩尔比为1～2:1，TMSN3与氧化锍叶立德衍生物的摩尔比为1～4:1。From the perspective of yield, selectivity and economy, it is further preferred that the molar ratio of the proton source to the sulfonium oxide ylide derivative is 1 to 2:1, and the molar ratio of TMSN 3 to the sulfonium oxide ylide derivative is 1 to 4: 1.
更优选的，更优的反应温度为-15℃，质子源与氧化锍叶立德衍生物的摩尔比为1.1:1；TMSN3与氧化锍叶立德衍生物的摩尔比为2:1。More preferably, the reaction temperature is -15°C, the molar ratio of the proton source to the sulfonium oxide ylide derivative is 1.1:1; the molar ratio of TMSN 3 to the sulfonium oxide ylide derivative is 2:1.
以质子源为苯甲酸的具体优选制备方法，包括如下步骤：以下式所示的氧化锍叶立德衍生物1、TMSN3和苯甲酸作为原料，在方酸酰胺作为催化剂的条件下合成具有三级立体中心的α-叠氮酮2，反应式如下：
A specific preferred preparation method using the proton source as benzoic acid includes the following steps: sulfonium oxide ylide derivative 1 represented by the following formula, TMSN 3 and benzoic acid are used as raw materials, and squarylamide is used as a catalyst to synthesize a third-order stereoscopic structure For the α-azido ketone 2 in the center, the reaction formula is as follows:
具体操作步骤如下：The specific steps are as follows:
根据上述反应式，在一个装有磁力搅拌子的4mL玻璃小瓶中，加入氧化锍叶立德衍生物1、苯甲酸、方酸酰胺催化剂和CHCl3。小瓶用可刺穿的螺帽和电工胶带小心密封，然后冷却至-15℃(此温度下可以得到最佳的选择性和收率。温度升高，不影响收率，但是影响ee；温度进一步降低，对Ee有利，但是收率会降低)。在相同温度下搅拌5分钟，加入TMSN3。然后继续在相同的温度下搅拌反应，并用薄层色谱(TLC)监测反应过程。反应完成后，直接进行硅胶柱层析(洗脱液:正己烷/乙酸乙酯＝20:1)，得到所需产物2；According to the above reaction formula, in a 4 mL glass vial equipped with a magnetic stirrer, add sulfonium oxide ylide derivative 1, benzoic acid, squarylamide catalyst and CHCl 3 . The vial is carefully sealed with a pierceable screw cap and electrical tape, and then cooled to -15°C (the best selectivity and yield can be obtained at this temperature. Increased temperature does not affect the yield, but affects the ee; the temperature further Reducing is beneficial to Ee, but the yield will decrease). Stir at the same temperature for 5 minutes and add TMSN 3 . The reaction was then continued to stir at the same temperature and the reaction progress was monitored using thin layer chromatography (TLC). After the reaction is completed, directly perform silica gel column chromatography (eluent: n-hexane/ethyl acetate = 20:1) to obtain the desired product 2;
氧化锍叶立德衍生物的用量为0.2mmol；苯甲酸的用量为0.22mmol；方酸酰胺催化剂衍生物的用量为氧化锍叶立德的20mol％；TMSN3的用量为0.4mmol；CHCl3的用量约为1mL。The dosage of sulfonium oxide ylide derivative is 0.2mmol; the dosage of benzoic acid is 0.22mmol; the dosage of squarylamide catalyst derivative is 20mol% of sulfonium oxide ylide; the dosage of TMSN 3 is 0.4mmol; the dosage of CHCl 3 is about 1mL .
本发明有以下优点：The invention has the following advantages:
1.反应条件温和；1. Mild reaction conditions;
2.反应操作简单，且收率和对映选择性很好；2. The reaction operation is simple, and the yield and enantioselectivity are very good;
3.除了上述基础研究价值外，本发明获得的手性产物在配体合成、生物活性化合物的合成方面也具有一定的应用价值。3. In addition to the above basic research value, the chiral product obtained by the present invention also has certain application value in the synthesis of ligands and bioactive compounds.
具体实施方式Detailed ways
在一个装有磁力搅拌子的4毫升小瓶中，加入氧化锍叶立德1(0.2mmol,1.0equiv)、苯甲酸(0.22mmol,1.1equiv)、最优手性催化剂(代号SQ3,27.6mg,0.04mmol,20mol％)和CHCl3(1.0mL)。小瓶用可刺穿的螺帽和电气胶带小心密封，然后冷却至-15℃。在相同温度下搅拌5分钟，加入TMSN3(52.6μL,0.4mmol,2.0equiv)。然后，在相同温度下搅拌，用薄层色谱(TLC)监测反应过程。反应完成后，直接进行硅胶柱层析(洗脱液:正己烷/乙酸乙酯＝20:1)，得到所需产物2。 In a 4 ml vial equipped with a magnetic stirrer, add sulfonium oxide ylide 1 (0.2mmol, 1.0equiv), benzoic acid (0.22mmol, 1.1equiv), and the optimal chiral catalyst (code SQ3, 27.6mg, 0.04mmol ,20 mol%) and CHCl 3 (1.0 mL). The vial is carefully sealed with a pierceable screw cap and electrical tape and then cooled to -15°C. Stir at the same temperature for 5 minutes and add TMSN 3 (52.6 μL, 0.4 mmol, 2.0 equiv). Then, stir at the same temperature and monitor the reaction process with thin layer chromatography (TLC). After the reaction is completed, silica gel column chromatography is directly performed (eluent: n-hexane/ethyl acetate = 20:1) to obtain the desired product 2.
实施例1：
Example 1:
产物为淡黄色油状物(120h,39.4mg,83％yield,90％ee)。The product was a light yellow oil (120h, 39.4mg, 83% yield, 90%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+145.1(c＝2.0,CHCl3).HPLC analysis of the product:Daicel OD‐H column；1％i‐PrOH in n‐hexane；0.5mL/min；retention times:29.3min(major),45.7min(minor).[α] D 25 : +145.1 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 0.5mL/min; retention times: 29.3min (major), 45.7min (minor).
1H NMR(400MHz,CDCl3)δ7.88(d,J＝7.4Hz,2H),7.50(t,J＝7.4Hz,1H),7.39–7.35(m,7H),5.73(s,1H)ppm. 1 H NMR (400MHz, CDCl 3 ) δ7.88 (d, J＝7.4Hz, 2H), 7.50 (t, J＝7.4Hz, 1H), 7.39–7.35 (m, 7H), 5.73 (s, 1H) ppm.
13C NMR(100MHz,CDCl3)δ194.4,134.3,133.8(two C),129.6,129.4,128.9,128.8,128.3,67.9ppm. 13 C NMR (100MHz, CDCl 3 ) δ 194.4, 134.3, 133.8 (two C), 129.6, 129.4, 128.9, 128.8, 128.3, 67.9ppm.
HRMS(ESI‐TOF)Calcd for C14H11N3NaO[M+Na]+:260.0800,found:260.0796.HRMS(ESI‐TOF)Calcd for C 14 H 11 N 3 NaO[M+Na] + :260.0800,found:260.0796.
实施例2：
Example 2:
产物为白色固体(120h,60.2mg,96％yield,85％ee)。The product was a white solid (120 h, 60.2 mg, 96% yield, 85% ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+133.0(c＝2.0,CHCl3).HPLC analysis of the product:DaicelIC column；3％i‐PrOH in n‐hexane；1.0mL/min；retention times:13.3min(major),15.5min(minor).[α] D 25 : +133.0 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel IC column; 3% i-PrOH in n-hexane; 1.0mL/min; retention times: 13.3min (major), 15.5min (minor).
1H NMR(400MHz,acetone‐d6)δ7.90(d,J＝8.3Hz,2H),7.56(d,J＝8.0Hz,2H),7.48–7.41(m,5H),7.33–7.26(m,4H),7.21–7.17(m,1H),6.11(s,1H) ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.90 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.48–7.41 (m, 5H), 7.33–7.26 ( m,4H),7.21–7.17(m,1H),6.11(s,1H) ppm.
13C NMR(100MHz,acetone‐d6)δ194.5,141.8,139.8,134.6,133.9,133.4,129.1,128.94,128.91,128.88,127.9,127.8,126.9,66.9ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.5,141.8,139.8,134.6,133.9,133.4,129.1,128.94,128.91,128.88,127.9,127.8,126.9,66.9ppm.
HRMS(ESI‐TOF)Calcd for C20H15N3NaO[M+Na]+:336.1113,found:336.1106.HRMS(ESI‐TOF)Calcd for C 20 H 15 N 3 NaO[M+Na] + :336.1113,found:336.1106.
实施例3：
Example 3:
产物为白色固体(120h,59.4mg,88％yield,90％ee)。The product was a white solid (120 h, 59.4 mg, 88% yield, 90% ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+133.0(c＝2.0,CHCl3).HPLC analysis of the product:DaicelIC column；3％i‐PrOH in n‐hexane；1.0mL/min；retention times:13.3min(major),15.5min(minor).[α] D 25 : +133.0 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel IC column; 3% i-PrOH in n-hexane; 1.0mL/min; retention times: 13.3min (major), 15.5min (minor).
1H NMR(400MHz,acetone‐d6)δ7.90(d,J＝8.3Hz,2H),7.56(d,J＝8.0Hz,2H),7.48–7.41(m,5H),7.33–7.26(m,4H),7.21–7.17(m,1H),6.11(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.90 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.48–7.41 (m, 5H), 7.33–7.26 ( m,4H),7.21–7.17(m,1H),6.11(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.5,141.8,139.8,134.6,133.9,133.4,129.1,128.94,128.91,128.88,127.9,127.8,126.9,66.9ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.5,141.8,139.8,134.6,133.9,133.4,129.1,128.94,128.91,128.88,127.9,127.8,126.9,66.9ppm.
HRMS(ESI‐TOF)Calcd for C20H15N3NaO[M+Na]+:336.1113,found:336.1106.HRMS(ESI‐TOF)Calcd for C 20 H 15 N 3 NaO[M+Na] + :336.1113,found:336.1106.
实施例4：
Example 4:
合成过程见式3(120h,44.7mg,89％yield,88％ee)，产物为淡黄色油状物。 The synthesis process is shown in formula 3 (120h, 44.7mg, 89% yield, 88%ee), and the product is a light yellow oil.
表征数据如下：The characterization data is as follows:
[α]D 25:+100.5(c＝2.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；1％i‐PrOH in n‐hexane；1.0mL/min；retention times:13.1min(major),19.8min(minor).[α] D 25 : +100.5 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 13.1min (major), 19.8min (minor).
1H NMR(400MHz,acetone‐d6)δ7.87–7.84(m,2H),7.44–7.40(m,1H),7.32–7.29(m,2H),7.22–7.20(m,2H),7.10–7.08(m,2H),6.00(s,1H),2.13(s,3H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.87–7.84(m,2H),7.44–7.40(m,1H),7.32–7.29(m,2H),7.22–7.20(m,2H),7.10 –7.08(m,2H),6.00(s,1H),2.13(s,3H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.6,139.2,134.6,133.7,131.4,130.1,128.83,128.80,128.4,67.0,20.3ppm. 13 C NMR (100MHz, acetone-d 6 ) δ 194.6, 139.2, 134.6, 133.7, 131.4, 130.1, 128.83, 128.80, 128.4, 67.0, 20.3ppm.
HRMS(ESI‐TOF)Calcd for C15H13N3NaO[M+Na]+:274.0956,found:274.0951.HRMS(ESI‐TOF)Calcd for C 15 H 13 N 3 NaO[M+Na] + :274.0956,found:274.0951.
实施例5：
Example 5:
产物为无色油状物(120h,48.8mg,92％yield,85％ee)。The product was colorless oil (120h, 48.8mg, 92% yield, 85%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+172.5(c＝2.0,CHCl3).HPLC analysis of the product:DaicelIC column；2％i‐PrOH in n‐hexane；1.0mL/min；retention times:9.1min(major),11.9min(minor).[α] D 25 : +172.5 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel IC column; 2% i-PrOH in n-hexane; 1.0mL/min; retention times: 9.1min (major), 11.9min (minor).
1H NMR(400MHz,acetone‐d6)δ7.88–7.86(m,2H),7.46–7.42(m,1H),7.34–7.30(m,2H),6.94(s,2H),6.88(s,1H),5.94(s,1H),2.13(s,6H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.88–7.86(m,2H),7.46–7.42(m,1H),7.34–7.30(m,2H),6.94(s,2H),6.88(s ,1H),5.94(s,1H),2.13(s,6H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.5,139.0,134.6,134.2,133.7,130.8,128.83,128.79,126.1,67.2,20.4ppm. 13 C NMR (100MHz, acetone-d 6 ) δ 194.5, 139.0, 134.6, 134.2, 133.7, 130.8, 128.83, 128.79, 126.1, 67.2, 20.4ppm.
HRMS(ESI‐TOF)Calcd for C16H15N3NaO[M+Na]+:288.1113,found:288.1109.HRMS(ESI‐TOF)Calcd for C 16 H 15 N 3 NaO[M+Na] + :288.1113,found:288.1109.
实施例6：
Example 6:
产物为无色油状物(168h,37.3mg,73％yield,94％ee)。The product was colorless oil (168h, 37.3mg, 73% yield, 94%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+119.9(c＝2.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；1％i‐PrOH in n‐hexane；1.0mL/min；retention times:15.6min(major),23.2min(minor).[α] D 25 : +119.9 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 15.6min (major), 23.2min (minor).
1H NMR(400MHz,acetone‐d6)δ7.88–7.86(m,2H),7.47–7.31(m,5H),7.09–7.04(m,2H),6.13(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.88–7.86(m,2H),7.47–7.31(m,5H),7.09–7.04(m,2H),6.13(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.4,163.0(d,1JC‐F＝246Hz),134.5,133.9,130.723(d,3JC‐F＝8Hz),130.716,128.9(2C),116.3(d,2JC‐F＝22Hz),66.3ppm.19F NMR(376MHz,acetone‐d6)δ-113.5ppm. 13 C NMR (100MHz, acetone-d 6 ) δ 194.4, 163.0 (d, 1 J C-F = 246Hz), 134.5, 133.9, 130.723 (d, 3 J C-F = 8Hz), 130.716, 128.9 (2C), 116.3 (d, 2 J C-F =22Hz), 66.3ppm. 19 F NMR (376MHz, acetone-d 6 ) δ-113.5ppm.
HRMS(ESI‐TOF)Calcd for C14H10FN3NaO[M+Na]+:278.0706,found:278.0702.HRMS(ESI‐TOF)Calcd for C 14 H 10 FN 3 NaO[M+Na] + :278.0706,found:278.0702.
实施例7：
Example 7:
产物为无色油状物(168h,40.2mg,74％yield,92％ee)。The product was a colorless oil (168h, 40.2mg, 74% yield, 92%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+83.2(c＝1.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；1％i‐PrOH in n‐hexane；1.0mL/min；retention times:16.4min(major),23.9min(minor).[α] D 25 : +83.2 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 16.4min (major), 23.9min (minor).
1H NMR(400MHz,acetone‐d6)δ8.05(d,J＝7.4Hz,2H),7.67–7.63(m,1H), 7.56–7.51(m,6H),6.33(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ8.05 (d, J = 7.4Hz, 2H), 7.67–7.63 (m, 1H), 7.56–7.51(m,6H),6.33(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.3,134.7,134.4,133.9,133.4,130.2,129.5,128.9(two C),66.3ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.3, 134.7, 134.4, 133.9, 133.4, 130.2, 129.5, 128.9 (two C), 66.3ppm.
HRMS(ESI‐TOF)Calcd for C14H10ClNO[M‐N3]+:229.0415,found:229.0417.HRMS(ESI‐TOF)Calcd for C 14 H 10 ClNO[M‐N 3 ] + :229.0415,found:229.0417.
实施例8：
Example 8:
产物为无色油状物(168h,35.4mg,56％yield,91％ee)。The product was colorless oil (168h, 35.4mg, 56% yield, 91%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+90.5(c＝1.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；1％i‐PrOH in n‐hexane；1.0mL/min；retention times:16.5min(major),24.4min(minor).[α] D 25 : +90.5 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 16.5min (major), 24.4min (minor).
1H NMR(400MHz,acetone‐d6)δ8.05–8.03(m,2H),7.67–7.62(m,3H),7.53–7.46(m,4H),6.30(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ8.05–8.03(m,2H),7.67–7.62(m,3H),7.53–7.46(m,4H),6.30(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.2,134.4,133.94,133.90,132.5,130.5,128.9(2C),123.0,66.4ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.2, 134.4, 133.94, 133.90, 132.5, 130.5, 128.9 (2C), 123.0, 66.4ppm.
HRMS(ESI‐TOF)Calcd for C14H10BrO[M‐N3]+:272.9910,found:272.9911.HRMS(ESI‐TOF)Calcd for C 14 H 10 BrO[M‐N 3 ] + :272.9910,found:272.9911.
实施例9：
Example 9:
产物为无色油状物(168h,31.6mg,50％yield,84％ee)。The product was colorless oil (168h, 31.6mg, 50% yield, 84%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+68.9(c＝1.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；1％i‐PrOH in n‐hexane；1.0mL/min；retention  times:16.8min(major),24.8min(minor).[α] D 25 : +68.9 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 1.0mL/min; retention times:16.8min(major),24.8min(minor).
1H NMR(400MHz,acetone‐d6)δ7.92–7.89(m,2H),7.59–7.58(m,1H),7.51–7.44(m,2H),7.39–7.25(m,4H),6.17(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.92–7.89(m,2H),7.59–7.58(m,1H),7.51–7.44(m,2H),7.39–7.25(m,4H),6.17 (s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.1,137.0,134.4,134.0,132.3,131.4,131.3,128.94,128.91,127.2,122.7,66.3ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.1, 137.0, 134.4, 134.0, 132.3, 131.4, 131.3, 128.94, 128.91, 127.2, 122.7, 66.3ppm.
HRMS(ESI‐TOF)Calcd for C14H10BrO[M‐N3]+:272.9910,found:274.9892.HRMS(ESI‐TOF)Calcd for C 14 H 10 BrO[M‐N 3 ] + :272.9910,found:274.9892.
实施例10：
Example 10:
产物为无色油状物(168h,36.1mg,67％yield,96％ee)。The product was colorless oil (168 h, 36.1 mg, 67% yield, 96% ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+97.8(c＝1.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；3％i‐PrOH in n‐hexane；1.0mL/min；retention times:8.6min(major),10.6min(minor).[α] D 25 : +97.8 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 3% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 8.6min (major), 10.6min (minor).
1H NMR(400MHz,acetone‐d6)δ7.78–7.76(m,2H),7.41–7.38(m,2H),7.15–7.05(m,4H),6.08(s,1H),2.20(s,3H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.78–7.76(m,2H),7.41–7.38(m,2H),7.15–7.05(m,4H),6.08(s,1H),2.20(s ,3H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.0,163.0(d,1JC‐F＝245Hz),144.9,131.9,130.9(d,4JC‐F＝3Hz),130.7(d,3JC‐F＝9Hz),129.5,129.0,116.2(d,2JC‐F＝22Hz),66.1,20.7ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.0, 163.0 (d, 1 J C-F = 245Hz), 144.9, 131.9, 130.9 (d, 4 J C-F = 3Hz), 130.7 (d, 3 J C ‐F ＝9Hz),129.5,129.0,116.2(d, 2 J C‐F ＝22Hz),66.1,20.7ppm.
19F NMR(376MHz,acetone‐d6)δ-113.7ppm. 19 F NMR (376MHz, acetone-d 6 ) δ-113.7ppm.
HRMS(ESI‐TOF)Calcd for C15H12FN3NaO[M+Na]+:292.0862,found:292.0859.HRMS(ESI‐TOF)Calcd for C 15 H 12 FN 3 NaO[M+Na] + :292.0862,found:292.0859.
实施例11：
Example 11:
产物为无色油状物(168h,47.4mg,83％yield,94％ee)。The product was colorless oil (168h, 47.4mg, 83% yield, 94%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+107.9(c＝2.0,CHCl3).HPLC analysis of the product:DaicelIC column；10％i‐PrOH in n‐hexane；1.0mL/min；retention times:10.4min(major),13.6min(minor).[α] D 25 : +107.9 (c=2.0, CHCl 3 ). HPLC analysis of the product:Daicel IC column; 10% i-PrOH in n-hexane; 1.0mL/min; retention times: 10.4min (major), 13.6min (minor).
1H NMR(400MHz,acetone‐d6)δ7.87–7.83(m,2H),7.41–7.38(m,2H),7.08–7.04(m,2H),6.85–6.81(m,2H),6.02(s,1H),3.69(s,3H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.87–7.83(m,2H),7.41–7.38(m,2H),7.08–7.04(m,2H),6.85–6.81(m,2H),6.02 (s,1H),3.69(s,3H)ppm.
13C NMR(100MHz,acetone‐d6)δ192.8,164.2,163.0(d,1JC‐F＝245Hz),131.3,131.2(d,4JC‐F＝3Hz),130.6(d,3JC‐F＝8Hz),127.1,116.2(d,2JC‐F＝22Hz),114.1,65.8,55.2ppm. 13 C NMR (100MHz, acetone-d 6 ) δ192.8, 164.2, 163.0 (d, 1 J C-F = 245Hz), 131.3, 131.2 (d, 4 J C-F = 3Hz), 130.6 (d, 3 J C ‐F ＝8Hz),127.1,116.2(d, 2 J C‐F ＝22Hz),114.1,65.8,55.2ppm.
19F NMR(376MHz,acetone‐d6)δ-113.7ppm. 19 F NMR (376MHz, acetone-d 6 ) δ-113.7ppm.
HRMS(ESI‐TOF)Calcd for C15H12FN3NaO2[M+Na]+:308.0811,found:308.0809.HRMS(ESI‐TOF)Calcd for C 15 H 12 FN 3 NaO 2 [M+Na] + :308.0811,found:308.0809.
实施例12：
Example 12:
产物为无色油状物(168h,53.1mg,87％yield,96％ee)。The product was colorless oil (168h, 53.1mg, 87% yield, 96%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+100.6(c＝1.5,CHCl3).HPLC analysis of the product:DaicelIC column；3％i‐PrOH in n‐hexane；1.0mL/min；retention times:12.3min(major),15.9min(minor). [α] D 25 : +100.6 (c=1.5, CHCl 3 ). HPLC analysis of the product:Daicel IC column; 3% i-PrOH in n-hexane; 1.0mL/min; retention times: 12.3min (major), 15.9min (minor).
1H NMR(400MHz,acetone‐d6)δ7.79(s,1H),7.14–7.11(m,2H),7.07–7.01(m,2H),6.76–6.66(m,4H),6.33–6.28(m,2H),5.59(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.79(s,1H),7.14–7.11(m,2H),7.07–7.01(m,2H),6.76–6.66(m,4H),6.33–6.28 (m,2H),5.59(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.6,163.0(d,1JC‐F＝246Hz),135.7,132.4,131.7,131.2,130.84,130.75(d,3JC‐F＝9Hz),129.7,129.2,128.8,127.8,127.2,123.9,116.3(d,2JC‐F＝22Hz),66.3ppm. 13 C NMR (100MHz, acetone-d 6 ) δ194.6, 163.0 (d, 1 J C-F = 246Hz), 135.7, 132.4, 131.7, 131.2, 130.84, 130.75 (d, 3 J C-F = 9Hz), 129.7 ,129.2,128.8,127.8,127.2,123.9,116.3(d, 2 J C-F =22Hz),66.3ppm.
19F NMR(376MHz,acetone‐d6)δ-113.4ppm. 19 F NMR (376MHz, acetone-d 6 ) δ-113.4ppm.
HRMS(ESI‐TOF)Calcd for C18H12FN3NaO[M+Na]+:328.0862,found:328.0858.HRMS(ESI‐TOF)Calcd for C 18 H 12 FN 3 NaO[M+Na] + :328.0862,found:328.0858.
实施例13：
Example 13:
产物为无色油状物(168h,52.7mg,79％yield,91％ee)。The product was a colorless oil (168 h, 52.7 mg, 79% yield, 91% ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+164.9(c＝1.0,CHCl3).HPLC analysis of the product:DaicelOD‐H column；1％i‐PrOH in n‐hexane；1.0mL/min；retention times:13.0min(major),23.6min(minor).[α] D 25 : +164.9 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 1% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 13.0min (major), 23.6min (minor).
1H NMR(400MHz,acetone‐d6)δ7.67–7.66(m,2H),7.59–7.54(m,2H),7.25–7.21(m,3H),6.27(s,1H),2.32(s,6H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.67–7.66(m,2H),7.59–7.54(m,2H),7.25–7.21(m,3H),6.27(s,1H),2.32(s ,6H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.7,163.0(d,1JC‐F＝246Hz),138.6,135.4,134.7,130.9(d,4JC‐F＝3Hz),130.7(d,3JC‐F＝9Hz),126.6,116.2(d,2JC‐F＝22Hz),66.1,20.2ppm. 13 C NMR (100MHz, acetone-d 6 ) δ 194.7, 163.0 (d, 1 J C-F = 246Hz), 138.6, 135.4, 134.7, 130.9 (d, 4 J C-F = 3Hz), 130.7 (d, 3 J C‐F ＝9Hz), 126.6, 116.2 (d, 2 J C‐F ＝22Hz), 66.1, 20.2ppm.
19F NMR(282MHz,acetone‐d6)δ-113.6ppm. 19 F NMR (282MHz, acetone-d 6 ) δ-113.6ppm.
HRMS(ESI‐TOF)Calcd for C16H14FO[M‐N3]+:241.1023,found:241.1026.HRMS(ESI‐TOF)Calcd for C 16 H 14 FO[M‐N 3 ] + :241.1023,found:241.1026.
实施例14：
Example 14:
产物为无色油状物(168h,40.2mg,54％yield,87％ee)。The product was colorless oil (168h, 40.2mg, 54% yield, 87%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+80.9(c＝1.0,CHCl3).HPLC analysis of the product:Daicel IC column；1％i‐PrOH in n‐hexane；1.0mL/min；retention times:16.7min(major),18.2min(minor).[α] D 25 : +80.9 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel IC column; 1% i-PrOH in n-hexane; 1.0mL/min; retention times: 16.7min (major), 18.2min (minor).
1H NMR(400MHz,acetone‐d6)δ8.07–8.05(m,2H),7.66–7.64(m,2H),7.59–7.49(m,6H),7.46–7.43(m,3H),6.33(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ8.07–8.05(m,2H),7.66–7.64(m,2H),7.59–7.49(m,6H),7.46–7.43(m,3H),6.33 (s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ193.5,134.8,133.7,133.3,131.7,131.6,130.3,130.0,129.2,129.1,128.7,128.6,122.3,92.9,88.1,66.4ppm. 13 C NMR (100MHz, acetone‐d 6 ) δ 193.5, 134.8, 133.7, 133.3, 131.7, 131.6, 130.3, 130.0, 129.2, 129.1, 128.7, 128.6, 122.3, 92.9, 88.1, 66.4ppm.
HRMS(ESI‐TOF)Calcd for C22H14ClO[M‐N3]+:329.0728,found:329.0727.HRMS(ESI‐TOF)Calcd for C 22 H 14 ClO[M‐N 3 ] + :329.0728,found:329.0727.
实施例15：
Example 15:
产物为无色油状物(168h,39.9mg,82％yield,88％ee)。The product was colorless oil (168h, 39.9mg, 82% yield, 88%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+140.6(c＝1.0,CH2Cl2).HPLC analysis of the product:Daicel OD‐H column；5％i‐PrOH in n‐hexane；1.0mL/min；retention times:11.2min(major),13.7min(minor).[α] D 25 : +140.6 (c=1.0, CH 2 Cl 2 ). HPLC analysis of the product:Daicel OD‐H column; 5% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 11.2min (major), 13.7min (minor).
1H NMR(400MHz,acetone‐d6)δ7.81–7.78(m,2H),7.41–7.39(m,2H),7.35–7.26(m,3H),7.04–7.02(m,1H),5.92(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.81–7.78(m,2H),7.41–7.39(m,2H),7.35–7.26(m,3H),7.04–7.02(m,1H),5.92 (s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ187.5,141.0,135.7,134.8,134.3,129.4,129.3, 128.7,128.3 67.5ppm. 13 C NMR (100MHz, acetone-d 6 ) δ187.5,141.0,135.7,134.8,134.3,129.4,129.3, 128.7,128.3 67.5ppm.
HRMS(ESI‐TOF)Calcd for C12H9OS[M‐N3]+:201.0369,found:201.0374.HRMS(ESI‐TOF)Calcd for C 12 H 9 OS[M‐N 3 ] + :201.0369,found:201.0374.
实施例16：
Example 16:
产物为无色油状物(168h,25.5mg,52％yield,89％ee)。The product was colorless oil (168h, 25.5mg, 52% yield, 89%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+77.6(c＝0.5,CHCl3).HPLC analysis of the product:Daicel OD‐H column；3％i‐PrOH in n‐hexane；1.0mL/min；retention times:9.5min(major),11.3min(minor).[α] D 25 : +77.6 (c=0.5, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 3% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 9.5min (major), 11.3min (minor).
1H NMR(400MHz,acetone‐d6)δ7.91–7.90(m,1H),7.61–7.58(m,2H),7.51(d,J＝6.4Hz,1H),7.29–7.24(m,2H),6.71–6.69(m,1H),6.01(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ7.91–7.90(m,1H),7.61–7.58(m,2H),7.51(d,J＝6.4Hz,1H),7.29–7.24(m,2H ),6.71–6.69(m,1H),6.01(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ182.5,163.1(d,1JC‐F＝245Hz),150.2,148.4,130.7(d,4JC‐F＝3Hz),130.6(d,3JC‐F＝9Hz),120.1,116.1(d,2JC‐F＝22Hz),112.7,65.9ppm. 13 C NMR (100MHz, acetone-d 6 ) δ182.5, 163.1 (d, 1 J C-F = 245Hz), 150.2, 148.4, 130.7 (d, 4 J C-F = 3Hz), 130.6 (d, 3 J C ‐F ＝9Hz),120.1,116.1(d, 2 J C‐F ＝22Hz),112.7,65.9ppm.
19F NMR(282MHz,acetone‐d6)δ-113.7ppm. 19 F NMR (282MHz, acetone-d 6 ) δ-113.7ppm.
HRMS(ESI‐TOF)Calcd for C12H8FO2[M‐N3]+:203.0503,found:203.0506.HRMS(ESI‐TOF)Calcd for C 12 H 8 FO 2 [M‐N 3 ] + :203.0503,found:203.0506.
实施例17：
Example 17:
产物为无色油状物(120h,43.7mg,76％yield,77％ee)。The product was colorless oil (120h, 43.7mg, 76% yield, 77%ee).
表征数据如下：The characterization data is as follows:
1H NMR(400MHz,acetone‐d6)δ8.09–8.07(m,2H),8.03–8.00(m,2H),7.96 –7.91(m,2H),7.65–7.63(m,1H),7.58–7.52(m,3H),7.47–7.44(m,2H),6.42(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ8.09–8.07(m,2H),8.03–8.00(m,2H),7.96 –7.91(m,2H),7.65–7.63(m,1H),7.58–7.52(m,3H),7.47–7.44(m,2H),6.42(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ194.5,134.6,133.8,133.43,133.42,132.0,129.5,128.9,128.8,128.2,128.0,127.8,127.0,126.8,125.7,67.4ppm. 13 C NMR (100MHz, acetone‐d 6 ) δ 194.5, 134.6, 133.8, 133.43, 133.42, 132.0, 129.5, 128.9, 128.8, 128.2, 128.0, 127.8, 127.0, 126.8, 125.7, 67.4ppm.
HRMS(ESI‐TOF)Calcd for C18H13N3NaO[M+Na]+:310.0956,found:310.0954.HRMS(ESI‐TOF)Calcd for C 18 H 13 N 3 NaO[M+Na] + :310.0956,found:310.0954.
实施例18：
Example 18:
产物为无色油状物(168h,23.5mg,46％yield,67％ee)。The product was colorless oil (168h, 23.5mg, 46% yield, 67%ee).
表征数据如下：The characterization data is as follows:
[α]D 25:+58.3(c＝1.0,CHCl3).HPLC analysis of the product:Daicel OD‐H column；3％i‐PrOH in n‐hexane；1.0mL/min；retention times:9.8min(major),11.4min(minor).[α] D 25 : +58.3 (c=1.0, CHCl 3 ). HPLC analysis of the product:Daicel OD‐H column; 3% i‐PrOH in n‐hexane; 1.0mL/min; retention times: 9.8min (major), 11.4min (minor).
1H NMR(400MHz,acetone‐d6)δ8.13–8.08(m,2H),7.50–7.39(m,5H),7.26–7.21(m,2H),6.21(s,1H)ppm. 1 H NMR (400MHz, acetone-d 6 ) δ8.13–8.08(m,2H),7.50–7.39(m,5H),7.26–7.21(m,2H),6.21(s,1H)ppm.
13C NMR(100MHz,acetone‐d6)δ193.1,165.8(d,1JC‐F＝253Hz),134.3,131.9(d,3JC‐F＝9Hz),131.2(d,4JC‐F＝3Hz),129.5,129.3,128.5,115.8(d,2JC‐F＝22Hz),67.2ppm. 13 C NMR (100MHz, acetone-d 6 ) δ193.1, 165.8 (d, 1 J C-F = 253Hz), 134.3, 131.9 (d, 3 J C-F = 9Hz), 131.2 (d, 4 J C-F =3Hz),129.5,129.3,128.5,115.8(d, 2 J C-F =22Hz),67.2ppm.
19F NMR(376MHz,acetone‐d6)δ-105.8ppm. 19 F NMR (376MHz, acetone-d 6 ) δ-105.8ppm.
HRMS(ESI‐TOF)Calcd for C14H10FO[M‐N3]+:213.0710,found:213.0713.HRMS(ESI‐TOF)Calcd for C 14 H 10 FO[M‐N 3 ] + :213.0710,found:213.0713.
应用例：
Application examples:
手性氨基醇是一类重要的医药中间体，同时也是一种重要的手性配体广泛地应用于手性合成化学(Chem.Rev.1996,96,835-875；J.Med.Chem.2005,48,4220-4223)。为了展示本发明获得的手性叠氮化合物可以转化为此类重要的化合物，本发明采用以下应用例进行说明：Chiral aminoalcohols are an important class of pharmaceutical intermediates and an important chiral ligand widely used in chiral synthetic chemistry (Chem. Rev. 1996, 96, 835-875; J. Med. Chem. 2005, 48,4220-4223). In order to demonstrate that the chiral azide compound obtained by the present invention can be converted into such important compounds, the present invention uses the following application examples to illustrate:
1)按照上图所示，首先制备2.0mmol级别的α-叠氮酮(R)-2b。1) As shown in the figure above, first prepare 2.0 mmol level of α-azido (R)-2b.
2)通过Pd/C催化加氢和Boc保护形成α-氨基酮3。向25mL圆底烧瓶中添加2b(62mg,0.2mmol,95％ee after re-crystallization)，Pd/C(10％on charcoal wetted with ca.55％water,12.4mg,20wt％)和乙酸乙酯(2.0mL)。使用真空泵将混合物脱气三次，充入N2。然后，通过注射器将Boc2O(56mL，0.24mmol，1.2equiv)添加到反应混合物中。将所得悬浮液在0℃下搅拌10分钟，将反应气氛更改为H2(气球)并搅拌1小时。接下来，通过硅藻土过滤，并用乙酸乙酯(10mL)清洗滤饼。减压下浓缩滤液、通过硅胶柱层析法纯化(洗脱液：正己烷/乙酸乙酯＝20:1至10:1)，获得无色固体产物3(67.4mg,87％yield,93％ee)。值得注意的是，经化合物3的单晶衍射可确定本发明产物的绝对构型。2) Formation of α-aminoketone 3 via Pd/C catalytic hydrogenation and Boc protection. To a 25mL round bottom flask, add 2b (62mg, 0.2mmol, 95%ee after re-crystallization), Pd/C (10% on charcoal wetted with ca.55%water, 12.4mg, 20wt%) and ethyl acetate ( 2.0mL). The mixture was degassed three times using a vacuum pump and filled with N 2 . Then, Boc 2 O (56 mL, 0.24 mmol, 1.2 equiv) was added to the reaction mixture via syringe. The resulting suspension was stirred at 0°C for 10 minutes, the reaction atmosphere was changed to H2 (balloon) and stirred for 1 hour. Next, filter through Celite and wash the filter cake with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 20:1 to 10:1) to obtain colorless solid product 3 (67.4 mg, 87% yield, 93% ee). It is worth noting that the absolute configuration of the product of the present invention can be determined by single crystal diffraction of compound 3.
3)进一步非对映选择还原3生成氨基醇4。在-20℃的N2条件下，向手性α-氨基酮3(0.2mmol，77.5mg，93％ee)的无水甲醇(2.0mL)溶液中缓慢加入NaBH4(0.6mmol，22.7mg，3.0equiv)。在相同温度下搅拌，直到氨基酮3完全转化(约5小时)。然后，通过缓慢添加水(5.0mL)小心地淬灭反应混合 物，并用乙酸乙酯萃取三次(3*10mL)，再用饱和NaCl水溶液(5mL)洗涤合并的有机层，并用无水Na2SO4进行干燥。过滤后，浓缩滤液以获得粗产物，并通过1H NMR分析确定d.r.值，最后通过硅胶柱层析进一步纯化粗产物，得到1,2-氨基醇产物4(60.8mg,78％yield,91％ee)。3) Further diastereoselective reduction of 3 produces aminoalcohol 4. To a solution of chiral α-aminoketone 3 (0.2 mmol, 77.5 mg, 93%ee) in anhydrous methanol (2.0 mL) at -20 °C under N2 conditions, NaBH4 (0.6 mmol, 22.7 mg, 3.0equiv). Stir at the same temperature until aminoketone 3 is completely converted (about 5 hours). Then, the reaction mixture was carefully quenched by slowly adding water (5.0 mL) The mixture was extracted with ethyl acetate three times (3*10 mL), and the combined organic layers were washed with saturated NaCl aqueous solution (5 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated to obtain the crude product, and the dr value was determined by H NMR analysis. Finally, the crude product was further purified by silica gel column chromatography to obtain 1,2-aminoalcohol product 4 (60.8 mg, 78% yield, 91% ee).
本发明所获得的手性叠氮化合物经铜催化的click反应可转化成相应的手性三氮唑类杂环化合物。值得注意的是研究证明含三级手性中心的α-羰基三氮唑类化合物具有一定的抗肿瘤活性(Eur.J.Med.Chem.2010,45,5044-5050；ARKIVOC 2012,279-296)，但受限于相关不对称催化合成方法的制约，目前为止尚未有含三级手性中心的α-羰基三氮唑类化合物的手性合成报道，故人们无法进一步探究手性中心的构型与药物活性之间的关系。基于此，本发明展示了所获得的手性叠氮化合物可以转化成相关的手性三氮唑杂环化合物：The chiral azide compound obtained by the present invention can be converted into the corresponding chiral triazole heterocyclic compound through a copper-catalyzed click reaction. It is worth noting that studies have proven that α-carbonyltriazole compounds containing tertiary chiral centers have certain anti-tumor activity (Eur.J.Med.Chem.2010,45,5044-5050; ARKIVOC 2012,279-296 ), but due to the constraints of related asymmetric catalytic synthesis methods, there have been no chiral synthesis reports of α-carbonyltriazole compounds containing tertiary chiral centers so far, so people cannot further explore the structure of the chiral centers. The relationship between type and drug activity. Based on this, the present invention demonstrates that the obtained chiral azide compounds can be converted into related chiral triazole heterocyclic compounds:
4)手性三唑5的合成：在25mL单颈圆底烧瓶中加入2b(62mg,0.2mmol,87％ee)和MeOH(1.0mL)。将得到的悬浮液冷却到0℃。再加入一份NaBH4(9.1mg,0.24mmol,1.2equiv)。反应混合物在相同温度下搅拌，直到2b完全转化。反应完成后(1.0h)，加入几滴HCl(1M)以淬灭反应，并用Et2O(3×10mL)萃取混合物。将组合的有机层用盐水(10ml)洗涤，在无水Na2SO4上干燥，过滤，真空浓缩，得到粗制的β-叠氮醇，无需进一步纯化，直接用于下一步。4) Synthesis of chiral triazole 5: Add 2b (62 mg, 0.2 mmol, 87% ee) and MeOH (1.0 mL) into a 25 mL single-neck round-bottom flask. The resulting suspension was cooled to 0°C. Add another portion of NaBH 4 (9.1 mg, 0.24 mmol, 1.2 equiv). The reaction mixture was stirred at the same temperature until complete conversion of 2b. After the reaction was complete (1.0 h), a few drops of HCl (1 M) were added to quench the reaction, and the mixture was extracted with Et 2 O (3 × 10 mL). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4 , filtered, and concentrated in vacuo to give crude β-azido alcohol which was used directly in the next step without further purification.
在N2条件下，将粗制的β-叠氮醇(0.2mmol)、CuSO4·5H2O(10.0mg,0.04mmol,20mol％)、抗坏血酸钠(16.0mg,0.08mmol,0.4equiv)、tBuOH(1.6mL)和H2O(0.8mL)装入10mL小瓶。在剧烈搅拌下，加入苯基乙炔(24.4mg,0.24mmol,1.2equiv)。在此期间，反应混合物的颜色变成黄色。反应混合物在40℃下搅拌24小时，然后用DCM(10mL)稀释，硅藻土过过滤、DCM(10mL)洗涤滤饼，将合并的有机层浓缩得到β-羟基三唑中间体，直接用于下一步操作，无需进一步纯化。Under N2 conditions, crude β-azido alcohol (0.2mmol), CuSO 4 ·5H 2 O (10.0mg, 0.04mmol, 20mol%), sodium ascorbate (16.0mg, 0.08mmol, 0.4equiv), tBuOH (1.6 mL) and H 2 O (0.8 mL) were charged into a 10 mL vial. With vigorous stirring, phenylacetylene (24.4 mg, 0.24 mmol, 1.2 equiv) was added. During this time, the color of the reaction mixture changed to yellow. The reaction mixture was stirred at 40°C for 24 hours, then diluted with DCM (10 mL), filtered through diatomaceous earth, and the filter cake was washed with DCM (10 mL). The combined organic layers were concentrated to obtain a β-hydroxytriazole intermediate, which was directly used The next step was performed without further purification.
将粗制的β-羟基三唑(0.2mmol)溶于无水DCM(2.0mL)中，冷却至0℃。再加入DMP(127mg,0.3mmol,1.5equiv)。在相同温度下搅拌反应混合物，直到β- 羟基三氮唑完全转化。反应完成后(约3小时)，加入NaHCO3水溶液(10mL,1.0M)，使反应淬灭。然后用DCM(3×5mL)萃取反应混合物。将合并的有机层用盐水(10mL)洗涤，用Na2SO4干燥，过滤，浓缩，得到粗产物。粗产品经硅胶柱层析法纯化(洗脱液:正己烷/乙酸乙酯＝5:1至3:1)，得到无色固体5(58.2mg，70％yield，86％ee)。Crude β-hydroxytriazole (0.2 mmol) was dissolved in anhydrous DCM (2.0 mL) and cooled to 0°C. Then add DMP (127 mg, 0.3 mmol, 1.5 equiv). Stir the reaction mixture at the same temperature until β- Hydroxytriazole is completely converted. After the reaction was completed (about 3 hours), NaHCO 3 aqueous solution (10 mL, 1.0 M) was added to quench the reaction. The reaction mixture was then extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine ( 10 mL), dried over Na2SO4 , filtered, and concentrated to give crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5:1 to 3:1) to obtain colorless solid 5 (58.2 mg, 70% yield, 86% ee).
比较例：Comparative example:
例1：其他类型催化剂对本发明反应结果的影响—手性磷酸

a Determined by crude 1H NMR anaylsis using CH2Br2as an internal standard.All the 
reactions described above provided clean conversion.b Determined by Chiral HPLC analysis. Example 1: Effect of other types of catalysts on the reaction results of the present invention—chiral phosphoric acid

a Determined by crude 1 H NMR anaylsis using CH 2 Br 2 as an internal standard.All the
reactions described above provided clean conversion. b Determined by Chiral HPLC analysis.
例2：其他类型催化剂对本发明反应结果的影响—其他氢键催化剂

a Determined by crude 1H NMR anaylsis using CH2Br2as an internal standard.b 
Determined by Chiral HPLC analysis.c The reaction gave a messy mixture,likely due to the incompatibility of the reaction with the basic cinchona alkaloid functionality.Example 2: The influence of other types of catalysts on the reaction results of the present invention - other hydrogen bonding catalysts

a Determined by crude 1 H NMR anaylsis using CH 2 Br 2 as an internal standard. b
Determined by Chiral HPLC analysis. c The reaction gave a messy mixture, likely due to the incompatibility of the reaction with the basic cinchona alkaloid functionality.
从以上两则比较例可以看出，本发明中采用的SQ3催化剂在对目标反应的 立体选择性控制中具有显著的优势；同时由于本发明反应条件比较温和，产物的光学纯度不会受到消旋化的影响(产物由于受羰基以及叠氮基的吸电子性影响，对酸碱敏感而易消旋化)。It can be seen from the above two comparative examples that the SQ3 catalyst used in the present invention is effective in the target reaction. It has significant advantages in stereoselectivity control; at the same time, because the reaction conditions of the present invention are relatively mild, the optical purity of the product will not be affected by racemization (the product is sensitive to acids and bases due to the electron-withdrawing properties of the carbonyl group and the azide group) And easy to racemize).
例3：手性质子源对本发明反应结果的影响—氨基酸作为手性质子

a Determined by crude 1H NMR analysis using CH2Br2as an internal standard.b 
Determined by chiral HPLC analysis.c ent‐SQ3was used as the catalyst.Example 3: Effect of chiral proton source on the reaction results of the present invention - amino acids as chiral protons

a Determined by crude 1 H NMR analysis using CH 2 Br 2 as an internal standard. b
Determined by chiral HPLC analysis. c ent‐SQ3was used as the catalyst.
例4：其他非手性质子源对本发明反应结果的影响—醇、羧酸作为质子源

Reaction scale:1a(0.1mmol),TMSN3(0.2mmol),proton source(0.11mmol),SQ3(0.01mmol),solvent(0.5
mL),24h.Yield was determined by 1H NMR spectra of the crude mixture using CH2Br2as an internal standard.Ee was determined by HPLC on a chiral stationary phase.Example 4: The influence of other achiral proton sources on the reaction results of the present invention - alcohols and carboxylic acids as proton sources

Reaction scale: 1a (0.1mmol), TMSN 3 (0.2mmol), proton source (0.11mmol), SQ3 (0.01mmol), solvent (0.5
mL),24h.Yield was determined by 1 H NMR spectra of the crude mixture using CH 2 Br 2 as an internal standard.Ee was determined by HPLC on a chiral stationary phase.
从以上两则比较例可以看出，质子源的种类只影响反应的收率(或者转化率)，而对产物的立体选择性没有明显影响，从侧面证明了质子源只是与TMSN3反应来产生HN3，而不参与立体化学控制过程。 It can be seen from the above two comparative examples that the type of proton source only affects the yield (or conversion rate) of the reaction, but has no obvious impact on the stereoselectivity of the product. This proves from the side that the proton source only reacts with TMSN 3 to produce HN 3 , does not participate in the stereochemical control process.

Claims (4)

  1. 一种含三级立体中心的α-叠氮酮的合成方法，其特征在于，所述的α-叠氮酮具有一个手性中心，结构式如下：
    A method for synthesizing an α-azido ketone containing a tertiary stereocenter, characterized in that the α-azido ketone has a chiral center and the structural formula is as follows:
    其中 中的任意一种；in any of;
    X＝Me、OMe、F、中的任意一种取代基；X＝Me、OMe、F、 any substituent in;
    中的任意一种； any of;
    Y＝Ph、Me、F、Br、Cl、中的任意一种取代基；Y＝Ph, Me, F, Br, Cl, any substituent in;
    合成方法包括：在方酸酰胺催化剂的作用下，氧化锍叶立德衍生物与通过TMSN3与质子源原位产生的叠氮化试剂HN3反应生成所述的α-叠氮酮，所述方酸酰胺催化剂结构式为其中Ar＝1-芘基，包括其相应的对应异构体；The synthesis method includes: under the action of squaryl acid amide catalyst, the sulfonium oxide ylide derivative reacts with the azide reagent HN 3 produced in situ by TMSN 3 and the proton source to generate the α-azido ketone, and the squaryl acid amide The structural formula of the amide catalyst is Where Ar=1-pyrenyl, including its corresponding enantiomer;
    氧化锍叶立德衍生物的结构式为 The structural formula of sulfonium oxide ylide derivatives is
  2. 根据权利要求1所述的含三级立体中心的α-叠氮酮的合成方法，其特征在于，原位产生的叠氮化试剂HN3的质子源为苯甲酸、N-叔丁氧羰基-L-脯氨酸、N-叔丁氧羰基‐D‐脯氨酸、N-叔丁氧羰基‐L‐亮氨酸、N-叔丁氧羰基‐D‐亮氨酸、N-叔丁氧羰基‐L‐叔亮氨酸、N-叔丁氧羰基‐D‐叔亮氨酸、N-叔丁氧羰基‐L‐缬氨 酸、N-叔丁氧羰基‐D‐缬氨酸、水、甲醇、六氟异丙醇、乙酸、对‐羟基苯甲酸、对氯苯甲酸中的任意一种。The synthesis method of α-azido ketones containing tertiary stereocenters according to claim 1, characterized in that the proton source of the azide reagent HN 3 produced in situ is benzoic acid, N-tert-butoxycarbonyl- L-proline, N-tert-butoxycarbonyl-D-proline, N-tert-butoxycarbonyl-L-leucine, N-tert-butoxycarbonyl-D-leucine, N-tert-butoxy Carbonyl-L-tert-leucine, N-tert-butoxycarbonyl-D-tert-leucine, N-tert-butoxycarbonyl-L-valine Any one of acid, N-tert-butoxycarbonyl-D-valine, water, methanol, hexafluoroisopropanol, acetic acid, p-hydroxybenzoic acid, and p-chlorobenzoic acid.
  3. 根据权利要求2所述的含三级立体中心的α-叠氮酮的合成方法，其特征在于，还包括如下步骤：将添加有氧化锍叶立德衍生物、质子源、方酸酰胺催化剂和CHCl3的体系冷却至-15～0℃；在相同温度下持续搅拌，并加入TMSN3，然后继续在相同的温度下搅拌至反应结束。The synthesis method of α-azido ketones containing tertiary stereocenters according to claim 2, further comprising the following steps: adding sulfonium oxide ylide derivatives, proton sources, squarylamide catalysts and CHCl 3 The system was cooled to -15~0°C; stirring was continued at the same temperature, TMSN 3 was added, and then stirring was continued at the same temperature until the reaction was completed.
  4. 根据权利要求3所述的含三级立体中心的α-叠氮酮的合成方法，其特征在于，质子源与氧化锍叶立德衍生物的摩尔比为1～2:1；TMSN3与氧化锍叶立德衍生物的摩尔比为1～4:1。 The synthesis method of α-azido ketones containing tertiary stereocenters according to claim 3, characterized in that the molar ratio of the proton source and the sulfonium oxide ylide derivative is 1 to 2:1; TMSN 3 and the sulfonium oxide ylide derivative The molar ratio of derivatives is 1 to 4:1.
PCT/CN2023/107817 2022-07-18 2023-07-18 SYNTHESIS METHOD FOR α-AZIDO KETONE CONTAINING TERTIARY STEREOCENTER WO2024017221A1 (en)

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