CN117247337A - 一种不对称合成1,2-反式氨基醇及其衍生物的方法 - Google Patents

一种不对称合成1,2-反式氨基醇及其衍生物的方法 Download PDF

Info

Publication number
CN117247337A
CN117247337A CN202311127876.8A CN202311127876A CN117247337A CN 117247337 A CN117247337 A CN 117247337A CN 202311127876 A CN202311127876 A CN 202311127876A CN 117247337 A CN117247337 A CN 117247337A
Authority
CN
China
Prior art keywords
cdcl
nmr
trans
tert
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311127876.8A
Other languages
English (en)
Inventor
稂琪伟
刘瑞雪
刘创基
蒙永娟
丁小兵
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Catalys Technology Co Ltd
Original Assignee
Shenzhen Catalys Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Catalys Technology Co Ltd filed Critical Shenzhen Catalys Technology Co Ltd
Priority to CN202311127876.8A priority Critical patent/CN117247337A/zh
Publication of CN117247337A publication Critical patent/CN117247337A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明属于化学合成技术领域，具体涉及一种不对称合成1,2‑反式氨基醇及其衍生物的方法。本发明通过1,2‑氨基酮的催化氢化不对称动态动力学拆分制备得到1,2‑反式氨基醇或其衍生物。该方法反应条件温和，对映体和非对映体选择性优异，催化剂载量低，高效高产率，且成功在麻黄碱中间体和间羟胺中间体实现克级规模的合成，相比传统方法，能够大大降低“三废”量，具有较好的应用前景。

Description

一种不对称合成1,2-反式氨基醇及其衍生物的方法
技术领域
本发明属于化学合成技术领域，具体涉及一种不对称合成1,2-反式氨基醇及其衍生物的方法。
背景技术
手性1,2-氨基醇是药物和活性分子的重要组成单元，比如在临床中有抗炎、平喘、止喘、止咳作用的麻黄碱或其类似物去甲麻黄碱，用于治疗休克和手术时低压症状的升压药间羟胺，广谱抗菌素氯霉素，以及强效且长效抗糖尿病药奥格列汀等药物均含有该结构。此外，手性1,2-氨基醇也是重要的手性配体，在不对称合成中有着重要作用。
1,2-氨基酮的动态动力学拆分不对称还原是合成手性1,2-氨基醇结构最直接和简单有效的方法。2009年，周其林小组发展了钌-双膦双胺催化体系对1,2-氨基酮的不对称氢化动态动力学拆分形成反式1,2-氨基醇的方法，其非对映体选择性最高达到>99/1dr，对映体选择性达到97％ee(J.Am.Chem.Soc.2009,131,4222–4223)。
2017年，张绪穆小组发展了Ir-f-amphox催化体系对1,2-氨基酮的不对称氢化动态动力学拆分形成顺式1,2-氨基醇的方法，该方法中几乎所有底物非对映体选择性达到>99/1dr，对映体选择性达到99％ee，催化剂的用量可以低至是S/C＝100000，该方法体现出了催化剂体系的广谱适用性和高活性高选择性(Org.Lett.2017,19,2548-2551)。
上述两个文献报道的方法中，氨基酮底物中氮原子上的取代基均为烷基。2020年，Martin Wills小组发展了NH保护基的1,2-氨基酮经转移氢化进行动态动力学拆分形成反式1,2-氨基醇的方法。该方法中，催化剂用量为1.5mol％，载量较大。值得一提的是，当R基团表示芳基时，普遍取得了较好的结果；而当R基团表示烷基如甲基时，其反应效果明显下降，非对映体选择性为79/21dr，两个异构体的光学纯分别为34％/82％ee(J.Org.Chem.2020,85,11309-11330)。
综合以上文献的优缺点，发展高效高选择性的制备1,2-氨基醇的方法具有重要的科学价值和实际意义。
发明内容
本发明提供了一种不对称合成1,2-反式氨基醇及其衍生物的方法，反应式如下：
所述反应中，化合物氨基酮式(1)在合适的有机溶剂中，在手性催化剂、碱和氢气存在下进行的，经不对称催化氢化动态动力学拆分得到氨基醇产物式(2)或其衍生物恶唑烷酮式(3)；
其中，式(1)、式(2)和式(3)中，Ar1和Ar2基团分别独立表示芳基，包括苯基、不同位置取代的芳基，含氧、硫、氮的杂芳环；R表示C1-C6的直连或支链烷烃；PG表示氮的保护基，选自甲基、苄基、苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲(或乙)氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基。
作为本发明的一种优选技术方案，所述手性催化剂由金属前体和手性配体络合得到，其中，金属选自钌、铑、铱，手性配体选自L1-L5：
其中，配体中的Ar基团表示为芳基，选自苯基、4-甲基苯基，3,5-二甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基4-甲氧基苯基；R1、R2分别独立为烷基、芳基；R3、R4独立为烷基、芳基或氢原子，R3和R4成环或不成环；R5表示烷基、芳基。
作为本发明的一种优选技术方案，所述的手性配体选自：
中的至少一种。
作为本发明的一种优选技术方案，所述的溶剂自：甲醇、乙醇、异丙醇、三氟乙醇、四氢呋喃、二氯甲烷和甲苯的至少一种，更优选为醇类溶剂，最优选为乙醇。
作为本发明的一种优选技术方案，所述的碱选自：叔丁醇钾、叔丁醇钠、叔丁醇锂、氢氧化钾、氢氧化钠、甲醇钾、甲醇钠、碳酸钠、碳酸钾和碳酸铯的至少一种，更优选叔丁醇钾、叔丁醇锂、氢氧化钠，更优选叔丁醇钾。
作为本发明的一种优选技术方案，所述反应温度范围为20至50℃，更优选30±5℃；氢气的压力范围为5至60个大气压，更优选40±5个大气压。
作为本发明的一种优选技术方案，合成化合物氨基醇式(2)包含以下步骤：化合物氨基酮式(1)在合适的有机溶剂中，在手性催化剂、碱和氢气存在下进行反应，经不对称催化氢化动态动力学拆分得还原产物，反应完成后，往反应液中经加稀酸调节至pH＝7±1，然后快速过一个硅胶短柱，收集滤液并浓缩得1,2-反式氨基醇式(2)。其中，化合物氨基醇式(2)选自：
作为本发明的一种优选技术方案，合成化合物环状氨基醇式(3)包含以下步骤：化合物氨基酮式(1)在合适的有机溶剂中，在手性催化剂、碱和氢气存在下进行反应，经不对称催化氢化动态动力学拆分得还原产物，反应完成后，直接进行浓缩或者加热操作得到恶唑烷酮式(3)。
本发明提供的一种不对称合成1,2-反式氨基醇及其衍生物的方法，可用于麻黄碱中间体和间羟胺中间体的合成。
本发明相对于现有技术的以下有益效果：
该反应通过动态动力学拆分的不对称催化氢化，可以直接获得相应的光学纯的合成1,2-反式氨基醇或其衍生物恶唑烷酮，具有优异的非对映和对映选择性(>99％dr，高达99％ee)；该反应在温和条件下进行，催化剂载量低，高效高产率，相比传统方法，能够大大降低“三废”量；该方法成功实现麻黄碱中间体和间羟胺中间体克级规模的合成，易于放大，具有较好的应用前景。
本发明的详细说明书
术语定义
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本发明中“Cq1-q2”表示所描述的基团的碳原子个数，例如，C1-6烷基表示含有1-6个碳原子的烷基。
术语“烷基”表示含有1至6个碳原子，饱和的直链或支链一价烃基基团。在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。烷基基团的实例包含，但并不限于，甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基、正戊基、2-戊基，等。
术语“氨基保护基”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，氨基保护基的实例包括但不限于甲基、苄基、苄氧羰基(-Cbz)、叔丁氧羰基(-Boc)、甲氧羰基(-COOMe或-CO2Me)、乙氧羰基(-COOEt或-CO2Et)、异丁基氧羰基(-COOiBu或-CO2 iBu)、异丙基氧羰基(-COOiPr或-CO2 iPr)、笏甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基。
具体实施方式
下面结合具体实施例对本发明做进一步的说明，但本发明不局限于此。
总实施例1底物氨基酮1合成
步骤1：在室温下，将酮S1(10mmol)溶于乙腈(30mL)中，并搅拌均匀，加入N-溴代琥珀酰亚胺(NBS，11mmol)和对甲苯磺酰胺(PTSA，15mmol)，加完后升温至50℃反应6小时。浓缩大部分溶剂，加入乙酸乙酯稀释，并相继用水、饱和碳酸氢钠和饱和食盐水洗涤，有机相用无水硫酸钠干燥，浓缩后得溴代酮S2，直接用于下一步反应。
步骤2：室温下，往二甲酰氨基钠(8.5mmol)的乙腈(30mL)悬浊液中滴加溴代酮S2(7mmol)的乙腈溶液(12mL)，加完后，升温至75℃反应8小时，反应完全后，趁热过滤，滤饼用乙腈洗涤，合并有机相，浓缩后加入HCl溶液(6mol/L,10mL)并回流30分钟，加入异丙醇共沸蒸除水，残余物用乙醚洗涤并真空干燥，得到氨基酮盐酸盐S3。
步骤3：将氨基酮盐酸盐S3(3mmol)和碳酸氢钠(7.5mmol)溶于水中，滴加二碳酸二叔丁酯(4.5mmol)的四氢呋喃溶液(9mL)，在室温下反应1.5小时，除去四氢呋喃，水相用乙酸乙酯萃取(3*10mL)，合并有机相，无水硫酸钠干燥，过滤并浓缩得到氨基酮底物1。
其中，化合物1的数据如下：
tert-Butyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)carbamate(1a):Whitesolid；65％yield.1H NMR(600MHz,CDCl3)δ7.92(d,J＝8.6Hz,2H),7.48–7.44(m,2H),5.48(d,J＝7.8Hz,1H),5.26–5.21(m,1H),1.45(s,9H),1.38(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ198.5,155.3,140.4,132.7,130.2,129.3,80.0,51.2,28.5,19.8.HRMS(ESI)Calcd.for C14H18ClNO3Na[M+Na]+:306.0873,Found:306.0870.
tert-Butyl(1-(4-fluorophenyl)-1-oxopropan-2-yl)carbamate(1b):Whitesolid；57％yield.1H NMR(600MHz,CDCl3)δ8.01(dd,J＝8.8,5.5Hz,2H),7.16(t,J＝8.5Hz,2H),5.50(d,J＝7.6Hz,1H),5.27–5.22(m,1H),1.45(s,9H),1.39(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ198.1,166.2(d,J＝255.2Hz),155.3,131.5(d,J＝9.1Hz),130.8(d,J＝1.5Hz),116.2(d,J＝21.1Hz),80.0,51.1,28.5,19.9.19F NMR(376MHz,CDCl3)δ-103.9.
tert-Butyl(1-(4-bromophenyl)-1-oxopropan-2-yl)carbamate(1c):Whitesolid；57％yield.1H NMR(600MHz,CDCl3)δ7.84(d,J＝8.3Hz,2H),7.63(d,J＝8.5Hz,2H),5.48(d,J＝7.8Hz,1H),5.25–5.20(m,1H),1.45(s,9H),1.38(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ198.7,155.3,133.1,132.3,130.3,129.1,80.0,51.1,28.5,19.8.
tert-Butyl(1-oxo-1-(p-tolyl)propan-2-yl)carbamate(1d):White solid；65％yield.1H NMR(600MHz,CDCl3)δ7.87(d,J＝7.9Hz,2H),7.28(d,J＝7.9Hz,2H),5.58(d,J＝7.7Hz,1H),5.29–5.24(m,1H),2.41(s,3H),1.45(s,9H),1.39(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ199.1,155.3,144.8,131.8,129.7,128.9,79.7,51.1,28.5,21.8,20.3.HRMS(ESI)Calcd.for C15H21NO3Na[M+Na]+:286.1419,Found:286.1414.
tert-Butyl(1-oxo-1-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate(1e):White solid；52％yield.1H NMR(600MHz,CDCl3)δ8.08(d,J＝8.1Hz,2H),7.76(d,J＝8.1Hz,2H),5.45(d,J＝7.9Hz,1H),5.31–5.26(m,1H),1.45(s,9H),1.40(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ198.9,155.3,137.3,135.1(q,J＝32.8Hz),129.1,126.6(q,J＝272.8Hz),126.03(q,J＝3.7Hz),80.2,51.5,28.5,19.5.19F NMR(376MHz,CDCl3)δ-63.2.HRMS(ESI)Calcd.for C15H18F3NO3Na[M+Na]+:340.1136,Found:340.1131.
tert-Butyl(1-oxo-1-(2-(trifluoromethyl)phenyl)propan-2-yl)carbamate(1f):Whitesolid；43％yield.1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.4Hz,1H),7.72(d,J＝7.3Hz,1H),7.68-7.56(m,2H),5.30(d,J＝8.0Hz,1H),5.01–4.94(m,1H),1.43(s,9H),1.31(d,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ203.0,155.4,137.3,131.9,131.0,128.3(q,J＝32.3Hz),127.3(q,J＝5.1Hz),123.5(q,J＝274.7Hz),80.1,54.8,28.4,17.5.19F NMR(376MHz,CDCl3)δ-58.2.HRMS(ESI)Calcd.for C15H18F3NO3Na[M+Na]+:340.1136,Found:340.1132.
tert-Butyl(1-oxo-1-(3-(trifluoromethyl)phenyl)propan-2-yl)carbamate(1g):White solid；44％yield.1H NMR(400MHz,CDCl3)δ8.24(s,1H),8.16(d,J＝7.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.64(t,J＝7.8Hz,1H),5.46(d,J＝7.9Hz,1H),5.33–5.26(m,1H),1.45(s,9H),1.41(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ198.5,155.3,135.1,131.7(q,J＝32.3Hz),130.2(q,J＝3.5Hz),129.7,125.7(q,J＝3.9Hz),123.7(q,J＝273.7Hz),80.2,51.3,28.5,19.5.19F NMR(376MHz,CDCl3)δ-62.9.HRMS(ESI)Calcd.forC15H18F3NO3Na[M+Na]+:340.1136,Found:340.1132.
tert-Butyl(1-(3-chlorophenyl)-1-oxopropan-2-yl)carbamate(1h):Whitesolid；55％yield.1H NMR(600MHz,CDCl3)δ7.95(t,J＝1.9Hz,1H),7.84(d,J＝7.8Hz,1H),7.58–7.54(m,1H),7.43(t,J＝7.9Hz,1H),5.47(d,J＝7.8Hz,1H),5.25–5.21(m,1H),1.45(s,9H),1.39(d,J＝7.2Hz,3H).13C NMR(151MHz,CDCl3)δ198.6,155.3,136.0,135.4,133.8,130.3,128.9,126.8,80.1,51.3,28.5,19.7.HRMS(ESI)Calcd.for C14H18ClNO3Na[M+Na]+:306.0873,Found:306.0869.
tert-Butyl(1-(3-fluorophenyl)-1-oxopropan-2-yl)carbamate(1i):Whitesolid；54％yield.1H NMR(600MHz,CDCl3)δ7.75(d,J＝7.8Hz,1H),7.66(d,J＝9.3Hz,1H),7.50–7.44(m,1H),7.31-7.28(m,1H),5.47(d,J＝7.8Hz,1H),5.26-5.21(m,1H),1.45(s,9H),1.39(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ198.6,163.1(d,J＝249.5Hz),155.3,136.5(d,J＝6.1Hz),130.7(d,J＝7.1Hz),124.5(d,J＝3.0Hz),120.9(d,J＝21.2Hz),115.6(d,J＝23.2Hz),80.0,51.4,28.5,19.7.19F NMR(376MHz,CDCl3)δ-111.3.HRMS(ESI)Calcd.for C14H18FNO3Na[M+Na]+:290.1168,Found:290.1163.
tert-Butyl(1-(3-bromophenyl)-1-oxopropan-2-yl)carbamate(1j):Whitesolid；52％yield.1H NMR(400MHz,CDCl3)δ8.09(t,J＝1.3Hz,1H),7.87(d,J＝7.8Hz,1H),7.71-7.68(m,1H),7.35(t,J＝7.9Hz,1H),5.51(d,J＝7.9Hz,1H),5.25-5.18(m,1H),1.43(s,9H),1.37(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ198.4,155.2,136.6,136.2,131.7,130.5,127.2,123.3,80.0,51.2,28.4,19.6.HRMS(ESI)Calcd.for C14H18BrNO3Na[M+Na]+:350.0368,Found:350.0363.
tert-Butyl(1-(3-methoxyphenyl)-1-oxopropan-2-yl)carbamate(1k):Whitesolid；63％yield.1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.7Hz,1H),7.48(t,J＝1.8Hz,1H),7.38(t,J＝7.9Hz,1H),7.17–7.10(m,1H),5.55(d,J＝7.4Hz,1H),5.30-5.22(m,1H),3.85(s,3H),1.45(s,9H),1.39(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)199.4,160.1,155.3,135.7,129.9,121.3,120.5,112.9,79.8,55.6,51.3,28.5,20.1.
tert-Butyl(1-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate(1l):Whitesolid；57％yield.1H NMR(400MHz,CDCl3)δ7.96(dd,9.3,2.3Hz,2H),6.95(dd,9.0,2.2Hz,2H),5.60(d,J＝7.7Hz,1H),5.27-5.20(m,1H),3.87(s,3H),1.45(s,9H),1.39(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ197.9,164.1,155.3,131.1,127.1,114.1,79.7,55.7,50.8,28.5,20.4.
tert-Butyl(1-oxo-1-phenylpropan-2-yl)carbamate(1m):White solid；85％yield.1H NMR(400MHz,CDCl3)δ7.97(d,J＝7.6Hz,2H),7.59(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),5.56(d,J＝7.7Hz,1H),5.33-5.25(m,1H),1.45(s,9H),1.40(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ199.6,155.3,134.4,133.9,129.0,128.8,79.8,51.2,28.5,20.1.
tert-Butyl(1-(2,5-difluorophenyl)-1-oxopropan-2-yl)carbamate(1n):White solid；49％yield.1H NMR(600MHz,CDCl3)δ7.59-7.56(m,1H),7.25-5.22(m,1H),7.16-7.12(m,1H),5.42(d,J＝7.1Hz,1H),5.13-5.08(m,1H),1.43(s,9H),1.38(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ197.0,158.9(dd,J＝244.6,1.5Hz),157.6(d,J＝250.7Hz),155.3,124.5(dd,J＝13.6,3.0Hz),122.0(dd,J＝24.2,9.1Hz),118.4(dd,J＝27.2,7.6Hz),117.3(dd,J＝25.7,3.0Hz),80.0,55.2,28.5,18.4.19F NMR(376MHz,CDCl3)δ-114.8,-117.1.HRMS(ESI)Calcd.forC14H17F2NO3Na[M+Na]+:308.1074,Found:308.1069.
tert-Butyl(1-(3,5-difluorophenyl)-1-oxopropan-2-yl)carbamate(1o):White solid；47％yield.1H NMR(600MHz,CDCl3)δ7.52-7.46(m,2H),7.06-7.03(m,1H),5.40(d,J＝7.8Hz,1H),5.40-5.14(m,1H)),1.44(s,9H),1.39(d,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ197.5,163.3(dd,J＝250.7,12.1Hz),155.2,137.5(t,J＝7.6Hz),111.8(dd,J＝19.6,6.0Hz),109.1(t,J＝25.7Hz),80.2,51.4,28.5,19.4.19F NMR(376MHz,CDCl3)δ-107.5.HRMS(ESI)Calcd.for C14H17F2NO3Na[M+Na]+:308.1074,Found:308.1069.
tert-Butyl(1-(2,4-dichlorophenyl)-1-oxopropan-2-yl)carbamate(1p):White solid；49％yield.1H NMR(600MHz,CDCl3)δ7.54(d,J＝8.3Hz,1H),7.46(d,J＝2.0Hz,1H),7.33(dd,J＝8.3,2.0Hz,1H),5.31(d,J＝7.4Hz,1H),5.04-4.99(m,1H),1.43(s,9H),1.32(d,J＝7.2Hz,3H).13C NMR(151MHz,CDCl3)δ201.2,155.3,137.9,135.4,132.6,130.7,130.4,127.4,80.1,54.7,28.4,17.7.HRMS(ESI)Calcd.for C14H17Cl2NO3Na[M+Na]+:340.0483,Found:340.0478.
tert-Butyl(1-([1,1'-biphenyl]-4-yl)-1-oxopropan-2-yl)carbamate(1q):White solid；50％yield.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.1Hz,2H),7.71(d,J＝8.3Hz,2H),7.63(d,J＝7.4Hz,2H),7.50-7.39(m,3H),5.59(d,J＝7.8Hz,1H),5.36-5.29(m,1H),1.47(s,9H),1.44(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ199.2,155.4,146.6,139.8,133.0,129.4,129.1,128.5,127.6,127.4,79.9,51.2,28.5,20.1.HRMS(ESI)Calcd.for C20H23NO3Na[M+Na]+:348.1576,Found:348.1571.
tert-Butyl(1-oxo-1-(thiophen-2-yl)propan-2-yl)carbamate(1r):Yellowishsolid；41％yield.1H NMR(600MHz,CDCl3)δ7.81(d,J＝3.8Hz,1H),7.70(dd,J＝4.9,1.1Hz,1H),7.16(dd,J＝4.9,3.8Hz,1H),5.44(d,J＝8.0Hz,1H),5.14-5.09(m,1H),1.46(d,J＝7.1Hz,3H),1.44(s,9H).13C NMR(151MHz,CDCl3)δ192.4,155.2,141.3,134.8,133.0,128.5,80.0,52.2,28.5,20.5.HRMS(ESI)Calcd.forC12H17NO3SNa[M+Na]+:278.0827,Found:278.0822.
tert-Butyl(1-(furan-2-yl)-1-oxopropan-2-yl)carbamate(1s):Yellowishsolid；43％yield.1H NMR(400MHz,CDCl3)δ7.62(d,J＝1.6Hz,1H),7.31(d,J＝3.6Hz,1H),6.56(dd,J＝3.6,1.7Hz,1H),5.40(d,J＝8.0Hz,1H),5.09-5.01(m,1H),1.43(s,9H),1.41(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ188.4,155.2,150.7,147.3,119.0,112.6,79.9,51.6,28.5,19.6.HRMS(ESI)Calcd.for C12H17NO4Na[M+Na]+:262.1055,Found:262.1050.
tert-Butyl(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)carbamate(1t):Yellowish solid；40％yield.1H NMR(400MHz,CDCl3)δ7.51–7.48(m,2H),6.91(d,J＝8.2Hz,1H),5.58(d,J＝7.7Hz,1H),5.22-5.14(m,1H),4.32–4.25(m,4H),1.43(s,9H),1.37(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ197.9,155.3,148.7,143.6,127.9,122.9,118.3,117.6,79.7,64.8,64.2,50.9,28.5,20.3.
tert-Butyl(2-oxo-1,2-diphenylethyl)carbamate(1u):White solid；52％yield.1H NMR(400MHz,CDCl3)δ7.95(d,J＝7.7Hz,2H),7.50(t,J＝7.4Hz,1H),7.41–7.34(m,4H),7.32–7.24(m,3H),6.27(d,J＝7.6Hz,1H),6.01(d,J＝7.6Hz,1H),1.43(s,9H).13CNMR(101MHz,CDCl3)δ196.2,155.1,137.6,134.7,133.7,129.3129.2,128.8128.4,128.2,80.1,59.9,28.5.
N-(1-(4-chlorophenyl)-1-oxopropan-2-yl)benzamide(1v):White solid；66％yield.1H NMR(400MHz,CDCl3)δ8.00(d,J＝8.6Hz,2H),7.85(d,J＝7.2Hz,2H),7.54–7.43(m,5H),7.29(d,J＝7.0Hz,1H),5.76-5.69(m,1H),1.54(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ198.2,166.8,140.8,134.1,132.3,131.9,130.3,129.5,128.8,127.2,50.6,20.0.HRMS(ESI)Calcd.for C16H14ClNO2Na[M+Na]+:310.0611,Found:310.0606.
Benzyl(1-(4-chlorophenyl)-1-oxopropan-2-yl)carbamate(1w):White solid；65％yield.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.2Hz,2H),7.47(d,J＝8.2Hz,2H),7.40–7.30(m,5H),5.81(d,J＝7.5Hz,1H),5.34–5.26(m,1H),5.13(s,2H),1.43(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ197.9,155.7,140.6,136.4,132.5,130.2,129.4,128.7,128.3,128.2,67.1,51.7,20.0.HRMS(ESI)Calcd.forC17H16ClNO3Na[M+Na]+:340.0711,Found:340.0711.
总实施例2底物氨基酮1a的不对称氢化配体和碱的筛选
以实施例2-1为例，在惰性气体氛围下，称取模板底物1a(0.1mmol)溶于1.0毫升异丙醇中于氢化小瓶中，加入叔丁醇钾(0.005mmol)，取[Ir(COD)Cl]2/配体L1-3[(S)-f-phamidol)]的络合物溶液，1a和催化剂的摩尔比为500/1，将氢化小瓶置于氢化釜中并密闭，先充入5个大气压氢气置换三次，然后充入40个大气压氢气，在30±5℃反应24小时。在通风橱中，小心释放釜中的氢气，取出氢化小瓶，并向反应液中加入稀盐酸(1mol/L)，调节pH至7±1，反应液快速过硅胶短柱除掉金属络合物和盐，所得的滤液浓缩得到氢化产物，反应的转化率通过1H NMR确定，产物的dr值及光学纯ee值通过HPLC测定。
按照实施例2-1的操作方法，通过置换不同的配体和碱，得到的结果如下：
实施例 配体 碱 转化率(％) dr ee(％)
实施例2-1 L1-3 tBuOK >99 96/4 >99
实施例2-2 L2-2 tBuOK 9 50/50 15
实施例2-3 L3-4 tBuOK 13 54/46 22
实施例2-4 L4-3 tBuOK 99 94/6 >99
实施例2-5 L5-2 tBuOK 95 92/8 >99
实施例2-6 L5-6 tBuOK 90 93/7 >99
实施例2-7 L1-3 Cs2CO3 >99 75.5/24.5 98
实施例2-8 L1-3 K2CO3 19 56/44 87
实施例2-9 L1-3 NaOH >99 95/5 >99
实施例2-10 L1-3 LiOH 44 92.5/7.5 95
实施例2-11 L1-3 tBuONa >99 78.5/21.5 97
实施例2-12 L1-3 tBuOLi >99 95/5 98
上述结果表明，实施例2-1至2-6中，配体L1-3[(S)-f-phamidol)]效果最优，获得了完全转换，具有良好的非对映选择性(dr)达到了96:4，对映选择性(ee)为99％；实施例2-6至2-12中，以L1-3配体，置换不同的碱，其反应活性和选择性有较大差异，其中，以氢氧化钠和叔丁醇锂结果较为优异，非对映选择性均可达到95:5dr，对映选择性可以分别达到>99％ee和98％ee。
总实施例3底物氨基酮1a的不对称氢化溶剂优化
按照实施例2-1的操作方法，以L1-3[(S)-f-phamidol)]配体，底物1a和催化剂的摩尔比为500/1，加入适当的碱(底物1a和碱的摩尔比为20/1)，氢气压力为40个大气压，对模型底物1a进行催化氢化，得到的结果如下：
实施例 溶剂 转化率(％) dr ee(％)
对比实施例2-1 iPrOH >99 96/4 >99
实施例3-1 MeOH 10 90/10 79
实施例3-2 EtOH >99 98.5/1.5 >99
实施例3-3 THF 36 93.5/6.5 96
实施例3-4 EtOAc 10 96.5/3.5 >99
实施例3-5 DCM 9 94/6 90
从结果表明，不同溶剂中反应情况差异很大，尽管都有较好的非对映选择性(dr)和对映体选择性(ee)，均达到90/10的dr，除甲醇外，其对映体选择性均大于等于90％ee；但其转化率差异明显，在异丙醇和乙醇中，获得了完全转化率，在甲醇、四氢呋喃、乙酸乙酯，二氯甲烷中的转化率较低，值得一提的是，在乙醇为溶剂时，相对于异丙醇，保持对映体选择性>99％ee的同时，其非对映选择性提高至98.5/1.5dr。
总实施例4不对称催化氢化条件优化
按照实施例2-1的操作方法，以L1-3配体，底物1和催化剂的摩尔比为500/1，加入适当的碱(底物1和碱的摩尔比为20/1)，氢气压力为40个大气压，对底物1进行催化氢化，遗憾的是，底物1b、1c、1f、1h、1j在该条件下反应基本不发生(实施例4-1至实施例4-5)。
考虑到不同底物取代基的中吸电子或给电子效应，导致基团NHBoc中的“NH”酸性有差异，从而引起碱用量的消耗不同。因此，重新以模型底物1a对碱的量进行筛选。从下表中实施例4-6至实施例4-10结果可以看出，碱的量对模型底物1a的不对称氢化影响较大，当碱的量小于5mol％时，其转化率明显降低，但其非对映选择性和对映选择性均能维持。实施例4-10中，碱的量为110mol％时，反应同样能顺利进行且保持相当优异的结果。在该条件下，进一步降低催化剂的用量(S/C＝500-10000)，反应均能以优异的结果进行不对称催化氢化(实施例4-10至实施例4-13)。
总实施例5不对称催化氢化合成氨基醇2的范围拓展
在上述条件筛选的基础上，综合考虑底物的适用范围，拓展不同底物的优化条件设定为：底物1用量为0.1mmol，以[Ir(COD)Cl]2/L1-3[(S)-f-phamidol)]为催化剂(0.2mol％)，乙醇为溶剂(1.0毫升)，tBuOK(110mol％)为碱，反应温度为30±5℃，氢气压力为40个大气压，反应时间为24小时。
参考实施例2-1的操作步骤，在该优化条件下，拓展了一系列氨基酮1的适用范围，结果如下：
/>
/>
结果表明，不管氢化底物化合物1在芳基上的取代基是吸电子基团，如氟、氯、溴、三氟甲基等，还是给电子基团，如甲氧基、甲基等都具有较好的效果，其产率为94％-99％，同时具有高水平的非对映选择性(94：6至>99：1dr)和优异的对映选择性(98％至99％ee)。
另外，在实施例5-17和实施例5-18中，当苯环换成芳香杂环如噻吩或呋喃时，也有较好的结果，其产率分别为95％和94％，非对映选择性分别为99：1dr和97：3dr，其对映选择性都高达99％ee；在实施例5-19中，二氢苯并[b][1,4]二氧杂环的底物反应结果虽然有95％产率和98：2dr的非对映选择性，但其对映选择性只有中等的82％ee。值得一提的是，在实施例5-21和实施例5-22中，改变甲基为苯基和改变氮上的取代基为苯甲酰基，反应也有很好的结果，其产率分别为94％和99％，非对映选择性分别为>99：1dr和92.5：7.5dr，其对映选择性都高达99％ee。
化合物2的数据如下：
tert-Butyl((1S,2R)-1-(4-chlorophenyl)-1-hydroxypropan-2-yl)carbamate(2a):White solid,99％yield,[α]23 D＝+14.2(c 0.1,MeOH).1H NMR(600MHz,CDCl3)δ7.24(d,J＝8.5Hz,2H),7.20(d,J＝8.6Hz,2H),4.75(s,1H),4.52(d,J＝7.9Hz,1H),3.91(s,1H),3.43(s,1H),1.39(s,9H),0.90(d,J＝6.9Hz,3H).13C NMR(151MHz,CDCl3)δ156.7,139.4,133.3,128.4,127.9,80.2,76.5,52.1,28.5,15.0.HRMS(ESI)Calcd.forC14H20ClNO3Na[M+Na]+:308.1024,Found:308.1025.The enantiomeric excess wasdetermined by HPLC on Chiralpak IK-3column.Conditions:3％isopropanol inhexane；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝9.10min,tR(minor)＝10.23min,13.27min,14.93min.tert-Butyl((1S,2R)-1-(4-fluorophenyl)-1-hydroxypropan-2-yl)carbamate(2b):White solid,96％yield,[α]23 D＝+16.0(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.29(dd,J＝8.5,5.5Hz,2H),7.04–7.00(m,2H),4.81(d,J＝3.4Hz,1H),4.63(d,J＝8.5Hz,1H),3.96(s,1H),3.53(s,1H),1.45(s,9H),0.97(d,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)δ162.3(d,J＝246.4Hz),156.6,136.6,128.1(d,J＝8.1Hz),115.1(d,J＝21.2Hz),80.1,76.5,52.1,28.5,15.0.19F NMR(376MHz,CDCl3)δ-115.4.HRMS(ESI)Calcd.for C14H20FNO3Na[M+Na]+:292.1320,Found:292.1319.Theenantiomeric excess was determined by HPLC on Chiralpak IK-3column.Conditions:3％isopropanol in hexane；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝9.82min,tR(minor)＝16.31min.
tert-Butyl((1S,2R)-1-(4-bromophenyl)-1-hydroxypropan-2-yl)carbamate(2c):white solid,99％yield,[α]23 D＝+15.1(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.49-7.43(m,2H),7.25-7.17(m,2H),4.79(d,J＝2.9Hz,1H),4.61(d,J＝7.5Hz,1H),3.97(s,1H),3.19(s,1H),1.45(s,9H),0.96(d,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)δ156.7,139.9,131.3,128.3,121.4,80.2,76.5,52.1,28.5,15.0.HRMS(ESI)Calcd.forC14H20BrNO3Na[M+Na]+:352.0519,Found:352.0519.The enantiomeric excess wasdetermined by HPLC on Chiralpak IK-3 column.Conditions:3％isopropanol inhexane；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝10.22min,tR(minor)＝11.90min,17.48min.
tert-Butyl((1S,2R)-1-hydroxy-1-(p-tolyl)propan-2-yl)carbamate(2d):White solid,96％yield,[α]23 D＝+16.4(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.22(d,J＝7.9Hz,2H),7.15(d,J＝7.9Hz,2H),4.81(d,J＝3.0Hz,1H),4.63(s,1H),3.99(s,1H),3.16(s,1H),2.34(s,3H),1.46(s,9H),0.98(d,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)δ137.9,137.2,129.0,126.4,79.9,52.1,28.5,21.2,15.1.HRMS(ESI)Calcd.for C15H23NO3Na[M+Na]+:288.1571,Found:288.1571.The enantiomeric excess was determined by HPLC onChiralpak IC-3 column.Conditions:hexane:isopropanol＝90:10；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝7.41min,tR(minor)＝18.85min.
tert-Butyl((1S,2R)-1-hydroxy-1-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate(2e):White solid,97％yield,[α]23 D＝-2.8(c 0.1,MeOH).1H NMR(600MHz,CDCl3)δ7.59(d,J＝7.9Hz,2H),7.45(d,J＝7.9Hz,2H),4.89(s,1H),4.64(d,J＝7.4Hz,1H),4.00(s,1H),3.73(s,1H),1.45(s,9H),0.98(d,J＝6.9Hz,3H).13C NMR(151MHz,CDCl3)δ156.7,145.1,129.9(q,J＝32.3Hz),125.3(q,J＝2.0Hz),124.9(q,J＝271.8Hz),80.3,76.6,52.2,28.5.19F NMR(376MHz,CDCl3)δ-62.4.C15H20F3NO3Na[M+Na]+:342.1288,Found:342.1287.The enantiomeric excess was determined by HPLC on Chiralpak AD-3column.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝7.47min,tR(minor)＝8.15min,9.17min,13.33min.
tert-Butyl
((1S,2R)-1-hydroxy-1-(2-(trifluoromethyl)phenyl)propan-2-yl)carbamate(2f):White solid,94％yield,[α]23 D＝+11.1(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.83(d,J＝7.9Hz,1H),7.66-7.53(m,2H),7.38(t,J＝7.7Hz,1H),5.13(s,1H),4.73(d,J＝9.0Hz,1H),3.99-3.90(m,1H),3.18(s,1H),1.37(s,9H),1.14(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ155.7,140.5,132.0,129.0,127.8,126.7(q,J＝5.4Hz),124.5(q,J＝274.1Hz),80.0,72.7,51.6,28.4,15.6.19F NMR(376MHz,CDCl3)δ-57.4.HRMS(ESI)Calcd.for C15H20F3NO3Na[M+Na]+:342.1288,Found:342.1289.The enantiomeric excesswas determined by HPLC on Chiralpak IK-3 column.Conditions:3％isopropanol inhexane；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝6.87min.
tert-Butyl((1S,2R)-1-hydroxy-1-(3-(trifluoromethyl)phenyl)propan-2-yl)carbamate(2g):White solid,96％yield,[α]23 D＝+9.7(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.55–7.44(m,3H),4.89(d,J＝2.8Hz,1H),4.60(d,J＝7.7Hz,1H),4.02(s,1H),3.86(s,1H),1.45(s,9H),0.99(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ156.8,142.0,130.6(q,J＝32.3Hz),130.0,128.6,124.4(q,J＝4.0Hz),124.3(q,J＝273.7Hz),123.4(q,J＝5.0Hz),80.3,76.7,52.2,28.5,15.1.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)Calcd.for C15H20F3NO3Na[M+Na]+:342.1288,Found:342.1290.Theenantiomeric excess was determined by HPLC on Chiralpak IA column.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝8.26min,tR(minor)＝9.79min.
tert-Butyl((1S,2R)-1-(3-chlorophenyl)-1-hydroxypropan-2-yl)carbamate(2h):White solid,97％yield,[α]23 D＝+13.5(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.36(d,J＝2.1Hz,1H),7.29–7.24(m,2H),7.22–7.19(m,1H),4.83(s,1H),4.66(d,J＝8.0Hz,1H),3.99(s,1H),3.70(s,1H),1.47(s,9H),0.99(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ156.7,143.1,134.3,129.5,127.7,126.7,124.7,80.2,76.5,52.2,28.5,15.0.HRMS(ESI)Calcd.for C14H20ClNO3Na[M+Na]+:308.1024,Found:308.1025.The enantiomeric excesswas determined by HPLC on Chiralpak IK-3 column.Conditions:3％isopropanol inhexane；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝9.32min,tR(minor)＝27.19min.
tert-Butyl((1S,2R)-1-(3-fluorophenyl)-1-hydroxypropan-2-yl)carbamate(2i):White solid,97％yield,[α]23 D＝+20.8(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.30(d,J＝7.0Hz,1H),7.09(d,J＝7.8Hz,2H),6.98-6.93(m,1H),4.85(s,1H),4.74-4.58(m,1H),3.99(s,1H),3.58(s,1H),1.46(s,9H),0.98(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ163.0(d,J＝247.5Hz),156.6,143.8,129.7(d,J＝8.1Hz),122.1,114.4(d,J＝21.2Hz),113.5(d,J＝22.2Hz),80.2,76.5,52.2,28.5,14.9.19F NMR(376MHz,CDCl3)δ-113.2.HRMS(ESI)Calcd.for C14H20FNO3Na[M+Na]+:292.1320,Found:292.1320.The enantiomericexcess was determined by HPLC on Chiralpak IK-3 column.Conditions:3％isopropanol in hexane；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝8.43min,tR(minor)＝28.46min.
tert-Butyl((1S,2R)-1-(3-bromophenyl)-1-hydroxypropan-2-yl)carbamate(2j):White solid,98％yield,[α]23 D＝+13.7(c 0.1,MeOH).1H NMR(600MHz,CDCl3)δ7.50(d,J＝2.2Hz,1H),7.40(d,J＝7.8Hz,1H),7.24(d,J＝7.7Hz,1H),7.20(t,J＝7.7Hz,1H),4.81(s,1H),4.63(d,J＝7.9Hz,1H),3.98(s,1H),3.65(s,1H),1.46(s,9H),0.98(d,J＝6.9Hz,3H).13C NMR(151MHz,CDCl3)δ156.7,143.4,130.6,129.8,129.7,125.2,122.6,80.2,76.5,52.2,28.5,15.0.HRMS(ESI)Calcd.forC14H20BrNO3Na[M+Na]+:352.0519,Found:352.0520.The enantiomeric excesswas determined by HPLC on Chiralpak IK-3column.Conditions:3％isopropanol inhexane；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝9.18min,tR(minor)＝10.15min,26.06min.
tert-Butyl((1S,2R)-1-hydroxy-1-(3-methoxyphenyl)propan-2-yl)carbamate(2k):White solid,98％yield,[α]23 D＝+13.6(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.23(t,J＝8.1Hz,1H),6.90–6.88(m,2H),6.80–6.77(m,1H),4.80(d,J＝3.0Hz,2H),3.96(s,1H),3.78(s,3H),3.57(s,1H),1.44(s,9H),0.96(d,J＝6.9Hz,3H).13CNMR(101MHz,CDCl3)δ159.6,156.4,142.7,129.2,118.8,113.1,111.7,79.8,76.5,55.3,52.0,28.5,14.7.Theenantiomeric excess was determined by HPLC onChiralpak IBN-3column.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝11.80min,tR(minor)＝12.47min.
tert-Butyl((1S,2R)-1-hydroxy-1-(4-methoxyphenyl)propan-2-yl)carbamate(2l):White solid,99％yield,[α]23 D＝+18.5(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.24(d,J＝8.4Hz,2H),6.91-6.83(m,2H),4.78(d,J＝3.1Hz,1H),4.72-4.61(m,1H),4.03-3.90(m,1H),3.80(s,3H),3.07(s,1H),1.45(s,9H),0.97(d,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)δ159.1,156.6,133.0,127.6,113.7,79.9,76.6,55.4,52.1,28.5,15.1.HRMS(ESI)Calcd.for C15H23NO4Na[M+Na]+:304.1520,Found:304.1521.The enantiomeric excesswas determined by HPLC on ChiralpakAD-H column.Conditions:hexane:isopropanol＝90:10；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝10.05min,tR(minor)＝11.55min.
tert-Butyl((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)carbamate(2m):Whitesolid,97％yield,[α]23 D＝+15.6(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.37–7.30(m,4H),7.29–7.27(m,1H),4.83(d,J＝3.0Hz,1H),4.71(d,J＝8.3Hz,1H),3.99(s,1H),3.43(s,1H),1.45(s,9H),0.97(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ156.5,140.9,128.2,127.5,126.5,79.9,76.8,52.1,28.5,14.9.The enantiomericexcess was determined byHPLC on Chiralpak OD-H column.Conditions:hexane:isopropanol＝97:3；flow rate＝0.8mL/min；UV detection at 223nm,30℃；tR(major)＝13.10min,tR(minor)＝21.13min.
tert-Butyl((1S,2R)-1-(2,5-difluorophenyl)-1-hydroxypropan-2-yl)carbamate(2n):White solid,98％yield,[α]23 D＝+13.7(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.19(t,J＝5.9Hz,1H),6.99-6.89(m,2H),5.11(d,J＝3.0Hz,1H),4.61(s,1H),4.06(s,1H),3.61(s,1H),1.45(s,9H),1.03(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ160.2(d,J＝2.0Hz),157.8(d,J＝2.0Hz),156.9(dd,J＝14.1,2.0Hz),130.0,116.2(dd,J＝25.3,8.1Hz),115.4(dd,J＝24.2,9.1Hz),80.5,71.3,51.6,28.5,15.5.19F NMR(376MHz,CDCl3)δ-118.7,-123.4.HRMS(ESI)Calcd.forC14H19F2NO3Na[M+Na]+:310.1226,Found:310.1225.The enantiomeric excesswas determined by HPLC on Chiralpak IK-3column.Conditions:3％isopropanol inhexane；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝7.35min,tR(minor)＝8.63min.
tert-Butyl((1S,2R)-1-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)carbamate(2o):White solid,95％yield,[α]23 D＝+18.1(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ6.89-6.86(m,2H),6.72-6.67(m,1H),4.82-4.81(m,1H),4.68-4.66(m,1H),3.96(s,1H),3.88(s,1H),1.45(s,9H),0.98(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ163.3(dd,J＝251.5,13.1Hz),159.9,139.0(t,J＝9.1Hz),109.2(dd,J＝19.2,7.1Hz),104.2(t,J＝25.3Hz),79.8,76.2,52.3,28.5,17.5.19F NMR(376MHz,CDCl3)δ-108.3.HRMS(ESI)Calcd.for C14H19F2NO3Na[M+Na]+:310.1226,Found:310.1227.The enantiomeric excesswas determined by HPLC on Chiralpak IAcolumn.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UVdetection at 223nm,30℃；tR(major)＝8.28min,tR(minor)＝9.61min.
tert-Butyl((1S,2R)-1-(2,4-dichlorophenyl)-1-hydroxypropan-2-yl)carbamate(2p):White solid,95％yield,[α]23 D＝+14.3(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.51(d,J＝8.4Hz,1H),7.34(d,J＝2.1Hz,1H),7.28(d,J＝2.1Hz,1H),5.24-5.12(m,1H),4.78(s,1H),4.09-3.96(m,1H),3.33(s,1H),1.44(s,9H),1.01(d,J＝8.0Hz,3H).13C NMR(101MHz,CDCl3)δ156.4,137.5,133.8,133.0,129.7129.2,127.2,80.2,73.1,50.7,28.5,14.9.HRMS(ESI)Calcd.for C14H19Cl2NO3Na[M+Na]+:342.0635,Found:342.0636.The enantiomeric excess was determined by HPLCon Chiralpak IK-3column.Conditions:3％isopropanol in hexane；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝6.93min,tR(minor)＝8.58min,19.29min.
tert-Butyl((1S,2R)-1-([1,1'-biphenyl]-4-yl)-1-hydroxypropan-2-yl)carbamate(2q):White solid,96％yield,[α]23 D＝+9.7(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.63-7.54(m,4H),7.43(q,J＝7.2Hz,4H),7.34(t,J＝7.3Hz,1H),4.90(s,1H),4.75(d,J＝7.7Hz,1H),4.05(s,1H),3.51(s,1H),1.47(s,9H),1.04(d,J＝6.4Hz,3H).13CNMR(101MHz,CDCl3)δ156.6,140.9,140.44,140.0,128.9,127.4,127.2,127.0,80.0,76.8,52.2,28.5,15.1.HRMS(ESI)Calcd.for C20H25NO3Na[M+Na]+:350.1727 Found:350.1727.The enantiomeric excess was determined by HPLC onChiralpak IK-3column.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝12.19min,tR(minor)＝17.58min,25.19min.
tert-Butyl((1R,2R)-1-hydroxy-1-(thiophen-2-yl)propan-2-yl)carbamate(2r):Yellowish solid,95％yield,[α]23 D＝+8.3(c 0.1,MeOH).1H NMR(600MHz,CDCl3)δ7.27-7.25(m,1H),7.05-6.97(m,1H),6.96(d,J＝3.5Hz,1H),5.05(d,J＝3.5Hz,1H),4.74-4.55(m,1H),4.10(s,1H),3.91(s,1H),1.48(s,9H),1.09(d,J＝6.9Hz,3H).13C NMR(151MHz,CDCl3)δ157.0,144.5,126.7,124.7,124.4,80.3,74.6,52.1,28.5,15.8.HRMS(ESI)Calcd.for C12H19SNO3Na[M+Na]+:280.0978,Found:280.0979.The enantiomericexcess was determined by HPLC on Chiralpak IAcolumn.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝11.55min,tR(minor)＝14.30min.
tert-Butyl((1R,2R)-1-(furan-2-yl)-1-hydroxypropan-2-yl)carbamate(2s):Yellowish solid,94％yield,[α]23 D＝+13.5(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.37(dd,J＝1.9,0.9Hz,1H),6.34(dd,J＝3.3,1.8Hz,1H),6.29-6.28(m,1H),4.76(d,J＝3.3Hz,1H),4.49(s,1H),4.09(s,1H),3.51(s,1H),1.44(s,9H),1.08(d,J＝6.9Hz,3H).13CNMR(101MHz,CDCl3)δ156.5,154.2,142.2,110.3,107.4,79.8,71.8,50.9,28.4,16.1.HRMS(ESI)Calcd.for C12H19NO4Na[M+Na]+:264.1207,Found:264.1206.The enantiomericexcess was determined by HPLC on Chiralpak AD-H column.Conditions:hexane:isopropanol＝95:5；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝15.92min,tR(minor)＝16.96min,21.83min,23.51min.
tert-Butyl
((1S,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-yl)carbamate(2t):Yellowish solid,95％yield,[α]23 D＝+15.5(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ6.86–6.79(m,3H),4.72(d,J＝3.0Hz,1H),4.66(s,1H),4.25(d,J＝7.1Hz,5H),3.95(s,1H),3.27(s,1H),1.45(s,9H),0.98(d,J＝6.9Hz,3H).13CNMR(101MHz,CDCl3)δ159.2,143.4,143.0,119.2,117.5,117.0,115.2,80.8,76.5,64.5,52.6,28.5,17.6.The enantiomeric excess was determined by HPLC onChiralpak IBN-3column.Conditions:hexane:isopropanol＝90:10；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝10.33min,tR(minor)＝11.15min,23.69min.
tert-Butyl((1R,2S)-2-hydroxy-1,2-diphenylethyl)carbamate(2u):Whitesolid,98％yield,[α]23 D＝+17.9(c 0.1,MeOH)1H NMR(400MHz,DMSO-d6)δ7.32–7.20(m,11H),5.36(s,1H),4.67(d,J＝7.9Hz,1H),4.58(t,J＝8.6Hz,1H),1.20(s,9H).13C NMR(101MHz,DMSO-d6)δ155.0,143.8,141.9,128.6,127.9,127.4,127.3,127.0,78.1,75.6,60.5,28.6.The enantiomeric excess was determinedby HPLC on Chiralpak IBN-3column.Conditions:hexane:isopropanol＝90:10；flow rate＝1.0mL/min；UV detectionat 223nm,30℃；tR(major)＝6.35min,tR(minor)＝6.95min.
N-((1S,2R)-1-(4-chlorophenyl)-1-hydroxypropan-2-yl)benzamide(2v):Whitesolid,99％yield,[α]23 D＝+10.9(c 0.1,MeOH).1H NMR(400MHz,CDCl3)δ7.76-7.73(m,2H),7.57-7.49(m,1H),7.49-7.40(m,2H),7.32(d,J＝1.1Hz,5H),4.95(d,J＝2.8Hz,1H),4.57-4.48(m,1H),1.12(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ168.5,139.29,133.6,132.02,128.9,128.5,128.0,127.1,76.4,51.5,14.9.HRMS(ESI)Calcd.forC16H16ClNO2Na[M+Na]+:312.0762,Found:312.0761.The enantiomeric excess wasdetermined by HPLC on Chiralpak AS-H column.Conditions:hexane:ethanol＝90:10；flow rate＝1.0mL/min；UV detection at 223nm,30℃；tR(major)＝7.32min,tR(minor)＝13.55min.
总实施例6不对称催化氢化合成恶唑烷酮3
在惰性气体氛围下，在氢化小瓶中，称取模板底物1a(0.1mmol)溶于1.0毫升乙醇中，加入叔丁醇钾(1.1mmol)，取[Ir(COD)Cl]2/配体L1-3的络合物溶液，1a和催化剂的摩尔比为500/1，将氢化小瓶置于氢化釜中并密闭，先充入5个大气压氢气置换三次，然后充入40个大气压氢气，在30±5℃反应24小时。在通风橱中，小心释放釜中的氢气，取出氢化小瓶，所得的反应液直接浓缩或者加热至50℃得到产物恶唑烷酮3，反应的转化率通过1H NMR确定，产物的dr值及光学纯ee值通过其相对应的氨基醇2进行测定。反应得到的结果如下：
/>
化合物3的数据如下：
(4R,5S)-5-(4-chlorophenyl)-4-methyloxazolidin-2-one(3a):ViscousSolid；95％yield,(c 0.12,MeOH).1H NMR(400MHz,CDCl3)δ7.39(d,J＝8.3Hz,2H),7.25(d,J＝8.2Hz,2H),5.85(s,1H),5.69(d,J＝7.9Hz,1H),4.24–4.17(m,1H),0.82(d,J＝6.5Hz,3H).13C NMR(101MHz,CDCl3)δ159.2,134.6,133.5,129.0,127.5,80.4,52.4,17.7.
(4R,5S)-5-(4-fluorophenyl)-4-methyloxazolidin-2-one(3b):Colorlessoil；95％yield,[α]23 D＝+76.6(c 0.15,MeOH).1H NMR(400MHz,CDCl3)δ7.32-7.24(m,2H),7.16-7.01(m,2H),5.87(s,1H),5.70(d,J＝7.9Hz,1H),4.23-4.16(m,2H),0.81(d,J＝6.5Hz,3H).13C NMR(101MHz,CDCl3)δ162.8(d,J＝248.5Hz),159.2,130.8(d,J＝3.0Hz),127.9(d,J＝9.1Hz),115.7(d,J＝22.2Hz),80.6,52.5,17.7.19FNMR(376MHz,CDCl3)δ-113.1.
(4R,5S)-5-(4-bromophenyl)-4-methyloxazolidin-2-one(3c):Viscous Solid；94％yield,(c 0.11,MeOH).1H NMR(400MHz,CDCl3)δ7.56-7.51(m,2H),7.20-7.15(m,2H),5.93(s,1H),5.66(d,J＝7.9Hz,1H),4.23-4.16(m,1H),0.81(d,J＝6.5Hz,3H).13C NMR(101MHz,CDCl3)δ159.1,134.0,131.9,127.8,122.7,80.5,52.3,17.7.
(4R,5S)-4-methyl-5-(p-tolyl)oxazolidin-2-one(3d):Colorless oil；96％yield,[α]23 D＝+117.3(c 0.16,MeOH).1H NMR(600MHz,CDCl3)δ7.22-7.15(m,4H),5.82(s,1H),5.68(d,J＝7.9Hz,1H),4.21-4.14(m,1H),2.36(s,3H),0.81(d,J＝6.5Hz,3H).13C NMR(151MHz,CDCl3)δ159.6,138.4,132.0,129.3,126.1,81.2,52.6,21.3,17.7.
实施例7克级规模合成麻黄碱中间体ent-2m
在惰性气体氛围下，在氢化小瓶中，称取底物1m(1.1g,4.4mmol)溶于10.0毫升乙醇中，加入叔丁醇钾(4.8mmol,0.54g)，取[Ir(COD)Cl]2/配体ent-L1-3[(R)-f-phamidol)]的络合物溶液，1m和催化剂的摩尔比为5000/1，将氢化小瓶置于氢化釜中并密闭，先充入5个大气压氢气置换三次，然后充入40个大气压氢气，在30±5℃反应24小时。在通风橱中，小心释放釜中的氢气，取出氢化小瓶，并向反应液中加入稀盐酸(1mol/L)，调节pH至7±1，反应液快速过硅胶短柱除掉金属络合物和盐，所得的滤液浓缩得到氢化产物ent-2m，产率98％，99:1dr,99％ee。
实施例8克级规模合成间羟胺中间体ent-2k
在惰性气体氛围下，于氢化小瓶中，称取底物1k(1.0g,3.58mmol)溶于10.0毫升乙醇中，加入叔丁醇钾(3.94mmol,0.44g)，取[Ir(COD)Cl]2/配体ent-L1-3[(R)-f-phamidol)]的络合物溶液，1k和催化剂的摩尔比为1000/1，将氢化小瓶置于氢化釜中并密闭，先充入5个大气压氢气置换三次，然后充入40个大气压氢气，在30±5℃反应24小时。在通风橱中，小心释放釜中的氢气，取出氢化小瓶，并向反应液中加入稀盐酸(1mol/L)，调节pH至7±1，反应液快速过硅胶短柱除掉金属络合物和盐，所得的滤液浓缩得到氢化产物ent-2k，产率98％，94:6dr,98％ee。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

1.一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，反应式如下：
所述反应中，化合物氨基酮式(1)在合适的有机溶剂中，在手性催化剂、碱和氢气存在下进行的，经不对称催化氢化动态动力学拆分得到氨基醇产物式(2)或其衍生物恶唑烷酮式(3)；
其中，式(1)、式(2)和式(3)中，Ar1和Ar2基团分别独立表示芳基，包括苯基、不同位置取代的芳基，含氧、硫、氮的杂芳环；R表示C1-C6的直连或支链烷烃；PG表示氮的保护基，选自甲基、苄基、苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲(或乙)氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基。
2.根据权利要求1所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，所述手性催化剂由金属前体和手性配体络合得到，其中，金属选自钌、铑、铱，手性配体选自L1-L5：
其中，配体中的Ar基团表示为芳基，选自苯基、4-甲基苯基，3,5-二甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基4-甲氧基苯基；R1、R2分别独立为烷基、芳基；R3、R4独立为烷基、芳基或氢原子，R3和R4成环或不成环；R5表示烷基、芳基。
3.根据权利要求2所述的方法，其特征在于，所述的手性配体为：
中的至少一种。
4.根据权利要求1所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，所述溶剂自：甲醇、乙醇、异丙醇、三氟乙醇、四氢呋喃、二氯甲烷和甲苯的至少一种。
5.根据权利要求1所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，所述碱选自：叔丁醇钾、叔丁醇钠、叔丁醇锂、氢氧化钾、氢氧化钠、甲醇钾、甲醇钠、碳酸钠、碳酸钾和碳酸铯的至少一种。
6.根据权利要求1所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，所述反应温度范围为20至50℃，氢气的压力范围为5至60个大气压。
7.根据权利要求1所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，合成化合物氨基醇式(2)包含以下步骤：化合物氨基酮式(1)在合适的有机溶剂中，在手性催化剂、碱和氢气存在下进行反应，经不对称催化氢化动态动力学拆分得还原产物，反应完成后，往反应液中经加稀酸调节至pH＝7±1，然后快速过一个硅胶短柱，收集滤液并浓缩得1,2-反式氨基醇式(2)。
8.根据权利要求7所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，化合物氨基醇式(2)选自：
9.根据权利要求1所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，合成化合物恶唑烷酮式(3)包含以下步骤：化合物氨基酮式(1)在合适的有机溶剂中，在手性催化剂、碱和氢气存在下进行反应，经不对称催化氢化动态动力学拆分得还原产物，反应完成后，直接进行浓缩或者加热操作得到恶唑烷酮式(3)。
10.根据权利要求1-9所述的一种不对称合成1,2-反式氨基醇及其衍生物的方法，其特征在于，可用于麻黄碱中间体和间羟胺中间体的合成。
CN202311127876.8A 2023-09-04 2023-09-04 一种不对称合成1,2-反式氨基醇及其衍生物的方法 Pending CN117247337A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311127876.8A CN117247337A (zh) 2023-09-04 2023-09-04 一种不对称合成1,2-反式氨基醇及其衍生物的方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311127876.8A CN117247337A (zh) 2023-09-04 2023-09-04 一种不对称合成1,2-反式氨基醇及其衍生物的方法

Publications (1)

Publication Number Publication Date
CN117247337A true CN117247337A (zh) 2023-12-19

Family

ID=89130457

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311127876.8A Pending CN117247337A (zh) 2023-09-04 2023-09-04 一种不对称合成1,2-反式氨基醇及其衍生物的方法

Country Status (1)

Country Link
CN (1) CN117247337A (zh)

Similar Documents

Publication Publication Date Title
JP5041501B2 (ja) アミド化合物を配位子とする遷移金属錯体を用いたアルコールの製造方法
CN1964942A (zh) 通过分子内烯丙基化制备2－氧代－1－吡咯烷衍生物的方法
US11306097B2 (en) Activation of carbonyl beta-carbons for chemical transformations
EP2172443B1 (en) Method for producing optically active amine
Baxendale et al. Synthesis of nornicotine, nicotine and other functionalised derivatives using solid-supported reagents and scavengers
Zappia et al. Oxazolidin-2-one ring, a popular framework in synthetic organic chemistry part 2 [1]. applications and modifications
Destro et al. Reaction of azides and enolisable aldehydes under the catalysis of organic bases and Cinchona based quaternary ammonium salts
CN107382644B (zh) 一种手性叔醇或叔醚类化合物的制备方法及应用
CN117247337A (zh) 一种不对称合成1,2-反式氨基醇及其衍生物的方法
US11465135B2 (en) Bifunctional chiral organocatalytic compound having excellent enantioselectivity, preparation method therefor, and method for producing non-natural gamma-amino acid from nitro compound by using same
CN109456253B (zh) 一种手性诱导合成(s)-3-(4-溴苯基)-哌啶或其盐的方法
CN113354554B (zh) 一种(2R,3S)-β′-羟基-β-氨基酸酯类衍生物及其制备方法
Weseliński et al. The asymmetric organocatalytic 1, 3-dipolar cycloaddition of alkyl pyruvate-derived nitrones and α, β-unsaturated aldehydes
WO2020064818A1 (en) Process for the preparation of sphingosine-1-phosphate receptor agonist
JP3598277B2 (ja) エタンスルホニルピペリジン誘導体の製造方法
CN111793017B (zh) 一种内酰胺化合物的制备方法
CN111440205A (zh) 一种联硼酸二醇酯、其制备方法、其中间体及其应用
Ella-Menye et al. Synthesis of chiral 2-oxazolidinones, 2-oxazolines, and their analogs
Ruano et al. Remote stereocontrol by sulfinyl groups: asymmetric alkylation of chiral 2-p-tolylsulfinyl benzyl carbanions
CN111056925A (zh) 一种手性二醇类化合物、手性冠醚类化合物及其制备方法
US20110237803A1 (en) Process
CN110981808B (zh) 银与碱协同催化合成非对映2-咪唑啉酮类化合物的方法
US20070276145A1 (en) Method of Preparing a Ring Compound Having Two Adjacent Chiral Centers
CN110734430A (zh) 用于合成取代的γ内酰胺的方法
US9050586B2 (en) Enantioselective organic anhydride reactions

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination