CN114478467B - 一种氟代环己酮螺1，3-二氧六环手性衍生物及其制备方法 - Google Patents
一种氟代环己酮螺1，3-二氧六环手性衍生物及其制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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Abstract
本发明涉及药物化学技术领域，具体的说是一种氟代环己酮螺1，3‑二氧六环手性衍生物及其制备方法和用途，本发明公开了一种氟代环己酮螺1，3‑二氧六环手性衍生物，还提供了前述化合物的制备方法，包括以下步骤：将1.0eq的底物1、1.5eq的水杨醛2、1.5eq的氧化剂DQ、10mol％的添加剂Add、1.0eq的碱Cs2CO3和20mol％的催化剂C加入反应封管中，在氩气保护下加入干燥的1ml的乙醚，混合物在常温下反应8小时，反应完成后浓缩纯化得到目标产物3。该制备方法操作简便、反应温和、收率高。本发明提供的化合物具有优良的抗菌活性，具有广阔的市场应用前景。
Description
技术领域
本发明涉及药物化学技术领域，具体说是一种氟代环己酮螺1，3-二氧六环手性衍生物及其制备方法和用途。
背景技术
螺环化合物广泛存在于天然产物、合成药物中，相关研究表明含有该骨架的化合物具有多种重要的生物活性和药物活性，对此类化合物的取代基修饰、结构类似物的衍生化以及进一步生物学活性再评价成为了研究热点。将手性氟原子引入药物骨架是一种优秀的修饰手段，不仅可以增加药效，还能改变药物的各种物理化学性质，但相关化合物合成手段较少或条件较为苛刻。
如何简便的制备收率高的氟代螺环是目前的研究难点。
发明内容
针对现有技术中的问题，本发明提供了一种氟代环己酮螺1，3-二氧六环手性衍生物及其制备方法和用途。
本发明解决其技术问题所采用的技术方案是：一种氟代环己酮螺1，3-二氧六环手性衍生物，所述化合物的通式为：
优选的，所述化合物选自如下结构式之一：
一种氟代环己酮螺1，3-二氧六环手性衍生物的制备方法，该方法包括以下步骤：将1.0eq的底物1、1.5eq的水杨醛2、1.5eq的氧化剂DQ、10mol％的添加剂Add、1.0eq的碱Cs2CO3和20mol％的催化剂C加入反应封管中，在氩气保护下加入干燥的乙醚(1ml)，混合物在常温下反应8小时，反应完成后浓缩纯化得到目标产物3；
制备化合物的技术路线如下所示：
优选的，底物1的制备方法，具体包括以下步骤：
步骤一：在圆底烧瓶中，依次加入1eq的37％水溶液的甲醛、4eq的乙酰乙酸乙酯、2eq乙酸铵和溶剂水，圆底烧瓶装上回流装置并放置在86℃中搅拌3h，反应完成后，将混合物过滤，把黄色固体用少量冷水和冷丙酮冲洗，固体通过真空干燥得到亮黄色粉末产物汉斯酯；
步骤二：在圆底烧瓶中，加入1eq的1,3-环己二酮、1eq的汉斯酯、3eq的取代苯甲醛、0.05eq的L-脯氨酸和溶剂DCM，在常温下反应24h，TLC监测点板，反应完成后将反应液减压浓缩得棕色固体，用甲醇清洗后得到白色固体状中间体；
步骤三：将上步所得的1eq的白色固体状中间体与1eq的Selectfluor试剂在氩气下溶于乙腈中，并加热回流24h，TLC监测点板，反应完成后用EA稀释，分别用饱和NaHCO3、水、饱和NaCl溶液萃取，用无水MgSO4干燥，浓缩后过柱得取代的1,3-环己二酮底物；
制备底物1的技术路线如下所示：
R＝(卤素、烷烃)取代的苯环、C6的烷基和杂环，
本发明还提供了所述的化合物的成肟产物和有机锌试剂进攻羰基产物的制备方法，技术路线如下：
(1)氟代环己酮螺1，3-二氧六环手性衍生物的成肟反应
(3)氟代环己酮螺1，3-二氧六环手性衍生物的亲核加成反应
优选的，一种氟代环己酮螺1，3-二氧六环手性衍生物在用于抗菌的用途。
本发明提供了一类新的化合物，其具有良好的抗菌效果，化合物的制备方法简便、反应温和、收率高，具有广阔的市场应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
附图说明
图1实施例1产物的单晶结构。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施方式，进一步阐述本发明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
除特别标注外，本发明所用试剂和测试设备均为常规的市售试剂和设备。
实施例1
(2R,2'S)-2'-苄基-2'-氟-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率99％,ee 98％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.97(dd,J＝7.8,1.2Hz,1H),7.60–7.57(m,1H),7.26–7.21(m,5H),7.18(t,J＝7.2Hz,1H),6.97(d,J＝8.4Hz,1H),3.50(dd,J＝15.0,13.2Hz,1H),3.41(dd,J＝36.0,14.4Hz,1H),2.74–2.68(m,1H),2.58–2.52(m,1H),2.50–2.42(m,2H),2.01–1.94(m,1H),1.82–1.75(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.8(C-F,2JC-F＝21.6Hz),158.7,154.6,136.7,133.1,130.6,129.8,128.2,127.2,123.5,116.6,113.6,107.9(C-F,2JC-F＝21.6Hz),99.6(C-F,1JC-F＝198.3Hz),37.6,35.4(C-F,2JC-F＝21.6Hz),31.0,18.5.
实施例1产物的单晶数据(参见图1和下表)：
实施例2
(2R,2'S)-2'-苄基-2'-氟-8-甲基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用3-甲基水杨醛).
白色固体，产率98％,ee 99％,dr 93:7；
1H NMR(600MHz,CDCl3)δ(ppm):7.81(dd,J＝7.8,1.2Hz,1H),7.44(d,J＝7.2Hz,1H),7.30–7.20(m,5H),7.08(t,J＝7.2Hz,1H),3.52–3.41(m,2H),2.76–2.70(m,1H),2.57–2.51(m,1H),2.48–2.41(m,2H),2.24(s,3H),2.00–1.93(m,1H),1.74–1.67(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝20.1Hz),159.0,152.6,137.8,133.2,130.7,128.2,127.4,127.1,126.2,122.9,113.2,107.8(C-F,2JC-F＝23.0Hz),99.2(C-F,1JC-F＝195.3Hz),37.6,34.8(C-F,2JC-F＝20.1Hz),30.5,18.8,14.8.
实施例3
(2R,2'S)-2'-苄基-2'-氟-8-溴-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用3-溴水杨醛).
白色固体，产率95％,ee 92％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.92(dd,J＝7.2,1.2Hz,1H),7.80(dd,J＝8.4,1.8Hz,1H),7.27–7.21(m,5H),7.08(t,J＝7.8Hz,1H),3.55(dd,J＝15.0,12.6Hz,1H),3.44(dd,J＝37.2,15.6Hz,1H),2.70–2.64(m,1H),2.62–2.57(m,1H),2.53–2.45(m,2H),2.05–1.98(m,1H),1.93–1.86(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.0(C-F,2JC-F＝20.1Hz),157.8,151.9,139.7,132.6,130.4,128.9,128.3,127.4,124.2,115.1,110.1,108.6(C-F,2J C-F＝20.1Hz),100.2(C-F,1JC-F＝199.7Hz),37.7,36.4(C-F,2JC-F＝21.6Hz),31.9,18.2.
实施例4
(2R,2'S)-2'-苄基-2'-氟-8-甲氧基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用3-甲氧基水杨醛).
白色固体，产率91％,ee 95％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.54(dd,J＝7.8,1.2Hz,1H),7.25–7.21(m,5H),7.26–7.21(m,5H),7.17(dd,J＝8.4,1.2Hz,1H),7.10(t,J＝7.2Hz,1H),3,90(s,3H),3.53(dd,J＝15.0,12.6Hz,1H),3.42(dd,J＝37.2,15.0Hz,1H),2.69–2.63(m,1H),2.59–2.54(m,1H),2.49–2.44(m,2H),2.02–1.95(m,1H),1.87–1.81(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.5(C-F,2JC-F＝20.1Hz),158.7,147.9,144.5,133.0,130.5,128.3,127.2,123.0,120.6,118.2,114.6,108.1(C-F,2JC-F＝20.1Hz),100.2(C-F,1JC-F＝198.2Hz),56.3,37.9,36.2(C-F,2JC-F＝21.6Hz),31.6,18.3.
实施例5
(2R,2'S)-2'-苄基-2'-氟-8-氯-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用3-氯水杨醛).
白色固体，产率90％,ee 80％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.88(dd,J＝7.8,1.2Hz,1H),7.65(dd,J＝8.4,1.2Hz,1H),7.27–7.21(m,5H),7.13(t,J＝7.8,1H),3.54(dd,J＝15.0,13.2Hz,1H),3.42(dd,J＝37.2,15.6Hz,1H),2.69–2.64(m,1H),2.62–2.57(m,1H),2.53–2.46(m,2H),2.06–1.98(m,1H),1.92–1.86(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.0(C-F,2JC-F＝20.1Hz),157.8,150.9,136.6,132.6,130.4,128.3,128.1,127.4,123.6,121.7,115.2,108.6(C-F,2JC-F＝20.1Hz),100.3(C-F,1JC-F＝199.7Hz),37.8,36.5(C-F,2JC-F＝21.5Hz),32.0,18.2.
实施例6
(2R,2'S)-2'-苄基-2'-氟-8-氟-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用3-氟水杨醛).
白色固体，产率92％,ee 94％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.74(d,J＝7.8,1H),7.41–7.38(m,1H),7.26–7.20(m,5H),7.13–7.10(m,1H),3.52(t,J＝14.4Hz,1H),3.40(dd,J＝36.6,15.0Hz,1H),2.66–2.57(m,2H),2.54–2.50(m,2H),2.05–1.97(m,1H),1.92–1.86(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):199.9(C-F,2JC-F＝18.6Hz),157.5,150.1(C-F,1JC-F＝248.6Hz),143.1(C-F,2JC-F＝12.9Hz),132.4,130.2,128.3,127.4,124.7(C-F,3JC-F＝4.4Hz),123.0(C-F,3JC-F＝2.9Hz),122.9,115.6,108.6(C-F,2JC-F＝18.6Hz),100.5(C-F,1JC-F＝199.7Hz),37.8,36.7(C-F,2JC-F＝21.5Hz),32.1,18.1.
实施例7
(2R,2'S)-2'-苄基-2'-氟-7-甲基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使4-甲基水杨醛).
白色固体，产率92％,ee 98％,dr 83:17；
1H NMR(600MHz,CDCl3)δ(ppm):7.82–7.81(m,1H),7.45(d,J＝7.2Hz,1H),7.30–7.21(m,5H),7.08(t,J＝8.4Hz,1H),3.52–3.41(m,2H),2.77–2.71(m,1H),2.57–2.51(m,1H),2.48–2.41(m,2H),2.24(s,1H),2.00–1.93(m,1H),1.74–1.67(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):201.1(C-F,2JC-F＝20.1Hz),158.9,154.7,148.6,133.3,130.9,129.7,128.3,127.2,124.8,117.0,111.0,107.9(C-F,2JC-F＝21.6Hz),99.5(C-F,1JC-F＝196.8Hz),37.7,35.1(C-F,2JC-F＝20.3Hz),30.9,22.1,18.9.
实施例8
(2R,2'S)-2'-苄基-2'-氟-7-溴-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用4-溴水杨醛).
白色固体，产率89％,ee 97％,dr 90:10；
1H NMR(600MHz,CDCl3)δ(ppm):7.80(d,J＝8.4,1H),7.30(dd,J＝8.4,2.4Hz,1H),7.28–7.22(m,5H),7.09(d,J＝1.2Hz,1H),3.46(t,J＝15.0Hz,1H),3.36(dd,J＝34.8,15.0Hz,1H),2.70–2.65(m,1H),2.58–2.53(m,1H),2.51–2.42(m,2H),2.04–1.97(m,1H),1.87–1.81(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.3(C-F,2JC-F＝20.1Hz),158.0,155.0,132.7,130.9,130.7,130.5,128.3,127.4,127.0,119.8,112.4,108.3(C-F,2J C-F＝21.5Hz),100.1(C-F,1JC-F＝198.2Hz),37.6,36.1(C-F,2JC-F＝20.1Hz),31.7,18.2.
实施例9
(2R,2'S)-2'-苄基-2'-氟-7-甲氧基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用4-甲氧水杨醛).
白色固体，产率91％,ee 96％,dr 86:14；
1H NMR(600MHz,CDCl3)δ(ppm):7.88(d,J＝8.4,1H),7.30–7.21(m,5H),6.70(dd,J＝9.0,2.4Hz,1H),6.43(d,J＝2.4Hz,1H),3.86(s,3H),3.52–3.48(m,1H),3.40(dd,J＝36.6,15.6Hz,1H),2.76–2.70(m,1H),2.55–2.50(m,1H),2.47–2.43(m,2H),2.00–1.93(m,1H),1.79–1.72(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):201.1(C-F,2JC-F＝20.1Hz),166.5,158.6,133.3,131.4,130.8,128.2,127.1,111.0,107.9(C-F,2JC-F＝23.0Hz),106.0,100.9,99.2(C-F,1JC-F＝196.8Hz),55.9,37.6,34.8(C-F,2JC-F＝21.5Hz),30.5,18.7.
实施例10
(2R,2'S)-2'-苄基-2'-氟-7-氯-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用4-氯水杨醛).
白色固体，产率93％,ee 90％,dr 91:9；
1H NMR(600MHz,CDCl3)δ(ppm):7.88(d,J＝9.0Hz,1H),7.28–7.23(m,5H),7.18(dd,J＝8.4,1.8Hz,1H),6.93(d,J＝1.8Hz,1H),3.47(t,J＝14.4Hz,1H),3.36(dd,J＝34.8,15.0Hz,1H),2.71–2.66(m,1H),2.58
–2.53(m,1H),2.52–2.43(m,2H),2.05–1.97(m,1H),1.87–1.81(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.3(C-F,2JC-F＝20.1Hz),157.9,155.1,142.5,132.7,130.7,130.5,128.3,127.4,124.1,116.9,112.0,108.3(C-F,2J C-F＝21.6Hz),100.1(C-F,1JC-F＝199.7Hz),37.6,36.1(C-F,2JC-F＝21.5Hz),31.7,18.2.
实施例11
(2R,2'S)-2'-苄基-2'-氟-6-氟-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用5-氟水杨醛).
白色固体，产率96％,ee 91％,dr 88:12；
1H NMR(600MHz,CDCl3)δ(ppm):7.86(d,J＝2.4Hz,1H),7.65(d,J＝3.0Hz,1H),7.28–7.23(m,4H),7.20(d,J＝7.8Hz,2H),3.50(t,J＝14.4Hz,1H),3.40(dd,J＝37.2,14.4Hz,1H),2.68–2.58(m,2H),2.53–2.47
(m,2H),2.07–2.00(m,1H),1.91–1.88(m,2H).
13C NMR(151MHz,CDCl3)δ(ppm):199.6(C-F,2JC-F＝18.9Hz),156.7,149.6,136.2,132.2,130.2,128.7,128.4,127.7,127.6,122.6,115.8,108.9(C-F,2J C-F＝20.1Hz),100.7(C-F,1JC-F＝201.0Hz),37.8,36.9(C-F,2JC-F＝21.5Hz),32.4,18.1.
实施例12
(2R,2'S)-2'-苄基-2'-氟-6-甲基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用5-甲基水杨醛).
白色固体，产率90％,ee 96％,dr 88:12；
1H NMR(600MHz,CDCl3)δ(ppm):7.76(d,J＝2.4Hz,1H),7.38(dd,J＝8.4,1.8Hz,1H),7.28–7.21(m,5H),6.87(d,J＝8.4Hz,1H),3.52–3.47(m,1H),3.40(dd,J＝36.0,15.0Hz,1H),2.74–2.68(m,1H),2.55–2.50(m,1H),2.48–2.41(m,2H),2.35(s,3H),1.99–1.92(m,1H),1.79–1.72(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝20.3Hz),159.0,152.5,137.5,133.3,133.2,130.7,129.6,128.2,127.1,116.4,113.3,107.8(C-F,2J C-F＝21.6Hz),99.4(C-F,1JC-F＝196.8Hz),37.6,35.1(C-F,2JC-F＝21.5Hz),30.8,20.5,18.5.
实施例13
(2R,2'S)-2'-苄基-2'-氟-6-甲氧基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用5-甲氧基水杨醛).
白色固体，产率88％,ee 93％,dr 80:20；
1H NMR(600MHz,CDCl3)δ(ppm):7.41(d,J＝3.0Hz,1H),7.28–7.22(m,5H),7.15(dd,J＝9.0,2.4Hz,1H),6.90(d,J＝9.0Hz,1H),3.83(s,3H),3.49(dd,J＝15.6,13.2Hz,1H),3.40(dd,J＝36.0,15.0Hz,1H),2.75–2.69(m,1H),2.56–2.50(m,1H),2.48–2.41(m,2H),1.99–1.93(m,1H),1.792–1.72(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝20.3Hz),159.0,152.5,137.5,133.3,133.2,130.7,129.6,128.2,127.1,116.4,113.3,107.8(C-F,2JC-F＝21.6Hz),99.4(C-F,1JC-F＝196.8Hz),37.6,35.1(C-F,2JC-F＝21.6Hz),30.8,20.5,18.5.
实施例14
(2R,2'S)-2'-苄基-2'-氟-6-溴-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用5-溴水杨醛).
白色固体，产率87％,ee 93％,dr 80:20；
1H NMR(600MHz,CDCl3)δ(ppm):8.07(d,J＝2.4Hz,1H),7.66(dd,J＝9.0,3.0Hz,1H),7.27–7.22(m,5H),6.84(d,J＝8.4Hz,1H),3.46(t,J＝9.0Hz,1H),3.37(dd,J＝35.4,15.6Hz,1H),2.71–2.66(m,1H),2.58–2.53(m,1H),2.51–2.42(m,2H),2.03–1.96(m,1H),1.85–1.78(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.3(C-F,2JC-F＝20.1Hz),157.4,153.7,139.4,132.7,132.2,130.5,128.3,127.3,118.4,115.8,115.0,108.2(C-F,2J C-F＝21.6Hz),100.0(C-F,1JC-F＝199.7Hz),37.6,36.0(C-F,2JC-F＝21.5Hz),31.5,18.2.
实施例15
(2R,2'S)-2'-苄基-2'-氟-6-氯-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用5氯水杨醛)
白色固体，产率93％,ee 95％,dr 86:14；
1H NMR(600MHz,CDCl3)δ(ppm):7.92(d,J＝1.8Hz,1H),7.51(dd,J＝9.0,3.0Hz,1H),7.27–7.22(m,5H),6.90(d,J＝8.4Hz,1H),3.46(t,J＝14.4Hz,1H),3.37(dd,J＝36.0,15.0Hz,1H),2.71–2.66(m,1H),2.58–2.53(m,1H),2.51–2.42(m,2H),2.03–1.96(m,1H),1.85–1.79(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.3(C-F,2JC-F＝20.1Hz),157.6,153.2,136.5,132.7,130.5,129.2,128.8,128.3,127.3,118.0,114.6,108.2(C-F,2J C-F＝21.5Hz),100.0(C-F,1JC-F＝199.7Hz),37.6,36.0(C-F,2JC-F＝21.5Hz),31.5,18.3.
实施例16
(2R,2'S)-2'-氟-2'-(2-甲基苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物使用水杨醛)
白色固体，产率98％,ee 97％,dr 90:10；
1H NMR(600MHz,CDCl3)δ(ppm):7.97(dd,J＝7.2,1.2Hz,1H),7.60–7.57(m,1H),7.22(d,J＝7.2Hz,1H),7.18(t,J＝7.8Hz,1H),7.13(d,J＝4.2Hz,2H),7.10–7.07(m,1H),7.00(d,J＝8.4Hz,1H),3.60(dd,J＝15.0,9.6Hz,1H),3.44(dd,J＝34.2,15.0Hz,1H),2.81–2.75(m,1H),2.57–2.51(m,2H),2.48–2.43(m,1H),2.30(s,3H),2.02–1.95(m,1H),1.81–1.74(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):201.1(C-F,2JC-F＝20.1Hz),158.6,154.6,138.2,136.6,131.7,131.0,130.4,129.8,127.2,125.6,123.5,116.6,113.7,108.0(C-F,2JC-F＝23.0Hz),100.0(C-F,1JC-F＝196.8Hz),37.4,31.2(C-F,2JC-F＝20.1Hz),30.7,20.0(C-F,3JC-F＝2.9Hz),18.5.
实施例17
(2R,2'S)-2'-氟-2'-(2-甲氧基苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物使用水杨醛)
白色固体，产率99％,ee 94％,dr 90:10；
1H NMR(600MHz,CDCl3)δ(ppm):7.93(dd,J＝8.4,2.4Hz,1H),7.58–7.55(m,1H),7.22–7.19(m,1H),7.14(t,J＝7.2Hz,1H),7.08(d,J＝7.8Hz,1H),6.96(d,J＝8.4Hz,1H),6.85–6.80(m,2H),3.73(s,3H),3.58
(dd,J＝33.6,14.4Hz,1H),3.40(t,J＝14.4Hz,1H),2.90–2.84(m,1H),2.61–2.57(m,2H),2.48–2.43(m,1H),2.10–2.02(m,1H),1.96–1.91(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.6(C-F,2JC-F＝15.8Hz),158.8,157.1,155.2,136.3,132.7,129.5,128.8,123.1,120.9,120.6,116.1,113.6,110.3,108.0(C-F,2JC-F＝18.6Hz),100.7(C-F,1JC-F＝203.9Hz),55.0,37.2,32.8,31.4(C-F,2JC-F＝23.0Hz),17.7.
实施例18
(2R,2'S)-2'-氟-2'-(2-溴苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物使用水杨醛)
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白色固体，产率99％,ee 96％,dr 94:6；
1H NMR(600MHz,CDCl3)δ(ppm):7.95(dd,J＝8.4,2.4Hz,1H),7.57–7.55(m,1H),7.52(dd,J＝8.4,1.8Hz,1H),7.34(d,J＝7.8Hz,1H),7.21–7.14(m,2H),7.08(td,J＝7.8,1.2Hz,1H),6.95(d,J＝8.4Hz,1H),3.77–3.67(m,2H),2.68–2.66(m,2H),2.60–2.55(m,1H),2.53–2.48(m,1H),2.05–1.968(m,1H),1.89–1.828(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.7(C-F,2JC-F＝18.6Hz),158.5,154.8,136.5,133.0,132.9,132.3(C-F,3JC-F＝2.9Hz),129.7,128.9,127.4,125.5,123.4,116.5,113.6,107.9(C-F,2JC-F＝20.1Hz),99.9(C-F,1JC-F＝201.2Hz),37.4,35.1(C-F,2JC-F＝20.1Hz),31.6,18.1.
实施例19
(2R,2'S)-2'-氟-2'-(3-甲基苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物使用水杨醛)
白色固体，产率86％,ee 96％,dr 91:9；
1H NMR(600MHz,CDCl3)δ(ppm):7.97(dd,J＝7.8,1.2Hz,1H),7.58(td,J＝7.8,2.4Hz,1H),7.19–7.13(m,2H),7.06–7.03(m,3H),6.97(d,J＝8.4Hz,1H),3.60(t,J＝14.4Hz,1H),3.37(dd,J＝36.6,15.6Hz,1H),2.73–2.67(m,1H),2.58–2.53(m,1H),2.50–2.42(m,2H),2.29(s,3H),2.02–1.95(m,1H),1.831–1.77(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.7(C-F,2JC-F＝20.1Hz),158.76,154.7,137.8,136.6,132.8,131.3,129.7,128.1,128.0,127.5,123.4,116.5,113.6,107.9(C-F,2JC-F＝21.5Hz),99.8(C-F,1JC-F＝1986.2Hz),37.7,35.5(C-F,2JC-F＝21.6Hz),31.2,21.3,18.4.19F NMR(564MHz,CDCl3,40℃)δ(ppm):-112.3.
实施例20
(2R,2'S)-2'-氟-2'-(3-氯苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物使用水杨醛)
白色固体，产率92％,ee 97％,dr 90:10；
1H NMR(600MHz,CDCl3)δ(ppm):7.99–7.97(m,1H),7.61–7.59(m,1H),7.30(s,1H),7.22–7.18(m,4H),6.98(d,J＝7.8Hz,1H),3.49–3.37(m,2H),2.79–2.73(m,1H),2.56–2.50(m,1H),2.48–2.42(m,2H),1.99–1.93(m,1H),1.77–1.70(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.8(C-F,2JC-F＝21.6Hz),158.5,154.4,136.8,135.3,133.9,130.9,129.9,129.3,129.1,127.3,123.7,116.7,113.6,107.7(C-F,2JC-F＝22.3Hz),98.6(C-F,1JC-F＝195.3Hz),37.4,34.0(C-F,2JC-F＝20.1Hz),30.2,18.6.
实施例21
(2R,2'S)-2'-氟-2'-(3-氟苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率99％,ee 96％,dr 87:13；
1H NMR(600MHz,CDCl3)δ(ppm):7.83(dd,J＝7.8,1.2Hz,1H),7.60(t,J＝7.8Hz,1H),7.23–7.18(m,2H),7.06(d,J＝7.2Hz,1H),7.02(d,J＝10.2Hz,1H),6.98(d,J＝7.8Hz,1H),6.92(t,J＝9.0Hz,1H),3.51–3.38(m,2H),2.78–2.72(m,1H),2.56–2.51(m,1H),2.49–2.44(m,2H),1.99–1.93(m,1H),1.78–1.73(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.8(C-F,2JC-F＝21.6Hz),162.5(C-F,1JC-F＝244.2Hz),158.6,154.4,136.8,135.7(C-F,3JC-F＝17.2Hz),129.9,129.5(C-F,3JC-F＝8.6Hz),126.5,123.7,117.8(C-F,2JC-F＝21.5Hz),116.7,114.0
(C-F,2JC-F＝21.6Hz),113.6,107.7(C-F,2JC-F＝21.5Hz),98.8(C-F,1JC-F＝195.3Hz),37.4,34.3(C-F,2JC-F＝21.6Hz),30.4,18.6.
实施例22
(2R,2'S)-2'-氟-2'-(3-甲氧基苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率99％,ee 97％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.98–7.96(m,1H),7.60–7.57(m,1H),7.19–7.16(m,2H),6.97(d,J＝8.4Hz,1H),6.86–6.77(m,3H),3.75(d,J＝3.0Hz,3H),3.48(t,J＝14.4Hz,1H),3.39(dd,J＝36.0,14.4Hz,1H),2.72–2.70(m,1H),2.57–2.52(m,1H),2.50–2.42(m,2H),2.00–1.95(m,1H),1.82–1.77(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.7(C-F,2JC-F＝21.5Hz),159.3,158.7,154.6,136.7,134.5,129.8,129.1,123.5,122.9,116.6,116.3,113.6,112.7,107.9(C-F,2JC-F＝21.6Hz),99.6(C-F,1JC-F＝198.2Hz),55.1,37.6,35.5(C-F,2JC-F＝20.1Hz),31.1,18.5.
实施例23
(2R,2'S)-2'-氟-2'-(3-溴苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率86％,ee 96％,dr 87:13；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝7.8,1.8Hz,1H),7.62–7.59(m,1H),7.46(s,1H),7.36(d,J＝8.4H,1H),7.24(d,J＝7.2Hz,1H),7.20(t,J＝7.8Hz,1H),7.13(t,J＝7.2Hz,1H),6.97(d,J＝8.4Hz,1H),3.48–3.36(m,2H),2.80–2.74(m,1H),2.55–2.51(m,1H),2.50–2.42(m,2H),1.98–1.93(m,1H),1.75–1.70(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.8(C-F,2JC-F＝22.3Hz),158.5,154.3,136.8,135.6,133.8,130.2,129.9,129.6,129.5,123.7,122.1,116.7,113.6,107.7(C-F,2JC-F＝23.0Hz),98.6(C-F,1JC-F＝194.0Hz),37.4,33.4(C-F,2JC-F＝21.5Hz),30.2,18.6.
实施例24
(2R,2'S)-2'-氟-2'-(4-氯苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率96％,ee 96％,dr 90:10；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝7.2,1.8Hz,1H),7.61–7.58(m,1H),7.23–7.18(m,5H),6.98(d,J＝8.4Hz,1H),3.48–3.36(m,2H),2.77–2.71(m,1H),2.56–2.50(m,1H),2.47–2.42(m,2H),1.99–1.92(m,1H),1.76–1.70(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝21.6Hz),158.6,154.4,136.8,133.1,132.2,131.8,129.9,128.3,123.7,116.7,113.6,107.7(C-F,2JC-F＝23.0Hz),98.7(C-F,1JC-F＝195.5Hz),37.4,33.8(C-F,2JC-F＝21.6Hz),30.3,18.6.
实施例25
(2R,2'S)-2'-氟-2'-(4-氟苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率90％,ee 96％,dr 92:8；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝8.4,1.8Hz,1H),7.61–7.58(m,1H),7.26–7.24(m,2H),7.19(t,J＝7.8Hz,1H),6.98(d,J＝8.4Hz,1H),6.94(t,J＝8,4Hz,2H),3.49–3.36(m,2H),2.77–2.71(m,1H),2.56–2.51(m,1H),2.47–2.42(m,2H),1.99–1.93(m,1H),1.78–1.71(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝21.5Hz),162.0(C-F,1JC-F＝244.1Hz),158.6,154.5,136.8,132.3(C-F,3JC-F＝7.2Hz),129.9,128.9,123.6,116.7,115.0(C-F,2JC-F＝20.1Hz),113.6,107.8(C-F,2JC-F＝21.5Hz),98.9(C-F,1JC-F＝195.3Hz),37.5,33.9(C-F,2JC-F＝20.1Hz),30.5,18.6.
实施例26
(2R,2'S)-2'-氟-2'-(4-溴苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率96％,ee 96％,dr 90:10；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝8.4,2.4Hz,1H),7.62–7.59(m,1H),7.38(d,J＝8.4H,2H),7.21–7.17(m,3H),6.98(d,J＝7.8Hz,1H),3.47–3.35(m,2H),2.78–2.72(m,1H),2.56–2.50(m,1H),2.46–2.42(m,2H),1.99–1.92(m,1H),1.76–1.69(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝22.3Hz),158.6,154.4,136.8,132.6,132.3,131.2,129.9,123.7,121.2,116.7,113.6,107.7(C-F,2J C-F＝23.1Hz),98.6(C-F,1JC-F＝195.3Hz),37.4,33.8(C-F,2JC-F＝20.1Hz),30.2,18.6.
实施例27
(2R,2'S)-2'-氟-2'-(4-甲基苄基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率99％,ee 98％,dr 93:7；
1H NMR(600MHz,CDCl3)δ(ppm):7.84(d,J＝8.4Hz,1H),7.28–7.22(m,5H),6.98(d,J＝8.4Hz,1H),6.78(s,1H),3.52–2.36(m,2H),2.74–2.69(m,1H),2.55–2.50(m,1H),2.47–2.42(m,2H),2.40(s,3H),1.99–1.93(m,1H),1.79–1.73(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝20.1Hz),158.8,154.6,148.5,133.2,130.7,129.60,128.2,127.1,124.6,116.8,110.9,107.8(C-F,2JC-F＝21.6Hz),99.3(C-F,1JC-F＝196.8Hz),37.6,35.0(C-F,2JC-F＝20.1Hz),30.7,22.0,18.6.
实施例28
(2R,2'S)-2'-氟-2'-(环己基甲基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率97％,ee 96％,dr 88:12；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝7.2,1.8Hz,1H),7.61–7.58(m,1H),7.23–7.18(m,5H),6.98(d,J＝8.4Hz,1H),3.48–3.36(m,2H),2.77–2.71(m,1H),2.56–2.50(m,1H),2.47–2.42(m,2H),1.99–1.92(m,1H),1.76–1.70(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.9(C-F,2JC-F＝21.6Hz),158.6,154.4,136.8,133.1,132.2,131.8,129.9,128.3,123.7,116.7,113.6,107.7(C-F,2JC-F＝23.0Hz),98.7(C-F,1JC-F＝195.5Hz),37.4,33.8(C-F,2JC-F＝21.6Hz),30.3,18.6.
实施例29
(2R,2'S)-2'-氟-2'-(萘-1-甲基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率99％,ee 99％,dr 95:5；
1H NMR(600MHz,CDCl3)δ(ppm):8.11(d,J＝8.4Hz,1H),8.00(dd,J＝7.2,1.2Hz,1H),7.82(d,J＝7.8Hz,1H),7.76(d,J＝8.4Hz,1H),7.64–7.61(m,1H),7.54(d,J＝6.6Hz,1H),7.49–7.44(m,2H),7.38(t,J＝7.8Hz,1H),7.21(t,J＝7.2Hz,1H),7.05(d,J＝8.4Hz,1H),4.10(dd,J＝15.0,9.0Hz,1H),3.86(dd,J＝33.6,15.0Hz,1H),2.78–2.73(m,1H),2.58–2.49(m,3H),1.98–1.92(m,1H),1.77–1.70(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):201.2(C-F,2JC-F＝23.0Hz),158.6,154.5,136.7,133.7,129.9,129.8,129.3,128.5,128.0,126.0,125.4,125.1,124.5(C-F,3JC-F＝2.9Hz),123.7,116.8,113.8,108.3(C-F,2JC-F＝24.5Hz),99.4(C-F,1JC-F＝195.3Hz),37.3,30.2,30.1,18.7.
实施例30
(2R,2'S)-2'-氟-2'-(噻吩-1-甲基)-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-3',4-二酮(合成底物时使用水杨醛)
白色固体，产率80％,ee 97％,dr 85:15；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝8.4,1.8Hz,1H),7.61–7.58(m,1H),7.21–7.17(m,2H),6.99(d,J＝8.4Hz,1H),6.95–6.91(m,2H),3.75–3.65(m,2H),2.81–2.75(m,1H),2.57–2.47(m,2H),2.45–2.41(m,1H),1.99–1.93(m,1H),1.78–1.71(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):200.6(C-F,2JC-F＝21.6Hz),158.5,154.4,136.8,134.1,129.9,128.4,126.8,125.3,123.7,116.7,113.6,107.7(C-F,2JC-F＝21.5Hz),98.4(C-F,1JC-F＝196.7Hz),37.4,30.5,29.3,18.6.
实施例31
实施例1的成肟反应：
将实施例1(0.1mmol)和盐酸羟胺(1.5eq)加入反应封管，在氩气保护下加入1毫升吡啶做溶剂，在常温下反应1h，使用薄层色谱监测反应，待反应完成后，用饱和食盐水萃取反应液3次，再将有机相液旋干，使用柱层析纯化，使用石油醚：乙酸乙酯＝8：1分离得到产物。
(2R,2'S)-2'-氟-2'-苄基-3'-羟基亚胺基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-4-酮
无色透明油状，产率95％,ee 96％，dr>19:1；
1H NMR(600MHz,CDCl3)δ(ppm):7.98(dd,J＝7.8,1.8Hz,1H),7.77(s,1H),7.60–7.57(m,1H),7.30(d,J＝7.8Hz,2H),7.26–7.16(m,4H),7.01(d,J＝7.8Hz,1H),3.59–3.41(m,2H),2.90–2.88(m,1H),2.44–2.30(m,3H),1.80–1.74(m,1H),1.60–1.54(m,1H).
13C NMR(151MHz,CDCl3)δ(ppm):159.3,154.7,154.6(C-F,2JC-F＝21.6Hz),136.6,134.7,131.2,129.8,127.8,126.5,123.3,116.9,113.7,106.9(C-F,2J C-F＝24.3Hz),95.9(C-F,1JC-F＝188.1Hz),34.7(C-F,2JC-F＝20.1Hz),30.2,20.6,19.2.
实施例32
实施例1的有机锌试剂亲核进攻反应：
将锌粉(1.5eq)、烯丙基溴(1.5eq)加入反应封管，在氩气保护下加入四氢呋喃做溶剂，在60℃下反应30min，再在0℃下加入实施例1，反应10min，使用薄层色谱监测反应，待反应完成后，用饱和食盐水萃取反应液3次，再将有机相液旋干，使用柱层析纯化，使用石油醚：乙酸乙酯＝8：1分离得到产物。
(2R,2'S)-3'-allyl-2'-benzyl-2'-fluoro-3'-hydroxy-4H-spiro[benzo[d][1,3]di oxine-2,1'-cyclohexan]-4-one(2R,2'S)-2'-氟-2'-苄基-3'-羟基-3'-烯丙基-4H-螺[苯并[1,3]二氧-2,1'-环己烷]-4-酮
无色透明油状，产率90％,ee 97％,dr>19:1；
1H NMR(600MHz,CDCl3)δ(ppm):7.95(dd,J＝8.4,1.8Hz,1H),7.62–7.59(m,1H),7.32(d,J＝8.4Hz,2H),7.24(t,J＝7.2Hz,2H),7.20–7.18(m,2H),6.98(d,J＝8.4Hz,1H),5.91–5.84(m,1H),5.15–5.08(m,2H),3.65–3.48(m,2H),2.96(s,1H),2.64–2.61(m,1H),2.41–2.37(m,1H),2.29–2.23(m,1H),2.11–2.05(m,1H),1.77–1.74(m,2H),1.62–1.56(m,2H).
13C NMR(151MHz,CDCl3)δ(ppm):158.5,153.8,136.6,136.1(C-F,3JC-F＝4.4Hz),132.9,131.0,129.9,127.9,126.3,123.7,118.8,116.9,113.9,107.9(C-F,2JC-F＝25.8Hz),76.2(C-F,2JC-F＝24.5Hz),40.7,33.9,29.3(C-F,2JC-F＝20.1Hz),32.0,29.5,16.4.
氟代环己酮螺1，3-二氧六环手性衍生物抑菌活性测试：
1.实验目的：
采用琼脂平皿二倍稀释法，测定受试化合物(化合物31和化合物32)对近2-3年成都地区医院收集的临床分离致病菌(包括耐甲氧西林金黄色葡萄球菌(MRSA)、甲氧西林敏感金黄色葡萄球菌(MSSA)、耐甲氧西林表皮葡萄球菌(MRSE)、甲氧西林敏感表皮葡萄球菌(MSSE)革兰阳性菌以及肺炎克雷伯(ESBLs+)、肺炎克雷伯(ESBLs-)、大肠埃希菌(ESBLs+)、大肠埃希菌(ESBLs-)等革兰阴性菌各4株左右，共计36株左右)的MIC值。
2.实验依据：
采取美国国家临床实验室标准化委员会(Clinical and Laboratory StandardsInstitute CLSI)推荐的琼脂二倍稀释法，进行最低抑菌浓度(MIC)的测定。
3.实验方法：
于无菌平皿内加入1ml供试药液，再加入融化的50℃MHA培养基14ml，混匀，使其每皿内所含药物终浓度依次为128、64、32、16、8、4、2、1、0.5、μg/ml；待冷却后用多点接种仪接种细菌，接种菌量约为104CFU/ml，盖上皿盖，放在培养箱中，36±1℃，孵育20-24h。培养结束后，进行肉眼观察，平皿内未见细菌生长的最低样品浓度即为其最低抑菌浓度(MIC)。同时设立不加任何样品的空白菌对照。
4.实验结果：化合物31对耐甲氧西林表皮葡萄球菌(MRSE)的MIC值为128ug/ml。对其显示活性；化合物32对耐甲氧西林表皮葡萄球菌(MRSE)的MIC值为64ug/ml。对其显示活性。
本发明制得的化合物能够有效抑制耐甲氧西林表皮葡萄球菌(MRSE)，具有良好的抗菌活性。对于其他化合物也一样具有抗菌的作用，实验方法和最终的效果都是一样的，为了减少重复的内容，故不再逐一列举其他化合物的实验内容。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (2)
1.一种氟代环己酮螺1，3-二氧六环手性衍生物，其特征在于：所述化合物的通式为：
或/>。
2.根据权利要求1所述的一种氟代环己酮螺1，3-二氧六环手性衍生物的制备方法，其特征在于：该方法包括以下步骤：将1.0 eq的底物1、1.5 eq的水杨醛2、1.5 eq的氧化剂DQ、10 mol %的添加剂Add、1.0 eq的碱Cs2CO3和20 mol %的催化剂C加入反应封管中，在氩气保护下加入干燥的1ml的乙醚，混合物在常温下反应8小时，反应完成后浓缩纯化得到目标产物3；
制备化合物的技术路线如下所示：
；
底物1的制备方法，具体包括以下步骤：
步骤一：在圆底烧瓶中，依次加入1 eq的37 % 水溶液的甲醛、4 eq的乙酰乙酸乙酯、2eq乙酸铵和溶剂水，圆底烧瓶装上回流装置并放置在86 ºC中搅拌3 h，反应完成后，将混合物过滤，把黄色固体用少量冷水和冷丙酮冲洗，固体通过真空干燥得到亮黄色粉末产物汉斯酯；
步骤二：在圆底烧瓶中，加入1 eq的1,3-环己二酮、1 eq的汉斯酯、3 eq的取代苯甲醛、0.05 eq的L - 脯氨酸和溶剂DCM，在常温下反应24 h，TLC监测点板，反应完成后将反应液减压浓缩得棕色固体，用甲醇清洗后得到白色固体状中间体；
步骤三：将上步所得的1 eq的白色固体状中间体与1 eq的Selectfluor试剂在氩气下溶于乙腈中，并加热回流24 h，TLC监测点板，反应完成后用EA稀释，分别用饱和NaHCO3、水、饱和NaCl溶液萃取，用无水MgSO4干燥，浓缩后过柱得取代的1,3-环己二酮底物；
制备底物1的技术路线如下所示：
；
R=苯环，
本发明还提供了所述的化合物的成肟产物和有机锌试剂进攻羰基产物的制备方法，技术路线如下：
（1）氟代环己酮螺1，3-二氧六环手性衍生物的成肟反应
；
（2）氟代环己酮螺1，3-二氧六环手性衍生物的亲核加成反应
。
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