CN105884728B - 一种手性2h-吡喃-2-酮衍生物的合成方法 - Google Patents
一种手性2h-吡喃-2-酮衍生物的合成方法 Download PDFInfo
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 14
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种手性2H‑吡喃‑2‑酮衍生物的合成方法：将式(1)所示α,β‑不饱和醛与式(2)所示1,3‑二羰化合物、催化剂、碱性物质、路易斯酸添加剂、分子筛、有机溶剂混合，在空气气氛、室温条件下搅拌反应14～24h，之后反应液经后处理，得到式(3)所示手性2H‑吡喃‑2‑酮衍生物；本发明所述的合成方法，底物适用范围广，产率高，选择性好；采用氧气作为氧化剂，环保经济；反应可以直接在空气中室温下进行，而不需要氮气保护、加热回流等操作，简便易行，利于工业化生产。
Description
(一)技术领域
本发明涉及一种手性2H-吡喃-2-酮衍生物的合成方法，具体涉及一种氧气参与下氮杂环卡宾/路易斯酸不对称催化α,β-不饱和醛与1,3-二羰基化合物反应合成手性2H-吡喃-2-酮衍生物的方法。
(二)背景技术
1832年，Wohler和Liebig发现氰根负离子(CN-)能催化苯甲醛的安息香缩合反应，这是类似卡宾催化可追溯的最早研究历史。在19世纪末和20世纪初，Buchner，Curtius，Staudinger和Kupfer在他们的研究中证明卡宾是确实存在的，但由于卡宾非常不稳定，所以难以分离得到。后来经过一系列的研究，发现氮杂环卡宾是相对稳定的结构，且能有效催化一系列反应。近年来氮杂环卡宾作为有机小分子催化剂更是迅速发展，同时在催化反应中一大类反应都要用到一定的氧化剂，但此类氧化剂价格十分昂贵，且原子经济性低。本发明主要是利用空气中的氧气代替了昂贵的氧化剂，而不影响反应效果。该方法一定程度上解决了用氮杂环卡宾作为催化剂的反应中氧化剂成本高的问题。
二氢吡喃酮及其衍生物是一类极其重要的有机合成中间体，广泛的应用于具有潜在生物药物活性的多取代γ-内酯、吡啶酮以及苯环型化合物中。已经报道的合成多取代的手性2H-吡喃-2-酮衍生物的方法通常都是采用手性氮杂环卡宾催化下的α,β-饱和(Angew.Chem.Int.Ed.2013,52,8588)或者不饱和醛(Angew.Chem.Int.Ed.2010,49,9266)与1,3-二羰基化合物在昂贵的氧化剂条件下反应而得；又或是采用手性氮杂环卡宾催化带有离去基团的α,β-不饱和醛以及炔醛与1,3-二羰基化合物而生成(Org.Lett.2011,13,4080,Org.Lett.2011,13,4708,Chem.Commun.2011,47,8670,Chem.Eur.J.2012,18,1914,J.Org.Chem.2013,78,6223)。然而在上述方法中，所涉及的氧化剂高昂的成本以及难以制备的带有离去基团的α,β-者不饱和醛严重制约了该化合物的合成，不易工业化。
(三)发明内容
本发明提供了一种手性2H-吡喃-2-酮衍生物的合成方法，该方法经济环保，操作简单，反应条件温和，利于工业化生产。
本发明采用如下技术方案：
一种手性2H-吡喃-2-酮衍生物的合成方法，所述的合成方法为：
将式(1)所示α,β-不饱和醛与式(2)所示1,3-二羰化合物、催化剂、碱性物质、路易斯酸添加剂、分子筛、有机溶剂混合，在空气气氛、室温(25℃)条件下搅拌反应14～24h(优选16～20h)，之后反应液经后处理，得到式(3)所示手性2H-吡喃-2-酮衍生物；所述式(2)所示1,3-二羰化合物与式(1)所示α,β-不饱和醛、催化剂、碱性物质、路易斯酸添加剂的投料物质的量之比为1：1.5～3：0.1～0.3：1～3：0.3～0.8，优选1：2：0.2：1.5：0.5。
式(1)、式(2)或式(3)中，
R1为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-硝基苯基、2-甲氧基苯基、2-硝基苯基、呋喃基、正丙基或正戊基；
R2为乙基、甲氧基、乙氧基、异丙氧基或苄氧基；
R3为甲基或乙基。
本发明中，所述的催化剂选自式(A)～(D)所示化合物之一：
所述的碱性物质为1,4-二氮杂二环[2.2.2]辛烷(DABCO)、4-二甲氨基吡啶(DMAP)、K2CO3或Cs2CO3。
所述的路易斯酸添加剂为LiCl、LiOTf、LiBF3或Sc(OTf)3。
所述的有机溶剂为四氢呋喃、甲苯或二氯甲烷；推荐所述有机溶剂的体积用量以式(1)所示α,β-不饱和醛的物质的量计为2～8mL/mmol，优选5mL/mmol。
所述的分子筛可以为或分子筛(有效孔径分别或的粉末状白色固体)；推荐所述分子筛的用量为20～200mg/0.1mmol式(2)所示1,3-二羰化合物，优选50～150mg/0.1mmol式(2)所示1,3-二羰化合物。
通常，所述的后处理方法为：反应结束后，先在反应液中加入0.5～1.5倍体积量的水(以稀释反应液及溶解无机盐)，再用二氯甲烷萃取，萃取液依次经无水硫酸钠干燥，过滤，减压浓缩得到浓缩物，所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物。
本发明的有益效果在于：
本发明由α,β-不饱和醛与1,3-二羰化合物反应合成2H-吡喃-2-酮衍生物的方法，底物适用范围广，产率高，选择性好；采用氧气作为氧化剂，环保经济；反应可以直接在空气中室温下进行，而不需要氮气保护、加热回流等操作，简便易行，利于工业化生产。
(四)附图说明
图1是实施例1制得产物的1H NMR谱图；
图2是实施例1制得产物的13C NMR谱图；
图3是实施例1制得产物的HPLC谱图；
图4是实施例2制得产物的1H NMR谱图；
图5是实施例2制得产物的13C NMR谱图；
图6是实施例2制得产物的HPLC谱图；
图7是实施例3制得产物的1H NMR谱图；
图8是实施例3制得产物的13C NMR谱图；
图9是实施例3制得产物的HPLC谱图；
图10是实施例4制得产物的1H NMR谱图；
图11是实施例4制得产物的13C NMR谱图；
图12是实施例4制得产物的HPLC谱图；
图13是实施例5制得产物的1H NMR谱图；
图14是实施例5制得产物的13C NMR谱图；
图15是实施例5制得产物的HPLC谱图。
(五)具体实施方式
下面通过具体实施例对本发明进行进一步的说明，但本发明的保护范围并不仅限于此。
分析薄层色谱(TLC)是在Merck 60F 254预涂硅胶板(0.2毫米厚)上进行的。洗脱后将板用Spectroline Model ENF-24061/F254nm紫外辐射(254纳米)进行显色。进一步显色是用高锰酸钾或高磷钼酸溶液染色的。使用活性中性Merck氧化铝90进行柱层析，使用适当体系的重蒸溶剂作为洗脱剂。
质子核磁共振谱(1H NMR)用的400分光光度计Bruker AMX(以CDCl3作为溶剂)。化学位移1H NMR谱报告为δ在每百万份数(ppm)为单位的低磁场SiMe4(δ0.0)，相应的氘代氯仿的信号为(δ7.26，单峰)。多重性被给定为：s(单峰)，d(双峰)，t(三重峰峰)，dd(双峰的双峰)或m(多重峰)。质子(n)的一个给定的谐振的数目由nH的指示。偶合常数报告为J值，赫兹。
碳核磁共振谱(13C NMR)报告为δ在每百万份数(ppm)为单位的低磁场SiMe4(δ0.0)，相应的氘代氯仿的信号为(δ77.0，三重峰)。
对映体过量通过高效液相色谱(HPLC)进行分析，使用的手性柱型号为CHIRALPAKAD-H，或者CHIRALCEL IB来确定。
旋光是用Haensdch旋光计(Polartronic MH8)用10厘米长的装样管(浓度为g/100毫升)测得。
高分辨质谱(HRMS)是用QTOF perimer为ESI+测得。
实施例1
称取催化剂A(14.6mg，0.04mmol，0.2eq)加入小烧瓶中，再加入分析级四氢呋喃(2ml)、肉桂醛(52.8mg，0.4mmol，2eq)和乙酰丙酮(20mg，0.2mmol，1eq)。然后称取DABCO(33.6mg，0.3mmol，1.5eq)、分子筛(100mg)和氯化锂(6.9mg，0.1mmol，0.5eq)也加入到小烧瓶中，将所得反应液在空气下室温搅拌14小时。反应完全后，将2mL水加入到小烧瓶中，再用二氯甲烷萃取(2mL×2)，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩得到浓缩物。所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物19mg(82％)；[α]D20＝-116.4(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ7.34(t,J＝7.5Hz,2H),7.28(d,J＝7.4Hz,1H),7.14(d,J＝7.5Hz,2H),4.14(d,J＝6.7Hz,1H),2.97(dd,J＝15.7,7.2Hz,1H),2.84(dd,J＝15.7,2.5Hz,1H),2.43(s,3H),2.12(s,3H)；13C NMR(126MHz,CDCl3)δ197.9,165.5,160.2,139.8,129.5,128.0,126.7,117.4,38.9,37.2,29.8,19.1；HRMS(ESI)calcd for C14H14O3(M+H)+:231.1016,Found:231.1043；94％e.e.as determined by HPLC(Chiralcel IB,80:20hexanes/i-PrOH,1mL/min),tr(major)＝9.5min,tr(minor)＝8.2min.
实施例2
称取催化剂A(14.6mg，0.04mmol，0.2eq)加入小烧瓶中，再加入分析级四氢呋喃(2ml)、4-甲氧基肉桂醛(64.8mg，0.4mmol，2eq)和乙酰丙酮(20mg，0.2mmol，1eq)。然后称取DABCO(33.6mg，0.3mmol，1.5eq、分子筛(100mg)和氯化锂(6.9mg，0.1mmol，0.5eq)也加入到小烧瓶中，将所得反应液在空气下室温搅拌14小时。反应完全后，将2mL水加入到小烧瓶中，再用二氯甲烷萃取(2mL×2)，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩得到浓缩物。所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1 的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物21mg(81％)；[α]D20＝-91.0(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ7.06(d,J＝8.6Hz,2H),6.86(d,J＝8.6Hz,2H),4.09(d,J＝5.9Hz,1H),3.78(s,3H),2.93(dd,J＝15.6,7.1Hz,1H),2.80(dd,J＝15.6,1.6Hz,1H),2.41(s,3H),2.12(s,3H)；13C NMR(126MHz,CDCl3)δ198.0,165.7,160.0,159.2,131.6,127.8,117.6,114.8,55.3,38.1,37.4,29.6,19.0；HRMS(ESI)calcd for C15H16O4(M+H)+:261.1121,Found:261.1507；85％e.e.as determined by HPLC(Chiralcel IB,85:15hexanes/i-PrOH,1mL/min),tr(major)＝12.6min,tr(minor)＝11.6min.
实施例3
称取催化剂A(14.6mg，0.04mmol，0.2eq)加入小烧瓶中，再加入分析级四氢呋喃(2ml)、4-氟肉桂醛(60mg，0.4mmol，2eq)和乙酰丙酮(20mg，0.2mmol，1eq)。然后称取DABCO(33.6mg，0.3mmol，1.5eq)、分子筛(100mg)和氯化锂(6.9mg，0.1mmol，0.5eq)也加入到小烧瓶中，将所得反应液在空气下室温搅拌14小时。反应完全后，将2mL水加入到小烧瓶中，再用二氯甲烷萃取(2mL×2)，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩得到浓缩物。所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物21mg(81％)；[α]D20＝-91.0(c0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ7.06(d,J＝8.6Hz,2H),6.86(d,J＝8.6Hz,2H),4.09(d,J＝5.9Hz,1H),3.78(s,3H),2.93(dd,J＝15.6,7.1Hz,1H),2.80(dd,J＝15.6,1.6Hz,1H),2.41(s,3H),2.12(s,3H)；13C NMR(126MHz,CDCl3)δ198.0,165.7,160.0,159.2,131.6,127.8,117.6,114.8,55.3,38.1,37.4,29.6,19.0；HRMS(ESI)calcd for C15H16O4(M+H)+:261.1121,Found:261.1507；85％e.e.as determined by HPLC(Chiralcel IB,85:15hexanes/i-PrOH,1mL/min),tr(major)＝12.6min,tr(minor)＝11.6min.
实施例4
称取催化剂A(14.6mg，0.04mmol，0.2eq)加入小烧瓶中，再加入分析级四氢呋喃(2ml)、4-氯肉桂醛(66.4mg，0.4mmol，2eq)和乙酰丙酮(20mg，0.2mmol，1eq)。然后称取DABCO(33.6mg，0.3mmol，1.5eq)、分子筛(100mg)和氯化锂(6.9mg，0.1mmol，0.5eq)也加入到小烧瓶中，将所得反应液在空气下室温搅拌14小时。反应完全后，将2mL水加入到小烧瓶中，再用二氯甲烷萃取(2mL×2)，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩得到浓缩物。所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物17mg(64％)；[α]D20＝-21.5(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ7.31(d,J＝8.5Hz,2H),7.09(d,J＝8.4Hz,2H),4.15(d,J＝6.6Hz,1H),2.96(dd,J＝15.7,7.3Hz,1H),2.80(dd,J＝15.7,2.5Hz,1H),2.43(d,J＝0.8Hz,3H),2.14(s,3H)；13C NMR(126MHz,CDCl3)δ197.4,165.3,160.6,138.2,133.8,129.6,128.1,117.2,38.1,36.9,29.8,19.2；HRMS(ESI)calcd for C14H13ClO3(M+H)+:265.0626,Found:265.0536；94％e.e.as determined by HPLC(Chiralcel IB,95:5hexanes/i-PrOH,1mL/min),tr(major)＝29.9min,tr(minor)＝23.5min.
实施例5
称取催化剂A(14.6mg，0.04mmol，0.2eq)加入小烧瓶中，再加入分析级四氢呋喃(2ml)、4-硝基肉桂醛(70.8mg，0.4mmol，2eq)和乙酰丙酮(20mg，0.2mmol，1eq)。然后称取DABCO(33.6mg，0.3mmol，1.5eq)、分子筛(100mg)和氯化锂(6.9mg，0.1mmol，0.5eq)也加入到小烧瓶中，将所得反应液在空气下室温搅拌14小时。反应完全后，将2mL水加入到小烧瓶中，再用二氯甲烷萃取(2mL×2)，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩得到浓缩物。所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物21mg(77％)；[α]D20＝-74.0(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ8.20(d,J＝8.7Hz,2H),7.34(d,J＝8.7Hz,2H),4.34(d,J＝6.7Hz,1H),3.02(dd,J＝15.9,7.5Hz,1H),2.85(dd,J＝15.9,2.3Hz,1H),2.47(s,3H),2.21(s,3H)；13C NMR(126MHz,CDCl3)δ196.6,164.7,161.2,147.6,147.3,127.8,124.6,117.2,38.3,36.3,30.2,19.5；HRMS(ESI)calcd for C14H13NO5(M+H)+:276.0866,Found:276.0923；90％e.e.as determined by HPLC(Chiralcel AD,90:10hexanes/i-PrOH,1mL/min),tr(major)＝26.9min,tr(minor)＝29.2min.
实施例6
化合物3a的制备，操作方法同实施例1，不同的试剂、用量条件及反应结果列于表1，反应式如下[a]：
催化剂结构式如下：
表1 实施例6各反应的条件及反应结果
[a]反应条件：1a(0.2mmol),2a(0.1mmol),A(0.02mmol),溶剂(1mL),反应时间14小时.[b]基于2a的分离所得产物的产率.[c]3a的ee值,通过HPLC手性固定相检测；主要对映体的绝对构型基于3a的旋光度确定.[d]0.1mmol LiCl.[e]LiCl(0.1mmol)和分子筛粉末(20mg).[f]LiCl(0.1mmol)和分子筛粉末(20mg).[g]LiCl(0.1mmol)和分子筛粉末(20mg).[h]LiOTf(0.1mmol).[i]LiBF3(0.1mmol)[j]Sc(OTf)3(0.1mmol).
实施例7
化合物3a～3q的制备：
称取催化剂A(14.6mg，0.04mmol，0.2eq)加入小烧瓶中，再加入分析级四氢呋喃(2ml)、化合物1(0.4mmol，2eq)和化合物2(0.2mmol，1eq)。然后称取DABCO(33.6mg，0.3mmol，1.5eq)、分子筛(100mg)和氯化锂(6.9mg，0.1mmol，0.5eq)也加入到小烧瓶中，将所得反应液在空气下室温搅拌14h。反应完全后，将2mL水加入到小烧瓶中，再用二氯甲烷萃取(2mL×2)，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩得到浓缩物。所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物。反应式如下：
所得产物3a～3q及其产率、ee值如下：
所得产物3a～3q的数据表征如下：
5-乙酰基-6-甲基-4-苯基-3,4-二氢-2H-吡喃-2-酮(3a):
无色油状物，产率:19mg(82％)；[α]D20＝-116.4(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ7.34(t,J＝7.5Hz,2H),7.28(d,J＝7.4Hz,1H),7.14(d,J＝7.5Hz,2H),4.14(d,J＝6.7Hz,1H),2.97(dd,J＝15.7,7.2Hz,1H),2.84(dd,J＝15.7,2.5Hz,1H),2.43(s,3H),2.12(s,3H)；13C NMR(126MHz,CDCl3)δ197.9,165.5,160.2,139.8,129.5,128.0,126.7,117.4,38.9,37.2,29.8,19.1；HRMS(ESI)calcd for C14H14O3(M+H)+:231.1016,Found:231.1043；94％e.e.as determined by HPLC(Chiralcel IB,80:20hexanes/i-PrOH,1mL/min),tr(major)＝9.5min,tr(minor)＝8.2min.
5-乙酰基-4-(4-甲氧基苯基)-6-甲基-3,4-二氢-2H-吡喃-2-酮(3b):
黄色固体，产率:21mg(81％)；[α]D20＝-91.0(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ7.06(d,J＝8.6Hz,2H),6.86(d,J＝8.6Hz,2H),4.09(d,J＝5.9Hz,1H),3.78(s,3H),2.93(dd,J＝15.6,7.1Hz,1H),2.80(dd,J＝15.6,1.6Hz,1H),2.41(s,3H),2.12(s,3H)；13C NMR(126MHz,CDCl3)δ198.0,165.7,160.0,159.2,131.6,127.8,117.6,114.8,55.3,38.1,37.4,29.6,19.0；HRMS(ESI)calcd for C15H16O4(M+H)+:261.1121,Found:261.1507；85％e.e.as determined by HPLC(Chiralcel IB,85:15hexanes/i-PrOH,1mL/min),tr(major)＝12.6min,tr(minor)＝11.6min.
5-乙酰基-4-(4-氟苯基)-6-甲基-3,4-二氢-2H-吡喃-2-酮(3c)
黄色固体，产率:18mg(73％)；[α]D20＝-72.0(c 0.6,CHCl3)；1H NMR(500MHz,CDCl3)δ7.12(dd,J＝8.7,5.2Hz,2H),7.03(t,J＝8.6Hz,2H),4.16(d,J＝6.2Hz,1H),2.95(dd,J＝15.7,7.2Hz,1H),2.81(dd,J＝15.7,2.5Hz,1H),2.43(d,J＝0.8Hz,3H),2.14(s,3H)；13C NMR(126MHz,CDCl3)δ197.6,165.4,163.3,161.3,160.4,135.4,128.4,116.5,38.1,37.2,29.8,19.1；HRMS(ESI)calcd for C14H13FO3(M+H)+:249.0921,Found:249.0977；91％e.e.as determined by HPLC(Chiralcel IB,85:15hexanes/i-PrOH,1mL/min),tr(major)＝12.4min,tr(minor)＝10.4min
5-乙酰基-4-(4-氯苯基)-6-甲基-3,4-二氢-2H-吡喃-2-酮(3d)
黄色油状物，产率:17mg(64％)；[α]D20＝-21.5(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ7.31(d,J＝8.5Hz,2H),7.09(d,J＝8.4Hz,2H),4.15(d,J＝6.6Hz,1H),2.96(dd,J＝15.7,7.3Hz,1H),2.80(dd,J＝15.7,2.5Hz,1H),2.43(d,J＝0.8Hz,3H),2.14(s,3H)；13CNMR(126MHz,CDCl3)δ197.4,165.3,160.6,138.2,133.8,129.6,128.1,117.2,38.1,36.9,29.8,19.2；HRMS(ESI)calcd for C14H13ClO3(M+H)+:265.0626,Found:265.0536；94％e.e.as determined by HPLC(Chiralcel IB,95:5hexanes/i-PrOH,1mL/min),tr(major)＝29.9min,tr(minor)＝23.5min.
5-乙酰基-6-甲基-4-(4-硝基苯基)-3,4-二氢-2H-吡喃-2-酮(3e)
黄色油状物，产率:21mg(77％)；[α]D20＝-74.0(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ8.20(d,J＝8.7Hz,2H),7.34(d,J＝8.7Hz,2H),4.34(d,J＝6.7Hz,1H),3.02(dd,J＝15.9,7.5Hz,1H),2.85(dd,J＝15.9,2.3Hz,1H),2.47(s,3H),2.21(s,3H)；13C NMR(126MHz,CDCl3)δ196.6,164.7,161.2,147.6,147.3,127.8,124.6,117.2,38.3,36.3,30.2,19.5；HRMS(ESI)calcd for C14H13NO5(M+H)+:276.0866,Found:276.0923；90％e.e.asdetermined by HPLC(Chiralcel AD,90:10hexanes/i-PrOH,1mL/min),tr(major)＝26.9min,tr(minor)＝29.2min.
5-乙酰基-4-(2-甲氧基苯基)-6-甲基-3,4-二氢-2H-吡喃-2-酮(3f)
白色固体，产率:21mg(80％)；[α]D20＝-35.6(c 0.8,CHCl3)；1H NMR(500MHz,CDCl3)δ7.26(td,J＝8.1,1.7Hz,1H),6.97(dd,J＝7.4,1.5Hz,1H),6.89(dd,J＝11.5,4.3Hz,2H),4.54–4.46(m,1H),3.86(s,3H),2.91–2.82(m,2H),2.42(d,J＝0.9Hz,3H),2.08(s,3H)；13C NMR(126MHz,CDCl3)δ198.3,166.2,160.4,156.5,129.1,127.2,127.1,121.1,116.4,110.9,55.2,35.0,32.9,29.3,19.0；HRMS(ESI)calcd for C15H16O4(M+H)+:261.112,Found:261.1283；93％e.e.as determined by HPLC(Chiralcel AD,98:2hexanes/i-PrOH,1mL/min),tr(major)＝18.5min,tr(minor)＝21.1min.
5-乙酰基-6-甲基-4-(2-硝基苯基)-3,4-二氢-2H-吡喃-2-酮(3g)
黄色油状物，产率:19mg(70％)；[α]D20＝-143.2(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ7.99(dd,J＝8.1,1.2Hz,1H),7.60–7.56(m,1H),7.48(td,J＝8.1,1.3Hz,1H),7.22(dd,J＝7.8,1.2Hz,1H),4.86(d,J＝6.7Hz,1H),3.07(dd,J＝16.1,7.7Hz,1H),3.00(dd,J＝16.1,2.4Hz,1H),2.48(d,J＝0.9Hz,3H),2.09(s,3H)；13C NMR(126MHz,CDCl3)δ196.7,165.0,162.0,148.7,134.3,134.1,129.1,128.2,125.7,116.4,35.8,34.2,29.7,19.3；HRMS(ESI)calcd for C14H13NO5(M+H)+:276.0866,Found:276.0931；92％e.e.asdetermined by HPLC(Chiralcel AD,95:5hexanes/i-PrOH,1mL/min),tr(major)＝18.7min,tr(minor)＝20.6min.
5-乙酰基-4-(4-呋喃-2-基)-6-甲基-3,4-二氢-2H-吡喃-2-酮(3c)
黄色油状物，产率:16mg(73％)；[α]D20＝-35.7(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ7.34(d,J＝1.2Hz,1H),6.28(dd,J＝3.2,1.9Hz,1H),6.09(d,J＝3.2Hz,1H),4.26(d,J＝6.6Hz,1H),3.04(dd,J＝15.9,2.1Hz,1H),2.84(dd,J＝15.9,6.8Hz,1H),2.37(s,3H),2.31(s,3H)； 13C NMR(126MHz,CDCl3)δ197.1,165.5,161.0,152.5,142.8,115.7,110.4,106.6,33.8,32.3,29.8,19.4；HRMS(ESI)calcd for C12H12O4(M+H)+:221.0808,Found:221.0834；87％e.e.as determined by HPLC(Chiralcel IB,90:10hexanes/i-PrOH,1mL/min),tr(major)＝11.0min,tr(minor)＝9.4min.
5-乙酰基-6-甲基-4-丙基-3,4-二氢-2H-吡喃-2-酮(3i)
黄色油状物，产率:14mg(71％)；[α]D20＝-4.3(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ2.98–2.90(m,1H),2.73(dd,J＝15.9,1.9Hz,1H),2.59(dd,J＝15.9,6.4Hz,1H),2.35(s,3H),2.27(s,3H),1.53–1.39(m,2H),1.33(dd,J＝8.1,4.2Hz,2H),0.91(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ197.7,167.0,158.8,120.4,35.6,33.1,32.1,30.2,19.8,19.3,13.8；HRMS(ESI)calcd for C11H16O3(M+Na)+:219.0992,Found:219.1066；77％e.e.as determined by HPLC(Chiralcel IB,90:10hexanes/i-PrOH,1mL/min),tr(major)＝8.0min,tr(minor)＝7.5min.
5-乙酰基-6-甲基-4-戊基-3,4-二氢-2H-吡喃-2-酮(3j)
黄色油状物，产率:16mg(71％)；[α]D20＝-2.1(c 0.7,CHCl3)；1H NMR(500MHz,CDCl3)δ2.95–2.87(m,1H),2.73(dd,J＝15.9,1.8Hz,1H),2.58(dd,J＝15.9,6.4Hz,1H),2.35(s,3H),2.27(s,3H),1.30(m,8H),0.87(t,J＝6.9Hz,3H)；13C NMR(126MHz,CDCl3)δ197.8,167.02,158.7,120.4,33.4,33.1,32.3,31.5,30.2,26.2,22.4,19.3,13.9；HRMS(ESI)calcd for C13H20O3(M+H)+:225.1485,Found:225.1408；80％e.e.as determined byHPLC(Chiralcel IB,95:5hexanes/i-PrOH,1mL/min),tr(major)＝8.6min,tr(minor)＝8.2min.
5-乙酰基-4,6-二苯基-3,4-二氢-2H-吡喃-2-酮(3k)
无色油状物，产率:20mg(69％)；[α]D20＝-1.8(c 0.8,CHCl3)；1H NMR(500MHz,CDCl3)δ7.58–7.53(m,2H),7.46–7.43(m,1H),7.32(t,J＝7.7Hz,2H),7.19(t,J＝7.3Hz,3H),7.15–7.11(m,1H),7.08–7.04(m,2H),4.24(dd,J＝7.1,3.1Hz,1H),2.99(dd,J＝16.0,7.6Hz,1H),2.86(dd,J＝16.0,3.6Hz,1H),1.83(d,J＝1.0Hz,3H).13C NMR(126MHz,CDCl3)δ195.8,166.5,154.7,140.0,138.4,133.1,129.1,128.8,128.7,127.6,126.8,117.8,39.5,36.2,19.0；HRMS(ESI)calcd for C19H16O3(M+H)+:293.1172,Found:293.1146；74％e.e.asdetermined by HPLC(Chiralcel IB,90:10hexanes/i-PrOH,1mL/min),tr(major)＝10.4min,tr(minor)＝9.6min.
6-乙基-2-氧代-4-苯基-3,4-二氢-2H-吡喃-5-羧酸乙酯(3l)
黄色油状物，产率:19mg(69％)；[α]D20＝-71.0(c 0.6,CHCl3)；1H NMR(500MHz,CDCl3)δ7.29(t,J＝7.4Hz,2H),7.23(dd,J＝10.5,4.2Hz,1H),7.13(d,J＝7.3Hz,2H),4.27–4.22(m,1H),4.12(q,J＝7.1Hz,2H),2.92(ddd,J＝13.7,12.1,7.5Hz,2H),2.87–2.77(m,2H),1.27(t,J＝7.5Hz,3H),1.18(t,J＝7.1Hz,3H)；13C NMR(126MHz,CDCl3)δ166.3,165.9,165.8,140.6,129.0,127.4,126.5,109.3,60.8,37.8,36.4,25.4,14.0,11.7；HRMS(ESI)calcd for C16H18O4(M+H)+:275.1278,Found:275.1105；92％e.e.as determined byHPLC(Chiralcel IB,95:5hexanes/i-PrOH,1mL/min),tr(major)＝6.9min,tr(minor)＝6.1min.
6-乙基-4-苯基-5-丙酰基-3,4-二氢-2H-吡喃-2-酮(3m)
黄色油状物，产率:19mg(74％)；[α]D20＝-54.2(c 0.8,CHCl3)；1H NMR(500MHz,CDCl3)δ7.34(t,J＝7.4Hz,2H),7.28(d,J＝7.4Hz,1H),7.14(d,J＝7.3Hz,2H),4.11(dd,J＝7.1,2.8Hz,1H),2.95(dd,J＝15.7,7.2Hz,1H),2.81(dd,J＝15.7,3.0Hz,1H),2.73(qd,J＝13.8,7.1Hz,2H),2.49(dq,J＝17.8,7.2Hz,1H),2.23(dq,J＝17.8,7.2Hz,1H),1.28(t,J＝7.4Hz,3H),0.94(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)13C NMR(126MHz,CDCl3)δ201.1,165.9,163.7,139.7,129.5,127.9,126.7,116.5,38.7,37.4,34.7,25.3,11.9,7.9；HRMS(ESI)calcd for C16H18O3(M+H)+:259.1329,Found:259.1298；90％e.e.as determinedby HPLC(Chiralcel IB,80:20hexanes/i-PrOH,1mL/min),tr(major)＝6.5min,tr(minor)＝5.5min.
6-甲基-2-氧代-4-苯基-3,4-二氢-2H-吡喃-5-羧酸甲酯(3n)
黄色油状物，产率:20mg(81％)；[α]D20＝-46.0(c 0.8,CHCl3)；1H NMR(500MHz,CDCl3)δ7.30(t,J＝7.4Hz,2H),7.24(t,J＝7.4Hz,1H),7.13(d,J＝7.3Hz,2H),4.26(d,J＝7.2Hz,1H),3.68(s,3H),2.94(dd,J＝15.8,7.5Hz,1H),2.83(dd,J＝15.8,2.1Hz,1H),2.48(s,3H).13CNMR(126MHz,CDCl3)δ166.4,166.0,161.7,140.4,129.1,127.5,126.6,109.7,51.9,37.8,36.5,18.9；HRMS(ESI)calcd for C14H14O4(M+H)+:247.0965,Found:247.0932；90％e.e.as determined by HPLC(Chiralcel IB,80:20hexanes/i-PrOH,1mL/min),tr(major)＝8.8min,tr(minor)＝6.3min.
6-甲基-2-氧代-4-苯基-3,4-二氢-2H-吡喃-5-羧酸乙酯(3o)
黄色油状物，产率:20mg(77％)；[α]D20＝-115.0(c 0.8,CHCl3)；1H NMR(500MHz,CDCl3)δ7.29(dd,J＝10.1,4.6Hz,2H),7.26–7.23(m,1H),7.15–7.12(m,2H),4.25(d,J＝7.4Hz,1H),4.13(q,J＝7.1Hz,2H),2.94(dd,J＝15.9,7.6Hz,1H),2.82(dd,J＝15.9,2.3Hz,1H),2.47(d,J＝0.8Hz,3H),1.18(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.0,165.9,161.2,140.6,129.0,127.4,126.6,110.0,60.8,37.8,36.3,18.8,14.0；HRMS(ESI)calcd for C15H16O4(M+H)+:261.1121,Found:261.0925；90％e.e.as determined by HPLC(Chiralcel IB,80:20hexanes/i-PrOH,1mL/min),tr(major)＝9.1min,tr(minor)＝6.5min.
6-甲基-2-氧代-4-苯基-3,4-二氢-2H-吡喃-5-羧酸异丙基酯(3p)
黄色油状物，产率:19mg(69％)；[α]D20＝-135.0(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ7.31–7.27(m,2H),7.25–7.21(m,1H),7.15–7.11(m,2H),4.98(dt,J＝12.5,6.2Hz,1H),4.23(d,J＝6.7Hz,1H),2.95(dd,J＝15.9,7.7Hz,1H),2.82(dd,J＝15.9,2.5Hz,1H),2.46(d,J＝0.9Hz,3H),1.23(d,J＝6.2Hz,3H),1.06(d,J＝6.2Hz,3H)；13C NMR(126MHz,CDCl3)δ166.2,165.4,160.9,140.8,128.9,127.4,126.6,110.3,68.4,37.9,36.3,21.9,21.5,18.8；HRMS(ESI)calcd for C16H18O4(M+H)+:275.1278,Found:275.1179；90％e.e.asdetermined by HPLC(Chiralcel IB,95:5hexanes/i-PrOH,1mL/min),tr(major)＝8.2min,tr(minor)＝6.4min.
6-甲基-2-氧代-4-苯基-3,4-二氢-2H-吡喃-5-羧酸苄酯(3q)
黄色油状物，产率:22mg(65％)；[α]D20＝-56.4(c 0.5,CHCl3)；1H NMR(500MHz,CDCl3)δ7.31(dd,J＝25.2,17.2Hz,6H),7.12(t,J＝7.2Hz,4H),5.11(q,J＝12.5Hz,2H),4.27(d,J＝7.4Hz,1H),2.95(dd,J＝15.9,7.7Hz,1H),2.82(d,J＝15.8Hz,1H),2.49(s,3H)；13C NMR(126MHz,CDCl3)δ165.9,165.7,162.0,140.5,135.6,129.1,128.5,128.2,127.9,127.6,126.6,109.6,66.6,37.9,36.4,18.9；HRMS(ESI)calcd for C20H18O4(M+H)+:323.1278,Found:323.1220；89％e.e.as determined by HPLC(Chiralcel IB,95:5hexanes/i-PrOH,1mL/min),tr(major)＝14.8min,tr(minor)＝11.0min。
Claims (9)
1.一种手性2H-吡喃-2-酮衍生物的合成方法，其特征在于，所述的合成方法为：
将式(1)所示α,β-不饱和醛与式(2)所示1,3-二羰化合物、催化剂、碱性物质、添加剂、分子筛、有机溶剂混合，在空气气氛、室温条件下搅拌反应14～24h，之后反应液经后处理，得到式(3)所示手性2H-吡喃-2-酮衍生物；所述式(2)所示1,3-二羰化合物与式(1)所示α,β-不饱和醛、催化剂、碱性物质、添加剂的投料物质的量之比为1：1.5～3：0.1～0.3：1～3：0.3～0.8；
式(1)、式(2)或式(3)中，
R1为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-硝基苯基、2-甲氧基苯基、2-硝基苯基、呋喃基、正丙基或正戊基；
R2为乙基、甲氧基、乙氧基、异丙氧基或苄氧基；
R3为甲基或乙基；
所述合成方法中，所述的催化剂选自式(A)～(D)所示化合物之一：
所述的碱性物质为1,4-二氮杂二环[2.2.2]辛烷、4-二甲氨基吡啶、K2CO3或Cs2CO3；
所述的添加剂为LiCl、LiOTf、LiBF4或Sc(OTf)3；
所述的有机溶剂为四氢呋喃、甲苯或二氯甲烷。
2.如权利要求1所述的合成方法，其特征在于，所述式(2)所示1,3-二羰化合物与式(1)所示α,β-不饱和醛、催化剂、碱性物质、添加剂的投料物质的量之比为1：2：0.2：1.5：0.5。
3.如权利要求1所述的合成方法，其特征在于，所述有机溶剂的体积用量以式(1)所示α,β-不饱和醛的物质的量计为2～8mL/mmol。
4.如权利要求3所述的合成方法，其特征在于，所述有机溶剂的体积用量以式(1)所示α,β-不饱和醛的物质的量计为5mL/mmol。
5.如权利要求1所述的合成方法，其特征在于，所述的分子筛为或分子筛。
6.如权利要求1或5之一所述的合成方法，其特征在于，所述分子筛的用量为20～200mg/0.1mmol式(2)所示1,3-二羰化合物。
7.如权利要求6所述的合成方法，其特征在于，所述分子筛的用量为50～150mg/0.1mmol式(2)所示1,3-二羰化合物。
8.如权利要求1所述的合成方法，其特征在于，所述反应的时间为16～20h。
9.如权利要求1所述的合成方法，其特征在于，所述的后处理方法为：反应结束后，先在反应液中加入0.5～1.5倍体积量的水，再用二氯甲烷萃取，萃取液依次经无水硫酸钠干燥，过滤，减压浓缩得到浓缩物，所得浓缩物进行柱层析分离，以乙酸乙酯：石油醚体积比为10：1的混合液作为洗脱剂，收集含目标化合物的洗脱液，减压蒸除溶剂并干燥，得到纯化产物。
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