<i>C</i>-乙烯基鼠李糖苷衍生物的合成及细胞毒活性探究

引用本文: 吉玉, 姚辉, 柳乂, 黄年玉, 刘明国. C-乙烯基鼠李糖苷衍生物的合成及细胞毒活性探究[J]. 有机化学, 2020, 40(7): 2051-2061. doi: 10.6023/cjoc202003037 shu

Citation: Ji Yu, Yao Hui, Liu Yi, Huang Nianyu, Liu Mingguo. Synthesis and Cytotoxic Activity of C-Vinyl-rhamnopyranoside Derivatives[J]. Chinese Journal of Organic Chemistry, 2020, 40(7): 2051-2061. doi: 10.6023/cjoc202003037 shu

C-乙烯基鼠李糖苷衍生物的合成及细胞毒活性探究

三峡大学生物与制药学院天然产物研究与利用湖北省重点实验室湖北宜昌 443002

通讯作者: 黄年玉, hny115@126.com; 刘明国, mgliu1966@163.com

基金项目:
国家自然科学基金（No.21602123）及三峡大学青年拔尖人才项目和研究生创新基金（No.SDYC2016121）资助项目

摘要: 报道了L-鼠李烯糖与炔丙酯在Au（Ⅰ）催化下通过分子间串联的1，3-酰氧基迁移/Ferrier重排策略，合成了C-乙烯基鼠李糖苷衍生物.通过同位素O¹⁸标记实验验证了C-糖基化机理.产物的绝对构型经X射线单晶衍射分析确定.利用噻唑蓝（MTT）法研究了产物的细胞毒活性，结果显示产物3i对人体胃癌细胞HGC-27具有良好的抑制作用，IC₅₀值为18.29 μmol·L^-1.该方法具有操作简单、高非对映选择性、反应条件温和等优点.

关键词:

English

Synthesis and Cytotoxic Activity of C-Vinyl-rhamnopyranoside Derivatives

Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang, Hubei 443002

Corresponding author: Huang Nianyu, E-mail: hny115@126.com; Liu Mingguo, E-mail: mgliu1966@163.com

Received Date: 14 March 2020
Revised Date: 19 April 2020
Available Online: 01 July 2020
Fund Project:
Project supported by the National Natural Science Foundation of China (No. 21602123), and the Youth Talent Development Foundation and Scientific Foundation from Graduate School of China Three Gorges University (No. SDYC2016121)

Abstract: A novel gold(Ⅰ)-catalyzed glycosylation method was described to synthesize C-vinyl-rhamnopyranoside derivatives using stable propargylic carboxylates and 3, 4-di-O-acetyl-L-rhamnal as starting materials, based on the tandem intermolecular 1, 3-acyloxy migration/Ferrier rearrangement. The C-glycosylation process has been verified by O¹⁸ isotopic labeling experiment, and the absolute configuration of synthesized products was determined by X-ray single crystal diffraction. The cytotoxic activity was investigated by methyl thiazolyl tetrazolium (MTT). It indicates that product 3i has strong inhibitory effect on human gastric cancer cells HGC-27 with IC₅₀ 18.29 μmol·L^-1. The described synthetic method was outstanding with easy-to-operate, high diastereoselectivity, and mild reaction condition.

Key words:

碳苷作为一类重要的糖苷类化合物, 因其对酸水解和酶促水解均表现出高稳定性, 被认为是一种稳定的药效基团, 广泛应用于医药、化工等领域^[1].其中, 鼠李糖碳苷衍生物是一类具有显著抗菌活性和抗肿瘤活性的化合物^[2].近年来具有生物活性的鼠李糖碳苷类天然产物和药物分子相继被报道.例如Vineomycinone B2 methyl ester^[3]、Polycarcinv^[4]、7-O-Glycosyl genisteins^[5].因此, 探索鼠李糖碳苷类化合物的高效合成在糖化学和医药研发领域具有重要的意义.

过渡金属催化偶联反应是构建碳苷键最有效的方法之一^[6].除了通过传统的催化偶联反应, 如Heck、Suzuki、Stille以及Negishi反应等, 近些年涌现出许多新型的金属催化体系, 提高了糖苷化反应的立体选择性^[7].但是如何简单高效地实现异头碳原子上的区域选择性和α/β立体选择性, 依然是当今糖化学研究难点之一.其中, 通过过渡金属催化偶联反应合成含C-乙烯基骨架的糖苷类化合物, 作为一类重要的合成中间体^[8], 以其显著抗菌活性、抗肿瘤活性^[9], 引起合成化学家的广泛关注.目前, 合成C-乙烯基鼠李糖苷的例子很少.例如, 过渡金属催化的烯醇三氟甲磺酸酯与鼠李烯糖的交叉偶联反应合成C-乙烯基鼠李糖苷^[10], 以及用Lewis酸催化的芳基乙炔与鼠李烯糖分子间串联的糖苷化反应和卤代过程合成C-乙烯基鼠李糖苷^[11].为了进一步拓展此类化合物的合成方法, 本工作探究了Ph₃PAuCl/ AgSbF₆催化下L-鼠李烯糖与炔丙酯发生分子间串联的1, 3-酰氧基迁移/Ferrier重排, 探讨了高收率、高立体选择性地合成C-乙烯基鼠李糖苷的反应.

1. 结果与讨论

为了获得C-乙烯基鼠李糖苷衍生物合成的最优反应条件, 本工作以L-鼠李烯糖(1a)和炔丙酯(2a)为模型反应, 首先评估了Au₂O₃、TiCl₄、Ni(CO)₄、PdCl₂、Ag₂CO₃诱导1a发生Ferrier重排生成C-乙烯基糖苷产物的能力, 然而反应24 h未检测到目标产物(表 1, Entries 1~5).当使用AuCl₃时, 室温条件反应6 h就能以21%的收率得到C-乙烯基鼠李糖苷产物3a(表 1, Entry 6).这一结果促使了对金催化剂进一步筛选(表 1, Entries 7~18), 最终确定Ph₃PAuCl和AgSbF₆组合催化剂的催化效果最佳, 能以58%的收率得到目标产物.随后对反应溶剂进行筛选(表 1, Entries 19~24), 发现以CH₃NO₂为溶剂时反应收率高, 达78%(表 1, Entry 22).最终确定了反应的最优条件:以CH₃NO₂为溶剂, Ph₃PAuCl/AgSbF₆ (5 mol%)为催化剂, 室温下反应6 h.

表 1

表 1 模型反应条件优化^a

Table 1. Optimization of reaction conditions for the model reaction

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Entry	Catalyst	Solvent	Time/h	Yield^b/%
1	Au₂O₃	CH₂Cl₂	24	N.D.
2	TiCl₄	CH₂Cl₂	24	N.D.
3	Ni(CO)₄	CH₂Cl₂	24	N.D.
4	PdCl₂	CH₂Cl₂	24	N.D.
5	Ag₂CO₃	CH₂Cl₂	24	N.D.
6	AuCl₃	CH₂Cl₂	6	21
7	AuBr₃	CH₂Cl₂	6	12
8	AuCl	CH₂Cl₂	6	31
9	Ph₃PAuCl	CH₂Cl₂	24	N.D.
10	AgSbF₆	CH₂Cl₂	24	N.D.
11	Au(CO)Cl/AgSbF₆	CH₂Cl₂	6	24
12	Ph₃PAuCl/AgSbF₆	CH₂Cl₂	6	58
13	Ph₃PAuNTf₂/AgSbF₆	CH₂Cl₂	6	42
14	Ph₃PAuCl/AgNO₃	CH₂Cl₂	6	28
15	Ph₃PAuCl/CH₃CO₂Ag	CH₂Cl₂	6	37
16	Ph₃PAuCl/Ag₂CO₃	CH₂Cl₂	6	45
17	Ph₃PAuCl/Ag₃PO₄	CH₂Cl₂	6	48
18	(C₅H₅N)AuCl₃/AgSbF₆	CH₂Cl₂	6	46
19	Ph₃PAuCl/AgSbF₆	DMF	6	N.D.
20	Ph₃PAuCl/AgSbF₆	CHCl₃	6	36
21	Ph₃PAuCl/AgSbF₆	Toluene	6	25
22	Ph₃PAuCl/AgSbF₆	CH₃NO₂	6	78
23	Ph₃PAuCl/AgSbF₆	CH₃CN	6	12
24	Ph₃PAuCl/AgSbF₆	EtOAc	6	N.D.
^aGeneral conditions: catalyst (5 mol%) was added into the mixture of 1a (107 mg, 0.5 mmol) and 2a (113 mg, 0.5 mmol) in corresponding solvent (5 mL). ^b Isolated yield. N.D.＝not detected.

在最优条件下对炔丙酯的适用范围进行了筛选(表 2).当R¹为苯基, R²为烷基时, 能够以良好的收率得到C-乙烯基鼠李糖苷衍生物, 且随着烷基(R²)空间位阻的增大, 收率有所降低(3a~3f).随后考察了苯环上所连取代基(R¹)的电子效应对反应的影响, 发现供电子效应的取代基不利于提高衍生物的收率(3g~3i, 3j~3m), 而拉电子效应的取代基有利于衍生物收率的提高(3q~3t).当R¹为杂环噻吩时, 能以68%的收率得到3u.当R¹、R²均为烷基时, 也能以较高的收率获得目标产物(3v~3x).当R¹为烷基, R²为芳基时, 同样也能获得较好的收率(3y).所得产物均为α构型, 通过对化合物3g的X射线单晶衍射分析也进一步验证了这一结果(图 1).

表 2

表 2 C-乙烯基鼠李糖苷衍生物的底物拓展

Table 2. Substrate scope for C--vinyl-rhamnopyranoside derivatives

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图 1

图 1. 化合物3g的晶体结构

Figure 1. X-ray single crystal structure of 3g

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为了研究鼠李烯糖保护基空间位阻的改变对反应的影响, 设计了实验(表 3).以苯甲酰基保护的鼠李烯糖(1b~1f)在上述最优条件下反应, 能以73%~78%的收率、高立体选择性得到C-乙烯基鼠李糖苷衍生4.烯糖保护基空间位阻的增大对反应收率和选择性几乎没有影响.通过上述实验说明, 该反应具有广泛的官能团耐受性和高非对映选择性, 为简单高效制备C-乙烯基鼠李糖苷衍生物提拱了新方法.

表 3

表 3 C-乙烯基鼠李糖苷衍生物的底物扩展

Table 3. Substrate expansion of C-vinyl-rhamnopyranoside derivatives

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Entry	R¹ (1)	R²	Yield/% (4)
1	Ph (1b)	Et	76 (4ba)
2	Ph (1b)	ⁱBu	73 (4bb)
3	2-ClC₆H₄ (1c)	ⁱBu	74 (4ca)
4	3-ClC₆H₄ (1d)	ⁱBu	75 (4da)
5	2-FC₆H₄ (1e)	ⁱBu	76 (4ea)
6	4-FC₆H₄ (1f)	ⁱBu	78 (4fa)

随后将该方法扩展到岩藻烯糖(1g)时, 发现对岩藻烯糖同样适用, 以高非对映选择性得到预期的C-乙烯基岩藻糖苷衍生物5 (Eq. 1), 其收率高于由鼠李烯糖反应时的产物.这可能是由于岩藻烯糖C4上基团的空间取向, 在糖苷化过程中更有利于联烯中间体的亲核进攻.

(1)

通过查阅相关文献^[12], 提出了如下可能反应机理(Scheme 1).在反应过程中, 金催化剂不仅可以作为路易斯酸, 促使烯糖发生Ferrier重排生成氧鎓离子C, 也能活化炔键发生分子内环化生成A, 随后发生1, 3-酰氧基迁移生成联烯B, 进而对C发生亲核进攻, 氧鎓离子解离得到C-乙烯基鼠李糖苷E.

图式 1

图式 1. 可能的反应机理

Scheme 1. Possible reaction mechanism

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为了验证反应机理经历炔丙酯迁移过程, 设计了同位素标记实验.利用L-鼠李烯糖1a与¹⁸O标记的炔丙酯2a-¹⁸O^[13]在最优条件下进行反应, 从3a-¹⁸O的¹³C NMR谱中可以清楚地看到¹⁸O标记的羰基碳在δ 198.76处有信号峰.同时, HRMS也证实了3a-¹⁸O的存在.这一结果充分证明炔丙酯在反应过程中发生了1, 3-酰氧基迁移(Eq. 2).

(2)

通常含有鼠李糖碳苷骨架的化合物具有良好的抗肿瘤活性, 促使我们对合成的新化合物3~5进行细胞毒活性研究.利用噻唑蓝(MTT)法, 选择三种人体癌细胞株[胃癌细胞(HGC-27)、宫颈癌细胞(Caski)和肝癌细胞(Hep-G2)]和人胃粘膜细胞(GES-1)进行体外细胞毒活性测试^[14].通过SPSS 13.0软件分别计算化合物对于不同细胞的IC₅₀值.测试结果(表 4)表明, 所有化合物对人胃粘膜细胞均表现出低毒性.化合物3i具有显著的体外胃癌细胞抑制增长活性, 其IC₅₀值为18.29 μmol•L^－¹.随着3i浓度的增加, 细胞毒活性也随之增加(图 2).

表 4

表 4 目标化合物的细胞毒活性

Table 4. Cytotoxic activity of target compounds

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化合物	IC₅₀值/(μmol•L^－¹)
化合物	胃癌细胞	宫颈癌细胞	肝癌细胞	人胃粘膜细胞
3a~3h	＞100	＞100	＞100	＞100
3i	18.29	＞100	＞100	＞100
3j~3o	＞100	＞100	＞100	＞100
3p	82.91	＞100	＞100	＞100
3q~3y	＞100	＞100	＞100	＞100
4ba	＞100	＞100	＞100	＞100
4bb	90.21	＞100	＞100	＞100
4ca~4fa	＞100	＞100	＞100	＞100
5a~5b	＞100	＞100	＞100	＞100

图 2

图 2. 化合物3i的胃癌细胞毒活性

Figure 2. Cytotoxities against HGC-27 cells of compound 3i

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2. 结论

在Au(Ⅰ)催化作用下, 炔丙酯与鼠李烯糖发生分子间串联的1, 3-酰氧基迁移/Ferrier重排反应, 以52%~92%的收率、高非对映选择性地合成了一系列C-乙烯基鼠李糖苷衍生物.通过¹H NMR, ¹³C NMR以及X射线单晶衍射分析确定所得产物的绝对构型.将该方法扩展到其它烯糖底物来探索其更多的潜在药用价值将在未来的研究中相继开展.

3. 实验部分

3.1 仪器与试剂

所有反应均在氮气氛围中进行.反应溶剂均参照标准方法进行无水无氧处理. Bruker AVANCE Ⅲ 400 MHz核磁共振仪, Oxford diffraction Gemini E型单晶衍射仪, Agilent 1290-6540 UHPLC Q-Tof型质谱仪.化合物1a~1f^[15]和2a~2y^[16]参考文献方法制备.其他商品化试剂购买后, 无需纯化直接使用.

3.2 实验方法

3.2.1 化合物3a~3y的合成

在25 mL的Schlenk管内, 依次加入L-鼠李烯糖1a (107 mg, 0.5 mmol), 炔丙酯2 (0.5 mmol), CH₃NO₂ (5 mL), 室温搅拌10 min后, 迅速加入Ph₃PAuCl (12.3 mg, 5 mol%)和AgSbF₆ (6.5 mg, 5 mol%).室温下搅拌6 h, 薄层色谱(TLC)检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.通过硅胶快速色谱法(石油醚/乙酸乙酯, V:V＝20:1)纯化残余物, 得到C-乙烯基鼠李糖苷衍生物3.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3a):无色油状, 128 mg, 产率78%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.93~7.90 (m, 2H), 7.61~7.56 (m, 1H), 7.50~7.46 (m, 2H), 5.98 (ddd, J＝10.3, 3.0, 1.6 Hz, 1H), 5.91~5.87 (m, 2H), 5.08 (br, 1H), 5.00 (dq, J＝7.6, 2.2 Hz, 1H), 3.85~3.79 (m, 1H), 2.09 (s, 3H), 1.93~1.86 (m, 2H), 1.42~1.33 (m, 2H), 1.10 (d, J＝6.4 Hz, 3H), 0.81 (t, J＝7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.9, 170.6, 138.5, 137.5, 135.3, 133.4, 130.0, 129.3, 128.7, 126.6, 73.1, 70.4, 66.9, 31.7, 22.4, 21.2, 17.5, 13.7. HRMS calcd for C₂₀H₂₄O₄Na [M+Na]⁺ 351.1567, found 351.1565.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-庚基-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3b):无色油状, 133 mg, 产率78%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.93~7.90 (m, 2H), 7.60~7.56 (m, 1H), 7.49~7.45 (m, 2H), 5.98 (ddd, J＝10.3, 3.0, 1.6 Hz, 1H), 5.91~5.87 (m, 2H), 5.08 (br, 1H), 5.00 (dq, J＝7.6, 2.2 Hz, 1H), 3.85~3.79 (m, 1H), 2.09 (s, 3H), 1.97~1.86 (m, 2H), 1.34~1.29 (m, 2H), 1.22~1.16 (m, 2H), 1.11 (d, J＝6.3 Hz, 3H), 0.78 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.9, 170.6, 138.4, 137.5, 135.5, 133.4, 130.1, 129.2, 128.6, 126.6, 73.1, 70.4, 66.9, 31.3, 29.5, 22.2, 21.2, 17.5, 13.8. HRMS calcd for C₂₁H₂₆O₄Na [M+Na]⁺ 365.1723, found 365.1724.

(2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3c):无色油状, 130 mg, 产率76%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.75~7.73 (m, 2H), 7.56~7.52 (m, 1H), 7.46~7.42 (m, 2H), 6.42 (t, J＝7.6 Hz, 1H), 6.06 (dd, J＝10.2, 1.9 Hz, 1H), 5.89 (ddd, J＝10.3, 4.8, 2.6 Hz, 1H), 5.40~5.38 (m, 1H), 4.88~4.86 (m, 1H), 4.16 (qd, J＝6.8, 2.4 Hz, 1H), 2.47 (t, J＝7.2 Hz, 2H), 2.09 (s, 3H), 1.74~1.67 (m, 1H), 1.32 (d, J＝6.8 Hz, 3H), 0.95 (d, J＝6.6 Hz, 3H), 0.91 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.6, 170.8, 149.5, 138.7, 138.1, 133.7, 132.0, 129.6, 128.1, 120.6, 71.0, 68.4, 66.0, 37.3, 28.7, 22.7, 22.6, 21.2, 16.0. HRMS calcd for C₂₁H₂₆O₄Na [M+Na]⁺ 365.1723, found 365.1724.

(2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3d):无色油状, 118 mg, 产率72%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.94~7.91 (m, 2H), 7.60~7.56 (m, 1H), 7.50~7.46 (m, 2H), 5.97 (ddd, J＝10.3, 2.9, 1.6 Hz, 1H), 5.90~5.87 (m, 1H), 5.67 (dd, J＝10.6, 1.2 Hz, 1H), 5.05~5.03 (m, 1H), 4.99 (dq, J＝7.6, 2.2 Hz, 1H), 3.83~3.77 (m, 1H), 2.28~2.19 (m, 1H), 2.08 (s, 3H), 1.11 (d, J＝6.4 Hz, 3H), 0.94 (d, J＝6.6 Hz, 3H), 0.90 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.7, 170.5, 141.5, 137.5, 136.2, 133.4, 130.0, 129.2, 128.6, 126.6, 73.1, 70.4, 66.9, 29.0, 22.7, 22.4, 21.2, 17.5. HRMS calcd for C₂₀H₂₄O₄Na [M+Na]⁺ 351.1567, found 351.1566.

(2S, 3R, 6R)-2-甲基-6-((Z)-4, 4-二甲基-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3e):无色油状, 111 mg, 产率65%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.98~7.96 (m, 2H), 7.59~7.56 (m, 1H), 7.49~7.46 (m, 2H), 5.96 (ddd, J＝10.3, 2.9, 1.6 Hz, 1H), 5.86 (dt, J＝10.4, 2.1 Hz, 1H), 5.73 (d, J＝1.1 Hz, 1H), 4.94 (dq, J＝7.3, 2.2 Hz, 1H), 4.85 (br, 1H), 3.78~3.71 (m, 1H), 2.05 (s, 3H), 1.08 (d, J＝6.4 Hz, 3H), 1.01 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 199.4, 170.6, 143.3, 137.5, 135.1, 133.3, 130.2, 129.6, 128.5, 126.3, 74.4, 70.3, 67.0, 34.1, 30.2, 21.1, 17.4. HRMS calcd for C₂₁H₂₆O₄Na [M+Na]⁺ 365.1723, found 365.1736.

(2S, 3R, 6R)-2-甲基-6-((Z)-1, 5-二苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3f):黄色油状, 144 mg, 产率74%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.79 (d, J＝7.5 Hz, 2H), 7.58~7.54 (m, 1H), 7.44~7.41 (m, 2H), 7.26~7.15 (m, 3H), 7.01 (d, J＝7.2 Hz, 2H), 5.96~5.87 (m, 3H), 5.04 (br, 1H), 5.00 (dd, J＝7.6, 1.2 Hz, 1H), 3.82~3.75 (m, 1H), 2.66 (t, J＝7.6 Hz, 2H), 2.27~2.21 (m, 2H), 2.10 (s, 3H), 1.09 (d, J＝6.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.7, 170.5, 140.8, 139.1, 137.3, 134.2, 133.5, 129.9, 129.2, 128.7, 128.5, 128.4, 126.8, 126.2, 126.1, 73.1, 70.4, 66.8, 35.4, 35.2, 31.6, 21.2, 17.6. HRMS calcd for C₂₁H₂₇O₄ [M+H]⁺ 391.1904, found 391.1910.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(对甲苯基)-5-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3g):无色油状, 131 mg, 产率65%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.72~7.70 (m, 2H), 7.24~7.15 (m, 5H), 7.03~7.00 (m, 2H), 5.94 (ddd, J＝10.3, 2.8, 1.5 Hz, 1H), 5.91~5.85 (m, 2H), 5.03 (br, 1H), 4.99 (dq, J＝7.6, 2.0 Hz, 1H), 3.80~3.76 (m, 1H), 2.65 (t, J＝7.6 Hz, 2H), 2.41 (s, 3H), 2.27~2.21(m, 2H), 2.10 (s, 3H), 1.09 (d, J＝6.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 196.9, 170.5, 147.9, 147.5, 140.9, 138.2, 134.9, 133.3, 129.6, 128.1, 128.1, 127.9, 125.8, 120.3, 70.7, 68.0, 65.9, 35.3, 34.9, 33.0, 30.0, 22.0, 20.6, 20.5, 15.6, 13.6. HRMS calcd for C₂₆H₂₈O₄Na [M+Na]⁺ 427.1880, found 427.1870.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-丁基苯基)-5-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3h):无色油状, 147 mg, 产率66%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.66~7.63 (m, 2H), 7.30~7.26 (m, 3H), 7.22~7.18 (m, 4H), 6.41 (t, J＝7.5 Hz, 1H), 5.98 (dd, J＝10.2, 1.4 Hz, 1H), 5.89 (ddd, J＝10.2, 4.1, 2.1 Hz, 1H), 5.35~5.34 (m, 1H), 4.84~4.82 (m, 1H), 4.14 (qd, J＝6.6, 2.3 Hz, 1H), 2.98~2.83 (m, 2H), 2.80~2.69 (m, 2H), 2.66 (t, J＝7.7 Hz, 2H), 1.83 (s, 3H), 1.66~1.60 (m, 2H), 1.40~1.34 (m, 2H), 1.30 (d, J＝6.8 Hz, 3H), 0.94 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.2, 170.9, 148.2, 147.8, 141.2, 138.5, 135.2, 133.6, 129.9, 128.5, 128.4, 128.2, 126.1, 120.6, 71.0, 68.4, 66.3, 35.7, 35.3, 33.3, 30.2, 22.4, 20.9, 15.9, 13.9. HRMS calcd for C₂₉H₃₄O₄Na [M+Na]⁺ 469.2349, found 469.2351.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲氧基苯基)-5-苯基- 2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3i):无色油状, 109 mg, 产率52%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.72~7.68 (m, 2H), 7.31~7.28 (m, 2H), 7.22~7.18 (m, 3H), 6.91~6.87 (m, 2H), 6.32 (t, J＝7.4 Hz, 1H), 5.98 (dd, J＝10.3, 1.3 Hz, 1H), 5.87 (ddd, J＝10.2, 4.6, 2.4 Hz, 1H), 5.30~5.29 (m, 1H), 4.85~4.82 (m, 1H), 4.11 (qd, J＝6.7, 2.5 Hz, 1H), 3.87 (s, 3H), 2.96~2.82 (m, 2H), 2.81~2.71 (m, 2H) 1.85 (s, 3H), 1.28 (d, J＝6.8 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 196.3, 170.9, 163.1, 146.7, 141.2, 138.5, 133.6, 132.2, 130.2, 128.5, 128.5, 126.1, 120.8, 113.4, 70.9, 68.4, 66.6, 55.5, 35.3, 30.1, 20.9, 16.0. HRMS calcd for C₂₆H₂₈O₅Na [M+Na]⁺ 443.1829, found 443.1844.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3j):无色油状, 112 mg, 产率68%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.83~7.82 (m, 2H), 7.28~7.26 (m, 2H), 5.98 (ddd, J＝10.3, 3.0, 1.6 Hz, 1H), 5.90~5.82 (m, 2H), 5.07~5.06 (m, 1H), 4.12 (qd, J＝4.1, 2.1 Hz, 1H), 3.85~3.79 (m, 1H), 2.43 (s, 3H), 2.09 (s, 3H), 1.96~1.88 (m, 2H), 1.11 (d, J＝6.4 Hz, 3H), 0.93 (t, J＝7.5 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.5, 171.0, 150.8, 149.2, 137.8, 135.6, 133.8, 130.2, 127.8, 120.9, 70.9, 68.7, 66.6, 29.1, 22.0, 21.3, 16.2, 15.4, 13.6. HRMS calcd for C₂₀H₂₄- O₄Na [M+Na]⁺ 351.1567, found 351.1569.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-乙基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3k):无色油状, 118 mg, 产率69%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.71~7.68 (m, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 6.35 (t, J＝7.7 Hz, 1H), 6.06 (dd, J＝10.2, 1.2 Hz, 1H), 5.88 (ddd, J＝10.2, 4.6, 2.4 Hz, 1H), 5.38~5.36 (m, 1H), 4.88~4.85 (m, 1H), 4.13 (qd, J＝6.8, 2.8 Hz, 1H), 2.71 (q, J＝7.6 Hz, 2H), 2.61~2.53 (s, 3H), 1.30 (d, J＝6.8 Hz, 3H), 1.25 (d, J＝2.6 Hz, 3H), 1.04 (t, J＝7.5 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.5, 171.0, 150.8, 149.2, 137.8, 135.6, 133.8, 130.2, 127.8, 120.9, 70.9, 68.7, 66.6, 29.1, 22.0, 21.3, 16.2, 15.4, 13.6. HRMS calcd for C₂₁H₂₆O₄Na [M+Na]⁺ 365.1723, found 365.1725.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-丁基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3l):无色油状, 135 mg, 产率73%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.69~7.67 (m, 2H), 7.27~7.23 (m, 2H), 6.36 (t, J＝7.6 Hz, 1H), 6.06 (dd, J＝10.2, 1.3 Hz, 1H), 5.89 (ddd, J＝10.2, 4.5, 2.5 Hz, 1H), 5.38~5.36 (m, 1H), 4.88~4.86 (m, 1H), 4.14 (qd, J＝6.7, 3.0 Hz, 1H), 2.67 (t, J＝7.6 Hz, 2H), 2.61~2.54 (m, 2H), 2.08 (s, 3H), 1.64~1.60 (m, 2H), 1.42~1.34 (m, 2H), 1.30 (d, J＝6.8 Hz, 3H), 1.05 (t, J＝7.5 Hz, 3H), 0.94 (t, J＝7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.4, 170.8, 150.7, 150.7, 147.8, 137.7, 135.4, 133.7, 130.0, 128.2, 120.7, 70.8, 68.6, 66.5, 35.7, 33.3, 22.4, 21.9, 21.2, 16.1, 14.0, 13.5. HRMS calcd for C₂₃H₃₀O₄Na [M+Na]⁺ 393.2036, found 393.2038.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲氧基苯基)-2-戊烯- 1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3m):无色油状, 110 mg, 产率64%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.80~7.77 (m, 2H), 6.94~6.90 (m, 2H), 6.26 (t, J＝7.6 Hz, 1H), 6.06 (dd, J＝10.2, 1.2 Hz, 1H), 5.87 (ddd, J＝10.3, 4.1, 2.3 Hz, 1H), 5.32~5.31 (m, 1H), 4.87~4.85 (m, 1H), 4.10 (qd, J＝6.5, 3.1 Hz, 1H), 3.86 (s, 3H), 2.58~2.51 (m, 2H), 2.06 (s, 3H), 1.28 (d, J＝6.8 Hz, 3H), 1.04 (t, J＝7.5 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 196.5, 170.8, 163.0, 148.9, 137.7, 133.5, 132.2, 130.4, 121.0, 113.4, 70.6, 68.7, 66.8, 55.5, 21.8, 21.2, 16.2, 13.6. HRMS calcd for C₂₀H₂₄O₅Na [M+Na]⁺ 367.1516, found 367.1531.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3n):黄色油状, 108 mg, 产率63%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.68~7.65 (m, 2H), 7.25~7.23 (m, 2H), 6.12~6.10 (m, 1H), 6.07 (dd, J＝10.2, 1.3 Hz, 1H), 5.88 (ddd, J＝10.2, 4.3, 2.5 Hz, 1H), 5.36~5.34 (m, 1H), 4.88~4.85 (m, 1H), 4.12 (qd, J＝6.8, 3.0 Hz, 1H), 3.42~3.33 (m, 1H), 2.42 (s, 3H), 2.07 (s, 3H), 1.29 (d, J＝6.8 Hz, 3H), 1.07 (d, J＝6.5 Hz, 3H), 0.98 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.5, 170.8, 155.3, 142.9, 135.8, 135.2, 133.8, 130.1, 128.9, 120.7, 70.6, 68.6, 66.7, 27.5, 22.5, 22.2, 21.6, 21.2, 16.1. HRMS calcd for C₂₁H₂₆O₄Na [M+Na]⁺ 365.1723, found 365.1725.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-乙基苯基)-5-甲基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3o):黄色油状, 133 mg, 产率72%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.84 (d, J＝8.1 Hz, 2H), 7.29 (d, J＝8.1 Hz, 2H), 5.98 (ddd, J＝10.3, 3.2, 1.8 Hz, 1H), 5.91~5.86 (m, 2H), 5.07 (br, 1H), 5.00 (dd, J＝7.7, 1.8 Hz, 1H), 3.86~3.79 (m, 1H), 2.72 (q, J＝7.6 Hz, 2H), 2.09 (s, 3H), 1.91~1.77 (m, 2H), 1.68~1.61 (m, 1H), 1.27 (t, J＝7.6 Hz, 3H), 1.11 (d, J＝6.2 Hz, 3H), 0.82 (t, J＝6.7 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.5, 170.6, 150.4, 139.2, 135.0, 133.7, 130.0, 129.5 128.1, 126.5, 73.2, 70.4, 66.7, 38.5, 29.0, 28.5, 22.4, 22.1, 17.5, 15.1. HRMS calcd for C₂₃H₃₀O₄Na [M+Na]⁺ 393.2036, found 393.2034.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-丁基苯基)-5-甲基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3p):无色油状, 139 mg, 产率70%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.70~7.68 (m, 2H), 7.25~7.23 (m, 2H), 6.39 (t, J＝7.6 Hz, 1H), 6.06 (dd, J＝10.3, 1.2 Hz, 1H), 5.88 (ddd, J＝10.2, 4.2, 2.5 Hz, 1H), 5.37~5.35 (m, 1H), 4.88~4.86 (m, 1H), 4.14 (qd, J＝6.7, 2.7 Hz, 1H), 2.66 (t, J＝7.7 Hz, 2H), 2.46 (t, J＝7.2 Hz, 2H), 2.08 (s, 3H), 1.76~1.68 (m, 1H), 1.64~1.59 (m, 2H), 1.42~1.34 (m, 2H), 1.31 (d, J＝6.8 Hz, 3H), 0.96~0.91 (m, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.4, 170.8, 148.6, 147.8, 138.6, 135.4, 133.8, 129.9, 128.2, 120.5, 70.9, 68.5, 66.2, 37.2, 35.6, 33.3, 28.6, 22.7, 22.6, 22.3, 21.2, 16.0, 13.9. HRMS calcd for C₂₃H₃₀O₄Na [M+Na]⁺ 421.2349, found 421.2351.

(2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(3-氟苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3q):黄色油状, 149 mg, 产率86%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.71 (dt, J＝7.7, 1.2 Hz, 1H), 7.61 (ddd, J＝9.3, 2.6, 1.5 Hz, 1H), 7.49~7.44 (m, 1H), 7.31~7.26 (m, 1H), 5.97 (ddd, J＝10.3, 2.8, 1.5 Hz, 1H), 5.90 (dt, J＝10.3, 2.0 Hz, 1H), 5.68 (dd, J＝10.7, 1.2 Hz, 1H), 5.03~5.01 (m, 1H), 4.99 (dq, J＝7.3, 3.7, 2.2 Hz, 1H), 3.82~3.75 (m, 1H), 2.27~2.15 (m, 1H), 2.08 (m, 3H), 1.12 (d, J＝6.4 Hz, 3H), 0.95 (d, J＝6.5 Hz, 3H), 0.91 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.4, 170.5, 162.8 (d, J_C_—_F＝247.0 Hz), 142.1, 139.7 (d, J_C_—_F＝6.0 Hz), 135.9, 130.19 (d, J_C_—_F＝8.0 Hz), 129.8, 126.6, 125.0, 120.5, 120.6, 120.3 115.7 (d, J_C_—_F＝22.0 Hz), 72.9, 70.2, 67.0, 29.1, 22.6, 22.4, 21.1, 17.4. HRMS calcd for C₂₀H₂₅FO₄ [M+H]⁺ 347.1653, found 347.1650.

(2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(4-氟苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3r):黄色油状, 145 mg, 产率84%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.82~7.77 (m, 2H), 7.15~7.09 (m, 2H), 6.10~6.04 (m, 2H), 5.89 (ddd, J＝10.0, 4.4, 2.4 Hz, 1H), 5.34~5.32 (m, 1H), 4.87~4.85 (m, 1H), 4.11 (qd, J＝6.7, 2.9 Hz, 1H), 3.42~3.32 (m, 1H), 2.07 (s, 3H), 1.19 (d, J＝6.8 Hz, 3H), 1.08 (d, J＝6.6 Hz, 3H), 0.99 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 196.6, 171.1, 165.5 (d, J_C_—_F＝252.0 Hz), 155.7, 136.0, 134.4 (d, J_C_—_F＝3.0 Hz), 133.9, 132.6 (d, J_C_—_F＝9.0 Hz), 121.1, 115.6 (d, J_C_—_F＝22.0 Hz), 71.0, 68.7, 66.8, 27.8, 22.8, 22.5, 21.5, 16.3. HRMS calcd for C₂₀H₂₃FO₄Na [M+Na]⁺ 369.1473, found 369.1478.

(2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(3, 5-二氟苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3s):无色油状, 168 mg, 产率92%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.46~7.40 (m, 2H), 7.06~7.01 (m, 1H), 5.98~5.89 (m, 2H), 5.70 (dd, J＝10.7, 1.2 Hz, 1H), 5.00~4.96 (m, 2H), 3.80~3.74 (m, 1H), 2.22~2.16 (m, 1H), 2.08 (s, 3H), 1.13 (d, J＝6.4 Hz, 3H), 0.96 (d, J＝6.5 Hz, 3H), 0.92 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 196.1, 170.5, 163.1 (dd, J_C_—_F＝249.0, 10.0 Hz), 140.7 (t, J_C_—_F＝7.0 Hz), 135.6, 129.6, 126.7, 115.3 (dd, J_C_—_F＝19.0, 7.0 Hz), 111.95, 108.6 (t, J_C_—_F＝26.0 Hz), 72.7, 70.0, 67.1, 29.2, 22.6, 22.3, 21.1, 18.2, 17.3. HRMS calcd for C₂₀H₂₃F₂O₄ [M+H]⁺ 365.1559, found 365.1567.

(2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(4-氟苯基)-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3t):无色油状, 148 mg, 产率82%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.82~7.77 (m, 2H), 7.14~7.09 (m, 2H), 6.35 (t, J＝7.6Hz, 1H), 6.04 (dd, J＝10.3, 1.2 Hz, 1H), 5.89 (ddd, J＝10.0, 4.4, 2.2 Hz, 1H), 5.35~5.33 (m, 1H), 4.88~4.85 (m, 1H), 4.13 (qd, J＝6.8, 2.8 Hz, 1H), 2.47~2.44 (m, 2H), 2.08 (s, 3H), 1.76~1.66 (m, 1H), 1.31 (d, J＝6.8 Hz, 3H), 0.95 (d, J＝6.7 Hz, 3H), 0.92 (d, J＝6.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 196.1, 170.8, 165.2 (d, J_C_—_F＝253.0 Hz), 148.4, 138.8, 134.2 (d, J_C_—_F＝3.0 Hz), 133.5, 132.2 (d, J_C_—_F＝9.0 Hz), 120.9, 115.3 (d, J_C_—_F＝22.0 Hz), 71.0, 68.4, 66.2, 37.3, 28.7, 22.7, 22.6, 21.2, 16.0. HRMS calcd for C₂₁H₂₅FO₄Na [M+Na]⁺ 383.1629, found 383.1628.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(3-基噻吩)-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3u):黄色油状, 114 mg, 产率68%. ¹H NMR (CDCl₃, 400 MHz) δ: 8.01 (dd, J＝2.9, 1.2 Hz, 1H), 7.55 (dd, J＝5.1, 1.2 Hz, 1H), 7.33 (dd, J＝5.1, 3.0 Hz, 1H), 5.97 (ddd, J＝10.3, 2.9, 1.6 Hz, 1H), 5.88 (dt, J＝10.3, 2.1 Hz, 1H), 5.85~5.81 (m, 1H), 5.06 (br, 1H), 5.00 (dq, J＝7.5, 2.2 Hz, 1H), 3.83~3.76 (m, 1H), 2.08 (s, 3H) 2.02~1.92 (m, 2H), 1.44~1.34 (m, 2H), 1.10 (d, J＝6.4 Hz, 3H), 0.84 (t, J＝7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 192.5, 170.6, 142.9, 139.6, 134.7, 134.3, 130.0, 127.2, 126.6, 126.5, 73.0, 70.4, 66.9, 31.8, 22.5, 21.2, 17.5, 13.7. HRMS calcd for C₁₈H₂₃O₄S [M+H]⁺ 357.1132, found 357.1132.

(2S, 3R, 6R)-2-甲基-6-((Z)-2-辛烯-4-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3v):黄色油状, 113 mg, 产率81%. ¹H NMR (CDCl₃, 400 MHz) δ: 5.94~5.83 (m, 3H), 5.00~4.97 (m, 2H), 3.76~3.70 (m, 1H), 2.71~2.55 (m, 2H), 2.08 (s, 3H), 1.85 (dd, J＝7.2, 1.1 Hz, 3H), 1.65~1.57 (m, 2H), 1.40~1.31 (m, 2H), 1.18 (d, J＝6.4 Hz, 3H), 0.92 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 206.1, 170.6, 141.0, 133.2, 130.4, 126.2, 71.7, 70.2, 66.8, 42.3, 25.7, 22.4, 21.1, 17.6, 15.3, 13.9. HRMS calcd for C₁₆H₂₅O₄ [M+H]⁺ 281.1747, found 281.1751.

(2S, 3R, 6R)-2-甲基-6-((Z)-2-十二烯-4-酮)-3, 6-二氢- 2H-吡喃-3-基乙酸酯(3w):无色油状, 124 mg, 产率74%. ¹H NMR (CDCl₃, 400 MHz) δ: 5.94~5.81 (m, 3H), 5.00~4.97 (m, 2H), 3.76~3.69 (m, 1H), 2.70~2.54 (m, 2H), 2.08 (s, 3H), 1.85 (dd, J＝7.2, 1.0 Hz, 3H), 1.66~1.58 (m, 2H), 1.32~1.24 (m, 10H), 1.18 (d, J＝6.4 Hz, 3H), 0.89~0.86 (m, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 206.1, 170.5, 141.0, 133.2, 130.4, 126.2, 71.7, 70.3, 66.7, 42.6, 31.8, 29.4, 29.3, 29.2, 23.6, 22.6, 21.1, 17.6, 15.3, 14.1. HRMS calcd for C₂₀H₃₃O₄ [M+H]⁺ 337.2373, found 337.2378.

(2S, 3R, 6R)-2-甲基-6-((Z)-2-甲基-3-壬烯-5-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3x):黄色油状, 117 mg, 产率76%. ¹H NMR (CDCl₃, 400 MHz) δ: 5.94~5.86 (m, 2H), 5.47 (dd, J＝10.2, 1.1 Hz, 1H), 5.00~4.94 (m, 2H), 3.75~3.69 (m, 1H), 2.70~2.53 (m, 3H), 2.08 (s, 3H), 1.64~1.56 (m, 3H), 1.39~1.32 (m, 2H), 1.18 (d, J＝6.4 Hz, 3H), 1.05 (d, J＝6.6 Hz, 3H), 0.97 (d, J＝6.6 Hz, 3H), 0.92 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 206.8, 170.9, 144.5, 138.5, 130.7, 126.5, 72.2, 70.5, 67.0, 43.0, 28.9, 26.0, 23.3, 23.2, 22.7, 21.4, 17.9, 14.2. HRMS calcd for C₁₈H₂₉O₄ [M+H]⁺ 309.2060, found 309.2063.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲基苯基)-1-庚烯-3-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3y):黄色油状, 116 mg, 产率65%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.14~7.09 (m, 4H), 6.69 (s, 1H), 6.01 (ddd, J＝10.3, 2.9, 1.5 Hz, 1H), 5.95 (dt, J＝10.3, 2.0 Hz, 1H), 5.14~5.12 (m, 1H), 5.04 (dq, J＝7.2, 2.4 Hz, 1H), 3.88~3.81 (m, 1H), 2.35 (s, 3H), 2.33~2.23 (m, 2H), 2.12 (s, 3H), 1.59~1.55 (m, 2H), 1.54~1.42 (m, 2H), 1.22 (d, J＝6.3 Hz, 3H), 0.79 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 209.4, 170.5, 141.3, 138.6, 132.4, 132.4, 130.2, 129.2, 128.6, 126.6, 73.1, 70.4, 67.0, 43.3, 25.7, 22.0, 21.3, 21.2, 17.7, 13.8. HRMS calcd for C₂₂H₂₉O₄ [M+H]⁺ 357.2060, found 357.2066.

3.2.2 化合物4的合成

在25 mL的Schlenk管内, 依次加入L-鼠李烯糖1 (0.5 mmol), 炔丙酯2 (0.5 mmol), CH₃NO₂ (5 mL), 室温搅拌10 min后, 迅速加入Ph₃PAuCl (12.3 mg, 5 mol%)和AgSbF₆ (6.5 mg, 5 mol%).室温下搅拌6 h, TLC检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.硅胶快速色谱法(石油醚/乙酸乙酯, V:V＝10:1)纯化残余物, 得到C-乙烯基鼠李糖苷衍生物4.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-苯基乙酸酯(4ba):无色油状, 143 mg, 产率76%. ¹H NMR (CDCl₃, 400 MHz) δ: 8.05~8.03 (m, 2H), 7.97~7.94 (m, 2H), 7.61~7.56 (m, 2H), 7.51~7.44 (m, 4H), 6.04~6.03 (m, 1H), 5.92 (td, J＝7.7, 1.2 Hz, 1H), 5.27~5.24 (m, 1H), 5.13 (br, 1H), 4.03~3.97 (m, 1H), 3.49 (d, J＝5.4 Hz, 1H), 2.05~1.88 (m, 2H), 1.19 (d, J＝6.3 Hz, 3H), 0.96 (t, J＝7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.8, 166.1, 137.9, 137.5, 136.7, 133.5, 133.2, 130.3, 130.1, 129.7, 129.3, 128.7, 128.4, 126.5, 73.1, 70.8, 67.2, 23.3, 17.6, 13.7. HRMS calcd for C₂₄H₂₄O₄Na [M+Na]⁺ 399.1567, found 399.1566.

(2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-苯基乙酸酯(4bb):无色油状, 148 mg, 产率73%. ¹H NMR (CDCl₃, 400 MHz) δ: 8.05~8.02 (m, 2H), 7.96~7.93 (m, 2H), 7.61~7.56 (m, 2H), 7.50~7.43 (m, 4H), 6.07~6.03 (m, 2H), 5.97 (td, J＝7.0, 1.2 Hz, 1H), 5.27~5.24 (m, 1H), 5.13 (br, 1H), 4.03~3.97 (m, 1H), 1.93~1.77 (m, 2H), 1.72~1.65 (m, 1H), 1.19 (d, J＝6.3 Hz, 3H), 0.84 (t, J＝6.9 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.9, 166.1, 139.2, 137.4, 134.4, 133.4, 133.2, 130.3, 130.1, 129.7, 129.3, 128.7, 128.4, 126.5, 73.2, 70.8, 67.1, 38.5, 28.6, 22.4, 22.2, 17.6. HRMS calcd for C₂₆H₂₈O₄ Na [M+Na]⁺ 427.1880, found 427.1881.

(2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(2-氯苯基)-乙酸酯(4ca):无色油状, 162 mg, 产率74%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.93~7.91 (m, 2H), 7.78 (dd, J＝7.7, 1.5 Hz, 1H), 7.60~7.55 (m, 1H), 7.49~7.41 (m, 4H), 7.35~7.29 (m, 1H), 6.08~6.03 (m, 2H), 5.95 (td, J＝7.1, 1.3 Hz, 1H), 5.28~5.26 (m, 1H), 5.13 (br, 1H), 4.04~3.97 (m, 1H), 1.90~1.75 (m, 2H), 1.69~1.63 (m, 1H), 1.22 (d, J＝6.3 Hz, 3H), 0.82 (t, J＝6.4 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.8, 165.4, 139.1, 137.4, 134.5, 133.7, 133.4, 132.7, 131.4, 131.1, 130.7, 130.1, 129.3, 128.7, 126.6, 126.0, 73.1, 71.5, 67.0, 38.5, 28.5, 22.4, 22.2, 17.7. HRMS calcd for C₂₆H₂₇ClO₄Na [M+Na]⁺ 461.1490, found 461.1491.

(2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(3-氯苯基)-乙酸酯(4da):无色油状, 164 mg, 产率75%. ¹H NMR (CDCl₃, 400 MHz) δ: 8.04 (t, J＝1.9 Hz, 1H), 7.95 (dt, J＝7.8, 1.4 Hz, 1H), 7.78~7.76 (m, 2H), 7.56~7.52 (m, 2H), 7.46~7.42 (m, 2H), 7.37 (t, J＝7.9 Hz, 1H), 6.42 (t, J＝7.4 Hz, 1H), 6.15 (dd, J＝10.2, 1.8 Hz 1H), 6.01 (ddd, J＝10.2, 4.7, 2.5 Hz, 1H), 5.46~5.44 (m, 1H), 5.12~5.10 (m, 1H), 4.31 (qd, J＝7.1, 2.4 Hz, 1H), 2.57~2.44 (m, 2H), 1.76~1.69 (m, 1H), 1.39 (d, J＝6.8 Hz, 3H), 0.88 (t, J＝7.2 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.6, 165.2, 149.2, 138.7, 138.0, 134.5, 133.1, 132.2, 131.9, 129.8, 129.7, 129.7, 128.2, 128.0, 120.4, 71.2, 69.4, 66.0, 37.3, 28.7, 22.6, 22.5, 16.0. HRMS calcd for C₂₆H₂₇ClO₄Na [M+Na]⁺ 461.1490, found 461.1491.

(2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(2-氟苯基)-乙酸酯(4ea):无色油状, 160 mg, 产率76%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.94~7.89 (m, 3H), 7.60~7.53 (m, 2H), 7.50~7.49 (m, 2H), 7.22~7.13 (m, 2H), 6.07~6.01 (m, 2H), 5.96 (td, J＝7.0, 1.2 Hz, 1H), 5.27~5.24 (m, 1H), 5.13 (br, 1H), 4.03~3.97 (m, 1H), 1.92~1.75 (m, 2H), 1.69~1.62 (m, 1H), 1.20 (d, J＝6.4 Hz, 3H), 0.83 (m, J＝6.4 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.9, 164.0, 164.0, 162.0 (d, J_C_—_F＝259.0 Hz), 139.1, 137.4, 134.7 (d, J_C_—_F＝9.0 Hz), 134.5, 133.4, 132.1, 130.4, 129.3, 128.7, 126.4, 124.0 (d, J_C_—_F＝4.0 Hz), 118.8, 118.7, 117.0 (d, J_C_—_F＝22.0 Hz), 73.2, 71.4, 66.9, 38.5, 28.6, 22.4, 22.2, 17.6. HRMS calcd for C₂₆H₂₇FO₄Na [M+Na]⁺ 445.1786, found 445.1784.

(2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(4-氟苯基)-乙酸酯(4fa):无色油状, 165 mg, 产率78%. ¹H NMR (CDCl₃, 400 MHz) δ: 8.09~8.06 (m, 2H), 7.78~7.76 (m, 2H), 7.56~7.52 (m, 1H), 7.46~7.42 (m, 2H), 7.12~7.6 (m, 2H), 6.40 (t, J＝7.4 Hz, 1H), 6.14 (dd, J＝10.3, 1.9 Hz, 1H), 6.01 (ddd, J＝10.3, 4.8, 2.5 Hz, 1H), 5.45~5.44 (m, 1H), 5.11~5.09 (m, 1H), 4.30 (qd, J＝6.8, 2.4 Hz, 1H), 2.57~2.43 (m, 2H), 1.75~1.66 (m, 1H), 1.39 (d, J＝6.8 Hz, 3H), 0.88 (t, J＝6.8 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.6, 165.8 (d, J_C_—_F＝253.0 Hz), 165.4, 148.8, 138.8, 138.1, 134.2, 132.4 (d, J_C_—_F＝9.0 Hz), 132.2, 129.7, 128.2, 126.3 (d, J_C_—_F＝3.0 Hz), 120.7, 115.5 (d, J_C_—_F＝22.0 Hz), 71.2, 69.1, 66.0, 37.3, 28.7, 22.6, 22.5, 16.1. HRMS calcd for C₂₆H₂₇- FO₄Na [M+Na]⁺ 445.1786, found 445.1784.

3.2.3 化合物5a~5b的合成

在25 mL的Schlenk管内, 依次加入L-岩藻烯糖1g (107 mg, 0.5 mmol), 炔丙酯2 (0.5 mmol)以及CH₃NO₂ (5 mL).室温搅拌10 min后, 迅速加入Ph₃PAuCl (12.3 mg, 5 mol%)和AgSbF₆ (6.5 mg, 5 mol%).室温下搅拌6 h, TLC检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.硅胶快速色谱法(PE:EtOAc, V:V＝20:1)纯化残余物, 得到C-乙烯基岩藻糖苷衍生物5.

(2S, 3S, 6R)-2-甲基-6-((Z)-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(5a):无色油状, 151 mg, 产率96%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.91~7.88 (m, 2H), 7.61~7.57 (m, 1H), 7.50~7.46 (m, 2H), 6.17~6.07 (m, 2H), 5.80 (td, J＝7.7, 1.3 Hz, 1H), 5.20~5.19 (m, 1H), 5.00 (dd, J＝4.8, 2.4 Hz, 1H), 4.06 (qd, J＝6.5, 2.4 Hz, 1H), 2.09 (s, 3H), 1.98~1.90 (m, 2H) 1.08 (d, J＝6.6 Hz, 3H), 0.94 (t, J＝7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.7, 170.9, 137.5, 137.4, 136.7, 133.4, 132.1, 129.1, 128.7, 124.7, 73.7, 66.2, 66.0, 23.2, 20.9, 16.0, 13.7. HRMS calcd for C₁₉H₂₂O₄Na [M+Na]⁺ 337.1410, found 337.1412.

(2S, 3S, 6R)-2-甲基-6-((Z)-5-甲基-1-(4-丁基苯基)-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(5b):无色油状, 183 mg, 产率92%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.73~7.71 (m, 2H), 7.26~7.24 (m, 2H), 6.17 (t, J＝7.5 Hz, 1H), 6.09 (dd, J＝10.1, 2.9 Hz, 1H), 5.95 (ddd, J＝10.2, 4.6, 2.4 Hz, 1H), 5.39 (br, 1H), 5.14~5.12 (m, 1H), 4.22 (qd, J＝6.6, 3.1 Hz, 1H), 2.67 (t, J＝7.7 Hz, 2H), 2.34 (t, J＝7.2 Hz, 2H), 1.77~1.70 (m, 1H), 1.66~1.60 (m, 2H), 1.42~1.32 (m, 2H), 1.16 (d, J＝6.5 Hz, 3H), 0.96~0.92 (m, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 197.3, 170.8, 148.4, 144.5, 139.5, 135.5, 132.6, 130.1, 128.4, 122.7, 69.0, 68.0, 66.8, 37.3, 35.7, 33.3, 29.7, 28.6, 22.6, 22.5, 22.4, 21.0, 15.5, 13.9. HRMS calcd for C₂₅H₃₄O₄Na [M+Na]⁺ 421.2349, found 421.2341.

3.2.4 化合物3a-¹⁸O的合成

在25 mL的Schlenk管内, 依次加入L-鼠李烯糖1a (54 mg, 0.25 mmol), 炔丙酯2a-¹⁸O (54 mg, 0.25 mmol), 以及CH₃NO₂ (3 mL).室温搅拌10 min后, 快速加入Ph₃PAuCl (6 mg, 5 mol%)和AgSbF₆ (3 mg, 5 mol%).室温下搅拌6 h, TLC检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.通过硅胶快速色谱法(石油醚/乙酸乙酯, V:V＝20:1)纯化残余物, 得到C-乙烯基鼠李糖苷衍生物3a-¹⁸O.

(2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-己烯-1-(酮- ¹⁸O))-3, 6-二氢-2H-吡喃-3-基乙酸酯(3a-¹⁸O):无色油状, 65 mg, 产率79%. ¹H NMR (CDCl₃, 400 MHz) δ: 7.93~7.90 (m, 2H), 7.60~7.56 (m, 1H), 7.49~7.46 (m, 2H), 5.98 (ddd, J＝10.3, 2.9, 1.6 Hz, 1H), 5.91~5.87 (m, 2H), 5.08 (br, 1H), 5.00 (dq, J＝7.6, 2.2 Hz, 1H), 3.85~3.79 (m, 1H), 2.09 (s, 3H), 1.95~1.86 (m, 2H), 1.42~1.34 (m, 2H), 1.11 (d, J＝6.3 Hz, 3H), 0.81 (t, J＝7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 198.8, 198.8, 170.5, 138.6, 137.5, 135.2, 133.4, 130.1, 129.2, 128.6, 126.6, 73.1, 70.4, 66.9, 31.7, 29.7, 22.4, 21.2, 17.5, 13.7. HRMS calcd for C₂₀H₂₄O₃¹⁸ONa [M+Na]⁺ 353.1609, found 353.1610.

辅助材料(Supporting Information) 化合物3, 4, 5的核磁谱图, 化合物3g (CCDC 1965665)的单晶结构数据.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图 1 化合物3g的晶体结构

Figure 1 X-ray single crystal structure of 3g

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图式 1 可能的反应机理

Scheme 1 Possible reaction mechanism

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图 2 化合物3i的胃癌细胞毒活性

Figure 2 Cytotoxities against HGC-27 cells of compound 3i

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表 1 模型反应条件优化^a

Table 1. Optimization of reaction conditions for the model reaction


Entry	Catalyst	Solvent	Time/h	Yield^b/%
1	Au₂O₃	CH₂Cl₂	24	N.D.
2	TiCl₄	CH₂Cl₂	24	N.D.
3	Ni(CO)₄	CH₂Cl₂	24	N.D.
4	PdCl₂	CH₂Cl₂	24	N.D.
5	Ag₂CO₃	CH₂Cl₂	24	N.D.
6	AuCl₃	CH₂Cl₂	6	21
7	AuBr₃	CH₂Cl₂	6	12
8	AuCl	CH₂Cl₂	6	31
9	Ph₃PAuCl	CH₂Cl₂	24	N.D.
10	AgSbF₆	CH₂Cl₂	24	N.D.
11	Au(CO)Cl/AgSbF₆	CH₂Cl₂	6	24
12	Ph₃PAuCl/AgSbF₆	CH₂Cl₂	6	58
13	Ph₃PAuNTf₂/AgSbF₆	CH₂Cl₂	6	42
14	Ph₃PAuCl/AgNO₃	CH₂Cl₂	6	28
15	Ph₃PAuCl/CH₃CO₂Ag	CH₂Cl₂	6	37
16	Ph₃PAuCl/Ag₂CO₃	CH₂Cl₂	6	45
17	Ph₃PAuCl/Ag₃PO₄	CH₂Cl₂	6	48
18	(C₅H₅N)AuCl₃/AgSbF₆	CH₂Cl₂	6	46
19	Ph₃PAuCl/AgSbF₆	DMF	6	N.D.
20	Ph₃PAuCl/AgSbF₆	CHCl₃	6	36
21	Ph₃PAuCl/AgSbF₆	Toluene	6	25
22	Ph₃PAuCl/AgSbF₆	CH₃NO₂	6	78
23	Ph₃PAuCl/AgSbF₆	CH₃CN	6	12
24	Ph₃PAuCl/AgSbF₆	EtOAc	6	N.D.
^aGeneral conditions: catalyst (5 mol%) was added into the mixture of 1a (107 mg, 0.5 mmol) and 2a (113 mg, 0.5 mmol) in corresponding solvent (5 mL). ^b Isolated yield. N.D.＝not detected.

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表 2 C-乙烯基鼠李糖苷衍生物的底物拓展

Table 2. Substrate scope for C--vinyl-rhamnopyranoside derivatives

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表 3 C-乙烯基鼠李糖苷衍生物的底物扩展

Table 3. Substrate expansion of C-vinyl-rhamnopyranoside derivatives


Entry	R¹ (1)	R²	Yield/% (4)
1	Ph (1b)	Et	76 (4ba)
2	Ph (1b)	ⁱBu	73 (4bb)
3	2-ClC₆H₄ (1c)	ⁱBu	74 (4ca)
4	3-ClC₆H₄ (1d)	ⁱBu	75 (4da)
5	2-FC₆H₄ (1e)	ⁱBu	76 (4ea)
6	4-FC₆H₄ (1f)	ⁱBu	78 (4fa)

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表 4 目标化合物的细胞毒活性

Table 4. Cytotoxic activity of target compounds

化合物	IC₅₀值/(μmol•L^－¹)
化合物	胃癌细胞	宫颈癌细胞	肝癌细胞	人胃粘膜细胞
3a~3h	＞100	＞100	＞100	＞100
3i	18.29	＞100	＞100	＞100
3j~3o	＞100	＞100	＞100	＞100
3p	82.91	＞100	＞100	＞100
3q~3y	＞100	＞100	＞100	＞100
4ba	＞100	＞100	＞100	＞100
4bb	90.21	＞100	＞100	＞100
4ca~4fa	＞100	＞100	＞100	＞100
5a~5b	＞100	＞100	＞100	＞100

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