CN105541774B - 3,4-二氢香豆素类化合物及其制备方法和用途 - Google Patents
3,4-二氢香豆素类化合物及其制备方法和用途 Download PDFInfo
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- CN105541774B CN105541774B CN201610019328.7A CN201610019328A CN105541774B CN 105541774 B CN105541774 B CN 105541774B CN 201610019328 A CN201610019328 A CN 201610019328A CN 105541774 B CN105541774 B CN 105541774B
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- carboxylic acid
- chroman
- ethyl esters
- methoxybenzamidos
- oxos
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- -1 3,4- dihydrocoumarin class compounds Chemical class 0.000 title claims abstract description 70
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims abstract description 11
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 7
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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Abstract
本发明提供了一种3,4‑二氢香豆素类化合物及其制备方法和用途，所述化合物为式I所示化合物，其立体异构体或其混合物形式：其中，R1选自氢；R2选自C6‑10芳基C2‑6炔基、C3‑8环烷基C2‑6炔基、三C1‑6烷基硅基C2‑6炔基、C6‑10芳基C1‑6烷基、C3‑8环烷基C1‑6烷基、三C1‑6烷基硅基C1‑6烷基、C1‑6烷基、C3‑8环烷基、C6‑10芳基、C5‑10杂芳基、C2‑6烯基、C2‑6炔基、C5‑10杂芳基C6‑10芳基；其中，C6‑10芳基可任选的被一个或多个独立选自氢、C1‑6烷基、C3‑8环烷基、C1‑6烷氧基、卤素、C2‑6烯基、C2‑6炔基的基团取代；C5‑10杂芳基可选的被一个或多个独立选自氢或对甲苯磺酰基的基团取代；或R1与R2同与他们连接的碳原子一起形成C5‑6环烷基。该类化合物能够用于治疗癌症相关疾病。
Description
技术领域
本发明涉及消旋或手性3,4-二氢香豆素类化合物，其合成方法，以及该类化合物在抑制肿瘤细胞增殖中的应用。
背景技术
3,4-二氢香豆素，又名二氢色满酮或苯并二氢吡喃酮，其衍生化合物有重要的生物活性，可用于治疗诸如癌症，烧伤，心血管以及风湿性疾病。而且，这类化合物已经展示出了潜在的抗水肿和抗炎活性。正是因为其广泛的生物活性，3,4-二氢香豆素衍生化合物已作为生物活性测试中的候选药物。鉴于此，高效，高对映选择性的合成这类化合物一直吸引着许多化学家和药物学家们的广泛关注。
传统关于3,4-二氢香豆素衍生化合物的合成方法相对较少，现有关于该类化合物的合成方法主要是通过甲氧基肉桂酸乙酯和2-萘酚来合成的。然而该方法仍然存在很大的局限性即：缺电子肉桂酸乙酯反应效率不高，产率较低，需要升高温度来提高反应效率。对于高效，高对映选择性的构建这类分子具有很大的挑战性，一直以来都受到化学家的关注。近年来，冯小明课题组，叶松课题组相继报道了这类化合物的合成，但大多数是基于富电子的o-QM。因此发展更加高效，更具有普适性的方法来构建3,4-二氢香豆素衍生化合物方法具有十分重要的意义。通过对已知方法的查阅，我们发现利用手性磷酸催化的策略，通过邻羟基苄醇和吖内酯的环化反应来直接构建3,4-二氢香豆素衍生化合物，尚未见文献报道。
基于以上分析，申请人拟发展磷酸催化的[4+2]环化反应来高效、高对映选择性地合成具有多取代的3,4-二氢香豆素类化合物，此方法简单，条件温和。并将这一类化合物用于抗肿瘤细胞增值活性的筛选，结果表明我们设计并合成的3,4-二氢香豆素类化合物对HepG2(肝癌细胞系)；MG63(骨肉瘤细胞系)；SW620(胶质瘤细胞系)等三种常见肿瘤细胞表现出良好的抑制活性，有极大的发展前景。
发明内容
本发明涉及一种3,4-二氢香豆素类化合物，所述化合物为式I所示化合物、其立体异构体或其混合物形式：
其中，R1选自氢；
R2选自C6-10芳基C2-6炔基、C3-8环烷基C2-6炔基、三C1-6烷基硅基C2-6炔基、C6-10芳基C1-6烷基、C3-8环烷基C1-6烷基、三C1-6烷基硅基C1-6烷基、C1-6烷基、C3-8环烷基、C6-10芳基、C5-10杂芳基、C2-6烯基、C2-6炔基、C5-10杂芳基C6-10芳基；其中，C6-10芳基可任选的被一个或多个独立选自氢、C1-6烷基、、C3-8环烷基、C1-6烷氧基、卤素、C2-6烯基、C2-6炔基的基团取代；C5-10杂芳基可选的被一个或多个独立选自氢或对甲苯磺酰基的基团取代。
或R1与R2同与他们连接的碳原子一起形成C5-6环烷基。
优选的，R2选自C6-10芳基乙炔基、C3-8环烷基乙炔基、三C1-6烷基硅基乙炔基、C6-10芳基乙基、C3-8环烷基乙基、C1-6烷基硅基乙基、C1-6烷基、C3-8环烷基、C6-10芳基、C5-10杂芳基、C2-6烯基、C2-6炔基、C5-10杂芳基C6-10芳基；其中，C6-10芳基可任选的被一个或多个独立选自氢、C1-6烷基、卤素或C2-6炔基的基团取代；C5-10杂芳基可选的被一个或多个独立选自氢或对甲苯磺酰基取代；或R1与R2同与他们连接的碳原子一起形成C5-6环烷基。
更进一步优选的，R2选自苯乙炔基、4-甲基苯乙炔基、4-氯苯乙炔基、3-氟苯乙炔基、环丙基乙炔基、三甲基硅基乙炔基、苯乙基、4-甲基苯乙基、4-氯苯乙基、3-氟苯乙基、环丙基乙基、三甲基硅基乙基、乙基、4-乙炔基苯基、环己基、2-噻吩基、乙烯基、或
或R1与R2同与他们连接的碳原子一起形成环戊烷基。
本发明基团中的波浪线表示与其他基团的连接点。
更优选的，式I的立体异构体具有Ia或Ib结构：
其中，R1、R2的的定义如上所述。
更具体的，本发明涉及一种化合物，选自：
3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯；
3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯；
4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯；
(3R,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯；
(3S,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯；
4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯；
4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯；
(3R,3aR)-3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯；
(3S,3aS)-3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯。
本发明还涉及一种式I所示化合物、其立体异构体或其混合物形式的制备方法，特征在于式I由邻羟基苄醇化合物A和吖内酯化合物B在催化剂的作用下通过[4+2]环化反应制得：
其中，催化剂可选为磷酸或手性磷酸，优选为磷酸二苯酯、R-CPA或S-CPA。R-CPA：Ar:9-Anthracenyl；S-CPA：Ar:9-Anthracenyl。
其中，催化剂的用量为A的5～20mol％，B与A的摩尔比为1:1～2:1，反应在有机溶剂下进行。
该反应对有机溶剂没有特别的要求，能够制备得到本发明式I化合物的有机溶剂皆可，优选二氯甲烷、甲苯。
该反应对温度没有特别的要求，能够制备得到本发明式I化合物的温度范围皆可，优选室温。
本发明探索发现，磷酸二苯酯催化条件下，通过邻羟基苄醇A和吖内酯B的[4+2]环化反应，可以高效、高选择性地合成式I结构的3,4-二氢香豆素类化合物；当选择R-CPA手性磷酸催化时，可以高效、高对映选择性地合成式Ia结构的手性3,4-二氢香豆素类化合物；当选择S-CPA手性磷酸催化时，可以高效、高对映选择性地合成式Ib结构的手性3,4-二氢香豆素类化合物。
本发明还发现，本发明涉及的3,4-二氢香豆素类化合物对HepG2(肝癌细胞系)；MG63(骨肉瘤细胞系)；SW620(胶质瘤细胞系)等三种常见肿瘤细胞生长具有抑制作用，因此，本发明涉及的化合物可用于制备抗肿瘤药物中的应用，优选的，可用于制备治疗肝癌、骨肉瘤、胶质瘤或其他恶性肿瘤的药物的应用。
发明的详细说明
除非有相反陈述，下列用在说明书和权利要求中的术语具有下述含义。
“烷基”指饱和的脂族烃基团。包括1至6个碳原子的直链或支链基团。例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。更优选的是含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。
“环烷基”指3至8元全碳单环、全碳5元/6元或6元/6元稠和环或多环稠和环(“稠和”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个或多个环具有完全连接的π电子系统，环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。
“芳基”表示6至10个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。“芳基”包括：
六元的碳芳香环，如，苯；
双环，其中至少有一个环是碳芳香环，如，萘，茚和1,2,3,4-四氢喹啉。
“杂芳基”表示5至10个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。杂芳基的例子，包括但不限于，吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、三唑、嘧啶、吡啶、吡啶酮、咪啶、吡嗪、哒嗪、吲哚、氮杂吲哚、苯并咪唑、吲哚啉、吲哚酮、喹啉、异喹啉、喹唑啉、噻吩并吡啶、噻吩并嘧啶等。此类基团的优选实施例为噻吩、三唑。
“烯基”表示具有1个或多个双键的直链或支链烃基。典型地为C2-C6烯基，例如乙烯基、烯丙基、丁烯基、丁二烯基、戊烯基或己烯基。
“炔基”表示具有1个或多个三键的直链或支链烃基。典型地为C2-C6炔基，例如乙炔基、丙炔基、丁炔基。
“烷氧基”表示-O-(未取代的烷基)和-O(未取代的环烷基)。代表性的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“卤素”表示氟、氯、溴或碘。
在一些实施方案中，“被一个或多个基团取代”是指在指定的原子或基团中的一个、两个、三个或四个氢原子分别被指定范围的基团中选出的相同或不同的基团替换。
具体实施方式
下面通过实例来具体说明本发明的Ⅰ以及II式中化合物的制备方法。这些实例仅对本发明进行说明，而不对本发明进行限制。
实施例1
化合物I-1 3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯的制备
在室温下，原料邻羟基苄醇A(44.8mg,0.2mmol),1.5当量的吖内酯B(78.9mg,0.3mmol)，10.0mol％的磷酸二苯酯(5mg,0.01mmol)溶于无水二氯甲烷中，用TLC检测反应直到反应完全，以V石油醚/V乙酸乙酯＝15:1-5:1柱层析直接得到式I-1目标产物，产率为84％。在实施例1中，邻羟基苄醇A为2-(1-羟基-3-苯基丙-2-炔-1-基)苯酚。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.89(d,J＝7.4Hz,2H),7.75(s,1H),7.60(d,J＝8.1Hz,1H),7.46(d,J＝6.5Hz,2H),7.35(t,J＝7.3Hz,4H),7.21(t,J＝7.3Hz,1H),7.13(d,J＝8.2Hz,1H),6.97(d,J＝8.5Hz,2H),5.65(s,1H),4.26–4.20(m,1H),4.06–4.01(m,1H),3.87(s,3H),0.90(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝166.10,165.25,162.90,162.11,150.29,131.80,129.29,129.04,128.75,128.35,127.35,124.97,124.80,122.07,120.80,116.26,113.87,86.93,82.69,65.13,63.58,55.41,36.86,13.42。
高分辨：计算值：[M+H]+:470.1598；实测值：470.1595.
实施例2
化合物I-2 3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(1-羟基-3-(对甲苯基)丙-2-炔-1-基)苯酚，其他条件不变，得到式I-2目标产物，产率为85％。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.88(d,J＝8.7Hz,2H),7.74(s,1H),7.60(d,J＝7.6Hz,1H),7.34(d,J＝7.8Hz,3H),7.20(d,J＝7.5Hz,1H),7.16–7.09(m,3H),6.95(s,2H),5.62(s,1H),4.25-4.20(m,1H),4.04-4.00(m,1H),3.86(s,3H),2.36(s,3H),0.89(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝166.03,165.21,162.84,162.14,150.23,138.94,129.26,129.05,128.97,127.37,124.95,124.76,120.90,118.95,116.19,113.82,87.03,81.91,65.12,63.53,55.39,36.85,21.43,13.40。
高分辨：计算值：[M+Na]+:506.1576，实测值：506.1566.
实施例3
化合物I-3 4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(3-(4-氯苯基)-1-羟基丙-2-炔-1-基)苯酚，其他条件不变，得到式I-3目标产物，产率为80％。
1H NMR(400MHz,CDCl3)δ(ppm)δ＝7.85(d,J＝8.8Hz,2H),7.69(s,1H),7.54(d,J＝7.6Hz,1H),7.38–7.22(m,5H),7.17(t,J＝7.5Hz,1H),7.09(d,J＝8.1Hz,1H),6.93(d,J＝8.8Hz,2H),5.64(s,1H),4.24-4.16(m,1H),4.05-3.97(m,1H),3.84(s,3H),0.88(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.81,164.94,162.66,161.77,150.03,134.67,132.86,129.12,128.97,128.54,127.07,124.69,120.37,120.34,116.20,113.75,85.80,83.73,65.05,63.66,55.48,36.96,13.60。
高分辨：计算值：[M+Na]+:526.1028，实测值：526.1035。
实施例4
化合物I-4 4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(3-(3-氟苯基)-1-羟基丙-2-炔-1-基)苯酚，其他条件不变，得到式I-4目标产物，产率为81％。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.89(d,J＝8.6Hz,2H),7.73(s,1H),7.57(d,J＝7.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.32–7.29(m,1H),7.24–7.20(m,2H),7.14(t,J＝8.5Hz,2H),7.07(t,J＝8.6Hz,1H),6.97(d,J＝8.6Hz,2H),5.66(s,1H),4.25-4.20(m,1H),4.07-4.01(m,1H),3.87(s,3H),0.90(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.79,164.87,162.63,161.92(d,J＝244.9Hz),160.70,149.99,129.84(d,J＝8.52Hz),129.07,128.97,127.54,127.53(d,J＝2.79Hz),124.68,124.63,123.59(d,J＝10.04Hz),120.26,118.43(d,J＝22.59Hz),116.15,115.92,113.72,85.62,83.68,64.99,63.65,55.42,36.87,13.55。
高分辨：计算值：[M+Na]+:510.1323，实测值：510.1328。
实施例5
化合物I-5 4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(3-环丙基-1-羟基丙-2-炔-1-基)苯酚，其他条件不变，得到式I-5目标产物，产率为79％。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.87(d,J＝8.4Hz,2H),7.64(s,1H),7.49(d,J＝7.6Hz,1H),7.31(t,J＝7.7Hz,1H),7.18(t,J＝7.5Hz,1H),7.07(d,J＝8.1Hz,1H),6.98(d,J＝8.3Hz,2H),5.32(s,1H),4.20–4.14(m,1H),4.02–3.97(m,1H),3.88(s,3H),1.30–1.27(m,1H),0.88(t,J＝7.1Hz,3H),0.83–0.80(m,2H),0.69–0.66(m,2H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝141.46,136.59,131.08,130.60,128.44,127.59,127.53,126.78,126.53,82.47,63.96,15.31。
高分辨：计算值：[M+Na]+:456.1418，实测值：456.1417。
实施例6
化合物I-6 3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(1-羟基-3-(三甲基硅基)丙-2-炔-1-基)苯酚，其他条件不变，得到式I-6目标产物，产率为80％。
1H NMR(400MHz,CDCl3)δ(ppm)δ＝7.87(d,J＝8.8Hz,2H),7.69(s,1H),7.51(d,J＝7.6Hz,1H),7.33(t,J＝7.7Hz,1H),7.19(t,J＝7.5Hz,1H),7.09(d,J＝8.0Hz,1H),6.98(d,J＝8.8Hz,2H),5.39(s,1H),4.22-4.17(m,1H),4.02–3.96(m,1H),3.88(s,3H),0.89(t,J＝7.1Hz,3H),0.20(s,9H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.73,164.74,162.63,161.84,149.97,129.10,128.81,127.13,124.83,124.64,120.34,116.06,113.74,99.12,92.13,64.87,63.48,55.46,37.15,13.52,-0.03。
高分辨：计算值：[M+Na]+:488.1500，实测值：488.1505.
实施例7
化合物I-7 4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-((4-乙炔基苯基)(羟基)甲基)苯酚，其他条件不变，得到式I-7目标产物，产率为82％。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.77(d,J＝8.7Hz,2H),7.47(d,J＝8.2Hz,2H),7.35–7.32(m,1H),7.23(s,1H),7.18(d,J＝8.0Hz,1H),7.07(d,J＝8.2Hz,3H),6.95(d,J＝8.7Hz,2H),6.90(d,J＝7.6Hz,1H),5.68(s,1H),4.18–4.12(m,1H),4.10–4.05(m,1H),3.87(s,3H),3.13(s,1H),1.04(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.63,165.33,162.57,162.15,151.05,135.66,132.21,129.94,128.95,128.59,128.17,127.51,124.81,124.20,122.31,116.41,113.76,82.76,78.28,66.49,63.66,55.47,47.34,13.51。
高分辨：计算值：[M+Na]+:492.1418，实测值：492.1418.
实施例8
化合物I-8 3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(羟基(噻吩-2-基)甲基)苯酚，其他条件不变，得到式I-8目标产物，产率为83％。
1H NMR(400MHz,CDCl3)δ(ppm)δ＝7.77(d,J＝8.8Hz,2H),7.37(s,1H),7.29(t,J＝5.2Hz,2H),7.13–7.04(m,3H),7.00(dd,J＝5.1,3.5Hz,1H),6.93–6.91(m,2H),6.88(d,J＝2.9Hz,1H),5.95(s,1H),4.16–4.07(m,2H),3.84(s,3H),0.99(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.72,165.32,162.57,162.00,150.50,136.74,129.03,128.76,128.69,127.49,126.79,126.08,124.99,124.25,123.11,116.17,113.75,66.85,63.73,55.48,43.33。
高分辨：计算值：[M+Na]+:474.0982，实测值：474.0970。
实施例9
化合物I-9 4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(环己基(羟基)甲基)苯酚，其他条件不变，得到式I-9目标产物，产率为85％。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.65(d,J＝8.4Hz,2H),7.32(t,J＝7.8Hz,1H),7.26(s,1H),7.16(t,J＝7.5Hz,1H),7.10(d,J＝8.1Hz,1H),6.93(s,1H),6.89(d,J＝8.4Hz,2H),4.27–4.19(m,2H),3.88(s,1H),3.83(s,3H),2.03(t,J＝11.7Hz,1H),1.78–1.61(m,5H),1.33–1.17(m,4H),1.14–1.11(t,J＝7.0Hz,3H),1.08–1.04(m,1H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝δ167.21,165.48,162.41,162.07,151.11,128.88,128.50,128.10,125.06,124.03,121.39,116.44,113.67,63.35,62.90,55.43,48.21,38.91,30.77,28.92,27.16,26.85,26.07,13.71。
高分辨：计算值：[M+H]+:452.2068，实测值：452.2083.
实施例10
化合物I-10 3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2-(1-羟基烯丙基)苯酚，其他条件不变，得到式I-10目标产物，产率为73％。
1H NMR(600MHz,CDCl3)δ＝7.83(d,J＝8.3Hz,2H),7.37(s,1H),7.31(t,J＝7.6Hz,1H),7.12(d,J＝7.4Hz,3H),6.96(d,J＝8.4Hz,2H),5.65–5.59(m,1H),5.51(d,J＝10.0Hz,1H),5.35(d,J＝16.8Hz,1H),4.91(d,J＝9.6Hz,1H),4.18–4.02(m,2H),3.87(s,3H),0.90(t,J＝6.8Hz,3H)。
13C NMR(100MHz,CDCl3)δ＝165.53,165.47,162.58,162.52,150.52,130.85,128.96,128.51,126.61,125.14,124.45,124.11,122.84,116.12,113.73,65.03,63.41,55.49,45.92,13.56。
高分辨：计算值：[M+Na]+:418.1261，实测值：418.1264.
实施例11
化合物I-11 3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯的制备
根据实施例1的制备方法，将邻羟基苄醇A换为2,3-二氢-1H-茚-1,7-二醇，其他条件不变，得到式I-11目标产物，产率为70％。
1H NMR(600MHz,CDCl3)7.83(d,J＝8.4Hz,2H),7.51(s,1H),7.18(t,J＝7.8Hz,1H),6.99(d,J＝7.4Hz,1H),6.94(d,J＝8.5Hz,2H),6.85(d,J＝8.1Hz,1H),4.64–4.60(m,1H),4.13–4.07(m,1H),4.02–3.97(m,1H),3.86(s,3H),2.99–2.88(m,2H),2.46–2.39(m,1H),1.72–1.64(m,1H),0.86(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ＝166.09,165.71,164.16,162.56,148.50,143.24,129.06,127.03,125.16,120.32,113.73,112.32,67.30,63.14,55.50,43.32,32.40,30.70,13.58。
高分辨：计算值：[M+Na]+:396.1442，实测值：396.1442.
实施例12
化合物Ia-1 (3R,4R)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯的制备
在室温下，原料邻羟基苄醇A(44.8mg,0.2mmol),1.5当量的吖内酯B(78.9mg,0.3mmol，5.0mol％R-CPA溶于无水甲苯中，直到TLC检测反应完全，以V石油醚/V乙酸乙酯＝15:1-5:1柱层析直接得到式Ia-1目标产物，产率为96％,d.r.>95:5,94％ee。在实施例12，邻羟基苄醇A为2-(1-羟基-3-苯基丙-2-炔-1-基)苯酚。1H NMR(600MHz,CDCl3)δ＝7.89(d,J＝7.4Hz,2H),7.75(s,1H),7.60(d,J＝8.1Hz,1H),7.46(d,J＝6.5Hz,2H),7.35(t,J＝7.3Hz,4H),7.21(t,J＝7.3Hz,1H),7.13(d,J＝8.2Hz,1H),6.97(d,J＝8.5Hz,2H),5.65(s,1H),4.26–4.20(m,1H),4.06–4.01(m,1H),3.87(s,3H),0.90(t,J＝7.1Hz,3H。
13C NMR(100MHz,CDCl3)δ＝166.10,165.25,162.90,162.11,150.29,131.80,129.29,129.04,128.75,128.35,127.35,124.97,124.80,122.07,120.80,116.26,113.87,86.93,82.69,65.13,63.58,55.41,36.86,13.42。
高分辨：计算值：[M+H]+:470.1598，实测值：470.1595.
实施例13
化合物Ia-2 (3R,4R)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(1-羟基-3-(对甲苯基)丙-2-炔-1-基)苯酚，其他条件不变，得到式Ia-2目标产物，产率为88％,d.r.>95:5,92％ee。
1H NMR(600MHz,CDCl3)δ＝7.87(d,J＝8.1Hz,2H),7.45(d,J＝6.7Hz,2H),7.41–7.38(m,3H),7.35(d,J＝8.0Hz,2H),6.23(s,1H),4.15(s,2H),2.44(s,3H),2.30–2.27(s,1H),1.83–1.79(m,4H),1.70(d,J＝12.9Hz,1H),1.36–1.27(m,5H).
13C NMR(100MHz,CDCl3)δ(ppm)δ＝158.54,144.01,139.50,135.33,131.90,129.60,129.29,128.81,128.76,125.29,113.49,43.48,43.35,30.25,25.85,25.80,21.53.
高分辨：计算值：[M+H]+:395.1788，实测值：395.1788.
实施例14
化合物Ia-3 (3R,4R)-4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(3-(4-氯苯基)-1-羟基丙-2-炔-1-基)苯酚，其他条件不变，得到式Ia-3目标产物，产率为79％,d.r.>95:5,96％ee。
1H NMR(600MHz,CDCl3)(400MHz,CDCl3)δ(ppm)δ＝7.85(d,J＝8.8Hz,2H),7.69(s,1H),7.54(d,J＝7.6Hz,1H),7.38–7.22(m,5H),7.17(t,J＝7.5Hz,1H),7.09(d,J＝8.1Hz,1H),6.93(d,J＝8.8Hz,2H),5.64(s,1H),4.24-4.16(m,1H),4.05-3.97(m,1H),3.84(s,3H),0.88(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.81,164.94,162.66,161.77,150.03,134.67,132.86,129.12,128.97,128.54,127.07,124.69,120.37,120.34,116.20,113.75,85.80,83.73,65.05,63.66,55.48,36.96,13.60。
高分辨：计算值：[M+Na]+:526.1028，实测值：526.1035.
实施例15
化合物Ia-4 (3R,4R)-4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(3-(3-氟苯基)-1-羟基丙-2-炔-1-基)苯酚，其他条件不变，得到式Ia-4目标产物，产率为72％,d.r.>95:5,94％ee。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.89(d,J＝8.6Hz,2H),7.73(s,1H),7.57(d,J＝7.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.32–7.29(m,1H),7.24–7.20(m,2H),7.14(t,J＝8.5Hz,2H),7.07(t,J＝8.6Hz,1H),6.97(d,J＝8.6Hz,2H),5.66(s,1H),4.25-4.20(m,1H),4.07-4.01(m,1H),3.87(s,3H),0.90(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.79,164.87,162.63,161.92(d,J＝244.9Hz),160.70,149.99,129.84(d,J＝8.52Hz),129.07,128.97,127.54,127.53(d,J＝2.79Hz),124.68,124.63,123.59(d,J＝10.04Hz),120.26,118.43(d,J＝22.59Hz),116.15,115.92,113.72,85.62,83.68,64.99,63.65,55.42,36.87,13.55。
高分辨：计算值：[M+Na]+:510.1323，实测值：510.1328。
实施例16
化合物Ia-5 (3R,4R)-4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(3-环丙基-1-羟基丙-2-炔-1-基)苯酚，其他条件不变，得到式Ia-5目标产物，产率为76％,d.r.>95:5,95％ee。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.87(d,J＝8.4Hz,2H),7.64(s,1H),7.49(d,J＝7.6Hz,1H),7.31(t,J＝7.7Hz,1H),7.18(t,J＝7.5Hz,1H),7.07(d,J＝8.1Hz,1H),6.98(d,J＝8.3Hz,2H),5.32(s,1H),4.20–4.14(m,1H),4.02–3.97(m,1H),3.88(s,3H),1.30–1.27(m,1H),0.88(t,J＝7.1Hz,3H),0.83–0.80(m,2H),0.69–0.66(m,2H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝141.46,136.59,131.08,130.60,128.44,127.59,127.53,126.78,126.53,82.47,63.96,15.31。
高分辨：计算值：[M+Na]+:456.1418，实测值：456.1417。
实施例17
化合物Ia-6 (3R,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(1-羟基-3-(三甲基硅基)丙-2-炔-1-基)苯酚，其他条件不变，得到式Ia-6目标产物，产率为92％,d.r.>95:5,92％ee。
1H NMR(400MHz,CDCl3)δ(ppm)δ＝7.87(d,J＝8.8Hz,2H),7.69(s,1H),7.51(d,J＝7.6Hz,1H),7.33(t,J＝7.7Hz,1H),7.19(t,J＝7.5Hz,1H),7.09(d,J＝8.0Hz,1H),6.98(d,J＝8.8Hz,2H),5.39(s,1H),4.22-4.17(m,1H),4.02–3.96(m,1H),3.88(s,3H),0.89(t,J＝7.1Hz,3H),0.20(s,9H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.73,164.74,162.63,161.84,149.97,129.10,128.81,127.13,124.83,124.64,120.34,116.06,113.74,99.12,92.13,64.87,63.48,55.46,37.15,13.52,-0.03。
高分辨：计算值：[M+Na]+:488.1500，实测值：488.1505.
实施例18
化合物Ia-7 (3R,4R)-4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-((4-乙炔基苯基)(羟基)甲基)苯酚，其他条件不变，得到式Ia-7目标产物，产率为92％,d.r.>95:5,92％ee。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.77(d,J＝8.7Hz,2H),7.47(d,J＝8.2Hz,2H),7.35–7.32(m,1H),7.23(s,1H),7.18(d,J＝8.0Hz,1H),7.07(d,J＝8.2Hz,3H),6.95(d,J＝8.7Hz,2H),6.90(d,J＝7.6Hz,1H),5.68(s,1H),4.18–4.12(m,1H),4.10–4.05(m,1H),3.87(s,3H),3.13(s,1H),1.04(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.63,165.33,162.57,162.15,151.05,135.66,132.21,129.94,128.95,128.59,128.17,127.51,124.81,124.20,122.31,116.41,113.76,82.76,78.28,66.49,63.66,55.47,47.34,13.51。
高分辨：计算值：[M+Na]+:492.1418，实测值：492.1418.
实施例19
化合物Ia-8 (3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(羟基(噻吩-2-基)甲基)苯酚，其他条件不变，得到式Ia-8目标产物，产率为66％,d.r.＝6.5:1,96％ee。
1H NMR(400MHz,CDCl3)δ(ppm)δ＝7.77(d,J＝8.8Hz,2H),7.37(s,1H),7.29(t,J＝5.2Hz,2H),7.13–7.04(m,3H),7.00(dd,J＝5.1,3.5Hz,1H),6.93–6.91(m,2H),6.88(d,J＝2.9Hz,1H),5.95(s,1H),4.16–4.07(m,2H),3.84(s,3H),0.99(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.72,165.32,162.57,162.00,150.50,136.74,129.03,128.76,128.69,127.49,126.79,126.08,124.99,124.25,123.11,116.17,113.75,66.85,63.73,55.48,43.33。
高分辨：计算值：[M+Na]+:474.0982，实测值：474.0970.
实施例20
化合物Ia-9 (3R,4R)-4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(环己基(羟基)甲基)苯酚，其他条件不变，得到式Ia-9目标产物，产率为70％,d.r.＝6.5:1,91％ee。
1H NMR(600MHz,CDCl3)δ(ppm)δ＝7.65(d,J＝8.4Hz,2H),7.32(t,J＝7.8Hz,1H),7.26(s,1H),7.16(t,J＝7.5Hz,1H),7.10(d,J＝8.1Hz,1H),6.93(s,1H),6.89(d,J＝8.4Hz,2H),4.27–4.19(m,2H),3.88(s,1H),3.83(s,3H),2.03(t,J＝11.7Hz,1H),1.78–1.61(m,5H),1.33–1.17(m,4H),1.14–1.11(t,J＝7.0Hz,3H),1.08–1.04(m,1H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝δ167.21,165.48,162.41,162.07,151.11,128.88,128.50,128.10,125.06,124.03,121.39,116.44,113.67,63.35,62.90,55.43,48.21,38.91,30.77,28.92,27.16,26.85,26.07,13.71。
高分辨：计算值：[M+H]+:452.2068，实测值：452.2083.
实施例21
化合物Ia-10 (3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2-(1-羟基烯丙基)苯酚，其他条件不变，得到式Ia-10目标产物，产率为82％,d.r.＝6:1,94％ee。
1H NMR(600MHz,CDCl3)δ＝7.83(d,J＝8.3Hz,2H),7.37(s,1H),7.31(t,J＝7.6Hz,1H),7.12(d,J＝7.4Hz,3H),6.96(d,J＝8.4Hz,2H),5.65–5.59(m,1H),5.51(d,J＝10.0Hz,1H),5.35(d,J＝16.8Hz,1H),4.91(d,J＝9.6Hz,1H),4.18–4.02(m,2H),3.87(s,3H),0.90(t,J＝6.8Hz,3H)。
13C NMR(100MHz,CDCl3)δ＝165.53,165.47,162.58,162.52,150.52,130.85,128.96,128.51,126.61,125.14,124.45,124.11,122.84,116.12,113.73,65.03,63.41,55.49,45.92,13.56。
高分辨：计算值：[M+Na]+:418.1261，实测值：418.1264.
实施例22
化合物Ia-11 (3R,3aR)-3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯的制备
根据实施例12制备方法，将邻羟基苄醇A换为2,3-dihydro-1H-indene-1,7-diol，其他条件不变，得到式Ia-11目标产物，产率为68％,d.r.>95:5,83％ee。
1H NMR(600MHz,CDCl3)7.83(d,J＝8.4Hz,2H),7.51(s,1H),7.18(t,J＝7.8Hz,1H),6.99(d,J＝7.4Hz,1H),6.94(d,J＝8.5Hz,2H),6.85(d,J＝8.1Hz,1H),4.64–4.60(m,1H),4.13–4.07(m,1H),4.02–3.97(m,1H),3.86(s,3H),2.99–2.88(m,2H),2.46–2.39(m,1H),1.72–1.64(m,1H),0.86(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ＝166.09,165.71,164.16,162.56,148.50,143.24,129.06,127.03,125.16,120.32,113.73,112.32,67.30,63.14,55.50,43.32,32.40,30.70,13.58。
高分辨：计算值：[M+Na]+:396.1442，实测值：396.1442.
实施例23
化合物II-1 3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯的制备
原料I-2(48.3mg,0.1mmol)溶解在无水甲醇中，加入10％钯/碳(10.0mg)，反应24h后，直接抽滤，滤液通过硅胶柱(V石油醚/V乙酸乙酯＝15:1-5:1)柱层析分离得到式II-1目标产物。产率为75％。
1H NMR(400MHz,CDCl3)δ＝7.68(d,J＝8.4Hz,2H),7.28(q,J＝8.3Hz,3H),7.15(t,J＝7.5Hz,1H),7.07(d,J＝8.0Hz,1H),6.97(d,J＝7.7Hz,2H),6.91–6.88(m,3H),4.28–4.25(m,1H),4.09–4.01(m,1H),3.95–3.88(m,1H),3.83(s,3H),3.04–2.87(m,1H),2.97–2.91(m,1H),2.17(s,3H),2.72–2.64(m,2H),0.80(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.78,165.12,163.33,162.30,150.87,137.23,135.33,128.93,128.86,128.04,127.89,125.06,124.77,124.51,124.28,116.19,113.39,65.58,63.02,55.36,38.48,34.52,29.77,20.95,13.37。
高分辨：计算值：[M+H]+:510.1887，实测值：510.1887。
实施例24
化合物II-2 (3R,4R)-3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯的制备
根据实施例23的制备方法，将原料I-2换为原料Ia-2，其他条件不变，得到式II-2的目标产物，产率为80％,d.r.>95:5,94％ee。
1H NMR(400MHz,CDCl3)δ＝7.68(d,J＝8.4Hz,2H),7.28(q,J＝8.3Hz,3H),7.15(t,J＝7.5Hz,1H),7.07(d,J＝8.0Hz,1H),6.97(d,J＝7.7Hz,2H),6.91–6.88(m,3H),4.28–4.25(m,1H),4.09–4.01(m,1H),3.95–3.88(m,1H),3.83(s,3H),3.04–2.87(m,1H),2.97–2.91(m,1H),2.17(s,3H),2.72–2.64(m,2H),0.80(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.78,165.12,163.33,162.30,150.87,137.23,135.33,128.93,128.86,128.04,127.89,125.06,124.77,124.51,124.28,116.19,113.39,65.58,63.02,55.36,38.48,34.52,29.77,20.95,13.37。
高分辨：计算值：[M+H]+:510.1887，实测值：510.1887。
实施例25
化合物III-1 3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯的制备
在室温下，CuTc溶解在无水甲苯中，加入原料I-7(0.1mmol,47.9mg)，直到TLC检测反应完全，随后用饱和NH4Cl溶液淬灭反应，二氯甲烷萃取，有机相无水硫酸钠干燥，通过硅胶柱(V石油醚/V乙酸乙酯＝5:1-2:1)柱层析分离得到式III-1目标产物。产率为78％。
1H NMR(400MHz,CDCl3)8.31(s,1H),7.99(d,J＝8.4Hz,2H),7.75(dd,J＝21.5,8.5Hz,4H),7.38–7.29(m,3H),7.21(s,1H),7.15(d,J＝8.4Hz,3H),7.05(t,J＝7.9Hz,1H),6.91(d,J＝8.8Hz,3H),5.67(s,1H),4.15–4.05(m,2H),3.85(s,3H),2.45(s,3H),1.04(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.69,165.42,162.59,162.22,151.09,147.26,146.36,135.86,132.63,130.29,129.04,128.95,128.61,128.46,127.57,126.18,124.85,124.23,122.41,119.08,116.44,113.78,66.57,63.69,55.49,47.31,22.01,21.95。
高分辨：计算值：[M+H]+:668.1935，实测值：668.1935。
实施例26
化合物III-2 (3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯的制备
根据实施例25的制备方法，将原料I-7换为原料Ia-7，其他条件不变，得到式III-2的目标产物，产率为80％,d.r.>95:5,92％ee。
1H NMR(400MHz,CDCl3)8.31(s,1H),7.99(d,J＝8.4Hz,2H),7.75(dd,J＝21.5,8.5Hz,4H),7.38–7.29(m,3H),7.21(s,1H),7.15(d,J＝8.4Hz,3H),7.05(t,J＝7.9Hz,1H),6.91(d,J＝8.8Hz,3H),5.67(s,1H),4.15–4.05(m,2H),3.85(s,3H),2.45(s,3H),1.04(t,J＝7.1Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm)δ＝165.69,165.42,162.59,162.22,151.09,147.26,146.36,135.86,132.63,130.29,129.04,128.95,128.61,128.46,127.57,126.18,124.85,124.23,122.41,119.08,116.44,113.78,66.57,63.69,55.49,47.31,22.01,21.95。
高分辨：计算值：[M+H]+:668.1935，实测值：668.1935。
实施例27
药理活性筛选实验
1、3,4-二氢香豆素衍生化合物普遍表现出一定的抗肿瘤细胞增值的活性，我们对所合成的化合物进行了如下3种临床常见肿瘤细胞活性测试：
HepG2(肝癌细胞系)；MG63(骨肉瘤细胞系)；SW620(胶质瘤细胞系)。
2、药物母液配制
将药物配成第1浓度(32ug/ml)的100*的母液(3.2mg/ml)。
3、测试方法
(1)取对数生长期的细胞，胰酶消化后调整为5*104/ml，每孔加入100ul细胞悬液(5000个)，培养过夜；
(2)按如下方式配制药物，每孔加入100ul含药物的培养基：
第1浓度：按1：100将100*母液稀释于培养基中，1.5培养基+15ul母液；
第2～6浓度：按照1:2的比例进行梯度稀释，1ml培养液+0.5ml上浓度药物；
(3)按如下方式布板：
(4)加药后24H和48H进行CCK8检测。
4、测试结果
对所有合成的化合物进行了生物活性测试，如表2所示，化合物I-2和I-6对HepG2(肝癌细胞系)；MG63(骨肉瘤细胞系)；SW620(胶质瘤细胞系)三种肿瘤细胞均表现出了良好的抑制活性。化合物I-9和II-1对HepG2(肝癌细胞系)表现出了较好的活性。
表2化合物对常见肿瘤细胞增殖活性的抑制情况(％)
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围，例如，将实施例12-22的R-CPA换为S-CPA，其他条件不变，可以得到相应Ib结构的化合物，此类化合物也应视为本发明的保护范围。
Claims (5)
1.一种式I所示化合物、其立体异构体或其混合物形式的制备方法，其特征在于式I由邻羟基苄醇化合物A和吖内酯化合物B在催化剂的作用下制得：
其中，R1选自氢；
R2选自C6-10芳基乙炔基、C3-8环烷基乙炔基、三C1-6烷基硅基乙炔基、C6-10芳基乙基、C3-8环烷基乙基、三C1-6烷基硅基乙基、C1-6烷基、C3-8环烷基、C6-10芳基、C5-10杂芳基、C2-6烯基、C2-6炔基、C5-10杂芳基C6-10芳基；其中，C6-10芳基可任选的被一个或多个独立选自氢、C1-6烷基、卤素或C2-6炔基的基团取代；C5-10杂芳基可选的被一个或多个独立选自氢或对甲苯磺酰基取代；
或R1与R2同与他们连接的碳原子一起形成C5-6环烷基；
催化剂为磷酸二苯酯、R-CPA或S-CPA。
2.根据权利要求1所述的制备方法，其中，
R2选自苯乙炔基、4-甲基苯乙炔基、4-氯苯乙炔基、3-氟苯乙炔基、环丙基乙炔基、三甲基硅基乙炔基、苯乙基、4-甲基苯乙基、4-氯苯乙基、3-氟苯乙基、环丙基乙基、三甲基硅基乙基、乙基、4-乙炔基苯基、环己基、2-噻吩基、乙烯基、或
或R1与R2同与他们连接的碳原子一起形成环戊烷基。
3.根据权利要求1所述的制备方法，立体异构体具有Ia或Ib结构：
其中，R1、R2如权利要求1所定义。
4.根据权利要求1所述的制备方法，其特征在于，所述化合物I为下列化合物，其立体异构体或其混合物形式：
3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(苯乙炔基)色满-3-羧酸乙酯；
3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧苯甲酰氨基)-2-氧代-4-(对甲苯基乙炔基)色满-3-羧酸乙酯；
4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-((对氯苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-((3-氟苯基)乙炔基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-(环丙基乙炔基)-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯；
(3R,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯；
(3S,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-((三甲基硅基)乙炔基)色满-3-羧酸乙酯；
4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-(4-乙炔基苯基)-3-(4-甲氧苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(噻吩-2-基)色满-3-羧酸乙酯；
4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3R,4R)-4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
(3S,4S)-4-环己基-3-(4-甲氧基苯甲酰氨基)-2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-乙烯基色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯；
(3R,3aR)-3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯；
(3S,3aS)-3-(4-甲氧基苯甲酰氨基)-2-氧代-3,3a,4,5-四氢-2H-环戊二烯并[de]苯并吡喃-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-4-(4-甲基苯乙基)2-氧代色满-3-羧酸乙酯；
3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯；
(3R,4R)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯；
(3S,4S)-3-(4-甲氧基苯甲酰氨基)-2-氧代-4-(4-(1-对甲苯磺酰基-1H-1,2,3-三唑-4-基)苯基)色满-3-羧酸乙酯。
5.根据权利要求1所述的制备方法，其中，催化剂的用量为A的5～20mol％，B与A的摩尔比为1:1～2:1，反应在有机溶剂下进行。
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