海洋天然产物Ypaoamide和Awajanomycin的不对称全合成研究及碳水化合物在手性配体和高聚物合成中的应用
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摘要
2-吡咯烷酮和2-哌啶酮的衍生物是很多天然产物的重要结构单元和合成砌块。这些天然产物大多具有重要的生理活性，在医药及生化上具有潜在的应用前景。它们中许多都具有比较复杂的结构，有的含有多个手性中心，因此，其不对称合成一直是国际上关注的具有挑战性的课题。
在本实验室已有研究工作的基础上，本论文的目的在于拓展手性合成砌块苹果酰亚胺和3-羟基戊二酰亚胺的多用性，将其应用于海洋天然产物ypaoamide(3)和awajanomycin(4)的全合成中。
Ypaoamide(3)是1996年从关岛海域的巨大鞘丝藻(Lyngbya majuscule)分离得到的次级代谢物，它是一种拒食性物质，会使海洋草食暗礁鱼类中毒或死亡，导致藻类过度繁殖。从其结构上分析，它是一个5-取代-α，β-不饱和吡咯烷酮衍生物。C-5位的手性中心处于插烯的羰基α-位，在碱性条件下易于发生外消旋化。其分子中含有烯醇甲醚结构，在酸性条件下易水解。
Awajanomycin(4)是2006年从日本淡路岛(Awajiishima Island)的顶孢霉菌AWA16-1分离出的哌啶酮类化合物，它对人体癌细胞具有很强的选择性抑制作用，其对人体肺部A549癌细胞的IC_(50)为27．5μg／mL，具有潜在的药用价值。它的主要结构是一个由γ-内酯和δ-内酰胺构成的双环骨架；骨架上有四个邻近的手性中心(C-1，C-8，C-5和C-4)；C-1位上是一个叔羟基；C-4位上的甲基处于直立键。
正是由于这两个化合物独特的结构以及构筑手性中心的困难，到目前为止还没有文献报道它们的全合成，其手性中心的构型还未确定。因此，进行ypaoamide和awajanomycin的全合成具有重要的意义和挑战性。
本论文取得的主要结果如下：
一、完成了(R)-ypaoamide的首次不对称全合成。
1．从4-溴代丁酸乙酯出发，经Wittig反应、交叉的Claisen酯缩合反应等九步反应，合成了ypaoamide的末端叔丁基取代的脂肪型侧链片段53，总收率9．7％。
2．在本实验室研究工作的基础上，以(S)-苹果酸为手性源，合成了N-烯丙基保护的苹果酰亚胺5b。通过对其进行高区域、高立体选择性的加成-还原脱氧化反应，经6步，以46％的总收率合成了ypaoamide的手性吡咯烷酮片段(4S，5R)-4-苄氧基-5-苄氧基苄基吡咯烷酮54b。
3．吡咯烷酮54b与长链片段53偶联，得到了重要的中间体89。通过对89的羟基上Boc保护-β-消除的一瓶两步反应得到了ypaoamide的前体化合物52a。通过对89进行选择性乙酰化再消除得到了ypaoamide的另一前体化合物52b。
4．探索了ypaoamide前体化合物52脱酚羟基保护的条件。由于52在碱性条件下会发生外消旋化，其烯醇甲醚结构在酸性条件下易水解，这给脱保护带来极大的难度。经多次尝试，最后采用柱状甲丝酵母脂肪酶(CCL，lipase fromCandida cylindracea)催化，实现了52b在温和的中性条件下的脱乙酰基保护，最终以总长19步，总收率1．0％完成了天然产物ypaoamide对映体化合物的首次不对称全合成。通过这一不对称合成证明了天然ypaoamide的绝对构型为S。
5．在以上研究工作的基础上，完成了海洋天然产物Microcolin B关键片段97的不对称合成。
二、进行了awajanomycin的不对称合成研究
1．以L-谷氨酸为手性源合成了保护的3-羟基戊二酰亚胺，经加成-还原脱氧化、羰基α-位引入甲氧酰基、环氧化等9步反应合成了awajanomycin的手性哌啶酮片段192b。
2．探索了合成高光学纯度的丙炔醇化合物(R)-215的方法。参照文献合成了钌催化剂(R，R)-221，并将其应用于炔基酮222的不对称氢转移还原，以大于90％的收率和大于98％的ee值得到了丙炔醇化合物(R)-215。用221的对映体(S，S)-221作为催化剂，即可得到(S)-215。215再经两步转化得到了awajanomycin的长链丙炔醇片段(R)-114a。这两个关键片段的合成为awajanomycin的不对称全合成打下了基础。
三、本论文的另一部分工作是碳水化合物在手性配体和含糖高聚物合成中的应用。
1、在本实验室研究工作的基础上，由天然的糖类化合物出发，分别合成了三种类型的叠氮基取代的碳水化合物；通过Staudinger-Vilarrasa反应实现了一级叠氮化合物243与2，2’-联二吡啶-3，3’-二羧酸的一步酰胺化，得到了二酰胺化合物255，它可作为不对称氟化反应的手性配体。这部分工作拓展了碳水化合物化学在不对称催化方面的应用。
2、在本实验室工作的基础上，由异麦芽酮糖(isomaltulose)出发，分别合成了两种含有叠氮基和末端炔基的糖类衍生物287和290；对以290为单体化合物通过Huisgen 1，3-二偶极环加成反应合成高分子化合物进行了初步研究。这部分工作拓展了碳水化合物化学在含糖高聚物研究方面的应用。
Pyrrolin-2-one and piperidin-2-one containing natural products possess a varietyof important bioactivities and show high potential for medical and biologicalapplications. The synthesis of such compounds represent a worthwhile andchallenging goal for the organic chemists particularly as most of the target moleculesare comprised of complex architechtural framework with several stereogenic centers.
One aim of this thesis is to further study on the important building blocks,protected malimides and glutarimides which were previously developed in ourlaboratory, as well as their application in the asymmetric synthesis of marine naturalproducts ypaoamide (3) and awajanomycin (4).
Ypaoamide (3) was isolated in 1996 from the marine cyanobacterium Lyngbyamajuscula at Ypao Beach on Guam and shown to be a new broadly acting feedingdeterrent. Its ecological significance has been studied. The enantioselective synthesisof ypaoamide (3) presents several challenges because that its structure contains a5-alkyl-α,β-unsaturated-pyrrolin-2-one portion which is subjected to racemizationunder basic condition and Z-β-methoxy-α,β-unsaturated imide moiety which isunstable under acidic condition.
Awajanomycin (4) was isolated in 2006 from the marine-derived fungusAcremonium sp. AWA16-1,collected from sea mud off Awajishima Island in Japan.Awajanomycin exhibited cytotoxic activity against the A549 cells with IC_(50) value of27.5μg/mL. It possesses a characteristicγ-lactone-δ-lactam core structure with a fullysubstituted 2-piperidinone ring bearing four chiral centers including a quaternarycarbon.
The intriguing structural features, in addition to the undeterminedstereochemistry and significant sytotoxicity make ypaoamide (3) and awajanomycin(4) attractive and challenging synthetic targets. To date no total synthesis of them hasbeen reported.
The main results and observations from these studies are listed as follows:
1.The first asymmetric total synthesis of ypaoamide (3) has been achieved.
(1) The unusual t-butyl lipid side chain of ypaoamide 53 was prepared in 9 stepsincluding Wittig reaction and cross-Claisen condensation with 9.7% overall yieldstarting from ethyl 4-bromobutyrate.
(2) The building block N-allyl malimide 5b was obtained starting from (S)-malic acid.Employing a highly chemo-, regio-, and stereoselective stepwise reductivep-benzyloxybenzylation of 5b, the 5-(p-benzyloxyphenylmethyl)-3-pyrrolin-2-oneportion 54b was prepared in 6 steps with 46% overall yield starting from malic acid.
(3) The key intermediate 89 was obtained through the coupling of pyrrolin-2-oneportion 54b with side chain segment 53. After a one-pot tandem hydroxyl Bocprotection-β-elimination process of 89, O-Boc protected ypaoamide 52a was obtainedAfter a selective acetylation-β-elimination process of 89, O-Ac ypaoamide 52b wasobtained.
(4) Studies on the deprotection of the phenolic hydroxyl group of ypaoamide. Becausethat its structure contains a 5-alkyl-α,β-unsaturated-pyrrolin-2-one portion which issubjected to racemization under basic condition and E-β-methoxy-α,β-unsaturatedimide moiety which is unstable under acidic condition, the deprotection was proved agreat challenge. Deacetylation of O-Ac ypaoamide 52b catalyzed by CCL (lipasefrom Candida cylindracea) gave (R)-3. Thus, the first asymmetric total synthesis of(R)-3 was achieved in 19 steps with 1.0% overall yield starting from ethyl4-bromobutyrate and N-allyl malimide 5b. The absolute configuration of the naturalypaoamide was determined as S.
(5) On the basis of the total synthesis of (R)-ypaoamide, the asymmetric synthesis ofthe key segment of marine natural product Microcolin B 97 was achieved.
2. Studies on the asymmetric synthesis of awajanomycin (4).
(1) The building block protected(S)-3-hydroxyl-glutarimide 6b was obtained startingfrom(S)-glutamic acid. Employing a stepwise reductive methylation of 6b, theintroduction of O-methoxycarbonyl group and an epoxidation, the piperidin-2-oneportion 192b was prepared in 9 steps starting from 6b.
(2) The asymmetric synthesis of (R)-215 was studied. Asymmetric catalytic transferhydrogenation of 222 catalyzed by the Ru catalyst 221 gave (R)-215 in 90% yield and98% ee. The chain side of awajanomycin (R)-114a was obtained from (R)-215 though2 steps. The synthesis of the two key segments founded the basis of the asymmetrictotal synthesis of awajanomycin.
3. The other part of this thesis is applications of carbohydrates in the synthesis ofchiral ligands and polymers.
(1) Based on the previous work of our laboratory, three types of azide derivativeswere prepared from natural carbohydrates. Employing Staudinger-Vilarrasa reaction,the coupling of primary azide 243 with 2,2'-bypyridine-3,3'-dicarboxylic acid wasachieved to give diamide 255 which can be used as a chiral ligand for enantioselectivefluorination. This work expanded the application of carbohydrates in chiral catalysis.
(2) Two glycomonomers 287 and 290 both with azido group and ynyl group wereobtained from isomaltulose. Employing Huisgen 1,3-dipolar cycloaddition, theformation and characters of the glycopolymer were studied. This work expanded theapplication of carbohydrates in glycopolymer synthesis.
在本实验室已有研究工作的基础上，本论文的目的在于拓展手性合成砌块苹果酰亚胺和3-羟基戊二酰亚胺的多用性，将其应用于海洋天然产物ypaoamide(3)和awajanomycin(4)的全合成中。
Ypaoamide(3)是1996年从关岛海域的巨大鞘丝藻(Lyngbya majuscule)分离得到的次级代谢物，它是一种拒食性物质，会使海洋草食暗礁鱼类中毒或死亡，导致藻类过度繁殖。从其结构上分析，它是一个5-取代-α，β-不饱和吡咯烷酮衍生物。C-5位的手性中心处于插烯的羰基α-位，在碱性条件下易于发生外消旋化。其分子中含有烯醇甲醚结构，在酸性条件下易水解。
Awajanomycin(4)是2006年从日本淡路岛(Awajiishima Island)的顶孢霉菌AWA16-1分离出的哌啶酮类化合物，它对人体癌细胞具有很强的选择性抑制作用，其对人体肺部A549癌细胞的IC_(50)为27．5μg／mL，具有潜在的药用价值。它的主要结构是一个由γ-内酯和δ-内酰胺构成的双环骨架；骨架上有四个邻近的手性中心(C-1，C-8，C-5和C-4)；C-1位上是一个叔羟基；C-4位上的甲基处于直立键。
正是由于这两个化合物独特的结构以及构筑手性中心的困难，到目前为止还没有文献报道它们的全合成，其手性中心的构型还未确定。因此，进行ypaoamide和awajanomycin的全合成具有重要的意义和挑战性。
本论文取得的主要结果如下：
一、完成了(R)-ypaoamide的首次不对称全合成。
1．从4-溴代丁酸乙酯出发，经Wittig反应、交叉的Claisen酯缩合反应等九步反应，合成了ypaoamide的末端叔丁基取代的脂肪型侧链片段53，总收率9．7％。
2．在本实验室研究工作的基础上，以(S)-苹果酸为手性源，合成了N-烯丙基保护的苹果酰亚胺5b。通过对其进行高区域、高立体选择性的加成-还原脱氧化反应，经6步，以46％的总收率合成了ypaoamide的手性吡咯烷酮片段(4S，5R)-4-苄氧基-5-苄氧基苄基吡咯烷酮54b。
3．吡咯烷酮54b与长链片段53偶联，得到了重要的中间体89。通过对89的羟基上Boc保护-β-消除的一瓶两步反应得到了ypaoamide的前体化合物52a。通过对89进行选择性乙酰化再消除得到了ypaoamide的另一前体化合物52b。
4．探索了ypaoamide前体化合物52脱酚羟基保护的条件。由于52在碱性条件下会发生外消旋化，其烯醇甲醚结构在酸性条件下易水解，这给脱保护带来极大的难度。经多次尝试，最后采用柱状甲丝酵母脂肪酶(CCL，lipase fromCandida cylindracea)催化，实现了52b在温和的中性条件下的脱乙酰基保护，最终以总长19步，总收率1．0％完成了天然产物ypaoamide对映体化合物的首次不对称全合成。通过这一不对称合成证明了天然ypaoamide的绝对构型为S。
5．在以上研究工作的基础上，完成了海洋天然产物Microcolin B关键片段97的不对称合成。
二、进行了awajanomycin的不对称合成研究
1．以L-谷氨酸为手性源合成了保护的3-羟基戊二酰亚胺，经加成-还原脱氧化、羰基α-位引入甲氧酰基、环氧化等9步反应合成了awajanomycin的手性哌啶酮片段192b。
2．探索了合成高光学纯度的丙炔醇化合物(R)-215的方法。参照文献合成了钌催化剂(R，R)-221，并将其应用于炔基酮222的不对称氢转移还原，以大于90％的收率和大于98％的ee值得到了丙炔醇化合物(R)-215。用221的对映体(S，S)-221作为催化剂，即可得到(S)-215。215再经两步转化得到了awajanomycin的长链丙炔醇片段(R)-114a。这两个关键片段的合成为awajanomycin的不对称全合成打下了基础。
三、本论文的另一部分工作是碳水化合物在手性配体和含糖高聚物合成中的应用。
1、在本实验室研究工作的基础上，由天然的糖类化合物出发，分别合成了三种类型的叠氮基取代的碳水化合物；通过Staudinger-Vilarrasa反应实现了一级叠氮化合物243与2，2’-联二吡啶-3，3’-二羧酸的一步酰胺化，得到了二酰胺化合物255，它可作为不对称氟化反应的手性配体。这部分工作拓展了碳水化合物化学在不对称催化方面的应用。
2、在本实验室工作的基础上，由异麦芽酮糖(isomaltulose)出发，分别合成了两种含有叠氮基和末端炔基的糖类衍生物287和290；对以290为单体化合物通过Huisgen 1，3-二偶极环加成反应合成高分子化合物进行了初步研究。这部分工作拓展了碳水化合物化学在含糖高聚物研究方面的应用。
Pyrrolin-2-one and piperidin-2-one containing natural products possess a varietyof important bioactivities and show high potential for medical and biologicalapplications. The synthesis of such compounds represent a worthwhile andchallenging goal for the organic chemists particularly as most of the target moleculesare comprised of complex architechtural framework with several stereogenic centers.
One aim of this thesis is to further study on the important building blocks,protected malimides and glutarimides which were previously developed in ourlaboratory, as well as their application in the asymmetric synthesis of marine naturalproducts ypaoamide (3) and awajanomycin (4).
Ypaoamide (3) was isolated in 1996 from the marine cyanobacterium Lyngbyamajuscula at Ypao Beach on Guam and shown to be a new broadly acting feedingdeterrent. Its ecological significance has been studied. The enantioselective synthesisof ypaoamide (3) presents several challenges because that its structure contains a5-alkyl-α,β-unsaturated-pyrrolin-2-one portion which is subjected to racemizationunder basic condition and Z-β-methoxy-α,β-unsaturated imide moiety which isunstable under acidic condition.
Awajanomycin (4) was isolated in 2006 from the marine-derived fungusAcremonium sp. AWA16-1,collected from sea mud off Awajishima Island in Japan.Awajanomycin exhibited cytotoxic activity against the A549 cells with IC_(50) value of27.5μg/mL. It possesses a characteristicγ-lactone-δ-lactam core structure with a fullysubstituted 2-piperidinone ring bearing four chiral centers including a quaternarycarbon.
The intriguing structural features, in addition to the undeterminedstereochemistry and significant sytotoxicity make ypaoamide (3) and awajanomycin(4) attractive and challenging synthetic targets. To date no total synthesis of them hasbeen reported.
The main results and observations from these studies are listed as follows:
1.The first asymmetric total synthesis of ypaoamide (3) has been achieved.
(1) The unusual t-butyl lipid side chain of ypaoamide 53 was prepared in 9 stepsincluding Wittig reaction and cross-Claisen condensation with 9.7% overall yieldstarting from ethyl 4-bromobutyrate.
(2) The building block N-allyl malimide 5b was obtained starting from (S)-malic acid.Employing a highly chemo-, regio-, and stereoselective stepwise reductivep-benzyloxybenzylation of 5b, the 5-(p-benzyloxyphenylmethyl)-3-pyrrolin-2-oneportion 54b was prepared in 6 steps with 46% overall yield starting from malic acid.
(3) The key intermediate 89 was obtained through the coupling of pyrrolin-2-oneportion 54b with side chain segment 53. After a one-pot tandem hydroxyl Bocprotection-β-elimination process of 89, O-Boc protected ypaoamide 52a was obtainedAfter a selective acetylation-β-elimination process of 89, O-Ac ypaoamide 52b wasobtained.
(4) Studies on the deprotection of the phenolic hydroxyl group of ypaoamide. Becausethat its structure contains a 5-alkyl-α,β-unsaturated-pyrrolin-2-one portion which issubjected to racemization under basic condition and E-β-methoxy-α,β-unsaturatedimide moiety which is unstable under acidic condition, the deprotection was proved agreat challenge. Deacetylation of O-Ac ypaoamide 52b catalyzed by CCL (lipasefrom Candida cylindracea) gave (R)-3. Thus, the first asymmetric total synthesis of(R)-3 was achieved in 19 steps with 1.0% overall yield starting from ethyl4-bromobutyrate and N-allyl malimide 5b. The absolute configuration of the naturalypaoamide was determined as S.
(5) On the basis of the total synthesis of (R)-ypaoamide, the asymmetric synthesis ofthe key segment of marine natural product Microcolin B 97 was achieved.
2. Studies on the asymmetric synthesis of awajanomycin (4).
(1) The building block protected(S)-3-hydroxyl-glutarimide 6b was obtained startingfrom(S)-glutamic acid. Employing a stepwise reductive methylation of 6b, theintroduction of O-methoxycarbonyl group and an epoxidation, the piperidin-2-oneportion 192b was prepared in 9 steps starting from 6b.
(2) The asymmetric synthesis of (R)-215 was studied. Asymmetric catalytic transferhydrogenation of 222 catalyzed by the Ru catalyst 221 gave (R)-215 in 90% yield and98% ee. The chain side of awajanomycin (R)-114a was obtained from (R)-215 though2 steps. The synthesis of the two key segments founded the basis of the asymmetrictotal synthesis of awajanomycin.
3. The other part of this thesis is applications of carbohydrates in the synthesis ofchiral ligands and polymers.
(1) Based on the previous work of our laboratory, three types of azide derivativeswere prepared from natural carbohydrates. Employing Staudinger-Vilarrasa reaction,the coupling of primary azide 243 with 2,2'-bypyridine-3,3'-dicarboxylic acid wasachieved to give diamide 255 which can be used as a chiral ligand for enantioselectivefluorination. This work expanded the application of carbohydrates in chiral catalysis.
(2) Two glycomonomers 287 and 290 both with azido group and ynyl group wereobtained from isomaltulose. Employing Huisgen 1,3-dipolar cycloaddition, theformation and characters of the glycopolymer were studied. This work expanded theapplication of carbohydrates in glycopolymer synthesis.
引文
1．《中国海洋药物》管华诗，耿美玉，王长云，2000，76，44．
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14.Ardeo,A.;Garcia,E.;Arrasate,S.;Lete,E.;Sotomayor,N.Tetrahedron Lett.2003,44,8445.
15．《基础有机化学》(第二版)，邢其毅，徐瑞秋，周政，裴伟伟，1993，北京：高等教育出版社．
16.Hutchins,R.O.;Milewski,C.A.;Maryanoff,B.E.J.Am.Chem.Soc.1973,95,3662.
17.Miyaoka,H.;Ta M.;mura,Yamada,Y.Tetrahedron 2000,56,8083.
18.Fraser,B.H.;Mulder,R.J.;Perlmutter,P.Tetrahedron 2006,62,2857.
19.Huang,P.Q.;Zheng,X.;Deng,X.M.Tetrahedron Lett.2001,42,9039.
20.Guggisberg,A,;Kramer,U.;Heidelberger,C.;Charubala,R.;Stephanous,E,;Hesse,M.;Schmid,H.Helv.Chim.Acta.1978,61,1050.
21.Wakabayashi,T.;Saito,M.Tetrahedron Lett.1977,93.
22.Mekouar,K.;Greene,A.E.J.Org.Chem.2000,65,5212.
23.Brooke,G.M.;Mohammed,S.;Whiting,M.C.Chem.Commun.1997,1512.
24．《有机合成》黄培强，靳立人，陈安齐，2004，北京：高等教育出版社．
25.Bosche,U.;Nubbemeyer,U.;Tetrahedron 1999,55,6883.
26.Kochhar,K.S.;Pinnick,H.W.J.Org.Chem.1984,49,3222.
27．《环肽类天然产物Melleumins的不对称全合成研究》，罗捷敏，厦门大学硕士学位论文(2008．6)．
28.Hosseini,M.;Kringrlum,H.;Murray,A.;Tonder,J.E.Org.Lett.2006,8,2103.
29.Schmidt,U.;Riedl,B.;Haas,G.;Griesser,H.;Vetter,A.;Weinbrenner,S.Synthesis 1993,216.
30.Lindsey,C.C.;Gomez-Diaz,C.;Villalba,J.M.;Pettus,T.R.R.Tetrahedron 2002,58,4559.
31.Parmar,V.S.;Kumar,A.;Bisht,K.S.;Mukherjee,S.;Prasad,A.K.;Sharma,S.K.;Wengel,J.Tetrahedron 1997,53,2163.
32.Luzzio,F.A.;Chen,J.J.Org.Chem.2008,73,5621.
1．《中国海洋化学》管华诗，耿美玉，王长云，2000，76，44．
2.(a)Enso,A.;Hasumi,K.;Sakai,K.;Kanabe,T.J.Antibiot.1985,38,920.(b)Rosen,T.;Heathcock,C.Tetrahedron 1986,42,4909.(c)McKenney,J.M.Clin.Pharm.1988,7,21.
3.Abdel-Lateff,A.;Konig,G.M.;Fisch,K.M.;Holler,U.;Jones,P.G.;Wright,A.D.J.Nat.Prod.2002,65,1605.
4.Jang,J.H.;Kanoh,K.;Adashi,K.;Shizuri,Y.J.Nat.Prod.2006,69,1358.
5.Rassu,G.;Auzzas,L.;Zambrano,V.;Burreddu,P.;Pinna,L.;Battistini,L.;Zanardi,F.;Casiraghi,G.J.Org.Chem.2004,69,1625.
6.Carswell,E.L.;Snapper,M.L.;Hoveyda,A.H.Angew.Chem.Int.Ed.2006,45,7230.
7.Koulocheri,S.D.;Magiatis,P.;Haroutounian,S.A.J..Org.Chem.2001,66,7915.
8.Zhou,W.S.;Lu,Z.H.;Xu,Y.M.;Liao,L.X.;Wang,Z.M.Tetrahedron 1999,55,11959.
9.Liao,W.W.;Ibrahem,I.;C6rdova,A.Chem.Commun.2006,674.
10.Godineau,E.;Landais,Y.J.Am.Chem.Soc.2007,129,12662-12663.
11.Wijdeven,M.A.;Wijtmans,R.;van den Berg,R.J.F.;Noorduin,W.;Schoemaker,H.E.;Sonke,T.;van Delft,F.L.;Blaauw,R.H.;Fitch,R.W.;Spande,T.F.;Daly,J.W.;Rutjes,F.P.J.T.Org.Lett.2008,10,4001-.
12.(a)Rudler,H.;Parlier,A.;Sandoval-Chavez,C.;Herson,P.;Daran,J.-C.Angew.Chem.,Int.Ed.2008,47,6843.(b)Sun,Z.;Yu,S.;Ding,Z.;Ma,D.J.Am.Chem.Soc.2007,129,9300.(c)Krow,G.R.;Huang,Q.;Szczepanski,S.W.;Hausheer,F.H.;Carroll,P.J.J.Org.Chem.2007,72,3458.
13.Hiroya,K.;Kawamoto,K.;Inamoto,K.;Sakamoto,T.;Doi,T.Tetrahedron Lett.2009,50,2115.
14.Huang,P.Q.Synlett 2006,8,1133.
15.(a)Cohen,N.;Saucy,G.J.Org.Chem.1980,45,582.(b)Gibbs,R.A.;Okamura,W.H.J.Am.Chem.Soc.1988,110,4062.(c)Trost,B.;Krisch,M.J.J.Am.Chem.Soc.1999,121,6131.(d)Myers,A.G.;Zheng,B.J.Am.Chem.Soc.1996,118,4492.(e)Oppolzer,W.;Radinov,R.N.;El-Sayed,E.J.Org.Chem.2001,66,4766.
16.Frantz,D.E.;Fassler,R.;Carreira,E.M.J.Am.Chem.Soc.2000,122,1806.
17.Jiang,B.;Chen,Z.;Xiong,W.Chem.Commun.2002,1524.
18.(a)Moore,D.;Pu,L.Org.Lett.2002,4,1855.(b)Gao,G.;Moore,D.;Xie,R.G.;Pu,L.Org.Lett.2002,4,4143.
19.Lu,G.;Li,X.S.;Chan,W.L.;Chan,A.S.C.Chem.Commun.2002,172.
20.Helal,C.J.;Magriotis,P.A.;Corey,E.J.J.Am.Chem.Soc.1996,118,10938.
21.Matsumura,K.;Hashiguchi,S.;Ikariya,T.;Noyori,R.J.Am.Chem.Soc.1997,119,8738.
22．《2，6-二取代-3-哌啶醇类生物碱Morusimic acid D的不对称合成研究》，于得胜，厦门大学硕士学位论文(2008．1)
23.Hanessian,S.;Yun,H.Y.;Hou,Y.H.;Tintelnot-Blomley,M.J.Org.Chem.2005,70,6746.
24.Kametani,T.;Surgenor,S.A.;Fukumoto,K.J.Chem.Soc.Perkin Trans 1 1981,920.
25.Cossy,J.;Mirguet,O.;Pardo,D.G.;Desmurs,J.R.Tetrahedron Lett.2001,42,7805.
26.Li,B.;Smith,M.B.Synthetic Communications 1995,25,1265.
27.Woo,K.C.;Jones,K.Tetrahedron Lett.1991,47,6949.
28.Herdeis,C.;Hubmann,H.P.Tetrahedron Asymmetry 1994,5,119.
29.Kirkham,J.E.D.;Courtney,T.D.L.;Lee,V.;Baldwin,J.E.Tetrahedron,2005,61,7219.
1．不对称催化反应进展殷元骐蒋耀忠主编北京科学出版社2000．6。
2.Di(?)guez,M.;P(?)mies,O.;Claver,C.Chem.Rev.2004,104,3189-3215.
3.Kaes,C.;Katz,A.;Hosseini,M.W.Chem.Rev.2000,100,3553-3590.
4.Sakai,S.;Sasaki,T.J.Am.Chem.Soc.1994,116,1587-1588.
5.Gottschaldt,M.;Koth,D.;M(?)ller,D.;Klette,I.;Rau,S.;G(?)rls,H.;Sch(?)ifer,B.;Baum,R.P.;Yano,S.Chem.Eur.J.2007,13,10273-10280.
6.Constable,E.C.;Frantz,R.;Housecroft,C.E.;Lacour,J.;Mahmood,A.Inorg.Chem.2004,43,4817-4819.
7.Assalit,A.;Billard,T.;Chambert,S.;Langlois,B.R.;Queneau,Y.;Coe,D.Tetrahedron:Asymmetry 2009,20,593-601.
8.Chapuis,H.;Strazewski,P.Tetrahedron,2006,62,12108-12115.
9.Garcia,J.;Urp(?),F.;Vilarrasa,J.Tetrahedron Lett.,1984,25,4841-4844.
10.Urpi,F.;Vilarrasa,J.Tetrahedron Lett.,1986,27,4623-4624.
11.Srinivasachari,S.;Liu,Y.;Zhang,G.;Prevette,L.;Reineke,T.J.Am.Chem.Soc.2006,128,8176.
12.(a)Hashimoto K.;Ohsawa R.;Imai,N.J.Polym.Sci.,PartA:Polym.Chem.,1999,37,303.(b)Hashimoto K.;Ohsawa R.;Saito,H.J.Polym.Sci.,Part A:Polym.Chem.,1999,37,2773.(c)Fu,Q.L.;Gowda,C.Bioconjugate Chem.,2002,12,271.
13.(a)Kolb,H.C.;Finn,M.G.;Sharpless,K.B.Angew.Chem.,2001,113,2056.(b)Kolb,H.C.;Finn,M.G.;Sharpless,K.B.Angew.Chem.,2001,40,2004.
14.Huisgen,R.in 1,3-Dipolar Cycloaddition Chemistry(Ed.:Padwa,A.),Wiley,New York,1984.
15.Rostovtsev,V.V.;Green,L.G.;Fokin,V.V.;Sharpless,K.B.Angew.Chem.Int.Ed.,2002,41,2596.
16.Dedola,S.;Nepogodiev,S.A.;Field,R.A.Org.Biomol.Chem.,2007,5,1006.
17.Temelkoff,D.P.;Zeller,M.;Norris,P.Carbohydr.Res.,2006,341,1081.
18. Nepogodiev, S. A.; Dedola, S.; Marmuse, L.; Oliveira, M. T.; Field, R. A. Carbohydr. Res., 2007, 342, 529.
19. (a) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc., 2004, 726, 1638. (b) Bodine, K. B.; Gin, D. Y.; Gin, M. S. Org. Lett., 2005, 7,4479.
20. Wan, Q.; Chen, J.; Chen, G.; Danishefsky, S. J. J. Org. Chem., 2006, 71, 8244.
21. Pierre, R.; ChamberJ., S.; Alirachedi, F.; Danel, M.; Trombotto, S.; Doutheau, A.;Queneau, Y. C. R. Chimie 2008,11, 61.
22. Cheaib, R.; Listkowski, A.; Chambert, S.; Doutheau, A.; Queneau, Y. Tetrahedron: Asymmetry 2008, 19, 1919.
2.Koehn,F.E.;Longley,R.E.;Reed,J.K.J.Nat.Prod.1992,55,613.
3.Nagle,D.G.;Paul,V.J.;Roberts,M.A.Tetrahedron Lett.1996,37,6263.
4.Jang,J.H.;Kanoh,K.;Adashi,K.;Shizuri,Y.J.Nat.Prod.2006,69,1358.5.(a)Huang,P.Q.Synlett 2006,8,1133.(b)Dai,C.F.;Cheng,F.;Xu,H.C.;Ruan,Y.P.;Huang,P.Q.J.Comb.Chem.2006,9,386.(c)Luo,J.M.;Dai,C.F.;Lin,S.Y.;Huang,P.Q.Chemistry-an Asian Journal 2009,4,328.(d)Xiao,K.J.;Liu,L.X.;Huang,P.Q.Tetrahedron:Asymmetry 2009,20,1181.
1.Review:Burja,A.M.;Banaigs,B.;Abou-Mansour,E.;Burgess,G.;Wright,P.C.Tetrahedron 2001,57,9347.
2.Nagle,D.G.;Camacho.F.T.;Paul,V.J.Marine Biology 1998,132,267.
3.Nagle,D.G.;Paul,V.J.;Roberts,M.A.Tetrahedron Lett.1996,37,6263.
4.Nagle,D.G.;Paul,V.J.Journal of Experimental Marine Biology and Ecology 1998,225,29.
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6.Courcambeck,J.;Bihel,F.;Michelis,C.D.;Quelever,G.;Kraus,J.L.J.Chem.Soc.,Perkin Trans.1 2001,1421.
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12．(a)黄培强．有机化学 2001，21，1065；(b)Huang，P．Q．Synlett 2006，8，1133；Huang,P.Q.;Wang,S.L.;Zheng,H.;Fei,X.S.Tetrahedron Lett.1997,38,271.(d)Huang,P.Q.;Wang,S.L.;Ye,J.L.;Ruan,Y.P.;Huang,Y.Q.;Zheng,H.;Gao,J.X.Tetrahedron 1998,54,12547.
13.Polniaszek,R.P.;Belmont,S.E.;Alvarez,R.;J.Org.Chem.1990,55,215.
14.Ardeo,A.;Garcia,E.;Arrasate,S.;Lete,E.;Sotomayor,N.Tetrahedron Lett.2003,44,8445.
15．《基础有机化学》(第二版)，邢其毅，徐瑞秋，周政，裴伟伟，1993，北京：高等教育出版社．
16.Hutchins,R.O.;Milewski,C.A.;Maryanoff,B.E.J.Am.Chem.Soc.1973,95,3662.
17.Miyaoka,H.;Ta M.;mura,Yamada,Y.Tetrahedron 2000,56,8083.
18.Fraser,B.H.;Mulder,R.J.;Perlmutter,P.Tetrahedron 2006,62,2857.
19.Huang,P.Q.;Zheng,X.;Deng,X.M.Tetrahedron Lett.2001,42,9039.
20.Guggisberg,A,;Kramer,U.;Heidelberger,C.;Charubala,R.;Stephanous,E,;Hesse,M.;Schmid,H.Helv.Chim.Acta.1978,61,1050.
21.Wakabayashi,T.;Saito,M.Tetrahedron Lett.1977,93.
22.Mekouar,K.;Greene,A.E.J.Org.Chem.2000,65,5212.
23.Brooke,G.M.;Mohammed,S.;Whiting,M.C.Chem.Commun.1997,1512.
24．《有机合成》黄培强，靳立人，陈安齐，2004，北京：高等教育出版社．
25.Bosche,U.;Nubbemeyer,U.;Tetrahedron 1999,55,6883.
26.Kochhar,K.S.;Pinnick,H.W.J.Org.Chem.1984,49,3222.
27．《环肽类天然产物Melleumins的不对称全合成研究》，罗捷敏，厦门大学硕士学位论文(2008．6)．
28.Hosseini,M.;Kringrlum,H.;Murray,A.;Tonder,J.E.Org.Lett.2006,8,2103.
29.Schmidt,U.;Riedl,B.;Haas,G.;Griesser,H.;Vetter,A.;Weinbrenner,S.Synthesis 1993,216.
30.Lindsey,C.C.;Gomez-Diaz,C.;Villalba,J.M.;Pettus,T.R.R.Tetrahedron 2002,58,4559.
31.Parmar,V.S.;Kumar,A.;Bisht,K.S.;Mukherjee,S.;Prasad,A.K.;Sharma,S.K.;Wengel,J.Tetrahedron 1997,53,2163.
32.Luzzio,F.A.;Chen,J.J.Org.Chem.2008,73,5621.
1．《中国海洋化学》管华诗，耿美玉，王长云，2000，76，44．
2.(a)Enso,A.;Hasumi,K.;Sakai,K.;Kanabe,T.J.Antibiot.1985,38,920.(b)Rosen,T.;Heathcock,C.Tetrahedron 1986,42,4909.(c)McKenney,J.M.Clin.Pharm.1988,7,21.
3.Abdel-Lateff,A.;Konig,G.M.;Fisch,K.M.;Holler,U.;Jones,P.G.;Wright,A.D.J.Nat.Prod.2002,65,1605.
4.Jang,J.H.;Kanoh,K.;Adashi,K.;Shizuri,Y.J.Nat.Prod.2006,69,1358.
5.Rassu,G.;Auzzas,L.;Zambrano,V.;Burreddu,P.;Pinna,L.;Battistini,L.;Zanardi,F.;Casiraghi,G.J.Org.Chem.2004,69,1625.
6.Carswell,E.L.;Snapper,M.L.;Hoveyda,A.H.Angew.Chem.Int.Ed.2006,45,7230.
7.Koulocheri,S.D.;Magiatis,P.;Haroutounian,S.A.J..Org.Chem.2001,66,7915.
8.Zhou,W.S.;Lu,Z.H.;Xu,Y.M.;Liao,L.X.;Wang,Z.M.Tetrahedron 1999,55,11959.
9.Liao,W.W.;Ibrahem,I.;C6rdova,A.Chem.Commun.2006,674.
10.Godineau,E.;Landais,Y.J.Am.Chem.Soc.2007,129,12662-12663.
11.Wijdeven,M.A.;Wijtmans,R.;van den Berg,R.J.F.;Noorduin,W.;Schoemaker,H.E.;Sonke,T.;van Delft,F.L.;Blaauw,R.H.;Fitch,R.W.;Spande,T.F.;Daly,J.W.;Rutjes,F.P.J.T.Org.Lett.2008,10,4001-.
12.(a)Rudler,H.;Parlier,A.;Sandoval-Chavez,C.;Herson,P.;Daran,J.-C.Angew.Chem.,Int.Ed.2008,47,6843.(b)Sun,Z.;Yu,S.;Ding,Z.;Ma,D.J.Am.Chem.Soc.2007,129,9300.(c)Krow,G.R.;Huang,Q.;Szczepanski,S.W.;Hausheer,F.H.;Carroll,P.J.J.Org.Chem.2007,72,3458.
13.Hiroya,K.;Kawamoto,K.;Inamoto,K.;Sakamoto,T.;Doi,T.Tetrahedron Lett.2009,50,2115.
14.Huang,P.Q.Synlett 2006,8,1133.
15.(a)Cohen,N.;Saucy,G.J.Org.Chem.1980,45,582.(b)Gibbs,R.A.;Okamura,W.H.J.Am.Chem.Soc.1988,110,4062.(c)Trost,B.;Krisch,M.J.J.Am.Chem.Soc.1999,121,6131.(d)Myers,A.G.;Zheng,B.J.Am.Chem.Soc.1996,118,4492.(e)Oppolzer,W.;Radinov,R.N.;El-Sayed,E.J.Org.Chem.2001,66,4766.
16.Frantz,D.E.;Fassler,R.;Carreira,E.M.J.Am.Chem.Soc.2000,122,1806.
17.Jiang,B.;Chen,Z.;Xiong,W.Chem.Commun.2002,1524.
18.(a)Moore,D.;Pu,L.Org.Lett.2002,4,1855.(b)Gao,G.;Moore,D.;Xie,R.G.;Pu,L.Org.Lett.2002,4,4143.
19.Lu,G.;Li,X.S.;Chan,W.L.;Chan,A.S.C.Chem.Commun.2002,172.
20.Helal,C.J.;Magriotis,P.A.;Corey,E.J.J.Am.Chem.Soc.1996,118,10938.
21.Matsumura,K.;Hashiguchi,S.;Ikariya,T.;Noyori,R.J.Am.Chem.Soc.1997,119,8738.
22．《2，6-二取代-3-哌啶醇类生物碱Morusimic acid D的不对称合成研究》，于得胜，厦门大学硕士学位论文(2008．1)
23.Hanessian,S.;Yun,H.Y.;Hou,Y.H.;Tintelnot-Blomley,M.J.Org.Chem.2005,70,6746.
24.Kametani,T.;Surgenor,S.A.;Fukumoto,K.J.Chem.Soc.Perkin Trans 1 1981,920.
25.Cossy,J.;Mirguet,O.;Pardo,D.G.;Desmurs,J.R.Tetrahedron Lett.2001,42,7805.
26.Li,B.;Smith,M.B.Synthetic Communications 1995,25,1265.
27.Woo,K.C.;Jones,K.Tetrahedron Lett.1991,47,6949.
28.Herdeis,C.;Hubmann,H.P.Tetrahedron Asymmetry 1994,5,119.
29.Kirkham,J.E.D.;Courtney,T.D.L.;Lee,V.;Baldwin,J.E.Tetrahedron,2005,61,7219.
1．不对称催化反应进展殷元骐蒋耀忠主编北京科学出版社2000．6。
2.Di(?)guez,M.;P(?)mies,O.;Claver,C.Chem.Rev.2004,104,3189-3215.
3.Kaes,C.;Katz,A.;Hosseini,M.W.Chem.Rev.2000,100,3553-3590.
4.Sakai,S.;Sasaki,T.J.Am.Chem.Soc.1994,116,1587-1588.
5.Gottschaldt,M.;Koth,D.;M(?)ller,D.;Klette,I.;Rau,S.;G(?)rls,H.;Sch(?)ifer,B.;Baum,R.P.;Yano,S.Chem.Eur.J.2007,13,10273-10280.
6.Constable,E.C.;Frantz,R.;Housecroft,C.E.;Lacour,J.;Mahmood,A.Inorg.Chem.2004,43,4817-4819.
7.Assalit,A.;Billard,T.;Chambert,S.;Langlois,B.R.;Queneau,Y.;Coe,D.Tetrahedron:Asymmetry 2009,20,593-601.
8.Chapuis,H.;Strazewski,P.Tetrahedron,2006,62,12108-12115.
9.Garcia,J.;Urp(?),F.;Vilarrasa,J.Tetrahedron Lett.,1984,25,4841-4844.
10.Urpi,F.;Vilarrasa,J.Tetrahedron Lett.,1986,27,4623-4624.
11.Srinivasachari,S.;Liu,Y.;Zhang,G.;Prevette,L.;Reineke,T.J.Am.Chem.Soc.2006,128,8176.
12.(a)Hashimoto K.;Ohsawa R.;Imai,N.J.Polym.Sci.,PartA:Polym.Chem.,1999,37,303.(b)Hashimoto K.;Ohsawa R.;Saito,H.J.Polym.Sci.,Part A:Polym.Chem.,1999,37,2773.(c)Fu,Q.L.;Gowda,C.Bioconjugate Chem.,2002,12,271.
13.(a)Kolb,H.C.;Finn,M.G.;Sharpless,K.B.Angew.Chem.,2001,113,2056.(b)Kolb,H.C.;Finn,M.G.;Sharpless,K.B.Angew.Chem.,2001,40,2004.
14.Huisgen,R.in 1,3-Dipolar Cycloaddition Chemistry(Ed.:Padwa,A.),Wiley,New York,1984.
15.Rostovtsev,V.V.;Green,L.G.;Fokin,V.V.;Sharpless,K.B.Angew.Chem.Int.Ed.,2002,41,2596.
16.Dedola,S.;Nepogodiev,S.A.;Field,R.A.Org.Biomol.Chem.,2007,5,1006.
17.Temelkoff,D.P.;Zeller,M.;Norris,P.Carbohydr.Res.,2006,341,1081.
18. Nepogodiev, S. A.; Dedola, S.; Marmuse, L.; Oliveira, M. T.; Field, R. A. Carbohydr. Res., 2007, 342, 529.
19. (a) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc., 2004, 726, 1638. (b) Bodine, K. B.; Gin, D. Y.; Gin, M. S. Org. Lett., 2005, 7,4479.
20. Wan, Q.; Chen, J.; Chen, G.; Danishefsky, S. J. J. Org. Chem., 2006, 71, 8244.
21. Pierre, R.; ChamberJ., S.; Alirachedi, F.; Danel, M.; Trombotto, S.; Doutheau, A.;Queneau, Y. C. R. Chimie 2008,11, 61.
22. Cheaib, R.; Listkowski, A.; Chambert, S.; Doutheau, A.; Queneau, Y. Tetrahedron: Asymmetry 2008, 19, 1919.