复杂活性天然产物 Psiguadial B 的 全合成研究

天然产物在医药、 农药、 食品等诸多领域都有重要应用， 一直都是科学家
尤其是有机化学家重点关注的领域。 天然产物全合成作为对天然产物了解、 制
备等方面的重要一环， 也是有机化学家的研究热点。 间苯三酚类天然产物是一
类重要的天然产物， 其结构类型多样， 并具广泛的生物活性， 一直是化学家和
生物学家的研究热点。 桃金娘科植物作为天然间苯三酚类化合物的重要来源之
一， 近年来受到了国内外学者的广泛关注， 从其中分离的部分化合物具有显著
的体外抗肿瘤活性， 如 psiguadial A， psiguadial B 等间苯三酚类天然产物。
本论文所研究的天然产物分子 Psiguadial B 显示了对阿霉素敏感型肝癌细
胞较强的细胞毒活性。 Psiguadial B 结构新颖， 拥有复杂的 4/7/6/6/6 五环环系，
包括一个反式四元环； 也具有双环[4.3.1]癸烷桥环骨架结构； 还包含 6 个复杂
手性中心， 两个为季碳手性中心。 因其重要生物学活性以及复杂的分子结构，
吸引了众多科学家的注意。 本论文的主要研究内容是探索一条高效、 简洁的合
成路线来实现对 psiguadial B 的全合成， 期望在解决构建反式四元环这个难题
的同时， 通过一种全新的策略来构建双环[4.3.1]癸烷骨架。 本文计划通过 Type II
[5+2]反应， 吡喃环构建反应和缩环反应， 完成该天然产物分子核心骨架的构建，
提高该分子的合成效率。 目前已经通过 Michael 加成反应将环丁烯酸甲酯和呋
喃片段连接起来， 并经过构型翻转得到了反式四元环结构； 随后通过 Type II
[5+2]环加成反应构建了比较有合成挑战性的双环[4.4.1]十一烷桥环骨架； 之后
通过 6π电环化反应构建吡喃环并引入苯基， 完成该天然产物分子中 4/7/7/6/6
五环环系， 实现了 psiguadial B 主要骨架结构的合成。 同时， 通过对目前所合
成化合物的单晶数据进行分析， 结果显示所得化合物的相对构型与天然产物
psiguadial B 的构型一致。
Psiguadial B 的核心骨架已基本完成构建， 为该天然产物分子以及该类天然
产物分子的全合成提供了一定的参考。 有助于此类天然产物全合成的探索。
 

Natural products have attracted extensive attention from scientists, especially
organic chemists, because of their applications in medicine, pesticides, food and so
on. Total synthesis of natural products, as one of important part for understanding
and preparation of natural products, is also focus for organic chemists. The
phloroglucinol natural products studied in this paper are a kind of important natural
products, because of their diverse structures and extensive biological activities, they
have been the focus by chemists and biologists.Myrtle plants, as one of the
important sources of natural resorcinols, have attracted extensive attention from
scholars in recent years. Some compounds isolated from these plants have
significant antitumor activities in vitro, such as psiguadial A, psiguadial B and other
natural products of resorcinol.
Psiguadial B, a natural product molecule studied in this thesis, showed strong
cytotoxicity to adriamycin-sensitive hepatocellular carcinoma cells. At the same
time, psiguadial B has a complex 4/7/6/6/6 pentacyclic ring system, in which both
small ring trans-quaternary ring and middle ring seven-membered ring are synthetic
challengeable rings. It also has a synthetic challengeable bicyclic [4.3.1] decane
bridge ring skeleton structure and contains six complex chiral centers and two
quaternary carbon chiral centers. Therefore, the important biological activity and
complex molecular structure of psiguadial B have attracted the attention of many
scientists. The main content of this thesis is to explore an efficient and concise
synthetic route to achieve the total synthesis of psiguadial B, and hoped that a new
strategy will be adopted to construct the bicyclic [4.3.1] decane skeleton. It is
planned that the core framework of the natural product will be constructed by the
reaction of Type II [5+2] reaction, pyran ring construction, and the reduction of ring,
to improve the synthesis efficiency of the molecule. In this thesis, the fragments of
methyl cyclobutyrate and furan have been linked by Michael addition reaction, and
the trans-quaternary ring structure has been obtained by configuration inversion.
Then, the bicyclic [4.4.1] undecane bridge ring skeleton with more synthetic
challenges has been constructed by type II [5+2] cycloaddition reaction. Then,
pyran ring has been constructed by 6  electrocyclization and phenyl has been
introduced into the natural product molecule; The 4/7/7/6/6 pentacyclic ring system
of the natural product molecule was completed, and the synthesis of the main
framework structure of psiguadial B was realized. At the same time, by analyzing
the single crystal data of the compound synthesized at present, the relative
configuration of the obtained compounds is consistent with that of the natural product psiguadial B.
The core skeleton of Psiguadial B has been basically constructed, which
provides a reference for the total synthesis of this natural product molecule and this
kind of natural product molecule. It is conducive to the exploration of the total
synthesis of such natural products.
 

[1] 汪秋安， 王明峰， 者为. 天然产物有机合成原理与实例[M]. 北京： 化学工业出版社， 2013： 1-5.
[2] Nicolaou K C, Yang Z, Liu J J, et al. Total Synthesis of Taxol[J]. Nature, 1994,367： 630-634.
[3] Holton R A, Kim H B, Somoza C, Liang F, et al. First Total Synthesis of Taxol.2. Completion of the C and D Rings[J]. J. Am. Chem. Soc., 1994, 116 ：1599-1600.
[4] Denis J N, Greene A E. A Highly Efficient, Practical Approach to NaturalTaxol[J]. J. Am. Chem. Soc., 1988, 110： 5917-5919.
[5] Guenard D, Potier P, et al. Taxol and Taxotere: Discovery, Chemistry, andStructure-Activity Relationships[J]. Acc. Chem. Res., 1993, 26： 160-167.
[6] Wöhler F. Ann. Phys. Chem., 1828, 12： 253.
[7] Robinson R B. A Synthesis of Tropinone[J]. J. Chem. Soc., 1917, 111 ：762-768.
[8] Woodward R B, Doering W E. The Total Synthesis of Quinine[J]. J. Am. Chem.Soc., 1944, 66： 849-850.
[9] Woodeard R B, Cava M P, Ollis W D, et al. The Total Synthesis ofStrychnine[J]. J. Am. Chem. Soc., 1954, 76： 4749-4751.
[10] Woodeard R B. The Total Synthesis of Vitamin B12[J]. Pure. Appl. Chem., 1973,33： 145-177.
[11] Suh E M, Kishi Y J. Synthesis of Palytoxin from Palytoxin Carboxylic Acid[J].J. Am. Chem. Soc., 1994, 116： 11205-11206.
[12] 中国科学院中国植物志编辑委员会.中国植物志[M]. 北京： 科学出版社, 53（ 1）： 28.
[13] Shao M, Wang Y , Liu Z, et al. Psiguadials A and B, Two NovelMeroterpenoids with Unusual Skeletons from the Leaves of PsidiumGuajava[J]. Org. Lett., 2010, 12（ 21）： 5040-5043.
[14] 中国科学院中国植物志编辑委员会.中国植物志[M]. 北京: 科学出版社,53（ 1)： 123.
[15] Shao M, Wang Y , Jian Y Q, et al. Guadial A and Psiguadials C and D, ThreeUnusual Meroterpenoids from Psidium Guajava[J]. Org. Lett., 2012, 14（ 20）：5262-5265.
[16] Qin X J, Yu Q, Yan H, et al. Meroterpenoids with Antitumor Activities fromGuava (Psidium Guajava)[J]. J. Agric. Food Chem., 2017, 65（ 24）： 4993-4999.
[17] Tang G H, Dong Z, Guo Y Q, et al. Psiguajadials A-K: Unusual PsidiumMeroterpenoids as Phosphodiesterase-4 Inhibitors from the Leaves of PsidiumGuajava[J]. Sci. Rep., 2017, 7（ 1047）： 1-14.
[18] Jian Y Q, Huang X J, Zhang D M, et al. Guapsidial A and Guadials B and C:Three New Meroterpenoids with Unusual Skeletons from the Leaves ofPsidium Guajava[J]. Chem. Eur. J., 2015, 21（ 25）： 9022-9027.
[19] Yang X L, Hsieh K L, Liu J K. Guajadial: An Unusual Meroterpenoid fromGuava Leaves Psidium Guajava[J]. Org. Lett., 2007, 9（ 24）： 5135-5138.
[20] Fu H Z, Luo Y M, Li C J, et al. Psidials A-C, Three Unusual Meroterpenoidsfrom the Leaves of Psidium Guajava L[J]. Org. Lett., 2010, 12（ 4）： 656-659.
[21] Gao Y , Wang G Q, Wei K, et al. Isolation and Biomimetic Synthesis of(±)-Guajadial B, A Novel Meroterpenoid from Psidium Guajava[J]. Org. Lett.,2012, 14（ 23）： 5936-5939.
[22] Gao Y, Li G T, Li Y, et al. Guajadials C-F, Four Unusual Meroterpenoids fromPsidium Guajava[J]. Nat. Prod. Bioprospect., 2013, 3（ 1）： 14-19.
[23] Yang X L, Hsieh K L, Liu J K. Diguajadial: A Dimer of the Meroterpenoidfrom the Leaves of Psidium Guajava[J]. Chin. J. Nat. Med., 2008, 6（ 5） ：333-335.
[24] Lawrence A L, Adlington R M, Baldwin J E, et al. A Short BiomimeticSynthesis of the Meroterpenoids Guajadial and Psidial A[J]. Org. Lett., 2010,12（ 8）： 1676-1679.
[25] Tran D N, Cramer N. Biomimetic Synthesis of (+)-Ledene, (+)-Viridiflorol,(-)-Palustrol, (+)-Spathulenol, and Psiguadial A, C, and D via the PlatformTerpene (+)-Bicyclogermacrene[J]. Chem. Eur. J., 2014, 20 （ 34 ） ：10654-10660.
[26] Mei G J, Liu X, Qiao C, et al. Type II Intramolecular
[5+2] Cycloaddition:Facile Synthesis of Highly Functionalized Bridged Ring Systems[J]. Angew.Chem. Int. Ed., 2015, 54： 1754–1758.
[27] Liu J Y, Wu J L, Fan J H, et al. Asymmetric Total Synthesis of Cyclocitrinol[J].J. Am. Chem. Soc., 2018, 140： 5365−5369.
[28] Liu X, Liu J Y, Wu J L, et al. Asymmetric Total Synthesis of CerorubenicAcid-III[J]. J. Am. Chem. Soc., 2019, 141： 2872−2877.
[29] Chapman L M, Beck J C, Wu L L, et al. Enantioselective Total Synthesis of(+)-Psiguadial B[J]. J. Am. Chem. Soc., 2016, 138（ 31）： 9803-9806.
[30] Newton C G, Tran D N, Wodrich M D, et al. One-step Multigram-scaleBiomimetic Synthesis of Psiguadial B[J]. Angew. Chem. Int. Ed., 2017, 56（ 44）： 13776-13780.
[31] Kinebuchi M, Uematsu R, Tanino K. Synthetic Studies on Psiguadial B:Construction of Bicyclo
[4.3.1]Decane Skeleton via Double CyclizationReaction of Alkyne Dicobalt Complex[J]. Tetrahedron Lett., 2017, 58（ 14）：1382-1386.
[32] 胡利军. 三种桃金娘科药用植物的间苯三酚-萜类加合物全合成研究[D].江苏： 中国药科大学博士学位论文, 2018： 70-82.
[33] Chapman L M, Beck J C, Wu L L, et al. Evolution of A Strategy for theEnantioselective Total Synthesis of (+)-Psiguadial B[J]. J. Org. Chem., 2018,83： 6066-6085.
[34] Dowling M S, Vanderwal C D. Ring-closing Metathesis of Allylsilanes as AFlexible Strategy Toward Cyclic Terpenes. Short Syntheses of Teucladiol,Isoteucladiol, Poitediol, and Dactylol and An Attempted Synthesis ofCaryophyllene[J]. J. Org. Chem., 2010, 75： 6908-6922.
[35] Willis N J, Bray C D. Ortho-quinone Methides in Natural Product Synthesis[J].Chem. Eur. J., 2012, 18： 9160–9173.
[36] Nair V, Treesa P M. Hetero Diels–Alder Trapping of3-Methylene-1,2,4-
[3H]Naphthalenetrione: An Efficient Protocol for theSynthesis of α- and β-Lapachone Derivatives[J]. Tetrahedron Letters, 2001, 42：4549–4551.
[37] Pathak T P, Sigman M S. Applications of Ortho-quinone Methide Intermediatesin Catalysis and Asymmetric Synthesis[J]. J. Org. Chem., 2011, 76 ：9210−9215.
[38] Van R W, Water D, Pettus T R R. O–Quinone Methides: IntermediatesUnderdeveloped and Underutilized in Organic Synthesis[J]. Tetrahedron, 2002,58： 5367 - 5405.
[39] Lesch B, Brase S. A Short Atom-economical entry to Tetrahydroxanthenones[J].Angew. Chem. Int. Ed., 2004, 43： 115–118.
[40] Nising C F, Ohnemiller U K, Brase S. The Total Synthesis of the FungalMetabolite Diversonol[J]. Angew. Chem. Int. Ed., 2006, 45： 307–309.
[41] Nising C F, Ohnemiller U K, Friedrich A. Diastereoselective Synthesis ofHighly Functionalized Tetrahydroxanthenols—unprecedented Access toPrivileged Structural Motifs[J]. Chem. Eur. J., 2006, 12： 3647–3654.
[42] Meister A C, Nieger M, Brase S. A Radical Access to Highly FunctionalizedTetrahydroxanthones[J]. Chem. Eur. J., 2013, 19： 10836–10839.
[43] Meister A C, Encinas A, Sahin H. Total Synthesis of Blennolide Mycotoxins:Design, Synthetic Routes and Completion[J]. Eur. J. Org. Chem., 2014 ：4861–4875.
[44] Xia A B, Wu C, Wang T, et al. Enantioselective Cascade Oxa-Michael–MichaelReactions of 2-Hydroxynitrostyrenes with Enones Using a Prolinol ThioetherCatalyst[J]. Adv. Synth. Catal., 2014, 356： 1753–1760.
[45] Nicolaou K C, Peng X S, Sun Y P. Total Synthesis and Biological Evaluation ofCortistatins A and J and Analogues Thereof[J]. J. Am. Chem. Soc., 2009, 131：10587–10597.
[46] Angeles A R, Waters S P, Danishefsky S J. Total Syntheses of (+)- and (-)-Peribysin E[J]. J. Am. Chem. Soc., 2008, 130： 13765–13770.
[47] Fudickar W, Vorndran K, Linker T. Auxiliary Controlled Singlet-oxygen EneReactions of Cyclohexenes[J]. Tetrahedron, 2006, 62： 10639-10646.
[48] Barrero A F, Herrador M M, Valdivia M V, et al. Synthesis of MonoterpenicAnalogues of Puupehenone and Puupehedione[J]. Tetrahedron Letters, 1998,39： 2425-2428.
[49] Maiti S, Sengupta S, Ciri C, et al. Enantiospecific Synthesis of8-Epipuupehedione from (R)-(−)-Carvone[J]. Tetrahedron Letters, 2001, 42：2389-2391.
[50] Barrero A F, Herrador M M, Arteaga P, et al. Mild and Rapid Method for theGeneration of o-Quinone Methide Intermediates. Synthesis of PuupehedioneAnalogues[J]. Tetrahedron, 2006, 62： 6012-6017.
[51] Beaudry C M, Malerich J P, Trauner D. Biosynthetic and BiomimeticElectrocyclizations[J]. Chem. Rev. 2005, 105： 4757-4778.