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Total Synthesis of Bioactive Natural Prod- Tancy SYNPACTS ▌1 Totalsynpacts Synthesis of (+)-Fusarisetin A: A Biomimetic Approach JunBiomimetic Yin, Synthesis ofShuanhu (+)-Fusarisetin A Gao* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, P. R. of China Fax +86(21)62604784; E-mail: [email protected] Received: 26.08.2013; Accepted after revision: 17.09.2013 Abstract: This article outlines our recent efforts to synthesize (+)-fusarisetin A, a naturally occurring 3-acyltetramic acid, by a route based on a hypothetical biosynthesis. Our research suggests that the biosynthesis of (+)-fusarisetin A might involve the aerobic oxidation of equisetin, possibly mediated by metal oxidants or by photochemically produced reactive oxygen species. Key words: radical reactions, total synthesis, biosynthesis, hetero- cycles, polycycles Natural products have proven to be an indispensable Jun Yin (left) was born in Shandong Province, China, in 1977. He 1 source of human therapeutic agents. Many significant received his bachelor’s degree in 2000 and his master’s degree in drugs are based on natural products or compounds derived organic chemistry in 2003, studying under Professor Jianwu Wang from natural products, such as penicillin (antibiotic), qui- at Shandong University. From 2003 to 2005, he worked at WuXi nine and artemisinin (antimalarials), lovastatin (lipid-con- AppTec. (Shanghai) as a chemist. From 2006 to 2011, he worked at 2 Roche R&D Center (China) Ltd. as a medicinal chemist. In 2011, he trol agent), and taxol and doxorubicin (anticancer drugs). joined Professor Shuanhu Gao’s group to pursue doctoral studies at Historically, these drugs have revolutionized human life the Department of Chemistry of East China Normal University. His by improving health standards and lengthening life expec- research projects focus on total synthesis of bioactive natural prod- tancy. These natural therapeutics have also served as driv- ucts. ing forces for the exploration of natural product synthesis, Shuanhu Gao (right) was born in Ningxia Province, China, in 1979. the growth of which not only promotes the development He received his B.S. degree from Lanzhou University in 2001. In 2006 he obtained his Ph.D. from Lanzhou University under the direc- of new synthetic methodologies, but also provides a plat- tion of Professor Yongqiang Tu. From 2007 to 2010, he was a post- form for further studies on medicinal chemistry and chem- doctoral fellow in Professor Chuo Chen’s group at the UT Southwestern Medical Center at Dallas. He began his independent ca- reer as a professor in the Department of Chemistry at East China Nor- OH Me Me OH mal University in October 2010. His current research interests focus N N 3 primarily on the synthesis of complex natural products and on medic- HO E O O E OH inal chemistry. O O 4 O D 1 O Me D C Me C 5 Me 16 Me ical biology. Therefore, natural product synthesis is an H B H H H H A A B H important aspect of both academic and pharmaceutical Me Me H H chemistry. originally proposed structure of revised structure of fusarisetin A (+)-fusarisetin A (1) The goal of natural product synthesis has been to provide the target molecule efficiently and in adequate amounts;3 19 Me R1 this requires practicing chemists to pay attention to such O O 2 N OH N OH 4 5a,b 3 issues as chemoselectivity, atom economy, step econ- E 5c–e 5f,g This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1 18 HO omy, and redox economy. In this SynPact article, we HO 4 22 17 Me O Me O wish to outline our recent efforts to achieve an efficient 16 Me20 Me 14 13 15 6 synthesis of (+)-fusarisetin A, a promising anticancer H B 7 5 H A 10 agent, based on a hypothetical biosynthesis of the mole- 21Me 12 8 R2 11 H 9 H cule. We believe that our scalable synthesis will permit equisetin (2) R1 = H, R2 = Me, trichosetin (3) structure–activity relationship studies and facilitate fur- 1 2 R = Me, R = CH2OH, ophiosetin (4) ther studies on the medicinal chemistry of this molecule. Figure 1 Structures of (+)-fusarisetin A and biogenetically related Tetramic acid based natural products6 typically contain a natural products pyrrolidine-2,4-dione moiety, which normally exists as a SYNLETT 2014, 25, 0001–0007 mixture of keto/enol tautomers (Scheme 1; I and II). Most Advanced online publication: 05.11.20130936-52141437-2096 tetramic acids carry acyl substituents in the C-3 position DOI: 10.1055/s-0033-1340153; Art ID: ST-2013-P0821-SP and can therefore generally form four detectable tauto- © Georg Thieme Verlag Stuttgart · New York 2 J. Yin, S. Gao SYNPACTS O R2 the corresponding peptide (A and B, respectively); this, in 3 3 O R HO R3 R turn, might be derived from a carboxylic acid and an ami- 4 N COOH fast 3 no acid. Because of their unique structures and potential 5 R1 2 O R N R2 2 O A biological activities, naturally occurring tetramic acids 1 N have attracted a considerable degree of interest from or- R1 1 R ganic chemists since the 1960s.6 I II R2 O (+)-Fusarisetin A (1; Figure 1), a new 3-acyltetramic acid, tetramic acid R3 HN COOH OH was isolated from the soil fungus Fusarium sp. FN080326 pyrrolidine-2,4-dione 1 R 7 carboxylic acid amino acid by Ahn and co-workers in 2011. As a fungal metabolite, (+)-fusarisetin A is a potent inhibitor of acinar morpho- H genesis, cell migration, and cell invasion in MDA-MB- H O O 231 cells. Investigations of cell growth and cell death in O R6 O R6 4 fast 3 this breast-cancer cell line indicated that (+)-fusarisetin A O O R5 7 5 does not exhibit significant cytotoxicity. These findings 5 O 5 O R N 2 R N 1 R6 N COOH suggest that (+)-fusarisetin A might be a valuable antican- R4 R4 R4 cer agent, especially for the inhibition of cancer-cell me- III IV B tathesis. Besides its promising biological activity, (+)- fusarisetin A (1) has some interesting structural features. slow slow It contains a pentacyclic ring system (A–B–C–D–E) that R5 R6 R6 O O includes a trans-decalin moiety (rings A and B), a spiro O O O O fast HN COOH moiety (rings C and E), and a 3-acyltetramic acid moiety R6 OH H H R4 (ring E). It has ten stereocenters, including two all-carbon 5 O carboxylic acid amino acid 5 O R N quaternary centers (C-1 and C-16) and a hetero-quaterna- R N 4 ry center (C-4). Ahn and co-workers confirmed the rela- 4 R R tive configuration of (+)-fusarisetin A by x-ray VI V crystallographic analysis. The absolute stereochemistry of 3-acyltetramic acid 1 was originally assigned by means of the exciton chirali- Scheme 1 Tetramic acids and 3-acyltetramic acids ty circular dichroism method, but was subsequently re- vised by Li and co-workers as a result of their chemical synthesis.8a The molecule has attracted considerable at- mers, consisting of the two pairs of rapidly interconvert- tention from the synthetic chemistry community since its ing internal tautomers III/IV and V/VI. Biogenetically, discovery. To date, four groups, including ourselves, have the construction of tetramic acids and 3-acyltetramic acids accomplished total syntheses of fusarisetin A. Li and co- might involve the formation of bond between the C-3 and workers achieved the first synthesis by using a palladium- C-4 atoms by an intramolecular Dieckmann cyclization of catalyzed oxygen-to-carbon allylic rearrangement to give OH O Me OH O N OH O N E Me 1 biomimetic HO 4 O cyclization coupling Me O Me 6 Me H B H 5 Me A Me H equisetin (2) Me aerobic polyenoylamino acid (5) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. oxidation O Me OH NH2 N O S-Enz HO O OH O O HO 1 4 O D (S)-serine (6) Me C 5 Me 6 Me H H Me H Me H (+)-fusarisetin A (1) Me unsaturated fatty acid (7) Scheme 2 Research plan based on a biosynthetic hypothesis Synlett 2014, 25, 1–7 © Georg Thieme Verlag Stuttgart · New York SYNPACTS Biomimetic Synthesis of (+)-Fusarisetin A 3 the enantiomer (−)-1; as a result, they revised the absolute for the exploration of its laboratory synthesis and biolog- configuration of the molecule.8a Theodorakis and co- ical functions. During our retrosynthetic analysis, we con- workers proposed a biosynthetic pathway from equisetin ducted a careful literature search that showed that, in (2) and they accomplished a biomimetic synthesis of (−)- addition to (+)-fusarisetin A, several other tetramic acids 1 by a one-pot radical cyclization/aminolysis approach.8b,c can be isolated from fungi. These biogenetically related 3- Recently, Yang and co-workers reported a synthesis of acyltetramic acids include equisetin (2),10 trichosetin (+)-1 in which their intramolecular version of the Pauson– (3),11 and ophiosetin (4)12 (Figure 1). Equisetin (2) was Khand reaction served as a key step.8d isolated from the white mold Fusarium equiseti in 1974, 9 and it shows strong antibiotic activity, HIV inhibitory ac- Our research group is interested in the synthesis of bioac- 10 tive natural products with anticancer potential. We con- tivity, and selective cytotoxicity to mammalian cells. sidered that (+)-fusarisetin A (1) would be a perfect target Surprisingly, we found that both (+)-fusarisetin A (1) and O OEt Me CHO Me 2 steps a) 10, CH2Cl2 b) HCl Me O O CHO 91% THF Me Me O Me O (+)-citronellal (8) 9 11, E:Z = 16:1 O OEt O OEt Me Me Me c) 13, LHMDS, THF d) DIBAL CHO 63% (2 steps) CH2Cl2 Me Me 94% 12 14, E/Z > 15:1 Me R H Me Me Me f) BF ⋅OEt 3 2 O CH2Cl2 H Me 15, R= CH OH Me e) DMP 2 16, R= CHO endo-selectivity EtO O CHO Me O Me then 18 g) 20, toluene H Me Me A B H 47% 68% (3 steps) Me H H H 17 Me H 19 OMe OTBS O Me N O O Me h) NaOMe, N OH MeOH, 72% O HO This document was downloaded for personal use only.
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