Literature Report 2. Divergent Asymmetric Total Synthesis of Mulinane Diterpenoids. Date :

Transcription

1 Literature Report 2 Divergent Asymmetric Total Synthesis of Mulinane Diterpenoids Reporter : Zhou-Hao Zhu Checker : Xiao-Yong Zhai Date : Liu, Y.-T.; Li, L.-P.; Xie, J.-H.*; Zhou, Q.-L. Angew. Chem. Int. Ed. 2017, 56, 12708

2 Contents 1 Introduction 2 Racemic Total Synthesis of Mulinane Diterpenoids 3 Asymmetic Total Synthesis of Mulinane Diterpenoids 4 Summary 2

3 CV of Prof. Xie Jian-Hua Background: B.S., Sichuan Normal College M.S., Nankai University (with Prof. Tian-Lin Liu) Ph.D., Nankai University (with Prof. Qi-Lin Zhou) Assistance Professor, Nankai University Associate Professor, Nankai University Xie Jian-Hua Postdoctoral Fellow, University of Maryland (with Prof. Micheal P. Doyle) 2011-now Professor, Nankai University Research Interests: The discovery and development of new catalytic synthetic methods The asymmetric total synthesis of various biologically active natural products The design and synthesis of new highly efficient chiral ligands and catalysts 3

4 Introduction Mulinic Acid Isomulinic Acid Mulin-11,13-diene Isolated from the Chilean shrub Mulinum crassifolium in 1990; A trans,cis-fused tricyclic core system with its 1,4-syn-quaternary carbon centers at the ring junctures; A folk medicine to treat ailments such as diabetes, bronchial and intestinal disorders; More than 30 mulinane diterpenoids have been isolated and identified from plants in the Apiaceae family. Loyola, L. A.; Morales, G.; Rodriguez, B.* et al. Tetrahedron 1990, 46,

5 Mulinane Diterpenoids Isolated from Apiaceae Marcos, I. S.; Díez, D. et al. in Studies in natural products chemistry, 2016, 48, 137 5

6 Racemic Synthesis of Mulinane Diterpenoids Reber, K. P.; Xu, J.; Guerrero, C. A.* et al. J. Org. Chem. 2015, 80,

7 Robinson Annulation 7

8 Anionic Oxy-Cope Rearrangement The driving force is that the product is an enolate, which can tautomerize to the corresponding carbonyl compound. This product will not equilibrate back to the other regioisomer. 8

9 Ring Closing Metathesis (RCM) 9

10 Saegusa-Ito Oxidation 10

11 Retrosynthetic Analysis Late-stage functional modification/functionalization 11

12 Retrosynthetic Analysis 12

13 Racemic Synthesis of Mulinane Diterpenoids 13

14 Racemic Synthesis of Mulinane Diterpenoids 14

15 Racemic Synthesis of Mulinane 1 15

16 Racemic Synthesis of Mulinane 2 and 3 16

17 Racemic Synthesis of Mulinane 3 and 4 17

18 Asymmetric Synthesis of Mulinane Diterpenoids Liu, Y.-T.; Li, L.-P.; Xie, J.-H.*; Zhou, Q.-L. Angew. Chem. Int. Ed. 2017, 56,

19 Retrosynthetic Analysis 19

20 Asymmetric Synthesis of Mulinane Diterpenoids Xie, J.-H.; Liu, X.-Y.; Zhou, Q.-L.* et al. Angew. Chem. Int. Ed. 2011, 50,

21 Asymmetric Synthesis of Mulinane Diterpenoids 21

22 Asymmetric Synthesis of Mulinane Diterpenoids 22

23 Asymmetric Synthesis of Mulinane Diterpenoids 23

24 Summary Steps, % overall yield; The first total synthesis of four members of Mulinane diterpenoids; Robinson annulation and ring-closing metathesis reaction; Diastereoselective anionic oxy-cope rearrangement; Novel vinylogous Saegusa oxidation. Guerrero, C. A. et al. J. Org. Chem. 2015, 80, Steps, % overall yield; The first divergent enantioselective total syntheses of 9 Mulinane diterpenoids; Iridium-catalyzed asymmetric enone hydrogenation; Intramolecular Friedel Crafts reaction; Homologation/ring-expansion reaction; Late-stage functional modification or functionalization. Xie, J.-H. et al. Angew. Chem. Int. Ed. 2017, 56,

25 The first paragraph Terpenoids, which are structurally fascinating molecules with intriguing biological activities, continue to challenge synthetic chemists with the complexity of their hydrocarbon scaffolds. For example, mulinane diterpenoids, first isolated in 1990 from the Chilean shrub Mulinum crassifolium, are used in traditional folk medicine to treat ailments such as diabetes and bronchial and intestinal disorders. To date, more than thirty mulinane diterpenoids have been isolated and identified from plants in the Apiaceae family (which includes the Azorella, Laretia, and Mulinum genera). These natural products are assumed to share the same biogenic precursor, mulin-11,13-diene, and to be generated through various oxygenation reactions. In preliminary biological studies, mulinane diterpenoids were found to possess a broad range of bioactivities including gastroprotective, antituberculosis, antiplasmodial, and antimicrobial activities. 25

26 The first paragraph Recently, semisynthetic analogues and biotransformation analogues of mulinane diterpenoids have been found to exhibit higher antituberculosis and gastroprotective activities than their parent diterpenoids. 26

27 The last paragraph In conclusion, we achieved divergent enantioselective total syntheses of seven mulinane diterpenoids along with two analogues from readily available cyclopentenone 14. Our synthetic strategy involved an iridium-catalyzed asymmetric enone hydrogenation to obtain the chiral starting material, an intramolecular Friedel Crafts reaction to construct the chiral fused tricyclic structure, a Birch reduction combined with conjugate methylation to set up the C8-methylated quaternary stereocenter, a homologation/ringexpansion reaction to furnish the trans,cis-fused tricyclic ring system, and late-stage functional modification or functionalization to complete the divergent enantioselective syntheses. This work represents the first example of asymmetric syntheses of mulinane diterpenoids and provides an efficient approach to the mulinane diterpenoids as well as to other types of tricyclic diterpenoids and their analogues. 27

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