Literature Report 1. Total Syntheses of Disorazoles A1 and B1 and Full Structural Elucidation of Disorazole B1

Transcription

1 Literature Report 1 Total Syntheses of Disorazoles A1 and B1 and Full Structural Elucidation of Disorazole B1 Reporter: Kui Liu Checker: Xiao-Yong Zhai Date: Nicolaou K C *; Bellavance G ; Buchman M ; Pulukuri K K Nicolaou, K. C. ; Bellavance, G.; Buchman, M.; Pulukuri, K. K. J. Am. Chem. Soc. 2017, 139,

2 Contents 1 Introduction 2 Some Important Reactions Used in This Article 3 Total Syntheses of Disorazoles A1 and B1 4 Summary 2

3 CV of Prof. Nicolaou, K. C. Background: B.Sc., Bedford College Ph.D., University College London Postdoc., Columbia University Postdoc., Harvard University Prof., University of Pennsylvania Prof., University of California, San Diego and Scripps Research Institute 2013-Now Prof., Rice University Research Interests: The group's research activities are centered around the total synthesis of architecturally novel and biologically important natural products which serve as opportunities for discovery and invention of novel synthetic strategies, methods, and enabling technologies for biology and medicine. 3

4 Introduction of Disorazoles Twenty-nine disorazoles were isolated from Sorangium cellulosum in The disorazoles are macrocyclic dilactones of two 2-pentadecyloxazol- 4-carboxylic acids. The disorazoles proved to be highly cytotoxic and active against fungi. Jansen, R. et al. Liebigs Ann. Chem. 1994,

5 Introduction of Disorazoles Jansen, R. et al. Liebigs Ann. Chem. 1994,

6 Stille Cross-Coupling 6

7 Suzuki Cross-Coupling 7

8 Yamaguchi Esterification 8

9 Yamaguchi Macrolactonization 9

10 Wittig Reaction 10

11 Retrosynthetic Analysis of Disorazole A1 11

12 Retrosynthetic Analysis of Disorazole B1 12

13 Synthesis of Vinyl Boronic Acid 4 and Iodide 5 TBS 9 H a) 10, TiCl 4 then i Pr 2 NEt then 9 89%, 12:1 dr N S 10 S TBS H N 11 b) 2,6-Iutidine TMSTf S S TBS TMS S TBS TMS 13 c) DIBAL-H (2.5 eq) 80% from N S 13

14 Synthesis of Vinyl Boronic Acid 4 and Iodide 5 14

15 Synthesis of Vinyl Bromide 6 15

16 Synthesis of Vinyl Bromide 6 16

17 Synthesis of Aldehyde 8 17

18 Total Synthesis of Disorazole A1 n Bu 3 Sn a) 5, PPh 3 i Pr 2 NEt then LiHMDS n Bu 3 Sn DMPU, (-)-8 76% TMS (-)-8 I 35 TBS TMS TBS 5 N b) 7, CuTc NMP 74% N 7 Br TMS 36 TBS 18

19 Total Synthesis of Disorazole A1 19

20 Total Synthesis of Disorazole A e) Et 3 N, DMAP TCBC 99% from 36 TBS N R TBS g) 3 SnH h) TCBC, Et 3 N then DMAP 48% 40: R = TMS 41: R = H f) Et 3 N 3HF 99% N N R R 42: R = TBS Disorazole A 1 : R = H i) TASF 17% N 20

21 Total Synthesis of Disorazole B1 n Bu 3 Sn a) 5, PPh 3 i Pr 2 NEt then LiHMDS n Bu 3 Sn DMPU, (-)-8 76% TMS (-)-8 I 35 TBS TMS TBS 5 N b) 7, CuTc NMP 74% N 7 Br TMS 36 TBS 21

22 Total Synthesis of Disorazole B1 22

23 Total Synthesis of Disorazole B1 23

24 Summary Disorazole A1: 18 steps, 1.59% overall yield Disorazole B1: 15 steps, 14.66% overall yield 6,8,23,25-tetra-epi-disorazole B1: 16 steps, 0.12% overall yield The first total syntheses of disorazoles A1 and B1 The syntheses were achieved through a series of coupling reactions, including Wittig reaction, Suzuki cross-coupling, Stille cross-coupling, Yamaguchi esterification ti and Yamaguchi macrolactonization ti 24

25 The First Paragraph 该类化合物的来源和生物活性 分析该类化合物在合成上的挑战 概括本文的工作内容 25

26 The First Paragraph The disorazoles are a distinguished class of tubulin binding antitumor agents due to their unique mode of action and high potencies against a broad range of cancer cell lines. Although too cytotoxic to be used as anticancer drugs, these natural products may become powerful payloads for antibody drug conjugates (ADCs), a hotly pursued paradigm for targeted personalized cancer therapies. Elegant total syntheses of disorazole C1 and related synthetic studies have been reported. From the members of this family of compounds, disorazole A1 (1, Figure 1) stands as the flagship, not only because it is the most studied, but also due to its single digit picomolar potencies and synthetically challenging structure. 26

27 The First Paragraph Indeed, a total synthesis of disorazole A1 has not been reported, despite several studies directed toward this goal. Disorazole B1 whose structure has only been partially assigned as 2 (C2 symmetric) or 3 (6,8,23,25- tetra-epi-disorazole B1, Figure 1) presents another challenging calling to both structural elucidation and total synthesis. In this communication, we report: (a) total synthesis of disorazole A1 (1); (b) total synthesis of disorazole B1 (2) and 6,8,23,25-tetra-epi-disorazole B1 (3); and (c) full assignment of disorazole B1 as structure 2. 27

28 The Last Paragraph 概述本文的工作内容 表明工作意义及潜在应用 28

29 The Last Paragraph Representing the first total syntheses of disorazoles A1 (1) and B1 (2), and revealing the full structural t assignment of disorazole B1, the described chemistry could lead to wide scope explorations of structure activity relationships (SARs) through analogue design, synthesis and biological evaluation within the disorazole family of compounds, from which highly potent cytotoxic agents may emerge as potential payloads for antibody drug conjugates (ADCs). 29

30 Acknowledgement 30

31 Appel Reaction 31

32 Still-Gennari Reaction R 1 R 1 R 1 1 P P R 1 M H H R 3 TS (anti) R 2 Base M R 2 -HBase K anti addition (slow) M R 1 P R 1 P R 2 R 1 R 2 R 1 P R 1 M R 1 R 1 R 1 P M R 2 R 3 H K syn addition (slower) R 1 1 P M R 1 R 3 M H TS (syn) R 2 R 2 R 3 M K anti (fast) P R 1 R 1 R 2 K cis (fast) R 3 K syn (fast) R 1 P R 1 P R 1 R 1 M K M R 1 R 3 trans R 3 M R 1 (fast) P P R 1 C 2 R 2 CH 2 2 R 2 C 2 R 2 R 1 R 3 R 3 C 2 R 2 cis oxaphosphetane (Z)-Alkene major (E)-Alkene minor trans oxaphosphetane P R 1 R 1 R 2 3 2

33 Sonogashira Cross-Coupling R 1 Cu R 1 X L n Pd (II) X [amine base]h + X - oxidative addition transmetallation R 2 CuX H R 2 amine base L n Pd (0) L n Pd (II) R 1 R 2 R 2 Coupled product R 1 reductive elimination 33

34 Dess-Martin xidation 34

35