Total Synthesis of Celastrol, Celastroid Natural Products

Transcription

1 Total Synthesis of Celastrol, Development of a Platform to Access Celastroid Natural Products Reporter: Jie Wang Checker: Bo Song Date: 2015/12/01 Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

2 Contents 1 Introduction 2 Total Synthesis of Celastrol, Wilforol A, Wilforic acid 3 Total Synthesis of dl-alnusenone, ctahydropicene 4 Summary 2

3 Introduction De Santana, C. F. Rev. Inst Antibiot. Recife 1971, 11, 37. 3

4 Introduction C Celastrol Tripterygium wilfordii Initially isolated from Tripterygium wilfordii Activities relevant to neuronal degeneration, inflammation Kiaei, M. et al. Neurodegener. Dis. 2005, 2,

5 Retrosynthesis of Celastrol C 2 Me Me Celastrol Polyene cascade Br Me Me Br FeCl 3,C 2 Cl 2 Me Me Me Me 5

6 Total Synthesis of Celastrol Br Me 2 N a) LDA, Me 2 NCMe TF, -78 o C, 91% b) MeLi, TF 89% 6 Br 7 NMe 2 8 c) Triethyl phosphonoacetate NaMDS, PhMe, 59% E/Z =6:1 Et 2 C oner-wadsworth-emmons olefination d) n BuLi, Ph 3 PMeBr 85% Et 2 C 9 10 Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

7 Total Synthesis of Celastrol Robinson annulation Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

8 Total Synthesis of Celastroid k) LiAl 4,Et 2, dr = 1.4:1 Me 99% Me Me Me Polyene cascade l) FeCl 3,C 2 Cl 2 38% Me m) B 3, 2 2,Na n) Jones reagent, Me 2 C Me Me 60% 2 step Me Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

9 Total Synthesis of Celastrol Two rounds of alkylation Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

10 Total Synthesis of Celastrol C 2 Me C 2 Me a) K, 1,4-dioxane/ 2, 99% b) BBr 3, C 2 Cl 2, 69% Me 21 wilforic acid 22 DDQ C 2 C 2 Tautomerization celastrol 1 23 Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

11 Total Synthesis of Celastrol Selenoxide elimination Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

12 Total Synthesis of Celastrol Siegel, D. et al. J. Am. Chem. Soc. 2015, 137,

13 Total Synthesis of dl-alnusenone C 2 5 Robinson annulation C 2 5 C a) K aq. C 3 72% C 3 29 Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

14 Total Synthesis of ctahydropicenes 33, 37 C 2 5 C 2 5 a) (C 2 5 ) 2 AlCN, C 6 6 ; K t Bu, t Bu, 90% CN C 3 C b) (C 6 5 ) 3 P=C 2,C % C 2 5 C 2 5 C 3 f) ( i Bu) 2 Al, C 6 6 ; N 2 4 2Cl, N 2 4 2, TEG, K 66% C 3 CN Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

15 Total Synthesis of ctahydropicenes 33, 37 Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

16 Total Synthesis of ctahydropicenes 33, 37 C 2 5 C 2 5 C 3 a) (C 2 5 ) 3 Al, CN, TF 86% 29 C 3 34 CN b) C 3 MgI, SCl 2, pyridine 95% C 2 5 C 2 5 C 3 c) ( i Bu) 2 Al, C 6 6 ; N 2 4 2Cl, N 2 4 2, TEG, K 67% C CN Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

17 Total Synthesis of ctahydropicenes 33, 37 Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

18 Total Synthesis of dl-alnusenone C 2 5 C 2 5 e) LiPPh 2,TF 90% C 3 ctahydropicene f) Li, N 3,C 3 I, 42% g) LiAl( t Bu) 3, 85% h) C 2 I 2,Zn(Cu) i) Cr 3 2Py C % C 3 39 Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

19 Total Synthesis of dl-alnusenone i) K t Bu, C 3 I j) Li, N 3 ;N 4 Cl 66% C 3 C k) LiAl 4, TF-Et 2 l) n BuLi, MPA-NEt 3, ClP(NMe 2 ) 2 m) Li, N 3, 47% 3 steps n) K t Bu, t Bu, C 3 I 67% dl-alnusenone 42 Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

20 Summary Pentacyclic framework of the celastroid class FeCl 3 -mediated polyene cascade 31 steps linear sequence, 0.5% yield Related : wilforic acid, wilforol A Celastrol Siegel, D. et al. J. Am. Chem. Soc. 2015, 137, Pentacyclic system of dl-alnusenone type Robinson annulation, Friedel-Crafts reaction 17 steps linear sequence, 0.9% yield dl-alnusenone Ireland, R. E. et al. J. Am. Chem. Soc. 1973, 95,

21 Celastrol was initially isolated from Tripterygium wilfordii (thunder of god vine) and later identified in a variety of plant species in the Celastracae family. The natural product has a wide array of promising activities relevant to neuronal degeneration, inflammation, diseases caused byprotein misfolding, cancer, and obesity. The related celastroid natural product, tingenone, has been examined in clinical trials for skin, stomach, and lymphoepithelioma and shown to possess moderate activity with minimal side effects. Medicinal chemistry optimization of the triterpene oleanolic acid arrived at CDD methyl ester. While not a member of the celastroid family, CDD methyl ester is similarly related, as it possesses a strong Michael acceptor within a triterpene scaffold and continues to be used in multiple clinical trials. 21

22 In conclusion, a platform utilizing a polyene cascade was developed to provide access to the pentacyclic framework of the celastroid class of triterpenoids, lending to the total synthesis of celastrol and related natural products wilforic acid, and wilforol A. The allylic alcohol cyclization precursor is accessed in >5 g quantities in 12 steps (longest linear) with an overall yield of 21%. The developed cascade employs ferric chloride as an activator in a dilute solution of C 2 Cl 2 to generate the pentacycle in 38% yield on gram scale and showcases the utility of this reagent for polyene cyclizations. Through this intermediate, the first syntheses of celastrol were completed in 31 and 32 (longest linear steps, respectively) as well as wilforic acid and wilforol A. 22