K. C. Nicolaou,. Philipp Heretsch, Abdelatif ElMarrouni, Christopher R

Presentation on theme: "K. C. Nicolaou,. Philipp Heretsch, Abdelatif ElMarrouni, Christopher R"— Presentation transcript:

1 TOTAL SYNTHESIS OF ∆ 12-PROSTAGLANDIN J3, A HIGHLY POTENT ANT SELECTIVE ANTILEUKEMIC AGENT
K. C. Nicolaou,* Philipp Heretsch, Abdelatif ElMarrouni, Christopher R. H. Hale, Kiran K. Pulukuri, Avinash K. Kudva, Vivek Narayan, and K. Sandeep Prabhu

2 Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

3 Introduction -natural product ∆12-Prostaglandin J3
Structure Property term Name ∆12-PGJ3 (1) Isolated from Isolated by Biological actitivity Selective Antileukemic Agent 20碳的天然物，由魚油omega-3 fatty acid得來 Prostagladin 若以cyclopentenone 為中心的話，在alfa的位置linking一條7碳的長鏈，在beta position linking hexanoic acid Prostagladin 具有2個chiral center 分別為C8 和 C15，而在C15 position 是一個具有立體位像的hydroxyl group

4 Introduction -Pathway for the formation of the A3/J3-IsoPs by the nonenzymatic peroxidation of EPA
Prostaglandin是由 omega-3 fatty acid 來，如圖所示，omega-3 fatty acid transform to prostagladin 是一個一連串 free radical reaction，free radical 容易在allic position react , so C7、C10、C13、C16產生了四種不一樣的途徑，而偏合成的prostagladin J3 由作用在C13的分支上延伸出來的產物

5 Introduction -relative natural product
所以我們就來細講prostagladin J3的由來及反應機制，首先起使物為omega-3二十碳鏈的fatty acid在 radical 的作用後，在alliyl position上產生出radical，經過racdical rearragement後，在C11 position 與氧鍵結，產生出peroxide racdical，而後peroxide radical 與C8-C9的DOUBLE boud 及C12 DOUBLE bind 做intramolecular cyclization，最後裂解氧化，進而形成PGE3及PGD3，而PGE3及PGD3脫水後，就可以分別形成產物PGA3及PGJ3，所以PG的意思為prostagladin，而有E、D、A、J四種構型，最後3個意思為在支鏈上具有多少個double，依據此歸類，即可得知命名

6 Introduction -relative natural product
所以類似天然物有這些，而本篇所要合成得天然物可能是由PGJ3轉變而來

7 Introduction -Total synthesis of ∆12-PGJ2, 15-deoxy-∆12,14-PGJ2, and related compounds
(Yuichi Kobayashi) Kobayashi團隊是利用已具有立體位向得acetyl group作為trost reaction，而後aldol reaction 在alfa碳上接上支鏈形成天然物的架構 Tetrahedron Letters. 2004, 45, 1199 –1202

8 Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

9 Retrosynthesis of ∆12-PGJ3

10 Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

11 Procedure of synthesis -Synthesis of the fragement 2
η2 π-allyl complex Malonate dirhodium tetracaprolactamate WEINREB魏因勒卜

12 Procedure of synthesis - Synthesis of the fragement 3
pyridinium tribromide

13 Procedure of synthesis -Total synthesis of the nature product
sodium chlorite (NaClO2) under mild acidic conditions(pinnick oxidation) 猜測:使用KMnO4可能會導致裂解，使用CrO3 可能會在allylic position接上Hydroxyl group and oxidation TMSCH2N2:Trimethylsilyldiazomethane

14 Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

15 CONCLUSION The asymmetric total synthesis of nature product ∆12-PGJ3 by using asymmetric Tsuji-Trost reaction and asymmetric Mukaiyama aldol reaction. the yield of the ∆12-PGJ3 is 5% (14step)

16 CONCLUSION

17 REFERENCE Angew. Chem. Int. Ed. 2014, 53, 10443 –10447
Tetrahedron Letters , 45, 1199–1202 Chem. Rev. 1996, 96,

18 THE END

19 Problem 較屬於紀念性文章 立體選擇用模型或3D chemdraw 定出結構後，解 出位向選擇