Literature Report I. Total Synthesis of (+)-Piperarborenine B. Reporter: Zheng Gu. Date:

Transcription

1 Literature Report I Total Synthesis of (+)-Piperarborenine B Reporter: Zheng Gu Checker: Bo Song Date: Hu, J. L.; Xie, Z. W.; Tang, Y. J. Am. Chem. Soc. 2016, 138, Panish, R. A.; Chintala, S. R.; Fox, J. M. Angew. Chem. Int. Ed. 2016, 55,

2 Curriculum Vitae of Zuowei Xie Education: 1983 B.S. Hangzhou University 1986 M.S. Shanghai Institute of rganic Chemistry 1990 Ph.D. Academic Position: Since 1995 Technische Universität Berlin/ Shanghai Institute t of rganic Chemistry The Chinese University of Hong Kong Research Interests: rganometallic chemistry of transition metal complexes, chemistry of boron clusters, carboranes and metallacarboranes, homogenous catalysis, small molecule activation and polymer synthesis. 2

3 Contents Introduction Total synthesis of (+)-piperarborenine B by Xie and Tang Total synthesis of (+)-piperarborenine B by Fox Summary 3

4 Introduction Me Me R 1 Me R 2 R 3 R 3 R 2 Me Me Me R 1 Piperarborenine i A R 1 = R 3 = H, R 2 = Me Piperarborenine B R 1 =R 2 =Me,R 3 =H Piperarborenine i C R 1 = Me, R 2 + R 3 = CH 2 Piperarborenine D R 1 =H,R 2 =R 3 =CH 3 Piperarborenine E R 1 =H,R 2 +R 3 =CH 2 Br H H H H 2 H R 2 H H Br H H H R 1 H H H H H Sceptrin H 2 Penitrem A-D 4

5 Introduction cis cis trans trans trans trans Piperarborenine B Piperarborenine D Isolated from the stems of the creeping shrub Piper arborescens; Pseudosymmetrical cyclobutane, cis-trans-cis and trans-trans-trans; Exhibiting in vitro cytotoxicity against P-388, HT-29, and A549 cancer cell lines (IC 50 <4μg/mL) 5

6 Introduction Photopromoted enantioselective [2+2] reactions a) Bach's work: cat. hv ( = 366 nm) PhCF -25 o 3, C H H H X X up to 94% ee Müller, C.; Miranda, M. A.; Bach, T. J. Am. Chem. Soc. 2011, 133, Du, J.; Skubi, K. L.; Yoon, T. P. Science 2014, 344,

7 Introduction rganocatalytic enantioselective [2+2] reactions Albrecht, Ł.; Dickmeiss, G.; Jørgensen, K. A. J. Am. Chem.Soc. 2012, 134, Conner, M. L.; Xu, Y.; Brown, M. K. J. Am. Chem. Soc. 2015, 137,

8 Enantioselective construction of cyclobutanes entry Lewis acid solvent L yield (%) ee (%) 1 a Cu(Tf) 2 CH 2 Cl 2 L i(cl 4 ) 2 6H 2 CH 2 Cl 2 L Cu(Cl 4 ) 2 6H 2 CH 2 Cl 2 L Cu(Cl 4 ) 2 6H 2 THF L Cu(Cl 4 ) 2 6H 2 THF L Cu(Cl 4 ) 2 6H 2 THF L Cu(Cl 4 ) 2 6H 2 THF L a 4 Å MS; Without Et 3 quench. Hu, J. L.; Xie, Z. W.; Tang, Y. J. Am. Chem. Soc. 2016, 138,

9 Mechanistic studies Cu(Cl 4 ) 2 6H 2 (10mol%) L1 (12 mol%) C 2 Me C 2 Me C 2 Me C 2 Me DCM, rt, 4 Å MS, 2 h TBSH 2 C Me Me 1i PMP 3a 80% recovered yield 50% ee C 2 Me C 2 Me PMP 3a 96% ee Cu(Cl 4 ) 2 6H 2 (10 mol%) L1 (12 mol%) DCM, rt, 4 Å MS, 2 h 3a + 81% recovered yield 50% ee TBSH 2 C 3i not observed (82% 1i recovered) Me Me Cu(Cl 4 ) 2 6H 2 (10mol%) L1 (12 mol%) C 2 Me C 2 Me DCM, -70 o C, 4 Å MS, 2 h quenched at -70 o C with Et 3 PMP 3a 99% recovered yield 96% ee Hu, J. L.; Xie, Z. W.; Tang, Y. J. Am. Chem. Soc. 2016, 138,

10 Substrate scope Hu, J. L.; Xie, Z. W.; Tang, Y. J. Am. Chem. Soc. 2016, 138,

11 Substrate scope Hu, J. L.; Xie, Z. W.; Tang, Y. J. Am. Chem. Soc. 2016, 138,

12 Total synthesis of (+)-piperarborenine B 12

13 Total synthesis of (+)-piperarborenine B Gutekunst. W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133,

14 Total synthesis of (+)-piperarborenine B 14

15 Bicyclobutanation/homoconjugate addition R Rh 2 2( (S-TTL) 3 (dcpa) toluene, -78 o C R C 2 t Bu 1) R'MgX, CuBr SMe 2 R P n Bu 3 3, RT, THF 2) H 3 + R' C 2 t Bu 2 C 2 t Bu up to 95% ee >50:1 dr up to 82% yield Rh Rh t Bu 3 Rh 2 2( (S-TTL) 3 (dcpa) Panish, R.; Chintala, S. R.; Fox, J. M. J. Am. Chem. Soc. 2013,, 135,,

16 Retrosynthetic analysis Me Me Me hydrolysis Me t Bu C-H activation Me Me C 2 t Bu Me Me Me (+)-Piperarborenine B DHP AuxH 19 Me Me Me MeS H 18 ozonolysis and amide coupling 2 C 2 t Bu Me Me Me Tsuji-Trost bicyclobutanation C 2 t Bu Me Veratraldehyde diazo transfer Me Me homoconjugate addition Panish, R. A.; Chintala, S. R.; Fox, J. M. Angew. Chem. Int. Ed. 2016, 55,

17 Total synthesis of (+)-piperarborenine B Synthesis of the substituted diazoester 17

18 Total synthesis of (+)-piperarborenine B Enantioselective synthesis of vinylcyclobutane Me Me Me C t 2 Bu 1) Rh 2 (S-TTL) 3(dCPA) 2) CuBr SMe 2, PPh 3, 14 C t 2 Bu Me 13 other catalysts ee (%) Rh 2 (S-TTL) 4 84 Rh 2 (S-PTTL) 4 77 Rh 2 (S-PTTL) 3 (TPA) Rh 2 (S-TTL) 3 (TPA) ) BHT, -78 o Cto-10 o C MgBr %, 4:1 dr 92% ee C 2 t Bu R H Ar Ar Ar t Bu 18

19 Total synthesis of (+)-piperarborenine B Me Me Me Me C 2 t Bu 1) 3, PPh 3 ;acl 2, ah 2 P 4, 2-Me-2-butene C 2 t Bu Pd(Ac) 2 3,4,5-(Me) 3 PhI 2) HATU, Et 3, DMF MeS H PivH, K 2C 3 2-(MeS)PhH 2 H 2, 110 o C, 12 h 66% yield 69% yield Me Me Me Me MeS H C t 2 Bu 1) (Boc) 2, DMAP 2) LiH, H 2 2 H Me then TFA 70% yield 19 Me 20 Me Me H Me Me Gutekunst. W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133,

20 Total synthesis of (+)-piperarborenine B Me Me H Me Me H (CCl) 2,DMF THF, 0 o CtoRT H Me 20 Me Me then 4 Å MS PhMe, 80 o C 75% yield Me Me Me (+)-Piperarborenine B 1 week, 10 steps 8% overall yield >400 mg prepared 20

21 Summary 21

22 The first paragraph The occurrence of cyclobutane frameworks in many natural products and biologically active compounds has aroused great interest in building these fascinating structures. Although enantioselective protocols have achieved remarkable breakthroughs, successful examples of asymmetric cyclobu- tanation are still limited. Accordingly, the appeal of developing new and effective enantioselective methods for the construction of new-fashioned cyclobutanes is urgent and necessary. Methylidenemalonate, which was first prepared by Perkin in 1886, has been found to be a very reactive candidate in [2+2] cycloadditions with electron-rich alkenes to form donor acceptor (D A) cyclobutanes in the presence of Lewis acid catalysts since However, to the best of our knowledge, an enantioselective version of this reaction has not been realized yet. 22

23 The first paragraph This can probably be ascribed to the high symmetry of the methylidene- malonate molecule, the remote chiral delivery to the prostereogenic olefin, and the fact that the resulting optically active D A cyclobutanes are likely to decompose into the racemic zwitterions promoted by Lewis acids, which makes the enantioselective cyclobutanation reaction a challenging problem. In this work, we have developed acu(ii)/bisoxazoline (BX)- catalyzed [2+2] cycloaddition of methylidenemalonate with multisubstituted alkenes that furnishes tri- and tetrasubstituted cyclobutanes with high diastereoselectivities and excellent ee s. In addition, optically active (+)-piperarborenine B was synthesized with this newly developed method in eight steps from methylidenemalonate and olefin in 17% overall yield with >99/1 dr and 99% ee. Herein we report these preliminary results. 23

24 The last paragraph In summary, the first asymmetric [2+2] cycloaddition of dimethyl methylidenemalonate with polysubstituted olefins has been developed using Cu(II)/SaBX as the catalyst, giving optically active cyclobutanes in high yields with >99/1 dr and up to >99% ee. The reaction has a broad substrate scope, in which mono-, di-, and trisubstituted alkenes all work well. This newly developed d method has been applied to the enantioselective totalt synthesis of (+)-piperarborenine B, which was completed in eight steps from methylidenemalonate and 2m in 17% overall yield with 99% ee. Further application of this reaction is an ongoing project in our laboratory. 24

25 Acknowledgment Thanks for your attention! 25