+)-Nominine: Development of a Dual Cycloaddition Strategy for the synthesis of the Hetisine Alkaloids

Transcription

1 Asymmetric Total Synthesis of (+)( +)-ominine: Development of a Dual Cycloaddition Strategy for the synthesis of the etisine Alkaloids C 2 R Kevin M. Peese Denmark Group eting Department of Chemistry University of Illinois at Urbana-Champaign Tuesday May 15, 2006

2 etisine Alkaloids: Background Classification: Family of >103 distinct natural products within the larger class of C 20 -diterpene alkaloids Isolation: Predominantly from Aconitum (monkshood) and Delphinium genera, but also Rumex, Consolida, and Spiraea Pharmacology: Active constituents of traditional Chinese medicines Biological activity: Vasodilating, immunomodulating, analgesic, and antiarrhythmic activities R 1 R 3 R 2 R 4 C 2 R 5 etisine Core ominine (R 1, R 2, R 3, R 4 = ; R 5 = ) Kobusine (R 1, R 2, R 4 = ; R 3, R 5 = ) etisine (R 3, R 5 =, R 1, R 2, R 4 = ) Aconitum sanyoense Wang, F.; Liang, X. C 20 -Diterpenoid Alkaloids. The Alkaloids, Academic Press: ew York, 2002; Vol. 59, pp

3 etisine Alkaloids: Biosynthesis PP ent-copalyl diphosphate synthase PP C 2 geranylgeranyl diphosphate (GGPP) ent-copalyl diphosphate (ent-cpp) ent-atisir-16-ene oxidation; "" C 2 C 2 C 2 R R hetisine type hetidine type atisine type Wang, F.; Liang, X. C 20 -Diterpenoid Alkaloids. The Alkaloids, Academic Press: ew York, 2002; Vol. 59, pp

4 etisine Alkaloids: Biosynthesis PP geranylgeranyl diphosphate (GGPP) ent-copalyl diphosphate synthase ent-copalyl diphosphate (ent-cpp) PP = PP non-classical cation ydride shift C 2 = C 2 ent-atisir-16-ene Wang, F.; Liang, X. C 20 -Diterpenoid Alkaloids. The Alkaloids, Academic Press: ew York, 2002; Vol. 59, pp

5 etisine Alkaloids: Previous Synthetic Approaches C 2 C 2 etisine Core Ac (±)-nominine (40 steps) Muratake,.; atsume, M. Angew. Chem. Int. Ed. 2004, 43, Tetrahedron Lett. 2002, 43, Ac Williams, C. M.; Mander, L.. et al. Tetrahedron 2005, 61, rg. Lett. 2003, 5, Shibanuma, Y.; kamoto, T. Chem. Pharm. Bull. 1985, 33, R hν + R R R Winkler, J. D.; Kwak, Y. J. Am. Chem. Soc. 2001, 123, Boc

6 Synthetic Strategy Early stage [3+2] Dipolar cycloaddition Late stage [4+2] Diels-Alder cycloaddition C 2 R Dual Cycloaddition Strategy: 1) Early stage dipolar cycloaddition 2) Late stage Diels-Alder cycloaddition

7 Synthetic Strategy: Biosynthetic Considerations PP ent-copalyl diphosphate synthase PP C 2 geranylgeranyl diphosphate (GGPP) ent-copalyl diphosphate (ent-cpp) ent-atisir-16-ene oxidation; "" C 2 C 2 C 2 R R hetisine type hetidine type atisine type Biosynthesis: 1) Complexity built slowly over an extended sequence 2) o single key step

8 Vinylogous Azomethine Ylide Approach R = R TMS Vinylogous azomethine cycloadditions: Z Z Bn Et 1) Tf 2 2) dimethyl maleate 3) TBAT C 2 Cl 2 2 C 2 C Tf Bn Et Epperson, M. T.; Gin, D. Y. Angew. Chem. Int. Ed. 2002, 41, TMS (62%, 1:1) Via: Tf Et 2 C 2 C Bn Ph F Ph Si Bu Ph 4 F TBAT C 2

9 Azomethine Ylide Model System Bn TMS TMS Model system Z S TMS (CCl) 2 DMS/Et 3 Et 2 TMS Linderman, R. J.; Suhr, Y. J. rg. Chem. 1988, 53, Bn 2 TMS Bn TMS ZnCl 2 C 2 Cl 2 C 2 Bn TMS (61%)

10 Azomethine Ylide Model System Scope TMS Tf or BzTf; TBAT C 2 Cl 2 R dipolarophile Cycloadducts Bn Bn Bn Bn 2 C 2 C Ph 2 S 2 C (42%) Bz 2 C (43%) Ph 2 S Bz 1.4:1 (26% for mixture) Bz 2 Bn 2 Bz 3:1 (27% for mixture) Bn undetermined isomer Bz

11 Application of Azomethine Ylide Model i) Al(C)Et 2 ii) CsF, then Tf 2 C C DIBAL-; ab 4 / quench toluene, 0 o C 2 Tf (69%) Tf (88%) i) TMSC, Et 2, 0 o C ii) Danishefsky's diene, C 2 ZnCl 2, C 2 Cl 2 TMS (87%) Bu 3 Sn Pd(PPh 3 ) 4, LiCl TF, TMS C 2 Tf (55%, 1.2:1 dr) C 2 TMS 1) BzTf or Tf 2) TBAT C 2 Cl 2 x R nly decomposition observed C 2 R=Bz,

12 Application of Azomethine Ylide Model I I CrCl 2, CI 3 TF, 0 o C hydrazine Et, 2 Cl (81%) (42%, 3:1 E:Z) i) TMSC, Et 2, 0 o C ii) Danishefsky's diene, ZnCl 2, C 2 Cl 2, Et 3 Pd(PPh 3 ) 4, C TMS C, 60 o C TMS C 2 (50%) I (43%) TMS C 2 1) BzTf or Tf 2) TBAT C 2 Cl 2 x C 2 R R=Bz, nly decomposition observed

13 Evolution of Dipole R Ylide is only transiently C 2 stable C 2 xidopyridinium betaines are stable and isolable Decomposition competitive with cycloaddition Decomposition makes investigation difficult xidopyridinium betaine dipoles are stable and isolable Stable dipole should allow more forcing conditions M ev LUM ev Dennis,.; Katritzky, A. R.; Takeuchi Y. J. Am. Chem. Soc. 1970, 92, Katritzky, A. R.; Dennis,. Chem. Rev. 1989, 89,

14 Diene Dipolarophile Preparation AlEt 2 C; CsF, Tf 2 C C (69%) Tf DIBAL-, 0 ºC toluene (99%) Tf 2 Cl Et 3 3 Å molecular sieves, then ab 4 C 2 (52%) Br 2 / water, 0 o C (99%) Bu 3 Sn Pd(PPh 3 ) 4, LiCl TF, Tf (82%) C 2 C 2

15 Diene Dipolarophile Cycloaddition x C 2 Cycloaddition pathway ot observed C 2 C 2 C 2 Six-membered ring transition state Conjugate Addition pathway C 2 and other alkene isomers

16 Ene-itrile Dipolarophile Preparation AlEt 2 C; CsF, Tf 2 C C (69%) Tf DIBAL-, 0 ºC toluene (99%) Tf 2 Cl Et 3 3 Å molecular sieves, then ab 4 (65%) C Br 2 50% Ac 0 ºC C (75%) KC, 18-crown-6 Pd(PPh 3 ) 4 Ph, 75 ºC Tf (82%) Peese, K. M.; Gin, D. Y. rg. Lett. 2005, 7,

17 Ene-itrile Dipolarophile Cycloaddition x C Cycloaddition pathway C ot observed C Slow! C Conjugate Addition pathway C Peese, K. M.; Gin, D. Y. rg. Lett. 2005, 7,

18 Unactivated Dipolarophiles Tf C Al 3 Pd(PPh 3 ) 4 Ph C (100%) LiAl 4 TF, reflux (93%) 2, water reflux (10%) 2 PMBCl, a PMB DMF maltol (86%) 250 Ts pyridine, 120 o C (40%) Tf C 2 Cl 2 (79%)

19 Unactivated Dipolarophiles x Cycloaddition pathway ot observed o reaction! x ot observed Complete conversion

20 Reversed Dipolarophile 10 Z 5 C-10 activated dipolarophile 10 5 Z C-5 activated dipolarophile C-10 activated dipolarophile: 5 10 Z cycloaddition transition state vs Z Conjugate Addition pathway 5 10 Z C-5 activated dipolarophile: Z vs. Z 10 )( Conjugate Addition pathway 10 Z 5 cycloaddition transition state increased steric congestion Peese, K. M.; Gin, D. Y. rg. Lett. 2005, 7,

21 Ene-Sulfone Dipolarophile Cycloaddition C C 1) a, TF, 2) 2 S 4 3) I, Li, / 2, 50 ºC (55%) C J. rg. Chem. 2002, 67, PhS, P 2 5 C 2 Cl 2 (84%) C SPh 1) DIBAL- toluene,0 ºC 2) mcpba C 2 Cl 2, 0 ºC 2 Cl S 2 Ph (77%) Br 2 / water, 0 ºC S 2 Ph (91%) Et 3, acb 3 3 Å molecular sieves S 2 Ph (75% for 2 steps) Peese, K. M.; Gin, D. Y. rg. Lett. 2005, 7,

22 Ene-Sulfone Dipolarophile Cycloaddition S 2 Ph [0.05 M] toluene reflux S 2 Ph (70%) via S 2 Ph S 2 Ph 1, 13 C, MQC, CSY IR, RMS = 2.5% S 2 Ph R R S 2 Ph Peese, K. M.; Gin, D. Y. rg. Lett. 2005, 7,

23 Ene-Sulfone Dipolarophile Cycloaddition S 2 Ph toluene reflux S 2 Ph (55%) S 2 Ph S 2 Ph S 2 Ph (13%) (5%) not observed

24 Ene-Sulfone Dipolarophile Preparation C SPh Br 2 C, C SPh Br (92%) i-prmgcl; BMCl, CuC (cat) TF Bn C SPh (81%) DIBAL- toluene, 0 o C Bn SPh (74%) mcpba DCM, 0 o C 2 Cl Bn 3 Å MS, TEA; Br 2 ab 4 1:1 Ac:water S 0 o C S 2 Ph 2 Ph S 2 Ph (41%) (74%) (62%) Bn Bn

25 Ene-Sulfone Dipolarophile Cycloaddition Bn Bn S 2 Ph Deconjugation S 2 Ph [0.05 M] toluene heat Cycloaddition S 2 Ph Bn (43%) S 2 Ph Bn 1, 13 C, MQC, CSY, MBC, IR, RMS Confirmed by X-ray S 2 Ph Bn not observed

26 Survey of Dipolarophiles Conditions R 2 R 1 R 1 R 2 R 1 R 2 Br C=C 2 C S 2 Ph S 2 Ph S 2 Ph SPh SPh Conditions toluene, 120 o C toluene, 120 o C toluene, 150 o C toluene, 180 o C toluene, 180 o C bserved Result deconjugation/cycloaddition decomposition decomposition epimerization of SPh slow decomposition Can the deconjugation pathway be disfavored?

27 Enoate Dipolarophile Preparation C 2 Et a/et ether I a DMS (83%) (66%) C(Et) 3 Ts Ph (83%) TBS TBS Sc(Tf) 3 (87%) t-buli; ClC 2 TF, -78 o C I (75%, 2 steps) I 2 /TMG TF TBS 80% Ac 50 o C (69%) 3 Cl TEA; ab 4, 4A MS Br 2 1:1 Ac:water 0 o C (54%, 2 steps)

28 Enoate Dipolarophile Cycloaddition C 2 Silica gel [0.01 M] toluene 180 C C 2 (12%) 1, 13 C, MQC, CSY, ne, IR, RMS Poor reproducibility! Deconjugation Cycloaddition C 2 C 2 C 2 Main byproduct in varying amounts Bright orange! not observed

29 itroalkene Dipolarophile Preparation 1) i-pr 2 MgBr; TMSCl, TEA, MPA, Et 2 2)TrCl 4, DCM, -78 o C (58%) ibu 2 KtBu tbu 2 (91%) CeCl ab 4 Et (69%) 2 1) TEA, 4Å MS, 3 Cl 4:1 TFA: 2 2 Br 2 1:1 Ac: water 0 o C 2 (34%) 2) ab(ac) 3, DCM (78%) 2 (64%)

30 itroalkene Dipolarophile Cycloaddition 2 20% conversion 2 + (1:4) 2 Reaction stalls at ~20% conversion!

31 itroalkene Dipolarophile Cycloaddition 2 equilibration 2 + (1:4) 2 Reaction reaches thermodynamic equilibrium! Are all the previous oxidopyridinium betaines in equilibrium?

32 Summary of xidopyridinium Betaines Substrate Conditions bserved Result Product(s) Structure C 2 C toluene, 160 o C toluene, 170 o C toluene, 190 o C Conjugate addition Conjugate addition o Reaction C 2 C mixture of alkene isomers 2 C Br Substrate Conditions bserved Result Product(s) Structure S 2 Ph S 2 Ph toluene, 120 o C toluene, 150 o C Complex mixture Complex mixture S 2 Ph S 2 Ph Bn S 2 Ph toluene, 120 o C toluene, 110 o C toluene, 120 o C toluene, 120 o C thyl group migration Dipolar Cycloaddition Sulfone deconjugation; dipolar cycloaddition Sulfone deconjugation; dipolar cycloaddition S 2 Ph major cycloadduct S 2 Ph Bn S 2 Ph S 2 Ph minor product S 2 Ph SPh Bn SPh C C 2 2 toluene, 180 o C toluene, 180 o C toluene, Si 2, 180 o C toluene, 110 o C o reaction except sulfoxide epimerization o reaction Ester deconjugation; dipolar cycloaddition Dipolar cycloaddition equilibrium C 2 2 (1:4) 2

33 Summary of xidopyridinium Betaines () Critical steric interaction R S 2 Ph R= R= R= major pathway toluene reflux R= major pathway S 2 Ph R= R= R R S 2 Ph R= R= isomeric cycloadducts

34 Shifting the Equilibrium Can the dipolar cycloaddition be made more thermodynamically favorable? R Energetic cost of breaking aromaticity ~43.3 kcal/mol R Energetic cost of breaking pyridine aromaticity ~35.2 kcal/mol isoquinoline-benzene ( kcal/mol) Bird, C. W. Tetrahedron 1992, 48, kcal/mol 43.3 kcal/mol 81.0 kcal/mol

35 xidoisoquinolinium Dipole Preparation xidoisoquinoliniums betaines are rare literature eed new method for oxidoisoquinolinium synthesis R R X + X + 2 2

36 xidoisoquinolinium Aza-Achmatowicz? Achmatowicz? Aza-Achmatowicz rearrangement for the preparation of oxidopyridinium betaines: R oxidation X X R R R Proposed aza-achmatowicz rearrangement for the preparation of oxidoisoquinolinium betaines: R R R oxidation X X R X X R 3 PR 3 R R then R

37 xidoisoquinolinium Dipole Preparation Cl t-buli; Et 2, -23 C Cl (52%) 1) a 3, acetone 2) AcCl, 3 (95% for 2 steps, 3:2 dr) C PBu 3 ; ab(ac) 3, C 2 Cl (99%) TFA salt 10% TFA in C 2 Cl 2 0 C 2 (74%, 3:3:2:2 dr)

38 xidoisoquinolinium Dipole Cycloaddition Dipole not detected at equilibrium! 2 Conjugate addition Cycloaddition kinetic isomer 2 thermodynamic isomer + 2 2:1 (kinetic ratio) ratio diminishes over time Via: Success: Equilibrium is shifted entirely towards cycloadducts! ew problems: Conjugate addition is main pathway and is irreversible itro group is of limited synthetic utility

39 Analysis ther cycloadditions may have failed for thermodynamic reasons! xidoisoquinolinium betaines shift equilibrium towards cycloadducts Conjugate additions irreversible ew Target! C

40 Ene-itrile Dipolarophile Revisited AlEt2 C; CsF, Tf 2 C Tf C (69%) 1) DIBAL-, Ph, 0 C 2) Zn(C) 2, Pd(PPh 3 ) 4, DMF, 60 C (77% for 2 steps) C C 3 PBu 3 ; ab(ac) 3 C 2 Cl 2 C (93%) 10% TFA in C 2 Cl 2 0 C C (79%, 3:3:2:2 dr) 180 C TF C 180 C, TF [recycle] (3.6:1) C (~20% per equilibration) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128,

41 Total Synthesis of (±)-ominine:( Advancement of the Synthesis C 1) ab 4, Et 2) SCl 2, C 2 Cl 2, reflux 3) Bu 3 Sn, AIB, Ph, reflux C (68% for 3 steps) 1) DIBAL-, Ph, 0 C 2) Ph 3 P=C 2, TF (97%) a o, i-pr; Cl(aq) 3:1 3 :TF, -78 C (82% for 2 steps) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128,

42 Total Synthesis of (±)-ominine:( Preparation of Diene acid or base x Unconjugated enone may be the more stable isomer! strong base x o alkene isomerization!

43 Total Synthesis of (±)-ominine:( A Fortuitous Discovery 9:1 : pyrrolidine 80 C x Conversion to one spot by TLC; MR shows complex mixture! Isolated after chromatography Structure confirmed by X-ray Equilibrating mixture of dieneamines [4+2] Crude product is mixture of enamine and ketone Complete hydrolysis occurs on silica Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128,

44 Total Synthesis of (±)-ominine:( Completion of Synthesis 9:1 : pyrrolidine 60 C (51% for 2 steps) (±)-nominine C 2 1) Ph 3 P=C 2, TF, 70 C 2) Se 2, t-bu, DCM, dr 7:1 (78%) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128,

45 Asymmetric Synthesis of (+)( +)-ominine: oveyda Conjugate Addition 2.5-5% R (S,S)-C ( ) n ( ) CuTf, ZnR' n 2 R' R n=1,2 ee=73-95% yields=53-98% Ph Ph S Ag Ag S Ph Ph (S,S)-C Brown, M. K.; ird, A. W.; Baxter, C. A.; oveyda, A.. Angew. Chem. Int. Ed. 2007, 46,

46 Asymmetric Synthesis of (+)( +)-ominine: Application of the oveyda thod Cr 3 Ac 2, Ac C 2 Cl 2 (56%) (S,S)-C (CuTf) 2 Ph Zn 2 MTBE, -30 o C DIBAL- pentane, -110 o C Tf (92%) Tf (91%, 92:8 er)

47 Asymmetric Synthesis of (+)( +)-ominine: Advancement to the Dipole Tf (92%) Zn(C) 2 Pd(PPh 3 ) 4 DMF, 60 o C C (82%) 3 PBu 3, ab(ac) 3 C 2 Cl 2 C (98%) 9:1 C 2 Cl 2 :TFA 0 C C (82%, 3:3:2:2 dr)

48 Asymmetric Synthesis of (+)( +)-ominine: Cycladdition and Recrystalization C 180 o C, TF C 180 o C, TF C (38% over 4 cycles) 92:8 er >99:1 er (isopropanol recrystalization, 69%)

49 Asymmetric Synthesis of (+)( +)-ominine: Completion of (+)( +)-ominine C 9 steps (17%) C 2 (+)-nominine [α] D = o (, c = 1.09) Literature rotation: [α] D = o (, no concentration given) chiai, E.; kamoto, T.; Sakai, S.; Saito, A. Yakugaku Zasshi 1956, 76, [α] D = o (no solvent or concentration given) Sakai, S.; Yamamoto, I.; Yamaguchi, K.; Takayama,.; Ito, M.; kamoto, T. Chem. Pharm. Bull. 1982, 30,

50 Synthesis of ther etisine Alkaloids A-ring oxygenation: A C 2 P Tf C 2 B-ring oxygenation: B C 2 C 2 PhCCl 6 6 C 2 Ph C 2 6 C 2 6 C 2

51 Synthesis of ther etisine Alkaloids C-ring oxygenation: C C 2 X X' [4+2] X X' C 2 C 2 G-ring oxygenation: G C 2 C 2 X X

52 Summary Total synthesis of (+)-nominine 1.3% total, 16 steps (longest linear sequence) Total synthesis of (±)-nominine 6.1% total, 15 steps (longest linear sequence) Dual cycloaddition strategy xidoisoquinolinium betaine cycloaddition Diels-Alder cycloaddition

53 Acknowledgments Professor David Y. Gin David Gin Group Pharmacia (Pfizer, Inc.) ational Institutes of ealth