Applications of Imine additions: Hemigramicidin S and Polycyclic Azepine Investigations. Adam Hoye Research Topic Seminar April 22 nd, 2006

Transcription

1 Applications of Imine additions: emigramicidin S and Polycyclic Azepine Investigations Adam oye esearch Topic Seminar April 22 nd, 2006 Adam Wipf Group 1 7/3/2006

2 Imine addition chemistry- statistics, general rxns, "Imine Addition" Papers Publications Year Source: SciFinder 2006 Imines as the new carbonyl Adam Wipf Group 2 7/3/2006

3 Selected eactions of Imines Kobayashi Asymmetric Mannich eaction: Zr(BIL) 2, (5 mol%), MI (10 mol%) TMS Me, C 2 Cl 2, -45 C Me 70% yield, 87% ee Mukaiyama Catalytic eduction: Ar Ar P() 2 Co 1 mol% P() 2 97% yield, 90% ee a(et) 2 B Charette rganozinc Addition: P() 2 Cu(Tf) 2 (6 mol%) BozPS (3 mol%) ZnMe 2 (2 eq.), Toluene, 0 C P() 2 87% yield, 97% ee Kobayashi, S.; Ishitani,,; Chem. ev., 1999, 99, Charette, A. B. et al.; Pure Appl. Chem., 2005, 77, Adam Wipf Group 3 7/3/2006

4 Imine methodology in the Wipf Group 2 ()P 2 ()P ' ' 1. Cp 2 Zr()Cl 2. ZnMe 2 1. Cp 2 Zr()Cl 2. ZnMe 2, imine 3. C 2 I 2 2 ()P ' 1. Cp 2 ZrCl 2, AlMe 3 2. imine 3. Zn(C 2 I )2 [Zn] ' P() 2 1. Cp 2 Zr()Cl 2. ZnMe 2 3. C 2 I 2, then imine 2 ()P ' 1. Cp 2 Zr()Cl 2. ZnMe 2 3. imine 4. Zn(C 2 I) 2 2 ()P 2 ()P ' Adam Wipf Group 4 7/3/2006

5 Imine methodology in the Wipf Group 2 ()P 2 ()P ' ' 1. Cp 2 Zr()Cl 2. ZnMe 2 1. Cp 2 Zr()Cl 2. ZnMe 2, imine 3. C 2 I 2 2 ()P ' 1. Cp 2 ZrCl 2, AlMe 3 2. imine 3. Zn(C 2 I )2 [Zn] ' P() 2 1. Cp 2 Zr()Cl 2. ZnMe 2 3. C 2 I 2, then imine 2 ()P ' 1. Cp 2 Zr()Cl 2. ZnMe 2 3. imine 4. Zn(C 2 I) 2 2 ()P 2 ()P ' Adam Wipf Group 5 7/3/2006

6 Cyclopropyl amino acids 2 C 2 TBDPS 2 ()P TBDPS 2 C 2 2 C 2 Adam Wipf Group 6 7/3/2006

7 Gramicidin S Isolated (and used) in 1943 (USS) - Gramicidins A-D (linear) potent antibacterials, act via membrane insertion and aggregation, thus increasing cell permeability (high hemolytic activity) -igid, symmetric β-strands connected by β-turns [(cyclo- D e-pro-val-rn- Leu) 2 ] -ydrophobic side chains (Val, Leu) on one face and polar residues (rn) on the other, GS binds well to lipid bilayers -o resistance to antibiotic activity has been found so far -GS mitochondrial targeting Wadhwani, P.; Afonin, S.; Ieronimo, M.; Buerck, J.; Ulrich, A. S.; J. rg. Chem. 2006, 71, 55 Wu, X.; Bu, X.; Wong, K. M.; Yan, W.; Guo, Z.; rg. Lett. 2003, 5, 1749 Adam Wipf Group 7 7/3/2006

8 Mitochondria -rganelle membrane highly bacterial in type (high affinity for Gramicidins) -Target of many cellular processes and proteins ( powerplant of cell ) -Proficient inducer of apoptosis (programmed cell death) -Primary production of ATP Adam Wipf Group 8 7/3/2006

9 eactive xygen Species (S) in ATP Production Superoxide dismutase traps S, but under conditions of high cellular stress, more S can be released, and damage to cells occurs. Adam Wipf Group 9 7/3/2006

10 Gramicidin in our group- Jingbo Xiao C 3 [C 3 ] 2 GS 2 C 3 F E-alkene Gramicidin S 2 F CF 3 2 [CF 3 ] 2 GS CF 3 2 [F 2 ]GS Wipf, P.; Xiao, J.; Jiang, J.; Belikova,. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, Xiao, J.; Westblum, B.; Wipf, P.; J. Am. Chem. Soc. 2005, 127, Adam Wipf Group 10 7/3/2006

11 emigramicidin Boc Cbz emigramicidin S-TEMP Wipf, P.; Xiao, J.; Jiang, J.; Belikova,. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, Adam Wipf Group 11 7/3/2006

12 emigramicidin Boc Cbz emigramicidin S-TEMP S scavenger moiety of superoxide dismutase β-turn mimic motif, bacterial membrane active - Acetylated amino fucntions reduce hemolytic activity Wipf, P.; Xiao, J.; Jiang, J.; Belikova,. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, Adam Wipf Group 12 7/3/2006

13 emigramicidin Synthesis TBDPS 1. Cp 2 Zr()Cl 2. ZnMe 2 3. Boc 4. TBAF Boc 74% 1. DMP 2. acl 2, a 2 P 4, 2-methyl-2-butene Boc -Pro-Val-rn(Cbz)-Me EDC, Bt, DMAP Me Boc Cbz 94% (3 steps) 1. a 2. 4-AT, EDC, Bt, DMAP 94% Boc Cbz Wipf, P.; Xiao, J.; Jiang, J.; Belikova,. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, Adam Wipf Group 13 7/3/2006

14 Biological Studies in vitro 4-AT 2 Boc Cbz Boc Cbz 5a 5b Wipf, P.; Xiao, J.; Jiang, J.; Belikova,. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, Adam Wipf Group 14 7/3/2006

15 Biological Studies in vivo - emorrhagic shock leads to cellular hypoxia, under which mitochondria leak electrons, leading to the formation of S ( 2 - ). Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude,. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; In Press, Adam Wipf Group 15 7/3/2006

16 Biological Studies in vivo - emorrhagic shock leads to cellular hypoxia, under which mitochondria leak electrons, leading to the formation of S ( 2 - ). ~55% of blood removed (60 min) Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude,. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; In Press, Adam Wipf Group 16 7/3/2006

17 Biological Studies in vivo - emorrhagic shock leads to cellular hypoxia, under which mitochondria leak electrons, leading to the formation of S ( 2 - ). ~55% of blood removed (60 min) solution administered Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude,. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; In Press, Adam Wipf Group 17 7/3/2006

18 Biological Studies in vivo - emorrhagic shock leads to cellular hypoxia, under which mitochondria leak electrons, leading to the formation of S ( 2 - ). ~55% of blood removed (60 min) Lifetime observed solution administered 6 hr Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude,. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; In Press, Adam Wipf Group 18 7/3/2006

19 Biological Studies in vivo - emorrhagic shock leads to cellular hypoxia, under which mitochondria leak electrons, leading to the formation of S ( 2 - ). ~55% of blood removed (60 min) Lifetime observed solution administered 6 hr KCl euthanization Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude,. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; In Press, Adam Wipf Group 19 7/3/2006

20 Biological Studies in vivo - emorrhagic shock leads to cellular hypoxia, under which mitochondria leak electrons, leading to the formation of S ( 2 - ). ~55% of blood removed (60 min) Lifetime observed solution administered 6 hr KCl euthanization Control: 1 rat after 60 min XJB-5-131: 6 rats after 60 min, 3 at 180 min, 1 at 6 hr!! Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude,. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; In Press, Adam Wipf Group 20 7/3/2006

21 Why Incorporate Peptide Isosteres? Boc Cbz Boc Cbz XJB XJB Even slight, seemingly innocuous changes in structure can have drastic biological consequences! Adam Wipf Group 21 7/3/2006

22 α-methyl-α,β-cyclopropyl-γ-amino Acids Cbz #! " C 2 Me Adam Wipf Group 22 7/3/2006

23 α-methyl-α,β-cyclopropyl-γ-amino Acids Me 2 C C 2 Me Wipf, P.; Stephenson, C.. J.; rg. Lett. 2005, 7, Adam Wipf Group 23 7/3/2006

24 Cyclopropyl Amino Acid Synthesis TBDPS 1. AlMe 3, Cp 2 ZrCl 2, 2, C 2 Cl 2, 0 C 2 ()P ZnEt 2, C 2 I 2, 2 ()P TBAF, Ac 2. P() 2, µw, 85% TBDPS DME, C 2 Cl 2, TBDPS TF (rac) 95% 91% 2 ()P 1. o- 2 C 6 4 SeC, PBu 3, TF 2 ()P 3, a/me 2 ()P 2. mcpba, a 2 P 4, -40 ˇC, then i-pr 2, -40 C to rt, 81% C 2 Cl 2, -78 C 98% C 2 Me 1. Cl, Me 2. C 2 C 2 40% 3 2 C C 2 C 2 Me 3 2 C C 2 C 2 Me Cbz-Cl, ac 3 EtAc, 2 97% Cbz Cbz C 2 Me C 2 Me Wipf, P.; Stephenson, C.. J.; rg. Lett. 2005, 7, Adam Wipf Group 24 7/3/2006

25 Interesting S Statistic Under normal metabolic conditions, each cell in our body is exposed to about molecules of superoxide each day. For a person weighing 150 pounds, this amounts to about 4 pounds of superoxide per year! Adam Wipf Group 25 7/3/2006

26 An Aside- Theory of Aging Mitochondria, xidants, and Aging. Balaban,. S.; emoto, S.; Finkel, T.; Cell, 2005, 120, Many believe the seeds of aging can be traced back to a chance encounter around 2 billion years ago between a host cell and an invading bacterium Adam Wipf Group 26 7/3/2006

27 Theory of Aging Mitochondria, xidants, and Aging. Balaban,. S.; emoto, S.; Finkel, T.; Cell, 2005, 120, Many believe the seeds of aging can be traced back to a chance encounter around 2 billion years ago between a host cell and an invading bacterium -In this case an agreement between host and invader formed (and has remained intact to this day). Adam Wipf Group 27 7/3/2006

28 Theory of Aging Mitochondria, xidants, and Aging. Balaban,. S.; emoto, S.; Finkel, T.; Cell, 2005, 120, Many believe the seeds of aging can be traced back to a chance encounter around 2 billion years ago between a host cell and an invading bacterium -In this case an agreement between host and invader formed (and has remained intact to this day). -At first roles were independent, then gradually responsibility shifted (cell- maintenance, bacterium- energy production), until specialization led to (eventually) the formation of muscles, etc. Adam Wipf Group 28 7/3/2006

29 but not the end of the story! -The eubacteria (mitochondria) did not immediately kill the host, but it may not have entered into the symbiotic agreement with full disclosure -The continuous production of S from ATP production pathway slowly but assuredly kills the host cell (oxidative damage)- the bacterium fulfillls its purpose! time Adam Wipf Group 29 7/3/2006

30 but not the end of the story! -The eubacteria (mitochondria) did not immediately kill the host, but it may not have entered into the symbiotic agreement with full disclosure -The contiguous production of S from ATP production pathway slowly but assuredly kills the host cell (oxidative damage)- the bacterium fulfillls its purpose! time -Mitochondrial DA employs a variant genetic code from the Proteobacteria family Adam Wipf Group 30 7/3/2006

31 Is the Mitocondrion like the Trojan horse? like omeo and Juliet? Adam Wipf Group 31 7/3/2006

32 Is the Mitocondrion does it matter??? Adam Wipf Group 32 7/3/2006

33 Imine methodology in the Wipf Group 2 ()P 2 ()P ' ' 1. Cp 2 Zr()Cl 2. ZnMe 2 1. Cp 2 Zr()Cl 2. ZnMe 2, imine 3. C 2 I 2 2 ()P ' 1. Cp 2 ZrCl 2, AlMe 3 2. imine 3. Zn(C 2 I )2 [Zn] ' P() 2 1. Cp 2 Zr()Cl 2. ZnMe 2 3. C 2 I 2, then imine 2 ()P ' 1. Cp 2 Zr()Cl 2. ZnMe 2 3. imine 4. Zn(C 2 I) 2 2 ()P 2 ()P ' Adam Wipf Group 33 7/3/2006

34 Alkynylimine Addition C Cp 2 ZrCl 2 2. ZnMe 2 3. P() 2 P() 2 C % 4. Zn(C 2 I) 2 P() 2 TIPS (66%) P() 2 C 2 Et (43%) Ts Me P() 2 (44%) P() 2 C 2 5 (55%) Wipf, P.; Stephenson, C.. J.; kumura, K.; J. Am. Chem. Soc., 2003, 125, Adam Wipf Group 34 7/3/2006

35 Proposed Mechanism 1. Cp 2 Zr()Cl 2. Me 2 Zn MeZn P() 2 4. Zn(C 2 I) 2 I 2 CZn P() 2 3. P() 2 I 2 CZn P() 2 IZn P() 2 10 C-C bonds formed, 2 C-C bonds broken! Adam Wipf Group 35 7/3/2006

36 Azaspirocycles (Unexpected result) Ar P() 2 a, MPA 65-96% I, TF, 70 C Ar P() 2 Mes Cl Cl Mes u PCy 3 C 2 Cl 2, reflux 63-84% Ar P() 2 2 ()P Ts C 2 Et a, MPA I, TF, 70 C 68% 2 ()P Ts 10 mol% Grubbs 2 nd gen. catalyst C 2 Cl 2, reflux ethylene 84% 2 ()P Ts desired Wipf, P.; Stephenson, C.. J.; Walczak, M. A. A.; rg. Lett., 2004, 6, Adam Wipf Group 36 7/3/2006

37 Macrocyclic Azepines in atural Products (-)-Strychnine Manzamine A Saraine A Upenamide Me 2 C Me Me (+)-Vinblastine Ac C 2 Me (-)-Ephedradine A Misenine Adam Wipf Group 37 7/3/2006

38 Metathesis-Based Synthetic routes C 2 Me Catalyst, Benzene, 50 C, 63% C 2 Me Manzamine A Martin; Tet. Lett., 1994, 35, 691 C 2 Me C 2 BDPS cat., 1 eq., rt, 5 days C 2 BDPS C 2 Et 30% Pandit; Tet. Lett., 1994, 35, 3191 Adam Wipf Group 38 7/3/2006

39 Acknowledgements -Prof. Dr. Wipf -Dr. Corey Stephenson -Dr. Chris Kendall -Dr. Jingbo Xiao -Maciej Walczak -Wipf Group Members Past and Present -I Adam Wipf Group 39 7/3/2006