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Applications of Imine additions:Hemigramicidin S and Polycyclic
Azepine Investigations
Adam HoyeResearch Topic Seminar
April 22nd, 2006
Adam Hoye @ Wipf Group 1 7/3/2006
Imine addition chemistry- statistics, general rxns,
Source: SciFinder 2006
"Imine Addition" Papers
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Imines as “the new carbonyl”
Adam Hoye @ Wipf Group 2 7/3/2006
Selected Reactions of Imines
Mukaiyama Catalytic Reduction:
Charette Organozinc Addition:
Kobayashi Asymmetric Mannich Reaction:
Kobayashi, S.; Ishitani, H,; Chem. Rev., 1999, 99, 1069-1094Charette, A. B. et al.; Pure Appl. Chem., 2005, 77, 1259-1267
Ph
N
H
HO Zr(BINOL)2, (5 mol%),NMI (10 mol%)
OMe
OTMS
, CH2Cl2, -45°C
Ph
NH
OH
O
OMe70% yield, 87% ee
NP(O)Ph2
O
N
O
Ar
N
O O
Ar
Co
1 mol%
Na(EtO)H2BOO
HNP(O)Ph2
97% yield, 90% ee
Ph H
NP(O)Ph2
Cu(OTf)2 (6 mol%)BozPHOS (3 mol%)
ZnMe2 (2 eq.), Toluene, 0°C Ph
HNP(O)Ph2
87% yield, 97% ee
Adam Hoye @ Wipf Group 3 7/3/2006
Imine methodology in the Wipf Group
[Zn]R' R
NP(O)Ph2
H
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
Ph2(O)PNH
R'R
1. Cp2Zr(H)Cl2. ZnMe2
1. Cp2Zr(H)Cl2. ZnMe2, imine3. CH2I2
1. Cp2ZrCl2, AlMe32. imine3. Zn(CH2I)2
1. Cp2Zr(H)Cl2. ZnMe23. CH2I2, then imine
1. Cp2Zr(H)Cl2. ZnMe23. imine4. Zn(CH2I)2
R
Adam Hoye @ Wipf Group 4 7/3/2006
Imine methodology in the Wipf Group
[Zn]R' R
NP(O)Ph2
H
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
Ph2(O)PNH
R'R
1. Cp2Zr(H)Cl2. ZnMe2
1. Cp2Zr(H)Cl2. ZnMe2, imine3. CH2I2
1. Cp2ZrCl2, AlMe32. imine3. Zn(CH2I)2
1. Cp2Zr(H)Cl2. ZnMe23. CH2I2, then imine
1. Cp2Zr(H)Cl2. ZnMe23. imine4. Zn(CH2I)2
R
Adam Hoye @ Wipf Group 5 7/3/2006
Cyclopropyl amino acids
Ph
Ph2(O)PNH R2
R1OTBDPS
H2N
Ph
CO2H
H2N
Ph
CO2H
H2N
Ph
CO2H
R1
OTBDPS
Adam Hoye @ Wipf Group 6 7/3/2006
Gramicidin S
HN
O
N
O
HN
O
NH
O
HN
Ph
O
NH2
NH
OHN
O
NH
O
Ph
NH
O
H2N
N
O
- Isolated (and used) in 1943 (USSR)- Gramicidins A-D (linear) potent antibacterials, act via membrane insertionand aggregation, thus increasing cell permeability (high hemolytic activity)-Rigid, symmetric β-strands connected by β-turns [(cyclo-DPhe-Pro-Val-Orn-Leu)2]-Hydrophobic side chains (Val, Leu) on one face and polar residues (Orn) onthe other, GS binds well to lipid bilayers-No resistance to antibiotic activity has been found so far-GS mitochondrial targeting
Wadhwani, P.; Afonin, S.; Ieronimo, M.; Buerck, J.; Ulrich, A. S.; J. Org. Chem. 2006, 71, 55Wu, X.; Bu, X.; Wong, K. M.; Yan, W.; Guo, Z.; Org. Lett. 2003, 5, 1749
Adam Hoye @ Wipf Group 7 7/3/2006
Mitochondria
-Organelle membrane highly bacterial in type (high affinity forGramicidins)-Target of many cellular processes and proteins (“powerplant of cell”)-Proficient inducer of apoptosis (programmed cell death)-Primary production of ATP
Adam Hoye @ Wipf Group 8 7/3/2006
Reactive Oxygen Species (ROS) in ATP Production
Superoxide dismutase traps ROS, but under conditions ofhigh cellular stress, more ROS can be released, and
damage to cells occurs.Adam Hoye @ Wipf Group 9 7/3/2006
Gramicidin in our group- Jingbo Xiao
Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, 12460.Xiao, J.; Westblum, B.; Wipf, P.; J. Am. Chem. Soc. 2005, 127, 5742.
O
N
O
HN
O
NH
O
HN
Ph
NH2
NH
OHN
O
Ph
NH
O
H2N
N
O
E-alkene Gramicidin S
O
N
O
HN
O
NH
O
HN
Ph
NH2
NH
OHN
O
Ph
NH
O
H2N
N
O
CF3CF3
[CF3]2GS
O
N
O
HN
O
NH
O
HN
Ph
NH2
NH
OHN
O
Ph
NH
O
H2N
N
O
FF
[F2]GS
O
N
O
HN
O
NH
O
HN
Ph
NH2
NH
OHN
O
Ph
NH
O
H2N
N
O
CH3CH3
[CH3]2GS
Adam Hoye @ Wipf Group 10 7/3/2006
Hemigramicidin
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
Hemigramicidin S-TEMPO
Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, 12460.
Adam Hoye @ Wipf Group 11 7/3/2006
Hemigramicidin
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
Hemigramicidin S-TEMPO
ROS scavenger moiety ofsuperoxide dismutase
β-turn mimic motif,bacterial membraneactive
- Acetylated amino fucntions reduce hemolytic activity
Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, 12460.
Adam Hoye @ Wipf Group 12 7/3/2006
Hemigramicidin Synthesis
Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, 12460.
H
OTBDPS
Ph
1. Cp2Zr(H)Cl2. ZnMe2
3.
NBoc
H NH
Boc
H
OH
4. TBAF
Ph
1. DMP
2. NaClO2, NaH2PO4,2-methyl-2-butene
NH
Boc
H
OH
Ph
O
74%
H-Pro-Val-Orn(Cbz)-OMe
EDC, HOBt, DMAP
94% (3 steps)
O
N
O
HN
O
NH
O
MeO
Ph
NHCbz
BocHN1. NaOH
2. 4-AT, EDC,HOBt, DMAP
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
94%
Adam Hoye @ Wipf Group 13 7/3/2006
Biological Studies in vitro
5b
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
HN
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
O
5a
NH2
NO
4-AT
Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E.; J. Am. Chem. Soc. 2005, 127, 12460.
Adam Hoye @ Wipf Group 14 7/3/2006
Biological Studies in vivo
Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; InPress, 2006.
- Hemorrhagic shock leads to cellular hypoxia, under which mitochondria leakelectrons, leading to the formation of ROS (O2•-).
Adam Hoye @ Wipf Group 15 7/3/2006
Biological Studies in vivo
Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; InPress, 2006.
- Hemorrhagic shock leads to cellular hypoxia, under which mitochondria leakelectrons, leading to the formation of ROS (O2•-).
~55% of blood removed(60 min)
Adam Hoye @ Wipf Group 16 7/3/2006
Biological Studies in vivo
Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; InPress, 2006.
- Hemorrhagic shock leads to cellular hypoxia, under which mitochondria leakelectrons, leading to the formation of ROS (O2•-).
~55% of blood removed(60 min)
solution administered
Adam Hoye @ Wipf Group 17 7/3/2006
Biological Studies in vivo
Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; InPress, 2006.
- Hemorrhagic shock leads to cellular hypoxia, under which mitochondria leakelectrons, leading to the formation of ROS (O2•-).
~55% of blood removed(60 min)
solution administered
Lifetime observed
6 hr
Adam Hoye @ Wipf Group 18 7/3/2006
Biological Studies in vivo
Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; InPress, 2006.
- Hemorrhagic shock leads to cellular hypoxia, under which mitochondria leakelectrons, leading to the formation of ROS (O2•-).
~55% of blood removed(60 min)
solution administered
Lifetime observed
6 hr KCleuthanization
Adam Hoye @ Wipf Group 19 7/3/2006
Biological Studies in vivo
Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P.; InPress, 2006.
- Hemorrhagic shock leads to cellular hypoxia, under which mitochondria leakelectrons, leading to the formation of ROS (O2•-).
~55% of blood removed(60 min)
solution administered
Lifetime observed
6 hr KCleuthanization
Control: 1 rat after 60minXJB-5-131: 6 ratsafter 60 min, 3 at 180min, 1 at 6 hr!!
Adam Hoye @ Wipf Group 20 7/3/2006
Why Incorporate Peptide Isosteres?
HN
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
O
XJB-5-125XJB-5-131
O
N
O
HN
O
NH
O
HN
Ph
NHCbz
BocHN
NO
Even slight, seemingly innocuous changes in structure can have drastic biological consequences!
Adam Hoye @ Wipf Group 21 7/3/2006
α-Methyl-α,β-Cyclopropyl-γ-Amino Acids
Ph
CbzNH
HN
O
CO2Me
Ph
!"#
Adam Hoye @ Wipf Group 22 7/3/2006
α-Methyl-α,β-Cyclopropyl-γ-Amino Acids
NH
HN
O
CO2Me
Ph
HN
NH
O
MeO2C
Ph
Ph
Ph O
O Ph
O
O
Ph
Wipf, P.; Stephenson, C. R. J.; Org. Lett. 2005, 7, 1137.
Adam Hoye @ Wipf Group 23 7/3/2006
Cyclopropyl Amino Acid Synthesis
ZnEt2, CH2I2,OTBDPS
1. AlMe3, Cp2ZrCl2,H2O, CH2Cl2, 0°C
2.
Ph
NP(O)Ph2
H
Ph OTBDPS
, µW,
DME, CH2Cl2,
Ph2(O)PNH
Ph OTBDPS
Ph2(O)PNH
(rac)
TBAF, AcOH
THF
85%
95% 91%
Ph OH
Ph2(O)PNH 1. o-NO2C6H4SeCN, PBu3, THF
2. mCPBA, Na2HPO4, -40°ˇC,then i-Pr2NH, -40°C to rt,
Ph
O3, NaOH/MeOHPh2(O)PNH
Ph CO2Me
Ph2(O)PNH
81%
CH2Cl2, -78°C
98%
1. HCl, MeOH
Ph
NH3
CO2Me Ph
NH3
CO2Me
O2C
OH
CO2H
OH
O2C
OH
CO2H
OHCbz-Cl, NaHCO3
EtOAc, H2O
Ph
CbzNH
CO2Me
Ph
CbzNH
CO2MeHO2C
OH
CO2H
OH
2.
40%
97%
Wipf, P.; Stephenson, C. R. J.; Org. Lett. 2005, 7, 1137.
Adam Hoye @ Wipf Group 24 7/3/2006
“Under normal metabolic conditions, each cell in ourbody is exposed to about 1010 molecules of superoxide
each day. For a person weighing 150 pounds, thisamounts to about 4 pounds of superoxide per year!”
http://lpi.oregonstate.edu/f-w97/reactive.html
Interesting ROS Statistic
Adam Hoye @ Wipf Group 25 7/3/2006
An Aside- Theory of Aging
- Many believe the seeds of aging can be traced back to a chanceencounter around 2 billion years ago between a host celland an invading bacterium
Mitochondria, Oxidants, and Aging. Balaban, R. S.; Nemoto, S.;Finkel, T.; Cell, 2005, 120, 483-495.
Adam Hoye @ Wipf Group 26 7/3/2006
Theory of Aging
- Many believe the seeds of aging can be traced back to a chanceencounter around 2 billion years ago between a host celland an invading bacterium
Mitochondria, Oxidants, and Aging. Balaban, R. S.; Nemoto, S.;Finkel, T.; Cell, 2005, 120, 483-495.
-In this case an agreement between host and invader formed (and has remained intact to this day).
Adam Hoye @ Wipf Group 27 7/3/2006
Theory of Aging
- Many believe the seeds of aging can be traced back to a chanceencounter around 2 billion years ago between a host celland an invading bacterium
Mitochondria, Oxidants, and Aging. Balaban, R. S.; Nemoto, S.;Finkel, T.; Cell, 2005, 120, 483-495.
-In this case an agreement between host and invader formed (and has remained intact to this day).
-At first roles were independent, then gradually responsibilityshifted (cell- maintenance, bacterium- energy production), untilspecialization led to (eventually) the formation of muscles, etc.
Adam Hoye @ Wipf Group 28 7/3/2006
…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 fulldisclosure…
-The continuous production of ROS from ATP production pathwayslowly but assuredly kills the host cell (oxidative damage)- thebacterium fulfillls its purpose!
time
Adam Hoye @ Wipf Group 29 7/3/2006
…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 fulldisclosure…
-The contiguous production of ROS from ATP production pathwayslowly but assuredly kills the host cell (oxidative damage)- thebacterium fulfillls its purpose!
-Mitochondrial DNA employs a variant genetic code from the Proteobacteria family
time
Adam Hoye @ Wipf Group 30 7/3/2006
Is the Mitocondrion…
…like the Trojan horse? …like Romeo and Juliet?
Adam Hoye @ Wipf Group 31 7/3/2006
Is the Mitocondrion…
…does it matter???
Adam Hoye @ Wipf Group 32 7/3/2006
Imine methodology in the Wipf Group
[Zn]R' R
NP(O)Ph2
H
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
R'
R
Ph2(O)PNH
Ph2(O)PNH
R'R
1. Cp2Zr(H)Cl2. ZnMe2
1. Cp2Zr(H)Cl2. ZnMe2, imine3. CH2I2
1. Cp2ZrCl2, AlMe32. imine3. Zn(CH2I)2
1. Cp2Zr(H)Cl2. ZnMe23. CH2I2, then imine
1. Cp2Zr(H)Cl2. ZnMe23. imine4. Zn(CH2I)2
R
Adam Hoye @ Wipf Group 33 7/3/2006
Alkynylimine Addition
Ph
H
NP(O)Ph2
1. Cp2ZrCl22. ZnMe2
3.
4. Zn(CH2I)2
C4H9
H
Ph
HNP(O)Ph2
C4H9
60%
Ph
HNP(O)Ph2
OTIPS(66%)
Ph
HNP(O)Ph2
NTs
CO2Et (43%)
HNP(O)Ph2MeO
OO
O(44%)
HNP(O)Ph2
Ph
(55%)
C2H5
Wipf, P.; Stephenson, C. R. J.; Okumura, K.; J. Am. Chem. Soc., 2003, 125, 14694-14695
Adam Hoye @ Wipf Group 34 7/3/2006
Proposed Mechanism
NP(O)Ph2
R
IH2CZn
Ph
NP(O)Ph2
R
IZn
Ph
R
H
1. Cp2Zr(H)Cl2. Me2Zn
3.
Ph
NP(O)Ph2
H
Ph
NP(O)Ph2
R
MeZn
4. Zn(CH2I)2
Ph
NP(O)Ph2
R
IH2CZn
10 C-C bonds formed, 2 C-C bonds broken!
Adam Hoye @ Wipf Group 35 7/3/2006
Azaspirocycles (Unexpected result)
Ar
HNP(O)Ph2
R
NaH, HMPA
I, THF, 70°C
Ar
NP(O)Ph2
R
65-96%
Ru
PhPCy3
NMesMesN
Cl
Cl
CH2Cl2, refluxN
Ar H
RP(O)Ph2
63-84%
Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A.; Org. Lett., 2004, 6, 3009-30012
NaH, HMPA
I, THF, 70°C
CH2Cl2, refluxethylene
10 mol% Grubbs 2nd
gen. catalyst
84%68%
Ph
Ph2(O)PNH
N
Ts
CO2Et Ph
Ph2(O)PN
N
TsPh
N NTsPh2(O)P
desired
Adam Hoye @ Wipf Group 36 7/3/2006
Macrocyclic Azepines in Natural Products
N
N
H
H
OH
NNH
Manzamine A
O
OH
H
H O
N
HN
H
(-)-Ephedradine A
O
NH
NHNHMeO2C
N
OH
H
N
Me
MeO
OH
CO2Me
OAc
N
(+)-Vinblastine
N
O
N
H
OH
(-)-Strychnine
N
O
N
O
O
H
H
H
H
H
HO
Upenamide
ON
N
Misenine
N
O N
H
H
Saraine A
Adam Hoye @ Wipf Group 37 7/3/2006
Metathesis-Based Synthetic routes
N
N
H
H
OH
NNH
Manzamine A
Pandit; Tet. Lett., 1994, 35, 3191
N
N OPh
CO2MeH
Catalyst, Benzene,50°C, 63%
N
N OPh
CO2MeH
Martin; Tet. Lett., 1994, 35, 691
O
N
OPh NCO2Et
CO2MeH
N
O N
CH2OBDPSH
O
cat., 1 eq.,rt, 5 days
N
N
H
H
O
CH2OBDPS
O
30%
O
Adam Hoye @ Wipf Group 38 7/3/2006
Acknowledgements
-Prof. Dr. Wipf
-Dr. Corey Stephenson-Dr. Chris Kendall-Dr. Jingbo Xiao-Maciej Walczak
-Wipf Group Members Past and Present
-NIH
Adam Hoye @ Wipf Group 39 7/3/2006