Applications of Imine additions: Hemigramicidin S and ...ccc.chem.pitt.edu/wipf/Topics/Adam.pdf ·...

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”


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


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



[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






R


Cyclopropyl amino acids

Ph

Ph2(O)PNH R2

R1OTBDPS

H2N

Ph

CO2H

H2N

Ph

CO2H

H2N

Ph

CO2H

R1

OTBDPS


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


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


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


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.


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



Hemigramicidin Synthesis


H

OTBDPS

Ph


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%


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



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







Lifetime observed

6 hr KCleuthanization







Lifetime observed

6 hr KCleuthanization

Control: 1 rat after 60minXJB-5-131: 6 ratsafter 60 min, 3 at 180min, 1 at 6 hr!!


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!


α-Methyl-α,β-Cyclopropyl-γ-Amino Acids

Ph

CbzNH

HN

O

CO2Me

Ph

!"#


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.


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.


“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


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.


Theory of Aging



-In this case an agreement between host and invader formed (and has remained intact to this day).


Theory of Aging



-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.


…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


…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


Is the Mitocondrion…

…like the Trojan horse? …like Romeo and Juliet?


Is the Mitocondrion…

…does it matter???



[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






R


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


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!


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


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


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


Acknowledgements

-Prof. Dr. Wipf

-Dr. Corey Stephenson-Dr. Chris Kendall-Dr. Jingbo Xiao-Maciej Walczak

-Wipf Group Members Past and Present

-NIH


Applications of Imine additions: Hemigramicidin S and ...ccc.chem.pitt.edu/wipf/Topics/Adam.pdf ·...

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