en route to photoactivatable enediynesvpopik.uga.edu/uga_2010.pdfkostikov,a.; popik, v.v....
Post on 23-Jan-2021
1 Views
Preview:
TRANSCRIPT
UGA, August 10, 2010
Light Chemistry:
Photoactivated Antibiotics, Photolabile
Protecting Groups, Photo Click Ligation, etc.
Vladimir V. Popik
UGA, August 10, 2010
O
H3CSSS
O
HO
HN
O
OCH3
O
CH3
NH
O
OHO
O NH
OCH3
O
OH
S
CH3
O
CH3I
OCH3H3CO
O
O
OHH3CO
HOH3CO
Natural Antitumor Enediyne Antibiotics
Calicheamicin 1
Dynemicin A
Esperamicin
Neocarzinostatin
O
O
O
OH
H3C
OCH3
O
O O
O
O
HO
OH
NHCH3
O
H3CSSS
O
HO
HO
HN
O
OCH3
O
CH3
NH
O
OHO
O NH
OCH3
O
OH
CH3S
CH3
OH
OH
O
O OH
HNO
CO2H
CO2H
Bergman Cyclization
C
Myers-Saito Cyclization
UGA, August 10, 2010
Photochemical Triggering of Bergman Cyclization
Ring Contraction
Stable ½ = 18 h at 360C
X h
Generation of a π-system
X Yh h
X
Yn nn
Removal ofblocking device
hBlockinggroup
activator
Poloukhtine, A.; Karpov, G.; Popik V.V. Curr.Topics Med.Chem., 2008, 8, 460;
Polukhtine, A.; Karpov, G.; Pandithavidana, D. R.; Kuzmin, A.; Popik, V.V. Aust. J. Chem. 2010, 63,1099
UGA, August 10, 2010
Synthesis of 2-Diazo-1,3-dioxocycloundeca-6-en-4,7-diyne
I
R R
SiMe3
b
R = NH2
R = N3Et2a
R = N3Et2R = I
c
d
SiMe3
X
X = H, OH
R = Oe
R2
OR1
O
O
f
R1= H, R
2= Me3Si
R1= TBS, R
2= Me3Si
R1= TBS, R
2= H
R1= TBS, R
2= I
g
h
i
ok
TBSO
O
I
O
X
X= H, OTBS
X= H, OH
X = O
m
n
j
OH
OTBSl
O
O
N2
(a) NaNO2, HCl, Et2NH, 86%; (b) HC CSiMe3, Pd(PPh3)2Cl2, CuI, PPh3, Et3N, THF, 400C; (c) CH3I, 1400C, 94% over two
steps; (d) HC C(CH2)3CH2OH, Pd(PPh)2Cl2, CuI, PPh3, Et3N, THF, r.t., 98%; (e) Dess-Martin periodinane, CH2Cl2, 82%; (f)
LDA, THF, -780C, ethyl acetate, 90%; (g) TBDMSCl, CH2Cl2, DMAP, 90%; (h) K2CO3, methanol, 97%; (i) I2, morpholine,
benzene, 500C, 91%; (j) DIBAL, CH2Cl2, 87%; (k) CrCl2, NiCl2, THF, 76% (both diastereomers); (l) Dess-Martin periodinane,
CH2Cl2, 92%; (m) HFaq, CH3CN, 88%; (n) Dess-Martin periodinane, CH2Cl2, 84%; (o) TosN3, DBU, CH2Cl2, 84%
UGA, August 10, 2010
Enediyne Ring Contraction by photo-Wolff reaction
Stable at 250C
84oC > 15 h
= 50 s
(MeOH)
No decomposition for 7
days at 840C
UGA, August 10, 2010
Tautomerization - Myers-Saito Cycloaromatization
G0= -11.7 kcal/mol G0 ~0
CO2R
O
O
CO2Me
C
H
O
CO2MeOH
CO2Me
D CO2R
OD
(CH3)2CHOD
kH / kD = 2.18
Rate-limiting
Very fast25oC < 100 ms
Karpov, G.; Kuzmin, A.; Popik, V. V.
J.Am.Chem.Soc. 2008, 130, 11771
Karpov, G.; Popik, V.V. J.Am.Chem.Soc.
2007, 129, 3792
B3LYP / 6-31++G(dp):
UGA, August 10, 2010
C
O
CO2R
OH
OO
C O
+
OH
CO2R
+
Enediyne Ring Contraction by photo-Wolff reaction
O
N2
O
i-PrOH
h
CO2R
OHOH
CO2R
+
3:1
0oC < 1 min
UGA, August 10, 2010
Photochemical Generation of Enediyne Triple Bond
= 0.2 – 0.9Quantitative
0 200 400 600 800 1000
-0.10
-0.05
0.00
0.05
0.10
0.15
380 nm
645 nm
Time / ps
IGNORES:
triplet sensitizers
triplet quenchers
singlet quenchers
radical traps
cationic traps
carbene traps
Poloukhtine, A.; Popik, V.V. J.Phys.Chem. A 2006 110 , 1749
UGA, August 10, 2010
Photo-generation of Enediyne Triple Bond
300 = 0.46
QuantitativeStable at 900C
Poloukhtine, A.; Popik, V.V. J.Org.Chem. 2005, 70 , 1297;
Poloukhtine, A.; Popik, V.V. Chem.Comm. 2005, 617
UGA, August 10, 2010
Generation and Cyclization of 9-Membered Ring Enediyne
i-PrOH
OH
25oC = 98 min
kH / kD = 5.18
Pronounced primary KIE in isopropanol –d8
OH
290 300 310 320 330
0.0
5.0x10-4
1.0x10-3
1.5x10-3
H = 13627 ± 216 cal mol-1
S = -30.66 ± 0.61 cal mol-1 deg-1
Observ
ed R
ate
/ s
-1
Temperature / oK
0 2 4 6 8 10 12 14
0.0
5.0x10-5
1.0x10-4
1.5x10-4
Ra
teo
bs / s
- 1
[2-Propanol] / M
k = (1.108 ± 0.058) 10-5 M
-1s
-1
Rate-limitingFast
2.90
Pandithavidana, D.R.; Poloukhtine, A.; Popik, V.V. J.Am.Chem.Soc. 2009, 131, 351
K ~ 10-11
UGA, August 10, 2010
9-Membered Ring Enediyne
Stable at 250C !
350 = 0.50
i-PrOH
@ 700C
= 6 h in neat i-PrOH
= 13 h in i-PrOH : H2O (1:1)
2.94
UGA, August 10, 2010
Photochemical Generation of EneYne-Allene
25oC ~ 5 min
0 200 400 600 800 1000 1200 1400 1600 1800
1.00
1.05
1.10
1.15
1.60
1.65
1.70
1.75 Cyclohexadiene / THF
k=(3.4±1.0)x10-3s
-1
k=(2.74±0.05)x10-3s
-1
Ab
so
rba
nce
@ 2
32
nm
Time / s
i-PropanolKuzmin, A.V.; Popik V.V. Chem.Commun. 2009, 5707
UGA, August 10, 2010
Aza-Enediyne
N
Ts
OH
R
N
Ts
OH
H
R = C6H7
OH OH½ 40oC= 154 h
R
N
Ts
OH
R = C7H7
CH3
550C
N
Ts
OH
1/2 ~ 3 h
(400C)
O
N
Ts
OH
½ = 30 min (400C)
UGA, August 10, 2010
Acid-Catalyzed Bergman Cyclization
N
Ts
OH
CN
H
Ts
HO
AH
RO
H
-H
O
N
Ts
OH
N
Ts
OH
HR
O
N
Ts
OHR
MeOH
O
N
Ts
OMeMe
-H
N
Ts
OH
Poloukhtine, A.; Rassadin, V.; Kuzmin, A.; Popik, V.V. J. Org. Chem. 2010, 75, ASAP article jo01238x.
UGA, August 10, 2010
Photonuclease Activity of Photoswitchable Enediynes
N2
O
O
Relaxed
Linear
Supercoiled
UGA, August 10, 2010
Light Penetration in Mammalian Tissues
Muscle penetration depth of light
Wavelength (nm)
Wavelength (nm)
UV Spectrum of Oxyhemoglobin
EE’
S0
S1
ENon-Resonant Two-photon
Excitation
UGA, August 10, 2010
Two-photon Photochemistry of Enediyne Precursor
0 1000 2000 3000
0.0
0.5
1.0
Yie
ld o
f E
nediy
ne
Time / s
O
O
O
O
O
800 nm
94 fs pulses, 1 kHz
MeOH
0.4 0.8
0.0
0.4
0.8
-3.5 -3.0
-1.5
-1.0
-0.5
0.0
Slope = 2.067 ± 0.020
Lo
g (
Ye
ild
of 2
)
Log (Pulse Energy)
Yile
d o
f E
ne
diy
ne
(1
0 m
in)
Pulse Energy / mJ
= 0.8 GM
100
20
100
0(1 )
fs
WR
fs
I dt t
C C e
Urdabaev, N.K.; Poloukhtine, A.; Popik,V.V. Chem.Comm. 2006, 454
UGA, August 10, 2010
O
MeO OMe
Nonresonant Two-photon Photochemistry
O
OMe OMe
= 0.5 GM
O
Me2N NMe2> 15 GM
= 0.02 GM
O O
N2
N N
O O
N2
= 5 GM = 407 GM
UGA, August 10, 2010
10-1
10-3
10-5
10-7
10-9
10-11
10-13
1x102
1x103
1x104
log
(kO
BS)
/ s
-1
[H+] / M
Arumugam, S.; Popik, V.V. J.Am.Chem.Soc. 2009, 131(33), 11892-9.
= 12 s
o-Quinone Methides
0.00 0.02 0.04 0.06 0.08 0.100
1x103
2x103
3x103
4x103
5x103
6x103
kquench
= (4.60 ± 0.56)*104 M
-1s
-1
kO
BS / s
-1
[CH2=CH-OEt] / M
kH2O/ kD2O = 1.85±0.14
= 7.4 ms
UGA, August 10, 2010
Photoactivatable Antimitotic Agents
O
O
O
O
OH
OO
O
HO
NH
O
O
R
O
O
R'
O
O
O
O
OH
n
PPG
O
NH
O
O
R
O
O
O
O
O
OO
OH
OO
O
HO
NH
OH
O
R
O
O
R'
h , H2O
-CO2
Taxol
(paclitaxel)
O
SB
R
Ar
R
h
R
Ar
R O SBROH
OHR
Ar
RHO SB+
+
UGA, August 10, 2010
H2O
+ ROH
OH
OR
hO
OH
OH
OEt
O OEt
O
OR
H
(2-Hydroxynaphth-3-yl)methyl Cage
EtOH
95%
OH
97%
O
OH
NHBoc
HO
O
O
OR
HO N
NH
O
O
OH
O
O
O
OH
89% (98%)
96%
97%
96%
92%(91%)
Kulikov, A.; Arumugam, S.; Popik, V.V. J.Org.Chem. 2008, 73(19), 7611.
UGA, August 10, 2010
2,5-Dihydroxybenzyl Cage
O
OH
O
O
ROH +
OH
OH
OR
h
250 300 350
0.0
0.5
Ab
so
rba
nce
Wavelegth / nm
MeOH or
MeCN/H2O
OH
CO2H
CO2H
H3C
H3CH3C
OHCl
80%
=0.2 - 0.3
100%
= 0.31
85%
= 0.5
55%
= 0.06 Kostikov, A.; Popik, V.V. J.Org.Chem. 2007, 72, 9190
UGA, August 10, 2010
Photolabile Protection for Glycols and Carbonyl Compounds
hO
OBnO
OBnOBn
O
OH
HO
O
OBnO
OBnOBn
O
O
O
[H]O
HOBnO
OBnOBn
HO
OH O
O R
R O O
OHR
R
O
R R
O+h
H2O
OHO O
300 nm
O O
O R
R
O
[H]
Kostikov, A.; Popik, V.V. J.Org.Chem. 2009, 74, 1802.
UGA, August 10, 2010
Photo-activation of Anomeric Position for Glycosylation
O
RORO
O
OR
RO
HO
O
RORO
O
OR
ROh
O
RORO
OR
RO
O
+
O
RORO
O
OR
ROO
RO
OR
OR
OR
HOO
RO
OR
OR
OR
UGA, August 10, 2010
Hetero-Diels-Alder Reaction of o-Quionone Methides
k > 104 M-1 s-1
UGA, August 10, 2010
Hetero-Diels-Alder Photo-Click
patterned irradiation
UGA, August 10, 2010
“Strain-Promoted” Azide Click Reaction
Conventional “Click” reaction
R= H, needs Cu+ catalysis
Cu+ is cytotoxic!
R= Alk or Ar – too slow
“Strain-promoted Click” reactiondoes not needmetal catalyst
Wittig, G.; Krebs. A. Chem. Ber. 1961, 94, 3260-3275;
Bertozzi et al. J. Am. Chem. Soc. 2004, 126, 15046-15047;
Boons et al. Angew. Chem. Int. Ed. 2008, 47, 2253-2255.
UGA, August 10, 2010
Metal – Free Azide Click on the Surface
UGA, August 10, 2010
Metal – Free Click Derivatization of Nanopartcles
UGA, August 10, 2010
Photochemical Generation of Dibenzocyclooctynes
250 300 350 400
0.0
0.5
1.0
1.5
2.0
(nm)
UGA, August 10, 2010
Using Photo-Click Reaction for the Live Cells Labeling
O
AcOAcO
HNAcO
OAc
ON3
N3Cell
N3
N3
N3
BuO
O
+
Fluorescent Tag
Upon irradiation
In the dark
Ac4ManNAz
In collaboration with Dr. Boons
Poloukhtine, A.A.; Mbua, N.E.;
Wolfert, M.A.; Boons, G.-J., Popik,
V.V. J.Am.Chem.Soc. 2009,
131(43), 15769
UGA, August 10, 2010
Photo-Click on the Brushes
1. Patterned Irradiation2. Rhodamine B– N3
3. Flood Irradiation4. Oregon Green – N3
Orski, S.V.; Poloukhtine, A.A.; Arumugam, S.; Mao, L.; Popik, V.V.; Locklin, J. J. Am. Chem. Soc. 2010, 132, ASAP article ja05066t.
In collaboration with Dr. Locklin
10 μm 10 μm 10 μm
(a) (b) (c)
UGA, August 10, 2010
The Team
• Dr. Selvanathan Arumugam• Alexander Kuzmin• Emmanuel Nekongo• Dewey Sutton• Natalia Zhegalova• Kevin Wickware
Alumni
• Dr. Gregory Karpov• Dr. Alexey Kostikov (PhD 2008)• Dr. Dinesh Pandithavidana (PhD 2009)• Dr. Andrei Poloukhtine• Dr. Victor Sorokoumov
Acknowledgements
Collaborators
Professor Geert-Jan BoonsMbua Eric NgalleDr. Margreet WolfretDr. Jun Guo
Professor Jason LocklinSara Orski
Money
• National Science Foundation (CHE-0631210; CHE-0842590)
• Georgia Cancer Coalition Distinguished Cancer Scholar Award
• Petroleum Research Fund (43444-AC4; 48353-AC4)
• The University of Georgia
top related