currentliteraturepresentation september25th,2010 ...ccc.chem.pitt.edu/wipf/current...
TRANSCRIPT
Current Literature Presentation
Nolan Griggs, Ph.D.
September 25th, 2010
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Bioorthogonal Reactions - Overview
Chemical reactions that do not interfere with biological processes."
O O
Bertozzi, C.R., Sletten, E.M.; , 6974.
SR
OO
H2N
HS
O
O
H2N
S
O
O
NH
SH
N3
MeO
O
Ph2P MeO
O
PNPhPh
NP
PhPh
O
NH
O
Ph2P
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Cyclooctynes - Overview
• Smallest stable, unsubstituted cycloalkyne
• Alkyne bond angle = ~156 °
• Strain energy = ~18 kcal/mol
Note: 3,3,7,7-tetramethylcycloheptyne has been prepared and isolated:
• The difference in hydrogenation enthalpies of cyclooctyne versus 4-octyne is ~10 kcal/mol1
Kimling, H., Krebs, A.; , 509.
1. Turner, R.B., Mallon, B.J. et al.; , 790.
Reactions of cyclooctynes:
Trimerization: Cycloadditions:Radical Reactions:
Rose-Bengal
O
O
Meier, H. , , 5, 235.
Krebs, A., Wilke, J.; , 109, 189-233
O
Ph
Ph
O
Ph
PhO2
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Applications - Bioorthogonal Reactions Using Cyclooctynes
• Protein Labelling:
N3
n
HN O
HN
S
NHHN
O
O3
O
O
(PEO-Biotin)Nn
NN
PEO-Biotin
Link, A.J., et al. , 103, 10180See also: Fernandez-Suarez, M., et al.; , 25, 1483
Nessen, M.A., et al.; , 8, 3702
• Lipid Labelling:
OO
O
O
O
O
P
O
SATEOSATEO
OO
N3
NEt2
Imaging in living cells
Neef, A.B., Schultz, C.; , 48, 1498.
Glycan imaging:
Baskin, J.M et al. , 104, 16793
• Applied in living mice and monitored inreal time.
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Title Paper - Difluorobenzocyclooctyne - Reactivity
TMS OTf
F
FCsF
• No C3-symmetric product was observed
• To test if DIFBO was indeed formed, in situ trapping with benzyl azide was performed:
TMS OTf
F
F CsF, BnN3
CH3CN, rt93% (1.6:1)
NN
N
F
F
Bn NN
N
F
F
Bn
58%35%
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Title Paper - Proposed Mechanism for the Formation of Dimers 13 and 14
• The formation of both dimers raises interesting questions:
1. Does the dimerization event occur selectively inside the -cyclodextrin cavity?
2. Can the -cyclodextrin cavity accomidate two molecules of BIFBO?
3. What is the rate difference between the trimerization event and reaction withO2?
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Title Paper - Conclusions and Significance
• A new substituted cyclooctyne (DIFBO) has been discovered with drasticallysuperior kinetics in 2+3 cycloadditions with benzyl azide.
• Due to the enhanced reactivity of DIFBO, complexation with b-cyclodextrinwas found to stabilize DIFBO allowing for easy storage and manipulation.
• The inclusion complex of DIFBO and -cyclodextrin produced two compoundspresumed to arise from a single antiaromatic intermediate, thus providing a .
possible means to further study antiaromaticity.
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