bologna 18-12-2013
TRANSCRIPT
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PHOTOINDUCED RADICAL HYDROPHOSPHONYLATION
OF SUGAR ALKENES
Eur. J. Org. Chem. 2013, 5370–5375
Samuele Staderini(a) , Alessandro Dondoni(a) , Alberto Marra(b)
a) Dipartimento di Chimica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italyb) Institut des Biomolécules Max Mousseron, UMR 5247, Ecole Nationale Supérieure de Chimie de Montpellier, 8 Rue de l’Ecole Normale, 34296 Montpellier cedex 5, France
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Hydrofunctionalization of terminal alkenes
R' H-E R'E
metal-basedcatalyst
or radicalinitiator
E = BR2, NR2, S iR2, SnR3,SR, (O)P(OR'')2
R'H
H E
Linear(Anti-Markovnikov)
Branched(Markovnikov)
RSR'
R'
RSR'
R S
R SH
Thiol-EneUseful metal-free ligation tool for functionalization of terminal thiols (sugars, protein) or for multivalent scaffold with terminal alkenes.
• High efficiency and regioselectivity
• Atom economy• Catalyzed by light• Orthogonality to a great
variety of other reactive groups
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Hydrophosphonylation of alkenes
Alkyl phosphonates obtained as products are important as phosphate isosteres, isopolar analogues.
O
OH
OH
HOHO
OP
O
OHOH
O
OH
OH
HOHO
PO
OHOH
O
O
OH
HOHO
OH
POOH
OH
O
OH
HOHO
OH
POOH
OH
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Hydrophosphonylation: a very well-known reaction
Michaelis-Arbuzov reaction
Transition-metal catalysis
Radical reactions1. Organic peroxides
2. Termic activation (AIBN)
3. Mn(Oac)2
a) D. Leca, L. Fensterbank, E. Lacôte, M. Malacria, Chem. Soc. Rev. 2005, 34, 858-865.
b) L. Coudray, J.-L. Montchamp, Eur. J. Org. Chem. 2008, 3601-3613
a) A. R. Stiles, W. E. Vaughan, F. F. Rust, J. Am. Chem. Soc. 1958, 80, 714-716.
b) S. R. Piettre, Tetrahedron Lett. 1996, 37, 2233-2236.
a) O. Tayama , A. Nakano, T. Iwahama, S. Sakaguchi, Y. Ishii, J. Org. Chem. 2004, 69, 5494-5496.
All these methods are quite attractive because they are operationally simple while using inexpensive and commercially available initiators and, most importantly, afford exclusively linear anti-Markovnikov adducts
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Disadvantages and limitations• Reactions tested by using rather simple
alkyl and aryl-substituted alkenes• Extension to more complex substrates
have not garnered much attention• Severity of conditions employed (heating
for several hours) may not be tolerated by delicate bioactive substrates
Photochemical approach has to be tested
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Photoinduced radical hydrophosponylation
R'
R'
(RO)2P
O
(RO)2PH
O
(RO)2P
O
R'(RO)2P
O
• Irradiation at Room Temperature
• Wavelength close to visible light
• Suitable amount of a photoinitiator
These conditions could permit to study addition on sensible biological substrates.Only one example is reported in literature, but not on sensible substrates as carbohydrates.This reaction would lead to glycosyl phosphonates, a class of hydrolytically stable glycosyl phosphate mimics reported to be of considerable importance as enzyme inhibitors.
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Model reaction
Run Eq. of 2 Time Solvent Yield (3a)
1 2.0 60 min MeOH <6%
2 5.0 60 min MeOH <20%
3 5.0 30 min neat 40%
4 20 30 min neat 46%
5 40 30 min neat 43%
6 100 30 min neat 91%
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Mechanism and Byproducts
• With small excess of H-phosphonate the radical intermediate is not able to break a P-H bond, so some other species (also polimers) are found in the crude mixture.
• Increasing the excess and removing the solvent this problem has been successfully overcome
• No Markovinkov product has been found• The pure product was isolated simply by vacuum distillation of
excess of H-phosphonate and filtration of the resulting residue through a short column of silica gel
O
OAcAcO
AcO
AcO
P(OCH3)2O
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Results
Galactose
Mannose
Glucose
N-Ac-Glucosamine
Sugar Alkene Product Yield [%]
91
91
90
94
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Results
Galactose-6,7-ene
5-exo-glucal
1-exo-glucal
Sugar Alkene Product Yield [%]
92
98
45
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1-Exo-glucal: a problematic case
OAcO
AcO
AcO
OAc
DPAP h
(MeO)2P(O)H OAcO
AcO
AcO
OAc
P
O
OMeOMe
OAcOAcO
OAc
AcO O
OAcOAcO
OAc
P
O
OMeOMe
OAc
Changing conditions is not effective in yield terms, the 2 byproducts are always found in
different ratio, the standard conditions give the best yield.
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Conclusions• Free-radical hydrophosphorilatyon is
promising as an efficient metal-free funcionalization tool
• Mild and neutral conditions enable the introduction of the phosphonate group in biomolecules
• Total atom economy• Total 1,2-regioselectivity to give
exclusively the anti-Markovnikov addition product
• The radical mechanism, similar to the photoinduced thiol-ene coupling one, is confirmed
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AcknowledgementsUniversità di Ferrara Dipartimento di Scienze Chimiche e Farmaceutiche
Ecole Nationale Superieure de Chimie Montpellier
And all of you for your attention!
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Broadening the library
O
OO
O
O
O
OO
O
O
O
OO
O
OOxalyl clorideDMSO / TEA -78°C -> -60°C
DCMdry 75%
MePPh3BrBuLi
THF dry35%
HO O
O
OMe
AcO
AcO
AcOO
OMe
HO
OH
HO
OH
O
OMe
AcO
AcO
AcO
IPPH3
imidazoleI2
Toluene52%
DBU
Toluene110°C30%
5-exo-glucal
Galacto-6,7-ene
O
OH
HO
HO
OH
O
OH
HO
HO
OH
POOH
OH
H. H Lee, P. G Hodgson, R. J Bernacki, W. Korytnyk, M. Sharma Carbohydr. Res. 1988, 176, 59-72.
C. McDonnell, L. Cronin, J. L O'Brien, P. V. Murphy J. Org. Chem. 2004, 69, 3565-3568
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Broadening the library
O
O
HO
HO
HO
OH
O
O
TESO
TESO
TESO
OTESTES-ClDIPEA
DCMPyr90%
N
SS CH3
O
O
LiHMDS / THF
DBU / THF
OAcO
AcO
AcO
OAc
TBAF / THF Ac2O / Pyr
60%
OTESO
TESO
TESO
OTES
S
OH
O
ON
S
O
CH2
TESO
TESO
TESO
OTES
O
CH2
HO
HO
HO
OH
D. Goyard, S. M. Telligmann, C. Goux-Henry, M. M. K. Boysen, E. Framery, D. Gueyrard, S. Vidal Tetrahedron Lett. 2010, 51, 374-377
1-exo-glucal
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The further step
RP
O
OMe
OMeP
O OMe
MeOR
P
O
OMe
OMe
R (MeO)2PH
O(MeO)2PH
O
R1S
R2 R1S
R2
SR1
R1S
R1SH
R1S
R2
R1SH
R1S
R2
SR1R2
(R1O)2(O)PR2
(R1O)2(O)PH (R1O)2(O)PR2
R2
(R1O)2(O)PH2(R1O)2(O)PR2
P(O)(OR1)2
(R1O)2(O)PH(R1O)2(O)PR2
P(O)(OR1)2
• Will hydrophosphonylation of alkynes be effective as thiol-yne?
• With 100eq of phosphonate will not be possibile to isolate the double bond intermediate.