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Glycochemistry and molecular recognition team Group Meeting -
Research Talk
Free-Radical Hydrophosphonylation of sugar alkenes
June 13th 2013
PhD Student:Samuele Staderini
Supervisor:Prof. A. Marra
Free-radical Hydrothiolation of alkenes and alkynes
Anti-Markovnikov selective reactions
hn
Thiol-ene Thiol-yne
Previous works
1
Study of protein – carbohydrate – fluorescein (or biotin) double coupling. 2 step different hydrothiolation of alkyne.
Lo Conte M., Staderini S., Marra A., Sanchez-Navarro M.,Davis B. G., Dondoni A. Chem. Commun., 2011, 47, 11086–1108811
Previous works
2Hydrothiolation of rigid scaffold for multivalent carbohydrate interactions with lectins
Lo Conte M., Staderini S., Chambery A., Berthet N., Dumy P., Renaudet O., Marra A., Dondoni A., Org. Biomol. Chem., 2012, 10, 3269
Previous works
3Complete hydrothiolation of alkyne clustes by carbohydrates and lectins binding evaluation
Marra A., Staderini S., Berthet N., Dumy P., Renaudet O., Dondoni A., Eur. J. Org. Chem 2013, 6, 1144-1149
Previous works
4
A method for the synthesis of a new family of 1-deoxy S-disaccharides has been established via free radical hydrothiolation of glycals
Staderini S., Chambery A., Marra A., Dondoni A., Tetrahedron Letters, 2012, 53, 702–704
Hydrophosponylation of alkenes
hn
Free-Radical hydrophosporylation of alkenes
Phosphonates: class of phosphorous derivatives that bear their own importance as phosphate isosteres or isopolar analogues.
Already available procedures• Hydrophosphonylation of alkenes
under transition-metal catalysis
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
• Radical reactions promoted by organic peroxides
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.
Glucose-1-phosphate
Glucose-6-phosphate
O
OHHO
HOHO
O P
O
OHOH
O
O
HO
HOHO
OH
P
O
OH
OH
Free-Radical hydrophosporilation of alkenes
Phosphonates: class of phosphorous derivatives that bear their own importance as phosphate isosteres or isopolar analogues.
Already available procedures
• Mn(OAc)2 in the presence of air
a) O. Tayama , A. Nakano, T. Iwahama, S. Sakaguchi, Y. Ishii, J. Org. Chem. 2004, 69, 5494-5496.
• Titanocene/epoxide system
a) C. Midrier, M. Lantsoght, J.-N. Volle, J.-L. Pirat, D. Virieux, C. V. Stevens Tetrahedron Lett. 2011, 52, 6693-6696.
Glucose-1-phosphate
Glucose-6-phosphate
O
OHHO
HOHO
O P
O
OHOH
O
O
HO
HOHO
OH
P
O
OH
OH
Thermal induced radical reactions
Photochemical method
Advantages: • Operationally simple• Inexpensive and commercially
available initiators • Afford exclusively linear anti-
Markovnikov adducts
Disadvantages:• No attention to complex
substrates• Severity of the conditions may
not be tolerated by delicate bioactive substrates
• Irradiation at room temperature • Wavelength close to visible light• Presence of small amounts of a suitable photoinitiator
Substrates
O
OH
HO
HO
HO
O P
O
OH
OH
OHO
HO
HO
OH
OP
O
OHHO
O
OH
HO
HO
HO
P
O
OH
OH
OHO
HO
HO
OH
P
O
OHHO
O
OH
HO
HO
HO
OHO
HO
HO
OH
Real isosters are obtainable starting from “particular” starting alkenes as 1-exo-glycals. At first we decided to use well known stable
molecules as models for optimization
O
OAc
AcOOAc
AcOO
OAc
AcO
AcOAcO
O
OAcAcO
AcO
AcOO
OAc
AcO
AcHNAcO
Substrates Synthesis
O
OAc
AcO
AcHNAcO
OAcO
GlucoseMannoseGalattose
N- Acetyl- Glucosamine
O
OH
HO
AcHNHO OH
O
OAc
AcO
AcHNAcO
Cl
AcOCl
SnBu3O
OAc
AcO
AcHNAcO
CH3CN60%
AIBN
>90%
NaH / BnBr
DMF
TMS
TMSOTfCH3CN
a) BCl3 / DCM /MeOH
b) Ac2O / Pyr / DMF
OAcOO
OMe
HOO
OMe
BnOO
BnO
70-80%>90% 55-60%
A. Giannis, K. Sandhoff Tetrahedron Lett. 1985, 26, 1479-1482
J. Cui, D. Horton Carbohydr. Res. 1998, 309, 319-330
Coupling reaction model
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%
7 100 9 hours neat 77%
Coupling reaction model
Low yield is due to the formation of a by-product (4) isolated by chromatography and, likely, polymers
Run Yield (3a) Product (4)
1 <6% ---
2 <20% ---
3 40% 12%
4 46% 25%
5 43% traces
6 91% ---
7 77% ---
The radical intermediate can react both with (MeO)2P(O)H to take a proton or with the terminal alkene of the sugar producing “dimers” and “polymers”.
In fact increasing equivalent of (MeO)2P(O)H we drive reaction in the first way playing with probabilities.
O
OAcAcO
AcO
AcO
P(OCH3)2O
J. M. Barks, B. C. Gilbert, A. F. Parsons, B. Upeandran, Tetrahedron Lett. 2001, 42, 3137-3140.
Coupling reaction model
Optimized conditions• 100 eq. of (MeO)2PHO• No solvent • 0,5 eq of DPAP
Pure product was isolated simply by distillation of the excess of H-phosphonate and filtration of the residue through a short column of silica to remove residual DPAP.
• Recovering the phosphonylating agent make this process highly sustainable and very likely scalable to multigram quantities
• UVA lamp furnishes low energy light (lmax 365 nm) which is known to leave unaltered even sensitive biomolecules such as carbohydrates and proteins
Glycosilalkyl phosphonatesThe others three allyl C-glycosides, i. e. the peracetylated mannose,
glucose and 2-acetamido-glucose derivatives 1b, 1c, and 1d respectively, were reacted with dimethyl H-phosphonate 2 under optimized conditions
Deprotection procedure
To finish this part of the project, the complete deprotection of the model alkene-phosphonate (galattose) has been optimized in a
two-step-one-pot procedure.
Galattose alkene synthesis
O
OO
O
OO
OO
HO
O
O
O
OO
O
O
OOxalyl clorideDMSO / TEA -78°C -> -60°C
DCM dry 75%
MePPh3BrBuLi
THF dry35%
H. H Lee, P. G Hodgson, R. J Bernacki, W. Korytnyk, M. Sharma Carbohydr. Res. 1988, 176, 59-72.
O
OMe
AcO
AcO
AcOO
OMe
HO
OH
HO
OH
O
OMe
AcO
AcO
AcO
IPPH3
imidazoleI2
Toluene52%
DBU
Toluene110°C30%
C. McDonnell, L. Cronin, J. L O'Brien, P. V. Murphy J. Org. Chem. 2004, 69, 3565-3568
5-exo-glycal synthesis
1-exo-glycal synthesis
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
Results
45
98
1-exo-glycal: a problematic case
1-exo-glucal has given us troubles, in fact the different reactivity and stability of this enol-ether drive coupling in some other wrong ways.
In standard conditions (0.5 eq DPAP, 30 min
irradiation) an adduct of DPAP and glucose is
found after purification
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
Decreasing DPAP to 0.1 eq only starting material (40%) and an unknown compound were found.
?Structure supposed by mass
data and NMR spectra
1-exo-glycal: a problematic case
1-exo-glucal has given us troubles, in fact the different reactivity and stability of this enol-ether drives coupling in some other wrong ways.
OAcO
AcO
AcO
OAc
DPAP h
(MeO)2P(O)H OAcO
AcO
AcO
OAc
P
O
OMeOMe
OAcOAcO
OAc
AcO O
Moving up to 0.3 eq of DPAP the good product (45%), starting material and DPAP adduct have
been found.
A reaction have been carried out without UV light and DPAP. After 1h at RT no starting materials and no good product were present. The formation of DPAP adduct is no easily evitable, because reducing DPAP equivalents the “rearragend” product appears. The best conditions are found to be with 0.5 eq of DPAP, 1h of irradiation and a distilled phosphonate.
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
Perspectives
• Could the equivalent reaction of thiol-yne coupling be carried out with phosphonates?
OAcO
AcO
AcO
OAc
OOAcO
AcO
AcO
OAc
O
P OMe
OMeO
OAcO
AcO
AcO
OAc
O P OMe
O
OMe(MeO)2P(O)HDPAP h
neat
Reaction with a propargyl glucoside and dimethyl phosphonate (100 eq) give a mixture of the two alkenes (Z and E). No double addition is found. The purification of two stereoisomers is quite easy. Repetition of this reaction on different substrates (i.e. lactose) gave the same result; as the phosphonate is less reactive on terminal double bond, it is completely unreactive with internal double bond.
Z E
• Could the alkenes-phosphonates be good starting material for a second coupling with a thiol?
Perspectives
• Could the alkenes-phosphonates be good starting material for a second coupling with a thiol?
First reaction carried out with gluco-SH have surprisingly gave the isomerization without traces of double addition product. To study this very particular case a set of reactions with the same substrates but different kind of thiols have been run. In both cases aromatic (MePhSH) and aliphatic (ethan-thiol) thiols gave no isomerization or coupling . Only using sugar thiol isomerization is effective.
Work in progress
OAcO
AcO
AcO
OAc
O
P OMe
OMeO
OAcO
AcO
AcO
OAc
O P OMe
O
OMeOHO
OHHO
OH
SH
DPAPMeOH
Perspectives – to do
• Generalize the mechanism of isomerization• Confirm the role of thiols in it• Study different model of thiol (sugar mimic, cyclic aliphatic
thiols) and different model of substrates (no sugars)• Try reverse addition: thiol first, phosphonate second• Try double addition on nitrile group
Work in progress
Exo-Glycals
Following step has been to move to glycals and different kind of sugars, like the real isoster of 6-phosphates.
O
OHHO
HOHO
O P
O
OHOH
O
O
HO
HOHO
OH
P
O
OH
OH
O
OHHO
HOHO
P
O
OHOH
OHO
HOHO
OH
P
O
OH
OH
O
OHHO
HOHO
OHO
HOHO
OH
O
OHHO
HOHO
O
OHHO
HOHO
P
OH
OHO
O
OAcAcO
AcOAcO
P(OCH3)2O
O
OAcAcO
AcO
AcO
O
OAcAcO
AcO
AcO
P(OCH3)2O
OOAcAcO
AcOAcO
Titanocene – epoxide radical mechanism
It had been shown early on that phosphinoyl and phosphonyl radicals were non planar and as a result had a variable degree of s-character.
M. Geoffroy, E. A. C. Lucken, Mol. Phys., 1971, 22, 257.C. M. L. Kerr, K. Webster, F. Williams, J. Phys. Chem., 1975, 79, 2650
In general, the more bent the radical, the faster its addition onto olefins
Quest for radical mediator
Tributyltin hydride: useful, this compound is toxic and its by-products are difficult to remove from reaction mixtures.
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