1. 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, Italy
b) 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
samuele.staderini@unife.it

2. Hydrofunctionalization of terminal
alkenes
R' H-E R'
E
metal-based
catalyst
or radical
initiator
E = BR2, NR2, SiR2, SnR3,
SR, (O)P(OR'')2
R'
H
H E
Linear
(Anti-Markovnikov)
Branched
(Markovnikov)
RS
R'
R'
RS
R'
R S
R SH
Thiol-Ene
Useful 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

3. Hydrophosphonylation of
alkenes
Alkyl phosphonates obtained as products are important as
phosphate isosteres, isopolar analogues.
O
OH
OH
HO
HO
O
P
O
OH
OH
O
OH
OH
HO
HO
P
O
OH
OH
O
O
OH
HO
HO
OH
PO
OH
OH
O
OH
HO
HO
OH
PO
OH
OH

4. Hydrophosphonylation: a very
well-known reaction
 Michaelis-Arbuzov
reaction
 Transition-metal
catalysis
 Radical reactions
1. 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

5. 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

6. 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

7. 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%

8. 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)2
O

9. Results
Galactose
Mannose
Glucose
N-Ac-Glucosamine
Sugar Alkene Product Yield [%]
91
91
90
94

10. Results
Galactose-6,7-ene
5-exo-glucal
1-exo-glucal
Sugar Alkene Product Yield [%]
92
98
45

11. 1-Exo-glucal: a problematic
case
OAcO
AcO
AcO
OAc
DPAP h
(MeO)2P(O)H OAcO
AcO
AcO
OAc
P
O
OMe
OMe
OAcO
AcO
OAc
AcO O
OAcO
AcO
OAc
P
O
OMe
OMe
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.

12. 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

13. Acknowledgements
Università di Ferrara
Dipartimento di
Scienze Chimiche e
Farmaceutiche
Ecole Nationale
Superieure de Chimie
Montpellier
And all of you for your attention!

15. Broadening the library
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Oxalyl cloride
DMSO / TEA -
78°C -> -60°C
DCM dry 75%
MePPh3Br
BuLi
THF dry
35%
HO O
O
OMe
AcO
AcO
AcO
O
OMe
HO
OH
HO
OH
O
OMe
AcO
AcO
AcO
I
PPH3
imidazole
I2
Toluene
52%
DBU
Toluene
110°C
30%
5-exo-glucal
Galacto-6,7-ene
O
OH
HO
HO
OH
O
OH
HO
HO
OH
PO
OH
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

16. Broadening the library
O
O
HO
HO
HO
OH
O
O
TESO
TESO
TESO
OTES
TES-Cl
DIPEA
DCM
Pyr
90%
N
S
S CH3
O
O
LiHMDS / THF
DBU / THF
O
AcO
AcO
AcO
OAc
TBAF / THF Ac2O / Pyr
60%
O
TESO
TESO
TESO
OTES
S
OH
O
O
N
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

17. The further step
R
P
O
OMe
OMe
P
O OMe
MeO
R
P
O
OMe
OMe
R (MeO)2PH
O
(MeO)2PH
O
R1
S
R2 R1
S
R2
S
R1
R1
S
R1
SH
R1
S
R2
R1
SH
R1
S
R2
S
R1
R2
(R1O)2(O)P
R2
(R1O)2(O)PH (R1O)2(O)P
R2
R2
(R1O)2(O)PH2(R1O)2(O)P
R2
P(O)(OR1)2
(R1O)2(O)PH(R1O)2(O)P
R2
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.