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

samuele.staderini@unife.it

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

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

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

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

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.

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%

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

Results

Galactose

Mannose

Glucose

N-Ac-Glucosamine

Sugar Alkene Product Yield [%]

91

91

90

94

Results

Galactose-6,7-ene

5-exo-glucal

1-exo-glucal

Sugar Alkene Product Yield [%]

92

98

45

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.

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

AcknowledgementsUniversità di Ferrara Dipartimento di Scienze Chimiche e Farmaceutiche

Ecole Nationale Superieure de Chimie Montpellier

And all of you for your attention!

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

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

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.