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.