research talk montpellier 28 november 2013
TRANSCRIPT
Free-Radical Hydrophosphonylation of alkynes
PhD Student: Samuele StaderiniSupervisor: Prof. Alberto Marra
Glycochemistry and molecular recognition team Group Meeting -
Research TalkNovember 28th 2013
Earlier this year…
RSR'
R'
RSR'
R S
R SH
R'
R'
(RO)2P
O
(RO)2PH
O
(RO)2P
O
R'(RO)2P
O
Dondoni A., Staderini S., Marra A. Eur. J. Org. Chem. 2013, 5370–5375
A study on radical addition of H-phosphonates to terminal alkenes have been reported
Earlier this year…
Results summary
The further step
R1S
R2 R1S
R2
SR1
R1S
R1SH
R1S
R2
R1SH
R1S
R2
SR1
R2
(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
From thiol-yne to hydrophosphonylation of alkynes
?
Preliminary studies
The 2 alkenes are separable on silica and
they have really peculiar NMR signals for the double bond
protons.In fact there’s a J
coupling also with the near phosphorus.
O
AcO
AcOOAc
OAc
OO
AcO
AcOOAc
OAc
O P
O
OMeOMeDPAP / h
min
(MeO)2PH 100 eq
O
Yield 93%E/Z ratio after
chromatography 1/1
E
Z
The intermediate
Could the vinyl phosphonates
be good starting material for a
second coupling with a thiol?
OAcO
AcO
AcO
OAc
OOAcO
AcO
AcO
OAc
O
P OMe
OMeO
OAcO
AcO
AcO
OAc
O P OMe
O
OMe(MeO)2P(O)H
DPAP h
neat
Lo Conte M., Staderini S., Marra A., Sanchez-Navarro M.,Davis B. G., Dondoni A. Chem. Commun., 2011, 47, 11086–1108811
The 2nd step: thiol-ene
O
AcO
AcOOAc
OAc
O P
O
OMeOMe
O
AcO
AcOOAc
OAc
O
PO OMeOMe
OSHHOHO
OH
OH
DPAP / h minMeOH
OSHHOHO
OH
OH
DPAP / h minMeOH
E
Z
O
AcO
AcOOAc
OAc
O P
O
OMeOMe
E
O
AcO
AcOOAc
OAc
O P
O
OMeOMe
E
2 eq
2 eq
Trying to use thiol-ene on the 2 alkenes obtained with the hydrophononylation no addition was observed;
actually only the E alkene was found as product both starting from Z and from E.
Mechanism of isomerization
O
AcO
AcOOAc
OAc
O
PO OMeOMe
Z
MeOH
No isomerization
MeOH
DPAP / h min
h min
-terpinene / DPAP / RSH
MeOH / h30 min
-terpinene
Various reactions have been carried out to understand the mechanism of the isomerization: Both in the first 2
cases, without thiol, and in the third, with a radical inhibitor, no isomerization has been found.
Mechanism of isomerization
Thiols tested:• Glucose-SH• Thiophenol• Ter-butylthiol
R
P
O
OMe
OMe
R'SH / Base
Michael Addition:Ionic mechanism R
P
O
OR'
OR' R
O
OR'
No additionNo isomerization
Bases tested:• DBU• Triethylamine
OHO
OH
SH
OH
HO
SH SH
N
N
N
Mechanism of isomerization
The radical on the thiol is formed and this attack the double bond to form the intermediate. This one can rotate to form the more stable alkene, that clearly is the E. Probably the intermediate is not able to react with a second thiol to close the cycle and this drive
“back” the reaction to the double bond.
R
P
O
OMe
OMeR
P
O
OMe
OMe
R'S S
R'
- R'S
R
P
O
OMe
OMe
E/Z 50/50 E/Z 95/5
All these evidences drive to a radical mechanism
Thiol tested1. glucose thiol2. N-acetyl-
glucosamine thiol3. thiophenol4. p-Me-thiophenol5. 2-mercapto-ethanol6. ethanthiol7. ter-butyl thiol8. cysteine9. cysteine-OMe-N-BOC10.thioglycerol
Reaction optimization
P
O
OMeOMe
DPAP / h
(MeO)2PH
OO
SHHO
HO
OH
OH
DPAP / hMeOH
P
O
OMeOMe
EE/Z 1:1
100 eq
Simple model: cycloexylacetyleneFocusing on the 2nd step• Thiol as catalyzer• Reaction time• Isomerization on
the raw product
3. thiophenol4. p-Me-thiophenol5. 2-mercapto-ethanol6. ethanthiol
Thiol tested
Reaction optimization
Initial E/Z ratio
Thiol Thiol eq Reaction time
Final E/Z ratio
50/50 glucose-SH
0,3 30 min 70/30
50/50 glucose-SH
0,5 30 min 80/20
50/50 glucose-SH
1,0 30 min 90/10
50/50 Me-cys-BOC
0,5 30 min 85/15
50/50 gluNAc-SH 0,5 30 min 85/15
P
O
OMe
OMeDPAP / h
MeOH
P
O
OMe
OMethiol
Reaction optimization
Initial E/Z ratio
Thiol Thiol eq Reaction time
Final E/Z ratio
0/100 glucose-SH
0,5 30 min 80/20
0/100 glucose-SH
1 30 min 95/5
0/100 glucose-SH
1 60 min 95/5
P
O
OMe
OMeDPAP / h
MeOH
P
O
OMe
OMethiol
Reaction optimization
Initial E/Z ratio
Thiol Thiol eq Reaction time
Final E/Z ratio
50/50 cysteine 1 60 min 95/5
50/50 cysteine 1 120 min 95/5
50/50 cysteine 2 60 min 95/5
P
O
OMe
OMeDPAP / h
MeOH
P
O
OMe
OMethiol
Final standard procedure
R RP
O
OMeOMeDPAP / h
min
(MeO)2PH
O
DPAP / hMeOH60 min
RP
O
OMeOMe
EE/Z 1:1
100 eq 1 eqR'SH
Several alkynes have been tested in these conditions to obtain an all-around overview of the reactivity
Sugars
O
AcO OAc
O
OAc
AcO OO
OAc
OO
OAcAcO
AcO
OAcAcO
OAc
OAcO
OAc
AcO
AcO
OBnO
OBn
BnO
BnO
O
O
O
O
O
Final standard procedure
R RP
O
OMeOMeDPAP / h
min
(MeO)2PH
O
DPAP / hMeOH60 min
RP
O
OMeOMe
EE/Z 1:1
100 eq 1 eqR'SH
Several alkynes have been tested in these conditions to obtain an all-around overview of the reactivity
Aliphaticmolecules
Aminoacids
MeO
OHN
O
O
S
Compound E/Z 1st step
Conditions 2nd step E/Z 2nd step Overall
Yield
50/50 1eq cys1h 95/5 78%
50/50 1eq cys1h 95/5 58%
50/50 1eq cys1h 95/5 83%
40/60(20% SM)
1,5 eq cys ??? ???
No addition have been founded on this substrate
50/50 1eq cys1h 95/5 92%
40/60 1eq cys
40/60 (crude)
100/0 (pure Z)
???
50/501eq
cysMeBOC1h
95/5 82%
OAcO
OAc
AcO
AcO
O
AcO OAc
O
OAc
AcO
OO
OAc
OO
OAcAcO
AcO
OAcAcO
OAc
O
O
O
O
O
OBnO
OBn
BnO
BnO
MeO
OHN
O
O
S
Conclusions
Big difference in reactivity between thiols and phosphonates and terminal alkynes.
Radical cycle is stopped after first addition (Mixture of alkenes).
A second addition with thiols is not possible. In these conditions alkenes equilibration takes place and E alkene is usually obtained almost pure.
Conclusions
Not all the thiols are able to equilibrate alkenes mixture.
In standard condition different alkynes can react differently with H-phosphonate and with thiols to give mixtures with different E/Z ratio both in 1st step and in 2nd.
Merci beaucoup pour votre attention et j’attende vous en
Italie!!!
Why shall pass from one to two?
Glucose-1-phosphate
Glucose-6-phosphate
O
OHHO
HOHO
O P
O
OHOH
O
O
HO
HOHO
OH
P
O
OH
OH
Phosphonates: class of phosphorous derivatives that bear their own importance
as phosphate isosteres or isopolar
analogues.
P
R
P
R'O O
OH
OHOH
HO
P
NH
P
R'O O
OH
OHOH
HO
R
Nitrogenous bisphosphonates
Non nitrogenous bisphosphonates
Bisphosphonates: used to treat
osteoporosis, bone metastasis, multiple myeloma and other conditions involving fragile, breakable
bone.
Why shall pass from one to two?
P
R
P
R'O O
OH
OHOH
HOP
NH
P
R'O O
OH
OHOH
HO
R
Nitrogenous bisphosphonates
Non nitrogenous bisphosphonates
Bisphosphonates: used to treat
osteoporosis, bone metastasis, multiple myeloma and other conditions involving fragile, breakable
bone.
P
P
R
O
OR'
OR'
O
R'O
OR'R
2 (MeO)2PH
O
If the hydrophosphonylation of alkynes reacts as
the thiol-yne, we’ll obtain this kind of
molecules, that could be interesting for
structure-activity relation studies.