universita’ degli studi di milano phd in chemical sciences xxii cycle
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UNIVERSITA’ DEGLI STUDI DI MILANOPhD IN CHEMICAL SCIENCES
XXII CYCLE
Daniele Sergio ZERLA
Matr. R07227Tutor: Chiar.mo Prof. E.CESAROTTI
Natural and unnatural aminoacids by catalytic reduction
with Rh(I)-diphosphine complexes; role of strong acids
in the synthesis of deuterium labelled histidine.
NH
NCOOMe
NHCOPh
DH
NH
NCOOMe
NHCOPh
[PP(Rh)COD]+ClO4
-
Solv. HBF4
D2
+NH
NCOOMe
NHCOPh
DD
O
O PPh2
PPh2
(S,S)-DIOP
P
P
(R,R)-Me-DUPHOS
PPh2
PPh2
(S,S)-BDPP
N O PPh2
PPh2
(R)-PROLOPHOS
Solv. S/C CatalystTime (h)
Yield
e.e.%
DH %
MeOH 1000/1 (-)MeDUPHOS 72 12 n.d. 40
MeOH 200/1 (-)MeDUPHOS 72 100 87,7 27
MeOD 200/1 (-)MeDUPHOS 72 100 89,1 0
MeOH 200/1 R-PROLOPHOS 72 100 67,9 75
MeOD 200/1 R-PROLOPHOS 72 72 69,3 11
NH
NCOOMe
NHCOPhNH
NCOOMe
NHCOPh
DD
NH
NCOOH
HN
DD
O
NH2
D-HistidineD-Histidine Unnatural labelledcarnosine
Unnatural labelledcarnosine
I_Synthesis of histidine and deuterium labelled histidineI_Synthesis of histidine and deuterium labelled histidine
ACIDSACIDS
hydrogenation
hydrogenation
deuterationdeuteration
HBF4HBF4
HClO4HClO4 CH3SO3HCH3SO3H
CF3SO3HCF3SO3H
Different ligandsDifferent ligands Different solventDifferent solvent
Different substrate/acidmolar ratio
Different substrate/acidmolar ratio
II_Use of different strong non coordinating acids in the synthesis of histidine by asymmetric catalytic reduction
II_Use of different strong non coordinating acids in the synthesis of histidine by asymmetric catalytic reduction
TOF (h-1) e.e. %
Ligand
S/acid acid
1/4 1/8 1/4 1/8
Me-DUPHOS
HBF4 5,3 12,3 80,9 94,4
HClO4 16,9 11,5 83,9 90,1
CH3SO3H 5,5 2,9 97,7 99,0
CF3SO3H 24,7 27,1 99,9 93,6
PROLOPHOS
HBF4 12,4 44,8 71,3 71,8
HClO4 17,3 14,9 55,2 31,7
CH3SO3H 10,5 11,1 71,9 43,3
CF3SO3H 10,3 31,9 18,5 23,6
HN
N
COOMe
NHCOPh
HN
N
COOMe
NHCOPh
[PP(Rh)COD]+ClO4-
CH3OH H2n acid
HYDROGENATIONHYDROGENATION
DEUTERATIONDEUTERATION
Solv. AcidoTOF(h-1) e.e. % HD %
1/4 1/8 1/12 1/4 1/8 1/12 1/4 1/8 1/12
CH3OH
HBF4 10,12 6,08 15,64 87,7 95,7 97,8 41 43 5
HClO4 4,77 10,37 3,00 86,5 91,1 96,0 45 42 21
CH3SO3H 1,71 6,02 2,26 92,6 93,7 96,8 47 40 33
CF3SO3H 4,57 12,51 18,78 83,9 91,1 95,9 43 33 81
CH3OD
HBF4 5,85 19,16 18,39 89,1 93,6 94,9 0 0 0
HClO4 18,75 3,5 11,08 95,6 93,5 94,3 0 0 0
CH3SO3H 4,61 1,02 0,98 93,8 98,0 97,2 0 0 0
CF3SO3H 35,68 28,63 34,64 94,0 96,2 98,5 0 0 0
HN
N
COOMe
NHCOPh
HN
N
COOMe
NHCOPh
[PP(Rh)COD]+ClO4-
solventn acid
D2
D D HN
N
COOMe
NHCOPh
D
+
HDD2
Cryst.
Yield % e.e. % Total yield
0 100 67,6 100
1 70 79,7 70
2 79 95,9 55,3
3 68,7 99,4 38
4 94 >99,9 35,7
FURTHER CRYSTALLIZATIONSFURTHER CRYSTALLIZATIONS
0
20
40
60
80
100
120
0 1 2 3 4 5
cryst.
e.e. %
total yield
HN
N
COOMe
NHCOPh
HN
N
COOMe
NHCOPh
[BDPP(Rh)COD]+ClO4-
CH3OH H24 HBF4
PRECIPITATION DURING REACTIONPRECIPITATION DURING REACTION
HN
N
COOMe
NHCOPh
0.05 M methanol solution0.05 M methanol solution
CH3OH or CH3ODH2 or D2
CH3OH or CH3ODH2 or D2
HBF4 or HClO4HBF4 or HClO4
HN
NH
COOMe
NHCOPhX-
Optically pure productas white solid salt
(45-55% yield)
Optically pure productas white solid salt
(45-55% yield)
Is the catalystactive after reaction?
Is the catalystactive after reaction?
RECYCLE OF CATALYSTRECYCLE OF CATALYST
H2 or D2H2 or D2
Solution containing catalyst
Solution containing catalyst
Catalyst solution was recycled 5 time without loss of
enantioselectivity
Catalyst solution was recycled 5 time without loss of
enantioselectivity
Yes, the catalyst was still active after first reactionYes, the catalyst was still active after first reaction
RuP
P Cl
N
Cl
N
N
NH2
H2N NH2
Ph Ph
N
N
NH2
Ph
Ph
Ph
PPh2
PPh2
PPh2PPh2
PPh2PPh2
BINAPBINAP
BDPPBDPP
ZEDPHOSZEDPHOS
DPENDPEN
AMPYAMPY
PANDAPANDA
R' R
O
OH O
Cat*, baseR' R
OH
*
R
O
OH O
Cat*, baseR
OH
*
Asymmetric Transfer Hydrogenation (ATH) of simple ketones Asymmetric Transfer Hydrogenation (ATH) of simple ketones catalysed by Ru(II)/diphosphine/diamine complexescatalysed by Ru(II)/diphosphine/diamine complexes
H2N
NH2
N
NH2
N
N
PhPh
Ph
H2N
DPEN ampy PANDA
P
CH3
PH3C
(R,R)-ZEDPHOS
P
CH3
PH3C
(R,R)-Xilyl-ZEDPHOS
PPh2
PPh2
(S,S)-BDPP
catalyst e.e.% TOF (h-1)
(R,R)-ZedPhosRuCl2(R,R)DPEN 65% 2370
(R,R)-ZedPhosRuCl2ampy 78% 10740
(R,R)-Xilyl ZedPhosRuCl2ampy 87% 7250
(R,R)-ZedPhosRuCl2PANDA 7% 450
(S,S)BDPPRuCl2PANDA 10% 32
DIAMINEDIAMINE
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