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