1. UNIVERSITA’ DEGLI STUDI DI MILANO PhD IN CHEMICAL SCIENCES XXII CYCLE Daniele Sergio ZERLA Matr. R07227 Tutor: 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.

2. [PP(Rh)COD] + ClO 4 - Solv. HBF 4 D 2 + Solv.S/CCatalyst Time (h) Yield e.e. % DH % MeOH1000/1(-)MeDUPHOS7212n.d.40 MeOH200/1(-)MeDUPHOS7210087,727 MeOD200/1(-)MeDUPHOS7210089,10 MeOH200/1R-PROLOPHOS7210067,975 MeOD200/1R-PROLOPHOS72 69,311 D-Histidine Unnatural labelled carnosine Unnatural labelled carnosine I_Synthesis of histidine and deuterium labelled histidine

3. ACIDS hydrogenation deuteration HBF 4 HClO 4 CH 3 SO 3 H CF 3 SO 3 H Different ligands Different solvent Different substrate/acid molar ratio Different substrate/acid molar 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

4. TOF (h -1 )e.e. % Ligand S/acid acid 1/41/81/41/8 Me-DUPHOS HBF 4 5,312,380,994,4 HClO 4 16,911,583,990,1 CH 3 SO 3 H5,52,997,799,0 CF 3 SO 3 H24,727,199,993,6 PROLOPHOS HBF 4 12,444,871,371,8 HClO 4 17,314,955,231,7 CH 3 SO 3 H10,511,171,943,3 CF 3 SO 3 H10,331,918,523,6 HYDROGENATION

5. DEUTERATION Solv.Acido TOF(h -1 )e.e. %HD % 1/41/81/121/41/81/121/41/81/12 CH 3 OH HBF 4 10,126,0815,6487,795,797,841435 HClO 4 4,7710,373,0086,591,196,0454221 CH 3 SO 3 H 1,716,022,2692,693,796,8474033 CF 3 SO 3 H 4,5712,5118,7883,991,195,9433381 CH 3 OD HBF 4 5,8519,1618,3989,193,694,9000 HClO 4 18,753,511,0895,693,594,3000 CH 3 SO 3 H 4,611,020,9893,898,097,2000 CF 3 SO 3 H 35,6828,6334,6494,096,298,5000

6. Cryst.Yield %e.e. %Total yield 010067,6100 17079,770 27995,955,3 368,799,438 494>99,935,7 FURTHER CRYSTALLIZATIONS

7. PRECIPITATION DURING REACTION 0.05 M methanol solution CH 3 OH or CH 3 OD H 2 or D 2 CH 3 OH or CH 3 OD H 2 or D 2 HBF 4 or HClO 4 Optically pure product as white solid salt (45-55% yield) Optically pure product as white solid salt (45-55% yield) Is the catalyst active after reaction? Is the catalyst active after reaction?

8. RECYCLE OF CATALYST H 2 or D 2 Solution containing catalyst Solution containing catalyst Catalyst solution was recycled 5 time without loss of enantioselectivity Yes, the catalyst was still active after first reaction

9. BINAP BDPP ZEDPHOS DPEN AMPY PANDA

10. Asymmetric Transfer Hydrogenation (ATH) of simple ketones catalysed by Ru(II)/diphosphine/diamine complexes DPEN ampy PANDA catalyste.e.%TOF (h -1 ) ( R,R )-ZedPhosRuCl 2 ( R,R )DPEN65%2370 ( R,R )-ZedPhosRuCl 2 ampy78%10740 ( R,R )-Xilyl ZedPhosRuCl 2 ampy87%7250 ( R,R )-ZedPhosRuCl 2 PANDA7%450 (S,S)BDPPRuCl 2 PANDA10%32 DIAMINE