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.

[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(-)MeDUPHOS ,727 MeOD200/1(-)MeDUPHOS ,10 MeOH200/1R-PROLOPHOS ,975 MeOD200/1R-PROLOPHOS72 69,311 D-Histidine Unnatural labelled carnosine Unnatural labelled carnosine I_Synthesis of histidine and deuterium labelled histidine

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

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

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, HClO 4 4,7710,373,0086,591,196, CH 3 SO 3 H 1,716,022,2692,693,796, CF 3 SO 3 H 4,5712,5118,7883,991,195, 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

Cryst.Yield %e.e. %Total yield , , ,955,3 368,799, >99,935,7 FURTHER CRYSTALLIZATIONS

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?

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

BINAP BDPP ZEDPHOS DPEN AMPY PANDA

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