Cp*Ru(PN) - - PowerPoint PPT Presentation
Cp*Ru(PN) Cp*Ru(II) & AMINE CATALYSTS FOR THE REDUCTION OF POLAR BONDS H 2
A-B A-H + B-H H2 KOt-C4H9
Cp*Ru(II)& AMINE CATALYSTS FOR THE REDUCTION OF POLAR BONDS
Ph = C6H5 precursor 16e amido Ru 18e amine hydride Ru L = NMe2 L = PPh2 Cp*Ru(PN) Cp*Ru(NN) Ru Cl Me2 N N H2 Ru Cl Ph2 P N H2 Me = CH3 Organometallics 2001, 20, 379-381 Organometallics 2003, 22, 4190-4192 effective for ketone effective for epoxide, etc Ru Cl L N H2 Ru L N H Ru H L N H2
The 83rd Annual Meeting of Chemical Society of Japan, 2003 N O O CH2Ph + H2 NHCH2Ph OH O Cp*Ru(PN)Cl KOt-C4H9
HYDROGENATION USING Cp*Ru(ll)PN COMPLEXES
2-propanol O O R' NR OH O * R' NHR Cp*RuCl(PN*) KOt-C4H9 + H2 Ru Cl Ph2 P N H2 R Cp*Ru(PN*) The 82nd Annual Meeting of Chemical Society of Japan, 2002
N H2Cl p-FC6H4 O O O (-)-paroxetine HCl N Ph Me O MeO (+)-femoxetine N
*
Ar O R N
*
Ar R HO key intermediate Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253-11258 N O O Ar R Hayashi, T. J. Org. Chem. 2001, 66, 6852-6856 Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204-11208
ASYMMERTIC SYNTHESIS OF (-)−PAROXETINE AND (+)−FEMOXETINE
(1) (2) N Ar O O N Ar O O CO2Me Ph N Li Ph N Ph Ph Li 97% ee With chiral base MeO2C CO2Me Ar HOOC CO2Me Ar pig liver esterase 95% ee With pig liver esterase Gill, C. D. Tetrahedron 2003, 59, 9213 Ivan, L. Tetrahedron Lett. 2000, 41, 5647 Ar = p-FC6H4 NC OMe O
DESYMMETRIZATION OF GLUTARIC ACID DERIVATIVES
R R
HYDROGENOLYSIS OF VARIOUS GLUTARIMIDES
H2 Cp*RuCl(PN) KOt-C4H9 + 2-propanol 30 atm S/C = 20, 18 h, [imide] = 0.2 M in 2-propanol, 80 °C Cp*RuCl(PN) Effect of N-substituents of imides N O O CH2Ph >99% conv N O O R NHR OH O N O O Ar Ph : p-CH3OC6H4 : p-NO2C6H4 : 88% >99% >99% Ar = Ru Cl Ph2 P N H2
N O O Me Me CH2Ph N CH3CH2 Me O O CH2Ph >99% S/C = 20, 18 h, 80 °C, [imide] = 0.2 M in 2-propanol 49%
HYDROGENOLYSIS OF N-BENZYL GLUTARIMIDES
N O O CH2Ph NHCH2Ph OH O + H2 Cp*RuCl(PN) KOt-C4H9 2-propanol 30 atm N O O CH2Ph N R1 R1 R1 R1 R2 R2 R2 R2 Me Me CH2Ph O O >99% N O O CH2Ph >99% conva >99%a
aS/C = 100
N O O CH2Ph >99%a Me Ph p-C6H4
O O 99c >99 OMe >99 93 90 75 93 91 >99 64 R = ee (%)b conv (%)a
aDetermined by 1H NMR analysis bDetermined by HPLC cTemperature is 60 °C
N R O O imide : Ru : base = 10 : 1: 1 [imide] = 0.2 M in 2-propanol + H2 30 atm 2-propanol 80 °C, 24 h Cp*RuCl(PN*) KOt-C4H9 * NHR OH O Ru Cl Ph2 P N H Cp*RuCl(PN*) Ar Ar
ASYMMETRIC HYDROGENOLYSIS OF IMIDES
Ar = p-FC6H4
SYNTHESIS OF CHIRAL PIPERIDINONE
H2 Cp*RuCl(PN*) KOt-C4H9 N O O
*
NH OH O Ar
*
N O Ar ADDP (n-C4H9)3P Ar + toluene Ar = p-FC6H4 >99% ee C6H5 96% ee 2-propanol 76% yield O O O O O O P21(#4) R1 = 0.048 Rw = 0.121 ORTEP FOR 3,4& (METHYLENDIOXY)PHENYL GLUTARIMIDE
Cp*Ru(PN*)Cl N Ar O O R HN
*
Ar HO O R Cp*Ru(PN*)Cl KOt-C4H9
SUMMARY
up to 99% ee Ru Cl Ph2 P N H N
*
Ar O R ADDP (n-C4H9)3P H2 H2 Cp*RuCl(PN) KOt-C4H9 + 2-propanol 30 atm S/C = 20, 18 h, [imide] = 0.2 M in 2-propanol, 80 °C Cp*RuCl(PN) N O O R NHR OH O Ru Cl Ph2 P N H2 R R
[RhCl(cod)]2 (0.03 eq) (C2H5)3N (1.0 eq) ArB(OH)2 ( 1.5 eq ) CO2CH3 CO2CH3 >99% yield O O O RNH2 (1.0 eq) (C2H5)3N (1.0 eq) toluene up to 97% yield reflux dioxane : H2O = 6 : 1 Ar CO2CH3 CO2CH3 KOH (2.2 eq) C2H5OH 84% yield CH3COCl reflux 95% yield N O O R CH3COCl reflux Ar Ar COOH O NHR up to 94% yield Ar
PREPARATION OF SUBSTRATES
(-)-Paroxetine HCl
APPLICATION TO USEFUL ASYMMETRIC SYNTHESIS(1)
Paxil / Seroxat by GlaxoSmith Kline Ar = p-F-C6H4 NH * O OH Ar R N O O Ar R Ru* cat KOt-C4H9 H2
1 2 3
N * O Ar R N * O Ar R CH3O O N * Ar R HO N * Ar Boc HO ADDP (n-C4H9)3P NaH (CH3O)2CO BH3
1)CAN 2)Boc2O Buchwald, S. L. J. Am.Chem. Soc. 2003, 125, 11253-11258 N H2Cl O O O Ar 1)Ar'OTs, Cs2CO3 2)CF3COOH O O Ar' =
1H NMR ( δ , CD2Cl2)
δ 7.27 (dd, 2H, J = 5.4, 8.8 Hz, FC6H4) 7.12 (t, 2H, J = 8.8 Hz, FC6H4) 6.87 (d, 1H, J = 8.6 Hz, NC6H3) 6.55 (d, 2H, J = 7.2 Hz, NC6H3 ) 6.03 (s, 2H, C6H3(OCH2O)) 3.55 (sep, 1H, J = 4.4, 4.4, 6.8 Hz, FC6H4CH) 3.11 (dd, 2H, J = 4.4, 16.3 Hz, CH2CON) 2.92 (dd, 2H, J = 11.3, 16.2 Hz, CH2CON) F N O O O O
ORTEP FOR 3,4& (METHYLENDIOXY)PHENYL GLUTARIMIDE
13C NMR ( δ , CD2Cl2)
δ 171.6, 148.3, 147.8, 128.2, 128.1, 121.8, 116.0, 115.7, 109.2, 108.2, 102.1, 40.2, 34.1
Found: C, 66.09; H, 4,34; N, 4.23% P21(#4) R1 = 0.048 Rw = 0.121 1 2 3 1 & 2 112.24° 2 3 1 2 & 3 99.159° 3 & 1 13.578°