Cp*Ru(PN) - PowerPoint PPT Presentation

キラ ル Cp*Ru(PN) 錯体による 対称グルタ ルイ ミ ド 類の不斉水素化 （ 東工大院理工） 伊藤正人・ ○小林知佳・ 碇屋隆雄

Cp*Ru(II) & AMINE CATALYSTS FOR THE REDUCTION OF POLAR BONDS H 2 KO t- C 4 H 9 L L L Ru Ru Ru N N N H Cl H H 2 H 2 A-H + B-H A-B precursor 18e amine hydride Ru 16e amido Ru Me = CH 3 Ph = C 6 H 5 Me 2 Ph 2 N P L = NMe 2 L = PPh 2 Ru Ru N N Cl Cl H 2 H 2 Cp*Ru(NN) Cp*Ru(PN) effective for ketone effective for epoxide, etc Organometallics 2001, 20, 379-381 Organometallics 2003, 22, 4190-4192

HYDROGENATION USING Cp*Ru(ll)PN COMPLEXES O OH Cp*Ru(PN)Cl KO t -C 4 H 9 N CH 2 Ph NHCH 2 Ph + H 2 2-propanol O O The 82nd Annual Meeting of Chemical Society of Japan, 2002 Cp*Ru(PN*) O OH Cp*RuCl(PN*) KO t -C 4 H 9 Ph 2 H 2 NR + NHR R' R R' * P Ru O O N Cl H 2 The 83rd Annual Meeting of Chemical Society of Japan, 2003

ASYMMERTIC SYNTHESIS OF (-) − PAROXETINE AND (+) − FEMOXETINE O p -FC 6 H 4 Ar Ar O * O * HO N H 2 Cl O N N R R (-)-paroxetine HCl key intermediate MeO Ph O Ar N Me (+)-femoxetine O N O Hayashi, T. J. Org. Chem. 2001, 66, 6852-6856 R Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253-11258 Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204-11208

DESYMMETRIZATION OF GLUTARIC ACID DERIVATIVES With chiral base Ph Ph Ar Ar (1) N N Li Li CO 2 Me Ph Ph O (2) O N O O N O NC OMe R R 97% ee Gill, C. D. Tetrahedron 2003, 59, 9213 With pig liver esterase Ar Ar pig liver esterase MeO 2 C CO 2 Me HOOC CO 2 Me 95% ee Ar = p -FC 6 H 4 Ivan, L. Tetrahedron Lett. 2000, 41, 5647

HYDROGENOLYSIS OF VARIOUS GLUTARIMIDES Effect of N -substituents of imides O OH Cp*RuCl(PN) Cp*RuCl(PN) KO t -C 4 H 9 Ph 2 + H 2 N R NHR P 2-propanol 30 atm Ru O O N Cl S/C = 20, 18 h, [imide] = 0.2 M in 2-propanol, 80 ° C H 2 O O N Ar N CH 2 Ph O O Ar = 88% Ph : >99% conv p -CH 3 OC 6 H 4 : >99% p- NO 2 C 6 H 4 : >99%

HYDROGENOLYSIS OF N -BENZYL GLUTARIMIDES O OH Cp*RuCl(PN) R 1 R 1 KO t -C 4 H 9 H 2 + N CH 2 Ph NHCH 2 Ph R 1 R 1 2-propanol 30 atm R 2 R 2 O R 2 R 2 O S/C = 20, 18 h, 80 ° C, [imide] = 0.2 M in 2-propanol O O O p -C 6 H 4 N CH 2 Ph Me N CH 2 Ph Ph N CH 2 Ph O O O >99% a >99% conv a >99% a O O O CH 3 CH 2 Me N CH 2 Ph N CH 2 Ph N CH 2 Ph Me Me Me O O O Me a S/C = 100 >99% 49% >99%

ASYMMETRIC HYDROGENOLYSIS OF IMIDES O OH Cp*RuCl(PN*) Cp*RuCl(PN*) KO t -C 4 H 9 Ar N R + H 2 Ar NHR * Ph 2 2-propanol P 30 atm 80 °C, 24 h O O Ru imide : Ru : base = 10 : 1: 1 N H Cl Ar = p -FC 6 H 4 [imide] = 0.2 M in 2-propanol O OMe O R = conv (%) a >99 >99 93 90 >99 ee (%) b 99 c 64 75 93 91 a Determined by 1 H NMR analysis c Temperature is 60 ° C b Determined by HPLC

SYNTHESIS OF CHIRAL PIPERIDINONE Ar Ar Ar ADDP Cp*RuCl(PN*) * * ( n -C 4 H 9 ) 3 P KO t -C 4 H 9 + H 2 2-propanol toluene O N O NH OH O N O O O O O O O 76% yield Ar = p -FC 6 H 4 >99% ee C 6 H 5 96% ee ORTEP FOR 3,4 & (METHYLENDIOXY)PHENYL GLUTARIMIDE P 2 1 (#4) R 1 = 0.048 R w = 0.121

SUMMARY O OH Cp*RuCl(PN) Cp*RuCl(PN) R R KO t -C 4 H 9 Ph 2 + H 2 N R NHR P 2-propanol 30 atm Ru O O N Cl S/C = 20, 18 h, [imide] = 0.2 M in 2-propanol, 80 ° C H 2 Ar Ar Ar Cp*Ru(PN*)Cl * * ADDP Ph 2 H 2 ( n -C 4 H 9 ) 3 P P O N O HO HN O N O Ru Cp*Ru(PN*)Cl N H KO t -C 4 H 9 Cl R R R up to 99% ee

PREPARATION OF SUBSTRATES ArB(OH) 2 ( 1.5 eq ) [RhCl(cod)] 2 (0.03 eq) CO 2 CH 3 CO 2 CH 3 KOH (2.2 eq) CH 3 COCl (C 2 H 5 ) 3 N (1.0 eq) Ar C 2 H 5 OH dioxane : H 2 O = 6 : 1 reflux CO 2 CH 3 CO 2 CH 3 >99% yield 84% yield 95% yield O O RNH 2 (1.0 eq) COOH CH 3 COCl (C 2 H 5 ) 3 N (1.0 eq) Ar O Ar NHR Ar N R reflux toluene reflux O O O up to 97% yield up to 94% yield

APPLICATION TO USEFUL ASYMMETRIC SYNTHESIS(1) Ar Ar Ar Ar O 3 Ru* cat ADDP * * NaH * ( n -C 4 H 9 ) 3 P 2 KO t -C 4 H 9 (CH 3 O) 2 CO CH 3 O 1 H 2 O N O O N O NH OH O N R R R R Ar = p -F-C 6 H 4 Ar Ar O * * Ar HO HO 1)CAN 1)Ar'OTs, Cs 2 CO 3 O BH 3 •THF O N N 2)CF 3 COOH 2)Boc 2 O N R Boc H 2 Cl O (-)-Paroxetine HCl Paxil / Seroxat O Ar' = by GlaxoSmith Kline Buchwald, S. L. J. Am.Chem. Soc. 2003, 125, 11253-11258

ORTEP FOR 3,4 & (METHYLENDIOXY)PHENYL GLUTARIMIDE O O O F N O 2 1 3 1 H NMR ( δ , CD 2 Cl 2 ) δ 7.27 (dd, 2H, J = 5.4, 8.8 Hz, FC 6 H 4 ) 7.12 (t, 2H, J = 8.8 Hz, FC 6 H 4 ) 6.87 (d, 1H, J = 8.6 Hz, NC 6 H 3 ) 6.55 (d, 2H, J = 7.2 Hz, NC 6 H 3 ) 6.03 (s, 2H, C 6 H 3 (OC H 2 O)) 3.55 (sep, 1H, J = 4.4, 4.4, 6.8 Hz, FC 6 H 4 C H) 3 2 1 3.11 (dd, 2H, J = 4.4, 16.3 Hz, C H 2 CON) 2.92 (dd, 2H, J = 11.3, 16.2 Hz, C H 2 CON) 1 & P 2 1 (#4) 13 C NMR ( δ , CD 2 Cl 2 ) 2 112.24 ° R 1 = 0.048 δ 171.6, 148.3, 147.8, 128.2, 128.1, 121.8, 116.0, 2 & 3 99.159 ° R w = 0.121 115.7, 109.2, 108.2, 102.1, 40.2, 34.1 3 & 1 13.578 ° Anal. Calcd. C 18 H 14 FNO 4 : C, 66.05; H, 4.31; N, 4.28. Found: C, 66.09; H, 4,34; N, 4.23%