M.C. White/MS. Taylor Chem 153 Hydrogenation-161 Week of october 21. 2002 Substrate-directed hydrogenations with cationic complexes (PF6) CH3 OH CO,Et OTBDPS OTBDPS OTBDPS 60: 40 anti: 65:35 PPh PhaP It was observed experimentally (and may have been predicted )that In contrast, hydrogenation with the cationic iridium hydrogenation of the enantiomerically enriched homoallylic alcohol CH3 OH complex Ir(cod)(pyr)(PCy3)]PF6 favored the formation with the neutral catalyst complex(Ph3 P)RhCI produced a 1: I of the mixture of diastereomeric products. Use of the cationic complex Rh(cod dppb )BF4 led to a preference, albeit small, for the COEt formation of the anti hydrogenation product. OTBDPS 50: 50 anti: svn Du bois JACS 2002. ASAP. Oct. 2002 fotf CH3 OH (5 mol%) COEt COEt OTBDPS OTBDPS OTBDPS >95: 5 ant: syn 75: 25 syn: anti General conditions. H2(1000),CH2Cl2t The use of chiral bidentate phosphine ligands 0 CH3 CO,H akes it possible to reinforce or partially override substrate bias CH3 CO2H Manzacidin c Manzacidin a
M.C. White/M.S. Taylor Chem 153 Hydrogenation -161- Week of October 21, 2002 Substrate-directed hydrogenations with cationic complexes It was observed experimentally (and may have been predicted) that hydrogenation of the enantiomerically enriched homoallylic alcohol with the neutral catalyst complex (Ph3P)3RhCl produced a 1:1 mixture of diastereomeric products. Use of the cationic complex Rh(cod)(dppb)BF4 led to a preference, albeit small, for the formation of the anti hydrogenation product. In contrast, hydrogenation with the cationic iridium complex Ir[(cod)(pyr)(PCy3)]PF6 favored the formation of the syn isomer. CO2Et OTBDPS CH3 OH CO2Et OTBDPS OH HN N O N H O CO2H CH3 Br P P Rh Et Et Et Et +OTf +OTf HN N O N H O CO2H CH3 Br CO2Et OTBDPS CH3 OH >95:5 anti:syn 75:25 syn:anti Manzacidin C Manzacidin A (5 mol%) (5 mol%) General conditions: H2 (1000psi), CH2Cl2, rt The use of chiral bidentate phosphine ligands makes it possible to reinforce or partially override substrate bias. Rh PP Du Bois JACS 2002, ASAP, Oct., 2002. CO2Et OTBDPS CH3 OH (PF6-) Ir(I) PCy3 N CO2Et OTBDPS OH (BF4-) Rh(I) Ph2 P P Ph2 CO2Et OTBDPS CH3 OH Ph3P Rh(I) Ph3P PPh3 Cl CO2Et OTBDPS CH3 OH 50:50 anti:syn + 65:35 syn:anti ()n= 3 + 60:40 anti:syn
M.W. Kanan/M C. white Chem 153 Hydrogenation -162 Week of october 21. 2002 Asymmetric hydrogenation in the synthesis of unnatural amino acids (CODRh. NH] OMe I atm H2, THF, Meo HO AcHN NHA OH HO COOMe L Asymmetric hydrogenation is a very general and Medoc reliable route to amino acids, which are key building blocks for the synthesis of many natural H2 InsertIo this example, the hydrogenation carried out in the presence of a nitro group Evans JACS2001(123)12411
M.W. Kanan/M.C. White Chem 153 Hydrogenation -162- Week of October 21, 2002 Asymmetric hydrogenation in the synthesis of unnatural amino acids OH F NO2 F NO2 1 atm. H2, THF, rt S O (COD)Rh Ph2P CMe3 + AcHN O OMe NHAc O MeO Rh L * L + Rh L L H * H R N H Rh L L H + R + 94% ee, 96% yield reductive elimination insertion * O O OH N H O H N NH H N O HO OH O HO O HO O H N O N H O OH HO O NH2 Cl Cl Teicoplanin aglycon Asymmetric hydrogenation is a very general and reliable route to amino acids, which are key building blocks for the synthesis of many natural products. In this example, the hydrogenation is carried out in the presence of a nitro group. O COOMe O NH H COOMe Rh L L S S * + Rh L * L O NH MeOOC R oxidative addition + SbF6- H2 H2 Evans JACS 2001 (123) 12411
M C. White, Chem 153 Hydrogenation -163- Week of october 21. 2002 Asymmetric hydrogenations of trisubstituted unfunctionalized” olefins Recall that Crabtree's catalyst is able to effect the efficient (PF6) hydrogenation of both tri-and tetrasubstituted olefins Replacement of the mor ridine ligands A ith the bidentate anodihydrooxazole ligand R in promoting the asymmetric hydrogenation of trisubstituted unfunctionalized olefins Crabtree's catalyst Pfaltz hydrogenation catalyst Counterion effects on conversion (and selectivity) can be dramatic onversion 57% ToIR is(pentafluorophenyl)- 84% H2. CH,Ch rt CFY 97%ee >99 cony tetrakis [3, 5-bis(trifluoromethyl- 05 mol%>99% phenyl]borate(BARF CF3 Pfaltz ACIEE 1998 37 2897
M.C. White, Chem 153 Hydrogenation -163- Week of October 21, 2002 Asymmetric hydrogenations of trisubstituted “unfunctionalized” olefins (PF6-) Ir(I) PCy3 N + Crabtree's catalyst Ar2P N O R Ir (PF6-) + Recall that Crabtree's catalyst is able to effect the efficient hydrogenation of both tri-and tetrasubstituted olefins. Replacement of the monophosphane and pyridine ligands with the bidentate phosphanodihydrooxazole ligand produces a catalyst that is highly effective in promoting the asymmetric hydrogenation of trisubstituted, unfunctionalized olefins. Pfaltz hydrogenation catalyst o-Tol2P N O Ir X + - Counterion effects on conversion (and selectivity) can be dramatic counterion catalyst loading conversion PF6- 4 mol% 57 % CF3 CF3 B _ tetrakis[3,5-bis(trifluoromethyl)- phenyl]borate (BARF) .05 mol% >99% F F B _ .1 mol% 84% F F F tetrakis(pentafluorophenyl)- borate hexafluorophosphate 4 4 Me Me * 97 % e.e, >99 % conv. H2, CH2Cl2, rt Pfaltz ACIEE 1998 37 2897
M.C. White Chem 153 Hydrogenation-164- Week of october 21. 2002 Titanocene hydrogenation of"unfunctionalized"olefins nan epor First asymmetric example 25 mol% Red-Al"(Li(H2AI(OCH2CH2OCH3))6 mol% LiAIH(OR)3(7.5 eg), H(16 psi), H2(latm,20°C heptane//THF,40℃ quantitative conversion 15%ee Stern TL1968(60)6313 Kagan ACIEE 1979(18)779. First asymmetric example resulting in high ee Asymmetric hydrogenation of "unfunctionalised"trisubstituted olefins E olefins are reduced more rapidly and with higher ees than Z olefins I mol% 1. 10 mol%.n-BuLi oPC H,(I atm) BuLi(I mol%), H,(I atm), -75oC 2.13 mol% PhSiH3 95%optical purity 3. olefin, H2(136 atm) all substrates reported are 79%yl 95%ee ring Vollhardt JACS 1987(109)8105 Buchwald JACS 1993(115)12569
M.C. White, Chem 153 Hydrogenation -164- Week of October 21, 2002 Titanocene hydrogenation of “unfunctionalized” olefins Ti(IV) Cl Cl 25 mol% LiAlH(OR)3 (7.5 eq), H2 (16 psi), heptane/THF, 40oC quantitative conversion Original report of catalytic hydrogenation activity: Stern TL 1968 (60) 6313. First asymmetric example: i-Pr Me Ti(IV) i-Pr Me Cl Cl "Red-Al" (Li(H2Al(OCH2CH2OCH3)2)] H2 (1 atm), 20 oC 1 mol% 6 mol% Ph Ph (S) 15 % ee Kagan ACIEE 1979 (18) 779. Ti(IV) Cl Cl 1. 10 mol%. n-BuLi, 0oC. H2 (1 atm) 2. 13 mol% PhSiH3 3. olefin, H2 (136 atm) 65oC 5 mol% Me Ph Asymmetric hydrogenation of "unfunctionalized" trisubstituted olefins Me all substrates reported are alkenes α to an aromatic ring. Ph Me * 79% yield 95% ee Buchwald JACS 1993 (115) 12569. First asymmetric example resulting in high ee Ph Ph (S) Ph Ph Ti(IV) Ph Ph 1 mol% n-BuLi (1 mol%), H2 (1 atm), -75oC Cl Cl 95% optical purity Vollhardt JACS 1987 (109) 8105. E olefins are reduced more rapidly and with higher ee's than Z olefins
M.C. White Chem 153 Hydrogenation-165- Week of october 21. 2002 Titanocene hydrogenation of"unfunctionalized olefins Synthesis of allyldicyclopentadienyltitanium(ll) complexes from dicyclopentadienyltitanium(v) dichloride H Mec Cl 2 MgCh Martin and Jellinek JoMC 1966 6)293: JOMC 1968 (12)149 Buchwald argues that the silane does not serve as a H source based on the following experime (EF-1, 2-diphenylpropene, 1, 2-diphenyl propar 10 mol%. n-BuLi 0C ulted which was 98% D by GCMS. Buchwald Trny CI H(I atm) 2. 13 mol% PhSih phenylsilane is to stabilize the catalyst during manipulations prior to starting the rxn. based on Martin and Jellinek papers a-bond metathesis olefin insertion Buchwald JACS 1993(115)12569
M.C. White, Chem 153 Hydrogenation -165- Week of October 21, 2002 Titanocene hydrogenation of “unfunctionalized” olefins Ti( IV) Cl Cl 1. 10 mol%. n-BuLi, 0oC. H2 (1 atm) 2. 13 mol% PhSiH3 Ti( III) H postulated intermediate based on Martin and Jellinek papers Buchwald argues that the silane does not serve as a H source based on the following experiment: when D2 was used in the hydrogenation of (E)-1,2-diphenylpropene, 1,2-diphenyl propane resulted which was 98% D2 by GCMS. Buchwald goes on to note that the only purpose of the phenylsilane is to stabilize the catalyst during manipulations prior to starting the rxn. 5 mol% Me Ph Me Ti(III) Ph note: regioselectivity of insertion not determined H H σ-bond metathesis * Ph Me * olefin insertion Buchwald JACS 1993 (115) 12569 Synthesis of allyldicyclopentadienyltitanium (III) complexes from dicyclopentadienyltitanium (IV) dichloride: Ti(IV) Cl Cl 2 equ. MgCl Ti(III) 2 MgCl2 H Ti(III) H Ti(III) Martin and Jellinek JOMC 1966 (6) 293; JOMC 1968 (12) 149