Reversible Interaction between Substrate and Ligand

Transcription

1 Reversible Interaction between Substrate and Ligand YoheiShimizu(D3) is is is Ser 271 P Lys P Zn 2+ Tyr P Lys 107 P 3 2- class 1 aldolase class 2 aldolase Glu 185 Asp 211 C 2 - C 2 - carboxypeptidase A macrophomate synthase (ature, 2003, 422, 185.) Enzyme igh substrate selectivity (specific interaction in the active site) Low substrate generality Mimic active site of enzyme with wide substrate generality. Contents Reversible directing group with covalent bond oncovalent bond interaction between substrate and ligand

2 Reversible directing group with covalent bond Utilize aldehyde/imine equilibrium for temporal directing group. Jun,C.-L.etal.J.rg.Chem.1997,62,1200. C amino-3-picoline Reversible aldimine formation. R Directing Group C 3 R for catalytic hydroacylation Ph 3 P Cl C 3 Rh PPh 3 R Suggs,J.W. J.Am.Chem.Soc.1979,101,489. 3:Rh(PPh 3 ) 3 Cl 4:2-amino-3-picoline 7: benzoic acid 8: aniline Jun,C.-L.etal. Angew. Chem. Int. Ed. 2000, 39, Without 2-amino-3-picoline, decarbonylation was serious problem. Benzoic acid accelerated imine formation. Aniline accelerated imine formation via transimination. Application of this catalyst to other reactions. C-C bond activation Ph nbu 15eq. Rh(PPh 3 ) 3 Cl(5mol%) 2-amino-3-picoline(20 mol%) toluene,150 o C 98% nbu Ph C 3 C 3 C 3 Ph 3 P Cl Rh Ph hydroacylation of alkynes Ph R nbu Ph 3 P Cl Rh Ph Rh(PPh 3 ) 3 Cl(5mol%) 2-amino-3-picoline(40 mol%) benzoicacid(20mol%) toluene,80 o C 92% R Ph 3 P Cl Rh Bu nbu R J.Am.Chem. Soc, 1999, 121, 880. Ph Angew. Chem. Int. Ed. 2002, 41, 2146.

3 Phosphite as reversible directing group (R 1 ) 3 P R 2 (R 1 ) 2 P(R 2 ) R 1 Lewis,.L.etal.J.Am.Chem.Soc.1986,108,2728. rtho directed C- activation C 2 4 (95 psi) Rucat.(6mol%) KPh(9 mol%) TF,177 o C (Ph) 2 P P(Ph) 2 Ru 13% KPh facilitated the exchange of phenol on the phosphite. 75% P(Ph) 3 P(Ph) 3 P(R 1 ) 2 P(R 1 ) 2 P(R 1 ) 2 M P(R 1 ) 2 M M Phosphite worked as temporal directing group. M Recent application of this type of reversible directing group. rthoarylation via directed C- activation t-bu Br RhCl(CD) 2 (5mol%) ClPiPr 2 (10mol%) Cs 2 C 3 (1.7eq) toluene, reflux t-bu CMe CMe 89% 1 2 Phosphinite did the same work as phosphite. To prevent contamination derived from phosphinite, substrate derived phosphinite was generated in situ. 6 3 Bedford,R.B.etal.Angew.Chem.Int.Ed.2003,42,112. Directed hydroformination 1)Rh(C) 2 acac(1mol%) (Me)(10mol%) C/ 2 (1:1,20bar) TF,MS4A,40 o C 2)PCC/Al 2 3 aac,c 2 Cl 2,rt 85% : =>99:<1 (PPh 3 : : =54:46) 5 Ph 2 P Rh 4 Breit,B.etalAngew.Chem.Int.Ed.2008,47,7346.

4 oncovalent bond interaction for molecular recognition Eary works organized space for specific substrate lipid bilayer Epoxidation occured only at the olefin of the side chain. Steroid attached porphirin catalyst in phospholipid bilayer organize rigid environmet which restrict the entrance of substrates. Low catalyst efficiency because of strong product binding. Groves,J.T.etal.JACS,1987,109,5045. Early successful work by Breslow group. cyclodextrin Recognize hydrophobic group. Fix substrate at appropriate position. Release products(reversible interaction). no oxidation without binding group no over oxidation to ketone >2 cyclodextrin was necessary to fix the substrate. 1(10mol%) PhI(5eq.) pyridine, 2 ; K aq. ca. 40% only 4 turnover Problem: oxidation of porphyrin core under the condition perfluorination addition of excess of pyridine Coordinates to Mn.(like thiolate in P450 system) Directs oxigen and substrates to the other side. attachment of pyridine moiety on porphyrin

5 oxidation resistent core intramolecular coordination of pyridine 0.1mol%ofcat.=>187turnover 1mol%ofcat.=>95turnover 0.02mol%ofcat.=>2000turnover Change the oxdation site. 5(10mol%) PhI(5eq.) pyridine, 2 ; a aq. Third binding group effeciently changed the regioselectivity. Different binding groups also changed the regioselectivity :7 :15 =1:3:1 6 :7 :15 =1:0:1 6 :7 :15 =1:1:2 Flexible moving of binding group in CD resulted in low selectivity?

6 ydrogen bond based recognition Crabtree, R..; Brudvig, G. W. et al. succeeded in developing effecient molecular recognitioncatalyst. Science, 2006, 312, recognition mode (two point hydrogen bond) Kemp's triacid recognition site spacer terpyridine-mn catalyst originallydevelopedfor 2 oxidationcatalyst oxdation resistant framework high oxidation ability Crabtree,R..;Brudvig,G.W.etal.Science,1999, 283, basic idea potential problems Ibuprofen as substrate condition C 2 -C 2 hydrogenbonding=>twopointbinding inhibit the rotation of the substrate Kemp's triacid U-turn motif => reasonably rigid maintain low pka condition => avoid calboxylate anion(potential ligand of center metal) C 3 C,xone(5eq.) terpy-mn cat.(1 mol%) b: recognition cat. 1c: lacking Kemp's triacid 4 5 Competitive inhibition of recognition.(4eq. Ac) Low cat. loading prevent bimolecular self oxidation of cat. CD 3 Cismore oxidation resistant. igh regioselectivity was achived by molecular recognition catalyst.

7 (4-methylcyclohexyl) acetic acid igh regioselectivity and stereoselectivity. Low conversion... Inhibition by 4-tert-butyl benzoic acid ibuprofen methylester ~ow was background reaction suppressed?~ Me 2 C ibuprofen methylester as substrate only 0.9% yield (without inhibitor: 30%) inhibitor active site is sterically blocked ibuprofen as substrate (c) reversal of inhibition cat.(0.5mol%) methyl ester(1 eq.) inhibitor(0.3 eq.) uncompetitive inhibition Ac(2.25 eq.) small enough to open the active site 3hr sampling 1.5% conversion 3hr sampling 34% conversion competitive inhibition These result suggested that catalyst recognize carboxylic acid reversible binding active site was sterically inhibited

8 abstraction-rebound mechanism DFT calculation [(terpy)mn()( -)Mn(S 4 )(terpy)] + longermn-bond(1.80~1.91acomparedtomn=:1.60a) highspindencityon reactivecenterhasamn IV - character abstraction step and rebound step are exothermic. Energy barrier is low. (6.5 kcal/mol for abstraction) hydrogen bond C- -Mn oxidized C- bond is relatively far from active site C-canreachtheactivesite without losing recognition The catalyst has enough flexibility enabling the approach of the substrate to the active site. Feature of this catalyst Suppresses the background reaction. Catalyst has reasonable rigidity and flexibility. ther than oxidation catalyst Breit, B. et al. used similar approach to phosphine ligand. hydrogen bond target reaction: hydroformination recognize carboxylic acid

9 Linear/branch selectivity could be observed using proper ligand. Ligand v L (rel) v B (rel) PPh v L :rateoflinearproduct v B :rateofbranchedproduct nly the lenear selective transition state was accelerated by the recognition catalyst. PPh 2 2 PPh Ar 2 P 2 2 Ar= pf-ph freeguanidine>cyclicguanidine(1vs16) meta>ortho(7vs10) pyridinering>benzenering(1vs7) control experiments entry3: Ligand moiety and recognition moityshouldbeinthesame molecule. entry4, entry5: Catalyst recognize the carboxylic group. It should beinthesamemolecule as the substrate.

10 differenciation of two terminal olefins 0hr Both terminal olefin reacted almost same rate. Linear/branch selectivity was poor. 9.5hr 25.3 hr 0hr 4hr Reaction rate of each olefin was significantly different(8.8:1). And linear/branch selectivity was also excellent. nly the reaction at, -unsaturated carboxylic group was accelerated by the recognition catalyst. 8.5hr DFT calculation of hydrometalation step 2 C This system showed rate dependent differenciation. Direction of hydrogen bondisdesirableints. 2Ligand1 Rh(acac)(C) 2 2 Rh C Carboxylic acid formed hydrogen bond with both guanidine ligands. Rotation of the alkene is the main cause of activation energy.(assisted by hydrogen bonding) ne point hydrogen bonding resulted in higher activation energy. Molecular recognition catalyst still need to be investigated. Substrate generality is still limited. Reaction pattern is also limited.