Controlling products during asymmetric photoreactions '•A H ,/\h hv/Sens' Ar Ar Ar = Ph H A A H SenS: R*O2C^CO2R* ee: 10.4% R* = (-)-menthyl o hv/Sens* /~~f| Sens: ^W*^* R*:A ee: 49% ~*T} o Sens: ] T ee: 4.4% R - -methylheptyl Because of very little difference in rates of formation of the two enantiomeric products normally there is 'zero' selectivity; ee: 0. • The best chiral induction in photoreactions are obtained in solid state. + + 2 1 Chiral crystallization Achiral molecule may crystallize in achiral space group. e.g., quartz, urea, maleic anhydride, 3 The most common space groups of organic crystalline compounds based upon a survey of 29059 crystal structure determinations space group number percentage P2j/c 10450 36.0 P-1 3986 13.7 3359 11.6 P21* 1957 6.7 C2/c 1930 6.6 Pbca 1261 4.3 Pnma 548 1.9 Pna21 513 1.8 Pbcn 341 1.2 P1* 305 1.1 *Chiral space group. 2 Ph —*-/f OH Ph -*■ OH HO ph"O:0^ Ph *> o-N 5 Chiral crystallization spontaneous chiral crys+alliza+ion > 44l£ 44 chiral crys+al optically active ma+erials wi+h permanent chirality Absolute asymmetric synthesis in the chiral crystalline environment Achiral R R R = COOi-Pr Ar O / ck^X ^ hv l-Pr sI-Pr hv hv Chiral Solution e.e : 0% Crystals e.e : 100% Me Ar HO Solution e.e : 0% Crystals e.e : 82% Solution e.e : 0% Crystals e.e : 100% R achiral O H O 6 3 Note that the two prochiral hydrogens are not equidistant from the carbonyl chromophore. The molecule being present in a chiral space group does not have another molecule that is mirror symmetric. Since only one prochiral hydrogen would be abstracted only one cyclobutanol enantiomer would be formed. 7 Essential Criteria for Asymmetric Photochemistry in the Crystalline State Molecules must crystallize in a chiral space group (non-centro symmetric form) Majority of achiral molecules crystallize in a non chiral space group (symmetric packing) P2t/n P212121 centrosymmetric non-centrosymmetric 8 4 Use of chiral hosts: Solid state photochemistry Chiral hosts upon inclusion of an achiral molecule may induce chirality on the achiral molecule. The above host-guest complexation would lead to diastereomeric (instead of enantiomeric) transition states . (S,S)-(-)- Ph- (S,S)-(-) Ph (S,S)-(-) Ph OMe hv O 6' °CH3 hv CH3 ,CH3 hv H3CO,_„ Me OMe Ph O Cl CI Me OH OH e.e.: 100% O Cl Cl Ph OH OH e.e.: 100% Cl Cl Ph OH OH e.e.: 100% In solution no chiral induction is obtained. 9 5 Most commonly occurring space groups 230 unique space groups of which only 65 are chiral space groups Chiral space groups (symmetry elements are rotational, translational and combinations of these) achiral space groups (symmetry elements are mirror, glide plane or center of inversion) Space group Total no. of crystals % P2i/ c 10450 36.0 P1 3986 13.7 3359 11.6 P21 1957 6.7 C2/ c 1930 6.6 Pbca 1261 4.3 Pnma 548 1.9 Pna21 513 1.8 Pbcn 341 1.2 P1 305 1.1 Chiral space group Ionic Chiral Auxillary Approach Reactive part Chiral auxliary Covalent Chiral Auxillary Approach Reactive part Chiral auxliary 6 Ionic chiral auxiliary approach: Solid state photochemistry The chiral auxiliary ensures that the reactant molecule crystallizes in a chiral space group. This would make the two diastereomeric reaction pathways to have different activation energies. 13 Ionic chiral auxiliary approach .coo hV^-ch, ^\.cooch3 ho.. 1- 'j hv ' CH2N2 workup crystals ■Me ee 97% .coo Ih /-YCOOCH3 °..X Ji HjNTNcH, ho kJ> hv CH3 CH2N2 workup crystals ee 80% ch3 o hv I " _ . ■coo H2NV crystals _ 6 f^j CH2N2 workup Jj^JjZ}''1 cooch3 h oh ee 97% The two prochiral hydrogens are distinguishable in the crystalline state. In solution no chiral induction is obtained. 14 7 16 8 % de Trans CB 97 Trans CB 90 Trans CB 92 Covalent chiral auxiliary approach: Photochemistry of a-Oxoamides 1 2 3 Medium 1 2 3 Solution (CH3CN) 19 35 46 Crystal 0 100 0 9 Diastereoselectivity obtained with various chiral auxiliaries in solid state Crystal structures C=0....y-Hi C=Q....y-H2 %de of p-lactam p-R-phenylethylamide / 99(B) 82(A) a) 2.814 Ao 5.077 Ao >99(A b) O O >99(B 2.737 Ao 5.214 Ao 96(B 2.781 Ao 5.052 Ao d) O O 2.618Ao 5.130 Ao e) 19 p-S-phenylalanine methyl esteramide 10 P 2i N—^ ^—^ N NH "V* (S) ^ \ Solution irradiation (MeOH) NH (R) ^ ^ \__/ Ihr Crystal irradiation Solution irradiation (MeOH) Ihr Crystal irradiation # Photoproducts analyzed on HPLC chiralcel-OD ~ A: First peak on HPLC ß-lactam photoproduct >99% de(A)~ >99% de(A)~ N O 21 Single crystal-to-Single Crystal Phototransformation 11 Photoproduct as Formed (P2J a = 6.4821 A b = 14.967 A c = 10.7528 A ß= 98.52° Cell volume 1031.71 A3 Photoproduct Recrystallized (P21) a = 8.5684 A b = 12.8865A c = 9.8260 A ß = 107.98° Cell volume 1031.99(30) A3 23 Soild State Photochemical Reactions Topochemical Reactions: Reaction in the solid state is preferred and occurs with a minimum amount of atomic and molecular movement. Topotactic Reactions: A phenomenon in which X ray quality single crystals of the reactant are continuously and quantitatively converted into single crystals of the product. Topotactic reactions are not common Asymmetric photoreactions within zeolites ■ Key is the cation binding to the included organic molecule. Confined space also imposes restrictions. ■ Details yet to be understood. 25 Asymmetric Photoreactions Within Zeolites 13 Chiral inductor approach A B C CD ^ ~*~ Chiral Inductor <^^$ D E F ABC Enantioselective Electrocylization of Achiral Tropolones O 28 14 Chiral Induction: Solution vs. Zeolite Enantioselectivity in Photoreactions-Generality (^^N^^^J^j) bv ^ fö^f + ^^fP NaY, Norephedrine, RT: 50%ee ■fa O NaY, Ephedrine, -55°C: 50%ee o O O (f^^]^ h! C^C3^" NaY, Ephedrine: 15%ee jF hv^ 1 + 1 NaY, Norephedrine, RT: 20%ee Ph* >h Ph Ph Ph Ph COOEt COOEt COOEt Ph Ph Ph *Ph ph Ph 30 Ph Solution ee was zero % in all the above cases NaY, Cyclohexyl ethyl amine, RT: 17%ee 15 .CO2Me hv CO2Me NaY/ephedrine hv -A O NaY/ephedrine hv HO0' CO2Me Ar OH NaY/pseudoephedrine hv NaY/norephedrine hv Na Y/norephedrine hv NaY/ephedrine OH 30% ee 44 % ee Chiral inductor approach A B C CE>> Achiral Reactant Chiral Inductor D E F A B Chiral auxiliary approach I- Achiral Reactant ' Covalent bond Chiral Auxiliary 32 35% ee 30% ee 40 % ee oh 37 % ee 31 O 16 Chiral Induction (Diastereoselectivity) Solution vs.Zeolite Hexane NaY 33 Solution de: 5% NaY de: 73% Solution de: 2% KY de: 81% Solution de: 0% NaY de: 88% Solution de: 3% RbY de: 88% Solution de: 2% LiY de: 80% Solution de: 0% NaY de: 71% 34 17 Chiral inductor approach A B C ■*— Achiral Reactant Chiral Inductor D E F Gumbo approach f Reactant Q Chiral Auxiliary — Chiral Inductor A B Chiral auxiliary approach 1- Achiral Reactant ^ Covalent bond Chiral Auxiliary A 36 B 18 Chiral induction within a chirally modified zeolite CH3 + v 53 % A L 90 % (A) L (-)-ephedrine / NaY d e O % d e O % Silica gel / (-)-ephedrine (CH2Cl2 / hexane) (-)-ephedrine 37 NaY Asymmetric Photoreactions Within Zeolites • Chiral Induction Depends on • Nature of the Cation • Number of Cations (Si/Al ratio) • Water Content Cation is the Key 3S 19 Chiral Induction Depends on the Nature Alkali Metal Ion Solution LiY NaY KY RbY CsY 2 (SS) 80 (SS) 28 (RR) 14 (RR) S (RR) S (RR) 39 Enantio and Diastereomeric Excess Depends on the Number of Cations Si/Al Ratio 2.4 6 15 4G (Na+) 7G 24 13 5 O o Ö (Na+) 8G 22 16 4 Á PH Ph (Ll+) 68 25 12 1G —{ O H COOCH3 \ (Na+) 78 1G 13 1G 40 20 Role of water CH3 H f"3 Á hv h ř"3 Ph Ph ph ph (RR-isomer) (SS-isomer) 2 % (SS) J v v. Solution Hexane / DCM 80 % (SS) LiY Dry 8 % (RR) LiY Wet 41 Solution Zeolite-Y Zeolite-Y with (Isotropic media) moisture less # of free cations ---------N----H--- O CH3-. O Cation 2-B 80-B LiY (dry) Si/ Al = 2.4 Cations/unitcell: 64 Silica 10-A LiY Si/ Al = 40 Cations/unitcell: 5 Zeolite-Y wet ~W (6) Cation coordinated to water 8-A LiY (wet) Si/ Al = 2.4 42 Ph Ph Ph K 21 Role of Cation-Carbonyl Dipolar Interaction Carboalkoxy vs Alkyl hv Ph Ph H COOMe H CH3 Zeolite LiY NaY KY RbY Solution % d.e. 83-B 28-A 80-A 47-A 2-B % d.e. 7-A 7-A 7-B 12-B 2-B X X X Ph Ph Ph Ph H 43 22 Importance of Cation-Chiral Auxiliary Binding: Phenyl vs Cyclohexyl .-Q COR A A Pff T>h Pff Ph NaY LiY AA ( Cor NaY NaY cor KY .....«h h *ch3 71 80 62 85 81 ..iiihH ch3 30 29 22 45 45 45 o Role of Cation-n Quadrupolar Interaction Phenyl vs Cyclohexyl A^A + A Ph Ph Ph Ph Ph Ph 1*1 H CH3 0 H CH3 Zeolite % d.e. % d.e. LiY 80-B 29-B NaY 28-A 24-A KY 14-A 26-A RbY 5-A 29-A CsY 5-A 37-A Solution 2-B 2-B 46 23 Cation Dependent Diastereomer Switch Amide of L-Valine methyl ester Ph Ph COOMe H AJ LiY 83 (SS) KY 80 (RR) Williams, E. A. et. al., JACS, 123, 12255-12265, (2001) NO - Co-ordination Valine OO - Co-ordination Bowers, M. T. et. al., JACS, 2001, 122, 3458-3464, (2000) «#75 Glycine 48 24 Chiral photochemistry in solution through covalent chiral auxiliary R ate (-)-8-C6H5-Menthyl >96% (-)-Menlhyl 57% (a) (b) Chiral photochemistry in solution through templation 25 Chiral photochemistry in solution through templation MeOOC MeOOC In the absence of template; e.e.: 0 In the presenceof template; e.e.: 82% Blocked One mode of approach blocked Chiral photochemistry in solution through templation 52 26 mucuuui •*> ninuaau Chiral Photochemistry Yostimisa Incoe V Ramamuittiy 27