all advantages of small molecule organocatalyst structural simplicity modularity Advantages of short peptide p catalysts

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1 An overview of selected organocatalysts applied in our group BIL-phosphate catalyzed self-coupling reaction Eur. JC, 004 ynlett, 004 TA., 005 TA, 006 BC, 009 Chem. Commun. 006 Eur. JC 007 Chem. Commun, 006 AC, 006 Catalysis Today, 007 C Asymmetric organocatalysis and autocatalysis Angew. Chem. 008 Angew. Chem. 009 C Et : p-me-h- or p-br--h- Akiyama-Terada catalyst Angew. Chem., 007 Chirality, 007 LEB, 009 JC, 010 Chem.Commun. 010 E Chem. Commun. 008 rg. Letters 010 C cat. (10 mol%) 3 C Me toluene, T up to 83% yield 85- >99% ee 8 examples a) Enamide / ketimine equilibrium 1 C Me 98% ee β-aminoketones roposed reaction mechanism b) Aza-ene type pathway 1 cat. C 3 C 3 C 3 C C C 1 C Me C Me C. Baudequin, A. Zamfir,. B. Tsogoeva, Chem. Commun. 008, 4637 Asymmetric organocatalytic hydrocyanation reactions ome advantages of the ligopeptide Approach TMC cat. (5 mol%) 6 Cl Cl reflux, 8h t-bu quant. yield C Et C Cl C up to 95% yield α-hydrazino acids cat % ee 9 examples A plausible reaction mechanism based on 9 i, 31 and 1 M studies modularity all advantages of small molecule organocatalyst structural simplicity i C TMC tbu Et i B C t Bu Et i t Bu A D Et Et C silica gel Me 3 i C Et C 0.89 ppm ppm ( 31 M) ( 31 M) i ppm ( 9 i M) i ppm ( 9 i M) Et A. Zamfir,. B. Tsogoeva, rg. Lett. 010, 1, 188 TMC ppm ( 9 i M) Et straightforward accessibility Advantages of short peptide p catalysts possibility to vary the nature of amino acids to improve the catalyst efficiency easier mechanistic investigations

2 -terminal primary amino dipeptide catalyzed 1,4-conjugate addition and aldol reaction ubstrate scope C (0.3 eq) (1,)-()-1,-diphenyl- () 1 ethylenediamine (0.3 eq) DMF, T up to 86% yield up to 91% ee h h C (0.3 eq) a (0.3 eq) -, T - h Cl Tsogoeva,. B.; Jagtap,. B. ynlett. 004, 64 h X X = EWG (0.3 eq) DM, T C X up to 96% yield up to 76% ee Tsogoeva,. B.; Wei,.-W. Tetrahedron: Asymmetry, 005, 16, 1947 "Most Cited aper Award" 78 % yield 70 % ee 95:5 syn/anti 9 % yield 41 % ee 97:3 syn/anti 100% yield 68 % ee 95:5 syn/anti Me 75 % yield 58 % ee 95:5 syn/anti 89 % yield 66 % ee 9:8 syn/anti 96 % yield 64 % ee 99:1 syn/anti h h 59 % yield 3 % yield 61 % ee 1 % ee 94:6 syn/anti Freund, M.; chenker,.; Tsogoeva,. B. rg. Biomol. Chem. 009, 7, 479 Design of bifunctional organocatalysts Asymmetric nitro-michael reactions catalyzed by thiourea-amine chiral linker (E) h () () () (0.15 equiv) Ac/ Toluene, T h () 85% yield 86 ee Tsogoeva,. B.; Wei,.-W. Chem. Commun. 006, 1451 DFT quantum-chemical calculations (B3LY/6-31G(d) ( ) ew chiral thiourea based bifunctional organocatalysts a b c a - E # rel, = 7.94 kcal/mol b r (C a -C b ) =.06 Å Transition state structure for the formation of the enantiomer. Yalalov, D. A.; Tsogoeva,. B.; chmatz,. Adv. ynth. Catal. 006, 348, 86

3 lausible multistep chiral thiourea-amine catalysis itro-michael addition catalyzed by derivatives of the new bifunctional catalyst Cat. (0.15 equiv) Ac (0.15 equiv); ( equiv) Toluene, T () h B h / (Ac) EI-M: m/z = 467. [M ] h h - h # h - - A h EI-M: m/z = [M ] 85%, 80%, 97%, 98%, 86% ee 89% ee 84% ee 91% ee Wei,.-W.; Yalalov, D. A.; Tsogoeva,. B.; chmatz,. Catalysis Today 007, 11, 151 cope of reactions Further applications for the new thiourea-amine catalaysts 98% 91% ee h h (0.15 equiv) ( equiv); Ac (0.15 equiv) Toluene, T Br 99% 90% ee Me 84% 91% ee 98% 90% ee C Et 8% 89% dr (syn:anti) = 80:0 dr (syn:anti) = 83:17 ee (syn) = 96% ee (syn) = 98% 88% dr (syn:anti) = 14:86 ee (anti) = >99% CEt α-amino acid derivatives

4 cope of Mannich-type reactions catalyzed by thiourea-amine 18 -incorporation experiment studied by EI-M 1 (15 mol%) CEt C Et toluene, T Bz Bz Bz Bz Et Et Et Et 50%, >99% ee 86%, >99% ee >99% ee (syn) 90% ee (syn) >99% ee (anti) 99% ee (anti) 40% de (anti) 7% de (anti) Bz Bz Bz Et Et Et 54%, >99% ee Br 80%, >99% ee 45%, 97% ee Bz Bz Bz Et Et Et Et >99% ee (syn) 89%, >94% ee (syn) 88%, >9% ee (syn) 87%, >96% ee (syn) >99% ee (anti) 9% de (anti) >9% ee (anti) 8% de (syn) >8% ee (anti) 19% de (syn) >94% ee (anti) 8% de (syn) Bz cat (15 mol%) 16 Bz Bz Et Et 18 (15 eq) C Et (10 eq) A toluene, T B m/z = 301 [M 1 a] m/z = 303 [M a] gon, 40 h A : B = 1 : 1.58 (peak intensity ratio) δ δ enol mechanism enamine mechanism Yalalov, D. A.; Tsogoeva,. B.; hubina, T. E.; Clark, T. Angew. Chemie Int. Ed. 008, 47, 664 Computational studies of asymmetric Mannich-type reaction 18 -marker experiment studied by EI-M (0.15 equiv) 1 CEt Toluene C Et up to 89% yield 8-99% ee Enamine: DFT quantum-chemical calculations l Me h h TM 3 o C / argon 16 Me A 18 Me m/z = 309 [M 1 4 ] m/z = 311 [M 4 ] (10 eq) A : B = 40 : 60 (peak intensity ratio) B Enol: B3W91/6-31G M/6-31G//B3W91/6-31G B3W91/6-31G M/6-31G//B3W91/6-31G B3W91/6-31G CF M/6-311G//B3W91/6-31G δ h h δ TM h h TM δ δ enol mechanism enamine mechanism Yalalov, D. A.; Tsogoeva,. B.; hubina, T. E.; Clark, T. Angew. Chemie Int. Ed. 008, 47, 664. Belot, A. Quintard,. Krause, A. Alexakis. Adv. ynth. Catal. 010, 35, 667.

5 Asymmetric catalysis vs. Asymmetric autocatalysis Asymmetric autocatalysis C A B Asymmetric catalysis with low ee Zn i r with high ee 3 A B Asymmetric autocatalysis Asymmetric autocatalysis is a process whereby a chiral reaction product is the catalyst in its own formation from achiral reactants. W. Wynberg 1989 i-r Zn Asymmetric autocatalysis C Zn i r Via dimeric or tetrameric Zn-complexes as active catalysts: Zn i-r Blackmond, Braun 001 ir Zn Zn ir Ercolani 009 ir irzn ir Zn ir Zn Zn ir ir ir ir on-enantioselective organo-autocatalysis When chiral product and catalyst are the same Aldol eaction: Me Me Me C Et (15 mol%, 98% ee) C Et C Et 4 days, T (0.5 mol l -1 ) 48 % y, 85% ee (). Fujisawa, T. akagawa, T. Mukaiyama, Adv. ynth. Catal. 004, 346, 141 Me Baylis-illman eaction: 3 - h - - h h h E 3 hc 3 3 Et C (0.5 mol l -1 ) Me C Et (15 mol%, 99% ee) 4 days, T C Et 4 % y, 94% ee () (Yields after subtraction of the initially added product catalyst) Me M. Mauksch,. B. Tsogoeva, I. M. Martynova,.-W. Wei. Angew. Chem. Int. Ed. 007, 46, 393 V. K. Aggarwal,. Y. Fulford and G. C. Lloyd-Jones, Angew. Chem., Int. Ed., 005, 44, 1706 romoted to ot aper. ighlighted in YFM, ynlett, Issue 8, 007.

6 roduct catalysis vs. roline catalysis When product and catalyst are the same Me Me Me Me Me Me CEt EtC (30 mol%) CEt () CEt ( roduct-catalyst) 98% ee up to 95% ee DFT Calculations with Gaussian03 rogram ackage at B3LY/6-31G level: CEt CEt 96% ee Et Me M. Mauksch,. B. Tsogoeva, I. M. Martynova,.-W. Wei. Angew. Chem. Int. Ed. 007, 46, 393 Me C (0 mol%) Me DM E C Et Me EI-M: / = [[Mroduct Meactant a] a] m/z CEt CEt 95% ee () A. Cordova, W. otz, G. Zhong, J.M. Betancort C. F. Barbas III. J. Am. Chem. oc. 00, 14, 184 Transition state structure for the formation of the enantiomer of Mannich roduct M. Mauksch,. B. Tsogoeva, I. M. Martynova,.-W. Wei. Angew. Chem. Int. Ed. 007, 46, 393 Asymmetric organoautocatalysis via product-templates rganoautocatalysis as a natural extension to organocatalysis Me Me Me CEt ( roduct-catalyst) EtC () CEt C up to 95% ee A Asymmetric organocatalysis B Template Autocatalysis = elf-eplication Et Me C Et T -T Me approach of the enol f from the h i-face i f Ca A Cb B Asymmetric organo-autocatalysis -T Working hypothesis B3LY/6-31G

7 Absolute Asymmetric ynthesis and pontaneous Mirror ymmetry Breaking The Frank model of mirror symmetry breaking in enantioselective autocatalysis Bifurcation in the enantiomer concentration Absolute Asymmetric ynthesis is the formation of enantiomerically enriched products from achiral precursors without the intervention of chiral chemical reagents or catalysts Kurt Mislow Collect. Czech Chem Commun. 003 A A Kondepudi and elson hys A, 1984 Crusats et al, ChemhysChem, 009 Mauksch et al, LEB, 009 ymmetry breaking: Mannich reaction under achiral conditions Me Me Asymmetric rgano-autocatalytic Mannich eaction Et C Acetone, T C Et (0.5 mol l -1 ) ymmetry Breaking: Mannich reaction under achiral conditions Entry eaction Time (days) Yield (%) ee (%) by LC ee (%) by 1 -M with Eu(tfc) () ().4 () () 9.1 () () - Me Me () () () 8. () Et C C Et () () () () () 3.9 () () ().4 () M. Mauksch,. B. Tsogoeva,.-W. Wei, I. M. Martynova, Chirality, 007, 19, 816

8 1.0E05 8.0E04 6.0E04 4.0E04.0E04 0.0E00 -.0E04 µv [min] Measurement of product enantiomeric excess in the Mannich reaction, run under achiral conditions Measurement of product enantiomeric excess in the Mannich reaction, run under achiral conditions Et C (0.5 mol l -1 ) Me Me 6 days, T C Et Acetone 35%, 9.5% ee () Et C Me days, T C Et 9.1% ee () (by chiral LC) Me LC chromatograms (chiral D column) 1 M (300 Mz, CDCl 3 ) signals of C 3 C group in ()- and ()- enantiomers in presence of Eu(tfc) 3 complex ( ) eak 1 ( ) eak UV_CI 1.5E05 Me µv ( ) eak UV_CI 9.5% ee () () () C Et rac 1.0E05 ( ) eak 1 9.1% ee () 5.0E04 0.0E [min] Deracemization in heterogenous system Asymmetric Autocatalysis in omogenous ystem Asymmetric Autocatalysis in eterogenous ystem W. L. oorduin, et al, JAC, 008, 130, 1158; Angew. Chem. Int. Ed., 008, 47, (solid) EtC ()-1 CEt EtC ()-1 (solid) A

9 Deracemization experiments with a Mannich-type reaction Deracemization process in the Mannich-type reaction at T 100,00 b - with glass beads c - without glass beads 90,00 80,00 a - without glass beads 70,00 60,00 ee [% %] 50,00 40,00 d-with glass beads a - with 17.4% ee of 1; 15 mol% of rac-3 b - with 17.5% ee of 1; 30 mol% of rac-3 30,0000 c - with 17.5% ee of 1; 30 mol% of rac-3 0,00 d - with 13.9 % ee of 1; 30 mol% of 4. B. Tsogoeva,.-W. Wei, M. Freund, M. Mauksch, Angew. Chemie Int. Ed. 009, 48, , time [days] tirring ate: 1300 rpm Deracemization process with an achiral catalyst at T Deracemization process in the Mannich-type reaction at 40 o C xcess [%] Enanti iomeric E tirring ate: 1300 rpm. 4-with glass beads 1-without glass beads -without glass beads 5-with glass beads 3-without glass beads 4 -Br-Bz EtC (10% ee) yrrolidine 1 - with 8 mol% yrrolidine - with 15 mol% yrrolidine 3 - with 4 mol% yrrolidine 4 - with 4 mol% yrrolidine, with with glass glass beads beads 5 - with 8 mol% yrrolidine, with with glass glass beads beads Time [days] -form] c Excess [% Enantiomeric Crystal hase ee olution hase ee Time [hours] a) with yrrolidine (8 mol%) (solid) c Excess [% -form] Enantiomeric Crystal hase ee olution hase ee tirring ate: 1300 rpm Time [hours] b) w/o yrrolidine 4 -Br-Bz 4 -Br-Bz 4 -Br-Bz EtC CEt EtC ()-1 ()-1 (15.8% ee).-w. Wei, M. Mauksch,. B. Tsogoeva, Chem. Eur. J. 009, 15, 1055 (solid)

10 Asymmetric Autocatalysis Asymmetric Autocatalysis is the major challenge in future Asymmetric ynthesis. omogenous ystems eterogenous ystems. Wynberg, Chimia, 1989, 43, 150