Asymmetric Brønsted Acid Catalysis: ACETALS & CONFINED CATALYSTS I n a u g u r a l ‐ D i s s e r t a t i o n zur Erlangung des Doktorgrades der Mathematisch‐Naturwissenschaftlichen Fakultät der Universität zu Köln vorgelegt von Ilija Čorić aus Zagreb (Kroatien) Köln 2012 Berichterstatter: Prof. Dr. Benjamin List Prof. Dr. Hans‐Günther Schmalz Prof. Dr. Axel Klein Tag der mündlichen Prüfung: 25 Juni 2012 TABLE OF CONTENTS TABLE OF CONTENTS ABSTRACT................................................................................................................. IV KURZZUSAMMENFASSUNG........................................................................................ V LIST OF SIMBOLS AND ABBREVIATIONS..................................................................... VI ACKNOWLEDGEMENTS ........................................................................................... VIII 1. INTRODUCTION...................................................................................................... 1 1.1. Acetals ....................................................................................................................1 1.2. Brønsted acid catalysis with small and unbiased substrates....................................3 2. BACKGROUND........................................................................................................ 5 2.1. Asymmetric catalysis...............................................................................................5 2.2. Asymmetric organocatalysis....................................................................................8 2.3. Asymmetric Brønsted acid catalysis ...................................................................... 11 2.4. Chiral phosphoric acids and derivatives ................................................................ 16 2.4.1. Chiral environment..........................................................................................16 2.4.2. Phosphoric acid derivatives.............................................................................18 2.5. Asymmetric synthesis of acetals............................................................................ 21 2.5.1. Chiral staring materials ...................................................................................21 2.5.2. Catalytic asymmetric methods........................................................................22 2.5.3. Catalytic asymmetric syntheses of N,X‐acetals (X = N, O, S, Se).....................26 3. OBJECTIVES OF THIS PH.D. WORK..........................................................................29 3.1. Catalytic Asymmetric Acetalizations...................................................................... 29 3.2. Confined Brønsted acids........................................................................................ 31 4. RESULTS AND DISCUSSION ....................................................................................32 4.1. Catalytic asymmetric transacetalization................................................................ 32 4.1.1. Reaction design and optimization...................................................................32 4.1.2. Substrate scope...............................................................................................34 4.1.3. Discussion........................................................................................................37 4.2. Kinetic resolution of homoaldols via catalytic asymmetric transacetalization ....... 41 4.2.1. Reaction design and optimization...................................................................41 4.2.2. Substrate scope...............................................................................................43 4.2.3. Utility of the products .....................................................................................48 I TABLE OF CONTENTS 4.2.4. Discussion........................................................................................................49 4.3. Catalytic asymmetric spiroacetalization ................................................................ 51 4.3.1. Reaction design and optimization...................................................................51 4.3.2. Substrate scope...............................................................................................57 4.3.3. Nonthermodynamic and thermodynamic spiroacetals ..................................60 4.3.4. Discussion........................................................................................................62 4.4. Confined Brønsted acids........................................................................................ 66 4.4.1. Design ..............................................................................................................66 4.4.2. Synthesis..........................................................................................................71 4.4.3. X‐Ray structures ..............................................................................................73 4.4.4. Discussion........................................................................................................77 5. SUMMARY ............................................................................................................80 5.1. Catalytic asymmetric transacetalization................................................................ 80 5.2. Kinetic resolution of homoaldols via catalytic asymmetric transacetalization ....... 81 5.3. Catalytic asymmetric spiroacetalization ................................................................ 82 5.4. Confined Brønsted acids........................................................................................ 83 6. OUTLOOK..............................................................................................................85 6.1. Kinetic resolutions of homoaldols ......................................................................... 85 6.2. Catalytic asymmetric transetherification............................................................... 86 6.3. Imidodiphosphoric acids as the second generation of stronger Brønsted acids ..... 87 7. EXPERIMENTAL SECTION .......................................................................................90 7.1. General Experimental Conditions.......................................................................... 90 7.2. Catalytic asymmetric transacetalization................................................................ 93 7.2.1. Starting materials ............................................................................................93 7.2.2. Products.........................................................................................................105 7.2.3. X‐Ray data for compound 3d ........................................................................114 7.3. Kinetic resolution of homoaldols via catalytic asymmetric transacetalization ..... 119 7.3.1. Optimization of the reaction conditions .......................................................119 7.3.2. Substrates......................................................................................................121 7.3.3. Products.........................................................................................................131 7.3.4. Transformations of 5c, determination of absolute configurations, and natural product syntheses ...................................................................................................147 II TABLE OF CONTENTS 7.4. Catalytic asymmetric spiroacetalization .............................................................. 152 7.4.1. Substrates......................................................................................................152 7.4.2. Products.........................................................................................................161 7.5. Confined Brønsted acids...................................................................................... 172 7.5.1. Synthesis........................................................................................................172 7.5.2. X‐Ray data for compounds 13a‐c ..................................................................200 8. BIBLIOGRAPHY ....................................................................................................226 9. APPENDIX ...........................................................................................................233 9.1. Erklärung............................................................................................................. 233 9.2. Lebenslauf........................................................................................................... 234 III ABSTRACT ABSTRACT The developments of Brønsted acid catalyzed asymmetric syntheses of acetals and a novel class of confined Brønsted acid catalysts are described. The first highly enantioselective intramolecular transacetalization reaction catalyzed by the chiral BINOL‐derived phosphoric acid TRIP was developed to access chiral acetals with the acetal carbon as the only stereogenic center. The practical utility of the catalytic asymmetric transacetalization reaction was demonstrated in a kinetic resolution of homoaldol acetals. Both secondary and tertiary homoaldols were resolved with high enantioselectivity using phosphoric acid STRIP based on a 1,1′‐spirobiindane backbone. The first catalytic asymmetric spiroacetalization reaction was developed, enabling access to small unfunctionalized spiroacetal compounds, including the