Graduate Theses and Dissertations

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1 University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 2008 Enantioselective Brønsted acid-catalyzed reaction methodology: Part a : enantioselective mannich reaction. Part b: enantioselective desymmetrization of meso-aziridines Emily Bretherick owland University of South Florida Follow this and additional works at: Part of the American Studies Commons Scholar Commons Citation owland, Emily Bretherick, "Enantioselective Brønsted acid-catalyzed reaction methodology: Part a : enantioselective mannich reaction. Part b: enantioselective desymmetrization of meso-aziridines" (2008). Graduate Theses and Dissertations. This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact scholarcommons@usf.edu.

2 Enantioselective BrØnsted Acid-Catalyzed eaction Methodology Part A: Enantioselective Mannich eaction Part B: Enantioselective Desymmetrization of meso-aziridines by Emily Bretherick owland A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Jon C. Antilla, Ph.D Kirpal Bisht, Ph.D. oman Manetsch, Ph.D. Peter Zhang, Ph.D. Date of Approval: July 3, 2008 Keywords: aziridine, desymmetrization, catalysis, phosphoric acid, BrØnsted Acid, Mannich, enantioselective, asymmetric Copyright 2008, Emily Bretherick owland

3 I would like to dedicate this to my husband, Gerald and my family. Thank you for loving and supporting me.

4 ACKWLEDGEMETS I would like to thank my research advisor, Dr. Jon Antilla, for giving me the opportunity to work in his lab and for lots of guidance. I would like to thank my husband, Dr. Gerald owland, for all of the support and help he has given me. I would like to thank my committee members, Dr. oman Manetsch, Dr. Peter Zhang, and Dr. Kirpal Bisht, for their time and assistance over the last few years. I want to thank all of my labmates at le Miss and USF. I would like to thank Dr. Haile Zhang, Dr. Yuxue Liang, Dr. Guilong Li for all of their help in the lab. I would also like to thank Qiang Zhang, Michelle Cortes-Salva, Gajendra Ingle, Shawn Larson, Kimberly Law, and Courtney Sobers. I want to thank my high school chemistry teacher Candice Golliver because she is the reason I majored in chemistry. I want to thank my undergraduate chemistry professors, Dr. Brent live and Dr. Tom Murray for teaching me that everything will work out if you try hard enough and for encouraging me to go to graduate school. I want to thank my other undergraduate professors, Dr. Anthony Blose and Dr. Donald oush for all the support they gave me as an undergraduate student. I want to thank my mom for everything she has done for me. I want to thank all of my family for being extremely supportive while I have pursued my degree. I want to thank my best friends Julie Bracey Sanderson and Johndra Upton for always being there for me whenever I needed someone to talk to.

5 TABLE F CTETS LIST F TABLES LIST F FIGUES LIST F SPECTA ABSTACT iii vi viii x CHAPTE 1: EATISELECTIVE BØSTED ACID-CATALYZED EACTI METHDLGY Introduction Mannich eaction Amidation and Imidation Hydrophosphonylation Friedel-Crafts eaction eduction Chemistry Cycloaddition eactions BrØnsted Acids used as Counterions Conclusion 25 CHAPTE 2: EATISELECTIVE MAICH EACTI Introduction Enantioselective rganocatalytic Mannich eaction Methodology Initial Developments of an Asymmetric Mannich eaction Conclusion 42 i

6 CHAPTE 3: EATISELECTIVE DESYMMETIZATI F MES- AZIIDIES Introduction Methodology for the Desymmetrization of meso-aziridines Enantioselective Desymmetrization of meso-aziridines Methodology Phosphoric Acid-Catalyzed Desymmetrization of meso-aziridines Conclusion 71 CHAPTE 4: EXPEIMETAL PCEDUES General Information Experimental Procedures for Chapter Experimental Procedures for Chapter 3 78 CHAPTE 5: SPECTA H and 13 C M for Chapter H and 13 C M for Chapter EFEECES 119 ABUT THE AUTH End Page ii

7 LIST F TABLES Table 1.1 Asymmetric Imine Amidation 6 Table 1.2 Asymmetric Imidation 7 Table 1.3 Akiyama s Enantioselective Hydrophosphonylation 8 Table 1.4 Terada s Enantioselective Friedel-Crafts eaction 9 Table 1.5 Terada s Friedel-Crafts eaction of Alkenes 9 Table 1.6 You s Friedel-Crafts eaction 10 Table 1.7 Antilla s Enantioselective Aza-Friedel-Crafts eaction: Variation of Imine 11 Table 1.8 Antilla s Enantioselective Aza-Friedel-Crafts eaction: Variation of Indole 11 Table 1.9 ueping s rganocatalytic eduction of Imines 13 Table 1.10 Lists Enantioselective Hydrogenation of Ketimines 14 Table 1.11 List s eductive Amination via Dynamic Kinetic esolution 16 Table 1.12 Antilla s eduction of α-imino Esters 17 Table 1.13 ueping s Asymmetric Synthesis of Isoquinuclidines with Two BrØnsted Acids 18 Table 1.14 Gong s Direct Aza Hetero-Diels-Alder eaction 19 Table 1.15 Terada s Tandem Aza-Ene eaction 20 Table 1.16 ueping s Asymmetric azarov Cyclization 21 Table 1.17 ueping s Alkynlation of α-imino Esters 23 iii

8 Table 2.1 Kobayashi s Enantioselective Mannich-Type eaction 28 Table 2.2 List s Proline Catalyzed Direct Mannich eaction 29 Table 2.3 Jacobsen s Thiourea catalyzed Mannich eaction 30 Table 2.4 Barbas s rganocatalytic Direct Mannich eaction with Aliphatic Aldehydes 30 Table 2.5 Barbas s rganocatalytic Direct Mannich eaction with Aromatic Aldehydes 31 Table 2.6 Akiyama s Asymmetric Mannich eaction 32 Table 2.7 Terada s Direct Mannich eaction 33 Table 2.8 Gong s Asymmetric Mannich eaction 34 Table 2.9 ueping s BrØnsted Acid Assisted Enantioselective BrØnsted Acid Catalyzed Direct Mannich eaction 35 Table 2.10 Schneider s Enantioselective Vinlylgous Mannich eaction 36 Table 2.11 Initial Investigations of an Enantioselective Mannich eaction Between Imines and β-keto Esters 37 Table 2.12 BrØnsted Acid-Catalyzed Addition of β-keto Esters to Imine with 4-Fluoro Substituent on the Aromatic ing 39 Table 2.13 BrØnsted Acid-Catalyzed Addition of Allylacetoacetate to -Boc protected Imines 40 Table 3.1 Yadav s InCl 3 -Catalyzed pening of Aziridines 47 Table 3.2 Hou s ing-pening of Aziridines with Trimethylsilyl Cyanide 48 Table 3.3 Meso-Aziridine pening with Zinc Chloride as a Catalyst 49 Table 3.4 Meso-Aziridine pening with Tributylphosphine as a Catalyst 49 iv

9 Table 3.5 Jacobsen s Desymmetrization of meso-aziridines 50 Table 3.6 Muller s Desymmetrization of meso--sulfonylaziridines 51 Table 3.7 Shibasaki s Desymmetrization of meso-aziridines with TMS-C 52 Table 3.8 Shibasaki s Desymmetrization of meso-aziridines with TMS-Azide 53 Table 3.9 Screening of Protecting Group on itrogen 56 Table 3.10 ptimization of eaction of Aziridine 195a with TMS-Azide 59 Table 3.11 ptimization of eaction of Aziridine 195f with TMS-Azide 61 Table 3.12 ptimization of eaction of Aziridine 195h with TMS-Azide 62 Table 3.13 Scope of Aziridine Substrate 64 v

10 LIST F FIGUES Figure 1.1. Thalomide and Carvone 2 Figure 1.2. Hydrogen Bonding Catalyts 3 Figure 1.3. Akiyama s Asymmetric Mannich eaction 4 Figure 1.4. Terada s Asymmetric Mannich eaction 4 Figure 1.5. Antilla s Friedel-Crafts eaction of Pyrroles to Imines 12 Figure 1.6 uping s Proposed Mechanistic Cycle for eduction of Imines 13 Figure 1.7 MacMillan s rganocatalytic eductive Amination 15 Figure 1.8 eductive Amination Proposed Mechanism 16 Figure 1.9 ueping s Mechanism for Synthesis of Isoquinuclidines 18 Figure 1.10 ueping s BrØnsted Acid and Metal-Catalyzed Alkynylation of α-imino Esters 22 Figure 1.11 Toste s Counterion-Mediated Enantioselective Hydroamination 24 Figure 1.12 Toste s Counterion-Mediated Hydroalkoxylation 24 Figure 1.13 List s Catalytic Asymmetric a-allylation of Aldehydes 25 Figure 2.1 Direct and Indirect Mannich eactions 27 Figure 2.2 Proposed Mechanistic Cycle for the BrØnsted Acid Assisted Asymmetric BrØnsted Acid-Catalyzed Mannich eaction 34 Figure 2.3 Initial easoning for the Addition of β-keto Esters to Imines 37 Figure 2.4 Tautamerization from VAPL Phosphoric Acid 38 Figure 2.5 ucleophilic Addition to Imines 41 vi

11 Figure 2.6 Schaus s Asymmetric Synthesis of Cyclic Urethane Derivatives 42 Figure 3.1 ing-pening of Aziridine in the Synthesis of Actinommycin D 45 Figure 3.2 Steps in the Synthesis of Tamiflu 45 Figure 3.3 Chiral Diamines 46 Figure 3.4 Preparation of 6-(3,5-Bis-trifluoromethylbenzoyl)-6- azabicyclo[3.1.0]hexane 57 Figure 3.5 Preparation of cis-1-(3,5-bis-trifluoromethylbenzoyl) 2,3- diphenylaziridine 57 Figure 3.6 Preparation of 3-xa-6-(3,5-bis-trifluoromethylbenzoyl)-6- azbicyclo[3.1.0]hexane 58 Figure 3.7 Preparation of 3-Carbobenzyloxy-6-(3,5- bistrifluorommethylbenzoyl)-3,6-diazbicyclo[3.1.0]hexane 58 Figure 3.8 Proposed Mechanism for the Phosphoric Acid-Catalyzed Desymmetrization of meso-aziridines 66 Figure 3.9 Figure 3.10 Figure H M eaction Array: Arrows Indicate Aziridine 186f 68 1 H M eaction Array: Arrows Indicate Product 196f 69 1 H M eaction Array: Arrows Indicate Intermediate 199f 70 vii

12 LIST F SPECTA Spectra Compound 136b 96 Spectra Compound 141b 97 Spectra Compound 136c 98 Spectra Compound 144a 99 Spectra Compound 144b 100 Spectra Compound 186a 101 Spectra Compound 186b 102 Spectra Compound 186c 103 Spectra Compound 186d 104 Spectra Compound 186e 105 Spectra Compound 186f 106 Spectra Compound 186g 107 Spectra Compound 186h 108 Spectra Compound 186i 109 Spectra Compound 196a 110 Spectra Compound 196b 111 Spectra Compound 196c 112 Spectra Compound 196d 113 Spectra Compound 196e 114 Spectra Compound 196f 115 viii

13 Spectra Compound 196g 116 Spectra Compound 196h 117 Spectra Compound 196i 118 ix

14 Enantioselective BrØnsted Acid-Catalyzed eaction Methodology Part A: Enantioselective Mannich eaction Part B: Enantioselective Desymmetrization of meso-aziridines Emily Bretherick owland ABSTACT The synthesis of enantiomerically pure compounds is of vital importance. Most biologically active natural products are chiral and require asymmetric synthesis, chiral resolution, or the use of naturally chiral starting materials for their preparation. rganocatalytic enantioselective reaction methodology is a continuously growing area in organic chemistry. The use of organocatalysts as a potentially environmentally friendly alternative to metal catalysts is appealing to the pharmaceutical industry. In this dissertation an enantioselective Mannich reaction using an organocatalyst was investigated. The reaction was between a β-keto ester and an imine electrophile catalyzed by vaulted biphenanthrol (VAPL) phosphoric acid. The reaction resulted in products with high yields, but low to moderate enantioselectivity and diastereoselectivity. The development of the first BrØnsted acid-catalyzed desymmetrization of mesoaziridines was also investigated. This is one of the first instances where a phosphoric acid has been used to catalyze a reaction that did not involve an imine. It was shown that the chiral VAPL phosphoric acid was an excellent catalyst for the reaction resulting in high yields and enantioselectivities for the chiral ring opened products. It was also shown, for the first time, that a vaulted binaphthol (VAL) phosphoric acid can also x

15 catalyze the ring-opening of meso-aziridines with comparable results to the VAPL phosphoric acid in some cases. Mechanistic M studies were used to probe the reaction, and it is believed that evidence leads one to conclude that a unique mechanism for phosphoric acid-catalysis is followed. The products that can be obtained from this reaction, 1,2-diamines, are of high value for synthetic chemists. They have been used as chiral auxiliaries, ligands, and precursors to natural products. xi

16 CHAPTE 1 EATISELECTIVE BSTED ACID-CATALYZED EACTI METHDLGY 1.1 Introduction The development of catalytic enantioselective reactions is a valuable strategy for modern organic synthesis. Several research laboratories around the world have focused on developing these types of reactions. 1 The chiral products obtained from such catalytic methodologies have been shown to be key steps in the synthesis of numerous natural products. 2 A large percentage of biologically active compounds are chiral, including the naturally occurring amino acids and enzymes. 3 Chiral natural products are important because of the biological activity of one enantiomer may be much different than the activity of the other enantiomer. 4 By synthesizing only the active enantiomer, there is much less waste produced. This also keeps down the cost of drugs because there is not as much starting material used in the reaction. In some cases, such as thalidomide, one enantiomer was used to decrease the symptoms of morning sickness and the other enantiomer was found to be teratogenic. 5 Therefore by using an untested racemic drug, detrimental side-effects from one of the enantiomers may be found. Another disadvantage of using racemic drugs, is the dosage may have to be increased so that the active enantiomer is given in an effective concentration. In some examples, such as thalidomide, if one enantiomer is given as a drug, it may racemize in the body. Another example where enantiomers have different properties is carvone. 6 The (S) enantiomer of 1

17 carvone is responsible for the flavor caraway and the () enantiomer is responsible for the flavor spearmint. H ()-Thalidomide (S)-Carvone 1 2 Figure 1.1 Thalidomide and Carvone Catalytic reaction methodology is extremely important in organic synthesis. The use of catalysts to perform organic transformations is an area that several research groups are developing. 2,6 For many reactions the presence of a catalyst leads to decreased reaction time, increased product formation, allows for more moderate reaction conditions, and also improved regio- and stereoselectivity. Until recently, catalysts were classified into two main categories: enzymes and metal complexes. ow there is another category of catalysts which many refer to organocatalyts. 7 rganocatalysis can be defined as the use of small organic molecules as catalysts and it represents an emerging area of organic methodology. The use of these catalysts have the potential to be an environmentally friendly alternative to metal catalysis. rganocatalysis appeals to large scale synthesis because of the relative lack of toxic byproducts that are commonly associated with some types of metal catalysis. rganocatlysts in many cases, are inexpensive, robust, and readily available. They are mostly bench stable and in some cases, do not require inert atmospheres, low temperatures, or exhaustively dry solvents like many metal-based systems. ne sub-type of organocatalysts are the hydrogen-bonding catalysts which are shown in Figure

18 The proline catalysts have been used most successfully for aldol reactions. 8 Chiral thioureas have particularly successful hydrogen-bonding frameworks used in the catalysis of the Strecker reaction, Mannich reaction, aza-henry as well as several others. 9 Hetero- Diels-Alder reactions have been catalyzed by TADDL, a simple chiral diol. 10 Phosphoric acids, such as BIL phosphoric acid, are also hydrogen-bonding catalysts. 9,11 These phosphoric acids are bi-functional catalysts that contain a Lewis base and a BrØnsted Acid site. Chiral phosphoric acids have been shown to be excellent catalysts for a wide variety of enantioselective transformations. H H C 2 H H t-bu H H S H t-bu Thiourea-based L-Proline catalyst TADDL Figure 1.2 Hydrogen Bonding Catalysts 1.2 Mannich eaction H 3 C H 3 C Ar Ar Ar H H Ar P H ()-BIL Phosphoric Acid Lewis Base Bronsted Acid Carbon-carbon bond forming reactions are one of the most highly developed reactions in organic chemistry. The Mannich reaction is a carbon-carbon bond forming reaction that involves the reaction of an enol with an iminium ion. 8,9,12 In 2004 Akiyama and co-workers reported the first example of a chiral phosphoric acid-catalyzed reaction. 13 It was shown that a chiral hindered BIL derived phosphoric acid was an excellent catalyst for an asymmetric Mannich eaction. The enantioselective catalytic addition of silyl enol ethers to ortho-hydroxy imines resulted in yields up to 100% and enantioselectivity up to 96% ee as shown in Figure 1.3 below. 3

19 H + TMS Me 1.5 equiv = Ph, 4-MeC 6 H 4, 4-FC 6 H 4, 4-ClC 6 H 4, 4-MeC 6 H 4 PA1 Toluene H H Me P H BIL PA1 = 4-2 C 6 H 4 Figure 1.3 Akiyama s Asymmetric Mannich eaction Terada and co-workers reported an enantioselective Mannich reaction as well. The addition of acetylacetone to -Boc protected Imines resulted in yields up to 99% and enantioselective excess up to 98%. 14 This was another example of a chiral BIL derived phosphoric acid being used as a catalyst as shown in Figure 1.4 below. Boc H Boc 2 mol% PA2 + CH Ac 2 Cl 2 H 1.1 equiv Ac = 4-MeC 6 H 4, p-fc 6 H 4, 4-BrC 6 H 4, 4-MeC 4 H 4 P H BIL PA2 =4-(!-naph)-C 6 H 4 Figure 1.4 Terada s Asymmetric Mannich eaction The above examples are only two of several asymmetric Mannich reactions catalyzed by a phosphoric acid. These two and others will be discussed in more detail in chapter 2. 4

20 1.3 Amidation and Imidation ur group was the first to report a chiral phosphoric acid-catalyzed enantioselective addition of amides to protected imines with sulfonamides. 15 Previous work for the addition of carbon nucleophiles to imines required electron-withdrawing groups on both the imine nitrogen and imine carbon atoms. The results for this VAPL phosphoric acid-catalyzed amidation indicated the reaction scope was found to be quite general. The reaction tolerated the presence of electron-withdrawing and donating substituents on the imines (Table 1.1, entries 9-12) as well as two examples of heteroaromatic substituents. The addition of a variety sulfonamides also resulted in product formation with high yields and high enantioselectivities. This reaction can be potentially used to synthesize retro-inverso peptide mimetics popularized by Goodman and co-workers. 16 With the success of the imine amidation, the methodology was extended to an enantioselective reaction between imines and imides. 17 This reaction also tolerated electron-withdrawing and donating substituents on the imine. Several substituted imides also produced excellent results. The VAPL phosphoric acid was shown to catalyze the imine imidation resulting in excellent yield and enantioselectivity (Table 1.2). 5

21 Table 1.1 Asymmetric Imine Amidation Ar Boc Catalyst H Boc + H 2 T, solvent Ar H P H BIL PA3 = H PA2 = 4(!-naph)-C 6 H 4 PA4 = 4("-naph)-C 6 H 4 Ph Ph P H VAPL PA5 Entry Ar mol% Acid Time Ph Ph Ph Ph Ph Ph S 7 Ph S 8 Ph S Ts Ts Ts Ts Ms Me Me 5 mol% PA3 4 mol% PA2 5 mol% PA4 5 mol% PA5 5 mol% PA5 5 mol% PA5 16 h 20 h 24 h 1 h 1 h 1 h 20 mol% PA5 50 h 20 mol% PA5 15 h ClC 6 H 4 4-BrC 6 H 4 4-CF 3 C 6 H 4 Ts Ts Ts 10 mol% PA5 10 mol% PA5 10 mol% PA5 17 h 13 h 20 h 12 4-MeC 6 H 4 Ts 10 mol% PA5 17 h 13 2-thienyl Ts 10 mol% PA5 17 h Cl Yield % ee % 95 <

22 Table 1.2 Asymmetric Imidation Ar Boc nitrogen 5 mol% PA5 H Boc nucleophile ether, T, 24h Ar Ph Ph P VAPL PA5 H Entry Ar ucleophile % Yield % ee 1 4-MeC 6 H 4 H Entry Ar ucleophile % Yield % ee 5 Ph MeC 6 H MeC 6 H 4 H MeC 6 H MeC 6 H 4 H MeC 6 H 4 Me H MeC 6 H 4 4-ClC 6 H MeC 6 H 4 Br H aph Hydrophosphonylation An enantioselective hydrophosphonylation was reported by Akiyama and coworkers, requiring the addition of a phosphite to an imine with a chiral BIL derived phosphoric acid catalyst. 18 The phosphoric acid hydrogen was used as a Brønsted acid to activate the aldimine. The phosphoryl oxygen was used as a Brønsted base to coordinate with the hydrogen of the phosphite and activate the oxygen of the phosphoryl. This lead to the high yields and enantioselectivities as shown in Table 1.3 below. 7

23 Table 1.3 Akiyama s Enantioselective Hydrophosphonylation Me H PMP 10 mol% PA6 + H P i-pr i-pr P i-pr m-xylene, T i-pr Entry % Yield % ee 1 Ph MeC 6 H BrC 6 H 4 CH=CH C 6 H 4 CH=CH CF 3 C 6 H 4 CH=CH P H BIL PA6 = 3,5-CF 3 C 6 H 3 H P Ar P H H Ar Proposed Transition State 1.5 Friedel-Crafts eaction Atom economical reactions are one goal that organic chemists try to achieve. The strategy serves to minimize waste and use up all the available reactants. The aza-friedel- Crafts reaction is one example of this type of atom economical reaction. 19 The reaction can be used to synthesize a wide variety of nitrogen-containing natural products and biologically active compounds. Several groups have reported aza-friedel-crafts reactions using chiral BrØnsted Acid catalysts. Terada and co-workers demonstrated an enantioselective Aza Friedel-Crafts reaction between a furan and -Boc protected imine. 20 Although there was a wide variety of substituents on the imine, only a single furan was used. Because of this, the reaction did not have a wide scope in terms of the nucleophile. The reaction did tolerate a variety of imines with electron-donating and 8

24 electron-withdrawing substituents. Imines were also used that contained heteroaromatic substituents. The reaction lead to products with yields up to 95% and enantioselective excess up to 97% (Table 1.4). Table 1.4 Terada s Enantioselective Friedel-Crafts eaction Boc H Boc + Me 2 mol% PA (CH 2 Cl) 2 Ar Ar H Entry % Yield % ee 1 4-MeC 6 H MeC 6 H BrC 6 H FC 6 H napth furyl Ph Me P H BIL PA7 = 3,5-dimesitylphenyl Terada and co-workers also reported a Friedel-Crafts reaction of electron rich alkenes. 21 A BIL derived phosphoric acid was used as the catalyst. It was shown that the system allowed for a variety of indoles with electron-withdrawing and donating substituents. They reported 11 examples with yields up to 98% and enantioselective excess up to 96% (Table 1.5). Table 1.5 Terada s Friedel-Crafts reaction of Alkenes Ar H Boc 2 mol% PA8 H Boc + H H CH 3 C, -20 o C, 12h H P H Ar BIL PA8 Ar = 2,3,6-i-PrC 6 H 2 9

25 In 2007 You and co-workers reported the addition of indole to -tosyl protected imines. 22 The reaction required five equivalents of indole and low temperatures. The reaction tolerated electron-donating groups on the imine, but a drop in enantioselectivity was observed when electron-withdrawing substituents were present (Table 1.6). Table 1.6 You s Friedel-Crafts eaction Ts H Ts 2 H 10 mol% PA9 1 + Toluene, -60 o C 1 H H 2 Entry 1 % Yield % ee 2 1 H H H 5-Me H 5-Br Me H 93 > Cl H CF 3 H Me H Ar Ar BIL PA9 Ar = 1-naphthyl P H ur group developed an enantioselective aza Friedel-Crafts reaction between several aryl substituted -benzoyl protected imines and substituted indoles catalyzed by a chiral BIL derived phosphoric acid. 23 The reaction required the use of only 5 mol% catalyst and 2 equivalents of imine. The reaction tolerated electron-donating and electron-withdrawing substituents on both the imine and on the indole. The only example that did not result in a 90% or greater enantioselectivity was the reaction with the 2-Me indole. This is believed to be because of steric hindrance of the indole. This Friedel- Crafts reaction resulted in yields up to 99% and enantioselective excess up to 96%. 10

26 Table 1.7 Antilla s Enantioselective Aza-Friedel-Crafts eaction: Variation of Imine 5 mol% PA10 Ph H Ph CH 2 Cl 2, -30! C 4 Å MS, 16 h Bn 30 Bn Entry % Yield % ee 1 H Cl Br F Me Me Me Me napth SiPh 3 P H SiPh 3 BIL PA10 Table 1.8 Antilla s Enantioselective Aza-Friedel-Crafts eaction: Variation of Indole Ph 5 mol% PA10 Ph H Ph + Ph CH 2 Cl 2, -30! C 4 Å MS, 16 h Bn 33 Bn Entry % Yield % ee SiPh Br C 2 Me Me Me Me Me P H SiPh 3 BIL PA10 11

27 Antilla and co-workers also extended this methodology to include the addition of pyrroles to imines (Figure 1.5) with yields up 97% and enantioselective excess up to 99%. 24 This reaction also tolerated a variety of substituents on the imine and pyrrole Ph mol% PA10 CH 3 Cl, -55 to -60 o C 1 Ph H BIL PA10 = SiPh 3 P H Figure 1.5 Antilla s Friedel-Crafts eaction of Pyrroles to Imines The above reactions mentioned were just a few Friedel-Crafts reactions, several other research groups have reported enantioselective Friedel-Crafts reactions using chiral phosphoric acid catalysts as well eduction Chemistry Current methodology for the asymmetric reduction of imines involves transition metal catalyzed transfer hydrogenation, high pressure hydrogenations, or hydrosilylations. 26 Several reactions have been reported that utilize nonmetallic catalysts such as chiral thioureas, diols, and phosphates for enantioselective organic transformations. 27 ecently several groups have been investigating chiral BrØnsted acids as an alternative to previously reported metal catalysis. In 2005 ueping and co-workers investigated a BrØnsted acid-catalyzed transfer hydrogenation. 28 This reaction utilized a chiral BIL phosphoric acid based catalyst for the enantioselective reduction of imines. The hydrogen source used for the reduction was Hantzsch dihydropyridine. As shown in Table 1.9, several aromatic ketimines were reduced resulting in high yields and 12

28 enantioselectivities. The mechanism for the reaction was also proposed as shown in Figure 1.6. The reaction proceeds via protonation of the imine with the phosphoric acid followed by hydrogen transfer from Hantzsch ester. Table 1.9 ueping s rganocatalytic eduction of Imines 36 1 Et Et 3 H mol% PA6 H * Entry % Yield % ee 1 2-napht Me PMP napht Me Ph FC 6 H 4 Me PMP FC 6 H 4 Me PMP MeC 6 H 4 Me PMP Me Me PMP P H BIL PA6 = 3,5-(CF 3 )-Ph Et 41 Et Ar Ar P H PA Et Ar Ar P H 38 H 1 Ar Ar P Figure 1.6 ueping s Proposed Mechanistic Cycle for eduction of Imines 40 Et 3 2 List and co-workers independently reported a reaction parallel to that of Et H H H H Et ueping s asymmetric catalytic hydrogenation of ketimines. 29 A chiral BIL 13

29 phosphoric acid based catalyst was used as well. Improved results were reported with Hantzsch ester serving as the hydride source for the enantioselective catalytic hydrogenation of ketimines, which was similar to ueping s hydrogenation. Several imines with electron-donating and electron-withdrawing substituents were reacted with Hantzsch s ester and the phosphoric acid, which resulted in yields up to 98% and enantioselective excess up to 88%. Table 1.10 List s Enantioselective Hydrogenation of Ketimines PMP Me eq. Hantzsch ester 1 mol% PA11 Entry % Yield % ee 1 Ph CC 6 H FC 6 H C 6 H MeC 6 H MeC 6 H H PMP Me 43 P H BIL PA11 = 2,2,4-i-Pr-Ph In 2006 MacMillan and co-workers reported the first organocatalytic reductive amination that includes a coupling between ketones and amines. 30 The reaction proceeds via hydrogen boding between a chiral phosphoric acid and the substrates along with Hantzsch s ester as a source of hydride for the reduction of an iminium species produced in situ. It was shown that aromatic and alkyl ketones worked well for the coupling and reduction with aromatic amines. It was also shown that aromatic ketones reacted with heterocyclic amines. All of these variants for the reaction resulted in products with high yield and enantioselectivity as shown below in Figure

30 X H 2 10 mol% PA10 H Me + HEH, o C h, benzene Me Me X H 2 10 mol% PA10 HEH, o C H Me h, benzene Me Me H 2 10 mol% PA10 H Me + HEH, o C h, benzene Me X 51 Me Me X Figure 1.7 MacMillan s rganocatalytic eductive Amination In 2006 List and co-workers published another reductive amination. This report demonstrated a coupling reaction between an aldehyde and aromatic amine, which was reduced via dynamic kinetic resolution. 31 The reaction proceeded through an imimium intermediate which was reduced with a hydride produced from Hantzsch s ester and a substituted BIL phosphoric acid catalyst, which is shown in Figure 1.8 as the proposed mechanism. Seventeen examples were reported as shown in Table 1.11 below with yields up to 96% and ee up to 98%. 15

31 Table 1.11 List s eductive Amination via Dynamic Kinetic esolution 1 H H t-bu 2 C C 2 Me Me + H 1.2 eq 53 H H 2 Me 5 mol% PA, benzene, 72 h Me 54 Me Entry % Yield % ee 1 Ph MeC 6 H naph BrC 6 H FC 6 H CF P H BIL PA11 = 2,2,4-i-Pr-Ph 1 Me 52 + H H 2 1 Me 2 1 H 2 H H 55 Me 56 1 Me 2 H 55 H 2 HX* 1 H Me 2 H Me t-bu 2 C C 2 Me t-bu 2 C H H C 2 Me 58 H 53 Figure 1.8 eductive Amination Proposed Mechanism In 2007 our group reported an enantioselective reduction of α-imino esters. 32 This was the first report of phosphoric acid-catalyzed reduction which produced acyclic α-amino esters. atural and unnatural α-amino acids are highly important compounds in pharmaceutical and biological industries. This reduction was another example of 16

32 VAPL phosphoric acid catalyst resulting in the highest yields and enantioselectivity for the reduction of α-imino esters. Several other groups have also reported enantioselective catalytic reductions of imines as well as pyridines and other heterocyclic compounds. 33 Table 1.12 Antilla s eduction of α-imino Esters 1 Et Et H H! C 2 Et 20 mol% PA5 1 C 2 Et Entry 1 2 % Yield % ee 1 Ph 4-MeC 6 H MeC 6 H 4 4-MeC 6 H ClC 6 H 4 4-MeC 6 H Ph Ph (CH 2 ) 5 CH 3 4-MeC 6 H CH 2 CH 2 4-MeC 6 H Ph Ph P H VAPL PA5 1.7 Cycloaddition eactions The synthesis of heterocyclic compounds is of great interest to chemists. umerous examples of heterocyclic natural products with vast biological importance have been isolated. 34 Most of these natural products are chiral. The development of enantioselective methodology to synthesis chiral heterocycles is of vital importance. Cycloaddition reactions are one route to the synthesis of heterocyclic compounds. 35 In 2006 ueping and Gong independently reported a BrØnsted acid-catalyzed aza- Diels-Alder reaction with cyclohexenone and aldimines. 36,37 The aza-diels-alder reaction is a great method for the preparation of piperidine derivatives. As shown in Table 1.13 ueping and co-workers prepared isoquinuclidines using a BIL derived chiral BrØnsted acid catalyst along with acetic acid to assist the catalytic cycle. 17

33 Isoquinuclidines are compounds that are found in naturally occurring biologically important alkaloids. 36 The proposed catalytic cycle, as shown in Figure 1.9 below, involves the acetic acid helping to equilibrate the cyclohexenone to the enol form. The enol then reacts with the iminium ion to form the Diels-Alder product. As shown in Table 1.13, several substituted imines were reacted with cyclohexenone resulting in moderate yields and enantioselectivity. Table 1.13 ueping s Asymmetric Synthesis of Isoquinuclidines with Two BrØnsted Acids 4-BrC 6 H 4 10 mol% PA12, cyclohexenone, 4-BrC 6H 4 AcH H Toluene, T Entry exo/endo % Yield % ee 1 Ph 1/ thienyl 1/ P H 3 4ClC 6 H 4 1/ FC 6 H 4 1/ ClC 6 H 4 1/ BIL PA12 = 4-biphenyl 2 Ar P Ar H PA Ar H P H 2 Ar achiral Bronsted Acid 1 H H Figure 1.9 ueping s Mechanism for Synthesis of Isoquinuclidines 18

34 Gong and co-workers aza Diels-Alder reaction also used a chiral BIL derived BrØnsted acid to catalyze the reaction between cyclohexenone and aldimines. 37 They reported ten examples resulting in moderate yields and enantioselectivity. It was also shown that the major product was in the endo conformation. Table 1.14 Gong s Direct Aza Hetero-Diels-Alder eaction PMP H Ar 5 mol% PA + Toluene, 20 o + C Ar H H Ar PMP PMP Entry Ar endo/exo % Yield % ee a 1 C 6 H 5 84/ ClC 6 H 4 81/ ClC 6 H 4 82/ ClC 6 H 4 81/ FC 6 H 4 80/ BrC 6 H 4 82/ a ee for major product BIL PA13 = 4-ClC 6 H 4 P H In 2007 Terada and co-workers developed a tandem aza-ene reaction that produced chiral piperidines which have several chiral centers. 38 The reaction was between -acyl imines and substituted enecarbamates. A chiral BIL derived phosphoric acid was used as the catalyst. It was observed that the major product was the trans-isomer and only two diastereomers were obtained. It was shown that aromatic, heteroaromatic, aliphatic and other substituted aldimines all gave good to excellent yields and excellent enantioselective excess a shown in Table 1.15 below. 19

35 Table 1.15 Terada s Tandem Aza-Ene eaction Cbz Cbz Boc H Cbz H H 2 mol% PA + Boc Boc CH 2 Cl 2, 0 o + C H H H H Entry trans/cis % Yield % ee a 1 4-BrC 6 H 4 94/6 > MeC 6 H 4 95/5 > furyl 88/ Ph-CH=CH- 95/ C 2 Me 88/ C 6 H 11 94/ a % ee is for trans isomer only P H BIL PA14 = 4-PhC 6 H 4 ueping and co-workers reported the first enantioselective organocatalytic electrocyclic reaction. 39 They investigated an asymmetric azarov cyclization. The azarov cyclization is a versatile method to prepare five membered-rings, which are key structural components of numerous natural products. It was shown that a chiral BIL derived BrØnsted acid catalyzed the cyclization. Several different substituted dienones were shown to cyclize in the presence of a phosphoric acid catalyst. A summary of the reaction is shown in Table Eleven examples were reported with high yields and moderate enantioselectivities. 20

36 Table 1.16 ueping s Asymmetric azarov Cyclization 1 2 mol% PA CHCl 3, 0 o C Entry 1 2 cis/trans % Yield % ee (cis) % ee (trans) 1 Me Ph 6/ CH 2 -nbu Ph 3.2/ Me 2-naph 9.3/ n-pr Ph 3.2/ n-pr 4-MeC 6 h 4 2.6/ n-pr 4-BrC 6 H 4 3.7/ P H BIL PA15 Ar = 9-phenanthryl 1.8 BrØnsted Acids used as Counterions Most of the previous work with BrØnsted acid catalysis has involved ion-pair formation or hydrogen bonding between the chiral phosphoric acid and the nucleophile. A new, emerging area of BrØnsted acid catalysis involves classic metal catalysis in the presence of chiral counterions. This methodology involves a BrØnsted acid activating the electrophile and a metal salt activating the nucleophile. ueping and co-workers proposed a catalytic mechanism (Figure 1.10) for the enantioselective alkynylation of α-imino esters as shown below. 40 In cycle A the imine and phosphoric acid form an ion pair. In cycle B the alkyne is activated by a metal salt. Then ion pair and activated alkyne then proceed to the final enantioselective product. The reactions that have been developed using this methodology would otherwise not occur without the combination of the phosphate counterion and metal catalyst. 21

37 P H PG 1 81 PG 2 C H 79 A [M] B 1 2 C 76 H P H PG H X M C 2 Figure 1.10 ueping s BrØnsted Acid and Metal-Catalyzed Alkynylation of α-imino Esters ueping and co-workers developed an enantioselective alkynylation of α-imino esters. 40 The reaction involved the addition of several alkynes to p-methoxyphenyl protected α-imino esters using a chiral BrØnsted acid in combination with silver acetate. The mild reaction conditions and no need to pre-form the catalyst are appealing. This is also the first time an organometallic compound had been added to an aldimine with a BIL phosphate. ueping reported eight examples with yields up to 93% and enantioselectivity up to 92%. 22

38 Table 1.17 ueping s Alkynylation of α-imino Esters PMP + 2 C H mol% PA15 5 mol% AgAc Toluene Entry % Yield % ee 1 Ph MeC 6 H MeC 6 H ,5-MeC 6 H t-BuC 6 H PMP H C 2 Ar P H Ar BIL PA15 Ar = 9-phenanthryl 78 Another example of counterion-mediated reaction is the hydroamination reported by Toste and co-workers in They investigated reactions that utilized a phosphate counterion derived from BIL with a gold complex. It was shown that the protonated phosphate, the phosphoric acid, alone did not catalyze the reaction and neither did the silver phosphate. It was also shown that the Ph(CH 3 ) 2 PAuCl alone did not catalyze the reaction, it was a combination of all three of the above reagents. The products of the hydroamination resulted in high yields and enantioselectivity, which is shown in Figure The scope of the reaction was expanded to a hydroalkoxylation reaction, with eight examples resulting in yields up to 96% and ee up to 97% as shown in Figure

39 HS 2 Mes HS 2 Mes HS 2 Mes HS 2 Mes 5 mol% Ph(CH 3 ) 2 PAuCl 5 mol% Ag-()-PA16 benzene, T, 48 h H H S 2 Mes H S 2 Mes S 2 Mes H S 2 Mes 97% Yield 96% ee 88% Yield 98% ee 84% Yield 99% ee 73% Yield 98% ee P H BIL PA16 = 2,4,6-i-Pr-C 6 H 2 Figure 1.11 Toste s Counterion-Mediated Enantioselective Hydroamination mol% dppm(aucl) 1 H 2 H 5 mol% Ag-()-PA benzene, T Figure 1.12 Toste s Counterion-Mediated Hydroalkoxylation An asymmetric α-allylation of aldehydes was reported by List and co-workers in This was another example of a counterion in metal catalysis. It was shown that chiral phosphoric acids induced chirality in a palladium-catalyzed α-allylation. This is the first example of an asymmetric catalytic α-allylation of α-branched aldeyhdes. Twelve examples were reported with yields up to 89% and ee up to 97%. 24

40 3 1.5 mol% PA mol% Pd(PPh 1 3 ) 4 + Ph MTBE, 40 o C, 8-24 h 2 CH 1 Ph then 2 HCl, Et 2 92 H 93 T, 0.5 h 2 CH 94 Figure 1.13 List s Catalytic Asymmetric α-allylation of Aldehydes 1.9 Conclusion Phosphoric acid catalysis has been shown to be a versatile type of catalysis for a large number of organic transformations. These organocatalysts have been developed as an alternative to metal catalysis. The development of enantioselective reaction methodology is highly important to the pharmaceutical and biological industries. Chiral phosphoric acids have been shown to be impressive catalysts for the synthesis of asymmetric products with high yields and enantioselectivity. Most of the phosphoric acid catalysis methodology involves the transformations of imines, but recently the methodology is branching out to include other types of compounds as well. The above examples are only a small amount of phosphoric acid-catalysis that have already been reported. There is still much more investigation to be done to realize the boundaries of asymmetric phosphoric acid-catalysis. 25

41 CHAPTE 2 PAT A: EATISELECTIVE MAICH EACTI 2.1 Introduction Carbon-carbon bond forming reactions are highly useful reactions in organic synthesis. The Mannich reaction, which involves the reaction of an enol with an iminium, has been highly investigated for the past several years. 43 It is very useful for the preparation of β-amino acids and β-lactams which are biologically important compounds. 44 Several researchers have employed metal-based catalysts for the enantioselective catalytic version of the Mannich reaction. ecently, several groups have been developing the reaction with organocatalysts. Initially, stoicheometric amounts of chiral acids were used, and then developed further with catalytic amounts of chiral acids. rganocatalysts such as proline and thiourea have been shown to be excellent chiral catalysts for asymmetric Mannich reactions. 8,9 Chiral phosphoric acids have also been shown to catalyze several asymmetric Mannich reactions. 11 Two major variations of the Mannich reaction have been developed. The direct variant involves unmodified ketone donors and amines. 8 The iminium ion is formed in situ in these cases. The indirect variant involves preformed enolate derivatives and preformed imines. Until recently, most of the Mannich reactions reported were of the indirect type. In general, it was easier to preform the imines and then react them with an enolate. The direct Mannich reactions sometimes lead to unwanted side products. 26

42 H H 2 3 Direct H preformed Imine + 1 ( 2 ) preformed enolate Indirect 3 2 Figure 2.1 Direct and Indirect Mannich eactions 2.2 Enantioselective rganocatalytic Mannich eaction Methodology The first truly catalytic enantioselective Mannich-type reaction with aldimines and silyl enolates was reported in 1997 by Kobayashi and co-workers. 45 They employed a catalytic amount of a chiral zirconium complex which was made in situ. Their method was based on chiral Lewis acid-catalysis. It was shown that aromatic aldimines as well as heterocyclic and aliphatic aldimines worked well for the reaction. The products obtained resulted in good to high yields and enantioselective excess. It was also shown that the Mannich reaction products were easily converted to β-amino esters by methylation of the phenolic H. 27

43 Table 2.1 Kobayashi s Enantioselective Mannich-Type eaction 1 H TMS 5-10 mol% Catalyst 3 2 CH 2 Cl 2, -45 o C Br Br H H Br Zr 98 Br Entry % Yield % ee 1 Ph Me Me Me ClC 6 H 4 Me Me Me naph Me Me Me Ph SEt H H ClC 6 H 4 SEt H H naph SEt H H 100 >98 The first enantioselective organocatalytic Mannich reaction was reported by List and co-workers in It was shown that (L)-proline was an excellent catalyst for a three component direct Mannich reaction. The reaction was between a ketone, aldehyde and p-anisidine. Several aldehydes were tested with various substituents resulting in moderate yields and good to excellent enantioselectivity. The aromatic and sterically hindered aldehydes (Table 2.2, entries 1-3) resulted in higher enantioselectivities than the other aldehydes tested. The observed low yields were due to the formation of aldol and condensation side products. 28

44 Table 2.2 List s Proline Catalyzed Direct Mannich eaction Me 35 mol% (L)-Proline H h H H Entry % Yield % ee C 6 H naph i-butyl n-butyl CH 2 CH 2 Ph i-pr PMP Jacobsen and co-workers reported an enantioselective synthesis of β-aryl-β-amino acids. 47 This Mannich reaction was between an enolate equivalent and aromatic -boc protected imines. A thiourea catalyst provided excellent results for the reaction. Low temperatures were required for optimum enantioselectivity and only 5 mol % of the chiral catalyst. The reaction tolerated electron-withdrawing and donating substituents in the ortho-, meta-, and para- position on the aromatic ring of the imine. It was also shown that heteroaromatic substituents also resulted in excellent enantioselectivity and yields. The reaction was very general with respect to the imines. It was determined that the β-amino acid products were easily deprotected with mild conditions. Fourteen examples were reported with excellent yields and enantioselectivities. 29

45 Table 2.3 Jacobsen s Thiourea catalyzed Mannich eaction Boc 1. 5 mol% 106 TBS HBoc + toluene, 48 h -i-pr 2. TFA, 2 min i-pr Entry % Yield % ee 1 Ph MeC 6 H MeC 6 H BrC 6 H BrC 6 H naph furyl pyridyl Ph Me t-bu 106 H S H H t-bu t-bu A direct organocatalytic Mannich reaction was developed by Barbas and coworkers in The reaction was between α-amino ethyl glyoxylate and several different aliphatic aldehydes catalyzed by L-proline. All of the enantioselectivities were excellent. The diastereoselectivities were observed to be dependent on the sterics and chain length of the aldehyde substituents. The longer the chain length, the higher the diastereoselectivity. This reaction is shown below in Table 2.4. Table 2.4 Barbas s rganocatalytic Direct Mannich eaction with Aliphatic Aldehydes PMP PMPH 2 H + 5 mol% L-Proline H Dioxane, 24 h, T C H C 2 Et 2 Et Entry % Yield dr % ee 1 i-pr 81 10: Me : Et : n-bu 81 3: n-pent 81 >19:1 >99 6 -CH 2 CH=CHC 5 H >19:

46 Barbas and co-workers extended their methodology to an organocatalytic Mannich reaction that utilized aromatic imines. The reaction required 30 mol % L- Proline and moderately low temperatures. Seven different aromatic imines were tested and all resulted in good yields and excellent enantioselectivity. As seen with the α-amino glyoxylate, the diastereoselectivity for this reaction was also dependent on the chain length of the aliphatic aldehyde. Again, the greater the chain length, the higher the diastereoselectivity. For example, an aldehyde with a pentane chain resulted in a dr of >19:1. The aldehydes with only methyl substituents resulted in a dr from only 3:1 to 10:1. Table 2.5 Barbas s rganocatalytic Direct Mannich eaction with Aromatic Aldehydes PMP mol% L-Proline PMP H DMF, 14 h, 4 + o C H 2. abh 4, DMF H 4 o C, 10 min Me 112 Entry % Yield dr % ee C 6 H : CC 6 H : BrC 6 H : ClC 6 H 4 81 >10: Ph 65 4: BrC 6 H 4 89 >19:1 99 In 2004 Akiyama and co-workers reported the first example of a phosphoric acidcatalyzed reaction. 13 It was reported that a chiral BIL derived phosphoric acid catalyzed an asymmetric Mannich-type reaction. The reaction was between a silyl enolate and ortho-hydroxy imine. Several BIL derived phosphoric acids were screened. It was determined that the 4-nitrophenyl substituent in the 3,3 position resulted in the highest enantioselectivity. The reaction required only 10 mol % phosphoric acid catalyst and low 31

47 temperatures to produce the optimum results. The reaction tolerated a variety of groups on the aromatic ring attached to the imine carbon and provided yields up to 100% and enantioselectivity up to 96% as shown in Table 2.6 below. Table 2.6 Akiyama s Asymmetric Mannich eaction H + TMS Me 1.5 equiv PA1 Toluene Entry % Yield % ee 1 Ph MeC 6 H FC 6 H ClC 6 H H H Me 115 P H BIL PA1 = 4-2 C 6 H 4 Terada and co-workers also reported an enantioselective Mannich reaction. Acetylacetone was added to -boc protected imines. 14 The scope of the imine is shown in Table 2.2 below. Six examples were reported with a variety of substituents on the aromatic ring of the imine. The reaction required 2 mol % of a BIL derived phosphoric acid and it was performed at room temperature. The reaction resulted in yields up to 99% and enantioselective excess up to 98%. 32

48 Table 2.7 Terada s Asymmetric Mannich eaction Boc + H 1.1 equiv Entry % Yield % ee 1 4-MeC 6 H BrC 6 H FC 6 H MeC 6 H MeC 6 H naph mol% PA2 CH 2 Cl 2 H Boc Ac 118 Ac P H BIL PA2 =4(!-naph)-C 6 H 4 Gong and co-workers developed a direct enantioselective Mannich reaction in It was shown that a chiral BIL derived phosphoric acid catalyst could be used to catalyze the reaction between simple ketones and imines. The imines were formed in situ from an aromatic amine and aromatic aldehyde. The major product from the reaction was the anti-selective conformation. ther than the report by Barbas and co-workers of a Mannich reaction of a simple ketone and α-imino ester, this was the first report of an anti-selective direct enantioselective Mannich reaction. 50 As shown below, several cyclohexanone derivatives and a variety of aromatic aldehydes containing both electrondonating and withdrawing substituents resulted in good diastereoselectivity and high yields and enantioselective excess. The tetrahydrothiopyran-4-one (entry 6-8) was less reactive than the other cyclohexanone derivatives and required the use of 2 mol % catalyst PA17 instead of the 0.5 mol % PA13 used for all the other reactions. It was also noted that the diastereoselectivity was highly dependent on both the aldehyde and ketone. 33

49 Table 2.8 Gong s Direct Asymmetric Mannich eaction H 0.5 mol% PA13 or 2 2 mol% PA17 H + + H PhCH X dr Entry X (anti/syn) % Yield % ee 1 CH 2 4-CF 3 C 6 H 4 77/ CH 2 4-BrC 6 H 4 83/ CH 2 4-MeC 6 H 4 81/ C 6 H 4 92/ Boc 4-2 C 6 H 4 80/20 > S 4-2 C 6 H 4 92/ S 3,5-F 2 C 6 H 3 98/ S 4-ClC 6 H 4 93/ P H BIL PA13 = 4-ClC 6 H 4 PA17 = Ph P H ueping and co-workers developed the first BrØnsted acid assisted asymmetric BrØnsted acid-catalyzed direct Mannich reaction. 51 A mechanism was proposed as shown in Figure 2.2. An achiral BrØnsted acid was used to activate the ketone by converting it to the enol form. This enol is then able to react with the iminium ion, which was formed from the chiral BrØnsted acid, which was derived from BIL, and the imine. The reaction was very general and tolerated aromatic imines with electrondonating and withdrawing substituents and heteroaromatic imines as well. The reaction produced β-amino ketones with moderate yields and good enantioselectivities as shown in Table * Ph H 2 1 achiral H BA Ph Ph HPA PA - H 1 2 H H Figure 2.2 Proposed Mechanistic Cycle for the BrØnsted Acid Assisted Asymmetric BrØnsted Acid-Catalyzed Mannich eaction 34