CATALYTIC ASYMMETRIC α-IMINOL REARRANGEMENT BY VANOL ZIRCONIUM COMPLEX By Xin Zhang A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2014 ABSTRACT CATALYTIC ASYMMETRIC α-IMINOL REARRANGEMENT BY VANOL ZIRCONIUM COMPLEX By Xin Zhang Catalytic asymmetric α-iminol rearrangement to the corresponding α-amino ketone is developed that is based on a chiral zirconium complex generated from the vaulted biaryl ligand VANOL. As many as 19 different asymmetric catalysts were examined to identify the first chiral catalyst for the asymmetric α-iminol rearrangement. Aluminate complexes of VANOL, VAPOL and 7,7’-tBu2VANOL were found very effective for this reaction giving up to 88% ee. The ne plus ultra catalyst for this reaction was discovered to be the VANOL zirconium complex, and for the majority of the substrates it gave 97% to >99% ee. An X-ray analysis of the crystal that was grown from the catalyst solution revealed that the zirconium has bonded to three VANOL molecules and this is also the first structure reported for zirconium with three bis-phenol ligands. ACKNOWLEDGEMENTS These 5 and half years I spent in MSU are definitely most precious time in my life, thanks to the offer for graduate study from MSU, I was able to learn organic chemistry, teach undergraduate courses, do research, make friends as well as experience and understand a lot more things out there. I feel so lucky to have the opportunity to meet all kind people around me, without their help, I would not be able to complete my PhD study. I would like to thank my advisor Professor Wulff, who allows me the full freedom to explore my research ideas. Without his support and suggestions, I would never have the opportunity to discover the methodology of catalytic asymmetric α-iminol rearrangement and VANOL aluminate and VANOL zirconium complex chiral catalysts. I feel so lucky to be one student in Professor Wulff’s group. I also would like to thank my PhD committee members Prof. Maleczka, Prof. Jackson, and Prof. Odom for their lectures in CEM 850, 851 and 852, and also their time and insightful suggestions for my research. I also would like to thank them for the support to my postdoc application. Members of the Wulff group are the best colleagues. In no particular order, I would like to thank Dr. Li Huang, Dr. Hong Ren, Dr. Yong Guan, Dr. Aman Desai, Dr. Anil Gupta, Dr. Dima Bervasov, Dr. Victor Prutyanov, Dr. Munmun Mukherjee, Dr. Nilanjana Majumdar, Dr. Wynter Osminski, Dr. Wenjun Zhao and Dr. Mathew iii Vetticatt, for their generous help and suggestions when I encountered difficulties in the experiments. Also thank them for many happy hours outside the lab. Yijing Dai, Yubai Zhou and Xiaopeng Yin are also active and creative soldiers in the lab. I also would like to express my grateful thanks to my best buddies in MSU, Greg Spahlinger, Dillon Cogan, Miles Kamaloski, Bob Philange and Jason Lam, et al, they added so many spices to my life in the past few years, best memories in my life. Last but not the least, I grew up with the priceless love from my parents, thanks mom and dad for their unconditional love and support for the last 28 years. iv TABLE OF CONTENTS LIST OF TABLES……………………………………………………………………...viii LIST OF FIGURES………………………………………………………………………x LIST OF SCHEMES…………………………………………………………………….xi CHAPTER ONE…………………………………………………………………………1 α-IMINOL REARRANGEMENT IN THE LITERATURE……………………………..1 1.1 Introduction………………………………………………………………………..…1 1.2 Methods developed for the α-iminol rearrangement in the literature…………..2 CHAPTER TWO…………………………………………………………………………8 α-IMINOL REARRANGEMENT CATALYZED BY SILICA GEL………..…………..8 2.1 Introduction…………………………………………………………………………..8 2.2 Initial results of the rearrangement by silica gel and other catalysts…………..9 2.3 Iminol rearrangement catalyzed by silica gel…………………………………...13 2.3.1 Synthesis of substrates: aldehydes and iminols……………………………13 2.3.2 Iminol rearrangement catalyzed by silica gel and Montmorillonite……….16 2.3.3 Comparison of sulfuric acid, silica gel and Montmorillonite K 10 with an acid sensitive substrate……………………………………………………….17 2.3.4 Rearrangement of a PMP protected iminol catalyzed by silica gel and Montmorillonite K 10….……………………………………………………….18 2.3.5 Tandem imine formation and rearrangement catalyzed by silica gel and Montmorillonite K 10….……………………………………………………….19 2.3.6 Synthesis of Ketamine analog by silica gel...……………………………….21 2.3.7 Proposed mechanism for the rearrangement catalyzed by silica gel….…23 2.4 Conclusion….………………………………………………………………………23 CHAPTER THREE…………………………………………………………………….24 CATALYTIC ASYMMETRIC α-IMINOL REARRANGEMENT CATALYZED BY VANOL ZIRCONIUM COMPLEX…………………………………………………….24 3.1 Introduction….……………………………………………………………………..24 3.2 Initial results of the rearrangement by other chiral catalysts…………………..25 3.2.1 α-Iminol rearrangement by VANOL/VAPOL-B3 complex….……………..25 3.2.2 α-Iminol rearrangement by VANOL hydrogen phosphate and its derivatives……………………………………………………………………..28 3.3 Rearrangement by VANOL aluminum complex 27…………………………….32 v 3.3.1 Initial results…………………………………………………………………...32 3.3.2 Optimization with the VANOL ligand……………………..………………...34 3.3.3 Synthesis of 7,7’-tBu2VANOL ligand 34……………………..…………….36 3.3.4 Optimization with 7,7’-tBu2VANOL ligand 34 in complex 27…………….37 3.3.5 Determination of absolute stereochemistry of 4a………………………….38 3.4 Rearrangement by VANOL zirconium complex………………………………...39 3.4.1 The Mannich type reaction with VAPOL zirconium complex………….....39 3.4.2 The iminol rearrangement with VANOL and VAPOL zirconium complex.40 3.4.3 Optimization of reaction conditions with VANOL zirconium complex.......41 3.4.4 Scope of the α-iminol rearrangement of aldimines..................................45 3.4.5 Preparation of amino alcohols from α-amino ketone 4s...........................50 3.4.6 Iminol rearrangement with ketimines.......................................................51 3.4.7 Stability of VANOL zirconium catalyst 46.................................................53 3.4.8 Crystal structure of the VANOL zirconium catalyst..................................54 3.4.9 Catalyst composition study......................................................................56 3.4.10 Catalyst 46 recycle study.......................................................................58 3.4.11 Control experiment................................................................................59 3.5 Kinetic resolution of racemic α-iminols by VANOL zirconium complex………61 3.6 Conclusion.....................................................................................................63 CHAPTER FOUR………………………………………………………………………64 MISCELLANEOUS PROJECTS……………………………………………………..64 4.1 Total synthesis of Rhinzochalin C……………………………………………….64 4.1.1 Introduction..............................................................................................64 4.1.2 Retrosynthetic analysis of Rhizochalin C.................................................66 4.1.3 Total synthesis of Rhizochalin C..............................................................67 4.1.3.1 Synthesis of the alkyne ffragment 83………………………………….67 4.1.3.2 Synthesis of the Weireb amind fragment 88……….………………….70 4.2 Mannich type reaction with zirconium catalyst………………………………….71 4.2.1 Synthesis of imine and ketene acetal......................................................71 4.2.2 Mannich type reaction with zirconium VAPOL/VANOL catalyst...............72 4.3 Cation induced rearrangement of allylic alcohols…………………..................74 4.4 Aziridinol rearrangement………………………………………………………….76 4.4.1 Introduction..............................................................................................76 4.4.2 Initial attempt and a catalyst screen.........................................................77 4.4.3 Synthesis of 3-substituted aziridinol substrates and their rearrangement80 4.4.4 Aziridinol rearrangement from (R)-102....................................................84 4.4.5 One attempt at the kinetic resolution of a racemic aziridinol....................86 CHAPTER FIVE………………………………………………………………………..87 EXPERIMENTAL SECTION………………………………………………………….87 vi 5.1 General information........................................................................................87 5.2 Experimental procedure for chapter two.........................................................88 5.2.1 General procedure for the preparation of aldehyde 2…………………….88 5.2.2 General procedure for the preparation of iminol 3……………………….103 5.2.3 Synthesis of amino ketone with silica gel and Montmorillonite K 10…...121 5.2.4 Synthesis of Ketamine analog 20………………………………………….122 5.3 Experimental procedure for chapter three....................................................128 5.3.1 Procedure 1: Reaction with (S)-VANOL BOROX catalyst 22.................128 5.3.2 Procedure 2: Reaction with (S)-VANOL hydrogen phosphate 23..........129 5.3.3 Procedure 3: Reaction with (S)-VANOL Al 27……………………...........129 5.3.4 Procedure 4: General procedure for rearrangement with catalyst (R)-46………………………………………………………………………...131 5.3.5 Procedure for the a-iminol rearrangement of in-situ generated imines..157 5.3.6 Determination of the stereochemistry of the product 4a………………...158 5.3.7 Synthesis of amino alcohols from amino ketones………………............162 5.3.8 Attempt in iminol rearrangement with ketimine………………................168 5.3.9 NMR study of crystal 61 in d6-DMSO…………………………................171 5.3.9.1 Preparation and X-ray study of the crystal 61………………............171 5.3.9.2 NMR results of the crystal 61 in d6-DMSO…………………............172 5.4 Experimental procedure for chapter four......................................................184 5.4.1 Experimental procedure for total synthesis of Rhizochalin C…………..184 5.4.2 Experimental procedure for Mannich type reaction………….…………..199 5.4.3 Experimental procedure for chloronium induced rearrangement of allylic alcohol………………………………………………………………...206 5.4.4 Experimental procedure for aziridinol rearrangement………….………..208 REFERENCES…………………………………………………………………….…227 vii LIST OF TABLES Table 2.1 Rearrangement of iminol 3a with heat, silica gel and Montmorillonite..10 Table 2.2 Screen of the rearrangement……………………………………………..11 Table 2.3 Synthesis of aldehydes 2………………...………………………………..13 Table 2.4 Synthesis of iminols 3………………...……………………………………15 Table 2.5 Iminol rearrangement catalyzed by silica gel………………...………….16 Table 2.6 Synthesis of rac-8 ………………...……………………………………….18 Table 2.7 Reaction progress for the tandem synthesis of 4a………………...……20 Table 3.1 Rearrangement of 3a by VANOL and VAPOL-B3 complex 22………..27 Table 3.2 α-Iminol rearrangement with VANOL/VAPOL hydrogen phosphates...30 Table 3.3 α-Iminol rearrangement with VANOL/VAPOL N-triflyl phosphoramides………………………………………………..………….31 Table 3.4 α-Iminol rearrangement with VANOL/VAPOL hydrogen phosphate salts…………………………………………..……………………………..32 Table 3.5 α-Iminol rearrangement with VANOL/VAPOL/BINOL Al complexes….33 Table 3.6 Temperature screen with VANOL-Al complex 27……………………….34 Table 3.7 Solvent screen with VANOL-Al complex 27……………………………..35 Table 3.8 Temperature screen with ligand 34 in aluminum complex 27………....38 Table 3.9 Catalyst loading screen with catalysts 45 and 46………......................42 Table 3.10 Concentration screen with catalyst 46……….....................................43 Table 3.11 Temperature screen with catalyst 46……….......................................44 viii Table 3.12 Solvent screen with catalyst 46………...............................................45 Table 3.13 Scope of the α-iminol rearrangement of aldimines………..................47 Table 3.14 Attempted rearrangement of α-iminol 59……….................................53 Table 3.15 Stability of the catalyst 46………........................................................54 Table 3.16 Catalyst composition study………......................................................58 Table 3.17 Catalyst recycle study………..............................................................59 Table 3.18 Control experiments………................................................................60 Table 3.19 Synthesis of racemic iminols………...................................................61 Table 4.1 Mannich type reaction with imine 90………..........................................73 Table 4.2 Mannich type reaction with imine 93………..........................................74 Table 4.3 Attempt in the gold induced rearrangement………...............................76 Table 4.4 Catalyst screen of the aziridinol rearrangement………........................79 Table 4.5 TfOH loading screen………..................................................................80 Table 5.1 Summary of the C NMR data in the aromatic region for crystal 61 studies…………………………………………………………183 ix LIST OF FIGURES Figure 2.1 Ketamine and its analog……….…….…….…………..……….………...21 Figure 2.2 Proposed rearrangement mechanism on the surface of silica gel……23 Figure 3.1 VANOL/VAPOL aluminum complex and BINOL aluminum complex...33 Figure 3.2 Crystal structure of 61……….…….…….…………..……….………......55 Figure 3.3 Crystal structure of 61……….…….…….…………..……….………......55 Figure 3.4 Reaction progress of 64a…………………………………………………63 Figure 4.1 Two-headed sphingolipids……….…….…….…………..………………65 Figure 5.1 One unit cell of crystal 61……………………………………………….172 Figure 5.2 1H NMR and 13C NMR of Crystal 61……………………………………174 Figure 5.3 1H NMR and 13C NMR of 1:3:2 Zr:VANOL:NMI made in d6-DMSO…175 Figure 5.4 1H NMR and 13C NMR of 1:3:2 Zr:VANOL:NMI heat to 100 °C……..176 Figure 5.5 1H NMR and 13C NMR of 1:3:2 Zr:VANOL:NMI made in toluene…...177 Figure 5.6 1H NMR and 13C NMR of NMI……………………….…….…………...178 Figure 5.7 1H NMR and 13C NMR of protonated NMI………………………..…...179 Figure 5.8 1H NMR and 13C NMR of (S)-VANOL……………………………..…...180 Figure 5.9 1H NMR and 13C NMR of bromobenzene………………………...…...181 Figure 5.10 1H NMR and 13C NMR of toluene………………………...….............182 x LIST OF SCHEMES Scheme 1.1 Pinacol and α-iminol rearrangement……………………………………1 Scheme 1.2 α-Iminol rearrangement by Prins and Schoppee……………………...2 Scheme 1.3 α-Iminol rearrangement promoted by heat……………………..……...3 Scheme 1.4 α-Iminol rearrangement promoted by Brønsted acid ………………...3 Scheme 1.5 α-Iminol rearrangement promoted by Lewis acid ……………….........4 Scheme 1.6 α-Iminol rearrangement promoted by Brønsted base……...………....5 Scheme 1.7 α-Iminol rearrangement through iminium intermediate……...………..6 Scheme 2.1 Silica gel catalyzed reactions……...…………………………………….8 Scheme 2.2 Montmorillonite clay catalyzed reactions……...……………………….9 Scheme 2.3 Preparation of model iminol 3a……...…………………………...……10 Scheme 2.4 Synthesis of iminol substrate 7……...…………………………...……17 Scheme 2.5 Rearrangement with a removable PMP group on the iminol……….19 Scheme 2.6 One-pot synthesis of 4a from aldehyde 2a…………………………...21 Scheme 2.7 Synthesis of Ketamine Analog 20…………………..……….………...21 Scheme 3.1 α-Iminol rearrangement catalyzed by proton…………………………24 Scheme 3.2 Asymmetric α-ketol and α-iminol rearrangements by Brunner……..25 Scheme 3.3 VANOL/VAPOL-B3 complex as chiral catalyst in various reactions.26 Scheme 3.4 Reactions catalyzed by VANOL/VAPOL……………………………...29 Scheme 3.5 Ligand screen with VANOL derivatives……………………………....36 xi Scheme 3.6 Synthesis of ligand (R)-34……………………………........................37 Scheme 3.7 Synthesis of (R)-4a from 39……………………………......................39 Scheme 3.8 Synthesis of VAPOL Zr catalyst 45 and VANOL Zr catalyst 46…….40 Scheme 3.9 Synthesis of chiral amino ester 49 and chelation between 45 and 47………………………………………………………………………………………..40 Scheme 3.10 Substituted anilines in α-iminol rearrangement…………………….49 Scheme 3.11 Tandem imine formation and α-iminol rearrangement of 2l……….50 Scheme 3.12 Synthesis of amino alcohols from α-amino ketone 4s …………….51 Scheme 3.13 Synthesis of α-iminol 59………………………………………………52 Scheme 3.14 Initial study of kinetic resolution of 64a………………………………62 Scheme 4.1 Multi-component catalytic asymmetric synthesis of cis-aziridine…..64 Scheme 4.2 Retrosynthetic analysis of Rhizochalin C……………………………..67 Scheme 4.3 Synthesis of alkyne fragment 83………………………………………69 Scheme 4.4 Synthesis of Weinreb amide fragment 88…………………………….70 Scheme 4.5 Synthesis of imines and ketene acetal………………………………..72 Scheme 4.6 Cation induced rearrangement of allylic alcohol……………………..75 Scheme 4.7 1,3 Hydroxyl shift of allylic alcohol ……………...…...………………..75 Scheme 4.8 Chloronium induced rearrangement of allylic alcohol ………………75 Scheme 4.9 Aziridinol rearrangement……………………………………………….77 Scheme 4.10 Synthesis of aziridinol…………………………………………………78 Scheme 4.11 Synthesis of PMP protected aziridinol and its rearrangement……81 Scheme 4.12 Synthesis of Cbz protected aziridinol and its rearrangement……..82 xii Scheme 4.13 Synthesis of propyl aziridinol at C-3 and its rearrangement………84 Scheme 4.14 Synthesis of (R)-102 and its rearrangement………………………..85 Scheme 4.15 Attempt in the kinetic resolution of racemic aziridinol……………...86 xiii CHAPTER ONE α-IMINOL REARRANGEMENT IN THE LITERATURE 1.1 Introduction 1 The Pinacol rearrangement was first described by Fittig in 1860. In the course of this reaction, protonation of one of the two OH groups occurs followed by loss of water, forming a carbocation. Rearrangement is initiated by this carbocation (Scheme 1.1, eq 1). If the substituents on the two alcohol carbons are not identical, the more stable carbocation forms to participate in the reaction. Scheme 1.1 Pinacol and α-iminol rearrangement R1 OHOH R4 R2 R1 N R2 OH R4 R3 R3 H H H R1 – H 2O R1 R2 H N R2 O O R4 R3 R1 H O R4 R3 R1 H N R2 R4 R3 R2 H O R4 R3 (eq 1) R1 NH R2 R3 O (eq 2) R4 Compounds containing vicinal imine and hydroxyl functional groups are known as α-iminols, and they can undergo a rearrangement reaction to yield the corresponding α-amino ketones through a mechanism related to that of the Pinacol rearrangement (Scheme 1.1, eq 2). Protonation of the imine is expected due to the greater basicity of the nitrogen atom relative to OH, and the positive charge is then delocalized to the imine carbon through resonance. Migration can then be initiated by both the push of the electron pair on oxygen and the pull of the positive charge on the carbocation. In this case, if R3=R4, the migration from the Si face or Re face will result in two enantiomers; if R3≠R4, it will result in two 1 regioisomers, each of which has two enantiomers. The α-iminol rearrangement is in fact a known process and was first reported 2 by Prins and Shoppee in 1943 (Scheme 1.2). A comprehensive review of this type of reaction appeared in 2003 that summarized the subsequent research 3 progress since Prins and Shoppee. Scheme 1.2 α-Iminol rearrangement by Prins and Schoppee NHPh O OH N Ph Prins and Shoppee's work AcO Ref 2 AcO H H 1.2 Methods developed for the α-iminol rearrangement in the literature Various methods to conduct the α-iminol rearrangement have been reported in 4-8 the literature. One is to utilize heat as the promoter; usually a temperature higher than 150 °C is necessary to overcome the activation barrier and initiate the 4 reaction (Scheme 1.3). The transition state of this reaction under heat has been proposed to proceed in a concerted manner where the C-C, O-H and C=N bonds 4 are partially broken and the new C-C and N-H bonds are partially formed. 2 Scheme 1.3 α-Iminol rearrangement promoted by heat OH Decalin reflux N Ph Ph O NH Ph Ph Stevens's work Ref 4 O H O H N N Ph Ph Ph Ph Another approach is to employ a catalyst to effect the reaction. There are three 9-12 commonly used catalysts in the literature: 1. Brønsted acids: HCOOH, 13 H2SO4, TsOH, CH3COOH, CF3CH2OH, 14,15 etc. 2. Lewis acids: Sc(OTf)3, 16 Cu(OTf)2, Zn(OTf)2, etc. 3. Brønsted base: Sodium methoxide, 18 TBAF, HCl, 17 DBU, etc. Scheme 1.4 α-Iminol rearrangement promoted by Brønsted acid HO N R HCOOH O McWhorter's work Ref 9 R N H R = aryl, alkyl H+ H O R N H 9 In the case of the Brønsted acid catalyzed rearrangement (Scheme 1.4), protonation of the imine was proposed to be the initial step. Next, the hydroxyl group provided an electron pair triggering the R group to migrate to the imine carbon, and deprotonation from the carbonyl completed the reaction. 3 The Brønsted acid catalyzed reaction proceeded at a faster rate compared to 3 the uncatalyzed reaction. 14 In the case of the Lewis acid catalyzed rearrangement (Scheme 1.5), the mechanism was proposed to be similar to the Brønsted acid promoted reaction. The coordination of the Lewis acid to the imine was the first step. Scheme 1.5 α-Iminol rearrangement promoted by Lewis acid PhthN PhthN N N H H N Sc(OTf) 3 OH Tambar's work Ref 14 N H O PhthN PhthN Sc 3+ PhthN Sc++ N N H OH PhthN 16 In the case of Brønsted base catalyzed rearrangement (Scheme 1.6), the deprotonation on the hydroxyl occurred with the aid of the base. Next, the electron pair on the negatively charged oxygen donated to the carbon forming a C=O double bond while the R group migrated to the imine carbon. The Brønsted base catalyzed reaction proceeded at a faster rate compared to 3 the uncatalyzed reaction. 4 Scheme 1.6 α-Iminol rearrangement promoted by Brønsted base N NH NaOMe NaOH HO PMB N N O PMB William's work Ref 16 N O O OMe N MeO H N O PMB N N O There are four examples of an α-Iminol rearrangement occurring with an iminium cation intermediate forming in the course of another reaction. The first 19 one is a platinum catalyzed indolizinone synthesis (scheme 1.7, eq 1), 20 second involves the iodination of olefin (scheme 1.7, eq 2), the third one is 21 copper catalyzed oxidative tandem cyclization (scheme 1.7, eq 3). 22 one is synthesis of heterocyclic systems (scheme 1.7, eq 4). 5 the and the last Scheme 1.7 α-Iminol rearrangement through iminium intermediate Et PtCl 2 ligand base OH N Et Bu Et O OH [Pt] N (eq-1) N Bu Bu I Ph NaH, I 2 N I Ph N O I I N O O I F 3C ONa F 3C ONa I O RHN R (eq-2) O CF 3 R O HN O HN Ph N O F 3C OH I Ph N R RHN [O] HN RHN O HN NHR R O H 2O (eq-3) RHN O O O O NHR RHN HN HN RNH 2 PtCl 2 O OH R OH NHR RHN O O [O] OH HN R N [Pt] Ph N (eq-4) OH O Ph Ph NHR O Ph R OH [Pt] HN O O N RHN NHR RHN O The α-iminol rearrangement has also served as an important step in the total 14 synthesis of complicated natural products and drugs, such as Trigonoliimine C , 16 23 Brevianamide B , and (S)-Ketamine . The reaction usually requires either high temperature, or strong acid/base catalysts, or both as described above. These harsh conditions mean that many sensitive compounds will not survive during the course of this reaction. Thus the development of milder conditions that do not 6 involve high temperatures, or strong acid/bases are worthy of serious investigation. All of the reported α-iminol rearrangement examples involve non-enantioselective reactions. One report does describe an attempt to enantioselectively conduct this reaction by using chiral nickel or lanthanum 24 complexes. While all of the chiral complexes examined were able to form the products, unfortunately all were racemic. An efficient catalytic asymmetric α-iminol rearrangement protocol that offers excellent enantioselectivity thus remains an unsolved challenging problem that would be a worthy undertaking. Chapters two and three will address these issues and try to provide some plausible solutions. 7 CHAPTER TWO α-IMINOL REARRANGEMENT CATALYZED BY SILICA GEL AND MONTMORILLONITE K 10 2.1 Introduction Silica gel is silicon dioxide in a granular and porous form. Usually it is used in organic synthesis as a stationary phase for column chromatography for the purpose of purification. Due to its acidity it is also used in acid-catalyzed reactions, such as the isomerization of allene and nucleophilic addition to aldehyde by Kropp 25 and coworkers (Scheme 2.1). Some modifications may also be made to silica gel to enhance its catalytic ability. Based on its acidity, silica gel is expected to catalyze the α-iminol rearrangement reaction as well. Scheme 2.1 Silica gel catalyzed reactions SiO2, DCM (eq 1) Kropp's work Additive: None, 41% CH 3COOH, 100% SiO2, DCM O Kropp's work OH (eq 2) Montmorillonite is a clay formed from phyllosilicate minerals. It was named after the commune Montmorillon in France. It has an empirical formula of 26 Na0.3Ca0.3Al2Mg2Si4O10(OH)2·nH2O, but since potassium, iron and other metals are common substitutes for the metal ions above, the exact ratio can vary widely. Montmorillonite is an efficient, heterogeneous and green catalyst in organic 8 synthesis and has been explored intensively; a comprehensive review on this 27 subject appeared in 2012. Some selected examples are listed in Scheme 2.2. Scheme 2.2 Montmorillonite clay catalyzed reactions Beckmann reaction N R1 OH Mont. K-10 O R1 R2 N H R2 Pinacol rearrangement Al-Mont. OH O OHOH Boc deprotection ArNHBoc Mont. K 10 ArNH2 Synthesis of Mannich base PBA N Mont. K 10 Ph CHO + AcNH2 + HN Ph PBA N H Ac Based on these results, Montmorillonite clay was also investigated as a catalyst for the α-iminol rearrangement reaction. 2.2 Initial results of the rearrangement by silica gel and other catalysts A model iminol 3a was prepared as shown in Scheme 2.3. Ethyl diethoxyacetate was treated with 2.5 equivalent of PhMgCl and following acid hydrolysis, yields the aldehyde 2a in 70% to 90% over two steps. The aldehyde 2a was converted to iminol 3a with aniline in 90% to 100% yield. 9 Scheme 2.3 Preparation of model iminol 3a O O O O 1) 2.5 equiv. PhMgCl 2) H + 1.1 equiv. aniline OH H 1 N OH H Ph Ph 70%-90% 2a O Ph Ph Ph 90%-100% 3a A summary of the rearrangement is provided in Table 2.1. In entries 1 and 2, the reaction was conducted with no catalyst by heating. It was discovered that at 80 °C the reaction was not proceeding after a prolonged 42 h. When the temperature was raised to 150 °C, the rearranged product 4a was observed in 20% yield, with a 30% recovery of 3a and the formation of a byproduct 4x in 50% that was tentatively assigned as an imine resulting from the oxidation of 4a. This result is consistent with the literature data that high temperatures are necessary to drive 3 the reaction. Table 2.1 Rearrangement of α-iminol 3a with heat, silica gel and Montmorillonite Ph N H Ph Ph OH toluene Ph Ph Ph 4a O 3a Entry Catalyst NH Temp Time Yield 1 none 80 °C 42 h 0% 2b none 150 °C 2h 20% 3 silica gel 60 °C 2h 30% 4 silica gel 80 °C 1h 95% 5 Mont. K 10 60 °C 1.5 h 100% a. Ph N Ph Ph 4x O Unless otherwise specified, the reaction was carried out on 0.1 mmol scale with no catalyst or 100 wt% silica gel or 100 wt% Montmorillonite K 10 in toluene 10 in the presence of air. b. The solvent was mesitylene, and yield was determined by NMR. Entries 3 and 4 involve the rearrangement in the presence of silica gel. The temperature could be significantly decreased to as low as 60 °C with the rearrangement still proceeding to give a 30% yield in 4a. At 80 °C, the reaction was complete in only 1 h, giving 95% yield. In the presence of Montmorillonite K 10 clay, this reaction went to completion with 100% yield in 1.5 h at 60 °C, which means the clay was a better catalyst than silica gel in this case. Table 2.2 Screen of the rearrangement Ph N H Ph OH Catayst 80 °C Ph Catalyst Ph Ph Ph 4a 3a Entry NH Solvent Time O Yieldb 1 1 equiv. HOAc Toluene 10 h no conversion 2 10 equiv. HOAc Toluene 15 h 40% S. M. 60% byproduct 3 1 equiv. H 2SO 4 DMF 4c 1 equiv. H 2SO 4 Toluene on silica gel 1h 90% 1.5 h 13% 5d 1 equiv. TsOH·H 2O DMF 1h 56% 6 1 equiv. Zn(OTf)2 DMF 2h 9% 7 1 equiv. NaOEt EtOH 1h No desired product a. Unless otherwise specified, the reaction was done on a 0.1 mmol scale at 80 °C in presence of air. b. yield was determined by NMR. c. Reaction was done at 60 °C. d. 44% aldehyde 2a was observed. 11 For comparison, a summary of the rearrangement with different catalysts is listed in Table 2.2. In entry 1, 1 equivalent acetic acid seemed not acidic enough to initiate the reaction. In entry 2, 10 equivalent acetic acid was added, but it produced the oxidized imine byproduct 4x, and no desired product 4a was observed. In entry 3, sulfuric acid was examined, and the result indicated that it was a good catalyst for this reaction, although it is much more acidic than silica gel. In entry 4, the reaction was done with 1 equivalent sulfuric acid absorbed in the silica gel. The combination of the two was not as good as silica gel alone (Table 2.1 entry 4). In entry 5, p-toluenesulfonic acid monohydrate was tested. The water present in the monohydrate partially hydrolyzed the iminol, resulting in a low yield. Zinc triflate was examined in entry 6, and the poor result indicated that this Lewis acid is not efficient in this reaction. In entry 7 the base sodium ethoxide gave a complex mixture perhaps because the base abstracted the α-proton in the product 4a leading to an Aldol reaction. In summary, the Brønsted acid sulfuric acid was a good catalyst in the α-iminol rearrangement, while the Lewis acid zinc triflate or the Brønsted base sodium ethoxide proved not to be a good choice. However, some acid sensitive compounds may not survive in the presence of sulfuric acid and thus mild catalysts, such as silica gel and Montmorillonite K 10 would be the preferred catalysts. 12 2.3 Iminol rearrangement catalyzed by silica gel and Montmorillonite 2.3.1 Synthesis of substrates: aldehydes and iminols The aldehydes in the series 2 were prepared via the Grignard reaction, followed by acid hydrolysis. The results are summarized in Table 2.3. All substrates were synthesized via the Grignard reaction except 2m, which was made by using the corresponding lithium reagent. Table 2.3 Synthesis of aldehydes 2 1 equiv. OEt EtO O + Mg R Br 2.5 equiv. 2.5 equiv. O H HO H 3C 2b 83% 2a 70%-90% O H HO 2e 67% Cl R O CH 3 H HO iPr 2c 56% CH 3 Cl O H HO 2 O H HO 5% HCl acetone 70 oC, 1 h OEt O iPr 2d 77% H 3C iPr nBu O O H HO H HO H HO Cy 2g 73% CH 3 nBu 2h 49% O O O O H HO H HO H HO H HO 2i 69% Cy 2j 61% 2k 77% tBu 13 Ph iPr OMe Ph tBu CH 3 H HO O 2f 78% R 2l 63% OMe Table 2.3 (cont’d) F COCH 3 CF 3 O O O H HO H HO H HO 2m 99% F 2nb 53% CF 3 O O nHexyl H HO nHexyl H HO 2p 71% 2o 55% COCH 3 O CH2Ph CH2Ph 2q 46% H HO 2r 57% a. Unless otherwise specified, the Grignard reagent was prepared from the corresponding bromide and magnesium metal in THF, and 5% HCl = 1.7 M HCl. b. 2m was prepared by an organolithium reagent at –78 °C. The yields of aldehydes were moderate because the acetal hydrolysis step produced some unknown byproducts that stayed at the origin on TLC. Lowering the temperature or using a milder acid may help to improve the yield, but this has not been tried. Iminols in the series 3 were prepared with the corresponding aldehyde 2 and aniline. The results are summarized in Table 2.4. 14 Table 2.4 Synthesis of iminols 3 1.1 equiv. PhNH 2 toluene O R H HO 2 Ph H HO Ph Cl N H HO 3e 100% Cl Ph N H HO 3i 93% Ph H HO F H HO CH2Ph CH2Ph 3q 100% 3d 84% H 3C 3h 95% nBu Ph Ph N H HO 3g 93% CH 3 iPr Ph N H HO H HO H HO 3j 98% Ph tBu CF 3 CF 3 3l 97% Ph N N H HO H HO PMP N COCH 3 nHexyl 3p 88% N R H HO R 3s R=Ph, 99%c 3t R=Cy, 81%c a. OMe nHexyl 3o 88% N H HO 3r 88% Ph COCH 3 Ph N 3n 90% 3k 95% iPr OMe Ph N Ph N H HO iPr N Ph CH 3 N nBu Ph H HO tBu R Ph H HO iPr 3cb – N H HO 3m 95% R N N N H HO Ph Ph Cy F CH 3 CH 3 3f 93% Cy Ph N H HO H 3C 3b 88% 3a 78%-100% N H 3 HO R Ph N Ph H HO 3w 80%d Unless otherwise specified, the reaction was done with 1 equivalent of aldehyde 2 and 1.1 equivalent aniline in toluene at room temperature for 30 min. b. The reaction for substrate 3c did not go to completion, and gave a mixture of aldehyde 2c : imine 3c = 1 : 3.2. c. The starting amine for 3s and 3t was 4-anisidine. d. The starting amine for 3w was benzyl amine. 15 2.3.2 Iminol rearrangement catalyzed by silica gel and Montmorillonite The next step is to test the substrates with silica gel. The results are summarized in Table 2.5. All substrates gave good to excellent yields of the iminol rearranged product 4 except for 3m. Table 2.5 Iminol rearrangement catalyzed by silica gela Ph N H R rac-4 O Ph NH NH R R HO 3 Ph Ph 100 wt% silica gel toluene, 80 °C, 1 h R Ph NH Ph NH NH CH 3 O CH 3 rac-4b 92% O rac-4a 95% Ph Ph NH CH 3 O iPr rac-4c 90% CH 3 NH Ph O iPr NH rac-4d 90% CH 3 Ph nBu iPr NH Cl O Ph Ph Cy NH O Ph Ph tBu O O F F 3C rac-4m 85% Ph O nC6H13 CF 3 NH O Ph nC6H13 O rac-4p 62%e, (85% f) Ph Ph rac-4l 88% O rac-4q 85% 16 Ph NH O rac-4o N/A Ph NH CH2Ph OMe O H 3COC PhH 2C NH MeO 99% rac-4n 0%c, (27% d) NH rac-4h 97% rac- 4kb Ph F NH NH Ph rac-4j 89% rac-4i 78% O iPr rac-4g 90% NH tBu O nBu rac-4f 99% rac-4e 40% Cl Cy O H 3C NH O rac-4r 83% COCH 3 a. Unless otherwise specified, the reaction was done on 0.1 mmol scale with 100 wt% silica gel in 0.3 mL toluene at 80 °C for 1 h, in presence of air. Yield in parenthesis was with Montmorillonite K 10. b. The reaction time was 3 h. c. The reaction time was 24 h. This substrate rac-4m was oxidized to imine under air, and no desired product was observed, see details in experimental section. d. The reaction was done with 100 wt% Montmorillonite K 10 under a nitrogen atmosphere for 38 h. Yield determined by NMR, 43% 3m and 29% byproduct was also identified. e. The reaction temperature was 90 °C. f. Reaction was run with Montmorillonite K 10, at 60 °C for 10 h. g. Reaction was run under N2. The substrate 4m was oxidized to an imine byproduct by air under the conditions of the reaction. 2.3.3 Comparison of sulfuric acid, silica gel and Montmorillonite K 10 with an acid sensitive substrate Iminol 7 was synthesized from 5. The alcohol was protected by a TBS group, and condensed with aldehyde 2a. Compound 7 has an acid sensitive TBS group and was designed to examine the stability toward the α-iminol rearrangement conditions with sulfuric acid, silica gel and Montmorillonite (Scheme 2.4). Scheme 2.4 Synthesis of iminol substrate 7 OH OTBS 1.1 equiv. TBSCl 100% NH 2 6 NH 2 5 O H Ph TBSO OH Ph N 1.1 equiv. 6 100% 7 H HO Ph Ph 2a Iminol 7 was subjected to the rearrangement conditions indicated in Table 2.6. 17 In entry 1, the reaction was run with sulfuric acid and this led to compound 9 instead of desired product 8 as a result of loss of TBS group. In entries 2 and 3, silica gel and Montmorillonite K 10 were used respectively. Both catalysts gave the desired product 8, with no cleavage of TBS; however, the clay catalyst gave a higher yield than silica gel. Therefore, Montmorillonite K 10 is a better catalyst for this acid sensitive substrate. Table 2.6 Synthesis of rac-8 TBSO N H 7 HO X Ph Ph Ph Ph Entry Catalyst NH Catalyst rac-8 X=OTBS rac-9 X=OH Sovent Temp,Time DMF 80 °C, 1h 0%, 56% 80 °C, 1h 70%, 0% 70 °C, 2 h 96%, 0% 1 1 equiv. H 2SO 4 2 100 wt% toluene silica gel 3 100 wt% toluene Montmorillonite K 10 O Yield 8, 9 a. Unless otherwise specified, reactions were run on 0.1 mmol scale in 0.3 mL solvent under the indicated conditions. 2.3.4 Rearrangement of a PMP protected iminol catalyzed by silica gel and Montmorillonite K 10 The protecting group on the nitrogen atom of the iminol could be changed to a removable p-methoxylphenyl (PMP) group if the aldehyde 2a was treated with p-anisidine instead of aniline. In this case, 10 was prepared in 100% yield (Scheme 2.5). 18 Scheme 2.5 Rearrangement with a removable PMP group on the iminol O Ph H Ph HO 2a PMP N H HO 1.1 equiv. 4-anisidine PMP H Toluene 100% HO Ph Ph Ph 10 PMP = p-methoxyphenyl PMP Ph N toluene Ph Ph 11 O 10 PMP NH N + Ph Ph 12 O Catalyst = 100 wt% silica gel, 80 °C, 3h under air: 11 = 65%, 12 = 32% under N 2: 11 = 92%, 12 = 0% Catalyst = 100 wt% Montmorillonite, 60 °C, 10h under air: 11 = 90%, 12 = 5% The rearrangement of 10 was carried out with silica gel, but something different was observed. First, the reaction rate was slower than the phenyl protected iminol 3a; second, the rearranged product 11 was partially oxidized to an imine byproduct 12 under air. A second run under N2 atmosphere eliminated the formation of byproduct 12. With Montmorillonite K 10 under air, the reaction temperature was lowered to 60 °C, and although the reaction time was longer, the formation of byproduct 12 was much less than with silica gel catalysis. 2.3.5 Tandem imine formation and rearrangement catalyzed by silica gel and Montmorillonite As previously described, the synthesis of amino ketone 4a was achieved from the iminol 3a. However, if 4a could be accessed directly from the aldehyde 2a this would shorten the synthesis by one step, namely the formation of iminol 3a 19 (Scheme 2.6). The progress of the reaction starting from 2a was monitored by NMR and the results are summarized in Table 2.7. In entry 1, the ratio of aldehyde:iminol:product was 1:2.7:3.3 at 1 h. This means that the formation of iminol 3a and its rearrangement were occurring at the same time in the reaction mixture. After 2.5 h, the aldehyde disappeared completely but the iminol 3a was still present. After 3.5 h some iminol was still present in the reaction mixture. This is to be contrasted to complete reaction in 1 h starting from iminol 3a (Table 2.5). This reaction rate difference may be related to the presence of water, which is formed by the condensation between aldehyde and aniline, and which might somehow decrease the catalytic activity of silica gel. Table 2.7 Reaction progress for the tandem synthesis of 4a O OH H Ph Ph 1.1 equiv. PhNH 2 Silica Gel Ph NH Ph Ph Toluene, 80 °C 4a 2a O Time aldehyde:iminol:product 2a:3a:4a 1 1h 1:2.7:3.3 2 2.5 h 0:1:3.4 3 3h 0:1:4 4 3.5 h 0:1:5 Entry a. Unless otherwise specified, the reaction was done on 0.2 mmol scale, 100 wt% silica gel was used, the progress was monitored by NMR. However, with Montmorillonite K 10 clay, the reaction was complete at 70 °C in 3 h. Again, the clay is a more efficient catalyst compared to silica gel in this case. 20 Scheme 2.6 One-pot synthesis of 4a from aldehyde 2a Ph O OH H 1.1 equiv. PhNH 2 Ph Ph Ph Ph NH Toluene O 4a 2a Catalyst = 100 wt% silica gel, 80 °C, 3.5 h, 80% Catalyst = 100 wt% Montmorillonite K 10, 70 °C, 3 h, 95% 2.3.6 Synthesis of Ketamine analog by silica gel Ketamine is a drug used in general anesthesia to put a patient to sleep for 28 surgery, 29 and it is also a candidate as an antidepressant. Studies have shown that the main side effect of Ketamine is that it causes hallucinations in some 30 cases. Figure 2.1 Ketamine and its analog Ph HN CH 3 O HN Cl O Ketamine analog 20 (S)-Ketamine 31 The synthesis of Ketamine has been described in some patents. Synthesis of Ketamine analog 20 was pursued as an initial evaluation of a potential synthesis of Ketamine. Scheme 2.7 Synthesis of Ketamine Analog 20 O + Cl 13 H OMe N Me 14 HCl 1 equiv. 2 equiv. Et 3N DCM, rt, 1.5h O OMe N Me 15 92% 21 Scheme 2.7 (cont’d) O 15 OMe N Me MgCl THF, 0 °C to rt, 0.5 h O O 1.1 equiv. Br 2 CHCl 3, AcOH, rt, 10 min, 100% 16 MeO 2 equiv. O 1.1 equiv. PhNH 2 110 °C, 0.5 h, 64% Br O 16 34% 1.5 equiv. NaOMe Et 2O, reflux, 12 h 18 53% 17 Ph N OH Silica gel 120 °C, toluene 2d O PhHN 18 20 83% 19 The synthesis started from benzoyl chloride and N,O-dimethylhydroxylamine, forming the Weinreb amide 15 in 92%. Then 15 was reacted with cyclopentyl Grignard reagent to form the ketone 16 in 34%. The yield was low because a substantial amount of byproduct benzaldehyde was observed in this step. Bromination and epoxidation giving the epoxide 18 in 53% yield. The iminol 19 4 was synthesized in 64% yield from epoxide 18 by heating with aniline. The rearrangement of 19 has been reported by refluxing in decalin (b. p. 4 189-191 °C) without catalyst (Scheme 1.3). In this work, with the addition of silica gel, the reaction temperature could be significantly reduced to 120 °C, affording product 20 in 83% yield; however, the reaction took two days to go to completion. 22 2.3.7 Proposed mechanism for the rearrangement catalyzed by silica gel A proposed mechanism for the silica gel catalyzed rearrangement is shown in Figure 2.2. The OH groups on the surface of silica gel may serve two purposes: one is to provide a proton to form a hydrogen bond with the imine nitrogen, which increased the positive charge density on the imine; the other is to provide an oxygen that accepts the proton from the OH in the substrate, which increases the negative charge density on the oxygen. Both effects favor the migration, thus this reaction proceeded smoothly even at much lower temperatures (i. e. 60 °C, Table 2.1 entry 3). Figure 2.2 Proposed rearrangement mechanism on the surface of silica gel Ph H Ph H Ph Ph OH N Ph OH O H H OH OH O OH OH surface of silica gel Ph N Ph surface of silica gel Ph H Ph Ph O HN Ph OH OH OH O N Ph H H OH OH O surface of silica gel surface of silica gel 2.4 Conclusion Silica gel and Montmorillonite K 10 clay were both very good catalysts for effectively promoting the iminol rearrangement. In many cases, the clay was superior to silica gel in terms of reaction rate and yield of the desired product. 23 CHAPTER THREE CATALYTIC ASYMMETRIC α-IMINOL REARRANGEMENT CATALYZED BY A VANOL ZIRCONIUM COMPLEX 3.1 Introduction An α-Iminol has a Re face and a Si face with respect to the C=N imine bond. The rearrangement may occur on the Re face, or Si face, and if R3=R4 this will afford two enantiomers (Scheme 3.1, assuming it was activated by a proton). When R3≠R4, the two migrating groups are not identical, and there will be two regioisomers in the product, each of which can have two enantiomers. Scheme 3.1 α-iminol rearrangement catalyzed by proton R1 N R2 OH R4 R3 R1 H H N R2 R1 H N R2 OH R4 R3 R 3 migrated R1HN R2 OH R4 R3 O + R3 R4 R1HN R 4 migrated R2 O R4 R3 + R1HN R2 O R3 R4 R1HN R2 O R4 R3 A review of catalytic asymmetric Pinacol-type rearrangements appeared in 32 2014. In 2003, Brunner and his coworkers reported the first attempt at a catalytic asymmetric α-iminol rearrangement, which is the only example reported 24 in the literature to date. Besides α-iminols, they examined α-ketols as well (Scheme 3.2). The catalysts they screened were several different nickel and 24 lanthanium complexes as well as Pr(tfc)3 and Eu(tfc)3. Scheme 3.2 Asymmetric α-ketol and α-iminol rearrangements by Brunner O OH HO 1: 2 NiCl 2/Ligand 21 O O N ~90% conversion < 50% ee X N CH 3 OH 1: 2 NiCl 2/Ligand 21 HN R O N N R Ligand 21 R = H, Me, iPr, tBu, iBu, benzyl, Ph CH 3 O X X = H or Cl X = H, 100% conversion, 0% ee X = Cl, 100% conversion, 0% ee X = Cl, with lanthanide chiral complex 0% ee product In the case of the α-ketol rearrangement, the conversion was very high but the ee could not be improved to greater than 50% after screening 34 different ligands. In the case of the α-iminol rearrangement, they screened ligand 21 with chiral nickel and lanthanide salts when R = isopropyl, but only obtained the racemic product with partial decomposition as well. Other chiral catalysts including La(acac)3/(21 R=iPr), LaCl3/(21 R=iPr), Pr(tfc)3 and Eu(tfc)3 were only able to give racemic products. Therefore, there is no example of an effective catalytic asymmetric α-iminol rearrangement in the literature. 3.2 Initial results of the rearrangement by other chiral catalysts 3.2.1 α-iminol rearrangement by VANOL/VAPOL-B3 complex VANOL/VAPOL-B3 complexes 22 33 are chiral Brønsted acids that have played 34,35,36,37 an important role in asymmetric catalytic cis aziridinations, 25 trans 38 aziridinations, 41 reactions 39,40 aza-Cope rearrangements, 42 and Ugi reactions heteroatom Diels-Alder (Scheme 3.3). Scheme 3.3 VANOL/VAPOL-B3 complex as chiral catalyst in various reactions Cis and trans aziridination Ar2 O N Ar1 Ar1 O B O O B O O B O cis aziridine when X = OEt trans aziridine when X = NHR Ar2 = phenyl 3,5-dimethyl-4-methoxyphenyl 3,5-ditertbutyl-4-methoxyphenyl OPh VANOL B3 PhCOOH R Ph + OTMS VAPOL B3 N C O + R Ar3 Ar3 Ph VAPOL B3 R = Alkyl, Aryl Ugi reaction O Bn + HN + Ar4 H Bn NH 2 R = Aryl, Akyl Ar3 = 3,5-dimethylphenyl Heteroatom Diels-Alder reaction OCH3 Ph N X R1 N2 Aza-Cope rearrangement O Ar3 Ar3 + H 2N R H (S)-VANOL/VAPOL-B3 complex 22 N X Y OPh Ar2 VANOL/VAPOL B3 Ar2 + R1 Ar2 Ph N R Bn O N Bn H N Ar4 O The proton in these complexes activates the imine substrate (Y+ = H-imine+) and hence subsequent asymmetric nucleophilic addition to the iminium occurred. It is also expected that these catalysts should catalyze the α-iminol rearrangement via protonation of the imine of the α-iminol, hopefully in good yield and enantioselectivity. However, VANOL/VAPOL-B3 complexes did not exhibit effective catalytic ability in this reaction (Table 3.1). VANOL-B3 22 gave 17% ee while VAPOL-B3 22 gave 0% ee in entries 1 and 4. In entry 2, one equivalent of benzoic acid (relative to the catalyst) was added during the preparation of the 26 catalyst, and presumably coordinates to one of the three-coordinate borons 39,40 forming a second tetra-coordinated boron. 39 for the Aza-Cope rearrangement, This catalyst proved to be optimal but ineffective in this reaction, giving only 2% ee. Table 3.1 Rearrangement of 3a by VANOL and VAPOL-B3 complex 22 Ph N H HO Ph Ph 25 mol% Chiral catalyst 75 °C 1 Catalyst 22 NH Ph Ph 3a Entry Ph (S)-4a Solvent O Time Yield (h) Ee (S)-VANOL-B3 Toluene 42 60% –17% (S)-VANOL-B3 Toluene 25 75% –2% 3 (S)-VANOL-B3 Toluene 50 22% –62% 4 (S)-VAPOL-B3 Toluene 20 73% 0% 5 (S)-VANOL-B3 Acetonitrile 45 73% –18% 6 (S)-VANOL-B3 THF 48 72% –9% 7 (S)-VANOL-B3 DCE 48 67% –2% 1:2 (S)-VANOL/B(OPh) 3 Toluene 63 56% –17% 1:1 (S)-VANOL/B(OPh) 3 Toluene 63 33% –30% b 2 c 8 d 9e a. Unless otherwise specified, all reactions were done on 0.1 mmol scale at 75 °C with 25 mol% catalyst 22 in 0.3 mL solvent in a Schlenk flask. The catalyst was prepared from the ligand and 3 equivalent of B(OPh)3. b. 1 equivalent benzoic acid (relative to the ligand) was added during preparation of the catalyst. c. The catalyst was prepared from a 1:3:2 mixture of d. ligand:BH3·SMe2:2,4,6-tri-tert-butylphenol. The catalyst was prepared from a e. 1:2 mixture of ligand:B(OPh)3. The catalyst was prepared from a 1:1 mixture of ligand:B(OPh)3. 27 In entry 3, a bulkier phenol, 2,4,6-tri-tert-butylphenol was used to prepare the catalyst. The t-butyl groups on the phenol were expected to create a more sterically demanding environment near the VANOL ligand, which may improve the enantioselectivity. In fact, it did improve the ee to 62%, but the reaction rate was greatly compromised; only 22% of 4a was observed after 50 h. In the following entries some different solvents, acetonitrile, THF and DCE were examined, but the results were not encouraging. Finally, the ratio between the ligand and B(OPh)3 was adjusted because it may form a different catalyst, but no significant improvement were observed (entries 8 and 9 in Table 3.1). To sum up, VANOL/VAPOL-B3 were not good catalysts for the α-iminol rearrangement. 3.2.2 α-iminol rearrangement by VANOL hydrogen phosphate its derivatives 43 VANOL and VAPOL hydrogen phosphate 44 and their derivatives were used as very effective chiral Brønsted acid catalysts in many catalytic asymmetric reactions, including amidation 47 benzoyloxylation of aryloxindoles, Pinacol 49 rearrangement, 45 of (Scheme imines, aza-Darzen 46 reaction, 48 desymmetrization of aziridines, 3.4). With these observations and that VANOL/VAPOL phosphoric acid and their derivatives were able to catalyze a wide range of reactions, these catalysts were also tested for the α-iminol rearrangement in the hope of observing excellent yield and enantioselectivity. 28 Scheme 3.4 Reactions catalyzed by VANOL/VAPOL hydrogen phosphates and derivatives Amidation of imine N Ph Ph O O P X O 23 X = OH 24 X = NHTf 25 X = OLi 26 X = OMg0.5 27 X = OCa0.5 Boc HN VAPOL 23 + NH 2Ts Ar Ar Aza-Darzens reaction O (S)-VANOL/VAPOL Phosphate O (R)-VAPOL 26 O O O N Boc O O R O Ar (S)-VAPOL 27 Ph O O N Boc Ph Desymmetrization of aziridines O R CF 3 N O Ar Benzoyloxylation of aryloxindole Ar Ph + O N Cl Ar O NHTs Ph O Ph + N Boc O VAPOL 23 + TMS-N3 CF 3 Pinacol rearrangement H 3CO R NH R N3 CF 3 CF 3 H 3CO OCH3 OH OH (R)-VAPOL 23 OCH3 CHO OCH3 H 3CO OCH3 OCH3 OCH3 H 3CO OCH3 OCH3 The first catalyst tested was (S)-VANOL hydrogen phosphate 23 (Table 3.2 entry 1). The reaction did not proceed at 45 °C, so a higher temperature 75 °C was tested. In this case, the reaction went to completion after half a day, but disappointingly, it only gave 2% ee. Next, (S)-VAPOL hydrogen phosphate 23 was examined, with a little improvement to 10% ee. These results indicated that the VANOL/VAPOL hydrogen phosphates are not good catalysts for the α-iminol 29 rearrangement. Table 3.2 α-Iminol rearrangement with VANOL/VAPOL hydrogen phosphates 23 Ph Ph N Ph H Ph Ph O O P OH O (S)-VANOL/VAPOL hydrogen phosphate 23 25 mol% 23 3a Entry Catalyst Ph Ph Ph HO NH (S)-4a Temp (°C) Solvent O Time Yield (h) Ee 1 (S)-VANOL 23 45 CH2Cl2 24 trace – 2 (S)-VANOL 23 75 CH2Cl2/MeCN 14 89% –2% 3 (S)-VAPOL 23 75 CH2Cl2/MeCN 48 60% –10% a. All reactions were done on 0.1 mmol scale with 25 mol% catalyst 23 in 0.3 mL solvent in a Schlenk flask. The next catalyst examined was VANOL and VAPOL N-triflyl phosphoramide 24 in Table 3.3. The results of rearrangement with VANOL and VAPOL N-triflyl phosphoramide gave essentially the same asymmetric induction, 24% ee, but yield was doubled with VANOL (entries 1 and 2). Solvents other than CCl4 were examined but led to reduced induction (entries 3-5). Entries 1, 6 and 7 list results from different temperatures, but lower temperatures did not lead to improved results and there was no reaction at room temperature. From these results, one can conclude that VANOL/VAPOL N-triflyl phosphoramides are not effective in the α-Iminol rearrangement. 30 Table 3.3 α-Iminol rearrangement with VANOL/VAPOL N-triflyl phosphoramides Ph N H HO 25 mol% Chiral catalyst Ph Ph Ph Ph O O P NHTf O (S)-VANOL/VAPOL N-trifyl phosphoramides 24 Ph Ph Ph 3a Entry NH (S)-4a Catalyst O Temp (°C) Solvent Time Yield (h) Ee 1 (S)-VANOL 24 60 CCl 4 36 100% –24% 2 (S)-VAPOL 24 60 CCl 4 41 45% –24% 3 (S)-VANOL 24 60 hexane 41 54% –14% 4 (S)-VANOL 24 60 benzene 41 58% –12% 5 (S)-VANOL 24 70 DCE 20 78% –12% 6 (S)-VANOL 24 40 CCl 4 48 complex mixture 7 (S)-VANOL 24 25 CCl 4 48 No Reaction a. All reactions were done on 0.1 mmol scale with 25 mol% catalyst 24 in 0.3 mL solvent in a Schlenk flask. The next catalyst candidate to be examined was the VANOL/VAPOL hydrogen phosphate salts 25 and 26. With salts 25 and 26, the rearrangement did not occur at 75 °C, but did at 100 °C. However, the yields and ees were extremely poor, probably because the high temperature favored dissociation of the metal cation, and the more the metal was separated from the ligand chiral environment, the less asymmetric induction it would provide. All chiral catalysts tested thus far failed to provide high yield and high enantioselectivity in the α-Iminol rearrangement. 31 Table 3.4 α-Iminol rearrangement with VANOL/VAPOL hydrogen phosphate salts Ph N H HO O O P O-M O Ph Ph (S)-VANOL/VAPOL Hydrogen phosphate salts 25/26 25 M = Li 26 M = Mg 0.5 10 mol% Chiral catalyst Ph Ph 3a Entry (S)-4a Catalyst Ph Ph CCl 4 Ph NH O Temp (°C) Time Yield (h) Ee 1 (S)-VANOL 25 75 14 trace – 2 (S)-VANOL 26 75 14 trace – 3 (S)-VANOL 25 100 24 30% –2% 4 (S)-VANOL 26 100 24 36% –8% a. Reactions were done in 0.1 mmol scale with 10 mol% catalyst in 0.3 mL solvent in a Schlenk flask. 3.3 Rearrangement by VANOL aluminum complex 27 3.3.1 Initial results The VANOL aluminum complex 27 is a new catalyst that has not been previously reported in literature. The idea of this new catalyst originated from the 50 utility of the known BINOL aluminum complex 28, asymmetric Michael 15,50 coworkers. addition reactions a very effective catalyst for developed by Shibasaki and The addition was proposed to occur when the aluminum in 28 activates the carbonyl substrate and the lithium phenoxide deprotonates the Michael donor. Based on the proposed mechanism for this bi-functional catalyst in the Michael reaction, it was wondered if the bi-functional mode of action could also induce an α-Iminol rearrangement. 32 Figure 3.1 VANOL/VAPOL aluminum complex and BINOL aluminum complex Ph Ph OH OH Ph Ph + LiAlH 4 0.5 equiv. Li O O Al O O Ph Ph VANOL/VAPOL Al 27 Li OH OH O O Al O O + LiAlH 4 0.5 equiv. ALB 28 Initial results with aluminum complexes 27 and 28 are listed in Table 3.5. the VANOL and VAPOL aluminum complexes both gave excellent yield and identical enantioselectivity, 68% ee. The corresponding BINOL catalyst 28 behaved very poorly, giving only 11% yield with 28% ee after a prolonged reaction time. Table 3.5 α-Iminol rearrangement with VANOL/VAPOL/BINOL Al complexes Ph N H HO Ph 3 mol% Chiral catalyst Ph Ph Ph Ph Toluene 3a Entry NH (S)-4a O Catalyst Temp (°C) Time (h) 1 (R)-VANOL-Al 27 70 19 100% 68% 2 (S)-VAPOL-Al 27 70 23 88% –68% 3 (S)-BINOL-Al 28 80 1 No Reaction 4b (S)-BINOL-Al 28 80 15 11% a. Yield Ee –28% Unless otherwise specified, all reactions were run on 0.1 mmol scale in toluene wth 3 mol% catalyst in a Schlenk flask under N2. b. The catalyst loading was 10 mol%. 33 3.3.2 Optimization with the VANOL ligand VANOL was chosen to be the ligand for further studies because it was as good as VAPOL and has a smaller molecular weight than VAPOL. The next step in the optimization was temperature screen in Table 3.6. At 70 °C, catalyst 27 gave 100% yield and 68% ee in 19 hours. At 60 °C, the reaction seemed to slow down dramatically, and at 45 °C, there was no reaction at all. The minimal temperature for this reaction was determined to be 70 °C. Table 3.6 Temperature screen with VANOL-Al complex 27 Ph N H HO Ph 3 mol% (R)-VANOL-Al 27 NH Ph Ph CCl 4 Ph Ph 3a (S)-4a O Entry Temp (°C) Time (h) Yield Ee 1 70 19 100% 68% 2 60 48 trace 3 45 6 No Reaction a. Unless otherwise specified, reaction were run in 0.1 mmol scale with 3 mol% catalyst in CCl4 in a Schlenk flask under N2. It was found the enantioselectivity was not affected greatly in different solvents, except for chloroform and DMF (Table 3.7). Nonpolar solvents including CCl4, toluene, benzene, m-xylene all gave excellent yield and good induction. More polar solvents, including DCE, THF, MeCN, and EtOAc all also gave the same excellent yield and good induction. Toluene was chosen to be the solvent in further studies. 34 Table 3.7 Solvent screen with VANOL-Al complex 27 Ph N Ph H HO Ph 3 mol% (R)-VANOL-Al 27 Ph Solvent, 70 °C Ph 3a Entry Solvent Time (h) Yield NH Ph (S)-4a Ee Entry O Solvent Time (h) Yield Ee THF 5 100% 68% 1 CCl 4 19 100% 68% 6 2 toluene 8 100% 68% 7 acetonitrile 14 100% 60% 3 benzene 14 96% 66% 8 EtOAc 14 99% 70% 4 m-xylene 6.5 100% 70% 9 4 No Reaction 5 1,2-DCE 9.5 100% 66% 10 4 No Reaction chloroform DMF a. Unless otherwise specified, all reaction were run on 0.1 mmol scale with 3 mol% catalyst at 70 °C in 0.3 mL solvent in a Schlenk flask under N2. Dr. Yong Guan suggested that derivatives of the VANOL ligand might provide better asymmetric induction. He observed improved enantioselectivity with 51 VANOL derivatives in the aziridination reactions, especially ligand 34 bearing tert-butyl groups at 7 and 7’ positions on VANOL which gave the best result. Therefore an evaluation of various VANOL derivatives was initiated. It was found that aryl substitutions at the 7 and 7’ positions on VANOL ligand, including 29, 30, 32, 33 and 35 improved the ee of the product from 68% to 82% (ligand 35). Ligand 31 has silyl groups at the 7 and 7’ positions, which enhanced the ee to 86%. Ligand 34, with tert-butyl groups at 7 and 7’ positions, gave 86%-90% ee over several trials. Thus, ligand 34 was chosen to be the optimal ligand for further studies. 35 Scheme 3.5 Ligand screen with VANOL derivatives Ph OH 3mol% (S)-7,7'-R2VANOL-Al Ph toluene, 85oC, 1h N H Ph Ph NHPh O Ph (R)-4a 3a tBu R Ph Ph OH OH R= tBu 29 63% yield, 74%ee Ph Si Ph tBu R= OMe tBu 30 96% yield , 71%ee 31 95% yield, 86%ee R (S)-VANOL derivative at 7, 7' R= R= R= 33 106% yield, 80%ee 32 96% yield, 80%ee iPr R= R= 34 100% yield, 86-90% ee iPr iPr 35 80% yield, 82% ee a. Unless otherwise specified, reactions were run on 0.1 mmol scale with 3 mol% catalyst, at 85 °C for 1 h in 0.3 mL toluene in a Schlenk flask under N2. 3.3.3 Synthesis of 7,7’-tBu2VANOL ligand 34 A synthesis of ligand 34 was carried out on gram scale according to the 51 procedure developed by Dr. Yong Guan. The synthesis started from commercially available ester 36. Hydrolysis of the ester gave the corresponding acid 37 in 100% yield, and the acid was then cyclized with phenyl acetylene through a ketene intermediate to afford the monomer 38 in 46% yield. Dimerization under heat in the presence of air in 70% and deracemization with (+)-sparteine gave the enantiopure ligand (R)-34 in 84% yield (1.5 gram). 36 Scheme 3.6 Synthesis of ligand (R)-34 OCH3 O 36 37 38 3 equiv. SOCl2 90 °C OH 1) 2 equiv. KOH H 2O, rt O 2) HCl 37 100% 1.3 equiv. Ph 7 equiv. KOH H 2O, 100 °C 2 equiv. (iPrCO) 2O Ph 190 °C, 24 h mineral oil 150 °C, air Ph Ph 1.5 equiv. CuCl 2 equiv. (+)-sparteine MeOH, DCM, rt OH OH OH 38 46% (R)-34 84%, >99% ee rac-34 70% 3.3.4 Optimization with 7,7’-tBu2VANOL ligand 34 in complex 27 The aluminum catalyst 27 formed from the 7,7’-t-butyl-VANOL ligand 34 was examined for the α-iminol rearrangement of 3a at different temperatures and the results are presented in Table 3.8. The maximal enantioselectivity was observed at 80 °C and 90 °C, but it seemed the ee of the product could not be improved to more than 88% with catalyst 27. A more efficient catalyst was sought and the results of this search are presented below. 37 Table 3.8 Temperature screen with ligand 34 in aluminum complex 27 Ph N H HO Ph Ph 3 mol% (R)-7,7'-tBu 2VANOL-Al 27 NH Ph Ph Toluene (S)-4a 3a Entry Temp (°C) Ph Time (h) Yield O Ee 1 60 48 32% conversion 2 70 8 100% 82% 3 80 1.5 94% 88% 4 90 1 85% 88% 5 100 0.5 100% 84% 6 110 0.25 100% 84% a. Unless otherwise specified, all reactions were run in 0.1 mmol scale in 0.3 mL toluene in a Schlenk flask under N2 with 3 mol% catalyst (R)-7,7’-tBu2VANOL-Al 27 derived from ligand (R)-34. 3.3.5 Determination of the absolute stereochemistry of 4a The absolute stereochemistry of 4a was determined by an independent synthesis of 4a starting from commercially available enantiopure amino ester 39. The first step was to neutralize the salt with sodium carbonate, and then couple the free amine with phenylboronic acid, to give the N-phenyl amino ester 40. Compound 40 was converted to the Weinreb amide and further converted to (R)-4a with phenyl Grignard reagent. Optical rotation and chiral HPLC both suggested this product (R)-4a is identical to the iminol rearrangement product 4a observed with (S)-VANOL-Al 27 as the catalyst. 38 Scheme 3.7 Synthesis of (R)-4a from 39 Ph NH 2·HCl OCH3 2 equiv. PhB(OH) 2 10 mol% Cu(OAc)2 DCM, reflux, air 1.5 equiv. Na 2CO 3 39 O 2.5 equiv. CH 3(OCH 3)NH·HCl 5 equiv. iPrMgCl Ph NH Ph OCH3 40 O 23% Ph NH Ph 41 64% CH 3 N CH 3 O Ph NH 3 equiv. PhMgCl Ph Ph O (R)-4a 65%, 90% ee O 3.4 Rearrangement by VANOL zirconium complex 3.4.1 The Mannich type reaction with VAPOL zirconium complex Zirconium VANOL/VAPOL catalysts 45 were first used in Mannich type 52 reactions by Dr. Wulff in 2001. In this reaction, Dr. Wulff and colleagues synthesized the VAPOL zirconium complex 45 with a 2:1:1 mixture of (S)-VAPOL 42, zirconium(IV) isopropoxide isopropanol adduct 43 and N-methylimidazole 44 (Scheme 3.8). This catalyst did an excellent job in the Mannich type reaction between imine 47 and ketene acetal 48 to give the beta-amino ester 49 with excellent yield and ee (Scheme 3.9 A). 39 Scheme 3.8 Synthesis of VAPOL Zr catalyst 45 and VANOL Zr catalyst 46 N Ph Ph OH OH + Zr(OiPr) 4(HOiPr) + toluene N CH 3 43 44 1 equiv. 1 equiv. rt, 30 min Ph Ph O O O O Zr Ph Ph N 2 equiv. VAPOL/VANOL 42 N CH 3 VAPOL Zr 45 VANOL Zr 46 The origin of the excellent enantioselectivity was proposed to be that the vicinal N and O atoms in imine 47 chelated to zirconium center in the catalyst 45 (Scheme 3.9 B), and the chiral ligand VAPOL on the zirconium atom hindered one side of the imine while leaving the other side open for attack by the ketene acetal. Scheme 3.9 Synthesis of chiral amino ester 49 and chelation between 45 and 47 CH 3 CH 3 OH OH A H 3C N + H 3C OTMS H 3C OCH3 (S)-VAPOL Zr 45 H 3C NH Ph Ph 48 47 O OCH3 H 3C CH 3 49 H Ph B C Ph N Ph O O * O Zr O OH * NMI 3.4.2 The iminol rearrangement with VANOL and VAPOL zirconium complex The fact that α-Iminol 3a also has vicinal N and O atoms was the reason that 40 this catalyst was examined for the α-Iminol rearrangement, because similar chelation may also occur between catalyst and substrate (Scheme 3.9 C). 52 Catalyst 45 and 46 were prepared according to a literature procedure (Scheme 3.8). Specifically, this involved mixing 2 equivalent of ligand (VAPOL for 45, VANOL for 46), 1 equivalent of zirconium(IV) isopropoxide isopropanol adduct 43 and 1 equivalent of N-methylimidazole 44 in toluene in a screw capped vial under air at room temperature for 30 min. The catalyst 45 gave a light yellow solution while 46 gave a white slurry. The appearance of white precipitate was taken as an indication of the successful formation of catalyst 46. Catalyst 45 did in fact effect the α-Iminol rearrangement, but the product 4a was only obtained with 28% ee. If the ligand VAPOL in catalyst 45 was replaced with VANOL (catalyst 46), the yield and ee of product 4a in the iminol rearrangement reaction dramatically improved to 94% and 97% respectively, with only 2.5 mol% catalyst loading (Table 3.9 entries 1 and 2). 3.4.3 Optimization of reaction conditions with VANOL Zr complex 46 With the encouraging result shown in entry 2 of table 3.9 in hand, various reaction conditions were probed with the VANOL Zr catalyst 46. Catalyst loading was examined first (Table 3.9). Initially, 5 mol% catalyst was used, but it was found that 2.5 mol% and also 1 mol% were as effective in terms of yield and asymmetric induction. The catalyst loading could be even as low as 0.5 mol% with nearly the same yield and ee of product 4a. However, with 0.1 mol% 46 very poor 41 results were observed. To obtain the highest asymmetric induction, 2.5 mol% catalyst was used for further reactions. Table 3.9 Catalyst loading screen with catalyst 45 and 46 Ph N H Ph 3a entry Ph OH Ph (R)-catalyst O Ph toluene, 80 °C, 1 h catalyst NH Ph (S)-4a catalyst loading (mol%) %yield 4a %ee 4a 1 VAPOL Zr 45 5 86 28 2 VANOL Zr 46 5 96 97 3 VANOL Zr 46 2.5 97 97 4 VANOL Zr 46 1 98 96 5 VANOL Zr 46 0.5 96 95 6 VANOL Zr 46 0.1 23 23 All reactions were run with 0.1 mmol substrate, indicated loading of catalyst 46 in 0.3 mL toluene under air in a screw capped vial at 80 °C for 1 h. All were isolated yield except entry 6, which was an NMR yield. Ee were determined with chiral HPLC. The effect of the concentration of the iminol substrate on the reaction was studied and summarized in Table 3.10. The experiment results suggest that the reaction concentration only slightly effects the performance of the catalyst in terms of yield and ee of product 4a. For example, when the concentration is varied from 1 M to 0.03 M, the ee for 4a improved from 95% to 97%. To achieve the highest asymmetric induction and lowest volume of solvent, 0.3 M was chosen for the further reactions. 42 Table 3.10 Concentration screen with catalyst 46 Ph N H Ph 3a 2.5 mol% (R)-Zr VANOL 46 OH Ph Ph NH O Ph toluene, 80 °C Ph (S)-4a Concentration of 3a [M] Time (h) %yield 4a %ee 4a 1 1 0.17 100 95 2 0.5 0.25 100 95 3 0.3 1 97 97 4 0.1 1 96 97 5 0.03 1 100 97 entry All reactions were run with 0.1 mmol substrate, 2.5 mol% catalyst 46, at the indicated concentration of 3a and reaction time in 0.3 mL toluene under air in a screw capped vial at 80 °C. All yields were isolated yield. The %ee was determined by HPLC. The effect of temperature on the rearrangement of 3a with VANOL Zr catalyst 46 was examined and the results are presented in Table 3.11. It was remarkable that the reaction with catalyst 46 was very temperature independent. When the reaction temperature was varied from 25 °C to 120 °C, the yield and enantioselectivity stayed essentially the same except that at 25 °C the reaction was not complete in two days. Even at 160 °C, the reaction was complete in only 30 seconds with surprisingly little loss in ee. For the reaction at 160 °C in mesitylene, the catalyst solution was pre-heated to 160 °C before the addition of the substrate, this is because it was found the reaction proceeded fast at 100 °C and 120 °C, the reaction may have completed at a lower temperature if it was not 43 pre-heated to 160 °C. To obtain the highest ee in shortest time period at the lowest temperature, 60 °C was found to be the optimal temperature and was used for further reactions. Table 3.11 Temperature screen with catalyst 46a Ph N H Ph 3a 2.5 mol% (R)-Zr VANOL 46 OH Ph toluene, temperature time Ph NH O Ph Ph 4a entry temp (°C) Time (h) %yield 4a %ee 4a 1 25 48 55 97 2 40 8 98 98 3 50 2.5 95 97.5 4 60 1 94 97 5 70 1 95 97 6 80 0.5 97 97 7 100 0.17 100 95 8 120 0.08 96 95 9b 160 0.008 95 89 a. Unless otherwise specified, all reactions were run with 0.1 mmol substrate, 2.5 mol% catalyst in 0.3 mL toluene under air in a screw capped vial and under the indicated temperature and time. All yields were isolated yield. The %ee was determined by HPLC. b. The catalyst solution was preheated to the indicated temperature before adding 3a, and the solvent was mesitylene. The effect of solvent on the rearrangement of 3a with VANOL Zr catalyst 46 was examined and the results are presented in Table 3.12. Aromatic solvents were very good for this reaction, including benzene, toluene and mesitylene. However, when a polar/coordinating solvent was used, the reaction rate was 44 greatly reduced, and the asymmetric induction was reduced slightly as well. The reason for the slower reaction rate and lower ee with polar/coordinating solvent is not clear at this point. This study identified toluene as the optimal solvent. Table 3.12 Solvent screen with catalyst 46 Ph N H Ph 3a entry OH Ph 2.5 mol% (R)-Zr VANOL 46 Ph NH O Ph solvent, 60 °C, 1 h Ph 4a solvent %yield 4a %ee 4a 1 Benzene 100 97 2 Toluene 94 97 3 Mesitylene 96 95 4 THF 6 95 5 Ethyl acetate 15 92 6 Acetonitrile 9 71 20 90 56 94 7 8 1,2-dichloroethane Chloroform All reactions were run with 0.1 mmol substrate, 2.5 mol% catalyst in 0.3 mL indicated solvent under air in a screw capped vial at 60 °C and stopped at 1 h. Yields in entry 1, 2 and 3 were isolated yields, the rest were determined with NMR. The %ee were determined by HPLC. 3.4.4 Scope of the α-iminol rearrangement of aldimines After optimization of the reaction conditions, the scope of the α-iminol rearrangement reaction was studied with both aryl and alkyl aldimines of the general type 3. A broad range of substrates was examined as shown in Table 3.13. Most of the substrates gave excellent yield and ee (>97%) except those with 45 ortho substitutions and para CF3 group on the migrating phenyl ring. In entries 2 and 3, the bulkier isopropyl group at the ortho position resulted in a lower ee than a smaller methyl group. Aryl aldimines with a methyl group on the meta position and para position gave excellent yield and induction (entries 4 and 5). Several substrates with substitutions in the para position were examined including F, Cy, iPr, nBu, Ph, tBu groups all of which gave excellent yield and ee, as well as the electron donating para methoxyl groups (entries 6-12). However, the electron withdrawing CF3 group in the para position rearranged with a sluggish reaction rate, and only the side product 4y could be observed. Deoxygenation of the reaction mixture by the freeze-pump-thaw method improved the results and good yield and moderate ee of the desired product 4m could be realized (entries 13 and 14). Despite the moderate asymmetric induction of the para CF3 substituted substrate 3m, the electron withdrawing para acetyl substituted substrate 3n underwent the rearrangement to give 4n with 97% ee. For aliphatic migrating groups, hexyl, benzyl, cyclohexyl were examined and all gave excellent yield and induction except a slight drop in ee with hexyl group (entries 16-18). 46 Table 3.13 Scope of the α-iminol rearrangement of aldimines Ph N H R 2.5 mol% (R)-Zr VANOL 46 OH toluene 60 °C, 1h R Ph NH O R R (S)-4 3 Series R % yieldb 4 % eec 4 1 a Ph 94 97 2 b 2-CH3C6H 4 88 84 3 c 2-iPrC 6H 4 95 –54d 4 d 3-CH3C6H 4 96 98 5 e 3-ClC6H 4 92 –93d,e 6 f 4-CH3C6H 4 92 98 7 g 4-nBuC 6H 4 95 99 8 h 4-iPrC 6H 4 98 99 9 i 4-CyC6H 4 97 94 10 j 4-tBuC 6H 4 100 > 99 11 k 4-PhC6H 4 100 > 99 12 l 4-(CH3O)C6H 4 90 13 m 4-FC6H 4 97 14 n 4-CF3C6H 4 <5f – 15 n 4-CF3C6H 4 74 73g 16 o 4-AcC6H 4 100 97 17 p n-hexyl 95 89 18 q benzyl 98 99 19 r cyclohexyl 97 98 Entry 47 98 > –99d Ph N O F 3C 4y CF 3 Table 3.13 (cont’d) a. Unless otherwise specified, all reactions were run with 0.1 mmol 3, 2.5 mol% (R)-catalyst 46 in 0.3 mL toluene under air in a screw capped vial at 60 °C for 1 h. b. Isolated yield. c. The %ee was determined by HPLC. d. (S)-catalyst 46 was used, thus (R)-product formed. e. Reaction was done under N2 atmosphere in Schlenk flask. f. This reaction gave 18% byproduct 4y and 70% starting 3m. g. Reaction was done under N2 on a reaction mixture that was deoxygenated by the freeze-pump-thaw method in a Schlenk flask. Imines bearing substituted arenes as well as a benzyl group on the nitrogen were also examined in this reaction (Scheme 3.10). For aniline derivatives, the p-methoxyl derivatives 4s and 4t, the p-ethyl ester 4u, and the 3-TBS protected methanol derivative 4v, all were formed in excellent yield and ee. When the aliphatic protecting group benzyl was used, the reaction required significantly higher temperature (120 °C) and the asymmetric induction dropped to 10% ee in the rearranged α-amino ketone 4w. The reaction scale in Scheme 3.10 was 0.1 mmol for all substrates. For 4s, the reaction could be conducted on a 40-fold larger scale (1.22 gram) than that for the reactions in Scheme 3.10, with only 1 mol% catalyst loading and still gave 94% yield and 95% ee. 48 Scheme 3.10 Substituted anilines in α-iminol rearrangement H 3CO H 3CO EtO 2C NH NH O 4u 60 °C, 0.5 h 88% yield, 96% ee 4t 80 °C, 2 h 97% yield, 94% ee 4s 80 °C, 1 h 98% yield, 98% ee TBSO NH O O NH Ph O NH O 4w 120 °C, 2 h, N 2 95% yield, 10% ee 4v 60 °C, 1 h 91% yield, 97% ee The condensation between the aldehydes 2 and aniline was spontaneous without any catalyst; therefore it was considered possible that the synthesis of amino ketone 4 could be achieved by reacting the aldehyde 2 with aniline in the presence of catalyst 46. The tandem imine formation and α-iminol rearrangement of 2l was performed by treating a mixture of aldehyde 2l and aniline with 2.5 mol% VANOL Zr catalyst 46 which gave the α-amino ketone 4l in 98% yield and >99% ee. This is essentially the same as the result of 100% yield and >99% ee when starting with the preformed imine 3l (see Table 3.13 entry 12). 49 Scheme 3.11 Tandem imine formation and α-iminol rearrangement of 2l O OH H + aniline 1.1 equiv. 2.5 mol% (S)-Zr VANOL 46 NH toluene, 60 °C, 1 h O 2l 4l 98% yield, >99% ee 3.4.5 Preparation of amino alcohols from α-amino ketone 4s The synthetic utility of α-iminol rearrangement methodology could be illustrated in the synthesis of amino alcohols 50 to 52 all of which are important as chiral 53-55 ligands in asymmetric synthesis and catalysis (Scheme 3.12). The amino ketone 4s from the rearrangement reaction could be reduced to anti-amino alcohol 50 with Super Hydride in good yield and ee as a single diastereomer (anti:syn >50:1). If the nitrogen was protected with an acetyl group, and the resulting derivative was reduced with Super Hydride, it gave the syn-amino alcohol 51 as a single diastereomer (syn:anti >50:1). Lastly, another one equivalent of phenyl Grignard reagent could be added to the ketone 4s to produce the third amino alcohol 52. The enantiopurity of 50, 51 and 52 could be enhanced to >99% ee after one crystallization from a mixture of hexanes and ethyl acetate with greater than 80% recovery as indicated in the Scheme 3.12. The %ee of 50, 51 and 52 were determined with the aid of an authentic racemic sample that was prepared from racemic 4s. Racemic 4s was prepared from 54, by installation of a bromine atom at the alpha carbon with copper bromide, and 50 then substitution of the bromine with p-methoxyaniline to give rac-4s. Scheme 3.12 Synthesis of amino alcohols from α-amino ketone 4s MeO MeO NH MeO 1) AcCl 2) Super-H 3) KOH NH Super-H NH O OH OH 4s 95% ee 50 anti:syn >50:1 80% yield, 92% ee >99% ee after crystalization 87% recovery 51 syn:anti >50:1 53% overal yield 92% ee PhMgCl >99% ee after crystalization 92% recovery MeO NH HO 52 76% yield, 93% ee >99% ee after crystalization 82% recovery H 3CO 2 equiv. CuBr2 Ph EtOAc, reflux, 1h Ph Br Ph Ph O 54 O 1.1 equiv. PMP-NH 2 1.1 equiv. Et 3N 5 mol% 4-DMAP DCM, rt, 2h NH rac-4s 81% 55 88% Ph Ph O 3.4.6 Iminol rearrangement with ketimines All α-iminol substrates examined in this work were generated from aldehyde 2 and the resulting aldimines underwent facile and highly enantioselective α-iminol rearrangement with VANOL Zr catalyst 46. To broaden the range of substrates, α-iminols derived from ketones were prepared and subjected to the same reaction conditions with catalyst 46. The synthesis of α-iminol 59 started from ethyl pyruvate 56. The ketone for the rearrangement was protected in the form of a diethyl acetal in quantitative yield, 51 and the ester group reacted with two equivalents of Grignard reagent, followed by acidic hydrolysis to give the methyl ketone 58 in 85% yield over two steps from 57. After extensive studies to effect the condensation of ketone 58 with p-methoxyaniline, the optimal catalyst was found to be Ti(OiPr)4, giving the desired α-iminol 59 in 68% yield. Scheme 3.13 Synthesis of α-iminol 59 2.5 equiv. CH(OEt) 3 O H 3C CO2Et 56 EtO H 3C OEt CO2Et EtO H 3C H 2SO 4, rt, 3 h CO2Et 57 100% O 5% HCl acetone 70 °C, 1 h 2.5 equiv. PhMgCl OEt OH H 3C THF, rt, 30 min 85% 57 58 O H 3C NH 2 OH 1 equiv. Ti(OiPr)4 N + OCH3 58 H 3CO toluene 70 °C, 2 h OH H 3C 59 68% 2 equiv. Unfortunately, it was found that α-iminol 59 did not undergo rearrangement with catalyst 46 at temperatures in the range 80 °C to 150 °C. Only the starting material 59 was observed in the 1H NMR spectrum of the crude reaction mixture. The reason for this is probably that the presence of the methyl group changed the electronic nature of the imine and the increased electron rich character of the imine resulted in increased stability of the imine that the zirconium catalyst 46 was 52 not able to initiate the rearrangement. To test this theory, an electron withdrawing CF3 group could be attached to the imine, but as of yet, this has not been done. Table 3.14 Attempted rearrangement of α-iminol 59 H 3CO OCH3 N H 3C OH 5 mol% (S)-Zr VANOL 46 HN toluene 59 O temp, time result 1 80 °C, 1 h No Reaction 2 100 °C, 1 h No Reaction 3 120 °C, 1 h No Reaction 4* 150 °C, 1 h imine started to hydrolyze Entry CH 3 60 All reactions were run with 0.1 mmol 59, 5 mol% catalyst 46 in 0.3 mL toluene at indicated temperature for 1 h in a Schlenk flask under air. *Entry 4 was done in mesitylene. 3.4.7 Stability of zirconium VANOL catalyst 46 For the preparation of zirconium VANOL catalyst 46, a 2:1:1 mixture of VANOL:Zr(OiPr)4(HOiPr):N-methylimidazole was added and stirred in toluene at room temperature for 30 minutes. The solution was clear initially, but after two minutes, a white solid precipitate began to appear in the solution, and this white slurry was used for the reaction. This solid catalyst was in fact stable for storage under air at room temperature. The catalyst was also remarkably stable as a 53 toluene suspension, which could be allowed to stand for 5 months and 10 days in a screw capped vial under air at room temperature as shown in Table 3.15 and still gave the same yield and asymmetric induction for 4a. Table 3.15 Stability of the catalyst 46 N OH H 2.5 mol% (S)-Zr VANOL 46 NH toluene, 60 °C, 1 h O 3a 4a Entry Age of catalyst* Yield of 4a Ee of 4a 1 Fresh 94% 97% 2 1 day 97% 97% 3 6 days 95% 97% 4 14 days 98% 95% 5 5 months 10 days 98% 97% Photo of catalyst *Time stored as a toluene suspension under air at room temperature. 3.4.8 Crystal structure of the zirconium VANOL catalyst The structure of the VANOL Zr catalyst for the α-iminol rearrangement was assumed to be the structure 46 (see Scheme 3.8). Crystals of a VANOL Zr complex 61 were grown from the catalyst solution in toluene containing a 2:1:1 ratio of VANOL : Zr(OiPr)4(HOiPr) : N-methylimidazole. The toluene was removed under high vacuum and the residue was dissolved in bromobenzene at 100 °C 54 and very slowly cooled to room temperature. These crystals were subjected to X-ray crystallographic analysis by Dr. Staples and Dr. Rheingold, and the result was not 2:1:1 VANOL : Zr : N-methylimidazole complex as expected, instead, it was the 3:1:2 complex 61 (see Figure 3.2 and 3.3). Figure 3.2 Crystal structure of 61 Ph Ph O O Ph Ph O H O H O H –2 Zr O O H O H N N CH 3 Ph Ph H N N CH 3 Figure 3.3 Crystal structure of 61 (visualization by Dr. Mathew Vetticatt) 55 The zirconium metal is bonded to six oxygens from three VANOL ligands and it is charge balanced with two protonated N-methylimidazoles. These imidazoles are not coordinated to the zirconium but rather are protonated. The protonated imidazoles are not H-bonded to the polyoxygenated dianionic core but rather to two water molecules which are in turn H-bonded to the oxygens of the catalyst core. The protons on the imidazole were located, but the protons on water were not. Thus the hydrogen bonding was inferred from the N-O distance (2.701 Å) between imidazole and water, and the O-O distance (2.689 Å) between water and the VANOL ligand. A second sample that was prepared with a 3:1:2 mixture of VANOL : Zr(OiPr)4(HOiPr) : N-methylimidazole exhibited the same unit cell as those grown from a 2:1:1 mixture above. See experimental section for the NMR study of the crystal 61 in d6-DMSO solution. The formula of the crystal 61 for each unit cell is Zr2(C32H20O2)6(C4H7N2)4(H2O)4(C6H5Br)6, Figure 3.2 and 3.3 are two presentations of half of the unit cell omitting the bromobenzene. 3.4.9 Catalyst composition study The chemical composition of compound 61 obtained by crystallization from the catalyst solution was 3:1:2, not 2:1:1. This suggested the possibility that compound 61 is the actual catalyst for α-iminol rearrangement. Given this discrepancy, catalysts generated with various ratios of VANOL : Zr(OiPr)4(HOiPr) : N-methylimidazole were prepared and their effects on the rearrangement reaction of 3a were examined and the results are presented in Table 3.16. In entries 1 and 56 6, no N-methylimidazole was added, and it turned out that this resulted in no formation of a detectible amount of product 4a. This indicates that N-methylimidazole is a crucial component of the active catalyst. In entries 2 and 3, excess N-methylimidazole was added and this slowed down the reaction. In entry 4, only 1 equivalent VANOL was used, and the asymmetric induction remained unchanged although the reaction rate was lower. In entry 7, the exact ratio that was revealed in the crystals of 61 was employed and there was no significant change in yield and ee. In entry 8, crystals of 61 were used, and the yield and ee of 4a was almost identical to that of the product with in-situ generated catalyst prepared from 2:1:1 ratio of the components. Apparently, both 2:1:1 and 3:1:2 stoichiometries gave the same catalyst and the real question is what is the actual structure of the catalyst in solution. Is it structure 61 or some other species? And also what is the mechanism of this reaction? This will have to await future studies. 57 Table 3.16 Catalyst composition study Ph N H Ph 3a OH Ph Ph 2.5 mol% (R)-Zr VANOL NMI NH O Ph toluene, 60 °C, 1 h Ph 4a entry Ratio [L]:[Zr]:[N] 1 [Zr] = Zr(OiPr) 4(HOiPr) [L] = (R)-VANOL [N] = N-Methylimidazole %yield 4a %ee 4a 2:1:0 0 – 2 2:1:1 94 97 3 2:1:2 70 97 4 2:1:20 8 96 5 1:1:1 33 97 6 3:1:1 98 98 7 3:1:0 0 – 8 3:1:2 80 96 9 3:1:2b 96 98 a. Unless otherwise specified, all reactions were run with 0.1 mmol 3a, 2.5 mol% catalyst in 0.3 mL toluene in a screw capped vial under air at 60 °C and stopped after 1 h. b. Crystals of 61 were used. 3.4.10 Catalyst 46 recycle study The catalyst 46 exhibited remarkable stability for storage in toluene under air (see Table 3.15). Thus it was of interest to determine how the catalyst would perform for more than one cycle. For the first cycle, the catalyst was prepared fresh and used immediately. The result was normal as expected (see Table 3.17 entry 1). After the first cycle was complete, excess hexane (10 times volume to toluene) was added to the solution at room temperature to precipitate the catalyst. After filtration through filter paper, the white solid catalyst was recovered and all was used directly in the next cycle. For the second cycle, the reaction time was 58 slightly longer than the first cycle, but the yield and ee of product was unchanged. For the third cycle, the catalyst performed poorly. However, the toluene solvent in this study was suspected to be somewhat wet, so this study needed to be reexamined. The loss of catalyst after each cycle is substantial, and thus perhaps a better method for precipitation of the catalyst would extend the number of cycles through which it can be reused. Table 3.17 Catalyst recycle study Ph N (S)-VANOL Zr catalyst OH H Ph cycles temp/time NH Ph Ph toluene Ph 3a Ph O (R)-4a cat. used yielda, ee cycle 1 b 60 °C/1 h cycle 2c 60 °C/3 h 0.0400 g recycled from cycle 1 100%, 98% cycle 3d 70 °C/7 h 0.0225 g recycled from cycle 2 25%e, 64% 5 mol% (0.0522 g) 100%, 98% a. All reactions were run with 1.04 mmol 3a in 2 mL toluene at the indicated temperature and time period. Yields were isolated yield, ee were determined by HPLC. b. The catalyst in cycle 1 was prepared from 0.05 mmol Zr(OiPr)4(HOiPr), 0.10 mmol (S)-VANOL and 0.05 mmol NMI. c. 0.0400 g catalyst was recycled from cycle 1 and all was used in cycle 2. d. 0.0225 g catalyst was recycled from cycle 2 and all was used in cycle 3. e. Yield determined by NMR, 70% unreacted starting material was also present. 3.4.11 Control experiment To examine if there’s a background reaction in the α-iminol rearrangement, control experiments were designed and the results are presented in Table 3.18. 59 The rearrangement without catalyst did not go at 80 °C but proceeded at 150 °C. However, the product was not stable at 150 °C in the presence of air (entry 3). In this reaction, the product 4a is oxidized to give a 50% yield of a product tentatively assigned as 4x (see Table 2.1). It was also found that Zr(OiPr)4(HOiPr) did not catalyze the reaction, however, in entries 4 and 5 if Zr(OiPr)4(HOiPr) and N-methylimidazole were both added, the reaction proceeds to a small extent, which means that N-methylimidazole was an important ingredient in the catalyst for the reactivity. This discovery is consistent with the results in Table 3.16 entries 1 and 6. Table 3.18 Control experiments NPh OH H Ph Ph Ph rac-4a 3a entry NHPh O Ph yield rac-4a catalyst Solvent time temp 1 None toluene 42h 80 oC 2 None Mesitylene 2h 150 oC 28%b 3 None Mesitylene 5h 150 oC 20%c 0% 4 5 mol% Zr(OiPr) 4(HOiPr) toluene 1h 80 oC 0% 5 5 mol% Zr(OiPr) 4(HOiPr) and NMI toluene 1h 80 oC 12% d a. Unless otherwise specified, all reactions were run with 0.1 mmol 3a under air and yields were determined by NMR. b. Reaction was run under N2, 71% 3a was unreacted. c. 30% 3a was unreacted and 50% side-product 4x (see Table 2.1). d. 60 79% 3a was unreacted. 3.5 Kinetic resolution of racemic α-iminol by VANOL zirconium complex The α-iminol rearrangement of all substrates examined at this point containe two identical migrating groups in the molecule. If the two migrating groups are different, the starting iminol would be racemic, and thus there may be a possibility that the zirconium VANOL catalyst would preferably convert the matched enantiomer to the amino ketone product leaving the unmatched enantiomer unreacted. The first few substrates were prepared from commercial 62. Addition of a Grignard reagent to the ketone in 62 followed by acidic hydrolysis gives aldehyde 63, which was converted to the racemic α-iminol 64 with p-methoxylaniline. Table 3.17 Synthesis of racemic iminols 1.0 equiv. OEt H 3CO 62 O THF, rt 30 min THF, rt 20 min R Br + Mg O yield Aldehyde 63 PMP OH H NH 2 OH Ph 63 yield Iminol 64 N H R Ph 5% HCl, acetone 70 °C, 1h 1.5 equiv. 1.5 equiv. R 1.1 equiv. Ph EtO R 64 yield Aldehyde 63 R yield Iminol 64 OMe a b OMe 71% 100% c OMe O 52% 98% 40% 100% CH 3 74% 95% d OMe 61 For the kinetic resolution of 64a, which contains 3,4,5-trimethoxylphenyl and phenyl as the migrating groups, it was found that the migration of phenyl group was more favorable than the trimethoxylphenyl group. The crude 1 H-NMR spectrum suggested that only phenyl group migrated, not the trimethoxylphenyl. It was also found that from the beginning up to 50% conversion (5.5 h), the reaction proceeded smoothly, but after 50% conversion, the reaction rate slowed down considerably. When the reaction was stopped at 50% conversion, the enantiopurity of 64a was determined to be >99% ee. The absolute stereochemistry of 65a was tentatively assigned as (S) according to previous results, and the remaining 64a was assumed to be enriched in the (R) enantiomer if the chelation mechanism between substrate and catalyst 46 is operated. These results suggest that kinetic resolution of racemic α-iminols is feasible and that future investigation of this process is warranted. Scheme 3.14 Initial study of kinetic resolution of 64a PMP PMP OMe N OH H OMe 2.5 mol% (R)-Zr VANOL 46 OMe toluene, 50 °C 0.2 M OMe NH + Ph Ph rac-64a PMP OMe N OH H OMe Ph OMe O OMe 65a 62 (R)-64a OMe Figure 3.4 Reaction progress of 64a 0.7" Conversion of 64a 0.6" 0.5" 0.4" 0.3" 0.2" 0.1" Time/h 0" 0" 5" 10" 15" 20" 25" 3.6 Conclusion A successful catalytic asymmetric α-iminol rearrangement methodology was established with a zirconium VANOL complex. The yield and ee of the rearrangement product was up to 100% and >99%, respectively. The catalyst was incredibly stable such that after storage for 5 month in toluene under air, the product was formed without loss in yield or enantioselectivity. A crystal of the catalyst was obtained and analyzed. In the crystal, a 3:1:2 ratio of VANOL:Zr:NMI was found instead of the expected 2:1:1 ratio. The actual active catalyst and mechanism for this reaction remains unknown, and further investigation is needed. 63 CHAPTER FOUR MISCELLANEOUS PROJECTS 4.1 Total synthesis of Rhizochalin C 4.1.1 Introduction Asymmetric catalytic aziridination is one of the useful methodologies in 34 organic synthesis that was developed in Dr. Wulff’s group. In this methodology, an imine and a diazoacetate or diazoacetamide, are the starting materials; their reaction can be catalyzed by a VAPOL/VANOL-B3 complex to afford the enantiopure aziridine as shown in Scheme 3.3. Recently, Dr. Anil Gupta developed the three-component cis-aziridination reaction as shown in 35 Scheme 4.1. The R group can be either electron-rich or electron-poor 56 aromatic ring or 1°, 2°, and 3° aliphatic chain, or an alkyne. Scheme 4.1 Multi-component catalytic asymmetric synthesis of cis-aziridine Ph HO B O B O O O B Ph Ph Ph MEDAM O R + MEDAM + NH2 N O in situ generated OEt (R)-VAPOL-B3 catalyst EtO2C R cis-aziridine N2 up to 98% yield and 98%ee MeO OMe MEDAM = 64 Two-headed sphingolipids (Figure 4.1) can be found in many marine sponges 57,58 such as Rhizochalina incrustata, Calyx, 61 62 Leucetta leptorhapsis, 59 Oceanapia phillipensis, 60 Oceanapia, 63 and one unidentified sponge. It was found that the two-headed sphingolipids have different kinds of bioactivities: 57 57 anti-bacterial activity, cytotoxic activity, 61 DNA-damaging activity, antifungal activity, 63 and inhibition of protein kinase C. 59,60 selective Rhizochalin is representative of the two-headed sphingolipid natural product with chiral amino alcohol functionalities on both ends. An asymmetric aziridination reaction followed by ring opening with an oxygen nucleophile could achieve both amino alcohol functionalities and the desired stereochemistry. Therefore, the two-headed sphinglipid compounds were chosen as an application of the asymmetric catalytic aziridination and subsequent ring opening methodology in natural product total synthesis. Figure 4.1 Two-headed sphingolipids OH HO HO O O NH 2 HO NH 2 O OH Rhizochalin 66 OH HO HO O NH 2 HO HO NH 2 Oceanapiside 67 65 O OH Figure 4.1 (cont’d) OH O NH 2 O HO HO OH O OH OH NH 2 Calyxoside 68 OH HO HO O O O O HN HO NH 2 O OH Rhizochalin A 69 HO HO HO O O NH 2 OH NH 2 O O OH Rhizochalin B 70 HO HO HO O O NH 2 OH HO O NH 2 OH Rhizochalin C 71 HO HO HO O O OH OH NH 2 O Rhizochalin D 72 NH 2 4.1.2 Retrosynthetic analysis of Rhizochalin C Rhizochalin C was selected as the first target molecule because it is simpler than the rest and once Rhizochalin C was successfully synthesized, the rest could also be made via similar routes. The retrosynthetic strategy of Rhizochalin C is 66 displayed in Scheme 4.2. The key disconnection is at the ketone carbon; the long chain could be constructed by a coupling reaction between a Weinreb amide and an acetylide, not an alkyl Gringard reagent because of the acidic NH proton. The chiral centers are generated from catalytic asymmetric aziridination and subsequent ring opening reaction with an oxygen nucleophile. Scheme 4.2 Retrosynthetic analysis of Rhizochalin C HO HO HO O O NH 2 OH HO O NH 2 OH Rhizochalin C 71 Bn O HN N BnO HN O + OBn O MEDAM 73 MEDAM N EtO 2C MEDAM 74 MEDAM N O 12 N O CO2Et 4 76 75 4.1.3 Total synthesis of Rhizochalin C The total synthesis of Rhizochalin C is envisioned by coupling between terminal alkyne fragment 83 and Weinreb amide fragment 88 (Schemes 4.3 and 4.4). 4.1.3.1 Synthesis of the alkyne fragment 83 Alkyne fragment 83 is to be synthesized from compound 78, but in fact, the price of terminal alkyne 78 is too high for large scale synthesis. Therefore 78 was 67 actually made by the alkyne zipper reaction from the cheaper internal alkynol 77. This reaction worked very well, yielding 70% of 78 on 120 mmol scale in Scheme 4.3. Next reaction was Swern oxidation of the terminal alcohol. This oxidation afforded an 80% yield of the corresponding aldehyde 79. Asymmetric catalytic aziridination was carried out in a multi-component mode: the imine formation between aldehyde 79 and MEDAM-NH2 was done in situ avoiding the isolation of the imine which provides for a broader substrate scope compared with the traditional aziridination reaction procedure beginning with a pre-formed imine. The multi-component aziridination was carried on a mixture of the aldehyde, amine and ethyl diazoacetate with 5 mol% of the (R)-VAPOL B3 catalyst, on a 40 mmol scale with 94% yield and 98% ee of the aziridine 76. Aziridine 76 was treated with TFA to afford the ring-opened product 80 in 80% yield as a single regioisomer. The TFA presumably protonates the nitrogen, and then trifluoroacetate anion attacks the β-carbon because it’s further from the electron withdrawing ester group. The positive charge would be expected to be better located on the β-carbon and thus giving the observed direction of ring opening. After the reaction, the trifluoroacetate was cleaved with NaOH in an ethanol water solution to afford the desired alcohol in 80% yield over two steps. The protection of the alcohol in 80 with BnBr was found be to solvent dependent: the reaction didn’t proceed in THF but did in DMF. This is probably because the more polar solvent DMF favored the formation of the alkoxide and thus the SN2 reaction. It was also found that a lower 68 temperature was necessary for this reaction because at room temperature a significant amount of an unidentified byproduct was formed. After the alcohol in 80 was protected with a benzyl group, reduction of the ester was carried out with LiAlH4 and this worked very well, yielding the desired product 82 in 85% yield. Scheme 4.3 Synthesis of alkyne fragment 83 3 equiv. NaH 1.1 equiv. (COCl) 2 1.1 equiv. DMSO ethylenediamine HO HO 77 79 80 20 mol% Bu 4NI DMF,0 °C, 80% 5 79 1) 1 equiv. CF 3COOH EtO 2C 0.9 equiv. MEDAM-NH 2 4 equiv. N 2CHCO2Et –20 °C, 14 h, 94%, 98% ee 1 equiv. NaH O Et 3N, DCM –78 °C, 80% 78 70% 5 mol% (R)-VAPOL 15 mol% B(OPh) 3 2 equiv. BnBr 5 45-60 °C, 2 h 76 N MEDAM 4 EtOH/H 2O, rt, 0.5 h EtO 2C 81 5 OBn 1.5 equiv. LiAlH 4 THF, rt, 20 h 85% MEDAM 5 EtO 2C 2) 1 equiv. NaOH MEDAM HN HN DCM, reflux, 16 h HN HO 82 80% 80 MEDAM 1) 1.5 equiv. MsCl Et 3N, THF 5 OBn OH MEDAM N 2) 1.5 equiv. LiAlH 4 THF, rt 5 OBn 78% 83 The next step was to convert the terminal alcohol in 82 to a leaving group and reduce it to a methyl group, however, when the MsCl and LiAlH4 sequence was employed, the result was that the aziridine 83 was obtained in 78% yield over the two steps instead of the planned methyl compound 74 (Scheme 4.2). Although the aziridine 83 was an unexpected product, it was later found that the 3-membered ring could be opened with H2 to give a methyl group. Therefore, the retrosynthesis in Scheme 4.2 was amended to include 83 in place of 74. 69 4.1.3.2 Synthesis of the Weinreb amide fragment 88 The synthesis of the Weinreb amide fragment 88 was initiated with lactone 84. Opening the lactone with N,O-dimethylhydroxylamine gave the alcohol 85 in 88% yield. Swern oxidation of the alcohol afforded the aldehyde 86 in 92%. The multi-component aziridination reaction of aldehyde 86 was carried out as normal on a small scale but became sluggish on a larger scale. Thus at the larger scale, reactions were carried out at room temperature in order to drive the reaction forward. Ring opening of the aziridine 75 with TFA as described in the synthesis of the alkyne fragment 83 in Scheme 4.3 gave the amino alcohol 87 in 84% yield over two steps. Scheme 4.4 Synthesis of Weinreb amide fragment 88 1.5 equiv. O O NH O O 12 84 1.5 equiv. Me 3Al N DCM, 0 °C to rt 14 OH 85 Et 3N, DCM –78 °C, 92% O O N O 14 H 86 12 h, 88% 5 mol% (R)-VAPOL 15 mol% B(OPh) 3 86 1.1 equiv. (COCl) 2 1.1 equiv. DMSO O O 0.9 equiv. MEDAM-NH 2 4 equiv. N 2CHCO2Et –20 °C, 14 h, 72%, 95% ee O O N 87 N 12 1) 1 equiv. CF 3COOH DCM, reflux, 16 h CO2Et 2) 1 equiv. NaOH 75 EtOH/H 2O, rt, 0.5 h O 1 equiv. TBSOTf OH 14 HN MEDAM N O CO2Et MEDAM 1.5 equiv. Et 3N THF, 0 °C, 30 min 94% O N 87 84% over two steps OTBS CO2Et 14 HN MEDAM 88 Finally protection of the alcohol with a TBS group afforded 88 in 94% yield. 70 Compounds 88 and 83 were ready to be coupled to form the long chain intermediate. This and additional steps are carried out by Wenjun Zhao. Please see Wenjun’s thesis for more details. 4.2 Mannich type reaction 4.2.1 Synthesis of Imine and ketene acetal A successful catalyst system for the Mannich reaction has been reported by the Wulff 52 group. This catalyst was prepared from a 2:1:1 ratio of VAPOL:Zr(OiPr)4(HOiPr):NMI and for this reason the catalyst was proposed to have the structure 45 (Schemes 3.8 and 3.9). The solid state structure of compound 61 (Figures 3.2 and 3.3) suggests that the VANOL Zr catalyst in the α-iminol rearrangement may contain three molecules of VANOL per zirconium. The question then arises, does the catalyst for the Mannich reaction have three molecules of VAPOL per zirconium? To investigate the possible answers to this question, imines 90, 93 and ketene acetal 89 were synthesized to be examined in a new study on the Mannich reaction, which examines the effect of changing the ratio of ligand to the zirconium on the reaction outcome (Scheme 4.5). The ketene acetal was made from deprotonation of methyl 2-methylpropionate and quenched with TMSCl. Imine 90 was made via the condensation between 2-aminophenol and benzaldehyde, and imine 93 was made via the same condensation reaction but the starting 2-amino-4,6-dimethylphenol 92 needed two extra step to prepare. Nitration of 2,4-dimethylphenol gave 91 in 68% yield. The use of dilute HNO3 resulted in lower yield, thus 90% HNO3 was used. Fuming HNO3 may give a 71 higher yield of 91, but this reaction has not been tried. Reduction of the nitro group with hydrazine gave the aminophenol 92 in 97% yield. Scheme 4.5 Synthesis of imines and ketene acetal O O THF 0 °C iPr 2NH + nBuLi TMS O TMSCl O THF, –78 °C THF, –78 °C 56% 89 OH O OH DCM, rt, 1 h N H + NH 2 77% 0.9 equiv. 90 OH 90% HNO 3, HOAc, 0 °C, 68% H 3C OH H 3C CH 3 91 CH 3 NO 2 7.5 equiv. NH 2NH 2 H 2O OH H 3C EtOH, graphite 100 °C 3.5 h, 97% CH 3 92 OH OH H 3C NH 2 92 CH 3 CH 3 O + NH 2 H DCM, rt, 1 h 90% 0.9 equiv. H 3C N 93 4.2.2 Mannich type reaction with zirconium VAPOL/VANOL catalyst The Mannich type reaction was reported in 2001 with a zirconium VAPOL catalyst that was thought to be 45, which was prepared from a 2:1:1 mixture of 52,64 VAPOL:Zr:NMI. This reaction was repeated with catalysts generated from VANOL and VAPOL as the ligand, and the results are summarized in Table 4.1 for imine 90 and 4.2 for imine 93. In Table 4.1, for entries 1-4 the ratio of VANOL:Zr:NMI was 2:1:1 for the catalyst assembly. The result indicated that the asymmetric induction was temperature dependent: ee reached a peak at 60 °C 72 and was lower at 25 °C and 100 °C. One possible theory to explain this observation is that the catalyst exists in an equilibrium of a 2:1:1 and a 3:1:2 (or other unknown ratios) complex of VANOL:Zr:NMI, and that the equilibrium constant between the two species is temperature dependent. Note that the absolute stereochemistry switches upon going from –45 °C to 25 °C. Table 4.1 Mannich type reaction with imine 90 X X OH X N + O TMS 20 mol% catalyst O toluene X NH O O 1.2 equiv. 89 X=H 90 OH X=H 94 X Catalyst temp/time 1 H 1.0 : 1.2 : 2.2 –45 °C/24 h 53%, –18% b 2 H 1.0 : 1.2 : 2.2 Zr : NMI : S-VANOL 25 °C/24 h 73%, 60% (78%, 60%)c 3 H 1.0 : 1.2 : 2.2 Zr : NMI : S-VANOL 60 °C/2 h 76%, 77% 4 H 1.0 : 1.2 : 2.2 Zr : NMI : S-VANOL 100 °C/0.5 h 88%, 66% 5 H 1 : 2: 3 Zr : NMI : S-VANOL 25 °C/24 h 89%, 77% (68%, 62%)c 6 H 1 : 2: 3 Zr : NMI : S-VAPOL 25 °C/24 h 75%, 93% Entry yield, ee a. Unless otherwise specified, all reactions were run with 0.125 mmol imine, 0.15 mmol ketene acetal and 20 mol% catalyst in 1 mL toluene at indicated temperature and time. All yields are isolated yield, ee determined by HPLC. b. Anil Gupta’s result. c. Data in parentheses was from a second run. In entry 5 the catalyst was prepared with 3:1:2 ratio this is to be compared with the data in entry 2. Initially higher asymmetric induction was seen with 3:1:2, but a second run gave similar result to the 2:1:1 ratio. In entry 6 the catalyst was 73 prepared with 3:1:2 VAPOL:Zr:NMI, and the result was similar to the result with 52 2:1:1 that was previously reported, which was 89% ee. In Table 4.2, imine 93 was used for the reaction. The data in entries 1 and 2 allow for a comparison of 3:1:2 and 2:1:1 ratios with VANOL as ligand, it turns out that both are equally efficient for the reaction. Entry 3 presents the results of the reaction for 3:1:2 ratio with VAPOL as ligand, and this result was also similar to 52 the result with a 2:1:1 ratio that was previously reported. Table 4.2 Mannich type reaction with imine 93 X X OH X N + O TMS 20 mol% catalyst O toluene OH X NH O O X = CH 3 93 Entry 1.2 equiv. 89 X 95 Catalyst temp/time yield, ee 1 CH 3 1.0 : 1.2 : 2.2 Zr : NMI : S-VANOL 25 °C/24 h 70%, 98% 2 CH 3 1 : 2: 3 Zr : NMI : S-VANOL 25 °C/24 h 70%, 98% 3 CH 3 1 : 2: 3 Zr : NMI : S-VAPOL 25 °C/24 h 83%, >99% All reactions were run with 0.125 mmol imine, 0.15 mmol ketene acetal and 20 mol% catalyst in 1 mL toluene at indicated temperature and time. All yields were isolated yields, the %ee was determined by HPLC. 4.3 Cation induced rearrangement of allylic alcohols For a tertiary allylic alcohol, it is possible to undergo a rearrangement reaction if the alkene was activated with an electrophile (Scheme 4.6). Scheme 4.6 Cation induced rearrangement of allylic alcohol 74 OH R E R O OH R R E E R R The electrophile can not be a proton because in this case the hydroxyl group would accept the proton and undergo a 1,3 hydroxyl shift reaction forming a more 65 stable C=C double bond (Scheme 4.7). Scheme 4.7 1,3 hydroxyl shift of allylic alcohol OH R H R HO R R A halonium is a good candidate for this reaction because it doesn’t react with tertiary alcohols. The reaction of an allylic alcohol 96 with a chloronium source gave a quantitative yield of the rearranged beta-chloroketone (Scheme 4.8). However, there are a number of research articles related to this reaction reported 66,67 in the literature; therefore it is not necessary to continue on this project to repeat other chemists’ results. Scheme 4.8 Chloronium induced rearrangement of allylic alcohol O O 1.1 equiv. 1.5 equiv. MgCl OH 46% Cl N O N Cl Cl O THF, rt, 1 h 100% 97 96 Another possible electrophile candidate is metal cation, for example, gold. Gold is known to have a strong affinity for olefin, so it is expected to coordinate to the double bond and hopefully will induce the rearrangement. Gold(I) chloride 75 dimethylsulfide complex was tested as the gold (I) source for this reaction (Table 4.3). Reactions were run with 0.1 mmol of 96 under the indicated conditions. The reaction in entry 1 was run at room temperature but there was no reaction. In entry 2, the reaction temperature was increased to 50 °C but the gold metal precipitated after 1 h, and no rearrangement was observed. The reaction in entry 3 was run under a N2 atmosphere so that the gold would not precipitate, but it was found that only 3% of the 1,3 hydroxyl shift product was formed. Further investigation is needed for this reaction. Table 4.3 Attempt in the gold induced rearrangement HO Ph Ph 10 mol% Au(SMe2)Cl O Ph Ph CH 3 98 CH 3CN 96 entry temp/time atmosphere result 1 25 °C, 1h air no reaction 2 50 °C, 30 min air gold precipitated OH 3 50 °C, 2h N2 3% Ph Ph 4.4 Aziridinol rearrangement 4.4.1 Introduction The mechanism of polymerization of oxetane under acidic conditions begins with protonation of oxygen, followed by ring opening with another oxetane 76 molecule (Scheme 4.9 A). This process inspired the consideration of a pinacol type rearrangement of a tertiary alcohol attached to an azetidine or aziridine that could be activated by a Brønsted acid or Lewis acid catalyst. Subsequent rearrangement may occur to form a γ or β amino ketone as the product (Scheme 4.9 B and C). Scheme 4.9 Aziridinol rearrangement H+ O H O O A HO O oxetane HO B P N R R Cat. (P=protecting group) HO C P N HO P Cat R R Cat. R N P O H N R R HO P Cat R R R N O P N H R R 4.4.2 Initial attempt and a catalyst screen To test this idea, the simple aziridines 102 and 103 were synthesized for the initial attempt. The synthesis begins with bromination of methyl acrylate, and then substitution of the two bromine atoms with p-anisidine or benzyl amine, followed by Grignard addition to the ester (Scheme 4.10). 77 Scheme 4.10 Synthesis of aziridinol CO2Me 1 equiv. Br 2 DCM 0°C, 1h 1.2 equiv. R-NH 2 2.5 equiv. Et 3N 10 mol% DMAP Br Br CO2Me 93% CO2Me THF, 70°C, 14h 100 R = p-CH 3OC6H 4, 70% 101 R = benzyl, 84% 99 R N 3 equiv. PhMgCl THF, rt, 30 min R N R N OH CO2Me 100 R = p-CH 3OC6H 4 101 R = benzyl 102 R = p-CH 3OC6H 4, 89% 103 R = benzyl, 100% The data in table 4.4 summarizes the results from the catalyst screen of the rearrangement reaction with 102 and 103. Silica gel was found to be a good catalyst for the α-iminol rearrangement (chapter 2), but it was not able to give any product in this reaction. For TiCl4 and H2SO4 catalyzed reactions, the ring was opened by Cl and H2O respectively. It was found that BF3·OEt2 was able to promote the reaction at room temperature in entries 4 and 5. After two hours the reaction was not complete, and if the reaction time was too long, some unidentified byproducts were formed as indicated by TLC and the yield of the desired product was moderate (entry 5). Ti(OiPr)4 was not able to catalyze the reaction, while TfOH did. When the protecting group on the nitrogen was changed from anisyl to benzyl, the reaction with TfOH required substantially higher temperature, i. e. 100 °C, and a low yield of 105 was observed due to formation of unidentified byproducts. Thus, to obtain high yield of the rearranged product, an 78 anisyl protecting group appeared to be necessary. Table 4.4 Catalyst screen of the aziridinol rearrangement R N O Conditions OH Ph R Ph S. M. 1 102 2 Catalyst Ph Ph 104 R = p-CH 3OC6H 4 105 R = benzyl 102 R = p-CH 3OC6H 4 103 R = benzyl Entry N H solvent temp,time 100wt% silica gel toluene 70°C, 1h 102 TiCl4 1 equiv. THF rt, 1h Cl opened the ring 3 102 H 2SO 4 1 equiv. DMF rt, 1h H 2O opened the ring 4 102 BF 3Et 2O 1 equiv. 3:1 MeCN:DCM rt, 2 h 5 102 BF 3Et 2O 1 equiv. 3:1 MeCN:DCM rt, 19 h 6 102 Ti(OiPr) 4 1 equiv. DCM rt, 2 h No RXN 7 102 TfOH 1 equiv. DCM rt, 3h 87% of 104 8 103 TfOH 1 equiv. DCE 70°C, 3h No RXN 9 103 TfOH 1 equiv. PhCl 100 °C, 3h 46% of 105 10 103 BF 3Et 2O 1 equiv. 70°C, 1h No RXN DCE result No RXN 102:104 = 4:5 64% of 104 Reactions were run with 0.1 mmol substrate in 0.3 mL solvent under the indicated conditions. Yields in entries 5, 7, 9 are isolated yields. A TfOH loading study was carried out in order to determine the minimal amount of the acid required for the reaction (Table 4.5). Unfortunately, when 50 mol% was used, only a 6% yield was observed after 21 h, and with 10 mol%, no detectible amount of product was observed after 21 h. Thus 1 equivalent of acid was necessary for a satisfactory yield. 79 Table 4.5 TfOH loading screen OMe MeO O TfOH N 102 Ph N H DCM, rt OH Ph Ph Ph 104 Entry TfOH time result 1 100 mol% 3h 87% 104 2 50 mol% 21 h 6% 104 3 10 mol% 21 h 0% 104 Reactions were run with 0.1 mmol 102 in 0.3 mL DCM with indicated conditions. Entry 1 was isolated yield, entries 2 and 3 were NMR yield. 4.4.3 Synthesis of 3-substituted aziridinol substrates and their rearrangement The synthesis of enantiopure 2,3-di-substituted aziridine substrates started with the cis aziridine 105 (>99% ee). The DAM group on the aziridine was removed under acidic conditions in the presence of anisole to give the N-H aziridine 106. The cleavage of DAM is necessary because 1) the DAM group is not stable under the acidic conditions of the rearrangement, 2) according to the results in Table 4.4, an aliphatic protecting group on the N would require very harsh condition in the rearrangement step, which may epimerize the alpha carbon. Thus, a PMP protecting group (PMP = p-methoxylphenyl) is desirable. The PMP group was 68 installed via a copper mediated coupling reaction with aryl boronic acid. The ester group in 107 could be converted to a tertiary alcohol with Grignard reagent 80 which gave 108 ready for the rearrangement. Unfortunately, it was found that neither TfOH or BF3·OEt2 could induce a rearrangement of 108 at room temperature to give 109. The 100% conversion of 108 was observed but it was not clear what happened in the reaction. At lower temperature, i. e. 0 °C, the reaction did not go after 1 h with either TfOH or BF3·OEt2, only starting material was observed. A white precipitate was observed, and presumably it’s the triflate salt or the BF3–aziridine adduct pair precipitated out from the solution, thus a more polar solvent that dissolves the salt or adduct may promote the reaction, but it has never been tried. Scheme 4.11 Synthesis of PMP protected aziridinol and its rearrangement DAM N Ph 2 equiv. TfOH anisole CO2Et 105 >99% ee H N 0 °C to rt, 2 h, 86% Ph CO2Et 5 mol% Cu(OAc)2 10 mol% nC9H19 COOH 1.5 equiv. PMP-B(OH) 2 1 equiv. 2,6-lutidine toluene, rt, 24 h Ph 106 PMP N CO2Et 107 PMP = p-methoxylphenyl MeO OMe DAM = PMP N Ph CO2Et 107 PMP N 3 equiv. PhMgCl THF, rt, 30 min 60% Ph 108 OH Ph Ph 1 equiv. TfOH or 1 equiv. BF 3Et 2O PMP DCM H N Ph O Ph Ph 109 0°C, 1 h, no reaction rt, 1 h, not observed Since the PMP protected aziridinol 108 did not gave the desired product, it was decided to replace the PMP group with electron withdrawing Cbz group to facilitate ring opening and hopefully the migration of a carbon group. The 81 synthesis started from the N-H aziridine 106. The ester group was converted to the tertiary alcohol with n-butyllithium since phenyl Grignard failed to give the desired alcohol. The aziridine was protected with Cbz group in 92% yield. Scheme 4.12 Synthesis of Cbz protected aziridinol and its rearrangement H N Ph 4 equiv. nBuLi CO2Et 106 H N Ph 110 OH nBu nBu H N 110 Cbz N 1.1 equiv. CbzCl 1.1 equiv. Et 3N THF, rt, 30 min 92% Ph THF, –78°C, 10 min, 50% OH nBu nBu Ph 111 OH nBu nBu 10 mol% TfOH DCM Cbz H N nBu O Ph nBu 112 rt, 30 min, not observed –78°C, 30 min, no reactoin It is known that the lone pair on the aziridine N does not conjugate to an adjacent carbonyl group (in this case the Cbz group), thus the nitrogen should be able to accept a proton and undergo the rearrangement. Unfortunately the reaction went to 100% conversion with 10 mol% TfOH at room temperature in 30 min, no desired product 109 was observed. Another run at a lower temperature, – 20 °C, There was no reaction with 10 mol% TfOH after 30 min at –78 °C or at – 20 °C, only starting material was recovered. A white solid precipitate was observed at both –78 °C and –20 °C, which probably was the protonated 111 that did not dissolve in DCM at –20 °C. thus a more polar solvent that dissolves the salt or adduct may promote the reaction, but it has never been tried. Since aziridines 108 and 111 with a phenyl group on C-3 did not give the 82 desired product, an aziridine with a propyl group on C-3 was synthesized since it is possible that ring opening at C-3 could be occurring via stabilization of positive charge on C-3 by the phenyl group. The synthesis of aziridinol with a propyl group at C-3 started with aziridine 113. The cleavage of the MEDAM group with TfOH gave good yield of the N-H aziridine 114. In the case of the Cbz protection, the butyl groups were added prior to the protection because a complex mixture was observed if both ester and Cbz groups are present in the molecule in the n-butyllithium addition step. Unfortunately, it was found that the treatment of aziridinol 116 with TfOH did not provide a clean rearrangement to the desired product. Instead, a complex mixture was observed according to TLC and the 1H NMR spectrum of the crude reaction mixture. For the PMP protection, a copper catalyzed coupling reaction was carried out to install the PMP group on the nitrogen atom, and then phenyl Gringard addition to the ester gave the aziridinol 119. Upon treatment with TfOH, it was found that there was no reaction at room temperature after 1 h, and reflux in DCM still gave no reaction. When the temperature was raised to 65 °C, reaction started to proceed very slowly, and at 70 °C for 5 h, the reaction was complete, but no desired product was observed. One new spot from the reaction mixture was isolated and judged from the NMR spectra it was tentatively identified as deoxybenzoin, which was formed possibly from a retro-Mannich reaction from 120. 83 Scheme 4.13 Synthesis of propyl aziridinol at C-3 and its rearrangement MeO OMe H N 2 equiv. TfOH anisole N CO2Et 115 OH nBu nBu 4 equiv. nBuLi CO2Et 65 °C, 30 min, 71% THF, –78°C, 15 min, 44% OH nBu nBu 115 114 113 96% ee H N H N Cbz N 1.1 equiv. CbzCl 1.1 equiv. Et 3N 10 mol% TfOH DCM, rt, 5 h OH nBu nBu THF, rt, 30 min, 93% 116 Cbz nBu H N O nBu 117 not observed H N CO2Et 114 OMe 5 mol% Cu(OAc)2 10 mol% nC9H19 COOH 1.5 equiv. PMP-B(OH) 2 1 equiv. 2,6-lutidine 3 equiv. PhMgCl THF, rt, 30 min 78% N toluene, rt, 24 h, 44% PMP = p-methoxylphenyl PMP N 119 PMP N CO2Et 119 118 1 equiv. TfOH PMP H N OH Ph Ph Ph O Ph OH Ph Ph 120 DCM, rt, 1 h, no reaction DCM,reflux, 1 h, no reaction DCE, 65 °C, 30 min, trace conversion DCE, 70 °C, 5 h, 100% conversion, no 120 observed 4.4.4 Aziridinol rearrangement from (R)-102 The rearrangement of 2,3-disubstituted aziridines 108, 111, 116 and 118 failed to produce a rearrangement product. The only aziridine that was found to undergo rearrangement was the racemic aziridine 102, which has no substitution in the 3 position (Table 4.4). Thus it is of interest to examine the rearrangement of optically pure 102. The synthesis started with commercial D-Serine ethyl ester hydrochloride 121 (Scheme 4.14). The yield of the aziridine 122 was low due to its 84 high volatility. It should be possible to achieve high yield because a similar 69 synthesis that started from the butyl ester of D-Serine gave a much better yield. The coupling reaction on the N-H aziridine has two known methods that have been reported for related aziridines involving either Cu 70,68 70 or Pd . The copper protocol was attempted with 122 and 123 was observed in 23% yield. Further optimization is needed to improve the yield for this step. Scheme 4.14 Synthesis of (R)-102 and its rearrangement NH 3Cl HO CO2Et 121 D-Serine ethyl ester hydrochloride PMP N 1) 1 equiv. KOH EtOH, rt, 5 min H N 2) 1 equiv. PPh 3 1 equiv. DIAD DCM, rt, 15 h CO2Et PMP N 123 CO2Et PMP = p-methoxylphenyl 123 23% 1 equiv. TfOH DCM, rt, 2.5 h OH Ph Ph CO2Et N toluene, rt, 24 h 122 22% over two steps 3 equiv. PhMgCl THF, rt, 30 min OMe 5 mol% Cu(OAc)2 10 mol% nC9H19 COOH 1.5 equiv. PMP-B(OH) 2 1 equiv. 2,6-lutidine (R)-102 69% yield, 99% ee PMP H N Ph O Ph (S)-104 95% yield, 96% ee The final step is to convert the ester 123 to the tertiary alcohol (R)-102 with phenyl Grignard reaction, which was achieved in 69% yield. The optical purity of (R)-102 was determined to be 99% ee by HPLC analysis. The rearrangement of (R)-102 with TfOH gave the final product 104 in 95% yield and 96% ee. The absolute configuration of product 104 has not been rigorously determined but is assumed to be S, because the migrating group is likely to open the ring from the opposite side of the nitrogen atom. 85 4.4.5 One attempt at the kinetic resolution of a racemic aziridinol The aziridinol 102 contains one chiral center in the molecule and was prepared in racemic form as shown in Scheme 4.10. One attempt was carried out with 2.5 mol% (S)-VANOL Zr catalyst 46 in toluene at 100 °C for 1 h but no reaction was observed. Future work should thus focus on screening more active catalysts for this kinetic resolution. Scheme 4.15 attempt in the kinetic resolution of racemic aziridinol H 3CO H 3CO N OH N 2.5 mol% (S)-VANOL Zr 46 OH (S)-102 not observed toluene 100 °C, 1 h No reaction H 3CO 102 O N H (S)-104 not observed 86 CHAPTER FIVE EXPERIMENTAL SECTION 5.1 General information Solvents for reactions were dried appropriately before use: toluene was dried by refluxing with sodium, THF was dried by refluxing with sodium and benzophenone as indicator, dichloromethane was dried by refluxing with CaH2. VANOL and VAPOL ligands, including their derivatives, were prepared according to 51 procedures reported in literature. All other reagents were directly used as purchased from either Aldrich or Alfa Aesar. Melting points were measured on a Thomas Hoover capillary melting point apparatus. IR spectra were taken on a Galaxy series FTIR-3000 spectrometer. 1H NMR, 13 C NMR and 19 F NMR were recorded on VXR-500 MHz instrument in CDCl3. CDCl3 was used as the internal standard for both 1H NMR (δ = 7.26) and 13 C NMR (δ = 77.0). Thin-layer chromatography (TLC) was performed on silica gel plates with F-254 indicator. Visualization was by short wave (254 nm) and long wave (365 nm) ultraviolet light, or by staining with phosphomolybdic acid in ethanol. The silica gel for column chromatography was purchased from Sorbent Technologies with the following specifications: standard grade, 60 Å porosity, 230 X 400 mesh particle size, 500-600 m2/g surface area and 0.4 g/mL bulk density. Chiral HPLC analysis was done using a Varian Prostar 210 Solvent Delivery Module with a Prostar 330 PDA Detector and a Prostar Workstation. Optical 87 rotation was obtained on a Perkin-Elmer 341 polarimeter at a wavelength of 589 nm (Sodium D line) using a 1.0 decimeter cell with a total volume of 1.0 mL. 5.2 Experimental procedures for chapter two 5.2.1 General procedure for the preparation of aldehyde 2 Br R 2.5 equiv + Mg 2.5 equiv 1) THF, rt to 70 °C 20 min 2) OEt EtO CO2Et 1 equiv THF, rt, 30 min 5 % HCl acetone 70 °C, 1 h O H HO R R 21 2 To a 50 mL clean and dry Schlenk flask was added Mg metal (40 mesh, 0.08g, 3.5 mmol, 2.5 equiv.), a small crystal of I2 and 2 mL THF. While stirring, the appropriate aryl or alkyl bromide (3.5 mmol, 2.5 equiv.) was added via a syringe (for solid bromide compound, it was dissolve in minimal amount of THF before addition). The flask was tightly sealed and the solution was stirred at room temperature for 10 min, then heated in a 70 °C oil bath until the Mg metal completely dissolved (usually it took less than 20 min). After being cooled down to room temperature, the flask was placed in a water bath and ethyl diethoxyacetate (0.25 mL in 2 mL THF, 1.4 mmol, 1 equiv.) was added dropwise and slowly via a syringe. The resulting mixture was stirred for another 30 min at room temperature then quenched by 5 mL saturated NH4Cl solution. The two layers were separated and the aqueous layer was extracted by ether (5 mL x 3). The combined organic 88 layer was concentrated under rotary vaporization and the crude residue was subjected to hydrolysis without purification. The crude acetal intermediate was transferred to a 20 mL Schlenk flask with 0.5 mL 5% HCl and enough acetone (usually it took 5 mL) to obtain a single layer homogenous solution. Thereafter, the flask was sealed and heated in a 70 °C oil bath for 1 h. After being cooled to room temperature, the solution was diluted by 10 mL CH2Cl2. The aqueous layer was separated and discarded; the organic layer was successively washed by NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under rotary vaporization. The crude residue was purified by silica gel column chromatography, 20:1 hexanes:EtOAc as eluent. 2-hydroxy-2,2-diphenylacetaldehyde (2a) 1 equiv. OEt EtO PhMgCl 2.5 equiv. 5% HCl acetone 70 oC, 1 h OEt O O Ph H HO Ph 2a Following the general procedure with a commercial 2M solution of phenylmagnesium chloride in THF (3.5 mL, 7.0 mmol, 2.5 equiv; 13.8 mL, 27.5 mmol and 50.0 mL, 100 mmol scale), the reaction afforded the product 2a as a 71 white solid in 70-90% yield over several trials. mp = 55-57 °C (Lit Spectral data for 2a: 1 52-55 °C). H NMR (CDCl3, 500 MHz) δ 4.41 (s, 1H), 7.38-7.42 (m, 10H), 10.00 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 83.45, 127.44, 128.51, 128.84, 89 71 139.29, 198.05; these NMR data are in agreement with the literature data. 2-hydroxy-2,2-di-o-tolylacetaldehyde (2b) OEt Br CH 3 + Mg 2.5 equiv EtO CO2Et 1 equiv 5 % HCl acetone 70 °C, 1 h THF, rt, 30 min 2.5 equiv O H HO H 3C CH 3 21b 2b Following the general procedure with 2-bromotoluene (0.42 mL, 3.5 mmol, 2.5 equiv), the reaction afforded the product 2b as a white wax-like solid (83%, 0.279 g, 1.16 mmol). mp = 46-49 °C. Spectral data for 2b: 1H NMR (CDCl3, 500 MHz) δ 2.08 (s, 6H), 4.36 (s, 1H), 7.17 (dd, J = 7.5, 1.5 Hz, 2H), 7.21 (td, J = 7.5, 1.5 Hz, 2H), 7.26 (td, J = 7.5, 1.5 Hz, 2H), 7.30 (dd, J = 7.5, 1.5 Hz, 2H), 10.09 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 21.30, 84.82, 126.33, 127.36, 128.53, 132.55, 137.13, 137.73, 197.99; IR (thin film) 3472s, 3063m, 3018m, 2930m, 2870m, 1716s, 1458s, 1336m, 1163m, 754s cm-1; HRMS (ESI-TOF) m/z found 223.1127 [(M-H2O+H)+; calcd. 223.1123 for C16H15O. 2-hydroxy-2,2-bis(2-isopropylphenyl)acetaldehyde (2c). OEt EtO Br i-Pr 2.5 equiv + Mg 2.5 equiv OEt O 1 equiv Amberlyst 15l acetone/H2O 25 oC, 24 h O H HO i-Pr 21c 2c 90 i-Pr The general procedure was followed with 1-bromo-2-isopropylbenzene (0.54 mL, 3.5 mmol, 2.5 equiv) and the Grignard reaction between the ester and 2-isopropylphenylmagnesium bromide was worked up and concentrated, the crude acetal was hydrolyzed with 0.5 g Amberlyst 15 ion-exchange resin (strongly acidic) in 10 mL 1:1 H2O:acetone solution at room temperature for 24 h. The resulting mixture was neutralized with 10 mL saturated NaHCO3 and diluted with 20 mL CH2Cl2. The aqueous layer was extracted with ether (10 mL x 3), the combined organic layer was washed with brine, dried over MgSO4, filtered through filter paper in Büchner funnel and concentrated under rotary evaporation. The crude product was purified by column chromatography with 20:1 hexanes:EtOAc as eluent. The product that was collected from the column was not pure by NMR, therefore it was washed with a small amount of hexanes. This afforded product 2c as a white solid (56%, 0.232 g, 0.784 mmol); mp = 119-121 °C. Spectral data for 2c: 1H NMR (CDCl3, 500 MHz) δ 1.01 (d, J = 7.0 Hz, 6H), 1.03 (d, J = 7.0 Hz, 6H), 3.15 (septet, J = 7.0 Hz, 2H), 4.46 (s, 1H), 7.19-7.23 (m, 3H), 7.34-7.40 (m, 5H), 10.22 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 24.08, 24.18, 29.84, 84.59, 125.96, 127.17, 127.92, 128.88, 137.51, 148.13, 198.98; IR (thin film) 3474br s, 3020m, 2966s, 2930s, 2868s, 1726s, 1483m, 1444m, 1153m, 1057m, 760s cm-1; HRMS (ESI-TOF) m/z found 279.1749 [(M-H2O+H)+; calcd. 279.1749 for C20H23O]. 91 2-hydroxy-2,2-di-m-tolylacetaldehyde (2d). OEt Br + Mg 2.5 equiv H 3C EtO CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h CH 3 O H HO THF, rt, 30 min 2.5 equiv H 3C 21d 2d Following the general procedure with 3-bromotoluene (0.42 mL, 3.5 mmol, 2.5 equiv), the reaction afforded the product 2d as a white wax-like solid (77%, 0.261 g, 1.09 mmol). mp = 33-35 °C. Spectral data for 2d: 1H NMR (CDCl3, 500 MHz) δ 2.35 (s, 6H), 4.33 (s, 1H), 7.14-7.19 (m, 6H), 7.28 (t, J = 7.5 Hz, 2H), 9.96 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.51, 83.38, 124.51, 127.97, 128.62, 129.18, 138.62, 139.34, 198.18; IR (thin film) 3481br s, 3028m, 2922m, 2860m, 1722s, 1604m, 1487m, 1332m, 1155s, 702s cm-1; HRMS (ESI-TOF) m/z found 223.1122 [(M-H2O+H)+; calcd. 223.1123 for C16H15O]. 2,2-bis(3-chlorophenyl)-2-hydroxyacetaldehyde (2e). OEt Br 2.5 equiv Mg Et 2O, rt, 20 min EtO COOEt 1 equiv Cl 2.5 equiv O 5% HCl acetone 80 °C, 1h OH H Cl Cl 21e2e The general procedure was followed with 1-bromo-3-chlorobenzene (0.50 mL, 4.1 mmol) with three exceptions: 1. The formation of the Grignard reaction 92 was carried out in diethyl ether in a round bottom flask with a condenser, 2. The hydrolysis of the acetal intermediate was carried out at 80 °C, and 3. The eluent was 8:1 hexane:EtOAc for the purification of the final product. This reaction afforded the product 2e (0.31g, 1.1 mmol, 67%) as a wax-like white solid; mp = 42-43 °C. Spectral data for 2e: 1H NMR (CDCl3, 500 MHz) δ 4.44 (s, 1H), 7.23-7.27 (m, 2H), 7.34-7.39 (m, 6H), 9.95 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 82.55, 125.39, 127.46, 129.01, 130.20, 135.15, 140.80, 196.75; IR (thin film) 3456s, 1726s, 1653s, 1576m, 1473m, 1419m, 1180m, 1082m cm-1; HRMS (ESI-TOF) m/z found 263.0024 [(M-H2O+H)+; calcd. 263.0030 for C14H9OCl2]. 2-hydroxy-2,2-di-p-tolylacetaldehyde (2f). CH 3 OEt Br EtO + Mg 2.5 equiv O CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h H HO THF, rt, 30 min CH 3 21f 2f 2.5 equiv CH 3 Following the general procedure with 4-bromotoluene (0.86 mL, 7.0 mmol, 2.5 equiv, the scale was doubled), this reaction afforded the product 2f as a colorless liquid (78%, 0.526 g, 2.18 mmol). Spectral data for 2f: 1H NMR (CDCl3, 500 MHz) δ 2.38 (s, 6H), 4.32 (s, 1H) 7.22 (d, J = 5.0 Hz, 4H), 7.25 (d, J = 5.0 Hz, 4H), 9.93 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.14, 83.21, 127.35, 129.48, 136.41, 138.32, 198.11; IR (neat) 93 3481br s, 3028m, 2922m, 1718s, 1510m, 1170m, 815m cm-1; HRMS (ESI-TOF) m/z found 223.1121 [(M-H2O+H)+; calcd. 223.1123 for C16H15O]. 2,2-bis(4-n-butylphenyl)-2-hydroxyacetaldehyde (2g). n-Bu OEt Br EtO CO2Et 1 equiv + Mg 2.5 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO THF, rt, 30 min n-Bu n-Bu 21g 2g 2.5 equiv Following the general procedure with 1-bromo-4-n-butylbenzene (0.62 mL, 3.5 mmol, 2.5 equiv), the reaction afforded the product 2g as a colorless liquid (73%, 0.332 g, 1.02 mmol). Spectral data for 2g: 1 H NMR (CDCl3, 500 MHz) δ 0.92 (t, J = 7.5 Hz, 6H), 1.35 (sextet, J = 7.5 Hz, 4H), 1.59 (qt, J = 7.5, 2.0 Hz, 4H) 2.61 (t, J = 7.5 Hz, 4H), 4.29 (s, 1H), 7.20 (d, J = 7.5 Hz, 4H), 7.26 (d, J = 7.5 Hz, 4H), 9.93 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 13.89, 22.32, 33.44, 35.26, 83.20, 127.31, 128.79, 136.57, 143.26, 198.10; IR (neat) 3487s, 3057s, 2930s, 2858s, 1718s, 1510s, 1414m, 1338m, 1170m, 831m cm-1; HRMS (ESI-TOF) m/z found 307.2064 [(M-H2O+H)+; calcd. 307.2062 for C22H27O]. 94 2,2-bis(4-isopropylphenyl)-2-hydroxyacetaldehyde (2h). i-Pr OEt Br + Mg 2.5 equiv EtO CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO THF, rt, 30 min i-Pr 2.5 equiv i-Pr 2h 21h Following the general procedure with 1-bromo-4-isopropylbenzene (0.53 mL, 3.5 mmol, 2.5 equiv), this reaction afforded the product 2h as a white solid (49%, 0.203 g, 0.686 mmol); mp = 80-81.5 °C. Spectral data for 2h: 1H NMR (CDCl3, 500 MHz) δ 1.25 (d, J = 7.5 Hz, 12H) 2.92 (septet, J = 7.5 Hz, 2H), 4.30 (s, 1H), 7.25 (d, J = 7.5 Hz, 4H), 7.29 (d, J = 7.5 Hz, 4H), 9.93 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 23.86, 33.79, 83.19, 126.83, 127.39, 136.70, 149.14, 198.11; IR (thin film) 3406s, 3028m, 2961s, 2870s, 1718s, 1506m, 1458m, 1342m, 1178m, 825m cm-1; HRMS (ESI-TOF) m/z found 279.1752 [(M-H2O+H)+; calcd. 279.1749 for C20H23O]. 2,2-bis(4-cyclohexylphenyl)-2-hydroxyacetaldehyde (2i). Cy OEt Br + Mg 2.5 equiv EtO CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO THF, rt, 30 min Cy Cy 2.5 equiv 21i 2i Following the general procedure with 1-bromo-4-cyclohexylbenzene (0.65 mL, 3.5 mmol, 2.5 equiv), thi reaction afforded the product 2i as a white solid (69%, 0.362 g, 0.966 mmol); mp = 155-156 °C. 95 Spectral data for 2i: 1H NMR (CDCl3, 500 MHz) δ 1.22-1.28 (m, 2H), 1.34-1.44 (m, 8H), 1.73-1.76 (m, 2H), 1.82-1.87 (m, 8H), 2.48-2.53 (m, 2H), 4.29 (s, 1H), 7.22 (d, J = 7.0 Hz, 4H), 7.28 (d, J = 7.0 Hz, 4H), 9.92 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 26.08, 26.81, 34.32, 44.22, 83.20, 127.20, 127.35, 136.65, 148.34, 198.11; IR (thin film) 3397s, 2920s, 2851s, 1720s, 1506m, 1448m, 1329m, 1170m cm-1; HRMS (ESI-TOF) m/z found 359.2375 [(M-H2O+H)+; calcd. 359.2375 for C26H31O]. 2,2-bis(4-t-butylphenyl)-2-hydroxyacetaldehyde (2j). t-Bu OEt Br + Mg 2.5 equiv EtO CO2Et 1 equiv THF, rt, 30 min t-Bu 2.5 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO 2j21j t-Bu Following the general procedure with 1-bromo-4-tert-butylbenzene (1.21 mL, 7.00 mmol, 2.5 equiv, the scale was doubled), the product was purified by recrystallization from hexanes to afford the product 2j as a white solid (61%, 0.555 g, 1.71 mmol); mp = 140-142 °C. Spectral data for 2j: 1H NMR (CDCl3, 500 MHz) δ 1.32 (s, 18H), 4.30 (s, 1H), 7.30 (d, J = 8.5 Hz, 4H), 7.41 (d, J = 8.5 Hz, 4H), 9.94 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 31.24, 34.57, 83.08, 125.69, 127.10, 136.28, 151.40, 198.11; IR (thin film) 3427br s, 2963s, 2868m, 1720s, 1506m, 1404m, 1109m, 823m cm-1; 96 HRMS (ESI-TOF) m/z found 307.2064 [(M-H2O+H)+; calcd. 307.2062 for C22H27O]. 2,2-di([1,1'-biphenyl]-4-yl)-2-hydroxyacetaldehyde (2k). Ph OEt Br EtO + Mg 2.5 equiv CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO THF, rt, 30 min Ph 21k 2k 2.5 equiv Ph Following the general procedure with 4-bromobiphenyl (0.81g, 3.5 mmol, 2.5 equiv), the reaction afforded the product 2k as a white solid (77%, 0.393 g, 1.08 mmol); mp = 142-143 °C. Spectral data for 2k: 1H NMR (CDCl3, 500 MHz) δ 4.44 (s, 1H), 7.37 (tt, J = 7.0, 1.5 Hz, 2H), 7.45 (tt, J = 8.0, 1.5 Hz, 4H), 7.49 (dt, J = 8.5, 2.0 Hz, 4H), 7.60 (dt, J = 8.5, 2.0 Hz, 4H), 7.65 (dt, J = 8.5, 2.0 Hz, 4H), 10.05 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 83.22, 127.12, 127.58, 127.62, 127.85, 128.83, 138.18, 140.29, 141.48, 197.74; IR (thin film) 3596br s, 3081m, 3053m, 3025m, 1718s, 1485s, 1174m, 1006m, 827m cm-1; HRMS (ESI-TOF) m/z found 347.1435 [(M-H2O+H)+; calcd. 347.1436 for C26H19O]. 97 2,2-bis(4-methoxylphenyl)-2-hydroxyacetaldehyde (2l). OMe OEt Br EtO + Mg 2.5 equiv CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO THF, rt, 30 min OMe 2.5 equiv 21l 2l OMe The general procedure was followed with 4-bromoanisole (0.44 mL, 3.5 mmol, 2.5 equiv) except the eluent for column chromatography was 3:1 to 2:1 hexanes:EtOAc. The reaction afforded the product 2l as a white solid (63%, 0.241 g, 0.882 mmol); mp = 90-91 °C. Spectral data for 2l: 1H NMR (CDCl3, 500 MHz) δ 3.81 (s, 6H), 4.26 (s, 1H), 6.91 (d, J = 8.5 Hz, 4H), 7.27 (d, J = 8.5 Hz, 4H), 9.88 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 55.30, 82.79, 114.17, 128.74, 131.40, 159.62, 197.78. The 1H NMR 72 data are in agreement with the literature data. 2,2-bis(4-fluorophenyl)-2-hydroxyacetaldehyde (2m). F OEt Br + Mg 2.5 equiv EtO CO2Et 1 equiv 5 % HCl acetone/H2O 70 °C, 1 h THF, rt, 30 min O H HO F 2.5 equiv 21m 2m F Following the general procedure with 1-bromo-4-fluorobenzene (0.39 mL, 3.5 mmol, 2.5 equiv), the reaction afforded the product 2m as a white wax-like solid (99%, 0.359g, 1.39 mmol); mp = 24-25 °C. 98 Spectral data for 2m: 1H NMR (CDCl3, 500 MHz) δ 4.40 (s, 1H), 7.11 (tt, J = 9.0, 2.5 Hz, 4H), 7.34 (tt, J = 9.0, 2.5 Hz, 4H), 9.93 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 82.57, 115.94 (d, J = 21.8 Hz), 129.24 (d, J = 8.5 Hz), 134.89, 162.73 (d, J = 247.5 Hz), 197.23; 19 F NMR (CDCl3, 470 MHz) δ –112.79; IR (thin film) 3474br s, 2853w, 1724s, 1603s, 1508s, 1230s, 1159m, 835s cm-1; HRMS (ESI-TOF) m/z found 231.0620 [(M-H2O+H)+; calcd. 231.0621 for C14H9OF2]. 2,2-bis(4-trifluoromethylphenyl)-2-hydroxyacetaldehyde (2n). CF 3 OEt Br EtO + n-BuLi 2.5 equiv CF 3 THF, –78 °C CO2Et 1 equiv 10 % HCl acetone/H2O 80 °C, 1 h O H HO THF, rt, 30 min 21n 2n 2.5 equiv CF 3 The acetal intermediate of this substrate was synthesized via a different method. To a 100 mL clean and dry round bottom flask were added 10 mL THF and 1-bromo-4-(trifluoromethyl)benzene (0.49 mL, 3.5 mmol, 2.5 equiv). The flask was sealed by a septum with a N2 balloon attached via a needle, and cooled to – 78 °C in an acetone dry ice bath for 5 min. Then a solution of n-butyllithum (2.2 M in pentane, 1.60 mL, 3.5 mmol, 2.5 equiv) was added dropwise via a syringe. The resulting solution was stirred at –78 °C for another 10 min before addition of ethyl diethoxyacetate (0.30 mL in 2 mL THF, 1.68 mmol, 1.25 equiv). Thereafter, the solution was gradually warmed up to room temperature and allowed to stir for 30 min. It was then quenched with saturated NH4Cl solution 10 mL. The two layers 99 were separated and the aqueous layer was extracted with ether (5 mL x 3). The combined organic layer was concentrated under rotary evaporation and the crude residue was subjected to hydrolysis without purification. The hydrolysis followed the general procedure except that a 10% solution of HCl was used and the temperature was 80 °C. A mixture of 20:1 to 5:1 hexanes:EtOAc was employed as the eluent during column chromatography. The reaction afforded the product 2n as a white solid (53%, 0.31 g, 0.89 mmol); mp = 72-74 °C. Spectral data for 2n: 1H NMR (CDCl3, 500 MHz) δ 4.53 (s, 1H), 7.52 (d, J = 8.0 Hz, 4H), 7.70 (d, J = 8.0 Hz, 4H), 10.03 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 82.85, 123.71 (q, J = 270.8 Hz), 126.01 (q, J = 3.7 Hz), 127.68, 131.09 (q, J = 32.5 Hz), 142.62, 196.66; 19 F NMR (CDCl3, 470 MHz) δ –62.82; IR (thin film) 3395s, 1732s, 1329s, 1126s, 1070s, 833m cm-1; HRMS (ESI-TOF) m/z found 331.0558 [(M-H2O+H)+; calcd. 331.0558 for C16H9OF6]. 2,2-bis(4-acetylphenyl)-2-hydroxyacetaldehyde (2o). O + Mg 2.5 equiv H 3C OEt OEt 2.5 equiv CH 3 OEt Br EtO CO2Et 1 equiv 10 % HCl acetone/H2O 80 °C, 1 h O H HO THF, rt, 30 min O 21o 2o H 3C Following the general procedure with 4-bromoacetophenone diethyl ketal (0.76 mL, 3.5 mmol, 2.5 equiv), the hydrolysis of all three acetals was carried out 100 with 10% HCl at 80 °C for 1 h. A mixture of 4:1 to 2:1 hexanes:EtOAc was used as eluent for column chromatography. The reaction afforded the product 2o as a light yellow solid (55%, 0.228 g, 0.771 mmol); mp = 106-107 °C. Rf = 0.25 in 2:1 hexanes:EtOAc. Spectral data for 2o: 1H NMR (CDCl3, 500 MHz) δ 2.59 (s, 6H), 4.59 (s, 1H), 7.47 (d, J = 8.5 Hz, 4H), 7.97 (d, J = 8.5 Hz, 4H), 10.02 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 26.70, 83.13, 127.47, 128.86, 137.12, 143.80, 196.92, 197.43; IR (thin film) 3443 br s, 3063w, 3005w, 2924w, 1732s, 1684s, 1603s, 1408s, 1359s, 1289s, 1190m, 1012m cm-1; HRMS (ESI-TOF) m/z found 297.1134 [(M+H)+; calcd. 297.1127 for C18H17O4]. 2-hexyl-2-hydroxyoctanal (2p). OEt Br + Mg 2.5 equiv EtO CO2Et 1 equiv THF, rt, 30 min 2.5 equiv 5 % HCl acetone/H2O 70 °C, 1 h O H HO nC6H13 nC6H13 21p 2p Following the general procedure with 1-bromohexane (0.49 mL, 3.5 mmol, 2.5 equiv), the reaction afforded the product 2p as a colorless liquid (71%, 0.227 g, 0.994 mmol). Spectral data for 2p: 1H NMR (CDCl3, 500 MHz) δ 0.86 (t, J = 7.0 Hz, 6H), 1.03-1.09 (m, 2H), 1.22-1.29 (m, 12H), 1.35-1.41 (m, 2H), 1.62-1.67 (m, 4H), 3.16 (s, 1H), 9.47 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 14.02. 22.50, 22.95, 29.55, 101 31.59, 36.25, 80.58, 204.69. IR (neat) 3516 br s, 2957s, 2930s, 2858s, 1728s, 1468m, 1379w, 1087m cm-1. HRMS (ESI-TOF) m/z found 211.2051 [(M-H2O+H)+; calcd. 211.2056 for C14H27O]. 2-benzyl-2-hydroxy-3-phenylpropanal (2q). OEt EtO MgCl 2.5 equiv CO2Et 1 equiv THF, rt, 30 min 5 % HCl acetone/H2O 70 °C, 1 h O H HO CH2Ph CH2Ph 21q 2q Following the general procedure with commercial benzylmagnesium chloride (1M in ether, 7.0 mL, 7.0 mmol, 2.5 equiv, the scale was doubled), this reaction afforded the product 2q as a white solid (46%, 0.313 g, 1.29 mmol); mp = 66-70 °C. Spectral data for 2q: 1H NMR (CDCl3, 500 MHz) δ 3.00 (d, J = 14.0 Hz, 2H), 3.08 (s, 1H), 3.17 (d, J = 14.0 Hz, 2H), 7.19-7.21 (m, 4H), 7.26-7.32 (m, 6H), 9.66 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 42.85, 80.86, 127.09, 128.40, 130.30, 134.75, 203.58; IR (thin film) 3493br s, 3086m, 3030s, 2928m, 1720s, 1641m, 1454s, 1109m, 814s, 752s, 700s cm-1; HRMS (ESI-TOF) m/z found 223.1119 [(M-H2O+H)+; calcd. 223.1123 for C16H15O]. 102 2,2-dicyclohexyl-2-hydroxyacetaldehyde (2r) OEt EtO MgCl CO2Et 5 % HCl acetone/H2O 70 °C, 1 h 1 equiv O H HO THF, rt, 30 min 2.5 equiv 21r 2r Following the general procedure with commercial cyclohexylmagnesium chloride (2M in ether, 3.5 mL, 7.0 mmol, 2.5 equiv, the scale was doubled), this reaction afforded the product 2r as a white solid (57%, 0.359 g, 1.60 mmol); mp = 65-67 °C. Spectral data for 2r: 1H NMR (CDCl3, 500 MHz) δ 0.92 (qd, J = 8.0, 2.5 Hz, 2H), 1.06-1.15 (m, 2H), 1.17-1.25 (m, 6H), 1.52 (dd, J = 6.0, 2.5 Hz, 2H), 1.66 (d, J = 12.5 Hz, 2H), 1.75-1.86 (m, 8H), 3.21 (s, 1H), 9.58 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 26.01, 26.27, 26.43, 26.59, 27.33, 40.36, 83.92, 206.61; IR (thin film) 3468 br s, 2930s, 2853s, 1720s, 1448s, 1329m, 1101m cm-1; HRMS (ESI-TOF) m/z found 225.1852 [(M+H)+; calcd. 225.1855 for C14H25O2]. 5.2.2 General procedure for the preparation of iminol 3 O H HO 21 2 R NH 2 + 20 mol% KHSO 4 toluene, rt, 0.5 h R Ph N H HO R R 22 3 1.1 equiv To a 20 mL vial was added the appropriate α-hydroxyl aldehyde (0.3-0.5 mmol, 1 equiv), solid KHSO4 (20 mol%), aniline (1.1 equiv) and toluene (1 mL). The vial was capped and the mixture was stirred at room temperature for 0.5 h. 103 Upon completion, the reaction mixture was neutralized with 0.1 mL Et3N and dried over MgSO4, then it was filtered through a filter paper in Buchner funnel and concentrated under rotary evaporation. The crude solid iminols were purified by recrystallization from hexanes; crude oil iminols were purified by a short flash column chromatography, 10:1 hexanes:EtOAc as eluent. 1,1-diphenyl-2-(phenylimino)ethan-1-ol (3a). O NH 2 + H 20 mol% KHSO 4 toluene, rt, 0.5 h N H HO HO 21a 2a Ph 1.1 equiv 22a 3a Following the general procedure with 2a (0.5 mmol, 10 mmol and 40 mmol scale), the reaction afforded 78-100% yield of the product 3a as a white solid over several trials; mp = 86-88 °C. Spectral data for 3a: 1H NMR (CDCl3, 500 MHz) δ 5.74 (br s, 1H), 7.17 (d, J = 7.5 Hz, 2H), 7.25 (t, J = 7.0 Hz, 2H), 7.32 (tt, J = 7.5, 1.0 Hz, 2H), 7.35-7.39 (m, 5H), 7.44 (d, J = 7.0 Hz, 4H), 8.47 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 78.76, 121.17, 126.81, 127.19, 127.78, 128.52, 129.21, 143.23, 148.58, 164.92; IR (thin film) 3399s, 3059s, 3028s, 1647s, 1595s, 1487s, 1448s, 1385m, 1325m, 1170m cm-1; HRMS (ESI-TOF) m/z found 270.1270 [(M-H2O+H)+; calcd. 270.1277 for C20H16N]. 104 2-(phenylimino)-1,1-di-o-tolylethan-1-ol (3b). Ph O NH 2 CH 3 + H HO H 3C 20 mol% KHSO 4 toluene, rt, 0.5 h N H HO H 3C CH 3 1.1 equiv 3b 22b 21b 2b Following the general procedure with 2b (0.117 g, 0.487 mmol), the reaction afforded the product 3b as a colorless liquid (88%, 0.135 g, 0.428 mmol). Spectral data for 3b: 1H NMR (CDCl3, 500 MHz) δ 2.12 (s, 6H), 5.78 (br s, 1H), 7.15-7.27 (m, 9H), 7.36-7.42 (m, 4H), 8.51 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.47, 80.33, 115.15, 121.12, 126.01, 126.72, 127.12, 127.86, 129.23, 132.43, 136.90, 141.24, 164.43; IR (neat) 3395br s, 3061s, 3018s, 2964s, 2928s, 1693s, 1645s, 1601s, 1502s, 1487s, 1460s, 1381s, 1325s, 1161m, 989m, 970m, 868m cm-1; HRMS (ESI-TOF) m/z found 298.1596 [(M-H2O+H)+; calcd. 298.1596 for C22H20N]. 1,1-bis(2-isopropylphenyl)-2-(phenylimino)ethan-1-ol (3c). O H HO i-Pr NH 2 i-Pr + 20 mol% KHSO 4 4 Å MS toluene, rt, 19 h Ph N H HO i-Pr i-Pr 1.1 equiv 21c 2c 22c 3c Following the general procedure with 2c (0.101g, 0.343 mmol), the formation of imine 3c was not complete after 19 h even in the presence of 0.30 g 4Å molecular sieves. The crude residue was a 1:3.2 mixture of aldehyde:imine as 105 judged from the 1H NMR spectrum (δ 10.19 for the aldehyde and δ 8.59 for the imine). This crude imine was taken directly on to the next step. 2-(phenylimino)-1,1-di-m-tolylethan-1-ol (3d). CH 3 O NH 2 + H HO 20 mol% KHSO 4 toluene, rt, 0.5 h Ph CH 3 N H HO 1.1 equiv H 3C H 3C 21d 2d 22d 3d Following the general procedure with 2d (0.129 g, 0.533 mmol), the reaction afforded the product 3d as a colorless liquid (84%, 0.142 g, 0.448 mmol). Spectral data for 3d: 1H NMR (CDCl3, 500 MHz) δ 2.36 (s, 6H), 5.71 (br s, 1H), 7.13-7.22 (m, 6H), 7.25-7.28 (m, 5H), 7.38 (t, J = 8.0 Hz, 2H), 8.47 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.61, 78.69, 115.13, 121.20, 124.24, 126.74, 127.75, 128.31, 128.49, 129.19, 138.24, 143.27, 165.11; IR (neat) 3381br s, 3032s, 2920s, 1647s, 1603s, 1498s, 1487s, 1153m, 1026w, 873m cm-1; HRMS (ESI-TOF) m/z found 298.1583 [(M+H)+; calcd. 298.1596 for C22H22NO]. 1,1-bis(3-chlorophenyl)-2-(phenylimino)ethan-1-ol (3e). Ph O OH H + PhNH 2 Cl 1.2 equiv KHSO 4 toluene, rt, 30 min N OH H Cl Cl Cl 2e 21e 106 22e3e Following the general procedure with 2e (0.10 g, 0.35 mmol), this reaction afforded the product 3e (0.12g, 0.35 mmol, 100%) as a colorless oil. Spectral data for 3e: 1H NMR (CDCl3, 500 MHz) δ 5.80 (s, 1H), 7.17 (dd, J = 8.5, 1.0 Hz, 2H), 7.27-7.36 (m, 7H), 7.39 (t, J = 8.0 Hz, 2H), 7.44-7.45 (m, 2H), 8.41 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 78.04, 121.19, 125.21, 127.23, 127.26, 128.25, 129.31, 129.89, 134.72, 144.76, 147.88, 163.09; IR (thin film) 3409s, 1660s, 1448s, 1330m, 1190m, 1050m cm-1; HRMS (ESI-TOF) m/z found 356.0611 [(M+H)+; calcd. 356.0609 for C20H16ONCl2]. 2-(phenylimino)-1,1-di-p-tolylethan-1-ol (3f). CH 3 CH 3 NH 2 O + H HO 21f 2f CH 3 20 mol% KHSO 4 toluene, rt, 0.5 h Ph N H HO 1.1 equiv 3f 22f CH 3 Following the general procedure with 2f (0.087 g, 0.36 mmol), the reaction afforded the product 3f as a white solid (93%, 0.106 g, 0.334 mmol); mp = 116-119 °C. Spectral data for 3f: 1H NMR (CDCl3, 500 MHz) δ 2.36 (s, 6H), 5.66 (br s, 1H), 7.15-7.19 (m, 5H), 7.25-7.26 (m, 2H), 7.33 (d, J = 8.0 Hz, 4H), 7.37 (t, J = 7.5 Hz, 2H), 8.42 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 21.10, 78.49, 121.14, 126.65, 127.09, 129.16, 137.43, 140.42, 148.76, 165.20 ( 1 aromatic carbon was not located); IR (thin film) 3402br s, 3026s, 2922s, 1647s, 1595s, 1510s, 1487s, 107 1452m, 1410m, 1379m, 1327m, 1167s, 985s cm-1; HRMS (ESI-TOF) m/z found 298.1592 [(M-H2O+H)+; calcd. 298.1596 for C22H20N]. 1,1-bis(4-butylphenyl)-2-(phenylimino)ethan-1-ol (3g). n-Bu n-Bu NH 2 O + H HO 21g 2g n-Bu 20 mol% KHSO 4 toluene, rt, 0.5 h Ph N H HO 1.1 equiv 22g 3g n-Bu Following the general procedure with 2g (0.114 g, 0.350 mmol), this reaction afforded the product 3g as a white solid (93%, 0.130 g, 0.325 mmol); mp = 75-77 °C. Spectral data for 3g: 1H NMR (CDCl3, 500 MHz) δ 0.94 (t, J = 7.5 Hz, 6H), 1.37 (sextet, J = 7.5 Hz, 4H), 1.61 (qt, J = 7.5, 2.5 Hz, 4H), 2.62 (d, J = 7.5 Hz, 4H), 5.68 (br s, 1H), 7.17-7.27 (m, 7H), 7.34-7.39 (m, 6H), 8.44 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 13.97, 22.39, 33.56, 35.29, 78.49, 121.18, 126.65, 127.06, 128.50, 129.16, 140.53, 142.42, 148.76, 165.27; IR (thin film) 3402s, 3024m, 2957s, 2930s, 2858s, 1647s, 1595m, 1508s, 1415m, 1167s, 981m cm-1; HRMS (ESI-TOF) m/z found 400.2638 [(M+H)+; calcd. 400.2640 for C28H34NO]. 108 1,1-bis(4-isopropylphenyl)-2-(phenylimino)ethan-1-ol (3h). i-Pr i-Pr NH 2 O + H HO 2h 21h Ph 20 mol% KHSO 4 toluene, rt, 0.5 h N H HO 1.1 equiv i-Pr 3h 22h i-Pr Following the general procedure with 2h (0.106 g, 0.355 mmol), this reaction afforded the product 3h as a white solid (95%, 0.125 g, 0.337 mmol); mp = 138-139 °C. Spectral data for 3h: 1H NMR (CDCl3, 500 MHz) δ 1.26 (d, J = 7.0 Hz, 12H), 2.92 (septet, J = 7.0 Hz, 2H), 5.68 (br s, 1H), 7.16-7.18 (m 2H), 7.23-7.25 (m, 4H), 7.26-7.27 (m, 2H), 7.36-7.39 (m, 5H), 8.44 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 23.95, 33.78, 78.44, 121.18, 126.52, 126.64, 127.11, 129.16, 140.66, 148.28, 148.77, 165.29; IR (thin film) 3412 br s, 2961s, 2870w, 1647s, 1484m, 1172m, 1055m cm-1; HRMS (ESI-TOF) m/z found 354.2220 [(M-H2O+H)+; calcd. 354.2222 for C26H28N]. 1,1-bis(4-cyclohexylphenyl)-2-(phenylimino)ethan-1-ol (3i). Cy Cy O NH 2 + H HO Cy 20 mol% KHSO 4 toluene, rt, 0.5 h Ph N H HO 1.1 equiv Cy 2i 21i 3i 22i 109 Following the general procedure with 2i (0.105 g, 0.278 mmol), the reaction afforded the product 3i as a white solid (93%, 0.117 g, 0.259 mmol); mp = 153-155 °C. Spectral data for 3i: 1H NMR (CDCl3, 500 MHz) δ 1.22-1.30 (m, 2H), 1.35-1.46 (m, 8H), 1.75 (dt, J = 12.5, 1.0 Hz, 2H), 1.84-1.89 (m, 8H), 2.48-2.53 (m, 2H), 5.68 (s, 1H), 7.16-7.18 (m, 2H), 7.21 (d, J = 8.0 Hz, 4H), 7.25 (tt, J = 7.5, 1.0 Hz, 2H), 7.35-7.39 (m, 5H), 8.44 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 26.14, 26.88, 34.39, 44.21, 78.46, 121.20, 126.63, 126.90, 127.08, 129.15, 140.63, 147.51, 148.77, 165.30; IR (thin film) 3375br s, 3032w, 2924s, 2851s, 1603s, 1498s, 1448m, 1278m, 1172m cm-1; HRMS (ESI-TOF) m/z found 452.2957 [(M+H)+; calcd. 452.2953 for C32H38NO]. 1,1-bis(4-t-butylphenyl)-2-(phenylimino)ethan-1-ol (3j). t-Bu t-Bu NH 2 O + H HO 21j2j t-Bu 20 mol% KHSO 4 toluene, rt, 0.5 h Ph N H HO 1.1 equiv 22j 3j t-Bu Following the general procedure with 2j (0.137 g, 0.422 mmol), this reaction afforded the product 3j as a white solid (98%, 0.165 g, 0.414 mmol); mp = 137-140 °C. Spectral data for 3j: 1H NMR (CDCl3, 500 MHz) δ 1.33 (s, 18H), 5.69 (br s, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.24-7.27 (m, 2H), 7.36-7.41 (m, 9H), 8.46 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 31.32, 34.53, 78.32, 121.19, 125.38, 110 126.63, 126.83, 129.16, 140.22, 148.78, 150.52, 165.29; IR (thin film) 3402br s, 3032m, 2963s, 2905m, 1647s, 1597s, 1506s, 1404m, 1363s, 1269m, 1109s, 831m cm-1; HRMS (ESI-TOF) m/z found 382.2534 [(M-H2O+H)+; calcd. 382.2535 for C28H32N]. 1,1-di([1,1'-biphenyl]-4-yl)-2-(phenylimino)ethan-1-ol (3k). Ph Ph NH 2 O + H HO 21k 2k 20 mol% KHSO 4 toluene, rt, 0.5 h Ph Ph N H HO 1.1 equiv Ph 22k 3k Following the general procedure with 2k (0.131 g, 0.360 mmol), the reaction afforded the product 3k as a white solid (95%, 0.150 g, 0.342 mmol); mp = 183-185 °C. Spectral data for 3k: 1H NMR (CDCl3, 500 MHz) δ 5.82 (s, 1H), 7.22 (dt, J = 7.5, 1.0 Hz, 2H), 7.28 (tt, J = 7.5, 1.0 Hz, 2H), 7.35-7.42 (m, 4H), 7.46 (t, J = 7.5 Hz, 4H), 7.57 (dt, J = 7.5, 1.0 Hz, 4H), 7.61-7.65 (m, 7H), 8.55 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 78.56, 121.21, 126.89, 127.14, 127.32, 127.44, 127.62, 128.80, 129.25, 140.60, 140.74, 142.17, 148.55, 164.61; IR (thin film) 3402br s, 1645s, 1485s, 1174m cm-1; HRMS (ESI-TOF) m/z found 440.2026 [(M+H)+; calcd. 440.2014 for C32H26NO]. 111 1,1-bis(4-methoxylphenyl)-2-(phenylimino)ethan-1-ol (3l) OMe OMe Ph O NH 2 + H HO 2l 21l OMe 20 mol% KHSO 4 toluene, rt, 0.5 h 1.1 equiv N H HO 3l 22l OMe Following the general procedure with 2l (0.086 g, 0.308 mmol), the reaction afforded the product 3l as a white solid (97%, 0.104 g, 0.300 mmol); mp = 90-94 °C. Spectral data for 3l: 1H NMR (CDCl3, 500 MHz) δ 3.82 (s, 6H), 5.67 (br s, 1H), 6.92 (dt, J = 9.0, 3.0 Hz, 4H), 7.16-7.18 (m, 3H), 7.25-7.27 (m, 1H), 7.35-7.39 (m, 5H), 8.39 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 55.32, 78.15, 113.83, 115.12, 121.14, 126.67, 128.46, 129.20, 135.46, 159.07, 165.12; IR (thin film) 3385br s, 3034m, 3003m, 2934m, 1647s, 1606s, 1508s, 1302m, 1251s, 1172s, 1033s, 831s cm-1; HRMS (ESI-TOF) m/z found 330.1492 [(M-H2O+H)+; calcd. 330.1494 for C22H20NO2]. 1,1-bis(4-fluorophenyl)-2-(phenylimino)ethan-1-ol (3m) F F O NH 2 + H HO 21m 2m F 20 mol% KHSO 4 toluene, rt, 0.5 h Ph N H HO 1.1 equiv 22m 3m F Following the general procedure with 2m (0.084 g, 0.36 mmol), this reaction afforded the product 3m as a colorless liquid (95%, 0.106 g, 0.346 mmol), 112 which was purified by flash column chromatography on silica gel with a 10:1 mixture of hexanes:EtOAc. Spectral data for 3m: 1H NMR (CDCl3, 500 MHz) δ 5.78 (br s, 1H), 7.08 (tt, J = 9.0, 2.5 Hz, 4H), 7.16-7.20 (m, 3H), 7.26-7.30 (m, 1H), 7.38-7.42 (m, 5H), 8.40 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 78.00, 115.14, 115.48 (d, J = 20.9 Hz), 118.62, 121.13, 128.93 (d, J = 8.0 Hz), 129.29, 138.85 (d, J = 2.9 Hz), 162.32 (d, J = 245.6 Hz), 164.06; 19F NMR (CDCl3, 470 MHz) δ –114.25; IR (neat) 3381br s, 3078s, 3029s, 1649s, 1603s, 1506s, 1224s, 1159s, 1091m, 1014m cm-1; HRMS (ESI-TOF) m/z found 306.1090 [(M-H2O+H)+; calcd. 306.1094 for C20H14NF2]. 1,1-bis(4-trifluoromethylphenyl)-2-(phenylimino)ethan-1-ol (3n). CF 3 CF 3 O NH 2 + H HO CF 3 Ph 20 mol% KHSO 4 toluene, rt, 0.5 h N H HO 1.1 equiv 3n 22n 21n2n CF 3 Following the general procedure with 2n (0.121 g, 0.349 mmol), the reaction afforded the product 3n as a white solid (90%, 0.133 g, 0.314 mmol); mp = 95-100 °C. Spectral data for 3n: 1H NMR (CDCl3, 500 MHz) δ 5.89 (br s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 8.5 Hz, 1H), 7.40 (t, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 4H), 7.66 (d, J = 8.5 Hz, 4H), 8.47 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 78.30, 121.13, 123.89 (q, J = 270.0 Hz), 125.69 (q, J = 3.7 Hz), 126.66, 127.43, 113 129.38, 130.34 (q, J = 32.7 Hz), 146.53, 147.76, 162.81; 19 F NMR (CDCl3, 470 MHz) δ –62.65; IR (thin film) 3391br s, 1653s, 1616s, 1489m, 1414s, 1325s, 1167s, 1126s, 1068s, 1018m, 841m cm-1; HRMS (ESI-TOF) m/z found 406.1040 [(M-H2O+H)+; calcd. 406.1030 for C22H14NF6]. 1,1'-((1-hydroxy-2-(phenylimino)ethane-1,1-diyl)bis(4,1-phenylene))bis(etha n-1-one) (3o). O O CH 3 O NH 2 + H HO 20 mol% KHSO 4 toluene, rt, 0.5 h Ph CH 3 N H HO CH 3 1.1 equiv 21o 2o CH 3 O 22o 3o O Following the general procedure with 2o (0.0455 g, 0.154 mmol), the crude product was purified by flash column chromatography on silica gel with 10:1 CH2Cl2:EtOAc as eluent. This reaction afforded the product 3o as a light yellow solid (88%, 0.0502 g, 0.136 mmol); mp = 168-169 °C. Spectral data for 3o: 1H NMR (CDCl3, 500 MHz) δ 2.62 (s, 6H), 5.88 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 8.5 Hz, 1H), 7.40 (t, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 4H), 7.99 (d, J = 8.5 Hz, 4H), 8.50 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 26.72, 78.57, 121.15, 127.25, 127.33, 128.69, 129.35, 136.65, 147.75, 147.92, 163.00, 197.56; IR (thin film) 3387 br s, 1684s, 1603s, 1408m, 1358m, 1267s cm-1; HRMS (ESI-TOF) m/z found 372.1595 [(M+H)+; calcd. 372.1600 for C24H22NO3]. 114 7-((phenylimino)methyl)tridecan-7-ol (3p). NH 2 O n-C6H13 H HO + 20 mol% KHSO 4 toluene, rt, 0.5 h Ph H HO n-C6H13 1.1 equiv 21p 2p N n-C6H13 n-C6H13 22p 3p Following the general procedure with 2p (0.104 g, 0.458 mmol), this reaction afforded the product 3p as a colorless liquid (88%, 0.122 g, 0.402 mmol), which was purified by flash column chromatography on silica gel with a 10:1 mixture of hexanes:EtOAc. Spectral data for 3p: 1H NMR (CDCl3, 500 MHz) δ 0.87 (t, J = 7.5 Hz, 6H), 1.14-1.31 (m, 14H), 1.43-1.51 (m, 2H), 1.63 (td, J = 7.5, 5.0 Hz, 2H), 1.71 (td, J = 7.5, 5.0 Hz, 2H), 4.23 (br s, 1H), 7.08 (d, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.79 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.08, 22.60, 23.30, 29.76, 31.78, 39.07, 75.60, 120.77, 126.14, 129.12, 149.81, 168.47; IR (thin film) 3458br s, 3030w, 2930s, 2858s, 1653s, 1595s, 1489m, 1466m, 1396m, 1136m, 1072m, 868m cm-1; HRMS (ESI-TOF) m/z found 286.2542 [(M-H2O+H)+; calcd. 286.2535 for C20H32N]. 2-benzyl-1-phenyl-3-(phenylimino)propan-2-ol (3q). NH 2 O H HO CH2Ph 20 mol% KHSO 4 toluene, rt, 0.5 h + N H HO CH2Ph 2q 21p Ph 1.1 equiv CH2Ph CH2Ph 3q 22p 115 Following the general procedure with 2q (0.147 g, 0.606 mmol), the reaction afforded the product 3q as a light yellow oil (100%, 0.191 g, 0.606 mmol), which was purified by flash column chromatography on silica gel with a 10:1 mixture of hexanes:EtOAc. Spectral data for 3q: 1 H NMR (CDCl3, 500 MHz) δ 3.13 (s, 4H), 4.15 (br s, 1H), 7.16-7.34 (m, 15H), 7.82 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 45.61, 76.03, 120.26, 125.78, 126.65, 128.04, 128.94, 130.58, 136.13, 150.15, 167.19; IR (neat) 3412 br s, 2063m, 3028s, 2920m, 1657m, 1599s, 1495s, 1254s, 1321m, 1086m, 1032m cm-1; HRMS (ESI-TOF) m/z found 316.1703 [(M+H)+; calcd. 316.1701 for C22H22NO]. 1,1-dicyclohexyl-2-(phenylimino)ethan-1-ol (3r). NH 2 O H HO 2r 21r 20 mol% KHSO 4 toluene, rt, 0.5 h + Ph N H HO 1.1 equiv 3r 22r Following the general procedure with 2r (0.198 g, 0.882 mmol), the reaction afforded the product 3r as a white solid (88%, 0.246 g, 0.776 mmol); mp = 84-86 °C. Spectral data for 3r: 1H NMR (CDCl3, 500 MHz) δ 0.97-1.27 (m, 11H), 1.58-1.93 (m, 11H), 4.22 (br s, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.21-7.25 (m, 1H), 7.36 (t, J = 8.0 Hz, 2H), 7.83 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 26.38, 26.51, 116 26.61, 26.76, 27.52, 41.94, 78.92, 120.73, 126.04, 129.12, 150.07, 168.69; IR (thin film) 3447br s, 2928s, 2853s, 1651s, 1597m, 1487m, 1448m, 1425m, 1099m, 1074m cm-1; HRMS (ESI-TOF) m/z found 300.2338 [(M-H2O+H)+; calcd. 300.2327 for C20H30NO]. 2-((4-methoxyphenyl)imino)-1,1-diphenylethan-1-ol (3s). MeO NH 2 O 20 mol% KHSO 4 toluene, rt, 0.5 h N + H HO H HO 21a2a OMe 1.1 equiv 3s22s Following the general procedure with 2a (0.961 g, 4.52 mmol) and 4-anisidine (0.607 g, 4.93 mmol, 1.1 equiv.), this reaction afforded the product 3s as a white solid (99%, 1.42 g, 4.48 mmol); mp = 77-79 °C. Spectral data for 3s: 1H NMR (CDCl3, 500 MHz) δ 3.82 (s, 3H), 5.85 (br s, 1H), 6.91 (dt, J = 9.0, 2.0 Hz, 2H), 7.20 (dt, J = 9.0, 2.0 Hz, 2H), 7.32 (tt, J = 7.5, 1.5 Hz, 2H), 7.38 (tt, J = 7.5, 1.5 Hz, 4H), 7.44 (dt, J = 7.0, 1.5 Hz, 4H), 8.47 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 55.52, 78.62, 114.35, 122.63, 127.18, 127.68, 128.64, 141.13, 143.49, 158.81, 162.42; IR (thin film) 3385br s, 3059s, 3026s, 2932s, 1643s, 1603s, 1506s, 1448s, 1248s, 1032s cm-1; HRMS (ESI-TOF) m/z found 318.1500 [(M+H)+; calcd. 318.1494 for C21H20NO2]. 117 1,1-dicyclohexyl-2-((4-methoxyphenyl)imino)ethan-1-ol (3t). MeO NH 2 O H HO 2r 21t 20 mol% KHSO 4 toluene, rt, 0.5 h N + H HO OMe 1.1 equiv 3t 22t The general procedure was followed with 2r (0.104 g, 0.465 mmol) and 4-anisidine (0.063 g, 0.51 mmol, 1.1 equiv) except that the reaction temperature was 50 °C for 2h. The reaction afforded the product 3t as a light yellow solid (81%, 0.124 g, 0.377 mmol); mp = 94-97 °C. Spectral data for 3t: 1H NMR (CDCl3, 500 MHz) δ 1.00 (qd, J = 12.5, 3.5 Hz, 2H), 1.13 (td, J = 12.5, 3.5 Hz, 2H), 1.17-1.28 (m, 6H), 1.28 (d, J = 10.0 Hz, 2H), 1.67 (d, J = 12.5 Hz, 2H), 1.75-1.83 (m, 6H), 1.92 (d, J = 12.5 Hz, 2H), 3.82 (s, 3H), 4.33 (br s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 7.84 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 26.40, 26.52, 26.62, 26.78, 27.55, 42.01, 55.54, 78.87, 114.31, 122.03, 142.68, 158.27, 166.65; IR (thin film) 3437 br s, 2928s, 2853s, 1647s, 1506s, 1448m, 1246s, 1035m cm-1; HRMS (ESI-TOF) m/z found 330.2434 [(M+H)+; calcd. 330.2433 for C21H32NO2]. 118 ethyl 4-((2-hydroxy-2,2-diphenylethylidene)amino)benzoate (3u). EtO 2C NH 2 O H HO + CO2Et 21a 2a N H 20 mol% 4 Å MS, toluene, rt, 0.5 h N H HO 3u 22u 1.1 equiv Following the general procedure with 2a (0.041 g, 0.19 mmol), ethyl 4-aminobenzoate (0.034 g, 0.21 mmol), in the presence of 20 mol% pyrrolidine and 0.050 g 4Å molecular sieves (no KHSO4 was added), the reaction afforded the product 3u as a colorless liquid (89%, 0.061 g, 0.17 mmol). Spectral data for 3u: 1H NMR (CDCl3, 500 MHz) δ 1.40 (t, J = 7.0 Hz, 3H), 4.38 (q, J = 7.0 Hz, 2H), 5.51 (s, 1H), 7.15 (dt, J = 8.0, 2.0 Hz, 2H), 7.33 (tt, J = 7.5, 2.0 Hz, 2H), 7.37-7.40 (m, 4H), 7.44 (dt, J = 7.0, 2.0 Hz, 4H), 8.05 (d, J = 9.0 Hz, 2H), 8.47 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.31, 61.02, 78.94, 120.86, 126.09, 127.15, 127.91, 128.58, 130.81, 142.87, 152.80, 160.04, 166.73; IR (neat) 3449br s. 3059m, 2980m, 1714s, 1653m, 1603s, 1493m, 1448s, 1277s, 1170s, 1101s cm-1; HRMS (ESI-TOF) m/z found 360.1602 [(M+H)+; calcd. 360.1600 for C23H22NO3]. 119 2-((3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)imino)-1,1-diphenylethan1-ol (7). NH 2 O 20 mol% KHSO 4 toluene, rt, 0.5 h TBSO N + H HO H HO OTBS 1.1 equiv 2a 21a 7 22v Following the general procedure with 2a (0.15 g, 0.70 mmol, 1 equiv) and 3-(((tert-butyldimethylsilyl)oxy)methyl)aniline (0.18 g, 0.77 mmol, 1.1 equiv), the reaction afforded the product 7 as a colorless liquid (100%, 0.31 g, 0.77 mmol). Spectral data for 7: 1H NMR (CDCl3, 500 MHz) δ 0.10 (s, 6H), 0.94 (s, 9H), 4.75 (s, 2H), 5.74 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.30-7.33 (m, 3H), 7.38 (t, J = 8.0 Hz, 4H), 7.44 (d, J = 8.0 Hz, 4H), 8.46 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 5.26, 18.41, 25.93, 64.46, 78.72, 118.41, 119.76, 124.20, 127.16, 127.73, 128.49, 129.02, 142.87, 143.26, 148.68, 164.89; IR (neat) 3393s, 2955s, 2932s, 2889s, 2856s, 1647s, 1601s, 1491s, 1375s, 1253s, 1172s, 1105s cm-1; HRMS (ESI-TOF) m/z found 432.2365 [(M+H)+; calcd. 432.2359 for C27H34NO2Si]. 120 2-(benzylimino)-1,1-diphenylethan-1-ol (3w) O OH H + BnNH 2 KHSO 4 toluene rt, 30 min Bn N OH H 1.1 equiv 21a 2a 22w 3w Following the general procedure with 2a (0.12 g, 0.55 mmol, 1 equiv) and benzyl amine (66 µL, 0.60 mmol, 1.1 equiv), this reaction afforded the product 3w (0.13 g, 0.44 mmol, 80%) as a white solid; mp = 78-80 °C. Spectral data for 3w: 1H NMR (CDCl3, 500 MHz) δ 4.80 (s, 2H), 5.78 (br s, 1H), 7.27-7.33 (m, 5H), 7.35-7.40 (m, 10H), 8.33 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 61.92, 78.28, 127.10, 127.27, 127.59, 127.81, 128.39, 128.60, 138.21, 143.62, 166.11; IR (thin film) 3408s, 1662s, 1448m, 1363m, 1172m, 1028w cm-1; HRMS (ESI-TOF) m/z found 302.1532 [(M+H)+; calcd. 302.1545 for C21H20ON]. 5.2.3 Synthesis of amino ketone with silica gel and Montmorillonite K 10 R1 100 wt% silica gel or montmorillonite K 10 N H R2 OH R2 toluene, 1 h R1 NH O R2 R2 4 3 General procedure: To a 20 mL screw cap vial was added iminol 3 (0.1 mmol), silica gel or montmorillonite K 10 (100 wt%) and 0.3 mL toluene. The cap was screwed tight and heated to 80 °C for silica gel and 60 °C for montmorillonite 121 under air for 1 h. After cooling to room temperature, the solution was directly subjected to silica gel column to afford the pure product 4. The complete analytical data for 4a-4w were all presented in section 5.3.4. 5.2.4 Synthesis of Ketamine analog 20 N-methoxy-N-methylbenzamide (15) O + Cl 13 H OMe N Me 14 HCl 1 equiv. 2 equiv. Et 3N DCM, rt, 1.5h O OMe N Me 15 92% N,O-dimethylhydroxyamine 14 (2.03 g, 19.2 mmol, 2.2 equiv.) was suspended and vigorously stirred in 10 mL CH2Cl2, followed by addition of Et3N (5.0 mL, 34 mmol, 4 equiv.). The resulting solution was vigorously stirred. After 30 min, benzoyl chloride 13 (2.0 mL, 16 mmol, 1 equiv) was added dropwise and allowed to stir at room temperature for 1 h. The mixture was washed with brine, dried over MgSO4, filtered on filter paper and concentrated on rotary vaporization. The crude product was purified by silica gel column chromatography, a 1:1 mixture of hexane:EtOAc as the eluent, to afford 15 (2.61 g, 15.8 mmol, 92%) as a colorless oil. Spectral data for 15: 1H NMR (CDCl3, 500 MHz) δ 3.34 (s, 3H), 3.54 (s. 3H), 7.38 (tt, J = 7.5, 1.5 Hz, 2H), 7.44 (tt, J = 7.5, 1.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H); 122 13 C NMR (CDCl3, 125 MHz) δ 33.76, 61.01, 127.98, 128.10, 130.52, 134.09, 73 169.91. These NMR data are in agreement with literature data. Cyclopentyl phenyl ketone (16) O 15 2 equiv. OMe N Me MgCl THF, 0 °C to rt, 0.5h O 16 34% To a 100 mL clean and dry Schlenk flask purged with N2 was added Mg (0.74 g, 31 mmol, 2 equiv.), a small crystal of I2, chlorocyclopentane (3.2 mL, 31 mmol, 2 equiv.) and 20 mL THF. The flask was sealed and the resulting mixture was heated in 70 °C oil bath for 1 h or until all Mg dissolved. The solution was allowed to cool to room temperature and 0 °C in ice bath. This cooled solution was transferred to a solution of 15 (2.61 g, 15.8 mmol, 1 equiv.) in 10 mL THF in a 250 mL round bottom flask with a pipette dropwise. After completion of the transfer, it was allowed to stir at room temperature for 30 min under N2 atmosphere. The reaction was quenched with 20 mL saturated NH4Cl solution and extracted with Et2O (10 mL x 2). The combined organic phase was washed with brine 10 mL, dried over MgSO4, filtered through filter paper and concentrated on rotary vaporization. The crude product was purified by silica gel column chromatography, a 20:1 mixture of hexane:EtOAc as the eluent, to afford 16 (0.93 g, 5.3 mmol, 34%) as a colorless oil. 123 Spectral data for 16: 1H NMR (CDCl3, 500 MHz) δ1.50-1.77 (m, 5H), 1.89-1.94 (m, 3H), 3.71 (quint. J = 8.0 Hz, 1H), 7.45 (tt, J = 7.5, 1.5 Hz, 2H), 7.54 (tt, J = 7.5, 1.5 Hz, 2H), 7.98 (dt, J = 7.5, 1.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 26.31, 29.96, 46.33, 128.44, 128.47, 132.68, 136.89, 202.77. These NMR data 74 are in agreement with literature data. Note: benzaldehyde (0.63 g, 38%) was also isolated as a byproduct. Synthesis of 16 via the reaction between 15 and Wittig reagent may give a better 73 yield. Or via the reaction between benzonitrile and Grignard reagent. (1-bromocyclopentyl)(phenyl)methanone (17) O 16 O 1.1 equiv. Br 2 CHCl 3, AcOH, rt, 10min Br 17 100% To a clean and dry 20 mL round bottom flask was added the ketone 16 (0.63 g, 3.6 mmol, 1 equiv.), acetic acid (1 mL) and chloroform (4 mL), while stirring, Br2 (0.2 mL, 4 mmol, 1.1 equiv.) was added dropwise via a syringe. During the addition of each drop of Br2, the dark color faded away instantaneously. The resulting solution was allowed to stir at room temperature for 10 min. Then the solution was successively washed with 10 mL saturated Na2S2O4 solution, 10 mL saturated Na2CO3 solution and 10 mL brine. The organic phase was dried over MgSO4, filtered through filter paper and concentrated on rotary vaporization. The crude product was purified by silica gel column chromatography, a 20:1 124 mixture of hexane:EtOAc as the eluent, to afford 17 (0.91 g, 3.6 mmol, 100%) as a white semi-solid. Spectral data for 17: 1H NMR (CDCl3, 500 MHz) δ 1.76-1.84 (m, 2H), 2.02-2.11 (m, 2H), 2.40-2.46 (m, 2H), 2.49-2.54 (m, 2H), 7.44 (tt, J = 7.5, 1.5 Hz, 2H), 7.54 (tt, J = 7.5, 1.5 Hz, 1H), 8.15 (dt, J = 7.5, 1.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 23.49, 40.99, 71.12, 128.14, 130.21, 132.77, 134.72, 195.26. The 1H 75 NMR data are in agreement with literature data. 2-methoxy-2-phenyl-1-oxaspiro[2.4]heptane (18) O Br 1.5 equiv. NaOMe Et 2O, reflux, 12h MeO O 18 53% 17 4 Compound 18 is synthesized according to a literature procedure. To a clean and dry 50 mL round bottom flask was added 5 mL methanol and sodium metal (cut into small chunks, 0.0644 g, 2.80 mmol. 1 equiv.), after addition of Na metal, the flask was seal with a septum and a N2 balloon was attached via a needle. After disappearance of the sodium metal, the solvent was removed under high vacuum and flushed with N2. To the flask was added 10 mL Et2O and bromoketone 17 (0.71 g in 10 mL Et2O, 2.8 mmol, 1 equiv.) and equipped with a water condenser, the top was seal with a septum and a N2 balloon was attached via a needle. The resulting mixture was heated to reflux for 18 h. After cooling to room temperature, the suspension was filtered through filter paper and 125 concentrated on rotary vaporization. The crude product was purified by vacuum distillation (0.2 mmHg, 160 °C) to afford the product 18 (0.30 g, 1.5 mmol, 53%) as a colorless oil. Spectral data for 18: 1H NMR (CDCl3, 500 MHz) δ 1.31-1.37 (m, 1H), 1.40-1.52 (m, 2H), 1.61-1.68 (m, 1H), 1.70-1.76 (m, 1H), 1.77-1.85 (m, 2H), 2.13-2.20 (m, 1H), 3.08 (s, 3H), 7.33 (tt, J = 7.5, 1.5 Hz, 1H), 7.38 (tt, J = 7.5, 1.5 Hz, 2H), 7.43 (dt, J = 7.5, 1.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 25.14, 25.23, 52.79, 78.35, 89.63, 127.47, 128.16, 128.29, 134.97. 1-(phenyl(phenylimino)methyl)cyclopentan-1-ol (19) MeO O 1.1 equiv. PhNH 2 110 °C, 0.5h, 64% 18 Ph N OH 19 4 Compound 19 is synthesized according to a literature procedure. To a 10 mL round bottom flask was added the methoxy epoxide 18 (0.30 g, 1.5 mmol, 1 equiv.) and aniline (0.14 mL, 1.6 mmol, 1.1 equiv.). The resulting solution was heated to 110 °C under air for 30 min. After it was cooled to room temperature, allow it to crystalize in the freezer. Then recrystallize in hexane to afford the pure product 19 (0.25 g, 0.94 mmol, 64%) as a yellow solid. mp = 77-81 °C. 126 Spectral data for 19: 1H NMR (CDCl3, 500 MHz) δ 1.59-1.66 (m, 2H), 1.79-1.84 (m, 2H), 1.92-2.03 (m, 4H), 5.40 (s, 1H), 6.65 (d, J = 7.5 Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 7.02-7.03 (m, 2H), 7.09 (t, J = 7.5 Hz, 2H), 7.19-7.24 (m, 3H); 13C NMR (CDCl3, 125 MHz) δ 24.09, 38.61, 84.40, 120.86, 123.66, 127.79, 128.10, 128.16, 128.31, 134.72, 148.90, 176.57. 2-phenyl-2-(phenylamino)cyclohexan-1-one (20) Ph N OH Silica gel 120 °C, toluene 2d O PhHN 20 83% 19 Synthesis of compound 20 from compound 19 has been reported in the 4 literature by refluxing in decalin without a catalyst. Below is a new procedure that has not been reported before. To a clean and dry 20 mL Schlenk flask was added 19 (0.0379 g, 0.143 mmol), silica gel (0.04 g, 100 wt%) and toluene 0.3 mL. The flask was purged with N2, sealed and heated to 120 °C for 48 h. Then cooled to room temperature. The solution was directly subjected to silica gel column chromatography, a 2:1 mixture of chloroform:hexane as the eluent, to afford 20 (0.0314 g, 0.118 mmol, 83%) as a white solid. mp = 157-158°C. Spectral data for 20: 1H NMR (CDCl3, 500 MHz) δ 1.82-1.89 (m, 1H), 1.94-2.06 (m, 4H), 2.30 (td, J = 13.0, 5.0 Hz, 1H), 2.45-2.48 (m, 1H), 3.15-3.21 (m, 127 1H), 5.46 (s, 1H), 6.46 (d, J = 8.0 Hz, 2H), 6.60 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 22.80, 28.38, 38.72, 39.32, 68.17, 115.02, 117.60, 127.49, 127.66, 128.64, 128.81, 139.09, 144.70, 209.10. 5.3 Experimental procedures for chapter three 5.3.1 Procedure 1: Reaction with (S)-VANOL BOROX catalyst 22 Ph 25 mol% 25 mol%BOROX (S)-22 1 (S)-VANOL N H OH Ph NH toluene, 75 °C, 42 h O 22a 3a 23a 4a The catalyst (S)-VANOL BOROX 22 was prepared as follows. To a 20 mL flame dried Schlenk flask was added (S)-VANOL (0.0438 g, 0.1 mmol, 1 equiv.), B(OPh)3 (0.0870 g, 0.3 mmol, 3 equiv) and toluene (1 mL), the flask was sealed and heated in an 80 °C oil bath under N2 for 30 min. Then the reaction mixture was cooled to room temperature. This catalyst stock solution was directly used in the rearrangement reaction without further treatment. To a 20 mL flame dried Schlenk flask was added the catalyst solution (0.25 mL, 0.025 mmol, 25 mol%), iminol 3a (0.0287 g, 0.100 mmol, 1 equiv) and 0.05 mL toluene. The flask was sealed and heated in a 75 °C oil bath under N2 for 42 h. After being cooled to room temperature, the crude product was purified by silica gel column chromatography with 2:1 hexanes:CHCl3 as eluent. The reaction 128 afforded the product 4a as a yellow solid (60%, 0.0172 g, 0.0600 mmol); the optical purity was determined to be –17% ee as described in section 5.3.4. (the detailed analytical data for 4a are listed after procedure 4). 5.3.2. Procedure 2: Reaction with (S)-VAPOL hydrogen phosphate 23 Ph 25 mol% (S)-23 25 mol% (S)-VANOL POH 7 N H OH Ph NH CCl 4, 60 °C, 14 h O 3a 22a 23a 4a To a 20 mL flame dried Schlenk flask was added the catalyst (S)-VAPOL POH 74b (0.015 g, 0.025 mmol, 25 mol%), iminol 3a (0.0287g, 0.100 mmol, 1 equiv.) and 0.3 mL CCl4. The flask was sealed and heated in a 60 °C oil bath under N2 for 14 h. After being cooled to room temperature, the crude product was purified by flash silica gel column chromatography with CHCl3 as eluent. The reaction afforded the product 4a as a yellow solid (100%, 0.0287 g, 0.100 mmol), the optical purity was determined to be –8% ee as described in section 5.3.4 (the detailed analytical data for 4a are listed after procedure 4). 5.3.3. Procedure 3: Reaction with (R)-VANOL Al 27 Ph 3 mol% (S)-27 3 mol% (R)-VANOL Al 11 N H OH Ph NH toluene, 70 °C, 8 h O 22a 3a 23a 4a The catalyst (R)-VANOL Al 27 was prepared as follows. To a 10 mL flame dried round bottom flask was added (R)-VANOL (0.0219 g, 0.0500 mmol, 2 equiv) 129 and THF (2.5 mL) under a nitrogen atmosphere, and then the solution was stirred for 1 min to dissolve the ligand. Then LiAlH4 (0.0010g, 0.025 mmol, 1 equiv) was added as a solid in one portion. The resulting solution was stirred at room temperature for 10 min before being used in the rearrangement reaction. Note: this aluminum catalyst solution was unstable for storage; it is necessary to prepare fresh catalyst for each reaction. To a 20 mL flame dried Schlenk flask was added the catalyst solution 11 (0.3 mL, 0.003 mmol, 3 mol%), the solvent was carefully removed by high vacuum and then iminol 3a (0.0287 g, 0.100 mmol, 1 equiv.) and 0.3 mL toluene were added. The flask was sealed and heated in a 70 °C oil bath under N2 for 8 h. After being cooled to room temperature, the crude product was purified by silica gel column chromatography with 2:1 hexanes:CHCl3 as eluent. The reaction afforded the product 4a as a yellow solid (100%, 0.0287 g, 0.100 mmol), the optical purity was determined to be 68% ee as described in section 5.3.4 (the detailed analytical data for 4a are listed after procedure 4) Ligand Screen on Derivatives of Catalyst 27. All reactions below were carried out according to procedure 3 at 85 °C under N2 for 1h, with various VANOL ligands which have substituents at both the 7 and 7’ positions. All ligands 51 were synthesized according to a literature procedure. are listed in Scheme 3.5. 130 The experimental results 5.3.4. Procedure 4: General procedure for rearrangement with catalyst (R)-46 toluene rt, 30 min (R)-VANOL + N-methylimidazole + Zr (OiPr) 4(HOiPr) (R)-46 2:1:1 The (R)-VANOL Zr catalyst 46 was prepared as follows. (R)-VANOL (44 mg, 0.1 mmol, 2 equiv), Zr(OiPr)4(HOiPr) zirconium(IV) isopropoxide isopropanol complex (19 mg, 0.05 mmol, 1 equiv) and 1 mL toluene were mixed under air at room temperature in a 20 mL vial, then N-methylimidazole (4 µL, 0.05 mmol, 1 equiv.) was added via a syringe. Soon after addition of N-methylimidazole, a white solid precipitate started to form. The resulting slurry was stirred at room temperature under air for 30 min before being used in the following asymmetric catalytic rearrangement of α-iminols. This catalyst solution (R)-46 could be stored in toluene for extended periods, with no compromise to the yield or ee of the rearranged product (see Table 3.15). Ph 2.5 mol% (R)-46 N OH H R R toluene, 60 oC, 1 h Ph NH R R O 3 4 The rearrangement reaction was carried out with the following optimal conditions: To a 20 mL vial under air was added 0.25 mL toluene, appropriate α-iminol 3 (0.1 mmol, 1 equiv) and the Zr-VANOL complex catalyst solution (R)-46 (0.05 M in toluene, 50 µL, 2.5 x 10-3 mmol, 2.5 mol%, this white slurry was 131 vigorously swirled and agitated while being drawn by a syringe). The vial was then capped, placed in a 60 °C oil bath and stirred under air for 1 h. Upon completion, the solution was cooled to room temperature and the crude product purified by flash column chromatography on silica gel with 3:1 to 1:1 hexanes:CHCl3 as eluent. Unless otherwise specified, all the following substrates were synthesized via this procedure 4. (S)-1,2-diphenyl-2-(phenylamino)ethan-1-one (4a). Ph N OH H 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Ph NH O 3a (S)-4a This reaction was carried out with procedure 4 on 3a (0.0286 g, 0.100 mmol) and afforded the product (S)-4a as a yellow solid (94%, 0.0269 g, 0.0943 mmol); mp = 89-92 °C; the optical purity was determined to be 97% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 11.4 min for the minor peak and 18.9 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4a: 1H NMR (CDCl3, 500 MHz) δ 5.62 (br s, 1H), 6.04 (s, 1H), 6.70-6.72 (m, 3H), 7.14 (t, J = 8.0 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.42-7.46 (m, 4H), 7.52 (t, J = 7.5 Hz, 1H), 8.00 (dd, J = 7.5, 1.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 62.88, 113.72, 118.04, 128.11, 128.15, 128.66, 128.85, 129.04, 129.22, 133.49, 135.05, 137.56, 145.90, 196.97; [α]20D = 132 +132.1° (c = 1.0, CH2Cl2) on 97% ee. These NMR data are in agreement with the 76 literature data. (S)-2-(phenylamino)-1,2-di-o-tolylethan-1-one (4b). Ph N OH 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Ph NH O 3b (S)-4b Following procedure 4 with 3b (0.0317 g, 0.101 mmol) afforded the product (S)-4b (88%, 0.0279 g, 0.0886 mmol) as a light yellow liquid. The optical purity was determined to be 84% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 5.8 min for the minor peak and 9.5 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4b: 1 H NMR (CDCl3, 500 MHz) δ 2.09 (s, 3H), 2.24 (s, 3H), 5.40 (br s, 1H), 5.94 (s, 1H), 6.59 (dd, J = 8.5, 0.5 Hz, 2H), 6.69 (dt, J = 8.5, 0.5 Hz, 1H), 7.06 (dd, J = 5.0, 3.5 Hz, 1H), 7.11-7.15 (m, 5H), 7.19 (t, J = 7.5 Hz, 1H), 7.31 (td, J = 7.5, 1.0 Hz, 1H) 7.34-7.39 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 19.42, 19.57, 62.65, 113.27, 117.80, 125.28, 126.67, 126.99, 127.76, 128.17, 129.28, 130.92, 131.09, 131.23, 134.42, 136.59, 137.27, 137.64, 146.08, 201.35; IR (thin film) 3399s, 3053m, 2926m, 1695s, 1603s, 1504s, 1300m, 1248m, 748m cm-1; HRMS (ESI-TOF) m/z found 316.1702 [(M+H)+; calcd. 316.1701 for C22H22NO]; [α]20D = +81.8° (c = 1.0, CH2Cl2) on 84% ee. 133 (R)-1,2-bis(2-isopropylphenyl)-2-(phenylamino)ethan-1-one (4c). Ph N OH iPr iPr 2.5 mol% (S)- VANOL Zr 46 toluene, 60 °C, 1 h Ph NH O iPr 3c iPr (R)-4c The reaction was performed with procedure 4 with catalyst (S)-46 on a sample of 3c (0.0522 g that was a mixture of 2c:3c (aldehyde:imine) = 1:3.2 (0.0422 g, 0.114 mmol of 3c). The reaction afforded the product (R)-4c as a white semi-solid (95%, 0.0402 g, 0.108 mmol), the optical purity was determined to be 54% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 4.0 min for the major peak and 6.6 min for the minor peak; Rf=0.60 in CHCl3. Spectral data for (R)-4c: 1H NMR (CDCl3, 500 MHz) δ 0.50 (d, J = 7.0 Hz, 3H), 0.55 (d, J = 7.0 Hz, 3H), 1.17 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H), 2.56 (septet, J = 7.0 Hz, 1H), 3.24 (septet, J = 7.0 Hz, 1H), 5.50 (d, J = 5.0 Hz, 1H), 6.11 (d, J = 5.0 Hz, 1H), 6.60 (d, J = 7.5 Hz, 2H), 6.67 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 3H), 7.15-7.19 (m, 3H), 7.26 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 23.25, 23.49, 24.46, 24.52, 28.54, 29.79, 62.03, 113.28, 117.65, 125.24, 125.90, 126.30, 126.38, 127.34, 128.52, 129.18, 130.78, 132.39, 137.71, 145.91, 147.39, 147.58, 202.07 (one aromatic carbon was not located); IR (thin film) 3402br s, 2964s, 2928s, 2868s, 1695s, 1606s, 1506s, 1487m, 1319m, 1032m, 760m cm-1; HRMS (ESI-TOF) m/z found 372.2331 134 [(M+H)+; calcd. 372.2327 for C26H30NO]; [α]20D = –39.3° (c = 0.66, CH2Cl2) on 54% ee. (S)-2-(phenylamino)-1,2-di-m-tolylethan-1-one (4d). Ph N OH H 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Ph NH O 3d (S)-4d Following procedure 4 with 3d (0.0310 g, 0.0985 mmol), the reaction afforded the product (S)-4d as a light yellow liquid (96%, 0.0298 g, 0.0946 mmol). The optical purity was determined to be 97.5% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 7.8 min for the minor peak and 11.7 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4d: 1 H NMR (CDCl3, 500 MHz) δ 2.28 (s, 3H), 2.38 (s, 3H), 5.42 (br s, 1H), 5.99 (s, 1H), 6.68 (d, J = 7.5 Hz, 2H), 6.69 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.24-7.28 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 21.37, 21.45, 62.66, 113.48, 117.76, 125.45, 126.07, 128.46, 128.50, 128.82, 128.91, 129.22, 129.44, 134.32, 135.03, 137.65, 138.55, 138.80, 146.23, 197.31; IR (neat) 3399s, 3051m, 2922m, 1682s, 1603s, 1506s, 1267m, 1151m, 748m cm-1; HRMS (ESI-TOF) m/z found 316.1700 135 [(M+H)+; calcd. 316.1701 for C22H22NO]; [α]20D = +117.0° (c = 1.0, CH2Cl2) on 97.5% ee. (R)-1,2-bis(3-chlorophenyl)-2-(phenylamino)ethan-1-one (4e). Ph N OH H Cl 5 mol% (S)- VANOL Zr 46 toluene, 70 °C, 6 h, N 2 Ph NH Cl Cl O Cl 3e (R)-4e General procedure 4 was followed with 3e (0.0356 g, 0.1 mmol) with three exceptions: 1. 5 mol% (S)-46 catalyst was used, 2. The reaction was at 70 °C for 6 h under N2 atmosphere (reaction was done in a Schlenk flask under N2 because the product was not stable under heat in presence of air). 3. The purification was as follows: hexanes (5 mL) was added to precipitate the catalyst after the reaction mixture was cooled to room temperature, and then the solid was removed by filtering through filter paper. The filtrate was concentrated on rotary vaporization and the residue was subjected to column chromatography with 1:1 hexane:CHCl3. The reaction afforded the product (R)-4e (0.0327g, 0.092 mmol, 92%) as a yellow oil. The optical purity was determined to be 93% ee with Chiralcel OD-H column, 90:10 hexane:iPrOH, 1 mL/min, 245 nm, 8.2 min for the major peak and 21.0 min for the minor peak. Spectral data for (R)-4e: 1 H NMR (CDCl3, 500 MHz) δ 5.42 (br s, 1H), 5.95 (s, 1H), 6.67 (d, J = 7.5 Hz, 2H), 6.74 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 136 2H), 7.21-7.27 (m, 2H), 7.35 (dt, J = 7.5, 1.5 Hz, 1H), 7.40-7.44 (m, 2H), 7.53-7.55 (m, 1H), 7.86 (dt, J = 8.0, 1.5 Hz, 1H), 7.95 (t, J = 1.5 Hz, 1H); 13 C NMR (CDCl3, 125 MHz) δ 62.37, 113.53, 118.36, 126.34, 126.82, 128.03, 128.66, 128.93, 129.36, 130.10, 130.40, 133.75, 135.12, 135.26, 136.26, 139.40, 145.52, 195.35; IR (thin film) 3404 s, 1684s, 1603s, 1506s, 1419m, 1204m cm-1; HRMS (ESI-TOF) m/z found 356.0595 [(M+H)+; calcd. 356.0609 for C20H16ONCl2]. ]; [α]20D = –105.5° (c = 1.0, CH2Cl2) on 93% ee. (S)-2-(phenylamino)-1,2-di-p-tolylethan-1-one (4f) Ph N OH H 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Ph NH O (S)-4f 3f Following procedure 4 with 3f (0.0353 g, 0.112 mmol), the reaction afforded the product (S)-4f as a light yellow solid (92%, 0.0325 g, 0.103 mmol); mp = 96-98 °C. The optical purity was determined to be 98% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 8.4 min for the minor peak and 18.4 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4f: 1 H NMR (CDCl3, 500 MHz) δ 2.25 (s, 3H), 2.38 (s, 3H), 5.44 (s, 1H), 5.99 (s, 1H), 6.68 (d, J = 8.5 Hz, 2H), 6.69 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.13 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H); 137 13 C NMR (CDCl3, 125 MHz) δ 21.09, 21.69, 62.16, 113.47, 117.66, 127.98, 129.02, 129.19, 129.36, 129.73, 132.42, 134.87, 137.77, 144.44, 146.20, 196.58; IR (thin film) 3399s, 3049m, 2922m, 1678s, 1604s, 1506s, 1319m, 1261m, 1174m, 748m cm-1; HRMS (ESI-TOF) m/z found 316.1700 [(M+H)+; calcd. 316.1701 for C22H22NO]; [α]20D = +127.6° (c = 1.0, CH2Cl2) on 98% ee. (S)-1,2-bis(4-n-butylphenyl)-2-(phenylamino)ethan-1-one (4g). Ph N OH H n-Bu n-Bu Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h n-Bu NH n-Bu O (S)-4g 3g Following procedure 4 with 3g (0.0434 g, 0.109 mmol), the reaction afforded the product (S)-4g as a light yellow solid (95%, 0.0413 g, 0.104 mmol); mp = 75-77 °C. The optical purity was determined to be 99% ee by Chiralcel OD-H column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 5.5 min for the minor peak and 11.6 min for the major peak; Rf=0.60 in CHCl3; Spectral data for (S)-4g: 1H NMR (CDCl3, 500 MHz) δ 0.89 (t, J = 7.5 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 1.27-1.39 (m, 4H), 1.53 (q, J = 8.0 Hz, 2H), 1.60 (q, J = 8.0 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H), 5.38 (br s, 1H), 6.00 (s, 1H), 6.67-6.70 (m, 3H), 7.11 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.91, 13.93, 22.35, 22.40, 33.10, 33.37, 35.27, 35.71, 138 62.17, 113.44, 117.64, 127.96, 128.71, 128.89, 129.07, 129.20, 132.66, 135.03, 142.77, 146.32, 149.31, 196.67; IR (thin film) 3406s, 3051m, 2930s, 2858m, 1678s, 1604s, 1506s, 1317m, 1261m, 1174m, 748m cm-1; HRMS (ESI-TOF) m/z found 400.2640 [(M+H)+; calcd. 400.2640 for C28H34NO]; [α]20D = +126.0° (c = 1.3, CH2Cl2) on 99% ee. (S)-1,2-bis(4-isopropylphenyl)-2-(phenylamino)ethan-1-one (4h). Ph N OH H i-Pr i-Pr Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h i-Pr NH i-Pr O (S)-4h 3h Following procedure 4 with 3h (0.0409 g, 0.110 mmol), the reaction afforded the product (S)-4h as a light yellow solid (98%, 0.0401 g, 0.108 mmol); mp = 72-74 °C. The optical purity was determined to be 99% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 12.1 min for the minor peak and 20.5 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4h: 1 H NMR (CDCl3, 500 MHz) δ 1.18 (d, J = 6.5 Hz, 6H), 1.25 (d, J = 6.5 Hz, 6H), 2.83 (septet, J = 7.0 Hz, 1H), 2.94 (septet, J = 7.0 Hz, 1H), 5.44 (br s, 1H), 6.00 (s, 1H), 6.67-6.70 (m, 3H), 7.12-7.16 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 23.57, 23.58, 23.82, 33.69, 34.24, 62.15, 113.49, 117.71, 126.80, 127.16, 128.02, 128.88, 129.20, 132.80, 135.05, 146.26, 148.62, 155.07, 196.57 139 (one aliphatic carbon was not located); IR (thin film) 3406s, 3051m, 2961s, 2870m, 1676s, 1604s, 1506s, 1315m, 1176m, 748m cm-1; HRMS (ESI-TOF) m/z found 372.2327 [(M+H)+; calcd. 372.2327 for C26H30NO]. [α]20D = +107.9° (c = 1.0, CH2Cl2) on 99% ee. (S)-1,2-bis(4-cyclohexylphenyl)-2-(phenylamino)ethan-1-one (4i). Ph N OH H Cy Cy Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Cy NH Cy O (S)-4i 3i Following procedure 4 with 3i (0.0446 g, 0.0990 mmol), the reaction afforded the product (S)-4i as a light yellow solid (97%, 0.0433 g, 0.0960 mmol); mp = 170-171 °C. The optical purity was determined to be 94% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 12.6 min for the minor peak and 26.0 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4i: 1H NMR (CDCl3, 500 MHz) δ 1.18-1.43 (m, 10H), 1.69-1.85 (m, 10H), 2.38-2.42 (m, 1H), 2.50-2.54 (m, 1H), 5.38 (br s, 1H), 5.97 (s, 1H), 6.65-6.68 (m, 3H), 7.10-7.13 (m, 4H), 7.26 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 25.98, 26.07, 26.66, 26.80, 33.96, 34.24, 44.10, 44.65, 62.12, 113.44, 117.66, 127.5, 127.50, 127.96, 129.16, 129.18, 132.76, 135.03, 146.29, 147.85, 154.23, 196.59; IR (thin film) 3400 br s, 2924s, 2851s, 1672s, 1604s, 1508s, 1172m, 997m cm-1; HRMS 140 (ESI-TOF) m/z found 434.2863 [(M-H2O+H)+; calcd. 434.2848 for C32H36N]; [α]20D = +69.3° (c = 1.0, CH2Cl2) on 94% ee. (S)-1,2-bis(4-t-butylphenyl)-2-(phenylamino)ethan-1-one (4j). Ph N OH H t-Bu t-Bu Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h t-Bu NH t-Bu O (S)-4j 3j Following procedure 4 with 3j (0.0426 g, 0.106 mmol), this reaction afforded the product (S)-4j as a light yellow solid (100%, 0.0425 g, 0.106 mmol); mp = 151-153 °C. The optical purity was determined to be >99% ee by Chiralcel OD-H column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 7.6 min for the minor peak and 11.8 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4j: 1H NMR (CDCl3, 500 MHz) δ 1.26 (s, 9H), 1.33 (s, 9H), 5.30 (br s, 1H), 6.01 (s, 1H), 6.65-6.70 (m, 3H), 7.14 (td, J = 8.0, 2.0 Hz, 2H), 7.32 (dd, J = 8.0, 2.0 Hz, 2H), 7.40 (dd, J = 8.0, 2.0 Hz, 2H), 7.46 (dd, J = 8.0, 2.0 Hz, 2H), 8.00 (dd, J = 8.0, 2.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 31.02, 31.25, 34.50, 34.17, 61.98, 113.39, 117.63, 125.67, 126.03, 127.73, 128.95, 129.21, 132.41, 134.72, 146.39, 150.89, 157.31, 196.61; IR (thin film) 3408s, 2964s, 1678s, 1603s, 1506s, 1267m, 1109m, 748m cm-1; HRMS (ESI-TOF) m/z found 400.2643 [(M+H)+; calcd. 400.2640 for C28H34NO]; [α]20D = +92.9° (c = 1.0, CH2Cl2) on >99% ee. 141 (S)-1,2-di([1,1'-biphenyl]-4-yl)-2-(phenylamino)ethan-1-one (4k) Ph N OH H Ph Ph Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Ph NH Ph O (S)-4k 3k Following procedure 4 with 3k (0.0343 g, 0.0779 mmol), this reaction afforded the product (S)-4k as a yellow solid (100%, 0.0342 g, 0.0779 mmol); mp = 196-199 °C. The optical purity was determined to be >99% ee by (R, R)-WHELK-O1 column, 99:1 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 63.0 min for the major peak and 69.2 min for the minor peak; Rf=0.60 in CHCl3. Spectral data for (S)-4k: 1H NMR (CDCl3, 500 MHz) δ 5.48 (br s, 1H), 6.12 (s, 1H), 6.70-6.75 (m, 3H), 7.17 (td, J = 7.5, 1.0 Hz, 2H), 7.31 (tt, J = 7.5, 1.0 Hz, 1H), 7.38-7.42 (m, 3H), 7.46 (tt, J = 7.5, 1.0 Hz, 2H), 7.50-7.54 (m, 4H), 7.57 (dd, J = 6.5, 2.0 Hz, 2H), 7.61 (dd, J = 7.5, 1.0 Hz, 2H), 7.68 (dt, J = 8.5, 2.0 Hz, 2H), 8.14 (dt, J = 8.5, 2.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 62.32, 113.51, 117.89, 127.01, 127.25, 127.36, 127.43, 127.84, 128.40, 128.53, 128.73, 128.97, 129.29, 129.56, 133.58, 136.73, 139.56, 140.32, 140.98, 146.10, 146.29, 196.38; IR (thin film) 3393s, 3031m, 2931m, 1666s, 1603s, 1506s, 1311m, 1170m, 743m cm-1; HRMS (ESI-TOF) m/z found 440.2028 [(M+H)+; calcd. 440.2014 for C32H26NO]; [α]20D = –13.0° (c = 1.0, CH2Cl2) on >99% ee. 142 (S)-1,2-bis(4-methoxylphenyl)-2-(phenylamino)ethan-1-one (4l) Ph N OH H OMe MeO Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 0.5 h MeO NH OMe O (S)-4l 3l Procedure 4 was followed with 3l (0.0332 g, 0.0961 mmol), except that the eluent for chromatography was CHCl3 and the reaction was complete after 0.5 h. The reaction afforded the product (S)-4l as a light yellow solid (90%, 0.0300 g, 0.0865 mmol); mp = 96-97 °C. The optical purity was determined to be 98% ee by Chiralcel OD-H column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 16.9 min for the minor peak and 60.7 min for the major peak; Rf=0.10 in CHCl3. Spectral data for (S)-4l: 1H NMR (CDCl3, 500 MHz) δ 3.72 (s, 3H), 3.84 (s, 3H), 5.19 (br s, 1H), 5.94 (s, 1H), 6.65-6.69 (m, 3H), 6.81 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 55.18, 55.47, 61.50, 113.46, 113.88, 114.42, 115.23, 117.61, 127.77, 129.18, 130.07, 131.21, 146.25, 159.19, 163.73, 195.42; IR (thin film) 3399s, 2934w, 2837w, 1672s, 1603s, 1508s, 1257s, 1170s, 1030m, 750m cm-1; HRMS (ESI-TOF) m/z found 348.1594 [(M+H)+; calcd. 348.1600 for C22H22NO3]; [α]20D = +92.0° (c = 1.0, CH2Cl2) on 98% ee. 143 (R)-1,2-bis(4-fluorophenyl)-2-(phenylamino)ethan-1-one (4m) Ph N F F Ph 2.5 mol% (S)- VANOL Zr 46 toluene, 60 °C, 1 h OH NH O F 3m F (R)-4m Following procedure 4 with (S)-46 and 3m (0.0330 g, 0.102 mmol), this reaction afforded the product (R)-4m as a light yellow wax-like semi-solid (97%, 0.0320 g, 0.0991 mmol). The optical purity was determined to be >99% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 14.1 min for the major peak and 41.5 min for the minor peak; Rf=0.60 in CHCl3. Spectral data for (R)-4m: 1H NMR (CDCl3, 500 MHz) δ 5.31 (br s, 1H), 5.97 (s, 1H), 6.65 (dd, J = 8.5, 1.0 Hz , 2H), 6.71 (td, J = 8.5, 1.0 Hz , 1H) 6.98 (td, J = 8.5, 2.0 Hz , 2H), 7.10-7.16 (m, 4H), 7.42 (ddt, J = 8.5, 5.5, 2.0 Hz, 2H), 8.03 (ddt, J = 8.5, 5.5, 2.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 61.85, 113.49, 116.02 (d, J = 21.8 Hz) 116.11 (d, J = 21.8 Hz), 118.12, 129.29, 129.69 (d, J = 8.5 Hz), 131.46, 131.54, 133.36 (d, J = 8.5 Hz), 145.75, 162.38 (d, J = 246.3 Hz), 165.92 (d, J = 255.0 Hz), 195.29; 19 F NMR (CDCl3, 470 MHz) δ –103.54, –113.37; IR (thin film) 3402s, 1684s, 1601s, 1508s, 1263s, 1155m, 995m, 837m, 798m, 750m cm-1. HRMS (ESI-TOF) m/z found 324.1199 [(M+H)+; calcd. 324.1200 for C20H16NOF2]; [α]20D = –85.1° (c = 1.0, CH2Cl2) on >99% ee. 144 (R)-2-(phenylamino)-1,2-bis(4-(trifluoromethyl)phenyl)ethan-1-one (4n). Ph N OH H CF 3 F 3C Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 70 °C, 2.5 h, N 2 F 3C NH CF 3 O (S)-4n 3n It was found necessary to perform the reaction of this substrate under an inert atmosphere. To a flame-dried Schlenk flask was added 3n (0.0444 g, 0.104 mmol), catalyst (R)-46 (0.2 mL in toluene, 10 mol%) and 0.1 mL toluene. The flask was sealed and cooled in liquid N2 for 5 min, then, the flask was connected to vacuum for 5 min and then sealed again. The flask was allowed to warm up to room temperature, which completed one cycle. The mixture was treated to three freeze-pump-thaw cycles and after the final warming to room temperature, the flask was filled with N2 gas and sealed. The reaction mixture was heated in a 70 °C oil bath for 2.5 h, and then cooled to room temperature. The crude product was directly purified by silica gel column chromatography with 2:1 hexanes: CHCl3 as eluent. The reaction afforded the product (S)-4n as a yellow semi-solid (74%, 0.0329 g, 0.0773 mmol). The optical purity was determined to be 73% ee on a (R,R)-WHELK-O1 column, 99:1 Hexane:iPrOH, 0.5 mL/min flow rate, 245 nm, 26.7 min for the major peak and 29.0 min for the minor peak; Rf=0.85 in CHCl3. Spectral data for (S)-4n: 1H NMR (CDCl3, 500 MHz) δ 5.43 (br s, 1H), 6.08 (s, 1H), 6.65 (d, J = 7.5 Hz, 2H), 6.74 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 2H), 145 7.56 (s, 4H), 7.73 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 8.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 62.71, 113.48, 118.54, 123.28 (q, J = 271.2 Hz), 123.69 (q, J = 270.2 Hz), 125.94 (q, J = 3.7 Hz), 126.22 (q, J = 3.7 Hz), 128.13, 129.13, 129.41, 130.61 (q, J = 33.1 Hz), 135.07 (q, J = 32.8 Hz), 137.45, 141.14, 145.29, 195.60; 19 F NMR (CDCl3, 470 MHz) δ –63.30, –62.78; IR (thin film) 3402 br s, 3057m, 2928m, 1695s, 1604s, 1506s, 1325s, 1170s, 1128s, 1068s, 1018m cm-1; HRMS (ESI-TOF) m/z found 424.1136 [(M+H)+; calcd. 424.1136 for C22H16NOF6]; [α]20D = +15.2° (c = 1.0, CH2Cl2) on 73% ee. Ph F 3C CF 3 N O 4y 24n Note: Exclusion of air is a must for this substrate because the product is sensitive to air under heat. If the reaction was performed with procedure 4, under air, an 18% yield of by-product 4y was obtained as well as a 70% recovery of 3n. The desired product 4n was not observed. (R)-1,1'-((1-oxo-2-(phenylamino)ethane-1,2-diyl)bis(4,1-phenylene))bis(ethan -1-one) (4o). Ph N Ph 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 3 h OH H O 3o O NH O (S)-4o O 146 O The rearrangement of 3o (0.0444 g, 0.120 mmol) was carried out with procedure 4 with the exception that 1 mL toluene was used due to the low solubility of the substrate 3o, and the reaction time was 3 h. The product was purified by column chromatography on silica gel with 8:1 to 3:1 hexanes:EtOAc as eluent to afford the product (S)-4o as a yellow semi-solid (100%, 0.0444 g, 0.120 mmol). The optical purity was determined to be 97% ee by (R, R)-WHELK-O1 column, 70:30 Hexane:iPrOH, 2 mL/min flow rate, 254 nm, 24.2 min for the major peak and 31.5 min for the minor peak; Rf= 0.3 in 2:1 Hexanes:EtOAc. Spectral data for (S)-4o: 1 H NMR (CDCl3, 500 MHz) δ 2.52 (s, 3H), 2.62 (s, 3H), 5.54 (br s, 1H), 6.09 (s, 1H), 6.67 (d, J = 8.5 Hz, 2H), 6.72 (t, J = 8.5 Hz, 1H), 7.15 (t, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 26.60, 26.87, 62.99, 113.55, 118.38, 128.34, 128.58, 129.02, 129.15, 129.36, 136.91, 138.03, 140.55, 142.46, 145.41, 195.96, 197.12, 197.32; IR (thin film) 3395 br s, 3053m, 2924s, 2855m, 1684s, 1603s, 1506s, 1311m, 1265s cm-1. HRMS (ESI-TOF) m/z found 372.1603 [(M+H)+; calcd. 372.1600 for C24H22NO3]; [α]20D = +55.3° (c = 1.0, CH2Cl2) on 97% ee. 147 (S)-8-(phenylamino)tetradecan-7-one (4p). Ph N H n-hexyl OH 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h n-hexyl Ph NH n-hexyl n-hexyl O (S)-4p 3p Following procedure 4 with 3p (0.0333 g, 0.110 mmol), this reaction afforded the product (S)-4p as a colorless liquid (95%, 0.0317 g, 0.105 mmol). The optical purity was determined to be 89% ee by Chiralcel OD-H column, 99:1 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 5.3 min for the minor peak and 8.3 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4p: 1H NMR (CDCl3, 500 MHz) δ 0.86 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 6.5 Hz, 3H), 1.24-1.38 (m, 14H), 1.55 (q, J = 7.5 Hz, 2H), 1.61-1.67 (m, 1H), 1.80-1.87 (m, 1H), 2.48 (t, J = 7.5 Hz, 2H), 3.99 (t, J = 7.0 Hz, 1H), 4.34 (br s, 1H), 6.56 (dd, J = 8.5, 1.0 Hz, 2H), 6.70 (td, J = 7.5, 1.0 Hz, 1H), 7.16 (td, J = 8.5, 2.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.02, 22.47, 22.54, 23.42, 25.26, 28.86, 29.17, 31.56, 31.59, 32.05, 38.72, 62.88, 113.00, 117.75, 129.35, 146.99, 212.50 ( 1 aliphatic carbon was not located); IR (neat) 3397s, 3053w, 2955s, 2930s, 2858s, 1713s, 1603s, 1506s, 1317m, 748m cm-1; HRMS (ESI-TOF) m/z found 304.2642 [(M+H)+; calcd. 304.2640 for C20H34NO]; [α]20D = +19.4° (c = 1.0, CH2Cl2) on 89% ee. 148 (S)-1,4-diphenyl-3-(phenylamino)butan-2-one (4q). Ph N H Bn OH 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h Bn Ph NH Bn Bn O (S)-4q 3q Following procedure 4 with 3q (0.0330 g, 0.105 mmol), this reaction afforded the product (S)-4q as a yellow liquid (98%, 0.0324 g, 0.103 mmol). The optical purity was determined to be >99% ee by (R, R)-WHELK-O1 column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 13.3 min for the minor peak and 17.2 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4q: 1H NMR (CDCl3, 500 MHz) δ 3.01 (dd, J = 13.5, 7.0 Hz, 1H), 3.11 (dd, J = 13.5, 7.0 Hz, 1H), 3.66 (d, J = 16.0 Hz, 1H), 3.73 (d, J = 16.0 Hz, 1H), 4.24 (br s, 1H), 4.37 (t, J = 7.0 Hz, 1H), 6.51 (dd, J = 8.5, 1.0 Hz, 2H), 6.74 (tt, J = 7.5, 1.0 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 7.14-7.19 (m, 4H), 7.25-7.33 (m, 6H); 13 C NMR (CDCl3, 125 MHz) δ 38.09, 47.19, 63.04, 113.34, 118.35, 127.08, 128.62, 128.78, 129.21, 129.42, 129.50, 129.63, 133.34, 136.45, 146.28, 209.26; IR (neat) 3400br s, 3062m, 3028m, 2924m, 1716s, 1603s, 1500s, 1496s, 1437m, 1317m cm-1; HRMS (ESI-TOF) m/z found 316.1699 [(M+H)+; calcd. 316.1701 for C22H22NO]; [α]20D = +28.0° (c = 1.0, CH2Cl2) on >99% ee. 149 (S)-1,2-dicyclohexyl-2-(phenylamino)ethan-1-one (4r) Ph N OH H 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 2.5 h Cy Cy Ph NH Cy Cy O 3r (S)-4r Following procedure 4 with 3r (0.0308 g, 0.103 mmol), this reaction afforded the product (S)-4r as a white solid (97%, 0.0299 g, 0.100 mmol); mp = 76-78 °C. The optical purity was determined to be 98% ee by Chiralcel OD-H column, 99.5:0.5 Hexane:iPrOH, 0.5 mL/min flow rate, 245 nm, 11.7 min for the minor peak and 15.6 min for the major peak; Rf=0.60 in CHCl3. Spectral data for (S)-4r: 1 H NMR (CDCl3, 500 MHz) δ 1.08-1.28 (m, 11H), 1.64-1.77 (m, 10H), 2.53-2.59 (m, 1H), 3.99 (d, J = 5.0 Hz, 1H), 4.41 (br s, 1H), 6.61 (dd, J = 8.5, 1.0 Hz, 2H), 6.70 (td, J = 8.5, 1.0 Hz, 1H), 7.14 (td, J = 8.5, 1.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 25.36, 25.71, 25.90, 26.04, 26.15, 26.28, 27.74, 28.16, 29.21, 30.72, 40.66, 48.29, 66.77, 113.56, 117.68, 129.22, 148.05, 214.35; IR (thin film) 3395s, 2930s, 2855s, 1705s, 1603s, 1506s, 1450m, 1317m, 1255m, 748m cm-1; HRMS (ESI-TOF) m/z found 300.2332 [(M+H)+; calcd. 300.2327 for C20H30NO]; [α]20D = +33.8° (c = 1.0, CH2Cl2) on 98% ee. 150 (S)-2-((4-methoxyphenyl)amino)-1,2-diphenylethan-1-one (4s). MeO MeO N OH H 2.5 mol% (R)- VANOL Zr 46 toluene, 80 °C, 1 h NH O (S)-4s 3s The rearrangement of 3s (0.0317 g, 0.10 mmol) was carried out following procedure 4 except that the reaction temperature was at 80 °C, and the eluent for column chromatography was 8:1 to 4:1 hexanes:EtOAc. The reaction afforded the product (S)-4s as a yellow solid (98%, 0.0311 g, 0.098 mmol). mp = 90-94 °C. The optical purity was determined to be 98% ee by (R, R)-WHELK-O1 column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 23.7 min for the major peak and 27.1 min for the minor peak; Rf=0.10 in CHCl3. Spectral data for (S)-4s: 1H NMR (CDCl3, 500 MHz) δ 3.71 (s, 3H), 5.14 (br s, 1H), 5.99 (s, 1H), 6.65 (dt, J = 9.0, 2.5 Hz, 2H), 6.74 (dt, J = 9.0, 2.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 8.0 Hz, 4H), 7.54 (t, J = 7.5 Hz, 1H), 8.00 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 55.70, 63.77, 114.84, 115.03, 128.08, 128.12, 128.67, 128.83, 129.06, 133.47, 135.15, 137.85, 140.36, 152.36, 197.45; IR (thin film) 3397br s, 3062m, 2932m, 2833m, 1684s, 1514s, 1238s, 1176m, 1035m, 819m cm-1. HRMS (ESI-TOF) m/z found 318.1507 [(M+H)+; calcd. 318.1494 for C21H20NO2]; [α]20D = +151.1° (c = 1.0, CH2Cl2) on 98% ee. 151 A second run on much larger scale (45x) was carried out under air at 80 °C for 2 h, with 1.5 mol% (S)-46 in 14 mL toluene on a 1.42 gram scale (4.48 mmol) and produced the product (R)-4s as a yellow solid (1.22 g, 3.81 mmol, 85% yield); mp = 93-95 °C. The optical purity was determined to be 98% ee; [α]20D = –130.7° (c = 1.0, CH2Cl2) on 98% ee. A 7% yield of byproduct 2-((4-methoxyphenyl)imino)-1,2-diphenylethan-1-one was also isolated. H 3CO N O A third run on 41 times larger scale was carried out under N2 atmosphere at 80 °C for 6 h, with 1 mol% (R)-46 on a 1.30 gram scale (4.10 mmol) and produced the product (S)-4s as a yellow solid (1.22 g, 3.85 mmol, 94% yield) and the optical purity was determined to be 95% ee. Notes: 1) A 7% yield of 2-((4-methoxyphenyl)imino)-1,2-diphenylethan-1-one was observed in this reaction as a by-product when air was present. 2) The product 4s epimerized partially when it was left on the silica gel column over night: the ee dropped from 98% to 82%. 3) Recrystallization from 20:1 hexanes:EtOAc improved the ee from 95% to >99% with 82% recovery. 152 (S)-1,2-dicyclohexyl-2-((4-methoxyphenyl)amino)ethan-1-one (4t). MeO MeO N H Cy OH 2.5 mol% (R)- VANOL Zr 46 toluene, 80 °C, 2 h Cy NH Cy Cy O (S)-4t 3t The rearrangement of 3t (0.0510 g, 0.154 mmol) was carried out with procedure 4 with the exception that the reaction temperature was 80 °C. After 2 h, the reaction afforded the product (S)-4t as a pale yellow solid (97%, 0.0495 g, 0.150 mmol); mp = 103-106 °C. The optical purity was determined to be 94% ee by Chiralcel OD-H column, 99:1 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 3.8 min for the minor peak and 4.2 min for the major peak; Rf=0.10 in CHCl3. Spectral data for (S)-4t: 1H NMR (CDCl3, 500 MHz) δ 1.07-1.43 (m, 11H), 1.57-1.76 (m, 10H), 2.53 (tt, J = 11.0, 3.5 Hz, 1H), 3.72 (s, 3H), 3.85 (d, J = 5.0 Hz, 1H), 4.11 (br s, 1H), 6.57 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 25.35, 25.71, 25.90, 26.07, 26.17, 26.31, 27.68, 28.15, 29.08, 30.77, 40.54, 48.30, 55.70, 68.52, 114.74, 115.37, 142.39, 152.32, 215.02. IR (thin film) 3391br m, 2930s, 2855s, 1705s, 1512s, 1450m, 1238s, 1039m cm-1. HRMS (ESI-TOF) m/z found 330.2436 [(M+H)+; calcd. 330.2433 for C21H32NO2]; [α]20D = +30.0° (c = 1.0, CH2Cl2) on 94% ee. 153 ethyl (R)-4-((2-oxo-1,2-diphenylethyl)amino)benzoate (4u). EtO 2C EtO 2C N OH H 2.5 mol% (S)- VANOL Zr 46 toluene, 60 °C, 0.5 h NH O (R)-4u 3u Following procedure 4 with (S)-46 and the imine 3u (0.0448 g, 0.125 mmol) this reaction was complete in 30 min and afforded the product (R)-4u as a white solid (88%, 0.0394 g, 0.110 mmol); mp = 145-147 °C. The optical purity was determined to be 96% ee by Chiralcel OD-H column, 90:10 Hexane:iPrOH, 1 mL/min flow rate, 287 nm, 9.1 min for the minor peak and 31.3 min for the major peak. Spectral data for (R)-4u: 1H NMR (CDCl3, 500 MHz) δ 1.34 (t, J = 7.0 Hz, 3H), 4.30 (q, J = 7.0 Hz, 2H), 5.92 (br s, 1H), 6.08 (s, 1H), 6.65 (dt, J = 9.0, 2.5 Hz, 2H), 7.22 (tt, J = 7.5, 2.0 Hz, 1H), 7.30 (tt, J = 7.5, 2.0 Hz, 2H), 7.46 (t, J = 7.5 Hz, 4H), 7.56 (tt, J = 7.5, 2.0 Hz, 1H), 7.84 (dt, J = 8.5, 2.0 Hz, 2H), 8.02 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 14.43, 60.21, 61.96, 112.35, 119.33, 128.07, 128.36, 128.76, 128.93, 129.19, 131.43, 133.79, 134.57, 136.88, 149.53, 166.70, 196.02; IR (thin film) 3393br s, 3066m, 2926s, 1686s, 1606s, 1525s, 1448m, 1278s, 1174s, 1105s cm-1; HRMS (ESI-TOF) m/z found 360.1606 [(M+H)+; calcd. 360.1600 for C23H22NO3]; [α]20D = –137.5° (c = 1.0, CH2Cl2) on 96% ee. 154 (S)-2-((3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-1,2-diphenyleth an-1-one (4v). TBSO N OH H 2.5 mol% (R)- VANOL Zr 46 toluene, 60 °C, 1 h TBSO NH O 7 3v (S)-4v Following procedure 4 with iminol 7 (0.0470 g, 0.1 mmol), this reaction afforded the product (S)-4v as a pale yellow liquid (91%, 0.0430 g, 0.09 mmol). The optical purity was determined to be 97% ee by (R, R)-WHELK-O1 column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 9.0 min for the major peak and 10.5 min for the minor peak. Spectral data for (S)-4v: 1 H NMR (CDCl3, 500 MHz) δ 0.07 (s, 6H), 0.94 (s, 9H), 4.64 (s, 2H), 5.42 (d, J = 6.0 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.18-7.19 (m, 1H), 7.20-7.29 (m, 3H), 7.42-7.46 (m, 3H), 7.54 (t, J = 8.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 5.23, 18.45, 26.01, 62.68, 64.99, 111.03, 112.09, 115.55, 128.05, 128.09, 128.67, 128.87, 129.02, 129.04, 133.49, 135.06, 137.74, 142.58, 146.18, 197.10; IR (neat) 3404s, 3061m, 2955s, 2928s, 2858s, 1688s, 1608s, 1491s, 1323m, 1253s, 1178m, 1101s, 1076s cm-1; HRMS (ESI-TOF) m/z found 432.2362 [(M+H)+; calcd. 432.2359 for C27H34NO2Si]; [α]20D = +90.8° (c = 1.0, CH2Cl2) on 97% ee. 155 (S)-2-(benzylamino)-1,2-diphenylethan-1-one (4w) Bn N OH H 2.5 mol% (S)- VANOL Zr 46 toluene, 120 °C, 2 h, N 2 Bn NH O 3w (R)-4w The rearrangement of 3w (0.0300 g, 0.100 mmol) was performed following general procedure 4 with two exceptions: 1. The reaction conditions were 120 °C for 2 h under N2 atmosphere (reaction was done in a Schlenk flask because the product was not stable at 120 °C in presence of air). 2. The workup and purification was as follows: hexanes (5 mL) was added to precipitate the catalyst after the reaction mixture was cooled to room temperature, and then the solid was removed by filtering through filter paper. The filtrate was concentrated by rotary vaporization and the residue was subjected to column chromatography with 8:1 to 4:1 hexane:EtOAc. The reaction afforded the product (R)-4w (0.0285 g, 0.095 mmol, 95%) as a white semi-solid. The optical purity was determined to be 10% ee with (R, R) WHELK-O1 column, 95:5 hexane:iPrOH, 1 mL/min, 245 nm, 16.2 min for the major peak and 18.0 min for the minor peak. Spectral data for (R)-4w: 1 H NMR (CDCl3, 500 MHz) δ 2.74 (br s, 1H), 3.76 (s, 2H), 5.31 (s, 1H), 7.26-7.28 (m, 2H), 7.32-7.39 (m, 10H), 7.49 (tt, J = 7.5, 1.5 Hz, 1H), 7.90 (dd, J = 8.0, 1.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 51.01, 66.23, 127.07, 127.98, 128.24, 128.38, 128.42, 128.53, 128.69, 129.04, 133.16, 156 135.68, 138.24, 139.73, 198.92. [α]20D = –2.5° (c = 1.0, CH2Cl2) on 10% ee. 77 These NMR data are in partial agreement with literature. Note: No rearrangement of 3w was observed at 80 °C after 19 h. The 1 H NMR spectrum of the crude reaction mixture showed only the presence of the starting imine 3w and the presence of aldehyde 2a resulting from partial hydrolysis of 3w. The presence of (R)-4w was detected. 5.3.5. Procedure for the a-Iminol rearrangement of in-situ generated Imines. O NH 2 OH H Ph 2.5 mol% (S)- VANOL Zr 46 toluene, 60 °C, 1 h + t-Bu t-Bu 2j t-Bu 1.1 equiv. NH t-Bu O (R)-4j To a 20 mL vial was added aldehyde 2j (0.0332 g, 0.102 mmol, 1 equiv), toluene 0.25 mL, (S)-46 catalyst solution (0.5 mL) prepared in section 4 and aniline (10 µL, 0.11 mmol, 1.1 equiv). The vial was capped and heated under air in a 60 °C oil bath for 1 h. Thereafter, the solution was cooled to room temperature and subjected to column chromatography on silica gel with 2:1 CHCl3:hexanes as eluent. The reaction afforded the product (R)-4j as a light yellow solid (0.0400 g, 0.100 mmol, 98% yield). mp = 132-135 °C; The optical purity was determined to be >99%. The Chiral HPCL conditions were identical to that described in section 5 for (S)-4j; 1H NMR and 13C NMR data were identical to that described in section 5 for (S)-4j; [α]20D = –84.0° (c = 1.0, CH2Cl2). 157 5.3.6. Determination of the stereochemistry of the product 4a. Methyl-(R)-2-phenyl-2-(phenylamino)acetate (40) NH 3Cl Ph Na 2CO 3 1.5 equiv CO2Me 2 equiv PhB(OH) 2 10 mol % Cu(OAc)2•H 2O H 2O 4 Å MS, CH2Cl2 reflux, air (R)-phenylclycine methyl ester hydrochloride NHPh Ph CO2Me (R)-31 (R)-40 To a 20 mL vial was added (R)-2-phenylglycine methyl ester hydrochloride (2.01 g, 10.0 mmol, 1 equiv) and Na2CO3 solution (2M, 7.5 mL, 15 mmol, 1.5 equiv) and 5 mL ether. The resulting mixture was stirred at room temperature for 10 min. The aqueous layer was extracted with EtOAc (5 mL x 3), and the combined organic layer was washed with brine, dried over MgSO4, filtered through filter paper in a Büchner funnel and concentrated under rotary evaporation. The crude amino ester was used in the next step without purification. To a three-necked round bottom flask equipped with a condenser was added copper(II) acetate monohydrate (0.11 g, 0.5 mmol, 10 mol%), 4 Å molecular sieves (3.05 g), PhB(OH)2 (1.28 g, 10 mmol, 2 equiv.), and 40 mL CH2Cl2. The resulting mixture was stirred at room temperature for 5 min and then the crude amino ester (0.85 g, 5 mmol, 1 equiv.) was added. The two open necks were sealed by septa. A gentle air flow was introduced via a needle attached to one of the septa. The mixture was heated to reflux for 14h, then cooled to room temperature, filtered through filter paper in Büchner funnel. 158 The filtrate was concentrated under rotary evaporation. The product was purified by column chromatography on silica gel with 10:1 hexanes:EtOAc as eluent. The reaction afforded the product (R)-40 as a white solid (23%, 0.29 g, 2.3 mmol); mp = 51-52 °C; Rf=0.45 in 4:1 hexanes:EtOAc. Spectral data for (R)-40: 1H NMR (CDCl3, 500 MHz) δ 3.73 (s, 3H), 5.08 (s, 1H), 5.39 (br s, 1H), 6.59 (d, J = 7.5 Hz, 2H), 6.72 (t, J = 7.5 Hz, 1H), 7.12 (tt, J = 7.5, 2.0 Hz, 2H), 7.30 (tt, J = 7.5, 2.0 Hz, 1H), 7.35 (tt, J = 7.5, 2.0 Hz, 2H), 7.49 (dt, J = 7.5, 2.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 52.85, 60.74, 113.42, 118.14, 127.26, 128.33, 128.89, 129.25, 137.57, 145.87, 172.31; [α]20D = –93.8° 78 (c = 1.0, CHCl3), [lit. –20.2° (c = 1.0, CHCl3) on 30% ee, and lit.9 +68.3° (c = 0.32, THF) on 98% ee for the (S)-enantiomer]. The 1H NMR data are in 78 agreement with the literature data. (R)-N-Methoxy-N-methyl-2-phenyl-2-(phenylamino)acetamide (41) Me + OMe N H 2 Cl – 2.5 equiv NHPh Ph CO2Me (R)-40 (R)-31 To a 10 mL PhHN Me N OMe Ph 5 equiv i-PrMgCl –45 °C, 1 h, THF flame-dried round O (R)-32 (R)-41 bottom flask was added N,O-dimethylhydroxylamine hydrochloride (0.10 g, 1.04 mmol, 2.5 equiv) and 2 mL THF at –45 °C in an acetonitrile dry ice bath for 5 min under a N2 atmosphere. Then iPrMgCl (2M in THF, 1.04 mL, 2.08 mmol, 5 equiv) was added dropwise and 159 stirred at the same temperature for 10 min. Then methyl (R)-2-phenyl-2-(phenylamino)acetate 40 (0.10 g in 1 mL THF, 0.41 mmol, 1 equiv) was added dropwise via a syringe. The resulting mixture was kept at –45 °C for another 1 h before being quenched with saturated NH4Cl solution. The solution was warmed up to room temperature, and extracted with EtOAc (5 mL x 3), dried over MgSO4, filtered through filter paper in Büchner funnel and concentrated via rotary evaporation. The product was purified by column chromatography on silica gel with 4:1 to 2:1 hexanes:EtOAc as eluent. The reaction afforded the product (R)-41 as a yellow liquid (64%, 0.0722 g, 0.262 mmol); Rf=0.05 in 4:1 hexanes:EtOAc. Spectral data for (R)-41: 1 H NMR (CDCl3, 500 MHz) δ 3.21 (s, 3H), 3.52 (s, 3H), 5.33 (br s, 1H), 5.51 (s, 1H), 6.66-6.71 (m, 3H), 7.13 (tt, J = 7.5, 2.0 Hz, 2H), 7.28 (tt, J = 7.5, 2.0 Hz, 1H), 7.35 (tt, J = 7.5, 2.0 Hz, 2H), 7.49 (dt, J = 7.5, 2.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 32.49, 57.73, 61.19, 113.64, 117.91, 127.92, 127.99, 128.71, 129.19, 138.40, 146.15 (the amide carbon was not located); [α]20D = –151.8° (c = 0.71, CH2Cl2). These NMR data are in agreement 79 with the literature data. 160 (R)-1,2-diphenyl-2-(phenylamino)ethan-1-one (4a) PhHN Me N OMe Ph O (R)-32 (R)-41 PhMgCl 3 equiv PhHN Ph Ph THF 0 °C, 15 min O (R)-23a (R)-4a To a 10 mL flame-dried round bottom flask was added the Weinreb amide (R)-41 prepared above (0.0581 g, 0.21 mmol, 1 equiv) and 1 mL THF. The resulting solution was cooled to 0 °C for 5 min in an ice bath and then PhMgCl (2M in THF, 0.31 mL, 0.63 mmol, 3 equiv.) was added dropwise via a syringe. The resulting mixture was kept at 0 °C for 15 min before being quenched with saturated NH4Cl solution. The solution was warmed up to room temperature, and extracted with EtOAc (5 mL x 3), dried over MgSO4, filtered through filter paper in Büchner funnel and concentrated under rotary evaporation. The crude product was purified by column chromatography on silica gel with 1:1 hexanes:CHCl3 as eluent. The reaction afforded the product (R)-4a as a yellow solid (65%, 0.0402 g, 0.137 mmol); mp = 76-81 °C. The 1H and 13 C NMR data were identical to the product (S)-4a from the rearrangement reaction of 3a in section 5.4. The optical purity was determined to be 90% ee by Chiralcel OD-H column, 97:3 Hexane:iPrOH, 1 mL/min flow rate, 245 nm, 11.4 min for the major peak and 18.9 min for the minor peak; [α]20D = –116.8° (c = 1.0, CH2Cl2) on 90% ee. The configuration of this compound is opposite to that of the product 4a obtained from the rearrangement using catalyst (R)-46. 161 5.3.7. Synthesis of amino alcohols from amino ketones. (1S,2R)-2-((4-methoxyphenyl)amino-1,2-diphenylethan-1-ol (50) H 3CO H 3CO NH Super-H 2 equiv NH THF, –78 °C, 15 min O (S)-23s (S)-4s 95% ee 95% ee 80% yield 92% ee >50:1 anti:syn OH (1S,2R )-25 (1S,2R)-50 ee improved to >99% by crystallization with 87% recovery To a 10 mL flame-dried round bottom flask was added the amino ketone (S)-4s (0.0756 g, 0.24 mmol, 1 equiv, 95% ee) and 2 mL THF. The solution was cooled to –78 °C in dry ice/acetone bath for 5 min under a N2 atmosphere and lithium triethylborohydride (0.48 mL, 1M in THF, 0.48 mmol, 2 equiv.) was added dropwise via a syringe. The resulting mixture was kept at –78 °C for 15 min before being quenched with saturated NH4Cl solution. The solution was then gradually warmed up to room temperature and extracted with ether (5 mL x 3), dried over MgSO4, filtered through filter paper in Büchner funnel and concentrated under rotary evaporation. The anti:syn ratio was greater than 50:1 by 1H NMR analysis of the crude reaction mixture. The product was purified by flash column chromatography on silica gel with 8:1 to 4:1 hexanes:EtOAc as eluent to afford the product 50 as a light yellow solid (80%, 0.0605 g, 0.19 mmol); mp = 80 115-116 °C (lit 121-124 °C). The optical purity was determined to be 92% ee by Chiralcel OD-H column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 220 nm, 19.3 min for the minor peak and 23.7 min for the major peak. 162 Spectral data for (1S,2R)-50 1 H NMR (CDCl3, 500 MHz) δ 2.51 (br s, 1H), 3.68 (s, 3H), 4.24 (br s, 1H), 4.61 (d, J = 4.5 Hz, 1H), 5.05 (d, J = 4.5 Hz, 1H), 6.50 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 7.09-7.11 (m, 2H), 7.14-7.15 (m, 2H), 7.24-7.29 (m, 6H); 13 C NMR (CDCl3, 125 MHz) δ 55.65, 64.65, 77.10, 114.67, 115.50, 126.58, 127.57, 127.90, 127.94, 128.19, 128.28, 138.67, 140.00, 140.71, 80 152.43; [α]20D = +50.7° (c = 1.0, CHCl3) on 90% ee, [lit +27.9°, c = 1.0, CHCl3, 80 on 93% ee]. The NMR data are in agreement with those in the literature. Note: The ee can be improved to >99% by crystallization from 10:1 hexanes:EtOAc with 87% recovery. Dissolution of 0.060 g product 50 (92% ee) in 1 mL EtOAc was followed by addition of 10 mL hexanes. The clear solution was cooled in freezer at –20 °C for 1h. The white crystals were collected to give 0.052 g of 50 (87% recovery) that was >99% ee. (S)-2-((4-methoxyphenyl)amino)-1,1,2-triphenylethan-1-ol (52) H 3CO H 3CO NH PhMgCl 3 equiv NH THF, 0 °C, 15 min O (S)-23s (S)-4s 95% ee 95% ee 76% yield 93% ee HO (S)-26 (S)-52 ee improved to >99% by crystallization with 82% recovery To a flame-dried 25 mL round bottom flask was added the amino ketone (S)-4s (0.0217 g, 0.068 mmol, 1 equiv, 95% ee) and 2 mL THF. The flask was sealed by a septum and a N2 balloon was attached via a needle. The flask was 163 cooled to 0 °C in an ice bath for 5 min. PhMgCl (2M in THF, 0.1 mL, 0.2 mmol, 3 equiv.) was added dropwise via a syringe. The resulting mixture was kept at 0 °C for 15 min then quenched with 3 mL of saturated NH4Cl solution. The mixture was warmed up to room temperature, extracted with ether (4 mL x 2), dried over MgSO4, filtered through filter paper in Büchner funnel and concentrated under rotary evaporation. The product was purified by column chromatography on silica gel with 16:1 to 10:1 hexanes:EtOAc as eluent to afford the product 52 as a white solid (76%, 0.0206 g, 0.0517 mmol); mp = 181-183 °C (lit.12 175-176 °C). The optical purity was determined to be 93% ee by Chiralcel OD-H column, 99:1 Hexane:iPrOH, 1 mL/min flow rate, 220 nm, 10.0 min for the minor peak and 31.2 min for the major peak. Spectral data for (S)-52: 1 H NMR (CDCl3, 500 MHz) δ 2.82 (s, 1H), 3.67 (s, 3H), 4.36 (br s, 1H), 5.21 (s, 1H), 6.39 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 7.08-7.19 (m, 7H), 7.27 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 55.63, 65.07, 81.15, 114.68, 114.70, 125.90, 126.81, 126.91, 127.34, 127.39, 127.77, 127.91, 128.38, 128.72, 138.12, 140.85, 143.96, 144.72, 152.00; [α]20D = +196.1° (c = 1.0, CH2Cl2) on 93% ee. The NMR data are in agreement with those reported for the 81 racemic compound. Note: The ee can be improved to >99% by crystallization from 10:1 hexanes:EtOAc with 82% recovery. A sample of 52 (0.0400 g, 93% ee) was 164 dissolved in 1 mL EtOAc followed by addition of 10 mL hexanes. The clear solution was cooled in freezer at –20 °C for 1 h. White crystals were collected to give 0.0328 g of 52 that was 82% recovery and >99% ee. (S)-N-(4-methoxyphenyl)-N-(2-oxo-1,2-diphenylethyl)acetamide (51) H 3CO H 3CO NH 1.5 equiv AcCl N Ac THF, 25 °C, 0.5 h O O (S)-4s (S)-23s Acylated (S)-33 4s 95% ee To a flame-dried 25 mL round bottom flask was added the amino ketone (S)-4s (0.20 g, 0.64 mmol, 1 equiv, 95% ee) and 10 mL THF. The flask was sealed by a septum and a N2 balloon was attached via a needle. Acetyl chloride (65 µL, 0.95 mmol, 1.5 equiv.) was added dropwise via a syringe. The mixture was stirred at room temperature for 30 min and then quenched with 3 mL saturated Na2CO3 solution. The aqueous layer was extracted with ether (5 mL x 2), and the combined organic layer was dried over MgSO4, filtered through filter paper in Büchner funnel and concentrated by rotary evaporation. The product was purified by flash column chromatography on silica gel with 4:1 to 2:1 hexanes:EtOAc as eluent to afford the acylated 4s product as a pale light yellow solid (75%, 0.17 g, 0.48 mmol); Rf = 0.05 in 4:1 hexanes:EtOAc; 123-125 °C. 165 mp = Spectral data for acylated 4s: 1 H NMR (CDCl3, 500 MHz) δ 1.89 (s, 3H), 3.73 (s, 3H), 6.66 (br s, 3H), 7.01-7.03 (m, 2H), 7.10-7.13 (m, 3H), 7.18 (s, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.94 (d, J = 7.5 Hz, 2H) (1 proton was not located); 13 C NMR (CDCl3, 125 MHz) δ 23.14, 55.28, 66.31, 113.67, 128.30, 128.43, 128.63, 128.84, 130.79, 131.84, 132.82, 132.91, 133.73, 135.57, 158.71, 171.39, 196.35; IR (thin film) 3063m, 2932m, 1695s, 1653s, 1516s, 1383m, 1248s, 1032m cm-1; HRMS (ESI-TOF) m/z found 360.1510 [(M+H)+; calcd. 360.1600 for C23H22NO3]; [α]20D = +169.6° (c = 1.0, CH2Cl2). (1S,2S)-2-((4-methoxyphenyl)amino)-1,2-diphenylethan-1-ol (51) H 3CO H 3CO N Ac Super-H 2 equiv O THF, 0 °C, 30 min KOH 3 equiv MeOH, 65 °C 30 min NH OH (1S,2S )-27 (1S, 2S)-51 70% yield 92% ee >50:1 syn:anti (S)-33 Acylated 4s To a flame-dried 10 mL round bottom flask was added the acylated amino ketone (0.17g, 0.47 mmol, 1 equiv) prepared above and 5 mL THF. The solution was cooled in an ice bath for 5 min under a N2 atmosphere and lithium triethylborohydride (1.9 mL, 1M in THF, 1.90 mmol, 4 equiv) was added dropwise via a syringe. The resulting mixture was stirred in an ice bath for 30 min before being quenched with 4 mL saturated NH4Cl solution. The solution was then gradually warmed up to room temperature, and extracted with ether (5 mL x 3), 166 dried over MgSO4, filtered through filter paper in a Büchner funnel and concentrated under rotary evaporation. The product was subjected to the next step without purification. The crude product was transferred to a 25 mL Schlenk flask with 5 mL MeOH and KOH (0.078 g, 1.4 mmol, 3 equiv) was added. The flask was sealed and heated in a 65 °C oil bath for 30 min. Thereafter the solution was cooled to room temperature, which was followed by addition of 5 mL water. The mixture was extracted with ether (5 mL x 3). The syn:anti ratio was greater than 50:1 by 1H NMR analysis of the crude reaction mixture. The combined ether layer was washed with brine and dried over MgSO4, filtered through filter paper in a Büchner funnel and concentrated with rotary evaporation. The product was purified by silica gel column chromatography with 4:1 hexane:EtOAc as eluent to afford the product (1S,2S)-51 as a white solid (70% over two steps, 0.10 g, 0.32 mmol). The optical purity was determined to be 92% ee by Chiralcel OD-H column, 95:5 Hexane:iPrOH, 1 mL/min flow rate, 220 nm, 18.7 min for the major peak and 22.6 min for the minor peak. Spectral data for (1S,2S)-51: 1 H NMR (CDCl3, 500 MHz) δ 2.90 (br s, 1H), 3.69 (s, 3H), 4.23 (br s, 1H), 4.42 (d, J = 7.0 Hz, 1H), 4.82 (d, J = 6.5 Hz, 1H), 6.53 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 7.17-7.18 (m, 2H), 7.22-7.28 (m, 8H); 13 C NMR (CDCl3, 125 MHz) δ 55.70, 66.17, 78.13, 114.64, 115.75, 126.70, 127.35, 127.46, 127.83, 128.17, 128.47, 140.21, 140.58, 141.30, 152.49; [α]20D = –35.5° (c = 0.9, CH2Cl2) on 92% ee (lit13 +30.7 (c=1, CHCl3) on 78% ee 167 (1R,2R)-51). The NMR data are in agreement with those reported in the 82 literature. Note: The ee can be improved to >99% by crystallization from 15:1 hexanes:EtOAc with 92% recovery. A sample of product 51 (92% ee, 0.10 g) was dissolved in 1 mL EtOAc and this was followed by addition of 15 mL hexanes. The clear solution was cooled in freezer at –20 °C for 1 h. White crystals were collected to give 0.092 g 51 that was a 92% recovery and >99% ee. 5.3.8. Attempt in iminol rearrangement with ketimine ethyl 2,2-diethoxypropanoate (57) O H 3C CO2Et 56 2.5 equiv. CH(OEt) 3 H 2SO 4, rt, 3 h EtO H 3C OEt CO2Et 57 100% To a clean and dry 20 mL round bottom flask was added ethyl pyruvate 56 (1.00 g, 8.61 mmol, 1 equiv.) and triethyl orthoformate (3.20 g, 21.5 mmol, 2.5 equiv.). The flask was sealed with a septum with a N2 balloon attached via a needle. To this stirring solution was added sulfuric acid (0.2 mL) dropwise. The resulting mixture was stirred at room temperature for 3 h and then diluted with 20 mL CH2Cl2. The reaction solution was successively washed with saturated Na2CO3 and brine, and dried over MgSO4, filtered through a filter paper and concentrated on rotary vaporization. The residue was exposed to high vacuum in 168 60 °C oil bath for 30 min to remove the diethyl sulfate and no more further purification was performed. The reaction afforded the product 57 (1.64 g, 8.61 mmol, 100%) as a colorless oil. Spectral data for 57: 1H NMR (CDCl3, 500 MHz) δ 1.23 (t, J = 7.0 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.53 (s, 3H), 3.44-3.51 (m, 2H), 2.55-3.61 (m, 2H), 4.25 (q, J = 7.0 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.16, 15.21, 21.99, 57.93, 61.45, 83 99.57, 170.08. These NMR data are in agreement with the literature data. 1-hydroxy-1,1-diphenylpropan-2-one (58) EtO H 3C OEt CO2Et 5% HCl acetone 70 °C, 1 h 2.5 equiv. PhMgCl O OH H 3C THF, rt, 30 min 85% 57 58 The synthesis of 58 is identical to that of compound 2. The reaction afforded 58 (0.97 g, 4.3 mmol, 85%) as a light yellow oil, which solidified in the freezer. mp. = 61-63 °C. Spectral data for 58: 1H NMR (CDCl3, 500 MHz) δ 2.28 (s, 3H), 4.87 (br s, 1H), 7.35-7.41 (m, 10H); 13 C NMR (CDCl3, 125 MHz) δ 26.21, 85.73, 128.07, 128.23, 128.48, 141.25, 208.61. These NMR data are in agreement with the 84 literature data. 169 2-((4-methoxyphenyl)imino)-1,1-diphenylpropan-1-ol (59) O NH 2 OH H 3C N + OCH3 58 H 3CO 1 equiv. Ti(OiPr)4 toluene 70 °C, 2 h OH H 3C 59 68% 2 equiv. To a 20 mL screw cap vial was added ketone 58 (0.90 g, 4.0 mmol, 1 equiv.), 4-methoxyaniline (0.98 g, 8.0 mmol, 2 equiv.) and 2 mL toluene. To this stirring solution was added Ti(OiPr)4 (1.18 mL, 4.00 mmol, 1 equiv.) dropwise via a syringe. The vial was capped and heated in a 70 °C oil bath for 2 h. After the reaction solution was cooled to room temperature, 1 mL Et3N and 10 mL CH2Cl2 were added. The resulting solution was successively washed with saturated Na2CO3 and brine, and dried over MgSO4, filtered through a filter paper and concentrated on rotary vaporization. The residue was subjected to silica gel chromatography, a mixture of 8:1 hexane:EtOAc as the eluent, to afford the product 59 (0.90 g, 2.7 mmol, 68%) as an orange color oil. Spectral data for 59: 1H NMR (CDCl3, 500 MHz) δ 1.88 (s 3H), 3.82 (s, 3H), 6.78 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 7.35 (tt, J = 7.0, 1.5 Hz, 2H), 7.39 (tt, J = 7.0, 1.5 Hz, 4H), 7.45 (dt, J = 7.0, 1.5 Hz, 4H), (the OH proton was not located); 13 C NMR (CDCl3, 125 MHz) δ 17.74, 55.49, 82.10, 114.36, 121.24, 127.64, 128.20, 128.38, 141.52, 143.54, 156.67, 172.79. IR (neat) 3285 br s, 2957 s, 1653 s, 1446 s, 1059 m cm-1; HRMS (ESI+) calc. 332.1651 for C22H22NO2 (M+H), found 332.1665. 170 5.3.9. NMR study of crystals 61 in d6-DMSO 5.3.9.1. Preparation and X-ray analysis of the crytals 61 A slurry of catalyst (S)-46 was generated from a 1:2:1 mixture of Zr(OiPr)4(HOiPr), (S)-VANOL and N-methylimidazole in toluene as described in section 5.3.4 and was subjected to high vacuum to remove all volatiles. Then 1 mL of bromobenzene was added and the mixture was heated in a 100 °C oil bath for 5-10 min to dissolve the solids. After all solids were dissolved, the solution was allowed to very slowly cool to room temperature and the crystals that formed were subjected to analysis. An X-ray diffraction study revealed the presence of a homoleptic zirconium atom with three VANOL ligands consisting of a six-coordinate dianionic zirconium hexa-aryloxide that was charged balanced with two protonated N-methylimidazoles. The unit cell contains two zirconium centers and seven molecules of the bromobenzene solvent (see Firgure 3.2 and 3.3). The ratio of zirconium:VANOL:NMI was 1:3:2 instead of 1:2:1 in the solution from which the crystals were grown. Therefore, a second sample of crystals was prepared from a 1:3:2 mixture of Zr(OiPr)4(HOiPr), (S)-VANOL and N-methylimidazole and X-ray analysis gave an identical unit cell to that above. These crystals did not melt up to 300 °C. At around 220 °C the color started to darken from light yellow to brown, and at around 260 °C the color become black. The hydrogens on the protonated imidazolium were located but the hydrogens on the water molecules in the unit cell were not located and were added at 171 reasonable positions. In Figure 5.1 is a picture of one complete unit cell. For the 85 detailed information of the crystal 61, see the literature. Figure 5.1 One unit cell of crystal 61 5.3.8.2. NMR results of crytals 61 in d6-DMSO NMR analysis of the crystal 61 was carried out in d6-DMSO. However, if 1:3:2 Zr(OiPr)4(HOiPr):(S)-VANOL:N-methylimidazole were mixed in d6-DMSO at room temperature for 1 h, no catalyst assembly was observed, only free (S)-VANOL ligand and free N-methylimidazole were observed. By heating this solution in a 100 °C oil bath for 5 min, still no catalyst assembly was observed. List of 1H (500 Hz) and 13C (125 Hz) NMR spectra (d6-DMSO, 25 °C): 1. Crystal of the catalyst 1:3:2 Zr:(S)-VANOL:N-methylimidazole (NMI), the crystal was grown from bromobenzene. 2. Mixture of 1:3:2 Zr(OiPr)4(HOiPr):(S)-VANOL:NMI made in d6-DMSO at room temperature. 172 3. Mixture of 1:3:2 Zr(OiPr)4(HOiPr):(S)-VANOL:NMI made in d6-DMSO heated to 100 °C for 5 min. 4. The catalyst of 1:3:2 Zr:(S)-VANOL:NMI slurry made in toluene, then volatiles removed. 5. NMI. 6. Mixture of 1:1 NMI:MsOH. 7. (S)-VANOL. 8. Bromobenzene. 9. Toluene. 173 Figure 5.2 1H NMR and 13C NMR of Crystal 61 1:3:2 Zr:(S)-VANOL:N-methylimidazole 6 and bromobenzene (d -DMSO, 25 °C) 2- O O O Zr O O O 174 + Me N N H 2 Figure 5.3 1H NMR and 13C NMR of 1:3:2 Zr:VANOL:NMI made in d6-DMSO mixture of 1:3:2 Zr(OiPr)4(HOiPr):(S)-VANOL :N-methylimidazole made in d 6 at 25 °C (d -DMSO, 25 °C) 175 6 -DMSO Figure 5.4 1H NMR and 13C NMR of 1:3:2 Zr:VANOL:NMI heat to 100 °C mixture of 1:3:2 Zr(OiPr)4(HOiPr):(S)-VANOL :N-methylimidazole made in d 6 6 -DMSO heat to 100 °C (d -DMSO, 25 °C) 176 Figure 5.5 1H NMR and 13C NMR of 1:3:2 Zr:VANOL:NMI made in toluene The catalyst of 1:3:2 Zr:(S)-VANOL:NMI slurry made in toluene, then volatiles removed 6 (d -DMSO, 25 °C) 177 Figure 5.6 1H NMR and 13C NMR of NMI N-methylimidazole 6 (d -DMSO, 25 °C) Me N N 178 Figure 5.7 1H NMR and 13C NMR of protonated NMI 1:1 N-methylimidazole:MsOH 6 (d -DMSO, 25 °C) O H 3C S O O 179 Me N N H Figure 5.8 1H NMR and 13C NMR of (S)-VANOL (S)-VANOL 6 (d -DMSO, 25 °C) Ph Ph 180 OH OH Figure 5.9 1H NMR and 13C NMR of bromobenzene Bromobenzene 6 (d -DMSO, 25 °C) Br 181 Figure 5.10 1H NMR and 13 C NMR of toluene Toluene 6 (d -DMSO, 25 °C) Me 182 Table 5.1 Summary of the 13C NMR data in the aromatic region for crystal 61 studies ppm crystal 61 (Grown in Toluene) crystal 61 (Grown in Bromobenzene) 117.65 117.66 120.07 120.97 120.08 120.99 H N S-VANOL N Me N N Me 117.70 119.97 120.15 120.89 122.19 122.21 123.00 123.00 123.03 124.37 124.37 125.00 125.77 126.01 126.53 126.56 124.43 124.96 125.00 127.19 127.36 127.19 127.36 127.85 128.01 128.53 128.66 129.17 129.35 129.69 126.01 126.54 126.57 Me Br 123.60 125.73 126.50 126.54 127.36 127.99 127.80 128.01 128.48 129.17 128.61 128.82 129.17 129.32 129.69 131.09 131.74 131.03 131.72 134.07 134.07 137.79 138.21 134.07 141.61 141.78 141.61 141.78 141.63 141.81 151.97 151.97 152.11 136.28 138.21 137.76 138.30 All data were collected in d6-DMSO at room temperature at 125 MHz. 183 5.4 Experimental procedures for chapter four 5.4.1. Experimental procedures for total synthesis of Rhizochalin C Oct-7-yn-1-ol (78) 3 equiv. NaH ethylenediamine HO HO 77 45-60 °C, 2 h 5 78 70% 86 This procedure was adapted from literature for the same molecule. To a flame-dried 500 mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added 150 mL of ethylenediamine. After addition, the flask was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. After cooling in an ice bath for 10 min, a dispersion of NaH (15.04 g, 376.5 mmol) in mineral oil (60 wt%) was added. The suspension was heated in an oil bath at 60 °C for 1h. After cooling to 45 °C, oct-3-yn-1-ol 77 (15.00 g, 119.3 mmol) was added via syringe. The resulting mixture was heated at 60 °C for 1h. Thereafter, it was cooled to room temperature and then further cooled in ice bath. The reaction was quenched with 10 mL of distilled water and with 6 M HCl solution until the solution became transparent. The crude mixture was extracted with ether (5 × 30 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 and dried over MgSO4. After filtration through filter paper, the solvent was removed under rotary vaporization. The crude product was purified by silica gel column chromatography with a mixture of 4:1 hexane:EtOAc 184 as eluent (Rf = 0.14) to afford the titled compound (12.03 g, 83.51 mmol, 70%) as a yellow liquid. Spectral data: 1H NMR (500 MHz, CDCl3) δ 1.26-1.38 (m, 4H), 1.43-1.51 (m, 4H), 1.87 (t, 1H, J = 2.5 Hz), 2.11 (dt, 2H, J = 2.5 Hz, 7.0 Hz), 2.41 (s, 1H), 3.53 (t, 2H, J = 7 Hz); 13 C NMR (125 MHz, CDCl3) δ 18.16, 25.10, 28.23, 28.35, 32.37, 62.45, 68.11, 84.46; These NMR data are in agreement with the literature 86 data. Oct-7-ynal (79) 1.1 equiv. (COCl) 2 1.1 equiv. DMSO HO 5 78 Et 3N, DCM –78 °C, 80% O 5 79 To a flame-dried 1000mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added 500mL CH2Cl2. After addition, the flask was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. The reaction flask was cooled in -78°C acetone dry ice bath. DMSO (5.5mL 60 mmol) and oxalyl chloride (5.5mL 60 mmol) were added via syringe and the resulting mixture was kept at -78 °C for 30 min, sequentially Oct-7-yn-1-ol 78 (6.51 g, 52 mmol) was then added to the flask via syringe. After it was stirred at -78 °C for 1h, 30 mL triethylamine was added to the flask. The solution was gradually warmed to room temperature. Then the reaction was quenched with aqueous NaOH (2.4 g, 60 mmol) solution (100mL). The aqueous 185 layer was separated and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over MgSO4. After filtration, the filtrate was concentrated under rotary evaporation. Distillation of the crude product under vacuum (100 °C / 0.5 mmHg) afforded the title product (5.17 g, 80%) as a colorless liquid. Rf = 0.33 (4:1 hexane:EtOAc). Spectral data: 1H NMR (300 MHz, CDCl3) δ 1.38-1.65 (m, 6H), 1.91 (t, 1H, J = 2.5 Hz), 2.17 (dt, 2H, J = 2.5, 7.0 Hz), 2.42 (dt, 2H, J = 1.8, 7.0 Hz), 9.74 (t, 1H, J = 1.8 Hz); 13C NMR (75 MHz, CDCl3) δ 18.17, 21.51, 28.09, 28.14, 43.70, 87 68.40, 84.18, 202.49. These data match that reported for this compound. (2S,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(hept-6-yn-1-yl )aziridine-2-carboxylate (76) 5 mol% (R)-VAPOL 15 mol% B(OPh) 3 O 5 79 0.9 equiv. MEDAM-NH 2 4 equiv. N 2CHCO2Et –20 °C, 14 h, 94%, 98% ee EtO 2C 76 N MEDAM 4 To a flame-dried 250mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added (R)-VAPOL (0.94g, 1.83mmol), B(OPh)3 (1.47g, 5.51mmol), MEDAM-NH2 (10.83g, 36.7mmol) and 70mL toluene. The flask was equipped with a condenser, sealed with a septum to which a nitrogen balloon was attached via a needle, and heated at 80°C for 0.5 h. Thereafter, the condenser was quickly removed and sealed with a septum to 186 which a nitrogen balloon was attached via a needle. The reaction mixture was cooled to -10°C by an immersion cooler. After cooling, 10.5 g 4Å powdered molecular sieve, oct-7-ynal 79 (5.00 g, 40.3 mmol) and ethyl diazoacetate (14 mL, 146.8 mmol, 4 equiv.) was successively added. The reaction mixture was kept at -20°C for 3h. Then it was diluted with 6 mL hexane, filtered through celite pad and the filtrate was concentrated under reduced pressure followed by exposure to high vacuum for 1h. The crude residue was purified by silica gel column chromatography, 4:1 hexane:EtOAc as eluent (Rf = 0.38), affording the product (16.79g, 94%) as a yellow oil. It was determined to be 98%ee by chiral HPLC analysis (CHIRAL OD-H column, 99:1 hexane:isopropanol at 222nm, flow rate: 0.7mL/min, retention time: R t = 6.91 min as the major enantiomer and R t = 4.87 min as the minor enantiomer). Specific Rotation: [α]D20 = –64.4°(c 1.0, CH2Cl2) on 98%ee. Spectral data for 76: 1H NMR (500 MHz, CDCl3) δ 1.07-1.13 (m, 1H), 1.20 (q, 2H, J = 6.0 Hz), 1.23 (t, 3H, J = 6.0 Hz), 1.33 (q, 3H, J = 6.0 Hz), 1.42-1.54 (m, 2H), 1.88 (t, 1H, J = 3.0 Hz), 1.94 (q, 1H, J = 6.0 Hz), 2.04 (dt, 2H, J = 3.0 Hz, 6.0 Hz), 2.19 (d, 1H, J = 6.0 Hz), 2.16 (s, 6H), 2.22 (s, 6H), 3.38 (s, 1H), 3.65 (s, 3H), 3.66 (s, 3H), 4.13-4.22 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ14.18, 15.94, 15.97, 18.00, 26.54, 27.61, 28.01, 28.26, 43.40, 46.63, 59.34, 59.39, 60.47, 68.04, 77.23, 84.25, 127.24, 128.01, 130.28, 137.64, 187 138.10, 155.73, 156.09, 169.45 (one aromatic carbon was not located); IR (NaCl, thin film, cm-1) 3287m, 2943s, 2858m, 2116w, 1742s, 1483s, 1457m, 1221s, 1183s, 1142m, 1014m; HRMS (ESI-TOF) calcd for C31H42NO4 m/z (M+H)+ 492.3114, meas 492.3106. (2S,3R)-ethyl-2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-3-hydr oxydec-9-ynoate (80) 1) 1 equiv. CF 3COOH EtO 2C 76 N MEDAM 4 DCM, reflux, 16 h HN MEDAM 5 EtO 2C 2) 1 equiv. NaOH EtOH/H 2O, rt, 0.5 h 80% 80 OH To a flame-dried 250mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added the aziridine 76 (14.55g 29.6mmol), 120mL CH2Cl2 and CF3COOH (2.33mL 30.0mmol). The flask was equipped with a condenser, sealed with a septum to which a nitrogen balloon was attached via a needle, and heated at 45°C oil bath for 13h. After it was cooled down to room temperature, the volatile was removed under reduced pressure. 170mL 15:2 EtOH:H2O solution with 1.12g NaOH was added to the flask and stirred at room temperature for 0.5h. Thereafter, ethanol was removed under reduced pressure. The residue was extracted with ethyl acetate (30mL×3), the combined organic layers were dried over MgSO4. After filtration, the filtrate was concentrated under 188 reduced pressure. The residue was purified by silica gel column chromatography, 4:1 hexane:EtOAc as eluent (Rf = 0.19), affording the product (9.63g, 60%) as a colorless oil. Specific Rotation: [α]D20=-25.8°(c 1.0, CH2Cl2). Spectral data for 80 :1H NMR (500 MHz, CDCl3) δ 1.22-1.29 (m, 2H), 1.25 (t, 3H, J = 7.5 Hz), 1.34-1.39 (m, 2H), 1.44-1.52(m, 4H), 1.90 (t, 1H, J = 3.0 Hz), 2.15 (dt, 2H, J = 3.0 Hz, 7.5 Hz ), 2.22 (s, 6H), 2.23 (s, 6H), 3.02 (d, 1H, J = 6.0 Hz), 3.60 (q, 1H, J = 6.0 Hz), 3.65 (s, 3H), 3.67 (s, 3H), 4.16(q, 2H, J = 7.5 Hz), 4.55 (s, 1H), 6.93 (s, 2H), 6.97 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 14.31, 16.18, 16.27, 18.30, 25.07, 28.35, 28.65, 33.57, 59.56, 59.59, 60.95, 63.71, 64.78, 68.16, 72.24, 84.55, 127.38, 127.81, 130.73, 130.81, 137.24, 139.13, 156.02, 156.06, 173.99; IR (NaCl, thin film, cm-1) 3464m, 3290, 2938s, 2859m, 2116w, 1731s, 1483s, 1463s, 1189m, 1142s, 1016s. HRMS (ESI-TOF) calcd for C31H44NO5 m/z (M+H)+ 510.3219, meas 510.3226. (2S,3R)-ethyl-3-(benzyloxy)-2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)a mino)dec-9-ynoate (81) HN MEDAM 5 EtO 2C 80 OH 2 equiv. BnBr 1 equiv. NaH 20 mol% Bu 4NI DMF,0 °C, 80% MEDAM HN EtO 2C 81 5 OBn To a flame-dried 10mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added α-amino-β-alcohol ester 80 (0.2133g 189 0.4mmol), 1.5mL DMF, BnBr (0.1367g 0.8mmol) and Bu4NI (0.0388g 0.08mmol). The flask was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. It was cooled in ice bath for 10min. Then 60% NaH in mineral oil (0.0166g 0.4mmol) suspended in 0.5mL DMF was added via syringe slowly. The reaction mixture was stirred for 18h (The ice melted and the temperature rose to room temperature in about 4 hours). Thereafter, the reaction was quenched with 5mL distilled water, and it was extracted with CH2Cl2 (10mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. After silica gel column chromatography, 4:1 hexane:EtOAc as eluent (Rf =0.19), 0.1400g product was obtained as colorless oil in 50% yield and 0.08g starting material. Specific Rotation: [α]D20= –26.2° (c 1.0 CH2Cl2). Spectral data for 81: 1H NMR (500 MHz, CDCl3) 1.09-1.19 (m, 1H), 1.22 (t, 2H, J = 6.0 Hz), 1.26-1.29 (m, 1H), 1.40 (q, 2H, J = 6.0 Hz), 1.50 (q, 2H, J = 6.0 Hz), 1.70-1.77 (m, 2H), 1.79-1.85 (m, 2H), 1.94 (t, 1H, J = 2.5 Hz), 2.16 (dt, 2H, J = 2.5 Hz, 7.5 Hz), 2.23 (s, 12H), 3.19 (s, 1H), 3.65 (s, 3H), 3.68 (s, 3H), 4.08-4.17 (m, 2H), 4.46 (d, 1H, J = 12.0 Hz), 4.55 (d, 1H, J = 12.0 Hz), 4.64 (s, 1H), 7.04 (s, 2H), 7.05 (s, 2H), 7.21-7.37 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 14.28, 16.17, 16.24, 18.35, 25.38, 28.42, 28.82, 30.82, 59.52, 59.56, 60.60, 61.07, 64.65, 68.22, 72.05, 80.71, 84.49, 127.46, 127.55, 127.83, 127.98, 128.22, 130.47, 130.55, 138.19, 138.32, 140.00, 155.86, 155.93, 174.07; IR (NaCl, thin film, cm-1) 3290m, 190 2938s, 2860s, 2116m, 1735s, 1483s, 1455s, 1220s, 1144s, 1017s. HRMS (ESI-TOF) calcd for C38H50NO5 m/z (M+H)+ 600.3689, meas 600.3694. 16-hydroxy-N-methoxy-N-methylhexadecanamide (85) 1.5 equiv. O O NH O O O 12 84 1.5 equiv. Me 3Al N DCM, 0 °C to rt 14 OH 85 12 h, 88% To a flame-dried 250mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added a solution of N,N,O-trimethylhydroxylammonium chloride (19.13g, 196mmol) in 200mL CH2Cl2. The flask was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. The resulting mixture was stirred in ice bath for 10min, then 98mL 2M trimethyl aluminum solution in toluene was added via syringe. It was stirred in ice bath for 30min. Thereafter, a solution of oxacyclohexadecan-2-one 84 (33.34g 131mmol) in 20mL CH2Cl2 was added to the flask. The reaction mixture was gradually warmed up to room temperature for 24h. Then the solution was diluted with 40mL CH2Cl2, cooled in ice bath to 0oC. 0.1M HCl solution was added dropwise to quench the reaction. The resulting solution was filtered with a celite pad in a sintered glass funnel; the filtration was dried over MgSO4 filtered, and concentrated under reduced 191 pressure and high vacuum. Recrystalization of the crude solid in hexane afforded 33.70 g product as a white solid in 81% yield. m. p. = 63-65°C. Spectral data for 85: 1H NMR (600 MHz, CDCl3) δ 1.21-1.29 (m, 20H), 1.51 (q, 2H, J = 7.2 Hz), 1.57 (q, 2H, J = 7.2 Hz), 1.73 (s, 1H), 2.36 (t, 2H, J = 7.2 Hz), 3.13 (s, 3H), 3.58 (t, 2H, J = 7.2 Hz), 3.63 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 24.60, 25.69, 29.35, 29.37, 29.38, 29.42, 29.50, 29.53, 29.55, 32.74, 61.12, 62.91, (one amide carbon and five aliphatic carbons not located); IR (KBr, thin film, cm-1) 3443s, 3120br m, 2912s, 2849s, 1651s, 1471s, 1401s, 1193m, 1071m, 984m, 717m, 600m; HRMS (ESI-TOF) calcd for C18H36NO3 m/z 316.2852 (M+H)+ meas 316.2844. N-methoxy-N-methyl-16-oxohexadecanamide (86) 1.1 equiv. (COCl) 2 1.1 equiv. DMSO O O N 14 OH 85 Et 3N, DCM –78 °C, 92% O O N O 14 H 86 To a flame-dried 250mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added 150mL CH2Cl2. The flask was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. DMSO (1.85mL, 22mmol), and oxalyl chloride (1.85mL, 22mmol) was successively added to the flask via syringe. The resulting mixture was cooled in -78°C acetone dry ice bath for 192 30min, then a solution of 16-hydroxy-N-methoxy-N-methylhexadecanamide 85 (6.55g 20mmL) in 10mL CH2Cl2 was added to the flask via syringe. The reaction mixture was stirred at -78 °C for 1h. Thereafter, 9mL triethylamine was added via a syringe. After the addition, it was allowed to gradually warm up to room temperature for 30min. Then the reaction was quenched with 10mL H2O, the aqueous layer was separated and extracted with 10mL CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated on reduced pressure and high vacuum. Recrystalization of the crude solid in hexane afforded 5.55g product as a white solid in 85% yield. m. p. = 34-36°C. Spectral data for 86: 1H NMR (500 MHz, CDCl3) δ 1.22-1.28 (m, 18H), 1.58-1.61 (m, 4H), 2.37-2.40 (m, 4H), 3.15 (s, 3H), 3.65 (s, 3H), 9.73 (t, 1H, J = 2 Hz); 13 C NMR (125 MHz, CDCl3) δ 22.05, 24.63, 25.70, 29.13, 29.31, 29.38, 29.40, 29.43, 29.47, 29.53, 29.57, 29.59, 43.89, 61.16, 202.97, one amide carbon and two aliphatic carbons not located; IR (KBr, thin film, cm-1) 3433br m, 3129br m, 2914s, 2850s, 1722s, 1664s, 1472s, 1396s, 1180w, 993w, 716w; HRMS (ESI-TOF) calcd 314.2695 for C18H34NO3 m/z (M+H)+ meas 314.2694. 193 (2S,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(15-(methoxy (methyl)amino)-15-oxopentadecyl)aziridine-2-carboxylate (75) O O N 5 mol% (R)-VAPOL 15 mol% B(OPh) 3 O 14 H 86 0.9 equiv. MEDAM-NH 2 4 equiv. N 2CHCO2Et –20 °C, 14 h, 72%, 95% ee MEDAM N O O N 12 CO2Et 75 To a flame-dried 50mL Schlenk flask equipped with a magnetic stir bar and filled with nitrogen gas was added (R)-VAPOL (0.0155g, 0.02mmol, 5 mol%), B(OPh)3 (0.0218g, 0.06mmol, 15 mol%) and MEDAM-NH2 (0.1535g, 0.5mmol, 0.9 equiv.) and 1mL toluene. The flask was sealed. The resulting mixture was heated at 80°C for 1h. Then it was cooled to room temperature and followed by cooling at -10°C with an immersion cooler. A nitrogen flow was introduced to the neck of the flask to avoid absorption of moisture. The flask was opened, and 0.15g 4Å molecular sieve, aldehyde 86 (0.1900g, 0.6mmol, 1 equiv.) and ethyl diazoacetate (0.2mL, 2mmol, 4 equiv.) was successively added at -10°C. The flask was sealed again. The resulting reaction mixture was stirred at -10°C for 16 h. Then it was warmed up to room temperature and diluted with 6mL hexane, filtered through celite pad in sintered glass funnel. The filtrate was concentrated under reduced pressure and followed by exposure to high vacuum for 1h. The crude oil was purified by silica gel column chromatography, 1:1:2 Et2O:CH2Cl2:hexane as eluent (Rf = 0.59 in 2:2:1 Et2O:CH2Cl2:hexane), 194 affording the product (0.2540 g, 72%) as a yellow oil. It was determined to be 95%ee by chiral HPLC analysis, CHIRAL OD-H column, 97:3 hexane:isopropanol at 222nm, flow rate: 1.0mL/min, retention time: Rt = 8.28min as the major enantiomer and Rt = 6.52min as the minor enantiomer. For a larger scale, the reaction needs longer time, and higher temperature. Starting with 86 (5.55 g, 17.7 mmol, 1 equiv.), the reaction was done at room temperature for 48 h, affording the product 75 (7.64 g, 11.7 mmol, 66%) as a yellow oil and the optical purity was determined to be 91% ee. Spectral data for 75: 1H NMR (500 MHz, CDCl3) δ 1.07-1.30 (m, 26H), 1.59 (q, 2H, J = 10.0 Hz), 1.93 (q, 2H, J =5.0 Hz), 2.16 (d, 1H, J = 5.0 Hz), 2.20 (s, 12H), 2.37 (t, 2H, J = 5.0 Hz ), 3.13 (s, 3H), 3.37 (s, 1H), 3.631 (s, 3H), 3.636 (s, 3H), 3.64 (s, 3H), 4.10-4.19 (m, 2H), 6.97 (s, 2H), 7.06 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.22, 15.99, 16.03, 24.55, 27.12, 27.84, 29.05, 29.31, 29.34, 29.39, 29.43, 29.49, 29.50, 29.51, 29.53, 31.81, 43.44, 46.88, 59.42, 60.49, 61.04, 77.22, 127.29, 127.99, 130.27, 130.32, 137.68, 138.08, 155.71, 156.05, 169.55, one amide carbon and three aliphatic carbons not located; IR (NaCl, thin film, cm-1) 2924s, 2853s, 1744s, 1668s, 1483s, 1221s, 1181s, 1142s, 1015s. 195 (2S,3R)-ethyl 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-3-hydroxy-18-(metho xy(methyl)amino)-18-oxooctadecanoate (87) MEDAM N O O N 12 75 CO2Et 1) 1 equiv. CF 3COOH DCM, reflux, 16 h 2) 1 equiv. NaOH EtOH/H 2O, rt, 0.5 h O O N OH 14 HN CO2Et MEDAM 87 84% over two steps To a flame-dried 50mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added the aziridine 75 (0.93g 1.4mmol), 10mL CH2Cl2 and CF3COOH (108µL 1.4mmol). The flask was quickly equipped with a condenser and the top was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. The resulting mixture was refluxed at 45°C for 16h. Then it was cooled to room temperature, the volatiles were removed under reduced pressure. A solution of 0.05g NaOH in 5mL 15:2 EtOH:H2O was added to the flask containing the residue after removal of the volatile. It was stirred at room temperature for 0.5h, then ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (20mL×3), the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, 1:1:2 Et2O:CH2Cl2:hexane as eluent (Rf = 0.51 in 2:2:1 Et2O:CH2Cl2:hexane), affording the product (0.80g, 84%) as a colorless oil. 196 Spectral data for 87: 1HNMR (300 MHz, CDCl3) δ 1.14-1.30 (m, 25H), 1.46-1.50 (m, 2H), 1.57 (q, 2H, J = 7.5 Hz), 2.19 (s, 6H), 2.20 (s, 6H), 2.36 (t, 2H, J = 7.5 Hz), 3.02 (d, 1H, J = 6.0Hz), 3.11 (s, 3H), 3.61-3.63 (m, 10H), 4.13 (q, 2H, J = 7.5 Hz), 4.54 (s, 1H), 6.93 (s, 2H), 6.96 (s, 2H); 13 C NMR (75 MHz, CDCl3) δ14.11, 15.97, 16.05, 24.45, 25.45, 29.23, 29.24, 29.31, 29.39, 29.42, 29.44, 31.67, 33.63, 59.31, 59.33, 60.64, 60.94, 63.38, 64.56, 72.26, 127.23, 127.65, 130.44, 130.51, 137.28, 139.15, 155.78, 155.81, 173.90, (one amide carbon and 5 aliphatic carbons not located). (2S,3R)-ethyl-2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-3-((tertbutyldimethylsilyl)oxy)-18-(methoxy(methyl)amino)-18-oxooctadecanoate (88) O O N 14 HN 87 O 1 equiv. TBSOTf OH CO2Et MEDAM 1.5 equiv. Et 3N THF, 0 °C, 30 min 94% O N OTBS CO2Et 14 HN MEDAM 88 To a flame-dried 25mL round bottom flask equipped with a magnetic stir bar and filled with nitrogen gas was added a solution of compound 29 (0.90g, 1.1mmol) in 10mL THF. The flask was quickly sealed with a septum to which a nitrogen balloon was attached via a needle. It was then added TBSOTf (0.25mL, 1.2mmol) and Et3N (0.2mL, 1.2mmol) via syringe. The resulting mixture was 197 stirred at room temperature for 30min. The volatiles were removed under reduced pressure and the crude product was purified by silica gel column chromatography, 1:1:2 Et2O:CH2Cl2:hexane as eluent (Rf = 0.69 in 2:2:1 Et2O:CH2Cl2:hexane). The product (0.34g, 36%) was obtained as colorless oil. Specific Rotation: [α]D20= –20.0°(c 1.0, CH2Cl2). Spectral data for 88: 1HNMR (500 MHz, CDCl3) δ -0.96 (s, 3H), -0.01 (s, 3H), 0.81 (s, 9H), 1.23-1.40 (m, 27H), 1.61 (q, 2H, J = 7.0 Hz), 1.90-1.99 (m, 1H), 2.21 (s, 12H), 2.39 (t, 2H, J = 7.0 Hz), 3.08 (s, 1H), 3.15 (s, 3H), 3.651 (s, 3H), 3.653 (s, 3H), 3.66 (s, 3H), 3.89 (m, 1H), 4.13-4.17 (m, 2H), 4.63 (s, 1H), 7.00 (s, 4H); 13 C NMR (125 MHz, CDCl3) δ -5.06, -4.32, 14.26, 16.12, 16.14, 17.92, 24.61, 25.73, 25.78, 29.39, 29.42, 29.47, 29.56, 29.62, 29.68, 29.80, 31.89, 34.06, 59.47, 59.49, 60.34, 61.10, 61.87, 64.02, 74.48, 127.38, 128.15, 130.33, 130.45, 138.18, 140.31, 155.74, 155.92, 174.07, (one amide carbon and 4 aliphatic carbons not located); IR (NaCl, thin film, cm-1) 3342m, 2927s, 2855s, 1738s, 1671s, 1463s, 1221s, 1150s, 1094s, 1018s, 940m, 836s, 776s; HRMS (ESI-TOF) calcd 813.5813 for C47H81N2O7Si m/z (M+H)+, meas 813.5831. 198 5.4.2. Experimental procedure for Mannich type reaction ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (89) O iPr 2NH + nBuLi O THF 0 °C THF, –78 °C TMSCl O TMS O THF, –78 °C 56% 89 To a flame-dried 100 mL round bottom flask was added isopropylamine (7.0 mL, 50 mmol, 1 equiv.) and 30 mL THF, the flask was sealed with a septum with a N2 balloon attached via a needle. The flask was cooled in an ice bath for 5 min, and then n-BuLi (2.5M in hexane, 20 mL, 50 mmol, 1 equiv.) was added dropwise. The resulting solution was stirred in the ice bath for another 30 min and followed by cooling to –78°C in an acetone dry ice bath for 5 min. Methyl isobutyrate (5.5 mL, 48 mmol, 0.95 equiv.) was added to the solution dropwise via a syringe. The resulting solution was stirred at –78 °C for 1 h before the slow addition of TMSCl (6.8 mL, 55 mmol, 1.1 equiv.). The flask was cooled at –78°C for another 30 min before warming up to room temperature. The mixture was filtered through celite pad and the filtrate was concentrated on rotary vaporization. The residue was subjected to partial vacuum distillation to afford the pure product 89 (4.60 g, 28.0 mmol, 56%) as a colorless oil. Spectra data for 89: 1H NMR (500 MHz, CDCl3) δ 0.19 (s, 3H), 1.50 (s, 3H), 1.56 (s, 3H), 3.48 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 0.02, 16.07, 16.81, 56.47, 88 90.85, 149.27. These NMR data are in agreement with the literature data. 199 2-(benzylideneamino)phenol (90) O OH + OH DCM, rt, 1 h N H NH 2 77% 0.9 equiv. 90 To a 20 mL round bottom flask was added 2-aminophenol (0.24 g, 2.2 mmol, 1.1 equiv.), 4 mL CH2Cl2, MgSO4 (0.20 g) and benzaldehyde (0.20 mL, 2.0 mmol, 1 equiv.). The mixture was stirred at room temperature for 1 h, and filtered through filter paper, concentrated on rotary vaporization. The residue was subjected to flask column chromatography, a 4:1 mixture of hexane:EtOAc as the eluent, to afford the pure product 90 (0.30 g, 1.5 mmol, 77%) as a yellow solid. mp. = 88-89 °C. Spectra data for 90: 1H NMR (500 MHz, CDCl3) δ 6.92 (td, J = 8.0, 1.5 Hz, 1H), 7.03 (dd, J = 8.0, 1.5 Hz, 1H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.27 (br s, 1H), 7.31 (dd, J = 8.0, 1.5 Hz, 1H), 7.48-7.51 (m, 3H), 7.93 (dd, J = 8.0, 1.5 Hz, 2H), 8.70 (s, 1H); 13 C NMR (125 MHz, CDCl3) δ 115.00, 115.84, 120.09, 128.81, 128.86, 128.94, 131.69, 135.43, 135.80, 152.31, 157.10. These NMR data are in 52 agreement with literature data. 200 2,4-dimethyl-6-nitrophenol (91) OH 90% HNO 3, HOAc, 0 °C, 68% H 3C CH 3 OH H 3C 91 NO 2 CH 3 To a 250 mL Erlenmeyer flask was added a magnetic stir bar, 2,4-dimethylphenol (3.00 mL, 24.1 mmol) and acetic acid (30 mL). The flask was cooled in ice bath for 5 min. To another 50 mL Erlenmeyer flask was added acetic acid (10 mL) and HNO3 (1.9 mL, c = 90%) and cooled in ice bath for 5 min. The HNO3 solution was transferred to the dimethylphenol solution dropwise with a pipette. After stirring in ice bath for 2 min, H2O (200 mL) was added in one portion to quench the reaction. The aqueous solution was divided into two portions, and both portions were extracted with DCM (20 mL x 4). The combined organic layer was successively washed with H2O (20 mL) and brine (20 mL) and dried over MgSO4. The solution was filtered through filter paper, and concentrated under rotary evaporation. The crude product was purified by silica gel column chromatography, with 8:1 hexanes:EtOAc as the eluent. The reaction afforded the 89 product 91 as a yellow solid (2.73 g, 16.4 mmol, 68%). m. p. = 68-69 °C (lit. 64-66 °C); Spectra data for 91: 1H NMR (500M Hz, CDCl3) δ 2.29 (s, 6H), 7.26 (s, 1H), 7.73 (s, 1H), 10.76 (s, 1H); 13 C NMR (125M Hz, CDCl3) δ 15.77, 20.29, 121.87, 128.93, 128.99, 132.97, 139.54, 151.77; The 1H NMR data was identical to that 201 89 reported in literature. Note: a second run was carried out on the same scale with 70% HNO3, the yield dropped to 44%. 2-amino-4,6-dimethylphenol (92) OH H 3C 91 NO 2 CH 3 7.5 equiv. NH 2NH 2 H 2O OH H 3C EtOH, graphite 100 °C 3.5 h, 97% 92 NH 2 CH 3 To a 100 mL RBF was added 4,6-dimethyl-2-nitrophenol 91 (1.76 g, 10.5 mmol), graphite (1.50 g), hydrazine monohydrate (1.28 mL, 26.3 mmol, 2.5 equiv.) and ethanol (30 mL). The flask was equipped with a condenser and the top was sealed by a septum with a needle attached to it. The flask was heated in a 100 °C oil bath for 3.5 h (another 5 equiv. of hydrazine monohydrate was added in two equal portions every other hour). The solution was allowed to cool to room temperature, and filtered though celite pad, the filter cake was washed by dichloromethane. The filtrate was concentrated under rotary evaporation and exposed to high vacuum to afford the pure product as a pale orange color solid 89 (1.40 g, 10.1 mmol, 97%). m. p. = 130-132 °C (lit. 127-129 °C); Spectra data for 92: 1H NMR (500M Hz, d6-DMSO) δ 2.03 (s, 6H), 4.42 (br s, 2H), 6.09 (s, 1H), 6.24 (s, 1H), 7.51 (br s, 1H); 13C NMR (125M Hz, d6-DMSO) δ 16.92, 20.95, 113.77, 119.46, 124.74, 128.50, 137.48, 139.68; and the NMR data 202 were also obtained in CDCl3: 1H NMR (500M Hz, CDCl3) δ 2.17 (s, 3H), 2.18 (s, 3H), 3.63 (br s, 3H), 6.40 (s, 1H), 6.43 (s, 1H); 13 C NMR (125M Hz, CDCl3) δ 15.98, 20.65, 115.38, 121.80, 124.55, 130.19, 134.92, 140.38; these NMR data 89 obtained in d6-DMSO were identical to those reported in literature. 2-(benzylideneamino)-4,6-dimethylphenol (93) CH 3 CH 3 O OH OH + H 3C NH 2 92 H DCM, rt, 1 h 90% 0.9 equiv. H 3C N 93 To a 20 mL round bottom flask was added 4,6-dimethyl-2-aminophenol 92 (0.30 g, 2.2 mmol, 1.1 equiv.), 4 mL CH2Cl2, MgSO4 (0.20 g) and benzaldehyde (0.20 mL, 2.0 mmol, 1 equiv.). The mixture was stirred at room temperature for 1 h, and filtered through filter paper, concentrated on rotary vaporization. The residue was subjected to flask column chromatography, a 4:1 mixture of hexane:EtOAc as the eluent, and then recrystallized in hexane to afford the pure product 93 (0.40 g, 2.0 mmol, 90%) as a yellow solid. mp. = 70-72 °C. Spectra data for 93: 1H NMR (500 MHz, CDCl3) δ 2.28 (s, 3H), 2.29 (s, 3H), 6.89 (s, 1H), 6.98 (s, 1H), 7.24 (br s, 1H), 7.47-7.49 (m, 3H), 7.90-7.92 (m, 2H), 8.67 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 15.65, 20.78, 113.58, 124.01, 128.44, 128.69, 128.82, 130.85, 131.47, 134.41, 135.97, 148.43, 156.43. These NMR 203 52 data are in agreement with literature data. methyl (R)-3-((2-hydroxyphenyl)amino)-2,2-dimethyl-3-phenylpropanoate (94) and methyl (R)-3-((2-hydroxy-3,5-dimethylphenyl)amino)-2,2-dimethyl3-phenylpropanoate (95) X OH X N + O TMS 20 mol% (S)-VANOL Zr 46 O toluene rt, 24 h 73%, 60% ee OH NH O O 1.2 equiv. 89 X=H 90 94 X OH X X = CH 3 93 N + O TMS O 20 mol% (S)-VANOL Zr 46 toluene rt, 24 h 70%, 98% ee 1.2 equiv. 89 H 3C CH 3 OH NH O O 95 The experimental procedure for the Mannich type reaction in Tables 4.1 and 52 4.2 are similar to a literature procedure. The catalyst 46 was prepared from a 2.2:1.0:1.2 mixture of (S)-VANOL : Zr(OiPr)4(HOiPr) : N-methylimidazole according to section 5.3.4 procedure 4. To this catalyst 46 (20 mol%, in 0.5 mL toluene in a Schlenk flask) was added aldimine 90 or 93 (0.125 mmol, 1 equiv.) and 0.5 mL toluene and the solution was stirred for 5 min. Then the silyl ketene acetal 89 (0.15 mmol, 1.2 equiv.) was added via a syringe. The reaction mixture was stirred at room temperature for 24 h. Excess hexane was added to precipitate the catalyst and the solids were filtered off through a filter paper. The filtrate was 204 concentrated on rotary vaporization and the residue was diluted in 2 mL THF, and 1.5 N HCl 0.2 mL was added. The solution was allowed to stir at room temperature for 30 min. Then the reaction was quenched with saturated NaHCO3 solution 5 mL. The aqueous phase was extracted with EtOAc (5 mL x 3) and the combined organic phase was washed with brine and dried over MgSO4. The solids were filtered off through a filter paper. The filtrate was concentrated on rotary vaporization and the residue subjected to silica gel column chromatography, 1 mixture of 10:1 hexane:EtOAc as the eluent, to afford the product, for 94 (0.0273 g, 0.0912 mmol, 73%) as a a yellow oil and for 95 (0.0299 g, 0.0875 mmol, 70%) as a yellow solid. Data for 94: The optical purity is 60% ee determined by Chirapak AD column, 90:10 hexane:HOiPr, 1 mL/min, 9.5 min for the major peak and 12.7 min for the minor peak. 1H NMR (500 MHz, CDCl3) δ 1.21 (s, 3H), 1.23 (s, 3H), 3.67 (s, 3H), 4.53 (br s, 1H), 4.85 (br s, 1H), 5.29 (s, 1H), 6.37 (dd, J = 8.0, 1.0 Hz, 1H), 6.52 (dt, J = 7.0, 1.0 Hz, 1H), 6.59 (dt, J = 8.0, 1.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 7.20-7.27 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 19.92, 24.24, 47.25, 52.43, 64.33, 133.23, 114.23, 117.54, 120.69, 127.22, 127.78, 128.15, 135.55, 138.90, 52 144.02, 178.10. These NMR data are in agreement with literature data. Data for 95: m. p. = 124-126 °C. The optical purity is 98% ee determined by Chirapak AS column, 90:10 hexane:HOiPr, 1 mL/min, 4.7 min for the minor peak and 5.8 min for the major peak. 1H NMR (500 MHz, CDCl3) δ 1.20 (s, 3H), 1.21 (s, 205 3H), 2.02 (s, 3H), 2.14 (s, 3H), 3.68 (s, 3H), 4.52 (s, 1H), 4.77 (br s, 1H), 4.97 (s, 1H), 6.01 (s, 1H), 6.27 (s, 1H), 7.16-7.28 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 15.60, 19.92, 20.78, 24.33, 47.39, 52.10, 64.88, 113.69, 121.04, 122.44, 127.45, 127.90, 128.43, 129.66, 135.02, 139.19, 140.89, 177.70. These NMR data are in 52 agreement with literature data. 5.4.3. Experimental procedure for chloronium induced rearrangement of allylic alcohol 1,1-diphenylprop-2-en-1-ol (96) O 1.5 equiv. MgCl OH 46% 96 To a flame-dried 50 mL round bottom flask was added benzophenone (0.63 g, 3.5 mmol, 1 equiv.), 10 mL THF and the flask was sealed with septum with a N2 balloon attached via a needle. Vinylmagnesium chloride (1M in THF, 5.0 mL, 5.0 mmol, 1.5 equiv.) was added dropwise via a syringe. The resulting mixture was allowed to stir at room temperature for 30 min. The reaction was quenched with 10 mL saturated NH4Cl solution, and extracted with Et2O (10 mL x 2). The combined organic phase was washed with brine, filtered through filter paper, concentrated on rotary vaporization. The residue was subjected to flash silica gel chromatography, a 20:1 mixture of hexane:EtOAc as the eluent, to afford the 206 product 96 (0.34 g, 1.6 mmol, 46%) as a colorless oil. Spectra data for 96: 1H NMR (500 MHz, CDCl3) δ 2.29 (s, 1H), 5.32 (s, 1H), 5.35 (dd, J = 7.0, 1.5 Hz, 1H), 6.50-6.55 (m, 1H), 7.28 (tt, J = 7.0, 1.5 Hz, 2H), 7.34 (tt, J = 7.5, 1.5 Hz, 4H), 7.40 (dt, J = 7.5, 1.5 Hz, 4H); 13 C NMR (125 MHz, CDCl3) δ 79.39, 114.01, 126.86, 127.28, 128.16, 143.46, 145.72. These NMR 90 data are in agreement with the literature data. 3-chloro-1,2-diphenylpropan-1-one (97) O 1.1 equiv. OH Cl N O N Cl Cl O THF, rt, 1 h 100% 97 96 To a 20 mL screw cap vial was added allylic alcohol 96 (0.0420 g, 0.200 mmol, 1 equiv.) and 1 mL THF, to this stirring solution was slowly added the chlorine source 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.0400 g, 0.200 mmol, 1 equiv.). The vial was capped and allowed to stir at room temperature for 1 h. The reaction was quenched with 10 mL hexane. The resulting suspension was filtered through filter paper, concentrated on rotary vaporization. The residue was subjected to flash silica gel chromatography, a 16:1 mixture of hexane:EtOAc as the eluent, to afford the product 97 (0.0490 g, 0.200 mmol, 100%) as a colorless oil. 207 Spectra data for 97: 1H NMR (500 MHz, CDCl3) δ 3.75 (dd, J = 11.0, 4.0 Hz, 1H), 4.33 (dd, J = 11.0, 4.0 Hz, 1H), 4.95 (dd, J = 11.0, 4.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.34 (d, J = 4.5 Hz, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.52 (tt, J = 7.5, 1.0 Hz, 1H), 7.98 (dd, J = 8.0, 1.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 45.28, 56.16, 128.15, 128.27, 128.64, 128.78, 129.29, 133.37, 136.11, 136.16, 196.95. These NMR 91 data are in agreement with the literature data. 5.4.4. Experimental procedure for aziridinol rearrangement methyl 2,3-dibromopropanoate (99) CO2Me 1 equiv. Br 2 DCM 0°C, 1h Br Br CO2Me 93% 99 To a 20 mL round bottom flask was added methyl acrylate (2.0 mL, 22 mmol, 1 equiv.) and CH2Cl2 5mL, the flask was sealed with a septum with a N2 balloon attached via a needle. The resulting mixture was cooled at 0 °C in an ice bath for 5 min. To this stirring solution was added Br2 (1.2 mL, 22 mL, 1 equiv.) dropwise via a syringe. After stirring at 0 °C for 1 h, the solution was warmed up to room temperature and successively washed with 5 mL saturated Na2S2O3, 5 mL saturated Na2CO3, and 5 mL brine, and then dried over MgSO4, filtered through filter paper, concentrated on rotary vaporization and the residue was subjected to flash silica gel chromatography, a 10:1 mixture of hexane:EtOAc as the eluent, to 208 afford the product 99 (5.09 g, 20.5 mmol, 93%) as a colorless oil. Spectra data for 99: 1H NMR (500 MHz, CDCl3) δ 3.69 (dd, J = 10.0, 4.5 Hz, 1H), 3.85 (s, 3H), 3.94 (dd, J = 11.5, 10.0 Hz, 1H), 4.46 (dd, J = 11.5, 4.5 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 29.61, 40.71, 53.40, 168.04. These NMR data are 92 in agreement with the literature data. Methyl-1-(4-methoxyphenyl)aziridine-2-carboxylate (100) 1.2 equiv. p-methoxyphenylamine 2.5 equiv. Et 3N 10 mol% DMAP Br Br CO2Me 99 THF, 70°C, 14h 70% OMe N CO2Me 100 To a 50 mL round bottom flask was added the dibromo ester 99 (2.02 g, 8.13 mmol, 1 equiv.) and 30 mL THF, to this stirring solution was added a solution of Et3N (2.81 mL, 20.3 mmol, 2.5 equiv.), p-methoxyphenylamine (1.20 g, 9.76 mmol, 1.2 equiv.) and 4-DMAP (0.099 g, 0.81 mmol, 10 mol%) in 10 mL THF. The flask was equipped with a water condenser and heated to 70 °C for 14 h. The flask was then cooled to room temperature, the solids were filtered off through a filter paper, and the filter cake was washed with ethyl ether (10 mL x 2). The filtrate was concentrated on rotary vaporization and the residue was subjected to flash silica gel chromatography, a 8:1 to 4:1 mixture of hexane:EtOAc as the eluent, to afford the product 100 (1.17 g, 5.69 mmol, 70%) as a yellow oil. Spectra data for 100: 1H NMR (500 MHz, CDCl3) δ 2.27 (dd, J = 6.0, 1.0 Hz, 209 1H), 2.63 (dd, J = 3.5, 1.0 Hz, 1H), 2.73 (dd, J = 6.0, 3.5 Hz, 1H), 3.76 (s, 3H), 3.80 (s, 3H), 6.79 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 34.06, 37.76, 52.47, 55.48, 114.27, 121.40, 145.68, 155.71, 170.64. 93 These 1H NMR data are in agreement with the literature data. methyl 1-benzylaziridine-2-carboxylate (101) Br Br CO2Me 99 1.2 equiv. Bn-NH 2 2.5 equiv. Et 3N 10 mol% DMAP Bn N THF, 70°C, 1 h 89% 101 CO2Me The procedure to synthesize 101 is identical to the synthesis of 100 above except benzyl amine was used and reaction was complete at 1 h. The reaction afforded 101 (1.01 g, 5.79 mmol, 89%) as a light yellow oil. Spectra data for 101: 1H NMR (500 MHz, CDCl3) δ 1.76 (dd, J = 6.5, 1.0 Hz, 1H), 2.21 (dd, J = 6.5, 3.5 Hz, 1H), 2.27 (dd, J = 3.5, 1.0 Hz, 1H), 3.55 (d, J = 4.5 Hz, 2H), 3.72 (s, 3H), 7.26-7.29 (m, 1H), 7.33-7.34 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 34.57, 37.34, 52.25, 63.91, 127.36, 128.06, 128.44, 137.67, 171.17. 94 These 1H NMR data are in agreement with the literature data. 210 (1-(4-methoxyphenyl)aziridin-2-yl)diphenylmethanol (102) OMe OMe 3 equiv. PhMgCl THF, rt, 30 min 89% N N CO2Me 102 100 OH Ph Ph To a flame-dried 20 mL round bottom flask was added the aziridine ester 100 (0.30 g, 1.45 mmol, 1 equiv.) and 10 mL THF. The flask was sealed with a septum with a N2 balloon attached via a needle. To this stirring solution was added PhMgCl (2M in THF, 2.2 mL, 4.4 mmol, 3 equiv.) dropwise. The resulting solution was stirred at room temperature for 30 min and then quenched with saturated NH4Cl solution 10 mL. The aqueous phase was extracted with ethyl ether (10 mL x 2), and the combined organic phase was washed with brine 10 mL, dried over MgSO4, filtered through filter paper, concentrated on rotary vaporization and the residue was dissolved in 5 mL hot hexane, then placed in the freezer for 30 min, the solid collected from the solution was washed with hexane until the solid is white. The reaction afforded the product 102 (0.45 g, 1.3 mmol, 89%) as a white solid. mp. = 112-113 °C. A second run with (R)-100 gave (R)-102 (0.0850 g, 0.259 mmol, 69%) as a yellow solid. The optical purity of (R)-102 was determined to be 99% ee by Chiralcel OD-H, 99:1 hexane:i-PrOH, 238 nm, 1 mL/min, 14.3 min for the minor enantiomer and 15.0 min for the major enantiomer. Spectra data for (R)-102: 1H NMR (500 MHz, CDCl3) δ 2.25 (d, J = 6.5 Hz, 211 1H), 2.53 (d, J = 3.5 Hz, 1H), 2.98 (dd, J = 6.5, 3.5 Hz, 1H), 3.72 (s, 3H), 3.79 (s, 1H), 6.52 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 7.29 (tt, J = 7.5, 2.0 Hz, 1H), 7.33 (tt, J = 7.5, 2.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.52 (d, J = 7.0 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 31.16, 47.84, 55.50, 74.31, 114.20, 121.22, 125.96, 126.62, 127.10, 127.45, 128.28, 128.34, 144.15, 146.09, 147.35, 155.45. IR (thin film) 3427 br m, 2928 m, 1508 s, 1448 m, 1242 s, 1033 m cm-1; HRMS (ESI-TOF) calcd 332.1651 for C22H22NO2 m/z (M+H)+, found . [α]D20= +57.5° (c 1.0, CH2Cl2) on 99% ee. (1-benzylaziridin-2-yl)diphenylmethanol (103) Bn N 3 equiv. PhMgCl THF, rt, 30 min CO2Me Bn N 100% 101 103 OH Ph Ph The procedure to synthesize 103 is identical to the synthesis of 102 above except the starting material is 101. The reaction afforded 103 (0.49 g, 1.6 mmol, 100%) as a white solid. mp. = 101-102 °C. Spectra data for 103: 1H NMR (500 MHz, CDCl3) δ 1.57 (d, J = 6.5 Hz, 1H), 2.05 (d, J = 3.5 Hz, 1H), 2.57 (dd, J = 6.5, 3.5 Hz, 1H), 3.47 (d, J = 13.5 Hz, 1H), 3.79 (d, J = 13.5 Hz, 1H), 3.87 (s, 1H), 7.20-7.30 (m, 8H), 7.32-7.37 (m, 4H), 7.44 (dt, J = 8.0, 1.5 Hz, 2H), 1 aromatic proton was not located; 13 C NMR (125 MHz, CDCl3) δ 30.54, 46.13, 63.05, 74.13, 125.80, 126.32, 126.34, 126.82, 127.04, 127.24, 128.04, 128.16, 128.35, 138.32, 144.93, 147.51. These NMR data are in 212 95 partial agreement with the literature data. 3-((4-methoxyphenyl)amino)-1,2-diphenylpropan-1-one (104) PMP N 102 OH Ph 1 equiv. TfOH DCM, 3 h, 87% MeO O N H Ph 104 Ph Ph To a flame-dried 10 mL round bottom flask was added aziridinol 102 (0.0331 g, 0.100 mmol, 1 equiv.) and 0.3 mL CH2Cl2. The flask was sealed with a septum with a N2 balloon attached via a needle. To this stirring solution was slowly added TfOH (9.24 µL, 0.105 mmol, 1.05 equiv.). The resulting orange color solution was allowed to stir at room temperature for 3 h (due to volatility of CH2Cl2, 0.1 mL CH2Cl2 was added to the reaction mixture every 1 h). The reaction was quenched with 1 drop of Et3N. The solvent was removed on rotary vaporization and the residue was subjected to silica gel chromatography, a 8:1 mixture of hexane:EtOAc as the eluent, to afford the product 104 (0.0287 g, 0.0879 mmol, 87%) as a yellow oil. A second run with 99% ee (R)-102 gave (S)-104 (0.0310 g, 0.0941 mmol, 94%) as a yellow oil. The optical purity of (S)-104 was determined to be 96% ee by Chiralcel OD-H, 97:3 hexane:i-PrOH, 245 nm, 1 mL/min, 12.8 min for the minor enantiomer and 15.8 min for the major enantiomer. Spectra data for (S)-104: 1H NMR (500 MHz, CDCl3) δ 3.51 (dd, J = 13.5, 6.0 Hz, 1H), 3.73 (br s, 1H), 3.76 (s, 3H), 3.95 (dd, J = 13.5, 8.0 Hz, 1H), 4.91 (dd, J = 213 8.0, 6.0 Hz, 1H), 6.61 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 7.26 (tt, J = 7.0, 2.0 Hz, 1H), 7.30-7.33 (m, 3H), 7.36 (t, J = 8.0 Hz, 3H), 7.47 (tt, J = 7.0, 1.0 Hz, 1H), 7.91 (dt, J = 7.0, 1.0 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 48.15, 52.95, 55.77, 114.57, 115.00, 127.55, 128.24, 128.53, 128.79, 129.27, 133.10, 136.39, 137.45, 141.54, 152.27, 199.20. IR (neat) 3399 br m, 2928 m, 1676 s, 1514 s, 1236 s, 1037 m cm-1; HRMS (ESI-TOF) calcd 332.1651 for C22H22NO2 m/z (M+H)+, found . [α]D20= –110.2°(c 1.0, CH2Cl2) on 96% ee. 3-(benzylamino)-1,2-diphenylpropan-1-one (105) Bn N 103 OH Ph Ph 1 equiv. TfOH PhCl, 4 h, 100 °C 45% O Bn N H Ph Ph 105 The synthesis procedure for 105 is similar to that of 104 above, except 103 was the starting material, solvent was PhCl and heated to 100 °C for 4 h with a water condenser. The reaction did not proceed at a lower temperature, i. e. 70 °C for 1 h. The reaction afforded 105 (0.0138 g, 0.0438 mmol, 45%) as a yellow oil. Spectra data for 105: 1H NMR (500 MHz, CDCl3) δ 1.79 (br s, 1H), 2.97 (dd, J = 12.0, 6.0 Hz, 1H), 3.45 (dd, J = 12.0, 8.0 Hz, 1H), 3.79 (d, J = 13.5 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 4.85 (dd, J = 8.0, 6.0 Hz, 1H), 7.20-7.32 (m, 10H), 7.37 (t, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 52.82, 54.04, 54.41, 126.93, 127.37, 128.04, 128.28, 128.40, 128.49, 128.78, 129.09, 133.00, 136.50, 137.79, 140.06, 199.30 214 ethyl (2R,3R)-1-(4-methoxyphenyl)-3-phenylaziridine-2-carboxylate (107) 5 mol% Cu(OAc)2 10 mol% nC9H19 COOH 1.5 equiv. PMP-B(OH) 2 1 equiv. 2,6-lutidine H N Ph CO2Et PMP N Ph toluene, rt, 24 h, 31% CO2Et 107 106 PMP = p-methoxylphenyl Compound 106 was synthesized according to a literature procedure. This 68 reaction procedure is the same to the literature. To a 20 mL flame-dried round bottom flask was added copper (II) acetate (0.0094 g, 0.052 mmol, 5 mol%), n-C9H18COOH (0.0172 g, 0.100 mmol, 10 mol%), 4-methoxyphenylboronic acid (0.22 g, 1.4 mmol, 1.5 equiv.) and toluene 2 mL. The resulting suspension was stirred slowly and 2,6-lutidine (0.11 mL, 0.95 mmol, 1 equiv.) was added via a syringe. After a few minutes, NH aziridine 106 (0.18 g, 0.95 mmol, 1 equiv.) was added and the resulting mixture was stirred vigorously at room temperature under air for 24 h. The reaction mixture was then diluted with 10 mL hexane, and the solids are filtered off through a filter paper. The filtrate was concentrated on rotary vaporization and the residue was subjected to silica gel chromatography, a 10:1 mixture of hexane:EtOAc as the eluent, to afford the product 107 (0.0862 g, 0.294 mmol, 31%) as a yellow oil. Spectra data for 107: 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 3H), 3.15 (d, J = 7.0 Hz, 1H), 3.53 (d, J = 7.0 Hz, 1H), 3.77 (s, 3H), 3.99 (dq, J = 9.5, 7.0 Hz, 1H), 4.07 (dq, J = 9.5, 7.0 Hz, 1H), 6.82 (dt, J = 9.0, 2.0 Hz, 2H), 7.00 (dt, J = 9.0, 2.0 Hz, 2H), 7.30 (tt, J = 7.0, 1.5 Hz, 1H), 7.35 (tt, J = 7.0. 1.5 Hz, 2H), 215 7.51 (dt, J = 7.0, 1.5 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 13.94, 45.83, 47.46, 55.51, 61.00, 114.41, 120.81, 127.68, 127.82, 128.07, 134.73, 145.73, 155.83, 167.82. These NMR data are in partial agreement with the literature data. 93 ((2R,3R)-1-(4-methoxyphenyl)-3-phenylaziridin-2-yl)diphenylmethanol (108) PMP N Ph CO2Et 107 PMP N 3 equiv. PhMgCl THF, rt, 30 min 60% Ph 108 OH Ph Ph The synthesis procedure of 108 is identical to 102 except it was purified with silica gel column, a 2:1 to 1:1 mixture of hexane:CH2Cl2 as the eluent. The reaction gave 108 (0.10 g, 0.27 mmol, 60%) as a white solid product. mp. = 155-156 °C. Spectra data for 108: 1H NMR (500 MHz, CDCl3) δ 3.23 (s, 1H), 3.34 (d, J = 6.0 Hz, 1H), 3.56 (d, J = 6.5 Hz, 1H), 3.73 (s, 3H), 6.59 (dt, J = 9.0, 2.0 Hz, 2H), 6.69 (dt, J = 9.0, 2.0 Hz, 2H), 7.17-7.21 (m, 5H), 7.24-7.31 (m, 4H), 7.38 (tt, J = 7.5, 1.5 Hz, 2H), 7.45 (dt, J = 7.0, 1.5 Hz, 2H), 7.53 (dt, J = 7.0, 1.5 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 46.79, 54.84, 55.54, 75.04, 114.30, 120.64, 125.64, 126.24, 126.97, 127.00, 127.03, 127.53, 127.87, 128.02, 128.32, 135.75, 144.33, 146.64, 147.99, 155.67. 216 5-((2R,3R)-3-phenylaziridin-2-yl)nonan-5-ol (110) H N Ph CO2Et 106 H N 4 equiv. nBuLi THF, –78°C, 10 min, 50% Ph 110 OH nBu nBu To a flame-dried 10 mL round bottom flask was added 0.5 mL THF and n-BuLi (2M in hexane, 0.60 mL, 1.2 mmol, 4 equiv.). The flask was sealed with a septum with a N2 balloon attached via a needle. The flask was cooled to –78 °C in a dry ice acetone bath for 5 min. The a solution of NH aziridine 106 (0.0620 g, 0.321 mmol, 1 equiv.) in 0.5 mL THF was added to the flask dropwise via a syringe. The resulting mixture was stirred at the same temperature for 10 min and then quenched with saturated NH4Cl solution. The aqueous phase was extracted with diethyl ether (10 mL x 2), washed with brine and dried over MgSO4. the solids are filtered off through a filter paper. The filtrate was concentrated on rotary vaporization and the residue was subjected to silica gel chromatography, a 10:1 mixture of hexane:EtOAc as the eluent, to afford the product 110 (0.0418 g, 0.160 mmol, 50%) as a white solid. mp. = 101-102 °C. Spectra data for 110: 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H), 1.21-1.41 (m, 11H), 1.50-1.53 (m, 2H), 2.12 (br s, 1H), 2.35 (d, J = 6.5 Hz, 1H), 3.29 (d, J = 6.5 Hz, 1H), 7.21 (t, J = 7.0 Hz, 1H), 7.30 (t, J = 7.0 Hz, 2H), 7.40 (d, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 14.03, 14.18, 23.32, 23.34, 25.30, 25.92, 36.81, 36.87, 40.60, 43.28, 71.85, 126.71, 127.69, 217 128.00, 137.25. Benzyl (2R,3R)-2-(5-hydroxynonan-5-yl)-3-phenylaziridine-1-carboxylate (111) H N Ph 110 OH nBu nBu Cbz N 1.1 equiv. CbzCl 1.1 equiv. Et 3N THF, rt, 30 min 92% Ph 111 OH nBu nBu To a 20 mL screw cap vial was added NH aziridine 110 (0.0400 g, 0.152 mmol, 1 equiv.), THF 1 mL and Et3N (0.025 mL, 0.18 mmol, 1.2 equiv.), while stirring, CbzCl (0.025 mL, 0.18 mmol, 1.2 equiv.) was added dropwise to the solution. The vial was capped and the resulting mixture was stirred at room temperature for 30 min. The solids are filtered off through a filter paper. The filter cake was thoroughly washed with diethyl ether. The filtrate was concentrated on rotary vaporization and the residue was subjected to silica gel chromatography, a 15:1 mixture of hexane:EtOAc as the eluent, to afford the product 111 (0.0559 g, 0.141 mmol, 92%) as a white solid. mp. = 80-82 °C. Spectra data for 111: 1H NMR (500 MHz, CDCl3) δ 0.85-0.89 (m, 6H), 1.13 (s, 1H), 1.27-1.42 (m, 10H), 1.56-1.66 (m, 2H), 2.80 (d, J = 6.5 Hz, 1H), 3.74 (d, J = 6.5 Hz, 1H), 5.20 (d, J = 6.5 Hz, 2H), 7.26 (t, J = 7.0 Hz, 1H), 7.31-7.38 (m, 7H), 7.43 (d, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.98, 14.06, 23.17, 23.25, 25.01, 25.63, 36.02, 39.35, 43.83, 50.72, 68.44, 72.82, 127.40, 127.48, 128.11, 218 128.28, 128.37, 128.58, 134.83, 135.59, 163.70. 5-((2R,3R)-3-propylaziridin-2-yl)nonan-5-ol (115) H N 4 equiv. nBuLi CO2Et THF, –78°C, 15 min, 44% H N 115 OH nBu nBu 114 Compound 114 was synthesized according to a literature procedure. The synthesis procedure for 115 is identical to that of 110. The reaction gave 115 (0.10 g, 0.44 mmol, 44%) as a light yellow solid product. mp. = 60-61 °C. Spectra data for 115: 1H NMR (500 MHz, CDCl3) δ 0.89-0.97 (m, 9H), 1.25-1.63 (m, 17H), 1.99-2.03 (m, 2H), 2.90 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 14.04, 14.08, 14.19, 21.86, 23.38, 23.49, 25.49, 25.97, 30.52, 35.20, 37.62, 40.17, 41.36, 70.59. benzyl (2R,3R)-2-(5-hydroxynonan-5-yl)-3-propylaziridine-1-carboxylate (116) H N 115 OH nBu nBu Cbz N 1.1 equiv. CbzCl 1.1 equiv. Et 3N THF, rt, 30 min, 95% 116 OH nBu nBu The synthesis procedure of 116 is identical to that of 111. The reaction gave 116 (0.0880g, 0.243 mmol, 95%) as a white wax-like solid. mp. = 52-53 °C. Spectra data for 116: 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 219 0.92 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H), 1.25-1.36 (m, 8H), 1.41-1.71 (m, 9H), 1.71-1.80 (m, 1H), 1.89 (s, 1H), 2.45-2.49 (m, 2H), 5.13 (s, 2H), 7.32-7.39 (m, 5H); 13 C NMR (125 MHz, CDCl3) δ 13.82, 14.02, 14.06, 21.48, 23.19, 23.37, 25.18, 25.71, 29.67, 35.92, 40.52, 43.65, 48.43, 68.20, 71.79, 127.94, 128.26, 128.53, 135.73, 163.99. ethyl (2R,3R)-1-(4-methoxyphenyl)-3-propylaziridine-2-carboxylate (118) 5 mol% Cu(OAc)2 10 mol% nC9H19 COOH 1.5 equiv. PMP-B(OH) 2 1 equiv. 2,6-lutidine H N CO2Et 114 toluene, rt, 24 h, 44% PMP = p-methoxylphenyl OMe N CO2Et 118 The synthesis procedure of 118 is identical to that of 107. The reaction gave 118 (0.22 g, 0.84 mmol, 44%) as a yellow oil. Spectra data for 118: 1H NMR (500 MHz, CDCl3) δ 1.01 (t, J = 7.0 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H), 1.50-1.58 (m, 1H), 1.59-1.70 (m, 2H), 1.72-1.80 (m, 1H), 2.38 (dt, J = 7.0, 5.0 Hz, 1H), 2.78 (d, J = 7.0 Hz, 1H), 3.75 (s, 3H), 4.24-4.32 (m, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.91, 14.35, 20.92, 30.18, 42.88, 46.28, 55.46, 61.20, 114.19, 120.96, 146.29, 155.51, 169.42. 220 ((2R,3R)-1-(4-methoxyphenyl)-3-propylaziridin-2-yl)diphenylmethanol (119) OMe 3 equiv. PhMgCl THF, rt, 30 min 78% PMP N N CO2Et 119 OH Ph Ph 118 The synthesis procedure of 119 is identical to that of 102 and 108, except it was purified with silica gel column, a 15:1 mixture of hexane:EtOAc as the eluent. The reaction gave 119 (0.0624 g, 0.156 mmol, 78%) as a white solid product. mp. = 145-147 °C. Spectra data for 119: 1H NMR (500 MHz, CDCl3) δ 0.95 (t, J = 7.0 Hz, 3H), 1.44-1.51 (m, 2H), 1.57-1.72 (m, 2H), 2.40-2.44 (m, 1H), 2.98 (d, J = 6.5 Hz, 1H), 3.72 (s, 3H), 4.31 (s, 1H), 6.51 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 7.29 (td, J = 7.5, 1.5 Hz, 2H), 7.35-7.39 (m, 4H), 7.53 (d, J = 7.0 Hz, 2H), 7.56 (d, J = 7.0 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.08, 21.91, 29.98, 46.41, 53.03, 55.50, 74.23, 114.18, 120.97, 125.97, 126.38, 126.80, 127.12, 128.11, 128.29, 144.82, 146.81, 149.13, 155.46. ethyl (R)-aziridine-2-carboxylate (122) NH 3Cl HO CO2Et 121 D-Serine ethyl ester hydrochloride 1) 1 equiv. KOH EtOH, rt, 5 min 2) 1 equiv. PPh 3 1 equiv. DIAD DCM, rt, 15 h H N CO2Et 122 22% over two steps 221 69 The synthesis of 122 is adapted from a literature procedure. To a 10 mL round bottom flask was added D-serine ethyl ester hydrochloride 121 (1.69 g, 10.0 mmol. 1 equiv.) and 5 mL EtOH, while stirring, a solution of KOH (0.56 g, 10 mmol, 1 equiv.) in 5 mL EtOH was added dropwise and the flask was sealed with a septum with a N2 balloon attached via a needle. The solution was allowed to stir at room temperature for 10 min. The solids were filtered through a filter paper and the filter cake was thoroughly washed with EtOH. The filtrate was concentrated on rotary vaporization. To the residue was added 10 mL CH2Cl2, and cooled in an ice bath for 5 min. PPh3 (2.63 g, 10.0 mmol, 1 equiv.) was added slowly to the stirring solution in several portions. After addition of PPh3, DIAD (2.0 mL, 10 mmol, 1 equiv.) was added dropwise via a syringe. Then the solution was allowed to warm to room temperature and stirred for 15 h. The solvent was removed on rotary vaporization. The residue was treated with a mixture of 1:1 Et2O:hexane 20 mL, and cooled in the freezer for 30 min to precipitate the phosphine oxide. The solids were filtered through a filter paper and the filter cake was thoroughly washed with a mixture of 1:1 Et2O:hexane. The filtrate was concentrated on rotary vaporization. The treatment with a mixture of 1:1 Et2O:hexane was repeated until no more solid formed after the treatment. The final residue was subjected to silica gel chromatography, a mixture of 1:1 Et2O:hexane as the eluent, to afford the product 122 (0.25 g, 2.2 mmol, 22%) as a yellow oil. The low yield was due to the high volatility of the product. A butyl ester or benzyl ester of D-Serine may improve the 222 69 yield. Spectra data for 122: 1H NMR (500 MHz, CDCl3) δ 1.25 (br s, 1H), 1.30 (t, J = 7.0 Hz, 3H), 1.86 (dd, J = 5.5, 1.5 Hz, 1H), 2.00 (dd, J = 3.0, 1.5 Hz, 1H), 2.51 (dd, J = 5.5, 3.0 Hz, 1H), 4.17-4.26 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 14.16, 27.21, 28.94, 61.58, 172.99. These 1H NMR data are in agreement with literature 96 data. ethyl (R)-1-(4-methoxyphenyl)aziridine-2-carboxylate (123) 5 mol% Cu(OAc)2 10 mol% nC9H19 COOH 1.5 equiv. PMP-B(OH) 2 1 equiv. 2,6-lutidine H N CO2Et 122 toluene, rt, 24 h, 23% OMe N CO2Et PMP = p-methoxylphenyl 123 The procedure for the synthesis of 123 is identical to that of 107 and 118. The reaction afforded 123 (0.11 g, 0.50 mmol, 23%) as a yellow oil. Spectra data for 123: 1H NMR (500 MHz, CDCl3) δ 1.31 (t, J = 7.0 Hz, 3H), 2.26 (dd, J = 6.0, 1.0 Hz, 1H), 2.62 (dd, J = 3.0, 1.0 Hz, 1H), 2.71 (dd, J = 6.0, 3.0 Hz, 1H), 3.75 (s, 3H), 4.20-4.31 (m, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 14.18, 34.00, 37.95, 55.47, 61.46, 114.24, 121.45, 145.72, 155.68, 170.17. These NMR data are in agreement with literature 97 data. 223 (R)-(1-(4-methoxyphenyl)aziridin-2-yl)diphenylmethanol (R-102) PMP N 3 equiv. PhMgCl THF, rt, 30 min PMP N OH Ph Ph CO2Et 123 (R)-102 69% yield, 99% ee The synthesis procedure of (R)-102 is identical to that of 102. The reaction gave the product (R)-102 (0.0850 g, 0.256 mmol, 69%) as a white solid. mp. = 112-113 °C. The optical purity of (R)-102 was determined to be 99% ee by Chiralcel OD-H, 99:1 hexane:i-PrOH, 238 nm, 1 mL/min, 14.3 min for the minor enantiomer and 15.0 min for the major enantiomer. Spectra data for (R)-102: 1H NMR (500 MHz, CDCl3) δ 2.25 (d, J = 6.5 Hz, 1H), 2.53 (d, J = 3.5 Hz, 1H), 2.98 (dd, J = 6.5, 3.5 Hz, 1H), 3.72 (s, 3H), 3.79 (s, 1H), 6.52 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 7.29 (tt, J = 7.5, 2.0 Hz, 1H), 7.33 (tt, J = 7.5, 2.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.52 (d, J = 7.0 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 31.16, 47.84, 55.50, 74.31, 114.20, 121.22, 125.96, 126.62, 127.10, 127.45, 128.28, 128.34, 144.15, 146.09, 147.35, 155.45. IR (thin film) 3427 br m, 2928 m, 1508 s, 1448 m, 1242 s, 1033 m cm-1; HRMS (ESI-TOF) calcd 332.1651 for C22H22NO2 m/z (M+H)+, found 332.1699. [α]D20= +57.5° (c 1.0, CH2Cl2) on 99% ee. 224 (S)-3-((4-methoxyphenyl)amino)-1,2-diphenylpropan-1-one (S-104) PMP N 1 equiv. TfOH DCM, rt, 2.5 h OH Ph Ph PMP H N Ph O Ph (S)-104 95% yield, 96% ee (R)-102 69% yield, 99% ee The synthesis procedure of (S)-104 is identical to that of 104. To a flame-dried 10 mL round bottom flask was added aziridinol (R)-102 (0.0331 g, 0.100 mmol, 1 equiv.) and 0.3 mL CH2Cl2. The flask was sealed with a septum with a N2 balloon attached via a needle. To this stirring solution was slowly added TfOH (9.24 µL, 0.105 mmol, 1.05 equiv.) via a syringe. The resulting orange color solution was allowed to stir at room temperature for 2.5 h (the reaction progress was monitored with 1HNMR, and due to volatility of CH2Cl2, 0.1 mL CH2Cl2 was added to the reaction mixture every 1 h). The reaction was quenched with 1 drop of Et3N. The solvent was removed on rotary vaporization and the residue was subjected to silica gel chromatography, a 8:1 mixture of hexane:EtOAc as the eluent, to afford the product (S)-104 (0.0310 g, 0.0941 mmol, 94%) as a yellow oil. The optical purity of (S)-104 was determined to be 96% ee by Chiralcel OD-H, 97:3 hexane:i-PrOH, 245 nm, 1 mL/min, 12.8 min for the minor enantiomer and 15.8 min for the major enantiomer. Spectra data for (S)-104: 1H NMR (500 MHz, CDCl3) δ 3.51 (dd, J = 13.5, 6.0 Hz, 1H), 3.73 (br s, 1H), 3.76 (s, 3H), 3.95 (dd, J = 13.5, 8.0 Hz, 1H), 4.91 (dd, J = 8.0, 6.0 Hz, 1H), 6.61 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 225 7.26 (tt, J = 7.0, 2.0 Hz, 1H), 7.30-7.33 (m, 3H), 7.36 (t, J = 8.0 Hz, 3H), 7.47 (tt, J = 7.0, 1.0 Hz, 1H), 7.91 (dt, J = 7.0, 1.0 Hz, 2H); 13 C NMR (125 MHz, CDCl3) δ 48.15, 52.95, 55.77, 114.57, 115.00, 127.55, 128.24, 128.53, 128.79, 129.27, 133.10, 136.39, 137.45, 141.54, 152.27, 199.20. IR (neat) 3399 br m, 2928 m, 1676 s, 1514 s, 1236 s, 1037 m cm-1; HRMS (ESI-TOF) calcd 332.1651 for C22H22NO2 m/z (M+H)+, found 332.1521. [α]D20= –110.2°(c 1.0, CH2Cl2) on 96% ee. 226 REFERENCES 227 REFERENCES (1) Fittig, R. Justus Liebigs Annalen der Chemie 1860, 114, 54. (2) Schoppee, C. W.; Prins, D. A. Helv. Chim. Acta. 1943, 26, 185. (3) Paquette, L. A.; Hofferberth, J. E. Organic Reactions 2003, 62, 477. (4) Stevens, C. L.; Thuillier, A.; Daniher, F. A. 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