Hydrogen Bond-Directed Stereospecific Interactions in (A) General Synthesis of Chiral Vicinal Diamines and (B) Generation of Helical Chirality with Amino Acids

HYDROGEN BOND-DIRECTED STEREOSPECIFIC INTERACTIONS IN (A) GENERAL SYNTHESIS OF CHIRAL VICINAL DIAMINES AND (B) GENERATION OF HELICAL CHIRALITY WITH AMINO ACIDS

Hyunwoo Kim

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Chemistry University of Toronto

Hyunwoo Kim

Doctor of Philosophy 2009 Department of Chemistry University of Toronto ABSTRACT

Hydrogen bonding interactions have been applied to the synthesis of chiral vicinal diamines and the generation of helical chirality. A stereospecific synthesis of vicinal diamines was developed by using the diaza-Cope rearrangement reaction driven by resonance-assisted hydrogen bonds

(RAHBs). This process for making a wide variety of chiral diamines requires only a single starting chiral diamine, 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN) and aldehydes. Experimental and computational studies reveal that this process provides one of the simplest and most versatile approaches to preparing chiral vicinal diamines including not only C2 symmetric diaryl and dialkyl diamines but also unsymmetrical alkyl-aryl and aryl-aryl diamines with excellent yields and enantiopurities.

Weak forces affecting kinetics and thermodynamics of the diaza-Cope rearrangement were systematically studied by combining experimental and computational approaches. These forces include hydrogen bonding effects, electronic effects, steric effects, and oxyanion effects.

As an example of tuning diamine catalysts, a vicinal diamine-catalyzed synthesis of warfarin is described. Detailed mechanistic studies lead to a new mechanism involving diimine intermediates.

Decreasing the NCCN dihedral angle by varying the diamine structure results in an increase of the enantioselectivity up to 92% ee.

Hydrogen bonds have been used to generate helical chirality in a highly stereospecific manner with a single amino acid and 2,2′-dihydroxybenzophenone. DFT computational and experimental data including circular dichroism (CD), X-ray crystallography and 1H NMR data provide insight into the origin of the stereospecificity. A signalling dizao group can be attached to the receptor for general sensing of amino acid enantiopurity.

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my supervisor, Professor Jik Chin, for his mentorship, guidance, and encouragement throughout my studies. His scientific insight and unbounded enthusiasm will always be a source of inspiration for me.

I would also like to thank Professors Andrei Yudin, Vy Dong, Mark Lautens, and Peter Guthrie for their discussions and suggestions while serving as members of my thesis defense committee. I extend my gratitude to Dr. Tim Burrow (NMR) and Dr. Alan Lough (X-ray) for their technical assistance.

The financial support from Government of Canada Awards, University of Toronto, and

DiaminoPharm Inc. is greatly acknowledged.

My time spent in the Chin group has been enjoyable and memorable. I would like to thank

Professor Hae-Jo Kim, Dr. Soon Mog So, Dr. Woosung Kim, Cindy Yen, Yen Nguyen, and Leo

Mui for their support and friendship. I wish to thank Cindy once again for helping my departmental seminar and for reading all my rough writing.

I would like to express my deepest gratitude to my parents. They have supported me in every way imaginable throughout my life and I could not have done this without them. This work is dedicated to them.

My final thanks are reserved for my beautiful wife Eunha. Everything that I have accomplished during my time here would definitely not be possible without the constant love, understanding, and support from her.

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TABLE OF CONTENTS

Chapter 1: Introduction to Vicinal Diamines ...... 1 1.1. Introduction ...... 1 1.2. Synthesis of chiral, vicinal diamines ...... 2 1.2.2. Production of DACH and DPEN ...... 3 1.2.2. Enantioselective synthesis of vicinal diamines ...... 4 1.3. Vicinal-diamine-based catalysts ...... 6 1.3.1. Steric and electronic tuning of catalyst structure ...... 8 1.3.2. New diamine designs ...... 13 1.3.3. Diamines on solid support ...... 15 1.3.4. Water-soluble diamine catalysts ...... 16 1.4. Diamine drugs ...... 16 1.4.1. Acyclic diamines ...... 17 1.4.2. Imidazolines ...... 18 1.4.3. Piperazines ...... 19 1.4.4. Other diamines ...... 19 1.5. Summary ...... 21 1.6. Plan of Study ...... 22

Chapter 2: Stereospecific Synthesis of Vicinal Diamines by the Diaza-Cope Rearrangement ...... 24 2.1. Introduction ...... 24 2.2. Diaryl vicinal diamines ...... 25 2.3. Dialkyl vicinal diamines ...... 37 2.3.1. Imidazolidine-dihydro-1,3-oxazines ...... 38 2.3.2. Synthesis of dialkyl vicinal diamines ...... 45 2.3.1. Origin of synthetic challenge ...... 50 2.3.2. Transition state geometries ...... 54 2.4. Unsymmetrical vicinal diamines ...... 56 2.4.1. Unsymmetrical diaryl diamines ...... 57 2.4.2. Unsymmetrical alkyl-aryl diamines ...... 59 2.5. Diastereoselective diaza-Cope Rearrangement ...... 62 2.6. Conclusions ...... 68 2.7. Experimental ...... 69

Chapter 3: Controlling Diaza-Cope Rearrangements with weak forces ...... 87

3.1. Introduction ...... 87 3.2. The electronic effect ...... 89 3.3. The hydrogen bonding effect ...... 94 3.4. The steric effect ...... 102 3.5. The oxyanion effect ...... 112 3.6. Interplay of weak forces on the thermodynamics ...... 117 3.7. Effect of weak forces on the kinetics ...... 121 3.8. Conclusions ...... 123 3.9. Experimental ...... 124

Chapter 4: Organocatalytic Synthesis of Warfarin ...... 128 4.1. Introduction ...... 128 4.2. Revision of imidazolidine catalyzed warfarin synthesis ...... 129 4.3. Vicinal diamine-catalyzed synthesis of warfarin ...... 134 4.4. Conclusions ...... 140 4.5. Experimental ...... 140

Chapter 5: Highly Stereospecific Generation of Helical Chirality by Imprinting with Amino Acids ...... 141

5.1. Introduction ...... 141 5.2. Generation of helical chirality with a single amino acid ...... 145 5.3. A universal sensor for amino acid enantiopurity ...... 154 5.4. Conclusions ...... 160 5.5. Experimental ...... 160

Conclusions ...... 169

Publications ...... 171

Appendix I: Selected NMR spectra ...... 173

Appendix II: HPLC Chromatograms ...... 233

Appendix III: Circular Dichroism Spectra ...... 250

Appendix IV: Computational Data ...... 256

List of Abbreviations

2D two dimensional A absorbance Å angstrom Ac acetyl AD asymmetric dihydroxylation Ar aryl B3LYP Becke, three-parameter, Lee-Yang-Parr BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn benzyl Bu butyl c concentration (g / 100 mL) cal calculated CD circular dichroism COD 1,5-cyclooctadiene concd concentrated conv conversion COSY correlation spectroscopy Cy cyclohexyl δ NMR chemical shift in parts per million d doublet (spectra), deuterium D absolute configuration, deuterium DACH 1,2-diaminocyclohexane dba dibenzylideneacetone DCR diaza-Cope rearrangement de diastereomeric excess d.r. diastereomeric ratio DFT density functional theory DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DPEN diphenylethylenediamine ε molar extinction coefficient E energy ee enantiomeric excess EI electron impact eq equilibrium

equiv equivalent(s) ESI electrospray ionization Et ethyl exp experimental G Gibbs free energy GOF goodness of fit H enthalpy HMPA hexamethylphosphoramide HPEN 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy i iso K equilibrium constant k rate constant λ wavelength L absolute configuration liq liquid M metal, molar (mol/L) M minus (left-handed helix) max maximum Me methyl Mes mesityl mol mole mp melting point Ms methanesulfonyl NMR nuclear magnetic resonance NOE nuclear Overhauser effect Np naphthyl ORTEP Oak Ridge thermal ellipsoid plot p para P plus (right-handed helix) Ph phenyl Piv pivaloyl (trimethylacetyl) pK negative logarithm of equilibrium constant PMP 1,2,2,5,5-pentamethylpiperidine ppm parts per million ppt precipitate Pr propyl

vii

Py pyridine Pybox pyridyl-bis(oxazoline) q quartet (spectra) rac racemic RAHB resonance-assisted hydrogen bond rel relative ROESY rotating-frame Overhauser spectroscopy RT room temperature s singlet (spectra), second (time) s secondary S entropy salen N-N′-ethylene bis(salicylimine) t triplet (spectra) t tertiary

t1/2 half-life T temperature (in Kelvins) TBS tri-n-butyl silyl Tf trifluoromethanesulfonic TFA trifluoroacetic acid THF tetrahydrofuran TMA tetramethylammonium TMS trimethylsilyl TPEN 1,2-bis(2,4,6-trimethylphenyl)-1,2-diaminoethane

tR retention time Ts toluenesulfonyl ts transition state UV-vis ultraviolet-visible w/w % weight percent ZPVE zero-point vibrational energy

viii

List of Amino Acid Abbreviations

1-Letter 3-Letter Amino Acid

A Ala alanine R Arg arginine N Asn asparagine D Asp aspartic acid C Cys cystein E Glu glutamic acid Q Gln glutamine G Gly glycine H His histidine I Ile isoleucine L Leu leucine K Lys lysine M Met methionine F Phe phenylalanine P Pro proline S Ser serine T Thr threonine W Trp tryptophan Y Tyr tyrosine V Val valine

CHAPTER 1

Introduction to Vicinal Diamines†

1.1. Introduction

Chiral vicinal diamines are of considerable interest as ligands for developing stereoselective catalysts and as intermediates in the synthesis of drugs (Figure 1-1). Diamine-based catalysts have been used for all types of reactions including oxidation, reduction, hydrolysis, and carbon-carbon- bond-forming reactions. Bioactive compounds that are based on vicinal diamines include anticancer, antiviral, antibacterial, antidepressant, and antihypertensive agents. In fact, the vicinal diamine structural motif could be considered ‘privileged’1 when it comes to developing catalysts and drugs.

Numerous publications, including several review articles,2-4 have appeared on the synthesis and applications of chiral diamines. Although much progress has been made, it has been a challenge to develop a facile, efficient, and general route to a wide range of chiral diamines in enantiomerically pure form. Such an approach would greatly facilitate the development of new diamine-based catalysts and drugs. It would also be useful for optimizing the performance of known diamine-based catalysts by tuning the steric and electronic properties of the attached ligands. Libraries of chiral diamines and their derivatives, such as imidazolines and piperazines, would be valuable for exploring the chiral space of selected drug receptors. This introductory chapter will summarize the reported methods for making chiral vicinal diamines and some diamine-based catalysts and drugs.

† This chapter and portions of chapter 2 have been published: Kim, H.; So, S. M.; Chin, J.; Kim, B. M. Alrichimica Acta 2008, 41, 77. 1 Yoon, T. P.; Jacobsen, E. N. Science, 2003, 299, 1691. 2 Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580. 3 Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. 4 Topics in Organometallic Chemistry; Lemaire, M. and Mangeney, P., Eds.; Springer: Berlin, 2005; Vol. 15, pp 1-287.

O (a)Ph Ph (b) O Rn NH H2N O R Ar NNAr Ts N Cl Ru N Cl AcHN O Cl Ph Ru O CO H Ph 2 H2N Cl PCy3 Ph LORABID® (antibacterial) ® for transfer for olefin TAMIFLU (antiviral) King Pharmaceuticals hydrogenation metathesis Hoffmann-La Roche O NH Cl O N

Ph N H2 N NN O O P N O O M N N Pt N t-Bu O O t-Bu Ph N O O O H2 Cl t-Bu t-Bu ® for C-C bond ELOXATIN (anticancer) Nutlin-3 (anticancer) for oxidation or hydrolysis formation Sanofi-Aventis Hoffmann-La Roche

Figure 1-1. Vicinal-diamine-based (a) catalysts and (b) bioactive compounds

1.2. Synthesis of chiral, vicinal diamines

The prevalence of the vicinal diamine motif in the structures of catalysts and bioactive compounds has led to the development of dozens of methods for the synthesis of vicinal diamines.

Some of the most practical routes to C2 symmetrical diaryl- and dialkyl-substituted primary diamines are shown in the ‘tree’ diagram in Scheme 1-1.

There is considerable interest in developing syntheses of vicinal diamines that are of broad scope.2 It is often difficult or tedious to make enantiomerically pure vicinal diamines on a large scale. Moreover, the efficient production of diphenylethylenediamine (DPEN)5 and 1,2-diamino-

5 (a) Williams, O. F.; Bailar, Jr. J. C. J. Am. Chem. Soc. 1959, 81, 4464. (b) Corey, E. J.; Kühnle, F. N. M. Tetrahedron Lett. 1997, 38, 8631.

2 cyclohexane (DACH)6 has undoubtedly contributed to the explosive growth of the field. However, a greater variation in the diamine structure is needed for discovering better catalysts and drugs.

NNH NN

Ph Ph Ar Ar TMS N CN 2 DPEN production CN Ar Reduction of imne Reductive Coupling DACH production

H2N NH2 H2N NH2 HO OH NH2 Ar Ar R R Ar Ar rac rac NH2 Optical Substitution resolution Reduction of phenyl

O H2N NH2 H2N NH2 Reductive Grignard Addition N N S Coupling N Ph Ph 2 Ar Ar R R + (+)or(-) (+) or (-) Ar tBuMgCl Diaryl diamine Dialkyl diamine

Scheme 1-1. Known syntheses of C2-symmetrical, primary vicinal diamines

1.2.1. Production of DACH and DPEN

1,2-Diaminocyclohexane (DACH) and 1,2-diphenylethylenediamine (DPEN) are the most commonly used diamine building blocks for the preparation of stereoselective catalysts (Figure 1-

1a). Racemic DACH was isolated as a by-product in the production of 1,6-hexanediamine, a monomer for the process of nylon 66.6a Resolution of the diamine by L- or D-tartaric acid produced

(R,R)- or (S,S)-DACH in enantiomerically pure form (Scheme 1-2a).6b Racemic DPEN can be

6 (a) Andrew I, S. U.S. Patent 3,187,045, 1965. (b) Whitney, T. A. U.S. Patent, 4,085,138, 1978.

3 prepared from hydrolysis of isoamarine, an intermediate that was characterized in early 1840s

(Scheme 1-2b).5a DPEN was also obtained in enantiopure form by resolution with tartaric acid. This synthetic approach for DPEN is particularly attractive because of the inexpensive starting materials.

However, hydrolysis of the imidazoline intermediate required harsh conditions.5b Corey and co- workers7 reported another practical route to making DPEN and its analogs from the Birch reduction of imidazole prepared from benzil and ammonia (Scheme 1-2c).

Resolution by N NH2 NH2 NH NH 3 NH Separation L-tartaric acid 2 2 + a) catalyst H2N N 2 3 NH2 NH2 NH2 (+) by-product (R,R)- DA CH

O Ph Ph Ph aq. NaOH liq. NH3 N N HN N HN N b) 120oC 155oC Al/Hg, H O Ph Ph 2 Ph Ph Ph Ph amarine isoamarine Resolution by Ph NH2 L-tartaric acid Ph NH2

Ph NH2 Ph NH2 Ph O Ph (+) NH4OAc, AcOH N (R,R)-DPEN c) + O 1. Li, THF-NH3,EtOH 2. HCl Ph O reflux Ph N 3, NaOH

Scheme 1-2. Practical synthesis of DACH and DPEN

1.2.2 Enantioselective synthesis of vicinal diamines

Vicinal diamines can be prepared from reductive coupling of imines (Scheme 1-3a).4 In general, the intermolecular reductive coupling gives a mixture of meso and dl diamines. Pederson and co-workers8 showed that niobium mediated reductive coupling of aromatic imines gives dl diamines with high diastereoselectivities. However this method gave poor yields and

7 (a) Pikul, S.; Corey, E. J. Org. Synth. 1993, 71, 22. (b) Corey, E. J.; Lee, D.-H.; Sarshar, S. Tetrahedron: Asymmetry 1995, 6, 3. 8 Roskamp, E. J.; Pedersen, S. F. J. Am. Chem. Soc. 1987, 109, 3152.

4 diastereoselectivities for the synthesis of dialkyl diamines. Although racemic diaryl diamines can be prepared by the coupling methods, resolution may be difficult or tedious for many of the diamines.9

Recently, samarium mediated reductive coupling of chiral sulfinyl imines has been reported by Xu and co-workers10 as a direct approach to synthesize enantiomerically pure diaryl vicinal diamines

(Scheme 1-3a). This method gives diamine enantiomers with variable yields (25-99%). The

Sharpless asymmetric dihydroxylation (or diamination) of alkenes can also lead to enantiopure diamines without the need for chiral resolution (Scheme 1-3b).11,12 This method has the advantage of being catalytic, although scale up may be difficult with a step requiring sodium azide.

O O O a) S 2SmI2/THF HCl, MeOH H N NH N t-Bu S NH HN S 2 2 HMPA, -78oC t-Bu t-Bu rt Ar Ar Ar Ar Ar

1. MsCl OH 2. NaN3 NH2 b) AD 3. LiAlH4

OH NH2

Scheme 1-3. Stereoselective synthesis of diamines

The synthesis of chiral alkyl diamines is more challenging than that of chiral aryl diamines (see

Chapter 2.3). 1,2-Bis(cyclohexyl)-1,2-diaminoethane was synthesized by reduction of DPEN

(Scheme 1-4a).13 The stereoselective synthesis of dialkyl diamines by addition of Grignard reagents

9 (a) Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.; Minami, S.; Ema, T. Bull. Chem. Soc. Jpn. 2004, 77, 1001. (b) Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.; Nakanishi, W.; Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008, 73, 133. 10 Zhong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6, 4747. 11 Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. 12 (a) Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T. Tetrahedron 1994, 50, 11827. (b) Hilgraf, R.; Pfaltz, A. Adv. Synth. Catal. 2005, 347, 61. 13 Ohkuma, T.; Ooka, H.; Ikariya, T. Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417.

5 to chiral bis-imines was successful only in the case where the bulky tert-butylmagnesium chloride was used (Scheme 1-4b).14

NH2 NH2 PtO2,H2 a) 85% NH2 NH2

O O HCO H b) + 2 t-BuMgCl H N N Na2SO4 Ph Ph 95% NH2 Ph

HCO2NH4

NH HN Pd(OH)2 83% H N NH Ph Ph 2 2 de >95%

Scheme 1-4. Known syntheses of dialkyl vicinal diamines

1.3. Vicinal-diamine-based catalysts

Chiral vicinal diamines are some of the most important ligands in the design of stereoselective catalysts.15 They have been utilized in creative ways to develop a wide variety of innovative chiral catalysts (see Figure 1-1). Some of the diamine-based, stereoselective catalysts developed to date include reduction, 16 oxidation, 17 and hydrolysis 18 catalysts. Other diamine-based compounds

14 Roland, S.; Mangeney, P.; Alexakis, A. Synthesis 1999, 2, 228. 15 For recent reviews of asymmetric catalysis, see: (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, E., Eds.; Comprehensive Asymmetric Catalysis; Springer: New York, 1999. (b) Ojima, I, Catalytic Asymmetric Synthesis; 2nd ed.; Wiley-VCH: Chichester, U. K., 2000. 16 (a) Noyori, R. Adv. Synth. Catal. 2003, 345, 15. (b) Jäkel. C.; Paciello, R. Chem. Rev. 2006, 106, 2912. 17 (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801. (b) McGarrigle, E. M.; Gilheany, D. G. Chem. Rev. 2005, 105, 1563. 18 Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.

6 catalyze a variety of carbon-carbon-bond-forming reactions such as allylic alkylation, 19 metathesis,20 Michael addition,21 aldol,22 Mannich,23 cycloaddition24 and Strecker25 reactions. Chiral vicinal diamines are useful not only for developing transition-metal-based catalysts but also organocatalysts. 26 Efficient methods for obtaining 1,2-diaminocyclohexane (DACH)6 and 1,2- diphenylethylenediamine (DPEN)5 in enantiomerically pure form have led to their widespread use over other vicinal diamines. However, a single vicinal diamine is not expected to be the best ligand for all catalysts. Even for a single catalytic system, one vicinal diamine is not expected to be the best for all substrates. A greater variation in the diamine structure may be useful for a number of applications in catalysis including (a) steric and electronic tuning of known catalysts, (b) designing new ligands, (c) developing polymer-supported catalysts, and (d) making water-soluble diamine- containing catalysts.

19 (a) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. 20 (a) Funk. T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840. (b)Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877. 21 (a) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583. (b) Luo, S.; Li, J.; Zhang, L.; Xu, H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273. (c) Berthiol, F.; Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem. Int. Ed. 2007, 46, 7803. 22 Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432. 23 (a) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. (b) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900. 24 (a) Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 14223. (b) Trost, B. M.; Fandric, D. R. J. Am. Chem. Soc. 2003, 125, 11836. (c) Kim, K. H.; Lee, S. S.; Lee, D.-W.; Ko, D. H.; Ha, D.-C. Tetrahedron Lett. 2005, 46, 5991. 25 (a) Wen, Y.; Xiong, Y.; Chang, L.; Huang, J.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72, 7715. (b) Su, J. T.; Vachal, P.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 197. 26 (a) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074. (b) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070. (c) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee. J. E. ; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed. 2008, 47, 7872. (d) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee. J. Y.; Chin, J. Song, C. E. Chem. Commun. 2008, 1208. For recent reviews of organocatalysis, see: (e) Lelais, G.; MacMillan, D. W. C. Adrichimica Acta, 2006, 39, 79. (f) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (g) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 5, 719. (h) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: Wiley-VCH: Weinheim, Germany, 2005.

1.3.1. Steric and electronic tuning of catalyst structure

It is well established that steric and electronic tuning of catalysts can result in dramatic improvements in reactivity and stereoselectivity. Jacobsen and Katsuki independently developed chiral, vicinal-diamine-based Mn complexes for catalytic epoxidation of cis alkenes. Extensive steric and electronic tuning of the salen based catalysts resulted in the development of highly reactive and stereoselective epoxidation catalysts 1 and 2.27,28 Not surprisingly, no single catalyst is the best for all substrates. Although 1 has a broad scope in the epoxidation of alkenes, Nicolaou et al.29 found that 2 is much better for the epoxidation of 3 in terms of yield and stereoselectivity

(Scheme 1-5). Thus, tuning of the salen ligand, including the diamine backbone, had a profound effect on the reactivity and selectivity of the catalyst.

PivO

3 Me OTBS NN Mn 1mol%2 NN O O NaOCl Mn Ph Ph O t-Bu O O t-Bu PivO

t-Bu t-Bu

Me OTBS 1 2 74%, 80% de

Scheme 1-5. Tuning of salen-based catalysts

More recently, Katsuki and co-workers30 reported a titanium-salan based epoxidation catalyst that uses 30% H2O2 as an oxidant (4) (Figure 1-2). Beller’s group developed an iron complex of 5

27 Jacobsen, E. N.; Zhang, W.; Güler, M. L. J. Am. Chem. Soc. 1991, 113, 6703. 28 Katsuki, T. Curr. Org. Chem. 2001, 5, 663. 29 Nicolaou, K. C.; Safina, B. S.; Funke, C.; Zak, M.; Zécri, F. J. Angew. Chem., Int. Ed. 2002, 41, 1937. 30 Sawada, Y.; Matsumoto, K.; Kondo, S.; Watanabe, H.; Ozawa, T.; Suzuki, K.; Saito, B.; Katsuki, T. Angew.

31 for catalytic epoxidation of trans alkenes with H2O2. Although this catalyst is not very stereoselective, iron has the advantage of being cheap and nontoxic. While the old oxidation catalysts 1 and 2 have been extensively tuned, the newer ones, 4 and 5, have yet to be tuned. Thus, it would be of considerable interest to tune the vicinal-diamine backbone of these environmentally friendly catalysts for higher reactivity and enantioselectivity.

H H O NN H Ph N S Ti O O O Ph N Bn H Ph O Ph 2 5 4

Figure 1-2. Oxidation catalysts that use hydrogen peroxide.

Interestingly, the same diamine-based salen ligand that was used in the manganese complex 1 for obtaining highly stereoselective epoxidations of cis alkenes also leads to highly stereoselective hydrolysis of epoxides when the manganese is exchanged with cobalt.18 Thus, a properly tuned ligand for one reaction can be highly effective for a completely different reaction.

Catalysts based on sterically bulky vicinal diamines can provide much improved stereoselectivity when compared to those based on less bulky diamines. Yamada and co-workers have shown that two such catalysts, 6 and 7 (Figure 1-3), are much more stereoselective than those based on less bulky diamines in cycloaddition32 and cyclopropanation33 reactions, in the borohydride reduction of ketones,34 and in the deuteration of aldehydes and imines.35

Chem., Int. Ed. 2006, 45, 3478. 31 Gelalcha, F. G.; Bitterlich, B.; Anilkumar, G.; Tse, M. K.; Beller, M. Angew. Chem., Int. Ed. 2007, 46, 7293. 32 Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457.

NN NN Co Co O O O O O O O O 6 7

Figure 1-3. Catalysts based on sterically bulky vicinal diamines.

One of the most remarkable chiral catalysts reported to date is the Noyori catalyst, 8,16 which is used for the hydrogenation of prochiral ketones (Figure 1-4).17 A turnover number of over a million has been reported for this highly stereoselective ruthenium catalyst, which consists of a chiral diphosphine ligand and a chiral vicinal diamine ligand. Ding and co-workers36 recently showed that the chiral diphosphine ligand can be replaced with an achiral one, leading to catalyst 9, without sacrificing the stereoselectivity of the reaction.

+ - Ar2 Cl H2 Ph2 H2 Cl P N P N Ru O Ru P N P N Ar2 Cl H2 Ph2 Cl H2

8 9

Figure 1-4. Vicinal-diamine-based catalysts for the hydrogenation of prochiral ketones.

33 Ikeno, T.; Iwakura, I.; Yamada, T. J. Am. Chem. Soc. 2002, 124, 15152. 34 (a) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew. Chem., Int. Ed. 1995, 34, 2145. (b) Sato, H.; Watanabe, H.; Ohtsuka, Y.; Ikeno, T.; Fukuzawa, S.-I.; Yamada, T. Org. Lett. 2002, 4, 3313. 35 (a) Miyazaki, D.; Nomura, K.; Ichihara, H.; Ohtsuka, Y.; Ikeno, T.; Yamada, T. New J. Chem. 2003, 27, 116, 4. (b) Miyazaki, D.; Nomura, K.; Yamashita, T.; Iwakura, I.; Ikeno, T.; Yamada, T. Org. Lett. 2003, 5, 3555. 36 Jing, Q.; Sandoval, C. A.; Wang, Z.; Ding, K. Eur. J. Org. Chem. 2006, 3606.

Noyori’s transfer-hydrogenation catalyst, 10, which uses isopropanol or formic acid instead of molecular hydrogen to reduce ketones, is also based on a chiral vicinal diamine.37 The availability of a wide range of chiral vicinal diamines should allow for tailor-fitting of the catalyst to the ketone substrate in order to achieve a high stereoselectivity. Mioskowski and co-workers38 showed that 11 is more reactive and stereoselective than 10 as a transfer-hydrogenation catalyst for the reduction of

β-keto ester 12 under dynamic kinetic resolution conditions to give 13 (Scheme 1-6). Electron- withdrawing sulfonyl groups increase the reactivity of the catalyst by acidifying the primary amine.

While the DPEN backbone itself was not tuned in this study, electron-withdrawing substituents on the phenyl rings are expected to further modulate the activity and selectivity of the catalyst.

Substituents on DPEN can significantly affect the basicity (or acidity) of the diamine. For example, the pKa value of the protonated decafluoro-DPEN is about three units lower than that of protonated

DPEN.9a

O OH

CO2Me 10 or 11 CO2Me

NMeR o NMeR HCO2H-Et3N, 45 C 12 13 10: 90% de, 94% ee SO2R Ph 11: 90% de. >99% ee η6-p-cymene N Ru Cl N Ph H2

10,R=4-MeC6H4 11,R=n-C4F9

Scheme 1-6. Electronic tuning of transfer-hydrogenation catalysts

Busacca et al. 39 reported on the steric and electronic tuning of the Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands that are used for the catalytic asymmetric Heck reaction

37 Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. 38 Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskowski, C. Chem. Commun., 2001, 2 572. 39 (a) Busacca, C. A.; Grossbach, D.; So, R. C.; O’Brien, E. M.; Spinelli, E. M. Org. Lett. 2003, 5, 595. (b)

(Scheme 1-7). The reactivity and stereoselectivity of the in situ formed palladium complex was reported to be highly sensitive to the structure of the chiral vicinal diamine in the imidazoline group.

The BIPI ligands have the advantage of being easier to tune than the phosphinooxazoline ligands and the BINAP ligands. The diamines in the BIPI ligands were initially synthesized by Corey’s7 or

Pedersen’s8 methods.

F 2-Np O BIPI ligand Pd dba 2 3 N F

PMP, Ph2O O N F N O 95oC, 18h N PAr2 OTf Me Me 38%, 87.6% ee F

Ar = 3,5-F2C6H3 optimized BIPI ligand structure

Scheme 1-7. Tuning of the BIPI ligand

R 1 N O P N R2 N OSiCl O OSiCl 3 14 3 71-98% 69:1 to 1:56 syn:anti + PhCHO * * Ph CH Cl ,-78oC 5-39% ee (syn) 2 2 81-92% ee (anti)

F3C CF 3

H NNH 2 2 H2NNH2 H2NNH2 H2NNH2

MeO OMe

H N NH H2NNH2 2 2 H2NNH2

Scheme 1-8. Tuning of chiral phosphoramide

Busacca, C. A.; Grossbach, D.; Campbell, S. J.; Dong, Y.; Eriksson, M. C.; Harris, R. E.; Jones, P. -J.; Kim, J.-Y.; Lorenz, J. C.; Mckellop, K. B.; O’Brien, E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So, R. C.; Spinelli, E. M.; Vitous, J.; Zavattaro, C. J. Org. Chem. 2004, 69, 5817.

In addition to the metal-based catalysts described above, many organocatalysts that incorporate chiral vicinal diamines are known. Denmark et al.40 reported that chiral, vicinal-diamine-based phosphoramide Lewis base 14 catalyzed the aldol addition of ketone silyl enolates to aromatic aldehydes (Scheme 1-8). Both the enantioselectivity and diastereoselectivity of the reaction were highly sensitive to the diamine portion of the organocatalyst.

1.3.2. New diamine designs

Chiral oxazoline ligands are useful in the design of many catalysts.41 Most of the oxazoline ligands are based on a few readily available chiral amino alcohols. Replacing chiral oxazoline ligands with a wide range of chiral diamine based imidazoline ligands should be of considerable interest.39 Beller and co-workers have recently reported that ruthenium complexes of chiral tridentate pyridinebisimidazolines (Pybim, 16) are effective catalysts for epoxidation and transfer- hydrogenation reactions.42,43 They found that Ru-Pybim complexes are much more reactive and stereoselective than the Ru-Pybox complex for transfer-hydrogenation of acetophenone (Scheme 1-

9).44

40 (a) Denmark, S. E.; Pham, S. M.; Stavenger, R. A.; Su, X.; Wong, K.–T.; Nishigaichi, Y. J. Org. Chem. 2000, 71, 3904. (b) Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong, K.-T.; Winter, S. B. D.; Choi, J. Y. J. Org. Chem. 1999, 64, 5817. 41 Desimoni, G.; Faita, G.; Jøgensen, K. A. Chem. Rev. 2006, 106, 3561. 42 Bhor, S.; Anikumar, G.; Tse, M. K.; Klawonn, M.; Döbler, C.; Bitterlich, B.; Grotevendt, A.; Beller, M. Org. Lett. 2005, 7, 3393. 43 Anilkumar, G.; Bhor, S.; Tse, M. K.; Klawonn, M.; Bitterlich, B.; Beller, M. Tetrahedron: Asymmetry 2005, 16, 3536. 44 Enthaler, S.; Hagemann, B.; Bhor, S.; Anikumar, G.; Tse, M. K.; Bitterlich, B.; Junge, K.; Erre, G.; Beller, M. Adv. Synth. Catal. 2007, 349, 853.

O OH RuCl2(PPh3)3, 15 or 16

NaOi-Pr, i-PrOH, 100oC, 1h

15:6% conv,11%ee 16:83%conv,98%ee

H H O N O N N N Ph Ph N N N N

Ph 15Ph Ph 16 Ph

Scheme 1-9. Transfer-hydrogenation with Pybox and Pybim based Ru(II) complexes.

There has been much interest in monodentate phosphorus ligands ever since the pioneering work by Feringa,45 Reetz,46 and Pringle.47 An ortho-hydroxyl-substituted DPEN can be converted to an interesting monodentate phosphorus ligand (DpenPhos). Ding and co-workers48 showed that

DpenPhos is an excellent ligand for the Rh(I)-catalyzed enantioselective hydrogenation of acrylates

(Scheme 1-10).

Bn H2, Rh(COD)2BF 4 CO Me DpenPhos ∗ N O H R 2 CO2Me 2 R2 O P N R CH Cl ,RT 1 2 2 R1 N O Bn Bn R1 =OAc,CH2CO2Me 100% conv R2 =H,n-Pr, i-Pr, Ph, 4-FC6H4 94 to >99% ee 3-ClC6H4,2-BrC6H4,2-Np DpenPhos

Scheme 1-10. Rh(I)-catalyzed enantioselective hydrogenation using DpenPhos.

45 Van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; Van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539. 46 Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. 47 Claver, C.; Fernandez, E.; Gillon, A.; Heslop. K.; Hyett, D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. 48 (a) Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127, 10488. (b) Liu, Y.; Sandoval, C. A.; Yamaguchi, Y.; Zhang, X.; Wang, Z.; Kato, K.; Ding, K. J. Am. Chem. Soc. 2006, 128, 14212.

1.3.3. Diamines on solid support

Chiral vicinal-diamine-based catalysts are often expensive to prepare, but their polymer- supported catalysts have the advantage of being recyclable.49 Diphenylethylenediamines (DPENs) with hydroxyl groups attached at the meta or para positions of the two benzene rings have been used to prepare various polymer-supported catalysts (Figure 1-5). 50 Such catalysts effected the stereoselective hydrogenation of ketones and epoxidation of olefins.

H O N

N O Cl O Ph2 H2 N N P N Mn Ru O O P N Cl Ph2 H2 Cl O

O O Cl Ph2 H2 Ts P N N Ru Ru P N Cl Ph2 H2 N Cl H2 O O

Figure 1-5. Chiral, vicinal-diamine-based catalysts on solid support.

49 Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217. 50 (a) Song, C. E.; Roh, E. J.; Yu, B. M.; Chi, D. Y.; Kim, S. C.; Lee, K.-J. Chem. Commun. 2000, 615. (b) Li, X.; Chen, W.; Hems, W.; King, F.; Xiao, J. Org. Lett. 2003, 5, 4559. (c) Li, X.; Wu, X.; Chen, W.; Hancock, F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321. (d) Itsuno, S.; Tsuji, A.; Takahashi, M. Tetrahedron Lett. 2003, 44, 3825.

1.3.4. Water-soluble diamine catalysts

The growing interest in green chemistry and the need for environmentally friendly catalytic systems has led to the development of water-soluble, chiral, vicinal-diamine ligands.51 Deng and co- workers52 reported water-soluble versions of Noyori’s transfer-hydrogenation catalyst (see Scheme

1-6) prepared from disulfonated N-tosyl-DPEN, 17 (Figure 1-6). These catalysts gave excellent results in the reduction of prochiral ketones, imines, and iminium ions in aqueous solvents.

O O OH HO P P HO OH

NaO3S SO3Na H2NNHTs H3C NH HN CH3 17

Figure 1-6. Water-soluble, chiral, vicinal diamine ligands.

1.4. Diamine drugs

A number of vicinal diamines possess a wide range of bioactivities. The amine groups are useful for modulating the solubility of the drug as well as for donating or accepting hydrogen bonds to and from a biological receptor. In addition, vicinal diamines can easily be converted to five- and six-membered rings like imidazolines and piperazines. These rigid heterocyclic compounds provide entropic advantage for binding to the biological target. Some representative diamines and diamine derivatives with interesting bioactivities are discussed below.

51 Mailet, C.; Praveen, T.; Janvier, P.; Minguet, S.; Evain, M.; Saluzzo, C.; Tommasino, M. L.; Bujoli, B. J. Org. Chem. 2002, 67, 8191. 52 (a) Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett. 2003, 5, 2103. (b) Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun. 2006, 1766.

1.4.1. Acyclic diamines

Ever since the serendipitous discovery by Rosenberg et al. 53 of the anticancer activity of cisplatin, there has been much interest in developing cisplatin analogues that are more active and less toxic (Figure 1-7). Oxaliplatin (ELOXATIN®, Sanofi-Aventis)54 is one such analogue that is based on a chiral vicinal diamine [(R,R)-1,2-diaminocyclohexane (DACH)] and that is used against colorectal cancer.55 Other studies indicate that it is also active against ovarian cancer,56 non-small- cell lung cancer, 57 and breast cancer. 58 The wide availability of DACH undoubtedly was an important factor in the discovery of oxaliplatin, as it was in the discovery of various stereoselective

DACH-based catalysts. In a recent breast cancer and prostate cancer cell line study, 18 showed the highest activity among a variety of platinum complexes.59

F H H 2 O 2 H3N Cl N O N O O Pt Pt Pt S H3N Cl N O O N O O H2 H2 cisplatin ELOXATIN® (S,S)-18

Figure 1-7. Cisplatin and other anticancer analogues

53 Rosenberg, B.; VanCamp, L.; Trosko, J. E.; Mansour, V. H. Nature 1969, 222, 385. 54 (a) Kidani, Y.; Inagaki, K.; Iigo, M.; Hoshi, A.; Kuretani, K. J. Med. Chem. 1978, 21, 1315. (b) Boga, C.; Fiorelli, C.; Savoia, D. Synthesis 2006, 285. 55 Levi, F.; Perpoint, B.; Garufi, C.; Focan, C.; Chollet, P.; Depres-Brummer, P.; Zidani, R.; Brienza, S.; Itzhaki, M.; Iacobelli, S.; Kunstlinger, F.; Gastiaburu, J.; Misset, J.-L. Eur. J. Cancer. 1993, 29A, 1280. 56 Soulié, P.; Bensmaïne, A.; Garrino, C.; Chollet, P.; Brain, E.; Fereses, C.; Jasmin, C.; Musset, M. ; Misset, J. L.; Cvitkovic, E. Eur. J. Cancer. 1997, 33, 1400. 57 Monnet, I.; Brienza, S.; Hugret, F.; Voisin, S.; Gastiaburu, J.; Saltiel, J. C.; Soulié, P.; Armand, J. P.; Cvitkovic, E.; Cremoux, H. Eur. J. Cancer. 1998, 37, 1124. 58 Garufi, C.; Nisticò, C.; Vaccaro, A.; D’Ottavio, A.; Zappalà, A. R.; Aschelter, A. M.; Terzoli, E. Ann. Oncol. 2001, 12, 179. 59 Dullin, A.; Dufrasne, F.; Gelbcke, M. Gust, R. Arch. der Pharm. 2004, 337, 654.

Interestingly, (S,S)-18 gave the best result against the MDA-MB 231 breast cancer cell line and

LnCaP/FGC prostate cancer cell line, while (R,R)-18 gave the best result against the MCF-7 breast cancer cell line. The chiral vicinal diamine ligand in 18 is difficult to prepare, requiring seven steps with an overall yield of about 10%.

1.4.2. Imidazolines

Scientists at Hoffmann-La Roche in Nutley, New Jersey, recently reported a novel strategy for cancer therapy. A cis imidazoline, that they named Nutlin-3, was shown to activate the p53 tumor suppressor pathway.60 Initially, they screened a library of cis imidazolines that was generated from a variety of meso vicinal diamines. Another series of cis imidazolines possessing anti-inflammatory activity have been reported by Merriman et al. 61 In addition to the cis imidazolines, trans imidazolines, similarly prepared from chiral vicinal diamines, also exhibited biological activities.

Clonidine, moxonidine, and ZANAFLEX® are imidazoline I1 receptor agonists that lower blood pressure. While all of these compounds are based on unsubstituted vicinal diamines, clonidine analogues made with chiral vicinal diamines were shown to be active (Figure 1-8).62 The diamine in

19 was prepared as a racemic mixture in low yield by the Grignard method (see Scheme 1-4b).

O NH Cl Cl O N H N NH N n NH O N Ar Cl N N R1 O R2 Cl 19

Figure 1-8. Bioactive imidazolines

60 Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E. A. Science 2004, 303, 8. 61 Merriman, G. H.; Ma, L.; Shum, P.; McGarry, D.; Volz, F.; Sabol, J. S.; Gross, A.; Zhao, Z.; Rampe, D.; Wang, L.; Wirtz-Brugger, F.; Harris, B. A.; Macdonald, D. Bioorg. Med. Chem. Lett. 2005, 15, 435. 62 Heinelt, U.; Lang, H.-J.; Hofmeister, A.; Wirth, K. PCT Int. Appl. WO2003053434, 2003.

1.4.3. Piperazines

Simple N-substituted piperazines are found in numerous drug molecules. However chiral piperazines are only beginning to make their mark as useful therapeutics. Chiral vicinal diamines can be readily converted into chiral piperazines and piperazinones. Tagat et al. 63 reported piperazine-based CCR5 antagonists as potent HIV inhibitors. Wurster and co-workers64 recently showed that a chiral, piperazine-based molecule, 20, is a selective α2C-adrenoceptor antagonist and has potential therapeutic use in several psychiatric disorders.

O N N N N N HN

N N OH

O N 20 CCR5 antagonist α2C -aderenoceptor antagonist

Figure 1-9. Bioactive piperazines

1.4.4. Other diamines

α,β-Diamino acids are a special class of chiral vicinal diamines that have potent bioactivities.65

For example, viomycin is an inhibitor of protein synthesis, and capreomycin IA, used for the treatment of tuberculosis, contains L-capreomycidine66 as a key structural element. In addition, the

63 Tagat, J. R.; McCombie, S. W.; Nazareno, D.; Labroli, M. A.; Xiao, Y.; Steensma, R. W.; Strizki, J. M.; Baroudy, B. M.; Cox, K.; Lachowicz, J.; Varty, G.; Watkins, R. J. Med. Chem. 2004, 47, 2405. 64 Höglund, I. P. J.; Silver, S.; Engström, M. T.; Salo, H.; Tauber, A.; Kyyrönen, H.-K.; Saarenketo, P.; Hoffrén, A. M.; Kokko, K.; Pohjanoksa, K.; Sallinen, J.; Savola, J.-M.; Wurster, S.; Kallatsa, O. A. J. Med. Chem. 2006, 49, 6351. 65 Viso, A.; de la Pradilla, R. F.; García, A.; Flores, A. Chem. Rev. 2005, 105, 3167. 66 Bycroft, B. W.; Cameron, D.; Croft, L. R.; Hassanali-Walji, A.; Johnson, A. W.; Webb, T. Nature 1971, 231, 301.

19 appearance of penicillin or cephalosporin-resistant pathogens has led to the development of loracarbef (LORABID®),67 a diamino acid based antibiotic (Figure 1-10).

O O O NH NH NH NH S S HO2C HN R R R NH N N N R Cl H2N O O 1 O CO H 2 CO2H CO2H L-capreomycidine penicillins cephalosporins LORABID®

Figure 1-10. Biologically active α,β-diamino acids and derivatives

There has been much recent interest in oseltamivir (TAMIFLU®) and zanamivir (RELENZA®) due to the possibility of a human influenza pandemic.68 The two inhibitors of sialidase (also known as neuraminidase) are effective therapeutics for the treatment of the avian H5N1 influenza virus.

Oseltamivir is a chiral vicinal diamine monoamide that is prepared from shikimic acid.69 The total synthesis of oseltamivir has been recently reported by several research groups.70

67 (a) Palomo, C.; Aizpurua, J. M.; Legido, M.; Galarza, R.; Deya, P. M.; Dunogues, J.; Picard, J. P.; Ricci, A.; Seconi, G. Angew. Chem., Int. Ed. 1996, 35, 1239. (b) Misner, J. W.; Fisher, J. W.; Gardner, J. P.; Pedersen, S. W.; Trinkle, K. L.; Jackson, B. G.; Zhang, T. Y. Tetrahedron Lett. 2003, 44, 5991. (c) Ciufolini, M. A.; Dong, Q. Chem. Commun. 1996, 881 68 Von Itzstein, M. Nature Review 2007, 6, 967. 69 (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M . S.; Mendel, D. B.; Tai, C. Y.; Laver, G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681-690. (b) Albrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. Chimia 2004, 58, 621-629. 70 (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310. (b) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312. (c) Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365. (d) Bromfield, K. M.; Gardén, H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem. Comm. 2007, 3183. (e) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734. (f) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J. Am. Chem. Soc. 2007, 129, 11892. (g) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5788. (h) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1070. (i) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304. (j) Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T. Angew. Chem., Int. Ed. 2009, 48, 4229.

O OH O H O H N O 2 O HO OH HO OH OH AcHN AcHN HO O HN NH 2 OH NH oseltamivir (TAMIFLU®) zanamivir (RELENZA®) shikimic acid

Figure 1-11. Vicinal-diamine-based antiviral agents and shikimic acid

1.5. Summary

Many stereoselective catalysts that we know today contain a chiral, vicinal-diamine structural element, and most of these catalysts are based on DACH or DPEN. However, the structural variation of these catalysts in the diamine backbone is generally hard to achieve due to the lack of general synthetic protocols. Despite the limited availability, some DPEN derivatives have been used not only to enhance the catalytic performance by steric and electronic tuning of catalyst structures but also to develop new catalysts. In addition, many bioacitive compounds themselves are based on diamines or their derivatives like imidazolines and piperazines. Synthetic methods of broad scope and high efficiency for making chiral vicinal diamines in enantiomerically pure form should facilitate the discovery of new catalysts and drugs.

1.6. Plan of study

Having recognized the importance of chiral vicinal diamines in catalysts and drugs, we became interested in the development of a general and efficient procedure for preparing a variety of chiral vicinal diamines in a unified way. In an innovative study, Vögtle et al showed over thirty years ago that a wide range of meso vicinal diamines can be prepared by the diaza-Cope rearrangement reaction.71 They showed that a single diamine, meso 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane

(meso HPEN), can be used to generate many new vicinal diamines (Scheme 1-11). Several bioactive meso diamines and their derivatives have been prepared by this method thus far.60,61,72

OH Ar = Ph, 4-MeOC6H4,2-MeOC6H4, NH2 H2N Ar 2,4,6-(MeO)3C6H2, 3,4,5-(MeO)3C6H2, 2,5-(MeO)2C6H3,2-EtOC6H4,4-MeC6H4, 2-MeC H ,2,4-MeC H ,2,4,6-Me C H , NH2 6 4 2 6 3 3 6 2 H2N Ar 4-Me2NC6H4,4-NCC6H4,4-PhC6H4,2-Py, OH 3-Py, 4-Py, 2-Furanyl, 4-FC6H4, 4-O2NC6H4, PhCC, PhCHCBr HPEN

O OH O 2 H2O 2 H2O Ar

OH OH

N Ar K N Ar

N Ar [3,3] N Ar OH OH

Scheme 1-11. Vögtle’s synthesis of meso vicinal diamines

Since chiral diamines are far more interesting than meso diamines in designing catalysts and drugs, it would be interesting if the above reaction can be applied for making chiral vicinal diamines. In this thesis, the synthetic scope of the above diaza-Cope rearrangement reaction for

71 Vogtle, F.; Goldschmitt, E. Chem. Ber. 1973, 109, 1. 72 (a) von Rauch, M.; Schlenk, M.; Gust, R. J. Med. Chem. 2004, 47, 915 (b) Gust, R.; Keilitz, R.; Schmidt, K. J. Med. Chem. 2002, 45,2325

22 making chiral vicinal diamines will be discussed (Chapter 2). Moreover, it was not clear why the above reaction for making meso diamines goes to completion. We will describe the effect of H- bonds and other weak forces on thermodynamics and kinetics of the diaza-Cope rearrangement reaction (Chapter 3). In addition, the use of chiral vicinal diamines for making catalysts and drugs will be demonstrated (Chapter 4).

In addition to H-bond directed stereocontrol of the diaza-Cope rearrangement reaction, we were interested in H-bond directed generation of helical chirality. Controlling helical chirality by stereogenic center-based chirality has been a topic of considerable challenge. Even in nature, a large number of L-amino acids are required to favor right-handed helical peptides over left-handed ones.73

It would be interesting to transfer amino acid chirality to helical chiraltiy in a small molecule through H-bond interactions. Our research plans are (a) generating helical chirality from amino acid chirality with a high degree of stereoselectivity and (b) developing a universal chirality sensor for amino acid enantiopurity (Chapter 5).

73 Scott, R. A.; Scheraga, H. A. J. Chem. Phys. 1966, 45, 2091.

CHAPTER 2

Stereospecific Synthesis of Vicinal Diamines by the Diaza-Cope Rearrangement†

2.1. Introduction

The diaza-Cope rearrangement was first used in 1973 by Vögtle and Goldschmitt1 to prepare a variety of meso vicinal diamines. This elegant method has been applied for preparing bioactive compounds based on meso vicinal diamines such as estrogen receptor agonists, 2 MDM2 antagonists,3 and P2X7 receptor antagonists4 (Figure 2-1). More recently, our group revealed by computational, spectroscopic, and crystallographic studies that resonance-assisted hydrogen bond

(RAHB)5 is the driving force behind the rearrangement reactions for making meso diamines.6 As we began to understand the rearrangement for making meso diamines, we became interested in developing the chiral version of this reaction. This chapter describes the synthetic scope of the

RAHB-directed diaza-Cope rearrangement reaction for preparing a variety of enantiopure, chiral vicinal diamines including not only C2 symmetric diaryl diamines but also dialkyl diamines and even mixed aryl-aryl or alkyl-aryl diamines. Since 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane

† Parts of this chapter have been published. Section 2.1: (a) Kim, H.; Nguyen, Y.; Yen, C. P.-H.; Chagal, L.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184. (b) Kim, H.-J.; Kim, H.; Alhakimi. G.; Jeong, E. J.; Thavarajah, N.; Studnicki. L.; Koprianiuk, A.; Lough, A. J. Suh, J.; Chin, J. J. Am. Chem. Soc. 2005, 127, 16370. Section 2.2: Kim, H.; Staikova, M.; Lough, A. J. Chin, J. Org. Lett. 2009, 11, 157. Section 2.4: Kim, H.; Choi, D. S.; Yen, C. P.-H.; Lough, A. J.; Song, C. E.; Chin, J. Chem. Commun. 2008, 1335. 1 Vogtle, F.; Goldschmitt, E. Chem. Ber. 1973, 109, 1. 2 (a) von Rauch, M.; Schlenk, M.; Gust, R. J. Med. Chem. 2004, 47, 915 (b) Gust, R.; Keilitz, R.; Schmidt, K. J. Med. Chem. 2002, 45,2325. 3 Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E. A. Science 2004, 303, 844. 4 Merriman, G. H.; Ma, L.; Shum, P.; McGarry, D.; Volz, F.; Sabol, J. S.; Gross, A.; Zhao, Z.; Rampe, D.; Wang, L.; Wirtz-Brugger, F.; Harris, B. A.; Macdonald, D. Bioorg. Med. Chem. Lett. 2005, 15, 435. 5 Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405. 6 Chin, J.; Mancin, F.; Thavarajah, N.; Lee, D.; Lough, A.; Chung, D. S. J. Am. Chem. Soc. 2003, 125, 15276.

(HPEN, 1)7 is the key starting material in the synthesis of all of our chiral vicinal diamines, we refer to it as the “mother” diamine, from which all “daughter” diamines are produced.

Estrogen receptor agonists

HO Cl R3 R1 N N

N N R2 R4 Cl HO

MDM2 antagonists OH O Br Cl O N O NH N N N N O O N N O O Br Cl

P2X7 Receptor Antagonists

H H N N n n N X N Ar R1 R2 Y

Figure 2-1. Bioactive imidazolines and piperazines based on meso vicinal diamines.

2.2. Diaryl vicinal diamines

A variety of new enantiopure diaryl vicinal diamines, “daughter” diamines, can be prepared from a single “mother” diamine (HPEN, 1) by simple two step reactions with readily available aldehydes through the stereospecific diaza-Cope rearrangement as shown in Scheme 2-1.

7 HPEN can be prepared by following literature procedures: (a) Bernhardt, G.; Gust, R.; Reile, H.; Orde, H.-D. v.; Müller, R.; Keller, C.; Spruß, T.; Schönenberger, H.; Burgemeister, T.; Mannschreck, A.; Range, K.-J.; Klement, U. J. Cancer Res. Clin. Oncol. 1992, 118, 210. (b) Gust, R.; Schönenberger, H. Eur. J. Med. Chem. 1993, 28, 103. A simpler and more efficient method developed in our group has been filed for a patent.

OH O NH 1) 2.5 equiv 2a-p 2 Ar Ar NH2

NH2 Ar NH 2) H2O 2 OH

(R,R)-HPEN (1) (S,S)-3a to (S,S)-3p 'Mother diamine' 'Daughter diamine'

3a 3b 3c 3d 3e 3f

F F Ar = F F

F NO2 CO2Me F Cl CF 3

3g 3h 3i 3j 3k 3l

OMe

CN NHAc OMe OH NMe2

3m 3n 3o 3p

Cl Me MeO OMe

OMe

Scheme 2-1. Mother diamine to daughter diamines

In order to test the scope of the rearrangement reaction for making chiral vicinal diamines, we studied the reaction of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN, 1) with a wide variety of aryl aldehydes including those with electron withdrawing (2a-2g) and donating (2h-2k) groups at the para position. In addition, we also studied the reaction of 1 with sterically bulky aryl aldehydes

(2l-2p). In all cases, the progress of the rearrangement reaction in DMSO-d6 can be conveniently monitored by 1H NMR spectroscopy. In a typical reaction, 2.5 equiv of an aldehyde is added to a solution of 1 (50 mM) dissolved in DMSO-d6. The mother diamine (1) reacts with the aldehydes

(2a-2p) to form the initial diimines (4a-4p Scheme 2-2). In general the initial diimines are not

26 isolated since they rearrange to the product diimines (5) at ambient temperature. The rearrangement reaction is considerably slower when aldehydes with strongly electron donating groups (2k) are

o used. In this case, heating the reaction solution (DMSO-d6) at 50 C for 2 h provides the rearranged diimine. Thus, the rearrangement reaction takes place whether benzaldehydes with electron donating, electron withdrawing, or sterically bulky substituents are used. The key signal for all the rearrangement reactions is the phenolic 1H NMR peaks of the product diimines (5). This RAHB signal appears as a singlet far downfield (δΗ = 12.4 to 13.7 ppm) of any other peaks. Figure 2-2 shows a typical 1H NMR spectrum taken after the rearrangement reaction is complete.

O H O H

N Ar [3,3] N Ar

N Ar N Ar

O H O H 4a-p 5a-p

Scheme 2-2. Stereospecific diaza-Cope rearrangement driven by RAHB

1 Figure 2-2. Partial H-NMR spectra for conversion of (a) 4k to (b) 5k taken in DMSO-d6

(a) (b)

Figure 2-3. Solid state molecular structures of (a) (S,S)-5b 8 and (b) (S,S)-5l 9 with 50%

probability thermal ellipsoids, and computed (molecular mechanics) global minimum

structures of (c) (S,S)-5b and (d) (S,S)-5l. All hydrogens except for the ones in the phenolic O-

H, imine C-H and diamine backbone C-H have been omitted for clarity.

8 Crystal data of 5b:

C28H22N4O6, T = 150(2) K, monoclinic, P21/n, Z = 4, a = 16.4941(7) Å, b = 8.9269(5) Å, c = 17.8748(9) Å, 3 2 α = 90º, β = 106.919(3)º, γ = 90º, V = 2518.0(2) Å , R1 = 0.0558, wR2 = 0.1390 for I> 2σ(I), GOF on F = 1.014. 9 Crystal data of 5l:

C30H28N2O4, T = 150(1) K, triclinic, P1, Z = 2, a = 9.2775(7) Å, b = 10.3554(8) Å, c = 13.6763(8) Å, α = 3 85.718(4)º, β = 73.325(4)º, γ = 83.745(4)º, V = 1249.87(15) Å , R1 = 0.0645, wR2 = 0.1580 for I> 2σ(I), GOF on F2 = 0.993.

Molecular mechanics and density functional theory (DFT) computation provide valuable insight into the diaza-Cope rearrangement reaction. The product diimines (5a-5p) formed from the reaction of 1 and aryl aldehydes (2a-2p) all have at least eleven freely rotating single bonds leading to hundreds of possible conformers. Interestingly, the global energy minimum conformers for 5b and 5l obtained by molecular mechanics computation closely match the corresponding crystal structures (Figure 2-3). While computed structures do not always correspond to crystal structures due to solvent effects and crystal packing, molecular mechanics computation provides a fast and reliable method for finding the global energy minimum conformers in our system.

Table 2-1. Computed energies of the diaza-Cope rearrangement by DFT computation

OH R OH R

N [3,3] N

N N

OH R OH R 4 5

a b 4 R ΔE (kcal / mol) Kcal 7 4b NO2 -9.9 1.7 × 10 4e Cl -7.6 3.8 × 105 - H -6.8 9.3 × 104 4i OMe -4.6 2.6 × 103 4j OH -4.7 2.5 × 103

4k NMe2 -2.2 44

a b o DFT at the B3LYP / 6-31G(d) level. ΔE = -RTlnKcal (Gas phase at 25 C).

Although molecular mechanics computation is useful for obtaining the global energy minimum conformer for the product diimine (5), it is not so useful for predicting the values of the equilibrium constants for the rearrangement reaction (Scheme 2-2). In contrast to the experimental results, molecular mechanics computation shows that the initial diimines (4) are much more stable than the corresponding rearranged diimines (5). However, DFT computation shows that the rearrangement

29 reactions with electron donating or withdrawing groups (Table 2-1) are all thermodynamically favorable in agreement with experimental results. DFT computation further shows that the reaction becomes increasingly less favorable with more electron donating substituents. This computational result is consistent with the observation that the rearrangement reaction takes place more slowly with electron donating substituents (e.g. 4k).10 Compared to the electron withdrawing substituents, electron donating substituents are better able to stabilize the starting diimine (4) by conjugation.

Thus the kinetics and thermodynamics of the rearrangement reaction (Scheme 2-2) are expected to become less favorable with electron donating substituents on the aryl ring.

DFT computation and experimental results clearly show that 5 is more stable than 4. This is presumably due to the stronger hydrogen bonds in 5 than in 4. It is interesting to consider why the

RAHBs in 5 should be stronger than regular hydrogen bonds in 4. Charged hydrogen bonds are known to be stronger than neutral hydrogen bonds.11 Thus hydrogen bond between ammonium and acetate is stronger than that between ammonia and acetic acid. In charged hydrogen bonds, the hydrogen bond is reinforced by favorable electrostatic interactions. It appears that in 5, delocalization of the lone pair electrons on the oxygen through to the nitrogen results in charge separation and strengthening of the hydrogen bond. Such delocalization is not possible in 4.

Resonance-assisted hydrogen bonds (RAHBs) play an important role not only in chemistry but also in biology. RAHBs may be found in Watson-Crick base pairing of DNA, α-helical and β-sheet structures of protein and pyridoxal phosphate dependent enzymatic processes.12

It has been shown that there is excellent agreement between the experimental and DFT computational activation enthalpies for the highly stereospecific sigmatropic rearrangement

10 Kim, H.-J.; Kim, H.; Alhakimi. G.; Jeong, E. J.; Thavarajah, N.; Studnicki. L.; Koprianiuk, A.; Lough, A. J. Suh, J.; Chin, J. J. Am. Chem. Soc. 2005, 127, 16370. 11 Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford University Press: New York, 1997. 12 Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry, 6th ed.; W. H. Freeman, 2006.

30 reactions. 13 To understand the origin of the stereospecificity, we considered three chair-like transition states for the diaza-cope rearrangement reaction (Scheme 2-3). Among these structures, ts-1 is expected to be the most stable since all aryl substituents are in pseudo-equatorial positions.

DFT computation shows that ts-1 is more stable than ts-2, and ts-3 by about 7.7 and 15.3 kcal/mol, respectively. Thus one phenyl group in the pseudo-axial position (ts-2) should result in about 4×105- fold decrease in the rate of rearrangement at ambient temperature. Reaction of (R,R)-4 through ts-1 is expected to produce (S,S)-5. In contrast, reaction of (R,R)-4 through ts-2 or ts-3 are expected to produce meso-5 or (R,R)-5 respectively (Scheme 2-3). Thus DFT computation indicates that the rearrangement should take place exclusively by ts-1 with apparent inversion in stereochemistry.

Indeed, chiral-phase HPLC and circular dichroism (CD) spectroscopy show that there is inversion of stereochemistry with all our rearrangement reactions (see below). We do not detect any meso-5 or (R,R)-5 by chiral-phase HPLC. Interestingly, there is a high degree of preorganization for the rearrangement reaction as the computed and crystal structures of 5b and 5l (Figure 2-3) all resemble the chair-like transition state (ts). Combination of computation, X-ray crystallography, chiral-phase

HPLC and CD spectroscopy can be used to support our proposed mechanism for the rearrangement reaction.

The stereospecificity of the rearrangement reaction was determined by chiral-phase HPLC. In general, chiral diamines are derivatized before introduction into the HPLC column.14 In our case, the product diimine can be directly injected into the column without derivatization. All of our rearrangement reactions (4 to 5) go to completion with excellent stereospecificity. There is no observable loss in enantiopurity on going from the initial diimines to the product diimines. This provides a convenient route to enantiopure daughter diamines (>99% ee) without the need for

13 Hrovat, D. A.; Chen, J.; Houk, K. N.; Borden, W. T. J. Am. Chem. Soc. 2000, 122, 7456. 14 Zhong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6, 4747.

31 tedious and time consuming optimization of resolution conditions for individual diamines. It has been shown that diamines like 3a are difficult to purify even after many cycles of resolution.15 All of our rearrangement reactions take place with apparent inversion of stereochemistry as expected from the chair-like transition state with all pseudo-equatorial substituents. This has been further confirmed by CD spectroscopy.

OH O H N N Ph N N O H Ph OH ΔH 1 ts-1 (S,S)-5

OH OH O H N ΔH2 N N

N N N O H Ph OH ΔH3 Ph OH ts-2 (R,R)-4 meso-5

OH O H Ph N N

N N O H Ph OH ts-3 (R,R)-5

‡ a ‡ ‡ ΔH (kcal/mol) ΔH - ΔH1 ts-1 15.4 - ts-2 23.1 7.7 ts-3 30.7 15.3 aDFT at the B3LYP / 6-31G(d) level

Scheme 2-3. Calculated activation enthalpies for possible chair-like transition states (ts)

To verify inversion of stereochemistry for the rearrangement reaction, absolute stereochemistry of the rearranged diimines (5) was determined by the exciton chirality method.16 Space coupling of

15 Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.; Minami, S.; Ema, T. Bull. Chem. Soc. Jpn. 2004, 77, 1001 16 Circular Dichroism: Principles and Applications, 2nd ed.; Berova, N., Nakanishi, K., Woody, R. W., Eds.; Wiley-VCH: New York, 2000.

32 chromophores in a chiral molecule gives rise to bisignate CD curves (Cotton effect) which enables one to determine absolute configuration and conformation of small molecules. Figure 2-4 shows CD and UV-vis spectra of 5a, 5b, 5i and 5p. In all cases, there are two strong Cotton effects of the same amplitude but of opposite signs in (R,R)-5 and (S,S)-5. The first Cotton effect at 333-341 nm is followed by the second Cotton effect at 308-316 nm (Table 2-2). According to the exciton chirality analysis, (R,R)-5 is expected to give a negative first Cotton effect followed by a positive second

Cotton effect. Similarly (S,S)-5 is expected to give a positive first Cotton effect followed by a negative second Cotton effect. Thus the CD spectra show that the diaza-Cope rearrangement reactions take place with inversion of stereochemistry.

Figure 2-4. Circular dichroism spectra of 5a, 5b, 5i, and 5p, (100 μM in THF at 25 °C, 1 cm

cell) and their UV-vis spectra.

Table 2. Circular dichroism Cotton effects of diimines.

1st Cotton 2nd Cotton Isosbetic point λ Compound max effect (nm) effect (nm) (nm) (nm, UV-vis) 5a 338 312 320 326

5b 341 316 334 330

5i 333 308 322 322

5p 335 313 326 317

(a) (S,S)-3n17 (b) (S,S)-3o18

Figure 2-5. Crystal structures of sterically hindered diamines (3n and 3o, 30% thermal

ellipsoid). Chloride counter-anion is not shown for clarity.

17 Crystal data of 3n: C16H24.25Cl2N2O1.125, T = 150(2) K, monoclinic, C2, Z = 16, a = 30.0290(11) Å, b = 15.9190(7) Å, 3 c = 19.3815(6) Å, α = 90º, β = 127.4090(17)º, γ = 90º, V = 7359.3(5) Å , R1 = 0.0785, wR2 = 0.2020 for I> 2σ(I), GOF on F2 = 1.019. 18 Crystal data of 3o: C70H82Cl16N6O4, T = 150(1) K, orthorhombic, C2221, Z = 4, a = 15.6507(7) Å, b = 22.6708(7) Å, 3 c = 19.8315(10) Å, α = 90º, β = 90º, γ = 90º, V = 7036.5(5) Å , R1 = 0.0652, wR2 = 0.1608 for I> 2σ(I), GOF on F2 = 0.995

Table 3. Stereospecific synthesis of daughter diamines

Diaminea Method Yield Diaminea Method Yield (%)b (%)b

F F F MeO F NH3Cl NH3Cl F F A 77 A 78 NH Cl NH Cl F 3 3 F MeO 3i F 3a F

O2N HO

NH3Cl NH3Cl A 73 A 74 NH3Cl NH3Cl O2N 3b HO 3j

Me N MeO2C 2

NH3Cl NH2 B 87 4HCl A 69 NH3Cl NH2 MeO C 3c 2 Me2N 3k

F OMe

NH3Cl NH3Cl A 87 A 79 NH3Cl NH3Cl F 3d OMe 3l

Cl Cl

NH3Cl NH3Cl A 78 A 81 NH Cl 3 NH3Cl Cl 3e Cl 3m

F3C Me

NH3Cl NH3Cl B 80 B 75 NH Cl 3 NH3Cl F3C 3f Me 3n

NH Cl 3 NH3Cl B 85 B 78 NH3Cl NH3Cl NC 3g 3o

MeO AcHN OMe

NH3Cl NH3Cl MeO B 90 MeO A 79 NH Cl 3 NH3Cl AcHN 3h OMe MeO 3p

a>99% ee of 5 is obtained when >99% ee of 1 is used, bIsolated yield.

A variety of organic solvents can be used for the synthesis of the rearranged diimines (5). In some cases, the rearranged diimine precipitates out of ethanol as a yellow solid in 70-80% yield

(method A). The rearranged diimine can also be prepared in DMSO (method B). Once the rearrangement is complete in DMSO, extraction was used to isolate the product diimine. The extract was dried and hydrolyzed (3 vol % concd HCl in THF) without further purification to the diamine dihydrochloride salt as a white powder in good yields (90-99%). The diamine dihydrochloride salt can be converted to the neutral form by extraction under basic conditions. Table 2-3 shows that a wide variety of diamines (3) can be prepared in high overall yields (70-90%) and excellent enantiopurity (>99% ee). Crystal structures of two of the bulky diamines are shown in Figure 2-5.

A wide variety of chiral vicinal diamines were prepared by the diaza-Cope rearrangement. DFT computational studies show that RAHB is the main driving force for all the rearrangement reactions regardless of the electron withdrawing, electron donating, or sterically bulky substituents. This method has several advantages compared to other methods for making chiral diamines (see Scheme

1-1). First, enantiopure mother diamine (HPEN, 1, >99% ee) provides enantiopure daughter diamines (3, >99% ee) in high overall yields (70-90%) without the need for individual resolution.

Second, the rearrangement reaction can be easily scaled up as it takes places under mild conditions without the need for any catalysts or additives. Third, the enantiomeric excess as well as absolute configuration of the new diamines can be conveniently determined from the intermediate diimines

(5) by using chiral-phase HPLC and CD spectroscopy. This simple and general process may be valuable not only for steric and electronic tuning of diamine-based catalysts but also for developing novel ligands and catalysts.

2.3. Dialkyl vicinal diamines

In the preceding section, we showed that a wide variety of aryl-substituted chiral vicinal diamines can be synthesized by the diaza-Cope rearrangement from the readily available 1,2-bis(2- hydroxyphenyl)-1,2-diaminoethane (HPEN, 1). However, it has been a challenge to synthesize alkyl-substituted vicinal diamines by the rearrangement reaction. 19 One difficulty is that alkyl imines undergo side reactions by forming enamine intermediates. Furthermore, alkyl substituents are in general less effective than aryl substituents for facilitating [3,3]-sigmatropic rearrangement reactions.20 While aryl-substituted chiral vicinal diamines are important as ligands for a wide variety of stereoselective catalysts,21 alkyl-substituted chiral vicinal diamines are found in many bioactive compounds22 including Tamiflu,23 Lorabid,24 and Eloxatin.25 Here we investigate why the alkyl-

19 Attempts with alkyl ketones failed: Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1. 20 (a) Hrovat, D. A.; Chen, J.; Houk, K. N.; Borden, W. T. J. Am. Chem. Soc. 2000, 122, 7456. (b) Gajewski, J. J. J. Am. Chem. Soc. 1979, 101, 4393. 21 (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580. (b) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936. (c) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (d) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (e) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818. (f) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840. (g) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. 22 Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. 23 (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M . S.; Mendel, D. B.; Tai, C. Y.; Laver, G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681. (b) Albrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. Chimia 2004, 58, 621. (c) Yeung,Y.- Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310. (d) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M .; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312. (e) Cong, X.; Yao, Z.−J. J. Org. Chem. 2006, 71, 5365. (f) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734. (g) Bromfield, K. M.; Gradén, H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem. Commun. 2007, 3183. (h) Shie, J.J.; Fang, J. −M.; Wang, S. −Y.; Tsai, K. −C. Cheng, Y.−S. E.; Yang, A. −S.; Hsiao, S. −C.; Su, C.Y.; Wong, C. −H. J. Am. Chem. Soc. 2007, 129, 11892. (i) Shie, J.−J.; Fang, J.−M.; Wong C.−H. Angew. Chem. Int. Ed. 2008, 47, 5788. (j) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew . Chem. Int. Ed. 2009, 48, 1070. (k) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem. Int. Ed. 2009, 48, 1304. For recent reviews, see (l) Farina, V.; Brown, J. D. Angew. Chem., Int. Ed. 2006, 45, 7330. (m) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839. 24 (a) Palomo, C.; Aizpurua, J. M.; Legido, M.; Galarza, R.; Deya, P. M.; Dunogues, J.; Picard, J. P.; Ricci, A.; Seconi, G. Angew. Chem., Int. Ed. 1996, 35, 1239. (b) Misner, J. W.; Fisher, J. W.; Gardner, J. P.; Pedersen, S. W.; Trinkle, K. L.; Jackson, B. G.; Zhang, T. Y. Tetrahedron Lett. 2003, 44, 5991. (c) Ciufolini, M. A.; Dong, Q. Chem. Commun. 1996, 881. 25 (a) Kidani, Y.; Inagaki, K.; Iigo, M.; Hoshi, A.; Kuretani, K. J. Med. Chem. 1978, 21, 1315. (b) Dullin, A.; Dufrasne, F. Gelbcke, M.; Gust, R. Arch. Pharm., Pharm. Med. Chem. 2004, 337, 654. (c) Boga, C.; Fiorelli, C.; Savoia, D. Synthesis 2006, 285.

37 substituted vicinal diamines are difficult to synthesize by the rearrangement reaction and how these difficulties may be overcome.

OH OH

NH2 O N Ph +2 (a) Ph NH2 RT N Ph OH OH

OH OH H NH2 O N +2 (b) RT N NH2

OH O 1 6a

Scheme 2-4. (a) Formation of the diimine (4) from 1 and benzaldehyde and (b) formation of the imidazolidine-dihydro-1,3-oxazine ring (6a) from 1 and isobutyraldehyde.

2.3.1. Imidazolidine-dihydro-1,3-oxazines

When benzaldehyde is added to 1, the corresponding diimine (4) is formed readily followed by the rearrangement reaction at ambient temperature (Scheme 2-4a). In sharp contrast, isobutyraldehyde is added to 1, a fused imidazolidine-dihydro-1,3-oxazine ring compound (6a) is formed (Scheme 2-4b). In principle, 1, 2, or 3 equiv of isobutyraldehyde could add to 1 to form one, two, three new rings, respectively. Fourteen different products could result from the cyclization reactions including all possible stereoisomers (Figure 2-6). Surprisingly, only one major product

(6a) is formed stereospecifically and regioselectively in excellent yield (>99%) when the diamine 1 is added to 2 or more equiv of the aldehyde.

Mono-ring adducts (3)

HN NH H2N HN H2N HN HO OH HO O HO O

Bi-ring adducts (7)

HN N HN N HN N HN N HO O HO O HO O HO O

NH HN NH HN NH HN O O O O O O

Tri-ring adducts (4)

N N N N N N N N O O O O O O O O

Figure 2-6. Fourteen possible stereoisomers for the reaction of (R,R)-1 and isobutyraldehyde

Figure 2-7a shows the crystal structure of the fused imidazolidine-dihydro-1,3-oxazine ring

(6a). Single crystals were grown by slow diffusion of diethyl ether into a methanolic solution of 6a.

There are two new stereogenic centers in the product (both R configuration, Scheme 2-4). One internal hydrogen bond can be seen between the phenolic group and the secondary amine group

(O…N, 2.73 Å; H…N, 1.99 Å; O…H, 0.84Å).

(a) (b)

Figure 2-7. (a) Crystal structure of 6a26 (50% thermal ellipsoid). (b) Global energy minimum

structure of 6a

In order to gain some insight into the stereoselective self-assembly of the fused ring 6a, we performed DFT computation at the B3LYP / 6-31G(d) level. The global energy minimum structure of the fused ring was determined by considering all possible stereoisomers. First, among four possible configurational isomers (Figure 2-8) we found that 6a is the most stable isomer. Other isomers are less stable at least by about 3.4 kcal/mol than 6a. This value translates to an equilibrium constant of about 300. Thus, over 99.7% of fused imidazolidine-dihydro-1,3-oxazine rings is expected to be in the configurational isomer 6a. Visual inspection may help to understand why 6a is the most stable configurational isomer. In 6a, the isopropyl group of the imidazolidine ring occupies the pseudo equatorial position to prevent 1,3-interaction with the ring hydrogen, and the other

26 Crystal data of 6a: C22H28N2O2, T = 100(2) K, orthorhombic, P2(1)2(1)2(1), Z = 8, a = 9.79070(10) Å, b = 18.3356(2) Å, 3 c = 22.0661(2) Å, α = 90º, β = 90º, γ = 90º, V = 3961.27(7) Å , R1 = 0.0246, wR2 = 0.0648 for I> 2σ(I), GOF on F2 = 1.013

40 isopropyl group of the dihydro-oxazine ring is placed in the pseudo axial position to avoid steric interaction with the existing isopropyl group.

HN N HN N HN N HN N HO O HO O HO O HO O

0.0 kcal/mol 3.4 kcal/mol 4.6 kcal/mol 6.1 kcal/mol

Figure 2-8. Configurational isomers of 6a and their relative energies.

Conformer Ф1(HCCH, Ф2 (HCCH, Erel (kcal/mol) degree) degree) 6a-A 60 60 8.9 6a-B 60 180 2.3 H 6a-C 60 -60 6.4 Φ H 1 H 6a-D 180 60 4.3 HN N H Φ2 HO O 6a-E 180 180 2.1 6a-F 180 -60 6.7 6a-G -60 60 2.6 6a-H -60 180 0.0 6a-I -60 -60 3.5

Table 2-4. Conformational isomers of 6a

Next, nine possible conformational isomers (6a-A to 6a-I) were considered in respect to dihedral angles involving the two isopropyl groups. DFT energies of these conformers are shown in

Table 2-4. This table shows that 6a-H is the most stable conformer and is at least 2.1 kcal/mol lower in energy than other conformers. The conformer 6a-H is expected to be the global energy minimum structure (over 98%) in the gas phase equilibrium. Interestingly, the global energy minimum

41 structure is in excellent agreement with the crystal structure (Figure 2-7). Thus the most stable of the many possible steroisomers of 6a is the one that is formed.

Finally, we considered the solution structure of 6a by taking 2D 1H NMR spectra (Figure 2-9 and 2-10). All proton signals in 6a were identified by analyzing a COSY spectrum (HA to HH in 6a,

Figure 2-9) and their indirect interactions through space were assigned by analyzing a ROESY spectrum (Figure 2-10). The ROESY spectrum reveals four remarkable nuclear Overhauser effect

(NOE) interactions; these include HA-HC, HC-HD, HB-HF, and HD-HE. In addition, HB creates no

NOE interaction with HC and HD. Consistent with the observed NOE signals, the crystal structure shows that the distances of HA-HC, HC-HD, HB-HF, and HD-HE are short (2.62 Å, 2.83 Å, 2.46 Å, and

2.20 Å, respectively) whereas the distances of HB-HC and HB-HD are long (3.60 Å and 3.73 Å, respectively).

The coupling constant (Figure 2-10) for the HD signal (9.9 Hz) is considerably larger than that

27 for the HC signal (2.4 Hz). Karplus equation can be used to approximate the values of the HDCCHF

o o (180 ) and HCCCHE (60 ) dihedral angles from the two coupling constants. The crystal structure

o o shows that the values of the HDCCHF and HCCCHE dihedral angles are 176.9 and 61.6 , respectively. Therefore, there is excellent agreement between the solid state structure, the solution structure, and the computed structure of compound 6a (Figure 2-7a, 2-10, and 2-7b, respectively).

27 Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870 – 2871

Figure 2-9. COSY spectrum of 6a

5 G H 4 3 E F

C 2 HN N D HO A B O

HB HD HC HA HE HF HE HF HG HH

11 3 3 55

Figure 2-10. ROESY spectrum of 6a

HB HD HE HF

4 E 1 F 2 C HN N D 3 HO O 3 A B

H H H H B D C A

2.3.2. Synthesis of dialkyl vicinal diamines

We propose that the fused ring (6a) is in equilibrium with the diimine (7a) which undergoes the diaza-Cope rearrangement (Scheme 2-5). When the solution of 6a in DMSO-d6 is heated at 150 oC for 3 h, the rearranged diimine (8a) is cleanly formed presumably through the initial dimine (7a).

Although isobutyraldehyde boils only at 63 oC, there is no escape of the aldehyde under the harsh reaction conditions. This may be because HPEN (1) can hold two equiv of alkyl aldehydes by formation of the fused ring (6a) at high temperature where the rearrangement reaction takes place.

OH OH OH H N N N

N N 150 oC N O OH OH 8a (R,R,R,R)-6a (R,R)-7a (S,S)-

Scheme 2-5. Diaza-Cope rearrangement of alkyl diimine.

The enatioselectivity of the rearrangement reaction was determined by chiral-phase HPLC.

(R,R)-6a gave (S,S)-8a in 93% isolated yield with no observable loss in enantiopurity (>99% ee).

The inversion of stereochemistry, confirmed by CD spectroscopy, is expected from the chair-like transition state with all equatorial substituents (see Scheme 2-3). The CD spectra for (R,R)-8a and

(S,S)-8a illustrate perfect symmetrical curves along with x-axis (Figure 2-11). A positive CD curve at 325nm is indirectly assigned for (S,S)-8a because it is similar in shape and sign to those of imines derived from salicyladehyde and several alkyl vicinal diamines, such as (1,2S)-diaminopropane,

(2S,3S)-diaminobutane, and (S,S)-1,2-diaminocyclohexane.28 Although the rearrangement reaction

28 Spodine, E.; Zolezzi, S.; Calvo. V.; Decinti, A. Tetrahedron: Asymmetry 2000, 11, 2277.

45 for making alkyl diimines requires considerably harsher conditions than for making aryl diimines, the yield and stereoselectivity remains exceptionally high.

80 N

N 60 OH

40 (S,S)-8a

0 CD/mdeg -20 OH

-40 N

N -60 OH

-80 (R,R)-8a

240 260 280 300 320 340 360 380 nm

Figure 2-11. CD spectra of 8a (1.0 mM in chloroform at 25 oC, 1mm cell in path length).

Our attempts using HPEN and alkyl aldehydes without isolating fused rings revealed that the removal of water is necessary for a clean conversion. Among several experimental protocols, we found that the azotropic removal of water using a Dean-Stark trap is the most efficient method.

Interestingly, toluene (bp = 111 oC) is an ideal solvent not only for removing water but also for promoting the rearrangement reaction. In a typical experiment, isobutyraldehyde (1.87 mL, 20.5 mmol) was added to a solution of HPEN (2.0 g, 8.2 mmol) in toluene (27 mL) at ambient temperature. The resulting solution was refluxed for 24 h with a Dean-Stark trap. After removal of

46 the solvent under reduced pressure, methanol was added to precipitate the product diimine (8a) as a yellow powder in 85% yield. Acid hydrolysis of the diimine 8a (705 mg, 2.0 mmol) gave the diamine dihydrochloride (9a) as a white powder in 91% yield (Table 2-5, entry 1).

Table 2-5. Synthesis of alkyl vicinal diamines

OH O OH

NH2 R N R HCl ClH3N R toluene THF NH2 reflux N R ClH3N R OH OH (R,R)-HPEN (S,S)-8 (S,S)-9

Entry R Yield of 8 d.r.b ee (%)c Yield of 9 (%)a (%)a 1 iso-propyl (a) 85 >20:1d >99 91 2 cyclohexyl (b) 80 >20:1d >99 95 3 cyclopropyl (c) 73 10:1e >99 90 4 methyl (d) 75 4:1 >99 95 5 ethyl (e) 71 10:1e >99 94 6 n-butyl (f) 80 10:1 >99 90

aIsolated yield. bratio of major (S,S)-8 and minor meso-8 determined by 1H NMR. cDetermined by HPLC using a Chiralpak AD-H column. dmeso diimines were not detected. e(S,S)-8 can be separated by precipitation from methanolic solutions.

A variety of alkyl aldehydes were used to make alkyl diamines by our method (Table 2-5).

Isobutyralhyde and cyclohexanecarboxaldehyde gave the rearranged products with high yield and excellent stereoselectivity (entry 1 and 2). Figure 2-12a shows the crystal structure of the rearranged diimine (S,S)-8b. When cyclopropanecarboxaldehyde and primary alkyl aldehydes were used, meso diimines were observed along with the desired chiral diimines in diastereomeric ratios ranging from

4:1 to 10:1 in favor of the chiral diimines (entry 3 to 6). The diastereomeric mixture containing meso and chiral diimines can be separated by selective precipitation or column chromatography.

Figure 2-12b shows the crystal structure of meso-8c selectively grown from the diastereomeric mixture. Although meso diimines are formed, the enantiopurity of chiral diimines still remains exceptionally high (>99%). This provides valuable information for speculating the transition state geometries and energies of the rearrangement (see Figure 2-17). Unfortunately, the rearrangement reaction does not take place with pivaldehyde (tert-butylacetaldehyde) even in harsh conditions

o (>180 C in DMSO-d6). The imidazolidine formed from HPEN and pivaldehyde remains in the solution. It appears that the tert-butyl groups prevent either the fused ring formation or the rearrangement reaction due to severe steric hindrance.

(a) (b)

Figure 2-12. Crystal structures of (a) (S,S)-8b29 and (b) meso-8c30. Thermal ellipsoids are

shown in 50% probability.

29 Crystal data of (S,S)-8b: C28H36N2O2, T = 150(2) K, orthorhombic, P2(1)2(1)2(1), Z = 4, a = 5.9303(3) Å, b = 10.3195(7) Å, 3 c = 39.850(3) Å, α = 90º, β = 90º, γ = 90º, V = 2438.7(3) Å , R1 = 0.0514, wR2 = 0.1223 for I> 2σ(I), GOF on F2 = 1.043. 30 Crystal data of meso-8c: C22H24N2O2, T = 150(1) K, monoclinic, P21/c, Z = 2, a = 5.9574(7) Å, b = 8.0235(5) Å, c = 19.484(2) Å, 3 α = 90º, β = 96.296(4)º, γ = 90º, V = 925.70(16) Å , R1 = 0.0564, wR2 = 0.1366 for I> 2σ(I), GOF on F2 = 1.075.

Acid hydrolysis of the rearranged diimines cleanly gave the corresponding damines as hydrogen chloride salts in high yields (90-95 %, Table 2-5). Figure 2-13 shows the crystal structure of (S,S)-9b. Our procedure combining the rearrangement and the hydrolysis can be easily scaled up in the laboratory keeping high yield and excellent enantioslectivity. Compared with the reported methods for preparing alkyl-substituted vicinal diamines (Scheme 1-4), our method displays a broad scope of the alkyl diamine structure including primary, secondary, and cyclic alkyl groups (Table 2-

5). Although the Grignard addition to chiral bis-imine can produce enantiopure 1,2-bis(tert-butyl)-

1,2-diaminoethane,31 this method failed to produce other dialkyl diamines in enantiomerically pure form such as 9a, 9c, 9d, and 9e. 32 Rac-1,2-diamino-1,2-diisopropylethane has been previously synthesized for the purpose of making NHE3 inhibitors.32 To our knowledge, our synthesis by the diaza-Cope rearrangement is the most simple and versatile method for preparing enantiopure, alkyl- substituted vicinal diamines.

Figure 2-13. Crystal structure of (S,S)-9b33 (50% thermal ellipsoid). Chloride anions were

omitted for clarity.

31 Roland, S.; Mangeney, P.; Alexakis, A. Synthesis 1999, 2, 228. 32 Heinelt, U.; Lang, H.-J.; Hofmeister, A.; Wirth, K. PCT Int. Appl. WO2003053434, 2003. 33 Crystal data of 9b: C14H32Cl2.67N2O0.67, T = 150(1) K, cubic, I(2)1(3), Z = 12, a = 17.9117(6) Å, b = 17.9117(6) Å, 3 c = 17.9117(6) Å, α = 90º, β = 90º, γ = 90º, V = 5746.6(3) Å , R1 = 0.0468, wR2 = 0.1041 for I> 2σ(I), GOF on F2 = 1.022.

2.3.3. Origin of synthetic challenge

One reason why a much harsher condition is required to make alkyl diamines than to make aryl diamines may be the alkyl/aryl substituent effect in the diaza-Cope rearrangement reaction. Detailed kinetic, stereochemical, and computational studies support a concerted mechanism with a chiar-like transition state for the rearrangement of unsubstituted 1,5-hexadiene.34 Aromatic substituents have shown to stabilize the transition state of the [3,3]-sigmatropic rearrangement reaction.13

To gain some insight into the substituent effect of the diaza-Cope rearrangement reaction, we computed the energy values (DFT at the B3LYP/6-31G(d) level) for 4, 5, 7d, and 8d (Figure 2-14) along with those for the two corresponding transition states (ts-1 and ts-4). A chair-like transition state with all pseudo equatorial substitutions was used in the computation of ts-1 and ts-4.

Preorganized, transition-state-like structures were used for the computation of the other four structures (4, 5, 7d, and 8d) as in our previous study (Section 3.2).

ts-4

ts-1 O H O H N N Ph ΔH = 19.3 Me ΔH =15.4 N N H Ph O O H Me

OH ΔH =-7.1 OH OH OH N Ph N Ph N Me N Me ΔH = -16.3 N Ph N Ph N Me N Me OH OH OH 4 5 7d OH 8d

Figure 2-14. Energy profile for the diaza-Cope rearrangement of aryl and alkyl diimines (ΔH and ΔH‡ values in kcal/mol)

34 (a) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441. (b) Woodward, R. B.; Hoffmann, R. The Conservation of Obital Symmetry; Verlag Chemie: Weinheim/Bergstr. Germany and Academic Press: New York, 1970. (c) Dewar, M. J. S. Angew. Chem., Int. Ed. Engl. 1971, 10, 761. (d) Wiest, O.; Black, K. A.; Houk, K. N. J. Am. Chem. Soc. 1994, 116, 10336. (e) Borden, W. T.; Davidson, E. R. Acc. Chem. Res. 1996, 29, 67.

The two imine bonds in 7d are isolated whereas in 8d, 4 and 5 they are conjugated with the aromatic rings. Thus the rearrangement of 7d to 8d is expected to be thermodynamically more favorable than the rearrangement of 4 to 5. Computation shows that the rearrangement of 7d is thermodynamically more favorable than for the rearrangement of 4 by about 9.2 kcal/mol. Despite the thermodynamic driving force, the energy barrier for the rearrangement of 7d is about 3.9 kcal/mol higher than that for the rearrangement of 4. On the basis of these calculations, the equilibrium constant for conversion of 7d to 8d is expected to be about 106 times greater than that for conversion of 4 to 5 but the rate of the latter reaction is expected to be about 103 times greater.

It is interesting to compare the two rearrangement reactions (Figure 2-14) in terms of the

Marcus equation. 35 Although the Marcus equation was initially derived for electron transfer reactions, it has since been used to analyze proton transfer reactions and other organic reactions.36

According to the Marcus equation (Equation 2-1), the kinetic barrier of a reaction (ΔG‡) is separated

‡ into the thermodynamic barrier (ΔG) and the so called intrinsic barrier of the reaction (ΔGo ; defined as the kinetic barrier in the absence of thermodynamic influence (ΔG = 0)). By solving the Marcus equation, the intrinsic barrier can be expressed in terms of the kinetic barrier and the thermodynamic barrier (Equation 2-2). The value of the intrinsic barrier for conversion of 7d to 8d based on the computed values of ΔG‡ and ΔG is 27.5 kcal/mol.37 Similarly the value of the intrinsic barrier for the conversion of 4 to 5 is 18.9 kcal/mol. Thus the alkyl/aryl substituent effect on the kinetics of the diaza-Cope rearrangement reaction appears to be significant (8.6 kcal/mol).

35 Marcus, R. A. J. Chem. Phys. 1956, 24, 966. 36 (a) Guthrie, J. P. J. Am. Chem. Soc. 2000, 122, 5529. (b) Guthrie, J. P. J. Am. Chem. Soc. 2000, 122, 5520. (c) Guthrie, J. P. J. Am. Chem. Soc. 1996, 118, 12878. (d) Murdoch, J. R. J. Am. Chem. Soc. 1972, 94, 4410. (e) Murdoch, J. R. J. Am. Chem. Soc. 1983, 105, 2159. (f) Murdoch, J. R. J. Am. Chem. Soc. 1983, 105, 2660 37 ΔH‡ and ΔH were used instead of ΔG‡ and ΔG.

∆ Equation 2-1 ∆ ∆ 1 4∆

∆ Equation 2-2 ∆ 2 ∆ ∆ ∆ ∆⁄2

In addition to the alkyl/aryl substituent effect, another reason why a much harsher condition is required to make alkyl diamines than to make aryl diamines may be the unfavorable equilibrium to form the diimine from the fused ring. In order to evaluate the effect of the fused ring, we computed the energy values (B3LYP/6-31G(d) level) for 6a, 7a, 8a, and ts-5 (Figure 2-15). The rearrangement of 7a to 8a appears to be less favorable than the rearrangement of 7d to 8d (Figure 2-

14 and 2-15). Increase of the activation barrier (∆∆H‡ = 1.6 kcal/mol) and decrease of the thermodynamic barrier (∆∆H = 3.7 kcal/mol) could result from increase of steric bulk from the methyl group to the isopropyl group. DFT computation further shows that the fused ring 6a is more stable than the initial diimine 7a by about 5.7 kcal/mol (∆H2 in Figure 2-15). This energy difference translates to an equilibrium ratio of about 1.5×104 for [6a]/[7a] at 25 oC. Consistent with the computational data, the initial diimine does not accumulate to any observable extent during the reaction of 6a to 8a.

ts-5

O H N iPr

ΔH2 =20.9 N O H iPr ΔH =26.6 1 ts-5

7a OH ΔH =5.7 OH H 2 N N OH N 6a N N O OH ΔH =-12.6 8a N 3 OH

Figure 2-15. Energy profile for the rearrangement of 6a. ΔH and ΔH‡ values in kcal/mol and

ΔS‡ value in cal/mol/K.

We determined the activation parameters for the rearrangement of the fused ring (6b) by measuring the rate constants at different temperature (103 oC to 134 oC, Figure 2-16). The Eyring plot gave the activation enthalpy (29.0 kcal/mol) and activation entropy (-4.4 cal/mol/K) for rearrangement of 6b (Figure 2-16). Interestingly, the measured activation enthalpy (29.0 kcal/mol)

‡ is in good agreement with the computed value of ∆H1 (26.6 kcal/mol) in Figure 2-15. The overall

‡ kinetic barrier of the reaction of 6a can be considered to be ∆H1 only if the rearrangement reaction is the rate-determining step. The agreement between computation and experiment indirectly supports this assumption. Thus, the rate of the fused ring compound (6) is expected to be about 104- fold slower than the rate of the rearrangement of 7. Although the kinetic barrier for making dialkyl diimines is significantly greater than that for making diaryl diimines due to the alkyl/aryl substituent effect and the formation of fused ring compounds, HPEN can be successfully used to make dialkyl vicinal diamines in good yield and excellent stereoselectivity.

Temperature k (s-1) (oC)

103 4.58 × 10-5 115 1.57 × 10-4 120 2.68 × 10-4 125 4.44× 10-4 134 9.28 × 10-4

a1 H NMR in DMSO-d6 (10 mM).

OH OH H N N

N ΔH=29.0 N O ΔS=-4.4 OH 6b 8b

Figure 2-16. Activation parameters for the rearrangement of 6b.

2.3.4. Transition state geometries

Doering and Roth38 reported that rac-3,4-dimethyl-1,5-hexadiene rearranges to a mixture of trans-trans and cis-cis octadienes in a 9:1 ratio under thermal rearrangement conditions (Scheme 2-

6). The former is favored by a difference in the free energy of activation of about 2.0 kcal/mol (-

RTln(kt,t/ks,s) where T = 435K and kt,t/ks,s = 9/1). This stereochemical outcome can be explained by two chair-like transition states with two methyl groups in axial or equatorial positions. Thus, in the

Cope rearrangement, the axial/equatorial substituent effect of the methyl group on the transition state is estimated to be about 1.0 kcal/mol.

trans-trans (90%) ΔΔG435K= 2.0 kcal/mol

cis-cis (10%)

Scheme 2-6. Rearrangement of rac-3,4-dimethyl-1,5-hexadiene

Similar to the Cope rearrangement, we determined the energy difference between chair-like transition states to explain the observed stereoselectivity in the alkyl-substituted diaza-Cope rearrangement. As we previously proposed, the chair-like transition state with all equatorial substituents leads to the chiral diimine, while that with one axial and three equatorial substituents leads to the meso diimine. Accordingly, ts-4 and ts-5 are expected to produce chiral diimines

38 Doering, W. von E.; Roth, W. R. Tetrahedron 1962, 18, 67.

54 whereas ts-4′ and ts-5′ are expected to produce meso diamines (Figure 2-17). DFT computation shows that the activation enthalpies for ts-4, ts-4′, ts-5, and ts-5′ are 19.3, 21.2, 20.9, and 25.5 kcal/mol, respectively. For the methyl substituent, the value of energy differences between ts-4 and ts-4′ (1.9 kcal/mol) translates to a diastereomeric ratio of 25:1. Similarly, for the isopropyl substituent, this value between ts-5 and ts-5′ (4.6 kcal/mol) translates to a diastereomeric ratio of

2400:1. Indeed, experimental data show that chiral and meso 1,2-diaminobutane (9d) is formed in a ratio of 4:1, whereas chiral 1,2-diamino-1,2-diisopropylethane (9a) is formed exclusively to any detectable extent. Thus, there is good agreement between the DFT computational data and the experimental data for axial/equatorial substituent effects on the transition state of the alkyl- substituted diaza-Cope rearrangement.

O O H H N N Me N N Me O H Me O H Me ts-4 ts-4'

ΔH=19.3kcal/mol ΔH=21.2kcal/mol

O O H H N N iPr N N iPr O H iPr O H iPr ts-5 ts-5'

ΔH=20.9kcal/mol ΔH=25.5kcal/mol

Figure 2-17. Chair transition states of the alkyl-substituted diaza-Cope rearrangement

It has been shown that the diimine formed between benzaldehyde and chiral DPEN racemizes by diaza-Cope rearrangement reaction.39 In principle, it should be possible to make alkyl vicinal

39 Vögtle, F.; Goldschmitt, E. Angew. Chem., Int. Ed. Engl. 1974, 13, 480

55 diamines from the reaction of chiral DPEN and alkyl aldehydes since the diaza-Cope rearrangement reaction is expected to be thermodynamically favorable. However, 1H NMR indicates that addition of two equiv of isobutyraldehyde to DPEN results in production of a mixture of compounds

(including the diimine, the imidazolidine, and an enamine formed between the imidazolidine and the aldehyde). This mixture gives many products upon heating. Thus the hydroxyl groups in 1 are crucial for preventing side reactions and also directing the rearrangement reaction cleanly to completion by resonance-assisted hydrogen bonds.

Understanding the diaza-Cope rearrangement reaction for making alkyl vicinal diamines is of considerable mechanistic and synthetic interest. Harsher conditions are required for making the alkyl diamines than for making the aryl diamines for two main reasons. First, alkyl aldehydes form fused ring compounds (6) with 1 whereas aryl aldehydes form diimines (4) with 1. Second, the intrinsic barrier for the diaza-Cope rearrangement reaction is much higher with alkyl substituents than with aryl substituents. Remarkably, the hydroxyl groups, in 1 not only facilitate the diaza-Cope rearrangement reaction but also suppress side reactions in the synthesis of alkyl vicinal diamines.

While more work is needed to show the usefulness of the diaza-Cope rearrangement reaction in the synthesis of complex bioactive compounds like tamiflu and lorabid, a detailed understanding of the mechanism has allowed the first stereospecific synthesis of alkyl-substituted vicinal diamines by the rearrangement reaction

2.4. Unsymmetrical vicinal diamines

The stereoselective synthesis of unsymmetrical vicinal diamines has been a topic of much recent interest because some of the most fascinating drugs such as tamiflu and relenza incorporate the unsymmetrical diamine functionality. Although simple and general synthetic procedure is highly

56 demanded, long synthetic transformations have commonly been used for the synthesis of unsymmetrical vicinal diamines. As one step synthetic procedure, an aldimine cross coupling was reported by Opatz and coworkers in 2005, 40 but stereoselective version of the aldimine cross coupling is not known to date. Here we report a simple and efficient synthesis of the highly challenging unsymmetrical vicinal diamines by the diaza-Cope rearrangement.

2.4.1. Unsymmetrical diaryl diamines

In the presence of two different aromatic aldehydes, HPEN (1) is expected to form homo or hetero diimines by statistical distribution. However, in principle, sequential addition of two aldehydes to 1 could result in formation of mixed initial diimine which undergo the rearrangement to produce the desired unsymmetrical diamines after hydrolysis (Scheme 2-7). Our initial attempts showed that when 1 equiv of p-fluorobenzaldehyde was added to HPEN followed by 1 equiv of o- anisaldehyde in solvents like CHCl3, THF, and EtOH, the rearranged products were formed in a ratio ranging from 1.4:1 to 2.6:1 for hetero to homo diimines. The hetero diimines are obtained slightly more than the statistical amount (1:1 for hetero to homo diimines).

OH O O OH

NH2 Ar1 Ar2 N Ar1

NH2 N Ar2

OH OH

1 [3,3]

H2N Ar1 H2O N Ar1

H2N Ar2 N Ar2 OH

Scheme 2-7. Synthetic procedure for preparing unsymmetrical, diaryl vicinal diamines

40 Kison, C.; Meyer, N.; Opatz, T. Angew. Chem., Int. Ed. 2005, 44, 5662.

Unsymmetrically substituted, chiral vicinal diamines can be prepared more selectively by a slight modification of the one-pot method. Addition of one equiv of aromatic aldehyde to HPEN (1) gives the five-membered-ring imidazolidine intermediate (10). We found that the imidazolidines are stable in DMSO, but they readily undergo dispropotionation to the diimines and amines in CHCl3 or

EtOH within hours. Electron deficient aromatic aldehydes are particularly well suited for the preparation of the five-membered-ring compound, and can be precipitated out of DMSO by addition of water. Addition of a second aldehyde to the imidazolidine intermediate gives the hetereo diimine, which rearranges to the product diimine. To our delight, we found that the unsymmetrical diimine is cleanly formed when the isolated imidazolidine is mixed with the second aldehyde in DMSO

(Scheme 2-8). Several unsymmetrical vicinal diamines (11a to 11d) were prepared by this procedure over 90% purity (<10% of homo diamines).

OH O OH O OH H NH2 Ar1 N Ar2 N Ar1 Ar1 NH DMSO N 2 H DMSO N Ar2 OH OH OH

1 10 [3,3] Isolated

10a:Ar1 =4-ClC6H4 10b:Ar1 =2,4-Cl2C6H4 OH

H2N Ar1 H O N Ar 11a:Ar1 =4-ClC6H4, Ar2 =2-FC6H4 2 1 11b:Ar1 =4-ClC6H4, Ar2 =2,4-Cl2C6H3 11c:Ar1 =2,4-Cl2C6H4, Ar2 =2-HOC6H4 H2N Ar2 N Ar2 11d:Ar1 =4-O2NC6H4, Ar2 =2-HOC6H4 11 OH

Scheme 2-8. A modified synthesis of unsymmetrical vicinal diamines.

The above process for synthesizing mixed diamines can be extended to mixed tetraamines

(Figure 2-18). Addition of a half equiv of a dialdehyde to one equiv of an isolated imidazolidine intermediate (10a) in DMSO gives the mixed tetraamine (11e). Although the reaction mixture

58 includes symmetrical diamines about 5-10%, only tetraamine is precipitated out of MeOH as a tetrahydrochloride salt form in excellent yield (80-93%). This reaction can be utilized to make a novel pentadentate ligand with four chiral centers in enantiomerically pure form.

O O OH N NH2 NH2 4HCl 1/2 H N N NH H 2 2 N HCl Cl N DMSO MeOH H OH Cl Cl (R,R)-10a (S.S,S,S)-11e

1 Figure 2-18. Synthesis of a tetraamine and its H NMR spectrum taken in D2O.

2.4.2. Unsymmetrical alkyl-aryl diamines

The breadth in scope of our method can be demonstrated in the synthesis of mixed alkyl-aryl vicinal diamines. Sequential addition of an aromatic aldehyde and an aliphatic aldehyde gives the fused imidazolidine-dihydro-1,3-oxazine-ring compound in a highly regioselective and stereospecific manner (Figure 2-19). The aromatic aldehyde forms the imidazolidine ring while the aliphatic aldehyde forms the dihydrooxazine ring. Interestingly, the identical fused ring is obtained when the addition sequence is reversed. DFT computation shows that this fused ring is about 1.9 kcal/mol more stable than the fused ring where the aliphatic aldehyde forms the imidazolidine ring

59 and the aromatic aldehyde forms the dihydrooxazine ring. This value translates to an equilibrium ratio of 25:1 at 298 K. Thus, both experimental and computational results support the rigioselective and stereoselective synthesis of the mixed alkyl-aryl imidazolidine-dihydro-1,3-oxazine.

O OH O F OH F OH F H H N H N N N N N H H O OH OH 10c 12a 10d

Figure 2-19. Rigioselective and stereoselective synthesis of the mixed imidazolidine- dihydro-

1 1,3- oxazine ring and partial H NMR spectra of 12a either from 10c or 10d taken in DMSO-d6

at ambient temperature.

Although the mixed alkyl-aryl fused ring is stable at ambient temperature, it cleanly gives the

o 1 rearranged diimine when heated at 100 C for 2 h. Monitoring the reaction by H NMR in DMSO-d6 revealed that the mixed alkyl-aryl diimines can be formed with good yield and purity (Scheme 2-9).

(S,S)-1,2-Diamino-1-(4-fluorophenyl)butane (14c) had previously been synthesized by a much

60 longer route and in a low overall yield (~10%) for the purpose of preparing cisplatin analogues.41

Our results clearly show that our method is more concise and efficient than the reported methods to make mixed aryl-alkyl diamines. Optimization of the synthetic procedure as well as kinetic and computational study is currently in progress.

OH OH R1 H R1 N [3,3] N R1 HCl ClH3N N o 100 C, 2 h N R2 H2O ClH3N R2

O R2 OH 12 13 14 >95% conv >90% purity

13 a b c d

R1 2-F 2-F 4-F 4-Cl

R2 Cy n-C5H11 Et Et

Scheme 2-9. Synthesis of mixed alkyl-aryl vicinal diamines.

In conclusion, we have demonstrated the synthesis of mixed aryl-aryl or alkyl-aryl dimines by a modified procedure of the RAHB-directed diaza-Cope rearrangement. Despite the inherent challenge for making mixed diimines, we have synthesized several mixed diimines including a tetraamine (11e) in high purity by isolating imidazolidine intermediates. Moreover, we have shown the rigioselective and stereoselective formation of mixed alkyl-aryl imidazolidine-1,3-dihydrooxazine. This allowed the synthesis of mixed alkyl-aryl diamines. Therefore, the diaza-Cope rearrangement reaction has been successfully extended to the synthesis of unsymmetrical, aryl-aryl or alkyl-aryl substituted vicinal dimines.

41 Dullin, A.; Dufrasne, F. Gelbcke, M.; Gust, R. Arch. Pharm., Pharm. Med. Chem. 2004, 337, 654.

2.5. Diastereoselective diaza-Cope rearrangement

The Cope rearrangement is an extensively studied organic reaction with considerable synthetic and mechanistic interest.42 Important variations of the reaction including the oxy-Cope,43 Claisen,44 and aza-Cope45 rearrangement reactions have also attracted much attention. Many of these reactions have been found to be particularly useful for making chiral molecules through stereospecifc transfer of chirality. We recently reported syntheses of chiral diamines through stereospecific transfer of chirality using diaza-Cope rearrangement reactions. Here we report the reaction of R-myrtenal with a racemic mixture of 1,2-bis-(2-hydroxyphenyl)-ethylenediamine (rac-1) to give a one to one mixture of RR-15 and RR-16′ (Scheme 2-10).46 This represents the first highly diastereoselective diaza-Cope rearrangement reaction producing one of the most bulky chiral diamine.

Reaction of 2 equiv of R-myrtenal (0.2 M) with rac-1 (0.1 M) in ethanol cleanly gave RR-15 and RR-16′ as a one to one mixture in excellent yield (Scheme 2-10). Figure 2-20 shows the crystal structures of RR-15 and RR-16′. Interestingly, the diimine (SR-16) formed between S-1 and R- myrtenal undergoes resonance assisted H-bond (RAHB) directed diaza-Cope rearrangement reaction to give RR-16′ within minutes in ethanol at ambient temperature while the diimine (RR-15) formed between R-1 and R-myrtenal does not rearrange to SR-15′ to any appreciable extent under the same condition (Scheme 2-10).

42 (a) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441. (b) Wilson, S. R. Org. React. 1993, 43, 93. (c) Hrovat, D. A.; Beno, B. R.; Lange, H.; Yoo, H.−Y.; Houk, K. N.; Borden, W. T. J. Am. Chem. Soc. 1999, 121, 10529 43 (a) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765. (b) Lee, E.; Shin, I. J.; Kim, T. S. J. Am. Chem. Soc. 1990, 112, 260. (c) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569. (d) Haeffner, F.; Houk, K. N. ; Reddy, Y. R.; Paquette, L. A. J. Am. Chem. Soc. 1999, 121, 11880. 44 (a) Claisen, L. Chem. Ber. 1912, 45, 3157. (b) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. 45 (a) Weston, M. H.; Nakajima, K.; Pavez, M.; Back, T. G. Chem. Commun. 2006, 3903. (b) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847. (c) Sugiura, M.; Mori, C.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 11038. (d) Fiedler, D.; Bergman, R. G.; Raymond, K. N. Angew. Chem. Int. Ed. 2004, 43, 6748. 46 The first R in RR-15 refers to the configuration of the diamine backbone (at both chirality centers) and the second R refers to the myrtenal configuration

O O H H N N

N N H H O O RR-15 SR-16

[3,3] slow[3,3] fast

O O H H N N

N N H H O O

SR-15' RR-16'

Scheme 2-10. Diastereoselective diaza-Cope rarrangement

RR-15 RR-16′

Figure 2-20. ORTEP diagrams of RR-1547 and RR-16′48 with 50% thermal ellipsoids. All

hydrogens except for those in the phenol, imine and diamines backbone have been omitted for

clarity.

47 Crystal data of RR-15: T = 150(2) K, trigonal, P31, Z = 9, a = 24.194(3) Å, b = 24.194(3) Å, c = 13.040(3) Å, α = 90º, β = 90º, γ = 120º, V = 6610.2(19) Å3, R1 = 0.0595, wR2 = 0.1017 for I > 2σ(I), GOF on F2 = 0.977.

Figure 2-21a shows the partial 1H NMR spectrum of the mixture of the diimines (RR-15 and

RR-16′) formed from the reaction of R-myrtenal with rac-1. The C-H signals for the diamine backbone of RR-15 and RR-16′ appear at δ 4.81 ppm and δ 4.27 ppm respectively. In addition, the alkene C-H signal for RR-16′ (δ 5.48 ppm) is clearly distinct from that of RR-15 (δ 6.04 ppm).49 The

NMR spectra for diimines RR-16′ (Figure 2-21b) and RR-15 (Figure 2-21c) were also obtained separately from the reactions of R-myrtenal with S-2 and R-2 respectively.

1 Figure 2-21. Partial H NMR spectra (DMSO-d6) from the reactions of R-myrtenal with (a)

rac-1 to give a 1:1 mixture of RR-15 and RR-16′, (b) S-1 to give RR-16′, and (c) R-1 to give

RR-15.

It is surprising that SR-16 rearranges to RR-16′ so much more readily than RR-15 rearranges to

SR-15′. The crystral structures of RR-15 and RR-16′ (Figure 2-20) together with computation (see below) provide valuable insights into the diastereoselectivity of the diaza-Cope rearrangement reaction. The crystal structure of RR-15 represents the first of its kind. While crystal structures of

‘rearranged’ diimines have been previously reported, it is generally difficult to get crystals of

48 Crystal data of RR-16′: T = 150(1) K, hexagonal, P6522, Z = 6, a = 14.1593(4) Å, b = 14.1593(4) Å, c = 25.3297(10) Å, α = 90º, β = 90º, γ = 120º, V = 4397.9(2) Å3, R1 = 0.0464, wR2 = 0.1194 for I > 2σ(I), GOF on F2 = 1.030. 49 1 The H NMR signal for the alkene C-H is a broad singlet in DMSO-d6 and a multiplet in CDCl3

‘initial’ diimines formed with 1 as they normally undergo rapid diaza-Cope rearrangement reactions. Although we did not obtain crystal structures of SR-15′ and SR-16, computation shows that their structures are analogous to those of RR-15 and RR-16′ respectively. Thus there is minimal structural change on going from RR-15 to SR-15′ and from SR-16 to RR-16′.

The rearrangements of RR-15 and SR-16 are expected to take place by chair-like six-membered ring transition states with all substitutents in the equatorial positions (ts-6 and ts-7). Consistent with this proposed mechanism, the crystal structure of the product (RR-16′) obtained from the rearrangement of SR-16 shows that inversion of stereochemistry about the diamine backbone has taken place with the rearrangement reaction. There is remarkable resemblance between the crystal structure of RR-15 (Figure 2-20) and the proposed structure of ts-6. Similarly the crystal structure of

RR-6′ (Figure 2-20) closely resembles the structure of ts-7. In this respect, the two crystal structures may be regarded as rare transition state analogs that provide valuable insights into the origin of the diastereoselectivity.

O O H H N N

N N O H H O ts-6 ts-7

If RR-15 resembles ts-6, why doesn’t it rearrange to SR-15′ as rapidly as SR-16 rearranges to

RR-16′ through ts-7? In order to understand the origin of the diastereoselectivity of the rearrangement reaction, we calculated the structures and energies of RR-15, SR-15′, SR-16, RR-16, ts-6, and ts-7 (Figure 2-22). There is excellent agreement between the crystal structures of RR-15 and RR-16′ with their computed global energy minimum structures. Computation further shows that the global energy minimum structures RR-15 and SR-15′ resemble that of ts-6 and global energy

65 minimum structures of SR-16 and RR-16′ resemble that of ts-7. In addition, there is structural resemblance between RR-15 and SR-16 (also between ts-6 and ts-7 and between SR-15′ and RR-

16′). The only major structural difference between RR-15 and SR-16 (and the other two pairs) is that the four myrtenal methyl groups in the former are pointed inwards whereas those in the latter are pointed outwards.

ts-6

3.74 ts-7

22.0

18.8

-15 0.53 0.97 RR SR-16 SR-15' 4.5 4.09

RR-16'

Figure 2-22. Energy profile for the rearrangement of RR-15 and SR-16 (energy values in

kcal/mol).

The computed distance between the imine carbons in RR-15 (3.84 Å) is greater than those in

SR-16 (3.64 Å). Thus, the steric congestion between the four myrtenal methyl groups in RR-15 that are pointed inwards (Scheme 2-10 & Figure 2-20) appear to decrease the rate of C-C bond formation (to give SR-15′). In SR-16, RR-16′ and ts-7, the four myrtenal methyl groups are pointing away from each other allowing rapid rearrangement. The steric congestion between the methyl groups in SR-16 is expected to be even greater than that in RR-15 since the two myrtenal groups in

SR-16 are directly bonded to each other. Figure 2-22 shows that the difference in computed energies of SR-15′ and RR-16′ (4.09 kcal/mol) is greater than that of RR-15 and SR-16 (0.53 kcal/mol). The computed transition state energy for ts-6 is about 3.74 kcal/mol higher than that for ts-7. Thus the computed energy barrier for the conversion of RR-15 to SR-15′ is higher than that for the conversion

66 of SR-16 to RR-16′ by about 3.21 kcal/mol. This translates to a rate ratio of about 230 to 1 for the rearrangement reaction in the gas phase at 25 ⁰C. Steric effect appears to play an important role in the diastereoselectivity of the rearrangement reaction. We recently showed that in chiral diamine catalyzed synthesis of warfarin, steric effect also plays an important role in the stereoselectivity.50

The value of the rate constant for the rearrangement of SR-16 to RR-16′ in (k = 9.6×10-5 s-1 at

25 °C, in DMSO-d6) is about four hundred times greater than that for the rearrangement of RR-15 to

SR-15′ (k = 2.4×10-7 s-1) in qualitative agreement with the above computation that excludes any solvent effects. The rearrangement of SR-16 to RR-16′ in ethanol is too fast for accurate measurement of the rate constant by 1H NMR methods. Hydrolysis of RR-16′ gave the sterically bulky diamine RR-17 in excellent yield. Chiral diamines including bulky ones such as 1,2-bis(2,4,6- trimethylphenyl)-1,2-diaminoethane (TPEN) have been shown to be useful as ligands for a variety of catalysts.51

O OH OH (i) NH2 NH2 NH2 + NH NH 2 (ii) H+ 2 NH2 OH OH rac-1 RR-17 R-1

Scheme 2-11. Chiral resolution by the diaza-Cope rearrangement.

Chiral resolution by diastereomeric salt formation is one of the most common and useful ways of separating racemic mixtures of amines (or acids). In this process, the solubility difference of the diastereomeric salts produced from the racemic mixture of an amine and enantiopure acid is used to separate the amine. We have shown that R-myrtenal reacts with racemic 1,2-bis(2-hydroxyphenyl)-

50 Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. 51 (a) Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25, 4731. (b) Kokura, A.; Tanaka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2006, 8, 3025. (c) Fujii, H.; Funahashi, Y. Angew. Chem., Int. Ed. 2001, 40, 40. (d) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 3638.

1,2-diaminoethane (rac-1) to give diamines R-1 and RR-17 after hydrolysis of the diimines (Scheme

2-11). While resolution by chemical rearrangement may not become the next general technique for separating racemic mixtures of amines or aldehydes, this represents the first highly diastereoselective diaza-Cope rearrangement reaction. In addition, we can pinpoint the origin of the diastereoselectivity by a combination of computational and crystallographical studies. The origin of the selectivity stems from the steric effect of the myrtenal methyl groups. There is excellent agreement between the transition state analog crystal structures (RR-15 and RR-16′) and their global energy minimum structures. Computation further shows that the energy barrier for the rearrangement of SR-16 to RR-16′ is significantly lower than that for the rearrangement of RR-15 to

SR-15′ (Figure 2-22) in agreement with the kinetic data.

2.6. Conclusions

The resonance-assisted hydrogen bond (RAHB) directed diaza-Cope rearrangement provides a convenient and efficient route to a wide range of “daughter” chiral, vicinal diamines in enantiomerically pure form starting from a single “mother” diamine (1 and HPEN). This method allows not only the synthesis of C2-symmetric diaryl diamines but also dialkyl diamines and even mixed aryl-aryl or alkyl-aryl diamines in excellent yields and enantiopurities. Some of the advantages of this method are: (a) the reaction is highly efficient and stereospecific; (b) no metals are required as catalysts or reagents; (c) the reaction generally takes place rapidly at ambient temperature; and (d) the reaction eliminates the need for tedious and time-consuming optimizations of the chiral resolution conditions. A reaction between R-(-)-myrtenal and racemic HPEN has been demonstrated to be the first highly diastereoselective diaza-Cope rearrangement. This reaction can be used for separating racemic HPEN as well as for preparing a bulkyl diamine containing α-pinene groups.

2.7. Experimental

General information: Commercially available compounds were used without further purification or drying. The 1H NMR and 13C NMR spectra were recorded on a Varian Mercury 300 spectrometer or a Varian Mercury 400 spectrometer. The High resolution mass spectra (HRMS) were obtained from the Department of Chemistry, University of Toronto (ESI or EI). Circular dichroism spectra were taken with a JASCO J-710 spectropolarimeter. UV-vis spectra were recorded on a PerkinElmer Lambda 900 spectrometer. HPLC analysis was performed on a Hewlett-

Packard 1090 Series HPLC, UV detection monitored at 254 nm, using a Chiralcel OD-H column or a Chiralpak AD-H column (25cm). Optical rotations were obtained at 589 nm using a Rudolph

Autopol IV polarimeter. Melting points were recorded using an Electrothermal IA 9100 digital melting point apparatus.

Computational methods: All calculations were carried out with Spartan ′06 from

Wavefunction Inc. DFT computation at B3LYP/6-31G(d) level 52 was used to calculate the optimized geometry and vibrational frequencies. A vibrational analysis was performed at each stationary point to confirm its identity as an energy minimum or a transition structure.53 In all cases the local minima had no imaginary frequencies, whereas the transition state structures led to exactly one imaginary frequency. The gas-phase enthalpy was calculated as ΔH298= ΔZPVE + ΔΔH0→298K +

ΔE0. Zero-point vibrational energy (ZPVE) and enthalpy change (ΔΔH0→298K) from 0 K to 298 K at

1 atm were obtained from vibrational frequencies.

Procedure A: To a cloudy solution of 2.2 g (10 mmol) of 1,2-bis(2-hydroxylphenyl)-1,2- diaminoethane (1) in 33 mL of ethanol was added 24 mmol of aryl aldehyde. The resulting clear

52 (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785. 53 Cramer, C. J., Essentials of Computational Chemistry, 2nd ed.; John Wiley and Sons: New York, 2004.

69 reaction mixture was stirred for 1 h at room temperature to give 5 as a yellow precipitate. The solid was filtered, washed with 10 mL of ethanol and dried in vacuum.

Procedure B: To a clear solution of 2.2 g (10 mmol) of 1,2-bis(2-hydroxylphenyl)-1,2- diaminoethane (1) in 50 mL of DMSO was added 24 mmol of aryl aldehyde. The resulting mixture was stirred overnight at room temperature, and then the mixture was poured into 150 ml of distilled water. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed with distilled water, and dried over sodium sulfate. After evaporation of the solvent, the residue was dried in vacuum.

Hydrolysis of diimines (5): To a clear solution of 5 (10 mmol) in 100 mL of THF was added

3.0 mL of 37 % HCl solution. Stirring the reaction mixture at ambient temperature for 3 h afforded the product as a white precipitate. The solid was filtered, and washed with THF to afford analytically pure 3 as the dihydrochloride salt.

1H-NMR (400 MHz, CD OD): δ 5.66 (s, 2H, C*H); 4.95 (br s, 6H, NH ). 19F- F F 3 3 F F NH3Cl NMR (376 MHz, CD3OD): δ -141.8, -151.0, -162.0. The enantiopurity was F F NH Cl F 3 confirmed by HPLC analysis (Chiralcel OD-H column, 5% isopropanol in F F 3a F hexane, 1.0 mL / min); (S,S)-5a tR = 5.2 min, (R,R)-5a tR = 6.2 min. HRMS (ESI)

+ 27 calculated for C14H7F10N2 [M+H] : 393.0444, Found: 393.0461. [α]D + 27 (c =1.0, CH3OH) for

27 (R,R)-3a, [α]D - 27 (c =1.0, CH3OH) for (S,S)-3a.

1 O2N H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 6H, NH3); 8.15 (d, J = 8.8 Hz, 4H,

NH3Cl ArH); 7.74 (d, J = 8.8 Hz, 4H, ArH); 5.41 (s, 2H, C*H). 13C-NMR (100 MHz, NH3Cl

O2N 3b DMSO-d6): δ 147.7, 139.9, 130.4, 123.6 (4 aromatic carbons), 55.72 (1 aliphatic

+ 26 carbon). HRMS (ESI) calculated for C14H15N4O4 [M+H] : 303.1087, Found: 303.1098. [α]D + 84

26 (c =1.0, H2O) for (R,R)-3b, [α]D - 84 (c =1.0, CH3OH) for (S,S)-3b.

1H-NMR (400 MHz, CD OD): δ 7.85 (d, J = 8.4 Hz, 4H, ArH); 7.49 (d, J = 8.4 MeO2C 3

NH3Cl 13 Hz, 4H, ArH); 5.23 (s, 2H, C*H); 4.86 (br s, 6H, NH3); 3.80 (s, 6H, CH3). C-

NH3Cl NMR (100 MHz, CD OD): δ 168.5 (1 carbonyl carbon), 138.1, 132.0, 131.2, MeO2C 3c 3

129.6 (4 aromatic carbons), 58.1, 53.5 (2 aliphatic carbons). HRMS (ESI) calculated for C18H21N2O4

+ 27 27 [M+H] : 329.1495, Found: 329.1512. [α]D + 47 (c =1.0, CH3OH) for (R,R)-3c, [α]D - 47 (c =1.0,

CH3OH) for (S,S)-3c.

1 F H-NMR (400 MHz, CD3OD): δ 7.39 (dd, J = 6.8, 11.6 Hz, 4H, ArH); 7.09 (t, J =

NH Cl 3 13 11.6 Hz, 4H, ArH); 5.11 (s, 2H, C*H); 4.86 (br s, 6H, NH3). C-NMR (100 MHz,

NH3Cl

F 3d DMSO-d6): δ 162.1 (d, J = 245 Hz), 131.2 (d, J = 8 Hz), 129.6 (d, J = 3 Hz), 115.4

(d, J = 21 Hz) (4 aromatic carbons), 56.0 (1 aliphatic carbon). The enantiopurity was confirmed by

HPLC analysis (Chiralcel OD-H column, 1% isopropanol in hexane, 0.5 mL / min); (R,R)-5d tR =

+ 20.5 min, (S,S)-5d tR = 22.3 min. HRMS (ESI) calculated for C14H15N2F2 [M+H] : 249.1197, Found:

27 27 249.1209. [α]D + 41 (c =1.0, CH3OH) for (R,R)-3d, [α]D - 41 (c =1.0, CH3OH) for (S,S)-3d.

1 Cl H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 6H, NH3); 7.42 (d, J = 8.8 Hz, 4H,

NH3Cl ArH); 7.36 (d, J = 8.8 Hz, 4H, ArH); 5.17 (s, 2H, C*H). 13C-NMR (100 MHz, NH3Cl

Cl 3e DMSO-d6): δ 133.8, 132.0, 130.8, 128.5 (4 aromatic carbons), 55.9 (1 aliphatic carbon). The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 50% isopropanol in hexane, 0.8 mL / min); (S,S)-5e tR = 22.4 min, (R,R)-5e tR = 27.6 min. HRMS (ESI)

+ 25 calculated for C14H15Cl2N2 [M+H] : 281.0606, Found: 281.0600. [α]D + 39 (c =1.0, CH3OH) for

(R,R)-3e.

1 F3C H-NMR (400 MHz, DMSO-d6): δ 9.42 (s, 6H, NH3); 7.70 (d, J = 8.0 Hz, 4H,

NH3Cl ArH); 7.63 (d, J = 8.0 Hz, 4H, ArH); 5.28 (s, 2H, C*H). 13C-NMR (100 MHz,

NH3Cl

F3C 3f DMSO-d6): δ 137.4, 129.8, 129.5 (q, J = 32 Hz), 125.4 (q, J = 3 Hz), 123.8 (q, J

= 271 Hz), 56.0. The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 10%

71 isopropanol in hexane, 1.0 mL / min); (S,S)-5f tR = 6.6 min, (R,R)-5f tR = 7.8 min. HRMS (ESI)

+ 25 calculated for C16H15N2F6 [M+H] : 349.1133, Found: 349.1137. [α]D + 33 (c =1.0, CH3OH) for

(R,R)-3f.

NC 1 H-NMR (400 MHz, D2O): δ 7.77 (d, J = 8.4 Hz, 4H, ArH); 7.44 (d, J = 8.4 Hz,

NH3Cl 13 4H, ArH); 5.16 (s, 2H, C*H). C-NMR (100 MHz, CD3OD): δ 138.7, 143.4, NH3Cl

NC 3g 130.8, 119.0, 114.7 (5 aromatic and sp carbons), 58.2 (1 aliphatic carbon). The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 50% isopropanol in hexane, 0.5 mL / min); (S,S)-5g tR = 22.1 min, (R,R)-5g tR = 24.9 min. HRMS (ESI) calculated for

+ 27 27 C16H15N4 [M+H] : 263.1291, Found: 263.1280. [α]D + 78 (c =1.0, CH3OH) for (R,R)-3g, [α]D -

78 (c =1.0, CH3OH) for (S,S)-3g.

1 AcHN H-NMR (400 MHz, D2O): δ 7.48 (d, J = 8.8 Hz, 4H, ArH); 7.25 (d, J = 8.8 Hz,

NH3Cl 13 4H, ArH); 5.07 (s, 2H, C*H); 2.18 (s, 6H, CH3). C-NMR (100 MHz,

NH3Cl D2O/CD3OD): δ 170.1, 139.8, 128.6, 125.7, 119.3 (5 aromatic and carbonyl AcHN 3h

+ carbons), 56.1, 22.2 (2 aliphatic carbons). HRMS (ESI) calculated for C18H22N4O2Na [M+Na] :

27 27 349.1634, Found: 349.1629. [α]D - 4.0 (c =1.0, CH3OH) for (R,R)-3h, [α]D + 4.0 (c =1.0,

CH3OH) for (S,S)-3h.

1 MeO H-NMR (400 MHz, DMSO-d6): δ 9.20 (s, 6H, NH3); 7.27 (d, J = 8.8 Hz, 4H,

NH3Cl 13 ArH); 6.83 (d, J = 8.8 Hz, 4H, ArH); 5.00 (s, 2H, C*H); 3.69 (s, 6H, OCH3). C-

NH3Cl NMR (100 MHz, DMSO-d6): δ 159.4, 130.1, 125.2, 113.8 (4 aromatic carbons), MeO 3i 56.2, 55.1 (2 aliphatic carbons). The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-

H column, 20% isopropanol in hexane, 0.8 mL / min); (R,R)-5i tR = 9.0 min, (R,R)-5i tR = 10.8 min.

+ 27 HRMS (ESI) calculated for C16H21N2O2[M+H] : 273.1597, Found: 273.1616. [α]D + 6.0 (c =1.0,

CH3OH) for (S,S)-3i.

1H-NMR (400 MHz, D O): δ 7.17 (d, J = 8.8 Hz, 4H, ArH); 6.95 (d, J = 8.8 Hz, HO 2

NH3Cl 13 4H, ArH); 5.02 (s, 2H, C*H). C-NMR (100 MHz, D2O, CH3OH as reference): δ

NH3Cl 157.7, 130.6, 122.7, 166.6 (4 aromatic carbons), 56.9 (1 aliphatic carbon). HRMS HO 3j

+ 27 (ESI) calculated for C14H17N2O2[M+H] : 245.1284, Found: 245.1298. [α]D - 10 (c =1.0, CH3OH)

27 for (R,R)-3j, [α]D + 10 (c =1.0, CH3OH) for (S,S)-3j.

1 H-NMR (400 MHz, D2O): δ 7.62 (d, J = 8.8 Hz, 4H, ArH); 7.52 (d, J = 8.8 Me2N

NH2 13 Hz, 4H, ArH); 5.22 (s, 2H, C*H); 3.25 (s, 12H, CH3). C-NMR (100 MHz, 4HCl NH2 D2O, CH3OH as reference): δ 144.0, 133.8, 131.1, 122.3 (4 aromatic Me2N 3k + carbons), 56.9, 46.8 (2 aliphatic carbons). HRMS (ESI) calculated for C18H24N3[M+H] : 282.1964,

27 Found: 282.1976 due to escape of NH3 under mass condition. [α]D + 37 (c =1.0, H2O) for (R,R)-

27 3k, [α]D - 37 (c =1.0, H2O) for (S,S)-3k.

1 OMe H-NMR (300 MHz, CDCl3): δ 7.23 (dd, J = 1.8, 9.0 Hz, 2H, ArH); 7.12 (dt, J = 1.8,

NH 2 7.5 Hz, 2H, ArH); 6.82 (dt, J = 1.2, 7.5 Hz, 2H, ArH); 6.76 (dd, J = 1.2, 8.1 Hz, 2H,

NH2 13 OMe 3l ArH); 4.46(s, 2H, C*H), 3.78 (s, 6H, OCH3). C-NMR (75 MHz, CDCl3): δ 157.1,

132.4, 128.2, 127.8, 120.5, 110.5 (6 aromatic carbons), 55.6, 55.4 (2 aliphatic carbons). HRMS

+ (ESI) calculated for C16H21N2O2 [M+H] : 273.1597, Found: 273.1588. The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 10% isopropanol in hexane, 0.8mL / min);

(R,R)-5l tR = 7.4 min, (S,S)-5l tR = 9.8 min.

1 Cl H-NMR (400 MHz, DMSO-d6): δ 9.64 (s, 6H, NH3); 8.09 (d, J = 6.8 Hz, 2H, ArH);

NH Cl 3 13 7.35-7.24 (m, 6H, ArH); 5.60 (s, 2H, C*H). C-NMR (100 MHz, DMSO-d6): δ NH3Cl

Cl 3m 132.9, 131.2, 131.0, 129.5, 129.4, 127.5 (6 aromatic carbons), 52.7 (1 aliphatic

+ carbon). HRMS (ESI) calculated for C14H15N2Cl2 [M+H] : 281.0606, Found: 281.0612. The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 5% isopropanol in hexane,

27 0.8mL / min); (S,S)-5m tR = 7.0 min, (R,R)-5m tR = 7.8 min. [α]D - 22 (c =1.0, CH3OH) for (R,R)-

27 3m, [α]D + 22 (c =1.0, CH3OH) for (S,S)-3m.

1 Me H-NMR (300 MHz, CDCl3): δ 7.58 (dd, J = 1.2, 7.6 Hz, 2H, ArH); 7.19 (dt, J =

NH2 1.2, 7.2 Hz, 2H, ArH); 7.09 (dt, J = 1.5, 7.2Hz, 2H, ArH); 7.01 (d, J = 7.6 Hz, 2H, NH2 13 Me 3n ArH); 4.34 (s, 2H, C*H); 2.12 (s, 6H, ArCH3). C-NMR (75 MHz, CDCl3): δ 142.0,

135.4, 130.5, 127.0, 126.9, 126.1 (6 aromatic carbons), 56.0, 19.8 (2 aliphatic carbons). HRMS

+ (ESI) calculated for C16H21N2 [M+H] : 241.1699, Found: 241.1713. The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 2% isopropanol in hexane, 0.5mL / min);

(S,S)–5n tR = 13.9 min, (R,R)-5n tR = 14.9 min.

1 H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 6H, NH3); 8.37 (d, J = 7.2 Hz, 2H, ArH);

8.20 (d, J = 6.4 Hz, 2H, ArH); 7.70 (d, J = 8.0 Hz, 2H, ArH); 7.58 (d, J = 8.0 Hz, NH3Cl

13 NH3Cl 4H); 7.43 (t, J = 7.2 Hz, 2H); 7.16 (t, J = 7.6 Hz, 2H, ArH); 6.43 (s, 2H, C*H). C-

3o NMR (100 MHz, D2O/DMSO-d6): δ 134.5, 131.9, 131.3, 130.3, 130.2, 129.0, 128.0,

126.8, 126.6, 123.5 (10 aromatic carbons), 53.1 (1 aliphatic carbon). HRMS (ESI) calculated for

+ C22H21N2 [M+H] : 313.1699, Found: 313.1698. The enantiopurity was confirmed by HPLC analysis

(Chiralcel OD-H column, 50% isopropanol in hexane, 0.8mL / min); (R,R)–5o tR = 6.7 min, (S,S)-5o

27 27 tR = 9.7 min. [α]D - 235 (c =1.0, H2O) for (R,R)-3o, [α]D + 235 (c =1.0, H2O) for (S,S)-3o.

1 MeO H-NMR (400 MHz, D2O): δ 6.21 (s, 4H, ArH); 5.51 (s, 2H, C*H); 3.81 (s, 6H, OMe 13 NH3Cl OCH3); 3.70 (s, 12H, OCH3). C-NMR (100 MHz, DMSO-d6): δ 161.8, 159.6, MeO MeO NH3Cl 158.2, 101.8, 90.5, 90.3 (6 aromatic carbons), 55.8, 55.7, 55.4, 46.0 (4 aliphatic OMe MeO 3p carbons). The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 10% isopropanol in hexane, 1.0mL / min); (R,R)–5p tR = 13.6 min, (S,S)-5p tR = 17.2 min.

+ HRMS (ESI) calculated for C20H26NO6 [M+H] : 376.1754, Found: 376.1757 due to escape of NH3

27 27 under mass condition. [α]D + 73 (c =1.0, CH3OH) for (R,R)-3p, [α]D - 73 (c =1.0, CH3OH) for

(S,S)-3p.

O OH HO H2N NH2 HN N HO OH HO O N N Neat, RT DMSO, 150oC 3h, 93% (R,R)-1 (R,R,R,R)-6a (S,S)-8a

G After adding (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (1.0 g) E F H C HN N D to isobutyraldehyde (1.87 mL) the mixture was kept at room temperature HO A B O for half an hour until the product (6a) precipitated out. The excess

(R,R,R,R)-6a isobutyraldehyde was removed in vacuo to afford the product as a yellow solid (1.45 g) in quantitative yield.

1 H-NMR (400 MHz, CD3OD): δ 7.19 (t, J = 7.8 Hz, 1H, ArH); 7.11 (t, J = 7.7 Hz, 1H, ArH); 6.96

(d, J = 7.6 Hz, 1H, ArH); 6.86 (d, J = 8.0 Hz, 1H, ArH); 6.78 – 6.82 (m, 3H, ArH); 6.21 (d, J = 8.0

Hz, 1H, ArH); 4.48 (d, J = 7.0 Hz, 1H, ArCHB); 4.35 (d, J = 9.9 Hz, 1H, NOCHDCH); 4.12 (d, J =

2.4 Hz, 1H, NNCHcCH); 3.88 (d, J = 7.0 Hz, 1H, ArCHA); 2.07 (m, 1H, CHCHE(CH3)2); 1.98 (m,

1H, CHCHF(CH3)2); 1.07 (d, J = 3.1 Hz, 1H, C(HG)3); 1.05 (d, J = 2.6 Hz, 1H, C(HG)3); 1.00 (d, J =

13 6.6 Hz, 1H, C(HH)3); 0.90 (d, J = 6.4 Hz, 1H, C(HH)3). C-NMR (100 MHz, CD3OD): δ 158.0,

152.9, 131.6, 130.5, 128.7, 127.9, 127.4, 125.7, 122.1, 120.6, 118.8, 117.5 (12 aromatic carbons),

93.4, 81.5, 71.3, 60.4, 31.4, 30.3, 20.0, 19.8, 19.4, 14.5 (10 aliphatic carbons). HRMS (ESI)

+ calculated for C22H28N2O2: 352.22. Found [M+H] : 353.22. The enantiopurity was confirmed by

HPLC analysis (Chiralcel OD-H column, 3% isopropanol in hexane, 1mL / min); (R,R,R,R)-6a tR =

25 10.5 min, (S,S,S,S)-6a tR = 12.1 min. [α]D + 124.4 (c =1.0, CHCl3) for (S,S,S,S)-6a, mp = 121 –

122oC.

The fused imidazolidine-dihydro-1,3-oxazine 6a (1 g) was dissolved in DMSO OH HO o N N (4.3 mL), and the resulting solution was heated at 150 C for 3 h. After cooling

the mixture, water was added. The aqueous layer was extracted with Et2O / (S,S)-8a

THF (10/1) three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. A yellow precipitate 8a was obtained from methanol in 93% yield (0.93 g).

1 H-NMR (300 MHz, CDCl3): δ 13.54 (br s, 2H, ArOH); 8.17 (s, 2H, Imine H); 7.26 (t, J = 7.1 Hz,

2H, ArH); 7.15 (d, J = 7.2 Hz, 2H, ArH); 6.94 (d, J = 8.4 Hz, 2H, ArH); 6.79 (t, J = 7.4 Hz, 2H,

ArH); 3.23 (br s, 2H, C*H); 2.13 (m, 2H, CH(CH3)2); 0.99 (d, J = 6.6 Hz, 6H, CH(CH3)2); 0.91 (d, J

13 = 6.6 Hz, 6H, CH(CH3)2). C-NMR (75 MHz, CDCl3): δ 165.8, 161.5, 132.4, 131.6, 118.7, 117.2 (6 aromatic carbons), 76.4, 28.6, 20.8, 17.6 (4 aliphatic carbons). HRMS (ESI) calculated for

+ C22H29N2O2 [M+H] : 353.2223. Found : 353.2222. The enantiopurity was confirmed by HPLC analysis (Chiralcel AD-H column, 5% isopropanol in hexane, 1.0 mL / min); (S,S)-8a tR = 4.9 min,

26 o (R,R)-8a tR = 9.0 min. [α]D + 144.8 (c =1.0, CHCl3) for (S,S)-8a, mp = 188 - 189 C.

OH O OH

NH2 R N R HCl ClH3N R toluene THF NH2 reflux N R ClH3N R OH OH (R,R)-1 (S,S)-8 (S,S)-9

Synthesis of 8a: In a typical experiment, isobutyraldehyde (1.87 mL, 20.5 mmol) was added to a solution of (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (2.0 g, 8.2 mmol) in toluene (27 mL) at ambient temperature. The resulting solution was refluxed for 24 h with a Dean-Stark trap. After removal of the solvent under reduced pressure, methanol was added to precipitate (S,S)-N,N′- bis(salicylidene)-1,2-isopropyl-1,2-diaminoethane (8a) as a yellow powder in 85% yield.

Synthesis of 9a: To a clear solution of (S,S)-8a (705 mg, 2.0 mmol) in 20 mL of THF was added 0.6 mL of 37% HCl solution. Stirring the mixture at 50 oC for 3 h afforded the diamine dihydrochloride

[(S,S)-9a] as a white powder in 91% yield.

1 H-NMR (300 MHz, CDCl3): δ 13.62 (br s, 2H, ArOH); 8.12 (s, 2H, Imine H); OH

N 7.25 (t, J = 7.8 Hz, 2H, ArH); 7.13 (d, J = 7.5 Hz, 2H, ArH); 6.94 (d, J = 8.7

N Hz, 2H, ArH); 6.78 (t, J = 7.5 Hz, 2H, ArH); 3.28 (d, J = 1.8 Hz, 2H, C*H); OH 8b 13 1.77 – 1.55 (m, 12H); 1.35 – 0.93 (m, 10H). C-NMR (75 MHz, CDCl3): δ

165.5, 161.61 132.4, 131.6, 118.6, 117.2 (6 aromatic carbons), 75.3, 38.4, 31.1, 28.2, 26.5, 26.5,

+ 26.4 (7 aliphatic carbons). HRMS (ESI) calculated for C28H36N2O2 [M+H] : 433.2849. Found:

433.2856. The enantiopurity was confirmed by HPLC analysis (Chiralcel AD-H column, 30%

26 isopropanol in hexane, 1.0 mL / min); (S,S)-8b tR = 4.4 min, (R,R)-8b tR = 18.4 min. [α]D +86.4 (c

o =1.0, CHCl3) for (S,S)-8b, mp = 200-201 C.

1H-NMR (400 MHz, CDCl ): δ 13.44 (br s, 2H, ArOH); 8.29 (s, 2H, Imine H); OH 3 N 7.27 (t, J = 8.0 Hz, 2H, ArH); 7.22 (d, J = 7.6 Hz, 2H, ArH); 6.95 (d, J = 8.0 Hz,

N 2H, ArH); 6.83 (t, J = 7.4 Hz, 2H, ArH); 2.87 (ddd, J = 1.6, 3.6, 8.4 Hz, 2H, OH 8c C*H); 1.21 – 1.29 (m, 2H); 0.61 – 0.68 (m, 2H), 0.50 – 0.57 (m, 2H), 0.35 –

13 0.41 (m, 2H), 0.23 – 0.29 (m, 2H). C-NMR (100 MHz, CDCl3): δ 164.7, 161.5, 132.5, 131.6,

+ 118.9, 118.7, 117.3, 77.9, 14.6, 3.9, 3.3. HRMS (ESI) calculated for C22H25N2O2 [M+H] : 349.1910.

Found: 349.1905. The enantiopurity was confirmed by HPLC analysis (Chiralcel AD-H column, 5%

27 isopropanol in hexane, 1.0 mL / min); (S,S)-8c tR = 7.3 min, (R,R)-8c tR = 9.6 min. [α]D -41.8 (c

o =1.0, CHCl3) for (S,S)-8c, mp = 128-129 C.

1 OH H-NMR (400 MHz, CDCl3): δ 13.36 (br s, 2H, ArOH); 8.31 (s, 2H, Imine H); N 7.30-7.19 (m, 4H, ArH); 6.78-6.80 (m, 4H, ArH); 3.49 (m, 2H, C*H); 1.38 (d, J = N 6.13 Hz, 6H). OH 8d

1 OH H-NMR (400 MHz, CDCl3): δ 13.42 (br s, 2H, ArOH); 8.27 (s, 2H, Imine H); N 7.27 (t, J = 7.8 Hz, 2H, ArH); 7.21 (d, J = 7.6 Hz, 2H, ArH); 6.96 (d, J = 8.0 Hz, N 2H, ArH); 6.83 (t, J = 7.6 Hz, 2H, ArH); 3.22 (dd, J = 5.0, 14.4 Hz, 2H, C*H); OH 8e 13 1.62 – 1.81 (m, 4H); 0.87 (t, J = 7.4 Hz, 6H). C-NMR (100 MHz, CDCl3): δ 165.2, 161.5, 132.4,

+ 131.6, 118.7, 118.7, 117.3, 75.1, 25.7, 10.9. HRMS (ESI) calculated for C20H25N2O2 [M+H] :

325.1910. Found: 325.1920. The enantiopurity was confirmed by HPLC analysis (Chiralcel AD-H column, 5% isopropanol in hexane, 1.0 mL / min); (S,S)-8e tR = 6.7 min, (R,R)-8e tR = 8.0 min.

27 o [α]D +46.6 (c =1.0, CHCl3) for (S,S)-8e, mp = 114-115 C.

1 OH H-NMR (400 MHz, CDCl3): δ 13.44 (br s, 2H, ArOH); 8.25 (s, 2H, Imine

N H); 7.27 (t, J = 7.8 Hz, 2H, ArH); 7.21 (dd, J = 1.6, 7.6 Hz, 2H, ArH); 6.97

N (d, J = 8.3 Hz, 2H, ArH); 6.83 (dt, J = 1.0, 7.5 Hz, 2H, ArH); 3.27 (m, 2H, OH 8f C*H); 1.73 – 0.81 (m, 18H).

1 H-NMR (400 MHz, DMSO-d6): δ 8.61 (s, 6H, NH3); 3.18 (d, J = 4.8 Hz, 2H, ClH N 3 13 NC*H); 2.08 – 2.13 (m, 2H, CH(CH3)2); 0.96 (dd, J = 6.8, 7.2 Hz, 12H, CH3). C-

ClH3N 9a NMR (100 MHz, DMSO-d6): δ 56.2, 27.4, 19.9, 17.5. HRMS (ESI) calculated for

+ 27 C8H21N2 [M+H] : 145.1699. Found: 145.1700. [α]D +5.4 (c =1.0, CH3OH) for (S,S)-9a. All of diamine dihydrochlorides melts above 200 oC and evaporates at that temperature.

1 H-NMR (400 MHz, DMSO-d6): δ 8.53 (s, 6H, NH3); 3.20 (d, J = 0.8 Hz, 2H,

13 ClH3N NC*H); 1.60 – 1.85 (m, 12H); 1.00 – 1.31 (m, 10H). C-NMR (100 MHz,

ClH3N DMSO-d6): δ 54.7, 36.3, 29.1, 27.8, 25.3, 25.2, 25.2. HRMS (ESI) calculated for 9b

+ 27 C14H29N2 [M+H] : 225.2325. Found: 225.2330. [α]D -26.4 (c =1.0, CH3OH) for (S,S)-9b.

1 H-NMR (400 MHz, CD3OD): δ 2.92 (ddd, J = 1.6, 3.0, 10.4 Hz, 2H, NC*H); 1.19 –

ClH3N 1.30 (m, 2H); 0.81 – 0.95 (m, 4H); 0.66 – 0.72 (m, 2H), 0.54 – 0.60 (m, 2H). 13C-

ClH3N 9c NMR (100 MHz CD3OD): δ 59.2, 9.6, 6.1, 3.5. HRMS (ESI) calculated for C8H21N2

+ 27 [M+H] : 145.1699. Found: 145.1700. [α]D -14.2 (c =1.0, CH3OH) for (S,S)-9c.

Meso-9d: 1H-NMR (400 MHz, D O): δ 3.65 (m, 2H, C*H); 1.43 (d, J = 6.7 Hz, 6H). ClH3N 2

1 ClH3N (S,S)-9d: H-NMR (400 MHz, D2O): δ 3.75 (m, 2H, C*H); 1.38 (d, J = 6.7 Hz, 6H). 9d

1 H-NMR (400 MHz, DMSO-d6): δ 8.58 (s, 6H, NH3); 3.39 (s, 2H, NC*H); 1.73 – ClH3N 1.78 (m, 2H); 1.53 – 1.59 (m, 2H); 0.97 (t, J = 7.2 Hz, 6H). 13C-NMR (100 MHz, ClH3N 9e + DMSO-d6): δ 53.1, 20.3, 10.2. HRMS (EI) calculated for C6H17N2 [M+H] : 117.1392.

27 Found: 117.1393. [α]D -22.4 (c =1.0, CH3OH) for (S,S)-9e.

OH O OH O OH OH H NH Ar1 Ar2 N Ar N Ar 2 N 1 [3,3] 1 H2O H2N Ar1 Ar1 NH DMSO N DMSO N Ar N Ar 2 H 2 2 H2N Ar2 OH OH OH OH 1 10 11

Synthesis of imidazolidines 10: To a clear solution of 2.2 g (10 mmol) of 1 in 33 mL of DMSO was added 10 mmol of aryl aldehyde. The resulting solution was stirred for 30 min at room temperature and then slowly poured into 200 mL of ice-cooled water. The precipitate was filtered and washed with distilled water. As the solid decomposed upon drying, the residual water was removed by extraction with diethyl ether. To prevent disproportionation of the product, the solvent was quickly dried over Na2SO4 and removed under reduced pressure to give the product as a yellow powder.

1 OH H-NMR (400 MHz, DMSO-d6): δ 11.30 (br s, 2H, OH); 7.60 (d, J = 8.4 Hz, H N Cl 2H, ArH); 7.49 (d, J = 8.4 Hz, 2H, ArH); 7.08-7.03 (m, 2H, ArH); 6.79 (d, J = N H OH 10a 7.4 Hz, 2H, ArH); 6.72 (t, J = 7.4 Hz, 2H, ArH); 6.64 (dt, J = 3.7, 8.4 Hz, 2H,

ArH); 5.27 (s, 1H, CH(NCH)2); 4.60 (br s, 1H, NH); 4.54 (d, J = 8.3 Hz, 1H, C*H); 4.42 (d, J = 8.3

13 Hz, 1H, C*H); 4.21 (br s, 1H, NH). C-NMR (100 MHz, DMSO-d6): δ 156.8, 141.3, 132.4, 129.1,

128.7, 128.5, 128.3, 128.1, 128.0, 124.2, 123.9, 118.3, 118.3, 115.9, 115.8, 73.7, 66.8, 64.5.

1 OH H-NMR (400 MHz, DMSO-d6): δ 11.06 (br s, 2H, OH); 7.87 (d, J = 8.4 Hz, Cl H N Cl 1H, ArH); 7.65 (d, J = 2.1 Hz, 1H, ArH); 7.53 (dd, J = 2.1, 8.4 Hz, 1H, ArH); N H OH 10b 7.08-7.01 (m, 2H, ArH); 6.88 (dd, J = 1.4, 7.6 Hz, 1H, ArH); 6.82 (dd, J = 1.4,

7.6 Hz, 1H, ArH); 6.74 (d, J = 8.0 Hz, 1H, ArH); 6.69-6.61 (m, 3H, ArH); 5.56 (s, 1H, CH(NCH)2);

4.68 (br s, 1H, NH); 4.51-4.45 (m, 2H, C*H); 4.17 (br s, 1H, NH).

Synthesis of unsymmetrical aryl-aryl vicinal diamines 11: To a stirred solution of 10 mmol of 10 in 33 mL of DMSO was added 11 mmol of the second aryl aldehyde. The resulting mixture was stirred overnight at ambient temperature. The mixture was slowly poured into 200 mL of ice-cooled water. The resulting yellow precipitate was filtered, washed with distilled water, and dried by passing air on the filter funnel. The dried mixed diimine was hydrolyzed to the diamine (11) dihydrochloride by following the above procedure.

1 F H-NMR (400 MHz, D2O): δ 7.50-7.45 (m, 1H, ArH); 7.42 (d, J = 8.4 Hz, 2H,

ClH3N ArH); 7.26 (d, J = 8.4 Hz, 2H, ArH); 7.22-7.17 (m, 3H, ArH); 5.32 (d, J = 8.3

ClH3N Hz, 1H, C*H); 5.14 (d, J = 8.3 Hz, 1H, C*H). Cl 11a

1 H-NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.3 Hz, 1H); 7.35-7.25 (m, 6H); 4.48 Cl Cl 13 H2N (d, J = 3.8 Hz, 1H, C*H); 4.24 (d, J = 3.8 Hz, 1H, C*H). C-NMR (100 MHz,

H2N CDCl3): δ 141.9, 139.5, 133.5, 133.5, 133.0, 129.6, 129.3, 128.7, 128.1, 127.3, Cl 11b

57.8, 57.4.

1 H-NMR (400 MHz, CDCl3): δ 7.35-7.32 (m, 2H); 7.21 (dd, J = 2.1, 8.3 Hz, 1H); Cl Cl

H2N 7.10 (dt, J = 1.6, 7.7 Hz, 1H); 6.82 (d, J = 8.1 Hz, 1H); 6.71 (dd, J = 1.4, 7.5 Hz,

H2N 1H); 6.62 (t, J = 7.4 Hz, 1H); 4.47 (d, J = 6.1 Hz, 1H, C*H); 4.30 (d, J = 6.1 Hz, HO 13 11c 1H, C*H). C-NMR (100 MHz, CDCl3): δ 158.3, 139.3, 133.6, 133.5, 129.7, 129.2,

128.9, 128.6, 127.2, 124.7, 118.8, 117.6, 59.8, 56.3.

One-pot synthesis of 11d: The compound 11d can be cleanly prepared by a one-pot synthesis from

1. To a clear solution of 1.2 g of 1 (5 mmol) in 17 mL of CHCl3 was added 0.76 g of 4-nitrobenzaldehyde (5 mmol) followed by 0.80 mL of salicyladehyde (7.5 mmol). The resulting mixture was stirred overnight at ambient temperature. 1H NMR spectra of the crude mixture showed that the mixed diimine was formed exclusively. After removing the solvent, the diimine was purified by recrystallization from EtOH (70% yield). Hydrolysis of diimine was carried out by using 3% concd

HCl in THF / EtOAc mixture (1:1, 0.1 M) to give 11d dihydrochloride as a white powder (86% yield).

1 HO H-NMR (400 MHz, D2O, 0.05% CH3OH as reference): δ 8.17 (d, J = 8.6 Hz, 2H,

H2N ArH); 7.53 (d, J = 8.6 Hz, 2H, ArH); 7.23 (t, J = 7.8 Hz, 1H, ArH); 6.94 (d, J =

H2N 7.6 Hz, 1H, ArH); 6.87 (d, J = 8.2 Hz, 1H, ArH); 6.76 (t, J = 7.6 Hz, 1H, ArH); NO2 11d 5.44 (d, J = 8.5 Hz, 1H, C*H); 5.15 (d, J = 8.5 Hz, 1H, C*H). 13C-NMR (100

MHz, D2O, 0.05% CH3OH as reference): δ 148.0, 142.1, 132.7, 125.6, 124.1, 122.9, 118.0, 114.2,

111.0, 109.9, 50.4, 49.0.

Synthesis of tetraamine 11e: To a stirred solution of 1.8 g of 10a (5 mmol) in 25 mL of DMSO was added 0.34 g of pyridine-2,6-dicarboxaldehyde (2.5 mmol). The resulting mixture was stirred overnight at ambient temperature. The mixture was slowly poured into 250 mL of ice-cooled water with vigorous stirring. The resulting yellow precipitate was filtered, washed with distilled water, and dried by passing air on the filter funnel. The dried mixed diimine was dissolved in THF / MeOH mixture (1:2, 0.1 M) and 3% concd HCl was added. A white solid precipitated within 10 min. After stirring for 3 h, the solid was filtered, washed with THF, and dried to afford 11e tetrahydrochloride as a white powder (90% yield).

1 4HCl H-NMR (400 MHz, D2O, residual CH3OH as reference): δ 7.51 (t, J = 7.9

NH2 NH2 H2N N NH2 Hz, 1H, py); 7.37 (d, J = 8.6 Hz, 4H, 4-ClC6H4); 7.13 (d, 8.6 Hz, 4H, 4-

ClC6H4); 7.09 (d, J = 7.9 Hz, 2H, py); 5.17 (d, J = 9.6 Hz, 2H, C*H); 4.95 (d,

Cl 11e 4HCl Cl J = 9.6 Hz, 2H, C*H).

NH NH 1 2 2 H-NMR (400 MHz, CDCl3): δ 7.31 (t, J = 7.7 Hz, 1H, py); 7.19 (d, J = 8.5 H2N N NH2

Hz, 4H, 4-ClC6H4); 7.12 (d, 8.5 Hz, 4H, 4-ClC6H4); 6.78 (d, J = 7.7 Hz, 2H,

13 Cl Cl py); 4.18 (d, J = 6.3 Hz, 2H, C*H); 3.94 (d, J = 6.3 Hz, 2H, C*H). C-NMR 11e

(100 MHz, CDCl3): δ 161.3, 142.1, 136.5, 132.7, 128.5, 128.4, 120.7, 63.2, 60.8.

O OH O F OH F OH F H H N H N N N N N H H O OH OH 10c 12a 10d

Rigoselective and stereoselective formation of fused aryl-imidazolidine alkyl-dihydro-1,3-oxazine rings (12): When cyclohexanecarboxaldehyde was added to 10c in DMSO-d6 at room temperature,

1H NMR showed that only one diastereomer of 12a was formed after 10 h. Partial 1H NMR spectra

(400 MHz, DMSO-d6): δ 5.37 (s, 1H, NNCHAr); 4.51 (d, J = 4.2 Hz, 1H, diamine C*H); 4.42 (d, J

= 4.2 Hz, 1H, diamine C*H); 4.05 (d, J = 9.7 Hz, 1H, ONCHCy). Compared with alkyl fused rings, the coupling constant of 9.7 Hz corresponds to the dihydrooxazine ring structure. DFT computation also shows that 12a is the global minimum structure. When 10d and 2-fluorobenzaldehyde were mixed under the same conditions, the fused ring formation was considerably slow (t1/2 ≈ 30 h), but the identical fused ring 12a was observed by 1H NMR.

OH O OH R1 H R1 N R2 N

N N R H DMSO-d6 2 OH OH 10 13

Isolated imidazolidines 10 (0.1 mmol) was mixed with alkyl aldehydes (0.11 mmol) in DMSO-d6 (1 mL) at ambient temperature. The NMR tube was heated either at 100 oC for 2 h or at 70 oC overnight. 1H NMR spectra showed the mixed alkyl-aryl diimines were formed cleanly with over

90% purity.

OH F 1 H-NMR (300 MHz, DMSO-d6): δ 13.45 (br s, 1H, RAHB-OH); 13.22 (br s, 1H, N RAHB-OH); 8.61 (s, 1H, Imine-H); 8.33 (s, 1H, Imine-H); 7.49-7.17 (m, 8H, N OH ArH); 6.87-6.79 (m, 4H, ArH); 5.16 (d, J = 6.6 Hz, 1H, ArC*H); 3.66 (dd, J = 4.5, 13a 6.6 Hz, 1H, CyC*H); 1.86-0.93 (m, 11H).

1 OH F H-NMR (300 MHz, DMSO-d6): δ 13.27 (br s, 1H, RAHB-OH); 13.21 (br s, N 1H, RAHB-OH); 8.62 (s, 1H, Imine-H); 8.43 (s, 1H, Imine-H); 7.50-7.18 (m, N OH 8H, ArH); 6.87-6.80 (m, 4H, ArH); 4.96 (d, J = 6.9 Hz, 1H, ArC*H); 3.84- 13b 3.77 (m 1H, n-BuC*H); 1.50-0.67 (m, 11H).

OH F 1 H-NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H, RAHB-OH); 13.23 (br s, N 1H, RAHB-OH); 8.57 (s, 1H, Imine-H); 8.41 (s, 1H, Imine-H); 7.48-7.19 (m, N OH 8H, ArH); 6.86-6.82 (m, 4H, ArH); 4.74 (d, J = 6.7 Hz, 1H, ArC*H); 3.69-3.64 13c (m 1H, EtC*H); 1.54-1.42 (m, 2H); 0.78 (t, J = 7.4 Hz, 3H).

OH Cl 1 H-NMR (400 MHz, DMSO-d6): δ 13.34 (br s, 1H, RAHB-OH); 13.19 (br s, N 1H, RAHB-OH); 8.58 (s, 1H, Imine-H); 8.41 (s, 1H, Imine-H); 7.44-7.27 (m, N OH 8H, ArH); 6.87-6.82 (m, 4H, ArH); 4.74 (d, J = 6.5 Hz, 1H, ArC*H); 3.69- 13d 3.64 (m 1H, EtC*H); 1.54-1.44 (m, 2H); 0.78 (t, J = 7.4 Hz, 3H).

O OH O H NH2 N

NH 2 EtOH, rt N H OH O R-1 RR-15

Synthesis of RR-15: To a clear solution of 22.4 mg (0.10 mmol) of (R,R)-1,2-bis(2- hydroxylphenyl)-1,2-diaminoethane (R-1) in 0.20 mL of ethanol was added 30 mg (0.20 mmol) of

(1R)-(-)-myrtenal. The resulting clear reaction mixture was stirred for half an hour at room temperature to give RR-15 as a white precipitate. The solid was filtered, washed with 0.5 mL of ethanol and dried in vacuum (90 % yield).

1 H NMR (400 MHz, CDCl3): δ 10.75 (s, 2H, ArOH), 7.53 (s, 2H, imine H), 7.04 (t, J = 7.6 Hz, 2H,

ArH), 6.81 (d, J = 8.4 Hz, 2H, ArH), 6,46 (t, J = 7.6 Hz, 2H, ArH), 6.36 (d, J = 7.2 Hz, 2H, ArH),

6.06 (m, 2H, α-pinene), 4.64 (s, 2H, C*H), 2.86 (t, J = 5.2 Hz, 2H, α-pinene), 2.48 – 2.33 (m, 6H, α- pinene), 2.15 (s, 2H, α-pinene), 1.38 (s, 6H, α-pinene), 1.03 (d, J = 9.2 Hz, 2H, α-pinene), 0.81 (s,

13 6H, α-pinene). C-NMR (100 MHz, CDCl3): δ 163.9, 156.8, 147.3, 138.8, 129.3, 128.8, 124.0,

119.9, 119.1 (7 aromatic and imine carbons, and 2 carbons of double bond of α-pinene), 78.5, 40.5,

40.4, 37.8, 32.8, 31.6, 26.3, 21.6 (8 carbons of α-pinene). X-ray quality crystals for compound RR-

15 was obtained by slow evaporation of its solution in CH2Cl2 / acetonitrile. HRMS (ESI) calculated

+ 27 o for C34H41N2O2 [M+H] : 509.3162. Found: 509.3175. [α]D + 200.6 (c =1.0, CHCl3), mp = 138 C.

O HO O O H H H N 2 N N

H N 2 EtOH, rt N N H HO H O O S-1 SR-16 RR-16'

Synthesis of RR-16′: To a clear solution of 22.4 mg (0.10 mmol) of (S,S)-1,2-bis(2- hydroxylphenyl)-1,2-diaminoethane (S-1) in 0.20 mL of ethanol was added 30 mg (0.20 mmol) of

(1R)-(-)-myrtenal. The resulting clear reaction mixture was stirred for half an hour at room temperature to give RR-16′ as a yellow precipitate. The solid was filtered, washed with 0.5 mL of ethanol and dried in vacuum (90 % yield).

1 H NMR (400 MHz, CDCl3): δ 13.13 (s, 2H, ArOH), 8.18 (s, 2H, imine H), 7.21 (t, J = 7.8 Hz, 2H,

ArH), 7.09 (d, J = 7.6 Hz, 2H, ArH), 6.88 (d, J = 8.0 Hz, 2H, ArH), 6.76 (t, J = 7.6 Hz, 2H, ArH),

5.43 (m, 2H, α-pinene), 4.08 (s, 2H, C*H), 2.54 (t, J = 5.2 Hz, 2H, α-pinene), 2.45 (dt, J = 8.8, 5.6

Hz, 2H, α-pinene), 2.27 (dt, J = 18, 2.8 Hz, 2H, α-pinene), 2.20 (dt, J = 18, 2.8 Hz, 2H, α-pinene),

2.08 (s, 2H, α-pinene), 1.31 (s, 6H, α-pinene), 1.29 (d, J = 6.1 Hz, 2H, α-pinene), 0.64 (s, 6H, α-

13 pinene). C-NMR (100 MHz, CDCl3): δ 165.5, 161.0, 145.9, 132.3, 131.7, 121.5, 118.9, 118.7,

116.9 (7 aromatic and imine carbons, and 2 carbons of double bond of α-pinene), 78.2, 42.7, 41.0,

38.3, 31.6, 31.5, 26.3, 21.2 (8 carbons of α-pinene). X-ray quality crystals for compound RR-16′

+ was obtained from DMSO-d6. HRMS (ESI) calculated for C34H41N2O2 [M+H] : 509.3162. Found:

27 o 509.3183. [α]D -66.4 (c =1.0, CHCl3), mp = 184 C.

O H NH Cl N HCl 3

CH CN N 3 NH3Cl H O RR-16' RR-17

Synthesis of RR-17: To a slurry of RR-16′ (1.0 mmol) in 10 mL of acetonitrile was added 0.2 mL of

37 % HCl solution. Stirring the reaction mixture at ambient temperature for 3 hrs afforded white precipitate. The solid was filtered, and the diamine dihydrochloride salt was washed with acetonitrile (2 x 3 mL) to afford analytically pure RR-17· 2HCl in 95 % yield.

1 H NMR (400 MHz, D2O): δ 5.91 (m, 2H), 4.22 (s, 2H, C*H), 2.55 (dt, J = 9.2, 5.6 Hz, 2H), 2.35 –

2.33 (m, 6H), 2.14 (s, 2H), 1.34 (s, 6H), 1.20 (d, J = 12.0 Hz, 2H), 0.70 (s, 6H). 13C-NMR (100

MHz, D2O/CD3OD): δ 138.76, 131.33 (2 carbons of double bond of α-pinene), 58.1, 41.5, 41.1,

+ 38.7, 32.4, 32.0, 26.0, 21.5 (8 carbons of α-pinene). HRMS (ESI) calculated for C20H33N2 [M+H] :

27 301.2638. Found: 301.2652. [α]D -22.1 (c =1.0, CHCl3).

CHAPTER 3

Controlling Diaza-Cope Rearrangements with weak forces†

3.1. Introduction

[3,3]-Sigmatropic rearrangements have attracted much attention from both theoretical and synthetic considerations (Scheme 3-1). 1 The Claisen 2 and oxy-Cope 3 rearrangements are [3.3]- sigmatropic reactions that have been widely used for natural and unnatural product synthesis. One common characteristic of the Claisen and oxy-Cope rearrangement is that the rearrangements are thermodynamically favorable due to the higher bond enthalpy of the C=O bond (728 kJ/mol) over that of the C=C bond (615 kJ/mol). It is more difficult to drive the Cope rearrangement to completion due to the symmetric nature of the reaction (Scheme 3-1). Ring strain or π−conjugation energy have been used to shift the Cope rearrangement equilibrium to one side.1 We wondered if weak forces such as steric, electronic and H-bond effects can be used to control the thermodynamics of [3,3]-sigmatropic reactions. The diaza-Cope reaction provides a convenient platform for studying the effects of weak forces on the rate and equilibrium for the [3,3]-sigmatropic reactions. A wide variety of the starting diimines for the diaza-Cope reaction can be easily prepared in one step from our vicinal diamines (Chapter 2) and aldehydes. This allows systematic investigation of the effects of weak forces on the rearrangement reaction.

† Part of this chapter has been published. Section 3.4: Kim, H.; Nguyen, Y.; Lough, A. J. Chin, J. Angew. Chem., Int. Ed. 2008, 47, 8678. 1 Hill, R. K. Cope, Oxy-Cope and Anionic Oxy-Cope Rearrangements. In Comprehesive Organic Synthesis; Vol. 5; Trost, B. M., Fleming, I., Paquette, L. A. Eds.; Pergamon: Oxford, 1991; pp 785-826. 2 (a) Hiersermann, M., Nubbemeyer, U. Eds. The Claisen Rearrangement: Methods and Applications; Wiley- VCH: Germany, 2007. (b) Castro, A. M. M. Chem. Rev. 2004, 104, 2939. (c) Hiersemann, M.; Abraham, L. Eur. J. Org. Chem. 2002, 1461. 3 (a) Berson, J. A.; Jones, M. Jr. J. Am. Chem. Soc. 1964, 86, 5019. (b) Paquette, L. A. Tetrahedron 1997, 53, 13971.

(a) Cope rearrangement (b) Oxy-Cope rearrangement

HO O

Scheme 3-1. [3,3]-Sigmatropic rearrangements: (a) Cope, (b) oxy-Cope, (c) Claisen and (d)

diaza-Cope rearrangement

MeO NO2 O O NH2 H2N + 2 + 2 NH2 H2N NO2 OMe

MeO NO2

MeO NO 2 MeO NO2

N [3,3] N

N N MeO NO 2 MeO NO2

Scheme 3-2. Vögtle’s observation on the diaza-Cope rearrangement driven by electronic effects

3.2. The electronic effect

Over thirty years ago, Vögtle and Goldschmitt published their seminal work on diaza-Cope rearrangement reaction.4 In one interesting study,4a they showed that the racemic diimine prepared from rac-1,2-bis(4-methoxyphenyl)-1,2-diaminoethane and 4-nitrobenzaldehyde undergoes the

4 (a) Vögtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1. (b) Vögtle, F.; Goldschmitt, E. Angew. Chem. Int. Ed. Engl. 1973, 12, 767. (c) Vögtle, F.; Goldschmitt, E. Angew. Chem. Int. Ed. Engl. 1974, 13, 480. 88

[3,3]-sigmatropic rearrangement to completion (Scheme 3.2). Since we prepared a variety of chiral vicinal diamines with electron donating and withdrawing groups (Chapter 2), we became interested in systematic investigation of the electronic effect on the diaza-Cope reaction.

X Y X Y K N exp N

N DMSO-d6 (10 mM) N RT, 2-6 days X Y X Y Initial diimine Rearranged diimine (1-6) (1'-6')

Scheme 3-3. Diaza-Cope rearrangement controlled by electronic effects

a Diimine X Y Kexp 1 H H 1 2 H OMe 0.115 3 H Me 0.311 4 H Cl 3.02 5 OMe Me 2.98

6 OMe NMe2 0.0559 aEquilibrium constant measured by 1H NMR at 25oC

Table 3-1. Measured equilibrium constants for the diaza-Cope rearrangement

Several diimines (2-6) were prepared by mixing the corresponding diamines and aldehydes in ethanol at high concentration (0.5 M) (Scheme 3-3). In all cases, we were able to obtain analytically pure diimines as precipitates within minutes in reasonable yields (>60%). The equilibration of the initial diamine (2-6) with their rearrangemed diimines (2′-6′) was monitored by 1H NMR (DMSO- d6, 10 mM). In general, the equilibrium was established within several days (2-6 days) at ambient temperature. It was assumed that the equilibrium had been reached when there was no further detectible change in the 1H NMR signals with time. The measured equilibrium constants are listed

89 in Table 3-1. It can be seen from Table 3-1 that the equilibrium favors the side with the more electron rich imine (or the side with more electron poor amine). Electron donating groups are expected to stabilize the imine bond by conjugation.5

The Hammett equation 6 is often used to evaluate electronic effects (Equation 3-1). 7 The substituent constants (σ) obtained by the ionization of benzoic acid derivatives in water has been frequently used to predict the equilibrium of a variety of organic reactions in solution. We used a modified Hammett equation (Equation 3-2) to study the electronic effect in the diaza-Cope reaction

(where Kexp is the equilibrium constant for the rearrangement reaction in Scheme 3-3 and Δσ is σY –

σX). Some σ values used in our experiment are listed in Table 3-2.

log (K / K0) = σ × ρ ( Equation 3-1)

log Kexp = Δσ × ρ ( Equation 3-2)

log Kexp = Δσ × (2.49) ( Equation 3-3)

Benzoic Acid Substituents σ

p-NMe2 -0.83

p-OMe -0.27

p-Me -0.17

H 0

p-Cl 0.23

p-NO2 0.78

Table 3-2. Some σ values

5 Layer, R. W. Chem. Rev. 1963, 63, 489. 6 Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96. 7 Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.

A Hammett plot (Figure 3-1) consisting of log (Keq) for the y-axis and Δσ for the x-axis gives a reasonable straight line with a ρ value of 2.49 (R2 = 0.941). The Hammett equation (Equation 3-3) can be used to calculate the values of the equilibrium constants for the rearrangement reaction. For example, the calculated value of the equilibrium constant for the rearrangement reaction of the diimine formed from 1,2-bis(4-methoxyphenyl)-1,2-diaminoethane and 4-nitrobenzaldehyde

(Scheme 3-2) is about 400 [Δσ × ρ = (0.78 + 0.27) × 2.49]. In Scheme 3-3, when X is dimethylamino group (σ = - 0.83) and Y is any electron withdrawing group (σ > 0), the equilibrium constant (Keq) for the rearrangement is expected to be greater than 100. Consistent with this calculation, we found that the rearrangement of the diimine (X = NMe2 and Y = H) goes to completion under our experimental conditions. Thus the Hammett equation is useful for estimating the values of the equilibrium constants for the diaza-Cope rearrangement (Scheme 3-3 and Equation

3-3).

Figure 3-1. The Hammett plot for the diaza-Cope rearrangement

In addition to fitting the observed data with the Hammett equation, we were interested in using

DFT computation to obtain the values of the equilibrium constants for the rearrangement reaction.

Molecular mechanics computation was used initially to find the global minimum structure of the diimines 2-6 and 2′-6′. These calculations show that the most stable conformation of the diimines is generally as shown in Figure 3-2. The two phenyl groups attached to the chiral carbons are in gauche orientation while the two imine groups are extended in parallel fashion (Figure 3-2). Crystal structures of a variety of diimines have been shown to be in this form. We previously referred to this type of structure as ‘preorganized’ for the reverable [3,3]-sigmatropic rearrangements through the chair-like transition state.8

X Y N

X Y

Figure 3-2. ‘Preorganized’ diimine structure

The global minimum structures obtained by molecular mechanics computation were further refined by DFT computation at the B3LYP/6-31G(d) level to calculate the change in energy for the rearrangement reaction. The computed change in energy as well as the measured change in free energy is shown in Table 3-3. Figure 3-3 shows a plot of the observed free energy change vs the computed energy change for the rearrangement reaction. The agreement between the experiment and computation is remarkably good with the value of slope (0.89) and intercept (0.075) approaching the theoretical values of one and zero, respectively. Although DFT computations gave

8 Kim, H.-J.; Kim, H.; Alhakimi. G.; Jeong, E. J.; Thavarajah, N.; Studnicki. L.; Koprianiuk, A.; Lough, A. J. Suh, J.; Chin, J. J. Am. Chem. Soc. 2005, 127, 16370.

92 excellent results, semi-empirical computations (AM1 or PM3) gave poor fits (AM1: slope = 7.54,

R2 = 0.587; PM3: slope = 0.334, R2 = 0.304).

ΔE a ΔG b Diimine X Y cal exp (kcal/mol) (kcal/mol) 1 H H 0 0 2 H OMe 1.66 1.28 3 H Me 0.625 0.692 4 H Cl -0.657 -0.654 5 OMe Me -1.03 -0.647

6 OMe NMe2 1.65 1.71

a b DFT at the B3LYP 6-31G(d) level ΔGexp = -RTln(Keq) at 298 K

Table 3-3. Calculated and experimental equilibrium energies

Figure 3-3. A Linear plot between calculated and experimental equilibrium energies

In summary, there is good linear free energy relationship between the logarithm of the equilibrium constants for the rearrangement and σ values of the electronic substituents with a

Hammett ρ value of 2.49. In addition, there is excellent agreement between the observed equilibrium constants for the rearrangement reaction and the equilibrium constants obtained by DFT computation.

3.3. The hydrogen bonding effect

In 1973, Vögtle and Goldschmitt synthesized a variety of meso diamines by the diaza-Cope rearrangement reaction (Scheme 3-4a).4 While this was an elegant study, it was not clear then what the driving force was that allowed the rearrangement reactions to go to completion under mild conditions. Since then, the concept of resonance-assisted hydrogen bond (RAHB) became more clearly understood and DFT computational methods have been shown to be reliable for calculating the energy of such hydrogen bonds (H-bonds).9 Almost thirty years after Vögtle’s original discovery of the diaza-Cope reaction for making meso diamines, our group found that the RAHB is the driving force behind the rearrangement reaction.10 In addition, we have developed a stereospecific synthesis of chiral vicinal diamines by the RAHB-promoted diaza-Cope rearrangement (Scheme 3-4b).8,11

The scope of this reaction has been described in detail in Chapter 2. Here we focus on the RAHB effect on the thermodynamics and kinetics of the diaza-Cope rearrangement.

9 Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405. 10 Chin, J.; Mancin, F.; Thavarajah, N.; Lee, D.; Lough, A.; Chung, D. S. J. Am. Chem. Soc. 2003, 125, 15276. 11 Kim, H.; Nguyen, Y.; Yen, C. H.-H.; Chagal, L.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184. 94

OH OH Ar = Ph, 4-MeOC H ,2-MeOC H , N Ar N Ar 6 4 6 4 [3,3] 2,4,6-(MeO)3C6H2,3,4,5-(MeO)3C6H2, (a) 2,5-(MeO)2C6H3,2-EtOC6H4,4-MeC6H4, N Ar N Ar 2-MeC6H4,2,4-Me2C6H3,2,4,6-Me3C6H2, 4-Me2NC6H4,4-NCC6H4,4-PhC6H4,2-Py, OH OH 3-Py, 4-Py, 2-Furanyl, 4-FC6H4, 4-O2NC6H4,PhCC,PhCHCBr

OH OH Ar' = N Ar' [3,3] N Ar' C6F5,4-O2NC6H4,4-MeO2CC6H4, (b) 4-FC6H4,4-ClC6H4,4-F3CC6H4, 4-NCC6H4,4-AcHNC6H4,4-MeOC6H4, N Ar' N Ar' 4-HOC6H4,4-Me2NC6H4,2-MeOC6H4, 2-ClC6H4,2-MeC6H4,1-Na, OH OH 2,4,6-(OMe)3C6H2 (R,R) >99% ee (S,S)

Scheme 3-4. The RAHB-driven diaza-Cope rearrangement of (a) meso diimines by Vögtle4a

and (b) chiral diimines by Chin.11

The term resonance-assisted hydrogen bond (RAHB) was introduced by Gilli et al 12 to describe the synergistic interplay between hydrogen bonding and π-delocalization.13 This RAHB was originally proposed to explain the abnormally strong intramolecular H-bonds formed in β- diketone enols where Gilli found several characteristic features (Figure 3-4a).12,14 These are (i) very short O-O bond distance (2.432 – 2.554 Å), (ii) lengthening of O-H bond (to 1.20 Å), (iii) lowering of the ν(OH) frequencies (2566 – 2675 cm-1), and (iv) downfield shift of the enolic proton resonance

(15.3 – 17.0 ppm). DFT computation shows that the energy of the RAHB (12.0 kcal/mol) in β- diketone enols is about two times greater than that of regular H-bonds (6.0 kcal/mol). Interestingly the RAHB is also found in heteroatomic H-bonds such as N-H-O system in β-enaminones (Figure 3-

4b).9 All experimental data (2.48 ≤ d(N−O) ≤ 2.65 Å, 2340 ≤ ν(NH) ≤ 3200 cm-1, 13 ≤ δ(NH) ≤ 18 ppm) support that these heteroatomic H-bonds can form strong H-bonds assisted by the π-

12 Gilli, G.; Bullucci, F.; Ferretti, V.; Bertolasi, V. J. Am. Chem. Soc. 1989, 111, 1023. 13 Jeffrey, G. A. An Introduction to Hydrogen Bonding, Oxford University Press; New York, 1997. 14 Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 1994, 116, 909.

95 delocalization. The RAHB energy of the N-H-O system obtained by DFT computation is estimated to be about 5.2 kcal/mol which is still about twice as large as the regular N-H-O hydrogen bond energy (2.5 kcal/mol). The RAHB can be found not only in a variety of organic molecules but also in some biological systems such as in double helical DNA, α-helical proteins, and imines formed between pyridoxal phosphate cofactor and amino acids (Figure 3-4).15

- R CO2 N H H H O O HN O 2- O O3PO R R R R N (a) β−enolone (b) β−enaminone (c) pyridoxal phosphate imine

H H N N H O N O H N

N N H N N N H N N N N N O N H O H Adenine Thymine Guanine Cytosine

(d) DNA base pairing

Figure 3-4. Resonance-assisted hydrogen bonding in (a) β-enolone, (b) β-enaminone, (c)

pyridoxal phosphate imine, and (d) DNA base pairing

It is interesting to consider why the RAHBs should be stronger than regular H-bonds. The intramolecular H-bonds in salicyl imine (I, Scheme 3-5) have been thoroughly characterized as

RAHBs on the basis of crystal, NMR, IR, and computational data.13, 16 We propose that delocalization of the lone pair electrons on the oxygen through to the nitrogen results in charge separation (I ↔ II). Charged H-bonds are known to be stronger than neutral H-bonds.13 In charged

15 Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry 6th ed, W. H. Freeman, 2006. 16 Filarowski, A.; Koll, A.; Glowiak, T. J. Chem. Soc., Perkin Trans. 2 2002, 835. 96

H-bonds, the H-bond is reinforced by favorable electrostatic interaction. Thus, the RAHBs can be strengthened by forming charged H-Bonds (I ↔ II). Such charge separation is not possible in III.

N N N H H H O O O

IIIIII

Scheme 3-5. Proposed π-delocalization of the resonance-assisted hydrogen bonds

There are two types of H-bonds in Scheme 3-4: regular H-bonds in the initial diimines and

RAHBs in the rearranged diimines. If the difference in the energy of the initial and rearranged diimines is solely due to the difference in the strength of the hydrogen bonds, the rearranged diimine is expected to be about 5.4 kcal/mol more stable than the initial diimine (2 × 5.2 kcal/mol - 2 × 2.5 kcal/mol). This energy difference translates to an equilibrium constant of about 105 for the rearrangement reaction. The values of the equilibrium constants for the rearrangements in Scheme

3-4b have been determined by DFT computation at the B3LYP/6-31G(d) level. The calculated energy differences and the corresponding equilibrium constants at 25 oC are listed in Table 3-4. This table shows that the RAHB effect dominates over the electronic effect. All of the computed equilibrium constants are significantly greater than unity and increase in value with increase in electron withdrawing ability of the substituent. Consistent with this calculation, experiments show that diimines formed between 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN) and aryl aldehydes with electron withdrawing or electron donating substituent all rearrange to completion

(see Chapter 2, Table 2-3). It is remarkable that the RAHB effect is stronger than electronic effects.

Table 3-4. Computed energies of the RAHB-promoted diaza-Cope rearrangement by the DFT

computation

OH R OH R

N [3,3] N

N N

OH R OH R

a b Entry R ΔE (kcal / mol) Kcal

7 1 NO2 -9.9 1.7 × 10 2 Cl -7.6 3.8 × 105 3 H -6.8 9.3 × 104 4 OMe -4.6 2.6 × 103 5 OH -4.7 2.5 × 103

6 NMe2 -2.2 44

aDFT at the B3LYP / 6-31G(d) level. bGas phase at 25 oC.

O 1.5M Ph O Ph Ph HN N H2N NH2 HN NH HO OH HO OH HO O

HPEN 7 8 30mM in CD3CN

k1 k-1

Ph Ph Ph Ph k2 N N N N HO OH HO OH

10 9

Scheme 3-6. Reaction mechanism for the reaction between HPEN and benzaldehyde

We wondered if the RAHB can influence not only the thermodynamics but also the kinetics of

1 the rearrangement reaction. When HPEN was mixed with benzaldehyde in CD3CN, complex H

NMR spectra were observed with three intermediates (7, 8 and 9, Scheme 3-6). Despite the complexity in the NMR spectra, we wanted to estimate the rate constant for the rearrangement (k2) in Scheme 3-6 by monitoring the time-dependent change in concentration of 8, 9 and 10 (Figure 3-

5).

Figure 3-5. Time-dependent partial 1H NMR spectra of the reaction between HPEN (30 mM)

and benzaldehyde (1.5 M) taken in CD3CN

When large excess of benzaldehyde (50 equiv) is added to HPEN, imidazolidine 7 forms and disappears rapidly under our reaction conditions (Figure 3-5 and 3-6). Thus, the overall reaction can be considered as a consecutive elementary reaction from 8 to 10 (Scheme 3-6). The rate equations for 8, 9 and 10 are given in Equations 3-4, 3-5, and 3-6.

Figure 3-6. Reaction profile for the reaction between HPEN and benzaldehyde monitored by

1 o H NMR in CD3CN at 25 C

d[8] = -k [8]+k [9] (Equation 3-4) dt 1 -1

d[9] = k [8]-(k + k )[9] (Equation 3-5) dt 1 -1 2

d[10] = k2 [9] (Equation 3-6) dt

d[8] -Kk2 = [8] = kobs [8], if [9]=K [8] (Equation 3-7) dt K +1

Although the exact solution of this set of equations is known,17 we intended to solve the rate equations by a reasonable assumption. The concentration of 9 slowly decreases during the course of the reaction, and thus the steady-state approximation is not applicable for this reaction (d[9]/dt ≠ 0,

Figure 3-6). However, the equilibrium ratio between 8 and 9 remains constant (Figure 3-7a). The equilibrium constant (K = [9]/[8] = 0.55) allows us to treat the rate of [8] as a pseudo-first order as shown in Equation 3-7.18

17 Lowry, T. M.; Johns, W. T. J. Chem. Soc. 1910, 97, 2634. 18 McDaniel, D. H.; Smoot, C. R. J. Phys. Chem. 1956, 60, 966. 100

(a) (b)

Figure 3-7. Plots for (a) the equilibrium constant and (b) the rate constant kobs.

In order to obtain the rate constants kobs in Equation 3-7, we first selected data points after the imidazolidine (7) disappeared (3600 sec), and plotted log([8]/[8]o) against time (sec). As shown in

2 Figure 3-7b, a good linear fitting (R = 0.9987) was obtained and the slope of the plot gave kobs

-4 -1 -3 -1 value of 4.56 × 10 s . Using the relationship, kobs = Kk2/(K+1) gave k2 value of 1.30 × 10 s .

The obtained rate for the RAHB-promoted diaza-Cope rearrangement (1.30 × 10-3) is about

150 times faster than that for the degenerate diaza-Cope rearrangement of 1 (8.70 × 10-6).4c As a result, the RAHB not only provides thermodynamic driving force but also enhances the reaction rate for the diaza-Cope rearrangement. Further discussion will continue in Section 3.6 to combine measured rate constants and calculated activation energies.

In summary, both experiment and DFT computation show that the RAHB effect is stronger than the electronic effect for the diaza-Cope rearrangement reaction. Moreover, the RAHB effect increases not only the equilibrium constant but also the rate constant for the rearrangement reaction.

101

3.4. The steric effect

The ring strain in cyclopropane has been reported to be about 28 kcal/mol based on its heat of combustion.19 In 1960, Vogel was the first to show that three or four-membered ring strain can be used to drive the Cope rearrangement to completion (Scheme 3-7a).20 The ring strain-driven Cope rearrangement of cis-1,2-divinylcyclopropane to 1,4-cycloheptadiene goes to completion even at

-20 oC and the half-life for the rearrangement at 35 oC is about 90 s. Since the early studies by

Vogel, ring strain has been widely used to control the equilibria in [3,3]-sigmatropic rearrangement reactions.21 Vögtle used the ring strain to control the diaza-Cope reaction (Scheme 3-7b).22 We wondered if in addition to ring strain, steric strain could also be used to control [3,3]-sigmatropic rearrangements. Although it is well known that strained molecules show remarkable reactivity, 23 it is not clear how steric strain could be used to drive [3,3]-sigmatropic rearrangements to completion.

N Ph N Ph N Ph N Ph b) N Ph N Ph N Ph N Ph H

Scheme 3-7. Ring strain-driven (a) Cope and (b) diaza-Cope rearrangements

In our previous attempts to synthesize a variety of chiral, vicinal diaryl diamines using the

RAHB-directed diaza-Cope rearrangement, we were surprised to find that the rearrangement of the

19 Schleyer, P. v. R.; Williams, J. E.; Blanchard, K. R. J. Am. Chem. Soc. 1970, 92, 2377. 20 (a) Vogel, E. Angew. Chem. 1960, 72, 4. (b) Vogel, E. Angew. Chem., Int. Ed. Engl. 1963, 2, 1. 21 Piers, E. Rearrangement of Divinylcyclopropanes. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon, Oxford, 1991; Vol. 5, pp 971-998. 22 Staab, H. A.; Vögtle, F. Tetrahedron Lett. 1965, 1, 51. 23 Hoffmann, R.; Hopf, H. Angew. Chem., Int. Ed. 2008, 47, 4474.

102 diimine (11) formed from HPEN and mesitaldehyde (2,4,6-trimethylbenzaldehyde) did not go to completion to 12 (Scheme 3-8). Some (~10%) of the initial diimine (11) remained at the end of the reaction. This suggested to us that the steric strain generated by mesityl groups may shift the portion of the equilibrium in the RAHB-promoted rearrangement of diimine 11. Since the steric strain appears to compete effectively with the RAHB effect, we became interested in studying the steric strain-driven diaza-Cope rearrangement reaction. For this study, the starting diamine, 1,2-bis(2,4,6- trimethylphenyl)-1,2-diaminoethane (TPEN)24 was prepared from the equilibrium reaction between

11 and 12.25

O O H H N N

N N H O H O

11 12

RAHB Steric strain

Scheme 3-8. Competition between RAHB and steric effect

The steric strain effect was first compared with the electronic effects. We prepared diimines from (S,S)-1,2-bis(2,4,6-trimethylphenyl)-1,2-diaminoethane (TPEN) and benzaldehydes with electron-donating or electron-withdrawing substituents (Scheme 3-9). The addition of aromatic aldehydes (2.5 equiv) to (S,S)-TPEN in ethanol and stirring the reaction mixture overnight at ambient temperature gave the corresponding rearranged diimines (13′ to 15′) in good isolated yields

(80-85%, Scheme 3-9). The identity of products (13′ to 15′) of the rearrangement reaction was

24 (a) Ikeno, T.; Iwakura, I.; Shibahara, A.; Hatanaka, M.; Kokura, A.; Tanaka, S.; Nagata, T.; Yamada, T. Chem. Lett. 2007, 36, 738. (b) Kokura, A.; Tanaka, S.; Shibahara, A.; Ikeno, T. ; Nagata, T.; Yamada, T. Chem. Lett. 2007, 36, 26. (c) Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics, 2006, 25, 4731. (d) Kokura, A.; Tanaka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2006, 8, 3025. (e) Fujii, H.; Funahashi, Y. Angew. Chem., Int. Ed. 2002, 41, 3638. 25 Enantiopure (S,S)-TPEN can be prepared from (R,R)-HPEN and mesitadehyde. For details, see Section 3.9. 103 confirmed by comparing their 1H NMR spectra with those of the diimines prepared from the corresponding diamine and mesitaldehyde. Although the initial diimines (13 to 15) were not isolated, their clean formation (δH = 5.6 ppm for 15, Figure 3-8) and conversion into the rearranged

1 diimine (δH = 4.8 ppm for 15′) could be readily monitored by H NMR. The equilibrium constants for the rearrangement in Scheme 3-9 must be greater than 102, as we did not observe any of the initial diimines by 1H NMR spectroscopy after equilibration. We were pleasantly surprised to find that the steric strain effect is large enough to drive the rearrangement to completion (Figure 3-8).

X X

N [3,3] N

N N

X X

13:X=NO2 13':X=NO2 14:X=OCH3 14':X=OCH3 15:X=H 15':X=H

Scheme 3-9. Steric strain effect driven diaza-Cope rearrangements

15′

1 Figure 3-8. Monitoring the conversion of 15 to 15′ by H NMR in DMSO-d6

104

Figure 3-9a shows the crystal structure of 13′ formed through the rearrangement of 13.26 This structure is ‘preorganized’8 for the reversible rearrangement reaction and resembles the computed transition state (TS) structure for the rearrangement of 13 (Figure 3-9b).

(a) (b)

Figure 3-9. (a) Crystal structure of 13′ (ORTEP diagram with thermal ellipsoids drawn at 50%

probability). (b) Computed structure (DFT) of the transition state for the rearrangement of 15

to 15′. All hydrogen atoms except those in the imine and diamine backbone have been omitted

for clarity.

We investigated the effect of steric strain on the rate and equilibrium constants for the rearrangement of 15 to 15′ by DFT computation (B3LYP at the 6-31G(d) level). The difference in computed energies of 15′ and 15 (5.5 kcal/mol) translates to an equilibrium concentration ratio of about 104:1 in favor of 15′ at 25 oC. 1H NMR data also showed complete conversion of 15 into 15′.

26 Crystal data of 13′: C34H34N4O4, T = 150(2)K, monoclinic, C2, Z = 4, a = 27.2150(16) Å, b = 8.7120(3) Å, c 3 = 14.1740(9) Å, α = 90º, β = 115.134(2)º, γ = 90º, V = 3042.4(3) Å , R1 = 0.0480, wR2 = 0.1120 for I> 2σ(I), GOF on F2 = 1.009.

105

Computation further revealed that the kinetic barrier for the conversion of 15 to 15′ (19.4 kcal/mol) is lower than the kinetic barrier (21.5 kcal/mol) for the rearrangement of the diimine (1) formed between DPEN and benzaldehyde. Consistent with these computation results, the experimental rate constant for the rearrangement of 15 to 15′ (4.19 × 10-5 s-1 at 25 oC, Figure 3-10) is greater than that for the rearrangement of 1 (8.70 × 10-6 s-1 at 25 oC).4c Our kinetic experiment and computation show that only a small amount of the steric strain is released at the transition state.

Although the computed strain effect (21.5 – 19.4 = 2.1 kcal/mol) is somewhat greater than the experimental steric strain effect (RTln(4.19 / 0.87) = 0.93 kcal/mol), the difference between the computed and experimental values is well within computational error.

Figure 3-10. Linear plot for measuring the rate constant for the conversion of 15 to 15′ at

o 1 25 C by H NMR in DMSO-d6

It is not intuitively obvious how the steric effect in 15 (or 13 and 14) manifests itself in driving the rearrangement reaction to completion. One possibility is that the steric repulsion between the two mesityl groups in 15 weakens the C-C bond that is cleaved in the rearrangement reaction. To gain insights into the steric effect for the reaction (Scheme 3-9), we dissected the rearrangement by

106 dividing 15 in two (Scheme 3-10) and examined the energetics of the ‘half’ compound 16. The rearrangement of the ‘half’ compound corresponds to a [1,3]-sigmatropic shift.

[1,3] (a) N N

16 16'

O O H [1,3] H (b) N N

17 17'

Scheme 3-10. Computed [1,3]-sigmatropic shifts directed by (a) steric effect and (b) hydrogen

bonding

Interestingly, DFT computation shows that the rearrangement of the “half” compound (16) is disfavored by about 1.9 kcal/mol, whereas the rearrangement of the “full” compound (15) is favored by about 5.5 kcal/mol. We suggest that the rearrangement of 16 is disfavored at least in part due to the decrease in imine conjugation. The C=N bond in the imine 16 can be planar with the phenyl group, whereas that in 16′ cannot be fully planar or conjugated with the mesityl group owing to steric effects. A loss in imine conjugation is also expected for the rearrangement of 15. However, the destabilization of 15 as a result of the steric repulsion of the two mesityl groups appears to be greater than the resonance stabilization of the imine group.

In sharp contrast to the reactions driven by steric energy, DFT computation shows that the rearrangement of the “half” compound (17) for the RAHB directed reaction is favored by about the same amount (3.8 kcal/mol) as the rearrangement of the corresponding full compound (6.8/2 kcal/mol) after statistical correction. We showed that a subtle difference in the strengths of the hydrogen bonds can drive diaza-Cope rearrangement reactions to completion.7,10 The RAHB in 17′ is expected to be a few kcal/mol more stable than the regular hydrogen bond in 17.

107

The rearrangement reactions in Scheme 3-9 most likely proceed via chair-like six-membered ring transition states (TS) with all substituents in the equatorial positions (Figure 3-9b). Consistent with this hypothesis, the rearrangements of the initial diimines (13 to 15) proceed with 100% chirality transfer, as observed for the RAHB-directed rearrangement reactions. Chiral phase HPLC showed that the stereospecificity for conversion of 15 into 15′ is exceptionally high (>99.5%), even though no H-bonds are involved.

X TS

We studied the rearrangement of 11 to 12 and the reverse reaction (Scheme 3-8) in detail to compare the steric effect and the H-bonding effect on the diaza-Cope rearrangement. The same ratios of 11 to 12 were observed at equilibration whether we started with 11 or 12. Diimine 12 is

o favored over 11 by a ratio of about 14:1 in CDCl3 at 25 C. The solvent effect on the equilibrium is small (toluene-d8: 17:1; DMSO-d6: 6:1). DFT computation (B3LYP/6-31G(d)) shows that 12 is more stable than 11 by 1.6 kcal/mol. This translates into an equilibrium ratio of 11 to 12 of about

15:1 at 25 oC, Both experimental and computational data show that 12 is more stable than 11. Thus, the H-bond effect appears to be somewhat stronger than the steric effect for the rearrangement reaction. Interestingly, this strong steric effect disappears if the mesityl group is replaced by the

2,4,6-trimethoxyphenyl 27 or ortho tolyl group. This result indicates that the mesityl group is necessary to create considerable steric effect.

27 A values for the methyl and methoxy group are 1.8 and 0.75 kcal/mol, respectively. 108

We determined the activation parameters for the interconversion of 11 and 12 by measuring the rate constants of the forward and reverse reactions at different temperatures (59 °C to 101 °C, Table

3-5). At 59 °C, the rate constants for the forward and reverse reactions are 1.1×10-4 s-1 and 2.8×10-5 s-1, respectively. The Eyring plot (Figure 3-11) gave the values of the activation entropy (-8.2 cal/mol/K) and activation enthalpy (22.9 kcal/mol) for conversion of 11 to 12. For the reverse reactions, the activation entropy and enthalpy are -0.7 cal/mol/K and 26.3 kcal/mol, respectively

(Figure 3-11).

OH OH

N N

OH OH

11 12

o a -1 a -1 b T( C) Keq kforward (s ) kreverse(s ) 59 3.88 1.10 × 10-4 2.82 × 10-5 72 3.33 3.89 × 10-4 1.17 × 10-4 78 3.05 6.74 × 10-4 2.21 × 10-4 86 2.95 1.48 × 10-3 5.02× 10-4 90 2.84 2.22× 10-3 7.83 × 10-4 101 2.58 5.88 × 10-3 2.28 × 10-3

a 1 b Measured by H NMR spectroscopy in DMSO-d6 (10 mM) Keq = kforward / kreverse

Table 3-5. Kinetic data for the interconversion of 11 and 12

An energy profile for interconversion of 11 to 12 was prepared with measured activation parameters (Figure 3-12). Interestingly, there is a considerable entropic driving force (ΔS = 7.5 cal/mol/K) for the steric effect driven diaza-Cope rearrangement of 12 to 11. Thus, the equilibrium constant for the formation of 12 increases with decreasing temperature (-TΔS, Table 3-5). The conversion of 11 into 12 is expected to result in a favorable enthalpy change due to the strengthening of the H-bonds and an unfavorable enthalpy change due to the increase in strain

109 energy associated with the steric effect. The net favorable enthalpy change (ΔH = -3.4 kcal/mol) indicates that more is gained from the strong hydrogen bonds than lost because of the steric effects.

The value of this experimental enthalpy change is in reasonably good agreement with the computed one above (-1.6 kcal/mol). The change in Gibbs free energy (ΔG) for the conversion of 11 into 12 is

-1.2 kcal/mol (-3.4+298×7.5×10-3) at 25 oC.

11 → 12 11 ← 12

Reaction ∆H‡ (kcal/mol) ∆S‡ (cal/mol/K) 11 → 12 22.9 -8.2 11 ← 12 26.3 -0.7

Figure 3-11. Eyring plots for the interconversion between 11 and 12

RAHB driven Steric strain driven rearrangement TS (11-12) rearrangement

ΔH1 =22.9 ΔH2 =26.3 ΔS1 =-8.2 ΔS2 =-0.7

11 ΔH =-3.4 ΔS =-7.5 12

Figure 3-12. Energy profile for interconversion of 11 to 12. (∆H and ∆H‡ values in kcal/mol,

∆S and ∆S‡ values in cal/mol/K). 110

Two consecutive diaza-Cope rearrangement reactions can be used to form (R,R)-DPEN from

(R,R)-HPEN with exceptionally high overall stereospecificity (Scheme 3-11). Although this approach does not serve as a highly practical synthetic route to (R,R)-DPEN, it demonstrates the excellent stereospecificity of the rearrangement reaction with and without RAHBs.

O OH OH OH 50oC NH2 N Mes then r.t. N Mes

NH2 r.t. 30min N Mes N Mes

OH OH OH

(R,R)-HPEN (R,R)-11 (S,S)-12 isolated

1:14 mixture aq. HCl / MeOH; NaOH

Ph N Mes Ph N Mes Ph H2N Mes

Ph N Mes Ph N Mes r.t. overnight H2N Mes

(R,R)-15' (S,S)-15 (S,S)-TPEN observed (Figure 3-8)

aq. HCl / MeOH Ph NH2

Ph NH2

(R,R)-DPEN

Scheme 3-11. Consecutive diaza-Cope rearrangements

In conclusion, we have demonstrated by experiment and DFT computation that steric strain can dramatically influence the equilibrium in [3,3]-sigmatropic reactions in a significant way. Its effect can overcome electronic effects and compete with the effect of resonance-assisted hydrogen bonds.

111

3.5. The oxyanion effect

The oxy-Cope rearrangement 28 is of particular interest as a useful synthetic route to δ,ε– unsaturated carbonyl compounds (Scheme 3-12a). However, in general this process requires harsh thermal conditions (200-400 oC), and is frequently accompanied by competing fragmentation reactions. A major advance in synthetic applications of the oxy-Cope rearrangement occurred in

1975, when Evans and Golob reported their remarkable findings. They showed that deprotonation of the 3-hydroxyl group in the oxy-Cope substrate resulted in a striking rate acceleration of 1010 to 1017 fold for the rearrangement reaction (Scheme 3-12b). 29 Since then, the anionic oxy-Cope rearrangement has been widely used in natural and unnatural product synthesis.30

HO HO O (a)

MO MO (b)

Scheme 3-12. (a) Oxy-Cope and (b) anionic oxy-Cope rearrangements

Baumann and Chen31 used DFT computation (B3LYP/6-31G(d) level) to obtain kinetic and thermodynamic barriers for the oxy-Cope and anionic oxy-Cope rearrangement (Figure 3-13). The computational data show that the oxyanion can significantly lower the kinetic and thermodynamic barrier of the rearrangement. The lowering of the kinetic barrier (ΔΔH‡ = 25.2 kcal/mol) and the thermodynamic barrier (ΔΔH = 17.8 kcal/mol) translate to about a 1020-fold and a 1013-fold increase of the rate and equilibrium constants respectively. It was reported that the computed values of the

28 Berson, J. A.; Jones, M. Jr., J. Am. Chem. Soc. 1964, 86, 5019. 29 Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765. 30 Bronson, J. J.; Danheiser, R. L. Charge-accelerated Rearrangements, In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon, Oxford, 1991; Vol. 5, pp 999. 31 Baumann, H.; Chen, P. Helv. Chim. Acta. 2001, 84, 124. 112 rate acceleration correspond closely to the experimental values obtained in the gas phase where the naked oxygen anion is generated.33 In the solution phase, the measured rate acceleration of the rearrangement is smaller (1012-fold) but can be increased by establishing a high degree of ion-pair dissociation.32 For example, the addition of crown ether in solution amplified the rate acceleration to

1017.29

(a) (b)

O ΔH = 31.4

ΔH =6.2(8.3)

ΔH =-3.2 O HO HO

O ΔH = -21.0 (-18.2)

Figure 3-13. Energy profiles for (a) the oxy-Cope and (b) anionic oxy-Cope rearrangement

calculated by DFT computation at the B3LYP/6-31G(d) level.32 B3LYP/6-31+G(d)

enthalpies33 are given in parentheses. Enthalpies are in kcal/mol.

We wondered if the anion effect can significantly lower the thermodynamic and kinetic barrier for the diaza-Cope rearrangement as demonstrated for the anionic oxy-Cope rearrangement. Our design of the diimine structure for the oxyanion-driven diaza-Cope rearrangements is shown in

Scheme 3-13. We anticipated that the delocalization of the oxyanion may increase the rate and equilibrium constants for the diaza-Cope rearrangement as in the case for the anionic oxy-Cope reaction. The electron donating oxyanion group may stabilize the rearranged imine by conjugation thereby increasing the rate and equilibrium constants for the reaction.

32 Schulze, S.; Santella, N.; Grabowski, J. J.; Lee, J. K. J. Org. Chem. 2001, 66, 7247. 113

HO KO KO R R R N KOtBu N [3,3] N

N N N R R R HO KO KO

Scheme 3-13. Oxyanion-driven diaza-Cope rearrangements. Curly arrows indicate delocalization of the oxyanion.

In order to estimate the strength of the oxyanion effect, we used DFT computation (at the

B3LYP/6-31G(d) or B3LYP/6-31+G(d) level) to compare the change in energies for the two rearrangement reactions in Figure 3-14. Remarkably, DFT computation shows that the oxyanion- driven diaza-Cope rearrangement is much more favorable than the hydroxyl group driven reaction

(ΔΔH = 23.6 kcal/mol). The value translates to about a 1017-fold increase in the equilibrium constant for the oxyanion driven reaction. The calculated oxyanion effect (25.3 kcal/mol) is significantly greater than the steric (5.5 kcal/mol) or the H-bond effect (6.8 kcal/mol) for the rearrangement reaction.

(a) (b)

ΔE = -25.3 kcal/mol ΔE = -1.70 kcal/mol

HO HO

N Ph N Ph

O O N Ph N Ph N Ph N Ph HO HO

N Ph N Ph O O

Figure 3-14. Energy profiles for oxyanion-promoted diaza-Cope rearrangement. Energies were calculated by DFT at the (a) B3LYP/6-31G(d) and (b) B3LYP/6-31+G(d) level.

114

The Hammett σ+ value for the oxyanion (σ+ = -4.27)33 has been reported and is greater in magnitude than the dimethylamino group (σ+ = -1.70).7 These Hammett parameters indicate that the oxyanion will provide much stronger electronic driving force for the diaza-Cope rearrangement than the dimethylamino group. Since DFT computation indicates that the oxyanion effect is the strongest effect among the weak forces, we became interested in using experimental data for directly comparing the oxyanion effect to electronic, steric and RAHB effects.

Several diimines prepared from 1,2-bis(4-hydroxyphenyl)-1,2-diaminoethane and aryl aldehydes were treated with KOtBu (2-5 equiv) to afford the corresponding potassium diphenolate salts 18-21 (Scheme 3-14).34 In our experiments, we intended to compare the oxyanion effect with the electronic effect (18, 19), the steric effect (20), and the RAHB effect (21). To our delight, all of the salts 18-21 smoothly rearranged to the products 18′-21′ within hours as monitored by 1H NMR in DMSO-d6. When compared with the electronic effects (18 and 19), the anionic effect readily drives the reactions to completion within 1 h at ambient temperature. The steric effect created by the mesityl groups in 20 is also defeated by the oxyanion effect in equilibration within 1 h.

Finally, 1H NMR data show that diimine 21 rearranges almost to completion to give 21′ after 6

o h in DMSO-d6 at 50 C. The equilibrium constant for the rearrangement reaction is about 20.

Although the rearrangement did not go to completion, it is clear that the oxyanion effect is stronger than the RAHB effect. Competing protonation and deprotonation at the 2-hydroxy and 4-hydroxy position in 21′ may prevent completion of the rearrangement reaction. Thus, the experimental data is in agreement with the DFT computational data in showing that the oxyanionic effect is stronger than the electronic, steric, and H-bond effects.

33 Binev, I.; Kuzmanova, R.; Kaneti, J.; Juchnowski, I.; J. Chem. Soc., Perkin Trans. 2 1982, 1533. 34 For experimental details, see: Nguyen, Y. M. H. M. Sc. Thesis, University of Toronto, 2008. 115

KO KO

N Ar N Ar

KO KO

18, Ar = 4-MeOC6H4 18' 19,Ar=4-Me2NC6H4 19' 20, Ar = 2,4,6-Me3C6H2 20' 21,Ar=2-HOC6H4 21'

Scheme 3-14. Oxyanion-driven diaza-Cope rearrangements

In summary, we demonstrated that the oxyanion effect dominates over other weak forces such as electronic, steric, and RAHB effects in diaza-Cope rearrangement reactions. Both experiment and

DFT computation show that the oxyanion effect is the strongest among weak forces studied. Thus, the oxyanion-driven diaza-Cope rearrangement may be useful for the synthesis of a variety of chiral vicinal diamines including HPEN ananlogs.

116

3.6. Interplay of weak forces on the thermodynamics

In the preceding sections, we investigated the effects of individual weak forces on the thermodynamics of the diaza-Cope rearrangement by experiment and computation. DFT computation revealed that the RAHB effect (rearrangement of HB-Ph35 : 6.8 kcal/mol, Scheme 3-

15) is stronger than the steric effect (rearrangement of Mes-Ph : 5.5 kcal/mol) or the electronic effect (rearrangement of MA-Ph : 3.3 kcal/mol). Consistent with the computational data, 1H NMR data showed that the rearrangement of HB-Ph, Mes-Ph, and MA-Ph all go to completion.

However, the equilibrium constant for the rearrangement reaction could not be determined by 1H

NMR methods as the starting diimines (HB-Ph, Mes-Ph, and MA-Ph) were not detectible after equilibration.

Ar N [3,3] Ar N

Ar N Ar N

HB-Ph Ar = 2-HOC6H5 Mes-Ph Ar = 2,4,6-Me 3C6H3 MA-Ph Ar = 4-Me2NC6H5

Scheme 3-15. Diaza-Cope rearrangements driven by the H-bonding (HB-Ph), the steric strain

(Mes-Ph), and the electronic (MA-Ph) effects

We became interested in finding experimental methods for measuring the RAHB, steric, and electronic effect for the rearrangement reaction. If the effects of weak forces on the rearrangement

35 In Sections 3.6 and 3.7, for convenience and clarity, all diimines are named as A-B, where the group A is attached to the diamine backbone and the group B is attached to the imine carbon. HB, Mes, MA, and MO represent 2-HOC6H5, 2,4,6-Me3C6H3, 4-Me2NC6H5, and 4-MeOC6H5, respectively. Below is shown the corresponding numeric designation for these diimines used in other sections. Ph-Ph HB-Ph Ph-HB Mes-Ph Ph-Mes HB-Mes Mes-HB MA-MO MO-MA 1 9 10 15 15′ 11 12 6′ 6

117 reaction is additive, the rearrangement of HB-Mes should be thermodynamically favorable by 1.3 kcal/mol (6.8 - 5.5 kcal/mol). Similarly, the rearrangement of Mes-MA should be thermodynamically favorable by 2.2 kcal/mol (5.5 - 3.3 kcal/mol). Since the values of the equilibrium constant for the rearrangement of HB-Mes and Mes-MA are expected to be small, they should be measurable by 1H NMR methods and compared with DFT computational data.

DFT computation reveals that the rearrangement of HB-Mes is thermodynamically favorable by 1.6 kcal/mol is close agreement with the above prediction (1.3 kcal/mol) based on the additivity of weak forces. Furthermore, the rearrangement of Mes-MA is thermodynamically favorable by 2.6 kcal/mol in good agreement with the prediction (2.2 kcal/mol).

The equilibrium constants for the rearrangement of HB-Mes and Mes-MA should be small enough to be measurable by 1H NMR methods if the effect of weak forces are additive as indicated by DFT computations. Figure 3-15a shows the 1H NMR spectrum of HB-Mes after the equilibrium has been reached for the rearrangement reaction. The equilibrium constant for the rearrangement reaction is about 14 as determined from the integration ratio of the imine C-H signals of the starting and the rearranged diimines. The measured equilibrium energy for the rearrangement of HB-Mes

(1.6 kcal/mol) is in excellent agreement with the DFT computational data (1.6 kcal/mol). Figure 3-

15b shows the 1H NMR spectrum of Mes-MA after equilibration. The equilibrium constant for the rearrangement of Mes-MA is about 13 as determined from the integration ratio of the imine C-H signals of the starting and the rearranged diimines. This value of the equilibrium energy (1.5 kcal/mol) too is in good agreement with the DFT computational data (2.6 kcal/mol).

118

OH OH N N

N N N N

OH OH N N HB-Mes Mes-HB Mes-MA MA-Mes

Mes-HB

MA-Mes

HB-Mes Mes-MA

o o K = 14 (25 C, CDCl3) K = 13 (25 C, DMSO-d6 with 10% CDCl3)

(a) (b)

Figure 3-15. Partial 1H NMR spectra of HB-Mes and Mes-MA after equilibration

As shown above, both DFT computation and 1H NMR experimental data support the notion that the effects of weak forces on the rearrangement reaction are additive. This allows the use of 1H

NMR data in series to estimate the individual effects of the RHAB, steric, and electronic effects for the rearrangement of HB-Ph, Mes-Ph, and MA-Ph respectively (Figure 3-16). For example, the electronic effect for the rearrangement of MA-Ph (3.0 kcal/mol) could be considered the addition of the electronic effect for the rearrangement of MO-Ph (1.3 kcal/mol) and the electronic effect for the rearrangement of MA-MO (1.7 kcal/mol). The steric effect for the rearrangement of Mes-Ph (4.5 kcal/mol) could be considered the addition of the electronic effect for the rearrangement of MA-Ph

(3.0 kcal/mol) and the effect for the rearrangement of Mes-MA (1.5 kcal/mol). Finally the RAHB effect for the rearrangement of HB-Ph (6.1 kcal/mol) could be considered the addition of the steric effect of the rearrangement of Mes-Ph (4.5 kcal/mol) and the effect for the rearrangement of HB-

Mes (1.6 kcal/mol). Thus 1H NMR data can be used in series to estimate the RAHB (6.1 kcal/mol),

119 steric (4.5 kcal/mol), and electronic effects (3.0 kcal/mol) for the rearrangement of HB-Ph, Mes-

Ph, and MA-Ph, respectively. This is in good agreement with the corresponding DFT computational data for the RAHB (6.8 kcal/mol), steric (5.5 kcal/mol), and electronic effect (3.3 kcal/mol).

HB-Mes RAHB effect

OH OH

N N ΔG =1.6 N N

OH OH

HB-Mes Mes-MA Steric effect

N N

N N ΔG =1.5 N N

N N

Mes-MA MA-MO Electronic effect (NMe2) N OMe N OMe

N N ΔG =1.7 N N

N OMe N OMe

MA-MO MO-Ph Electronic effect (OMe)

MeO MeO

N N ΔG =1.3 N N

MeO MeO MO-Ph Phenyl group effect

Figure 3-16. Interplay of weak forces on the thermodynamics of the diaza-Cope rearrangement

1 o on the basis of the equilibrium constants measured by H NMR spectroscopy at 25 C (∆G

values in kcal/mol).

In summary, both DFT computation and 1H NMR data show that the effects of weak forces on the diaza-Cope rearrangement are additive. This allows the use of 1H NMR data for estimating the individual RAHB, steric, and electronic effects for the rearrangement of HB-Ph, Mes-Ph, and MA-

Ph, respectively. There is good agreement between the DFT computational data and the 1H NMR data on the effects of weak forces on the rearrangement reaction.

120

3.7. Effect of weak forces on the kinetics

In the preceding sections we showed that H-bond, electronic and steric effects can dramatically influence the thermodynamics of the diaza-Cope reactions (Section 3.2 to 3.6). In addition, DFT computation can be used to calculate the thermodynamic effects of these weak forces in isolation and in combination on the rearrangement reaction. In this section, we compare experimental and

DFT computational data on the effects of some of the weak forces on the kinetics of the rearrangement reaction.

In order to study the H-bond and steric effects on the kinetics of the diaza-Cope reaction, I measured the rate of rearrangement of the diimine (HB-Ph) formed between HPEN and benzaldehyde and the rate of rearrangement of the diimine (Mes-Ph) formed between TPEN and benzaldehyde (Table 3-6). The rate of rearrangement of the diimine (Ph-Ph) formed between DPEN and benzaldehyde was measured by Vögtle.4c HB-Ph rearranges about a hundred times more rapidly than Ph-Ph at 25 oC. Thus the resonance-assisted hydrogen bond not only increases the equilibrium constant (105 fold) but also the rate constant (102 fold) for the rearrangement reaction. Mes-Ph rearranges about five times more rapidly than Ph-Ph at 25 oC. The steric effect due to the mesityl group not only increases the equilibrium constant (104 fold) but also the rate constant (5 fold) for the rearrangement reaction. We can see that the steric effect due to the mesityl group is weaker than the

RAHB effect for the rearrangement reaction.

It is interesting to study the interplay of H-bond and steric effects. The rate of rearrangement of

HB-Mes is about five times slower than the rate of rearrangement of Ph-Ph even though the equilibrium constant for the rearrangement of the former reaction is about ten times greater than that of the latter. Thus the Marcus equation cannot be used to fit all of the rate and equilibrium data for the rearrangement of Ph-Ph, HB-Ph, Mes-Ph, and HB-Mes.

121

OH OH

N N N N

OH OH

Ph-Ph HB-Ph

OH OH

N N N N

N N N N OH OH

Mes-Ph HB-Mes

Calculationa Experiment Diimine ‡ b -1 ΔE (kcal/mol) krel k298 (s ) krel HB-Ph 18.1 220 1.30 × 10-3 150 Mes-Ph 19.4 25 4.19 × 10-5 4.8 Ph-Ph 21.3 1 8.70 × 10-6 1 HB-Mes 22.9 0.5 1.77 × 10-6 0.2 aDFT at the B3LYP / 6-31G(d) level. bVibrational analysis is not applied.

Table 3-6. Calculated and experimental rate constants for the diaza-Cope rearrangement driven

by weak forces.

The energy barriers for the rearrangement of Ph-Ph, HB-Ph, Mes-Ph, and HB-Mes were calculated by DFT computation at the B3LYP/6-31G(d) level (Table 3-6). In agreement with experimental data, computation shows that the energy barrier is the lowest for the H-bond directed rearrangement reaction (HB-Ph) followed by the steric strain driven rearrangement reaction (Mes-

Ph). Furthermore, computation correctly shows that the energy barrier for the rearrangement of HB-

Mes is greater than that for the rearrangement of Ph-Ph even though the former reaction is thermodynamically more favorable than that of the latter reaction. Thus, there is good agreement between experimental and computational data on the effects of weak forces on the rate of the rearrangement reaction.

122

3.8. Conclusions

Weak forces such as H-bonding, electronic and steric effects can have profound effects on the equilibrium for the diaza-Cope rearrangement. The electronic effect can be studied systematically in terms of the Hammett equation. There is a linear relationship between the logarithm of the experimentally determined equilibrium constant (logKeq) for the rearrangement reaction and the ∆σ values with a ρ value of 2.49 (Figure 3-1). The electronic effect can be used to drive diaza-Cope reactions to completion (Keq > 100). We find that resonance-assisted hydrogen bond (RAHB) have even a greater effect than electronic effects in controlling the equilibrium for the rearrangement reaction. Interestingly, steric strain can also be used to drive diaza-Cope reactions to completion.

The oxyanion effect is one of the strongest forms of the electronic effect for the rearrangement reaction and it can be even stronger than the RAHB effect. DFT computation is useful for calculating the thermodynamic effects of these weak forces (steric, electronic and H-bond effects) in isolation as well as in combination. Thus the interplay of weak forces in the rearrangement reaction can be calculated reliably by DFT computation.

Experiments show that weak forces can increase not only the equilibrium but also the rate of the diaza-Cope rearrangement. DFT computation correctly shows the effects of weak forces on both the equilibrium and the reactivity of the rearrangement reaction. Thus, transition state structures and energies of the rearrangement can be calculated reliably by DFT computation but not by semi- empirical calculations such as AM1 and PM3. The diaza-Cope rearrangements driven by electronic, steric, or H-bond effects all take place with excellent stereospecificity. DFT computation reveals that the origin of the stereospecificity is due to the formation of a chair-like six-membered ring transition state with all equatorial substituents.

123

3.9. Experimental

General Information

Commercially available compounds were used without further purification or drying. The

1H NMR and 13C NMR spectra were recorded on a Varian 400 spectrometer. The High resolution mass spectra (HRMS) were obtained from the Department of Chemistry, University of Toronto (ESI or EI). Circular dichroism spectra were taken with a JASCO J-710 spectropolarimeter. UV-vis spectra were recorded on a PerkinElmer Lambda 900 spectrometer. HPLC analysis was performed on a Hewlett-Packard 1090 Series HPLC, UV detection monitored at 254 nm, using a Chiralcel OD-

H column (25cm). Optical rotations were obtained at 589 nm using a Rudolph Autopol IV polarimeter. Melting points were recorded using an Electrothermal IA 9100 digital melting point apparatus. All calculations were performed using Spartan ′06 for Windows from Wavefunction Inc.

Preparation of (S,S)-1,2-bis(2,4,6-trimethylphenyl)-1,2-diaminoethane (TPEN)

OH OH OH HCl / MeOH; NH2 N N H N [3,3] NaOH 2

NH2 N N H2N OH OH OH

(R,R)-HPEN (R,R)-11 (S,S)-12 (S,S)-TPEN

To a cloudy solution of (R,R)-HPEN (5.0 g, 20 mmol) in ethanol (41 mL) was OH N added mesitaldehyde (6.7 g, 45 mmol) at 0 oC. After the solution became clear,

N the flask was allowed to room temperature. A white solid precipitated out within OH (R,R)-11 minutes. After 30 minute, the solution was filtered, washed with ethanol, and

1 dried in vacuo to afford (R,R)-11 in 96% yield (9.9 g). H-NMR (400 MHz, CDCl3): δ 10.3 (s, 2H,

124

ArOH); 8.54 (s, 2H, Imine H); 7.11 (dt, J = 1.6, 7.8 Hz, 2H, ArH); 6.87 (dd, J = 0.8, 8.0 Hz, 2H,

ArH); 6.80 (s, 4H, ArH); 6.54 (dt, J = 0.8, 7.2 Hz, 2H, ArH); 6.46 (dd, J = 1.6, 7.6 Hz, 2H, ArH);

13 4.91(s, 2H, C*H); 2.27 (s, 12H, CH3); 2.25 (s, 6H, CH3). C-NMR (100 MHz, CDCl3): δ 164.0,

156.3, 140.7, 138.9, 130.2, 129.4, 129.1, 128.6, 124.6, 119.3, 117.0 (11 sp2-carbons), 81.2, 21.4,

3 + 21.2 (3 sp -carbons). HRMS (ESI) calculated for C34H37N2O2 [M+H] : 505.2849. Found: 505.2833.

27 o [α]D +138 (c =1.0, CHCl3) for (R,R)-11, mp = 121-122 C.

(R,R)-11 (5 g, 9.9 mmol) was dissolved in chloroform OH OH

N [3,3] N (200 mL), and the resulting solution was heated to 50

N N o C for 2 days until equilibrium reached (Keq = 9). The OH OH

11 (R,R)- (S,S)-12 better equilibrium ratio (Keq = 14) was obtained when the flask was kept at room temperature for 1 week. The solvent was evaporated out under reduced pressure, and the mixture was used for the next step. (S,S)-12 was also purified by recrystallization

1 using methanol. H-NMR (400 MHz, CDCl3): δ 13.17 (s, 2H, ArOH); 8.41 (s, 2H, Imine H); 7.24-

7.19 (m, 4H, ArH); 6.87-6.79 (m, 6H, ArH); 6.62 (s, 2H, ArH); 5.65 (s, 2H, C*H); 2.66 (s, 6H,

13 CH3); 2.20 (s, 6H, CH3); 1.84 (s, 6H, CH3). C-NMR (100 MHz, CDCl3): δ 165.6, 161.0, 137.2,

137.2, 136.9, 134.1, 132.5, 131.9, 131.3, 129.4, 119.1, 118.8, 117.0 (13 sp2-carbons), 71.2, 22.3,

3 + 21.0 (3 sp -carbons). HRMS (ESI) calculated for C34H37N2O2 [M+H] : 505.2849. Found: 505.2849.

27 o [α]D -197 (c =1.0, CHCl3) for (S,S)-12, mp = 159-160 C.

To a clear solution of mixture of (R,R)-11 and (S,S)-12 (5 g, 9.9 mmol) in methanol

H2N (100 mL) was added 12 M hydrochloric acid solution (25 mL). The solution was

H2N stirred overnight at ambient temperature, and then the aqueous layer was washed with

(S,S)-TPEN diethyl ether. The aqueous layer was basified with 6 M sodium hydroxide solution to pH 13, and the solution was extracted with diethyl ether. The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give (S,S)-TPEN as a colorless oil in

125

77% yield (2.8 g). The product was solidified using methanol and water following the literature

36 1 procedure. H-NMR (400 MHz, CDCl3): δ 6.79 (s, 2H, ArH); 6.54 (s, 2H, ArH); 4.72 (s, 2H,

13 C*H); 2.67 (s, 6H, CH3); 2.17 (s, 6H, CH3); 1.64 (s, 6H, CH3). C-NMR (100 MHz, CDCl3): δ

137.2, 137.1, 136.0, 131.3, 129.0 (5 sp2-carbons), 54.1, 21.6, 20.9, 20.6 (4 sp3-carbons). HRMS

+ 25 (ESI) calculated for C20H29N2 [M+H] : 297.2325. Found: 297.2327. [α]D -147 (c =1.0, CH3OH) for

(S,S)-TPEN-dihydrochloride.

Characterization of 13′, 14′ and 15′

X X

H N N N 2 X [3,3]

N H2N N X X

(S,S)-TPEN (S,S)-13:X=NO2 (R,R)-13':X=NO2 (S,S)-14:X=OCH3 (R,R)-14':X=OCH3 (S,S)-15:X=H (R,R)-15':X=H

To a clear solution of (S,S)-TPEN (120 mg, 0.40 mmol) in 1.0 mL of ethanol O2N N was added 150 mg (1.0 mmol) of p-nitrobenzaldehyde. The resulting clear

N reaction mixture was stirred overnight at room temperature to give (R,R)-13′ O2N (R,R)-13' as a white precipitate. The solid was filtered, washed with 1.0 ml of ethanol

1 and dried in vacuo (80% yield). H-NMR (400 MHz, CDCl3): δ 8.62 (s, 2H, Imine H); 8.06 (d, J =

8.8 Hz, 2H, ArH); 7.41 (d, J = 8.8 Hz, 2H, ArH); 6.81 (s, 4H, ArH); 4.75 (s, 2H, C*H); 2.29 (s, 12H

13 CH3); 2.26 (s, 6H, CH3). C-NMR (100 MHz, CDCl3): δ 163.2, 148.5, 147.3, 139.9, 138.6, 129.91,

129.8, 129.3, 123.6 (9 sp2-carbons), 82.9, 21.4, 21.3 (3 sp3-carbons). HRMS (ESI) calculated for

+ 27 o C34H35N4O4 [M+H] : 563.2652. Found: 563.2666. [α]D +55 (c =1.0, CHCl3), mp = 186-187 C.

36 Kurahashi, T.; Oda, K.; Sugimoto, M.; Ogura, T.; Fujii, H. Inorg. Chem. 2006, 45, 7709. 126

Although (R,R)-14′ was not able to be isolated as a solid, the clean H3CO N conversion was observed by 1H NMR. (S,S)-TPEN (30 mg, 0.10 mmol) was

N mixed with p-anisaldehyde (37 μL, 0.30 mmol) in DMSO-d6 (0.6 mL). The H3CO (R,R)-14' reaction mixture was heated to 50 oC for 6 h until reaction was complete

1 1 monitored by H NMR. H-NMR (400 MHz, CDCl3): δ 8.56 (s, 2H, Imine H); 7.21 (d, J = 8.8 Hz,

4H, ArH); 6.78 (s, 4H, ArH); 6.75 (d, J = 8.8 Hz, 4H, ArH); 4.73 (s, 2H, C*H); 3.66 (s, 6H, OCH3);

2.21 (s, 12H, CH3); 2.18 (s, 6H, CH3).

To a clear solution of (S,S)-TPEN (120 mg, 0.40 mmol) in 1.0 mL of ethanol was

N added 102 µL (1.0 mmol) of benzaldehyde. The resulting clear reaction mixture

N was stirred overnight at room temperature to give (R,R)-15′ as a white

(R,R)-15' precipitate. The solid was filtered, washed with 1.0 ml of ethanol and dried in

1 vacuo (85% yield). H-NMR (400 MHz, CDCl3): δ 8.59 (s, 2H, Imine H); 7.25-7.23 (m, 4H, ArH);

7.16-7.09 (m, 6H, ArH); 6.76 (s, 4H, ArH); 4.70 (s, 2H, C*H); 2.28 (s, 12H CH3); 2.24 (s, 6H,

13 CH3). C-NMR (100 MHz, CDCl3): δ 161.4, 142.0, 138.8, 138.4, 130.7, 129.6, 128.6, 128.0, 126.9

2 3 + (9 sp -carbons), 83.9. 21.3, 21.2 (3 sp -carbons). HRMS (ESI) calculated for C34H37N2 [M+H] :

473.2951. Found: 473.2933. The enantiopurity was confirmed by HPLC analysis (Chiralcel OD-H column, 3% isopropanol in hexane, 0.3 mL/min); (R,R)-15′ tR = 12.3min, (S,S)-15′ tR = 11.9 min.

27 o [α]D +44 (c =1.0, CHCl3), mp = 146-147 C.

127

CHAPTER 4

Organocatalytic Synthesis of Warfarin†

4.1. Introduction

Since the beginning of the new millennium, the field of organocatalysis has grown at a dynamic pace, providing a variety of enantioselective C-C, C-O, C-N, and C-halogen bond forming reactions.1 Among catalyst structures reported to date, primary or secondary amines have been widely applied to activate carbonyl compounds by forming enamine or iminium intermediates.

Moreover, primary amines have been modified into ureas, 2 thioureas,2, 3 or guanidiniums 4 for hydrogen bond donor catalysts. As our DCR method5 provides a variety of chiral, vicinal primary diamines, we became interested in developing new diamine-based organocatalysts as well as improving catalyst activity or stereoselectivity.

† This chapter has been published: Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. 1 For recent reviews, see: (a) MacMillan, D. W. C. Nature 2008, 455, 304. (b) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (c) List, B. Eds. Chem. Rev. 2007, 107, 5413 -5883. (d) Lelais, G.; MacMillan, D. W. C. Alrichimica Acta 2006, 39, 79. (e) Berkessel, A.; Groger, H. Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005. (f) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (g) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. 2 For reviews, see: (a) Connon, S. J. Chem. Commun. 2008, 2499. (b) Connon, S. J. Chem. Eur. J. 2006, 12, 5418. 3 (a) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee, J. Y.; Chin, J.; Song, C. E. Chem. Comm. 2008, 1208. (b) Oh, S. H. ;Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J. Song, C. E. Angew. Chem., Int. Ed. 2008, 47, 7872. 4 Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228. 5 (a) Kim, H.; So, S. M.; Kim, B. M.; Chin, J. Aldrichimica Acta 2008, 41, 77. (b) Kim, H.; Staikova, M.; Lough, A. J.; Chin, J. Org. Lett. 2009, 11, 157. (c) Kim, H.; Nguyen, Y.; Yen, C. P.-H.; Chagal, L.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184. (d) Kim, H.-J.; Kim, H.; Alhakimi, G.; Jeong, E. J.; Thavarajah, N.; Studnicki, L.; Koprianiuk, A.; Lough, A. J.; Suh, J.; Chin, J. J. Am. Chem. Soc. 2005, 127, 16370. (e) Kim, H.; Nguyen, Y.; Lough, A. J. Chin, J. Angew. Chem., Int. Ed. 2008, 47, 8678. (f) Kim, H.; Choi, D. S.; Yen, C. P.-H.; Lough, A. J.; Song, C. E. Chin, J. Chem. Commun. 2008, 1335.

128

4.2. Revision of imidazolidine-catalyzed warfarin synthesis

In an elegant and innovative study,6 a chiral imidazolidine (1) was used as a catalyst for stereoselective coupling of 4-hydroxycoumarin (2) and trans-4-phenyl-3-buten-2-one (3) to make warfarin (4), a widely prescribed anticoagulant used for treating thrombosis (Scheme 4-1). 7

However, the mechanism provided in the study leads one to predict the sense of stereoselectivity for the reaction that is opposite to the one observed. In the original report, the (R,R)-1 forms an aminal intermediate with the ketone substrate (Figure 4-1b). According to this figure, hydroxycoumarin is expected to attack from the Si face since the Re face is blocked. This leads one to predict that the

(R,R)-1 would give the S form of warfarin in conflict with the experimental result. Our interest in finding the correct mechanism and the origin of stereoselectivity led us to investigate chiral vicinal diamine (5-11) catalyzed synthesis of warfarin.

OH O OH Ph O 1 + O O O O 2 3 4

5 :R=(CH) H 2 4 Ph N O R NH2 6 :R=C6H5 7 :R=2-MeC6H4 8 N :R=2-ClC6H4 Ph OH R NH2 H 9 :R=2-MeOC6H4 10:R=4-MeOC6H4 1 11:R=1-Np

Scheme 4-1. Organocatalytic synthesis of optically active warfarin

6 Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955. 7 For stereoselective warfarin synthesis, see: (a) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413. (b) Demir, A. S.; Tanyeli, C.; Gülbeyaz, V.; Akgün, H. Turk. J. Chem. 1996, 20, 139-145. (c) Robinson, A.; Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321. (d) Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetradedron: Asymmetry 2001, 12, 707.

129

Ph Ph CO H (R,R) NH 2 (R,R) N Ph N CO 2H N H Ph Me Me

Ph Ph Re-attack Si-attack (a) (b)

Figure 4-1. Proposed (a) iminium and (b) aminal intermediates

Coumarin dimers (9) can be prepared from the reaction of 4-hydroxycoumarin with a variety of alkyl and aryl aldehydes including glyoxylic acid (Scheme 4-2a).8 We find that imidazolidines

(including 1) formed from diphenylethylenediamine (DPEN or 6) and aldehydes also react with 4- hydroxycoumarin (2) to give coumarin dimers and 6 (Scheme 4-2b). Thus 1 may not be the actual catalyst for making warfarin from 2 and 3 as previously thought. It may be that DPEN (6) formed from the reaction of 2 and 1 is the true catalyst for making warfarin. Indeed 6 and 5 (DACH) have already been shown to be catalysts for making warfarin.9

OH OH COOH OH O + (a) COOH O O O O O O 2 9

OH Ph H N Ph NH2 + COOH + 9 (b) N Ph NH O O Ph H 2 2 1 6

Scheme 4-2. Formation of coumarin dimer

8 (a) Sullivan, W. R.; Huebner, C. F.; Stahmann, M. A.; Link, K. P. J. Am. Chem. Soc. 1943, 65, 2288. (b) Khan, K. M.; Iqbal, S.; Lodhi, M. A.; Maharvi, G. M.; Ullah, Z.-; Choudhary, M. I.; Rahman, A.-u.-; Perveen, S. Bioorg. Med. Chem. 2004, 12, 1963. 9 Halland, N.; Jørgensen, K. A.; Hansen, T. PCT Int. Appl. 2003 WO 03/050105.

130

When 2 is added to 1 (20 mol %) dissolved in THF, the coumarin dimer (9) and DPEN (6) are formed cleanly and to completion within 24 h at ambient temperature as shown by 1H NMR spectra

1 (Figure 4-2a). The formation of the coumarin dimer (9) in DMSO-d6 can be monitored by H NMR spectroscopy within 3 h (Figure 4-2b).

OH H OH CO2H OH Ph N O Ph NH + 2 5 + O O Ph N OH THF (0.4 mL), rt H Ph NH2 24 h O O O O (29mg, 0.18mmol) (9.7mg, 0.036mmol)

1 H NMR was taken in DMSO-d6 OH H

O O

H Ph NH2 OH CO2H OH

Ph NH2 H H O O O O

Addition of bis-coumarin Addition of DPEN OH CO2H OH H Ph NH 2 H O O O O Ph NH2 H

(a)

131

OH H OH CO2H OH Ph N O Ph NH + 2 5 + N O O Ph OH DMSO-d (1 mL), rt NH H 6 O O O O Ph 2 (29mg, 0.18mmol) (9.7mg, 0.036mmol)

(peak at δ 5.6 ppm is due to CH2Cl2)

OH H

O O

OH CO H OH 2 H H Ph N O H O O O O Ph N H OH H H H Ph NH2

Ph NH2 H

(b) 3h

6.0 5.5 5.0 4.5 4.0 ppm

Figure 4-2. The reaction between imidazolidine (1) and hydroxycoumarin (2) in (a) THF after

24 h and (b) DMSO-d6 after 1, 2 and 3 h.

132

When 2 (Figure 4-3; C-H next to carbonyl) and 3 (Figure 4-3; vinyl C-H next to the carbonyl group) are added together to 1 (10 mol %) in THF-d8 (1 mL), warfarin (4; C-H at the chirality center) synthesis lags considerably behind the formation of the coumarin dimer (9; alkyl C-H).

These data provide interesting insights into the mechanism and the origin of stereoselectivity in vicinal diamine catalyzed synthesis of warfarin (4) as shown in Figure 4-4.

OH 3 2 O O

OH CO 2H OH OH Ph O

O O O O 9 O O 4 * 7h 18h 28h 45h 76h 100h 130h

7.0 6.0 5.0 4.0 ppm

1 Figure 4-3. H NMR spectra of the reaction mixture of 1, 2 and 3 taken in THF-d8. Time

dependent change in signals due to compounds 3, 9, 2 and 4. CH2Cl2 (*) as reference

133

4.3. Vicinal diamine-catalyzed synthesis of warfarin

Although the imidazolidine (1) breaks down to 6 and 9 rapidly during the catalytic synthesis of warfarin, the stereoselectivity is significantly lower (50% vs 78% ee) when the diamine (6) is used instead of the imidazolidine (1) to make the drug. We reasoned that the carboxylic acid group in 9 may be acting as a co-catalyst and enhancing the stereoselectivity of the diamine (6) catalyzed synthesis of warfarin. Indeed, acetic acid not only increases the rate but also dramatically increases the stereoselectivity for 6 catalyzed synthesis of warfarin (Table 4-1, entries 4-7). In contrast, acetic acid does not increase the rate or the stereoselectivity of 5 catalyzed synthesis of warfarin (entries 1-

3). The more basic alkyl diamine (5) is more reactive than the less basic aryl diamines (6) and does not require the co-catalyst. It may be that the rate-determining step for 6-catalyzed synthesis of warfarin is the imine formation step and is acid catalyzed. On the contrary, it appears that for 5- catalyzed synthesis of warfarin, the imine formation step is fast and not rate determining. Thus acetic acid is expected to increase the stereoselectivity by facilitating and activating the diimine pathway. The effect of acetic acid has not been reported in the previous study involving 5 and 6 catalyzed synthesis of warfarin.

We compared 5-11 catalyzed synthesis of warfarin with added acetic acid (Table 4-2). In a typical experiment, 10 mol % of the diamine was mixed with 2 (1 equiv), 3 (1.2 equiv) and acetic acid (10 fold excess) in THF (0.5 M) and stirred at ambient temperature for 24 h. Chiral-phase

HPLC was used to determine the enantiomeric excess of the product. We found that in general aryl diamines with electron donating groups (7, 9, 10, and 11) are more reactive but as selective than

DPEN (6) although that with a electron withdrawing group (8) is less reactive and selective than

DPEN (6). Under this catalyst search, the highest enantioselectivity of 92% ee was found with the diamine with ortho methyl groups (7). The reactivity and stereoselectivity of 9 and 10 are comparable indicating that the position of the substituent (ortho or para) is not important factor.

134

Indeed, all of the diamines give the same sense of stereoselectivity for the synthesis of warfarin.

Thus, a single unified mechanism appears to be operating for the synthesis of warfarin by all of the diamines.

Table 4-1. Effect of acetic acid on warfarin synthesis

OH OH Ph O O 10 mol% catalyst + 1.2 Ph THF, rt O O O O 3 2 H N NH H N NH 2 2 H 2 2 N O

N OH H (R,R)-5 (R,R)-6 (R,R)-1

Entry Catalyst AcOH T (h) Yielda (%) Eeb (%) (equiv) 1 (R,R)-5 - 12 98 54 2 (R,R)-5 2 12 97 55 3 (R,R)-5 10 24 99 47 4 (R,R)-6 - 48 88 50 5 (R,R)-6 2 72 85 67 6 (R,R)-6 10 48 94 86 7 (R,R)-6 20 24 99 84 8 (R,R)-1 - 130 80 78 (80c)

aYield of isolated product. bDetermined by chiral-phase HPLC. cLiterature value.

135

Table 4-2. Effect of diamine catalysts on warfarin synthesis

OH 10 mol% 5-11 OH Ph O O 10 equiv AcOH + 1.2 Ph THF, rt O O O O 2 3

H2N NH2 H2N NH2 H2N NH2 H2N NH2 Cl Cl

(R,R)-5 (R,R)-6 (R,R)-7 (R,R)-8

H2N NH2 H2N NH2 H2N NH2 MeO OMe

(R,R)-9 MeO (R,R)-10 OMe (R,R)-11

Entry Catalyst T (h) Yielda (%) Eeb (%) Anglec (deg)

1 (R,R)-5 24 98 47 69 2 (R,R)-6 48 94 86 52 3 (R,R)-7 24 99 92 46 4 (R,R)-8 48 97 67 57 5 (R,R)-9 24 99 86 53 6 (R,R)-10 24 99 84 53 7 (R,R)-11 24 97 88 52

aYield of product isolated after flash chromatography. bDetermined by HPLC using a Chiralpak AD-H column. cNCCN dihedral angle obtained by computation (molecular mechanics MMFF).

We propose that the mechanism of vicinal diamine catalyzed synthesis of warfarin involves the formation of the diimine intermediate (12) from the diamine and the ketone substrate (3). 1H NMR and ESI show that addition of acetic acid to 3 and DPEN (6) dissolved in CDCl3 results in complete conversion of the diamine to the corresponding diimine (Figure 4-4).

136

Ph Ph H N NH 2 2 O 10eq AcOH N N +10

CDCl3, RT, 12h

+ HRMS (ESI) calculated for C34H33N2 [M+H] : 469.2638, Found: 469.2631

H O

Ph H H Ph Ph Ph H N N H N N H H

87654

Figure 4-4. Diimine formation between DPEN (6) and trans-4-phenyl-3-buten-2-one (3)

In order to gain some insight into the origin of stereoselectivity in the diamine catalyzed synthesis of warfarin, we determined the global energy minimum structure (Figure 4-5a, DFT computation at the B3LYP/6-31G(d) level) of the diimine intermediate (12). Michael addition of 4- hydroxycoumarin (2) to 12 followed by hydrolysis of the imine moiety is expected to give warfarin.

Although we were not able to obtain the crystal structure of the putative intermediate, the crystal structure of the diimine (13) formed between the diamine (8) and trans-cinnamaldehyde was obtained as a model for the intermediate (Figure 4-5b).10 There is excellent agreement between the

10 Crystal data of 13: C40H32N2, T = 150(2) K, monoclinic, C2/c, Z = 8, a = 36.957(3) Å, b = 9.8273(9) Å, c = 3 16.7524(17) Å, α= 90º, β= 104.949(4)º, γ= 90º, V = 5878.3(9) Å , R1 = 0.0836, wR2 = 0.1979 for I> 2σ (I), GOF on F2 = 1.019.

137 computed structure of the proposed intermediate and the crystal structure of its model. Both compounds (12 and 13, Figure 4-5a and 4-5b) show extended structures with the two imine groups facing each other in a parallel fashion. In case of the diimine formed from the (R,R)-diamine, the two Si faces of the diimine (at the Michael attack position) are facing each other with the two Re faces exposed for nucleophilic attack by 4-hydroxycoumarin. Thus R-warfarin is expected to be the major product in the (R,R)-diamine catalyzed reaction. Indeed we find that in the (R,R)-11 catalyzed reaction, R-warfarin is the major product (88% ee, 97% yield). The explanation given in the original study for 1 catalyzed synthesis of warfarin leads one to predict the (R,R)-catalyst to give the S- warfarin in contrast to the R-warfarin observed. If (R,R)-1 was to be first converted to the corresponding (R,R)-diamine (6) according to Scheme 4-2b, the diamine is expected to catalyze the formation of R-warfarin as observed.

In the proposed intermediate (12) for the diamine catalyzed synthesis of warfarin, the stereoselectivity is expected to be at its greatest when there is maximum overlap between the two extended imines. In the diimine formed from 5, the overlap between the two imines is expected to be poor as the value of the computed NCCN dihedral angle (69º) is too large. Furthermore, the dihedral angle is rigidly held apart by the cyclohexane ring. In contrast, the values of the computed

NCCN dihedral angles in the aryl diimines formed from 6-11, are smaller (46º-57º) and more flexible. The smallest dihedral angle (46°) is found for the diimine formed with 7 which also gives the best stereoselectivity for warfarin synthesis (92% ee Table 4-2).

138

H R Np N Ph

Np N Ph H R

12:R=CH3 13:R=H

Figure 4-5. (a) Global energy minimum structure of 12. (b) Crystal structure of 13 (50%

thermal ellipsoid

139

4.4. Conclusions

In conclusion, we have shown that the imidazolidine (1) is converted to DPEN during the stereoselective synthesis of warfarin from 2 and 3. We suggest that DPEN (6) rather than 1 is the stereoselective catalyst since it is difficult to explain the observed sense of stereoselectivity in terms of 1 catalyzed synthesis of warfarin. Several vicinal diamines (6-11) have been shown to catalyze the stereoselective synthesis of warfarin. Acetic acid significantly enhances the reactivity and stereoselectivity of 1,2-diaryl-1,2-diaminoethanes (from about 50% ee to 90% ee). Furthermore, the stereoselectivity increases with decrease in the value of the NCCN dihedral angle of the proposed diimine intermediate (12). The observed sense of stereoselectivity for the diamine catalyzed synthesis of warfarin can be explained in terms of the computed structure of the diimine intermediate (12) and the crystal structure of an analog of this intermediate (13). These studies show that two substrates bound to the diamine catalyst control the stereoselectivity of warfarin synthesis.

4.5. Experimental

Stereoselective synthesis of warfarin

To a 1 dram vial equipped with a magnetic stirring bar was added trans-4-phenyl-3-buten-2- one (0.6 mmol), 4-hydroxycoumarin (0.5 mmol), and acetic acid (5 mmol) in THF (1 mL). The catalyst [(R,R)-7, 0.05 mmol] was added and the mixture was stirred at room temperature for 24 h.

The solvent and acetic acid was evaporated by nitrogen blowing. The crude reaction mixture was directly purified by flash column chromatography on silica gel using methanol / dichloromethane mixture to afford warfarin. The enantiomeric excess of the product was determined by HPLC (92% ee, CHIRALPAK AD-H column, 20% isopropanol in hexane, 1ml / min, (R) - warfarin tR = 5.6 min,

(S) - warfarin tR = 13.8 min).

140

CHAPTER 5

Highly Stereospecific Generation of Helical Chirality by Imprinting with Amino Acids†

5.1. Introduction

Helical or axial structures are ubiquitous in nature. Double helical DNA and α-helical peptides are well known helical structures, which play several essential roles in molecular biology such as transcription, signal transduction, and enzyme function (Figure 5-1a, b). 1 Helical structures in chemistry like helicene have been a topic of much interest.2 Unlike biological helices, helicenes

(and ortho-fused aromatic compounds) do not have stereogenic centers. Thus the right- and left- handed helicenes are equal in energy and often exist as racemic mixtures (Figure 5-1c). Recently, the helicene chemistry has grown from the field of academic curiosity to that of comprehensive research owing to their functions as optical switches, 3 molecular motors, 4 and DNA binders. 5

Therefore, helical structures combine beauty and function both in biology and in chemistry.

† This chapter has been published: Kim, H.; So, S. M.; Yen, C. P.-H.; Vinhato, E.; Lough, A. J.; Hong, J.-I.; Kim, H.-J.; Chin, J. Angew. Chem., Int. Ed. 2008, 47, 8657. 1 Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry 6th ed, W. H. Freeman, 2006. 2 Urbano, A. Angew. Chem., Int. Ed. 2003, 42, 3986. 3 (a) Chen, C.-T.; Chou, Y.-C. J. Am. Chem. Soc. 2000, 122, 7662. (b) Hassey, R.; Swain, E. J.; Hammer, N. I.; Venkataraman, D.; Barnes, M. D. Science 2006, 314, 1437. 4 (a) Kelly, T. R.; Cai, X.; Damkaci, F.; Panicker, S. B.; Tu, B.; Bushell, S. M.; Cornella, I.; Piggott, M. J.; Salives, R.; Cavero, M.; Zhao, Y.; Jasmin, S. J. Am. Chem. Soc. 2007, 129, 376. (b) Kelly, T. R.; De Silva, H.; Silva, R. A. Nature 1999, 401, 150. 5 (a) Xu, Y.; Zhang, Y. X.; Sugiyama, H.; Umano, T.; Osuga, H.; Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566. (b) Kim, Y. H.; Tishbee, A.; Gil-Av, E. Science 1981, 213, 1379.

141

(a) (b) (c)

Figure 5-1. Helical structures in biology and chemistry. (a) B-DNA, (b) α-helical peptide, (c)

left handed (top) and right handed (bottom) [7]helicene

The induced helical or axial chirality has been applied for determining the absolute configuration of chiral molecules based on their chiroptical properties. In 1996, Mazaleyrat 6 reported an unnatural amino acid incorporating a flexible biphenyl moiety (Scheme 5-1). According to the 1H NMR study, the axial enantiomers of this biphenyl group rapidly interconvert at ambient temperature but are separable at low temperature (i.e. 243K). The rotational barrier of the axial enantiomers was calculated to be 14 kcal/mol. In 2001, Rosini et al7 first controlled the equilibrium of the biphenyl structure by forming biphenyldioxolanes with chiral 1,2- or 1,3-diols (Figure 5-2a).

Although 1H NMR spectra showed that the diastereomeric ratio was modest (74:26 to 92:8), the prevailing sense of the twist of the biphenyl moiety resulted in predictable CD spectra which enabled one to determine the absolute configuration of chiral diols. Recently, this flexible biphenyl structure has further been applied for determining the absolute configuration of chiral acids8 and natural9 or unnatural amino acids10 (Figure 5-2b, 2c). However, the biphenyl chiraity sensors were

6 Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.; Tchertanov, L.; Guilhem, J. Tetrahedron Lett. 1996, 37, 2971. 7 Superchi, S.; Casarini, D.; Laurita, A.; Bavoso, A.; Rosini, C. Angew. Chem., Int. Ed. 2001, 40, 451. 8 Superchi, S.; Bisaccia, R.; Casarini, D.; Laurita, A.; Rosini, C. J. Am. Chem. Soc. 2006, 128, 6893. 9 Mazaleyrat, J.-P.; Wright, K.; Gaucher, A.; Toulemonde, N.; Wakselman, M.; Oancea, S.; Peggion, C.; Formaggio, F.; Setnička, V.; Keiderling, T. A.; Toniolo, C. J. Am. Chem. Soc. 2004, 126, 12874.

142 unable to quantitate enentiomeric excess of chiral analytes due to the incomplete induction of axial chirality from stereogenic center based chirality.

t t CO2 Bu CO2 Bu

NHBoc NHBoc

Scheme 5-1. Interconversion between P- and M-biphenyl-based α-amino acid

O R OMe R 2 O n O O NH N n R O M NHBoc Rs RL R1

(a) (b) (c)

Figure 5-2. Biphenyl analogs prepared from (a) diols, (b) acids, and (c) natural or unnatural

amino acids

In 2008, Alezra and Kouklovsky11 reported synthesis of quaternary α-amino acids using a tertiary aromatic amide for the memory of chirality (Scheme 5-2). Notably, a naphthyl group and a chiral bulky oxazolidin-5-one selectively generate axial chirality which is retained in the formation of enolate. When the enolate is attacked by an electrophile, the imprinted axial chirality on the enolate is subsequently transferred to the new stereogenic carbon center with high stereoselectivity

(78-96% ee). The diastereometic ratio of the starting amide was determined to be 100:12 by 1H

NMR spectroscopy at -78 oC. A control experiment replacing the naphthyl group with a phenyl group resulted in the formation of racemic products. This result supports the generation of axial

10 Dutot, L.; Wright, K.; Gaucher, A.; Wakselman, M.; Mazaleyrat, J.-P.; Zotti, M. D.; Peggion, C.; Formaggio, F.; Toniolo, C. J. Am. Chem. Soc. 2008, 130, 5986. 11 Branca, M.; Gori, D.; Guillot, R.; Alezra, V.; Kouklovsky, C. J. Am. Chem. Soc. 2008, 130, 5864. 143 chirality between the naphthyl group and the oxazolidin-5-one. Thus, this work represents an inventive idea of applying the induced axial chirality to the organic synthesis.

NH O O 2 base N N CO2H O O

- L-Val O O

Axial chirality generated Axial chirality retained O E-X NH2 N O CO2H 59-98% yield E 78-96% ee E O

Central chirality r egener ated

Scheme 5-2. Memory of axial chirality for the synthesis of quaternary α-amino acids

Although there has been much interest in stereoselective control of helical chirality, it is still challenging to generate helical chirality from stereogenic center-based chirality with a high degree of stereoselectivity. Even in natural peptides, a number of amino acid residues (L-form) are required collectively to favor the formation of the right handed helix over the left handed one. Scheraga12 calculated that the energy difference per residue is as small as a few tenths of a kcal/mol, and thus twenty residues would be expected to favor the right handed helix with a fraction of about 0.97 in the poly L-alanine molecule.

We became interested in finding minimal structural requirement of a receptor for generating helical chirality from amino acid chirality. If such receptor generates helical chirality with high stereospecificity, it will be useful not only to determine the absolute configuration but also to quantitate enantiomeric excess of amino acids. Moreover, the generation of helical chirality will

12 Scott, R. A.; Scheraga, H. A. J. Chem. Phys. 1966, 45, 2091. 144 provide valuable insight into both stereospecific folding13 and molecular recognition14 of natural or unnatural molecules. This chapter describes spectroscopic, crystallographic, and computational studies of a helical receptor for sensing amino acid enantiopurity.

5.2. Generation of helical chirality with a single amino acid

It has been reported that an enantiomeric pair of benzophenone exists in the crystal structure.15

According to the chirality notation, the left-handed or right-handed propeller structures are referred to as M- or P-conformer, respectively.16 Similarly, 2,2’-dihydroxybenzophenone (1) also exists as an equal mixture of rapidly interchanging P- and M-form in the solution (Scheme 5-3a). Compound

1 resembles [4]helicene in that they are both helical with four consecutive six-membered ring

(including hydrogen bonds in 1) (Figure 5-1c).

When excess of benzyl amine (10 equiv) was mixed with benzophenone derivatives (1 equiv) in DMSO-d6 (50 mM) at ambient temperature, the imines were readily formed with 2- hydroxybenzophenone and even faster with 2,2′-dihydroxybenzophenone (1). The measured

-5 -1 -4 -1 pseudo-first order rate constants are 3.67 × 10 s (t1/2 = 5.2 h) and 9.30 × 10 s (t1/2 = 12.4 min) for 2-hydroxybenzophenone and 1, respectively. Under the same conditions, it takes weeks to form imines with benzophenone. Thus, the two hydroxyl groups in 1 greatly activate the carbonyl group towards nucleophilic attack through double H-bonding. If the tetramethylammonium salt of alanine

13 Gellman, S. H. Acc. Chem. Res. 1998, 31, 173 14 (a) Wright, A. T.; Anslyn, E. V. Chem. Soc. Rev. 2006, 35, 14. (b) Castellano, R. K.; Nuckolls, C.; Rebek, J. Jr., J. Am. Chem. Soc. 1999, 121, 11156. (c) Park, H.; Kim, K. M.; Lee, A.; Ham, S.; Nam, W.; Chin, J. J. Am. Chem. Soc. 2007, 129, 1518. 15 (a) Fleischer, E. B.; Sung, N,; Hawkinson, S. J. Phys, Chem. 1968, 72, 4311. (b) Matsuura, T.; Koshima, H. J. Photochem. Photobiol., C: Photochem. Rev. 2005, 6, 7. 16 Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry, University Science Books, 2005.

145

(0.1 M) is added to a solution of 1 (0.1 M) in a protic solvent, such as CD3OD (Scheme 5-3c), two sets of signals are detected in the 1H NMR spectrum (Figure 5-3a). The two compounds in Scheme

5-3c are diastereomeric and are expected to give distinct NMR signals. However, if an aprotic

1 solvent, such as CD3CN is used (Scheme 5-3b), a remarkably clean H NMR spectrum results with just one set of signals (Figure 5-3b).

H H H O O H O O O O (a)

P-1 M-1

O O CH3 H -O O- H H O N H H H3C H N O O aprotic solvent O (b)

1-AL-G 1-AL-L

- - OOC CH3 H3C COO H H H O N H N O OH protic solvent OH (c)

L L 1-A -G* 1-A -L*

Scheme 5-3. Generating helical chirality in 2,2’-dihydroxybenzophenone 1 with a single amino

acid. AL = L-alanine, G = global minimum, L = local minimum.

146

Figure 5-3. The double signals in the 1H NMR spectrum of the alanine methyl group upon

formation of imine(s) with 1 in (a) CD3OD and (b) CD3CN.

Computation can be used to help explain the high stereospecificity for imine formation in an aprotic solvent such as CD3CN. DFT computation (B3LPY at the 6-31G(d) level) shows that the global minimum energy structure of the imine 1-AL-G formed between anionic L-alanine and 1 has two internal H-bonds (G in 1-AL-G stands for global energy minimum. Scheme 5-3b and Figure 5-

4a). One internal H-bond in 1-AL-G is a resonance-assisted hydrogen bond (RAHB)17,18 between the protonated imine and the phenonate oxyanion. The other internal H-bond in 1-AL-G is between alanine carboxylate anion and the remaining phenolic hydrogen atom. Such charged H-bonds are generally stronger than neutral H-bonds. The 1H NMR signals for the two H-bonds determined in

DMSO-d6 are shifted far downfield and are independent of concentration (Figure 5-5), as would be expected for strong intramolecular H-bonds.19 Comparing the structure of 1-AL-G and the structure of the receptor 1, it is evident that L-alanine generates axial chirality in the P form upon formation of the imine.

17 Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405. 18 Jeffrey, G. A. An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997. 19 Kumar, G. A.; McAllister, M. A. J. Org. Chem. 1998, 63, 6968.

147

(a) 1-AL-G (b) 1-AL-L

Figure 5-4. Computed structures of (a) 1-AL-G and (b) 1-AL-L at the B3LYP / 6-31G(d) level,

and crystal structures of (c) 1-AL-G* and (d) 1-AL-L* (thermal ellipsoids with 50% probability,

counter-cations are omitted for clarity). The structures in (a), (c) have helical chirality in the P

form; those in (b), (d) in the M form.

148

Figure 5-5. Concentration-dependent 1H NMR spectra of 1-AL-G (a) 20 mM, (b) 4.0 mM, (c)

0.8 mM, and (d) 0.2 mM in DMSO-d6

The second most stable minimum structure of the imine formed between anionic L-alanine and

1 is 1-AL-L (L in 1-AL-L stands for local energy minimum, Scheme 5-3b and Figure 5-4b). This local minimum structure also has the two strong internal H-bonds and is closely related to the structure of 1-AL-G. However, a comparison of the structures of the imine complexes and the receptor of the receptor (Scheme 5-3a and b) shows that 1-AL-L is in the M form whereas 1-AL-G is in the P form. It is likely that 1-AL-G and 1-AL-L are in equilibrium through rotation of the bond connecting the imine to one of the phenols. DFT computation shows that 1-AL-G is more stable than

1-AL-L by about 5.2 kcal/mol. It is interesting that the energy difference between 1-AL-G and 1-AL-

L is so large for such closely related and simple diastereomers with just two H-bonds. This energy difference translates to an equilibrium ratio of about 5.5 × 103 for [1-AL-G]/[1-AL-L] at 25 oC. Thus if both internal H-bonds are maintained in aprotic solvents, only one imine should form to any observable extent, as confirmed by 1H NMR spectroscopy (Figure 5-3b).

149

It is apparent from the computed structures that 1-AL-G is more stable than 1-AL-L owing to the relative positioning of the alanine methyl groups (Scheme 5-3b). The methyl group in 1-AL-G is positioned in an unhindered area, whereas the methyl group in 1-AL-L is in a sterically crowded area close to one of the phenol groups. Thus, L-alanine generates axial chirality in the P form stereospecifically upon formation of the imine complex in aprotic solvents (i.e., the equilibrium in

Scheme 5-3b favor 1-AL-G over 1-AL-L).

Protic solvents apprear to distrupt the charged internal H-bonds in 1-AL-G and 1-AL-L to give

1-AL-G* and 1-AL-L*, respectively (Scheme 5-3c). Indeed, crystal structures of 1-AL-G*20 and 1-

AL-L*21 reveal that the internal charged H-bonds can be broken while maintaining the resonance- assisted hydrogen bonds (Figure 5-4c and d). It appears that the weaker intramolecular H-bond breaks to form intermolecular H-bonds at the high concentrations required for crystallization.

Computation shows that 1-AL-G* and 1-AL-L* are of comparable energy,22 which is in agreement with the integration ratio of the two doublet signals in the 1H NMR spectrum (Figure 5-3a). Apart from using protic solvents, a base can be used in aprotic solvents to eliminate the stereospecificity by breaking the charged H-bond (Figure 5-6). Amino acid esters cannot form the charged H-bond and do not control the helical chirality (Figure 5-7).

20 L Crystal was grown in CH3NO2. Crystal data of 1-A -G*: C20.5H27.5N2.5O5, T = 150(2) K, , C 2/c, Z = 8, a = 3 37.757(3) Å, b = 7.4155(3) Å, c = 16.4442(12) Å, α = 90º, β = 115.008(3)º, γ = 90º, V = 4172.5(5) Å , R1 = 2 0.0580, wR2 = 0.1234 for I> 2σ(I), GOF on F = 1.015. At high concentrations required for crystallization, intermolecular charged H-bonds appear to be favored over the intramolecular one. 21 L Crystal was grown in CH3OH. Crystal data of 1-A -L*: C20H26N2O4, T = 150(2) K, , P 21/n, Z = 4, a = 3 11.7534(5) Å, b = 8.2201(5) Å, c = 23.1214(10) Å, α = 90º, β = 98.134(3)º, γ = 90º, V = 2211.38(19) Å , R1 2 = 0.0829, wR2 = 0.2389 for I> 2σ(I), GOF on F = 1.122. 22 The computed energy difference (DFT at the B3LYP 6-31G(d)) is 0.71 kcal/mol in favor of 1-AL-G* over 1- AL-L*. This value translates to an equilibrium constant of about 3.3 at 25 oC. 150

Figure 5-6. Partial 1H NMR spectra for addition of base (tetramethylammonium hydroxide,

L L TMAH) to 1-A -G in DMSO-d6: (a) 1-A -G, (b) 0.2 equiv of TMAH (c) 0.8 equiv of TMAH,

and (d) 1.0 equiv of TMAH.

H3C COOMe H3C COOMe H H O N H H N O

HO OH

1-A(OMe)L-G* 1-A(OMe)L-L*

ppm

Figure 5-7. 1H NMR spectra for the imine formed between 1 and L-alanine methyl ester

Helical contents of protein molecule are often measured with circular dichroism (CD) spectroscopy.23 CD spectroscopy has also been used to determine the absolute configurations and

23 Circular Dichroism: Principles and Applications; Nakanishi, K., Berova, N., Woody, R. W. Eds., Wiley- VCH: New York, 2nd ed. 2000.

151 the conformations of small organic molecules according to the exciton chirality method.24 This empirical approach has been applied for determining the absolute configuration of diols,29 diamines,25 biphenyls,26 binols27 and helicenes.28

CD spectra of 1-AL and 1-AD were taken in both protic and aprotic solvents. In a protic solvent like CH3OH where diasteromeric ratio was observed as 1:0.7 (Figure 5-3a), weak CD signals were measured (Figure 5-8b). Although small excess of one axial isomer give CD signals in CH3OH, these weak signals are too ambiguous to determine the absolute configuration of the diimine

L D complexes. On the contrary, in an aprotic solvent like CH3CN, 1-A -G and 1-A -G gave strong CD signals showing a perfect symmetric curve along with the x-axis (Figure 5-8a). The Cotton effects

(CD maxima) and UV-vis maxima are observed at 320 and 265 nm. Although the exciton coupling rule between the imine group (λmax = 320 nm) and the phenol group (λmax = 265 nm) can be used to determine the absolute configuration of 1-AL-G and 1-AD-G, the CD signals below 300 nm are likely to be disrupted by aromatic substituents of amino acids. Indeed, phenylalanine complexes (1-

FL-G and 1-FD-G) failed to show the Cotton effect at 320 nm despite the same UV-vis spectrum

(Figure 5-9). Thus, a modified helical receptor with isolated signalling region (> 300 nm) is required for developing a universal chirality sensor for the amino acid enantiopurity.

24 Harada, N.; Nakanishi, K. Acc. Chem. Res. 1972, 5, 257. 25 Kim, H.; Nguyen, Y.; Yen, C. P.-H.; Chagal, L.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 120, 12184. 26 Hosoi, S.; Kamiya, M.; Ohta, T. Org. Lett. 2001, 3, 3659. 27 Hanazaki, I.; Akimoto, H. J. Am. Chem. Soc. 1972, 94, 4102. 28 Martin, R. H. Angew. Chem., Int. Ed. Engl. 1974, 13, 649.

152

(a) 1-AL-G and 1-AD-G

(b) 1-AL-G* and 1-AD-G*

L D Figure 5-8. Circular dichroism spectra of 1-A and 1-A in (a) CH3CN and (b) CH3OH (100

μM, 1 cm cell, at 25 oC), and their UV-vis spectrum.

153

L D Figure 5-9 Circular dichroism spectra of 1-F -G and 1-F -G (100 μM in CH3CN, 1 cm cell, at

25 oC) and their UV-vis spectrum.

5.3. A universal sensor for amino acid enantiopurity

In order to amplify the signalling region of 1, we covalently attached diazo functional groups to the receptor 2 (Figure 5-10). Figure 5-10a shows the CD and UV spectra of the imines 2-AL-G and

2-AD-G formed between 2 and L-alanine and between 2 and D-alanine, respectively. A bisignate sign due to exciton coupling of the two hydroxyphenyl rings in 2-AL-G is observed around its UV maximum at 360 nm. The positive Cotton effect at 380 nm followed by the negative Cotton effect at

340 nm is in agreement with the computed structure (P helical chirality) of 2-AL-G (Figure 5-10).

Similarly the negative Cotton effect at 380 nm followed by the positive Cotton effect at 340 nm is in agreement with the structure of 2-AD-G (M helical chirality) formed with D-alanine.

154

(a)

O H3C O- (b) H H H O O O O N H CH H N 3 N O

N N N N N N azo

azo CH3 CH3 CH3 2 2-AL-G

Figure 5-10. (a) Circular dichroism spectra of 2-AL-G and 2-AD-G (50 μM in acetonitrile, 1

cm cell, at 25 oC) and their UV-vis spectrum. (b) Structure of 2 and 2-AL-G.

It is evident from Scheme 5-3 and the computational studies (Figure 5-4) that other natural or unnatural amino acids should behave similarly to alanine. Indeed, a wide variety of amino acids, including asparagines, phenylalanine, serine, and valine, all give one imine diastereomer each with

1 or 2 in aprotic solvent as shown by 1H NMR spectroscopy (see Appendix). Computation shows

155 that the stereospecificity increases with increase in the size of the amino acid side chain. Thus, alanine is expected to give the lowest stereospecificity (5500:1). Such a high degree of stereospecificity for generating helical chirality from stereogenic-center-based chirality has been observed with large biomolecules, such as proteins and nucleic acids, but not with small molecules.

CD spectra of the imines formed with different L-amino acids not only have the same bisignate sign

(P helicity) but they are also remarkably close in intensity (Figure 5-11 and Table 5-1). If the CDs were identical for different amino acids, a universal chirality sensor for all amino acids could be developed.

Figure 5-11. Overlay of circular dichroism spectra of imines formed from 2 and α-amino acids,

including alanine, asparagines, phenylalanine, serine, and valine (50 μM in acetonitrile, 1 cm

cell, at 25 oC).

156

Table 5-1. CD data for imines prepared from amino acids and 2 in CH3CN.

UV-vis1 CD2 Amino Ratio Acid 2 3 (mdegmax/Amax) Amax λMax (nm) mdegmax IP (nm)

L-Ala 1.84 360 64.5 361 35.0

L-Asn 1.84 355 67.8 355 36.8

L-Gln 2.06 363 77.4 357 37.6

L-Ile 2.02 363 66.2 363 32.8

L-Leu 2.11 363 69.6 362 33.0

L-Met 2.12 360 74.0 359 34.9

L-Phe 2.00 358 67.6 358 33.8

L-Ser 1.88 354 68.3 353 36.3

L-Thr 2.08 355 76.4 353 36.7

L-Trp 1.88 361 57.2 362 30.4

L-Tyr 1.96 360 66.0 359 33.7

L-Val 1.83 360 60.7 361 33.2

150 μM in acetonitrile, 1cm cell, at 25oC, 2ε / 10-4M-1cm-1, 3Isosbetic point

Our CD and 1H NMR spectroscopy results indicate that different α-amino acids form imines with 2 and generate helical chirality not only with the same sense but also with a high degree of stereospecificity. Thus 2 is an excellent chirality sensor for amino acids. There is an excellent correlation between CD absorption at 360 nm and enantiomeric excess of valine in the imine

157 complex formed with 2 (Figure 5-12). The crystal structure of the imine 2-VL-G*29 formed between

L-valine and 2 is analogous to that of 1-AL-G* (Figure 5-13). Although a variety of interesting chirality sensors have been developed for amino acids,30,31 none to date have been shown to interact with a high degree of stereospecificity. Previously reported sensors give different CD signals for different amino acids. In contrast, CD spectra obtained from the reaction of 2 and different amino acids are remarkably close (Table 5-1).

Figure 5-12. (a) CD Spectra of 2-V-G formed with valine of known enantiopurity (50 μM in

acetonitrile, 1 cm cell, at 25 oC). (b) Plot of CD absorption of 2-V-G at 360 nm vs

enantiopurity of valine.

29 L Crystal data of 2-V -G*: C36H44N6O5, Orthorhombic, T = 150(2) K, , P 21 21 21, Z = 4, a = 9.1543(3) Å, b 3 = 10.6637(5) Å, c = 39.7562(17) Å, α = 90º, β = 90º, γ = 90º, V = 3880.9(3) Å , R1 = 0.0615, wR2 = 0.1594 for I> 2σ(I), GOF on F2 = 1.092. 30 Folmer-Andersen, J. F.; Lynch, V. M.; Anslyn, E. V. J. Am. Chem. Soc. 2005, 127, 7986. 31 Borovkov, V. V.; Hembury, G. A.; Inoue, Y. Acc. Chem. Res. 2004, 37, 449.

158

(a) (b)

Figure 5-13. (a) Crystal structure of 2-VL-G* (thermal ellipsoid with 50% probability).

Counter-cation (tetramethylammonium) and water molecules are omitted for clarity. The

structural disorder of one phenol ring is shown. (b) Hydrogen bonds in the unit cell. All

hydrogens are omitted except ones in water, phenol, and iminium.

159

5.4. Conclusions

Generation of helical chirality with unprecedented stereospecificity has been achieved by imprinting of amino acid chirality onto a small molecule receptor 1. The control of the helical chirality is accomplished by an imine and two H-bonds between underivatized amino acids and the receptor. The excellent agreement between DFT computational and experimental data, including

CD and 1H NMR spectroscopy and X-ray crystallography, provides valuable insight into the origin of the stereospecificity. Furthermore, a universal chirality sensor 2 for amino acids has been developed by attaching a CD signal-amplifying group to 1.

5.5. Experimental

General Information

Commercially available compounds were used without further purification or drying. The 1H

NMR and 13C NMR spectra were recorded on a Varian Mercury 400 spectrometer or a Varian Unity

500 spectrometer. The High resolution mass spectra (HRMS) were obtained from the Department of

Chemistry, University of Toronto (ESI or EI). Circular dichroism spectra were taken with a JASCO

J-710 spectropolarimeter. UV-vis spectra were recorded on a PerkinElmer Lambda 900 spectrometer.

Preparation and characterization of 1-Amino acid

Typical procedure for synthesis of 1-Amino acid: To a stirred solution of 36.2 mg (0.20 mmol) of tetramethylammonium hydroxide pentahydrate and 0.22 mmol of DL-amino acid in 2.0 mL of methanol was added 42.8 mg (0.20 mmol) of 2,2′-dihydroxybenzophenone (1). The resulting

160 solution was stirred for 3 h at room temperature. After filtering the insoluble solid, all volatiles were removed under reduced pressure and the residue was dried in vacuo. The dried crude solid was dissolved again in minimum amount of methanol (less than 0.1 mL). Upon addition of diethyl ether

(2.0 mL) yellow solid precipitated out from the solution. The precipitate was filtered and dried to afford analytically pure 1-Amino aicdDL tetramethylammonium salt over 90% yield.

1-AlaDL

1 Yellow solid, 93% yield. H NMR (400 MHz, CD3CN): δ ppm 15.8 (br, 1H, RAHB OH); 13.4

(br, 1H, ArOH); 7.29 (ddd, J = 2.0, 7.1, 8.2 Hz, 1H, ArH); 7.19 (ddd, J = 2.0, 6.9, 8.3 Hz, 1H, ArH);

6.94-6.86 (m, 3H, ArH); 6.81 (dd, J = 0.9, 8.2 Hz, 1H, ArH); 6.63 (dd, J = 2.0, 7.9 Hz, 1H, ArH);

6.58 (ddd, J = 1.2, 6.9, 7.9 Hz, 1H, ArH); 3.96 (q, J = 6.4 Hz, 1H, C*H); 3.07 (s, 12H, TMA); 1.33

(d, J = 6.4 Hz, 3H, CH3).

1 H NMR (400 MHz, CD2Cl2): δ ppm 15.9 (br, 1H, RAHB OH); 7.31 (ddd, J = 2.1, 7.0, 8.2 Hz,

1H, ArH); 7.20 (ddd, J = 1.8, 7.1, 8.3 Hz, 1H, ArH); 7.00-6.90 (m, 3H, ArH); 6.84 (dd, J = 1.0, 8.3

Hz, 1H, ArH); 6.72 (dd, J = 1.7, 7.9 Hz, 1H, ArH); 6.57 (ddd, J = 1.2, 7.1, 8.0, 1H, ArH); 4.08 (q, J

= 6.5 Hz, 1H, C*H); 3.19 (s, 12H, TMA); 1.41 (d, J = 6.5 Hz, 3H, CH3).

1 H NMR (400 MHz, CD3OD): δ ppm 7.38-6.38 (m, 8H, ArH); 4.05, 4.00 (q, J = 6.9 Hz, 1H,

ArH); 3.19 (s, 12H, TMA); 1.55, 1.43 (d, J = 6.9 Hz, 3H, CH3).

1 H NMR (400 MHz, DMSO-d6): δ ppm 15.9 (br, 1H, RAHB OH); 13.6 (br, 1H, ArOH); 7.30

(ddd, J = 2.0, 7.1, 8.1 Hz, 1H, ArH); 7.23 (ddd, J = 2.4, 6.5, 8.3 Hz, 1H, ArH); 6.95-6.81 (m, 4H,

ArH); 6.62-6.56 (m, 2H, ArH); 3.83 (q, J = 6.5 Hz, 1H, C*H); 3.09 (s, 12H, TMA); 1.23 (d, J = 6.5

Hz, 3H, CH3).

13 C-NMR (100 MHz, DMSO-d6): δ ppm 171.9, 170.9, 163.1, 156.6, 131.8, 130.7, 130.4, 128.3,

123.2, 120.0, 119.8, 118.7, 117.4, 116.8 (14 sp2 carbons), 62.4, 54.4, 54.3, 54.3, 19.3 (5 sp3 carbons,

3 signals from tetramethylammonium).

161

1-AsnDL

1 Yellow solid, 90% yield. H NMR (400 MHz, DMSO-d6): δ ppm 15.5 (br, 1H, RAHB OH); 13.1

(br, 1H, ArOH); 7.28-7.24 (m 2H, ArH and NH); 7.19 (ddd, J = 1.8, 7.1, 8.2 Hz, 1H, ArH); 6.87-

6.82 (m, 3H, ArH); 6.78 (dd, J = 1.0, 8.2 Hz, 1H, ArH); 6.56-6.55 (m, 1H, ArH); 6.54 (s, 1H, NH);

6.50-6.47 (m, 1H, ArH); 4.16 (dd, J = 4.6, 8.5 Hz, 1H, C*H); 3.09 (s, 12H, TMA); 2.73 (dd, J = 4.6,

14.8 Hz, 1H, CH2); 2.46 (dd, J = 8.5, 14.8 Hz, 1H, CH2).

13 C-NMR (100 MHz, DMSO-d6): δ ppm 172.8, 171.7, 171.1, 162.6, 156.2, 131.7, 130.6, 130.2,

128.8, 123.6, 120.1, 119.7, 118.7, 117.2, 116.9 (15 sp2 carbons), 64.9, 64.7, 54.5, 54.4 54.3 (5 sp3 carbons).

1-PheDL

1 Yellow solid, 90% yield. H NMR (400 MHz, DMSO-d6): δ ppm 15.8 (br, 1H, RAHB OH); 13.3

(br, 1H, ArOH); 7.25-7.08 (m, 5H, ArH); 6.98-6.96 (m, 2H, ArH); 6.82 (dt, J = 0.9, 7.9, 2H, ArH);

6.65 (dt, J = 1.1, 7.4Hz, 1H, ArH); 6.55 (ddd, J = 1.2, 7.2, 8.3 Hz, 1H, ArH); 6.41 (dd, J = 1.6, 8.0

Hz, 1H, ArH); 5.85 (dd, J = 1.6, 7.5 Hz, 1H, ArH); 3.92 (dd, J = 3.2, 10.3 Hz, 1H, C*H); 3.22 (dd, J

= 3.2, 13.8 Hz, 1H, CH2); 3.10 (s, 12H, TMA); 2.89 (dd, J = 10.3, 13.8 Hz, 1H, CH2).

13 C-NMR (100 MHz, DMSO-d6): δ ppm 171.8, 171.1, 162.7, 156.2, 139.9, 131.8, 130.6, 130.2,

129.0, 127.9, 127.8, 125.5, 123.3, 119.8, 118.4, 117.2, 116.9 (17 sp2 carbons), 69.6, 54.4, 54.4, 54.3,

39.8 (5 sp3 carbons).

1-SerDL

1 Yellow solid, 94% yield. H NMR (400 MHz, DMSO-d6): δ ppm 15.6 (br, 1H, RAHB OH); 12.7

(br, 1H, ArOH); 7.28 (ddd, J = 3.1, 6.0, 8.1 Hz, 1H, ArH); 7.21 (ddd, J = 2.1, 6.8, 8.3 Hz, 1H, ArH);

6.92-6.80 (m, 4H, ArH); 6.61-6.54 (m, 2H, ArH); 4.89 (s, 1H, OH); 3.82-3.55 (m, 3H, CHCH2OH);

3.09 (s, 12H, TMA).

162

13 C-NMR (100 MHz, DMSO-d6): δ ppm 172.2, 171.5, 162.9, 155.9, 131.9, 130.6, 130.3, 128.5,

123.4, 120.0, 119.8, 119.1, 117.3, 116.9 (14 sp2 carbons), 68.5, 63.5, 54.5, 54.4, 54.3 (5 sp3 carbons).

1-ValDL

1 Yellow solid, 92% yield. H NMR (400 MHz, DMSO-d6): δ ppm 16.1 (br, 1H, RAHB OH); 13.4

(br, 1H, ArOH); 7.29 (ddd, J = 2.0, 7.1, 8.2 Hz, 1H, ArH); 7.23 (ddd, J = 2.6, 6.3, 8.3 Hz, 1H, ArH);

6.92-6.82 (m, 4H, ArH); 6.62-6.56 (m, 2H, ArH); 3.58 (d, J = 4.7 Hz, 1H, C*H); 3.09 (s, 12H,

TMA); 2.27 (dq, J = 4.7, 6.8 Hz, 1H, CH(CH3)2); 0.91 (d, J = 6.8 Hz, CH3); 0.75 (d, J = 6.8 Hz,

CH3).

13 C-NMR (100 MHz, DMSO-d6): δ ppm 172.2, 170.9, 163.4, 156.6, 131.8, 130.6, 130.3, 128.3,

123.3, 120.0, 119.8, 118.8, 117.4, 116.6 (14 sp2 carbons), 73.0, 54.4, 54.4, 54.3 29.8, 20.6, 18.2 (7 sp3 carbons).

Preparation and characterization of 2 and 2-Amino acidDL

o Synthesis of 2: A cooled (5 C) solution containing NaNO2 (10.5 mmol) and water (7.5 mL) was slowly added to a cooled solution of p-toluidine (10.5 mmol), 6M HCl (3.4 mL) and water (7.5 mL) to form the diazonium salt. The diazonium salt solution was then added drop-wise to a cooled solution of 2,2′-dihydroxybenzophenone (1, 5.0 mmol) dissolved in dilute sodium hydroxide (500 mg in 7.5 mL). The resulting solution was stirred for 2 h. To precipitate the azo-dye, the solution was acidified with 6 M HCl. The precipitate was filtered off and recrystallized from MeOH to give the compound 2 as a dark brown solid in 60% yield.

1 H NMR (400 MHz, DMSO-d6): δ ppm 11.4 (s, 2H, OH); 8.04 (dd, J = 2.5, 8.8 Hz, 2H, ArH);

7.97 (d, J = 2.5 Hz, 2H, ArH); 7.74 (d, J = 8.3 Hz, 4H); 7.36 (d, J = 8.3 Hz, 4H, ArH); 7.18 (d, J =

8.8Hz, 2H, ArH); 2.38 (s, 6H, CH3).

13 C-NMR (100 MHz, DMSO-d6): δ ppm 198.8, 160.3, 149.9, 144.6, 141.2, 129.9, 127.4, 126.5,

163

124.4, 122.3, 117.9 (11 sp2 carbons), 21.0 (1 sp3 carbon).

+ HRMS (ESI) calculated for C27H23N4O3 [M+H] : 451.1764. Found: 451.1755.

Typical procedure for synthesis of 2-Amino acid: To a stirred solution of 72.4 mg (0.40 mmol) of tetramethylammonium hydroxide pentahydrate and 0.40 mmol of DL-amino acid in 2.0 mL of methanol was added 90.1 mg (0.20 mmol) of compound 2. The resulting solution was stirred for 3 hours at room temperature. After adding 0.20 mmol of TFA, the mixture was filtered to remove excess of amino acid. All volatiles were removed under reduced pressure and the residue was dried in vacuum. The dried crude solid was recrystallized with THF and diethyl ether to give 2-Amino acidDL tetraammonium salt as a red solid over 90% yield.

2-PheDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.85 (dd, J = 2.6, 9.3 Hz, 1H, ArH); 7.81 (dd, J = 2.3, 8.8

Hz, 1H, ArH); 7.71 (d, J = 8.3 Hz, 2H, ArH); 7.56 (d, J = 8.3 Hz, 2H, ArH); 7.32 (d, J = 8.3 Hz, 2H,

ArH); 7.31 (s, 1H, ArH); 7.21 (d, J = 8.3 Hz, 2H, ArH); 7.18 – 7.02 (m, 6H, ArH); 6.81 (d, J = 9.2

Hz, 1H, ArH); 6.50 (d, J = 2.4 Hz, 1H, ArH); 4.16 (dd, J = 3.5, 10.0 Hz, 1H, C*H); 3.28 (dd, J = 3.5,

13.6 Hz, 1H, CH2); 3.10 (m, 1H, CH2); 3.05 (s, 12H, TMA); 2.39 (s, 3H, ArCH3); 2.31 (s, 3H,

ArCH3). Two hydrogen-bond peaks are not visible possibly due to solubility.

13 C-NMR (125 MHz, CD3CN): δ ppm 174.7, 173.5, 173.0 162.4, 151.7, 151.6, 144.5, 142.7,

141.7, 141.3, 135.4, 132.8, 130.8, 130.6, 130.4, 129.2, 127.4, 127.4, 125.6, 124.6, 123.2, 122.9,

120.8, 119.3, 117.6, 117.5 (26 sp2 carbons), 56.1, 56.0, 56.0 (tetramethyl ammonium), 68.2, 41.5,

21.5, 21.4 (4 sp3 carbons)

2-AlaDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.96 (d, J = 8.4 Hz, 1H, ArH); 7.88 (dd, J = 2.2, 8.9 Hz,

164

1H, ArH); 7.72 (d, J = 8.3 Hz, 2H, ArH); 7.68 (d, J = 2.2 Hz, 1H, ArH); 7.60 (d, J = 8.3 Hz, 2H,

ArH); 7.44 (d, J = 2.2 Hz, 1H, ArH); 7.32 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.1, 2H, ArH); 7.03

(d, J = 8.4 Hz, 1H, ArH); 6.96 (d, J = 8.9 Hz, 1H, ArH); 4.24 (q, J = 6.3 Hz, 1H, C*H); 3.08 (s, 12H,

TMA); 2.39 (s, 3H, ArCH3); 2.35 (s, 3H, ArCH3); 1.40 (d, J = 6.3 Hz, 3H, CH3).

2-AsnDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.97 (dd, J = 2.4, 8.8 Hz, 1H, ArH); 7.88 (dd, J = 2.4, 9.0

Hz, 1H, ArH); 7.74 (d, J = 8.3 Hz, 2H, ArH); 7.66 (d, J = 2.4 Hz, 1H, ArH); 7.60 (d, J = 8.3 Hz, 2H,

ArH); 7.38 (d, J = 2.4 Hz, 1H, ArH); 7.33 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.2, 2H, ArH); 7.07

(d, J = 8.8 Hz, 1H, ArH); 6.99 (d, J = 9.0 Hz, 1H, ArH); 6.63 (s, 1H, NH); 5.51 (s, 1H, NH); 4.46

(dd, J = 5.7, 6.6 Hz, 1H, C*H); 3.08 (s, 12H, TMA); 2.86 (dd, J = 5.7, 15.0 Hz, 1H, CH2); 2.71 (dd,

J = 6.6, 15.0 Hz, 1H, CH2); 2.40 (s, 3H, ArCH3); 2.35 (s, 3H, ArCH3).

2-GlnDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.95 (dd, J = 1.4, 8.5 Hz, 1H, ArH); 7.89 (dd, J = 2.5, 9.0

Hz, 1H, ArH); 7.73 (d, J = 8.3 Hz, 2H, ArH); 7.70 (d, J = 2.3 Hz, 1H, ArH); 7.60 (d, J = 8.3 Hz, 2H,

ArH); 7.44 (d, J = 2.4 Hz, 1H, ArH); 7.32 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.2, 2H, ArH); 7.04

(d, J = 8.9 Hz, 1H, ArH); 6.98 (dd, J = 2.0, 8.9 Hz, 1H, ArH); 6.17 (s, 1H, NH); 5.39 (s, 1H, NH);

4.12 (dd, J = 3.3, 8.0 Hz, 1H, C*H); 3.08 (s, 12H, TMA); 2.39 (s, 3H, ArCH3); 2.35 (s, 3H, ArCH3);

2.24 – 1.99 (m, 4H).

2-IleDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.94 (d, J = 8.9 Hz, 1H, ArH); 7.89 (d, J = 9.1 Hz, 1H,

ArH); 7.71 (d, J = 8.0 Hz, 2H, ArH); 7.63 (s, 1H, ArH); 7.59 (d, J = 8.0 Hz, 2H, ArH); 7.45 (s, 1H,

ArH); 7.31 (d, J = 8.0 Hz, 2H, ArH); 7.24 (d, J = 8.0 Hz, 2H, ArH); 6.99 (d, J = 8.6 Hz, 1H, ArH);

165

6.92 (d, J = 9.1 Hz, 1H, ArH); 4.00 (d, J = 4.8 Hz, 1H, C*H); 3.07 (s, 12H, TMA); 2.39 (s, 3H,

ArCH3); 2.35 (s, 3H, ArCH3); 2.14 – 2.11 (m, 1H); 1.77 – 1.72 (m, 1H); 1.19 – 1.12 (m, 1H); 0.92 –

0.87 (m, 6H).

2-LeuDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.93 (dd, J = 2.0, 8.9 Hz, 1H, ArH); 7.89 (dd, J = 2.5, 9.1

Hz, 1H, ArH); 7.70 (d, J = 8.3 Hz, 2H, ArH); 7.66 (d, J = 2.4 Hz, 1H, ArH); 7.60 (d, J = 8.3 Hz, 2H,

ArH); 7.49 (d, J = 2.2 Hz, 1H, ArH); 7.31 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.2 Hz, 2H, ArH);

7.02 (d, J = 7.7 Hz, 1H, ArH); 6.92 (d, J = 9.1 Hz, 1H, ArH); 4.15 (t, J = 6.7 Hz, 1H, C*H); 3.08 (s,

12H, TMA); 2.39 (s, 3H, ArCH3); 2.35 (s, 3H, ArCH3); 1.80 (t, J = 6.7 Hz, 2H, CH2CH(CH3)2);

1.57 (tt, J = 6.7, 13.7 Hz, 1H, CH2CH(CH3)2); 0.86 (d, J = 6.7 Hz, 3H, CH3); 0.63 (d, J = 6.7 Hz,

3H, CH3).

2-MetDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.93 (dd, J = 2.0, 8.7 Hz, 1H, ArH); 7.89 (dd, J = 2.4, 9.1

Hz, 1H, ArH); 7.71 (d, J = 8.2 Hz, 2H, ArH); 7.69 (s, 1H, ArH); 7.60 (d, J = 8.2 Hz, 2H, ArH); 7.45

(d, J = 2.3, 1H, ArH); 7.31 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.2 Hz, 2H, ArH); 7.03 (d, J = 8.8

Hz, 1H, ArH); 6.95 (d, J = 9.1 Hz, 1H, ArH); 4.24 (dd, J = 4.3, 8.1 Hz, 1H, C*H); 3.08 (s, 12H,

TMA); 2.59 – 2.52 (m, 1H); 2.39 (s, 3H, ArCH3); 2.35 (s, 3H, ArCH3); 2.29 – 2.52 (m, 1H); 2.11 –

2.02 (m, 1H); 1.96 (s, 3H, SCH3).

2-SerDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.95 (dd, J = 2.4, 8.8 Hz, 1H, ArH); 7.85 (dd, J = 2.4, 8.9

Hz, 1H, ArH); 7.71 (d, J = 8.3 Hz, 2H, ArH); 7.65 (d, J = 2.4 Hz, 1H, ArH); 7.56 (d, J = 8.3 Hz, 2H,

ArH); 7.35 (d, J = 2.4 Hz, 1H, ArH); 7.29 (d, J = 8.2 Hz, 2H, ArH); 7.22 (d, J = 8.2, 2H, ArH); 7.09

166

(d, J = 8.8 Hz, 1H, ArH); 6.97 (d, J = 8.9 Hz, 1H, ArH); 4.12 (t, J = 5.4 Hz, 1H, C*H); 3.85 (dd, J =

5.4, 10.9 Hz, 1H, CH2); 3.80 (dd, J = 5.4, 10.9 Hz, 1H, CH2); 3.07 (s, 12H, TMA); 2.39 (s, 3H,

ArCH3); 2.35 (s, 3H, ArCH3).

2-ThrDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.97 (dd, J = 2.2, 8.7 Hz, 1H, ArH); 7.90 (dd, J = 2.5, 9.1

Hz, 1H, ArH); 7.73 (d, J = 8.3 Hz, 2H, ArH); 7.66 (d, J = 2.4 Hz, 1H, ArH); 7.60 (d, J = 8.3 Hz, 2H,

ArH); 7.40 (d, J = 2.4 Hz, 1H, ArH); 7.32 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.2, 2H, ArH); 7.13

(d, J = 8.8 Hz, 1H, ArH); 6.97 (d, J = 9.1 Hz, 1H, ArH); 4.14 (dq, J = 2.5, 6.4 Hz, CH(OH)CH3);

4.02 (d, J = 2.5 Hz, 1H, C*H); 3.08 (s, 12H, TMA); 2.39 (s, 3H, ArCH3); 2.35 (s, 3H, ArCH3); 1.04

(d, J = 6.4 Hz, 3H, CH3).

2-TrpDL

1 H NMR (400 MHz, CD3CN): δ ppm 9.03 (s, 1H, NH); 7.85 (dd, J = 2.5, 9.1 Hz, 1H, ArH); 7.74

(dd, J = 2.5, 8.8 Hz, 1H, ArH); 7.70 (d, J = 8.3 Hz, 2H, ArH); 7.55 (d, J = 8.3 Hz, 2H, ArH); 7.35 (d,

J = 8.2 Hz, 2H, ArH); 7.29 (d, J = 8.0 Hz, 1H, ArH); 7.26 (d, J = 2.2 Hz, 2H, ArH); 7.22 (d, J = 8.2

Hz, 2H, ArH); 7.21 (d, J = 8.0 Hz, 1H, ArH); 6.93 – 6.81 (m, 4H, ArH); 6.66 (t, J = 7.5 Hz, 1H,

ArH); 6.44 (s, 1H, CHNH); 4.34 (dd, J = 3.8, 9.5 Hz, 1H, C*H); 3.45 – 3.39 (m, 1H, CH2); 3.23 –

3.18 (m, 1H, CH2); 3.05 (s, 12H, TMA); 2.42 (s, 3H, ArCH3); 2.33 (s, 3H, ArCH3).

2-TyrDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.87 (t, J = 10.0 Hz, 2H, ArH); 7.76 (d, J = 7.9 Hz, 2H,

ArH); 7.57 (d, J = 7.9 Hz, 2H, ArH); 7.34 (d, J = 7.9 Hz, 2H, ArH); 7.31 (s, 1H, ArH); 7.24 (d, J =

7.9 Hz, 2H, ArH); 6.97 – 6.76 (m, 5H, ArH); 6.57 (d, J = 7.9 Hz, 2H, ArH); 4.29 – 4.26 (m, 1H,

C*H); 3.24 – 3.15 (m, 2H, CH2); 3.06 (s, 12H, TMA); 2.41 (s, 3H, ArCH3); 2.34 (s, 3H, ArCH3).

167

2-ValDL

1 H NMR (400 MHz, CD3CN): δ ppm 7.96 (d, J = 8.2 Hz, 1H, ArH); 7.89 (dd, J = 2.3, 9.1 Hz,

1H, ArH); 7.72 (d, J = 8.3 Hz, 2H, ArH); 7.65 (d, J = 2.2 Hz, 1H, ArH); 7.60 (d, J = 8.3 Hz, 2H,

ArH); 7.45 (d, J = 2.4, 1H, ArH); 7.32 (d, J = 8.2 Hz, 2H, ArH); 7.25 (d, J = 8.3 Hz, 2H, ArH); 7.04

(d, J = 8.2 Hz, 1H, ArH); 6.95 (d, J = 9.1 Hz, 1H, ArH); 3.97 (d, J = 4.3 Hz, 1H, C*H); 3.08 (s, 12H,

TMA); 2.39 (s, 3H, ArCH3); 2.38 (m, 1H, CH(CH3)2); 2.35 (s, 3H, ArCH3); 1.04 (d, J = 6.6 Hz, 3H,

CH3); 0.88 (d, J = 6.6 Hz, 3H, CH3).

168

CONCLUSIONS

This thesis presents simple and general protocols for preparing chiral vicinal diamines and for generating helical chirality with amino acids on the basis of H-bond directed stereospecific interactions. In Chapter 2, I report the synthetic utility of chiral 1,2-bis(2-hydroxyphenyl)-1,2- diaminoethane (HPEN) in the synthesis of chiral vicinal diamines by the resonance assisted H-bond

(RAHB)-directed diaza-Cope rearrangement reaction. This process requires only HPEN and aldehydes as substrates to afford a wide range of chiral vicinal diamines including C2-symmetrical diaryl and dialkyl diamines as well as unsymmetrical aryl-aryl and alkyl-aryl diamines with excellent yields and enantiopurities. It is shown that the hydroxyl groups in HPEN not only provide thermodynamic driving forces by forming RAHBs but also suppress side reactions by forming fused imidazolidine-dihydro-1,3-oxazine ring intermediates with alkyl aldehydes .

Chiral vicinal diamines prepared by our protocol have been applied for understanding the effect of weak forces in the diaza-Cope rearrangement and for tuning stereoselective catalysts. In

Chapter 3, I report combined experimental and computational studies in order to reveal thermodynamic and kinetic effects of weak forces such as hydrogen bonding effects, electronic effects, steric effects, and oxyanion effects on the diaza-Cope rearrangement. The findings show that (a) all weak forces studied can be independently or cooperatively used to drive the diaza-Cope rearrangement reaction; (b) electronic effects are predictable by the Hammett equation; (c) significant steric strains are released by mesityl groups in TPEN; (d) oxyanion effect is found to be the strongest weak force; and (e) DFT computation can successfully evaluate all of the above weak force interactions. In Chapter 4, I report vicinal diamine-catalyzed stereoselective synthesis of warfarin. Based on a proposed mechanism involving diimine intermediate, tuning of the diamine structure with respect to the NCCN dihedral angle increases the stereoselectivity up to 92% ee.

169

In Chapter 5, I report a helical receptor, 2,2′-dihydroxybenzophenone, where helicity can be controlled with just two H-bonds from a single amino acid. The excellent agreement between experimental and computational data provides valuable insight into the origin of stereospecific helical turns. The signaling azo groups attached at the para position of the phenols allow sensing of amino acid enantiopurity by circular dichroism spectroscopy.

170

PUBLICATIONS

1. Hyunwoo Kim, Mima Staikova, Alan J. Lough, and Jik Chin Stereospecific Synthesis of Alkyl-Substituted Vicinal Diamines from the Mother Diamine: Overcoming the “Intrinsic Barrier” to the Diaza-Cope Rearrangement Reaction Org. Lett. 2009, 11, 151. Reproduced with permission from Org. Lett. Copyright 2009 American Chemical Society.

2. Hyunwoo Kim, Soon Mog So, B. Moon Kim, and Jik Chin Preparation of Chiral Diamines by the Diaza-Cope Rearrangement (DCR) Aldrichimica Acta 2008, 41, 77. Reproduced in part with permission from Aldrichimica Acta. Copyright 2009 Aldrich.

3. Hyunwoo Kim, Yen Nguyen, Cindy Pai-Hui Yen, Leonid Chagal, Alan J. Lough, B. Moon Kim, and Jik Chin

Stereospecific Synthesis of C2 Symmetrical Diamines from the Mother Diamine by Resonance- Assisted Hydrogen-Bond Directed Diaza-Cope Rearrangement J. Am. Chem. Soc. 2008, 130, 12184. Reproduced with permission from J. Am. Chem. Soc. Copyright 2009 American Chemical Society.

4. Hyunwoo Kim, Yen Nguyen, Alan J. Lough, and Jik Chin Stereospecific Diaza-Cope Rearrangement Driven by Steric Strain Angew. Chem. Int. Ed. 2008, 47, 8678. Reproduced with permission from Angew. Chem. Int. Ed. Copyright 2009 Wiley-VCH.

5. Hyunwoo Kim, Soon Mog So, Cindy Pai-Hui Yen, Elisangela Vinhato, Alan J. Lough, Jong-In Hong, Hae-Jo Kim, and Jik Chin. Highly Stereospecific Generation of Helical Chirality by Imprinting with Amino Acids: A Universal Sensor for Amino Acid Enantiopurity Angew. Chem. Int. Ed. 2008, 47, 8657. Reproduced with permission from Angew. Chem. Int. Ed. Copyright 2009 Wiley-VCH.

6. Hyunwoo Kim, Doo Seoung Choi, Cindy Pai-Hui Yen, Alan J. Lough, Choong Eui Song, and Jik Chin

171

7. Hae-Jo Kim, Hyunwoo Kim, Gamil Alhakimi, Eui June Jeong, Nirusha Thavarajah, Lisa Studnicki, Alicja Koprianiuk, Alan, J. Lough, Junghun Suh, and Jik Chin Preorganization in Highly Enantioselective Diaza-Cope Rearrangement Reaction J. Am. Chem. Soc. 2005, 127, 16370. Reproduced with permission from J. Am. Chem. Soc. Copyright 2009 American Chemical Society.

8. Hyunwoo Kim, Cindy Yen, Pilippa Preston, and Jik Chin Substrate-Directed Stereoselectivity in Vicinal Diamine-Catalyzed Synthesis of Warfarin Org. Lett. 2006, 8, 5239. Reproduced with permission from Org. Lett. Copyright 2009 American Chemical Society.

All compounds in this thesis were synthesized and characterized by the author. I wish to thank

the following coworkers and collaborators for their assistance.

Chapter 1: Dr. Soon Mog So and Prof. B. Moon Kim for helpful discussion

Chapter 2: Prof. Hae-Jo Kim for preliminary experiment. Yen Nguyen, Cindy Yen, and

Leonid Chagal for experimental assistance. Dr. Doo Seoung Choi for NMR experiment of the

diastereoselective rearrangement.

Chapter 3: Leo Mui and Dr. Elisângela Vinhato for NMR experiment of electronic effect-

driven diaza-Cope rearrangement. Yen Nguyen for NMR experiment of oxyanion-driven diaza-

Cope rearrangement

Chapter 4: Cindy Yen for preliminary mechanistic experiment. Phillippa Preston for

experimental assistance.

Chapter 5: Prof. Hae-Jo Kim for preliminary experiment. Dr. Soon Mog So and Cindy Yen for

experimental assistance.

172

Appendix I

Selected NMR Spectra

F F F F NH3Cl F F NH Cl F 3 F F II-3a F

1 H-NMR (400 MHz, CD3OD): δ 5.66 (s, 2H, C*H); 4.95 (br s, 6H, NH3)

19 F-NMR (376 MHz, CD3OD): δ -141.8, -151.0, -162.0.

173

O2N

NH3Cl

O2N II-3b

Residual THF (0.8 w/w %)

1 H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 6H, NH3); 8.15 (d, J = 8.8 Hz, 4H, ArH); 7.74 (d, J = 8.8 Hz, 4H, ArH); 5.41 (s, 2H, C*H).

13 C-NMR (100 MHz, DMSO-d6): δ 147.7, 139.9, 130.4, 123.6 (4 aromatic carbons), 55.7 (1 aliphatic carbon).

174

MeO2C

NH3Cl

MeO2C II-3c

1 H-NMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.4 Hz, 4H, ArH); 7.49 (d, J = 8.4 Hz, 4H, ArH); 5.23

(s, 2H, C*H); 4.86 (br s, 6H, NH3); 3.80 (s, 6H, CH3).

13 C-NMR (100 MHz, CD3OD): δ 168.5 (1 carbonyl carbon), 138.1, 132.0, 131.2, 129.6 (4 aromatic carbons), 58.1, 53.5 (2 aliphatic carbons).

175

NH3Cl

F II-3d

1 H-NMR (400 MHz, CD3OD): δ 7.39 (dd, J = 6.8, 11.6 Hz, 4H, ArH); 7.09 (t, J = 11.6 Hz, 4H,

ArH); 5.11 (s, 2H, C*H); 4.86 (br s, 6H, NH3).

13 C-NMR (100 MHz, DMSO-d6): δ 162.1 (d, J = 245 Hz), 131.2 (d, J = 8 Hz), 129.6 (d, J = 3 Hz), 115.4 (d, J = 21 Hz) (4 aromatic carbons), 56.0 (1 aliphatic carbon).

176

NH3Cl

Cl II-3e

1 H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 6H, NH3); 7.42 (d, J = 8.8 Hz, 4H, ArH); 7.36 (d, J = 8.8 Hz, 4H, ArH); 5.17 (s, 2H, C*H).

13 C-NMR (100 MHz, DMSO-d6): δ 133.8, 132.0, 130.8, 128.5 (4 aromatic carbons), 55.9 (1 aliphatic carbon).

177

F3C

NH3Cl

F3C II-3f

1 H-NMR (400 MHz, DMSO-d6): δ 9.42 (s, 6H, NH3); 7.70 (d, J = 8.0 Hz, 4H, ArH); 7.63 (d, J = 8.0 Hz, 4H, ArH); 5.28 (s, 2H, C*H).

13 C-NMR (100 MHz, DMSO-d6): δ 137.4, 129.8, 129.5 (q, J = 32 Hz), 125.4 (q, J = 3 Hz), 123.8 (q, J = 271 Hz), 56.0.

178

NH3Cl

NC II-3g

1 H-NMR (400 MHz, D2O): δ 7.77 (d, J = 8.4 Hz, 4H, ArH); 7.44 (d, J = 8.4 Hz, 4H, ArH); 5.16 (s, 2H, C*H).

13 C-NMR (100 MHz, CD3OD): δ 138.7, 143.4, 130.8, 119.0, 114.7 (5 aromatic and sp carbons), 58.2 (1 aliphatic carbon).

179

AcHN

NH3Cl

AcHN II-3h

1 H-NMR (400 MHz, D2O): δ 7.48 (d, J = 8.8 Hz, 4H, ArH); 7.25 (d, J = 8.8 Hz, 4H, ArH); 5.07 (s,

2H, C*H); 2.18 (s, 6H, CH3).

13 C-NMR (100 MHz, D2O/CD3OD): δ 170.1, 139.8, 128.6, 125.7, 119.3 (5 aromatic and carbonyl carbons), 56.1, 22.2(2 aliphatic carbons).

180

MeO

NH3Cl

MeO II-3i

Residual THF (1.5 w/w %)

1 H-NMR (400 MHz, DMSO-d6): δ 9.20 (s, 6H, NH3); 7.27 (d, J = 8.8 Hz, 4H, ArH); 6.83 (d, J = 8.8

Hz, 4H, ArH); 5.00 (s, 2H, C*H); 3.69 (s, 6H, OCH3).

13 C-NMR (100 MHz, DMSO-d6): δ 159.4, 130.1, 125.2, 113.8 (4 aromatic carbons), 56.2, 55.1 (2 aliphatic carbons).

181

NH3Cl

HO II-3j

1 H-NMR (400 MHz, D2O): δ 7.17 (d, J = 8.8 Hz, 4H, ArH); 6.95 (d, J = 8.8 Hz, 4H, ArH); 5.02 (s, 2H, C*H).

Reference CH3OH

13 C-NMR (100 MHz, D2O, CH3OH as reference): δ 157.7, 130.6, 122.7, 116.6 (4 aromatic carbons), 56.9 (1 aliphatic carbon).

182

Me2N

NH2 4HCl NH2

Me2N II-3k

1 H-NMR (400 MHz, D2O): δ 7.62 (d, J = 8.8 Hz, 4H, ArH); 7.52 (d, J = 8.8 Hz, 4H, ArH); 5.22 (s,

2H, C*H); 3.25 (s, 12H, CH3).

Reference CH3OH

13 C-NMR (100 MHz, D2O, CH3OH as reference): δ 144.0, 133.8, 131.1, 122.3 (4 aromatic carbons), 56.9, 46.8 (2 aliphatic carbons).

183

OMe

NH2

OMe II-3l

1 H-NMR (300 MHz, CDCl3): δ 7.23 (dd, J = 1.8, 9.0 Hz, 2H, ArH); 7.12 (dt, J = 1.8, 7.5 Hz, 2H, ArH); 6.82 (dt, J = 1.2, 7.5 Hz, 2H, ArH); 6.76 (dd, J = 1.2, 8.1 Hz, 2H, ArH); 4.46(s, 2H, C*H),

3.78 (s, 6H, OCH3).

13 C-NMR (75 MHz, CDCl3): δ 157.1, 132.4, 128.2, 127.8, 120.5, 110.5 (6 aromatic carbons), 55.6, 55.4 (2 aliphatic carbons).

184

NH3Cl

Cl II-3m

1 H-NMR (400 MHz, DMSO-d6): δ 9.64 (s, 6H, NH3); 8.09 (d, J = 6.8 Hz, 2H, ArH); 7.35-7.24 (m, 6H, ArH); 5.60 (s, 2H, C*H).

13 C-NMR (100 MHz, DMSO-d6): δ 132.9, 131.2, 131.0, 129.5, 129.4, 127.5 (6 aromatic carbons), 52.7 (1 aliphatic carbon).

185

NH2

Me II-3n

1 H-NMR (300 MHz, CDCl3): δ 7.58 (dd, J = 1.2, 7.6 Hz, 2H, ArH); 7.19 (dt, J = 1.2, 7.2 Hz, 2H, ArH); 7.09 (dt, J = 1.5, 7.2Hz, 2H, ArH); 7.01 (d, J = 7.6 Hz, 2H, ArH); 4.34 (s, 2H, C*H); 2.12 (s,

6H, ArCH3)

13 C-NMR (75 MHz, CDCl3): δ 142.0, 135.4, 130.5, 127.0, 126.9, 126.1 (6 aromatic carbons), 56.0, 19.8 (2 aliphatic carbons).

186

NH3Cl

II-3o

1 H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 6H, NH3); 8.37 (d, J = 7.2 Hz, 2H, ArH); 8.20 (d, J = 6.4 Hz, 2H, ArH); 7.70 (d, J = 8.0 Hz, 2H, ArH); 7.58 (d, J = 8.0 Hz, 4H); 7.43 (t, J = 7.2 Hz, 2H); 7.16 (t, J = 7.6 Hz, 2H, ArH); 6.43 (s, 2H, C*H).

13 C-NMR (100 MHz, D2O/DMSO-d6): δ 134.5, 131.9, 131.3, 130.3, 130.2, 129.0, 128.0, 126.8, 126.6, 123.5 (10 aromatic carbons), 53.1 (1 aliphatic carbon).

187

MeO OMe

NH3Cl MeO MeO NH3Cl OMe MeO II-3p

Reference CH3OH

1 H-NMR (400 MHz, D2O, CH3OH as reference): δ 6.21 (s, 4H, ArH); 5.51 (s, 2H, C*H); 3.81 (s,

6H, OCH3); 3.70 (s, 12H, OCH3).

13 C-NMR (100 MHz, DMSO-d6): δ 161.8, 159.6, 158.2, 101.8, 90.5, 90.3 (6 aromatic carbons), 55.8, 55.7, 55.4, 46.0 (4 aliphatic carbons).

188

HN N HO O

II-6a

189

OH HO

N N

II-8a

190

OH HO

N N

II-8b

191

OH HO

N N

II-8c

192

OH HO

N N

II-8e

193

ClH3N

II-9a

194

ClH3N

II-9b

195

ClH3N

ClH3N II-9c

196

ClH3N

ClH3N II-9e

197

OH H N Cl N H OH II-10a

ppm

198

OH Cl H N Cl N H OH II-10b

ppm

ClH3N

Cl II-11a

ppm

199

Cl Cl

H2N

H2N Cl II-11b

ppm

200

Cl Cl

H2N

H2N HO II-11c

ppm

201

H2N

NO2 II-11d

ppm

202

NH2 NH2 H2N N NH2

Cl Cl II-11e

ppm

203

OH F

OH II-13a

ppm

OH F

OH II-13b

ppm

204

OH F

OH II-13c

ppm

OH Cl

OH II-13d

ppm

205

1H NMR spectrum for diastereoselective reaction between (R)-(-)-myrtenal and racemic 1,2- bis(2-hydroxylphenyl)-1,2-diaminoethane.

49 mg of rac-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (0.20 mmol) was mixed with 2.2 equiv of (R)-(-)-myrtenal (0.44 mmol) in EtOH (0.2 mL). After stirring the mixture at ambient temperature for half an hour, the solvent was removed by nitrogen blowing. The crude mixture was 1 dissolved in CDCl3 for H NMR.

O OH O O H H NH 2 N N + NH2 N N H H OH O O

rac-1 RR-II-15 RR-II-16'

206

O H N

N H O RR-II-15

207

O H N

N H O

RR-II-16'

208

NH3Cl

RR-II-17

209

Solvent effect on the equilibrium of III-11 and III-12

OH OH

N N

N N OH OH III-11 III-12

11.28 0.80 0.92 13.47 13.91 1.00 0.92 0.92 13.47

10.0 5.0 0.0 ppm (f1)

o K = 14 (25 C, CDCl3) 4.76 0.90 5.57 1.00 5.69 1.00

10.0 5.0 0.0 ppm (f1)

o K = 6 (25 C, DMSO-d6)

210

17.03 1.02 14.78 0.82 17.03 1.02 17.09 1.00

10.0 5.0 0.0 ppm (f1)

o K = 17 (25 C, toluene-d8)

211

OH III-11

212

OH N

OH III-12

213

H2N

TPEN

214

O2N

O2N III-13'

215

H3CO N

H3CO III-14'

OCH3

216

III-15'

217

O H3C C H O O N H

H O

1-ala-G (CD3CN)

O H3C C H O O N H

H O

1- ala-G (CD2Cl2)

218

H3C CO O H3C COO H H O N H H N O

HO OH

1-ala-G* 1-ala-L*

(CD3OD)

219

O H3C C H O O N H

H O

1-ala-G (DMSO-d6)

220

H2N O O C H O O N H

H O

1-asn-G (DMSO-d6)

221

Ph O C H O O N H

H O

1-phe-G (DMSO-d6)

222

OH O C H O O N H

H O

1-ser-G (DMSO-d6)

223

CH3 O C H3C H O O N H

H O

1-val-G (DMSO-d6)

224

OH O OH

N N N N

2 (DMSO-d6)

225

O C H O O N H

H N O N

N N

2-phe-G (CD3CN)

226

O H3C C H O O N H

H N O N

N N

2-ala-G (CD3CN)

H2N O O C H O O N H

H N O N

N N

2-asn-G (CD3CN)

227

NH2

O O C H O O N H

H N O N

N N

2-gln-G (CD3CN)

O C H O O N H

H N O N

N N

2-ile-G (CD3CN)

228

O C H O O N H

H N O N

N N

2-leu-G (CD3CN)

S O C H O O N H

H N O N

N N

2-met-G (CD3CN)

229

OH O C H O O N H

H N O N

N N

2- ser- G (CD3CN)

OH O C H O O N H

H N O N

N N

2- thr- G (CD3CN)

230

O C H O O N H

H N O N

N N

2-trp-G (CD3CN)

O C H O O N H

H N O N

N N

2-tyr-G (CD3CN)

231

Appendix II

HPLC Chromatograms

Chiralcel OD-H column, 5% iPrOH in hexane, 1mL/min (a) Rac-II-5a

F F F HO F N F rac- F N F F HO F F

(b) RR-II-5a

F F F HO F N F RR F N F F HO F F

F F F HO F N F SS F N F F HO F F

232

Chiralcel OD-H column, 1% iPrOH in hexane, 0.5mL/min

(a) Rac-II-5d

F HO

N rac N

F HO

(b) RR-II-5d

F HO

N RR N

F HO

N SS N

F HO

233

Chrialcel OD-H column, 50% iPrOH in hexane, 0.8mL/min

(a) Rac-II-5e

Cl HO

N rac N

Cl HO

(b) RR-II-5e

Cl HO

N RR N

Cl HO

N SS N

Cl HO

234

Chrialcel OD-H column, 50% iPrOH in hexane, 0.8mL/min (a) Rac-II-5f

F3C HO

N rac N

F3C HO

(b) RR-II-5f

F3C HO

N RR N

F3C HO

N SS N

F3C HO

235

Chiralcel OD-H column, 50% iPrOH in hexane, 0.5mL/min

(a) Rac-II-5g

NC HO

N rac N

NC HO

(b) RR-II-5g

NC HO

N RR N

NC HO

N SS N

NC HO

236

Chrialcel OD-H column, 20% iPrOH in hexane, 0.8mL/min

(a) Rac-II-5i

MeO HO

N rac N

MeO HO

(b) RR-II-5i

MeO HO

N RR N

MeO HO

N SS N

MeO HO

237

Chrialcel OD-H column, 10% iPrOH in hexane, 0.8mL/min

(a) Rac-II-5l

Me O HO

N rac N

O HO Me

(b) RR-II-5l

Me O HO

N RR N

O HO Me

238

Chiralcel OD-H column, 5% iPrOH in hexane, 0.8mL/min

(a) Rac-II-5m

Cl HO

N rac N

Cl HO

(b) RR-II-5m

Cl HO

N RR N

Cl HO

N SS N

Cl HO

239

Chrialcel OD-H column, 2% iPrOH in hexane, 0.5mL/min

(a) Rac-II-5n

Me HO

N rac N

Me HO

(b) RR-II-5n

Me HO

N RR N

Me HO

240

Chiralcel OD-H column, 50% iPrOH in hexane, 0.8mL/min

(a) Rac-II-5o

N rac N

(b) RR-II-5o

N RR N

N SS N

241

Chiralcel OD-H column, 10% iPrOH in hexane, 1mL/min

(a) Rac-II-5p

CH H3CO 3 O HO

N H3CO rac- H CO 3 N

O HO H CO 3 CH3

(b) RR-II-5p

CH H3CO 3 O HO

N H3CO RR- H CO 3 N

O HO H CO 3 CH3

CH H3CO 3 O HO

N H3CO SS- H CO 3 N

O HO H CO 3 CH3

242

Chiralcel OD-H column, 3% iPrOH in Hexane, 1mL/min

(a) Rac II-6a

HN N HO O

rac

(b) R,R,R,R-II-6a prepared from (R,R)-1 (96% ee)

HN N HO O

(R,R,R,R)

HN N HO O

(S,S,S,S)

243

Chiralpak AD-H column, 5% iPrOH in Hexane, 1mL/min.

(a) Rac II-8a

OH HO

N N

rac

(b) SS-II-8a

OH HO

N N

(S,S)

OH HO

N N

(R,R)

244

Chiralpak AD-H column, 30% iPrOH in Hexane, 1mL/min

(a) Rac II-8b

OH HO

N N

rac

(b) SS-II-8b

OH HO

N N

(S,S)

OH HO

N N

(R,R)

245

Chiralpak AD-H column, 5% iPrOH in Hexane, 1mL/min

(a) Rac II-8c

OH HO

N N

rac

(b) SS-II-8c

OH HO

N N

(S,S)

OH HO

N N

(R,R)

246

Chiralpak AD-H column, 5% iPrOH in Hexane, 1mL/min.

(a) Rac II-8e

OH HO

N N

rac

(b) SS-II-8e

OH HO

N N

(S,S)

OH HO

N N

(R,R)

247

Chiralcel OD-H column, 3% iPrOH in Hexane, 0.3mL/min

(a) rac-III-15′ prepared from rac-DPEN and mesitaldehyde.

rac

(b) (S,S)-III-15′ prepared from (S,S)-DPEN and mesitaldehyde.

(S,S)

(R,R)

(d) (R,R)-III-15′ prepared from (S,S)-TPEN and benzaldehyde.

(R,R)

248

Chiralpak AD-H column, 20% iPrOH in Hexane, 1mL / min.

(a) rac-Warfarin obtained from Aldrich

OH Ph O

O O rac-warfarin

(b) (R)-Warfarin synthesized from (R,R)-IV-7 : 92%ee

OH Ph O

O O (R)-warfarin

249

Appendix III

Circular Dichroism Spectra

Circular dichroism spectra of 2-NL-G and 2-ND-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

Circular dichroism spectra of 2-FL-G and 2-FD-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

250

Circular dichroism spectra of 2-SL-G and 2-SD-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

Circular dichroism spectra of 2-VL-G and 2-VD-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

251

Circular dichroism spetra of 2-QL-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

Circular dichroism spectra of 2-IL-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

252

Circular dichroism spectra of 2-LL-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

Circular dichroism spectra of 2-ML-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

253

Circular dichroism spectra of 2-TL-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

Circular dichroism spectra of 2-WL-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

254

Circular dichroism spectra of 2-YL-G (50 μM in acetronitrile, 1 cm cell, at 25 oC) and their UV-vis spectrum.

255

Appendix IV

Computational Data

OH R OH R

N [3,3] N

N N

OH R OH R II-4 II-5

Energy of II-4 Energy of II-5 R ΔE (kcal/mol) K (hartree) (hartree) 298K

7 NO2 -1750.3698415 -1750.3855769 -9.9 1.7 × 10

Cl -2260.5629888 -2260.5751175 -7.6 3.8 × 105

H -1341.3723114 -1341.3830972 -6.8 9.3 × 104

OMe -1570.4214362 -1570.4288320 -4.6 2.6 × 103

OH -1491.8083236 -1491.8157563 -4.7 2.5 × 103

NMe2 -1609.3141114 -1609.3176883 -2.2 44

B3LYP / 6-31G (d) level

O O O H H H Ph N N N Ph N N N O H Ph O H Ph H Ph O Ph ts-1 ts-2 ts-3 Imaginary E ZPVE ΔH Molecule 0→298K Frequency (hartree) (kJ/mol) (kJ/mol) (cm-1)

II-4 -1341.3722595 1193.8984 72.1808 -

II-5 -1341.3830867 1193.0431 71.7509 -

TS1 -1341.3434615 1182.9787 71.9217 -203.11

TS2 -1341.3321727 1186.3585 71.0497 -185.16

TS3 -1341.3202683 1186.5370 71.3233 -205.14

B3LYP / 6-31G (d) level

256

b c f g a e d h b c f g

Selected bond distances (Å):

a (2.359), b (1.350), c (1.318), d (2.625)

e (2.186), f (1.354), g (1.317), h (2.341)

Imaginary E ZPVE ΔH Molecule 0→298K Frequency (hartree) (kJ/mol) (kJ/mol) (cm-1)

II-4 -1341.3722595 1193.8984 72.1808 -

II-5 -1341.3830867 1193.0431 71.7509 -

TS-1 -1341.3434615 1182.9787 71.9217 -203.11

II-6a -1115.1581978 1227.3589 64.364 -

II-7a -1115.1453650 1211.0988 70.9199 -

II-7b -1115.1659168 1214.1842 69.0277 -

TS-4 -1115.1094890 1206.1441 69.1448 -426.47

TS-4′ -1115.1025630 1208.1402 67.9998 -342.53

II-7e -957.8895796 912.7200 56.4684 -

II-7e -957.9160126 915.5911 54.6703 -

TS-5 -957.8556285 906.0002 54.869 -435.28

TS-5′ -957.8533251 908.8041 53.9157 -408.98

B3LYP / 6-31G (d) level

257

O O H H N N Molecule Energy (hartree)

N N H H RR-II-15 -1579.5638256 O O RR-II-15 SR-II-16 SR-II-16 -1579.5646739

O H H O SR-II-15 -1579.5653749 N N RR-II-16 -1579.5718981 N N O H H O ts-6 ts-7 TS-6 -1579.5287893

TS-7 -1579.5347485 O O H H N N

N N H H O O SR-II-15' RR-II-16'

X Y X Y K N exp N

N N

X Y X Y Initial diimine Rearranged diimine (1-6) (1'-6')

Energy of initial Energy of rearranged ΔE Diimine X Y cal diimine (hartree) diimine (hartree) (kcal/mol)

2 H OMe -1419.9688312 -1419.9661926 1.66

3 H Me -1269.5579724 -1269.5569767 0.625

4 H Cl -2110.1130526 -2110.1140997 -0.657

5 OMe Me -1498.6031257 -1498.6047627 -1.03

6 OMe NMe2 -1687.9042497 -1687.9016154 1.65

DFT at the B3LYP 6-31G (d) level

258

N [3,3] N

N N

A A ΔE=0kcal/mol

ΔE* = 21.5 kcal/mol

N N [3,3]

N N

III-15 III-15' ΔE = -5.5 kcal/mol ΔE*= 19.4 kcal/mol

Molecule Energy (hartree) Molecule Energy (hartree)

A -1190.9209257 III-15 -1426.8058131

III-15′ -1426.8145950

TS (A-A) -1190.8866770 TS (15-15′) -1426.7748609

DFT at the B3LYP 6-31G (d) level

259

O O [1,3] H [1,3] H N N N N

III-16 ΔE=1.9kcal/mol III-16' III-17 ΔE = -3.8 kcal/mol III-17'

O O H H N N N [3,3] [3,3] N

N N N N H H O O B ΔE=-6.8kcal/mol B' III-15 ΔE = -5.5 kcal/mol III-15'

O O H H N k N

N k' N

O H O H III-11 III-12 ΔE=-1.6kcal/mol

Molecule Energy (hartree) Molecule Energy (hartree)

III-15 -1426.8058131 III-17′ -671.2910299

III-15′ -1426.8145950 III-11 -1577.2666631

III-16 -714.0093445 III-12 -1577.2691466

III-16′ -714.0063240 B -1341.3722595

III-17 -671.2849826 B′ -1341.3830867

Equilibrium geometries were obtained by DFT computation at the B3LYP / 6-31G (d) level

260

HO HO O O

N Ph N Ph N Ph N Ph

HO HO O O C C' D D'

ΔE=-1.70kcal/mol ΔE = -25.3 kcal/mol

Molecule Level of calculation Energy (hartree)

C B3LYP 6-31G (d) -1341.3531882

C′ B3LYP 6-31G (d) -1341.3558908

D B3LYP 6-31+G (d) -1340.2269218

D′ B3LYP 6-31+G (d) -1340.2672837

261

OH OH

N N N [3,3] N [3,3]

N N N N

OH OH HB-Ph ΔE = -6.8 kcal/mol Ph-HB Mes-Ph ΔE = -5.5 kcal/mol Ph-Mes

Me2N Me2N OH OH N N N [3,3] N k

N N N k' N

Me2N Me2N OH OH MA-Ph ΔE = -3.3 kcal/mol Ph-MA HB-Mes ΔE = -1.6 kcal/mol Mes-HB

NMe2 NMe2

N N [3,3]

N N

NMe2 NMe2 Mes-MA ΔE=-2.6kcal/mol MA-Mes

Molecule Energy (hartree) Molecule Energy (hartree)

HB-Ph -1341.372260 Ph-MA -1458.859059

Ph-HB -1341.383087 HB-Mes -1577.266663

Mes-Ph -1426.805813 Mes-HB -1577.269147

Ph-Mes -1426.814595 Mes-MA -1694.743178

MA-Ph -1458.853826 MA-Mes -1694.747320

262

Geometry optimization of E and IV-12

Ph Ph Ph Ph

N N N N

E IV-12

Molecule Energy of E Relative energy Energy of IV-12 Relative energy of (hartree) of E (kcal/mol) (hartree) IV-12 (kcal/mol) Anti(H)-1 -1424.3563644 0.00 -1731.6337465 0.00 Anti(H)-2 -1424.3547235 1.03 -1731.6319453 1.13 Anti(H)-3 -1424.3536016 1.73 - - Anti(N)-1 -1424.3527421 2.27 - - Anti(N)-2 -1424.3511351 3.28 - - Anti(N)-3 -1424.3491808 4.51 - - Anti(Ph)-1 -1424.3518684 2.82 - - Anti(Ph)-2 -1424.3506185 3.61 - - Anti(Ph)-3 -1424.3495462 4.28 - -

DFT at the B3LYP 6-31G (d) level

Structures of E Ph

H H H N N Ph H Ph N Ph Ph N Ph

Ph H Ph N Ph Ph N Ph Ph N N H H H Anti(H)-1 Anti(N)-1 Anti(H)-2 Anti(H)-3 Ph Ph

Ph Ph Ph Ph

N Ph Ph Ph N Ph H Ph H Ph H H N N H N

Ph H H N H N Ph H H N N Ph Ph N Ph Ph Ph

Anti(Ph)-1 Anti(N)-3 Anti(N)-2 Anti(Ph)-2 Anti(Ph)-3 Ph Ph Ph

263

O O CH3 H -O O- H H O N H H H3C H N O O O

L L 1-A -G 1-A -L

Imaginary E ZPVE ΔH Molecule 0→298K Frequency (hartree) (kJ/mol) (kJ/mol) (cm-1)

1-AL-G -973.8631731 706.9746 49.0047 -

1-AL-L -973.8555515 708.6099 49.1946 -

B3LYP / 6-31G (d) level

264