POINT-TO-AXIAL CHIRALITY TRANSFER: I. ABSOLUTE STEREOCHEMICAL DETERMINATION OF CHIRAL PHOSPHORUS COMPOUNDS II. DESIGN AND DEVELOPMENT OF A PROGRAMMABLE ORGANOCATALYST By Debarshi Chakraborty A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2023 ABSTRACT This dissertation consists of two sections. The common thread between these two sections is the transfer of chirality (point to helical). In the first section, (Chapters I, II and III) the absolute stereochemical determination of chiral organic molecules using the principle of chirality transfer is described. The non-covalent interaction between the receptor and chiral analyte of interest leads to induction of helicity in the host-guest complex, and the helicity is measured by circular dichroism. In Chapter I, the design and development of the bis-porphyrin based hosts that perform as “reporters of chirality” has been discussed. Chapter II describes the development of a single chiroptical sensor for the absolute stereochemical determination of a-aminophosphonates and a- hydroxyphosphonates. In chapter III, a simple chiroptical solution for the determination of absolute configuration of P(V) chiral molecules has been discussed. The developed methodology has been successfully extended to determine the absolute stereochemistry at the P center of the antiviral Sofosbuvir. In the second part of the thesis (Chapters IV), design and application of a programmable enantiodivergent organocatalyst is described. The newly developed catalyst eliminates the requirement of two enantiomeric catalysts to afford antipodal products. The asymmetry in the racemic catalyst is introduced through coordination with chiral ligands and therefore can be programmed at will. To understand the chirality transfer phenomenon (point-to-axial to point) in depth, the sterics and electronics of the catalyst and the ligands are also explored. Dedicated to my ‘Kaku’ iii ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my advisor Professor Babak Borhan. I feel extremely lucky and privileged to be a part of his scientific family. He has been a great mentor and always encourages to think independently. He provided the freedom to work on our own ideas and that is something I would always cherish. He was there for me in my most vulnerable days during my stay in grad school. I would also like to thank him for letting me watch cricket, soccer, tennis in the lab, for those happy memories inside and outside the lab (camping and group parties) and for valuable career advice. I am grateful to all my committee members, Professor James E. Jackson, Professor Robert E. Maleczka Jr., and Professor Heedeok Hong for their support and guidance over the past few years. I would also like to thank Dr. Daniel Holmes (NMR), Dr. Richard Staples (Crystallography), Dr. Anthony Schilmiller (Mass spectrometry) for their time and help. I specially thank Dr. Ardeshir Azadnia for giving me the opportunity to teach organic labs at MSU. I am grateful to all the members of the Borhan group with whom I had the pleasure to work. All of you have been supportive, friendly, and most importantly humorous that made my journey a memorable one. I would like to thank Dr. Chrysoula Vasileiou for always helping me since I joined this group. My special gratitude to Dr. Hadi and Dr. Yi for your guidance and support during my early days in the Borhan lab. I am thankful for the friendship and unnumbered memories I have with Dr. Saeedeh, Dr. Dan, Dr. Aliakbar, iv Dr. Emily, Soham, Ankush, Mehdi and Aria. I thank James, Joban, and Channel for helping me in my research. I would like to thank Dr. Li, Dr. Badru, Dr. Eziz, Shuang, and Swetha for making those early days of graduate school memorable. I would like to express my sincere gratitude to my supportive family and friends. Without the support of my Amma, Maa and Dada I would have never made to graduate school. Thank you Maa for letting me dream and for motivating me to turn them into reality; thank you for showering me with light and hope. The guidance from my Dada has been instrumental in my academic journey since childhood. I would also like to thank Somnath, Swarup, Mrinmoy, Gora, Avishek and Prakash Da for their love, support, and suggestions. Lastly, I want to thank Esita. No words are enough to express my gratitude to her. The only reason I am writing this page today is because of her unconditional love and unwavering support. Literally, she did everything to keep me sane during those nervous moments of my graduate school. Thank you for everything. v TABLE OF CONTENTS LIST OF SYMBOLS AND ABBREVIATIONS…………………………………………….....vii CHAPTER I: ABSOLUTE STEREOCHEMICAL DETERMINATION OF CHIRAL ORGANIC MOLECULES THROUGH INDUCTION OF HELICITY IN BIS- PORPHYRIN HOSTS…………………………………………………………………...1 REFERENCES…………………………………………………………………….......23 CHAPTER II: ABSOLUTE STEREOCHEMICAL ASSIGNMENT OF a-AMINO AND a- HYDROXYPHOSPHONATES EMPLOYING A SINGLE CHIROPTICAL SENSOR………………………………………………………………………………..26 REFERENCES…………………………………………………………………………49 CHAPTER III: A CHIROPTICAL APPROACH FOR THE ABSOLUTE STEREOCHEMICAL DETERMINATION OF P-STEREOGENIC CENTER……………………………………………………………………………….51 REFERENCES………………………………………………………………………126 CHAPTER IV: POINT-TO-AXIAL-TO-POINT CHIRALITY TRANSFER: DESIGN AND DEVELOPMENT OF A PROGRAMMABLE ORGANOCATALYST…………….129 REFERENCES……………………………………………………………………….242 vi LIST OF SYMBOLS AND ABBREVIATIONS Å angstrom [a]D specific rotation A ECCD amplitude ABq AB quartet ACN acetonitrile AcOH acetic acid APCI atmospheric pressure chemical ionization Ar aromatic BINOL 1,1’-Bi-2-naphthol Bn benzyl Boc tert-butyloxycarbonyl CD circular dichroism CE Cotton effect cm centimeter d doublet DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DFT density functional theory DIBAL-H diisobutylaluminium hydride DMF dimethylformamide vii DMSO dimethyl sulfoxide DMI 1,3-dimethyl-2-imidazolidinone dr diastereomeric ratio ECCD exciton coupled circular dichroism ECD electronic circular dichroism equiv equivalents ESI electrospray Ionization EtOH ethanol etdm electronic transition dipole moment EtOAc ethyl acetate HBPin pinacolborane HOMO highest occupied molecular orbital HPLC high-performance liquid chromatography HRMS high resolution mass spectrometry IR infrared Ka association constant lcp left circularly polarized light LUMO lowest unoccupied molecular orbital M molar M minus Me methyl MeOH methanol viii MHz megahertz mg milligram Mg-TPP magnesium tetraphenylporphyrin min minute mM millimolar mmol millimole MPA methoxyphenyl acetic acid MTPA methoxy trifluoromethyl phenylacetic acid MS mass spectrometry m/z mass to charge ratio NaOAc sodium acetate Bu n-butyl nBuLi n-butyllithium NBS N-bromosuccinimide NH2Boc tert-butyl carbamate nm nanometer NMR nuclear magnetic resonance NIS N-iodosuccinimide ORD optical rotatory dispersion P plus Ph phenyl PhB(OH)2 phenylboronic acid ix PhLi phenyllithium PPh3 triphenylphosphine q quartet rcp right circularly polarized light rt room temperature s singlet t triplet TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMSOTf trimethylsilyl trifluoromethanesulfonate tz tweezer μg micro gram μM micro molar UV-vis ultraviolet-visible spectroscopy VCD vibrational circular dichroism X mole fraction Zn-TPFP zinc 5-(4-carboxyphenyl)-10,15,20-tri(pentafluorophenyl)porphyrin tweezer Zn-TPP zinc tetraphenylporphyrin Zn-TPP-tz zinc 5-(4-carboxyphenyl)-10,15,20- triphenylporphyrin tweezer > larger than < less than x CHAPTER I: ABSOLUTE STEREOCHEMICAL DETERMINATION OF CHIRAL ORGANIC MOLECULES THROUGH INDUCTION OF HELICITY IN BIS- PORPHYRIN HOSTS 1 I-1 Introduction Stereochemistry is a fundamental molecular property with important ramifications for structure, function, and activity of organic molecules. The basic building blocks of living organisms (amino acids and sugars) exhibit molecular handedness that has evolved over millions of years. The absolute stereochemistry of these building blocks is manifested in the structure and function of the cell machinery (e.g., enzymes, proteins, etc.), which are essential components of life. Most biologically active molecules and pharmaceutical agents are stereochemically-rich structures. Examples of the latter are citalopram, an antidepressant, sold as a racemic mixture of both the enantiomers (Figure I-1). Only the (S)-enantiomer has the desired effect.1 Thalidomide, the ‘morning sickness’ anti-nausea medicine for pregnant women, where the (R)-enantiomer was teratogenic, led to devastating malformities in embryonic development.2 Important to point out, the active (S)- enantiomer can racemize due to the presence of the acidic hydrogen at the chiral Citalopram Thalidomide Mecoprop F O O Me N NH O (R) CO2H N (R) O (R) Me O O Cl NC I-(R)-1 I-(R)-2 I-(R)-3 F O O Me N NH O (S) CO2H N (S) O (S) Me O O Cl NC I-(S)-1 I-(S)-2 I-(S)-3 Figure I-1. Represented enantiomers with different activities. 2 center. In the 1960’s almost 10,000 infants have been affected by this drug. Nearly 40% of them died and those that survived suffered from severe birth defects. Mecoprop, an herbicide, is used in many households as a weed killer. It is only the (R)-mecoprop that possesses the desired activity.3 Organic chemists have, and certainly will continue to design and develop tools and techniques to install stereocenters with precise selectivity to access important chiral molecules. In parallel to the advancements in stereoselective synthesis, there has been a growing interest and need for creative solutions to the challenge of absolute stereochemical determination of molecules with asymmetric centers. Under the current scenario, it is often the difficulty of assigning absolute stereochemistry, as opposed to synthesis, which has become a non-trivial challenge, requiring the attention of the community. There will not be a general solution to this problem, as each system will have its own unique requirements and challenges. However, the need for rapid, routine, and microscale analysis is apparent. This is especially true with parallel and high-throughput arrays for screening conditions and catalysts, generating many samples that require analysis. I-2 NMR based methods of determining absolute stereochemistry Direct detection of chirality, however, is not straightforward without the presence of a proper frame of reference. A reliable method is to compare the optical properties (i.e., optical rotation) of a compound to that of a known sample. This approach is valid only if the data of an authentic sample with known configuration is present in the literature. Most of the time, synthetic organic chemists developed new methodologies through different disconnections within the molecule. Therefore, finding the exact molecule in literature with 3 the desired configuration is often not possible. X-ray crystallography can provide an unambiguous assignment of configuration for molecules with heavy atoms due to its ability to yield high atomic resolution.4 Despite its remarkable success, this requires the molecule to be crystallizable in the first place. Often, obtaining a high-quality crystal is time consuming, laborious at times, and finding the right solvent or combination of solvents makes it even more tedious. In the past few decades, the NMR based Mosher model has been a cornerstone in determining the absolute stereochemistry of chiral organic molecules. Pioneered by Mosher, and further modified by Dale and other researchers,5-7 this approach has offered a practical method for the absolute stereochemical determination of chiral alcohols and HO2C CF3 HO2C CF3 H O H H O Ph OMe MeO Ph R2 CF3 R2 CF3 O R2 OH (S)-MTPA O (R)-MTPA 1 R1 Ph OMe R1 R MeO Ph I-4 shielding shielding ΔδRS = δ(R)- δ(S) I-4a I-4b H O R2 CF3 conformer consistent O lowest energy conformer with the empirical R1 Ph OMe according to Riguera Mosher model I-4a H CF3 H CF3 H MeO R1 R1 OMe OMe R2 R2 R1 R2 CF3 sp1 sp2 ap1 I-4aa I-4ab I-4ac shielding of R2 deshielding on R2 deshielding on R1 Figure I-2. Assignment of the absolute configuration of a secondary alcohol using Mosher ester protocol. The most representative conformers of MTPA esters. 4 amines. Derivatization of these functionalities with both enantiomers of a known chiral carboxylic acid or carboxylic acid chloride, and subsequent NMR analysis of the diastereomeric molecules (as esters or amides) can lead to the absolute stereochemical determination of the desired molecule (Figure I-2). Nonetheless, this technique is limited to only secondary chiral carbon center with a site for derivatization (i.e., hydroxyl or amino group), and relies on subtle chemical shift changes that can potentially lead to ambiguous assignment of the absolute stereochemistry. Mosher first represented an empirical model to determine the absolute configuration of chiral alcohols via an MTPA ester (Figure I-2). However, there are examples of chiral alcohols in the literature that do not agree with this model, making it difficult to determine their absolute stereochemistry. Through rigorous theoretical calculations, NMR and CD studies Riguera et al.8 found out that along with the conformer I-4aa predicted by Mosher, two other conformers I-4ab and I-4ac of the MTPA ester remain in equilibrium (Figure I-2). Due to the presence of three different but equally populated conformers the differences in their chemical shifts are either too small or inconsistent leading to the discrepances in the assignments of their absolute configuration. Another NMR based method that has been used widely for the determination of absolute configuration is the chiral solvating agent (CSA) based method.9-10 This protocol eliminates the necessity of any chemical derivatization and therefore no synthesis or purification prior to analysis is required. Furthermore, the difference in chemical shift of the NMR originates mainly from the non-covalent interactions (hydrogen bonding and p- stacking) between the chiral solvating agent and chiral analyte of interest. Nonetheless, 5 the major limitation of this protocol is the challenge in predicting a conformational model that can relate to chirality of the organic molecule with the changes in the NMR chemical shift. Moreover, subtle chemical shift changes and exclusiveness of a particular chiral solvating agent towards a small set of target molecules, limit the application of this technique. I-3 Absolute stereochemical determination of chiral organic molecules: chiroptical techniques An enabling alternative is to exploit the unique properties of chiroptical techniques, and optical rotatory dispersion (ORD) or circular dichroism (CD) to interrogate absolute stereochemistry. In these approaches, the stereochemical identity of a target molecule is translated into a detectable chiroptical response that ultimately leads to its absolute stereochemical determination. Fundamental to this tactic are the diastereomeric interactions of circularly polarized light, both left and right-handed components, with the chiral entities or complexes (Pfeiffer effect). Nonetheless, neither of these techniques can be independently utilized to assign the absolute configuration of a stereocenter since the sign of the resultant spectra in both instances is empirical in nature. A solution to this has entailed coupling of the results with theoretical spectra via computational methods. The computationally obtained spectrum provides the so-called frame of reference for the experimentally collected spectra. Nonetheless, the scope of these techniques is inadequate. The difficulties in predicting the lowest energy conformers in the solution phase stem from the flexibility (rotation around C-C bonds), complexity of the structures and their interactions with the solvent. 6 I-4 Exciton coupled circular dichroism: a non-empirical chiroptical approach Within the realm of chiroptical techniques, Exciton Coupled Circular Dichroism (ECCD) provides a non-empirical alternative to the assignment of helicity. The fundamentals of the ECCD approach are based on the pioneering work by Nakanishi and Harada,11-13 who showed that the through space exciton coupling between two or more helically oriented electric transition dipole moments (etdm) of independently conjugated chromophores leads to a bisignate Cotton effect, with a sign that is directly correlated to the helicity of the coupling chromophores. Their initial investigations exploited ECCD for the assignment of absolute configuration of conformationally rigid sterols I-5 and I-ent-5 (Figure I-3). The alcohol functionalities were derivatized as dibenzoates to introduce the required chromophoric entities. The solution to the absolute configuration was obtained La X readout of helicity Δε A La X O O Me s-trans H clockwise helicity O (+) ECCD couplet O H I-5 nm syn La X readout of helicity Δε A Me O O X La s-trans H O counter-clockwise helicity (-) ECCD couplet H O nm syn I-ent-5 Figure I-3. Absolute stereochemical assignment of rigid sterols via non-empirical Exciton Coupled Circular Dichroism. 7 from the ECCD spectra, which originated from the through space coupling of the benzoate groups. The sign of the ECCD spectrum is directly correlated to the specific helical arrangement of the chromophores, which arises from the absolute configuration of the derivatized carbinol stereocenters (Figure I-3). Since either the positive or negative ECCD signal is directly correlated to the clockwise or counterclockwise arrangement of the chromophores (helicity) respectively, the method unambiguously assigns the absolute configuration of the carbinol centers in a non-empirical fashion. Several groups have engaged in exploring CD active complexes to elucidate the absolute stereochemistry of organic molecules.14-18 The commonality in these approaches is the non-empirical readout of asymmetry via analysis of the resultant ECCD spectra. I-5 Porphyrin tweezer methodology: Absolute stereochemical determination of molecules with two sites of attachment One of the greatest successes of the ECCD method is that it can be applied to organic molecules that lack absorbing chromophores or a suitable site for derivatization. In this case, formation of a strong host-guest complex between the chiral analyte and an achiral host molecule containing two or more chromophores is highly desired. The chirality of the organic molecule of interest is transferred to the achiral host via noncovalent interactions. The observed chirality measured via circular dichroism is then correlated to the absolute stereochemistry of the guest molecule. The porphyrin tweezer methodology developed by Nakanishi and coworkers19 (Figure I-4) is one of the most utilized protocols for this class of organic molecules . In this approach, two porphyrin subunits tethered via a flexible alkyl chain constitute a molecular tweezer that functions 8 as a sensor of asymmetry for bound chiral guest molecules.20-23 The high extinction coefficient of porphyrin chromophores allows the determination of absolute configuration at a very low concentration. Chiral molecules containing two sites of attachments (for example diamines), form stable complexes with the I-C5-Zn-TPPtz 6, leading to the formation a complex with specific helicity of the porphyrin subunits with respect to each other. The key to absolute stereochemical determination lies in correlating the experimentally observed helical arrangement of the porphyrins with the chirality of the bound guest molecule. The porphyrin closest to the chiral center adopts an orientation to Ph Ph N N N N Ph Zn Ph Ph Zn Ph Zn Zn CD-silent N N N N I-C5-Zn-TPPtz 6 H CH3 O O H2 (– ) O O Zn N Zn ECCD I-C5-Zn-TPPtz 6 N H2 selected examples of chiral diamines complexed with 6 H CH3 H CONHMe NH2 H 2N H 2N NH2 I-7 I-8 MeO2C H H2 (–) ECCD (–) ECCD (+) Zn N Zn ECCD N MeO2C H H CH2OAc H2 H 2N NH2 H2N NH2 I-9 I-10 (+) ECCD (–) ECCD Figure I-4. Utilization of porphyrin tweezer methodology for the determination of absolute configuration of chiral diamines. 9 minimize steric repulsion with the larger group (L) on the chiral center. This event leads to a preponderance of either the P or M helical population, and thus a positive or negative ECCD signal is observed, respectively. This method has been utilized to report the absolute configuration of various molecules with two sites of attachment. Initially, the porphyrin tweezer methodology was effective in determining the absolute configuration of chiral molecules containing two strongly coordinating groups that bound to the divalent zinc center (i.e; diamines). The interaction of the Lewis basic nitrogen atoms with the Lewis acidic divalent zinc atoms of the tweezer was central to the transfer of chirality. Extending this approach to chiral diols or amino alcohols was not trivial. Reduced binding ability of the electronegative oxygen atom as a coordinating functionality led to weak complexation with I-C5-Zn-TPPtz 6, yielding either no ECCD spectra or weak signals that could not be correlated to the absolute stereochemistry of the guest diol molecule.24 This was demonstrated by measuring the binding affinity of 2- propanol with monomeric zinc porphyrin (Zn-TPP monoester I-11), exhibiting a substantially lower affinity as compared to iso-propylamine (Figure I-5, dashed box, Kassoc of 49 M-1 versus 11,400 M-1, respectively). Li et al.24 solved this problem by increasing the binding affinity for oxygen-based donors with the divalent zinc atoms embedded within the porphyrin by using electron deficient porphyrin rings. The polyfluorinated porphyrin analog (Zn-TPFP monoester I-12) was designed to enhance the Lewis acidity of the divalent zinc center, thus leading to stronger complexation with oxygen-based nucleophiles. Comparison of the HOMO and LUMO energies as well as the charge density on the zinc center in Zn-TPFP monoester I-12 with the parent zinc porphyrin Zn- 10 TPP monoester I-11 indicated a lower LUMO energy as well as a higher positive charge density on the zinc center (Figure I-5). These theoretically computed properties were further corroborated with experimentally obtained results. The association constants (Kassoc) of 2-propylamine and 2-propanol complexed with Zn-TPFP monoester I-12 showed much higher amine and alcohol affinities (~40x larger) in comparison to Zn-TPP monoester I-11 (Figure I-5). Based on the above understanding, I-C5-Zn-TPFPtz 13 was prepared and complexed with chiral diols in hexane, leading to consistent ECCD signals (Figures I-6a and I-6b). The choice of solvent for ECCD analysis is critical. It is of utmost importance that the solvent does not compete or interfere with the complexation of the chiral guest F F F F F N N F F F F N N Zn F Zn F N N N N F F F F CO2Me CO2Me Zn-TPP-monoester I-11 Zn-TPFP-monoester I-12 Mulliken electrostatic Kassoc Kassoc ELUMO ELUMO – EHOMO charge charge (iPrOH) (iPrNH2) eV eV of Zn2+ of Zn2+ M–1 M–1 I-11 –2.211 3.891 0.942 1.337 49±2 11400±950 I-12 –2.818 3.284 0.961 1.387 2170±140 473000±8700 Figure I-5. Lowering of LUMO energy via electronic manipulation. 11 molecule with the zincated porphyrin host system. Notably, in the case of erythro and threo diols, and 1,2-amino alcohols, the porphyrin bound to each stereogenic functionality governs the induced helicity of the bound porphyrins. Analogous to the mnemonic described for I-C5-Zn-TPPtz 6 with chiral diamines (Figure I-2), the sterics projected from the chiral centers of the guest molecules determine the respective arrangements of the bound porphyrins. As illustrated in Figure I-6c for erythro compounds (for instance I-16), a. C 6H 5 C6F5 C 6H 5 C6F5 N N N N N N N N C 6H 5 Zn C 6H 5 C6F5 Zn C6F5 C 6H Zn C 6H 5 C6F5 Zn C6F5 5 N N increase N N N N N N in Lewis acidity O O O O O O O O I-C5-Zn-TPPtz 6 I-C5-Zn-TPPtz 13 b. erythro and threo diols, amino alcohols and epoxy alcohols c. stereochemical model for erythro aminoalcohol Me Me Me HO HO Zn HO OH NH2 NH2 OH Ph Ph counter clockwise twist Ph H Me I-14 I-15 I-16 Ph H (+)-ECCD (+)-ECCD (+)-ECCD HO Me O Zn O HO OH Ph NHMe Ph OH I-16 Ph I-17 I-18 I-19 (_)-ECCD (_)-ECCD (+)-ECCD Figure I-6. a. Design of a highly Lewis acidic porphyrin tweezer host. b. Absolute stereochemical determination of erythro, threo diols, amino alcohols, and epoxy alcohols. c. Stereochemical model for erythro amino alcohol. 12 the two coordinating sites prefer the anti-arrangement to alleviate steric repulsion of the substituents on vicinal stereocenters. Furthermore, the porphyrin rings coordinate to the binding sites (oxygen or nitrogen atoms) anti to the largest group on the chiral center (phenyl and methyl groups). The porphyrin rings would further adopt a twist towards the small group (hydrogen), which in the illustrated case leads to a clockwise twist, and thus a positive ECCD signal. Notably prior to this work, absolute stereochemical determination of erythro diols via the dibenzoate methodology was not possible since the highest populated rotamer places the benzoates anti to each other. This is an ECCD silent conformation since no coupling of the chromophore’s electronic transition dipole moment C6F5 C6F5 C6F5 C6F5 N N N N N N N N C6F5 Zn C6F5 C6F5 C6F5 Zn C 6H 5 C6F5 Zn Zn C6F5 C6F5 N N rigidifying N N N N N N the linker Zn H HO Me O O O O O O O O I-C5-Zn-TPPtz 13 I-C3-Zn-TPPtz 20 Me O Zn H H I-21 Figure I-7. Design of a new host via rigidification of the linker. Stereochemical model to predict the absolute configuration of 1,n diols. ‘Side-on’ coordination, a new mode of binding to accommodate the long diols inside the cavity. 13 is possible. The use of the fluorinated tweezer I-C5-Zn-TPFPtz 13 was easily extended to these threo diols, as well as to epoxy alcohols (Figure I-6b).24 25 When a set of chiral 1,n-diols (n≥3) were complexed with I-C5-Zn-TPFPtz 13, the observed helicities were not predictable based on the binding mnemonic that was developed for 1,2-diols. The observed inconsistencies were attributed to the increased flexibility of the complex, resulting in multiple undesired conformations. These discrepancies were resolved by switching to a more rigid porphyrin tweezer that reduced the flexibility of the overall complex when bound with 1,n-diols (Figure I-7).26 Tweezer I- C3-Zn-TPFPtz 20 with a shorter alkyl linker (C3) was complexed with chiral diols shown in Figure I-7 to provide ECCD signals in full agreement with the predicted helicities. The shorter linker forced the ‘side-on’ binding to accommodate the diols of different chain lengths inside the cavity. This newly predicted ‘side-on’ binding as opposed to the regular ‘head-on’ binding was confirmed based on UV-vis data, computational modeling studies and X-ray studies of long chain diols. I-6 Porphyrin tweezer methodology: absolute stereochemical determination of molecules with one site of attachment The tweezer methodology was initially confined to chiral molecules with two sites of attachment. This methodology was later amended to sense the absolute configuration of chiral molecules with one site of attachment through a derivatization step prior to complexation with porphyrin tweezers. The strategy entailed the use of a “carrier”, which was installed on the chiral molecule to provide an additional binding site for complexation with the chromophoric tweezers. The constraints for a suitable carrier were set as follows: 14 a. It should bear an appropriate functionality for derivatization, b. It should have functional groups, preferably nitrogen-based motifs, for strong coordination to the zincated porphyrins; c. A desirable carrier would have a rigid framework, so that it will not add new conformations that could complicate prediction of stereochemistry; d. A carrier should be Zn-Porphyrin H 2N NH2 H 2N O R I-22 O R * 1 installation of a carrier * HO ( )n R Porphyrin-Zn N ( )n R’ (amide bond formation) H n = 0-3 chiral acid α-chiral carboxylic acid β, γ, δ-chiral carboxylic acid Ph Ph Ar Ar N N N N N N N N Ph Ph Ar Zn Ar Zn Zn Ph Zn Ph Ar Ar N N N N N N N N tBu tBu Ar = O O O O O O O O I-C5-Zn-TPPtz 6 I-C3-Zn-TPPtz 23 H CO2H H CO2H HO2C HO2C Ph OMe Me OPh OH I-24 I-25 I-28 I-29 (–) ECCD (–) ECCD (–) ECCD (–) ECCD H CO2H OH H CO2H HO2C OH OH Me Ph Et Me HO2C OH I-26 I-27 I-30 I-31 (–) ECCD (–) ECCD (–) ECCD (+) ECCD Figure I-8. Assignment of absolute stereochemistry for chiral carboxylic acids. Design of a rigidified and sterically encumbered host for sensing the asymmetry at the remote stereocenters. 15 achiral since the asymmetry of the unknown molecule should be the only chiral element that dictates the helicity of the bound porphyrin tweezer. Inspired from Nakanishi’s prior work,27-28 Yang et al.29 developed a rigid carrier 1,4- diamino benzene I-22 for facile derivatization with chiral carboxylic acids (Figure I-8). The resultant amides complexed with I-C5-Zn-TPPtz 6, generated ECCD signals consistent with the asymmetry of the guest molecule. Most of the methodologies discussed so far have the binding element next to the chiral carbon. Applying the same strategy to detect the absolute stereochemistry of chiral centers remote from the point of attachment is often fruitless. It was quickly realized that to sense the absolute configuration on remote stereocenters in chiral carboxylic acid, the sterics of the porphyrin substituents need to be revised. To achieve this goal, a new host with bulky 3,5 di-tertbutyl substituted phenyl rings was synthesized I-C3-Zn-TPPtz 23 (Figure I-8) and complexed with derivatized chiral carboxylic acids bearing b, g, d remote stereocenters.30 The resultant ECCD signals were consistent with the chirality of the guest molecules. 16 I-7 Determination of absolute configuration for molecules with one site of attachment without derivatization One of the major drawbacks of the porphyrin tweezer methodology is that it requires two sites of attachment. For molecules with one site of attachment, one need to attach a secondary binding element through derivatization. Based on Inoue’s work on the determination of the absolute configuration of chiral monoamines,31 Borhan and coworkers envisioned that further rigidification of the host tweezer system would be necessary such that a monodentate binder could exert its influence and force a preferred helicity of the host system.32 Further inspiration came from the elegant work of Feringa Ph Ph Ph Ph N HN Ph Ph NH N N HN Ph Ph NH N Ph N N Ph P:M = 1:1 Ph N N Ph NH H H HN NH H H HN O O O O I-MAPOL-(P)-32 I-MAPOL-(M)-32 Ph Ph chiral amines NHN Ph Me Ph NH N Me H H (S) (S) I-MAPOL-32 NH NH2 Ph N N NH H H H HN Ph I-33 O O (_) ECCD Figure I-9. I-MAPOL 32, a class of chiroptical reporter designed for chiral molecules with one binding site. Absolute stereochemical determination of chiral monoamine I-33, host-guest complexation via H-bonding. 17 and coworkers,33-34 where they had utilized the biphenol core to induce atropisomerism through hydrogen bonding interaction with chiral amino alcohols. The latter thoughts led to the design of a bis-porphyrin substituted biphenol I- MAPOL-32 shown in Figure I-9.32 Biphenol’s relatively low barrier to rotation (8-13 kcal/mol) enables the system to equally populate P and M helicities at any given temperature. Additionally, the anticipated intramolecular hydrogen bonding of the 2,2’- hydroxyl groups favors a syn arrangement of the porphyrins, i.e., having the porphyrin rings on the same side as opposed to having them rotate away (anti) to each other. The racemic P/M equilibrium can be perturbed through the interaction of the chiral guest molecule with the host system. As a proof of concept, chiral monoamines were complexed with I-MAPOL 32, noting that I-MAPOL 32 is not zincated, and thus the only mode of interaction would be through intermolecular hydrogen binding with the biphenol hydroxyl groups. Based on NMR analyses of the complex, a mnemonic was developed to predict the absolute configuration of the bound monoamines as function of the observed ECCD spectra. As illustrated in Figure I-9, it was hypothesized that the hydrogen bonding of the amine with the 2,2’-biphenol hydroxyl groups would orient the chiral molecule such that the substituents on the asymmetric center are positioned between the porphyrin rings on a 3-fold rotamer (looking through the C-N bond). The free rotation about the C-N bond enables the molecule to adopt an energetically preferred rotamer. As such, the most demanding steric element (cyclohexyl group in the illustration, Figure I-9) would occupy the most open quadrant between the two porphyrins placing the medium methyl group 18 gauche to the opposite porphyrin. Such orientation would lead to the formation of M- helicity for compound I-33. Indeed, this was observed experimentally. Extending this concept for chiral cyanohydrins was not fruitful. Surprisingly, no ECCD signal was observed. This was attributed to a weak hydrogen bonding interaction between I-MAPOL 32 and the hydroxyl group of cyanohydrin I-34. To improve the binding interaction, I-MAPOL 32 was zincated to potentially achieve a dual binding scenario. As Me OH Ph Ph (R) CN Ar Ph I-35 N N Ph H N N (R) C N Zn Zn N O N Ph N H N Ph Ph H H Ph O O N Ph Ph N N N Zn Zn N (+) ECCD N N N Ph Ph HO OH Ph Ph S Ph I-Zn-MAPOL-34 O N N Ph Ar (R) N N O S Zn Zn (R) Ph N N N H H N Ph I-36 O O (-) ECCD Simplified measurement of length (L) O 4.6 Å O 4.6 Å 2.8 Å 6.1 S Å S L L : Measured length I-37 I-38 Figure I-10. Absolute stereochemical determination of chiral cyanohydrin and chiral sulfoxide molecule. L parameter defined to measure the relative length of the substituents. discussed above, the porphyrin rings in I-MAPOL 32 were originally chosen only because 19 of their chromophoric value and were not intended for complexation with chiral molecules. Nonetheless, their zincation could provide a second coordination site along with the hydrogen bonding that could entropically aide complexation. In fact, addition of I-35 to I- Zn-MAPOL 34 resulted in a positive ECCD signal (Figure I-10).35 It was also found out that both the coordination to the divalent zinc atom, and hydrogen bonding with the biphenol core, were necessary to obtain a consistent ECCD signal. A binding mnemonic was proposed to correlate the sign of the ECCD signals to the stereochemical identity of the bound cyanohydrins. The hydroxyl group hydrogen bonds with the biphenol moiety of the host system whereas the nitrile group coordinates to the metal center. Such an arrangement directs the projection of the two remaining substituents towards the unbound porphyrin ring. As depicted in Figure I-10, placement of the larger tolyl group in the open quadrant is favored, leading to the preponderance of the P-helicity. With the successful utilization of I-Zn-MAPOL 34 for cyanohydrins, Borhan and coworkers turned their attention towards exploiting the binding ability of the Zn metal embedded in the porphyrin core. Sulfoxides contain a highly polarized sulfur oxygen bond that can potentially bind with Zn2+. Stemming from the strong binding affinity of sulfoxides with I-Zn-MAPOL 34 (i.e., Kassoc = 14,500 M-1),36 strong ECCD signals were obtained with low detection limits and high sensitivities. In many cases, a clear ECCD signal was observed with small sample amounts (i.e., <1 μg of sample per analysis), rendering this methodology suitable for analyses of compounds with limited quantities. The crystal structure of DMSO bound to Zn-TPP confirmed the coordination of sulfoxide to Zn2+ through its oxygen lone pair, and not via the lone pair on sulfur. With these boundary 20 conditions, the proposed mnemonic featured coordination of the oxygen atom of sulfoxide I-36 with the metallocenter, while orienting the lone pair of the sulfur atom towards the bound porphyrin (Figure I-10). This arrangement would project the remaining substituents towards the second porphyrin. Given the projected orientation of the substituents on I-36 towards the porphyrin ring not bound to the sulfoxide (larger p-tolyl vs smaller vinyl group), the M complex should be more stable than the P, leading to a negative ECCD signal. This agrees with the experimental results. The success for all methods discussed so far relies on the ability to correlate the relative size of the substituents on a chiral center, which is presumably dictating the helicity of the host-guest complex. Borhan and coworkers have mainly trusted A-strain values as a thermodynamic parameter to rank the substituents based on their relative size. Nonetheless, this analysis failed for chiral sulfoxides. Notably, sulfoxide I-37, the p- tolyl group would be considered “larger” than the phenyl group, although not by much based on A-strain values (the p-methyl substituent would not affect the A-strain value to any large degree), yet the host can discern their subtle steric differences. On the other hand, the lengths of these two substituents are substantially different. Length as a steric parameter is described best by the sterimol analysis, which considers “bulkiness” of a substituent in terms of its length and its width. Analogously, for sulfoxides the measured length L was considered as the distance from the sulfur atom to the furthest heavy atom. A representative example of such measurements is shown for the substituents on chiral sulfoxide I-37 (Figure I-10). Thus, revisiting the observed ECCD with I-37, the p-tolyl substituent is substantially “longer” than the phenyl group (6.1 Å vs 4.8 Å) and as 21 projected towards the unbound porphyrin, dictates steric differentiation to yield the observed signal. The perfect example to validate this assumption was found in I-38. Based on their A strain values one would anticipate tert-butyl to be larger than phenyl and this would lead to a positive signal for this compound. Nonetheless, an opposite signal was observed. This scenario could be rationalized by taking into consideration of their L values. The phenyl group is longer (4.8 Å) than the tert-butyl group (2.8 Å) and therefore compound I-38 would favor the formation of M helicity leading to the observed negative signal. In summary, porphyrin tweezers can function as reporters of chirality for molecules with two sites of attachment as well as for molecules where a secondary binding element could be appended via derivatization. Furthermore, Borhan and coworkers devised a new host system I-Zn-MAPOL 34 that allows for the chiroptical sensing of chiral molecules lacking suitable site for derivatization. The high sensitivity and fast response time offer a microscale, rapid and non-empirical solution for the absolute stereochemical determination of chiral organic molecules. 22 REFERENCES 1. Hyttel, J.; Bogeso, K. P.; Perregaard, J.; Sanchez, C., J. Neural. Transm. Gen. Sect. 1992, 88, 157-160. 2. Stephens, T. D.; Brynner, R. Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine; Perseus Publishing: Cambridge, MA, 2001. 3. Smith, G.; Kennard, C. H. L.; White, A. H.; Hodgson, P. G., Acta. Crystallogr. B. 1980, 36, 992-994. 4. Flack, H. D.; Bernardinelli, G., Chirality 2008, 20, 681-690. 5. Dale, J. A.; Mosher, H. S., J. Am. Chem. Soc. 1973, 95, 512-519. 6. Seco, J. M.; Quinoa, E.; Riguera, R., Tetrahedron: Asymmetry 2000, 11, 2781- 2791. 7. Seco, J. M.; Quinoa, E.; Riguera, R., Chem. Rev. 2012, 112, 4603-4641. 8. Blazewska, K. M.; Gajda, T., Tetrahedron: Asymmetry 2009, 20, 1337-1361. 9. Pirkle, W. H., J. Am. Chem. Soc. 1966, 88, 1837. 10. Uccello-Barretta, G.; Balzano, F., Top. Curr. Chem. 2013, 341, 69-131. 11. Harada, N.; Chen, S. L.; Nakanishi, K., J. Am. Chem. Soc. 1975, 97, 5345-5352. 12. Berova, N.; Polavarapu, P. L.; Nakanishi, K.; Woody, R. W. Comprehensive Chiroptical Spectroscopy, Vol. 2. Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules; Wiley: Hoboken, NJ, 2012. 13. Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy - Exciton Coupling in Organic Stereochemistry; University Science Books: Mill Valley, CA, 1983. 14. Borovkov, V. V.; Hembury, G. A.; Inoue, Y., Acc. Chem. Res. 2004, 37, 449-459. 15. Lu, H.; Kobayashi, N., Chem. Rev. 2016, 116, 6184-6261. 16. Pasini, D.; Nitti, A., Chirality 2016, 28, 116-123. 17. You, L.; Zha, D.; Anslyn, E. V., Chem. Rev. 2015, 115, 7840-7892. 23 18. Liu, M.; Zhang, L.; Wang, T., Chem. Rev. 2015, 115, 7304-7397. 19. Huang, X. F.; Rickman, B. H.; Borhan, B.; Berova, N.; Nakanishi, K., J. Am. Chem. Soc. 1998, 120, 6185-6186. 20. Berova, N.; Pescitelli, G.; Petrovic, A. G.; Proni, G., Chem. Commun. 2009, 5958- 5980. 21. Dhamija, A.; Mondal, P.; Saha, B.; Rath, S. P., Dalton Trans 2020, 49, 10679- 10700. 22. Pescitelli, G.; Di Bari, L.; Berova, N., Chem. Soc. Rev. 2014, 43, 5211-5233. 23. Valderrey, V.; Aragay, G.; Ballester, P., Coord. Chem. Rev. 2014, 258, 137-156. 24. Li, X.; Tanasova, M.; Vasileiou, C.; Borhan, B., J. Am. Chem. Soc. 2008, 130, 1885-1893. 25. Li, X.; Borhan, B., J. Am. Chem. Soc. 2008, 130, 16126-16127. 26. Li, X.; Burrell, C. E.; Staples, R. J.; Borhan, B., J. Am. Chem. Soc. 2012, 134, 9026-9029. 27. Huang, X.; Fujioka, N.; Pescitelli, G.; Koehn, F. E.; Williamson, R. T.; Nakanishi, K.; Berova, N., J. Am. Chem. Soc. 2002, 124, 10320-10335. 28. Kurtan, T.; Nesnas, N.; Li, Y. Q.; Huang, X.; Nakanishi, K.; Berova, N., J. Am. Chem. Soc. 2001, 123, 5962-5973. 29. Yang, Q.; Olmsted, C.; Borhan, B., Org. Lett. 2002, 4, 3423-3426. 30. Tanasova, M.; Anyika, M.; Borhan, B., Angew. Chem., Int. Ed. 2015, 54, 4274- 4278. 31. Borovkov, V. V.; Lintuluoto, J. M.; Inoue, Y., J. Am. Chem. Soc. 2001, 123, 2979- 2789. 32. Anyika, M.; Gholami, H.; Ashtekar, K. D.; Acho, R.; Borhan, B., J. Am. Chem. Soc. 2014, 136, 550-553. 33. Eelkema, R.; Feringa, B. L., J. Am. Chem. Soc. 2005, 127, 13480-13481. 34. Eelkema, R.; Feringa, B. L., Org. Lett. 2006, 8, 1331-1334. 24 35. Gholami, H.; Anyika, M.; Zhang, J.; Vasileiou, C.; Borhan, B., Chemistry 2016, 22, 9235-9239. 36. Gholami, H.; Zhang, J.; Anyika, M.; Borhan, B., Org. Lett. 2017, 19, 1722-1725. 25 CHAPTER II: ABSOLUTE STEREOCHEMICAL ASSIGNMENT OF a-AMINO AND a- HYDROXYPHOSPHONATES EMPLOYING A SINGLE CHIROPTICAL SENSOR 26 II-1 Introduction a-Amino and a-hydroxyphosphonates constitute an important family of biologically active molecules because of their desirable pharmacological properties.1-5 In particular, a-aminophosphonic acids are considered as structural analogues of natural a-amino acids, and thus are used as bioisosters in drug discovery platforms. Their structural similarity with the tetrahedral transition state for amide and ester hydrolysis has led to the development of a-amino and a-hydroxyphosphonates as potent enzyme inhibitors.6-7 Furthermore, their importance as antiviral and anticancer agents, antibiotics, neuro- modulators, plant growth regulators, herbicides, and many other applications8-10 (Figure II-1) has drawn significant attention from medicinal as well as synthetic chemists for their streamlined asymmetric preparation. It is thus not surprising that the efficacy and potency of this class of molecules is often determined by their absolute stereochemistry since it is N HN S NH S OEt Me P(O)(OH)2 N P OEt H H F O O N II-1 II-2 O pesticide antibiotic O O H R O N R N P OR NH N OR N P(O)(OH)2 OR H O O O P OR N H O II-3 II-4 II-5 clostripian inhibitor antibiotic hepatitis C virus NS3 protease inhibitor Figure II-1. Representative examples of important a-amino and hydroxyphosphonates. 27 their interactions with proteins and enzymes that is the key to their biological activity. The recent advancements in asymmetric synthesis have resulted in a plethora of enantioselective methods to access this class of compounds.11-14 Despite synthetic advances in this area, strategies, and methodologies for rapid determination of their absolute stereochemistry is less developed and remains as a critical bottleneck for structural analysis. II-2 Background Current strategy for the absolute stereochemical assignment of a-amino and a- hydroxyphosphonates heavily relies on Mosher ester (or amide) analysis.15 This protocol necessitates the formation of both Mosher diastereomers with the chiral analyte and subsequent analysis of their 1H and 31P NMR. Often, conformational analysis of the diastereomers is required to predict changes in the NMR data based on optimized conformations of the molecules. Typically for the absolute stereochemical determination of alcohols and amines, MTPA or MPA esters or amides are preferably used (Figure II- a. Chiral Derivatizing agents b. Chiral Solvating agents S F3C OMe OMe Ph P t Ph HO Bu CO2H Ph CO2H BocHN CO2H Ph II-6 II-7 II-8 II-11 MTPA MPA Boc-L-Phe phosphinothioic acid OH H N Ph Ph N N N P CO2H Me Me Cl O II-9 II-10 II-12 diazopholidine naproxen quinine Figure II-2. NMR based reagents to elucidate the stereochemistry of a-amino and hydroxyphosphonates. 28 2a), whereas for amino and hydroxyphosphonates the naproxen system II-10 is the only one that has been studied thoroughly (Figure II-2a).15 Furthermore, these studies are supported by theoretical calculations and low temperature NMR experiments. According to Gajda et al.15-16 naproxen esters and amides exist mainly in two conformers separated by the rotation around Ca-C(CO) bond. The most stable conformer is the ap conformer, where Ca-H bond is anti-periplanar to the Ca-C(CO) bond and is in the same plane as C1- H. Despite the success of this naproxen-based method, the overall process is slow, requiring chemical derivatization and chromatographic separation prior to analysis and limited to secondary stereocenters. Chiral solvating agents (CSA), (Figure II-2b) that form diastereomers via non- Me Cl O H O II-(R)-13 II-(R)-13 1 Me (R)-NapCl pyridine R X Ar α (EtO)2(O)P H H II-14a 1H X= O,NH NMR R most consistent conformers & XH 31P NMR (EtO)2(O)P II-14 H O II-(S)-13 Ar Me R 1 Me pyridine X α Cl (EtO)2(O)P H II-14b O II-(S)-13 (S)-NapCl Figure II-3. Assignment of the absolute configuration of the a-amino and hydroxyphosphonates by double derivatization with II-(R)-13 and II-(S)-13. covalent interactions has also been employed for the absolute stereochemical determination of a-amino and a-hydroxyphosphonates. Nonetheless, they do not provide a general solution for this class of compounds as the changes in 1H-NMR are empirical 29 and cannot be readily predicted. For example, the application of phosphinothionic acid II- 1117 and quinines II-1218-20 is limited to hydroxy phosphonates only. II-3 Absolute stereochemical determination of a-aminophosphonates A general chiroptical protocol that can determine the absolute stereochemistry of both a-amino and a-hydroxyphosphonates in a rapid manner has remained elusive. To this end, we sought to take advantage of the supramolecular host-guest chemistry where translation of chirality from a chiral guest molecule to the host-guest complex would result in a predictable circular dichroic output. This led to the development of a rapid, general, micro-scale, derivatization-free chiroptical procedure to assign the absolute stereochemistry of a-amino and a-hydroxyphosphonates in a non-empirical fashion utilizing the principles of Exciton Coupled Circular Dichroism (ECCD). In particular, the porphyrin tweezer methodology pioneered by Nakanishi,21 provided a general solution for the absolute stereochemical determination of chiral molecules that do not possess the required chromophores for exciton coupling. This methodology has been implemented successfully for the stereochemical determination of a variety of molecular families such as alcohols, amines, diols, diamines, amino acids, amino alcohols, epoxy alcohols, carboxylic acid, etc.22-27 Through bidentate coordination of its Zn-metallo centers with chiral guest molecule, the achiral porphyrin tweezer adopts a specific helicity that yields a significant ECCD signal. The observed signal is the direct consequence of the induced helicity, which in turn depends on the chirality of the guest molecule. Thus, the observed signal can be corelated with the absolute stereochemistry of the guest molecule in a non-empirical fashion. Molecules typically used as guests for 30 this protocol can be divided in two groups; those with two sites of attachment that can interact in a bidentate fashion with the porphyrin tweezer, and others with only one coordinating site available requiring alternate strategies for complexation with porphyrin tweezers or must rely on the use of different host molecules altogether. a-Amino and a- hydroxyphosphonates fall in the first category, where the phosphonate oxygen atom can provide one binding site and the nitrogen or oxygen atom in a-amino and a- hydroxyphosphonates, respectively, provide the second binding element. Our prior investigations with porphyrin tweezers have shown that success of this protocol in producing consistent ECCD signals is dependent on limiting the number of possible conformations upon host-guest complexation. To achieve the latter, two strategies have emerged; 1. Large binding affinity ensures a strong host-guest complexation, reducing energetically close-lying conformations that can complicate the ECCD spectrum; and 2. A smaller and/or rigid linker between the two porphyrin rings reduces conformational C6F5 C6F5 X RO OR N N N N Zn R P(O)(OR)2 X P Zn C6F5 II-15 O C6F5 Zn Zn C6F5 C6F5 H R N N X= NH2 or OH N N Induction of Helicity readout of helicity ECCD signal O O O O I-C3-Zn-TPFPtz 20 Figure II-4. Induction of helicity in host I-C3-Zn-TPFPtz 20 via transfer of chirality from II-15 through strong host-guest complexation. 31 flexibility. To this end, we envisioned the use of the fluorinated I-C3-Zn-TPFPtz-20,24 where the porphyrin rings are connected by a short C3 linker (Figure II-4). The fluorinated aryl rings lead to a more Lewis acidic Zn metal center that enhances the binding affinity with a-amino and a-hydroxyphosphonates. Gratifyingly, a strong positve ECCD signal (A = +264) was observed when only 5 equivalents of comopound II-(S)-16 was complexed with C3-Zn-TPFPtz-1 (1 µM) in hexane at 0 °C (Table II-1). Hexane was chosen as the solvent as it neither competes with the guest molecule in binding with the host, nor does it interact with the guest molecule to diminish the host-guest interaction. Figure II-5 depicts the binding titration of compound II-(S)-16 with the host. A closer inspection at the spectra reveals almost no shift of the absorbance maxima. It is known in the litetarure, that a bathochromic shift of ~12 nm for amine and ~8-10 nm for phosphonates are expected when they coordinate to Zn porphyrin.25, 27 Additionally, these two functional groups can bind to Zn porphyrin strongly, bringing the porphyrins in close proximity. Furthermore, it has been demonstrated, as the two porphyrins come closer a hypsochromic shift in their absorption spectra occurs. Presence of such opposing effects in the same system could explain the observed discrepency. The successful binding of II-(S)-16 with I-C3-Zn-TPFPtz-20 that resulted in a strong ECCD signal was followed with the examination of a number of structurally diverse aminophosphonates exhibiting branched alkyl or aryl groups (Table II-1). Next, the system was challenged with aminophosphonates that featured linear alkyl groups of different chain lengths, as well as alkene, alkyne and heteroatoms (Table II-1). 32 The binding of all of aminophosphonates with I-C3-Zn-TPFPtz-20 led to substantial ECCD signals without any complications. Figure II-5. UV-vis titration of I-C3-ZnTPFPtz 20 (1 µM) with II-(S)-16 at 0 °C in hexane. 33 Table II-1. ECCD of a-aminophosphonates with I-C3-Zn- TPFPtz-20 Phosphonate Predicted sign λ nm (Δε) A/Acorr NH2 424, +133 P(O)(OEt)2 positive +264b/+372 412, _131 II-(S)-16 NH2 425, _117 _198b/_220 negative P(O)(OEt)2 414, +81 II-(R)-17 NH2 424, _117 _253b/_278 negative 415, +136 P(O)(OEt)2 II-(R)-18 NH2 421, +106 positive +183b/+229 P(O)(OEt)2 414, _77 II-(S)-19 NH2 426, +32 positive +57b/+64 P(O)(OEt)2 417, -25 II-(S)-20 NH2 422, _27 _54b/_60 negative P(O)(OEt)2 415, +27 II-(R)-21 NH2 422, _28 _54c/_67 negative 7 P(O)(OEt)2 415, +26 II-(R)-22 NH2 426, +52 positive +88b/+100 414, _36 3 P(O)(OEt)2 II-(S)-23 NH2 425, +21 +66c/+72 positive 4 P(O)(OEt)2 416, _45 II-(S)-24 NH2 425, +87 positive +143b/+172 P(O)(OEt)2 413, _56 TBSO II-(S)-25 NH2 426, +144 positive +240a/+282 416, _96 TBSO P(O)(OEt)2 II-(S)-26 NH2 426, +122 Br positive +215a/+247 5 P(O)(OEt)2 416, _93 II-(S)-27 H 2N Me 425, -150 -335a P(O)(OEt)2 negative 414, +185 II-(R)-28 a. 1 equiv of guest b. 5 equiv of guest c. 10 equiv of guest 34 In general, (R) a-aminophosphonates produced a negative ECCD signal whereas (S) a-aminophosphonates generated a positive signal. We believe that stereochemical differentiation that leads to the induced ECCD of the host is driven by steric considerations of the guest substituents, yet caution is warranted as Cahn-Ingold-Prelog stereochemical assignment may not always follow steric preferences. In all examples listed in Table II-1 the larger substituent based on A strain values also has the third priority (phosphonate first and amino being second) by CIP rule. Correlation of the sign of the ECCD spectra for complexes generated between I-C3-Zn-TPFPtz-20 and the aminophosphonates with their known absolute stereochemistry provided the opportunity to derive a simple predictive binding mnemonic (Figure II-6a). A bidentate coordination between the phosphonate oxygen and nitrogen atom with the Zn-metallo centers would place compound II-(S)-16 between the two porphyrin rings. As depicted in Figure II-6a, the porphyrin coordinated to the oxygen atom does not dictate the helicity of the host-guest complex as the adjacent P center is achiral. The other porphyrin that binds the nitrogen atom is close to the asymmetric center. An energetically favorable conformer would dictate the smaller H atom towards the linker and place the larger cyclopentyl group (larger substituent based on A strain value), away from the nitrogen bound porphyrin ring in the open quadrant. Such orientation of the chromophores would result in a P helicity and a positive ECCD signal is expected. Indeed, substrate II-(S)-16 yielded a positive ECCD spectrum (Figure II-6a). Computational study (B3LYP/6-31G*) also agrees with the same intuitive reasoning as the conformer that adopts P-helicity is 0.83 kcal/mol more stable as compared to the M-helical conformer. The predicted signs of all a- 35 aminophosphonates presented in Table II-1 are consistent with the proposed binding model. In general, compounds with branched alkyl groups and aromatic substituents lead to a stronger ECCD signal. This can be rationalized based on the greater steric differentiation between the larger substituent and the H atom (based on the A strain value). a. Zn I-C3-Zn-TPFPtz-20 O EtO H 2N EtO P RS H RL P(O)(OEt)2 H 2N II-S-16 Zn b. M conformer P conformer disfavored favored Figure II-6. a. Proposed binding pnemonic to correlate the observed ECCD signal with the guest stereochemistry. b. Optimized (B3LYP/6-31G* level) P and M conformer of compound II-S-16 complexed with I-C3-Zn-TPFPtz-20. The calculation predicts P conformer to be 0.83 kcal/mol lower in energy. Phenyl groups at 10,20 positions are not shown here for clarity. 36 With the initial success of I-C3-Zn-TPFPtz-20 in determining the absolute stereochemistry of secondary a-aminophosphonates, the host system was then challenged with the tertiary aminophosphonate II-(R)-28. Notably, Mosher model is limited to a secondary chiral center and cannot be extended directly to determine the absolute configuration of a tertiary center. To determine the absolute chirality of II-(R)-28 via MTPA ester, Hammerschmidt et al.28 considered the Me group to be on the same plane as the carbonyl of the corresponding MTPA amide of II-(R)-28. Although the difference in 1H chemical shift matched with the model, the 31P NMR chemical shift difference turned out exactly the opposite to that expected from the predicted model. Furthermore, Mosher ester method has never been used as a general method to determine the absolute stereochemistry of tertiary aminophosphonates. When treated with I-C3-Zn-TPFPtz-20 under identical conditions compound II-(R)-28 yielded an ECCD signal consistent with the ECCD signal. The observed signal is in accordance with mnemonic (Figure II-6a) where Table II-2. ECCD of a-hydroxyphosphonates with I-C3- ZnTPFPtz-20 Phosphonate Predicted sign λ nm (Δε) A/Acorr OH positive 424, +122 P(O)(OEt)2 +194/+198 412, _72 II-(S)-29 OH 424, +81 positive +111/+173 P(O)(OEt)2 412, _30 II-(S)-30 OH 424, +40 P(O)(OEt)2 positive + 51/+88 413, +11 H 3C II-(S)-31 a. 1 equiv. of guest 37 the smaller Me group is pointed towards the linker and porphyrin slides away from the Ph group. This demonstrates the generality of our developed methodology. II-4 Absolute stereochemical determination of a-hydroxyphosphonates The successful implementation of I-C3-Zn-TPFPtz-20 as a “reporter of chirality” for the a-aminophosphonates prompted us to expand the generality of the methodology for a-hydroxyphosphonates. We surmised that I-C3-Zn-TPFPtz-20 should bind a- hydroxyphosphonates in a similar fashion with the hydroxyl oxygen serving as the secondary binding element. Thus, II-(S)-30 can be considered as the pseudo-enantiomer of II-(R)-17, since the R-amino group is replaced with an S-hydroxyl group, while the rest of the substituents are the same. As predicted, complexation of II-(S)-30 with I-C3-Zn- TPFPtz-20 leads to a negative ECCD signal, which is opposite to that observed with II- (R)-17. The observed ECCD spectra with II-(S)-29 and II-(S)-31 are also in full agreement with the predicted signs based on the proposed mnemonic (Table II-2). In summary, we have demonstrated a simple chiroptical procedure for the determination of absolute stereochemistry of a-aminophosphonates and a-hydroxy phosphonates. This protocol does not require derivatization or chromatographic separation prior to analysis. Strong host-guest complex formation leads to a discernable ECCD signal at a micromolar level. A simple binding model based on the size of the substituents can easily correlate the chirality of the guest with the observed ECCD spectra. 38 II-5 Experimental section II-5-1 Materials and general instrumentation Anhydrous solvents used for CD measurements were purchased from Aldrich and were spectra grade. Unless otherwise mentioned, solvents were purified as follows. CH2Cl2 was dried over CaH2. CD spectra were recorded on a JASCO J-810 spectropolarimeter, equipped with a temperature controller (Neslab 111) for low temperature studies, and are reported as Mol. CD / l [nm]. UV-vis spectra were recorded on an Agilent, Cary 100 UV- visible spectrophotometer equipped with temperature controller. UV-vis spectra were collected with scan rate of 100 nm/min. All the amino and hydroxyphosphonates were synthesized following literature procedure.11, 29-30 Compound I-C3-ZnTPFP-20 was synthesized following the protocol developed in our lab.24 II-5-2 General procedure for UV measurements I-C3-ZnTPFP-20 (1.0 µL of a 0.001M solution in anhydrous dichloromethane, 1.0 µmol) was added to hexane (1.0 mL) in a 1.0 cm UV-cell. The background spectrum was recorded from 350 nm to 480 nm at a scan rate of 100 nm/min. Chiral guests (1 up to 100 equivalents) from three different stock solutions in anhydrous dichloromethane [0.01M (for 10-100 equiv), 0.001M (for 1-10 equiv), 0.0001M (for 0.1-1 equiv)] were then added to the I-C3-ZnTPFP-20 solution. The UV-vis spectra were collected after each addition at 0 °C. 39 II-5-3 General procedure for CD measurements I-C3-ZnTPFP-20 (1.0 µL of a 0.001M solution in anhydrous dichloromethane, 1.0 µmol) was added to hexane (1.0 mL) in a 1.0 cm CD cell (cooled to 0 °C) to obtain a 1.0 µM solution. The background spectrum was recorded from 350 nm to 480 nm with a scan rate of 100 nm/min at 0 °C. Chiral aminophosphonate and hydroxyphosphonate from a stock solution in anhydrous dichloromethane (0.001 M for 1-10 equiv and 0.01 M for 10- 20 equiv) was added to the prepared host solution to afford the host-guest complex. The CD spectra were measured immediately (10 scans). The resultant ECCD spectra recorded in millidegrees were converted the molecular CD (Mol. CD) considering the host concentration of 1.0 µM. 40 NH2 P(O)(OEt)2 Figure II-7. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II- (S)-16 at 0 °C in hexane. NH2 P(O)(OEt)2 Figure II-8. Negative ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II-(R)-17 at 0 °C in hexane. 41 NH2 P(O)(OEt)2 Figure II-9. Negative ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II- (R)-18 at 0 °C in hexane. NH2 P(O)(OEt)2 Figure II-10. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II-(S)-19 at 0 °C in hexane. 42 NH2 P(O)(OEt)2 Figure II-11. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II-(S)-20 at 0 °C in hexane. NH2 P(O)(OEt)2 Figure II-12. Negative ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II-(R)-21 at 0 °C in hexane. 43 NH2 7 P(O)(OEt)2 Figure II-13. Negative ECCD spectrum of I-C3-ZnTPFP-20 complexed with 10 equiv of II-(R)- 22 at 0 °C in hexane. NH2 3 P(O)(OEt)2 Figure II-14. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II-(S)-23 at 0 °C in hexane. 44 NH2 4 P(O)(OEt)2 Figure II-15. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 10 equiv of II-(R)-24 at 0 °C in hexane. NH2 TBSO P(O)(OEt)2 Figure II-16. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 5 equiv of II-(R)-25 at 0 °C in hexane. 45 NH2 TBSO P(O)(OEt)2 Figure II-17. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 1 equiv of II- (R)-26 at 0 °C in hexane. NH2 Br 5 P(O)(OEt)2 Figure II-18. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 1 equiv of II-(R)-27 at 0 °C in hexane. 46 H 2N Me P(O)(OEt)2 Figure II-19. Negative ECCD spectrum of I-C3-ZnTPFP-20 complexed with 1 equiv of II-(R)-28 at 0 °C in hexane. OH P(O)(OEt)2 Figure II-20. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 1 equiv of II- (S)-29 at 0 °C in hexane. 47 OH P(O)(OEt)2 H 3C Figure II-21. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 1 equiv of II- (S)-30 at 0 °C in hexane. OH P(O)(OEt)2 Figure II-22. Positive ECCD spectrum of I-C3-ZnTPFP-20 complexed with 1 equiv of II- (S)-31 at 0 °C in hexane. 48 REFERENCES 1. Seto, H.; Kuzuyama, T., Nat. Prod. Rep. 1999, 16, 589-596. 2. Moonen, K.; Laureyn, I.; Stevens, C. V., Chem. Rev. 2004, 104, 6177-6215. 3. Palacios, F.; Alonso, C.; de Los Santos, J. M., Chem. Rev. 2005, 105, 899-931. 4. Kolodiazhnyi, O. 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Chem. 1999, 64, 1403-1406. 50 CHAPTER III: A CHIROPTICAL APPROACH FOR THE ABSOLUTE STEREOCHEMICAL DETERMINATION OF P-STEREOGENIC CENTER 51 III-1 Introduction Optically active P-stereogenic compounds have been widely applied as chiral ligands, organocatalysts and versatile synthons.1-4 Furthermore, several biologically active molecules, agrochemicals and pharmaceuticals possess P-chirogenic center (Figure III-1).1 Recently, phostine III-3, a P-chirogenic mimic of glucoside has shown promising activity in cancer treatment.1 With the advancement in asymmetric synthesis, a plethora of catalytic asymmetric methodologies has evolved over the years to access P-stereogenic compounds.5-15 Despite these recent progresses, there is a dearth of straightforward methods for the rapid stereochemical determination of P-stereogenic centers impeding further development of novel catalytic asymmetric methodologies. O OBn Ph Me O O O O P O N NH P O O P N(CH2CH2Cl)2 N O H OPh O BnO OH N O F H HO OBn III-1 III-2 III-3 Cytotoxan Sofosbuvir Phostine antitumoral antiviral antiproliferative Me Me tBu tBu MeO Me H P P P Ph H P Me tBu Ph P Me OMe tBu III-4 III-5 III-6 organocatalyst MiniPhos DIPAMP chiral ligand chiral ligand Figure III-1. Representative examples important P-chiral compounds. 52 III-2 Background Current methods for the absolute stereochemical determination of P-chiral centers rely on X-ray crystallography, optical rotation, 2D NMR spectroscopy and chemical derivatization to a known compound.16-22 These methods are generally slow and not a simple solution for most cases. Well diffracting crystals are required for X-ray analysis, a slow and laborious process that depends on the propensity of the molecule to form crystals. Over the years the Mosher ester method has been successfully employed for the determination of absolute stereochemistry of chiral amines and alcohols. One of the a. 2D NMR technique: P Ph H R H R (L)-Men Me Me (CH2)2PPh2 N Me N Me III-8 Pd Ph Pd Ph P Ph P (L)-Men H R Me (L)-Men P Ph P Me Ph III-10a Ph III-10b N formation of regioisomers Pd H R Cl 2 Me P Ph N Me III-7 4-BrC6H4 tBu Pd rotation around Pd-P bond III-9 P Ph 4-BrC6H4 t Bu III-11 b. Chiroptical technique: VCD VCD, ECD and QRD O O O tBu Ph P C11H9 P NH2 OH tBu H Ph OH III-12 III-13 III-14 HO OH verified with the NMR verified with the X-ray (S)-mandelic acid III-15 analysis of analysis of (R)-BINOL II-12: II-14 complex II-13: II-15 complex Figure III-2. Current techniques and their challenges to the assignment of absolute configuration. 53 major limitations of this methodology is the requirement of derivatization to form diastereomers. Often, P-chiral compounds do not possess convenient handles to functionalize, hence they are well suited for Mosher ester method. Homochiral ortho- palladated complexes III-7 have been implemented as a “reporter complex” to establish the stereochemistry of P-chiral compounds using 2D NMR spectroscopy (Figure III-2a).16, 22 These complexes bind with chiral phosphines, leading to diastereomeric forms, which are then separated. Their unique 1H NMR signals are analyzed to assign the absolute stereochemistry at the P center. Although this methodology has enjoyed some success, it is limited to symmetrically substituted bis or polydentate phosphines. Binding of non- symmetric bisphosphines leads to the formation of regioisomers that complicates the absolute stereochemical determination (Figure III-2a). Chiral mono-phosphines i.e; III-9 were initially envisaged to avoid regioisomer problem, however their high rotameric lability (free rotation around Pd-P bond) leads to ambiguous determination of their absolute stereochemistry (Figure III-2a). Less attention has been paid to unravel this problem using common chiroptical techniques. In 2002, Zygo et al.23 utilized VCD (Vibrational Circular Dichroism) to solve the absolute stereochemistry of a single substrate (S)-tert-butyl-1-(2-methylnaphthyl) phosphine oxide III-12 (Figure 2b). The absolute configuration was separately confirmed via NMR analysis of the complex formed between the substrate III-12 and (S)-mandelic acid III-14 (Figure 2b). Very recently, Drabowicz et al.24 exploited a combination of three different chiroptical techniques namely VCD (Vibrational Chiroptical Dichroism), ECD (Electronic 54 Circular Dichroism) and ORD (Optical Rotatory Dispersion) in determining the absolute configuration of (R)-tert-butylphenylphosphinoamidate III-13 (Figure 2b). The absolute configuration was independently verified via X-ray analysis of the complex formed between (R)-BINOL III-15 and the chiral analyte of interest III-13. Although chiroptical methods has gained a limited success (only two substrates), they are yet to become a routine method for this class of compounds. These chiroptical techniques are empirical in nature and require a consistent quantum mechanically predicted theoretical spectra to be matched with the experimentally observed data. The difficulty often stems from the inability to predict an accurate set of solution phase conformers and their respective theorical spectrum, due to the flexibility of the molecules and complexity of their structures. III-3 Absolute stereochemical determination of tertiary phosphine oxides With our prior experience in using porphyrin-based hosts as reporters of chirality, we set our goal to develop a simple, rapid, direct (derivatization free), and micro-scale methodology to assign the chirality of P-stereogenic compounds. We envisioned utilizing the principles of Exciton Coupled Circular Dichroism (ECCD) to develop a procedure that addresses this long-standing problem. The porphyrin tweezer methodology, a host-guest interacting system, has been used successfully for the absolute stereochemical determination of various functionalities as discussed earlier. A major limitation in using this strategy is the requirement for bidentate coordination between the metal centers and the chiral guest molecule to induce helicity within the host/guest complex. Mono- phosphines inherently lack the presence of a secondary coordination site and in most of 55 the cases do not possess a suitable functional group to append the required secondary binding element. Recently, our group has developed a new host system I-MAPOL-32,25 having a rigid bis-phenol backbone that brings the two porphyrin rings closer in proximity compared to a traditional tweezer, thus creating a cavity between the two porphyrin units.I-MAPOL-32, remains as a 1:1 mixture of its P and M stereoisomers at room temperature (Figure III-3). It is assumed that the intramolecular hydrogen bonding between the two hydroxy groups keep I-MAPOL 32 in its syn conformation where the porphyrins face each other. This equilibrium is shifted in one direction through its interaction with a chiral guest molecule. The induced chirality is analyzed via Circular Ar Ar Ar Ar Ar N N Ar N N Ar N N Ar N N M M M M Ar N N Ar N N N R R N Ar N R R N Ar O O P:M = 1:1 O O P-helicity M-helicity R = H, M= H,H, Ar = C6H5; I-MAPOL 32 R = H, M = Zn, Ar = C6H5; I-Zn-MAPOL 34 R = Me, M = Zn, Ar = C6H5; III-OMe Zn-MAPOL 16 R = H, M = Zn, Ar = C6F5; III-F30 Zn-MAPOL 17 RL RM RL RS RL RS CN S RS O HN O Zn Zn Zn Zn H H H H H H H H O O O O O O I-MAPOL 32 + monoamine I-Zn-MAPOL 34 + cyanohydrin I-Zn-MAPOL 34 + sulfoxide Figure III-3. MAPOL and its analogs, used in the absolute stereochemical determination of chiral amines, cyanohydrins, and sulfoxides. 56 Dichroism (CD) spectroscopy and correlated with the absolute chirality of the guest molecule. Using this concept, I-MAPOL 32 was initially employed as a reporter of chirality for chiral monoamines.25 Translation of point to axial chirality through hydrogen bonding interaction between the phenolic hydrogen atoms in the host with the chiral amine guest was key to its success. Host I-MAPOL 32 can function as both H-bond donor and as well as H-bond acceptor, thus forming a strong ECCD active host-guest complex with monoamines. On the other hand, I-Zn-MAPOL 34, the zincated version of host I-MAPOL 32 bears two orthogonal binding elements i.e., similar hydrogen bonding with phenolic moieties and additional ligand to metal coordination can take place with the zinc metallo centers embedded in the porphyrin core (Figure III-3). These properties made I-Zn- MAPOL 34, an excellent host to bind with chiral cyanohydrin molecules. In similarity with the monoamines, the hydroxyl group interacts with bi-phenolic moiety through H-bonding whereas the cyano group coordinates to the Zn metal. Although for cyanohydrin26 dual binding was necessary, S-chiral sulfoxides required coordination of the sulfoxide oxygen atom to the Zn metal to induce helicity in I-Zn-MAPOL 34 (Figure III-3).27 Intrigued by the results observed with S-chiral sulfoxides and literature preceding of phosphonates coordination with metallo mono-porphyrins28-31 we realized that a similar approach might provide an effective chiroptical solution for the absolute stereochemical assignment of P- chiral phosphorus oxides. Coordination between the Zn metal and the oxygen atom should yield a strongly bound host-guest complex, leading to the induction of helicity in the host-guest complex. Furthermore, phosphines do not bind strongly with Zn-porphyrins and alkyl phosphines are prone to aerobic oxidation. With recent advances in conversion 57 of phosphine oxides to phosphines with stereochemical fidelity,11-13 a routine method for the absolute stereochemical determination of phosphine oxides would automatically solve the problem with phosphines. First, we turned our attention to UV-vis measurements to explore the binding of phosphine oxides to I-Zn-MAPOL 34. Addition of phosphine oxide III-RP-19 to I-Zn- MAPOL 34 led to a redshift from 413 nm to 423 nm, indicating the binding event between the host and the guest molecules (Figure III-4). Gratifyingly, a strong negative ECCD signal (A = -667) was observed when only 5 equivalents of compound III-RP-19 were added to a solution of I-Zn-MAPOL 34 (1 µM) in hexane at 0 °C (Figure III-5). This low detection limit along with 10 nm redshift in the UV-vis is indicative of the strong binding Figure III-4. UV-vis titration of I-Zn-MAPOL 34 (1 µM) with III-RP-19 at 0 °C in hexane. 58 O A = -667 P I-Zn-MAPOL 34 Pr Me Hexane, 0 ℃ III-RP-19 Figure III-5. Strong ECCD signal is observed upon binding of III-RP-19 (5 equiv) to I- Zn-MAPOL 34 affinity for phosphine oxides with I-Zn-MAPOL 34. As anticipated, a positive ECCD signal was observed for III-SP-19, the enantiomer of III-RP-19, with nearly similar intensity under identical conditions (Table III-1). The strength of the ECCD signal was found to be sensitive to the temperature of measurement. Expectedly, the ECCD amplitude decreased with increasing temperature (Figure III-6). Nevertheless, a significant signal is observed even at 45 °C, further corroborating the strong binding between the host and Figure III-6. Temperature dependence on the amplitude of the ECCD signal of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-19 in hexane. 59 guest molecule. To test the sensitivity of the host system to different solvent impurities, the host-guest complex was titrated with different equivalents of acetone and ethyl acetate and their respective CD intensities were measured. Acetone and ethyl acetate showed diminution of signal only after 2000 equivalents. These data further support the intense binding between the host and the guest. Job’s plot analysis indicated the formation of a 1:1 complex (Figure III-7a). Titration of I-Zn-MAPOL 34 with excess of III- RP-19 provided a binding isotherm revealing a Kassoc of ~2.7 ´ 105 M-1 in hexane confirming our initial evidence of strong binding affinity (Figure III-7b). With these preliminary results in hand, a variety of molecules possessing an asymmetric phosphorous oxide moiety with different alkyl and aryl substituents were synthesized according to reported procedures.5 Complexation of these P-stereogenic compounds with I-Zn-MAPOL 34 resulted in strong ECCD signals centered around the Soret band of the host system (Table III-1). In general, all SP phosphorous oxides produce positive ECCD a b Figure III-7. a. Jobs plot of I-Zn-MAPOL 34 with III-RP-19 at 410 nm. b. Binding affinity measurement for III-RP-18 with I-Zn MAPOL 34. 60 spectra while RP phosphorous oxides yield negative ECCD spectra. In order to correlate the observed ECCD signal with the asymmetry of the phosphine oxides few more experiments were performed. 1. Attempts to obtain a single crystal of any of the host-guest complexes were unfruitful. Nonetheless, the crystal structure of the phosphine oxide III-RP-19 bound to the Zn- tetraphenylporphyrin (Zn-TPP) as a mimic of the porphyrin ring in I-Zn-MAPOL 34 was obtained (Figure III-9). The crystal structure confirmed the coordination between the oxygen atom in phosphine oxide and the zinc metal of the metal porphyrin. It was also evident that upon coordinating the zinc center, the chiral phosphine oxide III-RP-19 projects its smallest substituent (the methyl group) towards the porphyrin ring (Zn-O-P bond angle is 138°), thus pushing the medium and larger group away (Figure III-8). 2. A stronger CD signal (A = -1098 vs A = -667) with was observed when III-RP-19 was complexed with III-F30 Zn-MAPOL 17 (Figure III-9a). The larger amplitude is expected because of the higher binding affinity with the more Lewis acidic Zn metallo-center of the Pr Ph P O Me 138° N N N Zn N Figure III-8. The crystal structure of III-RP-19 bound to Zn-TPP. 61 fluorinated porphyrin. This observation further corroborates the oxygen to zinc coordination as the main binding element. 3. Binding of III-RP-19 with III-OMe Zn-MAPOL 16 produced a complex spectrum, (Figure III-9b) suggesting the presence of the hydroxyl groups in host I-Zn-MAPOL 34 is essential to yield a consistent ECCD signal. This observation can be justified because the intramolecular hydrogen bonding between the hydroxyl groups at the 2,2’ positions of a b Figure III-9. a. ECCD of III-RP-19 bound to III-F30 Zn-MAPOL 17 (red) and I-Zn- MAPOL 34 (blue). b. ECCD of III-RP-19 bound to III-OMe Zn-MAPOL 16 (blue) and I- Zn-MAPOL 34 (red). 62 Table III-1. ECCD of chiral phosphine oxides bound to I-Zn MAPOL 34 entry predicted sign λ nm, Δε A/Acorra O P Me 426, +127 positive +223b/+301 III-SP-18 419, -96 O P 426, -126 negative -233b/-347 III-RP-18 419, +107 Me O P Me 426, +279 positive +497b/+742 III-SP-19 419, -218 O P 426, -358 negative -667b/-844 III-RP-19 419, +309 Me O P Me 426, +308 positive +561b/+837 419, -253 III-SP-20 OMe O P 426, +74 Me positive 419, -70 +144c/+202 Ph III-SP-21 OMe O P 426, -203 Ph negative 419, +208 -411c/-561 Me III-R -21 P O negative 426, -561 Ph P O 419, +462 -1023b Me III-RP-22 O positive 426, +287 Me P O 419, -214 +501/+590b Ph III-SP-23 O negative 425, -434 Ph P 418, +351 -785/-872c O H III-RP-24 aA corresponds to the amplitude for the ECCD spectrum, while Acorr is the amplitude after correction for the enantiopurity. b5 equiv of phosphine oxide. c20 equiv of phosphine oxide. 63 the host system helps in rigidifying the favored CD active helical conformer, thereby reducing the number of other possible conformers for the host-guest complex. Based on these observations, a mnemonic was proposed to correlate the absolute stereochemistry of the host molecule with the observed CD signal. As depicted in Figure III-10, coordination of the oxygen lone pair with the Lewis acidic Zn center places the guest molecule III-RP-19 in the pocket between the two porphyrin rings of I-Zn-MAPOL 34. Minimization of steric interactions, between the substituents at the asymmetric P center and the porphyrin ring leads to I-Zn-MAPOL 34 adopting a specific helicity. After the initial O-Zn coordination the smallest group (Me) is projected towards the bound porphyrin and the other two substituents of the chiral center are pointed towards the unbound porphyrin ring. An energetically minimized conformer would be achieved by placing the larger Ph Ph Ph Ph Me Me Me Me N N Ph Ph P Ph N N N N Ph Ph P Ph N N (RP) O (RP) O Zn Zn Zn Zn Ph N N Ph N N N H H N Ph N N Ph H H O O O O P-helicity M-helicity positive ECCD negative ECCD top view top view Zn Zn Ph O Ph P Me P Me O Zn Zn P-(RP) complex Me M-(RP) complex disfavored Me favored Figure III-10. Proposed working model to correlate the observed signal with the stereochemistry of the guest phosphine oxide. 64 phenyl group (based on A strain values) in a less sterically hindered space, that is away from the unbound porphyrin. Such spatial arrangement would lead to the M-(RP) complex and a negative ECCD signal is anticipated. The latter speculation agrees with the observed ECCD signal for the complex of III-RP-19 with I-Zn-MAPOL 34 (Table III-1). The predicted signs of all phosphine oxides, based on their A strain values, are in full agreement with the experimentally observed values (Table III-1). The I-Zn-MAPOL 34 host system is capable of discerning small differences in relative size of the P-substituents with ease. For example, steric differentiation of methyl and ethyl, or phenyl and o-anisyl, leads to large ECCD signals, although their sizes are not significantly different (Table III- 1). It is also worth mentioning here that the length parameter L, that was used for the S- chiral sulfoxide molecules cannot predict the observed ECCD spectra. Based on the L values of the substituents, (nBu > Ph > Me) a negative ECCD spectra is expected for compound III-SP-20. Nonetheless, a positive spectrum is observed relating their A values i.e; Ph > nBu > Me. The successful application of I-Zn-MAPOL 34 to determine the absolute configuration of tertiary mono-phosphine oxides prompted the investigation of more complex substrates to examine the generality and applicability of our developed methodology. In this pursuit, compound III-RP-22 and its epimer III-SP-23 (differing chirality at P center only) both bearing multiple chiral centers was synthesized. Nonetheless, they produced opposite ECCD signals when complexed with I-Zn-MAPOL 34, thus highlighting the sensitivity of the host system to the asymmetry at the P-chiral center (Figure III-11a). Similar binding model (Figure III-10) can also predict the chirality 65 a b Figure III-11. a. ECCD spectra of I-Zn-MAPOL 34 with 5 equiv of III-RP-22 (red) and III-SP-23 (blue). b. ECCD spectra of I-Zn-MAPOL 34 with 5 equiv of III-RP-22 (red) and III-RP-24 (blue). of these two epimers considering the size of the substituents (based on A strain values) in the order of Ph > OMen > Me. Compound III-RP-24 (Ph > OMen > H) replacing Me group with a H atom, produced similar signal as III-RP-22 (Figure III-11b) reinforces our proposed binding model. III-4 Absolute stereochemical determination of P-chiral center of Sofosbuvir Next, the system was challenged with molecules that not only contain multiple stereocenters, but also have coordinating functionalities, which has the potential to bind with the zincated porphyrin. This would demonstrate the practical use of I-Zn-MAPOL 34 with a pharmaceutical API with a complex structure. Hence, we decided to analyze Sofosbuvir III-2, a commercial antiviral agent, widely used for the treatment of hepatitis C virus (HCV).15 In addition to the phosphoramidate functionality, sofosbuvir contains hydroxyl, ester, fluoride, and imide moieties, which could potentially bind to the zincated 66 porphyrin. Nonetheless, we posited that the strong binding affinity for phosphorous oxide complexation with the zincated porphyrin (~270,000 M-1) would still make this coordination as the primary binding mode. As a point of comparison, to date we have found amines and sulfoxides as the strongest binders of Zn-TPP, with binding affinities of ~11,000-15,000 M-1.27, 34 Complexation of Sofosbuvir III-2 with I-Zn-MAPOL 34 resulted in strong positive ECCD signal in hexane. Surprisingly, epi-Sofosbuvir (III-epi-2), epimeric only at the P-stereocenter, also resulted in a positive ECCD signal, albeit with lower amplitude (Figure III-12). We proposed that although various functional groups in sofosbuvir III-2, such as the ester, imide, fluoride, or hydroxyl, would have a substantially reduced binding affinity in comparison to the phosphoramidate, the presence of the second metalloporphyrin does not preclude the potential dual binding of other functional groups. In fact, the initial strong binding of the phosphoramidate would entropically favor the binding of another functional group with the second porphyrin leading to a bidentate coordination. Figure III-12. ECCD spectra of I-Zn-MAPOL 34 complexed with 1 equiv of III-2 (red) and III-epi-2 (blue) in hexane. 67 We surmised that the use of the non-interacting solvent, hexane, increases the availability for binding of a second functionality. It is noteworthy that the metalloporphyrin strategy (i.e., the porphyrin tweezer methodology or the Zn-MAPOL system for absolute stereochemical determination of most functional groups fails in polar solvents, presumably because of the attenuated binding affinities, either as a result of solvation of the functional group, and/or competing solvent coordination with the metalloporphyrin. Nonetheless, the high binding affinity of the phosphoramidate moiety with the zincated ) e (L medium (M) larg O O O O P O N NH O PhO O O P N NH N O NH O H OPh O O HO F HO F O O III-epi-2 III-2 Sofosbuvir epi-Sofosbuvir I-Zn-MAPOL 34 PhCl III-2 Zn Zn III-epi-2 M O L S P P L OS M III-2/I-34 III-epi-2/I-34 complex Zn Zn complex P-helicity M-helicity positive ECCD negative ECCD Figure III-13. Sofosbuvir III-2 and III-epi-2 bound to I-Zn-MAPOL 34 lead to positive and negative ECCD respectively in chlorobenzene. porphyrin suggests a solution to remove secondary interactions that originate from less efficient binding functionalities. The use of a more polar solvent would not only solvate 68 the interfering groups, but also, would decrease their binding affinity with the zincated porphyrin. This would eliminate the secondary interaction that interferes with desired sole stereo-differentiation based on the asymmetry of the P chiral center. After a quick survey, chlorinated solvents, such as dichloromethane, chloroform, and chlorobenzene provided the best balance, where sofosbuvir III-2, maintained its positive ECCD signal when bound to I-Zn-MAPOL 34, while complexation of III-epi-2 resulted in a negative ECCD signal (Figure III-13). The binding model follows the mnemonic proposed in Figure III-10, in which the smallest group (phenoxyl) on the P- stereogenic center points towards the bound porphyrin ring, while the medium (amino ester) and large (uracil) substituents on the phosphorus atom project towards the unbound porphyrin ring. To minimize steric interaction, the unbound porphyrin resides away from the larger group favoring P- helicity. This leads to the prediction of a positive ECCD signal for III-2, as observed experimentally. Expectedly, a counterclockwise twist would be favored in the binding of III-epi-2 with I-Zn-MAPOL 34, yielding a negative ECCD signal. Indeed, the measured ECCD signals are in full agreement with the proposed binding scenario (Figure III-13). 69 III-5 Absolute stereochemical determination of chiral bis-phosphine oxide After the primary accomplishment with mono-dentate P-chiral phosphine oxides, we envisaged that a similar treatment could provide an efficient protocol to determine the stereochemistry of bidentate P stereogenic ligands, a class of ligands used extensively in the literature for transition metal mediated homogeneous catalysis.1 The chiral ligand DIPAMP was first used in 1970 for an asymmetric hydrogenation to synthesize L-DOPA by Knowles at Monsanto (Figure III-14a).35 It was envisaged that the presence of the bis Zn-metallo center would lead to a bidentate coordination, yielding stronger complex formation in comparison to their monodentate analogues. As anticipated, the binding affinity of bisphosphine oxides with I-Zn-MAPOL 34 are much higher (300 times) as compared to their corresponding mono-phosphine oxide analogues (8.2´107 M-1 in a. DIPAMP ligand for asymmetric hydrogenation: AcO HO NHAc 1.H2/[Rh(R,R)-DIPAMP(COD)]BF4 (cat.) NHAc 2. H3O+ MeO CO2H HO CO2H III-25 III-26 L- DOPA b. α-chiral bis-phosphine ligands: Ph Ph Ph2P PPh2 P P Ph2P PPh2 Ph Ph III-27 III-28 III-29 (R,R)-Ph-BPE (R)-ProPHOS (R,R)-ChiraPHOS Figure III-14. a. Asymmetric hydrogenation to synthesize L-DOPA using DIPAMP ligand. b. Examples of important a-chiral bis-phosphine ligands used in transition metal catalyzed reactions. 70 comparison with ~2.7´105 M-1). The stoichiometry of the complex was found to be 1:1 employing the Job’s analysis (Figure III-15a). The investigation of the chirality was initiated with III-RP,RP-30, the corresponding a b Figure III-15. a. Jobs plot of I-Zn-MAPOL 34 with DPPOE at 408 nm. b. Binding affinity measurement of DPPOE with I-Zn-MAPOL 34. oxide of commercially available RP,RP-DIPAMP. Gratifyingly only 1 equivalent of III-RP,RP- 30 can produce strong ECCD signal in hexane (Table III-2). This low detection limit is consistent with its strong binding affinity to the Zn metallo centers. As predicted, the enantiomer III-SP,SP-30 produces the opposite signal. The concept was then extended to compound III-RP,RP-31, showcasing the practicality of our developed methodology. Figure III-17a depicts the proposed mnemonic for the stereodifferentiation that leads to the observed ECCD spectra. It was assumed that each asymmetric phosphorus center plays its part in orienting the attached porphyrin independently, leading to the preferred helicity of the host system. 71 Each porphyrin is bound to the phosphorus center in a way to minimize steric interactions with the larger of the two substituents (2-Me-C6H4 vs. Ph, III-RP,RP-31). In the proposed mnemonic the chain connecting the two phosphorus centers is not part of the stereodifferentiation. Also important is the fact that the two substituents on the phosphorus center are moved away from the biphenol linker to reduce steric interactions Table III-2. ECCD of chiral bisphosphine oxides with I-Zn- MAPOL 34 entry predicted sign λ nm, Δε A[a] O Ph 2-MeOC6H4 P positive 427, +416 P 2-MeOC6H4 418, -196 +612 Ph O III-SP,SP-30 O 2-MeOC6H4 Ph P 427, -426 P Ph negative -654 2-MeOC6H4 418, +228 O III-RP,RP-30 O 2-MeC6H4 Ph P P Ph negative 429, -1838 2-MeC H6 4 420, +1622 -3460 O III-RP,RP-31 O Ph P Ph Ph P Ph 429, +332 positive +586 421, -254 O III-R-32 O Ph P Ph 427, -1646 Ph P Ph negative -2770 419, +1124 O III-S,S-33 O Ph P Ph 427, +1862 Ph P Ph positive 419, -1248 +3110 O III-R,R-34 Ph Ph Ph P P Ph negative 427, -1350 -2154 418, +804 O O III-S,S-35 a. A corresponds to the amplitude of the ECCD spectrum with one equiv of guest. 72 with the linker. Such orientation would lead to the negative ECCD signal which is in accordance with the observed signal (Figure III-16a). So far, all the examples have demonstrated ‘chiral sensing’ of molecules with an asymmetric phosphorus center. Nonetheless, an important subset of the bidentate phosphorus ligands is not asymmetric at the P-center, rather at the adjacent carbon center (Figure III-16b).36-37 We envisaged that strong bidentate coordination between bisphosphine oxide and I-Zn-MAPOL 34 might allow us to determine the absolute chirality at the adjacent carbon center. Gratifyingly a strong positive ECCD signal is observed a. R RS L Zn O 2-MeC6H4 P O Ph P I-Zn-MAPOL 34 2-MeC6H4 P Ph RL = 2-MeC6H4 Rs = Ph O P O RL Zn RS III-RP,RP-31 M helicity b. Me O Zn Ph Ph P Ph I-Zn-MAPOL 34 O Ph P Ph P Ph RL = Me RS Me Rs = H RL RL O RS P III-R,R-34 Ph O Ph Zn P helicity Figure III-16. Proposed working model to correlate the chirality of the bisphosphine oxides with the observed ECCD signal. when compound III-R,R-34 was treated with I-Zn-MAPOL 34 under identical conditions. Table III-2 lists a number of these molecules complexed with I-Zn-MAPOL 34, where 73 consistently strong ECCD signals were observed. Figure III-16b depicts the proposed binding model that predicts helicity of the complex. As depicted, we believe the chirality at each carbon center is responsible for the helical twist of its adjacent porphyrin. The phenyl substituents on each phosphorus atom are placed in the most sterically open space, while between RL and RS, (the large and small a-carbon substituents, respectively) it is the smaller RS (H atom) that is oriented towards the linker. In this manner each porphyrin slides away from RL (phenyl) group placing it in the least sterically hindered space. Such an orientation leads to a clockwise (P-helical) helicity for III-R,R-34, that indeed matches with the observed positive ECCD signal. In summary, we have developed a simple chiroptical protocol for the direct assignment of absolute stereochemistry of chiral phosphorus compounds without the need for derivatization. The protocol is suitable for the stereochemical determination of phosphorus stereocenters in monophosphine oxides, phosphinates, phosphoramidates, as well as bis-phosphine oxides, chiral at either the P-center or the a-carbon. High binding affinities enable the detection of stereochemistry for P-stereogenic center of molecules with multiple functionalities that could also bind with the zincated porphyrin. Simple mnemonics for each class of molecules correlates the observed ECCD signal with the stereochemistry. Based on the strong binding affinities between the phosphine oxide and Zn metallo center we surmise that this work could be extended in future to a-chiral as well as distal chiral mono phosphine oxides. 74 III-6 Experimental Section III-6.1. Materials and general instrumentations Anhydrous solvents used for CD measurements were purchased from Aldrich and were spectra grade. Unless otherwise mentioned, solvents were purified as follows. CH2Cl2 was dried over CaH2 whereas THF and Et2O were dried over sodium (dryness was monitored by colorization of benzophenone ketyl radical); they were freshly distilled prior to use. NMR spectra were obtained using 500 MHz Varian NMR spectrometers and referenced using the residual 1H peak from the deuterated solvent for the proton NMR, the carbon shift of the solvent (77.0 ppm for CDCl3) for the 13C-NMR, and phosphoric acid (as the internal standard reference for the 31P-NMR measurements. Column chromatography was performed using Silicycle 60 Å, 35-75 µm silica gel. Pre-coated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, p-anisaldehyde stain or phosphomolybdic acid in EtOH stain. CD spectra were recorded on a JASCO J-810 spectropolarimeter, equipped with a temperature controller (Neslab 111) for low temperature studies, and are reported as Mol. CD / l [nm]. UV-vis spectra were recorded on an Agilent, Cary 100 UV-visible spectrophotometer equipped with temperature controller. UV spectra were collected with scan rate of 100 nm/min. Sofosbuvir and epi-sofusbuvir were generously gifted from Merck, Inc. 75 III-6.2. General procedure for UV-vis measurements, binding affinity calculations and Job plot analysis UV-vis measurement: I-Zn-MAPOL 34 (1.0 µL of a 0.001M solution in anhydrous dichloromethane, 1.0 µmol) was added to hexane (1.0 mL) in a 1.0 cm UV-cell. The background spectrum was recorded from 350 nm to 480 nm at a scan rate of 100 nm/min. Chiral phosphorus oxides (1 up to 500 equivalents) from four different stock solutions in anhydrous dichloromethane [0.1M (for 100-500 equiv), 0.01M (for 10-100 equiv), 0.001M (for 1-10 equiv), 0.0001M (for 0.1-1 equiv)] were then added to the I-Zn-MAPOL 34 solution. The UV spectra were collected after each addition. A representative UV-vis titration graph is shown in Figure III-17. Figure III-17. UV-vis titration of I-Zn-MAPOL 34 (1µM) with III-RP-19 at 0 °C in hexane. 76 Binding affinity measurements: The binding affinity was derived by fitting the UV-vis data (Fig- III-17) to the non-linear least square equation as reported by Shoji et. al.38 Figure III- 18 depicts the binding affinity measured for III-RP-19. Figure III-18. Binding affinity measurement for III-RP-19 titration with I- Zn-MAPOL 34. Jobs plot analysis: Job’s plot analysis was performed by measuring the changes in the UV-vis absorbance of I-Zn-MAPOL 34 upon addition of III-RP-19. Changes in the UV-vis absorbance (ΔAabs) were calculated by subtracting the absorbance at each titration point from the absorbance of free I-Zn-MAPOL 34 at 410 nm. The molar fraction of I-Zn- MAPOL 34 (XZn- MAPOL) was then multiplied with the change in the UV-vis absorbance (ΔAabs) for each titration point and was plotted against the molar fraction of III-RP-19. The 77 maxima at 0.5 III-RP-19 confirms the formation of a 1:1 complex between I-Zn-MAPOL 34 and phosphine oxide III-RP-19. Figure III-19. Job plot of I-Zn-MAPOL 34 with III-RP-19 at 410 nm. III-6.3. General procedure for CD measurement I-Zn-MAPOL 34 (1.0 µL of a 0.001M solution in anhydrous dichloromethane, 1.0 µmol) was added to hexane (1.0 mL) in a 1.0 cm CD cell (cooled to 0 °C) to obtain a 1.0 µM solution. The background spectrum was recorded from 350 nm to 480 nm with a scan rate of 100 nm/min at 0 °C. Chiral phosphine oxide from a stock solution in anhydrous dichloromethane (0.001 M for 1-10 equiv and 0.01 M for 10-20 equiv) was added to the prepared host solution to afford the host-guest complex. The CD spectra were measured immediately (10 scans). The resultant ECCD spectra recorded in millidegrees were converted the molecular CD (Mol. CD) considering the host concentration of 1.0 µM. 78 O P Me Figure III-20. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-SP-18 at 0 °C in hexane. O P Me Figure III-21. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-18 at 0 °C in hexane. 79 O P Me Figure III-22. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-SP-19 at 0 °C in hexane. O P Me Figure III-23. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-19 at 0 °C in hexane. 80 O P Me Figure III-24. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-SP-20 at 0 °C in hexane. OMe O P Ph Me Figure III-25. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-21 at 0 °C in hexane. 81 O Ph P O Me Figure III-26. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-22 at 0 °C in hexane. O Me P O Ph Figure III-27. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-SP-23 at 0 °C in hexane. 82 O Ph P O H Figure III-28. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-24 at 0 °C in hexane. O O O P O N NH N O H OPh O O HO F Figure III-29. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-2 at 0 °C in hexane. 83 O O O PhO P O N NH NH O HO F O O Figure III-30. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-epi-2 at 0 °C in hexane. O O O P O N NH N O H OPh O O HO F Figure III-31. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 20 equiv of III-2 at 0 °C in chlorobenzene. 84 O O O PhO P O N NH NH O HO F O O Figure III-32. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 20 equiv of III-epi-2 at 0 °C in chlorobenzene. O 2-MeOC6H4 P Ph Ph P 2-MeOC6H4 O Figure III-33. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-SP,SP-30 at 0 °C in hexane. 85 O Ph P 2-MeOC6H4 2-MeOC6H4 P Ph O Figure III-34. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-RP,RP-30 at 0 °C in hexane. O Ph P 2-MeOC6H4 2-MeC6H4 P Ph O Figure III-35. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-RP,RP-31 at 0 °C in hexane. 86 O Ph P Ph Ph P Ph O Figure III-36. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-R-32 at 0 °C in hexane. O Ph P Ph Ph P Ph O Figure III-37. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-S,S-33 at 0 °C in hexane. 87 O Ph P Ph Ph P Ph O Figure III-38. Positive ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-R,R-34 at 0 °C in hexane. Ph Ph Ph P P Ph O O Figure III-39. Negative ECCD spectrum of I-Zn-MAPOL 34 complexed with 1 equiv of III-S,S-35 at 0 °C in hexane. 88 III-6.4. Temperature dependence on the amplitude of the ECCD signal for I-Zn- MAPOL 34 complexed with III-RP-19 I-Zn-MAPOL 34 (1.0 µM) was complexed with 5 equiv of III-RP-19 (5.0 µmol) in hexane. With the increase in temperature the ECCD signal drops gradually, although significant signal is observed even at 45 °C. The same ECCD active solution at 45 °C increases signal intensity when cooled down to 0 °C with an intensity similar to the ECCD signal of the original complex at 0 °C. Figure III-40. Change in ECCD signal of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-19 in hexane at different temperatures. 89 Figure III-41. Temperature dependence on the amplitude of the ECCD signal of I- Zn-MAPOL 34 complexed with 5 equiv of III-RP-19 in hexane. 90 III-6.5. Solvent screening for I Zn-MAPOL 34 complexed with III-RP-19 and III-RP-22 Figure III-42. ECCD spectra of I-Zn-MAPOL 34 complexed with III-RP-19 at 0 °C in different solvents. Figure III-43. ECCD titration of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-19 at 0 °C with acetone. 91 Figure III-44. ECCD titration of I-Zn-MAPOL 34 complexed with 5 equiv of III-RP-19 at 0 °C with ethyl acetate. Figure III-45. ECCD titration of I-Zn-MAPOL 34 complexed with 20 equiv of III-RP-22 at 0 °C with acetone. 92 Figure III-46. ECCD titration of I-Zn-MAPOL 34 complexed with 20 equiv of III-RP-22 at 0 °C in ethyl acetate. 93 III-6.6. ECCD of III-MeO-Zn-MAPOL 16 complexed with chiral phosphorous oxide Figure III-47. ECCD of I-Zn-MAPOL 34 (red curve) and III-MeO-Zn-MAPOL 16 (blue curve) complexed with 5 equiv of III-RP-19 at 0 °C in hexane. Figure III-48. ECCD of I-Zn-MAPOL 34 (red curve) and III-MeO-Zn-MAPOL 16 (blue curve) complexed with 5 equiv of III-RP-18 at 0 °C in hexane. 94 Figure III-49. ECCD of I-Zn-MAPOL 34 (red curve) and III-MeO-Zn-MAPOL 16 (blue curve) complexed with 20 equiv of III-RP-21 at 0 °C in hexane. Figure III-50. ECCD of I-Zn-MAPOL 34 (red curve) and III-MeO-Zn-MAPOL 16 (blue curve) complexed with 5 equiv of III-RP-22 at 0 °C in hexane. 95 III-6.7. Synthesis of P-chiral phosphine oxides P-chiral phosphine oxides were synthesized following literature procedures.5, 18-19, 32-33 Optical purity was measured comparing their optical rotation values with the reported values. ethyl(methyl)(phenyl)phosphine oxide: O O P Me P Me III-SP-18 III-RP-18 III-SP-18 enantiomer: [a]D = -16.7 (c = 1.0, MeOH); ee = 68% III-RP-18 enantiomer: [a]D = +18.1 (c = 1.0, MeOH); ee = 74% 1H NMR (500 MHz, CDCl3) δ 7.72 – 7.67 (m, 2H), 7.54 – 7.46 (m, 3H), 2.03 – 1.83 (m, 2H), 1.69 (dd, J = 12.7, 1.4 Hz, 3H), 1.15 – 1.08 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 133.62, 132.86, 131.61 (d, J = 2.7 Hz), 130.07 (d, J = 9.3 Hz), 128.64 (d, J = 11.4 Hz), 24.64 (d, J = 71.4 Hz), 15.40 (d, J = 69.6 Hz), 5.73 (d, J = 5.1 Hz). 31P NMR (202 MHz, CDCl3) δ 39.11. methyl(phenyl)(propyl)phosphine oxide: O O P Me P Me III-SP-19 III-RP-19 96 III-SP-19 enantiomer: [a]D = -13.2 (c = 1.0, MeOH); ee = 78% III-RP-19 enantiomer: [a]D = +15.5 (c = 1.0, MeOH); ee = 92% 1H NMR (500 MHz, CDCl3) δ 7.73 – 7.69 (m, 2H), 7.53 – 7.48 (m, 3H), 2.00 – 1.81 (m, 3H), 1.69 (d, J = 12.7 Hz, 3H), 1.67 – 1.47 (m, 2H), 0.99 (td, J = 7.3, 1.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 134.15, 133.99, 131.55 (d, J = 2.6 Hz), 129.99 (d, J = 9.3 Hz), 128.63 (d, J = 11.4 Hz), 33.91 (d, J = 70.4 Hz), 16.32, 15.73 (d, J = 11.9 Hz), 15.56, 15.42 (d, J = 3.8 Hz). 31P NMR (202 MHz, CDCl3) δ 37.11. butyl(methyl)(phenyl)phosphine oxide: O P Me III-SP-20 [a]D = -11.5 (c = 1.0, MeOH); ee = 69% 1H NMR (500 MHz, CDCl3) δ 7.70 – 7.67 (m, 2H), 7.59 – 7.41 (m, 3H), 2.02 – 1.81 (m, 2H), 1.70 (d, J = 12.7 Hz, 3H), 1.66 – 1.42 (m, 2H), 1.42 – 1.32 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 134.16, 133.40, (131.55 (d, J = 2.8 Hz), 130.02 (d, J = 9.1 Hz), 128.64 (d, J = 11.4 Hz), 31.52 (d, J = 70.5 Hz), 24.03 (d, J = 15.2 Hz), 23.68 (d, J = 4.3 Hz), 16.04 (d, J = 69.5 Hz), 13.58. 31P NMR (202 MHz, CDCl3) δ 37.39 97 2-methoxyphenyl(methyl)(phenyl)phosphine oxide: OMe O P Ph Me III-RP-21 [a]D = +18.8 (c = 1.0, MeOH); ee = 71% 1H NMR (500 MHz, CDCl3) δ 7.97 (ddd, J = 13.1, 7.5, 1.8 Hz, 1H), 7.79 – 7.68 (m, 2H), 7.55 – 7.45 (m, 2H), 7.44 – 7.40 (m, 2H), 7.11 (tdd, J = 7.5, 1.8, 0.9 Hz, 1H), 6.89 (ddd, J = 8.5, 5.4, 0.9 Hz, 1H), 3.73 (s, 3H), 2.08 (d, J = 14.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 133.97 (d, J = 6.1 Hz), 133.88 (d, J = 2.8 Hz), 131.25 (d, J = 2.9 Hz), 130.26 (d, J = 10.4 Hz), 128.20 (d, J = 12.4 Hz), 121.04 (d, J = 11.3 Hz), 110.84 (d, J = 6.6 Hz), 55.28, 16.17 (d, J = 75.2 Hz). 31P NMR (202 MHz, CDCl3) δ 28.33. (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (RP)-methyl(phenyl) phosphinate: O Ph P O Me III-RP-22 1H NMR (500 MHz, CDCl3) δ 7.85 – 7.75 (m, 2H), 7.56 –7.50 (m, 1H), 7.49 – 7.44 (m, 2H), 4.27 (tdd, J = 10.7, 8.2, 4.5 Hz, 1H), 2.23 – 2.17 (m,1H), 1.83–1.79 (m, 1H), 1.71 – 1.55 (m, 5H), 1.39 – 1.29 (m, 2H), 1.04 –0.97 (m, 2H), 0.96 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.85 – 0.79 (m, 1H), 0.76 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 131.89 (d, J = 2.8 Hz), 130.82 (d, J = 10.1 Hz), 128.40 (d, J = 12.8 Hz), 76.37 (d, J = 98 7.1 Hz), 48.75 (d, J = 6.2 Hz), 43.21, 34.09, 31.43, 25.85, 22.95, 21.91, 21.10, 16.95, 16.14, 15.83. 31P NMR (202 MHz, CDCl3) δ 39.81. (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (SP)-methyl(phenyl) phosphinate: O Me P O Ph III-SP-23 1H NMR (500 MHz, CDCl3) δ 7.83 – 7.79 (m, 2H), 7.58 –7.51 (m, 1H), 7.51 – 7.45 (m, 2H), 3.97 (tdd, J = 10.5, 7.9, 4.5 Hz, 1H), 2.45 – 2.33 (m, 1H), 1.94 –1.88 (m, 1H), 1.72 (d, J = 14.5 Hz, 3H), 1.65 – 1.55 (m, 2H), 1.43 – 1.37 (m, 1H), 1.35 – 1.19 (m, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 10.3 Hz, 1H), 0.83 (d, J = 7.1 Hz, 1H), 0.31 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 131.97 (d, J = 2.6 Hz), 131.12 (d, J = 10.0 Hz), 128.41 (d, J = 12.8 Hz), 76.69, 48.76 (d, J = 6.8 Hz), 43.87, 34.07, 31.54, 25.36, 22.67, 21.98, 21.08, 16.96, 16.14, 15.15. 31P NMR (202 MHz, CDCl3) δ 40.49. dr = 12.5 :1 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (RP)-phenyl phosphinate: O Ph P O H III-RP-24 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.80 – 7.75 (m, 2H), 7.65 (d, J = 550 Hz, HP 1H), 7.60 – 7.57 (m, 1H), 7.52 – 7.48 (m, 2H), 4.25 (qd, J = 10.5, 4.5 Hz, 1H), 2.24 – 2.15 99 (m, 2H), 1.71 – 1.65 (m, 2H), 1.48 – 1.42 (m, 2H), 1.24 (q, J = 10.0 Hz, 1H), 1.04 (qd, , J = 15 Hz, 5 Hz, 1H), 0.95 (d, J = 7.0 Hz, 3H), 0.87 (m,7H), 13C NMR (126 MHz, CDCl3) δ 132.91 (d, J = 2.9 Hz), 130.63, (d, J = 11.8 Hz), 128.67 (d, J = 13.8 Hz), 78.96 (d, J = 7.4 Hz), 48.69 (d, J = 6.2 Hz), 43.49 (d, J = 1.1 Hz), 33.91, 31.63, 25.76, 22.89, 21.86, 20.99, 15.73. 31P NMR (202 MHz, CDCl3) δ 24.73. dr = 19:1 III-6.8. NMR Spectra: 7.26 cdcl3 1H NMR (500 MHz, CDCl3) O P Me III-RP-18 3.13 1.18 1.16 1.14 1.12 1.10 1.08 1.06 1.04 1.02 f1 (ppm) 1.90 2.81 2.23 7.8 7.7 7.6 7.5 7.4 f1 (ppm) 2.00 1.95 1.90 1.85 1.80 f1 (ppm) 1.90 2.81 2.23 3.00 3.13 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 100 13 200 190 180 C NMR (126 MHz, CDCl3) 170 134 133.74 160 133 132.98 150 132 131.74 131.72 131 133.74 140 132.98 f1 (ppm) 131.74 131.72 130 130.23 130.23 130.15 130.15 130 128.81 128.72 120 129 128.81 110 128.72 100 101 f1 (ppm) 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 P O 50 III-RP-18 Me 40 30 25.04 24.47 20 15.80 15.24 10 5.87 5.83 0 P NMR (202 MHz, CDCl3) 39.11 31 O P Me III-RP-18 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 102 7.26 cdcl3 1H NMR (500 MHz, CDCl3) O P Me III-RP-19 3.26 2.83 3.38 2.34 1.01 1.00 0.99 0.98 0.97 2.0 1.9 1.8 1.7 1.6 1.5 f1 (ppm) f1 (ppm) 2.00 3.06 7.8 7.7 7.6 7.5 7.4 f1 (ppm) 2.00 3.06 2.83 3.37 2.34 3.26 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 103 13 200 P O 190 III-RP-19 Me 135 180 134.29 134 133.53 C NMR (126 MHz, CDCl3) 170 133 160 132 131 131.69 131.67 150 f1 (ppm) 134.29 140 130.17 133.53 130 130.10 131.69 131.67 130 130.17 129 128.81 130.10 128.72 128.81 128.72 120 110 100 f1 (ppm) 104 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 16.5 16.46 60 16.3 50 16.1 40 15.9 34.33 15.91 33.77 30 f1 (ppm) 15.82 16.46 20 15.7 15.69 15.91 15.82 15.57 15.69 15.54 15.57 10 15.5 15.54 0 15.3 P NMR (202 MHz, CDCl3) 37.11 31 O P Me III-RP-19 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 105 7.26 cdcl3 1H NMR (500 MHz, CDCl3) O P Me III-SP-20 2.11 1.41 1.40 1.39 1.38 1.37 1.36 1.35 1.34 f1 (ppm) 2.38 1.65 1.60 1.55 1.50 1.45 f1 (ppm) 1.82 2.75 7.80 7.75 7.70 7.65 7.60 7.55 7.50 7.45 f1 (ppm) 2.35 2.00 1.95 1.90 1.85 f1 (ppm) 1.82 2.75 2.35 3.06 3.00 2.38 2.11 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 106 13 200 190 134.29 180 134 O 133.53 C NMR (126 MHz, CDCl3) III-SP-20 170 133 P Me 160 132 131 131.69 131.67 150 f1 (ppm) 130.19 134.29 140 130.12 133.53 130 130.11 131.69 131.67 130.19 130 130.12 129 128.81 130.11 128.72 128.81 120 128.72 128 110 100 107 f1 (ppm) 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 24.3 24.22 24.2 50 24.1 24.10 40 24.0 23.9 31.93 30 31.37 24.22 f1 (ppm) 24.10 23.83 20 23.83 23.80 23.8 23.80 16.45 15.89 10 13.72 23.7 0 23.6 37.39 P NMR (202 MHz, CDCl3) 31 O P Me III-SP-20 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 108 7.26 cdcl3 1H NMR (500 MHz, CDCl3) 1.00 1.98 1.06 8.00 7.95 7.90 7.85 7.80 7.75 7.13 7.12 7.11 7.10 7.09 f1 (ppm) f1 (ppm) OMe O P Ph Me 2.05 2.03 III-RP-21 1.07 7.52 7.50 7.48 7.46 7.44 7.42 7.40 6.905 6.895 6.885 6.875 6.865 f1 (ppm) f1 (ppm) 1.00 1.06 1.07 3.47 3.53 1.98 2.05 2.03 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 109 C NMR (126 MHz, CDCl3) 13 77.41 cdcl3 77.16 cdcl3 134.13 111.01 134.09 134.02 55.42 16.60 134.01 131.40 131.37 76.91 cdcl3 130.44 110.95 130.35 16.00 128.38 128.29 121.22 121.13 OMe O P 134.13 134.09 131.40 130.44 128.38 Ph 134.02 134.01 131.37 130.35 128.29 Me III-RP-21 111.01 110.95 121.22 121.13 136 135 134 133 132 131 130 129 128 127 f1 (ppm) 111.10 111.05 111.00 110.95 110.90 110.85 f1 (ppm) 121.4 121.3 121.2 121.1 121.0 f1 (ppm) 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 110 P NMR (202 MHz, CDCl3) 31 28.33 OMe O P Ph Me III-RP-21 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 111 7.26 cdcl3 1H NMR (500 MHz, CDCl3) 1.77 0.92 1.82 1.83 3.11 3.12 1.15 3.06 7.80 7.75 7.70 7.65 7.60 7.55 7.50 7.45 1.05 1.00 0.95 0.90 0.85 0.80 0.75 f1 (ppm) f1 (ppm) O Ph P O Me III-RP-22 1.77 1.05 1.02 0.92 1.05 2.00 1.85 3.11 5.32 3.12 1.82 1.15 3.05 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 112 13 200 190 180 132.03 C NMR (126 MHz, CDCl3) 170 132 132.01 160 131 131.00 130.92 150 130 140 f1 (ppm) 132.03 132.01 131.00 130 130.92 129 128.58 128.48 128.58 120 128.48 128 110 100 90 113 f1 (ppm) 77.41 cdcl3 80 77.16 cdcl3 76.91 cdcl3 76.53 76.48 70 60 Ph P O O 50 Me 48.92 III-RP-22 48.87 43.35 40 34.23 31.57 30 25.99 23.08 22.05 21.24 20 17.09 16.28 15.97 10 0 39.81 P NMR (202 MHz, CDCl3) 31 O Ph P O Me III-RP-22 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 114 7.26 cdcl3 1H NMR (500 MHz, CDCl3) O Me P O Ph III-SP-23 1.91 1.00 1.95 1.21 3.35 2.71 1.50 3.61 3.52 1.61 3.38 7.9 7.8 7.7 7.6 7.5 7.4 2.0 1.5 1.0 f1 (ppm) f1 (ppm) 1.91 1.24 1.23 1.21 3.52 3.40 1.00 3.35 2.71 1.61 1.95 1.50 3.61 3.38 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 115 13 200 Me P O 190 O III-SP-23 Ph 180 C NMR (126 MHz, CDCl3) 170 160 133 133.05 132.12 150 132.10 132 132.04 140 131.30 133.05 131.22 132.12 132.10 131 130 132.04 130 131.30 131.22 f1 (ppm) 128.60 128.50 120 110 129 128.60 128.50 100 128 f1 (ppm) 116 90 77.41 cdcl3 80 77.16 cdcl3 76.91 cdcl3 76.83 70 60 50 48.92 48.87 44.01 40 34.21 31.68 30 25.50 22.80 22.12 20 21.21 17.10 16.28 15.29 10 0 P NMR (202 MHz,CDCl3) 40.49 31 O Me P O Ph III-SP-23 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 117 7.26 cdcl3 1H NMR (500 MHz, CDCl3) O Ph P O 7.26 cdcl3 H III-RP-24 0.44 1.81 0.86 1.80 0.44 2.00 2.07 1.98 1.14 1.19 2.97 7.14 8.2 8.0 7.8 7.6 7.4 7.2 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 f1 (ppm) f1 (ppm) 0.44 1.82 0.44 1.14 2.00 2.07 1.98 0.86 1.14 1.19 1.80 2.97 7.14 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 118 13 200 190 180 C NMR (126 MHz, CDCl3) 170 133.05 133 133.03 160 132 150 131.60 130.81 140 131 130 130.72 133.05 130.52 133.03 131.60 f1 (ppm) 130.81 130 130.72 130.52 128.87 129 128.87 128.76 120 128.76 110 128 100 f1 (ppm) 119 Ph 90 H P O 79.13 80 79.07 O 77.42 cdcl3 III-RP-24 77.16 cdcl3 76.91 cdcl3 70 60 50 48.85 48.80 43.63 43.62 40 34.04 31.77 30 25.90 23.03 20 22.00 21.13 15.87 10 0 24.73 P NMR (202 MHz, CDCl3) 31 O Ph P O H III-RP-24 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 f1 (ppm) 120 III-6.9. Crystal structure of III-RP-19 bound to Zn-TPP Experimental. Single purple needle-shaped crystals of were used as received. A suitable crystal (0.43×0.07×0.03) mm3 was selected and mounted on a nylon loop with paratone oil on a Bruker APEX-II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 the structure was solved with the olex2.solve structure solution program, using the Charge Flipping solution method. The model was refined with version of XL using Least Squares minimization. Crystal Data. C55.17H44.33N4OPZn, Mr = 875.62, hexagonal, P61 (No. 169), a = 28.1290(8) Å, b = 28.1290(8) Å, c = 10.2773(4) Å, a = 90°, b = 90°, g = 120°, V = 7042.4(5) Å3, T = 173(2) K, Z = 6, Z' = 1, µ(CuKa) = 1.376, 21473 reflections measured, 8298 unique (Rint = 0.2745) which were used in all calculations. The final wR2 was 0.2611(all data) and R1 was 0.0880 (I > 2(I)). 121 Formula C55.17H44.33N4OPZn Dcalc./ g cm-3 1.239 µ/mm-1 1.376 Formula Weight 875.62 Colour purple Shape needle Size/mm3 0.43×0.07×0.03 T/K 173(2) Crystal System hexagonal Flack Parameter 0.07(4) Hooft Parameter 0.05(4) Space Group P61 a/Å 28.1290(8) b/Å 28.1290(8) c/Å 10.2773(4) a/° 90 b/° 90 g/° 120 V/Å3 7042.4(5) Z 6 Z' 1 Wavelength/Å 1.541838 122 Radiation type CuKa Qmin/° 1.813 Qmax/° 68.215 Measured Refl. 21473 Independent Refl. 8298 Reflections Used 3791 Rint 0.2745 Parameters 556 Restraints 8 Largest Peak 0.831 Deepest Hole -0.468 GooF 0.957 wR2 (all data) 0.2611 wR2 0.2059 R1 (all data) 0.1980 R1 0.0880 123 A purple needle-shaped crystal with dimensions 0.43×0.07×0.03 mm3 was mounted on a nylon loop with paratone oil. Data were collected using a Bruker APEX-II CCD diffractometer equipped with an Oxford Cryosystems low-temperature device, operating at T = 173(2) K. Data were measured using w of 1.00° per frame for 495.00 s using CuKa radiation (sealed tube, 40 kV, 30 mA). The total number of runs and images was based on the strategy calculation from the program COSMO (BRUKER, V1.61, 2009). The achieved resolution was Q = 68.215. Cell parameters were retrieved using the SAINT (Bruker, V8.34A, after 2013) software and refined using SAINT (Bruker, V8.34A, after 2013) on 1949 reflections, 9% of the observed reflections. Data reduction was performed using the SAINT (Bruker, V8.34A, after 2013) software which corrects for Lorentz polarization. The final completeness is 99.20 out to 68.215 in Q. A multi-scan absorption correction was performed using SADABS-2012/1 (Bruker,2012) was used for absorption correction. wR2(int) was 0.0778 before and 0.0604 after correction. The Ratio of minimum to maximum transmission is 0.7866. The l/2 correction factor is 0.0015. The absorption coefficient µ of this material is 1.376 mm-1 at this wavelength (l = 1.54178Å) and the minimum and maximum transmissions are 0.5924 and 0.7531. SADABS-2012/1 (Bruker,2012) was used for absorption correction. wR2(int) was 0.0778 before and 0.0604 after correction. The Ratio of minimum to maximum transmission is 0.7866. The l/2 correction factor is 0.0015. The structure was solved in the space group P61 by Charge Flipping using the 124 olex2.solve structure solution program. The structure was refined by Least Squares using version 2014/6 of XL incorporated in Olex2. All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model. There is a single molecule in the asymmetric unit, which is represented by the reported sum formula. In other words: Z is 6 and Z' is 1. The Flack parameter was refined to 0.07(4). Determination of absolute structure using Bayesian statistics on Bijvoet differences using the Olex2 results in 0.05(4). Note: The Flack parameter is used to determine chirality of the crystal studied, the value should be near 0, a value of 1 means that the stereochemistry is wrong, and the model should be inverted. A value of 0.5 means that the crystal consists of a racemic mixture of the two enantiomers. 125 REFERENCES 1. Dutartre, M.; Bayardon, J.; Juge, S., Chem. Soc. Rev. 2016, 45, 5771-5794. 2. Grabulosa, A.; Granell, J.; Muller, G., Coord. Chem. Rev. 2007, 251, 25-90. 3. Warner, C. J. A.; Reeder, A. T.; Jones, S., Tetrahedron: Asymmetry 2016, 27, 136- 141. 4. Loup, J.; Muller, V.; Ghorai, D.; Ackermann, L., Angew. Chem. Int. Ed. 2019, 58, 1749-1753. 5. Adams, H.; Collins, R. C.; Jones, S.; Warner, C. J. A., Org. Lett. 2011, 13, 6576- 6579. 6. Beaud, R.; Phipps, R. J.; Gaunt, M. J., J. Am. Chem. Soc. 2016, 138, 13183- 13186. 7. Bergin, E.; O'Connor, C. T.; Robinson, S. 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Shoji, Y.; Tashiro, K.; Aida, T., J. Am. Chem. Soc. 2006, 128, 10690-10691. 128 CHAPTER IV: POINT-TO-AXIAL-TO-POINT CHIRALITY TRANSFER: DESIGN AND DEVELOPMENT OF A PROGRAMMABLE ORGANOCATALYST 129 IV-1 Introduction Over the past few years interest in the design and synthesis of supramolecular catalysts that can mimic the catalytic efficacy of enzymes has intensified. In particular, the area of artificial switchable metal catalyst and organocatalyst have witnessed tremendous progress in the past decade.1-5 The most exciting part of this area of research is the control over catalyst’s reactivity. The catalyst can be triggered ‘ON’ or ‘OFF’ simply by an external stimulus that ranges from light, heat, acidity of the medium, solvent, coordination of a ligand, redox to mechanical force. Within this realm of switchable catalysis, only a few offer the possibility of dynamic control in the stereochemistry of the chiral catalyst itself.6-8 The chiral switchable catalyst kinetically favors the formation of a particular enantiomer of the product, whereas in its enantiomeric state, opposite enantiomer of the product is favored. Asymmetric organic synthesis has evolved over the years from employing stoichiometric chiral auxiliaries to the use of chiral catalyst. A common thread for either strategy has been the utilization of enantiomeric mediators to access antipodal products. The switchable chiral catalyst offers a new paradigm in this area, as it would eliminate the necessity of the availability of both the enantiomers of the same catalyst. From a practical standpoint, this strategy would eliminate the unnecessary steps required to synthesize both the enantiomeric forms of the catalyst. From a design point of view, different external effectors that can control the stereochemistry of the catalyst in a predictable manner are discussed below. 130 IV-2 Light, and heat driven chiral switchable catalyst In 2011, Nobel laureate Feringa and co-workers designed a unidirectional molecular motor and employed that as a chiral switchable catalyst in the sulfa-Michael addition to a,b -unsaturated ketone (Figure IV-1).9-10 The bifunctional chiral catalyst contains a Bronsted acidic site to activate the ketone moiety, as well as a Bronsted basic a. Me2N N NMe2 H H NH N N CF3 312 nm, 20 ℃ S On state >99% N N H Off state CF3 NH IV-(R,R)-(P,P)-E-1 NH S IV-(R,R)-(M,M)-Z-1 CF3 CF3 -10 ℃, 100% 70 ℃, 70% Me2N N NMe2 H H NH N N CF3 312 nm, -60 ℃ S On state N N 81% H CF3 Off state NH NH IV-(R,R)-(M,M)-Z-1 S IV-(R,R)-(P,P)-Z-1 CF3 CF3 b. O 0.3 mol% er = 75:25 IV-(R,R)-(M,M)-Z-1 S SH O OMe MeO CD2Cl2 IV-4 + -15 ℃, 15h O IV-2 IV-3 0.3 mol% er = 77:23 IV-(R,R)-(M,M)-Z-1 S IV-ent-4 OMe Figure IV-1. a. Design of a light driven unidirectional molecular motor. b. Example of a light driven switchable catalysis in a Michael addition reaction. 131 site to generate the nucleophilic sulfa anion. The catalyst in its IV-(R,R)-(P,P)-E-1 form is inactive as its catalytic sites are far away from each other and therefore cannot activate both the electrophilic as well as nucleophilic components simultaneously. Irradiation of IV-(R,S,S)-8 IV-(R)-5 IV-(R,S,S)-6 BF4 AuxO Ph P P Ph OAux Ph Rh Ph HO Ph P P Ph OH AuxO Ph P P Ph OAux Ph Ph Ph Ph BF4 50% 61% 61% Aux-Cl [Rh(cod)2]BF4 70 ℃ AuxO Ph P P Ph OAux + Ph Ph K2CO3, DCM DCM, RT, 2h CDCl3 Rh RT, 48 h 6h 39% BF4 >99% HO Ph P P Ph OH AuxO Ph P P Ph OAux AuxO Ph P P Ph OAux IV-(S,S,S)-9 Ph Ph Ph Ph Ph Ph Rh 50% 39% IV-(S)-5 IV-(S,S,S)-7 IV-(S,S,S)-9 O O Aux = (S) 5 mol% IV-(R,S,S)-8/ IV-(S,S,S)-9 (61/39) CO2Me er = 87:13 -40 ℃ NHAc CO2Me 10 atm H2 IV-(R)-11 NHAc CDCl3, 48 h 5 mol% CO2Me IV-(S,S,S)-9 (>99) er = 96:4 IV-10 -10 ℃ NHAc IV-(S)-11 Figure IV-2. Design and application of a temperature driven chiral switchable catalyst. IV-(R,R)-(P,P)-E-1 with light (312 nm) at 20 °C led to E-Z photoisomerization and a helix inversion. The newly formed IV-(R,R)-(M,M)-Z-1 state can perform bifunctionally as it brings both of the active sites in closer proximity. A thermal helix inversion of the latter leads to IV-(R,R)-(P,P)-Z-1(Figure IV-1a). A final photoirradiation, followed by thermal 132 inversion brings the molecular motor to its original state. When IV-(R,R)-(M,M)-Z-1 was subjected to the reaction condition, IV-4 was observed with 50% ee . On the other hand, IV-(R,R)-(P,P)-Z-1 led to the formation of the enantiomer IV-ent-4 with almost identical enantioselectivity (Figure IV-1b). Since their pioneering work, Feringa and coworkers have developed several other switchable molecular motors and employed them as programmble organocatalysts in many different asymmetric reactions.8 In 2015, Storch and Trapp developed a chiral switchable catalytic system where the temperature was employed as an external stimulus (Figure IV-2).11 Functionalization of the racemic tropos BIPHEP ligand with a chiral auxiliary perturbed the equilibrium and favored the formation of one diastreomer over the other (61:39). The point chirality of the appended chiral auxiliary was translated to the chiral axis of the biphenyl core. Complexation of the equilibrium mixture with Rh(I) restricted the free rotation around the chiral axis. Intriguingly, when this mixture was heated at 70 °C for 6 h, the equilibrium shifted completely towards the minor diastereomer IV-(S,S,S)-9 and did not change even after prolonged cooling. The catalytic properties of the mixture or the pure minor diastereomer was then tested in the asymmetric hydrogenation of a prochiral cinnamate IV-10. Interestingly, for the mixture a non-linear chiral amplification of the product enantioselectivity was observed. 133 IV-3 Redox driven chiral switchable catalyst CF3 CF3 CF3 O CF3 O NH CF3 NH N N CF3 H H HN O HN L-ascorbic acid (NH4)2Ce(NO3)6 X N N S CuI HN O CuII N O N N HN CF3 N HO IV-∆-12 IV-∧-12 CF3 S O O 5 mol% IV-∆-12 O O O O er = 86:14 NO2 O O IV-13 IV-15 10 mol% Et3N + RT, 24h O O NO2 5 mol% IV-∧-12 O O IV-14 er = 85:15 NO2 IV-ent-15 Figure IV-3. Design and application of a redox driven chiral switchable catalyst. In 2012, Canary and coworkers reported a redox driven programmable chiral catalyst (Figure IV-3).12 Inspired from their own work,13 they designed a multidentate ligand attached with a bis-urea site that can potentially act as an organocatalyst. The hard carboxylate group of the methionine derived ligand coordinates to Cu (II). Such coordination resulted in a negative helicity of the quinolines. When the Cu (II) is reduced to Cu (I) by ascorbic acid, a reorganization around the metal center occurs. Now the soft Cu(I) metal center is coordinated via the soft sulfide atom. As a result, the chirality 134 between the quinolines is inverted and positive helicity is formed. This system could be reversed back to its original from simply by oxidizing the metal center via ceric ammonium nitrate. The enantiomeric forms of the catalyst were able to deliver the antipodal products in a nitro-Michael addition reaction with almost equal but opposite enantioselectivity. IV-4 Solvent driven chiral switchable catalyst Suginome and co-workers showed a solvent dependent helical inversion of polymeric ligands.14 In particular, the polymer IV-16 containing chiral ether side chains and diphenyl phosphino pendants exhibited switching of helicity from P to M as the solvent was switched from cycloocatane to n-octane (Figure IV-4). The Pd-catalyzed hydrosilylation of styrene with ligand IV-(P)-16 afforded the product IV-(S)-17 with 90% ee in cyclooctane. When the same reaction was carried out in n-octane with ligand IV- N O N ~990 P P n-octane N P P H o-Tol cyclooctane P 60 ℃, 16 h P N Ph ~10 P IV-(P)-16 IV-(M)-16 Ph IV-16 SiCl3 1.2 mol% IV-(P)-16 IV-(S)-17 er = 95: 5 0.5 mol% cyclooctane [PdCl(π-allyl)]2 + 0 ℃, 12 h SiCl3 1.2 mol% IV-(M)-16 IV-(R)-17 HSiCl3 n-octane er = 97:3 Figure IV-4. Example of a solvent driven chiral switchable catalyst. 135 (M)-16, that resulted in the formation of IV-(R)-17 with opposite but similar enantioselectivity. IV-5 Ligand driven chirality switching of catalyst The examples of switchable catalysis discussed so far contain the asymmetric element within the catalyst. Biphenyl ligands are easily synthesized without any asymmetric synthesis and tropos in nature, can freely rotate around its dynamic chiral axis. To generate enantioenriched biphenyl ligands for asymmetric catalysis an external trigger is required. This could be achieved by interaction of the racemic ligands with a chiral stimulus (Figure IV-5). The energetic difference between the diastereomeric adducts would allow the system to re-equilibrate favoring the formation of one adduct over the other. There are two possible ways to access this- 1. Employment of a chiral Sax catalyst chiral Sax catalyst bias substrate chiral bias equilibrium shift chiral product Rax catalyst Rax catalyst bias X % ee Examples: NTf2- OAux H BF4- Cl H2 Ph2 N Ph Ph2 N Ph2 P P P Ru Ru+ Rh+ P P O P Ph2 Cl N Ph Ph2 OMe Ph2 H2 OAux IV-(S)-18 IV-(S)-19 IV-(S)-20 Figure IV-5. Design and examples of chiral ligand driven switchable catalysts. 136 ligand that could interact via non-covalent interactions. 2. Attachment of a chiral moiety with the ligands. In both instances, the chiral information of the external trigger must be transferred to the chiral axis of the biphenyl to perturb the initial equilibrium mixture. In 1999, Mikami15 and later other groups8, 11, 16 developed such system where a co-ligand transferred its chiral information to the biphenyl axis through a shared metal center (Figure IV-5). One of the major disadvantages of such strategy is that the external ligand O MeO MeO R + H O O O O POPh2 O Ph H POPh2 POPh2 O Chiralpak IA POPh2 SiCl4 two column msfHPLC O O 25 ℃ O O OH MeO racemic up to 91% ee MeO R Ph IV-(S)-22 IV-21 HO Ph IV-23 up to 83% ee O Cl H Cl Me N H H NHMe N N - - Ph2 BF4 O Ph2 BF4 Ph O P O P O IV-25 O Rh+ Rh+ O O O P O P Ph2 Ph2 N N H H IV-26 Cl Cl 34% ee IV-24 site for non-covalent H2 interactions O O H H Me N Me N OMe OMe O O Ph Ph IV-28 IV-27 12% ee Figure IV-6. Examples of chiral switchable catalysts where catalytic site and chirality induction site are in opposite part of the catalyst. 137 was playing a key role in the reactivity and selectivity of the catalyst at the same time as it was coordinating to the reactive metal site. In 2014, Trapp group redesigned a new type of tropos ligand.17 Electron rich aromatic units were attached to the backbone of the ligands that can non-covalently interact with the external chiral stimulus. This would allow the transfer of chirality without the participation of the original catalytic site. Initially, they used a two-step multi stopped flow chiral HPLC technique to isolate the enantioenriched ligand and directly used the enantiopure bisphosphine oxide catalyst in an asymmetric reaction at lower temperature to prevent any racemization (Figure IV-6). Recently, Trapp group reported on the deracemization of the tropos ligand in situ and were only able to achieve 12% ee in the product (Figure IV-6).18 H + MePh2SiBPin P P P B B G IV-31 IV-32 BG H P P P B B Ph Ph B G Pd2(dba)3 P P P B B BG SiPh2Me H 2N OH IV-(P)-29 IV-(M)-29 IV-(M)-30 BPin IV-(R,R)-33, 87% ee B(OH)2 N N N PrO N PrO N N Ar2P ~300 ~20 ~20 Figure IV-7. Induction of chirality to polymeric dynamic racemic ligands and its application to silaboration of an alkene. 138 In 2018, Suginome and coworkers employed a similar strategy for their polymeric dynamically racemic ligands.19 Helical chirality was induced within poly(quinoxaline-2,3- diyl) via condensation of the chiral diol or aminoalchols on the pendant boronyl group at the 5-position of the quinoxaline ring (Figure IV-7). The induced chirality of the ligand was then translated to the product via a palladium catalyzed asymmetric silaboration of meso- methylenecyclopropene. Ph Ph N Ph Ph N N N Zn Zn Me O N N N Me O Ph Ph N Ph Ph Ph P P Ph P P Ph Ph O Me Ph O Me Ph II-(R,R)-33 II-(S,S)-33 P- helicity M- helicity Ph Ph IV-34 Ph Ph catalytic site N Ph Ph N N N N N Ph Ph P O N N Zn O Zn P O P characteristics of a ligand Zn O Zn N N P Ph N N Ph a. bidentate co-ordination Ph N N N N Ph b. transfers chirality c. must not participate in the reaction IV-(P)-35 IV-(M)-35 Figure IV-8. Design of a bis-porphyrin based chiral bis-phosphineoxide driven programmable catalyst. 139 IV-6 Design and application of a ligand driven enantiodivergent programmable organocatalyst Based on our work with the MAPOL host system20-23 and inspired from the work of Trapp17-19 and Suginome19 on ligand driven chiral switchable catalyst, we were intrigued to design a bis porphyrin tropos organocatalyst IV-34 that could be deracemized in situ, through its interaction with an external chiral ligand (Figure IV-8). The strong host-guest complexation through a ligand to metal coordination would facilitate the transfer of the point chirality to the chiral axis of the catalyst. Since the stereochemical identity of the catalyst is dictated by the asymmetry of the ligand, it could be switched easily by changing ligand’s chirality. Intrigued by the strong binding affinity of bisphosphine oxides with I-Zn- a. Maruoka’s catalyst: IV-38 N H 10 mol% MeO2C O O O PhCH3, RT, 40 h + BnO2C Me Ph H MeO2C Ph BnO2C-CH=PPh3 DCM, RT Me IV-39 IV-36 IV-37 83%, dr > 20:1, 91% ee b. Our catalyst: Ph Ph N Ph Ph N N N Zn Zn N N Ph N N Ph N H IV-38 IV-40 N H Figure IV-9. a. Stereoselective conjugate addition of aldehydes to electron deficient olefins developed by Maruoka. b. Our designed programmable organocatalyst IV-40 inspired from Maruoka’s catalyst IV-38. 140 MAPOL 34, we quickly surmised that the bisphosphine oxide could serve the purpose of the desired chiral ligand. Such a strong interaction would not only enable efficient chirality transfer, but it would also hold the induced chirality under the reaction condition in presence of other interferences i.e; substrates, products etc. (Figure IV-8). Drawing inspiration from Maruoka’s enamine catalyst IV-38 (Figure IV-9a),24 we designed our programmable catalyst IV-40 (Figure IV-9b). Our proposed catalyst contains Previous approach: HN NH H H N N Ph OH OH Ph N Ph Ph N N N IV-41 Zn Zn N N Ph N H H N Ph Ph O O NH HN O IV-42 O Ph Ph I-Zn-MAPOL 34 Current approach: BPin Ph Ph N N Ph Zn Ph N Ph Ph N N N N N Zn Zn N N Ph N N Ph Ph IV-43 Br Br N H N IV-40 Boc IV-44 Figure IV-10. Newly designed retrosynthetic approach for the synthesis of IV-40. 141 a secondary amine unit as its catalytic site for the enamine catalysis and the bis-porphyrin receptors that will serve the purpose of a host for the ligand. Considering the chiral ligands might interfere with the stereochemical outcome of the product, the catalytic amine unit and porphyrin receptors are placed in the opposite direction. However, we realized the difficulties in scaling up the synthesis of the catalyst. Typically, I-Zn-MAPOL 34 is synthesized following a literature procedure developed in our group (Figure IV-10).22 The bis-pyrromethane unit IV-41 is made initially and then the porphyrin units are built upon that core through acid catalyzed condensation with IV-42, which is made separately. This last step of the synthesis is challenging and the overall yield for this route was low (<4%). To enable a more practical synthesis of our proposed catalyst IV-40, we revised our synthetic strategy for the bis-porphyrin receptors. We envisioned a convergent route i.e; synthesis of the mono-porphyrin unit IV-43 separately Br Br O (PhCO)2O2, Br2 O O2, KOH, DMI CO2H PhNO2, 120 ℃, RT, 12 h, 73% CO2H O O 3 h, 55% IV-45 Br IV-46 Br IV-47 Br Br NaBH4, BF3.OEt2 CH2OH PBr3 (1 equiv) CH2Br THF, 7 h, 88% CH2OH -40 ℃ to RT CH2Br 4 h, 80% Br IV-48 Br IV-49 Br NaH, NH2Boc NBoc 2.5 h, 59% Br IV-44 Figure IV-11. Forward synthesis of the coupling partner IV-44. 142 and then coupling with the backbone partner IV-44 would circumvent the multiple bond formation in the key step unlike our previous strategy. H 1. PhCHO, TFA (CH2O)n, InCl3 N HN DCM, 3.5 h, RT Ph Ph N 55 ℃, 3 h, 62% NH HN 2. DDQ, 0.5 h, 41% H NH N IV-50 IV-51 H IV-52 H Br 1. PhLi, THF, 2.5 h 1. NBS, pyridine 2. H2O, 10 min N HN CHCl3,15 min, 97% N N Ph Ph Ph Zn Ph 3. DDQ, 1 h NH N 2. Zn(OAc)2, DCM, N N 2.5 h, 75% 12 h, quant. Ph Ph IV-53 IV-54 BPin 20 mol% Pd(PPh3)2Cl2 N N HBPin, Et3N Ph Zn Ph 1,2 DCE, 105 ℃, 24 h, 82% N N Ph IV-43 Ph Ph 4 equiv BPin N Ph Ph N Br N N Br 1. Pd(PPh3)4 (30 mol%) Zn Zn N N K3PO4, toluene N N reflux, 20 h, 56% Ph N N Ph + Ph Zn Ph 2. TMSOTf, Lutidine, N N DCM, 4 h N 80% Boc Ph IV-44 IV-43 N H IV-40 Figure IV-12. Forward synthesis of the coupling partner IV-43 and final steps for the synthesis of IV-40. 143 The synthesis of the fragment IV-44 commenced with commercially available IV-45 (Figure IV-11). The dibromination of IV-45 followed by an oxidative cleavage with H2O2 gave rise to compound IV-46 in 73% yield.25 A subsequent reduction with sodium borohydride, followed by a di-bromination and finally a cyclization with Boc carbamate resulted in the desired product IV-44. The borylated counterpart IV-43 was synthesized following a literature procedure with little modification (Figure IV-12).26 Condensation of pyrrole IV-50 with paraformaldehyde in presence of indium chloride gave rise to dipyrromethene IV-51 in 62% yield. The dipyrromethene was then converted to mono-porphyrin IV-52 with 41% yield. A subsequent nucleophilic addition of phenyllithium to IV-52, followed by oxidation with DDQ produced compound IV-53 in 75% yield.27 Bromination of IV-53 with NBS, a quantitative zincation followed by Miyaura borylation yielded the desired boronic ester IV- 43.26 Two coupling partners were then subjected to Suzuki-Miyaura coupling conditions to provide the Boc protected catalyst IV-NBoc-40.28 Initial attempts to drop the Boc group under acidic condition led to the concomitant removal of the Zn metal from the porphyrin core. Finally, the Boc group was deprotected under basic conditions to produce the desired catalyst IV-40 keeping the Zn metals intact (Figure IV-12). With both the catalyst IV-40 and chiral bis-phosphine oxide III-(S,S)-33 in hand, we tested the exact reaction conditions as Maruoka’s.24 Gratifyingly, the anticipated syn diastereomer was formed in 45% ee in our initial trial in toluene. After an extensive evaluation of solvents, the enantiomeric excess increased to 64% in chlorobenzene (Scheme IV-1, entry 1). Notably, no enantioinduction in the product was observed when the reaction was run in solvents like THF or methanol. These solvents can potentially 144 coordinate to the Zn metal center and outcompete the bis-phosphine oxides as they are present in a large excess. To test the ligand driven switchability of our designed catalyst IV-40, the reaction was run with III-(R,R)-33. As anticipated, enantiomeric product was formed with almost identical enantioselectivity (Scheme IV-1, entry 2). Furthermore, we explored different phosphine oxides with chirality at phosphorus, chirality at carbon with various chain lengths. Unfortunately, the enantioselectivity did not increase (Scheme IV- 1, entries 4-6). The mono-phosphine oxide III-RP-19 led to nearly racemic product (Scheme IV-1, entry 7). We attribute this interesting observation to the binding of mono- phosphine oxide from the outside of the porphyrin cavity, and therefore, not inducing any preferred helicity for the host-guest complex. It also corroborates the fact that a bidentate 1. IV-40 (5 mol%) L (5 mol%) MeO O O O O Solvent (0.2 mL), RT + BnO2C Me Ph H MeO2C Ph 2. BnO2C-CH=PPh3 DCM, RT Me IV-36 IV-37 IV-ent-39 0.1 mmol 0.05 mmol 40-48 h, > 90% O Entry Solvent Ligand dr er Ph Me Me Me C6H5Cl III-(S,S)-33 7:1 82:18a Ph P P Ph Ph Ph 1 Ph Ph P P Ph 2 C6H5Cl III-(R,R)-33 8:1 20:80a O Me O O 3 C6H5Cl III-(S,S)-33 11:1 82:18 III-(S,S)-33 III-(S,S)-35 4 C6H5Cl III-(S,S)-35 9:1 68:32 O 5 Ph O Me C6H5Cl III-(RP,RP)-31 10:1 76:24 P Pr P P 6 C6H5Cl III-(RP,RP)-30 10:1 61:39 Me Me O Ph 7 C6H5Cl III-(RP)-19 9:1 53:47 III-(RP)-19 III-(RP,RP)-31 8 C6H4Cl2 III-(S,S)-33 7:1 84:16 Ph O OMe 9 CHCl3 III-(S,S)-33 16:1 76:24 P P 10 C6H4BrClb III-(S,S)-33 9:1 85:15 OMe O Ph a. 10 mol% of catalyst and ligand b. 1,3- disubstitution. III-(RP,RP)-30 Scheme IV-1. Selected optimization studies of the Michael addition reaction with our designed programmable catalyst IV-40 and bisphosphine oxide ligands. 145 coordination is necessary to deracemize the catalyst during the reaction. Further optimization of the reaction led to the 5 mol% of the catalyst and 1,3 chlorobromobenzene as the optimal condition with the desired enantiomer forming in 70% ee (Scheme IV-1, entry 10). a. H N N H H H H Me Me IV-55 IV-56 b. Ph Ph Ph Ph N Ph Ph N N Ph Ph N N N N N Zn Zn Zn Zn N N N N Ph N N Ph Ph N N Ph Ph N N H IV-40 H IV-57 Figure IV-13. a. Predicted approach of the electrophile in the enantioinduction step for Maruoka’s enanmine catalysis. b. Design of a Ph substituted C1 catalyst IV-57. 146 IV-7 Steric manipulation of the programmable catalyst In comparison to Maruoka’s catalyst the ee’s from our programmable catalyst was low. We began by evaluating the steric influence of substituents to improve the selectivity. Our modeling study with Maruoka’s system revealed how the facial selectivity is attained in the enantioinduction step (Figure IV-13a). It was realized that the Re face of the intermediate enamine IV-55, formed after the initial condensation between the amine and aldehyde, is blocked by the unsubstituted C-3 position of the catalyst (Figure IV-13a). Therefore, the Michael acceptor IV-37 approaches the enamine from its less sterically encumbered bottom face i.e; the Si face. We postulated that substitution at one of the C- Br Br Br I CO2H MeI, Ag2CO3 CO2H Cat. Pd(OAc)2, NIS CO2H CO2H 40 ℃,18 h, 72% CO2Me DMF, 100 ℃, 24 h CO2Me Br Br Br IV-47 IV-58 IV-59 Br I Br Ph Cat. Pd(PPh3)2Cl2 MeI, DBU CO2Me PhB(OH)2, Na2CO3 CO2Me 100 ℃, 8 h CO2Me THF: H2O CO2Me 30%, 2 steps 60 ℃, 12 h, 76% Br Br IV-60 IV-61 Ph Ph Ph N Ph Ph N 1. DIBAL-H, RT,12 h Br 1. IV-43 (4 equiv) N N 2. PBr3, RT, 24 h Cat. Pd(PPh3)4, reflux Zn Zn NBoc 2. TMSOTf, lutidine N N 3. NaH, NH2Boc, 12 h Ph N N Ph 38%, 3 steps 47%, 2 steps Br IV-62 Ph N H IV-57 Figure IV-14. Synthesis of the Ph substituted C1 catalyst IV-57. 147 3 position of the catalyst could further prevent the approach of the electrophile IV-37 from the Re face and might enhance the enantioselectivity. To this end, we redesigned our parent catalyst IV-40 and specifically substituted at the C-3 position with a phenyl group 1. IV-57 (5 mol%) III-(S,S)-33 (5 mol%) MeO2C O O O 1,3-C6H4BrCl, RT Me + BnO2C H MeO2C Ph 2. BnO2C-CH=PPh3 Ph DCM, RT Me IV-36 IV-37 IV-ent-39 85%, dr = 6:1, er = 70:30 Scheme IV-2. Syn selective conjugate addition with catalyst IV-57 and III- (S,S)-33. (Figure IV-13b). The Ph group was chosen initially for the ease of synthesis. The newly designed C1 catalyst IV-57 were synthesized following the similar protocol as the parent catalyst IV-40 (Figure IV-14). Mono-methylation of the previously synthesized IV-47 with MeI afforded compound IV-58 in 72% yield. A subsequent carboxylic acid directed C-H iodination resulted in IV-59, which was then converted to the diester without further purification. The diester IV-60 was converted to the coupling partner IV-62 following routine procedures in 3 steps. Finally, a Suzuki-Miyaura coupling and a Boc deprotection N N H H H H H H H H Me Me IV-63a IV-63b Re face blocked Si face blocked Figure IV-15. Two energetically close conformers (1 kcal/mol) of the mimic IV-63 catalyst block the opposite faces of the enamine. 148 afforded the final catalyst IV-57. Surprisingly, a decrease in enantioselectivity to 40% ee was observed when the IV-57 was subjected to the reaction condition. To gain insight into this undesired outcome, a conformational study was done with a mimic of Maruoka’s catalyst IV-63 (Figure IV-15). The study revealed that the undesired conformer IV-63b blocks the desired Si face of the intermediate and is only 1 kcal/mol higher in energy (DFT/B3LYP/6-31G*) as compared to the desired conformer IV-63a. Concomitant presence of both the conformers in the reaction could be one of the many reasons of lowered enantioselectivity in this case. At this point, we were also uncertain of the P/M III-(S,S)-33 IV-NBoc-40 + 0.5 equiv III-(S,S)-33 IV-NBoc-40 + 1.0 equiv III-(S,S)-33 IV-NBoc-40 + 1.5 equiv III-(S,S)-33 IV-NBoc-40 + 2.0 equiv III-(S,S)-33 Figure IV-16. 31P NMR titration studies of IV-NBoc-40 (6mM) with III-(S,S)-33 at room temperature in CDCl3. 149 helicity ratio in any of our actual catalytic system. Knowing this ratio is critically important as it would suggest if the observed selectivity were the result of the P/M ratio, or it was inherent under the conditions used for an enantiopure catalyst. IV-8 Electronic manipulation of the catalyst From the 31P NMR studies of the Boc protected catalyst IV-NBoc-40 complexed with III-(S,S)-33, it was evident that the coordination of the bis-phosphine oxide with the Zn metal is dynamic in nature. 29-31 Figure IV-16 displays the 31P NMR spectra at room temperature in CDCl3 resulting from the complexation between IV-NBoc-40 and III-(S,S)- 33. The free ligand III-(S,S)-33 appears at ~ 36.8 ppm. As the complex is formed, an upfield chemical shift in the 31P NMR is observed. With the increase in the equivalents of the ligand, only broad 31P peak at ~ 36 ppm, instead of two distinct peaks, one for the bound and one for the unbound ligand, was witnessed. Cooling the mixture down to -80 °C did not change the scenario. The broad chemical shift represents the weighted average of the two sets of phosphorus nuclei because of fast exchange between the coordinated and non-coordinated phosphine oxide. This result suggested that the binding between the catalyst and the ligand may not be as strong as desired. This might lead to a certain degree of ligand-unbound catalyst, that could potentially drive the background reaction and lower the enantioselectivity. To saturate the catalyst with ligand, we envisaged to increase the amount of the ligand in the reaction. Unfortunately, increasing the ligand amount led to poor enantioselectivity presumably due to the formation of 1:2 or 2:3 type catalyst:ligand complex where the ligand binds from the outside of the cavity and therefore, no helicity would be preferred. To this end, we planned to increase the binding affinity between the host catalyst and the guest ligand. The role of electronics of 150 the porphyrin ring to increase the binding affinity was evaluated. From our prior experience,32 we surmised that the per-fluorination of the porphyrin ring would lower the LUMO energy at the Zn center, making it strongly Lewis acidic. To test our hypothesis, a new catalyst with per-fluorinated bis-porphyrin IV-70 was designed and synthesized O C6F5 C6F5 O Cat. InCl3 C6F5 Cl pyrrole, 56% mesitylMgBr, 15% NH HN C6F5 H NH HN C6F5 C6F5 IV-64 O IV-65 O C6F5 C6F5 1. NaBH4 NH N N N Zn(OAc)2 C6F5 C6F5 C6F5 Zn C6F5 NH HN 91% N HN N N IV-51 2. Yb(OTf)3 H H 3. DDQ, 22% IV-66 IV-67 C6F5 C6F5 N N N N NBS Cat. Pd(PPh3)2Cl2 C6F5 Zn C6F5 C6F5 Zn C6F5 96% HBPin, 56% N N N N Br BPin IV-68 IV-69 C6F5 C6F5 N C6F5 C6F5 N N N Zn Zn 1. IV-44, N N Cat. Pd(PPh3)4, reflux C6F5 N N C6F5 2. TMSOTf, lutidine 52%, 2 steps N H IV-70 Figure IV-17. Synthesis of the per-fluorinated highly Lewis acidic Zn center containing catalyst IV-70. 151 following a similar strategy as the other catalysts (Figure IV-17). Our investigation began with the 31P NMR studies between IV-70 and the ligand III-(S,S)-33. As depicted in Figure IV-18, addition of 0.6 equivalent of III-(S,S)-33 to a CDCl3 solution of IV-70 led to a 2 ppm shift of III-(S,S)-33 in the 31P NMR confirming their binding. In presence of excess ligand, two separate peaks for bound and unbound ligand appeared. It is worth mentioning that similar studies with catalyst IV-40 only showed the presence of a broad single peak. The CD study (Figure IV-19) further confirmed that III-(S,S)-33 binds stronger to IV-70 (A=2229 vs A=1322, larger ECCD amplitude) in comparison to the non-fluorinated one IV-40. Unfortunately, when the catalyst IV-70 was subjected to the reaction condition, none of the desired product was formed. Instead, the Michael acceptor IV-37 was recovered completely. NMR studies (Figure IV-20) between IV-71 and IV-72 disclosed III-(S,S)-33 IV-NBoc-70 + 0.6 equiv III-(S,S)-33 IV-NBoc-70 + 2 equiv III-(S,S)-33 Figure IV-18. 31P NMR titration studies of IV-NBoc-70 (6mM) with III-(S,S)-33 at room temperature. 152 that the secondary amine of the catalyst tightly coordinates to the Zn metallo center of Zn-TPP. Such coordination is further strengthened in catalyst IV-70 due to the presence of the highly Lewis acidic Zn metal center. This observation led us to the conclusion that Figure IV-19. ECCD spectrum of IV-70 (blue) and IV-40 (red) complexed with 1 equivalent of III-(S,S)-33 at room temperature in PhCl. such a strong coordination is preventing the amine in IV-70 to react with the aldehyde IV- 36 to from the initial iminium ion that isomerizes to enamine. Therefore, enhancement of the Lewis acidity on the Zn metal center is not a solution to the problem. To circumvent this fundamental challenge, we explored the possibilty of employing other metallo porphyrins with oxophllic property. Mg porphyrins bind stronger to oxygen nucleophiles compared to nitrogen nucleophiles due to their high oxophilicity.33-35 Therefore, a Mg based catalyst provides two major advantages- 1. It would enhance the binding affinity between the catalyst and the bis-phosphine oxide ligands. 2. The intermolecular amine- Mg porphyrin coordination would be reduced. To explore the binding of Mg porphyrin with 153 a H Br Br Hd Hc d Hb H H b Ha N c H H IV-71 Ph Br Ph N Hd N HN Zn Br N Ph Ha N d Hc Hb c H H H b Ph H a Ph N N Ph Zn Ph N N Ph IV-72 Figure IV-20. Room temperature 1H NMR studies in CDCl3 show the ligand to metal coordination between IV-71 and IV-72 (Zn-TPP). phosphine oxides, a 31P NMR study was performed (Figure IV-21). Zn-TPP bound to excess triphenyl phosphine oxide shows the presence of only one NMR peak that is probably the average of the bound and unbound phosphine oxide. Notably, two separate peaks were observed when Mg-TPP was complexed with 1.5 equivalent of triphenylphosphine oxide. The peak at 29.3 ppm clearly matches with the unbound one, whereas the new peak at 25.5 ppm is from the phosphine oxide bound to Mg-TPP. It is worth mentioning here that the upfield chemical shift of phosphine oxide upon 154 coordination is due to the diamagnetic anisotropy of the porphyrin ring. Synthesis of IV- Mg-40 is currently underaway. Ph3PO Zn-TPP + 1.5 equiv Ph3PO Mg-TPP + 1.5 equiv Ph3PO Figure IV-21. Room temperature 31P NMR studies of triphenylphosphine oxide with Zn- TPP and Mg-TPP. IV-9 Binding affinity enhancement using bispyridine ligands In parallel, we explored the possibility of enhancing the binding strength by increasing the donor ability of the ligand. This would allow us to enhance the binding affinity without changing the metal or the electronics of the metal. This hypothesis could be tested either by changing the substituents on the phosphine oxide ligands or changing to a completely new set of ligands with different coordinating group that binds stronger 155 than phosphine oxides to Zn metallo porphyrin. After a quick survey of literature, it appeared that pyridine binds stronger to Zn mono-porphyrin than triphenylphosphine L Ar Ar Ar Ar N N N N L N Zn N Zn N Ar N Ar toluene Ar Ar RT IV-73 IV-74 IV-74a, L = pyridine: Ka = 1.9 x 103 M-1 Ar = 3,5-di-tBu-C6H4 IV-74b, L = Ph3PO: Ka = 6.3 x 102 M-1 O Ph N H N N H N Ph O IV-75 Figure IV-22. Pyridine binds stronger to Zn porphyrins than the triphenylphosphine oxide. Rath’s bi-pyridine ligand IV-75. + IV-75 Figure IV-23. ECCD spectrum (red) of IV-40 complexed with 1 equivalent of III-(S,S)- 33 in PhCl. The helicity completely switches (blue) as 1 equivalent of IV-75 was added to the mixture. 156 oxide (Figure IV-22).29 Inspired from the work of Rath and co-workers,36 a series of bis- pyridine ligands were synthesized following literature protocols. To test our hypothesis, an initial ECCD study was performed with the bispyridine ligand. When 1 equivalent of IV-(S,S)-75 ligand was added to a preformed 1:1 complex of IV-40 and III-(S,S)-33 a complete switch in the ECCD signal from negative to positive is observed (Figure IV-23). This newly formed signal is consistent with the positive ECCD signal observed with the 1:1 complex of IV-40 and IV-(S,S)-75 albeit lower intensity. These observations led us to two conclusions- 1. IV-(S,S)-75 ligand binds stronger to IV- 40 than III-(S,S)-33. 2. Coordination of III-(S,S)-33 ligand to the catalyst IV-40 is dynamic in nature, again consistent with our NMR results (Figure IV-16). 1. IV-40 (5 mol%) L (5 mol%) MeO O O O O CHCl3 (0.25 mL), RT + BnO2C Me Ph H MeO2C Ph 2. BnO2C-CH=PPh3 DCM, RT Me IV-36 IV-37 IV-ent-39 0.1 mmol 0.05 mmol 40-48 h, > 90% O Ph Me O Ph H N Ph P P Ph N Entry Ligand dr er N Ph H 16:1 76:24 O Me N Ph O 1 III-(S,S)-33 IV-(S,S)-75 21:1 27:73 III-(S,S)-33 IV-(S,S)-75 2 3 IV-(S,S)-76 24:1 23:77 N N N N 4 IV-(S,S)-77 27:1 29:71 5 IV-(S,S)-78 29:1 50:50 NH HN NH HN O O O O 6 IV-(S,S)-79 30:1 50:50 IV-(S,S)-76 IV-(S,S)-77 O Ph H OMe P N OMe O O MeO N P MeO H P NH HN P Ph O MeO OMe MeO OMe IV-(S,S)-78 IV-(S,S)-79 Scheme IV-3. Optimization studies with bis-pyridine and bis- phosphoramidate ligands. 157 Figure IV-24. ECCD titration of IV-40 with different equivalents of IV-(S,S)-79 in CHCl3 at room temperature. With this initial data in hand, different bis-pyridine and bis-phosramidate ligands were tested under the reaction condition (Scheme IV-3). Notably, all these reactions were performed in chloroform as these ligands were insoluble in 1,3-bromochlorobenzene. The Figure IV-25. UV-vis titration of IV-40 with different equivalents of IV-(S,S)-79 in CHCl3 at room temperature. 158 best enantioselectivity was observed with IV-(S,S)-76 (Entry 3). Surprisingly, IV-(S,S)-78 and IV-(S,S)-79 afforded completely racemic product. To gain insight into these unexpected outcomes, we studied the host-guest complex formation between these ligands and the catalyst IV-40 via UV-vis and circular dichroism experiments. As shown in Figure IV-24, ligand IV-(S,S)-79 was unable to induce any helicity in the catalyst. Furthermore, UV-vis study reveals no shift in the absorption maxima (Figure IV-25). Based on the studies, it is evident no coordination between the ligand and the metal has taken place. We attribute such discrepancies to the presence of C-H…O hydrogen bonding between the phosphoramidite oxygen and the acidic C-H of chloroform. The putative hydrogen bonding would prevent the ligand to coordinate to the Zn center and therefore the catalyst IV-40 would remain racemic throughout the reaction. Observation of similar hydrogen bonding of phosphine oxide in chloroform has been reported in the literature.37 Further screening of these type of ligands is currently underway. In summary, we have developed an enantiodivergent programmable catalyst. Enantiomeric products can be afforded from a single racemic entity. Our catalyst eliminates the requirement of two enantiomeric catalysts to afford antipodal products. The asymmetry in the racemic catalyst can be introduced through coordination with ligands and therefore can be programmed at will. Different types of other catalysts are currently being explored to showcase the generality of our developed methodology. 159 IV-10 Experimental Section IV-10.1. Materials and general instrumentations Anhydrous solvents used for CD measurements were purchased from Aldrich and were spectra grade. Unless otherwise mentioned, solvents were purified as follows. CH2Cl2 was dried over CaH2 whereas THF and Et2O were dried over sodium (dryness was monitored by colorization of benzophenone ketyl radical); they were freshly distilled prior to use. NMR spectra were obtained using 500 MHz Varian NMR spectrometers and referenced using the residual 1H peak from the deuterated solvent for the proton NMR, the carbon shift of the solvent (77.0 ppm for CDCl3) for the 13C-NMR, and phosphoric acid as the internal standard reference for the 31P-NMR measurements. Column chromatography was performed using Silicycle 60 Å, 35-75 µm silica gel. Pre-coated 0.25 mm thick silica gel 60 F254 plates were used for analytical TLC and visualized using UV light, p-anisaldehyde stain or phosphomolybdic acid in EtOH stain. CD spectra were recorded on a JASCO J-810 spectropolarimeter, equipped with a temperature controller (Neslab 111) for low temperature studies, and are reported as Mol. CD / l [nm]. UV-vis spectra were recorded on an Agilent, Cary 100 UV-visible spectrophotometer equipped with temperature controller. UV-vis spectra were collected with scan rate of 100 nm/min. 160 IV-10.2. General procedure for UV-vis and CD measurements UV-vis measurement: The host IV-40 (1.0 µL of a 0.001M solution in anhydrous dichloromethane, 1.0 µmol) was added to the solvent (1.0 mL) in a 1.0 cm UV-cell. The background spectrum was recorded from 350 nm to 500 nm at a scan rate of 100 nm/min. The guest molecule (1 up to 500 equivalents) from four different stock solutions in anhydrous dichloromethane [0.1M (for 100-500 equiv), 0.01M (for 10-100 equiv), 0.001M (for 1-10 equiv), 0.0001M (for 0.1-1 equiv)] were then added to the IV-40 solution. The UV-vis spectra were collected after each addition at room temperature. CD measurement: IV-40 (1.0 µL of a 0.001M solution in anhydrous dichloromethane, 1.0 µmol) was added to the solvent (1.0 mL) in a 1.0 cm CD cell to obtain a 1.0 µM solution. The background spectrum was recorded from 350 nm to 500 nm with a scan rate of 100 nm/min. at room temperature. The guest from a stock solution in anhydrous dichloromethane (0.001 M for 1-10 equiv and 0.01 M for 10-20 equiv) was added to the prepared host solution to afford the host-guest complex. The CD spectra were measured immediately (10 scans). The resultant ECCD spectra recorded in millidegrees were converted the molecular CD (Mol. CD) considering the host concentration of 1.0 µM. 161 Figure IV-26. ECCD spectrum of IV-40 (1 µM) complexed with one equivalent of III- (S,S)-33 in different solvents at room temperature. Figure IV-27. UV-vis titration of IV-40 (1 µM) with different equivalents of III-(S,S)-33 in CHCl3 at room temperature. 162 Figure IV-28. ECCD titration of IV-40 (1 µM) with different equivalents of III-(S,S)-33 in CHCl3 at room temperature. Figure IV-29. UV-vis titration of IV-40 (1 µM) with different equivalents of III-(S,S)-33 in 1,3-bromochlorobenzene at room temperature. 163 Figure IV-30. ECCD titration of IV-40 (1 µM) with different equivalents of III-(S,S)- 33 in 1,3-bromochlorobenzene at room temperature. Figure IV-31. ECCD spectrum of IV-40 (1 µM) with one equivalent of III-(S,S)-33 in 1,3-bromochlorobenzene (red) and chloroform (blue) at room temperature. 164 Figure IV-32. UV-vis titration of IV-40 (1 µM) with different equivalents of IV-(S,S)-76 in CHCl3 at room temperature. Figure IV-33. ECCD titration of IV-40 (1 µM) with different equivalents of IV-(S,S)-76 in CHCl3 at room temperature. 165 IV-10.3. Synthesis of catalyst IV-40 Br O (PhCO)2O2, Br2 O PhNO2, 120 ℃, O O 3 h, 55% Br IV-45 IV-46 Synthesis of IV-46:38 A mixture of IV-45 (5.0 g, 0.21 mol), (PhCO)2O2 (500 mg, 21 mmol) and bromine (0.6 mL) in nitrobenzene (40 mL) was heated to 120 °C. After initiation of the reaction, additional bromine (2 mL) was added dropwise. The reaction mixture was stirred for 3 h and then allowed to cool down to RT. Hexane (40 mL) was added to the mixture. The precipitate was filtered, washed with hexane, and dried under vacuum to afford the desired product IV-46 in 55% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J = 1.7 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H), 7.67 (dd, J = 8.3, 1.7 Hz, 2H). 13C NMR (126 MHz, Chloroform-d) δ 178.93, 136.01, 133.52, 132.20, 132.19, 129.91, 127.48. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C14H7O2Br2+ 364.8813; Found 364.8816. Br Br O O2, KOH, DMI CO2H O RT, 12 h, 73% CO2H Br Br IV-46 IV-47 166 Synthesis of IV-4725: A mixture of IV-46 (300 mg, 0.82 mmol), KOH powder (150 mg, 2.68 mmol) in DMI (7 mL) was stirred overnight at RT under oxygen atmosphere (O2 balloon). The reaction mixture was quenched with 1M HCl (pH = 2-3) and extracted with ether. The organic layer was then washed with brine, dried over Na2SO4, concentrated in vacuo, and purified via column chromatography (60% EtOAc/hexane) to afford the desired product IV-47 in 73% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.67 (dd, J = 8.4 Hz, 2.1 Hz, 2H), 7.42 (d, J = 2.1 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.79, 143.78, 132.57, 131.63, 130.45, 129.31, 124.92. HRMS (TOF MS ES-) m/z: [M-H]- Calcd for C14H7O4Br2- 396.8711; Found 396.8708. Br Br CO2H NaBH4, BF3.Et2O CH2OH CO2H THF, 7 h, reflux CH2OH 88% Br Br IV-47 IV-48 Synthesis of IV-48: A solution of BF3.OEt2 (0.48 mL, 3.75 mmol) in dry THF (3 mL) was added slowly to a solution of NaBH4 (285 mg, 7.50 mmol) and IV-47 (100 mg, 0.25 mmol) in dry THF (5 mL) under argon atmosphere. The mixture was heated to reflux for 7 h. After cooling down to RT, the reaction was quenched with dropwise addition of H2O at 0 °C. The solvent was removed in vacuo and the crude mixture was re-dissolved in CH2Cl2 and stirred for 0.5 h. The mixture was then transferred to a separatory funnel and the two 167 layers separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (40% EtOAc/hexane) gave the desired product IV-48 in 88% yield. 1H NMR (500 MHz, DMSO-d6) δ 7.65 – 7.57 (m, 2H), 7.55-7.45 (m, 2H), 7.36 – 7.24 (m, 2H), 5.28-5.10 (m, 2H), 4.20-4.02 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 139.24, 138.86, 131.22, 130.74, 129.36, 119.42, 60.11. HRMS (TOF MS ES-) m/z: [M+Cl]- Calcd for C14H12O2Br2Cl- 404.8893; Found 404.8882. Br Br CH2OH PBr3 CH2Br CH2OH -40 ℃ to RT CH2Br 4 h, 80% Br Br IV-48 IV-49 Synthesis of IV-49: To a flame dried round bottom flask compound IV-48 (40 mg, 0.11 mmol) was dissolved in dry CH2Cl2 (2 mL) and PBr3 (0.22 mL, 1M in CH2Cl2) was added dropwise at -40 °C under argon atmosphere. The mixture was warmed to RT and stirred for 4 h before being quenched with H2O at 0 °C. The crude was extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo. Purification via column chromatography (1-2% EtOAc/hexane) afforded the desired product IV-49 in 80% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.57 (dd, J = 8.3 Hz, 2.1 Hz, 2H), 7.45-7.39 (m, 4H), 4.27 (d, J = 10.3 Hz, 2H), 4.14 (d, J = 10.3 Hz, 2H). 13C NMR (126 MHz, Chloroform-d) δ 139.74, 134.95, 132.79, 132.30, 132.28, 122.40, 30.53. 168 HRMS (TOF MS AP+) m/z: [M-2HBr+H]+ Calcd for C14H9Br2+ 334.9071; Found 334.9063. Br Br CH2Br NaH, NH2Boc NBoc CH2Br 2.5 h, 59% Br Br IV-49 IV-44 Synthesis of IV-44: To a flame dried round bottom flask NaH (80 mg, 2.0 mmol) was suspended in dry DMF (3 mL). To that solution was transferred a mixture of IV-49 (200 mg, 0.40 mmol) and tert-butyl carbamate (52 mg, 0.44 mmol) in dry DMF (3 mL) dropwise over 10 mins at 0 °C. The mixture was warmed to RT and stirred for 2.5 h before being quenched with H2O at 0 °C. The crude was extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. Purification via column chromatography (2% EtOAc/hexane) afforded the desired product IV-44 in 59% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.63 (d, J = 2.0 Hz, 2H), 7.52 (dd, J = 8.1 Hz, 2.1 Hz, 2H), 7.34-7.20 (m, 2H), 4.17 (br, 4H), 1.51 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 154.09, 141.18, 133.33, 131.70, 131.20, 130.93, 80.32, 47.44, 46.64, 28.51. HRMS (TOF MS ES+) m/z: [M-C4H9]+ Calcd for C15H10Br2NO2+ 393.9078; Found 393.9079. (CH2O)n, InCl3 N 55 ℃, 3 h, 54% NH HN H IV-50 IV-51 169 Synthesis of IV-51: Paraformaldehyde (350 mg, 11.66 mmol) dissolved in pyrrole (70 mL) was degassed for 15 min. The solution was heated at 55 °C for 10 min before InCl3 (258 mg, 1.16 mmol) was added. The mixture was stirred at 55 °C for 3 h. After cooling to RT, powdered NaOH (1.86 g, 46.64 mmol) was added and stirred for another 1 h at RT. The mixture was then filtered, and the excess pyrrole was removed via distillation. Purification via column chromatography (10% EtOAc/hexane) gave the desired product IV-51 in 54% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.74 (br, 2H), 6.65-6.61 (m, 1H), 6.18-6.14 (m, 2H), 6.07-6.02 (m, 2H), 3.96 (s, 2H). 13C NMR (126 MHz, Chloroform-d) δ 129.09, 117.36, 108.34, 106.46, 26.36. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C9H9N2+ 145.0766; Found 145.0778. H 1. PhCHO, TFA N HN DCM, 3.5 h, RT Ph Ph NH HN 2. DDQ, 0.5 h, 41% NH N IV-51 H IV-52 Synthesis of IV-52: IV-51 (300 mg, 2.08 mmol) was dissolved in 400 mL of CH2Cl2 and degassed for 15 mins. To this solution benzaldehyde (0.21 mL, 2.08 mmol) was added, followed by trifluoroacetic acid (0.1 mL, 1.30 mmol). The round bottom flask was rapidly wrapped with aluminum foil and the mixture was stirred for 3.5 h. To the reaction mixture was added DDQ (613 mg, 2.7 mmol) and stirred for 30 mins. Finally, Et3N (2 mL) was added to quench the reaction mixture. The mixture was run through a pad of silica and 170 washed with CH2Cl2 until black impurities start appearing. Purification via recrystallization (CH2Cl2/MeOH) gave the desired product IV-52 in 41% yield. 1H NMR (500 MHz, Chloroform-d) δ 10.33 (s, 2H), 9.41 (d, J = 4.5 Hz, 4H), 9.09 (d, J = 4.5 Hz, 4H), 8.31 – 8.26 (m, 4H), 7.84-7.80 (m, 6H), -3.11 (s, 2H). 13C NMR (126 MHz, Chloroform- d) δ 147.31, 145.33, 141.52, 135.00, 131.76, 131.20, 127.86, 127.12, 119.24, 105.41. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C32H23N4+ 463.1923; Found 463.1923. H H 1. PhLi, THF, 2.5 h N HN N HN 2. H2O, 10 min Ph Ph Ph Ph 3. DDQ, 1 h NH N NH N 2.5 h, 75% H Ph IV-52 IV-53 Synthesis of IV-5327: To a flame dried round bottom flask compound IV-52 (462 mg, 1 mmol) was dissolved in dry THF (250 mL). To that solution was added PhLi (13 mL, 1.9 M in Bu2O) at -78 °C under argon atmosphere. The solution was stirred at that temperature for 30 min and then warmed to RT. After stirring at RT for 2.5 h, H2O (9 mL) was added to the mixture and stirred for further 30 min before DDQ (1.20 g, 5.27 mmol) was added. The mixture was stirred for 0.5 h and filtered under suction. The filtrate was concentrated in vacuo, dissolved in CH2Cl2, and washed with water, followed by brine. The crude was then dried over Na2SO4, concentrated in vacuo, re-dissolved in CH2Cl2 and passed through a pad of silica, washed with CH2Cl2. The solvent was removed again and MeOH was added to allow precipitation. The precipitate was filtered, and the residue 171 was further purified via recrystallization (CH2Cl2/MeOH) to afford the desired compound IV-53 in 75% yield. 1H NMR (500 MHz, Chloroform-d) δ 10.23 (s, 1H), 9.35 (d, J = 4.6 Hz, 2H), 9.03 (d, J = 4.6 Hz, 2H), 8.90 (ABq, 4.8 Hz, 4H), 8.27 – 8.21 (m, 6H), 7.82 – 7.73 (m, 9H), -2.99 (s, 2H). 13C NMR (126 MHz, Chloroform-d) δ 142.72, 141.91, 134.85, 134.65, 131.60, 131.44 130.86, 127.86, 126.97, 126.70, 120.73, 119.78, 104.94. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C38H27N4+ 539.2236; Found 539.2231. H Br N HN N HN NBS, pyridine Ph Ph Ph Ph CHCl3,15 min, 97% NH N NH N Ph Ph IV-53 IV-53a Synthesis of IV-53a: Pyridine (89 µL, 1.1 mmol) was added to a solution of compound IV-53 (118 mg, 0.22 mmol) in chloroform (40 mL). The solution was cooled to 0 °C and NBS (66mg, 0.37 mmol) was added. The mixture was stirred at that temperature and then quenched with acetone (3 mL). The solvent was removed in vacuo, the crude was dissolved in CH2Cl2 and washed with brine solution. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford IV-54 in 97% yield. 1H NMR (500 MHz, Chloroform-d) δ 9.68 (d, J = 4.8 Hz, 2H), 8.91 (d, J = 4.8 Hz, 2H), 8.81 (s, 4H), 8.23 – 8.17 (m, 6H), 7.83 – 7.72 (m, 9H), -2.74 (s, 2H). 172 13C NMR (126 MHz, Chloroform-d) δ 141.89, 141.79, 134.58, 134.51, 134.47, 127.91, 127.88, 126.79, 121.03, 120.83, 102.93. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C38H26BrN4+ 617.1341; Found 617.1335. Br Br N HN N N Zn(OAc)2, DCM Ph Ph Ph Zn Ph RT, 12 h, quant. NH N N N Ph Ph IV-53a IV-54 Synthesis of IV-54: To a solution of IV-54 (88 mg, 0.14 mmol) in CHCl3 (30 mL) and MeOH (10 mL) at RT was added Zn(OAc)2•2H2O (628 mg, 2.85 mmol) in one portion. The reaction mixture was stirred for 12 h, after which it was suction filtered, and the filtrate was concentrated in vacuo. The resulting pink solids were re-dissolved in CH2Cl2, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo to give the title compound IV-55 in quantitative yield. 1H NMR (500 MHz, Chloroform-d) δ 9.76 (d, J = 4.7 Hz, 2H), 8.98 (d, J = 4.7 Hz, 2H), 8.88 (s, 4H), 8.21-8.15 (m, 6H), 7.80 – 7.70 (m, 9H). HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C38H24BrN4Zn+ 679.0476; Found 679.0457. 173 Br BPin 20 mol% N N Pd(PPh3)2Cl2 N N HBPin, Et3N Ph Zn Ph Ph Zn Ph 1,2 DCE, 105 ℃, N N 24 h, 82% N N Ph Ph IV-54 IV-43 Synthesis of IV-4326: To a flame dried round bottom flask was added 1,2 dichloroethane (120 mL) and degassed for 30 min. To that flask IV-54 (600 mg, 0.88 mmol), pinacolborane (4.5 mL, 30.8 mmol), triethylamine (1.6 mL, 11.44 mmol) and Pd(PPh3)2Cl2 (124 mg, 0.18 mmol) were added sequentially under an argon atmosphere. The mixture was refluxed for 12 h before cooling down to RT. The solvent was then removed in vacuo and the crude was dissolved in dichloromethane, washed with H2O, and dried over Na2SO4. The crude was purified via column chromatography (8% EtOAc/hexane) to afford the desired product IV-43 in 82% yield. 1H NMR (500 MHz, Chloroform-d) δ 9.95 (d, J = 4.7 Hz, 2H), 9.11 (d, J = 4.7 Hz, 2H), 8.95 (ABq, 4.7 Hz, 4H), 8.27-8.21 (m, 6H), 7.81 – 7.72 (m, 9H), 1.87 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 154.47, 150.45, 150.05, 149.38, 142.91, 142.81, 134.53, 134.39, 133.04, 132.91, 132.20, 131.59, 127.58, 127.52, 126.58, 126.56, 122.67, 121.01, 85.30, 25.40. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C44H36BN4O2Zn+ 727.2223; Found 727.2195. 174 Ph Ph BPin N Ph Ph N Br N N Br Zn Zn N N 30 mol% Pd(PPh3)4 N N K3PO4 Ph N N Ph + Ph Zn Ph toluene, reflux N N 20 h, 56% N Boc Ph IV-44 IV-43 N Boc IV-NBoc-40 Synthesis of IV-NBoc-4028: K3PO4 (53 mg, 0.25 mmol) was added to an oven dried round bottom flask. The flask was flame dried under vacuum and filled with argon. To the flux was then added toluene (5.4 mL), IV-43 (65 mg, 0.089 mmol), IV-44 (10 mg, 0.022 mmol) under argon atmosphere and the mixture was degassed for 30 min. Finally, Pd(PPh3)4 (7.6 mg, 0.0066 mmol) was added to the mixture and refluxed for 20 h before cooling down to room temperature. The solvent was removed in vacuo and the crude was dissolved in CH2Cl2. The organic layer was washed with H2O, followed by brine solution, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (12% EtOAc/hexane) gave IV-NBoc-40 in 56% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.96 – 8.84 (m, 12H), 8.80 (br, 4H), 8.52 (s, 2H), 8.29 (br, 2H), 8.23 – 8.11 (m, 8H), 8.00 (br, 4H), 7.95 – 7.84 (m, 2H), 7.80 – 7.62 (m, 14H), 7.54 (br, 4H), 4.89 (br, 4H), 1.69 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 154.38, 150.32, 150.30, 150.26, 150.11, 143.52, 142.88, 142.77, 138.84, 134.53, 134.51, 134.45, 134.25, 134.04, 132.27, 132.12, 132.10, 131.88, 128.63, 128.02, 127.60, 127.52, 126.65, 126.59, 126.54, 121.35, 121.28, 120.18, 80.43, 48.61, 47.75, 28.73. 175 HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C95H66N9O2Zn2+ 1492.3922; Found 1492.3794. IV-10.4. Synthesis of catalyst IV-57 Br Br CO2H MeI, Ag2CO3 CO2H CO2H 40 ℃,18 h, 72% CO2Me Br Br IV-47 IV-58 Synthesis of IV-5839: To a solution of IV-47 (160 mg, 0.40 mmol) and Ag2CO3 (55 mg, 0.20 mmol) in a sealed tube, MeI (75 µL, 1.20 mmol) was added. The mixture was warmed to 40 °C and stirred for 18 h. After cooling to RT, the reaction was quenched with 2M HCl (12 mL). The crude mixture was then extracted with EtOAc (3x20 mL) and the combined organic layer was washed with H2O, brine and dried over Na2SO4. Purification by column choromatography (30% EtOAc/hexane) resulted the final product IV-58 in 72% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.94 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 3.66 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 168.42, 166.39, 144.02, 143.40, 133.01, 132.91, 132.02, 131.54, 130.97, 130.96, 127.84, 127.24, 127.00, 126.56, 52.21. HRMS (TOF MS ES-) m/z: [M-H]- Calcd for C15H9O4Br2- 410.8868; Found 410.8865. 176 Br Br I Br I CO2H Cat. Pd(OAc)2, NIS CO2H MeI, DBU CO2Me CO2Me DMF, 100 ℃, 24 h CO2Me 100 ℃, 8 h CO2Me 30%, 2 steps Br Br Br IV-58 IV-59 IV-60 Synthesis of IV-6040: A mixture of IV-58 (300 mg, 0.72 mmol), Pd(OAc)2 (16 mg, 0.072 mmol) and N-iodosuccinimide (212 mg, 0.94 mmol) in DMF (3.6 mL) was stirred for 24 h at 100 °C in a sealed tube. After cooling to RT, the mixture was diluted with ethyl acetate (150 mL). The organic layer was then washed with 0.5 M HCl (4x30 mL), followed by brine, dried over Na2SO4 and concentrated in vacuo. To the crude, dissolved in 3 mL dry THF was added DBU (0.26 mL, 1.75 mmol). MeI (0.44 mL, 7.2 mmol) was added and stirred at 100 °C for 8 h. The mixture was cooled to RT and quenched with 3M HCl (20 mL). The crude mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column choromatography (3% EtOAc/hexane) resulted the final product IV-60 in 30% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 3.69 (s, 3H), 3.58 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.65, 166.01, 141.09, 140.47, 140.42, 137.56, 133.63, 131.85, 131.83, 131.61, 128.67, 126.45, 123.43, 92.13, 52.47, 52.33. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C16H12O4Br2+ 552.8147; Found 552.8149. 177 Br I Br Ph Cat. Pd(PPh3)2Cl2 CO2Me PhB(OH)2, Na2CO3 CO2Me CO2Me THF: H2O CO2Me 60 ℃, 12 h, 76% Br Br IV-60 IV-61 Synthesis of IV-61: To a solution of anhydrous THF (0.8 mL) and degassed H2O (0.2 mL) were added IV-60 (100 mg, 0.18 mmol), PhB(OH)2 (26 mg, 0.21 mmol) and Na2CO3 (40 mg, 0.36) sequentially. Pd(PPh3)Cl2 (12.8 mg, 0.018 mmol) was then added to the mixture and stirred at 60 °C for 12 h. After cooling to RT, H2O was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (3% EtOAc/hexane) afforded the desired product IV-61 in 76% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.86 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.40 – 7.34 (m, 5H), 3.68 (s, 3H), 3.27 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 168.31, 166.38, 142.01, 141.48, 141.01, 139.22, 133.95, 133.75, 131.95, 131.74, 131.43, 130.91, 130.68, 130.24, 129.02, 128.47, 128.17, 128.04, 126.33, 123.20, 52.23, 51.88. HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C22H17O4Br2+ 502.9494; Found 502.9492. Br Ph Br Ph CO2Me DIBAL-H CH2OH CO2Me 0 ℃ to RT, CH2OH 12 h, 81% Br Br IV-61 IV-61a 178 Synthesis of IV-61a: To a flame dried round bottom flask was added substrate IV-61(41 mg, 0.08 mmol) in dry CH2Cl2 (0.5 mL). The solution was cooled to 0 °C and DIBAL-H (1 mL, 1M in hexane) was added dropwise uner argon atomosphere. The mixture was warmed to RT and stirred for 12 h. The mixture was quenched with MeOH, poured onto sodium potassium tartrate solution and stirred for 15 mins. The crude was extracted with CH2Cl2, dried over Na2SO4, concentrated in vacuo and purified via column chromatography to afford the desired product IV-61a in 81% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J = 8.2, 2.1 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.50 – 7.39 (m, 6H), 7.36 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 4.40 (ABq, J = 11.9 Hz, 2H), 4.24 (ABq, J = 11.3 Hz, 2H), 3.41 (b, 1H), 2.68 (b, 1H). 13C NMR (126 MHz, Chloroform-d) δ 145.72, 142.11, 140.89, 139.36, 138.08, 134.57, 133.04, 132.28, 132.11, 132.03, 131.82, 131.66, 131.52, 129.27, 128.36, 127.93, 121.56, 121.44, 61.99, 58.94. HRMS (TOF MS ES+) m/z: [M-H2O+H]+ Calcd for C20H15OBr2+ 428.9490; Found 428.9472. Br Ph Br Ph CH2OH PBr3 CH2Br CH2OH 0 ℃ to RT, CH2Br 24 h, 78 % Br Br IV-61a IV-61b Synthesis of IV-61b: To a flame dried round bottom flask compound IV-61a (22 mg, 0.05 mmol) was dissolved in dry CH2Cl2 (1 mL) and PBr3 (0.1 mL, 1M in CH2Cl2) was added dropwise at 0 °C under argon atmosphere. The mixture was warmed to RT and stirred for 179 24 h before being quenched with H2O at 0 °C. The crude was extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo. Purification via column chromatography (hexane) afforded the desired product IV-61b in 78% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 8.3, 2.1 Hz, 1H), 7.51 – 7.49 (m, 2H), 7.48 – 7.42 (m, 7H), 4.21 (ABq, J = 2.6 Hz, 2H), 4.19 (ABq, J = 10.3 Hz, 2H). 13C NMR (126 MHz, Chloroform-d) δ 145.45, 140.92, 140.04, 138.80, 134.89, 133.70, 132.90, 132.46, 132.28, 132.26, 132.08, 128.88, 128.43, 128.14, 122.29, 122.14, 30.91, 29.41. HRMS (TOF MS AP+) m/z: [M-2HBr+H]+ Calcd for C20H13Br2+ 410.9384; Found 410.9365. Br Ph Ph Br CH2Br NaH, NH2Boc NBoc CH2Br 0 ℃ to RT, 12 h, 60 % Br Br IV-61b IV-62 Synthesis of IV-62: To a flame dried round bottom flask NaH (12 mg, 0.30 mmol) was suspended in dry DMF (0.3 mL). To that solution was transferred a mixture of IV-61b (24 mg, 0.042 mmol) and tert-butyl carbamate (6.3 mg, 0.054 mmol) in dry DMF (0.3 mL) dropwise over 10 min at 0 °C. The mixture was warmed to RT and stirred 12 h before being quenched with H2O at 0 °C. The crude was extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. Purification via column chromatography (2% EtOAc/hexane) afforded the desired product IV-62 in 60% yield. 180 1H NMR (500 MHz, Chloroform-d) δ 7.75 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 – 7.46 (m, 4H), 7.46 – 7.40 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 4.45 (s, 2H), 4.19 (s, 2H), 1.57 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 153.51, 144.87, 142.47, 141.46, 139.45, 133.19, 132.98, 131.91, 131.48, 130.79, 130.52, 130.09, 129.32, 128.48, 127.81, 122.40, 121.81, 80.04, 46.25, 43.61, 28.17. Ph Ph BPin N Ph Ph N Br N N Br Zn Zn N N N N Pd(PPh3)4, K3PO4 Ph N N Ph + Ph Zn Ph toluene, reflux Ph N N 20 h, 56% N Boc Ph Ph IV-62 IV-43 N Boc IV-NBoc-57 Synthesis of IV-NBoc-5728: K3PO4 (53 mg, 0.25 mmol) was added to an oven dried round bottom flask. The flask was flame dried under vacuum and filled with argon. To the flux was then added toluene (5.4 mL), IV-43 (65 mg, 0.089 mmol), IV-62 (11.6 mg, 0.022 mmol) under argon atmosphere and the mixture was degassed for 30 min. Finally, Pd(PPh3)4 (7.6 mg, 0.066 mmol) was added to the mixture and refluxed for 20 h before cooling down to room temperature. The solvent was removed in vacuo and the crude was dissolved in CH2Cl2. The organic layer was washed with H2O, followed by brine solution, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (15% EtOAc/hexane) gave IV-NBoc-40 in 72% yield. 181 1H NMR (500 MHz, Chloroform-d) δ 8.87 (br, 16H), 8.57 (br, 1H), 8.57 (br, 1H), 8.31 (br, 2H), 8.21 – 8.06 (m, 9H), 7.96 (d, J = 7.6 Hz, 2H), 7.88 (br, 1H), 7.80 – 7.59 (m, 17H), 7.56 – 7.48 (m, 3H), 7.56 – 7.48 (m, 2H), 5.54 (br, 4H), 1.52 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 153.76, 150.19, 150.16, 150.15, 150.13, 150.01, 143.34, 142.72, 142.61, 141.13, 140.97, 140.07, 139.07, 136.03, 134.37, 134.31, 134.14, 133.82, 133.53, 132.19, 132.13, 131.98, 131.96, 131.79, 130.98, 129.97, 128.46, 128.25, 127.48, 127.39, 126.52, 126.45, 121.25, 121.22, 121.16, 120.12, 119.86, 80.05, 47.32, 44.50, 28.28. HRMS (TOF MS ES+) m/z: [M+2H]2+ Calcd for C101H71N9O2Zn22+ 784.7157; Found 784.7111. 182 IV-10.5. Synthesis of catalyst IV-70 O C6F5 C6F5 C6F5 Cl NH HN mesitylMgBr, 15% NH HN C6F5 C6F5 O O IV-64 IV-65 Synthesis of IV-6541: To a flame-dried round bottom flask substrate IV-64 (906 mg, 2.90 mmol) was added to toluene (5.8 mL) under argon atmosphere, and stirred for 10 min. The solution was then cooled to 0 °C, after which mesitylMgBr (1 M in THF, 12.2 mL, 12.2 mmol) was added dropwise over 15 min, and stirred for a further 30 min at 0 °C. Following this, 2,3,4,5,6- pentafluorobenzoyl chloride (0.85 mL, 5.89 mmol) was added dropwise, and the reaction was maintained at 0 °C for another 1 h. The mixture was then poured onto 100 mL of cold sat. aq. NH4Cl solution and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, and finally concentrated in vacuo. Purification via column chromatography (10% EtOAc/hexane) resulted the final product IV-65 in 15% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.72 (br, 2H), 6.90-6.85 (m, 2H), 6.05 (s, 1H), 6.03- 6.00 (m, 2H). 19F NMR (470 MHz, DMSO-d6) δ -140.84– -140.99 (m,2F), -142.43 – -142.60 (m, 4F), - 152.86 (t, J = 22.2 Hz, 2F), -155.73 (t, J = 22.4 Hz, 1F), -160.71 – - 160.94(m, 4F), -162.2 – - 162.38(m, 2F). HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C29H10N2O2F15+ 701.0346; Found 701.0339. 183 C6F5 C6F5 1. NaBH4, 0.5 h NH HN NH N NH HN C6F5 C6F5 2. Yb(OTf)3, 1.5 h C6F5 C6F5 N HN O O 3. DDQ, 0.5 h 22% IV-65 H IV-66 Synthesis of IV-6641: To a solution of IV-65 (200 mg, 0.286 mmol), THF (8.6 mL) and MeOH (2.9 mL) at RT was added NaBH4 (540.2 mg, 14.3 mmol) portion wise over 10 min. Following the addition, the reaction mixture was stirred for 20 min, after which it was poured into a separating funnel consisting of sat. aq. NH4Cl (60 mL) and ethyl acetate (60 mL). The layers were separated, and the organic layer was washed with H2O (60 mL), brine (60 mL), dried (Na2SO4), and transferred to a 250 mL round bottom flask before being concentrated in vacuo. The flask containing the crude material was purged with a stream of argon for 5 min after which CH2Cl2 (114 mL) and IV-51 (41.8 mg, 0.286 mmol) were added sequentially. The mixture was then heated to 34 °C and Yb(OTf)3 (234.2 mg, 0.38 mmol) added in one portion. The mixture was stirred for 1 h 30 min at 34 °C after which it was cooled to RT and DDQ (194.8 mg, 0.858 mmol) was added. Following an additional 30 min stirring, Et3N (0.26 mL, 1.85 mmol) was added dropwise to the reaction. The reaction mixture was filtered through a pad of SiO2 eluting with CH2Cl2 and the solvent was removed in vacuo. Purification by column chromatography (20% CH2Cl2/hexane) afforded the title compound IV-66 in 22% yield. 1H NMR (500 MHz, Chloroform-d) δ 10.39 (s, 1H), 9.48 (d, J = 4.7 Hz, 2H), 8.98 (d, J = 4.6 Hz, 2H), 8.96 – 8.90 (m, 4H), -3.13 (br, 2H). 184 19F NMR (470 MHz, Chloroform-d) δ -136.46 – -136.64 (m, 6F), -151.70 (t, J = 20.8 Hz, 3F), -161.47 – -161.70 (m, 6F). HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C38H12N4F15+ 809.0822; Found 809.0811. C6F5 C6F5 NH N N N Zn(OAc)2 C6F5 C6F5 C6F5 Zn C6F5 DCM/MeOH N HN N N RT, 16 h, 91% H H IV-66 IV-67 Synthesis of IV-6741: To a solution of IV-66 (409 mg, 0.51 mmol) in CHCl3 (90 mL) and MeOH (30 mL) at RT was added Zn(OAc)2•2H2O (2.78 g, 12.8 mmol) in one portion. The reaction mixture was stirred for 16 h, after which it was suction filtered, and the filtrate was concentrated in vacuo. The resulting pink solids were re-dissolved in CH2Cl2 (300 mL), washed with H2O, brine (500 mL), dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography (Hexane:CH2Cl2, 1:1) gave the title compound IV- 67 in 91% yield. 1H NMR (500 MHz, Chloroform-d) δ 10.42 (s, 1H), 9.54 (d, J = 4.5 Hz, 2H), 9.06 (d, J = 4.5 Hz, 2H), 9.04 – 8.97 (m, 4H). 19F NMR (470 MHz, Chloroform-d) δ -136.67 - 137.20 (m, 6F), -152.05 – -153.14 (m, 6F), -161.68 - 162.24 (m, 6F). HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C38H10F15N4Zn+ 870.9957; Found 870.9920. 185 C6F5 C6F5 N N N N NBS, pyridine C6F5 Zn C6F5 C6F5 Zn C6F5 CHCl3, 1 h, 96% N N N N H Br IV-67 IV-68 Synthesis of IV-6841: To a solution of IV-67 (95.3 mg, 0.109 mmol) in CHCl3 (22 mL) at 0 °C was added pyridine (29.7 μL, 0.368 mmol) followed by NBS (19.5 mg, 0.109 mmol). The reaction mixture was stirred for 30 min at 0 °C, after which additional pyridine (15.0 μL, 0.186 mmol) and NBS (9.70 mg, 54.5 μmol) were added. After 30 min the reaction was quenched by the addition of acetone (12 mL) and concentrated in vacuo. Purification by column chromatography (30% DCM/hexane) gave IV-68 in 96% yield. 1H NMR (500 MHz, Chloroform-d) δ 9.84 (d, J = 4.7 Hz, 2H), 8.90 (d, J = 4.7 Hz, 2H), 8.89 – 8.83 (m, 4H). 19F NMR (470 MHz, Chloroform-d) δ -137.06 (br, 6F) -152.46 (br, 3F) -162.06 (br, 6F). HRMS (TOF MS ES+) m/z: [M+H]+ Calcd for C38H9BrF15N4Zn+ 948.9063; Found 948.9010. C6F5 C6F5 N N N N Cat.Pd(PPh3)2Cl2 C6F5 Zn C6F5 C6F5 Zn C6F5 HBPin, 56% N N N N Br BPin IV-68 IV-69 186 Synthesis of IV-6926: To a flame dried round bottom flask was added 1,2 dicholorethane (41 mL) and degassed for 30 min. To that flask IV-68 (390 mg, 0.41 mmol), pinacolborane (2.1 mL, 14.35 mmol), triethylamine (0.74 mL, 5.3 mmol) and Pd(PPh3)2Cl2 (43 mg, 0.06 mmol) were added sequentially under an argon atmosphere. The mixture was refluxed for 12 h before cooling down to RT. The solvent was then removed in vacuo and the crude was dissolved in dichloromethane, washed with H2O, and dried over Na2SO4. The crude was purified via column chromatography to afford the desired product IV-69 in 56% yield. 1H NMR (500 MHz, Chloroform-d) δ 10.02 (d, J = 4.7 Hz, 2H), 9.02 (d, J = 4.7 Hz, 2H), 8.96-8.93 (m, 4H), 1.87 (s, 6H). 19F NMR (470 MHz, Chloroform-d) δ -136.66 – -137.20 (m, 6F), -152.46 – -152.90 (m, 3F), -162.00 – -162.42 (m, 6F). HRMS (TOF MS ES+) m/z: [M]+ Calcd for C44H20BF15N4O2Zn+ 996.0731; Found 997.0729. C6F5 C6F5 BPin N C6F5 F5C6 N Br N N Br Zn Zn Cat. Pd(PPh3)4, N N N N K3PO4 C6F5 N N C6F5 + F5C6 Zn C6F5 toluene, reflux N N 20 h, 74% N Boc C6F5 IV-44 IV-69 N Boc IV-NBoc-70 Synthesis of IV-NBoc-7028: K3PO4 (80 mg, 0.38 mmol) was added to an oven dried round bottom flask. The flask was flame dried under vacuum and filled with argon. To the flux was then added toluene (7.8 mL), IV-69 (119 mg, 0.14 mmol), IV-44 (15 mg, 0.034 187 mmol) under argon atmosphere and the mixture was degassed for 30 min. Finally, Pd(PPh3)4 (12 mg, 0.01 mmol) was added to the mixture and refluxed for 20 h before cooling down to room temperature. The solvent was removed in vacuo and the crude was dissolved in CH2Cl2. The organic layer was washed with H2O, followed by brine solution, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (15% EtOAc/hexane) gave IV-NBoc-70 in 74% yield. 1H NMR (500 MHz, Chloroform-d) δ 9.04 (d, J = 4.6 Hz, 4H), 8.93 – 8.85 (m, 8H), 8.76 (br, 4H), 8.48 (s, 2H), 8.26 (d, J = 6.3 Hz, 2H), 7.86 (br, 2H), 4.84 (br, 2H), 4.60 (br, 2H), 1.57 (s, 9H). 19F NMR (470 MHz, Chloroform-d) δ -136.52 – -137.59 (m, 12F), -152.18 – -152.33 (m, J = 22.4, 6F), -161.50 – -162.73 (m, 12F). IV-10.6. General procedure for the deprotection of the Boc group under basic condition42 To a vigorously stirred solution of IV-NBoc-40 (30 mg, 0.02 mmol) and 2,6 lutidine (58 µL, 0.5 mmol) in CH2Cl2 at 0 °C was added trimethylsilyl triflate (54 µL, 0.3 mmol) dropwise under argon atmosphere. After 15 min, the ice bath was removed, and the mixture was stirred at room temperature for 3.5 h. The reaction mixture was placed in an ice-bath again and quenched with saturated NH4Claq (0.5 mL) and stirred for 15 min at room temperature. Subsequently the mixture was extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo. To the crude mixture was added acetonitrile and the solid was filtered. The residue was washed with several portions of acetonitrile to remove excess 2,6-lutidine and dried under vacuum to afford the desired product IV-40 in 84% 188 yield. The product was used directly to the conjugate addition reaction without any further purification. Catalyst IV-56 and IV-70 were synthesized similarly from IV-NBoc-56 and IV-NBoc-70 respectively. IV-10.7. General procedure for the syn-selective asymmetric Michael addition reaction catalyzed by programmable racemic catalyst To a solution of amine catalyst IV-40 (3.5 mg, 0.0025 mmol) in 1-bromo-3-chlorobenzene (0.2 mL) in a small vial was added III-RP-19 (1.2 mg, 0.0025 mmol) and stirred for 20 min. To the mixture was added aldehyde IV-36 (7.2 µL, 0.10 mmol) and electrophile IV-37 (9.5 mg, 0.05 mmol) at room temperature. The reaction mixture was then stirred for 48 h. All volatiles were subsequently removed in vacuo and the crude mixture was dissolved in CH2Cl2 (1 mL) and benzyl 2-(triphenylphosphoranylidene)acetate (64 mg, 0.15 mmol) was added. The olefination reaction was allowed to proceed until complete consumption of the conjugate addition adduct. After solvent removal, the crude was passed through a plug of silica gel and washed with 20% EtOAc/hexane mixture (400 mL). After removing the solvent, the crude was purified via column chromatography (6% EtOAc/Hexane) on silica gel to afford the corresponding product IV-ent-39 as an inseparable diastereomeric mixture. The spectral data matched the reported in the literature. HPLC analysis for IV-ent-39: Chiralpak IA, 98:2 hexane/i-PrOH, flow rate = 0.42 mL/min, λ = 240 nm, retention time = 104.4 min (major), 1132.4 min (minor). 189 IV-10.8. NMR spectra: 2.51 dmso H NMR (500 MHz, DMSO-d6) 1 2.50 dmso 2.50 dmso 2.50 dmso 2.49 dmso Br CO2H CO2H Br IV-47 1.72 2.14 2.19 2.00 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 f1 (ppm) 190 13 200 190 180 Br Br 170 166.79 C NMR (126 MHz, DMSO-d6) IV-47 160 CO2H CO2H 150 143.78 140 132.57 131.63 130 130.45 129.31 124.92 120 110 100 191 f1 (ppm) 90 80 70 60 50 40.02 dmso 39.85 dmso 39.69 dmso 40 39.52 dmso 39.35 dmso 39.19 dmso 30 39.02 dmso 20 10 0 2.50 dmso 1H NMR (500 MHz, DMSO-d6) Br CH2OH CH2OH Br IV-48 4.46 1.76 2.00 1.85 4.16 4.14 4.12 4.10 4.08 4.06 4.04 4.02 f1 (ppm) 7.65 7.60 7.55 7.50 7.45 7.40 7.35 7.30 f1 (ppm) 1.76 2.00 1.85 1.99 4.46 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 192 13 200 Br Br 190 180 IV-48 CH2OH 170 C NMR (126 MHz, DMSO-d6) CH2OH 160 150 140 139.24 138.86 131.22 130 130.74 129.36 120 119.42 110 100 f1 (ppm) 193 90 80 70 60 60.11 50 40.02 dmso 39.85 dmso 39.69 dmso 40 39.52 dmso 39.35 dmso 39.19 dmso 30 39.02 dmso 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br CH2Br CH2Br Br IV-49 2.00 3.94 2.11 2.14 7.65 7.60 7.55 7.50 7.45 7.40 7.35 4.30 4.25 4.20 4.15 4.10 f1 (ppm) f1 (ppm) 2.00 2.11 3.94 2.14 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 194 C NMR (126 MHz, CDCl3) 13 77.39 cdcl3 139.85 77.14 cdcl3 122.51 30.63 135.05 132.89 132.40 132.38 76.89 cdcl3 Br CH2Br CH2Br Br IV-49 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 195 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br Br 7.26 cdcl3 N Boc IV-44 1.99 2.00 0.94 0.85 7.7 7.6 7.5 7.4 7.3 7.2 f1 (ppm) 1.99 4.25 2.00 0.94 0.85 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 196 C NMR (126 MHz, CDCl3) 13 80.45 77.41 cdcl3 154.23 141.31 133.47 122.59 77.16 cdcl3 47.58 28.65 131.82 131.33 131.04 76.91 cdcl3 46.78 Br Br N Boc IV-44 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 197 7.26 cdcl3 1H NMR (500 MHz, CDCl3) NH HN IV-51 1.94 1.94 6.18 6.16 6.14 6.12 6.10 6.08 6.06 6.04 6.02 f1 (ppm) 1.92 2.00 1.94 1.94 2.31 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 198 C NMR (126 MHz, CDCl3) 13 77.41 cdcl3 77.16 cdcl3 129.20 108.45 117.46 106.56 76.91 cdcl3 26.47 NH HN IV-51 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 199 7.26 cdcl3 1H NMR (500 MHz, CDCl3) H N HN Ph Ph NH N H IV-52 3.98 3.82 4.01 6.11 9.5 9.4 9.3 9.2 9.1 9.0 8.3 8.2 8.1 8.0 7.9 7.8 f1 (ppm) f1 (ppm) 2.00 3.98 3.82 4.01 6.11 1.96 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 200 C NMR (126 MHz, CDCl3) 13 77.41 cdcl3 147.31 135.00 77.16 cdcl3 119.24 105.41 131.76 145.33 131.20 141.52 127.86 127.12 76.91 cdcl3 H N HN Ph Ph NH N H IV-52 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 201 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 H N HN Ph Ph NH N 1.93 1.87 3.78 Ph 9.4 9.3 9.2 9.1 9.0 8.9 8.8 IV-53 f1 (ppm) 5.91 9.05 8.3 8.2 8.1 8.0 7.9 7.8 7.7 f1 (ppm) 1.00 1.93 1.87 3.78 5.91 9.05 1.85 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 202 C NMR (126 MHz, CDCl3) 13 77.41 cdcl3 77.16 cdcl3 142.72 104.94 141.91 134.85 134.65 131.56 76.91 cdcl3 130.86 127.86 126.97 126.70 120.73 119.78 H N HN Ph Ph NH N Ph IV-53 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 203 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 Br N HN Ph Ph NH N Ph IV-53a 6.00 9.25 1.62 1.71 3.58 8.3 8.2 8.1 8.0 7.9 7.8 7.7 9.7 9.6 9.5 9.4 9.3 9.2 9.1 9.0 8.9 8.8 8.7 8.6 f1 (ppm) f1 (ppm) 1.62 1.71 3.58 6.00 9.25 1.86 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 204 C NMR (126 MHz, CDCl3) 13 77.41 cdcl3 77.16 cdcl3 142.00 103.04 141.90 134.69 134.62 134.58 76.91 cdcl3 128.02 127.99 127.06 126.90 121.14 120.94 Br N HN Ph Ph NH N Ph IV-53a 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 205 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 Br N N Ph Zn Ph N N 1.67 1.73 3.53 10.0 9.5 9.0 f1 (ppm) Ph IV-54 5.76 9.20 8.2 8.1 8.0 7.9 7.8 7.7 f1 (ppm) 1.67 1.73 3.53 5.76 9.20 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 206 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 BPin N N Ph Zn Ph N N 6.22 9.43 Ph 8.4 8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 IV-43 f1 (ppm) 2.00 2.00 3.97 10.0 9.5 9.0 f1 (ppm) 2.00 12.36 2.00 3.97 6.22 9.43 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 207 13 200 Ph 190 180 N N Ph Zn IV-43 BPin N N C NMR (126 MHz, CDCl3) 170 160 Ph 154.57 150.55 150 150.15 149.48 143.01 142.91 140 134.63 134.49 133.15 130 133.02 132.30 131.69 127.68 120 127.62 126.68 126.66 110 122.77 121.11 100 208 f1 (ppm) 90 85.40 80 77.42 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 50 40 30 25.50 20 10 0 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 Ph Ph N Ph Ph N N N Zn Zn N N Ph N N Ph 14.57 4.00 2.10 5.90 3.74 2.39 N 7.75 7.70 7.65 7.60 7.55 7.50 Boc 8.20 8.15 8.10 8.05 8.00 7.95 7.90 7.85 f1 (ppm) f1 (ppm) IV-NBoc-40 3.89 7.92 3.86 8.95 8.90 8.85 8.80 8.75 f1 (ppm) 3.89 7.92 3.86 3.72 9.41 1.95 2.00 2.10 5.90 3.74 2.39 14.57 4.00 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 209 13 200 Ph Ph 190 N N Zn N 180 N Ph C NMR (126 MHz, CDCl3) 170 N Boc 160 IV-NBoc-40 Ph 154.38 150.32 N 150.30 150.26 150 N Zn N 150.11 143.52 N 142.88 140 Ph 142.77 Ph 138.84 134.53 134.51 130 134.45 134.25 134.04 120 132.27 132.12 132.10 131.88 110 128.63 127.60 127.52 100 126.65 f1 (ppm) 126.59 210 126.54 121.35 90 121.28 120.18 80.43 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 50 48.61 47.75 40 30 28.73 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br CO2H CO2Me Br IV-58 0.52 1.01 0.46 7.62 7.61 7.60 7.59 7.58 7.57 f1 (ppm) 1.00 0.98 7.95 7.93 7.91 7.89 7.87 7.85 f1 (ppm) 1.80 7.38 7.37 7.36 7.35 7.34 7.33 f1 (ppm) 1.00 3.20 0.98 0.52 1.01 0.46 1.80 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 211 13 200 Br Br 190 IV-58 180 CO2H CO2Me C NMR (126 MHz, CDCl3) 133.15 170 133 133.05 168.56 166.53 160 132 132.16 131.68 131.11 150 131 144.16 143.54 140 130 129 133.15 133.05 132.16 f1 (ppm) 131.68 130 131.11 127.99 127.38 128 127.99 127.14 120 126.70 127.38 127 127.14 110 126.70 100 f1 (ppm) 212 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 52.35 50 40 30 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br I CO2Me CO2Me 0.98 1.15 1.16 1.01 1.02 Br 8.0 7.9 7.8 7.7 7.6 7.5 7.4 IV-60 f1 (ppm) 0.98 1.15 3.58 1.16 1.01 1.02 3.59 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 213 13 200 Br Br 190 IV-60 I 180 CO2Me CO2Me C NMR (126 MHz, CDCl3) 170 167.80 166.16 160 141.24 140.62 150 140.57 141.24 140.62 140 140.57 137.71 133.78 137.71 132.00 130 131.98 142 141 140 139 138 137 136 135 134 133 132 131 131.76 128.82 126.60 120 123.58 110 133.78 100 132.00 131.98 214 f1 (ppm) 131.76 f1 (ppm) 92.28 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 52.62 50 52.48 40 30 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br Ph CO2Me CO2Me Br IV-61 1.00 0.54 1.45 0.93 1.17 5.30 7.8 7.7 7.6 7.5 7.4 f1 (ppm) 1.00 3.24 3.23 0.54 1.45 0.93 1.17 5.30 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 215 13 200 Br Br 190 IV-61 180 CO2Me Ph C NMR (126 MHz, CDCl3) CO2Me 170 168.44 166.51 160 142.14 141.62 141.14 142.14 139.35 141.62 150 141.14 139.35 133.88 140 132.09 131.88 131.56 133.88 131.05 132.09 142 140 138 136 134 132 130 128 126 124 130 130.82 131.88 129.15 131.56 128.60 131.05 128.31 120 130.82 128.18 129.15 126.46 128.60 123.34 110 128.31 128.18 126.46 100 f1 (ppm) f1 (ppm) 123.34 216 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 52.36 50 52.01 40 30 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br Ph CH2OH CH2OH Br IV-61a 1.00 0.91 6.10 0.93 0.90 1.08 1.13 2.23 7.55 7.50 7.45 7.40 7.35 7.30 4.45 4.40 4.35 4.30 4.25 4.20 f1 (ppm) f1 (ppm) 1.00 1.08 1.47 1.36 0.91 6.10 1.13 0.93 0.90 2.23 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 217 13 200 Br Br 190 IV-61a 180 CH2OH Ph CH2OH C NMR (126 MHz, CDCl3) 170 145.87 160 142.26 141.03 139.50 133.5 138.23 150 134.71 133.19 133.19 132.43 140 133.0 131.96 131.80 131.67 129.41 130 128.51 132.5 132.0 132.43 128.08 121.70 120 121.59 f1 (ppm) 131.96 131.80 110 131.67 100 131.5 f1 (ppm) 218 131.0 90 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 62.14 60 59.08 50 40 30 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br Ph CH2Br CH2Br Br IV-61b 1.00 1.80 7.40 1.15 2.26 1.13 7.60 7.55 7.50 7.45 7.40 4.35 4.30 4.25 4.20 4.15 4.10 4.05 f1 (ppm) f1 (ppm) 1.00 1.15 1.80 2.26 7.40 1.13 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 219 13 200 Br Br 190 IV-61b CH2Br Ph 180 CH2Br C NMR (126 MHz, CDCl3) 170 145.59 160 141.06 140.17 138.94 135.03 150 133.83 134 133.83 133.04 132.59 140 133.04 132.42 133 132.59 132.40 132.42 132.22 132.40 129.01 130 132 132.22 128.57 128.28 122.42 122.28 120 131 130 110 f1 (ppm) 100 129 129.01 128.57 f1 (ppm) 128.28 220 128 90 80 77.42 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 50 40 31.05 30 29.54 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Br Br Ph N Boc IV-62 1.00 0.99 0.95 1.03 4.70 1.38 1.22 7.75 7.70 7.65 7.60 7.55 7.50 7.45 7.40 7.35 f1 (ppm) 1.00 2.22 2.18 8.06 0.99 0.95 1.03 4.70 1.38 1.22 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 221 13 200 Br 190 N IV-62 Boc 180 Br Ph C NMR (126 MHz, CDCl3) 170 160 153.66 134 150 133.34 145.02 133 133.12 142.62 141.61 140 139.60 132 132.06 133.34 131.63 133.12 130 132.06 131.63 131 130 130.94 130.94 130.67 130.67 120 130.24 130.24 f1 (ppm) 129.47 129.47 128.63 110 127.96 129 122.55 128.63 121.96 100 90 128 127.96 222 f1 (ppm) 127 80.19 80 77.41 cdcl3 77.16 cdcl3 76.91 cdcl3 70 60 50 46.39 43.76 40 30 28.32 20 10 0 7.26 cdcl3 1H NMR (500 MHz, CDCl3) Ph Ph N Ph Ph N N N Zn Zn N N Ph N N Ph Ph N Boc IV-NBoc-57 16.00 17.87 1.35 2.29 9.23 1.39 3.86 1.26 1.59 2.50 9.0 8.8 8.6 8.4 8.2 8.0 7.8 7.6 7.4 f1 (ppm) 16.00 1.35 11.88 1.26 2.29 9.23 1.39 1.59 17.87 3.86 2.50 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 223 Ph Ph 13 200 N N Zn N 190 N Ph N 180 Boc Ph C NMR (126 MHz, CDCl3) 170 IV-NBoc-57 N Ph N Zn N 160 N 153.90 150.33 143.47 Ph 150.30 142.86 Ph 150.27 150 142.75 150.14 140 141.10 143.47 139.20 142.86 140 136.17 142.75 134.51 141.27 134.45 141.10 135 132.33 139.20 130 132.27 136.17 132.13 134.51 130 132.10 134.45 120 131.92 133.96 f1 (ppm) 130.11 133.67 128.60 132.33 128.39 132.27 110 127.61 132.13 125 127.53 132.10 126.65 131.92 100 126.58 131.11 121.39 130.11 224 f1 (ppm) 121.36 128.60 120 121.29 128.39 90 120.26 127.61 119.99 127.53 126.65 80 126.58 121.39 121.36 121.29 70 120.26 119.99 80.19 77.41 cdcl3 60 77.16 cdcl3 76.91 cdcl3 50 47.46 44.64 40 30 28.41 20 10 0 2.51 dmso 1H NMR (500 MHz, DMSO-d6) 2.50 dmso 2.50 dmso 2.50 dmso 2.49 dmso C6F5 NH HN C6F5 C6F5 O O IV-65 0.99 1.93 6.07 6.06 6.05 6.04 6.03 6.02 6.01 6.00 f1 (ppm) 2.00 1.98 0.99 1.93 13.5 13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 225 19 -100 C6F5 -105 O -140.5 -140.88 2.01 -140.90 -110 -140.93 IV-65 NH HN C6F5 -141.0 -140.95 O F NMR (470 MHz, DMSO-d6) -115 -141.5 -142.0 C6F5 -120 f1 (ppm) -125 -142.48 -142.49 -152.82 -130 -142.5 4.19 -142.53 2.01 -152.86 -142.54 -152.91 -135 -143.0 -140.88 -140.90 -140.93 -140 2.01 -140.95 -152.5 -153.0 -153.5 -154.0 -154.5 -155.0 -155.5 -156.0 4.19 -142.48 -142.49 -142.53 -145 -150 -142.54 226 f1 (ppm) -152.82 2.01 -152.86 -155.68 -152.91 -155 0.98 -155.73 -155.68 0.98 -155.73 -155.77 -155.77 f1 (ppm) -160.76 -160 4.14 -160.77 2.00 -160.81 -160.82 -160.86 -165 -160.87 -160.5 -160.76 -160.77 -162.23 -160.81 -162.24 4.14 -162.28 -170 -160.82 -160.86 -162.29 -161.0 -160.87 -162.33 -162.34 -175 -161.5 -180 f1 (ppm) -185 -162.0 -162.23 -162.24 -190 2.00 -162.28 -162.29 -162.33 -162.5 -162.34 -195 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 C6F5 NH N C6F5 C6F5 N HN H IV-66 2.07 2.03 4.00 9.6 9.5 9.4 9.3 9.2 9.1 9.0 8.9 8.8 f1 (ppm) 1.03 2.07 2.03 4.00 1.66 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 227 19 -100 C6F5 -105 -136.45 -110 -136.48 -136.50 N NH F NMR (470 MHz, CDCl3) H -136.53 IV-66 -115 -136.55 -136.55 HN N C6F5 6.03 -136.57 f1 (ppm) -120 -136.60 -136.62 C6F5 -125 -136.65 -130 -136.48 -136.75 -136.50 -135 -151.5 -136.53 6.03 -136.55 -136.57 -136.60 -140 -136.62 -151.6 -151.66 -145 -150 -151.7 3.00 -151.70 228 f1 (ppm) f1 (ppm) -151.74 -151.66 3.00 -151.70 -151.74 -151.8 -155 -161.49 -161.51 -161.54 -161.56 -160 -161.59 6.00 -151.9 -161.61 -161.62 -165 -161.63 -161.66 -161.68 -170 -161.3 -161.49 -175 -161.51 -161.54 -161.56 -161.5 -161.7 6.00 -161.59 -180 -161.61 -161.62 -161.63 f1 (ppm) -161.66 -185 -161.68 -190 -161.9 -195 -162.1 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 C6F5 N N C6F5 Zn C6F5 N N 2.05 1.99 4.03 9.7 9.6 9.5 9.4 9.3 9.2 9.1 9.0 8.9 H f1 (ppm) IV-67 1.00 2.05 1.99 4.03 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 229 -136.85 -152.32 -161.93 -161.95 F NMR (470 MHz, CDCl3) 19 -152.36 -152.38 -161.98 -136.90 -152.43 -161.99 -162.03 -152.47 -162.04 -152.32 -161.93 -152.36 -161.95 -152.38 -161.98 -161.99 -152.43 -162.03 -152.47 -162.04 2.87 5.89 -152.1 -152.3 -152.5 -152.7 -152.9 -161.6 -161.8 -162.0 -162.2 -162.4 f1 (ppm) f1 (ppm) -136.85 -136.90 C6F5 N N C6F5 Zn C6F5 N N 6.00 H -136.5 -136.7 -136.9 -137.1 -137.3 IV-67 f1 (ppm) 6.00 2.87 5.89 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 -180 -185 -190 -195 f1 (ppm) 230 7.26 cdcl3 1H NMR (500 MHz, CDCl3) C6F5 N N C6F5 Zn C6F5 N N Br 0.90 1.00 2.18 IV-68 9.86 9.85 9.84 9.83 9.82 8.90 8.85 f1 (ppm) f1 (ppm) 0.90 1.00 2.18 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 231 7.26 cdcl3 H NMR (500 MHz, CDCl3) 1 C6F5 N N C6F5 Zn C6F5 N N 1.93 1.87 3.70 10.0 9.8 9.6 9.4 9.2 9.0 8.8 BPin f1 (ppm) IV-69 1.93 12.00 1.87 3.70 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 232 -136.98 -152.52 -162.13 F NMR (470 MHz, CDCl3) 19 -152.57 -162.19 -152.60 -152.71 -162.25 -152.75 -162.29 -152.79 C6F5 N N C6F5 Zn C6F5 -152.52 -152.57 -162.13 -152.60 -162.19 N N -152.71 -152.75 -162.25 -152.79 -162.29 BPin IV-69 3.04 6.28 -151.0 -151.5 -152.0 -152.5 -153.0 -153.5 -154.0 -154.5 -161.4 -161.8 -162.2 -162.6 -163.0 f1 (ppm) f1 (ppm) 6.00 3.04 6.28 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 -180 -185 -190 -195 f1 (ppm) 233 7.26 cdcl3 1 H NMR (500 MHz, CDCl3) C6F5 C6F5 N C6F5 F5C6 N N N Zn Zn N N C6F5 N N C6F5 4.00 8.01 4.10 2.30 2.34 1.15 1.17 9.0 8.8 8.6 8.4 8.2 8.0 7.8 7.6 7.4 N f1 (ppm) Boc IV-NBoc-70 10.46 4.00 1.15 2.46 2.48 8.01 4.10 2.30 2.34 1.17 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 f1 (ppm) 234 -136.70 -152.35 -136.76 -161.86 -161.91 F NMR (470 MHz, CDCl3) 19 -136.84 -161.94 -136.88 -136.97 -137.02 -152.39 -161.96 -161.99 -162.04 -137.09 -137.14 -152.44 -162.11 -162.16 C6F5 C6F5 N C6F5 F5C6 N -152.35 N N -152.39 -152.44 Zn Zn N N C6F5 N N C6F5 -161.86 -161.91 -161.94 N 2.97 -161.96 -161.99 -162.04 Boc -162.11 -162.16 IV-NBoc-70 -151.6 -152.0 -152.4 -152.8 -153.2 f1 (ppm) -136.70 -136.76 -136.84 -136.88 -136.97 -137.02 -137.09 -137.14 5.91 -161.4 -161.6 -161.8 -162.0 -162.2 -162.4 -162.6 -162.8 f1 (ppm) 6.00 -136.4 -136.8 -137.2 -137.6 -138.0 f1 (ppm) 6.00 2.97 5.91 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 -180 -185 -190 -195 f1 (ppm) 235 IV-10.9. Crystal structure of IV-NBoc-40 Experimental. Single red needle crystals of IV-NBoc-40 used as received. A suitable crystal with dimensions 0.20 × 0.07 × 0.04 mm3 was selected and mounted on a nylon loop with paratone oil on a XtaLAB Synergy, Dualflex, HyPix diffractometer. The crystal was kept at a steady T = 100.00(10) K during data collection. The structure was solved with the ShelXS solution program using direct methods and by using Olex2 as the graphical interface. The model was refined with ShelXL 2018/3 using full matrix least squares minimisation on F2. 236 Crystal Data. C95H67N9O3Zn2, Mr = 1513.31, monoclinic, P21/n (No. 14), a = 19.0993(4) Å, b = 12.9001(3) Å, c = 31.9564(8) Å, b = 93.374(2)°, a = g = 90°, V = 7859.9(3) Å3, T = 100.00(10) K, Z = 4, Z' = 1, µ(Cu Ka) = 1.203, 25242 reflections measured, 9015 unique (Rint = 0.0363) which were used in all calculations. The final wR2 was 0.2016 (all data) and R1 was 0.0675 (I≥2 s(I)). 237 Compound IV-NBoc-40 Formula C95H67N9O3Zn2 Dcalc./ g cm-3 1.279 µ/mm-1 1.203 Formula Weight 1513.31 Color red Shape needle Size/mm3 0.20×0.07×0.04 T/K 100.00(10) Crystal System monoclinic Space Group P21/n a/Å 19.0993(4) b/Å 12.9001(3) c/Å 31.9564(8) a/° 90 b/° 93.374(2) g/° 90 V/Å3 7859.9(3) Z 4 Z' 1 Wavelength/Å 1.54184 Radiation type Cu Ka 238 Qmin/° 2.629 Qmax/° 59.997 Measured 25242 Refl's. Indep't Refl's 9015 Refl's I≥2 s(I) 6829 Rint 0.0363 Parameters 980 Restraints 0 Largest Peak 0.996 Deepest Hole -0.572 GooF 1.060 wR2 (all data) 0.2016 wR2 0.1776 R1 (all data) 0.0893 R1 0.0675 239 A red needle-shaped crystal with dimensions 0.20×0.07×0.04 mm3 was mounted on a nylon loop with paratone oil. Data were collected using a XtaLAB Synergy, Dualflex, HyPix diffractometer equipped with an Oxford Cryosystems low-temperature device, operating at T = 100.00(10) K. Data were measured using w scans of 0.5° per frame for 45.0/180.0 s using Cu Ka radiation (micro-focus sealed X-ray tube, 50 kV, 1 mA). The total number of runs and images was based on the strategy calculation from the program CrysAlisPro. The achieved resolution was Q = 59.997. Cell parameters were retrieved using the CrysAlisPro software and refined using CrysAlisPro on 8374 reflections, 33 % of the observed reflections. Data reduction was performed using the CrysAlisPro software which corrects for Lorentz polarization. The final completeness is 77.20 out to 59.997 in Q CrysAlisPro 1.171.40.84a. Numerical absorption correction based on gaussian integration over a multifaceted crystal model Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. The structure was solved in the space group P21/n (# 14) by using direct methods using the ShelXS structure solution program. 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